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Characterization of the biology and infectivity of Leishmania infantum viscerotropic and dermotropic strains isolated from HIV+ and HIV- patients in the murine model of visceral leishmaniasis

  • Cunha, Joana
  • Carrillo, Eugenia
  • Sanchez Herrero, Carmen
  • Cruz, Israel
  • Moreno, Javier
  • Cordeiro-da-Silva, Anabela
BACKGROUND: Leishmaniasis is a group of diseases with a variety of clinical manifestations. The form of the disease is highly dependent on the infective Leishmania species and the immunological status of the host. The infectivity of the parasite strain also plays an important role in the progression of the infection. The aim of this work is to understand the influence of the natural infectivity of Leishmania strains in the outcome of visceral leishmaniasis. METHODS: In this study we have characterized four strains of L. infantum in terms of molecular typing, in vitro cultivation and differentiation. Two strains were isolated from HIV+ patients with visceral leishmaniasis (Bibiano and E390M), one strain was isolated from a cutaneous lesion in an immunocompetent patient (HL) and another internal reference strain causative of visceral leishmaniasis (ST) also from an immunocompetent patient was used for comparison. For this objective, we have compared their virulence by in vitro and in vivo infectivity in a murine model of visceral leishmaniasis. RESULTS: Molecular typing unraveled a new k26 sequence attributed to MON-284 zymodeme and allowed the generation of a molecular signature for the identification of each strain. In vitro cultivation enabled the production of promastigotes with comparable growth curves and metacyclogenesis development. The HL strain was the most infective, showing the highest parasite loads in vitro that were corroborated with the in vivo assays, 6 weeks post-infection in BALB/c mice. The two strains isolated from HIV+ patients, both belonging to two different zymodemes, revealed different kinetics of infection. CONCLUSION: Differences in in vitro and in vivo infectivity found in the murine model were then attributed to intrinsic characteristics of each strain. This work is supported by other studies that present the parasite's inherent features as factors for the multiplicity of clinical manifestations and severity of leishmaniasis., This work was supported by FCT project number PTDC/BIA‒MIC/11866/2011, FEDER Ciência 2010 project number PTDC/SAU‒FCF/101017/2008 and MICINN project number PIM2010‒ENI00627. JC was supported by fellowship from FCT code SFRH/BD/48626/2008 and CS by Contratos de Técnicos de apoyo a la investigación en el SNS code AES-FIS-2011., Sí
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Glossina palpalis palpalis populations from Equatorial Guinea belong to distinct allopatric clades

  • Cordon-Obras, Carlos
  • Cano-Ochando, Jordi
  • Knapp, Jenny
  • Nebreda, Paloma
  • Ndong-Mabale, Nicolas
  • Ncogo-Ada, Policarpo Ricardo
  • Ndongo-Asumu, Pedro
  • Navarro, Miguel
  • Pinto, Joao
  • Benito, Agustin
  • Bart, Jean Mathieu
BACKGROUND: Luba is one of the four historical foci of Human African Trypanosomiasis (HAT) on Bioko Island, in Equatorial Guinea. Although no human cases have been detected since 1995, T. b. gambiense was recently observed in the vector Glossina palpalis palpalis. The existence of cryptic species within this vector taxon has been previously suggested, although no data are available regarding the evolutionary history of tsetse flies populations in Bioko. METHODS: A phylogenetic analysis of 60 G. p. palpalis from Luba was performed sequencing three mitochondrial (COI, ND2 and 16S) and one nuclear (rDNA-ITS1) DNA markers. Phylogeny reconstruction was performed by Distance Based, Maximum Likelihood and Bayesian Inference methods. RESULTS: The COI and ND2 mitochondrial genes were concatenated and revealed 10 closely related haplotypes with a dominant one found in 61.1% of the flies. The sequence homology of the other 9 haplotypes compared to the former ranged from 99.6 to 99.9%. Phylogenetic analysis clearly clustered all island samples with flies coming from the Western African Clade (WAC), and separated from the flies belonging to the Central Africa Clade (CAC), including samples from Mbini and Kogo, two foci of mainland