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Item does not contain fulltext PURPOSE: Thermal perception, including thermal sensation (TS), influences exercise performance in the heat. TS is a widely used measure and we examined the impact of initial TS (iTS) on performance loss during exercise in simulated Tokyo environmental conditions among elite athletes. METHODS: 105 Elite outdoor athletes (endurance, skill, power and mixed trained) participated in this crossover study. Participants performed a standardized exercise test in control (15.8 ± 1.2 °C, 55 ± 6% relative humidity (RH)) and simulated Tokyo (31.6 ± 1.0 °C, 74 ± 5% RH) conditions to determine performance loss. TS was assessed ± 5 min prior to exercise (iTS) and every 5 min during the incremental exercise test (TS). Based on iTS in the Tokyo condition, participants were allocated to a neutral (iTS = 0, n = 11), slightly warm (iTS = 1, n = 50), or warm-to-hot (iTS = 2/3, n = 44) subgroup. RESULTS: For the whole cohort iTS was 1 [1-2] and TS increased to 3 [3-3] at the end of exercise in the Tokyo condition. Average performance loss was 26.0 ± 10.7% in the Tokyo versus control condition. The slightly warm subgroup had less performance loss (22.3 ± 11.3%) compared to the warm-to-hot subgroup (29.4 ± 8.5%, p = 0.003), whereas the neutral subgroup did not respond different (28.8 ± 11.0%, p = 0.18) from the slightly warm subgroup. CONCLUSION: iTS impacted the magnitude of performance loss among elite athletes exercising in hot and humid conditions. Athletes with a warm-to-hot iTS had more performance loss compared to counterparts with a slightly warm iTS, indicating that pre-cooling strategies and/or heat acclimation may be of additional importance for athletes in the warm-to-hot iTS group to mitigate the impact of heat stress. 01 februari 2022

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Objective We examined the impact of simulated Tokyo 2020 environmental condition on exercise performance, thermoregulatory responses and thermal perception among Dutch elite athletes. Methods 105 elite athletes from different sport disciplines performed two exercise tests in simulated control (15.9 ± 1.2 °C, relative humidity (RH) 55 ± 6%) and Tokyo (31.6 ± 1.0 °C, RH 74 ± 5%) environmental conditions. Exercise tests consisted of a 20-min warm-up (70% HRmax), followed by an incremental phase until volitional exhaustion (5% workload increase every 3 min). Gastrointestinal temperature (Tgi), heart rate, exercise performance and thermal perception were measured. Results Time to exhaustion was 16 ± 8 min shorter in the Tokyo versus the control condition (− 26 ± 11%, whereas peak power output decreased with 0.5 ± 0.3 W/kg (16 ± 7%). Greater exercise-induced increases in Tgi (1.8 ± 0.6 °C vs. 1.5 ± 0.5 °C, p Tgi (38.9 ± 0.6 °C vs. 38.7 ± 0.4 °C, p Tgi (range 0.7–3.5 °C) and peak Tgi (range 37.6–40.4 °C) were found in the Tokyo condition, with greater Tgi responses in endurance versus mixed- and skill-trained athletes. Peak thermal sensation and thermal comfort scores deteriorated in the Tokyo condition, with aggravated responses for power versus endurance- and mixed-trained athletes. Conclusion Large performance losses and Tgi increases were found among elite athletes exercising in simulated Tokyo conditions, with a substantial interindividual variation and significantly different responses across sport disciplines. These findings highlight the importance of an individual approach to optimally prepare athletes for safe and maximal exercise performance during the Tokyo Olympics.

Contains fulltext : 238809.pdf (Publisher’s version ) (Open Access) The environmental conditions during the Tokyo Olympic and Paralympic Games are expected to be challenging, which increases the risk for participating athletes to develop heat-related illnesses and experience performance loss. To allow safe and optimal exercise performance of Dutch elite athletes, the Thermo Tokyo study aimed to determine thermoregulatory responses and performance loss among elite athletes during exercise in the heat, and to identify personal, sports-related, and environmental factors that contribute to the magnitude of these outcomes. For this purpose, Dutch Olympic and Paralympic athletes performed two personalized incremental exercise tests in simulated control (15°C, relative humidity (RH) 50%) and Tokyo (32°C, RH 75%) conditions, during which exercise performance and (thermo)physiological parameters were obtained. Thereafter, athletes were invited for an additional visit to conduct anthropometric, dual-energy X-ray absorptiometry (DXA), and 3D scan measurements. Collected data also served as input for a thermophysiological computer simulation model to estimate the impact of a wider range of environmental conditions on thermoregulatory responses. Findings of this study can be used to inform elite athletes and their coaches on how heat impacts their individual (thermo)physiological responses and, based on these data, advise which personalized countermeasures (i.e. heat acclimation, cooling interventions, rehydration plan) can be taken to allow safe and maximal performance in the challenging environmental conditions of the Tokyo 2020 Olympic and Paralympic Games.

Variants in the ryanodine receptor-1 gene (RYR1) have been associated with a wide range of neuromuscular conditions, including various congenital myopathies and malignant hyperthermia (MH). More recently, a number of RYR1 variants, mostly MH-associated, have been demonstrated to contribute to rhabdomyolysis events not directly related to anesthesia in otherwise healthy individuals. This review focuses on RYR1-related rhabdomyolysis in the context of several clinical presentations (i.e., exertional rhabdomyolysis, exertional heat illnesses and MH), and conditions involving a similar hypermetabolic state, in which RYR1 variants may be present (i.e., neuroleptic malignant syndrome and serotonin syndrome). The variety of triggers that can evoke rhabdomyolysis, on their own or in combination, as well as the number of potentially associated complications, illustrates that this is a condition relevant to several medical disciplines. External triggers include but are not limited to strenuous physical exercise, especially if unaccustomed or performed under challenging environmental conditions (e.g., high ambient temperature or humidity), alcohol/illicit drugs, prescription medication (in particular statins, other anti-lipid agents, antipsychotics and antidepressants) infection, or heat. Amongst all patients presenting with rhabdomyolysis, genetic susceptibility is present in a proportion, with RYR1 being one of the most common genetic causes. Clinical clues for a genetic susceptibility include recurrent rhabdomyolysis, creatine kinase (CK) levels above 50 times the upper limit of normal, hyperCKemia lasting for 8 weeks or longer, drug/medication doses insufficient to explain the rhabdomyolysis event, and positive family history. For the treatment or prevention of RYR1-related rhabdomyolysis, the RYR1 antagonist dantrolene can be administered, both in the acute phase or prophylactically in patients with a history of muscle cramps and/or recurrent rhabdomyolysis events. Aside from dantrolene, several other drugs are being investigated for their potential therapeutic use in RYR1-related disorders. These findings offer further therapeutic perspectives for humans, suggesting an important area for future research.

