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Predrill risk assessment for the presence of nonhydrocarbon gases in oil and methane reservoirs is challenging and perhaps commonly an underestimated task. Although the same assessment principles apply for source and migration scenarios, the interplay of both play elements in basin history is different because of diverse origins and oftentimes unusual occurrences of nonhydrocarbon gases. The southern upper Permian Zechstein-2-Carbonate (Ca2) fairway in northwestern Germany represents such a setting, where CO2 contents >60 vol. % have been encountered in an otherwise methane-dominated area. The CO2 is well constrained to be the product from thermal decomposition of ultra–deeply buried Devonian carbonates (part I published in this issue). In this study (part II), CO2-rich tectonic veins sampled for part I have been directionally reoriented in drill cores, showing a dominant northeast-southwest strike. Only very few faults can be identified in seismic data, connecting the deep CO2 source through the approximately 3-km-thick Carboniferous section with the Ca2 reservoir. Fluid inclusion analyses of hydrothermal cements from the northeast-striking veins reveal up to 100 mol % CO2, formation temperatures up to 315°C, and near-lithostatic pressure conditions. The northeast strike of the faults is parallel to the main contraction direction during Late Cretaceous basin inversion and therefore marks the most likely timing for CO2 migration. The high CO2 content wells are located within the hanging wall of seismically defined northeast-striking faults, enabling lateral injection of CO2 into downthrown Ca2 fault blocks. This pattern enhances predictability of nonhydrocarbon gases for neighboring trap structures and in similar petroliferous basins.

Comprehensive targeted Next Generation Sequencing (NGS) panels are routinely used in modern molecular cancer diagnostics. In molecular tumor boards the detected genomic alterations are often discussed to decide the next treatment options for the cancer patient. With the increasing size and complexity of NGS panels, the discussion of these results becomes increasingly complex, especially if they are reported in a text-based form, as it is the standard in current molecular pathology. We developed the Molecular Tumor Profiling pilot (MTPpilot) software to enable an efficient and quick analysis and visualization of complex NGS results, thanks to a combination of automated annotations and interactive tools. The software is tailored for the use at molecular tumor boards to aid clinical decision making. It is freely available as a web-application at https://www.mtppilot.org.

We report a measurement of the π- photoproduction beam asymmetry for the reaction γp→π-Δ++ using data from the GlueX experiment in the photon beam energy range 8.2-8.8 GeV. The asymmetry ς is measured as a function of four-momentum transfer t to the Δ++ and compared to phenomenological models. We find that ς varies as a function of t: negative at smaller values and positive at higher values of |t|. The reaction can be described theoretically by t-channel particle exchange requiring pseudoscalar, vector, and tensor intermediaries. In particular, this reaction requires charge exchange, allowing us to probe pion exchange and the significance of higher-order corrections to one-pion exchange at low momentum transfer. Constraining production mechanisms of conventional mesons may aid in the search for and study of unconventional mesons. This is the first measurement of the process at this energy. © 2021 American Physical Society.

BackgroundArticular involvement is underestimated in systemic sclerosis (SSc), but represents a major cause of disability and is a marker of disease severity. There is no approved effective therapy for arthritis in SSc and immunosuppressive treatments are given to SSc patients by analogy with rheumatoid arthritis (RA), but with limited effect. The last few years have revolutionized the understanding of the pathogenesis of RA by deciphering the heterogeneity of synovium at both the cellular and molecular levels. Nevertheless, the pathogenesis of joint involvement in SSc remains largely unknown.ObjectivesTo characterize the synovium in SSc at tissue and cellular levels and to compare it with RA synovium.MethodsNine consecutive patients fulfilling SSc classification criteria and having joint synovitis were included. Patients with overlap with other autoimmune rheumatic diseases were excluded. Synovial tissues (8 wrists, 1 knee) were obtained by ultrasound-guided biopsy and were compared to those obtained from five RF and CCP positive RA patients (3 wrists, 3 knees). Tolerance of the procedure was assessed after 3-5 days. Histological analysis of the synovium determined the Krenn synovitis score (0-9) and stratified the synovial tissue according to previously published histological features1. One biopsy, without synovial tissue, was not processed further. ScRNA-seq libraries were prepared with 10X Genomics technology and sequenced on NovaSeq 6000. Integrated bioinformatics analysis used Cell Ranger and Seurat software. Overexpressed genes were selected using log2 ratio (>0.25) and false discovery rate adjusted p value (< 0.05). For pathway enrichment analysis, Enrichr software was used.ResultsOf the nine SSc-patients, 6 were women, median age was 65 [IQR: 58-67] years, median disease duration was 2 [0.5-5] years and 2 had diffuse cutaneous subtype. The antibody status was as follows: anti-Scl70 (2), anti-centromere (2), anti-RNA polymerase III (3), anti-Ku (1) and isolated ANA (1). In the RA cohort, 4/5 were women, median age was 56 [54-59] years and median disease duration 6.5 [5-7.5] years. Synovial biopsy was well-tolerated by all the patients. Krenn synovitis score was lower in SSc as compared to RA across the three components of the synovitis score (lining layer, stroma and inflammatory infiltrate). In SSc, 7/8 (87.5%) biopsies were characterized by a pauci-immune pathotype, whereas in RA 3/6 (50%) were pauci-immune. Due to the low inflammatory pauci-immune pathotype in all but one SSc patients, we focused the scRNA sequencing analysis on synovial fibroblasts (SF) (number of SF studied: 4876 in SSc and 5885 in RA). We identified four clusters of SF with respective marker genes: SF1 (CXCL12, APOE, RARRES2, CCL2), SF2 (PRG4, MMP1, MMP3, CD55), SF3 (POSTN, ASPN, COMP, COL1A1) and SF4 (FN1, TIMP1, SERPIN2, PRELP). Comparison between SSc and RA SF subtypes showed differences in the proportion of the clusters between both diseases with higher enrichment of SF2 corresponding to the lining SF in SSc. 741 genes were differentially expressed between SSc and RA SF with 414 genes overexpressed in SSc SF. Pathway enrichment analysis of these 414 genes identified TGF-β (p.adj: 3.708e-18) and interferon (p.adj: 1.071e-8) signaling pathways. TGF-β signaling was enriched across all the clusters of SF, whereas interferon signaling mostly in sublining SF. The most overexpressed genes in SSc included PLCG2 (encoding the signaling enzyme PLCγ2, which plays a regulatory role in various immune pathways), PCOLCE2 (encoding a procollagen C-endopeptidase enhancer) and the transcription factor AHR (negative regulator of TGF-β).ConclusionSynovitis in SSc differs from RA synovitis both at histological and molecular levels. By highlighting the low inflammatory nature of the synovium and the enrichment in TGF-β and interferon signaling pathways in SSc SF, our study questions the use of the same immunosuppressive therapies in RA and SSc. These results are the basis for the development of specific targeted therapies for arthritis in SSc.References[1]Humby F, et al. Ann Rheum Dis 2019;78:761–72.Disclosure of InterestsMiranda Houtman: None declared, Raphael Micheroli: None declared, Kristina Bürki: None declared, Chantal Pauli: None declared, Sam G. Edalat: None declared, Mojca Frank Bertoncelj: None declared, Oliver Distler Speakers bureau: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur.Grant/research support from: Kymera, Mitsubishi Tanabe, Boehringer Ingelheim, Caroline Ospelt: None declared, Muriel Elhai Speakers bureau: BMS.

