Study protocol to investigate the efficacy of confocal laser endomicroscopy-based selective single-elimination diet over standard fivefold elimination diet in patients with endomicroscopically proven food intolerance: app-assisted, monocentric, double-blind, randomised and controlled trial in Germany.

INTRODUCTION: Imprecise nutritional recommendations due to a lack of diagnostic test accuracy are a frequent problem for individuals with adverse reactions to foods but no precise diagnosis. Consequently, patients follow very broad and strict elimination diets to avoid uncontrolled symptoms such as diarrhoea and abdominal pain. Dietary limitations and the uncertainty of developing gastrointestinal symptoms after the inadvertent ingestion of food have been demonstrated to reduce the quality of life (QoL) of affected individuals and subsequently might increase the risk of malnutrition and intestinal dysbiosis. This trial aims to investigate the effects of a tailored diet based on the confocal laser endoscopy (CLE) examination result to limit the side effects of unspecific and broad elimination diets and to increase the patient's QoL. METHODS AND ANALYSIS: The study is designed as a prospective, double-blind, monocentric, randomised and controlled trial conducted at the University Hospital of Schleswig-Holstein, Campus Lübeck, Germany. One hundred seventy-two patients with non-IgE-related food allergies and positive CLE results will be randomised to either a tailored diet or a standard fivefold elimination diet. The primary endpoints are the difference between the end and the start of the intervention in health-related QoL and the sum score of the severity of symptoms after 12 weeks. Key secondary endpoints are changes in the severity of symptoms, further QoL measurements, self-assessed state of health and number of days with a pathologically altered stool. Microbiome diversity and metabolome of stool, urine and blood will also be investigated. Safety endpoints are body composition, body mass index and adverse events. ETHICS AND DISSEMINATION: The study protocol was accepted by the ethical committee of the University of Lübeck (AZ: 22-111) on 4 May2022. Results of the study will be published in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: German Clinical Trials Register (DRKS00029323).

Routine Screening for Peripartum Depression in the Gynecologic and Pediatric Setting - Evaluation of an Adapted EPDS Version.

PURPOSE: The aim of the study was to investigate the feasibility and acceptability of a routine screening for peripartum depression (PD) by gynecologists and pediatricians. In addition, it was investigated whether two separate Plus Questions (PQ) of the "EPDS-Plus" are valid for screening experiences of violence or a traumatic birth and whether they can be associated with symptoms of PD. METHODS: Using the EPDS-Plus the prevalence of PD was investigated in 5235 women. The convergent validity of the PQ with the Childhood Trauma Questionnaire (CTQ) and Salmon's Item List (SIL) was assessed using correlation analysis. The association between the experience of violence and/or traumatic birth experience and PD was subjected to the chi-square test. Furthermore, a qualitative analysis for acceptance and satisfaction by the practitioners was performed. RESULTS: The prevalence was 9.94%/10.18% for antepartum/postpartum depression. The convergent validity of the PQ showed strong correlation with CTQ (p<0.001) and SIL (p<0.001). For violence and PD, a significant association was found. There was no significant association for traumatic birth experience and PD. There was a high level of satisfaction and acceptance of the EPDS-Plus questionnaire. CONCLUSION: Screening for peripartum depression is feasible in regular care and can help to identify depressed as well as potentially traumatized mothers, especially in preparing trauma-sensitive birth care and treatment. Therefore, specialized peripartum "psych" treatment for all affected mothers in all regions has to be implemented.

C5aR1 activation in mice controls inflammatory eosinophil recruitment and functions in allergic asthma.

