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Abstract Background Preoperative medical consultations add expense and burden for patients and the impact of these consults on patient outcomes is conflicting. Previous work suggests that 10–40% of preoperative medical consult recommendations are not followed. This limits measurement of the effect of perioperative medical consultation on patient outcomes and represents a quality gap, given the patient time and healthcare cost associated with consultation. We aimed to measure, characterize, and understand reasons for missed recommendations from preoperative medical consultation. Methods This explanatory, sequential mixed-methods study used chart audits followed by semi-structured interviews. Chart audit of consecutive patients seen in preoperative medical clinic were reviewed to measure the proportion and characterize the type of recommendations that were not completed (“missed”). This phase informed the interview participants and questions. The interview guide was developed using the Consolidated Framework for Implementation Research and the Theoretical Domains Framework. Template analysis was used to understand drivers and barriers of missed recommendations Results Chart audit included 255 patients (n=161, 63.1% female) seen in preadmission clinic between April 1 and April 30, 2019. 55.7% of patients had all recommendations followed (n=142). Postoperative anticoagulation management and postoperative cardiac biomarker surveillance recommendations were least commonly followed (50.0%, n=28, and 68.9%, n=82, respectively). Eighteen surgical team members were interviewed. Missed recommendations were both unintentional and intentional, and the key drivers differed by these categories. Unintentionally missed recommendations occurred due to individual-level factors (drivers: knowledge of the consultation note, lack of routine for reviewing the consultation note, and competing demands on time) and systems-level factors (driver: lack of role clarity). Intentionally missed recommendations occurred due to user error due (drivers: lack of knowledge of guidelines or evidence) and appropriate modifications (driver: need to adapt a preoperative plan for a complicated postoperative course). Conclusions Only 55.7% of consult notes had all recommendations followed, suggesting a quality gap in perioperative medical care. Qualitative data suggests multiple drivers of missed recommendations that should be targeted to improve the efficiency of care for these patients.

Adding to the versatile class of ionic liquids, we report a new series of hydrophilic polyethylene glycol-functionalized room-temperature ionic liquids, offering interesting thermo- and electrochemical behavior as well as remarkable surface properties. A scalable and generally applicable synthetic procedure for the preparation of N,N’-bis(polyethylene glycol)imidazolium salts, generally abbreviated as [(mPEGn)2Im][A] (n = 2‒6, A = I‒, OMs‒, PF6‒, NTf2‒) was developed. These ionic liquids were studied concerning their thermo- and electrochemical properties, such as phase transition behavior, decomposition temperature, viscosity, and density, as well as electrical conductivity and electrochemical stability, using i.a. differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), electrochemical impedance spectroscopy (EIS) and linear sweep voltammetry (LSV). Additionally, the surface properties were investigated by angle-resolved X-ray photoelectron spectroscopy (ARXPS) and the pendant drop method. Molecular dynamics simulations complement the studies and provide insight into the molecular structure of the ionic liquids and their specific orientation at the liquid-vacuum interface.

Abstract Background Previous data from a 2‐year randomized controlled trial (CRAD001ADE12) indicated that mammalian target of rapamycin (mTOR) inhibition by everolimus slowed cyst growth in patients with autosomal‐dominant polycystic kidney disease (ADPKD). During the trial, we noted body weight loss in some patients, particularly in women. We hypothesized that everolimus causes body weight reduction by reduced food intake and/or metabolic changes, which could lead to cachexia. Methods Within a sub‐analysis of the CRAD001ADE12 trial, body weight course was investigated regarding sex‐specific differences in 433 adult ADPKD patients (everolimus, n = 215; placebo, n = 218). One hundred four out of 111 patients who participated in the clinical trial centre in Berlin were evaluated under everolimus/placebo therapy (on drug: everolimus, n = 48; placebo, n = 56) and after therapy (off drug: everolimus, n = 15; placebo, n = 18). Eating habits and nutrient/caloric intake were evaluated by validated questionnaires. Systemic and local metabolism was evaluated in four patients after an oral glucose load (OGL) by using calorimetry and adipose/muscle tissue microdialysis. Results Within the 2‐year CRAD001ADE12 trial, a significant body weight loss was observed in female patients on everolimus versus placebo (P = 0.0029). Data of the Berlin Cohort revealed that weight loss was greater in women on everolimus versus men (P

