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Marcus Panning,Thomas Laue,Stephan Olschlager,Markus Eickmann,Stephan Becker,Sabine Raith,Marie-Claude Georges Courbot,Mikael Nilsson,Robin Gopal,Ake Lundkvist,Antonino di Caro,David Brown,Hermann Meyer,Graham Lloyd,Beate M Kummerer,Stephan Gunther,Christian Drosten A network of European biosafety level 4 laboratories has designed the first industry-standard molecular assay for all filoviruses species, based on the strain collections of all participants. It uses 5 optimized L gene primers and 3 probes, as well as an internal control with a separate detection p... ( view more )robe. Detection limits (probit analysis, 95% detection chance) were as follows: Zaire ebolavirus, 487 copies/mL of plasma; Sudan ebolavirus Maleo, 586 copies/mL; Sudan ebolavirus Gulu, 1128 copies/mL; Cote d'Ivoire ebolavirus, 537 copies/mL; Reston ebolavirus, 4546 copies/mL; Lake Victoria marburgvirus Musoke, 860 copies/mL; and Lake Victoria marburgvirus Ravn, 1551 copies/mL. The assay facilitates reliable detection or exclusion screening of filovirus infections. ( view less ) Ahmed Madisch,Stephan Hellmig,Stephan Schreiber,Birgit Bethke,Manfred Stolte,Stephan Miehlke BACKGROUND: Collagenous colitis is a chronic inflammatory bowel disease of unknown origin. In some cases of collagenous colitis, histomorphological features are comparable to other inflammatory bowel diseases. AIM: To assess functional NOD2/CARD15 polymorphisms for the susceptibility to collagenous... ( view more ) colitis in a case-control study. MATERIALS AND METHODS: Seventy-five patients with symptomatic collagenous colitis and 534 healthy blood donors were genotyped for SNP 8, 12, and 13 of the NOD2/CARD15 gene using TaqMan technology. Susceptibility to collagenous colitis was tested using Chi(2)-test comparing the carrier status of the rare allele. RESULTS: The carrier frequency of the rare allele in SNP 8, 12, and 13 was 9.5, 1.3, and 8.1% in patients with collagenous colitis and 8.9, 1.1, and 8.4% in healthy blood donors, respectively. There were no significant differences in allele-, genotype, and carrier frequency (p>0.05). CONCLUSION: Our data suggest that functional polymorphisms in the NOD2/CARD15 gene might not be involved in the susceptibility to collagenous colitis. ( view less ) Rainer Moog,Thomas Zeiler,Hans-Gert Heuft,Bernhard Stephan,Eike G Fischer,Volker Kretschmer,Regina Rödel-Spieker,Erwin Strasser,Jürgen Zingsem,Roger Moog,Berckard Stephan,Stephan Strasser BACKGROUND: A new cell separator (COM.TEC, Fresenius) was recently developed aimed at efficient collection of WBC-reduced single-donor PLT concentrates (SDPs). STUDY DESIGN AND METHODS: Five German centers collected 554 WBC-reduced SDPs with help of the COM.TEC cell separator. Two multicenter cell ... ( view more )counting studies were performed at the beginning and at the end of the study to document uniform counting results among the participating centers. RESULTS: A total of 441 (79.6%) PLT collections were included in the study according to the protocol. A total of 342 single-dose and 99 double-dose SDPs were collected. For single-dose SDPs, an average blood volume of 2826 +/- 409 mL was processed in a donation time of 55 +/- 11 minutes. Mean PLT yield of these products was 3.11 x 1011+/- 0.40 x 1011 and the WBC contamination was 0.11 x 106+/- 0.20 x 106. For double-dose SDPs (PLT count, 5.29 +/- 0.93 x 1011), 3943 +/- 639 mL was processed. The average difference between the target and the collected PLT concentration was -2.8 +/- 12.0 percent for single-dose SDPs and -1.8 +/- 9.5 for double-dose SDPs, respectively. The collection efficiency was 53.7 +/- 5.8 percent for single-dose SDPs and 58.2 +/- 6.2 percent for double-dose SDPs. If all results of each sample from the counting study were set to unity (to the mean over all centers), most PLT determinations were very similar to the mean, for example, near or 1 if set to unity. CONCLUSION: The COM.TEC machine makes it possible to obtain WBC-reduced SDPs that comply with current standards. ( view less ) E Stephan,E Kunkel Hundhausen's statements to valuation of repeating training courses show essential deficiencies: Quotations of specialitic authors are placed in a not right context. Relevant empiric results which would withdraw the basis of all his conclusions are not reported by him. So he argues in opposition to ... ( view more )published empiric dates (see Winkler 1988, Stephan 1988) and logical arguments (see Stephan 1988), which prove that persons comprised in reality examinations had a above-averades traffic risk. Moreover, he overlooks in his exclusive 'calculatory valuation' that his argue of 'detour production' on the one hand violates the public claim on traffic security and on the other hand the constitutional claim of the alcohol conspicious drivers on proportion of national sanctions and measures. Also in case subsequent trained drivers do not represent a population being