Hospitalizaciones evitables por problemas de salud sensibles a cuidados ambulatorios: construcción y validación de la lista Uruguaya de patologías

Introducción: Las hospitalizaciones por Ambulatory Care Sensitive Conditions es un indicador que mide la utilización de los servicios hospitalarios por problemas de salud que podrían haber sido prevenidos en el primer nivel de atención. El concepto se refiere a los procesos en que la atención ambulatoria efectiva puede ayudar a disminuir los riesgos de hospitalización, en un segundo nivel de atención. El objetivo del estudio fue construir y validar una lista uruguaya de problemas de salud sensibles a cuidados ambulatorios (PSSCA) según CIE-10. Metodología: Para la construcción de la lista inicial de códigos de PSSCA se realizó una revisión de los listados existentes y se propuso un listado inicial que fue validado a través del Método Delphi. Se propone un listado de 99 códigos diagnósticos de PSSCA adaptado a nuestro entono sanitario. Los mismos permiten identificar y cuantificar problemas de salud que pueden producir hospitalizaciones potenciamente evitables mediante cuidados ambulatorios accesibes y oportunos en el primer nivel de atención. Resultados: Se conformó un panel de 12 expertos. A partir de los datos obtenidos, considerando los 99 diagnósticos clasificados por CIE-10, éstos se pueden subclasificar en función de si la patología es infecciosa o no, obteniendo un resultado general de 62 patologías en un total de 99 que pueden ser clasificadas como infecciosas, lo que se corresponde a un 62 %. Discusión: De la comparación de la lista uruguaya de PSSCA a la que hemos arribado y las listas validadas utilizadas para la construcción inicial del listado de patologías propuesto, podemos decir que la primera presenta un mayor porcentaje de coincidencia con la lista de patologías de Bello Horizonte. Podemos mencionar que la mayoría de los problemas de salud identificados con base en el listado de PSSCA, son sensibles de ser resueltos con la atención primaria oportuna y de calidad que podría evitar o disminuir de una manera significativa su hospitalización. Conclusiones: Este trabajo describe el proceso de construcción y validación de una lista de códigos de PSSCA adaptados al contexto uruguayo a través del método Delphi. Hemos arribado a un listado que comprende un total de 99 diagnósticos, agrupadas en un total de diecinueve categorías que considera la especificidad del contexto uruguayo del indicador.

Introduction: Hospitalizations for Ambulatory Care Sensitive Conditions is an indicator that measures the use of hospital services for health problems that could have been prevented at the first level of care. The concept refers to the processes in which effective outpatient care can help reduce the risks of hospitalization, at a second level of care. The objective of the study was to build and validate a Uruguayan list of health problems sensitive to outpatient care (PSS-CA) according to ICD-10. Methodology: To construct the initial list of PSSCA codes, a review of the existing lists was carried out and an initial list was proposed that was validated through the Delphi Method. A list of 99 PSSCA diagnostic codes adapted to our healthcare environment is proposed. They make it possible to identify and quantify health problems that can lead to potentially avoidable hospitalizations through accessible and timely outpatient care at the first level of care. Results: A panel of 12 experts was formed. From the data obtained, considering the 99 diagnoses classified by ICD-10, these can be subclassified depending on whether the pathology is infectious or not, obtaining a general result of 62 pathologies in a total of 99 that can be classified as infectious, which corresponds to 62%. Discussion: From the comparison of the Uruguayan list of PSSCA that we have arrived at and the validated lists used for the initial construction of the proposed list of pathologies, we can say that the first presents a higher percentage of coincidence with the list of pathologies of Bello Horizonte . We can mention that most of the health problems identified based on the PSSCA list are sensitive to being resolved with timely and quality primary care that could prevent or significantly reduce hospitalization. Conclusions: This work describes the process of construction and validation of a list of PSSCA codes adapted to the Uruguayan context through the Delphi method. We have arrived at a list that includes a total of 99 diagnoses, grouped into a total of nineteen categories that consider the specificity of the Uruguayan context of the indicator.

Introdução: As Internações por Condições Sensíveis à Atenção Ambulatorial são um indicador que mede a utilização de serviços hospitalares para problemas de saúde que poderiam ter sido evitados no primeiro nível de atenção. O conceito refere-se aos processos em que um atendimento ambulatorial eficaz pode auxiliar na redução dos riscos de internação, em um segundo nível de atenção. O objetivo do estudo foi construir e validar uma lista uruguaia de problemas de saúde sensíveis à atenção ambulatorial (PSS-CA) segundo a CID-10. Metodologia: Para construir a lista inicial de códigos PSSCA foi realizada uma revisão das listas existentes e foi proposta uma lista inicial que foi validada através do Método Delphi. É proposta uma lista de 99 códigos de diagnóstico PSSCA adaptados ao nosso ambiente de saúde. Permitem identificar e quantificar problemas de saúde que podem levar a hospitalizações potencialmente evitáveis ​​através de cuidados ambulatórios acessíveis e oportunos no primeiro nível de cuidados. Resultados: Foi formado um painel de 12 especialistas. A partir dos dados obtidos, considerando os 99 diagnósticos classificados pela CID-10, estes podem ser subclassificados consoante a patologia seja infecciosa ou não, obtendo-se um resultado geral de 62 patologias num total de 99 que podem ser classificadas como infecciosas, o que corresponde para 62%. Discussão: A partir da comparação da lista uruguaia de PSSCA a que chegamos e das listas validadas utilizadas para a construção inicial da lista de patologias proposta, podemos dizer que a primeira apresenta um maior percentual de coincidência com a lista de patologias de Belo Horizonte. Podemos mencionar que a maioria dos problemas de saúde identificados com base na lista PSSCA são sensíveis para serem resolvidos com cuidados primários oportunos e de qualidade que possam prevenir ou reduzir significativamente a hospitalização. Conclusões: Este trabalho descreve o processo de construção e validação de uma lista de códigos PSSCA adaptados ao contexto uruguaio através do método Delphi. Chegamos a uma lista que inclui um total de 99 diagnósticos, agrupados em um total de dezenove categorias que consideram a especificidade do contexto uruguaio do indicador.

