Publications by authors named "Michael Boschmann"

77 Publications

Effects of Daytime Dry Fasting on Hydration, Glucose Metabolism and Circadian Phase: A Prospective Exploratory Cohort Study in Bahá'í Volunteers.

Front Nutr 2021 29;8:662310. Epub 2021 Jul 29.

Institute of Social Medicine, Epidemiology and Health Economics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

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. To test the safety and effects of BF on hydration, metabolism, and the circadian clock. 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 ( = 11) and qualitative interviews ( = 13), the results of which will be published separately. Exploratory data analysis revealed that serum osmolality ( = 34, < 0.001) and 24-hour urine osmolality (n = 34, = 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, < 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 ( = 16, < 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. 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. https://www.clinicaltrials.gov/, identifier: NCT03443739.
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http://dx.doi.org/10.3389/fnut.2021.662310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358295PMC
July 2021

Skin Sodium Accumulates in Psoriasis and Reflects Disease Severity.

J Invest Dermatol 2021 Jul 6. Epub 2021 Jul 6.

Center of Cardiology - Cardiology I, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany; Center for Thrombosis and Hemostasis (CTH), University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.

Sodium can accumulate in the skin at concentrations exceeding serum levels. A high sodium environment can lead to pathogenic T helper 17 cell expansion. Psoriasis is a chronic inflammatory skin disease in which IL-17‒producing T helper 17 cells play a crucial role. In an observational study, we measured skin sodium content in patients with psoriasis and in age-matched healthy controls by Sodium-23 magnetic resonance imaging. Patients with PASI > 5 showed significantly higher sodium and water content in the skin but not in other tissues than those with lower PASI or healthy controls. Skin sodium concentrations measured by Sodium-23 spectroscopy or by atomic absorption spectrometry in ashed-skin biopsies verified the findings with Sodium-23 magnetic resonance imaging. In vitro T helper 17 cell differentiation of naive CD4 cells from patients with psoriasis markedly induced IL-17A expression under increased sodium chloride concentrations. The imiquimod-induced psoriasis mouse model replicated the human findings. Extracellular tracer Chromium-51-EDTA measurements in imiquimod- and sham-treated skin showed similar extracellular volumes, rendering excessive water of intracellular origin. Chronic genetic IL-17A‒driven psoriasis mouse models underlined the role of IL-17A in dermal sodium accumulation and inflammation. Our data describe skin sodium as a pathophysiological feature of psoriasis, which could open new avenues for its treatment.
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http://dx.doi.org/10.1016/j.jid.2021.06.013DOI Listing
July 2021

Resting Energy Expenditure of Master Athletes: Accuracy of Predictive Equations and Primary Determinants.

Front Physiol 2021 22;12:641455. Epub 2021 Mar 22.

German Aerospace Center (DLR), Institute of Aerospace Medicine, Cologne, Germany.

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 < 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 ( < 0.001), FFM ( < 0.001), FM ( = 0.007), sex ( = 0.045) and interestingly temperature ( = 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.
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http://dx.doi.org/10.3389/fphys.2021.641455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020034PMC
March 2021

Effects of dietary protein-load and alkaline supplementation on acid-base balance and glucose metabolism in healthy elderly.

Eur J Clin Nutr 2020 08;74(Suppl 1):48-56

DZHK (German Centre for Cardiovascular Research), Berlin, Germany.

Background/objectives: Metabolism is controlled by macro- and micronutrients. Protein-rich diets should lead to latent acidosis at tissue level with further negative implications. Food supplements with alkaline salts are available and popular pretending to prevent these changes.

Subjects/methods: Within a randomised double-blind placebo-controlled trial we tested the hypotheses that (1) a 4-week protein-rich diet induces a latent tissue acidosis and (2) an alkaline supplement can compensate this. Acid-base balance and important metabolic parameters were determined before and after 4 weeks of supplementation by peripheral blood samples, indirect calorimetry and muscle microdialysis before and after a protein-rich test meal.

Results: Fourty volunteers were randomised 1:1 to either verum or placebo supplements. Protein-rich diet by itself did not significantly affect acid-base balance. Alkaline supplementation increased plasma bicarbonate concentration without changing pH. Postprandial increases in serum glucose and insulin tended to be lower for verum vs. placebo. Resting and postprandial energy metabolism, and carbohydrate and fat oxidation did not differ significantly before and after supplementation in both groups. In muscle, postprandial glucose uptake and aerobic glucose oxidation were significantly higher for verum. In addition, verum significantly increased serum magnesium concentrations.

Conclusions: Four weeks of protein-rich diet did not significantly influence acid-base balance. However, alkaline supplementation improved systemic and tissue acid-base parameters and oxidative glucose metabolism.
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http://dx.doi.org/10.1038/s41430-020-0695-3DOI Listing
August 2020

Quantifying technical confounders in microbiome studies.

Cardiovasc Res 2021 02;117(3):863-875

Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany.

Aims: Recent technical developments have allowed the study of the human microbiome to accelerate at an unprecedented pace. Methodological differences may have considerable impact on the results obtained. Thus, we investigated how different storage, isolation, and DNA extraction methods can influence the characterization of the intestinal microbiome, compared to the impact of true biological signals such as intraindividual variability, nutrition, health, and demographics.

Methods And Results: An observative cohort study in 27 healthy subjects was performed. Participants were instructed to collect stool samples twice spaced by a week, using six different methods (naive and Zymo DNA/RNA Shield on dry ice, OMNIgene GUT, RNALater, 95% ethanol, Zymo DNA/RNA Shield at room temperature). DNA extraction from all samples was performed comparatively using QIAamp Power Fecal and ZymoBIOMICS DNA Kits. 16S rRNA sequencing of the gut microbiota as well as qPCRs were performed on the isolated DNA. Metrics included alpha diversity as well as multivariate and univariate comparisons of samples, controlling for covariate patterns computationally. Interindividual differences explained 7.4% of overall microbiome variability, whereas the choice of DNA extraction method explained a further 5.7%. At phylum level, the tested kits differed in their recovery of Gram-positive bacteria, which is reflected in a significantly skewed enterotype distribution.

