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Biomedical subjects

A Ibáñez

Publications and source records attributed to A Ibáñez.

At least 19 recordsLinked to original sources
PubMed2006

Central role of supporting cells in cochlear homeostasis and pathology.

HYPOTHESIS: Supporting cells have a crucial role in degenerative and regenerative events of primary sensorial hair cells of the organ of Corti. This new role should determine future studies about pathophysiology of hearing loss and its regenerative treatment. SUPPORTING EVIDENCE: Recent findings suggest an active role of supporting cells in the maintenance of hair cell function and structure. Evidences of high energy consumption and close proximity to auditory nervous fibers suggesting K+ active exchange, preferential expression of specific proteins and antigens, presence of glucocorticoids receptors, affinity for cisplatin and regenerative potential give the supporting cells an important role in homeostasis of the organ of Corti and in some specific diseases affecting this structure. CONCLUSION: As well as glial cells provide protection and regeneration to neural tissues, supporting cells may provide the necessary metabolic and electrolitic conditions for hair cells mechanical and bioelectrical function. This opens new possibilities for the treatment of apparently "irreversible" destruction of the inner ear.

Animals↗
PubMed2005

Phenotypic variability in familial prion diseases due to the D178N mutation.

BACKGROUND: Between January 1993 and December 2003, 19 patients with familial prion diseases due to the D178N mutation were referred to the regional epidemiological registry for spongiform encephalopathies in the Basque Country in Spain, a small community of some 2,100,000 inhabitants. METHODS: Ten further patients belonging to the same pedigrees were retrospectively ascertained through neurological or neuropathological records. In four of the patients, the diagnosis was confirmed by analysing DNA obtained from paraffin blocks. In this article, we report on the clinical, genetic, and pathological features of the 23 patients carrying the D178N mutation confirmed by genetic molecular analysis. Haplotyping studies suggest a founder effect among Basque born families, explaining in part this unusually high incidence of the D178N mutation in a small community. Only two patients (8%) lack familial antecedents. RESULTS: We have observed a phenotypic variability even among homozygous 129MM patients. Our findings challenge the currently accepted belief that MM homozygosity in codon 129 is always related to a fatal familial insomnia (FFI) phenotype. Indeed, seven out of 17 patients with a 129MM genotype in this series presented with a Creutzfeldt-Jakob disease (CJD) clinicopathological picture. CONCLUSIONS: The considerable clinical and pathological overlapping observed among homozygous 129MM patients favours the view that FFI and CJD178 are the extremes of a spectrum rather than two discrete and separate entities. Other genetic or environmental factors apart from the polymorphism in codon 129 may play a role in determining the phenotypic expression of the D178N mutation in the PRNP gene.

Adult↗
PubMed2004

Plasma von Willebrand factor, soluble thrombomodulin, and fibrin D-dimer concentrations in acute onset non-rheumatic atrial fibrillation.

OBJECTIVE: To investigate whether new onset acute atrial fibrillation (AF) of < 48 hours' duration creates a prothrombotic state in the absence of anticoagulation and to assess the evolution in research indices after spontaneous or pharmacological cardioversion. METHODS: 24 patients were recruited with first onset acute non-rheumatic AF, in whom sinus rhythm was restored within 48 hours of arrhythmia onset, without anticoagulant treatment. Atrial mechanical function was assessed by transmitral inflow. Soluble thrombomodulin and von Willebrand factor concentrations (both as indices of endothelial damage or dysfunction) and fibrin D-dimer concentrations (as an index of thrombogenesis) were measured. Blood samples were drawn and echocardiographic studies were performed at days 1, 3, 7, and 30 after cardioversion. Research indices were compared with those of 24 healthy participants, 24 patients with chronic AF, and 24 patients with ischaemic heart disease in sinus rhythm. RESULTS: Patients with AF had higher concentrations of soluble thrombomodulin (acute AF 12.1 (4.1) ng/ml; chronic AF 11.8 (4.6) ng/ml), von Willebrand factor (acute AF 137.2 (36.9) ng/ml; chronic AF 133.1 (25.0) ng/ml), and fibrin D-dimer concentrations (acute AF 2.35 (2.68) microg/ml; chronic AF 1.12 (0.65) microg/ml) than did healthy controls (5.9 (2.7) ng/ml, 86.7 (33.2) ng/ml, and 0.39 (0.28) microg/ml, respectively) and patients with ischaemic heart disease (7.4 (3.7) ng/ml, 110.0 (29.0) ng/ml, and 0.99 (0.73) microg/ml, respectively) (all p < 0.05). Day 30 concentrations of fibrin D-dimer were higher in patients with acute AF than in patients with chronic AF (p = 0.038) but sTM and von Willebrand factor concentrations were not different (both not significant). There were no significant changes in research indices or echocardiographic parameters after cardioversion (all p > 0.05). CONCLUSIONS: There was evidence among patients with acute onset AF of endothelial damage or dysfunction and increased thrombogenesis, which persisted up to 30 days after cardioversion.

