Stress-Related Chronic Fatigue Syndrome: A Case Report with a Positive Response to Alpha-Methyl-P-Tyrosine (AMPT) Treatment.

Chronic fatigue syndrome (CFS) is a heterogeneous disorder with a genetically associated vulnerability of the catecholamine metabolism (e.g., catechol O-methyltransferase polymorphisms), in which environmental factors have an important impact. Alpha-methyl-p-tyrosine (AMPT; also referred to as metyrosine) is an approved medication for the treatment of pheochromocytoma. As a tyrosine hydroxylase inhibitor, AMPT may be a potential candidate for the treatment of diseases involving catecholamine alterations. However, only small-scale clinical trials have tested AMPT repurposing in a few other illnesses. The current case report compiles genetic and longitudinal biochemical data for over a year of follow-up of a male patient sequentially diagnosed with sustained overstress, neurasthenia, CFS (diagnosed in 2012 as per the Center for Disease Control (CDC/Fukuda)), and postural orthostatic tachycardia syndrome (POTS) over a 10-year period and reports the patient's symptom improvement in response to low-medium doses of AMPT. This case was recognized as a stress-related CFS case. Data are reported from medical records provided by the patient to allow a detailed response to treatment targeting the hyperadrenergic state presented by the patient. We highlight the lack of a positive response to classical approaches to treating CFS, reflecting the limitations of CFS diagnosis and available treatments to alleviate patients' symptoms. The current pathomechanism hypothesis emphasizes monoamine alterations (hyperadrenergic state) in the DA/adrenergic system and a dysfunctional autonomic nervous system resulting from sympathetic overactivity. The response of the patient to AMPT treatment highlights the relevance of pacing with regard to stressful situations and increased activity. Importantly, the results do not indicate causality between AMPT and its action on the monoamine system, and future studies should evaluate the implications of other targets.

Relationship Between Exposure to Emotional Neglect and the Inflammatory Biomarkers Neutrophil-to-Lymphocyte, Monocyte-to-Lymphocyte, and Platelet-to-Lymphocyte Ratios in Patients With First-Episode Psychosis.

Aim: To assess whether exposure to childhood traumatic experiences is linked to the inflammatory markers neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) in people with a first-episode psychosis.Methods: A cross-sectional study was performed in 83 patients (21 females and 62 males) with a diagnosis of a first psychotic episode. All participants completed the self-reported Spanish version of the Childhood Trauma Questionnaire (CTQ). NLR, MLR, and PLR were calculated in each patient.Results: Highest CTQ scores were noted on the emotional neglect and abuse domains (mean ± SD = 10.92 ± 4.41; mean ± SD = 10.93 ± 4.78, respectively), being lowest for the sexual abuse domain (mean ± SD = 6.12 ± 2.41). Backward stepwise linear regressions showed that high emotional neglect significantly predicted increased PLR (ß = 0.452, P = .036), older age and high emotional neglect predicted increased NLR (ß = 0.483, P = .036; ß = 0.442, P = .06, respectively), and high emotional neglect, low physical neglect, high total Positive and Negative Syndrome Scale (PANSS) score, and cannabis and alcohol use predicted increased MLR (ß = 0.698, P = .003; ß = 0.672, P = .033; ß = 0.296, P = .027; ß = 0.390, P = .069; ß = 0.560, P = .078, respectively).Conclusions: Our results highlight the relationship between the exposure to emotional neglect and the inflammatory biomarkers NLR, MLR, and PLR in patients with a first-episode psychosis. This study has benefitted from controlling for confounders such as body mass index, smoking status, symptom severity, and alcohol and cannabis use.

Sirtuin 3 Mediated by Spinal cMyc-Enhancer of Zeste Homology 2 Pathway Plays an Important Role in Human Immunodeficiency Virus-Related Neuropathic Pain Model.

BACKGROUND: Clinical data demonstrate that chronic use of opioid analgesics increases neuropathic pain in people living with human immunodeficiency virus (HIV). Therefore, it is important to elucidate the molecular mechanisms of HIV-related chronic pain. In this study, we investigated the role of the transcription factor cMyc, epigenetic writer enhancer of zeste homology 2 (EZH2), and sirtuin 3 (Sirt3) pathway in HIV glycoprotein gp120 with morphine (gp120M)-induced neuropathic pain in rats. METHODS: Neuropathic pain was induced by intrathecal administration of recombinant gp120 with morphine. Mechanical withdrawal threshold was measured using von Frey filaments, and thermal latency using the hotplate test. Spinal expression of cMyc, EZH2, and Sirt3 were measured using Western blots. Antinociceptive effects of intrathecal administration of antisense oligodeoxynucleotide against cMyc, a selective inhibitor of EZH2, or recombinant Sirt3 were tested. RESULTS: In the spinal dorsal horn, gp120M upregulated expression of cMyc (ratio of gp120M versus control, 1.68 ± 0.08 vs 1.00 ± 0.14, P = .0132) and EZH2 (ratio of gp120M versus control, 1.76 ± 0.05 vs 1.00 ± 0.16, P = .006), and downregulated Sirt3 (ratio of control versus gp120M, 1.00 ± 0.13 vs 0.43 ± 0.10, P = .0069) compared to control. Treatment with intrathecal antisense oligodeoxynucleotide against cMyc, GSK126 (EZH2 selective inhibitor), or recombinant Sirt3 reduced mechanical allodynia and thermal hyperalgesia in this gp120M pain model. Knockdown of cMyc reduced spinal EZH2 expression in gp120M treated rats. Chromatin immunoprecipitation (ChIP) assay showed that enrichment of cMyc binding to the ezh2 gene promoter region was increased in the gp120M-treated rat spinal dorsal horn, and that intrathecal administration of antisense ODN against cMyc (AS-cMyc) reversed the increased enrichment of cMyc. Enrichment of trimethylation of histone 3 on lysine residue 27 (H3K27me3; an epigenetic mark associated with the downregulation of gene expression) binding to the sirt3 gene promoter region was upregulated in the gp120M-treated rat spinal dorsal horn; that intrathecal GSK126 reversed the increased enrichment of H3K27me3 in the sirt3 gene promoter. Luciferase reporter assay demonstrated that cMyc mediated ezh2 gene transcription at the ezh2 gene promoter region, and that H3K27me3 silenced sirt3 gene transcription at the gene promoter region. CONCLUSION: These results demonstrated that spinal Sirt3 decrease in gp120M-induced neuropathic pain was mediated by cMyc-EZH2/H3K27me3 activity in an epigenetic manner. This study provided new insight into the mechanisms of neuropathic pain in HIV patients with chronic opioids.

Risk of endometrial cancer after RRSO in BRCA 1/2 carriers: a multicentre cohort study.

