β2 integrin-mediated crawling on endothelial ICAM-1 and ICAM-2 is a prerequisite for transcellular neutrophil diapedesis across the inflamed blood-brain barrier

In acute neuroinflammatory states such as meningitis, neutrophils cross the blood-brain barrier (BBB) and contribute to pathological alterations of cerebral function. The mechanisms that govern neutrophil migration across the BBB are ill defined. Using live-cell imaging, we show that LPS-stimulated BBB endothelium supports neutrophil arrest, crawling, and diapedesis under physiological flow in vitro. Investigating the interactions of neutrophils from wild-type, CD11a(-/-), CD11b(-/-), and CD18(null) mice with wild-type, junctional adhesion molecule-A(-/-), ICAM-1(null), ICAM-2(-/-), or ICAM-1(null)/ICAM-2(-/-) primary mouse brain microvascular endothelial cells, we demonstrate that neutrophil arrest, polarization, and crawling required G-protein-coupled receptor-dependent activation of β2 integrins and binding to endothelial ICAM-1. LFA-1 was the prevailing ligand for endothelial ICAM-1 in mediating neutrophil shear resistant arrest, whereas Mac-1 was dominant over LFA-1 in mediating neutrophil polarization on the BBB in vitro. Neutrophil crawling was mediated by endothelial ICAM-1 and ICAM-2 and neutrophil LFA-1 and Mac-1. In the absence of crawling, few neutrophils maintained adhesive interactions with the BBB endothelium by remaining either stationary on endothelial junctions or displaying transient adhesive interactions characterized by a fast displacement on the endothelium along the direction of flow. Diapedesis of stationary neutrophils was unchanged by the lack of endothelial ICAM-1 and ICAM-2 and occurred exclusively via the paracellular pathway. Crawling neutrophils, although preferentially crossing the BBB through the endothelial junctions, could additionally breach the BBB via the transcellular route. Thus, β2 integrin-mediated neutrophil crawling on endothelial ICAM-1 and ICAM-2 is a prerequisite for transcellular neutrophil diapedesis across the inflamed BBB.

Mus Hs 1629 - Missae II : 1 ex db, 2 ex Gb : canto, alto, tenore, basso, 2 violini, alto viola, 2 corni, tympani et organo

Besetzung: Coro S, Coro A, Coro T, Coro B, Vl 1 2, Va, Trp 1 2, Timp, Org

Ms. Ff. Mus. 1503 - Am 2ten Christ=Feyertage : Wie theuer ist deine Güte, Gott, daß pp. ; C. A. T. B., 2 Clarinetti, 2 Flauti traversi, 2 Hautbois se piace, 2 Violini, 1 Viola, Violoncello et Organo

