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Objective: The research on psychotherapy for posttraumatic stress disorder (PTSD) stems predominantly from a cognitive-behavioral orientation while other approaches are underrepresented. We evaluated dialogical exposure in trauma therapy (DET), a treatment for PTSD combining cognitive-behavioral elements with an interpersonal, gestalt-based framework., Methods: In this uncontrolled pilot trial, 25 PTSD patients were treated with DET in an outpatient setting and 21 completed therapy., Results: There was a significant reduction in self-rated PTSD symptoms from pre- to posttreatment. Effect sizes were large in the completer sample and moderate to large in the intent-to-treat sample. General psychopathology also decreased significantly. The dropout rate was rather low at 16%., Conclusion: These results show that further research on DET as a treatment for PTSD is warranted.

A limit on a possible cosmological variation of the proton-to-electron mass ratio μ is derived from methanol (CH3OH) absorption lines in the benchmark PKS1830-211 lensing galaxy at redshift z=0.89 observed with the Effelsberg 100-m radio telescope, the Institute de Radio Astronomie Millimétrique 30-m telescope, and the Atacama Large Millimeter/submillimeter Array. Ten different absorption lines of CH3OH covering a wide range of sensitivity coefficients K(μ) are used to derive a purely statistical 1σ constraint of Δμ/μ=(1.5±1.5)×10(-7) for a lookback time of 7.5 billion years. Systematic effects of chemical segregation, excitation temperature, frequency dependence, and time variability of the background source are quantified. A multidimensional linear regression analysis leads to a robust constraint of Δμ/μ=(-1.0±0.8(stat)±1.0(sys))×10(-7).

The heat transport mediated by near-field interactions in networks of plasmonic nanostructures is shown to be analogous to a generalized random walk process. The existence of superdiffusive regimes is demonstrated both in linear ordered chains and in three-dimensional random networks by analyzing the asymptotic behavior of the corresponding probability distribution function. We show that the spread of heat in these networks is described by a type of Lévy flight. The presence of such anomalous heat-transport regimes in plasmonic networks opens the way to the design of a new generation of composite materials able to transport heat faster than the normal diffusion process in solids.

Objective: To study altered hemopexin concentrations in peritoneal fluid (PF) samples from patients with endometriosis. Recent data implicate a role of altered iron metabolism in endometriosis patients. Hemopexin is the major transport protein for heme. Like iron, heme exposure to the epithelial surface can provoke oxidative stress on the peritoneal epithelium. Therefore, altered hemopexin concentrations and heme scavenging in PF might play a role in the pathophysiology of endometriosis., Design: Prospective explorative study., Setting: Academic tertiary care center., Patient(s): Eighty symptomatic patients scheduled for laparoscopy for the diagnosis and/or therapy of endometriosis., Intervention(s): Aspiration of PF samples during laparoscopy., Main Outcome Measure(s): Hemopexin and heme concentration in PF., Result(s): At laparoscopy, 47 of 80 (58.8%) patients exhibited endometriosis, and 33 (41.2%) were proven disease-free (CO). By means of ELISA significantly lower concentrations of hemopexin in the samples from patients with endometriosis (endometriosis 0.377 ± 0.16 mg/mL) compared with controls (disease-free 0.479 ± 0.20 mg/mL) could be demonstrated. Heme levels in the samples were not significantly different between groups (endometriosis 9.130 ± 6.124 μM and disease-free 9.990 ± 4.485 μM). There was no significant correlation between heme and hemopexin levels (Pearson's correlation coefficient r = -0.146). Demographic data between the groups were comparable., Conclusion(s): These data provide further evidence that hemopexin is significantly down-regulated in PF samples from patients with endometriosis compared with controls. This study confirms recent findings in two-dimensional gel electrophoresis demonstrating a down-regulation of hemopexin in PF from patients with endometriosis in a larger series of samples., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

We experimentally demonstrate DC functionality of graphene-based hot electron transistors, which we call graphene base transistors (GBT). The fabrication scheme is potentially compatible with silicon technology and can be carried out at the wafer scale with standard silicon technology. The state of the GBTs can be switched by a potential applied to the transistor base, which is made of graphene. Transfer characteristics of the GBTs show ON/OFF current ratios exceeding 10(4).

Background: Platelet-derived growth factors (PDGF)-AA and -CC mediate renal fibroblast proliferation and/or renal fibrosis. Whereas PDGF-CC binds to both the PDGF receptors (PDGFRs)-αα- and -αβ, PDGF-AA binds more selectively to the αα-receptor, suggesting potential differences in the biological activities., Methods: We compared signal transduction, gene expression as well as changes in the proteome induced by PDGF-AA and -CC in rat renal fibroblasts, which express both PDGFR subunits. The growth factor concentrations used were chosen based on their equipotency in inducing rat renal fibroblast proliferation., Results: Both PDGF-AA and PDGF-CC induced phosphorylation and activation of extracellular signal-regulated kinase 1 (ERK1) and ERK2. Renal fibroblast proliferation induced by either PDGF-AA or -CC could be blocked by signal transduction inhibitors of the mitogen-activated protein kinase (MAPK)-, Janus-kinase (JAK)/signal transducers and activators of transcription (STAT) and phosphatidyl-inositol-3-kinase (PI3K) pathway, pointing to the involvement of all the three pathways. However, quantitative differences between both the stimulations were minor. Additive or synergistic effects by stimulating simultaneously with PDGF-AA and -CC were not observed. Using a proteomic approach we found eleven differentially expressed proteins, which were quantitatively altered after treatment with either PDGF-AA or PDGF-CC. The regulation of calreticulin and inorganic pyrophosphatase 1 could be verified by western blotting., Conclusions: PDGF-AA and -CC exhibit almost identical biological effects on signal transduction and proteome in cultured renal fibroblasts, suggesting that the ligands exert their activity essentially through the commonly bound PDGFR-αα. Nonetheless, two differentially expressed proteins were identified which might be involved in the development of renal failure.

