Role of CB2 cannabinoid receptor in the development of food addiction in male mice.

The endocannabinoid system plays an important role in multiple behavioral responses due to its wide distribution in the central nervous system. The cannabinoid CB1 receptor was associated to the loss of behavioral control over food intake occurring during food addiction. The cannabinoid CB2 receptor (CB2R) is expressed in brain areas canonically associated with addictive-like behavior and was linked to drug-addictive properties. In this study, we evaluated for the first time the specific role of the CB2R in food addiction by using a well-validated operant mouse model of long-term training to obtain highly palatable food. We have compared in this model the behavioral responses of wild-type mice, mutant mice constitutively lacking CB2R, and transgenic mice overexpressing CB2R. The lack of CB2R constitutes a protective factor for the development of food addiction and the impulsive and depressive-like behavior associated. In contrast, the overexpression of CB2R induces a vulnerable phenotype toward food addiction after long-term exposure to highly palatable chocolate pellets. Relevant transcriptomic changes were associated to resilience and vulnerability to food addiction depending on the genotype, which provides a mechanistic explanation for these behavioral changes. Therefore, CB2R may constitute a potential therapeutic target for the loss of eating control and the comorbid emotional effects associated to food addiction.

Vulnerability to addiction.

Addiction is a chronic brain disease that has dramatic health and socioeconomic consequences worldwide. Multiple approaches have been used for decades to clarify the neurobiological basis of this disease and to identify novel potential treatments. This review summarizes the main brain networks involved in the vulnerability to addiction and specific innovative technological approaches to investigate these neural circuits. First, the evolution of the definition of addiction across the Diagnostic and Statistical Manual of Mental Disorders (DSM) is revised. We next discuss several innovative experimental techniques that, combined with behavioral approaches, have allowed recent critical advances in understanding the neural circuits involved in addiction, including DREADDs, calcium imaging, and electrophysiology. All these techniques have been used to investigate specific neural circuits involved in vulnerability to addiction and have been extremely useful to clarify the neurobiological basis of each specific component of the addictive process. These novel tools targeting specific brain regions are of great interest to further understand the different aspects of this complex disease. This article is part of the special issue on 'Vulnerabilities to Substance Abuse.'.

100% peer review in radiation oncology: is it feasible?

PURPOSE: Peer review has been proposed as a strategy to ensure patient safety and plan quality in radiation oncology. Despite its potential benefits, barriers commonly exist to its optimal implementation in daily clinical routine. Our purpose is to analyze peer-review process at our institution. METHODS AND MATERIALS: Based on our group peer-review process, we quantified the rate of plan changes, time and resources needed for this process. Prospectively, data on cases presented at our institutional peer-review conference attended by physicians, resident physicians and physicists were collected. Items such as time to present per case, type of patient (adult or pediatric), treatment intent, dose, aimed technique, disease location and receipt of previous radiation were gathered. Cases were then analyzed to determine the rate of major change, minor change and plan rejection after presentation as well as the median time per session. RESULTS: Over a period of 4 weeks, 148 cases were reviewed. Median of attendants was six physicians, three in-training-physicians and one physicist. Median time per session was 38 (4-72) minutes. 59.5% of cases presented in 1-4 min, 32.4% in 5-9 min and 8.1% in ≥ 10 min. 79.1% of cases were accepted without changes, 11.5% with minor changes, 6% with major changes and 3.4% were rejected with indication of new presentation. Most frequent reason of change was contouring corrections (53.8%) followed by dose or fractionation (26.9%). CONCLUSION: Everyday group consensus peer review is an efficient manner to recollect clinical and technical data of cases presented to ensure quality radiation care before initiation of treatment as well as ensuring department quality in a feedback team environment. This model is feasible within the normal operation of every radiation oncology Department.

