Immature Platelet Fraction and Thrombin Generation: Preeclampsia Biomarkers / Fração de plaquetas imaturas e geração de trombina: Biomarcadores da pré-eclâmpsia

Abstract Preeclampsia, a human pregnancy syndrome, is characterized by elevated blood pressure and proteinuria after the 20th week of gestation. Its etiology remains unknown, and its pathophysiological mechanisms are related to placental hypoperfusion, endothelial dysfunction, inflammation, and coagulation cascade activation. Recently, the role of the complement system has been considered. This syndrome is one of the main causes of maternal and fetal mortality and morbidity. This article discusses the hypothesis of preeclampsia being triggered by the occurrence of inadequate implantation of the syncytiotrophoblast, associated with bleeding during the first stage of pregnancy and with augmented thrombin generation. Thrombin activates platelets, increasing the release of antiangiogenic factors and activating the complement system, inducing the membrane attack complex (C5b9). Immature platelet fraction and thrombin generation may be possible blood biomarkers to help the early diagnosis of preeclampsia.

Resumo A pré-eclâmpsia, uma síndrome da gestação humana, é caracterizada por elevação da pressão arterial e proteinúria patológica após a 20ª semana de gestação. Sua etiologia permanece desconhecida, e seus mecanismos fisiopatológicos estão relacionados à hipoperfusão placentária, disfunção endotelial, inflamação, e ativação da cascata de coagulação. Recentemente, o papel do sistema do complemento foi considerado. Essa síndrome é uma das principais causas de morbidade e mortalidade materna e fetal. Este artigo discute a hipótese de a pré-eclâmpsia ser desencadeada pela ocorrência da implantação inadequada do sinciciotrofoblasto, associada ao sangramento durante o primeiro trimestre da gravidez com aumento da geração de trombina. A trombina ativa plaquetas, aumentando a liberação de fatores antiangiogênicos na circulação e ativando o sistema do complemento, especialmente o complexo de ataque de membrana (C5b9). Portanto, a fração de plaquetas imaturas e a geração de trombina podem ser possíveis biomarcadores sanguíneos para auxílio no diagnóstico precoce da pré-eclâmpsia.

Research Advances on the Pathogenesis and Treatment of Hemolytic Uremic Syndrome --Review / 中国实验血液学杂志

Hemolytic uremic syndrome (HUS) is clinically rare, with high mortality and case fatality rates. In recent years, the research on HUS has been intensified and the pathophysiological mechanism has been continuously improved. At present, the main mechanism of pathogenesis is the excessive activation of complement alternative pathways mediated by complement-related gene mutations or the existence of antibodies. The treatment methods and strategies are also constantly updated, mainly including complement-blocking drugs such as Eculizumab, Lavalizumab, and Ravulizumab. In this review, the new developments in the pathogenesis and treatment of HUS is summarized, and provide references for the clinical treatment of HUS.

Nephrotic syndrome associated with primary atypical hemolytic uremic syndrome / Síndrome nefrótica associada à síndrome hemolítico-urêmica atípica primária

Abstract Primary atypical hemolytic-uremic syndrome is a rare disease characterized by non-immune microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction; it is related to alterations in the regulation of the alternative pathway of complement due to genetic mutations. The association with nephrotic syndrome is unusual. We present here a pediatric patient diagnosed with primary atypical hemolytic-uremic syndrome associated with nephrotic syndrome who responded to eculizumab treatment.

Resumo A síndrome hemolítico-urêmica atípica primária é uma doença rara, caracterizada por anemia hemolítica microangiopática não-imune, trombocitopenia e disfunção renal; está relacionado a alterações na regulação da via alternativa do complemento devido a mutações genéticas. A associação com a síndrome nefrótica é incomum. Apresentamos aqui um paciente pediátrico com diagnóstico de síndrome hemolítico-urêmica atípica primária associada à síndrome nefrótica que respondeu ao tratamento com eculizumab.

An in vitro model mimicking the complement system to favor directed phagocytosis of unwanted cells

