RESUMO
Innate immunity, and more specifically the complement system, has arised renewed interest in the medical field in recent years. Many innovative complement-inhibiting drugs have appeared, acting at various levels of the complement cascade. These drugs have made it possible to transform poor prognosis of certain diseases. Many of them are currently being tested in clinical trials for various indications. Many questions appear about their optimal use and their future indications. This article recalls the fundamental role of the complement system in the human organism. It then discusses the diseases in which the complement is involved on the pathophysiological level. The third part details the different classes of complement inhibitors and briefly recalls the indications for which these treatments seem the most promising. Finally, we end with a discussion that highlights the different aspects and questions induced by these new treatments.
Assuntos
Inativadores do Complemento , Imunidade Inata , Humanos , Inativadores do Complemento/farmacologia , Inativadores do Complemento/uso terapêuticoAssuntos
COVID-19 , Transplante de Células-Tronco Hematopoéticas , Criopreservação , Humanos , Pandemias , SARS-CoV-2RESUMO
This study aimed to describe the contamination of sink drains (SDs) with carbapenemase-producing Enterobacterales (CPE) in three intensive care units (ICUs), and to assess the risk of transmission to hospitalized patients. All SDs were sampled monthly for CPE screening by culture. Rectal screening for CPE carriage was conducted weekly for hospitalized patients. CPE were isolated from 22% of SD samples. Some SDs remained colonized with the same strain for several months. No CPE acquisition occurred among hospitalized patients during the study. Certain strategies, such as systematic sampling of SDs in ICUs for screening for contamination by CPE, should be discouraged apart from during outbreaks.
Assuntos
Infecções por Enterobacteriaceae , beta-Lactamases , Proteínas de Bactérias , Surtos de Doenças , Infecções por Enterobacteriaceae/diagnóstico , Infecções por Enterobacteriaceae/epidemiologia , Infecções por Enterobacteriaceae/prevenção & controle , Humanos , Unidades de Terapia IntensivaRESUMO
OBJECTIVE: To compare the minimum inhibitory concentrations (MIC) of the ceftazidime-avibactam (CZA) combination versus ceftazidime alone (TZ) for Stenotrophomonas maltophilia. PATIENTS AND METHODS: MIC comparison was performed by E-tests. We assumed that CZA was more effective in vitro than TZ alone when CZA led to a category change from "Resistant" with TZ alone to "Susceptible" or "Intermediate" with CZA, or if the MIC of CZA was at least 4-fold lower than the MIC of TZ for TZ-susceptible isolates. RESULTS: For the 54 clinical isolates included in the study, CZA showed better results in terms of the proportion of susceptible isolates (66.7% vs. 38.9%, P<0.01), MIC50 (2µg/mL vs. 12µg/mL, P<0.05), and MIC distribution. According to our definition, CZA was also more effective in vitro than TZ alone for 50% of the isolates. CONCLUSION: Using CZA for empirical treatments in severe or polymicrobial infections with S. maltophilia seems appropriate.
Assuntos
Compostos Azabicíclicos/farmacologia , Ceftazidima/farmacologia , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Stenotrophomonas maltophilia/efeitos dos fármacos , Ácidos Clavulânicos/farmacologia , Fibrose Cística/complicações , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla , Humanos , Testes de Sensibilidade Microbiana , Estudos Multicêntricos como Assunto , Ticarcilina/farmacologiaRESUMO
Sink drains of six intensive care units (ICUs) were sampled for screening contamination with extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBLE). A high prevalence (59.4%) of sink drain contamination was observed. Analysing the data by ICU, the ratio 'number of ESBLE species isolated in sink drains/total number of sink drains sampled' was highly correlated (Spearman coefficient: 0.87; P = 0.02) with the ratio 'number of hospitalization days for patients with ESBLE carriage identified within the preceding year/total number of hospitalization days within the preceding year'. Concurrently, the distribution of ESBLE species differed significantly between patients and sink drains.
