Dopamine and Norepinephrine Tissue Levels in the Developing Limbic Brain Are Impacted by the Human CHRNA6 3'-UTR Single-Nucleotide Polymorphism (rs2304297) in Rats.

We previously demonstrated that a genetic single-nucleotide polymorphism (SNP, rs2304297) in the 3' untranslated region (UTR) of the human CHRNA6 gene has sex- and genotype-dependent effects on nicotine-induced locomotion, anxiety, and nicotine + cue-induced reinstatement in adolescent rats. This study aims to investigate how the CHRNA6 3'-UTR SNP influences dopaminergic and noradrenergic tissue levels in brain reward regions during baseline and after the reinstatement of drug-seeking behavior. Naïve adolescent and adult rats, along with those undergoing nicotine + cue reinstatement and carrying the CHRNA6 3'-UTR SNP, were assessed for dopamine (DA), norepinephrine (NE), and metabolites in reward pathway regions. The results reveal age-, sex-, and genotype-dependent baseline DA, NE, and DA turnover levels. Post-reinstatement, male α6GG rats show suppressed DA levels in the Nucleus Accumbens (NAc) Shell compared to the baseline, while nicotine+ cue-induced reinstatement behavior correlates with neurotransmitter levels in specific brain regions. This study emphasizes the role of CHRNA6 3'-UTR SNP in the developmental maturation of the dopaminergic and noradrenergic system in the adolescent rat brain, with tissue levels acting as predictors of nicotine + cue-induced reinstatement.

Impact of tobacco smoke constituents on nicotine-seeking behavior in adolescent and adult male rats.

Introduction: Given the rapid increase in teen vaping over recent years it is critical to understand mechanisms underlying addiction and relapse to tobacco use at this age. To evaluate the role of non-nicotine constituents in cigarette smoke, our lab has previously established a model of intravenous self-administration of aqueous cigarette smoke extract (CSE). We now compare the sensitivity of male adolescent and adult rats who have self-administered CSE or nicotine to reinstatement with the pharmacological stressor, yohimbine, with and without cues. Methods: Adolescents and adults, aged postnatal day (P) 34 and 84, were tested for the effect of yohimbine (0-2.5 mg/kg) on plasma corticosterone levels to establish a dose that was an effective stressor at both ages. Separate groups of animals were trained to lever press for food before beginning 1-hour drug self-administration sessions for nicotine or CSE (15 µg/kg/infusion nicotine content). Once stable responding was reached, drug was removed, and behavior extinguished. Drug-seeking behavior was reinstated with yohimbine, cues, or a combination of yohimbine and cues. Results: Although adolescents and adults showed different dose-responses for yohimbine-induced corticosterone release, a dose of 2.5 mg/kg increased stress hormone levels at both ages. Whereas both ages displayed similar responding for CSE and nicotine, adolescents self-administered more CSE and nicotine as compared to adults. Cues and cues + stress reinstated responding to a greater extent in animals that had self-administered CSE, regardless of age. Discussion: These findings suggest that non-nicotine tobacco smoke constituents influence later but not earlier stages of addiction in both adolescent and adult male rats.

Male and Female Sprague Dawley Rats Exhibit Equivalent Natural Reward, Nicotine Self-Administration, Extinction, and Reinstatement During Adolescent-Initiated Behaviors.

