Fibrosis quística: epidemiología, clínica, diagnóstico y tratamiento / Cystic fibrosis: Epidemiology, clinical manifestations, diagnosis and treatment

La fibrosis quística es una enfermedad genética y multisistémica. La principal comorbilidad en la edad adulta es la afectación respiratoria, con la presencia de bronquiectasias, infección bronquial crónica y obstrucción al flujo aéreo. Hasta hace una década los tratamientos estaban dirigidos a favorecer el drenaje de secreciones, reducir las exacerbaciones respiratorias, controlar la infección bronquial crónica y enlentecer el deterioro funcional, pero con la llegada de los moduladores del gen cystic fibrosis transmembrane conductance regulator (CFTR) el paradigma de la fibrosis quística se ha modificado. Este novedoso tratamiento da un paso más frente al tratamiento de esta enfermedad, es capaz de mejorar la producción de proteína CFTR defectuosa y aumentar su expresión en la superficie celular, para así conseguir un mejor funcionamiento del intercambio iónico fluidificando las secreciones respiratorias y reduciendo la obstrucción al flujo aéreo. Además, en la actualidad hay diferentes líneas de investigación orientadas a corregir el defecto genético causante de la fibrosis quística (AU)

Cystic fibrosis is a genetic and multisystemic disease. The main comorbidity in adulthood is respiratory involvement, with the presence of bronchiectasis, chronic bronchial infection and airflow obstruction. Until a decade ago, treatments were aimed at favoring secretion drainage, reducing respiratory exacerbations, controlling chronic bronchial infection and slowing functional deterioration, but with the advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, the cystic fibrosis paradigm has changed. This novel treatment goes a step further in the management of this disease, it is able to improve the production of defective CFTR protein and increase its expression on the cell surface, thus achieving a better functioning of ion exchange, fluidizing respiratory secretions and reducing airflow obstruction. In addition, there are currently different lines of research aimed at correcting the genetic defect that causes cystic fibrosis (AU)

Cystic fibrosis: Epidemiology, clinical manifestations, diagnosis and treatment. / Fibrosis quística: epidemiología, clínica, diagnóstico y tratamiento.

Cystic fibrosis is a genetic and multisystemic disease. The main comorbidity in adulthood is respiratory involvement, with the presence of bronchiectasis, chronic bronchial infection and airflow obstruction. Until a decade ago, treatments were aimed at favoring secretion drainage, reducing respiratory exacerbations, controlling chronic bronchial infection and slowing functional deterioration, but with the advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, the cystic fibrosis paradigm has changed. This novel treatment goes a step further in the management of this disease, it is able to improve the production of defective CFTR protein and increase its expression on the cell surface, thus achieving a better functioning of ion exchange, fluidizing respiratory secretions and reducing airflow obstruction. In addition, there are currently different lines of research aimed at correcting the genetic defect that causes cystic fibrosis.

The cannabinoids mechanism of action: an overview / Mecanismo de ação dos canabinoides: visão geral

ABSTRACT BACKGROUND AND OBJECTIVES: The discovery of the psychoactive agent of Cannabis sativa (tetrahydrocannabinol - THC) in the second half of the 20th century originated the research that later came to identify dozens of other substances from this plant, including cannabinoids, terpenes and flavonoids. Ensuing description of their interaction sites in animals and humans, together with endogenous ligands, transport proteins as well as synthesis and degradation enzymes, revealed what came to be known as the endocannabinoid system. Several receptors participate in this system. CONTENTS: The first receptors to be discovered were called CB1 and CB2, both are G protein-coupled (GPCR). It is noteworthy that CB1 receptors are among the most abundant and widely distributed GPCR in the mammalian brain, with marked expression in basal ganglia, cerebellum and hippocampus, for instance; on the other hand, they are scarce in areas of the brainstem related to breathing control. In light of the multiplicity of pharmacological effects of cannabinoids, concomitant with the lack of more clarifying studies on their mechanisms of action despite the great interest in research on their therapeutic application, it is necessary to deepen the knowledge in this area. CONCLUSION: Considering the literature research conducted for the composition of this article, it is possible to conclude that cannabinoids have a broad spectrum of action mechanisms in the human body, and that more robust clinical studies are needed to better understand their broad therapeutic potential.

RESUMO JUSTIFICATIVA E OBJETIVOS: A descoberta do princípio psicoativo da Cannabis sativa (tetrahidrocanabinol - THC) na segunda metade do século XX inaugurou pesquisas que posteriormente vieram a identificar dezenas de outras substâncias a partir dessa planta, incluindo canabinoides, terpenos e flavonoides. A subsequente descrição dos sítios de interação dessas substâncias em animais e humanos, assim como seus ligantes endógenos, proteínas de transporte e enzimas de síntese e degradação, revelou o que veio a ser conhecido como sistema endocanabinoide. Diversos receptores participam deste sistema. CONTEÚDO: Os primeiros receptores a serem descobertos foram denominados CB1 e CB2, ambos são acoplados à proteína G (GPCR). É importante ressaltar que os receptores CB1 estão entre os GPCRs mais abundantes e amplamente distribuídos do encéfalo de mamíferos, com marcada expressão, por exemplo, em gânglios da base, cerebelo e hipocampo; em contrapartida, são escassos em áreas do tronco cerebral relacionadas ao controle da respiração. Diante da multiplicidade de efeitos farmacológicos dos canabinoides, concomitante à falta de estudos mais esclarecedores sobre seus mecanismos de ação apesar do grande interesse na pesquisa de sua aplicação terapêutica, é preciso aprofundar o conhecimento nessa área. CONCLUSÃO: Considerando as pesquisas bibliográficas realizadas para a composição deste artigo, é possível concluir que os canabinoides possuem um amplo espectro de mecanismos de ação no organismo humano, e que mais estudos clínicos robustos são necessários para que seja possível entender melhor o seu amplo potencial terapêutico.

