Kidney Dysfunction Increases Mortality and Incident Events after Young Stroke: The FUTURE Study.

BACKGROUND: In about 30% of young stroke patients, no cause can be identified. In elderly patients, kidney dysfunction has been suggested as a contributing risk factor for mortality as well as stroke. There are hypotheses that novel non-traditional risk factors, like chronic inflammation and oxidative stress, are involved in chronic kidney disease, affecting the cerebral microvasculature that would in turn lead to stroke. Our objective is to investigate the influence of kidney dysfunction on long-term mortality and incident vascular events after stroke in young adults aged 18 through 50 and if this relationship would be independent of other cardiovascular risk factors. METHODS: We prospectively included 460 young stroke patients with an ischemic stroke or transient ischemic attack admitted to our department between January 1, 1980 and November 1, 2010. Follow-up was done between 2014 and 2015. Estimated glomerular filtration rate (eGFR) was calculated from baseline creatinine levels and was divided in 3 subgroups: eGFR 120 ml/min/1.73 m2. Cox proportional hazard models were used to determine the effect of kidney dysfunction on mortality and incident vascular events, adjusting for cardiovascular risk factors. RESULTS: An eGFR <60 (HR 4.6; 95% CI 2.6-8.2) was associated with an increased risk of death and an increased risk of incident stroke (HR 4.1; 95% CI 1.9-9.0) independent of cardiovascular risk factors, but it was not associated with other vascular events. The point estimate for the 15-year cumulative mortality was 70% (95% CI 46-94) for patients with a low eGFR, 24% (95% CI 18-30) for patients with a normal eGFR and 30% (95% CI 12-48) for patients with a high eGFR. The point estimate for the 15-year cumulative risk of incident stroke was 45% (95% CI 16-74) for patients with a low eGFR, 13% (95% CI 9-17) for patients with a normal eGFR and 8% (95% CI 0-18) for patients with a high eGFR. CONCLUSIONS: Kidney dysfunction is related to long-term mortality and stroke recurrence, but not to incident cardiovascular disease, on average 11 years after young stroke. This warrants a more intensive follow-up of young stroke patients with signs of kidney dysfunction in the early phase. In addition, the clear association between kidney dysfunction and incident stroke seen in our young stroke population might be a first step in the recognition of kidney dysfunction as a new risk factor for the development of stroke at young age. Also, it can lead to new insights in the etiological differences between cardiovascular and cerebrovascular disease.This study was funded by the Dutch Epilepsy Fund (grant number 10-18)

Temperature and Resource Availability May Interactively Affect Over-Wintering Success of Juvenile Fish in a Changing Climate

The predicted global warming may affect freshwater systems at several organizational levels, from organism to ecosystem. Specifically, in temperate regions, the projected increase of winter temperatures may have important effects on the over-winter biology of a range of organisms and especially for fish and other ectothermic animals. However, temperature effects on organisms may be directed strongly by resource availability. Here, we investigated whether over-winter loss of biomass and lipid content of juvenile roach (Rutilus rutilus) was affected by the physiologically relatively small (2-5°C) changes of winter temperatures predicted by the Intergovernmental Panel on Climate Change (IPCC), under both natural and experimental conditions. This was investigated in combination with the effects of food availability. Finally, we explored the potential for a correlation between lake temperature and resource levels for planktivorous fish, i.e., zooplankton biomass, during five consecutive winters in a south Swedish lake. We show that small increases in temperature (+2°C) affected fish biomass loss in both presence and absence of food, but negatively and positively respectively. Temperature alone explained only a minor part of the variation when food availability was not taken into account. In contrast to other studies, lipid analyses of experimental fish suggest that critical somatic condition rather than critical lipid content determined starvation induced mortality. Our results illustrate the importance of considering not only changes in temperature when predicting organism response to climate change but also food-web interactions, such as resource availability and predation. However, as exemplified by our finding that zooplankton over-winter biomass in the lake was not related to over-winter temperature, this may not be a straightforward task

Behavioural Thermoregulatory Tactics in Lacustrine Brook Charr, Salvelinus fontinalis

The need to vary body temperature to optimize physiological processes can lead to thermoregulatory behaviours, particularly in ectotherms. Despite some evidence of within-population phenotypic variation in thermal behaviour, the occurrence of alternative tactics of this behaviour is rarely explicitly considered when studying natural populations. The main objective of this study was to determine whether different thermal tactics exist among individuals of the same population. We studied the behavioural thermoregulation of 33 adult brook charr in a stratified lake using thermo-sensitive radio transmitters that measured hourly individual temperature over one month. The observed behavioural thermoregulatory patterns were consistent between years and suggest the existence of four tactics: two “warm” tactics with both crepuscular and finer periodicities, with or without a diel periodicity, and two “cool” tactics, with or without a diel periodicity. Telemetry data support the above findings by showing that the different tactics are associated with different patterns of diel horizontal movements. Taken together, our results show a clear spatio-temporal segregation of individuals displaying different tactics, suggesting a reduction of niche overlap. To our knowledge, this is the first study showing the presence of behavioural thermoregulatory tactics in a vertebrate