The combination of an exacerbated workload and impermeable nature of the personal protective equipment (PPE) worn by COVID-19 healthcare workers increases heat strain. We aimed to compare the prevalence of heat strain symptoms before (routine care without PPE) versus during the COVID-19 pandemic (COVID-19 care with PPE), identify risk factors associated with experiencing heat strain, and evaluate the access to and use of heat mitigation strategies. Dutch healthcare workers (n = 791) working at COVID-19 wards for ≥1 week, completed an online questionnaire to assess personal characteristics, heat strain symptoms before and during the COVID-19 pandemic, and the access to and use of heat mitigation strategies. Healthcare workers experienced ~25× more often heat strain symptoms during medical duties with PPE (93% of healthcare workers) compared to without PPE (30% of healthcare workers; OR = 25.57 (95% CI = 18.17–35.98)). Female healthcare workers and those with an age

Contains fulltext : 238795.pdf (Publisher’s version ) (Closed access) BACKGROUND: Emerging evidence suggests that increasing dietary nitrate intake may be an effective approach to improve cardiovascular health. However, the effects of a prolonged elevation of nitrate intake through an increase in vegetable consumption are understudied. OBJECTIVE: Our primary aim was to determine the impact of 12 wk of increased daily consumption of nitrate-rich vegetables or nitrate supplementation on blood pressure (BP) in (pre)hypertensive middle-aged and older adults. METHODS: In a 12-wk randomized, controlled study (Nijmegen, The Netherlands), 77 (pre)hypertensive participants (BP: 144 ± 13/87 ± 7 mmHg, age: 65 ± 10 y) either received an intervention with personalized monitoring and feedback aiming to consume ∼250-300 g nitrate-rich vegetables/d (∼350-400 mg nitrate/d; n = 25), beetroot juice supplementation (400 mg nitrate/d; n = 26), or no intervention (control; n = 26). Before and after intervention, 24-h ambulatory BP was measured. Data were analyzed using repeated measures ANOVA (time × treatment), followed by within-group (paired t-test) and between-group analyses (1-factor ANOVA) where appropriate. RESULTS: The 24-h systolic BP (SBP) (primary outcome) changed significantly (P-interaction time × treatment = 0.017) with an increase in the control group (131 ± 8 compared with 135 ± 10 mmHg; P = 0.036); a strong tendency for a decline in the nitrate-rich vegetable group (129 ± 10 compared with 126 ± 9 mmHg; P = 0.051) which was different from control (P = 0.020); but no change in the beetroot juice group (133 ± 11 compared with 132 ± 12 mmHg; P = 0.56). A significant time × treatment interaction was also found for daytime SBP (secondary outcome, P = 0.011), with a significant decline in the nitrate-rich vegetable group (134 ± 10 compared with 129 ± 9 mmHg; P = 0.006) which was different from control (P = 0.010); but no changes in the beetroot juice (138 ± 12 compared with 137 ± 14 mmHg; P = 0.41) and control group (136 ± 10 compared with 137 ± 11 mmHg; P = 0.08). Diastolic BP (secondary outcome) did not change in any of the groups. CONCLUSIONS: A prolonged dietary intervention focusing on high-nitrate vegetable intake is an effective strategy to lower SBP in (pre)hypertensive middle-aged and older adults. This trial was registered at www.trialregister.nl as NL7814.

Active secretion of bile salts into the canalicular lumen drives bile formation and promotes biliary cholesterol and phospholipid output. Disrupting hepatic bile salt uptake, by inhibition of sodium‐taurocholate cotransporting polypetide (NTCP; Slc10a1) with Myrcludex B, is expected to limit bile salt flux through the liver and thereby to decrease biliary lipid excretion. Here, we show that Myrcludex B–mediated NTCP inhibition actually causes an increase in biliary cholesterol and phospholipid excretion whereas biliary bile salt output and bile salt composition remains unchanged. Increased lysosomal discharge into bile was excluded as a potential contributor to increased biliary lipid secretion. Induction of cholesterol secretion was not a consequence of increased ATP‐binding cassette subfamily G member 5/8 activity given that NTCP inhibition still promoted cholesterol excretion in Abcg8−/− mice. Stimulatory effects of NTCP inhibition were maintained in Sr‐b1−/− mice, eliminating the possibility that the increase in biliary lipids was derived from enhanced uptake of high‐density lipoprotein–derived lipids. NTCP inhibition shifts bile salt uptake, which is generally more periportally restricted, toward pericentral hepatocytes, as was visualized using a fluorescently labeled conjugated bile salt. As a consequence, exposure of the canalicular membrane to bile salts was increased, allowing for more cholesterol and phospholipid molecules to be excreted per bile salt. Conclusion: NTCP inhibition increases biliary lipid secretion, which is independent of alterations in bile salt output, biliary bile salt hydrophobicity, or increased activity of dedicated cholesterol and phospholipid transporters. Instead, NTCP inhibition shifts hepatic bile salt uptake from mainly periportal hepatocytes toward pericentral hepatocytes, thereby increasing exposure of the canalicular membrane to bile salts linking to increased biliary cholesterol secretion. This process provides an additional level of control to biliary cholesterol and phospholipid secretion.

Liver fibrosis is characterized by the accumulation of extracellular matrix proteins, mainly composed of collagen. Hepatic stellate cells (HSCs) mediate liver fibrosis by secreting collagen. Vitamin C (ascorbic acid) is a cofactor of prolyl-hydroxylases that modify newly synthesized collagen on the route for secretion. Unlike most animals, humans cannot synthesize ascorbic acid and its role in liver fibrosis remains unclear. Here, we determined the effect of ascorbic acid and prolyl-hydroxylase inhibition on collagen production and secretion by human HSCs. Primary human HSCs (p-hHSCs) and the human HSCscell line LX-2 were treated with ascorbic acid, transforming growth factor-beta (TGFβ) and/or the pan-hydroxylase inhibitor dimethyloxalylglycine (DMOG). Expression of collagen-I was analyzed by RT-qPCR (COL1A1), Western blotting, and immunofluorescence microscopy. Collagen secretion was determined in the medium by Western blotting for collagen-I and by HPLC for hydroxyproline concentrations. Expression of solute carrier family 23 members 1 and 2 (SLC23A1/SLC23A2), encoding sodium-dependent vitamin C transporters 1 and 2 (SVCT1/SVCT2) was quantified in healthy and cirrhotic human tissue. In the absence of ascorbic acid, collagen-I accumulated intracellularly in p-hHSCs and LX-2 cells, which was potentiated by TGFβ. Ascorbic acid co-treatment strongly promoted collagen-I excretion and enhanced extracellular hydroxyproline concentrations, without affecting collagen-I (COL1A1) mRNA levels. DMOG inhibited collagen-I release even in the presence of ascorbic acid and suppressed COL1A1 and alpha-smooth muscle actin (αSMA/ACTA2) mRNA levels, also under hypoxic conditions. Hepatocytes express both ascorbic acid transporters, while p-hHSCs and LX-2 express the only SVCT2, which is selectively enhanced in cirrhotic livers. Human HSCs rely on ascorbic acid for the efficient secretion of collagen-I, which can be effectively blocked by hydroxylase antagonists, revealing new therapeutic targets to treat liver fibrosis.

The amplitude of the innate immune response reflects the degree of physiological stress imposed by exercise load. An optimal balance of exercise intensity and duration is essential for a balanced immune system and reduces the risk of dysfunction of the immune system. Therefore, it is hypothesized that neutrophils, as key players in the innate immune system, can be used as biomarker in detecting overtraining. The aim was to monitor the state of the innate immune system by phenotyping neutrophils during consecutive bouts of prolonged exercise. Study subjects were recruited from a cohort of walkers participating in a walking event on 3 consecutive days. Participants with immune deficiencies were excluded. Questionnaires to determine the physiological status of the participants were completed. Analysis of neutrophil receptor expression was done by a point‐of‐care fully automated flow cytometer. A total of 45 participants were recruited, of whom 39 participants were included for data analysis. Study participants had a median age of 64 (58‐70) years. The absolute numbers CD16dim/CD62Lbright and CD16bright/CD62Ldim neutrophils were increased after the first 2 days of exercise followed by an adaptation/normalization after the third day. Participants with activated neutrophils (high CD11b expression) had an impaired physical feeling indicated by the participant on a lower visual analog scale compared to participants who did not have activated neutrophils (P = 0.017, P = 0.022). Consecutive days of prolonged exercise results in an initial systemic innate immune response, followed by normalization/adaptation. Increased neutrophil activation was associated with impaired physical feeling measured by a validated VAS score indicated by the participant. Fully automated point‐of‐care flow cytometry analysis of neutrophil phenotypes in a field laboratory might be a useful tool to monitor relevant differences in the systemic innate immune response in response to exercise., Graphical Abstract Fully automated flow cytometry analysis of neutrophils obtained in a field laboratory after repetitive prolonged exercise.

