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Background and purpose Females are more sensitive than males to both the acute and prolonged effects of psychomotor stimulants. In females, this is regulated by oestradiol, which enhances dopamine release in the dorsal striatum. In this study, we tested the acute effect of oestradiol on dopamine release in the nucleus accumbens (NAc) shell after cocaine administration and investigated which oestradiol receptors (ERs) contribute to sex differences in the response to cocaine. Experimental approach The ability of oestradiol benzoate (EB) to acutely modulate the effect of cocaine on phasic dopamine release in the NAc shell was measured by fast-scan cyclic voltammetry in anaesthetized male and female rats. The roles of ER subtypes, ERα and ERβ, was determined with selective agonists. Key results EB acutely enhanced the effect of cocaine on stimulated dopamine release from the NAc shell in females but not in male rats only at levels of stimulation expected to optimally saturate dopamine transporters. Enhanced dopamine release after cocaine administration was also observed in females after selective activation of ERβ but not ERα. EB attenuated the effect of cocaine on NAc shell dopamine reuptake in males but not in females. Conclusions and implications Oestradiol acutely and rapidly regulates dopamine release in females and dopamine reuptake in males. In females, oestradiol rapidly enhances the effect of cocaine on dopamine release, likely via activation of ERβ. The effect of oestradiol in males is not seen with selective receptor subtype activation, a topic deserving of further study. Linked articles This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.

Predicting substrates for enzymes of unknown function is a major postgenomic challenge. Substrate discovery, like inhibitor discovery, is constrained by our ability to explore chemotypes; it would be expanded by orders of magnitude if reactive sites could be probed with fragments rather than fully elaborated substrates, as is done for inhibitor discovery. To explore the feasibility of this approach, substrates of six enzymes from three different superfamilies were deconstructed into 41 overlapping fragments that were tested for activity or binding. Surprisingly, even those fragments containing the key reactive group had little activity, and most fragments did not bind measurably, until they captured most of the substrate features. Removing a single atom from a recognized substrate could often reduce catalytic recognition by 6 log-orders. To explore recognition at atomic resolution, the structures of three fragment complexes of the β-lactamase substrate cephalothin were determined by X-ray crystallography. Substrate discovery may be difficult to reduce to the fragment level, with implications for function discovery and for the tolerance of enzymes to metabolite promiscuity. Pragmatically, this study supports the development of libraries of fully elaborated metabolites as probes for enzyme function, which currently do not exist.

Females exhibit more rapid escalation of cocaine use and enhanced cocaine-taking behavior as compared to males. While ovarian hormones likely play a role in this increased vulnerability, research has yet to examine the role of estradiol in affecting the behavioral and neurological response to cocaine in a brain region- and sex-specific way.First, we examined stereotypy and locomotor sensitization after repeated cocaine administration (10 mg/kg i.p.) in intact (SHAM) and castrated (CAST) males, and ovariectomized (OVX) females treated with 5 μg estradiol benzoate (EB) or vehicle (OIL). Next, we used in vivo microdialysis to examine the effects of acute EB treatment on cocaine-induced DA in the regions mediating the display of these behaviors (i.e., the dorsolateral striatum, DLS; and the nucleus accumbens, NAc; respectively).We find that EB enhances sensitization of cocaine-induced stereotypy in OVX females after 12 days of cocaine treatment, and after a 10-day withdrawal. Similarly, the OVX/EB females show enhanced locomotor sensitization compared to the other three groups on the same days. Using in vivo microdialysis to assess the neurochemical response, we find that EB rapidly enhances cocaine-induced DA in DLS dialysate of OVX females but not CAST males, and has no effect in NAc of either sex.With these experiments, we show that there are sex differences in the effects of estradiol to preferentially enhance the response to cocaine in the DLS over the NAc in females, which may contribute to the preferential sensitization of stereotypy in females.

In bacteria, 3',5'-adenosine bisphosphate (pAp) is generated from 3'-phosphoadenosine 5'-phosphosulfate in the sulfate assimilation pathway, and from coenzyme A by the transfer of the phosphopantetheine group to the acyl-carrier protein. pAp is subsequently hydrolyzed to 5'-AMP and orthophosphate, and this reaction has been shown to be important for superoxide stress tolerance. Herein, we report the discovery of the first instance of an enzyme from the amidohydrolase superfamily that is capable of hydrolyzing pAp. Crystal structures of Cv1693 from Chromobacterium violaceum have been determined to a resolution of 1.9 Å with AMP and orthophosphate bound in the active site. The enzyme has a trinuclear metal center in the active site with three Mn(2+) ions. This enzyme (Cv1693) belongs to the Cluster of Orthologous Groups cog0613 from the polymerase and histidinol phosphatase family of enzymes. The values of kcat and kcat/Km for the hydrolysis of pAp are 22 s(-1) and 1.4 × 10(6) M(-1) s(-1), respectively. The enzyme is promiscuous and is able to hydrolyze other 3',5'-bisphosphonucleotides (pGp, pCp, pUp, and pIp) and 2'-deoxynucleotides with comparable catalytic efficiency. The enzyme is capable of hydrolyzing short oligonucleotides (pdA)5, albeit at rates much lower than that of pAp. Enzymes from two other enzyme families have previously been found to hydrolyze pAp at physiologically significant rates. These enzymes include CysQ from Escherichia coli (cog1218) and YtqI/NrnA from Bacillus subtilis (cog0618). Identification of the functional homologues to the experimentally verified pAp phosphatases from cog0613, cog1218, and cog0618 suggests that there is relatively little overlap of enzymes with this function in sequenced bacterial genomes.

High- versus low-novelty exploration predicts a variety of behavioral differences. For example, rats selectively bred for high-novelty exploration (bred-high responders, bHR) exhibit exaggerated aggression, impulsivity, and proclivity to addictive behaviors compared with low-novelty reactive rats (bred-low responders, bLRs), which are characterized by a high anxiety/depressive-like phenotype. Since bHR/bLR rats exhibit differences in dopaminergic circuitry and differential response to rewarding stimuli (i.e., psychostimulants, food), the present study examined whether they also differ in another key hedonic behavior-sex. Thus, adult bHR/bLR males were given five 30-min opportunities to engage in sexual activity with a receptive female. Sexual behavior and motivation were examined and compared between the groups. The bHR/bLR phenotype affected both sexual motivation and behavior, with bLR males demonstrating reduced motivation for sex compared with bHR males (i.e., fewer animals copulated, longer latency to engage in sex). The bHR males required more intromissions at a faster pace per ejaculation than did bLR males. Thus, neurobiological differences that affect motivation for drugs of abuse, aggression, and impulsivity in rats also affect sexual motivation and performance.