BackgroundThe synovium is the primary location of inflammation in various rheumatic diseases. However, specific differences of joint inflammation have not been explored on a single-cell level so far.ObjectivesTo characterize the synovium of rheumatoid arthritis (RA), psoriatic arthritis (PsA), spondyloarthritis (SpA) and undifferentiated arthritis (UA) based on clinical and histological characteristics and single-cell RNA sequencing (scRNA-seq).MethodsWe performed ultrasound (US) guided synovial biopsy in patients fulfilling classification criteria: 10 RA, 4 PsA, 4 SpA and 3 UA. 3 osteoarthritis (OA) samples were obtained from surgery. Clinical data were collected at time of biopsy. Histological analysis of the synovium included Krenn score [1], synovial pathotype [2], vascularization [3] and presence of lymphoid follicles. OA histology was not available. We prepared scRNA-seq libraries with 10X Genomics and sequenced on NovaSeq 6000. ScRNA-seq data was analysed with Cell Ranger, Seurat and Harmony R packages. We selected overexpressed genes using log2 ratio (>0.25) and FDR adjusted p value < 0.05.ResultsPatients showed typical disease characteristics. In RA, 6/10 were seropositive, 8/10 were female and median age was 59 years (IQR 12). Patients with PsA, SpA and UA were seronegative. 2/4 SpA and 1/4 PsA patients were HLA-B27 positive. Median age was 53 years in PsA (IQR 14.2), 52.5 in SpA (IQR 14.8) and 53 in UA (IQR 3.5). In PsA 3/4, SpA 2/4 and UA 1/3 patients were male.RA joints had significantly higher B-Mode US scores compared to PsA and SpA joints (mean B-Mode Score: RA 2.7; PsA 2; SpA 2). Correspondingly, RA patients reported a significantly higher amount of swelling in the biopsied joint compared to PsA and SpA (mean “Swelling-Score”: RA 6.85; PsA 4.25; SpA 4).Histology showed no clear differences in the cell composition; most joints showed a lympho-myeloid pathotype. Mean Krenn Score was highest in RA (4.78) and lowest in SpA (3.33). PD-Mode US score showed a significant positive association with histological vascularization. Lymphoid follicles were significantly more seen in RA compared to all other diseases.Integration of scRNA-seq data revealed 16 cell clusters with respective marker gene: PRG4 synovial fibroblasts (SF), THY1 SF, ACTA2 smooth muscle cells, VWF endothelial cells, TPSB2 mastcells, IGHG plasma cells, CD79 B-cells, CD69 T-Cells, CCL5 natural killer cells, DMTN Treg-cells, CXC2 neutrophil granulocytes, TREM2 macrophages, CD48 macrophages, CLEC10A macrophages, CD4 dendritic cells, MKI67 proliferating cells. OA had the lowest and RA the highest number of inflammatory cells within the synovium. SpA synovium had the highest number of neutrophils. Re-Clustering of only SF revealed 4 subtypes: PRG4 SF (3578 cells), CXCL12 SF (4539 cells), POSTN SF (2387 cells) and MFAP5 SF (1734 cells). Top 5 marker genes are shown in the Table 1. Most differentially expressed genes in OA were found in PRG4 SF; the previously described OA specific gene CSN1S1 [3] was not only underexpressed in RA but also in other inflammatory joint diseases (Figure 1). PGF, a gene associated with pathological angiogenesis, was one of the top discriminator genes, highly expressed in PsA SF (mostly PRG4 SF). RA SF (mostly CXCL12 SF) showed a high expression of CHI3L1, which is a RA specific autoantigen. High expression of hemoglobin genes was found in SpA PRG4 SF; an unexplored but previously described finding [5, 6].Table 1.Top 5 synovial fibroblast (SF) marker genes.ClusterGenePRG4 SFPRG4CSN1S1MMP3CRTAC1HTRA1CXCL12 SFAPOECXCL12CCL2PTGDSCD74POSTN SFCOMPCOL1A1POSTNCILPPTNMFAP5 SFMFAP5SFRP2APODCXCL14CFDConclusionWe were able to compare the synovium of the most common chronic inflammatory joint diseases on various levels for the first time. The findings set the path for future diagnostic, prognostic, and therapeutic approaches in inflammatory joint diseases.References[1]Krenn et al, Histopath. 2006[2]Humby et al, ARD 2019[3]Kennedy et al, AR 2010[4]Galligan et al, GI 2007[5]Yeremenko et al, A&R 2012[6]Park et al, JRD 2016Disclosure of InterestsNone declared

