Europe In The Global Economy: Matching The U.S.?

Stadtentwicklung, Weltwirtschaft, Wettbewerb, Deutschland, Europäische Wirtschafts- und Währungsunion, Vereinigte Staaten, Urban development, World economy, Competition, Germany, European Economic and Monetary Union, United States

Regulation of antimicrobial peptides in the gastrointestinal tract

The intestinal epithelium has an enormously large surface, which is constantly exposed to high amounts of pathogens and commensal bacteria. In order to prevent pathogens or other microorganisms from overcoming this barrier, good protection is needed. In the small intestine, human α-defensin 5 (HD-5) and 6 (HD-6) are important components of this barrier. Paneth cells, which are secretory epithelial cells, produce these antimicrobial peptides. The cells are located at the base of the crypt in the small intestine, where they play a central role in the microbial defense and regulating the composition of the intestinal microbiota. In ileal Crohn's disease, which belongs to the inflammatory bowel diseases, HD-5 and HD-6 levels are reduced, which leads to a changed composition of the intestinal flora and a poorer barrier function of the intestinal mucosa. Underlying mechanisms are genetically but also non-genetically influencing the Paneth cell function on different levels. The Wnt signaling pathway plays a key role in maintaining intestinal homeostasis. On the one hand it keeps the intestinal epithelial cells in a proliferating state, on the other hand it regulates the differentiation and maturation of Paneth cells. It is also instrumental in the regulation of HD-5 and -6. Former results from our group revealed a link between the decreased expression of HD-5 and -6 and the Wnt transcription factor TCF-4. Independent of inflammation, patients with ileal Crohn's disease show decreased TCF-4 expression levels. But not only TCF-4 is affected, our group could also show that the receptor LRP6, which is essential for the stabilization of β-catenin in the cytoplasm is affected. Studies showed a decreased expression in ileal Crohn's disease. The results of genetic investigations are also exciting; In the LRP6 gene, a polymorphism was identified that occurs significantly more frequently in a subgroup (patients> 18) than in healthy subjects. In the present work the consequences of a disturbed Paneth cell function, but also potential causes were further investigated. Emphasis was placed on the patient side, but the microbial side of the balance was also examined using animal models. It could be shown that LRP6 directly regulates the expression of HD-5 and -6 whereas the expression of LRP5, as a co-expressed receptor of LRP6, is barely altered in patients and also in vitro there is no evidence for a direct regulation of HD-5 and -6. It was possible to show the high heterogeneity of LRP5 in several populations studied and no genetic association in all subgroups of Crohn's disease was found. Studying TCF-1 expression revealed decreased levels in patients with ileal Crohn's disease. Further results from a knockout mouse model showed that a TCF-1 knockout leads to a lower expression of cryptdines (mouse α-defensins). Furthermore, the role of antimicrobial peptides in the intestine could be further clarified in a rat liver cirrhosis model, since the transfer of commensal bacteria occurring here through the intestinal epithelium could be explained by a reduced expression of some antimicrobial peptides. Although many factors which play a role in the development of ileal Crohn's disease are still unknown, the present work has provided new insights into the mechanisms that lead to a well-balanced homeostasis at the epithelial site in the small intestine. Furthermore, the important role of the Wnt signaling pathway for the development of ileal Crohn's disease was underlined. Hopefully, these additional insights into the complex pathogenesis of the disease will one day provide new approaches to therapy.Das Epithel des Darmes besitzt eine enorm große Oberfläche, welche ständig erheblichen