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Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome1-5 (ARDS), for which there are no effective pharmacological therapies. Necroptosis is an attractive entry point for therapeutic intervention in ARDS and related inflammatory conditions because it drives pathogenic lung inflammation and lethality during severe IAV infection6-8 and can potentially be targeted by receptor interacting protein kinase 3 (RIPK3) inhibitors. Here we show that a newly developed RIPK3 inhibitor, UH15-38, potently and selectively blocked IAV-triggered necroptosis in alveolar epithelial cells in vivo. UH15-38 ameliorated lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, without compromising antiviral adaptive immune responses or impeding viral clearance. UH15-38 displayed robust therapeutic efficacy even when administered late in the course of infection, suggesting that RIPK3 blockade may provide clinical benefit in patients with IAV-driven ARDS and other hyper-inflammatory pathologies.
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Lesión Pulmonar , Necroptosis , Infecciones por Orthomyxoviridae , Inhibidores de Proteínas Quinasas , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Animales , Femenino , Humanos , Masculino , Ratones , Células Epiteliales Alveolares/patología , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/virología , Células Epiteliales Alveolares/metabolismo , Virus de la Influenza A/clasificación , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/inmunología , Virus de la Influenza A/patogenicidad , Lesión Pulmonar/complicaciones , Lesión Pulmonar/patología , Lesión Pulmonar/prevención & control , Lesión Pulmonar/virología , Ratones Endogámicos C57BL , Necroptosis/efectos de los fármacos , Infecciones por Orthomyxoviridae/complicaciones , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/mortalidad , Infecciones por Orthomyxoviridae/virología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidores , Síndrome de Dificultad Respiratoria/complicaciones , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/prevención & control , Síndrome de Dificultad Respiratoria/virologíaRESUMEN
V-ATPase, which comprises 13-14 subunits, is essential for pH homeostasis in all eukaryotes, but its proper function requires a regulator to assemble its subunits. While RAVE (regulator of H+-ATPase of vacuolar and endosomal membranes) and Raboconnectin-3 complexes assemble V-ATPase subunits in Saccharomyces cerevisiae and humans, respectively, the function of the RAVE complex in fungal pathogens remains largely unknown. In this study, we identified two RAVE complex components, Rav1 and Wdr1, in the fungal meningitis pathogen Cryptococcus neoformans, and analyzed their roles. Rav1 and Wdr1 are orthologous to yeast RAVE and human Rabconnectin-3 counterparts, respectively, forming the hybrid RAVE (hRAVE) complex. Deletion of RAV1 caused severe defects in growth, cell cycle control, morphogenesis, sexual development, stress responses, and virulence factor production, while the deletion of WDR1 resulted in similar but modest changes, suggesting that Rav1 and Wdr1 play central and accessary roles, respectively. Proteomics analysis confirmed that Wdr1 was one of the Rav1-interacting proteins. Although the hRAVE complex generally has V-ATPase-dependent functions, it also has some V-ATPase-independent roles, suggesting a unique role beyond conventional intracellular pH regulation in C. neoformans. The hRAVE complex played a critical role in the pathogenicity of C. neoformans, and RAV1 deletion attenuated virulence and impaired blood-brain barrier crossing ability. This study provides comprehensive insights into the pathobiological roles of the fungal RAVE complex and suggests a novel therapeutic strategy for controlling cryptococcosis.
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Criptococosis , Cryptococcus neoformans , Proteínas de Saccharomyces cerevisiae , ATPasas de Translocación de Protón Vacuolares , Humanos , Proteínas de Saccharomyces cerevisiae/metabolismo , Cryptococcus neoformans/genética , Cryptococcus neoformans/metabolismo , ATPasas de Translocación de Protón Vacuolares/genética , Saccharomyces cerevisiae/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismoRESUMEN
Nanopore sensing has been successfully used to characterize biological molecules with single-molecule resolution based on the resistive pulse sensing approach. However, its use in nanoparticle characterization has been constrained by the need to tailor the nanopore aperture size to the size of the analyte, precluding the analysis of heterogeneous samples. Additionally, nanopore sensors often require the use of high salt concentrations to improve the signal-to-noise ratio, which further limits their ability to study a wide range of nanoparticles that are unstable at high ionic strength. Here, a new paradigm in nanopore research that takes advantage of a polymer electrolyte system to comprise a conductive pulse sensing approach is presented. A finite element model is developed to explain the conductive pulse signals observed and compare these results with experiments. This system enables the analytical characterization of heterogeneous nanoparticle mixtures at low ionic strength . Furthermore, the wide applicability of the method is demonstrated by characterizing metallic nanospheres of varied sizes, plasmonic nanostars with various degrees of branching, and protein-based spherical nucleic acids with different oligonucleotide loadings. This system will complement the toolbox of nanomaterials characterization techniques to enable real-time optimization workflow for engineering a wide range of nanomaterials.
