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There is a need for new and effective oral asthma therapies. Dexpramipexole, an oral eosinophil-lowering drug, has not previously been studied in asthma.
We sought to evaluate the ...safety and efficacy of dexpramipexole in lowering blood and airway eosinophilia in subjects with eosinophilic asthma.
We performed a randomized, double-blind, placebo-controlled proof-of-concept trial in adults with inadequately controlled moderate to severe asthma and blood absolute eosinophil count (AEC) greater than or equal to 300/μL. Subjects were randomly assigned (1:1:1:1) to dexpramipexole 37.5, 75, or 150 mg BID (twice-daily) or placebo. The primary end point was the relative change in AEC from baseline to week 12. Prebronchodilator FEV1 week-12 change from baseline was a key secondary end point. Nasal eosinophil peroxidase was an exploratory end point.
A total of 103 subjects were randomly assigned to dexpramipexole 37.5 mg BID (N = 22), 75 mg BID (N = 26), 150 mg BID (N = 28), or placebo (N = 27). Dexpramipexole significantly reduced placebo-corrected AEC week-12 ratio to baseline, in both the 150-mg BID (ratio, 0.23; 95% CI, 0.12-0.43; P < .0001) and the 75-mg BID (ratio, 0.34; 95% CI, 0.18-0.65; P = .0014) dose groups, corresponding to 77% and 66% reductions, respectively. Dexpramipexole reduced the exploratory end point of nasal eosinophil peroxidase week-12 ratio to baseline in the 150-mg BID (median, 0.11; P = .020) and the 75-mg BID (median, 0.17; P = .021) groups. Placebo-corrected FEV1 increases were observed starting at week 4 (nonsignificant). Dexpramipexole displayed a favorable safety profile.
Dexpramipexole demonstrated effective eosinophil lowering and was well tolerated. Additional larger clinical trials are needed to understand the clinical efficacy of dexpramipexole in asthma.
Electrochemical liquid electron microscopy has revolutionized our understanding of nanomaterial dynamics by allowing for direct observation of their electrochemical production. This technique, ...primarily applied to inorganic materials, is now being used to explore the self-assembly dynamics of active molecular materials. Our study examines these dynamics across various scales, from the nanoscale behavior of individual fibers to the micrometer-scale hierarchical evolution of fiber clusters. To isolate the influences of the electron beam and electrical potential on material behavior, we conducted thorough beam–sample interaction analyses. Our findings reveal that the dynamics of these active materials at the nanoscale are shaped by their proximity to the electrode and the applied electrical current. By integrating electron microscopy observations with reaction–diffusion simulations, we uncover that local structures and their formation history play a crucial role in determining assembly rates. This suggests that the emergence of nonequilibrium structures can locally accelerate further structural development, offering insights into the behavior of active materials under electrochemical conditions.
...we determined whether EoP levels correlated with EoEHSS histologic metrics. Given that the EoEHSS evaluates both eosinophil inflammation (EI, ie, eosinophil abscesses, eosinophil surface layering, ...and surface epithelial alteration) and pathologic features independent of tissue eosinophilia (ie, basal zone hyperplasia BZH, dilated intercellular spaces, dyskeratotic epithelial cells, and lamina propria fibrosis), we investigated the relationship between blood EoP levels and each pathologic feature assessed by the EoEHSS (Fig 1, E). ...future studies with larger patient cohorts and longitudinal assessments of EoP levels within individuals are needed before this potential biomarker is ready for clinical application.Appendix Abbreviation Pathologic feature Description EI Eosinophil inflammation Intraepithelial eosinophils quantified in the most densely inflamed hpf EA Eosinophil abscesses Solid mass of intraepithelial eosinophils SL Eosinophil surface layering Linear alignment of at least 3 intraepithelial eosinophils positioned parallel to the epithelial surface BZH Epithelial basal zone hyperplasia Basal zone comprising >15% of the total epithelial thickness DIS Dilated intercellular spaces Circumferential paracellular spaces around squamous epithelial cells that exhibit intercellular bridges SEA Surface epithelial alteration Altered tinctorial properties of the surface epithelial cells that manifest as darker red staining DEC Dyskeratotic epithelial cells Individual cells with deeply eosinophilic cytoplasm and small, round hyperchromatic nuclei LPF Lamina propria fibrosis Thickened connective tissue fibers in the lamina propria Table E1 Pathologic features of EoEHSS Characteristic Inactive EoE (PEC < 15/hpf) Active EoE (PEC ≥ 15/hpf) Significance (P) Number (n) 14 17 — Age (y),† median (interquartile range) 8.0 (3.3-13.1) 14.3 (6-16.9) .07 (NS) Sex: male, % 50 65 .48 (NS) Atopy,‡ % 79 82 >.99 (NS) PEC (eos/hpf), median (interquartile range) 0.5 (0-3) 52 (36-86) <.001 Absolute blood EoP count (EoP/mL blood), median (interquartile range) 13.5 (5.5-30.3) 37 (20.5-49.0) <.001 Table E2 Subjects' demographic characteristics∗
