Amygdala-specific changes in Cacna1c, Nfat5, and Bdnf expression are associated with stress responsivity in mice: A possible mechanism for psychiatric disorders.

The CACNA1C gene encodes the alpha-1c subunit of the Cav1.2 calcium channel, a regulator of neuronal calcium influx involved in neurotransmitter release and synaptic plasticity. Genetic data show a role for CACNA1C in depressive symptoms underlying different psychiatric diagnoses. However, the mechanisms involved still require further exploration. This study aimed to investigate sex and region-specific changes in the Cacna1c gene and behavioral outcomes in mice exposed to chronic stress. Moreover, we evaluated the Nuclear factor of activated T-cells 5 (Nfat5) and the Brain-derived neurotrophic factor (Bdnf) as potential upstream and downstream Cacna1c targets and their correlation in stressed mice and humans with depression. Male and female Swiss mice were exposed to chronic unpredictable stress (CUS) for 21 days. Animal-integrated emotionality was assessed using the sucrose splash test, the tail suspension, the open-field test, and the elevated-plus-maze. Gene expression analysis was performed in the amygdala, prefrontal cortex, and hippocampus. Human data for in silico analysis was obtained from the Gene Expression Omnibus. CUS-induced impairment in integrated emotional regulation was observed in males. Gene expression analysis showed decreased levels of Cacna1c and Nfat5 and increased levels of Bdnf transcripts in the amygdala of stressed male mice. In contrast, there were no major changes in behavioral responses or gene expression in female mice after stress. The expression of the three genes was significantly correlated in the amygdala of mice and humans. The strong and positive correlation between Canac1c and Nfat5 suggests a potential role for this transcription factor in Canac1c expression. These changes could impact amygdala reactivity and emotional responses, making them a potential target for psychiatric intervention.

A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder.

Objective: Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors' previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD. Methods: Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures. Results: The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events. Conclusions: This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine's full potential as a treatment for chronic PTSD.Reprinted from Am J Psychiatry 2021; 178:193-202, with permission from American Psychiatric Association Publishing. Copyright © 2021.

Behavioral flexibility impacts on coping and emotional responses in male mice submitted to social defeat stress.

Behavioral flexibility permits the appropriate behavioral adjustments in response to changing environmental demands. The present study aimed to evaluate if variability in baseline flexibility can enable differences in coping strategies, changes in neuroplasticity, and behavioral outcomes in responses to chronic social defeat stress (CSDS). Male C57BL6 mice were submitted to the Morris Water Maze (MWM) using an extended protocol for reversal learning to assess. The animals were divided into low and high behavioral flexibility groups based on their performance on the last day of acquisition versus the four days of reversal learning. The CSDS was applied for ten consecutive days, and coping strategies were evaluated during the physical interaction on the first and last day of stress. A battery of behavioral tests to assess social and emotional behavior was conducted 24 h after the CSDS protocol. The complexity of prefrontal cortex (PFC) neuronal morphology was evaluated by the Golgi-Cox method. Animals with High Flexibility exhibited changes in their CSDS coping strategies, from active to passive coping, during the CSDS protocol. Low Flexibility mice had no alterations in the coping strategies during CSDS. After social stress, High Flexibility was associated with reduced social interaction with an aggressive Swiss mouse, higher latency to immobility in the tail suspension test, and reduced latency to self-care in the sucrose splash test. High Flexibility mice also displayed higher dendritic complexity on pyramidal neurons from the prelimbic and infralimbic prefrontal cortex compared to Low Flexibility mice. These results suggest That High Flexibility is associated with increased neuroplasticity in cortical areas and better emotional responses related to behavioral despair and motivation. However, exposure to CSDS reversed the beneficial effects of High Flexibility in male mice. Thus, this study suggests that baseline variability in behavioral flexibility, even in inbred strains, might be associated with differences in coping strategies, PFC morphology, and behavioral responses to social stress.

