Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, P-inter= 2.6 x 10(-8)). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDAR-ADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10(-8)), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10(-8)), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10(-4)). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.Peer reviewe

Entwicklung von Life-on-a-Chip Systemen zur Charakterisierung und Manipulation dynamischer Effekte adhärenter Zellen

Im Bereich biomedizinischer Anwendungen hinsichtlich regenerativem Gewebewachstum sowie optimierter medizinischer Implantate ist das Verständnis der Zelladhäsion, -migration und -proliferation von großer Bedeutung. Wird ein Fremdkörper ins Gewebe eingebracht, so wird dieser zunächst von Zellen besiedelt. Ob diese darauf anhaften können, liegt im Adhäsionsvermögen der Zellen und den Wechselwirkungen zwischen Zelle und Substrat. Anschließend erfolgt die Migration in Kombination mit der Proliferation, bei der das Implantat oder künstliche Gewebe mit dem umliegenden Gewebe verwächst. Die vorliegende Arbeit beschäftigt sich mit der Adhäsion sowie der beschleunigten und gerichteten Migration von Zellen und betrachtet dabei die drei elementaren Herausforderungen • Zelladhäsion auf medizinischen Implantaten unter statischen und dynamischen Bedingungen • Manipulation der Zellmigration durch akustische Oberflächenwellen mit dem Ziel beschleunigter Wundheilung • Gerichtetes Wachstum von Zellen auf strukturierten Oberflächen Zur Charakterisierung der Adhäsion von Zellen auf Implantaten dient ein auf dem Effekt akustischer Strömung basierendes Lab-on-a-Chip System, bei dem physiologische Bedingungen wie pH-Wert und Temperatur, sowie das Implantatmaterial beliebig variiert werden können. Somit lassen sich zum einen Infektionen bei der Einheilung des Implantats simulieren als auch verschiedene Substrate testen. Durch Analyse des Effekts der einwirkenden Scherkräfte auf die zeitliche Ablöserate lässt sich weiterhin das individuelle Adhäsionsvermögen der Zellen auf dem Substrat bestimmen. Es zeigt sich, dass die maximale Adhäsion unter statischen Bedingungen bei 37 °C und einem pH-Wert von 7,4 sowie einer Oberflächenrauigkeit von Rq = 3,76 μm auf Titanimplantaten vorliegt. Unter dynamischen, sprich Flussbedingungen findet eine stärkere Ablösung der Zellen bei hohen Temperaturen und niedrigeren pH-Werten statt. Bei Scherraten von bis zu ca. 7000 s -1 zeigt sich ein exponentieller Abfall der mit Zellen belegten Fläche. Im zweiten Teil der Arbeit wird eine neue Technik zur dynamischen Stimulation der Zellmigration vorgestellt, welche die Wundheilung in einem Life-on-a-Chip System beschleunigt. Neben der erstmaligen phänomenologischen Charakterisierung des Effekts, wurde gezeigt, dass sowohl die direkte Einwirkung des mechanischen, sowie elektrischen Anteils der akustischen Oberflächenwellen zur künstlichen Wundheilung beitragen. In Voruntersuchungen wurde das Potential gezeigt, dieses Prinzip zukünftig auf flexible Materialien zu übertragen. Diese stellen somit den Grundstein für neuartige aktive Implantate zur beschleunigten Regeneration von beschädigtem Gewebe dar. Der letzte Teil der Arbeit widmet sich der Herstellung strukturierter Oberflächen für gerichtetes Zellwachstum. Hierbei wird das Potential hydrophiler Strukturen auf hydrophobem Untergrund sowie ferroelektrisch polarisierten Domänen untersucht, um Zellen entlang eines vorgegebenen Pfades zu führen. Die Oberflächen sind dabei weder topographisch geprägt, noch werden die Zellen chemotaktisch oder durotaktisch gelenkt. Dabei zeigte sich, dass die Zellen entlang der hydrophilen Struktur wandern, während hydrophobe Bereiche gemieden werden. Die positive ferroelektrische Strukturierung konnte durch verschiedene Methoden nachgewiesen werden. Weiterhin konnte durch selektives Ätzen der Domänen 80 nm tiefe Bereiche hergestellt werden, welche sich als Nanokanäle bzw. Nanobarrieren eignen. Diese Techniken können zur gezielten Strukturierung von Implantaten weiterentwickelt werden. Die in dieser Arbeit entwickelten Systeme konnten erfolgreich zur Charakterisierung sowie aktiven Manipulation der Zelladhäsion und -migration verwendet werden. Sie liefern somit einen entscheidenden Beitrag zur Forschung und Entwicklung von Implantaten und biomedizinischen Anwendungen zur gezielten und beschleunigten Regeneration von Gewebe.The understanding of cell adhesion, migration and proliferation is of great importance in the field of biomedical applications, regenerative tissue growth and optimizing medical implants. When implementing a foreign subject into living tissue, it is first colonized by cells. Whether those cells are able to stick onto the substrate depends on the adhesiveness of the cells as well as the interactions between cell and substrate. Afterwards, the migration in combination with the proliferation sets in, which combines the implant or artificial tissue with the surrounding tissue. This thesis examines the adhesion, as well as the advanced and directed migration of cells, and considers the three fundamental challenges • Cell adhesion on medical implants under static and dynamic conditions • Manipulation of cell migration applying acoustic surface waves towards the aim of enhanced wound healing • Cell guidance on structured surfaces A lab-on-a-chip system based on the effect of acoustic flow is used to characterize the adhesion of cells on medical implants in which physiological conditions such as pH and temperature as well as the implant material can be varied as desired. Thus, infections during the healing of the implant can be simulated and various substrates can be investigated. By analyzing the effect of the applied shear forces on the time dependent detachment rates, the individual adhesive strength of the cells on the substrate can be determined. The maximum adhesion under static conditions is found at 37 °C and a pH of 7.4 as well as a surface roughness of Rq = 3.76 μm on titanium implants. Underdynamic, i.e. flowconditions, thecells are more strongly detached at high temperatures and lower pH values. At shear rates of up to approx. 7000 s -1, an exponential decay of the area occupied by cells is shown. The second part of this thesis introduces a new ultrasound-like technique for the dynamic stimulation of cell migration, which accelerates wound healing in a life-on-a-chip system. Apart of the primal phenomenological characterization of this effect, it was shown that both, the direct impact of the mechanical as well as the electrical part of the surface acoustic waves contribute to the advanced wound healing. Preliminary inquiries showed the potential to transfer this concept of fast wound healing to flexible materials in the future. These studies constitute the basis for novel active implants in the field of advanced regeneration of damaged tissue. The last part of the work is devoted to the production of structured surfaces for cell guidance. Here, the scope of hydrophilic structures on hydrophobic substrates and ferroelectrically polarized domains is investigated in order to move cells along a prescribed path. Neither are the surfaces topographically textured nor are the cells chemotactically or durotactically directed. It was shown that the cells migrate along the hydrophilic structure while avoiding hydrophobic areas. The positive ferroelectric structuring could be demonstrated by various methods. Furthermore, by selective etching of the domains, 80 nm-deep regions could be produced which are suitable as nanochannels or nanobarriers. These techniques can be further developed for systematical structuring of implants. The systems developed in this work have been successfully used for the characterization and active manipulation of cell adhesion and migration. They thus make a decisive contribution to the research and development of implants and biomedical applications for the selected and rapid regeneration of living tissue

