Locus Ceruleus Dynamics Are Suppressed during Licking and Enhanced Postlicking Independent of Taste Novelty.

Attending to salient sensory attributes of food, such as tastes that are new, displeasing, or unexpected, allows the procurement of nutrients without food poisoning. Exposure to new tastes is known to increase norepinephrine (NE) release in taste processing forebrain areas, yet the central source for this release is unknown. Locus ceruleus norepinephrine neurons (LC-NE) emerge as a candidate in signaling salient information about taste, as other salient sensory stimuli (e.g., visual, auditory, somatosensation) are known to activate LC neurons. To determine if LC neurons are sensitive to features of taste novelty, we used fiber photometry to record LC-NE activity in water-restricted mice that voluntarily licked either novel or familiar substances of differential palatability (saccharine, citric acid). We observed that LC-NE activity was suppressed during lick bursts and transiently activated upon the termination of licking and that these dynamics were independent of the familiarity of the substance consumed. We next recorded LC dynamics during brief and unexpected consumption of tastants and found no increase in LC-NE activity, despite their responsiveness to visual and auditory stimuli, revealing selectivity in LC's responses to salient sensory information. Our findings suggest that LC activity during licking is not influenced by taste novelty, implicating a possible role for non-LC noradrenergic nuclei in signaling critical information about taste.

Partial or Complete Loss of Norepinephrine Differentially Alters Contextual Fear and Catecholamine Release Dynamics in Hippocampal CA1.

Background: Contextual fear learning is heavily dependent on the hippocampus. Despite evidence that catecholamines contribute to contextual encoding and memory retrieval, the precise temporal dynamics of their release in the hippocampus during behavior is unknown. In addition, new animal models are required to probe the effects of altered catecholamine synthesis on release dynamics and contextual learning. Methods: We generated 2 new mouse models of altered locus coeruleus-norepinephrine (NE) synthesis and utilized them together with GRABNE and GRABDA sensors and in vivo fiber photometry to investigate NE and dopamine (DA) release dynamics in the dorsal hippocampal CA1 during contextual fear conditioning. Results: Aversive foot shock increased both NE and DA release in the dorsal CA1, while freezing behavior associated with recall of fear memory was accompanied by decreased release. Moreover, we found that freezing at the recent time point was sensitive to both partial and complete loss of locus coeruleus-NE synthesis throughout prenatal and postnatal development, similar to previous observations of mice with global loss of NE synthesis beginning postnatally. In contrast, freezing at the remote time point was compromised only by complete loss of locus coeruleus-NE synthesis beginning prenatally. Conclusions: Overall, these findings provide novel insights into the role of NE in contextual fear and the precise temporal dynamics of both NE and DA during freezing behavior and highlight complex relationships between genotype, sex, and NE signaling.

Natural locus coeruleus dynamics during feeding.

Recent data demonstrate that noradrenergic neurons of the locus coeruleus (LC-NE) are required for fear-induced suppression of feeding, but the role of endogenous LC-NE activity in natural, homeostatic feeding remains unclear. Here, we found that LC-NE activity was suppressed during food consumption, and the magnitude of this neural response was attenuated as mice consumed more pellets throughout the session, suggesting that LC responses to food are modulated by satiety state. Visual-evoked LC-NE activity was also attenuated in sated mice, suggesting that satiety state modulates LC-NE encoding of multiple behavioral states. We also found that food intake could be attenuated by brief or longer durations of LC-NE activation. Last, we found that activation of the LC to the lateral hypothalamus pathway suppresses feeding and enhances avoidance and anxiety-like responding. Our findings suggest that LC-NE neurons modulate feeding by integrating both external cues (e.g., anxiogenic environmental cues) and internal drives (e.g., satiety).

Chemogenetic stimulation of tonic locus coeruleus activity strengthens the default mode network.

