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Purpose The Ad26.COV2.S vaccine is a replication-incompetent human adenovirus type 26 vector encoding the SARS-CoV-2 spike protein. In a phase 1-2a trial, a single dose of Ad26.COV2.S induced SARS-CoV-2 spike-specific antibodies in ≥ 96% of healthy adults. To investigate vaccine immunogenicity in HIV-1-infection, we measured SARS-CoV-2 spike-specific antibodies in Ad26.COV2.S vaccinated HIV-1-infected patients and analyzed the presence of pre-existing Ad26 neutralizing antibodies. Methods We included all Ad26.COV2.S vaccinated HIV-1-infected patients of Erlangen HIV cohort fulfilling all inclusion criteria. The study cohort consisted of 15 HIV-1-infected patients and three HIV-1-uninfected subjects who received the Ad26.COV2.S vaccine between April and November 2021. Pre-vaccination sera were collected between October 2014 and June 2021, post-vaccination sera between June and December 2021. Neutralizing antibodies towards Ad26 were determined by a FACS-based inhibition assay measuring the expression of SARS-CoV-2 spike and adenoviral proteins in HEK293T cells after in-vitro transduction with Ad26.COV2.S or the control ChAdOx1-S. Results Six out of 15 HIV-1-infected patients failed to develop SARS-CoV-2-specific antibodies and four patients developed weak antibody responses after vaccination with Ad26.COV2.S. Pre-vaccination sera of four of the six vaccine non-responders showed neutralizing activity towards Ad26.COV2.S but not toward the ChAdOx1-S vaccine at 1:50 dilution. After Ad26.COV2.S vaccination, 17 of the 18 subjects developed strong Ad26-neutralizing activity and only one of the 18 subjects showed neutralizing activity towards the ChAdOx1-S vaccine. Conclusion Ad26.COV2.S vaccination showed a high failure rate in HIV-1-infected patients. Pre-existing immunity against Ad26 could be an important contributor to poor vaccine efficacy in a subgroup of patients.

The analysis of T-cell responses in HIV-1-infected controllers may contribute to a better understanding of the protective components of the immune system. Here, we analyzed the HIV-1-specific T-cell response in a 59-year-old HIV-1-infected controller, infected for at least seven years, who presented with low viral loads ranging from 800 cells/µL. In γ-IFN-ELISpot assays using freshly isolated PBMCs, he displayed a very strong polyclonal T-cell response to eight epitopes in Gag, Nef and Rev; with the dominant responses directed against the HLA-B*57-epitope AISPRTLNAW and against a so-far-unknown epitope within Rev. Further analyses using peptide-stimulated T-cell lines in γ-IFN-ELISpot assays delineated the peptide RQRQIRSI (Rev-RI8) as a newly defined HLA-B*52-restricted epitope located within a functionally important region of Rev. Peptide-stimulation assays in 15 HLA-B*52-positive HIV-1-infected subjects, including the controller, demonstrated recognition of the Rev-RI8 epitope in 6/15 subjects. CD4 counts before the start of antiviral therapy were significantly higher in subjects with recognition of the Rev-RI8 epitope. Targeting of the Rev-RI8 epitope in Rev by CTL could contribute to the positive association of HLA-B*52 with a more favorable course of HIV-1-infection.

Despite antiretroviral therapy (ART), immune exhaustion persists in HIV infection and limits T cell responses to HIV or other pathogens. Moreover, HIV infection results in the loss of pre-existing immunity. Here, we investigated the effect of blocking the PD-1 pathway on recall IFNγ responses to tetanus toxoid (TT) and measles virus (MV) antigens in HIV-infected persons on ART with prior TT and MV immunity. The ex vivo treatment of lymphocytes with anti-PD-1 and anti-PD-L1 antibodies significantly increased TT- and MV-specific IFNγ responses. The responses to TT and MV antigens alone or in combination with antibodies blocking the PD-1 pathway positively correlated with CD4 T cell levels. Furthermore, T cell PD-1 expression levels inversely correlated with recall IFNγ responses in combination with antibodies blocking the PD-1 pathway but not with IFNγ responses to antigens only. Our study suggested that targeting the PD-1 pathway may boost vaccine-induced pre-existing immunity in HIV-infected persons on ART depending on the degree of immune exhaustion.

