PubMed Health⌕ Search

Biomedical subjects

F Valdivieso

Publications and source records attributed to F Valdivieso.

At least 19 recordsLinked to original sources
PubMed2002

APOE genotype in cerebrovascular disease and vascular dementia.

BACKGROUND: The fact that the allele epsilon 4 of the Apolipoprotein E (APOE) gene could act like a risk factor not only in late-onset familial and sporadic Alzheimer's disease (AD) but also in cerebrovascular disease (CVD) and vascular dementia (VaD) is still controversial. METHODS: In order to study if epsilon 4 allele is overrepresented not only in AD but also in CVD and VaD, APOE genotyping was undertaken in a series of 247 patients: 26 cases with VaD, 41 cases with CVD but without cognitive impairment (CVD-C), 83 cases with AD and 97 aged-matched "healthy controls" (HC). RESULTS: Percentages of subjects bearing one or two copies of the epsilon 4 allele was much higher in AD patients (54%) than in either CVD-C (29%) (p<0.05), VaD (15%) (p<0.001) or HC (13%) (p<0.001). CONCLUSIONS: These results strengthen the hypothesis that involves the APOE epsilon 4 allele as a predisposing factor for AD, but not for CVD or VaD.

Aged↗
PubMed2002

Contribution of APOE promoter polymorphisms to Alzheimer's disease risk.

OBJECTIVE: To determine whether the effects of APOE promoter polymorphisms on AD are independent of the APOE-epsilon4 allele. BACKGROUND: Recently, the -491 A-->T and -219 G-->T polymorphisms located in the APOE promoter have been suggested to be risk factors for AD. However, the effects of these polymorphisms have not always been reproduced in case-control studies, possibly because of the strong linkage disequilibrium existing at this locus or the characteristics of the populations studied. METHODS: Data collection was performed from six independent samples (1,732 patients with AD and 1,926 control subjects) genotyped for APOE exon 4 and the two APOE promoter polymorphisms. The risks associated with the APOE polymorphisms for developing AD were estimated using logistic regression procedures and calculation of odds ratios with 95% CI adjusted by age, sex, and collection center. Independence of the APOE promoter polymorphisms was tested by stratification for APOE-epsilon4 and tertile design was used for age stratification. RESULTS: The independence of the -491 AA genotype was observed in the whole sample whereas the independence of the -219 TT genotype was observed only in the oldest population. CONCLUSION: The -491 and -219 APOE promoter polymorphisms incur risk for AD in addition to risk associated with the APOE-epsilon4 allele, with age accentuating the effect of the -219 TT genotype. Because these polymorphisms appear to influence apoE levels, these results suggest that APOE expression is an important determinant of AD pathogenesis.

Aged↗
PubMed2001

Interaction of alpha-2-macroglobulin and HSV-1 during infection of neuronal cells.

We describe the effect of pretreatment with alpha-2-macroglobulin (A2M) on the susceptibility of the human neuroblastoma SKNMC cell line to infection by herpes virus type 1 (HSV-1). ELISA and co-immunoprecipitation experiments confirmed the A2M-HSV-1 interaction in vitro. Indirect immunofluorescence shows that A2M exacerbated the cytopathic effect induced after HSV-1 infection. However, A2M-pretreated SKNMC cells notably produced fewer HSV-1 particles than did the untreated cells, suggesting that A2M could induce a restrictive infection. Furthermore, high levels of HSV-1 and A2M induced the production of nitric oxide (NO) in SKNMC. Preliminary results suggest that A2M might induce apoptosis in HSV-1-infected cells. These findings affirm the conclusion that A2M may interact directly with HSV-1 and modulate the course of the infection in SKNMC human neuroblastoma cells.

Apoptosis↗
PubMed2000

Identification of amino acid residues of transcription factor AP-2 involved in DNA binding.

AP-2 is a cell-type specific, developmentally regulated transcription factor which has been described as a critical regulator of gene expression during vertebrate development and embryogenesis. Although the overall domains of this factor necessary for their activity have been identified, the exact identity of AP-2 amino acid residues responsible for its interaction with the DNA structure has not yet been described. Here, we describe the identification of a region of AP-2 which was protected by an oligonucleotide probe containing its binding site from trypsin digestion, monitored by peptide mapping by MALDI-TOF mass spectrometry. Furthermore, we analyzed the relative in vitro DNA-binding activity, the stimulatory potency on the AP-2-dependent APOE promoter, as well as the ability to inhibit the effect of the wild-type protein of each one of a set of single-site substitution AP-2 mutants spanning the identified region. Taken together, our data clearly demonstrate that the region between amino acid residues 252-260 of AP-2 is essential for its DNA-binding activity. Particularly, the individual substitution in any of the residues 253, 254, 255, 257 or 260 is sufficient for completely abolishing the interaction with DNA and the stimulation of APOE promoter activity. These results indicate a crucial role of this region in the formation of an active DNA-binding domain and strongly suggest that these residues provide direct contacts with the DNA structure at the AP-2 binding site.

