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Inhalation of hypertonic saline has a modest beneficial effect on lung function and the frequency of exacerbations in patients with cystic fibrosis. In this article, the investigators provide in vivo and in vitro data suggesting that this therapeutic effect derives from sustained acceleration of mucus clearance. The investigators provide in vivo and in vitro data suggesting that the therapeutic effect of inhaled hypertonic saline derives from sustained acceleration of mucus clearance. Mucus clearance defends the lung against inhaled bacteria. The efficiency of mucus clearance depends on an adequate volume of airway surface liquid (i.e., hydration). 1 One hypothesis for the pathogenesis of lung disease in patients with cystic fibrosis is that a lack of regulation of sodium absorption and chloride secretion causes depletion of airway surface liquid, slows mucus clearance, and promotes the formation of adherent mucus plaques on airway surfaces. Mucus plaques and plugs obstruct airways and provide the nidus for infection. 2 , 3 On the basis of this hypothesis, therapies that increase the volume of airway surface liquid, and hence mucus . . .

Aims/hypothesis Brown adipose tissue (BAT) activation increases energy consumption and may help in the treatment of obesity. Cold exposure is the main physiological stimulus for BAT thermogenesis and the sympathetic nervous system, which innervates BAT, is essential in this process. However, cold-induced BAT activation is impaired in obese humans. To explore the therapeutic potential of BAT, it is essential to determine whether pharmacological agents can activate BAT. Methods We aimed to determine whether BAT can be activated in lean and obese humans after acute administration of an orally bioavailable sympathomimetic. In a randomised, double-blinded, crossover trial, we administered 2.5 mg/kg of oral ephedrine to nine lean (BMI 22 ± 1 kg/m 2 ) and nine obese (BMI 36 ± 1 kg/m 2 ) young men. On a separate day, a placebo was administered to the same participants. BAT activity was assessed by measuring glucose uptake with [ 18 F]fluorodeoxyglucose and positron emission tomography–computed tomography imaging. Results BAT activity was increased by ephedrine compared with placebo in the lean, but unchanged in the obese, participants. The change in BAT activity after ephedrine compared with placebo was negatively correlated with various indices of body fatness. Conclusions/interpretation BAT can be activated via acute, oral administration of the sympathomimetic ephedrine in lean, but not in obese humans.

This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy) in vitro and in 16 healthy subjects. The clinical study used a double-blind, randomized, placebo-controlled, four-session, crossover design. In vitro, duloxetine blocked the release of both 5-HT and NE by MDMA or by its metabolite 3,4-methylenedioxyamphetamine from transmitter-loaded human cells expressing the 5-HT or NE transporter. In humans, duloxetine inhibited the effects of MDMA including elevations in circulating NE, increases in blood pressure and heart rate, and the subjective drug effects. Duloxetine inhibited the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevations in plasma MDMA levels. The findings confirm the important role of MDMA-induced 5-HT and NE release in the psychotropic effects of MDMA. Duloxetine may be useful in the treatment of psychostimulant dependence. Clinicaltrials.gov NCT00990067.

Background Fatty acids increase ATP‐binding cassette ABC transporter A12 (ABCA12) levels via an increase in peroxisome proliferator‐activated receptor β/δ (PPAR β/δ). Promoting lipid transport to lamellar granules has been suggested to improve epidermal barrier function in patients with dry skin. Objective We investigated whether mevalonolactone (MVL) produced by Saccharomycopsis fibuligera improves dry skin by promoting ABCA12 expression and the amount of free fatty acids in epidermal keratinocytes. Methods We examined whether MVL increases ABCA12 mRNA and protein levels and the amount of Nile red‐positive lipids in cultured epidermal keratinocytes and in a three‐dimensional epidermal model by cell staining. Promotion of fatty acid production by MVL was analyzed by liquid chromatography‐mass spectrometry. We also evaluated whether MVL addition increases PPAR β/δ mRNA expression in cultured keratinocytes. Based on the results, a randomized controlled trial was conducted in which milky lotions containing MVL and placebo were applied to dry facial skin of healthy female volunteers in winter. Results MVL increased ABCA12 mRNA and protein levels and lamellar granule number and size. Fatty acid analysis revealed that MVL elevated myristic acid, palmitic acid, and palmitoleic acid levels as well as PPAR β/δ mRNA expression. In human tests, milky lotions containing MVL were shown to significantly improve transepidermal water loss (TEWL) in the stratum corneum compared to placebo. Conclusion The results suggest that MVL increases fatty acid uptake and ABCA12, promotes fatty acid transport to lamellar granules, and improves epidermal barrier function in dry skin through increased expression of PPAR β/δ.