BACKGROUND: Opsonization, is the molecular mechanism by which target molecules promote interactions with phagocyte cell surface receptors to remove unwanted cells by induced phagocytosis. We designed an in vitro system to demonstrate that this procedure could be driven to eliminate adipocytes, using peptides mimicking regions of the complement protein C3b to promote opsonization and enhance phagocytosis. Two cell lines were used: (1) THP-1 monocytes differentiated to macrophages, expressing the C3b opsonin receptor CR1 in charge of the removal of unwanted coated complexes; (2) 3T3-L1 fibroblasts differentiated to adipocytes, expressing AQP7, to evaluate the potential of peptides to stimulate opsonization. (3) A co-culture of the two cell lines to demonstrate that phagocytosis could be driven to cell withdrawal with high efficiency and specificity. RESULTS: An array of peptides were designed and chemically synthesized p3691 and p3931 joined bound to the CR1 receptor activating phagocytosis (p < 0.033) while p3727 joined the AQP7 protein (p < 0.001) suggesting that opsonization of adipocytes could occur. In the co-culture system p3980 and p3981 increased lipid uptake to 91.2% and 89.0%, respectively, as an indicator of potential adipocyte phagocytosis. CONCLUSIONS: This in vitro model could help understand the receptor­ligand interaction in the withdrawal of unwanted macromolecules in vivo. The adipocyte-phagocytosis discussed may help to control obesity, since peptides of C3b stimulated the CR1 receptor, promoting opsonisation and phagocytosis of lipidcontaining structures, and recognition of AQP7 in the differentiated adipocytes, favored the phagocytic activity of macrophages, robustly supported by the co-culture strategy.

Incremental Validity between the Wartegg and Rorschach tests (R-PAS) / Validade Incremental entre o Teste de Wartegg e o Rorschach (R-PAS) / Validad Incremental entre la Prueba de Wartegg y Rorschach (R-PAS)

Abstract Incremental validity indicates how much a measure can add prevision to a criterion, more than what can be previewed by other sources of data. In other words, it means how an instrument can complement and aid on information comprehension derived from another. The objective of the study was to verify evidence of incremental validity between the Wartegg and the Rorschach tests (R-PAS). A total of 40 subjects with ages varying between 21 to 70 years participated, divided into two groups, one composed by schizophrenia diagnosis and another, by subjects with a history of psychiatric diseases. Everybody responded to the Rorschach and Wartegg tests. The results indicated predictive capacity among the instruments of 75% for the variable Formal Quality, 98% for Movement and 100% for Content. New studies are suggested about validity evidences with larger samples as well as the analysis of other variables, not explored in this study.

Resumo Validade incremental diz respeito ao quanto uma medida pode adicionar à previsão de um critério, acima do que pode ser previsto por outras fontes de dados, ou seja, de que forma um instrumento pode complementar e auxiliar na compreensão de informações obtidas por outro. O objetivo do estudo foi verificar evidências de validade incremental entre o Teste de Wartegg e o Rorschach (R-PAS). Participaram 40 sujeitos, com idades entre 21 a 70 anos, divididos em dois grupos, um composto por pacientes com diagnóstico de esquizofrenia e outro por sujeitos sem histórico de doença psiquiátrica. Todos responderam o Rorschach e o Teste de Wartegg. Os resultados indicaram capacidade preditiva entre os instrumentos de 75% para a variável Qualidade Formal, 98% para Movimento e 100% para Conteúdo. Sugere-se novos estudos acerca das evidências de validade, com amostras maiores e também análise de outras variáveis não exploradas no presente estudo.

Resumen Validad incremental dice respecto a lo cuanto una medida puede añadir a la previsión de un criterio, más de lo que puede ser previsto por otras fuentes de datos, o sea, de cual manera un instrumento puede complementar y auxiliar en la comprensión de informaciones obtenidas por otro. El objetivo del estudio fue verificar la evidencia de validez incremental entre la Prueba de Wartegg y lo Rorschach (R-PAS). Participado 40 sujetos con edades entre 21 y 70 años, divididos en dos grupos, un compuesto por pacientes con diagnóstico de esquizofrenia y otro, por sujetos sin histórico de enfermedad psiquiátrica. Todos respondieron a lo Roraschach y a la Prueba de Wartegg. Los resultados indicaron capacidad predictiva entre los instrumentos de 75% para la variable Calidad formal, 98% para Movimiento y 100% para Contenido. Se sugieren nuevos estudios acerca de las evidencias de validad, con amuestras mayores y también análisis de otras variables no exploradas en el presente estudio.

