TASK-1 current is inhibited by phosphorylation during human and canine chronic atrial fibrillation.

Atrial fibrillation (AF) is a common arrhythmia with significant morbidities and only partially adequate therapeutic options. AF is associated with atrial remodeling processes, including changes in the expression and function of ion channels and signaling pathways. TWIK protein-related acid-sensitive K+ channel (TASK)-1, a two-pore domain K+ channel, has been shown to contribute to action potential repolarization as well as to the maintenance of resting membrane potential in isolated myocytes, and TASK-1 inhibition has been associated with the induction of perioperative AF. However, the role of TASK-1 in chronic AF is unknown. The present study investigated the function, expression, and phosphorylation of TASK-1 in chronic AF in atrial tissue from chronically paced canines and in human subjects. TASK-1 current was present in atrial myocytes isolated from human and canine hearts in normal sinus rhythm but was absent in myocytes from humans with AF and in canines after the induction of AF by chronic tachypacing. The addition of phosphatase to the patch pipette rescued TASK-1 current from myocytes isolated from AF hearts, indicating that the change in current is phosphorylation dependent. Western blot analysis showed that total TASK-1 protein levels either did not change or increased slightly in AF, despite the absence of current. In studies of perioperative AF, we have shown that phosphorylation of TASK-1 at Thr383 inhibits the channel. However, phosphorylation at this site was unchanged in atrial tissue from humans with AF or in canines with chronic pacing-induced AF. We conclude that phosphorylation-dependent inhibition of TASK-1 is associated with AF, but the phosphorylation site responsible for this inhibition remains to be identified.

Ability to induce atrial fibrillation in the peri-operative period is associated with phosphorylation-dependent inhibition of TWIK protein-related acid-sensitive potassium channel 1 (TASK-1).

Peri-operative atrial fibrillation (peri-op AF) is a common complication following thoracic surgery. This arrhythmia is thought to be triggered by an inflammatory response and can be reproduced in various animal models. Previous work has shown that the lipid inflammatory mediator, platelet-activating factor (PAF), synthesized by activated neutrophils, can induce atrial and ventricular arrhythmias as well as repolarization abnormalities in isolated ventricular myocytes. We have previously shown that carbamylated PAF-induced repolarization abnormalities result from the protein kinase C (PKC) ε-dependent phosphorylation of the two-pore domain potassium channel TASK-1. We now demonstrate that canine peri-op AF is associated with the phosphorylation-dependent loss of TASK-1 current. Further studies identified threonine 383 in the C terminus of human and canine TASK-1 as the phosphorylation site required for PAF-dependent inhibition of the channel. Using a novel phosphorylation site-specific antibody targeting the phosphorylated channel, we have determined that peri-op AF is associated with the loss of TASK-1 current and increased phosphorylation of TASK-1 at this site.

Morphological features of the neonatal brain support development of subsequent cognitive, language, and motor abilities.

Knowledge of the role of brain maturation in the development of cognitive abilities derives primarily from studies of school-age children to adults. Little is known about the morphological features of the neonatal brain that support the subsequent development of abilities in early childhood, when maturation of the brain and these abilities are the most dynamic. The goal of our study was to determine whether brain morphology during the neonatal period supports early cognitive development through 2 years of age. We correlated morphological features of the cerebral surface assessed using deformation-based measures (surface distances) of high-resolution MRI scans for 33 healthy neonates, scanned between the first to sixth week of postmenstrual life, with subsequent measures of their motor, language, and cognitive abilities at ages 6, 12, 18, and 24 months. We found that morphological features of the cerebral surface of the frontal, mesial prefrontal, temporal, and occipital regions correlated with subsequent motor scores, posterior parietal regions correlated with subsequent language scores, and temporal and occipital regions correlated with subsequent cognitive scores. Measures of the anterior and middle portions of the cingulate gyrus correlated with scores across all three domains of ability. Most of the significant findings were inverse correlations located bilaterally in the brain. The inverse correlations may suggest either that a more protracted morphological maturation or smaller local volumes of neonatal brain tissue supports better performance on measures of subsequent motor, language, and cognitive abilities throughout the first 2 years of postnatal life. The correlations of morphological measures of the cingulate with measures of performance across all domains of ability suggest that the cingulate supports a broad range of skills in infancy and early childhood, similar to its functions in older children and adults.