specially high relapse dangered, they should be offered the possibility to choose their own milder alternative (shortening of blocking period when having been successful as a course member). This should only be realized when the traffic security is not affected. The attempt to achieve an own valuation of the course success by economic founded scales must be judged as failed because of the not exactly termed premises and the logical consequences as well. ( view less ) G E Stephan,D R McMullin,K H StephanWe examine nations which deviate significantly from the -2/3 size-density slope previously observed for the aggregated political subdivisions of 98 modern nations and previously derived from the theory of time-minimization. We correct Stephan's original list of deviant nations, demonstrate that all... ( view more ) slopes more negative than -2/3 were due to the erroneous inclusion of cities in the original data sets, develop a theory to account for the less negative deviant slopes, and test the theory both through statistical manipulation of current data and through analysis of available historical data. ( view less ) Holger Cynis,Jens-Ulrich Rahfeld,Anett Stephan,Astrid Kehlen,Birgit Koch,Michael Wermann,Hans-Ulrich Demuth,Stephan Schilling Mammalian glutaminyl cyclase isoenzymes (isoQCs) were identified. The analysis of the primary structure of human isoQC (h-isoQC) revealed conservation of the zinc-binding motif of the human QC (hQC). In contrast to hQC, h-isoQC carries an N-terminal signal anchor. The cDNAs of human and murine isoQ... ( view more )Cs were isolated and h-isoQC, lacking the N-terminal signal anchor and the short cytosolic tail, was expressed as a fusion protein in Escherichia coli. h-isoQC exhibits 10fold lower activity compared to hQC. Similar to hQC, h-isoQC was competitively inhibited by imidazoles and cysteamines. Inactivation by metal chelators suggests a conserved metal-dependent catalytic mechanism of both isoenzymes. A comparison of the expression pattern of m-isoQC and murine QC revealed ubiquitous expression of both enzymes. However, murine QC transcript formation was higher in neuronal tissue, whereas the amount of m-isoQC transcripts did not vary significantly between different organs. h-isoQC was exclusively localized within the Golgi complex, obviously retained by the N-terminus. Similar resident enzymes of the Golgi complex are the glycosyltransferases. Golgi apparatus retention implies a "housekeeping" protein maturation machinery conducting glycosylation and pyroglutamyl formation. For these enzymes, apparently similar strategies evolved to retain the proteins in the Golgi complex. ( view less ) René Gobbelé,Kathrin Lamberty,Klaas E Stephan,Ulrike Stegelmeyer,Helmut Buchner,John C Marshall,Gereon R Fink,Till D Waberski In a recent fMRI study with identical word stimuli we demonstrated task-dependent lateralization of brain activity during visual processing, with left-hemispheric activations for letter decisions and right-hemispheric activations for visuospatial decisions (Stephan, K.E., Marshall, J.C., Friston, K... ( view more ).J., Rowe, J.B., Ritzl, A., Zilles, K., Fink, G.R., 2003. Lateralized Cognitive Processes and Lateralized Task Control in the Human Brain. Science 301, 384-386). In order to explore the temporal dynamics of these lateralized processes we here recorded multichannel event-related potentials (ERPs) using the same stimuli. ERP data were analysed with current source density reconstruction (CDR). Contrasting the ERP results elicited by the two tasks, source deconvolution showed enhanced activity during letter decisions in Broca's area from 200-250 ms during letter decisions and during visuospatial decisions in the right posterior parietal cortex (PPC) from 175-200 ms and 250-275 ms. Prior to these activations ERP data revealed an initiation of activity within the anterior cingulate cortex (ACC) from 125-150 ms followed by a late activation of this region from 400-425 ms. Consistent with our previous fMRI study the current electrophysiological data support the notion that lateralized cognitive processes may depend on task requirements rather than stimulus properties. The current results extend our previous findings as they allow insights into the temporal dynamics of these lateralized processes and their relations to task control processes. The temporal deconvolution of ERPs suggests an early differential involvement of Broca's area in letter-processing and of PPC during visuospatial processing. In addition, activation of ACC prior and after this differential activation is consistent with previous findings suggesting that this area may be involved in cognitive control. ( view less ) Eric M Reiman,Kewei Chen,Richard J Caselli,Gene E Alexander,Daniel Bandy,Jennifer L Adamson,Wendy Lee,Ashley Cannon,Elizabeth A Stephan,Dietrich A Stephan,Andreas Papassotiropoulos We recently implicated a cluster of nine single nucleotide polymorphisms from seven