Abstract Background Sepsis‐induced intensive care unit‐acquired weakness (ICUAW) features profound muscle atrophy and attenuated muscle regeneration related to malfunctioning satellite cells. Transforming growth factor beta (TGF‐β) is involved in both processes. We uncovered an increased expression of the TGF‐β receptor II (TβRII)‐inhibitor SPRY domain‐containing and SOCS‐box protein 1 (SPSB1) in skeletal muscle of septic mice. We hypothesized that SPSB1‐mediated inhibition of TβRII signalling impairs myogenic differentiation in response to inflammation. Methods We performed gene expression analyses in skeletal muscle of cecal ligation and puncture‐ (CLP) and sham‐operated mice, as well as vastus lateralis of critically ill and control patients. Pro‐inflammatory cytokines and specific pathway inhibitors were used to quantitate Spsb1 expression in myocytes. Retroviral expression plasmids were used to investigate the effects of SPSB1 on TGF‐β/TβRII signalling and myogenesis in primary and immortalized myoblasts and differentiated myotubes. For mechanistical analyses we used coimmunoprecipitation, ubiquitination, protein half‐life, and protein synthesis assays. Differentiation and fusion indices were determined by immunocytochemistry, and differentiation factors were quantified by qRT‐PCR and Western blot analyses. Results SPSB1 expression was increased in skeletal muscle of ICUAW patients and septic mice. Tumour necrosis factor (TNF), interleukin‐1β (IL‐1β), and IL‐6 increased the Spsb1 expression in C2C12 myotubes. TNF‐ and IL‐1β‐induced Spsb1 expression was mediated by NF‐κB, whereas IL‐6 increased the Spsb1 expression via the glycoprotein 130/JAK2/STAT3 pathway. All cytokines reduced myogenic differentiation. SPSB1 avidly interacted with TβRII, resulting in TβRII ubiquitination and destabilization. SPSB1 impaired TβRII‐Akt‐Myogenin signalling and diminished protein synthesis in myocytes. Overexpression of SPSB1 decreased the expression of early (Myog, Mymk, Mymx) and late (Myh1, 3, 7) differentiation‐markers. As a result, myoblast fusion and myogenic differentiation were impaired. These effects were mediated by the SPRY‐ and SOCS‐box domains of SPSB1. Co‐expression of SPSB1 with Akt or Myogenin reversed the inhibitory effects of SPSB1 on protein synthesis and myogenic differentiation. Downregulation of Spsb1 by AAV9‐mediated shRNA attenuated muscle weight loss and atrophy gene expression in skeletal muscle of septic mice. Conclusions Inflammatory cytokines via their respective signalling pathways cause an increase in SPSB1 expression in myocytes and attenuate myogenic differentiation. SPSB1‐mediated inhibition of TβRII‐Akt‐Myogenin signalling and protein synthesis contributes to a disturbed myocyte homeostasis and myogenic differentiation that occurs during inflammation.