The Impact of Pre-Exercise Carbohydrate Meal on the Effects of Yerba Mate Drink on Metabolism, Performance, and Antioxidant Status in Trained Male Cyclists.

INTRODUCTION: The consumption of yerba mate (YM), a source of antioxidants, in a fasted state increases fatty acid oxidation (FATox) during low-moderate-intensity exercise and improves performance in high-intensity exercise. However, the impact of a pre-exercise carbohydrate (CHO) meal on YM effects during exercise is unknown. OBJECTIVE: We investigated the effects of yerba mate drink (YMD) consumed in the fasted state (YMD-F) or after a CHO meal (YMD-CHO) on measurements of metabolism, performance, and blood oxidative stress markers in cycling exercise. METHODS: In a randomized, repeated-measures, crossover design, eight trained male cyclists ingested (i) YMD-CHO, (ii) YMD-F, or (iii) control-water and CHO meal (Control-CHO). The YMD (an infusion of 5 g of ultrarefined leaves in 250 mL of water) was taken for 7 days and 40 min before exercise. CHO meal (1 g/kg body mass) was consumed 60 min before exercise. The cycling protocol included a 40-min low-intensity (~ 53% V̇O2peak) constant load test (CLT); a 20-min time trial (TT); and 4 × 10-s all-out sprints. Blood samples and respiratory gases were collected before, during, and/or after tests. RESULTS: During CLT, YMD-CHO increased FATox ~ 13% vs. YMD-F (P = 0.041) and ~ 27% vs. Control-CHO (P < 0.001). During TT, YMD-CHO increased FATox ~ 160% vs. YMD-F (P < 0.001) and ~ 150% vs. Control-CHO (P < 0.001). Power output during TT improved ~ 3% (P = 0.022) in YMD-CHO vs. Control-CHO and was strongly correlated with changes in serum total antioxidant capacity (r = -0.87) and oxidative stress index (r = 0.76) at post-exercise in YMD-CHO. Performance in sprints was not affected by YMD. CONCLUSION: CHO intake did not negate the effect of YMD on FATox or TT performance. Instead, a synergism between the two dietary strategies may be present. Clinical Trial Registration NCT04642144. November 18, 2020. Retrospectively registered.

Whole blood transcriptional signatures associated with rapid antidepressant response to ketamine in patients with treatment resistant depression.

Ketamine has rapid and sustained antidepressant effects in patients with treatment-resistant depression (TRD). However, the underlying mechanisms of action are not well understood. There is increasing evidence that TRD is associated with a pro-inflammatory state and that ketamine may inhibit inflammatory processes. We thus investigated whole blood transcriptional profiles related to TRD and gene expression changes associated with treatment response to ketamine. Whole blood was collected at baseline (21 healthy controls [HC], 26 patients with TRD) and then again in patients with TRD 24 hours following a single intravenous infusion of ketamine (0.5 mg/kg). We performed RNA-sequencing and analyzed (a) baseline transcriptional profiles between patients with TRD and HC, (b) responders vs. non-responders before ketamine treatment, and (c) gene expression signatures associated with clinical improvement. At baseline, patients with TRD compared to HC showed a gene expression signature indicative of interferon signaling pathway activation. Prior to ketamine administration, the metabotropic glutamate receptor gene GRM2 and the ionotropic glutamate receptor gene GRIN2D were upregulated in responders compared to non-responders. Response to ketamine was associated with a distinct transcriptional signature, however, we did not observe gene expression changes indicative of an anti-inflammatory effect. Future studies are needed to determine the role of the peripheral immune system in the antidepressant effect of ketamine.

Pacemaker use for the treatment of reflex-mediated syncope: 40-year experience at a single paediatric institution.

