Eosinophilic inflammation has been implicated in the pathogenesis, severity, and treatment responsiveness of chronic rhinosinusitis with nasal polyps (CRSwNP).
We sought to assess the efficacy and ...safety of benralizumab-mediated eosinophil depletion for treating CRSwNP.
The phase 3 OSTRO study enrolled patients with severe CRSwNP who were symptomatic despite treatment with intranasal corticosteroids and who had a history of systemic corticosteroid (SCS) use and/or surgery for nasal polyps (NP). Patients were randomized 1:1 to treatment with benralizumab 30 mg or placebo every 4 weeks for the first 3 doses and every 8 weeks thereafter. Coprimary end points were change from baseline to week 40 in NP score (NPS) and patient-reported mean nasal blockage score reported once every 2 weeks.
The study population comprised 413 randomized patients (207 in the benralizumab group and 206 in the placebo group). Benralizumab significantly improved NPS and nasal blockage score compared to placebo at week 40 (P ≤ .005). Improvements in Sinonasal Outcome Test 22 score at week 40, time to first NP surgery and/or SCS use for NP, and time to first NP surgery were not statistically significant between treatment groups. Nominal significance was obtained for improvement in difficulty in sense of smell score at week 40 (P = .003). Subgroup analyses suggested influences of comorbid asthma, number of NP surgeries, sex, body mass index, and baseline blood eosinophil count on treatment effects. Benralizumab was safe and well tolerated.
Benralizumab, when added to standard-of-care therapy, reduced NPS, decreased nasal blockage, and reduced difficulty with sense of smell compared to placebo in patients with CRSwNP. Trial registration: ClinicalTrials.gov NCT03401229
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Abstract Posttraumatic stress disorder (PTSD) is one of the most common psychiatric disorders. Despite the extensive study of the neurobiological correlates of this disorder, the underlying ...mechanisms of PTSD are still poorly understood. Recently, a study demonstrated that dexamethasone (Dex), a synthetic glucocorticoid, can up-regulate p11, known as S100A10-protein which is down-regulated in patients with depression, ( Yao et al., 1999; Huang et al., 2003 ) a common comorbid disorder in PTSD. These observations led to our hypothesis that traumatic stress may alter expression of p11 mediated through a glucocorticoid receptor. Here, we demonstrate that inescapable tail shock increased both prefrontal cortical p11 mRNA levels and plasma corticosterone levels in rats. We also found that Dex up-regulated p11 expression in SH-SY5Y cells through glucocorticoid response elements (GREs) within the p11 promoter. This response was attenuated by either RU486, a glucocorticoid receptor (GR) antagonist or mutating two of three glucocorticoid response elements (GRE2 and GRE3) in the p11 promoter. Finally, we showed that p11 mRNA levels were increased in postmortem prefrontal cortical tissue (area 46) of patients with PTSD. The data obtained from our work in a rat model of inescapable tail shock, a p11-transfected cell line and postmortem brain tissue from PTSD patients outline a possible mechanism by which p11 is regulated by glucocorticoids elevated by traumatic stress.
In this study, simulated "poor" repairs applied to transverse incisions in the iliac arteries of 40 rats were the basis for comparing the effect of variations in blood flow on thromboembolism. Using ...vital microscopy and digital image processing, we performed 2 experiments. In the first experiment (n = 20), the reduction of post-repair blood flow by approximately 50% resulted in an 83% reduction in the total number of emboli appearing in the microcirculation of the cremaster muscle distal to the repair. In the second experiment (n = 20), the same reduction in blood flow typically resulted in larger repair-site thrombi which required significantly more time to grow to their maximum size. We conclude that reducing pedicle artery blood flow to approximately half in our rat model during reperfusion can protect the downstream microcirculation from embolic injury without increasing the incidence of thrombotic occlusion.
Toluene is widely used as a component in industrial solvents and many toluene-containing products are abused via inhalation. While many studies have demonstrated its inhibitory effects on neuronal ...activity, the effects of toluene on receptor signaling in proliferating and differentiating neural precursor cells are presently unclear. Here, using digital video microscopy and Ca2+ imaging, we investigated the effects of acute exposure to toluene on the function of muscarinic acetylcholine receptors (mAChRs) expressed in neural precursor cells. The neural precursor cells were isolatedfrom embryonic day 13 (E13) rat cortex and expanded in serum-free medium containing basic fibroblast growth factor (bFGF). We found that the acetylcholine (ACh) analog carbachol (CCh) induced a dose-dependent increase in cytosolic Ca2+, which was blocked by the muscarinic receptor antagonist atropine in a reversible manner. Toluene was added to the perfusion medium and concentrations of toluene in the medium were determined by gas chromatographic analysis. Following imaging, the cells were fixed and processed for 5-bromo-2'-deoxyuridine (BrdU, cell proliferation marker) and beta-tubulin (TuJ1, neuronal marker) immunostaining. In the 5 day culture, most cells continued to divide (BrdU+), while afew cells differentiated into young neurons (TuJ1-). The CCh-induced Ca2+ elevations in proliferating (BrdU+TuJ1-) neural precursor cells were significantly reduced by acute exposure to 0.15 mM toluene and completely blocked by 10 mM toluene. Toluene's inhibition of muscarinic receptor-mediated Ca2+ signaling was rapid, reversible and dose-dependent with an IC50 value 0.5 mM. Since muscarinic receptors mediate cell proliferation and differentiation during neural precursor cell development, these results suggest that depression of muscarinic signaling may play a role in toluene's teratogenic effect on the developing nervous system.
Although free tissue transfer success has been greatly improved by developments in operating microscopes, microsutures, microinstruments, and technique, free flap and replant failure remain a ...significant problem under certain adverse circumstances. The nature of these failures is often multifactorial and remains poorly understood. A greater understanding of the processes involved would provide the potential for greater pharmacological control of any adverse conditions prevailing and would thus offer the prospect of more effective adjunctive therapy in the presence of such adverse conditions. Research endeavors in this area have been hindered by the absence of good research models. The isolated rat cremaster muscle model is a recently developed model that simulates the conditions of free tissue transfer. Using this model, both thrombus formation and numerous microcirculatory parameters can be measured. The microcirculatory parameters studied to date include the formation of thromboembolism, capillary perfusion, vessel diameters, red blood cell velocity, leukocyte-endothelium interaction, and microvascular leakage. The isolated rat cremaster muscle model addresses many of the shortcomings of earlier research models and offers the promise of answering at least some of the many unanswered questions relating to free flap and replant failure.
