Seasonal congestive heart failure mortality and hospitalisation trends, Quebec 1990-1998

STUDY OBJECTIVE: To describe seasonal congestive heart failure (CHF) mortality and hospitalisations in Quebec, Canada between 1990-1998 and compare trends in CHF mortality and morbidity with those in France. DESIGN: Population cohort study. SETTING: Province of Quebec, Canada. PATIENTS: Mortality data were obtained from the Quebec Death Certificate Registry and hospitalisation from the Quebec Med-Echo hospital discharge database. Cases with primary ICD-9 code 428 were considered cases of CHF. RESULTS: Monthly CHF mortality was higher in January, declined until September and then rose steadily (p<0.05). Hospital admissions for CHF declined from May until September (moving averages analysis p<0.0001). Seasonal mortality patterns observed in Quebec were similar to those observed in France. CONCLUSION: CHF mortality in Quebec is highest during the winter and declines in the summer, similar to observations in France and Scotland. This suggests that absolute temperatures may not necessarily be that important but increased CHF mortality is observed once environmental temperatures fall below a certain "threshold" temperature. Alternatively better internal heating and warmer clothing required for survival in Quebec may ameliorate mortality patterns despite colder external environments.     

Family of two patients with congenital lipoid adrenal hyperplasia due to StAR mutation

We are reporting the case of two sisters born to nonrelated French Canadian parents. Patient A is of female phenotype with 46,xy, and patient B with 46,xx. The children had severe manifestations of mineralocorticoid deficiency at the age of 11 and 4.5 months, respectively. Residual cortisol secretion seemed present until the age of 3 years for patient A and until 15 months in the case of her sister. Both patients responded to glucocorticoid and Florinef treatment. Patient A did not show any androgen secretion and gonadectomy was performed at the age of 13.4 years; estrogen therapy was started at the age of 14 years resulting in a good breast development and an increase of growth velocity. In patient B, a progressive development of secondary sex characters occurred at 11.6 years of age followed at 14 years by menarche associated with a normal secretion of LH, FSH and estradiol; regular menstruations continued up to her last visit at the age of 25 years. We identified a homozygous L275P mutation on the StAR gene of both patients and a heterozygous L275P mutation on that of their mother and father. In transfection analysis in COS-1 cells, the mutant L275P was well-expressed, but its StAR activity was 87% impaired. The remaining activity of the L275P StAR mutant is consistent with the moderate severity of clinical onset of manifestations.     

Errorless academic compliance training: improving generalized cooperation with parental requests in children with autism

OBJECTIVE: Children with autism often demonstrate distress and oppositionality when exposed to requests to complete academic or household tasks. Errorless academic compliance training is a success-focused, noncoercive intervention for improving child cooperation with such activities. In the present study, the authors evaluated treatment and generalization effects of this intervention on four children diagnosed with autism. METHOD: In a multiple baseline across-subjects design, parents delivered a range of academic and nonacademic requests to their children to determine the probability of compliance for each request. A hierarchy of academic requests ranging from those yielding high compliance (level 1) to those yielding low compliance (level 4) was then developed. Treatment began with the concentrated delivery of level 1 requests, with praise and reward for compliant responses. Over several weeks, children were gradually introduced to requests from subsequent probability levels with continued reward for compliance. RESULTS: High compliance levels were demonstrated throughout and following treatment. Evidence of generalization to untrained academic requests and nonacademic requests emerged. Treatment gains were maintained up to 6 months after treatment. CONCLUSIONS: Errorless academic compliance training appears to be an effective intervention for enhancing generalized compliance in children with autism.     

Pharmacokinetics of omeprazole in healthy adults and in children with gastroesophageal reflux disease

Studies of the pharmacokinetics of omeprazole in children with gastroesophageal reflux disease (GERD) remain scarce despite the vast number of reports on its efficacy. The objectives of this study were to assess the pharmacokinetics of omeprazole in healthy adults and in children with GERD. Omeprazole (Losec, delayed-release capsules) was administered orally to 18 healthy adults (mean age 36.8 years) and 12 children with GERD (mean age 6.1 years). Blood samples were collected over 5 hours, and plasma concentrations were assessed using liquid chromatography. Population pharmacokinetic parameters were calculated using NONMEM. A 1-compartment model with zero-order absorption and a lag time was used. The population approach was well suited to the limited number of samples available, and residual variability was low. Oral clearance (CL/F) and apparent volume of distribution (V(ss)/F) in healthy adults (Mean +/- SD: 0.62 +/- 0.27 L/h/kg and 0.76 +/- 0.26 L/kg, respectively) were not significantly different than those in children with GERD (0.51 +/- 0.34 L/h/kg and 0.66 +/- 0.25 L/kg, respectively). Healthy adults displayed a statistically significantly longer delay in drug absorption (Lag time: 0.62 +/- 0.15 hours) as compared with that observed in children with GERD (0.12 +/- 0.03 hours, P < 0.05). On the basis of these findings, omeprazole dosings on a milligram-per-kilogram basis are recommended with no further adjustments for the treatment of GERD in children.     