von Telemann

Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial

BACKGROUND Postoperative hemithoracic radiotherapy has been used to treat malignant pleural mesothelioma, but it has not been assessed in a randomised trial. We assessed high-dose hemithoracic radiotherapy after neoadjuvant chemotherapy and extrapleural pneumonectomy in patients with malignant pleural mesothelioma. METHODS We did this phase 2 trial in two parts at 14 hospitals in Switzerland, Belgium, and Germany. We enrolled patients with pathologically confirmed malignant pleural mesothelioma; resectable TNM stages T1-3 N0-2, M0; WHO performance status 0-1; age 18-70 years. In part 1, patients were given three cycles of neoadjuvant chemotherapy (cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 given every 3 weeks) and extrapleural pneumonectomy; the primary endpoint was complete macroscopic resection (R0-1). In part 2, participants with complete macroscopic resection were randomly assigned (1:1) to receive high-dose radiotherapy or not. The target volume for radiotherapy encompassed the entire hemithorax, the thoracotomy channel, and mediastinal nodal stations if affected by the disease or violated surgically. A boost was given to areas at high risk for locoregional relapse. The allocation was stratified by centre, histology (sarcomatoid vs epithelioid or mixed), mediastinal lymph node involvement (N0-1 vs N2), and T stage (T1-2 vs T3). The primary endpoint of part 1 was the proportion of patients achieving complete macroscopic resection (R0 and R1). The primary endpoint in part 2 was locoregional relapse-free survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00334594. FINDINGS We enrolled patients between Dec 7, 2005, and Oct 17, 2012. Overall, we analysed 151 patients receiving neoadjuvant chemotherapy, of whom 113 (75%) had extrapleural pneumonectomy. Median follow-up was 54·2 months (IQR 32-66). 52 (34%) of 151 patients achieved an objective response. The most common grade 3 or 4 toxic effects were neutropenia (21 [14%] of 151 patients), anaemia (11 [7%]), and nausea or vomiting (eight [5%]). 113 patients had extrapleural pneumonectomy, with complete macroscopic resection achieved in 96 (64%) of 151 patients. We enrolled 54 patients in part 2; 27 in each group. The main reasons for exclusion were patient refusal (n=20) and ineligibility (n=10). 25 of 27 patients completed radiotherapy. Median total radiotherapy dose was 55·9 Gy (IQR 46·8-56·0). Median locoregional relapse-free survival from surgery, was 7·6 months (95% CI 4·5-10·7) in the no radiotherapy group and 9·4 months (6·5-11·9) in the radiotherapy group. The most common grade 3 or higher toxic effects related to radiotherapy were nausea or vomiting (three [11%] of 27 patients), oesophagitis (two [7%]), and pneumonitis (two [7%]). One patient died of pneumonitis. We recorded no toxic effects data for the control group. INTERPRETATION Our findings do not support the routine use of hemithoracic radiotherapy for malignant pleural mesothelioma after neoadjuvant chemotherapy and extrapleural pneumonectomy. FUNDING Swiss Group for Clinical Cancer Research, Swiss State Secretariat for Education, Research and Innovation, Eli Lilly.

Transforming growth factor β2 (TGF-β2)-induced connective tissue growth factor (CTGF) expression requires sphingosine 1-phosphate receptor 5 (S1P5) in human mesangial cells

Transforming growth factor β2 (TGF-β2) is well known to stimulate the expression of pro-fibrotic connective tissue growth factor (CTGF) in several cell types including human mesangial cells. The present study demonstrates that TGF-β2 enhances sphingosine 1-phosphate receptor 5 (S1P5) mRNA and protein expression in a time and concentration dependent manner. Pharmacological and siRNA approaches reveal that this upregulation is mediated via activation of classical TGF-β downstream effectors, Smad and mitogen-activated protein kinases. Most notably, inhibition of Gi with pertussis toxin and downregulation of S1P5 by siRNA block TGF-β2-stimulated upregulation of CTGF, demonstrating that Gi coupled S1P5 is necessary for TGF-β2-triggered expression of CTGF in human mesangial cells. Overall, these findings indicate that TGF-β2 dependent upregulation of S1P5 is required for the induction of pro-fibrotic CTGF by TGF-β. Targeting S1P5 might be an attractive novel approach to treat renal fibrotic diseases.

The physiological roles of ICAM-1 and ICAM-2 in neutrophil migration into tissues

PURPOSE OF REVIEW Neutrophil extravasation from the blood into tissues is initiated by tethering and rolling of neutrophils on endothelial cells, followed by neutrophil integrin activation and shear resistant arrest, crawling, diapedesis and breaching the endothelial basement membrane harbouring pericytes. Endothelial intercellular cell adhesion molecule (ICAM)-1 and ICAM-2, in conjunction with ICAM-1 on pericytes, critically contribute to each step. In addition, epithelial ICAM-1 is involved in neutrophil migration to peri-epithelial sites. The most recent findings on the role of ICAM-1 and ICAM-2 for neutrophil migration into tissues will be reviewed here. RECENT FINDINGS Signalling via endothelial ICAM-1 and ICAM-2 contributes to stiffness of the endothelial cells at sites of chronic inflammation and junctional maturation, respectively. Endothelial ICAM-2 contributes to neutrophil crawling and initiation of paracellular diapedesis, which then proceeds independent of ICAM-2. Substantial transcellular neutrophil diapedesis across the blood-brain barrier is strictly dependent on endothelial ICAM-1 and ICAM-2. Endothelial ICAM-1 or ICAM-2 is involved in neutrophil-mediated plasma leakage. ICAM-1 on pericytes assists the final step of neutrophil extravasation. Epithelial ICAM-1 rather indirectly promotes neutrophil migration to peri-epithelial sites. SUMMARY ICAM-1 and ICAM-2 are involved in each step of neutrophil extravasation, and have redundant but also distinct functions. Analysis of the role of endothelial ICAM-1 requires simultaneous consideration of ICAM-2.

