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Vulnerability to develop cocaine use disorder depends upon an unpredictable combination of genetic and non-genetic risk factors. Early life adversity and adolescence are critical non-genetic risk factors, and haplotypes of the monoamine oxidase (MAO) genes are among genetic variations increasing the risk of drug-related problems. However, data on the interactions between inheritable risk factors and early life stress (ES) with respect to predisposition to cocaine abuse are limited. Here, we show that a mouse model containing both genetic (low-activity alleles of the MAO A gene; MAOANeo) and environmental (i.e., ES) variables displays a long lasting increased sensitivity to repeated in vivo cocaine psychomotor stimulant actions associated with a reduction of GABAA receptor-mediated inhibition of dopamine neurons of the ventral tegmental area (VTA). Depolarization-induced suppression of inhibition (DSI), a 2-arachidonoylglycerol (2-AG)-dependent form of short-term plasticity, also becomes readily expressed by dopamine neurons from MAOANeoES mice treated repeatedly with cocaine. Activation of either dopamine D2 or CB1 receptors is required for cocaine-induced DSI expression, decreased GABA synaptic efficacy, and hyperlocomotion. Next, in vivo pharmacological enhancement of 2-AG signaling during repeated cocaine exposure occludes its actions both in vivo and ex vivo. This data extends our knowledge of the multifaceted sequelae imposed by this gene by environment interaction in VTA dopamine neurons of male pre-adolescent mice, contributing to our understanding of neural mechanisms of vulnerability for early onset cocaine use disorder.

Due to their polyphenolic content, vegetable foods have neuroprotective effects which provide health benefits for specific human groups. Thus, they may be a useful dietary component for women who experience mnesic variations during postpartum, and here we examined the hypothesis that polyphenols can differentially enhance memory functioning. In particular, we aimed to associate the dietary intake of polyphenols with different memory systems in Argentinian postpartum women. The daily intakes of polyphenol groups were calculated using a validated food frequency questionnaire and the Phenol-Explorer database. Short-term memory (STM), long-term memory (LTM), learning (L), lexical-semantic memory (LSM), and working memory (WM) were assessed. Partial Least Squares (PLS) regression models were used to analyze the dietary polyphenols (predictors) and memory domains (responses), taking into account demographic, obstetric, and psychological factors. The sample included 71 women, with an average age of 29.59 years (SE = 0.73). Most of these women lived in a couple (91%), were unemployed (63%), and had ≥12 years of formal education (72%). STM, LTM, L, and LSM correlated with lignans and anthocyanins, with LTM also being correlated with flavanones, flavonols, and tyrosols, and L and LSM also being associated with flavonols. A significant correlation was also found between WM and lignans. In conclusion, a cognitive improvement was demonstrated, mainly associated with the intake of lignans and anthocyanins, in the STM, LTM, WM, L, and LSM systems of postpartum women. This is the first study to our knowledge suggesting a role of polyphenolic effects on memory functioning during postpartum.

In oncology, adherence to oral antineoplastic medication is a key element of treatment, on which the success of any therapeutic intervention depends. Given their widespread use in clinical practice, it is important to identify tools that can facilitate the monitoring and self-management of the patient at home, to avoid the consequences of employing ineffective treatment. One of the tools available today to take action on this phenomenon is mobile health technology. The aim of this review is to describe published studies relating to the use of mobile health to promote adherence to oral antineoplastic medication. This scoping review was conducted using the framework proposed by Arksey and O'Malley, adapted according to Levac et al. Of 1320 articles identified, only seven met the eligibility criteria and therefore were included in the review. All seven articles involved the use of digital means to measure adherence to treatment, patient satisfaction, acceptability and feasibility of the digital means used, and presence of symptoms, but not the effectiveness of the digital instrument used. In conclusion, the use of digital means to assist adherence of cancer patients to oral antineoplastic medication is widely recognized, but its effectiveness in clinical practice is poorly supported by the nature of the published studies.

Stress has a negative impact on cognitive functioning and occupational well-being. The aim of this study was to assess the relationship among perceived stress, cognitive complaints and work engagement in public employees from Córdoba, Argentina. In this cross-sectional study, self-report questionnaires were administered to 240 participants. Spanish versions of the following instruments were used: Perceived Stress Scale (PSS), Utrecht Work Engagement Scale (UWES), Memory Failures in Everyday (MFE), Executive Complaint Questionnaire (ECQ). Statistical analysis included ANOVA, path analysis, and multiple logistic regression. Stressed workers showed lower work engagement and more cognitive complaints, even after adjusting for demographic variables. Negative associations were also observed between work engagement and cognitive complaints, suggesting that cognitive difficulties are related to engagement. Given the relation among stress, cognition, and work engagement, it is important to consider these factors to foster workers’ health and work productivity.

