Hybrid surgical ablation for persistent or long standing persistent atrial fibrillation: A French single centre experience.

BACKGROUND: Hybrid ablation for the treatment of atrial fibrillation is a single combined procedure consisting in a minimally thoracoscopic surgical ablation followed by a catheter ablation. This promising technique is recommended in persistent atrial fibrillation according to the current guidelines but is not routinely performed in France, mainly due to the absence of reimbursement by the French National Health Insurance. AIMS: The aim of this prospective and single-centre study was to analyse, for the first time in France, the feasibility, efficacy and complication rates of hybrid ablation in patients with persistent atrial fibrillation. METHODS: Hybrid ablation was performed in 15 consecutive patients (13 men, mean age 61±6 years) with persistent (7 patients) or long standing persistent (8 patients) atrial fibrillation. RESULTS: Hybrid ablation was completed in 14/15 patients. Eleven patients returned in sinus rhythm during the procedure. Two patients (13%) had major per-procedural complications and 2 had minor complications. During an average follow-up of 25±6 months, 6 patients (40%) underwent a redo catheter ablation because of atrial tachycardia, mainly peri-mitral atrial flutter. At 1 year follow up, 14/15 patients were in sinus rhythm, including 11 free of antiarrhythmic drugs.

Usefulness of interim analyses in portending study results in antipsychotic and antidepressant trials.

It is unknown whether interim analyses portend final study results. Fatigue, pressure to complete trials and recruitment differences may mitigate against this. We examined the similarity of efficacy results of the first and second half of recruited patients to complete trials and explore possible intervening variables. Using data from the NewMeds repository of patient level data from placebo-controlled randomized trials of antipsychotics (AP) (22 studies, n=7056) and antidepressants (AD) (39 studies, n=12,217) we compared treatment effect size (placebo vs. active treatment) of the first and second half of patients recruited in completed trials. We found that in AP studies median difference in treatment effect between cohorts was -0.03, indicating that overall first and second cohorts yielded similar results. In AD studies, median difference between cohorts was 0.04, indicating that overall the second cohort had slightly larger active-placebo-difference. Overall, on average there were minimal differences in effect size between the first and the second cohorts, and in 30 of 39 trials interim results were a good estimate of the results on the 2nd cohort. In AD trials first and second cohort results were more similar when the proportion of patients per study centre and recruitment time of the two cohorts was similar. Results suggest that interim analyses in AD and AP studies may reliably serve to estimate ultimate effects and, at least in AD trials, are more accurate when the same sites are used to a similar extent and recruitment time of the two consequent cohorts is similar.

Efficacy of ziprasidone in dysphoric mania: pooled analysis of two double-blind studies.

BACKGROUND: Dysphoric mania is a common and often difficult to treat subset of bipolar mania that is associated with significant depressive symptoms. OBJECTIVE: This post hoc analysis was designed to evaluate the efficacy of ziprasidone in the treatment of depressive and other symptoms in a cohort of patients with dysphoric mania. METHODS: Pooled data were examined from two similarly designed, 3-week placebo-controlled trials in acute bipolar mania. Patients scoring >/=2 on at least two items of the extracted Hamilton Rating Scale for Depression (HAM-D) met criteria for dysphoric mania and were included in the post hoc analysis. Changes from baseline in symptom scores were evaluated by a mixed-model analysis of covariance. RESULTS: 179 patients with dysphoric mania were included in the post hoc analysis (ziprasidone, n=124; placebo, n=55). Beginning at day 4, HAM-D scores were significantly lower at all visits in patients treated with ziprasidone compared with those treated with placebo (p<0.05). Ziprasidone-treated patients also demonstrated significant improvements on the Mania Rating Scale and all secondary efficacy measures, and had significantly higher response and remission rates compared with placebo. LIMITATIONS: The main limitations are the use of a post hoc analysis and the pooling of two studies with slightly different designs. CONCLUSION: In this analysis, ziprasidone significantly improved both depressive and manic mood symptoms in patients with dysphoric mania, suggesting that it might be a useful treatment option in this patient population. Further prospective controlled trials are needed to confirm these findings.

Early onset anxiolytic efficacy after a single dose of pregabalin: double-blind, placebo- and active-comparator controlled evaluation using a dental anxiety model.