Mecanismos de pago en salud: resultados de ejecución del pago asociado a diagnóstico en cirugía bariátrica en su primer año de implementación en Chile / Healthcare payment mechanism: Execution results of bundled payment program for bariatric surgery diagnosis in its first year of implementation in Chile

Introducción Más de 600 mil personas en Chile viven con obesidad mórbida. La incorporación de intervenciones terapéuticas eficaces, seguras y costo-efectivas es crítica para los sistemas de salud y esquemas de aseguramiento. En el año 2022 se incorporaron al arancel de modalidad de libre elección del Fondo Nacional de Salud dos códigos de pago asociado a diagnóstico para cirugía bariátrica: gástrico y manga gástrica. El objetivo fue caracterizar la ejecución del programa de mecanismo de pago tipo pago asociado a diagnóstico de cirugía bariátrica en su primer año de implementación. Métodos Estudio descriptivo y observacional de abordaje pragmático de la ejecución nacional del pago asociado a diagnóstico en cirugía bariátrica. Se examinaron variables de caracterización sociodemográfica (sexo, tramos etarios y tramos del Fondo nacional de Salud) y caracterización de cirugías según código desagregadas por prestador público o privado, periodo de emisión, gasto unitario, copago, y préstamos médicos, entre marzo y diciembre de 2022. Resultados Se registraron n = 13 118 cirugías (45,81% versus 54,19% manga), de las cuales n = 2424 (18,48%) emplearon préstamos médicos. Un 85,01% (p = 0,01) de los procedimientos fueron en mujeres; en personas entre 35 y 39 años (20,15%); y 45,12% en beneficiarios del tramo B. El 99,21% de las cirugías se realizó en prestadores privados. Diez de estos concentraron el 50% de la actividad (rango n = 1200 a 426 cirugías anuales; n = 4,8 a 1,7 cirugías por día hábil). El gasto total del programa fue $71 626 948 350 CLP, explicando un 5,04% de la actividad total del Programa nacional de Pago Asociado a Diagnóstico. Conclusiones La implementación de este bono para cirugía bariátrica benefició a más de 13 mil personas que viven con obesidad, mayormente mujeres, en edades productivas, y con capacidad de compra. Como estrategia de equidad, independientemente de la vía de acceso mediante el bono, será importante cautelar la actividad en la red pública.

Introduction More than 600 thousand people in Chile live with morbid obesity. Effective, safe, cost-effective therapeutic interventions are critical for healthcare systems and insurance schemes. In 2022, two bundled payment codes for bariatric surgery (gastric bypass and gastric sleeve) were incorporated into the National Health Fund's free-choice modality fee scheme. The objective was to characterize the execution of this payment mechanism program associated with bariatric surgery diagnosis in its first year of implementation.More than six hundred thousand people in Chile are estimated to live with morbid obesity. Effective, safe, cost-effective therapeutic interventions are critical for health systems and insurance schemes. In 2022, FONASA incorporated two Bariatric Surgery codes into the Free Choice Modality: Gastric Bypass and Sleeve Gastrectomy. Our objective was to characterize the execution of the Bariatric Surgery Bundled Payment Program in its first year of implementation. Methods Descriptive and observational study of the pragmatic approach of the national execution of the payment associated with diagnosis in bariatric surgery. We examined sociodemographic variables (sex, age brackets, and National Health Fund tranches) and characterization of surgeries by code broken down by public or private provider, period of issue, unit cost, co-payment, and medical loans between March and December 2022. Results We recorded n = 13 118 surgeries (45.81% bypass versus 54.19% sleeve), of which n = 2424 (18.48%) used medical loans. A total of 85.01% (p = 0.01) of the procedures were in women, in people between 35 and 39 years of age (20.15%), and 45.12% in beneficiaries of tranche B. Private providers performed a total of 99.21% of the surgeries. Ten accounted for 50% of the activity (range n = 1200 to 426 surgeries per year; n = 4.8 to 1.7 surgeries per working day). Total program expenditure was $71 626 948 350 CLP, accounting for 5.04% of the total activity of the national Diagnosis Associated Payment Program. Conclusions The implementation of this bariatric surgery voucher benefited more than 13 thousand people living with obesity, mostly women of productive ages and with purchasing capacity. As an equity strategy, regardless of the access route through the voucher, it will be important to safeguard the activity in the public network.