BACKGROUND: Pulmonary eosinophils comprise at least two distinct populations of resident eosinophils (rEOS) and inflammatory eosinophils (iEOS), the latter recruited in response to pulmonary inflammation. Here, we determined the impact of complement activation on rEOS and iEOS trafficking and function in two models of pulmonary inflammation. METHODS: BALB/c wild-type and C5ar1-/- mice were exposed to different allergens or IL-33. Eosinophil populations in the airways, lung, or mediastinal lymph nodes (mLN) were characterized by FACS or immunohistochemistry. rEOS and iEOS functions were determined in vivo and in vitro. RESULTS: HDM and IL-33 exposure induced a strong accumulation of iEOS but not rEOS in the airways, lungs, and mLNs. rEOS and iEOS expressed C3/C5 and C5aR1, which were significantly higher in iEOS. Initial pulmonary trafficking of iEOS was markedly reduced in C5ar1-/- mice and associated with less IL-5 production from ILC2 cells. Functionally, adoptively transferred pulmonary iEOS from WT but not from C5ar1-/- mice-induced airway hyperresponsiveness (AHR), which was associated with significantly reduced C5ar1-/- iEOS degranulation. Pulmonary iEOS but not rEOS were frequently associated with T cells in lung tissue. After HDM or IL-33 exposure, iEOS but not rEOS were found in mLNs, which were significantly reduced in C5ar1-/- mice. C5ar1-/- iEOS expressed less costimulatory molecules, associated with a decreased potency to drive antigen-specific T cell proliferation and differentiation into memory T cells. CONCLUSIONS: We uncovered novel roles for C5aR1 in iEOS trafficking and activation, which affects key aspects of allergic inflammation such as AHR, ILC2, and T cell activation.

Efficacy of the Digital Therapeutic sinCephalea in the prophylaxis of migraine in patients with episodic migraine: study protocol for a digital, randomized, open-label, standard treatment controlled trial.

BACKGROUND: The German government implemented the Digital Healthcare Act in order to bring Digital Therapeutics into standard medical care. This is one of the first regulatory pathways to reimbursement for Digital Therapeutics (DTx). The Digital Therapeutic sinCephalea is intended to act as a prophylactic treatment of migraine by reducing the migraine days. For this, sinCephalea determines personalized nutritional recommendations using continuous glucose monitoring (CGM) data and enables the patients to follow a personalized low-glycemic nutrition. Migraine is a headache disorder with the highest socioeconomic burden. Emerging evidence shows that CGM-based personalized nutritional recommendations are of prophylactic use in episodic migraine. However, prospective data are yet missing to demonstrate clinical effectiveness. This study is designed to fill this gap. METHODS: Patients between 18 and 65 years of age with proven migraine and a minimal disease severity of 3 migraine days per month are included. After a 4-week baseline phase as a pre-study, patients are randomized to the DTx intervention or a waiting-list control. The objective of the study is to show differences between the intervention and control groups regarding the change of migraine symptoms and of effects of migraine on daily life. DISCUSSION: To our knowledge, this is the first systematic clinical trial with a fully digital program to enable patients with migraine to follow a personalized low-glycemic nutrition in order to reduce their number of migraine days and the migraine-induced impact on daily life. Designing a clinical study using a digital intervention includes some obstacles, which are addressed in this study approach. TRIAL REGISTRATION: German Registry of Clinical Studies (Deutsches Register Klinischer Studien) DRKS-ID DRKS00024657. Registered on March 8, 2021.

A nutritional supplement based on a synbiotic combination of Bacillus subtilis DSM 32315 and L-alanyl-L-glutamine improves glucose metabolism in healthy prediabetic subjects - A real-life post-marketing study.

Introduction: Impaired glucose homeostasis is a significant risk factor for cardiometabolic diseases, whereas the efficacy of available standard therapies is limited, mainly because of poor adherence. This post-marketing study assessed the glucose-lowering potential of a synbiotic-based formulation. Methods: One hundred ninety-two participants were enrolled in a digital nutrition program with continuous glucose monitoring (CGM) and received a study product comprising Bacillus subtilis DSM 32315 and L-alanyl-L-glutamine. Participants underwent a first sensor phase without supplementation, followed by a 14-day supplementation phase without sensor, and completed by a second sensor phase while continuing supplementation. Fasting glucose levels were determined before and after supplementation by CGM. In addition, the postprandial glycemic response to an oral glucose challenge, body weight, HbA1c concentrations, and BMI was analyzed. Subgroup analyses of subjects with elevated glucose and HbA1c levels vs. normoglycemic subjects were performed. Results: Supplementation with the study product resulted in significant improvements in glucose parameters (delta values: fasting glucose -2,13% ± 8.86; iAUC0-120 -4.91% ± 78.87; HbA1c: -1.20% ± 4.72) accompanied by a significant weight reduction (-1.07 kg ± 2.30) in the study population. Subgroup analyses revealed that the improvements were mainly attributed to a prediabetic subgroup with elevated fasting glucose and HbA1c values before supplementation (delta values: fasting glucose -6.10% 4± 7.89; iAUC0-120 -6.28% ± 115.85; HbA1c -3.31% ± 4.36; weight: -1.47 kg ± 2.82). Conclusion: This study indicates that the synbiotic composition is an effective and convenient approach to counteract hyperglycemia. Further placebo-controlled studies are warranted to test its efficacy in the treatment of cardiometabolic diseases.

