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Biomedical subjects

A Jimenez

Publications and source records attributed to A Jimenez.

At least 19 recordsLinked to original sources
PubMed2001

Reverse microdialysis of N-methyl-D-aspartic acid into the lateral hypothalamus of rats: effects on feeding and other behaviors.

The effects of reverse microdialysis of N-methyl-D-aspartic acid (NMDA) into the lateral hypothalamus (LH) on feeding and other behaviors were examined. Consistent with similar studies utilizing central microinjections, NMDA reverse microdialysed into the rat LH rapidly elicited a strong concentration-dependent stimulation of feeding. The minimum perfusate concentration of NMDA needed to elicit feeding with reverse microdialysis was 660 microM, a concentration 1/50 of that needed with pressure injections. Further, eating responses could be consistently elicited in sequential tests separated by 2-4 h in the same subject, and the magnitude of the eating in the first and second tests was highly correlated (r=0.87). Behavioral analysis revealed that the main response to NMDA consisted of eating without the concomitant hyperactivity produced by central microinjections of this agonist. The other behaviors exhibited during NMDA administration were those that normally occur during spontaneous feeding in rats. Also, rats precisely compensated for the increased food intake elicited by NMDA by reducing spontaneous feeding during the subsequent nocturnal phase, so as to maintain normal daily intakes. In contrast, N-methyl-L-aspartate (NMLA) reverse microdialysed in to the LH (660 microM) did not elicit feeding nor affect any other behaviors we examined. These data support a role for LH glutamate and NMDA receptors in the control of feeding.

Animals↗
PubMed2001

Hypermethylation of the calcitonin gene in acute lymphoblastic leukaemia is associated with unfavourable clinical outcome.

We analysed calcitonin (CALC1) gene hypermethylation using semiquantitative differential polymerase chain reaction in 105 patients with adult (n = 49) and childhood (n = 56) acute lymphoblastic leukaemia (ALL), and studied the association of CALC1 hypermethylation with clinical presentation features and disease outcome. We also investigated the possible relationship between CALC1 methylation status and expression of the cell cycle inhibitor gene p57KIP2. We observed CALC1 hypermethylation in bone marrow cells from 43% (45 out of 105) of ALL patients. Clinical, molecular and laboratory features did not differ significantly between hypermethylated and hypomethylated patients, only T-cell lineage was associated with hypermethylation (14% vs. 47%, P = 0025). Complete remission rate was similar in both groups although hypermethylated patients had a higher relapse rate (68% vs. 19%, P < 0.00001) and mortality rate (55% vs. 36%, P = 0.06) than hypomethylated patients. Estimated disease-free survival (DFS) at 6 years was 66.1% for hypomethylated patients and 5.3% for hypermethylated patients (P < 0,00001). Multivariate analysis from potential prognostic factors demonstrated that CALC1 methylation status was an independent prognostic factor in predicting DFS (P = 0.0001). Separate analysis of adult and childhood ALL patients showed similar results to the whole series. In addition, hypermethylated patients showed downregulation of p57KIP2 expression. Our results suggest that CALC1 gene hypermethylation is associated with an enhanced risk of relapse independently of known poor-prognostic factors and we describe, for the first time, a possible implication of the p57KIP2 gene in the genesis and prognosis of ALL.

Adult↗
PubMed2001

E1A3 as a unique, naturally occurring BCR-ABL transcript in an indolent case of chronic myeloid leukaemia.

A woman with Ph-positive chronic myeloid leukaemia (CML) with an atypical e1a3 BCR-ABL hybrid gene is described. To our knowledge, this is the first report of this transcript type as a unique naturally occurring BCR-ABL fusion in a CML patient. This case was characterized by a low leucocyte count and a very indolent course without treatment. Because the deletion of ABL exon 2 sequences results in deletion of an essential part of the ABL SH3 domain, our case suggests that this ABL SH3 domain is not absolutely necessary for efficient induction of a myeloproliferative disease in the context of BCR-ABL/p190.

Aged↗
PubMed2001

EMA: a differentiation antigen related to node metastatic capacity of breast carcinomas.