Elexacaftor/tezacaftor/ivacaftor-real-world clinical effectiveness and safety. A single-center Portuguese study / Elexacaftor/tezacaftor/ivacaftor-efetividade clínica e segurança no mundo real. Estudo unicêntrico português

ABSTRACT Objective: To evaluate the effectiveness of treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) and to characterize its safety profile in cystic fibrosis (CF) patients in a real-world clinical setting. Methods: This was a prospective observational study carried out in a CF referral center in Portugal involving adult CF patients who started treatment with ELX/TEZ/IVA. Clinical characteristics of the patients were collected, and effectiveness and safety data were evaluated. Results: Of the 56 patients followed in the center at the time of the study, 28 were eligible for ELX/TEZ/IVA treatment in accordance with the Portuguese National Authority for Medicines and Health Products at the time of the study. Of these, 24 met the follow-up time requirement to be included in the clinical effectiveness analysis. The mean follow-up time was 167.3 ± 96.4 days. Adverse events were generally mild and self-limited. Significant improvements in lung function, BMI, sweat chloride concentration, and number of pulmonary exacerbations were observed. No significant differences in outcomes between F508del homozygous and heterozygous patients were found. The effectiveness of this new CFTR modulator combination also applied to patients with advanced lung disease. Conclusions: Treatment with ELX/TEZ/IVA showed effective improvement in real-world clinical practice, namely in lung function, BMI, sweat chloride concentration, and number of pulmonary exacerbations, with no safety concerns.

RESUMO Objetivo: Avaliar a efetividade do tratamento com elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) e caracterizar seu perfil de segurança em pacientes com fibrose cística (FC) em um cenário clínico de mundo real. Métodos: Estudo observacional prospectivo realizado em um centro de referência em FC de Portugal com pacientes adultos com FC que iniciaram o tratamento com ELX/TEZ/IVA. As características clínicas dos pacientes foram coletadas, e os dados de efetividade e segurança, avaliados. Resultados: Dos 56 pacientes acompanhados no centro na época do estudo, 28 eram elegíveis para o tratamento com ELX/TEZ/IVA de acordo com a Autoridade Nacional do Medicamento e Produtos de Saúde. Destes, 24 atenderam ao requisito de tempo de acompanhamento para inclusão na análise de efetividade clínica. O tempo médio de acompanhamento foi de 167,3 ± 96,4 dias. Os eventos adversos foram geralmente leves e autolimitados. Foram observadas melhoras significativas na função pulmonar, no IMC, na concentração de cloreto no suor e no número de exacerbações pulmonares. Não foram encontradas diferenças significativas nos resultados entre os pacientes homozigotos e heterozigotos para F508del. A efetividade dessa nova combinação de moduladores da CFRT em fibrose cística também se aplica a pacientes com doença pulmonar avançada. Conclusões: O tratamento com ELX/TEZ/IVA demonstrou melhora efetiva na prática clínica real, a saber, na função pulmonar, no IMC, na concentração de cloreto no suor e no número de exacerbações pulmonares, sem preocupações de segurança.

Use of elexacaftor+tezacaftor+ivacaftor in individuals with cystic fibrosis and at least one F508del allele: a systematic review and meta-analysis / Uso de elexacaftor + tezacaftor + ivacaftor em indivíduos com fibrose cística com pelo menos um alelo F508del: revisão sistemática e meta-análise

ABSTRACT Objective: To evaluate the effect of treatment with the combination of three cystic fibrosis transmembrane conductance regulator (CFTR) modulators-elexacaftor+tezacaftor+ivacaftor (ETI)-on important clinical endpoints in individuals with cystic fibrosis. Methods: This was a systematic review and meta-analysis of randomized clinical trials that compared the use of ETI in individuals with CF and at least one F508del allele with that of placebo or with an active comparator such as other combinations of CFTR modulators, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) methodology. We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to December 26th, 2022. The risk of bias was assessed using the Cochrane risk-of-bias tool, and the quality of evidence was based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results: We retrieved 54 studies in the primary search. Of these, 6 met the inclusion criteria and were analyzed (1,127 patients; 577 and 550 in the intervention and control groups, respectively). The meta-analysis revealed that the use of ETI increased FEV1% [risk difference (RD), +10.47%; 95% CI, 6.88-14.06], reduced the number of acute pulmonary exacerbations (RD, −0.16; 95% CI, −0.28 to −0.04), and improved quality of life (RD, +14.93; 95% CI, 9.98-19.89) and BMI (RD, +1.07 kg/m2; 95% CI, 0.90-1.25). Adverse events did not differ between groups (RD, −0.03; 95% CI, −0.08 to 0.01), and none of the studies reported deaths. Conclusions: Our findings demonstrate that ETI treatment substantially improves clinically significant, patient-centered outcomes.

RESUMO Objetivo: Avaliar o efeito do tratamento com a combinação de três moduladores da proteína cystic fibrosis transmembrane conductance regulator (CFTR, reguladora de condutância transmembrana em fibrose cística) - elexacaftor + tezacaftor + ivacaftor (ETI) - sobre desfechos clínicos importantes em indivíduos com fibrose cística. Métodos: Revisão sistemática e meta-análise de ensaios clínicos randomizados que compararam o uso de ETI em indivíduos com fibrose cística com pelo menos um alelo F508del com o uso de placebo ou de um comparador ativo como outras combinações de moduladores da CFTR. O estudo foi realizado seguindo as recomendações Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) e a metodologia Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO). Foram realizadas buscas nos seguintes bancos de dados: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials e ClinicalTrials.gov, desde a sua criação até 26 de dezembro de 2022. O risco de viés foi avaliado por meio da ferramenta de risco de viés da Cochrane, e a qualidade das evidências foi determinada com base no sistema Grading of Recommendations Assessment, Development and Evaluation (GRADE). Resultados: Foram identificados 54 estudos na busca primária. Destes, 6 preencheram os critérios de inclusão e foram analisados (1.127 pacientes: 577 pacientes intervenção e 550 pacientes controle). A meta-análise revelou que o uso de ETI aumentou o VEF1 em porcentagem do previsto [diferença de risco (DR): +10,47%; IC95%: 6,88-14,06], reduziu o número de exacerbações pulmonares agudas (DR: −0,16; IC95%: −0,28 a −0,04) e melhorou a qualidade de vida (DR: +14,93; IC95%: 9,98-19,89) e o IMC (DR: +1,07 kg/m2; IC95%: 0,90-1,25). Os eventos adversos não diferiram entre os grupos (DR: −0,03; IC95%: −0,08 a 0,01), e nenhum dos estudos relatou óbitos. Conclusões: Nossos achados demonstram que o tratamento com ETI melhora substancialmente os desfechos clinicamente significativos centrados no paciente.

