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Biomedical subjects

J Yagüe

Publications and source records attributed to J Yagüe.

At least 19 recordsLinked to original sources
PubMed2005

No association of the Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) to multiple sclerosis.

Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by neurons and immune cells, promotes neuronal survival and repair during development and after CNS injury. The BDNF-Val66Met polymorphism is functional and induces abnormal intracellular trafficking and decreased BDNF release. Therefore, we investigated the impact of the BDNF-Val66Met polymorphism on the susceptibility and clinical course in a case-control study of 224 multiple sclerosis (MS) Spanish patients and 177 healthy controls. We found no evidence for association to susceptibility or severity of the disease in our population. Moreover, we did not observe, in a subgroup of 12 MS patients, that the methionine substitution at position 66 in the prodomain had negative impact in the capacity to produce BDNF by peripheral blood mononuclear cells (PBMC).

Adult↗
PubMed2004

Hypocomplementaemia as an immunological marker of morbidity and mortality in patients with primary Sjogren's syndrome.

OBJECTIVE: To analyse the prevalence and clinical significance of hypocomplementaemia in a large series of patients with primary Sjogren's syndrome (SS), focusing on the association of low complement levels with clinical manifestations, immunological features, lymphoproliferative disorders and mortality. METHODS: Complement determinations (C3 and C4 levels, CH50 activity) were made in 336 consecutive patients with primary SS (313 women and 23 men, mean age 58.5 yr). We also analysed complement levels in 46 patients with SS associated with hepatitis C virus (HCV) infection and 184 with HCV-related cryoglobulinaemia as control groups. RESULTS: Hypocomplementaemia was detected in 81 (24%) of patients with primary SS, low CH50 being detected in 51 (15%), low C3 values in 42 (12%) and low C4 values in 39 (12%). In the multivariate analysis, patients with low C4 levels showed a higher prevalence of peripheral neuropathy, cutaneous vasculitis, RF, cryoglobulins and lymphoma compared with those with normal C4 levels. The analysis of the 218 SS patients followed prospectively since 1994 showed a lower probability of survival in patients with hypocomplementaemia (with low C3, C4 or CH50 levels) at protocol entry. SS-HCV patients presented a higher frequency of hypocomplementaemia than patients with primary SS (76 vs 24%, P<0.001); nine (20%) of these patients had persistent, unquantifiable complement levels. CONCLUSION: Hypocomplementaemia is closely associated with systemic expression and adverse outcomes (lymphoma development and death) in patients with primary SS. Our results support the inclusion of complement determination at diagnosis as a predictor of the outcome of patients with primary SS and its routine determination in the clinical follow-up.

Aged↗
PubMed2004

Clinical and genetic features of human prion diseases in Catalonia: 1993-2002.

We describe the clinical and genetic characteristics of the 85 definite or probable human prion diseases cases died between January 1993 and December 2002 in Catalonia (an autonomous community of Spain, 6 million population). Seventy-three (86%) cases were sporadic Creutzfeld-Jakob diseases (sCJD) (49 definite, 24 probable), with a median age at onset of 66 years. The clinical presentation was dementia in 29 cases, ataxia in 14 and visual symptoms in five. The median survival was 3 months. The 14-3-3 assay was positive in 93% cases, 62% presented periodic sharp wave complexes (PSWC) in EEG but only 18% the typical signs on MRI. Forty-eight sCJD were studied for codon 129 PRNP polymorphism: 69% were methionine/methionine (M/M), 14.5% valine/valine (V/V) and 16.5% M/V. Six out of seven V/V cases did not present PSWC and in two survival was longer than 20 months. Eleven cases (13%) were genetic: five familial fatal insomnia and six familial CJD (fCJD). Up to four (67%) fCJD lacked family history of disease, two presented seizures early at onset and one neurosensorial deafness. The only iatrogenic case was related to a dura mater graft. No case of variant CJD was registered. The study confirms in our population the consistent pattern reported worldwide on human prion diseases. Atypical features were seen more frequently in sporadic 129 V/V CJD and fCJD cases.

14-3-3 Proteins↗
PubMed2004

Hypocomplementemia in systemic lupus erythematosus and primary antiphospholipid syndrome: prevalence and clinical significance in 667 patients.

