3-hydroxykynurenine suppresses CD4+ T-cell proliferation, induces T-regulatory-cell development, and prolongs corneal allograft survival

Copyright © 2011 Association for Research in Vision and Ophthalmology. This article is available open access through the publisher’s website at the link below.Purpose. IDO (indoleamine 2,3-dioxygenase) modulates the immune response by depletion of the essential amino acid tryptophan, and IDO overexpression has been shown to prolong corneal allograft survival. This study was conducted to examine the effect of kynurenines, the products of tryptophan breakdown and known to act directly on T lymphocytes, on corneal graft survival. Methods. The effects of kynurenines on T-cell proliferation and death, T-regulatory-cell development, and dendritic cell function, phenotype, and viability were analyzed in vitro. The effect of topical and systemic administration of 3-hydroxykynurenine (3HK) on orthotopic murine corneal allograft survival was examined. Results. T-lymphocyte proliferation was inhibited by two of the four different kynurenines: 3HK and 3-hydroxyanthranilic acid (3HAA). This effect was accompanied by significant T-cell death. Neither 3HK nor 3HAA altered dendritic cell function, nor did they induce apoptosis or pathogenicity to corneal endothelial cells. Administration of systemic and topical 3HK to mice receiving a fully mismatched corneal graft resulted in significant prolongation of graft survival (median survival of control grafts, 12 days; of treated, 19 and 15 days, respectively; P < 0.0003). While systemic administration of 3HK was associated with a significant depletion of CD4+ T, CD8+ T, and B lymphocytes in peripheral blood, no depletion was found after topical administration. Conclusions. The production of kynurenines, in particular 3HK and 3HAA, may be one mechanism (in addition to tryptophan depletion) by which IDO prolongs graft survival. These molecules have potential as specific agents for preventing allograft rejection in patients at high rejection risk.Fight for Sight and the Wellcome Trust

Lipid rescue of massive verapamil overdose: a case report

<p>Abstract</p> <p>Introduction</p> <p>Massive intentional verapamil overdose is a toxic ingestion which can cause multiorgan system failure and has no currently known antidote.</p> <p>Case Presentation</p> <p>The patient is a 41-year-old Caucasian woman who ingested 19.2 g of sustained release verapamil in a suicide attempt. Our patient became hypotensive requiring three high-dose vasopressors to maintain arterial pressure. She also developed acute respiratory failure, bradycardic ventricular rhythm necessitating continuous transvenous pacing, and anuric renal failure. Our patient was treated with intravenous calcium, bicarbonate, hyperinsulinemic euglycemic therapy and continuous venovenous hemodialysis without success. On the fourth day after hospital admission continuous intravenous lipid therapy was initiated. Within three hours of beginning lipid therapy, our patient's vasopressor requirement decreased by half. Within 24 hours, she was on minimal vasopressor support and regained an underlying junctional rhythm. After three days of lipid infusion, she no longer required inotropic agents to maintain blood pressure or pacing to maintain stable hemodynamics.</p> <p>Conclusions</p> <p>Intravenous fat emulsion therapy may be an effective antidote for massive verapamil toxicity.</p

Experimenting with ecosystem interaction networks in search of threshold potentials in real-world marine ecosystems

Thresholds profoundly affect our understanding and management of ecosystem dynamics, but we have yet to develop practical techniques to assess the risk that thresholds will be crossed. Combining ecological knowledge of critical system interdependencies with a large-scale experiment, we tested for breaks in the ecosystem interaction network to identify threshold potential in real-world ecosystem dynamics. Our experiment with the bivalves Macomona liliana and Austrovenus stutchburyi on marine sandflats in New Zealand demonstrated that reductions in incident sunlight changed the interaction network between sediment biogeochemical fluxes, productivity, and macrofauna. By demonstrating loss of positive feedbacks and changes in the architecture of the network, we provide mechanistic evidence that stressors lead to break points in dynamics, which theory predicts predispose a system to a critical transition

Intermittent bioirrigation and oxygen dynamics in permeable sediments: An experimental and modeling study of three tellinid bivalves

