Genetic variation of TLR4 influences immunoendocrine stress response: an observational study in cardiac surgical patients

Introduction: Systemic inflammation (e.g. following surgery) involves Toll-like receptor (TLR) signaling and leads to an endocrine stress response. This study aims to investigate a possible influence of TLR2 and TLR4 single nucleotide polymorphisms (SNPs) on perioperative adrenocorticotropic hormone (ACTH) and cortisol regulation in serum of cardiac surgical patients. To investigate the link to systemic inflammation in this context, we additionally measured 10 different cytokines in the serum. Methods: 338 patients admitted for elective cardiac surgery were included in this prospective observational clinical cohort study. Genomic DNA of patients was screened for TLR2 and TLR4 SNPs. Serum concentrations of ACTH, cortisol, interferon (IFN)-, interleukin (IL)-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)- and granulocyte macro-phage-colony stimulating factor (GM-CSF) were determined before surgery, immediately post surgery and on the first postoperative day. Results: 13 patients were identified as TLR2 SNP carrier, 51 as TLR4 SNP carrier and 274 pa-tients as non-carrier. Basal levels of ACTH, cortisol and cytokines did not differ between groups. In all three groups a significant, transient perioperative rise of cortisol could be ob-served. However, only in the non-carrier group this was accompanied by a significant ACTH rise, TLR4 SNP carriers had significant lower ACTH levels compared to non-carriers ((mean[95% confidence intervals]) non-carriers: 201.9[187.7 to 216.1]pg/ml; TLR4 SNP car-riers: 149.9[118.4 to 181.5]pg/ml; TLR2 SNP carriers: 176.4[110.5 to 242.3]pg/ml). Compared to non-carriers, TLR4 SNP carriers showed significant lower serum IL-8, IL-10 and GM-CSF peaks ((mean[95% confidence intervals]): IL-8: non-carriers: 42.6[36.7 to 48.5]pg/ml, TLR4 SNP carriers: 23.7[10.7 to 36.8]pg/ml; IL-10: non-carriers: 83.8[70.3 to 97.4]pg/ml, TLR4 SNP carriers: 54.2[24.1 to 84.2]pg/ml; GM-CSF: non-carriers: 33.0[27.8 to 38.3]pg/ml, TLR4 SNP carriers: 20.2[8.6 to 31.8]pg/ml). No significant changes over time or between the groups were found for the other cytokines. Conclusions: Regulation of the immunoendocrine stress response during systemic inflamma-tion is influenced by the presence of a TLR4 SNP. Cardiac surgical patients carrying this ge-notype showed decreased serum concentrations of ACTH, IL-8, IL-10 and GM-CSF. This finding might have impact on interpreting previous and designing future trials on diagnosing and modulating immunoendocrine dysregulation (e.g. adrenal insufficiency) during systemic inflammation and sepsis

Improved resource efficiency and cascading utilisation of renewable materials

In light of various environmental problems and challenges concerning resource allocation, the utilisation of renewable resources is increasingly important for the efficient use of raw materials. Therefore, cascading utilisation (i.e., the multiple material utilisations of renewable resources prior to their conversion into energy) and approaches that aim to further increase resource efficiency (e.g., the utilisation of by-products) can be considered guiding principles. This paper therefore introduces the Special Volume “Improved Resource Efficiency and Cascading Utilisation of Renewable Materials”. Because both research aspects, resource efficiency and cascading utilisation, belong to several disciplines, the Special Volume adopts an interdisciplinary perspective and presents 16 articles, which can be divided into four subjects: Innovative Materials based on Renewable Resources and their Impact on Sustainability and Resource Efficiency, Quantitative Models for the Integrated Optimisation of Production and Distribution in Networks for Renewable Resources, Information Technology-based Collaboration in Value Generating Networks for Renewable Resources, and Consumer Behaviour towards Eco-friendly Products. The interdisciplinary perspective allows a comprehensive overview of current research on resource efficiency, which is supplemented with 15 book reviews showing the extent to which textbooks of selected disciplines already refer to resource efficiency. This introductory article highlights the relevance of the four subjects, presents summaries of all papers, and discusses future research directions. The overall contribution of the Special Volume is that it bridges the resource efficiency research of selected disciplines and that it presents several approaches for more environmentally sound production and consumption

