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PurposeNon-invasive non-obtrusive continuous and real-time monitoring of core temperature (Tc) may enhance pacing strategies, the efficacy of heat mitigation measures, and early identification of athletes at risk for heat-related disorders. The Estimated Core Temperature (ECTemp™) algorithm uses sequential heart rate (HR) values to predict Tc. We examined the validity of ECTemp™ among elite athletes exercising in the heat.Methods101 elite athletes performed an exercise test in simulated hot and humid environmental conditions (ambient temperature: 31.6 ± 1.0°C, relative humidity: 74 ± 5%). Tc was continuously measured using a validated ingestible telemetric temperature capsule system. In addition, HR was continuously measured and used to compute the estimated core temperature (Tc−est) using the ECTemp™ algorithm.ResultsAthletes exercised for 44 ± 10 min and n = 5,025 readouts of Tc (range: 35.8–40.4°C), HR (range: 45–207 bpm), and Tc−est (range: 36.7–39.9°C) were collected. Tc−est demonstrated a small yet significant bias of 0.15 ± 0.29°C (p < 0.001) compared to Tc, with a limit of agreement of ±0.45°C and a root mean square error of 0.35 ± 0.18°C. Utilizing the ECTemp™ algorithm as a diagnostic test resulted in a fair to excellent sensitivity (73–96%) and specificity (72–93%) for Tc−est thresholds between 37.75 and 38.75°C, but a low to very-low sensitivity (50–0%) for Tc−est thresholds >39.0°C, due to a high prevalence of false-negative observations.ConclusionECTemp™ provides a valuable and representative indication of thermal strain in the low- to mid-range of Tc values observed during exercise in the heat. It may, therefore, be a useful non-invasive and non-obtrusive tool to inform athletes and coaches about the estimated core temperature during controlled hyperthermia heat acclimation protocols. However, the ECTemp™ algorithm, in its current form, should not solely be used to identify athletes at risk for heat-related disorders due to low sensitivity and high false-negative rate in the upper end of the Tc spectrum.

Major sporting events are often scheduled in thermally challenging environments. The heat stress may impact athletes but also spectators. We examined the thermal, cardiovascular, and perceptual responses of spectators watching a football match in a simulated hot and humid environment. A total of 48 participants (43 ± 9 years; n = 27 participants n = 21 participants ≥50 years, n = 21) watched a 90 min football match in addition to a 15 min baseline and 15 min halftime break, seated in an environmental chamber (Tair = 31.9 ± 0.4 °C; RH = 76 ± 4%). Gastrointestinal temperature (Tgi), skin temperature (Tskin), and heart rate (HR) were measured continuously throughout the match. Mean arterial pressure (MAP) and perceptual parameters (i.e., thermal sensation and thermal comfort) were scored every 15 min. Tri (37.3 ± 0.4 °C to 37.4 ± 0.3 °C, p = 0.11), HR (76 ± 15 bpm to 77 ± 14 bpm, p = 0.96) and MAP (97 ± 10 mm Hg to 97 ± 10 mm Hg, p = 0.67) did not change throughout the match. In contrast, an increase in Tskin (32.9 ± 0.8 °C to 35.4 ± 0.3 °C, p < 0.001) was found. Further, 81% of participants reported thermal discomfort and 87% a (slightly) warm thermal sensation at the end of the match. Moreover, the thermal or cardiovascular responses were not affected by age (all p-values > 0.05). Heat stress induced by watching a football match in simulated hot and humid conditions does not result in substantial thermal or cardiovascular strain, whereas a significant perceptual strain was observed.

The aim of this study was to investigate volatile organic compounds (VOCs) in exhaled breath as possible non-invasive markers to monitor the inflammatory response in inflammatory bowel disease (IBD) patients as a result of repeated and prolonged moderate-intensity exercise. We included 18 IBD patients and 19 non-IBD individuals who each completed a 30, 40, or 50 km walking exercise over three consecutive days. Breath and blood samples were taken before the start of the exercise event and every day post-exercise to assess changes in the VOC profiles and cytokine concentrations. Proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS) was used to measure exhaled breath VOCs. Multivariate analysis, particularly ANOVA-simultaneous component analysis (ASCA), was employed to extract relevant ions related to exercise and IBD. Prolonged exercise induces a similar response in breath butanoic acid and plasma cytokines for participants with or without IBD. Butanoic acid showed a significant correlation with the cytokine IL-6, indicating that butanoic acid could be a potential non-invasive marker for exercise-induced inflammation. The findings are relevant in monitoring personalized IBD management.