Conclusion: DNA extraction methods had the highest impact on observed microbiome variability, and were comparable to interindividual differences, thus may spuriously mimic the microbiome signatures of various health and nutrition factors. Conversely, collection methods had a relatively small influence on microbiome composition. The present study provides necessary insight into the technical variables which can lead to divergent results from seemingly similar study designs. We anticipate that these results will contribute to future efforts towards standardization of microbiome quantification procedures in clinical research.
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http://dx.doi.org/10.1093/cvr/cvaa128DOI Listing
February 2021

Near real-time bedside detection of spinal cord ischaemia during aortic repair by microdialysis of the cerebrospinal fluid.

Eur J Cardiothorac Surg 2020 09;58(3):629-637

University Department of Cardiac Surgery, Heart Centre Leipzig, Leipzig, Germany.

Objectives: Spinal cord ischaemia (SCI) remains the most devastating complication after thoraco-abdominal aortic aneurysm (TAAA) repair. Its early detection is crucial if therapeutic interventions are to be successful. Cerebrospinal fluid (CSF) is readily available and accessible to microdialysis (MD) capable of detecting metabolites involved in SCI [i.e. lactate, pyruvate, the lactate/pyruvate ratio (LPR), glucose and glycerol] in real time. Our aim was to evaluate the feasibility of CSF MD for the real-time detection of SCI metabolites.

Methods: In a combined experimental and translational approach, CSF MD was evaluated (i) in an established experimental large animal model of SCI with 2 arms: (a) after aortic cross-clamping (AXC, N = 4), simulating open TAAA repair and (b) after total segmental artery sacrifice (Th4-L5, N = 8) simulating thoracic endovascular aortic repair. The CSF was analysed utilizing MD every 15 min. Additionally, CSF was collected hourly from 6 patients undergoing open TAAA repair in a high-volume aortic reference centre and analysed using CSF MD.

Results: In the experimental AXC group, CSF lactate increased 3-fold after 10 min and 10-fold after 60 min of SCI. Analogously, the LPR increased 5-fold by the end of the main AXC period. Average glucose levels demonstrated a 1.5-fold increase at the end of the first (preconditioning) AXC period (0.60±0.14 vs 0.97±0.32 mmol/l); however, they decreased below (to 1/3 of) baseline levels (0.60±0.14 vs 0.19±0.13 mmol/l) by the end of the experiment (after simulated distal arrest). In the experimental segmental artery sacrifice group, lactate levels doubled and the LPR increased 3.3-fold within 30 min and continued to increase steadily almost 5-fold 180 min after total segmental artery sacrifice (P < 0.05). In patients undergoing TAAA repair, lactate similarly increased 5-fold during ischaemia, reaching a maximum at 6 h postoperatively. In 2 patients with intraoperative SCI, indicated by a decrease in the motor evoked potential of >50%, the LPR increased by 200%.

Conclusions: CSF is widely available during and after TAAA repair, and CSF MD is feasible for detection of early anaerobic metabolites of SCI. CSF MD is a promising new tool combining bedside availability and real-time capacity to potentially enable rapid detection of imminent SCI, thereby maximizing chances to prevent permanent paraplegia in patients with TAAA.
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http://dx.doi.org/10.1093/ejcts/ezaa124DOI Listing
September 2020

Hypoxia and exercise interactions on skeletal muscle insulin sensitivity in obese subjects with metabolic syndrome: results of a randomized controlled trial.

Int J Obes (Lond) 2020 05 9;44(5):1119-1128. Epub 2019 Dec 9.

Experimental and Clinical Research Center (ECRC), a joint collaboration between the Max-Delbrück Center for Molecular Medicine and the Charité Universitätsmedizin, Berlin, Germany, and Helios Clinics Berlin, Berlin, Germany.

Background: Physical activity improves insulin sensitivity in obesity. Hypoxia training is claimed to augment this effect. We tested the hypothesis that normobaric hypoxia training would improve insulin sensitivity in obese patients with metabolic syndrome.

Methods: In a randomized controlled trial, 23 obese men with metabolic syndrome who were not informed of the FiO conditions underwent a 6-week physical exercise intervention under ambient (n = 11; FiO 21%) conditions or hypoxia (n = 12; FiO 15%) using a normobaric hypoxic chamber. Three 60-min sessions of interval training were performed each week at 60% of individual V̇O. Assessment of myocellular insulin sensitivity by euglycemic hyperinsulinemic clamp was performed in 21 of these subjects before and after 6 weeks of training. Comprehensive phenotyping also included biopsies of subcutaneous adipose tissues.

Results: The intermittent moderate physical exercise protocol did not substantially change the myocellular insulin sensitivity within 6 weeks under normoxic conditions (ISI: 0.035 (IQR 0.016-0.075) vs. 0.037 (IQR 0.026-0.056) mg* kg *min/(mU* l); p = 0.767). In contrast, ISI improved during hypoxia training (0.028 (IQR 0.018-0.035) vs. 0.038 (IQR 0.024-0.060) mg * kg *min/(mU *l); p < 0.05). Between group comparison of ISI change revealed a small difference between groups (Cohen's d = 0.26). Within the hypoxic group, improvement of ISI during training was associated with individual increase of circulating vascular endothelial growth factor (VEGF) levels (r = 0.678, p = 0.015), even if mean VEGF levels were not modified by any training condition. Atrial natriuretic peptide (ANP) system components were not associated with increased ISI during hypoxic training.