Abstract The purpose of the study was to develop prediction models to estimate physical activity (PA)-related energy expenditure (AEE) based on accelerometry and additional variables in free-living adults. In 50 volunteers (20–69 years) PA was determined over 2 weeks using the hip-worn Actigraph GT3X + as vector magnitude (VM) counts/minute. AEE was calculated based on total daily EE (measured by doubly-labeled water), resting EE (indirect calorimetry), and diet-induced thermogenesis. Anthropometry, body composition, blood pressure, heart rate, fitness, sociodemographic and lifestyle factors, PA habits and food intake were assessed. Prediction models were developed by context-grouping of 75 variables, and within-group stepwise selection (stage I). All significant variables were jointly offered for second stepwise regression (stage II). Explained AEE variance was estimated based on variables remaining significant. Alternative scenarios with different availability of groups from stage I were simulated. When all 11 significant variables (selected in stage I) were jointly offered for stage II stepwise selection, the final model explained 70.7% of AEE variance and included VM-counts (33.8%), fat-free mass (26.7%), time in moderate PA + walking (6.4%) and carbohydrate intake (3.9%). Alternative scenarios explained 53.8–72.4% of AEE. In conclusion, accelerometer counts and fat-free mass explained most of variance in AEE. Prediction was further improved by PA information from questionnaires. These results may be used for AEE prediction in studies using accelerometry

IntroductionAtrial natriuretic peptide (ANP), a hormone secreted from the heart, controls cardiovascular and renal functions including arterial blood pressure and natriuresis. ANP also exerts metabolic effects in adipose tissue, liver and skeletal muscle, and interacts with the secretion of adipokines. We tested the hypothesis that ANP lowers concentrations of the anorexigenic adipokine leptin in healthy humans in vivo.MethodsHuman ANP or matching placebo was infused intravenously (iv) into healthy men in a controlled clinical trial.ResultsWithin 135 minutes of iv ANP infusion, we observed an acute decrease in plasma leptin levels compared to controls. Free fatty acids markedly increased with ANP infusion in vivo, indicating activated lipolysis. In human SGBS adipocytes, ANP suppressed leptin release.DiscussionThe study shows that the cardiac hormone ANP reduces the levels of the anorexigenic adipokine leptin in healthy humans, providing further support for ANP as a cardiomyokine in a heart - adipose tissue axis. (registered in the German Clinical Trials Register and the WHO International Clinical Trials Registry Platform was granted under DRKS00024559)

Cachexia is associated with poor prognosis in heart failure. Here the authors show that mice and patients with cardiac cachexia display reduced skeletal muscle expression and circulating levels of Musclin. Musclin ablation in skeletal muscle worsens, while its muscle-specific overexpression ameliorates heart failure in mice.

Objective: In the field of non-treatable muscular dystrophies, promising new gene and cell therapies are being developed and are entering clinical trials. Objective assessment of therapeutic effects on motor function is mandatory for economical and ethical reasons. Main shortcomings of existing measurements are discontinuous data collection in artificial settings as well as a major focus on walking, neglecting the importance of hand and arm movements for patients’ independence. We aimed to create a digital tool to measure muscle function with an emphasis on upper limb motility.Methods: suMus provides a custom-made App running on smartwatches. Movement data are sent to the backend of a suMus web-based platform, from which they can be extracted as CSV data. Fifty patients with neuromuscular diseases assessed the pool of suMus activities in a first orientation phase. suMus performance was hence validated in four upper extremity exercises based on the feedback of the orientation phase. We monitored the arm metrics in a cohort of healthy volunteers using the suMus application, while completing each exercise at low frequency in a metabolic chamber. Collected movement data encompassed average acceleration, rotation rate as well as activity counts. Spearman rank tests correlated movement data with energy expenditure from the metabolic chamber.Results: Our novel application “suMus,” sum of muscle activity, collects muscle movement data plus Patient-Related-Outcome-Measures, sends real-time feedback to patients and caregivers and provides, while ensuring data protection, a long-term follow-up of disease course. The application was well received from the patients during the orientation phase. In our pilot study, energy expenditure did not differ between overnight fasted and non-fasted participants. Acceleration ranged from 1.7 ± 0.7 to 3.2 ± 0.5 m/sec2 with rotation rates between 0.9 ± 0.5 and 2.0 ± 3.4 rad/sec. Acceleration and rotation rate as well as derived activity counts correlated with energy expenditure values measured in the metabolic chamber for one exercise (r = 0.58, p < 0.03).Conclusion: In the analysis of slow frequency movements of upper extremities, the integration of the suMus application with smartwatch sensors characterized motion parameters, thus supporting a use in clinical trial outcome measures. Alternative methodologies need to complement indirect calorimetry in validating accelerometer-derived energy expenditure data.