Níveis inatos de C3 e C4 em pacientes curados para a leishmaniose visceral e associação com os aspectos clínico-laboratoriais / Innate levels of C3 and C4 in patients cured for visceral leishmaniasis and association with clinical and laboratory aspects

Introdução: assim que inoculada pelo flebotomíneo, a Leishmania entra em contato com o sistema complemento, sendo que poucos estudos têm avaliado os níveis inatos dos componentes iniciais C3 e C4. Objetivo: avaliar os níveis inatos dos componentes C3 e C4 do sistema complemento em pacientes curados de leishmaniose visceral (LV) e sua associação com aspectos clínico-laboratoriais no momento de diagnóstico da doença. Metodologia: foram estudados 29 pacientes com LV curada. Os níveis de C3 e C4 séricos foram dosados pela técnica de imunodifusão radial simples, após um tempo médio de 59,48 meses pós-tratamento, formados os grupos: C3: baixo (< 84 mg/dl; n=10), normal (84 a 193 mg/dl; n=14) e elevado (> 193 mg/dl; n=5); C4: muito baixo (< 20 mg/dl; n=10), baixo (20 a 40 mg/dl; n=15) e normal (> 40 mg/dl; n=4). Os dados clínicos e laboratoriais empregados para as análises foram coletados por levantamento dos prontuários, considerando o período de diagnóstico da doença de cada paciente. Resultados: foi observada uma correlação positiva fraca entre os níveis de C3 e C4 (rho=0,46; p=0,01). Verificou-se que a maioria dos pacientes sintomáticos no momento do diagnóstico apresentavam níveis inatos normais de C3 e baixos de C4. Pacientes com C3 baixo apresentaram maiores níveis do hematócrito em relação ao grupo C3 normal (p=0,0406). Conclusão: conclui-se que o componente C3 do sistema complemento está associado às alterações do hematócrito, sugerindo o acompanhamento dos seus níveis em pacientes com LV.

Introduction: once inoculated by the sand fly, Leishmania comes into contact with the complement system, and few studies have evaluated the innate levels of the initial components C3 and C4. Objective: to evaluate the innate levels of the C3 and C4 components of the complement system in patients cured of visceral leishmaniasis (VL) and its association with clinical and laboratory aspects at the time of diagnosis of the disease. Methodology: twenty-nine patients with cured VL were studied. Serum C3 and C4 levels were measured by simple radial immunodiffusion technique, after an average time of 59.48 months post-treatment, forming the groups: C3: low (< 84 mg/dl; n=10), normal (84 to 193 mg/dl; n=14) and high (> 193 mg/dl; n=5); C4: very low (< 20 mg/dl; n=10), low (20 to 40 mg/dl; n=15) and normal (> 40 mg/dl; n=4). The clinical and laboratory data used for the analyzes were collected by surveying the medical records, considering the period of diagnosis of the disease of each patient. Results: a weak positive correlation was observed between C3 and C4 levels (rho=0.46; p=0.01). Most symptomatic patients at the time of diagnosis were found to have normal C3 and low C4 levels. Low C3 patients had higher levels of hematocrit compared to the normal C3 group (p=0.0406). Conclusion: in conclusion, the C3 component of the complement system is associated with changes in the hematocrit, suggesting the monitoring of its levels in patients with VL.

Erros inatos de imunidade: tempo de diagnóstico e episódios infecciosos em pacientes ambulatoriais / Inborn errors of immunity: time to diagnosis and infections in outpatients

Introdução: Os erros inatos de imunidade (EII) são distúrbios que ocasionam danos no desenvolvimento e/ou função do sistema imunológico. O diagnóstico muitas vezes não é realizado de imediato devido ao pouco conhecimento sobre as doenças, que leva a complicações graves e diminui a sobrevida e qualidade de vida desses pacientes. O objetivo desse estudo foi avaliar o tempo para o diagnóstico e as ocorrências infecciosas que acometeram pacientes com EII no decorrer de sua vida até o momento do diagnóstico. Método: Foi realizado um estudo transversal, retrospectivo, em pacientes atendidos pelo serviço de Alergia, Imunologia e Pneumologia do Complexo Hospital de Clínicas da Universidade Federal do Paraná (CHC-UFPR), no período de junho de 1993 a março de 2019. Foram excluídos pacientes sem história prévia ao diagnóstico e com diagnóstico não confirmado de EII ou indefinido. Resultados: Dos 57 pacientes incluídos no estudo, a maioria (n = 34) era do sexo masculino. A idade ao diagnóstico variou de 2 até 38 anos, sendo a média 9 anos. Dentre as imunodeficiências, 43 (75,4%) tinham deficiência de anticorpos, 10 (17,5%) deficiência combinada, 3 (5,3%) deficiência de fagócitos e 1 (1,8%) deficiência de complemento. Em relação às infecções, os pacientes apresentaram mais de um episódio infeccioso, e também sofreram acometimento em mais de um sítio anatômico. As infecções mais frequentes foram as do trato respiratório inferior (80,7%), seguido das infecções do trato respiratório superior (50,9%). Foi encontrado um atraso médio de diagnóstico de 66,1 meses, sendo que 10,5% dos pacientes foram a óbito. Conclusão: Apesar de já serem bem caracterizados, os EII ainda possuem diagnóstico tardio, levando os pacientes a complicações graves, e até à morte.

