ABSTRACT
Guidelines on resource allocation, ethics, triage processes with admission and discharge criteria from critical care and palliative care units during the pandemia are here presented. The interdisciplinary and multi-society panel that prepared these guidelines represented by bioethicists and specialists linked to the end of life: clinicians, geriatricians, emergentologists, intensivists, and experts in palliative care and cardiopulmonary resuscitation. The available information indicates that approximately 80% of people with COVID-19 will develop mild symptoms and will not require hospital care, while 15% will require intermediate or general room care, and the remaining 5% will require assistance in intensive care units. The need to think about justice and establish ethical criteria for allocation patients arise in conditions of exceeding available resources, such as outbreaks of diseases and pandemics, with transparency being the main criterion for allocation. These guides recommend general criteria for the allocation of resources relies on bioethical considerations, rooted in Human Rights and based on the value of the dignity of the human person and substantial principles such as solidarity, justice and equity. The guides are recommendations of general scope and their usefulness is to accompany and sustain the technical and scientific decisions made by the different specialists in the care of critically ill patients, but given the dynamic nature of the pandemic, a process of permanent revision and adaptation of recommendations must be ensured.
Se presentan las guías sobre ética de asignación de recursos, procesos de triaje con criterios de ingreso y egreso de unidades de cuidados críticos y atención paliativa durante la pandemia. El panel interdisciplinario y multisocietario que las preparó estuvo representado por bioeticistas y por especialistas vinculados al fin de la vida: clínicos, geriatras, emergentólogos, intensivistas, expertos en cuidados paliativos y en reanimación cardiopulmonar. La información disponible indica que aproximadamente 80% de las personas con COVID-19 desarrollarán síntomas leves y no requerirán asistencia hospitalaria, mientras que 15% precisará cuidados intermedios o en salas generales, y el 5% restante requerirá de asistencia en unidades de cuidados intensivos. La necesidad de pensar en justicia y establecer criterios éticos de asignación surgen en condiciones de superación de los recursos disponibles, como en brotes de enfermedades y pandemias, siendo la transparencia el principal criterio para la asignación. Estas guías recomiendan criterios generales de asignación de recursos en base a consideraciones bioéticas, enraizadas en los Derechos Humanos y sustentadas en el valor de la dignidad de la persona humana y principios sustanciales como la solidaridad, la justicia y la equidad. Las guías son recomendaciones de alcance general y su utilidad consiste en acompañar y sostener las decisiones técnicas y científicas que tomen los distintos especialistas en la atención del paciente crítico, pero dado el carácter dinámico de la pandemia, debe asegurarse un proceso de revisión y readaptación permanente de las recomendaciones.
Subject(s)
Coronavirus Infections , Decision Making/ethics , Emergency Medical Services/ethics , Health Care Rationing/economics , Pandemics , Pneumonia, Viral , Triage/ethics , Betacoronavirus , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Critical Care/ethics , Critical Care/standards , Humans , Palliative Care , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , Practice Guidelines as Topic , Resource Allocation , SARS-CoV-2 , Societies, MedicalABSTRACT
Se presentan las guías sobre ética de asignación de recursos, procesos de triaje con criterios de ingreso y egreso de unidades de cuidados críticos y atención paliativa durante la pandemia. El panel interdisciplinario y multisocietario que las preparó estuvo representado por bioeticistas y por especialistas vinculados al fin de la vida: clínicos, geriatras, emergentólogos, intensivistas, expertos en cuidados paliativos y en reanimación cardiopulmonar. La información disponible indica que aproximadamente 80% de las personas con COVID-19 desarrollarán síntomas leves y no requerirán asistencia hospitalaria, mientras que 15% precisará cuidados intermedios o en salas generales, y el 5% restante requerirá de asistencia en unidades de cuidados intensivos. La necesidad de pensar en justicia y establecer criterios éticos de asignación surgen en condiciones de superación de los recursos disponibles, como en brotes de enfermedades y pandemias, siendo la transparencia el principal criterio para la asignación. Estas guías recomiendan criterios generales de asignación de recursos en base a consideraciones bioéticas, enraizadas en los Derechos Humanos y sustentadas en el valor de la dignidad de la persona humana y principios sustanciales como la solidaridad, la justicia y la equidad. Las guías son recomendaciones de alcance general y su utilidad consiste en acompañar y sostener las decisiones técnicas y científicas que tomen los distintos especialistas en la atención del paciente crítico, pero dado el carácter dinámico de la pandemia, debe asegurarse un proceso de revisión y readaptación permanente de las recomendaciones.
Guidelines on resource allocation, ethics, triage processes with admission and discharge criteria from critical care and palliative care units during the pandemia are here presented. The interdisciplinary and multi-society panel that prepared these guidelines represented by bioethicists and specialists linked to the end of life: clinicians, geriatricians, emergentologists, intensivists, and experts in palliative care and cardiopulmonary resuscitation. The available information indicates that approximately 80% of people with COVID-19 will develop mild symptoms and will not require hospital care, while 15% will require intermediate or general room care, and the remaining 5% will require assistance in intensive care units. The need to think about justice and establish ethical criteria for allocation patients arise in conditions of exceeding available resources, such as outbreaks of diseases and pandemics, with transparency being the main criterion for allocation. These guides recommend general criteria for the allocation of resources relies on bioethical considerations, rooted in Human Rights and based on the value of the dignity of the human person and substantial principles such as solidarity, justice and equity. The guides are recommendations of general scope and their usefulness is to accompany and sustain the technical and scientific decisions made by the different specialists in the care of critically ill patients, but given the dynamic nature of the pandemic, a process of permanent revision and adaptation of recommendations must be ensured.
