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1.
JAMA Netw Open ; 3(9): e2022058, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32965501

RESUMO

Importance: Coronavirus disease 2019 (COVID-19) is an acute respiratory illness with a high rate of hospitalization and mortality. Biomarkers are urgently needed for patient risk stratification. Red blood cell distribution width (RDW), a component of complete blood counts that reflects cellular volume variation, has been shown to be associated with elevated risk for morbidity and mortality in a wide range of diseases. Objective: To investigate whether an association between mortality risk and elevated RDW at hospital admission and during hospitalization exists in patients with COVID-19. Design, Setting, and Participants: This cohort study included adults diagnosed with SARS-CoV-2 infection and admitted to 1 of 4 hospitals in the Boston, Massachusetts area (Massachusetts General Hospital, Brigham and Women's Hospital, North Shore Medical Center, and Newton-Wellesley Hospital) between March 4, 2020, and April 28, 2020. Main Outcomes and Measures: The main outcome was patient survival during hospitalization. Measures included RDW at admission and during hospitalization, with an elevated RDW defined as greater than 14.5%. Relative risk (RR) of mortality was estimated by dividing the mortality of those with an elevated RDW by the mortality of those without an elevated RDW. Mortality hazard ratios (HRs) and 95% CIs were estimated using a Cox proportional hazards model. Results: A total of 1641 patients were included in the study (mean [SD] age, 62[18] years; 886 men [54%]; 740 White individuals [45%] and 497 Hispanic individuals [30%]; 276 nonsurvivors [17%]). Elevated RDW (>14.5%) was associated with an increased mortality risk in patients of all ages. The RR for the entire cohort was 2.73, with a mortality rate of 11% in patients with normal RDW (1173) and 31% in those with an elevated RDW (468). The RR in patients younger than 50 years was 5.25 (normal RDW, 1% [n = 341]; elevated RDW, 8% [n = 65]); 2.90 in the 50- to 59-year age group (normal RDW, 8% [n = 256]; elevated RDW, 24% [n = 63]); 3.96 in the 60- to 69-year age group (normal RDW, 8% [n = 226]; elevated RDW, 30% [104]); 1.45 in the 70- to 79-year age group (normal RDW, 23% [n = 182]; elevated RDW, 33% [n = 113]); and 1.59 in those ≥80 years (normal RDW, 29% [n = 168]; elevated RDW, 46% [n = 123]). RDW was associated with mortality risk in Cox proportional hazards models adjusted for age, D-dimer (dimerized plasmin fragment D) level, absolute lymphocyte count, and common comorbidities such as diabetes and hypertension (hazard ratio of 1.09 per 0.5% RDW increase and 2.01 for an RDW >14.5% vs ≤14.5%; P < .001). Patients whose RDW increased during hospitalization had higher mortality compared with those whose RDW did not change; for those with normal RDW, mortality increased from 6% to 24%, and for those with an elevated RDW at admission, mortality increased from 22% to 40%. Conclusions and Relevance: Elevated RDW at the time of hospital admission and an increase in RDW during hospitalization were associated with increased mortality risk for patients with COVID-19 who received treatment at 4 hospitals in a large academic medical center network.


Assuntos
Infecções por Coronavirus/mortalidade , Índices de Eritrócitos , Eritrócitos , Hospitalização , Pneumonia Viral/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Biomarcadores/sangue , Boston/epidemiologia , Coronavirus , Infecções por Coronavirus/sangue , Feminino , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Admissão do Paciente , Pneumonia Viral/sangue , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Síndrome Respiratória Aguda Grave
2.
PLoS Pathog ; 16(8): e1008131, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866196

