Error analysis of truncated expansion solutions to high-dimensional parabolic PDEs

We study an expansion method for high-dimensional parabolic PDEs which constructs accurate approximate solutions by decomposition into solutions to lower-dimensional PDEs, and which is particularly effective if there are a low number of dominant principal components. The focus of the present article is the derivation of sharp error bounds for the constant coefficient case and a first and second order approximation. We give a precise characterisation when these bounds hold for (non-smooth) option pricing applications and provide numerical results demonstrating that the practically observed convergence speed is in agreement with the theoretical predictions

Comparison between B·R·A·H·M·S PCT direct, a new sensitive point-of-care testing device for rapid quantification of procalcitonin in emergency department patients and established reference methods - a prospective multinational trial

Background: Procalcitonin (PCT) is increasingly being used for the diagnostic and prognostic work up of patients with suspected infections in the emergency department (ED). Recently, B·R·A·H·M·S PCT direct, the first high sensitive point-of-care test (POCT), has been developed for fast PCT measurement on capillary or venous blood samples. Methods: This is a prospective, international comparison study conducted in three European EDs. Consecutive patients with suspicion of bacterial infection were included. Duplicate determination of PCT was performed in capillary (fingertip) and venous whole blood (EDTA), and compared to the reference method. The diagnostic accuracy was evaluated by correlation and concordance analyses. Results: Three hundred and three patients were included over a 6-month period (60.4% male, median age 65.2 years). The correlation between capillary or venous whole blood and the reference method was excellent: r2=0.96 and 0.97, sensitivity 88.1% and 93.0%, specificity 96.5% and 96.8%, concordance 93% and 95%, respectively at a 0.25 μg/L threshold. No significant bias was observed (-0.04 and -0.02 for capillary and venous whole blood) although there were 6.8% and 5.1% outliers, respectively. B·R·A·H·M·S PCT direct had a shorter time to result as compared to the reference method (25 vs. 144 min, difference 119 min, 95% CI 110-134 min, p<0.0001). Conclusions: This study found a high diagnostic accuracy and a faster time to result of B·R·A·H·M·S PCT direct in the ED setting, allowing shortening time to therapy and a more wide-spread use of PCT

Identification of differential expressed genes in tumors of the prostate and bladder