Amino Acid Sequence↗
PubMed2000

Apolipoprotein E gene promoter polymorphisms in Alzheimer's disease.

Alzheimer's disease, the most frequent form of senile dementia, presents in the vast majority of cases as a multifactorial trait, where a series of genetic and environmental risk factors converge. The increasing body of data, both epidemiological and functional, is strengthening the evidence that apolipoprotein E (APOE, gene; apoE, protein) is a true susceptibility factor for the onset of the common form of Alzheimer's disease. The E4 isoform of apoE remains to date as the main genetic risk factor for the disease, although the mechanisms responsible for this association are not well understood. It is also clear that apoE4 is not necessary or sufficient to cause the disease, indicating that other risk and protecting factors exist. ApoE is upregulated in response to nervous system injury, suggesting that it could have a neuroprotective role; on the other hand, there is evidence indicating that apoE is neurotoxic when present at high levels. Thus, apoE levels seem to be relevant for the functionality of the protein. The APOE proximal promoter hosts numerous regulatory elements, raising the possibility that polymorphisms in this region could produce variation in apoE levels by altering APOE transcriptional activity, which could finally result in AD susceptibility. We will review here the current evidence on the relationship between APOE proximal promoter polymorphisms, APOE gene transcriptional activity and apoE protein levels, and risk for AD.

Alzheimer Disease↗
PubMed2000

Alzheimer's risk associated with human apolipoprotein E, alpha-2 macroglobulin and lipoprotein receptor related protein polymorphisms: absence of genetic interactions, and modulation by gender.

Apolipoprotein E (apoE), the lipoprotein receptor related protein (LRP) and alpha-2 macroglobulin (alpha2M) have been proposed as a functional complex involved in amyloid clearance, a crucial event for Alzheimer's disease development. In this work, we present an epidemiological approach aimed to study the interactions among these genes, age and gender. This approach did not reveal significant associations between the genes; however, the present study indicated that the risk associated with APOE promoter and LRP gene polymorphisms is modulated by gender.

Age Factors↗
PubMed2000

A polymorphism in the tau gene associated with risk for Alzheimer's disease.

Searching for tau genetic variations which could be associated with risk for Alzheimer's disease (AD), we have performed a mutational analysis of a region containing the whole exon 11 of the tau gene, which encodes a microtubule binding region critical for tau self-assembly, and we have found a biallelic polymorphism at position +34 of intron 11 (IVS11 + 34G/A). We have analyzed the allelic frequencies of this polymorphism in a case-control sample (167 clinically diagnosed AD and 194 controls) and found that the presence of any G allele (genotypes AG + GG) is associated with a five-fold AD risk in individuals carrying the apolipoprotein E4 allele, strongly suggesting that the combined effect of tau and apoE is relevant in relation with AD pathogenesis.

Age of Onset↗
PubMed1999

Apolipoprotein E promoter and alpha2-macroglobulin polymorphisms are not genetically associated with Chinese late onset Alzheimer's disease.

In this study, we investigated two newly reported polymorphisms in association with late onset Alzheimer's disease (AD) in Chinese. They were a -491 A/T polymorphism in the Apolipoprotein E (APOE) promoter region and a five base pair deletion at exon 18 of alpha2-Macroglobin (A2M). There were 196 AD and 180 normal controls (N), which were age- and sex-matched. APOE epsilon4 alleles were significantly increased in AD vs. N (chi2 = 33.3, P < 0.000001). However, neither the -491 A/T (chi2 = 1.13, P = 0.29) nor A2M (chi2 = 0.18, P = 0.67) polymorphism was associated with AD risk, suggesting that these polymorphisms do not represent risk factors for AD in the Chinese population.

Age of Onset↗
PubMed1999

Transcription factor AP-2 activity is modulated by protein kinase A-mediated phosphorylation.

