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M Pascual

Publications and source records attributed to M Pascual.

At least 55 records · Page 3Linked to original sources
PubMed2001

Distribution of HERV-LTR elements in the 5'-flanking region of HLA-DQB1 and association with autoimmunity.

We established the detailed polymorphism of the 5'-flanking region and the first exon of the human leukocyte antigen (HLA)-DQB1 alleles. One hundred and forty-five Spanish rheumatoid arthritis (RA) patients and 200 healthy voluntary blood donors from southern Spain along with 42 B-cell lines were analyzed for the presence of the retrovirus-derived long terminal repeats (LTRs) LTR3, LTR5, and LTR13. LTR3 positivity was always associated with certain DQB1 alleles, i.e., *0302, *0402, *0601, *0202, and *0305. Sequencing analysis of the 5'-flanking region of DQB1*0301, *0303 and *0502 alleles in homozygous B-cell lines showed the absence of LTR3 and a massive deletion of 5635 base pairs. The undetected deletion in the flanking region of some DQB1 alleles and a lack of stratification for HLA typing explain previously reported associations of the LTR3 element with RA and type I diabetes (IDDM). LTR5 showed identical distribution to LTR3, consistent with a previously suggested LTR3-LTR5 tandem arrangement. LTR13 positivity was associated with DQB1*0302, *0303, and *0402 alleles. Distributions of the LTR elements in all B-cell lines, RA patients, and controls could be explained entirely by linkage disequilibrium with DQB1 alleles, independently of the haplotypes carrying them. LTR elements are known to regulate gene expression. Therefore, a possible involvement of LTR13 in the association of DQB1*0302, *0303, and *0402 with IDDM requires further investigation. The sequencing results of the DQB1 first exon demonstrated that DQB1*0601 was generated by a recombination event between a DR53 and a non-DR53 haplotype. Our results shed new light on the phylogeny of the HLA region and the possible contribution of DQB1 to susceptibility to autoimmunity.

Alleles↗
PubMed2001

Glia and fetal alcohol syndrome.

Glial cells and their interactions with neurons play vital roles during the ontogeny of the nervous system and in the adult brain. Alcohol intake during pregnancy can cause mental retardation and neurobehavioral disorders as well as fetal alcohol syndrome (FAS). Clinical and experimental evidence indicate that in utero alcohol exposure induces structural and functional abnormalities in gliogenesis and in glial-neuronal interactions, suggesting a potential role of glial cells on ethanol-induced developmental brain abnormalities. In vivo studies have shown ethanol-associated alterations in the migration of neurons and radial glial as well as in astrogliogenesis and myelin development. In astrocytes in primary culture, ethanol has been found to (1) impair cell growth and differentiation, (2) decrease the levels of glialfibrillary acidic protein or GFAP (an astrocyte marker) and its gene expression and (3) interfere with the stimulatory effect of trophic factors affecting their release and receptor expression. Evidence also suggests that ethanol affects intracellular protein trafficking, which may mediate some effects of ethanol on astroglial cells. These findings suggest that glial cells are target of ethanol toxicity during brain development and may underlie the neurodevelopmental abnormalities observed after in utero alcohol exposure and in FAS.

Animals↗
PubMed2001

The telomeric part of the HLA region predisposes to rheumatoid arthritis independently of the class II loci.

We have evaluated the possible contribution of genes besides DQ and DR to the association of HLA with rheumatoid arthritis (RA). To this end, we have looked at the allele distributions of six microsatellites, D6S1014, D6S2673, TNFalpha, MIB, C1-2-5, and C1-3-2 among 132 RA patients and 254 controls. We have defined 19 microsatellite clusters corresponding to previously described ancestral haplotypes. One of them was D6S1014*143-D6S273*139-TNFalpha*99-MIB*350-C1-2-5*196-C1-3-2*354, often found associated with DQB1*0201-DRB1*0301. As part of this microsatellite cluster, the allele MIB*350 was found to be a RA-predisposing factor, independent of DRB1*0301 and RA-predisposing haplotypes DQB1*03-DRB1*04 and DQB1*0501-DRB1*01. We conclude that the telomeric part of the HLA region contains a locus conferring predisposition to RA independently of HLA class II.

Arthritis, Rheumatoid↗
PubMed2001

Managing the highly sensitized transplant recipient and B cell tolerance.

