Clinical Implications of High-Sensitivity Troponin Elevation Levels in Non-ST-Segment Elevation Myocardial Infarction Patients: Beyond Diagnostics.

Standard troponin has long been pivotal in diagnosing coronary syndrome, especially Non-ST-Segment Elevation Myocardial Infarction (NSTEMI). The recent introduction of high-sensitivity troponin (hs-cTnI) has elevated it to the gold standard. Yet, its nuanced role in predicting angiographic lesions and clinical outcomes, notably in specific populations like obesity, remains underexplored. Aim: To evaluate the association between hs-cTnI magnitude in NSTEMI patients and angiographic findings, progression to acute heart failure, and its performance in obesity. Methods: Retrospective study of 208 NSTEMI patients at a large university center (2020-2023). Hs-cTnI values were assessed for angiographic severity, acute heart failure, and characteristics in the obese population. Data collected and diagnostic performance were evaluated using manufacturer-specified cutoffs. Results: 97.12% of patients had a single culprit vessel. Hs-cTnI elevation correlated with angiographic stenosis severity. Performance for detecting severe coronary disease was low, with no improvement using a higher cutoff. No association was found between hs-cTnI and the culprit vessel location. Hs-cTnI did not predict acute heart failure progression. In the obese population, hs-cTnI levels were higher, but acute heart failure occurred less frequently than in non-obese counterparts. Conclusions: In NSTEMI, hs-cTnI elevation is associated with significant stenosis, but not with location or acute heart failure. Obesity correlates with higher hs-cTnI levels but a reduced risk of acute heart failure during NSTEMI.

Insights into dike nucleation and eruption dynamics from high-resolution seismic imaging of magmatic system at the East Pacific Rise.

Models of magmatic systems suggest that the architecture of crustal magma bodies plays an important role in where volcanic eruptions occur, but detailed field observations are needed to evaluate them. We present ultrahigh-resolution reflection images of magma bodies beneath a region of multiple eruptions along the East Pacific Rise derived from three-dimensional seismic surveying. The observations reveal magma bodies with elongate ridges and troughs vertically aligned with seafloor eruptive fissures that we interpret as remnant dike root zones where repeat dikes nucleate. We document a triangular feeder zone to the axially centered magma body from the off-axis source for a newly forming seamount of the Lamont chain and infer bottom-up eruption triggering due to recharge from this deeper source. The findings indicate that magma bodies are sculpted by both processes of magma recharge from below and magma extraction to the surface, leaving a morphological imprint that contributes to localization of dike nucleation and eruption sites at the East Pacific Rise.

Are there disciplinary boundaries in the comparative study of primate cognition?

A view continues to gain momentum that regards investigation of the cognition of great apes in captive settings as affording us a model for human cognitive evolution. Researchers from disciplines such as comparative psychology, anthropology, and even archaeology, seem eager to put their theories to the test by using great apes as their chosen experimental model. Questions addressed currently by comparative psychologists have long been the object of attention by neurophysiologists, psychobiologists and neuroscientists, who, however, often use rodents and monkeys as the species of choice. Whereas comparative psychology has been influenced greatly by ethology, much neuroscience has developed against a background of physiology and medicine. This separation of the intellectual contexts wherein they have arisen and flourished has impeded the development of fluid interaction between comparative psychologists and researchers in the other disciplines. We feel that it would be beneficial for comparative psychologists and neuroscientists to combine research endeavours far more often, in order to address common questions of interest related to cognition. We regard interdisciplinary cross-pollination to be particularly desirable, even if many comparative psychologists lack deep expertise about the workings of the brain, and even if many neuroscientists lack expert knowledge about the behaviour of different species. Furthermore, we believe that anthropology, archaeology, human evolutionary studies, and related disciplines, may well provide us with significant contextual knowledge about the physical and temporal background to the evolution in humans of specific cognitive skills. To that end, we urge researchers to dismantle methodological, conceptual and historical disciplinary boundaries, in order to strengthen cross-disciplinary cooperation in order to broaden and deepen our insights into the cognition of nonhuman and human primates.

O-RADS Classification for Ultrasound Assessment of Adnexal Masses: Agreement between IOTA Lexicon and ADNEX Model for Assigning Risk Group.