Introduction: Inborn errors of immunity (IEIs) cause damage in the development and/or function of the immune system. The diagnosis is often not done immediately because of lack of knowledge about the disorders, leading to serious complications and decreasing the survival and quality of life of these patients. The aim of this study was to evaluate time to diagnosis and occurrence of infections that affected patients with IEI throughout their life-span until the diagnosis. Methods: A retrospective crosssectional study was performed in patients treated at the Division of Allergy, Immunology and Pulmonology of the Complexo Hospital de Clínicas at Universidade Federal do Paraná, from June 1993 to March 2019. Patients with no history prior to diagnosis and those with unconfirmed diagnosis of IIE or undefined diagnosis were excluded from the study. Results: Of the 57 patients included in the study, most were male (n = 34). The mean age at the time of diagnosis was 9 years, ranging from 2 to 38 years. Among the immunodeficiencies, 43 (75.4%) patients had antibody deficiency disorder, 10 (17.5%) had combined immunodeficiency, 3 (5.3%) had phagocyte deficiency and 1 (1.8%) had complement disorder. Regarding infections, patients had more than one infectious episode and were affected in more than one anatomical site. The most frequent infections were those of the lower respiratory tract (80.7%), followed by upper respiratory tract infections (50.9%). A mean diagnosis delay of 66.1 months was found, and 10% of the patients died. Conclusion: Despite being well characterized, IEIs still have late diagnosis, leading patients to serious complications and even death.

Urinary Biomarkers may Complement the Cleveland Score for Prediction of Adverse Kidney Events After Cardiac Surgery: A Pilot Study

BACKGROUND: The ability of urinary biomarkers to complement established clinical risk prediction models for postoperative adverse kidney events is unclear. We assessed the effect of urinary biomarkers linked to suspected pathogenesis of cardiac surgery-induced acute kidney injury (AKI) on the performance of the Cleveland Score, a risk assessment model for postoperative adverse kidney events. METHODS: This pilot study included 100 patients who underwent open-heart surgery. We determined improvements to the Cleveland Score when adding urinary biomarkers measured using clinical laboratory platforms (neutrophil gelatinase-associated lipocalin [NGAL], interleukin-6) and those in the preclinical stage (hepcidin-25, midkine, alpha-1 microglobulin), all sampled immediately post-surgery. The primary endpoint was major adverse kidney events (MAKE), and the secondary endpoint was AKI. We performed ROC curve analysis, assessed baseline model performance (odds ratios [OR], 95% CI), and carried out statistical reclassification analyses to assess model improvement. RESULTS: NGAL (OR [95% CI] per 20 concentration-units wherever applicable): (1.07 [1.01–1.14]), Interleukin-6 (1.51 [1.01–2.26]), midkine (1.01 [1.00–1.02]), 1-hepcidin-25 (1.08 [1.00–1.17]), and NGAL/hepcidin-ratio (2.91 [1.30–6.49]) were independent predictors of MAKE and AKI (1.38 [1.03–1.85], 1.08 [1.01–1.15], 1.01 [1.00–1.02], 1.09 [1.01–1.18], and 3.45 [1.54–7.72]). Category-free net reclassification improvement identified interleukin-6 as a model-improving biomarker for MAKE and NGAL for AKI. However, only NGAL/hepcidin-25 improved model performance for event- and event-free patients for MAKE and AKI. CONCLUSIONS: NGAL and interleukin-6 measured immediately post cardiac surgery may complement the Cleveland Score. The combination of biomarkers with hepcidin-25 may further improve diagnostic discrimination.

Novel Associations between Related Proteins and Cellular Effects of High-Density Lipoprotein

BACKGROUND AND OBJECTIVES: Recent studies have examined the structure-function relationship of high-density lipoprotein (HDL). This study aimed to identify and rank HDL-associated proteins involved in several biological function of HDL.METHODS: HDLs isolated from 48 participants were analyzed. Cholesterol efflux capacity, effect of HDL on nitric oxide production, and vascular cell adhesion molecule-1 expression were assessed. The relative abundance of identified proteins in the highest vs. lowest quartile was expressed using the normalized spectral abundance factor ratio.RESULTS: After adjustment by multiple testing, six proteins, thyroxine-binding globulin, alpha-1B-glycoprotein, plasma serine protease inhibitor, vitronectin, angiotensinogen, and serum amyloid A-4, were more abundant (relative abundance ratio ≥2) in HDLs with the highest cholesterol efflux capacity. In contrast, three proteins, complement C4-A, alpha-2-macroglobulin, and immunoglobulin mu chain C region, were less abundant (relative abundance ratio <0.5). In terms of nitric oxide production and vascular cell adhesion molecule-1 expression, no proteins showed abundance ratios ≥2 or <0.5 after adjustment. Proteins correlated with the functional parameters of HDL belonged to diverse biological categories.CONCLUSIONS: In summary, this study ranked proteins showing higher or lower abundance in HDLs with high functional capacities and newly identified multiple proteins linked to cholesterol efflux capacity.

