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Sabol J.K.,University of California at Davis | Wei W.,University of California at Davis | Lopez-Hoyos M.,Hospital Universitario Marques Of Valdecilla Idival | Seo Y.,University of California at Davis | And 2 more authors.
Matrix Biology | Year: 2014

Heparan sulfate (HS) is a complex and highly variable polysaccharide, expressed ubiquitously on the cell surface as HS proteoglycans (HSPGs), and found in the extracellular matrix as free HS fragments. Its heterogeneity due to various acetylation and sulfation patterns endows a multitude of functions. In animal tissues, HS interacts with a wide range of proteins to mediate numerous biological activities; given its multiple roles in inflammation processes, characterization of HS in human serum has significant potential for elucidating disease mechanisms. Historically, investigation of HS was limited by its low concentration in human serum, together with the complexity of the serum matrix. In this study, we used a modified mass spectrometry method to examine HS disaccharide profiles in the serum of 50 women with rheumatoid arthritis (RA), and compared our results to 51 sera from healthy women. Using various purification methods and online LC-MS/MS, we discovered statistically significant differences in the sulfation and acetylation patterns between populations. Since early diagnosis of RA is considered important in decelerating the disease's progression, identification of specific biomolecule characterizations may provide crucial information towards developing new therapies for suppressing the disease in its early stages. This is the first report of potential glycosaminoglycan biomarkers for RA found in human sera, while acknowledging the obvious fact that a larger population set, and more stringent collection parameters, will need to be investigated in the future. © 2014 .

PubMed | Biomedical Research Institute Sant Pau, Hospitales Universitarios Virgen Macarena y Virgen del Rocio, Autonomous University of Barcelona, Hospital Universitario La Paz and 7 more.
Type: Journal Article | Journal: The Journal of infection | Year: 2016

Most available information on carbapenemase-producing Enterobacteriaceae (CPE) is usually associated with specific types of infection or patient or with descriptions of outbreaks. The aim of this study was to comprehensively analyse the clinical epidemiology, clinical features and outcomes of colonisation and infections due to CPE in Spain.A multicentre prospective cohort study was carried out in 34 Spanish hospitals from February to May 2013. All new patients testing positive for CPE in clinical samples were included. Logistic regression was used to identify predictors of mortality.Overall, 245 cases were included. The most frequent organism was Klebsiella pneumoniae (74%) and the carbapenemases belonged to the OXA-48 (74%), metallo--lactamase (MBL) (24%) and KPC (2%) groups. Acquisition was nosocomial in 145 cases (60%) and healthcare-associated (HCA) in 91 (37%); 42% of the latter were nursing home residents, in whom OXA-48-producing K. pneumoniae ST405 predominated. MBLs and OXA-48 predominated in ICU and medical patients, respectively. Overall, 67% of patients had infections. The most frequent infections identified in this study were urinary tract (43%) and skin structure (21%) infections, and 10% of infections were bacteraemic. Crude mortality was 20%. Inappropriate antibiotic therapy was independently associated with an increased risk of death (OR=3.30; 95% CI: 1.34-8.11).We found some differences in the epidemiology of CPE depending on the type of carbapenemase produced. Although a low proportion of CPE infections were bacteraemic, active antibiotic therapy was a protective factor for reducing mortality.

PubMed | University Hospital of Tuebingen, Hospital Universitario La Paz, Universitatsklinikum Cologne, Hospitales Universitarios Virgen Macarena y Virgen del Rocio and 28 more.
Type: Journal Article | Journal: Antimicrobial agents and chemotherapy | Year: 2016

The spread of extended-spectrum--lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) is leading to increased carbapenem consumption. Alternatives to carbapenems need to be investigated. We investigated whether -lactam/-lactamase inhibitor (BLBLI) combinations are as effective as carbapenems in the treatment of bloodstream infections (BSI) due to ESBL-E. A multinational, retrospective cohort study was performed. Patients with monomicrobial BSI due to ESBL-E were studied; specific criteria were applied for inclusion of patients in the empirical-therapy (ET) cohort (ETC; 365 patients), targeted-therapy (TT) cohort (TTC; 601 patients), and global cohort (GC; 627 patients). The main outcome variables were cure/improvement rate at day 14 and all-cause 30-day mortality. Multivariate analysis, propensity scores (PS), and sensitivity analyses were used to control for confounding. The cure/improvement rates with BLBLIs and carbapenems were 80.0% and 78.9% in the ETC and 90.2% and 85.5% in the TTC, respectively. The 30-day mortality rates were 17.6% and 20% in the ETC and 9.8% and 13.9% in the TTC, respectively. The adjusted odds ratio (OR) (95% confidence interval [CI]) values for cure/improvement rate with ET with BLBLIs were 1.37 (0.69 to 2.76); for TT, they were 1.61 (0.58 to 4.86). Regarding 30-day mortality, the adjusted OR (95% CI) values were 0.55 (0.25 to 1.18) for ET and 0.59 (0.19 to 1.71) for TT. The results were consistent in all subgroups studied, in a stratified analysis according to quartiles of PS, in PS-matched cases, and in the GC. BLBLIs, if active in vitro, appear to be as effective as carbapenems for ET and TT of BSI due to ESLB-E regardless of the source and specific species. These data may help to avoid the overuse of carbapenems. (This study has been registered at ClinicalTrials.gov under registration no. NCT01764490.).

