The microenvironment of the cochlea is maintained by the barrier between the systemic circulation and the fluids inside the stria vascularis. However, the mechanisms that control the permeability of the intrastrial fluid-blood barrier remain largely unknown. The barrier comprises endothelial cells connected to each other by tight junctions and an underlying basement membrane. In a recent study, we found that the intrastrial fluid-blood barrier also includes a large number of perivascular cells with both macrophage and melanocyte characteristics. The perivascular-resident macrophage-like melanocytes (PVM/Ms) are in close contact with vessels through cytoplasmic processes. Here we demonstrate that PVM/Ms have an important role in maintaining the integrity of the intrastrial fluid-blood barrier and hearing function. Using a cell culture-based in vitro model and a genetically induced PVM/M-depleted animal model, we show that absence of PVM/Ms increases the permeability of the intrastrial fluid-blood barrier to both lowand high-molecular-weight tracers. The increased permeability is caused by decreased expression of pigment epithelial-derived factor, which regulates expression of several tight junction-associated proteins instrumental to barrier integrity. When tested for endocochlear potential and auditory brainstem response, PVM/ M-depleted animals show substantial drop in endocochlear potential with accompanying hearing loss. Our results demonstrate a critical role for PVM/Ms in regulating the permeability of the intrastrial fluid-blood barrier for establishing a normal endocochlear potential hearing threshold. mouse cochlea | paracellular permeability | tight junction | capillary T he intrastrial fluid-blood barrier separates the stria vascularis (SV) from peripheral circulation. The integrity of the barrier is critical for maintaining inner ear homeostasis, especially for sustaining the endocochlear potential (EP), an essential driving force for hearing function (1-4). Disruption of the barrier is closely associated with a number of hearing disorders, including autoimmune inner ear disease, noise-induced hearing loss, agerelated hearing loss, and several genetically linked diseases (5-10). Despite the importance of the intrastrial fluid-blood barrier, little is understood about regulation of the barrier and the mechanisms that control its permeability.In the classic view, the intrastrial fluid-blood barrier comprises basement membrane and endothelial cells (ECs) that connect to each other with tight junctions (11) to form a diffusion barrier that prevents most blood-borne substances from entering the ear (2). In a recent study, we found that the intrastrial fluid-blood barrier also includes a large number of pericytes and perivascular-resident macrophage-like melanocytes (PVM/Ms) (12, 13). The PVM/Ms are not observed in other capillary regions such as in capillary beds of the spiral ligament. The PVM/Ms are in close contact with vessels through cytoplasmic processes. The structural complexity of PVM/Ms' capillar...

BackgroundAdequate bowel preparation is required for magnetic resonance enterography (MRE), which can be achieved by administering contrast solution after mid-gut tubing or taking contrast solution orally. We present the design of randomized controlled trial (RCT) to compare the efficacy and compliance of bowel preparation between mid-gut tubing and oral administering for MRE in patients with Crohn’s disease (CD).Methods/designThis is an open-label, multicenter RCT. Ninety-six patients with CD in need of MRE examination and mid-gut tubing (prepared for fecal microbiota transplantation and/or enteral nutrition), aged ≥ 14 years, will be included. Patients will be randomized 1:1 into either bowel preparation by oral administering (oral group) or bowel preparation through mid-gut transendoscopic enteral tubing (TET) (tubing group). The primary outcome measures are: (1) degree of discomfort before/during/after bowel preparation for MRE using a visual 5-grade scale (1 = few, 5 = very severe); and (2) grade of bowel distention evaluated by a 5-grade scale (1 = 0–20% segmental distention, 2 = 20–40% distention, 3 = 40–60% distention, 4 = 60–80% distention, 5 = 80–100% distention). The secondary outcome measure is the accuracy of lesion detection through MRE confirmed by colonoscopy which is evaluated by a 5-point scale.DiscussionThe outcome of this study is expected to provide a novel effective clinical protocol of bowel preparation for MRE in patients with CD. We hope to highlight the concept of physician–patient satisfaction based on different methods of bowel preparation for MRE.Trial registrationClinicalTrials.gov, NCT03541733. Registered on 30 May 2018.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-3101-x) contains supplementary material, which is available to authorized users.

Background The global dissemination of colistin resistance encoded by mcr-1 has been attributed to extensive use of colistin in livestock, threatening colistin efficacy in medicine. The emergence of mcr-1 in common pathogens, such as Escherichia coli, is of particular concern. China banned the use of colistin in animal feed from May 1, 2017. We investigated subsequent changes in mcr-1 prevalence in animals, humans, food, and the environment, and the genomic epidemiology of mcr-1-positive E coli (MCRPEC).Methods Sampling was done before (October to December, 2016) and after (October to December, 2017, and 2018, respectively) the colistin ban. 3675 non-duplicate pig faecal samples were collected from 14 provinces (66 farms) in China to measure intervention-related changes in mcr-1 prevalence. 15 193 samples were collected from pigs, healthy human volunteers, patients colonised or infected with Enterobacteriaceae who were admitted to hospital, food and the environment in Guangzhou, to characterise source-specific mcr-1 prevalence and the wider ecological effect of the ban. From these samples, 688 MCRPEC were analysed with whole genome sequencing, plasmid conjugation, and S1 pulsed-field gel electrophoresis with Southern blots to characterise associated genomic changes. FindingsAfter the ban, mcr-1 prevalence decreased significantly in national pig farms, from 308 (45%) of 684 samples in 2016 to 274 (19%) of 1416 samples in 2018 (p<0•0001). A similar decrease occurred in samples from most sources in Guangzhou (959 [19%] of 5003 samples in 2016; 238 [5%] of 4489 samples in 2018; p<0•0001). The population structure of MCRPEC was diverse (23 sequence clusters); sequence type 10 clonal complex isolates were predominant (247 [36%] of 688). MCRPEC causing infection in patients admitted to hospital were genetically more distinct and appeared less affected by the ban. mcr-1 was predominantly found on plasmids (632 [92%] of 688). Common mcr-1 plasmid types included IncX4, IncI2, and IncHI2 (502 [76%] of 656); significant increases in IncI2-associated mcr-1 and a distinct lineage of mcr-1-associated IncHI2 were observed post ban. Changes in the frequency of mcr-1-associated flanking sequences (ISApl1-negative MCRPEC), 63 core genome single nucleotide polymorphisms, and 30 accessory genes were also significantly different after the ban (Benjamini-Hochberg-adjusted p<0•05), consistent with rapid genetic adaptation in response to changing selection pressures. Interpretation A rapid, ecosystem-wide, decline in mcr-1 was observed after the use of colistin in animal feed was banned, with associated genetic changes in MCRPEC. Withdrawal of antimicrobials from animal feed should be an important One Health measure contributing to the wider control of antimicrobial resistance globally.

