We examined the associations of Epstein–Barr virus (EBV) status with characteristics and outcomes of posttransplantation lymphoproliferative disorder (PTLD) by studying 176 adult solid organ ...transplant recipients diagnosed with PTLD between 1990 and 2013 (58 33% EBV‐negative; 118 67% EBV‐positive). The proportion of EBV‐negative cases increased over time from 10% (1990–1995) to 48% (2008–2013) (p < 0.001). EBV‐negative PTLD had distinct characteristics (monomorphic histology, longer latency) though high‐risk features (advanced stage, older age, high lactate dehydrogenase, central nervous system involvement) were not more common compared to EBV‐positive PTLD. In multivariable analysis, EBV negativity was not significantly associated with worse response to initial therapy (adjusted odds ratio, 0.84; p = 0.75). The likelihood of achieving a complete remission (CR) was not significantly different for EBV‐negative versus EBV‐positive PTLD including when therapy was reduction of immunosuppression alone (35% vs. 43%, respectively, p = 0.60) or rituximab (43% vs. 47%, p = 1.0). EBV negativity was also not associated with worse overall survival (adjusted hazard ratio, 0.91; p = 0.71). Our findings indicate that EBV status is not prognostic or predictive of treatment response in adults with PTLD. The high proportion of EBV‐negative disease diagnosed in recent years highlights the need for new strategies for prevention and management of EBV‐negative PTLD.
In a study of 176 solid organ transplant recipients with posttransplantation lymphoproliferative disorder, the authors show that the proportion of Epstein–Barr virus–negative cases has increased over time, but Epstein–Barr virus negativity is not associated with high‐risk features, worse response to initial therapy, or worse overall survival.
Background
Mast cells (MCs) and vasoactive intestinal polypeptide (VIP) have been proposed as regulators of the intestinal barrier and inflammation. Our aim was to map the distribution in ...inflammatory bowel disease (IBD) and murine colitis.
Methods
MCs, VIP, and VIP‐receptors (VPACs) were quantified by immunofluorescence and enzyme‐immunoassay (EIA) in ileal tissues (villus epithelium (VE) and adjacent VE, ie, VE next to the follicle‐associated epithelium, (FAE)) from Crohn's disease (CD; n = 16) and non‐IBD patients, and in colonic specimens of ulcerative colitis (UC; n = 12) and healthy controls (HCs). In addition, VIP levels were measured in plasma from HCs, non‐IBD, and IBD in remission (CD n = 30; UC n = 30). Colon, ileum, and plasma from mice with dextran sulfate sodium (DSS)‐induced colitis and control mice were analyzed likewise.
Key Results
FAE‐adjacent VE in ileum of CD possessed more MCs (P < 0.05) and MCs expressing VPAC1 (P < 0.05), but not VPAC2, compared to controls. Both adjacent and regular VE of CD had more MCs co‐localizing/in close proximity to VIP (P < 0.05). In UC colon, more MCs (P < 0.0005), MCs close to VIP (P < 0.0005), and MCs expressing VPAC1 (P < 0.05) were found compared to controls. VIP levels were elevated in plasma from CD and UC compared to controls (P < 0.0005). Colon of DSS mice showed more MCs and MCs close to VIP (P < 0.05) compared to control mice. In vitro experiments revealed MCs expressing VPACs and internalized VIP after 120 minutes of VIP‐stimulation.
Conclusions and Inferences
Communication between MCs and VIP is upregulated during IBD and mice colitis. In CD patients, the epithelium next to FAE seems to be more involved than the surrounding VE, suggesting increased MC‐VIP‐interactions in this intestinal region.
Mast cells play an important role in IBD; however, the role of VIP has been conflicting and studies are mostly lacking. We found increased numbers of mast cells expressing VPAC1 and more mast cells co‐localizing/in close proximity to VIP in IBD patients and mice with colitis. Our results are important for the understanding of the pathogenesis of intestinal disorders and in the consideration of VIP as a therapeutic target.
Abstract
Background
The first visible signs of Crohn’s disease (CD) are microscopic erosions over the follicle-associated epithelium (FAE). The aim of the study was to investigate the effects of ...human α-defensin 5 (HD5) on adherent-invasive Escherichia coli LF82 translocation and HD5 secretion after LF82 exposure in an in vitro model of human FAE and in human FAE ex vivo.
Methods
An in vitro FAE-model was set up by the coculture of Raji B cells and Caco-2-cl1 cells. Ileal FAE from patients with CD and controls were mounted in Ussing chambers. The effect of HD5 on LF82 translocation was studied by LF82 exposure to the cells or tissues with or without incubation with HD5. The HD5 secretion was measured in human FAE exposed to LF82 or Salmonella typhimurium. The HD5 levels were evaluated by immunofluorescence, immunoblotting, and ELISA.
