Die Rolle von Integrin β 3 bei Diabetes Mellitus und seinen Folgeerkrankungen

Diese Arbeit befasst sich mit den Auswirkungen des Leu33Pro Polymorphismus (RS 5918) des Integrin β 3 Gens auf die inflammatorische Aktivität von humanen Makrophagen im Zusammenhang mit dem Auftreten von Folgeerkrankungen bei Diabetes Mellitus. Integrin β 3 ist ein heterodimeres Membranprotein. Neben mechanischen Funktionen der Zelladhäsion werden Funktionen in der Signalübermittlung zwischen den Zellen vermittelt. Es hat Einfluss auf die Proteinbiosynthese, Genexpression und auch auf die Differenzierung von Zellen. Der untersuchte Polymorphismus resultiert in einer konstitutionellen Aktivierung des Integrin β 3. In diversen Studien kann gezeigt werden, dass Diabetiker eine erhöhte Prävalenz des untersuchten Polymorphismus im Vergleich zur Normalbevölkerung haben. Zudem haben Diabetiker ebenfalls ein erhöhtes Risiko für arteriosklerotische Veränderungen, die eine Folgeerkrankung des Diabetes darstellen. Deshalb wird in dieser Studie ein möglicher Zusammenhang zwischen dem Polymorphismus und den diabetischen Folgeerkrankungen untersucht. Es wurden 186 an Diabetes Mellitus erkrankte Patienten auf diesen Polymorphismus untersucht. Von diesen Patienten wurden verschiedene Laborparameter sowie anthropometrische Daten gesammelt, um einen Zusammenhang zwischen klinisch-laborchemischen Parametern und der Präsenz dieses Polymorphismus zu untersuchen. Des Weiteren wurden periphere Blutmonozyten von insgesamt 21 Patienten isoliert und in vitro zu Makrophagen differenziert. Ziel dieser Experimente war die Untersuchung der inflammatorischen Aktivität der Makrophagen in Abhängigkeit des RS 5918 Polymorphismus im Integrin β 3 Gen, da Inflammation eine wichtige pathophysiologische Rolle bei diabetischen Folgeerkrankungen spielt. Der Polymorphismus hatte in der untersuchten Kohorte eine homozygote Häufigkeit von 3,23 % und eine heterozygote Häufigkeit von 26,34 %. Daraus resultierte, dass fast 30 % der Untersuchten mindestens haploinsuffizient für den RS 5918 Polymorphismus im Integrin β 3 Gen waren. Aus den laborchemischen und anthropometrischen Daten war ein trendhafter Zusammenhang zwischen dem Vorhandensein des Polymorphismus und der Erkrankungshäufigkeit der diabetischen Nephropathie erkennbar. Zudem korreliert der untersuchte Polymorphismus mit statistisch signifikant niedrigeren γ-GT Werten. Ein statistisch signifikanter Zusammenhang des Polymorphismus mit den weiteren untersuchten Folgeerkrankungen konnte nicht gezeigt werden. Zusätzlich konnte keinmolekularbiologisch bedeutsamer Einfluss des untersuchten Polymorphismus auf die hier gemessenen Parameter der inflammatorischen Aktivität von Makrophagen gezeigt werden. Zusammenfassend kann festgestellt werden, dass es zum Teil trendhafte Effekte des untersuchten Polymorphismus auf die inflammatorische Aktivität humaner Makrophagen gibt. Ferner gibt es einen möglichen Zusammenhang mit Folgeerkrankungen des Diabetes Mellitus. Dies bedarf aber weiterer wissenschaftlicher Prüfungen.The role of integrin β 3 in diabetes mellitus and its secondary diseases This thesis deals with the effects of the Leu33Pro polymorphism (RS 5918) of the integrin β 3 gene on the inflammatory activity of human macrophages in connection with the occurrence of secondary diseases in diabetes mellitus. Integrin β 3 is a heterodimeric membrane protein that, in addition to mechanical functions of cell adhesion, also mediates important functions in signal transduction between cells. It has an influence on protein biosynthesis, gene expression and also on the differentiation of cells. The investigated polymorphism results in a constitutional activation of integrin β 3. In various studies it can be shown that diabetics have an increased prevalence of the investigated polymorphism compared to the normal population. In addition, diabetics also have an increased risk of arteriosclerotic changes, which are a secondary disease of diabetes. Therefore, this study investigates a possible correlation between the polymorphism and diabetic secondary diseases. 186 patients suffering from diabetes mellitus were examined for this polymorphism. From these patients, various laboratory parameters, as well as anthropometric data were collected to investigate a relationship between clinical laboratory chemical parameters and the presence of this polymorphism. Furthermore, peripheral blood monocytes from a total of 21 patients were isolated and differentiated in vitro to macrophages. The aim of these experiments was to investigate the inflammatory activity of macrophages, since inflammation plays an important pathophysiological role in diabetic secondary diseases. The polymorphism had a homozygous frequency of 3.23% and a heterozygous frequency of 26.34% in the examined cohort. As a result, almost 30% of the examined cohort were at least haploinsufficient for the integrin β 3 gene. From the laboratory chemical and anthropometric data, a trendy correlation between the presence of the polymorphism and the incidence of diabetic nephropathy can be seen. In addition, the polymorphism investigated results in statistically significant lower γ-GT values. A statistical correlation of the polymorphism with the other secondary diseases investigated cannot be shown. In addition, no molecular-biologically significant influence of the polymorphism under investigation on the parameters of inflammatory activity of macrophages measured here could be shown. In summary, it can be stated that there are partially trend-like effects of the investigated polymorphism on the inflammatory activity of human macrophages. Furthermore, there is a possible connection with secondary diseases of diabetes mellitus. This requires further scientific research