The objective of the study was to analyse the prevalence and clinical significance of hypocomplementemia in a large series of patients diagnosed either with systemic lupus erythematosus (SLE) or with primary antiphospholipid syndrome (APS) and its association with the main clinical, hematological and immunological features of these diseases. Between 1992 and 2003, complement determinations (C3 and C4 levels, CH50 activity) were performed in 597 consecutive patients diagnosed with SLE (530 women and 67 men, mean age 32.6 years) and 70 with primary APS (57 women and 13 men, mean age 38.7) visited in our department. Complement determinations are routinely made at the first visit of patients and yearly during the follow-up. SLE and primary APS were diagnosed according to current classification criteria. Hypocomplementemia was detected in 371 (62%) of SLE patients. Compared with patients with normal complement values, those with hypocomplementemia showed a higher prevalence of female gender (P < 0.001), fever (P = 0.021), nephropathy (P < 0.001), cutaneous vasculitis (P = 0.023), positive anti-dsDNA antibodies (P = 0.012) and cryoglobulinemia (P < 0.001). In addition, patients with hypocomplementemia showed a higher prevalence of APS-related features such as hemolytic anemia (P = 0.001) and antiphospholipid antibodies (P < 0.001). Hypocomplementemia was prospectively related to accumulated hospitalization in SLE patients but not with the accumulated number of lupus flares or with the survival after follow-up of five years. In contrast, 33 (47%) patients with primary APS presented low complement values, which were associated with a higher prevalence of livedo reticularis (P = 0.022), thrombocytopenia (P = 0.004), lupus anticoagulant (P = 0.013), positive IgM-aCL (P = 0.039), positive ANA (P = 0.002) and anti-dsDNA (P = 0.046). The diagnostic value of hypocomplementemia in patients with SLE is based on the association with disease activity, immune-complex mediated manifestations (glomerulonephritis, cryoglobulinemia) and APS-related features (livedo reticularis, hemolytic anemia and aPL). Hypocomplementemia was found in nearly half of patients with primary APS, and was associated with some APS features (livedo reticularis, thrombocytopenia, aPL) but also with SLE-related immunological markers (ANA and anti-dsDNA), identifying a subset of patients with primary APS with a higher risk of evolving to SLE. These results clearly support the routine determination of complement factors in the clinical follow-up of patients with SLE and primary APS.

Adult↗
PubMed2002

The role of interleukin-10 promoter polymorphisms in the clinical expression of primary Sjögren's syndrome.

OBJECTIVE: To analyse the role of polymorphisms of the interleukin-10 promoter region in the epidemiologic, clinical and immunologic characteristics of patients with primary Sjögren's syndrome (SS). METHODS: Sixty-three consecutive patients (59 women and four men; mean age 57 yr; range 20-83 yr) were studied in our Unit. All patients fulfilled four or more of the modified diagnostic criteria for SS proposed by the European Community Study Group in 1996. As controls, 150 healthy volunteers were recruited from the medical and laboratory staff working in our hospital. All the samples from patients and controls were analysed by PCR amplification and direct sequencing. RESULTS: The frequency of the interleukin-10 (IL-10) GCC haplotype was higher (0.48 vs 0.34, P=0.006) and the frequency of the IL-10 ACC haplotype lower (0.25 vs 0.39, P=0.005) in patients with primary SS compared with healthy controls. In the genotype analysis, the frequency of the GCC/ATA genotype was higher (29 vs 11%, P=0.001) and that of the ACC/ACC genotype lower (3 vs 12%, P=0.044) in patients with primary SS compared with healthy controls. GCC-carriers showed an earlier onset of the disease (48.06+/-14.98 yr vs 57.53+/-14.20 yr, P=0.034). The existence of systemic involvement (defined by cutaneous vasculitis, peripheral neuropathy, renal and/or pulmonary involvement) was more frequent in carriers of the GCC haplotype, although the difference did not reach statistical significance (40 vs 27%, P=0.278). No significant differences in the haematologic (hypergammaglobulinaemia, elevated ESR) and immunologic (ANA, RF, anti-Ro/SS-A and anti-La/SS-B antibodies) parameters were observed in carriers of the GCC haplotype. CONCLUSION: We describe an abnormal distribution of IL-10 promoter haplotypes in patients with primary SS compared with healthy controls. This consists of a predominance of the GCC haplotype, mainly related to a higher frequency of the heterozygote haplotype GCC/ATA. The presence of the GCC haplotype does not originate a different immunologic pattern but leads to an earlier onset of primary SS.

Adult↗
PubMed2001

MRI and CSF oligoclonal bands after autologous hematopoietic stem cell transplantation in MS.