Acute Disease↗
PubMed2001

Plasma testosterone and pathological gambling.

The authors studied plasma testosterone levels and psychological characteristics of male pathological gamblers. Twenty-nine male pathological gamblers and a group of healthy volunteers matched for age and gender were compared on levels of plasma testosterone and scores on the Eysenck Personality Questionnaire (EPQ) and the Psychopathic Deviance scale of the Minnesota Multiphasic Personality Inventory (MMPI). Plasma testosterone levels were similar in the pathological gambling and comparison group (476.06 ng/100 ml vs. 560.71 ng/100 ml). Patients had higher scores on the Neuroticism subscales of the EPQ (13.83 vs. 10.83) and the Psychopathic Deviance scale of the MMPI (27.03 vs. 21.03), but not on any of the other subscales of the EPQ. Testosterone levels did not correlate with the psychological ratings. Testosterone levels are probably not related to impulsivity in pathological gambling.

Adult↗
PubMed2001

Electrochemical enzyme immunoassays on microchip platforms.

A microfluidic device for conducting electrochemical enzyme immunoassays is described. The new "lab-on-a-chip" protocol integrates precolumn reactions of alkaline phosphatase-labeled antibody (anti-mouse IgG) with the antigen (mouse IgG), followed by electrophoretic separation of the free antibody and antibody-antigen complex. The separation is followed by a postcolumn reaction of the enzyme tracer with the 4-aminophenyl phosphate substrate and a downstream amperometric detection of the liberated 4-aminophenol product Factors influencing the reaction, separation, and detection processes were optimized, and the analytical performance was characterized. An applied field strength of 256 V/cm results in free antibody and antibody-antigen complex migration times of 125 and 340 s, respectively. A remarkably low detection limit of 2.5 x 10(-16) g/mL (1.7 x 10(-18) M) is obtained for the mouse IgG model analyte. Such combination of a complete integrated immunoassay, an attractive analytical performance, and the distinct miniaturization/portability advantages of electrochemical microsystems offers considerable promise for designing self-contained and disposable chips for decentralized clinical diagnostics or on-site environmental testing.

Alkaline Phosphatase↗
PubMed2001

Absence of genetic diversity reduction in the HIV-1 integrated proviral LTR sequence population during successful combination therapy.

We report the integrated proviral LTR sequence variation in four patients on highly active antiretroviral therapy (HAART). Integrated proviral fragments of LTR taken from four time points were PCR amplified from PBMCs and 10 to 12 individual clones were sequenced for each time point. Intrasample genetic distances and phylogenetic reconstruction of all LTR sequences demonstrated that 1-2 years of successful HAART did not significantly reduce the genetic repertoire of the integrated reservoir of HIV-1.

Anti-HIV Agents↗
PubMed2001

Pathological gambling: addiction or compulsion?

