13C-carbohydrate breath tests: impact of physical activity on the rate-limiting step in lactose utilization

BACKGROUND: 13CO2 breath tests can be used to monitor carbohydrate digestion in the small intestine. However, after ingestion of 13C-substrates, 13CO2 excretion in breath originates from two sources: a digestive/oxidative fraction, derived from the small intestine, and a fermentation fraction, derived from undigested substrate spill-over in the colon. In this study, the determinants of the digestive/oxidative fraction were analysed in order to improve the sensitivity/specificity of the 13C-carbohydrate breath tests. METHODS: 13C-carbohydrate breath tests were performed in healthy adults using 13C-lactose, pre-digested 13C-lactose, 13C-glucose, and 13C-galactose as substrates. The effect of exercise (bicycling, 50 W), increasing the metabolism of digested/absorbed substrate, on the outcome of the test was analysed. RESULTS: In rest, no difference was observed in the 4-h cumulative percentage dose recovered in breath (4-h cPDR) after administration of glucose, pre-digested lactose, and lactose, which were 20.3 +/- 4.5%, 19.2 +/- 5.5%, and 19.9 +/- 4.9%, respectively. The 13CO2 excretion rate after 13C-galactose consumption was significantly slower than after 13C-glucose consumption. Exercise increased 4-h cPDR of 13C-glucose significantly: 76.0 +/- 1.0% vs. 22.7 +/- 2.3%. This effect was also observed using 13C-lactose as substrate: 66.1 +/- 6.2% vs. 19.6 +/- 3.9%. One subject had non-symptomatic lactose maldigestion indicated by a positive H2 breath test. The 13CO2 breath test of this subject in rest was indistinguishable from that of the others (4-h cPDR 16.6 vs. 19.6 +/- 3.9%), whereas the test was clearly indicative during exercise (4-h cPDR 20.5 vs. 66.1 +/- 6.2%). CONCLUSION: In healthy volunteers in rest, glucose oxidation is the rate-limiting step in lactose conversion into 13CO2. Increase of metabolism (for instance, by exercise) can shift this step to intestinal hydrolysis of lactose, making the 13C-lactose breath test more sensitive.     

Cholestasis induced by sulphated glycolithocholic acid in the rat: protection by endogenous bile acids

Sulphated glycolithocholic acid (SGLC) causes cholestasis in experimental animals, despite its sulphated form. In the present study, the cholestatic potency and the pharmacokinetics of SGLC were investigated in rats under two conditions: (a) in the presence of an intact circulating bile acid pool and (b) after exhaustion of the bile acid pool by 24 h of bile diversion. Intravenous administration of SGLC (8 mumol/100 g body weight) to rats with an intact bile acid pool did not cause cholestasis. However, biliary phospholipid and cholesterol concentrations were reduced by 40% and 29% respectively during the first hour after administration. When the same dose of the bile acid was injected in rats with a 24 h biliary drainage, a complete cessation of bile production was observed within 1 h. Twelve hours after the onset of cholestasis, bile production gradually increased again, showed a marked overshoot, and reached control levels after 3 days. In the recovery phase, biliary phospholipid and cholesterol concentrations were greatly reduced. The absence of endogenous bile acids did not change the hepatic clearance rate of a tracer dose of radiolabelled SGLC, but markedly decreased its biliary excretion rate. It was concluded that the hepatotoxic effect of SGLC is much more pronounced in rats with an exhausted bile acid pool, possibly due to a slower biliary excretion of the toxic compound. This phenomenon may have clinical implications for patients with a contracted bile acid pool.     

Separate transport systems for biliary secretion of sulfated and unsulfated bile acids in the rat.