The default mode network (DMN) of the brain is functionally associated with a wide range of behaviors. In this study, we used functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and spectral fiber photometry to investigate the selective neuromodulatory effect of norepinephrine (NE)-releasing noradrenergic neurons in the locus coeruleus (LC) on the mouse DMN. Chemogenetic-induced tonic LC activity decreased cerebral blood volume (CBV) and glucose uptake and increased synchronous low-frequency fMRI activity within the frontal cortices of the DMN. Fiber photometry results corroborated these findings, showing that LC-NE activation induced NE release, enhanced calcium-weighted neuronal spiking, and reduced CBV in the anterior cingulate cortex. These data suggest that LC-NE alters conventional coupling between neuronal activity and CBV in the frontal DMN. We also demonstrated that chemogenetic activation of LC-NE neurons strengthened functional connectivity within the frontal DMN, and this effect was causally mediated by reduced modulatory inputs from retrosplenial and hippocampal regions to the association cortices of the DMN.

Assessment of Mapping the Brain, a Novel Research and Neurotechnology Based Approach for the Modern Neuroscience Classroom.

Neuroscience research is changing at an incredible pace due to technological innovation and recent national and global initiatives such as the BRAIN initiative. Given the wealth of data supporting the value of course-based undergraduate research experiences (CUREs) for students, we developed and assessed a neurotechnology CURE, Mapping the Brain. The goal of the course is to immerse undergraduate and graduate students in research and to explore technological advances in neuroscience. In the laboratory portion of the course, students pursued a hypothesis-driven, collaborative National Institutes of Health (NIH) research project. Using chemogenetic technology (Designer Receptors Exclusively Activated by Designer Drugs-DREADDs) and a recombinase-based intersectional genetic strategy, students mapped norepinephrine neurons, and their projections and explored the effects of activating these neurons in vivo. In lecture, students compared traditional and cutting-edge neuroscience methodologies, analyzed primary literature, designed hypothesis-based experiments, and discussed technological limitations of studying the brain. Over two consecutive years in the Program at North Carolina State University, we assessed student learning and perceptions of learning based on Society for Neuroscience's (SfN) core concepts and essential principles of neuroscience. Using analysis of student assignments and pre/post content and perception-based course surveys, we also assessed whether the course improved student research article analysis and neurotechnology assessment. Our analyses reveal new insights and pedagogical approaches for engaging students in research and improving their critical analysis of research articles and neurotechnologies. Our data also show that our multifaceted approach increased student confidence and promoted a data focused mentality when tackling research literature. Through the integration of authentic research and a neurotechnology focus, Mapping the Brain provides a unique model as a modern neuroscience laboratory course.

Elimination of galanin synthesis in noradrenergic neurons reduces galanin in select brain areas and promotes active coping behaviors.

Accumulating evidence indicates that disruption of galanin signaling is associated with neuropsychiatric disease, but the precise functions of this neuropeptide remain largely unresolved due to lack of tools for experimentally disrupting its transmission in a cell type-specific manner. To examine the function of galanin in the noradrenergic system, we generated and crossed two novel knock-in mouse lines to create animals lacking galanin specifically in noradrenergic neurons (GalcKO-Dbh). We observed reduced levels of galanin peptide in pons, hippocampus, and prefrontal cortex of GalcKO-Dbh mice, indicating that noradrenergic neurons are a significant source of galanin to those brain regions, while midbrain and hypothalamic galanin levels were comparable to littermate controls. In these same brain regions, we observed no change in levels of norepinephrine or its major metabolite at baseline or after an acute stressor, suggesting that loss of galanin does not affect noradrenergic synthesis or turnover. GalcKO-Dbh mice had normal performance in tests of depression, learning, and motor-related behavior, but had an altered response in some anxiety-related tasks. Specifically, GalcKO-Dbh mice showed increased marble and shock probe burying and had a reduced latency to eat in a novel environment, indicative of a more proactive coping strategy. Together, these findings indicate that noradrenergic neurons provide a significant source of galanin to discrete brain areas, and noradrenergic-specific galanin opposes adaptive coping responses.

Predictive biomarkers for response to EGFR-directed monoclonal antibodies for advanced squamous cell lung cancer.