An overview of recent results obtained at the tokamak ASDEX Upgrade (AUG) is given. A work flow for predictive profile modelling of AUG discharges was established which is able to reproduce experimental H-mode plasma profiles based on engineering parameters only. In the plasma center, theoretical predictions on plasma current redistribution by a dynamo effect were confirmed experimentally. For core transport, the stabilizing effect of fast ion distributions on turbulent transport is shown to be important to explain the core isotope effect and improves the description of hollow low-Z impurity profiles. The L–H power threshold of hydrogen plasmas is not affected by small helium admixtures and it increases continuously from the deuterium to the hydrogen level when the hydrogen concentration is raised from 0 to 100%. One focus of recent campaigns was the search for a fusion relevant integrated plasma scenario without large edge localised modes (ELMs). Results from six different ELM-free confinement regimes are compared with respect to reactor relevance: ELM suppression by magnetic perturbation coils could be attributed to toroidally asymmetric turbulent fluctuations in the vicinity of the separatrix. Stable improved confinement mode plasma phases with a detached inner divertor were obtained using a feedback control of the plasma β. The enhanced Dα H-mode regime was extended to higher heating power by feedback controlled radiative cooling with argon. The quasi-coherent exhaust regime was developed into an integrated scenario at high heating power and energy confinement, with a detached divertor and without large ELMs. Small ELMs close to the separatrix lead to peeling-ballooning stability and quasi continuous power exhaust. Helium beam density fluctuation measurements confirm that transport close to the separatrix is important to achieve the different ELM-free regimes. Based on separatrix plasma parameters and interchange-drift-Alfvén turbulence, an analytic model was derived that reproduces the experimentally found important operational boundaries of the density limit and between L- and H-mode confinement. Feedback control for the X-point radiator (XPR) position was established as an important element for divertor detachment control. Stable and detached ELM-free phases with H-mode confinement quality were obtained when the XPR was moved 10 cm above the X-point. Investigations of the plasma in the future flexible snow-flake divertor of AUG by means of first SOLPS-ITER simulations with drifts activated predict beneficial detachment properties and the activation of an additional strike point by the drifts. This work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014–2018 and 2019–2020 under Grant Agreement No. 633053. The views and opinions expressed herein do not necessarily reflect those of the European Commission. Peer Reviewed "Article signat per més de 50 autors/es: U. Stroth, D. Aguiam, E. Alessi, C. Angioni, N. Arden, R. Arredondo Parra, V. Artigues, O. Asunta, M. Balden, V. Bandaru, A. Banon-Navarro, K. Behler, A. Bergmann, M. Bergmann, J. Bernardo, M. Bernert, A. Biancalani, R. Bielajew, R. Bilato, G. Birkenmeier, T. Blanken, V. Bobkov, A. Bock, T. Body, T. Bolzonella, N. Bonanomi, A. Bortolon, B. Böswirth, C. Bottereau, A. Bottino, H. van den Brand, M. Brenzke, S. Brezinsek, D. Brida, F. Brochard, C. Bruhn, J. Buchanan, A. Buhler, A. Burckhart, Y. Camenen, B. Cannas, P. Cano Megias, D. Carlton, M. Carr, P. Carvalho, C. Castaldo, M. Cavedon, C. Cazzaniga, C. Challis, A. Chankin, C. Cianfarani, F. Clairet, S. Coda, R. Coelho, J.W. Coenen, L. Colas, G. Conway, S. Costea, D. Coster, T. Cote, A.J. Creely, G. Croci, D.J. Cruz Zabala, G. Cseh, A. Czarnecka, I. Cziegler, O. D'Arcangelo, A. Dal Molin, P. David, C. Day, M. de Baar, P. de Marné, R. Delogu, S. Denk, P. Denner, A. Di Siena, J.J. Dominguez Palacios Durán, D. Dunai, A. Drenik, M. Dreval, R. Drube, M. Dunne, B.P. Duval, R. Dux, T. Eich, S. Elgeti, A. Encheva, K. Engelhardt, B. Erdös, I. Erofeev, B. Esposito, E. Fable, M. Faitsch, U. Fantz, M. Farnik, H. Faugel, F. Felici, O. Ficker, S. Fietz, A. Figueredo, R. Fischer, O. Ford, L. Frassinetti, M. Fröschle, G. Fuchert, J.C. Fuchs, H. Fünfgelder, S. Futatani, K. Galazka, J. Galdon-Quiroga, D. Gallart Escolà, A. Gallo10, Y. Gao11, S. Garavaglia3, M. Garcia Muñoz16, B. Geiger21, L. Giannone1, S. Gibson32, L. Gil2, E. Giovannozzi18, S. Glöggler1, M. Gobbin8, J. Gonzalez Martin, T. Goodman, G. Gorini, T. Görler, D. Gradic, G. Granucci, A. Gräter, H. Greuner, M. Griener, M. Groth, A. Gude, L. Guimarais, S. Günter, G. Haas, A.H. Hakola, C. Ham, T. Happel, N. den Harder, G. Harrer, J. Harrison, V. Hauer, T. Hayward-Schneider, B. Heinemann, T. Hellsten, S. Henderson, P. Hennequin, A. Herrmann, E. Heyn, F. Hitzler, J. Hobirk, K. Höfler, J.H. Holm, M. Hölzl, C. Hopf, L. Horvath, T. Höschen, A. Houben, A. Hubbard, A. Huber, K. Hunger, V. Igochine, M. Iliasova, T. Ilkei, K. Insulander Björk, C. Ionita-Schrittwieser, I. Ivanova-Stanik, W. Jacob, N. Jaksic, F. Janky, A. Jansen van Vuuren, A. Jardin, F. Jaulmes, F. Jenko, T. Jensen, E. Joffrin, A. Kallenbach, S. Kálvin, M. Kantor, A. Kappatou, O. Kardaun, J. Karhunen4, C.-P. Käsemann, S. Kasilov, A. Kendl, W. Kernbichler, E. Khilkevitch, A. Kirk, S. Kjer Hansen, V. Klevarova, G. Kocsis, M. Koleva, M. Komm, M. Kong, A. Krämer-Flecken, K. Krieger, A. Krivska, O. Kudlacek, T. Kurki-Suonio, B. Kurzan, B. Labit, K. Lackner, F. Laggner, A. Lahtinen, P.T. Lang, P. Lauber, N. Leuthold, L. Li, J. Likonen, O. Linder, B. Lipschultz, Y. Liu, A. Lohs, Z. Lu, T. Luda di Cortemiglia, N.C. Luhmann, T. Lunt, A. Lyssoivan, T. Maceina, J. Madsen, A. Magnanimo, H. Maier, J. Mailloux, R. Maingi, O. Maj, E. Maljaars, P. Manas, A. Mancini, A. Manhard, P. Mantica, M. Mantsinen, P. Manz, M. Maraschek, C. Marchetto, L. Marrelli, P. Martin, A. Martitsch, F. Matos, M. Mayer, M.-L. Mayoral, D. Mazon, P.J. McCarthy, R. McDermott, R. Merkel, A. Merle, D. Meshcheriakov, H. Meyer, D. Milanesio, P. Molina Cabrera, F. Monaco, M. Muraca, F. Nabais, V. Naulin, R. Nazikian, R.D. Nem, A. Nemes-Czopf, G. Neu, R. Neu, A.H. Nielsen, S.K. Nielsen, T. Nishizawa, M. Nocente, J.-M. Noterdaeme, I. Novikau, S. Nowak, M. Oberkofler, R. Ochoukov, J. Olsen, F. Orain, F. Palermo, O. Pan, G. Papp, I. Paradela Perez, A. Pau, G. Pautasso, C. Paz-Soldan, P. Petersson, P. Piovesan, C. Piron, U. Plank, B. Plaum, B. Plöck, V. Plyusnin, G. Pokol, E. Poli, L. Porte, T. Pütterich, M. Ramisch, J. Rasmussen, G. Ratta, S. Ratynskaia, G. Raupp, D. Réfy, M. Reich1, F. Reimold, D. Reiser, M. Reisner, D. Reiter, T. Ribeiro, R. Riedl, J. Riesch, D. Rittich, J.F. Rivero Rodriguez, G. Rocchi, P. Rodriguez-Fernandez, M. Rodriguez-Ramos, V. Rohde, G. Ronchi, A. Ross, M. Rott, M. Rubel, D.A. Ryan, F. Ryter, S. Saarelma, M. Salewski, A. Salmi, O. Samoylov, L. Sanchis Sanchez, J. Santos, O. Sauter, G. Schall, K. Schlüter, K. Schmid, O. Schmitz, P.A. Schneider, R. Schrittwieser, M. Schubert, C. Schuster, T. Schwarz-Selinger, J. Schweinzer, E. Seliunin, A. Shabbir, A. Shalpegin, S. Sharapov, U. Sheikh, A. Shevelev, G. Sias, M. Siccinio, B. Sieglin, A. Sigalov, A. Silva, C. Silva, D. Silvagni, J. Simpson, S. Sipilä, E. Smigelskis, A. Snicker, E. Solano, C. Sommariva, C. Sozzi, G. Spizzo, M. Spolaore, A. Stegmeir, M. Stejner, J. Stober, E. Strumberge1, G. Suarez Lopez, H.-J. Sun, W. Suttrop, E. Sytova, T. Szepesi, B. Tál, T. Tala, G. Tardini, M. Tardocchi, D. Terranova, M. Teschke, E. Thorén, W. Tierens, D. Told, W. Treutterer, G. Trevisan, E. Trier, M. Tripský, M. Usoltceva, M. Valisa, M. Valovic, M. van Zeeland, F. Vannini, B. Vanovac, P. Varela, S. Varoutis, N. Vianello, J. Vicente, G. Verdoolaege, T. Vierle, E. Viezzer, I. Voitsekhovitch, U. von Toussaint, D. Wagner, X. Wang, M. Weiland, A.E. White, M. Willensdorfer, B. Wiringer, M. Wischmeier, R. Wolf, E. Wolfrum, Q. Yang, Q. Yu, R. Zagórski, I. Zammuto, T. Zehetbauer, W. Zhang, W. Zholobenko, M. Zilker, A. Zito, H. Zohm, S. Zoletnik and the EUROfusion MST1 Team "

