المؤلفون: Dafang Zhong, Xiuli Li, Cen Xie, Kan Zhong, Yifan Zhang, Xiaoyan Chen

المصدر: Antimicrobial Agents and Chemotherapy. 58:4153-4161

مصطلحات موضوعية: Adult, Male, medicine.medical_specialty, Organic anion transporter 1, Urinary system, Urine, Organic Anion Transporters, Sodium-Independent, Pharmacology, Kidney, Transfection, Cell Line, Young Adult, Organic Anion Transport Protein 1, Sulfate conjugate, Pharmacokinetics, Internal medicine, medicine, Humans, Pharmacology (medical), Renal Insufficiency, Infusions, Intravenous, Mechanisms of Action: Physiological Effects, biology, Probenecid, Chemistry, Kidney metabolism, Middle Aged, Anti-Bacterial Agents, HEK293 Cells, Infectious Diseases, Endocrinology, medicine.anatomical_structure, Nitroimidazoles, Area Under Curve, biology.protein, Female, Cimetidine, Protein Binding, medicine.drug

الوصف: Morinidazole is a novel 5-nitroimidazole antimicrobial drug that undergoes extensive metabolism in humans via N + -glucuronidation ( N + -glucuronide of S -morinidazole [M8-1] and N + -glucuronide of R -morinidazole [M8-2]) and sulfation (sulfate conjugate of morinidazole [M7]). Our objectives were to assess the effects of renal impairment on the pharmacokinetics (PK) of morinidazole and to elucidate the potential mechanisms. In this parallel-group study, healthy subjects and patients with severe renal impairment received an intravenous infusion of 500 mg of morinidazole. Plasma and urine samples were collected and analyzed. The areas under the plasma concentration-time curves (AUC) for M7, M8-1, and M8-2 were 15.1, 20.4, and 17.4 times higher, respectively, in patients with severe renal impairment than in healthy subjects, while the AUC for morinidazole was 1.5 times higher. The urinary recovery of the major metabolites was not significantly different between the two groups over 0 to 48 h, but the renal clearances of M7, M8-1, and M8-2 in patients were 85.3%, 92.5%, and 92.2% lower, respectively. In vitro transporter studies revealed that M7 is a substrate for organic anion transporter 1 (OAT1) and OAT3 ( K m = 28.6 and 54.0 μM, respectively). Only OAT3 transported M8-1 and M8-2. Morinidazole was not a substrate for the transporter-transfected cells examined. These results revealed that the function or activity of renal uptake transporters might be impaired in patients with severe renal impairment, which accounted for dramatically increased plasma exposure and reduced renal clearance of the conjugated metabolites of morinidazole, the substrates of renal transporters in patients. It will help clinicians to adjust the dose in patients with severe renal impairment and to predict possible transporter-based drug-drug interactions.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::09cfe9ff424dc5e8a387903141215b15Test
https://doi.org/10.1128/aac.02414-14Test

المؤلفون: Xi Huang, Minhao Wu, Meiyu Li, Yi Wang, Yongjian Wu, Dandan Li, Yuanqing Zhang, Qiuchan Deng, Jieying Pu

المصدر: Infection and Immunity. 84:56-66

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Phagocyte, Interleukin-1beta, Immunology, Caspase 1, Inflammation, Ubiquitin-Activating Enzymes, Biology, Autophagy-Related Protein 7, Microbiology, Cell Line, Young Adult, 03 medical and health sciences, Phagocytosis, NLR Family, Pyrin Domain-Containing 3 Protein, Autophagy, medicine, Humans, Macrophage, Secretion, RNA, Small Interfering, Macrophages, Membrane Proteins, Inflammasome, Bacterial Infections, Cell biology, CARD Signaling Adaptor Proteins, Cytoskeletal Proteins, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, Pseudomonas aeruginosa, Beclin-1, Female, RNA Interference, Parasitology, medicine.symptom, Apoptosis Regulatory Proteins, Carrier Proteins, Microtubule-Associated Proteins, medicine.drug