Lipocalin 2 (LCN2) belongs to the superfamily of lipocalins which represent a group of small secreted proteins classified as extracellular transport proteins expressed in many tissues. LCN2 is strongly increased in experimental models of acute and chronic liver injuries. To investigate the function of LCN2 in normal liver homeostasis and under conditions of inflammatory liver injury, we comparatively analyzed hepatic extracts taken from Lcn2-deficient and wild type mice under basal conditions and after stimulation with lipopolysaccharides. Liver was chemically and mechanically lysed and extracts were subjected to 2-D-DIGE after minimal labeling (G200 and G300 dyes) using an appropriate internal standard (G100). Afterwards MALDI TOF MS and MS/MS were used to identify differentially expressed proteins. Proteins that were identified to be differentially expressed include for example the chloride intracellular channel protein 4 (CLIC4), aminoacylase 1 and transketolase. The altered expression of respective genes was confirmed by Western blot analysis and further validated by quantitative real time PCR. Altogether, the complex expression alterations in mice lacking LCN2 under normal conditions and after exposure to inflammatory stimuli reveal that LCN2 has essential function in liver homeostasis and in the onset of inflammatory responses in which LCN2 expression dramatically increases., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The standard model of physics is built on the fundamental constants of nature, but it does not provide an explanation for their values, nor require their constancy over space and time. Here we set a limit on a possible cosmological variation of the proton-to-electron mass ratio μ by comparing transitions in methanol observed in the early universe with those measured in the laboratory. From radio-astronomical observations of PKS1830-211, we deduced a constraint of Δμ/μ = (0.0 ± 1.0) × 10(-7) at redshift z = 0.89, corresponding to a look-back time of 7 billion years. This is consistent with a null result.

Objective: Changes in fundus autofluorescence (AF) are observed in various retinal disorders. Lipofuscin accumulation within the retinal pigment epithelium (RPE) is a source of fundus AF (FAF); however, the causes of short-term increases in FAF observed in inflammatory conditions or after laser treatment are unknown. Here, we describe an RPE cell culture model that is useful for investigations of FAF., Methods: ARPE-19 cells were cultured in 2-well chamber slides. Cells were exposed to isolated rabbit photoreceptor outer segments (POS) to mimic in vivo phagocytic activity. The AF of RPE cells exposed to POS was measured before and after focal coagulation of the cultures. AF was measured over a period of 4 weeks. Cell lysates were examined by two-dimensional (2D) gel electrophoresis and mass spectrometry analysis., Results: The exposure of ARPE cells to POS did not lead to increased AF; however, after coagulation, cells exposed to POS showed a statistically significant increase in AF (p < 0.05). 2D electrophoresis of the cell lysates revealed changes in 3 proteins. One of these proteins, identified by mass spectrometry as ezrin-radixin-moesin-binding phosphoprotein 50, was reduced in the coagulated cell population., Conclusions: We have established an in vitro model of RPE cells in culture that can be used to evaluate the development of AF and changes in cellular proteins that accompany laser photocoagulation., (Copyright © 2012 S. Karger AG, Basel.)

Many modern theories predict that the fundamental constants depend on time, position or the local density of matter. Here we develop a spectroscopic method for pulsed beams of cold molecules, and use it to measure the frequencies of microwave transitions in CH with accuracy down to 3 Hz. By comparing these frequencies with those measured from sources of CH in the Milky Way, we test the hypothesis that fundamental constants may differ between the high- and low-density environments of the Earth and the interstellar medium. For the fine structure constant we find Δα/α=(0.3 ± 1.1) × 10⁻⁷, the strongest limit to date on such a variation of α. For the electron-to-proton mass ratio we find Δμ/μ=(-0.7 ± 2.2) × 10⁻⁷. We suggest how dedicated astrophysical measurements can improve these constraints further and can also constrain temporal variation of the constants.

Caregiver education programs can support participants in a role that is often challenging. Research is needed to determine the effectiveness of these programs; however, recruitment for such studies can be difficult. The objectives of this study were to explore 1) how multiple sclerosis (MS) caregivers respond to recruitment materials for a research study evaluating a caregiver education program, including aspects of the materials that encourage or discourage their interest in participation; and 2) what recommendations MS caregivers have for improving study recruitment advertising. Qualitative interviews were conducted with seven MS caregivers. Participants were asked about their reactions to advertisements for a pilot study intended to evaluate an MS caregiver education program. Participants were also asked to reflect on factors that would influence their decision to participate in the program and to provide suggestions to improve recruitment materials. Data were analyzed using a constant-comparative approach. Study findings indicated that the language and visual design of the advertisements influenced the participants' initial responses. Some caregivers first responded to the fact that the program was part of a research study, and these caregivers had overall negative responses to the advertising, such as concern that the program was being "tested." Other caregivers first considered the personal relevance of the program. These caregivers had neutral-to-positive responses to the flyers and weighed the relevance of the program against the research and logistical aspects. Participants provided recommendations to improve the recruitment materials. While recruiting for caregiver education research can be challenging, piloting recruitment materials and using a variety of advertising options may improve response.