The tokamak à configuration variable (TCV) continues to leverage its unique shaping capabilities, flexible heating systems and modern control system to address critical issues in preparation for ITER and a fusion power plant. For the 2019–20 campaign its configurational flexibility has been enhanced with the installation of removable divertor gas baffles, its diagnostic capabilities with an extensive set of upgrades and its heating systems with new dual frequency gyrotrons. The gas baffles reduce coupling between the divertor and the main chamber and allow for detailed investigations on the role of fuelling in general and, together with upgraded boundary diagnostics, test divertor and edge models in particular. The increased heating capabilities broaden the operational regime to include T e/T i ∼ 1 and have stimulated refocussing studies from L-mode to H-mode across a range of research topics. ITER baseline parameters were reached in type-I ELMy H-modes and alternative regimes with ‘small’ (or no) ELMs explored. Most prominently, negative triangularity was investigated in detail and confirmed as an attractive scenario with H-mode level core confinement but an L-mode edge. Emphasis was also placed on control, where an increased number of observers, actuators and control solutions became available and are now integrated into a generic control framework as will be needed in future devices. The quantity and quality of results of the 2019–20 TCV campaign are a testament to its successful integration within the European research effort alongside a vibrant domestic programme and international collaborations.

Krypton can be a tool to refine and analyse the H–L power threshold in detail, as a proxy for L–H threshold, taking into account radiative losses in the region where the H–L transition takes place and, thus, decouple the power flux over the pedestal top to the one over the separatrix. The commonly used ITPA 2008 L–H threshold scaling does not account for radiation but it is often assumed that it should be compared to the net power crossing the separatrix. Yet, dedicated analyses are still lacking. At ASDEX Upgrade, krypton radiates dominantly at the very edge of the confined plasma (ρ pol between 0.97 and 1.01). Recent results show that L–H and H–L transitions are initiated close to ρ pol = 0.98. As such, the bulk of krypton radiation is between the separatrix and a potential source location for the transition. Scans in krypton seeding level and heating power have been performed to study and compare the influence of the powers radiated from inside the separatrix and the pedestal top on the plasma confinement state. The heating power is compared to the usual L–H power scaling but corrected by either of these two radiations for seeded H–L transitions. The power scaling is shown to remain valid for higher input and radiated powers, up to 3–5 times the non-seeded L–H power threshold of AUG, when the radiation inside the separatrix is subtracted from the input power. Additionally, kinetic and radiation profiles are used to run TRANSP analyses to compare the edge ion heat to past studies from unseeded discharges. Using this physical parameter gives a reference point from a very different parameter range of input and radiated powers, densities and back, instead of forward, transition.

It has been experimentally observed that at ASDEX Upgrade (AUG) plasmas at relatively high shaping, an increase of gas fuelling corresponds to an increase of the frequency and intensity of the type-I edge localised modes (ELMs). At high enough fuelling, the plasma enters the quasi continuous exhaust (QCE) regime. We have performed ideal ballooning n → ∞ stability analysis on four AUG discharges, comparing the type-I ELM dominated phases, with the phases that are in the QCE regime. The results of this study show that as the gas puff increases, the plasma gets more ballooning unstable in the pedestal region, especially very close to the separatrix, at the pedestal bottom. On the contrary, in the middle of the pedestal, the discharges are more ballooning stable. Here the locally negative magnetic shear has a stabilising effect on ballooning modes, allowing access to the second stability region. Our analysis of the ballooning stability and the confinement factor H98 suggest that with optimisation of the pedestal shape, good confinement without type-I ELMs can be achieved. Necessary ingredients are that the region of the highest pressure gradient is not ideal ballooning limited, while the pedestal bottom is ballooning unstable. Ideal stability analysis of 36 simulated ITER profiles shows that, similarly to the experimental cases from AUG, a high pedestal top pressure can be maintained concomitant with a ballooning instability at the pedestal bottom, making QCE a promising scenario.