Technological advances and increased utilization of medical testing and procedures have prompted greater attention to ensuring the patient safety of radiation use in the practice of adult cardiovascular medicine. In response, representatives from cardiovascular imaging societies, private payers, government and nongovernmental agencies, industry, medical physicists, and patient representatives met to develop goals and strategies toward this end; this report provides an overview of the discussions. This expert “think tank” reached consensus on several broad directions including: the need for broad collaboration across a large number of diverse stakeholders; clarification of the relationship between medical radiation and stochastic events; required education of ordering and providing physicians, and creation of a culture of safety; development of infrastructure to support robust dose assessment and longitudinal tracking; continued close attention to patient selection by balancing the benefit of cardiovascular testing and procedures against carefully minimized radiation exposures; collation, dissemination, and implementation of best practices; and robust education, not only across the healthcare community, but also to patients, the public, and media. Finally, because patient radiation safety in cardiovascular imaging is complex, any proposed actions need to be carefully vetted (and monitored) for possible unintended consequences.

Family-focused prevention programs for community samples have potentially broad, clinically relevant implications but few studies have examined whether any program benefits continue to be observed over the long term. Although benefits of a marital conflict focused parent education program, the Happy Couples and Happy Kids (i.e., HCHK) program, were supported in a study based on pre-test, post-test, 6-month follow-up, and 1-year follow-up assessments, the longer-term stability of treatment effects has not been established. Couples with children between 4 and 8 years of age who had previously participated in the HCHK study completed a two-year follow-up, including a parent-only group (PO, n = 12); parent–child group (PC, n = 15); and a self-study group (SS, n = 12). Greater knowledge about the effects of marital conflict on families and behavioral improvements in constructive conflict, and specifically in problem-solving behaviors, were observed at the two-year follow-up for couples who received the HCHK program. Reflecting an innovative analysis of mediating mechanisms, change-to-change analyses showed that these changes were linked with improvements in other family processes over time, including marital satisfaction, parenting and child adjustment. The findings support the relatively long-term efficacy of brief, psychoeducational programs for educating community samples about marital conflict and family processes.

We developed prototype real-time 3-D intracardiac echocardiography catheters with integrated micromotors, allowing internal oscillation of a low-profile 64-element, 6.2-MHz phased-array transducer in the elevation direction. Components were designed to facilitate rotation of the array, including a low-torque flexible transducer interconnect and miniature fixtures for the transducer and micromotor. The catheter tip prototypes were integrated with two-way deflectable 10-Fr catheters and used in in vivo animal testing at multiple facilities. The 4-D ICE catheters were capable of imaging a 90° azimuth by up to 180° elevation field of view. Volume rates ranged from 1 vol/sec (180° elevation) to approximately 10 vol/sec (60° elevation). We successfully imaged electrophysiology catheters, atrial septal puncture procedures, and detailed cardiac anatomy. The elevation oscillation enabled 3-D visualization of devices and anatomy, providing new clinical information and perspective not possible with current 2-D imaging catheters.

Background— Obstructive sleep apnea (OSA) may be associated with pulmonary vein antrum isolation (PVAI) failure. The aim of the present study was to investigate if treatment with continuous positive airway pressure (CPAP) improved PVAI success rates. Methods and Results— From January 2004 to December 2007, 3000 consecutive patients underwent PVAI. Patients were screened for OSA and CPAP use. Six hundred forty (21.3%) patients had OSA. Patients with OSA had more procedural failures ( P =0.024) and hematomas ( P P P =0.001). At the end of the follow-up period (32±14 months), 79% of the non-CPAP and 68% of the CPAP group were free of atrial fibrillation ( P =0.003). Not using CPAP in addition to having non-PV triggers strongly predicted procedural failure (hazard ratio, 8.81; P Conclusions— OSA was an independent predictor for PVAI failure. Treatment with CPAP improved PVAI success rates. Patients not treated with CPAP in addition to having higher prevalence of non-PV triggers were 8 times more likely to fail the procedure.

Background— Together with pulmonary veins, many extrapulmonary vein areas may be the source of initiation and maintenance of atrial fibrillation. The left atrial appendage (LAA) is an underestimated site of initiation of atrial fibrillation. Here, we report the prevalence of triggers from the LAA and the best strategy for successful ablation. Methods and Results— Nine hundred eighty-seven consecutive patients (29% paroxysmal, 71% nonparoxysmal) undergoing redo catheter ablation for atrial fibrillation were enrolled. Two hundred sixty-six patients (27%) showed firing from the LAA and became the study population. In 86 of 987 patients (8.7%; 5 paroxysmal, 81 nonparoxysmal), the LAA was found to be the only source of arrhythmia with no pulmonary veins or other extrapulmonary vein site reconnection. Ablation was performed either with focal lesion (n=56; group 2) or to achieve LAA isolation by placement of the circular catheter at the ostium of the LAA guided by intracardiac echocardiography (167 patients; group 3). In the remaining patients, LAA firing was not ablated (n=43; group 1). At the 12±3-month follow-up, 32 patients (74%) in group 1 had recurrence compared with 38 (68%) in group 2 and 25 (15%) in group 3 ( P Conclusions— The LAA appears to be responsible for arrhythmias in 27% of patients presenting for repeat procedures. Isolation of the LAA could achieve freedom from atrial fibrillation in patients presenting for a repeat procedure when arrhythmias initiating from this structure are demonstrated.

Background— Catheter ablation of atrial fibrillation is associated with the potential risk of periprocedural stroke, which can range between 1% and 5%. We developed a prospective database to evaluate the prevalence of stroke over time and to assess whether the periprocedural anticoagulation strategy and use of open irrigation ablation catheter have resulted in a reduction of this complication. Methods and Results— We collected data from 9 centers performing the same ablation procedure with the same anticoagulation protocol. We divided the patients into 3 groups: ablation with an 8-mm catheter off warfarin (group 1), ablation with an open irrigated catheter off warfarin (group 2), and ablation with an open irrigated catheter on warfarin (group 3). Outcome data on stroke/transient ischemic attack and bleeding complications during and early after the procedures were collected. Of 6454 consecutive patients in the study, 2488 were in group 1, 1348 were in group 2, and 2618 were in group 3. Periprocedural stroke/transient ischemic attack occurred in 27 patients (1.1%) in group 1 and 12 patients (0.9%) in group 2. Despite a higher prevalence of nonparoxysmal atrial fibrillation and more patients with CHADS2 (congestive heart failure, hypertension, age >75 years, diabetes mellitus, and prior stroke or transient ischemic attack) score >2, no stroke/transient ischemic attack was reported in group 3. Complications among groups 1, 2, and 3, including major bleeding (10 [0.4%], 11 [0.8%], and 10 [0.4%], respectively; P >0.05) and pericardial effusion (11 [0.4%], 11 [0.8%], and 12 [0.5%]; P >0.05), were equally distributed. Conclusion— The combination of an open irrigation ablation catheter and periprocedural therapeutic anticoagulation with warfarin may reduce the risk of periprocedural stroke without increasing the risk of pericardial effusion or other bleeding complications.

