A Metalloproteinase Mirolysin of Tannerella forsythia Inhibits All Pathways of the Complement System

Recent reports focusing on virulence factors of periodontal pathogens implicated proteinases as major determinants of remarkable pathogenicity of these species, with special emphasis on their capacity to modulate complement activity. In particular, bacteria-mediated cleavage of C5 and subsequent release of C5a seems to be an important phenomenon in the manipulation of the local inflammatory response in periodontitis. In this study, we present mirolysin, a novel metalloproteinase secreted by Tannerella forsythia, a well-recognized pathogen strongly associated with periodontitis. Mirolysin exhibited a strong effect on all complement pathways. It inhibited the classical and lectin complement pathways due to efficient degradation of mannose-binding lectin, ficolin-2, ficolin-3, and C4, whereas inhibition of the alternative pathway was caused by degradation of C5. This specificity toward complement largely resembled the activity of a previously characterized metalloproteinase of T. forsythia, karilysin. Interestingly, mirolysin released the biologically active C5a peptide in human plasma and induced migration of neutrophils. Importantly, we demonstrated that combination of mirolysin with karilysin, as well as a cysteine proteinase of another periodontal pathogen, Prevotella intermedia, resulted in a strong synergistic effect on complement. Furthermore, mutant strains of T. forsythia, devoid of either mirolysin or karilysin, showed diminished survival in human serum, providing further evidence for the synergistic inactivation of complement by these metalloproteinases. Taken together, our findings on interactions of mirolysin with complement significantly add to the understanding of immune evasion strategies of T. forsythia and expand the knowledge on molecular mechanisms driving pathogenic events in the infected periodontium.

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial.

Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12-month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7-11 weeks after HTx or standard cyclosporine immunosuppression. Ninety-five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm(3) and 13.8 ± 28.0 mm(3) [all p-values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor-1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus-based CNI-free can potentially be considered in suitable de novo HTx recipients.

Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial.

In a randomized, open-label trial, everolimus was compared to cyclosporine in 115 de novo heart transplant recipients. Patients were assigned within 5 days posttransplant to low-exposure everolimus (3–6 ng/mL) with reduced-exposure cyclosporine (n = 56), or standard-exposure cyclosporine (n = 59), with both mycophenolate mofetil and corticosteroids. In the everolimus group, cyclosporine was withdrawn after 7–11 weeks and everolimus exposure increased (6–10 ng/mL). The primary efficacy end point, measured GFR at 12 months posttransplant, was significantly higher with everolimus versus cyclosporine (mean ± SD: 79.8 ± 17.7 mL/min/1.73 m2 vs. 61.5 ± 19.6 mL/min/1.73 m2; p < 0.001). Coronary intravascular ultrasound showed that the mean increase in maximal intimal thickness was smaller (0.03 mm [95% CI 0.01, 0.05 mm] vs. 0.08 mm [95% CI 0.05, 0.12 mm], p = 0.03), and the incidence of cardiac allograft vasculopathy (CAV) was lower (50.0% vs. 64.6%, p = 0.003), with everolimus versus cyclosporine at month 12. Biopsy-proven acute rejection after weeks 7–11 was more frequent with everolimus (p = 0.03). Left ventricular function was not inferior with everolimus versus cyclosporine. Cytomegalovirus infection was less common with everolimus (5.4% vs. 30.5%, p < 0.001); the incidence of bacterial infection was similar. In conclusion, everolimus-based immunosuppression with early elimination of cyclosporine markedly improved renal function after heart transplantation. Since postoperative safety was not jeopardized and development of CAV was attenuated, this strategy may benefit long-term outcome.

Plasma NGAL and glomerular filtration rate in cardiac transplant recipients treated with standard or reduced calcineurin inhibitor levels.

AIM Predictors of renal recovery following conversion from calcineurin inhibitor- to proliferation signal inhibitor-based therapy are lacking. We hypothesized that plasma NGAL (P-NGAL) could predict improvement in glomerular filtration rate (GFR) after conversion to everolimus. PATIENTS & METHODS P-NGAL was measured in 88 cardiac transplantation patients (median 5 years post-transplant) with renal dysfunction randomized to continuation of conventional calcineurin inhibitor-based immunosuppression or switching to an everolimus-based regimen. RESULTS P-NGAL correlated with measured GFR (mGFR) at baseline (R(2) = 0.21; p < 0.001). Randomization to everolimus improved mGFR after 1 year (median [25-75 % percentiles]: ΔmGFR 5.5 [-0.5-11.5] vs -1 [-7-4] ml/min/1.73 m(2); p = 0.006). Baseline P-NGAL predicted mGFR after 1 year (R(2) = 0.18; p < 0.001), but this association disappeared after controlling for baseline mGFR. CONCLUSION P-NGAL and GFR correlate with renal dysfunction in long-term heart transplantation recipients. P-NGAL did not predict improvement of renal function after conversion to everolimus-based immunosuppression.