cholesterol-related genes in the risk of Alzheimer's disease (AD) in a European cohort, and we proposed calculating an aggregate cholesterol-related genetic score (CREGS) to characterize a person's risk. In a separa... ( view more )te study, we found that apolipoprotein E (APOE) epsilon4 gene dose, an established AD risk factor, was correlated with fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements of hypometabolism in AD-affected brain regions in a cognitively normal American cohort, and we proposed using PET as a presymptomatic endophenotype to help assess putative modifiers of AD risk. Thus, the objective in the present study is to determine whether CREGS is related to PET measurements of hypometabolism in AD-affected brain regions. DNA and PET data from 141 cognitively normal late middle-aged APOE epsilon4 homozygotes, heterozygotes and noncarriers were analyzed to evaluate the relationship between CREGS and regional PET measurements. Cholesterol-related genetic risk scores were associated with hypometabolism in AD-affected brain regions, even when controlling for the effects of APOE epsilon4 gene dose. The results support the role of cholesterol-related genes in the predisposition to AD and support the value of neuroimaging in the presymptomatic assessment of putative modifiers of AD risk. ( view less ) Barbara Bernasconi,Eva Karamitopolou-Diamantiis,Luigi Tornillo,Alessandro Lugli,Dolores Di Vizio,Stephan Dirnhofer,Stephan Wengmann,Katharyna Glatz-Krieger,Falko Fend,Carlo Capella,Luigi Insabato,Luigi M Terracciano Extranodal marginal zone B-cell lymphomas (mucosa-associated lymphoid tissue [MALT] lymphomas) of the gastrointestinal tract have been known to have characteristic chromosomal aberrations including trisomies of chromosomes 3, 12, and 18. However, knowledge of the clinical significance of cytogeneti... ( view more )c changes in MALT lymphomas is still limited. In the present study, the frequency of the numeric and structural aberrations of the chromosomes 1, 3, 12, 18 and X and of the MALT1 gene as well as their potential clinical significance were analyzed by using fluorescent in situ hybridization on a tissue microarray containing 257 tissue samples from 203 cases of surgically resected primary gastric lymphomas including 115 cases of MALT lymphomas, 88 cases of diffuse large B-cell lymphomas (DLBCLs, 75 with an associated MALT lymphoma, so-called ex-MALT DLBCL, and 13 de novo), and 54 controls cases of Helicobacter pylori-associated chronic gastritis. Clinical follow-up information was available in 137 cases. Trisomies 1, 3, 12, and 18 were detected in 3.3%, 44.4%, 12.3%, and 19.2% of MALT lymphomas and in 11.1%, 42.2%, 26.5%, and 22.0% of ex-MALT DLBCLs, respectively. In addition, we found gains of the X chromosome in 36.4% of MALT lymphomas, in 34.5% of ex-MALT DLBCLs, and in 36.4% of de novo DLBCLs. Structural and/or numeric abnormalities of the MALT1 gene were observed in 37.0% of MALT lymphomas and in 22.2% of ex-MALT DLBCLs. In de novo DLBCL, trisomies for chromosomes 3, 12, 18, and X were found in 42.9%, 10.0%, 11.1%, and 36.4%, respectively, whereas alterations of MALT1 (namely, translocations) were found in 20.0% of the cases. An unexpected high and previously unreported gain of chromosome X in gastric MALT lymphomas was found. This tumor appears, therefore, to be a genetically unstable neoplasia. Our results point out that t(11;18) and aneuploidy may be both involved in lymphomagenesis and that at least a subset of MALT lymphomas may progress toward high-grade neoplasia. ( view less ) Stephan Rüegg,Yvonne Naegelin,Martin Hardmeier,David T Winkler,Stephan Marsch,Peter Fuhr Levetiracetam (LEV) is a broad-spectrum antiepileptic drug with no known interactions and a favorable profile of adverse events. These properties make it a good candidate for use in critically ill patients. An intravenous formulation of LEV was recently approved. The present study retrospectively a... ( view more )ssesses the safety and efficacy of LEV in the first 50 critically ill patients treated with intravenous LEV. Indications for use were seizure prophylaxis, acute symptomatic seizures, and all forms of status epilepticus. There were no major adverse effects, although less prominent changes may have been masked by the already severely compromised condition of these patients. Two patients (4%) had transiently lowered platelet counts (55,000 and 82,000, respectively). Efficacy, defined as cessation of seizure activity or prevention of its recurrence, was observed in 41 of 50 patients (82%). Antiepileptic treatment of critically ill patients with LEV seems to be effective and safe according to the data for this small cohort, but this observation warrants further prospective investigation in a larger number of patients. ( view less ) Salah-Eddin Al-Batran,Joerg Thomas Hartmann,Stephan Probst,Harald Schmalenberg,Stephan Hollerbach,Ralf Hofheinz,Volker Rethwisch,Gernot Seipelt,Nils Homann,Gerhard