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Mendez-Hernandez C.,Complutense University of Madrid | Mendez-Hernandez C.,Institute of Salud Carlos III | Rodriguez-Una I.,Complutense University of Madrid | Gonzalez-de-la Rosa M.,University of La Laguna | And 3 more authors.
Acta Ophthalmologica | Year: 2016

Purpose: The computer program laguna onhe determines optic nerve head haemoglobin (ONH Hb) on retinal photographs based on detecting colour differences. This study compares the diagnostic capacity of Laguna ONhE with that of spectral domain optical coherence tomography (OCT) and confocal tomography (HRT III). Methods: In a prospective, observational, cross-sectional study, glaucomatous (n = 66) and healthy (n = 52) eyes were examined by Spectralis OCT, HRT III and Laguna ONhE. The following Laguna ONhE variables were determined: ONH Hb across the vertical disc diameter (8&20 Hb), estimated cup–disc ratio (C/D) and the glaucoma discriminant function (GDF), which combines the slope of Hb amount with the mean in 8&20 Hb. The three diagnostic methods were compared by calculating areas under ROC curves (AUCs). Correlations between variables were assessed through Spearman's rho coefficient. Results: Areas under ROC curves (AUCs) were 0.785 (95% CI: 0.700–0.863) for GDF, 0.807 (95% CI: 0.730–0.883) for OCT retinal nerve fibre layer thickness (OCT-RNFL) and 0.714 (95% CI: 0.618–0.810) and 0.721 (95% CI: 0.628–0.815) for the HRT III variable GPS (glaucoma probability score) and vertical C/D ratio, respectively. Glaucoma discriminant function (GDF) was correlated with OCT-RNFL (0.587, p 0.001; 0.507, p 0.045; and −0.119, p 0.713 for mild, moderate and advanced glaucoma, respectively), mostly so with inferior OCT-RNFL (0.622; p < 0.001). Glaucoma discriminant function (GDF)-HRT III correlations were lower (rim area 0.471, p < 0.0001; rim/disc area 0.426, p < 0.0001; vertical C/D −0.413, p < 0.0001; GPS −0.408, p < 0.0001; rim volume 0.341, p < 0.0001). Conclusion: Similar diagnostic power was observed for Laguna ONhE, Spectralis OCT and HRT III. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd


Infantes S.,Institute Of Salud Carlos Iii | Infantes S.,Institute Salud Carlos III | Lorente E.,Institute Of Salud Carlos Iii | Lorente E.,Institute Salud Carlos III | And 9 more authors.
Molecular and Cellular Proteomics | Year: 2010

Cytotoxic T lymphocyte (CTL)-mediated death of virus-infected cells requires prior recognition of short viral peptide antigens that are presented by human leukocyte antigen (HLA) class I molecules on the surface of infected cells. The CTL response is critical for the clearance of human respiratory syncytial virus (HRSV) infection. Using mass spectrometry analysis of complex HLA-bound peptide pools isolated from large amounts of HRSV-infected cells, we identified nine naturally processed HLA-B27 ligands. The isolated peptides are derived from six internal, not envelope, proteins of the infective virus. The sequences of most of these ligands are not conserved between different HRSV strains, suggesting a mechanism to explain recurrent infection with virus of different HRSV antigenic subgroups. In addition, these nine ligands represent a significant fraction of the proteome of this virus, which is monitored by the same HLA class I allele. These data have implications for vaccine development as well as for analysis of the CTL response. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Quijada-Fraile P.,Hospital 12 Of Octubre | O'Callaghan M.,Hospital Sant Joan Of Deu | Martin-Hernandez E.,Hospital 12 Of Octubre | Montero R.,Institute Of Salud Carlos Iii | And 16 more authors.
Orphanet journal of rare diseases | Year: 2014

