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San Lazzaro di Savena, Italy

Delogu G.,Catholic University of the Sacred Heart | Goletti D.,National Institute for Infectious Diseases
Journal of Rheumatology | Year: 2014

The risk of developing active tuberculosis (TB) is higher in patients taking immunosuppressive drugs, either as a result of reactivation of a latent TB infection (LTBI) or following a new infection with Mycobacterium tuberculosis (Mtb). We discuss the pathogenesis and spectrum of Mtb infection in light of its implication for the management of patients following biologic regimens. Among recent findings, during LTBI, Mtb can persist in the host for decades, localizing in many tissues and assuming different metabolic states that protect the bacilli from the harsh host immune defenses. Despite the strong host T cell response against Mtb, the bacilli may also replicate and multiply in vivo, and any event impairing immune function may lead to active and uncontrolled bacteria replication and active disease. The classic dichotomy between active and latent disease is being reconsidered in favor of a continuous and dynamic spectrum extending from infection to disease that can coexist in the same individual. This TB spectrum results from the dynamic interaction between the host immune system and the bacilli and can be maintained in equilibrium for decades, although treatments affecting the host immune cells may result in disease reactivation © 2014. All rights reserved.

Di Sano F.,University of Rome Tor Vergata | Bernardoni P.,University of Rome Tor Vergata | Piacentini M.,University of Rome Tor Vergata | Piacentini M.,National Institute for Infectious Diseases
Experimental Cell Research | Year: 2012

The endoplasmic reticulum (ER) consists of the nuclear envelope and a peripheral network of tubules and membrane sheets. The tubules are shaped by a specific class of curvature stabilizing proteins, the reticulons and DP1; however it is still unclear how the sheets are assembled. The ER is the cellular compartment responsible for secretory and membrane protein synthesis. The reducing conditions of ER lead to the intra/inter-chain formation of new disulphide bonds into polypeptides during protein folding assessed by enzymatic or spontaneous reactions. Moreover, ER represents the main intracellular calcium storage site and it plays an important role in calcium signaling that impacts many cellular processes. Accordingly, the maintenance of ER function represents an essential condition for the cell, and ER morphology constitutes an important prerogative of it. Furthermore, it is well known that ER undergoes prominent shape transitions during events such as cell division and differentiation. Thus, maintaining the correct ER structure is an essential feature for cellular physiology. Now, it is known that proper ER-associated proteins play a fundamental role in ER tubules formation. Among these ER-shaping proteins are the reticulons (RTN), which are acquiring a relevant position. In fact, beyond the structural role of reticulons, in very recent years new and deeper functional implications of these proteins are emerging in relation to their involvement in several cellular processes. © 2012 Elsevier Inc.

Fung S.,University of Toronto | Kwan P.,University of British Columbia | Fabri M.,University of Novi Sad | Horban A.,Medical University of Warsaw | And 11 more authors.
Gastroenterology | Year: 2014

Background & Aims Tenofovir disoproxil fumarate (TDF) is active against lamivudine-resistant hepatitis B virus (HBV) infection, but data to support its clinical efficacy in this setting are limited. Methods In a prospective, double-blind, 96-week trial, patients were randomly assigned (1:1) to groups given TDF (300 mg, n = 141) or a combination of emtricitabine (FTC, 200 mg; n = 139) and TDF (300 mg, FTC/TDF). Patients were hepatitis B e antigen (HBeAg)-positive or HBeAg-negative, with levels of HBV DNA ≥3 log10 IU/mL and lamivudine resistance mutations (HBV polymerase or reverse transcriptase amino acid substitutions rtM204I/V ± rtL180M by INNO-LiPA Multi-DR v3; Innogenetics, Inc, Alpharetta, GA). The primary end point was proportion with HBV DNA <69 IU/mL (Roche COBAS Taqman assay; Roche Molecular Systems, Inc, Pleasanton, CA). Results Patient groups were well matched for demographic and disease characteristics, including region (60% from Europe), HBV genotype (45% genotype D), HBeAg status (47% HBeAg-positive), and duration of lamivudine treatment (mean, 3.8 years). At week 96 of treatment, 89.4% of patients in the TDF group and 86.3% in the FTC/TDF group had levels of HBV DNA <69 IU/mL (P =.43). HBeAg loss and seroconversion did not differ between groups; only 1 patient (0.7%) in the FTC/TDF group lost hepatitis B surface antigen. Treatment was well tolerated; confirmed renal events (creatinine increase of ≥0.5 mg/dL [>44 umol/L], creatinine clearance <50 mL/min, or level of PO4 <2 mg/dL [<0.65 mmol/L]) were generally mild and infrequent (<1%). Small reductions (<2%) in mean bone mineral density of hip and spine were detected by dual-energy x-ray absorptiometry in both groups. No TDF resistance developed through 96 weeks of treatment. Conclusions TDF alone is safe and effective for treatment of patients with lamivudine-resistant, chronic HBV infection. Clinical Trials.gov No, NCT00737568. © 2014 by the AGA Institute.