The paper addresses the passivation of Germanium surfaces by using layered La 2 O 3 /ZrO 2 high- k dielectrics deposited by Atomic Layer Deposition to be applied in Ge-based MOSFET devices. Improved electrical properties of these multilayered gate stacks exposed to oxidizing and reducing ambient during thermal post treatment in presence of thin Pt cap layers are demonstrated. The results suggest the formation of thin intermixed La x Ge y O z interfacial layers with thicknesses controllable by oxidation time. This formation is further investigated by XPS, EDX/EELS and TEM analysis. An additional reduction annealing treatment further improves the electrical properties of the gate dielectrics in contact with the Ge substrate. As a result low interface trap densities on (1 0 0) Ge down to 3 × 10 11  eV -1  cm -2 are demonstrated. The formation of the high- k La x Ge y O z layer is in agreement with the oxide densification theory and may explain the improved interface trap densities. The scaling potential of the respective layered gate dielectrics used in Ge-based MOS-based device structures to EOT of 1.2 nm or below is discussed. A trade-off between improved interface trap density and a lowered equivalent oxide thickness is found.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Aberrant Hedgehog (Hh) signaling is characteristic of the embryonal subtype (ERMS) and of fusion-negative alveolar RMS. In the mouse, ERMS-like tumors can be induced by mutations in the Hh receptor Patched1 (Ptch). As in humans these tumors show increased Hh pathway activity. Here we demonstrate that the treatment with the active form of vitamin D(3), calcitriol, inhibits Hh signaling and proliferation of murine ERMS in vivo and in vitro. Concomitantly, calcitriol activates vitamin D receptor (Vdr) signaling and induces tumor differentiation. In addition, calcitriol inhibits ERMS growth in Ptch-mutant mice, which is, however, a rather late response. Taken together, our results suggest that exogenous supply of calcitriol could be beneficial in the treatment of RMS, especially in those which are associated with aberrant Hh signaling activity.

Objectives: In 2004, a novel grading system for papillary non-invasive bladder cancer was introduced; low grade (LG) and high grade (HG) in lieu of the former G1, G2, G3. This change allowed for increased reproducibility as well as diminished interobserver variability in histopathological grading among individual pathologists. Matrix Assisted Laser Desorption/Ionization Time of Flight Imaging Mass Spectrometry (MALDI TOF IMS) was evaluated as an automatic and objective tool to assist grading of urothelial neoplasms and to facilitate accuracy., Design and Methods: To separate G1 (LG, n=27) and G3 (HG, n=21) papillary tumors MALDI TOF IMS was performed using an appropriate algorithm. Thereafter, the automatic assignment of a separate G2 (n=31) group was completed., Results: G1 (LG) and G3 (HG) tumors were separated with an overall cross validation of 97.18%. G2 tumors indicated a true positive rate of 78.3% for LG and 87.5% for HG, respectively., Conclusions: MALDI TOF IMS is a powerful support tool to ascertain pathological diagnosis/grading., (Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Activation of the Hedgehog (Hh)-signaling pathway due to deficiency in the Hh receptor Patched1 (Ptch) is the pivotal defect leading to formation of basal cell carcinoma (BCC). Recent reports provided evidence of Ptch-dependent secretion of vitamin D(3)-related compound, which functions as an endogenous inhibitor of Hh signaling by repressing the activity of the signal transduction partner of Ptch, Smoothened (Smo). This suggests that Ptch-deficient tumor cells are devoid of this substance, which in turn results in activation of Hh-signaling. Here, we show that the application of the physiologically active form of vitamin D(3), calcitriol, inhibits proliferation and growth of BCC of Ptch mutant mice in vitro and in vivo. This is accompanied by the activation of the vitamin D receptor (Vdr) and induction of BCC differentiation. In addition, calcitriol inhibits Hh signaling at the level of Smo in a Vdr-independent manner. The concomitant antiproliferative effects on BCC growth are stronger than those of the Hh-specific inhibitor cyclopamine, even though the latter more efficiently inhibits Hh signaling. Taken together, we show that exogenous supply of calcitriol controls the activity of 2 independent pathways, Hh and Vdr signaling, which are relevant to tumorigenesis and tumor treatment. These data suggest that calcitriol could be a therapeutic option in the treatment of BCC, the most common tumor in humans.