There is considerable debate about the appropriate conceptualization of pathological gambling and its place in psychiatric nosology. The authors examined the existing research on different areas of pathological gambling to find evidence for a particular model of this disorder. There are 2 dominant models of pathological gambling: as a nonpharmacologic addiction and as an obsessive-compulsive spectrum disorder. The data available from different areas seem to converge in suggesting that pathological gambling has characteristics that are similar to those of substance abuse, and less close to those of obsessive-compulsive disorder, although those conceptualizations are not mutually exclusive. An alternative model of pathological gambling is that it constitutes a heterogeneous disorder with some subtypes resembling obsessive-compulsive disorder, and other subtypes being closer to substance abuse disorders. Improved understanding of the conceptualization of this disorder may help improve the quality of the treatments available.

Gambling↗
PubMed2001

Psychiatric comorbidity in pathological gamblers seeking treatment.

OBJECTIVE: The authors' goal was to determine the frequency of psychiatric comorbidity among treatment-seeking pathological gamblers, compare the severity of gambling and psychological problems in gamblers with and without comorbid disorders, and investigate differences between gamblers with and without comorbid disorders in the dopamine D(2) receptor gene (DRD(2)). METHOD: Sixty-nine pathological gamblers who consecutively applied to a specialized outpatient treatment program were evaluated with structured interviews, self-report questionnaires, and psychological scales and were genotyped for a DRD(2) polymorphism. RESULTS: A comorbid psychiatric disorder was present in 43 (62.3%) of the gamblers. The most frequent diagnoses were personality disorders (N=29 [42.0%]), alcohol abuse or dependence (N=23 [33.3%]), and adjustment disorders (N=12 [17.4%]). Gamblers with comorbid psychiatric disorders had gambling scores and psychological scale scores indicating greater severity of gambling and psychopathology. Significant differences in DRD(2) allele distribution were found in gamblers with and without comorbid disorders. CONCLUSIONS: Psychiatric comorbidity is common among pathological gamblers and is associated with greater severity of clinical problems. The DRD(2) gene could be a liability genetic factor for psychiatric comorbidity in pathological gambling.

Comorbidity↗
PubMed2000

Genetic evolution of GB virus C/hepatitis G virus (GBV-C/HGV) under interferon pressure.

The epidemiology and clinical features of chronic GBV-C/HGV infection have largely been explored, but there is little information about the mechanisms enabling GBV-C/HGV to cause persistent infection. Since analysis of the genomic variation of GBV-C/HGV under interferon pressure might provide some insight into this issue, we analyzed the nucleotide sequence variation of the 5'NC and NS3 regions in GBV-C/HGV isolates obtained sequentially from seven patients co-infected with HCV and treated with interferon. A reduction of GBV-C/HGV-RNA serum level below the detection limit of the RT-PCR assay was observed during treatment in all patients, but upon interferon withdrawal, viral RNA remained undetectable in only two patients. Among the five patients who did not clear GBV-C/HGV-RNA, viral strains emerging after treatment were identical to those present at baseline in three cases. In a further case, in whom GBV-C/HGV-RNA re-emerged during therapy (breakthrough episode), several mutations appeared in relapse samples. In the remaining patient, with a mixed infection before therapy, only one of the two GBV-C/HGV strains present at baseline was detected upon treatment withdrawal. These data raise the possibility that positive selection may act over GBV-C/HGV genome during interferon therapy, and contribute to persistence of infection with this virus.

Base Sequence↗
PubMed2000

Human immunodeficiency virus type 1 population bottleneck during indinavir therapy causes a genetic drift in the env quasispecies.