Equatorial Guinea. Consistent with mitochondrial data, analysis of the microsatellite motif present in the ITS1 sequence exhibited two closely related genotypes, clearly divergent from the genotypes previously identified in Mbini and Kogo. CONCLUSIONS: We report herein that tsetse flies populations circulating in Equatorial Guinea are composed of two allopatric subspecies, one insular and the other continental. The presence of these two G. p. palpalis cryptic taxa in Equatorial Guinea should be taken into account to accurately manage vector control strategy, in a country where trypanosomiasis transmission is controlled but not definitively eliminated yet., We thank Dr Francis Raoul for his statistical assistance with R and Dr Martin Donnelly for his valuable comments. This work has been supported by ‘Fondo de Investigacion Sanitaria (FIS)’ (PI10/01128) and by VI PN de I + D + I 2008–2011, ISCIII -Subdirección General de Redes y Centros de Investigación Cooperativa RD12/0018/0001 and RD12/0018/0015 (RICET). JMB is supported by Miguel Servet Fellowship CP09/00300., Sí
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Papular dermatitis due to Leishmania infantum infection in seventeen dogs: diagnostic features, extent of the infection and treatment outcome

  • Lombardo, Gabriella
  • Pennisi, Maria Grazia
  • Lupo, Tiziana
  • Chicharro, Carmen
  • Solano-Gallego, Laia
BACKGROUND: This study describes immunological responses, diagnostic features, follow up and treatment outcomes from seventeen dogs with papular dermatitis due to Leishmania infection diagnosed by cytology or real time-PCR. METHODS: Specific Leishmania humoral and cellular immune responses were evaluated by means of an immunofluorescence antibody test in all cases and a delayed-type hypersensitivity (DTH) reaction to leishmanin in eight cases. The extent of infection was studied in several tissues including blood, lymph node, conjunctival and oral swabs, by means of PCR, at the time of diagnosis and during follow-up. Culture was performed on nine dogs from cutaneous lesions and lymph node aspirates and molecular typing was carried out on isolates based on ITS-1, ITS-2 and Haspb gene sequencing analysis. RESULTS: Cytological and molecular results from fine needle aspirates of papules were diagnostic in 8 out of 13 (61.5%) cases and in 14 out of 15 dogs (93.3%), respectively. In all dogs, specific anti-Leishmania antibody levels were low or absent. Blood and lymph node PCRs and lymph node culture were negative in all dogs. Three out of the nine dogs (33%) were positive by culture from cutaneous lesions. The three isolates were identified as ITS type A, however, polymorphism was observed in the Haspb gene (PCR products of 626 bp, 962 bp and 371 bp). DTH response was positive in all tested dogs at the time of diagnosis. The majority of dogs were successfully treated with only N-methylglucamine antimoniate, after which cutaneous lesions disappeared or were reduced to depigmented, flattened scars. All dogs remained seronegative and the majority of dogs were negative by PCR in several tissues during follow-up. CONCLUSIONS: This study points out that papular dermatitis due to L. infantum is probably an underestimated benign cutaneous problem, associated with a parasite specific cell mediated immunity and a poor humoral immune response. Papular dermatitis is seen in young dogs, and appears to be a mild disease with restricted parasite dissemination and a good prognosis. PCR can be used as a non-invasive method to routinely evaluate papules if Leishmania infection is suspected in cases in which parasites are not visualized by cytology., The authors thank Dr. Carmen Cañavate (Instituto de Salud Carlos III, Madrid, Spain) for kindly providing L. infantum promastigotes for leishmanin skin test; Laura Perillo for her collaboration in cytopathology; Antonino Lombardo (Studio Veterinario Lombardo, Mascalucia, CT, Italy) for his collaboration in collecting the clinical cases. The authors are grateful to Francesca Soutter (Royal Veterinary College) for the English revision of the manuscript. The authors are also grateful to technicians of the CreNaL laboratory, IZS, Sicily for their technical help. The authors also thank the reviewers for the constructive critical revision of the manuscript. Laia Solano-Gallego holds a Ramón y Cajal senior researcher contract awarded by the Spanish Ministerio de Economia y Competitividad and the European Social Fund. Publication of the CVBD9 thematic series has been sponsored by Bayer HealthCare - Animal Health division., Sí