Subject(s)
Humans , Health Care Rationing/economics , Coronavirus Infections/therapy , Coronavirus Infections/epidemiology , Decision Making/ethics , Emergency Medical Services/ethics , Pandemics , Palliative Care , Pneumonia, Viral/therapy , Pneumonia, Viral/epidemiology , Triage/ethics , Practice Guidelines as Topic , Critical Care/standards , Critical Care/ethics , Betacoronavirus , SARS-CoV-2 , COVID-19ABSTRACT
BACKGROUND: Resuscitation of septic patients regarding goals, monitoring aspects and therapy is highly variable. Our aim was to characterize cardiovascular and fluid management of sepsis in Argentina, a low and middle-income country (LMIC). Furthermore, we sought to test whether the utilization of dynamic tests of fluid responsiveness, as a guide for fluid therapy after initial resuscitation in patients with persistent or recurrent hypoperfusion, was associated with decreased mortality. METHODS: Secondary analysis of a national, multicenter prospective cohort study (n = 787) fulfilling Sepsis-3 definitions. Epidemiological characteristics, hemodynamic management data, type of fluids and vasopressors administered, physiological variables denoting hypoperfusion, use of tests of fluid responsiveness, and outcomes, were registered. Independent predictors of mortality were identified with logistic regression analysis. RESULTS: Initially, 584 of 787 patients (74%) had mean arterial pressure (MAP) < 65 mm Hg and/or signs of hypoperfusion and received 30 mL/kg of fluids, mostly normal saline (53%) and Ringer lactate (35%). Vasopressors and/or inotropes were administered in 514 (65%) patients, mainly norepinephrine (100%) and dobutamine (9%); in 22%, vasopressors were administered before ending the fluid load. After this, 413 patients (53%) presented persisting or recurrent hypotension and/or hypoperfusion, which prompted administration of additional fluid, based on: lactate levels (66%), urine output (62%), heart rate (54%), central venous O2 saturation (39%), central venous-arterial PCO2 difference (38%), MAP (31%), dynamic tests of fluid responsiveness (30%), capillary-refill time (28%), mottling (26%), central venous pressure (24%), cardiac index (13%) and/or pulmonary wedge pressure (3%). Independent predictors of mortality were SOFA and Charlson scores, lactate, requirement of mechanical ventilation, and utilization of dynamic tests of fluid responsiveness. CONCLUSIONS: In this prospective observational study assessing the characteristics of resuscitation of septic patients in Argentina, a LMIC, the prevalent use of initial fluid bolus with normal saline and Ringer lactate and the use of norepinephrine as the most frequent vasopressor, reflect current worldwide practices. After initial resuscitation with 30 mL/kg of fluids and vasopressors, 413 patients developed persistent or recurrent hypoperfusion, which required further volume expansion. In this setting, the assessment of fluid responsiveness with dynamic tests to guide fluid resuscitation was independently associated with decreased mortality.
ABSTRACT
Dentre as diversas síndromes geriátricas, emerge a Síndrome da Fragilidade no idoso. Diante dessa temática, o objetivo do estudo foi avaliar idosos em atendimento ambulatorial quanto à Síndrome da Fragilidade, à Condição Nutricional e ao Nível de Funcionalidade Familiar. Trata-se de um estudo descritivo-exploratório, quantitativo, analítico-descritivo. Este estudo concluiu que idosos em risco nutricional apresentam-se mais vulneráveis à Síndrome de Fragilidade; portanto, apresentam maiores perdas funcionais.
Among the several geriatric syndromes, fragility syndrome emerges in the elderly. In view of this theme the objective of the study was to evaluate the elderly in outpatient care regarding Fragility Syndrome, Nutritional Condition and Family Functionality Level. This is a descriptive-exploratory, quantitative, analytical, descriptive study. This study concluded that elderly people at nutritional risk are more vulnerable to Fragility Syndrome, therefore, greater functional losses.
Entre los diversos síndromes geriátricos, emerge el Síndrome de la Fragilidad en el anciano. Ante esta temática, el objetivo del estudio fue evaluar ancianos en atención ambulatoria en cuanto al Síndrome de la Fragilidad, a la Condición Nutricional y al Nivel de Funcionalidad Familiar. Se trata de un estudio descriptivo-exploratorio, cuantitativo, analítico-descriptivo. Este estudio concluyó que los ancianos en riesgo nutricional se presentan más vulnerables al Síndrome de Fragilidad; por lo tanto, presentan mayores pérdidas funcionales.