Utilizing maternal prenatal cognition as a predictor of newborn brain measures of intellectual development.

Identifying reliable indicators of cognitive functioning prior to age five has been challenging. Prior studies have shown that maternal cognition, as indexed by intellectual quotient (IQ) and years of education, predict child intelligence at school age. We examined whether maternal full scale IQ, education, and inhibitory control (index of executive function) are associated with newborn brain measures and toddler language outcomes to assess potential indicators of early cognition. We hypothesized that maternal indices of cognition would be associated with brain areas implicated in intelligence in school-age children and adults in the newborn period. Thirty-seven pregnant women and their newborns underwent an MRI scan. T2-weighted images and surface-based morphometric analysis were used to compute local brain volumes in newborn infants. Maternal cognition indices were associated with local brain volumes for infants in the anterior and posterior cingulate, occipital lobe, and pre/postcentral gyrus - regions associated with IQ, executive function, or sensori-motor functions in children and adults. Maternal education and executive function, but not maternal intelligence, were associated with toddler language scores at 12 and 24 months. Newborn brain volumes did not predict language scores. Overall, the pre/postcentral gyrus and occipital lobe may be unique indicators of early intellectual development in the newborn period. Given that maternal executive function as measured by inhibitory control has robust associations with the newborn brain and is objective, brief, and easy to administer, it may be a useful predictor of early developmental and cognitive capacity for young children.

Epicardial border zone overexpression of skeletal muscle sodium channel SkM1 normalizes activation, preserves conduction, and suppresses ventricular arrhythmia: an in silico, in vivo, in vitro study.

BACKGROUND: In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel (SCN5A) is largely inactivated, contributing to low action potential upstroke velocity (V(max)), slow conduction, and reentry. We hypothesized that a fast inward current such as the skeletal muscle sodium channel (SkM1) operating more effectively at depolarized membrane potentials might restore fast conduction in epicardial border zones and be antiarrhythmic. METHODS AND RESULTS: Computer simulations were done with a modified Hund-Rudy model. Canine myocardial infarcts were created by coronary ligation. Adenovirus expressing SkM1 and green fluorescent protein or green fluorescent protein alone (sham) was injected into epicardial border zones. After 5 to 7 days, dogs were studied with epicardial mapping, programmed premature stimulation in vivo, and cellular electrophysiology in vitro. Infarct size was determined, and tissues were immunostained for SkM1 and green fluorescent protein. In the computational model, modest SkM1 expression preserved fast conduction at potentials as positive as -60 mV; overexpression of SCN5A did not. In vivo epicardial border zone electrograms were broad and fragmented in shams (31.5 +/- 2.3 ms) and narrower in SkM1 (22.6 +/- 2.8 ms; P=0.03). Premature stimulation induced ventricular tachyarrhythmia/fibrillation >60 seconds in 6 of 8 shams versus 2 of 12 SkM1 (P=0.02). Microelectrode studies of epicardial border zones from SkM1 showed membrane potentials equal to that of shams and V(max) greater than that of shams as membrane potential depolarized (P<0.01). Infarct sizes were similar (sham, 30 +/- 2.8%; SkM1, 30 +/- 2.6%; P=0.86). SkM1 expression in injected epicardium was confirmed immunohistochemically. CONCLUSIONS: SkM1 increases V(max) of depolarized myocardium and reduces the incidence of inducible sustained ventricular tachyarrhythmia/fibrillation in canine infarcts. Gene therapy to normalize activation by increasing V(max) at depolarized potentials may be a promising antiarrhythmic strategy.

Prenatal socioeconomic status and social support are associated with neonatal brain morphology, toddler language and psychiatric symptoms.

