Performance of adenosine deaminase in synovial fluid for the diagnosis of tuberculous arthritis: A systematic review and meta-analysis.

OBJECTIVES: Adenosine deaminase (ADA) activity has shown good performance in diagnosing pleural, peritoneal, and meningeal tuberculosis. This meta-analysis aimed to evaluate the performance of measuring ADA activity in synovial fluid for the early diagnosis of joint tuberculosis. METHODS: We searched published information in MEDLINE, Embase, Cochrane Library, Web of Science, and MedRxiv databases, as well as unpublished information in the American College of Rheumatology and European League Against Rheumatism for conference abstracts (2012-2021). We also scanned the reference lists of articles. Two reviewers independently applied the criteria for selection, assessed quality, and extracted data (PROSPERO number CRD42021284472). RESULTS: Seven independent studies (N=305 subjects) that compared ADA activity in synovial fluid with a composite reference diagnostic method for tuberculosis were included. Overall, the risk of bias was judged low. Studies were classified as high quality (n=3; 148 subjects) and low quality (n=4; 157 subjects). Pooled sensitivity and specificity of ADA activity was 94% (95% confidence interval [CI], 0.89-98; I2=23%) and 88% (95% CI, 83-92; I2=83%), respectively. The random-effects model for pooled diagnostic Odds ratio was 67.1 (95%CI, 20.3-222.2; I2=30%). The receiver operating characteristic curve area was 0.96 (95% CI, 0.92-0.99). Meta-regression did not identify the quality of the study, country of publication, or the type of assay as a source of heterogeneity. CONCLUSIONS: Measuring ADA activity in synovial fluid demonstrates good performance for the early diagnosis of joint tuberculosis.

Performance of adenosine deaminase in synovial fluid for the diagnosis of tuberculous arthritis: A systematic review and meta-analysis / Rendimiento de la adenosina desaminasa en el líquido sinovial para el diagnóstico de la artritis tuberculosa: una revisión sistemática y metaanálisis

Objectives: Adenosine deaminase (ADA) activity has shown good performance in diagnosing pleural, peritoneal, and meningeal tuberculosis. This meta-analysis aimed to evaluate the performance of measuring ADA activity in synovial fluid for the early diagnosis of joint tuberculosis. Methods: We searched published information in MEDLINE, Embase, Cochrane Library, Web of Science, and MedRxiv databases, as well as unpublished information in the American College of Rheumatology and European League Against Rheumatism for conference abstracts (2012–2021). We also scanned the reference lists of articles. Two reviewers independently applied the criteria for selection, assessed quality, and extracted data (PROSPERO number CRD42021284472). Results: Seven independent studies (N=305 subjects) that compared ADA activity in synovial fluid with a composite reference diagnostic method for tuberculosis were included. Overall, the risk of bias was judged low. Studies were classified as high quality (n=3; 148 subjects) and low quality (n=4; 157 subjects). Pooled sensitivity and specificity of ADA activity was 94% (95% confidence interval [CI], 0.89–98; I2=23%) and 88% (95% CI, 83–92; I2=83%), respectively. The random-effects model for pooled diagnostic Odds ratio was 67.1 (95%CI, 20.3–222.2; I2=30%). The receiver operating characteristic curve area was 0.96 (95% CI, 0.92–0.99). Meta-regression did not identify the quality of the study, country of publication, or the type of assay as a source of heterogeneity. Conclusions: Measuring ADA activity in synovial fluid demonstrates good performance for the early diagnosis of joint tuberculosis.(AU)

Objetivos: La actividad de la adenosina desaminasa (ADA) ha mostrado un buen desempeño en el diagnóstico de la tuberculosis pleural, peritoneal y meníngea. Este metaanálisis tuvo como objetivo evaluar el rendimiento de la medición de la actividad de la ADA en el líquido sinovial para el diagnóstico precoz de la tuberculosis articular. Métodos: Se realizaron búsquedas de resúmenes de congresos en la información publicada en las bases de datos MEDLINE, Embase, Cochrane Library, Web of Science y MedRxiv, así como en información no publicada en el American College of Rheumatology y la European League Against Rheumatism (2012-2021). También se escanearon las listas de referencias de los artículos. Dos revisores aplicaron de forma independiente los criterios de selección, evaluaron la calidad y extrajeron los datos (número PROSPERO CRD42021284472). Resultados: Se incluyeron siete estudios independientes (n=305 sujetos) que compararon la actividad de la ADA en el líquido sinovial con un método diagnóstico compuesto de referencia para la tuberculosis. En general, el riesgo de sesgo se consideró bajo. Los estudios se clasificaron como de alta calidad (n=3; 148 sujetos) y de baja calidad (n=4; 157 sujetos). La sensibilidad y la especificidad agrupadas de la actividad de la ADA fueron del 94% (intervalo de confianza [IC] del 95%: 0,89-98; I2=23%) y del 88% (IC95%: 83-92; I2=83%), respectivamente. El modelo de efectos aleatorios para el odds ratio diagnóstico agrupado fue de 67,1 (IC95%: 20,3-222,2; I2=30%). El área de la curva característica de operación del receptor fue de 0,96 (IC95%: 0,92-0,99). La metarregresión no identificó la calidad del estudio, el país de publicación o el tipo de ensayo como fuente de heterogeneidad.Conclusiones: La medición de la actividad de ADA en el líquido sinovial demuestra un buen rendimiento para el diagnóstico precoz de la tuberculosis articular.(AU)

Intraoperative adenosine for pheochromocytoma with myocardial infarction and SARS-CoV-2. Case report / Adenosina intraoperatoria para feocromocitoma con infarto miocárdico y SARS-CoV-2. Reporte de caso

Abstract Pheochromocytomas are neuroendocrine tumors capable of synthetizing, storing and releasing catecholaminergic hormones that may lead to lifethreatening hemodynamic instability. The COVID-19 pandemic has increased the risks and perioperative complexity of the patients undergoing pheochromocytoma-associated adrenalectomy. This article discusses the use of adenosine for the management of hypertensive crisis during this intervention, as well as the need to individualize the suitable timing for surgery after recent COVID-19 infection. This article discusses the case of a patient with a finding of right adrenal incidentaloma; further studies determined a metanephrines secreting pheochromocytoma. Following hospital admission for preoperative optimization, the eve of the procedure the patient developed an acute myocardial infarction and subsequently SARS-CoV-2 symptomatic infection. Intraoperatively, hypertensive peaks were managed with continuous adenosine perfusion. The patient was discharged after 48 hours. Preoperative optimization positively influences the intraoperative management of patients with pheochromocytoma. The intraoperative use of adenosine allows for adequate and safe control of hypertensive crises. Each situation must be individualized in patients pending surgery, with a recent COVID-19 infection.

Resumen Los feocromocitomas son tumores neuroendocrinos capaces de sintetizar, almacenar y liberar hormonas catecolaminérgicas que pueden provocar inestabilidad hemodinámica con compromiso vital. La pandemia por COVID-19 ha aumentado los riesgos y la complejidad perioperatoria de los pacientes sometidos a adrenalectomía por feocromocitoma. Describimos el uso de adenosina para manejar las crisis hipertensivas durante esta intervención, así como establecer la necesidad de individualizar el momento quirúrgico idóneo tras infección reciente por COVID-19. Presentamos el caso de un paciente con hallazgo de incidentaloma suprarrenal derecho cuya ampliación de estudio se orientó como feocromocitoma secretor de metanefrinas. Tras ingreso hospitalario para optimización preoperatoria, el día previo al procedimiento presentó un infarto agudo de miocardio y posteriormente una infección sintomática por SARS-CoV-2. Intraoperatoriamente se manejaron los picos hipertensivos con perfusión continua de adenosina. Tras 48 horas recibió el alta hospitalaria. La optimización preoperatoria influye positivamente en el manejo intraoperatorio de los pacientes con feocromocitoma. El uso intraoperatorio de adenosina permite un adecuado y seguro control de las crisis hipertensivas. En pacientes pendientes de cirugía con infección reciente por COVID-19 se requiere individualizar cada situación.

