Offspring pay sooner, parents pay later:Experimental manipulation of body mass reveals trade-offs between immune function, reproduction and survival

Introduction: Life-history theory predicts that organisms trade off survival against reproduction. However, the time scales on which various consequences become evident and the physiology mediating the cost of reproduction remain poorly understood. Yet, explaining not only which mechanisms mediate this trade-off, but also how fast or slow the mechanisms act, is crucial for an improved understanding of life-history evolution. We investigated three time scales on which an experimental increase in body mass could affect this trade-off: within broods, within season and between years. We handicapped adult skylarks (Alauda arvensis) by attaching extra weight during first broods to both adults of a pair. We measured body mass, immune function and return rates in these birds. We also measured nest success, feeding rates, diet composition, nestling size, nestling immune function and recruitment rates.Results: When nestlings of first broods fledged, parent body condition had not changed, but experimental birds experienced higher nest failure. Depending on the year, immune parameters of nestlings from experimental parents were either higher or lower than of control nestlings. Later, when parents were feeding their second brood, the balance between self-maintenance and nest success had shifted. Control and experimental adults differed in immune function, while mass and immune function of their nestlings did not differ. Although weights were removed after breeding, immune measurements during the second brood had the capacity to predict return rates to the next breeding season. Among birds that returned the next year, body condition and reproductive performance a year after the experiment did not differ between treatment groups.Conclusions: We conclude that the balance between current reproduction and survival shifts from affecting nestlings to affecting parents as the reproductive season progresses. Furthermore, immune function is apparently one physiological mechanism involved in this trade-off. By unravelling a physiological mechanism underlying the trade-offs between current and future reproduction and by demonstrating the different time scales on which it acts, our study represents an important step in understanding a central theory of life-history evolution.</p

Ethanol consumption impairs vestibulo-ocular reflex function measured by the video head impulse test and dynamic visual acuity

Ethanol affects many parts of the nervous system, from the periphery to higher cognitive functions. Due to the established effects of ethanol on vestibular and oculomotor function, we wished to examine its effect on two new tests of the vestibulo-ocular reflex (VOR): the video head impulse test (vHIT) and dynamic visual acuity (DVA). We tested eight healthy subjects with no history of vestibular disease after consumption of standardized drinks of 40% ethanol. We used a repeated measures design to track vestibular function over multiple rounds of ethanol consumption up to a maximum breath alcohol concentration (BrAC) of 1.38‰. All tests were normal at baseline. VOR gain measured by vHIT decreased 25% by the highest BrAC level tested in each subject. Catch-up saccades were negligible at baseline and increased in number and size with increasing ethanol consumption (from 0.13° to 1.43° cumulative amplitude per trial). DVA scores increased by 86% indicating a deterioration of acuity, while static visual acuity (SVA) remained unchanged. Ethanol consumption systematically impaired the VOR evoked by high-acceleration head impulses and led to a functional loss of visual acuity during head movement.NHMR

Are antimicrobial defences in bird eggs related to climatic conditions associated with risk of trans-shell microbial infection?

INTRODUCTION: All bird eggs are exposed to microbes in the environment, which if transmitted to the developing embryo, could cause hatching failure. However, the risk of trans-shell infection varies with environmental conditions and is higher for eggs laid in wetter environments. This might relate to generally higher microbial abundances and diversity in more humid environments, including on the surface of eggshells, as well as the need for moisture to facilitate microbial penetration of the eggshell. To protect against microbial infection, the albumen of avian eggs contains antimicrobial proteins, including lysozyme and ovotransferrin. We tested whether lysozyme and ovotransferrin activities varied in eggs of larks (Alaudidae) living along an arid-mesic gradient of environmental aridity, which we used as a proxy for risk of trans-shell infection. RESULTS: Contrary to expectations, lysozyme activity was highest in eggs from hotter, more arid locations, where we predicted the risk of trans-shell infection would be lower. Ovotransferrin concentrations did not vary with climatic factors. Temperature was a much better predictor of antimicrobial protein activity than precipitation, a result inconsistent with studies stressing the importance of moisture for trans-shell infection. CONCLUSIONS: Our study raises interesting questions about the links between temperature and lysozyme activity in eggs, but we find no support for the hypothesis that antimicrobial protein deposition is higher in eggs laid in wetter environments

Environmental proxies of antigen exposure explain variation in immune investment better than indices of pace of life.