The Identification of Immune-Related Plasma Proteins Associated with Spontaneous Preterm Delivery and Intra-Amniotic Infection in Women with Premature Cervical Dilation or an Asymptomatic Short Cervix

BACKGROUND: We aimed to investigate whether various immune-related plasma proteins, alone or in combination with conventional clinical risk factors, can predict spontaneous preterm delivery (SPTD) and intra-amniotic infection in women with premature cervical dilation or a short cervix (≤ 25 mm).METHODS: This retrospective study included 80 asymptomatic women with premature cervical dilation (n = 50) or a short cervix (n = 30), who underwent amniocentesis at 17–29 weeks. Amniotic fluid (AF) was cultured, and maternal plasma was assayed for interleukin (IL)-6, matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1, and complements C3a and C5a, using enzyme-linked immunosorbent assay (ELISA) kits. The primary outcome measures were SPTD at < 32 weeks and positive AF cultures.RESULTS: The plasma levels of IL-6, C3a, and C5a, but not of MMP-9 and TIMP-1, were significantly higher in women with SPTD at < 32 weeks than in those who delivered at ≥ 32 weeks. The women who delivered at < 32 weeks had more advanced cervical dilatation, and higher rates of antibiotic and tocolytic administration and were less likely to be given vaginal progesterone than those who delivered at ≥ 32 weeks. Using a stepwise regression analysis, a combined prediction model was developed, which included the plasma IL-6 and C3a levels, and cervical dilatation (area under the curve [AUC], 0.901). The AUC for this model was significantly greater than that for any single variable included in the predictive model. In the univariate analysis, plasma IL-6 level was the only significant predictor of intra-amniotic infection.CONCLUSION: In women with premature cervical dilation or a short cervix, maternal plasma IL-6, C3a, and C5a levels could be useful non-invasive predictors of SPTD at < 32 weeks. A combination of these biomarkers and conventional clinical factors may clearly improve the predictability for SPTD, as compared with the biomarkers alone. An increased plasma level of IL-6 predicted intra-amniotic infection.

Research Advances in Follicular Regulatory T Cells in Ocular Myasthenia Gravis / 中国医学科学院学报

Myasthenia gravis(MG)is a B cell-mediated,T cell-dependent,complements-involved autoimmune disease.Ocular myasthenia gravis(OMG)is a typical MG,with its symptoms limited to the extraocular muscles.The occurrence and development of a variety of autoimmune diseases including OMG are closely associated with the imbalanced expression of follicular regulatory T cells(Tfr cells).Therefore,Tfr cells may be a new research topic for OMG.

La cirugía pediátrica cubana ante la COVID-19: repercusión y enfrentamiento / Cuban pediatric surgery facing COVID-19: impacts and confrontations

La COVID-19 tiene un impacto significativo en la salud pública a nivel internacional y nacional, por tanto, en la cirugía pediátrica. En Cuba, el Ministerio de Salud Pública ha implementado un protocolo para enfrentar esta contingencia. Como un complemento de este protocolo nacional, la cirugía pediátrica cubana ha pautado las Particularidades en la atención del paciente quirúrgico pediátrico, con el objetivo de presentar un análisis del impacto que ha tenido la COVID-19 en la especialidad, así como de las acciones de enfrentamiento que se acometen a corto, mediano y largo plazo, herramientas técnicas necesarias para realizar el trabajo de la cirugía pediátrica y otras especialidades afines en este contexto epidemiológico. La repercusión de la COVID-19 en la cirugía pediátrica para los pacientes, familiares, cirujanos y residentes de la especialidad no solo se pone de manifiesto ahora, sino que también tendrá consecuencias posteriores, razones por la que se trazan estrategias y acciones concretas, de las cuales algunas ya se han puesto en práctica y se han publicado. En general, la COVID-19 ha producido una verdadera crisis sanitaria sin precedentes que tiene y tendrá un negativo impacto biológico, psicológico y social en pacientes, familiares y la comunidad, no solo en el momento actual sino en el futuro. La cirugía pediátrica cubana sufre afectaciones, pero se toman previsiones, se aprenden lecciones y se implementan nuevos métodos que harán mejor la práctica asistencial y docente en el futuro(AU)