Most atrial fibrillation (AF) ablation studies have consisted predominantly of males; accordingly, there is a paucity of information on the safety and efficacy of catheter ablation in a large cohort of female AF patients.The purpose of this study was to evaluate catheter ablation for AF in female patients.From January 2005 to May 2008, 3265 females underwent pulmonary vein antrum isolation. Success rates, patient profiles, and complications were collected.Approximately 16% of our population was female (P.001). Females were older (59 +/- 13 vs. 56 +/- 19 years; P.01) and had a lower prevalence of paroxysmal atrial fibrillation (PAF; 46% vs. 55%; P.001). Females failed more antiarrhythmics (4 +/- 1 vs. 2 +/- 3; P = .04) and were referred later for catheter ablation (6.51 +/- 7 vs. 4.85 +/- 6.5 years; P = .02) than males. More females failed ablation (31.5% vs. 22.5%; P = .001) and had nonantral sites of firing than males (P.001). Female patients had 11 (2.1%) hematomas versus 27 (0.9%) in males.Five times as many males underwent catheter ablation than females. Females failed more ablations possibly because of a higher prevalence of nonantral firing, non-PAF, and longer history of AF. Females had more bleeding complications than males.

Background— Left atrioesophageal fistula is a rare but devastating complication that may occur after catheter ablation of atrial fibrillation. We used capsule endoscopy to assess esophageal injury after catheter ablation for atrial fibrillation in a population randomized to undergo general anesthesia or conscious sedation. Methods and Results— Fifty patients undergoing atrial fibrillation ablation for paroxysmal symptomatic atrial fibrillation refractory to antiarrhythmic drugs were enrolled and randomized, including those undergoing the procedure under general anesthesia (25 patients, group 1) and those receiving conscious sedation with fentanyl or midazolam (25 patients, group 2). All patients underwent esophageal temperature monitoring during the procedure. The day after ablation, all patients had capsule endoscopy to assess the presence of endoluminal tissue damage of the esophagus. We observed esophageal tissue damage in 12 (48%) patients of group 1 and 1 esophageal tissue damage in a single patient (4%) of group 2 ( P P < 0.003). The time to peak temperature was 9�7 seconds in group 1 and 21�9 seconds in group 2, and this difference was statistically significant ( P Conclusion— The use of general anesthesia increases the risk of esophageal damage detected by capsule endoscopy.

Popping, char and perforation are complications that can occur following catheter ablation. We measured the amount of grams (g) applied to the endocardium during ablation using a sensor incorporated in the long sheath of a robotic system. We evaluated the relationship between lesion formation, pressure, and the development of complications.Using a robotic navigation system, lesions were placed in the left atrium (LA) at six settings, using a constant duration (40 seconds) and flow rate of either 17 cc/min or 30 cc/min with an open irrigated catheter (OIC). Evidence of complications was noted and lesion location recorded for later analysis at necropsy.Lesions using 30 Watts (W) were more likely to be transmural at higher (40 g) than lower (30 g) pressures (75% vs 25%, P0.001). Significantly higher number of lesions using40 g of pressure demonstrated "popping" and crater formation as compared with lesions with 20-30 g of pressure (41% vs 15%, P = 0.008). A majority of lesions placed using higher power (45 W) with higher pressures (40 g) were associated with char and crater formation (66.7%). No lesions using 10 g of pressure were transmural, regardless of the power. Lesions placed with a power setting less than 35 W were more likely to result in "relative" sparing of the endocardial surface than lesions at a power setting higher than 35 W (62% vs 33.3%, P = 0.02) regardless of the pressure.When using an OIC, lower power settings (or=35 W) and lower/medium contact pressure were more likely to show a "relative" spared endocardial surface. Overall, contact pressure between 20 g and 30 g and a power setting of 40 W appeared to achieve transmurality by preserving safety.

Joseph P. Drozda, Jr, MD, FACC, Chair Vincent J. Bufalino, MD, FACC Joseph G. Cacchione, MD, FACC Christopher P. Cannon, MD, FACC W. Don Creighton, MD Pamela S. Douglas, MD, MACC T. Bruce Ferguson, Jr, MD, FACC Raymond J. Gibbons, MD, FACC Harlan M. Krumholz, MD, FACC Frederick A. Masoudi

Introduction: Around 30% of patients do not respond to cardiac resynchronization therapy (CRT). Nonischemic cardiomyopathy has been identified as an independent predictor of response to CRT, probably due to the absence of compact scar. Methods and results: The relationship between cardiac scar, ischemia, and hibernation (both at the left-ventricular pacing site and as a total burden) and response to CRT was studied in patients with ischemic cardiomyopathy using the perfusion-viability positron emission tomography (PET) test. Sixty-six patients with ischemic cardiomyopathy and traditional criteria for CRT were included. All patients underwent PET scan prior to CRT. Using PET, the amount and location of scarred, ischemic, and hibernating myocardium were characterized. No revascularization was indicated. Responders were defined by an improvement of left-ventricular ejection fraction (LVEF) ≥ 5% and/or New York Heart Association (NYHA) class ≥ 1 degree. During a mean follow-up of 26.2 ± 22.2 months, there was a significant improvement in NYHA class and reverse remodeling in patients with the LV lead inserted remotely from the scar. However, reverse remodeling of a similar degree was present also in patients with extensive scarring including the lateral wall. The presence of ischemia, hibernation, or nontransmural scar at the pacing-site did not significantly modify the outcome of CRT as compared with viable myocardium. There were only 38% of CRT-nonresponders. Neither the extent of scar, ischemia, hibernation, or viability predicted outcome or mortality. Twenty patients died during the follow-up, one patient underwent heart transplant. Conclusions: At follow-up, response to CRT is observed regardless of the presence of extensive scarring. Left ventricular (LV) pacing at sites with ischemia, hibernation, or nontransmural scar does not appear to modify the effect of CRT as compared to viable tissue.

Aims: Catheter ablation is an effective treatment for atrial fibrillation (AF). The outcome of AF ablation in septuagenarians is not clear. Our aim was to evaluate success rate, outcome, and complication rate of AF ablation in septuagenarians. Methods and Results: We collected data from 174 consecutive patients over 75 years of age who underwent AF ablation from 2001 to 2006. AF was paroxysmal in 55%. High-risk CHADS score (≥2) was present in 65% of the population. Over a mean follow-up of 20 ± 14 months, 127 (73%) maintained sinus rhythm (SR) with a single procedure, whereas 47 patients had recurrence of AF. Twenty of them had a second ablation, successful in 16 (80%). Major acute complications included one CVA and one hemothorax (2/194 [1.0%]). During the follow-up, three patients had a CVA within the first 6 weeks after ablation. Warfarin was discontinued in 138 out 143 patients (96%) who maintained SR without AADs with no embolic event occurring over a mean follow-up of 16 ± 12 months. Conclusion: AF ablation is a safe and effective treatment for AF in septuagenarians.