Subject(s)
Humans , Male , Female , Middle Aged , Aged , Aged, 80 and over , Frailty/etiology , Nutritional Status , Surveys and Questionnaires , Family Relations/psychology , Ambulatory Care , Correlation of DataABSTRACT
ABSTRACT Objective To evaluate factorial and construct validity of the Brazilian Portuguese version of the Bergen Facebook Addiction Scale (BFAS-BR). Methods A sociodemographic questionnaire, the Brazilian Portuguese versions of Online Cognition Scale (OCS-BR) and of BFAS-BR were applied to a sample of Health Undergraduate (n = 356). Construct validity evidences were verified through the Confirmatory Factor Analysis. Discriminant validity was examined by correlational analysis between the version of the BFAS-BR and OCS-BR. Results Proposed factorial model of BFAS did not present a good quality adjustment. So, a model restructuring was necessary from behavioral addiction theoretical views and new model presented satisfactory adjustment quality and construct validity evidence. Correlation between both tested scales was strong (ρ = 0.707) and, therefore, they measure the same construct. Conclusion The BFAS-BR show adequate factorial and construct validity.
RESUMO Objetivo Avaliar a validade fatorial e de construto da versão em português brasileiro da Bergen Facebook Addiction Scale (BFAS-BR). Métodos Um questionário sociodemográfico e as versões em português brasileiro da Online Cognition Scale (OCS-BR) e da BFAS-BR foram aplicados em uma amostra de universitários de cursos de Saúde (n = 356). As evidências da validade de construto foram verificadas por meio da Análise Fatorial Confirmatória. A validade discriminante foi examinada pela análise correlacional das BFAS-BR e OCS-BR. Resultados O modelo fatorial proposto da BFAS não apresentou bom ajuste. Então, um modelo reestruturado foi necessário a partir das concepções teóricas das adições de comportamento. O novo modelo apresentou qualidade de ajustamento satisfatório e evidências de validade de construto. A correlação entre as versões em português de ambas as escalas testadas foi forte (ρ = 0,707). Conclusões A versão em português da Bergen Facebook Addiction Scale apresentou adequada validade de construto.
ABSTRACT
ABSTRACT Objective To evaluate construct validity and reliability of the Portuguese (Brazil) version of Online Cognition Scale (OCS-BR). Methods Portuguese (Brazil) versions of Online Cognition Scale (OCS), of Internet Addiction Test (IAT) and socio demographic questionnaire was applied to a sample (n = 359) of health university students. Construct validity evidence was verified through the factorial and convergent validity by Confirmatory Factor Analysis (CFA) and internal consistency and stability analysis through Cronbach’s alpha and intraclass correlation coefficient (ICC) respectively. Discriminative power of items were analyzed using item-total correlation and point biserial correlation. Results OCS-BR presented satisfactory evidence of construct validity. The instrument showed Cronbach’s alpha of 0.91 and ICC of 0.91. Conclusion Portuguese (Brazil) version of OCS shows items consistently gatherd to measure the Problematic Internet Use (PIU) construct, it is considered s stable instrument in time and with sufficient evidence of construct validity.
RESUMO Objetivo Avaliar a validade de construto e a confiabilidade da versão em português (Brasil) da Online Cognition Scale (OCS-BR). Métodos As versões em português (Brasil) da Online Cognition Scale (OCS), da Internet Addiction Test (IAT) e um questionário sociodemográfico foram aplicados em uma amostra (n = 359) de estudantes universitários de saúde. A evidência de validade de construto foi verificada por meio da validade fatorial e convergente pela Análise Fatorial Confirmatória e pela análise da consistência internal e estabilidade pelo alpha de Cronbach e coeficiente de correlação intraclasse (ICC), respectivamente. O poder discriminativo de itens foi analisado usando a correlação item-total e a correlação do ponto bisserial. Resultados A OCS-BR apresentou evidência satisfatória de validade de construto. O instrumento apresentou o alpha de Cronbach de 0,91 e ICC de 0,91. Conclusão A versão em Português (Brasil) de OCS mostra itens consistentemente reunidos para medir o construto Uso Problemático de Internet, sendo considerado um instrumento estável no tempo e com evidência suficiente de validade de construto.
ABSTRACT
BACKGROUND: Most hospitalized older adults have reduced functional and physiological reserves, rendering them more vulnerable to the effects of a series of circumstances beyond the existence of health conditions unrelated to the reason for the hospitalization, usually worsening the hospitalization outcome. Despite the theoretical support for the idea that mobility improvement in the hospitalized patient carries multiple benefits, this idea has not been fully translated into clinical practice. AIMS: Our objective was to assess if an exercise intervention involving patients and families could modify the cognitive and affective progression of hospitalized older patients, from admission to discharge and 30 days after discharge. METHODS: This was a prospective intervention study with blinded outcome progression. Patients were recruited over a 3-month period and prospectively followed up. The intervention consisted in a supervised individualized graduated exercise program and education of ward and team staff, patients and caregivers to actively encourage mobility and functional independence. RESULTS: A total of 29 patients were recruited. Mean age was 86.1 (SD 4.92), and 18 (62 %) were women. At discharge, we found a significant improvement in Mini-mental State Examination (p = 0.008), Trail making Test-A (p = 0.03), and verbal fluency (p = 0.019). One month after discharge, Geriatric Depression Scale-Yesavage and Delirium Rating Scale-revised-98 remained statistically different. CONCLUSIONS: This pilot study shows that an exercise program is feasible, and can be suitable to prevent cognitive and affective decline during acute hospitalization of older adults. It is a challenge for the new models of hospitalization to change the actual disease-centered view to the patient-centered view, optimizing traditionally neglected aspects such as functional, cognitive and affective recovery after hospitalization.
