Biomarker Predictors of Delirium in Acutely Ill Patients: A Systematic Review.

Delirium is a serious and common disorder that affects up to 80% of acutely ill patients, mainly the aged. In recent years, several studies pointed out possible biomarkers that could be used alone or in combination with other resources in the diagnosis and follow-up of critically ill patients who develop delirium. In this context, a systematic review was conducted to determine the predictive value of several biomarkers in acutely (critically and noncritically) ill adult patients with delirium. Studies that used the confusion assessment method (CAM) and CAM-intensive care unit as the diagnostic method were considered. The most recent search was performed in November 2017. There was no language restriction. Initially, 626 articles were screened and 39 were included in the study. A comprehensive evaluation of the abstracts resulted in the exclusion of 202 studies, leaving 39 articles as potentially relevant. Inflammatory markers, S100ß and cortisol, could predict delirium occurrence in a specific subgroup population of critically ill patients.

Acetylcholinesterase activity in the rat brain after pneumococcal meningitis.

Pneumococcal meningitis is a life-threatening disease characterized by acute purulent infection of the meninges causing neuronal injury, cortical necrosis and hippocampal apoptosis. Cholinergic neurons and their projections are extensively distributed throughout the central nervous system. The aim of this study was to assess acetylcholinesterase activity in the rat brain after pneumococcal meningitis. In the hippocampus, frontal cortex and cerebrospinal fluid, acetylcholinesterase activity was found to be increased at 6, 12, 24, 48 and 96 hr without antibiotic treatment, and at 48 and 96 hr with antibiotic treatment. Our data suggest that acetylcholinesterase activity could be related to neuronal damage induced by pneumococcal meningitis.

Antioxidant treatment prevents cognitive impairment and oxidative damage in pneumococcal meningitis survivor rats.

Pneumococcal meningitis is associated with the highest fatality case ratios in the world. Most of patients that survive present neurologic sequelae at later times as well as biochemicals alterations such as oxidative stress in both earlier and later times after central nervous system infection. In this context, we evaluated the effect of antioxidant treatment on memory and oxidative parameters in the hippocampus of meningitis survivor rats 10 days after infection. To this aim, the animals underwent a magna cistern tap receiving either 10 µL sterile saline as a placebo or an equivalent volume of a Streptococcus pneumoniae suspension at the concentration 5x10(9) cfu/mL. The animals submitted to meningitis were divided into the following groups: 1) treated with antibiotic, 2) treated with basic support plus N-acetylcysteine, 3) treated with basic support plus deferoxamine, 4) treated with basic support plus N-acetylcysteine and deferoxamine, or 5) treated with N-acetylcysteine plus deferoxamine. Ten days after meningitis, the animals underwent inhibitory avoidance and habituation to an open field tasks and, immediately after, were assessed for oxidative damage in the hippocampus and cortex. The meningitis group showed significantly decreased performance in latency retention compared with the sham group in the inhibitory avoidance task. In the open-field task, the meningitis group presented memory impairment after meningitis. All these memory impairments were prevented by N-acetylcysteine plus deferoxamine with or without basic support and its isolate use. In addition, there was an increase of lipid phosphorylation in cortex and hippocampus and all the combined antioxidants attenuated lipid phosphorylation in both structures. On the other hand, there was an increase of protein phosphorylation in cortex and N-acetylcysteine plus deferoxamine with or without basic support prevented it. Thus, we hypothesize that oxidative stress may be related to cognitive impairment in pneumococcal meningitis.

Time-dependent behavioral recovery after pneumococcal meningitis in rats.

Alterations in hippocampus frequently occur following bacterial meningitis, despite antibiotic treatment. We investigated the cognitive performance in rats submitted to bacterial meningitis after 10, 30, and 60 days. To this aim, we utilized male Wistar rats submitted to either sham (control) or meningitis by Streptococcus pneumoniae, and followed by the initiation of the antibiotic treatment at 16 h after inoculation. The animals underwent six behavioral tasks 10, 30 and 60 days after surgery. We demonstrated that some of the learning and memory impairment, demonstrated 10 days after the induction of meningitis, persists up to 30 days, but not 60 days after induction.

The Role of Secretase Pathway in Long-term Brain Inflammation and Cognitive Impairment in an Animal Model of Severe Sepsis.

