The influence of caffeine on lymphocyte activation after prolonged high-intensity exercise

Many athletes consume caffeine for its known ergogenic effects. Since being legitimised by its 2004 removal from the World Anti-Doping Agency prohibited list of substances, caffeine s ability to enhance performance has led to its widespread use amongst the athletic population. However, despite caffeine s prevalence, little research has focused on the effect of caffeine ingestion on immune function both at rest and in response to exercise in humans. Therefore, the aim of this thesis was to investigate the influence of typically-used doses of caffeine (typical daily intake in training and competition doses) on aspects of innate and acquired immunity in response to prolonged exercise. At rest both a high (6 mg kg-1) and low dose (2 mg kg-1) of caffeine had little effect on antigen-stimulated T (CD4+ and CD8+) or natural killer (NK) lymphocyte activation, while a high dose of caffeine only increased the number of antigen-stimulated NK cells expressing CD69 1 h following caffeine ingestion (Chapter 4). In response to prolonged high intensity continuous cycling both high and low doses of caffeine increased the natural state of activation as well as the antigen-stimulated activation of NK cells 1 h after exercise cessation (Chapters 5 and 6). However, at the same time-point a high dose of caffeine decreased CD4+ and CD8+ cell activation (Chapter 5). One hour after high intensity intermittent shuttle running, a high dose of caffeine attenuated the exercise-induced increase in NK cell activation both in terms of the number of cells expressing CD69 and their geometric mean fluorescence intensity expression of CD69 (Chapter 7). These effects did not occur in response to intermittent exercise when 2 mg kg-1 caffeine was instead ingested in 3 repeated doses throughout the day (Chapter 7). In conclusion, the findings of this thesis demonstrate the complex actions of caffeine on antigen-stimulated T and NK lymphocyte activation 1 h after prolonged intensive exercise. However, the biological significance of these findings in terms of caffeine s potential to alter an individuals susceptibility to infection following prolonged high intensity exercise are yet to be determined

Effect of a single and repeated dose of caffeine on antigen-stimulated human natural killer cell CD69 expression after high-intensity intermittent exercise

Several studies investigating the effect of caffeine on immune function following exercise have used one large bolus dose of caffeine. However, this does not model typical caffeine consumption. Therefore, the purpose of this study was to investigate whether small repeated doses of caffeine ingested throughout the day would elicit a similar response as one large bolus dose ingested 1 h prior to exercise on antigen-stimulated NK cell CD69 expression following strenuous intermittent exercise. In a randomized cross-over design, 15 healthy males completed six 15 min blocks of intermittent running consisting of maximal sprinting interspersed with less intense running and walking. Participants had ingested either 0 (PLA), 2 mg kg−1 body mass (BM) caffeine on three separate occasions during the day (3× CAF) or one dose of 6 (1× CAF) mg kg−1 BM caffeine, 1 h before exercise. At 1-h post-exercise, the number of antigen-stimulated CD3−CD56+ cells expressing CD69 was lower on 1× CAF compared with PLA [P < 0.05; PLA: 42.0 (34.0) × 106 cells L−1, 1× CAF: 26.2 (25.0) × 106 cells L−1], with values on 1× CAF at this time point remaining close to pre-supplement. 1× CAF tended to attenuate the exercise-induced increase in geometric mean fluorescence intensity of CD69 expression on antigen-stimulated CD3−CD56+ cells 1-h post-exercise [P = 0.055; PLA: 141 (28)%, 1× CAF: 119 (20)%]. These findings suggest that although one large bolus dose of caffeine attenuated the exercise-induced increase in antigen-stimulated NK cell CD69 expression 1 h following strenuous intermittent exercise, this attenuation at no point fell below pre-supplement values and caffeine does not appear to depress NK cell CD69 expression

The influence of caffeine on lymphocyte activation after prolonged high intensity exercise

Many athletes consume caffeine for its known ergogenic effects. Since being legitimised by its 2004 removal from the World Anti-Doping Agency prohibited list of substances, caffeine s ability to enhance performance has led to its widespread use amongst the athletic population. However, despite caffeine s prevalence, little research has focused on the effect of caffeine ingestion on immune function both at rest and in response to exercise in humans. Therefore, the aim of this thesis was to investigate the influence of typically-used doses of caffeine (typical daily intake in training and competition doses) on aspects of innate and acquired immunity in response to prolonged exercise. At rest both a high (6 mg kg-1) and low dose (2 mg kg-1) of caffeine had little effect on antigen-stimulated T (CD4+ and CD8+) or natural killer (NK) lymphocyte activation, while a high dose of caffeine only increased the number of antigen-stimulated NK cells expressing CD69 1 h following caffeine ingestion (Chapter 4). In response to prolonged high intensity continuous cycling both high and low doses of caffeine increased the natural state of activation as well as the antigen-stimulated activation of NK cells 1 h after exercise cessation (Chapters 5 and 6). However, at the same time-point a high dose of caffeine decreased CD4+ and CD8+ cell activation (Chapter 5). One hour after high intensity intermittent shuttle running, a high dose of caffeine attenuated the exercise-induced increase in NK cell activation both in terms of the number of cells expressing CD69 and their geometric mean fluorescence intensity expression of CD69 (Chapter 7). These effects did not occur in response to intermittent exercise when 2 mg kg-1 caffeine was instead ingested in 3 repeated doses throughout the day (Chapter 7). In conclusion, the findings of this thesis demonstrate the complex actions of caffeine on antigen-stimulated T and NK lymphocyte activation 1 h after prolonged intensive exercise. However, the biological significance of these findings in terms of caffeine s potential to alter an individuals susceptibility to infection following prolonged high intensity exercise are yet to be determined.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Does Caffeine Influence Salivary IgA Responses In A Dose-Dependent Manner Following High-Intensity Treadmill Exercise?