INTRODUCTION: Reflex-mediated syncope occurs in 15% of children and young adults. In rare instances, pacemakers are required to treat syncopal episodes associated with transient sinus pauses or atrioventricular block. This study describes a single centre experience in the use of permanent pacemakers to treat syncope in children and young adults. MATERIALS AND METHODS: Patients with significant pre-syncope or syncope and pacemaker implantation from 1978 to 2018 were reviewed. Data collected included the age of presentation, method of diagnosis, underlying rhythm disturbance, age at implant, type of pacemaker implanted, procedural complications and subsequent symptoms. RESULTS: Fifty patients were identified. Median age at time of the first syncopal episode was 10.2 (range 0.3-20.4) years, with a median implant age of 14.9 (0.9-34.3) years. Significant sinus bradycardia/pauses were the predominant reason for pacemaker implant (54%), followed by high-grade atrioventricular block (30%). Four (8%) patients had both sinus pauses and atrioventricular block documented. The majority of patients had dual-chamber pacemakers implanted (58%), followed by ventricular pacemakers (38%). Median follow-up was 6.7 (0.4-33.0) years. Post-implant, 4 (8%) patients continued to have syncope, 7 (14%) had complete resolution of their symptoms, and the remaining reported a decrease in their pre-syncopal episodes and no further syncope. Twelve (24%) patients had complications, including two infections and eight lead malfunctions. CONCLUSIONS: Paediatric patients with reflex-mediated syncope can be treated with pacing. Complication rates are high (24%); as such, permanent pacemakers should be reserved only for those in whom asystole from sinus pauses or atrioventricular block has been well documented.

Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial.

OBJECTIVE: Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression. METHODS: Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively. RESULTS: The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred. CONCLUSIONS: The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.

Role of nitric oxide signaling in the antidepressant mechanism of action of ketamine: A randomized controlled trial.

Ketamine is an N-methyl-D-aspartate receptor antagonist with rapid antidepressant effects. Studies suggest that inhibition of nitric oxide synthesis plays a role in the mechanism of action of ketamine. This randomized, placebo-controlled study investigated whether co-administration of sodium nitroprusside, a nitric oxide donor, compared to placebo, would attenuate the antidepressant and dissociative effects of ketamine. Sixteen ketamine responders were randomized to a double-blind infusion of ketamine co-administered with placebo or sodium nitroprusside. Our findings show no difference between the two conditions suggesting that the nitric oxide pathway may not play a primary role in ketamine's antidepressant or dissociative effects. The study is registered at clinicaltrials.gov (NCT03102736).

A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors' previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD. METHODS: Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures. RESULTS: The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events. CONCLUSIONS: This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine's full potential as a treatment for chronic PTSD.

Mount Sinai's Center for Stress, Resilience and Personal Growth as a model for responding to the impact of COVID-19 on health care workers.

The COVID-19 pandemic is anticipated to have a prolonged adverse mental health impact on health care workers (HCWs). The supportive services implemented by the Mount Sinai Hospital System in New York for its workers culminated in the founding of the Mount Sinai Center for Stress, Resilience, and Personal Growth (CSRPG). CSRPG is an innovative mental health and resilience-building service that includes strong community engagement, self- and clinician-administered screening, peer co-led resilience training workshops, and care matching. The long-term sustainability of similar programs across the United States will require federal funding.

Adverse event rate during inpatient sotalol initiation for the management of supraventricular and ventricular tachycardia in the pediatric and young adult population.