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Nanopartículas , Nanoporos , Ácidos Nucleicos , Proteínas , NanotecnologíaRESUMEN
Enzymes serve as pivotal components in various biotechnological applications across several industries. Understanding enzyme inhibition sheds light on how certain compounds disrupt biochemical pathways, facilitating the design of targeted drugs for combating diseases. On the other hand, reversible inhibition or enhancement of activity can unlock new ways of controlling industrial reactions and boosting the catalytic activity of native enzymes that are taken out of their natural environments. Over the last two decades, immobilizing enzymes on nanomaterial-based solid supports has emerged as an especially promising approach for tuning enzyme activity. Nanomaterials not only inhibit enzymes but also enhance their performance, showcasing their versatility. This Concept highlights significant advancements in utilizing nanomaterials for enzyme modulation and discusses future prospects for leveraging this phenomenon in developing sophisticated molecular systems and downstream applications.
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PURPOSE: To investigate the association between visual outcomes and choroidal changes in patients with macula-off rhegmatogenous retinal detachment. METHODS: This study retrospectively reviewed 63 eyes of patients with macula-off rhegmatogenous retinal detachment who underwent vitrectomy. Their fellow eyes were analyzed as a control group. The choroidal vascularity index (CVI), ellipsoid zone/external limiting membrane integrity, central foveal thickness, and subfoveal choroidal thickness were documented and analyzed. Linear regression analyses were performed to identify factors affecting the final best-corrected visual acuity. RESULTS: Eyes with rhegmatogenous retinal detachment showed increased CVI (68.8 ± 4.1) compared with the control group (66.1 ± 8.8, P = 0.028). Multivariate linear regression analysis revealed that patients with a poor final best-corrected visual acuity had a longer detachment duration ( P = 0.002), worse baseline best-corrected visual acuity ( P = 0.034), thinner central foveal thickness ( P = 0.005), and greater CVI ( P = 0.001) and were more likely to be tamponated with silicone oil ( P = 0.001). Choroidal vascularity index was particularly increased in eyes with poor ellipsoid zone/external limiting membrane integrity, prolonged detachment duration, thin central foveal thickness, and worse best-corrected visual acuity. CONCLUSION: Increased CVI could indicate poor visual outcomes in patients with macula-off rhegmatogenous retinal detachment. Choroidal remodeling could be associated with the disruption of the ellipsoid zone/external limiting membrane integrity.
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Mácula Lútea , Desprendimiento de Retina , Humanos , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/cirugía , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Agudeza Visual , Mácula Lútea/cirugía , VitrectomíaRESUMEN
BMS906024, a γ-secretase inhibitor that blocks Notch signaling, was previously shown to inhibit Cryptosporidium parvum growth in vitro. A structure-activity relationship (SAR) analysis of BMS906024 reported herein demonstrates the importance of the stereochemistry of the C-3 benzodiazepine and the succinyl ß-substituent. However, concomitant removal of the succinyl α-substituent and switching the primary amide with secondary amides was tolerated. For example, 32 (SH287) inhibited C. parvum growth in HCT-8 host cells with an EC50 = 6.4 nM and an EC90 = 16 nM; however, blocking C. parvum growth with BMS906024 derivatives was correlative with inhibition of Notch signaling, highlighting that additional SAR analysis will be needed to separate these two activities.