Marital conflict is related to well-being in children and adults (E. M. Cummings & P. T. Davies, 2002). Marital conflict is likely most effectively ameliorated before it becomes clinically significant. However, families without significant problems may be unwilling to participate in couples therapies or other lengthy or intensive interventions. Responding to this gap, the authors developed a 4-session psychoeducational program about marital conflict for community families. Couples with children 4-8 years of age were randomly blocked into 1 of 3 groups: (1) a parent-only group (n = 24), (2) a parent-child group (n = 33), or (3) a self-study group (n = 33). Pre- and posttest and 6-month and 1-year assessments were conducted. This report evaluates (a) whether participation in a psychoeducational program for parents improved marital conflict, especially concerning ways of expressing disagreements, and (b) whether changes in marital conflict subsequently improved marital satisfaction, parenting, and child adjustment. Greater constructive and less destructive marital conflict was observed at all assessments for treatment groups, and these changes were linked with improvements in other family processes. The findings support the promise of brief, psychoeducational programs for improving marital conflict for community samples.

PV isolation at the antrum (PVAI) has improved safety and efficacy of ablation procedures for atrial fibrillation (AF). AF triggers from the superior vena cava (SVC) may compromise the outcome of PVAI. Purpose: We evaluated the (1) incidence of SVC triggers, (2) feasibility of empiric SVC electrical isolation (SVCI) as an adjunct to PVAI, and (3) SVCI safety. Methods and Results: Of 190 patients (group I), 24 (12%) showed SVC triggers. Following PVAI, seven patients had AT originating from the SVC and three had AF. After SVCI, all 24 patients were arrhythmia-free 450 ± 180 days post procedure. In the subsequent 217 patients (group II), empirical SVCI was performed following PVAI. Sixty-six of all 407 patients (16%) experienced recurrence of AF. A repeat procedure in 25 of the 66 patients showed that five (20%) had AF recurrence initiated by SVC triggers, of whom four were among group I patients (4/190; 2%) and one was from group II (1/217; 0.4%), (P < 0.05). Transient diaphragmatic paralysis can be avoided by pacing at the lateral aspect of the SVC using high output (30 mA). There was no SVC stenosis on CT scans before or 3 months after the procedure. There was no sinus node injury. Conclusions: The SVC harbors the majority of non-PV triggers of AF. SVCI is feasible, safe, and may be considered as an adjunctive strategy to PVAI for ablation of AF. The long-term favorable outcome of this hybrid approach remains to be evaluated in a larger series of patients.

Objectives We aimed at assessing the feasibility and efficacy of remote magnetic navigation (MN) and ablation in patients with atrial fibrillation (AF). Background This novel MN system could facilitate standardization of the procedures, reducing the importance of the operator skill. Methods After becoming familiar with the system in 48 previous patients, 45 consecutive patients with AF were considered for ablation using the Niobe II remote magnetic system (Stereotaxis, St. Louis, Missouri) in a stepwise approach: circumferential pulmonary vein ablation (CPVA), pulmonary vein antrum isolation (PVAI), and, if failed, PVAI using the conventional approach. Remote navigation was done using the coordinate or the wand approach. Ablation end point was electrical disconnection of the pulmonary veins (PVs). Results Using the coordinate approach, the target location was reached in only 60% of the sites, whereas by using the wand approach 100% of the sites could be reached. After step 2 ablation, only 1 PV in 4 patients (8%) could be electrically isolated. Charring on the ablation catheter tip was seen in 15 (33%) of the cases. In 23 patients, all PVs were isolated with the conventional thermocool catheter, and in 22 patients only the right PVs were isolated with the conventional catheter. After a mean follow-up period of 11 ± 2 months, recurrence was seen in 5 patients (22%) with complete PVAI and in 20 patients (90%) with incomplete PVAI. Conclusions Remote navigation using a magnetic system is a feasible technique. With the present catheter technology, effective lesions cannot be achieved in most cases. This appears to impact the cure rate of AF patients.

Objectives We sought to test how catheter ablation using an open irrigation catheter (OIC) compares with standard catheters for pulmonary vein antrum isolation. Background Open irrigation catheters have the advantage of delivering greater power without increasing the temperature of the catheter tip, which enables deeper and wider lesions without the formation of coagulum on catheters. Methods Catheter ablation was performed using an 8-mm catheter (8MC) or an OIC. Patients were randomized to 3 groups: 8MC; OIC-1, OIC with a higher peak power (50 W); and OIC-2, OIC with lower peak power (35 W). Results A total of 180 patients were randomized to the 3 treatment strategies. Isolation of pulmonary vein antra was achieved in all patients. The freedom from atrial fibrillation was significantly greater in the 8MC and OIC-1 groups compared with the OIC-2 group (78%, 82%, and 68%, respectively, p = 0.043). Fluoroscopy time was lower in OIC-1 compared with OIC-2 and 8MC (28 ± 1 min, 53 ± 2 min, and 46 ± 2 min, respectively, p = 0.001). The mean left atrium instrumentation time was lower in the OIC-1 compared with the OIC-2 and 8MC groups (59 ± 3 min, 90 ± 5 min, and 88 ± 4 min, respectively, p = 0.001). However, there was a greater incidence of “pops” in the OIC-1 (100%, 0%, 0%, p Conclusions Although there was a decrease in fluoroscopy and left atrium instrumentation time with the use of OIC at higher power, this setting was associated with increased cardiovascular and gastrointestinal complications.

Pulmonary Vein Total Occlusion Following Catheter Ablation for Atrial Fibrillation: Clinical Implications After Long-Term Follow-UpLuigi Di Biase, Tamer S. Fahmy, Oussama M. Wazni, Rong Bai, Dimpi ...

