1,721,168 research outputs found
Bone diseases associated with human immunodeficiency virus infection: pathogenesis, risk factors and clinical management
No full textBone disorders such as osteopenia and osteoporosis have been recently reported in patients infected with the human immunodeficiency virus (HIV), but their etiology remains still unknown. The prevalence estimates vary widely among the different studies and can be affected by concomitant factors such as the overlapping of other possible conditions inducing bone loss as lypodystrophy, advanced HIV-disease, advanced age, low body weight or concomitant use of other drugs. All the reports at the moment available in the literature showed a higher than expected prevalence of reduced bone mineral density (BMD) in HIV-infected subjects both naïve and receiving potent antiretroviral therapy compared to healthy controls. This controversial can suggest a double role played by both antiretroviral drugs and HIV itself due to immune activation and/or cytokines disregulation. An improved understanding of the pathogenesis of bone disorders can result in better preventative and therapeutic measures. However, the clinical relevance and the risk of fractures remains undefined in HIV-population. The clinical management of osteopenia and osteoporosis in HIV-infected subjects is still being evaluated. Addressing potential underlying bone disease risk factors (e.g., smoking and alcohol intake, use of corticosteroids, advanced age, low body weight), evaluating calcium and vitamin D intake, and performing dual x-ray absorptiometry in HIV-infected individuals who have risk factors for bone disease can be important strategies to prevent osteopenia and osteoporosis in this population. The administration of bisphosphonates (e.g., alendronate), with calcium and vitamin D supplementation, may be a reasonable and effective option to treat osteoporosis in these subjects
Microbial translocation in the pathogenesis of HIV infection and AIDS
Get PDFIn pathogenic simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections, the translocation of microbial products from the gastrointestinal (GI) tract to portal and systemic circulation has been proposed as a major driver of the chronic immune activation that is associated with disease progression. Consistently, microbial translocation is not present in nonpathogenic SIV infections of natural host species. In vivo studies demonstrated that HIV/SIV-associated microbial translocation results from a series of immunopathological events occurring at the GI mucosa: (i) early and severe mucosal CD4+ depletion, (ii) mucosal immune hyperactivation/persistent inflammation; (iii) damage to the integrity of the intestinal epithelium with enterocyte apoptosis and tight junction disruption; and (iv) subverted the gut microbiome, with a predominance of opportunistic bacteria. Direct in situ evidence of microbial translocation has been provided for SIV-infected rhesus macaques showing translocated microbial products in the intestinal lamina propria and distant sites. While the mechanisms by which microbial translocation causes immune activation remain controversial, a key pathogenic event appears to be innate immunity activation via Toll-like receptors and other pathogen recognition receptors. Accumulating clinical observations suggest that microbial translocation might affect HIVdisease progression, response to therapy, and non-AIDS comorbidities. Given its detrimental effect on overall immunity, several interventions to prevent/block microbial translocation are currently under investigation as novel therapeutic agents for HIV/AIDS
PATHOGENESIS OF POOR IMMUNE RECOVERY ON COMBINATION ANTIRETROVIRAL THERAPY (CART): THE ROLE OF THE GASTROINTESTINAL TRACT AND MICROBIAL TRANSLOCATION
Get PDFIn the era of combination antiretroviral therapy (cART), a remarkable reduction in AIDS-related morbidity and mortality rates has been described. However, 15%–30% of treated individuals display a discordant response to cART, which consists of inefficient CD4+ T-cell recovery despite effective virological control. These subjects are referred to as “Immunological Non Responders” (INRs) and remain at a considerable higher risk of HIV progression and mortality from both AIDS and non-AIDS events and poorly responsive to experimental treatments. It is thus critical to investigate the underlying mechanisms of poor immune recovery on effective cART and elaborate targeted interventional strategies for this population in a timely manner.
T-cell activation has been described an independent factor of poor CD4+ T-cell recovery on cART and INR have been shown to present significant higher levels of peripheral immune activation compared to Full Responders (FR).
Building on prior evidence of the translocation of microbial bioproducts through the gastrointestinal (GI) tract as a cause of immune activation in HIV disease, studies addressing the pathogenesis of inefficient CD4+ T-cell recovery in INR have shown increased levels of circulating lipopolysaccharide (LPS) in this setting. Despite evidence of an association between microbial translocation parameters and expression of activation markers in INR, whether stimulation with microbial components per se results in the induction of T-cell activation markers in this population is unknown. Further, a biological model explaining the precise mechanisms by which exposure to microbial components causes T-cell activation in HIV disease is currently lacking. Finally, literature has so far not disentangled the possible links between GI barrier damage and poor immune reconstitution in the course of effective cART in INR.
The overall objective of the present study was to understand whether damage of the GI tract and microbial-induced T-cell activation feature HIV-infected individuals with poor immune recovery on cART.
Specific Aim 1: Comparative study of gut junctional complexes in HIV-infected individuals with different CD4+ T-cell recovery on cART.