Actualización en fibrosis quística estándares de atención para pacientes con diagnóstico de fibrosis quística con terapia moduladora: informe de la Sociedad Europea de Fibrosis Quística 2023 / Standards of care for patients with a diagnosis of cystic fibrosis who are on modulator therapy: report of the European Fibrosis Cystic Society 2023

La fibrosis quística ha entrado en la era de la terapia específica con los moduladores, útiles en variantes genéticas definidas por estudio molecular, con resultados clínicos exitosos. Este es un resumen de la publicación reciente de la Sociedad Respiratoria Europea que establece los estándares de cuidado para los pacientes que reciben este tratamiento.

Cystic fibrosis has entered the era of specific therapy called modulators, useful in genetic variants defined by molecular study, with successful clinical results. This is a summary of the recent publication of the European Respiratory Society that establishes the standards of care for patients receiving this treatment.

Actualización en fibrosis quística: uso de exacaftor/tezacaftor/ivacaftor/en pacientes con fibrosis quística port-trasplante pulmonar / Use of exacaftor/tezacaftor/ivacaftor in cystic patients post lung transplantation

El uso de moduladores de CFTR en pacientes con fibrosis quística post trasplante pulmonar es un tema todavía controversial. Varias publicaciones reportan los beneficios del modulador elexacaftor/tezacaftor/ivacaftor en los síntomas extrapulmonares de la fibrosis quística, especialmente enfermedad sinusal, síntomas gastrointestinales y diabetes. Un número alto de pacientes debe discontinuar el tratamiento por mala tolerancia, sin embargo, no se describen interacciones de importancia con el tratamiento inmunosupresor. Se debe considerar para su uso los riesgos versus beneficios en forma individual en cada paciente.

The use of CFTR modulators in patients with cystic fibrosis after lung transplantation is still a controversial issue. Several publications report the benefits of the use of the modulator elexacaftor/tezacaftor/ivacaftor on extrapulmonary symptoms of cystic fibrosis, especially sinus disease, gastrointestinal symptoms and diabetes. A high number of patients must discontinue treatment due to poor tolerance; however, no significant interactions with immunosuppressive treatment have been described. The individual risk-benefit of each patient should be considered for its use.

Fibrosis quística: patogenia bacteriana y moduladores del CFTR (regulador de conductancia transmembranal de la fibrosis quística).

Cystic fibrosis is an autosomal recessive inherited disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). CFTR is a protein that transports ions across the membrane of lung epithelial cells. Loss of its function leads to the production of thick sticky mucus, where various bacterial pathogens can establish and adapt, contributing to the gradual loss of lung function. In this review, evidence of the molecular mechanisms used by Pseudomonas aeruginosa and Burkholderia cenocepacia to survive and persist in the pulmonary environment will be provided. Additionally, new therapeutic strategies based on CFTR function modulators will be described.

La fibrosis quística es una enfermedad hereditaria autosómica recesiva que se origina por mutaciones en el gen regulador de conductancia transmembranal de la fibrosis quística (CFTR, cystic fibrosis transmembrane conductance regulator). El CFTR es una proteína que transporta iones a través de la membrana de las células epiteliales pulmonares. La pérdida de su función conlleva la producción de un moco pegajoso y espeso, donde se pueden establecer y adaptar diversos patógenos bacterianos que contribuyen a la pérdida gradual de la función pulmonar. En este artículo de revisión se dará evidencia de los mecanismos moleculares que utilizan Pseudomonas aeruginosa y Burkholderia cenocepacia para sobrevivir y persistir en el ambiente pulmonar. Adicionalmente, se describirán las nuevas estrategias de terapia a base de moduladores de la función del CFTR.

Fibrosis quística: patogenia bacteriana y moduladores del CFTR (regulador de conductancia transmembranal de la fibrosis quística) / Cystic fibrosis: bacterial pathogenesis and CFTR (cystic fibrosis transmembrane conductance regulator) modulators

Resumen La fibrosis quística es una enfermedad hereditaria autosómica recesiva que se origina por mutaciones en el gen regulador de conductancia transmembranal de la fibrosis quística (CFTR, cystic fibrosis transmembrane conductance regulator). El CFTR es una proteína que transporta iones a través de la membrana de las células epiteliales pulmonares. La pérdida de su función conlleva la producción de un moco pegajoso y espeso, donde se pueden establecer y adaptar diversos patógenos bacterianos que contribuyen a la pérdida gradual de la función pulmonar. En este artículo de revisión se dará evidencia de los mecanismos moleculares que utilizan Pseudomonas aeruginosa y Burkholderia cenocepacia para sobrevivir y persistir en el ambiente pulmonar. Adicionalmente, se describirán las nuevas estrategias de terapia a base de moduladores de la función del CFTR.

Abstract Cystic fibrosis is an autosomal recessive inherited disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). CFTR is a protein that transports ions across the membrane of lung epithelial cells. Loss of its function leads to the production of thick sticky mucus, where various bacterial pathogens can establish and adapt, contributing to the gradual loss of lung function. In this review, evidence of the molecular mechanisms used by Pseudomonas aeruginosa and Burkholderia cenocepacia to survive and persist in the pulmonary environment will be provided. Additionally, new therapeutic strategies based on CFTR function modulators will be described.