The European Registry for Patients with Mechanical Circulatory Support (EUROMACS): first annual report

The European Registry for Patients with Mechanical Circulatory Support (EUROMACS) was founded on 10 December 2009 with the initiative of Roland Hetzer (Deutsches Herzzentrum Berlin, Berlin, Germany) and Jan Gummert (Herz- und Diabeteszentrum Nordrhein-Westfalen, Bad Oeynhausen, Germany) with 15 other founding international members. It aims to promote scientific research to improve care of end-stage heart failure patients with ventricular assist device or a total artificial heart as long-term mechanical circulatory support. Likewise, the organization aims to provide and maintain a registry of device implantation data and long-term follow-up of patients with mechanical circulatory support. Hence, EUROMACS affiliated itself with Dendrite Clinical Systems Ltd to offer its members a software tool that allows input and analysis of patient clinical data on a daily basis. EUROMACS facilitates further scientific studies by offering research groups access to any available data wherein patients and centres are anonymized. Furthermore, EUROMACS aims to stimulate cooperation with clinical and research institutions and with peer associations involved to further its aims. EUROMACS is the only European-based Registry for Patients with Mechanical Circulatory Support with rapid increase in institutional and individual membership. Because of the expeditious data input, the European Association for Cardiothoracic Surgeons saw the need to optimize the data availability and the significance of the registry to improve care of patients with mechanical circulatory support and its potential contribution to scientific intents; hence, the beginning of their alliance in 2012. This first annual report is designed to provide an overview of EUROMACS' structure, its activities, a first data collection and an insight to its scientific contributions.

Na 1 Nachlass Max Horkheimer, 96 - Korrespondenzen u.a. mit Jürgen Habermas (p. III 6, 1-421)