BACKGROUND: The O-RADS system is a new proposal for establishing the risk of malignancy of adnexal masses using ultrasound. The objective of this study is to assess the agreement and diagnostic performance of O-RADS when using the IOTA lexicon or ADNEX model for assigning the O-RADS risk group. METHODS: Retrospective analysis of prospectively collected data. All women diagnosed as having an adnexal mass underwent transvaginal/transabdominal ultrasound. Adnexal masses were classified according to the O-RADS classification, using the criterion of the IOTA lexicon and according to the risk of malignancy determined by the ADNEX model. The agreement between both methods for assigning the O-RADS group was estimated using weighted Kappa and the percentage of agreement. The sensitivity and specificity of both approaches were calculated. RESULTS: 454 adnexal masses in 412 women were evaluated during the study period. There were 64 malignant masses. The agreement between the two approaches was moderate (Kappa: 0.47), and the percentage of agreement was 46%. Most disagreements occurred for the groups O-RADS 2 and 3 and for groups O-RADS 3 and 4. The sensitivity and specificity for O-RADS using the IOTA lexicon and O-RADS using the ADNEX model were 92.2% and 86.1%, and 85.9% and 87.4%, respectively. CONCLUSION: The diagnostic performance of O-RADS classification using the IOTA lexicon as opposed to the IOTA ADNEX model is similar. However, O-RADS group assignment varies significantly, depending on the use of the IOTA lexicon or the risk estimation using the ADNEX model. This fact might be clinically relevant and deserves further research.

Diverse therapeutic developments for post-traumatic stress disorder (PTSD) indicate common mechanisms of memory modulation.

Post-traumatic stress disorder (PTSD), characterized by abnormally persistent and distressing memories, is a chronic debilitating condition in need of new treatment options. Current treatment guidelines recommend psychotherapy as first line management with only two drugs, sertraline and paroxetine, approved by U.S. Food and Drug Administration (FDA) for treatment of PTSD. These drugs have limited efficacy as they only reduce symptoms related to depression and anxiety without producing permanent remission. PTSD remains a significant public health problem with high morbidity and mortality requiring major advances in therapeutics. Early evidence has emerged for the beneficial effects of psychedelics particularly in combination with psychotherapy for management of PTSD, including psilocybin, MDMA, LSD, cannabinoids, ayahuasca and ketamine. MDMA and psilocybin reduce barrier to therapy by increasing trust between therapist and patient, thus allowing for modification of trauma related memories. Furthermore, research into the memory reconsolidation mechanisms has allowed for identification of various pharmacological targets to disrupt abnormally persistent memories. A number of pre-clinical and clinical studies have investigated novel and re-purposed pharmacological agents to disrupt fear memory in PTSD. Novel therapeutic approaches like neuropeptide Y, oxytocin, cannabinoids and neuroactive steroids have also shown potential for PTSD treatment. Here, we focus on the role of fear memory in the pathophysiology of PTSD and propose that many of these new therapeutic strategies produce benefits through the effect on fear memory. Evaluation of recent research findings suggests that while a number of drugs have shown promising results in preclinical studies and pilot clinical trials, the evidence from large scale clinical trials would be needed for these drugs to be incorporated in clinical practice.

Effects of propranolol on the modification of trauma memory reconsolidation in PTSD patients: A systematic review and meta-analysis.

Post-traumatic stress disorder (PTSD) develops after an exposure to a life-threatening event and is characterized by intrusive memories. According to memory reconsolidation theory retrieval of memory under certain conditions leads to its labilization and subsequent re-storage which could be disrupted by drugs. Propranolol has been the most commonly investigated drug for memory reconsolidation therapy in clinical trials. Intervention with propranolol have shown mixed results in PTSD patients with some studies showing improvement in symptoms while other failing to replicate these findings. We conducted a systematic review and meta-analysis to determine the efficacy of trauma memory disruption by propranolol on PTSD symptoms and physiological responses in PTSD patients. 3224 publications were assessed for eligibility. Seven studies on effects of propranolol on PTSD symptoms and 3 studies on effects of propranolol on physiological responses were incorporated in the meta-analyses. Overall, results indicate that propranolol did not show a beneficial effect on PTSD symptoms (standardized mean difference: 1.29; 95% CI = -2.16 - 0.17). Similarly, propranolol did not influence skin conductance (standardized mean difference: 0.77; 95% CI = -1.85 - 0.31) or EMG response (standardized mean difference: 0.16; 95% CI = -0.65 - 0.33). However, propranolol significantly reduced heart rate after trauma memory recall compared to placebo (standardized mean difference: 0.67; 95% CI = -1.27 to -0.07). This study finds a lack of evidence for the efficacy of propranolol on traumatic memory disruption, in PTSD patients, to recommend its routine clinical use. However, a high level of heterogeneity, variation in propranolol dosage and inadequate sample sizes mean that these findings require cautious interpretation.