RESUMO

Invasion of hepatocytes by Plasmodium sporozoites initiates the pre-erythrocytic step of a malaria infection. Subsequent development of the parasite within hepatocytes and exit from them is essential for starting the disease-causing erythrocytic cycle. Identification of signaling pathways that operate in pre-erythrocytic stages provides insight into a critical step of infection and potential targets for chemoprotection from malaria. We demonstrate that P. berghei homologs of Calcium Dependent Protein Kinase 1 (CDPK1), CDPK4 and CDPK5 play overlapping but distinct roles in sporozoite invasion and parasite egress from hepatocytes. All three kinases are expressed in sporozoites. All three are required for optimal motility of sporozoites and consequently their invasion of hepatocytes. Increased cGMP can compensate for the functional loss of CDPK1 and CDPK5 during sporozoite invasion but cannot overcome loss of CDPK4. CDPK1 and CDPK5 expression is downregulated after sporozoite invasion. CDPK5 reappears in a subset of late stage liver stages and is present in all merosomes. Chemical inhibition of CDPK4 and depletion of CDPK5 in liver stages implicate these kinases in the formation and/or release of merosomes from mature liver stages. Furthermore, depletion of CDPK5 in merosomes significantly delays initiation of the erythrocytic cycle without affecting infectivity of hepatic merozoites. These data suggest that CDPK5 may be required for the rupture of merosomes. Our work provides evidence that sporozoite invasion requires CDPK1 and CDPK5, and suggests that CDPK5 participates in the release of hepatic merozoites.


Assuntos
Regulação para Baixo , Regulação Enzimológica da Expressão Gênica , Malária/epidemiologia , Merozoítos/enzimologia , Plasmodium berghei/enzimologia , Proteínas Quinases/biossíntese , Proteínas de Protozoários/biossíntese , Esporozoítos/enzimologia , Animais , Eritrócitos/enzimologia , Eritrócitos/parasitologia , Feminino , Células Hep G2 , Humanos , Fígado/enzimologia , Fígado/parasitologia , Malária/patologia , Camundongos
3.
Einstein (Sao Paulo) ; 18: eAO5446, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32935828

RESUMO

OBJECTIVE: To assess the level of knowledge of emergency pediatricians on red blood cell transfusions and their reactions. METHODS: Written survey with emergency pediatricians from a pediatric hospital. RESULTS: Less than 20% of pediatricians showed appropriate knowledge on prescribing red blood cells and recognition of transfusion reactions. There was no significant statistical regarding time since graduation and blood transfusion classes in undergraduate studies or during medical residency. CONCLUSION: Pediatricians have insufficient knowledge about red blood cell transfusions and recognition of transfusion reactions.


Assuntos
Transfusão de Eritrócitos , Prescrições/estatística & dados numéricos , Reação Transfusional , Criança , Eritrócitos , Humanos , Pediatras
4.
BMC Pulm Med ; 20(1): 246, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938454

RESUMO

BACKGROUND: Myospherulosis develops as the result of a reaction between exogenous lipids and red blood cells (RBC) of the patient, being the latter injured when perceived as a foreign body by the immune system, triggering an intense inflammatory response. CASE PRESENTATION: A 63-year-old man with a history of dyslipidemia, Barret's esophagus, and coronary disease, who was taken to thoracoscopy and left inferior lobectomy due to the presence of a pulmonary mass. A primary pulmonary adenocarcinoma was diagnosed. On follow up a PET-CT was performed, in which a metabolically active lesion was described adjacent to the prior lobectomy, suggesting a local relapse. EBUS-TBNA was then performed, obtaining a sample from which histopathological pattern compatible with myospherulosis was obtained. CONCLUSIONS: Although it is a rare entity, myospherulosis has a well-defined morphological pattern. By not recognizing myospherulosis as a benign lesion, a patient's risk of invasive cancer can be overestimated. It is a phenomenon found with increasing frequency and has been reported in different tissues, however, this is the first report in the literature of myospherulosis of the lung. Greater awareness is required regarding the existence of this phenomenon.