To explore the dynamic nature of geochemical conditions in bioirrigated marine permeable sediments, we studied the hydraulic activity of three tellinacean bivalve molluscs (the Pacific species Macoma nasuta and Macomona liliana, and the northern Atlantic and Pacific species Macoma balthica). We combined porewater pressure sensing, time-lapse photography and oxygen imaging to quantify the durations and frequencies of tellinid irrigation activity and the associated oxygen dynamics in the sediment. Porewater pressure records of all tellinids were dominated by intermittent porewater pressurization, induced by periodic water injection into the sediment through their excurrent siphons, which resulted in intermittent oxygen supply to subsurface sediments. The irrigation (two–12 minutes long) and intervals between subsequent irrigation bouts (1.5–13 minutes) varied among tellinid species and individual sizes. For large M. liliana and M. nasuta, the average intervals between irrigation bouts were sufficiently long (10 minutes and four minutes, respectively) to allow complete oxygen consumption in between irrigation bouts in all tested sediment types. Irrigation patterns of smaller conspecifics and the smaller species M. balthica were characterized by significantly shorter separation of irrigation bouts, which resulted in more continuous oxygenation of the sediment. Transport-reaction modeling confirmed these species- and size-specific geochemical signatures and indicated that the geochemical character of the sediment is largely conditioned by the interplay between temporal irrigation patterns and sedimentary oxygen consumption rates. For large tellinids, model simulations indicated that oscillatory rather than stationary geochemical conditions are prevalent in a wide range of sediment types, with oxic pockets collapsing completely between periods of active irrigation. Based on the model results we developed analytical approximations that allow estimation of spatio-temporal characteristics of sediment oxygenation for a wide range of sediment types and infaunal activity patterns. Our results emphasize the need to consider the intermittent nature of bioirrigation when studying the geochemical impact of infauna in permeable sediments

Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous meningitis in HIV-infected adults: a prospective cohort study.

BACKGROUND: WHO recommends Xpert MTB/RIF as initial diagnostic testing for tuberculous meningitis. However, diagnosis remains difficult, with Xpert sensitivity of about 50-70% and culture sensitivity of about 60%. We evaluated the diagnostic performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis. METHODS: We prospectively obtained diagnostic cerebrospinal fluid (CSF) specimens during screening for a trial on the treatment of HIV-associated cryptococcal meningitis in Mbarara, Uganda. HIV-infected adults with suspected meningitis (eg, headache, nuchal rigidity, altered mental status) were screened consecutively at Mbarara Regional Referral Hospital. We centrifuged CSF, resuspended the pellet in 2 mL of CSF, and tested 0·5 mL with mycobacteria growth indicator tube culture, 1 mL with Xpert, and cryopreserved 0·5 mL, later tested with Xpert Ultra. We assessed diagnostic performance against uniform clinical case definition or a composite reference standard of any positive CSF tuberculous test. FINDINGS: From Feb 27, 2015, to Nov 7, 2016, we prospectively evaluated 129 HIV-infected adults with suspected meningitis for tuberculosis. 23 participants were classified as probable or definite tuberculous meningitis by uniform case definition, excluding Xpert Ultra results. Xpert Ultra sensitivity was 70% (95% CI 47-87; 16 of 23 cases) for probable or definite tuberculous meningitis compared with 43% (23-66; 10/23) for Xpert and 43% (23-66; 10/23) for culture. With composite standard, we detected tuberculous meningitis in 22 (17%) of 129 participants. Xpert Ultra had 95% sensitivity (95% CI 77-99; 21 of 22 cases) for tuberculous meningitis, which was higher than either Xpert (45% [24-68]; 10/22; p=0·0010) or culture (45% [24-68]; 10/22; p=0·0034). Of 21 participants positive by Xpert Ultra, 13 were positive by culture, Xpert, or both, and eight were only positive by Xpert Ultra. Of those eight, three were categorised as probable tuberculous meningitis, three as possible tuberculous meningitis, and two as not tuberculous meningitis. Testing 6 mL or more of CSF was associated with more frequent detection of tuberculosis than with less than 6 mL (26% vs 7%; p=0·014). INTERPRETATION: Xpert Ultra detected significantly more tuberculous meningitis than did either Xpert or culture. WHO now recommends the use of Xpert Ultra as the initial diagnostic test for suspected tuberculous meningitis. FUNDING: National Institute of Neurologic Diseases and Stroke, Fogarty International Center, National Institute of Allergy and Infectious Disease, UK Medical Research Council/DfID/Wellcome Trust Global Health Trials, Doris Duke Charitable Foundation

Choice of activity-intensity classification thresholds impacts upon accelerometer-assessed physical activity-health relationships in children

It is unknown whether using different published thresholds (PTs) for classifying physical activity (PA) impacts upon activity-health relationships. This study explored whether relationships between PA (sedentary [SED], light PA [LPA], moderate PA [MPA], moderate-to-vigorous PA, vigorous PA [VPA]) and health markers differed in children when classified using three different PTs

“It's such a vicious cycle”: Narrative accounts of the sportsperson with epilepsy