The impact of emergence of genetic resistance, soon after the beginning of antiretroviral therapy, on the genotype of other viral loci not implicated in the development of resistance was studied in four human immunodeficiency type 1 (HIV-1)-infected patients subjected to indinavir monotherapy. Two patients were chosen because they showed no decrease in virus load during the study period and two were selected because they showed a rapid decline in plasma viraemia after the initiation of therapy and a virus rebound after 12 weeks of treatment. The evolution of virus sequences was analysed within the four infected patients by examining virus sequences spanning the protease and C2-V3 env genes by RT-PCR of plasma samples obtained at the beginning and after 12 weeks of therapy. PCR products from the two genomic regions from the two sample points per patient were cloned and 10-15 clones from each sample were sequenced. Genotypic indinavir resistance was present in the four patients after 12 weeks of therapy. The overall protease and C2-V3 env regions quasispecies diversity at time zero was higher than that after 12 weeks of therapy, but this difference was more significant in the two patients who showed a reduction in virus load soon after the initiation of treatment. C2-V3 env sequences indicated that changes during emergence of resistance to indinavir were only detected in the two patients who showed a drastic reduction in virus load. Thus, a temporal relationship was observed between the start of therapy, a drastic reduction in virus load and a drift in the HIV-1 env quasispecies.

Amino Acid Sequence↗
PubMed1999

Mutational analysis of Phe160 within the "palm" subdomain of human immunodeficiency virus type 1 reverse transcriptase.

The highly conserved Phe160 residue is located in the "palm" subdomain of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), and makes contact with Tyr115, a residue which is involved in deoxynucleoside triphosphate (dNTP) binding and fidelity of DNA synthesis. Five mutant RTs having Tyr, Trp, Ile, Ala or Gln instead of Phe160 were obtained by site-directed mutagenesis. F160Y and F160W retained substantial DNA polymerase activity, whereas the catalytic efficiency of nucleotide incorporation of mutants F160I, F160A and F160Q was less than 10 % that of the wild-type RT, using poly(rA).oligo(dT)20 as the template-primer. The low catalytic efficiency of mutants F160I, F160A and F160Q was due to their lower affinity for the dNTP substrate. F160Y displayed similar kinetic parameters as the wild-type RT in nucleotide insertion assays carried out with heteropolymeric DNA/DNA template-primers. However, nucleotide affinity was two- to sixfold reduced in the case of mutant F160W. Fidelity assays revealed similar misinsertion and mispair extension ratios for the three enzymes, although F160W showed a slightly higher accuracy of DNA synthesis, particularly in the presence of high concentrations of dNTP. When introduced in an infectious proviral clone, mutations F160I, F160A and F160Q rendered non-viable virus. The importance of Phe160 for polymerase function and viral replication could be mediated by its interaction with Tyr115, as suggested by the analysis of the available crystal structures of HIV-1 RT.

Amino Acid Substitution↗
PubMed1999

Quantification of integrated and total HIV-1 DNA after long-term highly active antiretroviral therapy in HIV-1-infected patients.

OBJECTIVE: To assess the impact of long-term virus suppression on the peripheral blood CD4 T cells integrated and total HIV-1 DNA loads in patients receiving highly active antiretroviral therapy (HAART). METHODS: A total of 10 HIV-1-infected patients receiving a triple combination therapy (two nucleoside analogues and one protease inhibitor) were longitudinally studied to compare integrated and total HIV-1 DNA loads. HIV-1 DNA quantification was performed using a quantitative nested polymerase chain reaction (PCR) on genomic peripheral blood mononuclear cell (PBMC) DNA obtained at baseline and at 48 weeks of HAART. RESULTS: All the study patients showed an early and sustained decrease in plasma HIV-1 RNA to below the limit of detection (200 copies/ml). Concordant with the plasma viral decline, a significant increase in the CD4 T cell count was observed (P = 0.007). A statistically significant fivefold decrease in total HIV-1 DNA was detected after 48 weeks of HAART (P = 0.005). However, no statistically significant change was noted after the therapy when the integrated HIV-1 DNA copy number was compared (P = 0.333). Taken together, these results suggest that in the patients analysed the integrated HIV-1 DNA does not decay rapidly after HAART. CONCLUSION: Within the study cohort the total amount of PBMC HIV-1 DNA decreased drastically after 48 weeks of HAART. Nevertheless, the integrated HIV-1 DNA did not significantly decay during this period. Although the data presented here are limited by the number of patients analysed, our findings suggest that 48 weeks of HAART does not significantly reduce the integrated HIV-1 proviral DNA load in the latently infected CD4 T cell reservoir.

