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Aims: Activity in the renin-angiotensin system (RAS) may influence the susceptibility to cardiac arrhythmia. To study the effect of basal RAS activity on cardiac repolarization during myocardial stress induced by hypoglycaemia or hypoxaemia in healthy humans. Methods and Results: Ten subjects with high RAS activity and 10 subjects with low RAS activity were studied on three different occasions: (i) hypoglycaemia (nadir P-glucose 2.7 +/- 0.5 mmol/L), (ii) hypoxaemia (nadir pO(2) 5.8 +/- 0.5 kPa), and (iii) normoglycaemic normoxia (control day). QT parameters were registered by Holter monitoring. Hypoglycaemia and hypoxaemia induced QTc prolongation (P < 0.001, both stimuli). The QT/RR slope and the VR increased as a function of hypoglycaemia, but were unaffected by hypoxaemia. Low RAS activity was associated with a steeper QT/RR slope in the recovery phase after both stimuli: hypoglycaemia: P = 0.04; hypoxia: P = 0.03. RAS activity had no impact on QTc [P = 0.48 (hypoglycaemia) and P = 0.40 (hypoxaemia)] or any of the other outcome variables. Conclusion: Basal RAS activity has significant impact on QT dynamics, but not the corrected QT interval, during recovery from hypoglycaemia and hypoxaemia. The impact, however, is modest and more subtle than initially expected. The clinical relevance is unclear. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated whether or not changes in body composition following moderate hypoxic exposure for 4 weeks were different compared to sea level exposure., Methods: In a randomized crossover design, nine trained participants were exposed to 2320 m of altitude or sea level for 4 weeks, separated by > 3 months. Body fat percentage (BF%), fat mass (FM), and fat-free mass (FFM) were determined before and after each condition by dual X-ray absorptiometry (DXA) and weekly by a bioelectrical impedance scanner to determine changes with a high resolution. Training volume was quantified during both interventions., Results: Hypoxic exposure reduced (P < 0.01) BF% by 2 ± 1 percentage points and increased (P < 0.01) FFM by 2 ± 2% determined by DXA. A tending time × treatment effect existed for FM determined by DXA (P = 0.06), indicating a reduced FM in hypoxia by 8 ± 7% (P < 0.01). Regional body analysis revealed reduced (P < 0.01) BF% and FFM and an increased (P < 0.01) FFM in the truncus area. No changes were observed following sea level. Bioelectrical impedance determined that BF%, FM, and FFM did not reveal any differences between interventions. Urine specific gravity measured simultaneously as body composition was identical. Training volume was similar between interventions (509 ± 70 min/week vs. 432 ± 70 min/week, respectively)., Conclusions: Four weeks of altitude exposure reduced BF% and increased FFM in trained individuals as opposed to sea level exposure. The results also indicate that a decrease in FM is greater at altitude compared to sea level. Changes were specifically observed in the truncus area., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Aims: Anesthesia often reduces mean arterial pressure (MAP) to a level that may compromise cerebral blood flow. We evaluated whether phenylephrine treatment of anesthesia-induced hypotension affects internal carotid artery (ICA) blood flow and whether anesthesia affects ICA flow and CO 2 reactivity., Material and Methods: The study included twenty-seven patients (65 ± 11 years; mean ± SD) undergoing esophageal resection ( n = 14), stomach resection ( n = 12), or a gastroentero anastomosis ( n = 1) during combined propofol-remifentanil and thoracic epidural anesthesia. Duplex ultrasound evaluated ICA blood flow. Evaluations were before and after induction of anesthesia, before and after the administration of phenylephrine as part of standard care to treat anesthesia-induced hypotension at a MAP below 60 mmHg, and the hypocapnic reactivity of ICA flow was determined before and during anesthesia., Results: Induction of anesthesia reduced MAP from 108 ± 12 to 66 ± 16 mmHg ( P < 0.0001) and ICA flow from 340 ± 92 to 196 ± 52 mL/min ( P < 0.0001). Phenylephrine was administered to 24 patients (0.1-0.2 mg) and elevated MAP from 53 ± 8 to 73 ± 8 mmHg ( P = 0.0001) and ICA flow from 191 ± 43 to 218 ± 50 mL/min ( P = 0.0276). Furthermore, anesthesia reduced the hypocapnic reactivity of ICA flow from 23 (18-33) to 14%/kPa (10-22; P = 0.0068)., Conclusion: Combined propofol-remifentanil and thoracic epidural anesthesia affect ICA flow and CO 2 reactivity. Phenylephrine partly restored ICA flow indicating that anesthesia-induced hypotension contributes to the reduction in ICA flow., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Anaesthesiology Clinical Pharmacology.)

Context: The Arg16 variant in the β2-receptor gene is associated with increased risk of severe hypoglycemia in subjects with type 1 diabetes mellitus., Objective: We hypothesized that the Arg16 variant is associated with decreased metabolic and symptomatic responses to recurrent hypoglycemia., Methods: Twenty-five healthy male subjects selected according to ADRB2 genotype and being homozygous for either Arg16 (AA; n = 13) or Gly16 (GG; n = 12) participated in 2 consecutive trial days with 3 periods of hypoglycemia (H1-H3) induced by a hyperinsulinemic hypoglycemic clamp. The main outcome measure was mean glucose infusion rate (GIR) during H1-H3., Results: During H1-H3, there was no difference between AA or GG subjects in GIR, counter-regulatory hormones (glucagon, epinephrine, cortisol, growth hormone), or substrate levels of lactate, glycerol, and free fatty acids (FFAs), and no differences in symptom response score or cognitive performance (trail making test, Stroop test). At H3, lactate response was reduced in both genotype groups, but AA subjects had decreased response (mean ± standard error of the mean of area under the curve) of glycerol (-13.1 ± 3.8 μmol L-1 hours; P = .0052), FFA (-30.2 ± 11.1 μmol L-1 hours; P = .021), and β-hydroxybutyrate (-0.008 ± 0.003 mmol L-1 hour; P = .027), while in GG subjects alanine response was increased (negative response values) (-53.9 ± 20.6 μmol L-1 hour; P = .024)., Conclusion: There was no difference in GIR between genotype groups, but secondary outcomes suggest a downregulation of the lipolytic and β-hydroxybutyrate responses to recurrent hypoglycemia in AA subjects, in contrast to the responses in GG subjects., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Current markers of iron deficiency (ID), such as ferritin and hemoglobin, have shortcomings, and hepcidin and erythroferrone (ERFE) could be of clinical relevance in relation to early assessment of ID. Here, we evaluate whether exposure to altitude-induced hypoxia (2,320 m) alone, or in combination with recombinant human erythropoietin (rHuEPO) treatment, affects hepcidin and ERFE levels before alterations in routine ID biomarkers and stress erythropoiesis manifest. Two interventions were completed, each comprising a 4-wk baseline, a 4-wk intervention at either sea level or altitude, and a 4-wk follow-up. Participants ( n = 39) were randomly assigned to 20 IU·kg body wt -1 rHuEPO or placebo injections every second day for 3 wk during the two intervention periods. Venous blood was collected weekly. Altitude increased ERFE ( P ≤ 0.001) with no changes in hepcidin or routine iron biomarkers, making ERFE of clinical relevance as an early marker of moderate hypoxia. rHuEPO treatment at sea level induced a similar pattern of changes in ERFE ( P < 0.05) and hepcidin levels ( P < 0.05), demonstrating the impact of accelerated erythropoiesis and not of other hypoxia-induced mechanisms. Compared with altitude alone, concurrent rHuEPO treatment and altitude exposure induced additive changes in hepcidin ( P < 0.05) and ERFE ( P ≤ 0.001) parallel with increases in hematocrit ( P < 0.001), demonstrating a relevant range of both hepcidin and ERFE. A poor but significant correlation between hepcidin and ERFE was found ( R 2 = 0.13, P < 0.001). The findings demonstrate that hepcidin and ERFE are more rapid biomarkers of changes in iron demands than routine iron markers. Finally, ERFE and hepcidin may be sensitive markers in an antidoping context.