A Digital Therapeutic Allowing a Personalized Low-Glycemic Nutrition for the Prophylaxis of Migraine: Real World Data from Two Prospective Studies.

Migraine is a headache disorder associated with a high socioeconomic burden. The digital therapeutic sinCephalea provides an individualized low-glycemic diet based on continuous glucose measurement and is intended to provide a non-pharmacological migraine prophylaxis. We performed two prospective studies with migraine patients who used sinCephalea over a period of 16 weeks. The patients used a headache diary and recorded their migraine-related daily life impairments using the assessment tools HIT-6 and MIDAS for a pre versus post comparison. In addition, continuous glucose data of patients were compared to healthy controls. In both studies, patients reported a reduction of headache and migraine days as well as reductions in HIT-6 and MIDAS scores. More specifically, migraine days decreased by 2.40 days (95% CI [-3.37; -1.42]), HIT-6 improved by 3.17 points (95% CI [-4.63; -1.70]) and MIDAS by 13.45 points (95% CI [-22.01; -4.89]). Glucose data suggest that migraine patients have slightly increased mean glucose values compared to healthy controls, but drop into a glucose range that is below one's individual standard range before a migraine attack. In conclusion, sinCephalea is a non-pharmacological, digital migraine prophylaxis that induces a therapeutic effect within the range of pharmacological interventions.

Prenatal sonographic findings in confirmed cases of Wolf-Hirschhorn syndrome.

BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is a common genetic condition and prenatal diagnosis is difficult due to heterogeneous expression of this syndrome and rather non-specific ultrasound findings. Objective of this study was to examine the prenatal ultrasound findings in fetuses with Wolf-Hirschhorn syndrome (WHS). METHODS: Retrospective assessment of 18 pregnancies that were seen at three tertiary referral centers (Universities of Bonn, Tuebingen and Nuernberg / Germany). Findings of prenatal ultrasound examinations, genetic results and outcome were compared. Additionally, findings of our study were compared to previous small case series from the literature and then compared to data on postnatal frequencies and abnormalities in affected patients. RESULTS: Median gestational age at the time of examination was 23 + 1 weeks' (range: 13 + 4 to 29 + 1 weeks') with female-to-male ratio of > 2.5:1. Most frequent ultrasound findings were facial abnormalities, symmetric IUGR and microcephaly that presented in 94.4, 83.3 and 72.2% of cases, respectively. The combination of microcephaly and hypoplastic nasal bone was a particularly characteristic finding. Growth retardation presented in all fetuses > 20 weeks, but not below. Other frequent abnormalities included cardiac anomalies in 50 and single umbilical artery (SUA) in 44.4% of fetuses. CONCLUSION: WHS should be considered in the presence of symmetric IUGR together with microcephaly, hypoplastic nasal bone and facial abnormalities on prenatal ultrasound. Genetic testing by chromosomal microarray analysis (CMA) is strongly recommended in this context.

PalatinoseTM (Isomaltulose) and Prebiotic Inulin-Type Fructans Have Beneficial Effects on Glycemic Response and Gut Microbiota Composition in Healthy Volunteers-A Real-Life, Retrospective Study of a Cohort That Participated in a Digital Nutrition Program.