Aim/hypothesis To assess whether low-dose glucocorticoid treatment induces adverse metabolic effects, as is evident for high glucocorticoid doses. Methods In a randomised placebo-controlled double-blind (participants and the investigators who performed the studies and assessed the outcomes were blinded) dose–response intervention study, 32 healthy men (age 22 ± 3 years; BMI 22.4 ± 1.7 kg/m 2 ) were allocated to prednisolone 7.5 mg once daily ( n  = 12), prednisolone 30 mg once daily ( n  = 12), or placebo ( n  = 8) for 2 weeks using block randomisation. Main outcome measures were glucose, lipid and protein metabolism, measured by stable isotopes, before and at 2 weeks of treatment, in the fasted state and during a two-step hyperinsulinaemic clamp conducted in the Clinical Research Unit of the Academic Medical Centre, Amsterdam, the Netherlands Results Prednisolone, compared with placebo, dose dependently and significantly increased fasting plasma glucose levels, whereas only prednisolone 30 mg increased fasting insulin levels (29 ± 15 pmol/l). Prednisolone 7.5 mg and prednisolone 30 mg decreased the ability of insulin to suppress endogenous glucose production (by 17 ± 6% and 46 ± 7%, respectively, vs placebo). Peripheral glucose uptake was not reduced by prednisolone 7.5 mg, but was decreased by prednisolone 30 mg by 34 ± 6% ( p  < 0.0001). Compared with placebo, prednisolone treatment tended to decrease lipolysis in the fasted state ( p  = 0.062), but both prednisolone 7.5 mg and prednisolone 30 mg decreased insulin-mediated suppression of lipolysis by 11 ± 5% and 34 ± 6%, respectively. Finally, prednisolone treatment increased whole-body proteolysis during hyperinsulinaemia, which tended to be driven by prednisolone 30 mg (5 ± 2%; p  = 0.06). No side effects were reported by the study participants. All participants completed the study and were analysed. Conclusions/interpretation Not only at high doses but also at low doses, glucocorticoid therapy impaired intermediary metabolism by interfering with the metabolic actions of insulin on liver and adipose tissue. These data indicate that even low-dose glucocorticoids may impair glucose tolerance when administered chronically. Trial registration: ISRCTN83991850 Funding: The study was funded by the Dutch Top Institute Pharma T1-106.

Ketone bodies are neuroprotective in neurological disorders such as epilepsy. We randomly studied nine healthy human subjects twice-with and without continuous infusion of 3-hydroxybutyrate-to define potential underlying mechanisms, assessed regionally (parietal, occipital, temporal, cortical grey, and frontal) by PET scan. During 3-hydroxybutyrate infusions concentrations increased to 5.5±0.4 mmol/l and cerebral glucose utilisation decreased 14%, oxygen consumption remained unchanged, and cerebral blood flow increased 30%. We conclude that acute 3-hydroxybutyrate infusion reduces cerebral glucose uptake and increases cerebral blood flow in all measured brain regions, without detectable effects on cerebral oxygen uptake though oxygen extraction decreased. Increased oxygen supply concomitant with unchanged oxygen utilisation may contribute to the neuroprotective effects of ketone bodies.

Strength Training Increases Insulin-Mediated Glucose Uptake, GLUT4 Content, and Insulin Signaling in Skeletal Muscle in Patients With Type 2 Diabetes Mads K. Holten 1 2 , Morten Zacho 2 , Michael Gaster 3 , Carsten Juel 2 4 , Jørgen F.P. Wojtaszewski 2 5 and Flemming Dela 1 2 1 Department of Medical Physiology, the Panum Institute, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark 2 Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen, Denmark 3 Departments of Endocrinology and of Pathology, Odense University Hospital, Odense, Denmark 4 August Krogh Institute, Copenhagen, Denmark 5 Institute of Exercise and Sport Sciences, Faculty of Natural Sciences, University of Copenhagen, Copenhagen, Denmark Address correspondence and reprint requests to Flemming Dela, MD, Department of Medical Physiology, the Panum Institute, University of Copenhagen, Blegdamsvej 3, DK 2200 Copenhagen N, Denmark. E-mail: f.dela{at}mfi.ku.dk Abstract Strength training represents an alternative to endurance training for patients with type 2 diabetes. Little is known about the effect on insulin action and key proteins in skeletal muscle, and the necessary volume of strength training is unknown. A total of 10 type 2 diabetic subjects and 7 healthy men (control subjects) strength-trained one leg three times per week for 6 weeks while the other leg remained untrained. Each session lasted no more than 30 min. After strength training, muscle biopsies were obtained, and an isoglycemic-hyperinsulinemic clamp combined with arterio-femoral venous catheterization of both legs was carried out. In general, qualitatively similar responses were obtained in both groups. During the clamp, leg blood flow was higher ( P < 0.05) in trained versus untrained legs, but despite this, arterio-venous extraction glucose did not decrease in trained legs. Thus, leg glucose clearance was increased in trained legs ( P < 0.05) and more than explained by increases in muscle mass. Strength training increased protein content of GLUT4, insulin receptor, protein kinase B-α/β, glycogen synthase (GS), and GS total activity. In conclusion, we found that strength training for 30 min three times per week increases insulin action in skeletal muscle in both groups. The adaptation is attributable to local contraction-mediated mechanisms involving key proteins in the insulin signaling cascade. CS, citrate synthase FFA, free fatty acid G6P, glucose-6-phosphate GS, glycogen synthase HAD, hydroxyacyl-3-dehydrogenase HRP, horseradish peroxidase IRS-1, insulin receptor substrate-1 LDH, lactate dehydrogenase PI, phosphatidylinositol PKB, protein kinase B PMSF, phenylmethylsulfonyl fluoride PVDF, polyvinylidiene diflouride RM, repetition maximum Footnotes Accepted October 17, 2003. Received July 7, 2003. DIABETES