Assuntos
Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Eritrócitos , Granuloma/patologia , Lipídeos , Pneumopatias/patologia , Brônquios , Humanos , Masculino , Pessoa de Meia-Idade
5.
Eur Rev Med Pharmacol Sci ; 24(16): 8585-8591, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32894566

RESUMO

Some surface proteins of the newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can bind to the hemoglobin molecule of an erythrocyte, which leads to the destruction of the structure of the heme and the release of harmful iron ions to the bloodstream. The degradation of hemoglobin results in the impairment of oxygen-carrying capacity of the blood, and the accumulation of free iron enhances the production of reactive oxygen species. Both events can lead to the development of oxidative stress. In this case, oxidative damage to the lungs leads then to the injuries of all other tissues and organs. The use of uridine, which preserves the structure of pulmonary alveoli and the air-blood barrier of the lungs in the course of experimental severe hypoxia, and dihydroquercetin, an effective free radical scavenger, is promising for the treatment of COVID-19. These drugs can also be used for the recovery of the body after the severe disease.


Assuntos
Infecções por Coronavirus/patologia , Estresse Oxidativo , Pneumonia Viral/patologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Eritrócitos/citologia , Eritrócitos/metabolismo , Eritrócitos/virologia , Depuradores de Radicais Livres/farmacologia , Depuradores de Radicais Livres/uso terapêutico , Hemoglobinas/metabolismo , Humanos , Estresse Oxidativo/efeitos dos fármacos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/fisiologia , Quercetina/análogos & derivados , Quercetina/farmacologia , Quercetina/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Uridina/farmacologia , Uridina/uso terapêutico
6.
Rev Lat Am Enfermagem ; 28: e3337, 2020.
Artigo em Português, Espanhol, Inglês | MEDLINE | ID: mdl-32876294

RESUMO

OBJECTIVE: to determine the microbiological characteristics of the red blood cells obtained with the cell saver in heart surgery patients on an extra-body circuit. METHOD: a cross-sectional and descriptive study conducted with 358 patients scheduled for heart surgery where the saver was used. Sociodemographic variables were collected, as well as from the saver and of the microbial identification in the re-infusion bag proceeding from the cell saver. Informed consent performed. RESULTS: of the 170 GRAM+ bacteria isolations, the most frequent species were Staphylococcus epidermidis in 69% (n=138) of the cases and Streptococcus sanguinis with a report of 10% (n=20). Significant differences were found in the Staphylococcus epidermidis strain in patients with a Body Mass Index ≥25 (p=0.002) submitted to valve surgery (p=0.001). Vancomycin was the antimicrobial which resisted the Staphylococcus epidermidis strain with a minimum inhibitory concentration of >16 µg/ml. CONCLUSION: the microbiological characteristics of the red blood cells obtained after processing autologic blood recovered with the cell saver during heart surgery are of GRAM+ bacterial origin, the most isolated species being Staphylococcus epidermidis. Consequently, in order to reduce the presence of these GRAM+ cocci, an antibiotic should be added to the cell saver reservoir, according to a previously established protocol.


Assuntos
Bacteriemia/epidemiologia , Procedimentos Cirúrgicos Cardíacos , Estudos Transversais , Eritrócitos , Humanos , Testes de Sensibilidade Microbiana
7.
Nat Commun ; 11(1): 4015, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782246

RESUMO

Intracellular pathogens mobilize host signaling pathways of their host cell to promote their own survival. Evidence is emerging that signal transduction elements are activated in a-nucleated erythrocytes in response to infection with malaria parasites, but the extent of this phenomenon remains unknown. Here, we fill this knowledge gap through a comprehensive and dynamic assessment of host erythrocyte signaling during infection with Plasmodium falciparum. We used arrays of 878 antibodies directed against human signaling proteins to interrogate the activation status of host erythrocyte phospho-signaling pathways at three blood stages of parasite asexual development. This analysis reveals a dynamic modulation of many host signalling proteins across parasite development. Here we focus on the hepatocyte growth factor receptor (c-MET) and the MAP kinase pathway component B-Raf, providing a proof of concept that human signaling kinases identified as activated by malaria infection represent attractive targets for antimalarial intervention.