Manejo de la membrana neovascular coroidea secundaria a toxoplasmosis ocular / Management of the neovascular choroidal membrane secondary to ocular toxoplasmosis

Paciente de 12 años diagnosticado de toxoplasmosis congénita sin tratamiento sistémico en el momento actual que acude por disminución de la agudeza visual (AV) en su ojo izquierdo (OI). A la exploración se objetiva una AV en su OI de 0,05 y al examen funduscópico un foco de coriorretinitis adyacente a una cicatriz macular pigmentada y una gran hemorragia subretiniana asociada. Tras confirmar el diagnóstico de membrana neovascular coroidea (MNVC) secundaria a toxoplasmosis ocular, se inicia tratamiento con fármacos anti-toxoplásmicos sistémicos y 2 dosis de anti-VEGF intravítreos separadas por un mes de diferencia. Finalmente, alcanza una AV en el OI de 0,4, y se logra una reabsorción de la hemorragia quedando una cicatriz pigmentada macular inactiva. El uso de anti-VEGF intravítreos en cuadros de toxoplasmosis ocular se han asociado a la reactivación de antiguas lesiones, por lo que se recomienda el uso profiláctico de fármacos anti-toxoplásmicos orales en estos casos

A 12-year-old patient diagnosed with congenital toxoplasmosis, with no systemic treatment at the time, who presented with a decreased visual acuity (VA) in his left eye (LE). On examination, VA in the LE was 0.05 and the fundus examination revealed a focus of chorioretinitis adjacent to a pigmented macular scar, as well as a large associated subretinal haemorrhage. After confirming the diagnosis of choroidal neovascular membrane secondary to ocular toxoplasmosis, treatment was started with systemic anti-toxoplasmosis drugs and two anti-VEGF intravitreal injections separated by one month. Finally, the patients had a VA in LE of 0.4, with reabsorption of the haemorrhage, leaving an inactive pigmented macular scar. The use of anti-VEGF intravitreal injections in cases of ocular toxoplasmosis has been associated with a reactivation of old lesions, so the prophylactic use of oral anti-toxoplasmosis drugs is recommended in these cases

Management of the neovascular choroidal membrane secondary to ocular toxoplasmosis. / Manejo de la membrana neovascular coroidea secundaria a toxoplasmosis ocular.

A 12-year-old patient diagnosed with congenital toxoplasmosis, with no systemic treatment at the time, who presented with a decreased visual acuity (VA) in his left eye (LE). On examination, VA in the LE was 0.05 and the fundus examination revealed a focus of chorioretinitis adjacent to a pigmented macular scar, as well as a large associated subretinal haemorrhage. After confirming the diagnosis of choroidal neovascular membrane secondary to ocular toxoplasmosis, treatment was started with systemic anti-toxoplasmosis drugs and two anti-VEGF intravitreal injections separated by one month. Finally, the patients had a VA in LE of 0.4, with reabsorption of the haemorrhage, leaving an inactive pigmented macular scar. The use of anti-VEGF intravitreal injections in cases of ocular toxoplasmosis has been associated with a reactivation of old lesions, so the prophylactic use of oral anti-toxoplasmosis drugs is recommended in these cases.

Evolución de la incidencia del cáncer de piel y labio durante el periodo 1978-2007 / Changes in the Incidence of Skin and Lip Cancer Between 1978 and 2007

Introducción: El objetivo del estudio es analizar la tendencia temporal en la incidencia del cáncer de piel a nivel mundial, europeo y español durante el período comprendido entre 1978-2007. Material y métodos: Se estudiaron la incidencia y la tendencia del cáncer de piel en el período 1978-2007 a través de la publicación Cancer Incidence in Five Continents usando las tasas estandarizadas por edad y sexo por 100.000 habitantes. Resultados: La incidencia del melanoma cutáneo ha aumentado desde 1978 a 2002, pero en el último periodo 2003-2007 disminuye a nivel mundial. Las incidencias máximas se registraron en Australia y en la población de raza blanca de Hawaii. En España la incidencia de melanoma se triplicó en ambos sexos al final del período. La incidencia del cáncer cutáneo no melanoma aumentó durante el período de estudio (1978-2007), con tasas más elevadas en varones. Las incidencias máximas se registraron en Australia, Brasil y en la población europea de Zimbabue. En España la incidencia de cáncer cutáneo no melanoma llegó a duplicarse o triplicarse en ambos sexos al final del período. Limitaciones: No se ha podido analizar el período más actual 2008-2012 debido a un retraso de 5 años en la publicación de los datos por parte del IARC. Conclusiones: El aumento de la incidencia del cáncer de piel ajustando por los cambios en el envejecimiento de la población sugiere que las medidas de prevención primaria son insuficientes o inadecuadas. La disminución de la incidencia de melanoma en Australia en el último período apoya la eficacia de medidas de prevención iniciadas hace varias décadas (AU)