BACKGROUND: Kearns-Sayre syndrome (KSS) is a mitochondrial DNA deletion syndrome that presents with profound cerebral folate deficiency and other features. Preliminary data support the notion that folinic acid therapy might be useful in the treatment of KSS patients. Our aim was to assess the clinical and neuroimaging outcomes of KSS patients receiving folinic acid therapy.PATIENTS: We recruited eight patients with diagnoses of KSS. Four cases were treated at 12 de Octubre Hospital, and the other two cases were treated at Sant Joan de Déu Hospital. Two patients refused to participate in the treatment protocol.METHODS: Clinical, biochemical and neuroimaging data (magnetic resonance imaging or computed tomography scan) were collected in baseline conditions and at different time points after the initiation of therapy. Cerebrospinal fluid 5-methyltetrahydrofolate levels were analysed with HPLC and fluorescence detection. Large-scale mitochondrial DNA deletions were analysed by Southern blot.TREATMENT PROTOCOL: The follow-up periods ranged from one to eight years. Cases 1-4 received oral folinic acid at a dose of 1 mg/kg/day, and cases 6 and 8 received 3 mg/kg/day.RESULTS: No adverse effects of folinic acid treatment were observed. Cerebral 5-methyltetrahydrofolate deficiencies were observed in all cases in the baseline conditions. Moreover, all three patients who accepted lumbar puncture after folinic acid therapy exhibited complete recoveries of their decreased basal cerebrospinal fluid 5-methyltetrahydrofolate levels to normal values. Two cases neurologically improved after folinic therapy. Disease worsened in the other patients. Post-treatment neuroimaging was performed for the 6 cases that received folinic acid therapy. One patient exhibited improvements in white matter abnormalities. The remaining patients displayed progressions in subcortical cerebral white matter, the cerebellum and cerebral atrophy.CONCLUSIONS: Four patients exhibited clinical and radiological progression of the disease following folinic acid treatment. Only one patient who was treated in an early stage of the disease exhibited both neurological and radiological improvements following elevated doses of folinic acid, and an additional patient experienced neurological improvement. Early treatment with high-dose folinic acid therapy seems to be advisable for the treatment of KSS.TRIAL REGISTRATION: Eudrac T2007-00-6748-23.


De Diego Damia A.,Hospital Universitari i Politecnic La Fe | Cortijo Gimeno J.,Consorcio Hospital General Universitario | Cortijo Gimeno J.,Institute Of Salud Carlos Iii | Cortijo Gimeno J.,University of Valencia | And 6 more authors.
Archivos de Bronconeumologia | Year: 2011

Introduction: Cigarette smoke is the main cause of inflammation in COPD. The mechanisms that differentiate smokers who develop COPD are diverse. In this study, we analyzed the presence of cytokines in the respiratory secretions of smokers with or without COPD and the secretory properties of the differentiated bronchial epithelium obtained from the individuals themselves after exposure to tobacco smoke. Material and methods: Twenty-seven smokers were studied, 12 of whom had COPD that had not been previously treated with steroids. In 11, samples were obtained by means of induced sputum, and the remaining samples were collected from bronchial aspiration after bronchoscopy. Concentrations of IL-8, IL-13 and TNFα in the supernatant were determined. The results obtained were compared between individuals with and without COPD, and we studied their relationship with the severity of COPD as expressed by the degree of obstruction, dyspnea, presence of hypersecretion and intensity of smoking. Bronchial epithelial cell cultures were obtained by air-liquid interface in 4 smokers. The samples were exposed to increasing concentrations of cigarette smoke (5-20%) and the epithelial mRNA expressions of MUC5AC, IL8 and TNFα were determined. Results: COPD patients had significantly higher values of IL-8 than healthy smokers (41 [22] vs. 21 [12] pM). The values of IL-8 correlated significantly with the severity of the obstruction (r = 0.6; p < 0.05), dyspnea (r = 0.45; p < 0.05) and the presence of hypersecretion. There was no relationship between cytokines and the intensity or duration of the tobacco habit. Cigarette smoke produced a dose-dependent increase in the expression of RNAm for Muc5AC, IL8 and TNFα. Conclusions: There are differences in cytokine production (fundamentally IL8) between smokers and smokers with COPD which could be explained by the direct action of cigarette smoke on epithelial cells. © 2011 SEPAR.