Mengen von Pathogenen und kommensalen Bakterien ausgesetzt ist. Um zu verhindern, dass Pathogene oder auch andere Mikroorganismen diese Barriere überwinden, ist ein guter Schutz nötig. Im Dünndarm sind die humanen α- Defensine 5 (HD-5) und 6 (HD-6) wichtige Komponenten dieser Barriere. Diese antimikrobiellen Peptide werden von Panethzellen produziert. Panethzellen sind sekretorischen Epithelzellen und befinden sich an der Basis der Krypte im Dünndarm. Dort spielen sie eine zentrale Rolle bei der mikrobiellen Abwehr und der Regulation der bakteriellen Zusammensetzung der Darmflora. Bei Morbus Crohn des Dünndarms, diese Erkrankung zählt zu den chronisch entzündlichen Darmerkrankungen, kommt es zu einer verminderten Expression von HD-5 und HD-6 und dadurch zu einer veränderten Zusammensetzung der Darmflora und zu einer schlechteren Barrierefunktion der Darmmukosa. Grundlage hierfür sind verschiedene genetische aber auch nicht- genetische Defekte, welche die Panethzellfunktion auf verschiedenen Ebenen beeinflussen. Der Wnt Signalweg spielt eine zentrale Rolle, wenn es darum geht die Homöostase im Darm aufrecht zu erhalten. Er hält die intestinalen Epithelzellen einerseits in einem proliferierenden Zustand, andererseits reguliert er die Differenzierung und das Ausreifen der Panethzellen. Ebenso ist er an der Regulation von HD-5 und -6 maßgeblich beteiligt. Unsere Arbeitsgruppe konnte bereits zeigen, dass es eine Verbindung zwischen der verminderten Expression von HD-5 und -6 und dem Wnt Transkriptionsfaktor TCF-4 gibt. Entzündungsunabhängig zeigen Patienten mit Morbus Crohn des Dünndarms eine verminderte TCF-4 Expression. Aber nicht nur TCF-4 ist betroffen, es konnte auch gezeigt werden, dass der Rezeptor LRP6 betroffen ist, welcher für die Stabilisierung von ß- Catenin im Cytoplasma essentiell ist. Untersuchungen zeigten eine verminderte Expression bei Morbus Crohn Patienten. Spannend sind auch die Ergebnisse genetischer Untersuchungen; im LRP6 Gen wurde ein Polymorphismus identifiziert, der in einer Untergruppe (Patienten >18) deutlich häufiger auftritt als in Gesunden. In der hier vorgestellten Arbeit wurde an diese Ergebnisse angeknüpft und die Folgen einer gestörten Panethzellfunktion, aber auch die Faktoren die potentiell dazu führen, weiter untersucht. Hierbei wurde ein Schwerpunkt auf die Patientenseite gelegt, aber auch die mikrobielle Seite wurde mithilfe von Modellen untersucht. Es konnte gezeigt werden, dass LRP6 die Expression von HD-5 und -6 direkt reguliert während die Expression von LRP5, als ein Co-Rezeptor von LRP6, in Patienten kaum verändert ist und sich auch in vitro keine Hinweise auf eine direkte Regulation von HD-5 und -6 finden lassen. Ebenso zeigte sich, dass LRP5 sehr heterogen in mehreren untersuchten Populationen vorliegt und keine genetische Assoziation in allen untersuchten Subgruppen von Morbus Crohn vorliegt. Die Untersuchungen von TCF-1 zeigten eine erniedrigte Expression in Patienten mit Morbus Crohn des Dünndarms. Ergebnisse aus einem Knockout Mausmodell zeigten, dass ein TCF-1 Knockout zu einer niedrigeren Expression von Cryptdinen führt. Weiter konnte in einem Leberzirrhose- Tiermodel die Rolle antimikrobieller Substanzen weiter geklärt werden, da der hier auftretende Übertritt von kommensalen Bakterien durch das Darmepithel mit einer verminderten Expression einiger antimikrobieller Peptide erklärt werden konnte. Obwohl immer noch viele Faktoren, die in der Entstehung von Morbus Crohn des Dünndarms eine Rolle spielen unbekannt sind, konnte die hier vorliegende Arbeit neue Einblicke in die Mechanismen liefern, die das Aufrechterhalten der Balance zwischen Bakterien und Mensch im Dünndarm ermöglichen. Weiter wurde die wichtige Rolle des Wnt Signalwegs für die Entstehung von Morbus Crohn des Dünndarms unterstrichen. Hoffentlich ermöglichen diese weiteren Einblicke in die komplexe Pathogenese der Erkrankung eines Tages neue Ansätze für eine Therapie

Efficient Determination of Material Parameters for Robust Process Simulation of Semi-Crystalline Thermoplastic Composites