Introduction: The aim of this study was to analyze trends in the incidence of skin cancer worldwide, in Europe, and in Spain between 1978 and 2007. Material and methods: Skin cancer incidence and trends for the period 1978 to 2007 were investigated using the age- and sex-standardized rates (per 100,000 population) published in the Cancer Incidence in Five Continents series. Results: The incidence of cutaneous melanoma increased progressively from 1978 to 2002 but decreased in the last period analyzed (2003-2007). The highest rates were reported for Australia and the white population in Hawaii. In Spain, the incidence of melanoma tripled in both sexes over the study period. The incidence of nonmelanoma skin cancer also increased between 1978 and 2007, and higher rates were detected in men. The highest incidence rates were recorded in Australia, Brazil, and among the European inhabitants of Zimbabwe. In Spain, the incidence of nonmelanoma skin cancer had doubled or tripled in both sexes by the end of the study period. Limitations: We were unable to analyze data for the period 2008 to 2012 due to a 5-year delay in the publication of data by the International Agency for Research on Cancer. Conclusions: The rise in the incidence of skin cancer, assessed using age-standardized rates, suggests that primary prevention measures are insufficient or inappropriate. The reduction in the incidence of cutaneous melanoma in Australia between 2003 and 2007 suggests that the preventive strategies initiated several decades earlier in that country have been effective (AU)

Changes in the Incidence of Skin and Lip Cancer Between 1978 and 2007. / Evolución de la incidencia del cáncer de piel y labio durante el periodo 1978-2007.

INTRODUCTION: The aim of this study was to analyze trends in the incidence of skin cancer worldwide, in Europe, and in Spain between 1978 and 2007. MATERIAL AND METHODS: Skin cancer incidence and trends for the period 1978 to 2007 were investigated using the age- and sex-standardized rates (per 100,000 population) published in the Cancer Incidence in Five Continents series. RESULTS: The incidence of cutaneous melanoma increased progressively from 1978 to 2002 but decreased in the last period analyzed (2003-2007). The highest rates were reported for Australia and the white population in Hawaii. In Spain, the incidence of melanoma tripled in both sexes over the study period. The incidence of nonmelanoma skin cancer also increased between 1978 and 2007, and higher rates were detected in men. The highest incidence rates were recorded in Australia, Brazil, and among the European inhabitants of Zimbabwe. In Spain, the incidence of nonmelanoma skin cancer had doubled or tripled in both sexes by the end of the study period. LIMITATIONS: We were unable to analyze data for the period 2008 to 2012 due to a 5-year delay in the publication of data by the International Agency for Research on Cancer. CONCLUSIONS: The rise in the incidence of skin cancer, assessed using age-standardized rates, suggests that primary prevention measures are insufficient or inappropriate. The reduction in the incidence of cutaneous melanoma in Australia between 2003 and 2007 suggests that the preventive strategies initiated several decades earlier in that country have been effective.

Coriorretinitis placoide sifilítica. Caso clínico / Syphilitic placoid chorioretinitis. A case-report

CASO CLÍNICO: Presentamos el caso de una mujer de 45 años sin antecedentes de interés y con una pérdida súbita de visión en su ojo izquierdo secundaria a una uveítis posterior bilateral. Tras despistaje, se diagnosticó de coriorretinitis placoide posterior aguda sifilítica, y recibió tratamiento con penicilina intravenosa. Discusión: Existen múltiples manifestaciones oculares de la sífilis que pueden simular cuadros y etiologías muy diversas. El tratamiento anti-treponémico normalmente produce una rápida y positiva respuesta en pacientes afectos. El diagnóstico precoz y certero de estos pacientes es por tanto crucial aunque, en ocasiones, los daños anatómicos y funcionales son irreversibles