Contains fulltext : 229904.pdf (Publisher’s version ) (Open Access) BACKGROUND AND OBJECTIVES: The role of exercise in the management of inflammatory bowel disease (IBD) is inconclusive as most research focused on short or low-intensity exercise bouts and subjective outcomes. We assessed the effects of repeated prolonged moderate-intensity exercise on objective inflammatory markers in IBD patients. METHODS: In this study, IBD patients (IBD walkers, n = 18), and a control group (non-IBD walkers, n = 19), completed a 30, 40 or 50 km walking exercise on four consecutive days. Blood samples were taken at baseline and every day post-exercise to test for the effect of disease on exercise-induced changes in cytokine concentrations. A second control group of IBD patients who did not take part in the exercise, IBD non-walkers (n = 19), was used to test for the effect of exercise on faecal calprotectin. Both IBD groups also completed a clinical disease activity questionnaire. RESULTS: Changes in cytokine concentrations were similar for IBD walkers and non-IBD walkers (IL-6 p = .95; IL-8 p = .07; IL-10 p = .40; IL-1β p = .28; TNF-α p = .45), with a temporary significant increase in IL-6 (p

Background & aims Annexin A11 was identified as autoantigen in IgG4-related cholangitis (IRC), a B-cell driven disease. Annexin A11 modulates calcium-dependent exocytosis, a crucial mechanism for insertion of proteins into their target membranes. Human cholangiocytes form an apical ‘biliary bicarbonate umbrella’ regarded as defense against harmful hydrophobic bile acid influx. The bicarbonate secretory machinery comprises the chloride/bicarbonate exchanger AE2 and the chloride channel ANO1. We aimed to investigate the expression and function of annexin A11 in human cholangiocytes and a potential role of IgG1/IgG4-mediated autoreactivity against annexin A11 in the pathogenesis of IRC. Methods Expression of annexin A11 in human liver was studied by immunohistochemistry and immunofluorescence. In human control and ANXA11 knockdown H69 cholangiocytes, intracellular pH, AE2 and ANO1 surface expression, and bile acid influx were examined using ratio microspectrofluorometry, cell surface biotinylation, and 22,23-3H-glycochenodeoxycholic acid permeation, respectively. Annexin A11-mEmerald and ANO1-mCherry localization in H69 cholangiocytes after incubation with IRC patient serum containing anti-annexin A11 IgG1/IgG4-autoantibodies or disease control serum was investigated by live-cell microscopy. Results Annexin A11 was strongly expressed in human cholangiocytes, but not hepatocytes. Knockdown of ANXA11 led to reduced plasma membrane expression of ANO1, but not AE2, alkalization of intracellular pH and uncontrolled bile acid influx. High intracellular calcium conditions led to annexin A11 membrane shift and colocalization with ANO1. Incubation with IRC patient serum inhibited annexin A11 membrane shift and reduced ANO1 surface expression. Conclusion Cholangiocellular annexin A11 mediates apical membrane abundance of the chloride channel ANO1, thereby supporting biliary bicarbonate secretion. Insertion is inhibited by IRC patient serum containing anti-annexin A11 IgG1/IgG4-autoantibodies. Anti-annexin A11 autoantibodies might contribute to the pathogenesis of IRC by weakening the ‘biliary bicarbonate umbrella’. Lay summary We previously identified annexin A11 as specific autoantigen in IgG4-related cholangitis (IRC), a B-cell driven disease targeting the bile ducts. Human cholangiocytes are protected against harmful hydrophobic bile acid influx by an apical defence mechanism referred to as the ‘biliary bicarbonate umbrella’. We found that annexin A11 is required for the formation of a robust bicarbonate umbrella by modulating the plasma membrane expression of the anion channel ANO1. Binding of patient IgG4/IgG1 annexin A11 autoantibodies inhibits annexin A11 function possibly contributing to bile duct damage by weakening the biliary bicarbonate umbrella in patients with IRC.

BACKGROUND Neutrophils and monocytes are key immune effector cells in inflammatory bowel disease (IBD) that is associated with chronic inflammation in the gut. Patients with stable IBD who perform exercise have significantly fewer flare-ups of the disease, but no underlying mechanism has been identified. Therefore, the aim of this study was to compare the responsiveness/refractoriness of these innate immune cells after repeated bouts of prolonged exercise in IBD patients and controls. METHODS Patients with IBD and age- and gender-matched healthy controls were recruited from a cohort of walkers participating in a 4-day walking event. Blood analysis was performed at baseline and after 3 days of walking. Responsiveness to the bacterial/mitochondrial-stimulus N-Formylmethionine-leucyl-phenylalanine (fMLF) was tested in granulocytes and monocytes by measuring the expression of activation markers after adding this stimulus to whole blood. RESULTS In total 38 participants (54 ± 12 years) were included in this study: 19 walkers with and 19 walkers without IBD. After 3 days of prolonged exercise, a significant increase in responsiveness to fMLF was observed in all participants irrespective of disease. However, IBD patients showed significantly less responsiveness in neutrophils and monocytes, compared with non-IBD walkers. CONCLUSIONS Increased responsiveness of neutrophils and monocyte to fMLF was demonstrated after repetitive bouts of prolonged exercise. Interestingly, this exercise was associated with relative refractoriness of both neutrophils and monocytes in IBD patients. These refractory cells might create a lower inflammatory state in the intestine providing a putative mechanism for the decrease in flare-ups in IBD patients after repeated exercise.

Despite the availability of structured treatments for personality disorders (PDs), still 1 in 4 patients drop out of treatment. Knowledge of whether maladaptive personality traits can lead to dropout in psychotherapeutic treatment programs of PDs is important for the purpose of a suitable indication for such treatments, especially in the light of the new alternative model of personality disorders (AMPD), which is used more and more in clinical practice. The current study investigated whether pathological personality traits of the alternative model of personality disorders, as operationalized with the Personality Inventory for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (PID-5), and dimensional scores of PDs on the Personality Diagnostic Questionnaire-4+, could serve as predictors for dropout in an intensive (day)clinical setting for the treatment of mainly Cluster C and mild Cluster B PDs. The main finding of this study was that high scores on the PID-5 trait scales Perceptual Dysregulation, Unusual Belief and Experiences, Suspiciousness, and Rigid Perfectionism, and low scores on Restricted Affectivity and the Personality Diagnostic Questionnaire-4+ avoidant PD dimensional score, were significantly predictive for dropout from treatment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background: It is unknown whether protein supplementation can enhance recovery of exercise-induced muscle damage in older adults who have a disturbed muscle protein synthetic response. We assessed whether protein supplementation could attenuate exercise-induced muscle damage and soreness after prolonged moderate-intensity walking exercise in older adults. Methods: In a double-blind, placebo-controlled intervention study, 104 subjects (81% male, &ge, 65 years) used either a protein (n = 50) or placebo supplement (n = 54) during breakfast and directly after exercise. Within a walking event, study subjects walked 30/40/50 km per day on three consecutive days. Muscle soreness and fatigue were determined with a numeric rating scale, and creatine kinase (CK) concentrations and serum inflammation markers were obtained. Results: Habitual protein intake was comparable between the protein (0.92 &plusmn, 0.27 g/kg/d) and placebo group (0.97 &plusmn, 0.23 g/kg/d, p = 0.31). At baseline, comparable CK concentrations were found between the protein and the placebo group (110 (IQR: 84&ndash, 160 U/L) and 115 (IQR: 91&ndash, 186 U/L), respectively, p = 0.84). Prolonged walking (protein: 32 &plusmn, 9 km/d, placebo: 33 &plusmn, 6 km/d) resulted in a cumulative increase of CK in both the protein (∆283 (IQR: 182&ndash, 662 U/L)) and placebo group (∆456 (IQR: 209&ndash, 885 U/L)) after three days. CK elevations were not significantly different between groups (p = 0.43). Similarly, no differences in inflammation markers, muscle soreness and fatigue were found between groups. Conclusions: Protein supplementation does not attenuate exercise-induced muscle damage, muscle soreness or fatigue in older adults performing prolonged moderate-intensity walking exercise.