Additional file 2. Kaplan-Meier curves for duration of neutropenia in days in a patient subpopulation Diseases (A) ICI Treatment (B) other immune-related adverse events = irAE (C). Neutropenia therapy with steroids (D), IVIG (+ Steroids) (E) and other secondary salvage therapy (+/− IVIG) (F). Significance threshold was defined as

Additional file 1. Scatterplots with correlation of onset of neutropenia in weeks for Hemoglobin (A) and Thrombocytes (B). Significance threshold was defined as

We report measurements of the photon beam asymmetry ς for the reaction γ - p→K+ς0(1193) using the GlueX spectrometer in Hall D at Jefferson Lab. Data were collected by using a linearly polarized photon beam in the energy range of 8.2-8.8 GeV incident on a liquid hydrogen target. The beam asymmetry ς was measured as a function of the Mandelstam variable t, and a single value of ς was extracted for events produced in the u channel. These are the first exclusive measurements of the photon beam asymmetry ς for the reaction in this energy range. For the t channel, the measured beam asymmetry is close to unity over the t range studied, -t=(0.1-1.4)(GeV/c)2, with an average value of ς=1.00±0.05. This agrees with theoretical models that describe the reaction via the natural-parity exchange of the K∗(892) Regge trajectory. A value of ς=0.41±0.09 is obtained for the u channel integrated up to -u=2.0 (GeV/c)2. © 2020 American Physical Society.

Additional file 3 Kaplan-Meier curves for response of salvage treatments in days for IVIG alone (A) other salvage therapy (+/−) IVIG (B). A p-value of

We report on the measurement of the beam asymmetry ς for the reactions γ - p→pη and γ - p→pη′ from the GlueX experiment using an 8.2-8.8-GeV linearly polarized tagged photon beam incident on a liquid hydrogen target in Hall D at Jefferson Laboratory. These measurements are made as a function of momentum transfer -t with significantly higher statistical precision than our earlier η measurements and are the first measurements of η′ in this energy range. We compare the results to theoretical predictions based on t-channel quasiparticle exchange. We also compare the ratio of ςη to ςη′ to these models as this ratio is predicted to be sensitive to the amount of ss exchange in the production. We find that photoproduction of both η and η′ is dominated by natural parity exchange with little dependence on -t. © 2019 American Physical Society.

Background:The heterogeneity of synovial tissues from patients with arthritis could contribute to the interpatient variability in disease course, prognosis and treatment response. Single-cell RNA sequencing (scRNA-seq) permits in-depth analysis of tissue heterogeneity, which could facilitate drug discovery and patient stratification for precision medicine.Objectives:To construct a comprehensive landscape of synovial cell types and molecular pathways in arthritis by integrating our and published scRNA-seq data, generated across different scRNA-seq technologies [Smart-seq2, Drop-seq], cell preparation protocols [dissociated unsorted, sorted cells] and types of arthritis [undifferentiated (UA), rheumatoid arthritis, osteoarthritis].Methods:Synovial tissues were obtained by ultrasound-guided biopsy from patients with UA [not fulfilling the classification criteria for a specific arthritis, n=3]. Biopsies were disintegrated [enzymatic and mechanical disruption] and cell viability assessed with trypan blue. ScRNA-seq libraries [2 per patient] were prepared with 10X Genomics Drop-Seq and sequenced on NovaSeq6000. Bioinformatics analysis of our and published [n=35] datasets1-3was performed using Seurat protocol4with correction for batch effects and filtering low-quality cells. Functional enrichment analysis of marker genes in clusters was done with STRING Protein-Protein networks. Synovitis was assessed with ultrasound and histology.Results:Our tissue disintegration protocol resulted in good cell yield and viability (92%, 72%, 100%). The synovial cellular heterogeneity detected by scRNA-seq reflected the histological findings [Krenn score, pathotype]. These were supported with the ultrasound and clinically assessed disease activity. The integrated analysis of 41 datasets from 38 donors yielded 41845 scRNA-seq cell profiles, 50% contributed by our dataset. An independent analysis of our data and their integration with published data showed that different scRNA-seq methods and protocols can identify all the major synovial cell types and their activation states (Figure 1) with large heterogeneity between donors. We identified a previously undescribed synovial cell population, which was located near the fibroblast cluster, was negative for canonical cell markers, but highly enriched in cell division genes (80% of marker genes). These cells comprised a mixed population of CD34-, podoplanin (PDPN)highor PDPNlowcells that were mostly negative for the sub-lining fibroblast marker THY. Furthermore, they appeared to be highly secretory (extracellular matrix components) and their gene expression profile was inclined towards cell migration, vascular development and insulin growth factor-dependent processes.Figure 1.Heatmap with top 20 cluster gene markers, gene enrichment analysis and UMAP plot of synovial cell clusters.Conclusion:By integrating synovial scRNA-seq data from 41845 cells, we identified a previously undescribed, highly proliferative and secretory synovial cell population in arthritis. We increased the number of known scRNA-seq synovial cell profiles in arthritis by two-fold and demonstrated the robustness of synovial scRNA-seq data outputs across different technologies and protocols. This broadens the current knowledge of synovial tissue heterogeneity and pathology in arthritis.References:[1]Stephenson W. et al. Nat Commun 2017.[2]Mizoguchi F. et al. Nat Commun 2017.[3]Zhang F. et al. Nat Immunol 2018.[4]Stuart T et al. Cell 2019Acknowledgments:This work is supported by Vontobel Foundation and medAlumni University of ZurichDisclosure of Interests:Sam G. Edalat: None declared, Raphael Micheroli: None declared, Tadeja Kuret: None declared, Kristina Buerki: None declared, Chantal Pauli: None declared, Snežna Sodin-Šemrl: None declared, Adrian Ciurea Consultant of: Consulting and/or speaking fees from AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Merck Sharp & Dohme, Novartis and Pfizer., Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Caroline Ospelt Consultant of: Consultancy fees from Gilead Sciences., Gregor Rot: None declared, Mojca Frank-Bertoncelj: None declared

We examine the proposition of a stationary assistive robot arm in the kitchen. Based on a preliminary business plan and with the aim of generating engineering requirements, a multi-disciplinary project was established to examine the wider ramifications of such assistive technology in the household, in a Swiss context, in the fields of health and social wellbeing. Additionally the engineering aspects as well as the business aspects were examined. We detail both the individual methodologies used in this study, the results achieved and discuss the results in a wider context.