Asperuloside Enhances Taste Perception and Prevents Weight Gain in High-Fat Fed Mice.

Asperuloside is an iridoid glycoside found in many medicinal plants that has produced promising anti-obesity results in animal models. In previous studies, three months of asperuloside administration reduced food intake, body weight, and adipose masses in rats consuming a high fat diet (HFD). However, the mechanisms by which asperuloside exerts its anti-obesity properties were not clarified. Here, we investigated homeostatic and nutrient-sensing mechanisms regulating food intake in mice consuming HFD. We confirmed the anti-obesity properties of asperuloside and, importantly, we identified some mechanisms that could be responsible for its therapeutic effect. Asperuloside reduced body weight and food intake in mice consuming HFD by 10.5 and 12.8% respectively, with no effect on mice eating a standard chow diet. Fasting glucose and plasma insulin were also significantly reduced. Mechanistically, asperuloside significantly reduced hypothalamic mRNA ghrelin, leptin, and pro-opiomelanocortin in mice consuming HFD. The expression of fat lingual receptors (CD36, FFAR1-4), CB1R and sweet lingual receptors (TAS1R2-3) was increased almost 2-fold by the administration of asperuloside. Our findings suggest that asperuloside might exert its therapeutic effects by altering nutrient-sensing receptors in the oral cavity as well as hypothalamic receptors involved in food intake when mice are exposed to obesogenic diets. This signaling pathway is known to influence the subtle hypothalamic equilibrium between energy homeostasis and reward-induced overeating responses. The present pre-clinical study demonstrated that targeting the gustatory system through asperuloside administration could represent a promising and effective new anti-obesity strategy.

Are oral oestrogens effective in preventing urinary tract infection in postmenopausal woman. / Son efectivos los estrógenos orales en la prevención de infección del tracto urinario en mujeres posmenopáusicas.

INTRODUCCIÓN: La infección del tracto urinario es una patología frecuente, con un alto riesgo de recurrencia, por lo que representa un importan-te motivo de consulta. Dentro de la población más afectada se encuentran las mujeres postmenopáusicas debido a la caída de los niveles de estrógenos, tanto locales como sistémicos, perdiéndose la barrera protectora de la vía urinaria contra agentes patógenos. Entre las variadas medidas que potencialmente disminuirían el riesgo de infección urinaria se ha planteado el uso de estrógenos, sin embargo, no está claro si realmente son efectivos. MÉTODOS: Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud a nivel mundial, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis, preparamos tablas de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos seis revisiones sistemáticas que en conjunto incluyen siete estudios primarios, de los cuales, cuatro son ensayos aleatorizados. Concluimos que no está claro si los estrógenos orales disminuyen el riesgo de desarrollar infección del tracto urinario sintomática, porque la certeza de la evidencia es muy baja.

Pooled Time Series Modeling Reveals Smoking Habit Memory Pattern.

Smoking is a habit that is hard to break because nicotine is highly addictive and smoking behavior is strongly linked to multiple daily activities and routines. Here, we explored the effect of gender, age, day of the week, and previous smoking on the number of cigarettes smoked on any given day. Data consisted of daily records of the number of cigarettes participants smoked over an average period of 84 days. The sample included smokers (36 men and 26 women), aged between 18 and 26 years, who smoked at least five cigarettes a day and had smoked for at least 2 years. A panel data analysis was performed by way of multilevel pooled time series modeling. Smoking on any given day was a function of the number of cigarettes smoked on the previous day, and 2, 7, 14, 21, 28, 35, 42, 49, and 56 days previously, and the day of the week. Neither gender nor age influenced this pattern, with no multilevel effects being detected, thus the behavior of all participants fitted the same smoking model. These novel findings show empirically that smoking behavior is governed by firmly established temporal dependence patterns and inform temporal parameters for the rational design of smoking cessation programs.

Amelioration of age-related brain function decline by Bruton's tyrosine kinase inhibition.