The detection of anti-donor-HLA antibodies in a renal allograft recipient's serum, either at the time of or after transplantation, is usually associated with specific antibody-mediated clinical syndromes. These can be divided temporally into three categories: hyperacute rejection, acute humoral rejection and chronic humoral rejection. With the identification of new immunosuppressive drug combinations, more-effective control of alloantibody production has been recently achieved in humans. Thus, prevention and/or treatment of antibody-mediated allograft injury are now possible. Ultimately, the induction of mixed hematopoietic chimerism may allow us to overcome the problem of allosensitization and accept an allograft without chronic immunosuppression.

Animals↗
PubMed2001

Microsatellite variation in colonizing and palearctic populations of Drosophila subobscura.

The recent colonization of North America by Drosophila subobscura has provided a great opportunity to analyze a colonization process from the beginning. A comparative study using 10 microsatellite loci was conducted for five European and two North American populations. No genetic differentiation between European populations was detected, indicating that gene flow is high among them and that the microsatellites used in the present work represent neutral markers not subject to differentiation due to selection. Extensive reduction in the number of alleles and a significant decrease in heterozygosity in colonizing populations were detected that could be explained by the founder effect and a subsequent quick but not infinite expansion. Assuming that all alleles present in the colonized area were carried by the sample of colonizers, we estimated that most probably 4-11 individuals expanded in the new area. F(ST) and the chord distance measures reflect the colonization process more accurately, since drift has been the major force in differentiating the Old and New World populations, and thus other measures considering allele size differences, such as Rho(ST) and deltamu2, are less reliable for studying nonequilibrium populations. Finally, our results were consistent with the two-phase microsatellite mutational model, indicating that most alleles are generated by gain or loss of a repeat unit, while some alleles originate by more complex mutations.

Alleles↗
PubMed2001

The kidney transplant program at the Massachusetts general hospital.

Between February 1963 and December 2000, 1,627 kidney transplants were performed at the Massachusetts General Hospital. The majority (62%) were from cadaveric donors, although in recent years (1996-2000) 52% have been allografts from living donors, with an increase in living unrelated donors. The introduction of CsA and OKT3 in 1984 was associated with a significant improvement in actuarial renal allograft survival, although a persistent late attrition of allografts continues beyond the first year after transplantation. As reported in other centers, current actuarial survival for living unrelated allografts is superior to that of cadaveric allografts, and is quite similar to that observed in recipients of non-HLA identical living-related transplants. Our preliminary laparoscopic donor nephrectomy experience is encouraging as excellent allograft survival and function has been observed, with minimal morbidity associated with the procedure and a low rate of conversion to open nephrectomy. Recent changes in immunosuppressive protocols have resulted in lower early acute rejection rates, however the incidence of delayed graft function remains unchanged in cadaveric renal transplantation. The role of humoral immunity in allograft rejection has been progressively clarified and new approaches to control donor specific alloantibody production have been shown to be effective. Current clinical studies are ongoing to determine the optimal type and dose of calcineurin inhibitors beyond the first year after transplantation and to study whether avoidance of steroids is safe and feasible. Finally, an innovative tolerance induction protocol using the mixed chimerism approach has been successfully accomplished in selected patients with end-stage renal disease secondary to multiple myeloma. These encouraging observations emphasize that major changes from current immunosuppressive regimens are likely to occur over the next few years as more approaches to tolerance induction are explored clinically.

Graft Rejection↗
PubMed2000

Cholera dynamics and El Niño-Southern Oscillation.

Analysis of a monthly 18-year cholera time series from Bangladesh shows that the temporal variability of cholera exhibits an interannual component at the dominant frequency of El Niño-Southern Oscillation (ENSO). Results from nonlinear time series analysis support a role for both ENSO and previous disease levels in the dynamics of cholera. Cholera patterns are linked to the previously described changes in the atmospheric circulation of south Asia and, consistent with these changes, to regional temperature anomalies.

Bangladesh↗
PubMed2000

Involvement of Fcgamma receptor IIIA genotypes in susceptibility to rheumatoid arthritis.

