Dissecting T Cell Contraction In Vivo Using a Genetically Encoded Reporter of Apoptosis

SummaryContraction is a critical phase of immunity whereby the vast majority of effector T cells die by apoptosis, sparing a population of long-lived memory cells. Where, when, and why contraction occurs has been difficult to address directly due in large part to the rapid clearance of apoptotic T cells in vivo. To circumvent this issue, we introduced a genetically encoded reporter for caspase-3 activity into naive T cells to identify cells entering the contraction phase. Using two-photon imaging, we found that caspase-3 activity in T cells was maximal at the peak of the response and was associated with loss of motility followed minutes later by cell death. We demonstrated that contraction is a widespread process occurring uniformly in all organs tested and targeting phenotypically diverse T cells. Importantly, we identified a critical window of time during which antigen encounters act to antagonize T cell apoptosis, supporting a causal link between antigen clearance and T cell contraction. Our results offer insight into a poorly explored phase of immunity and provide a versatile methodology to study apoptosis during the development or function of a variety of immune cells in vivo

Hemophagocytic syndrome: a dilemma chasing the intensivists

Hemophagocytic lymphohistiocytosis or hemophagocytic syndrome is represented by an uncontrolled inflammatory response characterized by marked histiocyte activation and a cytokine storm. The entity may present a primary or genetic type, and the secondary type is usually triggered by infectious diseases of any kind, autoimmune disease, or neoplasia. This entity, although well described and with definite diagnostic criteria, still remains misdiagnosed because of the overlap presentation with other inflammatory processes. The authors present the case of a 13-year-old girl who was submitted to an appendicectomy complicated with a pericolic abscess, which required a second operation in order to be drained surgically. During the postoperative period of this second surgical procedure, the patient remained febrile, developing cytopenias, and multiple organ failure. Unfortunately, she died despite the efforts of the intensive care. The autopsy findings were characteristic of hemophagocytic syndrome. The authors report the case to call attention to this diagnosis whenever unexpected outcomes of infections are experienced

New bounds for Tsallis parameter in a noncommutative phase-space entropic gravity and nonextensive Friedmann equations

In this paper, we have analyzed the nonextensive Tsallis statistical mechanics in the light of Verlinde's formalism. We have obtained, with the aid of a noncommutative phase-space entropic gravity, a new bound for Tsallis nonextensive (NE) parameter (TNP) that is clearly different from the ones present in the current literature. We derived the Friedmann equations in a NE scenario. We also obtained here a relation between the gravitational constant and the TNP.Comment: 15 pages. Final version to appear in Physica

Tributo ao centenário da Síndrome de Waterhouse-Friderichsen: relato de caso

The Waterhouse-Friderichsen Syndrome was first reported by Rupert Waterhouse exactly 100 years ago on March 4th, 1911. It is an acute infectious disease that generally progress to a lethal outcome despite the adoption of all available resources of an intensive therapy unit. We describe an illustrativecase of meningococcal meningitis C. This report details the clinical, pathological and therapeutic features of a patient of 3 years and 4 months who had a fulminating evolution, despite adherence to updated recommendations for the treatment of pediatric septic shock. We stress the little change in clinicaland pathological aspects of Waterhouse-Friderichsen Syndrome during the last 100 years, despite tremendous advances in therapy and technology of the pediatric intensive care.A síndrome de Waterhouse-Friderichsen teve o relato pioneiro de Rupert Waterhouse há exatamente 100 anos em 4 de março de 1911. É uma síndrome infecciosa aguda de evolução catastrófica que requer a utilização de todos os recursos disponíveis de terapia intensiva e geralmente evolui para o êxito letal.Nós descrevemos um caso ilustrativo de meningite meningocócica C que ilustra aspectos clínicos, terapêuticos e anatomopatológicos de uma criança de 3 anos e 4 meses atendida em um Hospital Universitário com evolução fatal, apesar da aderência às recomendações vigentes atualizadas para o tratamento do choque séptico pediátrico. Salientamos a pouca mudança no aspecto clínico e anatomopatológicoda síndrome de Waterhouse-Friderichsen nos últimos 100 anos, apesar da enorme evolução terapêutica e tecnológica que acompanha a terapia intensiva pediátrica

Out of equilibrium: understanding cosmological evolution to lower-entropy states

Despite the importance of the Second Law of Thermodynamics, it is not absolute. Statistical mechanics implies that, given sufficient time, systems near equilibrium will spontaneously fluctuate into lower-entropy states, locally reversing the thermodynamic arrow of time. We study the time development of such fluctuations, especially the very large fluctuations relevant to cosmology. Under fairly general assumptions, the most likely history of a fluctuation out of equilibrium is simply the CPT conjugate of the most likely way a system relaxes back to equilibrium. We use this idea to elucidate the spacetime structure of various fluctuations in (stable and metastable) de Sitter space and thermal anti-de Sitter space.Comment: 27 pages, 11 figure

Estudo prospectivo comparativo de sistema especialista de prescrição médica na redução de erro e sobrecarga de trabalho médico