Despite tremendous efforts in disclosing the pathophysiological and epidemiological factors associated with liver fibrogenesis, non-invasive diagnostic measures to estimate the clinical outcome and progression of liver fibrogenesis are presently limited. Therefore, there is a mandatory need for methodologies allowing the reasonable and reliable assessment of the severity and/or progression of hepatic fibrogenesis. We here performed proteomic serum profiling by matrix-assisted laser desorption ionization time-of-flight mass spectrometry in 179 samples of patients chronically infected with hepatitis C virus and 195 control sera. Multidimensional analysis of spectra allowed the definition of algorithms capable to distinguish class-specific protein expression profiles in serum samples. Overall about 100 peaks could be detected per single spectrum. Different algorithms including protein peaks in the range of 2000 and 10,000 Da were generated after pre-fractionation on a weak cation exchange surface. A specificity of 93% with a sensitivity of 86% as mean of the test set results was found, respectively. The nature of three of these protein peaks that belonged to kininogen-1 and thymosin-β(4) was further analysed by tandem mass spectrometry (MS)/MS. We further found that kininogen-1 mRNA was significantly down-regulated in cirrhotic livers. We have identified kininogen-1 and thymosin-β(4) as potential new biomarkers for human chronic hepatitis C and conclude that serum profiling is a reliable technique to identify hepatitis-associated expression patterns. Based on the high throughput capability, the identified differential protein panel may serve as a diagnostic marker and warrants further validation in larger cohorts., (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Endometriosis is determined by local and systemic proinflammatory dysregulation and therefore differential protein expression in peritoneal fluid (PF). Of highest interest is lesion formation and the establishment and persistence of endometriosis. In this study we analyzed well-characterized PF samples of patients with ovarian or peritoneal endometriosis and compared them to control samples. We found 11 proteins differentially regulated, of which some might play a key role in the pathogenesis of endometriosis., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Schottky barrier SOI-MOSFETs incorporating a La(2)O(3)/ZrO(2) high-k dielectric stack deposited by atomic layer deposition are investigated. As the La precursor tris(N,N'-diisopropylformamidinato) lanthanum is used. As a mid-gap metal gate electrode TiN capped with W is applied. Processing parameters are optimized to issue a minimal overall thermal budget and an improved device performance. As a result, the overall thermal load was kept as low as 350, 400 or 500 °C. Excellent drive current properties, low interface trap densities of 1.9 × 10(11) eV(-1) cm(-2), a low subthreshold slope of 70-80 mV/decade, and an I(ON)/I(OFF) current ratio greater than 2 × 10(6) are obtained.

In this work, we demonstrate an approach to tune the electrical behavior of our Ω-gated germanium-nanowire (Ge-NW) MOSFETs by focused ion beam (FIB) implantation. For the MOSFETs, 35 nm thick Ge-NWs are covered by atomic layer deposition (ALD) of a high-κ gate dielectric. With the Ω-shaped metal gate acting as implantation mask, highly doped source/drain (S/D) contacts are formed in a self-aligned process by FIB implantation. Notably, without any dopant activation by annealing, the devices exhibit more than three orders of magnitude higher I(ON) currents, an improved I(ON)/I(OFF) ratio, a higher mobility and a reduced subthreshold slope of 140 mV/decade compared to identical Ge-NW MOSFETs without FIB implantation.

A panel of biomarkers for the early detection of bladder cancer has not yet been identified. Many different molecules, including DNA, RNA or proteins have been reported but none have provided adequate sensitivity for a single-tier screening test or a test to replace cystoscopy. Therefore, multimarker panels are discussed at present to give a more-precise answer to the biomarker quest. Mass spectrometry or 2D gel-electrophoresis have evolved greatly within recent years and are capable of analyzing multiple proteins or peptides in parallel with high sensitivity and specificity. However, transmission of screening results from one laboratory to another is still the main pitfall of those methods; a fact that emphasizes the need for consistent and standardized procedures as suggested by the Human Proteome Organization (HUPO). In this article, recent results in screening approaches and other proteomic techniques used for biomarker evaluation in bladder cancer are discussed with a focus on serum and tissue biomarkers.

Results of molecular pathology have supported changes in the 2004 WHO classification of urothelial cancer. Since then new molecular data such as the distribution pattern of the fibroblast growth factor receptor 3 (FGFR3) has further supported the principle of low and high grade entities of urothelial carcinoma. Animal experiments with knockout mice and conditional knockout systems reveal important parallels to humans and results emphasize the cellular context as a trigger for malignancy. One special feature of the urothelium is its high protection of the urothelial cells by members of the retinoblastoma gene family, efficiently inhibiting invasion even in the presence of p53 mutations. In search of the tumor stem cell phenotype the basal cell phenotype is the focus of attention providing a high clonogenic potential. At the same time detailed analysis of the distribution of mutations in the mitochondrial genome within the urothelium will help to gain insight into the spreading of normal cell or tumor cell clones. The overall data in urological oncology provide evidence that diagnostic and prognostic tools for urothelial cancer can only be reached with multiparametric approaches.

