ZED1227 – vielversprechende medikamentöse Therapie der Zöliakie?

Zöliakie ist eine T‑Zell-vermittelte Autoimmunerkrankung des Dünndarms, welche 0,2–2 % der Bevölkerung betrifft [1,2,3]. Ausgelöst wird die Erkrankung durch die Einnahme von Gluten im Getreide und verwandten Getreidesorten bei prädisponierten Patienten mit einem HLA-DQ2- und HLA-DQ8-Genotyp. Autoantikörper gegen die Gewebstransglutaminase 2 sind entscheidend an der Pathophysiologie der Erkrankung beteiligt. Typische Symptome der Zöliakie sind Diarrhoe, Gewichtsverlust und Malnutrition, es können jedoch auch atypische oder unspezifische Beschwerden, wie z. B. Müdigkeit, Anämie, Osteoporose, auftreten. Die Erkrankung kann mit anderen Autoimmunerkrankungen wie dem Typ-1-Diabetes assoziiert sein [4,5,6,7,8]. Diagnostisch werden insbesondere Serum-Antikörper gegen die Transglutaminase 2 bestimmt; die Bestätigung der Erkrankung erfolgt durch den histologischen Nachweis einer Zottenatrophie und Kryptenhyperplasie. Charakteristisch ist auch eine intraepitheliale Lymphozyteninfiltration im Duodenum

A Dataset of Anatomical Environments for Medical Robots: Modeling Respiratory Deformation

Anatomical models of a medical robot's environment can significantly help guide design and development of a new robotic system. These models can be used for benchmarking motion planning algorithms, evaluating controllers, optimizing mechanical design choices, simulating procedures, and even as resources for data generation. Currently, the time-consuming task of generating these environments is repeatedly performed by individual research groups and rarely shared broadly. This not only leads to redundant efforts, but also makes it challenging to compare systems and algorithms accurately. In this work, we present a collection of clinically-relevant anatomical environments for medical robots operating in the lungs. Since anatomical deformation is a fundamental challenge for medical robots operating in the lungs, we describe a way to model respiratory deformation in these environments using patient-derived data. We share the environments and deformation data publicly by adding them to the Medical Robotics Anatomical Dataset (Med-RAD), our public dataset of anatomical environments for medical robots

Quantifying and addressing the impact of measurement error in network models

Network psychometric models are often estimated using a single indicator for each node in the network, thus failing to consider potential measurement error. In this study, we investigate the impact of measurement error on cross-sectional network models. First, we conduct a simulation study to evaluate the performance of models based on single indicators as well as models that utilize information from multiple indicators per node, including average scores, factor scores, and latent variables. Our results demonstrate that measurement error impairs the reliability and performance of network models, especially when using single indicators. The reliability and performance of network models improves substantially with increasing sample size and when using methods that combine information from multiple indicators per node. Second, we use empirical data from the STAR*D trial (n = 3,731) to further evaluate the impact of measurement error. In the STAR*D trial, depression symptoms were assessed via three questionnaires, providing multiple indicators per symptom. Consistent with our simulation results, we find that when using sub-samples of this dataset, the discrepancy between the three single-indicator networks (one network per questionnaire) diminishes with increasing sample size. Together, our simulated and empirical findings provide evidence that measurement error can hinder network estimation when working with smaller samples and offers guidance on methods to mitigate measurement error.Stress and Psychopatholog

Autonomous Medical Needle Steering In Vivo

The use of needles to access sites within organs is fundamental to many interventional medical procedures both for diagnosis and treatment. Safe and accurate navigation of a needle through living tissue to an intra-tissue target is currently often challenging or infeasible due to the presence of anatomical obstacles in the tissue, high levels of uncertainty, and natural tissue motion (e.g., due to breathing). Medical robots capable of automating needle-based procedures in vivo have the potential to overcome these challenges and enable an enhanced level of patient care and safety. In this paper, we show the first medical robot that autonomously navigates a needle inside living tissue around anatomical obstacles to an intra-tissue target. Our system leverages an aiming device and a laser-patterned highly flexible steerable needle, a type of needle capable of maneuvering along curvilinear trajectories to avoid obstacles. The autonomous robot accounts for anatomical obstacles and uncertainty in living tissue/needle interaction with replanning and control and accounts for respiratory motion by defining safe insertion time windows during the breathing cycle. We apply the system to lung biopsy, which is critical in the diagnosis of lung cancer, the leading cause of cancer-related death in the United States. We demonstrate successful performance of our system in multiple in vivo porcine studies and also demonstrate that our approach leveraging autonomous needle steering outperforms a standard manual clinical technique for lung nodule access.Comment: 22 pages, 6 figure