0\. Titelblatt und Inhaltsverzeichnis 1\. Einleitung 1 1.1 Epidemiologie und Diagnostik des Prostatakarzinoms 2 1.2 Überblick über das Harnblasenkarzinom 7 1.3 Wnt- und Ras- Signaltransduktionswege 9 1.4 Auswahl von Methoden zur Bestimmung der differentiellen mRNA-Expression 11 2\. Zielsetzung 16 3\. Material und Methoden 17 3.1 Puffer und Lösungen 17 3.2 Plasmidisolierung 18 3.3 DNA und RNA Quantifizierung mit PicoGreen bzw. RiboGreen 19 3.4 Sequenzierung 19 3.5 Isolierung von spezifischen BAC-Klonen 21 3.6 Northern Hybridisierungen 22 3.7 Mikrodissektion 25 3.8 Poly-A+-RNA Präparation 26 3.9 cDNA Synthese 27 3.10 Affymetrix Chipexperimente 32 3.11 Quantitative "TaqMan" PCR 35 3.12 LOH-Untersuchung 37 3.13 In silico Analysen 41 3.14 Proteinchemische Methoden 43 4\. Ergebnisse 48 4.1 Affymetrix Chipauswertung von 54 Patienten mit Prostataumoren und Prostatazelllinien 48 4.2 Analyse an Hand des Expressionsprofils ähnlich gruppierter Versuche und Gene 56 4.3 Kandidatengene aus dem Wnt-Signalweg 63 4.4 Chimerin-1, ein Kandidatengen aus dem Ras-Signalweg 75 4.5 Kandidatengen Ponsin 79 5\. Diskussion 93 5.1 Methodische Aspekte der Expressionsuntersuchung von Prostatageweben 93 5.2 Clusteranalyse der Expressionsprofile von Prostatanormal-und tumorgeweben 96 5.3 Auswahl von herunterregulierten Genen in Tumoren der Prostata 100 6\. Zusammenfassung 111 7\. Summary 113 8\. Literatur 115 9\. Anhang 127 9.1 Histologie der 54 untersuchten Prostatagewebepaare 127 9.2 Danksagung 129 9.3 Lebenslauf 130 9.4 Erklärung 131Das Prostatakarzinom ist der häufigste maligne Tumor des Mannes. Sein Auftreten, vor allem im hohen Alter, rückt ihn bei einer steigenden Lebenserwartung der Bevölkerung weiter in den Mittelpunkt des Interesses. Zur Analyse dieses Tumors wurde das Expressionsprofil des Tumor- und Normalgewebes von 54 Prostatapatienten durch Affymetrix-Chiphybridisierungen untersucht. Aus den mikrodissezierten Tumor- und Normalgeweben wurde die Poly-A+-RNA präpariert und in aufeinander folgenden Runden von cDNA-Synthese und in vitro Transkription linear amplifiziert. Die Chipdaten der 108 Patientengewebe wurden mit einem speziell entwickelten Algorithmus ausgewertet und führte zur Identifikation von 124 in Prostatatumoren herunterregulierten und weiteren 104 in Tumoren hochregulierten Sequenzen, die in einer Gruppenanalyse (Clusteranalyse) untersucht wurden. Die Clusteranalyse zeigte eine deutliche Trennung der Tumor- von ihren korrespondierenden Normalgeweben mit einer Sensivität von 94% bei einer Spezifität von 72%. Eine Auftrennung der Gewebe entsprechend ihrer histologischen Klassifikationen wie auch eine Gruppierung der Tumorproben entsprechend ihres Grades und Stadiums war nicht in allen Fällen möglich, da die histologischen Merkmalen nicht eindeutig mit den molekularen Profilen übereinstimmten. Für eine nähere Untersuchung wurden aus der Liste der in den Prostatatumoren herunterregulierten Gene drei ausgesucht und ein viertes auf Grund einer ähnlichen Funktion ausgewählt. Die Herunterregulation des WIF-1 in den Prostatatumoren war sehr deutlich und konnte auch in Brust- und Lungentumoren gezeigt werden. Die Ursache der Herunterregulation ist unbekannt, da WIF-1 in der Region 12q14.3 lokalisiert ist, für die in Prostatatumoren bisher noch keine chromosomalen Aberrationen identifiziert wurden. Immunhistochemische Färbungen von Prostata- und Harnblasentumoren konnten den Verlust der Expression in einem Teil der Tumoren bestätigen. Aus dem Signalweg der Wnt-Proteine konnte das sFRP1 als ein weiteres Gen, mit einer ähnlichen Funktion wie WIF-1, auf dem Chip identifiziert werden. sFRP1 zeigte keine Regulation in Prostatatumoren, ist jedoch in der häufig in Harnblasentumoren verlorenen Region 8p11.22 lokalisiert. Die reduzierte Genexpression in Blasentumoren konnte in Northern- Hybridierungen gezeigt werden und LOH-Untersuchungen bestätigten den häufigen Verlust der Region. Immunhistochemische Untersuchungen mit einem sFRP1-Antikörper zeigten den Verlust der Expression in 26% der untersuchten Harnblasentumore. Als drittes Gen mit einer Herunterregulation in Prostatatumoren wurde das Chimerin-1 ausgewählt, das eine hemmende Wirkung auf die Signalweiterleitung Ras-ähnlicher Rho-Proteine hat. Auch für dieses Gen konnte die differentielle RNA-Expression bestätigt werden. Für das Adaptorprotein Ponsin konnte die differentielle Expression in RNA-Studien bestätigt werden, die Proteinexpression zeigte sich jedoch nicht als differentiell zwischen Normal- und Tumorepithelien, sondern wies auf ein methodisches Problem der manuellen Mikrodissektion hin. Auch konnte in einer LOH-Untersuchung kein signifikanter Hinweis auf einen Verlust des Gens gefunden werden.The carcinoma of the prostate is the most frequent tumor among men. Its appearance mainly with higher age has moved it to the focus of cancer research because of the rising life expectancy of the population. For the analysis of this type of tumor the expression profile of normal and tumor tissues from 54 patients was analyzed by Affymetrix chip hybridisations. After microdissection of normal and tumor tissue the poly-A+-RNA was prepared, linear amplified in repetitive rounds of cDNA synthesis and in vitro transcription. The chip data of 108 patient tissues were analysed by a special devolved algorithm and led to the identification of 124 sequences that were down regulated and further 104 sequences with an up regulation in prostate tumors, that were analyzed by cluster analysis. The cluster analysis showed a distinct separation of tumor from its corresponding normal tissue with a sensitivity of 94% and a specificity of 72%. Separation of the tissues according to their histological classification and clustering the tumors according to their grad and stage was not possible in all cases, because the histological features did not harmonize with the molecular profile. For a detailed analysis of down regulated genes in prostate tumors, three were selected from this group and a fourth gene was chosen because of its similar function. The down regulation of WIF-1 in prostate tumors was very clear and could also be shown for breast and lung tumors. The reason for the down regulation is not known. WIF-1 is located in the region 12q14.3, this area has up to now not been correlated with any chromosomal aberration in prostate tumors. Immunohistochemical staining of prostate and bladder tumors confirmed the loss of expression in a subset of tumors. From the Wnt-signal transduction pathway the gene sFRP1 could be identified on the chip as a further gene with a similar function to WIF-1. sFRP1 shows no differential expression in prostate tumors, but is located in the region of 8p11.22 which is often lost in bladder tumors. The reduced gene expression in bladder carcinomas could be shown in Northern blots and LOH analysis confirmed the loss of the region. Immunohistochemical analysis with an sFRP1-Antibody showed the loss of expression in 26% of the analyzed bladder tumors. As a third gene with a down regulation in prostate tumors Chimerin-1 was chosen to be studied more closely because of its suppressing function on the signal transduction of the Ras-related Rho-Proteins. The differential RNA- expression for this gene could be confrimed. For the adaptor protein Ponsin the differential RNA expression could be confirmed, but the protein expression was not differential between normal and tumor epithelia and this highlighted a possible methodical problem of manual microdissection. The LOH-analysis gave no significant result for a loss of the gene

