Academic literature on the topic '2003 i-838'

RESUMEN:El objetivo del artículo es aproximarnos a la controvertida biografía del comisario Manuel Brabo Portillo. El trabajo está basado en fuentes primarias y secundarias. El método utilizado es empírico. En el imaginario del mundo sindicalista revolucionario, Brabo Portillo era el policía más odiado, la reencarnación de la cara más turbia del Estado. Fue, así mismo, un espía alemán relacionado con el hundimiento de barcos españoles, el asesinato del empresario e ingeniero Barret y el primer jefe de los terroristas vinculados a la patronal barcelonesa. La conflictividad que afectó a España en el período de la Primera Guerra Mundial es fundamental para entender los orígenes del terrorismo vinculado al pistolerismo, que marcó la historia político social española del primer tercio del siglo XX.PALABRAS CLAVE: Brabo Portillo, pistolerismo, espionaje, sindicalismo, Primera Guerra Mundial.ABSTRACT:The objective of the article is an approach to the controversial biography of Police Chief Manuel Brabo Portillo. The work is based on primary and secondary sources. The method used is empirical. In the imagery of the revolutionary syndicalist world, Brabo Portillo was the most hated policeman, the reincarnation of the murkiest face of the state. He was also a German spy connected with the sinking of Spanish ships, the murder of businessman and engineer Josep Barret and the first head of the terrorists linked to Barcelona employers. The conflict that affected Spain during the period of the First World War is fundamental in order to understand the origins of terrorism linked to pistolerismo, which marked Spanish social political history during the first third of the twentieth century.KEY WORDS: Brabo Portillo, pistolerismo, espionage, syndicalism, First World War. BIBLIOGRAFÍAAisa, M., La efervescencia social de los años 20. Barcelona 1917-1923, Barcelona, Descontrol, 2016.Aguirre de Cárcer, N., La neutralidad de España durante la Primera Guerra Mundial (1914-1918). I. Bélgica, Madrid, Ministerio de Asuntos Exteriores, 1995.Alonso, G., “’Afectos caprichosos’: Tradicionalismo y germanofilia en España durante la Gran Guerra”, Hispania Nova, 15, 2017, pp. 394-415.Amador, A., El Terror blanco en Barcelona. Las bombas y los atentados personales. Actuación infernal de una banda de asesinos al servicio de la burguesía. El asesinato como una industria, Tarragona, Talleres gráf. Gutenberg, [1920?].Anglés, C., “Contra los sindicatos. Los procesos de la organización obrera. La impostura nunca ha sido justicia”, Solidaridad Obrera, 836 (1/8/1918), p. 1.Balcells, A., El Pistolerisme. Barcelona (1917-1923), Barcelona, Pòrtic, 2009.Ben-Ami, S., La Dictadura de Primo de Rivera (1923-1930), Barcelona, Planeta, 1984.Bengoechea, S., Organització patronal i conflictivitat social a Catalunya. Tradició i corporativisme entre finals de segle i la dictadura de Primo de Rivera, Barcelona, PAM, 1994.Bengoechea, S., El locaut de Barcelona (1919-1920), Barcelona, Curial, 1998.Bengoechea, S., “1919: La Barcelona colpista. L’aliança de patrons i militars contra el sistema liberal”, Afers, 23/24 (1996), pp. 309-327.Brabo Portillo, M., Ensayo sobre policía científica, Barcelona, Gassó Hermanos, [190?].Bravo Portillo, M. y Samper, A., Programa para los exámenes de ingreso ó ascenso en plazas de oficiales de cuarta clase de la Hacienda Pública, Madrid, Mateu, 1906.Bueso, A., Recuerdos de un cenetista, Barcelona, Ariel, 1976.Burgos y Mazo, M. de, El verano de 1919 en Gobernación, Imprenta de E. Pinós-Cuenca, 1921.Calderón, F. de