Conclusions: Physical training under hypoxic conditions could partially augment the favorable effects of exercise alone on myocellular insulin sensitivity in obese men with metabolic syndrome. Concomitant changes in VEGF might represent an underlying pathophysiological mechanism.
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http://dx.doi.org/10.1038/s41366-019-0504-zDOI Listing
May 2020

Normobaric hypoxic conditioning in men with metabolic syndrome.

Physiol Rep 2018 Dec;6(24):e13949

Experimental & Clinical Research Center (ECRC), a joint collaboration between Max-Delbrück Center for Molecular Medicine and Charité Universitätsmedizin, Berlin, Germany.

The evidence that physical exercise lowers metabolic and cardiovascular risk is undisputed. Normobaric hypoxia training has been introduced to facilitate the effects of exercise. We tested the hypothesis that hypoxia training augments exercise-related effects. We randomized 23 men with metabolic-syndrome to single-blinded exercise at normoxia (FiO 21%) or hypoxia (FiO 15%). Six weeks endurance training on a treadmill, 3 days per week, over 60 min at 60% VO max was required. The study included the following: (1) metabolic phenotyping by indirect calorimetry and adipose and muscle tissue microdialysis to gain insight into effects on resting, postprandial, and exercise metabolism, (2) cardiac imaging, and (3) biopsies. Primary endpoint was the change in cardiorespiratory fitness; secondary endpoints were as follows: changes in body weight, waist circumference, blood pressure, cardiac dimensions, and adipose and muscle tissue metabolism and gene expression. Our subjects reduced waist circumference and improved several cardiovascular risk markers including blood pressure. However, these effects were similar in both training groups. Cardiac dimensions were not influenced. We focused on glucose metabolism. After an oral glucose load, adipose tissue metabolism was significantly shifted to a more lipolytic state under hypoxia, whereas muscle metabolism was similar under both conditions. Postprandial energy expenditure was significantly increased under hypoxia, whereas activity energy expenditure was improved under normoxia. Gene expression was not consistently influenced by FiO . Adipose tissue triglyceride lipase, leptin, and hypoxia-inducible factor-alpha expression were increased by normoxia but not hypoxia.
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http://dx.doi.org/10.14814/phy2.13949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299242PMC
December 2018

Metabolic, Mental and Immunological Effects of Normoxic and Hypoxic Training in Multiple Sclerosis Patients: A Pilot Study.

Front Immunol 2018 29;9:2819. Epub 2018 Nov 29.

Experimental and Clinical Research Center Cooperation Between Charité Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine, Berlin, Germany.

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. 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. Energy expenditure did not change due to training in both groups, but was rather fueled by fat than by carbohydrate oxidation after HO training ( = 0.002). Maximal workload increased by 40 Watt and 42 Watt in the NO and HO group, respectively (both < 0.0001). Distance patients walked in 6 min increased by 25 m and 27 m in the NO and HO group, respectively (NO = 0.02; HO = 0.01). Beck Depression Inventory score markedly decreased in both groups (NO = 0.03; HO = 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. 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. ClinicalTrials.gov; NCT02509897; http://www.clinicaltrials.gov.
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http://dx.doi.org/10.3389/fimmu.2018.02819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281996PMC
October 2019

Lifestyle interventions in Muslim patients with metabolic syndrome-a feasibility study.

Eur J Clin Nutr 2019 05 11;73(5):805-808. Epub 2018 Dec 11.

Experimental & Clinical Research Center - a joint co-operation between Charité Universitätsmedizin Berlin and Max-Delbrück Center for Molecular Medicine, Berlin, Lindenberger Weg 80, 13125, Berlin, Germany.

Obesity, metabolic syndrome, and type-2 diabetes mellitus are common in Muslim patients living in Germany, most of whom are of Turkish origin. Lifestyle interventions must be tailored to religion and ethnicity. We tested the body weight-reducing effect of a 30% calorie-reduced intake diet, adjusted to individual energy expenditure, eating habits, and food preferences in a Turkish-background cohort. Eighty subjects were randomized to activity advice only or to a step-count device to monitor and document physical activity before and after the 12-week intervention. Fifty-three patients completed the study. Lifestyle interventions were effective in these Muslim subjects. Body weight was reduced by 6%; activity monitoring provided a modestly increased effect to 8%. Blood glucose, HbA1c, triglycerides and cholesterol improved also substantially. Subjects receiving metformin could reduce their dosage. Our data show that Muslim Turkish patients respond to interventions if these are tailored to their needs.
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http://dx.doi.org/10.1038/s41430-018-0371-zDOI Listing
May 2019

Metabolic Barriers to Weight Gain in Patients With Anorexia Nervosa: A Young Adult Case Report.

Front Psychiatry 2018 18;9:199. Epub 2018 May 18.

Department of Psychosomatic Medicine and Psychotherapy, LWL-Universitätsklinikum, Ruhr-Universität Bochum, Bochum, Germany.

Over-proportionally high energy requirements in some patients with anorexia nervosa (AN) have been reported, but their exact origin remains unclear. To objectively measure metabolic alterations in an AN patient with high energy requirements as judged by clinical observation. We present the case of a young woman with AN (index patient, IP; 19 years, admission BMI 13.9 kg/m). After 3 months of treatment at BMI 17.4 kg/m, 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). 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). 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/.
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http://dx.doi.org/10.3389/fpsyt.2018.00199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968865PMC
May 2018

Salt-responsive gut commensal modulates T17 axis and disease.

Nature 2017 11 15;551(7682):585-589. Epub 2017 Nov 15.

Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (T17) cells, which can also contribute to hypertension. Induction of T17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating T17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased T17 cells and increased blood pressure. Our results connect high salt intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.
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http://dx.doi.org/10.1038/nature24628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070150PMC
November 2017

Validity and reliability of total body volume and relative body fat mass from a 3-dimensional photonic body surface scanner.

PLoS One 2017 3;12(7):e0180201. Epub 2017 Jul 3.

Molecular Epidemiology Research Group, Max Delbrück Center for Molecular Medicine, Berlin, Germany.

Objective: 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.

Methods: 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.

Results: Mean BV and %BF were higher using 3DPS compared to ADP, (3DPS-ADP BV difference 1.1 ± 0.9 L, p<0.01; %BF difference 7.0 ± 5.6, p<0.01), yet the disagreement was not associated with gender, age or body mass index (BMI). Reliability was excellent for 3DPS BV (ICC, 0.998) and good for 3DPS %BF (ICC, 0.982). Results were similar for the standard scan and the relaxed scan but somewhat weaker for the exhaled scan.

Conclusions: Although BV and %BF are higher than ADP measurements, our data indicate good validity and reliability for an application of 3DPS in epidemiological studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180201PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495384PMC
October 2017

Systemic and tissue-specific effects of aliskiren on the RAAS and carbohydrate/lipid metabolism in obese patients with hypertension.

J Am Soc Hypertens 2017 Aug 12;11(8):488-497. Epub 2017 Jun 12.

Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany; Institute of Aerospace Medicine, German Aerospace Center (DLR) and Chair of Aerospace Medicine, University of Cologne, Cologne, Germany.

Aliskiren penetrates adipose and skeletal muscle in hypertensive patients with abdominal obesity and reduces renin-angiotensin-aldosterone system activity. After discontinuation, blood pressure-lowering effects are observed possibly through drug-tissue binding. We performed microdialysis evaluation of adipose tissue and skeletal muscle before and during an insulin-modified frequently sampled intravenous glucose tolerance test (IM-FSIGT). Aliskiren 300 mg (n = 8) or amlodipine 5 mg (n = 8) once daily were administered during a 12-week randomized treatment period. Aliskiren elicited variable changes in median interstitial angiotensin II (Ang II) in adipose (2.60-1.30 fmol/mL) and skeletal muscle (2.23-0.68 fmol/mL); amlodipine tended to increase adipose and skeletal muscle Ang II (P = .066 for skeletal muscle treatment difference). Glucose/insulin increased median plasma Ang II 1 hour after glucose injection (1.04-2.50 fmol/mL; P = .001), which was markedly attenuated by aliskiren but not amlodipine. Aliskiren increased glucose disposition index (P = .012) and tended to increase acute insulin response to glucose (P = .067). Fasting adipose glycerol (-17%; P = .064) and fasting muscle glucose dialysate (-17%; P = .025) were decreased by aliskiren but not amlodipine. In summary, aliskiren decreased Ang II production in response to glucose/insulin stimulus and elicited metabolic effects in adipose and skeletal muscle suggestive of increased whole-body glucose utilization.
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http://dx.doi.org/10.1016/j.jash.2017.06.002DOI Listing
August 2017

Longer-term impact of hemiparetic stroke on skeletal muscle metabolism-A pilot study.

Int J Cardiol 2017 Mar 21;230:241-247. Epub 2016 Dec 21.

Center for Stroke Research Berlin, Charité Medical School Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany; Department of Cardiology, Charité Medical School Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. Electronic address:

Background: Hemiparetic stroke leads to structural and metabolic alterations of skeletal muscle tissue, thereby contributing to functional impairment associated with stroke. In situ metabolic processes at tissue level in skeletal muscle have not been investigated. We hypothesize that muscular metabolic capacity is limited after hemiparetic stroke, and that changes affect rather the paretic than non-paretic limb.

Methods: Nine male hemiparetic stroke survivors (age, 62±8years; BMI, 28±4kg/m; median stroke latency, 23months ranging from 7 to 34months poststroke) underwent dynamic in situ measurements of carbohydrate and lipid metabolism at fasting condition and during oral glucose tolerance testing, using bilateral microdialysis. Results were compared to 8 healthy male subjects of similar age and BMI.

Results: Tissue perfusion, fasting and postprandial profiles of interstitial metabolites glucose, pyruvate, lactate and glycerol did not differ between paretic and non-paretic muscle. Patients displayed higher fasting and postprandial dialysate glycerol levels compared to controls (P<0.001) with elevated plasma FFA (fasting FFA; 0.63±0.23 vs. 0.29±0.17mmol/L; P=0.004). Glycolytic activity was higher in patients vs. controls, with increased lactate production upon glucose load (P<0.001).

Conclusions: An elevated lipolytic and glycolytic activity on tissue level suggests an impaired substrate metabolism with blunted oxidative metabolism in bilateral skeletal muscle in patients after hemiparetic stroke. Muscular metabolic properties did not differ between paretic and non-paretic leg. Further work is needed to investigate the clinical impact of this impaired muscular metabolic capacity in post-stroke patients.
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http://dx.doi.org/10.1016/j.ijcard.2016.12.143DOI Listing
March 2017

Tracking CNS and systemic sources of oxidative stress during the course of chronic neuroinflammation.

Acta Neuropathol 2015 Dec 31;130(6):799-814. Epub 2015 Oct 31.

Institut für Neuropathologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.