Predicting material behaviour during and after consolidation using process simulation will be a decisive factor in the breakthrough of fibre reinforced high-temperature thermoplastics for primary aerospace structures. Since the materials are constantly being optimized with respect to processing and component properties, a new method is being developed to adapt existing material models for process simulations in order to quickly react to such modifications. A DoE analysis is carried out to find the model parameters with a significant effect on the process simulation which are then experimentally determined for CF/LM PAEK and implemented in an existing material model. By comparing the process-induced spring-in of vacuum-consolidated V-angles with the values derived from simulation, the adapted material model as well as the new methodology for a simplified adaptation of existing material models to novel materials is validated

Street-based adolescents at high risk of HIV in Ukraine

BACKGROUND: Ukraine has the highest HIV prevalence in Europe, with young people disproportionately represented among populations at high risk. One particularly vulnerable group comprises adolescents who live or work on the streets. This study aimed to measure the extent and distribution of HIV risk behaviours among street-based adolescents in four Ukrainian cities as part of a regional UNICEF HIV prevention programme for most-at-risk adolescents. METHODS: A cross-sectional behavioural survey was conducted of 805 adolescents (aged 10-19 years) in the cities of Kiev, Donetsk, Dnepropetrovsk and Nikolaev. Using location-based network and convenience sampling, 200 adolescents were reached in each site and were administered a standardised questionnaire on drug use, sexual behaviour, condom use, HIV knowledge, access to prevention services, experience of violence and contact with state institutions and police. RESULTS: Considerable levels of HIV risk behaviour were found, including injecting drug use among 15.5% of the sample. Almost three-quarters of adolescents had experienced sexual debut, most before the age of 15 years. Male-to-male sexual behaviour was reported by just under 10% of boys. Condom use was low although varied by partner type. There were high rates of forced sex, and 75.5% of respondents reported police harassment. CONCLUSIONS: Street-based adolescents in Ukraine are at significant risk of contracting HIV due to involvement in injecting drug use and unprotected sex in personal and commercial exchanges, including male-to-male sex. This group initiates risk behaviours at early ages, and does not appear to have good access to prevention and other health services

System and method for dissolving gases in fluids and for delivery of dissolved gases

Apparatus and methods are disclosed for facilitating dissolution of one or more gases into a liquid. Preferred gases for use with the apparatus are oxygen, air, and ozone. An apparatus of the present invention includes a dissolution tank that includes a pressure vessel, at least one liquid spray nozzle, and a fluid outlet. The apparatus also includes a gas source, an element for passing fluid into the pressure vessel, and a discharge device connected to the fluid outlet, which discharge device is provided with at least one orifice. Preferred applications include wastewater treatment, treatment of drinking water, fermentation, and bioremediation

System and method for dissolving gases in liquids

Apparatus and methods for dissolving a gas into a liquid comprises a saturation tank, a high pressure liquid pump in fluid communication with the tank, and a pressurized gas source in communication with a regulated gas head space of the saturation tank is described. The saturation tank comprises a pressure vessel for containing the liquid and has a regulated gas head space above the liquid. It contains at least one liquid spray nozzle that permits passage of liquid into the pressure vessel, and an outlet for the liquid containing dissolved gas. Upon passing the gas-containing liquid into a second fluid, the gas is released in the form of microbubbles. The microbubbles aid in flocculation of suspended particles and promote dissolution of the gas in the second fluid. Preferred gases for use with the apparatus are oxygen, air, and ozone. Anticipated uses include treatment of rivers, streams, and ponds in natural or industrial settings, as well as smaller scale applications

System and method for dissolving gases in fluids and for delivery of dissolved gases

Apparatus and methods are disclosed for facilitating dissolution of one or more gases into a liquid. Preferred gases for use with the apparatus are oxygen, air, and ozone. This apparatus comprises a dissolution tank that includes a pressure vessel, at least one liquid spray nozzle, and a fluid outlet. It also comprises a gas source, means for passing fluid into the pressure vessel, and a discharge device connected to the fluid outlet, which discharge device is provided with at least one orifice. Preferred applications include wastewater treatment, treatment of drinking water, fermentation and bioremediation

Community and service provider views to inform the 2013 WHO consolidated antiretroviral guidelines:key findings and lessons learnt