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Investigating hydraulic loads on a crossbar block ramp using two different computational fluid dynamics models and a physical validation model

Crossbar block ramps provide bed stability and facilitate ecological connectivity in rivers. Two major sources of uncertainty in determining their design loads are their massively turbulent flow and backwater influence. Here, they were addressed using two computational fluid dynamics (CFD) models (created with OpenFOAM) of a complete crossbar block ramp by recording loads (forces and moments) on single crossbars. To model turbulence, the first model used the Reynolds-averaged Navier-Stokes (RANS) approach, and the second model used Large Eddy Simulation (LES). The flow in both models was transient and the free surface was tracked. Their mesh was identical and consisted of about 30.3 million cells distributed on 480 processor cores. The computed sampling interval was 180 s. The CFD models were tested against measurements of water level and pressure from a physical model. All models were in the same scale, 1: 20/3. Three discharges representing three typical flow regimes were studied in each model. Characteristics of the flow regimes were reproduced in all models. The RANS model was up to 5.3 times faster, but produced excessive waves, which likely caused over- and underestimation of crossbar loads. The LES model showed good agreement to the physical model and could be used for load predictions. However, a longer sampling interval as well as a larger variety of discharges would be required to obtain stochastically reliable estimations for the maximum loads. Both models indicated that unsteady waves in the wake-interference flow regime must be considered to find critical loads. The results can support decisions on the methods for future investigations of hydraulic loads on crossbar block ramps

Do small incisions need only minimal anesthesia? — anesthetic management in laparoscopic and robotic surgery

Laparoscopic techniques have established themselves as a major part of modern surgery. Their implementation in every surgical discipline has played a vital part in the reduction of perioperative morbidity and mortality. Precise robotic surgery, as an evolution of this, is shaping the present and future operating theatre that an anesthetist is facing. While incisions get smaller and the impact on the organism seems to dwindle, challenges for anesthetists do not lessen and could even become more demanding than in open procedures. This review focuses on the pathophysiological effects of contemporary laparoscopic and robotic procedures and summarizes anesthetic challenges and strategies for perioperative management

Accuracy and Systematic Biases of Heart Rate Measurements by Consumer-Grade Fitness Trackers in Postoperative Patients: Prospective Clinical Trial

Background: Over the recent years, technological advances of wrist-worn fitness trackers heralded a new era in the continuous monitoring of vital signs. So far, these devices have primarily been used for sports. Objective: However, for using these technologies in health care, further validations of the measurement accuracy in hospitalized patients are essential but lacking to date. Methods: We conducted a prospective validation study with 201 patients after moderate to major surgery in a controlled setting to benchmark the accuracy of heart rate measurements in 4 consumer-grade fitness trackers (Apple Watch 7, Garmin Fenix 6 Pro, Withings ScanWatch, and Fitbit Sense) against the clinical gold standard (electrocardiography). Results: All devices exhibited high correlation (r≥0.95; P<.001) and concordance (rc≥0.94) coefficients, with a relative error as low as mean absolute percentage error <5% based on 1630 valid measurements. We identified confounders significantly biasing the measurement accuracy, although not at clinically relevant levels (mean absolute error<5 beats per minute). Conclusions: Consumer-grade fitness trackers appear promising in hospitalized patients for monitoring heart rate

Avoidable blood loss in critical care and patient blood management: scoping review of diagnostic blood loss