Subject(s)
Cognition , Exercise , Family , Hospitalization , Aged, 80 and over , Cognition/physiology , Female , Humans , Male , Pilot Projects , Prospective StudiesABSTRACT
Objetivo Avaliar a equivalência semântica e a confiabilidade da Bergen Facebook Addiction Scale para o português (Brasil). Métodos O processo consistiu em cinco passos: tradução; retradução; revisão técnica e avaliação da equivalência semântica por profissionais; avaliação do instrumento por compreensão verbal por uma amostra de profissionais (n = 10) e de estudantes (n = 37); análise de consistência interna e estabilidade por meio do coeficiente de Cronbach e coeficiente de correlação intraclasse (CCI) respectivamente, em uma amostra de 359 estudantes de graduação. Resultados O instrumento apresentou no fim um excelente nível de compreensão verbal pela população-alvo, alfa de Cronbach de 0,92 e CCI de 0,81. Conclusão A versão adaptada do instrumento para o uso em nosso ambiente resultou em um instrumento equivalente do ponto de visão de equivalência semântica, assegurando a transferência do significado geral e referencial, mantendo níveis satisfatórios de confiabilidade. .
Objective To evaluate the semantic equivalence and confiability of the Bergen Facebook Addiction Scale into Portuguese (Brazil). Methods The process consisted of five steps: translation; back-translation; technical review and evaluation of semantic equivalence by professionals; evaluation instrument as verbal comprehension by a professional sample (n = 10) and students (n = 37); analysis of internal consistency and stability through Cronbach coefficient and intraclass correlation coefficient (ICC) respectively, in a sample of 359 undergraduate students. Results The instrument presented at the end an excellent level of verbal comprehension by the target population, Cronbach’s alpha of 0.92 and ICC of 0.81. Conclusion The adapted version of the instrument for use in our environment resulted in an equivalent instrument from the point of view of semantic equivalence, ensuring the transfer of general and referential meaning, maintaining satisfactory levels of reliability. .
ABSTRACT
This study evaluated the semantic equivalence of the Online Cognition Scale in Brazilian Portuguese. The process included five steps: translation, back-translation, technical review, evaluation of semantic equivalence by trained professionals, and evaluation of the instrument for content understanding by a group of professionals (n = 10) and students (n = 37). The instrument was translated and adapted to Portuguese, showing a high level of verbal comprehension by the target population. The adapted version for use in Brazil resulted in an equivalent instrument from the semantic and content point of view, ready for evaluation of its psychometric qualities in the Brazilian cultural context.
Subject(s)
Behavior, Addictive/diagnosis , Internet , Surveys and Questionnaires , Translations , Adult , Brazil , Compulsive Behavior/diagnosis , Cross-Cultural Comparison , Female , Humans , Male , Semantics , Young AdultABSTRACT
Este estudo teve por objetivo realizar a avaliação da equivalência semântica da Online Cognition Scale para o português (Brasil). O processo consistiu em cinco etapas: tradução; retrotradução; revisão técnica e avaliação da equivalência semântica por profissionais capacitados; avaliação do instrumento quanto à compreensão verbal por uma amostra de profissionais (n = 10) e estudantes (n = 37). O instrumento foi traduzido e adaptado para o português, apresentando, ao final, excelente nível de compreensão verbal pela população alvo. A versão do instrumento adaptada para uso em nosso meio resultou em um instrumento equivalente do ponto de vista da equivalência semântica e de conteúdo, estando pronto para iniciar o estudo de suas qualidades psicométricas no contexto cultural brasileiro.
This study evaluated the semantic equivalence of the Online Cognition Scale in Brazilian Portuguese. The process included five steps: translation, back-translation, technical review, evaluation of semantic equivalence by trained professionals, and evaluation of the instrument for content understanding by a group of professionals (n = 10) and students (n = 37). The instrument was translated and adapted to Portuguese, showing a high level of verbal comprehension by the target population. The adapted version for use in Brazil resulted in an equivalent instrument from the semantic and content point of view, ready for evaluation of its psychometric qualities in the Brazilian cultural context.
El objetivo de este estudio fue llevar a cabo la evaluación de la equivalencia semántica de la Online Cognition Scale en portugués (Brasil). El proceso consistió en cinco etapas: traducción, retrotraducción, revisión técnica y evaluación de la equivalencia semántica de los profesionales; habilitación de instrumentos como la comprensión verbal por una muestra de profesionales (n = 10) y estudiantes (n = 37). El instrumento fue traducido y adaptado al portugués, con un excelente nivel final de comprensión verbal por parte de la población objetivo. La versión adaptada del instrumento para su uso en nuestro contexto, que dio como resultado un instrumento equivalente desde el punto de vista semántico y del contenido, está lista para que comience el estudio de sus propiedades psicométricas en el contexto cultural brasileño.