The increased legal availability of cannabis has led to a common misconception that it is a safe natural remedy for, among others, pregnancy-related ailments such as morning sickness. Emerging clinical evidence, however, indicates that prenatal cannabis exposure (PCE) predisposes offspring to various neuropsychiatric disorders linked to aberrant dopaminergic function. Yet, our knowledge of how cannabis exposure affects the maturation of this neuromodulatory system remains limited. Here, we show that male, but not female, offspring of Δ9-tetrahydrocannabinol (THC)-exposed dams, a rat PCE model, exhibit extensive molecular and synaptic changes in dopaminergic neurons of the ventral tegmental area, including altered excitatory-to-inhibitory balance and switched polarity of long-term synaptic plasticity. The resulting hyperdopaminergic state leads to increased behavioral sensitivity to acute THC exposure during pre-adolescence. The neurosteroid pregnenolone, a US Food and Drug Administration (FDA) approved drug, rescues synaptic defects and normalizes dopaminergic activity and behavior in PCE offspring, thus suggesting a therapeutic approach for offspring exposed to cannabis during pregnancy.

Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes towards it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase of dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related-behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure.HighlightsPCE female offspring do not manifest a disease-relevant phenotypePrenatal THC does not affect female dopaminergic neuronsPCE female mesolimbic dopamine function is less responsive to acute THC

Allosteric modulators of G protein coupled receptors (GPCRs), including GABABRs (GABABRs), are promising therapeutic candidates. While several positive allosteric modulators (PAM) of GABABRs have been characterized, only recently the first negative allosteric modulator (NAM) has been described. In the present study, we report the characterization of COR758, which acts as GABABR NAM in rat cortical membranes and CHO cells stably expressing GABABRs (CHO-GABAB). COR758 failed to displace the antagonist [3H]CGP54626 from the orthosteric binding site of GABABRs showing that it acts through an allosteric binding site. Docking studies revealed a possible new allosteric binding site for COR758 in the intrahelical pocket of the GABAB1 monomer. COR758 inhibited basal and GABABR-stimulated O-(3-[35Sthio)-triphosphate ([35S]GTPγS) binding in brain membranes and blocked the enhancement of GABABR-stimulated [35S]GTPγS binding by the PAM GS39783. Bioluminescent resonance energy transfer (BRET) measurements in CHO-GABAB cells showed that COR758 inhibited G protein activation by GABA and altered GABABR subunit rearrangements. Additionally, the compound altered GABABR-mediated signaling such as baclofen-induced inhibition of cAMP production in transfected HEK293 cells, agonist-induced Ca2+ mobilization as well as baclofen and the ago-PAM CGP7930 induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in CHO-GABAB cells. COR758 also prevented baclofen-induced outward currents recorded from rat dopamine neurons, substantiating its property as a NAM for GABABRs. Altogether, these data indicate that COR758 inhibits G protein signaling by GABABRs, likely by interacting with an allosteric binding-site. Therefore, COR758 might serve as a scaffold to develop additional NAMs for therapeutic intervention.

Allosteric modulators of G protein coupled receptors (GPCRs), including GABA

Las modificaciones neurobiológicas que experimenta la mujer durante el puerperio, junto con los consecuentes cambios psicosociales, determinan variaciones en el funcionamiento cognitivo. Con el objetivo de describir las variaciones cognitivas que ocurren durante el postparto y sus factores determinantes, se desarrolló una revisión narrativa a partir de la búsqueda bibliográfica en PubMed y Google Scholar. Se evidenció un constante crecimiento del número de publicaciones a lo largo de los años (PubMed= 186; Google Scholar= 26730). El análisis de los artículos permitió: a) Caracterizar las funciones cognitivas durante el puerperio; b) Analizar los efectos neuropsicológicos producidos por los cambios endocrinológicos y anatomofisiológicos; c) Analizar el efecto de la calidad del sueño sobre la cognición; d) Analizar las funciones cognitivas en función de las experiencias obstétricas. En conclusión, la mujer puérpera se caracteriza por presentar variaciones en sus funciones cognitivas, las cuales están determinadas por cambios estructurales, funcionales, psicológicos y sociales. Es necesario fomentar investigaciones neuropsicológicas en esta población, ya que la atención del posparto todavía se centra en el cuidado del recién nacido, sin abordar a la mujer puérpera de manera integral. The neurobiological modifications that women experience during the puerperium, together with the consequent psychosocial changes, lead to variations in cognitive functions. In order to describe the cognitive variations that occur during postpartum and the determining factors, a narrative review was conducted by means of a bibliographic search in PubMed and Google Scholar. A steady increase in the number of published works was located (PubMed = 186; Google Scholar = 26,730). The analysis of the articles made it possible to: a) characterize the cognitive functions during the puerperium; b) analyze the neuropsychological effects produced by the endocrinological and anatomophysiological changes; c) analyze the effect of the quality of sleep on cognition; d) analyze cognitive functions according to obstetric experiences. In conclusion, puerperal women are characterized by variations in their cognitive functions, which are determined by structural, functional, psychological and social changes. It is necessary to conduct neuropsychological research in this population, since postpartum care still focuses on the care of the newborn, without addressing the puerperal woman in a comprehensive manner. Fil: Carrizo, Eugenia. Universidad Nacional de Córdoba. Facultad de Medicina; Argentina Fil: Domini, Julia. Universidad Nacional de Córdoba. Facultad de Medicina; Argentina Fil: Quezada, Ruth Yohana Julieta. Universidad Nacional de Córdoba. Facultad de Medicina; Argentina Fil: Serra, Silvana Valeria. Universidad Nacional de Córdoba. Facultad de Medicina; Argentina Fil: Soria, Elio Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina Fil: Miranda, Agustín Ramiro. Universidad Nacional de Córdoba; Argentina