Robotic Catheter Manipulation. Objectives: The aims of this study were to demonstrate the safety and the feasibility of the robotic catheter remote control system (CCS) in endocardial navigation in all cardiac chambers, as well as facilitation of the transseptal puncture. Background: CCS has been developed to facilitate control and precise positioning of catheters within the cardiovascular system. Methods: CCS consists of a remote catheter manipulator, a set up joint, a physician workstation, and a steerable guide catheter (SGC) and sheath. A conventional 4-mm tip catheter was inserted through the SGC to perform mapping of five predefined targets in each cardiac chamber. Seven mongrel dogs were used in this study. Intracardiac echocardiography and three-dimensional (3-D) electroanatomical mapping were integrated with CCS to facilitate catheter manipulation and to guide transseptal puncture. The time to complete the transseptal puncture and the time to complete access to the predefined targets in each cardiac chamber were measured. Gross and microscopic examinations of the accessed and ablation sites were performed to evaluate safety. Results: Transseptal puncture was performed successfully in all animals with a mean time of 7 ± 3 minutes. Procedure times to access the five targets in the right atrium, right ventricle, left atrium, and left ventricle were 5.6 ± 1.7, 4.6 ± 1.5, 13.5 ± 11.0, 7.0 ± 2.9 minutes, respectively. There were no intracardiac damages associated with catheter manipulation noted in the excised hearts. Conclusions: Endocardial catheter navigation and mapping using the robotic catheter remote control is safe and feasible. Moreover, the CCS could be used to perform transseptal puncture and left atrial instrumentation.

Atrial Fibrillation in Heart Transplant Patients. Background: The incidence of atrial fibrillation (AF) in heart transplant patients has not been well documented. Methods: To determine the incidence of AF in a cohort of patients undergoing cardiac transplantation, clinical data were obtained from a prospectively collected database for all consecutive orthotopic heart transplantation (OHT) patients and for all consecutive coronary artery bypass graft (CABG) surgery patients between January 1984 and March 2004 at our institution. A cohort of 1,714 OHT patients and low-risk CABG (normal ejection fraction [EF] and no left ventricular hypertrophy [LVH]) patients were age- and sex-matched. Results: The average age in the two groups was 56 ± 7 years with 87% male and 81% white race and body mass index (BMI) of 26 ± 4. There were 3 cases of AF (0.3%) in the OHT group and 757 cases of AF (21%) in the low-risk CABG group. The strongest independent predictor of freedom from postoperative AF was having had a transplant (odds ratio [OR] 96, 95% confidence interval [CI] 13-720). The incidence of AF, atrial flutter (AFL), and supraventricular tachycardia (SVT) in OHT was 0.33,2.8%, and 1.3%, respectively. Given that incidence of AF, AFL, and SVT in historical post-CABG population is 25%, 17%, and 4.3%, transplanted patients appear to have lower incidence of AF, AFL, and SVT than the reference population. Consistent with this, transplanted patients underwent few ablation procedures for atrial arrhythmias. Additionally, the three patients with AF had bicaval anastomoses suggesting the possibility of PACs originating in the donor superior vena cava (SVC) or IVC (inferior vena cava) initiating AF in these patients. Conclusions: In a cohort study of transplant and low-risk CABG patients, the strongest independent predictor of freedom from AF is having undergone transplant surgery. One potential explanation for the markedly lower incidence of AF may be effective isolation of thoracic veins with documented cases retaining the native SVC.

Recent studies have demonstrated that premature ventricular contractions (PVCs) originating from the Purkinje system are responsible for initiation of ventricular fibrillation (VF) in patients with and without structural heart disease. Ablation of the PVCs has been shown to be feasible. We report 2 patients with repetitive VF associated with cardiac amyloidosis. Each episode of ventricular arrhythmia was preceded by monomorphic PVC. The electrical storms were drug resistant. Electrophysiological testing was performed and the sites of earliest activation were localized within the left ventricle in the absence of significant scar tissue. After ablation, PVCs subsided and there were no further VF recurrences.

Objective: To assess prospectively whether preimplantation B-type natriuretic peptide (BNP) and C reactive protein (CRP) concentrations predict future appropriate therapies from an implantable cardioverter-defibrillator (ICD). Design and setting: Prospective cohort study conducted in a tertiary cardiac care centre. Methods: 345 consecutive patients undergoing first time ICD implantation were prospectively studied. Serum BNP and CRP concentrations were obtained the day before ICD implantation. Patients were followed up with device interrogation to assess for appropriate shocks or antitachycardia pacing. Inappropriate therapies were excluded. Mean (SD) follow up was 13 (5) months. Results: Patients had ischaemic (71%), primary dilated (17%), and valvar or other cardiomyopathies (12%). About half (52%) had ICDs implanted for primary prevention. Sixty three (18%) received appropriate ICD therapies. Serum creatinine, β blocker, statin, and angiotensin converting enzyme inhibitor usage did not differ between therapy and no therapy groups. By univariate comparison, ejection fraction (p = 0.048), not taking amiodarone (p = 0.033), and BNP concentration (p = 0.0003) were risk factors for ICD therapy. However, by Cox regression multivariate analysis, only BNP above the 50th centile was a significant predictor (hazard ratio 2.19, 95% confidence interval 1.07 to 4.71, p = 0.040). Median BNP was 573 ng/l versus 243 ng/l in therapy and no therapy patients, respectively (p = 0.0003). More patients with BNP above the 50th centile (27% v 10%, p = 0.006) received ICD therapies. Conclusions: A single preimplantation BNP concentration determination is independently predictive of ICD therapies in patients with cardiomyopathies undergoing first time ICD implantation. CRP was not independently predictive of ICD therapies when compared with BNP.

Advancing the process-oriented study of links between interparental discord and child adjustment, 2 multimethod prospective tests of emotional security as an explanatory mechanism are reported. On the basis of community samples, with waves spaced 2 years apart, Study 1 (113 boys and 113 girls, ages 9-18) identified emotional security as a mediator in a 2-wave test, whereas Study 2 (105 boys and 127 girls, ages 5-7) indicated emotional security as an intervening mechanism in a 3-wave test. Relations between discord and emotional security increased as children moved into adolescence in Study 1. Emotional security was identified as an explanatory mechanism for both internalizing and externalizing problems in children.

Catheter ablation has significantly transformed the clinical management of atrial fibrillation (AF). The safety and efficacy of this procedure are not well understood in patients with pacemakers and defibrillators.The purpose of this study was to study the impact of radiofrequency catheter ablation of AF in patients with pacemakers and implantable cardiac defibrillators.We studied 86 patients with pacemakers and defibrillators (group I) and a similar number of age- and gender-matched controls (group II) who underwent AF ablation between 1999 and 2004. Clinical and procedural variables were compared between the two groups. In group I, various generator and lead parameters were compared before and after the procedure. Resurgence of clinical AF after 2 months was considered recurrence.Both groups were similar with regard to age, gender, body mass index, and type of AF. Group I had a higher incidence of diabetes (17% vs 6%, P = .03), coronary artery disease (25% vs 13%, P = .05), less prolonged AF (31 +/- 21 vs 45 +/- 30 months, P.001), lower left ventricular ejection fraction (49 +/- 13% vs 52 +/- 9%, P = .03), and left ventricular end-diastolic dimensions (4.97 +/- 0.81 vs 4.72 +/- 0.67, P = .03). No changes in the sensing and pacing thresholds, impedance of atrial and ventricular leads, or defibrillator coil impedance after AF ablation were observed in group I. Atrial lead dislodgment was seen in two patients. Transient abnormal but "expected" pulse generator behavior was seen in 25% of patients without permanent malfunction. Stroke (1% vs 1%, P = 1.000), pulmonary vein stenosis (2% vs 1%, P = .77), and AF recurrence rates at 12 months were similar between groups I and II, respectively (19% vs 21%, P = .73).AF ablation is safe and efficacious in patients with pacemakers and defibrillators.