Accumulation of neurotoxic bilirubin due to a transient neonatal or persistent inherited deficiency of bilirubin glucuronidation activity can cause irreversible brain damage and death. Strategies to inhibit bilirubin production and prevent neurotoxicity in neonatal and adult settings seem promising. We evaluated the impact of Bvra deficiency in neonatal and aged mice, in a background of unconjugated hyperbilirubinemia, by abolishing bilirubin production. We also investigated the disposal of biliverdin during fetal development. In Ugt1−/− mice, Bvra deficiency appeared sufficient to prevent lethality and to normalize bilirubin level in adults. Although biliverdin accumulated in Bvra-deficient fetuses, both Bvra−/− and Bvra−/−Ugt1−/− pups were healthy and reached adulthood having normal liver, brain, and spleen histology, albeit with increased iron levels in the latter. During aging, both Bvra−/− and Bvra−/−Ugt1−/− mice presented normal levels of relevant hematological and metabolic parameters. Interestingly, the oxidative status in erythrocytes from 9-months-old Bvra−/− and Bvra−/−Ugt1−/− mice was significantly reduced. In addition, triglycerides levels in these 9-months-old Bvra−/− mice were significantly higher than WT controls, while Bvra−/−Ugt1−/− tested normal. The normal parameters observed in Bvra−/−Ugt1−/− mice fed chow diet indicate that Bvra inhibition to treat unconjugated hyperbilirubinemia seems safe and effective.

Abstract 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.

Volatile organic compounds (VOCs) in exhaled breath provide insights into various metabolic processes and can be used to monitor physiological response to exercise and medication. We integrated and validated in situ a sampling and analysis protocol using proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS) for exhaled breath research. The approach was demonstrated on a participant cohort comprising users of the cholesterol-lowering drug statins and non-statin users during a field campaign of three days of prolonged and repeated exercise, with no restrictions on food or drink consumption. The effect of prolonged exercise was reflected in the exhaled breath of participants, and relevant VOCs were identified. Most of the VOCs, such as acetone, showed an increase in concentration after the first day of walking and subsequent decrease towards baseline levels prior to walking on the second day. A cluster of short-chain fatty acids including acetic acid, butanoic acid, and propionic acid were identified in exhaled breath as potential indicators of gut microbiota activity relating to exercise and drug use. We have provided novel information regarding the use of breathomics for non-invasive monitoring of changes in human metabolism and especially for the gut microbiome activity in relation to exercise and the use of medication, such as statins.

Multidrug-resistant Salmonella enterica serovar Heidelberg isolates are frequently recovered in the Netherlands from poultry meat imported from South America. Our aim was to retrospectively assess the characteristics of the antimicrobial determinants, gene content and the clonal relatedness of 122 unique S. Heidelberg isolates from chicken meat from Brazil (n = 119) and Argentina (n = 3) that were imported between 2010 and 2015. These isolates were subjected to antimicrobial susceptibility testing, PCR and Illumina HiSeq2500 whole genome sequencing. Draft genomes were assembled to assess the gene content, and the phylogenetic relationships between isolates were determined using single nucleotide polymorphisms. Ciprofloxacin-resistance was identified in 98.4% of the isolates and 83.7% isolates showed resistance to the extended-spectrum cephalosporins cefotaxime and ceftazidime (83.6% and 82.8% respectively). Of the latter, 97.1% exhibited an AmpC phenotype and contained blaCMY-2, whereas the remaining three isolates contained an extended spectrum beta-lactamase. Of the 99 extended-spectrum cephalosporins-resistant isolates harboring CMY-2 plasmids, 56.6% contained the incompatibility group I1 replicon. Phylogenetic cluster analysis showed that all isolates from Brazil clustered together, with 49% occurring in clusters larger than 5 isolates that revealed intra-cluster similarities based on geographical location and/or resistance profiles. The remaining isolates were classified in smaller clusters or as singletons, highlighting the large diversity of S. Heidelberg in the poultry chain in Brazil that was revealed by this study. Considering the potential public health risk associated with multidrug-resistant S. Heidelberg in imported poultry, collaborative whole genome sequencing-based surveillance is needed to monitor the spread, pathogenic properties and epidemiological distribution of these isolates.