Role of Histone Methyltransferase in Fibrosis and Traditional Chinese Medicine Treatment： A Review / 中国实验方剂学杂志

Fibrosis， a tumor-like lesion between benign tissue and malignant tumor， mostly occurs in the liver， kidney， heart， lung， bone marrow and other organs and tissues. It can affect almost every organ and eventually induce multiple organ failure and cancers， seriously endangering human life. It will be of great importance to prevent cancer if the disease can be opportunely blocked in the fibrotic stage. The pathogenesis of fibrosis is still not completely clear. It is of great clinical significance to study the occurrence， development， and mechanism of fibrosis as well as to screen new therapeutic targets. Enhancer of zeste homolog 2 （EZH2） is mainly located in the nucleus and involved in the formation of the polycomb repressive complex 2. EZH2 is a methyltransferase which makes the lysine on position 27 of histone H3 （H3K27me3） undergo trimethyl modification induces gene silencing through classical or nonclassical actions， so as to inhibit or activate transcription. EZH2 plays a critical role in cell growth， proliferation， differentiation， and apoptosis， which is regulated by different targets and signaling pathways. EZH2 regulates the transformation of myofibroblasts and participates in the fibrosis of multiple organs. Recent studies have shown that EZH2 plays a role in fibrosis-related pathophysiological processes such as epithelial-mesenchymal transition， oxidative stress， and inflammation. EZH2 as the target of fibrosis， EZH2 inhibitors， and EZH2-related traditional Chinese medicine （TCM） formula and active compounds have gradually become hot research directions. EZH2 may be a powerful target for organ fibrosis. Exploring the structure， function， and distribution of EZH2， the role of EZH2 in fibrosis， the EZH2 inhibitors， and TCM formulas and active components targeting EZH2 has great meanings. This paper reviews the research progress in EZH2 and fibrosis， providing new ideas for the diagnosis， treatment， and drug development of fibrosis.

Research progress on drug treatment and drug resistance mechanism of gastrointestinal stromal tumors / 中国临床药理学与治疗学

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal-derived tumors of the gastrointestinal tract. Tyrosine kinase inhibitors (TKIs) are the cornerstone of GIST therapy, but mutations in resistance genes pose many problems for treatment, especially the heterogeneity of KIT resistance mutations. In recent years, with the release of a number of GIST related drug research and experimental results, the great potential of targeted therapy, immunotherapy and combination therapy to treat GIST in different directions has been revealed, providing more therapeutic directions for GIST. This article will review the experimental research and future direction in recent years.

Investigating the effect and mechanism of Sophorae Flavescentis Radix and Rhizoma Smilacis Glabrae combination in ameliorating psoriatic lesions / 中国药理学通报

Aim In this study, a mouse model of psoriasis-like lesions induced by 62. 5 mg imiquimod was used to explore the effect and mechanism of Sophorae Flavescentis Radix and Rhizoma Smilacis Glabrae combination for the topical treatment of psoriasis. Methods Firstly, the topical administration of Sophorae Flavescentis Radix and Rhizoma Smilacis Glabrae combination for treating psoriasis in progressive and recurrent stages was evaluated by psoriatic mouse model and HE staining. Secondly, immunohistochemistry was used to study the regulatory effects of Sophorae Flavescentis Radix and Rhizoma Smilacis Glabrae combination on the pivotal pathological mechanism of psoriasis-the positive feedback loop between the abnormal proliferation of keratinocytes and skin immune microenvironment. Finally, metabolomics technology was used to explore whether Sophorae Flavescentis Radix and Rhizoma Smilacis Glabrae combination topically treat psoriasis by regulating inflammation-related metabolism and lipid metabolism pathways. Results The combination of Sophorae Flavescentis Radix and Rhizoma Smilacis Glabrae alleviated psoriasis-like lesions in mice. It effectively relieved the recurrence after the cure of psoriatic lesions in mice, and the efficacy is comparable to that of benweimod. The combination of Sophorae Flavescentis Radix and Rhizoma Smilacis Glabrae inhibited the proliferation of mouse epidermal keratinocytes and reduced the number of T cells in the skin. The potential molecular mechanism was that the combination of Sophorae Flavescentis Radix and Rhizoma Smilacis Glabrae regulated arachidonic acid metabolism, sphin- golipid metabolism, tryptophan metabolism and phenylalanine metabolism. Conclusions The combination of Sophora Flavescens Radix and Rhizoma Smilacis Glabrae can relieve psoriasis-like lesions in mice by inhibiting the proliferation of epidermal keratinocytes and reducing the number of T cells in the skin and regulating metabolism to intervene psoriasis recurrence. This study provides a potential topical drug of psoriasis for relieving psoriasis recurrence.

Effects of 2-dodecyl-6-methoxycyclohexa-2,5-diene-l ,4-dione on resisting hepatic fibrosis induced by CC14 in rats and its mechanisms via TGF-pi/Smads signaling pathway / 中国药理学通报

Aim To investigate the effects of 2-dode-cyl-6-methoxycyclohexa-2 , 5-diene-l, 4-dione ( DM-DD) on resisting hepatic fibrosis induced by carbon tetrachloride ( CC14 ) in rats and the underlying mechanisms , with a specific focus on the TGF-pi/Smads signaling pathway. Methods The hepatic fibrosis model was replicated using 50% CC14. Various parameters, including levels of aspartate transferase ( AST) , ala-nine transferase ( ALT ) , albumin/globulin ( A/G ) , total protein (TP) , total bilirubin (T-BIL) , hyaluron-ic acid ( HA ) , laminin ( LN ) , collagen type Ж ( Col Ж) , and collagen type IV(ColIV) in the blood, were measured. Liver tissue lesions and fiber formation were observed using HE and Masson staining. The expression levels of a smooth muscle actin (a-SMA) , collagen type I ( Col I ) , transformed growth factor (TGF-pi), Smad2, and Smad7 proteins were assessed using immunohistochemistry. a-SMA, Coll, TGF-pi, and Smad7 mRNA levels in liver tissue were measured by RT-PCR. Additionally, the expression levels of TGF-pi, Smad4, and Smad7 proteins in liver tissue were determined by Western blot. Results In comparison to the normal control group, the model group exhibited significantly elevated levels of AST, ALT, TP, T-BIL, HA, LN, Col Ш and Col IV in serum. But A/G level notably decreased. Successful modeling was confirmed by the presence of extensive fiber formations observed through HE and Massonstaining in liver tissue. The DMDD administration group demonstrated a notable decrease levels of AST, ALT, TP, T-BIL, HA, LN, Col III, and CollV, but A/G was significantly elevated when compared to the model group. Furthermore, a-SMA, Coll, TGF-f31, Smad2 and Smad4 mRNA and protein levels in the DMDD administration group were significantly reduced, while Smad7 significantly declined. HE and Masson staining results reflected a marked reduction in fibrous hyper-plasia. Conclusion DMDD exhibits a protective effect against CCl4-induced hepatic fibrosis, and its mechanism appears to be associated with the TGF-fJl/ Smads signaling pathway.