Background— The role of pulmonary vein (PV) isolation in ablative treatment of atrial fibrillation (AF) has been debated in conflicting reports. We sought to compare PV conduction in patients who had no AF recurrence (group I), patients who could maintain sinus rhythm on antiarrhythmic medication (group II), and patients who had recurrent AF despite antiarrhythmic medication (group III) after PV antrum isolation (PVAI). Methods and Results— PV conduction was examined in consecutive patients undergoing second PVAI for AF recurrence. We also recruited some patients cured of AF to undergo a repeat, limited electrophysiological study at >3 months after PVAI. All patients underwent PVAI with an intracardiac echocardiography (ICE)–guided approach with complete isolation of all 4 PV antra (PVA). The number of PVs with recurrent conduction and the shortest atrial to PV (A-PV) conduction delay was measured with the use of consistent Lasso positions defined by ICE. Late AF recurrence was defined as AF >2 months after PVAI with the patient off medications. Patients in groups I (n=26), II (n=37), and III (n=44) did not differ at baseline (38% permanent AF; ejection fraction 53±6%). Recurrence of PV–left atrial (LA) conduction was seen in 1.7±0.8 and 2.2±0.8 PVAs for groups II and III but only in 0.2±0.4 for group I ( P =0.02). In patients with recurrent PV-LA conduction, the A-PV delay increased from the first to second procedure by 69±47% for group III, 267±110% for group II, and 473±71% for group I ( P Conclusions— The majority of patients with drug-free cure show no PV-LA conduction recurrence. Substantial A-PV delay is seen in patients able to maintain sinus rhythm on antiarrhythmic medication or cured of AF compared with patients who fail PVAI.

Background— Multiple morphologies, hemodynamic instability, or noninducibility may limit ventricular tachycardia (VT) ablation in patients with arrhythmogenic right ventricular dysplasia (ARVD). Substrate-based mapping and ablation may overcome these limitations. We report the results and success of substrate-based VT ablation in ARVD. Methods and Results— Twenty-two patients with ARVD were studied. Traditional mapping for VT was limited because of multiple/changing VT morphologies (n=14), nonsustained VT (n=10), or hemodynamic intolerance (n=5). Sinus rhythm CARTO mapping was performed to define areas of “scar” ( Conclusions— Substrate-based ablation of VT in ARVD can achieve a good short-term success rate. However, recurrences become increasingly common during long-term follow-up.

Ventricular Tachycardia and the Scar Border Zone. Introduction: It is unknown if identification of scar border zones by electroanatomical mapping correlates with successful ablation sites determined from mapping during ventricular tachycardia (VT) post-myocardial infarction (MI). We sought to assess the relationship between successful ablation sites of hemodynamically stable post-MI VTs determined by mapping during VT with the scar border zone defined in sinus rhythm. Methods and Results: Forty-six patients presenting with hemodynamically stable, mappable monomorphic VT post-MI and who had at least one such VT successfully ablated were prospectively included in the study. In each patient, VT was ablated by targeting regions during VT that exhibited early activation, ′ isolated mid-diastolic potentials, and concealed entrainment suggesting a critical isthmus site. Prior to ablation, a detailed sinus-rhythm CARTO voltage map of the left ventricle was obtained. A voltage

Objectives The goal of this study was to assess the impact of left atrial scarring (LAS) on the outcome of patients undergoing pulmonary vein antrum isolation (PVAI) for atrial fibrillation (AF). Background Left atrial scarring may be responsible for both the perpetuation and genesis of AF. Methods A total of 700 consecutive patients undergoing first-time PVAI were studied. Before ablation, extensive voltage mapping of the left atrium (LA) was performed using a multipolar Lasso catheter guided by intracardiac echocardiography (ICE). Patients with LAS were defined by a complete absence of electrographic recording by a circular mapping catheter in multiple LA locations, and this was validated by electroanatomic mapping. All four pulmonary vein antra and the superior vena cava were isolated using an ICE-guided technique. Patients were followed at least nine months for late AF recurrence. Univariate and multivariate analyses were performed to assess the predictive value of LAS and other variables on outcome. Results Of 700 patients, 42 had LAS, which represented 21 ± 11% of the LA surface area by electroanatomic mapping. Patients with LAS had a significantly higher AF recurrence (57%) compared with non-LAS patients (19%, p = 0.003). Also, LAS was associated with a significantly larger LA size, lower ejection fraction, and higher C-reactive protein levels. Univariate analysis revealed age, nonparoxysmal AF, and LAS as predictors of recurrence. Multivariate analysis showed LAS as the only independent predictor of recurrence (hazard ratio 3.4, 95% confidence interval 1.3 to 9.4; p = 0.01). Conclusions Pre-existent LAS in patients undergoing PVAI for AF is a powerful, independent predictor of procedural failure. Left atrial scarring is associated with a lower EF, larger LA size, and increased inflammatory markers.

Predictors of VT or VF in Electrical Storm. Introduction: Electrical storm (ES) is characterized by either refractory ventricular tachycardia (VT) or ventricular fibrillation (VF). However, little is known about the prevalence, predictors, and mortality implications of the causative arrhythmia in ES. We sought to assess the prevalence, predictors, and survival significance of VT and VF as the causative arrhythmia of ES in implantable cardioverter defibrillator (ICD) patients. Methods and Results: Consecutive patients from January 2000 to December 2002 who presented to the ICD clinic with >2 separate ventricular arrhythmic episodes requiring shock within 24 hours were included in the study. ICD interrogation confirmed the number of shocks and provided electrograms for interpretation of the causative arrhythmia. Patients were grouped as VF or VT according to the causative arrhythmia. Their prevalence, predictors, and mortality rates were compared. Of 2,028 patients assessed in the ICD clinic, 208 (10%) presented with ES. VF was the cause of ES in 99 of 208 patients, for an overall prevalence of 48%. Original ICD indication, coronary artery disease, and amiodarone therapy were predictive for the causative arrhythmia. There was no mortality difference between the VT and VF groups; however, both groups had significantly increased mortality compared to a control ICD population without ES. Conclusion: VF is the causative arrhythmia for a sizable proportion of patients with ES. The initial ICD indication, coronary artery disease, and amiodarone therapy are predictors of the causative arrhythmias in ES. There does not appear to be any mortality difference between ES patients with VT and VF, but mortality is increased in patients with ES versus control ICD patients without ES.

