Mechanism for sortase localization and the role of sortase localization in efficient pilus assembly in Enterococcus faecalis.

Pathogenic streptococci and enterococci primarily rely on the conserved secretory (Sec) pathway for the translocation and secretion of virulence factors out of the cell. Since many secreted virulence factors in gram-positive organisms are subsequently attached to the bacterial cell surface via sortase enzymes, we sought to investigate the spatial relationship between secretion and cell wall attachment in Enterococcus faecalis. We discovered that sortase A (SrtA) and sortase C (SrtC) are colocalized with SecA at single foci in the enterococcus. The SrtA-processed substrate aggregation substance accumulated in single foci when SrtA was deleted, implying a single site of secretion for these proteins. Furthermore, in the absence of the pilus-polymerizing SrtC, pilin subunits also accumulate in single foci. Proteins that localized to single foci in E. faecalis were found to share a positively charged domain flanking a transmembrane helix. Mutation or deletion of this domain in SrtC abolished both its retention at single foci and its function in efficient pilus assembly. We conclude that this positively charged domain can act as a localization retention signal for the focal compartmentalization of membrane proteins.

Optimal target localization for subthalamic stimulation in patients with Parkinson disease

OBJECTIVE To further determine the causes of variable outcome from deep brain stimulation of the subthalamic nucleus (DBS-STN) in patients with Parkinson disease (PD). METHODS Data were obtained from our cohort of 309 patients with PD who underwent DBS-STN between 1996 and 2009. We examined the relationship between the 1-year motor, cognitive, and psychiatric outcomes and (1) preoperative PD clinical features, (2) MRI measures, (3) surgical procedure, and (4) locations of therapeutic contacts. RESULTS Pre- and postoperative results were obtained in 262 patients with PD. The best motor outcome was obtained when stimulating contacts were located within the STN as compared with the zona incerta (64% vs 49% improvement). Eighteen percent of the patients presented a postoperative cognitive decline, which was found to be principally related to the surgical procedure. Other factors predictive of poor cognitive outcome were perioperative confusion and psychosis. Nineteen patients showed a stimulation-induced hypomania, which was related to both the form of the disease (younger age, shorter disease duration, higher levodopa responsiveness) and the ventral contact location. Postoperative depression was more frequent in patients already showing preoperative depressive and/or residual axial motor symptoms. CONCLUSION In this homogeneous cohort of patients with PD, we showed that (1) the STN is the best target to improve motor symptoms, (2) postoperative cognitive deficit is mainly related to the surgery itself, and (3) stimulation-induced hypomania is related to a combination of both the disease characteristics and a more ventral STN location.

Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

OBJECTIVES This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. BACKGROUND AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. METHODS We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). RESULTS We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. CONCLUSIONS The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

Focal hemodynamic patterns of status epilepticus detected by susceptibility weighted imaging (SWI).

OBJECTIVE To investigate pathological findings in the susceptibility weighted imaging (SWI) of patients experiencing convulsive (CSE) or non-convulsive status epilepticus (NCSE) with focal hyperperfusion in the acute setting. METHODS Twelve patients (six with NCSE confirmed by electroencephalogram (EEG) and six patients with CSE with seizure event clinically diagnosed) underwent MRI in this acute setting (mean time between onset of symptoms and MRI was 3 h 8 min), including SWI, dynamic susceptibility contrast MR imaging (DSC) and diffusion-weighted imaging (DWI). MRI sequences were retrospectively evaluated and compared with EEG findings (10/12 patients), and clinical symptoms. RESULTS Twelve out of 12 (100 %) patients showed a focal parenchymal area with pseudo-narrowed cortical veins on SWI, associated with focal hyperperfused areas (increased cerebral blood flow (CBF) and mean transit time (MTT) shortening), and cortical DWI restriction in 6/12 patients (50 %). Additionally, these areas were associated with ictal or postical EEG patterns in 8/10 patients (80 %). Most frequent acute clinical findings were aphasia and/or hemiparesis in eight patients, and all of them showed pseudo-narrowed veins in those parenchymal areas responsible for these symptoms. CONCLUSION In this study series with CSE and NCSE patients, SWI showed focally pseudo-narrowed cortical veins in hyperperfused and ictal parenchymal areas. Therefore, SWI might have the potential to identify an ictal region in CSE/NCSE. KEY POINTS • The focal ictal brain regions show hyperperfusion in DSC MR-perfusion imaging. • SWI shows focally diminished cortical veins in hyperperfused ictal regions. • SWI has the potential to identify a focal ictal region in CSE/NCSE.