Subject(s)
Adult , Female , Humans , Male , Young Adult , Behavior, Addictive/diagnosis , Internet , Surveys and Questionnaires , Translations , Brazil , Cross-Cultural Comparison , Compulsive Behavior/diagnosis , SemanticsABSTRACT
Administration of the thienopyridine P2Y12 receptor antagonist, clopidogrel, increased the erosive arthritis induced by peptidoglycan polysaccharide (PG-PS) in rats or by injection of the arthritogenic K/BxN serum in mice. To determine if the detrimental effects are caused exclusively by clopidogrel, we evaluated prasugrel, a third-generation thienopyridine pro-drug, that contrary to clopidogrel is mostly metabolized into its active metabolite in the intestine. Prasugrel effects were examined on the PG-PS-induced arthritis rat model. Erosive arthritis was induced in Lewis rats followed by treatment with prasugrel for 21 days. Prasugrel treated arthritic animals showed a significant increase in the inflammatory response, compared with untreated arthritic rats, in terms of augmented macroscopic joint diameter associated with significant signs of inflammation, histomorphometric measurements of the hind joints and elevated platelet number. Moreover, fibrosis at the pannus, assessed by immunofluorescence of connective tissue growth factor, was increased in arthritic rats treated with prasugrel. In addition to the arthritic manifestations, hepatomegaly, liver granulomas and giant cell formation were observed after PG-PS induction and even more after prasugrel exposure. Cytokine plasma levels of IL-1 beta, IL-6, MIP1 alpha, MCP1, IL-17 and RANTES were increased in arthritis-induced animals. IL-10 plasma levels were significantly decreased in animals treated with prasugrel. Overall, prasugrel enhances inflammation in joints and liver of this animal model. Since prasugrel metabolites inhibit neutrophil function ex-vivo and the effects of both clopidogrel and prasugrel metabolites on platelets are identical, we conclude that the thienopyridines metabolites might exert non-platelet effects on other immune cells to aggravate inflammation.
Subject(s)
Arthritis, Experimental/pathology , Granuloma/pathology , Joints/pathology , Liver/pathology , Piperazines/adverse effects , Platelet Aggregation Inhibitors/adverse effects , Prodrugs/adverse effects , Thiophenes/adverse effects , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/immunology , Clopidogrel , Cytokines/biosynthesis , Cytokines/immunology , Female , Granuloma/chemically induced , Granuloma/immunology , Inflammation/chemically induced , Inflammation/immunology , Inflammation/pathology , Joints/immunology , Liver/immunology , Peptidoglycan , Prasugrel Hydrochloride , Rats , Rats, Inbred Lew , Ticlopidine/adverse effects , Ticlopidine/analogs & derivativesABSTRACT
Clopidogrel and prasugrel belong to a thienopyridine class of oral antiplatelet drugs that, after having been metabolized in the liver, can inhibit platelet function by irreversibly antagonizing the P2Y(12) receptor. Furthermore, thienopyridines influence numerous inflammatory conditions, but their effects on neutrophils have not been evaluated, despite the important role of these cells in inflammation. Therefore, we investigated the effect of prasugrel metabolites on neutrophils to further clarify the role of thienopyridines in inflammation. Interestingly, a prasugrel metabolite mixture, produced in vitro using rat liver microsomes, significantly inhibited N-formyl-methionyl-leucyl-phenylalanine (fMLP)- and platelet-activating factor (PAF)-induced neutrophil activation. More specifically, prasugrel metabolites inhibited neutrophil transmigration, CD16 surface expression, and neutrophil-platelet aggregation. Moreover, prasugrel metabolite pretreatment also significantly decreased fMLP- or PAF-induced extracellular-signal-regulated kinase phosphorylation as well as calcium mobilization. To determine the target of prasugrel in neutrophils, the role of both P2Y(12) and P2Y(13) receptors was studied using specific reversible antagonists, AR-C69931MX and MRS2211, respectively. Neither antagonist had any direct effect on the agonist-induced neutrophil functional responses. Our findings indicate that prasugrel metabolites may directly target neutrophils and inhibit their activation, suggesting a possible explanation for their anti-inflammatory effects previously observed. However, these metabolites do not act through either the P2Y(12) or P2Y(13) receptor in neutrophils.