P. [Rico Ariza, E.] y Romero, I., Memorias de un terrorista. Novela episódica de la tragedia barcelonesa, Barcelona, [s.e.], [1924?].Carden, R. M., German Policy Toward Neutral Spain, 1914-1918, London, Routledge, 2014.Cardona, G., Los Milans del Bosch, una familia de armas tomar. Entre la revolución liberal y el franquismo, Barcelona, Edhasa, 2005.Casal Gómez, M., La Banda Negra. El origen y la actuación de los pistoleros en Barcelona (1918-1921), 2ª. Edición, Barcelona, Icaria, 1977.Calle Velasco, M. D. de la, “Sobre los orígenes del estado social en España”, Ayer, 25 (1997), pp. 127-150.D’Ors, E., “La unidad de Europa”, La Vanguardia, (1/12/1914), p. 7.Díaz Plaja, F., Francófilos y germanófilos. Los españoles en la guerra europea, Barcelona, Dopesa, 1973.Díez, P., Memorias de un anarcosindicalista de acción, Barcelona, Bellaterra, 2006.Domingo Méndez, R., “La Gran Guerra y la neutralidad española: entre la tradición historiográfica y las nuevas líneas de investigación”, Spagna Contemporanea, 34 (2008), pp. 27-44.Esculies, J., “España y la Gran Guerra. Nuevas aportaciones historiográficas”, Historia y Política, 32 (2014), pp. 47-70.Esdaile, Ch. J., La Quiebra del liberalismo, 1808-1939, Barcelona, Crítica, 2001.Foix, P., Los Archivos del terrorismo blanco. El fichero Lasarte (1910-1930), Madrid, Las Ediciones de la Piqueta, 1978.Forcadell, C., Parlamentarismo y bolchevización. El movimiento obrero español, 1914-1918, Barcelona, Crítica, 1978.Fuentes Codera, M., “El somni del retorn a l’Imperi: Eugeni d’Ors davant la Gran Guerra”, Recerques, 55 (2007), pp. 73-93.Fuentes Codera, M., “Germanófilos y neutralistas. Proyectos tradicionalistas y regeneracionistas para España (1914-1918)”, Ayer, 91/3 (2013), pp. 63-92.Fuentes Codera, M., España en la Primera Guerra Mundial. Una movilización cultural, Madrid, Akal, 2014.García Oliver, J., El Eco de los pasos, Paris/Barcelona, Ruedo Ibérico, 1978.García Sanz, F., España en la Gran Guerra, Madrid, Galaxia Gutenberg, 2014.Giráldez, E., “Brabo Portillo ¡Yo te acuso, Asesino!”, Solidaridad Obrera, 840 (5/8/1918), p. 1.Golden, L., “Les dones com avantguarda; El rebombori del pa del gener 1918”, L’Avenç (1981), pp. 45-52.Golden, L., “The women in command. The Barcelona women’s consumer war of 1918”, UCLA Historical Journal (1985), pp. 5-32.E. González Calleja y F. del Rey Reguillo, La Defensa armada contra la revolución. Una historia de las guardias cívicas en la España del siglo XX, Madrid, CSIC, 1995.González Calleja, E., La Razón de la fuerza. Orden público, subversión y violencia política en la España de la Restauración, 1875-1917, Madrid, CSIC, 1998.González Calleja, E., El Máuser y el sufragio. Orden público, subversión y violencia política en la crisis de la Restauración (1917-1931), Madrid, CSIC, 1999.González Calleja, E., (ed.), Políticas del miedo. Un balance del terrorismo en Europa, Madrid, Biblioteca Nueva, 2002.González Calleja, E., La España de Primo de Rivera. La modernización autoritaria 1923-1930, Madrid, Alianza Editorial, 2005.González Calleja, E., El laboratorio del miedo. Una historia general del terrorismo, Barcelona, Crítica, 2013.González Calleja, E. y Aubert, P., Nidos de espías. España, Francia y la Primera Guerra Mundial, Madrid, Alianza, 2014.González Calleja, E. (coord.), Anatomía de una crisis. 