Background: Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs. Design: Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized. Results: Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of ≥200) and/or gene copy numbers of EGFR (e.g. ≥40% cells with ≥4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in ≥10% of analyzed cells) derive greater therapeutic benefits from EGFR-directed mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents. Conclusions: Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.

Randomized phase III study of docetaxel plus bavituximab in previously treated advanced non-squamous non-small-cell lung cancer.

Background: Bavituximab is a monoclonal antibody that targets phosphatidylserine in the presence of ß2 glycoprotein 1 (ß2GP1) to exert an antitumor immune response. This phase III trial determined the efficacy of bavituximab combined with docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and methods: Key eligibility criteria included advanced non-squamous NSCLC with disease progression after treatment with platinum-based doublet chemotherapy, evidence of disease control after at least two cycles of first-line therapy, presence of measurable disease, ECOG performance status 0 or 1, adequate bone marrow and organ function, and no recent history of clinically significant bleeding. Eligible patients were randomized 1 : 1 to receive up to six 21-day cycles of docetaxel plus either weekly bavituximab 3 mg/kg or placebo until progression or toxicity. The primary end point was overall survival (OS). Results: A total of 597 patients were enrolled. Median OS was 10.5 months in the docetaxel + bavituximab arm and was 10.9 months in the docetaxel + placebo arm (HR 1.06; 95% CI 0.88-1.29; P = 0.533). There was no difference in progression-free survival (HR 1.00; 95% CI 0.82-1.22; P = 0.990). Toxicities were manageable and similar between arms. In subset analysis, among patients with high baseline serum ß2GP1 levels ≥200 µg/ml, a nonsignificant OS trend favored the bavituximab arm (HR 0.82; 95% CI 0.63-1.06; P = 0.134). Among patients who received post-study immune checkpoint inhibitor therapy, OS favored the bavituximab arm (HR 0.46; 95% CI 0.26-0.81; P = 0.006). Conclusions: The combination of bavituximab plus docetaxel is not superior to docetaxel in patients with previously treated advanced NSCLC. The addition of bavituximab to docetaxel does not meaningfully increase toxicity. The potential benefit of bavituximab observed in patients with high ß2GP1 levels and in patients subsequently treated with immune checkpoint inhibitors requires further investigation. Clinical trial number: NCT01999673.

Recombinase-Dependent Mouse Lines for Chemogenetic Activation of Genetically Defined Cell Types.

Chemogenetic technologies, including the mutated human Gq-coupled M3 muscarinic receptor (hM3Dq), have greatly facilitated our ability to directly link changes in cellular activity to altered physiology and behavior. Here, we extend the hM3Dq toolkit with recombinase-responsive mouse lines that permit hM3Dq expression in virtually any cell type. These alleles encode a fusion protein designed to increase effective expression levels by concentrating hM3Dq to the cell body and dendrites. To illustrate their broad utility, we targeted three different genetically defined cell populations: noradrenergic neurons of the compact, bilateral locus coeruleus and two dispersed populations, Camk2a+ neurons and GFAP+ glia. In all three populations, we observed reproducible expression and confirmed that activation of hM3Dq is sufficient to dose-dependently evoke phenotypic changes, without extreme phenotypes associated with hM3Dq overexpression. These alleles offer the ability to non-invasively control activity of diverse cell types to uncover their function and dysfunction at any developmental stage.

Prevalence of erectile dysfunction in a cohort of Italian hypertensive subjects.

The aim of this study was to evaluate the prevalence of erectile dysfunction (ED) in a cohort of Italian hypertensive men and the association with clinical and biochemical data. The study involved 270 consecutive hypertensive subjects aged 40-70 years evaluated in Italian Hypertension Centers of six hospitals from Liguria and Piedmont. ED was assessed through the self-administered questionnaire of the International Index of Erectile Function. Clinical history with ongoing drug treatment, various clinical parameters, biochemical data and evidence about the presence of subclinical target organ damage was collected. Twenty-seven subjects refused to answer the questionnaire (10%). Among the 243 remained subjects, 123 presented ED (50.6%). ED was highly related to age, systolic blood pressure, pulse pressure, smoking status, statin therapy and kidney function. The addition of a thiazide diuretic to an inhibitor of the renin-angiotensin system significantly increased the prevalence of ED. The prevalence of ED increased in relation with the number of hypotensive drug classes taken by the patients. ED was highly prevalent in this cohort of Italian hypertensive subjects and was associated with other cardiovascular risk factors, such as age, smoking status and kidney function. The role of ED as an early marker of cardiovascular disease is discussed.