Terapia endocrina para la prevención primaria del cáncer de seno: Revisión sistemática y metaanálisis actualizado / Endocrine therapy for primary prevention of breast cancer: Systematic review and updated meta-analysis

Introducción. Debido a que el cáncer de seno es una enfermedad asociada a una significativa tasa de morbilidad y mortalidad cuando se diagnostica en el período sintomático, se han hecho enormes esfuerzos orientados hacia la prevención primaria de esta enfermedad. Métodos. Se realizó una búsqueda de todos los experimentos clínicos aleatorizados que evaluaran la eficacia de la terapia endocrina para la reducción del riesgo de desarrollar cáncer de seno. La calidad metodológica de los estudios seleccionados fue valorada utilizando la herramienta de la Colaboración Cochrane para medir el riesgo de sesgo en ensayos aleatorizados. Se evaluó la heterogeneidad de los estudios primarios elegibles utilizando los estadísticos T², I², H². El sesgo de publicación fue evaluado mediante el test de Harbord y mediante la gráfica de funnel plot. La medida de efecto utilizada en este metaanálisis fue el riesgo relativo (RR) con el cálculo de los intervalos de confianza (IC) del 95%. Resultados. Encontramos doce experimentos clínicos aleatorizados que reclutaron a 68.180 mujeres, las cuales fueron asignadas al azar para recibir algún tipo terapia endocrina para reducir el riesgo de desarrollar cáncer de seno o placebo. La terapia endocrina en conjunto redujo el riesgo proporcional de cáncer de seno (invasivo más in situ) en un 42 %, resultado estadísticamente significativo RR 0,58 (IC95% 0,50 ­ 0,69). Conclusiones. La terapia endocrina es el manejo estándar de prevención en mujeres sanas con riesgo de desarrollar cáncer de seno no hereditario.

Introduction. Because breast cancer is a disease associated with a significant morbidity and mortality rate when diagnosed in the symptomatic period, enormous efforts have been made towards the primary prevention of this disease. Methods. A search was conducted for all randomized clinical trials evaluating the efficacy of endocrine therapy in reducing the risk of developing breast cancer. The methodological quality of the selected studies was assessed using the Cochrane Collaboration tool to assess risk of bias in randomized trials. Heterogeneity of eligible primary studies was assessed using the T², I², H² statistics. Publication bias was evaluated using the Harbord test and the funnel plot. The effect measure used in this meta-analysis was the relative risk (RR) with the calculation of the 95% confidence intervals (CI).Results. We found twelve randomized clinical trials that recruited 68,180 women who were randomly assigned to receive some type of endocrine therapy to reduce the risk of developing breast cancer or placebo. Endocrine therapy as a whole reduced the proportional risk of breast cancer (invasive plus in situ) by 42%, a statistically significant result RR 0.58 (95% CI 0.50 - 0.69). Conclusions. Endocrine therapy is the standard preventive management in healthy women at risk of developing non-hereditary breast cancer.

Moduladores de la expresión de la alta capacidad intelectual / Modulation of the expression of high intellectual capacity

La investigación reciente desmitifica y redefine la alta capacida d intelectual (ACI) frente al concepto tradicional monolítico y estático, basado en la heredabilidad e identificación mediante un alto cociente intelectual. Este concepto se sustituye por otro en el que la ACI es entendida como un fenómeno complejo de naturaleza genética y ambiental, multidimensional, diverso, moldeable, dinámico y en desarrollo, resultado de la covariación a lo largo de la trayectoria de vida entre fuerzas endógenas y exógenas, que van modulando y diferenciando el alto potencial (factor predictor) en competencias hacia la óptima expresión, o no, de la eminencia en la adultez. La ACI supone la conjunción de una diversidad biológica de partida (el alto potencial), una diversidad psicológica (explotación de los recursos biológicos en funciones útiles y conocimiento), y una diversidad contextual configurada por diferentes condiciones familiares, y contextos socioculturales y económicos. El objetivo del trabajo es presentar una revisión de la investigación actual sobre los factores predictores y moduladores de la ACI, desde una perspectiva neuroconstructivista. Se concluye y discute la incidencia de variables moduladoras en las diversas trayectorias de desarrollo del potencial hacia la posible eminencia adulta, y las implicaciones diagnósticas y educativas que se derivan.

Recent research demystifies and redefines high intellectual ability (HIA) against the traditional monolithic and static concept which was based on heritability and identification through an intelligence quotient. This concept is replaced by another in which the HIA is understood as a complex phenomenon of a genetic and environmental nature This is the result of a covariation along the life path between endogenous and exogenous forces, modulators of the high potential (predictor factor) towards the optimal expression, or not, of its eminence in adulthood. Then, HIA implies the conjunction of a starting biological diversity (the high potential), a psychological diversity related to the exploitation of biological resources in useful functions and knowledge, and a contextual diversity configured by different family conditions, as well as socio-cultural and economic contexts. The aim of this work is to present from a neuroconstructivist perspective a review of the current HIA research on the predictive and modulating factors. In the conclusions, we discuss the incidence of the modulating variables in the various trajectories of potential development towards possible adult eminence and the diagnostic and educational implications that are derived.

L-PRF y Ciclo Celular. Revisión Narrativa / L-PRF and cell cycle. Narrative Review

RESUMEN: Los concentrados plaquetarios han emergido como un potencial material regenerativo, utilizado de forma aislada o como andamiaje para otros materiales de injerto. Son extractos de sangre, obtenidos después de procesar una muestra de sangre completa, mediante centrifugación. El primer reporte data de 1970, con un CP utilizado como pegamento para mejorar cicatrización de heridas de piel. En 1998, se usaron en cirugía oral y maxilofacial. Desde entonces, se han desarrollado diferentes técnicas y una variedad de preparaciones. Entre ellas, cabe destacar el plasma rico en plaquetas, fibrina rica en plaquetas y leucocitos (L-PRF) y plasma rico en factores de crecimiento (PRGF). El desarrollo de estos biomateriales, se debe en parte, a la posibilidad de alterar la concentración de mediadores químicos liberados en una lesión que provoque la formación de un coágulo, que pueda madurar conforme transcurran las fases del proceso inflamatorio y concluya con la regeneración íntegra del tejido dañado. El objetivo de este manuscrito fue describir las principales vías de señalización intracelular que se activan en presencia del L-PRF en cirugía oral, y sus efectos en la regulación del ciclo celular.