Background: Assessing detailed metabolism in exercising persons minute-to-minute has not been possible. We developed a “drop-of-blood” platform to fulfill that need. Our study aimed not only to demonstrate the utility of our methodology, but also to give insights into unknown mechanisms and new directions.Methods: We developed a platform, based on gas chromatography and mass spectrometry, to assess metabolism from a blood-drop. We first observed a single volunteer who ran 13 km in 61 min. We particularly monitored relative perceived exertion (RPE). We observed that 2,3-bisphosphoglycerate peaked at RPE in this subject. We next expanded these findings to women and men volunteers who performed an RPE-based exercise protocol to RPE at Fi O 2 20.9% or Fi O 2 14.5% in random order.Results: At 6 km, our subject reached his maximum relative perceived exertion (RPE); however, he continued running, felt better, and finished his run. Lactate levels had stably increased by 2 km, ketoacids increased gradually until the run’s end, while the hypoxia marker, 2,3 bisphosphoglycerate, peaked at maximum relative perceived exertion. In our normal volunteers, the changes in lactate, pyruvate, ß hydroxybutyrate and a hydroxybutyrate were not identical, but similar to our model proband runner.Conclusion: Glucose availability was not the limiting factor, as glucose availability increased towards exercise end in highly exerted subjects. Instead, the tricarboxylic acid→oxphos pathway, lactate clearance, and thus and the oxidative capacity appeared to be the defining elements in confronting maximal exertion. These ideas must be tested further in more definitive studies. Our preliminary work suggests that our single-drop methodology could be of great utility in studying exercise physiology.

Context: The use of daytime napping as a countermeasure in sleep disturbances has been recommended but its physiological evaluation at high altitude is limited.Objective: To evaluate the neuroendocrine response to hypoxic stress during a daytime nap and its cognitive impact.Design, Subject, and Setting: Randomized, single-blind, three period cross-over pilot study conducted with 15 healthy lowlander subjects (8 women) with a mean (SD) age of 29(6) years (Clinicaltrials identifier: NCT04146857, https://clinicaltrials.gov/ct2/show/NCT04146857?cond=napping&draw=3&rank=12).Interventions: Volunteers underwent a polysomnography, hematological and cognitive evaluation around a 90 min midday nap, being allocated to a randomized sequence of three conditions: normobaric normoxia (NN), normobaric hypoxia at FiO2 14.7% (NH15) and 12.5% (NH13), with a washout period of 1 week between conditions.Results: Primary outcome was the interbeat period measured by the RR interval with electrocardiogram. Compared to normobaric normoxia, RR during napping was shortened by 57 and 206 ms under NH15 and NH13 conditions, respectively (p < 0.001). Sympathetic predominance was evident by heart rate variability analysis and increased epinephrine levels. Concomitantly, there were significant changes in endocrine parameters such as erythropoietin (∼6 UI/L) and cortisol (∼100 nmol/L) (NH13 vs. NN, p < 0.001). Cognitive evaluation revealed changes in the color-word Stroop test. Additionally, although sleep efficiency was preserved, polysomnography showed lesser deep sleep and REM sleep, and periodic breathing, predominantly in men.Conclusion: Although napping in simulated altitude does not appear to significantly affect cognitive performance, sex-dependent changes in cardiac autonomic modulation and respiratory pattern should be considered before napping is prescribed as a countermeasure.