Investment in immune defences is predicted to covary with a variety of ecologically and evolutionarily relevant axes, with pace of life and environmental antigen exposure being two examples. These axes may themselves covary directly or inversely, and such relationships can lead to conflicting predictions regarding immune investment. If pace of life shapes immune investment then, following life history theory, slow-living, arid zone and tropical species should invest more in immunity than fast-living temperate species. Alternatively, if antigen exposure drives immune investment, then species in antigen-rich tropical and temperate environments are predicted to exhibit higher immune indices than species from antigen-poor arid locations. To test these contrasting predictions we investigated how variation in pace of life and antigen exposure influence immune investment in related lark species (Alaudidae) with differing life histories and predicted risks of exposure to environmental microbes and parasites. We used clutch size and total number of eggs laid per year as indicators of pace of life, and aridity, and the climatic variables that influence aridity, as correlates of antigen abundance. We quantified immune investment by measuring four indices of innate immunity. Pace of life explained little of the variation in immune investment, and only one immune measure correlated significantly with pace of life, but not in the predicted direction. Conversely, aridity, our proxy for environmental antigen exposure, was predictive of immune investment, and larks in more mesic environments had higher immune indices than those living in arid, low-risk locations. Our study suggests that abiotic environmental variables with strong ties to environmental antigen exposure can be important correlates of immunological variation.Financial support came from the Schure-Beijerinck-Poppings Fonds (to NPCH and AH), BirdLife Netherlands (to BIT), NSF grant IBN 0212587 (to JBW), and VENI and VIDI grants from the Netherlands Organisation for Scientific Research (to KDM and BIT).This is the accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007%2Fs00442-014-3136-y

Wild Skylarks Seasonally Modulate Energy Budgets but Maintain Energetically Costly Inflammatory Immune Responses throughout the Annual Cycle

A central hypothesis of ecological immunology is that immune defences are traded off against competing physiological and behavioural processes. During energetically demanding periods, birds are predicted to switch from expensive inflammatory responses to less costly immune responses. Acute phase responses (APRs) are a particularly costly form of immune defence, and, hence, seasonal modulations in APRs are expected. Yet, hypotheses about APR modulation remain untested in free-living organisms throughout a complete annual cycle. We studied seasonal modulations in the APRs and in the energy budgets of skylarks Alauda arvensis, a partial migrant bird from temperate zones that experiences substantial ecological changes during its annual cycle. We characterized throughout the annual cycle changes in their energy budgets by measuring basal metabolic rate (BMR) and body mass. We quantified APRs by measuring the effects of a lipopolysaccharide injection on metabolic rate, body mass, body temperature, and concentrations of glucose and ketone. Body mass and BMR were lowest during breeding, highest during winter and intermediate during spring migration, moult and autumn migration. Despite this variation in energy budgets, the magnitude of the APR, as measured by all variables, was similar in all annual cycle stages. Thus, while we find evidence that some annual cycle stages are relatively more energetically constrained, we find no support for the hypothesis that during these annual cycle stages birds compromise an immune defence that is itself energetically costly. We suggest that the ability to mount an APR may be so essential to survival in every annual cycle stage that skylarks do not trade off this costly form of defence with other annual cycle demands

The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence

Funding: This work was funded by the European Research Council [http://erc.europa.eu/], AJPB (STRIFE Advanced Grant; C-2009-AdG-249793). The work was also supported by: the Wellcome Trust [www.wellcome.ac.uk], AJPB (080088, 097377); the UK Biotechnology and Biological Research Council [www.bbsrc.ac.uk], AJPB (BB/F00513X/1, BB/K017365/1); the CNPq-Brazil [http://cnpq.br], GMA (Science without Borders fellowship 202976/2014-9); and the National Centre for the Replacement, Refinement and Reduction of Animals in Research [www.nc3rs.org.uk], DMM (NC/K000306/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments We thank Dr. Elizabeth Johnson (Mycology Reference Laboratory, Bristol) for providing strains, and the Aberdeen Proteomics facility for the biotyping of S. cerevisiae clinical isolates, and to Euroscarf for providing S. cerevisiae strains and plasmids. We are grateful to our Microscopy Facility in the Institute of Medical Sciences for their expert help with the electron microscopy, and to our friends in the Aberdeen Fungal Group for insightful discussions.Peer reviewedPublisher PD

PSMA-PET/CT-guided salvage radiotherapy in recurrent or persistent prostate cancer and PSA < 0.2 ng/ml.

PURPOSE The purpose of this retrospective, multicenter study was to assess efficacy of PSMA-PET/CT-guided salvage radiotherapy (sRT) in patients with recurrent or persistent PSA after primary surgery and PSA levels < 0.2 ng/ml. METHODS The study included patients from a pooled cohort (n = 1223) of 11 centers from 6 countries. Patients with PSA levels > 0.2 ng/ml prior to sRT or without sRT to the prostatic fossa were excluded. The primary study endpoint was biochemical recurrence-free survival (BRFS) and BR was defined as PSA nadir after sRT + 0.2 ng/ml. Cox regression analysis was performed to assess the impact of clinical parameters on BRFS. Recurrence patterns after sRT were analyzed. RESULTS The final cohort consisted of 273 patients; 78/273 (28.6%) and 48/273 (17.6%) patients had local or nodal recurrence on PET/CT. The most frequently applied sRT dose to the prostatic fossa was 66-70 Gy (n = 143/273, 52.4%). SRT to pelvic lymphatics was delivered in 87/273 (31.9%) patients and androgen deprivation therapy was given to 36/273 (13.2%) patients. After a median follow-up time of 31.1 months (IQR: 20-44), 60/273 (22%) patients had biochemical recurrence. The 2- and 3-year BRFS was 90.1% and 79.2%, respectively. The presence of seminal vesicle invasion in surgery (p = 0.019) and local recurrences in PET/CT (p = 0.039) had a significant impact on BR in multivariate analysis. In 16 patients, information on recurrence patterns on PSMA-PET/CT after sRT was available and one had recurrent disease inside the RT field. CONCLUSION This multicenter analysis suggests that implementation of PSMA-PET/CT imaging for sRT guidance might be of benefit for patients with very low PSA levels after surgery due to promising BRFS rates and a low number of relapses within the sRT field

The prognostic significance of a negative PSMA-PET scan prior to salvage radiotherapy following radical prostatectomy.