Maternal, fetal, and placental conditions associated with medically indicated late preterm and early term delivery: a retrospective study.

OBJECTIVE: Our objectives were: (1) to examine the association between maternal, fetal, and placental phenotypes of preterm delivery and medically indicated early delivery of singletons during the late preterm and early term periods; and (2) to identify the specific maternal, fetal, and placental conditions associated with these early deliveries. DESIGN: Retrospective study. SETTING: City of London and Middlesex County, Ontario, Canada. SAMPLE: Singleton live deliveries, at 34-41 weeks of gestation to women in London and Middlesex. METHODS: We obtained data from a city-wide perinatal database (2002-2011; n = 25 699). We used multinomial logistic regression for multivariable analyses. MAIN OUTCOME MEASURE: The outcome was the occurrence of medically indicated late preterm (34-36 weeks of gestation) and early term (37-38 weeks of gestation) delivery, versus delivery at full term (39-41 weeks of gestation). RESULTS: After controlling for confounding factors, all phenotypes were associated with increased odds of medically indicated late preterm and early term delivery. Within the maternal phenotype, chronic maternal medical conditions were associated with increased odds of medically indicated early term delivery (e.g. for gastrointestinal disease, adjusted odds ratio, aOR 1.72, 95% CI 1.47-2.00; for anaemia, aOR 1.40, 95% CI 1.20-1.63), but not late preterm delivery. CONCLUSIONS: The aetiology of medically indicated early delivery close to full term is heterogeneous. Patterns of associations suggest slightly different conditions underlying the late preterm and early term phenotypes, with chronic maternal medical conditions being associated with early term delivery but not with late preterm delivery. These results have implications for the prevention of early delivery as well as the identification of high-risk groups among those born early. TWEETABLE ABSTRACT: The aetiology of medically indicated late preterm and early term delivery is heterogeneous.

Biological determinants of spontaneous late preterm and early term birth: a retrospective cohort study.

OBJECTIVE: Our aim was to examine the association between biological determinants of preterm birth (infection and inflammation, placental ischaemia and other hypoxia, diabetes mellitus, other) and spontaneous late preterm (34-36 weeks) and early term (37-38 weeks) birth. DESIGN: Retrospective cohort study. SETTING: City of London and Middlesex County, Canada. SAMPLE: Singleton live births, delivered at 34-41 weeks to London-Middlesex mothers following spontaneous labour. METHODS: Data were obtained from a city-wide perinatal database on births between 2002 and 2011 (n = 17,678). Multivariable analyses used multinomial logistic regression. MAIN OUTCOME MEASURE: The outcome of interest was the occurrence of late preterm (34-36 weeks) and early term (37-38 weeks) birth, compared with full term birth (39-41 weeks). RESULTS: After controlling for covariates, there were associations between infection and inflammation and late preterm birth (aOR = 2.07, 95% CI 1.65, 2.60); between placental ischaemia and other hypoxia and late preterm (aOR = 2.21, 95% CI 1.88, 2.61) and early term (aOR = 1.25, 95% CI 1.13, 1.39) birth; between diabetes mellitus and late preterm (aOR = 3.89, 95% CI 2.90, 5.21) and early term (aOR = 2.66, 95% CI 2.19, 3.23) birth; and between other biological determinants (polyhydramnios, oligohydramnios) and late preterm (aOR = 2.81, 95% CI 1.70, 4.64) and early term (aOR = 1.89, 95% CI 1.32, 2.70) birth. CONCLUSIONS: Our findings show that delivery following spontaneous labour even close to full term may be a result of pathological processes. Because these biological determinants of preterm birth contribute to an adverse intrauterine environment, they have important implications for fetal and neonatal health.