(1) Background: Insulin resistance (IR) is a characteristic pathophysiologic feature in heart failure (HF). We tested the hypothesis that skeletal muscle metabolism is differently impaired in patients with reduced (HFrEF) vs. preserved (HFpEF) ejection fraction. (2) Methods: carbohydrate and lipid metabolism was studied in situ by intramuscular microdialysis in patients with HFrEF (59 ± 14y, NYHA I-III) and HFpEF (65 ± 10y, NYHA I-II) vs. healthy subjects of similar age during the oral glucose load (oGL); (3) Results: There were no difference in fasting serum and interstitial parameters between the groups. Blood and dialysate glucose increased significantly in HFpEF vs. HFrEF and controls upon oGT (both p < 0.0001), while insulin increased significantly in HFrEF vs. HFpEF and controls (p < 0.0005). Muscle tissue perfusion tended to be lower in HFrEF vs. HFpEF and controls after the oGL (p = 0.057). There were no differences in postprandial increases in dialysate lactate and pyruvate. Postprandial dialysate glycerol was higher in HFpEF vs. HFrEF and controls upon oGL (p = 0.0016); (4) Conclusion: A pattern of muscle glucose metabolism is distinctly different in patients with HFrEF vs. HFpEF. While postprandial IR was characterized by impaired tissue perfusion and higher compensatory insulin secretion in HFrEF, reduced muscle glucose uptake and a blunted antilipolytic effect of insulin were found in HFpEF.

Background: Religiously motivated Bahá'í fasting (BF) is a form of intermittent dry fasting celebrated by abstaining from food and drinks during daylight hours every year in March for 19 consecutive days.Aim: To test the safety and effects of BF on hydration, metabolism, and the circadian clock.Methods: Thirty-four healthy Bahá'í volunteers (15 women) participated in this prospective, exploratory cohort study. Laboratory examinations were carried out in four study visits: before fasting (V0), in the third week of fasting (V1) as well as 3 weeks (V3) and 3 months (V4) after fasting. Data collection included blood and urine samples, anthropometric measurements and bioelectrical impedance analysis. At V0 and V1, 24- and 12-hour urine and serum osmolality were measured. At V0–V2, alterations in the circadian clock phase were monitored in 16 participants. Our study was augmented by an additional survey with 144 healthy Bahá'í volunteers filling out questionnaires and with subgroups attending metabolic measurements (n = 11) and qualitative interviews (n = 13), the results of which will be published separately.Results: Exploratory data analysis revealed that serum osmolality (n = 34, p < 0.001) and 24-hour urine osmolality (n = 34, p = 0.003) decreased during daytime fasting but remained largely within the physiological range and returned to pre-fasting levels during night hours. BMI (body mass index), total body fat mass, and resting metabolic rate decreased during fasting (n = 34, p < 0.001), while body cell mass and body water appeared unchanged. The circadian phase estimated by transcript biomarkers of blood monocytes advanced by 1.1 h (n = 16, p < 0.005) during fasting and returned to pre-fasting values 3 weeks after fasting. Most observed changes were not detectable anymore 3 months after fasting.Conclusions: Results indicate that BF (Bahá'í fasting) is safe, has no negative effects on hydration, can improve fat metabolism and can cause transient phase shifts of circadian rhythms.Trial Registration:https://www.clinicaltrials.gov/, identifier: NCT03443739.