Valor Prognóstico da Imagem de Ressonância Magnética Cardíaca de Perfusão em Estresse com Adenosina em Idosos com Doença Arterial Coronariana Conhecida ou Suspeita / Prognostic Value of Adenosine Stress Perfusion Cardiac Magnetic Resonance Imaging in Older Adults with Known or Suspected Coronary Artery Disease

Resumo Fundamento: Há dados limitados sobre o valor prognóstico da ressonância magnética cardíaca (RMC) em estresse em pacientes idosos. Objetivo: Determinar o valor prognóstico da RMC em estresse com adenosina em idosos com doença arterial coronariana (DAC) conhecida ou suspeita. Métodos: Entre 2010 e 2015, pacientes consecutivos com 65 anos ou mais encaminhados para RMC em estresse com adenosina foram acompanhados para a ocorrência de eventos cardíacos graves (morte cardíaca e infarto do miocárdio não-fatal) e eventos cardiovasculares adversos maiores (ECAM) que também incluíram hospitalização por insuficiência cardíaca e acidente vascular cerebral isquêmico. As análises univariadas e multivariadas foram realizadas para determinar o valor prognóstico da isquemia miocárdica, com valor de p <0,05 considerado estatisticamente significante. Resultados: Após um período médio de seguimento de 50,4 meses em 324 pacientes (48% do sexo masculino, 73±7 anos), ocorreram 21 eventos cardíacos graves e 52 ECAM. Pacientes com isquemia miocárdica (n=99) apresentaram taxas significantemente maiores de eventos cardíacos graves (HR 5,25 [IC 95% 2,11-13,04], p<0,001) e ECAM (HR 3,01 [IC 95% 1,75-5,20], p<0,001) do que aqueles sem isquemia. A análise multivariada determinou a isquemia como preditor independente de eventos cardíacos graves (HR 3,14 [IC 95% 1,22-8,07], p=0,02) e ECAM (HR 1,91 [IC 95% 1,02-3,59], p=0,04). A isquemia forneceu um valor prognóstico incremental sobre fatores clínicos e fração de ejeção do ventrículo esquerdo para predizer eventos cardíacos graves e ECAM (p<0,01 para ambos). Nenhum evento adverso grave ocorreu durante ou imediatamente após os exames de RMC. Conclusão: A RMC em estresse com adenosina é segura e demonstra valor prognóstico em idosos com DAC conhecida ou suspeita.

Abstract Background: There is limited data on the prognostic value of stress cardiac magnetic resonance (CMR) in older adults. Objective: To determine the prognostic value of adenosine stress CMR in older individuals with known or suspected coronary artery disease (CAD). Methods: Between 2010 and 2015, consecutive patients aged 65 years or older referred for adenosine stress CMR were followed for the occurrence of severe cardiac events (cardiac death and nonfatal myocardial infarction) and major adverse cardiovascular events (MACE) that also included hospitalization for heart failure and ischemic stroke. Univariate and multivariate analyses were performed to determine the prognostic value of myocardial ischemia, with p-value <0.05 considered statistically significant. Results: After a mean follow-up period of 50.4 months in 324 patients (48% male, 73±7 years), 21 severe cardiac events and 52 MACE occurred. Patients with myocardial ischemia (n=99) had significantly higher rates of severe cardiac events (HR 5.25 [95% CI 2.11-13.04], p<0.001) and MACE (HR 3.01 [95% CI 1.75-5.20], p<0.001) than those without ischemia. Multivariable analysis determined ischemia as an independent predictor of severe cardiac events (HR 3.14 [95% CI 1.22-8.07], p=0.02) and MACE (HR 1.91 [95%CI 1.02-3.59], p=0.04). Ischemia provided an incremental prognostic value over clinical factors and left ventricular ejection fraction for predicting severe cardiac events and MACE (p<0.01 for both). No severe adverse events occurred during or immediately after CMR examinations. Conclusion: Adenosine stress CMR is safe and has prognostic value in older adults with known or suspected CAD.

Modelagem celular in vitro da Doença de Huntington com ácido 3-nitropropiônico e ácido quinolínico & Avaliação das funções neuroprotetoras da adenosina / In vitro cell modeling of Huntington's Disease with 3-nitropropionic acid and quinolinic acid and evaluation of the neuroprotective functions of adenosine

A Doença de Huntington (Huntington's disease - HD) trata-se de uma patologia neurodegenerativa hereditária caracteriza por meio da expressão das proteínas huntingtinas mutantes (mHtt), das mortes dos neurônios espinhais médios (medium spiny neurons MSNs) GABAérgicos D2-positivos do striatum e da hipercinesia. Uma hipótese se refere à função das mHtts de potencializarem os efeitos excitotóxicos das estimulações dos receptores de NMDA (NMDAR) por meio da inibição da succinato desidrogenase, resultando em desequilibrio das [Ca2+]i, estresse oxidativo e apoptose. A adenosina agonista dos receptores purinérgicos P1 tem sido descrita por conta das suas funções neuroprotetoras e neuromodulatórias. Assim, estabelecemos dois modelos in vitro da HD fundamentados nas neurodiferenciações das linhagens murinas de célula-tronco embrionárias E14-TG2a e progenitoras neurais do hipocampo HT-22; seguidas pelos tratamentos com ácido quinolínico (QA) agonista seletivo dos NMDARs , na ausência e na presença do ácido 3-nitropropiônico (3-NP) inibidor irreversível da succinato desidrogenase. Estes modelos foram utilizados nas avaliações das funções neuroprotetoras da adenosina. Os neurônios pós-mitóticos das culturas de E14-TG2a diferenciadas foram caracterizados conforme os MSNs GABAérgicos do striatum; enquanto os neurônios HT-22 diferenciados foram caracterizados de modo inespecífico. Metodologia: imunofluorescência (microscopia e citometria); PCR em tempo real; análise das variações dos potenciais das membranas plasmáticas e das variações transientes das [Ca2+]i por microfluorimetria; e quantificações das reduções do AlamarBlue® (% de sobrevida celular) e das atividades extracelulares de LDH (U/L) (necrose) por espectrometria. Avaliamos a capacidade do 3-NP de potencializar os efeitos excitotóxicos do QA comparando dois grupos de neurônios HT-22 diferenciados: QA 8mM (EC50) (controle); e 3-NP 5mM/QA 8mM. Avaliarmos o potencial neuroprotetor da adenosina comparando quatro grupos de neurônios HT-22 diferenciados: QA 8mM; adenosina 250µM/QA 8mM; 3-NP 5mM/QA 8mM; 3-NP 5mM/adenosina 250µM/QA 8mM. Os neurônios pós-mitóticos derivados das E14TG2a foram classificados como MSNsGABAérgicos do striatum integrantes de uma cultura neuronal heterogênea semelhante às conexões nigroestriatais, corticoestriatais, striatonigral e striatopallidal. Os neurônios HT-22 diferenciados perfaziam uma cultura neuronal heterogênea, não totalmente madura, composta por neurônios glutamatérgicos, dopaminérgicos, colinérgicos e GABAérgicos. Os neurônios HT-22 diferenciados 3-NP 5mM apresentaram menores % de sobrevida celular após os tratamentos com QA 8mM por 24h (p<0.05); e maiores amplitudes das variações das [Ca2+]i dependentes do QA 8mM (p<0.05) (cinética 6 minutos). Por outro lado, os neurônios HT-22 diferenciados pré- tratados com 3-NP 5mM apresentaram menores atividades extracelulares de LDH após o tratamento com QA 8mM por 24h menor proporção de necrose. Os pré-tratamentos com adenosina 250µM indicaram uma tendência dos efeitos neuroprotetores (p>0.05) maiores % de sobrevida celular; menores atividades extracelulares de LDH; e menores amplitudes das variações transientes das [Ca2+]i. Em conjunto, nossos resultados indicam que a inibição da succinato desidrogenase potencializa os efeitos excitotóxicos dos NMDARs por meio da alteração das [Ca2+]i e, provavelmente, dos mecanismos de morte celular; enquanto a adenosina apenas tendeu à neuroproteção