Fernandez A.,Sant Joan de Deu SSM | Saameno J.A.B.,Institute Of Salud Carlos Iii | Saameno J.A.B.,University of Malaga | Pinto-Meza A.,Sant Joan de Deu SSM | And 8 more authors.
British Journal of Psychiatry | Year: 2010

The World Health organization (WHO) has stated that the three leading causes of burden of disease In 2030 are projected to include HIV/AIDS, unipolar depression and schaemic heart disease. Aims To estimate health-related quality of life (HRQoL) and qualityadjusted life-year (QALY) losses associated with mental disorders and chronic physical conditions in primary healthcare using data from the diagnosis and treatment of mental disorders In primary care (DASMAP) study, an epidemiological survey carried out with primary care patients in Catalonia (Spain). Method A cross-sectional survey of a representative sample of 3815 primary care patients. A preference-based measure of health was derived from the 12-ltem Short Form Health Survey (SF-12): the Short Form-6D (SF-6D) multi-attribute healthstatus classification. Each profile generated by this questionnaire has a utility (or weight) assigned, we used non-parametric quantile regressions to model the association between both mental disorders and chronic physical condition and SF-6D scores. Results Conditions associated with SF-6D were: mood disorders, ß=-0.20 (95% Cl -0.18 to -0.21); pain, ß=-0.08 (95%Cl -0.06 to -0.09) and anxiety, ß=-0.04 (95% Cl -0.03 to -0.06). The top three causes of QALY losses annually per 100000 participants were pain (5064), mood disorders (2634) and anxiety (805). Conclusions Estimation of QALY losses showed that mood disorders ranked second behind pain-related chronic medical conditions.


Perrinjaquet M.,Karolinska Institutet | Vilar M.,Karolinska Institutet | Vilar M.,Institute Of Salud Carlos Iii | Ibanez C.F.,Karolinska Institutet
Journal of Biological Chemistry | Year: 2010

The signaling mechanisms by which neurotrophic receptors regulate neuronal survival and axonal growth are still incompletely understood. In the receptor tyrosine kinase RET, a receptor for GDNF (glial cell line-derived neurotrophic factor), the functions of the majority of tyrosine residues that become phosphorylated are still unknown. Here we have identified the protein-tyrosine phosphatase SHP2 as a novel direct interactor of RET and the first effector known to bind to phosphorylated Tyr687 in the juxtamembrane region of the receptor. We show that SHP2 is recruited to RET upon ligand binding in a cooperative fashion, such that both interaction with Tyr687 and association with components of the Tyr1062 signaling complex are required for stable recruitment of SHP2 to the receptor. SHP2 recruitment contributes to the ability of RET to activate the PI3K/AKT pathway and promote survival and neurite outgrowth in primary neurons. Furthermore, we find that activation of protein kinase A (PKA) by forskolin reduces the recruitment of SHP2 to RET and negatively affects ligand-mediated neurite outgrowth. In agreement with this, mutation of Ser696, a known PKA phosphorylation site in RET, enhances SHP2 binding to the receptor and eliminates the effect of forskolin on ligand-induced outgrowth. Together, these findings establish SHP2 as a novel positive regulator of the neurotrophic activities of RET and reveal Tyr687 as a critical platform for integration of RET and PKA signals. We anticipate that several other phosphotyrosines of unknown function in neuronal receptor tyrosine kinases will also support similar regulatory functions. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Turrientes M.-C.,Ramon y Cajal Hospital | de Ayala A.P.,Ramon y Cajal Hospital | Norman F.,Ramon y Cajal Hospital | Navarro M.,Ramon y Cajal Hospital | And 4 more authors.
Emerging Infectious Diseases | Year: 2011

To determine whether increased migration is associated with an increase in incidence of toxocariasis (visceral larva migrans), we analyzed clinical data obtained from immigrants from Latin America. Although infection with Toxocara sp. roundworm larvae is distributed worldwide, seroprevalence is highest in tropical and subtropical areas.


