2,086 research outputs found
Evaluation of early and late presentation of patients with ocular mucous membrane pemphigoid to two major tertiary referral hospitals in the United Kingdom
PURPOSE: Ocular mucous membrane pemphigoid (OcMMP) is a sight-threatening autoimmune disease in which referral to specialists units for further management is a common practise. This study aims to describe referral patterns, disease phenotype and management strategies in patients who present with either early or established disease to two large tertiary care hospitals in the United Kingdom.\ud
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PATIENTS AND METHODS: In all, 54 consecutive patients with a documented history of OcMMP were followed for 24 months. Two groups were defined: (i) early-onset disease (EOD:<3 years, n=26, 51 eyes) and (ii) established disease (EstD:>5 years, n=24, 48 eyes). Data were captured at first clinic visit, and at 12 and 24 months follow-up. Information regarding duration, activity and stage of disease, visual acuity (VA), therapeutic strategies and clinical outcome were analysed.\ud
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RESULTS: Patients with EOD were younger and had more severe conjunctival inflammation (76% of inflamed eyes) than the EstD group, who had poorer VA (26.7%=VA<3/60, P<0.01) and more advanced disease. Although 40% of patients were on existing immunosuppression, 48% required initiation or switch to more potent immunotherapy. In all, 28% (14) were referred back to the originating hospitals for continued care. Although inflammation had resolved in 78% (60/77) at 12 months, persistence of inflammation and progression did not differ between the two phenotypes. Importantly, 42% demonstrated disease progression in the absence of clinically detectable inflammation.\ud
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CONCLUSIONS: These data highlight that irrespective of OcMMP phenotype, initiation or escalation of potent immunosuppression is required at tertiary hospitals. Moreover, the conjunctival scarring progresses even when the eye remains clinically quiescent. Early referral to tertiary centres is recommended to optimise immunosuppression and limit long-term ocular damage.\ud
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Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza
Pandemic influenza A virus (IAV) remains a significant threat to global health. Preparedness relies primarily upon a single class of neuraminidase (NA) targeted antivirals, against which resistance is steadily growing. The M2 proton channel is an alternative clinically proven antiviral target, yet a near-ubiquitous S31N polymorphism in M2 evokes resistance to licensed adamantane drugs. Hence, inhibitors capable of targeting N31 containing M2 (M2-N31) are highly desirable. Rational in silico design and in vitro screens delineated compounds favouring either lumenal or peripheral M2 binding, yielding effective M2-N31 inhibitors in both cases. Hits included adamantanes as well as novel compounds, with some showing low micromolar potency versus pandemic âswineâ H1N1 influenza (Eng195) in culture. Interestingly, a published adamantane-based M2-N31 inhibitor rapidly selected a resistant V27A polymorphism (M2-A27/N31), whereas this was not the case for non-adamantane compounds. Nevertheless, combinations of adamantanes and novel compounds achieved synergistic antiviral effects, and the latter synergised with the neuraminidase inhibitor (NAi), Zanamivir. Thus, site-directed drug combinations show potential to rejuvenate M2 as an antiviral target whilst reducing the risk of drug resistance
Macrophage Subset Sensitivity to Endotoxin Tolerisation by Porphyromonas gingivalis
Macrophages (MΊs) determine oral mucosal responses; mediating tolerance to commensal microbes and food whilst maintaining the capacity to activate immune defences to pathogens. MΊ responses are determined by both differentiation and activation stimuli, giving rise to two distinct subsets; pro-inflammatory M1- and anti-inflammatory/regulatory M2- MΊs. M2-like subsets predominate tolerance induction whereas M1 MΊs predominate in inflammatory pathologies, mediating destructive inflammatory mechanisms, such as those in chronic P.gingivalis (PG) periodontal infection. MΊ responses can be suppressed to benefit either the host or the pathogen. Chronic stimulation by bacterial pathogen associated molecular patterns (PAMPs), such as LPS, is well established to induce tolerance. The aim of this study was to investigate the susceptibility of MΊ subsets to suppression by P. gingivalis. CD14hi and CD14lo M1- and M2-like MΊs were generated in vitro from the THP-1 monocyte cell line by differentiation with PMA and vitamin D3, respectively. MΊ subsets were pre-treated with heat-killed PG (HKPG) and PG-LPS prior to stimulation by bacterial PAMPs. Modulation of inflammation was measured by TNFα, IL-1ÎČ, IL-6, IL-10 ELISA and NFÎșB activation by reporter gene assay. HKPG and PG-LPS differentially suppress PAMP-induced TNFα, IL-6 and IL-10 but fail to suppress IL-1ÎČ expression in M1 and M2 MΊs. In addition, P.gingivalis suppressed NFÎșB activation in CD14lo and CD14hi M2 regulatory MΊs and CD14lo M1 MΊs whereas CD14hi M1 pro-inflammatory MΊs were refractory to suppression. In conclusion, P.gingivalis selectively tolerises regulatory M2 MΊs with little effect on pro-inflammatory CD14hi M1 MΊs; differential suppression facilitating immunopathology at the expense of immunity
Murine model for Fusarium oxysporum invasive fusariosis reveals organ-specific structures for dissemination and long-term persistence