OBJECTIVE: To investigate a possible association of Fcgamma receptor IIIA (FcgammaRIIIA) gene polymorphism at position 158 with susceptibility to, and the outcome of, rheumatoid arthritis (RA). METHODS: One hundred seventeen RA patients and 142 unrelated healthy control subjects from the same geographic area were studied. Genotyping for FcgammaRIIIA-158V/F was performed by a method based on polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis using amplification-created restriction sites. HLA-DRB1 typing by PCR-sequence-specific oligonucleotide hybridization (reverse hybridization) was also performed. RESULTS: Allele and genotype distributions in healthy controls were similar to those reported in other populations. The overall distribution of genotypes in the patients was significantly different from that in the controls (P = 0.023, by chi-square test from 3 x 2 contingency table). An overrepresentation of the FcgammaRIIIA-158FF genotype in the patients was observed (for 158FF versus non-158FF P = 0.01, odds ratio [OR] 1.98, 95% confidence interval [95% CI] 1.16-3.4). However, the FcgammaRIIIA-158VF genotype was increased in controls (for 158VF versus non-158VF P = 0.021, OR 0.54, 95% CI 0.32-0.92). No associations were found with any of a series of clinical parameters. Analysis of FcgammaRIIIA-158FF along with shared epitope showed that the presence of both factors increased the susceptibility to RA (P = 0.0009, OR 3.6, 95% CI 1.63-8.01); however, they probably do not interact to produce this effect. CONCLUSION: These results indicate that the FcgammaRIIIA-158 genotypes confer differential susceptibility to RA in our study population. Further studies to elucidate the role of this polymorphism in the pathogenesis of RA and other autoimmune diseases are warranted.

Adult↗
PubMed2000

Prevalence of hepatitis C virus-associated mixed cryoglobulinemia after liver transplantation.

Hepatitis C virus (HCV) infection is associated with mixed cryoglobulinemia and membranoproliferative glomerulonephritis. After orthotopic liver transplantation (OLT), isolated cases of HCV-associated mixed cryoglobulinemia have been reported. We determined the prevalence and clinical characteristics of mixed cryoglobulinemia in HCV-infected liver transplant recipients at our institution. Between January 1991 and February 1998, a total of 191 OLTs were performed in 178 patients. Among these transplant recipients, 53 patients (29.8%) had positive serological test results for HCV infection by second-generation enzyme-linked immunosorbent assay. We studied 31 HCV-positive (HCV+) and 21 HCV-negative (HCV-) transplant recipients (control group). Renal and liver function studies were performed, and cryoglobulin, rheumatoid factor, C3, C4, and serum HCV RNA levels and genotype were determined. Results were compared using unpaired Student's t-test for continuous variables and Fisher's exact test for categorical variables. Baseline characteristics were similar between the groups. Six patients in the HCV+ group (19%) had mixed cryoglobulins present at the time of evaluation compared with none in the HCV- group (P =. 036). The only parameter associated with cryoglobulins in the HCV+ group was rheumatoid factor (P <.01). In 3 HCV+ patients with cryoglobulins, extrarenal signs of cryoglobulinemia were present. Glomerulonephritis was found in 4 HCV+ patients. Two patients with purpura and cryoglobulinemia had reduced clinical manifestations after antiviral therapy. In conclusion, mixed cryoglobulinemia was found in approximately 20% of the HCV+ liver transplant recipients. The presence of purpura or glomerulonephritis suggests HCV-associated mixed cryoglobulinemia, a clinical syndrome that may respond favorably to antiviral therapy.

Adult↗
PubMed2000

Nerve growth factor but not neurotrophin-3 is synthesized by hippocampal GABAergic neurons that project to the medial septum.

Conventional uptake of neurotrophins takes place at axon terminals via specific receptors, and is followed by retrograde transport. Recent studies demonstrated that, with the exception of nerve growth factor, other neurotrophins may be delivered anterogradely to the region containing the receptor expressing neurons. In this study we used a triple labeling method that combines retrograde tract tracing, in situ hybridization and immunocytochemistry to examine whether non-principal cells projecting from the hippocampus to the septum synthesize nerve growth factor. Our results show that, on average, 59% of the horseradish peroxidase-labeled hippocamposeptal nonpyramidal neurons also display nerve growth factor messenger RNA hybridization signal. The ratio was slightly higher in the CA1 stratum oriens and the hilus of the dentate gyrus (64 and 62%, respectively) compared to stratum oriens of the CA3 region (58%). In addition, we demonstrated that many nerve growth factor-positive septally projecting neurons also contain the calcium-binding protein calbindin D-28K, whereas nerve growth factor-negative projecting cells mostly lack this neurochemical marker. In contrast to nerve growth factor, neurotrophin-3 has never been found in hippocamposeptal cells. Hippocamposeptal GABAergic cells are reciprocally connected with the medial septum, thus they are in a key position to regulate nerve growth factor release as a function of the activity level in the septohippocampal system. Furthermore, our results raise the intriguing possibility that nerve growth factor may be transported also in an anterograde manner. Regardless of the direction of transport, the presence of nerve growth factor in hippocamposeptal cells suggests that long distance fast synaptic mechanisms and slow neurotrophin action are coupled in these neurons.

