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Commensal microbiota are well known to play an important role in antiviral immunity by providing immune inductive signals; however, the consequence of dysbiosis on antiviral immunity remains unclear. We demonstrate that dysbiosis caused by oral antibiotic treatment directly impairs antiviral immunity following viral infection of the vaginal mucosa. Antibiotic-treated mice succumbed to mucosal herpes simplex virus type 2 infection more rapidly than water-fed mice, and also showed delayed viral clearance at the site of infection. However, innate immune responses, including type I IFN and proinflammatory cytokine production at infection sites, as well as induction of virus-specific CD4 and CD8 T-cell responses in draining lymph nodes, were not impaired in antibiotic-treated mice. By screening the factors controlling antiviral immunity, we found that IL-33, an alarmin released in response to tissue damage, was secreted from vaginal epithelium after the depletion of commensal microbiota. This cytokine suppresses local antiviral immunity by blocking the migration of effector T cells to the vaginal tissue, thereby inhibiting the production of IFN-γ, a critical cytokine for antiviral defense, at local infection sites. These findings provide insight into the mechanisms of homeostasis maintained by commensal bacteria, and reveal a deleterious consequence of dysbiosis in antiviral immune defense.

Injectable depot medroxyprogesterone acetate (DMPA) is one of the most popular contraception methods in areas of high HIV seroprevalence. Evidence is accumulating that use of DMPA might be associated with an increased risk of HIV-1 acquisition by women; however, mechanisms of this association are not completely understood. The goal of this study was to gain insight into mechanisms underlying the possible link between use of DMPA and risk of HIV-1 acquisition, exploring transcription profiling of ectocervical tissues. Healthy women received either DMPA (n = 31) or combined oral contraceptive (COC), which has not been linked to an increased risk of HIV acquisition (n = 32). We conducted a comparative microarray-based whole-genome transcriptome profiling of human ectocervical tissues before and after 6 weeks of hormonal contraception use. The analysis identified that expression of 235 and 76 genes was significantly altered after DMPA and COC use, respectively. The most striking effect of DMPA, but not COC, was significantly altered expression (mostly downregulation) of many genes strategically involved in the maintenance of mucosal barrier function; the alterations, as indicated by Ingenuity Pathway Analysis (IPA), were most likely due to the DMPA-induced estrogen deficiency. Furthermore, IPA predicted that transcriptome alterations related to ectocervical immune responses were in general compatible with an immunosuppressive effect of DMPA, but, in some women, also with an inflammatory-like response. Our results suggest that impairment of cervicovaginal mucosal integrity in response to DMPA administration is an important mechanism contributing to the potential increased risk of HIV-1 acquisition in DMPA users. ClinicalTrials.gov NCT01421368. This study was supported by the United States Agency for International Development (USAID) under Cooperative Agreement GPO-A-00-08-00005-00.

BackgroundIn a tertiary center setting we aimed to study the diagnostic accuracy and clinical impact of EUS-guided biopsy sampling (EUS-FNB) with a reverse bevel needle compared with that of fine needle aspiration (EUS-FNA) in the work-up of subepithelial lesions (SEL).MethodsAll patients presenting with SELs referred for EUS-guided sampling were prospectively included in 2012–2015. After randomization of the first pass modality, dual sampling with both EUS-FNB and EUS-FNA was performed in each lesion. Outcome measures in an intention-to-diagnose analysis were the diagnostic accuracy, technical failures, and adverse events. The clinical impact was measured as the performance of additional diagnostic procedures post-EUS and the rate of unwarranted resections compared with a reference cohort of SELs sampled in the same institution 2006–2011.ResultsIn 70 dual sampling procedures of unique lesions (size: 6–220 mm) the diagnostic sensitivity for malignancy and the overall accuracy of EUS-FNB was superior to EUS-FNA compared head-to-head (90 vs 52%, and 83 vs 49%, both p < 0.001). The adverse event rate of EUS-FNB was low (1.2%). EUS-FNB in 2012–2015 had a positive clinical impact in comparison with the reference cohort demonstrated by less cases referred for an additional diagnostic procedure, 12/83 (14%) vs 39/73 (53%), p < 0.001, and fewer unwarranted resections in cases subjected to surgery, 3/48 (6%) vs 12/35 (34%), p = 0.001.ConclusionsEUS-FNB with a reverse bevel needle is safe and superior to EUS-FNA in providing a conclusive diagnosis of subepithelial lesions. This biopsy sampling approach facilitates a rational clinical management and accurate treatment.