Organic semiconductor distributed feedback laser pixels for lab-on-a-chip applications fabricated by laser-assisted replication

The integration of organic semiconductor distributed feedback (DFB) laser sources into all-polymer chips is promising for biomedical or chemical analysis. However{,} the fabrication of DFB corrugations is often expensive and time-consuming. Here{,} we apply the method of laser-assisted replication using a near-infrared diode laser beam to efficiently fabricate inexpensive poly(methyl methacrylate) (PMMA) chips with spatially localized organic DFB laser pixels. This time-saving fabrication process enables a pre-defined positioning of nanoscale corrugations on the chip and a simultaneous generation of nanoscale gratings for organic edge-emitting laser pixels next to microscale waveguide structures. A single chip of size 30 mm [times] 30 mm can be processed within 5 min. Laser-assisted replication allows for the subsequent addition of further nanostructures without a negative impact on the existing photonic components. The minimum replication area can be defined as being as small as the diode laser beam focus spot size. To complete the fabrication process{,} we encapsulate the chip in PMMA using laser transmission welding

High-Energy Scraper System for the S-DALINAC Extraction Beam Line - Commissioning Run

The S-DALINAC is a thrice recirculating, superconducting linear electron accelerator at TU Darmstadt. It delivers electron beams in cw-mode with energies up to 130 MeV. The high-energy scraper system has been installed in its extraction beam line to reduce the energy spread and improve the energy stability of the beam for the experiments operated downstream. It comprises three scraper slits within a dispersion-conserving chicane consisting of four dipole magnets and eight quadrupole magnets. The primary scraper, located in a dispersive section, allows to improve and stabilize the energy spread. In addition energy fluctuations can be detected. Scraping of x- and y-halo is implemented in two positions enclosing the position of the primary scraper. We will present technical details and results of the first commissioning run of the recently installed system at the S DALINAC. Besides improving on the energy spread, it proved to be a valuable device to observe energy spread and energy fluctuations as well as to reduce background count rates next to the experimental areas

Microbial uptake in oral mucosa-draining lymph nodes leads to rapid release of cytotoxic CD8+ T cells lacking a gut-homing phenotype.

The gastrointestinal (GI) tract constitutes an essential barrier against ingested microbes, including potential pathogens. Although immune reactions are well studied in the lower GI tract, it remains unclear how adaptive immune responses are initiated during microbial challenge of the oral mucosa (OM), the primary site of microbial encounter in the upper GI tract. Here, we identify mandibular lymph nodes (mandLNs) as sentinel lymphoid organs that intercept ingested Listeria monocytogenes (Lm). Oral Lm uptake led to local activation and release of antigen-specific CD8+ T cells that constituted most of the early circulating effector T cell (TEFF) pool. MandLN-primed TEFF disseminated to lymphoid organs, lung, and OM and contributed substantially to rapid elimination of target cells. In contrast to CD8+ TEFF generated in mesenteric LN (MLN) during intragastric infection, mandLN-primed TEFF lacked a gut-seeking phenotype, which correlated with low expression of enzymes required for gut-homing imprinting by mandLN stromal and dendritic cells. Accordingly, mandLN-primed TEFF decreased Lm burden in spleen but not MLN after intestinal infection. Our findings extend the concept of regional specialization of immune responses along the length of the GI tract, with CD8+ TEFF generated in the upper GI tract displaying homing profiles that differ from those imprinted by lymphoid tissue of the lower GI tract