Epithelial membrane antigen (EMA), also known as MUC1, is a mucinous glycoprotein fixed to the luminal domain of the epithelial cell membrane of normal breast ducts. However, in breast cancer cells, it is usually dispersed in the cytoplasm. EMA staining patterns of 330 breast carcinomas were examined, and three groups formed: lineal (16%), cytoplasmic (75%), and negative (9%). Although these patterns were somewhat related to histological cancer types, this was not statistically significant. However, EMA showed statistically significant univariate relationships to tumor grade, tumor size, estrogen and progesterone receptors, and nodal stage. Logistic regression analysis showed that among these variables, all of which were univariately related to node metastasis, only tumor size and EMA were independent nodal stage predictors. A combined analysis of these two factors revealed that the statistical probability of a tumor metastasizing to four or more nodes increased in each tumor size group from 0.9% to 12% for pT1, from 2% to 29% for pT2 and from 10% to 63% for pT3, depending on the EMA staining. The tumors showing a lineal pattern were the least metastasizing, while the EMA-negative tumors were the most. After recognizing these relationships between EMA staining patterns and other well-known differentiation markers and the lymph node metastatic capacity of carcinomas, and considering the results obtained by others on survival, one might conclude that EMA is both a differentiation marker and a histological prognostic factor.

Axilla↗
PubMed2000

Molecular characterization of FMN1, the structural gene for the monofunctional flavokinase of Saccharomyces cerevisiae.

Flavokinase catalyzes the transfer of the gamma-phosphoryl group of ATP to riboflavin to form the flavocoenzyme FMN. Consistent patterns of sequence similarities have identified the open reading frame of unknown function YDR236c as a candidate to encode flavokinase in Saccharomyces cerevisiae. In order to determine whether the product of this gene corresponds to yeast flavokinase, its coding region was amplified from S. cerevisiae genomic DNA by polymerase chain reaction and expressed in Escherichia coli. The purified form of the expressed recombinant protein efficiently catalyzed the formation of FMN from riboflavin and ATP. In contrast to bifunctional prokaryotic flavokinase/FAD synthetase enzymes, the yeast enzyme did not show accompanying FAD synthetase activity. Deletion of YDR236c produced yeast mutants unable to grow on rich medium; however, the growth of the ydr236cDelta mutants could be rescued by the addition of FMN to the medium. Overexpression of YDR236c caused a 50-fold increase in flavokinase specific activity in yeast cells. These findings demonstrate that YDR236c corresponds to the gene encoding a monofunctional flavokinase in yeast, which we propose to be designated as FMN1. The FMN1 gene codes for a 25-kDa protein with characteristics of signals for import into mitochondria. By immunoblotting analysis of Saccharomyces subcellular fractions, we provide evidence that the Fmn1 protein is localized in microsomes and in mitochondria. Analysis of submitochondrial fractions revealed that the mitochondrial form of Fmn1p is an integral protein of the inner membrane exposing its COOH-terminal domain to the matrix space. A similarity search in the data base banks revealed the presence of sequences homologous to yeast flavokinase in the genome of several eukaryotic organisms such as Schizosaccharomyces pombe, Arabidopsis thaliana, Drosophila melanogaster, Caenorhabditis elegans, and humans.

Amino Acid Sequence↗
PubMed2000

Non-NMDA receptor-mediated mechanisms are involved in levodopa-induced motor response alterations in Parkinsonian rats.