Contains fulltext : 207107.pdf (Publisher’s version ) (Open Access) Exercising in a hot and humid environment increases core body temperature, which may limit exercise performance. The risk of exercise-induced hyperthermia and associated performance decrement in Olympic sailing athletes is largely unknown. Therefore, this study aimed to compare thermoregulatory responses and performance indicators of elite sailors in a cool versus hot and humid environment. Seven elite athletes from four different Olympic sailing classes (Laser, RS:X, Finn, 470) performed cycling and/or rowing exercise in a cool (18 degrees C) and hot (33 degrees C) environment, while core body temperature (TC), skin temperature (TSK), exercise performance (covered distance), and rating of perceived exertion were measured continuously. TC increased significantly more in the hot environment (37.6 +/- 0.2 degrees C to 39.1 +/- 0.1 degrees C) compared to the cool environment (37.5 +/- 0.1 degrees C to 38.5 +/- 0.2 degrees C; p = 0.002), but the increase in TC between conditions differed substantially within individuals (range: 0.3 degrees C - 0.9 degrees C). Exercise performance decreased by 6.2 +/- 2.9% in the hot environment (p = 0.013, range: 2.3%-9.5%), but more importantly, exercise performance was strongly inversely related to peak TC (R = -0.78, p = 0.039). Rating of perceived exertion (cool: 14.2 +/- 0.6; hot: 13.9 +/- 1.2) and increase in TSK (cool: 0.5 +/- 1.0 degrees C; hot: 0.9 +/- 0.3 degrees C) did not differ between conditions (p = 0.59 and p = 0.36, respectively). To conclude, a larger increase in TC and substantial exercise performance decrement were observed in the hot versus cool environment. As a further matter, large inter-individual differences were observed across athletes with an inverse relationship between TC and exercise performance, which stresses the importance of appropriate and personalized interventions to reduce thermoregulatory burden of elite sailors during exercise in the heat.

Item does not contain fulltext OBJECTIVES: Obesity is characterized by a pro-inflammatory state, which plays a role in the pathogenesis of metabolic and cardiovascular disease. An exercise bout causes a transient increase in pro-inflammatory cytokines, whilst training has anti-inflammatory effects. No previous study examined whether the exercise-induced increase in pro-inflammatory cytokines is altered with repeated prolonged exercise bouts and whether this response differs between lean and overweight/obese individuals. DESIGN: Lean (n=25, BMI 22.9+/-1.5kg/m(2)) and age-/sex-matched overweight/obese (n=25; BMI 27.9+/-2.4kg/m(2)) individuals performed walking exercise for 30, 40 or 50km per day on four consecutive days (distances similar between groups). METHODS: Circulating cytokines (IL-6, IL-10, TNF-alpha, IL-1beta and IL-8) were examined at baseline and

Contains fulltext : 203382.pdf (Publisher’s version ) (Open Access) BACKGROUND: An inadequate protein intake may offset the muscle protein synthetic response after physical activity, reducing the possible benefits of an active lifestyle for muscle mass. We examined the effects of 12 weeks of daily protein supplementation on lean body mass, muscle strength, and physical performance in physically active older adults with a low habitual protein intake (

Gene editing to correct inherited liver disorders has promise for future therapeutic intervention, but lack of effective and safe delivery of the gene-editing machinery to hepatocytes complicates its clinical application. Two studies now report efficient delivery to the liver of non-human primates, providing proof of concept for novel treatment of inherited hypercholesterolaemia.

We sincerely thank Dr. Javitt for his interest in and perspective on our paper (1). He indicates that aspecific effects of Myrcludex B should be considered an explanation for increased biliary cholesterol and phospholipid secretion after Myrcludex B treatment as partial hepatectomy (PH) also leads to an increased contribution of pericentral hepatocytes to bile salt uptake and secretion but biliary cholesterol and phospholipid secretion are not affected. In our opinion, non-specific Myrcludex B-induced activation of canalicular or sinusoidal transporters seems unlikely given the absence of NTCP homology with these transporters and our data from experiments with SR-B1 or ABCG8 null mice. Myrcludex B is an NTCP-specific peptide showing minimal uptake by hepatocytes.

Hydrophobic bile salts are considered to promote liver fibrosis in cholestasis. However, evidence for this widely accepted hypothesis remains scarce. In established animal models of cholestasis, e.g., by Mdr2 knockout, cholestasis and fibrosis are both secondary to biliary damage. Therefore, to test the specific contribution of accumulating bile salts to liver fibrosis in cholestatic disease, we applied the unique model of inducible hepatocellular cholestasis in cholate-fed Atp8b1G308V/G308V mice. Glycochenodeoxycholate (GCDCA) was supplemented to humanize the murine bile salt pool, as confirmed by HPLC. Biomarkers of cholestasis and liver fibrosis were quantified. Hepatic stellate cells (HSC) isolated from wild-type mice were stimulated with bile salts. Proliferation, cell accumulation, and collagen deposition of HSC were determined. In cholestatic Atp8b1G308V/G308V mice, increased hepatic expression of &alpha, SMA and collagen1a mRNA and excess hepatic collagen deposition indicated development of liver fibrosis only upon GCDCA supplementation. In vitro, numbers of myofibroblasts and deposition of collagen were increased after incubation with hydrophobic but not hydrophilic bile salts, and associated with EGFR and MEK1/2 activation. We concluded that chronic hepatocellular cholestasis alone, independently of biliary damage, induces liver fibrosis in mice in presence of the human bile salt GCDCA. Bile salts may have direct pro-fibrotic effects on HSC, putatively involving EGFR and MEK1/2 signaling.

Item does not contain fulltext The purpose of this study was to examine the effects of 12 weeks collagen peptide (CP) supplementation on knee pain and function in individuals with self-reported knee pain. Healthy physically active individuals (n = 167; aged 63 [interquartile range = 56-68] years) with self-reported knee pain received 10 g/day of CP or placebo for 12 weeks. Knee pain and function were measured with the Visual Analog Scale (VAS), the Lysholm questionnaire, and the Knee injury and Osteoarthritis Outcome Score (KOOS). Furthermore, we assessed changes in inflammatory, cartilage, and bone (bio)markers. Measurements were conducted at baseline and after 12 weeks of supplementation. Baseline VAS did not differ between CP and placebo (4.7 [2.5-6.1] vs. 4.7 [2.8-6.2], p = 0.50), whereas a similar decrease in VAS was observed after supplementation (-1.6 ± 2.4 vs. -1.9 ± 2.6, p = 0.42). The KOOS and Lysholm scores increased after supplementation in both groups (p values < 0.001), whereas the increase in the KOOS and Lysholm scores did not differ between groups (p = 0.28 and p = 0.76, respectively). Furthermore, CP did not impact inflammatory, cartilage, and bone (bio)markers (p values > 0.05). A reduced knee pain and improved knee function were observed following supplementation, but changes were similar between groups. This suggests that CP supplementation over a 12-week period does not reduce knee pain in healthy, active, middle-aged to elderly individuals. Novelty CP supplementation over a 12-week period does not reduce knee pain in healthy, active, middle-aged to elderly individuals. CP supplementation over a 12-week period does not impact on inflammatory, cartilage, and bone (bio)markers in healthy, active, middle-aged to elderly individuals. 01 juli 2020

Contains fulltext : 224865.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 220725.pdf (Publisher’s version ) (Closed access)

Exposure to extreme cold environments is potentially life‐threatening. However, the world record holder of full‐body ice immersion has repeatedly demonstrated an extraordinary tolerance to extreme cold. We aimed to explore thermoregulatory, metabolic, and cardiovascular responses during 88 min of full‐body ice immersion. We continuously measured gastrointestinal temperature (Tgi), skin temperature (Tskin), blood pressure, and heart rate (HR). Oxygen consumption (VO2) was measured at rest, and after 45 and 88 min of ice immersion, in order to calculate the metabolic heat production. Tskin dropped significantly (28–34°C to 4–15°C) and VO2 doubled (5.7–11.3 ml kg−1 min−1), whereas Tgi (37.6°C), HR (72 bpm), and mean arterial pressure (106 mmHg) remained stable during the first 30 min of cold exposure. During the remaining of the trial, Tskin and VO2 remained stable, while Tgi gradually declined to 37.0°C and HR and mean arterial blood pressure increased to maximum values of 101 bpm and 115 mmHg, respectively. Metabolic heat production in rest was 169 W and increased to 321 W and 314 W after 45 and 80 min of ice immersion. Eighty‐eight minutes of full‐body ice immersion resulted in minor changes of Tgi and cardiovascular responses, while Tskin and VO2 changed markedly. These findings may suggest that our participant can optimize his thermoregulatory, metabolic, and cardiovascular responses to challenge extreme cold exposure., We investigated the thermoregulatory, metabolic, and cardiovascular responses of the world record holder of full‐body ice immersion when exposed to 88 min of ice immersion. Ice immersion resulted in minor changes of Tgi and cardiovascular responses, while Tskin and VO2 changed markedly.

