Alhama de Granada, Spain
Alhama de Granada, Spain

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Llibre J.M.,Autonomous University of Barcelona | Pulido F.,Institute Investigacion Hospital 12 Of Octubre I12 | Garcia F.,Hospitales Universitarios Of Granada | Garcia Deltoro M.,Consorcio Hospital General Universitario Of Valencia | And 2 more authors.
AIDS reviews | Year: 2015

Dolutegravir is a novel integrase strand-transfer inhibitor that displays potent in vitro activity and a remarkably different resistance profile. Its robust pharmacokinetic/pharmacodynamic properties - long plasma t1/2, high plasma inhibition quotient, and slow dissociation rate from the integrase complex - suggest it should present a high barrier to resistance development. This has been confirmed in pivotal phase III studies of initial therapy, with none out of 1,118 treated individuals selecting resistance-associated mutations at the integrase or reverse transcriptase. In integrase-naive subjects with virological failure, a rescue intervention with dolutegravir has shown significantly higher rates of virological suppression than raltegravir, as well as significantly lower rates of selection of resistance both at the integrase and against the optimized background. Unexpectedly, a mutation rarely selected in this scenario (R263K) induces a fitness cost that prevents HIV-1 from evading drug pressure, and accumulation of further secondary mutations does not occur and has not been able to compensate the replication capacity deficit in the aftermath of the appearance of a single drug resistance mutation. Therefore, both in vitro and in vivo, it leads the virus to a previously unnoticed evolutionary pathway with low chances to develop resistance to both dolutegravir and other families of antiretrovirals present in the background. This high genetic barrier to resistance development in early stages of antiretroviral treatment can help preserve future treatment options in patients who fail antiretroviral therapy.


Llibre J.M.,University Hosp Germans Trias jol | Llibre J.M.,Autonomous University of Barcelona | Pulido F.,Institute Investigacion Hospital | Garcia F.,Hospitales Universitarios Of Granada | And 3 more authors.
AIDS Reviews | Year: 2014

Dolutegravir is a novel integrase strand-transfer inhibitor that displays potent in vitro activity and a remarkably different resistance profile. Its robust pharmacokinetic/pharmacodynamic properties - long plasma t1/2, high plasma inhibition quotient, and slow dissociation rate from the integrase complex - suggest it should present a high barrier to resistance development. This has been confirmed in pivotal phase III studies of initial therapy, with none out of 1,118 treated individuals selecting resistance-associated mutations at the integrase or reverse transcriptase. In integrase-naive subjects with virological failure, a rescue intervention with dolutegravir has shown significantly higher rates of virological suppression than raltegravir, as well as significantly lower rates of selection of resistance both at the integrase and against the optimized background. Unexpectedly, a mutation rarely selected in this scenario (R263K) induces a fitness cost that prevents HIV-1 from evading drug pressure, and accumulation of further secondary mutations does not occur and has not been able to compensate the replication capacity deficit in the aftermath of the appearance of a single drug resistance mutation. Therefore, both in vitro and in vivo, it leads the virus to a previously unnoticed evolutionary pathway with low chances to develop resistance to both dolutegravir and other families of antiretrovirals present in the background. This high genetic barrier to resistance development in early stages of antiretroviral treatment can help preserve future treatment options in patients who fail antiretroviral therapy.


PubMed | Hospitales Universitarios Of Granada
Type: Journal Article | Journal: Bioanalysis | Year: 2016

Human populations are widely exposed to numerous so-called endocrine-disrupting chemicals, exogenous compounds able to interfere with the endocrine system. This exposure has been associated with several health disorders. New analytical procedures are needed for biomonitoring these xenobiotics in human matrices. A quick and inexpensive methodological procedure, based on sample treatment by dispersive liquid-liquid microextraction, is proposed for the determination of bisphenols, parabens and benzophenones in samples.LOQs ranged from 0.4 to 0.7 ng ml(-1) and RSDs from 4.3 to 14.8%.This methodology was satisfactorily applied in the simultaneous determination of a wide range of endocrine-disrupting chemicals in human milk samples and is suitable for application in biomonitoring studies.