ABSTRACT: Platelet concentrates (PC) have emerged as a potential regenerative material, used in isolation or as scaffolding for other graft materials. They are blood extracts, obtained after processing a sample of whole blood, by centrifugation. The first report dates from 1970, with a PC used glue to improve the healing of skin wounds. In 1998, they were used in oral and maxillofacial surgery. Since then, different techniques and a variety of preparations have been developed. These include platelet-rich plasma, fibrin rich in platelets and leukocytes (L-PRF) and plasma rich in growth factors (PRGF). The development of these biomaterials, is due in part to the possibility of altering the concentration of chemical mediators released in a lesion that causes the formation of a clot, which can mature as the phases of the inflammatory process pass and conclude with the complete regeneration of the damaged tissue. The aim of this manuscript was to describe the main intracellular signaling pathways that are activated in the presence of LPRF in oral surgery, and its effects on the regulation of the cell cycle.

Adherence to synthetic disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis: Results of the OBSERVAR Study. / Adherencia al tratamiento con fármacos moduladores de la enfermedad sintéticos en la artritis reumatoide. Resultados del estudio OBSERVAR.

BACKGROUND: Treatment compliance with disease-modifying antirheumatic drugs (DMARD) is essential to achieve the therapeutic goals in rheumatoid arthritis (RA). However, despite the need for good compliance, there is evidence that patients with RA frequently fail to use DMARD for the control of RA. Thus, the main objective of the OBSERVAR study is to evaluate the reasons for the lack of therapeutic adherence to synthetic DMARD in these patients. PATIENTS AND METHODS: A Delphi process involving 18 randomly selected Spanish rheumatologists determined the level of agreement with 66 causes of noncompliance selected from the literature in relation to synthetic DMARD in RA. RESULTS: The reasons for noncompliance were consistent in 75.7%, although 3 reasons (4.5%) were highly consistent: 1) not knowing what to do in the case of an adverse event with DMARD; 2) not having undergone adherence screening by health personnel for early detection of "noncompliant patients"; and 3) not having undergone interventions or strategies that improve adherence. CONCLUSION: In order to improve adherence to RA treatment with synthetic DMARD, the patient should be adequately informed of each new treatment introduced, the patient's compliance profile should be incorporated into the clinical routine and the patient's motivation for therapeutic compliance be reinforced through the methods available to us.

Antiplatelet Therapy in Breast Cancer Patients Using Hormonal Therapy: Myths, Evidence and Potentialities - Systematic Review / Terapia Antiplaquetária em Pacientes com Câncer de Mama em Uso de Terapia Hormonal: Mitos, Evidências e Potencialidades - Revisão Sistemática

Abstract Breast cancer is the most frequently diagnosed tumor in women worldwide, with a significant impact on morbidity and mortality. Chemotherapy and hormone therapy have significantly reduced mortality; however, the adverse effects are significant. Aspirin has been incorporated into clinical practice for over 100 years at a low cost, making it particularly attractive as a potential agent in breast cancer prevention and as an adjunct treatment to endocrine therapy in the prophylaxis of cardiovascular complications. The objective of this study was to evaluate the role of aspirin in reducing the incidence of breast cancer and to evaluate the impact of its use on morbidity and mortality and reduction of cardiovascular events as adjuvant therapy during breast cancer treatment with selective estrogen receptor modulators. A systematic review was performed using the PRISMA methodology and PICO criteria, based on the MEDLINE, EMBASE and LILACS databases. The original articles of clinical trials, cohort, case-control studies and meta-analyses published from January 1998 to June 2017, were considered. Most studies showed an association between the use of selective estrogen receptor modulators and the increase in thromboembolic events. The studies suggest a protective effect of aspirin for cardiovascular events during its concomitant use with selective estrogen receptor modulators and in the prevention of breast cancer. This systematic review suggests that aspirin therapy combines the benefit of protection against cardiovascular events with the potential reduction in breast cancer risk, and that the evaluation of the benefits of the interaction of endocrine therapy with aspirin should be further investigated.

Resumo O câncer de mama é o tumor mais frequentemente diagnosticado em mulheres de todo o mundo, com impacto importante na morbimortalidade. A quimioterapia e a terapia hormonal reduziram significativamente a mortalidade, mas os efeitos adversos são consideráveis. A aspirina está incorporada à prática clínica há mais de 100 anos, com baixo custo, tornando-a particularmente atraente como potencial agente na prevenção do câncer de mama e auxiliar durante o tratamento endócrino, na profilaxia de complicações cardiovasculares. Objetivou-se avaliar o papel da aspirina na redução da incidência do câncer de mama e avaliar o impacto de seu uso na morbimortalidade e na redução de eventos cardiovasculares como terapia adjuvante durante o tratamento do câncer de mama com moduladores seletivos do receptor do estrogênio. Procedeu-se à revisão sistemática utilizando-se a metodologia PRISMA e os critérios PICO, nas bases MEDLINE, EMBASE e LILACS. Foram considerados os artigos originais do tipo ensaio clínico, coorte, caso-controle e metanálises, publicados no período de janeiro de 1998 até junho de 2017. Na maioria dos estudos, houve relação entre o uso dos moduladores seletivos do receptor do estrogênio e o aumento de eventos tromboembólicos. Os estudos sugerem efeito protetor da aspirina para eventos cardiovasculares em uso concomitante aos moduladores seletivos do receptor do estrogênio e na prevenção do câncer de mama. Esta revisão sistemática sugere que o tratamento com aspirina combina o benefício da proteção contra eventos cardiovasculares com a potencial redução do risco de câncer de mama, e que a avaliação dos benefícios da interação da terapia endócrina com a aspirina deve ser melhor investigada.