Erros médicos preveníveis(EMP) em hospitais excedem às mortes causadas por acidentes \ud automobilísticos, câncer de mama e AIDS. O Institute of Medicine estima até 98.000 mortes \ud causadas por EMP. O risco é aumentado quando os EMPs ocorrem em pacientes criticamente \ud enfermos ou com medicações que variam com o peso do paciente. A demora da primeira \ud prescrição é uma preocupação em UTI. Fadiga e sobrecarga podem comprometer a segurança \ud numa UTI pediátrica. Objetivos: Comparar a funcionalidade de um Sistema Especialista(SE) \ud experimental com a prescrição médica convencional Materiais/Métodos: Após termo de \ud consentimento, pediatras de um hospital universitário são convidados a fazer a prescrição de 10 \ud itens medicamentosos completos(soro de manutenção, adenosina, adrenalina, atropina, \ud difenilhidantoína, vancomicina , ceftadizima, anfotericina_B, dobutamina, fentanil) para uma \ud criança hipotética. Comparou-se a prescrição convencional com a prescrição feita no SE, após \ud um treinamento prévio de 2 minutos. Uma equipe(médicos, enfermeiras e farmacêuticas) \ud avaliaram os EMPs. Comparações feitas pelo X2, teste exato de fisher, teste t-student pareado ou \ud Wilconson, quando aplicáveis. Significância considerada: p<0.05. Resultados:13 médicos \ud residentes e 7 assistentes participaram do estudo com tempo médio de formação de 10,1+/-9 anos \ud . Constatados 57 casos de EMP (9 ilegibilidades, 23 omissões, 6 erros de dose, 14 erros de \ud diluição e 5 erros de velocidade de infusão) pela prescrição convencional comparado com 1 \ud duplicação de medicação na prescrição por SE(p<0,001). O tempo médio de prescrição dos 10 \ud medicamentos utilizando a abordagem ONE TOUCH do SE foi de 22,4 +/- 5,6 segundos_[13-36 \ud segundos] e estava significantemente abaixo do tempo de prescrição convencional (média:557 +/- \ud 164 segundos; p=0,00088). O tempo médio de prescrição com SE foi 27 vezes(IC95% 21,5-\ud 32,5)) mais rápido que a convencional com economia de 89,1 minutos em uma UTI de 10 leitos. \ud Conclusão:Embora não infalível, o uso de SE requer pouco tempo de treinamento e resulta em \ud significante diminuição de erros e sobrecarga de trabalho

Standardized Whole-Blood Transcriptional Profiling Enables the Deconvolution of Complex Induced Immune Responses

SummarySystems approaches for the study of immune signaling pathways have been traditionally based on purified cells or cultured lines. However, in vivo responses involve the coordinated action of multiple cell types, which interact to establish an inflammatory microenvironment. We employed standardized whole-blood stimulation systems to test the hypothesis that responses to Toll-like receptor ligands or whole microbes can be defined by the transcriptional signatures of key cytokines. We found 44 genes, identified using Support Vector Machine learning, that captured the diversity of complex innate immune responses with improved segregation between distinct stimuli. Furthermore, we used donor variability to identify shared inter-cellular pathways and trace cytokine loops involved in gene expression. This provides strategies for dimension reduction of large datasets and deconvolution of innate immune responses applicable for characterizing immunomodulatory molecules. Moreover, we provide an interactive R-Shiny application with healthy donor reference values for induced inflammatory genes

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Evaluation of the dead-space : tidal volume ratio as a predictor of success in the removal of mechanical ventilation of critically ill children

O momento ideal para a extubação de crianças graves é ainda difícil de ser avaliado. A razão entre espaço morto e volume corrente (Vd/Vt), como valor preditiva de extubação bem sucedida, já foi testada em adultos e crianças. O objetivo deste trabalho foi avaliar a eficácia do Vd/Vt, como preditivo do sucesso da extubação, em crianças de uma UTI pediátrica geral. Após aplicação dos critérios de inclusão e exclusão, testou-se o Vd/Vt em 86 pacientes extubados num período de 16 meses. Nos estudos estatísticos o índice Vd/Vt médio não discriminou os grupos de falha e sucesso na extubação nas análises uni e multivariada. O valor do índice, com corte em 0,65, foi limitado na sensibilidade e especificidade e mediano na razão de verossimilhança. O estudo sugere que o índice Vd/Vt, pode ser considerado como complementar aos dados de avaliação clínica no momento da extubação.The ideal moment for extubation of critically ill children is still difficult to determine. The dead-space : tidal volume ratio (Vd/Vt) has been tested as predictor of extubation failure in adults and children. The purpose of this study was to evaluate the efficacy of the Vd/Vt as a predictor of the success of extubation in children admitted to a pediatric intensive care unit. After the inclusion and exclusion criteria, 86 patients were studied during 16 months. The statistical study revealed that the mean Vd/Vt was not able to discriminate between failure and success of extubation in the multivariate analysis. The utility of the Vd/Vt was limited, in terms of sensibility and specificity, using a cutoff of 0,65, but was medially satisfactory in the likelihood ratio. This study suggests that the Vd/Vt can only be considered as complementary to the routine clinical evaluation prior to extubation