PubMed | Hospitales Universitarios Of Granada, Copenhagen University, Gabriel René Moreno Autonomous University and CIBER ISCIII
Type: | Journal: Environmental research | Year: 2016

This study examined the potential association of maternal serum levels of o,p-DDT and p,p-DDE with gestation time and with anthropometric measurements and thyroid-stimulating hormone (TSH) levels of newborns in a Bolivian birth cohort. Two hundred mothers were consecutively recruited between January and March 2013 at the Hospital de la Mujer Dr. Percy Boland in Santa Cruz de la Sierra. Potential confounders were derived from an ad hoc questionnaire. o,p-DDT and p,p-DDE were quantified in cord serum by high-resolution gas chromatography coupled with mass spectrometry. Multivariable linear regression analyses were performed, with POP concentrations as independent variables and log-transformed newborn birth outcomes (newborn weight, gestational age, head circumference, birth height, ponderal index, and TSH levels) as dependent variables. o,p-DDT was detected in 82.5% of samples at median concentration of 0.22ng/mL and p,p-DDE in 86.5% of samples at median concentration of 1.01ng/mL. Opposite associations with birth weight were found for p,p-DDE (=0.012, p=0.006) and o,p-DDT (=-0.014, p=0.039), and these associations were stronger when both chemicals were entered in the same model. p,p-DDE was negatively associated with gestation time (=-0.004, p=0.012), and o,p-DDT was borderline negatively associated with newborn head circumference (=-0.004, p=0.054). We observed no relevant changes in the magnitude of the coefficients or in statistical significance after adjustment for newborn TSH levels. This study indicates a possible impact of prenatal exposure to o,p-DDT and p,p-DDE on newborn anthropometric measurements in a population showing evidence of recent exposure to the pesticide DDT.


Fernandez-Guerrero I.M.,Grupo de Investigacion Urgencias Procesos y patologias | Fernandez-Guerrero I.M.,Hospitales Universitarios Of Granada | Burillo-Putze G.,Hospital Universitario Of Canarias | Martin-Sanchez F.J.,Complutense University of Madrid
Emergencias | Year: 2015

A journal is generally considered to be of higher quality to the extent that it publishes articles that are cited. A journal’s articles are not all cited equally, however; rather, citations of only a select group of titles accounts for most of a journal’s impact factor. This study aimed to identify the characteristics of Emergencias’s most highly cited articles and compare their impact to that of papers by other authors in Spain, in Spanish, and internationally in the field of emergency medicine. Between 2008 and 2015, Emergencias published 975 articles, which received 2207 citations. The most-cited article received 52, and the group of 20 most-cited articles accumulated a total of 519 cites (23.5%). Even though Emergencias is published in Spanish and was included in Journal Citation Reports only recently (2008), some of the published articles have had considerable impact. The most-cited article (EVADUR Study) was in the top 2% (98th percentile) of all publications by authors in Spain, and in the top 1% of articles published in Spanish or in emergency medicine. © 2015, Grupo Saned. All rights reserved.


Villacorta P.J.,University of Granada | Salmeron-Garcia A.,Hospitales Universitarios Of Granada | Pelta D.A.,University of Granada | Cabeza J.,Hospitales Universitarios Of Granada | And 2 more authors.
Analyst | Year: 2015

We evaluated the use of the peptide mass fingerprint (PMF) obtained by matrix assisted laser desorption and ionization (MALDI) time-of-flight mass spectrometry (TOF-MS) to track changes in the structure of a protein. The first problem we had to overcome was the inherent complexity of the PMF, which makes it difficult to compare. We dealt with this problem by developing a cluster-based comparison algorithm which takes into account the proportional error made by the mass spectrometer. This procedure involves grouping together similar masses in an intelligent manner, so that we can determine which data correspond to the same peptide (any slight differences can be explained as experimental errors), and which of them are too different and thus more likely to represent different peptides. The proposed algorithm was applied to track changes in a commercially available monoclonal antibody (mAb), namely rituximab (RTX), prepared under the usual hospital conditions and stored refrigerated (4°C) and frozen (-20°C) for a long term study. PMFs were obtained periodically over three months. For each checked time, five replicates of the PMFs were obtained in order to evaluate the similarities between them by means of the occurrences of the particular peptides (m/z). After applying the algorithm to the PMF, different approaches were used to analyse the results. Surprisingly, all of them suggested that there were no differences between the two storage conditions tested, i.e. the RTX samples were almost equally well preserved when stored refrigerated at 4°C or frozen at -20°C. The cluster-based methodology is new in protein mass spectrometry and could be useful as an easy test for major changes in proteins and biopharmaceutics for diverse applications in industry and other fields, and could provide additional stability data in relation to the practical use of anticancer drugs. This journal is © The Royal Society of Chemistry.


