The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Comparação dos métodos de pesquisa de parasitas intestinais utilizados nos laboratórios clínicos em Cabo Verde com o método de Ritchie modificado – O caso de Rincão

Os parasitas intestinais constituem um problema médico-sanitário de grande importância, tanto pela frequência que ocorrem como causarem muitas vezes, distúrbios orgânicos capazes de incapacitarem os indivíduos infectados, reduzindo a resistência do organismo, predispondo-o inclusive a outras infecções ( MARCONDES et al., 2003 ) . Devido a estas incapacitações e maleficência que estes podem causar ao homem, tornase necessário que seja feito um diagnóstico fidedigno, através de técnicas sensíveis e específicas, pois o diagnóstico laboratorial constitui um processo importante e essencial no mecanismo de controlo e combate aos parasitas intestinais. Várias técnicas são usadas na identificação destes microrganismos, entre os quais o exame direto ou a fresco e vários métodos de concentração, como o método de Willis, Faust e Cols,Ritchie modificado, técnicas de sedimentação como Hoffmam, Pons e Janer, método de Baermann, método de Graham ( fita adesiva ) , métodos de coloração com a hematoxilina férrica, coloração tricrómica, assim como o uso de técnicas moleculares e testes rápidos ( DOLDMAN, 2009 ) . Utilizado na pesquisa sobretudo de ovos de helmintos, o método de concentração de Willis fundamenta-se na propriedade que determinados ovos têm em flutuarem na superfície de uma solução saturada com cloreto de sódio e ficarem na superfície, aderindo assim a uma lamela colocada a superfície e observada ao microscópio ( NEVES, 2005) . O método de concentração difásico de Ritchie modificado constitui uma das técnicas mais utilizadas na pesquisa de quistos de protozoários e helmintos. Esta baseia-se na sedimentação por centrifugação e lavagem do material com éter, um solvente orgânico que forma uma fase apolar, retendo os artefactos vegetais e lípidos contida na amostra, durante a centrifugação da suspensão de fezes ( REY, 2001) . Para um melhor diagnóstico, é importante associar aos métodos de pesquisa de parasitas intestinais, métodos indirectos, como a avaliação da eosinofilia sanguínea, esteatoreia e a pesquisa de cristais de Charcot-Leyden nas fezes, ou seja, métodos auxiliares na pesquisa e identificação de parasitas intestinais ( ENGELKIRK et ENGELKIRK, 2008 ) . O estudo teve como objetivo avaliar a sensibilidade e especificidades das técnicas utilizadas no diagnóstico de parasitas intestinais, comparando com as técnicas utilizadas nos laboratórios públicos de análises clínicas em Cabo Verde com o método de Ritchie modificado.

Comparação dos métodos de pesquisa de parasitas intestinais utilizados nos laboratórios clínicos em Cabo Verde com o método de Ritchie modificado.

As parasitoses intestinais constituem um grave problema de saúde pública, sendo o diagnóstico laboratorial essencial na sua identificação e controlo, tornando- se importante a escolha do método de eleição no processo, para que seja feito um diagnóstico fidedigno, através de técnicas sensíveis e específicas. Várias técnicas são usadas na identificação e pesquisas destes microrganismos, entre os quais o exame directo/ a fresco, métodos de concentração, como método de Willis, método de Faust e Cols, método bifásico de Ritchie modificado, técnicas de sedimentação como Hoffmam, Pons e Janer, método de Baermann, método de Graham (fita adesiva), métodos de coloração como hematoxilina férrica, coloração tricrômica, assim como uso de técnicas moleculares e testes rápidos (DOLDMAN, 2009). O presente estudo teve como objectivo avaliar a sensibilidade e especificidades das técnicas utilizadas no diagnóstico de parasitas intestinais nos laboratórios públicos de análises clínicas em Cabo Verde comparativamente ao método de Ritchie modificado. O estudo envolveu a análise de 251 amostras recolhidas em crianças dos 2 a 12 anos da comunidade de Rincão de Santa Catarina. Os métodos de diagnóstico laboratoriais utilizados foram os métodos de concentração de Willis, Ritchie modificado por Sales de Cunha e exame a fresco/directo. As amostras foram analisadas na Unidade Sanitária Base de Rincão e no Laboratório análises Clínica do Hospital Regional Santiago Norte. Para análise estatística, foram utilizadas Excel (2007), SPSS (versão 17). O método de Ritchie modificado mostrou ser mais sensível que o método de concentração de Willis. Também verificou-se a necessidade da realização de técnicas cada vez mais sensíveis no diagnóstico laboratorial dos parasitas intestinais nos laboratórios de análises clínicas estatais no Pais.

Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6×10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

Advances in vaccination against Helicobacter pylori.

A vaccination against Helicobacter pylori may represent both prophylactic and therapeutic approaches to the control of H. pylori infection. Different protective H. pylori-derived antigens, such as urease, vacuolating cytotoxin A, cytotoxin-associated antigen, neutrophil-activating protein and others can be produced at low cost in prokaryote expression systems and most of these antigens have already been administered to humans and shown to be safe. The recent development by Graham et al. of the model of H. pylori challenge in humans, the recent published clinical trials and the last insight generated in animal models of H. pylori infection regarding the immune mechanisms leading to vaccine-induced Helicobacter clearance will facilitate the evaluation of immunogenicity and efficacy of H. pylori vaccine candidates in Phase II and III clinical trials.