A randomized,controlled trial of the effectiveness of nebulized therapy with epinephrine compared with albuterol and saline in infants hospitalized for acute viral bronchiolitis

OBJECTIVE: In previously well infants hospitalized with acute viral bronchiolitis, the effectiveness of repeated nebulized therapy with epinephrine (EPI) was compared with treatment with albuterol (ALB) or saline placebo (PLAC). STUDY DESIGN: In this randomized, double-blind, parallel-group, controlled trial, infants received study nebulizations every 1 to 6 hours and were assessed twice daily by the research team. The primary outcome was length of hospital stay (LOS). Secondary outcomes included the time from admission until the infant had normal hydration, oxygenation, and minimal respiratory distress. RESULTS: A total of 149 infants were randomized; 50 were allocated to receive racemic EPI, 51 were given ALB, and 48 received PLAC. Baseline characteristics and pre-enrollment symptoms, signs, and therapy were similar between groups. There were no group differences in the primary outcome measure, mean LOS (hours)(+/- SD): EPI = 59.8 (62), ALB = 61.4 (54), and PLAC = 63.3 (47); P =.95 by intent-to-treat analysis. Group differences were not statistically significant in any of the secondary outcomes. CONCLUSIONS: There were no group differences in the effectiveness of therapy for infants hospitalized with bronchiolitis. Based on these results, we do not recommend routine use of either nebulized EPI or ALB in this patient group.     

Effect of mdr1a P-glycoprotein gene disruption, gender, and substrate concentration on brain uptake of selected compounds

Purpose. This study assessed the influence of mdr1a P-glycoprotein (P-gp) gene disruption, gender and concentration on initial brain uptake clearance (Cl _up) of morphine, quinidine and verapamil. Methods. Cl _up of radiolabeled substrates was determined in P-gp-competent and deficient [mdr1a(–/–)] mice by in situ brain perfusion. Brain:plasma distribution of substrates after i.v. administration was determined in both strains. Results. Genetic disruption of mdr1a P-gp resulted in 1.3-, 6.6- and 14-fold increases in Cl _up for morphine, verapamil and quinidine, respectively. With the exception of small differences for verapamil, gender did not affect Cl _up. Saturable transport of verapamil and quinidine was observed only in P-gp-competent mice, with apparent IC ₅₀ values for efflux of 8.6 ± 2.3 M and 36 ± 2 M, respectively. VerapamilCl _up was 50% higher in mdr1a(+/–) vs. mdr1a(+/+) mice; no such difference was observed for quinidine. In P-gp-competent mice, uptake of verapamil and quinidine was unaffected by organic vehicles. Plasma decreased VER Cl _up to a greater extent in the presence of P-gp. The influence of P-gp in situ was lower than, but correlated with, the effect in vivo. Conclusions. P-gp decreases Cl _up of morphine, verapamil and quinidine in situ with little or no influence of gender, but this effect cannot fully account for the effects of P-gp in vivo. P-gp is the only saturable transport mechanism for verapamil and quinidine at the murine blood-brain barrier. The influence of protein binding on Cl _up may be enhanced by P-gp-mediated efflux.     

New diarylmethylpiperazines as potent and selective nonpeptidic delta opioid receptor agonists with increased In vitro metabolic stability

Nonpeptide delta opioid agonists are analgesics with a potentially improved side-effect and abuse liability profile, compared to classical opioids. Andrews analysis of the NIH nonpeptide lead SNC-80 suggested the removal of substituents not predicted to contribute to binding. This approach led to a simplified lead, N, N-diethyl-4-[phenyl(1-piperazinyl)methyl]benzamide (1), which retained potent binding affinity and selectivity to the human delta receptor (IC(50) = 11 nM, mu/delta = 740, kappa/delta > 900) and potency as a full agonist (EC(50) = 36 nM) but had a markedly reduced molecular weight, only one chiral center, and increased in vitro metabolic stability. From this lead, the key pharmacophore groups for delta receptor affinity and activation were more clearly defined by SAR and mutagenesis studies. Further structural modifications on the basis of 1 confirmed the importance of the N, N-diethylbenzamide group and the piperazine lower basic nitrogen for delta binding, in agreement with mutagenesis data. A number of piperazine N-alkyl substituents were tolerated. In contrast, modifications of the phenyl group led to the discovery of a series of diarylmethylpiperazines exemplified by N, N-diethyl-4-[1-piperazinyl(8-quinolinyl)methyl]benzamide (56) which had an improved in vitro binding profile (IC(50) = 0.5 nM, mu/delta = 1239, EC(50) = 3.6 nM) and increased in vitro metabolic stability compared to SNC-80.     

Maternal alphafetoprotein screening by the polypropylene tube immunoradiometric assay on dried blood

The polypropylene tube immunoradiometric assay for alphafetoprotein (AFP) determination was applied to maternal serum along with a radioimmunoassay technique during the second trimester of pregnancy. Blood from pregnant women was collected by finger prick on strips of chromatography paper (Schleicher and Schuell No. 903C) and air dried. A 4.75 mm disc spot was eluted in anti-AFP coated tubes containing 1.0 ml of assay medium. After one hour the medium was vortexed and the tubes washed and counted on a Concept 4tm (Micromedic Systems, Horsham, PA. 19044). The sensitivity of the technique is about 9 micrograms/l (35 ng/l in the assay) by the Rodbard formula. The concordance between the dried blood and the serum RIA tests in normal pregnancies was over 90 per cent at the 95th and 97th percentiles. This assay on dried blood spotted on chromatography paper was tested on 1003 patients and proved to be an ideal alternative to whole serum screening techniques: it minimizes sample manipulations and can easily be integrated into an existing newborn screening programme.