COVID-19 has a significative impact in public health at the national and international levels, and as a consequence in pediatric surgery. In Cuba, the Ministry of Public Health has implemented a protocol to face this contingency. As a complement of this national protocol, Cuban pediatric surgery as specialty has provided guidelines called Special features in the care of pediatric surgical patients, with the aim of presenting an analysis of the impact that COVID-19 has had in this specialty, as well as the confrontation actions that are being carried out in the short, medium and long terms, technical tools needed to perform the pediatric surgery work and in other related specialties in this epidemiological context. The impact of COVID-19 in pediatric surgery for patients, relatives, surgeons and residents of the specialty is not only manifesting now but it will have further consequences; so, there are strategies and concret actions being created, from which some has been already implemented and published. In general terms, COVID-19 has actually produced an unprecedented sanitary crisis that has and will have a negative biological, psychologic and social impact in patients, relatives and communities, not only in this moment but in the future times. Cuban pediatric surgery suffers affectations, but provisions have been taken, lessons are learned and new methods have been implemented that will make the care and teaching practices better in the future(AU)

Involvement of HSP90 in ischemic postconditioning-induced cardioprotection by inhibition of the complement system, JNK and inflammation

Abstract Purpose To investigate whether heat shock protein 90 (HSP90) is involved in complement regulation in ischemic postconditioning (IPC). Methods The left coronary artery of rats underwent 30 min of occlusion, followed by 120 min of reperfusion and treatment with IPC via 3 cycles of 30s reperfusion and 30s occlusion. The rats were injected intraperitoneally with 1 mg/kg HSP90 inhibitor geldanamycin (GA) after anesthesia. Eighty rats were randomly divided into four groups: sham, ischemia-reperfusion (I/R), IPC and IPC + GA. Myocardial infarct size, apoptosis index and the expression of HSP90, C3, C5a, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1β and c-Jun N-terminal kinase (JNK) were assessed. Results Compared with the I/R injury, the IPC treatment significantly reduced infarct size, release of troponin T, creatine kinase-MB, and lactate dehydrogenase, and cardiomyocyte apoptosis. These beneficial effects were accompanied by a decrease in TNF-α, IL-1β, C3, C5a and JNK expression levels. However, all these effects were abrogated by administration of the HSP90 inhibitor GA. Conclusion HSP90 exerts a profound effect on IPC cardioprotection, and may be linked to the inhibition of the complement system and JNK, ultimately attenuating I/R-induced myocardial injury and apoptosis.

Doenças associadas à deficiência do sistema complemento / Diseases associated with the deficiency of the complement system

Introdução: O sistema complemento é composto por diversas proteínas plasmáticas e é um importante mecanismo de defesa da imunidade inata e adquirida, que exerce funções homeostáticas e fisiológicas, como a remoção de células apoptóticas e complexos imunes. A deficiência neste mecanismo pode ser hereditária ou adquirida, e leva ao aumento da susceptibilidade a doenças infecciosas e não infecciosas, raras e fatais. Objetivo: Descrever as principais causas e consequências da deficiência do sistema complemento e relacioná-las com múltiplas patologias. Material e Métodos: Trata-se de uma revisão bibliográfica narrativa, tendo como base de dados, artigos publicados no Scientific Electronic Library Online (SciELO), National Library of Medicine (PubMed), Medical Literature Analysis and retrieval System Online (MEDLINE), nos últimos 5 anos. Resultados: A associação do complemento e doenças foram observadas em situações de deficiência do sistema complemento, anormalidades na regulação e nas inflamações. Mutações genéticas ou aumento do consumo do complemento levam à ativação imprópria ou excessiva do complemento, podendo conduzir a consequências lesivas e ao desenvolvimento de diversas doenças, como, lúpus eritematoso sistêmico, síndrome urêmica hemolítica atípica, glomerulopatia C3, hemoglobinúria paroxística noturna, glomerulonefrite pós-infecciosas, artrite reumatoide, dentre outras. Conclusão: É evidente a participação do sistema complemento na patogênese e patogenia de diversas doenças. O investimento em pesquisas, que visem ampliar o entendimento do papel do mecanismo do sistema complemento, pode contribuir para o desenvolvimento de intervenções terapêuticas paliativas e ou de cura de diversas doenças, com a consequente melhoria da qualidade de vida dos indivíduos acometidos.