1917 y los españoles, Madrid, Alianza, 2017.Granados de Siles, J., “El escandaloso espionaje de Barcelona”, Solidaridad Obrera, 793 (19/6/1918), p. 1.Gual Villalbí, P., Memorias de un industrial de nuestro tiempo, Barcelona, Sociedad General de Publicaciones, [193?].León-Ignacio, J., Los años del pistolerismo. Ensayo para una guerra civil, Barcelona, Planeta, 1981.León-Ignacio, J., “Brabo Portillo, comisario y político”, Historia y vida, 181 (1983), pp. 68-73.Llates, R., 30 anys de vida catalana, Barcelona, Aedos, 1969.Madrid, F., Ocho meses y un día en el Gobierno Civil de Barcelona (confesiones y testimonios), Barcelona-Madrid, Las ediciones de la flecha, 1932.Manent, J., Records d’un sindicalista llibertari català, 1916-1943, París, Edicions Catalanes de París, 1976.Marquès, J., Història de l’organització sindical tèxtil “El Radium”, Barcelona, La Llar del Llibre, 1989.Márquez, B. y Capo, J. M., Las Juntas militares de defensa, Barcelona, Librería Sintes, 1923.Martínez Fiol, D., El catalanisme i la Gran Guerra (1914-1918). Antologia, Barcelona, La Magrana, 1988.Martínez Fiol, D. y Esculies Serrat, J., L’Assemblea de Parlamentaris de 1917 i la Catalunya rebel, Barcelona, Generalitat de Catalunya, 2017.Martínez Fiol, D. y Esculies Serrat, J., 1917. El año en que España pudo cambiar, Sevilla, Renacimiento, 2018.M.C.C., “El ‘affaire’ Brabo Portillo”, publicado en El Parlamentario y reproducido por Solidaridad Obrera, 926 (2/11/1918), p. 1.Mendoza, E., La verdad sobre el caso Savolta, Barcelona, Seix y Barral, 1975.Morales Lezcano, V., El colonialismo hispano-francés en Marruecos (1898-1927), Madrid, Siglo XXI, 1976.Navarra, A., 1914. Aliadófilos y germanófilos en la cultura española, Madrid, Cátedra, 2014.Navarra, A., Aliadòfils i germanòfils a Catalunya durant la Primera Guerra Mundial, Barcelona, Generalitat-CHCC, 2016.Nisk, “¡Inocente Brabo!”, Solidaridad Obrera, 789 (15/6/1918), p, 1.Pestaña, Á.,“A vuela pluma” y “En Libertad”, Solidaridad Obrera, 840-841 (5-6/8/1918), p. 1.Pestaña, Á., Terrorismo en Barcelona. Memorias inéditas, Barcelona, Planeta, [1979].Pradas Baena, M. A., L’anarquisme i les lluites socials a Barcelona 1918-1923. La repressió obrera i la violència, Barcelona, PAM, 2003.Pujadas, X., Marcel·lí Domingo i el marcel·linisme, [Barcelona], PAM, 1996.Roig, M., Rafael Vidiella. L’aventura de la revolució, Barcelona, Laia, 1976.Romero Salvadó, F. J., “Crisi, agonia i fi de la monarquía liberal (1914-1923)”, Segle XX. Revista catalana d’història, 1 (2008), pp. 57-82.Romero Salvadó, F. J. y Smith, A. (eds.), The Agony of Spanish Liberalism. FromRevolution to Dictatorship 1913-23, Houndmills, Basingstoke, Palgrave Macmillan, 2010.Rosenbusch, A., “Los servicios de información alemanes: sabotaje y actividad secreta”, Andalucía en la historia, 45 (2014), pp. 24-29.Rosenbusch, A., “Guerra Total en territorio neutral: Actividades alemanas en España durante la Primera Guerra Mundial”, Hispania Nova, 15 (2017), pp. 350-372.S. A., “Historia de un ‘bravo’ muy pillo”, La Campana de Gracia, 2569 (28/6/1918), p. 4.S.A., L’Esquella de la Torratxa, (12/7 y 30/8/ y 12/9/1918), pp. 447, 451, 456, 458, 568, 577 y 592.S. A., “A cada puerco le llega su San Martín” y “La muerte de Batet”, Solidaridad Obrera, 711 y 712 (9 y 10/1/1918), p. 1.S. A., Solidaridad Obrera, 713-716 (11-14/1/1918), p. 1.S. 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Abstract A connected even {[}2,2s] -factor of a graph G is a connected factor with all vertices of degree i(i=2,4,\ldots ,2s) , where s\ge 1 is an integer. In this paper, we show that a \tfrac{k+1}{s+2} -tough k-tree has a connected even {[}2,2s] -factor and thereby generalize the result that a \tfrac{k+1}{3} -tough k-tree is Hamiltonian in [Hajo Broersma, Liming Xiong, and Kiyoshi Yoshimoto, Toughness and hamiltonicity in k-trees, Discrete Math. 307 (2007), 832–838].