Objectives We report on the initiation of ventricular fibrillation (VF) storm in patients with ischemic cardiomyopathy (ICM) and the results of targeted ablation to treat VF storm. Background Monomorphic premature ventricular contractions (PVCs) have been shown to initiate VF in patients without structural heart disease. Methods A total of 29 patients with ICM and documented VF initiation were identified. In 21 patients, VF storm was controlled with antiarrhythmic drugs and/or treatment of heart failure. Eight patients with VF (mean 52 ± 25 episodes) refractory to medical management required ablation. All patients underwent three-dimensional electroanatomical mapping using CARTO (Biosense-Webster Inc., Diamond Bar, California), and PVCs were mapped when present. Scarred areas were identified using voltage mapping. Results Monomorphic PVCs initiated VF in all 29 identified patients. Five of eight patients requiring ablation had frequent PVCs that allowed PVC mapping. The earliest activation site was consistently located in the scar border zone. The PVCs were always preceded by a Purkinje-like potential (PLP). Ablation was successfully performed at these sites. In three patients, infrequent PVCs prevented mapping, but PLPs were recorded around the scar border. Ablation targeting these potentials along the scar border was successfully performed. During follow-up (10 ± 6 months), one patient had a single VF episode and another developed sustained, monomorphic ventricular tachycardia. There was no recurrence of VF storm. Conclusions Ventricular fibrillation in ICM is triggered by monomorphic PVCs originating from the scar border zone with preceding PLPs; targeting these PVCs may prevent VF recurrence. In the absence of PVCs, both substrate mapping and ablation appear to be equally effective.

ObjectivesThe goal of this study was to determine if parasympathetic nerves in the anterior fat pad (FP) can be stimulated at the time of coronary artery bypass surgery (CABG), and if dissection of this FP decreases the incidence of postoperative atrial fibrillation (AF).BackgroundThe human anterior epicardial FP contains parasympathetic ganglia and is often dissected during CABG. Changes in parasympathetic tone influence the incidence of AF.MethodsFifty-five patients undergoing CABG were randomized to anterior FP preservation (group A) or dissection (group B). Nerve stimulation was applied to the FP before and after surgery. Sinus cycle length (CL) was measured during stimulation. The incidence of postoperative AF was recorded.ResultsOf the 55 patients enrolled, 26 patients were randomized to group A, and 29 patients were randomized to group B. In all of the 55 patients, the FP was identified before initiating cardiopulmonary bypass by CL prolongation with stimulation (865.5 ± 147.9 ms vs. 957.9 ± 155.1 ms, baseline vs. stimulation, p < 0.001). In group A, stimulation at the conclusion of surgery increased sinus CL (801.8 ± 166.4 ms vs. 890.9 ± 178.2 ms, baseline vs. stimulation, p < 0.001). In group B, repeat stimulation failed to increase sinus CL (853.6 ± 201.6 ms vs. 841.4 ± 198.4 ms, baseline vs. stimulation, p = NS). The incidence of postoperative AF in group A (7%) was significantly less than that in group B (37%) (p < 0.01).ConclusionsThis is the first study demonstrating that direct stimulation of the human anterior epicardial FP slows sinus CL. This parasympathetic effect is eliminated with FP dissection. Preservation of the human anterior epicardial FP during CABG decreases incidence of postoperative AF.

Objective To compare the mood and somatic effects during the initial 2 months of medroxyprogesterone acetate (MPA) or progesterone combined with conjugated equine estrogen (CEE) in early postmenopausal women. Design Twenty-three nondepressed, early postmenopausal women (average age, 52.5 years) completed a 91-day, single-blind pilot study with the following sequence of treatments: 1 week of no substance; 2 weeks of placebo; 2 weeks of progestogen only; 1 week of placebo; and 2 months of "standard hormone replacement therapy cycles," which consisted of (in order) 2 weeks of 0.625 mg CEE, 2 weeks of CEE plus progestogen, 2 weeks of CEE, and 2 weeks of CEE plus progestogen. Ten women who completed the study received MPA (5 mg/day) as their progestogen, and 13 who completed the study received micronized, oil-suspended progesterone (200 mg/day) as their progestogen. All participants made daily assessments of mood using the Profile of Mood States and daily recordings of somatic symptoms. All subjects had plasma follicle-stimulating hormone of greater than 35 IU/L and had not had spontaneous vaginal bleeding for more than 1 year. Results None of the hormone treatments had a detectable effect on mood. MPA users reported more vaginal bleeding and breast tenderness than progesterone users. Conclusions In contrast with the widely held belief among psychiatrists that progesterone depresses mood, neither of the progestogens we used in normal, nondepressed and nonanxious women showed this effect. Absence of an effect on mood was also found when the results of the two progestogens were combined. The lesser side effects of the micronized progesterone-containing regimen suggest that some women may prefer it to an MPA-containing regimen.

The gonadal hormone estradiol modulates mesolimbic dopamine systems in the female rat. This modulatory effect is thought to be responsible for the observed effects of estradiol on motivated behaviors. Dopamine acting in the nucleus accumbens is thought to be important for the attribution of incentive motivational properties to cues that predict reward delivery, while dopamine in the striatum is associated with the expression of repetitive or stereotyped behaviors. Elevated concentrations of estradiol are associated with increased motivation for sex or cues associated with access to a mate, while simultaneously attenuating motivation for food. This shift in motivational salience is important for adaptive choice behavior in the natural environment. Additionally, estradiol's adaptive effects on motivation can be maladaptive when increasing motivation for non-natural reinforcers, such as drugs of abuse. Here we discuss the effect of estradiol on mesotelencephalic dopamine transmission and subsequent effects on motivated behaviors.

The bacterial C-P lyase pathway is responsible for the metabolism of unactivated organophosphonates under conditions of phosphate starvation. The cleavage of the C-P bond within ribose-1-methylphosphonate-5-phosphate to form methane and 5-phospho-ribose-1,2-cyclic phosphate (PRcP) is catalyzed by the radical SAM enzyme PhnJ. In Escherichia coli the cyclic phosphate product is hydrolyzed to ribose-1,5-bisphosphate by PhnP. In this study, we describe the discovery and characterization of an enzyme that can hydrolyze a cyclic phosphodiester directly to a vicinal diol and inorganic phosphate. With PRcP, this enzyme hydrolyzes the phosphate ester at carbon-1 of the ribose moiety to form ribose-2,5-bisphosphate, and then this intermediate is hydrolyzed to ribose-5-phosphate and inorganic phosphate. Ribose-1,5-bisphosphate is neither an intermediate nor a substrate for this enzyme. Orthologues of this enzyme are found in the human pathogens Clostridium difficile and Eggerthella lenta. We propose that this enzyme be called cyclic phosphate dihydrolase (cPDH) and be designated as PhnPP.