Participación ciudadana en Colombia. Revisión documental

El objetivo es analizar la eficacia de los procesos de participación ciudadana en Colombia. Como metodología se optó por la investigación cualitativa, bajo el enfoque hermenéutico y como estrategia la revisión documental por medio de la cual se recuperaron diferentes documentos científicos que giraban alrededor de los temas de interés para aclarar las preguntas de investigación. Entre los resultados se encontró que, a pesar de que la Constitución Política de 1991 definió los parámetros para la participación, aún existe mucha apatía y desconocimiento sobre ellos y, finalmente, se concluyó que, entre los factores que impiden las buenas prácticas en el ejercicio de participación ciudadana, están las brechas digitales, el abstencionismo electoral, el desconocimiento de la población y la apatía de los gobernantes de integrar a la población en las decisiones del país.

This article aims to analyze the effectiveness of citizen participation processes in Colombia. As a methodology, qualitative research was chosen, under the hermeneutical approach, and as a strategy, the documentary review where different scientific documents that revolved around the topics of interest were recovered to clarify the research questions. Among the results, it was found that even though the Political Constitution of 1991 defined the parameters for participation, there is still a lot of apathy and ignorance about them. It was finally concluded that among the factors that prevent good practices in the exercise of citizen participation are the digital gaps, electoral abstentionism, ignorance of the population, and the apathy of the rulers to integrate the people in the country's decisions.

O objetivo é analisar a eficácia dos processos de participação cidadã na Colômbia. Como metodologia, optou-se pela pesquisa qualitativa, sob a abordagem hermenêutica e, como estratégia, a revisão documental onde foram recuperados diferentes documentos científicos que giravam em torno dos temas de interesse para esclarecer as questões de pesquisa. Entre os resultados, verificou-se que, apesar da Constituição Política de 1991 ter definido os parâmetros para a participação, ainda há muita apatia e desconhecimento sobre eles e, por fim, concluiu-se que dentre os fatores que impedem as boas práticas no exercício de participação cidadã, são as lacunas digitais, o abstencionismo eleitoral, o desconhecimento da população e a apatia dos governantes em integrar a população nas decisões do país.

Mecánica Tusígena / Cough Mechanics

El control neurológico de la tos o la neurofisiología de la tos, implica una serie de eventos complejos en el sistema nervioso que coordinan y desencadenan este reflejo protector pulmonar. Esta intrincada red de señales nerviosas y coordinación muscular se origina en los receptores de la tos, pasa por el centro de la tos en el bulbo raquídeo y finalmente activa los músculos necesarios para la adecuada eliminación del agente irritante. Este mecanismo involucra, la detección del estímulo por receptores especializados, transducción de señales que viajan a lo largo de fibras nerviosas aferentes hacia el sistema nervioso central, centro integrador a nivel del bulbo raquídeo, en el centro de la tos es donde se procesa las señales de los receptores y se coordina la respuesta. La integración de las señales y la respuesta radica en este centro de la tos y en la corteza cerebral quien regula y modula la tos. El control neuronal cortical de la tos implica la participación consciente y voluntaria de la corteza cerebral en la percepción, regulación y adaptación de la tos. La coordinación muscular requiere que la señal viaje por vías nerviosas eferentes motoras hacia los músculos involucrados, la contracción muscular se integra en una secuencia específica que desencadena las fases de la tos, inspiración máxima, compresión y expulsiva.

The neurological control of cough, or the neurophysiology of cough, involves a series of complex events in the nervous system that coordinate and trigger this lung protective reflex. This intricate network of nerve signals and muscle coordination originates from the cough receptors, passes through the cough center in the medulla oblongata, and finally activates the muscles necessary for proper elimination of the irritant. This mechanism involves the detection of the stimulus by specialized receptors, transduction of signals that travel along afferent nerve fibers towards the central nervous system, integrating center at the level of the medulla oblongata, in the cough center is where the signals are processed. receptors and the response is coordinated. The integration of signals and response resides in this cough center and in the cerebral cortex, which regulates and modulates coughing. Cortical neural control of cough involves the conscious and voluntary participation of the cerebral cortex in the perception, regulation, and adaptation of cough. Muscle coordination requires that the signal travel through efferent motor nerve pathways to the muscles involved; muscle contraction is integrated into a specific sequence that triggers the cough, maximum inspiration, compression, and expulsive phases.