The beta-coronavirus SARS-CoV-2 induces severe disease (COVID-19) mainly in elderly persons with risk factors, whereas the majority of patients experience a mild course of infection. As the circulating common cold coronaviruses OC43 and HKU1 share some homologous sequences with SARS-CoV-2, beta-coronavirus cross-reactive T-cell responses could influence the susceptibility to SARS-CoV-2 infection and the course of COVID-19. To investigate the role of beta-coronavirus cross-reactive T-cells, we analyzed the T-cell response against a 15 amino acid long peptide (SCoV-DP15: DLSPRWYFYYLGTGP) from the SARS-CoV-2 nucleoprotein sequence with a high homology to the corresponding sequence (QLLPRWYFYYLGTGP) in OC43 and HKU1. SCoV-DP15-specific T-cells were detected in 4 out of 23 (17.4%) SARS-CoV-2-seronegative healthy donors. As HIV-1 infection is a potential risk factor for COVID-19, we also studied a cohort of HIV-1-infected patients on antiretroviral therapy. 44 out of these 116 HIV-1-infected patients (37.9%) showed a specific recognition of the SCoV-DP15 peptide or of shorter peptides within SCoV-DP15 by CD4+ T-cells and/or by CD8+ T-cells. We could define several new cross-reactive HLA-I-restricted epitopes in the SARS-CoV-2 nucleoprotein such as SPRWYFYYL (HLA-B*07, HLA-B*35), DLSPRWYFYY (HLA-A*02), LSPRWYFYY (HLA-A*29), WYFYYLGTGP and WYFYYLGT. Epitope specific CD8+ T-cell lines recognized corresponding epitopes within OC43 and HKU1 to a similar degree or even at lower peptide concentrations suggesting that they were induced by infection with OC43 or HKU1. Our results confirm that SARS-CoV-2-seronegative subjects can target SARS-CoV-2 not only by beta-coronavirus cross-reactive CD4+ T-cells but also by cross-reactive CD8+ cytotoxic T-cells (CTL). The delineation of cross-reactive T-cell epitopes contributes to an efficient epitope-specific immunomonitoring of SARS-CoV-2-specific T-cells. Further prospective studies are needed to prove a protective role of cross-reactive T-cells and their restricting HLA alleles for control of SARS-CoV-2 infection. The frequent observation of SARS-CoV-2-reactive T-cells in HIV-1-infected subjects could be a reason that treated HIV-1 infection does not seem to be a strong risk factor for the development of severe COVID-19.

BACKGROUND: It has been reported that HIV-1-specific cytotoxic T cells (CTL) recognizing the HLA-A2-restricted p17 epitope SLYNTVATL (SL9) can cross-react with the HLA-A2-restricted influenza matrix epitope GILGFVFTL (GL9). So far, the prevalence of GL9-cross-reacting HIV-1-specific CTL in larger cohorts of HIV-1-infected patients is unknown, and there are no data yet on whether SL9/GL9-cross-reactive CTL may influence the course of HIV-1 infection. METHODS: We analyzed the presence of SL9/GL9-cross-reacting CTL in a cohort of 175 HLA-A2-positive HIV-1-infected patients. Peripheral blood mononuclear cells were stimulated in vitro with SL9 and GL9 peptides, and outgrowing cell lines regarding cross-reactivity and recognition of viral variants in γ-interferon enzyme-linked immunospot assays were analyzed. RESULTS: SL9- and GL9-specific CTL could be generated in 52.6% and 53.7% of 175 patients, respectively. Both SL9- and GL9-specific CTL were more frequently observed in patients on antiretroviral therapy (ART). Of the 92 SL9-specific CTL and the 94 GL9-specific CTL, 65.2% and 66%, respectively, showed at least partial SL9/GL9 cross-reactivity. SL9/GL9-cross-reactive CTL could be detected in 42.9% of the 175 patients. Recognition of SL9 was associated with lower viral loads and higher CD4 cell counts in patients on ART. Patients with GL9/SL9 cross-reactivity displayed similar CD4 cell counts than patients without GL9/SL9-cross-reactive cells. GL9/SL9-cross-reactive cells were associated with higher viral loads in patients on ART. CONCLUSIONS: Partially SL9/GL9-cross-reactive CTL are frequently observed in HIV-1-infected patients. So far, we could not detect a significant influence of the presence of SL9/GL9-cross-reacting CTL on the course of HIV-1 infection.

Objectives Strategies to cure HIV-1 infection require the eradication of viral reservoirs. An innovative approach for boosting the cytotoxic T-lymphocyte response is the transfer of T-cell receptors (TCRs). Previously, we have shown that electroporation of TCR-encoding mRNA is able to reprogram CD8 T cells derived from healthy donors. So far, it is unknown whether the transfer of HIV-1-specific TCRs is capable to reprogram CD8 T cells of HIV-1-infected patients. To assess the efficiency of TCR-transfer by mRNA electroporation and the functionality of reprogramed T cells in HIV-1-infected patients, we performed an in-vitro analysis of TCR-transfer into T cells from HIV-1-infected patients in various stages of disease and from healthy controls. Methods Peripheral blood mononuclear cells from 16 HIV-1-infected patients (nine HLA-A02-positive, seven HLA-A02-negative) and from five healthy controls were electroporated with mRNA-constructs encoding TCRs specific for the HLA-A02/HIV-1-gag p17 epitope SLYNTVATL (SL9). Functionality of the TCRs was measured by γIFN-ELISpot assays. Results SL9/TCR transfection into peripheral blood mononuclear cells from both HLA-A02-positive and HLA-A02-negative HIV-1-infected patients and from healthy blood donors reprogramed T cells for recognition of SL9-presenting HLA-A02-positive cells in γIFN-ELISpot assays. SL9/TCR-transfer into T cells from an immunodeficient AIDS patient could induce recognition of SL9-expressing target cells only after reversion of T-cell dysfunction by antiretroviral therapy. Conclusion The transfer of HIV-1-p17-specific TCRs into T cells is functional both in HIV-1-infected patients as well as in healthy blood donors. TCR-transfer is a promising method to boost the immune system against HIV-1.

H2S signals via protein persulfidation. To be regulatory the modification will have to be reversible. Using a new method for persulfide detection, we discover this missing link and show that thioredoxin system acts as depersulfidase in vivo., Hydrogen sulfide (H2S) has emerged as a signalling molecule capable of regulating several important physiological functions such as blood pressure, neurotransmission and inflammation. The mechanisms behind these effects are still largely elusive and oxidative posttranslational modification of cysteine residues (protein persulfidation or S-sulfhydration) has been proposed as the main pathway for H2S-induced biological and pharmacological effects. As a signalling mechanism, persulfidation has to be controlled. Using an improved tag-switch assay for persulfide detection we show here that protein persulfide levels are controlled by the thioredoxin system. Recombinant thioredoxin showed an almost 10-fold higher reactivity towards cysteine persulfide than towards cystine and readily cleaved protein persulfides as well. This reaction resulted in H2S release suggesting that thioredoxin could be an important regulator of H2S levels from persulfide pools. Inhibition of the thioredoxin system caused an increase in intracellular persulfides, highlighting thioredoxin as a major protein depersulfidase that controls H2S signalling. Finally, using plasma from HIV-1 patients that have higher circulatory levels of thioredoxin, we could prove depersulfidase role in vivo.