Propofol Inhibits Glioma Stem Cell Growth and Migration and Their Interaction with Microglia via BDNF-AS and Extracellular Vesicles

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. GBM contains a small subpopulation of glioma stem cells (GSCs) that are implicated in treatment resistance, tumor infiltration, and recurrence, and are thereby considered important therapeutic targets. Recent clinical studies have suggested that the choice of general anesthetic (GA), particularly propofol, during tumor resection, affects subsequent tumor response to treatments and patient prognosis. In this study, we investigated the molecular mechanisms underlying propofol\u27s anti-tumor effects on GSCs and their interaction with microglia cells. Propofol exerted a dose-dependent inhibitory effect on the self-renewal, expression of mesenchymal markers, and migration of GSCs and sensitized them to both temozolomide (TMZ) and radiation. At higher concentrations, propofol induced a large degree of cell death, as demonstrated using microfluid chip technology. Propofol increased the expression of the lncRNA BDNF-AS, which acts as a tumor suppressor in GBM, and silencing of this lncRNA partially abrogated propofol\u27s effects. Propofol also inhibited the pro-tumorigenic GSC-microglia crosstalk via extracellular vesicles (EVs) and delivery of BDNF-AS. In conclusion, propofol exerted anti-tumor effects on GSCs, sensitized these cells to radiation and TMZ, and inhibited their pro-tumorigenic interactions with microglia via transfer of BDNF-AS by EVs

Endoplasmic Reticulum Stress Is Reduced in Tissues of Obese Subjects After Weight Loss

OBJECTIVE—Obesity is associated with insulin resistance and type 2 diabetes, although the mechanisms linking these pathologies remain undetermined. Recent studies in rodent models revealed endoplasmic reticulum (ER) stress in adipose and liver tissues and demonstrated that ER stress could cause insulin resistance. Therefore, we tested whether these stress pathways were also present in obese human subjects and/or regulated by weight loss

Oncostatin m is produced in adipose tissue and is regulated in conditions of obesity and type 2 diabetes

CONTEXT: Adipose tissue is a highly active endocrine organ that secretes many factors that affect other tissues and whole-body metabolism. Adipocytes are responsive to several glycoprotein 130 (gp130) cytokines, some of which have been targeted as potential antiobesity therapeutics. OBJECTIVE: Oncostatin M (OSM) is a gp130 family member known to inhibit adipocyte differentiation in vitro, but its effects on other adipocyte properties are not characterized. The expression of OSM in white adipose tissue (WAT) has not been evaluated in the context of obesity. Thus, our objective was to examine the expression of adipose tissue OSM in obese animals and humans. DESIGN: OSM expression was examined in adipose tissues from mice with diet-induced and genetic obesity and in obese humans as well as in fractionated adipose tissue from mice. Murine adipocytes were used to examine OSM receptor expression and the effects of OSM on adipocytes, including the secretion of factors such as plasminogen activator inhibitor 1 and IL-6, which are implicated in metabolic diseases. RESULTS: OSM expression is increased in rodent and human obesity/type 2 diabetes mellitus. In humans, OSM levels correlate with body weight and insulin and are inversely correlated with glucose disposal rate as measured by hyperinsulinemic-euglycemic clamp. OSM is not produced from the adipocytes in WAT but derives from cells in the stromovascular fraction, including F4/80(+) macrophages. The specific receptor of OSM, OSM receptor-β, is expressed in adipocytes and adipose tissue and increased in both rodent models of obesity examined. OSM acts on adipocytes to induce the expression and secretion of plasminogen activator inhibitor 1 and IL-6. CONCLUSIONS: These data indicate that WAT macrophages are a source of OSM and that OSM levels are significantly induced in murine and human obesity/type 2 diabetes mellitus. These studies suggest that OSM produced from immune cells in WAT acts in a paracrine manner on adipocytes to promote a proinflammatory phenotype in adipose tissue

