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Gaedigk A.,Toxicology and Therapeutic Innovation | Gaedigk A.,University of Missouri - Kansas City | Garcia-Ribera C.,Autonomous University of Barcelona | Jeong H.-E.,Inje University | And 2 more authors.
Pharmacogenomics | Year: 2014

A Han Chinese patient failed CYP2D6 genotype analysis with the AmpliChip CYP450 Test™. The CYP2D6 gene locus of the patient and her son were extensively genotyped including copy number variation and gene resequencing. Two SNPs were discovered on the patient's CYP2D61 allele, -498C>A and 1661G>C, while the son's CYP2D61 allele had -498C>A only. AmpliChip failure was attributed to the presence of a CYP2D61 allele carrying the 1661G>C SNP. Functional analyses of -498C>A did not reveal altered activity in vitro or in vivo suggesting that both novel CYP2D61 subvariants are functional. The implementation of pharmacogenetics-guided drug therapy relies on accurate clinical-grade genotype analysis. Although the AmpliChip is a reliable platform, numerous allelic (sub)variants and gene arrangements are not detected or may trigger no calls. While such cases may be rare, the clinical/genetic testing community must be aware of the challenges of CYP2D6 testing on the AmpliChip platform and implications regarding accuracy of test results. © 2014 Future Medicine Ltd. Source


Aragones G.,Rovira i Virgili University | Guardiola M.,Rovira i Virgili University | Barreda M.,Rovira i Virgili University | Marsillach J.,University of Washington | And 7 more authors.
Journal of Lipid Research | Year: 2011

Experimental studies showed that paraoxonase-3 (PON3) retards lipoprotein oxidation. Our objective was to describe a new assay to measure serum PON3 concentrations and report their reference values in a population-based study. The infl uence of PON3 promoter polymorphisms and their relationships with PON1 and lipid profi le were also studied. We generated an anti-PON3 antibody by inoculating rabbits with a synthetic peptide specific to mature PON3. This antibody was used to develop an ELISA. The average regression line of standard plots (n = 8) was y = 0.9587 (0.3392) log 10 x + 1.9466 (0.0861) [ r 2 = 0.924 (0.0131); P < 0.001]. There was no cross reaction with PON1. Detection limit was 0.24 mg/l. Imprecision was ≤ 13.2%. Reference interval (n = 356) was 1.00-2.47 mg/l. PON3 was observed in HDL particles containing apolipoprotein (apo)A-I and PON1, but not apoA-II or apoE. Serum PON3 concentrations showed a moderate infl uence (about 10% variation) by PON3 promoter polymorphisms. Our study describes for the fi rst time a method to measure serum PON3 concentrations. This method offers new opportunities in the investigation of the properties and role of PON3 in cardiovascular disease, with possible implications in clinical practice. Copyright © 2011 by the American Society for Biochemistry and Molecular Biology, Inc. Source


Deza G.,Hospital del Mar Parc de Salut Mar | Martin-Ezquerra G.,Hospital del Mar Parc de Salut Mar | Gomez J.,Laboratori Of Referencia Of Catalonia | Villar-Garcia J.,Hospital del Mar Parc de Salut Mar | And 2 more authors.
Sexually Transmitted Infections | Year: 2016

Objectives To describe the clinical characteristics and therapeutic outcomes from male patients diagnosed of Haemophilus spp urethritis. Methods A chart review of patients who presented to our hospital from January 2013 to December 2014 with symptoms of acute urethritis in which Haemophilus spp was isolated in their urethral samples was performed. Results Haemophilus spp was isolated in 52 out of 413 urethral samples (12.6%) received in our laboratory from patients with symptoms of acute urethritis during the study period. Seven cases corresponded to Haemophilus influenzae and 45 cases to Haemophilus parainfluenzae. The most common clinical presentation was mucopurulent urethral discharge (71%). Eight per cent were HIV-infected patients, and 60% were men who have sex with men. Haemophilus spp was isolated as a single pathogen in 6.8% (28 of 413) of cases. Seventeen per cent of Haemophilus spp were ?-lactamase producers. All patients reported having practiced unprotected insertive oral sex the month before consultation, and five of them denied having had another sexual contact apart from this exposure. In all cases in which follow-up was available, empirical treatment achieved a complete clinical resolution. Conclusions Haemophilus spp was considered a pathogen in at least 6.8% of the patients from the evaluated area. It affected men regardless their sexual orientation or HIV status. Unprotected oral sex could play a role in its transmission. The limitations of the study (small sample size and lack of a representative control group) do not allow to prove the true pathogenic role of Haemophilus spp in acute urethritis. Source