The galanin receptor agonist, galnon, attenuates cocaine-induced reinstatement and dopamine overflow in the frontal cortex.

Relapse represents one of the most significant problems in the long-term treatment of drug addiction. Cocaine blocks plasma membrane monoamine transporters and increases dopamine (DA) overflow in the brain, and DA is critical for the motivational and primary reinforcing effects of the drug as well as cocaine-primed reinstatement of cocaine seeking in rats, a model of relapse. Thus, modulators of the DA system may be effective for the treatment of cocaine dependence. The endogenous neuropeptide galanin inhibits DA transmission, and both galanin and the synthetic galanin receptor agonist, galnon, interfere with some rewarding properties of cocaine. The purpose of this study was to further assess the effects of galnon on cocaine-induced behaviors and neurochemistry in rats. We found that galnon attenuated cocaine-induced motor activity, reinstatement and DA overflow in the frontal cortex at a dose that did not reduce baseline motor activity, stable self-administration of cocaine, baseline extracellular DA levels or cocaine-induced DA overflow in the nucleus accumbens (NAc). Similar to cocaine, galnon had no effect on stable food self-administration but reduced food-primed reinstatement. These results indicate that galnon can diminish cocaine-induced hyperactivity and relapse-like behavior, possibly in part by modulating DA transmission in the frontal cortex.

[Salvage HIFU after radiotherapy and salvage radiotherapy after HIFU in locally recurrent prostate cancer: Retrospective analysis of morbidity]. / Traitements de rattrapage par HIFU après radiothérapie première et par radiothérapie après HIFU première dans la récidive locale du cancer de prostate: analyse rétrospective de la toxicité

OBJECTIVES: To evaluate the toxicity of therapeutic sequences High Intensity Focused Ultrasound (HIFU)-salvage radiotherapy (HIFU-RT) or radiotherapy-salvage HIFU (RT-HIFU) in case of locally recurrent prostate cancer. MATERIALS AND METHODS: Nineteen patients had a local recurrence of prostate cancer. Among them, 10 patients were treated by HIFU-RT and 9 patients by RT- HIFU (4 by external beam radiotherapy [EBR] and 5 by brachytherapy [BRACHY]). Urinary side effects were assessed using CTCAE v4. RESULTS: At the time of the initial management, the median age was 66.5 years (53-72), the median PSA was 10.8ng/mL (3.4-50) and the median initial Gleason score was 6.3 (5-8). Median follow-up after salvage treatment was 46.3 months (2-108). Thirty percent of the patients in the HIFU-RT group and 33.3 % of the patients in the RT-HIFU group, all belonging to the sub-group BRACHY-HIFU, had urinary complication greater than or equal to grade 2. Among all the patients, only 1 had grade 1 gastrointestinal toxicity. CONCLUSION: BRACHY-HIFU sequence seems to be purveyor of many significant urinary side effects. A larger database is needed to confirm this conclusion.

Obstetric conditions and the placental weight ratio.

INTRODUCTION: To elucidate how obstetric conditions are associated with atypical placental weight ratios (PWR)s in infants born: (a) ≥37 weeks gestation; (b) at ≥33 but <37 weeks gestation; and (c) <33 weeks gestation. METHODS: The study included all in-hospital singleton births in London, Ontario between June 1, 2006 and March 31, 2011. PWR was assessed as <10th or >90th percentile by gestational age-specific local population standards. Multivariable analysis was carried out using multinomial logistic regression with blockwise variable entry in order of temporality. RESULTS: Baseline factors and maternal obstetric conditions associated with PWR <10th percentile were: increasing maternal height, overweight and obese body mass indexes (BMI), large for gestational age infants, smoking, and gestational diabetes. Obstetric factors associated with PWR >90th percentile were: underweight, overweight and obese BMIs, smoking, preeclampsia, placenta previa, and placental abruption. In particular, indicators of hypoxia and altered placental function were generally associated with elevated PWR at all gestations. DISCUSSION: An association between obstetric conditions associated with fetal hypoxia and PWR ≥90th percentile was illustrated. CONCLUSIONS: The multivariable findings suggest that the PWR is similarly increased regardless of the etiology of the hypoxia.