We investigated whether immature reticulocyte fraction (IRF) and immature reticulocytes to red blood cells ratio (IR/RBC) are sensitive biomarkers for low-dose recombinant human erythropoietin (rhEpo) treatment at sea level (SL) and moderate altitude (AL) and whether multi (FACS) or single (Sysmex-XN) fluorescence flow cytometry is superior for IRF and IR/RBC determination. Thirty-nine participants completed two interventions, each containing a 4-week baseline, a 4-week SL or AL (2,230 m) exposure, and a 4-week follow-up. During exposure, rhEpo (20 IU kg -1 ) or placebo (PLA) was injected at SL (SL rhEpo , n = 25, SL PLA n = 9) and AL (AL rhEpo , n = 12, AL PLA n = 27) every second day for 3 weeks. Venous blood was collected weekly. Sysmex measurements revealed that IRF and IR/RBC were up to ~70% (P < 0.01) and ~190% (P < 0.001) higher in SL rhEpo than SL PLA during treatment and up to ~45% (P < 0.001) and ~55% (P < 0.01) lower post-treatment, respectively. Compared with AL PLA , IRF and IR/RBC were up to ~20% (P < 0.05) and ~45% (P < 0.001) lower post-treatment in SL rhEpo , respectively. In AL rhEpo , IRF and IR/RBC were up to ~40% (P < 0.05) and ~110% (P < 0.001) higher during treatment and up to ~25% (P < 0.05) and ~40% (P < 0.05) lower post-treatment, respectively, compared with AL PLA . Calculated thresholds provided ~90% sensitivity for both biomarkers at SL and 33% (IRF) and 66% (IR/RBC) at AL. Specificity was >99%. Single-fluorescence flow cytometry coefficient of variation was >twofold higher at baseline (P < 0.001) and provided larger or similar changes compared to multi-fluorescence, albeit with smaller precision. In conclusion, IRF and IR/RBC were sensitive and specific biomarkers for low-dose rhEpo misuse at SL and AL., (© 2021 John Wiley & Sons, Ltd.)

Purpose: To investigate whether patients with normal tension glaucoma (NTG) show an enhanced stress response to reduced oxygen supply compared to age-matched healthy controls, measured by serum adrenaline and endothelin-1 (ET-1) levels and changes in distal finger temperature., Methods: A thorough clinical characterization of patients with NTG and age-matched controls was performed prior to inclusion in the study. Twelve patients with NTG and eleven healthy controls met the inclusion criteria and were enrolled in the study. All subjects underwent a two-day investigation. Participants were randomly exposed to either hypoxia or normoxia during the first visit. Hypoxia or normoxia was induced for two hours through a tightly fitting face mask. In addition, the peripheral circulation was assessed with a thermographic camera. Blood samples were obtained before, during, and after hypoxia or normoxia to evaluate systemic stress molecules such as catecholamines and ET-1 levels., Results: In patients with NTG, reduced oxygen supply induced an increase in peripheral blood adrenaline ( p  < 0.05) and a decrease during recovery ( p  < 0.01). A difference in distal finger temperature was shown in patients with NTG under hypoxia compared to normoxia (exposure: p  < 0.05; recovery: p  < 0.05). Hypoxia induced an increase in peripheral blood ET-1 levels in both groups (NTG: p  < 0.01; controls: p  < 0.05)., Conclusion: Patients with NTG had an enhanced physiological stress response as a consequence of hypoxia compared with age-matched controls. Although more studies are needed, the present study supports the involvement of vascular risk factors in the pathophysiology of NTG., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Line Marie Dalgaard et al.)

This study evaluated whether recombinant human erythropoietin (rhEpo) treatment combined with chronic hypoxia provided an additive erythropoietic response and whether the athlete biological passport (ABP) sensitivity improved with hypoxia. Two interventions were completed, each containing 4 weeks baseline, 4 weeks exposure at sea level or 2,320 m of altitude, and 4 weeks follow-up. Participants were randomly assigned to 20 IU·kg bw -1 rhEpo or placebo injections every second day for 3 weeks during the exposure period at sea level (rhEpo n = 25, placebo n = 9) or at altitude (rhEpo n = 12, placebo n = 27). Venous blood was analyzed weekly. Combining rhEpo and hypoxia induced larger changes compared with rhEpo or hypoxia alone for [Hb] (p < 0.001 and p > 0.05, respectively), reticulocyte percentage (p < 0.001), and OFF-hr score (p < 0.01 and p < 0.001, respectively). The most pronounced effect was observed for reticulocyte percentage with up to ~35% (p < 0.001) and ~45% (p < 0.001) higher levels compared with rhEpo or hypoxia only, respectively. The ABP sensitivity for the combined treatment was 54 and 35 percentage points higher for [Hb] (p < 0.05) and reticulocyte percentage (p < 0.05), respectively, but similar for OFF-hr score, compared with rhEpo at sea level. Across any time point, [Hb] and OFF-hr score combined identified 14 unique true-positive participants (56%) at sea level and 12 unique true-positive participants (100%) at altitude. However, a concurrent reduction in specificity existed at altitude. In conclusion, rhEpo treatment combined with hypoxic exposure provided an additive erythropoietic response compared with rhEpo or hypoxic exposure alone. Correspondingly, ABP was more sensitive to rhEpo at altitude than at sea level, but a compromised specificity existed with hypoxic exposure., (© 2020 John Wiley & Sons, Ltd.)

Sprint-interval training (SIT) is efficient at improving maximal aerobic capacity and anaerobic fitness at sea-level and may be a feasible training strategy at altitude. Here, it was evaluated if SIT intensity can be maintained in mild to moderate hypoxia. It was hypothesized that 6 x 30 s Wingate sprint performance with 2 min active rest between sprints can be performed in hypoxic conditions corresponding to ~3,000 m of altitude without reducing mean power output (MPO). In a single-blinded, randomized crossover design, ten highly-trained male endurance athletes with a maximal oxygen uptake ([Formula: see text]O2max) of 68 ± 5 mL O2 × min-1 × kg-1 completed 6 x 30 s all-out Wingate cycling sprints separated by two-minute active recovery on four separate days in a hypobaric chamber. The ambient pressure within the chamber on each experimental day was 772 mmHg (~0 m), 679 mmHg (~915 m), 585 mmHg (~ 2,150 m), and 522 mmHg (~3,050 m), respectively. MPO was not different at sea-level and up to ~2,150 m (~1% and ~3% non-significant decrements at ~915 and ~2,150 m, respectively), whereas MPO was ~5% lower (P<0.05) at ~3,050 m. Temporal differences between altitudes was not different for peak power output (PPO), despite a main effect of altitude. In conclusion, repeated Wingate exercise can be completed by highly-trained athletes at altitudes up to ~2,150 m without compromising MPO or PPO. In contrast, MPO was compromised in hypobaric hypoxia corresponding to ~3,050 m. Thus, SIT may be an efficient strategy for athletes sojourning to moderate altitude and aiming to maintain training quality., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Military-, rescue- and law-enforcement personnel require a high physical capacity including muscular strength. The present study hypothesized that 9 weeks of volume matched concurrent short frequent training sessions increases strength more efficiently than less frequent longer training sessions., Design: A randomized training intervention study with functional and physiological tests before and after the intervention., Methods: Military conscripts (n=290) were assigned to micro-training (four 15-min strength and four 15-min endurance bouts weekly); classical-training (one 60-min strength and one 60-min endurance training session weekly) or a control-group (two 60-min standard military physical training sessions weekly)., Results: There were no group difference between micro-training and classical-training in measures of strength. Standing long jump remained similar while shotput performance was reduced (P≤0.001) in all three groups. Pull-up performance increased (P≤0.001) in micro-training (7.4±4.6 vs. 8.5±4.0 repetitions, n=59) and classical-training (5.7±4.1 vs. 7.1±4.2 repetitions, n=50). Knee extensor MVC increased (P≤0.01) in all groups (micro-training, n=30, 11.5±8.9%; classical-training, n=24, 8.3±11.5% and control, n=19, 7.5±11.8%) while elbow flexor and hand grip MVC remained similar. Micro-training increased (P≤0.05) type IIa percentage from 32.5±11.0% to 37.6±12.3% (n=20) and control-group increased (P≤0.01) type IIax from 4.4±3.0% to 11.6±7.9% (n=8). In control-group type I, fiber size increased (P≤0.05) from 5121±959μm to 6481±2084μm (n=5). Satellite cell content remained similar in all groups., Conclusions: Weekly distribution of low-volume concurrent training completed as either eight 15-min bouts or two 60-min sessions of which 50% was strength training did not impact strength gains in a real-world setting., (Copyright © 2020 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Background: Anaesthesia reduces mean arterial pressure (MAP), and to preserve organ perfusion, vasopressors are often used to maintain MAP above 60 mmHg. Cognitive dysfunction is common following major surgery and may relate to intra-operative cerebral hypoperfusion., Objective: The aim of this study was to evaluate whether internal carotid artery (ICA) blood flow increases when MAP is kept higher than 60 mmHg using noradrenaline., Design: A randomised, cross-over trial., Setting: Department of Anaesthesia, Rigshospitalet, Copenhagen, Denmark, from December 2017 to April 2018., Patients: Patients with median [IQR] age 71 [63 to 75] years underwent pancreaticoduodenectomy (n = 19), total pancreatic resection (n = 1) or gastro-entero anastomosis (n = 2) during combined propofol-remifentanil and thoracic epidural anaesthesia., Intervention: MAP was maintained between 60 to 65, 70 to 75 and 80 to 85 mmHg, in a random order, by noradrenaline infusion at a stable level of anaesthesia., Main Outcome Measures: Primary outcome was change in ICA flow at MAP 60 to 65 vs. 80 to 85 mmHg. Secondary outcomes were change in ICA flow at MAP 60 to 65 vs. 70 to 75 and 70 to 75 vs. 80 to 85 mmHg. Duplex ultrasound evaluated ICA flow., Results: A (mean ± SD) increase in MAP from 62 ± 1 to 82 ± 1 mmHg elevated ICA flow from 196 ± 53 to 226 ± 61 ml min (mean difference 31 ml min; 95% CI 19 to 42; P < 0.0001). An increase in MAP from 62 ± 1 to 72 ± 1 mmHg elevated ICA flow to 210 ± 52 ml min (P = 0.0271) and ICA flow increased further (P = 0.0165) when MAP was elevated to 82 ± 1 mmHg., Conclusion: During combined propofol-remifentanil and thoracic epidural anaesthesia, ICA flow increased by approximately 15% when the MAP was elevated from about 60 to 80 mmHg. Treatment of a reduction in MAP brought about by anaesthesia seems to enhance ICA flow., Trial Registration: Clinicaltrials.gov ID: NCT03309917.

