Post Hoc Analysis of a Randomized Controlled Trial on Fasting and Plant-Based Diet in Rheumatoid Arthritis (NutriFast): Nutritional Supply and Impact on Dietary Behavior

This study aimed at comparing the nutrient supply and dietary behaviors during a plant-based diet (PBD) combined with time-restricted eating (TRE) to standard dietary recommendations in rheumatoid arthritis patients. In this open-label, randomized, controlled clinical trial, patients were assigned to either a 7-day fast followed by an 11-week PBD including TRE (A) or a 12-week anti-inflammatory diet following official German guidelines (German Nutrition Society, DGE) (B). Dietary habits were assessed by 3-day food records at weeks -1, 4 and 9 and food frequency questionnaires. 41 out of 53 participants were included in a post-hoc per protocol analysis. Both groups had similar energy, carbohydrate, sugar, fiber and protein intake at week 4. Group A consumed significantly less total saturated fat than group B (15.9 +/- 7.7 vs. 23.2 +/- 10.3 g/day; p = 0.02). Regarding micronutrients, group B consumed more vitamin A, B-12, D, riboflavin and calcium (each p <= 0.02). Zinc and calcium were below recommended intakes in both groups. Cluster analysis did not show clear group allocation after three months. Hence, dietary counselling for a PBD combined with TRE compared to a standard anti-inflammatory diet does not seem to lead to two different dietary clusters, i.e., actual different dietary behaviors as expected. Larger confirmatory studies are warranted to further define dietary recommendations for RA

Protocol for a multicentre cross-sectional, longitudinal ambulatory clinical trial in rheumatoid arthritis and Parkinson's disease patients analysing the relation between the gut microbiome, fasting and immune status in Germany (ExpoBiome).

peer reviewed[en] INTRODUCTION: Chronic inflammatory diseases like rheumatoid arthritis (RA) and neurodegenerative disorders like Parkinson's disease (PD) have recently been associated with a decreased diversity in the gut microbiome, emerging as key driver of various diseases. The specific interactions between gut-borne microorganisms and host pathophysiology remain largely unclear. The microbiome can be modulated by interventions comprising nutrition.The aim of our clinical study is to (1) examine effects of prolonged fasting (PF) and time-restricted eating (TRE) on the outcome parameters and the immunophenotypes of RA and PD with (2) special consideration of microbial taxa and molecules associated with changes expected in (1), and (3) identify factors impacting the disease course and treatment by in-depth screening of microorganisms and molecules in personalised HuMiX gut-on-chip models, to identify novel targets for anti-inflammatory therapy. METHODS AND ANALYSIS: This trial is an open-label, multicentre, controlled clinical trial consisting of a cross-sectional and a longitudinal study. A total of 180 patients is recruited. For the cross-sectional study, 60 patients with PD, 60 patients with RA and 60 healthy controls are recruited at two different, specialised clinical sites. For the longitudinal part, 30 patients with PD and 30 patients with RA undergo 5-7 days of PF followed by TRE (16:8) for a period of 12 months. One baseline visit takes place before the PF intervention and 10 follow-up visits will follow over a period of 12 months (April 2021 to November 2023). ETHICS AND DISSEMINATION: Ethical approval was obtained to plan and conduct the trial from the institutional review board of the Charité-Universitätsmedizin Berlin (EA1/204/19), the ethics committee of the state medical association (Landesärztekammer) of Hessen (2021-2230-zvBO) and the Ethics Review Panel (ERP) of the University of Luxembourg (ERP 21-001 A ExpoBiome). The results of this study will be disseminated through peer-reviewed publications, scientific presentations and social media. TRIAL REGISTRATION NUMBER: NCT04847011

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Efficacy of therapeutic fasting and plant-based diet in patients with rheumatoid arthritis (NutriFast): study protocol for a randomised controlled clinical trial