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Fatal congenital Chagas' disease in a non-endemic area: a case report

  • Flores-Chavez, Maria
  • Faez, Yamile
  • Olalla, José M
  • Cruz, Israel
  • Garate, Teresa
  • Rodríguez, Mercedes
  • Blanc, Pilar
  • Cañavate, Carmen
The early diagnosis of congenital Chagas' disease is very important if infected newborns, whether symptomatic or not, are to receive adequate treatment. This paper describes the complications arising in the diagnosis of a newborn with fatal congenital Chagas' disease in Spain, a non-endemic area where visceral leishmaniasis is present., We gratefully acknowledge financial support from the Fondo de Investigación Sanitaria (RETIC-RICET, RD06/0021/0009 and RD06/0021/0019), Sí
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Lactococcus garvieae: a small bacteria and a big data world

  • López-Campos, Guillermo
  • Aguado-Urda, Mónica
  • Blanco, María Mar
  • Gibello, Alicia
  • Cutuli, María Teresa
  • Lopez-Alonso, Victoria
  • Martin-Sanchez, Fernando
  • Fernández-Garayzábal, José F
OBJECTIVE: To describe the importance of bioinformatics tools to analyze the big data yielded from new "omics" generation-methods, with the aim of unraveling the biology of the pathogen bacteria Lactococcus garvieae. METHODS: The paper provides the vision of the large volume of data generated from genome sequences, gene expression profiles by microarrays and other experimental methods that require biomedical informatics methods for management and analysis. RESULTS: The use of biomedical informatics methods improves the analysis of big data in order to obtain a comprehensive characterization and understanding of the biology of pathogenic organisms, such as L. garvieae. CONCLUSIONS: The "Big Data" concepts of high volume, veracity and variety are nowadays part of the research in microbiology associated with the use of multiple methods in the "omic" era. The use of biomedical informatics methods is a requisite necessary to improve the analysis of these data., This research was supported by grants AGL2009-12447 and AGL2012-35419 from the Spanish Ministry of Economy and Competiveness. The funders had no role in study design, data collection and analysis or preparation of the manuscript., Sí
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The EPIRARE proposal of a set of indicators and common data elements for the European platform for rare disease registration

  • Taruscio, Domenica
  • Mollo, Emanuela
  • Gainotti, Sabina
  • Posada de la Paz, Manuel
  • Bianchi, Fabrizio
  • Vittozzi, Luciano
BACKGROUND: The European Union acknowledges the relevance of registries as key instruments for developing rare disease (RD) clinical research, improving patient care and health service (HS) planning and funded the EPIRARE project to improve standardization and data comparability among patient registries and to support new registries and data collections. METHODS: A reference list of patient registry-based indicators has been prepared building on the work of previous EU projects and on the platform stakeholders' information needs resulting from the EPIRARE surveys and consultations. The variables necessary to compute these indicators have been analysed for their scope and use and then organized in data domains. RESULTS: The reference indicators span from disease surveillance, to socio-economic burden, HS monitoring, research and product development, policy equity and effectiveness. The variables necessary to compute these reference indicators have been selected and, with the exception of more sophisticated indicators for research and clinical care quality, they can be collected as data elements common (CDE) to all rare diseases. They have been organized in data domains characterized by their contents and main goal and a limited set of mandatory data elements has been defined, which allows case notification independently of the physician or the health service. CONCLUSIONS: The definition of a set of CDE for the European platform for RD patient registration is the first step in the promotion of the use of common tools for the collection of comparable data. The proposed organization of the CDE contributes to the completeness of case ascertainment, with the possible involvement of patients and patient associations in the registration process., This work is part of the activities of the project titled “Building Consensus and synergies for the EU Registration of Rare Disease Patients” (EPIRARE), funded by the European Commission within the framework of the Health Project, Work Plan 2010 (Grant n. 20101202)., Sí