Background: Anemia remains one of the most common comorbidities in intensive care patients worldwide. The cause of anemia is often multifactorial and triggered by underlying disease, comorbidities, and iatrogenic factors, such as diagnostic phlebotomies. As anemia is associated with a worse outcome, especially in intensive care patients, unnecessary iatrogenic blood loss must be avoided. Therefore, this scoping review addresses the amount of blood loss during routine phlebotomies in adult (>17 years) intensive care patients and whether there are factors that need to be improved in terms of patient blood management (PBM). Methods: A systematic search of the Medline Database via PubMed was conducted according to PRISMA guidelines. The reported daily blood volume for diagnostics and other relevant information from eligible studies were charted. Results: A total of 2167 studies were identified in our search, of which 38 studies met the inclusion criteria (9 interventional studies and 29 observational studies). The majority of the studies were conducted in the US (37%) and Canada (13%). An increasing interest to reduce iatrogenic blood loss has been observed since 2015. Phlebotomized blood volume per patient per day was up to 377 mL. All interventional trials showed that the use of pediatric-sized blood collection tubes can significantly reduce the daily amount of blood drawn. Conclusion: Iatrogenic blood loss for diagnostic purposes contributes significantly to the development and exacerbation of hospital-acquired anemia. Therefore, a comprehensive PBM in intensive care is urgently needed to reduce avoidable blood loss, including blood-sparing techniques, regular advanced training, and small-volume blood collection tubes

Distinct binding specificity of the multiple PDZ domains of INADL, a human protein with homology to INAD from Drosophila melanogaster

PDZ domains are protein-protein interaction modules that typically bind to short peptide sequences at the carboxyl terminus of target proteins. Proteins containing multiple PDZ domains often bind to different trans-membrane and intracellular proteins, playing a central role as organizers of multimeric complexes. To characterize the rules underlying the binding specificity of different PDZ domains, we have assembled a novel repertoire of random peptides that are displayed at high density at the carboxyl terminus of the capsid D protein of bacteriophage lambda. We have exploited this combinatorial library to determine the peptide binding preference of the seven PDZ domains of human INADL, a multi-PDZ protein that is homologous to the INAD protein of Drosophila melanogaster. This approach has permitted the determination of the consensus ligand for each PDZ domain and the assignment to class I, class II, and to a new specificity class, class IV, characterized by the presence of an acidic residue at the carboxyl-terminal position. Homology modeling and site-directed mutagenesis experiments confirmed the involvement of specific residues at contact positions in determining the domain binding preference. However, these experiments failed to reveal simple rules that would permit the association of the chemical characteristics of any given residue in the peptide binding pocket to the preference for specific amino acid sequences in the ligand peptide. Rather, they suggested that to infer the binding preference of any PDZ domain, it is necessary to simultaneously take into account all contact positions by using computational procedures. For this purpose we extended the SPOT algorithm, originally developed for SH3 domains, to evaluate the probability that any peptide would bind to any given PDZ domain

In-line filtration of intravenous infusion may reduce organ dysfunction of adult critical patients

Background: The potential harmful effects of particle-contaminated infusions for critically ill adult patients are yet unclear. So far, only significant improved outcome in critically ill children and new-borns was demonstrated when using in-line filters, but for adult patients, evidence is still missing. Methods: This single-centre, retrospective controlled cohort study assessed the effect of in-line filtration of intravenous fluids with finer 0.2 or 1.2 μm vs 5.0 μm filters in critically ill adult patients. From a total of n = 3215 adult patients, n = 3012 patients were selected by propensity score matching (adjusting for sex, age, and surgery group) and assigned to either a fine filter cohort (with 0.2/1.2 μm filters, n = 1506, time period from February 2013 to January 2014) or a control filter cohort (with 5.0 μm filters, n = 1506, time period from April 2014 to March 2015). The cohorts were compared regarding the occurrence of severe vasoplegia, organ dysfunctions (lung, kidney, and brain), inflammation, in-hospital complications (myocardial infarction, ischemic stroke, pneumonia, and sepsis), in-hospital mortality, and length of ICU and hospital stay. Results: Comparing fine filter vs control filter cohort, respiratory dysfunction (Horowitz index 206 (119–290) vs 191 (104.75–280); P = 0.04), pneumonia (11.4% vs 14.4%; P = 0.02), sepsis (9.6% vs 12.2%; P = 0.03), interleukin-6 (471.5 (258.8–1062.8) ng/l vs 540.5 (284.5–1147.5) ng/l; P = 0.01), and length of ICU (1.2 (0.6–4.9) vs 1.7 (0.8–6.9) days; P  0.20) and acute kidney injury (11.8% vs 13.7%; P = 0.11) was not significantly different between the cohorts. Conclusions: In-line filtration with finer 0.2 and 1.2 μm filters may be associated with less organ dysfunction and less inflammation in critically ill adult patients. Trial registration: The study was registered at ClinicalTrials.gov (number: NCT02281604)