Novel methods improve prediction of species' distributions from occurrence data

Prediction of species' distributions is central to diverse applications in ecology, evolution and conservation science. There is increasing electronic access to vast sets of occurrence records in museums and herbaria, yet little effective guidance on how best to use this information in the context of numerous approaches for modelling distributions. To meet this need, we compared 16 modelling methods over 226 species from 6 regions of the world, creating the most comprehensive set of model comparisons to date. We used presence-only data to fit models, and independent presence-absence data to evaluate the predictions. Along with well-established modelling methods such as generalised additive models and GARP and BIOCLIM, we explored methods that either have been developed recently or have rarely been applied to modelling species' distributions. These include machine-learning methods and community models, both of which have features that may make them particularly well suited to noisy or sparse information, as is typical of species' occurrence data. Presence-only data were effective for modelling species' distributions for many species and regions. The novel methods consistently outperformed more established methods. The results of our analysis are promising for the use of data from museums and herbaria, especially as methods suited to the noise inherent in such data improve.

The immune space: a concept and template for rationalizing vaccine development.

Abstract Empirical testing of candidate vaccines has led to the successful development of a number of lifesaving vaccines. The advent of new tools to manipulate antigens and new methods and vectors for vaccine delivery has led to a veritable explosion of potential vaccine designs. As a result, selection of candidate vaccines suitable for large-scale efficacy testing has become more challenging. This is especially true for diseases such as dengue, HIV, and tuberculosis where there is no validated animal model or correlate of immune protection. Establishing guidelines for the selection of vaccine candidates for advanced testing has become a necessity. A number of factors could be considered in making these decisions, including, for example, safety in animal and human studies, immune profile, protection in animal studies, production processes with product quality and stability, availability of resources, and estimated cost of goods. The "immune space template" proposed here provides a standardized approach by which the quality, level, and durability of immune responses elicited in early human trials by a candidate vaccine can be described. The immune response profile will demonstrate if and how the candidate is unique relative to other candidates, especially those that have preceded it into efficacy testing and, thus, what new information concerning potential immune correlates could be learned from an efficacy trial. A thorough characterization of immune responses should also provide insight into a developer's rationale for the vaccine's proposed mechanism of action. HIV vaccine researchers plan to include this general approach in up-selecting candidates for the next large efficacy trial. This "immune space" approach may also be applicable to other vaccine development endeavors where correlates of vaccine-induced immune protection remain unknown.

Off-axis vortices in trapped Bose-condensed gases: Angular momentum and frequency splitting

We consider noncentered vortices and their arrays in a cylindrically trapped Bose-Einstein condensate at zero temperature. We study the kinetic energy and the angular momentum per particle in the Thomas-Fermi regime and their dependence on the distance of the vortices from the center of the trap. Using a perturbative approach with respect to the velocity field of the vortices, we calculate, to first order, the frequency shift of the collective low-lying excitations due to the presence of an off-center vortex or a vortex array, and compare these results with predictions that would be obtained by the application of a simple sum-rule approach, previously found to be very successful for centered vortices. It turns out that the simple sum-rule approach fails for off-centered vortices.

Immune activation alters cellular and humoral responses to yellow fever 17D vaccine.

Background. Defining the parameters that modulate vaccine responses in African populations will be imperative to design effective vaccines for protection against HIV, malaria, tuberculosis, and dengue virus infections. This study aimed to evaluate the contribution of the patient-specific immune microenvironment to the response to the licensed yellow fever vaccine 17D (YF-17D) in an African cohort. Methods. We compared responses to YF-17D in 50 volunteers in Entebbe, Uganda, and 50 volunteers in Lausanne, Switzerland. We measured the CD8+ T cell and B cell responses induced by YF-17D and correlated them with immune parameters analyzed by flow cytometry prior to vaccination. Results. We showed that YF-17D-induced CD8+ T cell and B cell responses were substantially lower in immunized individuals from Entebbe compared with immunized individuals from Lausanne. The impaired vaccine response in the Entebbe cohort associated with reduced YF-17D replication. Prior to vaccination, we observed higher frequencies of exhausted and activated NK cells, differentiated T and B cell subsets and proinflammatory monocytes, suggesting an activated immune microenvironment in the Entebbe volunteers. Interestingly, activation of CD8+ T cells and B cells as well as proinflammatory monocytes at baseline negatively correlated with YF-17D-neutralizing antibody titers after vaccination. Additionally, memory T and B cell responses in preimmunized volunteers exhibited reduced persistence in the Entebbe cohort but were boosted by a second vaccination. Conclusion. Together, these results demonstrate that an activated immune microenvironment prior to vaccination impedes efficacy of the YF-17D vaccine in an African cohort and suggest that vaccine regimens may need to be boosted in African populations to achieve efficient immunity. Trial registration. Registration is not required for observational studies. Funding. This study was funded by Canada's Global Health Research Initiative, Defense Threat Reduction Agency, National Institute of Allergy and Infectious Diseases, Bill & Melinda Gates Foundation, and United States Agency for International Development.

Reassessing the status of antiphospholipid syndrome in systemic lupus erythematosus.

The antiphospholipid syndrome was initially described in 1986. To reassess the validity of antiphospholipid antibodies in systemic lupus erythematosus (SLE), 95 patients with SLE were studied. Their antiphospholipid antibody profile was analysed and correlated with clinical findings such as thrombosis, abortions, or thrombocytopenia. A low prevalence of these antibodies was found (13 patients; 14%) with a high specificity for thrombosis (92%) and abortions (92%). The importance of anticardiolipin antibodies as a risk factor for thrombosis or abortions, or both, in patients with SLE is reaffirmed by this work.