OBJECTIVE: To know the risk of endometrial cancer (EC) in a population of women with BRCA 1/2 pathogenic or likely pathogenic variants after risk-reducing salpingo-oophorectomy (RRSO). METHODS: The study cohort included data from 857 women with BRCA mutations who underwent RRSO visited four hospitals in Catalonia, Spain, from January 1, 1999 to April 30, 2019. Standardized incidence ratio (SIR) of EC was calculated in these patients using data from a regional population-based cancer registry. RESULTS: After RRSO, eight cases of EC were identified. Four in BRCA 1 carriers and four in BRCA2 carriers. The expected number of cases of EC was 3.67 cases, with a SIR of 2.18 and a 95% CI (0.93-3.95). CONCLUSIONS: In our cohort, the risk of EC in BRCA1/2 carriers after RRSO is not greater than expected. Hysterectomy is not routinely recommended for these patients.

Regional collaboration for the development of national childhood cancer plans in Latin America and the Caribbean.

This article aims to describe the activities conducted by the National Childhood Cancer Plan Working Group to support the development of national childhood cancer plans in Latin America and the Caribbean in the period 2019-2022, and to present the stage of plan development. The Working Group activities were supported by the Pan American Health Organization and St. Jude Children's Research Hospital, which is the World Health Organization (WHO) Collaborating Centre for Childhood Cancer. Year after year, the workshops and activities developed with the Working Group mobilized key stakeholders: pediatric oncologists, representatives of the Ministry of Health, foundations supporting childhood cancer initiatives, and hospital administrators. As of February 2023, one regional framework is in place, approved by the Council of Ministries of Health of Central America and the Dominican Republic, nine countries are currently implementing national plans or laws that include childhood cancer, and ten countries are writing new plans. The WHO three-step framework helped to guide the Working Group activities. All plans were supported by a situational analysis, which highlighted the importance of having systematized data for evidence-based policies. To increase implementation success, an accompanying budget and timeline help to ensure the adequate implementation of the interventions. More than anything, committed stakeholders remain the most fundamental element to successfully write and approve a national childhood cancer plan. This is an opportunity to share these countries' experience so the strategy can be adapted to support other countries developing a childhood cancer plan and extended to other public health areas.

En este artículo se describen las actividades realizadas por el grupo de trabajo del plan nacional contra el cáncer infantil dirigidas a brindar apoyo para la formulación de planes nacionales contra el cáncer infantil en América Latina y el Caribe en el período 2019-2022, así como la presentación de la etapa de formulación de los planes. Las actividades del Grupo de Trabajo contaron con el apoyo de la Organización Panamericana de la Salud y el St. Jude Children's Research Hospital, que es el centro colaborador de la Organización Mundial de la Salud (OMS) contra el cáncer infantil. Año tras año, los talleres y actividades llevados a cabo con el grupo de trabajo han logrado convocar a las principales partes interesadas: especialistas en oncología pediátrica, representantes del Ministerio de Salud, fundaciones que apoyan iniciativas contra el cáncer infantil y gerentes de los hospitales. Desde febrero del 2023, existe un marco regional, aprobado por el Consejo de Ministerios de Salud de Centroamérica y República Dominicana; nueve países ya están aplicando planes o leyes nacionales en los que se incluye el cáncer infantil, y diez países están redactando nuevos planes. Para orientar las actividades del Grupo de Trabajo, se recurrió al marco en tres pasos de la OMS. Todos los planes se sustentaron en un análisis de situación lo que subraya la importancia de contar con datos sistematizados para que las políticas puedan estar basadas en evidencias. Asimismo, si se pretende aumentar el éxito de la aplicación, sería conveniente contar con un presupuesto y un cronograma que aseguren la aplicación adecuada de las intervenciones. Las partes interesadas implicadas siguen siendo, ante todo, el componente más trascendente en la redacción y aprobación exitosa de un plan nacional contra el cáncer infantil. Esta es una oportunidad para transmitir la experiencia de estos países, con el fin de que la estrategia pueda adaptarse para brindar apoyo a otros países que estén elaborando un plan contra el cáncer infantil y que puede hacerse extensiva a otros ámbitos de la salud pública.

Este artigo visa a descrever as atividades realizadas pelo Grupo de Trabalho para Planos Nacionais de Combate ao Câncer infantil a fim de prestar apoio ao desenvolvimento de planos nacionais de combate ao câncer infantil na América Latina e no Caribe no período de 2019 a 2022 e apresentar a atual fase de desenvolvimento dos planos. As atividades do Grupo de Trabalho receberam apoio da Organização Pan-Americana da Saúde e do St. Jude Children's Research Hospital, o Centro Colaborador em Câncer infantil da Organização Mundial da Saúde (OMS). Ano após ano, as oficinas e atividades desenvolvidas com o Grupo de Trabalho mobilizaram as principais partes interessadas: oncologistas pediátricos, representantes dos ministérios da saúde, fundações que apoiam iniciativas de combate ao câncer infantil e administradores de hospitais. Até fevereiro de 2023, havia uma estrutura regional em vigor aprovada pelo Conselho de Ministros da Saúde da América Central e da República Dominicana, nove países estavam implementando planos ou leis nacionais que incluíam o câncer infantil e dez países estavam elaborando novos planos. A estrutura de três etapas da OMS ajudou a orientar as atividades do Grupo de Trabalho. Todos os planos estavam embasados em uma análise situacional, o que destacou a importância de dispor de dados sistematizados para políticas baseadas em evidências. Para aumentar o sucesso da implementação, um orçamento e um cronograma correspondentes ajudam a garantir a implementação adequada das intervenções. Acima de tudo, o compromisso das partes interessadas continua sendo o elemento mais fundamental para elaborar e aprovar com sucesso um plano nacional de combate ao câncer infantil. Esta é uma oportunidade de compartilhar a experiência desses países para que a estratégia possa ser adaptada a fim de apoiar outros países na elaboração de um plano de combate ao câncer infantil e possa ser estendida a outras áreas de saúde pública.

Advances in the Global Initiative for Childhood Cancer: implementation in Latin America and the Caribbean.

This report describes the status of childhood cancer control initiatives in Latin America and the Caribbean (LAC). Progress between 2017 and 2023 is measured using the outcome indicators from the Pan American Health Organization (PAHO) childhood cancer logic model aligned with the World Health Organization Global Initiative for Childhood Cancer (GICC). This report also describes the advances, barriers, and facilitators for the implementation of the GICC at the Regional level. Methods used in this report encompassed a comprehensive approach, incorporating a literature review, interviews, surveys, and a Delphi study developed by the technical team of the PAHO Non-Communicable Diseases and Mental Health Department and by the GICC LAC working group. Since 2017, there has been a substantial increase in the number of countries that have included childhood cancer in their national regulations. Currently, 21 LAC countries are involved in the GICC implementation, activities, and dialogues. However, the objectives for 2030 will only be achieved if Member States overcome the barriers to accelerating the pace of initiative implementation. There is an urgent need to increase the efforts in childhood cancer control in LAC, especially regarding the prioritization of timely detection, essential diagnostics, access to cancer treatment, palliative care, and close follow-up of children and adolescents with cancer.