Introduction: Caffeine ingestion is associated with enhanced athletic performance, with doses as low as 2 mg.kg-1 body mass (BM) proving ergogenic. Bishop et al. (2006) have shown that ingesting a 6 mg.kg-1 BM dose of caffeine 1 h prior to 90 min of cycle exercise at 70%causes a transient increase in saliva Immunoglobulin A (IgA) concentration both during and immediately following exercise. However, no research has identified if the same response occurs with either lower or higher doses of caffeine. As such the purpose of this study was to examine the dose-response effects of caffeine ingestion on salivary IgA responses following high-intensity running. Methods: In a double blind randomised crossover design, 12 endurance trained male runners (age: 29 ± 3, 62.7 ± 5.1 mL·kg·min-1, mean ± SD) ran for 70 min at 80% 60 min after ingesting 0 (PLA), 2 (2CAF), 4 (4CAF), 6 (6CAF) or 8 (8CAF) mg·kg-1 BM of caffeine. For PLA, 6 mg·kg-1 BM of cornflour was ingested. Unstimulated whole saliva samples were obtained before supplementation, pre-exercise, after 35 min of exercise, immediately post-exercise and 1 h post-exercise. Saliva IgA was determined using ELISA, while caffeine concentrations were determined via HPLC. Results: Saliva caffeine concentrations were significantly increased at all time points (pre-, mid-, post- and 1 h post-exercise) when compared to pre-supplement in a dose-dependent manner (P\u3c0.001; peak concentration: PLA: 0 ± 0; 2CAF: 10 ± 3; 4CAF: 22 ± 8; 6CAF: 40 ± 9; 8CAF: 44 ± 9 μM). However, there was no dose-response effect of caffeine on either saliva IgA concentration or secretion rate before, during or after exercise. In fact neither caffeine nor exercise affected saliva IgA secretion rate or concentration. Conclusion: These findings suggest that caffeine ingestion (from 2-8 mg.kg-1 BM) 60 min prior to prolonged high-intensity treadmill running has no effect on saliva IgA responses following exercise. As such it can be suggested that athletes wanting to consume caffeine for ergogenic purposes can potentially do so (up to a dose of 8 mg.kg-1 BM) without reducing mucosal immunity

Beyond icosahedral symmetry in packings of proteins in spherical shells

The formation of quasi-spherical cages from protein building blocks is a remarkable self-assembly process in many natural systems, where a small number of elementary building blocks are assembled to build a highly symmetric icosahedral cage. In turn, this has inspired synthetic biologists to design de novo protein cages. We use simple models, on multiple scales, to investigate the self-assembly of a spherical cage, focusing on the regularity of the packing of protein-like objects on the surface. Using building blocks, which are able to pack with icosahedral symmetry, we examine how stable these highly symmetric structures are to perturbations that may arise from the interplay between flexibility of the interacting blocks and entropic effects. We find that, in the presence of those perturbations, icosahedral packing is not the most stable arrangement for a wide range of parameters; rather disordered structures are found to be the most stable. Our results suggest that (i) many designed, or even natural, protein cages may not be regular in the presence of those perturbations, and (ii) that optimizing those flexibilities can be a possible design strategy to obtain regular synthetic cages with full control over their surface properties.Comment: 8 pages, 5 figure

A Randomised Controlled Trial of Extended Anticoagulation Treatment Versus Standard Treatment for the Prevention of Recurrent VTE and Post-thrombotic Syndrome in Patients Being Treated for a First Episode of Unprovoked VTE (The ExACT Study)

Venous thromboembolism (VTE) is prevalent and impactful, with a risk of death, morbidity and recurrence. Post‐thrombotic syndrome (PTS) is a common consequence and associated with impaired quality of life (QoL). The ExACT study was a non‐blinded, prospective, multicentred randomised controlled trial comparing extended versus limited duration anticoagulation following a first unprovoked VTE (proximal deep vein thrombosis or pulmonary embolism). Adults were eligible if they had completed ≥3 months anticoagulation (remaining anticoagulated). The primary outcome was time to first recurrent VTE from randomisation. The secondary outcomes included PTS severity, bleeding, QoL and D‐dimers. Two‐hundred and eighty‐one patients were recruited, randomised and followed up for 24 months (mean age 63, male:female 2:1). There was a significant reduction in recurrent VTE for patients receiving extended anticoagulation [2·75 vs. 13·54 events/100 patient years, adjusted hazard ratio (aHR) 0·20 (95% confidence interval (CI): 0·09 to 0·46, P < 0·001)] with a non‐significant increase in major bleeding [3·54 vs. 1·18 events/100 patient years, aHR 2·99 (95% CI: 0·81–11·05, P = 0·10)]. Outcomes of PTS and QoL were no different between groups. D‐dimer results (on anticoagulation) did not predict VTE recurrence. In conclusion, extended anticoagulation reduced VTE recurrence but did not reduce PTS or improve QoL and was associated with a non‐significant increase in bleeding. Results also suggest very limited clinical utility of D‐dimer testing on anticoagulated patients

Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial

BACKGROUND: Rituximab is often used as rescue therapy in interstitial lung disease (ILD) associated with connective tissue disease (CTD), but has not been studied in clinical trials. This study aimed to assess whether rituximab is superior to cyclophosphamide as a treatment for severe or progressive CTD associated ILD. METHODS: We conducted a randomised, double-blind, double-dummy, phase 2b trial to assess the superiority of rituximab compared with cyclophosphamide. Patients aged 18-80 years with severe or progressive ILD related to scleroderma, idiopathic inflammatory myositis, or mixed CTD, recruited across 11 specialist ILD or rheumatology centres in the UK, were randomly assigned (1:1) to receive rituximab (1000 mg at weeks 0 and 2 intravenously) or cyclophosphamide (600 mg/m2 body surface area every 4 weeks intravenously for six doses). The primary endpoint was rate of change in forced vital capacity (FVC) at 24 weeks compared with baseline, analysed using a mixed-effects model with random intercepts, adjusted for baseline FVC and CTD type. Prespecified secondary endpoints reported in this Article were change in FVC at 48 weeks versus baseline; changes from baseline in 6 min walk distance, diffusing capacity of the lung for carbon monoxide (DLCO), physician-assessed global disease activity (GDA) score, and quality-of-life scores on the St George's Respiratory Questionnaire (SGRQ), King's Brief Interstitial Lung Disease (KBILD) questionnaire, and European Quality of Life Five-Dimension (EQ-5D) questionnaire at 24 and 48 weeks; overall survival, progression-free survival, and time to treatment failure; and corticosteroid use. All endpoints were analysed in the modified intention-to-treat population, which comprised all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT01862926). FINDINGS: Between Dec 1, 2014, and March 31, 2020, we screened 145 participants, of whom 101 participants were randomly allocated: 50 (50%) to receive cyclophosphamide and 51 (50%) to receive rituximab. 48 (96%) participants in the cyclophosphamide group and 49 (96%) in the rituximab group received at least one dose of treatment and were included in analyses; 43 (86%) participants in the cyclophosphamide group and 42 (82%) participants in the rituximab group completed 24 weeks of treatment and follow-up. At 24 weeks, FVC was improved from baseline in both the cyclophosphamide group (unadjusted mean increase 99 mL [SD 329]) and the rituximab group (97 mL [234]); in the adjusted mixed-effects model, the difference in the primary endpoint at 24 weeks was -40 mL (95% CI -153 to 74; p=0·49) between the rituximab group and the cyclophosphamide group. KBILD quality-of-life scores were improved at 24 weeks by a mean 9·4 points (SD 20·8) in the cyclophosphamide group and 8·8 points (17·0) in the rituximab group. No significant differences in secondary endpoints were identified between the treatment groups, with the exception of change in GDA score at week 48, which favoured cyclophosphamide (difference 0·90 [95% CI 0·11 to 1·68]). Improvements in lung function and respiratory-related quality-of-life measures were observed in both treatment groups. Lower corticosteroid exposure over 48 weeks of follow-up was recorded in the rituximab group. Two (4%) of 48 participants who received cyclophosphamide and three (6%) of 49 who received rituximab died during the study, all due to complications of CTD or ILD. Overall survival, progression-free survival, and time to treatment failure did not significantly differ between the two groups. All participants reported at least one adverse event during the study. Numerically fewer adverse events were reported by participants receiving rituximab (445 events) than those receiving cyclophosphamide (646 events). Gastrointestinal and respiratory disorders were the most commonly reported adverse events in both groups. There were 62 serious adverse events of which 33 occurred in the cyclophosphamide group and 29 in the rituximab group. INTERPRETATION: Rituximab was not superior to cyclophosphamide to treat patients with CTD-ILD, although participants in both treatment groups had increased FVC at 24 weeks, in addition to clinically important improvements in patient-reported quality of life. Rituximab was associated with fewer adverse events. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with CTD-ILD requiring intravenous therapy. FUNDING: Efficacy and Mechanism Evaluation Programme (Medical Research Council and National Institute for Health Research, UK)

Radio Astronomy

Contains table of contents for Section 4 and reports on five research projects.National Science Foundation Grant AST 92-24191MIT Lincoln Laboratory Agreement BX-4975National Aeronautics and Space Administration/Goddard Space Flight Center Grant NAS 5-31376National Aeronautics and Space Administration/Goddard Space Flight Center Grant NAG5-10MIT Leaders for Manufacturing Progra