CLINICAL CASE: We report the case of a 45-year-old woman, with unremarkable past medical history, who presented with acute visual loss in her left eye due to bilateral posterior uveitis. After the screening, she was diagnosed with acute syphilitic placoid chorioretinitis and was treated with intravenous penicillin. DISCUSSION: Clinical manifestations of ocular syphilis are extremely heterogeneous and may mimic several aetiologies. Anti-treponema treatment usually induces a quick and positive response in affected patients. Prompt and proper diagnosis of these patients is crucial, although anatomical and functional damage may persist

Syphilitic placoid chorioretinitis. A case-report. / Coriorretinitis placoide sifilítica. Caso clínico.

CLINICAL CASE: We report the case of a 45-year-old woman, with unremarkable past medical history, who presented with acute visual loss in her left eye due to bilateral posterior uveitis. After the screening, she was diagnosed with acute syphilitic placoid chorioretinitis and was treated with intravenous penicillin. DISCUSSION: Clinical manifestations of ocular syphilis are extremely heterogeneous and may mimic several aetiologies. Anti-treponema treatment usually induces a quick and positive response in affected patients. Prompt and proper diagnosis of these patients is crucial, although anatomical and functional damage may persist.

The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.

Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.

A post-training intrahippocampal anxiogenic dose of the neurosteroid pregnenolone sulfate impairs passive avoidance retention.

Pregnenolone sulfate (PregS) is a neurosteroid that acts as a negative modulator of the GABA(A) receptor complex and a positive modulator of glutamate NMDA receptors. PregS improves learning and memory when centrally or systemically administered. However, systemic high doses of PregS, which facilitate the passive avoidance retention, have been shown to impair this learning when a high foot-shock punishment was used. Moreover, moderate or high PregS doses present a well documented anxiogenic-like profile in several animal models of anxiety. In previous experiments, we have shown that unilateral intrahippocampal 5 ng of PregS improves spatial recognition memory and reverses learning impairment induced by co-administration of alcohol and nicotine. In the present experiment, we analyzed the effects of bilateral intrahippocampal 5 ng of PregS on the passive avoidance task, using a high foot-shock punishment (0.5 mA), as well as on anxiety-like behaviour measured in the open field test in the same experimental subjects. As a control, we have injected the neurosteroid allopregnanolone (AlloP) into the hippocampus, which produces opposite behavioural and neurochemical profiles to those of PregS, by acting as a positive GABA(A) modulator and showing anxiolytic and sedative behavioural effects. Results showed that bilateral intrahippocampal 5 ng of PregS deteriorated passive avoidance retention but also presented an anxiogenic-like profile in the open field test, decreasing the locomotion and the time spent in the central zone without affecting either total activity or time spent in the periphery of the field (thigmotaxis). AlloP administration did not affect passive avoidance retention, and also showed a non anxiolytic-like profile, possibly related to fluctuations of endogenous AlloP concentrations induced by the stress generated by the high foot-shock punishment received before the anxiety tests. In conclusion, a post-training intrahippocampal anxiogenic dose of the neurosteroid PregS impairs passive avoidance retention. These results highlight the important role of the hippocampus in several behavioural effects of neurosteroids on learning, memory processes and anxiety.

Neonatal finasteride induces anxiogenic-like profile and deteriorates passive avoidance in adulthood after intrahippocampal neurosteroid administration.