Few studies have assessed the association of parental socioeconomic status (SES) with brain measures in neonates, at a time when exposure to the postnatal environment is minimal. Social support may buffer the adverse consequences of SES, and has been associated with better cognitive - emotional development in children. We studied the association of prenatal SES and social support with neonatal brain structure, and toddler cognition, and psychiatric symptoms. In a sample of 37 healthy neonates, we correlated a measure of SES and marital/partner status (an index of social support) with morphological features of the cerebral surface measured on high-resolution MRI scans between the 1st - 6th weeks of postnatal life. We then assessed how SES relates to cognitive and behavioral outcomes at age 24-months. We found that neonates born to mothers with lower SES had greater local volumes at the surface of the right occipital lobe, left temporal pole, and left inferior frontal and anterior cingulate regions. Partner status moderated the associations of SES on neonatal brain morphology. Lower SES was associated with poorer language scores and less severe ADHD and ODD symptoms. In summary, SES was associated with neonatal brain structure and language and behavioral outcomes at toddler age. Future studies with a greater sample size and longitudinal MRI scans will help to determine whether prenatal SES continues to relate to early brain development in the same or different brain regions.

Cocaine-exposed infant behavior during Still-Face: risk factor analyses.

Prenatal cocaine exposure and the role of gender were evaluated using risk factor analyses to determine whether 6-month-old cocaine-exposed male infants demonstrated greater disruptions in infant-caregiver socioemotional interactions during a Still-Face test. Overall, non-cocaine-exposed infants spent more time looking at toys, compared with cocaine-exposed infants; nonexposed female infants spent more time scanning the environment, compared with nonexposed male infants. When caregiver behavior during the Still-Face was evaluated, differences emerged in amount of time the caregiver spent vocalizing to the infant. She vocalized more to a cocaine-exposed infant compared with a nonexposed one; she reduced vocalizing more during the test if the cocaine-exposed infant was female. An exposure by gender interaction emerged in the amount of change in caregiver vocalizations; however, the overarching hypothesis that male cocaine-exposed infants are at higher risk than nonexposed male, nonexposed female, and cocaine-exposed female infants was not supported. Because this interaction was evident in this cohort at 24 months, future research is needed to determine at what age an interaction begins to emerge in this cohort.

Improvement of Immediate Performance in Neonatal Resuscitation Through Rapid Cycle Deliberate Practice Training.

BACKGROUND: Simulation training is an effective method to teach neonatal resuscitation (NR), yet many pediatrics residents do not feel comfortable with NR. Rapid cycle deliberate practice (RCDP) allows the facilitator to provide debriefing throughout the session. In RCDP, participants work through the scenario multiple times, eventually reaching more complex tasks once basic elements have been mastered. OBJECTIVE: We determined if pediatrics residents have improved observed abilities, confidence level, and recall in NR after receiving RCDP training compared to the traditional simulation debriefing method. METHODS: Thirty-eight pediatrics interns from a large academic training program were randomized to a teaching simulation session using RCDP or simulation debriefing methods. The primary outcome was the intern's cumulative score on the initial Megacode Assessment Form (MCAF). Secondary outcome measures included surveys of confidence level, recall MCAF scores at 4 months, and time to perform critical interventions. RESULTS: Thirty-four interns were included in analysis. Interns in the RCDP group had higher initial MCAF scores (89% versus 84%, P < .026), initiated positive pressure ventilation within 1 minute (100% versus 71%, P < .05), and administered epinephrine earlier (152 s versus 180 s, P < .039). Recall MCAF scores were not different between the 2 groups. CONCLUSIONS: Immediately following RCDP interns had improved observed abilities and decreased time to perform critical interventions in NR simulation as compared to those trained with the simulation debriefing. RCDP was not superior in improving confidence level or retention.

Age-associated changes in electrophysiologic remodeling: a potential contributor to initiation of atrial fibrillation.