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Nitric oxide compounds have different effects profiles on human articular chondrocyte metabolism

  • de Andrés, María C
  • Maneiro, Emilia
  • Martín, Miguel A
  • Arenas, Joaquín
  • Blanco, Francisco J
INTRODUCTION: The pathogenesis of osteoarthritis (OA) is characterized by the production of high amounts of nitric oxide (NO), as a consequence of up-regulation of chondrocyte-inducible nitric oxide synthase (iNOS) induced by inflammatory cytokines. NO donors represent a powerful tool for studying the role of NO in the cartilage in vitro. There is no consensus about NO effects on articular cartilage in part because the differences between the NO donors available. The aim of this work is to compare the metabolic profile of traditional and new generation NO donors to see which one points out the osteoarthritic process in the best way. METHODS: Human healthy and OA chondrocytes were isolated from patients undergoing joint replacement surgery, and primary cultured. Cells were stimulated with NO donors (NOC-12 or SNP). NO production was evaluated by the Griess method, and apoptosis was quantified by flow cytometry. Mitochondrial function was evaluated by analysing respiratory chain enzyme complexes, citrate synthase (CS) activities by enzymatic assay, mitochondrial membrane potential (Δψm) by JC-1 using flow cytometry, and ATP levels were measured by luminescence assays. Glucose transport was measured as the uptake of 2-deoxy-[(3)H]glucose (2-[(3)H]DG). Statistical analysis was performed using the Mann-Whitney U test. RESULTS: NOC-12 liberates approximately ten times more NO2- than SNP, but the level of cell death induced was not as profound as that produced by SNP. Normal articular chondrocytes stimulated with NOC-12 had reduced activity from complexes I, III y IV, and the mitochondrial mass was increased in these cells. Deleterious effects on ΔΨm and ATP levels were more profound with SNP, and this NO donor was able to reduce 2-[(3)H]DG levels. Both NO donors had opposite effects on lactate release, SNP diminished the levels and NOC-12 lead to lactate accumulation. OA chondrocytes incorporate significantly more 2-[(3)H]DG than healthy cells. CONCLUSIONS: These findings suggest that the new generation donors, specifically NOC-12, mimic the OA metabolic process much better than SNP. Previous results using SNP have to be considered prudently since most of the effects observed can be induced by the interactions of secondary products of NO., The authors express appreciation to the Department of Orthopedics and the Tissue Bank of the Complejo Hospitalario Universitario de A Coruña for providing cartilage samples. This study was supported by grants from the Fondo Investigación Sanitaria, Madrid, Spain: (CIBER- CB06/01/0040; PI-12/00329; RETIC-RIER-RD12/0009/0018; and Proteo-Red/ISCIII); Ministerio Ciencia e Innovación, Madrid, Spain: PLE2009-0144 and FEDER (European Community)., Sí
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Mammographic density and risk of breast cancer according to tumor characteristics and mode of detection: a Spanish population-based case-control study

  • Pollan-Santamaria, Marina
  • Ascunce, Nieves
  • Ederra, María
  • Murillo, Alberto
  • Erdozáin, Nieves
  • Alés-Martínez, Jose Enrique
  • Pastor-Barriuso, Roberto