Temperature dependent pH regulation in stenothermal Antarctic and eurythermal temperate eelpout (Zoarcidae): an in vivo NMR study

Temperature dependent adjustments of intracellular pH are thought to play a major role in the maintenance of protein function. Comparative studies were carried out in two species from the same fish family (Zoarcidae), the stenothermal Antarctic eelpout (Pachycara brachycephalum) and the eurythermal eelpout (Zoarces viviparus) to find out whether pH regulation is modified by temperature in both closely related species and to what extent the respective pattern differs between eurytherms and stenotherms. Previous invasive studies had compared individual animals sampled at various temperatures thereby suggesting that a decrease in intracellular pH (pHi) values occurs at rising temperatures as predicted by the alpha-stat hypothesis of acid-base regulation. The present study used non-invasive in vivo 31P-NMR spectroscopy in non-anaesthetized, unrestrained fish for long term online recordings in individual specimens. Control spectra obtained at T= 0 °C for P. brachycephalum and at 12 °C for Z. viviparus indicated low stress conditions as well as a high stability of energy and acid-base status over time periods longer than 1 week. Temperature changes had no influence on the concentration of high-energy phosphates like phosphocreatine or ATP. Temperature induced pH changes were monitored continuously in a range between 0 and 6 °C for polar and 12 to 18 °C for temperate eelpout. A pHi change of around -0.015 pH units/°C was observed within both species in accordance with the alpha-stat hypothesis, however, extrapolation to the same temperature revealed different set points of pH regulation in the two species. These findings confirm that an alpha-stat pattern of pH regulation can be found in stenothermal Antarctic animals, however, at setpoints deviating from an alphastat pattern in a between species comparison

Oxygen limited thermal tolerance in Antarctic fish investigated by MRI and 31P-MRS

The hypothesis of an oxygen limited thermal tolerance was tested in the Antarctic teleost Pachycara brachycephalum. Using flow-through respirometry, in vivo 31P-NMR spectroscopy and MRI, we studied energy metabolism, intracellular pH (pHi), blood-flow and oxygenation between 0 and 13°C under normoxia (PO2: 20,3 to 21,3kPa) and hyperoxia (PO2: 45kPa). Hyperoxia reduced the metabolic increment and the rise in arterial blood-flow observed under normoxia. The normoxic increase of blood-flow levelled off beyond 7°C, indicating a cardiovascular capacity limitation. Ventilatory effort displayed an exponential rise in both groups. In the liver, blood oxygenation increased, whereas in white muscle it remained unaltered (normoxia) or declined (hyperoxia). In both groups, the slope of pHi changes followed the alpha-stat pattern below 6°C, whereas it decreased above. In conclusion, aerobic scope declines around 6°C under normoxia, marking the pejus temperature Tp. By reducing circulatory costs, hyperoxia improves aerobic scope but is unable to shift the breakpoint in pH regulation or lethal limits. Hyperoxia appears beneficial at sublethal temperatures, but no longer beyond when cellular or molecular functions become disturbed

Thermal sensitivity of cellular energy budgets in Antarctic fish hepatocytes

Oxygen demand elicited by the main cellular energy consumers was examined in isolated hepatocytes of sub-Antarctic and high-Antarctic notothenioid and zoarcid (Pachycara brachycephalum) fish with respect to the role of cellular metabolism in co-defining thermal tolerance. The relative proportions of energy allocated to protein and RNA/DNA synthesis, ion regulation and ATP synthesis were quantified between 0 and 15°C by analysis of inhibitor sensitive cellular respiration. In all investigated species, protein synthesis constituted 25-37%, RNA synthesis 24-35%, Na+/K+-ATPase 40-45% and mitochondrial ATP synthesis 57-65% of total respiration. The sub-Antarctic nototheniid Lepidonotothen larseni displayed lower cellular protein synthesis rates but somewhat higher active ion regulation activities than its high-Antarctic confamilials, as is typical for more eurythermal species. Assumed thermal optima were mirrored in minimized overall cellular energy demand. Onset of thermal stress indicated by elevated energy turnover became visible between 3 and 0°C as well as beyond 6°C in the sub-Antarctic L. larseni and P. brachycephalum; whereas the high-Antarctic species displayed progressively rising respiration rates during warming with a cellular energetic minimum at 0°C.Sub-Antarctic fish showed signs of cold-eurythermy and appear to live close to their lower limit of thermal tolerance, while high-Antarctic notothenioids show high degrees of energetic efficiency at 0°C. All cellular preparations maintained energy budgets over a wide thermal range, supporting the recent concept that thermal limits are set by oxygen and associated energy limitations at the whole organism level