Polymorphisms and DNA methylation of gene TP53 associated with extra-axial brain tumors

The p53 tumor suppressor gene is the most frequently mutated gene in human cancer; this gene is mutated in up to 50% of human tumors. It has a critical role in the cell cycle, apoptosis and cell senescence, and it participates in many crucial physiological and pathological processes. Polymorphisms of p53 have been suggested to be associated with genetically determined susceptibility in various types of cancer. Another process involved with the development and progression of tumors is DNA hypermethylation. Aberrant methylation of the promoter is an alternative epigenetic change in genetic mechanisms, leading to tumor suppressor gene inactivation. In the present study, we examined the TP53 Arg72Pro and Pro47Ser polymorphisms using PCR-RFLP and the pattern of methylation of the p53 gene by methylation-specific PCR in 90 extra-axial brain tumor samples. Patients who had the allele Pro of the TP53 Arg72Pro polymorphism had an increased risk of tumor development ( odds ratio, OR = 3.23; confidence interval at 95%, 95% CI = 1.71-6.08; P = 0.003), as did the allele Ser of TP53 Pro47Ser polymorphism (OR = 1.28; 95% CI = 0.03-2.10; P = 0.01). Comparison of overall survival of patients did not show significant differences. In the analysis of DNA methylation, we observed that 37.5% of meningiomas, 30% of schwannomas and 52.6% of metastases were hypermethylated, suggesting that methylation is important for tumor progression. We suggest that TP53 Pro47Ser and Arg72Pro polymorphisms and DNA hypermethylation are involved in susceptibility for developing extra-axial brain tumors.

Endothelial Nitric Oxide Synthase Haplotypes Associated with Aura in Patients with Migraine

There is strong evidence implicating nitric oxide (NO) in the pathophysiology of migraine and aura. Therefore, genetic polymorphisms in the endothelial NO synthase (eNOS) gene have been studied as candidate markers for migraine susceptibility. We compared for the first time the distribution of eNOS haplotypes including the three clinically relevant eNOS polymorphisms (T(-786)C in the promoter, rs2070744; Glu298Asp in exon 7, rs1799983; and a 27 bp variable number of tandem repeats in intron 4) and two additional tagging single-nucleotide polymorphisms (rs3918226 and rs743506) in 178 women with migraine (134 without aura and 44 with aura) and 117 healthy controls (control group). Genotypes were determined by TaqMan allele discrimination assay, real-time polymerase chain reaction, and polymerase chain reaction followed by fragment separation by electrophoresis. The GA (rs743506) genotype was more common in the control group than in women with migraine (odds ratio = 0.47, 95% confidence interval [CI] 0.29-0.78, p<0.01). No significant differences were found in allele distributions for the five eNOS polymorphisms. However, the haplotypes including the variants ""C C a Glu G"" and the variants ""C C b Glu G"" were more common in women with migraine with aura than in women with migraine without aura (odds ratio = 30.71, 95% CI = 1.61-586.4 and odds ratio = 17.26, 95% CI = 1.94-153.4, respectively; both p<0.0015625). These findings suggest that these two eNOS haplotypes affect the susceptibility to the presence of aura in patients with migraine.

Bone Marrow Concentrate and Bovine Bone Mineral for Sinus Floor Augmentation: A Controlled, Randomized, Single-Blinded Clinical and Histological Trial-Per-Protocol Analysis

Purpose: The purpose of this work was to evaluate the potential of substituting autogenous bone (AB) by bone marrow aspirate concentrate (BMAC). Both AB and BMAC were tested in combination with a bovine bone mineral (BBM) for their ability of new bone formation (NBF) in a multicentric, randomized, controlled, clinical and histological noninferiority trial. Materials and Methods: Forty-five severely atrophied maxillary sinus from 26 patients were evaluated in a partial cross-over design. As test arm, 34 sinus of 25 patients were augmented with BBM and BMAC containing mesenchymal stem cells. Eleven control sinus from 11 patients were augmented with a mixture of 70% BBM and 30% AB. Biopsies were obtained after a 3-4-month healing period at time of implant placement and histomorphometrically analyzed for NBF. Results: NBF was 14.3%+/- 1.8% for the control and nonsignificantly lower (12.6%+/- 1.7%) for the test (90% confidence interval: -4.6 to 1.2). Values for BBM (31.3%+/- 2.7%) were significantly higher for the test compared with control (19.3%+/- 2.5%) (p < 0.0001). Nonmineralized tissue was lower by 3.3% in the test compared with control (57.6%; p = 0.137). Conclusions: NBF after 3-4 months is equivalent in sinus, augmented with BMAC and BBM or a mixture of AB and BBM. This technique could be an alternative for using autografts to stimulate bone formation.