Ms. Ff. Mus. 1146 - Fer. Michael : Ich bin getrost im Leben und ; p a canto, alto, tenore, basso, 2 clarini, 2 violini, 2 hautb., viola, violoncello, volono, bassono, ed organo

di Telemann

Na 1 Nachlass Max Horkheimer, 654 - "The Aftermath of National Socialism"; "National Socialism and Philosophy"; "The Idea of Philosophy"; "Programm einer Intereuropäischen Akademie" (p. IX 36a.1-4-IX 39.1-2)

"The Aftermath of National Socialism. On the Cultural Aspects of the Collapse of National Socialism". Vorlesungsreihe des Instituts für Sozialforschung, März 1945; 1. Vorlesungsankündigung und Typoskripte der Beiträge von: Theodor W. Adorno, "The Fate of the Arts" (= "What National Socialism Has Done to the Arts"); Frederick Pollock, "Prejudice and the Social Classes"; Leo Löwenthal, "The Aftermath of Totalitarian Terror". Bibliographie, Typoskripte, geheftet, mit eigenhändiger Korrektur von Frederick Pollock, 93 Blatt; 2. Vorlesungsankündigung, als Typoskript vervielfältigt, 1 Blatt; 3. Max Horkheimer: "Totalitarism and the Crisis of European Culture". Eigene Notizen zur Vorlesung, 3 Blatt; 4. Theodor W. Adorno: Notizen zur Vorlesungsreihe. Typoskript, 2 Blatt; Max Horkheimer: "National Socialism and Philosophy". Seminar Frühjahr 1945; 1. Protokolle zu den Sitzungen vom 5.2, 24.4., 1.5. und 8.5.1945. Typoskript mit eigenhändiger Korrektur, 16 Blatt; 2. Dasselbe. Gebunden, 16 Blatt; 3. Eigenhändige Notizen, 8 Blatt; Max Horkheimer: "The Idea of Philosophy". Vorlesung Winter 1945/46; 1. Eigenhändige Notizen, 3 Blatt; 2. Eigenhändige Notizen, 4 Blatt; 3. Eigenhändige Notizen, 2 Blatt; 4. Abschriften aus Werken unter anderem von Friedrich von Bezold, Karl Lamprecht, Richard Pietchman, Leopold von Ranke, Edwin R.A. Seligman. Typoskripte, 8 Blatt; 5. Paul Tillich: "Conscience in Western Thought and the Idea a Transmoral Conscience". Sonderdruck aus: Crozer Quarterly, Vol. XXII, Nr. 4, Oktober 1945, 6 Blatt; Max Horkheimer: Programm einer Intereuropäischen Akademie, 1944/45 (?); 1. Typoskriptfassungen, englisch. a) Typoskript, 18 Blatt b) Typoskript mit handschriftlicher Korrektur von Theodor W. Adorno (GS 12, S.195-213), 18 Blatt c) Typoskript (Kopie) mit handschriftliche Korrektur, 18 Blatt (Kopie 1989 aus der Hoover Institution, Standford, California) d) Typoskript mit eigenhändiger Korrektur, 17 Blatt e) Korrektur-Teilstücke, Typoskripte mit eigenhändiger Korrektur, 2 Blatt; 2. Zeitungsausschnitt 1944, 1 Blatt;