Mucous membrane pemphigoids (MMPs) and bullous pemphigoid (BP) are autoimmune bullous diseases that share physiopathological features: both can result from autoantibodies directed against BP180 or BP230 antigens. An association has been reported between BP and intake of gliptins, which are dipeptidyl peptidase-IV inhibitors used to treat type 2 diabetes mellitus. Clinical and immunological differences have been reported between gliptin-induced BPs and classical BPs: mucosal involvement, non-inflammatory lesions, and target BP180 epitopes other than the NC16A domain. Those findings accorded gliptins extrinsic accountability in triggering MMP onset. Therefore, we examined gliptin intrinsic accountability in a cohort of 313 MMP patients. To do so, we (1) identified MMP patients with gliptin-treated (challenge) diabetes; (2) selected those whose interval between starting gliptin and MMP onset was suggestive or compatible with gliptin-induced MMP; (3) compared the follow-ups of patients who did not stop (no dechallenge), stopped (dechallenge) or repeated gliptin intake (rechallenge); (4) compared the clinical and immunological characteristics of suggestive-or-compatible-challenge patients to 121 never-gliptin-treated MMP patients serving as controls; and (5) individually scored gliptin accountability as the trigger of each patient's MMP using the World Health Organization-Uppsala Monitoring Center, Naranjo- and Begaud-scoring systems. 17 out of 24 gliptin-treated diabetic MMP patients had suggestive (≤12 weeks) or compatible challenges. Complete remission at 1 year of follow-up was more frequent in the 11 dechallenged patients. One rechallenged patient's MMP relapsed. These 17 gliptin-treated diabetic MMP patients differed significantly from the MMP controls by more cutaneous, less buccal, and less severe involvements and no direct immunofluorescence IgA labeling of the basement membrane zone. Multiple autoantibody-target antigens/epitopes (BP180-NC16A, BP180 mid- and C-terminal parts, integrin α6β4) could be detected, but not laminin 332. Last, among the 24 gliptin-treated diabetic MMP patients, five had high (I4-I3), 12 had low (I2-I1) and 7 had I0 Begaud intrinsic accountability scores. These results strongly suggest that gliptins are probably responsible for some MMPs. Consequently, gliptins should immediately be discontinued for patients with a positive accountability score. Moreover, pharmacovigilance centers should be notified of these events.

The adequacy of exposure of purine analogs as measured by 6-thioguanine nucleotides concentrations in the setting of combination therapy remains poorly understood. The aim of this study was to investigate the relationship between the mean corpuscular volume (MCV) value (as a surrogate marker of 6-thioguanine nucleotides concentration) and Crohn's disease outcomes in the setting of combination therapy with infliximab.MethodsThe SONIC trial was a randomized controlled trial comparing infliximab to azathioprine and to infliximab plus azathioprine in 508 Crohn's disease patients. An increase of at least 7 femtoliter (fL) of the MCV (ΔMCV) was used for statistical analysis.ResultsAt week 26, the mean increase of MCV was similar among patients treated with azathioprine alone (mean of 7.9 fL) or in combination with infliximab (mean of 8.5 fL). In the azathioprine group, 63.6% of patients with ΔMCV >7 were in steroid-free clinical remission at week 26 as compared with 33.3% of patients without ΔMCV >7 (P = 0.0046). In the combination therapy group, ΔMCV above 7 was associated with mucosal healing (75.0% for ΔMCV >7 versus 47.1% for ΔMCV <7, P = 0.0172) but not with steroid-free clinical remission. Patients with a ΔMCV above 7 were more likely to have infliximab trough level above 3 μg/mL at week 30 (68.4% versus 38.8% for ΔMCV <7, P = 0.0032).ConclusionsThese results suggest that ΔMCV above 7 (which is a surrogate for a higher 6-thioguanine nucleotides concentration) leads to improved Crohn's disease outcomes, even when combined with infliximab. It also suggests the possibility that a lower azathioprine exposure might be less effective in combination therapy.