Purpose: Studies often assess the impact of sex on the relation between core body temperature (CBT), whole-body sweat rate (WBSR), and heat production during exercise in laboratory settings, but less is known in free-living conditions. Therefore, the authors compared the relation between CBT, WBSR, and heat production between sexes in a 15-km race under cool conditions. Methods: During 3 editions of the Seven Hills Run (Nijmegen, the Netherlands) with similar ambient conditions (8–12°C, 80–95% relative humidity), CBT and WBSR were measured among 375 participants (52% male) before and immediately after the 15-km race. Heat production was estimated using initial body mass and mean running speed, assuming negligible external work. Results: Men finished the race in 76 (12) minutes and women in 83 (13) minutes (P P P P = .71, ES = 0.04). Men demonstrated a greater increase in CBT (1.5°C [0.8°C] vs 1.3°C [0.7°C], respectively, P = .013, ES = 0.31); the sex difference remains after correcting for heat production (P = .004). WBSR was larger in men (18.0 [6.9] g/min) than in women (11.4 [4.7] g/min; P R2 = .395, P Conclusions: WBSR was associated with heat production, irrespective of sex, during a self-paced 15-km running race in cool environmental conditions. Men had a higher ΔCBT than women.

International audience; BACKGROUND & AIMS: Progressive familial intrahepatic cholestasis type 3 (PFIC3), for which there are limited therapeutic options, often leads to end-stage liver disease before adulthood due to impaired ABCB4-dependent phospholipid transport to bile. Using adeno-associated virus serotype 8 (AAV8)-mediated gene therapy, we aimed to restore the phospholipid content in bile to levels that prevent liver damage, thereby enabling stable hepatic ABCB4 expression and long-term correction of the phenotype in a murine model of PFIC3. METHODS: Ten-week-old Abcb4(-/-) mice received a single dose of AAV8-hABCB4 (n=10) or AAV8-GFP (n=7) under control of a liver specific promoter via tail vein injection. Animals were sacrificed either 10 or 26weeks after vector administration to assess transgene persistence, after being challenged with a 0.1% cholate diet for 2weeks. Periodic evaluation of plasma cholestatic markers was performed and bile duct cannulation enabled analysis of biliary phospholipids. Liver fibrosis and the Ki67 proliferation index were assessed by immunohistochemistry. RESULTS: Stable transgene expression was achieved in all animals that received AAV8-hABCB4 up to 26weeks after administration. AAV8-hABCB4 expression restored biliary phospholipid excretion, increasing the phospholipid and cholesterol content in bile to levels that ameliorate liver damage. This resulted in normalization of the plasma cholestatic markers, alkaline phosphatase and bilirubin. In addition, AAV8-hABCB4 prevented progressive liver fibrosis and reduced hepatocyte proliferation for the duration of the study. CONCLUSION: Liver-directed gene therapy provides stable hepatic ABCB4 expression and long-term correction of the phenotype in a murine model of PFIC3. Translational studies that verify the clinical feasibility of this approach are warranted. LAY SUMMARY: Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a severe genetic liver disease that results from impaired transport of lipids to bile, which makes the bile toxic to liver cells. Because therapeutic options are currently limited, this study aims to evaluate gene therapy to correct the underlying genetic defect in a mouse model of this disease. By introducing a functional copy of the missing gene in liver cells of mice, we were able to restore lipid transport to bile and strongly reduce damage to the liver. The proliferation of liver cells was also reduced, which contributes to long-term correction of the phenotype. Further studies are required to evaluate whether this approach can be applied to patients with PFIC3.

The nuclear receptor Farnesoid X Receptor (FXR) is activated by bile acids and controls multiple metabolic processes, including bile acid, lipid, carbohydrate, amino acid and energy metabolism. Vitamin A is needed for proper metabolic and immune control and requires bile acids for efficient intestinal absorption and storage in the liver. Here, we analyzed whether FXR regulates vitamin A metabolism. Compared to control animals, FXR-null mice showed strongly reduced (>90%) hepatic levels of retinol and retinyl palmitate and a significant reduction in lecithin retinol acyltransferase (LRAT), the enzyme responsible for hepatic vitamin A storage. Hepatic reintroduction of FXR in FXR-null mice induced vitamin A storage in the liver. Hepatic vitamin A levels were normal in intestine-specific FXR-null mice. Obeticholic acid (OCA, 3 weeks) treatment rapidly reduced (>60%) hepatic retinyl palmitate levels in mice, concurrent with strongly increased retinol levels (>5-fold). Similar, but milder effects were observed in cholic acid (12 weeks)-treated mice. OCA did not change hepatic LRAT protein levels, but strongly reduced all enzymes involved in hepatic retinyl ester hydrolysis, involving mostly post-transcriptional mechanisms. In conclusion, vitamin A metabolism in the mouse liver heavily depends on the FXR and FXR-targeted therapies may be prone to cause vitamin A-related pathologies.

Background: Magnesium is essential for health and performance. Sub-optimal levels have been reported for older persons. In addition, physical exercise is known to temporally decrease magnesium blood concentrations. Objective: To investigate these observations in conjunction we assessed total (tMg) and ionized magnesium (iMg) concentrations in plasma and whole blood, respectively, during 4 consecutive days of exercise in very old vital adults. Design: 68 participants (age 83.7±1.9 years) were monitored on 4 consecutive days at which they walked 30–40km (average ∼8 hours) per day at a self-determined pace. Blood samples were collected one or two days prior to the start of exercise (baseline) and every walking day immediately post-exercise. Samples were analysed for tMg and iMg levels. Results: Baseline tMg and iMg levels were 0.85±0.07 and 0.47±0.07 mmol/L, respectively. iMg decreased after the first walking day (−0.10±0.09 mmol/L, p

Objective: The discomfort caused by rectal probes and esophageal probes for the estimation of body core temperature has triggered the development of gastrointestinal (GI) capsules that are easily accepted by athletes and workers due to their non-invasive characteristics. We compare two new GI capsule devices with rectal temperature during cycle ergometer exercise and rest. Approach: Eight participants followed a protocol of (i) 30 min exercise with a power output of 130 W, (ii) 5 min rest, (iii) 10 min self-paced maximum exercise, and (iv) 15 min rest. Core temperature was measured using two GI-capsule devices (e-Celsius and myTemp) and rectal temperature. Main results: The myTemp system provided only slightly different temperatures to the rectal temperature probe during rest and exercise. However, the factory-calibrated e-Celsius system showed a systematic rectal temperature underestimation of 0.2 °C that is corrected in the 2018 versions. Both GI capsules reacted faster to temperature changes in the body compared to the rectal temperature probe during the rest period following maximum exercise. Significance: The GI-capsules react faster to temperature changes in the body compared to the rectal temperature probe, in particular during the rest period following exercise.