En este artículo se describe la situación de las iniciativas para el control del cáncer infantil en América Latina y el Caribe. Para medir los progresos entre el 2017 y el 2023, se utilizan los indicadores de resultados del modelo lógico del cáncer infantil de la Organización Panamericana de la Salud (OPS) que es coherente con la Iniciativa Mundial contra el Cáncer Infantil de la Organización Mundial de la Salud. También se describen los avances, los obstáculos y los elementos que han facilitado la aplicación de esa iniciativa en la Región Los métodos utilizados en este trabajo incluyeron un enfoque integral que incorporó una revisión bibliográfica, entrevistas, encuestas y un estudio de tipo Delfos llevado a cabo por el equipo técnico del Departamento de Enfermedades No Transmisibles y Salud Mental de la OPS y por el grupo de trabajo de América Latina y el Caribe de la Iniciativa Mundial contra el Cáncer Infantil de la Organización Mundial de la Salud.Desde el 2017 ha habido un incremento considerable en el número de países que incorporan el cáncer infantil en sus regulaciones nacionales. En la actualidad, 21 países de América Latina y el Caribe participan en la puesta en práctica, las actividades y las deliberaciones de la Iniciativa Mundial contra el Cáncer Infantil de la Organización Mundial de la Salud. No obstante, los objetivos para el 2030 solo podrán alcanzarse si los Estados Miembros son capaces de superar los obstáculos que dificultan la aceleración del ritmo de aplicación de esta iniciativa. Existe una necesidad urgente de aumentar las actividades dirigidas al control del cáncer infantil en América Latina y el Caribe, en especial en lo que respecta a priorizar la detección temprana, los medios de diagnóstico esenciales, el acceso a los tratamientos oncológicos, los cuidados paliativos y el seguimiento estricto de la población infantil y adolescente con cáncer.

Este relatório descreve a situação das iniciativas de controle do câncer infantil na Região da América Latina e do Caribe (ALC). O progresso alcançado entre 2017 e 2023 foi medido usando os indicadores de resultados intermediários do modelo lógico de câncer infantil da Organização Pan-Americana da Saúde (OPAS), em linha com a Iniciativa Global para o Câncer Infantil (GICC) da Organização Mundial da Saúde. O relatório também descreve os avanços, as barreiras e os facilitadores para a implementação da iniciativa em nível regional. Os métodos utilizados neste relatório aplicaram uma abordagem abrangente que incluiu revisão da literatura, entrevistas, levantamentos e um estudo Delphi desenvolvido pela equipe técnica do Departamento de Doenças Não Transmissíveis e Saúde Mental da OPAS e pelo grupo de trabalho da GICC para a ALC.Desde 2017, houve um aumento significativo no número de países que passaram a incluir o câncer infantil em regulamentações nacionais. Atualmente, 21 países da América Latina e do Caribe estão envolvidos na implementação da GICC, bem como em atividades e diálogos relacionados. No entanto, os objetivos para 2030 só serão alcançados se os Estados Membros superarem as barreiras ao aceleramento do ritmo de implementação da iniciativa. Existe uma necessidade urgente de intensificar os esforços de controle do câncer infantil na ALC, especialmente no tocante à priorização da detecção em tempo hábil, diagnósticos essenciais, acesso a tratamentos oncológicos, cuidados paliativos e acompanhamento cuidadoso de crianças e adolescentes com câncer.

Partnering to implement the Global Initiative for Childhood Cancer in the Americas: prioritizing systems strengthening.

Working with PAHO/WHO to prioritize childhood cancer in the context of systems strengthening is central to St. Jude Children's Research Hospital (SJCRH)'s role as WHO Collaborating Centre for Childhood Cancer. This manuscript focuses on how SJCRH and PAHO/WHO have partnered to apply C5 (Country Collaboration for Childhood Cancer Control) to define and implement priority actions regionally, strengthening Ministry programs for childhood cancer, while implementing the Global Initiative for Childhood Cancer since 2018. Using C5, a tool developed by SJCRH, PAHO/WHO and SJCRH co-hosted regional/national workshops engaging authorities, clinicians and other stakeholders across 10 countries to map health systems needs and prioritize strategic activities (spanning Central America, Dominican Republic, Haiti, Brazil and Uruguay). SJCRH provided English/Spanish/Portuguese C5 versions/templates for analysis/prioritization exercises, and worked with PAHO/WHO and country teams to implement C5, analyze findings, and develop outputs. In an eight-country regional workshop, countries defined priorities within national/regional initiatives and ranked their value and political will, incorporating country-specific surveys and stakeholder dialogues. Each country prioritized one strategic activity for 2022-2023, exchanged insights via storytelling, and disseminated and applied results to inform country-specific and regional action plans. National workshops analyses have been incorporated into cancer control planning activities and collaborative work regionally. Implementation success factors include engaging actors beyond the clinic, enabling flexibility, and focusing on co-design with stakeholders. Joint implementation of C5 catalyzed prioritization and accelerated strategic activities to improve policies, capacity, and quality of care for children in the Americas, supporting Ministries to integrate childhood cancer interventions as part of systems strengthening.

La colaboración con la OPS/OMS para priorizar el cáncer infantil en el contexto del fortalecimiento de los sistemas es fundamental para la labor del St. Jude Children's Research Hospital (SJCRH) como centro colaborador de la OMS contra el cáncer infantil. Este artículo se centra en la alianza entre el SJCRH y la OPS/OMS en la aplicación de la herramienta C5 (colaboración nacional para el control del cáncer infantil) para definir y ejecutar medidas prioritarias a nivel regional, fortalecer los programas contra el cáncer infantil del ministerio y poner en marcha la Iniciativa Mundial contra el Cáncer Infantil desde el 2018. Con C5, una herramienta elaborada por el SJCRH, la OPS/OMS y este hospital organizaron conjuntamente talleres regionales y nacionales con autoridades, personal médico y otras partes interesadas en diez países para determinar cuáles son las necesidades de los sistemas de salud y priorizar las actividades estratégicas (en América Central, República Dominicana, Haití, Brasil y Uruguay). El SJCRH proporcionó versiones y plantillas de C5 en inglés, español y portugués para actividades de análisis y priorización y trabajó con la OPS/OMS y los equipos de país para ejecutar la herramienta C5, analizar los resultados y elaborar productos. En un taller regional de ocho países, se definieron las prioridades en las iniciativas regionales y nacionales, se clasificó su valor y la voluntad política y se incorporaron encuestas específicas para cada país y diálogos con las partes interesadas. Cada país priorizó una actividad estratégica para el período 2022-2023, intercambió ideas por medio de narrativas, y difundió y aplicó los resultados para fundamentar planes de acción tanto regionales como específicos para el país. Los análisis de los talleres nacionales se han incorporado a las actividades de planificación del control del cáncer y al trabajo colaborativo a nivel regional. Entre los factores de éxito de la ejecución se encuentra involucrar a los agentes más allá de lo clínico, permitir que haya flexibilidad y centrarse en un diseño elaborado en colaboración con las partes interesadas. La ejecución conjunta de la herramienta C5 catalizó la priorización y aceleró las actividades estratégicas para mejorar las políticas, la capacidad y la calidad de la atención infantil en la Región de las Américas y brindó apoyo a los ministerios para integrar las intervenciones contra el cáncer infantil en el fortalecimiento de los sistemas.