Status of Serum Magnesium in Different Stages of CKD Patients: A Tertiary Care Hospital Study in Bangladesh

Background: In chronic kidney disease (CKD), renal regulatory mechanisms may be insufficient to balance intestinal magnesium absorption hence insufficient to maintain homeostasis. But related data are relatively sparse and not readily available, especially in Bangladesh context. Aim of the study: The aim of the study was to assess the pattern of serum magnesium level in different stages of CKD patients. Material & Methods: This descriptive cross-sectional study was conducted in the Department of Medicine and the Department of Nephrology, Dhaka Medical College Hospital (DMCH) for nine months’ period. Approval for the study was taken from the ethical review committee of DMC before the commencement of the study. Diagnosed patients of chronic kidney disease (CKD) were approached for the inclusion of the study. Informed written consent was taken from each patient. All patients were subjected to detailed history taking, physical examination, and relevant investigations. For the study purpose, serum magnesium was done for all patients. Results: After compiling data from all participants, statistical analysis was performed using the statistical package for social science (SPSS) version 22 for windows, and a p < 0.05 was considered statistically significant. Mean age of the patients was 53 years with male predominance (male 64% vs female 36%). Of all, 6.7% of cases had hypomagnesemia and 55.3% had hypermagnesemia. The mean serum magnesium level was 2.68±0.81 mg/dl. Assessment of serum magnesium in a different stages of CKD showed that hypermagnesemia is associated with higher staging (p<0.05), and there is a negative correlation between lower e-GFR with serum magnesium ((r=-0.753, p<0.01). Conclusion: Nearly two-third of CKD patients were found with altered magnesium level in the form of hypomagnesemia or hypermagnesemia in this study. Serum magnesium was found increased in higher stages of CKD. That means serum magnesium level increases along with higher stage of the disease. Urinary magnesium excretion also decreases when eGFR of patient decreased.

Relación estructura-función de la enzima uroporfirinógeno descarboxilasa: implicancias para la comprensión y el tratamiento de la porfiria cutánea tarda / Structure-function relationship of the enzyme uroporphyrinogen decarboxylase: implications for the understanding and treatment of porphyria cutanea tarda / Relação estrutura-função da enzima uroporfirinogênio descarbioxilase: implicações para a compreensão e tratamento da porfiria cutânea tardia / Reconocimiento a la trayectoria del Prof. Dr. Juan Miguel Castagnino†

Resumen La uroporfirinógeno descarboxilasa humana (UROD-h) es la quinta enzima del camino biosintético del hemo y su actividad deficiente, relacionada a mutaciones en su gen, se encuentra asociada a un subgrupo de porfirias. El objetivo de este trabajo fue estudiar la relación entre la dimerización de la enzima y su actividad enzimática y comprobar si la dimerización de UROD-h es imprescindible tanto para la primera etapa de la reacción (urogen→heptagen), como para la segunda etapa (heptagen→coprogen). Con ese objetivo, se expresó y purificó la UROD-h hasta homogeneidad, se analizó el comportamiento dímero-monómero bajo distintas condiciones que pudieran desplazar el equilibrio de dimerización y se evaluó la actividad enzimática en dichas condiciones. Los resultados obtenidos sugieren que la especie activa para la primera etapa de la reacción es el homodímero y que tanto el dímero como el monómero se comportan como especies activas para la segunda etapa de la reacción. Se propone que mutaciones clínicas como la Y311C, existentes en pacientes con porfiria cutánea tarda, podrían afectar la estabilidad del dímero y podrían ser el blanco para futuras terapias génicas.

Abstract Human uroporphyrinogen decarboxylase (UROD-h) is the fifth enzyme in the heme biosynthetic pathway and its deficient activity, related to mutations in its gene, is associated with a subset of porphyrias. The objective of this work was to study the relationship between the dimerisation of the enzyme and its enzymatic activity and to verify if the dimerisation of UROD-h is essential both for the first stage of the reaction (urogen→heptagen), and for the second stage (heptagen→ coprogen). With this objective, the UROD-h was expressed and purified to homogeneity, the dimer- monomer behaviour was analysed under different conditions, which could shift the dimerisation equilibrium, and the enzymatic activity was evaluated under these conditions. The results obtained suggest that the active species for the first stage of the reaction is the homodimer, and both the dimer and the monomer behaved as active species for the second stage of the reaction. It is proposed that clinical mutations such as Y311C, existing in porphyria cutanea tarda patients, could affect dimer stability and could be the target of future gene therapies.

Resumo A enzima uroporfirinogênio descarboxilase humana (UROD-h) é a quinta enzima da via biossintética do heme e sua atividade deficiente, relacionada com mutações em seu gene, está associada a um subgrupo de porfirias. O objetivo deste trabalho foi estudar a relação entre a dimerização da enzima e sua atividade enzimática e comprovar se a dimerização da UROD-h é imprescindível tanto para a primeira etapa da reação (urogênio→heptagênio), quanto para a segunda etapa (heptagênio→coprogênio). Com esse objetivo, a UROD-h foi expressa e purificada até a homogeneidade, o comportamento de dímero-monômero foi analisado sob diversas condições, que puderam deslocar o equilíbrio de dimerização, e a atividade enzimática foi avaliada em tais condições. Os resultados obtidos sugerem que a espécie ativa para a primeira etapa da reação é o homodímero, e tanto o dímero quanto o monômero se comportam como espécies ativas para a segunda etapa da reação. Propõe-se que mutações clínicas como Y311C, existentes em pacientes com porfiria cutânea tardia, poderiam afetar a estabilidade do dímero e poderiam ser o alvo de futuras terapias gênicas em porfiria cutânea tardia.