We recently reported that APOE promoter activity is stimulated by cAMP, this effect being mediated by factor AP-2 [Garcia et al. (1996) J. Neurosci. 16, 7550-7556]. Here, we study whether cAMP-induced phosphorylation modulates the activity of AP-2. Recombinant AP-2 was phosphorylated in vitro by protein kinase A (PKA) at Ser239. Mutation of Ser239 to Ala abolished in vitro phosphorylation of AP-2 by PKA, but not the DNA binding activity of AP-2. Cotransfection studies showed that PKA stimulated the effect of AP-2 on the APOE promoter, but not that of the S239A mutant. Therefore, cAMP may modulate AP-2 activity by PKA-induced phosphorylation of this factor.

Amino Acid Substitution↗
PubMed1999

DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer's disease presenilin-1 gene: two novel mutations.

Many different mutations that cause Alzheimer's disease (AD) have been found in the presenilin-1 gene (PSEN1) and are associated with the most aggressive forms of the disease. With the aim of screening for PSEN1 genetic variations, we developed a method based on denaturing gradient gel electrophoresis (DGGE) that allows the mutational analysis of all the coding exons and the proximal promoter of PSEN1 using only four DGGE gels. The analysis by this methodology of a sample of 58 early-onset AD (EOAD) patients nonselected for family history resulted in finding four genetic variants within the PSEN1 coding region, two of which are novel mutations (M233L and A409T), whereas the other two have been reported previously (L282R and E318G). We also found a novel mutation within the PSEN1 proximal promoter (-280 C-->G) that, interestingly, provokes significant changes in the transcriptional activity of the gene in cell lines of neuronal and astrocytic, but not hepatic origin. These data strongly suggest that the region around -280 of PSEN1 promoter contains a regulatory element that controls its transcription specifically in neural cells.

Adult↗
PubMed1999

[Antimicrobial resistance of agents causing urinary tract infections in 11 Chilean hospitals. PRONARES project].

BACKGROUND: The computer program WHONET generates a common database to analyze local or general antimicrobial resistance of bacteria. A surveillance of agents causing urinary tract infections in Chile has been performed using this program. AIM: To report the results after 12 months of urinary tract infection agent surveillance. MATERIAL AND METHODS: Since November, 1997, a surveillance of in vitro antimicrobial resistance, using agar diffusion techniques, has been performed in 20 to 40 bacterial strains per month, isolated from 11 hospitals in the country. Results have been analyzed using WHONET program. RESULTS: In first 12 months, 3144 strains, 1625 coming from outpatients, have been studied. Seventy four percent of isolated strains were E coli, 19% were other enterobacteria, 4.1% were non fermenting bacilli and 2.1% were Gram (+) cocci. Sixty five percent of E coli strains were resistant to ampicillin, 11% to cefazolin, 2.5% to cefuroxime, 19% to ceftriaxone, 9% to ceftazidime, 4.2% to gentamicin 1.3% to amikacin, 5.6% to ciprofloxacin, 8.4% to grepafloxacin, 4.3% to nitrofurantoin and 43% to trimeproprim/sulphamethoxazole. Eighty two percent of other enterobacteria strains were resistant to ampicillin, 45.5% to cefazolin, 33.5% to cefuroxime, 26.6% to ceftriaxone, 21.5% to ceftazidime, 30.3% to gentamicin 17.2% to amikacin, 21% to ciprofloxacin, 16.3% to grepafloxacin, 48.2% to nitrofurantoin and 44.6% to trimeproprim/sulphamethoxazole. There were differences in betalactamic resistance among hospitals. CONCLUSIONS: Noteworthy is the high resistance rates to third generation cephalosporins, evidenced when the new cutoff values for E coli and Klebsiella spp are used. This national surveillance provides updated information on antimicrobial resistance of agents causing urinary tract infections.

Chile↗
PubMed1999

[Emergence of resistance to macrolides in Streptococcus pyogenes].

BACKGROUND: Diseases produced by Streptoccocus pyogenes are still a problem in Chile, as in the rest of the world. It exhibits in vitro susceptibility to different antimicrobials, but penicillin continues to be the treatment of choice. Alternative drugs have been developed for allergic patients, such as erythromycin, new macrolides and cephalosporins. Nevertheless, resistant strains are appearing due to the indiscriminate use of macrolides. AIM: To assess present antimicrobial susceptibility of S Pyogenes strains isolated from chilean patients. MATERIAL AND METHODS: The susceptibility to penicillin, macrolides, clindamycin, cephalotin and vancomycin of 153 S Pyogenes strains, obtained from different health centers of the Metropolitan Region and isolated between 1996 and 1998, was assessed using the Kirby-Bauer method. Agar dilution minimal inhibitory concentration was then determined to macrolide resistant strains. RESULTS: All strains were susceptible to penicillin. There was a 7.2% cross-resistance to macrolides. CONCLUSIONS: These results confirm that S Pyogenes resistance to macrolides has increased considerably in the Metropolitan Region of Chile during the last years.