Cataldo M.A.,National Institute for Infectious Diseases | Tacconelli E.,University Cattolica Sacro Cuore | Grilli E.,National Institute for Infectious Diseases | Pea F.,University of Udine | Petrosillo N.,National Institute for Infectious Diseases
Journal of Antimicrobial Chemotherapy | Year: 2012

Objectives: To summarize available evidence on the effect of continuous infusion (CoI) of vancomycin compared with intermittent infusion (InI) in adult patientswith Gram-positive infections. Methods: MEDLINE, EMBASE and Cochrane databases were searched. Randomized clinical trials (RCTs) and observational studies that comparatively assessed CoI and InI of vancomycin in terms of mortality, clinical cure, toxicity rates and serum drug exposure [trough concentration(Cmin) for InI and steady-state concentration (Css) for CoI; area under the curve at 24 h (AUC24) for both] were included. Meta-analysis was conducted combining and analysing the relative risk (RR) and computing a summary RR of the effects with 95% confidence interval (CI). The standardized mean difference was calculated for continuous outcomes. The I2 test was calculated to assess heterogeneity across studies. Results: One RCT and five observational studies were included in the analysis. Compared with InI, CoI of vancomycin was associated with a significantly lower risk of nephrotoxicity (RR 0.6, 95% CI 0.4-0.9, P=0.02;I2=0). Overall mortality was not different between the two groups (RR 1.03, 95% CI 0.7-1.6, P=0.9; I2=0). Conclusions: Our meta-analysis suggests that administration of vancomycin for the treatment ofGram-positiveinfections by CoI is associated with a significantly lower risk of nephrotoxicity when compared with InI of the drug.RCTs are needed to define the impact on mortality rate and on the pharmacodynamic activity in terms of AUC/MIC ratio. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Mussini C.,University of Modena and Reggio Emilia | Lorenzini P.,National Institute for Infectious Diseases | Cozzi-Lepri A.,University College London | Lapadula G.,University of Milan Bicocca | And 7 more authors.
The Lancet HIV | Year: 2015

Background: In patients with HIV, immune reconstitution after antiretroviral therapy (ART) is often incomplete. We assessed the probability of patients reaching a CD4/CD8 ratio of 1 or more after the start of ART and its association with the onset of non-AIDS-defining events and death. Methods: We did an analysis of the ICONA cohort, which recruited treatment-naive patients with HIV in Italy. We included participants in the cohort who started ART, reached an undetectable viral load (≤80 copies per mL), and had a CD4/CD8 ratio of less than 0·8 at the time of an undetectable viral load. We defined ratio normalisation in patients as two consecutive values of 1 or more. We used Kaplan-Meier curves to estimate the cumulative probability of ratio normalisation. We then used Poisson regression models to identify factors independently associated with normalisation and with progression to non-AIDS-defining events or death. Findings: We included 3236 participants, enrolled between Jan 22, 1997, and Feb 25, 2013. At the start of ART, median CD4/CD8 ratio in our population was 0·39 (IQR 0·26-0·55). 458 (14%) patients reached a CD4/CD8 ratio of 1 or more; the estimated probability of normalisation was 4·4% (95% CI 3·7-5·2) by 1 year from baseline, 11·5% (10·2-13·0) by 2 years, and 29·4% (26·7-32·4) by 5 years. Factors associated with normalisation were high pre-ART CD4 cell counts, a high CD4/CD8 ratio at baseline, and negative cytomegalovirus serological findings. The incidence rate of non-AIDS-defining events for patients with a CD4/CD8 ratio of less than 0·30 (4·2 per 100 patient-years, 95% CI 3·4-5·3) was double that for those with a ratio of 0·30-0·45 (2·3, 2·1-2·5) or more than 0·45 (2·2, 1·7-2·9). A ratio of less than 0·30 was independently associated with an increased risk of non-AIDS-defining events or death compared with one of more than 0·45. Interpretation: Few patients had normalised CD4/CD8 ratios, even though they had viral suppression. Low ratios were associated with increased risk of serious events and deaths. The CD4/CD8 ratio could be used by clinicians to identity patients at risk of non-AIDS-related events. Funding: AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp & Dohme, ViiV Italy. © 2015 Elsevier Ltd.

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