Resting energy expenditure (REE) is determined mainly by fat-free mass (FFM). FFM depends also on daily physical activity. REE normally decreases with increased age due to decreases in FFM and physical activity. Measuring REE is essential for estimating total energy expenditure. As such, there are a number of different equations in use to predict REE. In recent years, an increasing number of older adults continue to participate in competitive sports creating the surge of master athletes. It is currently unclear if these equations developed primarily for the general population are also valid for highly active, older master athletes. Therefore, we tested the validity of six commonly-used equations for predicting REE in master athletes. In conjunction with the World Masters Athletic Championship in Malaga, Spain, we measured REE in 113 master athletes by indirect calorimetry. The most commonly used equations to predict REE [Harris & Benedict (H&B), World Health Organization (WHO), Müller (MÜL), Müller-FFM (MÜL-FFM), Cunningham (CUN), and De Lorenzo (LOR)] were tested for their accuracies. The influences of age, sex, height, body weight, FFM, training hours per week, phase angle, ambient temperature, and athletic specialization on REE were determined. All estimated REEs for the general population differed significantly from the measured ones (H&B, WHO, MÜL, MÜL-FFM, CUN, all p < 0.005). The equation put forward by De Lorenzo provided the most accurate prediction of REE for master athletes, closely followed by FFM-based Cunningham’s equation. The accuracy of the remaining commonly-used prediction equations to estimate REE in master athletes are less accurate. Body weight (p < 0.001), FFM (p < 0.001), FM (p = 0.007), sex (p = 0.045) and interestingly temperature (p = 0.004) are the significant predictors of REE. We conclude that REE in master athletes is primarily determined by body composition and ambient temperature. Our study provides a first estimate of energy requirements for master athletes in order to cover adequately athletes’ energy and nutrient requirements to maintain their health status and physical performance.

Background: Physical activity might attenuate inflammation and neurodegeneration in multiple sclerosis (MS). Erythropoietin, which is produced upon exposure to hypoxia, is thought to act as a neuroprotective agent in MS. Therefore, we studied the effects of intermittent hypoxic training on activity energy expenditure, maximal workload, serum erythropoietin, and immunophenotype focusing on regulatory and IL-17A-producing T cells.Methods: We assigned 34 relapsing-remitting MS patients within a randomized, single blind, parallel-group study to either normoxic (NO) or hypoxic (HO) treadmill training, both 3 times/week for 1 h over 4 weeks (Clinicaltrials.gov identifier: NCT02509897). Before and after training, activity energy expenditure (metabolic chamber), maximal workload (incremental treadmill test), walking ability, depressive symptoms (Beck Depression Inventory I), serum erythropoietin concentrations, and immunophenotype of peripheral blood mononuclear cells (PBMCs) were assessed.Results: Energy expenditure did not change due to training in both groups, but was rather fueled by fat than by carbohydrate oxidation after HO training (P = 0.002). Maximal workload increased by 40 Watt and 42 Watt in the NO and HO group, respectively (both P < 0.0001). Distance patients walked in 6 min increased by 25 m and 27 m in the NO and HO group, respectively (NO P = 0.02; HO P = 0.01). Beck Depression Inventory score markedly decreased in both groups (NO P = 0.03; HO P = 0.0003). NO training shifted Treg subpopulations by increasing and decreasing the frequency of CD39+ and CD31+ Tregs, respectively, and decreased IL-17A-producing CD4+ cells. HO training provoked none of these immunological changes. Erythropoietin concentrations were within normal range and did not significantly change in either group.Conclusion: 4 weeks of moderate treadmill training had considerable effects on fitness level and mood in MS patients, both under normoxic and hypoxic conditions. Additionally, NO training improved Th17/Treg profile and HO training improved fatty acid oxidation during exercise. These effects could not be attributed to an increase of erythropoietin.Clinical Trial Registration: ClinicalTrials.gov; NCT02509897; http://www.clinicaltrials.gov