To evaluate acute onset of anxiolytic activity using a dental anxiety model, 89 patients were randomised to double-blind single dose pregabalin 150 mg, alprazolam 0.5 mg or placebo 4 h before a scheduled dental procedure. A Dental Anxiety Total score >12 (moderate-to-severe) without meeting Diagnostic and Statistical Manual of Mental Disorders (Fourth edition) (DSM-IV) anxiety disorder criteria was required. Efficacy and safety, assessed 2, 2.5, 3, 3.5 and 4 h postdose, included 100 mm Visual Analogue Scale for Anxiety (VAS-Anxiety; primary outcome), 100 mm VAS-Sedation and Time-to-Onset of Action Scale (TOAS), a patient-rated anti-anxiety drug-benefit scale (no [0] to full benefit [10]). Mixed model analysis found significantly greater VAS-A improvement slopes for pregabalin (t = -2.47; P = 0.014) and alprazolam (t = -2.39; P = 0.018). There was a significant improvement versus placebo in the TOAS from 2 h through endpoint in alprazolam patients and from 3 h onward in pregabalin patients. Pregabalin produced significantly greater increases in VAS-Sedation versus placebo from 2.5 h through 4 h (2 h onward for alprazolam). Notably, there was a higher correlation between TOAS and VAS-Sedation (r = +0.58) than VAS-Anxiety (r = -0.50) on Spearman's analysis. The majority of Adverse Effects (AEs) were mild, and the most frequent for pregabalin, alprazolam, and placebo, respectively, were fatigue (N = 7, 7, 3), dizziness (N = 6, 3, 3), attention disturbance (N = 3, 1, 0), somnolence (N = 3, 0, 0), feeling abnormal (N = 0, 2, 0) and balance disorder (N = 0, 2, 0). These results suggest that onset of clinically meaningful anxiolytic effect after single-dose pregabalin occurs within the first 3-4 h. Additional research is needed to determine whether anxiolytic effect occurs in generalized anxiety disorder populations by day 1 or within 3-4 h post-first dose.

[Analysis of the interaction between nicotinic acetylcholine receptor and Na+,K(+)-ATPase in the rat skeletal muscle and the Torpedo electric organ membrane preparation].

The interaction between the nicotinic acetylcholine receptor and Na+,K(+)-ATPase described previously was further studied in isolated rat diaphragm and in a membrane preparation of Torpedo californica electric organ. Three specific agonists of the nicotinic receptor: acetylcholine, nicotine and carbamylcholine (100 nmol/L each), all hyperpolarized the non-synaptic membranes of muscle fibers by up to 4 mV. Competitive antagonists of nicotinic acetylcholine receptor, d-tubocurarine (2 mcmol/L) or alpha-bungarotoxin (5 nmol/L) completely blocked the acetylcholine-induced hyperpolarization indicating that the effect requires binding of the agonists to their specific sites. The noncompetitive antagonist, proadifen (5 mcmol/L), exerted no effect on the amplitude of hyperpolarized but decreased K0.5 for this effect from 28.3 +/- 3.6 nmol/L to 7.1 +/- 2.3 nmol/L. Involvement of the Na+,K(+)-ATPase was suggested by data demonstrating that three specific Na+,K(+)-ATPase inhibitors: ouabain, digoxin or marinobufagenin (100 nmol/L each), all inhibit the hyperpolarizing effect of acetylcholine. Acetylcholine did not affectation either the catalytic activity of the Na+,K(+)-ATPase purified from sheep kidney or the transport activity of the Na+,K(+)-ATPase in the rat erythrocytes, i. e. in preparations not containing acetylcholine receptors. Hence, acetylcholine does not directly affect the Na+,K(+)-ATPase. In a Torpedo membrane preparation, ouabain (< or = 100 nmol/L) increased the binding of the fluorescent ligand: Dansyl-C6-choline (DCC). No ouabain effect was observed either when the agonist binding sites of the receptor were occupied by 2 mmol/L carbamylcholine, or in the absence Mg2+, when the binding of ouabain to the Na+,K(+)-ATPase is negligible. These results indicate that ouabain only affects specific DCC binding and only when bound to the Na+,K(+)-ATPase. The data obtained suggest that, in two different systems, the interaction between the nicotinic acetylcholine receptor and the Na+,K(+)-ATPase specifically involve the ligand binding sites of these two proteins.