Extracellular vesicles (EVs) released by cells have a role in intercellular communication to regulate a wide range of biological processes. Two types of EVs can be recognized. Exosomes, which are released from multi-vesicular bodies upon fusion with the plasma membrane, and ectosomes, which directly bud from the plasma membrane. How cells regulate the quantity of EV release is largely unknown. One of the initiating events in vesicle biogenesis is the regulated transport of phospholipids from the exoplasmic to the cytosolic leaflet of biological membranes. This process is catalyzed by P4-ATPases. The role of these phospholipid transporters in intracellular vesicle transport has been established in lower eukaryotes and is slowly emerging in mammalian cells. In Caenorhabditis elegans (C. elegans), deficiency of the P4-ATPase member TAT-5 resulted in enhanced EV shedding, indicating a role in the regulation of EV release. In this study, we investigated whether the mammalian ortholog of TAT-5, ATP9A, has a similar function in mammalian cells. We show that knockdown of ATP9A expression in human hepatoma cells resulted in a significant increase in EV release that was independent of caspase-3 activation. Pharmacological blocking of exosome release in ATP9A knockdown cells did significantly reduce the total number of EVs. Our data support a role for ATP9A in the regulation of exosome release from human cells.

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.

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 αSMA 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.

Total hip or knee replacement is effective in improving joint function, quality of life, and pain reduction. The oldest old population with joint replacements (TJR) is underrepresented in current literature. We compared health-related and functional characteristics of oldest olds with and without TJR. Participants (aged 85 years) were divided into a group with and without TJR. Comorbidity, physical and joint functioning, daily living activities, quality of life, and mortality were recorded. Thirty-eight of 599 participants (6.3%) received a TJR in the past. Participants with a TJR had slightly less comorbidities, walked slower (P=0.006), and complained more about hip-pain (P=0.007). Mortality of those with a TJR was lower during the first 8-year followup (P=0.04). All other characteristics were comparable between groups. We conclude that subjects with a TJR performed equally well, besides showing a lower gait speed and a higher frequency of hip-pain. Except for the lower gaitspeed, having a TJR is not associated with poorer health.

Mutations in ATP8B1 (FIC1) underlie cases of cholestatic disease, ranging from chronic and progressive (progressive familial intrahepatic cholestasis) to intermittent (benign recurrent intrahepatic cholestasis). The ATP8B1-deficient mouse serves as an animal model of human ATP8B1 deficiency.We investigated the effect of genetic background on phenotypes of ATP8B1-deficient and wild-type mice, using C57Bl/6 (B6), 129, and (B6-129) F1 strain backgrounds. B6 background resulted in greater abnormalities in ATP8B1-deficient mice than did 129 and/or F1 background. ATP8B1-deficient pups of B6 background gained less weight. In adult ATP8B1-deficient mice at baseline, those of B6 background had lower serum cholesterol levels, higher serum alkaline phosphatase levels, and larger livers. After challenge with cholate-supplemented diet, these mice exhibited higher serum alkaline phosphatase and bilirubin levels, greater weight loss and larger livers. ATP8B1-deficient phenotypes in mice of F1 and 129 backgrounds are usually similar, suggesting that susceptibility to manifestations of ATP8B1 deficiency may be recessive. We also detected differences in hepatobiliary phenotypes between wild-type mice of differing strains.Our results indicate that the ATP8B1-deficient mouse in a B6 background may be a better model of human ATP8B1 deficiency and highlight the importance of informed background strain selection for mouse models of liver disease.