Animals↗
PubMed2000

IL-6 promoter polymorphisms in rheumatoid arthritis.

We investigated the possible association between the IL-6 promoter polymorphisms, at positions -622 and -174, and susceptiblity to, and/or outcome of, rheumatoid arthritis (RA). A total of 163 patients with RA and 157 healthy controls were genotyped for IL-6 using a PCR-RFLP method. The -622 and -174 alleles were in complete linkage disequilibrium. No difference was observed in the distribution of IL-6 promoter genotype or allele frequencies between RA patients and controls. However, a significant difference in the mean age at disease onset between IL-6 genotypes was observed. The present data appear to rule out an important role of IL-6 promoter polymorphisms in the susceptibility to RA. However, IL-6 genotypes may contribute to the pathogenesis of the disease by influencing the age at disease onset.

Adult↗
PubMed2000

High density of long dinucleotide microsatellites in Drosophila subobscura.

We isolated 96 dinucleotide repeats with five or more tandemly repeated units from a subgenomic Drosophila subobscura library. The mean repeat unit length of microsatellite clones in D. subobscura is 15, higher than that observed in other Drosophila species. Population variation was assayed in 32-40 chromosomes from Barcelona, Spain, using 18 randomly chosen microsatellite loci. Positive correlation between measures of variation and perfect repeat length measures (mean size, most common, and longest allele) is consistent with a higher mutation rate in loci with longer repeat units. Levels of microsatellite variation measured as variance in repeat number and heterozygosity in D. subobscura were similar to those of Drosophila pseudoobscura and higher than those of Drosophila melanogaster and Drosophila simulans. Our data suggest that higher levels of microsatellite variation, and possibly density, in D. subobscura compared with D. melanogaster are due to both a higher average effective population and a higher intrinsic slippage rate in the former species.

Alleles↗
PubMed2000

Genetic variation in the spread of Drosophila subobscura from a nonequilibrium population.

Drosophila subobscura was first identified in North America in the early 1980s, and a newer D. subobscura population in Utah appears to have been established more than 10 years later. In this study, we use nuclear microsatellite allele frequencies, mitochondrial restriction fragment length polymorphism (RFLP) allele frequencies, and computer simulations to investigate possible scenarios of how this species has spread across North America. Our method develops a 95% confidence interval for the maximum and minimum number of founders that could have colonized the new population given various scenarios for spread. Unlike many other methods, it may be applied to nonequilibrium source populations given certain conditions. We find that observed allele frequency differences between newer and older D. subobscura populations are consistent with very few inseminated females being transported east from the coast in a single step or with larger numbers of colonizers invading after several intermediate steps. They are not consistent with a large, panmictic population of D. subobscura colonizing Utah in a single step.

Animals↗
PubMed2000

Altered intestinal transport of amino acids in cirrhotic rats: the effect of insulin-like growth factor-I.

The intestine is an important target organ for insulin-like growth factor-I (IGF-I), an anabolic hormone synthesized in the liver upon growth hormone (GH) stimulation. Levels of IGF-I are reduced in cirrhosis, and altered GH/IGF-I axis may contribute to malnutrition in cirrhotic patients. Our aim was to study Na(+)-dependent jejunal transport of amino acids (L-leucine, L-proline, L-glutamic acid, and L-cysteine) in cirrhotic rats and to analyze the effect of IGF-I on this function. IGF-I or saline was administered for 2 wk to rats with CCl(4)-induced cirrhosis and saline was administered to healthy control rats. Transport of amino acids was assessed in brush-border membrane vesicles (BBMV) using (14)C- or (35)S-labeled amino acids, and the kinetic constants V(max) and K(t) were determined. Na(+)-independent uptake of L-leucine, L-proline, L-glutamic acid, and L-cysteine by BBMV was similar in all groups. Na(+)-dependent uptake of all four amino acids was significantly diminished in cirrhotic rats compared with both controls and IGF-I-treated cirrhotic rats. The latter two groups exhibited similar V(max) and K(t), whereas untreated cirrhotic rats had reduced V(max) and increased K(t) compared with normal controls and IGF-I-treated cirrhotic animals. In conclusion, the transport of all four tested amino acids by BBMV is impaired in cirrhotic rats, and low doses of IGF-I can correct this defect.

Amino Acids↗