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

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.

Na 1 Nachlass Max Horkheimer, 37 - Korrespondenzen u.a. mit Dorthy I. Mulgrave (p. I 18, 335-517)

1 Brief von Margot von Mendelssohn an Max Horkheimer, 20.05.1948; 6 Briefe zwsichen Charles E. Merriam und Max Horkheimer, 1940-1941; 4 Briefe zwischen Josef Messinger und Max Horkheimer, 1940; 1 Curriculum Vitae von Alfred Meusel an Max Horkheimer; 1 Brief von Max Horkheimer an Gerhard Meyer, 17.10.1938; 3 Briefe zwischen Hans A. Meyer und Max Horkheimer´09.10.1939, 1947; 2 Briefe zwischen Julie Meyer und Max Horkheimer, 12.04.1941, 15.04.1941; 43 Briefe zwischen Hermann Meyer-Lindenberg, Oscar Meyer und Max Horkheimer sowie Briefwechsel mit Hadley Cantril; 2 Briefe zwischen Hadley Cantril und Theodor W. Adorno, 22.05.1941, 28.05.1941; 1 Brief von Jerome Michael an Margot von Mendelssohn, 10.01.1941; 2 Briefe und 2 Beilagen zwischen Joseph Mire und Max Horkheimer, 16.03.1941, 28.03.1941; 6 Briefe zwischen Mitchell, Silberberg & Knupp, Los Angeles und Max Horkheimer, 1942, 1943; 1 Brief von Friedrich Pollock an Wesley C. Mitchell, 06.08.1940; 3 Briefe zwischen Hans Mohr und Max Horkheimer, 29.03.1946, 1946; 1 Brief von Herbert Moeller Morton an Max Horkheimer, 25.02.1940; 1 Brief von Max Horkheimer an den Chairman of the Committee on General Scholarships, Cambridge Massachusetts, 01.03.1940; 2 Briefe von David H. Moses an Max Horkheimer, 1939; 1 Brief von Franz Neumann an Philip Mosley, 28.04.1941; 49 Briefe zwischen Dorthy I. Mulgrave und Max Horkheimer, 1936-1940; 1 Brief von Max Horkheimer an das Municipal Court, San Francisco, 24.12.1948;

Na 1 Nachlass Max Horkheimer, 652 - Vorlesungen: "National Socialism", "Autoritarian doctrines and modern European institutions", "Eclipse of Reason" (p. IX 35a.1-2-IX 36.1-5b)

"National Socialism": 1. Ankündigung einer Vorlesungsreihe November/Dezember 1941 von: Herbert Marcuse, A.R.L. Gurland, Franz Neumann, Otto Kirchheimer, Frederick Pollock. a) als Typoskript verfielfältigt, 1 Blatt, b) Typoskript, 1 Blatt; 2. Antwortbrief auf Einladungen zur Vorlesungsreihe, von Neilson, William A.; Packelis, Alexander H.; Michael, Jerome; McClung Lee, Alfred; Youtz, R.P.; Ginsburg, Isidor; Ganey, G.; Nunhauer, Arthur. 8 Blätter; "Autoritarian doctrines and modern European institutions" (1924): 1. Vorlesungs-Ankündigung Typoskript, 2 Blatt; 2. Ankündigungen der Vorlesungen von Neumann, Franz L.: "Stratification and Dominance in Germany"; "Bureaucracy as a Social and Political Institution", Typoskript, 2 Blatt; 3. Evans, Austin P.: 1 Brief (Abschrift) an Frederick Pollock, New York, 26.2.1924; "Eclipse of Reason", Fünf Vorlesungen 1943/44:; 1. I. Lecture. a) Typoskript mit eigenhändigen Korrekturen, 38 Blatt b) Typoskript, 29 Blatt c) Typoskript mit eigenhändigen und handschriftlichen Korrekturen, 31 Blatt d) Teilstück, Typoskript mit eigenhändigen Korrekturen, 2 Blatt e) Entwürfe, Typoskript mit eigenhändigen Korrekturen, 6 Blatt; 2. II. Lecture. a) Typoskript mit eigenhändigen Korrekturen, 27 Blatt, b) Typoskript mit handschriftlichen Korrekturen, 37 Blatt; 3. III. Lecture. Typoskript mit eigenhändigen Korrekturen, 27 Blatt; 4. IV. Lecture. Typoskript mit eigenhändigen Korrekturen, 23 Blatt; 5. V. Lecture. a) Typoskript mit eigenhändigen Korrekturen, 25 Blatt, b) Teilstücke, Typoskript mit eigenhändigen und handschriftlichen Korrekturen, 3 Blatt;