Precision oncology is a clinical approach aimed towards tailoring treatment strategies for patients based on the genetic profile of each patient's cancer. The integration of a living biobank, consisting of patient-derived tumor organoids and PDXs, with next generation sequencing approaches and high-throughput drug screening help to guide clinical decision-making and clinical trial development.Tumor organoids derived from fresh tumor samples were used for in vitro and in vivo high-throughput drug testing.Over a period of two years we established 56 in vitro tumor organoids and 19 in vivo xenografts from 18 different solid tumor types. Tumor morphology and molecular profiles show good concordance between the in vitro and in vivo models compared to their native tumor. High-throughput drug screening (up to 160 drugs) has been tested on eight tumor organoid lines. Seven of them underwent an additional combination drug screen. We nominated several targeted small molecules and novel combinations that have been validated in corresponding xenograft models.This precision medicine approach outlines the integration of genomic data with drug screening from personalized preclinical cancer models to guide precision cancer care. It also fuels next generation research and has been implemented for clinical trial development.

UNLABELLED CASE 1: A few days after returning from a holiday in Italy a 50-year-old man developed acute gastrointestinal symptoms, followed by headache, fever and joint pains. After transitory remission he had a relapse with fever, headache and meningitis 2 weeks later. Cerebrospinal fluid contained gram-negative diplococci, but no bacteria grew on culture. Under the suspected diagnosis of meningitis he was treated with penicillin. Ten days later he suddenly developed deafness in his right ear. The various signs and symptoms gradually disappeared and the patient was discharged after 24 days in hospital. Retrospectively serological tests indicated sandfly fever (SF) virus infection with serotype Toscana. This is thought to be the first reported case of deafness associated with this disease. CASE 2: One week after returning from a holiday in Tunisia a 34-year-old man fell ill with fever, headache, rigor, nausea, joint pains and a maculopapular rash for which he was treated as an outpatient. The symptoms improved after 7 days, except for the headache which persisted another 5 days. Serology demonstrated an acute infection by SF virus, serotype Sicilian. CONCLUSION Sandfly fever should be included in the differential diagnosis of headache, fever and signs of meningitis in persons who have recently been to mediterranean countries.

BACKGROUND Sulfido-Leukotrienes are important inflammatory mediators of bronchial asthma, intolerance of acetylsalicylic acid (ASA), polyposis nasi and allergic rhinitis. Receptorantagonists like Montelukast constitute a well-established asthma- and ASA intolerance-therapy. The aim of our study was to evaluate changes in patients Health-Related-Quality-of-Life (HRQL) during Montelukast-monotherapy of nasal polyposis. METHODS The study was performed in a prospective, double blind and placebo-controlled matter. The study included 30 patients of our ENT outpatient's dept. (77 % male, mean age 49 yrs), suffering from nasal polyposis grade II to IV. Polyps were endoscopically graded, nasal Eosinophilic Cationic Protein (ECP) was measured, and HRQL-score was taken prior to and four weeks after Montelukast-(0 - 0 - 10 mg) compared to placebo. An established HRQL-questionnaire - including 25 items, summarized in 6 symptom-groups - was used. Given was a symptom-score of 1 (not troubled) to 4 (extremely troubled). RESULTS Patients treated with Montelukast improved their nasal symptoms (Delta HRQL-score 0.58 +/- 0.94, P < 0.01), practical problems (Delta HRQL-score 0.42 +/- 0.71, P < 0.05), headaches (Delta HRQL-score 0.38 +/- 0.56, P < 0.05), non-nasal symptoms (Delta HRQL-score 0.35 +/- 0.92, P < 0.05), sleep (Delta HRQL-score 0.26 +/- 0.71) and emotional problems (Delta HRQL-score 0.18 +/- 0.75). Intranasal ECP (Delta 210.67 ng/ml +/- 332.68) and polyp grading (Delta 0.72 +/- 1.77) tended to improve as well, but did not reach statistical significance. Patients treated with placebo revealed no significant changes neither in HRQL-score, ECP, nor polyp grading. CONCLUSIONS Montelukast-therapy of nasal polyposis significantly improved patient's HRQL in 4 out of 6 symptom-groups. Measuring HRQL proofed to constitute a more sensitive tool than looking at eosinophilic parameters of inflammation or polyp size.

The tissue-specific glycosylation of the carcinoma (CA)-associated antigen epithelial cell adhesion molecule (EpCAM) was studied in 60 patients suffering from head and neck CAs, and 26 pairs of autologous healthy thyroid and CA biopsies. EpCAM was glycosylated in all tumor samples in which its expression was detectable (73%). Additionally, in 80.7% of patients, tumor-derived EpCAM was heavily glycosylated while EpCAM derived from autologous thyroid was not (76.2%) or weakly (23.8%). Four cases showed a similar glycosylation pattern (15.3%) and one case displayed a reverse pattern (3.8%). Additionally, the expression and glycosylation of EpCAM were assessed in tumor adjacent and distant tissue. EpCAM was glycosylated in tumor-adjacent while it was not or only weakly expressed in tumor distant tissue where it was unglycosylated. Thus, EpCAM is differentially glycosylated in healthy tissue and tumor cells of the head and neck area.