Huntington's disease (HD) is a hereditary neurodegenerative pathology characterized by mutant huntingtin proteins (mHtt) expression, striatum D2-positive GABAergic medium spiny neurons (MSNs) cell death and hyperkinetic motor symptoms development. One hypothesis refers to the principle that mHtt potentiates the excitotoxic effects of NMDA receptor (NMDAR) stimulation by the inhibition of mitochondrial succinate dehydrogenase, resulting in [Ca2+]i imbalance, oxidative stress and apoptosis. Adenosine P1 purinergic receptor agonist is related to neuroprotective and neuromodulatory functions. Thus, we established two in vitro HD models based on the neurodifferentiation of murine embryonic stem cell lines E14-TG2a and hippocampal neuroprogenitor cell line HT-22 followed by treatment with quinolinic acid (QA) selective agonist of NMDARs , in the absence and in the presence of 3-nitropropionic acid (3-NP) irreversible inhibitor of succinate dehydrogenase. These models were used to assess the neuroprotective functions of adenosine. Post-mitotic neurons from differentiated E14-TG2a cultures were characterized according to striatum's GABAergic MSNs; while the differentiated HT-22 neurons were characterized in a non-specific way. Methodology included immunofluorescence (microscopy and cytometry); real-time PCR; analysis of variations in the plasma membrane potentials and of transient variations in the [Ca2+]i by microfluorimetry; and quantification of AlamarBlue® reductions (% cell survival) and of extracellular LDH activity (U/L) (necrosis) by spectrometry. We evaluated the ability of 3-NP to potentiate the excitotoxic effects of QA by comparing two groups of differentiated HT-22 neurons: 8mM QA (control); and 5mM 3-NP/8mM QA. We evaluated the neuroprotective potential of adenosine comparing four groups of differentiated HT-22 neurons: QA 8mM; 250µM adenosine/8mM QA; 5mM 3-NP/8mM QA; 5mM 3-NP/250µM adenosine/8mM QA. Postmitotic neurons derived from E14TG2a were classified as striatums GABAergic MSNs that are part of a heterogeneous neuronal culture similar to nigrostriatal, corticostriatal, striatonigral, and striatopallidal connections. Differentiated HT-22 neurons consisted of a heterogeneous neuronal culture and not fully mature glutamatergic,dopaminergic, cholinergic and GABAergic neurons. Differentiated HT-22 neurons following 5mM 3-NP treatment showed lower % cell survival after treatments with 8mM QA for 24h (p<0.05); and higher amplitudes of the variations of [Ca2+]i induced by 8mM QA (p<0.05) (kinetics 6 minutes). On the other hand, differentiated HT-22 neurons 5mM 3-NP showed lower extracellular LDH activities after treatment with 8mM QA for 24h indicating a lower proportion of necrotic cells. Pretreatments with 250µM adenosine indicated a trend towards neuroprotective effects, such as higher percentages of cell survival; lower extracellular LDH activities; and lower amplitudes of transient variations of [Ca2+]i. Taken together, our results indicate that succinate dehydrogenase inhibition potentiated the excitotoxic effects of NMDARs by altering [Ca2+]i and, probably, cell death mechanisms, while adenosine only to neuroprotection

Treatment and Outcome in Deficiency of Adenosine Deaminase 2: A Literature Review

Objectives: Deficiency of adenosine deaminase 2 (DADA2) is a rare disease with varying phenotypes and disease outcomes. We evaluated the treatment of DADA2 and explored the factors associated with disease outcome.Methods: A systemic literature review of DADA2 was conducted. Cases were included if they had documented detailed genotypes, phenotypes, treatment protocols, and outcomes. Patients were categorized as having uncontrolled and controlled disease. Factors associated with disease outcome were analyzed using logistic regression models.Results: The study population comprised 242 DADA2 patients with data on treatment protocols and responses, of whom 17 required no treatment. Tumor necrosis factor a inhibitors (TNFi) were effective in 78.6% (103/131). Hematological abnormalities and increased acute phase reactants are independently associated with the effectiveness of TNFi (OR, 0.21 [95%CI, 0.07-0.661; P=.007] and 9.62 [95%CI, 2.31-40.00; P=.002, respectively). Among the 225 patients requiring active treatment, 157 (69.8%) had controlled disease and 68 (30.2%) uncontrolled disease. Neither age of disease onset nor genotype was associated with disease outcome. Increased acute phase reactant values, constitutional symptoms, neurological symptoms, and treatment with TNFi were independently associated with disease control, while recurrent infections and severe vascular events were the main causes of mortality (10/21 and 6/21, respectively).Conclusion: In patients requiring treatment, symptoms of systemic inflammation and vasculitis and treatment with TNFi are associated with disease control. Recurrent infections and severe vascular events should be treated intensively, as they are the main causes of death. Hematological abnormalities should be monitored, as they decrease the effectiveness of TNFi (AU)

Objetivos: El déficit de adenosina desaminasa 2 (DADA2) es una enfermedad rara con diferentes fenotipos y una evolución variable de laenfermedad. Nuestro objetivo es resumir los tratamientos de DADA2 y explorar los factores asociados con la evolución de la enfermedad.Métodos: Se realizó una revisión bibliográfica sistémica de DADA2. Los casos que se incluyeron fueron aquellos que habían documentadoel genotipo, fenotipos, protocolo de tratamiento y evolución. Los pacientes se clasificaron en grupos controlados y no controlados. Losfactores asociados con la evolución de la enfermedad se analizaron con modelos de regresión logística.Resultados: Se incluyeron un total de 242 pacientes con DADA2 con los protocolos de su tratamiento y la respuesta al mismo, 17 de los cualesno requirieron tratamiento. La eficacia general de los inhibidores de TNF-a (TNFi) fue del 78,6% (103/131). Las anomalías hematológicasy el aumento de los reactantes de fase aguda se asociaron de forma independiente con la eficacia del TNFi, OR = 0,21 (IC del 95%: 0,07 a0,661, p = 0,007) y 9,62 (IC del 95%: 2,31 a 40,00, p = 0,002), respectivamente. Entre los 225 pacientes que requirieron tratamiento activo,157 (69,8%) pacientes estaban en el grupo controlado y 68 (30,2%) en el grupo no controlado. Ni la edad de inicio de la enfermedad niel genotipo se asociaron con la evolución de la enfermedad. El aumento de los reactantes de fase aguda (APR), el deterioro constitucional,los síntomas neurológicos y el tratamiento con TNFi, se asociaron de forma independiente con el control de la enfermedad, mientras quelas infecciones recurrentes y los eventos vasculares graves fueron las principales causas de mortalidad (10/21 y 6/21, respectivamente).Conclusión: Los síntomas de inflamación sistémica, la vasculitis y el tratamiento con TNFi se asociaron con el control de la enfermedad enaquellos pacientes con DADA2 que requirieron tratamiento.

Determinación del valor de adenosina deaminasa en tuberculosis pleural / Determination of the adenosine deaminase value in pleural tuberculosis

Resumen La determinación de adenosina deaminasa (ADA) es de utilidad en países donde la prevalencia de tuberculosis (TB) es alta/moderada. El objetivo del trabajo fue analizar el punto de corte de ADA en pacientes con tuberculosis en nuestra institución. Se incluyeron todos los pacientes con derrame pleural, desde mayo del 2016 a marzo 2019. Se excluyeron aquellos con serología positiva para HIV y los trasudados. Todos fueron agrupados en los siguientes diagnósticos: TB, neoplasia, paraneumónico u otro de causa no aclarada. Se efectuó determinación de ADA y cultivo para micobacterias a todas las muestras de líquido pleural. Se realizó una curva ROC para establecer el mejor punto de corte de ADA para el diagnóstico de TB. Se recolectó información de 309 pacientes, se incluyeron 220, 87 tuvieron diagnóstico de TB. El mejor punto de corte obtenido para el ADA fue de 52 U/l, con una sensibilidad de 79% y una especificidad de 90%. El área bajo la curva (AUC) resultó de 0.90. En los menores de 40 años, el mejor punto de corte fue de 41 U/l, por debajo del obtenido para el total de la población en estudio. En nuestra población, el punto de corte para el valor de ADA en exudado pleural para el diagnóstico de tuberculosis de 52 U/l, presentó la mayor especificidad y sensibilidad.