PubMed | University of Barcelona, Hospital Universitario Ramon jal And Instituto Ramon jal Of Investigacion Sanitaria Irycis, Hospital Universitario Marques Of Valdecilla Idival, University of Cantabria and 2 more.
Type: Comparative Study | Journal: Diagnostic microbiology and infectious disease | Year: 2016

Amoxicillin-clavulanate MICs of 160 Escherichia coli isolates with characterized resistance mechanisms were obtained by 2 MIC gradient strip brands, 3 automated systems, and reference ISO microdilution method using EUCAST (fixed 2g/mL clavulanate) and CLSI (2:1 ratio) criteria. Discrepancies, mainly obtained with gradient strips, lead to an essential agreement range of 76.2-92.5.

PubMed | Hospital Universitario Marques Of Valdecilla Idival, Gerencia de Atencion Primaria. Servicio Cantabro de Salud, University of Barcelona, Hospital Universitario 12 Of Octubre and Hospital Clinico Universitario Virgen Arrixaca
Type: | Journal: Transplant immunology | Year: 2016

The aim of this study was to find noninvasive T-cell markers able to predict rejection or infection risk after kidney transplantation. We prospectively examined T-lymphocyte subsets after cell culture stimulation (according to CD38, CD69, CD95, CD40L, and CD25 expression) in 79 first graft recipients from four centers, before and after transplantation. Patients were followed up for one year. Patients who rejected within month-1 (n=10) showed high pre-transplantation and week-1 post-transplantation percentages of CD95(+), in CD4(+) and CD8(+) T-cells (P<0.001 for all comparisons). These biomarkers conferred independent risk for early rejection (HR:5.05, P=0.061 and HR:75.31, P=0.004; respectively). The cut-off values were able to accurately discriminate between rejectors and non-rejectors and Kaplan-Meier curves showed significantly different free-of-rejection time rates (P<0.005). Patients who rejected after the month-1 (n=4) had a higher percentage of post-transplantation CD69(+) in CD8(+) T-cells than non-rejectors (P=0.002). Finally, patients with infection (n=41) previously showed higher percentage of CD38(+) in CD8(+) T-cells at all post-transplantation times evaluated, being this increase more marked in viral infections. A cut-off of 59% CD38(+) in CD8(+) T-cells at week-1, week-2 and month-2 reached 100% sensitivity for the detection of subsequent viral infections. In conclusion, predictive biomarkers of rejection and infection risk after transplantation were detected that could be useful for the personalized care of kidney recipients.

Garcia-Leon G.,CSIC - National Center for Biotechnology | Ruiz de Alegria Puig C.,Hospital Universitario Marques Of Valdecilla Idival | Garcia de la Fuente C.,Hospital Universitario Marques Of Valdecilla Idival | Martinez-Martinez L.,Hospital Universitario Marques Of Valdecilla Idival | And 3 more authors.
Clinical Microbiology and Infection | Year: 2015

Stenotrophomonas maltophilia is the only known bacterium in which quinolone-resistant isolates do not present mutations in the genes encoding bacterial topoisomerases. The expression of the intrinsic quinolone resistance elements smeDEF, smeVWX and Sm. qnr was analysed in 31 clinical S.maltophilia isolates presenting a minimum inhibitory concentration (MIC) range to ciprofloxacin between 0.5 and > 32 μg/mL; 11 (35.5%) overexpressed smeDEF, 2 (6.5%) presenting the highest quinolone MICs overexpressed s. meVWX and 1 (3.2%) overexpressed Sm. qnr. Both strains overexpressing smeVWX presented changes at the Gly266 position of SmeRv, the repressor of smeVWX. Changes at the same position were previously observed in invitro selected S.maltophilia quinolone-resistant mutants, indicating this amino acid is highly relevant for the activity of SmeRv in repressing smeVWX expression. For the first time SmeVWX overexpression is associated with quinolone resistance of S.maltophilia clinical isolates. © 2015 European Society of Clinical Microbiology and Infectious Diseases.