Na 1 Nachlass Max Horkheimer, 600 - Korrespondenzen u.a. mit Friedrich Pollock (p. VI 42, 211-386)

Briefwechsel zwischen Max Horkheimer, Frederick Pollock und Karl August und Olga Wittfogel; 2 Briefe zwischen Edith B. Bernett und Max Horkheimer, April 1940; 2 Briefe zwischen Max Horkheimer und Philip Vaudrin, Juli 1939; 3 Briefe an David H. Stevens von Max Horkheimer, 26.03.1938; 1 Brief von A. Radcliffe an Frederick Pollock, 18.11.1937; 3 Briefe an Max Horkheimer von der Columbia University Faculty of Political Science (New York), November 1937; 2 Briefe von der Columbia University Department of History (New York) an Max Horkheimer, November 1937; 1 Brief an Max Horkheimer von Sharon Beard, 27.11.1937; 1 Brief von Ruth Benedict an Max Horkheimer, 19.11.1937; 1 Brief an Max Horkheimer von Franz Boas, 19.11.1937; 1 Brief von R. E. Chaddock an Max Horkheimer, 21.11.1937; 1 Brief an Max Horkheimer von Ch'ao-ting Chi, 19.11.1937; 1 Brief von J. M. Clark an Max Horkheimer, 22.11.1937; 1 Brief an Dr. Wertheimer von Morris R. Cohen, 29.11.1937; 1 Brief von Alfred E. Cohn an Max Horkheimer, 26.11.1937; 1 Brief an Max Horkheimer von John J. Coss, 22.11.1937; 1 Brief von George S. Counts an Max Horkheimer, 24.11.1937; 1 Brief an Max Horkheimer von A. P. Evans, 22.11.1937; 3 Briefe von Gertrude Stewart an Max Horkheimer, 20. - 24.11.1937; 1 Brief an Max Horkheimer von L. C. Goodrich, 22.11.1937; 1 Brief von John W. Innes an Max Horkheimer, 20.11.1937; 1 Brief an Max Horkheimer von Philip C. Jessup, 24.11.1937; 1 Brief von John A. Krout an Max Horkheimer, 23.11.1937; 1 Brief an Max Horkheimer von Bruno Lasker, 20.11.1937; 1 Brief von Samuel McCune Lindsay an Max Horkheimer, 24.11.1937; 1 Brief an Max Horkheimer von K. N. Llewellyn, 26.11.1937; 1 Brief von R. S. Lynd an Max Horkheimer, [November 1937]; 1 Brief an Max Horkheimer von R. M. MacIver, 19.11.1937; 1 Brief von Julian W. Mack an Max Horkheimer, 24.11.1937; 1 Brief an Max Horkheimer von Arthur Maxmahon, 20.11.1937; 1 Brief von Jerome Michael an Max Horkheimer, 26.11.1937; 1 Brief an Max Horkheimer von Wesley C. Mitchell, 22.11.1937; 1 Brief von der Columbia University School of Business (New York) an Max Horkheimer, 22.11.1937; 2 Briefe zwischen Max Horkheimer und der John Simon Guggenheim Memorial Foundation (New York), November 1937; 2 Briefe von der Columbia University Department of Psychology (New York) an Max Horkheimer, November 1937; 1 Brief an Max Horkheimer von Goodwin Watson, 23.11.1937; 1 Brief von Otto Nathan an Max Horkheimer, 26.11.937; 1 Brief an Max Horkheimer von John K. Norton, 23.11.1937; 1 Brief von der Columbia University Department of Chinese (New York) an Max Horkheimer, 23.11.1937; 1 Brief an Max Horkheimer von Gerold Tanquary Robinson, 19.11.1937; 1 Brief von der Columbia University Department of Public Law and Government (New York) an Max Horkheimer, 22.11.1937; 1 Brief an Max Horkheimer von R. C. Sailer, 20.11.1937; 1 Brief von Herbert W. Schneider an Max Horkheimer, 22.11.1937; 1 Brief an Max Horkheimer von R. L. Schuyler, 20.11.1937; 1 Brief von Pauline Steorns an Max Horkheimer, 22.11.1937; 1 Brief an Max Horkheimer von Frank Tannenbaum, 19.11.1937; 1 Brief von Alfred Vagés an Max Horkheimer, 26.11.1937;