[b]Background: [/b]A comprehensive assessment of central auditory processing disorders includes parent questionnaires. The Scale of Auditory Behaviors (SAB) was developed to evaluate the limitations and difficulties perceived by guardians of children in everyday activities. The aim of the study was to provide normative data for the SAB for Argentinian healthy children. [b]Material/ Methods:[/b] The parents and guardians of eighty-four children aged 4 and 5 years old, representative of the Argentinian population, completed a sociodemographic questionnaire and the SAB. Normative data were expressed as Mean ± Standard Deviation. Internal consistency was calculated using Cronbach’s alphas. [b]Results:[/b] The norms for Argentinian children are: 48.60±7.57. Values

Cannabis is the illicit drug most widely used by pregnant women worldwide. Its growing acceptance and legalization have markedly increased the risks of child psychopathology, including psychotic-like experiences, which lowers the age of onset for a first psychotic episode. As the majority of patients with schizophrenia go through a premorbid condition long before this occurs, understanding neurobiological underpinnings of the prodromal stage of the disease is critical to improving illness trajectories and therapeutic outcomes. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of prenatal cannabinoid exposure (PCE), exhibit extensive molecular and synaptic changes in dopaminergic neurons of the ventral tegmental area (VTA), converging on a hyperdopaminergic state. This leads to a silent psychotic-like endophenotype that is unmasked by a single exposure to THC. Here, we further characterized the VTA dopamine neuron and sensorimotor gating functions of PCE rats exposed to acute stress or a challenge of the D2 receptor agonist apomorphine, by using in vivo single-unit extracellular recordings and Prepulse Inhibition (PPI) analyses. At pre-puberty, PCE male rat offspring display a reduced population activity of VTA dopamine neurons in vivo, the majority of which are tonically active. PCE male progeny also exhibit enhanced sensitivity to dopamine D2 (DAD2) receptor activation and a vulnerability to acute stress, which is associated with compromised sensorimotor gating functions. This data extends our knowledge of the multifaceted sequelae imposed by PCE in the mesolimbic dopamine system of male pre-adolescent rats, which renders a neural substrate highly susceptible to subsequent challenges that may trigger psychotic-like outcomes.

Aggressive behavior (AB) is a multifaceted disorder based on the interaction between genetic and environmental factors whose underlying mechanisms remain elusive. The best-characterized gene by environment (GxE) interaction for AB is the relationship between child neglect/abuse and low-activity alleles of the monoamine-oxidase A (MAOA) gene. MAOA oxidizes monoamines like serotonin and dopamine, whose aberrant signaling at discrete developmental ages plays a pivotal role in the ontogeny of AB. Here, we investigated the impact of this GxE on dopamine function at pre-adolescence by exposing hypomorphic MAOA (MAONeo) mice to early life stress (ES) and by performing behavioral and ex vivo electrophysiological analyses in the ventral tegmental area (VTA) and the prefrontal cortex (PFC). MAOANeo ES mouse dopamine neurons exhibited an enhanced post-synaptic responsiveness to excitatory inputs, aberrant plasticity in the PFC, and an AB. Systemic administration of the selective antagonist at dopamine D1 receptors SCH23390 fully restored PFC function and rescued AB. Collectively, these findings reveal that dysfunctional mesocortical dopamine signaling at pre-adolescence ties to AB in the MAOANeo ES mouse, and identify dopamine D1 receptor as a molecular target to be exploited for an age-tailored therapy. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.

