Antiretroviral treatment strategies and immune reconstitution in treatment-naïve HIV-infected patients with advanced disease.

Treatment-naïve advanced HIV-infected patients have a lower life expectancy than those treated early with highly active antiretroviral therapy (HAART). Early treatment allows greater immunological recovery, a reduction of AIDS progression, a reduced risk of related illnesses, and lower mortality compared with HAART initiation in advanced disease. Given the numbers with advanced disease worldwide and the high cost of care, strategies encouraging early detection may be life saving and cost effective. Factors associated with increased clinical progression include higher baseline HIV viral load and older age, emphasizing the need for early viral load suppression. HAART initiation faces many challenges; interactions between antiretroviral agents and drugs used to treat life-threatening opportunistic infections may cause subtherapeutic antiretroviral exposure and the development of resistance or supratherapeutic levels resulting in adverse effects. Immune reconstitution inflammatory syndrome can be another cause of suboptimal outcomes. The management of patients with advanced HIV infection should include rapid short-term immune reconstitution to limit the risk of disease progression plus aggressive antiviral treatment to achieve rapid virological suppression. Clear evidence on the optimal regimen and agents to use to target advanced HIV disease is lacking. Therefore, antiretroviral treatment for these patients has to be carefully tailored to the individual according to many variables

Fifteen years follow-up of photorefractive keratectomy up to 10 D of myopia: outcomes and analysis of the refractive regression

PURPOSE: To evaluate outcomes of photorefractive keratectomy up to -10.00 D of myopia and -4.50 of astigmatism and to develop a predictive model for the refractive changes in the long term. SETTING: Vissum Corporation and Miguel Hernandez University (Alicante, Spain). DESIGN: Retrospective-prospective observational series of cases. METHODS: This study included 33 eyes of 33 patients aged 46.79±7.04 years (range 40-57) operated with the VISX 20/20 excimer laser with optical zones of 6 mm. No mitomycin C was used in any of these cases. The minimum follow-up was 15 years. The main outcome measures were: uncorrected and corrected distance visual acuity, manifest refraction and corneal topography. Linear regression models were developed from the observed refractive changes over time. RESULTS: Safety and efficacy indexes at 15 years were 1.18 and 0.83, respectively. No statistically significant differences were detected for any keratometric variable during the follow-up (p≥0.103). 15 years after the surgery 54.55% of the eyes were within ±1.00 D of spherical equivalent and 84.85% within ±2.00 D. The uncorrected distance visual acuity at 15 years was 20/25 or better in 60.6% of the eyes and 20/40 or better in 72.73% of the eyes. The correlation between the attempted and the achieved refractions was r=0.948 (p<0.001) at 1 year, and r=0.821 (p<0.001) at 15 years. No corneal ectasia was detected in any case during the follow-up. CONCLUSIONS: Photorefractive keratectomy is a safe refractive procedure in the long term within the range of myopia currently considered suitable for its use, although its efficacy decreases with time, especially, in high myopia. The model developed predicts a myopic regression of 2.00 D at 15 years for an ablation depth of 130 µm

COVID-19 Mortality and Stress to the Hospital System From High Patient Load

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Accretion and nuclear activity of quiescent supermassive black holes. II: optical study and interpretation

Our X-ray study of the nuclear activity in a new sample of six quiescent early-type galaxies, and in a larger sample from the literature, confirmed (Soria et al., Paper I) that the Bondi accretion rate of diffuse hot gas is not a good indicator of the supermassive black hole (SMBH) X-ray luminosity. Here we suggest that a more reliable estimate of the accretion rate must include the gas released by the stellar population inside the sphere of influence of the SMBH, in addition to the Bondi inflow of hot gas across that surface. We use optical surface-brightness profiles to estimate the mass-loss rate from stars in the nuclear region: we show that for our sample of galaxies it is an order of magnitude higher (~ 10^{-4} - 10^{-3} M_sun/yr) than the Bondi inflow rate of hot gas, as estimated from Chandra (Paper I). Only by taking into account both sources of fuel can we constrain the true accretion rate, the accretion efficiency, and the power budget. Radiatively efficient accretion is ruled out, for quiescent SMBHs. For typical radiatively inefficient flows, the observed X-ray luminosities of the SMBHs imply accretion fractions ~ 1 - 10% (ie, ~ 90 - 99% of the available gas does not reach the SMBH) for at least five of our six target galaxies, and most of the other galaxies with known SMBH masses. We discuss the conditions for mass conservation inside the sphere of influence, so that the total gas injection is balanced by accretion plus outflows. We show that a fraction of the total accretion power (mechanical plus radiative) would be sufficient to sustain a self-regulating, slow outflow which removes from the nuclear region all the gas that does not sink into the BH (``BH feedback''). The rest of the accretion power may be carried out in a jet, or advected. We also discuss scenarios that would lead to an intermittent nuclear activity.Comment: 15 pages, accepted by ApJ. See also our Paper I, astro-ph/051129