Weber H.,Goethe University Frankfurt | Weber H.,University of Würzburg | Kittel-Schneider S.,Goethe University Frankfurt | Heupel J.,University of Würzburg | And 24 more authors.
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics | Year: 2015

Attention deficit/ hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder featuring complex genetics with common and rare variants contributing to disease risk. In a high proportion of cases, ADHD does not remit during adolescence but persists into adulthood. Several studies suggest that NOS1, encoding nitric oxide synthase I, producing the gaseous neurotransmitter NO, is a candidate gene for (adult) ADHD. We here extended our analysis by increasing the original sample, adding two further samples from Norway and Spain, and conducted subgroup and co-morbidity analysis. Our previous finding held true in the extended sample, and also meta-analysis demonstrated an association of NOS1 ex1f-VNTR short alleles with adult ADHD (aADHD). Association was restricted to females, as was the case in the discovery sample. Subgroup analysis on the single allele level suggested that the 21-repeat allele caused the association. Regarding subgroups, we found that NOS1 was associated with the hyperactive/impulsive ADHD subtype, but not to pure inattention. In terms of comorbidity, major depression, anxiety disorders, cluster C personality disorders and migraine were associated with short repeats, in particular the 21-repeat allele. Also, short allele carriers had significantly lower IQ. Finally, we again demonstrated an influence of the repeat on gene expression in human post-mortem brain samples. These data validate the role of NOS-I in hyperactive/impulsive phenotypes and call for further studies into the neurobiological underpinnings of this association. © 2015 Wiley Periodicals, Inc.


Olivares I.,Institute Of Salud Carlos Iii | Pernas M.,Institute Of Salud Carlos Iii | Casado C.,Institute Of Salud Carlos Iii | Lopez-Gabndez C.,Institute Of Salud Carlos Iii
AIDS Reviews | Year: 2016

HIV-1 infections are characterized by the integration of the reverse transcribed genomic RNA into the host chromosomes making up the provirus. In addition to the integrated proviral DNA there are other forms of linear and ciicular unintegrated viral DNA in HIV-1-infected cells. One of these forms, known as two-long terminal repeat circles, has been extensively studied and characterized both in in vitro infected cells and in cells from patients. Detection of two-long temiinal repeat circles has been proposed as a marker of antiretroviral treatment efficacy or ongoing replication in patients with undetectable viral load. But not all authors agree with this use because of the uncertainty about the lifespan of the two-long temiinal repeat circles. We review the major studies estimating the half-life of the two-long temiinal repeat circles as well as those proposing its defection as a marker of ongoing replication or therapeutic efficacy. We also review the characteristic of these circular forms and the difficulties in its detection and quantification. The variety of approaches and methods used in the two-long temiinal repeat quantification as well as the low reliability of some methods make the comparison between results difficult. We conclude that it is not possible to draw a clear supposition about the lifespan of two-long terminal repeat circles and consequently they should not be used as a marker of ongoing replication without a careful analysis of the methods and results.


PubMed | University of Barcelona, University of Würzburg, University of Bergen, Goethe University Frankfurt and 3 more.
Type: | Journal: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics | Year: 2015

Attention deficit/ hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder featuring complex genetics with common and rare variants contributing to disease risk. In a high proportion of cases, ADHD does not remit during adolescence but persists into adulthood. Several studies suggest that NOS1, encoding nitric oxide synthase I, producing the gaseous neurotransmitter NO, is a candidate gene for (adult) ADHD. We here extended our analysis by increasing the original sample, adding two further samples from Norway and Spain, and conducted subgroup and co-morbidity analysis. Our previous finding held true in the extended sample, and also meta-analysis demonstrated an association of NOS1 ex1f-VNTR short alleles with adult ADHD (aADHD). Association was restricted to females, as was the case in the discovery sample. Subgroup analysis on the single allele level suggested that the 21-repeat allele caused the association. Regarding subgroups, we found that NOS1 was associated with the hyperactive/impulsive ADHD subtype, but not to pure inattention. In terms of comorbidity, major depression, anxiety disorders, cluster C personality disorders and migraine were associated with short repeats, in particular the 21-repeat allele. Also, short allele carriers had significantly lower IQ. Finally, we again demonstrated an influence of the repeat on gene expression in human post-mortem brain samples. These data validate the role of NOS-I in hyperactive/impulsive phenotypes and call for further studies into the neurobiological underpinnings of this association. 2015 Wiley Periodicals, Inc.

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