Recent findings indicate that neurosteroids could act as important keys during the brain development. Fluctuations in neonatal allopregnanolone (AlloP) could result in altered pharmacological properties of the GABA(A) receptor system in adulthood. Recent studies demonstrated that neurosteroids play a critical role in regulating normal neurodevelopment in the hippocampus. The aim of the present work is to screen whether developmentally altered neurosteroid levels influence the behavioral response to adult intrahippocampal administration of AlloP, a GABA(A) positive modulating neurosteroid, and pregnenolone sulfate (PregS), a GABA(A) negative modulator in rats. For this purpose, pups received AlloP (10 mg/kg, s.c.), a 5alpha-reductase inhibitor (finasteride, 50 mg/kg, s.c.) or vehicle from the fifth to the ninth postnatal day. At maturity (i.e. 90 days old) a bilateral cannula was implanted into the hippocampus. After recovery from surgery, animals received an administration of AlloP (0.2 microg/0.5 microl), PregS (5 ng/0.5 microl) or vehicle in each hippocampus 5 min before they were tested in the elevated plus maze (EPM) and immediately after the passive avoidance training session, and retention was tested 24 h later. Results indicated that neonatal finasteride treatment deteriorated passive avoidance retention and elicited an anxiogenic-like effect in the EPM test in adulthood, as seen by the reduction of open arm entries and in the time spent in the open arms. Intrahippocampal PregS administration also disrupted passive avoidance, possibly related to its anxiogenic profile. Fluctuations in neonatal AlloP affect the aversive learning and the anxiety-related behavior in adulthood, and this effect could be in part mediated by alterations of the mature functions of the hippocampus, possibly via the GABA(A) receptor. These data point to the role of GABAergic neurosteroids in critical periods of vulnerability that influence normal development of GABAergic pathways in the CNS.

[Involvement of neurosteroids in normal and pathological behaviour]. / Implicación de los neuroesteroides en la conducta normal y patológica.

INTRODUCTION: The nervous system synthesises steroids (then called neurosteroids) de novo from cholesterol. These substances play a role in a number of functions related to the allosteric modulation of the main ionotropic receptors in the central nervous system (CNS). AIM: To describe the most important behavioural and cognitive processes in which neurosteroids are involved and which can open up new perspectives for research focused above all on their possible therapeutic use in pathologies affecting the CNS, such as the cognitive impairment associated to neurodegenerative diseases, addictions like alcoholism, anxiety disorders, and epilepsy and convulsive behaviour. DEVELOPMENT: We provide a brief outline of the concept of neurosteroids, their synthesis, how they act on receptors for neurotransmitters and their distribution throughout nerve tissue. We then offer an extensive, up-to-date, critical review of the main psychological processes that they are involved in. CONCLUSIONS: Neurosteroids offer an important therapeutic potential. In epileptiform behaviour, no tolerance is developed to the anticonvulsive effects of these substances with repeated administration, unlike the case of benzodiazepines, although the study of synthetic analogues and agents that step up the synthesis of neurosteroids in the CNS seems to be decisive owing to the limitation imposed by the long-term systemic use of hormones. In anxiety disorders, they offer several advantages that are comparable to the prototypical anxiolytic agents, that is, benzodiazepines, but also their chief side effects, such as sedation. In cognitive impairment, the enormous potential for cognitive enhancement in animal models is not reproduced in humans with dementia, although controlled clinical trials are needed to evaluate the benefits and risks of replacement therapy with steroids.

Implicación de los neuroesteroides en la conducta normal y patológica / Involvement of neurosteroids in normal and pathological behaviour

Introducción. El sistema nervioso sintetiza esteroides (denominados entonces neuroesteroides) de novo a partir del colesterol. Estas sustancias participan en numerosas funciones relacionadas con la modulación alostérica de los principales receptores ionotrópicos del sistema nervioso central (SNC). Objetivo. Describir los procesos conductuales y cognitivos más importantes en los que participan los neuroesteroides, y que pueden abrir nuevas perspectivas de investigación enfocadas sobre todo a su posible uso terapéutico en patologías del SNC como el deterioro cognitivo asociado a enfermedades neurodegenerativas, a adicciones como el alcoholismo, a los trastornos de ansiedad y a la epilepsia y la conducta convulsiva. Desarrollo. Se describe sucintamente el concepto de neuroesteroide, su síntesis, sus acciones sobre los receptores para neurotransmisores y su distribución por el tejido nervioso. Posteriormente se revisan de una manera extensa, actualizada, y crítica los principales procesos psicológicos en los que están implicados. Conclusiones. Los neuroesteroides presentan un importante potencial terapéutico. En la conducta epileptiforme, los efectos anticonvulsionantes de estas sustancias no se hacen tolerantes con su administración repetida, como ocurre en el caso de las benzodiacepinas, aunque el estudio de análogos sintéticos y de agentes que aumentan la síntesis de neuroesteroides en el SNC parece determinante debido a la limitación que plantea la utilización sistémica de hormonas a largo plazo. En los trastornos de ansiedad presentan ventajas comparables a los ansiolíticos prototípicos, las benzodiacepinas, pero también sus principales efectos adversos, como la sedación. En el deterioro cognitivo, el enorme potencial facilitador cognitivo observado en modelos animales no se reproduce en humanos con demencia, aunque se precisen ensayos clínicos controlados para evaluar beneficios y riesgos de los tratamientos sustitutivos con esteroides