[Functional interaction between nicotinic cholinergic receptors and Na, K-ATPase in the skeletal muscles]. / Funktsional'naia sviaz' nikotinovykh kholinoretseptorov i Na, K-ATFazy v skeletnoi myshtse.

Acetylcholine (ACh) hyperpolarized the rat diaphragm muscle fibers by 4.5 +/- 0.8 mV (K0.5 = = 36 +/- 6 nmol/l). The AC-induced hyperpolarization was blocked by d-tubocurarine and ouabain in nanomolar concentrations. This effect of ACh was not observed in cultured C2C12 muscle cells and in Xenopus oocytes with expressed embryonic mouse muscle nicotinic acetylcholine receptors (nAChR) or with neuronal alpha 4 beta 2 nAChR. In membrane preparations from the Torpedo californica electric organ, containing both nAChR and Na, K-ATPase, 10 nmol/l ouabain modulated the binding kinetics of the cholinergic ligand dansyl-C6-choline to the nAChR. These results suggest that in-sensitive alpha 2 isoform) and nAChR in a state with high affinity to Ach and d-tubocurarine may form a functional complex in which binding of ACh to nAchR is coupled to activation of the Na, K-ATPase.

Feasibility of atmospheric pressure desorption/ionization on silicon mass spectrometry in analysis of drugs.

The feasibility of atmospheric pressure desorption/ionization on silicon mass spectrometry (AP-DIOS-MS) for drug analysis was investigated. It was observed that only compounds with relative high proton affinity are efficiently ionized under AP-DIOS conditions. The limits of detection (LODs) achieved in MS mode with midazolam, propranolol, and angiotensin II were 80 fmol, 20 pmol, and 1 pmol, respectively. In MS/MS mode the LODs for midazolam and propranolol were 10 fmol and 5 pmol, respectively. The good linearity (r(2) > 0.991), linear dynamic range of 3 orders of magnitude, and reasonable repeatability showed that the method is suitable for quantitative analysis.

[Porcine kidney extract contains a specific inhibitor of the ouabain-sensitive alpha2-isoform of Na, K-ATPase present in rat diaphragm fibres]. / Ekstrakt pochek svin'i soderzhit spetsificheskii ingibitor ouabain-chuvstvitel'noi alfa2 izoformy Na, K-ATFazy myshechnykh volokon diafragmy krysy.

In experiments on isolated rat diaphragm muscle, acetylcholine (100 nmol/l) hyperpolarized muscle fibres due to activation of the alpha 2 isoform of Na,K-ATPase. This hyperpolarization was blocked in a dose-dependent manner by ouabain (K0.5 = 8 +/- 4 nmol/l) as well as by a solution of porcine kidney extract (10 kDa cut-off filtration), with the K0.5 approximately equal to a 1:20,000-fold dilution. The inhibitory activity of the developed slowly over a period of 3 hours and, in contrast to ouabain, was still present after 1 hour of washing. Ouabain, but not the extract, inhibits Rb+ uptake in human erythrocytes that only express the alpha = 1 isoform of Na, K-ATPase. Our data suggest that in rat skeletal muscle the alpha 1 isoform of Na,K-ATPase is primarily responsible for ionic homeostasis, while the alpha 2 isoform provides a "regulatable" function and may be controlled by cholinergic stimulation and/or endogenous digitalis-like factors (EDLFs). Porcine kidney extract contains a factor (M. W. < 10 kDa) that selectively inhibits the rat alpha 2 isoform and differs from ouabain. Our experimental protocol can be used as a highly sensitive physiological assay for factors that selectively inhibit the alpha 2 isoform of Na,K-ATPase.

Quantitative determination of 1 -hydroxypyrene in bovine urine samples using high-performance liquid chromatography with fluorescence and mass spectrometric detection.

An analytical method was developed to determine quantitatively 1-hydroxypyrene (OHP) in bovine urine samples. The procedure includes an enzymatic hydrolysis to cleave the conjugated metabolite, an enrichment step using solid phase extraction with a non-polar rinse step and elution with dichloromethane. A final clean-up on silicagel was performed before high-performance liquid chromatography (HPLC) analysis and fluorescence detection. Alternatively, HPLC and electrospray ionization in the negative ion mode applying selective ion monitoring acquisition revealed to be a highly sensitive detection method allowing the quantitation of low pg of OHP in the urine samples. The method was successfully applied to the determination of OHP in bovine urine samples from animals living in urban and rural areas. Urine concentrations of OHP were significantly higher (median 8.6 microg l(-1)) of bovines living close to a highway.