Na 1 Nachlass Max Horkheimer, 656 - Dokumente zur Geschichte des Instituts für Sozialforschung (p. IX 49a-IX 55.1-5)

Max Horkheimer: Über Wissenschaft und Technologie in Israel. Begrüßungsrede für Mr. Ben Sira, gehalten am 8.1.1949; 1. Notizen zur Rede, 10 Blatt; 2. David Ben Gurion, "Science and Technology in Israel", Sonderdruck, 2 Blatt; Über die Antisemitismus-Forschungen des Instituts für Sozialforschung. Protokoll einer Sitzung der Frankfurter Gesellschaft für Christlich-Jüdische Zusammenarbeit, 16.Mai 1949. Typoskript (Kopie), 2 Blatt; Max Horkheimer: Über Arbeit und Pläne des Instituts für Sozialforschung in Frankfurt. Vortrag, gehalten 1949 in Frankfurt (Clubabend). Manuskript, 3 Blatt; Zur Begründung eines Instituts für Sozialforschung, 1922; 1. Senckenbergische Naturforschende Gesellschaft, Frankfurt: 1 Brief mit Unterschrift (Kopie) an die Universität Frankfurt, Kuratorium, Frankfurt, 22.8.1922; 2. Felix Weil und Kurt Albert Gerlach: "Denkschrift über die Begründung eines Instituts für Sozialforschung" (1922). Typoskript (Kopie), 5 Blatt; Carl Grünberg: Festrede, gehalten zur Einweihung des Instituts für Sozialforschung an der Universität Frankfurt am Main, am 22.6.1924. a) Kopie (Auszug) aus dem Abdruck der Rede in Frankfurter Universitätsreden 1924, 3 Blatt b) Sonderdruck Frankfurter Universitätsreden 1924, 16 Seiten; Darstellungen des Instituts für Sozialforschung (1925-51); 1. Gesellschaft für Sozialforschung, Frankfurt: "Institut für Sozialforschung an der Universität Frankfurt am Main". Sonderdruck (Kopie), Frankfurt, 1925, 29 Seiten; 1a. Hermann Weil: "Bericht über das Heimatfest in Waibstadt am 3. und 4. September und die feierliche Übergabge meines Mausoleums in den Schutz der Stadt Waibstadt". Sonderdruck, 1927, 7 Seiten; 1b. Felix Weil, 1 Brief mit Unterschrift (Kopie) an den Minister für Wissenschaft, Kunst und Volksbildung Berlin. Frankfurt, 1.11.1929, Typoskript, 31 Blatt; 1c. Columbia University: "Report of the President of Columbia University for 1934" (darin S.7: Erwähnung des Instituts für Sozialforschung und der Zeitschrift für Sozialforschung), Sonderdruck, New York, 1934, 80 Seiten; 2. "International Institute of Social Research: A short Description of Its History and Aims", New York 1935, Sonderdruck, 15 Seiten; 3. Briefbogen des Instituts für Sozialforschung mit den Namen des Research Staff und des Advisory Committee, 1 Blatt; 4. "International Institute of Social Research. A Report On Its History, Aims and Activities 1933-1938". Sonderdruck, New York 1939, 36 Seiten; 5. "Research Bureau For Post-War Economics and Its Cooperating Institutions. Annual Repost", Sonderdruck, New York, Mai 1939, 17 Seiten; 5a. Los Angeles University of Applied Education: "General