Chronic dopaminomimetic administration to parkinsonian animal models or Parkinson's disease patients leads to characteristic alteration in motor response. Previous studies suggested that the nonphysiologic stimulation of dopaminergic receptors on striatal medium spiny neurons enhances the synaptic efficacy of juxtaposed glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype. Resultant NMDA receptor sensitization due to differential changes in subunit phosphorylation appears to favor alterations in striatal output in ways that influence motor function. To detail the involvement of NMDA receptors further as well as to determine whether similar functional changes might develop in alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, the effects of selective antagonist of AMPA receptors (6-nitro-7-sulfamoyl-benzo[f]-quinoxaline-2,3 (1H,4H)-dione sodium salt, NBQX, 10 mg/kg) on levodopa-induced response alterations in 6-hydroxydopamine (6-OHDA) lesioned rats were compared with drugs which act competitively (3-(+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonicacid, CPP, 6.25 mg/kg) or noncompetitively (dextromethorphan, 40 mg/kg) to block NMDA receptors, or a nonselective inhibitor of glutamatergic transmission (2-amino-6-trifluoromethoxy benzothiazole, riluzole, 5 mg/kg). We found that the shortened duration of the motor response to levodopa, which underlies human wearing-off fluctuations, was reversed to a similar degree by the acute coadministration of CPP, NBQX, or riluzole (n = 4-6) but dextromethorphan did not. These observations strengthen the possibility that a reduction in levodopa-associated changes in motor response by inhibitors of glutamatergic transmission acting generally or selectively at the glutamate binding-sites may relate to their ability to attenuate pathologic gain in striatal glutamatergic function. The capacity of NBQX to reverse these altered responses suggests that an enhanced synaptic efficacy of striatal AMPA receptors may also participate in the generation of these motor response changes in levodopa-treated parkinsonian rats.

Animals↗
PubMed2000

Molecular analysis of lineage-specific chimerism and minimal residual disease by RT-PCR of p210(BCR-ABL) and p190(BCR-ABL) after allogeneic bone marrow transplantation for chronic myeloid leukemia: increasing mixed myeloid chimerism and p190(BCR-ABL) detection precede cytogenetic relapse.

We studied lineage-specific chimerism and minimal residual disease (MRD) in sequential posttransplant samples from 55 patients who underwent unmanipulated (n = 44) or partially T-cell-depleted (n = 11) allogeneic bone marrow transplantation (BMT) for chronic myeloid leukemia (CML). Chimerism was assessed by polymerase chain reaction (VNTR [variable number of tandem repeats]-PCR) analysis in highly purified CD19+, CD3+, CD15+, and CD56+ cell fractions, whereas MRD was investigated in whole blood by reverse transcriptase-PCR (RT-PCR) of both p210(BCR-ABL) and p190(BCR-ABL) hybrid transcripts. Of 55 patients, 14 (including 6 T-cell-depleted patients) had cytogenetic relapse at 5-80 months and progressed to hematologic relapse, while 41 patients remained in prolonged cytogenetic remission 12-107 months post-BMT. Before leukemia recurrence, patients in the relapse group showed a consistent evolution pattern sequentially featured by persistent p210(BCR-ABL) positivity, increasing mixed chimerism (MC) in myeloid cells, p190(BCR-ABL) positivity, and, finally, cytogenetic relapse. Myeloid MC preceded cytogenetic relapse by 2-12 months, whereas p190(BCR/ABL) was detected 1-6 months prior to cytogenetic relapse in 11 patients and concomitant with cytogenetic relapse in 3 patients. In the remission group, all patients invariably tested negative for p190(BCR-ABL); 10 patients tested positive for p210(BCR-ABL) at variable time-points but showed persistent full donor chimerism (DC), whereas 31 patients tested p210(BCR-ABL) negative and displayed full DC or transient MC due to the persistence of recipient T cells. Two patients in the relapse group were successfully reinduced into molecular remission with donor lymphocyte infusion. Sequential molecular analysis after such treatment showed the inverse pattern to that observed prior to relapse, ie, progressive disappearance of p190(BCR-ABL) transcripts, conversion of myeloid chimerism to donor type, and, finally, p210(BCR-ABL) negativity. We conclude that lineage-specific chimerism and p190(BCR-ABL) messenger RNA (mRNA) analyses contribute a better characterization of CML evolution after BMT and enable early identification of patients at the highest risk of relapse. (Blood. 2000;95:2659-2665)

Adolescent↗
PubMed2000

Longitudinal studies in the epidemiology of vesicular stomatitis on Costa Rican dairy farms.