Introduction: Treatment of diabetic foot ulcers is complex and often protracted. Hyperbaric oxygen treatment (HBOT) improves wound healing in diabetic ulcers and serves as an important adjunct to regular diabetic wound care. Endothelial dysfunction plays a central role in diabetes-related vascular complications and may be evaluated by a non-invasive technique called peripheral arterial tonometry which measures a reactive hyperaemia index (RHI). We hypothesized that endothelial function measured by peripheral arterial tonometry is impaired in diabetic foot ulcer patients and that HBOT might improve endothelial function., Methods: Endothelial function was prospectively assessed by peripheral arterial tonometry in 22 subjects with diabetic foot ulcers and 17 subjects without diabetes during courses of HBOT. Endothelial function was evaluated before first (baseline) and 30th treatments, and at 90-day follow-up. Serum insulin growth factor-I (IGF-I) concentrations were determined by immunoassay. Results were compared to 23 healthy subjects., Results: No baseline differences were found in endothelial function between subjects with diabetes, HBOT patients without-diabetes and healthy control subjects (RHI; 1.26, 1.61 and 1.81, respectively). No significant changes in RHI were found in patients with (P = 0.17) or without (P = 0.30) diabetes during courses of HBOT. At 90-day follow-up IGF-I was significantly reduced in the subjects with diabetes (P = 0.001) and unchanged in the group without diabetes (P = 0.99)., Conclusions: We found no significant differences in RHI between subjects with diabetic foot ulcers and patients without diabetes, nor improvement in endothelial function assessed by peripheral arterial tonometry during courses of HBOT., (Copyright: This article is the copyright of the authors who grant Diving and Hyperbaric Medicine a non-exclusive licence to publish the article in electronic and other forms.)

Purpose: To assess novel differences in serum levels of glucose, lactate and amino acids in patients with normal-tension glaucoma (NTG) compared to age-matched controls, at baseline and in response to universal hypoxia., Methods: Twelve patients diagnosed with NTG and eleven control subjects underwent normobaric hypoxia for 2 hr. Peripheral venous blood samples were taken at baseline, during hypoxia and in the recovery phase. Serum glucose and lactate levels were measured by a blood gas analyser. Amino acids were analysed by high-performance liquid chromatography., Results: Baseline levels of lactate and total amino acids were significantly lower in patients with NTG compared to healthy controls. No differences were seen in blood glucose levels between the two groups. Lactate levels remained unchanged during hypoxia in the control group, but increased in patients with NTG. In the recovery phase, total amino acid levels were reduced in the control group, whereas no changes were found in patients with NTG., Conclusion: Reduced serum levels of lactate and total amino acids were identified as potential markers for NTG. Moreover, significant differential regulatory patterns of certain amino acids were found in patients with NTG compared to control subjects. Overall, our results suggest a link between systemic energy metabolites and NTG and support a novel understanding of glaucoma as an inner retinal manifestation of a systemic condition., (© 2019 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Ageing reduces cerebral blood flow (CBF), while mean arterial pressure (MAP) becomes elevated. According to 'the selfish brain' hypothesis of hypertension, a reduction in vertebral artery blood flow (VA) leads to increased sympathetic activity and thus increases MAP. In twenty-two young (24 ± 3 years; mean ± SD) and eleven elderly (70 ± 5 years) normotensive men, duplex ultrasound evaluated whether the age-related reduction in CBF affects VA more than internal carotid artery (ICA) blood flow. Pulse-contour analysis evaluated MAP while near-infrared spectroscopy determined frontal lobe oxygenation and transcranial Doppler middle cerebral artery mean blood velocity (MCA V mean ). During supine rest, MAP (90 ± 13 versus 78 ± 9 mmHg; P<0·001) was elevated in the older subjects while their frontal lobe oxygenation (68 ± 7% versus 77 ± 7%; P<0·001), MCA V mean (49 ± 9 versus 60 ± 12 cm s -1 ; P = 0·016) and CBF (754 ± 112 versus 900 ± 144 ml min -1 ; P = 0·004) were low reflected in VA (138 ± 48 versus 219 ± 50 ml min -1 ; P<0·001) rather than in ICA flow (616 ± 96 versus 680 ± 120 ml min -1 ; P = 0·099). In conclusion, blood supply to the brain and its oxygenation are affected by ageing and the age-related decline in VA flow appears to be four times as large as that in ICA and could be important for the age-related increase in MAP., (© 2019 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

