Here we report the discovery of MED6-189, a new analogue of the kalihinol family of isocyanoterpene (ICT) natural products. MED6-189 is effective against drug-sensitive and -resistant P. falciparum strains blocking both intraerythrocytic asexual replication and sexual differentiation. This compound was also effective against P. knowlesi and P. cynomolgi. In vivo efficacy studies using a humanized mouse model of malaria confirms strong efficacy of the compound in animals with no apparent hemolytic activity or apparent toxicity. Complementary chemical biology, molecular biology, genomics and cell biological analyses revealed that MED6-189 primarily targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses in P. falciparum revealed that a mutation in PfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. The high potency of MED6-189 in vitro and in vivo, its broad range of efficacy, excellent therapeutic profile, and unique mode of action make it an excellent addition to the antimalarial drug pipeline.
Three-quarters of the patients with acute lymphoblastic leukemia (ALL), show numerical or structural chromosomal alterations, which are important factors in leukemogenesis. The use of Multiplex Ligation-dependent Probes Amplification (MLPA) has been mainly limited for searching copy number alterations of genes, suggesting that MLPA could detect numerical alterations in cancer. However, the use of MLPA in pediatrics to analyze subtelomeric sequences for aneuploidy detection has not been considered in previous studies. The aim of this study was to identify aneuploidy for the first time using MLPA and correlate the results with karyotype and DNA-index (DI), from preB ALL patients. Forty-two bone marrow samples were analyzed by cytogenetics and flow cytometry to determine the DI. The chromosomal gains and/or losses were detected by the SALSA MLPA P036 Subtelomere Mix 1 probemix®. The chromosomal number matched in 36 out of 42 samples between MLPA and karyotype (R2=0.7829, p=3.7×10-10), 18/42 between MLPA and DI (R2=0.1556, p=0.023), and 20/42 between karyotype and DI (R2=0.1509, p=0.015). MLPA results correlated with karyotype and DI. The use of MLPA led us to identify a gained marker chromosome. Our results indicate that MLPA could be a useful and fast alternative tool for aneuploidy identification in pediatric leukemia.
Aneuploidy , Multiplex Polymerase Chain Reaction/methods , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Bone Marrow Examination/methods , Child , Chromosome Aberrations , Cytogenetics , Female , Flow Cytometry , Humans , Karyotyping , Male
The optimization of graphene growth on copper foils using an atmospheric pressure chemical vapor deposition setup is reported. CH4 and H2 were used as precursor gases and Raman spectroscopy as the main graphene characterization technique. Different growth parameters, including temperature and reaction time, the molar ratio of CH4/H2 in the feed and total flow of gases during the reaction step, were studied in detail. It was shown that graphene growth was not homogeneous in the entire sample, multilayer graphene was present in most of the sample, however as the synthesis parameters were optimized, graphene gained better quality, obtaining bilayer graphene over most of the sheet in the final optimized sample. Homemade software was used to analyze the quality of the synthesised graphene, obtaining a more quality graphene according to the synthesis parameters optimized. An optimal bilayer graphene sample was prepared at the lowest growth time (10 min) and the highest synthesis temperature (1050 °C), using a CH4/H2 flow ratio and a total flow rate ratio of precursors of 7% and 60 Nml (CH4 + H4) per min respectively.
No disponible
Adolescent , Adult , Female , Male , Middle Aged , Child , Humans , Prognosis , Pneumonia/complications , Pneumonia/diagnosis , Pneumonia/epidemiology , Community Medicine/standards , Community Medicine/organization & administration , Community Health Services/methods , Critical Care/methods , Critical Care/standards , Critical Care/organization & administration , Indicators of Morbidity and Mortality , Lung Diseases, Obstructive/complications , Lung Diseases, Obstructive/diagnosis , Pneumonia/mortality , Pneumonia/pathology , Comorbidity , Streptococcal Infections/etiology , Streptococcal Infections/diagnosis , Lung Diseases, Obstructive/complications , Lung Diseases, Obstructive/diagnosis
In recent years, there has been a dramatic increase in the number of infections caused by multidrug-resistant Gram-positive microorganisms, making necessary the search for alternative antibacterial agents. Linezolid is a new synthetic antimicrobial agent with activity against multidrug-resistant Gram-positive cocci. The objective of this study was to determine the in vitro activity of linezolid against 74 clinical isolates of methicillin-resistant Staphylococcus aureus. Minimal inhibitory concentrations were determined by an agar dilution method following NCCLS criteria. Vancomycin, teicoplanin, rifampicin, trimethoprim-sulfamethoxazole and linezolid were studied at concentrations ranging from 128 to 0.008 mg/l. All of the isolates were susceptible to vancomycin, teicoplanin, and linezolid while four strains (5.4%) were resistant to rifampicin and five (6.7%) to trimethoprim-sulfamethoxazole. Linezolid showed excellent in vitro activity against 74 clinical isolates of methicillin-resistant Staphylococcus aureus with an MIC ranging from 0.25 to 2 mg/l
Acetamides/pharmacology , Anti-Bacterial Agents/pharmacology , Methicillin Resistance , Oxazolidinones/pharmacology , Staphylococcus aureus/drug effects , Humans , Linezolid