Abstract The determination of adenosine deaminase (ADA) is useful in countries where the prevalence of tuberculosis (TB) is high/ moderate. The objective of this study was to analyze the cut-off point for ADA in patients with TB at our institu tion. All patients with pleural effusion were included, from May 2016 to March 2019, except those with positive serology for HIV and transudates. They were grouped into the following diagnoses: TB, neoplasm, parapneumonic or other with an unclear cause. ADA determination and culture for mycobacteria were performed on all samples of pleural fluid. A ROC curve was performed to establish the best ADA cut-off point for the diagnosis of TB. Information was collected from 309 patients; 220 were included and 87 had a diagnosis of TB. The best cut-off point obtained for ADA was 52 U/l, with a sensitivity of 79% and a specificity of 90%. The area under the curve (AUC) was 0.90. In patients under 40 years old the best cut-off point was 41 U/l, below that obtained for the total study population. In our population the cut-off point for the ADA value in pleural exudate for the diagnosis of tuberculosis of 52 U/l presents the highest specificity and sensitivity.

Performance of the quantification of adenosine deaminase and determination of the lactate dehydrogenase/adenosine deaminase ratio for the diagnosis of pleural tuberculosis in children and adolescents / Desempenho da quantificação de adenosina desaminase e determinação da relação lactato desidrogenase/adenosina desaminase para o diagnóstico de tuberculose pleural em crianças e adolescentes

ABSTRACT Objective: To evaluate the accuracy of determining the adenosine deaminase (ADA) level, the 2'-deoxyadenosine/ADA ratio, and the LDH/ADA ratio in pleural fluid for the diagnosis of pleural tuberculosis (PT) in children and adolescents. Methods: This was a retrospective cross-sectional study conducted at a tertiary hospital in a high-tuberculosis-incidence area, between 2001 and 2018. All patients with ADA in pleural fluid and a confirmed diagnosis of PT (cPT) or parapneumonic effusion (PPE) were included. Results: The cPT and PPE groups comprised 25 and 68 individuals, respectively. At a cutoff of 40 U/L, ADA measurement showed the following: sensitivity, 88%; specificity, 31%; positive predictive value (PPV), 32%; negative predictive value (NPV), 88%; and overall accuracy, 46%. The best cutoffs were an ADA level of 125 U/L, a 2'-deoxyadenosine/ADA ratio of 0.5, and an LDH/ADA ratio of 8.3, with AUC of 0.67, 0.75, and 0.82, respectively. The sensitivity, specificity, PPV, NPV, and overall accuracy of the 125 U/L ADA cutoff were 84%, 65%, 47%, 92%, and 70%, respectively, compared with 79%, 79%, 59%, 91%, and 79%, respectively, for the 8.3 LDH/ADA ratio cutoff. Changing the LDH/ADA ratio cutoff to 3.0 increased the specificity to 98%. Conclusions: The ADA level and the 2'-deoxyadenosine/ADA ratio are not good biomarkers for the diagnosis of PT in pediatric patients. Determination of the LDH/ADA ratio provides the best overall accuracy for the diagnosis of PT in such patients.

RESUMO Objetivo: Avaliar a acurácia da determinação do nível de adenosina desaminase (ADA), da relação 2'-desoxiadenosina/ADA e da relação LDH/ADA no líquido pleural para o diagnóstico de tuberculose pleural (TP) em crianças e adolescentes. Métodos: Estudo transversal retrospectivo realizado em um hospital terciário em uma área de alta incidência de tuberculose entre 2001 e 2018. Todos os pacientes com determinação de ADA no líquido pleural e com diagnóstico confirmado de TP (TPc) ou de derrame parapneumônico (DPP) foram incluídos. Resultados: Os grupos TPc e DPP foram compostos por 25 e 68 indivíduos, respectivamente. Num ponto de corte de 40 U/L, a medida de ADA mostrou o seguinte: sensibilidade, 88%; especificidade, 31%; valor preditivo positivo (VPP), 32%; valor preditivo negativo (VPN), 88%; e acurácia geral, 46%. Os melhores pontos de corte foram ADA de 125 U/L, relação 2'-desoxiadenosina/ADA de 0,5 e relação LDH/ADA de 8,3, com ASC de 0,67, 0,75 e 0,82, respectivamente. A sensibilidade, especificidade, VPP, VPN e acurácia geral do ponto de corte de 125 U/L para ADA foram de 84%, 65%, 47%, 92% e 70%, respectivamente, em comparação com 79%, 79%, 59%, 91% e 79%, respectivamente, para o ponto de corte de 8,3 para a relação LDH/ADA. Ao alterar o ponto de corte da relação LDH/ADA para 3,0 a especificidade aumentou para 98%. Conclusões: O nível de ADA e a relação 2'-desoxiadenosina/ADA não são bons biomarcadores para o diagnóstico de PT em pacientes pediátricos. A determinação da relação LDH/ADA fornece a melhor acurácia geral para o diagnóstico de PT nesses pacientes.

Electroacupuncture alleviates inflammatory pain via adenosine suppression and its mediated substance P expression / A eletroacupuntura alivia a dor inflamatória por meio da supressão de adenosina e da expressão mediada de substância P

ABSTRACT Background: Acupuncture has been widely used for alleviating pain. However, its mechanisms remain largely enigmatic. Objective: In the present study, we focused on whether the analgesic effect of electroacupuncture is related to its regulation on adenosine and substance P expression. Methods: We established chronic inflammatory pain model in rats through a single injection of Complete Freund's Adjuvant, and then we treated animals using daily electroacupuncture. We applied seven bilateral sessions of electroacupuncture (ST36 and BL60, 0.5 to 1.5 mA, initial strength of 0.5 mA, increased by 0.5 mA every 10 minutes, for 30 minutes per session, one section per day) to Complete Freund's Adjuvant rats for seven days. The analgesic effect of electroacupuncture was evaluated by measuring paw withdrawal threshold in rats that received mechanical and thermal stimulation. Results: Daily electroacupuncture stimulation effectively increased paw withdrawal threshold in Complete Freund's Adjuvant rats. Electroacupuncture increased the adenosine level in zusanli. A further study showed that electroacupuncture could decrease substance P, neurokinin-1 receptor, tumor necrosis factor-alpha, interleukin-1β, interleukin-6 and CD68 levels in dorsal root ganglion. Interestingly, direct injection of adenosine A1 or substance P receptor antagonists, or dorsal nerve root transection could significantly impair electroacupuncture induced analgesic actions in Complete Freund's Adjuvant rats could and reduce the levels of substance P, neurokinin-1 receptor, tumor necrosis factor-alpha, interleukin-1β, interleukin-6 and CD68. Finally, we confirmed that direct injection of adenosine A1 receptor agonist replicated the analgesic effect of electroacupuncture. Conclusion: Our results indicate regulation of adenosine-mediated substance P secretion. Substance P-mediated pathway may be involved in the analgesia process by electroacupuncture in rats.