Jimenez-Varo E.,Hospitales Universitarios Of Granada | Jimenez-Varo E.,University of Granada | Canadas-Garre M.,Hospitales Universitarios Of Granada | Gutierrez-Pimentel M.J.,Complejo Hospitalario Of Granada | And 2 more authors.
Pharmacogenetics and Genomics | Year: 2014

Aim: To develop an acenocoumarol (ACN) dosing algorithm for patients with atrial fibrillation or venous thromboembolism, considering the influence on the stable ACN dose of clinical factors and gene polymorphisms, including CYP2C9z.ast2/z.ast3, VKORC1, CYP4F2z.ast3, ABCB1, APOE, CYP2C19z.ast2/z.ast17, and GGCX.Methods and results: A retrospective observational study was carried out to obtain clinical and pharmacogenetic dose algorithms by multiple linear regression of results in a cohort of 134 patients under treatment with a stable ACN dose for atrial fibrillation or venous thromboembolism and to test them in an independent validation cohort of 30 patients. The pharmacogenetic dosing algorithm included CYP2C9, VKORC1, and APOE, which explained 56.6% of the variability in the stable ACN dose. Lower deviation from the stable dose and increased accuracy were shown by the pharmacogenetic algorithm, which correctly classified 67% of patients with a deviation of up to 20%.Conclusion: The variability in the stable ACN dose was better explained by a pharmacogenetic algorithm including clinical and genetic factors (CYP2C9, VKORC1, and APOE) than by a clinical algorithm, providing a more accurate dosage prediction. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


PubMed | Hospitales Universitarios Of Granada, Escuela Andaluza de Salud Publica and University of Granada
Type: Journal Article | Journal: Environmental science & technology | Year: 2016

Despite growing in vitro and in vivo evidence of the putative role of persistent organic pollutants (POPs) in the induction of oxidative damage in cell structures, this issue has been poorly addressed from an epidemiologic perspective. The aim of this study was to explore associations between adipose tissue POP concentrations and the in situ oxidative microenvironment. A cross-sectional study was conducted in a subsample (n = 271) of a previously established cohort, quantifying levels of eight POPs and four groups of oxidative stress biomarkers in adipose tissue. Associations were explored using multivariate linear regression analyses adjusted for potential confounders. We assessed the combined effect of POPs on oxidative stress/glutathione system biomarkers using weighted quantile sum regression (WQS). Increased concentrations of p,p-DDE, HCB, -HCH, dicofol, and PCBs (congeners -138, -153, and -180) were predominantly associated with higher lipid peroxidation (TBARS) [exp() = 1.09-1.78, p < 0.01-0.04)] and SOD activity [exp() = 1.13-1.48, p < 0.01-0.05)] levels. However, only a few associations were observed with glutathione system biomarkers, e.g., PCB-180 with total glutathione [exp() = 1.98, p = 0.03]. The WQS index was found to be positively associated with SOD activity, and PCB-138, PCB-180, and -HCH were the main contributors to the index. Likewise, the WQS index was positively associated with TBARS levels, with the three PCBs acting as the main contributors. This is the first epidemiological evidence of the putative disruption by POPs of the adipose tissue oxidative microenvironment. Our results indicate that POP exposure may enhance alternative pathways to the glutathione detoxification route, which might result in tissue damage. Further research is warranted to fully elucidate the potential health implications.


PubMed | Hospital Universitario San Cecilio, Hospitales Universitarios Of Granada and University of Granada
Type: Journal Article | Journal: Breast care (Basel, Switzerland) | Year: 2015

Metastases of lobular breast cancer are commonly encountered at the level of lungs, bones, brain and liver, whereas lesions in the gastrointestinal tract are rarely seen.A case of a patient with metastases in the right colon and gallbladder originating from an invasive lobular carcinoma is described.Adequate diagnostic procedures should be performed in patients with a history of breast cancer and who show gastrointestinal symptoms to rule out the potential presence of gastrointestinal metastases.


PubMed | Hospitales Universitarios Of Granada and University of Granada
Type: Journal Article | Journal: Journal of pharmaceutical sciences | Year: 2016

Research into the effects that exposure to light can have on therapeutic proteins is essential for ensuring the quality and safety of the medicines in which they are used. It is important to understand the effects of light on aggregation to help avoid undesirable colloidal instabilities, both in the original medicines and in the formats in which they are finally administered. In this study, 5 marketed therapeutic mAbs, namely bevacizumab, cetuximab, infliximab, rituximab, and trastuzumab, were investigated for this purpose. The medicines and 2 diluted preparations in 0.9 NaCl (2 mg/mL and 5 mg/mL)-commonly used in clinical practice-were subjected to controlled light-accelerated degradation. The formation of aggregates was monitored by size-exclusion chromatography. The results indicated that light induced protein aggregation. This process of protein damage was influenced above all by mAb concentration, although the particular characteristics of each mAb were also important. Photodegradation also produced the fragmentation of the mAbs. The damage caused to the mAbs as a result of light-induced aggregation and/or fragmentation was demonstrated both in the medicines and in the diluted preparation forms. These findings should be carefully considered when handling the medicines for administration and when recommending beyond-use dates in normal hospital conditions.

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