Background: Over-proportionally high energy requirements in some patients with anorexia nervosa (AN) have been reported, but their exact origin remains unclear.Objective: To objectively measure metabolic alterations in an AN patient with high energy requirements as judged by clinical observation.Materials and Methods: We present the case of a young woman with AN (index patient, IP; 19 years, admission BMI 13.9 kg/m2). After 3 months of treatment at BMI 17.4 kg/m2, we assessed her resting energy expenditure (REE), respiratory exchange ratio (RER), diet-induced thermogenesis (DIT), seated non-exercise physical activity (NEPA in Volt by infrared sensors), and exercise activity thermogenesis (EAT) in a metabolic chamber; body composition (bioimpedance analysis), energy intake (15d-food protocol), physical activity (accelerometry) and endocrine parameters. The IP was compared for REE, RER, DIT and seated NEPA to six AN patients (AN-C) and four healthy women (HC-1), and for EAT to another six healthy women (HC-2).Results: Our IP showed high REE (110% of predicted REE according to Harris & Benedict) and high seated NEPA (47% increase over AN-C, 40% over HC-1), whereas DIT (IP: 78 vs. HC-1: 145 ± 51 kJ/180 min) and EAT (IP: 157 vs. HC-2: 235 ± 30 kJ/30 min) were low, when compared with HC. The other AN patients showed a lower REE (AN: 87 ± 2% vs. HC: 97 ± 2% predicted) at increased DIT (AN: 187 ± 91 vs. HC: 145 ± 51 kJ/180 min) when compared with HC. RER of the IP was low (IP: 0.72 vs. 0.77 in AN-C; 0.77 in HC-1 and 0.80 in HC-2).Conclusions: Complex and variable disturbances of energy metabolism might exist in a subgroup of patients with AN during refeeding, which could lead to unexpectedly high energy requirements. Future studies need to confirm the existence, and investigate the characteristics and prevalence of this subgroup.Clinical trial Registry number: NCT02087280, https://www.clinicaltrials.gov/

Three-dimensional photonic body surface scanners (3DPS) feature a tool to estimate total body volume (BV) from 3D images of the human body, from which the relative body fat mass (%BF) can be calculated. However, information on validity and reliability of these measurements for application in epidemiological studies is limited.Validity was assessed among 32 participants (men, 50%) aged 20-58 years. BV and %BF were assessed using a 3DPS (VitusSmart XXL) and air displacement plethysmography (ADP) with a BOD POD® device using equations by Siri and Brozek. Three scans were obtained per participant (standard, relaxed, exhaled scan). Validity was evaluated based on the agreement of 3DPS with ADP using Bland Altman plots, correlation analysis and Wilcoxon signed ranks test for paired samples. Reliability was investigated in a separate sample of 18 participants (men, 67%) aged 25-66 years using intraclass correlation coefficients (ICC) based on two repeated 3DPS measurements four weeks apart.Mean BV and %BF were higher using 3DPS compared to ADP, (3DPS-ADP BV difference 1.1 ± 0.9 L, p

ObjectivesSystemic inflammation is a major risk factor for critical-illness myopathy (CIM) but its pathogenic role in muscle is uncertain. We observed that interleukin 6 (IL-6) and serum amyloid A1 (SAA1) expression was upregulated in muscle of critically ill patients. To test the relevance of these responses we assessed inflammation and acute-phase response at early and late time points in muscle of patients at risk for CIM.DesignProspective observational clinical study and prospective animal trial.SettingTwo intensive care units (ICU) and research laboratory.Patients/subjects33 patients with Sequential Organ Failure Assessment scores ≥ 8 on 3 consecutive days within 5 days in ICU were investigated. A subgroup analysis of 12 patients with, and 18 patients without CIM (non-CIM) was performed. Two consecutive biopsies from vastus lateralis were obtained at median days 5 and 15, early and late time points. Controls were 5 healthy subjects undergoing elective orthopedic surgery. A septic mouse model and cultured myoblasts were used for mechanistic analyses.Measurements and main resultsEarly SAA1 expression was significantly higher in skeletal muscle of CIM compared to non-CIM patients. Immunohistochemistry showed SAA1 accumulations in muscle of CIM patients at the early time point, which resolved later. SAA1 expression was induced by IL-6 and tumor necrosis factor-alpha in human and mouse myocytes in vitro. Inflammation-induced muscular SAA1 accumulation was reproduced in a sepsis mouse model.ConclusionsSkeletal muscle contributes to general inflammation and acute-phase response in CIM patients. Muscular SAA1 could be important for CIM pathogenesis.Trial registrationISRCTN77569430.

