Listening In on the Past: What Can Otolith δ18O Values Really Tell Us about the Environmental History of Fishes?

Oxygen isotope ratios from fish otoliths are used to discriminate marine stocks and reconstruct past climate, assuming that variations in otolith δ18O values closely reflect differences in temperature history of fish when accounting for salinity induced variability in water δ18O. To investigate this, we exploited the environmental and migratory data gathered from a decade using archival tags to study the behaviour of adult plaice (Pleuronectes platessa L.) in the North Sea. Based on the tag-derived monthly distributions of the fish and corresponding temperature and salinity estimates modelled across three consecutive years, we first predicted annual otolith δ18O values for three geographically discrete offshore sub-stocks, using three alternative plausible scenarios for otolith growth. Comparison of predicted vs. measured annual δ18O values demonstrated >96% correct prediction of sub-stock membership, irrespective of the otolith growth scenario. Pronounced inter-stock differences in δ18O values, notably in summer, provide a robust marker for reconstructing broad-scale plaice distribution in the North Sea. However, although largely congruent, measured and predicted annual δ18O values of did not fully match. Small, but consistent, offsets were also observed between individual high-resolution otolith δ18O values measured during tag recording time and corresponding δ18O predictions using concomitant tag-recorded temperatures and location-specific salinity estimates. The nature of the shifts differed among sub-stocks, suggesting specific vital effects linked to variation in physiological response to temperature. Therefore, although otolith δ18O in free-ranging fish largely reflects environmental temperature and salinity, we counsel prudence when interpreting otolith δ18O data for stock discrimination or temperature reconstruction until the mechanisms underpinning otolith δ18O signature acquisition, and associated variation, are clarified

Acute kidney disease and renal recovery : consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of > 90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD

High-intensity interval training improves VO2peak, maximal lactate accumulation, time trial and competition performance in 9–11-year-old swimmers

Training volume in swimming is usually very high when compared to the relatively short competition time. High-intensity interval training (HIIT) has been demonstrated to improve performance in a relatively short training period. The main purpose of the present study was to examine the effects of a 5-week HIIT versus high-volume training (HVT) in 9–11-year-old swimmers on competition performance, 100 and 2,000 m time (T100 m and T2,000 m), VO2peak and rate of maximal lactate accumulation (Lacmax). In a 5-week crossover study, 26 competitive swimmers with a mean (SD) age of 11.5 ± 1.4 years performed a training period of HIIT and HVT. Competition (P < 0.01; effect size = 0.48) and T2,000 m (P = 0.04; effect size = 0.21) performance increased following HIIT. No changes were found in T100 m (P = 0.20). Lacmax increased following HIIT (P < 0.01; effect size = 0.43) and decreased after HVT (P < 0.01; effect size = 0.51). VO2peak increased following both interventions (P < 0.05; effect sizes = 0.46–0.57). The increases in competition performance, T2,000 m, Lacmax and VO2peak following HIIT were achieved in significantly less training time (~2 h/week)

Influence of the central-to-peripheral arterial stiffness gradient on the timing and amplitude of wave reflections

In individuals with compliant aortas, peripheral muscular artery stiffness exceeds central elastic artery stiffness. With ageing, central stiffness increases, with little change in peripheral stiffness, resulting in a reversal of the normal stiffness gradient. This reversal may reduce wave reflection amplitude, due to movement of the major “effective” reflection site further from the heart. To test this, we investigated the relationship among arterial stiffness gradients (normal and reversed), wave reflection amplitude and reflection site distance. Subjects aged ≥50years were recruited from the Anglo-Cardiff Collaborative Trial. Central stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV). In study 1, peripheral PWV was also measured in the arm (carotid-radial, crPWV), and in study 2 in the leg (femoral- dorsalis pedis, fpPWV). Reflection site distance was calculated from cfPWV and reflected wave travel time. Subjects were dichotomized into those with a normal stiffness gradient (peripheral>central PWV), or a reversed gradient (peripheral<central PWV). In study 1, reflection site distance was greater in subjects with a reversed gradient (P<0.01), whereas time to reflection was lower (P<0.001). Both augmentation pressure (P<0.001) and augmentation index (P<0.05) were greater in subjects with a reversed gradient. In study 2, augmentation pressure, augmentation index and reflection site distance were greater in subjects with a reversed stiffness gradient (P<0.01, P<0.05 and P<0.01, respectively), and time to reflection was not different between groups. A reversed arterial stiffness gradient is associated with increased reflection site distance and a paradoxical increase in reflected wave amplitude, and augmentation index