Purpose of Review: The WHO classification of urothelial cancer in 2004 has made changes based on the insights of molecular genetics, indicating bladder cancer with entities that are genetically stable versus those that are genetically instable. Seen as work in progress, the need of further validation is obvious. Clinical studies based on solid histological diagnosis are as necessary as the definition of more molecular features of bladder cancer., Recent Findings: Solid histological diagnosis includes sufficient clinical information and adequate tissue processing. This combined with molecular data will lead to a more clear-cut distinction between benign and malignant and possibly to another change in terminology with higher concordance to other epithelial tumours. Whereas the identification of FGFR3 mutations has led to a better distinction of at least two pathways of urothelial carcinogenesis, additional multiparametric approaches may help improve the still inadequate search for urine and blood markers indicative of bladder cancer and/or its progression. Proteomic profiling, sets of epigenetic markers, and micro RNAs will be given as examples., Summary: Recent data mainly support the concept of the WHO 2004 classification of bladder cancer. We are optimistic that an even more clear-cut distinction between benign recurring, nonprogressing tumours and more aggressive tumours will enable us to focus and limit chemotherapy.

Background: Despite continuing research for accurate bladder cancer biomarkers, the analytes suffer from lack of sensitivity and specificity., Objective: To search for discriminating protein patterns in serum, we used magnetic bead-based separation followed by matrix-assisted laser desorption ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS) to identify patients with bladder cancer., Design, Setting and Participants: In total, serum samples from 105 patients with bladder cancer, 98 healthy controls, and 45 prostate cancer patients were included in this study., Measurements: Serum samples were fractionated by means of surface-activated magnetic beads and were subsequently analyzed with MALDI-TOF MS. Multidimensional data analysis was done to generate algorithms capable of distinguishing between cancer patients and healthy individuals. The algorithms were trained using a training set of 41 bladder cancer patients and 39 healthy controls and were validated with an independent test set of 64 bladder cancer patients and 59 healthy controls. Additionally, 45 prostate cancer samples were used as a third test set., Results and Limitations: In the training set, patients with bladder cancer could be identified with an overall sensitivity of 94.1% and specificity of 89.2%. Similar results could be achieved for the test set, showing 96.4% sensitivity and 86.5% specificity. Even the presence of low-stage tumors could be predicted with 96% sensitivity and could be distinguished from higher stage or grade tumors with a sensitivity of 77.3%. Distinction between other tumor stages, however, resulted in lower sensitivity values., Conclusions: These findings demonstrate that screening for serum protein patterns using MALDI-TOF MS shows high sensitivity and specificity in identifying patients with bladder cancer, regardless of tumor stage. Due to high-throughput capability, the identified differential protein panel may improve the detection of bladder cancer.

We study the quantum and thermal fluctuations of eddy (Foucault) currents in thick metallic plates. A Casimir interaction between two plates arises from the coupling via quasistatic magnetic fields. As a function of distance, the relevant eddy current modes cross over from a quantum to a thermal regime. These modes alone reproduce previously discussed thermal anomalies of the electromagnetic Casimir interaction between good conductors. In particular, they provide a physical picture for the Casimir entropy whose nonzero value at zero temperature arises from a correlated, glassy state.

In this letter, we demonstrate the simultaneous vertical integration of self-contacting and highly oriented nanowires (NWs) into airbridge structures, which have been developed into surround gated metal oxide semiconductor field effect transistors (MOSFETs). With the use of conventional photolithography, reactive ion etching (RIE), and low pressure chemical vapor deposition, a suspended vertical NW architecture is formed on a silicon on insulator (SOI) substrate where the nanodevice will later be fabricated on. The vapor-liquid-solid (VLS) grown Si-NWs are contacted to prepatterned airbridges by a self-aligned process, and there is no need for postgrowth NW assembly or alignment. Such vertical NW architecture can be easily integrated into existing ICs processes opening the path to a new generation of nonconventional nano devices. To demonstrate the potential of this method, surround gated vertical MOSFETs have been fabricated with a highly simplified integration scheme combining top-down and bottom-up approaches, but in the same way, one can think about the realization of integrated nano sensors on the industrial scale.

Unlabelled: Hepatic cirrhosis is a life-threatening disease arising from different chronic liver disorders. One major cause for hepatic cirrhosis is chronic hepatitis C. Chronic hepatitis C is characterized by a highly variable clinical course, with at least 20% developing liver cirrhosis within 40 years. Only liver biopsy allows a reliable evaluation of the course of hepatitis C by grading inflammation and staging fibrosis, and thus serum biomarkers for hepatic fibrosis with high sensitivity and specificity are needed. To identify new candidate biomarkers for hepatic fibrosis, we performed a proteomic approach of microdissected cirrhotic septa and liver parenchyma cells. In cirrhotic septa, we detected an increasing expression of cell structure associated proteins, including actin, prolyl 4-hydroxylase, tropomyosin, calponin, transgelin, and human microfibril-associated protein 4 (MFAP-4). Tropomyosin, calponin, and transgelin reflect a contribution of activated stellate cells/myofibroblasts to chronic liver injury. The expression of tropomyosin, transgelin, and MFAP-4, an extracellular matrix associated protein, were further evaluated by immunohistochemistry. Tropomyosin and MFAP-4 demonstrated high serum levels in patients with hepatic cirrhosis of different causes., Conclusion: A quantitative analysis of MFAP-4 serum levels in a large number of patients showed MFAP-4 as novel candidate biomarker with high diagnostic accuracy for prediction of nondiseased liver versus cirrhosis [area under receiver operating characteristic curve (AUC) = 0.97, P < 0.0001] as well as stage 0 versus stage 4 fibrosis (AUC = 0.84, P < 0.0001), and stages 0 to 3 versus stage 4 fibrosis (AUC = 0.76, P < 0.0001).

Water masers are found in dense molecular clouds closely associated with supermassive black holes at the centres of active galaxies. On the basis of the understanding of the local water-maser luminosity function, it was expected that masers at intermediate and high redshifts would be extremely rare. However, galaxies at redshifts z > 2 might be quite different from those found locally, not least because of more frequent mergers and interaction events. Here we use gravitational lensing to search for masers at higher redshifts than would otherwise be possible, and find a water maser at redshift 2.64 in the dust- and gas-rich, gravitationally lensed type-1 quasar MG J0414+0534 (refs 6-13). The isotropic luminosity is 10,000 (, solar luminosity), which is twice that of the most powerful local water maser and half that of the most distant maser previously known. Using the locally determined luminosity function, the probability of finding a maser this luminous associated with any single active galaxy is 10(-6). The fact that we see such a maser in the first galaxy we observe must mean that the volume densities and luminosities of masers are higher at redshift 2.64.

The Standard Model of particle physics assumes that the so-called fundamental constants are universal and unchanging. Absorption lines arising in molecular clouds along quasar sightlines offer a precise test for variations in the proton-to-electron mass ratio, mu, over cosmological time and distance scales. The inversion transitions of ammonia are particularly sensitive to mu as compared to molecular rotational transitions. Comparing the available ammonia spectra observed toward the quasar B0218+357 with new, high-quality rotational spectra, we present the first detailed measurement of mu with this technique, limiting relative deviations from the laboratory value to |Deltamu/mu| < 1.8 x 10(-6) (95% confidence level) at approximately half the universe's current age-the strongest astrophysical constraint to date. Higher-quality ammonia observations will reduce both the statistical and systematic uncertainties in these observations.

We derive closed expressions for the Casimir-Polder potential between metal nanoparticles as well as for the light-induced interaction owing to the gradient force. Within the validity of the dipole approximation, the maximum interaction energy turns out to be proportional to the plasma frequency, and it is comparable to the thermal energy at T=300 K. On the other hand, the light-induced interaction depends linearly on the light intensity, and only for strongly focused laser beams (10-100 mW/microm(2)) does it become comparable in strength to the Casimir-Polder interaction.

Matrix metalloproteinases (MMPs), in particular MMP-2 and MMP-9, are involved in colon cancer progression and metastasis due to their ability to degrade extracellular matrix (ECM) components. In previous studies we described the MMP-9 hemopexin like domain (MMP-9-PEX) as an MMP-9 antagonist. In the present study it was examined whether recombinant MMP-9-PEX has an inhibitory effect on migration and adhesion of colorectal carcinoma cells. Furthermore, we searched for MMP-9 substrate binding sites within the MMP-9-PEX by surface plasmon resonance. Migration of SW620 and LS174 cells was investigated in a modified Boyden chamber assay. In the presence of 0.2 microg/ml MMP-9-PEX migration of SW620 was decreased by 34%, while addition of 0.4 microg/ml diminished migration by 56%. Migration of LS174 cells was not affected by MMP-9-PEX. Adhesion studies were performed on 96-well plates coated with gelatin, collagen type I, and laminin, respectively. In the presence of MMP-9-PEX, adhesion of SW620 cells to these coating substrates was significantly inhibited. Surface plasmon resonance studies revealed binding of collagen type I and IV, elastin, and fibrinogen to proMMP-9 as well as to MMP-9-PEX. However, equilibrium constants (Kd) indicated a higher affinity of proMMP-9 to the matrix proteins. This could indicate that there is more than one binding site for matrix components within the entire proMMP-9 molecule. Since migration and adhesion of metastatic colorectal carcinoma cells were reduced by MMP-9-PEX, this recombinant MMP-9 antagonist might be of therapeutical interest.

We investigated the changes in the hepatic proteome in murine models for toxic-induced fibrogenesis and sclerosing cholangitis. A comprehensive comparison of protein changes observed is made and the mechanistical basis of the expression changes is discussed. Hepatic fibrosis was induced by repetitive intraperitoneal CCl4 treatment of BALB/c mice or developed spontaneously in BALB/c-ATP-binding cassette, subfamily B, member 4 (Abcb4) knock out mice. Fibrosis was verified by a morphometric score and assessment of hydroxyproline content of liver tissue, respectively. The innovative difference in-gel electrophoresis (DIGE) technique was used to analyse protein expression levels of the mouse proteome. Results were confirmed by Western blotting and real-time RT-PCR. In CCl4-induced fibrosis 20 out of 40 and in BALB/c-Abcb4(-/-) mice 8 out of 28 differentially expressed proteins were identified utilizing DIGE. Only two proteins, selenium-binding protein (Sbp2) and carbonic anhydrase 3, have been unidirectionally expressed (i.e. down-regulated) in both models. Relevant differences in the pathogenesis of toxically induced liver fibrosis and sclerosing cholangitis exist. The only novel protein with regard to liver fibrosis depicting a unidirectional expression pattern in both animal models was Sbp2. An explicit protein function could not be clarified yet.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) plays a crucial role in the pathogenesis of hepatic fibrosis and thus may represent an important therapeutic target in the design of anti-fibrotic strategies for chronic liver disease. We present an innovative therapy based on the assignment of inactivated enzymes acting as scavengers for TIMP-1. Hepatic fibrosis was induced in BALB/c mice by repetitive intraperitoneal CCl4 injection. The animals were treated with proteolytic inactive matrix metalloproteinase-9 mutants (E402Q, H401A, E402H/H411E) using adenovirus-mediated gene transfer. Application of these MMP-9 mutants inhibited fibrogenesis, which was indicated by decreasing portal and periportal accumulation of collagen. Total hydroxyproline of liver tissue, the morphometric stage of fibrosis as well as mRNA expression of marker proteins for hepatic fibrosis in livers of E402Q- and H401A-treated mice were significantly reduced. MMP-9 mutants suppressed transdifferentiation of hepatic stellate cells to the myofibroblast like phenotype in vitro and in vivo. Moreover, adenoviral application of the mutants MMP-9-H401A and -E402Q led to increased apoptosis of activated hepatic stellate cells, thought to be the main promoters of hepatic fibrosis. Application of MMP-9 mutants as TIMP-1 scavengers may provide a new therapeutic strategy for hepatic fibrosis.