Wilhelm,Gunter Schuch,Jan Stoehlmacher,Hans Günter Derigs,Susanna Hegewisch-Becker,Johannes Grossmann,Claudia Pauligk,Akin Atmaca,Carsten Bokemeyer,Alexander Knuth,Elke Jäger,Arbeitsgemeinschaft Internistische Onkologie  PURPOSE: This study was designed to compare fluorouracil, leucovorin, and oxaliplatin with fluorouracil, leucovorin, and cisplatin in patients with advanced gastric cancer. PATIENTS AND METHODS: Patients with previously untreated advanced adenocarcinoma of the stomach or esophagogastric junction we... ( view more )re randomly assigned to receive either fluorouracil 2,600 mg/m(2) via 24-hour infusion, leucovorin 200 mg/m(2), and oxaliplatin 85 mg/m(2) (FLO) every 2 weeks or fluorouracil 2,000 mg/m(2) via 24-hour infusion, leucovorin 200 mg/m(2) weekly, and cisplatin 50 mg/m(2) every 2 weeks (FLP). The primary end point was progression-free survival (PFS). RESULTS: Two hundred twenty patients (median age, 64 years; metastatic, 94%) were randomly assigned. FLO was associated with significantly less (any grade) anemia (54% v 72%), nausea (53% v 70%), vomiting (31% v 52%), alopecia (22% v 39%), fatigue (19% v 34%), renal toxicity (11% v 34%), thromboembolic events (0.9% v 7.8%), and serious adverse events related to the treatment (9% v 19%). FLP was associated with significantly less peripheral neuropathy (22% v 63%). There was a trend toward improved median PFS with FLO versus FLP (5.8 v 3.9 months, respectively; P = .077) and no significant difference in median overall survival (10.7 v 8.8 months, respectively). However, in patients older than 65 years (n = 94), treatment with FLO resulted in significantly superior response rates (41.3% v 16.7%; P = .012), time to treatment failure (5.4 v 2.3 months; P < .001), and PFS (6.0 v 3.1 month; P = .029) and an improved OS (13.9 v 7.2 months) as compared with FLP, respectively. CONCLUSION: FLO reduced toxicity as compared with FLP. In older adult patients, FLO also seemed to be associated with improved efficacy. ( view less ) Ursula E A Fittschen,Nicolas H Bings,Stephan Hauschild,Stephan Förster,Arne F Kiera,Ezer Karavani,Andreas Frömsdorf,Julian Thiele,Gerald Falkenberg The characteristics of dried residues of picodroplets of single-, two-, and three-element aqueous solutions, which qualify these as reference materials in the direct analysis of single particles, single cells, and other microscopic objects using, e.g., laser ablation inductively coupled plasma time... ( view more )-of-flight mass spectrometry (LA-ICP-TOF-MS) and micro-X-ray fluorescence (MXRF), were evaluated. Different single-, two-, and three-element solutions (0.01-1 g/L) were prepared in picoliter volume (around 130 pL) with a thermal inkjet printing technique. An achievable dosing precision of 4-15% was calculated by total reflection X-ray fluorescence (TXRF) determination of the transferred elemental mass of an array of 100 droplets. The size of the dried residues was determined by optical microscopy to be 5-20 microm in diameter depending on the concentration and the surface material. The elemental distribution of the dried residues was determined with synchrotron micro-X-ray fluorescence (SR-MXRF) analyses. The MXRF results show high uniformity for element deposition of every single droplet with an RSTD of 4-6% depending on the concentration of spotted solution. The shape and height profile of dried residues from picoliter droplets were studied using atomic force microscopy (AFM). It was found that these dry to give symmetrical spherical segments with maximum heights of 1.7 microm. The potential of this technique for direct LA-ICP-TOF-MS analysis is shown. ( view less ) Carsten Kruschinski,Thomas Skripuletz,Sammy Bedoui,Kerstin Raber,Rainer H Straub,Torsten Hoffmann,Karsten Grote,Roland Jacobs,Michael Stephan,Reinhard Pabst,Stephan von Hörsten Genetic and hygienic factors influence susceptibility to asthma. In autoimmune and inflammatory diseases, additional effects of the psychosocial environment have been demonstrated that might also play a role in asthma. In this study, the impact of different early postnatal stressors on an OVA-induc... ( view more )ed model of asthma was tested in adulthood. Fischer 344 rats were subjected to either repeated handling stimulation (HA), maternal separation (MS), or were left undisturbed in their first 4 wk of life. Behavioral differences were characterized at the age of 4 mo. At 5 mo of age, immunological cellular and serologic changes were investigated and experimental asthma was induced. Results show significantly increased exploratory behavior and reduced anxiety in HA rats compared with MS and controls. Without further behavioral or immunological challenges, HA animals exhibited an increased ex vivo NK cell cytotoxicity but no other obvious immunological differences. After induction of asthma, in contrast, MS animals exhibited proinflammatory effects in leukocyte subset composition including increased eosinophil numbers, whereas levels