Anti-HIV Agents↗
PubMed1999

Human immunodeficiency virus type 1 genetic evolution in patients with prolonged suppression of plasma viremia.

Treatment of human immunodeficiency virus type 1 (HIV-1)-infected patients with combination drug regimens results in a reduction of plasma viral load to levels below the limit of detection. To investigate the genomic fluctuations in HIV-1 populations from long-term responders to antiviral therapies we analyzed the viral sequence evolution of env and pol genes from sequential peripheral blood mononuclear cell (PBMC) DNA samples of three infected patients. Analyses of sequences covering the V3 and flanking env regions obtained from blood samples at the beginning of the therapy and at 14 or 24 months from baseline revealed that HIV-1 quasispecies continue to evolve in the three patients following combination antiretroviral therapy. Minor drug-resistant mutant subpopulations were also searched for and found in one patient. Interestingly, no minor resistant subpopulations were found in the other two patients despite the fact that they showed evidence of ongoing viral replication. Finally, the genetic analysis of the env gene shows a reduction in PBMC env viral population diversity after long-term response to the therapy in all the patients analyzed.

Anti-HIV Agents↗
PubMed1998

Prevalence and genotypes of GB virus C/hepatitis G virus (GBV-C/HGV) and hepatitis C virus among patients infected with human immunodeficiency virus: evidence of GBV-C/HGV sexual transmission.

The development of new antiretroviral agents may improve survival of HIV-infected individuals, and therefore chronic viral hepatitis may become more relevant in these patients. The presence of GBV-C/HGV and hepatitis C virus (HCV) RNA were investigated by reverse transcriptase-nested polymerase chain reaction in plasma from 168 Spanish HIV-infected patients belonging to four different risk groups: intravenous drug users (IVDUs), hemophiliacs, homosexuals, and heterosexuals. GBV-C/HGV-RNA and HCV-RNA were detected in 18% and 43% of the patients, respectively. The prevalence of current infection with these viruses was notably high, 19% for GBV-C/HGV and 69% for HCV, among individuals with parenteral risk of infection (intravenous drug abusers and hemophiliacs), but sexual transmission with GBV-C/HGV was also suggested because 16.5% of patients with sexual risk, either homosexual or heterosexual, had GBV-C/HGV-RNA in plasma. Although investigation of GBV-C/HGV-RNA possibly underestimates the actual prevalence of infection with GBV-C/HGV, the above data suggest that sexual contact may play a relevant role in the spread of this virus. Phylogenetic analysis showed no evidence for clustering of NS3 sequences into different genotypes or subtypes of GBV-C/HGV.

Adolescent↗
PubMed1998

Genetic evolution of hepatitis G virus in chronically infected individual patients.

Comparative sequence analysis of different isolates of hepatitis G virus (HGV) has demonstrated significant intersubject genetic heterogeneity, but few data on intrasubject genetic evolution have been reported. To further investigate the genetic diversification of the HGV genome, 36 plasma samples from eleven patients chronically infected with HGV serially obtained 2-4 years apart were analysed. We determined the viral nucleotide sequence of the 5' non-coding (NC) and the NS3 regions by directly sequencing the RT-PCR amplified products obtained from the viral RNAs. Intrasubject sequence variation was found to be 1.3-2.4 x 10(-3) base substitutions per genome site per year within the 5' NC region and 1.3-9.4 x 10(-3) base substitutions per genome site per year within the NS3 region. Depending on the genomic region analysed (i.e. 5' NC or NS3 region), pairwise comparisons and phylogenetic reconstructions showed that intersubject genetic distances were 17.5- to 20.8-fold greater than intrasubject ones. Overall, the evolution rate of HGV in the regions analysed is not significantly different from that found in hepatitis C virus.

Chronic Disease↗