Exogenous glutathione reverses meropenem resistance in carbapenem-resistant Klebsiella pneumoniae.

Background: The rate of carbapenem-resistant Klebsiella pneumoniae (CRKP) infection has been increasing rapidly worldwide and, poses a significant risk to human health. Effective methods are urgently needed to address treatment failures related to antibiotic resistance. Recent research has reported that some drugs in combination with antibiotics have displayed synergistic killing of resistant bacteria. Here, we investigated whether glutathione (GSH) can synergize with meropenem, and enhance its effectiveness against CRKP. Methods: Synergistic activity was assessed by checkerboard and time-killing assays. The mechanism of these combinations was assessed by total ROS and membrane permeability assays. The bacterial metabolites were assessed by LC‒MS/MS. Results: The FICIs of GSH and meropenem were approximately 0.5 and the combined treatment with GSH and meropenem resulted in a more than 2log10 CFU/mL reduction in bacteria compared to the individual treatments. These findings indicated the synergistic effect of the two drugs. Moreover, the meropenem MIC of CRKP was reduced to less than 4 mg/L when combined with 6 mg/mL GSH, indicating that GSH could significantly reverse resistance to meropenem in bacteria. The production of ROS in bacteria was determined by flow cytometry. After adding GSH, the ROS in the GSH group and the combined group was significantly higher than that in the control and meropenem groups, but there was no significant difference between the combined and GSH groups. The metabolic disturbance caused by GSH alone and in combination with meropenem was significant intracellularly and extracellularly, especially in terms of glycerophospholipid metabolism, indicating that the synergistic effect of the combined use of GSH and meropenem was relevant to glycerophospholipid metabolism. In addition, we measured the cell membrane permeability. The cell membrane permeability of the combination group was significantly higher than that of the blank control or monotreatment groups. This confirmed that the GSH can serve as a meropenem enhancers by disturbing glycerophospholipid metabolism and increasing cell membrane permeability. Conclusion: GSH and meropenem display a synergistic effect, wherein GSH increases the sensitivity of CRKP to meropenem. The synergy and susceptibility effects are thought to related to the increased membrane permeability resulting from the perturbations in glycerophospholipid metabolism, presenting a novel avenue for CRKP treatment.

Differences and similarities of high-resolution computed tomography features between pneumocystis pneumonia and cytomegalovirus pneumonia in AIDS patients.

BACKGROUND: Accurately differentiating pneumocystis from cytomegalovirus pneumonia is crucial for correct therapy selection in AIDS patients. Hence, the goal of this study was to compare the computerized tomography (CT) features of pneumocystis pneumonia and cytomegalovirus pneumonia in AIDS patients and identify clinical hallmarks to accurately distinguish these two pathologies. METHODS: A total of 112 AIDS patients (78 with pneumocystis pneumonia and 34 cytomegalovirus pneumonia) at Beijing Ditan Hospital from January 2017 to May 2019 were included in this study. Two experienced chest radiologists retrospectively reviewed CT images for 17 features including ground-glass opacity, consolidation, nodules, and halo sign. Binary logistic regression analyses were conducted to identify the significant parameters that distinguished pneumocystis pneumonia from cytomegalovirus pneumonia. Correlations were analyzed by Pearson or Spearman correlation analyses. Result were considered significant if P < 0.05. RESULTS: The presence of consolidation, halo signs, and nodules (all P < 0.05) were significantly more frequent in patients with cytomegalovirus pneumonia than in those with pneumocystis pneumonia. Small nodules (32.5% in cytomegalovirus pneumonia, 6.41% in pneumocystis pneumonia, P < 0.001) without perilymphatic distribution were particularly common in patients with cytomegalovirus pneumonia. Large nodules were not found in any of patients with cytomegalovirus pneumonia. The presence of ground-glass opacity, reticulation, and bronchial wall thickening (all P > 0.05) were common in both groups. CONCLUSIONS: Analysis of consolidation, nodules, and halo signs may contribute to the differential diagnosis of pneumocystis pneumonia or cytomegalovirus pneumonia. However, some CT features considered typical in one or other diseases appear with similar frequency in both cohorts of AIDS patients. CT features are potentially useful for the differential diagnosis of pneumocystis pneumonia and cytomegalovirus pneumonia in AIDS patients.

GLRB variants regulate nearby gene expression in human brain tissues.

A recent genome-wide association study (GWAS) identified four genetic variants rs78726293, rs191260602, rs17035816 and rs7688285 in GLRB gene to be associated with panic disorder (PD) risk. In fact, GWAS is an important first step to investigate the genetics of human complex diseases. In order to translate into opportunities for new diagnostics and therapies, we must identify the genes perturbed by these four variants, and understand how these variant functionally contributes to the underlying disease pathogenesis. Here, we investigated the effect of these four genetic variants and the expression of three nearby genes including PDGFC, GLRB and GRIA2 in human brain tissues using the GTEx (version 6) and Braineac eQTLs datasets. In GTEx (version 6) dataset, the results showed that both rs17035816 and rs7688285 variants could significantly regulate PDGFC and GLRB gene expression. In Braineac dataset, the results showed that rs17035816 variant could significantly regulate GLRB and GRIA2 gene expression. We believe that these findings further provide important supplementary information about the regulating mechanisms of rs17035816 and rs7688285 variants in PD risk.