The functional dynamics and cellular sources of oxidative stress are central to understanding MS pathogenesis but remain elusive, due to the lack of appropriate detection methods. Here we employ NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX enzymes) in vivo to identify inflammatory monocytes, activated microglia, and astrocytes expressing NOX1 as major cellular sources of oxidative stress in the central nervous system of mice affected by experimental autoimmune encephalomyelitis (EAE). This directly affects neuronal function in vivo, indicated by sustained elevated neuronal calcium. The systemic involvement of oxidative stress is mirrored by overactivation of NOX enzymes in peripheral CD11b(+) cells in later phases of both MS and EAE. This effect is antagonized by systemic intake of the NOX inhibitor and anti-oxidant epigallocatechin-3-gallate. Together, this persistent hyper-activation of oxidative enzymes suggests an "oxidative stress memory" both in the periphery and CNS compartments, in chronic neuroinflammation.
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http://dx.doi.org/10.1007/s00401-015-1497-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654749PMC
December 2015

Clinical effects of phosphodiesterase 3A mutations in inherited hypertension with brachydactyly.

Hypertension 2015 Oct 17;66(4):800-8. Epub 2015 Aug 17.

From the Children's' Hospital, Department of Pediatric Cardiology, Friedrich-Alexander University Erlangen, Erlangen, Germany (O.T.); Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany (J.T., J.J.); Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany (C.S., A.A., P.G.M., E.B.-K., I.H., A.M., Y.W.-N., J.S.-M., E.K., S.B., F.C.L.); Experimental and Clinical Research Center (ECRC), a joint co-operation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany (A.A., P.G.M., E.B.-K., I.H., C.L., K.M., M.B., G.R., A.M., Y.W.-N., W.U., A.T., J.S.-M., S.B., F.C.L.); Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA (P.G.M.); Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA (P.G.M.); Department of Cardiology/Nephrology, Helios-Klinikum Berlin, Berlin, Germany (S.E., W.U., A.T., J.S.-M.); Department of Nephrology, Hannover University Medical School, Hannover, Germany (C.L.); Staatliche Technikerschule Berlin, Berlin, Germany (C.L.); Cardiology Section, VA Salt Lake City Health Care System, UT (M.A.M.); Departments of Internal Medicine and Pharmacology and Toxicology, University of Utah, Salt Lake City (M.A.M.); Blood Transfusion Center, Deutsches Rotes Kreuz, Oldenburg, Germany (T.M., A.D., S.G.); Division of Nephrology and Hypertension, Department of Medicine, Eastern Virginia Medical School, Norfolk, VA (H.R.T.); Hampton Veterans Affairs Medical Center, Hampton, VA (H.R.T); German Centre for Cardiovascular Research (DZHK), Berlin, Germany (E.K.); and Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN (F.C.L.).

Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the protein kinase A-mediated phosphorylation of phosphodiesterase 3A resulting in enhanced cAMP-hydrolytic affinity and accelerated cell proliferation. The phosphorylated vasodilator-stimulated phosphoprotein is diminished, and parathyroid hormone-related peptide is dysregulated, potentially accounting for all phenotypic features. Untreated patients die prematurely of stroke; however, hypertension-induced target-organ damage is otherwise hardly apparent. We conducted clinical studies of vascular function, cardiac functional imaging, platelet function in affected and nonaffected persons, and cell-based assays. Large-vessel and cardiac functions indeed seem to be preserved. The platelet studies showed normal platelet function. Cell-based studies demonstrated that available phosphodiesterase 3A inhibitors suppress the mutant isoforms. However, increasing cGMP to indirectly inhibit the enzyme seemed to have particular use. Our results shed more light on phosphodiesterase 3A activation and could be relevant to the treatment of severe hypertension in the general population.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.06000DOI Listing
October 2015

Metabolic response to epigallocatechin-3-gallate in relapsing-remitting multiple sclerosis: a randomized clinical trial.

Am J Clin Nutr 2015 Mar 14;101(3):487-95. Epub 2015 Jan 14.

From the Experimental & Clinical Research Center-a joint cooperation between Charité-Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Berlin, Germany (AM, JS, M Bock, LK, NP, and M Boschmann); NeuroCure Clinical Research Center (AM, M Bock, and FP) and Medical Clinic for Cardiology and Angiology Campus Mitte (ML), Charité-Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Berlin, Germany (ML); University of Bonn, Institute of Nutritional and Food Sciences, Bonn, Germany (BFZ); Institute Prof. Dr. Georg Kurz GmbH, Köln, Germany (BFZ); Department of Biostatistics, Clinical Research Unit of Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Berlin, Germany (AK); and Clinical and Experimental Multiple Sclerosis Research Center, Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany (FP).

Background: Muscle weakness and fatigue are common symptoms in multiple sclerosis (MS). Green tea catechins such as (-)epigallocatechin-3-gallate (EGCG) are known to improve energy metabolism at rest and during exercise.

Objective: We tested the hypothesis that EGCG improves energy metabolism and substrate utilization in patients with MS.

Design: Eighteen patients (8 men) with relapsing-remitting MS (expanded disability status scale score <4.5, all receiving glatiramer acetate) participated in this randomized, double-blind, placebo-controlled, crossover trial at a clinical research center. All patients received EGCG (600 mg/d) and placebo over 12 wk (4-wk washout in between). After each intervention, fasting and postprandial energy expenditure (EE), as well as fat oxidation (FAOx) and carbohydrate oxidation (CHOx) rates, were measured either at rest or during 40 min of exercise (0.5 W/kg). At rest, blood samples and microdialysates from adipose tissue and skeletal muscle were also taken.

Results: At rest, postprandial EE and CHOx, as well as adipose tissue perfusion and glucose supply, were significantly lower in men but higher in women receiving EGCG compared with placebo. During exercise, postprandial EE was lower after EGCG than after placebo, indicating an increased working efficiency (men > women). After placebo, exercise EE was mainly fueled by FAOx in both men and women. After EGCG, there was a shift to a higher and more stable CHOx during exercise in men but not in women.