RESUMO Introdução: A acupuntura tem sido amplamente utilizada para alívio de dor. No entanto, seus mecanismos são muito pouco conhecidos. Objetivo: Investigar a relação entre o efeito analgésico da eletroacupuntura e a regulação da expressão de adenosina e de substância P. Métodos: Utilizou-se um modelo de dor inflamatória crônica em ratos por injeção única do Adjuvante Completo de Freund e, em seguida, os animais foram tratados com eletroacupuntura diariamente. Foram aplicadas sete sessões bilaterais de eletroacupuntura (ST36 e BL60, 0,5 a 1,5 mA, força inicial de 0,5 mA, aumentada em 0,5 mA a cada 10 minutos, 30 minutos por sessão, uma sessão por dia) em ratos com Adjuvante Completo de Freund, por sete dias. O efeito analgésico da eletroacupuntura foi avaliado pela medida do limiar de retirada da pata em ratos que receberam estimulações mecânica e térmica. Resultados: A estimulação diária com eletroacupuntura aumentou efetivamente o limiar de retirada da pata em ratos com Adjuvante Completo de Freund. A eletroacupuntura aumentou o nível de adenosina na região zusanli. Estudos posteriores mostraram que a eletroacupuntura poderia diminuir os níveis de substância P, receptor de neurocinina-1, fator de necrose tumoral-alpha, interleucina-1β, interleucina-6 e CD68 nos gânglios da raiz dorsal. Curiosamente, a injeção direta de antagonistas do receptor de adenosina A1 ou de substância P, ou a transecção da raiz do nervo dorsal, podem prejudicar significativamente as ações analgésicas induzidas pela eletroacupuntura em ratos com Adjuvante Completo de Freund e reduzir os níveis de substância P, receptor de neurocinina-1, fator de necrose tumoral-alfa, interleucina-1β, interleucina-6 e CD68. Por fim, confirmamos que a injeção direta de um agonista do receptor da adenosina A1 reproduziu os efeitos analgésicos da eletroacupuntura. Conclusão: Nossos resultados indicam a regulação da secreção da substância P mediada pela adenosina. A via mediada pela substância P pode estar envolvida no processo de analgesia por eletroacupuntura em ratos.

Evaluation of Myocardial Perfusion by Computed Tomography - Principles, Technical Background and Recommendations / Avaliação da Perfusão Miocárdica por Tomografia Computadorizada - Princípios, Fundamentação Técnica e Recomendações

Abstract Coronary computed tomography angiography (CCTA) has gained a prominent role in the evaluation of coronary artery disease. However, its anatomical nature does not allow the evaluation of the functional repercussion of coronary obstructions. It has been made possible to evaluate Myocardial computed tomography perfusion (Myocardial CTP) recently, based on myocardial contrast changes related to coronary stenoses. Several studies have validated this technique against the anatomical reference method (cardiac catheterization) and other functional methods, including myocardial perfusion scintigraphy and fractional flow reserve. The Myocardial CTP is performed in conjunction with the CCTA, a combined analysis of anatomy and function. The stress phase (with assessment of myocardial perfusion) can be performed before or after the resting phase (assessment of resting perfusion and coronary arteries), and different acquisition parameters are proposed according to the protocol and type of equipment used. Stressors used are based on coronary vasodilation (e.g. dipyridamole, adenosine). Image interpretation, similar to other perfusion assessment methods, is based on the identification and quantification of myocardial perfusion defects. The integration of both perfusion and anatomical findings is fundamental for the examination interpretation algorithm, allowing to define if the stenoses identified are hemodynamically significant and may be related to myocardial ischemia.

Resumo A angiografia coronariana por tomografia computadorizada (ACTC) assumiu um papel de destaque na avaliação da doença arterial coronariana. Entretanto, sua natureza anatômica não permitia a avaliação da repercussão funcional das obstruções coronarianas. Recentemente, tornou-se possível a avaliação da perfusão miocárdica por tomografia computadorizada (PMTC), baseando-se nas alterações de contrastação miocárdicas relacionadas às estenoses coronarianas. Diversos estudos permitiram validar esta técnica perante o método anatômico de referência (cateterismo cardíaco) e outros métodos funcionais, incluindo cintilografia de perfusão miocárdica e a reserva de fluxo fracionada. A PMTC é realizada conjuntamente com a ACTC, em uma análise combinada de anatomia e função. A fase de estresse (com avaliação da perfusão miocárdica) pode ser realizada antes ou depois da fase de repouso (avaliação da perfusão de repouso e artérias coronárias), e diferentes parâmetros de aquisição são propostos conforme o protocolo e o tipo de equipamento utilizados. Os agentes estressores utilizados baseiam-se na vasodilatação coronariana (ex: dipiridamol, adenosina). A interpretação das imagens, semelhante a outros métodos de avaliação perfusional, baseia-se na identificação e quantificação de defeitos de perfusão miocárdicos. A integração dos achados perfusionais e anatômicos é parte fundamental do algoritmo de interpretação do exame, permitindo definir se as estenoses identificadas são hemodinamicamente significativas, podendo se relacionar com isquemia miocárdica.

Adenosina para presillamiento de aneurismas cerebrales: revisión de la literatura actual / Adenosine for clamping of cerebral aneurysms: review of current literature

Resumen: El presillamiento de aneurismas cerebrales sigue siendo una cirugía bastante compleja aun con los avances en las neurociencias. El objetivo de este tipo de cirugía es evitar su ruptura y ocasionar daños colaterales en la misma, al tratar de exponer al máximo tanto el cuello del aneurisma para su manipulación como la oclusión temporal de la arteria proximal a éste. El uso de paro cardíaco transanestésico en el presillamiento de aneurismas cerebrales es una técnica empleada para cierto tipo de aneurismas cerebrales y existen varios métodos para realizarlo, desde la hipotermia profunda o severa, estimulación ventricular rápida hasta llegar al paro circulatorio con el uso de adenosina. En esta revisión de la literatura se darán las bases enfocadas en el uso de adenosina para el presillamiento de aneurismas cerebrales y, aunque parezca un método inocuo y que no requiere mucha preparación y logística, sólo debe realizarse por personal experto en neuroanestesiología para lograr obtener un mejor resultado para el paciente.

Abstract: The clipping of cerebral aneurysms remains a very complex surgery even with advances in neurosciences. The goal of surgery in the clipping of cerebral aneurysms is to prevent rupture and cause collateral damage in the same, trying to expose both the neck of the aneurysm to its maximum for clipping as well as temporary occlusion of the artery proximal to it. The use of trananesthetic cardiac arrest in the clipping of cerebral aneurysms is a technique used for certain types of cerebral aneurysms and there are several methods to perform it, from deep or severe hypothermia, passing through ventricular pacemaker at high frequencies until it reaches the circulatory arrest with the use of adenosine. This review of the literature will focus on the use of adenosine for the clipping of cerebral aneurysms and, although it seems a safe method and does not require much logistical preparation, it should only be performed by expert personnel in neuroanesthesiology to achieve a better result for the patient.

Atrial fibrillation with hemodynamic instability after the use of the third dose of adenosine during surgery for 7 intracranial aneurysms: case report / Fibrilación auricular con inestabilidad hemodinámica tras el uso de tercera dosis de adenosina durante cirugía de siete aneurismas intracraneales: reporte de caso

Abstract Adenosine-induced asystole is a technique that prevents and controls the intraoperative rupture of cerebral aneurysm, facilitating temporary, and/or definitive clipping of the aneurysm. This is the case of a 58-year-old woman who underwent clipping of 7 intracranial aneurysms, who was induced asystole with adeno-sine 3 times and developed atrial fibrillation with hemodynamic instability after the last dose. Adenosine has been shown to be useful and safe, however, its use should be planned and possible cardiological complications should be considered.

Resumen La asistolia inducida por adenosina es una técnica que previene y controla la ruptura intraoperatoria de aneurisma cerebral, facilitando el clipaje temporal y/o definitivo del mismo. Presentamos el caso de una mujer de 58 años intervenida para clipaje de 7 aneurismas intracraneales, a quien se le indujo asistolia con adenosina en 3 oportunidades y desarrolló fibrilación auricular con inestabilidad hemodinámica tras la última dosis. La adenosina ha demostrado ser útil y segura, sin embargo, debe planificarse su uso y considerar eventuales complicaciones cardiológicas.