Knowledge and Attitudes of Young People in Nigeria about HIV/AIDS---A systematic review

Background: HIV/AIDS has remained one of Nigeria's biggest health and social issues for decades. People aged between 10 and 24 are the most affected. Research into why this population subset is affected is very pertinent. We therefore conducted a systematic review of the Knowledge and Attitudes of young people in Nigeria about HIV/AIDS to understand where the gaps between knowledge and attitudes can be bridged. ^ Methods: We conducted searches in Medline, PubMed, African Index Medicus, Cumulative Index of Nursing and Allied Health. WHO and UNAIDS documents were also searched. Other journals were hand searched. Searches were for studies between 1986 (when HIV/AIDS was first reported in Nigeria) till date. In addition, data abstraction and quality assessment were done. ^ Results: 279 titles and abstracts were found and 33 articles in full text were appraised critically and 17 articles were selected based on our criteria. This revealed a dearth of well conducted studies in the literature despite the enormity of the HIV/AIDS epidemic. Constructs for Knowledge and attitudes were itemized on two tables for each article based on the Health Belief Model. Even though many of the studies showed high level of knowledge about HIV/AIDS, it did not impact attitudes about the disease. Also fear and anxiety prevented participants from acquiring knowledge. These recurring themes arguably were not limited to any region or area, background or group. ^ Conclusion: There is a need for future research to be culturally sensitive with a focus on attitudes and correction of misconceptions about HIV/AIDS among our youth.^

El juego en los procesos de intervención escolar. 16H264

1) Indagación bibliográfica y reseñas críticas. Ampliación de la consulta bibliográfica y reelaboración de tramas conceptuales y analíticas destinadas a la observación y el análisis. 2) Fichaje de bibliografía seleccionada. Profundización, análisis y continuación de los fichajes de autores: De Certau, Michel, Peirce, Charles: (1908) Un argumento olvidado a favor de la realidad de Dios, en The Hibbert Journal., Vigotsky L.: (1991, 2000, 1996,1997, 2001) Obras Escogidas I, II, III, IV, V. Ed. Aprendizaje Visor, Bruner, J.: (1995)Acción, pensamiento y lenguaje .Ed. Alianza. Madrid. 3)Hemos incluido en los análisis aportes de la producción de la tesis doctoral de la Dra. Raquel Alarcón, Título: "Alfabetización semiótica en los umbrales. Cita en sitios de borde" (Tesis doctoral. Inédita), CEA, UNC, Sept, 2010. 4) Revisión de los cronogramas previstos acordes con las posibilidades y disponibilidades que requirieron las instancias de indagaciones propuestas. Sistematizaciones de los informes parciales. Análisis de las propuestas de planificación de los IFD y producciones curriculares oficiales vigentes. 4) Producción del informe final

De difuntos prestados, viudas errantes y cuerpos remendados : La narrativa como dispositivo de construcción de memorias sociales en Colombia

Sin nombres, sin rostros ni rastros es un cuento escrito por Jorge Eliécer Pardo Rodríguez, ganador del concurso nacional de cuento sobre desaparición forzada, Sin Rastro, realizado en el 2008. Este texto narrativo que sirve como dispositivo de memoria, permite analizar las formas que adquiere la ausencia y el pasado traumático en la literatura colombiana; reflexionar en torno a la "ampliación del espacio biográfico" y la construcción de memorias sociales de la violencia política en Colombia y, debatir en torno al carácter estético, político y comunicativo que constituyen este tipo de soportes de memoria. Es por esto, que se describen los hechos violentos ocurridos entre 1986 y 1994 en el departamento de Valle del Cauca, noroccidente colombiano, conocidos como la "Masacre ampliada de Trujillo". La referencia a estos hechos violentos, posibilita al lector interrogar el cuento de Pardo Rodríguez y acercarse a la forma en que se comunica una experiencia particular de dolor en medio de la guerra. De otro lado, se presentan algunas reflexiones en torno al relato y a la tensión entre realidad y ficción, para hacer un breve análisis de este cuento a partir de algunas de las categorías que expone Bruner en el texto Los usos del relato