Introducción: El proteasoma regula la proteostasis y puede verse comprometido en enfermedades neurodegenerativas. Por lo tanto, nuestro objetivo fue correlacionar la actividad del proteasoma con el nivel de polifenoles en el telencéfalo durante la edad adulta de ratones. Métodos: Se analizaron la actividad del proteasoma, polifenoles y otras variables (glucosa e hidroperóxidos) en telencéfalos de ratones hembras Balb/c (n = 20, edad = 4-12 meses), utilizando métodos multivariados. Resultados: Se encontraron los siguientes valores: actividad proteasomal = 3,1 ± 0,6 FI/μg de proteínas tisulares, glucosa = 0,1 ± 0,0 μg/μg, hidroperóxidos = 363,4 ± 96,6 OD/μg y polifenoles = 0,1±0,0 ng/μg. Los polifenoles reducidos durante el envejecimiento mostraron una correlación directa con el proteasoma (coeficiente de Pearson = 0,43, p=0,0590 y un coeficiente de regresión lineal multivariante = 17,85, p=0,0216). Glucosa e hidroperóxidos no estuvieron implicados (p>0,1). Esta correlación fue confirmada por regresión parcial de mínimos cuadrados (beta = 0,67). Conclusión: La actividad proteasomal puede afectarse durante el envejecimiento y ser promovida por el nivel telencefálico de polifenoles. Así, estos compuestos dietéticos podrían ser beneficiosos para el cerebro adulto. µg. Polyphenols reduced during aging showed a direct correlation with proteasome (Pearson's coefficient = 0.43, p = 0.0590, and a multivariate linear regressive coefficient = 17.85, p = 0.0216), with glucose and hydroperoxides being not involved (p_0.1). This correlation was confirmed by partial least square regression (beta = 0.67).CONCLUSION_ Proteasome activity can be affected during ageing, and promoted by telencephalic polyphenol levels. Thus, these diet compounds might exert benefits in adult brain_ Fil: Miranda, Agustín Ramiro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Fonoaudiología; Argentina Fil: Cortez, Mariela Valentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Nutrición; Argentina Fil: Serra, Silvana Valeria. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Fonoaudiología; Argentina Fil: Soria, Elio Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Biología Celular; Argentina

Purpose To explore adherence to oral hormone treatment in patients with metastatic prostate cancer (mCRPC) and to identify the factors that influence it. Methods A qualitative exploratory study was conducted at the National Cancer Institute of Rome. Patients aged >18 years with castration-resistant prostate cancer (mCRPC) and who were using oral hormone drugs were recruited. Semi-structured interviews were used for data collection, subsequently transcribed verbatim and analysed using Ritchie and Spencer's framework analysis. Results The sample included 13 patients with a median age of 72 who were treated, on average, for seven months with abiraterone acetate (AA) (76.9%) and enzalutamide (ENZ) (23.1%). Five themes were identified: expression of the concept of adherence, favouring factors, obstacle factors, functional strategies and levels of adherence. Conclusions The patients express a good level of adherence, which they define in different ways—the helping relationship with the attending physician, the support of the family members and the few side effects of the drugs. For the future, it is recommended to perform a multicentre mixed method study to explain the levels of adherence and distress in women with breast cancer.

The neurobiological modifications that women experience during the puerperium, together with the consequent psychosocial changes, lead to variations in cognitive functions. In order to describe the cognitive variations that occur during postpartum and the determining factors, a narrative review was conducted by means of a bibliographic search in PubMed and Google Scholar. A steady increase in the number of published works was located (PubMed = 186; Google Scholar = 26,730). The analysis of the articles made it possible to: a) characterize the cognitive functions during the puerperium; b) analyze the neuropsychological effects produced by the endocrinological and anatomophysiological changes; c) analyze the effect of the quality of sleep on cognition; d) analyze cognitive functions according to obstetric experiences. In conclusion, puerperal women are characterized by variations in their cognitive functions, which are determined by structural, functional, psychological and social changes. It is necessary to conduct neuropsychological research in this population, since postpartum care still focuses on the care of the newborn, without addressing the puerperal woman in a comprehensive manner.Las modificaciones neurobiológicas que experimenta la mujer durante el puerperio, junto con los consecuentes cambios psicosociales, determinan variaciones en el funcionamiento cognitivo. Con el objetivo de describir las variaciones cognitivas que ocurren durante el postparto y sus factores determinantes, se desarrolló una revisión narrativa a partir de la búsqueda bibliográfica en PubMed y Google Scholar. Se evidenció un constante crecimiento del número de publicaciones a lo largo de los años (PubMed= 186; Google Scholar= 26730). El análisis de los artículos permitió: a) Caracterizar las funciones cognitivas durante el puerperio; b) Analizar los efectos neuropsicológicos producidos por los cambios endocrinológicos y anatomofisiológicos; c) Analizar el efecto de la calidad del sueño sobre la cognición; d) Analizar las funciones cognitivas en función de las experiencias obstétricas. En conclusión, la mujer puérpera se caracteriza por presentar variaciones en sus funciones cognitivas, las cuales están determinadas por cambios estructurales, funcionales, psicológicos y sociales. Es necesario fomentar investigaciones neuropsicológicas en esta población, ya que la atención del posparto todavía se centra en el cuidado del recién nacido, sin abordar a la mujer puérpera de manera integral.