Experiencia en la generación de estrategias de monitorización y evaluación en la implantación de Guías de Práctica Clínica en España / Experience Generating Evaluation and Monitoring Strategies in the Implementation of Clinical Practice Guidelines in Spain / Experiência na geração de estratégias de monitoramento e avaliação na implementação de manuais de prática clínica na Espanha

Introducción. La monitorización de la utilización del conocimiento y la evaluación de resultados permiten conocer la aplicación de la evidencia, cambios en los conocimientos y actitudes, el impacto en resultados de salud y la integración y el mantenimiento de las prácticas adoptadas. Existen debilidades relacionadas con la falta de sistematización, limitaciones de los registros y calidad del proceso. El objetivo de este artículo es describir la experiencia en la generación de estrategias de monitorización y evaluación de resultados de implantación de Guías de Buenas Prácticas en España. División de temas tratados. En primer lugar, se revisan los procesos de medición de resultados en la implantación de Guías, en el marco del Programa Best Practice Spotlight Organizations®, cuya herramienta para liderar el cambio incluye la monitorización y evaluación como una de las seis fases del ciclo de acción. En segundo lugar, se analizan las estrategias de monitorización y evaluación propuestas en la literatura, destacando la Asociación Profesional de Enfermeras de Ontario. Finalmente, se analizan las estrategias de monitorización y evaluación generadas por dos instituciones españolas participantes en el programa, centradas en adecuación de registros, explotación y análisis de indicadores, desarrollo de herramientas, procedimientos de evaluación y mecanismos de difusión y retroalimentación. Conclusiones. La definición de estrategias de monitorización y evaluación planificada de forma temprana contribuye a la viabilidad de la evaluación de la implantación y su sostenibilidad. Es necesario adaptarlas al contexto, con estrategias transversales que alcancen a toda la institución, facilitadas por la institución. Palabras clave: Ciencia de la Implementación; Práctica Clínica Basada en la Evidencia; Evaluación de Resultado en la Atención de Salud; Mecanismos de Evaluación de la Atención de Salud; Indicadores de Calidad de la Atención de Salud

Introduction. Monitoring the usage of knowledge and evaluating results permits one to know the application of the evidence, knowledge, and attitude changes, the impact on health results, integration, and maintenance of the adopted practices. There exist weaknesses related to lack of systematization, limitation of the records, and quality of the process. This article's objective is to describe the experience generating monitoring strategies and evaluation of the results regarding the implementation of good practice guides in Spain. Topics for Reflection. In the first place, the measurement process of the results regarding the implementation of guides are reviewed, in the Best Practice Spotlight Organizations® program frame, whose tool to lead the change includes monitoring and evaluation as one of the sixth phases of the action cycle. In the second place, monitoring and evaluation strategies proposed in the literature are analyzed, highlighting the Professional Nurses Association of Ontario. Finally, the monitoring and evaluation strategies are analyzed by two Spanish institutions participating in the program, focused on the adequation of records, exploitation and indicator analysis, tools development, evaluation procedures, dissemination, and feedback mechanisms. Conclusions: The definition of monitoring and evaluation strategies planned in advance contributes to the viability of the evaluation regarding the implementation and its sustainability. Is necessary to adapt them to the context, with transversal strategies that reach the whole institution, facilitated by the institution. Keywords: Implementation Science; Evidence-Based Practice; Outcome Assessment, Health Care; Health Care Evaluation Mechanisms; Quality Indicators, Health Care

Introdução. Monitorizar a utilização do conhecimento e avaliar os resultados permite-nos conhecer a aplicação das evidências, as mudanças nos conhecimentos e atitudes, o impacto nos resultados de saúde e a integração e manutenção das práticas adotadas. Existem fragilidades relacionadas à falta de sistematização, limitações de registros e qualidade do processo. O objetivo deste artigo é descrever a experiência na geração de estratégias de monitoramento e avaliação dos resultados da implementação de Manuais de Boas Práticas na Espanha. Divisão dos temas abordados. Em primeiro lugar, são revistos os processos de medição de resultados na implementação dos Manuais, no âmbito do Programa Best Practice Spotlight Organizations®, cuja ferramenta para liderar a mudança inclui a monitorização e avaliação como uma das seis fases do ciclo de ação. Em segundo lugar, são analisadas as estratégias de monitoramento e avaliação propostas na literatura, com destaque para a Associação Profissional de Enfermeiros de Ontário. Por fim, são analisadas as estratégias de monitoramento e avaliação geradas por duas instituições espanholas participantes do programa, focadas na adaptação de registros, exploração e análise de indicadores, desenvolvimento de ferramentas, procedimentos de avaliação e mecanismos de divulgação e feedback. Conclusões. A definição de estratégias de monitoramento e avaliação planeadas antecipadamente contribui para a viabilidade da avaliação da implementação e para a sua sustentabilidade. É necessário adaptá-los ao contexto, com estratégias transversais que alcancem toda a instituição, facilitadas pela instituição. Palavras-chave: Ciência da Implementação; Prática Clínica Baseada em Evidências; Avaliação de Resultados em Cuidados de Saúde; Mecanismos de Avaliação da Assistência à Saúde; Indicadores de Qualidade em Assistência à Saúde

In vitro evaluation for estrogenic mechanisms of the disinfectant benzalkonium chloride as an emerging contaminant