INTRODUCTION: The initiation of nicotine and tobacco use peaks during adolescence. How adolescent males and females differ based on the acquisition of nicotine use and nicotine-seeking behavior is less understood. Our current studies develop a preclinical intravenous self-administration and reinstatement paradigm in male and female Sprague Dawley rats to evaluate how sex impacts the acquisition of nicotine self-administration and nicotine-seeking, when behavior is initiated during adolescence. AIMS AND METHODS: Male and female adolescent rats were food trained under a fixed-ratio one (FR1) schedule of reinforcement and progressively increased to FR5. Animals were implanted with catheters and began nicotine self-administration (0.015 mg/kg/infusion) at FR5 during adolescence on postnatal day 34. Upon reaching stable reinforced responding, animals were tested for progressive ratio (PR) schedules of reinforcement followed by extinction via the removal of drug and associated cues for a minimum of 5 days or until responding was reduced to ≤25% of baseline. Reinstatement testing began for cue only, nicotine only, and a combination of nicotine plus cues using a Latin square design. Animals returned to extinction conditions for 2 days minimum between testing. RESULTS: No sex differences were observed for natural rewards, acquisition, and PR schedules of nicotine self-administration, days to extinction, and reinstatement condition. CONCLUSIONS: Our findings provide evidence that sex does not impact natural rewards, nicotine reinforcement, reward, and reinstatement, when behavior is initiated during adolescence. Our study offers a feasible approach for assessing nicotine-seeking in male and female Sprague Dawley rats during the unique developmental window of adolescence. IMPLICATIONS: This study demonstrates the impact of nicotine and associated cues in the reinstatement of nicotine-seeking in male and female rats when behavior is initiated during adolescence. Findings support the equivalent impact of nicotine and the nonpharmacological stimuli of cues between male and female adolescent rats that began nicotine self-administration during adolescence.

Sex- and genotype-dependent nicotine plus cue-primed reinstatement is enhanced in adolescent Sprague Dawley rats containing the human CHRNA6 3'-UTR polymorphism (rs2304297).

Rationale: Large-scale human candidate gene studies have indicated that a genetic variant (rs2304297) in the alpha(α)6 nicotinic acetylcholine receptor (nAChR) subunit, encoded by the CHRNA6 gene, may play a key role in adolescent nicotine addictive behavior. We hypothesized that the polymorphism selectively enhances nicotine + cue-primed reinstatement, but not nicotine- or cue-reinstatement in α6 GG (risk) vs. α6 CC (non-risk) allele carriers, without having baseline effects on natural rewards. Methods: Using CRISPR-Cas9 genomic engineering, we developed a humanized rat line with the human gene variant of the CHRNA6 3'-UTR C 123 G polymorphism in Sprague-Dawley rats. Genetically modified adolescent male and female rats were food trained under a fixed-ratio (FR)1 schedule of reinforcement and progressively increased to FR5. Animals were implanted with catheters and began nicotine self-administration (15 µg/kg/infusion) at FR5. Upon reaching stable responding, reinforced behavior was extinguished by removal of drug and cues. Reinstatement testing began for cue only, nicotine only, and nicotine + cue in a Latin Square Design. Animals were returned to extinction conditions for 2 days minimum between testing. Results: For natural food rewards, nicotine self-administration, progressive ratio, and extinction, adolescent male and female (α6 GG and α6 CC ) rats exhibited equivalent behaviors. Male α6 GG rats show enhanced nicotine + cue-primed reinstatement when compared with male α6 CC rats. This genotype effect on reinstatement was not seen in female rats. Conclusion: Our findings support the in vivo functional role of the human CHRNA6 3'-UTR SNP genetic variant in sex-dependently enhancing nicotine seeking behavior in adolescent rats. Overall, the findings support clinical and preclinical data highlighting a role of α6 nAChRs mediating sex heterogeneity in substance use and related phenotypes.

Adaptación transcultural y validación de un contenido del cuestionario Texas Textbook Evaluation Tool (T-TET) de evaluación de libros de texto para ciencias de la salud / Cross-Cultural Adaptation and Content Validation of Texas Textbook Evaluation Tool (T-TET) a Book Evaluation Questionnaire for Health Sciences / Adaptação transcultural e validação de um questionário para as ciências da saúde