It is well-appreciated that the diet is a crucial tool to counteract cardiometabolic disturbances due to its impact on blood glucose concentration and gut microbiome. This retrospective analysis aimed to examine whether the inclusion of isomaltulose and prebiotic inulin-type fructans (ITF) into the habitual diet has an impact on glycemic control and gut microbiota. Furthermore, we examined interindividual differences in glycemic response to sugar replacement with isomaltulose. We retrospectively analyzed data of 117 individuals who participated in a digital nutrition program including a 14-day continuous glucose measurement. Participants underwent six test days with sweetened drinks (isomaltulose vs. sucrose) consumed with their usual breakfasts and lunches. Dinner was supplemented with ITF for 11 days. Postprandial glycemia and 24 h-glycemic variability were determined following test meals and days, respectively. Fecal microbiota was analyzed by 16S rRNA sequencing before and after test phase. Meals with isomaltulose-sweetened drinks compared to meals with sucrose-sweetened drinks induced lower postprandial glycemia. Moreover, glucose oscillations over 24 h were lower on isomaltulose when compared to sucrose test days and improved further during ITF supplementation. Furthermore, ITF modulated gut microbiota composition beneficially. Responder analysis revealed that 72% of participants benefited from the sugar replacement with isomaltulose and that their gut microbiota differed from the low responders. Taken together, the incorporation of isomaltulose and ITF into the habitual diet was shown to be an effective strategy to improve glucose control and beneficially modulate gut microbiota, and thereby aid to maintain metabolic health. Data indicate interindividual differences in glycemic response to ingredients and suggest that gut microbiota might be somehow related to it.

A Digital Health Application Allowing a Personalized Low-Glycemic Nutrition for the Prophylaxis of Migraine: Proof-of-Concept Data from a Retrospective Cohort Study.

BACKGROUND: Migraine is a headache disorder with the highest socioeconomic burden. The aim of this study was to deliver the first proof-of-concept data of the potential role of an individual low-glycemic diet provided by a novel digital health application in the prophylaxis of migraine. METHODS: We analyzed data from a retrospective survey of individuals who participated in a digital nutrition program that provides dietary recommendations based on the individual analysis of continuous glucose measurement from an up to 14-day test phase. A total of 84 individuals completed the retrospective digital survey. The endpoints were changes in the number of migraine days, average duration of attacks, average pain severity, frequency of intake of pain medication, absenteeism, and presenteeism before and after program participation. RESULTS: The intraindividual comparisons of the endpoints before and after program participation revealed decreases in migraine frequency and other patient-relevant migraine parameters. Moreover, patients with a baseline migraine frequency of two and more migraine days per month and adherence to the dietary recommendations (n = 40) showed a mean reduction in migraine days by 33% with a 50%-responder rate of 38%. CONCLUSIONS: The data provides emerging evidence that an individualized low-glycemic diet based on continuous glucose measurement could be a promising approach for a diet-based, non-pharmacological migraine prophylaxis. However, future research is required to confirm the implied effectiveness.

Fungal lysozyme leverages the gut microbiota to curb DSS-induced colitis.

Colitis is characterized by colonic inflammation and impaired gut health. Both features aggravate obesity and insulin resistance. Host defense peptides (HDPs) are key regulators of gut homeostasis and generally malfunctioning in above-mentioned conditions. We aimed here to improve bowel function in diet-induced obesity and chemically induced colitis through daily oral administration of lysozyme, a well-characterized HDP, derived from Acremonium alcalophilum.C57BL6/J mice were fed either low-fat reference diet or HFD ± daily gavage of lysozyme for 12 weeks, followed by metabolic assessment and evaluation of colonic microbiota encroachment. To further evaluate the efficacy of intestinal inflammation, we next supplemented chow-fed BALB/c mice with lysozyme during Dextran Sulfate Sodium (DSS)-induced colitis in either conventional or microbiota-depleted mice. We assessed longitudinal microbiome alterations by 16S amplicon sequencing in both models.Lysozyme dose-dependently alleviated intestinal inflammation in DSS-challenged mice and further protected against HFD-induced microbiota encroachment and fasting hyperinsulinemia. Observed improvements of intestinal health relied on a complex gut flora, with the observation that microbiota depletion abrogated lysozyme's capacity to mitigate DSS-induced colitis.Akkermansia muciniphila associated with impaired gut health in both models, a trajectory that was mitigated by lysozyme administration. In agreement with this notion, PICRUSt2 analysis revealed specific pathways consistently affected by lysozyme administration, independent of vivarium, disease model and mouse strain.Taking together, lysozyme leveraged the gut microbiota to curb DSS-induced inflammation, alleviated HFD-induced gastrointestinal disturbances and lowered fasting insulin levels in obese mice. Collectively, these data present A. alcalophilum-derived lysozyme as a promising candidate to enhance gut health.