Cardioprotective Effect of Crocin Combined with Voluntary Exercise in Rat: Role of Mir-126 and Mir-210 in Heart Angiogenesis / Efeito Cardioprotetor de Crocina Combinado com Exercício Voluntário em Ratos: Papel do Mir-126 e Mir-210 na Angiogênese Cardíaca

Abstract Background: Crocin is reported to have a wide range of biological activities such as cardiovascular protection. Recent epidemiologic studies have shown that exercise reduces cardiovascular morbidity and mortality in the general population. Objective: The aim of this study was to evaluate the effect of crocin and voluntary exercise on miR-126 and miR-210 expression levels and angiogenesis in the heart tissue. Methods: Animals were divided into 4 groups: control, exercise, crocin, and exercise-crocin. Animals received oral administration of crocin (50 mg/kg) or performed voluntary exercise alone or together for 8 weeks. Akt, ERK1/2 protein levels, miR-126 and miR-210 expression were measured in the heart tissue. Immunohistochemical method was used to detect CD31 in the heart tissue. Results: Akt and ERK1/2 levels of the heart tissue were higher in crocin treated group and voluntary exercise trained group after 8 weeks. Combination of crocin and exercise also significantly enhanced Akt and ERK1/2 levels in the heart tissue. MiR-126, miR-210 expression and CD31 in the heart increased in both crocin and voluntary exercise groups compared with control group. In addition, combination of exercise and crocin amplified their effect on miR-126 and miR-210 expression, and angiogenesis. Conclusion: Crocin and voluntary exercise improve heart angiogenesis possibly through enhancement of miR-126 and miR-210 expression. Voluntary exercise and diet supplementation with crocin could have beneficial effects in prevention of cardiovascular disease.

Resumo Fundamentos: A crocina tem uma vasta gama de atividades biológicas, tais como a proteção cardiovascular. Estudos epidemiológicos recentes demonstraram que o exercício reduz a morbidade e a mortalidade cardiovasculares na população em geral. Objetivo: O objetivo deste estudo foi avaliar o efeito da crocina e do exercício voluntário nos níveis de expressão miR-126 e miR-210 e na angiogênese no tecido cardíaco. Métodos: Os animais foram divididos em 4 grupos: controle, exercício, crocina e exercício-crocina. Os animais receberam a administração oral de crocina (50 mg/kg) ou realizaram exercício voluntário sozinhos ou em conjunto durante 8 semanas. Os níveis de proteína Akt, ERK1/2, e a expressão de miR-126 e miR-210 foram medidos no tecido cardíaco. O método imunohistoquímico foi utilizado para detectar CD31 no tecido cardíaco. Resultados: Os níveis de Akt e ERK1/2 do tecido cardíaco foram maiores no grupo tratado com crocina e no grupo de exercício voluntário após 8 semanas. A combinação de crocina e exercício também aumentou significativamente os níveis de Akt e ERK1/2 no tecido cardíaco. A expressão de MiR-126, miR-210 e CD31 no coração aumentou tanto em no grupo de crocina como no grupo de exercício voluntário em comparação com o grupo de controle. Além disso, a combinação de exercício e crocina amplificou seu efeito na expressão de miR-126 e miR-210 e angiogênese. Conclusão: A Crocina e o exercício voluntário melhoram a angiogênese cardíaca possivelmente através do aumento da expressão de miR-126 e miR-210. O exercício voluntário e a suplementação dietética com crocina podem ter efeitos benéficos na prevenção de doenças cardiovasculares.

Comparative study of topical vs. intravenous tranexamic acid regarding blood loss in total knee arthroplasty / Estudo comparativo com uso do ácido tranexâmico tópico e intravenoso em relação à perda sanguínea na artroplastia total do joelho

ABSTRACT Objective: To compare topical vs. intravenous tranexamic acid (TA) in total knee arthroplasty regarding blood loss and transfusion., Methods: Ninety patients were randomized to receive TA intravenously (20 mg/kg in 100 mL of saline; group IV), topically (1.5 g in 50 mL of saline, sprayed over the operated site, before release of the tourniquet; topical group), or intravenous saline (100 mL with anesthesia; control group). The volume of drained blood in 48, h, the amount of transfused blood, and the serum levels of hemoglobin and hematocrit before and after surgery were evaluated., Results: The groups were similar for gender, age, weight, laterality, and preoperative hemoglobin and hematocrit levels (p> 0.2). The hemoglobin level dropped in all groups when comparing the preoperative and the 48-h evaluations: the control group decreased 3.8 mg/dL on average, while the IV, group had a decrease of 3.0, and the topical group, of 3.2 (p= 0.019). The difference between the control and IV, groups was confirmed by Bonferroni test (p= 0.020). The difference between the control group and the topical group was not significant (p= 0.130), although there was less reduction in hemoglobin in the topical group; the comparison between the IV, group and the topical group was also not significant (p= 1.000). Conclusion: Using topic and IV, tranexamic acid decreased blood loss and the need for transfusion in total knee arthroplasty. Topical application showed results similar to IV use regarding the need for blood transfusion, but without the possible side effects of IV, administration.