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Criptosporidiosis , Cryptosporidium parvum , Cryptosporidium , Humanos , Relación Estructura-ActividadRESUMEN
The use of DNA-based nanostructures as probes has led to significant advances in chemical and biological sensing, allowing the detection of analytes in complex media, the understanding of fundamental biological processes, and the ability to diagnose diseases based on molecular signatures. The utility of these structures arises both from DNA's inherent ability to selectively recognize and bind a variety of chemical species and from the unique properties observed when DNA is restructured at the nanoscale. In this Minireview, we chronicle the most commonly used signal transduction strategies that have been interfaced with various DNA-based nanostructures. We discuss the types of analytes and the detection scenarios that are sought after, delineate the advantages and disadvantages of each signaling strategy, and outline the key considerations that guide the selection of each signaling method.
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Técnicas Biosensibles , Nanoestructuras , Técnicas Biosensibles/métodos , ADN/química , Nanoestructuras/química , Transducción de SeñalRESUMEN
PURPOSE: To examine the incidence and risk of retinal artery occlusion (RAO) in patients who have undergone dialysis in Korea. METHODS: A nationwide, population-based study using South Korean national health insurance data from 2004 to 2013 was used for analysis. All patients who began dialysis between 2004 and 2013 and the same number of control subjects were selected via propensity score matching. The incidence of RAO in the dialysis and control cohorts was calculated for 2004 to 2013 using washout data from 2003. The multivariable Cox proportional hazards model was used to evaluate the risk of developing RAO in dialysis patients. Cumulative RAO incidence curves were generated using the Kaplan-Meier method. Whether dialysis modalities influenced the incidence of RAO was also evaluated. RESULTS: Seventy-six thousand seven hundred and eighty-two end-stage renal disease patients on dialysis were included in the dialysis cohort, and 76,782 individuals were included in the control cohort. During the study period, 293 patients in the dialysis cohort and 99 patients in the control cohort developed RAO. The person-years incidence of RAO was significantly higher in the dialysis cohort than in the control cohort (dialysis = 1.1/1,000 person-years; control = 0.3/1,000 person-years; P < 0.001). The incidence of RAO was not significantly different between the two methods of dialysis (hemodialysis vs. peritoneal dialysis; P = 0.25, log-rank test). CONCLUSION: The current study provided epidemiological evidence that undergoing dialysis for end-stage renal disease was associated with an increased risk of developing RAO. The incidence of RAO rapidly increased as the duration of dialysis increased. These results strengthen the significant role of the renal function in retinal vascular disease.
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Fallo Renal Crónico/terapia , Diálisis Renal/efectos adversos , Oclusión de la Arteria Retiniana/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Niño , Preescolar , Bases de Datos Factuales , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Programas Nacionales de Salud/estadística & datos numéricos , Modelos de Riesgos Proporcionales , República de Corea/epidemiología , Oclusión de la Arteria Retiniana/fisiopatología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: To analyze the long-term effects of persistent subretinal fluid (SRF) on visual/anatomic outcomes according to the type of macular neovascularization (MNV) during relaxed treat-and-extend regimen with anti-vascular endothelial growth factor (anti-VEGF) agents in age-related macular degeneration (AMD) patients. METHODS: Patients with fovea-involving type 1 or type 2 MNV, treated with a relaxed treat-and-extend regimen for 2 years were retrospectively reviewed. Eyes with SRF observed more than three times per year were defined as the 'persistent SRF (+) group'. To exclude the effects of IRF as much as possible, the eyes with persistent IRF were excluded. The effects of persistent SRF on the best-corrected visual acuity (BCVA), central subfield retinal thickness (CST), and changes in the photoreceptor layer (PRL) thickness and outer retinal bands (external limiting membrane, ellipsoid zone, and cone outer segment tip line) after anti-VEGF injection were analyzed for each MNV type. RESULTS: Seventy-seven eyes with type 1 MNV (44 eyes with persistent SRF) and 53 eyes with type 2 MNV (18 eyes with persistent SRF) were enrolled. Following a relaxed treat-and-extend regimen with anti-VEGF agents, BCVA and CST improved for each MNV type. In comparison between persistent SRF (+) and persistent SRF (-) group, there were no differences in the amount of change in BCVA and CST between the two groups for each MNV type during 2-year follow-up periods. In addition, there were no differences in the amount of reduction in PRL thickness and state of the outer retinal bands between the two groups for each MNV type. CONCLUSIONS: Using a relaxed treat-and-extend regimen with anti-VEGF agents, persistent SRF did not have additional effects on visual and anatomic outcomes by 2 years, regardless of the MNV type.