A colaboração com a OPAS/OMS para priorizar o câncer infantil no contexto do fortalecimento dos sistemas é fundamental para o papel do St. Jude Children's Research Hospital (SJCRH) como Centro Colaborador da OMS para o Câncer Infantil. Este artigo mostra como o SJCRH e a OPAS/OMS se associaram para aplicar a ferramenta C5 (Colaboração Nacional para Controle do Câncer Infantil), com o propósito de definir e implementar ações prioritárias regionalmente, fortalecendo programas ministeriais para o câncer na infância, durante a implementação da Iniciativa Global para o Câncer Infantil desde 2018. Com auxílio da C5, uma ferramenta desenvolvida pelo SJCRH, a OPAS/OMS e o SJCRH organizaram conjuntamente oficinas regionais/nacionais com a participação de autoridades, profissionais de saúde e outras partes interessadas em 10 países, com a finalidade de mapear as necessidades dos sistemas de saúde e priorizar atividades estratégicas (abrangendo América Central, República Dominicana, Haiti, Brasil e Uruguai). O SJCRH forneceu versões/modelos da C5 em inglês, espanhol e português para exercícios de análise/priorização e colaborou com a OPAS/OMS e as equipes dos países para implementar a C5, analisar resultados e desenvolver produtos. Em uma oficina regional com oito países, foram definidas as prioridades das iniciativas nacionais/regionais e classificados seu valor e vontade política, incorporando levantamentos nacionais e diálogos entre as partes interessadas. Cada país priorizou uma atividade estratégica para 2022-2023, trocou conhecimentos por meio da narração de histórias e disseminou e aplicou os resultados para informar planos de ação nacionais e regionais. As análises das oficinas nacionais foram incorporadas às atividades de planejamento para controle do câncer e ao trabalho conjunto no âmbito regional. Entre os fatores de êxito da implementação estão o engajamento de agentes de fora do segmento da saúde, a oferta de flexibilidade e a ênfase no planejamento conjunto com as partes interessadas. A implementação conjunta da C5 catalisou a priorização e acelerou atividades estratégicas para aprimorar as políticas, a capacidade e a qualidade da atenção às crianças nas Américas, apoiando os ministérios na integração das intervenções contra o câncer infantil como parte do fortalecimento dos sistemas.

Role of Tumor Necrosis Factor Receptor 1-Reactive Oxygen Species-Caspase 11 Pathway in Neuropathic Pain Mediated by HIV gp120 With Morphine in Rats.

BACKGROUND: Recent clinical research suggests that repeated use of opioid pain medications can increase neuropathic pain in people living with human immunodeficiency virus (HIV; PLWH). Therefore, it is significant to elucidate the exact mechanisms of HIV-related chronic pain. HIV infection and chronic morphine induce proinflammatory factors, such as tumor necrosis factor (TNF)α acting through tumor necrosis factor receptor I (TNFRI). HIV coat proteins and/or chronic morphine increase mitochondrial superoxide in the spinal cord dorsal horn (SCDH). Recently, emerging cytoplasmic caspase-11 is defined as a noncanonical inflammasome and can be activated by reactive oxygen species (ROS). Here, we tested our hypothesis that HIV coat glycoprotein gp120 with chronic morphine activates a TNFRI-mtROS-caspase-11 pathway in rats, which increases neuroinflammation and neuropathic pain. METHODS: Neuropathic pain was induced by repeated administration of recombinant gp120 with morphine (gp120/M) in rats. Mechanical allodynia was assessed using von Frey filaments, and thermal latency using hotplate test. Protein expression of spinal TNFRI and cleaved caspase-11 was examined using western blots. The image of spinal mitochondrial superoxide was examined using MitoSox Red (mitochondrial superoxide indicator) image assay. Immunohistochemistry was used to examine the location of TNFRI and caspase-11 in the SCDH. Intrathecal administration of antisense oligodeoxynucleotide (AS-ODN) against TNFRI, caspase-11 siRNA, or a scavenger of mitochondrial superoxide was given for antinociceptive effects. Statistical tests were done using analysis of variance (1- or 2-way), or 2-tailed t test. RESULTS: Intrathecal gp120/M induced mechanical allodynia and thermal hyperalgesia lasting for 3 weeks ( P < .001). Gp120/M increased the expression of spinal TNFRI, mitochondrial superoxide, and cleaved caspase-11. Immunohistochemistry showed that TNFRI and caspase-11 were mainly expressed in the neurons of the SCDH. Intrathecal administration of antisense oligonucleotides against TNFRI, Mito-Tempol (a scavenger of mitochondrial superoxide), or caspase-11 siRNA reduced mechanical allodynia and thermal hyperalgesia in the gp120/M neuropathic pain model. Spinal knockdown of TNFRI reduced MitoSox profile cell number in the SCDH; intrathecal Mito-T decreased spinal caspase-11 expression in gp120/M rats. In the cultured B35 neurons treated with TNFα, pretreatment with Mito-Tempol reduced active caspase-11 in the neurons. CONCLUSIONS: These results suggest that spinal TNFRI-mtROS-caspase 11 signal pathway plays a critical role in the HIV-associated neuropathic pain state, providing a novel approach to treating chronic pain in PLWH with opioids.

Advances in the Global Initiative for Childhood Cancer: implementation in Latin America and the Caribbean / Adelantos en la Iniciativa Mundial contra el Cáncer Infantil: aplicación en América Latina y el Caribe / Avanços na Iniciativa Global para o Câncer Infantil da OMS: implementação na América Latina e no Caribe

ABSTRACT This report describes the status of childhood cancer control initiatives in Latin America and the Caribbean (LAC). Progress between 2017 and 2023 is measured using the outcome indicators from the Pan American Health Organization (PAHO) childhood cancer logic model aligned with the World Health Organization Global Initiative for Childhood Cancer (GICC). This report also describes the advances, barriers, and facilitators for the implementation of the GICC at the Regional level. Methods used in this report encompassed a comprehensive approach, incorporating a literature review, interviews, surveys, and a Delphi study developed by the technical team of the PAHO Non-Communicable Diseases and Mental Health Department and by the GICC LAC working group. Since 2017, there has been a substantial increase in the number of countries that have included childhood cancer in their national regulations. Currently, 21 LAC countries are involved in the GICC implementation, activities, and dialogues. However, the objectives for 2030 will only be achieved if Member States overcome the barriers to accelerating the pace of initiative implementation. There is an urgent need to increase the efforts in childhood cancer control in LAC, especially regarding the prioritization of timely detection, essential diagnostics, access to cancer treatment, palliative care, and close follow-up of children and adolescents with cancer.