Additive genetic relationship of longevity with fertility and production traits in Nellore cattle based on bivariate models

Survival or longevity is an economically important trait in beef cattle. The main inconvenience for its inclusion in selection criteria is delayed recording of phenotypic data and the high computational demand for including survival in proportional hazard models. Thus, identification of a longevity-correlated trait that could be recorded early in life would be very useful for selection purposes. We estimated the genetic relationship of survival with productive and reproductive traits in Nellore cattle, including weaning weight (WW), post-weaning growth (PWG), muscularity (MUSC), scrotal circumference at 18 months (SC18), and heifer pregnancy (HP). Survival was measured in discrete time intervals and modeled through a sequential threshold model. Five independent bivariate Bayesian analyses were performed, accounting for cow survival and the five productive and reproductive traits. Posterior mean estimates for heritability (standard deviation in parentheses) were 0.55 (0.01) for WW, 0.25 (0.01) for PWG, 0.23 (0.01) for MUSC, and 0.48 (0.01) for SC18. The posterior mean estimates (95% confidence interval in parentheses) for the genetic correlation with survival were 0.16 (0.13-0.19), 0.30 (0.25-0.34), 0.31 (0.25-0.36), 0.07 (0.02-0.12), and 0.82 (0.78-0.86) for WW, PWG, MUSC, SC18, and HP, respectively. Based on the high genetic correlation and heritability (0.54) posterior mean estimates for HP, the expected progeny difference for HP can be used to select bulls for longevity, as well as for post-weaning gain and muscle score.

Prevalence of fibromyalgia in a low socioeconomic status population

Background: The aim of this study was to estimate the prevalence of fibromyalgia, as well as to assess the major symptoms of this syndrome in an adult, low socioeconomic status population assisted by the primary health care system in a city in Brazil. Methods: We cross-sectionally sampled individuals assisted by the public primary health care system (n = 768, 35-60 years old). Participants were interviewed by phone and screened about pain. They were then invited to be clinically assessed (304 accepted). Pain was estimated using a Visual Analogue Scale (VAS). Fibromyalgia was assessed using the Fibromyalgia Impact Questionnaire (FIQ), as well as screening for tender points using dolorimetry. Statistical analyses included Bayesian Statistics and the Kruskal-Wallis Anova test (significance level = 5%). Results: From the phone-interview screening, we divided participants (n = 768) in three groups: No Pain (NP) (n = 185); Regional Pain (RP) (n = 388) and Widespread Pain (WP) (n = 106). Among those participating in the clinical assessments, (304 subjects), the prevalence of fibromyalgia was 4.4% (95% confidence interval [2.6%; 6.3%]). Symptoms of pain (VAS and FIQ), feeling well, job ability, fatigue, morning tiredness, stiffness, anxiety and depression were statically different among the groups. In multivariate analyses we found that individuals with FM and WP had significantly higher impairment than those with RP and NP. FM and WP were similarly disabling. Similarly, RP was no significantly different than NP. Conclusion: Fibromyalgia is prevalent in the low socioeconomic status population assisted by the public primary health care system. Prevalence was similar to other studies (4.4%) in a more diverse socioeconomic population. Individuals with FM and WP have significant impact in their well being.

Haplotype distribution of five nuclear genes based on network genealogies and Bayesian inference indicates that Trypanosoma cruzi hybrid strains are polyphyletic