Material Hub – Ordnung im Chaos der Werkstoffdatenquellen

Neuartige Materialien spielen eine entscheidende Rolle in Innovationsprozessen und sind die Voraussetzung für eine Vielzahl neuer Produkte. Der Standort Dresden stellt mit der Exzellenz-Universität TU Dresden und einer Vielzahl an außeruniversitären Einrichtungen ein bedeutendes europäisches Zentrum auf dem Gebiet der Materialforschung dar. Das breite wissenschaftliche und technologische Spektrum sowie die enorme Forschungsdichte in Kombination mit einer hohen fachlichen Vernetzung führen einerseits zu Synergieeffekten unter den Wissenschaftlern und verschaffen andererseits der Wirtschaft einen enormen Standortvorteil. Sollen diese Vorteile voll ausgenutzt werden, bedarf es eines vereinheitlichten, intuitiven Informationszugangs. Aktuell werden Materialdaten jedoch typischerweise auf einer Vielzahl separierter, teilweise eingeschränkt zugänglicher Datenbestände gehalten und sind nach heterogenen Schemas und in variierendem Detailgrad beschrieben. Zwar existieren bereits Rechercheportale, diese sind jedoch domänenspezifisch, kostenpflichtig oder bieten nur auf spezielle Zielgruppen zugeschnittene Bedienoberflächen, die für andere Nutzer kaum bedienbar sind. Verteilte Recherchen über mehrere Datenquellen und Portale sind zeitaufwändig und mühsam. Abhilfe soll die hier vorgestellte integrierte Material-Recherche-Plattform Material Hub schaffen. Sie muss den Anforderungen von Herstellern und Zulieferern, deren Daten sie enthält ebenso entsprechen wie den Anforderungen der Anwender aus Forschung, Industrie und Handwerk. Diese den Wissenschaftsraum Dresden integrierende Plattform soll weitere erstklassige Forschungs- und Innovationsleistungen stimulieren, Kooperationen begünstigen und die Vermarktung innovativer Ideen und Lösungen wesentlich erleichtern. Außerdem soll Material Hub die Sichtbarkeit und Reichweite der Dresdner Materialforschung erhöhen und so die bereits vorhandene Leistungsfähigkeit signifikant stärken. Gegenstand dieses Artikels ist das technische Grundkonzept des Material Hub. Ein wesentlicher Aspekt besteht dabei in der Zusammenführung verschiedener Datenquellen in einem zentralen Rechercheportal. Integriert werden Forschungsdaten, Herstellerinformationen und Anwendungsbeispiele, die sowohl hinsichtlich Domäne als auch hinsichtlich Detailgrad und 1 gefördert aus Mitteln der Europäischen Union und des Europäischen Fonds für regionale Entwicklung zugrundeliegendem Schema heterogen sind. Dazu wird in Abstimmung mit Werkstoffwissenschaftlern ein Schema zur Materialbeschreibung sowie eine semantische Wissensbasis konzipiert, die z. B. Synonyme und inhaltliche Zusammenhänge modelliert. Basierend darauf werden die Datenbestände indexiert und für die Recherche zugänglich gemacht. Die Benutzeroberfläche unterstützt mehrere Suchmasken, von der klassischen Stichwortsuche über die facettierte Suche bis hin zu stärker geführten Ansätzen, um zielgruppenspezifischen Anwendungsfällen durch geeignete UI-Konzepte gerecht zu werden. Neben konzeptionellen Ansätzen behandelt dieser Artikel erste Implementierungs- und Evaluationsergebnisse

APOBEC3B Activity Is Prevalent in Urothelial Carcinoma Cells and Only Slightly Affected by LINE-1 Expression