الوصف: Assembly of the inflammasome has recently been identified to be a critical event in the initiation of inflammation. However, its role in bacterial killing remains unclear. Our study demonstrates that Pseudomonas aeruginosa infection induces the assembly of the NLRP3 inflammasome and the sequential secretion of caspase1 and interleukin-1β (IL-1β) in human macrophages. More importantly, activation of the NLRP3 inflammasome reduces the killing of P. aeruginosa in human macrophages, without affecting the generation of antimicrobial peptides, reactive oxygen species, and nitric oxide. In addition, our results demonstrate that P. aeruginosa infection increases the amount of the LC3-II protein and triggers the formation of autophagosomes in human macrophages. The P. aeruginosa -induced autophagy was enhanced by overexpression of NLRP3, ASC, or caspase1 but was reduced by knockdown of these core molecules of the NLRP3 inflammasome. Treatment with IL-1β enhanced autophagy in human macrophages. More importantly, IL-1β decreased the macrophage-mediated killing of P. aeruginosa , whereas knockdown of ATG7 or Beclin1 restored the IL-1β-mediated suppression of bacterial killing. Collectively, our study explores a novel mechanism employed by P. aeruginosa to escape from phagocyte killing and may provide a better understanding of the interaction between P. aeruginosa and host immune cells, including macrophages.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7880516cae30510116866fdf19496a82Test
https://doi.org/10.1128/iai.00945-15Test

المؤلفون: Laura Ambra Nicolini, Chiara Orlandi, Andrea De Maria, Giancarlo Orofino, Lorenzo Moretta, Ena Wang, Emanuele Pontali, Chiara Dentone, Maria Libera Ascierto, Lucia Taramasso, Antonio Di Biagio, Francesco Marras, Francesco M. Marincola, Anna Casabianca, Federica Bozzano, Mauro Magnani

المصدر: Journal of Virology. 91

مصطلحات موضوعية: CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, Adoptive cell transfer, Cell, DNA, HIV-1, interferons, lentiviruses, natural killer cells, reservoir, HIV Infections, Virus Replication, Cohort Studies, Interferon gamma, biology, Middle Aged, Virus-Cell Interactions, Killer Cells, Natural, medicine.anatomical_structure, Lentivirus, Natural killer cells, Female, medicine.drug, Adult, DNA Copy Number Variations, Virus Integration, Immunology, Lentiviruses, Microbiology, Interferon-gamma, 03 medical and health sciences, Immune system, Virology, medicine, Humans, Reservoir, Natural Cytotoxicity Triggering Receptor 3, Interferon-gamma production, Natural Cytotoxicity Triggering Receptor 1, biology.organism_classification, 030104 developmental biology, Viral replication, Insect Science, DNA, Viral, Interferons

الوصف: The size of lentiviral DNA reservoirs reflects the effectiveness of immune responses against lentiviruses. So far, abundant information has been gathered on the control of HIV-1 replication. Understanding the innate mechanisms contributing to containment of the HIV DNA reservoir, however, are only partly clarified and are relevant to guiding interventions for reservoir containment or eradication. We studied the contribution of natural killer (NK) cell functional features in HIV patients controlling replication either spontaneously (HIV controllers [HIC]) or after progression and antiretroviral treatment (progressor patients [PP]). An inverse correlation between HIV DNA copy numbers (either total or integrated) in circulating CD4 + cells and NK cell function was observed. Induced interferon gamma (IFN-γ) production and NKp46/NKp30 activating receptor-induced expression correlated inversely with reservoir size. The correlation was present not only for a homogeneous cohort of HIC patients but also when PP were included in the analysis. Adaptive (NKG2C + CD57 + ) NK cell features were not associated with reservoir size. However, a distinct set of 370 differentially expressed transcripts was found to underlie functional differences in NK cells controlling HIV DNA reservoir size. In proof-of-principle in vitro experiments of CD4 + cell infection with HIV-1, purified NK cells with the above-mentioned functional/transcriptional features displayed 10- and 30-fold higher abilities to control HIV replication and DNA burdens in vitro , respectively, than those of other NK cells. Thus, NK cells with a specific functional and transcriptional signature contribute to control of the HIV reservoir in CD4 + cells. Their selection, expansion, and/or adoptive transfer may support strategies to eradicate HIV-1 infection or to safely deescalate antiretroviral treatment. IMPORTANCE The most relevant feature of HIV-1 infection is represented by its DNA reservoir size in the body, which guarantees lifelong infection and resumption of virus replication after antiretroviral treatment interruption. So far, there has been little success in the identification of factors contributing to HIV-1 reservoir containment. In this study, by studying quantitative total and integrated HIV-1 DNA levels and NK cells in HIV-1 patients with either progressive or nonprogressive disease, we observed that inducible IFN-γ and natural cytotoxicity receptor (NCR) expression in a specific subset of NK cells with a characteristic transcriptional signature represents a correlate for HIV-1 reservoir control. This represents an advance in our understanding of the mechanism(s) that controls the lentivirus reservoir. Monitoring, selection, expansion, and adoptive transfer of these NK cells may allow monitoring of treatment efficacy and the likelihood of reservoir control and may support protocols for HIV-1 eradication.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::02985b8db7053f0b3fc76a81983035d8Test
https://doi.org/10.1128/jvi.00647-17Test