Assuntos
Antimaláricos/farmacologia , Eritrócitos/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Eritrócitos/parasitologia , Interações Hospedeiro-Parasita , Humanos , Concentração Inibidora 50 , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Fosforilação/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/metabolismo , Plasmodium falciparum/fisiologia , Análise Serial de Proteínas , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Nat Commun ; 11(1): 3825, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732874

RESUMO

The malaria parasite interfaces with its host erythrocyte (RBC) using a unique organelle, the parasitophorous vacuole (PV). The mechanism(s) are obscure by which its limiting membrane, the parasitophorous vacuolar membrane (PVM), collaborates with the parasite plasma membrane (PPM) to support the transport of proteins, lipids, nutrients, and metabolites between the cytoplasm of the parasite and the cytoplasm of the RBC. Here, we demonstrate that the PV has structure characterized by micrometer-sized regions of especially close apposition between the PVM and the PPM. To determine if these contact sites are involved in any sort of transport, we localize the PVM nutrient-permeable and protein export channel EXP2, as well as the PPM lipid transporter PfNCR1. We find that EXP2 is excluded from, but PfNCR1 is included within these regions of close apposition. We conclude that the host-parasite interface is structured to segregate those transporters of hydrophilic and hydrophobic substrates.


Assuntos
Lipídeos , Malária Falciparum/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/metabolismo , Transporte Biológico , Membrana Celular/metabolismo , Citoplasma/metabolismo , Citoplasma/parasitologia , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Interações Hospedeiro-Parasita , Humanos , Membranas Intracelulares/metabolismo , Membranas Intracelulares/parasitologia , Malária Falciparum/parasitologia , Plasmodium falciparum/fisiologia , Transporte Proteico , Vacúolos/metabolismo , Vacúolos/parasitologia
9.
PLoS Pathog ; 16(8): e1008230, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797076

RESUMO

Neutrophil extracellular traps (NETs) evolved as a unique effector mechanism contributing to resistance against infection that can also promote tissue damage in inflammatory conditions. Malaria infection can trigger NET release, but the mechanisms and consequences of NET formation in this context remain poorly characterized. Here we show that patients suffering from severe malaria had increased amounts of circulating DNA and increased neutrophil elastase (NE) levels in plasma. We used cultured erythrocytes and isolated human neutrophils to show that Plasmodium-infected red blood cells release macrophage migration inhibitory factor (MIF), which in turn caused NET formation by neutrophils in a mechanism dependent on the C-X-C chemokine receptor type 4 (CXCR4). NET production was dependent on histone citrullination by peptidyl arginine deiminase-4 (PAD4) and independent of reactive oxygen species (ROS), myeloperoxidase (MPO) or NE. In vitro, NETs functioned to restrain parasite dissemination in a mechanism dependent on MPO and NE activities. Finally, C57/B6 mice infected with P. berghei ANKA, a well-established model of cerebral malaria, presented high amounts of circulating DNA, while treatment with DNAse increased parasitemia and accelerated mortality, indicating a role for NETs in resistance against Plasmodium infection.


Assuntos
Eritrócitos/imunologia , Armadilhas Extracelulares/imunologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Malária/imunologia , Neutrófilos/imunologia , Plasmodium/imunologia , Receptores CXCR4/metabolismo , Animais , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Armadilhas Extracelulares/metabolismo , Armadilhas Extracelulares/parasitologia , Humanos , Malária/metabolismo , Malária/parasitologia , Malária/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Neutrófilos/parasitologia , Parasitemia/imunologia , Parasitemia/metabolismo , Parasitemia/parasitologia , Parasitemia/patologia
10.
Beijing Da Xue Xue Bao Yi Xue Ban ; 52(4): 750-754, 2020 Aug 18.
Artigo em Chinês | MEDLINE | ID: mdl-32773814