OBJECTIVE: Although the incidence of atrial fibrillation (AF) increases with age, the cellular electrophysiological changes that render the atria of aged individuals more susceptible to AF remain poorly understood. We hypothesized that dispersion of atrial repolarization increases with aging, creating a substrate for initiation of AF. METHODS: Four groups of dogs were studied: adult and old dogs in normal sinus rhythm (SR) and adult and old dogs with chronic AF (CAF) induced by rapid atrial pacing. In each dog, action potentials (AP) were recorded with microelectrodes from isolated endocardial preparations of four regions of right atrium and three regions of left atrium. Two indices of AP duration (APD) heterogeneity were obtained in each dog by calculating standard deviation (SD) and the coefficient of variation (COV=[SD/mean] x 100%). RESULTS: In SR groups, APD averaged across all regions was significantly longer in old than in adult tissues. Both indices of APD heterogeneity were higher in old dogs in comparison to adult. At both ages, CAF was associated with significant APD shortening and a decrease in APD adaptation to rate. While CAF significantly increased both indices of APD heterogeneity in adult dogs, it significantly decreased them in old dogs. CONCLUSIONS: The increase of spatial variability in repolarization in old atria may contribute to the initiation of AF in the aged. CAF-induced APD shortening and a decrease in APD adaptation appear to be important for the maintenance of sustained AF in both adult and old atria. The CAF-induced increase in dispersion of repolarization may be important for AF stabilization in adults, while previously reported fibrosis and slowed conduction of premature beats may be important in the old for both AF initiation during SR and subsequent stabilization of AF.

Region-specific, pacing-induced changes in repolarization in rabbit atrium: an example of sensitivity to the rare.

OBJECTIVE: In subsets of patients paroxysmal firing of ectopic foci in pulmonary veins or coronary sinus is an important cause of atrial fibrillation. This appears to represent a rare event overriding a dominant sinus mechanism to alter the rhythmic firing of the atrium. Hence, we tested the hypothesis that a rare stimulation pattern might alter the myocardial substrate, making it more susceptible to the initiation of arrhythmias. METHODS: In isolated right and left rabbit atria, a "rare" burst pacing protocol (BPP) was applied as follows: over 3 h, preparations were driven for 4.5 min from sinus node (SN) or Bachmann's bundle (BB) regions at cycle length (CL)=400 ms followed by 30 s of stimulation from coronary sinus (CS) or pulmonary vein (PV) at CL=200 ms. Microelectrodes were used to record action potentials at the end of 4.5 min of pacing at CL=400 ms. We then intervened with 5-min bigeminal pacing to probe atrial vulnerability to arrhythmias: S1 was delivered from SN or BB and S2 from CS or PV, respectively. S1-S2 interval was the shortest eliciting a propagated response. RESULTS: BPP shortened repolarization in CS and PV regions but not in SN or BB, resulting in increased dispersion of repolarization in right and decreased in left atria. Propranolol, atropine and losartan failed to alter the decrease in repolarization induced by BPP whereas apamin, nifedipine and ryanodine prevented BPP effects. Before BPP, bigeminy did not induce arrhythmias in either atrium, but after BPP, bigeminy significantly increased the incidence of arrhythmias in the right atrium. CONCLUSIONS: BPP from foci outside the regions of dominant activation alters dispersion of atrial repolarization. Modulation of apamin-sensitive channels may contribute to the shortening of repolarization in CS and PV regions. Alterations of atrial repolarization gradient create an arrhythmogenic substrate and may be an early step in atrial electrophysiologic remodeling.

Increased Late Sodium Current Contributes to the Electrophysiological Effects of Chronic, but Not Acute, Dofetilide Administration.