RESUMEN En este artículo se describe la situación de las iniciativas para el control del cáncer infantil en América Latina y el Caribe. Para medir los progresos entre el 2017 y el 2023, se utilizan los indicadores de resultados del modelo lógico del cáncer infantil de la Organización Panamericana de la Salud (OPS) que es coherente con la Iniciativa Mundial contra el Cáncer Infantil de la Organización Mundial de la Salud. También se describen los avances, los obstáculos y los elementos que han facilitado la aplicación de esa iniciativa en la Región Los métodos utilizados en este trabajo incluyeron un enfoque integral que incorporó una revisión bibliográfica, entrevistas, encuestas y un estudio de tipo Delfos llevado a cabo por el equipo técnico del Departamento de Enfermedades No Transmisibles y Salud Mental de la OPS y por el grupo de trabajo de América Latina y el Caribe de la Iniciativa Mundial contra el Cáncer Infantil de la Organización Mundial de la Salud. Desde el 2017 ha habido un incremento considerable en el número de países que incorporan el cáncer infantil en sus regulaciones nacionales. En la actualidad, 21 países de América Latina y el Caribe participan en la puesta en práctica, las actividades y las deliberaciones de la Iniciativa Mundial contra el Cáncer Infantil de la Organización Mundial de la Salud. No obstante, los objetivos para el 2030 solo podrán alcanzarse si los Estados Miembros son capaces de superar los obstáculos que dificultan la aceleración del ritmo de aplicación de esta iniciativa. Existe una necesidad urgente de aumentar las actividades dirigidas al control del cáncer infantil en América Latina y el Caribe, en especial en lo que respecta a priorizar la detección temprana, los medios de diagnóstico esenciales, el acceso a los tratamientos oncológicos, los cuidados paliativos y el seguimiento estricto de la población infantil y adolescente con cáncer.

RESUMO Este relatório descreve a situação das iniciativas de controle do câncer infantil na Região da América Latina e do Caribe (ALC). O progresso alcançado entre 2017 e 2023 foi medido usando os indicadores de resultados intermediários do modelo lógico de câncer infantil da Organização Pan-Americana da Saúde (OPAS), em linha com a Iniciativa Global para o Câncer Infantil (GICC) da Organização Mundial da Saúde. O relatório também descreve os avanços, as barreiras e os facilitadores para a implementação da iniciativa em nível regional. Os métodos utilizados neste relatório aplicaram uma abordagem abrangente que incluiu revisão da literatura, entrevistas, levantamentos e um estudo Delphi desenvolvido pela equipe técnica do Departamento de Doenças Não Transmissíveis e Saúde Mental da OPAS e pelo grupo de trabalho da GICC para a ALC. Desde 2017, houve um aumento significativo no número de países que passaram a incluir o câncer infantil em regulamentações nacionais. Atualmente, 21 países da América Latina e do Caribe estão envolvidos na implementação da GICC, bem como em atividades e diálogos relacionados. No entanto, os objetivos para 2030 só serão alcançados se os Estados Membros superarem as barreiras ao aceleramento do ritmo de implementação da iniciativa. Existe uma necessidade urgente de intensificar os esforços de controle do câncer infantil na ALC, especialmente no tocante à priorização da detecção em tempo hábil, diagnósticos essenciais, acesso a tratamentos oncológicos, cuidados paliativos e acompanhamento cuidadoso de crianças e adolescentes com câncer.

Regional collaboration for the development of national childhood cancer plans in Latin America and the Caribbean / Colaboración regional para la formulación de planes nacionales contra el cáncer infantil en América Latina y el Caribe / Colaboração regional para o desenvolvimento de planos nacionais de combate ao câncer infantil na América Latina e no Caribe

ABSTRACT This article aims to describe the activities conducted by the National Childhood Cancer Plan Working Group to support the development of national childhood cancer plans in Latin America and the Caribbean in the period 2019-2022, and to present the stage of plan development. The Working Group activities were supported by the Pan American Health Organization and St. Jude Children's Research Hospital, which is the World Health Organization (WHO) Collaborating Centre for Childhood Cancer. Year after year, the workshops and activities developed with the Working Group mobilized key stakeholders: pediatric oncologists, representatives of the Ministry of Health, foundations supporting childhood cancer initiatives, and hospital administrators. As of February 2023, one regional framework is in place, approved by the Council of Ministries of Health of Central America and the Dominican Republic, nine countries are currently implementing national plans or laws that include childhood cancer, and ten countries are writing new plans. The WHO three-step framework helped to guide the Working Group activities. All plans were supported by a situational analysis, which highlighted the importance of having systematized data for evidence-based policies. To increase implementation success, an accompanying budget and timeline help to ensure the adequate implementation of the interventions. More than anything, committed stakeholders remain the most fundamental element to successfully write and approve a national childhood cancer plan. This is an opportunity to share these countries' experience so the strategy can be adapted to support other countries developing a childhood cancer plan and extended to other public health areas.

RESUMEN En este artículo se describen las actividades realizadas por el grupo de trabajo del plan nacional contra el cáncer infantil dirigidas a brindar apoyo para la formulación de planes nacionales contra el cáncer infantil en América Latina y el Caribe en el período 2019-2022, así como la presentación de la etapa de formulación de los planes. Las actividades del Grupo de Trabajo contaron con el apoyo de la Organización Panamericana de la Salud y el St. Jude Children's Research Hospital, que es el centro colaborador de la Organización Mundial de la Salud (OMS) contra el cáncer infantil. Año tras año, los talleres y actividades llevados a cabo con el grupo de trabajo han logrado convocar a las principales partes interesadas: especialistas en oncología pediátrica, representantes del Ministerio de Salud, fundaciones que apoyan iniciativas contra el cáncer infantil y gerentes de los hospitales. Desde febrero del 2023, existe un marco regional, aprobado por el Consejo de Ministerios de Salud de Centroamérica y República Dominicana; nueve países ya están aplicando planes o leyes nacionales en los que se incluye el cáncer infantil, y diez países están redactando nuevos planes. Para orientar las actividades del Grupo de Trabajo, se recurrió al marco en tres pasos de la OMS. Todos los planes se sustentaron en un análisis de situación lo que subraya la importancia de contar con datos sistematizados para que las políticas puedan estar basadas en evidencias. Asimismo, si se pretende aumentar el éxito de la aplicación, sería conveniente contar con un presupuesto y un cronograma que aseguren la aplicación adecuada de las intervenciones. Las partes interesadas implicadas siguen siendo, ante todo, el componente más trascendente en la redacción y aprobación exitosa de un plan nacional contra el cáncer infantil. Esta es una oportunidad para transmitir la experiencia de estos países, con el fin de que la estrategia pueda adaptarse para brindar apoyo a otros países que estén elaborando un plan contra el cáncer infantil y que puede hacerse extensiva a otros ámbitos de la salud pública.