RESUMO

OBJECTIVE: To compare the blood parameters related to erythrocyte and platelet between baseline and 3 months after initial periodontal therapy in patients with both type 2 diabetes mellitus and chronic periodontitis (DM-P). METHODS: According to the International Symposium on Classification of Periodontal Diseases and Conditions in 1999 and the diagnostic criteria of type 2 diabetes mellitus proposed by the World Health Organization in 1999, 35 patients with DM-P were recruited. All the participants received initial periodontal therapy, including oral hygiene instruction, scaling, and root planning provided by one senior periodontist. Original diet, exercise, and medication for blood glucose control were unchanged for all the participants. At baseline and 3 months after initial periodontal therapy, the clinical periodontal parameters, including probing depth (PD), bleeding index (BI) and clinical attachment loss (CAL); erythrocyte-related indexes, including red blood cell (RBC) count, hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), RBC volume distribution width (RDW); platelet-related indexes, including platelet (PLT) count, mean platelet volume (MPV), platelet distribution width (PDW), plateletocrit (PCT) were measured and compared. RESULTS: Compared with baseline, the periodontal parameters, including PD [(3.370±0.601) mm vs. (2.729±0.431) mm], BI [2.160 (1.550~3.410) vs. 1.420 (1.000~2.970)] and CAL [(3.307±1.577) mm vs. (2.990±1.587) mm], were significantly reduced (P < 0.001) three months after the initial periodontal therapy; the erythrocyte-related indexes, including RBC count [(4.727±0.392)×1012/L vs. (4.825±0.394)×1012/L, P=0.010], HGB [(145.886±11.792) g/L vs. (149.200±12.979) g/L, P=0.007] and HCT [43.40% (37.50%~48.50%) vs. 43.80% (38.50%~53.20%), P=0.003], were significantly increased three months after the initial periodontal therapy; PLT count [(216.714±61.900)×109/L vs. (205.886±62.051)×109/L, P=0.016] was significantly reduced 3 months after the initial periodontal therapy. CONCLUSIONS: The initial periodontal therapy can significantly improve blood parameters related to RBC and PLT, which might decrease the risk of vascular complications in DM-P patients.


Assuntos
Periodontite Crônica , Diabetes Mellitus Tipo 2 , Plaquetas , Eritrócitos , Hematócrito , Humanos
14.
Sci Total Environ ; 737: 140304, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32783869

RESUMO

Despite the damaging effects of pesticides glyphosate (Gly), atrazine (Atra) and fipronil (Fip) on different organisms, the mutagenic, genotoxic and morphotoxic potential of testudine erythrocytes in freshwater remains unknown. Thus, the aim of the present study is to assess the toxicological potential of these compounds in Podocnemis expansa (Amazonian turtles) neonates from eggs artificially incubated in substrate at different concentrations of herbicides Gly and Atra and insecticide Fip. Micronucleus test and other nuclear abnormalities, as well as comet assay and morphometric measurements taken of models' circulating erythrocytes were used as toxicity biomarkers. Pups exposed to Gly (groups Gly-65 ppb and Gly-6500 ppb) were the ones recording the largest amount of nuclear abnormalities; erythrocytes with multilobulated, notched and displaced nucleus were mostly frequent in groups Atra-2 ppb and Gly -65 ppb. All treatments (Gly-6500 ppb, Atra-2 ppb, Atra-200 ppb, Fip-4 ppb and Fip-400 ppb), except for group Gly-65 ppb, led to decreased erythrocyte area, increased "nuclear area: erythrocyte area" ratio, as well as to decreased erythrocyte and erythrocyte nuclei circularity, which highlights the clear effect on the size and shape of these cells. On the other hand, the comet assay did not evidence any genotoxic effect caused by the assessed pesticides. This is a pioneer study on the mutagenic and morphotoxic potential of pesticides in P. expansa eclodides exposed in ovo to Gly, Atra and Fip; therefore, it is an insight on how these compounds can affect the health of these animals.