BACKGROUND: Drugs are screened for delayed rectifier potassium current (IKr) blockade to predict long QT syndrome prolongation and arrhythmogenesis. However, single-cell studies have shown that chronic (hours) exposure to some IKr blockers (eg, dofetilide) prolongs repolarization additionally by increasing late sodium current (INa-L) via inhibition of phosphoinositide 3-kinase. We hypothesized that chronic dofetilide administration to intact dogs prolongs repolarization by blocking IKr and increasing INa-L. METHODS AND RESULTS: We continuously infused dofetilide (6-9 µg/kg bolus+6-9 µg/kg per hour IV infusion) into anesthetized dogs for 7 hours, maintaining plasma levels within the therapeutic range. In separate experiments, myocardial biopsies were taken before and during 6-hour intravenous dofetide infusion, and the level of phospho-Akt was determined. Acute and chronic dofetilide effects on action potential duration (APD) were studied in canine left ventricular subendocardial slabs using microelectrode techniques. Dofetilide monotonically increased QTc and APD throughout 6.5-hour exposure. Dofetilide infusion during ≥210 minutes inhibited Akt phosphorylation. INa-L block with lidocaine shortened QTc and APD more at 6.5 hours than at 50 minutes (QTc) or 30 minutes (APD) dofetilide administration. In comparison, moxifloxacin, an IKr blocker with no effects on phosphoinositide 3-kinase and INa-L prolonged APD acutely but no additional prolongation occurred on chronic superfusion. Lidocaine shortened APD equally during acute and chronic moxifloxacin superfusion. CONCLUSIONS: Increased INa-L contributes to chronic dofetilide effects in vivo. These data emphasize the need to include time and INa-L in evaluating the phosphoinositide 3-kinase inhibition-derived proarrhythmic potential of drugs and provide a mechanism for benefit from lidocaine administration in clinical acquired long QT syndrome.

Atrial gradient as a potential predictor of atrial fibrillation.

OBJECTIVES: We tested the utility and comparability of the atrial gradient and atrial ERP as early markers of electrical remodeling and a propensity to atrial fibrillation (AF). BACKGROUND: Pacing at physiologic rates from the left atrium alters the atrial gradient and is associated with atrial tachyarrhythmias. At these physiologic rates, there is no change in the atrial effective refractory period (ERP). METHODS: Sixty-one chronically instrumented mongrel dogs in complete heart block were paced from the left or right atrium at 400 to 900 bpm for 46 +/- 3 days. Dogs were monitored weekly and electrophysiologic studies conducted to determine changes in the atrial gradient, ERP, and rhythm. RESULTS: Rapid atrial pacing was associated with concordant decreases in atrial gradient, ERP, and occurrence of AF. Incidence of AF increased with increasing pacing rate. Although there ultimately was an equal incidence of AF with left atrial and right atrial pacing, the onset of AF occurred earlier with left atrial pacing. As expected, ERP decreased in both atria. Animals with long control ERP did not fibrillate. CONCLUSIONS: Rapid pacing induces changes in atrial gradient, which can be used as a noninvasive marker of electrical remodeling. AF is accompanied by decreases in atrial gradient and ERP, and the incidence is highest in dogs with short control ERP.

Left atrial pacing induces memory and is associated with atrial tachyarrhythmias.

OBJECTIVE: Transiently altering the atrial activation sequence induces atrial memory, manifested as an altered atrial gradient as measured in electrocardiographic XYZ leads. We hypothesized that protracted periods of left atrial impulse initiation alter the atrial gradient in a manner predictive of arrhythmias. METHODS: A total of 12 chronically instrumented mongrel dogs in complete heart block were paced AV sequentially from the left or right atrium for 7-28 days, and then recovered in normal sinus rhythm for 21 days. Rate histograms were recorded during the entire period, and electrophysiological studies were conducted to note changes in the atrial gradient, effective refractory period and atrial rhythm. No atrial arrhythmias were seen in eight control animals that were instrumented but not paced. RESULTS: Left atrial pacing was associated with a decreased atrial gradient and occurrence of atrial tachycardias that appeared during pacing and persisted during recovery from pacing. In contrast, right atrial pacing did not alter the atrial gradient significantly. Atrial tachycardias occurring during right atrial pacing disappeared after cessation of pacing, when dogs recovered in sinus rhythm. The effective refractory period did not change in either group. CONCLUSIONS: Pacing-induced impulse initiation from the left atrium alters the atrial gradient and is associated with atrial tachycardias. These changes in atrial gradient occur in the absence of ERP changes and may be early predictors of an arrhythmogenic substrate.