One of the hallmarks of aging is the progressive accumulation of senescent cells in organisms, which has been proposed to be a contributing factor to age-dependent organ dysfunction. We recently reported that Bruton's tyrosine kinase (BTK) is an upstream component of the p53 responses to DNA damage. BTK binds to and phosphorylates p53 and MDM2, which results in increased p53 activity. Consistent with this, blocking BTK impairs p53-induced senescence. This suggests that sustained BTK inhibition could have an effect on organismal aging by reducing the presence of senescent cells in tissues. Here, we show that ibrutinib, a clinically approved covalent inhibitor of BTK, prolonged the maximum lifespan of a Zmpste24-/- progeroid mice, which also showed a reduction in general age-related fitness loss. Importantly, we found that certain brain functions were preserved, as seen by reduced anxiety-like behaviour and better long-term spatial memory. This was concomitant to a decrease in the expression of specific markers of senescence in the brain, which confirms a lower accumulation of senescent cells after BTK inhibition. Our data show that blocking BTK has a modest increase in lifespan in Zmpste24-/- mice and protects them from a decline in brain performance. This suggests that specific inhibitors could be used in humans to treat progeroid syndromes and prevent the age-related degeneration of organs such as the brain.

Son efectivos los estrógenos orales en la prevención de infección del tracto urinario en mujeres posmenopáusicas / Are oral oestrogens effective in preventing urinary tract infection in postmenopausal woman

INTRODUCCIÓN: La infección del tracto urinario es una patología frecuente, con un alto riesgo de recurrencia, por lo que representa un importan-te motivo de consulta. Dentro de la población más afectada se encuentran las mujeres postmenopáusicas debido a la caída de los niveles de estrógenos, tanto locales como sistémicos, perdiéndose la barrera protectora de la vía urinaria contra agentes patógenos. Entre las variadas medidas que potencialmente disminuirían el riesgo de infección urinaria se ha planteado el uso de estrógenos, sin embargo, no está claro si realmente son efectivos. MÉTODOS: Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud a nivel mundial, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis, preparamos tablas de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos seis revisiones sistemáticas que en conjunto incluyen siete estudios primarios, de los cuales, cuatro son ensayos aleatorizados. Concluimos que no está claro si los estrógenos orales disminuyen el riesgo de desarrollar infección del tracto urinario sintomática, porque la certeza de la evidencia es muy baja.

Correction: Intensive longitudinal modelling predicts diurnal activity of salivary alpha-amylase.

[This corrects the article DOI: 10.1371/journal.pone.0209475.].

Intensive longitudinal modelling predicts diurnal activity of salivary alpha-amylase.

Salivary alpha-amylase (sAA) activity has been widely used in psychological and medical research as a surrogate marker of sympathetic nervous system activation, though its utility remains controversial. The aim of this work was to compare alternative intensive longitudinal models of sAA data: (a) a traditional model, where sAA is a function of hour (hr) and hr squared (sAAj,t = f(hr, hr2), and (b) an autoregressive model, where values of sAA are a function of previous values (sAAj,t = f(sAA j,t-1, sAA j,t-2, …, sAA j,t-p). Nineteen normal subjects (9 males and 10 females) participated in the experiments and measurements were performed every hr between 9:00 and 21:00 hr. Thus, a total of 13 measurements were obtained per participant. The Napierian logarithm of the enzymatic activity of sAA was analysed. Data showed that a second-order autoregressive (AR(2)) model was more parsimonious and fitted better than the traditional multilevel quadratic model. Therefore, sAA follows a process whereby, to forecast its value at any given time, sAA values one and two hr prior to that time (sAA j,t = f(SAAj,t-1, SAAj,t-2) are most predictive, thus indicating that sAA has its own inertia, with a "memory" of the two previous hr. These novel findings highlight the relevance of intensive longitudinal models in physiological data analysis and have considerable implications for physiological and biobehavioural research involving sAA measurements and other stress-related biomarkers.

Trace amine-associated receptor 1: a multimodal therapeutic target for neuropsychiatric diseases.