Previous studies have demonstrated that Helicobacter pylori (Hp) delays its entry into macrophages and persists inside megasomes, which are poorly acidified and accumulate early endosome autoantigen ...1. Herein, we explored the role of Hp urease in bacterial survival in murine peritoneal macrophages and J774 cells. Plasmid‐free mutagenesis was used to replace ureA and ureB with cat in Hp Strains 11637 and 11916. ureAB null Hp lacked detectable urease activity and did not express UreA or UreB as judged by immunoblotting. Deletion of ureAB had no effect on Hp binding to macrophages or the rate or extent of phagocytosis. However, intracellular survival of mutant organisms was impaired significantly. Immunofluorescence microscopy demonstrated that (in contrast to parental organisms) mutant Hp resided in single phagosomes, which were acidic and accumulated the lysosome marker lysosome‐associated membrane protein‐1 but not early endosome autoantigen 1. A similar phenotype was observed for spontaneous urease mutants derived from Hp Strain 60190. Treatment of macrophages with bafilomycin A1, NH4Cl, or chloroquine prevented acidification of phagosomes containing mutant Hp. However, only ammonium chloride enhanced bacterial viability significantly. Rescue of ureAB null organisms was also achieved by surface adsorption of active urease. Altogether, our data indicate a role for urease and urease‐derived ammonia in megasome formation and Hp survival.
Francisella tularensis uses both pre‐ and post‐assembly mechanisms to inhibit NADPH oxidase activity at its own phagosome and throughout infected human neutrophils.
Ft is a facultative intracellular ...pathogen that infects many cell types, including neutrophils. In previous work, we demonstrated that the type B Ft strain LVS disrupts NADPH oxidase activity throughout human neutrophils, but how this is achieved is incompletely defined. Here, we used several type A and type B strains to demonstrate that Ft‐mediated NADPH oxidase inhibition is more complex than appreciated previously. We confirm that phagosomes containing Ft opsonized with AS exclude flavocytochrome b558 and extend previous results to show that soluble phox proteins were also affected, as indicated by diminished phosphorylation of p47phox and other PKC substrates. However, a different mechanism accounts for the ability of Ft to inhibit neutrophil activation by formyl peptides, Staphylococcus aureus, OpZ, and phorbol esters. In this case, enzyme targeting and assembly were normal, and impaired superoxide production was characterized by sustained membrane accumulation of dysfunctional NADPH oxidase complexes. A similar post‐assembly inhibition mechanism also diminished the ability of anti‐Ft IS to confer neutrophil activation and bacterial killing, consistent with the limited role for antibodies in host defense during tularemia. Studies of mutants that we generated in the type A Ft strain Schu S4 demonstrate that the regulatory factor fevR is essential for NADPH oxidase inhibition, whereas iglI and iglJ, candidate secretion system effectors, and the acid phosphatase acpA are not. As Ft uses multiple mechanisms to block neutrophil NADPH oxidase activity, our data strongly suggest that this is a central aspect of virulence.
Background Plantar keratoderma is a common finding in pachyonychia congenita, significantly impairing ambulation and quality of life. Due to the variation of pain reporting in pachyonychia congenita ...clinical studies, it is difficult to evaluate the efficacy of treatment outcomes for painful plantar keratodermas. Objectives To objectively analyse associations between plantar pain and activity levels in pachyonychia congenita patients using a wristband tracker. Methods Pachyonychia congenita patients and matched normal controls wore wristband activity trackers and completed a daily digital survey to record their highest and total pain scores (0-10 scale) each day for 28 consecutive days during four different seasons. Results Twenty four participants (12 pachyonychia congenita patients and 12 matched normal controls) completed the study. Pachyonychia congenita patients walked 1801.30 fewer steps/day (95% CI, -3666.4, 64.1) than normal controls (P 0.072) and had greater average total 5.26; SD, 2.10 and highest (6.92; SD, 2.35) daily pain than normal controls 0.11 (SD, 0.47), 0.30 (SD, 0.22), respectively (P 0.001, both). On average, for each one unit increase in daily highest pain level, pachyonychia congenita activity decreased 71.54 steps/day (SE, 38.90, P 0.066). Limitation The study had a small number of participants, limiting statistical power. Only pachyonychia congenita patients, ages 18 years or older, with keratin 6a, keratin 16, and keratin 17 mutations were included, limiting generalizability. Conclusion Pachyonychia congenita patients were less active with significantly higher pain than normal controls. There was an inverse correlation between pain and activity. Our findings suggest that wristband tracker technology may be used to evaluate treatment efficacy in future trials on severe plantar pain; therapeutic interventions that decrease plantar pain should correlate with significant increases in activity using wristband trackers.