Hypertension and low HDL cholesterol were associated with reduced kidney function across the age spectrum: a collaborative study

Purpose: To determine if the associations among established risk factors and reduced kidney function vary by age. Methods: We pooled cross-sectional data from 14,788 nondiabetics aged 40 to 100 years in 4 studies: Cardiovascular Health Study, Health, Aging, and Body Composition Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-Stage Disease cohort. Results: Hypertension and low high-density lipoprotein (HDL) cholesterol were associated with reduced cystatin C-based estimated glomerular filtration rate (eGFR) across the age spectrum. In adjusted analyses, hypertension was associated with a 23 (95% confidence interval [CI], 0.1, 4.4), 5.1 (95% Cl, 4.1, 6.1), and 6.9 (95% CI, 3.0, 10.4) mL/min/1.73 m(2) lower eGFR in participants 40 to 59, 60 to 79, and at least 80 years, respectively (P for interaction < .001). The association of low HDL cholesterol with reduced kidney function was also greater in the older age groups: 4.9 (95% CI, 3.5, 6.3), 7.1 (95% CI, 6.0, 83), 8.9 (95% CI, 5.4,11.9) mL/min/1.73 m(2) (P for interaction < .001). Smoking and obesity were associated with reduced kidney function in participants under 80 years. All estimates of the potential population impact of the risk factors were modest. Conclusions: Hypertension, obesity, smoking, and low HDL cholesterol are modestly associated with reduced kidney function in nondiabetics. The associations of hypertension and HDL cholesterol with reduced kidney function seem to be stronger in older adults. (C) 2013 Elsevier Inc. All rights reserved.Keywords: Serum cystatin C, Urinary albumin excretion, Cardiovascular disease, Renal dysfunction, Population risk, Predictors, Atherosclerosis, Blood pressure, Coronary heart diseas

Treatment of irritable bowel syndrome with diarrhoea using titrated ondansetron (TRITON): study protocol for a randomised controlled trial

Background: Irritable bowel syndrome with diarrhoea (IBS-D) affects up to 4% of the general population. Symptoms include frequent, loose, or watery stools with associated urgency, resulting in marked reduction of quality of life and loss of work productivity. Ondansetron, a 5HT3 receptor antagonist, has had an excellent safety record for over 20 years as an antiemetic, yet is not widely used in the treatment of IBS-D. It has, however, been shown to slow colonic transit and in a small randomised, placebo-controlled, cross-over pilot study, benefited patients with IBS-D. Methods: This trial is a phase III, parallel group, randomised, double-blind, multi-centre, placebo-controlled trial, with embedded mechanistic studies. Participants (n = 400) meeting Rome IV criteria for IBS-D will be recruited from outpatient and primary care clinics and by social media to receive either ondansetron (dose titrated up to 24 mg daily) or placebo for 12 weeks. Throughout the trial, participants will record their worst abdominal pain, worst urgency, stool frequency, and stool consistency on a daily basis. The primary endpoint is the proportion of “responders” in each group, using Food and Drug Administration (FDA) recommendations. Secondary endpoints include pain intensity, stool consistency, frequency, and urgency. Mood and quality of life will also be assessed. Mechanistic assessments will include whole gut transit, faecal tryptase and faecal bile acid concentrations at baseline and between weeks 8 and 11. A subgroup of participants will also undergo assessment of sensitivity (n = 80) using the barostat, and/or high-resolution colonic manometry (n = 40) to assess motor patterns in the left colon and the impact of ondansetron. Discussion: The TRITON trial aims to assess the effect of ondansetron across multiple centres. By defining ondansetron’s mechanisms of action we hope to better identify patients with IBS-D who are likely to respond