RESUMO Objetivo: Comparar o uso de ácido tranexâmico (AT) tópico e intravenoso na artroplastia total de joelho com relação à perda de sangue e necessidade de transfusão. Métodos: Foram randomizados 90 pacientes para receber AT por via intravenosa (20 mg/kg em 100 mL de solução salina; grupo IV, ), tópico (1,5 g em 50 mL de solução salina, antes de soltar o torniquete; grupo tópico) ou solução salina intravenosa (100 mL com anestesia; grupo controle). O volume de sangue drenado em 48 horas, a quantidade de sangue transfundido e as concentrações sérias de hemoglobina e hematócrito foram avaliados antes e depois da cirurgia. Resultados: Os grupos eram semelhantes quanto a sexo, idade, lateralidade e concentrações pré-operatórias de hemoglobina e hematócrito (p > 0,2). A concentração de hemoglobina diminuiu em todos os grupos quando as avaliações pré-operatória e em 48 horas foram comparadas: o grupo controle teve redução média de 3,8 mg/dL, enquanto o grupo IV, teve diminuição de 3,0 e o grupo tópico, de 3,2 (p = 0,019). A diferença entre os grupos controle e IV, foi confirmada pelo teste de Bonferroni (p = 0,020). A diferença entre os grupos controle e tópico não foi significativa (p = 0,130), apesar de haver uma menor diminuição da hemoglobina no grupo tópico; a comparação entre os grupos IV, e tópico também não foi significativa (p = 1,000). Conclusão: O uso de AT tópico e IV, reduziu as perdas sanguíneas e a necessidade de transfusão na artroplastia total do joelho. O uso tópico mostrou resultado semelhante ao uso IV, em relação à necessidade de transfusão sanguínea, porém sem os possíveis efeitos colaterais da administração IV.

Estrés hemodinámico inducido por ejercicio: bases fisiológicas e impacto clínico / Exercise-induced shear stress: Physiological basis and clinical impact

La regulación fisiológica de la función vascular es esencial para la salud cardiovascular y depende de un adecuado control de mecanismos moleculares desencadenados por células endoteliales en respuesta a estímulos mecánicos y químicos inducidos por flujo sanguíneo. La disfunción endotelial es uno de los principales factores de riesgo de enfermedad cardiovascular, donde un desequilibrio entre la síntesis de moléculas vasodilatadoras y vasoconstrictoras constituye uno de sus principales mecanismos. En este contexto, el estrés de flujo es uno de los estímulos más importantes para mejorar la función vascular, gracias a que la mecanotransducción endotelial generada por la estimulación de diversos mecanosensores endoteliales induce la generación de estímulos intracelulares que culmina con un incremento en la biodisponibilidad de moléculas vasodilatadoras como el óxido nítrico y, a largo plazo, con la inducción de mecanismos angiogénicos. Estos mecanismos permiten proporcionar el sustento fisiológico a los efectos del ejercicio físico sobre la salud vascular. En la presente revisión se discuten los mecanismos moleculares implicados en la respuesta vascular modulada por estrés de flujo inducido por ejercicio y su impacto en la reversión del daño vascular asociado a las enfermedades cardiovasculares más prevalentes en nuestra población.

The physiological regulation of vascular function is essential for cardiovascular health and depends on adequate control of molecular mechanisms triggered by endothelial cells in response to mechanical and chemical stimuli induced by blood flow. Endothelial dysfunction is one of the major risk factors for cardiovascular disease, where an imbalance between synthesis of vasodilator and vasoconstrictor molecules is one of its main mechanisms. In this context, the shear stress is one of the most important mechanical stimuli to improve vascular function, due to endothelial mechanotransduction, triggered by stimulation of various endothelial mechanosensors, induce signaling pathways culminating in increased bioavailability of vasodilators molecules such as nitric oxide, that finally trigger the angiogenic mechanisms. These mechanisms allow providing the physiological basis for the effects of exercise on vascular health. In this review it is discussed the molecular mechanisms involved in the vascular response induced by shear stress and its impact in reversing vascular injury associated with the most prevalent cardiovascular disease in our population.

Topical vs. intravenous administration of tranexamic acid in knee arthroplasty and prevalence of deep venous thrombosis: a randomized clinical trial / Uso tópico versus intravenoso de ácido tranexâmico na artroplastia de joelho e prevalência de trombose venosa profunda: estudo clínico randomizado

BACKGROUND: Tranexamic acid (TXA) is widely used in orthopedic surgery to reduce perioperative bleeding. Since TXA inhibits fibrinolysis, there is concern that it may increase the risk of thromboembolic events. OBJECTIVES: To verify the prevalence of deep venous thrombosis (DVT) in patients receiving TXA during total knee arthroplasty and to compare topical with intravenous administration of the drug. METHODS: All patients admitted for total knee arthroplasty due to primary arthrosis between June and November of 2014 were recruited consecutively. Thirty patients were randomized to a "topical group&" (1.5 g TXA diluted in 50ml saline sprayed over the area operated, before tourniquet release), 30 to an intravenous; (20mg/kg TXA in 100 ml of saline, given at the same time as anesthesia), and 30 to a control group (100 ml of saline, given at the same time as anesthesia). All patients had duplex ultrasound scans of the legs on the 15th postoperative day. RESULTS: Deep venous thrombosis events occurred in five of the 90 patients operated (one out of 30 in the topical group [3.3%], four out of 30 in the control group [13.3%], and zero in the intravenous group). All were confirmed by duplex ultrasound scans and all were asymptomatic. Prevalence rates of DVT were similar between groups (p = 0.112 for control vs. intravenous; p = 0.353 for control vs. topical; and p =1.000 for intravenous vs. topical, according to two-sided exact tests). CONCLUSIONS: Both topical and intravenous administration of TXA are safe with regard to occurrence of DVT, since the number of DVT cases in patients given TXA was not different to the number in those given placebo.