We aimed to analyze the structure and function of gut JC in Immunological Non Responder (INR) and Full Responder (FR) and to assess whether the fecal microbiome and/or HIV reservoirs may represent underlying causes of gut epithelial barrier dysfunction in course of treated HIV disease.
Specific Aim 2: Expression of activation markers on immune cells following stimulation with microbial components in HIV-infected individuals with different CD4+ T-cell recovery on cART.
We aimed to study the expression of activation markers on immune cells following stimulation with microbial components in HIV-infected individuals with different CD4+ T-cell recovery on cART. We analyzed the effect of LPS in vitro stimulation on T-cell activation markers (CD38 and HLA-DR) in HIV-infected patients with different CD4+ recovery on cART and then set up an in vitro model to assess the TLR-mediated signalling pathways in monocyte-derived macrophages (MDM) and PBMCs in a similar study population.
Our experiments revealed:
i) Immunohistochemical and statistical evidence of INR presenting the lowest expression of junctional complex (JC) proteins at mucosal (ileum and colon) sites, with electron microscopy proof of dilated intercellular spaces;
ii) A negative correlation of CD4+ T-cell counts with intestinal JC protein expression as well as HIV reservoirs in the gut and peripheral blood;
iii) A higher proportion of HLA-DR-expressing CD4+ and CD8+ T-cells in INR following lipopolysaccharide (LPS) in vitro stimulation, yet the CD38+CD8+ pool only is significantly expanded according to the degree of immunological impairment;
iv) Up-regulation of T-cell activation markers following broad microbial challenge in INR, as well as heightened expression of effector and pathogen specific response genes prior to stimulation and selective upregulation of type I interferons following ssRNA stimulation;
v) Preserved response of monocyte-derived macrophages (MDM) from INR following broad microbial challenge.
Our findings show that incomplete immunological response in the course of effective cART associates with severe damage of the GI epithelial barrier and increased size of the HIV reservoir both at mucosal sites and in circulating T-cells, thus suggesting to target the GI tract in the elaboration of interventional strategies for INR.
We also demonstrate the uniqueness of the CD8+CD38+ T-cells subset in depicting T-cell activation following LPS stimulation in individuals with poor CD4+ T-cell recovery, strengthening its possible exploitation in the clinic to monitor the immune response to cART.
Consistently with these findings, we show the up-regulation of activation markers on T-cells from INR following ssRNA which appears to be involved in TLR-mediated signaling of non-CD14-dependent pathways, highlighting the importance of low-level viremia/HIV reservoirs as sources of persistent antigenic stimulation in this setting
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Immunological mechanisms of interleukin-2 (IL-2) treatment in HIV/AIDS disease
No full textHIV establishes a chronic infection that is marked by the progressive depletion of CD4+ T-cells, yet the mechanisms by which this depletion arises are a matter of controversy. Evidence is accumulating that T CD4+ depletion is not effected solely by virus-mediated killing and that mechanisms involving T-cell dynamics play a major role in the pathogenesis of HIV infection. Hence antiretroviral therapy, by controlling viral replication alone, invariably fails to achieve the broadest immune reconstitution. This issue has strengthened the rationale to widely explore new adjuvant immunotherapy. Most work has been performed on IL-2, given its potential to correct HIVdriven immune defects, possibly translating in a more effective immune competency. Important insights stem from the IL-2-mediated immune reconstitution pattern, with a rise in peripheral turnover and thymopoiesis, IL-7 synthesis and functional markers, resulting in the correction of the skewed T-cell immunophenotype and cytokine milieu. Combined, these findings suggest that IL-2 has a beneficial effect in correcting the severe disruption in T-cell homeostasis induced by HIV, through the interaction with T-cells and cytokine microenvironment. However, whether or not these immunologic effects translate in an actual immunologic competency and therefore clinical benefit, still awaits demonstration from ongoing large, controlled clinical studies
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Distinguishing Latent from Active Mycobacterium tuberculosis Infection Using Elispot Assays: Looking Beyond Interferon-gamma
Get PDFMycobacterium tuberculosis (MTB) is a global heath epidemic, its threat amplified by HIV infection and the emergence of multidrug-resistant tuberculosis (MDR-TB). Interferon (IFN)-gamma release assays (IGRAs) have improved the accuracy of detection of MTB exposure in some subject groups as compared to the Tuberculin Skin Test (TST). However, as IFN-gamma is produced by both fully rested and more recently activated populations of memory T cells, it is not surprising that the measurement of this cytokine alone cannot accurately distinguish Latent TB Infected (LTBI) subjects from those with active (infectious) disease. Accurate and rapid diagnosis of infectious individuals would allow medication to be properly allocated and other actions taken to more effectively curtail MTB spread. Analysis of multi-cytokine profiles ex vivo after stimulation of PBMCs from LTBI and active MTB subjects indicate the real possibility of successfully discerning these two disease states within 24 hours of a subject’s blood draw. Due to the unparalleled sensitivity, low cost, and ease of use of Elispot assays, we propose that via a multiplex Elispot platform the accurate distinction of LTBI from active MTB-infected individuals is within reach
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