The ATM and ATR inhibitors CGK733 and caffeine suppress cyclin D1 levels and inhibit cell proliferation

The ataxia telangiectasia mutated (ATM) and the ATM- related (ATR) kinases play a central role in facilitating the resistance of cancer cells to genotoxic treatment regimens. The components of the ATM and ATR regulated signaling pathways thus provide attractive pharmacological targets, since their inhibition enhances cellular sensitivity to chemo- and radiotherapy. Caffeine as well as more specific inhibitors of ATM (KU55933) or ATM and ATR (CGK733) have recently been shown to induce cell death in drug-induced senescent tumor cells. Addition of these agents to cancer cells previously rendered senescent by exposure to genotoxins suppressed the ATM mediated p21 expression required for the survival of these cells. The precise molecular pharmacology of these agents however, is not well characterized. Herein, we report that caffeine, CGK733, and to a lesser extent KU55933, inhibit the proliferation of otherwise untreated human cancer and non-transformed mouse fibroblast cell lines. Exposure of human cancer cell lines to caffeine and CGK733 was associated with a rapid decline in cyclin D1 protein levels and a reduction in the levels of both phosphorylated and total retinoblastoma protein (RB). Our studies suggest that observations based on the effects of these compounds on cell proliferation and survival must be interpreted with caution. The differential effects of caffeine/CGK733 and KU55933 on cyclin D1 protein levels suggest that these agents will exhibit dissimilar molecular pharmacological profiles

Hemorrhage-Adjusted Iron Requirements, Hematinics and Hepcidin Define Hereditary Hemorrhagic Telangiectasia as a Model of Hemorrhagic Iron Deficiency

BACKGROUND: Iron deficiency anemia remains a major global health problem. Higher iron demands provide the potential for a targeted preventative approach before anemia develops. The primary study objective was to develop and validate a metric that stratifies recommended dietary iron intake to compensate for patient-specific non-menstrual hemorrhagic losses. The secondary objective was to examine whether iron deficiency can be attributed to under-replacement of epistaxis (nosebleed) hemorrhagic iron losses in hereditary hemorrhagic telangiectasia (HHT). METHODOLOGY/PRINCIPAL FINDINGS: The hemorrhage adjusted iron requirement (HAIR) sums the recommended dietary allowance, and iron required to replace additional quantified hemorrhagic losses, based on the pre-menopausal increment to compensate for menstrual losses (formula provided). In a study population of 50 HHT patients completing concurrent dietary and nosebleed questionnaires, 43/50 (86%) met their recommended dietary allowance, but only 10/50 (20%) met their HAIR. Higher HAIR was a powerful predictor of lower hemoglobin (p = 0.009), lower mean corpuscular hemoglobin content (p<0.001), lower log-transformed serum iron (p = 0.009), and higher log-transformed red cell distribution width (p<0.001). There was no evidence of generalised abnormalities in iron handling Ferritin and ferritin(2) explained 60% of the hepcidin variance (p<0.001), and the mean hepcidinferritin ratio was similar to reported controls. Iron supplement use increased the proportion of individuals meeting their HAIR, and blunted associations between HAIR and hematinic indices. Once adjusted for supplement use however, reciprocal relationships between HAIR and hemoglobin/serum iron persisted. Of 568 individuals using iron tablets, most reported problems completing the course. For patients with hereditary hemorrhagic telangiectasia, persistent anemia was reported three-times more frequently if iron tablets caused diarrhea or needed to be stopped. CONCLUSIONS/SIGNIFICANCE: HAIR values, providing an indication of individuals' iron requirements, may be a useful tool in prevention, assessment and management of iron deficiency. Iron deficiency in HHT can be explained by under-replacement of nosebleed hemorrhagic iron losses