5 Briefe mit Antwort an Inga Haag, 1951-1955; 1 Brief mit Antwort von Jürgen Habermas an Max Horkheimer, 1955; 1 Brief von Ministerialrat i. R. Theodor Häbich an Max Horkheimer, 1957; 2 Briefe mit Antwort von cand. phil. Walter Hähnle an Max Horkheimer, 1955, 1957; 1 Brief mit Antwort von Sekretärin Jutta Hagen an Max Horkheimer, 1956; 1 Dissertationsauszug von Volker Freiherr von Hagen, 1954; 1 Brief mit Antwort von Julia Hagenbucher an Max Horkheimer, 1951/1952; 1 Entwurf zu einem Gratulationsschreiben von Max Horkheimer an Professor Otto Hahn, ohne Jahr; 2 Drucksachen von Obermagistratsrat Julius Hahn, 1953, 1955; 1 Brief mit Antwort von Theodor W. Adorno, von Dr. Hans Hahn an Max Horkheimer, 1952; 1 Brief von Theodor W. Adorno an Dr. Hans Hahn, 1952; 1 Danksagung von Rabbi Hugo Hahn, 1955; 3 Briefe mit Antwort von Paul Hahn an Max Horkheimer, 1951-1958; 1 Brief von Max Horkheimer an die Gebrüder Haldy, 1952; 1 Brief mit Antwort und Beilage von Professor George W. F. Hallgarten an Max Horkheimer, 1950; 1 Rundschreiben von Arzt und Psychotherapeut Hans Hammer, 1957; 1 Brief von Max Horkheimer an Margarete Hampf-Solm, 1955; 1 Brief mit Antwort von Professor Eduardo Hamuy an Max Horkheimer, 1952; 1 Brief von der Stadtärztin Dr. med. Carola Hannappel an Max Horkheimer, 1951; 1 Brief von Hansenmeister an Max Horkheimer, 1951; 1 Brief mit Antwort und Beilage von der Buchhandlung Ludwig Häntzschel an Max Horkheimer, 1958; 1 Brief von Professor Frederick Harris Harbison an Max Horkheimer, 1952; 3 Briefe mit Antwort von Robert Harcourt an Max Horkheimer, 1958; 1 Brief von Karl Hardach an Max Horkheimer, 1957; 1 Brief mit Antwort von Emilie Harlacher an Max Horkheimer, 1952; 1 Drucksache mit Antwort von Oberkirchenrat Otto L. A. von Harling an Max Horkheimer, 1955; 1 Brief mit Antwort von Gertrud Harms an Max Horkheimer, 1955; 2 Brief mit Antwort von Professor Wolfgang Hartke an Max Horkheimer, 1954-1956; 2 Briefe mit antwort von Max Horkheimer an Senator Georg Hartmann, 1951, 1954; 3 briefe mit Antwort und Beilage von Ökonom Heinz Hartmann an Max Horkheimer, 1956-1958; 1 Brief mit Antwort von Professor Wilbert E. Moore an Max Horkheimer, 1957; 3 Briefe mit Antwort und Beilage von Dr. phil. Leo Hartmann an Max Horkheimer, 1957-1858; 1 Brief mit Antowort von Dr. phil. Eckardt Mesch an Max Horkheimer, 1957; 1 Brief mit Antwort von Luzie Hatch an Max Horkheimer, 1954; 1 Brief von Max Horkheimer an den Direktor H. W. Haupt, 1950; 1 Drucksache von Haus Schwalbach, 1951; 4 Briefe mit Antwort von Professor Gottfried und Ellen Hausmann an Max Horkheimer, 1951-1958; 6 Briefe mit Antwort von Eva Haussner an Max Horkheimer, 1957, 1958; 1 Brief mit Antwort von Professor Robert J. Havighurst an Max Horkheimer, 1951; 1 Brief mit Beilage von Herbert Hax an Max Horkheimer, 1955; 2 Briefe mit Antwort und Beilage von Jean Louis Hébarre an Max Horkheimer, 1950-1952; 1 Brief mit Antwort von dem Hebedienst für Elektrizität, Gas und Wasser an Max Horkheimer, 1951; 5 Briefe mit Antwort und Beilage von Professor Otto Heckmann an Max Horkheimer, 1952, 1954; 1 Brief von Melvin J. Lasky an August Heckscher, 1957; 3 Briefe mit Antwort von Marie Heep an Max Horkheimer, 1956-1858; 1 Brief von der Buchhandlung Thekla Heer an Max Horkheimer, 1953; 1 Brief mit Antwort von dem Verleger Jakob Hegner an Max Horkheimer, 1955; 1 Brief von Dr. phil. Rudolf M. Heilbrunn an Max Horkheimer, 1953; 1 Brief mit Antwort von Professor Eduard Heimann an Max Horkheimer, 1952; 1 Brief von Professor Eduard Heimann an Theodor W. Adorno, 1957; 1 Brief mit Antwort von stud. phil. Wolfgang Heinrich an Max Horkheimer, 1958; 1 Brief von Max Horkheimer an den Direktor Helmuth Heintzmann, 1955; 1 Aktennotiz von Professor Bernhard Heller, 1956; 1 Brief mit Antwort von Philipp A. Heller an Max Horkheimer, 1952; 1 Brief von Max Horkheimer an Assistent Winfried Hellmann, 1957; 2 Briefe mit Antwort von Professor Arthur Henkel an Max Horkheimer, 1953/1954; 1 Brief von Max Horkheiemr an Dorothy Henkel, 1952; 2 Briefe mit Antwort von Dr. jur. Werner Hennig an Max Horkheimer, 1951; 1 Brief von Max Horkheimer an Professor Wilhelm Hennis, 1957; 3 Briefe mit Antwort und Beilage von Professor Fritz Hepner an Max Horkheimer, 1953; 1 Brief von Max Horkheimer an den Hessischer Minister für Erziehung und Volksbildung, 1950; 1 Brief mit Antwort von Professor Henrietta Herbolsheimer an Max Horkheimer, 1957/1958; 2 Briefe mit Antwort von P. G. Herbst an Max Horkheimer, 1952; 1 Brief von Max Horkheimer an den Herder Verlag, 1953; 2 Briefe mit Antwort, Beilagen und Aktennotizen von Guenter R. Herz an Max Horkheimer, 1956-1957; 2 Briefe mit Antwort unv Beilagen von Professor Theodor W. Adorno, von Dr. phil. Günther Herzberg an Max Horkheimer, 1951-1953; 1 Brief von Professor Theodor W. Adrono an Dr. phil. Günther Herzberg, 1951; 1 Brief von Dr. phil. G. Herzfeld an Max Horkheimer, 1952; 1 Brief von dem Herzog-Film an Max Horkheimer, 1952; 1 Brief mit Antwort von Professor Theodor W. Adorno, von Professor Erich Herzog an Max Horkheimer, 1952; 1 Brief von Professor Theodor W. Adorno an