Chagas disease is still a major public health problem in Latin America. Its causative agent, Trypanosoma cruzi, can be typed into three major groups, T. cruzi I, T. cruzi II and hybrids. These groups each have specific genetic characteristics and epidemiological distributions. Several highly virulent strains are found in the hybrid group; their origin is still a matter of debate. The null hypothesis is that the hybrids are of polyphyletic origin, evolving independently from various hybridization events. The alternative hypothesis is that all extant hybrid strains originated from a single hybridization event. We sequenced both alleles of genes encoding EF-1 alpha, actin and SSU rDNA of 26 T. cruzi strains and DHFR-TS and TR of 12 strains. This information was used for network genealogy analysis and Bayesian phylogenies. We found T. cruzi I and T. cruzi II to be monophyletic and that all hybrids had different combinations of T. cruzi I and T. cruzi II haplotypes plus hybrid-specific haplotypes. Bootstrap values (networks) and posterior probabilities (Bayesian phylogenies) of clades supporting the monophyly of hybrids were far below the 95% confidence interval, indicating that the hybrid group is polyphyletic. We hypothesize that T. cruzi I and T. cruzi II are two different species and that the hybrids are extant representatives of independent events of genome hybridization, which sporadically have sufficient fitness to impact on the epidemiology of Chagas disease.

Interaction between polymorphisms of the Human Leukocyte Antigen and HPV-16 Variants on the risk of invasive cervical cancer

Background: Persistent infection with oncogenic types of human papillomavirus (HPV) is the major risk factor for invasive cervical cancer (ICC), and non-European variants of HPV-16 are associated with an increased risk of persistence and ICC. HLA class II polymorphisms are also associated with genetic susceptibility to ICC. Our aim is to verify if these associations are influenced by HPV-16 variability. Methods: We characterized HPV-16 variants by PCR in 107 ICC cases, which were typed for HLA-DQA1, DRB1 and DQB1 genes and compared to 257 controls. We measured the magnitude of associations by logistic regression analysis. Results: European ( E), Asian-American ( AA) and African (Af) variants were identified. Here we show that inverse association between DQB1*05 ( adjusted odds ratio [ OR] = 0.66; 95% confidence interval [CI]: 0.39-1.12]) and HPV-16 positive ICC in our previous report was mostly attributable to AA variant carriers ( OR = 0.27; 95% CI: 0.10-0.75). We observed similar proportions of HLA DRB1*1302 carriers in E-P positive cases and controls, but interestingly, this allele was not found in AA cases ( p = 0.03, Fisher exact test). A positive association with DRB1*15 was observed in both groups of women harboring either E ( OR = 2.99; 95% CI: 1.13-7.86) or AA variants ( OR = 2.34; 95% CI: 1.00-5.46). There was an inverse association between DRB1*04 and ICC among women with HPV-16 carrying the 350T [83L] single nucleotide polymorphism in the E6 gene ( OR = 0.27; 95% CI: 0.08-0.96). An inverse association between DQB1*05 and cases carrying 350G (83V) variants was also found ( OR = 0.37; 95% CI: 0.15-0.89). Conclusion: Our results suggest that the association between HLA polymorphism and risk of ICC might be influenced by the distribution of HPV-16 variants.

Predictive Validity of Waterlow Scale for Pressure Ulcer Development Risk in Hospitalized Patients

AIM: We sought to evaluate the predictive validity of the Waterlow Scale in hospitalized patients. SUBJECTS AND SETTING: The study was conducted at a general private hospital with 220 beds and a mean time of hospitalization of 7.4 days and a mean occupation rate of approximately 80%. Adult patients with a Braden Scale score of 18 or less and a Waterlow Scale score of 16 or more were studied. The sample consisted of 98 patients with a mean age of 71.1 +/- 15.5 years. METHODS: Skin assessment and scoring by using the Waterlow and Braden scales were completed on alternate days. Patients were examined at least 3 times to be considered for analysis. The data were submitted to sensitivity and specificity analysis by using receiver operating characteristic (ROC) curves and positive (+LR) and negative (-LR) likelihood ratios. RESULTS: The cutoff scores were 17, 20, and 20 in the first, second, and third assessment, respectively. Sensitivity was 71.4%, 85.7%, and 85.7% and specificity was 67.0%, 40.7%, and 32.9%, respectively. Analysis of the area under the ROC curve revealed good accuracy (0.64, 95% confidence interval [CI]: 0.35-0.93) only for the cutoff score 17 in the first assessment. The results also showed probabilities of 14%, 10%, and 9% for the development of pressure ulcer when the test results were positive (+LR) and of 3% (-LR) when the test results were negative for the cutoff scores in the first, second, and third assessment, respectively. CONCLUSION: The Waterlow Scale achieved good predictive validity in predicting pressure ulcer in hospitalized patients when a cutoff score of 17 was used in the first assessment.