Introducción: La actualización y evaluación de libros de texto es esencial en el proceso educativo; sin embargo, en idioma español no se encuentran instrumentos para evaluarlos en el área de ciencias de la salud. Objetivo: Llevar a cabo la adaptación transcultural y validación de contenido del instrumento Texas Textbook Eva-luation Tool. Método: Estudio descriptivo de corte transversal con componente psicométrico. Se realizó la adaptación transcul-tural con traducción directa, síntesis de traducciones, traducción inversa, consolidación de traducciones en juicio de expertos y aplicación de una prueba piloto. Todo ello seguido del análisis de fiabilidad interobservador y la consistencia interna a través del alfa ordinal y el análisis factorial confirmatorio.Resultados: Se modificó un ítem que obtuvo un 36,66% de discrepancia. Se obtuvo un alfa de Cronbach de 0,98 y una kappa de Cohen de 0,91. Las pruebas de esfericidad de Barlett y Kaiser-Meyer-Olkin dieron como resulta-do 0,00 y 0,93, respectivamente. Así, se obtuvo en el análisis factorial confirmatorio que todas las variables se agrupan en las seis dimensiones propuestas. Conclusiones: Se realizó una apropiada implementación de los métodos. Los resultados obtenidos destacan la confianza e idoneidad del instrumento. El instrumento presenta una excelente consistencia interna, y se comprobó que mide las dimensiones para las que fue diseñado.

Introduction: The updating and evaluation of textbooks is essential in the educational process, however, in the Spanish language there are no instruments to evaluate them in Health Sciences. Objective: To make a cross-cultural adaptation and content validation of the Texas Textbook Evaluation Tool. Method: Cross-sectional descriptive study with a psychometric component, cross-cultural adaptation is carried out with direct translation, translation synthesis, reverse translation, consolidation of trans-lations in expert judgment and pilot test application. Followed by inter-observer reliability analysis and internal consistency through ordinal alpha and confirmatory factor analysis. Results: One item was modified that obtained a 36% discrepancy. An ordinal alpha of 0.98 and Cohen's Kappa index of 0.91 were obtained. The Bartlett and Kaiser-Meyer-Olkin sphericity tests resul-ted in 0.00 and 0.93 respectively, obtaining in the confirmatory factorial analysis that all the variables are grouped in the 6 proposed dimensions. Conclusions: An appropriate implementation of the methods, the results obtained highlight the con-fidence and suitability of the instrument. The instrument has excellent internal consistency, and it was verified that it measures the dimensions for which it was designed.

Introdução: A atualização dos livros de texto é essencial no processo educacional em Ciências da Saúde, mas no idioma espanhol não há instrumentos para sua avaliação. Objetivo: Adaptação transcultural e validação do instrumento Texas Textbook Evaluation Tool. Método: A tradução, retrotradução, teste piloto, confiabilidade, consistência interna e análise de fatores exploratórios foram abrangidos. Resultados: Um item foi modificado com uma discrepância de 36,66%. Foi obtido um coeficiente alfa de Cronbach de 0,98 e o índice Kappa de Cohen de 0,91. Os testes de esfericidade de Barlett e Kaiser-Meyer-Olkin resultaram em 0,00 e 0,93 respetivamente. Conclusões: Os métodos foram implementados adequadamente, e os resultados obtidos destacam a confiança e adequação do instrumento

Variables clínicas del parto en posición vertical y horizontal: revisión exhaustiva de literatura / Clinical Behavior of Vertical and Horizontal Deliveries: Exhaustive Literature Review / Variáveis clínicas do parto em posição vertical e horizontal: revisão abrangente de literatura