Introduction. The nervous system synthesises steroids (then called neurosteroids) de novo from cholesterol. These substances play a role in a number of functions related to the allosteric modulation of the main ionotropic receptors in the central nervous system (CNS). Aim. To describe the most important behavioural and cognitive processes in which neurosteroids are involved and which can open up new perspectives for research focused above all on their possible therapeutic use in pathologies affecting the CNS, such as the cognitive impairment associated to neurodegenerative diseases, addictions like alcoholism, anxiety disorders, and epilepsy and convulsive behaviour. Development. We provide a brief outline of the concept of neurosteroids, their synthesis, how they act on receptors for neurotransmitters and their distribution throughout nerve tissue. We then offer an extensive, up-to-date, critical review of the main psychological processes that they are involved in. Conclusions. Neurosteroids offer an important therapeutic potential. In epileptiform behaviour, no tolerance is developed to the anticonvulsive effects of these substances with repeated administration, unlike the case of benzodiazepines, although the study of synthetic analogues and agents that step up the synthesis of neurosteroids in the CNS seems to be decisive owing to the limitation imposed by the long-term systemic use of hormones. In anxiety disorders, they offer several advantages that are comparable to the prototypical anxiolytic agents, that is, benzodiazepines, but also their chief side effects, such as sedation. In cognitive impairment, the enormous potential for cognitive enhancement in animal models is not reproduced in humans with dementia, although controlled clinical trials are needed to evaluate the benefits and risks of replacement therapy with steroids

The neurosteroid pregnenolone sulfate neutralized the learning impairment induced by intrahippocampal nicotine in alcohol-drinking rats.

The effects of intrahippocampal administration of nicotine and the neurosteroids pregnenolone sulfate and allopregnanolone on acquiring the lever-press response and extinction in a Skinner box were examined using voluntary alcohol-drinking rats. A free-choice drinking procedure that implies early availability of the alcoholic solution (10% ethanol v/v+3% glucose w/v in distilled water) was used. Alcohol and control rats were deprived of food and assigned at random to six groups. Each group received two consecutive intrahippocampal (dorsal CA1) injections immediately after 1-h of drinking ethanol and before the free lever-press response shaping and extinction session. The groups were: saline-saline; saline-pregnenolone sulfate (5 ng, 24 microM); saline-allopregnanolone (0.2 microg, 1.26 microM); nicotine (4.6 microg, 20 mM)-saline; nicotine-pregnenolone sulfate; nicotine-allopregnanolone. Blood alcohol concentrations were assessed the day before conditioning. The combination of the oral self-administration of ethanol and the intrahippocampal injection of nicotine deteriorated the ability to acquire the lever-press response. This effect was neutralized by intrahippocampal pregnenolone sulfate (negative modulator of the GABA(A) receptor complex), and it was not affected by intrahippocampal allopregnanolone (positive GABA receptor complex A modulator). Pregnenolone sulfate and allopregnanolone had no effects per se on lever-press acquisition, neither in alcohol-drinking rats nor in controls. Alcohol consumption facilitated operant extinction just as anxiolytics that act as positive modulators of the GABA receptor complex A receptors do, possibly reducing the anxiety or aversion related to non-reinforcement. This effect was increased by intrahippocampal nicotine.