Background: Assessment of language is very important to detect atypically developed children. In this sense, psycholinguistic abilities are predictors of developmental functioning. The aim of this study was to compare ages of psycholinguistic processes between atypically and typically developed children. Material/Methods: In this cross-sectional study, six-, seven- and eight-year-old children from Cordoba (Argentina) (n= 28) were evaluated with the Spanish version of Illinois Test of Psycholinguistic Abilities (S-ITPA). Statistical analysis included Student’s t-test in order to find differences between groups. Results: In the six-year-old sample, those with atypical language showed significantly lower psycholinguistic ages in: global psycholinguistic age, auditory association, and verbal expression, auditory reception, auditory sequential memory, grammatical closu re, and auditory closure, manual expression. In seven-year-old sample differences were found in grammatical closure and auditory closure. In eight-year-old group, atypical language sample showed lower psycholinguistic ages in auditory association, verbal expression and auditory sequential memory. Conclusions: This evidence establishes a limit stage corresponding to 6 years of age, which reflects the consolidation and integrity of language and the aptitudes involved. In later ages (e.g. seven and eight years), results may be biased by acquired formal learning abilities.

Neurocognitive assessment by dichotic digit test provides selective stimulation of auditory pathway with contralateral suppression of the ipsilateral showing interhemispheric differences in concurrent tasks. In order to recognize the pattern of responses, recovery order of digits and latencies heard the original test was modified with the addition of a record of an audio track of the responses. The sample includes subjects with a history in hearing specialization linked to the music and listen to comprehensive second language, normoacoustic without otologic diseases or neurological. Sets 20 pairs of dichotic digits with a digital recording for recording the subject's responses was used. The results reveal: right ear advantage in the pattern of correct answers and the order in which the information provided is retrieved. As for the pattern of intrasets latencies an increase to the fourth repeated / digit recovered and more blunder is observed. Declining intratest latencies in the second part of the test suggest positive training. These modifications allow new prospects and existing applications with behavioral tests.

La evaluación audiocognitiva mediante el test de dígitos dicóticos ofrece la estimulación selectiva contralateral de vía auditiva con supresion de la ipsilateral mostrando diferencias interhemisfericas en tareas concurrentes. Con el objetivo de reconocer el patron de respuestas, orden de recuperación de los digitos escuchados y latencias se modifico el test original con el agregado de un registro de una pista de audio de las respuestas obtenidas. La muestra incluye sujetos con antecedentes en especializacion auditiva ligado a la musica y a la escucha comprensiva de segundas lenguas, normoacúsicos, sin patologías otologicas, ni neurologicas. Se utilizó 20 set de pares de digitos dicóticos con una grabacion digital para el registro de las respuestas del sujeto. Los resultado revelan: ventaja de oido derecho tanto en el patron de respuestas correctas o no y en el orden en que se recupera la información entregada. En cuanto al patron de latencias intrasets se observa un aumento hacia el cuarto digito repetido/recuperado y con mayor desacierto. La disminucion de las latencias intratest en la segunda parte del test sugieren entrenamiento positivo. Estos analisis con las modificaciones panteadas permiten nuevas perspectivas y aplicaciones a las existentes con las pruebas comportamentales. Fil: Serra, Silvana Valeria. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Fonoaudiologia; Argentina Fil: Diaz Nocera, Aden. Universidad Nacional de Córdoba; Argentina. Facultad de Ciencias Médicas. Argentina; Argentina Fil: Brizuela, Monica Liliana. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Fonoaudiologia; Argentina Fil: Baydas, Lorena. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Fonoaudiologia; Argentina Fil: Fotinos, Jerónimo. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Computación; Argentina Fil: Soria, Elio Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina. Facultad de Ciencias Médicas. Cátedra de Histología, Embriología y Genética. Córdoba; Argentina Fil: Lucini, María Bernarda. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Fonoaudiologia; Argentina Fil: Serra, Mariel Amanda Isabel. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Fonoaudiologia; Argentina

Allopregnanolone plays a role in the stress response and homeostasis. Alterations in the estrogen milieu during the perinatal period influence brain development in a manner that persists into adulthood. Accordingly, we showed that a single administration of estradiol benzoate (EB) on the day of birth decreases brain allopregnanolone concentrations in adult female rats. We examined whether the persistent decrease in allopregnanolone concentrations, induced by neonatal EB treatment, might affect sensitivity to stress during adulthood. Female rats were treated with 10 μg of EB or vehicle on the day of birth. During adulthood, the response to acute foot shock stress was assessed by measuring changes in brain allopregnanolone and corticosterone levels, as well as extracellular dopamine output in the medial prefrontal cortex (mPFC). Neonatal EB treatment enhanced stress-stimulated allopregnanolone levels in the hypothalamus, as well as extracellular dopamine output in the mPFC; this latest effect is reverted by subchronic progesterone treatment. By contrast, neonatal EB treatment did not alter stress-induced corticosterone levels, sensitivity to hypothalamic-pituitary-adrenal (HPA) axis negative feedback, or abundance of glucocorticoid and mineralocorticoid receptors. The persistent decrease in brain allopregnanolone concentrations, induced by neonatal EB treatment, enhances stress-stimulated allopregnanolone levels and extracellular dopamine output during adulthood. These effects are not associated to an impairment in HPA axis activity. Heightened sensitivity to stress is a risk factor for several neuropsychiatric disorders; these results suggest that exposure to estrogen during development may predispose individuals to such disorders.