Risk factors for neonatal transfers from the Sapopemba free-standing birth centre to a hospital in Sao Paulo, Brazil

Objective: to identify risk factors associated with neonatal transfers from a free-standing birth centre to a hospital. Design: epidemiological case-control study. Setting: midwifery-led free-standing birth centre in Sao Paulo, Brazil. Participants: 96 newborns were selected from 2840 births between September 1998 and August 2005. Cases were defined as all new borns transferred from the birth centre to a hospital (n = 32), and controls were defined as new borns delivered at the same birth centre, during the same time period, and who had not been transferred to a hospital (n = 64). Measurements and findings: data were collected from medical records available at the birth centre. Univariate and multivariate analyses were performed using logistic regression. The multivariate analysis included outcomes with p<0.25, specifically: smoking during pregnancy, prenatal care appointments, labour complications, weight in relation to gestational age, and one-minute Apgar score. Of the foregoing outcomes, those that remained in the full regression model as a risk factor associated with neonatal transfer were: smoking during pregnancy [p = 0.009, odds ratio (OR) = 4.1,95% confidence interval (CI) 1.03-16.33], labour complications (p<0.001, OR = 5.5, 95% CI 1.06-28.26) and one-minute Apgar score <= 7 (p<0.001, OR = 7.8,95% CI 1.62-37.03). Key conclusions and implications for practice: smoking during pregnancy, labour complications and one-minute Apgar score <= 7 were confirmed as risk factors for neonatal transfer from the birth centre to a hospital. The identified risk factors can help to improve institutional protocols and formulate hypotheses for other studies. (C) 2009 Elsevier Ltd. All rights reserved.

Effectiveness of local anaesthetics with and without vasoconstrictors for perineal repair during spontaneous delivery: Double-blind randomised controlled trial

Objective: to investigate the use of local anaesthetics, in the presence or absence of vasoconstrictors, for perineal repair during spontaneous delivery. Design: double-blind, randomised-controlled trial. Setting: a birth centre, in the city of Sao Paulo, Brazil. Participants: from June to December 2004, a total of 96 women were allocated into three groups (first-degree perineal lacerations, second-degree perineal lacerations or episiotomy), and treated with local anaesthesia (1% lidocaine or 1% lidocaine with epinephrine) (n = 16 per treatment per group). Interventions: an initial local infiltration of the anaesthetic solution was given so that episiotomy could be carried out (5 ml) and to suture spontaneous lacerations (1 ml), followed by repeated doses (1 ml) until pain was completely inhibited. Measurements and findings: the main outcome measurement was the volume of anaesthetic used during episiotomy and perineal suture. Our data suggest that the concomitant use of the vasoconstrictor resulted in a significantly lower average volume used in the treatment of first-degree (1 ml, 95% confidence interval (0) 0.4-1.6) and second-degree (3.7 ml, 95% CI 1.6-5.8) lacerations (p = 0.002 and 0.001, respectively). A 0.3 ml (95% CI 1.5-2.1) average decrease in anaesthetic volume was observed with episiotomy (p = 0.724). The maximum volume of anaesthetic used with and without vasoconstrictor was 1-2 ml in 95% and 3-4 ml in 50% of first-degree lacerations, respectively, and 1-6 ml in 88% and 7-15 ml in 81% of second-degree lacerations, respectively. For episiotomy, the maximum dose was 15 ml, regardless of anaesthetic solution used. Key conclusions: our data confirm the hypothesis that the use of anaesthetics in conjunction with vasoconstrictors is more effective than anaesthetics alone in the repair of perineal lacerations, but not for episiotomy. (C) 2007 Elsevier Ltd. All rights reserved.