Correlação entre métodos de monitoramento de limpeza e desinfecção de superfícies ambulatoriais / Correlación entre métodos de monitoreo de limpieza y desinfección de superficies en unidades ambulatorias / Correlation among monitoring methods of surface cleaning and disinfection in outpatient facilities

Resumo Objetivo Avaliar a correlação entre cultura microbiológica, teste de ATP por bioluminescência e inspeção visual na monitorização da eficiência da limpeza e da desinfecção de superfícies de uma unidade ambulatorial e determinar o valor de corte de ATP-bioluminescência capaz de indicar superfície limpa em relação à avaliação microbiológica. Métodos Estudo exploratório, longitudinal e correlacional. Foram realizadas 720 avaliações em cinco superfícies antes e após a limpeza e a desinfecção. Nos resultados, foram realizadas análises de duas proporções, a correlação de Spearman e a curva ROC. Resultados Ocorreram proporções semelhantes (p≥0,05) entre as taxas de reprovação apenas entre ATP-bioluminescência e contagem de colônias aeróbias (CCA) quando somadas as avaliações de todas as superfícies antes e depois da limpeza e da desinfecção. Houve correlação significativa entre os métodos de quantificação de ATP e a contagem microbiana para o balcão da recepção e a maca. A análise ROC indicou que a quantificação de ATP apresentou resultado significativo na comparação com a CCA (p=0,044). Conclusão Embora discreta, houve correlação significativa entre os métodos de quantificação de ATP e contagem microbiana para duas superfícies. Sugere-se que superfícies que apresentam valores ≤49 unidades relativas de luz estão limpas.

Resumen Objetivo Analizar la correlación entre cultivo microbiológico, prueba de ATP por bioluminiscencia e inspección visual en el monitoreo de la eficiencia de la limpieza y desinfección de superficies en una unidad ambulatoria y determinar el valor de referencia de ATP-bioluminiscencia que indique que la superficie está limpia con relación a la evaluación microbiológica. Métodos Estudio exploratorio, longitudinal y correlacional. Se realizaron 720 evaluaciones en cinco superficies antes y después de la limpieza y desinfección. En los resultados, se realizaron análisis de dos proporciones: la correlación de Spearman y la curva ROC. Resultados Hubo proporciones semejantes (p≥0,05) entre los índices de reprobación solo entre ATP-bioluminiscencia y recuento de colonias aerobias (RCA) cuando se sumaron las evaluaciones de todas las superficies antes y después de la limpieza y desinfección. Hubo una correlación significativa entre los métodos de cuantificación de ATP y el recuento microbiano en el mostrador de la recepción y la camilla. El análisis ROC indicó que la cuantificación de ATP presentó un resultado significativo en la comparación con el RCA (p=0,044). Conclusión Hubo una correlación significativa, aunque discreta, entre los métodos de cuantificación de ATP y recuento microbiano en dos superficies. Se sugiere que las superficies que presentan valores ≤49 unidades relativas de luz están limpias.

Abstract Objectives To evaluate the correlation among microbiological culture, ATP bioluminescence assay, and visual inspection in monitoring the effectiveness of surface cleaning and disinfection in an outpatient facility and determine the ATP bioluminescence cutoff capable of indicating a clean surface regarding microbiological evaluation. Methods Exploratory, cross-sectional, and correlation study consisting of 720 evaluations in five surfaces before and after cleaning and disinfection. The results were used to run two-proportions tests, calculate Spearman's correlation, and plot the receiver operating characteristic curve. Results Similar proportions (p≥0.05) occurred for non-approval rates between ATP-bioluminescence and aerobic colony count only when the evaluations of all the surfaces before and after cleaning and disinfection were put together. There was a significant correlation between the ATP quantification and microbial count methods for the reception desk and the stretcher. Receiver operating characteristic analysis indicated that ATP quantification showed a significant result in comparison with aerobic colony count (p=0.044). Conclusion There was a discrete correlation between the ATP quantification and microbial count methods for two surfaces. It is suggested that surfaces showing values ≤49 relative light units are clean.

Muscle strength and caffeine supplementation: are we doing more of the same? / Força muscular e suplementação de cafeína: estamos fazendo mais do mesmo? / Fuerza muscular y suplementación de cafeína: ¿estamos haciendo más del mismo?

ABSTRACT The purpose of this review was to examine in the current literature the advances made in terms of the effects of caffeine supplementation on maximum strength and its associated mechanisms since the publication of two important papers in 2010. Searches were carried out in the PubMed, Medline, Scielo and Web of Science databases for articles published after 2010. Sixteen studies were included based on inclusion and exclusion criteria. Five studies did not report changes in maximal voluntary strength (31.3%). Four of them used isometric muscle contractions, although this may not be a key factor because five other studies also used isometric contractions and reported ergogenic effects. Furthermore, these four studies evaluated small muscle groups and volunteers were not accustomed to consuming caffeine. Caffeine produced ergogenic effects in eleven of the sixteen studies analyzed (68.8%). None of the doses were clearly related to ergogenic effects; however, a dose of at least 3 mg/kg of caffeine is probably necessary. Caffeine ergogenicity was affected by various factors. There was a lack of standardized protocols and controls for intervening factors (e.g., circadian cycles and nutritional states), which could affect results. An ideal caffeine supplementation protocol that is useful for future research, athletes, and physical activity practitioners, has yet to be defined. A small advance made since 2010 involved a possible lack of gender difference; it would appear that caffeine supplementation affects men and women equally. Level of Evidence I; Systematic Review of Level I Studies.

RESUMO O objetivo desta revisão foi examinar na literatura atual os avanços feitos com relação aos efeitos da suplementação de cafeína sobre a força máxima e seus mecanismos associados a partir de 2010, ano em foram publicados dois importantes artigos. As buscas foram realizadas nas bases de dados PubMed, Medline, Scielo e Web of Science procurando-se artigos publicados após 2010. Dezesseis estudos foram incluídos com base nos critérios de inclusão e exclusão. Cinco estudos não relataram alterações da força voluntária máxima (31,3%). Quatro deles usaram contrações musculares isométricas, embora isso possa não ser um fator chave, porque outros cinco estudos também usaram contrações isométricas e relataram efeitos ergogênicos. Além disso, esses quatro estudos avaliaram pequenos grupos musculares e os voluntários não eram habituados à cafeína. A cafeína produziu efeitos ergogênicos em 11 dos 16 estudos analisados (68,8%). Nenhuma dose foi claramente relacionada com efeitos ergogênicos; contudo, há indícios da necessidade de uma dose de pelo menos 3 mg/kg de cafeína. A ergogenicidade da cafeína foi afetada por vários fatores. Havia uma falta de protocolos padronizados e controle de fatores intervenientes (por exemplo, ciclo circadiano e estado nutricional) que poderiam afetar os resultados. Ainda é preciso definir um protocolo ideal de suplementação de cafeína que seja útil para futuras pesquisas, atletas e praticantes de atividade física. Um pequeno avanço feito desde 2010 envolveu a possível falta de diferença de gênero - parece que a suplementação de cafeína afeta homens e mulheres igualmente. Nível de Evidência I; Revisão Sistemática de Estudos de Nível I.

RESUMEN El objetivo de esta revisión fue examinar en la literatura actuallos avances hechos con respecto a los efectos del suplemento de cafeína sobre la fuerza máxima y sus mecanismos asociados desde 2010, año en que se publicaron dos artículos importantes. Las búsquedas se realizaron en las bases de datos PubMed, Medline, Scielo y Web of Science, por artículos publicados después de 2010. Se incluyeron 16 estudios basados en los criterios de inclusión y exclusión. Cinco estudios no reportaron cambios de la fuerza voluntaria máxima (31,3%). Cuatro de ellos usaron contracciones musculares isométricas, aunque esto puede no ser un factor clave, porque otros cinco estudios también utilizaron contracciones isométricas y reportaron efectos ergogénicos. Además, estos cuatro estudios evaluaron grupos musculares pequeños y los voluntarios no tenían el hábito de consumo de cafeína. La cafeína produjo efectos ergogénicos en 11 de los 16 estudios analizados (68,8%). Ninguna dosis fue claramente relacionada con efectos ergogénicos, sin embargo, hay indicios de la necesidad de una dosis de al menos 3 mg/kg de cafeína. La ergogenicidad de la cafeína se vio afectada por varios factores. Hubo una falta de protocolos y controles estandarizados de factores intervinientes (por ejemplo, ciclo circadiano y estado nutricional) que podrían afectar los resultados. Todavía es necesario definir un protocolo ideal de suplemento de cafeína que sea útil para futuras investigaciones, atletas y practicantes de actividad física. Un pequeño avance hecho desde 2010 involucró la posible falta de diferencia de género - parece que el suplemento de cafeína afecta a hombres y mujeres igualmente. Nivel de Evidencia I; Revisión sistemática de estudios de Nivel I.