Conclusions: Our data indicate that EGCG given to patients with MS over 12 wk improves muscle metabolism during moderate exercise to a greater extent in men than in women, possibly because of sex-specific effects on autonomic and endocrine control.
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http://dx.doi.org/10.3945/ajcn.113.075309DOI Listing
March 2015

[Nutrition sciences in the treatment of eating disorders].

Psychother Psychosom Med Psychol 2015 Jan 16;65(1):33-5. Epub 2015 Jan 16.

Experimental and Clinical Research Center (ECRC) Campus Buch, Charité-Universitätsmedizin Berlin.

Several studies provide evidence for the existence of a hypermetabolic state of biological origin in recently weight recovered patients with anorexia nervosa. It remains unclear if current nutritional rehabilitation strategies are consistent with the resulting high energy requirements. Further insight into specific pathophysiological characteristics of energetic efficiency in patients with anorexia nervosa will help us to provide evidence based nutritional guidance. Basic nutritional research in this field is urgently required.
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http://dx.doi.org/10.1055/s-0034-1394404DOI Listing
January 2015

Catabolic signaling and muscle wasting after acute ischemic stroke in mice: indication for a stroke-specific sarcopenia.

Stroke 2014 Dec 28;45(12):3675-83. Epub 2014 Oct 28.

From the Department of Innovative Clinical Trials, University Medical Centre, Göttingen, Germany (J.S., S.v.H., S.D.A.); Centre for Stroke Research Berlin (S.S., K.P., A.R., N.S., U.D., W.D.), Applied Cachexia Research, Department of Cardiology, Virchow-Klinikum (A.T., S.v.H., S.D.A.), Departments of Neurology and Experimental Neurology (A.R., O.E., A.M., U.D.), NeuroCure Clinical Research Center (A.M.), and Experimental and Clinical Research Center (M.B.), Charité-Universitätsmedizin Berlin, Berlin, Germany; and German Center for Cardiovascular Diseases (DZHK), Partner Site, Berlin, Germany (U.D., W.D.).

Background And Purpose: Muscle wasting is a common complication accompanying stroke. Although it is known to impair poststroke recovery, the mechanisms of subacute catabolism after stroke have not been investigated in detail. The aim of this study is to investigate mechanisms of local and systemic catabolism and muscle wasting (sarcopenia) in a model of ischemic stroke systematically.

Methods: Changes in body composition and catabolic activation in muscle tissue were studied in a mouse model of acute cerebral ischemia (temporal occlusion of the middle cerebral artery). Tissue wasting (nuclear magnetic resonance spectroscopy), tissue catabolism (caspases-3 and -6, myostatin), and proteasome activity were assessed. Food intake, activity levels, and energy expenditure were assessed, and putative mechanisms of postischemic wasting were tested with appropriate interventions.

Results: Severe weight loss in stroke animals (day 3: weight loss, -21.7%) encompassed wasting of muscle (-12%; skeletal and myocardium) and fat tissue (-27%). Catabolic signaling and proteasome activity were higher in stroke animals in the contralateral and in the ipsilateral leg. Cerebral infarct severity correlated with catabolic activity only in the contralateral leg but not in the ipsilateral leg. Lower energy expenditure in stroke animals together with normal food intake and activity levels suggests compensatory mechanisms to regain weight. Interventions (high caloric feeding, β-receptor blockade, and antibiotic treatment) failed to prevent proteolytic activation and muscle wasting.

Conclusions: Catabolic pathways of muscle tissue are activated after stroke. Impaired feeding, sympathetic overactivation, or infection cannot fully explain this catabolic activation. Wasting of the target muscle of the disrupted innervation correlated to severity of brain injury. Our data indicate the presence of a stroke-specific sarcopenia.
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http://dx.doi.org/10.1161/STROKEAHA.114.006258DOI Listing
December 2014

Inflammation-induced acute phase response in skeletal muscle and critical illness myopathy.

PLoS One 2014 20;9(3):e92048. Epub 2014 Mar 20.

Experimental and Clinical Research Center (ECRC), a Cooperation between Max Delbrück Center and Charité Universitätsmedizin Berlin, Campus Buch, Berlin, Germany; Charité Universitätsmedizin Berlin, Campus Virchow, Cardiology, Berlin, Germany.

Objectives: Systemic 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.

Design: Prospective observational clinical study and prospective animal trial.

Setting: Two intensive care units (ICU) and research laboratory.

Patients/subjects: 33 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 Results: Early 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.

Conclusions: Skeletal muscle contributes to general inflammation and acute-phase response in CIM patients. Muscular SAA1 could be important for CIM pathogenesis.

Trial Registration: ISRCTN77569430.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0092048PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961297PMC
December 2014

Increased catabolic state in spinocerebellar ataxia type 1 patients.

Cerebellum 2014 Aug;13(4):440-6

Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin and Max-Delbrück-Centrum für Molekulare Medizin, Lindenberger Weg 80, 13125, Berlin, Germany,

Autosomal dominant spinocerebellar ataxia type 1 (SCA1) is a genetic movement disorder with neuronal loss in the cerebellum, brainstem, and other cerebral regions. The course of SCA1 is accompanied with progressive weight loss and amyotrophia-the causes for that remain, however, unclear. We tested the hypothesis that an imbalance between energy intake and expenditure contributes to weight loss in SCA1 patients. Anthropometric measures, energy intake (food records), and resting (calorimetry) and free-living (accelerometry) energy expenditure were determined in 10 patients with genetically proven SCA1 and 10 healthy controls closely matched for age, sex, and body composition. At rest, energy expenditure per kilogram fat-free mass was 22 % and fat oxidation rate 28 % higher in patients vs. controls indicating an increased catabolic state. Under free-living conditions, total energy expenditure and daily step counts were significantly lower in patients vs. controls. However, most patients were able to maintain energy intake and expenditure in a balanced state. Resting energy expenditure, fat oxidation, and activity energy expenditure per step count are higher, whereas 24-h total energy expenditure is lower in SCA1 patients vs. healthy controls. An altered autonomic nervous system activity, gait ataxia, and a decreased physical activity might contribute to this outcome.
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http://dx.doi.org/10.1007/s12311-014-0555-6DOI Listing
August 2014

Fasting therapy - an expert panel update of the 2002 consensus guidelines.