Peer reviewedPublisher PD
Arsenic species in weathering mine tailings and biogenic solids at the Lava Cap Mine Superfund Site, Nevada City, CA
A systematic approach to performing a comprehensive transesophageal echocardiogram. A call to order
<p>Abstract</p> <p>Background</p> <p>While the order for a clinical transthoracic examination is fairly standardized, there is considerable variability between laboratories and even among physicians in the same laboratory with regard to the order for transesophageal echocardiograms (TEE). A systematic approach is desirable for more efficient use of physician and patient time, avoidance of inadvertent omission of important views, and to facilitate study review.</p> <p>Methods</p> <p>We propose a standardized approach to TEE data acquisition in which cardiac structures are systematically identified and characterized at sequential positions and imaging planes to facilitate organized, efficient and comprehensive assessment.</p> <p>Results</p> <p>Our approach to TEE study begins in the mid-esophagus with the imaging plane at 0°. Based on the specific indication for the TEE, a cardiac structure (e.g., mitral valve, left atrial appendage, or interatrial septum) is chosen as the primary focal point for a comprehensive, multiplane analysis. This structure is assessed in 20° â 30° increments as the imaging plane is advanced from 0° to 165°. Using the aortic valve as a reference point, pertinent cardiac structures are then assessed as the imaging plane is reduced to 135°, to 90°, to 40 â 60° and then back to 0°. The probe is then advanced into the stomach to obtain transgastric images at 0°, 90°, and 120°. Finally, the thoracic aorta and pulmonary artery are assessed as the probe is withdrawn from the body. Using this method, an organized and comprehensive TEE can be performed in 10 â 15 minutes.</p> <p>Conclusion</p> <p>A standardized and systematic TEE approach is described for efficient and comprehensive TEE study.</p
Barriers and progress in the treatment of low back pain
Low back pain is a common and costly condition and for most people is likely to be a recurrent problem throughout their lifetime. The management of patients with low back pain has been positively influenced by the rise in high quality clinical trials and systematic reviews in recent decades, and this body of evidence, synthesized in many clinical practice guidelines, has improved our knowledge about which treatments for low back pain are useful and which are not. For the largest group of patients, those with non-specific low back pain for whom a clear diagnosis cannot be given, the reality is that the treatments we have to offer tend to produce small effects, often only in the short term and none appear to effectively change long-term prognosis. This commentary summarizes the array of treatments currently available, notes the results of recent trials and guidelines and considers alternative approaches that may prove more valuable in achieving better patient outcomes in the future
Comparison of survival between malignant neuroendocrine tumours of midgut and pancreatic origin
Jet production in charged current deep inelastic eâșp scatteringat HERA
The production rates and substructure of jets have been studied in charged current deep inelastic eâșp scattering for QÂČ > 200 GeVÂČ with the ZEUS detector at HERA using an integrated luminosity of 110.5 pbâ»Âč. Inclusive jet cross sections are presented for jets with transverse energies E_{T}^{jet} > 5 GeV. Measurements of the mean subjet multiplicity, â©n_{sbj}âȘ, of the inclusive jet sample are presented. Predictions based on parton-shower Monte Carlo models and next-to-leading-order QCD calculations are compared to the measurements. The value of α_{s} (M_{z}), determined from â©n_{sbj}âȘ at y_{cut} = 10â»ÂČ for jets with 25 < E_{T}^{jet} < 119 GeV, is α_{s} (M_{z}) = 0.1202 ± 0.0052 (stat.)_{-0.0019}^{+0.0060} (syst.)_{-0.0053}^{+0.0065} (th.). The mean subjet multiplicity as a function of QÂČ is found to be consistent with that measured in NC DIS
Strong interface-induced spin-orbit coupling in graphene on WS2
Interfacial interactions allow the electronic properties of graphene to be
modified, as recently demonstrated by the appearance of satellite Dirac cones
in the band structure of graphene on hexagonal boron nitride (hBN) substrates.
Ongoing research strives to explore interfacial interactions in a broader class
of materials in order to engineer targeted electronic properties. Here we show
that at an interface with a tungsten disulfide (WS2) substrate, the strength of
the spin-orbit interaction (SOI) in graphene is very strongly enhanced. The
induced SOI leads to a pronounced low-temperature weak anti-localization (WAL)
effect, from which we determine the spin-relaxation time. We find that
spin-relaxation time in graphene is two-to-three orders of magnitude smaller on
WS2 than on SiO2 or hBN, and that it is comparable to the intervalley
scattering time. To interpret our findings we have performed first-principle
electronic structure calculations, which both confirm that carriers in
graphene-on-WS2 experience a strong SOI and allow us to extract a
spin-dependent low-energy effective Hamiltonian. Our analysis further shows
that the use of WS2 substrates opens a possible new route to access topological
states of matter in graphene-based systems.Comment: Originally submitted version in compliance with editorial guidelines.
Final version with expanded discussion of the relation between theory and
experiments to be published in Nature Communication
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