Abstract A connected even [ 2 , 2 s ] {[}2,2s] -factor of a graph G is a connected factor with all vertices of degree i ( i = 2 , 4 , … , 2 s ) i(i=2,4,\ldots ,2s) , where s ≥ 1 s\ge 1 is an integer. In this paper, we show that a k + 1 s + 2 \tfrac{k+1}{s+2} -tough k-tree has a connected even [ 2 , 2 s ] {[}2,2s] -factor and thereby generalize the result that a k + 1 3 \tfrac{k+1}{3} -tough k-tree is Hamiltonian in [Hajo Broersma, Liming Xiong, and Kiyoshi Yoshimoto, Toughness and hamiltonicity in k-trees, Discrete Math. 307 (2007), 832–838].

Abstract Abstract 838 Eradication of minimal residual disease (MRD) during the first months of ALL treatment is associated with improved disease-free survival (DFS). We hypothesized that alemtuzumab, a humanized anti-CD52 monoclonal antibody, might be an effective, novel agent for eradication of MRD. In CALGB 10102, we tested dose escalation of alemtuzumab in sequential cohorts of CD52+ cases to a target dose of 30 mg administered SC 3 times/week for 4 weeks (12 doses) during post-remission therapy. Dose limiting toxicity (DLT) was defined as the inability to proceed with protocol treatment within 6 weeks after the last dose of alemtuzumab. Eligible patients (pts) had ≥10% lymphoblast CD52 expression at diagnosis determined in a CALGB reference laboratory. Antimicrobial prophylaxis for cytomegalovirus (CMV) and Pneumocystis carinii was mandated. The 10102 therapy consisted of 6 monthly chemotherapy modules followed by maintenance therapy for a total of 2 years (Stock et al. ASH 2005, abstr 145); 299 untreated ALL pts were eligible and enrolled from 2003–2007. We previously reported (Lozanski et al. ASH 2007, abstr 2386) that 70% were CD52+ and eligible to receive Alemtuzumab (70% of B-cell ALL; 53% of T-cell ALL; 100% of Ph+ cases). Results: Twenty-four pts in remission (CR1) received Alemtuzumab as their fourth treatment module during the Phase I portion of the study. The median age was 37 years (18-77 years); 18 (80%) had B-cell ALL; 5 (19%) had T-cell ALL. 17/24 cases had evaluable cytogenetics after central review: 5 had favorable, 8 intermediate-risk, 2 poor-risk cytogenetics (neither were Ph+), and 2 were not classifiable (miscellaneous abnormalities). Non-hematologic toxicities were mild. SC alemtuzumab was well tolerated. Grade 3-4 myelosuppression was reported during 4 weeks of alemtuzumab treatment in 4 pts; 2 pts had Grade 3-4 lymphopenia. 4 pts had DLT: subsequent treatment was delayed in 2 due to transient CMV viremia; 1 developed Staph aureus empyema; and 1 had prolonged myelosuppression but did not receive G-CSF support as recommended by the protocol. 3 pts relapsed with ALL immediately following completion of the alemtuzumab module. Serial assessment of MRD using quantitative clone-specific PCR was possible in 11/24 cases. There was a median 1-log decrease in MRD during alemtuzumab therapy in the 20 and 30 mg cohorts. However, there was a 2-log rise during alemtuzumab therapy in one pt who relapsed 6 weeks later. Pharmacokinetic analysis revealed rising alemtuzumab serum levels during treatment in all dose cohorts, and levels were still detectable in some pts 10 weeks after completing alemtuzumab. During subsequent post-remission therapy, 8 pts developed CMV viremia, 2 had Herpes simplex infections, and 3 had Herpes zoster reactivation. There was not a significant correlation between serum alemtuzumab level and change in MRD or risk of viral infection. The median follow-up time for the 14 surviving pts is 51 months (49-54 months). Median DFS is 53 months (95% CI, 39 – not reached); median overall survival is 55 months (95% CI, 42- not reached). Conclusions: CD52 is expressed in the majority