Professor Erich Herzog, 1952; 1 Brief mit Antwort von dem Verlag Otto H. Hess an Max Horkheimer, 1954; 1 Brief von Professor Gerhard Hess an Max Horkheimer, 1953; 1 Drucksachevon dem Hessischer Arbeitsausschuss gegen Rekrutierung, 1952; 1 Brief mit Beilage von dem Hotel Hessischer Hof an Max Horkheimer, 1956; 1 Brief mit Antwort von dem Hessischer Landesverband für Erwachsenenbildung an Max Horkheimer, 1956; 2 Briefe mit Antwort und Beilage von Marc Heurgon an Max Horkheimer, 1958; 1 Brief mit Beilage von Ruth Heydebrand an Max Horkheimer, [1955]; 1 Brief mit Antwort von Professor Frederick W. J. Heuser an Max Horkheimer, 1954; 2 Briefe mit Antwort von Professor Joh Erich Heyde an Max Horkheimer, 1958; 1 Befürwortung von Wolf von Heydebrand an Max Horkheimer, 1954; 1 Brief mit Antwort von Professor Heinz Joachim Heydorn an Max Horkheimer, 1953; 1 Brief mit Antwort und Beilage von dem Arzt Otto Heymann an Max Horkheimer, 1955; 5 Briefe zwischen dem Devisenberater und Steuerhelfer Joseph Christ und Max Horkheimer, 1955, 1956, 1961; 1 Brief von dem Office of the United States High Commissioner for Germany an Max Horkheimer, 1953; 1 Lebenslauf von Elen B. Hill, ohne Jahr; 1 Brief von Kurt H. Wolff an Max Horkheimer, 1952; 1 Brief von Rolf Himmelreich an Max Horkheimer, 1956; 1 Brief mit Antwort von Dr. Rolf Hinder an Max Horkheimer, 1953; 1 Brief mit Antwort von Anton Hinsinger an Max Horkheimer, 1953; 1 Brief mit Antwort von dem Hippokrates-Verlag an Max Horkheimer, 1952; 1 Brief von Bernice L. Hirsch anMax Horkheimer, 1957; 4 Briefe und Beilagen zwischen dem Historiker und Soziologe Helmut Hirsch an Max Horkheimer, 1951-1954, 25.05.1951; 3 Briefe mit Antwort von Lux Hirsch an Max Horkheimer, 1958; 1 Brief mit Antwort von Trude Hirschberg an Max Horkheimer, 1951; 1 Brief mit Antwort von Ingineur Paul F. Hirschfelder an Max Horkheimer, 1952; 1 Brief von Johannes Hirzel an Max Horkheimer, 1955; 1 Brief mit Antwort von dem Historisches Seminar Köln an Max Horkheimer, 1956; 1 Brief mit Antwort und Beilage von Professor Wolfgang Hochheimer an Professor Theodor W. Adorno, 1952; 2 Briefe von Max Horkheimer an Professor Wolfgang Hochheimer, 1953, 1954; 2 Memoranden von der Deutschen Gesellschaft für Psychologie, 1953; 1 Brief mit Beilage von Stud. phil. Erna Hochleitner an Max Horkheimer, 1956; 1 Brief mit Antwort von Professor Helmut Coing an Max Horkheimer, 1957; 3 Briefe mit Antwort von der Hochschule für Sozialwissenschaften Wilhelmshaven an Max Horkheimer, 1957, 1958; 1 Brief von Max Horkheimer an die Hochschule für Wirtschafts- und Sozialwissenschaften Nürnberg, 1953; 2 Drucksachen von dem Hochschul-Dienst, 1952; 2 Drucksachen von der Hochschule für politische Wissenschaften München, 1952; 1 Brief mit Antwort von Dr. Wolfram Hodermann an Max Horkheimer, 1951; 4 Briefe zwischen Dr. phil. Walter Höllerer und Max Horkheimer, 1956; 1 Brief mit Antwort von Privatdozent Dr. phil. Walter Hoeres anMax Horkheimer, 1956; 2 Briefe mit Antwort von Stud. phil. Charlotte Hoffmann an Max Horkheimer, 1950; 3 Briefe mit Antwort und Beilage von Professor Walter Hoffmann an Max Horkheimer, 1950-1955; 1 Brief mit Antwort von Wolfhart E. V. Hoffmann an Max Horkheimer, 1953; 1 Brief von Max Horkheimer an Dr. Werner Hofmann, 1956; 1 Glückwunschtelegramm mit Antwort von Ernst und Karl Hohner, 1953; 1 Brief von Dozent Uvo Hölscher an Max Horkheimer, 1950; 2 Briefe mit Antwort von Professor Dr. med. K. Holldack an Max Horkheimer, 1957; 2 Briefe mit Antwort von Dipl. Landwirt Bernhard Hollenhorst an Max Horkheimer, 1956; 1 Brief von Hans Heinz Holz an Max Horkheimer, 1951; 2 Briefe mit Antwort und Beilage von Dr. phil. Rudolf Holzinger an Max Horkheimer, 1951, 1952; 1 Brief mit Antwort von Jakob Hommen an Max Horkheimer, 1953; 1 Brief von Adele Hoppe anMax Horkheimer, 1953; 1 Brief mit Antwort von Dr. jur. Anton Horn an Max Horkheimer, 1954; 1 Brief mit Antwort von Dr. phil. Emil Horn an Max Horkheimer, 1953; 1 Brief von der Landesabgeordneten Ruth Horn an H. Maidon, 1953; 1 Brief mit Antwort von Reg.-Direktor Dr. phil. Kurt Horstmann an Max Horkheimer, 1953; 1 Brief von dem Hotel Baur au Lac an H. Maidon, 1958; 2 Briefe mit 1 Antwort von dem Hotel Frankfurter Hof an Max Horkheimer, 1956, 1958; 1 Brief mit Antwort von dem Hotel Stafflenberg an H. Maidon, 1953; 1 Brief von dem Hotel Vier Jahreszeiten, München an Max Horkheimer, 1951; 1 Brief von Max Horkheimer an Jean J. Hubener, 1951; 2 Briefe mit Antwort und Beilage von Susanna Huber-Weisser an Max Horkheimer, 1956; 1 Todesanzeige von dem Sozialgerichtsdirektor Gustav Adolf Hünniger, 1955; 1 Brief von dem Oberstudiendirektor F. Huf an Max Horkheimer, 1952; 1 Brief mit Antwort von Professor H. D. Huggins an Max Horkheimer, 1954; 2 Briefe mit 1 Antwort und 1 Beilage von dem Humboldt-Verlag, Wien-Stuttgart an Max Horkheimer, 1951; 1 Brief von Helge Pross an stud. rer. pol. Kristian Hungar, 1957; 1 Brief von Helmut Hungerland an Max Horkheimer, 1950; 1 Brief mit Antwort von James R. Huntley an Max Horkheimer, 1954; 1 Brief von Professor Robert Maynard Hutchins an Max Horkheimer, 1957;