Adoptive TCR transfer against rapidly mutating targets, such as HIV-1 or cancer, must counteract corresponding immune escape. Hence, we generated T cells expressing two additional receptors (TETARs) specific for HIV-1 by TCR mRNA electroporation. An HLA-A2–restricted gag-specific TCR and an HLA-B13–restricted nef-specific TCR were chosen. When both TCRs were transfected simultaneously, strong competitive effects occurred that were overcome by replacing the human constant domains of one TCR with murine counterparts and adapting the amounts of TCR-RNA used for transfection. The resulting TETAR responded to both epitopes with cytokine secretion and cytotoxic function. Cell sorting revealed that one individual cell indeed recognized both epitopes. The T cells diminished their reactivity to each epitope after stimulation but sequentially killed targets that presented the gag epitope and then targets that presented the nef epitope, or vice versa. Taken together, TETARs represent a sophisticated tool to study TCR functionality and might be a useful strategy in immunotherapy.

Introduction HIV type-1 (HIV-1) protease (PR) and cleavage site (CS) mutations accumulate in protease-inhibitor-resistant isolates. HIV-1 CS mutation 431V is the most frequent treatment-associated CS mutation; however, little is known about its origin in treatment-naive HIV-1 isolates. Recently, it has been shown that the CS mutation 431V is located within the human leukocyte antigen (HLA)-B*13-restricted cytotoxic T- lymphocyte (CTL) epitope RQANFLGKI (RI9). Therefore, we investigated whether the presence of CS mutation 431V might additionally be related to immune escape. Methods CTL recognition of RI9 and of RI9 variants carrying the 431V or the 436R mutation was analysed by ELISPOT in nine HLA-B*13-positive HIV-1-infected patients. Treatment-naive HIV-1-infected patients with primary drug-resistant HIV-1 isolates ( n=58) or carrying 431V ( n=4) were genotyped for HLA class I alleles. Results ELISPOT analysis showed different patterns of CTL recognition of RI9. CS mutation 431V could abrogate recognition by RI9-specific CTL in a subgroup of patients. Nevertheless, in our study, the occurrence of 431V in treatment-naive HIV-1 without primary drug resistance could not be explained by HLA-B*13-mediated immune selection. In patients with primary drug-resistant HIV-1 isolates, the frequency of HLA-B*13 was not increased and HLA-B*13 did not correlate with CS mutations 436R or 431V. Conclusions HIV-1 CS mutation 431V can abrogate CTL recognition, indicating interactions between development of drug resistance and the CTL response. However, we could not find evidence that the presence of 431V in treatment-naive HIV-1 isolates with and without primary drug resistance is related to immune selection by HLA-B*13 or other HLA class I alleles.

To determine the influence of human immunodeficiency virus type 1 (HIV-1)-specific CD8+T cells on the development of drug resistance mutations in the HIV-1 protease, we analyzed protease sequences from viruses from a human leukocyte antigen class I (HLA class I)-typed cohort of 94 HIV-1-positive individuals. In univariate statistical analyses (Fisher's exact test), minor and major drug resistance mutations as well as drug-associated polymorphisms showed associations with HLA class I alleles. All correlations withPvalues of 0.05 or less were considered to be relevant without corrections for multiple tests. A subset of these observed correlations was experimentally validated by enzyme-linked immunospot assays, allowing the definition of 10 new epitopes recognized by CD8+T cells from patients with the appropriate HLA class I type. Several drug resistance-associated mutations in the protease acted as escape mutations; however, cells from many patients were still able to generate CD8+T cells targeting the escape mutants. This result presumably indicates the usage of different T-cell receptors by CD8+T cells targeting these epitopes in these patients. Our results support a fundamental role for HLA class I-restricted immune responses in shaping the sequence of the HIV-1 protease in vivo. This role may have important clinical implications both for the understanding of drug resistance pathways and for the design of therapeutic vaccines targeting drug-resistant HIV-1.

As only 10 - 30 % of patients with a Pelizaeus Merzbacher disease (PMD) phenotype carry mutations of the proteolipid protein (PLP) gene, we were interested if the degree and time-dependent progression of abnormal MRI and MRS findings would discriminate patients with mutations of the PLP gene (Pelizaeus Merzbacher disease, PMD) from patients without a defect of the PLP gene (Pelizaeus Merzbacher-like disease, PMLD). For a standardised intraindividual follow-up and for comparison of the degree of hypomyelination, we have applied a newly developed semiquantitative myelination score on a total of 18 MRI series of 4 PMD and 4 PMLD patients. We found severe hypomyelination (50 % of normal) in 2 PMD and in 2 PMLD patients, moderate hypomyelination (75 % of normal) in 2 PMD and mild hypomyelination (75 % of normal) in 2 PMLD patients. Our score revealed a clear correlation between the degree of hypomyelination and the severity of clinical handicap in PMD but not in PMLD patients. MRS showed heterogeneous cerebral metabolite patterns in both patient groups and seems to reflect a mixture of unspecific changes due to primary hypomyelination and secondary gliosis and demyelination. Neither by MRI nor by MRS were patterns found that would allow differentiation between PMD and PMLD patients.

Epileptische Anfalle gehoren zu den haufigsten neurologischen Notfallen im Kindes- und Jugendalter. Nach erstmaligem Auftreten eines Krampfanfalls ist eine rasche Klarung der zugrundeliegenden Ursache in Hinblick auf eine moglichst fruhe zielgerichtete Behandlung von groser Bedeutung. Als mogliche Ursachen kommen Raumforderungen, Blutungen oder Traumen, infektiose Erkrankungen des Zentralnervensystems, Stoffwechselerkrankungen, Elektrolytentgleisungen, Drogen- oder Alkoholabusus sowie Schlafentzug in Frage. In nur etwa 1% sind die Anfalle Ausdruck einer Epilepsie. Wir berichten den Fall einer bis dato immer gesund gewesenen 17-jahrigen, die wegen eines erstmals aufgetretenen, generalisierten tonisch-klonischen Anfalls an unserer Abteilung aufgenommen wurde. In der Anamnese fanden sich seit zwei Tagen bestehende starke Kopfschmerzen, die erfolgreich analgetisch behandelt wurden. Im klinisch physikalischen Status war eine Adipositas auffallig, im neurologischen Status, im Labor sowie in der craniellen Computertomographie zeigten sich keine pathologischen Befunde, sodass die Patientin primar unter der Verdachtsdiagnose einer idiopathischen Epilepsie mit Antiepileptika behandelt wurde. Unter Therapie kam es zu einer Gesichtsfeldeinschrankung und schlieslich zu weiteren generalisierten Anfallen. Eine erweiterte Diagnostik mit Lumbalpunktion, Bestimmung der Schilddrusenhormone und einem Drogenscreening blieb ebenfalls ohne pathologischen Befund. Schlieslich lieferte eine gezielte Befragung und die Harnanalyse den entscheidenden Hinweis fur die Ursache des Anfallgeschehens, welches nun doch als Symptom einer schweren Grunderkrankung zu werten war.