Objective:The objective was to evaluate community and healthcare worker (HCW) values and preferences on key topics to inform the development of the 2013 WHO consolidated guidelines for antiretroviral therapy in low and middle income countries. Design:Cross-sectional e-survey and e-forum discussion; focus group discussions (FGDs) Methods:Data were collected on community perspectives regarding a range of potential clinical and operational recommendations in the 2013 guidelines between November 2012 and January 2013 through an e-survey (n = 1088) and e-forum (n = 955). Additional FGDs were held with people living with HIV (PLHIV) in Malawi and Uganda (n = 88) on antiretroviral therapy (ART) use among pregnant women. Two surveys were also undertaken on similar topics covered in the e-survey for health care workers caring for adults (n = 98) and children (n = 348). Results:There were 1088 e-survey respondents from 117 countries: of whom 37.7% (298/791) were females, 49.9% (431/864) PLHIV, and 20.9% (174/831) from low-income countries. The proportion of e-survey respondents who supported raising the CD4 T-cell threshold for ART initiation in adults from 350 to 500 cells/μl was 51.0% (355/696), and regardless of CD4 T-cell count for all pregnant females 89.8% (607/676), HIV serodiscordant partners 71.9% (486/676), and all children on diagnosis of infection 47.4% (212/447). E-survey respondents strongly supported discontinuing use of stavudine (72.7%, 416/572), task-shifting/sharing from doctors to nurses (75.2%, 275/365) and from nurses to community health workers (71.1%, 261/367) as strategies to expand access to HIV testing, care, and treatment. Focus group discussion respondents identified service capacity, and social and legal concerns as key considerations influencing the decisions of women living with HIV to continue ART after the risk of vertical transmission has passed. Key lessons learnt in these consultations included the need for piloting and validation of questions; sufficient time to adequately disseminate the survey; and consideration of using FGDs and mobile phone technology to improve participation of people with limited internet access. Conclusion:Community participation in guideline development processes is important to ensure that their perspectives are considered in the resulting recommendations. Communities should be actively involved in the adaptation, implementation, and accountability processes related to the guidelines

Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohn's Disease

Ileal Crohn's Disease (CD), a chronic small intestinal inflammatory disorder, is characterized by reduced levels of the antimicrobial peptides DEFA5 (HD-5) and DEFA6 (HD-6). Both of these α-defensins are exclusively produced in Paneth cells (PCs) at small intestinal crypt bases. Different ileal CD–associated genes including NOD2, ATG16L1, and recently the β-catenin–dependant Wnt transcription factor TCF7L2 have been linked to impaired PC antimicrobial function. The Wnt pathway influences gut mucosal homeostasis and PC maturation, besides directly controlling HD-5/6 gene expression. The herein reported candidate gene study focuses on another crucial Wnt factor, the co-receptor low density lipoprotein receptor-related protein 6 (LRP6). We analysed exonic single nucleotide polymorphisms (SNPs) in a large cohort (Oxford: n = 1,893) and prospectively tested 2 additional European sample sets (Leuven: n = 688, Vienna: n = 1,628). We revealed an association of a non-synonymous SNP (rs2302685; Ile1062Val) with early onset ileal CD (OR 1.8; p = 0.00034; for homozygous carriers: OR 4.1; p = 0.00004) and additionally with penetrating ileal CD behaviour (OR 1.3; p = 0.00917). In contrast, it was not linked to adult onset ileal CD, colonic CD, or ulcerative colitis. Since the rare variant is known to impair LRP6 activity, we investigated its role in patient mucosa. Overall, LRP6 mRNA was diminished in patients independently from the genotype. Analysing the mRNA levels of PC product in biopsies from genotyped individuals (15 controls, 32 ileal, and 12 exclusively colonic CD), we found particularly low defensin levels in ileal CD patients who were carrying the variant. In addition, we confirmed a direct relationship between LRP6 activity and the transcriptional expression of HD-5 using transient transfection. Taken together, we identified LRP6 as a new candidate gene in ileal CD. Impairments in Wnt signalling and Paneth cell biology seem to represent pathophysiological hallmarks in small intestinal inflammation and should therefore be considered as interesting targets for new therapeutic approaches