Excitation functions of the differential cross sections dσ dgw , analyzing powers AN and spin correlation parameters ANN, ASS and ASL have been measured with internal targets at the Cooler Synchrotron COSY. Data were taken continously during the acceleration and deceleration of the internal beam for kinetic energies between 450 and 2500 MeV and scattering angles 30° ⩽ σcm ⩽ 90°. Details of the experimental method are presented. The results provide excitation functions and angular distributions of high precision and internal consistency. No evidence for narrow structures are found. Upper limits on the coupling of narrow resonances to elastic scattering in the mass range √s = 2.2…2.8 GeV are deduced. The data have significant impact on phase shift solutions.

To show the equivalence of the transpulmonary thermodilution method to the direct Fick principle in children.Prospective single-centre study.A 16-bed paediatric cardiac ICU and a cardiac catheterisation laboratory at an university affiliated centre for paediatric cardiology and congenital heart disease.We consecutively investigated 18 patients (mean age 12.1 +/- 6.4 years) during cardiac catheterisation and after corrective cardiac operation.We prospectively defined limits of equivalence for cardiac index (CI) for both methods of +/- 0.25 l/min x m(2). We measured oxygen consumption for determination of CI by Fick as the clinical "gold standard" and performed a set of three transpulmonary thermodilution measurements. The mean CI(Fick) was 2.88 +/- 1.07 l/min x m(2) (range 1.10-4.62 l/min x m(2)) and CI(TPID)was 2.85 +/- 1.03 l/min x m(2)(range 1.02-4.49 l/min x m(2)). The mean difference between CI(Fick) and CI(TPID)was 0.030 +/- 0.168 l/min x m(2), and limits of agreement -0.306 to 0.366 l/min x m(2)(90% confidence interval -0.040 to 0.099 l/min x m(2)). The regression equation was : CI(Fick)=1.0244 x CI(TPID)-0.040, r(2) = 0.976, P0.0001. The intraclass coefficient of reliability for three repeated measurements of CI(TPID) was 0.97, the corresponding lower limit of the 95% confidence interval was 0.94.We demonstrated the equivalence of CI measurement by transpulmonary thermodilution and the Fick principle in children. This new method may improve hemodynamic monitoring and management in seriously ill children.

BACKGROUND Leiomyoma and Leiomyosarkoma are not often found in ENT-diseases. PATIENTS We report on a 62-year old female patient presenting with a 3 x 4 cm tumor in the oropharynx that had developed within a period of about three weeks. The patient complained of increasing dysphagia and dyspnea especially when lying on the left side. To secure breathing the patient had to be primarily ventilated by placing a needle percutaneously through the conical ligament and was then intubated. For this procedure the patient was positioned on the right side. The tumor measuring 3 cm, was removed surgically. RESULTS The tumor turned out to be a leiomyomatous neoplasia of undetermined malignant potential. Since an unfavourable behaviour of such neoplasms cannot be excluded, patients with tumors of this type should be followed closely. CONCLUSIONS In this case the tumor leads to an acute dyspnoea and a special procedure of anesthesia was necessary. Therapeutic considerations and differential diagnosis of this very rare tumor of the oropharynx are discussed by reviewing the literature.

Hintergrund und Fragestellung. In der Literatur finden sich Hinweise, dass die Plattenepithelkarzinome der Ohrmuschel im Vergleich zu anderen Lokalisationen eine schlechtere Prognose haben. Patienten/Methodik. In einer retrospektiven Studie wurden 88 Patienten mit einer Behandlung ihres Plattenepithelkarzinoms der Ohrmuschel im Zeitraum von 1975–1990 untersucht. Ergebnisse. Pratherapeutische Lymphknotenmetastasen lagen bei 8 Patienten vor (9%); 83 Patienten (94%) wurden in kurativer Intention behandelt. Die Therapie war in allen Fallen operativ. Eine postoperative Strahlentherapie wurde bei 3 Patienten durchgefuhrt; 5 Patienten verstarben an ihrem Tumor (5,7%). Von den 83 kurativ behandelten Patienten verstarben im Beobachtungszeitraum lediglich 2 an ihrem Tumor (Uberlebensrate von 98% nach 2 Jahren und 95% nach 5 Jahren). Die Rezidivrate lag nach 1 Jahr bei 7%, nach 2 Jahren bei 13% und nach 5 Jahren bei 18%. Bei positivem Halslymphknotenstatus war die Prognose bezuglich lokaler Tumorkontrolle und Uberleben deutlich schlechter. Schlussfolgerungen. Wir empfehlen primar die operative Therapie mit einem Sicherheitsabstand von 5–10 mm. Bei Nachweis von metastasenverdachtigen Halslymphknoten in der Sonographie, einer Tumorgrose uber 4 cm, Knorpelinfiltration oder einer vertikalen Tumordicke uber 5 mm ist die “neck dissection” mit Parotidektomie indiziert.

Suppressed cellular immunity is common in patients with squamous cell carcinoma of the head and neck (HNSCC). It was demonstrated in previous studies that administration of interleukin 2 (IL-2) results in enhanced antitumoral immunity in vitro as well as in vivo. Since the serum half-life of IL-2 is relatively short, repeated applications are necessary to achieve therapeutically effective serum concentrations, but this strategy might cause severe side effects. Therefore, methods that provide high local cytokine levels over a prolonged period of time without the need for repeated injections are desirable. Gene therapy as an innovative treatment approach using tumor cells stably transduced to produce IL-2 might meet these criteria. In vitro manipulated tumor cells, if readministered in the vicinity of non-manipulated tumor cells, may enhance a specific anti-tumor response in vivo without systemic side effects. The present manuscript reviews the current literature dealing with IL-2-protein and -gene therapy with special emphasis on head and neck cancer. Our own in vitro results with IL-2 gene therapy in conjunction with published data from other authors argue in favour of an in vivo approach for this therapeutic strategy that is currently in progress in our department.