Martinez-Martinez L.,Hospital Universitario Marques Of Valdecilla Idival | Martinez-Martinez L.,University of Cantabria | Gonzalez-Lopez J.J.,Autonomous University of Barcelona
Enfermedades Infecciosas y Microbiologia Clinica | Year: 2014

The most important mechanism of carbapenem resistance in Enterobacteriaceae is the production of carbapenemases, although resistance can also result from the synergistic activity between AmpC-type or (to a lesser extent) extended-spectrum beta-lactamases combined with decreased outer membrane permeability. Three major molecular classes of carbapenemases are recognized: A, B and D. Classes A and D are serine-beta-lactamases, whereas class B are metallo-beta-lactamases (their hydrolytic activity depends on the presence of zinc). In addition to carbapenems, carbapenemases also hydrolyze other beta-lactams, but the concrete substrate profile depends on the enzyme type. In general terms, class A enzymes are to some extent inhibited by clavulanic acid, and class B enzymes do not affect monobactams and are inhibited by zinc chelators. Given Enterobacteriaceae producing carbapenemases usually also contain gene coding for other mechanisms of resistance to beta-lactams, it is not unusual for the organisms to present complex beta-lactam resistance phenotypes. Additionally, these organisms frequently contain other genes that confer resistance to quinolones, aminoglycosides, tetracyclines, sulphonamides and other families of antimicrobial agents, which cause multiresistance or even panresistance. Currently, the most important type of class A carbapenemases are KPC enzymes, whereas VIM, IMP and (particularly) NDM in class B and OXA-48 (and related) in class D are the more relevant enzymes. Whereas some enzymes are encoded by chromosomal genes, most carbapenemases are plasmid-mediated (with genes frequently located in integrons), which favors the dissemination of the enzymes. Detailed information of the genetic platforms and the context of the genes coding for the most relevant enzymes will be presented in this review. © 2014 Elsevier España, S.L. All rights reserved.

PubMed | Hospital Universitario Marques Of Valdecilla Idival and University of Cantabria
Type: Journal Article | Journal: PloS one | Year: 2016

Corynebacterium striatum is an opportunistic pathogen, often multidrug-resistant, which has been associated with serious infections in humans. Aminoglycosides are second-line or complementary antibiotics used for the treatment of Corynebacterium infections. We investigated the susceptibility to six aminoglycosides and the molecular mechanisms involved in aminoglycoside resistance in a collection of 64 Corynebacterium striatum isolated in our laboratory during the period 2005-2009. Antimicrobial susceptibility was determined using E-test. The mechanisms of aminoglycoside resistance were investigated by PCR and sequencing. The 64 C. striatum were assessed for the possibility of clonal spreading by Pulsed-field Gel Electrophoresis (PFGE). Netilmicin and amikacin were active against the 64 C. striatum isolates (MICs90 = 0.38 and 0.5 mg/L, respectively). Twenty-seven of the 64 C. striatum strains showed a MIC90 for kanamycin > 256 mg/L, and 26 out the 27 were positive for the aph(3)-Ic gene. Thirty-six out of our 64 C. striatum were streptomycin resistant, and 23 out of the 36 carried both the aph(3)-Ib and aph(6)-Id genes. The gene aac(3)-XI encoding a new aminoglycoside 3-N acetyl transferase from C. striatum was present in 44 out of the 64 isolates, all of them showing MICs of gentamicin and tobramycin > 1 mg/L. CS4933, a C. striatum showing very low susceptibility to kanamycin and streptomycin, contains an aminoglycoside resistance region that includes the aph(3)-Ic gene, and the tandem of genes aph(3)-Ib and aph(6)-Id. Forty-six major PFGE types were identified among the 64 C. striatum isolates, indicating that they were mainly not clonal. Our results showed that the 64 clinical C. striatum were highly resistant to aminoglycosides and mostly unrelated.

PubMed | Hospital Universitario Marques Of Valdecilla Idival, Valdecilla Tumor Biobank Unit, Fundacion Jimenez Diaz and Laboratorio Of Genomica Del Cancer
Type: Journal Article | Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | Year: 2016

Plasmablastic lymphoma is an uncommon aggressive non-Hodgkin B-cell lymphoma type defined as a high-grade large B-cell neoplasm with plasma cell phenotype. Genetic alterations in MYC have been found in a proportion (~60%) of plasmablastic lymphoma cases and lead to MYC-protein overexpression. Here, we performed a genetic and expression profile of 36 plasmablastic lymphoma cases and demonstrate that MYC overexpression is not restricted to MYC-translocated (46%) or MYC-amplified cases (11%). Furthermore, we demonstrate that recurrent somatic mutations in PRDM1 are found in 50% of plasmablastic lymphoma cases (8 of 16 cases evaluated). These mutations target critical functional domains (PR motif, proline rich domain, acidic region, and DNA-binding Zn-finger domain) involved in the regulation of different targets such as MYC. Furthermore, these mutations are found frequently in association with MYC translocations (5 out of 9, 56% of cases with MYC translocations were PRDM1-mutated), but not restricted to those cases, and lead to expression of an impaired PRDM1/Blimp1 protein. Our data suggest that PRDM1 mutations in plasmablastic lymphoma do not impair terminal B-cell differentiation, but contribute to the oncogenicity of MYC, usually disregulated by MYC translocation or MYC amplification. In conclusion, aberrant coexpression of MYC and PRDM1/Blimp1 owing to genetic changes is responsible for the phenotype of plasmablastic lymphoma cases.

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