To compare endoscopic epitympanic exploration with conventional canal wall up (cortical) mastoidectomy for mucosal chronic otitis media in terms of post-operative outcomes. Seventy-six patients diagnosed with chronic otitis media (mucosal variety) were randomly assigned to two treatment groups: endoscopic epitympanic exploration and conventional canal wall up (cortical) mastoidectomy. The groups were compared in terms of: post-operative anatomical outcomes (graft uptake), middle-ear physiological outcomes (post-operative tympanometry), audiological outcomes (air-bone gap), surgical time, post-operative pain, vertigo, and long-term complications such as retraction pocket and re-perforation. There was a statistically significant difference between the groups in terms of mean air-bone gap at 12 months, surgical time, and median post-operative pain measured at 6 hours (p < 0.05). No statistically significant differences were noted in terms of: graft uptake at 1, 3 and 6 months, mean air-bone gap at 3 and 6 months, tympanometry at 3, 6 and 12 months, vertigo at 1 week, or long-term complications. Endoscopic epitympanic exploration resulted in significantly better long-term audiological outcomes, shorter operating time and less pain compared with conventional canal wall up (cortical) mastoidectomy.

Dysplasia in a Barrett's esophagus (BE) is associated with an increased risk for developing esophageal adenocarcinoma. Ablation using the HALO system has shown promise for the treatment of BE with dysplasia. The objective of this study was to assess the safety and efficacy of a stepwise regimen of circumferential and focal ablation using the HALO system for the treatment of BE with dysplasia. BE patients with low-grade dysplasia (LGD) or high-grade dysplasia (HGD) were enrolled. Primary circumferential ablation was followed every 3 months by further circumferential ablation or focal ablation until complete endoscopic eradication of BE was achieved. At 3- or 6-month intervals, depending on baseline grade, targeted and four quadrant random biopsies were obtained to assess the histological response to ablation. A complete response (CR) is defined as all biopsies negative for intestinal metaplasia (IM) (CR-IM) or dysplasia (CR-D) at last available follow-up. A total of 63 patients were treated (57 men; median age 71 years; median BE length 5 cm), with worst grade of dysplasia being LGD (n=39) and HGD (n=24). Follow-up is available for 62 patients (median 24 months). Overall, CR-IM is 79% and CR-D is 89%. For the LGD cohort, CR-IM is 87% and CR-D is 95%. For the HGD cohort, CR-IM is 67% and CR-D is 79%. Stepwise circumferential and focal ablation of BE containing dysplasia appears to be a safe and effective intervention, achieving a CR for dysplasia in 95% and 79% of LGD and HGD patients, respectively.