The imperative to prevent and treat childhood obesity: why the world cannot afford to wait.

In the past 20 years, the prevalence of obesity in the United States increased almost 50% among adults and by 300% in children. Today, 9.7% of all U.S. infants up to 2 years old have abnormally high weight-for-recumbent length; 25% of children under age 5 are either overweight or obese; and 17% of adolescents are obese. Ethnic disparities in the rates of obesity are also large and apparent in childhood. Further, 44% of obese adolescents have metabolic syndrome. Obese children tend to become obese adults; thus, in a decade, young adults will likely have much higher risks of chronic disease, which has tremendous implications for the healthcare system. However, early childhood may be the best time to prevent obesity. Teachers' healthy eating choices are positively associated with changes in body mass index percentiles for children, for example. In addition, 8 million children attend afterschool programs, which can successfully promote health and wellness and successfully treat obesity. This childhood epidemic of obesity and its health-related consequences in adolescents should be a clinical and public health priority. However, this major public health problem cannot be managed solely in clinical settings. Rather, public health strategies must be integrated into home and family, school and community-based settings.

Exercise offers anxiolytic potential: a role for stress and brain noradrenergic-galaninergic mechanisms.

Although physical activity reduces anxiety in humans, the neural basis for this response is unclear. Rodent models are essential to understand the mechanisms that underlie the benefits of exercise. However, it is controversial whether exercise exerts anxiolytic-like potential in rodents. Evidence is reviewed to evaluate the effects of wheel running, an experimental mode of exercise in rodents, on behavior in tests of anxiety and on norepinephrine and galanin systems in neural circuits that regulate stress. Stress is proposed to account for mixed behavioral findings in this literature. Indeed, running promotes an adaptive response to stress and alters anxiety-like behaviors in a manner dependent on stress. Running amplifies galanin expression in noradrenergic locus coeruleus (LC) and suppresses stress-induced activity of the LC and norepinephrine output in LC-target regions. Thus, enhanced galanin-mediated suppression of brain norepinephrine in runners is supported by current literature as a mechanism that may contribute to the stress-protective effects of exercise. These data support the use of rodents to study the emotional and neurobiological consequences of exercise.

Voluntary exercise offers anxiolytic potential and amplifies galanin gene expression in the locus coeruleus of the rat.

Although exercise improves anxiety in humans, it is controversial whether exercise is anxiolytic in rodents. We tested the hypothesis that stress influences the effect of exercise on anxiety-like and defensive behaviors. To explore the neurobiological mechanisms of exercise, we also examined whether exercise alters gene expression for the stress-related peptide galanin. Rats were housed in the presence or absence of a running wheel for 21 d. A subset of these rats were (1) not injected or received a single high, dose of the ß-carboline FG7142 (inverse agonist at the benzodiazepine receptor site) immediately prior to testing or (2) were injected repeatedly with vehicle or FG7142 during the last 10d of exercise. On day 22, anxiety-like and defensive behaviors were measured in the elevated plus maze, shock probe defensive burying, and defensive withdrawal tests. Locus coeruleus prepro-galanin mRNA was measured by in situ hybridization. Exercise and sedentary rats that were not injected exhibited similar behavior in all tests, whereas FG7142 injected immediately prior to the test battery produced intense avoidance and immobility consistent with an anxiety-like response. However, exercise produced anxiolytic-like and active defensive behaviors in the test battery relative to the sedentary condition in rats injected repeatedly with vehicle or FG7142. Exercise also increased prepro-galanin mRNA in the locus coeruleus relative to sedentary controls. These data suggest that the emergence of enhanced adaptive behavior after chronic voluntary exercise is influenced by stress. Our data support a role for galanin in the beneficial consequences of wheel running.

Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats.

Dysregulation in signaling of the endocannabinoid 2-arachidonoylglycerol (2-AG) is implicated in hyperresponsiveness to stress. We hypothesized that blockade of monoacylglycerol lipase (MGL), the primary enzyme responsible for 2-AG deactivation in vivo, would produce context-dependent anxiolytic effects in rats. Environmental aversiveness was manipulated by varying illumination of an elevated plus maze. Percentage open arm time and numbers of open and closed arm entries were measured in rats receiving a single intraperitoneal (i.p.) injection of either vehicle, the MGL inhibitor JZL184 (1-8mg/kg), the benzodiazepine diazepam (1mg/kg), the cannabinoid CB(1) receptor antagonist rimonabant (1mg/kg), or JZL184 (8mg/kg) coadministered with rimonabant (1mg/kg). JZL184 (8mg/kg) produced anxiolytic-like effects (i.e., increased percentage open arm time and number of open arm entries) under high, but not low, levels of environmental aversiveness. Diazepam produced anxiolytic effects in either context. Rimonabant blocked the anxiolytic-like effects of JZL184, consistent with mediation by CB(1). Anxiolytic effects of JZL184 were preserved following chronic (8mg/kg per day×6 days) administration. Chronic and acute JZL184 treatment similarly enhanced behavioral sensitivity to an exogenous cannabinoid (WIN55,212-2; 2.5mg/kg i.p.) 24 or 72h following the terminal injection, suggesting a pervasive effect of MGL inhibition on the endocannabinoid system. We attribute our results to alterations in emotion rather than locomotor activity as JZL184 did not alter the number of closed arm entries in the plus maze or produce motor ataxia in the bar test. Our results demonstrate that JZL184 has beneficial, context-dependent effects on anxiety in rats, presumably via inhibition of MGL-mediated hydrolysis of 2-AG. These data warrant further testing of MGL inhibitors to elucidate the functional role of 2-AG in controlling anxiety and stress responsiveness. Our data further implicate a role for 2-AG in the regulation of emotion and validate MGL as a therapeutic target.

The Early External Cephalic Version (ECV) 2 Trial: an international multicentre randomised controlled trial of timing of ECV for breech pregnancies.

OBJECTIVE: To investigate whether initiating external cephalic version (ECV) earlier in pregnancy might increase the rate of successful ECV procedures, and be more effective in decreasing the rate of non-cephalic presentation at birth and of caesarean section. DESIGN: An unblinded multicentred randomised controlled trial. SETTING: A total of 1543 women were randomised from 68 centres in 21 countries. POPULATION: Women with a singleton breech fetus at a gestational age of 33(0/7) weeks (231 days) to 35(6/7) weeks (251 days) of gestation were included. METHODS: Participants were randomly assigned to having a first ECV procedure between the gestational ages of 34(0/7) (238 days) and 35(6/7) weeks of gestation (early ECV group) or at or after 37(0/7) (259 days) weeks of gestation (delayed ECV group). MAIN OUTCOME MEASURES: The primary outcome was the rate of caesarean section; the secondary outcome was the rate of preterm birth. RESULTS: Fewer fetuses were in a non-cephalic presentation at birth in the early ECV group (314/765 [41.1%] versus 377/768 [49.1%] in the delayed ECV group; relative risk [RR] 0.84, 95% CI 0.75, 0.94, P=0.002). There were no differences in rates of caesarean section (398/765 [52.0%] versus 430/768 [56.0%]; RR 0.93, 95% CI 0.85, 1.02, P=0.12) or in risk of preterm birth (50/765 [6.5%] versus 34/768 [4.4%]; RR 1.48, 95% CI 0.97, 2.26, P=0.07) between groups. CONCLUSION: External cephalic version at 34-35 weeks versus 37 or more weeks of gestation increases the likelihood of cephalic presentation at birth but does not reduce the rate of caesarean section and may increase the rate of preterm birth.