Forsch Komplementmed 2013 16;20(6):434-43. Epub 2013 Dec 16.

Klinik Buchinger Wilhelmi, Überlingen, Deutschland.

Fasting for medical purpose (fasting therapy) has a long tradition in Europe and is established as a defined therapeutic approach in specialized fasting hospitals or within clinical departments for integrative medicine. In 2002, the first guidelines for fasting therapy were published following an expert consensus conference; here we present a revised update elaborated by an expert panel. Historical aspects and definitions, indications, methods, forms, and accompanying procedures of fasting as well as safety and quality criteria of fasting interventions are described. Fasting has shown beneficial effects in various chronic diseases with highest level of evidence for rheumatic diseases. Preliminary clinical and observational data and recently revealed mechanisms of fasting and caloric restriction indicate beneficial effects of fasting also in other chronic conditions such as metabolic diseases, pain syndromes, hypertension, chronic inflammatory diseases, atopic diseases, and psychosomatic disorders. Fasting can also be applied for preventing diseases in healthy subjects. In order to guarantee successful use of fasting and to ensure adherence of all safety and quality standards it is mandatory that all interventions during fasting are guided/accompanied by physicians/therapists trained and certified in fasting therapy.
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http://dx.doi.org/10.1159/000357602DOI Listing
April 2015

Anthropometric, hemodynamic, metabolic, and renal responses during 5 days of food and water deprivation.

Forsch Komplementmed 2013 16;20(6):427-33. Epub 2013 Dec 16.

Institute for Social Medicine, Epidemiology, and Health Economics, Charité - Universitätsmedizin Berlin, Germany.

Background: Although there is considerable research in the field of fasting and fluid restriction, little is known about the impact of food and water deprivation (FWD) on body circumferences and vital parameters.

Methods: During 5 days of FWD in 10 healthy adults, hemodynamic, metabolic, and renal parameters, such as weight, 5 circumferences at neck, waist, hip, chest at axilla, chest at nipples, and 1 new oblique hip circumference were measured daily. For each circumference, new quotients of daily circumference-to-weight decrease were calculated. The set of employed parameters quantified and monitored dieting persons' compliance and efficacy of the method.

Results: The values of blood pressure, heart rate, hemoglobin oxygen saturation, glucose, K(+), Na(+), Cl(-), urea, creatinine, and serum osmolality proved to be stable. The mean creatinine clearance increased up to 167%. The mean daily weight decrease (1,390 ± 60 g) demonstrated the effectiveness of FWD in weight reduction. The daily decrease of all measured circumferences and the values of the corresponding circumference-to-weight decrease quotients reflected considerable volume decrease in all measured body parts per day and kg of weight loss during FWD.

Conclusion: The intervention of 5 FWD days in 10 healthy adults was found to be safe, decreased weight and all measured circumferences, and improved renal function considerably.
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http://dx.doi.org/10.1159/000357718DOI Listing
April 2015

Fasting therapy - old and new perspectives.

Forsch Komplementmed 2013 16;20(6):410-1. Epub 2013 Dec 16.

Experimental and Clinical Research Center (ECRC), Berlin, Germany.

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http://dx.doi.org/10.1159/000357828DOI Listing
April 2015

Resting energy expenditure and the effects of muscle wasting in patients with chronic heart failure: results from the Studies Investigating Comorbidities Aggravating Heart Failure (SICA-HF).

J Am Med Dir Assoc 2013 Nov 2;14(11):837-41. Epub 2013 Oct 2.

Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Klinikum, Berlin, Germany.

Objectives: Muscle wasting is common in patients with chronic heart failure (HF) and worsens functional status. Protein catabolism is characteristic of muscle wasting and contributes to resting energy expenditure (REE). Glucagonlike peptide 1 (GLP-1) is linked to REE in healthy individuals. We aimed to evaluate (1) whether REE is elevated in patients with HF with muscle wasting, and (2) whether basal GLP-1 levels are linked to REE in HF.

Design: Cross-sectional study.

Setting: Ambulatory patients with HF were recruited at the Charité Medical School, Campus Virchow-Klinikum, Berlin, Germany.

Participants: A total of 166 patients with HF and 27 healthy controls participating in the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) were enrolled. GLP-1 was measured in 55 of these patients.

Measurements: Body composition was measured by dual-energy X-ray absorptiometry (DEXA). Muscle wasting was defined as appendicular lean mass of at least 2 SDs below values of a healthy young reference group. REE was measured by indirect calorimetry. GLP-1 was assessed by ELISA.

Results: Thirty-four of 166 patients (mean age 67.4 ± 10.2 years, 77.7% male, New York Heart Association class 2.3 ± 0.6) presented with muscle wasting. REE in controls and patients with muscle wasting was significantly lower than in patients without muscle wasting (1579 ± 289 and 1532 ± 265 vs 1748 ± 359 kcal/d, P = .018 and P = .001, respectively). REE normalized for fat-free mass (FFM) using the ratio method (REE/FFM) and analysis of covariance was not different (P = .23 and .71, respectively). GLP-1 did not significantly correlate with REE (P = .49), even not after controlling for FFM using multivariable regression (P = .15).