Assuntos
Infecções por Enterobacteriaceae/microbiologia , Enterobacteriaceae/enzimologia , Unidades de Terapia Intensiva/estatística & dados numéricos , beta-Lactamases/genética , Enterobacteriáceas Resistentes a Carbapenêmicos , Portador Sadio/epidemiologia , Citrobacter/isolamento & purificação , Infecção Hospitalar/epidemiologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Enterobacteriaceae/isolamento & purificação , Infecções por Enterobacteriaceae/epidemiologia , França/epidemiologia , Humanos , Klebsiella pneumoniae/isolamento & purificação , Inquéritos e Questionários , beta-Lactamases/efeitos dos fármacosAssuntos
Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Microbiologia Ambiental , Unidades de Terapia Intensiva , Klebsiella pneumoniae/isolamento & purificação , Técnicas Bacteriológicas , Enterobacteriáceas Resistentes a Carbapenêmicos/classificação , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Surtos de Doenças , Eletroforese em Gel de Campo Pulsado , França , Hospitais Universitários , Humanos , Infecções por Klebsiella/epidemiologia , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/classificação , Klebsiella pneumoniae/genética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
CAR-T cells are genetically modified human lymphocytes and gene therapy medicinal products. They are developed to treat cancers that express a membrane antigen targeted by the CAR. The FDA approved the two first-in-class medicinal products in 2017 and EMA in August 2018; both are autologous CAR-T cells targeting CD19 that is expressed at the surface of normal B-cells throughout their differentiation, and on B-cell lymphoid malignancies. Clinical efficacy was demonstrated for B-cell acute lymphoblastic leukemias, non-Hodgkin's lymphoma and chronic lymphocytic leukemia, although the marketing authorizations are less liberal in terms of indications. Manufacturing of these personalized treatments necessitates that a novel organization and supply chain be set in place, to ensure product preservation, patient safety and compliance with complex regulatory requirements. Side effects are commensurate with clinical efficacy and can be life-threatening: proper management imposes tight coordination between various specialists, particularly between hematologists and intensive care practitioners. High pricing for these treatments is part of a long-term trend for increasing costs of innovations in hematology and oncology; it questions the ability of healthcare systems to sustain their reimbursement.
Assuntos
Imunoterapia Adotiva , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Antígenos CD19/imunologia , Humanos , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologiaRESUMO
Essentials Neutrophil extracellular traps (NETs) are generated during deep vein thrombosis (DVT). The role of interferon γ (IFNγ) and natural killer (NK) cells in NET formation was studied. IFNγ promote venous thrombosis through NET formation. NK cell depletion reduces DVT. SUMMARY: Background Neutrophils contribute to venous thrombosis through the release of neutrophil extracellular traps (NETs), but the mechanism triggering their formation remains unclear. In vitro data show that interferon (IFN)-γ induces the formation of NETs. Objectives To determine whether IFN-γ and the transcription factor T-box expressed on T cells (Tbet) promote venous thrombosis through neutrophil activation. Methods Venous thrombosis was induced by flow restriction in the inferior vena cava in IFN-γ-/- , Tbet-/- or wild-type (WT) mice. After 48 h, thrombus size was measured by the use of high-frequency ultrasound. NET formation was determined by immunofluorescence. Results and Conclusions Thrombus formation was reduced in Tbet-/- and IFN-γ-/- mice, suggesting that Tbet/IFN-γ-expressing cells are required for venous thrombosis. The number of NETs formed during thrombosis was significantly lower in Tbet-/- and IFN-γ-/- mice. NET formation was also decreased in WT mice treated with an IFN-γ-blocking antibody. Injection of recombinant IFN-γ into IFN-γ-/- mice rescued the phenotype. Natural killer (NK) cells were specifically depleted prior to venous thrombosis induction. NK cell depletion results in decreased NET formation and smaller thrombi, suggesting that NK cells are required for thrombus development. In depleted mice, adoptive transfer of WT NK cells induced a similar thrombosis burden as in WT mice. In contrast, adoptive transfer of IFN-γ -/- NK cells resulted in thrombi similar in size to those in depleted mice. In vitro, we showed that WT neutrophils released fewer NETs when they were cocultured with IFN-γ-/- NK cells. This study demonstrates that NK cell-dependent IFN-γ production is crucial for thrombus development by promoting the formation of NETs by neutrophils.