of IgE and the allergy-specific cytokine IL-13 were reduced compared with HA. There was a most remarkable increase of adrenocorticotropin in HA animals, comparing pre- to postchallenge plasma levels. These data demonstrate for the first time that early postnatal stimulative or adverse experiences exert long-lasting changes of the "neuroendocrinoimmune" interface in adulthood, resulting in either protective or aggravating mechanisms in allergic airway disease. Thus, in addition to genetic and hygienic factors, nongenetically acquired individual differences contribute to the pathobiology of asthma. ( view less ) Peter Wenaweser,Jean-François Surmely,Stephan Windecker,Marco Roffi,Mario Togni,Michael Billinger,Stephane Cook,Rolf Vogel,Christian Seiler,Otto M Hess,Bernhard Meier The clinical value of early exercise stress testing (EST) after coronary stenting to predict long-term clinical outcomes is unknown. Of 1,000 unselected patients who underwent coronary stenting, 446 random patients underwent early EST the day after intervention. Clinical long-term outcomes (41 +/- ... ( view more )20 months) were correlated with normal (n = 314 [70%]) or positive (n = 102 [23%]) EST results. Patients with inconclusive test results (n = 30 [7%]) were excluded from the analysis. Overall mortality was significantly higher in patients with positive EST results (9.3% vs 3.9%, p = 0.04). Major adverse cardiac events and cardiac mortality also tended to be higher in patients with positive stress test results (45.4% vs 35.4%, p = 0.08, and 4.1% vs 1.1%, p = 0.05, respectively). Patients with the combination of positive stress test results and incomplete revascularization appeared to be the group at highest risk for major adverse cardiac events (47.1% vs 33.3% for patients with normal stress test results and complete revascularization, p = NS). Negative stress test results reduced (odds ratio 0.329, 95% confidence interval 0.120 to 0.905, p = 0.031) and a lower ejection fraction increased (odds ratio 0.942, 95% confidence interval 0.897 to 0.989, p = 0.017) the risk for death. In conclusion, an early stress test after coronary stenting provides important prognostic information. Positive stress test results, especially in combination with incomplete revascularization, are associated with higher mortality, a trend toward more repeat revascularization procedures, and higher risk for major adverse cardiac events. ( view less ) Dirk Stephan,Mahbuba Siddiqua,Anh Ta Hoang,Jill Engelmann,Stephan Winter,Edgar Maiss Okra mosaic virus (OkMV) is a tymovirus infecting members of the family Malvaceae. Early infections in okra (Abelmoschus esculentus) lead to yield losses of 12-19.5%. Besides intensive biological characterizations of OkMV only minor molecular data were available. Therefore, we determined the comple... ( view more )te nucleotide sequence of a Nigerian isolate of OkMV. The complete genomic RNA (gRNA) comprises 6,223 nt and its genome organization showed three major ORFs coding for a putative movement protein (MP) of M r 73.1 kDa, a large replication-associated protein (RP) of M r 202.4 kDa and a coat protein (CP) of M r 19.6 kDa. Prediction of secondary RNA structures showed three hairpin structures with internal loops in the 5'-untranslated region (UTR) and a 3'-terminal tRNA-like structure (TLS) which comprises the anticodon for valine, typical for a member of the genus Tymovirus. Phylogenetic comparisons based on the RP, MP and CP amino acid sequences showed the close relationship of OkMV not only to other completely sequenced tymoviruses like Kennedya yellow mosaic virus (KYMV), Turnip yellow mosaic virus (TYMV) and Erysimum latent virus (ErLV), but also to Calopogonium yellow vein virus (CalYVV), Clitoria yellow vein virus (CYVV) and Desmodium yellow mottle virus (DYMoV). This is the first report of a complete OkMV genome sequence from one of the various OkMV isolates originating from West Africa described so far. Additionally, the experimental host range of OkMV including several Nicotiana species was determined. ( view less ) Michael Bodmer,Bettina Link,Nathalie Grignaschi,Oliver Kummer,Stephan Ruegg,Manuel Haschke,Stephan Krähenbühl The authors present a patient with refractory epilepsy who was treated with very high doses (up to 4 mg/min) of intravenous midazolam, phenytoin, carbamazepine, and other antiepileptics. Because it was known from the literature that the half-life of midazolam can increase at high dosage, the kineti... ( view more )cs of midazolam (MDZ), 1'-hydroxymidazolam, and 4-hydroxymidazolam were assessed at steady state (dosage 1 mg/min) and after stopping treatment. Total body clearance of MDZ (33 L/kg) and intrinsic hepatic clearance (19 mL/min/kg) at steady state were both five to 10 times higher than after normal therapeutic doses, demonstrating hepatic cytochrome (CYP) 3A induction. Despite the high body clearance, the half-life of MDZ was in the range of 24 hours, approximately 10 times higher