Inflammatory cytokines are related to impaired learning and memory processes in the central nervous system, contributing to the cognitive dysfunction present in sepsis survivors. In sepsis, brain of survivors presented increased deposition of amyloid-beta (Aß) peptide and this was associated with cognitive impairment. However, it is not known if the upregulation of secretase pathway is involved the deposition of Aß peptide and consequent development of cognitive impairment in survivors. The aim of the study is to evaluate the effects of secretase inhibitors on behavioral, Aß accumulation, and neuroinflammatory parameters in rats submitted to sepsis. Sepsis was induced by cecal ligation and perforation in Wistar rats, and the activity of alpha-, beta-, and gamma-secretases was determined in the hippocampus and prefrontal at different times. Additionally, in a different cohort of animal's epigallocatechin gallate, a beta-secretase inhibitor or a gamma-secretase inhibitor was administrated once a day for three consecutive days. Fifteen or 30 days after sepsis induction, Aß content, TNF-α, IL-1ß, and IL-6 and cognitive performance were determined. There was no increase in alpha-secretase activity. Both beta- and gamma-secretase activities increased, mainly late after sepsis. The inhibition of beta- or gamma-secretases improved cognitive performance 10 days after sepsis induction, and beta-secretase inhibition improved cognitive performance up to 30 days after sepsis induction. Furthermore, beta-secretase inhibition decreased IL-1ß and Aß brain levels. It was demonstrated that during sepsis development there was an increase in the amyloidogenic route, and the inhibition of this pathway promoted attenuation of neuroinflammation, Aß peptide content, and improvement of cognitive impairment.

Protective effects of fecal microbiota transplantation in sepsis are independent of the modulation of the intestinal flora.

OBJECTIVE: The aim of this study was to investigate the protective effects of probiotics and fecal transplantation on inflammatory and oxidative parameters in the intestines of two rat models of sepsis. METHODS: Rats were treated with prebiotics, probiotics, or symbiotics and exposed to lipopolysaccharide (LPS) or zymosan after 15 d to induce endotoxemia. Oxidative damage and inflammation were analyzed, and histologic examination of the intestinal tissue was performed. Fecal microbiota transplantation (FMT) was carried out in LPS- and zymosan-induced rat models of sepsis. RESULTS: Supplementation with symbiotics for 15 d effectively reduced the inflammatory parameters compared with supplementation for 7 d. Probiotics, prebiotics, and symbiotics exerted different effects on the evaluated parameters. In general, Lactobacillus rhamnosus and L. casei exerted better local protective effects. Evaluation of the role of the intestinal microbiota through FMT revealed its protective effects irrespective of the previous treatment with probiotics. CONCLUSION: Probiotic strains significantly differ among themselves and exert different effects on the host's health. Symbiotics and FMT could offer additional immunomodulatory benefits to drug therapy, thus serving as a new therapeutic alternative in pediatric patients with sepsis.

Principais variantes do SARS-CoV-2 notificadas no Brasil / Main SARS-CoV-2 variants notified in Brazil

O surgimento de variantes do SARS-CoV-2 (Coronavírus-2 da Síndrome Respiratória Aguda Grave) em diversos países gera preocupação para as autoridades de saúde do mundo. As variantes do SARS-CoV-2 apresentam mutações, principalmente na proteína S, que estão relacionadas a maior transmissibilidade, tornando-se dominantes em determinadas regiões em curto espaço de tempo. Essas mutações parecem estar associadas também a maior virulência, resistência aos anticorpos tanto monoclonais quanto produzidos em resposta a infecção prévia ou vacina, além da maior frequência de reinfecções. Nesta revisão, foram descritas as variantes Alfa, Beta, Gama, Delta, Zeta e Lambda classificadas como variantes de preocupação e de interesse, segundo a Organização Mundial da Saúde. Estas variantes foram notificadas no Brasil até o momento, e a revisão aborda suas principais características e os possíveis impactos sobre a saúde humana.

The emergence of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) variants in a lot of countries raises concern for health authorities around the world. The SARS-CoV-2 variants present mutations, mainly in the S protein, which are related to increase transmissibility, becoming dominant in certain regions in a short time. These mutations also seem to be associated with higher virulence, resistance to both monoclonal antibodies and those produced in response to previous infection or vaccine and to the most frequency of re-infections. In this review, the Alpha, Beta, Gamma, Delta, Zeta and Lambda variants classified as concern and interest variants, according to the World Health Organization, was described. These variants have been reported in Brazil until now, and the review addresses their main characteristics and possible impacts on human health.