The existing optical microscopes form an image by collecting photons emitted from an object. Here we report on the experimental realization of microscopy without the need for direct optical communication with the sample. To achieve this, we have scanned a single gold nanoparticle acting as a nanoantenna in the near field of a sample and have studied the modification of its intrinsic radiative properties by monitoring its plasmon spectrum.

We measured the angular rotation and proper motion of the Triangulum Galaxy (M33) with the Very Long Baseline Array by observing two H2O masers on opposite sides of the galaxy. By comparing the angular rotation rate with the inclination and rotation speed, we obtained a distance of 730 +/- 168 kiloparsecs. This distance is consistent with the most recent Cepheid distance measurement. M33 is moving with a velocity of 190 +/- 59 kilometers per second relative to the Milky Way. These measurements promise a method to determine dynamical models for the Local Group and the mass and dark-matter halos of M31, M33, and the Milky Way.

Proteomics became a more and more important technique for the large-scale analysis of proteins during the last years. Two-dimensional (2D) electrophoresis as a major tool of proteomics is a powerful method to compare two different biological stages (e. g. healthy and diseased tissue) and to find differences in their protein pattern. One major problem in proteomics is the gel to gel variation of two-dimensional gel electrophoresis, which could cause artefacts in the detection of expression differences. The "difference in gel electrophoresis" (DIGE) technique allows the separation of two proteomes in the same gel. The protein pools were labelled with different fluorescent dyes and equal amounts of protein were separated in the same gel. Another advantage of DIGE is the possibility to separate an internal standard labelled with a third dye in the same gel to allow quantitative expression analysis. We compared proteomes of three different fibrosis models with the appropriate control (tissue inhibitor of metalloproteinases-1 (TIMP-1) overexpressing HepG2 cells in comparison to a HepG2 control, freshly isolated HSC in comparison to activated HSC and healthy mouse liver in comparison to fibrotic mouse liver). Among the differentially expressed proteins several were already found to be relevant for fibrosis but we also detected some proteins like the selenium binding protein 2 which might be relevant for hepatic fibrosis.

Concomitant consumption of benzodiazepines (BZDs) and opioids is a major problem in patients with opioid dependence. It may have substantial impact on morbidity, mortality and clinical course. The current retrospective study aims to determine whether there are differences in the additional use of BZDs among addicts regularly taking methadone or codeine medications in treatment and untreated addicts injecting heroin. The records of 1,685 patients admitted for detoxification were analyzed using bivariate analysis and multiple logistic regression analysis. Demographic and drug related variables were considered, both as possible confounders and predictors of concomitant BZD use. Daily intake of BZDs was reported in 44.4% of the patients. Patients treated with methadone or codeine medications report daily intake of BZDs significantly more often than the heroin-dependent patients (p < 0.01). Using multiple regression analyses, the results were confirmed as independent from the assessed possible confounders. Further we found that daily use of alcohol or barbiturates, early onset of opioid use (p < 0.01), unemployment, having a substance dependent family member with, and a history of imprisonment (for all p < 0.05) were associated with concomitant daily consumption of BZDs in opioid dependent subjects. These finding underline the need to further explore the causes, interactions and consequences of concomitant BZD and opiate use.

Background/aim: Injection drug users (IDUs) have a high risk of acquiring an infection with the human immunodeficiency virus (HIV). To improve counseling and prevention, a better understanding of risk factors and predictors for an infection must be gained. This retrospective study has the aim to determine the risk factors for acquisition of HIV infection other than sharing of needles/syringes., Methods: The study population consisted of all patients admitted to the detoxification unit between 1991 and 1996 who met ICD-10 criteria for opioid dependency, who reported to share needles, and who agreed to have an antibody test. Possible risk factors were assessed by interview. Cross tables based on bivariate logistic regression were constructed to estimate the relative odds. Multiple logistic regression modeling procedures were used to adjust possible confounding factors., Results: A total of 1,049 out of 1,656 patients admitted were included into the study. 4.8% of the patients were HIV-1 seropositive. The prevalence was higher among older patients and among patients living with a significant other substance drug user with substance dependency, after a longer duration of drug use, and after coinfection with hepatitis B virus and/or hepatitis C virus (HCV). Using multiple logistic regression analyses and including all individually significant risk factors, we found only coinfection with HCV to remain significant. 92% of the HIV-infected patients were also HCV infected. In the group younger than 23 years of age, a total of 53.5% of the IDUs were still seronegative for HIV, hepatitis A and B virus, and HCV., Conclusions: Despite the high rate of HCV coinfection (92%) in HIV-infected patients, we found more than 50% of IDUs younger than 23 years to be neither infected with HCV nor with HIV. Early prevention strategies against infectious diseases should especially focus on young IDUs.