Eosinophilic esophagitis (EoE) can coexist in individuals with food allergy.
To evaluate the characteristics of food-allergic patients with and without coexisting EoE using a large food allergy ...patient registry.
Data were derived from 2 Food Allergy Research & Education, Inc, Patient Registry surveys. A series of multivariable regression models were used to evaluate associations between demographic, comorbidity, and food allergy characteristics and the likelihood of reporting EoE.
Five percent (n = 309) of registry participants (n = 6074; ages <1 year->80 years, mean, 20.20 ± 15.37 years) reported having EoE. The odds of having EoE were significantly greater in male participants (adjusted odds ratio aOR, 1.3; 95% CI, 1.04-1.72) and those with comorbid asthma (aOR, 2.0; 95% CI, 1.55-2.49), allergic rhinitis (aOR, 1.8; 95% CI, 1.37-2.22), oral allergy syndrome (aOR, 2.8; 95% CI, 2.09-3.70), food protein-induced enterocolitis syndrome (aOR, 2.5; 95% CI, 1.34-4.84), and hyper-IgE syndrome (aOR, 7.6; 95% CI, 2.93-19.92), though not atopic dermatitis (aOR, 1.3; 95% CI, 0.99-1.59), when adjusting for demographics (sex, age, race, ethnicity, and geographic location). Those with a greater number of food allergies (aOR, 1.3; 95% CI, 1.23-1.32), more frequent food-related allergic reactions (aOR, 1.2; 95% CI, 1.11-1.24), previous anaphylaxis (aOR, 1.5; 95% CI, 1.15-1.83), and health care utilization for food-related allergic reactions (aOR, 1.3; 95% CI, 1.01-1.67)-specifically intensive care unit admission (aOR, 1.2; 95% CI, 1.07-1.33)-were more likely to have EoE after controlling for demographics. However, no significant difference in ever using epinephrine for food-related allergic reactions was detected.
These self-reported data showed that coexisting EoE is associated with an increased number of food allergies, food-related allergic reactions per year, and measures of reaction severity, calling attention to the likely increased health care needs of food-allergic patients with EoE.
A fundamental step in the life cycle of Francisella tularensis is bacterial entry into host cells. F. tularensis activates complement, and recent data suggest that the classical pathway is required ...for complement factor C3 deposition on the bacterial surface. Nevertheless, C3 deposition is inefficient and neither the specific serum components necessary for classical pathway activation by F. tularensis in nonimmune human serum nor the receptors that mediate infection of neutrophils have been defined. In this study, human neutrophil uptake of GFP-expressing F. tularensis strains live vaccine strain and Schu S4 was quantified with high efficiency by flow cytometry. Using depleted sera and purified complement components, we demonstrated first that C1q and C3 were essential for F. tularensis phagocytosis, whereas C5 was not. Second, we used purification and immunodepletion approaches to identify a critical role for natural IgM in this process, and then used a wbtA2 mutant to identify LPS O-Ag and capsule as prominent targets of these Abs on the bacterial surface. Finally, we demonstrate using receptor-blocking Abs that CR1 (CD35) and CR3 (CD11b/CD18) acted in concert for phagocytosis of opsonized F. tularensis by human neutrophils, whereas CR3 and CR4 (CD11c/CD18) mediated infection of human monocyte-derived macrophages. Altogether, our data provide fundamental insight into mechanisms of F. tularensis phagocytosis and support a model whereby natural IgM binds to surface capsular and O-Ag polysaccharides of F. tularensis and initiates the classical complement cascade via C1q to promote C3 opsonization of the bacterium and phagocytosis via CR3 and either CR1 or CR4 in a phagocyte-specific manner.
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