Results
There was an increased LF82 translocation across the FAE-model compared with Caco-2-cl1 (P < 0.05). Incubation of cell/tissues with HD5 before LF82 exposure reduced bacterial passage in both models. Human FAE showed increased LF82 translocation in CD compared with controls and attenuated passage after incubation with sublethal HD5 in both CD and controls (P < 0.05). LF82 exposure resulted in a lower HD5 secretion in CD FAE compared with controls (P < 0.05), whereas Salmonella exposure caused equal secretion on CD and controls. There were significantly lower HD5 levels in CD tissues compared with controls.
Conclusions
Sublethal HD5 reduces the ability of LF82 to translocate through FAE. The HD5 is secreted less in CD in response to LF82, despite a normal response to Salmonella. This further implicates the integrated role of antimicrobial factors and barrier function in CD pathogenesis.
Abstract
Background and Aims
Patients with Crohn’s disease CD harbour an increased number of adherent-invasive E. coli AIEC. The strain LF82, identified in the ileal mucosa of CD patients, has been ...extensively studied for pathogenic mechanisms. However, understanding of the interaction of LF82 with the intestinal mucosa of CD patients is lacking.
Methods
Here, we investigated the importance of long polar fimbriae LPF type 1 pili and the carcinoembryonic antigen-related cell-adhesion molecule 6 CEACAM6 for translocation of LF82 in an in vitro model of follicle-associated epithelium FAE, and in the FAE and villus epithelium VE of patients with CD and controls, using Ussing chambers.
Results
Significantly greater LF82 passage occurred in the FAE model compared with in the VE Caco-2cl1 mono-culture. Moreover, bacterial translocation was inhibited by either LPF disruption or pre-incubation with anti-CEACAM6 antibody. Tissue mounted in Ussing chambers showed significantly higher LF82 passage in FAE from patients with CD compared with control FAE, that was diminished in LF82 lacking LPF and by blocking host CEACAM6. Interestingly, addition of LF82 to the CD FAE tissues significantly increased paracellular permeability of 51Chromium-EDTA compared with baseline, and the increase was inhibited by anti-CEACAM6. Immunofluorescence and immunoblots showed higher expression of CEACAM6 in FAE of patients with CD compared with in FAE from controls.
Conclusions
These data suggest that the FAE of CD patients is a site of vulnerability for invasion by LF82 via a mechanism that requires both bacterial LPF and host CEACAM6. Further, LF82 has the ability to increase paracellular passage through the FAE of patients with CD. These data can help define novel therapeutic targets in CD for the prevention of clinical recurrence.
We report here the synthesis and characterization of a family of copper(I) metal precursors based around cyclopentadienyl and isocyanide ligands. The molecular structures of several ...cyclopentadienylcopper(I) isocyanide complexes have been unambiguously determined by single-crystal X-ray diffraction analysis. Thermogravimetric analysis of the complexes highlighted the isopropyl isocyanide complex (η5-C5H5)Cu(CNiPr) (2a) and the tert-butyl isocyanide complex (η5-C5H5)Cu(CNtBu) (2b) as possible copper metal chemical vapor deposition (CVD) precursors. Further modification of the precursors with variation of the substituents on the cyclopentadienyl ligand system (varying between H, Me, Et, and iPr) has allowed the affect that these changes would have on features such as stability, volatility, and decomposition to be investigated. As part of this study, the vapor pressures of the complexes 2b, (η5-MeC5H4)Cu(CNtBu) (3b), (η5-EtC5H4)Cu(CNtBu) (4b), and (η5-iPrC5H4)Cu(CNtBu) (5b) over a 40–65 °C temperature range have been determined. Low-pressure chemical vapor deposition (LP-CVD) was employed using precursors 2a and 2b to synthesize thin films of metallic copper on silicon, gold, and platinum substrates under a H2 atmosphere. Analysis of the thin films deposited onto both silicon and gold substrates at substrate temperatures of 180 and 300 °C by scanning electron microscopy and atomic force microscopy reveals temperature-dependent growth features: Films grown at 300 °C are continuous and pinhole-free, whereas films grown at 180 °C consist of highly crystalline nanoparticles. In contrast, deposition onto platinum substrates at 180 °C shows a high degree of surface coverage with the formation of high-density, continuous, and pinhole-free thin films. Powder X-ray diffraction and X-ray photoelectron spectroscopy (XPS) both show the films to be high-purity metallic copper.
Purpose
Indications for nipple-sparing mastectomy (NSM) have broadened to include the risk reducing setting and locally advanced tumors, which resulted in a dramatic increase in the use of NSM. The ...Oncoplastic Breast Consortium consensus conference on NSM and immediate reconstruction was held to address a variety of questions in clinical practice and research based on published evidence and expert panel opinion.
Methods
The panel consisted of 44 breast surgeons from 14 countries across four continents with a background in gynecology, general or reconstructive surgery and a practice dedicated to breast cancer, as well as a patient advocate. Panelists presented evidence summaries relating to each topic for debate during the in-person consensus conference. The iterative process in question development, voting, and wording of the recommendations followed the modified Delphi methodology.