The antidepressant efficacy of electroconvulsive therapy (ECT) is correlated to the quality of the seizure as measured by EEG but has also been linked to the magnitude of changes in hemodynamic variables. Muscarinic receptor antagonists are frequently used in the treatment, and are known to affect the hemodynamic response. We hypothesized that atropine and glycopyrrolate alter the hemodynamic and autonomic hormonal response to ECT. In a randomized, cross-over study design 23 patients received either atropine, glycopyrrolate or placebo before ECT. Hemodynamic variable, EEG and EMG, and blood adrenaline, noradrenaline and pancreatic polypeptide was determined. No geriatric patients were included. Hemodynamic changes with ECT can be divided into three phases: Drop in blood pressure and pulse rate in 1st post-stimulus phase was less when using 1 mg atropine. In 2nd post-stimulus phase atropine gave a higher systolic blood pressure. No differences were seen in hormone levels after ECT in the three interventions. A significant longer tonic clonic seizure was seen in the glycopyrrolate group and a tendency of the same was seen with atropine. The study found that the changes in hemodynamic variables induced by ECT can be altered by concomitant administration of muscarinic receptor antagonist., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Studies of the resting brain measurements of cerebral blood flow (CBF) show large interindividual and regional variability, but the metabolic basis of this variability is not fully established. The aim of the present study was to reassess regional and interindividual relationships between cerebral perfusion and glucose metabolism in the resting brain. Regional quantitative measurements of CBF and cerebral metabolic rate of glucose (CMR glc ) were obtained in 24 healthy young men using dynamic [ 15 O]H 2 O and [ 18 F]fluorodeoxyglucose positron emission tomography (PET). Magnetic resonance imaging measurements of global oxygen extraction fraction (gOEF) and metabolic rate of oxygen ([Formula: see text]) were obtained by combined susceptometry-based sagittal sinus oximetry and phase contrast mapping. No significant interindividual associations between global CBF, global CMR glc , and [Formula: see text] were observed. Linear mixed-model analysis showed a highly significant association of CBF with CMR glc regionally. Compared with neocortex significantly higher CBF values than explained by CMR glc were demonstrated in infratentorial structures, thalami, and mesial temporal cortex, and lower values were found in the striatum and cerebral white matter. The present study shows that absolute quantitative global CBF measurements appear not to be a valid surrogate measure of global cerebral glucose or oxygen consumption, and further demonstrates regionally variable relationship between perfusion and glucose metabolism in the resting brain that could suggest regional differences in energy substrate metabolism. NEW & NOTEWORTHY Using method-independent techniques the study cannot confirm direct interindividual correlations of absolute global values of perfusion with oxygen or glucose metabolism in the resting brain, and absolute global perfusion measurements appear not to be valid surrogate measures of cerebral metabolism. The ratio of both perfusion and oxygen delivery to glucose metabolism varies regionally, also when accounting for known methodological regional bias in quantification of glucose metabolism.

Context: Severe hypoglycemic events are unevenly distributed in people with type 1 diabetes, making a genetic influence probable. Of the common adrenoceptor β-2 receptor gene (ADRB2) polymorphisms, the Arg16 allele is associated with receptor downregulation and reduced agonist-mediated endogenous glucose production., Objective: We tested the hypothesis that the Arg16 variant is associated with severe hypoglycemia., Method: A cohort of 311 patients with type 1 diabetes reported severe hypoglycemic events retrospectively in a validated questionnaire. The patients were characterized by diabetes history, state of hypoglycemia awareness, C-peptide status, HbA1c, and ADRB2 genotype., Results: The ADRB2 Gly16Arg genotype distribution was in Hardy-Weinberg equilibrium. The rate of severe hypoglycemia differed among all genotypes (P = 0.01). Patients homozygous for the Arg16 genotype (AA; n = 60) had a relative rate (RR) of severe hypoglycemia of 2.2 (95% CI, 1.3 to 3.6) compared with patients homozygous for the Gly16 genotype (GG; n = 116; P = 0.002). Among patients with impaired awareness or unawareness (n = 175), those with the AA genotype (n = 33) had an RR of severe hypoglycemia of 3.2 (95% CI, 1.7 to 6.0) compared with patients with the GG genotype (n = 58; P < 0.000). Genotype was not associated with state of hypoglycemia awareness per se, as assessed by any of three classification methods. The difference was not explained by other risk factors., Conclusion: Genetic polymorphism in ADRB2 is associated with risk of severe hypoglycemia in individuals with type 1 diabetes, especially in those with impaired hypoglycemia awareness.

Purpose: Experiments have shown that hyperbaric oxygen (HBO2) therapy reduces cyanide-induced cerebral distress. The exact mechanism behind HBO2's neuroprotective effect is unknown, but has been proposed to be mediated by an increased neuronal nitric oxide (NO) bioavailability, which may compete with cyanide for the active site of cytochrome oxidase in the mitochondrial respiratory chain. We hypothesized that the ameliorating effect of HBO2 is caused by an increased bioavailability of NO, which can be attenuated by injection of the selective neuronal NO synthase inhibitor, 7-nitroindazole, preceding the HBO2 procedure., Methods: A total of 41 anesthetized female Sprague-Dawley rats were allocated to four groups: 1) vehicle [1.2 ml isotonic NaCl via intra-arterial administration]; 2) cyanide [5.4 mg/kg potassium CN (KCN) intra-arterial] plus 7-nitroindazole [25 mg/kg 7-nitroindazole via intraperitoneal injection]; 3) cyanide plus 7-nitroindazole plus HBO2 [284 kPa for 90 minutes]; 4) cyanide plus 7-nitroindazole plus normobaric oxygen [101.3 kPa for 90 minutes]. Cerebral interstitial lactate, glucose, glycerol and pyruvate were evaluated by means of microdialysis., Results: HBO2 during inhibition of nNOS worsened cerebral metabolism compared to both solely CN-intoxicated animals and normobaric oxygen-treated animals. This was indicated by elevated lactate (in mM; 0.85 vs. 0.63 and 0.42, P=0.006 and P ⟨ 0.001, respectively), glycerol (in mM; 46 vs. 17 and 14, both P ⟨ 0.001), glucose (in mM; 0.58 vs. 0.31 and 0.32, both P ⟨ 0.001)., Conclusions: The results indicate that a specific nNOS inhibition offsets the ameliorating effect of HBO2 during cerebral CN intoxication. However, other factors might contribute to this neuroprotective effect as well., Competing Interests: The authors of this paper declare no conflicts of interest exist with this submission., (Copyright© Undersea and Hyperbaric Medical Society.)

Background: Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, but its use is impeded by its cognitive side effects. Novel treatments that can counteract these side effects may therefore improve current treatment strategies for depression. The present randomized trial investigates (1) whether short-term add-on treatment with erythropoietin (EPO) can reduce the cognitive side -effects of ECT and (2) whether such effects are long-lasting. Further, structural and functional magnetic resonance imaging (MRI) will be used to explore the neural underpinnings of such beneficial effects of EPO. Finally, the trial examines whether potential protective effects of EPO on cognition are accompanied by changes in markers of oxidative stress, inflammation, and neuroplasticity., Methods/design: The trial has a double-blind, randomized, placebo-controlled, parallel group design. Patients with unipolar or bipolar disorder with current moderate to severe depression referred to ECT (N = 52) are randomized to receive four high-dose infusions of EPO (40,000 IU/ml) or placebo (saline). The first EPO/saline infusion is administered within 24 h before the first ECT. The following three infusions are administered at weekly intervals immediately after ECT sessions 1, 4, and 7. Cognition assessments are conducted at baseline, after the final EPO/saline infusion (3 days after eight ECT sessions), and at a 3 months follow-up after ECT treatment completion. The neuronal substrates for potential cognitive benefits of EPO are investigated with structural and functional MRI after the final EPO/saline infusion. The primary outcome is change from baseline to after EPO treatment (3 days after eight ECT sessions) in a cognitive composite score spanning attention, psychomotor speed, and executive functions. With a sample size of N = 52 (n = 26 per group), we have ≥ 80% power to detect a clinically relevant between-group difference in the primary outcome measure at an alpha level of 5% (two-sided test). Behavioral, mood, and blood-biomarker data will be analyzed using repeated measures analysis of covariance. Functional MRI data will be preprocessed and analyzed using the FMRIB Software Library., Discussion: If EPO is found to reduce the cognitive side effects of ECT, this could have important implications for future treatment strategies for depression and for the scientific understanding of the neurobiological etiology of cognitive dysfunction in patients treated with ECT., Trial Registration: ClinicalTrials.gov, NCT03339596 . Registered on 10 November 2017.