This study aimed to evaluate in vitro the possible mechanisms underlying the estrogenic potential of benzalkonium chloride (BAC) as a disinfectant emerging contaminant. Effects of BAC at the environmentally-relevant concentrations on estrogen synthesis and estrogen receptor (ER) signaling were assessed using the H295R steroidogenesis assay and the MCF-7 proliferation assay, respectively. Results showed that exposure to BAC at concentrations of 1.0-1.5 mg/L for 48 h significantly increased estradiol production of H295R cells in a concentration-dependent manner. Transcription of steroidogenic genes 3β‐HSD2, 17β‐HSD1, 17β‐HSD4, and CYP19A were significantly enhanced by BAC. In ER-positive MCF-7 cells, exposure to 0.5-1.5 mg/L BAC for 48 h significantly promoted cell proliferation and increased the expressions of ERα and G-protein coupled estrogen receptor 1. Flow cytometry analysis showed that 0.5-1.5 mg/L BAC significantly decreased the percentage of cells in G0/G1 phase, increased the percentage in S phase, and BAC at concentrations of 1.0 and 1.5 mg/L increased the G2/M phase cells. Findings of the study suggested that BAC at environmentally-relevant concentrations might act as a xenoestrogen through its inhibitory effect on steroidogenesis and ER-mediated mechanism.

The amygdala lesioning due to status epilepticus - Changes in mechanisms controlling chloride homeostasis

Objective: Amygdala has been demonstrated as one of the brain sites involved in the control of cardiorespiratory functioning. The structural and physiological alterations induced by epileptic activity are also present in the amygdala and reflect functional changes that may be directly associated with a sudden unexpected death. Seizures are always associated with neuronal damage and changes in the expression of cation-chloride cotransporters and Na/K pumps. In this study, the authors aimed to investigate if these changes are present in the amygdala after induction of status epilepticus with pilocarpine, which may be directly correlated with Sudden Unexpected Death in Epilepsy (SUDEP). Methods: Pilocarpine-treated wistar rats 60 days after Status Epilepticus (SE) were compared with control rats. Amygdala nuclei of brain slices immunostained for NKCC1, KCC2 and α1-Na+/K+-ATPase, were quantified by optical densitometry. Results: The amygdaloid complex of the animals submitted to SE had no significant difference in the NKCC1 immunoreactivity, but KCC2 immunoreactivity reduced drastically in the peri-somatic sites and in the dendritic-like processes. The α1-Na+/K+-ATPase peri-somatic immunoreactivity was intense in the rats submitted to pilocarpine SE when compared with control rats. The pilocarpine SE also promoted intense GFAP staining, specifically in the basolateral and baso-medial nuclei with astrogliosis and cellular debris deposition. Interpretation: The findings revealed that SE induces lesion changes in the expression of KCC2 and α1-Na + /K + -ATPase meaning intense change in the chloride regulation in the amygdaloid complex. These changes may contribute to cardiorespiratory dysfunction leading to SUDEP.

The nonsynaptic plasticity in Parkinson's disease: Insights from an animal model

Abstract Background The 6-OHDA nigro-striatal lesion model has already been related to disorders in the excitability and synchronicity of neural networks and variation in the expression of transmembrane proteins that control intra and extracellular ionic concentrations, such as cation-chloride cotransporters (NKCC1 and KCC2) and Na+/K+-ATPase and, also, to the glial proliferation after injury. All these non-synaptic mechanisms have already been related to neuronal injury and hyper-synchronism processes. Objective The main objective of this study is to verify whether mechanisms not directly related to synaptic neurotransmission could be involved in the modulation of nigrostriatal pathways. Methods Male Wistar rats, 3 months old, were submitted to a unilateral injection of 24 µg of 6-OHDA, in the striatum (n= 8). The animals in the Control group (n= 8) were submitted to the same protocol, with the replacement of 6-OHDA by 0.9% saline. The analysis by optical densitometry was performed to quantify the immunoreactivity intensity of GFAP, NKCC1, KCC2, Na+/K+-ATPase, TH and Cx36. Results The 6-OHDA induced lesions in the striatum, were not followed by changes in the expression cation-chloride cotransporters and Na+/K+-ATPase, but with astrocytic reactivity in the lesioned and adjacent regions of the nigrostriatal. Moreover, the dopaminergic degeneration caused by 6-OHDA is followed by changes in the expression of connexin-36. Conclusions The use of the GJ blockers directly along the nigrostriatal pathways to control PD motor symptoms is conjectured. Electrophysiology of the striatum and the substantia nigra, to verify changes in neuronal synchronism, comparing brain slices of control animals and experimental models of PD, is needed.

Apoyo/control docente a las relaciones sociales, cohesión de clase y consecuencias positivas y negativas en educación física / Apoio/controle docente nas relações sociais, coesão de classe e consequências positivas e negativas na educação física / Teacher support/control of social relationships, class cohesion, and positive/negative consequences in physical education

El objetivo del estudio fue examinar la relación entre el apoyo/control docente a las relaciones sociales de los estudiantes y la implicación y las conductas disruptivas, y examinar el efecto mediador de la cohesión de clase. Participaron 718 estudiantes de Educación Física entre los 15 y 18 años (M = 15.65; DT = .70). Los resultados del estudio correlacional mostraron que el apoyo docente hacia las relaciones sociales se relacionó positivamente con la implicación y negativamente con las conductas disruptivas. En cambio, el control a las relaciones sociales se relacionó negativamente con la implicación y positivamente con las conductas disruptivas. Finalmente, los resultados mostraron que la cohesión de la clase medió entre el apoyo a las relaciones sociales y la implicación. En conclusión, el apoyo a las relaciones sociales y la cohesión de clase pueden producir un impacto significativo en la implicación y comportamientos disruptivos. (AU)