of adult ALL cases. Addition of alemtuzumab to front-line therapy is feasible and provides reduction in MRD, but is associated with viral infections. Dose escalation of alemtuzmab was not associated with DLT. Based on these results, the 30 mg dose of alemtuzumab was explored in an additional 70 patients in the Phase II portion of the study. The encouraging DFS results reported here require confirmation from longer follow-up of the larger Phase II cohort of patients. Disclosures: Stock: Genzyme: Research Funding. Off Label Use: The testing of alemtuzumab for treatment of ALL in adults. Lozanski:Genzyme: Research Funding. Vij:CELGENE: Honoraria, Research Funding, Speakers Bureau. Powell:Antisoma: Research Funding. Sher:invivoscribe: Employment. Richards:Genzyme: Employment. Sung:genzyme: Employment.

Abstract Hepatic iron content is increased in patients with PCT and phlebotomy-induced iron depletion corrects the clinical and biochemical phenotype. Approximately 20 percent of patients with PCT are homozygous for mutations of the hemochromatosis gene (HFE) but the cause of iron overload in most patients is unknown. Hepatic URO-D activity is markedly reduced when PCT is manifest and URO-D activity improves following iron depletion. Most patients with PCT have no mutations of the URO-D gene (sporadic PCT) but approximately 1/3 of cases are heterozygous for URO-D mutations (familial PCT) (BLOOD. 2000; 95:1565–71). To determine the mechanism by which iron overload causes PCT we created 3 murine models: Mice with one null allele of Uro-d (Uro-d+/−) and 2 null Hfe alleles (Hfe−/ −) (PNAS.2001; 98:259–64); Uro-d+/− mice treated with iron-dextran, aminolevulinic acid (ALA) and polychlorinated biphenyls (PCB) and; wild type mice treated with iron, ALA and PCB (J. Biochem. Mol. Toxicol.2001; 15:287–93). All models accumulate uroporphyrin in the liver and all have hepatic URO-D activity of 25% or less but Western blots revealed no change in URO-D protein. An iron deficient diet prevented the PCT phenotype in Uro-d+/−, Hfe−/ − animals and greatly attenuated the phenotype in animals treated with ALA and PCB (Env. Toxicol. Pharmacol.2005; 417–23). Liver homogenates from all porphyric models were heat denatured and clarified by centrifugation. The supernatants inhibited the activity of purified recombinant human URO-D (rhURO-D) by approximately 60%. The inhibitory activity was further purified by solid phase extraction and HPLC. The fraction containing the inhibitory activity did not fluoresce. Mass spectrometry of this fraction demonstrated a dominant peak with a mass of 835 Da and an absorption maximum of approximately 500 nM, the optical signature of a porphomethene. An inhibitor with identical properties was generated by partially oxidizing the uroporphyrinogen (837 Da) substrate of URO-D under UV light. Full oxidation of either the inhibitor purified from porphyric mouse liver or from partially oxidized, enzymatically generated uroporphyrinogen (either isomer I or III) yielded a compound with a mass of 831 Da and an absorption maximum of approximately 400 nM, indicating that the fully oxidized inhibitor was uroporphyrin. Tandem mass spectrometry of the 835 Da inhibitor indicated that the inhibitor was a tetrapyrrole. Collectively these data indicate that the inhibitor is a porphomethene derived form uroporphyrinogen through oxidation of a single bridge carbon between adjacent pyrrole rings. An inhibitor of rhURO-D was also identified in heat-denatured cytosol from liver biopsy samples obtained from four humans with PCT. We conclude that clinical expression of PCT requires an iron dependant oxidation reaction that generates a porphomethene inhibitor of URO-D.