Twenty-three Costa Rican dairy herds from an vesicular stomatitis (VS) endemic area were under an active surveillance between April 1997 and March 1999. Ninety-two confirmed cases of VS New Jersey were found. Factors associated with clinical cases of VS virus New Jersey were: Parity (animals of parity 4 or 5 were 5.3 times more likely to present a clinical case than animals of parity 3 and lower; on the other hand, animals of parity 6 and higher showed an odds 4.6 times greater than animals of parity 3 and lower.) Ecological life zone (animals in premountain moist forest were 7.4 times more likely to present clinical cases than animals in lower mountain rain forest). Factors associated with seropositivity at the time of birth were farm and breed (Jersey calves had an odds 14.7 times greater than Holstein calves). Seroconversion, defined as the first twofold increase in the titers of the blood, was associated with farm and showed four peaks during the study period, September (wet season) 1997, February (dry season) 1998, September 1998, and February 1999. Finally, time to event analysis showed difference between farms and age, older animals showed the first seroconversion earlier than younger animals.

Age Distribution↗
PubMed2000

Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and progression.

We assessed the effects of 78 potential chemopreventive agents in the F344 rat using two assays in which the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon was the measure of efficacy. In both assays ACF were induced by the carcinogen azoxymethane (AOM) in F344 rats by two sequential weekly injections at a dose of 15 mg/kg. Two weeks after the last AOM injection, animals were evaluated for the number of aberrant crypts detected in methylene blue stained whole mounts of rat colon. In the initiation phase protocol agents were given during the period of AOM administration, whereas in the post-initiation assay the chemopreventive agent was introduced during the last 4 weeks of an 8 week assay, a time when ACF had progressed to multiple crypt clusters. The agents were derived from a priority listing based on reports of chemopreventive activity in the literature and/or efficacy data from in vitro models of carcinogenesis. During the initiation phase carboxyl amidoimidazole, p-chlorphenylacetate, chlorpheniramine maleate, D609, diclofenac, etoperidone, eicosatetraynoic acid, farnesol, ferulic acid, lycopene, meclizine, methionine, phenylhexylisothiocyanate, phenylbutyrate, piroxicam, 9-cis-retinoic acid, S-allylcysteine, taurine, tetracycline and verapamil were strong inhibitors of ACF. During the post-initiation phase aspirin, calcium glucarate, ketoprofen, piroxicam, 9-cis-retinoic acid, retinol and rutin inhibited the outgrowth of ACF into multiple crypt clusters. Based on these data, certain phytochemicals, antihistamines, non-steroidal anti-inflammatory drugs and retinoids show unique preclinical promise for chemoprevention of colon cancer, with the latter two drug classes particularly effective in the post-initiation phase of carcinogenesis.

Animals↗
PubMed1999

A single nucleotide change in the MNR1 (VCX1/HUM1) gene determines resistance to manganese in Saccharomyces cerevisiae.

Several spontaneous Mn2+-resistant mutants were isolated from Saccharomyces cerevisiae strain W303-1b. All displayed an identical semidominant resistance phenotype. The gene responsible for this phenotype from one of these mutants, as well as that from the wild-type, was cloned and sequenced, which allowed the identification of a single nucleotide change in the former. Further sequencing work with the remaining mutants, as well as with others on the MNAR1 gene (Bianchi et al., 1981), indicated that all displayed the same mutation (mnr1 allele). In addition, MNR1 was shown to correspond to VCX1 and HUM1, which determine a vacuolar membrane protein. The nucleotide sequence has been deposited at EMBL, with Accession No. AJ001272.

Amino Acid Sequence↗
PubMed1999

Elevated non-transferrin bound iron in the lungs of patients with Pneumocystis carinii pneumonia.