المؤلفون: Ashley Shepard, James Nugent, Arlinda Baummer-Carr, Sean M. Stainton, Marguerite L. Monogue, David P. Nicolau, Joseph L. Kuti

مصطلحات موضوعية: 0301 basic medicine, Adult, Male, Microdialysis, medicine.medical_specialty, Tazobactam, Adolescent, 030106 microbiology, Cmax, Urology, Biological Availability, Penicillanic Acid, Microbial Sensitivity Tests, Clinical Therapeutics, Permeability, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, In vivo, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Pharmacology, Chemistry, Half-life, Middle Aged, Diabetic Foot, Surgery, Anti-Bacterial Agents, Cephalosporins, Infectious Diseases, medicine.anatomical_structure, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Area Under Curve, Ceftolozane, Female, Gram-Negative Bacterial Infections, Subcutaneous tissue, medicine.drug, Half-Life

الوصف: Ceftolozane-tazobactam displays potent activity against Gram-negative bacteria that can cause diabetic foot infections (DFI), making it an attractive treatment option when few alternatives exist. The pharmacokinetics and tissue penetration of ceftolozane-tazobactam at 1.5 g every 8 h (q8h) in patients ( n = 10) with DFI were compared with those in healthy volunteers ( n = 6) using in vivo microdialysis. In the patient participants, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: maximum concentration ( C max ), 55.2 μg/ml (range, 40.9 to 169.3 μg/ml); half-life ( t 1/2 ), 3.5 h (range, 2.3 to 4.7 h); and area under the concentration-time curve (AUC) from time zero to 8 h (AUC 0–8 ), 191.6 μg · h/ml (range, 147.1 to 286.6 μg · h/ml). The median AUC for tissue (AUC tissue ; where AUC tissue was the AUC 0–8 for tissue for ceftolozane)/AUC for plasma for each antibiotic corrected by the fraction of free drug ( f AUC plasma ) was 0.75 (range, 0.35 to 1.00), resulting in a mean free time above 4 μg/ml (the Pseudomonas aeruginosa susceptibility breakpoint) in tissue of 99.8% (range, 87.5 to 100%). In the patient participants, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: C max , 14.2 μg/ml (range, 7.6 to 64.2 μg/ml); t 1/2 , 2.0 h (range, 0.7 to 2.4 h); and AUC 0–8 , 27.1 μg · h/ml (range, 15.0 to 70.0 μg · h/ml). The AUC tissue (where AUC tissue was the AUC from time zero to the time of the last measureable concentration in tissue for tazobactam)/ f AUC plasma for tazobactam was 1.18 (range, 0.54 to 1.44). In the healthy volunteers, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: C max , 91.5 μg/ml (range, 65.7 to 110.7 μg/ml); t 1/2 , 1.9 h (range, 1.6 to 2.1 h); and AUC 0–8 , 191.3 μg · h/ml (range, 118.1 to 274.3 μg · h/ml). The median AUC tissue / f AUC plasma was 0.87 (range, 0.54 to 2.20), resulting in a mean free time above 4 μg/ml in tissue of 93.8% (range, 87.5 to 100%). In the healthy volunteers, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: C max , 17.5 μg/ml (range, 15.4 to 27.3 μg/ml); t 1/2 , 0.7 h (range, 0.6 to 0.8 h); and AUC 0–8 , 22.2 μg · h/ml (range, 19.2 to 36.4 μg · h/ml). The AUC tissue / f AUC plasma for tazobactam was 0.85 (range, 0.63 to 2.10). Both ceftolozane and tazobactam penetrated into subcutaneous tissue with exposures similar to those of free drug in plasma in both patients with DFI and healthy volunteers. These data suggest that ceftolozane-tazobactam at 1.5 g q8h can achieve the optimal exposure with activity against susceptible Gram-negative pathogens in the tissue of patients with DFI. (This study has been registered at ClinicalTrials.gov under identifier NCT02620774.)