Assuntos
Atrazina , Praguicidas , Animais , Dano ao DNA , Eritrócitos/efeitos dos fármacos , Humanos , Recém-Nascido , Testes para Micronúcleos , Mutagênicos
15.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1307-1311, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798417

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of different types of red blood cell (RBC) transfusion and hormone therapy in patients with autoimmune hemolytic anemia (AIHA). METHODS: The clinical data and serological characteristics of 40 patients with AIHA treated in our hospital from 2014 to 2018 were collected and analyzed retrospectively. The efficacy and safety of different type of RBC transfusion and hormone therapy were evaluated according to the principle of minimally incompatible RBC transfusion after cross-matching. RESULTS: Among 40 patients with AIHA, the female cases were more than the male cases, the cases of secondary AIHA was more than cases of primary AIHA, and the warm autoantibodies were in the majority. 11 cases of AIHA underwent 26 times minimally incompatible red blood cell transfusions. The total effective rate was 46.2%, the partial efficiency was 23.1%, and total inefficiency was 30.8%. Among them, the same type of non-washing red blood cell group showed efficiency of 42.1%, partial effective rate of 21.1%, and inefficiency of 36.8%; the same type of washed red blood cell group showed efficiency of 57.1%, partial effective rate of 28.6%, and inefficiency of 14.3%. the infusion effects was not significanly different between the two groups, and no hemolytic transfusion reaction occurred. In the hormone-treated group, the complete remission rate was 15.2%, the partial remission rate was 63.6%, and the ineffective rate was 21.2%. Among them, the side effects appeared in 2 patients after using hormones. CONCLUSION: When AIHA patients need blood transfusion, use the same type of non-washed red blood cells or homologous washed cells is relatively safe, and the difference in efficacy is not significant. The partial remission of patients received hormone therapy is much higher than that of red blood cell transfusion, but the side effects easily happen.


Assuntos
Anemia Hemolítica Autoimune , Autoanticorpos , Transfusão de Sangue , Transfusão de Eritrócitos , Eritrócitos , Feminino , Humanos , Masculino , Estudos Retrospectivos
16.
Exp Parasitol ; 217: 107958, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32730769

RESUMO

Anaplasma marginale is the causative agent of the severe bovine anaplasmosis. The tick Rhipicephalus microplus is one of the main vectors of A. marginale in tropical and subtropical regions of the world. After the tick bite, the bacterium invades and proliferates within the bovine erythrocytes leading to anemia, impairment of milk production and weight loss. In addition, infection can cause abortion and high mortality in areas of enzootic instability. Immunization with live and inactivated vaccines are employed to control acute bovine anaplasmosis. However, they do not prevent persistent infection. Consequently, infected animals, even if immunized, are still reservoirs of the bacterium and contribute to its dissemination. Antimicrobials are largely employed for the prophylaxis of bovine anaplasmosis. However, they are often used in sublethal doses which may select pre-existing resistant bacteria and induce genetic or phenotypic variations. Therefore, we propose a new standardized in vitro assay to evaluate the susceptibility of A. marginale strains to different antimicrobials. This tool will help health professionals to choose the more adequate treatment for each herd which will prevent the selection and spread of resistant strains. For that, we initially evaluated the antimicrobial susceptibility of two field isolates of A. marginale (Jaboticabal and Palmeira) infecting bovines. The least susceptible strain (Jaboticabal) was used for the standardization of an antimicrobial assay using a culture of Ixodes scapularis-derived tick cell line, ISE6. Results showed that enrofloxacin (ENRO) at 0.25, 1 or 4 µg/mL and oxytetracycline (OTC) at 4 or 16 µg/mL are the most efficient treatments, followed by OTC at 1 µg/mL and imidocarb dipropionate (IMD) at 1 or 4 µg/mL. In addition, this proposed tool has technical advantages compared to the previously established bovine erythrocyte culture. Thereby, it may be used to guide cattle farmers to the correct use of antimicrobials. The choice of the most suitable antimicrobial is essential to eliminate persistent infections, prevent the spread of resistant strains and help controlling of bovine anaplasmosis.