BACKGROUND: Sotalol is an important antiarrhythmic drug in the pediatric population. Given the risk of proarrhythmia, sotalol is initiated in inpatient settings, with adult studies as recent as 2015 supporting this practice. OBJECTIVE: The purpose of this study was to determine the frequency of adverse events (AEs) during sotalol initiation for the management of atrial, supraventricular, or ventricular arrhythmias in pediatric patients. METHODS: A retrospective cohort analysis of pediatric patients 21 years or younger initiated on oral sotalol for supraventricular tachycardia or ventricular tachycardia (VT) at Boston Children's Hospital from January 1, 2007, through July 1, 2016, was performed. The primary end point was an AE defined as significant bradycardia, new or increased ventricular arrhythmias, conduction block, or corrected QT interval (QTc) prolongation, resulting in dose reduction or cessation. RESULTS: There were 190 patients who met inclusion criteria, with 110 patients (58%) 6 months or younger. A total of 115 patients (60%) had congenital heart disease. Arrhythmias for which sotalol was initiated included atrioventricular reciprocating tachycardia/atrioventricular nodal reciprocating tachycardia (n = 105 [55%]), atrial flutter (n = 31 [16%]), ectopic atrial tachycardia (n = 26 [14%]), VT (n = 21 [11%]), and atrial fibrillation (n = 7 [4%]). The median pre-sotalol QTc was 438 ms (interquartile range 348-530 ms). Five patients (3%) (aged 0.1-18 years) had AEs including bradycardia <40 beats/min (n = 2) and <100 beats/min (n = 1) and QTc prolongation (n = 2). All 5 patients with AEs had repaired congenital heart disease. CONCLUSION: The incidence of AEs in pediatric patients initiating sotalol for atrial tachycardia, supraventricular tachycardia, or VT is low (3%), with no deaths or malignant rhythms reported in this series.

The Real-World Utility of the LINQ Implantable Loop Recorder in Pediatric and Adult Congenital Heart Patients.

OBJECTIVES: This study sought to determine the practical use of the recently introduced LINQ implantable loop recorder (LINQ-ILR) in a cohort of pediatric and adult congenital arrhythmia patients. BACKGROUND: Correlating symptoms to a causative arrhythmia is a key aspect of diagnosis and management in clinical electrophysiology. METHODS: Retrospective review of clinical data, implantation indications, findings, and therapeutic decisions in patients who underwent LINQ-ILR implantation from April 1st, 2014 to January 30th, 2017 at Boston Children's Hospital. RESULTS: A total of 133 patients were included, of which 76 (57%) were male. The mean age at implantation was 15.7 ± 9.1 years with a duration of follow-up of 11.8 months. Congenital heart disease was present in 34 patients (26%), a confirmed genetic diagnosis in 50 (38%), and cardiomyopathy in 22 (26%), and the remainder were without a previous diagnosis. Syncope was the most common indication for LINQ-ILR implantation, occurring in 59 patients (44%). The median time to diagnosis was 4.5 months, occurring in 78 patients (59%). Cardiac device placement occurred in 17 patients (22%), a medication change in 9 (12%), electrophysiology study/ablation in 5 (6%), or LINQ-ILR explantation in 42 (54%). Infection or erosion occurred in 5 patients. Syncope was correlated with a diagnostic transmission (54% vs. 31%, p = 0.01). CONCLUSIONS: The LINQ-ILR is an important diagnostic tool, providing useful data in more than one-half of patients in <6 months. Adverse events are low. Patient selection is critical and undiagnosed syncope represents an important presenting indication for which a LINQ-ILR implant should be considered.

Utility of incomplete right bundle branch block as an isolated ECG finding in children undergoing initial cardiac evaluation.

