The PML-RAR alpha transcript in long-term follow-up of acute promyelocytic leukemia patients

Background and Objectives. Detection of PML-RAR alpha transcripts by RT-PCR is now established as a rapid and sensitive method for diagnosis of acute promyelocytic leukemia (APL), Although the majority of patients in longterm clinical remission are negative by consecutive reverse transcription polymerase chain reaction (RT-PCR) assays, negative tests are still observed in patients who ultimately relapse. Conversion from negative to positive PCR has been observed after consolidation and found to be a much stronger predictor of relapse. This study reports on 47 APL patients to determine the correlation between minimal residual disease (MRD) status and clinical outcome in our cohort of patients. Design and Methods. The presence of PML-RAR alpha t transcripts was investigated in 47 APL patients (37 adults and 10 children) using a semi-nested reverse transcriptase-polymerase chain reaction to evaluate the prognostic value of RT-PCR tests. Results. All patients achieved complete clinical remission (CCR) following induction treatment with all-trans retinoic acid (ATRA) and chemotherapy (CHT) or ATRA alone. Patients were followed up between 2 and 117.6 months (median: 37 months). Relapses occurred in 11 patients (9 adults and 2 children) between 11.4 and 19 months after diagnosis (median: 15.1 months) while 36 patients (28 adults and 8 children) remained in CCR, Seventy-five percent of patients carried the PML-RARa long isoform (bcr 1/2) which also predominated among the relapsed cases (9 of 11) but did not associate with any adverse outcome (p = 0.37), For the purpose of this analysis, minimal residual disease tests were clustered into four time-intervals: 0-2 months, 3-5 months, 5-9 months and 10-24 months. Interpretation and Conclusions. Children showed persisting disease for longer than adults during the first 2 months of treatment, At 2 months, 10 (50%) of 20 patients who remained in CCR and 4 (80%) of 5 patients who subsequently relapsed were positive. Patients who remained in CCR had repeatedly negative results beyond 5.5 months from diagnosis. A positive MRD test preceded relapse in 3 of 4 tested patients. The ability of a negative test to predict CCR (predictive negative value, PNV) was greater after 6 months (> 83%), while the ability of a positive test to predict relapse (predictive positive value, PPV) was most valuable only beyond 10 months (100%). This study (i) highlights the prognostic value of RT-PCR monitoring after treatment of APL patients but only from the end of treatment, (ii) shows an association between conversion to a positive test and relapse and (iii) suggests that PCR assessments should be carried out at 3-month intervals to provide a more accurate prediction of hematologic relapses but only after the end of treatment, (C) 2001, Ferrata Storti Foundatio

What Can Information Encapsulation Tell Us About Emotional Rationality?

What can features of cognitive architecture, e.g. the information encapsulation of certain emotion processing systems, tell us about emotional rationality? de Sousa proposes the following hypothesis: “the role of emotions is to supply the insufficiency of reason by imitating the encapsulation of perceptual modes” (de Sousa 1987: 195). Very roughly, emotion processing can sometimes occur in a way that is insensitive to what an agent already knows, and such processing can assist reasoning by restricting the response-options she considers. This paper aims to provide an exposition and assessment of de Sousa’s hypothesis. I argue information encapsulation is not essential to emotion-driven reasoning, as emotions can determine the relevance of response-options even without being encapsulated. However, I argue encapsulation can still play a role in assisting reasoning by restricting response-options more efficiently, and in a way that ensures which options emotions deem relevant are not overridden by what the agent knows. I end by briefly explaining why this very feature also helps explain how emotions can, on occasion, hinder reasoning

Rodent models of Parkinson's disease: beyond the motor symptomatology

Parkinson's disease (PD) is classically characterized by motor symptoms; however, non-motor symptoms (NMS) are increasingly recognized as relevant in disease-state, given the associated alterations in mood (depression and anxiety) and cognition. Here, particularly in regards to NMS, we aimed to compare the motor, emotional and cognitive behavior of three animal models of PD that trigger dopaminergic (DAergic) degeneration on both brain hemispheres: (i) the 6-hydroxydopamine (6-OHDA, 8 or 6 µg) lesion model; (ii) the paraquat (PQ) induced model, and (iii) a genetic model based on a-synuclein overexpression (a-syn). 6-OHDA and a-syn vector were injected bilaterally in the substantia nigra pars compacta (SNpc) of adult male Wistar rats; as for PQ delivery, micro-osmotic pumps were implanted in the interscapular region. Motor deficits were observed in all models, with histological analysis of tyrosine hydroxylase positive cells in the SNpc revealing a significant loss of DAergic neurons in all animal models. In addition, the a-syn animal model also presented a reduction in exploratory activity, and the 6-OHDA and PQ animals displayed a significant increase in both depressive- and anxiety-like behavior. Interestingly, cognitive impairment (working memory) was only observed in the 6-OHDA model. Overall, these PD models are suitable for mimicking the motor symptoms associated to PD, with each encompassing other relevant NMS components of the disorder that may prove beneficial for further studies in PD.We would like to acknowledge the funds attributed by the Portuguese Foundation for Science and Technology (FCT), the PhD scholarships to E L. Campos (SFRH/BD/47311/2008) and M. M. Carvalho (SFRH/BD/51061/2010) and the Post-Doctoral fellowship to A. C. Cristovao (SFRH/BPD/69643/2010), and to Fundacao Calouste de Gulbenkian-Programme to Support Cutting Edge Research in Life Sciences and ICVS for funding this work. We want to further acknowledge Joao Cerqueira and Nadine Correia Santos for their contribution to this work