Diagnostic Accuracy of Pleural Fluid Adenosine Deaminase for Diagnosing Tuberculosis. Meta-analysis of Spanish Studies. / Eficacia diagnóstica de la adenosina desaminasa en líquido pleural para diagnosticar tuberculosis. Metaanálisis de estudios españoles.

OBJECTIVE: To evaluate the usefulness of pleural fluid adenosine deaminase (ADA) for diagnosing tuberculous pleural effusions in the Spanish population, according to laboratory technique and cut-off point, and to compare the results with other populations. METHODS: Meta-analysis of diagnostic studies on pleural fluid ADA in the Spanish population, extracted from the PubMed and Embase databases from inception until July 2017, with no language restrictions. The overall diagnostic accuracy of ADA and that of each of the measurement techniques (Giusti, manual and automated kinetic methods) and selected cut-offs were analyzed. The QUADAS-2 tool was used to evaluate the quality of studies. A bivariate random effects model was used. Results were compared with those obtained from previous meta-analyses in non-Spanish populations. RESULTS: Sixteen studies in a total of 4,147 patients, 1,172 of whom had tuberculous pleural effusions, were included. ADA had 93% sensitivity, 92% specificity, positive likelihood ratio of 12, negative likelihood ratio of 0.08, and an area-under-the-curve of 0.968 for identifying tuberculosis. There were no differences in diagnostic accuracy between the techniques used for ADA measurement or the selected cut-offs. In 73 studies from non-Spanish populations a trend toward lower ADA sensitivity (88%, 95% CI:86%-90%) and specificity (88%, 95% CI: 86%-90%) was noted, but differences did not reach statistical significance. CONCLUSIONS: Pleural fluid ADA in the Spanish population shows good diagnostic accuracy (regardless of the measurement technique or cut-off), similar to that reported in non-Spanish populations.

Tuberculous Pleural Effusion: Clinical Characteristics of 320 Patients. / Derrame pleural tuberculoso: características clínicas de 320 pacientes.

OBJECTIVES: To analyze the clinical and radiological characteristics and features of pleural fluid (PF) in patients with tuberculous pleural effusion (TPE). METHODS: Retrospective analysis of TPEs treated in our clinic over the last 23years. RESULTS: We included 320 patients with TPE (70% men; median age 33years). Mycobacterium tuberculosis was identified in the sputum or PF of 36% of the patients by microscopic examination, solid and liquid media cultures, or nucleic acid amplification tests. The greatest percentage of positive microbiological findings were associated with human immunodeficiency virus (HIV) co-infection (OR: 3.27), and with the presence in PF of proteins <4g/dL (OR: 3.53), neutrophils >60% (OR: 3.23), and glucose <40mg/dL (OR: 3.17). Pleural adenosine deaminase <35U/L was associated with TPEs that occupied less than half of the hemithorax (OR: 6.36) and with PF lactate dehydrogenase levels <500U/L (OR: 8.09). Radiological pulmonary opacities (30%) were more common in TPE occupying less than half of the hemithorax (OR: 2.73), in bilateral TPE (OR: 4.48), and in older patients (OR: 1.02). Factors predicting mortality were: HIV co-infection (OR: 24), proteins in PF <5g/dL (OR: 10), and greater age (OR: 1.05). CONCLUSIONS: Patients with TPE and HIV co-infection and those with lower concentrations of proteins in PF had higher rates of positive microbiological results and death. Moreover, older patients had more pulmonary opacities and a higher incidence of death.

Efeitos da 5-iodotubercidina em linhagens de melanoma humano parentais e resistentes ao inibidor de BRAF / Effects of 5-iodotubercidin on human melanoma lines of parental and resistant to the BRAF inhibitor

O melanoma é responsável por menos de 5% dos cânceres de pele, porém, 95% das mortes ocorrem devido a ocorrência de metástases. O melanoma metastático é refratário às terapias convencionais e rapidamente adquire resistência às terapias como as oncogene-dirigidas, como o inibidor de BRAF, da via de MAPK. Estudos prévios de screening in silico do nosso grupo, onde se utilizou as bases de dados TCGA e GEO, identificaram o gene adenosina quinase (ADK) como sendo diferencialmente expresso entre o melanoma invasivo e os nevus. A 5-iodotubercidina (5-ITu) é um potente inibidor farmacológico da ADK que dentre os diversos efeitos relatados na literatura destaca-se pelo potencial genotóxico. Os danos no DNA são os principais ativadores de checkpoint do ciclo celular, que levam a parada do ciclo celular transitória ou permanente, além de induzir morte celular, levando a hipótese de que ADK possa ser potencial agente anti-melanoma. Este trabalho objetivou avaliar a expressão do gene ADK em melanomas humanos e quimiorresistentes ao inibidor de BRAF (iBRAF), avaliou os impactos de 5-ITu sobre a proliferação, progressão do ciclo celular e morte celular e por fim avaliamos sua capacidade de aumentar a sensibilidade das células. Foi realizado PCR em tempo real para avaliar os níveis de expressão de mRNA de ADK em linhagens de melanoma e na cultura primária de melanócitos; a fim de avaliar a citotoxicidade de 5-ITu foram realizados os ensaios de exclusão por azul de tripan e de apoptose - Anexina V e PI e em modelo de esferoide, usando live/dead; também foi avaliada a influência de 5-ITu sobre a capacidade clonogênica e seus efeitos sobre a proliferação celular, a partir dos ensaios de ciclo celular e avaliação de marcadores de proliferação por imunofluorescência; as linhagens foram submetidas a diferentes regimes de tratamento com 5-ITu e o iBRAF, a fim de avaliar a curva de crescimento e a sensibilidade ao iBRAF por MTT níveis de expressão de mRNA de ADK maiores nas linhagens tumorais em relação aos melanócitos. 5-ITu mostrou-se capaz de inibir a proliferação (IC50) das linhagens de melanoma em concentrações de 1,9 a 3,5 µM. 5-ITu não foi capaz de induzir inviabilidade celular, apesar de reduzir a quantidade de células viáveis em todas as condições de tratamento, também não foi capaz de induzir aumento significativo de células apoptóticas, nem mesmo necróticas. No entanto, o tratamento com 5-ITu reduziu a capacidade clonogênica de linhagens de melanoma e promoveu parada de ciclo celular nas fases G1 e G2/M, levou ao aumento da população subG1. O tratamento com 5-ITu promoveu a redução da expressão de marcadores de proliferação, como ki67, e a combinação de tratamentos 5-ITu e iBraf foi capaz de aumentar o tempo de dobramento das linhagens de melanoma, embora tenha se mostrado incapaz de sensibilizar as células de melanoma ao tratamento com iBRAF. Desse modo, pode-se concluir que 5-ITu induz o efeito citostático e se mostra um potente agente antiproliferativo para melanoma parental e resistente