Progressive familial intrahepatic cholestasis type 1 (PFIC1) is caused by mutations in the gene encoding the phospholipid flippase ATP8B1. Apart from severe cholestatic liver disease, many PFIC1 patients develop extrahepatic symptoms characteristic of cystic fibrosis (CF), such as pulmonary infection, sweat gland dysfunction and failure to thrive. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel essential for epithelial fluid transport. Previously it was shown that CFTR transcript levels were strongly reduced in livers of PFIC1 patients. Here we have investigated the hypothesis that ATP8B1 is important for proper CFTR expression and function. We analyzed CFTR expression in ATP8B1-depleted intestinal and pulmonary epithelial cell lines and assessed CFTR function by measuring short-circuit currents across transwell-grown ATP8B1-depleted intestinal T84 cells and by a genetically -encoded fluorescent chloride sensor. In addition, we studied CFTR surface expression upon induction of CFTR transcription. We show that CFTR protein levels are strongly reduced in the apical membrane of human ATP8B1-depleted intestinal and pulmonary epithelial cell lines, a phenotype that coincided with reduced CFTR activity. Apical membrane insertion upon induction of ectopically-expressed CFTR was strongly impaired in ATP8B1-depleted cells. We conclude that ATP8B1 is essential for correct apical localization of CFTR in human intestinal and pulmonary epithelial cells, and that impaired CFTR localization underlies some of the extrahepatic phenotypes observed in ATP8B1 deficiency. (C) 2016 Elsevier B.V. All rights reserved.

UNLABELLED ATP11C is a homolog of ATP8B1, both of which catalyze the transport of phospholipids in biological membranes. Mutations in ATP8B1 cause progressive familial intrahepatic cholestasis type1 in humans, which is characterized by a canalicular cholestasis. Mice deficient in ATP11C are characterized by a conjugated hyperbilirubinemia and an unconjugated hypercholanemia. Here, we have studied the hypothesis that ATP11C deficiency interferes with basolateral uptake of unconjugated bile salts, a process mediated by organic anion-transporting polypeptide (OATP) 1B2. ATP11C localized to the basolateral membrane of central hepatocytes in the liver lobule of control mice. In ATP11C-deficient mice, plasma total bilirubin levels were 6-fold increased, compared to control, of which ∼65% was conjugated and ∼35% unconjugated. Plasma total bile salts were 10-fold increased and were mostly present as unconjugated species. Functional studies in ATP11C-deficient mice indicated that hepatic uptake of unconjugated bile salts was strongly impaired whereas uptake of conjugated bile salts was unaffected. Western blotting and immunofluorescence analysis demonstrated near absence of basolateral bile salt uptake transporters OATP1B2, OATP1A1, OATP1A4, and Na(+) -taurocholate-cotransporting polypeptide only in central hepatocytes of ATP11C-deficient liver. In vivo application of the proteasome inhibitor, bortezomib, partially restored expression of these proteins, but not their localization. Furthermore, we observed post-translational down-regulation of ATP11C protein in livers from cholestatic mice, which coincided with reduced OATP1B2 levels. CONCLUSIONS ATP11C is essential for basolateral membrane localization of multiple bile salt transport proteins in central hepatocytes and may act as a gatekeeper to prevent hepatic bile salt overload. Conjugated hyperbilirubinemia and unconjugated hypercholanemia and loss of OATP expression in ATP11C-deficient liver strongly resemble the characteristics of Rotor syndrome, suggesting that mutations in ATP11C can predispose to Rotor syndrome. (Hepatology 2016;64:161-174).

BACKGROUND & AIMS: ATP8B1 deficiency is an autosomal recessive liver disease characterized by intrahepatic cholestasis. ATP8B1 mutation p.I661T, the most frequent mutation in European patients, results in protein misfolding and impaired targeting to the plasma membrane. Similarly, mutations in cystic fibrosis transmembrane conductance regulator (CFTR), associated with cystic fibrosis, impair protein folding and trafficking. The aim of this study was to investigate whether compounds that rescue CFTR F508del trafficking are capable of improving p.I661T-ATP8B1 plasma membrane expression.METHODS: The effect of CFTR corrector compounds on plasma membrane expression of p.I661T-ATP8B1 was evaluated by cell surface biotinylation and immunofluorescence. ATPase activity was evaluated of a purified analogue protein carrying a mutation at the matching position (p.L622T-ATP8A2).RESULTS: The clinically used compounds, 4-phenylbutyric acid (4-PBA), suberoylanilide hydroxamic acid (SAHA) and N-butyldeoxynojirimycin (NB-DNJ) improved p.I661T-ATP8B1 plasma membrane targeting. Compounds C4, C5, C13 and C17 also significantly increased plasma membrane expression of p.I661T-ATP8B1. SAHA and compound C17 upregulated ATP8B1 transcription. p.I661T-ATP8B1 was partly targeted to the canalicular membrane in polarized cells, which became more evident upon treatment with SAHA and/or C4. p.L622T-ATP8A2 showed phospholipid-induced ATPase activity, suggesting that mutations at a matching position in ATP8B1 do not block functionality. Combination therapy of SAHA and compound C4 resulted in an additional improvement of ATP8B1 cell surface abundance.CONCLUSIONS: This study shows that several CFTR correctors can improve trafficking of p.I661T-ATP8B1 to the plasma membrane in vitro. Hence, these compounds may be suitable to be part of a future therapy for ATP8B1 deficiency and other genetic disorders associated with protein misfolding.LAY SUMMARY: Compounds that improve the cellular machinery dealing with protein homeostasis (proteostasis) and allow for proper folding of proteins with (mild) missense mutations are called proteostasis regulators (Balch, Science 2008). Such compounds are potentially of high therapeutic value for many (liver) diseases. In this manuscript, we investigated whether compounds identified in screens as CFTR folding correctors are actually proteostasis regulators and thus have a broader application in other protein folding diseases. Using these compounds, we could indeed show improved trafficking to the (apical) plasma membrane of a mutated ATP8B1 protein, carrying the p.I661T missense mutation. This is the most frequently identified mutation in this rare cholestatic disorder. Importantly, ATP8B1 shows no similarity to CFTR. These data are important in providing support for the concept that rare, genetic liver diseases can potentially be treated using a generalized strategy.

The disease-associated phospholipid flippase ATP8B1 decreases Cdc42 mobility at the apical membrane to ensure the formation of a single apical domain and to maintain healthy lumen architecture., During yeast cell polarization localization of the small GTPase, cell division control protein 42 homologue (Cdc42) is clustered to ensure the formation of a single bud. Here we show that the disease-associated flippase ATPase class I type 8b member 1 (ATP8B1) enables Cdc42 clustering during enterocyte polarization. Loss of this regulation results in increased apical membrane size with scattered apical recycling endosomes and permits the formation of more than one apical domain, resembling the singularity defect observed in yeast. Mechanistically, we show that to become apically clustered, Cdc42 requires the interaction between its polybasic region and negatively charged membrane lipids provided by ATP8B1. Disturbing this interaction, either by ATP8B1 depletion or by introduction of a Cdc42 mutant defective in lipid binding, increases Cdc42 mobility and results in apical membrane enlargement. Re-establishing Cdc42 clustering, by tethering it to the apical membrane or lowering its diffusion, restores normal apical membrane size in ATP8B1-depleted cells. We therefore conclude that singularity regulation by Cdc42 is conserved between yeast and human and that this regulation is required to maintain healthy tissue architecture.