Subject(s)
Neutrophils/drug effects , Piperazines/pharmacology , Purinergic P2Y Receptor Antagonists/pharmacology , Thiophenes/pharmacology , Animals , Blotting, Western , CD11b Antigen/biosynthesis , Calcium/metabolism , Cell Separation , Cell Survival/drug effects , Chemotaxis, Leukocyte/drug effects , Humans , Inflammation/chemically induced , Inflammation/pathology , Lipopolysaccharides , Lung/pathology , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver , Peroxidase/metabolism , Piperazines/metabolism , Platelet Aggregation/drug effects , Prasugrel Hydrochloride , Purinergic P2 Receptor Antagonists/pharmacology , Purinergic P2Y Receptor Antagonists/metabolism , Receptors, Purinergic P2Y12/drug effects , Thiophenes/metabolismABSTRACT
The P2Y12 receptor plays a crucial role in the regulation of platelet activation by several agonists, which is irreversibly antagonized by the active metabolite of clopidogrel, a widely used anti-thrombotic drug. In this study, we investigated whether reduction of platelet reactivity leads to reduced inflammatory responses using a rat model of erosive arthritis. We evaluated the effect of clopidogrel on inflammation in Lewis rats in a peptidoglycan polysaccharide (PG-PS)-induced arthritis model with four groups of rats: 1) untreated, 2) clopidogrel-treated, 3) PG-PS-induced, and 4) PG-PS-induced and clopidogrel-treated. There were significant differences between the PG-PS+clopidogrel group when compared to the PG-PS group including: increased joint diameter and clinical manifestations of inflammation, elevated plasma levels of pro-inflammatory cytokines (IL-1 beta, interferon (IFN) gamma, and IL-6), an elevated neutrophil blood count and an increased circulating platelet count. Plasma levels of IL-10 were significantly lower in the PG-PS+clopidogrel group compared to the PG-PS group. Plasma levels of platelet factor 4 (PF4) were elevated in both the PG-PS and the PG-PS+clopidogrel groups, however PF4 levels showed no difference upon clopidogrel treatment, suggesting that the pro- inflammatory effect of clopidogrel may be due to its action on cells other than platelets. Histology indicated an increase in leukocyte infiltration at the inflammatory area of the joint, increased pannus formation, blood vessel proliferation, subsynovial fibrosis and cartilage erosion upon treatment with clopidogrel in PG-PS-induced arthritis animals. In summary, animals treated with clopidogrel showed a pro-inflammatory effect in the PG-PS-induced arthritis animal model, which might not be mediated by platelets. Elucidation of the mechanism of clopidogrel-induced cell responses is important to understand the role of the P2Y12 receptor in inflammation.
Subject(s)
Arthritis, Experimental/chemically induced , Peptidoglycan/adverse effects , Purinergic P2Y Receptor Antagonists/pharmacology , Receptors, Purinergic P2Y12/metabolism , Ticlopidine/analogs & derivatives , Animals , Arthritis, Experimental/blood , Arthritis, Experimental/complications , Arthritis, Experimental/pathology , Clopidogrel , Cytokines/blood , Disease Models, Animal , Drug Synergism , Female , Inflammation/blood , Inflammation/chemically induced , Inflammation/complications , Inflammation/pathology , Leukocytosis/complications , Neutrophils/drug effects , Neutrophils/metabolism , Platelet Aggregation/drug effects , Rats , Thrombocytosis/complications , Ticlopidine/pharmacologyABSTRACT
PI3Ks (phosphoinositide 3-kinases) play a critical role in platelet functional responses. PI3Ks are activated upon P2Y12 receptor stimulation and generate pro-aggregatory signals. P2Y12 receptor has been shown to play a key role in the platelet aggregation and thromboxane A2 generation caused by co-stimulation with Gq or Gz, or super-stimulation of Gi pathways. In the present study, we evaluated the role of specific PI3K isoforms alpha, beta, gamma and delta in platelet aggregation, thromboxane A2 generation and ERK (extracellular-signal-regulated kinase) activation. Our results show that loss of the PI3K signal impaired the ability of ADP to induce platelet aggregation, ERK phosphorylation and thromboxane A2 generation. We also show that Gq plus Gi- or Gi plus Gz-mediated platelet aggregation, ERK phosphorylation and thromboxane A2 generation in human platelets was inhibited by TGX-221, a PI3Kbeta-selective inhibitor, but not by PIK75 (a PI3Kalpha inhibitor), AS252424 (a PI3Kgamma inhibitor) or IC87114 (a PI3Kdelta inhibitor). TGX-221 also showed a similar inhibitory effect on the Gi plus Gz-mediated platelet responses in platelets from P2Y1-/- mice. Finally, 2MeSADP (2-methyl-thio-ADP)-induced Akt phosphorylation was significantly inhibited in the presence of TGX-221, suggesting a critical role for PI3Kbeta in Gi-mediated signalling. Taken together, our results demonstrate that PI3Kbeta plays an important role in ADP-induced platelet aggregation. Moreover, PI3Kbeta mediates ADP-induced thromboxane A2 generation by regulating ERK phosphorylation.