Purpose: Cold water immersion (CWI) is the most effective treatment for exertional heat stroke (EHS). However, knowledge on core temperature response during CWI treatment and the relation with patient characteristics (i.e., sex, anthropometrics) is limited. Therefore, the current study aimed to examine the core temperature response (in °C) during CWI treatment of recreational athletes participating in large running events and investigate the impact of sex and anthropometric characteristics on the cooling rate (in °C·min−1). Methods: This observational study includes 57 athletes (n = 22 females; 39%) who suffered from EHS during an exercise event in the Netherlands. After admission to the medical facilities, a rectal temperature (T rec) probe was inserted and all clothing was removed before immersion in an ice bath (6.4 ± 1.6°C). Rectal temperature was continuously measured throughout treatment, and treatment was continued until T rec ≤ 38.9°C or based on the decision of the emergency physician. Results: Initial T rec did not differ between males (41.3 ± 0.9°C) and females (41.2 ± 0.8°C, P = 0.83). A nonlinear response to CWI was observed, with the decrease in T rec beginning after 6 min of CWI. The decrease in T rec did not differ between both sexes (ptime*sex = 0.96). The cooling rate did not differ between males (0.21 ± 0.15°C·min−1) and females (0.19 ± 0.08°C·min−1, P = 0.55), and was not related to body mass, body surface area and body surface area to mass ratio (all P values >0.05). Conclusions: We demonstrated that the cooling rate during CWI did not differ between men and women suffering from EHS, and that the T rec response to CWI is nonlinear and not dependent on anthropometric characteristics. This suggests that no sex differentiation is needed in the EHS treatment guidelines and confirms the necessity to continuously monitor T rec during treatment. [ABSTRACT FROM AUTHOR]

The liver has many functions including the regulation of nutrient and metabolite levels in the systemic circulation through efficient transport into and out of hepatocytes. To sustain these functions, hepatocytes display large functional heterogeneity. This heterogeneity is reflected by zonation of metabolic processes that take place in different zones of the liver lobule, where nutrient‐rich blood enters the liver in the periportal zone and flows through the mid‐zone prior to drainage by a central vein in the pericentral zone. Metabolite transport plays a pivotal role in the division of labor across liver zones, being either transport into the hepatocyte or transport between hepatocytes through the blood. Signaling pathways that regulate zonation, such as Wnt/β‐catenin, have been shown to play a causal role in the development of metabolic dysfunction‐associated steatohepatitis (MASH) progression, but the (patho)physiological regulation of metabolite transport remains enigmatic. Despite the practical challenges to separately study individual liver zones, technological advancements in the recent years have greatly improved insight in spatially divided metabolite transport. This review summarizes the theories behind the regulation of zonation, diurnal rhythms and their effect on metabolic zonation, contemporary techniques used to study zonation and current technological challenges, and discusses the current view on spatial and temporal metabolite transport. [ABSTRACT FROM AUTHOR]

UnlabelledATP11C 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.ConclusionsATP11C 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).

BackgroundMutations in ATP8B1 (FIC1) underlie cases of cholestatic disease, ranging from chronic and progressive (progressive familial intrahepatic cholestasis) to intermittent (benign recurrent intrahepatic cholestasis). The ATP8B1-deficient mouse serves as an animal model of human ATP8B1 deficiency.Methodology/principal findingsWe investigated the effect of genetic background on phenotypes of ATP8B1-deficient and wild-type mice, using C57Bl/6 (B6), 129, and (B6-129) F1 strain backgrounds. B6 background resulted in greater abnormalities in ATP8B1-deficient mice than did 129 and/or F1 background. ATP8B1-deficient pups of B6 background gained less weight. In adult ATP8B1-deficient mice at baseline, those of B6 background had lower serum cholesterol levels, higher serum alkaline phosphatase levels, and larger livers. After challenge with cholate-supplemented diet, these mice exhibited higher serum alkaline phosphatase and bilirubin levels, greater weight loss and larger livers. ATP8B1-deficient phenotypes in mice of F1 and 129 backgrounds are usually similar, suggesting that susceptibility to manifestations of ATP8B1 deficiency may be recessive. We also detected differences in hepatobiliary phenotypes between wild-type mice of differing strains.Conclusions/significanceOur results indicate that the ATP8B1-deficient mouse in a B6 background may be a better model of human ATP8B1 deficiency and highlight the importance of informed background strain selection for mouse models of liver disease.