Objectives: There is an abundance of quantitative and medical research promoting the benefits of exercise for people with epilepsy. However, the psychosocial barriers and benefits of exercising for the sportsperson/people with epilepsy (SWE) are absent. This research aims to present the narratives of SWE over time and as a result, develop further understanding of the psychosocial impact of exercising with epilepsy. Method: A holistic-content and structural narrative analysis were used to explore the exercise experiences of three SWE over the course of one year. A creative non-fictional technique was used to present first person narratives, therefore providing the SWE's voice for the reader. Results: Narratives of ‘vicious cycle’ and ‘roller coaster’ presented complex and multi-thematic storied forms, with time and the hidden nature of epilepsy having a strong impact on narrative formation. Vicious cycle presented the cycle of desiring to exercise, but prevented from exercising because of uncontrolled seizures. This resulted in frustration and feelings of a lack of control, which subsequently increased the desire to exercise and created a cycle with no clear end. Roller coaster presented the constant psychosocial and physical undulations that epilepsy can create for a SWE over time. Conclusion: These narratives reveal that exercising with epilepsy has a constant and on-going positive and negative impact on the life of SWE. However, these narratives also show that it may be through the process of acceptance of their body's limitations that a healthier mental and physical state may result for the SWE

Measuring sexual behaviours and attitudes in hard-to-reach groups. A comparison of a non-probability web survey with a national probability sample survey

Introduction: Hard-to-reach and minority groups are often at higher risk for adverse sexual health outcomes. While such groups are therefore of interest to sexual health researchers, it can be difficult to locate and recruit sufficient sample sizes using probability sampling methods. This study aims to establish whether web-panel surveys can provide a viable less resource intensive means of boosting sample sizes of two hard-to-reach groups (people of Black African ethnicity, and gay men) for a sexual health survey, and the extent of any bias. Methods: Results from a national probability sample survey (Natsal-3, administered using a computer-assisted personal interview (CAPI) and self-interview (CASI) with 15,162 participants), which included 211 black African participants and 83 gay men, were compared with results from a web-panel survey (using identical questions) of 529 black Africans and 592 gay men. Web-panel survey results for socio-demographics were compared with external benchmarks, and for sexual behaviours and attitudes reported in Natsal-3. Odds ratios (ORs) were used to examine differences between variables and the average absolute OR, along with the number of estimates for which the web-panel survey differed significantly from the benchmarks, were used to summarise survey performance. Results: At least 18% of estimates differed significantly between surveys for gay and black African men, and 28% for black African women. For black African women average absolute ORs were: 1.6 for attitudinal questions asked in CAPI, 1.5 for attitudinal CASI questions, 3.2 for behaviour questions asked in CAPI and for 1.7 for behaviour CASI. For black African men average absolute ORs were: 1.5 for attitudinal questions asked in CAPI, 1.8 for attitudinal CASI questions, 2.5 for behavioural questions asked in CAPI and 1.6 for behavioural questions asked in CASI=1.6. For gay men, average absolute ORs were: 2.2 for attitudinal questions asked in CAPI, 2.8 for attitudinal CASI questions, 1.8 for behavioural questions asked in CAPI to 1.6 for behavioural questions asked in CASI. Discussion: Web-panel surveys may be able to sample hard-to-reach groups but may not be able to replace probability-sample surveys where accurate population-level estimates of sensitive sexual behaviours are required. Differences between web and CASI responses, where mode effects may be similar, suggest web-panel survey selection bias

Men, rheumatoid arthritis, psychosocial impact and self-management: A narrative review.

Rheumatoid arthritis (RA) is a chronic disease affecting fewer men than women. We systematically reviewed the literature on impact and self-management of RA men. Twenty eight papers were included, and grouped into two categories: Psychosocial impact of RA; and Coping and self-management. This review finds gender differences relating to quality of life; work; distress; self-management; coping; and support. We conclude there is a dearth of literature focussing on RA men only, and mixed gender studies include insufficient men to draw strong conclusions about men. Thus, further research is needed to understand the support needs of men with RA in depth

Manual / Issue 7 / Alchemy

Manual, a journal about art and its making. Alchemy. The seventh issue. Manual 7 (Alchemy) prompts the unexpected and emergent to manifest. To engage as an alchemist/artist is to be the perpetual student of the present moment, to synthesize culture, so-called science, and the implications of existential borders into a discipline that is repeatable, a practice. Art and alchemy are not singular, unified pursuits. Their practitioners are trans-disciplinary, disjointed, and solitary in their practice, and their labor and the ordering of their lives become porous, overlaid in the pursuit of other-than or beyond-dominant modes of understanding. Alchemy and art are not about finding resolution, but building the capacity for curiosity, formulating questions that invest fields of knowledge with possibility, prompting the unexpected and emergent to manifest. —Bryan McGovern Wilson, from the introduction to Issue 7: Alchemy Softcover, 76 pages. Published 2016 by the RISD Museum. Manual 7 (Alchemy) contributors include Markus Berger, Rachel Berwick, Stephen S. Bush, CA Conrad, Florence Friedman, Doreen Garner, Michael Grugl, Kate Irvin, Mimi Leveque, Dominic Molon, Douglas R. Nickel, Emily J. Peters, Elizabeth A. Williams, Bryan McGovern Wilson, and Diming Stella Zhong.https://digitalcommons.risd.edu/risdmuseum_journals/1033/thumbnail.jp