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Degeneración Macular , Degeneración Macular Húmeda , Inhibidores de la Angiogénesis/uso terapéutico , Angiografía con Fluoresceína , Humanos , Inyecciones Intravítreas , Degeneración Macular/tratamiento farmacológico , Estudios Retrospectivos , Líquido Subretiniano , Tomografía de Coherencia Óptica , Factor A de Crecimiento Endotelial Vascular , Agudeza Visual , Degeneración Macular Húmeda/tratamiento farmacológicoRESUMEN
We report a compact, simple source of terahertz radiation that can be tuned to well-defined frequencies spanning â¼1.4 to 10 THz, based on difference-frequency generation in an HMQ-TMS crystal. The pair of pump pulses required for this process is obtained by optical parametric generation in an aperiodically-poled lithium niobate crystal; the center wavelength of this pair of pulses is around 1.45 µm. We obtained 40 nJ THz pulses using 38 µJ, 0.85 ns pump pulses.
RESUMEN
We demonstrate the first megahertz (MHz) repetition-rate, broadband terahertz (THz) source based on optical rectification in the organic crystal HMQ-TMS driven by a femtosecond Yb:fibre laser. Pumping at 1035 nm with 30 fs pulses, we achieve few-cycle THz emission with a smooth multi-octave spectrum that extends up to 6 THz at -30 dB, with conversion efficiencies reaching 10-4 and an average output power of up to 0.38 mW. We assess the thermal damage limit of the crystal and conclude a maximum fluence of â¼1.8 mJ·cm-2 at 10 MHz with a 1/e2 pump beam diameter of 0.10 mm. We compare the performance of HMQ-TMS with the prototypical inorganic crystal gallium phosphide (GaP), yielding a tenfold electric field increase with a peak on-axis field strength of 7 kV·cm-1 and almost double the THz bandwidth. Our results further demonstrate the suitability of organic crystals in combination with fibre lasers for repetition-rate scaling of broadband, high-power THz sources for time-domain spectroscopic applications.
RESUMEN
Inosine-5'-monophosphate dehydrogenase (IMPDH) is a potential target for microorganisms. However, identifying inhibitor design determinants for IMPDH orthologs continues to evolve. Herein, a series of mycophenolic anilide inhibitors of Cryptosporidium parvum and human IMPDHs are reported. Furthermore, molecular docking of 12 (e.g. SH-19; CpIMPDH Ki,app = 0.042 ± 0.015 µM, HsIMPDH2 Ki,app = 0.13 ± 0.05 µM) supports different binding modes with the two enzymes. For CpIMPDH the inhibitor extends into a pocket in an adjacent subunit. In contrast, docking suggests the inhibitor interacts with Ser276 in the NAD binding site in HsIMPDH2, as well as an adjacent pocket within the same subunit. These results provide further guidance for generating IMPDH inhibitors for enzymes found in an array of pathogenic microorganisms, including Mycobacterium tuberculosis.