Objetivo: describir la experiencia en la práctica de Histerectomía Laparoscópica Total (HLT) con énfasis en las complicaciones presentadas.Metodología: el presente es un estudio de cohorte histórica en el cual se incluyeron las pacientes que fueron intervenidas entre diciembre de 2002 y abril de 2008 y en quienes, además, se completó al menos 90% de la información requerida en un formulario prediseñado. Durante la investigación, se evaluaron las características sociodemográficas, las indicaciones de cirugía, el porcentaje de laparoconversión y las causas de la misma, el tiempo quirúrgico, la pérdida sanguínea estimada, el tiempo de hospitalización, el número de dosis de analgésicos requeridos, los días de incapacidad y las complicaciones intraoperatorias y postoperatorias.Resultados: en total se incluyeron 837 pacientes, cuya edad promedio fue 42,7 años. 83,8% de las mujeres eran ASA I (American Society of Anesthesiologists) y la principal enfermedad de base fue la hipertensión arterial (9,9%). En 822 de ellas, el procedimiento se llevó a cabo por laparoscopia mientras que 15 (1,7%) requirieron laparoconversión. Las indicaciones más frecuentes para la cirugía fueron miomatosis (43,8%) y hemorragia uterina anormal (36,1%). Adicional a esto, el tiempo quirúrgico promedio fue 85,9 minutos, la pérdida sanguínea media fue de 60,6 mL y la tasa total decomplicaciones llegó a ser 12,5%; de lacuales,3,1% lo constituyeron complicaciones mayores.Conclusiones: la tasa de complicaciones de la histerectomía laparoscópica total es similar a la informada en la literatura y está acompañada de una estancia hospitalaria breve.

Introduction. Intussusception is a common abdominal emergency in infants and children. Ultrasonography and barium enema are very useful in diagnosis and treatment of this condition. The aim of the study was to assess the accuracy of ultrasound-guided saline enema for intussusception and to determine if some factors may improve the outcome of this technique. Material and methods. Intussusception was diagnosed in 63 patients at the Clinic of Pediatric Surgery in Novi Sad. The study period was divided into two 2-year phases: phase I, from 2001 through 2002, and phase II, from 2003 through 2004. During phase I, besides barium enema and fluoroscopy, we started using ultrasonography and ultrasound-guided hydrostatic saline enema in the diagnosis and reduction of intussusception. In phase II, this method of reduction was routinely used in all cases. Our technique of ultrasonic reduction was similar to the conventional hydrostatic barium reduction, except the reservoir was higher than that of barium, analgosedation ot patients was performed and in case of difficult and prolonged reduction, gentle manual pressure to the abdomen at right lower quadrant was used. Results. In phase I the diagnostic accuracy of ultrasonography in detecting intussusception was 53.8% , and 100% in phase II. The success rate of ultrasound-guided saline enema was 55.5% in phase I, and 83.8% in phase II. Only 6 patients (16.2%) underwent operative manual reduction of intussusception in phase II. There were no cases with bowel gangrene or perforations in both groups. Conclusions. Ultrasonography is a useful screening tool in the diagnosis of intussusception. The main advantage of hydrostatic reduction with ultrasound guidance is avoidance of ionizing radiation. The success rate of this method of reduction may be increased with an integrated team approach to the management and with modifications of the technique.