Anti-Bacterial Agents↗
PubMed1998

The -491 A/T polymorphism in the regulatory region of the apolipoprotein E gene and early-onset Alzheimer's disease.

The -491 polymorphism in the promoter region of the apolipoprotein E gene (APOE) has been suggested to be associated with increased risk for Alzheimer's disease (AD) independent of APOE status. We studied the association between the -491 polymorphism and risk for early-onset Alzheimer's disease in 99 Dutch and 78 Spanish patients. In patients with early-onset AD, we found no consistent relationship with a single allele of the -491 polymorphism. Linkage disequilibrium between the polymorphism and the APOE gene was found which most likely might explain the inconsistent findings.

Age of Onset↗
PubMed1998

Identification of a novel mutation (Leu282Arg) of the human presenilin 1 gene in Alzheimer's disease.

Many different mutations, causative of Alzheimer's disease, have been found in the presenilin-1 gene (PS-1). We have developed a screening method based on denaturing gradient gel electrophoresis (DGGE), which allows the mutational analysis of the whole exon 9 of PS-1. Upon the screening of a Spanish sample of early onset familial Alzheimer disease cases, we have found a novel mutation in the PS-1 gene. The mutation (a T to G transition) results in a change of the amino acid at position 282 of the presenilin protein from leucine to arginine. This mutation is located in the hydrophobic domain number 7 (exon 9) close to the site of physiological cleavage processing. The average of onset of the affected members of this family is 43+/-5 years, and the average age of exitus of affected members is 56+/-3 years. The possibility to determine the specific pathologic mechanisms of this mutation is now open.

Adult↗
PubMed1998

Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene.

In this work, we explored the existence of genetic variants within the apolipoprotein E gene transcriptional regulatory region, using a denaturing gradient gel electrophoresis screening of a region comprising nucleotides -1017 to +406. Upon a population study, three new polymorphic sites (-491, -427 and -219) and two mutations were found. Functional effects of the polymorphisms, assayed by transient transfection and electrophoretic mobility shift assays in a human hepatoma cell line, showed that polymorphisms at sites -491 and -219 of the APOE promoter produce variations in the transcriptional activity of the gene, most probably through differential binding of nuclear proteins.

Adolescent↗
PubMed1998

A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia.

The epsilon4 allele of the apolipoprotein E gene (APOE) has been associated with an increased risk of developing Alzheimer's disease (AD; refs 1,2). However, it is apparent that the APOEepsilon4 allele alone is neither necessary nor sufficient to cause the disease. We have recently found three new polymorphisms within the APOE transcriptional regulatory region (M.J.A. et al., manuscript submitted) and now establish an association between one of these polymorphisms (-491A/T) and dementia as observed in Alzheimer's disease, in two independent clinical populations. The results suggest that homozygosity of a common variant (-491A) is associated with increased risk for AD, and that this association is independent of APOEepsilon4 status. In vitro studies suggest that the -491A/T polymorphism may increase risk for AD by altering the level of ApoE protein expression.

Alleles↗
PubMed1998

Risk for Alzheimer's disease correlates with transcriptional activity of the APOE gene.

While the straightepsilon4 allele of apolipoprotein E ( APOE, gene; ApoE, protein) is widely accepted as a major genetic risk factor for the late onset form of Alzheimer's disease (AD), recent evidence points to variations in ApoE levels as another important factor. We have previously reported that a common variant in the regulatory region of APOE (-491A) is associated with risk for late onset AD. In this report we analyze the association of another APOE promoter polymorphism (-427T/C) with AD in two case-control clinical samples and demonstrate a correlation between APOE promoter transcriptional activity and risk for AD. The association studies show that the allelic variant (-427C) and the haplotype [-491A-427C] of the APOE promoter are associated with increased risk for AD. Study of the transcriptional activity of the common haplotypes defined by combination of the -491 and -427 alleles indicated that the risk for late onset AD positively correlates with transcriptional activity of the APOE gene, suggesting that increases in the local expression of ApoE could be responsible for the association of APOE promoter polymorphism with AD.

Aged↗