Introduction: The complement system is composed of several plasma proteins and is an important defense mechanism of innate and acquired immunity, which exerts homeostatic and physiological functions, such as the removal of apoptotic cells and immune complexes. Deficiency in this mechanism may be hereditary or acquired, and leads to increased susceptibility to infectious and non-infectious, rare and fatal diseases. Objective: To describe the main causes and consequences of the deficiency of the complement system and to relate them to multiple pathologies. Material and Methods: This is a bibliographical narrative review, based on data published in SciELO (Scientific Electronic Library Online), PubMed (National Library of Medicine), MEDLINE (Medical Literature Analysis and retrieval System Online), last five years. Results:The associations of complement and diseases were observed in situations of deficiency of the complement system, abnormalities in regulation and inflammation. Genetic mutations lead to inappropriate or excessive activation of the complement, as well as increased the consumption of the complement. This can lead to harmful consequences and the development of several diseases, such as systemic lupus erythematosus, atypical hemolytic uremic syndrome, C3 glomerulopathy, nocturnal paroxysmal hemoglobinuria, postpartum glomerulonephritis, infectious diseases, rheumatoid arthritis, among others. Conclusion: The participation of the complement system in the pathogenesis and pathogenesis of several diseases is evident. Investing in research, aimed at broadening the understanding of the role of the complement system mechanism, may contribute to the development of palliative therapeutic interventions and or cure of various diseases, with the consequent improvement in the quality of life of affected individuals.

C3a Receptor Inhibition Protects Brain Endothelial Cells Against Oxygen-glucose Deprivation/Reperfusion

The complement cascade is a central component of innate immunity which plays a critical role in brain inflammation. Complement C3a receptor (C3aR) is a key mediator of post-ischemic cerebral injury, and pharmacological antagonism of the C3a receptor is neuroprotective in stroke. Cerebral ischemia injures brain endothelial cells, causing blood brain barrier (BBB) disruption which further exacerbates ischemic neuronal injury. In this study, we used an in vitro model of ischemia (oxygen glucose deprivation; OGD) to investigate the protective effect of a C3aR antagonist (C3aRA, SB290157) on brain endothelial cells (bEnd.3). Following 24 hours of reperfusion, OGD-induced cell death was assessed by TUNEL and Caspase-3 staining. Western blot and immunocytochemistry were utilized to demonstrate that OGD upregulates inflammatory, oxidative stress and antioxidant markers (ICAM-1, Cox-2, Nox-2 and MnSOD) in endothelial cells and that C3aRA treatment significantly attenuate these markers. We also found that C3aRA administration restored the expression level of the tight junction protein occludin in endothelial cells following OGD. Interestingly, OGD/reperfusion injury increased the phosphorylation of ERK1/2 and C3aR inhibition significantly reduced the activation of ERK suggesting that endothelial C3aR may act via ERK signaling. Furthermore, exogenous C3a administration stimulates these same inflammatory mechanisms both with and without OGD, and C3aRA suppresses these C3a-mediated responses, supporting an antagonist role for C3aRA. Based on these results, we conclude that C3aRA administration attenuates inflammation, oxidative stress, ERK activation, and protects brain endothelial cells following experimental brain ischemia.

Social Interaction Test in Home Cage as a Novel and Ethological Measure of Social Behavior in Mice

Sociability is the disposition to interact with one another. Rodents have a rich repertoire of social behaviors and demonstrate strong sociability. Various methods have been established to measure the sociability of rodents in simple and direct ways, which includes reciprocal social interaction, juvenile social play, and three-chamber social tests. There are possible confounding factors while performing some of these tasks, such as aggression, avoidance of interaction by the stimulus mouse, exposure to a new environment, and lengthy procedures. The present study devised a method to complement these shortcomings and measure sociability as a group in the home cage setting, which prevents group-housed mice from isolation or exposure to a new environment. The home cage social test can allow high-throughput screening of social behaviors in a short amount of time. We developed two types of home cage setup: a home cage social target interaction test that measures sociability by putting the wire cage in the center area of the cage and a home cage two-choice sociability and social preference test that measures both sociability or social preference by putting cage racks at opposite sides of the cage. Interestingly, our results showed that the two types of home cage setup that we used in this study can extract abnormal social behaviors in various animal models, similar to the three-chamber assay. Thus, this study establishes a new and effective method to measure sociability or social preference that could be a complementary assay to evaluate the social behavior of mice in various setup conditions.