[Blended Learning in Critical Care to Improve Quality of Care the ERIC-Training]. / Blended-Learning-Konzepte in der Intensivmedizin am Beispiel des ERIC-Trainings.

Communication and teamwork skills are, besides clinical knowledge, key components of high quality care in modern intensive care units. In light of high staff fluctuations among intensive care unit teams and disparities in clinical experience, an ongoing training is essential to ensure optimal performance in stressfull situations. Further, when implementing new procedures, an adequate concept for staff education is of utmost importance. Blended learning is a novel approach, combining autonomous web-based education and on-site workshops in order to improve the training process. Enhanced Recovery after Intensive Care (ERIC) is a newly developed telemedical intervention targeted at improving evidence-based practice in critical care, guided by quality indicators defined by the German Interdisciplinary Society of Emergency and Critical Care Medicine (DIVI). This telemedical intervention is supplemented with a blended-learning concept combining an e-learning website, simulator-based workshops and on-site training in order to expand the knowledge and practical skills regarding adherence to the quality indicators.

Development and initial evaluation of a novel simulation model for comprehensive brain tumor surgery training.

BACKGROUND: Increasing technico-manual complexity of procedures and time constraints necessitates effective neurosurgical training. For this purpose, both screen- and model-based simulations are under investigation. Approaches including 3D printed brains, gelatin composite models, and virtual environments have already been published. However, quality of brain surgery simulation is limited due to discrepancies in visual and haptic experience. Similarly, virtual training scenarios are still lacking sufficient real-world resemblance. In this study, we introduce a novel simulator for realistic neurosurgical training that combines real brain tissue with 3D printing and augmented reality. METHODS: Based on a human CT scan, a skull base and skullcap were 3D printed and equipped with an artificial dura mater. The cerebral hemispheres of a calf's brain were placed in the convexity of the skullcap and tumor masses composed of aspic, water, and fluorescein were injected in the brain. The skullcap and skull base were placed on each other, glued together, and filled up with an aspic water solution for brain fixation. Then, four surgical scenarios were performed in the operating room as follows: (1) simple tumor resection, (2) complex tumor resection, (3) navigated biopsy via burr hole trepanation, and (4) retrosigmoidal craniotomy. Neuronavigation, augmented reality, fluorescence, and ocular-as well as screen-based (exoscopic)-surgery were available for the simulator training. A total of 29 participants performed at least one training scenario of the simulator and completed a 5-item Likert-like questionnaire as well as qualitative interviews. The questionnaire assessed the realism of the tumor model, skull, and brain tissue as well as the capability for training purposes. RESULTS: Visual and sensory realism of the skull and brain tissue were rated,"very good," while the sensory and visual realism of the tumor model were rated "good." Both overall satisfaction with the model and eligibility of the microscope and neurosurgical instruments for training purposes were rated with "very good." However, small size of the calf's brain, its limited shelf life, and the inability to simulate bleedings due to the lack of perfusion were significant drawbacks. CONCLUSION: The combination of 3D printing and real brain tissue provided surgical scenarios with very good real-life resemblance. This novel neurosurgical model features a versatile setup for surgical skill training and allows for efficient training of technological support like image and fluorescence guidance, exoscopic surgery, and robotic technology.

Monitor-based exoscopic 3D4k neurosurgical interventions: a two-phase prospective-randomized clinical evaluation of a novel hybrid device.