Background: Electroconvulsive therapy (ECT) continues to be the most efficacious treatment for severe depression and other life-threatening acute psychiatric conditions. Treatment efficacy is dependent upon the induced seizure quality, which may be influenced by a range of treatment related factors. Recently, the time interval from anesthesia to the electrical stimulation (ASTI) has been suggested to be an important determinant of seizure quality., Methods: We measured ASTI in 73 ECT sessions given to 22 individual patients, and analyzed its influence on five seizure quality parameters (EEG seizure time, power, coherence, postictal suppression, and peak heart rate)., Results: Longer ASTI was significantly associated with higher peak heart rate during the seizure (p = .003). After adjustment for confounders, the association continued to be significant, even after Bonferroni correction for multiple comparisons (p = .005). ASTI was not significantly associated with other seizure parameters., Limitations: The relatively low number of sessions may lead to false negative findings. The study did not include clinical outcomes., Conclusions: Longer ASTI is associated with higher peak heart rate; a phenomenon which is thought to reflect better seizure propagation to subcortical areas of the brain. The finding indicates that delay of stimulation after anesthesia could be a simple way of improving seizure quality and thereby the clinical effect of ECT., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: The objective of this review is to investigate existing literature in order to delineate whether the use of anaesthesia and timing of seizure induction in a new and optimised way may improve the efficacy of electroconvulsive therapy (ECT)., Methods: PubMed/MEDLINE was searched for existing literature, last search on 24 June 2015. Relevant clinical studies on human subjects involving choice of anaesthetic, ventilation and bispectral index (BIS) monitoring in the ECT setting were considered. The references of relevant studies were likewise considered., Results: Propofol yields the shortest seizures, etomidate and ketamine the longest. Etomidate and ketamine+propofol 1 : 1 seems to yield the seizures with best quality. Seizure quality is improved when induction of ECT is delayed until the effect of the anaesthetic has waned - possibly monitored with BIS values. Manual hyperventilation with 100% O2 may increase the pO2/pCO2-ratio, which may be correlated with better seizure quality., Conclusion: Etomidate or a 1 : 1 ketamine and propofol combination may be the best method to achieve general anaesthesia in the ECT setting. There is a need for large randomised prospective studies comparing the effect of methohexital, thiopental, propofol, ketamine, propofol+ketamine 1 : 1 and etomidate in the ECT treatment of major depressed patients. These studies should investigate safety and side effects, and most importantly have antidepressant efficacy and cognitive side effects as outcome measures instead of seizure quality.

Erythropoietin (EPO) is expressed in human brain tissue, but its exact role is unknown. EPO may improve the efficiency of oxidative metabolism and has neuroprotective properties against hypoxic injuries in animal models. We aimed to investigate the effect of recombinant human EPO (rHuEPO) administration on healthy cerebral metabolism in humans during normoxia and during metabolic stress by inhalation of 10% O 2 hypoxic air. Twenty-four healthy men participated in a two-arm double-blind placebo-controlled trial. rHuEPO was administered as a low dose (5,000 IU) over 4 wk ( n = 12) or as a high dose (500 IU·kg body wt -1 ·day -1 ) for three consecutive days ( n = 12). Global cerebral blood flow (CBF) and metabolic rate of glucose (CMR glc ) were measured with positron emission tomography. CBF, metabolic rate of oxygen ([Formula: see text]), and cerebral lactate concentration were measured by magnetic resonance imaging and spectroscopy. Low-dose treatment increased hemoglobin and was associated with a near-significant decrease in CBF during baseline normoxia. High-dose treatment caused no change in CBF. Neither treatment had an effect on normoxia CMR glc , [Formula: see text], or lactate concentration or an effect on the cerebral metabolic response to inhalation of hypoxic air. In conclusion, the study found no evidence for a direct effect of rHuEPO on cerebral metabolism. NEW & NOTEWORTHY We demonstrate with magnetic resonance imaging and positron emission tomography that administration of erythropoietin does not have a substantial direct effect on healthy human resting cerebral blood flow or effect on cerebral glucose and oxygen metabolism. Also, administration of erythropoietin did not have a direct effect on the metabolic response to acute hypoxic stress in healthy humans, and a suggested neuroprotective effect from erythropoietin is therefore likely not a direct effect of erythropoietin on cerebral metabolism.

The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt intake, according to instructions from a dietitian. Renal clearance studies were done for measurements of renal plasma flow, glomerular filtration rate (GFR) and the segmentel tubular handling of sodium and water (lithium clearance). rhEPO increased arterial blood pressure, total peripheral resistance, and renal vascular resistance, and decreased renal plasma flow in the high-dose rhEPO intervention and tended to decrease GFR. In spite of the decrease in renal perfusion, rhEPO tended to decrease reabsorption of sodium and water in the proximal tubule and induced a prompt decrease in circulating levels of renin and aldosterone, independent of changes in red blood cell mass, blood volumes, and blood pressure. We also found changes in biomarkers showing evidence that rhEPO induced a prothrombotic state. Our results suggest that rhEPO causes a direct downregulation in proximal tubular reabsorption that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Free radical toxicity is considered as a key mechanism in the neuronal damage occurring after aneurysmal subarachnoid haemorrhage (SAH). We measured markers of DNA and RNA damage from oxidation (8-oxodG and 8-oxoGuo, respectively) in cerebrospinal fluid from 45 patients with SAH on day 1-14 after ictus and 45 age-matched healthy control subjects. At baseline, both markers were significantly increased in patients compared to controls (p values < .001), and exhibited a progressive further increase (to >20-fold above control levels) from day 5-14. None of the markers predicted the occurrence of vasospasms or mortality, although there was a trend that the 8-oxoGuo marker was more strongly associated with mortality than the 8-oxodG marker. We conclude that SAH leads to a massive increase in damage to nucleic acids from oxidative stress, which is likely to play a role in neuronal dysfunction and death. As only patients in need of a ventriculostomy catheter were included in the study, the findings cannot necessarily be extrapolated to all patients with SAH.

Cerebral non-oxidative carbohydrate consumption may be driven by a β 2 -adrenergic mechanism. This study tested whether the 46G > A (G16R) single nucleotide polymorphism of the β 2 -adrenergic receptor gene ( ADRB2 ) influences the metabolic and cerebrovascular responses to administration of adrenaline. Forty healthy Caucasian men were included from a group of genotyped individuals. Cardio- and cerebrovascular variables at baseline and during a 60-min adrenaline infusion (0.06 μg kg -1 min -1 ) were measured by Model flow, near-infrared spectroscopy and transcranial Doppler sonography. Blood samples were obtained from an artery and a retrograde catheter in the right internal jugular vein. The ADRB2 G16R variation had no effect on baseline arterial glucose, but during adrenaline infusion plasma glucose was up to 1.2 mM (CI 95 : 0.36-2.1, P < 0.026) higher in the Gly 16 homozygotes compared with Arg 16 homozygotes. The extrapolated steady-state levels of plasma glucose was 1.9 mM (CI 95 : 1.0 -2.9, P NLME < 0.0026) higher in the Gly 16 homozygotes compared with Arg 16 homozygotes. There was no change in the cerebral oxygen glucose index and the oxygen carbohydrate index during adrenaline infusion and the two indexes were not affected by G16R polymorphism. No difference between genotype groups was found in cardiac output at baseline or during adrenaline infusion. The metabolic response of glucose during adrenergic stimulation with adrenaline is associated to the G16R polymorphism of ADRB2 , although without effect on cerebral metabolism. The differences in adrenaline-induced blood glucose increase between genotypes suggest an elevated β 2 -adrenergic response in the Gly 16 homozygotes with increased adrenaline-induced glycolysis compared to Arg 16 homozygotes.