Presença de RNA do SARS-CoV-2 em fezes de pacientes com COVID-19 / Presence of SARS-CoV-2 RNA in faeces of COVID-19 patients

A COVID-19, doença causada pelo novo Coronavírus, alastrou-se rapidamente por todos os continentes promovendo uma pandemia. Estudos relacionados à fisiopatologia da COVID-19 demonstraram que o vírus SARS-CoV-2 invade células da mucosa intestinal, sendo eliminado nas fezes, alertando para possibilidade da transmissão da doença por via fecal-oral. A presença do vírus nas fezes aventou também a expectativa de utilizar essa amostra biológica para fins diagnósticos. Nesta revisão, resumimos os estudos recentes relacionados à investigação da presença do RNA do SARS-CoV-2 nas fezes de pacientes com COVID-19.

Inhibition of matrix metalloproteinases-2 and -9 prevents cognitive impairment induced by pneumococcal meningitis in Wistar rats.

Pneumococcal meningitis is a relevant clinical disease characterized by an intense inflammatory reaction into the subarachnoid and ventricular spaces, leading to blood-brain barrier breakdown, hearing loss, and cognitive impairment. Matrix metalloproteinases (MMPs) are capable of degrading components of the basal laminin, thus contributing to BBB damage and neuronal injury. In the present study, we evaluated the effects of MMP-2, MMP-9, and MMP-2/9 inhibitors on BBB integrity, learning, and memory in Wistar rats subjected to pneumococcal meningitis. The animals underwent a magna cistern tap and received either 10 µL sterile saline as a placebo or an equivalent volume of a Streptococcus pneumoniae suspension at a concentration of 5 × 10(9)cfu/mL. The rats were randomized into different groups that received adjuvant treatment with MMP-2, MMP-9 or MMP-2/9 inhibitors. The BBB integrity was evaluated, and the animals were habituated to open-field and object recognition tasks 10 days after meningitis induction. Adjuvant treatments with inhibitors of MMP-2 or MMP-2/9 prevented BBB breakdown in the hippocampus, and treatments with inhibitors of MMP-2, MMP-9 or MMP-2/9 prevented BBB breakdown in the cortex. Ten days after meningitis induction, the animals that received adjuvant treatment with the inhibitor of MMP-2/9 demonstrated that animals habituated to the open-field task faster and enhanced memory during short-term and long-term retention test sessions in the object recognition task. Further investigation is necessary to provide support for MMP inhibitors as an alternative treatment for bacterial meningitis; however, these findings suggest that the meningitis model could be a good research tool for studying the biological mechanisms involved in the behavioral alterations associated with pneumococcal meningitis.

Anxious phenotype potentiates damage in peripheral organs of animals submitted to sepsis / Fenótipo ansioso potencializa danos em órgãos periféricos de animais submetidos à sepse

Introduction: Anxiety and sepsis are important public health problems that present high morbidity, mortality and significant economic repercussions. The present study investigated the presence of oxidative damage in peripheral organs in two lines of animals that are bred for high and low freezing responses to contextual cues that are previously associated with foot shock (Carioca High-conditioned Freezing [CHF] and Carioca Low-conditioned Freezing [CLF]) associated to sepsis. Methods: Animals were subject to sepsis by the cecal ligation and perforation (CLP) or sham operated. 24 hours and 10 days after sepsis animals were euthanized and removed adrenal, kidney, lung, serum, heart for the determination of carbonyl protein levels and adrenal for check weight this structure. Results: Sepsis increased oxidative damage in different systemic organs, included serum. There wasn't a significant increase in protein carbonyls in heart and kidney. Anxious phenotype potentiates this damage. Conclusion: These findings suggest that an anxious phenotype plus sepsis may induce more pronounced organs damage, and promote more alterations in the HPA axis. These findings may help to explain, at least in part, the common point of the mechanisms involved with the pathophysiology of sepsis and anxiety.