The effect of relocation after a natural disaster.

Twenty-five women remaining in a city devastated by an earthquake were compared with 24 relocated survivors and 25 comparison women. The women were administered a structured PTSD interview, the Hamilton Depression Scale, and SCL-90-R. The women in both exposed groups showed significantly more symptoms of avoidance, arousal, and total PTSD than the comparison group. The women in the relocated city had significantly higher depression scores than the women in the earthquake city. On the SCL-90-R, relocated women were most symptomatic and comparison group women were least symptomatic. Relocation after a disaster appears to be associated more with risk for depression than with PTSD in situations where recovery is delayed following the trauma.

Differences between adolescents and young adults at presentation to an eating disorders program.

OBJECTIVE: To describe differences between adolescents and adults in clinical presentation of eating disorders. METHODS: Data from the charts of 622 female patients treated for an eating disorder in a division of adolescent medicine between 1980 and 1994 were coded and computerized. General categories included demographic and family factors, weight loss and weight changes, eating-related behaviors, diagnosis and severity, and treatment issues. Differences between the 438 patients who were aged 9-19 years (adolescents) and 184 patients who were aged 20-46 years (adults) were analyzed. RESULTS: Adolescents were more likely than adults (p <.05) to have a diagnosis of "eating disorder not otherwise specified," lower global severity score, greater denial and less desire for help, weight loss > or = 3 lb/month, lower original and maximum weights, and history of fasting and elimination of junk food from their diets. Adults were more likely than adolescents (p <.05) to have >1 year of weight loss, greater total weight loss, history of binge eating and laxative use, history of diuretic and ipecac use, diagnosis of bulimia nervosa, and prior use of psychiatric medications. Adolescents and adults did not differ (p >.05) in parents' occupational level; height, weight, and percent ideal body weight at presentation; original percent ideal body weight; use of diet pills, elimination of meat and use of a low-fat diet; daily calorie intake; prior eating disorder hospitalizations; and hospitalization during the course of treatment. CONCLUSIONS: The findings in this study document and confirm that there are important differences between adolescents and adults that must be taken into account in the evaluation and treatment of patients with eating disorders.

Psychiatric disorders in adolescents exposed to domestic violence and physical abuse.

The relationship between abuse and psychiatric diagnoses was investigated in two groups of physically abused adolescents, 57 living in homes with interparental violence and 32 in homes without such violence, and in 96 nonabused adolescents living in nonviolent homes. Adolescents in the first group were found to be at greater risk for depression, separation anxiety disorder, post-traumatic stress disorder, and oppositional defiant disorder than were those in the second group. Adolescents in the first group also appeared more vulnerable to anxiety and depression.

An examination of bias in volunteer subject selection: findings from an in-depth child abuse study.

Remarkably few reported studies tested the assumption that a research sample can be constructed which is representative of the population of interest. In order to investigate potential volunteer bias in abuse research, we utilized a database assembled for an NIMH funded study investigating the relationship among adolescent physical abuse, suicidal behavior, and psychopathology. Extensive information was available concerning the nonparticipant pool from which this sample was assembled, allowing for a comprehensive assessment of possible sample bias. The volunteer sample of 99 abused families who agreed to participate in our study was compared on a large number of variables with a random sample of 99 abused families who declined to participate. Comparisons of the two groups did not support the hypothesis that the non-participating families represented a more dysfunctional population. The two groups were far more similar to, than disparate from, each other.

A preliminary study of a cartoon measure for children's reactions to chronic trauma.