Influence of O6-benzylguanine on the anti-tumour activity and normal tissue toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea and molecular combinations of 5-fluorouracil and 2-chloroethyl-1-nitrosourea in mice

Previous studies have demonstrated that novel molecular combinations of 5-fluorouracil (5FU) and 2-chloroethyl-1-nitrosourea (CNU) have good preclinical activity and may exert less myelotoxicity than the clinically used nitrosoureas such as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). This study examined the effect of O6-alkylguanine-DNA-alkyltransferase (ATase) depletion by the pseudosubstrate O6-benzylguanine (BG) on the anti-tumour activity and normal tissue toxicity in mice of three such molecular combinations, in comparison with BCNU. When used as single agents at their maximum tolerated dose, all three novel compounds produced a significant growth retardation of BCNU-resistant murine colon and human breast xenografts. This in vivo anti-tumour effect was potentiated by BG, but was accompanied by severe myelotoxicity as judged by spleen colony forming assays. However, while tumour resistance to BCNU was overcome using BG, this was at the expense of enhanced bone marrow, gut and liver toxicity. Therefore, although this ATase-depletion approach resulted in improved anti-tumour activity for all three 5-FU:CNU molecular combinations, the potentiated toxicities in already dose-limiting tissues indicate that these types of agents offer no therapeutic advantage over BCNU when they are used together with BG. © 1999 Cancer Research Campaig

Metastasis Suppressors and the Tumor Microenvironment

The most dangerous attribute of cancer cells is their ability to metastasize. Throughout the process of metastasis, tumor cells interact with other tumor cells, host cells and extracellular molecules. This brief review explores how a new class of molecules – metastasis suppressors – regulate tumor cell–microenvironmental interactions. Data are presented which demonstrate that metastasis suppressors act at multiple steps of the metastatic cascade. A brief discussion for how metastasis suppressor regulation of cellular interactions might be exploited is presented

Ice-confined construction of a large basaltic volcano—Austurfjöll massif, Askja, Iceland

Austurfjöll is the largest basaltic glaciovolcanic massif at Askja volcano (Central Iceland), and through detailed studies of its volcanological and geochemical characteristics, we provide a detailed account of the sequence and structure of the ice-confined construction of a large Icelandic basaltic volcano. In particular, Austurfjöll represents a geometry of vents, and resulting glaciovolcanic morphology, not previously documented in ice-confined basaltic volcanoes. Austurfjöll was constructed during two major phases of basaltic volcanism, via seven eruptive episodes through disperse fissure-dominated eruptions. The earliest episode involved a rare and poorly exposed example of subaerial activity, and this was succeeded by six episodes involving the eruption of ice-confined pillow lavas and numerous overlapping fissure eruptions of phreatomagmatic tephra. Evidence of local subaerial lavas and tephras indicates the local growth of eruptive centers above englacial lake levels, and subsequent flooding, but no prolonged subaerial activity. Localized ice-contact facies, paleowater levels, and diamictons indicate the position and thickness of the ice was variable during the construction of Austurfjöll, and eruptive activity likely occurred in multiple and variable level meltwater lakes during the last glacial period. Lithofacies evidence including gradational transitions from effusive to explosive deposits, superposition of fragmental facies above coherent facies, and drainage channels suggest that changes in eruptive style were driven largely by external factors such as drainage and the increasing elevation of the massif. This study emphasizes the unique character of Austurfjöll, being composed of large pillow lava sheets, numerous (> 40) overlapping glaciovolcanic tindars, and only localized emergent deposits, as a product of its prolonged ice-confined eruptive history, contrasts with previous descriptions of tuyas and tindars