Microorganisms colonize various ecological niches in the human habitat, as they do in nature. Predominant forms of multicellular communities called biofilms colonize human tissue surfaces. The gastrointestinal tract is home to a profusion of microorganisms with intertwined, but not identical, lifestyles: as isolated planktonic cells, as biofilms and in biofilm-dispersed form. It is therefore of major importance in understanding homeostatic and altered host–microorganism interactions to consider not only the planktonic lifestyle, but also biofilms and biofilm-dispersed forms. In this Review, we discuss the natural organization of microorganisms at gastrointestinal surfaces, stratification of microbiota taxonomy, biogeographical localization and trans-kingdom interactions occurring within the biofilm habitat. We also discuss existing models used to study biofilms. We assess the contribution of the host–mucosa biofilm relationship to gut homeostasis and to diseases. In addition, we describe how host factors can shape the organization, structure and composition of mucosal biofilms, and how biofilms themselves are implicated in a variety of homeostatic and pathological processes in the gut. Future studies characterizing biofilm nature, physical properties, composition and intrinsic communication could shed new light on gut physiology and lead to potential novel therapeutic options for gastrointestinal diseases. In this Review, Motta, Vergnolle and colleagues describe the organization of microorganisms into planktonic, biofilm and biofilm-dispersed forms in the gastrointestinal tract. The role of the host–biofilm relationship in gut homeostasis and disease is discussed. Key points Bacteria adopt different lifestyles in their natural habitats, from single planktonic cells to biofilm communities. Polymicrobial biofilms naturally grow throughout the gastrointestinal tract, both at the epithelial surface and in the lumen as mucin-attached and food particle-attached colonies. The biofilm lifestyle influences metabolic behaviour of the microbiota but more research is needed to characterize gut biofilm-specific metabolites and their effects on the host response in health and disease. Polymicrobial and trans-kingdom interactions occur in gut biofilms; deciphering the nature of such interactions might improve our current understanding of the homeostatic relationship between the host and its gut microbiota. Abnormal biofilm features are associated with gastrointestinal diseases; characterization of biofilm alterations and cause-to-effect studies are warranted to elucidate their role in pathophysiology. Investigating biogeographical redistribution of biofilms at mucosal surfaces might provide new tools to characterize microbial alterations associated with gastrointestinal diseases and options for therapeutic intervention.

The histological changes that occur in the squamous epithelium in response to acute acid challenge was examined in healthy controls and proton pump inhibitor-treated gastroesophageal reflux disease (GERD) patients and related to the state of untreated erosive GERD in a saline-controlled, randomized perfusion study. In the basal state a stepwise significant increase in the thickness of the basal cell layer, papillary length, and dilatation of intercellular spaces (DIS) was seen when the three groups were compared. Acid perfusion induced a slight increase in the height of the basal cell layer mainly in healthy volunteers; this layer appears to be reactive to acute acid challenge as well as to acid suppressive therapy. DIS increases promptly in response to acute acid exposure in the healthy epithelium but no changes were seen in the lengths of the papillae or regarding DIS in the GERD patients. A protective effect of luminal nitric oxide on DIS development is suggested.

Methylene blue (MB) selectively stains specialized intestinal metaplasia (SIM) and may assist in surveying a columnar-lined esophagus for Barrett's esophagus associated dysplasia. This is a prospective, randomized crossover study comparing 4-quadrant random biopsies (4QB) versus MB-directed biopsies for the detection of SIM and dysplasia in 48 patients with long segment Barrett's esophagus (LSBE). Patients randomly underwent two endoscopies over a 4-wk time period with either 4QB or MB-directed biopsies as their first or second exam. Our aim was to correlate stain intensity with histology. The sensitivity of MB for SIM and dysplasia was 75.2% and 83.1%, respectively. The yield of 4QB for identifying nondysplasia SIM was 57.6% (523/917) and for dysplasia was 12% (111/917). Dark staining was significantly associated with histologic grade (P < 0.007). The final diagnosis was correct in 43 (90%) patients using MB and in 45 (94%) using 4QB. The 4QB technique missed dysplasia in 3 of 21 patients while MB biopsies missed dysplasia in 5 of 21 patients. The discordance between the two techniques was not significant (P= 0.727, McNemar's test). The mean number of biopsies taken during 4QB was 18.92 +/- 6.36 and with MB was 9.23 +/- 2.89 (P < 0.001). MB requires significantly fewer biopsies than 4QB to evaluate for SIM and dysplasia. Dark staining correlates more with HGD than LGD in our experience. While MB is not more accurate than 4QB, MB may help to define areas to target for biopsy during surveillance endoscopy in patients with LSBE.