Companies use non-native language (L2) as a service tool, and they may incur in occupational psychosocial risks. Interlanguage can be chronic under poor communicative situations, leading to fossilization. It could be an adverse effect because of its impact in productivity and occupational health. Thus, our aim was to establish factors of this psychosocial risk.348 information and communication technologists (ICT) were analyzed. They were native Spanish speakers with normal hearing, and used English as a work tool. Age, gender, L2 stages and errors were recorded in relation to fossilization risk. Statistical methods were applied for categorical data (p0.05).After gender and age adjustments, a significant inverse association was found between L2 stages and fossilization risk (p0.0001), with higher risk being in the acquisition stage. Also, L2 errors showed a significant direct relation with fossilization risk (p=0.0005).Summing up, ICT in acquisition L2 had upper psychosocial risk to fossilization with mechanistic execution of it, under poorer communicative formats. This results have high sanitary impact given they involved a massively demanded professionals.

Aims. Companies use non-native language as a service tool, and they may incur in occupational psychosocial risks. Interlanguage can be chronic under poor communicative situations, leading to fossilization. It could be an adverse effect because of its impact in productivity and occupational health. Thus, our aim was to establish factors of this psychosocial risk.Methods. 348 information and communication technologists (ICT) were analyzed. They were native Spanish speakers with normal hearing, and used English as a work tool. Age, gender, L2 stages and errors were recorded in relation to fossilization risk. Statistical methods were applied for categorical data (pResults. After gender and age adjustments, a significant inverse association was found between L2 stages and fossilization risk (pConclusions. Summing up, ICT in acquisition L2 had upper psychosocial risk to fossilization with mechanistic execution of it, under poorer communicative formats. This results have high sanitary impact given they involved a massively demanded professionals.

The mammary gland, the unique organ that primarily form at puberty, is an ideal model to study the functions of homeobox (HB) genes in both development and tumorigenesis. HB genes comprise a large family of developmental regulators that have a critical role in cell growth and differentiation. In the normal mammary gland, homeobox genes are involved in ductal formation, epithelial branching, and lobulo-alveolar development by regulating epithelial proliferation and differentiation. The HB genes are controlled in a spatial and temporal manner in both stromal and epithelial cells. They are coordinately regulated by hormones and extracellular matrix, suggesting that many signaling pathways are involved in homeobox gene functions. When homeobox genes are misexpressed in animal models, different defects are displayed in mammary gland development. Aberrant expression of homeobox genes, overexpressed or downregulated, is found in primary carcinomas and in breast cancer. The Otx1 HB gene is a classic regulatory of nervous system development during embryogenesis. Postnatally Otx1 is transcribed in the anterior pituitary gland, where activates transcription of the pituitary hormones, and plays a role in hematopoiesis, enhancing pluripotent cells, and erythroid differentiation. Otx1 can still be detected in mature cells of the erythroid and megacaryocytic lineage. During cyclical development of mammary gland, the Otx1 gene is overexpressed in lactation, confirming a role of this transcription factor in cell differentiation. Recent studies report that Otx1 is overexpressed in breast cancer. Otx1 is expressed during embryogenesis, and it is expressed again during carcinogenesis, implying its possible function in differentiation of neoplastic cells.

The autosomic dominant KID Syndrome (MIM 148210), due to mutations in GJB2 (connexin 26, Cx26), is an ectodermal dysplasia with erythematous scaly skin lesions, keratitis and severe bilateral sensorineural deafness. The Cx26 protein is a component of gap junction channels in epithelia, including the cochlea, which coordinates the exchange of molecules and ions. Here, we demonstrate that different Cx26 mutants (Cx26D50N and Cx26G11E) cause cell death in vitro by the alteration of intra-cellular calcium concentrations. These results help to explain the pathogenesis of both the hearing and skin phenotypes, since calcium is also a potent regulator of the epidermal differentiation process.