Objective The effects of hormonal therapy, estrogen-based hormone replacement therapy (HRT), and anti-tumor hormone therapy, such as tamoxifen, on the physiological uptake of the endometrium on 2-deoxy-2[ 18 F]fluoro- d -glucose ([ 18 F]F-FDG) positron emission tomography (PET) in postmenopausal women have not been determined. We explored the effect of hormone therapy, particularly HRT, on physiological uptake in the endometrium of postmenopausal women. Materials and methods Postmenopausal women receiving hormone therapy who underwent cancer screening using PET/computed tomography (CT) between June 2016 and April 2023 were included in the hormone therapy group ( n  = 21). Postmenopausal women with no history of hormone therapy were included in the control group ( n  = 49). First, the physiological endometrial uptake at menopausal age and at least 1 year thereafter was compared quantitatively (SUVmax) and qualitatively (4-point scale) in the control group, to assess when the endometrium ceased to show significant physiological [ 18 F]F-FDG uptake after menopause. Endometrial uptake was compared between the hormone therapy and control groups. The association between HRT duration (months) and endometrial uptake (SUVmax) was evaluated. Endometrial thickness, measured using transvaginal ultrasonography, was also compared between the two groups. Results Endometrial uptake was significantly reduced both qualitatively and quantitatively ( P  < 0.05) at least 1 year after menopause in control patients, by which time most women (89.8%) no longer had significant endometrial uptake. The hormone therapy group ( n  = 21) showed higher FDG uptake in the endometrium compared to the control group (median SUVmax: 2.3 vs 1.9, P  = 0.0011), as well as a higher visual score ( P  < 0.0001). HRT duration did not correlate with endometrial uptake ( P  = 0.097). Endometrial thickness in the hormone therapy group was significantly thicker than in the control group (median: 3.9 mm vs 1.8 mm, P  = 0.002). Conclusion Hormone therapy may affect physiological uptake in the endometrium in postmenopausal women.

Nasal potential difference (NPD) is used as a biomarker of the cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) activity. We evaluated methods to detect changes in chloride and sodium transport by NPD based on a secondary analysis of a Phase II CFTR-modulator study. Thirty-nine subjects with CF who also had the G551D-CFTR mutation were randomized to receive ivacaftor (Kalydeco™; also known as VX-770) in four doses or placebo twice daily for at least 14 days. All data were analyzed by a single investigator who was blinded to treatment assignment. We compared three analysis methods to determine the best approach to quantify changes in chloride and sodium transport: (1) the average of both nostrils; (2) the most-polarized nostril at each visit; and (3) the most-polarized nostril at screening carried forward. Parameters of ion transport included the PD change with zero chloride plus isoproterenol (CFTR activity), the basal PD, Ringer's PD, and change in PD with amiloride (measurements of ENaC activity), and the delta NPD (measuring CFTR and ENaC activity). The average and most-polarized nostril at each visit were most sensitive to changes in chloride and sodium transport, whereas the most-polarized nostril at screening carried forward was less discriminatory. Based on our findings, NPD studies should assess both nostrils rather than a single nostril. We also found that changes in CFTR activity were more readily detected than changes in ENaC activity, and that rigorous standardization was associated with relatively good within-subject reproducibility in placebo-treated subjects (± 2.8 mV). Therefore, we have confirmed an assay of reasonable reproducibility for detecting chloride-transport improvements in response to CFTR modulation.

In patients with myocardial infarction, ticagrelor reduces cardiovascular and sepsis-related mortality, and can cause dyspnea. It is suggested that this is caused by adenosine receptor stimulation, because in preclinical studies, ticagrelor blocks the nucleoside transporter and increases cellular ATP release. We now investigated the effects of ticagrelor on the adenosine system in humans in vivo. In a double-blinded, placebo-controlled cross-over trial in 14 healthy subjects, we have tested whether ticagrelor (180 mg) affects adenosine- and dipyridamole-induced forearm vasodilation, as surrogates of nucleoside uptake inhibition and adenosine formation, respectively. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was measured. Primary endpoint was adenosine-induced vasodilation. Ticagrelor did not affect adenosine- or dipyridamole-induced forearm vasodilation. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was not affected by ticagrelor. In vitro, ticagrelor dose-dependently inhibited nucleoside uptake, but only at supra-physiological concentrations. In conclusion, at relevant plasma concentration, ticagrelor does not affect adenosine transport, nor adenosine formation in healthy subjects. Therefore, it is unlikely that this mechanism is a relevant pleiotropic effect of ticagrelor. ClinicalTrials.gov NCT01996735.