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Anilidas/farmacología , Antiparasitarios/farmacología , Cryptosporidium parvum/enzimología , Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Anilidas/química , Antiparasitarios/química , Sitios de Unión/efectos de los fármacos , Criptosporidiosis/tratamiento farmacológico , Criptosporidiosis/parasitología , Cryptosporidium parvum/metabolismo , Inhibidores Enzimáticos/química , Humanos , IMP Deshidrogenasa/metabolismo , Simulación del Acoplamiento Molecular , Fenoles/química , Fenoles/farmacologíaRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid ß (Aß) in the brain. Although several studies reported possible mechanisms involved in Aß pathology, much remains unknown. Previous findings suggested that a protein regulated in development and DNA damage response 1 (REDD1), a stress-coping regulator, is an Aß-responsive gene involved in Aß cytotoxicity. However, we still do not know how Aß increases the level of REDD1 and whether REDD1 mediates Aß-induced synaptic dysfunction. To elucidate this, we examined the effect of Aß on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on Aß-induced synaptic dysfunction. Lastly, we observed the effect of REDD1 shRNA on memory deficit in an AD-like mouse model. Through the experiments, we found that Aß-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, Aß injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked Aß-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that Aß may increase REDD1 translation rather than transcription. Aß activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked Aß-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and Aß blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked Aß-induced synaptic deficits. REDD1 shRNA also blocked Aß-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in Aß pathology and could be a target for AD therapy.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/farmacología , Hipocampo/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Trastornos de la Memoria/metabolismo , Sinapsis/metabolismo , Factores de Transcripción/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Anisomicina/farmacología , Dactinomicina/farmacología , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Masculino , Trastornos de la Memoria/genética , Trastornos de la Memoria/patología , Pruebas de Memoria y Aprendizaje , Ratones , Biosíntesis de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-fyn/metabolismo , ARN Interferente Pequeño , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Proteínas Quinasas S6 Ribosómicas/antagonistas & inhibidores , Proteínas Quinasas S6 Ribosómicas/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/genética , Sinapsis/patología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Factores de Transcripción/genética , Regulación hacia ArribaRESUMEN
We report on generation of strong and broadband terahertz (THz) pulses via collinearly phase-matched optical rectification of near-infrared femtosecond pulses in the organic nonlinear optical HMB-TMS (2-(4-hydroxy-3-methoxystyryl)-3-methylbenzo[d]thiazol-3-ium 2,4,6-trimethylbenzenesulfonate) single crystals which exhibit optimal molecular orientation and large macroscopic optical nonlinearity for efficient THz wave generation. Single-cycle THz pulses with a peak electric field strength of 0.66 MV/cm and a bandwidth from 0.1 to 5.4 THz are achieved from an HMB-TMS crystal with only a 2-mm clear aperture pumped by 1350 nm pulses at moderate fluences. The generated THz energy is about 1 µJ and the corresponding pump-to-THz energy conversion efficiency reaches 0.23%.
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We present the generation of high-peak-electric-field terahertz pulses via collinear optical rectification in a 2-(4-hydroxy-3-methoxystyryl)-1-methilquinolinium-2,4,6-trimethylbenzenesulfonate (HMQ-TMS) organic crystal. The crystal is pumped by an amplified ytterbium laser system, emitting 170-fs-long pulses centered at 1030 nm. A terahertz peak electric field greater than 200 kV/cm is obtained for 420 µJ of optical pump energy, with an energy conversion efficiency of 0.26% - about two orders of magnitude higher than in common inorganic crystals collinearly pumped by amplified femtosecond lasers. An open-aperture Z-scan measurement performed on an n-doped InGaAs thin film using such terahertz source shows a nonlinear increase in the terahertz transmission of about 2.2 times. Our findings demonstrate the potential of this terahertz generation scheme, based on ytterbium laser technology, as a simple and efficient alternative to the existing intense table-top terahertz sources. In particular, we show that it can be readily used to explore nonlinear effects at terahertz frequencies.
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Three rapidly growing mycobacterial strains, MOTTH4W, MOTT36WT and MOTT68W, were isolated from the sputa of three independent Korean patients co-infected with Mycobacterium yongonense Type II strains. The 16S rRNA gene sequences of all three strains were unique, which were closest to that of Mycobacterium chelonae subsp. bovis KCTC 39630T (99.9â% similarity). Multilocus sequence typing analysis targeting 10 housekeeping genes including hsp65 and rpoB revealed the distinct phylogenetic location of these strains, which were clustered with M. chelonae subsp. chelonae ATCC 35752T and M. chelonae subsp. bovis KCTC 39630T. Phylogenetic analysis based on whole genome sequences revealed a 95.89â% average nucleotide identity (ANI) value with M. chelonae subsp. chelonae, slightly higher than the 95.0â% ANI criterion for determining a novel species. In addition, phenotypic characteristics such as a smooth colony morphology and growth inhibition at 37 °C, distinct MALDI-TOF MS profiles of extracted total lipids due to surface glycopeptidolipids, and distinct drug susceptibility profiles further supported the taxonomic characterization of these strains as representing a novel subspecies of Mycobacterium chelonae. Mycobacterium chelonae subsp. gwanakae subsp. nov. is proposed and the type strain is MOTT36WT (=KCTC 29127T=JCM 32454T).