Silver sheathed Tl-1223 tapes were prepared by a powder-in-tube process. The critical current density of short samples was 18 kA/cm2 at 77 K. Longer tapes up to 1.2 m, prepared by sequential pressing, had a critical current density of 12 kA/cm2. From these tapes we have wound two coils. A solenoid coil with 5 windings was made of 8 tapes with a total length of 4.5 m. At 77 K the critical current of the coil was 23 A in the self generated magnetic field (18 Gauss at the centre of the coil). Using an iron yoke the critical current remained at 22 A while the generated magnetic field increased to 120 Gauss. A pancake coil with 15 windings, made of 5 tapes with a total length of 5 m, generated a magnetic field of 149 Gauss at the critical current of 12 A. From measurements of the critical current density of our tapes in applied magnetic fields, we conclude that coils made of Tl-1223 tapes can be used to generate higher magnetic fields at 77 K.

Sera from patients with sandfly fever caused by Toscana virus (TOSV) infection were tested by immunoblot for specific antibody response to TOSV derived from infected Vero-E6 cells. The 28 kDa TOSV nucleoprotein (N) was identified as the major immunodominant protein recognized by immunoblot. In sera of patients with acute TOSV infection, specific antibodies of the IgM, IgA, and IgG class were detected. Using sandfly fever virus, serotypes Sicilian (SFSV) and Naples (SFNV), as antigens for immunoblot, TOSV antibody-positive sera cross-reacted with the corresponding N proteins. These sera reacted for IgM and IgG by SFSV immunoblot, and for IgM by SFNV immunoblot. The diagnosis of sandfly fever may be confirmed by TOSV immunoblot.

The endurance of psychotherapeutic effects after conclusion of inpatient treatment is examined in a follow-up study of 49 patients with psychosomatic, neurotic, and personality disorders. The perspective is not symptomatological but rather relates to the concrete changes occurring in the lives of the patients after treatment. The investigators hypothesized that the probability of progressively coping with life demands depends on the extent to which patients have gained insight into their central psychological problems. Using the Heidelberg Structural Change Scale (HSCS) to gauge the extent to which patients succeed in gaining cognitively and emotionally definitive insight into their intrapsychic conflicts and the structural vulnerabilities determining their condition, the authors were able to confirm their hypothesis. The HSCS, compared with other measures, offered the only possibility of predicting progressive (i.e., symptomatic) changes. The authors concluded that the demands of external life present opportunities for therapy success to be realized as progressive changes and that these changes can form a basis for further positive development.

Background: Cow's milk is one of the most common causes of food allergy. In two-thirds of patients, adverse symptoms following milk ingestion are caused by IgE-mediated allergic reactions, whereas for one-third, the mechanisms are unknown. Aim of this study was to investigate whether patients suffering from non-IgE-mediated cow's milk protein intolerance can be distinguished from persons without cow's milk protein intolerance based on serological measurement of IgG and IgA specific for purified cow's milk antigens. Methods: We determined IgG 1-4 subclass and IgA antibody levels to purified recombinant αS1-casein, αS2-casein, β-casein, κ-casein, α-lactalbumin, and β-lactoglobulin in four patient groups by ELISA: Patients with IgE-mediated cow's milk allergy (CMA, n = 25), patients with non-IgE-mediated cow's milk protein intolerance (CMPI, n = 19), patients with gastrointestinal symptoms not associated with cow's milk ingestion (GI, n = 15) and control persons without gastrointestinal problems (C, n = 26). Cow's milk-specific IgE levels were determined by ImmunoCAP. Results: Only CMA patients had IgE antibodies to cow's milk. Cow's milk allergic patients mounted the highest IgG 1 and IgG 4 antibody levels to αS1-casein, αS2-casein, β-casein, κ-casein, and α-lactalbumin. No elevated levels of IgG 4, IgA, and complement-binding IgG subclasses (IgG 1, IgG 2, IgG 3) to purified cow's milk allergens were found within the CMPI patients compared to persons without cow's milk protein intolerance (GI and C groups). Conclusion: Cow's milk protein intolerant patients cannot be distinguished from persons without cow's milk protein intolerance on the basis of IgG subclass or IgA reactivity to cow's milk allergens. © 2011 John Wiley & Sons A/S.

Sulfido-Leukotrienes are important inflammatory mediators of bronchial asthma, intolerance of acetylsalicylic acid (ASA), polyposis nasi and allergic rhinitis. Receptorantagonists like Montelukast constitute a well-established asthma- and ASA intolerance-therapy. The aim of our study was to evaluate changes in patients Health-Related-Quality-of-Life (HRQL) during Montelukast-monotherapy of nasal polyposis.The study was performed in a prospective, double blind and placebo-controlled matter. The study included 30 patients of our ENT outpatient's dept. (77 % male, mean age 49 yrs), suffering from nasal polyposis grade II to IV. Polyps were endoscopically graded, nasal Eosinophilic Cationic Protein (ECP) was measured, and HRQL-score was taken prior to and four weeks after Montelukast-(0 - 0 - 10 mg) compared to placebo. An established HRQL-questionnaire - including 25 items, summarized in 6 symptom-groups - was used. Given was a symptom-score of 1 (not troubled) to 4 (extremely troubled).Patients treated with Montelukast improved their nasal symptoms (Delta HRQL-score 0.58 +/- 0.94, P0.01), practical problems (Delta HRQL-score 0.42 +/- 0.71, P0.05), headaches (Delta HRQL-score 0.38 +/- 0.56, P0.05), non-nasal symptoms (Delta HRQL-score 0.35 +/- 0.92, P0.05), sleep (Delta HRQL-score 0.26 +/- 0.71) and emotional problems (Delta HRQL-score 0.18 +/- 0.75). Intranasal ECP (Delta 210.67 ng/ml +/- 332.68) and polyp grading (Delta 0.72 +/- 1.77) tended to improve as well, but did not reach statistical significance. Patients treated with placebo revealed no significant changes neither in HRQL-score, ECP, nor polyp grading.Montelukast-therapy of nasal polyposis significantly improved patient's HRQL in 4 out of 6 symptom-groups. Measuring HRQL proofed to constitute a more sensitive tool than looking at eosinophilic parameters of inflammation or polyp size.