BACKGROUND: Promoting a disruptive innovation in microsurgery, exoscopes promise alleviation of physical strain and improved image quality through digital visualization during microneurosurgical interventions. This study investigates the impact of a novel 3D4k hybrid exoscope (i.e., combining digital and optical visualization) on surgical performance and team workflow in preclinical and clinical neurosurgical settings. METHODS: A pre-clinical workshop setting has been developed to assess usability and implementability through skill-based scenarios (neurosurgical participants n = 12). An intraoperative exploration in head and spine surgery (n = 9) and a randomized clinical study comparing ocular and monitor mode in supratentorial brain tumor cases (n = 20) followed within 12 months. Setup, procedure, case characteristics, surgical performance, and user experience have been analyzed for both ocular group (OG) and monitor group (MG). RESULTS: Brain tumor cases using frontal, frontoparietal, or temporal approaches have been identified as favorable use cases for introducing exoscopic neurosurgery. Mean monitor distance and angle were 180 cm and 10°. Surgical ergonomics when sitting improved significantly in MG compared with OG (P = .03). Hand-eye coordination required familiarization in MG. Preclinical data showed a positive correlation between lateral camera inclination and impact on hand-eye coordination (rs = 0.756, P = .01). There was no significant added surgical time in MG. Image quality in current generation 3D4k monitors has been rated inferior to optic visualization yet awaits updates. CONCLUSIONS: The hybrid exoscopic device can be integrated into established neurosurgical workflows. Currently, exoscopic interventions seem most suited for cranial tumor surgery in lesions that are not deep-seated. Ergonomics improve in monitor mode compared to conventional microsurgery.

Does Telemedical Support of First Responders Improve Guideline Adherence in an Offshore Emergency Scenario? A Simulator-Based Prospective Study.

OBJECTIVE: To investigate, in a simulator-based prospective study, whether telemedical support improves quality of emergency first response (performance) by medical non-professionals to being non-inferior to medical professionals. SETTING: In a simulated offshore wind power plant, duos (teams) of offshore engineers and teams of paramedics conducted the primary survey of a simulated patient. PARTICIPANTS: 38 offshore engineers and 34 paramedics were recruited by the general email invitation. INTERVENTION: Teams (randomised by lot) were supported by transmission technology and a remote emergency physician in Berlin. OUTCOME MEASURES: From video recordings, performance (17 item checklist) and required time (up to 15 min) were quantified by expert rating for analysis. Differences were analysed using two-sided exact Mann-Whitney U tests for independent measures, non-inferiority was analysed using Schuirmann one-sided test. The significance level of 5 % was Holm-Bonferroni adjusted in each family of pairwise comparisons. RESULTS: Nine teams of engineers with, nine without, nine teams of paramedics with and eight without support completed the task. Two experts quantified endpoints, insights into rater dependence were gained. Supported engineers outperformed unsupported engineers (p<0.01), insufficient evidence was found for paramedics (p=0.11). Without support, paramedics outperformed engineers (p<0.01). Supported engineers' performance was non-inferior (at one item margin) to that by unsupported paramedics (p=0.03). Supported groups were slower than unsupported groups (p<0.01). CONCLUSIONS: First response to medical emergencies in offshore wind farms with substantially delayed professional care may be improved by telemedical support. Future work should test our result during additional scenarios and explore interdisciplinary and ecosystem aspects of this support. TRIAL REGISTRATION NUMBER: DRKS00014372.

Short-term high-fat diet feeding protects from the development of experimental allergic asthma in mice.