OBJECTIVE: To analyze the MRI and CSF oligoclonal bands (OB) changes in patients with MS who underwent an autologous hematopoietic stem cell transplantation (AHSCT). BACKGROUND: AHSCT is evaluated as an alternative therapy in severe MS. In previous series of AHSCT for MS, data on MRI or OB outcome were limited or not provided. METHODS: Five patients with a median Kurtzke's EDSS score of 6.5, more than two attacks, and confirmed worsening of the EDSS in the previous year received an AHSCT. Hematopoietic stem cells were mobilized with cyclophosphamide (3 g/m2) and granulocyte colony-stimulating factor (5 microg/kg/d). The graft was T cell depleted by positive CD 34+ selection. Conditioning regimen included BCNU (300 mg/m(2)), cyclophosphamide (150 mg/kg in 3 days), and antithymocyte globulin (60 mg/kg in 4 days). MRI scans were scheduled at baseline and 1, 3, 6, and 12 months and OB analysis at baseline and 3 and 12 months post-AHSCT. RESULTS: Four patients had a stable or improved EDSS after a median follow-up of 18 months (range, 12 to 24 months). The fifth patient's condition deteriorated during AHSCT. She partially improved and remained stable after month 3 after AHSCT. The baseline CSF OB persisted 1 year after AHSCT. MRI studies after AHSCT showed no enhanced T1 lesions and no new or enlarging T2 lesions. The median percentage change of T2 lesion load was -11.8% (range, -26.6 to -4.0%). All patients had a decrease of corpus callosum area at 1 year (median, 12.4%; range, 7.8% to 20.5%) that did not progress in the two patients evaluated at 2 years after AHSCT. CONCLUSIONS: Although the persistence of CSF OB suggests the lymphocytes were not eliminated from the CNS, the follow-up MRI studies showed no enhanced T1 brain lesions and a reduction in the T2 lesion load that correlated with the clinical stabilization of MS after AHSCT.

Adult↗
PubMed2001

The impact of the introduction of the 14-3-3 protein assay in the surveillance of sporadic Creutzfeldt-Jakob disease in Catalonia.

The 14-3-3 assay in the CSF has a high predictive value for the diagnosis of sporadic Creutzfeldt-Jakob disease (CJD). Our objective was to analyse the trends in mortality and incidence rates of CJD in Catalonia, an autonomous community of Spain, setting the cut off point the date when the 14-3-3 assay was incorporated to our CJD surveillance system. Only definite and probable cases according to the criteria adapted from Masters and colleagues were included for the analysis. Familial cases were excluded after genetic analysis of the PrP gen. We found a quasi threefold increase in the incidence and mortality rates for CJD after introduction of the 14-3-3 assay in our surveillance system in 1997 as compared with the period 1993-1996. Our findings suggest an improvement of case ascertainment in part due to the introduction of the 14-3-3 assay in the surveillance system.

14-3-3 Proteins↗
PubMed2001

Cryoglobulinemia in systemic lupus erythematosus: prevalence and clinical characteristics in a series of 122 patients.

OBJECTIVES: To determine the prevalence and nature of cryoglobulins in 122 patients with systemic lupus erythematosus (SLE) and identify the clinical and immunologic features related to their presence. METHODS: In a cross-sectional study, we investigated 122 consecutive patients (106 women and 16 men) with SLE who fulfilled the 1982 revised criteria of the American College of Rheumatology for the classification of SLE. All patients had documented medical histories and underwent a medical interview as well as a routine general physical examination by a qualified internist, and their clinical and serologic characteristics were collected on a protocol form. Serum samples were obtained at 37 degrees C, and cryoglobulinemia was estimated by centrifugation at 4 degrees C after incubation for 7 days in all patients. The type of cryoglobulinemia was identified by agarose gel electrophoresis and immunofixation. RESULTS: Cryoglobulins were detected in the sera of 31 SLE patients (25%): 20 patients (65%) had a cryocrit lower than 1%, 8 (26%) had percentages ranging between 1% and 5%, and only 3 patients (9%) had a cryocrit over 5%. Only cutaneous vasculitis (39% v 16%; P = .01) was more prevalent in patients with than in those without cryoglobulins. Rheumatoid factor (RF) (42% v 15%; P = .002) and low CH50 levels (84% v 49%; P <.001) were more prevalent in SLE patients with cryoglobulins. Hepatitis C virus (HCV) infection was investigated in 24 of the 31 cryoglobulinemic SLE patients and was detected in 5 (21%). In comparison, 4 (5%) of the 75 noncryoglobulinemic SLE patients studied were positive (P = 0.035; odds ratio, 4.67). Patients with a cryocrit greater than 1% showed a higher frequency of HCV infection than those with a cryocrit less than or equal to 1% (46% v 0%, P = .01). CONCLUSIONS: Cutaneous vasculitis, RF, hypocomplementemia, and HCV infection were associated with cryoglobulins in SLE patients. Testing for HCV infection is therefore recommended for patients with SLE and cryoglobulinemia to identify this subset of patients for prognostic and therapeutic reasons.