Conclusions: Differences in REE are attributable to lower FFM. GLP-1 does not relate to REE in patients with HF, possibly because of HF-related effects on REE.
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http://dx.doi.org/10.1016/j.jamda.2013.08.008DOI Listing
November 2013

Altered expression of cyclin A 1 in muscle of patients with facioscapulohumeral muscle dystrophy (FSHD-1).

PLoS One 2013 3;8(9):e73573. Epub 2013 Sep 3.

Experimental and Clinical Research Center, a joint co-operation of Charité University Medicine and Max-Delbrück Center for Molecular Medicine, Franz-Volhard Center for Clinical Research, Berlin, Germany.

Objectives: Cyclin 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).

Methods: Muscle 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.

Results: cDNA 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.

Conclusions: In 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073573PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760810PMC
May 2014

Long-lasting improvements in liver fat and metabolism despite body weight regain after dietary weight loss.

Diabetes Care 2013 Nov 20;36(11):3786-92. Epub 2013 Aug 20.

Corresponding author: Stefan Engeli,

Objective: Weight loss reduces abdominal and intrahepatic fat, thereby improving metabolic and cardiovascular risk. Yet, many patients regain weight after successful diet-induced weight loss. Long-term changes in abdominal and liver fat, along with liver test results and insulin resistance, are not known.

Research Design And Methods: We analyzed 50 overweight to obese subjects (46 ± 9 years of age; BMI, 32.5 ± 3.3 kg/m2; women, 77%) who had participated in a 6-month hypocaloric diet and were randomized to either reduced carbohydrates or reduced fat content. Before, directly after diet, and at an average of 24 (range, 17-36) months follow-up, we assessed body fat distribution by magnetic resonance imaging and markers of liver function and insulin resistance.

Results: Body weight decreased with diet but had increased again at follow-up. Subjects also partially regained abdominal subcutaneous and visceral adipose tissue. In contrast, intrahepatic fat decreased with diet and remained reduced at follow-up (7.8 ± 9.8% [baseline], 4.5 ± 5.9% [6 months], and 4.7 ± 5.9% [follow-up]). Similar patterns were observed for markers of liver function, whole-body insulin sensitivity, and hepatic insulin resistance. Changes in intrahepatic fat und intrahepatic function were independent of macronutrient composition during intervention and were most effective in subjects with nonalcoholic fatty liver disease at baseline.

Conclusions: A 6-month hypocaloric diet induced improvements in hepatic fat, liver test results, and insulin resistance despite regaining of weight up to 2 years after the active intervention. Body weight and adiposity measurements may underestimate beneficial long-term effects of dietary interventions.
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http://dx.doi.org/10.2337/dc13-0102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816862PMC
November 2013

mTOR and regulation of energy homeostasis in humans.

J Mol Med (Berl) 2013 Oct 12;91(10):1167-75. Epub 2013 Jun 12.

Campus Virchow Klinikum, Medical Department, Division of Nephrology and Medical Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany,

Patients treated with the mammalian or mechanistic target of rapamycin (mTOR) inhibitor everolimus in order to slow progression of autosomal-dominant polycystic kidney disease (ADPKD) showed a significant reduction of body weight. Although the detailed mechanism of how mTOR inhibition interferes with body weight regulation is rather unclear, present data suggest that this effect is mediated by both central and peripheral mechanisms. These findings in ADPKD patients are in contrast to well-documented effects of hypothalamic mTOR on regulation of energy homeostasis and eating behavior in rodents. In a number of rodent models, the mTOR inhibitor rapamycin induces increased food intake, which is accompanied by increased body weight. However, animal data are inconsistent. This review highlights some of the regulatory signals and key mechanisms that are important for balancing energy intake and energy expenditure with a special focus on adipose tissue-derived adipokines and their interaction with mTOR regarding local regulation of tissue perfusion and metabolism and overall systemic energy homeostasis. Specifically, clinical aspects of an impaired mTOR signaling pathway regarding the development of obesity and type-2 diabetes mellitus will be discussed.
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http://dx.doi.org/10.1007/s00109-013-1057-6DOI Listing
October 2013

Immune cells control skin lymphatic electrolyte homeostasis and blood pressure.

J Clin Invest 2013 Jul 3;123(7):2803-15. Epub 2013 Jun 3.

Department of Biomedicine, University of Bergen, Bergen, Norway.

The skin interstitium sequesters excess Na+ and Cl- in salt-sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and activate the tonicity-responsive enhancer-binding protein (TONEBP, also known as NFAT5) to initiate expression and secretion of VEGFC, which enhances electrolyte clearance via cutaneous lymph vessels and increases eNOS expression in blood vessels. It is unclear whether this local MPS response to osmotic stress is important to systemic blood pressure control. Herein, we show that deletion of TonEBP in mouse MPS cells prevents the VEGFC response to a high-salt diet (HSD) and increases blood pressure. Additionally, an antibody that blocks the lymph-endothelial VEGFC receptor, VEGFR3, selectively inhibited MPS-driven increases in cutaneous lymphatic capillary density, led to skin Cl- accumulation, and induced salt-sensitive hypertension. Mice overexpressing soluble VEGFR3 in epidermal keratinocytes exhibited hypoplastic cutaneous lymph capillaries and increased Na+, Cl-, and water retention in skin and salt-sensitive hypertension. Further, we found that HSD elevated skin osmolality above plasma levels. These results suggest that the skin contains a hypertonic interstitial fluid compartment in which MPS cells exert homeostatic and blood pressure-regulatory control by local organization of interstitial electrolyte clearance via TONEBP and VEGFC/VEGFR3-mediated modification of cutaneous lymphatic capillary function.
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http://dx.doi.org/10.1172/JCI60113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696542PMC
July 2013
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