Background: Previous studies have shown beneficial effects of therapeutic fasting and plant-based dietary interventions on disease activity in patients with rheumatoid arthritis (RA) for a duration of up to 1 year. To date, the effects of such interventions on the gut microbiome and on modern diagnostic markers in patients with RA have not been studied. This trial aims to investigate the clinical effects of therapeutic fasting and a plant-based diet in patients with RA, additionally considering current immunological diagnostic tools and microbiome analyses. Methods/design: This trial is an open-label, single-centre, randomised, controlled, parallel-group clinical trial. We will randomly assign 84 patients with RA under a stable standard therapy to either (1) therapeutic fasting followed by a plant-based dietary intervention or (2) to a conventional nutritional counselling focusing on an anti-inflammatory dietary pattern according to the recommendations of the Deutsche Gesellschaft für Ernährung (German society for nutrition). Primary outcome parameter is the group difference from baseline to 12 weeks on the Health Assessment Questionnaire (HAQ). Other secondary outcomes include established clinical criteria for disease activity and treatment response in RA (Disease Activity Score 28, Simple Disease Activity Index, ACR-Response Criteria), changes in self-reported health and physical functional ability, mood, stress, quality of life, dietary behaviour via 3-day food records and a modified Food Frequency Questionnaire, body composition, changes in the gut microbiome, metabolomics and cytometric parameters. Outcomes will be assessed at baseline and day 7, after 6 weeks, 12 weeks and after 6 months. Ethics and dissemination: Ethical approval to process and analyse data, and to publish the results was obtained through the institutional review board of Charite-Universitätsmedizin Berlin. Results of this trial will be disseminated through peer-reviewed publications and scientific presentations

Enhanced late INa induces proarrhythmogenic SR Ca leak in a CaMKII-dependent manner

Objective: Enhanced late Na current (late I-Na) induces Na-dependent Ca overload as well as proarrhythmogenic events on the cellular level that include spatio-temporally uncoordinated diastolic Ca release from the sarcoplasmic reticulum (SR) and delayed afterdepolarizations (DADs). The Ca/calmodulin-dependent protein kinase II (CaMKII) gets activated upon increases in [Ca](1) and mediates diastolic SR Ca leak as well as DADs. Rationale: We hypothesized that increased late I-Na (in disease-comparable ranges) exerts proarrhythmogenic events in isolated ventricular mouse myocytes in a manner depending on CaMKII-dependent SR Ca leak. We further tested whether inhibition of disease-related late I-Na may reduce proarrhythmogenic SR Ca leak in myocytes from failing human hearts. Methods: Ventricular myocytes were isolated from healthy wildtype (WT), failing CaMKII delta c transgenic (TG) mouse, and failing human hearts. ATX-II (0.25-10 nmol/L) was used to enhance late I-Na. Spontaneous Ca loss from the SR during diastole (Ca sparks), DADs, non-triggered diastolic Ca transients in myocytes and premature beats of isometrically twitching papillary muscles were used as readouts for proarrhythmogenic events. CaMKII autophosphorylation was assessed by immunoblots. Late I-Na was inhibited using ranolazine (Ran, 10 mu mol/L) or 'FIX (2 mu mol/L), and CaMKII by KN-93 (1 mu mol/L) or ALP (1 mu mol/L). Results: In WTmyocytes, sub-nanomolar ATX-II exposure (0.5 nmol/L) enhanced late I-Na by -60%, which resulted in increased diastolic SR Ca loss despite unaltered SR Ca content. In parallel, DADs and non-triggered diastolic Ca transients arose. Inhibition of enhanced late I-Na by RAN or TTX significantly attenuated diastolic SR Ca loss and suppressed DADs as well as mechanical altemans in mouse and diastolic SR Ca loss in failing human myocytes. ATX-II caused Ca-dependent CaMKII-activation without changes in protein expression, which was reversible by Ran or AIP. Conversely, CaMKII-inhibition decreased diastolic SR Ca loss, DADs and non-triggered diastolic Ca transients despite ATX-II-exposure. Finally, failing mouse myocytes with increased CaMKII activity (TG CaMKII delta c) showed an even aggravated diastolic SR Ca loss that was associated with an increased frequency of non-triggered diastolic Ca transients upon enhanced late I-Na. Conclusions: Increased late 'Na (in disease-comparable ranges) induces proarrhythmogenic events during diastole in healthy and failing mouse myocytes, which are mediated via CaMKII-dependent SR Ca loss. Inhibition of late I-Na not only attenuated these cellular arrhythmias in mouse myocytes but also in failing human myocytes indicating some antiarrhythmic potential for an inhibition of the elevated late I-Na/CaMKII signaling pathway in this setting. (c) 2014 Elsevier Ltd. All rights reserved