: We describe a patient with human immunodeficiency virus type-1 (HIV) infection and alveolar echinococcosis (AE) with a focus on two messages. Despite being severely immunocompromised over years the patient exhibited a long-term asymptomatic course of AE. This is in clear contrast to reports describing accelerated courses of AE in immunocompromised patients. The patient had therapeutic mebendazole drug levels with only 1/10 of the normal drug dose. He was co-treated with protease inhibitors for his HIV infection. These drugs are known as strong inhibitors of cytochrome P450 3A4 (CYP3A4)-dependent metabolism. We speculate that benzimidazoles and protease inhibitors interfere at the CYP3A4-level. The first report of co-infection of HIV and accelerated AE was in a young girl with an extremely low CD4 cell count and an abrogated lymphoproliferative responsiveness to parasite antigen stimulation. Since the CD4 cell count in our patient remained in the range of 27-150 cells/µl, we speculate that there was a critical threshold of immunosupression for constraining AE. Initial treatment with albendazole for AE added to the current highly active antiretroviral treatment (HAART), and suppressive toxoplasmosis therapy became complicated by pancytopenia. After full recovery of the bone marrow, mebendazole was introduced with a new HAART and the previously prescribed toxoplasmosis maintenance therapy. Surprisingly, efficient mebendazole levels were achieved with an uncommonly low dose. These observations suggest that the benzimidazoles, albendazole and mebendazole, may interact with protease inhibitors, which are known for their strong inhibition of the CYP3A4

Because of its distinct anatomy, pathogens can quickly reach the middle ear of a child and cause acute otitis media. Depending on the age of the child, the clinical symptoms can vary from intense earaches, fever, pressure sensation and hearing loss to vomiting, diarrhea and refusal of food by infants. The progression of otitis media through four phases can be observed in an otoscopic examination. To improve Eustachian tube ventilation in uncomplicated cases, nose drops to reduce swelling along with pain therapy are employed first. Antibiotics can be administered to reduce the rate of complications from, for example, mastoiditis, paresis of the facial nerve, and labyrinthitis. In recurrent middle ear infections, an operative therapy should also be considered.

Background: Clinical outcome of patients with head and neck squamous cell carcinoma (SCCHN) depends on several risk factors like the presence of locoregional lymph node or distant metastases, stage, localisation and histologic differentiation of the tumour. Circulating tumour cells in the bone marrow indicate a poor prognosis for patients with various kinds of malignoma. The present study examines the clinical relevance of occult tumour cells in patients suffering from SCCHN. Patients and Methods: Bone marrow aspirates of 176 patients suffering from SCCHN were obtained prior to surgery and stained for the presence of disseminated tumour cells. Antibodies for cytokeratin 19 were used for immunohistochemical detection with APAAP on cytospin slides. Within a clinical follow-up protocol over a period of 60 months, the prognostic relevance of several clinicopathological parameters and occult tumour cells was evaluated. Results: Single CK19-expressing tumour cells could be detected in the bone marrow of 30.7% of the patients. There is a significant correlation between occult tumour cells in the bone marrow and relapse. Uni- and multivariate analysis of all clinical data showed the metastases in the locoregional lymph system and detection of disseminated tumour cells in the bone marrow to be statistically highly significant for clinical prognosis. Conclusion: The detection of minimal residual disease underlines the understanding of SCCHN as a systemic disease. Further examination of such cells will lead to a better understanding of the tumour biology, as well as to improvement of diagnostic and therapeutic strategies.

Most cases of Duchenne muscular dystrophy are caused by dystrophin gene mutations that disrupt the mRNA reading frame. Artificial exclusion (skipping) of a single exon would often restore the reading frame, giving rise to a shorter, but still functional dystrophin protein. Here, we analyzed the ability of antisense U7 small nuclear (sn)RNA derivatives to alter dystrophin pre-mRNA splicing. As a proof of principle, we first targeted the splice sites flanking exon 23 of dystrophin pre-mRNA in the wild-type muscle cell line C2C12 and showed precise exon 23 skipping. The same strategy was then successfully adapted to dystrophic immortalized mdx muscle cells where exon-23-skipped dystrophin mRNA rescued dystrophin protein synthesis. Moreover, we observed a stimulation of antisense U7 snRNA expression by the murine muscle creatine kinase enhancer. These results demonstrate that alteration of dystrophin pre-mRNA splicing could correct dystrophin gene mutations by expression of specific U7 snRNA constructs.

Tenascin, an extracellular matrix glycoprotein, is transiently present in embryonic tissue, in benign granulation tissue, but also in several highly anaplastic tumors like fibrosarcoma, melanoma and squamous cell carcinoma of the skin. This study was performed to validate elevated Tenascin serum levels as a possible marker for head and neck squamous cell carcinomas (HNSCC).Tenascin serum levels were evaluated in patients with primary (n = 92) and with recurrent (n = 28) HNSCC. Patients with benign, non inflammatory ear, nose and throat diseases (n = 16) served as the control. The Tenascin serum levels were measured by ELISA (Aventis).Serum Tenascin concentrations of patients with benign ENT diseases ranged between 0.37 and 2.19 micrograms/ml (n = 16, mean +/- SD: 1.23 +/- 0.59 micrograms/ml), of patients with HNSCC (primary diagnosis) between 0.05 and 8.75 micrograms/ml (n = 92, mean +/- SD: 1.81 (1.36 micrograms/ml) and of patients with recurrent HNSCC between 0.53 and 10.0 micrograms/ml (n = 28, mean +/- SD: 2.78 +/- 2.2 micrograms/ml).We found a significant elevation of Tenascin serum levels only in patients with higher tumor stages (T4/UICC4) (p0.01/p0.1) or recurrent disease compared to Tenascin serum levels in healthy controls. Thereby Tenascin serum levels cannot be used clinically as a routine serum marker for the control of head and neck cancer. Further investigations are necessary to evaluate whether the measurement of Tenascin levels as tumor markers could offer additional information to the clinical outcome of patients with HNSCC.