Morphological features of the neonatal brain following exposure to regional anesthesia during labor and delivery.

INTRODUCTION: Recent animal and human epidemiological studies suggest that early childhood exposure to anesthesia may have adverse effects on brain development. As more than 50% of pregnant women in the United States and one-third in the United Kingdom receive regional anesthesia during labor and delivery, understanding the effects of perinatal anesthesia on postnatal brain development has important public health relevance. METHODS: We used high-resolution magnetic resonance imaging (MRI) to assess the effects of regional anesthesia during labor and delivery as part of a larger study of perinatal exposures on the morphological features of the neonatal brain. We mapped morphological features of the cortical surface in 37 healthy infants, 24 exposed and 13 unexposed to regional anesthesia at delivery, who were scanned within the first 6 weeks of life. RESULTS: Infants exposed to maternal anesthesia compared with unexposed infants had greater local volumes in portions of the frontal and occipital lobes bilaterally and right posterior portion of the cingulate gyrus. Longer durations of exposure to anesthesia correlated positively with local volumes in the occipital lobe. CONCLUSIONS: Anesthesia exposure during labor and delivery was associated with larger volumes in portions of the frontal and occipital lobes and cingulate gyrus in neonates. Longitudinal MRI studies are needed to determine whether these morphological effects of anesthesia persist and what their consequences on cognition and behavior may be.

SkM1 and Cx32 improve conduction in canine myocardial infarcts yet only SkM1 is antiarrhythmic.

AIMS: Reentry accounts for most life-threatening arrhythmias, complicating myocardial infarction, and therapies that consistently prevent reentry from occurring are lacking. In this study, we compare antiarrhythmic effects of gene transfer of green fluorescent protein (GFP; sham), the skeletal muscle sodium channel (SkM1), the liver-specific connexin (Cx32), and SkM1/Cx32 in the subacute canine infarct. METHODS AND RESULTS: Immediately after ligation of the left anterior descending artery, viral constructs were implanted in the epicardial border zone (EBZ). Five to 7 days later, efficient restoration of impulse propagation (narrow QRS and local electrogram duration) occurred in SkM1, Cx32, and SkM1/Cx32 groups (P< 0.05 vs. GFP). Programmed electrical stimulation from the EBZ induced sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) in 15/22 GFP dogs vs. 2/12 SkM1, 6/14 Cx32, and 8/10 SkM1/Cx32 (P< 0.05 SkM1 vs. GFP). GFP, SkM1, and SkM1/Cx32 had predominantly polymorphic VT/VF, whereas in Cx32 dogs, monomorphic VT predominated (P< 0.05 for Cx32 vs. GFP). Tetrazolium red staining showed significantly larger infarcts in Cx32- vs. GFP-treated animals (P< 0.05). CONCLUSION: Whereas SkM1 gene transfer reduces the incidence of inducible VT/VF, Cx32 therapy to improve gap junctional conductance results in larger infarct size, a different VT morphology, and no antiarrhythmic efficacy.

Effect of skeletal muscle Na(+) channel delivered via a cell platform on cardiac conduction and arrhythmia induction.

BACKGROUND: In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel is largely inactivated, contributing to slow conduction and reentry. We have demonstrated that adenoviral delivery of the skeletal muscle Na(+) channel (SkM1) to epicardial border zones normalizes conduction and reduces induction of ventricular tachycardia/ventricular fibrillation. We now studied the impact of canine mesenchymal stem cells (cMSCs) in delivering SkM1. METHODS AND RESULTS: cMSCs were isolated and transfected with SkM1. Coculture experiments showed cMSC/SkM1 but not cMSC alone and maintained fast conduction at depolarized potentials. We studied 3 groups in the canine 7d infarct: sham, cMSC, and cMSC/SkM1. In vivo epicardial border zones electrograms were broad and fragmented in sham, narrower in cMSCs, and narrow and unfragmented in cMSC/SkM1 (P<0.05). During programmed electrical stimulation of epicardial border zones, QRS duration in cMSC/SkM1 was shorter than in cMSC and sham (P<0.05). Programmed electrical stimulation-induced ventricular tachycardia/ventricular fibrillation was equivalent in all groups (P>0.05). CONCLUSION: cMSCs provide efficient delivery of SkM1 current. The interventions performed (cMSCs or cMSC/SkM1) were neither antiarrhythmic nor proarrhythmic. Comparing outcomes with cMSC/SkM1 and viral gene delivery highlights the criticality of the delivery platform to SkM1 antiarrhythmic efficacy.

