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

Seroprevalence of Schmallenberg virus infection in sheep and goats flocks in Germany, 2012-2013

Schmallenberg virus (SBV) is a member of the family Bunyaviridae and mainly affects ruminants. It is transmitted by biting midges, first and foremost Culicoides spp., and causes congenital malformations reflected in arthrogryposis-hydranencephaly (AH) syndrome. The aim of this study was to collect data on the emergence of SBV as a new arthropod-borne disease introduced into Europe in 2011. Germany was located in the core region of the 2011/2012 epidemic. Following two seroprevalence studies in the north-west of Germany in 2012, this study focused on the epidemiology and distribution of SBV throughout 130 small ruminant flocks in the whole country. Blood samples were obtained of 30 animals per flock and a SBV-specific questionnaire was used to collect operating data of the farms. The median within-herd seroprevalence for all 130 flocks tested was 53.3% with a total range from 0% to 100%. The median within-herd seroprevalence for goats was 30% [interquartile range (IQR): 40.3%] and 57% for sheep (IQR: 43.3%). Small ruminant flocks kept permanently indoors or housed overnight had a significantly lower seroprevalence than flocks kept permanently outdoors. In addition, this study revealed a significantly lower seroprevalence in the north-east of Germany. These results show that small ruminants in Germany are still at risk of contracting new SBV infections following incomplete seroconversion of flocks especially in the north-east of Germany. This might contribute to SBV becoming enzootic in central and northern Europe. Furthermore, the survey revealed that housing animals at least during mating and early pregnancy may reduce the risk of new SBV infections and may thus be an option to reduce losses as long as there is no licensed vaccine available on the German market

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

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

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

β3-integrin Leu33Pro gain of function variant does not modulate inflammatory activity in human derived macrophages in diabetes

Objective: We aimed to investigate the association between the Leu33Pro (rs5918) polymorphism in 83-integrin with diabetic complications and inflammatory function of macrophages depending on the genotype in subjects with diabetes mellitus. Material and methods: We determined the Leu33Pro polymorphism in 186 diabetic subjects and collected laboratory data. Monocytes from 24 patients were collected for macrophage differentiation to determine the inflammatory activity by treating with different stimulants. Results: We could demonstrate that human derived differentiated macrophages expressed 83-integrin. Their secretory capacity upon inflammatory stimulation did not reveal any differences depending on the Leu33Pro variant. We found trends for an association of the polymorphism with the presence of diabetic nephropathy (p = 0.071), as well as with creatinine [1.32 mg/dL (1) vs. 0.98 mg/dL (0)] (p = 0.029 in recessive model) and glomerular filtration rate [75.6 ml/min +/- 22 vs. 62.3 ml/min +/- 25] (p = 0.076 in recessive model) as quantitative markers of kidney function. Conclusion: Despite the expression of 83-integrin in human macrophages, the Leu33Pro polymorphism in 83-integrin does not modify the inflammatory response upon stimulation but might play a role in the progression of diabetic nephropathy. Further studies are necessary to substantiate such a hypothesis

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

The use of non-invasive continuous blood pressure measuring (ClearSight^®) during central neuraxial anaesthesia for caesarean section — a retrospective validation study

Background: The close monitoring of blood pressure during a caesarean section performed under central neuraxial anaesthesia should be the standard of safe anaesthesia. As classical oscillometric and invasive blood pressure measuring have intrinsic disadvantages, we investigated a novel, non-invasive technique for continuous blood pressure measuring. Methods: In this monocentric, retrospective data analysis, the reliability of continuous non-invasive blood pressure measuring using ClearSight^® (Edwards Lifesciences Corporation) is validated in 31 women undergoing central neuraxial anaesthesia for caesarean section. In addition, patients and professionals evaluated ClearSight^® through questioning. Results: 139 measurements from 11 patients were included in the final analysis. Employing Bland–Altman analyses, we identified a bias of −10.8 mmHg for systolic, of −0.45 mmHg for diastolic and of +0.68 mmHg for mean arterial blood pressure measurements. Pooling all paired measurements resulted in a Pearson correlation coefficient of 0.7 for systolic, of 0.67 for diastolic and of 0.75 for mean arterial blood pressure. Compensating the interindividual differences in linear regressions of the paired measurements provided improved correlation coefficients of 0.73 for systolic, of 0.9 for diastolic and of 0.89 for mean arterial blood pressure measurements. Discussion: Diastolic and mean arterial blood pressure are within an acceptable range of deviation from the reference method, according to the Association for the Advancement of Medical Instrumentation (AAMI) in the patient collective under study. Both patients and professionals prefer ClearSight^® to oscillometric blood pressure measurement in regard of comfort and handling

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