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Mycobacterium chelonae/clasificación , Filogenia , Esputo/microbiología , Técnicas de Tipificación Bacteriana , ADN Bacteriano/genética , Genes Bacterianos , Humanos , Tipificación de Secuencias Multilocus , Infecciones por Mycobacterium/microbiología , Mycobacterium chelonae/genética , Mycobacterium chelonae/aislamiento & purificación , ARN Ribosómico 16S/genética , República de Corea , Análisis de Secuencia de ADNRESUMEN
Mycobacterium avium complex (MAC) is the most common etiologic organisms of nontuberculous mycobacteria (NTM) lung disease. In this study, we aimed to retrospectively investigate the differences in drug susceptibility patterns of two major MAC species; Mycobacterium avium and Mycobacterium intracellulare. A total of 1883 major two MAC isolates (1060 M. avium and 823 M. intracellulare) from respiratory specimens were included in this study during the period 2011â2016. The minimum inhibitory concentrations (MICs) were determined by broth microdilution method and MIC50/MIC90 values were derived from MIC distribution. M. intracellulare had generally low susceptible rates than M. avium for almost all tested antimicrobials except ethambutol and amikacin. The susceptible rate to clarithromycin was >94% of the MAC without significant differences between the two species. The MIC50 values of ciprofloxacin, clarithromycin, linezolid, moxifloxacin, and rifampicin were higher in M. intracellulare than in M. avium, contrary to the results of ethambutol with a higher MIC50 in M. avium. In general, M. intracellulare showed a higher resistance rate and higher MIC50 values than M. avium. Differences between this study and previous reports suggest regional differences in drug susceptibility profile of MAC species.
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Antituberculosos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Pruebas de Sensibilidad Microbiana/métodos , Complejo Mycobacterium avium/efectos de los fármacos , Mycobacterium avium/efectos de los fármacos , Amicacina/farmacología , Ciprofloxacina/farmacología , Claritromicina/farmacología , Etambutol/farmacología , Fluoroquinolonas/farmacología , Humanos , Linezolid/farmacología , Moxifloxacino , Mycobacterium avium/aislamiento & purificación , Complejo Mycobacterium avium/aislamiento & purificación , Infección por Mycobacterium avium-intracellulare/microbiología , Estudios Retrospectivos , Rifampin/farmacologíaRESUMEN
BACKGROUND: Treatment outcomes of patients with Mycobacterium abscessus subspecies abscessus lung disease are poor, and the microbial characteristics associated with treatment outcomes have not been studied systematically. The purpose of this study was to identify associations between microbial characteristics and treatment outcomes in patients with M. abscessus lung disease. METHODS: Sixty-seven consecutive patients with M. abscessus lung disease undergoing antibiotic treatment for ≥12 months between January 2002 and December 2012 were included. Morphotypic and genetic analyses were performed on isolates from 44 patients. RESULTS: Final sputum conversion to culture negative occurred in 34 (51%) patients. Compared to isolates from 24 patients with persistently positive cultures, pretreatment isolates from 20 patients with final negative conversion were more likely to exhibit smooth colonies (9/20, 45% vs 2/24, 8%; P = .020), susceptibility to clarithromycin (7/20, 35% vs 1/24, 4%; P = .015), and be of the C28 sequevar with regard to the erm(41) gene (6/20, 30% vs 1/24, 4%; P = .035). Mycobacterium abscessus lung disease recurred in 5 (15%) patients after successful completion of antibiotic therapy. Genotypic analysis revealed that most episodes (22/24, 92%) of persistently positive cultures during antibiotic treatment and all cases of microbiologic recurrence after treatment completion were caused by different M. abscessus genotypes within a patient. CONCLUSIONS: Precise identification to the subspecies level and analysis of mycobacterial characteristics could help predict treatment outcomes in patients with M. abscessus lung disease. Treatment failures and recurrences are frequently associated with multiple genotypes, suggesting reinfection. CLINICAL TRIALS REGISTRATION: NCT00970801.