than after normal therapeutic doses. The volume of distribution at steady state was 33 L/kg, approximately 50 times higher than after normal therapeutic doses. The free fraction of MDZ was 58% at steady state, much higher than the 3% to 6% at normal therapeutic doses. The kinetics of intravenous MDZ is strongly dependent on its dose and on hepatic CYP3A activity. Even in patients with hepatic CYP3A induction, the half-life of MDZ increases with high doses as a result of a rise in its volume of distribution, which is a consequence of an increase in the free fraction of MDZ. ( view less ) Jutta Schade,Michael Stephan,Andreas Schmiedl,Leona Wagner,André J Niestroj,Hans-Ulrich Demuth,Nadine Frerker,Christian Klemann,Kerstin A Raber,Reinhard Pabst,Stephan von Hörsten The expression of dipeptidyl peptidase 4 (DP4, CD26) affects T-cell recruitment to lungs in an experimental rat asthma model. Furthermore, the gene of the structural homologous DP10 represents a susceptibility locus for asthma in humans, and the functional homologous DP8/9 are expressed in human le... ( view more )ukocytes. Thus, although several mechanisms may account for a role of DP4-like peptidases in asthma, detailed information on their anatomical sites of expression and function in lungs is lacking. Therefore, bronchi and lung parenchyma were evaluated using immunohistochemistry and histochemical/enzymatic activity assays, as well as quantitative real-time PCR for this family of peptidases in naïve and asthmatic rat lungs derived from wild-type F344 and DP4-deficient F344 rat strains. Surprisingly, results show not only that the induction of experimental asthma increases DP4 enzymatic activity in the bronchoalveolar lavage fluid and parenchyma, but also that DP8/9 enzymatic activity is regulated and, as well as the expression of DP10, primarily found in the bronchial epithelium of the airways. This is the first report showing a differential and site-specific DP4-like expression and function in the lungs, suggesting a pathophysiologically significant role in asthma. ( view less ) Markus Bickel,Stephan Zangos,Thomas Lutz,Johannes Eisen,Gabi Knecht,Frank D Goebel,Catherine M Crespi,Volkmar Jacobi,Schlomo Staszewski,Stephan Klauke Several studies have shown reduction of visceral adipose tissue (VAT) using recombinant human growth hormone (r-hGH) in HIV-1+ patients, but whether these effects are maintained after the end of treatment is unknown. In a prospective, randomized study we previously studied the effects of r-hGH 4 mg... ( view more ) daily vs 3 times/week over 12 weeks, followed by a 2 mg daily maintenance dose for an additional 12 weeks. T1 weighted MRI flash sequences were performed of the face, abdomen and at mid-thigh level (MTF) at baseline, week 12, week 24 and at follow-up.Of 20 subjects who completed the 24-week study, follow-up is available for 16 patients (15 male, mean age 44.8 y, mean duration of HIV infection 13.5 y). After a median time of follow-up of 9 months, VAT remained overall 18% below baseline level (p =0.005). MTF was significantly reduced by 12% compared to its baseline level (p =0.03). Fasting glucose levels significantly improved by 21% compared to baseline (p =0.006). These results suggest that the achieved reduction of VAT using r-hGH in lipodystrophic HIV+ patients is in part maintained after a median follow-up of 9 months. ( view less ) Stephan Budweiser,Felix Heidtkamp,Rudolf A Jörres,Frank Heinemann,Michael Arzt,Stephan Schroll,Kathrin Schmidbauer,Andre P Hitzl,Michael Pfeifer BACKGROUND: The 6-min walk distance (6-MWD) is a global marker of functional capacity and prognosis in chronic obstructive pulmonary disease (COPD), but less explored in other chronic respiratory diseases. OBJECTIVE: To study the role of 6-MWD in chronic hypercapnic respiratory failure (CHRF). METH... ( view more )ODS: In 424 stable patients with CHRF and non-invasive ventilation (NIV) comprising COPD (n = 197), restrictive diseases (RD; n = 112) and obesity-hypoventilation-syndrome (OHS; n = 115), the prognostic value of 6-MWD for long-term survival was assessed in relation to that of body mass index (BMI), lung function, respiratory muscle function and laboratory parameters. RESULTS: 6-MWD was reduced in patients with COPD (median 280 m; quartiles 204/350 m) and RD (290 m; 204/362 m) compared to OHS (360 m; 275/440 m; p < 0.001 each). Overall mortality during 24.9 (13.1/40.5) months was 22.9%. In the 424 patients with CHRF, 6-MWD independently predicted mortality in addition to BMI, leukocytes and forced expiratory volume in 1 s (p < 0.05 each). In COPD, 6-MWD was strongly associated with mortality using the median [p < 0.001, hazard ratio (HR) = 3.75, 95% confidence interval (CI): 2.24-6.38] or quartiles as cutoff levels. In contrast, 6-MWD was only significantly associated with impaired survival in RD patients when it was reduced to 204 m or less (1st quartile; p = 0.003, HR = 3.31, 95% CI: 1.73-14.10), while in OHS 6-MWD