The negative charge of phosphatidylserine in lipid bilayers of secretory vesicles and plasma membranes couples the domains of positively charged amino acids of secretory vesicle SNARE proteins with similar domains of plasma membrane SNARE proteins enhancing fusion of the two membranes to promote exocytosis of the vesicle contents of secretory cells. Our recent study of insulin secretory granules (ISG) (MacDonald, M. J., Ade, L., Ntambi, J. M., Ansari, I. H., and Stoker, S. W. (2015) Characterization of phospholipids in insulin secretory granules in pancreatic beta cells and their changes with glucose stimulation. J. Biol. Chem. 290, 11075–11092) suggested that phosphatidylserine and other phospholipids, such as phosphatidylethanolamine, in ISG could play important roles in docking and fusion of ISG to the plasma membrane in the pancreatic beta cell during insulin exocytosis. P4 ATPase flippases translocate primarily phosphatidylserine and, to a lesser extent, phosphatidylethanolamine across the lipid bilayers of intracellular vesicles and plasma membranes to the cytosolic leaflets of these membranes. CDC50A is a protein that forms a heterodimer with P4 ATPases to enhance their translocase catalytic activity. We found that the predominant P4 ATPases in pure pancreatic beta cells and human and rat pancreatic islets were ATP8B1, ATP8B2, and ATP9A. ATP8B1 and CDC50A were highly concentrated in ISG. ATP9A was concentrated in plasma membrane. Gene silencing of individual P4 ATPases and CDC50A inhibited glucose-stimulated insulin release in pure beta cells and in human pancreatic islets. This is the first characterization of P4 ATPases in beta cells. The results support roles for P4 ATPases in translocating phosphatidylserine to the cytosolic leaflets of ISG and the plasma membrane to facilitate the docking and fusion of ISG to the plasma membrane during insulin exocytosis.

Previous studies have shown that exercise-induced changes in cytokine profiles depend on exercise duration and intensity. Studies are generally limited to a single day, and insight into the time course during multiple days of exercise is lacking. Therefore, this study assessed cytokine responses during multiple days of moderate intensity exercise in men and women. Fifty males (58.9 ± 9.9 years) and fifty females (50.9 ± 11.2 years) were monitored on 4 consecutive days at which they walked on average ~9 h/d at a self-determined pace. Blood samples were collected 1 or 2 days prior to the start of the exercise (baseline) and every walking day immediately post-exercise. Blood samples were analyzed for IL-6, IL-8, IL-10, IL-1β, and TNF-α concentrations. All cytokine concentrations increased from baseline to post-exercise at day 1 (P < .001). Thereafter, concentrations decreased from day 1 to day 2 (P < .01), remaining rather stable during the next days. IL-1β and TNF-α were higher in men at baseline and during all days. In conclusion, exercise-induced cytokine increases attenuated on subsequent days, although daily workload remained constant. Men and women showed different baseline levels but similar exercise responses. These results suggest that individuals adapt rapidly to this type of repeated exercise.

The aim of the present case study was to use real-time observations to investigate ultramarathon runners' timing of food and fluid intake per 15 km and per hour, and total bodyweight loss due to dehydration. The study included 5 male ultramarathon runners observed during a 120 km race. The research team members followed on a bicycle and continuously observed their dietary intake using action cameras. Hourly carbohydrate intake ranged between 22.1 and 62.6 g/h, and fluid intake varied between 260 and 603 mL/h. These numbers remained relatively stable over the course of the ultra-endurance marathon. Runners consumed food and fluid on average 3-6 times per 15 km. Runners achieved a higher total carbohydrate consumption in the second half of the race (p = 0.043), but no higher fluid intake (p = 0.08). Energy gels contributed the most to the total average carbohydrate intake (40.2 ± 25.7%). Post-race weight was 3.6 ± 2.3% (range 0.3-5.7%) lower than pre-race weight, revealing a non-significant (p = 0.08) but practical relevant difference. In conclusion, runners were able to maintain a constant timing of food and fluid intake during competition but adjusted their food choices in the second half of the race. The large variation in fluid and carbohydrate intake indicate that recommendations need to be individualized to further optimize personal intakes.

OBJECTIVES: An accurate and non-invasive measurement of core body temperature (Tc) is of great importance to quantify exercise-induced increases in Tc in athletes or to assess changes in Tc in patient populations. The use of ingestible gastrointestinal telemetric temperature capsules is widely accepted as a surrogate marker for Tc, but widespread implementation is lacking due to the high costs of these disposable capsules. A new and cheaper temperature capsule system (i.e. myTemp) was recently introduced. The aim of present study is to determine the validity and test-retest reliability of the myTemp system. DESIGN: Ex-vivo experimental study. METHODS: Fifteen ingestible temperature capsules (myTemp, Nijmegen, Netherlands) were tested in a highly temperature controlled water bath, in which the water temperature gradually increased from 34°C to 44°C. The study protocol was performed twice for each temperature capsule. RESULTS: Mean difference between myTemp temperature and water bath temperature was -0.001±0.005°C (Limit of Agreement (LOA): ±0.011°C) during Trial 1 (p=0.11) and -0.001±0.006°C (LOA: ±0.012°C) during Trial 2 (p=0.039). Furthermore, an Intraclass Correlation Coefficient (ICC) of 1.00 was found for both trials. A systematic difference between Trials 1 and 2 of 0.004±0.008°C (LOA: ±0.015°C) was found (p

Exercise and dehydration may be associated with a compromised kidney function and potential signs of kidney injury. However, the kidney responses to exercise of different durations and hypohydration levels are not yet known. Therefore, we aimed to compare the effects of acute versus prolonged exercise and dehydration on estimated glomerular filtration rate (eGFR) and kidney injury biomarkers in healthy male adults. A total of 35 subjects (23 ± 3 years) were included and invited for two study visits. Visit 1 consisted of a maximal cycling test. On Visit 2, subjects performed a submaximal exercise test at 80% of maximal heart rate until 3% hypohydration. Blood and urine samples were taken at baseline, after 30 min of exercise (acute effects; low level of hypohydration) and after 150 min of exercise or when 3% hypohydration was achieved (prolonged effects, high level of hypohydration). Urinary outcome parameters were corrected for urinary cystatin C, creatinine, and osmolality. Subjects dehydrated on average 0.6 ± 0.3% and 2.9 ± 0.7% after acute and prolonged exercise, respectively (P 0.05), and elevated osmolality corrected uNGAL concentrations after acute and prolonged exercise (all P-values

The enterohepatic circulation of bile salts is an important physiological route to recycle bile salts and ensure intestinal absorption of dietary lipids. The Na+-taurocholate cotransporting polypeptide SLC10A1 (NTCP) plays a key role in this process as the major transporter of conjugated bile salts from the plasma compartment into the hepatocyte. Here we present the first patient with NTCP deficiency, who was clinically characterized by mild hypotonia, growth retardation, and delayed motor milestones. Total bile salts in plasma were extremely elevated (up to 1,500 μM, ref.

Progressive familial intrahepatic cholestasis (PFIC) types 1 and 3 are severe cholestatic liver diseases caused by deficiency of ATB8B1 and ABCB4, respectively. Mouse models for PFIC display mild phenotypes compared with human patients, and this can be explained by the difference in bile salt pool composition. Mice, unlike humans, have the ability to detoxify hydrophobic bile salts by cytochrome P450-mediated (re)hydroxylation and thus have a less toxic bile salt pool. We have crossed mouse models for PFIC1 and PFIC3 with Hrn mice that have a reduced capacity to (re)hydroxylate bile salts. Double transgenes were obtained by backcrossing Atp8b1(G308V/G308V) and Abcb4(-/-) mice with Hrn mice that have a liver-specific disruption of the cytochrome P450 reductase gene and therefore have markedly reduced P450 activity. In these mice, a more hydrophobic bile salt pool was instilled by cholic acid supplementation of the diet, and bile formation and liver pathology was studied. As opposed to single transgenes, Atp8b1(G308V/G308V)/Hrn and Abcb4(-/-)/Hrn mice rapidly developed strong cholestasis that was evidenced by increased plasma bilirubin and bile salt levels. The bile salt pool was more toxic in both models; Atp8b1(G308V/G308V)/Hrn mice had a more hydrophobic plasma pool compared with the single transgene, whereas Abcb4(-/-)/Hrn mice had a more hydrophobic biliary pool compared with the single transgene. In line with these findings, liver damage was not aggravated in Atp8b1(G308V/G308V)/Hrn but was more severe in Abcb4(-/-)/Hrn mice. These data indicate that bile salt pool composition is a critical determinant in the initiation and progression of cholestasis and liver pathology in PFIC1 and PFIC3. Most importantly, our data suggest that the hydrophobicity of the plasma bile salt pool is an important determinant of the severity of cholestasis, whereas the hydrophobicity of the biliary bile salt pool is an important determinant of the severity of liver pathology.