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::268a55c72e6ed2e4295afdf25b8b27b6Test
https://europepmc.org/articles/PMC5700352Test/

المؤلفون: Veronica D. Gonzalez, Alex Lund Laursen, Karolin Falconer, Nina Weis, Johan K. Sandberg, Annette Alaeus, Kim Blom, Birgitte Mørn, Olle Reichard

المصدر: BASE-Bielefeld Academic Search Engine

مصطلحات موضوعية: Adult, Male, T-Lymphocytes, T cell, Hepatitis C virus, Immunology, Alpha interferon, HIV Infections, Hepacivirus, Biology, Lymphocyte Activation, medicine.disease_cause, Antiviral Agents, Microbiology, Virus, Young Adult, T-Lymphocyte Subsets, Interferon, Antiretroviral Therapy, Highly Active, Virology, Ribavirin, medicine, Humans, Interferon alfa, Interferon-alpha, virus diseases, Hepatitis C, Chronic, Middle Aged, Viral Load, medicine.disease, ADP-ribosyl Cyclase 1, digestive system diseases, medicine.anatomical_structure, Insect Science, Disease Progression, HIV-1, Coinfection, Pathogenesis and Immunity, Female, Viral load, medicine.drug

الوصف: Chronic immune activation is a driver of human immunodeficiency virus type 1 (HIV-1) disease progression. Here, we describe that subjects with chronic hepatitis C virus (HCV)/HIV-1 coinfection display sharply elevated immune activation as determined by CD38 expression in T cells. This occurs, despite effective antiretroviral therapy, in both CD8 and CD4 T cells and is more pronounced than in the appropriate monoinfected control groups. Interestingly, the suppression of HCV by pegylated alpha interferon and ribavirin treatment reduces activation. High HCV loads and elevated levels of chronic immune activation may contribute to the high rates of viral disease progression observed in HCV/HIV-1-coinfected patients.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cd7aceb0b1c29eac84c07b2e7647feaeTest
https://doi.org/10.1128/jvi.01211-09Test

المؤلفون: Peter Schneebergen, Susan V. Snijders, Jan L. Nouwen, Marjan Koolen, Henri A. Verbrugh, Alex van Belkum, Jeroen Schouten, Jolanda Maaskant

المساهمون: Medical Microbiology & Infectious Diseases, Medical Oncology

المصدر: Journal of Clinical Microbiology, 44, 6, pp. 2233-6
Journal of Clinical Microbiology, 44(6), 2233-2236. American Society for Microbiology
Journal of Clinical Microbiology, 44, 2233-6

مصطلحات موضوعية: Microbiology (medical), Adult, Male, medicine.medical_specialty, Staphylococcus aureus, Adolescent, Epidemiology, medicine.medical_treatment, education, Nose, medicine.disease_cause, Staphylococcal infections, Peritoneal dialysis, Peritoneal Dialysis, Continuous Ambulatory, Risk Factors, Internal medicine, medicine, Humans, Aged, business.industry, Catheter exit site, Middle Aged, Staphylococcal Infections, medicine.disease, Surgery, Pathogenesis and modulation of inflammation [N4i 1], medicine.anatomical_structure, Carriage, Carrier State, Vancomycin, Female, Microbial pathogenesis and host defense [UMCN 4.1], business, medicine.drug

الوصف: The epidemiology and risks of Staphylococcus aureus carriage in continuous peritoneal dialysis (CPD) patients was studied in a single tertiary-care institution. On outpatient visits samples for culture were routinely taken prospectively from the CPD catheter exit site and the vestibulum nasi. Seventy-five patients with at least one culture positive for S. aureus in this period were included: 43 had genotypically identical S. aureus strains in over 80% of the cultures and were classified as persistent carriers; 32 were intermittent carriers. Persistent carriage was associated with a threefold higher risk for CPD-related infections and sixfold higher rates of vancomycin consumption compared to those for the intermittent carriers. No methicillin or vancomycin resistance was detected.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6457df531d68f0a72d7765f33d0e77bfTest
https://europepmc.org/articles/PMC1489388Test/