Introdução: Ansiedade e sepse são importantes problemas de saúde pública que apresentam alta morbidade, mortalidade e repercussões econômicas significativas. O presente estudo investigou a presença de dano oxidativo em órgãos periféricos em duas linhagens de animais criados para respostas de alta (CHF) e baixa (CLF) ansiedade associado a sepse. Métodos: Os animais foram submetidos a sham (controle) ou sepse por ligação e perfuração cecal (CLP). 24 horas e 10 dias após a sepse os animais foram eutanasiados e estruturas foram removidas: adrenal, rim, pulmão, soro e coração para a determinação dos níveis de proteínas carboniladas e adrenal para verificação do peso dessa estrutura. Resultados: A sepse aumentou o dano oxidativo em diferentes órgãos sistêmicos, incluindo o soro. Não houve um aumento significativo de proteínas carbonilas no coração e nos rins. Fenótipo ansioso potencializa esse dano. Conclusão: Esses achados sugerem que um fenótipo ansioso associado a sepse pode induzir dano mais pronunciado aos órgãos e promover mais alterações no eixo HPA. Esses achados podem ajudar a explicar, pelo menos em parte, o ponto comum dos mecanismos envolvidos na fisiopatologia da sepse e da ansiedade.

Extratos de plantas de uso popular contra infecções orais / Plant extracts of popular use against oral infections / Extractos de plantas de uso popular contra infecciones orales

Objetivo: Avaliar o efeito antibacteriano de extratos de plantas de uso popular sobre bactérias relacionadas ao desenvolvimento da cárie e infecções endodônticas. Métodos: Estudo experimental realizado na Universidade do Extremo Sul Catarinense, em 2015, no qual tinturas de Artemisia absinthium, Laurus nobilis, Bidens pilosa, Achillea millefolium L e Foeniculum vulgare, nas concentrações hidroalcoólicas de 5%, 10%, 15%, 20% em meio de cultura ágar Mueller Hinton, tiveram sua ação antibacteriana mensurada contra cepas de S. mutans e E. faecalis. Usou-se o método de difusão em meio sólido e a sensibilidade inibitória foi analisada pela presença e tamanho de halos de inibição, sendo grupo controle a clorexidina 0,12%. Utilizou-se nível de significância p<0,05. Resultados: Não houve inibição sobre a cepa de E. faecalis em nenhuma das tinturas, entretanto, observou-se efeito inibitório das tinturas de Artemisia absinthium, Laurus nobilis e Bidens pilosa sobre as cepas de S. mutans nas concentrações testadas. Conclusão: As tinturas de plantas de uso popular investigadas não apresentaram efeitos antimicrobianos sobre E. faecalis, causadora de infecções endodônticas, porém, três delas demonstraram efeitos inibitórios contra S. mutans, principal responsável pela cárie dentária.

Objetive: To assess the antibacterial effect of plant extracts of popular use on bacteria related to the development of caries and endodontic infections. Methods: Experimental study conducted at the University of the Extreme South of Santa Catarina in 2015 in which dyes of Artemisia absinthium, Laurus nobilis, Bidens pilosa, Achillea millefolium L and Foeniculum vulgare at hydro-alcoholic concentrations of 5%, 10%, 15% and 20% in Mueller Hinton agar growth-medium had their antibacterial activity against strains of S. mutans and E. faecalis measured. The solid medium diffusion method was used and the inhibitory activity was analyzed according to the presence and size of inhibition halos ­ control and chlorhexidine 0.12%. Significance level was set at α=0.05. Results: There was no inhibition on the strains of E. faecalis in any of the dyes; however, it was observed an inhibitory effect of Artemisia absinthium, Laurus nobilis and Bidens pilosa dyes on the strains of S. mutans at the concentrations tested. Conclusion: The dyes of plants of popular use assessed showed no antimicrobial effects on E. faecalis, which causes endodontic infections; however, three of them presented inhibitory effects against S. mutans, which is mainly responsible for caries.