It has been established that bile salts play a role in the regulation of hepatic lipid metabolism. Accordingly, overt signs of steatosis have been observed in mice with reduced bile salt synthesis. The aim of this study was to identify the mechanism of hepatic steatosis in mice with bile salt deficiency due to a liver specific disruption of cytochrome P450 reductase. In this study mice lacking hepatic cytochrome P450 reductase (Hrn) or wild type (WT) mice were fed a diet supplemented with or without either 0.1% cholic acid (CA) or 0.025% obeticholic acid, a specific FXR-agonist Feeding a CA-supplemented diet resulted in a significant decrease of plasma ALT in Hrn mice. Histologically, hepatic steatosis ameliorated after CA feeding and this was confirmed by reduced hepatic triglyceride content (115.5 +/- 7.3 mg/g liver and 47.9 +/- 4.6 mg/g liver in control- and CA-fed Hrn mice, respectively). The target genes of FXR-signaling were restored to normal levels in Hrn mice when fed cholic acid. VLDL secretion in both control and CA-fed Hrn mice was reduced by 25% compared to that in WT mice. In order to gain insight in the mechanism behind these bile salt effects, the FXR agonist also was administered for 3 weeks. This resulted in a similar decrease in liver triglycerides, indicating that the effect seen in bile salt fed Hrn animals is FXR dependent In conclusion, steatosis in Hrn mice is ameliorated when mice are fed bile salts. This effect is FXR dependent. Triglyceride accumulation in Hrn liver may partly involve impaired VLDL secretion. (c) 2014 Elsevier B.V. All rights reserved

Item does not contain fulltext Exercise-induced increase in core body temperature may lead to the development of hyperthermia (>40.0 degrees C) and/or decreased performance levels. This study examined the effects of wearing a cooling vest during a 5-km time trial on thermoregulatory responses and performance. 10 male masters athletes (42+/-10 years) performed a 5-km time trial on a motorized treadmill in a climate chamber (25 degrees C, 55% relative humidity) with and without a cooling vest. Split times, heart rate, core-, skin- and cooling vest temperature were measured every 500 m. Subjects also rated thermal comfort and level of perceived exertion. The cooling vest significantly decreased heart rate (p

Our knowledge on the molecular mechanisms of red blood cell aging is mostly derived from in vitro studies. The Four Days Marches of Nijmegen in the Netherlands, the world&rsquo, s largest yearly walking event, constitutes a unique possibility to study the effect of mechanical and biochemical stressors occurring during moderate-intensity exercise on red blood cell aging in vivo. Therefore, longitudinal measurements were performed of biophysical, immunological, and functional red blood cell characteristics that are known to change during aging. Our data show that moderate-intensity exercise induces the generation of a functionally improved red blood cell population with a higher deformability and a decreased tendency to aggregate. This is likely to be associated with an early removal of the oldest red blood cells from the circulation, as deduced from the (dis)appearance of removal signals. Thus, the physiological red blood cell aging process maintains homeostasis in times of moderate-intensity exercise-induced stress, probably by accelerated aging and subsequent removal of the oldest, most vulnerable red blood cells.

Deficiency of the phospholipid flippase ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) causes progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1). Apart from cholestasis, many patients also suffer from diarrhea of yet unknown etiology. Here we have studied the hypothesis that intestinal ATP8B1 deficiency results in bile salt malabsorption as a possible cause of PFIC1/BRIC1 diarrhea. Bile salt transport was studied in ATP8B1-depleted intestinal Caco-2 cells. Apical membrane localization was studied by a biotinylation approach. Fecal bile salt and electrolyte contents were analyzed in stool samples of PFIC1 patients, of whom some had undergone biliary diversion or liver transplantation. Bile salt uptake by the apical sodium-dependent bile salt transporter solute carrier family 10 (sodium/bile acid cotransporter), member 2 (SLC10A2) was strongly impaired in ATP8B1-depleted Caco-2 cells. The reduced SLC10A2 activity coincided with strongly reduced apical membrane localization, which was caused by impaired apical membrane insertion of SLC10A2. Moreover, we show that endogenous ATP8B1 exists in a functional heterodimer with transmembrane protein 30A (CDC50A) in Caco-2 cells. Analyses of stool samples of post-transplant PFIC1 patients demonstrated that bile salt content was not changed, whereas sodium and chloride concentrations were elevated and potassium levels were decreased. The ATP8B1–CDC50A heterodimer is essential for the apical localization of SLC10A2 in Caco-2 cells. Diarrhea in PFIC1/BRIC1 patients has a secretory origin to which SLC10A2 deficiency may contribute. This results in elevated luminal bile salt concentrations and consequent enhanced electrolyte secretion and/or reduced electrolyte resorption.

Purpose:Exercise increases core body temperature (TC) due to metabolic heat production. However, the exercise-induced release of inflammatory cytokines including interleukin-6 (IL-6) may also contribute to the rise in TC by increasing the hypothalamic temperature set point. This study investigated whether the exercise-induced increase in TC is partly caused by an altered hypothalamic temperature set point.Methods:Fifteen healthy, active men age 36 ± 14 y were recruited. Subjects performed submaximal treadmill exercise in 3 randomized test conditions: (1) 400 mg ibuprofen and 1000 mg acetaminophen (IBU/APAP), (2) 1000 mg acetaminophen (APAP), and (3) a control condition (CTRL). Acetaminophen and ibuprofen were used to block the effect of IL-6 at a central and peripheral level, respectively. TC, skin temperature, and heart rate were measured continuously during the submaximal exercise tests.Results:Baseline values of TC, skin temperature, and heart rate did not differ across conditions. Serum IL-6 concentrations increased in all 3 conditions. A significantly lower peak TC was observed in IBU/APAP (38.8°C ± 0.4°C) vs CTRL (39.2°C ± 0.5°C, P = .02) but not in APAP (38.9°C ± 0.4°C) vs CTRL. Similarly, a lower ΔTC was observed in IBU/APAP (1.7°C ± 0.3°C) vs CTRL (2.0°C ± 0.5°C, P < .02) but not in APAP (1.7°C ± 0.5°C) vs CTRL. No differences were observed in skin temperature and heart-rate responses across conditions.Conclusions:The combined administration of acetaminophen and ibuprofen resulted in an attenuated increase in TC during exercise compared with a CTRL. This observation suggests that a prostaglandin-E2-induced elevated hypothalamic temperature set point may contribute to the exercise-induced rise in TC.

Contains fulltext : 182501.pdf (Publisher’s version ) (Open Access) Exercise may lead to kidney injury through several mechanisms. Urinary Kidney Injury Molecule-1 (uKIM1) and Neutrophil Gelatinase-Associated Lipocalin (uNGAL) are known biomarkers for acute kidney injury, but their response to repetitive exercise remains unknown. We examined the effects of a single versus repetitive bouts of exercise on markers for kidney injury in a middle-aged population. Sixty subjects (aged 29-78 years, 50% male) were included and walked 30, 40 or 50 km for three consecutive days. At baseline and after exercise day 1 and 3, a urine sample was collected to determine uNGAL and uKIM1. Furthermore, urinary cystatin C, creatinine, and osmolality were used to correct for dehydration-related changes in urinary concentration. Baseline uNGAL was 9.2 (5.2-14.7) ng/mL and increased to 20.7 (11.0-37.2) ng/mL and 14.2(8.0-26.3) ng/mL after day 1 and day 3, respectively, (P