Adolescent↗
PubMed2000

An N-acetylated natural ligand of human histocompatibility leukocyte antigen (HLA)-B39. Classical major histocompatibility complex class I proteins bind peptides with a blocked NH(2) terminus in vivo.

Sequence-independent interactions involving the free peptidic NH(2) terminus are thought to be an essential feature of peptide binding to classical major histocompatibility complex (MHC) class I proteins. Challenging this paradigm, a natural Nalpha-acetylated ligand of human histocompatibility leukocyte antigen (HLA)-B39 was identified in this study. It matched the NH(2)-terminal sequence of two human helicases, was resistant to aminopeptidase M, and was produced with high yield from a synthetic 30 mer with the sequence of the putative parental protein by the 20S proteasome. This is the first reported natural ligand of classical MHC class I antigens that has a blocked NH(2) terminus.

Acetylation↗
PubMed2000

Peptide specificity of the Amerindian B*3905 allotype: molecular insight into selection mechanisms driving HLA class I evolution in indigenous populations of the Americas.

HLA-B*3905 is apparently restricted to Amerindian populations and presents a wide geographical distribution, from Mexico to Argentina. It differs from B*3901, one of the founder HLA class I alleles of Central and South Amerindians, by a single nucleotide substitution leading to an Asp74Tyr change in the gene product. The peptide specificity of the B*3905 protein was characterized by pool sequence analysis of B*3905-bound peptides and by sequencing of a set of individual ligands, using electrospray ion trap mass spectrometry. The results indicate a double effect of the B*3905 mutation. First, pocket B specificity was shifted towards an increased preference for His at peptide position 2, which is the main anchor for B39-bound peptides, relative to B*3901. Second, at peptide position 3 acidic residues were favored, and aromatic residues disfavored, relative to B*3901. These features approach the peptide specificity of B*3905 to B*3801 and B*1509, allotypes absent from Central and South Amerindians. Together with B*3909, B*3905 is the second HLA-B39 subtype whose polymorphism results in a shift of peptide specificity towards that of HLA-B allotypes absent from these populations. This suggests that HLA-B39 evolution in Central and South America may be an antigen-driven adaptive response, leading to generate antigen-presenting properties absent from the HLA class I repertoire of the ancestral population.

Amino Acid Motifs↗
PubMed2000

Interaction between interleukin-6 and the natural anticoagulant system in acute stroke.

Inflammatory reactions mediated by cytokines are involved in the pathogenesis of acute stroke. Decrease in circulating levels of protein C (PC) and protein S (PS) induced by inflammatory cytokines has been postulated as a potential mechanism for a procoagulant tendency during acute stroke. The procoagulant state associated with impairments in natural anticoagulants may induce microvascular obstruction leading to a tissue perfusion reduction that worsens cerebral ischemia. Interleukin-6 (IL-6) regulate the synthesis of C4b-binding protein (C4BP), an acute-phase protein that also regulates PS plasma levels. We measured IL-6, C4BP, erythrocyte sedimentation rate (ESR), total and free PS and PC in 44 patients with acute ischemic stroke to determine if IL-6 decreases circulating levels of natural anticoagulants through the C4BP pathway and if these acute changes in natural anticoagulants may have clinical implications. Patients with higher levels of IL-6 had more severe neurologic deficits on admission, greater infarct size, higher levels of acute-phase reactants, and lower levels of free PS. IL-6 was significantly correlated with C4BP, ESR, and free PS levels. PC levels were also lower in the group of patients with greater IL-6, but differences were not statistically significant. No correlations were found between C4BP and natural anticoagulants. Severe neurologic deficit, greater infarct volume, atrial fibrillation, increased levels of inflammatory parameters (ESR and IL-6), and reduced levels of free PS were associated with disabling stroke at 3 months, but only neurologic severity and ESR remained as independent predictors of stroke disability on multiple regression analysis. Inflammatory reactions mediated by IL-6 during the acute phase of stroke influence the modulation of free PS. However, variations in free PS levels do not have implications for clinical outcome in stroke patients. The link between proinflammatory cytokines and free PS in the acute phase of stroke is not related to the C4BP pathway.

Blood Coagulation↗
PubMed2000

A post-translational modification of nuclear proteins, N(G),N(G)-dimethyl-Arg, found in a natural HLA class I peptide ligand.