Machine-Learning Based Automatic and Real-time Detection of Mouse Scratching Behaviors

Scratching is a main behavioral response accompanied by acute and chronic itch conditions, and has been quantified as an objective correlate to assess itch in studies using laboratory animals. Scratching has been counted mostly by human annotators, which is a time-consuming and laborious process. It has been attempted to develop automated scoring methods using various strategies, but they often require specialized equipment, costly software, or implantation of device which may disturb animal behaviors. To complement limitations of those methods, we have adapted machine learning-based strategy to develop a novel automated and real-time method detecting mouse scratching from experimental movies captured using monochrome cameras such as a webcam. Scratching is identified by characteristic changes in pixels, body position, and body size by frame as well as the size of body. To build a training model, a novel two-step J48 decision tree-inducing algorithm along with a C4.5 post-pruning algorithm was applied to three 30-min video recordings in which a mouse exhibits scratching following an intradermal injection of a pruritogen, and the resultant frames were then used for the next round of training. The trained method exhibited, on average, a sensitivity and specificity of 95.19% and 92.96%, respectively, in a performance test with five new recordings. This result suggests that it can be used as a non-invasive, automated and objective tool to measure mouse scratching from video recordings captured in general experimental settings, permitting rapid and accurate analysis of scratching for preclinical studies and high throughput drug screening.

Recent Concepts of Guillain-Barré Syndrome

Guillain-Barré syndrome (GBS) is a representative form of post-infectious autoimmune neuropathy with heterogenous manifestations. It was originally considered as an ascending demyelinating polyneuropathy in Western countries. However, the discovery of anti-ganglioside antibodies on the basis of molecular mimicry theory could help us better understand various kinds of focal and regional variants as well as axonal type of GBS those were frequently found from Asian countries. Recent development of new techniques about anti-ganglioside complex antibodies is making more detailed descriptions for specific or unusual clinical manifestations. It has been regarded that GBS has good prognosis if treated properly as early as possible, but it still shows high mortality and morbidity rate with frequent long term neurologic and medical complications. Unfortunately, there are only two options for medical treatment, intravenous immunoglobulin and plasmapheresis, for the last 100 years. Several clinical studies on new immunotherapy targeting complement activating system with background of molecular mimicry using animal model are underway. We hope that these new treatments will be helpful for the future patients.

The Potential Role of Biomarkers Associated with ASCVD Risk: Risk-Enhancing Biomarkers

Serum cholesterol is major risk factor and contributor to atherosclerotic cardiovascular disease (ASCVD). Therapeutic cholesterol-lowering drugs, especially statin, revealed that reduction in low-density lipoprotein cholesterol (LDL-C) produces marked reduction of ASCVD events. In the preventive scope, lower LDL-C is generally accepted as better in proven ASCVD patients and high-risk patient groups. However, in patients with low to intermediate risk without ASCVD, risk assessment is clinically guided by traditional major risk factors. In this group, the complement approach to detailed risk assessment about traditional major risk factors is needed. These non-traditional risk factors include ankle-brachial index (ABI), high-sensitivity C-reactive protein (hsCRP) level, lipoprotein(a) (Lp[a]), apolipoprotein B (apoB), or coronary artery calcium (CAC) score. CAC measurements have an additive role in the decision to use statin therapy in non-diabetic patients 40–75 years old with intermediate risk in primary prevention. This review comprises ASCVD lipid/biomarkers other than CAC. The 2013 and 2018 American College of Cardiology/American Heart Association (ACC/AHA) guidelines suggest these factors as risk-enhancing factors to help health care providers better determine individualized risk and treatment options especially regarding abnormal biomarkers. The recent 2018 Korean guidelines for management of dyslipidemia did not include these biomarkers in clinical decision making. The current review describes the current roles of hsCRP, ABI, LP(a), and apoB in personal modulation and management of health based on the 2018 ACC/AHA guideline on the management of blood cholesterol.

Comparison of Skin Stimulation Method and Topical Anesthetic Cream on Pain and Heart Rate Variability during Arteriovenous Fistula Puncture in Hemodialysis Patients

PURPOSE: The purpose of this was to compare effects of application of the skin stimulation method and topical anesthetic cream on pain, heart rate variability and satisfaction according to nursing intervention methods during arteriovenous fistula puncture in chronic renal failure hemodialysis patients. METHODS: This study was a crossover design. Participants were 36 patients with chronic renal failure receiving hemodialysis treatment. Two forms of intervention were applied to participants, and then pain and heart rate variability were measured during the puncture. RESULTS: There were no statistically significant differences according to each treatment in vein pain and artery pain. Also, there were no statistically significant differences according to each treatment in stress index, sympathetic activity (LF), parasympathetic activity (HF) and sympathetic activity/parasympathetic activity (LF/HF ratio). Satisfaction with application of skin stimulation method was statistically higher than that of topical anesthetic cream application. CONCLUSION: This suggests that application of the skin stimulation method complements disadvantages of topical anesthetic cream application and demonstrates possibility of application as a nursing intervention method which can be conveniently used by nurses in clinical practice.