Sorli L.,Infectious Diseases Service | Luque S.,Pharmacy Service | Grau S.,Pharmacy Service | Berenguer N.,Pharmacy Service | And 7 more authors.
BMC Infectious Diseases | Year: 2013

Background: Data regarding the most efficacious and least toxic schedules for the use of colistin are scarce. The aim of this study was to determine the incidence and the potential risk factors of colistin-associated nephrotoxicity including colistin plasma levels.Methods: A prospective observational cohort study was conducted for over one year in patients receiving intravenous colistin methanesulfonate sodium (CMS). Blood samples for colistin plasma levels were collected immediately before (Cmin) and 30 minutes after CMS infusion (Cmax). Renal function was assessed at baseline, on day 7 and at the end of treatment (EOT). Severity of acute kidney injury (AKI) was defined by the RIFLE (risk, injury, failure, loss, and end-stage kidney disease) criteria.Results: One hundred and two patients met the inclusion criteria. AKI related to CMS treatment on day 7 and at the end of treatment (EOT) was observed in 26 (25.5%) and 50 (49.0%) patients, respectively. At day 7, Cmin (OR, 4.63 [2.33-9.20]; P < 0.001) was the only independent predictor of AKI. At EOT, the Charlson score (OR 1.26 [1.01-1.57]; P = 0.036), Cmin (OR 2.14 [1.33-3.42]; P = 0.002), and concomitant treatment with ≥ 2 nephrotoxic drugs (OR 2.61 [1.0-6.8]; P = 0.049) were independent risk factors for AKI. When Cmin was evaluated as a categorical variable, the breakpoints that better predicted AKI were 3.33 mg/L (P < 0.001) on day 7 and 2.42 mg/L (P < 0.001) at EOT.Conclusions: When using the RIFLE criteria, colistin-related nephrotoxicity is observed in a high percentage of patients. Cmin levels are predictive of AKI. Patients who receive intravenous colistin should be closely monitored and Cmin might be a new useful tool to predict AKI. © 2013 Sorlí et al.; licensee BioMed Central Ltd. Source


Hernandez J.,Laboratori Of Referencia Of Catalonia | Garca-Solaesa V.,University of Salamanca | Snchez S.,University of Salamanca | Isidoro-Garca M.,University of Salamanca
Pharmacogenomics | Year: 2011

Background: CYP2D6 is a major drug-metabolizing enzyme. Polymorphic variation includes copy number variants such as gene deletions, duplications and multiplications of functional and nonfunctional gene units. In this article we describe the first systematic characterization of a CYP2D6*9x2 gene duplication. CYP2D6*9 is an allelic variant conferring reduced enzymatic activity. This novel gene duplication was discovered in two unrelated Spanish psychiatric patients. Both subjects were initially tested with the AmpliChip CYP450 test, which indicated the presence of a duplication and the CYP2D6*9 allele, but did not make a genotype call. The goal of the study was to resolve this issue by characterizing the CYP2D6 gene locus in these patients. Materials & methods: Both individuals and one offspring were regenotyped using our own CYP2D6 genotyping strategy employing long-range PCR and TaqMan-based SNP detection. In addition, gene resequencing and genotyping of duplication-specific long-range PCR products and quantitative gene copy number analysis was applied. Results: The duplication was mapped to the CYP2D6*9 allele and copy number analysis determined a CYP2D6*9x2 gene duplication in all three individuals. Because CYP2D6*9x2 is not recognized by the AmpliChip CYP450 test, this structural arrangement was responsible for the 'no call on the AmpliChip CYP450 test report. Conclusion: The full characterization of this allele will aid in the interpretation of AmpliChip CYP450 test results for clinical and research applications. Original submitted 8 June 2011; Revision submitted 18 July 201. © 2011 Future Medicine Ltd. Source

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