Neurological and developmental outcomes of prenatally cocaine-exposed offspring from 12 to 36 months.

Second generation studies of prenatal cocaine exposure failed to find gross deficits after controlling for confounders. Concern remained that exposure could cause subtle deficits. This prospective, cohort study evaluated effects of cocaine on development at 12, 18, 24, and 36 months. From 1991-1993, 361 mother-infant pairs were recruited from the Children's Hospital of New York, Presbyterian Medical Center's prenatal clinic or delivery room suite. Mothers were assigned to the cocaine group based on report of prenatal cocaine use or positive urine toxicology. Control mothers were enrolled from the same clinic and matched for age and socioeconomic status (SES). Women with serious medical problems were excluded from either group. Of the retained cohort, at 12 months, 147 infants were exposed and 89 were unexposed case controls. Both groups were raised in impoverished environments with few supports. Developmental evaluations were conducted blinded to group. Cross-sectional analysis revealed cocaine-related deficits in neurological exams and speech across all time periods, in spite of catch up in weight, length, and head circumference. Overall analysis of development was evaluated using Generalized Estimating Equations regression analysis. Bayley Mental [Badj = -6.5 (CI--9.4, -3.5, p < or = 0.001)] and Psychomotor [Badj = -3.9 (CI--7.4, -0.5, p = 0.02)] Developmental Indices showed deficits after controlling for confounders. Males were more vulnerable to cocaine exposure for height, motor development, and emotional regulation. Dose-response relationships existed for abnormal neurological exams (Ptrends < 0.08), Mental Development Index (MDI) (Ptrend < 0.001), and Psychomotor Development Index (PDI) (Ptrend < 0.001) deficits. Although nonexposed children performed poorly, cocaine-exposed children showed worse performance. Both groups showed declines at 18 months in mental and psychomotor development from which only nonexposed children rebounded. Overall, cocaine exposure adds an additional risk to disadvantaged children's development. Cocaine-exposed children are less resilient to effects of these multiple risks.

Evaluation of KCB-328, a new IKr blocking antiarrhythmic agent in pacing induced canine atrial fibrillation.

HYPOTHESIS: KCB-328 is a new potassium channel blocker, which prolongs action potential duration with exhibition of minimal reverse use dependence. We tested the efficacy and proarrhythmic potential of KCB-328, dofetilide and propafenone in the pacing induced canine model of atrial fibrillation (AF). METHODS: Mongrel dogs in complete heart block were paced for 1-6 weeks to produce AF, and given KCB-328 or dofetilide. A subset then received propafenone 14+/-3 days after testing the first drug. RESULTS: KCB-328 prolonged right and left atrial (RA and LA) activation times and AF cycle length (CL), terminating AF in 3 of 6 dogs. RA effective refractory period (ERP) and ventricular ERP and QT interval were prolonged. Dofetilide terminated AF in 1/6 dogs, and increased AF CL and ventricular ERP and QT interval. Dofetilide's reverse use dependency on the QT interval was greater than KCB-328. Propafenone prolonged RA and LA activation times and AF CL and terminated AF in 8 of 9 dogs. One death occurred with dofetilide, none with KCB-328 or propafenone. CONCLUSION: The spectrum of effect of the three drugs differed significantly: propafenone showed the greatest success in AF termination, and both propafenone and KCB-328 appeared less proarrhythmic than dofetilide in this model.