Assuntos
Coagulação Sanguínea , Armadilhas Extracelulares/metabolismo , Células Matadoras Naturais/metabolismo , Neutrófilos/metabolismo , Veia Cava Inferior/metabolismo , Trombose Venosa/metabolismo , Animais , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Armadilhas Extracelulares/imunologia , Interferon gama/genética , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Transdução de Sinais , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Veia Cava Inferior/imunologia , Trombose Venosa/genética , Trombose Venosa/imunologiaRESUMO
This corrects the article DOI: 10.1038/bmt.2012.225.
RESUMO
OBJECTIVES: Prosthetic joint infections (PJI) are responsible for significant morbidity and mortality and their number continues to rise. Their management remains complex, especially the microbiological diagnosis. Besides 'homemade' tests developed by several teams, new molecular biology methods are now available with different analytical performance and usability. METHODS: We studied the performances of one of these tests: ITI® multiplex PCR (mPCR) by the Curetis® company and compared it to either 'optimized' culture or 16S rRNA PCR. We performed a retrospective multicentre study to assess the contributions of mPCR in the diagnosis of PJI. We randomly selected 484 intraoperative specimens among 1252 of various types (biopsy, bone, tissue around the prosthesis, synovial fluid) from 251 patients in seven different hospitals. Each sample was treated according to the recommendations of the manufacturer. RESULTS: In all, 154 out of 164 (93.9%) samples negative in culture were negative with the mPCR. Among the 276 positive samples in culture, 251 (90.9%) were monomicrobial, of which 119 (47.4%) were positive with the mPCR, and 25 (9.1%) were polymicrobial, of which 12 (48%) were positive with the mPCR. The concordance rate of mPCR with culture was 58.1% (53.6%-62.7%) and the concordance rate with 16S rRNA PCR was 70.1% (65.5%-74.6%). CONCLUSION: This new standardized molecular test showed a lack of detection when the bacterial inoculum was low (number of positive media per sample and number of colonies per media) but can be useful when patients have received antibiotic therapy previously.
Assuntos
Prótese Articular/microbiologia , Staphylococcus aureus Resistente à Meticilina/genética , Reação em Cadeia da Polimerase Multiplex/métodos , Infecções Relacionadas à Prótese/diagnóstico , Infecções Relacionadas à Prótese/microbiologia , Infecções Estafilocócicas/diagnóstico , Proteínas de Bactérias/genética , Humanos , Resistência a Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Proteínas de Ligação às Penicilinas/genética , Infecções Relacionadas à Prótese/mortalidade , RNA Ribossômico 16S/genética , Estudos Retrospectivos , Infecções Estafilocócicas/microbiologiaAssuntos
Discite/microbiologia , Infecções por Bactérias Gram-Positivas , Lactobacillus , Idoso de 80 Anos ou mais , Discite/diagnóstico , Discite/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/diagnóstico , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Humanos , MasculinoRESUMO
Breast cancer carrying BRCA mutation may be highly sensitive to DNA-damaging agents. We hypothesized a better outcome for BRCA-mutated (BRCA(mut)) metastatic breast cancer (MBC) patients receiving high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HDC AHSCT) versus unaffected BRCA (BRCA wild type; (BRCA(wt))) or patients without documented BRCA mutation (BRCA untested (BRCA(ut))). All female patients treated for MBC with AHSCT at Institut Paoli-Calmettes between 2003 and 2012 were included. BRCA(mut) and BRCA(wt) patients were identified from our institutional genetic database. Overall survival (OS) was the primary end point. A total of 235 patients were included. In all, 15 patients were BRCA(mut), 62 BRCA(wt) and 149 BRCA(ut). In multivariate analyses, the BRCA(mut) status was an independent prognostic factor for OS (hazard ratio (HR): 3.08, 95% confidence interval (CI): 1.10-8.64, P=0.0326) and PFS (HR: 2.52, 95% CI :1.29-4.91, P=0.0069). In this large series of MBC receiving HDC AHSCT, we report a highly favorable survival outcome in the subset of patients with documented germline BRCA mutations.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Adulto , Antineoplásicos/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Terapia Combinada , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Mutação , Metástase Neoplásica , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoAssuntos
Separação Celular/instrumentação , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucócitos Mononucleares/citologia , Manejo de Espécimes/métodos , Algoritmos , Antígenos CD34/metabolismo , Células Sanguíneas , Remoção de Componentes Sanguíneos , Separação Celular/métodos , Humanos , Transplante Autólogo , Transplante HomólogoRESUMO
BACKGROUND: Growth arrest-specific 6 (Gas6)-deficient mice are protected against venous thromboembolism (VTE), suggesting a role for Gas6 in this disorder. We previously demonstrated that Gas6 induces forkhead box O1 (FoxO-1) phosphorylation through the phosphoinositide 3-kinase-Akt pathway. FoxO-1 regulates the expression of vascular cell adhesion molecule-1 (VCAM-1), a molecule that has been implicated in VTE. OBJECTIVES: To assess the role of FoxO-1 in Gas6-dependent VCAM-1 expression. METHODS: Thrombin was used to stimulate endothelial cells (ECs). Wild-type (WT) and Gas6(-/-) ECs were transfected with small interfering RNA targeting Axl or FoxO-1, a luciferase-coupled plasmid containing the FoxO-1 consensus sequence, and a phosphorylation-resistant FoxO-1 mutant, or treated with an Akt inhibitor. VCAM-1 mRNA expression was measured by real time-qPCR. VCAM-1 protein expression and FoxO-1 and Akt phosphorylation were assessed by western blot analysis. FoxO-1 localization was assessed by immunofluorescence. Adhesion of bone marrow mononuclear cells (BM-MCs) on ECs was assessed by fluorescence. RESULTS AND CONCLUSIONS: Thrombin induces both VCAM-1 expression and FoxO-1 phosphorylation and nuclear exclusion in WT ECs only. Silencing of FoxO-1 enhances VCAM-1 expression in both WT and Gas6(-/-) ECs. Inhibition of Akt or FoxO-1 phosphorylation prevents VCAM-1 expression in WT ECs. These data show that Gas6 induces FoxO-1 phosphorylation, leading to derepression of VCAM-1 expression. BM-MC-EC adhesion is increased by thrombin in WT ECs. BM-MC-EC adhesion is further increased when FoxO-1 is silenced, but decreased when FoxO-1 phosphorylation is inhibited. These results demonstrate that the Gas6-FoxO-1 signaling axis plays an important role in VCAM-1 expression in the context of VTE by promoting BM-MC-EC adhesion.
Assuntos
Células Endoteliais/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Trombina/farmacologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Células da Medula Óssea/metabolismo , Adesão Celular , Células Cultivadas , Células Endoteliais/metabolismo , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Genótipo , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Fenótipo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Transfecção , Molécula 1 de Adesão de Célula Vascular/genética , Tromboembolia Venosa/genética , Tromboembolia Venosa/metabolismoRESUMO
We report the case of a 43-year-old man with a Mycoplasma hominis brain abscess occurring after a cranial trauma, which was identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The presence of colonies on classic blood agar plates and the use of MALDI-TOF MS, a valuable diagnostic tool that identified M. hominis due to its presence in the VITEK MS database, allowed the rapid diagnosis of this infection.
Assuntos
Abscesso Encefálico/diagnóstico , Infecções por Mycoplasma/diagnóstico , Mycoplasma hominis , Adulto , Humanos , Masculino , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizAssuntos
Neoplasias Hematológicas/terapia , Depleção Linfocítica/métodos , Linfócitos T/fisiologia , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Estudos de Coortes , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Irmãos , Doadores de Tecidos , Doadores não Relacionados , Adulto JovemRESUMO
In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. Literature and intra-laboratories studies suggest that attached segment is representative of cord blood unit (CBU). Nevertheless, some discrepancies have been observed when analyzing large data registries. To address these issues, we have listed recommendations to increase the standardization of segment processing and quality control (QC), information on units of measurement and specifications and action to be taken in case of out of specifications QC results on segment.