RESUMO Este artigo visa a descrever as atividades realizadas pelo Grupo de Trabalho para Planos Nacionais de Combate ao Câncer infantil a fim de prestar apoio ao desenvolvimento de planos nacionais de combate ao câncer infantil na América Latina e no Caribe no período de 2019 a 2022 e apresentar a atual fase de desenvolvimento dos planos. As atividades do Grupo de Trabalho receberam apoio da Organização Pan-Americana da Saúde e do St. Jude Children's Research Hospital, o Centro Colaborador em Câncer infantil da Organização Mundial da Saúde (OMS). Ano após ano, as oficinas e atividades desenvolvidas com o Grupo de Trabalho mobilizaram as principais partes interessadas: oncologistas pediátricos, representantes dos ministérios da saúde, fundações que apoiam iniciativas de combate ao câncer infantil e administradores de hospitais. Até fevereiro de 2023, havia uma estrutura regional em vigor aprovada pelo Conselho de Ministros da Saúde da América Central e da República Dominicana, nove países estavam implementando planos ou leis nacionais que incluíam o câncer infantil e dez países estavam elaborando novos planos. A estrutura de três etapas da OMS ajudou a orientar as atividades do Grupo de Trabalho. Todos os planos estavam embasados em uma análise situacional, o que destacou a importância de dispor de dados sistematizados para políticas baseadas em evidências. Para aumentar o sucesso da implementação, um orçamento e um cronograma correspondentes ajudam a garantir a implementação adequada das intervenções. Acima de tudo, o compromisso das partes interessadas continua sendo o elemento mais fundamental para elaborar e aprovar com sucesso um plano nacional de combate ao câncer infantil. Esta é uma oportunidade de compartilhar a experiência desses países para que a estratégia possa ser adaptada a fim de apoiar outros países na elaboração de um plano de combate ao câncer infantil e possa ser estendida a outras áreas de saúde pública.

Partnering to implement the Global Initiative for Childhood Cancer in the Americas: prioritizing systems strengthening / Alianzas para ejecutar la Iniciativa Mundial contra el Cáncer Infantil en la Región de las Américas: priorizar el fortalecimiento de los sistemas / Parceria para implementar a Iniciativa Global para o Câncer Infantil nas Américas: priorização do fortalecimento dos sistemas

ABSTRACT Working with PAHO/WHO to prioritize childhood cancer in the context of systems strengthening is central to St. Jude Children's Research Hospital (SJCRH)'s role as WHO Collaborating Centre for Childhood Cancer. This manuscript focuses on how SJCRH and PAHO/WHO have partnered to apply C5 (Country Collaboration for Childhood Cancer Control) to define and implement priority actions regionally, strengthening Ministry programs for childhood cancer, while implementing the Global Initiative for Childhood Cancer since 2018. Using C5, a tool developed by SJCRH, PAHO/WHO and SJCRH co-hosted regional/national workshops engaging authorities, clinicians and other stakeholders across 10 countries to map health systems needs and prioritize strategic activities (spanning Central America, Dominican Republic, Haiti, Brazil and Uruguay). SJCRH provided English/Spanish/Portuguese C5 versions/templates for analysis/prioritization exercises, and worked with PAHO/WHO and country teams to implement C5, analyze findings, and develop outputs. In an eight-country regional workshop, countries defined priorities within national/regional initiatives and ranked their value and political will, incorporating country-specific surveys and stakeholder dialogues. Each country prioritized one strategic activity for 2022-2023, exchanged insights via storytelling, and disseminated and applied results to inform country-specific and regional action plans. National workshops analyses have been incorporated into cancer control planning activities and collaborative work regionally. Implementation success factors include engaging actors beyond the clinic, enabling flexibility, and focusing on co-design with stakeholders. Joint implementation of C5 catalyzed prioritization and accelerated strategic activities to improve policies, capacity, and quality of care for children in the Americas, supporting Ministries to integrate childhood cancer interventions as part of systems strengthening.

RESUMEN La colaboración con la OPS/OMS para priorizar el cáncer infantil en el contexto del fortalecimiento de los sistemas es fundamental para la labor del St. Jude Children's Research Hospital (SJCRH) como centro colaborador de la OMS contra el cáncer infantil. Este artículo se centra en la alianza entre el SJCRH y la OPS/OMS en la aplicación de la herramienta C5 (colaboración nacional para el control del cáncer infantil) para definir y ejecutar medidas prioritarias a nivel regional, fortalecer los programas contra el cáncer infantil del ministerio y poner en marcha la Iniciativa Mundial contra el Cáncer Infantil desde el 2018. Con C5, una herramienta elaborada por el SJCRH, la OPS/OMS y este hospital organizaron conjuntamente talleres regionales y nacionales con autoridades, personal médico y otras partes interesadas en diez países para determinar cuáles son las necesidades de los sistemas de salud y priorizar las actividades estratégicas (en América Central, República Dominicana, Haití, Brasil y Uruguay). El SJCRH proporcionó versiones y plantillas de C5 en inglés, español y portugués para actividades de análisis y priorización y trabajó con la OPS/OMS y los equipos de país para ejecutar la herramienta C5, analizar los resultados y elaborar productos. En un taller regional de ocho países, se definieron las prioridades en las iniciativas regionales y nacionales, se clasificó su valor y la voluntad política y se incorporaron encuestas específicas para cada país y diálogos con las partes interesadas. Cada país priorizó una actividad estratégica para el período 2022-2023, intercambió ideas por medio de narrativas, y difundió y aplicó los resultados para fundamentar planes de acción tanto regionales como específicos para el país. Los análisis de los talleres nacionales se han incorporado a las actividades de planificación del control del cáncer y al trabajo colaborativo a nivel regional. Entre los factores de éxito de la ejecución se encuentra involucrar a los agentes más allá de lo clínico, permitir que haya flexibilidad y centrarse en un diseño elaborado en colaboración con las partes interesadas. La ejecución conjunta de la herramienta C5 catalizó la priorización y aceleró las actividades estratégicas para mejorar las políticas, la capacidad y la calidad de la atención infantil en la Región de las Américas y brindó apoyo a los ministerios para integrar las intervenciones contra el cáncer infantil en el fortalecimiento de los sistemas.