INTRODUCTION: The trace amines, endogenous amines closely related to the biogenic amine neurotransmitters, have been known to exert physiological and neurological effects for decades. The recent identification of a trace amine-sensitive G protein-coupled receptor, trace amine-associated receptor 1 (TAAR1), and subsequent development of TAAR1-selective small-molecule ligands, has renewed research into the therapeutic possibilities of trace amine signaling. Areas covered: Recent efforts in elucidating the neuropharmacology of TAAR1, particularly in neuropsychiatric and neurodegenerative disease, addiction, and regulation of arousal state, will be discussed. Focused application of TAAR1 mutants, synthetic TAAR1 ligands, and endogenous biomolecules such as 3-iodothyronamine (T1AM) has yielded a basic functional portrait for TAAR1, despite a complex biochemistry and pharmacology. The close functional relationship between TAAR1 and dopaminergic signaling is likely to underlie many of its CNS effects. However, TAAR1's influences on serotonin and glutamate neurotransmission will also be highlighted. Expert opinion: TAAR1 holds great promise as a therapeutic target for mental illness, addiction, and sleep disorders. A combination of preclinical and translationally driven studies has solidified TAAR1 as a key node in the regulation of dopaminergic signaling. Continued focus on the mechanisms underlying TAAR1's regulation of serotonin and glutamate signaling, as well as dopamine, will yield further disease-relevant insights.

Are probiotics effective in preventing urinary tract infection? / ¿Son efectivos los probióticos en prevenir infecciones del tracto urinario?

INTRODUCTION: Urinary tract infection is the most common bacterial infection and recurrences are common. Probiotics have been proposed as an alternative to decrease this risk. However, it is not clear if they are really effective. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified six systematic reviews including nine studies overall, of which seven were randomized trials. We concluded it is not clear whether probiotics decrease the risk of symptomatic urinary tract infection, because the certainty of the evidence is very low.

INTRODUCCIÓN: La infección del tracto urinario es la infección bacteriana más común y su recurrencia es frecuente. Entre las variadas medidas que potencialmente disminuirían este riesgo se ha planteado el uso de probióticos. Sin embargo, no está claro si realmente son efectivos. MÉTODOS: Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud a nivel mundial, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos seis revisiones sistemáticas que en conjunto incluyeron nueve estudios, entre ellos siete ensayos aleatorizados. Concluimos que no está claro si los probióticos disminuyen el riesgo de infección urinaria sintomática, porque la certeza de la evidencia es muy baja.

Replacement treatment during extinction training with the atypical dopamine uptake inhibitor, JHW-007, reduces relapse to methamphetamine seeking.

There are currently no approved medications to effectively counteract the effects of methamphetamine (METH), reduce its abuse and prolong abstinence from it. Data accumulated in recent years have shown that a range of N-substituted benztropine (BZT) analogues possesses psychopharmacological features consistent with those of a potential replacement or "substitute" treatment for stimulant addiction. On the other hand, the evidence that antidepressant therapy may effectively prevent relapse to stimulant seeking is controversial. Here, we compared in rats the ability of the BZT analogue and high affinity dopamine (DA) reuptake inhibitor, JHW-007, and the antidepressant, trazodone, administered during extinction sessions after chronic METH self-administration, to alter METH-primed reinstatement of drug seeking. The data showed that trazodone produced paradoxical effects on lever pressing during extinction of METH self-administration, decreasing active, but increasing inactive, lever pressing. JHW-007 did not have any observable effects on extinction training. Importantly, JHW-007 significantly attenuated METH-primed reinstatement, whereas trazodone enhanced it. These findings lend support to the candidacy of selective DA uptake blockers, such as JHW-007, as potential treatments for METH addiction, but not to the use of antidepressant medication as a single therapeutic approach for relapse prevention.

A Neurophysiological and Behavioral Assessment of Interventions Targeting Attention Bias and Sense of Control in Binge Drinking.

Attention bias modification (ABM) can decrease the selective visual attention paid to alcohol-related cues but has not been found to reliably reduce alcohol craving. Here, a cognitive intervention to decrease craving by increasing sense of control (Shamloo and Cox, 2014) was used as a complement. We investigated the effects of two such interventions administered singly or in combination. Participants were 41 binge drinkers (BDs) and 10 non-binge drinkers (NBDs). BDs received either ABM, sense of control training, both interventions, or no intervention, and were compared with NBDs who received no intervention. Groups were assessed on alcohol attention bias change including both reaction times and cue-elicited ERPs (visual dot-probe task), alcohol craving change, and alcohol consumption. BDs exhibited higher attention bias scores than NBDs. ABM had no effect on BDs' behavioral or electrophysiological markers of attention bias. Sense of control training did not increase personal sense of control but protected against decreased task accuracy and against increased craving. BDs receiving the combined intervention consumed less alcohol in a bogus taste test than participants receiving no intervention. Taken together, the results suggest that ABM procedure may reduce alcohol consumption if combined with sense of control training.