ObjectivesCyclin A1 regulates cell cycle activity and proliferation in somatic and germ-line cells. Its expression increases in G1/S phase and reaches a maximum in G2 and M phases. Altered cyclin A1 expression might contribute to clinical symptoms in facioscapulohumeral muscular dystrophy (FSHD).MethodsMuscle biopsies were taken from the Vastus lateralis muscle for cDNA microarray, RT-PCR, immunohistochemistry and Western blot analyses to assess RNA and protein expression of cyclin A1 in human muscle cell lines and muscle tissue. Muscle fibers diameter was calculated on cryosections to test for hypertrophy.ResultscDNA microarray data showed specifically elevated cyclin A1 levels in FSHD vs. other muscular disorders such as caveolinopathy, dysferlinopathy, four and a half LIM domains protein 1 deficiency and healthy controls. Data could be confirmed with RT-PCR and Western blot analysis showing up-regulated cyclin A1 levels also at protein level. We found also clear signs of hypertrophy within the Vastus lateralis muscle in FSHD-1 patients.ConclusionsIn most somatic human cell lines, cyclin A1 levels are low. Overexpression of cyclin A1 in FSHD indicates cell cycle dysregulation in FSHD and might contribute to clinical symptoms of this disease.

ObjectivesMetabolic flexibility is defined as ability to adjust fuel oxidation to fuel availability. Multiple sclerosis (MS) results in reduced muscle strength and exercise intolerance. We tested the hypothesis that altered metabolic flexibility contributes to exercise intolerance in MS patients.MethodsWe studied 16 patients (all on glatiramer) and 16 matched healthy controls. Energy expenditure (EE), and carbohydrate (COX) and lipid oxidation (LOX) rates were determined by calorimetry, before and after an oral glucose load. We made measurements either at rest (canopy device) or during 40 min low-grade (0.5 W/kg) exercise (metabolic chamber). We also obtained plasma, and adipose tissue and skeletal muscle dialysate samples by microdialysis to study tissue-level metabolism under resting conditions.ResultsAt rest, fasting and postprandial plasma glucose, insulin, and free fatty acid levels did not differ between patients and controls. Fasting and postprandial COX was higher and LOX lower in patients. In adipose, fasting and postprandial dialysate glucose, lactate, and glycerol levels were higher in patients vs. controls. In muscle, fasting and postprandial dialysate metabolite levels did not differ significantly between the groups. During exercise, EE did not differ between the groups. However, COX increased sharply over 20 min in patients, without reaching a steady state, followed by an immediate decrease within the next 20 min and fell even below basal levels after exercise in patients, compared to controls.ConclusionsGlucose tolerance is not impaired in MS patients. At rest, there is no indication for metabolic inflexibility or mitochondrial dysfunction in skeletal muscle. The increased adipose tissue lipolytic activity might result from glatiramer treatment. Autonomic dysfunction might cause dysregulation of postprandial thermogenesis at rest and lipid mobilization during exercise.

Reduced circulating natriuretic peptide concentrations are independently associated with insulin resistance and type 2 diabetes, while increased natriuretic peptide levels appear to be protective. Observations in vitro and in heart failure patients suggest that atrial natriuretic peptide (ANP) promotes adiponectin release, an adipokine with insulin sensitizing properties. We tested the hypothesis that ANP acutely raises adiponectin levels in 12 healthy men. We infused ANP intravenously over 135 minutes while collecting venous blood and adipose tissue microdialysates at baseline and at the end of ANP-infusion. We obtained blood samples at identical time-points without ANP infusion in 7 age and BMI matched men. With infusion, venous ANP concentrations increased ∼10 fold. Systemic and adipose tissue glycerol concentrations increased 70% and 80%, respectively (P