Subject(s)
GTP-Binding Protein alpha Subunits, Gi-Go/blood , Phosphatidylinositol 3-Kinases/blood , Platelet Aggregation/physiology , Thromboxane A2/blood , Adenosine Diphosphate/pharmacology , Animals , Blood Platelets/drug effects , Blood Platelets/metabolism , Humans , In Vitro Techniques , Isoenzymes/antagonists & inhibitors , Isoenzymes/blood , MAP Kinase Signaling System/drug effects , Mice , Mice, Knockout , Morpholines/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Platelet Aggregation/drug effects , Protein Kinase Inhibitors/pharmacology , Pyrimidinones/pharmacology , Receptors, Purinergic P2/deficiency , Receptors, Purinergic P2/genetics , Receptors, Purinergic P2Y1 , Signal Transduction/drug effectsABSTRACT
Increasing research findings argue for a link between brain cholesterol turnover and Alzheimer's disease (AD). High cerebral levels of this lipid increase Ass load. The elimination of cerebral cholesterol involves two mechanisms, dependent of apolipoprotein E and cholesterol 24-hydroxylase (CYP46). CYP46 is a gene associated with AD; the most studied single nucleotide polymorphism is the rs754203, which changes T-->C. Some studies describe that this polymorphism is possibly associated with loss of function of CYP46; others describe that it is possibly associated with cerebral cholesterol accumulation or an increase of CYP46 activity leading to an accumulation of the 24S-hydroxycholesterol in cerebrospinal fluid. Publications about this subject around the world are controversial. Some studies associate the T allele with AD and others the C allele. The aim of this review is to describe and summarize the findings of the researches about the relationship between CYP46 and AD that have been published in the past 9 years.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/genetics , Cholesterol/metabolism , Polymorphism, Genetic/genetics , Steroid Hydroxylases/genetics , Steroid Hydroxylases/metabolism , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Base Sequence/genetics , Brain/metabolism , Brain/physiopathology , Brain Chemistry/genetics , Cholesterol 24-Hydroxylase , Genetic Markers , Genetic Predisposition to Disease/genetics , HumansABSTRACT
BACKGROUND: Polymorphism of the gene for apolipoprotein E (APOE) is an important risk factor for the development of Alzheimer's disease. The epsilon4 allele of the APOE gene has been linked with a number of neuropsychiatric illnesses, and also with stress and depression among geriatric populations. OBJECTIVE: To identify APOE-epsilon4 polymorphism and correlate this with cognitive deficit among the elderly population of the island of Fernando de Noronha. METHOD: Neuropsychiatric tests (mini-mental state examination, verbal fluency test and clock drawing test) were applied to 52 elderly people without Alzheimer's disease. DNA was isolated from peripheral blood and genotyping of APOE was done by the PCR-RFLP method. RESULTS: 87% of the elderly population (mean age 69.6+/-7.0) had cognitive deficit. CONCLUSION: The observed frequency of the epsilon4 allele was 10%, but the correlation between the presence of epsilon4 and cognitive deficit in this population was not statistically significant.
Subject(s)
Apolipoprotein E4/genetics , Cognition Disorders/genetics , Polymorphism, Genetic , Age Factors , Aged , Aged, 80 and over , Alleles , Alzheimer Disease/diagnosis , Alzheimer Disease/genetics , Analysis of Variance , Brazil/epidemiology , Brief Psychiatric Rating Scale , Chi-Square Distribution , Cognition/physiology , Cognition Disorders/epidemiology , Cognition Disorders/psychology , Educational Status , Female , Genotype , Geriatric Assessment , Humans , Male , Middle Aged , Neuropsychological Tests , Sex FactorsABSTRACT
BACKGROUND: Polymorphism of the gene for apolipoprotein E (APOE) is an important risk factor for the development of Alzheimer's disease. The ε4 allele of the APOE gene has been linked with a number of neuropsychiatric illnesses, and also with stress and depression among geriatric populations. OBJECTIVE: To identify APOE-ε4 polymorphism and correlate this with cognitive deficit among the elderly population of the island of Fernando de Noronha. METHOD: Neuropsychiatric tests (mini-mental state examination, verbal fluency test and clock drawing test) were applied to 52 elderly people without Alzheimer's disease. DNA was isolated from peripheral blood and genotyping of APOE was done by the PCR-RFLP method. RESULTS: 87 percent of the elderly population (mean age 69.6±7.0) had cognitive deficit. CONCLUSION: The observed frequency of the ε4 allele was 10 percent, but the correlation between the presence of ε4 and cognitive deficit in this population was not statistically significant.
INTRODUÇÃO: Polimorfismos no gene da apoliproteína E (APOE) são importantes fatores de risco para o desenvolvimento da doença de Alzheimer (DA). O alelo ε4 do gene APOE tem sido relacionado com declínio cognitivo e algumas doenças neuropsiquiátricas, primariamente a doença de Alzheimer. OBJETIVO: Identificar os polimorfismos de APOE-ε4 e relacionar com deficit cognitivo na população idosa da ilha de Fernando de Noronha. MÉTODO: Foram aplicados testes neuropsiquiátricos (mini exame do estado mental, teste de fluência verbal e teste do relógio) em 52 idosos sem DA. O DNA foi isolado do sangue periférico e a genotipagem de APOE foi realizada por PCR-RFLP. RESULTADOS: 87 por cento da população idosa com idade média de 69.6±7.0 apresentou déficit cognitivo. Foi observada uma freqüência de 10 por cento do alelo ε4. CONCLUSÃO: Não foi encontrada significância estatística quando relacionada a presença deste alelo e déficit cognitivo nos idosos avaliados.