Are vaginal estrogens effective for preventing urinary tract infection in postmenopausal women? / ¿Son los estrógenos vaginales efectivos para prevenir infecciones urinarias en mujeres postmenopáusicas?

INTRODUCTION: Urinary tract infection commonly affects postmenopausal women, probably because of the changes in vaginal flora secondary to estrogen deficiency. So, the use of vaginal estrogens could revert this process and then decrease the risk of infection. However, it is not clear whether they are really effective. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified seven systematic reviews including four primary studies overall and all were randomized trials. We concluded it is not clear whether vaginal estrogens decrease the risk of symptomatic urinary infection because the certainty of the available evidence is very low.

INTRODUCCIÓN: La infección del tracto urinario es una patología frecuente. Afecta principalmente a mujeres postmenopáusicas, probablemente por cambios en la flora de la mucosa secundarios a la disminución de estrógenos. Se ha planteado que el uso de estrógenos vaginales podría disminuir el riesgo de infección urinaria, sin embargo, no está claro si realmente son efectivos. MÉTODOS: Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis, preparamos tablas de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos siete revisiones sistemáticas que en conjunto incluyen cuatro estudios primarios, de los cuales, todos son ensayos aleatorizados. Concluimos que no está claro si los estrógenos vaginales disminuyen el riesgo de desarrollar una infección urinaria sintomática, porque la certeza de la evidencia disponible es muy baja.

Interaction Between the Trace Amine-Associated Receptor 1 and the Dopamine D2 Receptor Controls Cocaine's Neurochemical Actions.

Recent evidence suggests that the trace amine-associated receptor 1 (TAAR1) plays a pivotal role in the regulation of dopamine (DA) transmission and cocaine's actions. However, the underlying mechanisms through which TAAR1 activation mediates these effects have not yet been elucidated. Here, we used fast-scan cyclic voltammetry to measure DA dynamics and explore such mechanisms. We show, first, that the full TAAR1 agonist, RO5256390, dose-dependently blocked cocaine-induced inhibition of DA clearance in slices of the nucleus accumbens. Second, subthreshold inhibition of PKA or PKC phosphorylation did not prevent TAAR1 suppression of cocaine effects whereas subeffective doses of the DA D2 receptor antagonist, L-741,626, rescued cocaine's ability to produce changes in DA uptake in the presence of full TAAR1 activation, thus indicating that TAAR1 modulation of cocaine effects requires simultaneous DA D2 receptor activation. Predictably, inhibition of glycogen synthase kinase-3 (GSK-3), which results from activation of D2/TAAR1 heterodimers, fully reproduced the inhibitory effects of TAAR1 activation on cocaine-induced changes in DA transmission. Collectively, the present observations reveal that the ability of TAAR1 to regulate cocaine effects is linked to cooperative interactions with D2 autoreceptors and associated downstream molecular targets converging on GSK-3 and suggest a new mechanism to disrupt cocaine neurochemical actions.

Relapse to cocaine seeking in an invertebrate.

Addiction is characterised by cycles of compulsive drug taking, periods of abstinence and episodes of relapse. The extinction/reinstatement paradigm has been extensively used in rodents to model human relapse and explore underlying mechanisms and therapeutics. However, relapse to drug seeking behaviour has not been previously demonstrated in invertebrates. Here, we used a cocaine conditioned place preference (CPP) paradigm in the flatworm, planarian, followed by extinction and reinstatement of drug seeking. Once baseline preference was established for one of two distinctly textured environments (i.e. compartments with a coarse or smooth surface), planarian received pairings of cocaine (5µM) in the non-preferred, and vehicle in the most preferred, environment, and were tested for conditioning thereafter. Cocaine produced robust CPP, measured as a significant increase in the time spent in the cocaine-paired compartment. Subsequently, planarian underwent extinction training, reverting back to their original preference within three sessions. Brief exposure to cocaine (5µM) or methamphetamine (5µM) reinstated cocaine-seeking behaviour. By contrast, the high affinity dopamine transporter inhibitor, (N-(n-butyl)-3α-[bis (4-fluorophenyl) methoxy]-tropane) (JHW007), which in rodents exhibits a neurochemical and behavioural profile distinct from cocaine, was ineffective. The present findings demonstrate for the first time reinstatement of extinguished cocaine seeking in an invertebrate model and suggest that the long-term adaptations underlying drug conditioning and relapse are highly conserved through evolution.