During the past decade, catheter ablation of atrial fibrillation (AF) has evolved rapidly from an investigational procedure to its current status as a commonly performed ablation procedure in many major hospitals throughout the world. Surgical ablation of AF, using either standard or minimally invasive techniques, is also performed in many major hospitals throughout the world. In 2007, an initial Consensus Statement on Catheter and Surgical AF Ablation was developed as a joint effort of the Heart Rhythm Society, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society.1 The 2007 document was also developed in collaboration with the Society of Thoracic Surgeons and the American College of Cardiology. Since the publication of the 2007 document, there has been much learned about AF ablation, and the indications for these procedures have changed. Therefore the purpose of this 2012 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a Task Force, convened by the Heart Rhythm Society, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society and charged with defining the indications, techniques, and outcomes of this procedure. Included within this document are recommendations pertinent to the design of clinical trials in the field of AF ablation, including definitions relevant to this topic. This statement summarizes the opinion of the Task Force members based on an extensive literature review as well as their own experience. It is directed to all health care professionals who are involved in the care of patients with AF, particularly those who are undergoing, or are being considered for, catheter or surgical ablation procedures for AF. This statement is not intended to recommend or promote catheter ablation of AF. Rather the ultimate judgment regarding care of a particular patient …

While a good deal of information has been garnered in the last few decades regarding the neural and hormonal control of female sexual behavior, literature elucidating these mechanisms with respect to female sexual motivation has been scarce. We believe that one reason for this is the lack of a standardized paradigm that will quantify female sexual motivation while allowing for sexual interaction to occur. Here we describe a two-chambered apparatus that utilizes operant responding (nose poking) to quantify female sexual motivation. During the test, the female exhibits nose pokes to gain access to a sexually active male, with whom she is allowed to mate. Therefore, this apparatus allows for examination of sexual behavior as well as quantification of sexual motivation by assessing the number of nose pokes the female will exhibit within a fixed interval to gain access to the male. We report that hormone priming significantly increases sexual motivation in the female as indicated by the number of nose pokes she will exhibit to gain access to the male. Additionally, hormone primed females enter the male compartment after a shorter period and spend more time in direct contact with the male compared to when they are not hormone primed. In contrast, when females are not hormone primed they spend more time in view, but out of reach, of the male. This paradigm will help to advance the study of female sexual motivation, providing a method for quantifiable assessment of female sexual motivation while allowing for sexual activity to occur.

Background Gender and enhanced novelty reactivity can predispose certain individuals to drug abuse. Previous research in male and female rats selectively bred for high or low locomotor reactivity to novelty found that bred High Responders (bHRs) acquire cocaine self-administration more rapidly than bred Low Responders (bLRs) and that bHR females in particular self-administered more cocaine than the other groups. The experiments presented here aimed to determine whether an individual's sex and behavioral phenotype interact to affect motivation to take cocaine. Methods We examined motivation for taking cocaine in two experiments using a range of doses on a progressive ratio (PR) schedule of responding in bHR or bLR males and females. Additionally, we included a measure of continuing to respond in the absence of reinforcement, a feature of addiction that has been recently incorporated into tests of animal models on the basis of the criteria for substance use disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Statistical analyses were performed using PASW Statistics 18.0 software. Data were analyzed using repeated-measures analysis of variance followed by a Bonferroni correction post hoc test when applicable. Results We found sex differences as well as effects of novelty reactivity on the motivation to self-administer cocaine. Specifically, females demonstrated higher breaking points on the PR schedule compared with males, regardless of phenotype, and bHR males and females exhibited higher motivation than bLR animals at a number of the doses studied. Conclusions An individual's sex continues to be a predisposing factor with respect to drug abuse liability and can be compounded by additional individual differences such as reactivity to novelty.

Otopteropus cartilagonodus (Megachiroptera, Pteropodidae) is a rare, small-bodied cynopterine bat endemic to Luzon Island in the Philippine Archipelago. Twenty-two female and seven male O. cartilagonodus were collected during March and May of 1988. Observations were made on early embryonic development and the morphology of ovaries, uteri, and testes. All females collected during March were pregnant, and their uterine swellings occurred within a narrow size range (2–4 mm in diameter). Moreover, the embryos of all eight females captured in March and examined histologically were all within or just before the primitive-streak stage of development. The uterine swellings of females captured in May ranged from 15 to 20 mm in diameter, and their extrapolated birth dates were in late May or June. The synchrony of embryologie development and the apparent lack of developmental progress during March suggests that O. cartilagonodus has a prolonged period at the primitive-streak stage of embryonic development. The morphology of the embryo, embryonic membranes, and uterus at these stages is similar to that of two other cynopterine fruit bats, Cynopterus sphinx and Haplonycteris fischeri .

Human renal dipeptidase, an enzyme associated with glutathione metabolism and the hydrolysis of beta-lactams, is similar in sequence to a cluster of approximately 400 microbial proteins currently annotated as nonspecific dipeptidases within the amidohydrolase superfamily. The closest homologue to the human renal dipeptidase from a fully sequenced microbe is Sco3058 from Streptomyces coelicolor. Dipeptide substrates of Sco3058 were identified by screening a comprehensive series of l-Xaa-l-Xaa, l-Xaa-d-Xaa, and d-Xaa-l-Xaa dipeptide libraries. The substrate specificity profile shows that Sco3058 hydrolyzes a broad range of dipeptides with a marked preference for an l-amino acid at the N-terminus and a d-amino acid at the C-terminus. The best substrate identified was l-Arg-d-Asp (k(cat)/K(m) = 7.6 x 10(5) M(-1) s(-1)). The three-dimensional structure of Sco3058 was determined in the absence and presence of the inhibitors citrate and a phosphinate mimic of l-Ala-d-Asp. The enzyme folds as a (beta/alpha)(8) barrel, and two zinc ions are bound in the active site. Site-directed mutagenesis was used to probe the importance of specific residues that have direct interactions with the substrate analogues in the active site (Asp-22, His-150, Arg-223, and Asp-320). The solvent viscosity and kinetic effects of D(2)O indicate that substrate binding is relatively sticky and that proton transfers do not occurr during the rate-limiting step. A bell-shaped pH-rate profile for k(cat) and k(cat)/K(m) indicated that one group needs to be deprotonated and a second group must be protonated for optimal turnover. Computational docking of high-energy intermediate forms of l/d-Ala-l/d-Ala to the three-dimensional structure of Sco3058 identified the structural determinants for the stereochemical preferences for substrate binding and turnover.