Assuntos
Anaplasma marginale/efeitos dos fármacos , Anaplasmose/prevenção & controle , Antibacterianos/farmacologia , Vetores Aracnídeos/citologia , Doenças dos Bovinos/prevenção & controle , Rhipicephalus/citologia , Anaplasmose/tratamento farmacológico , Anaplasmose/microbiologia , Animais , Antibacterianos/uso terapêutico , Vetores Aracnídeos/parasitologia , Brasil , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Doenças dos Bovinos/microbiologia , Linhagem Celular , Enrofloxacina/farmacologia , Eritrócitos/microbiologia , Imidocarbo/análogos & derivados , Imidocarbo/farmacologia , Imidocarbo/uso terapêutico , Masculino , Testes de Sensibilidade Microbiana , Oxitetraciclina/farmacologia , Oxitetraciclina/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Rhipicephalus/parasitologia
17.
PLoS Comput Biol ; 16(7): e1008069, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32716940

RESUMO

Nitric oxide (NO) is a gaseous signaling molecule that plays an important role in neurovascular coupling. NO produced by neurons diffuses into the smooth muscle surrounding cerebral arterioles, driving vasodilation. However, the rate of NO degradation in hemoglobin is orders of magnitude higher than in brain tissue, though how this might impact NO signaling dynamics is not completely understood. We used simulations to investigate how the spatial and temporal patterns of NO generation and degradation impacted dilation of a penetrating arteriole in cortex. We found that the spatial location of NO production and the size of the vessel both played an important role in determining its responsiveness to NO. The much higher rate of NO degradation and scavenging of NO in the blood relative to the tissue drove emergent vascular dynamics. Large vasodilation events could be followed by post-stimulus constrictions driven by the increased degradation of NO by the blood, and vasomotion-like 0.1-0.3 Hz oscillations could also be generated. We found that these dynamics could be enhanced by elevation of free hemoglobin in the plasma, which occurs in diseases such as malaria and sickle cell anemia, or following blood transfusions. Finally, we show that changes in blood flow during hypoxia or hyperoxia could be explained by altered NO degradation in the parenchyma. Our simulations suggest that many common vascular dynamics may be emergent phenomena generated by NO degradation by the blood or parenchyma.


Assuntos
Encéfalo/fisiologia , Circulação Cerebrovascular , Óxido Nítrico/metabolismo , Anemia Falciforme/fisiopatologia , Arteríolas , Transfusão de Sangue , Sistema Livre de Células , Simulação por Computador , Difusão , Células Endoteliais/metabolismo , Eritrócitos/metabolismo , Hemodinâmica , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Malária/fisiopatologia , Mitocôndrias/metabolismo , Músculo Liso/metabolismo , Oscilometria , Distribuição de Poisson , Transdução de Sinais , Vasodilatação
18.
PLoS One ; 15(7): e0236375, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726331

RESUMO

BACKGROUND: Malaria in pregnancy causes maternal, fetal and neonatal morbidity and mortality, and maternal innate immune responses are implicated in pathogenesis of these complications. The effects of malaria exposure and obstetric and demographic factors on the early maternal immune response are poorly understood. METHODS: Peripheral blood mononuclear cell responses to Plasmodium falciparum-infected erythrocytes and phytohemagglutinin were compared between pregnant women from Papua New Guinea (malaria-exposed) with and without current malaria infection and from Australia (unexposed). Elicited levels of inflammatory cytokines at 48 h and 24 h (interferon γ, IFN-γ only) and the cellular sources of IFN-γ were analysed. RESULTS: Among Papua New Guinean women, microscopic malaria at enrolment did not alter peripheral blood mononuclear cell responses. Compared to samples from Australia, cells from Papua New Guinean women secreted more inflammatory cytokines tumor necrosis factor-α, interleukin 1ß, interleukin 6 and IFN-γ; p<0.001 for all assays, and more natural killer cells produced IFN-γ in response to infected erythrocytes and phytohemagglutinin. In both populations, cytokine responses were not affected by gravidity, except that in the Papua New Guinean cohort multigravid women had higher IFN-γ secretion at 24 h (p = 0.029) and an increased proportion of IFN-γ+ Vδ2 γδ T cells (p = 0.003). Cytokine levels elicited by a pregnancy malaria-specific CSA binding parasite line, CS2, were broadly similar to those elicited by CD36-binding line P6A1. CONCLUSIONS: Geographic location and, to some extent, gravidity influence maternal innate immunity to malaria.