Aim: To evaluate whether muscle vasodilatation plays a role for hypotension developed during central hypovolaemia, muscle oxygenation (S m O 2 ) was examined during (pre)syncope induced by head-up tilt (HUT). Skin blood flow (SkBF) and oxygenation (S skin O 2 ) were determined because evaluation of S m O 2 may be affected by superficial tissue oxygenation. Furthermore, we evaluated cerebral oxygenation (S c O 2 ) and middle cerebral artery mean blood flow velocity (MCAv mean )., Methods: Twenty healthy male volunteers (median age 24 years; range 19-38) were subjected to passive 50° HUT for 1 h or until (pre)syncope. S c O 2 and S m O 2 (near-infrared spectroscopy), MCAv mean (transcranial Doppler) along with mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) (Modelflow ® ) were determined., Results: (Pre)syncopal symptoms appeared in 17 subjects after 11 min (median; range 2-34) accompanied by a decrease in MAP, SV, CO and TPR, while HR remained elevated. During (pre)syncope, S c O 2 decreased [73% (71-76; mean and 95% CI) to 68% (65-71), P < 0.0001] along with MCAv mean [40 (37-43) to 32 (29-35) cm s -1 , P < 0.0001]. In contrast, S m O 2 increased [63 (56-69)% to 71% (65-78), P < 0.0001], while S skin O 2 [64% (58-69) to 53% (47-58), P < 0.0001] and SkBF [71 (44-98) compared to a baseline of 99 (72-125) units, P = 0.020] were reduced., Conclusion: We confirm that the decrease in MAP during HUT is associated with a reduction in indices of cerebral perfusion. (Pre)syncope was associated with an increase in S m O 2 despite reduced S skin O 2 and SkBF, supporting that muscle vasodilation plays an important role in the circulatory events leading to hypotension during HUT., (© 2017 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Purpose: To determine the effects of a blockade of nitric oxide (NO) synthesis on hyperbaric oxygen (HBO₂) therapy during cyanide (CN) intoxication., Methods: 39 anesthetized female Sprague-Dawley rats were exposed to CN intoxication (5.4 mg/kg intra-arterially) with or without previous nitric oxide synthase (NOS) inhibition by L-NG-nitroarginine methyl ester (L-NAME) injection (40 mg/kg intraperitoneally). Subsequently, either HBO₂ therapy (284 kPa/90 minutes), normobaric oxygen therapy (100% oxygen/90 minutes) or nothing was administered. Intracerebral microdialysis was used to measure the interstitial brain concentration of lactate, glucose, glycerol and lactate/pyruvate ratios., Results: L-NAME potentiated CN intoxication by higher maximum and prolonged lactate (in mM: 0. 5 ± 0.3 vs. 0.7 ± 0.4, P ⟨ 0.005) concentrations compared with solely CN-intoxicated rats. The same trend was found for mean glucose, glycerol and lactate/pyruvate ratio levels. During HBO₂ treatment a sustained reduction occurred in mean lactate levels (in mM: 0.5 ± 0.5 vs. 0.7 ± 0.4, P ⟨ 0.01) regardless of NOS blockade by L-NAME. The same trend was found for mean glucose and glycerol levels., Conclusion: The results suggest that blocking NOS using L-NAME can worsen acute CN intoxication. HBO₂ treatment can partially overcome this block and continue to ameliorate CN intoxication., Competing Interests: The authors of this paper declare no conflicts of interest exist with this submission.

The aim was to investigate whether 6 weeks of normobaric "Live High-Train Low" (LHTL) using altitude tents affect highly trained athletes incremental peak power, 26-km time-trial cycling performance, 3-min all-out performance, and 30-s repeated sprint ability. In a double-blinded, placebo-controlled cross-over design, seven highly trained triathletes were exposed to 6 weeks of normobaric hypoxia (LHTL) and normoxia (placebo) for 8 h/day. LHTL exposure consisted of 2 weeks at 2500 m, 2 weeks at 3000 m, and 2 weeks at 3500 m. Power output during an incremental test, ~26-km time trial, 3-min all-out exercise, and 8 × 30 s of all-out sprint was evaluated before and after the intervention. Following at least 8 weeks of wash-out, the subjects crossed over and repeated the procedure. Incremental peak power output was similar after both interventions [LHTL: 375 ± 74 vs. 369 ± 70 W (pre-vs-post), placebo: 385 ± 60 vs. 364 ± 79 W (pre-vs-post)]. Likewise, mean power output was similar between treatments as well as before and after each intervention for time trial [LHTL: 257 ± 49 vs. 254 ± 54 W (pre-vs-post), placebo: 267 ± 57 vs. 267 ± 52 W (pre-vs-post)], and 3-min all-out [LHTL: 366 ± 68 vs. 369 ± 72 W (pre-vs-post), placebo: 365 ± 66 vs. 355 ± 71 W (pre-vs-post)]. Furthermore, peak- and mean power output during repeated sprint exercise was similar between groups at all time points (n = 5). In conclusion, 6 weeks of normobaric LHTL using altitude tents simulating altitudes of 2500-3500 m conducted in a double-blinded, placebo-controlled cross-over design do not affect power output during an incremental test, a ~26-km time-trial test, or 3-min all-out exercise in highly trained triathletes. Furthermore, 30 s of repeated sprint ability was unaltered.

Purpose: To compare mean global cerebral blood flow (CBF) measured by phase-contrast mapping magnetic resonance imaging (PCM MRI) and by 15 O-H 2 O positron emission tomography (PET) in healthy subjects. PCM MRI is increasingly being used to measure mean global CBF, but has not been validated in vivo against an accepted reference technique., Materials and Methods: Same-day measurements of CBF by 15 O-H 2 O PET and subsequently by PCM MRI were performed on 22 healthy young male volunteers. Global CBF by PET was determined by applying a one-tissue compartment model with measurement of the arterial input function. Flow was measured in the internal carotid and vertebral arteries by a noncardiac triggered PCM MRI sequence at 3T. The measured flow was normalized to total brain weight determined from a volume-segmented 3D T 1 -weighted anatomical MR-scan., Results: Mean CBF was 34.9 ± 3.4 mL/100 g/min measured by 15 O-H 2 O PET and 57.0 ± 6.8 mL/100 g/min measured by PCM MRI. The measurements were highly correlated (P = 0.0008, R 2  = 0.44), although values obtained by PCM MRI were higher compared to 15 O-H 2 O PET (absolute and relative differences were 22.0 ± 5.2 mL/100 g/min and 63.4 ± 14.8%, respectively)., Conclusion: This study confirms the use of PCM MRI for quantification of global CBF, but also that PCM MRI systematically yields higher values relative to 15 O-H 2 O PET, probably related to methodological bias., Level of Evidence: 3 J. Magn. Reson. Imaging 2017;45:692-699., (© 2016 The Authors Journal of Magnetic Resonance Imaging published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Gly16arg polymorphism of the adrenergic β2-receptor is associated with the elevated cardiac output (Q) in healthy gly16-homozygotic subjects. We questioned whether this polymorphism also affects Q and regional cerebral oxygen saturation (SCO2) during anesthesia in vascular surgical patients., Methods: One hundred sixty-eight patients (age 71 ± 6 years) admitted for elective surgery were included. Cardiovascular variables were determined before and during anesthesia by intravascular pulse contour analysis (Nexfin) and SCO2 by cerebral oximetry (INVOS 5100C). Genotyping was performed with the TaqMan assay., Results: Before anesthesia, Q and SCO2 were 4.7 ± 1.2 L/min and 66% ± 8%, respectively, and linearly correlated (r = 0.35, P < .0001). In patients with the gly16gly genotype baseline, Q was approximately 0.4 L/min greater than in arg16 carriers (CI95: 0.0-0.8, Pt test = .03), but during anesthesia, the difference was 0.3 L/min (Pmixed-model = .07). Post hoc analysis revealed the change in SCO2 from baseline to the induction of anesthesia to be on average 2% greater in gly16gly homozygotes than in arg16 patients when adjusted for the change in Q (P = .03; CI95: 0.2-4.0%)., Conclusions: This study suggests that the β2-adrenoceptor gly16gly genotype is associated with the elevated resting Q. An interesting trend to greater frontal lobe oxygenation at induction of anesthesia in patients with gly16gly genotype was found, but because of insufficient sample size and lack of PCO2 control throughout the measurements, the presented data may only serve as the hypothesis generating for future studies. The confidence limits indicate that the magnitude of the effects may range from clinically insignificant to potentially important.

Introduction: Nitric oxide (NO) likely plays a pivotal role in the pathogenesis of sepsis. Arginine is a substrate for NO, whereas the methylated arginines-asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA)-are endogenous by-products of proteolysis that inhibit NO production.We investigated if high-plasma levels of ADMA, SDMA, and arginine/ADMA ratio were associated with 90-day mortality in patients with severe sepsis or septic shock., Methods: We included 267 adult patients admitted to intensive care unit with severe sepsis or septic shock. The patients had previously been included in the randomized controlled trial "Scandinavian Starch for Severe Sepsis and Septic Shock (6S)." ADMA, SDMA, and arginine/ADMA ratio were measured in plasma. The risk of death within 90 days was estimated in multivariate Cox regression analyses adjusted for gender, age ≥65 years, major cardiovascular disease, diabetes, hypertension, respiratory failure, vasopressor treatment, highest quartile of creatinine and bilirubin, and lowest quartile of platelet count. In the regression analyses missing values were estimated using multiple imputation., Results: Twenty-five patients had missing data in one or more of the baseline variables and 44 patients had missing methylarginine values. Both ADMA and SDMA were independently associated with 90-day mortality (ADMA: hazard ratio 1.54; 95% CI, 1.00-2.38; P = 0.046, and SDMA: hazard ratio 1.78; 95% CI, 1.14-2.72; P = 0.011). Arginine/ADMA ratio was not associated with 90-day mortality neither in univariate nor in multivariate analyses. The difference in mortality between patients with high and low ADMA was most pronounced in the first week after inclusion., Conclusions: High levels of ADMA and SDMA in plasma were associated with increased 90-day mortality in patients with severe sepsis or septic shock. Interfering with the methylarginine-NO systems may be a novel target in these patients.