Variability on red blood cell transfusion practices among Brazilian neonatal intensive care units

BACKGROUND: Guidelines for red blood cell (RBC) transfusions exist; however, transfusion practices vary among centers. This study aimed to analyze transfusion practices and the impact of patients and institutional characteristics on the indications of RBC transfusions in preterm infants. STUDY DESIGN AND METHODS: RBC transfusion practices were investigated in a multicenter prospective cohort of preterm infants with a birth weight of less than 1500 g born at eight public university neonatal intensive care units of the Brazilian Network on Neonatal Research. Variables associated with any RBC transfusions were analyzed by logistic regression analysis. RESULTS: Of 952 very-low-birth-weight infants, 532 (55.9%) received at least one RBC transfusion. The percentages of transfused neonates were 48.9, 54.5, 56.0, 61.2, 56.3, 47.8, 75.4, and 44.7%, respectively, for Centers 1 through 8. The number of transfusions during the first 28 days of life was higher in Center 4 and 7 than in other centers. After 28 days, the number of transfusions decreased, except for Center 7. Multivariate logistic regression analysis showed higher likelihood of transfusion in infants with late onset sepsis (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.8-4.4), intraventricular hemorrhage (OR, 9.4; 95% CI, 3.3-26.8), intubation at birth (OR, 1.7; 95% CI, 1.0-2.8), need for umbilical catheter (OR, 2.4; 95% CI, 1.3-4.4), days on mechanical ventilation (OR, 1.1; 95% CI, 1.0-1.2), oxygen therapy (OR, 1.1; 95% CI, 1.0-1.1), parenteral nutrition (OR, 1.1; 95% CI, 1.0-1.1), and birth center (p < 0.001). CONCLUSIONS: The need of RBC transfusions in very-low-birth-weight preterm infants was associated with clinical conditions and birth center. The distribution of the number of transfusions during hospital stay may be used as a measure of neonatal care quality.

Ascorbic acid concentration is reduced in the secondary aqueous humour of glaucomatous patients

P>Background: We aimed to evaluate the ascorbic acid concentration in secondary aqueous humour (AH) from glaucomatous patients and to compare it with primary AH from primary open-angle glaucoma patients and non-glaucomatous patients. Methods: Primary AH samples were prospectively obtained from clinically uncontrolled primary open-angle glaucoma patients and senile cataract patients (controls) prior to trabeculectomy and cataract surgery. Secondary AH samples were obtained from eyes with previous intraocular surgery, prior to trabeculectomy or cataract surgery. AH (0.1 mL) was aspirated by inserting a 26-gauge needle into the anterior chamber just before surgery and then immediately stored at -80 degrees C. The ascorbic acid concentration was determined in a masked fashion by high-pressure liquid chromatography. Results: A total of 18 patients with senile cataract, 16 glaucomatous patients with primary AH (no previous intraocular surgery) and 11 glaucomatous patients with secondary AH (previous intraocular surgery) were included. There was no difference in mean age between groups (P = 0.15). The mean +/- standard deviation concentration of ascorbic acid in the secondary AH from glaucomatous patients (504 +/- 213 mu mol/L [95% confidence interval {CI}, 383-624]) was significantly lower than the concentration of ascorbic acid found in the primary aqueous of primary open-angle glaucoma (919 +/- 427 mu mol/L [95% CI, 709-1128]) and control patients (1049 +/- 433 mu mol/L [95% CI, 848-1249]; P < 0.01, Kruskal-Wallis test). Conclusions: The ascorbic acid concentration in secondary AH of glaucomatous patients was approximately twofold lower in comparison with primary AH of glaucomatous and cataract patients. The implications of a reduced concentration of ascorbic acid in the secondary AH deserve further investigation.

Bioequivalence assay between orally disintegrating and conventional tablet formulations in healthy volunteers

The purpose of this study was to evaluate bioequivalence of two commercial 8 mg tablet formulations of ondansetrona available ill the Brazilian market. In this study, a simple, rapid, sensitive and selective liquid chromarography-tandem mass spectrometry method is described for the determination of ondansetron in human plasma samples. The method was validated over a concentration range of 2.5-60 ng/ml and used in a bioequivalence trial between orally disintegrating and conventional tablet ondansetron formulations, to assess its usefulness in this kind of Study. Vonau flash (R) (Biolab Sanus Farmaceutica, Brazil, as test formulations) and Zofran (R) (GlaxoSmithKline, Brazil, as reference formulation) were evaluated following a single 8 mg close to 23 healthy volunteers of both genders. The dose was administered after an overnight fast according to a two-way crossover design. Bioequivalence between the products was determinated by Calculating 90% confidence interval (90% CI) for the ratio of C(max), AUC(0-t) and AUC(0-(sic)) values for the test and reference products, using logarithmically transformed data. The 90% confidence interval for the ratio of C(max) (87.5-103.8%), AUC(0-t) (89.3-107.2%) and AUC(0--(sic)) (89.7-106.0%) values for the test and reference products is Within the 80-125% interval, proposed by FDA, EMEA and ANVISA. It was concluded that two ondansetron formulations are bioequivalent ill their rate and extent of absorption. (C) 2008 Elsevier B.V. All rights reserved.