Catalogue 1947-48" (mit Erwähnungen des Instituts für Sozialforschung bzw. von Mitarbeitern), Druck, 56 Seiten; 6. Einladung zur Eröffnung des Instituts für Sozialforschung am 14. November 1951. Sonderdruck, Frankfurt 1951, 2 Blatt; Über das Institut für Sozialforschung 1924-31. Tabellarische Zusammenstellung, 1931, Typoskript mit eigenhändigen und handschriftlichen Ergänzungen, 5 Blatt; Max Horkheimer: "Die gegenwärtige Lage der Sozialphilosophie und die Aufgaben eines Instituts für Sozialforschung". Öffentliche Antrittsvorlesung bei Übernahme des Lehrstuhls für Sozialphilosophie und der Leitung des Instituts für Sozialforschung, 24.1.1931, Kopie (Auszug) aus dem Abdruck der Rede in Frankfurter Universitätsreden 1931, 4 Blatt; "History and Program of the Institute of Social Research". Veröffentlicht unter dem Titel "International Institute of Social Research. A Short Description of Its History and Aims", New York (1934 od. 1935), Typoskript, 6 Blatt.; "A Digest of the History, Program and Needs of the International Institute of Social Research". 1934, als Typoskript vervielfältigt, 4 Blatt; Julian Gumperz: "Notes for a talk", Über Ziele und Methoden der Arbeit des Instituts für Sozialforschung, 1934. Typoskript mit handschriftlicher Korrektur, 10 Blatt; "Report of the President of Columbia University for the year ending June 30, 1934".Auszug daraus, 1934, Typoskript, 1 Blatt; Über Geschichte und Tätigkeiten des Instituts für Sozialforschung. Verschiedene Berichte, ca. 1934-1937: 1. Über Geschichte, Tätigkeiten und Ziele des Instituts, nicht vor 1934, Typoskript, 5 Blatt; 2. Bericht an den Präsidenten der Columbia University, 14.3.1936, Typoskript, 2 Blatt; 3. "Dr. Horkheimer's Paper Delivered on the Occasion of an Institute Luncheon Given to the Faculty of Social Sciences of Columbia University on January 12th, 1937". Typoskript, 13 Blatt; 4. Bericht an den Präsidenten der Columbia University. 18.3.1937, Typoskript, 3 Blatt; 5. Über Programm, Mitglieder und Tätigkeiten des Instituts, 1937, a) Typoskript, 2 Blatt, b) Entwurf, Typoskript, 4 Blatt; 6. Publikationsliste 1937, Typoskript, 1 Blatt; Über "Autorität und Familie" und die "Zeitschrift für Sozialforschung". 1937, Typoskript, französisch, mit eigenhändigen Korrekturen, 4 Blatt; Max Horkheimer: Über das Institut für Sozialforschung 1938: 1. Typoskript, englische Fassung, mit handschriftlichen Korrekturen, 38 Blatt; 2. Typoskript, deutsche Fassung mit eigenhändigen Korrekturen, 37 Blatt (G.S. 12, S. 132-164); 3. Julian Gumperz: 1 Brief an Herbert Marcuse, New York, 30.8.1938; 4. Teilstück aus früherer Fassung (?), Typoskript, 1 Blatt, 5. Entwurf zu 2., a) Typoskript, 1 Blatt, b) Typoskript mit eigenhändigen Korrekturen und Ergänzungen, 2 Blatt;