Objetivo: Evaluar el efecto antibacteriano de extractos de plantas de uso popular sobre bacterias relacionadas al desarrollo de caries e infecciones endodónticas. Métodos: Estudio experimental realizado en la Universidad del Extremo Sur de Santa Catarina em 2015 en el cual tinturas de Artemisia absinthium, Laurus nobilis, Bidens pilosa, Achillea millefolium L y Foeniculum vulgare, em las concentraciones hidroalcohólicas del 5%, 10%, 15%, 20% en medio de cultivo agar Mueller Hinton, tuvieron su acción antibacteriana medida contra cepas de S. mutans e E. faecalis. Se utilizó el método de difusión en medio sólido y la sensibilidad inhibitoria fue analizada por la presencia y tamaño de halos de inhibición, teniendo como el grupo control la clorhexidina 0,12%. Se utilizó el nivel de significación de p<0,05. Resultados: No hubo inhibición sobre la cepa de E. faecalis en ninguna de las tinturas, sin embargo, se observó el efecto inhibitorio de las tinturas de Artemisia absinthium, Laurus nobilis y Bidens pilosa sobre las cepas de S. mutans en las concentraciones testadas. Conclusión: Las tinturas de plantas de uso popular investigadas no presentaron efectos antimicrobianos sobre el E. faecalis, causadora de infecciones endodónticas, sin embargo, tres de ellas han demostrado efectos inhibitorios contra el S. mutans, el principal responsable de la caries dentales.

alpha-Tocopherol as an antiretroviral therapy supplement for HIV-1-infected patients for increased lymphocyte viability.

The aim of our study was to evaluate the benefits of supplementation with 800 mg/day of alpha-tocopherol with regard to cellular viability in HIV-1 seropositive patients undergoing anti-retroviral therapy. A total of 29 patients participated in the study, of whom 14 were given the supplement and 15 a placebo. The analyses were carried out before treatment commenced and after 60, 120 and 180 days. The plasma levels of HIV-1 RNA showed a significant decrease as a consequence of treatment time in the groups studied (p = 0.0001), although the difference between the treatments over time was not verified (p = 0.7343). The percentage of viable lymphocytes showed a significant increase as a consequence of treatment time in both groups studied (p = 0.0002) and a significant difference between the treatments over time (p = 0.0472). The percentage of lymphocytes in apoptosis showed a significant reduction over time (p = 0.0003), as well as a significant difference between the treatments over time (p = 0.0321). The significant increase in cellular viability indicates that supplementation with alpha-tocopherol offers an additional positive effect on cellular preservation in HIV-1 individuals undergoing anti-retroviral therapy; however, it represents an additional risk of anti-retroviral therapeutic failure, possibly due to drug-drug interaction involving up-regulation of metabolic clearance.

The effect of N-acetylcysteine supplementation upon viral load, CD4, CD8, total lymphocyte count and hematocrit in individuals undergoing antiretroviral treatment.

Individuals infected with the human immunodeficiency virus (HIV-1) present with decreased CD4, a progressive increase in viral load, compromised cell immune defense, and hematologic alterations. The aim of this study was to assess the serum viral load, CD4, CD8, lymphocyte count and hematocrit at the beginning of antiretroviral therapy in individuals who were supplemented with N-acetylcysteine (NAC). Twenty volunteers participated in this double-blind, placebo-controlled 180-day study. Ten participants received 600 mg of NAC per day (NAC group) and the other ten serving as a control group received placebo. The above mentioned parameters were determined before treatment, and after 60, 120 and 180 days. In NAC-treated patients hematocrit remained stable and an increase in CD4 cell count took place earlier than that in the control group.

An evaluation of antiretroviral therapy associated with alpha-tocopherol supplementation in HIV-infected patients.

In HIV-infected patients, an increase in the production of oxygen-reactive species (ROS) is observed, with a consequent reduction of plasma levels of antioxidants such as alpha-tocopherol. The nuclear transcription factor-kappaB (NF-kappaB) is activated by a prooxidant state in the infected T cells through the release of its inhibitory subunit I-kappaB. The aim of the present work was to evaluate the behavior of hematological parameters and markers of anemia in HIV-infected patients who underwent antiretroviral therapy associated with 800 mg/day alpha-tocopherol supplementation. Blood samples were collected from supplemented (n=9) and not-supplemented (n=9) HIV-seropositive patients (n=18). We observed a decreased viral load in the alpha-tocopherol-supplemented group (p<0.05); other changes, such as an increase in the CD4/CD8 ratio, in the hematocrit and in the hemoglobin concentration were also observed, though lacking statistical significance. We conclude that antiretroviral therapy in association with alpha-tocopherol (800 mg/day) supplementation is more effective in reducing viral load levels and also, possibly, in recovering other hematological parameters after a 60-day period of use.