RESUMO A colaboração com a OPAS/OMS para priorizar o câncer infantil no contexto do fortalecimento dos sistemas é fundamental para o papel do St. Jude Children's Research Hospital (SJCRH) como Centro Colaborador da OMS para o Câncer Infantil. Este artigo mostra como o SJCRH e a OPAS/OMS se associaram para aplicar a ferramenta C5 (Colaboração Nacional para Controle do Câncer Infantil), com o propósito de definir e implementar ações prioritárias regionalmente, fortalecendo programas ministeriais para o câncer na infância, durante a implementação da Iniciativa Global para o Câncer Infantil desde 2018. Com auxílio da C5, uma ferramenta desenvolvida pelo SJCRH, a OPAS/OMS e o SJCRH organizaram conjuntamente oficinas regionais/nacionais com a participação de autoridades, profissionais de saúde e outras partes interessadas em 10 países, com a finalidade de mapear as necessidades dos sistemas de saúde e priorizar atividades estratégicas (abrangendo América Central, República Dominicana, Haiti, Brasil e Uruguai). O SJCRH forneceu versões/modelos da C5 em inglês, espanhol e português para exercícios de análise/priorização e colaborou com a OPAS/OMS e as equipes dos países para implementar a C5, analisar resultados e desenvolver produtos. Em uma oficina regional com oito países, foram definidas as prioridades das iniciativas nacionais/regionais e classificados seu valor e vontade política, incorporando levantamentos nacionais e diálogos entre as partes interessadas. Cada país priorizou uma atividade estratégica para 2022-2023, trocou conhecimentos por meio da narração de histórias e disseminou e aplicou os resultados para informar planos de ação nacionais e regionais. As análises das oficinas nacionais foram incorporadas às atividades de planejamento para controle do câncer e ao trabalho conjunto no âmbito regional. Entre os fatores de êxito da implementação estão o engajamento de agentes de fora do segmento da saúde, a oferta de flexibilidade e a ênfase no planejamento conjunto com as partes interessadas. A implementação conjunta da C5 catalisou a priorização e acelerou atividades estratégicas para aprimorar as políticas, a capacidade e a qualidade da atenção às crianças nas Américas, apoiando os ministérios na integração das intervenções contra o câncer infantil como parte do fortalecimento dos sistemas.

Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue.

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.

The non-selective adenosine antagonist theophylline reverses the effects of dopamine antagonism on tremor, motor activity and effort-based decision-making.

Considerable evidence indicates that adenosine and dopamine systems interact in the regulation of basal ganglia function. Nonselective adenosine antagonists such as the methylxanthine caffeine as well as selective adenosine A2A antagonists have been shown to produce antiparkinsonian and antidepressant effects in animal models. The present studies were conducted to assess if another methylxantine, theophylline, can reverse motor and motivational impairments induced by dopamine antagonism in rats. RESULTS: Theophylline (3.75-30.0 mg/kg, IP) reversed tremulous jaw movements (TJMs), catalepsy, and locomotor suppression induced by the dopamine D2 antagonist pimozide. It also reversed TJMs induced by the muscarinic receptor agonist pilocarpine, which is a well-known tremorogenic agent. Parallel studies assessed the ability of theophylline (5.0-20.0 mg/kg, IP) to reverse the changes in effort-related choice behavior induced by the dopamine D1 antagonist ecopipam (0.2 mg/kg, IP) and the D2 antagonist haloperidol (0.1 mg/kg, IP). Rats were tested on two different operant choice tasks which assess the tendency to work for a preferred reinforcer by lever pressing (for palatable pellets or a high 5% sucrose solution) vs. approaching and consuming a less preferred reinforcer (freely available lab chow or a less concentrated 0.3% sucrose solution). Theophylline restored food and sucrose-reinforced lever pressing in animals treated with the D2 antagonist. However, it was unable to reverse the effects of the D1 antagonist. Overall, the effects of theophylline resembled those previously reported for adenosine A2A antagonists, and suggest that theophylline could be clinically useful for the treatment of motor and motivational symptoms in humans.

Tensorial and bipartite block models for link prediction in layered networks and temporal networks.

Many real-world complex systems are well represented as multilayer networks; predicting interactions in those systems is one of the most pressing problems in predictive network science. To address this challenge, we introduce two stochastic block models for multilayer and temporal networks; one of them uses nodes as its fundamental unit, whereas the other focuses on links. We also develop scalable algorithms for inferring the parameters of these models. Because our models describe all layers simultaneously, our approach takes full advantage of the information contained in the whole network when making predictions about any particular layer. We illustrate the potential of our approach by analyzing two empirical data sets: a temporal network of e-mail communications, and a network of drug interactions for treating different cancer types. We find that multilayer models consistently outperform their single-layer counterparts, but that the most predictive model depends on the data set under consideration; whereas the node-based model is more appropriate for predicting drug interactions, the link-based model is more appropriate for predicting e-mail communication.

Regulation of cell cycle progression by cell-cell and cell-matrix forces.

It has long been proposed that the cell cycle is regulated by physical forces at the cell-cell and cell-extracellular matrix (ECM) interfaces1-12. However, the evolution of these forces during the cycle has never been measured in a tissue, and whether this evolution affects cell cycle progression is unknown. Here, we quantified cell-cell tension and cell-ECM traction throughout the complete cycle of a large cell population in a growing epithelium. These measurements unveil temporal mechanical patterns that span the entire cell cycle and regulate its duration, the G1-S transition and mitotic rounding. Cells subjected to higher intercellular tension exhibit a higher probability to transition from G1 to S, as well as shorter G1 and S-G2-M phases. Moreover, we show that tension and mechanical energy are better predictors of the duration of G1 than measured geometric properties. Tension increases during the cell cycle but decreases 3 hours before mitosis. Using optogenetic control of contractility, we show that this tension drop favours mitotic rounding. Our results establish that cell cycle progression is regulated cooperatively by forces between the dividing cell and its neighbours.

Individual differences in the energizing effects of caffeine on effort-based decision-making tests in rats.

Motivated behavior is characterized by activation and high work output. Nucleus accumbens (Nacb) modulates behavioral activation and effort-based decision-making. Caffeine is widely consumed because of its energizing properties. This methylxanthine is a non-selective adenosine A1/A2A receptor antagonist. Adenosine receptors are highly concentrated in Nacb. Adenosine agonists injected into Nacb, shift preference towards low effort alternatives. The present studies characterized effort-related effects of caffeine in a concurrent progressive ratio (PROG)/free reinforcer choice procedure that requires high levels of work output, and generates great variability among different animals. Male Sprague-Dawley rats received an acute dose of caffeine (2.5-20.0 mg/kg, IP) and 30 min later were tested in operant boxes. One group was food-restricted and had to lever pressed for high carbohydrate pellets, another group was non-food-restricted and lever pressed for a high sucrose solution. Caffeine (2.5 and 5.0 mg/kg) increased lever pressing in food-restricted animals that were already high responders. However, in non-restricted animals, caffeine (5.0 and 10.0 mg/kg) increased work output only among low responders. In fact, caffeine (10.0 and 20.0 mg/kg) in non-restricted animals, reduced lever pressing among high responders in the PROG task, and also in a different group of animals lever pressing in an easy task (fixed ratio 7 schedule) that uniformly generates high levels of responding. Caffeine did not modify sucrose preference or consumption under free access conditions. Thus, when animals do not have a homeostatic need, caffeine can help those not very intrinsically motivated to work harder for a more palatable reward. However, caffeine can disrupt performance of animals intrinsically motivated to work hard for a better reward.

Cotinine administration improves impaired cognition in the mouse model of Fragile X syndrome.