had not any prognostic value. CONCLUSIONS: In patients with CHRF and NIV, 6-MWD was predictive for long-term survival particularly in COPD. In RD only severely reduced 6-MWD predicted mortality, while in OHS 6-MWD was relatively high and had no prognostic value. These results support a disease-specific use of 6-MWD in the routine assessment of patients with CHRF. ( view less ) Stephan Rüegg,Patrick Hunziker,Stephan Marsch,Christian Schindler OBJECTIVE: The goal of the work described here was to investigate the influence of environmental factors on admissions of patients with status epilepticus (SE) to the intensive care unit (ICU). METHODS: This retrospective cohort study analyzed all admissions to a university hospital ICU because of ... ( view more )SE. Poisson regression and likelihood ratio tests were employed to determine associations between environmental factors and the incidence of SE. RESULTS: Data on 184 patients (mean age: 57, range: 18-89) indicated a significant (P<0.0001) diurnal pattern, with admissions peaking between 4 and 5 PM and reaching a minimum in the early morning. No significant weekly, monthly, or seasonal pattern was observed. Admissions varied significantly across the lunar cycle (P=0.003), peaking at Day 3 after new moon and being minimal 3 days before new moon. The incidence of SE increased on bright days (P=0.04) and with the duration of daily sunshine (P=0.03). High relative humidity (P<0.01), high temperature (P<0.05), and dark days (P=0.02) were significantly protective factors. The incidence of SE on weekends was significantly lower in the subgroup of patients with known epilepsy (P=0.004), and the risk of nonconvulsive SE was significantly higher in summer (P=0.04). CONCLUSIONS: Admissions of patients with SE to the ICU are significantly associated with several environmental protective and precipitating factors, such as diurnal, weekly, and lunar cycles and weather variables. ( view less ) Stephan Meckel,Thomas M Glücker,Martin Kretzschmar,Klaus Scheffler,Ernst-Wilhelm Radü,Stephan G Wetzel BACKGROUND: Time-resolved (TR) contrast-enhanced 3D MR angiography has recently received considerable attention for the workup of cerebrovascular diseases, foremost dural arteriovenous fistula and arteriovenous malformation, and potentially for the evaluation of dural sinus thrombosis. Thereby, the... ( view more ) dynamic visualization of cerebral vessels is enabled similar to the principle of digital subtraction angiography. Yet, its voxel size is relatively large due to an inherent trade-off between the desired spatial and temporal resolutions. The goal of this study was to evaluate whether the limited spatial resolution of TR MR venography (MRV) is sufficient to visualize dural venous sinuses. METHODS: The prospective study included 20 patients without compromise of cerebral venous outflow. Two neuroradiologists independently graded the quality of visualization of 11 predefined dural venous sinuses on images of fast TR contrast-enhanced MRV (1.5 s/dataset; voxel size, 2 x 2 x 2.2 mm; acquisition time, 37.5 s) in comparison to time-of-flight (TOF) MRV (voxel size, 0.8 x 0.8 x 4 mm; acquisition time, 3 min 51 s) and steady-state contrast-enhanced 3D (VIBE) MRV (voxel size, 1.1 x 0.9 x 1.5 mm; acquisition time, 2 min 46 s). RESULTS: The torcular Herophili (p < 0.001), left (p < 0.001) and right (p < 0.01) transverse sinus, and right jugular bulb (p < 0.05) were visualized better at TR MRV than at TOF MRV. For visualization of the small inferior sagittal sinus, TR MRV was inferior to VIBE (p < 0.001) and TOF (p < 0.05) sequences. The visibility of all other dural sinuses was equal. CONCLUSION: Despite the inferior spatial resolution, TR MRV depicted some large dural sinuses more clearly than TOF MRV. To overcome the visualization of smaller venous structures, TR MRV can be applied complementarily with high-resolution steady-state contrast-enhanced MRV. ( view less ) Marion Weintraud,Peter Marhofer,Adrian Bösenberg,Stephan Kapral,Harald Willschke,Michael Felfernig,Stephan Kettner BACKGROUND: Ultrasonographic observation of peripheral nerve blocks enables direct visualization of the spread of local anesthetic around the targeted nerves. Similarly, ultrasonography may be used to determine the site of local anesthetic placement when landmark-based techniques are used. We perfo... ( view more )rmed a study to determine the actual location of local anesthetic when ilioinguinal/iliohypogastric nerve blocks are performed using landmark-based techniques in children in an attempt to explain a failed block. METHODS: After induction of general anesthesia (1 minimum alveolar anesthetic concentration halothane and laryngeal mask airway), 62 children scheduled for inguinal surgery received an ilioinguinal/iliohypogastric nerve block based on standard anatomical landmarks. Ultrasonography was then used to determine the actual location of local anesthetic placement. The anesthesiologist performing