Presentation of peptides derived from endogenous proteins by class I major histocompatibility complex molecules is essential both for immunological self-tolerance and induction of cytotoxic T-cell responses against intracellular parasites. Despite frequent and diverse post-translational modification of eukaryotic cell proteins, very few class I-bound peptides with post-translationally modified residues are known. Here we describe a natural dodecamer ligand of HLA-B39 (B*3910) derived from an RNA-binding nucleoprotein that carried N(G),N(G)-dimethyl-Arg. Although common among RNA-binding proteins, this modification was not previously known among natural class I ligands. The sequence of this peptide was determined by Edman degradation and electrospray ion trap mass spectrometry. The fragmentation pattern of the dimethyl-Arg side chain observed with this latter technique allowed us to unambiguously assign the isomeric form of the modified residue. The post-translationally modified ligand was a prominent component (1-2%) of the B*3910-bound peptide repertoire. The dimethyl-Arg residue was located in a central position of the peptide, amenable to interacting with T-cell receptors, and most other residues in the middle region of the peptide were Gly. These structural features strongly suggest that the post-translationally modified residue may have a major influence on the antigenic properties of this natural ligand.

Arginine↗
PubMed1999

Fibronectin upregulates gelatinase B (MMP-9) and induces coordinated expression of gelatinase A (MMP-2) and its activator MT1-MMP (MMP-14) by human T lymphocyte cell lines. A process repressed through RAS/MAP kinase signaling pathways.

T-lymphocyte migration into tissues requires focal degradation of the basement membrane. In this study, we show that transient adherence to fibronectin induces the production of activated forms of matrix metalloproteinase-2 (MMP-2) and MMP-9, as well as downregulation of tissue inhibitor of metalloproteinase-2 (TIMP-2) by T-cell lines. MMP-2 activation was likely achieved by inducing a coordinated expression of membrane-type matrix metalloproteinase-1 (MMP-14), a major activator of MMP-2. Blocking monoclonal antibodies against alpha4, alpha5, and alphav integrins strongly reduced MMP-2 and MMP-9 production induced by fibronectin. Disrupting actin cytoskeleton organization by cytochalasin D strongly enhanced fibronectin-induced MMP-2 and MMP-9 expression. Inhibiting Src tyrosine kinases with herbimycin A reduced MMP-2 and MMP-9 production with no effect on cell attachment. By contrast, G-protein inhibition by pertussis toxin, or transfection with a dominant negative mutant of Ha-Ras strongly increased fibronectin-induced MMP-2 and MMP-9. Inhibition of PI3 kinase, MAPkinase (MEK1), or p38 MAPkinase by wortmannin, PD 98059, or SB 202190, respectively, strongly promoted fibronectin-induced MMP2 and MMP-9. Cells at high density lost their ability to synthesize MMP-2 and MMP-9 in response to fibronectin and MMP expression was restored by transfection with a dominant-negative mutant of Ha-Ras or by treatment with wortmannin, PD 98059, or SB 202190. Our findings suggest that adhesion to fibronectin transduces both stimulatory (through Src-type tyrosin kinases) and inhibitory signals (through Ras/MAPKinase signaling pathways) for MMP-2 and MMP-9 expression by T lymphocytes and that their relative predominance is regulated by additional stimuli related to cell adhesion, motility, and growth.

Androstadienes↗
PubMed1999

High-sensitivity analysis and sequencing of peptides and proteins by quadrupole ion trap mass spectrometry.

This paper describes experience with the commercially available LCQ quadrupole ion trap mass spectrometer applied to the off-line analysis of peptides and proteins. The standard front end of the electrospray probe was replaced with a micromanipulator which, with the aid of a magnifying device, allowed the use of a variety of miniaturized spraying interfaces. The low sample consumption and extended analysis times of these devices were ideally suitable to obtain improved results in terms of sensitivity and mass accuracy. This needed a careful optimization of the number of ions stored inside the trap (ion target parameter) and required spectrum averaging of many scans. A method is presented for the mathematical fitting of ZoomScan spectra to theoretical isotopic distributions, which allowed the mass determination of large peptides with more accuracy than that achieved by conventional deconvolution algorithms. A very simple on-line desalting configuration is also described which needed no external micro-high-performance liquid chromatographic pumps, and can be easily mounted using the built-in syringe delivery system of the LCQ. This set-up allowed extended analysis times of 'in-gel' protein digests in subpicomole amounts. Finally, the multiple fragmentation capabilities of the ion trap were found to be extremely useful for the analysis of peptide modifications such as phosphorylation and for sequencing individual peptides from highly complex MHC-bound peptide pools.

Animals↗