OBJECTIVE: The aim of the present work was to determine the concentrations of iron and iron-binding proteins in the lungs of patients suffering from Pneumocystis carinii (PCP), which is crucial for justifying the treatment with iron-chelating agents in this disease. PATIENTS AND METHODS: Bronchoalveolar lavage was performed in 10 HIV patients with PCP and five healthy controls. Total iron and iron-binding proteins (transferrin, ferritin and lactoferrin) were measured in acellular bronchoalveolar lavage fluid (BALF) in both groups. Iron was determined by atomic absorption spectrometry; transferrin and lactoferrin were measured using specific enzyme-linked immunosorbent assays (ELISA); and ferritin concentration was quantified by automated immunonephelometry. RESULTS: Our findings in patients with PCP demonstrated a six- to seven-fold increase of total iron levels and an eight-fold increase of ferritin in bronchoalveolar lavage fluid when compared with controls. No significant differences were found in transferrin or lactoferrin levels. Moreover, our results suggest that this iron is non-transferrin bound. CONCLUSION: Non-transferrin bound iron is increased in the lower respiratory tracts of PCP patients. This finding would lend experiment support to the use of iron-chelating agents in this disease.

AIDS-Related Opportunistic Infections↗
PubMed1999

LC method development for ibuprophen and validation in different pharmaceuticals.

An isocratic LC method for the simultaneous determination of ibuprophen (IBU) and its degradation product (4-isobutylacetophenone) has been developed and validated for different pharmaceuticals (sachets, tablets and gels). The chromatographic separation was achieved with phosphoric acid solution (pH 3.2)-acetonitrile (50:50, v/v) as mobile phase, a Hypersil C18 column and UV detection at 254 nm. In all cases, sample preparation was required before HPLC analysis.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Systemic administration of NMDA and AMPA receptor antagonists reverses the neurochemical changes induced by nigrostriatal denervation in basal ganglia.

In Parkinson's disease, nigrostriatal denervation leads to an overactivity of the subthalamic nucleus and its target areas, which is responsible of the clinical manifestations of the disease. Because the subthalamic nucleus uses glutamate as neurotransmitter and is innervated by glutamatergic fibers, pharmacological blockade of glutamate transmission might be expected to restore the cascade of neurochemical changes induced by a dopaminergic denervation within the basal ganglia. To test this hypothesis, two types of glutamate antagonists, the NMDA receptor antagonist MK-801 and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist LY293558, were administered systemically, either alone or in combination with L-DOPA, in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway. The effect of treatment was assessed neurochemically by analyzing at the cellular level the functional activity of basal ganglia output structures and the subthalamic nucleus using the expression levels of the mRNAs coding for glutamic acid decarboxylase and cytochrome oxidase, respectively, as molecular markers of neuronal activity. The present study shows that treatment with glutamate antagonists, and particularly with AMPA antagonists, alone or in combination with L-DOPA, reverses the overactivity of the subthalamic nucleus and its target areas induced by nigrostriatal denervation. These results furnish the neurochemical basis for the potential use of glutamate antagonists as therapeutic agents in Parkinson's disease.

Animals↗
PubMed1999

Parathyroid function as a determinant of the response to calcitriol treatment in the hemodialysis patient.