BACKGROUND: A close association between obesity and asthma has been described. The nature of this association remains elusive, especially with respect to allergic asthma. Controversial findings exist regarding the impact of short-term high-fat diet (HFD) feeding on the development of allergic asthma. OBJECTIVE: To delineate the impact of short-term HFD feeding on the development of experimental allergic asthma. METHODS: Female C57BL/6JRJ mice were fed with a short-term HFD or chow diet (CD) for 12 weeks. Allergic asthma was induced by intraperitoneal OVA/alum sensitization followed by repeated OVA airway challenges. We determined airway hyperresponsiveness (AHR) and pulmonary inflammation by histologic and flow cytometric analysis of immune cells. Furthermore, we assessed the impact of HFD on dendritic cell (DC)-mediated activation of T cells. RESULTS: Female mice showed a mild increase in body weight accompanied by mild metabolic alterations. Upon OVA challenge, CD-fed mice developed strong AHR and airway inflammation, which were markedly reduced in HFD-fed mice. Mucus production was similar in both treatment groups. OVA-induced increases in DC and CD4+ T-cell recruitment to the lungs were significantly attenuated in HFD-fed mice. MHC-II expression and CD40 expression in pulmonary CD11b+ DCs were markedly lower in HFD-fed compared to CD-fed mice, which was associated in vivo with a decreased T helper (Th) 1/17 differentiation and Treg formation without impacting Th2 differentiation. CONCLUSIONS/CLINICAL RELEVANCE: These findings suggest that short-term HFD feeding attenuates the development of AHR, airway inflammation, pulmonary DC recruitment and MHC-II/CD40 expression leading to diminished Th1/17 but unchanged Th2 differentiation. Thus, short-term HFD feeding and associated metabolic alterations may have protective effects in allergic asthma development.

Seasonal Clock Changes Are Underappreciated Health Risks-Also in IBD?

Today, daylight saving time is observed in nearly 80 countries around the world, including the European Union, the USA, Canada, and Russia. The benefits of daylight saving time in energy management have been questioned since it was first introduced during World War I and the latest research has led to varying results. Meanwhile, adverse effects of seasonal time shifts on human biology have been postulated and the European Union is planning to abandon the biannual clock change completely. Medical studies have revealed a correlation of seasonal time shifts with increased incidences of several diseases including stroke, myocardial infarction, and unipolar depressive episodes. Moreover, studies in mice have provided convincing evidence, that circadian rhythm disruption may be involved in the pathogenesis of inflammatory bowel diseases, mainly by disturbing the intestinal barrier integrity. Here, we present previously unpublished data from a large German cohort indicating a correlation of seasonal clock changes and medical leaves due to ulcerative colitis and Crohn's disease. Furthermore, we discuss the health risks of clock changes and the current attempts on reforming daylight saving time from a medical perspective.

[Causes, Diagnostic and Therapeutical Procedures of Malassimilation]. / Ursachen, Diagnostik und Behandlung der Malassimilation.

Patients with malassimilation suffer from disturbed exploitation of available nutrients, which can affect macro- and micronutrients. Malassimilation can be subdivided in maldigestion and malabsorption. Many different disorders, especially gastrointestinal diseases, can lead to malassimilation. The wide variety of differential diagnoses necessitates big diagnostic as well as financial efforts in order to assure good clinical care. This review provides an overview on diagnostic as well as therapeutic processes of patients with malassimilation and gives practical advice for their physicians and therapists.

Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine.

Endogenous circadian clocks regulate 24-h rhythms of physiology and behavior. Circadian rhythm disruption (CRD) is suggested as a risk factor for inflammatory bowel disease. However, the underlying molecular mechanisms remain unknown. Intestinal biopsies from Per1/2 mutant and wild-type (WT) mice were investigated by electron microscopy, immunohistochemistry, and bromodeoxyuridine pulse-chase experiments. TNF-α was injected intraperitoneally, with or without necrostatin-1, into Per1/2 mice or rhythmic and externally desynchronized WT mice to study intestinal epithelial cell death. Experimental chronic colitis was induced by oral administration of dextran sodium sulfate. In vitro, caspase activity was assayed in Per1/2-specific small interfering RNA-transfected cells. Wee1 was overexpressed to study antiapoptosis and the cell cycle. Genetic ablation of circadian clock function or environmental CRD in mice increased susceptibility to severe intestinal inflammation and epithelial dysregulation, accompanied by excessive necroptotic cell death and a reduced number of secretory epithelial cells. Receptor-interacting serine/threonine-protein kinase (RIP)-3-mediated intestinal necroptosis was linked to increased mitotic cell cycle arrest via Per1/2-controlled Wee1, resulting in increased antiapoptosis via cellular inhibitor of apoptosis-2. Together, our data suggest that circadian rhythm stability is pivotal for the maintenance of mucosal barrier function. CRD increases intestinal necroptosis, thus rendering the gut epithelium more susceptible to inflammatory processes.-Pagel, R., Bär, F., Schröder, T., Sünderhauf, A., Künstner, A., Ibrahim, S. M., Autenrieth, S. E., Kalies, K., König, P., Tsang, A. H., Bettenworth, D., Divanovic, S., Lehnert, H., Fellermann, K., Oster, H., Derer, S., Sina, C. Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine.