OBJECTIVE The reverse transcriptase (RT) M184V mutation within the HLA-A2-restricted HIV-1 cytotoxic T lymphocyte (CTL) epitope VL9 (VIYQYMDDL; RT 179-187) not only induces drug escape against lamivudine but also abolished recognition by a CTL clone derived from a long-term non-progressor. To test whether the variant VL9 epitope containing the M184V mutation represents a new CTL epitope, we studied recognition of this epitope in a cohort of HLA-A2-positive HIV-1-infected patients. METHODS Peripheral blood mononuclear cells isolated from 28 HIV-1-infected patients were stimulated with the peptide VIYQYVDDL, containing the M1 84V mutation. Outgrowing cell lines were tested for specific recognition in a standard chromium-release assay. RESULTS In one subject, a CTL line could be isolated recognizing the peptide VIYQYVDDL in conjunction with HLA-A2. The CTL clone also recognized the M1841 mutation, but it failed to recognize the wild-type epitope VIYQYMDDL. CONCLUSION CTL can specifically recognize lamivudine-resistant HIV-1 variants. Therefore, the cellular immune response could have an important influence on the control of drug-resistant virus. Furthermore, this demonstrates that the immune system can generate new CTL specificities even in patients with advanced disease, as the M184V HIV variants emerges only after drug treatment. Specific immunotherapy against this epitope might be helpful in delaying or preventing lamivudine resistance.

The purpose of this study was to evaluate the efficacy of high-dose chemotherapy (HDC) with busulfan, melphalan and thiotepa (BUMELTT) followed by autologous PBSC infusion in treating patients with advanced ovarian cancer. Thirty-one patients, 18 with stage III/IIIc and 13 with stage IV ovarian cancer, were treated with BU (12 mg/kg), MEL (100 mg/m2) and TT (500 mg/m2) and autologous PBSC rescue. Fifteen patients were in clinical complete remission (CR) at treatment; 11 had platinum-sensitive disease. Sixteen patients were not in CR; two had platinum-sensitive disease. The probabilities of overall survival (OS), event-free survival (EFS) and relapse (R) for all patients at 18 months were 0.57, 0.30 and 0.63; for patients in CR, the rates were 0.87, 0.44 and 0.49 and for patients not in CR, 0.38, 0.13 and 0.81. Two patients (6.5%) died of treatment-related causes. Among the 13 patients with platinum-sensitive disease, all are still alive, with seven having relapsed 129-1021 days after PBSC infusion. OS, EFS and R were 1.00, 0.52 and 0.48. Of the 18 patients with platinum-resistant disease, four remain alive (two in remission). Six patients did not respond and eight relapsed from days 104-429. The OS, EFS and R were 0.33, 0.11 and 0.78. We conclude that BUMELTT is well tolerated in patients with advanced ovarian cancer and results are equivalent to other published HDC regimens.

Some individuals in well-defined cohorts have now been infected with HIV-1 for well over a decade and yet remain clinically asymptomatic with normal CD4 counts. To determine immunologic and virologic parameters in these individuals, we examined 10 persons from the San Francisco City Clinic with firmly documented infection of 11-15 years duration who had maintained stable CD4 counts above 500 cells/microliters. Our results indicate that long-term nonprogressors are a heterogeneous group with respect to viral load and HIV-1-specific immune responses, and that progression can occur even after 15 years of stable infection. However, in a subset of persons with the lowest viral loads and persistent nonprogressive infection, we detected strong CTL responses, whereas neutralizing antibody studies revealed weak to undetectable titers against a panel of 10 primary isolates. This study demonstrates that a vigorous in vivo activated HIV-1-specific CTL response can be part of the host immune response in stable nonprogressive HIV-1 infection, and that circulating activated CTL can be detected in the setting of an extremely low viral load. These results also indicate that long-term nonprogressing HIV-1 infection does not require the presence of broadly cross-reactive neutralizing antibodies.

Numerous virus-specific, class I-restricted cytotoxic T lymphocyte (CTL) epitopes have been identified, yet little information is available regarding the specificity of the CTL response in persons of the same human histocompatibility leukocyte antigen (HLA) type. In this study, the human immunodeficiency virus (HIV) 1 envelope-specific CTL response was evaluated in five HLA-B14-positive persons. CTL responses specific for a previously described nine-amino acid epitope in gp41 (aa 584-592, ERYLKDQQL) could be identified in all subjects, and CTL clones specific for this epitope could be isolated from four persons. Despite heterogeneous T cell receptor usage, the fine specificity of the clones was similar, as defined by recognition of alanine-substituted peptides as well as peptides representing natural HIV-1 sequence variants. Correlation with in vivo virus sequences revealed that the dominant species in two of the subjects represented poorly recognized variants, with a K-->Q substitution at amino acid 588, whereas no variants were observed in the other two subjects. Although clonal type-specific responses to these dominant variants could be identified, the magnitude of these responses remained small, and the dominant CTL response was directed at the minor in vivo variant. These studies indicate that despite similar epitope-specific immunologic pressure in persons of the same HLA type, the in vivo quasispecies may differ, and that the major in vivo immune response to a given CTL epitope can be directed at a minor variant.