BACKGROUND: Bolus calcitriol (CTR) is used for the treatment of secondary hyperparathyroidism in dialysis patients. Although CTR treatment reduces parathyroid hormone (PTH) levels in many dialysis patients, a significant number fail to respond. METHODS: To learn whether or not an analysis of parathyroid function could further illuminate the response to CTR, a PTH-calcium curve was performed before and after at least two months of CTR treatment in 50 hemodialysis patients with a predialysis intact PTH of greater than 300 pg/ml. RESULTS: For the entire group (N = 50), CTR treatment resulted in a 24% reduction in predialysis (basal) PTH from 773 +/- 54 to 583 +/- 71 pg/ml (P < 0.001), whereas ionized calcium increased from 1.10 +/- 0.02 to 1.22 +/- 0.02 mM (P < 0.001); however, maximal and minimal PTH did not change from pre-CTR values. Based on whether or not the basal PTH decreased by 40% or more during CTR treatment, patients were divided into responders (Rs, N = 25) and nonresponders (NRs, N = 25). Before CTR, the NR group was characterized by a greater basal (959 +/- 80 vs. 586 +/- 51 pg/ml, P < 0.001) and maximal (1899 +/- 170 vs. 1172 +/- 108 pg/ml, P < 0. 001) PTH and serum phosphorus (6.14 +/- 0.25 vs. 5.14 +/- 0.34 mg/dl, P < 0.01). Logistical regression analysis showed that the pre-CTR basal PTH was the most important predictor of the post-CTR basal PTH, and a pre-CTR basal PTH of 750 pg/ml represented a 50% probability of a response. Basal PTH correlated with the ionized calcium in the NR group (r = 0.59, P = 0.002) but not in the R group (r = 0.06, P = NS). In the R group, an inverse correlation was present between ionized calcium and the basal/maximal PTH ratio, an indicator of whether calcium is suppressing basal PTH secretion relative to the maximal secretory capacity (maximal PTH) r = -0.55, P = 0.004; in the NR group, this correlation approached significance but was positive (r = 0.34, P = 0.09). After CTR treatment, serum calcium increased in both groups, and despite marked differences in basal PTH (Rs, 197 +/- 25 vs. NRs, 969 +/- 85 pg/ml), an inverse correlation between ionized calcium and basal/maximal PTH was present in both groups (Rs, r = -0.61, P = 0.001, and NRs, r = -0.60, P = 0.001). CONCLUSIONS: (a) Dynamic testing of parathyroid function provided insights into the pathophysiology of PTH secretion in hemodialysis patients. (b) The magnitude of hyperparathyroidism was the most important predictor of the response to CTR. (c) Before CTR treatment, PTH was sensitive to calcium in Rs, and serum calcium was PTH driven in NRs, and (d) after the CTR-induced increase in serum calcium, calcium suppressed basal PTH relative to maximal PTH in both groups.

Calcitriol↗
PubMed1999

Temporal variations in blood glutathione peroxidase (GSHPx) activity in sheep at pasture in a Mediterranean area.

The present study evaluates blood GSHPx activity in 18 sheep flocks at range, to identify those seasons with the highest risk of selenium deficiency. Samples were taken from 1108 15-day-old lambs during the two usual lambing periods in this geographical area (autumn-winter and spring-summer). The overall mean values in the first period (146.69 +/- 3.41 i.u./g Hb) was higher than in the second one (107.50 +/- 3.53 i.u./g Hb). This may be explained by the special features of the climate in the Mediterranean area, which allow an optimum growth of grass from October to May. Therefore, the lambs born in spring-summer are from pregnancies in months when feeding is based only upon grazing. However, lambs born in autumn-winter comes from ewes gestating during the summer, when supplementation with cereal grains is given. As a conclusion, lambs born in spring-summer in this area are at higher risk to selenium-deficiency related disorders.

Animals↗
PubMed1998

Role of the ascorbate-glutathione cycle of mitochondria and peroxisomes in the senescence of pea leaves

We investigated the relationship between H2O2 metabolism and the senescence process using soluble fractions, mitochondria, and peroxisomes from senescent pea (Pisum sativum L.) leaves. After 11 d of senescence the activities of Mn-superoxide dismutase, dehydroascorbate reductase (DHAR), and glutathione reductase (GR) present in the matrix, and ascorbate peroxidase (APX) and monodehydroascorbate reductase (MDHAR) activities localized in the mitochondrial membrane, were all substantially decreased in mitochondria. The mitochondrial ascorbate and dehydroascorbate pools were reduced, whereas the oxidized glutathione levels were maintained. In senescent leaves the H2O2 content in isolated mitochondria and the NADH- and succinate-dependent production of superoxide (O2.-) radicals by submitochondrial particles increased significantly. However, in peroxisomes from senescent leaves both membrane-bound APX and MDHAR activities were reduced. In the matrix the DHAR activity was enhanced and the GR activity remained unchanged. As a result of senescence, the reduced and the oxidized glutathione pools were considerably increased in peroxisomes. A large increase in the glutathione pool and DHAR activity were also found in soluble fractions of senescent pea leaves, together with a decrease in GR, APX, and MDHAR activities. The differential response to senescence of the mitochondrial and peroxisomal ascorbate-glutathione cycle suggests that mitochondria could be affected by oxidative damage earlier than peroxisomes, which may participate in the cellular oxidative mechanism of leaf senescence longer than mitochondria.

Journal Article↗