Aim: This study investigated the effect of repeated infusions of recombinant human erythropoietin (EPO) on markers of inflammation in patients with affective disorders and whether any changes in inflammatory markers were associated with improvements on verbal memory., Methods: In total, 83 patients were recruited: 40 currently depressed patients with treatment-resistant depression (TRD) (Hamilton Depression Rating Scale-17 items (HDRS-17) score >17) (sub-study 1) and 43 patients with bipolar disorder (BD) in partial remission (HDRS-17 and Young Mania Rating Scale (YMRS)⩽14) (sub-study 2). In both sub-studies, patients were randomised in a double-blind, parallel-group design to receive eight weekly intravenous infusions of EPO (Eprex; 40,000IU/ml) or saline (0.9% NaCl). Plasma concentrations of interleukin 6 (IL-6), interleukin 18 (IL-18) and high sensitive c-reactive protein (hsCRP) were measured at week 1 (baseline) and weeks 5, 9 and 14. HDRS-17 and neuropsychological function was assessed at weeks 1, 9 and 14 using a test battery including the RAVLT Auditory Verbal Learning Test (primary depression and primary cognition outcomes in the original trial)., Results: EPO had no cumulative effect on plasma levels of IL-6 or IL-18 but increased hsCRP levels in patients with TRD (mean±SD change in ng/L: EPO: 0.43±1.64; Saline: -0.90±2.43; F(1,39)=4.78, p=0.04). EPO had no effects on inflammatory markers in BD. There was no correlation between change in inflammatory markers and change in verbal memory., Conclusions: Repeated EPO infusions had no effect on IL-6 and IL-18 levels but produced a modest increase in hsCRP levels in patients with TRD. Changes over time in inflammatory markers were not correlated with changes in cognition suggesting that modulation of the inflammatory pathway is not a putative mechanism of the EPO-associated improvement of cognition in affective disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The sensitivity of the adaptive model of the Athlete Biological Passport (ABP) and reticulocyte percentage (ret%) in detection of recombinant human erythropoietin (rHuEPO) misuse was evaluated using both a long-term normal dose and a brief high dose treatment regime. Sixteen subjects received either 65 IU rHuEPO × kg -1 every second day for two weeks (normal-dose), 390 IU rHuEPO × kg -1 on three consecutive days (high-dose), or frequent placebo treatment for 13 days in a randomized, placebo-controlled, double-blind crossover design. Blood variables were measured 4, 11, and 25 days following treatment initiation. The ABP based on haemoglobin concentration ([Hb]) and OFF-hr score ([Hb] - 60 × √ret%) yielded atypical profiles following both normal-dose and high-dose treatment (0 %, 31 %, 13 % vs. 21 %, 33 %, 20 % at days 4, 11, and 25 after normal and high dose, respectively). Including ret% as a stand-alone marker for atypical blood profiles increased (P < 0.05) the sensitivity of the adaptive model at day 11 to 63 % and 67 % for normal-dose and high-dose rHuEPO administration, respectively. In conclusion, ~30 % of subjects injecting a normal-dose rHuEPO for two weeks or a high-dose rHuEPO for three days will present an atypical ABP profile. Including ret% as a stand-alone parameter improves the sensitivity two-fold. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

The aim of the present study was to examine changes in cerebral metabolism by magnetic resonance imaging of healthy subjects during inhalation of 10% O2 hypoxic air. Hypoxic exposure elevates cerebral perfusion, but its effect on energy metabolism has been less investigated. Magnetic resonance imaging techniques were used to measure global cerebral blood flow and the venous oxygen saturation in the sagittal sinus. Global cerebral metabolic rate of oxygen was quantified from cerebral blood flow and arteriovenous oxygen saturation difference. Concentrations of lactate, glutamate, N-acetylaspartate, creatine and phosphocreatine were measured in the visual cortex by magnetic resonance spectroscopy. Twenty-three young healthy males were scanned for 60 min during normoxia, followed by 40 min of breathing hypoxic air. Inhalation of hypoxic air resulted in an increase in cerebral blood flow of 15.5% (p = 0.058), and an increase in cerebral metabolic rate of oxygen of 8.5% (p = 0.035). Cerebral lactate concentration increased by 180.3% ([Formula: see text]), glutamate increased by 4.7% ([Formula: see text]) and creatine and phosphocreatine decreased by 15.2% (p[Formula: see text]). The N-acetylaspartate concentration was unchanged (p = 0.36). In conclusion, acute hypoxia in healthy subjects increased perfusion and metabolic rate, which could represent an increase in neuronal activity. We conclude that marked changes in brain homeostasis occur in the healthy human brain during exposure to acute hypoxia., (© The Author(s) 2015.)

Background: Arterial hypotension is frequent in patients undergoing anesthesia and may aggravate the outcome. Common genetic variations may influence the cardiovascular response to anesthesia. In this retrospective cohort study, we tested whether variation in the gene encoding the β2-adrenergic receptor (ADRB2) influences perioperative arterial blood pressure and consequently the use of vasopressors., Methods: Five hundred seventy-one Danish Caucasians undergoing neurosurgery were genotyped for 5 marker single-nucleotide polymorphisms (SNPs) within ADRB2 (Gly16Arg, Gln27Glu, Thr164Ile, Arg175Arg, and Gly351Gly). A pairwise tagging principle was used to identify ADRB2 haplotypes. Mean arterial blood pressure (MAP) was recorded in the supine awake state and, together with administration of vasopressors (ephedrine and/or phenylephrine), for 30 minutes after induction of general anesthesia (sevoflurane/remifentanil or propofol/remifentanil)., Results: Four hundred thirteen (72%) patients received ephedrine and/or phenylephrine. Only baseline MAP (P < 0.001) and the Arg175Arg SNP (P = 0.01) were associated with nadir perioperative MAP. The Gly16Arg SNP but no other SNPs showed a trend toward an association with the amount of vasopressors used during anesthesia with Arg16 homozygotes receiving less ephedrine equivalents. The Arg16-Gln27-Thr164-Arg175-Gly351 haplotype was associated with approximately 13% lower vasopressor requirements than the most common Gly16-Glu27-Thr164-Arg175-Gly351 haplotype (P = 0.01)., Conclusions: Gly16 carriers received larger amounts of vasopressor compared with Arg16 homozygotes. This corresponds to previous studies demonstrating that the Gly16 allele in ADRB2 is associated with vasodilation and high cardiac output.

Central hypovolemia, defined as diminished blood volume in the heart and pulmonary vascular bed, is still an unresolved problem from a therapeutic point of view. The development of pharmaceutical agents targeted at specific angiotensin II receptors, such as the non-peptidergic AT2-receptor agonist compound 21, is yielding many opportunities to uncover more knowledge about angiotensin II receptor profiles and possible therapeutic use. Cardiovascular, anti-inflammatory, and neuroprotective therapeutic use of compound 21 have been suggested. However, there has not yet been a focus on the use of these agents in a hypovolemic setting. We argue that the latest debates on the effect of angiotensin II during hypovolemia might guide for future studies, investigating the effect of such agents during experimentally simulated central hypovolemia. The purpose of this review is to examine the role of angiotensin II during episodes of central hypovolemia. To examine this, we reviewed results from studies with three experimental models of simulated hypovolemia: head up tilt table test, lower body negative pressure, and hemorrhage of animals. A systemic literature search was made with the use of PubMed/MEDLINE for studies that measured variables of the renin-angiotensin system or its effect during simulated hypovolemia. Twelve articles, using one of the three models, were included and showed a possible organ-protective effect and an effect on the sympathetic system of angiotensin II during hypovolemia. The results support the possible organ-protective vasodilatory role for the AT2-receptor during hypovolemia on both the kidney and the splanchnic tissue.