Introducción: El trabajo de parto representa el acontecimiento más importante durante la culminación del periodo de gestación y, por lo tanto, la adecuada elección de su posición, ya sea vertical u horizontal, resulta indispensable para minimizar las complicaciones maternas y neonatales. Objetivo: Llevar a cabo una revisión de la literatura sobre el comportamiento clínico del parto vertical y horizontal, describiendo los principales resultados en diferentes países del mundo. Método: Revisión documental mediante la búsqueda de la literatura entre 2009 y 2020 en bases de datos especializadas. Resultados: La posición vertical se asoció con una menor duración del trabajo de parto, dolor referido y necesidad de episiotomía; no obstante, esta posición puede incrementar el riesgo de hemorragia posparto y daño perineal. Conclusión: La variedad de desenlaces obstétricos y neonatales asociados a las posiciones de parto vertical y horizontal hacen complejo definir una posición de parto óptima; por lo tanto, se recomienda la libre elección de acuerdo con las características que presente cada paciente

Introduction: Parturition represents the most important event during the culmination of the gestation period and, therefore, the appropriate choice of its position, whether vertical or horizontal, it is essential to minimize maternal and neonatal complications. Objective: To carry out a review of the literature on the clinical behavior of vertical and horizontal delivery, describing the main results in different countries of the world. Method: Document review by searching the literature between the years 2009 and 2020, available in Specialized Databases. Results: The vertical position was associated with a shorter duration of labor obstetric, referred pain, and episiotomy; however, this position may increase the risk of postpartum hemorrhage and perineal damage. Conclusion: The variety of obstetric and neonatal outcomes associated with vertical and horizontal delivery positions make it difficult to define an optimal delivery position and, therefore, free choice is recommended according to the characteristics of each patient

Introdução: O trabalho de parto representa o acontecimento mais importante no final do período gestacional e, portanto, a escolha apropriada da posição, seja vertical ou horizontal, é indispensável para minimizar as complicações maternas e neonatais. Objetivo: Realizar uma revisão bibliográfica sobre o comportamento clínico do parto vertical e hori-zontal, descrevendo os principais resultados em diferentes países do mundo. Método: Revisão documental através de pesquisa da literatura em bases de dados especializadas entre os anos 2009 e 2020. Resultados: A posição vertical foi associada a uma duração mais curta do parto, dor referida e ne-cessidade de episiotomía; contudo, esta posição pode aumentar o risco de hemorragia pós-parto e dano perineal. Conclusão: A variedade de resultados obstétricos e neonatais associados às posições de parto vertical e horizontal torna complexa a escolha de uma posição de parto ótima; por conseguinte, recomen-da-se a livre escolha de acordo com as caraterísticas de cada paciente

Eficacia y seguridad de la estimulación magnética transcraneal en pacientes con afasia no fluente, posterior a ictus isquémico. Ensayo clínico controlado, aleatorizado y doble ciego / Efficacy and safety of transcranial magnetic stimulation in patients with non-fl uent aphasia, following an ischaemic stroke. A controlled, randomised and double-blind clinical trial

Introducción. La afasia no fluente es una complicación frecuente en pacientes postictus isquémico y la estimulación magnética transcraneal repetitiva (EMTr) representa una de las posibles alternativas de tratamiento. Objetivo. Evaluar la eficacia y la seguridad de la EMTr en pacientes con afasia no fluente postictus isquémico. Pacientes y métodos. Ensayo clínico controlado doble ciego, aleatorizado, en pacientes postictus isquémico que fueron asignados a recibir 10 sesiones (una diaria) de tratamiento activo o placebo de EMTr, sin adición de terapia del lenguaje. Las características basales fueron comparadas inicialmente, y la eficacia entre el grupo activo frente al grupo placebo el día 30 se evaluó a través de una prueba U de Mann-Whitney. Resultados. Se incluyó a 82 pacientes: grupo activo (n = 41) y grupo placebo (n = 41). Se encontraron diferencias basales estadísticamente significativas entre los grupos a favor del placebo en los dominios del test de Boston de compresión auditiva (p = 0,024), denominación (p = 0,014) y praxis (p = 0,026), e igualmente ocurrió el día 30 en los dominios de denominación (p = 0,037) y lectura (p = 0,001). Se presentaron 39 reacciones adversas, 23 en el grupo activo (26,83%) frente a 16 (21,96%) en el grupo placebo (p = 0,290), y la mayoría correspondía a episodios de cefalea leve. Conclusión. La EMTr es una terapia segura, pero dadas las condiciones de este estudio, no pudo demostrarse la eficacia de la EMTr frente al placebo en pacientes con afasia no fluente con afectación del área de Broca posterior a un ictus isquémico