The coexistence of mental retardation and retinitis pigmentosa has been well described in a number of congenital syndromes such as the Lawrence-Moon and Bardet-Biedl disorders. In contrast to this, little information is available regarding the association of acquired dementia with retinitis pigmentosa. This report summarizes the clinical features of a developmentally normal adult having the unusual symptom complex of retinitis pigmentosa, early-onset dementia, sensorineural hearing loss, and sensorimotor neuropathy. Though the coexistence of retinitis pigmentosa and dementia in this particular patient may be completely coincidental, it could be representative of a previously unrecognized subset of dementing illness. The literature pertaining to related symptom complexes is reviewed and discussed.

A randomized, double-blind study examining the effectiveness and tolerance of a standardized hypericum preparation when compared to maprotiline was performed in a group of 102 patients with depression, in accordance with ICD-10, F 32.1. The study was conducted in the offices of neurology and psychiatry specialists. The patients received, over a period of 4 weeks, either 3 x 300 mg of the hypericum extract or 3 x 25 mg maprotiline pills of identical appearance. Effectiveness was determined using the Hamilton Depression Scale (HAMD), the Depression Scale according to von Zerssen (D-S), and the Clinical Global Impression Scale (CGI). The total score of the HAMD scale dropped during the 4 weeks of therapy in both treatment groups by about 50%. The mean values of the D-S scale and the CGI scale showed similar results, and after 4 weeks of therapy, no significant differences in either treatment group were noticed. The onset of the effects occurred up to the second week of treatment, but were observed earlier with maprotiline than with the hypericum extract. On the other hand, maprotiline treatment resulted in more cases of tiredness, mouth dryness, and heart complaints.

Background: HIV-1 protease is subjected to dual selection pressure exerted by protease inhibitors (PIs) and cytotoxic T lymphocytes (CTL). Recently, we identified KMIGGIGGF (KF9) as a HLA-B*1501-restricted CTL epitope, including several major PI resistance mutations (M46I/L, I47A/V, G48V, I50V). To assess potential interactions between KF9-specific CTL and emergence of these important resistance mutations, we studied CTL recognition of the mutations and analyzed protease sequences in an HLA-I-typed patient cohort. Methods: CTL recognition of KF9 and resistance mutations in KF9 were studied in 38 HLA-B*1501-positive HIV-1-infected patients using variant KF9 peptides in interferon-γ enzyme-linked immunospot assays. Protease sequences were analyzed in 302 HLA-I-typed HIV-1-infected patients. Results: G48V abolished KF9 recognition by CTL in all patients. Furthermore, M46I, I47A, and I50V could impair or abolish CTL recognition in many patients. In contrast, M46L and I47V showed good CTL recognition in nearly all patients. HIV-1 protease sequence analysis showed no statistical correlation between the occurrence of resistance mutations in KF9 and HLA-B*1501. Viral load in patients failing therapy with KF9 mutations was significantly lower in HLA-B*1501-positive patients in comparison with HLA-B*1501-negative patients. Conclusions: PI mutations, G48V, M46I, and I47A, can abrogate CTL recognition, indicating potential interactions between development of drug resistance and CTL response. However, we could not find evidence that development of these PI mutations is influenced by KF9-specific CTL.

Objectives: To study the role of cytotoxic T-lymphocyte (CTL) escape for disease progression in HIV-1 infection, we analyzed the CTL response to the dominant human leukocyte antigen (HLA)-B8-restricted CTL epitope FLKEKGGL (FL8) in HIV-1 Nef. Methods: HIV-1 nef genes derived from 56 patients were analyzed by polymerase chain reaction (PCR)-based sequencing. T-cell responses against FL8 and mutated FL8 variants were detected by γ-interferon (γ-IFN) enzyme linked immunospot (ELISPOT) assay. Results: The longitudinal analysis of an HIV-1-infected patient with good control of HIV-1 viremia for several years demonstrated an association of rising viremia with the emergence of CTL escape mutations within the HLA-B8-restricted Nef-specific CTL epitopes FLKEKGGL and WPAIRERM. Analysis of nef genes in 56 HIV-1-infected patients demonstrated a significant correlation between the occurrence of mutations in the FL8 epitope and the presence of HLA-B8. The mutations within the FL8 epitope could decrease CTL recognition; however, there was strong variation regarding the recognition of viral variants between individual donors. The presence of FL8 mutations was associated with lower CD4 cell counts and higher viral loads. Conclusions: Our data demonstrate a strong CTL selection pressure on the immunodominant HLA-B8-restricted CTL epitope FL8 in HIV-1 Nef. The association of FL8 mutations with lower CD4 cell counts indicates an important role of CTL escape mutations for disease progression.

This study investigated the usefulness of the Contingent Negative Variation (CNV) in the assessment of therapeutic efficacy of a nootropic substance, Cerebrolysin ® . A total of 41 geriatric patients with the diagnosis of moderate organic brain syndrome of different etiology were included in this randomized placebo-controlled double-blind study

In an attempt to improve indicators of validity for the therapeutic efficacy of nootropics, the effects of Cerebrolysin(R) were compared across three different dimensions of variables in a randomized placebo-controlled double-blind study. A group of 27 geriatric patients suffering from an organic brain syndrome with moderate cognitive impairment of a vascular or/and degenerative nature received a series of ten Cerebrolysin + multivitamin infusions. They were compared to a second group with 14 clinically comparable patients, who received multivitamin infusions alone. Pre-posttreatment differences from (1) clinical scales (SCAG, Plutchik Geriatric Rating Scale and a self-evaluation scale); (2) psychometric test performance (trail-making and maze subtests from the Nürnberg Age Inventory); and (3) event-related brain activity (contingent negative variation (CNV) amplitude) were in favor of the Cerebrolysin-treated group. A high degree of association as well as high classification rates (95% joint correct classification) underlined their clinical significance. It was concluded that the multidimensional measurement approach could increase the clinical validity of nootropic drug effects.

The cytotoxic T-lymphocytes (CTL) response to three histocompatibility leukocyte antigen (HLA)-A2-restricted CTL epitopes was investigated in a cohort of 51 HLA-A2-positive human immunodeficiency-1 (HIV-1)-infected subjects. CTL activity was evaluated by testing peptide stimulated peripheral blood mononuclear cells (PBMC) in chromium release assays. The most prevalent CTL response was directed to the RT-peptide ILKEPVHGV (IV9) recognized by 37.3%. The p17-peptide SLYNTVATL (SL9), reported to be the immunodominant epitope in chronically infected untreated patients, was recognized only by 13.7%. Only 9.8% recognized both IV9 and SL9, and none recognized the RT-peptide VIYQYMDDL (VL9). CTL activity correlated significantly with absolute CD8 T-cell counts but not with CD4 counts, viral load, or antiviral therapy. Analysis of the recognition patterns of amino acid substitutions in the IV9 epitope revealed the presence of at least four functionally different T-cell receptors (TCR) in this cohort. All analyzed mutations within the TCR recognition site of this epitope could abrogate CTL recognition by individual CTL clones, but all were fully immunogenic for other CTL clones with peptide-sensitizing capacities similar to that of IV9. Further studies should be performed to evaluate whether a convergent epitope vaccination strategy using immunogenic variants of CTL epitopes is a feasible approach to broaden the TCR repertoire and to inhibit CTL escape.

