Background: Pseudomonas aeruginosa flagellin binds to the membrane-tethered mucin, MUC1. Results: Flagellin drives NEU1 to desialylate MUC1, thereby increasing its adhesiveness for Pseudomonas aeruginosa and its shedding. Conclusion: P. aeruginosa hijacks host NEU1 through its flagellin. Significance: P. aeruginosa mobilizes NEU1 to enhance its pathogenicity, but the host retaliates by releasing MUC1 as a hyperadhesive decoy receptor.
Circadian rhythm was disrupted in patients with severe sepsis, as reflected by disordered diurnal variation of urinary 6-SMT excretion. Light levels were low, exhibited limited diurnal variation, and did not entrain circadian rhythms in these patients.
Neuraminidase-1 (NEU1) is the predominant sialidase expressed in human airway epithelia and lung microvascular endothelia where it mediates multiple biological processes. We tested whether the NEU1-selective sialidase inhibitor, C9-butyl-amide-2-deoxy-2,3-dehydro-N-acetylneuraminic acid (C9-BA-DANA), inhibits one or more established NEU1-mediated bioactivities in human lung cells. We established the IC50 values of C9-BA-DANA for total sialidase activity in human airway epithelia, lung microvascular endothelia and lung fibroblasts to be 3.74 µM, 13.0 µM and 4.82 µM, respectively. In human airway epithelia, C9-BA-DANA dose-dependently inhibited flagellin-induced, NEU1-mediated mucin-1 ectodomain desialylation, adhesiveness for Pseudomonas aeruginosa and shedding. In lung microvascular endothelia, C9-BA-DANA reversed NEU1-driven restraint of cell migration into a wound and disruption of capillary-like tube formation. NEU1 and its chaperone/transport protein, protective protein/cathepsin A (PPCA), were differentially expressed in these same cells. Normalized NEU1 protein expression correlated with total sialidase activity whereas PPCA expression did not. In contrast to eukaryotic sialidases, C9-BA-DANA exerted far less inhibitory activity for three selected bacterial neuraminidases (IC50 > 800 µM). Structural modeling of the four human sialidases and three bacterial neuraminidases revealed a loop between the seventh and eighth strands of the β-propeller fold, that in NEU1, was substantially shorter than that seen in the six other enzymes. Predicted steric hindrance between this loop and C9-BA-DANA could explain its selectivity for NEU1. Finally, pretreatment of mice with C9-BA-DANA completely protected against flagellin-induced increases in lung sialidase activity. Our combined data indicate that C9-BA-DANA inhibits endogenous and ectopically expressed sialidase activity and established NEU1-mediated bioactivities in human airway epithelia, lung microvascular endothelia, and fibroblasts in vitro and murine lungs in vivo.
The globalization of medical research and global health's increasing popularity worldwide have resulted in greater geographic, ethnic, and socioeconomic diversity of studies published in the scientific literature. Yet the geographic distribution, authorship representation, and subject trends among Low-/Low-Middle-Income Country (LIC/LMIC)-based scientific publications remain largely unknown. This analysis assesses these gaps in knowledge. We performed a comprehensive bibliometric analysis of all scientific articles published between January 2014 and June 2016 in the four most prominent general medicine and five most prominent general global health journals based on impact factor. The African region, containing 24% of the global LIC/LMIC population, accounted for 49.9% of all publications. Corresponding authors with either exclusive or joint appointment to a LIC/ LMIC institution were present in 26.2% of all included articles. Over one-quarter (28.8%) of all publications did not list a local author. Nearly two-thirds (62.1%) of articles published in global health journals and roughly half (52.4%) in general medicine journals involved infectious diseases. Non-HIV infectious disease studies were by far the most frequent subject areas across all journals. The trends identified in this study may help to inform the evolution and prioritization of future research efforts, thereby allowing global health to remain truly global.
Background
Sleepiness and fatigue are commonly reported by family members of intensive care unit (ICU) patients. Sleep deprivation may result in cognitive deficits. Sleep deprivation and cognitive blunting have not been quantitatively assessed in this population. We sought to determine the proportion of family members of ICU patients that experience excessive daytime sleepiness, sleep-associated functional impairment, and cognitive blunting.
Methods
Multicenter, cross-sectional survey of family members of patients admitted to ICUs at the University of Maryland Medical Center, Johns Hopkins University Hospital, and Christiana Hospital. Family members of ICU patients were evaluated using the Epworth Sleepiness Scale, a validated survey assessing sleepiness in everyday situations (normal, less than 10); the Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10), a questionnaire quantifying the impact of sleepiness on daily activities (normal, at least 17.9); and psychomotor vigilance testing, a test of cognitive function, in relation to sleep deprivation (normal mean reaction time less than 500 ms).
Results
A total of 225 family members were assessed. Of these, 50.2 % (113/225) had Epworth scores consistent with excessive daytime sleepiness. Those with sleepiness experienced greater impairment in performing daily activities by FOSQ-10 (15.6 ± 3.0 vs 17.4 ± 2.2, p < 0.001). Cognitive blunting was found in 13.3 % (30/225) of family members and 15.1 % (14/93) of surrogate decision-makers. Similar rates of cognitive blunting as reported by mean reaction time of at least 500 ms were found among family members whether or not they reported sleepiness (15.0 % (17/113) vs. 11.6 % (13/112), p = 0.45).
Conclusions
Half of the family members of ICU patients suffer from excessive daytime sleepiness. This sleepiness is associated with functional impairment, but not cognitive blunting.
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