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Antibacterianos/uso terapéutico , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/microbiología , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Micobacterias no Tuberculosas , Anciano , Antibacterianos/farmacología , Claritromicina/farmacología , Claritromicina/uso terapéutico , Farmacorresistencia Microbiana , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Micobacterias no Tuberculosas/clasificación , Micobacterias no Tuberculosas/efectos de los fármacos , Micobacterias no Tuberculosas/genética , Micobacterias no Tuberculosas/aislamiento & purificación , Recurrencia , Estudios Retrospectivos , Esputo/microbiología , Resultado del TratamientoRESUMEN
Macrolide antibiotics are cornerstones in the treatment of Mycobacterium massiliense lung disease. Despite the emergence of resistance, limited data on macrolide-resistant M massiliense lung disease are available. This study evaluated the clinical features and treatment outcomes of patients and the molecular characteristics of macrolide-resistant M massiliense isolates. We performed a retrospective review of medical records and genetic analyses of clinical isolates from 15 patients who had macrolide-resistant M massiliense lung disease between September 2005 and February 2015. Nine patients (60%) had the nodular bronchiectatic form of the disease, and six (40%) had the fibrocavitary form. Before the detection of macrolide resistance, three patients (20%) were treated with macrolide monotherapy, four (27%) with therapy for presumed Mycobacterium avium complex infections, and eight (53%) with combination antibiotic therapy for M massiliense lung disease. The median treatment duration after the detection of resistance was 18.7 months (interquartile range, 11.2 to 39.8 months). Treatment outcomes were poor, with a favorable outcome being achieved for only one patient (7%), who underwent surgery in addition to antibiotic therapy. The 1-, 3-, and 5-year mortality rates were 7, 13, and 33%, respectively. Of the 15 clinical isolates, 14 (93%) had point mutations at position 2058 (n = 9) or 2059 (n = 5) of the 23S rRNA gene, resulting in macrolide resistance. Our study indicates that treatment outcomes are poor and mortality rates are high after the development of macrolide resistance in patients with M massiliense lung disease. Thus, preventing the development of macrolide resistance should be a key consideration during treatment.
Asunto(s)
Antibacterianos/farmacología , Enfermedades Pulmonares/microbiología , Macrólidos/farmacología , Mycobacterium/efectos de los fármacos , Adolescente , Adulto , Anciano , Antibacterianos/uso terapéutico , Femenino , Humanos , Macrólidos/uso terapéutico , Masculino , Persona de Mediana Edad , Mycobacterium/patogenicidad , Infecciones por Mycobacterium/tratamiento farmacológico , Infecciones por Mycobacterium/microbiología , Complejo Mycobacterium avium/efectos de los fármacos , Complejo Mycobacterium avium/patogenicidad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Macrolide antibiotics are mainstays in the treatment of lung disease due to the Mycobacterium abscessus complex. Although previous studies have reported development of acquired macrolide resistance in this species, limited data are available on the outcomes of lung disease due to macrolide-resistant Mycobacterium abscessus subsp. abscessus This study evaluated the clinical features, treatment outcomes, and molecular characteristics of macrolide-resistant isolates of M. abscessus subsp. abscessus We performed a retrospective review of medical records and genetic analysis of clinical isolates from 13 patients who had acquired macrolide-resistant M. abscessus subsp. abscessus lung disease between November 2006 and March 2016. Eleven (85%) patients had the nodular bronchiectatic form of the disease, and two (15%) patients had the fibrocavitary form. When acquired macrolide resistance was detected, 10 (77%) patients were on antibiotic therapy for M. abscessus subsp. abscessus, and three (23%) patients were on therapy for lung disease due to other nontuberculous mycobacteria. The median treatment duration after detecting resistance was 24.0 months (interquartile range, 16.0 to 43.0 months). Treatment outcomes were poor, and final sputum culture conversion was achieved in only one (8%) patient, after resectional surgery. All 13 clinical isolates demonstrated point mutations at position 2058 (n = 10) or 2059 (n = 3) of the 23S rRNA gene, which resulted in acquired macrolide resistance. This study indicates that treatment outcomes are very poor after the development of acquired macrolide resistance in patients with M. abscessus subsp. abscessus lung disease. Thus, more effective measures are needed to prevent development and effectively treat macrolide-resistant M. abscessus subsp. abscessus lung disease.