En los últimos años se ha producido un incremento importante en el número de infecciones causadas por microorganismos grampositivos multirresistentes, lo que hace necesario la búsqueda de agentes antibacterianos alternativos. La linezolida es un nuevo antimicrobiano de síntesis que presenta actividad frente a microorganismos grampositivos multirresistentes. El objetivo de este estudio fue determinar la actividad in vitro de la linezolida frente a 74 aislamientos clínicos de Staphylococcus aureus resistentes a la meticilina. Las concentraciones mínimas inhibitorias fueron determinadas por el método de dilución en agar siguiendo las recomendaciones del NCCLS. Se probaron los siguientes antibióticos a concentraciones de 128 mg/l a 0,008 mg/l: vancomicina, teicoplanina, rifampicina, trimetoprima-sulfametoxazol y linezolida. Todas las cepas fueron sensibles a vancomicina, teicoplanina y linezolida, cuatro cepas (5,4 por ciento) mostraron resistencia a rifampicina y cinco (6,7 por ciento) a trimetoprima-sulfametoxazol. La linezolida mostró una excelente actividad in vitro frente a los 74 aislamientos estudiados, con CMI entre 0,25 mg/l y 2 mg/l (AU)
Humans , Methicillin Resistance , Staphylococcus aureus , Oxazolidinones , Anti-Bacterial Agents , Acetamides
Acinetobacter is a Gram-negative coccobacillus frequently associated with nosocomial infections, especially pneumonia in patients using mechanical ventilators in ICUs. Many of the clinical isolates of Acinetobacter baumannii are now resistant to most antibiotics, including the betalactams, making these infections difficult to treat. We compared the in vitro activity of betalactam agents (ampicillin, piperacillin and ticarcillin), betalactamase inhibitors (clavulanic acid, sulbactam and tazobactam) alone and in combination with betalactam agents (amoxicillin-clavulanic acid, ampicillin-sulbactam, piperacillin-tazobactam and ticarcillin-clavulanic) against 156 clinical isolates of A. baumannii using an agar dilution method. In general, we observed a low susceptibility to the betalactam agents tested (ampicillin: 1.9% susceptibility; piperacillin: 10.2%; ticarcillin: 19.8%). We did not observe a significant reduction of the MIC in the combination of betalactam agents and betalactamase inhibitors; only ampicillin/sulbactam showed a high antimicrobial activity (84.6% compared to 14.1%, 37.8% and 33.9% for amoxicillin-clavulanic acid, piperacillin-tazobactam and ticarcillin-clavulanic acid, respectively). Sulbactam was the only betalactamase inhibitor which showed good in vitro activity, with a low MIC(50) and MIC(90) (8 and 32 mg/l, respectively) similar to ampicillin/sulbactam (2 and 16 mg/l, respectively). Sulbactam could be a good therapeutic alternative for the treatment of multiresistant A. baumannii infections.
Acinetobacter/drug effects , Anti-Bacterial Agents/pharmacology , beta-Lactamase Inhibitors , Humans , Microbial Sensitivity Tests , beta-Lactams
Eryngium amethystinum (amethyst sea holly) is a herbaceous plant commonly grown as an ornamental perennial in U.S.D.A. hardiness zones 3 to 8. The plant thrives in dry areas with infertile soils and the flowers are often used in dried floral arrangements. Canna spp. (Canna), soft perennials (U.S.D.A. zone 9 and above), are becoming popular flowering plants because of their bright flowers and spectacular foliage. There are a variety of species that fall under the heading Canna spp., of which the most popular are C. glauca, C. indica, C. edulis, and C. iridiflora. Hybrids of Aquilegia (garden columbine), a hardy perennial (U.S.D.A. zones 3 to 9), flower in late spring through early summer. The genus is made up of a wide variety of cultivars. E. amethystinum exhibiting severe mosaic, yellowing, and stunting, along with Canna plants exhibiting severe stunting, chlorotic and distorted foliage, and mosaic, and garden columbine plants exhibiting stunting, leaf curl, chlorosis, and mosaic, collected from commercial plantings throughout the central Ohio area, were analyzed for the presence of virus infection with viral-associated, double-stranded RNA (dsRNA) analysis. dsRNA analysis resulted in a banding profile typical of that seen with members of the cucumovirus family of plant viruses. Plants positive for cucumovurus-like dsRNA were tested with a direct antibody sandwich enzyme-linked immunosorbent assay (ELISA). ELISA results confirmed the presence of cucumber mosaic virus (CMV) in all symptomatic plants tested. No evidence of dsRNA or CMV was found in any of the asymptomatic plants tested. Because all of these hosts are common in the perennial garden, they could serve as a reservoir host of CMV for other plants in the garden. This is the first report of CMV in E. amethystinum, Canna spp., and Aquilegia hybrids in Ohio.
Although opportunistic infections after bone marrow transplantation (BMT) are very common, only five cases of Pseudallescheria boydii infection have been reported in the literature, two of which were autopsy findings. A case of Scedosporium apiospermum infection after BMT, treated initially with amphotericin B (total dose of 2.5 g) and then with itraconazole (for 25 days), is reported here. When the patient failed to improve, Scedosporium apiospermum pneumonia was diagnosed and therapy was changed. The patient was treated successfully with miconazole (600 mg/8h for 32 days) and ketoconazole (200 mg/8h for 7 days) plus surgery.
Bone Marrow Transplantation/adverse effects , Mycetoma/diagnosis , Pseudallescheria , Adult , Amphotericin B/therapeutic use , Antifungal Agents/therapeutic use , Female , Humans , Itraconazole/therapeutic use , Mycetoma/drug therapy , Pneumonia/diagnosis , Pneumonia/drug therapy