O objetivo do estudo foi examinar a relação entre o apoio/controle do professor nas relações sociais dos alunos e o envolvimento intraclasse e comportamentos disruptivos, além de examinar o efeito mediador da coesão de classe. Participaram 718 alunos de Educação Física entre 15 e 18 anos (M = 15.65; SD = .70). Os resultados do estudo correlacional mostraram que o apoio do professor às relações sociais foi positivamente relacionado ao envolvimento e negativamente relacionado aos comportamentos disruptivos. Em contraste, o controle das relações sociais foi negativamente relacionado ao envolvimento e positivamente relacionado aos comportamentos disruptivos. Por fim, os resultados mostraram que a coesão de classe mediava o apoio às relações sociais e o envolvimento. Em conclusão, o apoio às relações sociais e à coesão de classe pode ter um impacto significativo no envolvimento e nos comportamentos disruptivos. (AU)

The aim of the study was to examine the relationship between teacher support/control of students' social relations and class engagement and disruptive behaviors, as well as to examine the mediating effect of class cohesion. 718 Physical Education students between 15 and 18 years participated (M = 15.65; SD = .70) in this study. The results of the correlational study showed that teacher support for relatedness was positively related to engagement and negatively related to disruptive behaviors. In contrast, relatedness control was negatively related to engagement and positively related to disruptive behaviors. Finally, the results showed that class cohesion mediated relatedness support and engagement. In conclusion, relatedness support and class cohesion can significantly impact engagement and disruptive behaviors. (AU)

The feasibility of oral targeted drug delivery: Gut immune to particulates?

Targeted drug delivery is constantly updated with a better understanding of the physiological and pathological features of various diseases. Depending on high safety, good compliance and many other undeniable advantages, attempts have been undertaken to complete an intravenous-to-oral conversion of targeted drug delivery. However, oral delivery of particulates to systemic circulation is highly challenging due to the biochemical aggressivity and immune exclusion in the gut that restrain absorption and access to the bloodstream. Little is known about the feasibility of targeted drug delivery via oral administration (oral targeting) to a remote site beyond the gastrointestinal tract. To this end, this review proactively contributes to a special dissection on the feasibility of oral targeting. We discussed the theoretical basis of oral targeting, the biological barriers of absorption, the in vivo fate and transport mechanisms of drug vehicles, and the effect of structural evolution of vehicles on oral targeting as well. At last, a feasibility analysis on oral targeting was performed based on the integration of currently available information. The innate defense of intestinal epithelium does not allow influx of more particulates into the peripheral blood through enterocytes. Therefore, limited evidence and lacking exact quantification of systemically exposed particles fail to support much success with oral targeting. Nevertheless, the lymphatic pathway may serve as a potentially alternative portal of peroral particles into the remote target sites via M-cell uptake.

The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer

Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG). Mutants of IDH1 or IDH2 can produce d-2-hydroxyglutarate (D-2HG) with α-KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2, implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.

Recent advances in diverse nanosystems for nitric oxide delivery in cancer therapy

Gas therapy has been proven to be a promising and advantageous treatment option for cancers. Studies have shown that nitric oxide (NO) is one of the smallest structurally significant gas molecules with great potential to suppress cancer. However, there is controversy and concern about its use as it exhibits the opposite physiological effects based on its levels in the tumor. Therefore, the anti-cancer mechanism of NO is the key to cancer treatment, and rationally designed NO delivery systems are crucial to the success of NO biomedical applications. This review summarizes the endogenous production of NO, its physiological mechanisms of action, the application of NO in cancer treatment, and nano-delivery systems for delivering NO donors. Moreover, it briefly reviews challenges in delivering NO from different nanoparticles and the issues associated with its combination treatment strategies. The advantages and challenges of various NO delivery platforms are recapitulated for possible transformation into clinical applications.

Building on the backbone of CD47-based therapy in cancer: Combination strategies, mechanisms, and future perspectives

Described as a "don't eat me" signal, CD47 becomes a vital immune checkpoint in cancer. Its interaction with signal regulatory protein alpha (SIRPα) prevents macrophage phagocytosis. In recent years, a growing body of evidences have unveiled that CD47-based combination therapy exhibits a superior anti-cancer effect. Latest clinical trials about CD47 have adopted the regimen of collaborating with other therapies or developing CD47-directed bispecific antibodies, indicating the combination strategy as a general trend of the future. In this review, clinical and preclinical cases about the current combination strategies targeting CD47 are collected, their underlying mechanisms of action are discussed, and ideas from future perspectives are shared.

Liver cell therapies: cellular sources and grafting strategies / 医学前沿

The liver has a complex cellular composition and a remarkable regenerative capacity. The primary cell types in the liver are two parenchymal cell populations, hepatocytes and cholangiocytes, that perform most of the functions of the liver and that are helped through interactions with non-parenchymal cell types comprising stellate cells, endothelia and various hemopoietic cell populations. The regulation of the cells in the liver is mediated by an insoluble complex of proteins and carbohydrates, the extracellular matrix, working synergistically with soluble paracrine and systemic signals. In recent years, with the rapid development of genetic sequencing technologies, research on the liver's cellular composition and its regulatory mechanisms during various conditions has been extensively explored. Meanwhile breakthroughs in strategies for cell transplantation are enabling a future in which there can be a rescue of patients with end-stage liver diseases, offering potential solutions to the chronic shortage of livers and alternatives to liver transplantation. This review will focus on the cellular mechanisms of liver homeostasis and how to select ideal sources of cells to be transplanted to achieve liver regeneration and repair. Recent advances are summarized for promoting the treatment of end-stage liver diseases by forms of cell transplantation that now include grafting strategies.