Background: Erythropoietin (EPO) is produced in the liver during fetal life, but after birth the production shifts to the kidneys. The liver maintains a production capacity of 10% of the total EPO-production, but can be up-regulated to 100%. Previous studies have demonstrated both elevated and reduced concentrations of EPO in cirrhosis. Increased EPO concentrations could be expected due to anemia, hypoxia, renal hypoperfusion, or EPO-mediated hepatoprotective mechanisms. In contrast, poor hepatic production capacity may cause reduced EPO concentrations in cirrhosis. In the present paper we aimed to study hepatic and renal venous concentrations of EPO in relation to the severity of the disease., Materials and Methods: We included 24 patients with alcoholic cirrhosis and eight age-matched healthy controls. All had a full catheterization performed with the determination of EPO concentrations in the hepatic, renal and femoral veins and artery. All patients were clinically, biochemically, and hemodynamically characterized., Results: The median arterial EPO concentrations in the cirrhotic patients and controls were 7.1 mIU/mL (range 3.5-179) and 7.2 mIU/mL (range 3.8-15.3), respectively. In the patient group we found no significant correlations to stage of disease of hemodynamic derangement., Conclusion: We found no significant differences in EPO concentrations across the liver, kidney, or peripheral circulation in the patient or control groups; and no significant correlations to clinical, biochemical, or hemodynamic characteristics. This suggests that hepatic EPO synthesis is not enhanced in cirrhosis, but larger scale studies are needed to clarify this question.

Background and Purpose: Delayed cerebral ischemia (DCI) is a serious and frequent complication following subarachnoid hemorrhage. Treatments with convincing effect are lacking and the pathophysiology behind DCI remains poorly understood. Neuropeptide Y (NPY) is a potent endogenous vasoconstrictor and a role of NPY in the development of DCI has been proposed. This study investigated the relationship between plasma-NPY and cerebral blood flow (CBF), cerebral vasospasm, DCI, and clinical outcome., Methods: In 90 patients with subarachnoid hemorrhage, NPY was measured in peripheral blood days 2 to 11. Any occurrence of DCI was recorded and CBF was quantified day 3 and day 8 using computed tomography (CT) perfusion. CT angiography was performed day 8. Clinical outcome was assessed after 3 months., Results: No correlation was found between plasma-NPY and CBF or angiographic vasospasm. The correlation between reduced plasma-NPY and DCI reached borderline statistical significance (P=0.05). Increased levels of NPY measured on days 2 to 4 were correlated to good outcome (P=0.006)., Conclusions: Our findings in peripheral blood were not supportive of a causal relationship between NPY secretion and DCI. Although high levels of plasma-NPY were correlated with good clinical outcome, NPY did not show promise as a clinically useful biomarker.

Free diving is associated with extreme hypoxia. This study evaluated the combined effect of maximal static breath holding and underwater swimming on plasma biomarkers of tissue hypoxemia: erythropoietin, neuron-specific enolase and S100B, C-reactive protein, pro-atrial natriuretic peptide, and troponin T. Venous blood samples were obtained from 17 competing free divers before and 3 h after sessions of static apnea and underwater swimming. The heart was evaluated by echocardiography. Static apnea for 293 ± 78 s (mean ± SD) and subsequent 88 ± 21 m underwater swimming increased plasma erythropoietin from 10.6 ± 3.4 to 12.4 ± 4.1 mIU/L (P = 0.013) and neuron-specific enolase from 14.5 ± 5.3 to 24.6 ± 6.4 ng/mL (P = 0.017); C-reactive protein decreased from 0.84 ± 1.0 to 0.71 ± 0.67 mmol/L (P = 0.013). In contrast, plasma concentrations of S100B (P = 0.394), pro-atrial natriuretic peptide (P = 0.549), and troponin T (P = 0.125) remained unchanged and, as assessed by echocardiography, the heart was not affected. In competitive free divers, bouts of static and dynamic apnea increase plasma erythropoietin and neuron-specific enolase, suggesting that renal and neural tissue, rather than the heart, is affected by the hypoxia developed during apnea and underwater swimming., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Schizophrenia is associated with increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of the nitric oxide synthase, and the L-arginine:ADMA ratio are markers of endothelial dysfunction that predict mortality and adverse outcome in a range of cardiovascular disorders. Increased ADMA levels may also lead to increased oxidative stress. We hypothesized that ADMA and the L-arginine:ADMA ratio are increased in somatically healthy schizophrenia patients treated with atypical antipsychotics (AAP), and that the ADMA and the L-arginine: ADMA ratio are positively correlated to measures of oxidative stress., Methods: We included 40 schizophrenia patients treated with AAP, but without somatic disease or drug abuse, and 40 healthy controls. Plasma concentrations of ADMA and L-arginine were determined by high-performance liquid chromatography. Data were related to markers of systemic oxidative stress on DNA, RNA and lipids, as well as measures of medication load, duration of disease and current symptomatology., Results: Plasma ADMA and the L-arginine:ADMA ratio did not differ between schizophrenia patients and controls. Furthermore, ADMA and the L-arginine:ADMA ratio showed no correlations with oxidative stress markers, medication load, or Positive and Negative Syndrome Scale scores., Conclusions: Schizophrenia and treatment with AAP was not associated with increased levels of plasma ADMA or the L-arginine:ADMA ratio. Furthermore, plasma levels of ADMA were not associated with levels of systemic oxidative stress in vivo.

Background and Purpose: Delayed ischemic neurological deficits (DINDs) are a major contributing factor for poor outcome in patients with subarachnoid hemorrhage. In this trial, we investigated the therapeutic potential of prostacyclin, an endogen substance with known effect on vascular tone and blood flow regulation, on factors related to DIND., Methods: This trial is a single-center, randomized, blinded, clinical, pilot trial with 3 arms. Ninety patients were randomized to continuous infusion of prostacyclin 1 ng/kg per minute, prostacyclin 2 ng/kg per minute, or placebo. The intervention was initiated day 5 after subarachnoid hemorrhage and discontinued day 10. Primary outcome was the difference in change from baseline in global cerebral blood flow. Secondary outcome measures were occurrence of DIND, angiographic vasospasm, and clinical outcome at 3 months., Results: No statistically significant difference in change of global cerebral blood flow was found between the intervention groups. The observed incidence of DIND and angiographic vasospasm was markedly higher in the placebo group, although this difference was not statistically significant. No statistically significant differences in safety parameters or clinical outcome were found between the 3 groups., Conclusions: Administration of prostacyclin to patients with subarachnoid hemorrhage may be safe and feasible. Global cerebral blood flow after subarachnoid hemorrhage is not markedly affected by administration of prostacyclin in the tested dose range. It may be possible that the observed reduction in the point estimates of DIND and vasospasm in the prostacyclin groups represents an effect of prostacyclin as this trial was not powered to investigate the effect of prostacyclin on these outcomes., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT01447095., (© 2014 American Heart Association, Inc.)

Background: The discovery of potential anti-apoptotic and cytoprotective effects of recombinant human erythropoietin (rHuEPO) has led to clinical trials investigating the use of high-dose, short-term rHuEPO therapy for tissue protection in conditions such as stroke and myocardial infarction. Experimental studies have been favourable, but the clinical efficacy has yet to be validated., Materials and Methods: We have reviewed clinical studies regarding the use of high-dose, short-term rHuEPO therapy for tissue protection in humans with the purpose to detail the safety and efficacy of rHuEPO for this indication. A systematic literature search was performed using the PubMed/MEDLINE database for randomized, placebo-controlled clinical trials., Results: Twenty-six randomized controlled trials that enrolled 3176 patients were included. The majority of trials (20 trials including 2724 patients) reported no effect of rHuEPO therapy on measures of tissue protection. Five trials including 1025 patients reported safety concerns in the form of increased mortality or adverse event rates. No studies reported reduced mortality., Conclusions: Evidence is sparse to support a tissue-protective benefit of rHuEPO in humans. Moreover, a number of studies indicate that short-term administration of high-dose rHuEPO is associated with an increased risk of mortality and serious adverse events. Further work is needed to elucidate the mechanisms of toxicity of rHuEPO in humans., (© 2014 Stichting European Society for Clinical Investigation Journal Foundation.)