Geochemical investigation of ODP Leg 113 sites

Dissolved organic carbon (DOC) was determined in pore water extracted from pelagic and hemipelagic sediments recovered during Leg 113. DOC concentration varied between 1.82 and 13.6 mg C/L which is one to two orders of magnitude less than previously reported for hemipelagic sediments. It is argued that this difference is related to differences in the intensity of degradation of organic matter. As a first approximation it is found that in reducing sediments, the level of DOC is proportional to the intensity of sulfate reduction. It is suggested that DOC is formed by different mechanisms in oxic and reducing environments.

Interstitial-water chemistry of ODP Leg 113 sites

Variations in the distribution of major elements and stable oxygen isotopes in ODP Leg 113 pore water are not related to lithology and thus appear to be controlled by minor constituents. Petrographic observations and geochemical considerations indicate that alteration of calc-alkalic volcanic material dispersed in the sediment is an important process. A diagenetic reaction is constructed that involves transformation of volcanic glass into smectite, zeolite (represented by phillipsite), chert, and iron sulfide. Mass balance calculations reveal that alteration of less than 10% (volume) of volcanogenic material may account for the observed depletion of magnesium, potassium, and 18O and enrichment of calcium. Alteration of this amount of volcanic glass produces less than 4% (volume) of smectite and zeolite. Hence, mass balance is obtained without having to invoke unreasonable large amounts of volcanic matter or interactions between seawater and basement.

Isotope record and major element chemistry of intestitial waters of ODP Leg 104 sites

The variations in major elements and isotope composition (87Sr/86Sr, delta18O, deltaD) of interstitial waters in Leg 104 sediments is most probably caused by the alteration of volcanic matter. A reaction scheme where volcanic glass reacts with pore-water magnesium and potassium to form trioctahedral smectite, phillipsite, and chert is proposed. Model calculations demonstrate that the pore waters may evolve their negative 6180 signatures without recourse to unreasonably large amounts of volcanic detritus or external sources.