OBJECTIVE: This study evaluates the ability of experienced pediatric electrophysiologists (EPs) to reliably classify incomplete right bundle branch block (IRBBB) and assesses its clinical utility as an isolated ECG finding in a group of healthy outpatient children without prior cardiac evaluation. DESIGN: We performed a retrospective analysis of all electrocardiographic and echocardiographic records at Boston Children's Hospital between January 1, 2005, and December 31, 2014. Echocardiographic diagnoses were identified if registered between the date of the index electrocardiogram and the ensuing year. A selected subset of 473 ECGs was subsequently reanalyzed in a blinded manner by six pediatric EPs to determine the consistency with which the finding of IRBBB could be assigned. RESULTS: Of the 331 278 ECGs registered in the BCH database, 32 127 (9.7%) met inclusion criteria and were analyzed for the prevalence of isolated right bundle conduction disturbance findings. The mean age was 12.1 ± 4.0 years, and the population was 49% male. Of the 32 127 ECGs, 72.5% were coded normal, 3.0% were coded IRBBB, and 0.5% were coded complete right bundle branch block (CRBBB). A total of 7.3% of patients coded as normal had an ensuing echocardiogram, compared to 12.5% coded IRBBB. Echo findings were recorded in 0.1% of normal and 0.2% of IRBBB. Patients with ASD-secundum type were no more likely to have isolated IRBBB on previous ECG than the general population (2.5% vs 3.0%). Analysis of inter-reader variability in ECG findings and conduction disturbance identification was high (range of IRBBB prevalence 1-20% among readers). Reinterpretation of ECGs using explicit diagnostic criteria did not demonstrate consistent discrimination of IRBBB and Normal ECGs. CONCLUSIONS: IRBBB is not uncommon in a healthy school age population and is observed to have high inter-reader variability. It was associated with increased use of echocardiographic exam but was not associated with increased rate of echocardiographic findings when compared with rates for normal ECGs.

Cardiac Events During Competitive, Recreational, and Daily Activities in Children and Adolescents With Long QT Syndrome.

BACKGROUND: The 2005 Bethesda Conference Guidelines advise patients with long QT syndrome against competitive sports. We assessed cardiac event rates during competitive and recreational sports, and daily activities among treated long QT syndrome patients. METHODS AND RESULTS: Long QT syndrome patients aged ≥4 years treated with anti-adrenergic therapy were included. Demographics included mechanism of presentation, corrected QT interval pretreatment, symptom history, medication compliance, and administration of QT-prolonging medications. Corrected QT interval ≥550 ms or prior cardiac arrest defined high risk. Sports were categorized by cardiovascular demand per the 2005 Bethesda Conference Guidelines. Each was classified as recreational or competitive. One hundred seventy-two patients (90; 52% female) with median age 15.2 years (interquartile range 11.4, 19.4) were included. Evaluation was performed for family history (102; 59%), incidental finding (34; 20%), and symptoms (36; 21%). Median corrected QT interval was 474 ms (interquartile range 446, 496) and 14 patients (8%) were deemed high risk. Treatment included ß-blockers (171; 99%), implantable cardioverter-defibrillator (27; 16%), left cardiac sympathetic denervation (7; 4%), and pacemaker (3; 2%). Sports participation was recreational (66; 38%) or competitive (106; 62%), with 92 (53%) exercising against the Bethesda Conference Guidelines. There were no cardiac events in competitive athletes and no deaths. There were 13 cardiac events in 9 previously symptomatic patients during either recreational exercise or activities of daily life. CONCLUSIONS: In this cohort of appropriately managed children with long QT syndrome, cardiac event rates were low and occurred during recreational but not competitive activities. This study further supports the need for increased assessment of arrhythmia risk during exercise in this patient population.

The effects of a HTR2B stop codon and testosterone on energy metabolism and beta cell function among antisocial Finnish males.

Herein, we examined insulin resistance (IR), insulin sensitivity (IS), beta cell activity, and glucose metabolism in subjects with antisocial personality disorder (ASPD), and whether the serotonin 2B (5-HT2B) receptor and testosterone have a role in energy metabolism. A cohort of subjects belonging to a founder population that included 98 ASPD males, aged 25-30, was divided into groups based on the presence of a heterozygous 5-HT2B receptor loss-of-function gene mutation (HTR2B Q20*; n = 9) or not (n = 89). Serum glucose and insulin levels were measured in a 5 h oral glucose tolerance test (75 g) and indices describing IR, IS, and beta cell activity were calculated. Body mass index (BMI) was also determined. Concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were measured in cerebrospinal fluid, and testosterone levels from serum. An IR-like state comprising high IR, low IS, and high beta cell activity indices was observed among ASPD subjects without the HTR2B Q20* allele. By contrast, being an ASPD HTR2B Q20* carrier appeared to be preventive of these pathophysiologies. The HTR2B Q20* allele and testosterone predicted lower BMI independently, but an interaction between HTR2B Q20* and testosterone lead to increased insulin sensitivity among HTR2B Q20* carriers with low testosterone levels. The HTR2B Q20* allele also predicted reduced beta cell activity and enhanced glucose metabolism. Reduced 5-HT2B receptor function at low or normal testosterone levels may be protective of obesity. Results were observed among Finnish males having an antisocial personality disorder, which limits the generality.