Monitoring C3aR Expression Using a Floxed tdTomato-C3aR Reporter Knock-in Mouse.

C3a exerts multiple biologic functions through activation of its cognate C3a receptor. C3-/- and C3aR-/- mice have been instrumental in defining important roles of the C3a/C3aR axis in the regulation of acute and chronic inflammatory diseases, including ischemia/reperfusion injury, allergic asthma, autoimmune nephritis, and rheumatoid arthritis. Surprisingly little is known about C3aR expression and function in immune and stromal cells. To close this gap, we generated a floxed tandem-dye Tomato (tdTomato)-C3aR reporter knock-in mouse, which we used to monitor C3aR expression in cells residing in the lung, airways, lamina propria (LP) of the small intestine, brain, visceral adipose tissue, bone marrow (BM), spleen, and the circulation. We found a strong expression of tdTomato-C3aR in the brain, lung, LP, and visceral adipose tissue, whereas it was minor in the spleen, blood, BM, and the airways. Most macrophage and eosinophil populations were tdTomato-C3aR+ Interestingly, most tissue eosinophils and some macrophage populations expressed C3aR intracellularly. BM-derived dendritic cells (DCs), lung-resident cluster of differentiation (CD) 11b+ conventional DCs (cDCs) and monocyte-derived DCs, LP CD103+, and CD11b+ cDCs but not pulmonary CD103+ cDCs and splenic DCs were tdTomato-C3aR+ Surprisingly, neither BM, blood, lung neutrophils, nor mast cells expressed C3aR. Similarly, all lymphoid-derived cells were tdTomato-C3aR-, except some LP-derived type 3 innate lymphoid cells. Pulmonary and LP-derived epithelial cells expressed at best minor levels of C3aR. In summary, we provide novel insights into the expression pattern of C3aR in mice. The floxed C3aR knock-in mouse will help to reliably track and conditionally delete C3aR expression in experimental models of inflammation.

Anti-GP2 IgA autoantibodies are associated with poor survival and cholangiocarcinoma in primary sclerosing cholangitis.

OBJECTIVE: Pancreatic autoantibodies (PABs), comprising antibodies against glycoprotein 2 (anti-GP2), are typically associated with complicated phenotypes in Crohn's disease, but have also been observed with variable frequencies in patients with UC. In a previous study, we observed a high frequency of primary sclerosing cholangitis (PSC) in patients with anti-GP2-positive UC. We therefore aimed to characterise the role of anti-GP2 in PSC. DESIGN: In an evaluation phase, sera from 138 well-characterised Norwegian patients with PSC were compared with healthy controls (n=52), and patients with UC without PSC (n=62) for the presence of PABs by indirect immunofluorescence. Further, 180 German patients with PSC served as a validation cohort together with 56 cases of cholangiocarcinoma without PSC, 20 of secondary sclerosing cholangitis (SSC) and 18 of autoimmune hepatitis. RESULTS: Anti-GP2 IgA specifically occurred at considerable rates in large bile duct diseases (cholangiocarcinoma=36%, PSC and SSC about 50%). In PSC, anti-GP2 IgA consistently identified patients with poor survival during follow-up (Norwegian/German cohort: p Log Rank=0.016/0.018). Anti-GP2 IgA was associated with the development of cholangiocarcinoma in both PSC cohorts, yielding an overall OR of cholangiocarcinoma in patients with anti-GP2 IgA-positive PSC of 5.0 (p=0.001). Importantly, this association remained independent of disease duration, bilirubin level and age. CONCLUSIONS: Anti-GP2 IgA can be hypothesised as a novel marker in large bile duct diseases. In particular, in PSC, anti-GP2 IgA identified a subgroup of patients with severe phenotype and poor survival due to cholangiocarcinoma. Anti-GP2 IgA may therefore be a clinically valuable tool for risk stratification in PSC.