Preliminary psychometric properties of a new instrument, Angie/Andy Cartoon Trauma Scales (ACTS), are presented. Angie/Andy features a cartoon-based methodology, measuring trauma-related sequelae of prolonged, repeated abuse. A sample of 208 children comprised intrafamilial trauma, extrafamilial trauma, combined trauma, and nontrauma groups. Angie/Andy demonstrated high internal consistency, with coefficient alphas from 0.70 to 0.95. The three trauma groups scored significantly higher than the nontrauma group on all scales (p's < 0.0001). Generally, the most severely traumatized group scored significantly higher than the less severely traumatized groups. The number of types of violence exposures correlated with Angie/Andy scores from 0.55 to 0.74. The frequency and severity of trauma exposure correlated with Angie/Andy scores from 0.44 to 0.56. The Angie/Andy parent version correlated with a standardized parent scale from 0.71 to 0.81. Parent/child agreement was significant. Angie/Andy is a promising tool for clinical assessment of chronic childhood abuse.

Perception of family functioning and depressive symptomatology in individuals with anorexia nervosa or bulimia nervosa.

This study investigated the relationship between the perception of family functioning and depressive symptomatology in individuals with eating disorders (EDs). Subjects were evaluated by diagnostic clinical interview using DSM-III-R criteria for EDs, the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L), and two self-report measures, the Beck Depression Inventory (BDI) and the Family Assessment Device (FAD). A significant association was found between self-reported depressive symptomatology and perceived poor family functioning. Subjects with bulimia nervosa (BN) reported a significantly more dysfunctional family background than subjects with anorexia nervosa (AN). In our sample, the presence of self-reported depressive symptomatology was a more powerful predictive variable for perceived family dysfunction than the diagnosis of affective disorder. Also, the diagnosis of BN was a more consistent predictor of dysfunctional family interaction than the diagnosis of affective disorder. Depressive symptoms and EDs seem to play different roles in the way in which they contribute to dysfunctional family patterns.

Physically abused adolescents: behavior problems, functional impairment, and comparison of informants' reports.

OBJECTIVE: This study, like earlier studies that focused on younger abused children, ascertained whether physically abused adolescents exhibited increased internalizing and externalizing behaviors. Relevance to pediatric practice is discussed. DESIGN: A cross-sectional design was used to compare the behavior of physically abused adolescents and comparison adolescents using self-reports, parent reports, and teacher reports. The level of agreement among raters was also examined. PARTICIPANTS: The subjects were 99 physically abused adolescents between the ages of 12 and 18 years, who were recruited from Child Protective Services. Comparison subjects were 99 community-recruited nonabused adolescents who were matched for age, gender, and income with the abused adolescents. MEASURES: The behavior of the adolescents was assessed using the Child Behavior Checklist, and the comparable Youth Self-Report and Teacher Report Form, which are widely used measures of behavioral and emotional problems. The Child Global Assessment Scale was also used as a measure of functional impairment and of the need for mental health services. RESULTS: Parents and teachers rated the problems of abused adolescents as significantly greater than the problems of nonabused adolescents on all checklist subscales. Abused adolescents reported significantly greater problems only on externalizing behavior subscales. In addition, based on interviewer ratings, physically abused adolescents exhibited significantly greater functional impairment. CONCLUSIONS: Similar to previous research on abused children, physically abused adolescents exhibit externalizing and internalizing behavior problems and experience greater functional impairment. Parent, teacher, and adolescent reports of externalizing behaviors were similar, but physically abused adolescents reported fewer internalizing behaviors than did the other informants.

Oxidation of the skeletal muscle Ca2+ release channel alters calmodulin binding.

This study presents evidence for a close relationship between the oxidation state of the skeletal muscle Ca2+ release channel (RyR1) and its ability to bind calmodulin (CaM). CaM enhances the activity of RyR1 in low Ca2+ and inhibits its activity in high Ca2+. Oxidation, which activates the channel, blocks the binding of 125I-labeled CaM at both micromolar and nanomolar Ca2+ concentrations. Conversely, bound CaM slows oxidation-induced cross-linking between subunits of the RyR1 tetramer. Alkylation of hyperreactive sulfhydryls (<3% of the total sulfhydryls) on RyR1 with N-ethylmaleimide completely blocks oxidant-induced intersubunit cross-linking and inhibits Ca2+-free 125I-CaM but not Ca2+/125I-CaM binding. These studies suggest that 1) the sites on RyR1 for binding apocalmodulin have features distinct from those of the Ca2+/CaM site, 2) oxidation may alter the activity of RyR1 in part by altering its interaction with CaM, and 3) CaM may protect RyR1 from oxidative modifications during periods of oxidative stress.