LBA5000 Background: The epidermal growth factor receptor (EGFR) has been found to be overexpressed in 55-98% of advanced epithelial ovarian cancer. This trial evaluated the efficacy of maintenance erlotinib, an EGFR tyrosine kinase inhibitor, after first-line chemotherapy. Methods: Eligible patients (pts) had high-risk FIGO stage I or stage II-IV epithelial ovarian, peritoneal or fallopian tube cancer and were not selected for EGFR expression. All patients underwent first line therapy (6-9 cycles of 3-weekly platinum-based chemotherapy (CT)) and showed no signs of progression at the end of CT. Patients were randomised to maintenance erlotinib 150 mg daily for 2 years or observation. Primary endpoint was progression-free survival (PFS) by RECIST in combination with GCIG CA125 criteria. The final design provided 80% power to detect a PFS hazard ratio (HR) of 0.80 with 2-sided log-rank test at 5% after 632 events in 830 patients. Stratifications factors were stage, institution, age, response to and type of first-line CT. Immunohistochemistry (IHC) and FISH for EGFR, and EGFR mutation analyses were performed in 330 patients. The study was registered as NCT00263822 and EudraCT number 2004-004333-34. Results: Between Oct 2005 and Feb 2008, 835 pts were randomised by 125 institutions from 10 countries. The most important baseline characteristics, PFS and OS are summarized in the table. Median follow-up was 51 months. 25% of the patients stopped erlotinib due to side effects (of these 67% due to rash). The predictive value of IHC and FISH for EGFR, and EGFR mutations are being evaluated and will be presented at the meeting. Conclusions: In the overall study populationmaintenance erlotinib after first-line treatment in ovarian cancer did not improve progression-free or overall survival. [Table: see text]

Abstract Background IMU-838 (vidofludimus calcium) is a well-tolerated and orally available small molecule inhibitor of dihydroorotate dehydrogenase (DHODH) and is currently in phase 2 clinical development for ulcerative colitis (UC). Here, we investigated the effect of IMU-838 on different immune cell subsets and analysed the mechanism of action in more detail in T cells. Methods The effect of IMU-838 on regulatory macrophages (Mregs) was investigated by adding IMU-838 or anti-TNFα antibodies (infliximab, adalimumab), alone or in combination, in a mixed lymphocyte reaction assay, determining Mregs (CD206+CD14+) by FACS analysis. To investigate the effect of IMU-838 on human T and B cells, PBMC were stimulated with PHA (48h) or Oligonucleotide 2006-PTO (70h), respectively. An affinity-dependent effect of IMU-838 was assessed on CD8 T cells from OT-I and OT-III mice, containing a high and a low affinity T cell receptor (TCR), respectively, for OVA257-264 peptide. These cells were stimulated with ovalbumin (OVA) peptide loaded splenocytes or anti-CD3/anti-CD28 for 3 days. Oxidative phosphorylation (OXPHOS) and glycolysis in murine T cells was investigated by the Seahorse/Agilent technique in murine CD4 and CD8 T cells activated with anti-CD3/anti-CD28 with or without IMU-838. Results IMU-838 slightly induced Mregs, but strongly and dose-dependently decreased TNFα and IL-6 secretion. Anti-TNFα antibodies alone strongly induced Mregs, but also increased IL-6 levels. When IMU-838 was added, Mregs induction was even higher, and IL-6 was reduced. Besides reducing proinflammatory cytokines secreted by macrophages, IMU-838 also inhibits proliferation of activated B and T cells, as well as inflammatory T cell cytokine secretion, IL-17A, IL-17F and IFNγ, and increased apoptosis up to 3-fold compared to vehicle control. By investigating IMU-838’s role on affinity related activity status of T cells, it was shown that IMU-838 strongly inhibited cell proliferation in the peptide stimulated high affinity, but not in the low affinity, CD8 T cells. Peptide stimulated high affinity T cells show an upregulation of OXPHOS and glycolysis pathways, which are involved in the generation of the cell’s energy supply, compared to low affinity cells. IMU-838 strongly inhibited OXPHOS and glycolysis in both CD4 and CD8 T cells. Conclusion IMU-838 reduces the proinflammatory immune cell response by inducing Mregs, reducing pro-inflammatory cytokine secretion and reducing immune cell proliferation. DHODH is only important in cells that received a strong stimulus and are highly metabolically active. Therefore, IMU-838 will only specifically target these cells and will still allow for a normal immune response, representing a huge safety advantage for treatment of IBD patients.

