Females have a more severe clinical course than males in terms of several inflammatory lung conditions. Notably, females with cystic fibrosis (CF) suffer worse outcomes, particularly in the setting of infection. Sex hormones have been implicated in experimental and clinical studies; however, immune mechanisms responsible for this sex-based disparity are unknown and the specific sex hormone target for therapeutic manipulation has not been identified. The objective of this study was to assess mechanisms behind the impact of female sex hormones on host immune responses to We used wild-type and CF mice, which we hormone manipulated, inoculated with , and then examined for outcomes and inflammatory responses. Neutrophils isolated from mice and human subjects were tested for responses to We found that female mice inoculated with died earlier and showed slower bacterial clearance than males ( < 0.0001). Ovariectomized females supplemented with 17β-estradiol succumbed to challenge earlier than progesterone- or vehicle-supplemented mice ( = 0.0003). 17β-Estradiol-treated ovariectomized female mice demonstrated increased lung levels of inflammatory cytokines, and when rendered neutropenic the mortality difference was abrogated. Neutrophils treated with 17β-estradiol demonstrated an enhanced oxidative burst but decreased killing and earlier cell necrosis. The estrogen receptor (ER) antagonist ICI 182,780 improved survival in female mice infected with and restored neutrophil function. We concluded that ER antagonism rescues estrogen-mediated neutrophil dysfunction and improves survival in response to ER-mediated processes may explain the sex-based mortality gap in CF and other inflammatory lung illnesses, and the ER blockade represents a rational therapeutic strategy.
BACKGROUND:Long-term outcomes and efficacy of partial stapled hemorrhoidopexy are not known.OBJECTIVE:The purpose of this study was to compare the long-term clinical efficacy and safety of partial stapled hemorrhoidopexy with circumferential stapled hemorrhoidopexy.DESIGN:This was a parallel group, randomized, noninferiority clinical trial.SETTINGS:The study was conducted at a single academic center.PATIENTS:Patients with grade III/IV hemorrhoids between August 2011 and November 2013 were included.INTERVENTIONS:Three hundred patients were randomly assigned to undergo either partial stapled hemorrhoidopexy (group 1, n = 150) or circumferential stapled hemorrhoidopexy (group 2, n = 150).MAIN OUTCOME MEASURES:The primary outcome was the rate of recurrent prolapse at a median follow-up period of 5 years with a predefined noninferiority margin of 3.75%. Secondary outcomes included incidence and severity of postoperative pain, fecal urgency, anal continence, and the frequency of specific complications, including anorectal stenosis and rectovaginal fistula.RESULTS:The visual analog scores in group 1 were less than those in group 2 (p < 0.001). Fewer patients in group 1 experienced postoperative urgency compared with those in group 2 (p = 0.001). Anal continence significantly worsened after both procedures, but the difference between preoperative and postoperative continence scores was higher for group 2 than for group 1. Postoperative rectal stenosis did not develop in patients in group 1, although it occurred in 8 patients (5%) in group 2 (p = 0.004). The 5-year cumulative recurrence rate between group 1 (9% (95% CI, 4%–13%)) and group 2 (12% (95% CI, 7%–17%)) did not differ significantly (p = 0.137), and the difference was within the noninferiority margin (absolute difference, –3.33% (95% CI, –10.00% to 3.55%)).LIMITATIONS:The study was limited because it was a single-center trial.CONCLUSIONS:Partial stapled hemorrhoidopexy is noninferior to circumferential stapled hemorrhoidopexy for patients with grade III to IV hemorrhoids at a median follow-up period of 5 years. However, partial stapled hemorrhoidopexy was associated with reduced postoperative pain and urgency, better postoperative anal continence, and minimal risk of rectal stenosis. See Video Abstract at http://links.lww.com/DCR/A790.Trial registration (chictr.org) identifier is chiCTR-trc-11001506.
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