It is not clear whether high mammographic density (MD) is equally associated with all subtypes of breast cancer (BC). We investigated the association between MD and subsequent BC, considering invasiveness, means of detection, pathologic subtype, and the time elapsed since mammographic exploration and BC diagnosis. METHODS: BC cases occurring in the population of women who attended screening from 1997 through 2004 in Navarre, a Spanish region with a fully consolidated screening program, were identified via record linkage with the Navarre Cancer Registry (n = 1,172). Information was extracted from the records of their first attendance at screening in that period. For each case, we randomly selected four controls, matched by screening round, year of birth, and place of residence. Cases were classified according to invasiveness (ductal carcinoma in situ (DCIS) versus invasive tumors), pathologic subtype (considering hormonal receptors and HER2), and type of diagnosis (screen-detected versus interval cases). MD was evaluated by a single, experienced radiologist by using a semiquantitative scale. Data on BC risk factors were obtained by the screening program in the corresponding round. The association between MD and tumor subtype was assessed by using conditional logistic regression. RESULTS: MD was clearly associated with subsequent BC. The odds ratio (OR) for the highest MD category (MD >75%) compared with the reference category (MD <10%) was similar for DCIS (OR = 3.47; 95% CI = 1.46 to 8.27) and invasive tumors (OR = 2.95; 95% CI = 2.01 to 4.35). The excess risk was particularly high for interval cases (OR = 7.72; 95% CI = 4.02 to 14.81) in comparison with screened detected tumors (OR = 2.17; 95% CI = 1.40 to 3.36). Sensitivity analyses excluding interval cases diagnosed in the first year after MD assessment or immediately after an early recall to screening yielded similar results. No differences were seen regarding pathologic subtypes. The excess risk associated with MD persisted for at least 7 to 8 years after mammographic exploration. CONCLUSIONS: Our results confirm that MD is an important risk factor for all types of breast cancer. High breast density strongly increases the risk of developing an interval tumor, and this excess risk is not completely explained by a possible masking effect., This work was supported by research grants from Eli Lilly and Company (EV1 1082/08); and the Spanish Federation of Breast Cancer Patients (Federación Española de Cáncer de Mama) (FECMA 485 EPY 1170-10)., Sí
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Obesity and survival in operable breast cancer patients treated with adjuvant anthracyclines and taxanes according to pathological subtypes: a pooled analysis

  • Pajares, Bella
  • Pollan-Santamaria, Marina
  • Martín, Miguel
  • Mackey, John R
  • Lluch, Ana
  • Gavila, Joaquín
  • Vogel, Charles
  • Ruiz-Borrego, Manuel
  • Calvo, Lourdes
  • Pienkowski, Tadeusz
  • Rodríguez-Lescure, Álvaro
  • Seguí, Miguel Angel
  • Tredan, Olivier
  • Antón, Antonio
  • Ramos, Manuel
  • Cámara, María del Carmen
  • Rodríguez-Martín, César
  • Carrasco, Eva
  • Alba, Emilio
Obesity is an unfavorable prognostic factor in breast cancer (BC) patients regardless of menopausal status and treatment received. However, the association between obesity and survival outcome by pathological subtype requires further clarification. METHODS: We performed a retrospective analysis including 5,683 operable BC patients enrolled in four randomized clinical trials (GEICAM/9906, GEICAM/9805, GEICAM/2003-02, and BCIRG 001) evaluating anthracyclines and taxanes as adjuvant treatments. Our primary aim was to assess the prognostic effect of body mass index (BMI) on disease recurrence, breast cancer mortality (BCM), and overall mortality (OM). A secondary aim was to detect differences of such prognostic effects by subtype. RESULTS: Multivariate survival analyses adjusting for age, tumor size, nodal status, menopausal status, surgery type, histological grade, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, chemotherapy regimen, and under-treatment showed that obese patients (BMI 30.0 to 34.9) had similar prognoses to that of patients with a BMI < 25 (reference group) in terms of recurrence (Hazard Ratio [HR] = 1.08, 95% Confidence Interval [CI] = 0.90 to 1.30), BCM (HR = 1.02, 0.81 to 1.29), and OM (HR = 0.97, 0.78 to 1.19). Patients with severe obesity (BMI ≥ 35) had a significantly increased risk of recurrence (HR = 1.26, 1.00 to 1.59, P = 0.048), BCM (HR = 1.32, 1.00 to 1.74, P = 0.050), and OM (HR = 1.35, 1.06 to 1.71, P = 0.016) compared to our reference group. The prognostic effect of severe obesity did not vary by subtype. CONCLUSIONS: Severely obese patients treated with