Effects of Prolonged Fasting during Inpatient Multimodal Treatment on Pain and Functional Parameters in Knee and Hip Osteoarthritis: A Prospective Exploratory Observational Study

Preliminary clinical data suggest that pain reduction through fasting may be effective for different diagnoses. This uncontrolled observational clinical study examined the effects of prolonged modified fasting on pain and functional parameters in hip and knee osteoarthritis. Patients admitted to the inpatient department of Internal Medicine and Nature-based Therapies of the Immanuel Hospital Berlin between February 2018 and December 2020 answered questionnaires at the beginning and end of inpatient treatment, as well as at 3, 6, and 12 months after discharge. Additionally, selected blood and anthropometric parameters, as well as subjective pain ratings, were routinely assessed during the inpatient stay. Fasting was the only common intervention for all patients, being performed as part of a multimodal integrative treatment program, with a daily caloric intake of p p p p p p p p < 0.001, d = 0.43). The results suggest that patients with osteoarthritis of the lower extremities may benefit from prolonged fasting as part of a multimodal integrative treatment to improve quality of life, pain, and disease-specific functional parameters. Confirmatory randomized controlled trials are warranted to further investigate these hypotheses

Protocol for a multicentre cross-sectional, longitudinal ambulatory clinical trial in rheumatoid arthritis and Parkinson’s disease patients analysing the relation between the gut microbiome, fasting and immune status in Germany (ExpoBiome)

Introduction Chronic inflammatory diseases like rheumatoid arthritis (RA) and neurodegenerative disorders like Parkinson’s disease (PD) have recently been associated with a decreased diversity in the gut microbiome, emerging as key driver of various diseases. The specific interactions between gut-borne microorganisms and host pathophysiology remain largely unclear. The microbiome can be modulated by interventions comprising nutrition.The aim of our clinical study is to (1) examine effects of prolonged fasting (PF) and time-restricted eating (TRE) on the outcome parameters and the immunophenotypes of RA and PD with (2) special consideration of microbial taxa and molecules associated with changes expected in (1), and (3) identify factors impacting the disease course and treatment by in-depth screening of microorganisms and molecules in personalised HuMiX gut-on-chip models, to identify novel targets for anti-inflammatory therapy.Methods and analysis This trial is an open-label, multicentre, controlled clinical trial consisting of a cross-sectional and a longitudinal study. A total of 180 patients is recruited. For the cross-sectional study, 60 patients with PD, 60 patients with RA and 60 healthy controls are recruited at two different, specialised clinical sites. For the longitudinal part, 30 patients with PD and 30 patients with RA undergo 5–7 days of PF followed by TRE (16:8) for a period of 12 months. One baseline visit takes place before the PF intervention and 10 follow-up visits will follow over a period of 12 months (April 2021 to November 2023).Ethics and dissemination Ethical approval was obtained to plan and conduct the trial from the institutional review board of the Charité-Universitätsmedizin Berlin (EA1/204/19), the ethics committee of the state medical association (Landesärztekammer) of Hessen (2021–2230-zvBO) and the Ethics Review Panel (ERP) of the University of Luxembourg (ERP 21–001 A ExpoBiome). The results of this study will be disseminated through peer-reviewed publications, scientific presentations and social media.Trial registration number NCT04847011