Neurocognitive Impairment in HIV-Infected Naïve Patients with Advanced Disease: The Role of Virus and Intrathecal Immune Activation

Objective. To investigate intrathecal immune activation parameters and HIV-RNA in HIV-associated neurocognitive disorders (HAND) of advanced naïve HIV-infected patients and to evaluate their dynamics before and after initiation of antiretroviral therapy (ART). Methods. Cross-sectional and longitudinal analysis of HIV RNA, proinflammatory cytokines (IL-6, IL-10, INF-γ, TNF-α, TGF-β1, and TGF-β2) and chemokines (MIP-1α, MIP-1β, and MCP-1) in plasma and cerebrospinal fluid (CSF) of HIV-infected patients with CD4 <200/μL. Results. HAND was diagnosed at baseline in 6/12 patients. Baseline CSF HIV-RNA was comparable in patients with or without HAND, whereas CSF concentration of IL-6 and MIP-1β, proinflammatory cytokines, was increased in HAND patients. CSF evaluation at 12 weeks was available in 10/12 cases. ART greatly reduced HIV-RNA in all patients. Nevertheless, IL-6 and MIP-1β remained elevated after 12 weeks of therapy in HAND patients, in whom CSF HIV RNA decay was slower than the plasmatic one as well. Conclusion. Immune activation, as indicated by inflammatory cytokines, but not higher levels of HIV-RNA is observed in advanced naïve HIV-infected patients with HAND. In HAND patients, ART introduction resulted in a less rapid clearance of CSF viremia compared to plasma and no modifications of intratechal immune activation

NK Cells Infiltrating a MHC Class I-Deficient Lung Adenocarcinoma Display Impaired Cytotoxic Activity toward Autologous Tumor Cells Associated with Altered NK Cell-Triggering Receptors

Abstract NK cells are able to discriminate between normal cells and cells that have lost MHC class I (MHC-I) molecule expression as a result of tumor transformation. This function is the outcome of the capacity of inhibitory NK receptors to block cytotoxicity upon interaction with their MHC-I ligands expressed on target cells. To investigate the role of human NK cells and their various receptors in the control of MHC-I-deficient tumors, we have isolated several NK cell clones from lymphocytes infiltrating an adenocarcinoma lacking β2-microglobulin expression. Unexpectedly, although these clones expressed NKG2D and mediated a strong cytolytic activity toward K562, Daudi and allogeneic MHC-class I+ carcinoma cells, they were unable to lyse the autologous MHC-I− tumor cell line. This defect was associated with alterations in the expression of natural cytotoxicity receptor (NCR) by NK cells and the NKG2D ligands, MHC-I-related chain A, MHC-I-related chain B, and UL16 binding protein 1, and the ICAM-1 by tumor cells. In contrast, the carcinoma cell line was partially sensitive to allogeneic healthy donor NK cells expressing high levels of NCR. Indeed, this lysis was inhibited by anti-NCR and anti-NKG2D mAbs, suggesting that both receptors are required for the induced killing. The present study indicates that the MHC-I-deficient lung adenocarcinoma had developed mechanisms of escape from the innate immune response based on down-regulation of NCR and ligands required for target cell recognition

A Web-based Architecture for Interoperability of Lexical Resources

In this paper we present aWeb Service Architecture for managing high level interoperability of Language Resources (LRs) by means of a Service Oriented Architecture (SOA) and the use of ISO standards, such as ISO LMF. We propose a layered architecture which separates the management of legacy resources (data collection) from data aggregation (workflow) and data access (user requests). We provide a case study to demonstrate how the proposed architecture is capable of managing data exchange among different lexical services in a coherent way and show how the use of a lexical standard becomes of primary importance when a protocol of interoperability is defined