Determination of chlorpheniramine in human plasma by HPLC-ESI-MS/MS: application to a dexchlorpheniramine comparative bioavailability study

In the present study a fast, sensitive and robust validated method to quantify chlorpheniramine in human plasma using brompheniramine as internal standard (IS) is described. The analyte and the IS were extracted from plasma by LLE (diethyl ether-dichloromethane, 80:20, v/v) and analyzed by HPLC-ESI-MS/MS. Chromatographic separation was performed using a gradient of methanol from 35 to 90% with 2.5 mm NH(4)OH on a Gemini Phenomenex C(8) 5 mu m column (50 x 4.6 mm i.d.) in 5.0 min/run. The method fitted to a linear calibration curve (0.05-10 ng/mL, R > 0.9991). The precision (%CV) and accuracy ranged, respectively: intra-batch from 1.5 to 6.8% and 99.1 to 106.6%, and inter-batch from 2.4 to 9.0%, and 99.9 to 103.1%. The validated bioanalytical procedure was used to assess the comparative bioavailability in healthy volunteers of two dexchlorpheniramine 2.0 mg tablet formulations (test dexchlorpheniramine, Eurofarma, and reference Celestamine (R), Schering-Plough). The study was conducted using an open, randomized, two-period crossover design with a 2 week washout interval. Since the 90% confidence interval for C(max) and AUC ratios were all within the 80-125% interval proposed by ANVISA and FDA, it was concluded that test and reference formulations are bioequivalent concerning the rate and the extent of absorption. Copyright (C) 2009 John Wiley & Sons, Ltd.

Outcome with calcium channel antagonists after myocardial infarction: A community-based study

Objectives. We sought to estimate the risk of death and recurrent myocardial infarction associated with the use of calcium antagonists after myocardial infarction in a population-based cohort study. Background. Calcium antagonists are commonly prescribed after myocardial infarction, but their long-term effects are not well established. Methods. Patients 25 to 69 years old with a suspected myocardial infarction were identified and followed up through a community-based register of myocardial infarction and cardiac death (part of the World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease [MONICA] Project in Newcastle, Australia). Data were collected by review of medical records, in-hospital interview and review of death certificates. Results. From 1989 to 1993, 3,982 patients with a nonfatal suspected myocardial infarction were enrolled in the study. At hospital discharge, 1,001 patients were treated with beta-adrenergic blocking agents, 923 with calcium antagonists, 711 with both beta-blockers and calcium antagonists and 1,346 with neither drug. Compared with patients given beta-blockers, patients given calcium antagonists were more likely to suffer myocardial infarction or cardiac death (adjusted relative risk [RR] 1.4, 95% confidence interval [CI] 1.0 to 1.9), cardiac death (RR 1.6, 95% CI 1.0 to 2.7) and death from all causes (RR 1.7, 95% CI 1.1 to 2.6). Compared with patients given neither beta-blockers nor calcium antagonists, patients given calcium antagonists were not at increased risk of myocardial infarction or cardiac death (RR 1.0, 95% CI 0.8 to 1.3), cardiac death (RR 0.9, 95% CI 0.6 to 1.2) or death from all causes (RR 1.0, 95% CI 0.7 to 1.3). No excess in risk of myocardial infarction or cardiac death was observed among patients taking verapamil (RR 0.9, 95% CI 0.6 to 1.6), diltiazem (RR 1.1, 95% CI 0.8 to 1.4) or nifedipine (RR 1.3, 95% CI 0.7 to 2.2) compared,vith patients taking neither calcium antagonists nor beta-blockers. Conclusions. These results are consistent with randomized trial data showing benefit from beta blockers after myocardial infarction and no effect on the risk of recurrent myocardial infarction and death with the use of calcium antagonists. Comparisons between beta-blockers and calcium antagonists favor beta blockers because of the beneficial effects of beta-blockers and not because of adverse effects of calcium antagonists. (C) 1998 by the American College of Cardiology.