Hydrodynamic and label-free sorting of circulating tumor cells from whole blood

We demonstrate continuous, passive, and label-free sorting of different in vitrocancercell lines (MV3, MCF7, and HEPG2) as model systems for circulating tumorcells (CTCs) from undiluted whole blood employing the non-inertial lift effect as driving force. This purely viscous, repulsive cell-wall interaction is sensitive to cell size and deformability differences and yields highly efficient cell separation and high enrichment factors. We show that the performance of the device is robust over a large range of blood cell concentrations and flow rates as well as for the different cell lines. The collected samples usually contain more than 90% of the initially injected CTCs and exhibit average enrichment factors of more than 20 for sorting from whole blood samples

Breaking barriers: exploring mechanisms behind opening the blood–brain barrier

Abstract The blood–brain barrier (BBB) is a selectively permeable membrane that separates the bloodstream from the brain. While useful for protecting neural tissue from harmful substances, brain-related diseases are difficult to treat due to this barrier, as it also limits the efficacy of drug delivery. To address this, promising new approaches for enhancing drug delivery are based on disrupting the BBB using physical means, including optical/photothermal therapy, electrical stimulation, and acoustic/mechanical stimulation. These physical mechanisms can temporarily and locally open the BBB, allowing drugs and other substances to enter. Focused ultrasound is particularly promising, with the ability to focus energies to targeted, deep-brain regions. In this review, we examine recent advances in physical approaches for temporary BBB disruption, describing their underlying mechanisms as well as evaluating the utility of these physical approaches with regard to their potential risks and limitations. While these methods have demonstrated efficacy in disrupting the BBB, their safety, comparative efficacy, and practicality for clinical use remain an ongoing topic of research