the block was blinded to the ultrasonographic investigation. Successful blocks were recorded either when the local anesthetic surrounded the nerves or were based on clinical signs after skin incision. RESULTS: In 14% of the blocks, the local anesthetic was administered correctly around the nerves resulting in successful blocks. In the remaining 86%, the local anesthetic was administered in adjacent anatomical structures (iliac muscle 18%, transverse abdominal muscle 26%, internal oblique abdominal muscle 29%, external oblique abdominal muscle 9%, subcutaneous 2%, and peritoneum 2%), and 45% of these blocks failed. CONCLUSION: Accurate placement of local anesthetic around the ilioinguinal/iliohypogastric nerves in children is seldom possible when landmark-based techniques are used. In the majority of patients, the local anesthetic was inaccurately placed in adjacent anatomical structures with unpredictable block results. ( view less ) Stephan Loschen,Jörg Bätzing-Feigenbaum,Gabriele Poggensee,Christiane Cordes,Bettina Hintsche,Michael Rausch,Stephan Dupke,Silvia Gohlke-Micknis,Jana Rödig,Osamah Hamouda,Claudia KüchererThe sensitivity and specificity of the human immunodeficiency virus (HIV) type 1-specific immunoglobulin G capture enzyme-linked immunosorbent assay (BED-CEIA) were compared with those of the avidity index method to identify recent HIV infection using a panel of 148 samples (81 patients) representi... ( view more )ng durations of infection ranging from 0 to 222 weeks. The results from the two tests were similar (sensitivity of 80% versus 74% [P = 0.53]; specificity of 86% versus 82% [P = 0.67]). ( view less ) Stephan J Ott,Nour Eddine El Mokhtari,Ateequr Rehman,Philip Rosenstiel,Stephan Hellmig,Tanja Kühbacher,Markus Lins,Rüdiger Simon,Stefan Schreiber Bacterial DNA has been found in coronary plaques and it has therefore been concluded that bacteria may play a role as trigger factors in the chronic inflammatory process underlying coronary atherosclerosis. However, the microbial spectrum is complex and it is not known whether microorganisms other ... ( view more )than bacteria are involved in coronary disease. Fungal 18S rDNA signatures were systematically investigated in atherosclerotic tissue obtained through catheter-based atherectomy of 38 patients and controls (unaffected coronary arteries) using clone libraries, denaturating gradient gel analysis (DGGE), in situ hybridization and fluorescence in situ hybridization (FISH). Fungal DNA was found in 35 of 38 (92.11%) coronary heart disease patients by either polymerase chain reaction (PCR) with universal primers or in situ hybridization analysis (n = 5), but not in any control sample. In a clone library with more than 350 sequenced clones from pooled patient DNA, an overall richness of 19 different fungal phylotypes could be observed. Fungal profiles of coronary heart disease patients obtained by DGGE analysis showed a median richness of fungal species of 5 (range from 2 to 9) with a high interindividual variability (mean similarity 18.83%). For the first time, the presence of fungal components in atherosclerotic plaques has been demonstrated. Coronary atheromatous plaques harbour diverse and variable fungal communities suggesting a polymicrobial contribution to the chronic inflammatory aetiology. ( view less ) Andor Pivarcsi,Anja Müller,Andreas Hippe,Juliane Rieker,Anke van Lierop,Martin Steinhoff,Stephan Seeliger,Robert Kubitza,Ulrich Pippirs,Stephan Meller,Peter A Gerber,Ruediger Liersch,Erich Buenemann,Eniko Sonkoly,Ulrike Wiesner,Thomas K Hoffmann,Leonid Schneider,Roland Piekorz,Elaine Enderlein,Julia Reifenberger,Ulrich-Peter Rohr,Rainer Haas,Petra Boukamp,Ingo Haase,Bernd Nürnberg,Thomas Ruzicka,Albert Zlotnik,Bernhard Homey The novel keratinocyte-specific chemokine CCL27 plays a critical role in the organization of skin-associated immune responses by regulating T cell homing under homeostatic and inflammatory conditions. Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumo... ( view more )r immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPK-signaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas. In vivo, precancerous skin lesions as well as cutaneous carcinomas showed significantly elevated levels of phosphorylated ERK compared with normal skin, suggesting the activation of EGFR-Ras signaling pathways in keratinocyte-derived malignancies. In vitro, exogenous stimulation of the EGFR-Ras signaling pathway through EGF or transfection of the dominant-active form of the Ras oncogene (H-RasV12) suppressed whereas an EGFR tyrosine kinase inhibitor increased CCL27 mRNA and protein production in keratinocytes. In mice, neutralization of CCL27 led to decreased leukocyte recruitment to cutaneous tumor sites and significantly enhanced primary tumor growth. Collectively, our data identify a mechanism of skin tumors to evade host antitumor immune responses. ( view less )
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