Die Judenfrage : Der Spiegel ; Beiträge zur sittlichen und künstlerischen Kultur ; Heft Nr. 14/15, II. Jg.

hrsg. von Robert Prechtl

Defining barriers in caring for seriously-ill children in a resource-limited setting: An observational study of 2 children's hospitals in Haiti

Background. According to the WHO 2007 country report, Haiti lags behind the Millennium Development Goal of reducing child mortality and maintains the highest under-5 mortality rate in the Western hemisphere. 3 Overall, few studies exist that seek to better grasp barriers in caring for a seriously ill child in a resource-limited setting and only a handful propose sustainable, effective interventions. ^ Objectives. The objectives of this study are to describe the prevalence of serious illnesses among children hospitalized at 2 children's hospitals in Port au Prince, to determine the barriers faced when caring for seriously ill children, and to report hospital outcomes of children admitted with serious illnesses. ^ Methods. Data were gathered from 2 major children's hospitals in Port au Prince, Haiti (Grace Children's Hospital [GCH] and Hopital d l'Universite d'Etat d'Haiti [HUEH]) using a triangulated approach of focus group discussions, physician questionnaires, and retrospective chart review. 23 pediatric physicians participated in focus group discussions and completed a self-administered questionnaire evaluating healthcare provider knowledge, self-efficacy, and perceived barriers relating to the care of seriously ill children in a resource-limited setting. A sample of 240 patient charts meeting eligibility criteria was abstracted for pertinent elements including sociodemographics, documentation, treatment strategies, and outcomes. Factors associated with mortality were analyzed using χ2 test and Fisher exact test [Minitab v.15]. ^ Results. The most common primary diagnoses at admission were gastroenteritis with moderate dehydration (35.5%), severe malnutrition (25.8%), and pneumonia (19.3%) for GCH, and severe malnutrition (32.6%), sepsis (24.7%), and severe respiratory distress (18%) for HUEH. Overall, 12.9% and 27% of seriously ill patients presented with shock to GCH and HUEH, respectively. ^ Shortage of necessary materials and equipment represented the most commonly reported limitation (18/23 respondents). According to chart data, 9.4% of children presenting with shock did not receive a fluid bolus, and only 8% of patients presenting with altered mental status or seizures received a glucose check. 65% of patients with meningitis did not receive a lumbar puncture due to lack of materials. ^ Hospital mortality rates did not differ by gender or by institution. Children who died were more likely to have a history of prematurity (OR 4.97 [95% CI 1.32-18.80]), an incomplete vaccination record (OR 4.05 [95% CI 1.68-9.74]), or a weight for age ≤3rd percentile (OR 6.1 [95% CI 2.49-14.93]. Case-fatality rates were significantly higher among those who presented with signs of shock compared with those who did not (23.1% vs. 10.7%, RR=2.16, p=0.03). Caregivers did not achieve shock reversal in 21% of patients and did not document shock reversal in 50% of patients. ^ Conclusions. Many challenges face those who seek to optimize care for seriously ill children in resource-limited settings. Specifically, in Haiti, qualitative and quantitative data suggest major issues with lack of supplies, pre-hospital factors, including malnutrition as a comorbidity, and early recognition and management of shock. A tailored intervention designed to address these issues is needed in order to prospectively evaluate improvements in child mortality in a high-risk population.^

Age determination, planktic foraminifera and stable istopes of sediment core MSM05/5_712-2

A sediment core from the West Spitsbergen continental margin was studied to reconstruct climate and paleoceanographic variability during the last ~9 ka in the eastern Fram Strait. Our multiproxy evidence suggests that the establishment of the modern oceanographic configuration in the eastern Fram Strait occurred stepwise, in response to the postglacial sea-level rise and the related onset of modern sea-ice production on the shallow Siberian shelves. The late Early and Mid Holocene interval (9 to 5 ka) was generally characterized by relatively unstable conditions. High abundance of the subpolar planktic foraminifer species Turborotalita quinqueloba implies strong intensity of Atlantic Water (AW) inflow with high productivity and/or high AW temperatures, resulting in a strong heat flux to the Arctic. A series of short-lived cooling events (8.2, 6.9. and 6.1 ka) occurred superimposed on the warm late Early and Mid Holocene conditions. Our proxy data imply that simultaneous to the complete postglacial flooding of Arctic shallow shelves and the initiation of modern sea-ice production, strong advance of polar waters initiated modern oceanographic conditions in the eastern Fram Strait at ~5.2 ka. The Late Holocene was marked by the dominance of the polar planktic foraminifer species Neogloboquadrina pachyderma, a significant expansion of sea ice/icebergs, and strong stratification of the water column. Although planktic foraminiferal assemblages as well as sea surface and subsurface temperatures suggest a return of slightly strengthened advection of subsurface Atlantic Water after 3 ka, a relatively stable cold-water layer prevailed at the sea surface and the study site was probably located within the seasonally fluctuating marginal ice zone during the Neoglacial period.