AIM The optimal management for early recurrent prostate cancer following radical prostatectomy (RP) in patients with negative prostate-specific membrane antigen positron-emission tomography (PSMA-PET) scan is an ongoing subject of debate. The aim of this study was to evaluate the outcome of salvage radiotherapy (SRT) in patients with biochemical recurrence with negative PSMA PET finding. METHODS This retrospective, multicenter (11 centers, 5 countries) analysis included patients who underwent SRT following biochemical recurrence (BR) of PC after RP without evidence of disease on PSMA-PET staging. Biochemical recurrence-free survival (bRFS), metastatic-free survival (MFS) and overall survival (OS) were assessed using Kaplan-Meier method. Multivariable Cox proportional hazards regression assessed predefined predictors of survival outcomes. RESULTS Three hundred patients were included, 253 (84.3%) received SRT to the prostate bed only, 46 (15.3%) additional elective pelvic nodal irradiation, respectively. Only 41 patients (13.7%) received concomitant androgen deprivation therapy (ADT). Median follow-up after SRT was 33 months (IQR: 20-46 months). Three-year bRFS, MFS, and OS following SRT were 73.9%, 87.8%, and 99.1%, respectively. Three-year bRFS was 77.5% and 48.3% for patients with PSA levels before PSMA-PET ≤ 0.5 ng/ml and > 0.5 ng/ml, respectively. Using univariate analysis, the International Society of Urological Pathology (ISUP) grade > 2 (p = 0.006), metastatic pelvic lymph nodes at surgery (p = 0.032), seminal vesicle involvement (p 0.5 ng/ml (p = 0.004), and lack of concomitant ADT (p = 0.023) were significantly associated with worse bRFS. On multivariate Cox proportional hazards, seminal vesicle infiltration (p = 0.007), ISUP score >2 (p = 0.048), and pre SRT PSA level > 0.5 ng/ml (p = 0.013) remained significantly associated with worse bRFS. CONCLUSION Favorable bRFS after SRT in patients with BR and negative PSMA-PET following RP was achieved. These data support the usage of early SRT for patients with negative PSMA-PET findings

The maximum standardized uptake value in patients with recurrent or persistent prostate cancer after radical prostatectomy and PSMA-PET-guided salvage radiotherapy-a multicenter retrospective analysis

Purpose This study aims to evaluate the association of the maximum standardized uptake value (SUVmax) in positron-emission tomography targeting prostate-specific membrane antigen (PSMA-PET) prior to salvage radiotherapy (sRT) on biochemical recurrence free survival (BRFS) in a large multicenter cohort.Methods Patients who underwent (68) Ga-PSMA11-PET prior to sRT were enrolled in four high-volume centers in this retrospective multicenter study. Only patients with PET-positive local recurrence (LR) and/or nodal recurrence (NR) within the pelvis were included. Patients were treated with intensity-modulated-sRT to the prostatic fossa and elective lymphatics in case of nodal disease. Dose escalation was delivered to PET-positive LR and NR. Androgen deprivation therapy was administered at the discretion of the treating physician. LR and NR were manually delineated and SUVmax was extracted for LR and NR. Cox-regression was performed to analyze the impact of clinical parameters and the SUVmax-derived values on BRFS.Results Two hundred thirty-five patients with a median follow-up (FU) of 24 months were included in the final cohort. Two-year and 4-year BRFS for all patients were 68% and 56%. The presence of LR was associated with favorable BRFS (p = 0.016). Presence of NR was associated with unfavorable BRFS (p = 0.007). While there was a trend for SUVmax values &gt;= median (p = 0.071), SUVmax values &gt;= 75% quartile in LR were significantly associated with unfavorable BRFS (p = 0.022, HR: 2.1, 95%CI 1.1-4.6). SUVmax value in NR was not significantly associated with BRFS. SUVmax in LR stayed significant in multivariate analysis (p = 0.030). Sensitivity analysis with patients for who had a FU of &gt; 12 months (n = 197) confirmed these results.Conclusion The non-invasive biomarker SUVmax can prognosticate outcome in patients undergoing sRT and recurrence confined to the prostatic fossa in PSMA-PET. Its addition might contribute to improve risk stratification of patients with recurrent PCa and to guide personalized treatment decisions in terms of treatment intensification or de-intensification. This article is part of the Topical Collection on Oncology-Genitourinary