Trazos e influencias de los programas de transferencia de renta condicionada / Outlines and influences of the cash conditional transfers

Nuevos enfoques de análisis muestran que las políticas públicas son el resultado de articulaciones complejas entre marcos referenciales diversos. Algunas investigaciones centran su atención en los procesos por los cuales se desarrollan los aprendizajes, las convergencias, la difusión y la transferencia en políticas públicas. Este artículo analiza la difusión de programas de transferencia de renta condicionada desarrollados en América Latina y el Caribe. Muestra los epicentros de las ideas originales y la incidencia de las comunidades epistémicas locales así como de los organismos internacionales. El debate que esos actores generaron, contribuyó a la adopción de medidas similares en el resto del continente, mediante un movimiento de difusión en forma de ola. La adopción del modelo se verifica a pesar de las diferentes situaciones socio-políticas entre los países receptores. La adopción generalizada del nuevo modelo, re-definió la orientación de las políticas de asistencia en el S XXI.

New approaches of analysis show that the public policies are the result of complex joints between diverse referential frames. Some investigations center his attention on the processes for which there develop the learnings, the convergences, the diffusion and the transfer in public policies. This article analyzes the diffusion of cash conditional transfer programs developed in Latin America and the Caribe. It shows the epicenters of the original ideas and the incident of the local epistemic communities as well as of the international organizations. The debate that these actors generated, contributed to the adoption of similar measures in the rest of the continent, by means of a movement of diffusion in the shape of wave. The adoption of the model happens in spite of the different socio-political situations between the countries recipients. The widespread adoption of the new model, re-defined the orientation of the policies of assistance in the S XXI.

Genetics of impulsive behaviour.

Impulsivity, defined as the tendency to act without foresight, comprises a multitude of constructs and is associated with a variety of psychiatric disorders. Dissecting different aspects of impulsive behaviour and relating these to specific neurobiological circuits would improve our understanding of the etiology of complex behaviours for which impulsivity is key, and advance genetic studies in this behavioural domain. In this review, we will discuss the heritability of some impulsivity constructs and their possible use as endophenotypes (heritable, disease-associated intermediate phenotypes). Several functional genetic variants associated with impulsive behaviour have been identified by the candidate gene approach and re-sequencing, and whole genome strategies can be implemented for discovery of novel rare and common alleles influencing impulsivity. Via deep sequencing an uncommon HTR2B stop codon, common in one population, was discovered, with implications for understanding impulsive behaviour in both humans and rodents and for future gene discovery.

Multiple accessory pathways in the young: the impact of structural heart disease.

BACKGROUND: The presence of multiple accessory pathways (MultAP) is described in structural heart disease (SHD) such as Ebstein's anomaly and cardiomyopathies. Structural defects can impact the tolerability of tachyarrhythmia and can complicate both medical management and ablation. In a large cohort of pediatric patients with and without SHD undergoing invasive electrophysiology study, we examined the prevalence of MultAP and the effect of both MultAP and SHD on ablation outcomes. METHODS: Accessory pathway number and location, presence of SHD, ablation success, and recurrence were analyzed in consecutive patients from our center over a 16-year period. RESULTS: In 1088 patients, 1228 pathways (36% retrograde only) were mapped to the right side (TV) in 18%, septum (S) in 39%, and left side (MV) in 43%. MultAP were present in 111 pts (10%), involving 250 distinct pathways. SHD tripled the risk of MultAP (26% SHD vs 8% no SHD, P < .001). Multivariable adjusted risk factors for MultAP included Ebstein's (OR 8.7[4.4-17.5], P < .001) and cardiomyopathy (OR 13.3[5.1-34.5], P < .001). Of 1306 ablation attempts, 94% were acutely successful with an 8% recurrence rate. Ablation success was affected by SHD (85% vs 95% for no SHD, P < .01) but not by MultAP (91% vs 94% for single, P = .24). Recurrence rate was higher for SHD (17% SHD vs 8% no SHD, P < .05) and MultAP (19% MultAP vs 8% single, P < .001). CONCLUSIONS: MultAP are found in 10% of pediatric patients, and are more common in SHD compared to those with normal hearts. Both the presence of MultAP and SHD negatively influence ablation outcomes.