The HECT-type E3 ubiquitin ligase Itch is absent in the non-agouti-lethal 18H or Itchy mice, which develop a severe immunological disease. Several of the known Itch substrates are relevant for epidermal development and homeostasis, such as p63, Notch, c-Jun and JunB. By analysing Itchy mice before the onset of immunological alterations, we investigated the contribution of Itch in skin development and wound healing. Itchy newborn mice manifested hyperplastic epidermis, which is not present in adulthood. Itch(-/-) cultured keratinocytes showed overexpression of proliferating markers and increased capability to proliferate, migrate and to repair a scratch injury in vitro. These data correlated with improved in vivo wound healing in Itchy mice, at late time points of the repair process when Itch is physiologically upregulated. Despite healing acceleration, epidermal remodelling was delayed in the scars of Itch(-/-) mice, as indicated by enhanced epidermal thickening, keratinocyte proliferation and keratin 6 expression, and retarded keratin 14 polarization to the basal layer. Itch(-/-) keratinocyte prolonged activation was not associated with increased immune cell persistence in the scars. Our in vitro and in vivo results indicate that Itch plays a role in epidermal homeostasis and remodelling and this feature does not seem to depend on immunological alterations.

The ectodermal dysplasias are a group of inherited autosomal dominant syndromes associated with heterozygous mutations in the Tumor Protein p63 ( TRP63 ) gene. Here we show that, in addition to their epidermal pathology, a proportion of these patients have distinct levels of deafness. Accordingly, p63 null mouse embryos show marked cochlea abnormalities, and the transactivating isoform of p63 (TAp63) protein is normally found in the organ of Corti. TAp63 transactivates hairy and enhancer of split 5 (Hes5) and atonal homolog 1 (Atoh1), components of the Notch pathway, known to be involved in cochlear neuroepithelial development. Strikingly, p63 null mice show morphological defects of the organ of Corti, with supernumerary hair cells, as also reported for Hes5 null mice. This phenotype is related to loss of a differentiation property of TAp63 and not to loss of its proapoptotic function, because cochleas in mice lacking the critical Bcl-2 homology domain (BH-3) inducers of p53- and p63-mediated apoptosis—Puma, Noxa, or both—are normal. Collectively, these data demonstrate that TAp63, acting via the Notch pathway, is crucial for the development of the organ of Corti, providing a molecular explanation for the sensorineural deafness in ectodermal dysplasia patients with TRP63 mutations.

Despite the fact that murine cells are not permissive for human immunodeficiency virus type 1 (HIV-1) infection, several investigators have constructed transgenic (Tg) mice to model HIV-1-induced diseases to overcome this restriction. The generation of Tg mice expressing selected HIV-1 genes revealed that Nef harbors a major disease determinant. HIV-1 Nef protein is a molecular adapter able to interact with several cellular partners, interfering with cellular functions. The phenotype of Nef Tg mice was extensively characterized regarding in vivo development of AIDS-like disease and the effects of Nef expression in T lymphocytes, but the functions eventually corrupted by Nef in monocytes and macrophages was less studied. Nef treatment of human monocyte-derived macrophages induces the internalization of the protein and modulates the production and secretion of different chemokines and cytokines by activating specific intracellular signaling pathways (i.e., NF-jB, MAPK, and IRF3). Therefore we set up an in vitro murine macrophage-based model using stabilized cell lines and primary peritoneal macrophages, and treated them with recombinant myristoylated NefSF2 (recNef). Like human cells, murine macrophages responded to Nef treatment, activating IKK-a and IKK-b, JNK, and p38 MAP kinases. Activation of the NF-jB pathway is mandatory for the synthesis and release of a pool of cytokines and chemokines, including IFN-beta, that induce tyrosine phosphorylation of the signal transducer and activator of transcription (STAT)-1, STAT-2, and STAT-3, in an autocrine and paracrine manner, confirming that murine macrophages respond to Nef similarly to human ones. These data extend the results previously obtained in human primary macrophages, allowing the use of murine cells in culture to study signaling events modulated by Nef in myeloid-derived cells. In particular, it may be feasible to use macrophages derived from mice knocked out in specific signaling intermediates to obtain greater insight into the mechanism of Nef-induced effects.

Lamellar Ichthyosis (LI) is a form of congenital ichthyosis that is caused by mutations in the TGM1 gene that encodes for the transglutaminase 1 (TG1) enzyme. Functional inactivation of TG1 could be due to mutations, deletion or insertions. In this study, we have screened 16 patients affected by LI and found six new mutations: two transition/transversion (R37G, V112A), two nonsense mutations and two putative splice site both leading to a premature stop codon. The mutations are localized in exons 2 (N-terminal domain), 5, 11 (central catalytic domain), and none is located in the two beta-barrel C-terminal domains. In conclusion, this study expands the current knowledge on TGM1 mutation spectrum, increasing the characterization of mutations would provide more accurate prenatal genetic counselling for parents at-risk individuals.