Plasma IL-8 is a diagnostic parameter of early-onset bacterial infection (EOBI) in neonates but has a short half-life. The detergent-lysed whole-blood (DLWB) IL-8 consists of both extracellular and cell-bound IL-8. The objective of this study was to investigate kinetics of plasma and DLWB IL-8 in healthy newborns and those with suspected EOBI and to test the hypothesis that determination of DLWB IL-8 results in higher sensitivity for EOBI detection. Sixty-one neonates with clinical and serologic signs of EOBI composed the study group; 188 neonates with risk factors but without EOBI served as control subjects. IL-8 concentrations were determined in plasma and DLWB. In the control group, DLWB IL-8 concentrations were 280-fold higher (9599 pg/mL; SD 4433) up to 24 h post partum than corresponding plasma levels (34.2 pg/mL; SD 18.1). The sensitivity of DLWB versus plasma IL-8 for EOBI was 0.97 versus 0.71 after 6 h and 0.70 versus 0.32 after 24 h. Corresponding values for specificity were 0.95 versus 0.90 after 6 h and 0.92 versus 0.99 after 24 h. After 24 h, the negative predictive value for DLWB versus plasma IL-8 was 0.80 versus 0.66. DLWB IL-8 showed a higher sensitivity for EOBI within 6 h after first clinical suspicion than plasma IL-8. It also remained elevated longer. Our results suggest that DLWB IL-8 results in a higher sensitivity for EOBI.

We report on theoretical studies of the inhibition of the spontaneous emission process in subwavelength dielectric media. We discuss the modification of the spontaneous emission rate as a function of the size and shape of the medium as well as the position of the emitter in it.

We consider light propagation in a finite photonic crystal. The transmission and reflection from a one-dimensional system are described in an effective medium theory, which reproduces exactly the results of transfer matrix calculations. We derive simple formulas for the reflection from a semi-infinite crystal, the local density of states in absorbing crystals, and discuss defect modes and negative refraction.

We present Hubble Space Telescope/Wide-Field and Planetary Camera 2 images in Halpha + [N ii] lambdalambda6548, 6583 lines and continuum radiation and a VLA map at 8 GHz of the H2O gigamaser galaxy TXS 2226-184. This galaxy has the most luminous H2O maser emission known to date. Our red continuum images reveal a highly elongated galaxy with a dust lane crossing the nucleus. The surface brightness profile is best fitted by a bulge plus exponential disk model, favoring classification as a highly inclined spiral galaxy (i=70&j0;). The color map confirms that the dust lane is aligned with the galaxy major axis and is crossing the putative nucleus. The Halpha + [N ii] map exhibits a gaseous, jetlike structure perpendicular to the nuclear dust lane and the galaxy major axis. The radio map shows compact, steep spectrum emission that is elongated in the same direction as the Halpha + [N ii] emission. By analogy with Seyfert galaxies, we therefore suspect that this alignment reflects an interaction between the radio jet and the interstellar medium. The axes of the nuclear dust disk, the radio emission, and the optical line emission apparently define the axis of the active galactic nucleus. The observations suggest that in this galaxy the nuclear accretion disk, obscuring torus, and large-scale molecular gas layer are roughly coplanar. Our classification of the host galaxy strengthens the trend for megamasers to be found preferentially in highly inclined spiral galaxies.

We tested the specularity of the ref lection of slow atoms from an evanescent-wave mirror at normal incidence. In two of the three prisms that we tested the atoms were ref lected diffusely. This nonspecular ref lection appears to be correlated with the rms roughness of the surface supporting the evanescent wave. Only the highest quality surface (rms roughness of the order of 0.1 nm) leads to specular ref lection. This discovery imposes stringent limits on the use of these mirrors in atomic-optics experiments.

Active galactic nuclei are thought to be powered by gas falling into a massive black hole; the different types of active galaxy may arise because we view them through a thick torus of molecular gas at varying angles of inclination. One way to determine whether the black hole is surrounded by a torus, which would obscure the accretion disk around the black hole along certain lines of sight, is to search for water masers, as these exist only in regions with plentiful molecular gas. Since the first detection of an extra-galactic water maser in 1979, they have come to be associated primarily with active galaxies, and have even been used to probe the mass of the central engine. Here we report the detection of a water giga-maser in the radio galaxy TXFS2226-184. The strength of the emission supports a recently proposed theory of maser pumping that allows for even more powerful masers, which might be detectable at cosmological distances. Water masers may accordingly provide a way to determine distances to galaxies outside the usual distance ladder, providing an independent calibration of the Hubble constant.