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Key Points• RUNX1/RUNX1T1-based MRD status at 1, 2, and 3 months after HSCT could discriminate patients at high risk of post-HSCT relapse.• Rather than c-KIT mutations, MRD monitoring allows further rapid identification of patients at high risk of relapse after allo-HSCT.We asked whether minimal residual disease (MRD) determined by RUNX1/RUNX1T1 transcript levels could identify allogeneic hematopoietic stem cell transplantation (allo-HSCT) t(8;21) (q22;q22) acute myeloid leukemia patients who are at high risk for relapse, together with the impact of c-KIT mutations. Ninety-two consecutive adult t(8;21) patients who received allo-HSCT in complete remission were enrolled. MRD status at 1, 2, and 3 months after HSCT identified relapse patients (P 5 .05, P < .001, P 5 .0001, respectively). The 2-year cumulative incidence of relapse (CIR) and leukemia-free survival (LFS) was 32% vs 9% (P 5 .01) and 55% vs 70% (P 5 .12) for patients with and without c-KIT mutations, respectively. In multivariate analysis, MRD at the first 3 months after HSCT, rather than c-KIT mutations, was an independent factor for CIR (P 5 .001) and LFS (P 5 .001).In addition, 17 patients received donor lymphocyte infusion (DLI) as interventional therapy for MRD, and the 2-year CIR and LFS for patients with or without DLI was 24% vs 87% (P 5 .001) and 64% vs 0% (P < .001), respectively. In conclusion, MRD monitoring early after transplant allows further rapid identification of t(8;21) patients at high risk of relapse and was more predictive of relapse risk than

Animal models have indicated that intestinal microbiota influence acute graft-versus-host disease (aGVHD) by modulating immune homeostasis. But, in humans, the mechanism by which the microbiota induces aGVHD remains unclear. In this study, we investigated the relationship between the intestinal microbiota and T cell subsets in patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT) to explore the mechanism by which microbiota induced aGVHD. Based on aGVHD, this study was categorized into two groups: grades II–IV aGVHD (aGVHD group, n = 32) and grade 0–I aGVHD (non-aGVHD group, n = 49). The intestinal microbiota was detected by 16S rRNA gene sequencing, and the T cell subsets and histone 3 (H3) acetylation in CD4+ T cells in the peripheral blood was assayed by flow cytometry at the time of engraftment. The aGVHD group had greater low microbial diversity than the non-aGVHD group (56.3 versus 24.5%, p = 0.004). The bacterial community was depleted of Clostridia (e.g., the Lachnospiraceae and Ruminococcaceae families) and enriched for Gammaproteobacteria (e.g., the Enterobacteriaceae family) in the aGVHD group compared with the non-aGVHD group. The relative abundance of Lachnospiraceae and Ruminococcaceae was positively correlated with the Treg/Th17 ratio counts (r = 0.469 and 0.419; p < 0.001 and <0.001, respectively), whereas Enterobacteriaceae was negatively correlated with the Treg/Th17 ratio (r = −0.277; p = 0.012). The level of acetylated H3 in CD4+ T cells was not only correlated with Lachnospiraceae/Ruminococcaceae, but also with the Treg/Th17 ratio (r = 0.354; p = 0.001). In conclusions, our results suggest that decreased Lachnospiraceae and Ruminococcaceae and increased Enterobacteriaceae, correlate with a Treg/Th17 imbalance, which might be through acetylated H3 in CD4+ T cells. These findings suggest that intestinal microbiota might induce aGVHD by influencing the Treg/Th17 balance.

Results indicate that T-614 therapy 50 mg/day is effective and well tolerated, and represents a new option for the treatment of patients with active RA.

Metabolic fingerprints of biofluids encode diverse diseases and particularly urine detection offers complete noninvasiveness for diagnostics of the future.P resent urine detection affords unsatisfactory performance and requires advanced materials to extract molecular information, due to the limited biomarkers and high sample complexity.Herein, we report plasmonic polymer@Ag for laser desorption/ionization mass spectrometry (LDI-MS) and sparse-learning-based metabolic diagnosis of kidney diseases.U sing only 1 mLo fu rine without enrichmento rp urification, polymer@Ag afforded urine metabolic fingerprints (UMFs) by LDI-MS in seconds. Analysis by sparse learning discriminated lupus nephritis from various other non-lupus nephropathies and controls.W e combined UMFs with urine protein levels (UPLs) and constructed an ew diagnostic model to characterizes ubtypes of kidney diseases.Our work guides urine-based diagnosis and leads to new personalized analytical tools for other diseases.