anthracyclines and taxanes present a worse prognosis regarding recurrence, BCM, and OM than patients with BMI < 25. The magnitude of the harmful effect of BMI on survival-related outcomes was similar across subtypes., This work was supported by the Spanish Breast Cancer Research Group (Grupo Español de Investigación de Cáncer de Mama) (GEICAM). No funding was received for the data analyses or the writing of this manuscript. Clinical trials GEICAM/9805 and BCIRG 001 were funded by Sanofi Aventis. GEICAM/9906 and GEICAM/2003-02 were partially funded by Bristol-Myers Squibb. These funding bodies were not involved in the collection and interpretation of the data or in the decision to publish. EA and MM were also supported by FEDER (RECTICC-RD12/0036/0076). We thank all the participating patients, clinicians, GEICAM and local research staff. We thank Hosanna Soler Vila, PhD, who provided medical writing services on behalf of GEICAM., Sí
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Host adaptive immunity deficiency in severe pandemic influenza

  • Bermejo-Martin, Jesus F
  • Martin-Loeches, Ignacio
  • Rello, Jordi
  • Antón, Andrés
  • Almansa, Raquel
  • Xu, Luoling
  • Lopez-Campos, Guillermo
  • Pumarola, Tomás
  • Ran, Longsi
  • Ramirez, Paula
  • Banner, David
  • Cheuk Ng, Derek
  • Socias, Lorenzo
  • Loza, Ana
  • Andaluz, David
  • Maravi, Enrique
  • Gómez-Sánchez, Maria J
  • Gordón, Mónica
  • Gallegos, Maria C
  • Fernandez, Victoria
  • Aldunate, Sara
  • León, Cristobal
  • Merino, Pedro
  • Blanco, Jesús
  • Martin-Sanchez, Fernando
  • Rico, Lucia
  • Varillas, David
  • Iglesias, Veronica
  • Marcos, Maria Ángeles
  • Gandía, Francisco
  • Bobillo, Felipe
  • Nogueira, Begoña
  • Rojo, Silvia
  • Resino, Salvador
  • Castro, Carmen
  • Ortiz de Lejarazu, Raul
  • Kelvin, David
INTRODUCTION: Pandemic A/H1N1/2009 influenza causes severe lower respiratory complications in rare cases. The association between host immune responses and clinical outcome in severe cases is unknown. METHODS: We utilized gene expression, cytokine profiles and generation of antibody responses following hospitalization in 19 critically ill patients with primary pandemic A/H1N1/2009 influenza pneumonia for identifying host immune responses associated with clinical outcome. Ingenuity pathway analysis 8.5 (IPA) (Ingenuity Systems, Redwood City, CA) was used to select, annotate and visualize genes by function and pathway (gene ontology). IPA analysis identified those canonical pathways differentially expressed (P < 0.05) between comparison groups. Hierarchical clustering of those genes differentially expressed between groups by IPA analysis was performed using BRB-Array Tools v.3.8.1. RESULTS: The majority of patients were characterized by the presence of comorbidities and the absence of immunosuppressive conditions. pH1N1 specific antibody production was observed around day 9 from disease onset and defined an early period of innate immune response and a late period of adaptive immune response to the virus. The most severe patients (n = 12) showed persistence of viral secretion. Seven of the most severe patients died. During the late phase, the most severe patient group had impaired expression of a number of genes participating in adaptive immune responses when compared to less severe patients. These genes were involved in antigen presentation, B-cell development, T-helper cell differentiation, CD28, granzyme B signaling, apoptosis and protein ubiquitination. Patients with the poorest outcomes were characterized by proinflammatory hypercytokinemia, along with elevated levels of immunosuppressory cytokines (interleukin (IL)-10 and IL-1ra) in serum. CONCLUSIONS: Our findings suggest an impaired development of adaptive immunity in the most severe cases of pandemic influenza, leading to an unremitting cycle of viral replication and innate cytokine-chemokine release. Interruption of this deleterious cycle may improve disease outcome., The study was scientifically sponsored by the Spanish Society for Critical Care Medicine (SEMICYUC). Funding: MICCIN-FIS/JCYL-IECSCYL-SACYL (Spain): Programa de Investigación Comisionada en Gripe, GR09/0021-EMER07/050- PI081236-RD07/0067. CIHR-NIH-Sardinia Recherché-LKSF Canada support DJK., Sí
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