Heterozygous mutations in TP63 cause a wide spectrum of autosomal dominant developmental disorders variably affecting skin, limbs, and face. TP63 encodes p63, a protein expressed in two main isoforms (Tap63 and ΔNp63) with critical roles in both cell differentiation and development. Some analyses suggest a relationship of the mutation site to the observed clinical picture, although this link is inconsistent. This suggests an appreciable phenotypic continuity within the TP63-related disorders. We report a 3-month-old boy ascertained for congenital scalp erosion and mild features of ectodermal dysplasia. His mother showed full-blown characteristics of Rapp-Hodgkin syndrome plus intense abdominal and popliteal freckling. Molecular investigation identified the novel TP63 mutation c.1697delG. We used a luciferase reporter assay to compare the effects on the p63 transactivation (TA) activity of c.1697delG with that of the p.Arg280Cys and p.Gln634X mutations, associated with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome and isolated split hand/foot malformation, respectively. These results demonstrated complex behavior of c.1697delG in the TA of genes involved in epidermal differentiation and development and shed further light in the physiopathology of TP63-related disorders. © 2011 Wiley Periodicals, Inc.

The p53 transcription factor has a critical role in cell stress response and in tumor suppression. Wild-type p53 protein is a growth modulator and its inactivation is a critical event in malignant transformation. It has been recently demonstrated that wild-type p53 has developmental and differentiation functions. Indeed an over-expression of p53 in tumor cells induces asymmetrical division avoiding self-renewal of cancer stem cells (CSCs) and instead promoting their differentiation. In this study, 28 human breast carcinomas have been analyzed for expression of wild-type p53 and of a pool of non-clustered homeobox genes. We demonstrated that orthodenticle homolog 1 gene (OTX1) is transcribed in breast cancer. We established that the p53 protein directly induces OTX1 expression by acting on its promoter. OTX1 has been described as a critical molecule for axon refinement in the developing cerebral cortex of mice, and its activity in breast cancer suggests a synergistic function with p53 in CSC differentiation. Wild-type p53 may regulate cellular differentiation by an alternative pathway controlling OTX1 signaling only in breast cancer cells and not in physiological conditions. © 2011 Macmillan Publishers Limited All rights reserved.

Contains fulltext : 95808.pdf (Publisher’s version ) (Open Access) Heterozygous mutations of p63, a key transcription factor in epithelial development, are causative in a variety of human ectodermal dysplasia disorders. Although the mutation spectrum of these disorders displays a striking genotype-phenotype association, the molecular basis for this association is only superficially known. Here, we characterize the transcriptional activity and protein stability of DeltaNp63 mutants (that is, mutants of a p63 isoform that lacks the N-terminal transactivation domain) that are found in ectrodactyly-ectodermal dysplasia-cleft syndrome (EEC), ankyloblepharon-ectodermal dysplasia-clefting syndrome (AEC) and nonsyndromic split-hand/split-foot malformation (SHFM). DNA-binding and sterile alpha motif (SAM) domain mutants accumulate in the skin of EEC and AEC syndrome patients, respectively, and show extended half lives in vitro. By contrast, C-terminal mutations found in SHFM patients have half-lives similar to that of the wild-type protein. The increased half-life of EEC and AEC mutant proteins was reverted by overexpression of wild-type DeltaNp63. Interestingly, the mutant proteins exhibit normal binding to and degradation by the E3 ubiquitin ligase Itch. Finally, EEC and AEC mutant proteins have reduced transcriptional activity on several skin-specific gene promoters, whereas SHFM mutant proteins are transcriptionally active. Our results, therefore, provide evidence for a regulatory feedback mechanism for p63 that links transcriptional activity to regulation of protein homeostasis by an unknown mechanism. Disruption of this regulatory mechanism might contribute to the pathology of p63-related developmental disorders.

Pachyonychia congenita (PC, OMIM #615726) is a rare autosomal-dominant genodermatosis divided into two subtypes: PC-1 (Jadassohn-Lewandowski type, OMIM#167200) and PC-2 (Jackson-Lawler type, OMIM#167210). Both subtypes manifest with hypertrophic onychodystrophy and a variable degree of focal palmoplantar keratoderma (PPK), angular cheilitis and follicular keratoses of elbows, knees and hips. PC-1 usually shows most prominent leukokeratosis and is associated with K6a and K16 mutations. PC-2 shows [...]

KID syndrome (MIM 148210) is an ectodermal dysplasia characterized by the occurrence of localized erythematous scaly skin lesions, keratitis and severe bilateral sensorineural deafness. KID syndrome is inherited as an autosomic dominant disease, due to mutations in the gene encoding gap junction protein GJB2 (connexin 26, Cx26). Cx26 is a component of gap junction channels in the epidermis and in the stria vascularis of the cochlea. These channels play a role in the coordinated exchange of molecules and ions occurring in a wide spectrum of cellular activities. In this paper we describe two patients with Cx26 mutations cause cell death by the alteration of protein trafficking, membrane localization and probably interfering with intracellular ion concentrations. We discuss the pathogenesis of both the hearing and skin phenotypes.