One hundred and five outpatients with mild depressions of short duration were treated in a double-blind study with either 3 x 300 mg hypericum extract or placebo. The therapy phase was 4 weeks. The effectiveness was judged according to the Hamilton Depression Scale after 2 and 4 weeks. The values of the mean basic score in these periods fell from 15.8 to 9.6 or 7.2 in the active group, and in the placebo group, from 15.8 to 12.3 and 11.3. The difference between active and placebo groups were statistically significant with P < .05 and P < .01 achieved after 2 and 4 weeks, respectively. In the active group, 28 of 42 patients (67%) and, in the placebo group, 13 of 47 Patients (28%) responded to treatment. Notable side effects were not found.

To date, 25 controlled therapy studies have investigated the antidepressive effectiveness of hypericum extracts. A total of 1592 treatment cases have been included. The dosage was typically 300 to 900 mg total extract daily; therapy duration was 2 to 6 weeks. Fifteen studies were performed comparing hypericum extracts with placebo, 10 studies as comparative studies. This paper presents an overview of their results.

A sunlight deficiency, as is experienced at our latitude in winter, induces a seasonal affective disorder (SAD) or winter depression in some people. First line of treatment of this form of depression is bright-light therapy, as a type of substitution therapy. SAD is treated with similar success using antidepressant drugs like hypericum (St. John's wort). Phototherapy also has an antidepressive effect on non-seasonal depressions, albeit not quite as pronounced. When using phototherapy light is transformed into electric impulses in the retina. These impulses are transmitted to the hypothalamus and the central nervous structures controlling metabolism, hormones and the circadian rhythms. These processes are governed by very complex regulatory mechanisms. Feedback loop mechanisms induce constant adaptation of the photosensitivity of the retinal photoreceptors while also controlling the central nervous structures. New findings on the interaction and interweaving of depression, light, metabolism, hormones and circadian rhythms support the following hypothesis: The photodynamic impact of hypericum magnifies the effect of normal light, as if the patient were subject to continuous light therapy. The photosensitizing effect of hypericum is thus not only of interest as an undesirable side-effect but also for its therapeutic effects.

In this paper, we compare the computational and sociological study of norms, and resimulate previous simulations (Conte and Castelfranchi 1995a, Castelfranchi, Conte and Paolucci 1998) under slightly different conditions. First, we analyze the relation between norms, social inequality and functional change more closely. Due to our results, the hypothesis stating that the "finder-keeper" norm while controlling aggression efficaciously reduces social inequality holds only in quite egalitarian societies. Throughout a variety of inegalitarian societies, it instead increases social inequality. This argument which can be traced back to Marx is being investigated by use of computer simulations of artificial societies. Second, we remodel normative behaviour from a sociological point of view by implementing Haferkamp's theory of action approach to deviant behaviour. Following the game theoretic models, the computational study of norms has up to now ignored the importance of power in explaining how norms affect social behaviour, how norms emerge, become established and internalized, and change. By simulating Haferkamp and repeating the Conte and Castelfranchi experiments, we demonstrate that it is possible to integrate power into computational models of norms.

Summary: A prominent feature of HIV infection is a progressive anergy of T cells and an increase of activation-dependent T-cell death. CD80 (B7.1), the ligand of CD28, is an important co-stimulatory molecule on antigen-presenting cells that delivers an essential second signal for T-cell activation. To test whether immunologic dysfunction in HIV disease involves CD80, we studied CD80 expression on circulating monocytes in heparinized whole blood of 33 HIV-infected patients and 13 controls. Most monocytes in patients and controls expressed significant amounts of CD80. There was no statistical difference of mean fluorescence intensity (MFI) of CD80 expression when all HIV-infected patients were compared with healthy controls. However, asymptomatic patients in clinical Centers for Disease Control and Prevention (CDC) stage A showed a significantly stronger CD80 expression than did healthy controls. Additionally, patients receiving antiretroviral therapy exhibited significantly higher CD80 expression than did patients not receiving therapy and healthy controls. We did not find a correlation with the presence of HIV p24 antigenemia and counts of CD4+ and CD8+ T cells. Although we studied CD80 expression only on circulating monocytes and not in HIV-infected monocytes or in activated macrophages, our data do not support a role for a general impairment of CD80 expression in induction of anergy in HIV disease.

We report on the first HLA B13-restricted minimal cytotoxic T lymphocyte (CTL) epitope RQDILDLWI (RI9, amino acids 106-114 in HIV-1 Nef). In most patients the frequency of RI9-specific CTL exceeded the number of CTL against other epitopes, indicating that RI9 is a dominant epitope in HLA B13-positive patients. Targeting this conserved Nef epitope may be an important factor for the published association of HLA B13 with a favourable course of HIV-1 infection.

In a multicenter, placebo-controlled double-blind trial, the effect on depression (ICD 10 F 32.1) of treatment with an innovative highly concentrated hypericum preparation was investigated. The study contained 97 outpatients who received 100 to 120 mg of the hypericum extract bid. The course of the illness was assessed with the Hamilton Depression Scale (HAMD), the von Zerssen Depressivity Scale (D-S) and the Clinical Global Impression Scale (CGIS). Treatment resulted in an appreciable improvement in the symptoms of depression, and the 70% response rate (n = 43), corresponded to that of chemical antidepressants. The preparation also showed an anxiolytic effect. The substance was extremely well tolerated, and no side-effects were reported by any of the patients.

Rechtsverstose, die im Rahmen einer schizophrenen Grunderkrankung und unter gleichzeitigem Alkoholeinflus begangen wurden, fanden bisher in der Literatur kaum besonderes Augenmerk. Bereits die Frage der Haufigkeit eines symptomatischen Alkoholabusus bei schizophrenen Patienten ist noch unzureichend geklart.