Biliary secretion of 3 alpha-sulfated bile acids has been studied in Wistar rats with an autosomal recessive defect in the hepatic transport of bilirubin. Liver function, established by measurement of various enzymes in plasma, by enzyme histochemical methods, and by electron microscopy, appeared to be normal in these rats. Serum levels of unconjugated, monoglucuronidated, and diglucuronidated bilirubin were 0.62, 1.62, and 6.16 mumol/liter, respectively, compared with 0.17, 0.08, and 0.02 mumol/liter in control rats. Biliary bilirubin secretion was strongly reduced in the mutant animals: 0.21 +/- 0.03 vs. 0.39 +/- 0.03 nmol/min per 100 g body wt in control rats. Despite normal biliary bile acid output, bile flow was markedly impaired in the mutant animals, due to a 53% reduction of the bile acid-independent fraction of bile flow. The transport maximum for biliary secretion of dibromosulphthalein (DBSP) was also drastically reduced (-53%). Biliary secretion of intravenously administered trace amounts of the 3 alpha-sulfate esters of 14C-labeled taurocholic acid (-14%), taurochenodeoxycholic acid (-39%), taurolithocholic acid (-73%), and glycolithocholic acid (-91%) was impaired in the jaundiced rats compared with controls, in contrast to the biliary secretion of the unsulfated parent compounds. Hepatic uptake of sulfated glycolithocholic acid was not affected in the jaundiced animals. Preadministration of DBSP (15 mumol/100 g body wt) to normal Wistar rats significantly impaired the biliary secretion of sulfated glycolithocholic acid, but did not affect taurocholic acid secretion. We conclude that separate transport systems in the rat liver exist for biliary secretion of sulfated and unsulfated bile acids; the sulfates probably share secretory pathways with the organic anions bilirubin and DBSP. The described genetic defect in hepatic transport function is associated with a reduced capacity to secrete sulfated bile acids into bile; this becomes more pronounced with a decreasing number of hydroxyl groups on the sulfated bile acid's molecule.     

Inflammatory response to cardiopulmonary bypass using roller or centrifugal pumps.

BACKGROUND: The inflammatory response in 29 patients undergoing coronary artery bypass grafting using either roller or centrifugal (CFP) pumps was evaluated in a prospective study. METHODS: Patients were randomized in roller pump (n = 15) and CFP (n = 14) groups. Terminal complement complex activation (SC5b-9) and neutrophil activation (elastase) were assessed during the operation. Cytokine production (tumor necrosis factor-alpha, interleukin-6, interleukin-8) and circulating adhesion molecules (soluble endothelial-leukocyte adhesion molecule-1 and intercellular adhesion molecule-1) were assessed after the operation. RESULTS: Release of SC5b-9 after stopping cardiopulmonary bypass and after protamine administration was higher in the CFP group (p = 0.01 and p = 0.004). Elastase level was higher after stopping cardiopulmonary bypass using CFP (p = 0.006). Multivariate analysis confirmed differences between roller pump and CFP groups in complement and neutrophil activation. After the operation, a significant production of cytokines was detected similarly in both groups, with peak values observed within the range of 4 to 6 hours after starting cardiopulmonary bypass. However, interleukin-8 levels were higher using CFP 2 hours after starting cardiopulmonary bypass (p = 0.02). Plasma levels of adhesion molecules were similar in both groups within the investigation period. CONCLUSIONS: During the operation, CFP caused greater complement and neutrophil activation. After the operation, the inflammatory response was similar using either roller pump or CFP.     

European Society of Cardiology quality indicators for the care and outcomes of adults with pulmonary arterial hypertension. Developed in collaboration with the Heart Failure Association of the European Society of Cardiology

Aims

To develop a suite of quality indicators (QIs) for the evaluation of the care and outcomes for adults with pulmonary arterial hypertension (PAH).

Methods and results

We followed the European Society of Cardiology (ESC) methodology for the development of QIs. This included (i) the identification of key domains of care for the management of PAH, (ii) the proposal of candidate QIs following systematic review of the literature, and (iii) the selection of a set of QIs using a modified Delphi method. The process was undertaken in parallel with the writing of the 2022 ESC/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension and involved the Task Force chairs, experts in PAH, Heart Failure Association (HFA) members and patient representatives. We identified five domains of care for patients with PAH: structural framework, diagnosis and risk stratification, initial treatment, follow-up, and outcomes. In total, 23 main and one secondary QIs for PAH were selected.

Conclusion

This document presents the ESC QIs for PAH, describes their development process and offers scientific rationale for their selection. The indicators may be used to quantify and improve adherence to guideline-recommended clinical practice and improve patient outcomes.