Introduction. Non-fluent aphasia is a frequent complication in post-ischemic stroke patients, with repetitive transcranial magnetic stimulation (rTMS) being one of the possible treatment alternatives. Aim. To assess the efficacy and safety of rTMS in patients with non-flent after-ischemic stroke aphasia. Patients and methods. Double blind, randomized controlled clinical trial in post-stroke patients who were assigned to receive 10 sessions (one daily) of active treatment or placebo of rTMS, without the addition of language therapy. The baseline characteristics were compared initially and the efficacy between the active group versus the placebo group at day 30 was evaluated through a Mann-Whitney U test. Results. 82 patients were included: active group (n = 41) and placebo group (n = 41). At baseline, statistically significant differences were found between the groups in favor of the placebo in the domains of the Boston test of auditory compression (p = 0.024), denomination (p = 0.014) and praxis (p = 0.026), and also occurred on the 30th day in the naming domains (p = 0.037) and reading (p = 0.001). There were 39 adverse reactions: 23 (26.83%) in the active group vs 16 (21.96%) in the placebo group (p = 0.290); the majority corresponded to episodes of mild headache. Conclusion. rTMS is a safe therapy, however, given the conditions of this study, we could not demonstrate the efficacy of rTMS versus placebo in patients with non-fluent aphasia with involvement of Broca's area after an ischemic stroke

Use of QSPR Modeling to Characterize In Vitro Binding of Drugs to a Gut-Restricted Polymer.

PURPOSE: Polymeric drugs, including patiromer (Veltassa®), bind target molecules or ions in the gut, allowing fecal elimination. Non-absorbed insoluble polymers, like patiromer, avoid common systemic drug-drug interactions (DDIs). However, the potential for DDI via polymer binding to orally administered drugs during transit of the gastrointestinal tract remains. Here we elucidate the properties correlated with drug-patiromer binding using quantitative structure-property relationship (QSPR) models. METHODS: We selected 28 drugs to evaluate for binding to patiromer in vitro over a range of pH and ionic conditions intended to mimic the gut environment. Using this in vitro data, we developed QSPR models using step-wise linear regression and analyzed over 100 physiochemical drug descriptors. RESULTS: Four descriptors emerged that account for ~70% of patiromer-drug binding in vitro: the computed surface area of hydrogen bond accepting atoms, ionization potential, electron affinity, and lipophilicity (R 2 = 0.7, Q 2 = 0.6). Further, certain molecular properties are shared by nonbinding, weak, or strong binding compounds. CONCLUSIONS: These findings offer insight into drivers of in vitro binding to patiromer and describe a useful approach for assessing potential drug-binding risk of investigational polymeric drugs.

Endometriosis cutánea: a propósito de un caso / Cutaneous endometriosis: about a case

Se presenta el caso de mujer de 38 años quien consulta por presentar tumoración dolorosa en región inguinal izquierda de aproximadamente ocho meses de evolución. La endometriosis extrapélvica se define como la presencia de tejido endometrial en sitios distantes del útero. Su presentación es muy variada y su verdadera prevalencia es desconocida. La sospecha clínica es fundamental y parte del hecho de que los síntomas por lo general tienen un comportamiento cíclico.

Patient: female, 38 years old who complains of a painful tumor in left inguinal region. Approximately eight months of evolution. Extrapelvic endometriosis is defined as the presence of endometrial tissue in places far from the uterus. Its presentation is quite varied and its true prevalence is unknown. Clinical suspicion is basic and comes from the fact that symptoms, generally, have a cyclic presentation.