Assuntos
Imunidade Inata/genética , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Complicações Parasitárias na Gravidez/imunologia , Adolescente , Adulto , Austrália/epidemiologia , Antígenos CD36/genética , Eritrócitos/imunologia , Eritrócitos/parasitologia , Eritrócitos/patologia , Feminino , Número de Gestações/imunologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-6/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/parasitologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/parasitologia , Leucócitos Mononucleares/patologia , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Pessoa de Meia-Idade , Papua Nova Guiné/epidemiologia , Plasmodium falciparum/patogenicidade , Gravidez , Complicações Parasitárias na Gravidez/parasitologia , Complicações Parasitárias na Gravidez/patologia , Linfócitos T/imunologia , Linfócitos T/parasitologia , Adulto Jovem
19.
Proc Natl Acad Sci U S A ; 117(29): 17041-17048, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32632001

RESUMO

A central task in developmental biology is to learn the sequence of fate decisions that leads to each mature cell type in a tissue or organism. Recently, clonal labeling of cells using DNA barcodes has emerged as a powerful approach for identifying cells that share a common ancestry of fate decisions. Here we explore the idea that stochasticity of cell fate choice during tissue development could be harnessed to read out lineage relationships after a single step of clonal barcoding. By considering a generalized multitype branching process, we determine the conditions under which the final distribution of barcodes over observed cell types encodes their bona fide lineage relationships. We then propose a method for inferring the order of fate decisions. Our theory predicts a set of symmetries of barcode covariance that serves as a consistency check for the validity of the method. We show that broken symmetries may be used to detect multiple paths of differentiation to the same cell types. We provide computational tools for general use. When applied to barcoding data in hematopoiesis, these tools reconstruct the classical hematopoietic hierarchy and detect couplings between monocytes and dendritic cells and between erythrocytes and basophils that suggest multiple pathways of differentiation for these lineages.


Assuntos
Linhagem da Célula , Código de Barras de DNA Taxonômico/métodos , Animais , Linhagem da Célula/genética , Linhagem da Célula/fisiologia , Árvores de Decisões , Células Dendríticas/citologia , Eritrócitos/citologia , Hematopoese/genética , Hematopoese/fisiologia , Leucócitos/citologia , Modelos Biológicos , Biologia de Sistemas
20.
Proc Natl Acad Sci U S A ; 117(30): 17727-17736, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32665441

RESUMO

Erythrocytes naturally capture certain bacterial pathogens in circulation, kill them through oxidative stress, and present them to the antigen-presenting cells (APCs) in the spleen. By leveraging this innate immune function of erythrocytes, we developed erythrocyte-driven immune targeting (EDIT), which presents nanoparticles from the surface of erythrocytes to the APCs in the spleen. Antigenic nanoparticles were adsorbed on the erythrocyte surface. By engineering the number density of adsorbed nanoparticles, (i.e., the number of nanoparticles loaded per erythrocyte), they were predominantly delivered to the spleen rather than lungs, which is conventionally the target of erythrocyte-mediated delivery systems. Presentation of erythrocyte-delivered nanoparticles to the spleen led to improved antibody response against the antigen, higher central memory T cell response, and lower regulatory T cell response, compared with controls. Enhanced immune response slowed down tumor progression in a prophylaxis model. These findings suggest that EDIT is an effective strategy to enhance systemic immunity.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos/imunologia , Eritrócitos/imunologia , Imunização , Animais , Formação de Anticorpos/imunologia , Antígenos/química , Biomimética , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Feminino , Humanos , Camundongos , Nanopartículas , Baço/imunologia , Vacinação , Vacinas , Ensaios Antitumorais Modelo de Xenoenxerto
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