Interaction between FKBP5 and childhood trauma and risk of aggressive behavior.

CONTEXT: Childhood trauma may predispose individuals to aggressive behavior, and both childhood trauma and aggressive behavior are associated with hypothalamic-pituitary-adrenal axis dysregulation. OBJECTIVE: To determine whether there would be an interaction between genetic variation in FKBP5 and childhood trauma in predicting aggressive behavior. DESIGN: Cross-sectional study. Four FKBP5 single-nucleotide polymorphisms used in previous studies (rs3800373, rs9296158, rs1360780, and rs9470080) were genotyped. Three diplotypes were derived from 2 major putatively functional haplotypes regulating protein expression that were previously associated with glucocorticoid receptor sensitivity. SETTING: Penitentiary District of Abruzzo-Molise in central Italy. PARTICIPANTS: A population of 583 male Italian prisoners recruited between 2005 and 2008. MAIN OUTCOME MEASURES: A comprehensive analysis of aggression and impulsivity was undertaken using the Brown-Goodwin Lifetime History of Aggression (BGHA) questionnaire, the Buss-Durkee Hostility Inventory (BDHI), and the Barratt Impulsiveness Scale (BIS). A history of childhood trauma was investigated with the Childhood Trauma Questionnaire. The interaction between the FKBP5 diplotypes and childhood trauma on measures of aggression was analyzed. Analyses were replicated with a second behavioral measure of aggression: violent behavior in jail. Individual single-nucleotide polymorphism analysis was performed. RESULTS: Childhood trauma had a significant effect on BGHA and BDHI scores but not on BIS scores. We observed a significant influence of the FKBP5 high-expression diplotype on both a lifetime history of aggressive behavior (BGHA) (P = .012) and violent behavior in jail (P = .025) but only in individuals exposed to childhood trauma, in particular to physical abuse. No main effect of the FKBP5 diplotypes was observed. CONCLUSION: These data suggest that childhood trauma and variants in the FKBP5 gene may interact to increase the risk of overt aggressive behavior.

Discovery and management of diaphragmatic hernia related to abandoned epicardial pacemaker wires in a pregnant woman with {S,L,L} transposition of the great arteries.

Epicardial pacemaker leads placed during childhood are often not removed when transvenous systems are placed later in life. The risk of complications related to retained pacemaker leads and generators is not clear but is generally considered low. We report the case of a 23-year-old pregnant woman who presented with left upper quadrant pain at 20 weeks gestation. The patient was born with {S,L,L} transposition of the great arteries and had high-grade conduction disease in infancy compelling epicardial pacemaker placement. A standard transvenous pacemaker was placed at age 9 years, without removal of the epicardial system. The patient's abdominal pain was attributed to herniation of abdominal contents through a diaphragmatic defect at the site of the abandoned epicardial pacing wire. Her pain improved spontaneously but worsened later in pregnancy leading to repair of the diaphragmatic hernia via anterolateral thoracotomy at 30 weeks gestation. The procedure was well tolerated by mother and fetus. At 38 3/7 weeks gestation, the patient underwent uneventful delivery by cesarean section for breech presentation. This case illustrates the importance of multidisciplinary collaboration in the care of women with congenital heart disease.