Cotinine is the major metabolite of nicotine and has displayed some capacity for improving cognition in mouse models following chronic administration. We tested if acute cotinine treatment is capable of improving cognition in the mouse model of Fragile X syndrome, Fmr1-/- knockout mice, and if this is related to inhibition by cotinine treatment of glycogen synthase kinase-3ß (GSK3ß), which is abnormally active in Fmr1-/- mice. Acute cotinine treatment increased the inhibitory serine-phosphorylation of GSK3ß and the activating phosphorylation of AKT, which can mediate serine-phosphorylation of GSK3ß, in both wild-type and Fmr1-/- mouse hippocampus. Acute cotinine treatment improved cognitive functions of Fmr1-/- mice in coordinate and categorical spatial processing, novel object recognition, and temporal ordering. However, cotinine failed to restore impaired cognition in GSK3ß knockin mice, in which a serine9-to-alanine9 mutation blocks the inhibitory serine phosphorylation of GSK3ß, causing GSK3ß to be hyperactive. These results indicate that acute cotinine treatment effectively repairs impairments of these four cognitive tasks in Fmr1-/- mice, and suggest that this cognition-enhancing effect of cotinine is linked to its induction of inhibitory serine-phosphorylation of GSK3. Taken together, these results show that nicotinic receptor agonists can act as cognitive enhancers in a mouse model of Fragile X syndrome and highlight the potential role of inhibiting GSK3ß in mediating the beneficial effects of cotinine on memory.

Adenosine A2A receptor deletion affects social behaviors and anxiety in mice: Involvement of anterior cingulate cortex and amygdala.

Blockade of adenosine A2A receptors can potentiate motivation to work for natural reinforcers such as food. Conspecific interaction is a potent natural reinforcer in social animals that can be manifested as preference for social exploration versus other sources of novel stimulation. Deficiencies in this type of motivated behavior (social withdrawal) have been seen in several pathologies such as autism and depression. However, the role of A2A receptors in motivation for social interaction has not been widely explored. Social interaction paradigms evaluate the natural preference of animals for exploring other conspecifics, and the ability to differentiate between familiar versus novel ones. Anxiety is one of the factors that can induce avoidance of social interaction. In the present study, adenosine A2A knockout (A2AKO) and wild-type (WT) mice were assessed for social and anxiety-related behaviors. c-Fos immunoreactivity was evaluated as a measure of neuronal activation in brain areas involved in different aspects of motivation and emotional processes. Although A2AKO mice showed an anxious profile, they displayed higher levels of sociability and were less sensitive to social novelty. WT mice displayed a typical pattern of social recognition 24h later, but not A2AKO mice, which explored equally both conspecifics. There were no differences between strains in aggressiveness, perseverance or social odor preferences. c-Fos immunoreactivity in A2AKO mice was higher in anterior cingulate and amygdala compared to WT mice. Thus, A2A receptors appear to be potential targets for the improvement of pathologies related to social function.

Internalizing and externalizing personality and subjective effects in a sample of adolescent cannabis users. / Personalidad internalizante y externalizante y efectos subjetivos en una muestra de adolescentes consumidores de cánnabis.

Cannabis is the illicit substance most widely used by adolescents. Certain personality traits such as impulsivity and sensation seeking, and the subjective effects experienced after substance use (e.g. euphoria or relaxation) have been identified as some of the main etiological factors of consumption. This study aims to categorize a sample of adolescent cannabis users based on their most dominant personality traits (internalizing and externalizing profile). Then, to make a comparison of both profiles considering a set of variables related to consumption, clinical severity and subjective effects experienced. From a cross-sectional design, 173 adolescents (104 men and 69 women) aged 13 to 18 asking for treatment for cannabis use disorder in an Addictive Behavior Unit (UCAD) from the hospital were recruited. For the assessment, an ad hoc protocol was employed to register consumption, the Millon Adolescent Clinical Inventory (MACI) and the Addiction Research Center Inventory (ARCI) 49-item short form were also administered. Factor analysis suggested a two-profile solution: Introverted, Inhibited, Doleful, Dramatizing (-), Egotistic (-), Self-demeaning and Borderline tendency scales composed the internalizing profile, and Submissive (-), Unruly, Forceful, Conforming (-) and Oppositional scales composed the externalizing profile. The comparative analysis showed that the internalizing profile has higher levels of clinical severity and more subjective effects reported than the externalizing profile. These results suggest the need to design specific intervention strategies for each profile.

El cánnabis es la sustancia ilícita más consumida por los adolescentes. Determinados rasgos de personalidad, como la impulsividad y la búsqueda de sensaciones, así como los efectos subjetivos experimentados tras el consumo (p.e. euforia o relajación), se han identificado como algunos de los principales factores etiológicos de consumo. Este estudio tiene por objetivo categorizar a una muestra de adolescentes consumidores de cánnabis en función de sus rasgos de personalidad más predominantes (perfil internalizante y externalizante) para, posteriormente, realizar una comparación de ambos perfiles a partir de un conjunto de variables asociadas al consumo, la gravedad clínica y los efectos subjetivos experimentados. A partir de un diseño transversal, se reclutaron 173 adolescentes (104 hombres y 69 mujeres) de 13 a 18 años, que demandaron tratamiento por Trastorno por Uso de Cánnabis en la Unidad de Conductas Adictivas (UCAD) del Hospital. Para la evaluación se utilizó un protocolo ad hoc para registrar el consumo, el Inventario Clínico para Adolescentes de Millon (MACI) y la versión abreviada del Addiction Research Center Inventory (ARCI)-49. El análisis factorial sugirió una solución en 2 perfiles: las escalas Introvertido, Inhibido, Pesimista, Histriónico (-), Egocéntrico (-), Autopunitivo y Tendencia límite forman el perfil internalizante, y las escalas Sumiso (-), Rebelde, Rudo, Conformista (-) y Oposicionista el externalizante. El análisis comparativo mostró que el perfil internalizante presenta mayores niveles de gravedad clínica y reporta más efectos subjetivos que el externalizante. Estos resultados sugieren la necesidad de diseñar estrategias de intervención específicas para cada perfil.

ATP: The crucial component of secretory vesicles.

The colligative properties of ATP and catecholamines demonstrated in vitro are thought to be responsible for the extraordinary accumulation of solutes inside chromaffin cell secretory vesicles, although this has yet to be demonstrated in living cells. Because functional cells cannot be deprived of ATP, we have knocked down the expression of the vesicular nucleotide carrier, the VNUT, to show that a reduction in vesicular ATP is accompanied by a drastic fall in the quantal release of catecholamines. This phenomenon is particularly evident in newly synthesized vesicles, which we show are the first to be released. Surprisingly, we find that inhibiting VNUT expression also reduces the frequency of exocytosis, whereas the overexpression of VNUT drastically increases the quantal size of exocytotic events. To our knowledge, our data provide the first demonstration that ATP, in addition to serving as an energy source and purinergic transmitter, is an essential element in the concentration of catecholamines in secretory vesicles. In this way, cells can use ATP to accumulate neurotransmitters and other secreted substances at high concentrations, supporting quantal transmission.