Clinical and Economic Impact of Diabetes Mellitus on Percutaneous and Surgical Treatment of Multivessel Coronary Disease Patients

BACKGROUND: Our aims were to compare coronary artery bypass grafting (CABG) and stenting for the treatment of diabetic patients with multivessel coronary disease enrolled in the Arterial Revascularization Therapy Study (ARTS) trial and to determine the

Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis

© 2010 Cascão et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration and before treatment (VERA). Methods: Cytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed. Results: VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1b and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led to clinical improvement but without an impact on the cytokine pattern. Conclusions: VERA patients already display increased levels of cytokines related with Th17 polarization and neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis.This work was supported by a grant from Sociedade Portuguesa de Reumatologia/Schering-Plough 2005. RAM and RC were funded by Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/30247/2006 and SFRH/BD/40513/2007, respectively. MMS-C was funded by Marie Curie Intra-European Fellowship PERG-2008-239422 and a EULAR Young Investigator Award

A New Endemic Focus of Chagas Disease in the Northern Region of Veraguas Province, Western Half Panama, Central America

Background: Chagas disease was originally reported in Panama in 1931. Currently, the best knowledge of this zoonosis is restricted to studies done in historically endemic regions. However, little is known about the distribution and epidemiology of Chagas disease in other rural areas of the country. Methods and Findings: A cross-sectional descriptive study was carried out between May 2005 – July 2008 in four rural communities of the Santa Fe District, Veraguas Province. The study included an entomologic search to collect triatomines, bloodmeal type identification and infection rate with trypanosomes in collected vectors using a dot- blot and PCR analysis, genotyping of circulating Trypanosoma cruzi (mini-exon gene PCR analysis) and the detection of chagasic antibodies among inhabitants. The vector Rhodnius pallescens was more frequently found in La Culaca and El Pantano communities (788 specimens), where it was a sporadic household visitor. These triatomines presented darker coloration and larger sizescompared with typical specimens collected in Central Panama. Triatoma dimidiata was more common in Sabaneta de El Macho (162 specimens). In one small sub-region (El Macho), 60 % of the houses were colonized by this vector. Of the examined R. pallescens, 54.7.0 % (88/161) had fed on Didelphis marsupialis, and 24.6 % (34/138) of T. dimidiata specimens collected inside houses were positive for human blood. R. pallescens presented an infection index with T. cruzi of 17.7 % (24/ 136), with T. rangeli of 12.5 % (17/136) and 50.7 % (69/136) were mixed infections. In 117 T. dimidiata domestic specimens th

Characterization and Evaluation of Layered Bi2WO6 Nanosheets as a New Antibacterial Agent

Background: Pathogenic microorganisms are causing increasing cases of mortality and morbidity, along with alarming rates of ineffectiveness as a result of acquired antimicrobial resistance. Bi2WO6 showed good potential to be used as an antibacterial substance when exposed to visible light. This study demonstrates for the first time the dimension-dependent antibacterial activity of layered Bi2WO6 nanosheets. Materials and methods: The synthesized layered Bi2WO6 nanosheets were prepared by the hydrothermal method and characterized by powder X-ray diffraction (XRD), scanning electron microscopy (SEM), atomic force microscopy (AFM), and Raman and Fourier transform infrared spectroscopy (FTIR). Antibacterial and antibiotic-modulation activities were performed in triplicate by the microdilution method associated with visible light irradiation (LEDs). Results: Bi2WO6 nanosheets were effective against all types of bacteria tested, with MIC values of 256 µg/mL against Escherichia coli standard and resistant strains, and 256 µg/mL and 32 µg/mL against Staphylococcus aureus standard and resistant strains, respectively. Two-dimensional (2D) Bi2WO6 nanosheets showed antibacterial efficiency against both strains studied without the presence of light. Conclusions: Layered Bi2WO6 nanosheets revealed dimension-dependent antibacterial activity of the Bi2WO6 system.The authors thank Conselho Nacional de Desenvolvimento Científico e Tecnológico— CNPq, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—CAPES, and Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico—FUNCAP (Proc. BP4-00172-00232.01.00/20 and Proc. PR2-0101-00006.01.00/15) for the financial support. The authors would also like to thank the educational institutions UFCA, URCA, and UNILEÃO for their support during the experiments

The effects of chronic stress on hippocampal adult neurogenesis and dendritic plasticity are reversed by selective MAO-A inhibition.

