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Poveda E.,Charles III University of Madrid | Anta L.,Charles III University of Madrid | Blanco J.L.,Hospital Clinic | Casado J.L.,Hospital Ramon y Cajal | And 6 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2010

The presence of resistance mutations in patients failing tipranavir or darunavir was examined at the national drug resistance database of the Spanish AIDS Research Network. Although mutations emerging during tipranavir and darunavir failures differed considerably, cross-resistance was found in up to half of the patients tested. Interestingly, mutation 54L, which is associated with tipranavir hypersusceptibility, was selected in half of the darunavir failures. Thus, resistance testing seems mandatory to ensure the benefit of the sequential use of these drugs. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Beretta L.,University of Milan | Rueda B.,Institute Parasitologia y Biomedicina Lo pez Neyra | Marchini M.,University of Milan | Santaniello A.,University of Milan | And 12 more authors.
Rheumatology | Year: 2012

Objective: To determine the role of Class II HLAs in SSc patients from Italy and Spain and in SSc patients of Caucasian ancestry. Methods: Nine hundred and forty-four SSc patients (Italy 392 patients; Spain 452 patients) and 1320 ethnically matched healthy controls (Italy 398 patients; Spain 922 patients) were genotyped up to the fourth digit by PCR with sequence-specific oligonucleotides for HLA-DRB1, DQA1 and DQB1 loci. Patients included 390 ACA-positive and 254 anti-topo I-positive subjects. Associations between SSc or SSc-specific antibodies and HLA alleles or HLA haplotypes were sought via the chi-square test after 10 000-fold permutation testing. A meta-analysis including this study cohort and other Caucasoids samples was also conducted. Results: In both the cohorts, the strongest association was observed between the HLA-DRB1*1104 allele and SSc or anti-topo I antibodies. The HLA-DRB1*1104 -DQA1*0501 -DQB1*0301 haplotype was overrepresented in Italian [odds ratio (OR) = 2.069, 95% asymptotic CIs (CI 95) 1.486, 2.881; P < 0.001] and in Spanish patients (OR = 6.707, CI 95 3.974, 11.319; P < 0.001) as well as in anti-topo-positive patients: Italy (OR = 2.642, CI 95 1.78, 3.924; P < 0.001) and Spain (OR = 20.625, CI 95 11.536, 36.876; P < 0.001). In both the populations we also identified an additional risk allele (HLA-DQB1*03) and a protective allele (HLA-DQB1*0501) in anti-topo-positive patients. The meta-analysis showed different statistically significant associations, the most interesting being the differential association between HLA-DRB1*01 alleles and ACAs (OR = 1.724, CI 95 1.482, 2.005; P < 0.001) or topo I antibodies (OR = 0.5, CI 95 0.384, 0.651; P < 0.001). Conclusions: We describe multiple robust associations between SSc and HLA Class II antigens in Caucasoids that may help to understand the genetic architecture of SSc. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.


Carmona F.D.,Institute Parasitologia y Biomedicina Lopez Neyra | Gutala R.,University of Texas Health Science Center at Houston | Simeon C.P.,Hospital Valle de Hebron | Carreira P.,Hospital 12 de Octubre | And 15 more authors.
Annals of the Rheumatic Diseases | Year: 2012

Objective: Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are related chronic autoimmune diseases of complex aetiology in which the interferon (IFN) pathway plays a key role. Recent studies have reported an association between IRF7 and SLE which confers a risk to autoantibody production. A study was undertaken to investigate whether the IRF7 genomic region is also involved in susceptibility to SSc and the main clinical features. Methods: Two case-control sets of Caucasian origin from the USA and Spain, comprising a total of 2316 cases of SSc and 2347 healthy controls, were included in the study. Five single nucleotide polymorphisms (SNPs) in the PHRF1-IRF7-CDHR5 locus were genotyped using TaqMan allelic discrimination technology. A meta-analysis was performed to test the overall effect of these genetic variants on SSc. Results: Four out of five analysed SNPs were significantly associated with the presence of anticentromere autoantibodies (ACA) in the patients with SSc in the combined analysis (rs1131665: p FDR=6.14 × 10 -4, OR=0.78; rs4963128: p FDR=6.14 × 10 -4, OR=0.79; rs702966: p FDR=3.83 × 10 -3, OR=0.82; and rs2246614: p FDR=3.83 × 10 -3, OR=0.83). Significant p values were also obtained when the disease was tested globally; however, the statistical significance was lost when the ACA-positive patients were excluded from the study, suggesting that these associations rely on ACA positivity. Conditional logistic regression and allelic combination analyses suggested that the functional IRF7 SNP rs1131665 is the most likely causal variant. Conclusions: The results show that variation in the IRF7 genomic region is associated with the presence of ACA in patients with SSc, supporting other evidence that this locus represents a common risk factor for autoantibody production in autoimmune diseases.


Gonzalez-Moles M.,University of Granada | Scully C.,Eastman Dental Institute | Ruiz-Avila I.,Hospital Clinico San Cecilio
Oral Diseases | Year: 2012

The development of multiple oral tumours, seen in up to 30% of patients with a primary oral squamous cell carcinoma, is sometimes attributable to the presence of genetically altered premalignant fields and has important prognostic implications. Molecular techniques available for the definitive diagnosis of such a field (loss of heterozygosity analysis of 3p, 9p and 17p and study of TP53 tumour suppressor gene mutation) are expensive, complex and not universally available, hampering their routine application. Nevertheless, molecular diagnosis is essential for modern assessment of the risk of multiple tumours and for decisions on the appropriate preventive and therapeutic approaches. This article reviews current knowledge on molecular findings in premalignant fields in the oral cavity and oropharynx and provides an update on criteria for their identification, discussing the clinical and therapeutic implications. © 2011 John Wiley & Sons A/S.


Poveda E.,Charles III University of Madrid | Anta L.,Charles III University of Madrid | Blanco J.L.,Hospital Clinic | Perez-Elias M.J.,Hospital Ramon y Cajal | And 6 more authors.
AIDS | Year: 2010

The prevalence of etravirine resistance mutations was examined in genotypes derived from 1343 HIV-infected patients failing nevirapine or efavirenz in the resistance database of the Spanish AIDS Research Network (ResRIS). Overall, etravirine-resistant genotypes were recognized in 18.7% of patients, with no significant differences between failures under nevirapine or efavirenz. Thus, more than 80% patients with prior failure to nonnucleoside reverse transcriptase inhibitors could potentially benefit from etravirine rescue therapy. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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