The method of iterated resolvents is used to obtain an effective Hamiltonian for neighbouring qubits in the Kane solid state quantum computer. In contrast to the adiabatic gate processes inherent in the Kane proposal we show that free evolution of the qubit-qubit system, as generated by this effective Hamiltonian, combined with single qubit operations, is sufficient to produce a controlled-NOT (c-NOT) gate. Thus the usual set of universal gates can be obtained on the Kane quantum computer without the need for adiabatic switching of the controllable parameters as prescribed by Kane. Both the fidelity and gate time of this non-adiabatic c-NOT gate are determined by numerical simulation., 8 pages, No figures

A qualitative study is presented, investigating the subjective experiences of counsellors in consulting pregnant women expecting a child with genetic defects. The aim of the study was an exploration of consultation criteria that were used in these consultations, to systematically expand the currently used theoretical based consultation concepts by the perspectives of those involved in the consultation process. The study is part of a collaborative study, dealing with the development of consultation criteria for pregnant women. Data consist of extensive written consultation transcripts, describing typical case setting at different time points during a consultation process. We used a content-analytical approach to systematically categorize the variety of single topics mentioned in these transcripts. Typical consultation settings at different time points during consultation were compared. Data are presented using illustrated text material.

Leiomyoma and Leiomyosarkoma are not often found in ENT-diseases.We report on a 62-year old female patient presenting with a 3 x 4 cm tumor in the oropharynx that had developed within a period of about three weeks. The patient complained of increasing dysphagia and dyspnea especially when lying on the left side. To secure breathing the patient had to be primarily ventilated by placing a needle percutaneously through the conical ligament and was then intubated. For this procedure the patient was positioned on the right side. The tumor measuring 3 cm, was removed surgically.The tumor turned out to be a leiomyomatous neoplasia of undetermined malignant potential. Since an unfavourable behaviour of such neoplasms cannot be excluded, patients with tumors of this type should be followed closely.In this case the tumor leads to an acute dyspnoea and a special procedure of anesthesia was necessary. Therapeutic considerations and differential diagnosis of this very rare tumor of the oropharynx are discussed by reviewing the literature.

Suppressed cellular immunity is common in patients with squamous cell carcinoma of the head and neck (HNSCC). It was demonstrated in previous studies that administration of interleukin 2 (IL-2) results in enhanced antitumoral immunity in vitro as well as in vivo. Since the serum half-life of IL-2 is relatively short, repeated applications are necessary to achieve therapeutically effective serum concentrations, but this strategy might cause severe side effects. Therefore, methods that provide high local cytokine levels over a prolonged period of time without the need for repeated injections are desirable. Gene therapy as an innovative treatment approach using tumor cells stably transduced to produce IL-2 might meet these criteria. In vitro manipulated tumor cells, if readministered in the vicinity of non-manipulated tumor cells, may enhance a specific anti-tumor response in vivo without systemic side effects. The present manuscript reviews the current literature dealing with IL-2-protein and -gene therapy with special emphasis on head and neck cancer. Our own in vitro results with IL-2 gene therapy in conjunction with published data from other authors argue in favour of an in vivo approach for this therapeutic strategy that is currently in progress in our department.

Squamous cell carcinoma of the pinna seems to be associated with a worse prognosis as compared to other locations.We studied 88 patients treated between 1975 and 1990 for a squamous cell carcinoma of the pinna.Lymph node metastases were present in eight cases (9%) prior to treatment. Treatment was intended to be curative in 83 patients (94%). Tumor therapy was operative in all cases. Radiotherapy was instituted postoperatively in three patients; five patients (5.7%) died due to the tumor. Of 83 curatively treated patients, only 2 died of tumor progression. The survival rate was 98% after 2 years and 95% after 5 years. The recurrence rate was 7% after 1 year, 13% after 2 years, and 18% after 5 years. The outcome with regard to local tumor control and survival was significantly poorer when neck metastases were present.We recommend tumor excision with wide margins (5-10 mm) as first-line treatment. Neck dissection with parotidectomy is indicated when suspicious lymph nodes are detected by ultrasound sonography, the tumor diameter is4 cm, cartilaginous invasion is present, and vertical tumor thickness is5 mm.

Di(2-ethylhexyl) phthalate (DEHP) is the most commonly used plasticizer in polyvinyl chloride (PVC) plastics, and is therefore a major constituent of continuous ambulatory peritoneal dialysis (CAPD) bags. Because DEHP is not chemically bound, it leaches out of the plastic matrix. Recently, we found that leukocyte function in vitro is impaired by a mixture of metabolites of DEHP. In the present study, we investigated the metabolism of DEHP in patients on CAPD. The study group consisted of 10 stable patients, on CAPD for at least 6 months, using a plasticizer-containing PVC PD system [ANDY Plus (Fresenius Medical Care, Bad Homburg, Germany)]. Effluent dialysate and urine samples were collected over 24 hours, and a 10 mL blood sample was drawn. Concentrations of DEHP and its metabolites mono(2-ethylhexyl) phthalate (MEHP), phthalic acid (PA), and 2-ethylhexanol (2-EH) were determined in urine, dialysate, and serum using gas chromatography/mass spectrometry. Additionally, the degree of glucuronidation of the phthalic acid esters in urine were determined. In serum, dialysate, and urine, PA was the predominant metabolite of DEHP (0.205 +/- 0.067 mg/L, 0.284 +/- 0.180 mg/L, and 1.34 +/- 1.00 mg/L, respectively), but concentrations of MEHP were low (0.0100 +/- 0.0056 mg/L, 0.022 +/- 0.008 mg/L, 0.011 +/- 0.0064 mg/L, respectively). Urinary MEHP was glucuronidated to approximately 15%. PA was 35% eliminated as a glucuronide. Unlike healthy subjects, PD patients do not eliminate DEHP mainly in the form of MEHP or MEHP metabolites. They further break these compounds down to PA. The fact that concentrations of PA in urine exceed by far the respective serum concentrations indicates that PA is secreted by the kidney. Further research on the toxicological aspects of plasticizers in uremic patients should take these findings into account.