Online first version - Oct 14, 2014There is accumulating evidence that adult neurogenesis and dendritic plasticity in the hippocampus are neuroplastic phenomena, highly sensitive to the effects of chronic stress and treatment with most classes of antidepressant drugs, being involved in the onset and recovery from depression. However, the effects of antidepressants that act through the selective inhibition of monoamine oxidase subtype A (MAO-A) in these phenomena are still largely unknown. In the present study, adult neurogenesis and neuronal morphology were examined in the hippocampus of rats exposed to chronic mild stress (CMS) and treated with the selective reversible MAO-A inhibitor (RIMA) drug, pirlindole and the selective serotonin reuptake inhibitor (SSRI), fluoxetine. The results provide the first demonstration that selective MAO-A inhibition with pirlindole is able to revert the behavioural effects of stress exposure while promoting hippocampal adult neurogenesis and rescuing the stress-induced dendritic atrophy of granule neurons.This research was funded by a collaborative research project established between ICVS and Grupo Tecnimede

Impact of Dreissena fouling on the physiological condition of native and invasive bivalves : interspecific and temporal variations

The impact of Dreissena fouling on unionids has hardly been studied in Europe, despite the fact that in some ecosystems (e.g. Lake Balaton, Hungary) infestations of several hundreds to a thousand individuals per unionid have been observed. At present, the zebra mussel Dreissena polymorpha is a dominant species in Lake Balaton and in the last decade three other invasive bivalves were introduced, potentially increasing the pressure on native unionid survival. We examined whether the fouling of dreissenids (zebra and quagga (D. rostriformis bugensis) mussels) has a negative impact on native (Anodonta anatina, Unio pictorum and U. tumidus) and invasive (Corbicula fluminea and Sinanodonta woodiana) bivalves and whether there are any interspecific and temporal variations in fouling intensity and physiological condition measured by standard condition index and glycogen content. A significant negative impact was detected on native unionids only in July and September (no impact was detected in May), when the fouling rate was high. For invasive species, a significant negative impact was detected on S. woodiana with a high level of dressenid infestation; whereas no significant impact was detected on C. fluminea. Overall, this study confirms that Dreissena may threaten unionid species including the invasive S. woodiana, although high interspecific and temporal variations were observed. This situation should be taken into account in future ecological and conservational assessments because species respond differently to Dreissena fouling and effects seem to be more pronounced in late summer/early autumn. In addition, this study provides the first evidence that the invasive C. fluminea appear to be less vulnerable to dressenid fouling.The study was supported by the Hungarian Scientific Fund (KTIA-OTKA) under the contract No. CNK80140

IRX-2, a Novel Immunotherapeutic, Enhances Functions of Human Dendritic Cells

Background: In a recent phase II clinical trial for HNSCC patients, IRX-2, a cell-derived biologic, promoted T-cell infiltration into the tumor and prolonged overall survival. Mechanisms responsible for these IRX-2-mediated effects are unknown. We hypothesized that IRX-2 enhanced tumor antigen-(TA)-specific immunity by up-regulating functions of dendritic cells (DC). Methodology/Principal Findings: Monocyte-derived DC obtained from 18 HNSCC patients and 12 healthy donors were matured using IRX-2 or a mix of TNF-α, IL-1β and IL-6 ("conv. mix"). Multicolor flow cytometry was used to study the DC phenotype and antigen processing machinery (APM) component expression. ELISPOT and cytotoxicity assays were used to evaluate tumor-reactive cytotoxic T lymphocytes (CTL). IL-12p70 and IL-10 production by DC was measured by Luminex® and DC migration toward CCL21 was tested in transwell migration assays. IRX-2-matured DC functions were compared with those of conv. mix-matured DC. IRX-2-matured DC expressed higher levels (p<0.05) of CD11c, CD40, CCR7 as well as LMP2, TAP1, TAP2 and tapasin than conv. mix-matured DC. IRX-2-matured DC migrated significantly better towards CCL21, produced more IL-12p70 and had a higher IL12p70/IL-10 ratio than conv. mix-matured DC (p<0.05 for all). IRX-2-matured DC carried a higher density of tumor antigen-derived peptides, and CTL primed with these DC mediated higher cytotoxicity against tumor targets (p<0.05) compared to the conv. mix-matured DC. Conclusion: Excellent ability of IRX-2 to induce ex vivo DC maturation in HNSCC patients explains, in part, its clinical benefits and emphasizes its utility in ex vivo maturation of DC generated for therapy. © 2013 Schilling et al