Melanoma accounts for less than 5% of skin cancers, but 95% of deaths occur due to metastases. Metastatic melanoma is refractory to conventional therapies and rapidly acquires resistance to therapies such as oncogene-directed, such as the BRAF inhibitor, of the MAPK pathway. Previous studies of screening in silico of our group, using the databases TCGA and GEO, identified the adenosine kinase gene (ADK) as differentially expressed between invasive melanoma and nevus. 5-iodotubercidin (5-ITu) is a potent pharmacological inhibitor of ADK that among the several effects reported in the literature stands out for the genotoxic potential. DNA damage is the main activator of the cell cycle checkpoint, which leads to transient or permanent cell cycle arrest, in addition to inducing cell death, leading to the hypothesis that ADK may be a potential anti-melanoma agent. This work aimed to evaluate the expression of the ADK gene in human melanomas and chemoresistants to the BRAF inhibitor (iBRAF), evaluated the impacts of 5-ITu on proliferation, cell cycle progression and cell death and finally we evaluated its ability to increase the sensitivity of cells. Real-time PCR was performed to assess the levels of ADK mRNA expression in melanoma lines and primary melanocyte culture; in order to evaluate the cytotoxicity of 5-ITu, the trypan blue and apoptosis - Annexin V and PI exclusion and blue spheroid models were performed using live / dead; the influence of 5-ITu on the clonogenic capacity and its effects on cell proliferation, from the cell cycle assays and the evaluation of proliferation markers by immunofluorescence; the cell lines were submitted to different treatment regimens with 5-ITu and iBRAF in order to evaluate the growth curve and the sensitivity to iBRAF by MTT levels of mRNA expression of ADK higher in the tumor lines in relation to the melanocytes. 5-ITu was able to inhibit the proliferation (IC 50) of melanoma lines at concentrations of 1.9 to 3.5 181;M. 5-ITu was not able to induce cell non-viability, although it reduced the amount of viable cells in all treatment conditions, nor was it able to induce a significant increase in apoptotic or even necrotic cells. However, treatment with 5-ITu reduced the clonogenic capacity of melanoma cells and promoted cell cycle arrest in the G1 and G2 / M phases, leading to an increase in the subG1 population. Treatment with 5-ITu promotes the reduction of expression of proliferation markers, such as ki67, and the combination of 5-ITu and iBRAF treatments was able to increase the doubling time of melanoma cells, although it has been shown to be unable to sensitize melanoma cells to treatment with iBRAF. Thus, it can be concluded that 5-ITu induces the cytostatic effect and shows a potent antiproliferative agent for parental and resistant melanoma

Fenómeno de no reflujo en la angioplastia coronaria: incidencia, características clínico-angiográficas y eficacia del tratamiento / No-reflow phenomenon in coronary angioplasty: incidence, clinical-angiographic characteristics and efficacy of treatment

Resumen: Introducción: el fenómeno de no reflujo (NR) coronario se define como la persistencia de un flujo inadecuado menor a TIMI 3 durante la angioplastia coronaria (ATC), en ausencia de obstáculo macroscópico en las arterias coronarias epicárdicas. Objetivo principal: determinar la incidencia de NR en pacientes tratados con ATC por cualquier indicación. Objetivos secundarios: describir las características clínicas y angiográficas de la población con NR, características del procedimiento de angioplastia, así como el tratamiento y el valor pronóstico del NR. Métodos: estudio observacional, prospectivo, unicéntrico, sobre el total de ATC realizadas en un centro de cardiología intervencionista entre octubre de 2016 y enero de 2017, excluyendo la reestenosis intrastent y la enfermedad de injertos venosos. Se definieron dos grupos: control (flujo normal) y con fenómeno de NR. Se analizaron variables clínicas, angiográficas, terapéuticas y pronósticas. Resultados: se incluyó un total de 322 pacientes, 291 control y 31 NR. La incidencia de NR fue de 9,6%, presentándose en 20,7% de los síndromes coronarios agudos con elevación de ST (SCAcST), en 6,3% de los síndromes coronarios agudos sin elevación de ST (SCAsST) y en 3% de las anginas estables. La adenosina a dosis altas fue el tratamiento más utilizado. Se comprobó una mejoría significativa del flujo coronario evaluado por TIMI Frame Count asociado al tratamiento instituido (39,4±1,6 pretratamiento vs 21,9±1,2 postratamiento, p<0,001). A tres meses, en los pacientes con NR vesus control se observó una mayor incidencia de ángor (6,6% vs 1,1% respectivamente, p=0,001), nueva coronariografía (10% vs 1,1%, p=0,017) y nueva ATC (19% vs 1,1%, p=0,009). Conclusiones: la incidencia de NR en pacientes sometidos a ATC fue de 9,6%, presentándose más frecuentemente en el SCAcST. La adenosina intracoronaria a dosis altas fue el tratamiento más frecuentemente instituido y fue eficaz para mejorar significativamente el flujo coronario.

Summary: Introduction: no-reflow phenomenon is defined as persistence of inadequate flow less than TIMI 3 during coronary angioplasty in the absence of an obstacle in epicardial coronary arteries. Primary endpoint: to determine the incidence of no-reflow in patients treated with coronary angioplasty performed for any indication. Secondary endpoints: to describe the clinical and angiographic characteristics, procedural characteristics, treatment and prognostic value of no-reflow phenomenon. Methods: this is an observational, prospective and unicentric trial including all coronary angioplasties performed in an interventional Cardiology center between October 2016 and January 2017, excluding instent reestenosis and coronary vein grafts disease. Two groups were defined: control (normal coronary flow) and no-reflow phenomenon. Clinical, angiographic and prognostic variables were analyzed. Results: 322 patients were included, 291 control and 31 no-reflow. No-reflow incidence was 9.6%, occurring in 20.7% of acute coronary syndromes with ST segment elevation, 6.3% in non-ST segment elevation syndromes and 3% in stable coronary artery disease. High dose adenosine was the most frequently used agent for no-reflow treatment. No-reflow treatment was associated with a significant improvement in coronary flow measured by TIMI Frame Count (39.4±1.6 pretreatment vs 21.9±1.2 postreatment, p<0.001). At 3 month follow up, no-reflow patients vs control had a higher incidence of angina pectoris (6.6% vs 1.1% respectively, p=0.001), coronary angiography (10% vs 1.1%, p=0.017) and coronary angioplasty (19% vs 1.1%, p=0.009). Conclusions: no-reflow incidence in patients treated with coronary angioplasty was 9.6%, occurring more frequently in ST segment elevation syndromes. High dose adenosine was the most frequently used agent for no-reflow treatment and significantly improved coronary flow.

Involvement of adenosine A1 receptor in electroacupuncture-mediated inhibition of astrocyte activation during neuropathic pain / Envolvimento do receptor de adenosina A1 na inibição da ativação de astrócitos mediada por eletroacupuntura durante a dor neuropática

ABSTRACT Neuropathic pain is a chronic pain condition caused by damage or dysfunction of the central or peripheral nervous system. Electroacupuncture (EA) has an antinociceptive effect on neuropathic pain, which is partially due to inhibiting astrocyte activation in the spinal cord. We found that an intrathecal injection of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist, reversed the antinociceptive effects of EA in a chronic constriction injury-induced neuropathic pain model. The expression of GFAP in L4-L6 spinal cord was significantly upgraded, while DPCPX suppressed the effect of the EA-mediating inhibition of astrocyte activation, as well as wiping out the EA-induced suppression of cytokine content (TNF-α). These results indicated that the adenosine A1 receptor is involved in EA actions during neuropathic pain through suppressing astrocyte activation as well as TNF-α upregulation of EA, giving enlightenment to the mechanisms of acupuncture analgesia and development of therapeutic targets for neuropathic pain.

RESUMO A dor neuropática é uma condição de dor crônica causada por dano ou disfunção do sistema nervoso central ou periférico. A eletroacupuntura (EA) tem um efeito antinociceptivo durante a dor neuropática, que é parcialmente devido à inibição da ativação de astrócitos na medula espinhal. Descobrimos que a injeção intratecal de 8-ciclopentil-1,3-dipropilxantina (DPCPX), um antagonista seletivo do receptor de adenosina A1, reverteu os efeitos antinociceptivos da EA no modelo de dor neuropática induzida por lesão por constrição crônica (CCI). A expressão da GFAP na medula espinal L4-L6 foi significativamente melhorada, enquanto a DPCPX suprimiu o efeito da inibição mediadora da EA na ativação de astrócitos, bem como eliminou a supressão induzida pela EA do conteúdo de citocina (TNF-α). Esses resultados indicam que o receptor de adenosina A1 está envolvido nas ações da EA durante a dor neuropática, suprimindo a ativação astrocitária, bem como o aumento da TNF-α na EA, fornecendo esclarecimentos sobre os mecanismos de analgesia da acupuntura e o desenvolvimento de alvos terapêuticos para dor neuropática.