CONTEXTO: O ácido tranexâmico é amplamente utilizado em cirurgia ortopédica para reduzir a hemorragia perioperatória. Como o ácido tranexâmico inibe a fibrinólise, há uma preocupação de que ele possa aumentar o risco de eventos tromboembólicos. OBJETIVOS: Verificar se o uso do ácido tranexâmico é seguro em relação à prevalência de trombose venosa profunda em pacientes submetidos a artroplastia total do joelho, e comparar as administrações tópica e intravenosa desse medicamento. MÉTODOS: Todos os pacientes consecutivamente admitidos para artroplastia total do joelho devido a artrose primária entre junho e novembro de 2014 foram recrutados. Os pacientes foram randomizados em um "grupo tópico" (1,5 g de ácido tranexâmico diluído em 50 ml de solução salina cobrindo toda a área operada antes de liberar o torniquete), um "grupo intravenoso" (20 mg/kg de ácido tranexâmico em 100 ml de solução salina no momento da anestesia) e um "grupo controle" (100 ml de solução salina com a anestesia). No 15º dia de pós-operatório, todos os pacientes foram submetidos a ultrassonografia vascular com Doppler de membros inferiores, independentemente de sintomas. RESULTADOS: Dos 90 pacientes operados, apenas cinco apresentaram trombose venosa profunda (um no grupo tópico e quatro no grupo controle). CONCLUSÕES: Tanto a administração tópica quanto a intravenosa de ácido tranexâmico são seguras em termos de ocorrência de trombose venosa profunda, pois o número de casos de trombose venosa profunda foi semelhante quando comparamos os pacientes que receberam ácido tranexâmico e os que receberam placebo. Novos estudos, com amostras maiores, são necessários para confirmar esse achado.

[Exercise-induced shear stress: Physiological basis and clinical impact]. / Estrés hemodinámico inducido por ejercicio: bases fisiológicas e impacto clínico.

The physiological regulation of vascular function is essential for cardiovascular health and depends on adequate control of molecular mechanisms triggered by endothelial cells in response to mechanical and chemical stimuli induced by blood flow. Endothelial dysfunction is one of the major risk factors for cardiovascular disease, where an imbalance between synthesis of vasodilator and vasoconstrictor molecules is one of its main mechanisms. In this context, the shear stress is one of the most important mechanical stimuli to improve vascular function, due to endothelial mechanotransduction, triggered by stimulation of various endothelial mechanosensors, induce signaling pathways culminating in increased bioavailability of vasodilators molecules such as nitric oxide, that finally trigger the angiogenic mechanisms. These mechanisms allow providing the physiological basis for the effects of exercise on vascular health. In this review it is discussed the molecular mechanisms involved in the vascular response induced by shear stress and its impact in reversing vascular injury associated with the most prevalent cardiovascular disease in our population.

Perfil de expressão de microRNAs circulantes após uma sessão aguda de exercício em indivíduos com doença arterial periférica: papel da N-acetilcisteína / Profile microRNAs expression of current after an acute exercise session in individuals with peripheral artery disease: role of n-acetylcysteine

A Doença arterial periférica (DAP) é uma manifestação clínica da aterosclerose, quando esta afeta principalmente as artérias que irrigam os membros inferiores. O exercício aeróbico provoca nos membros afetados pela doença um ciclo de reperfusão-isquemia que desencadeia uma resposta sistêmica aguda caracterizada por aumento do estresse oxidativo, inflamação e disfunção endotelial. Assim, uma terapia antioxidante pode ser uma terapia alternativa para esses pacientes. Os microRNAs (miRNAs) foram recentemente reconhecidos como reguladores pós-transcricionais, e a identificação desses pode elucidar mecanismos gênicos adicionais pelos quais o exercício é atuante, levando a identificação de genes que são modulados, abrindo perspectivas de abordagens de terapia gênica que podem levar à reversão do quadro da doença arterial periférica. Objetivo: Verificar o efeito de uma sessão aguda de exercício aeróbico máxima com e sem uso do antioxidante Nacetilcisteína (NAC) sobre a expressão de microRNAs e marcadores inflamatórios e de estresse oxidativo circulantes em pacientes com DAP. Métodos: Foram recrutados pacientes com DAP estágio II do Ambulatório da Disciplina de Cirurgia Vascular do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Os pacientes foram submetidos a duas sessões experimentais após a suplementação de NAC ou Placebo. Foi analisado o perfil de expressão de microRNAs circulantes dos indivíduos em repouso e após o exercício máximo, e confirmado a expressão gênica dos miRNAs alterados após o exercício e de seus alvos; e dos níveis plasmáticos de endotelina-1 (ET-1), proteína quimiotática de monócitos-1 (MCP-1), molécula de adesão intercelular-1 (ICAM-1), molécula de adesão celular vascular-1 (VCAM-1), substâncias reativas ao ácido tiobarbitúrico, 8- isoprostano e glutationa. Resultados: O tratamento com NAC não alterou o xvii tempo de caminhada, as respostas hemodinâmicas e cardiopulmonar dos...

Peripheral arterial disease (PAD) is a clinical manifestation of atherosclerosis, when it mainly affects the arteries supplying the lower limbs. Aerobic exercise causes the member affected by the disease cycle of reperfusion-ischemia triggers an acute systemic response characterized by increased oxidative stress, inflammation and endothelial dysfunction. Thus, an antioxidant therapy is an alternative therapy for these patients. MicroRNAs (miRNAs) have been recognized as posttranscriptional regulators, and identifying these may elucidate additional gene mechanisms by which the exercise is active, leading to identification of genes that are modulated, opening prospects of gene therapy approaches that can lead to picture reversal of peripheral arterial disease. Aim: To determine the effect of an acute bout of maximal aerobic exercise with and without the antioxidant N-acetylcysteine (NAC) on the expression of microRNAs and inflammatory markers and circulating oxidative stress in patients with PAD. Methods: We recruited patients with PAD stage II Clinic of Vascular Surgery of Hospital das Clinicas, Faculty of Medicine, University of São Paulo. The patients underwent two experimental sessions after supplementation of NAC or placebo. the expression profile of circulating microRNAs of individuals at rest and after maximal exercise was analyzed and confirmed the gene expression of miRNAs changed after exercise and its targets; and plasma levels of endothelin-1 (ET-1), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) cell vascular cell adhesion molecule-1 (VCAM-1) , reactive substances to thiobarbituric acid, 8-isoprostane and glutathione. Results: Treatment with NAC did not change the walking time, and cardiopulmonary hemodynamic responses of patients with PAD. The rest blood flow in the leg of these patients was higher after the completion of the exercise and treatment with NAC did not change this...