“Candidatus phytoplasma asteris” and related strains (i.e., aster yellows group 16SrI) have been associated with diseases of numerous plant species worldwide. Symptoms of aster yellows (AY) have been reported on rapeseed/canola (Brassica napus and B. rapa) crops in Saskatchewan (SK) and Manitoba, Canada since 1953 (2). Symptoms generally include stunting, virescence, leaf yellowing or purpling, phyllody, and formation of bladder-like siliques. A total of 120 mature B. rapa cv. AC Sunbeam plants exhibiting AY symptoms were collected in commercial fields near Medstead, SK during 2003 and 2004 (one field per year). As described previously (4), total genomic DNA was extracted from leaf, stem, roots, and seeds collected from the 120 plants, from seeds from the seed lots sown in 2003 and 2004, and from leaf and stem tissue of 20 greenhouse-grown plants from each seed lot. The latter DNA samples were assayed for phytoplasma DNA by a nested polymerase chain reaction (PCR) assay incorporating phytoplasma universal 16S rRNA primer pairs P1/P6 (1) followed by R16R2/R16F2 (4). Seed samples analyzed from the 2003 and 2004 seed lots and tissues of the 40 greenhouse-grown plants all tested negative for phytoplasma DNA using this assay. Leaf, stem, and/or root tissues of all plants collected in the field in 2003 (60 plants) and 2004 (60 plants) and 71.1% (315 of 443) of seed samples (five seeds per sample) tested positive for the presence of phytoplasma DNA, as evidenced by the presence of an expected band of 1.2 kb on the gels after the second amplification with primers R16R2/R16F2. Nested PCR products from plant samples collected in 2003 were cloned, sequenced, and compared with phytoplasma sequences archived in the GenBank nucleotide database. On this basis, phytoplasmas detected in plants or their seeds collected in 2003 were found to be most similar (98.8%) to CHRY (Accession No. AY180956), a 16SrI-A subgroup strain, or were most similar (98.9%) to isolate 99UW89 (Accession no. AF268407), a known 16SrI-B subgroup strain. Sequences of phytoplasmas detected in plants or their seeds in 2004 were obtained by direct sequencing of rRNA products amplified from samples using PCR incorporating primer pairs P1/P6 and P4/P7 (3). Analysis of sequence data revealed that phytoplasmas in these plants were all most similar (99.5%) to AY-WB (Accession no. AY389828), a 16SrI-A subgroup member. The nucleotide sequences have been deposited with GenBank under Accession nos. DQ404346, DQ404347, and DQ411470. To our knowledge, this is the first report of 16SrI-A and 16SrI-B subgroup phytoplasmas infecting plants and seed of B. rapa in Saskatchewan. References: (1) I.-M. Lee et al. Phytopathology, 83:834, 1993. (2) W. E. Sackston. Can. Plant Dis. Surv. 33:41, 1953. (3) L. B. Sharmila et al. J. Plant Biochem. Biotech. 13:1, 2004. (4) E. Tanne et al. Phytopathology, 91:741, 2001.