Results
Consensus recommendations were reached in 35, majority recommendations in 24, and no recommendations in the remaining 12 questions. The panel acknowledged the need for standardization of various aspects of NSM and immediate reconstruction. It endorsed several oncological contraindications to the preservation of the skin and nipple. Furthermore, it recommended inclusion of patients in prospective registries and routine assessment of patient-reported outcomes. Considerable heterogeneity in breast reconstruction practice became obvious during the conference.
Conclusions
In case of conflicting or missing evidence to guide treatment, the consensus conference revealed substantial disagreement in expert panel opinion, which, among others, supports the need for a randomized trial to evaluate the safest and most efficacious reconstruction techniques.
A multi-disciplinary study of two major submarine canyons, Baltimore Canyon and Norfolk Canyon, off the US mid-Atlantic coast focused on the ecology and biology of canyon habitats, particularly those ...supporting deep-sea corals. Historical data on deep-sea corals from these canyons were sparse with less than 750 records for the mid-Atlantic region, with most being soft sediment species. This study substantially increased the number of deep-sea coral records for the target canyons and the region. Large gorgonians were the dominant structure-forming coral taxa on exposed hard substrates, but several species of scleractinians were also documented, including first observations of Lophelia pertusa in the mid-Atlantic Bight region. Coral distribution varied within and between the two canyons, with greater abundance of the octocoral Paragorgia arborea in Baltimore Canyon, and higher occurrence of stony corals in Norfolk Canyon; these observations reflect the differences in environmental conditions, particularly turbidity, between the canyons. Some species have a wide distribution (e.g., P. arborea, Primnoa resedaeformis, Anthothela grandiflora), while others are limited to certain habitat types and/or depth zones (e.g., Paramuricea placomus, L. pertusa, Solenosmilia variabilis). The distribution of a species is driven by a combination of factors, which include availability of appropriate physical structure and environmental conditions. Although the diversity of the structure-forming corals (gorgonians, branching scleractinians and large anemones) was low, many areas of both canyons supported high coral abundance and a diverse coral-associated community. The canyons provide suitable habitat for the development of deep-sea coral communities that is not readily available elsewhere on the sedimented shelf and slope of the Mid-Atlantic Bight.
Adults with poultry exposure living in rural central Thailand are prospectively studied for evidence of avian influenza virus infections. Report details enrollment methods, findings of enrollment ...questionnaire data, and the serological investigation of enrollment sera.
Background.
Regions of Thailand reported sporadic outbreaks of A/H5N1 highly pathogenic avian influenza (HPAI) among poultry between 2004 and 2008. Kamphaeng Phet Province, in north-central Thailand had over 50 HPAI poultry outbreaks in 2004 alone, and 1 confirmed and 2 likely other human HPAI infections between 2004 and 2006.
Methods.
In 2008, we enrolled a cohort of 800 rural Thai adults living in 8 sites within Kamphaeng Phet Province in a prospective study of zoonotic influenza transmission. We studied participants' sera with serologic assays against 16 avian, 2 swine, and 8 human influenza viruses.
Results.
Among participants (mean age 49.6 years and 58% female) 65% reported lifetime poultry exposure of at least 30 consecutive minutes. Enrollees had elevated antibodies by microneutralization assay against 3 avian viruses: A/Hong Kong/1073/1999(H9N2), A/Thailand/676/2005(H5N1), and A/Thailand/384/2006(H5N1). Bivariate risk factor modeling demonstrated that male gender, lack of an indoor water source, and tobacco use were associated with elevated titers against avian H9N2 virus. Multivariate modeling suggested that increasing age, lack of an indoor water source, and chronic breathing problems were associated with infection with 1 or both HPAI H5N1 strains. Poultry exposure was not associated with positive serologic findings.
Conclusions.
These data suggest that people in rural central Thailand may have experienced subclinical avian influenza infections as a result of yet unidentified environmental exposures. Lack of an indoor water source may play a role in transmission.
The Quaternary sediments sampled by continuous 120-m-long drill cores from Bear Lake (Utah-Idaho) comprise one of the longest lacustrine sequences recovered from an extant lake. The cores serve as a ...good case study for the construction of an age model for sequences that extend beyond the range of radiocarbon dating. From a variety of potential age indicators, we selected a combination of radiocarbon ages, one magnetic excursion (correlated to a standard sequence), and a single Uranium-series age to develop an initial data set. The reliability of the excursion and U-series data require consideration of their position with respect to sediments of inferred interglacial character, but not direct correlation with other paleoclimate records. Data omitted from the age model include amino acid age estimates, which have a large amount of scatter, and tephrochronology correlations, which have relatively large uncertainties.
Because the initial data set was restricted to the upper half of the BL00-1 core, we inferred additional ages by direct correlation to the independently dated paleoclimate record from Devils Hole. We developed an age model for the entire core using statistical methods that consider both the uncertainties of the original data and that of the curve-fitting process, with a combination of our initial data set and the climate correlations as control points. This age model represents our best estimate of the chronology of deposition in Bear Lake. Because the age model contains assumptions about the correlation of Bear Lake to other climate records, the model cannot be used to address some paleoclimate questions, such as phase relationships with other areas.
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