Subject(s)
Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , /genetics , Cognition Disorders/genetics , Polymorphism, Genetic , Age Factors , Alleles , Analysis of Variance , Alzheimer Disease/diagnosis , Alzheimer Disease/genetics , Brief Psychiatric Rating Scale , Brazil/epidemiology , Chi-Square Distribution , Cognition Disorders/epidemiology , Cognition Disorders/psychology , Cognition/physiology , Educational Status , Genotype , Geriatric Assessment , Neuropsychological Tests , Sex FactorsABSTRACT
Platelets release insulin-like growth factor-1 (IGF-1) from alpha granules upon activation. We have investigated the regulation of IGF-1 in G(i)-dependent pathways leading to Akt activation and the role of IGF-1 in platelet activation. IGF-1 alone failed to induce platelet aggregation, but IGF-1 potentiated 2-MeSADP-induced platelet aggregation in a concentration-dependent manner. IGF-1 triggered platelet aggregation in combination with selective P2Y(1) receptor activation. IGF-1 also caused platelet aggregation without shape change when combined with selective G(z) stimulation by epinephrine, suggesting the role of IGF-1 in platelet aggregation by supplementing G(i) pathways. The potentiating effect of IGF-1 was not affected by intracellular calcium chelation. Importantly, IGF-1 was unable to potentiate platelet aggregation by the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin, suggesting a critical regulation by PI3-K. Moreover, the potentiating effect of IGF-1 was abolished by the presence of PI3-K p110alpha inhibitor PIK-75. Stimulation of platelets with IGF-1 resulted in phosphorylation of Akt, a downstream effector of PI3-K, which was completely inhibited by wortmannin. IGF-1-induced Akt phosphorylation was abolished by PIK-75 suggesting the contribution of PI3-K p110alpha for activation of Akt by IGF-1. These results demonstrate that IGF-1 plays a role in potentiating platelet aggregation by complementing G(i)- but not G(q)-signaling pathways via PI3-K p110alpha.
Subject(s)
GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , Insulin-Like Growth Factor I/physiology , Phosphatidylinositol 3-Kinases/metabolism , Platelet Activation , Signal Transduction , Cells, Cultured , GTP-Binding Protein alpha Subunits, Gq-G11 , Humans , Protein Isoforms , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
OBJETIVO: Comparar as medidas antropométricas da envergadura e circunferência braquial para avaliação do estado nutricional de idosos em relação ao índice de Massa Corporal. MÉTODOS: Foram estudados 308 idosos residentes em instituições asilares públicas e particulares em Pernambuco, Brasil. RESULTADOS: A sensibilidade do índice de Massa Corporal, tendo a envergadura como preditora da estatura, no diagnóstico da desnutrição, foi de 93,5 por cento, com especificidade de 82,0 por cento. Com relação ao diagnóstico de sobrepeso e obesidade, o cálculo do índice de Massa Corporal, utilizando a envergadura, demonstrou sensibilidade de 44,5 por cento e 83,3 por cento e especificidade de 87,0 por cento e 100,0 por cento, respectivamente. A circunferência braquial apresentou, no diagnóstico de desnutrição, sensibilidade e especificidade de 89,0 por cento e 87,0 por cento, respectivamente. CONCLUSÃO: Em idosos, o uso da envergadura em substituição à altura no cálculo do índice de Massa Corporal, mostrou-se um bom indicador no diagnóstico de desnutrição e de obesidade, no entanto não se observou o mesmo em relação ao diagnóstico de sobrepeso. A medida da circunferência braquial foi também um bom indicador para determinar desnutrição em idosos.
OBJECTIVE: This study compared anthropometric measurements (arm span and circumference) used in the assessment of nutritional status of the elderly in relation to Body Mass Index. METHODS: The sample consisted of 308 elderly living in private and public nursing homes in the State of Pernambuco, northeast Brazil. RESULTS: Body Mass Index sensitivity with height being determined by arm span in the diagnosis of malnutrition was 93.5 percent, with a specificity of 82 percent. With regard to the diagnosis of overweight and obesity, the sensitivity was 44.5 percent and 83.3 percent and specificity 87.0 percent and 100.0 percent respectively. Among those diagnosed with malnutrition, arm circumference showed a sensitivity and specificity of 89.0 percent and 87.0 percent respectively. CONCLUSION: We conclude that using arm span as a proxy for height when calculating Body Mass Index is a good indicator of malnutrition and obesity; however, the same was not observed for the overweight. Arm circumference was also found to be a good indicator of malnutrition in the elderly.
Subject(s)
Humans , Male , Aged , Anthropometry , Nutrition AssessmentABSTRACT
We have previously shown that ADP-induced thromboxane generation in platelets requires signalling events from the G(q)-coupled P2Y1 receptor (platelet ADP receptor coupled to stimulation of phospholipase C) and the G(i)-coupled P2Y12 receptor (platelet ADP receptor coupled to inhibition of adenylate cyclase) in addition to outside-in signalling. While it is also known that extracellular calcium negatively regulates ADP-induced thromboxane A2 generation, the underlying mechanism remains unclear. In the present study we sought to elucidate the signalling mechanisms and regulation by extracellular calcium of ADP-induced thromboxane A2 generation in platelets. ERK (extracllular-signal-regulated kinase) 2 activation occurred when outside-in signalling was blocked, indicating that it is a downstream event from the P2Y receptors. However, blockade of either P2Y1 or the P2Y12 receptors with corresponding antagonists completely abolished ERK phosphorylation, indicating that both P2Y receptors are required for ADP-induced ERK activation. Inhibitors of Src family kinases or the ERK upstream kinase MEK [MAPK (mitogen-activated protein kinase)/ERK kinase] abrogated ADP-induced ERK phosphorylation and thromboxane A2 generation. Finally ADP- or G(i)+G(z)-induced ERK phosphorylation was blocked in the presence of extracellular calcium. The present studies show that ERK2 is activated downstream of P2Y receptors through a complex mechanism involving Src kinases and this plays an important role in ADP-induced thromboxane A2 generation. We also conclude that extracellular calcium blocks ADP-induced thromboxane A2 generation through the inhibition of ERK activation.