The most common mutational signature in urothelial carcinoma (UC), the most common type of urinary bladder cancer is assumed to be caused by the misdirected activity of APOBEC3 (A3) cytidine deaminases, especially A3A or A3B, which are known to normally restrict the propagation of exogenous viruses and endogenous retroelements such as LINE-1 (L1). The involvement of A3 proteins in urothelial carcinogenesis is unexpected because, to date, UC is thought to be caused by chemical carcinogens rather than viral activity. Therefore, we explored the relationship between A3 expression and L1 activity, which is generally upregulated in UC. We found that UC cell lines highly express A3B and in some cases A3G, but not A3A, and exhibit corresponding cytidine deamination activity in vitro. While we observed evidence suggesting that L1 expression has a weak positive effect on A3B and A3G expression and A3B promoter activity, neither efficient siRNA-mediated knockdown nor overexpression of functional L1 elements affected catalytic activity of A3 proteins consistently. However, L1 knockdown diminished proliferation of a UC cell line exhibiting robust endogenous L1 expression, but had little impact on a cell line with low L1 expression levels. Our results indicate that UC cells express A3B at levels exceeding A3A levels by far, making A3B the prime candidate for causing genomic mutations. Our data provide evidence that L1 activation constitutes only a minor and negligible factor involved in induction or upregulation of endogenous A3 expression in UC

Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an important subgroup of ALS. We recently reported specific SPTLC1 variants resulting in sphingolipid overproduction as a cause for juvenile ALS. Here, we report six patients from six independent families with a recurrent, de novo, heterozygous variant in SPTLC2 c.778G>A [p.Glu260Lys] manifesting with juvenile ALS. METHODS: Clinical examination of the patients along with ancillary and genetic testing, followed by biochemical investigation of patients' blood and fibroblasts, was performed. RESULTS: All patients presented with early-childhood-onset progressive weakness, with signs and symptoms of upper and lower motor neuron degeneration in multiple myotomes, without sensory neuropathy. These findings were supported on ancillary testing including nerve conduction studies and electromyography, muscle biopsies and muscle ultrasound studies. Biochemical investigations in plasma and fibroblasts showed elevated levels of ceramides and unrestrained de novo sphingolipid synthesis. Our studies indicate that SPTLC2 variant [c.778G>A, p.Glu260Lys] acts distinctly from hereditary sensory and autonomic neuropathy (HSAN)-causing SPTLC2 variants by causing excess canonical sphingolipid biosynthesis, similar to the recently reported SPTLC1 ALS associated pathogenic variants. Our studies also indicate that serine supplementation, which is a therapeutic in SPTLC1 and SPTCL2-associated HSAN, is expected to exacerbate the excess sphingolipid synthesis in serine palmitoyltransferase (SPT)-associated ALS. CONCLUSIONS: SPTLC2 is the second SPT-associated gene that underlies monogenic, juvenile ALS and further establishes alterations of sphingolipid metabolism in motor neuron disease pathogenesis. Our findings also have important therapeutic implications: serine supplementation must be avoided in SPT-associated ALS, as it is expected to drive pathogenesis further

Assessing a risk tailored intervention to prevent disabling low back pain - protocol of a cluster randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Although most patients with low back pain (LBP) recover within a few weeks a significant proportion has recurrent episodes or will develop chronic low back pain. Several mainly psychosocial risk factors for developing chronic LBP have been identified. However, effects of preventive interventions aiming at behavioural risk factors and unfavourable cognitions have yielded inconsistent results. Risk tailored interventions may provide a cost efficient and effective means to take systematic account of the individual risk factors but evidence is lacking.</p> <p>Methods/Design</p> <p>This study will be a cluster-randomised controlled trial comparing screening and a subsequent risk tailored intervention for patients with low back pain to prevent chronic low back pain compared to treatment as usual in primary care. A total of 600 patients from 20 practices in each study arm will be recruited in Berlin and Goettingen. The intervention comprises the following elements: Patients will be assigned to one of four risk groups based on a screening questionnaire. Subsequently they receive an educational intervention including information and counselling tailored to the risk group. A telephone/email consulting service for back pain related problems are offered independent of risk group assignment. The primary outcomes will be functional capacity and sick leave.</p> <p>Discussion</p> <p>This trial will evaluate the effectiveness of screening for risk factors for chronic low back pain followed by a risk tailored intervention to prevent chronic low back pain. This trial will contribute new evidence regarding the flexible use of individual physical and psychosocial risk factors in general practice.</p> <p>Trial registration</p> <p>ISRCTN 68205910</p

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis