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Biomedical subjects

M Perez

Publications and source records attributed to M Perez.

At least 19 recordsLinked to original sources
PubMed1998

Tumor necrosis factor-induced apoptosis stimulates p53 accumulation and p21WAF1 proteolysis in ME-180 cells.

Tumor necrosis factor (TNF)-mediated apoptotic signaling has been characterized by activation of specific protease or protein kinase cascades that regulate the onset of apoptosis. TNF has also been shown to induce oxidative or genotoxic stress in some cell types, and apoptotic potential may be determined by the cellular response to this stress. To determine the role of genotoxic stress in TNF-mediated apoptosis, we examined cellular accumulation of p53 in TNF-treated ME-180 cells selected for apoptotic sensitivity (ME-180S) or resistance (ME-180R) to TNF. Although TNF was able to activate receptor-mediated signaling in either cell line, p53 accumulation was measurable only in apoptotically sensitive ME-180S cells. TNF-induced changes in p53 levels were detected 1 h after treatment, and peak levels were measurable 4-8 h after TNF exposure. TNF was unable to induce p21WAF1 in either cell line but affected the stability of this protein in apoptotically responsive ME-180S cells. Evidence of p21WAF1 proteolysis was detected by monitoring the appearance of a 16-kDa immunoblottable p21WAF1 fragment, which became detectable 4 h after TNF addition and increased in content before the onset of DNA fragmentation (16-24 h). The kinetics of p21WAF1 proteolysis closely paralleled those of poly(ADP-ribose) polymerase, suggesting cleavage of p21WAF1 by activation of an apoptotic protease. Pretreatment of ME-180S cells with the apoptotic protease inhibitor YVAD blocked TNF-induced apoptosis and prevented both poly(ADP-ribose) polymerase and p21WAF1 degradation but did not affect p53 induction. These results provide evidence for the early onset of genotoxic stress in cells committed to TNF-mediated apoptosis and for divergence in propagation of this signal in non-responsive cells. In addition, TNF-induced p21WAF1 proteolysis may be mediated by an apoptotic protease and may contribute to the apoptotic process by disrupting p53 signaling, altering cell cycle inhibition, and limiting cellular recovery from genotoxic stress.

Amino Acid Chloromethyl Ketones↗
PubMed1998

Relationship between helminthic infection and IgE response in atopic and nonatopic children in a tropical environment.

BACKGROUND: Although IgE antibody is clearly involved in allergic reactions to environmental allergens, this immunoglobulin is an important component of host-protective immune responses against the helminthic parasites that are endemic in the majority of the world population. However, these infections not only stimulate the production of antiparasite IgE antibody but can nonspecifically induce polyclonal IgE synthesis that results in highly elevated total serum IgE levels. Such polyclonal stimulation can diminish specific IgE antibody responses and cause saturation of mast cell Fc epsilon receptors, thus inhibiting allergic reactivity. This may represent a mechanism of immune evasion by the parasite. OBJECTIVE: Because an atopic disposition is generally recognized to be associated with elevated IgE synthesis against environmental allergens, the aim of this study was to evaluate the influence of atopy on the antiparasite response. To this end, we examined two groups of Venezuelan children in whom the intestinal helminth Ascaris lumbricoides is endemic but that differ greatly in their level of atopy. One group was from an island population (Coche Island) that has a very strong atopic background and in which the prevalence of allergic disease is extremely high. The other was a group of nonatopic children belonging to a mainland population (Barrio Los Erasos) that is of comparable socioeconomic level and has an exposure to helminthic infection similar to that of the island group but a relatively low expression of allergic diseases. RESULTS: Although the living conditions and the prevalence of Ascaris infection of the two groups were comparable, the intensity of the parasitic infection was considerably higher in the nonatopic mainland children (geometric mean values of eggs per gram of feces: Barrio Los Erasos, 7621; Coche Island, 1435; p < 0.001). In addition, their total serum IgE levels were significantly more elevated than in the atopic island group (geometric mean: Barrio Los Erasos, 2172; Coche Island, 941 IU/ml; p < 0.001). In contrast, the specific anti-Ascaris response was much stronger in the atopic children (geometric mean: Barrio Los Erasos, 0.30; Coche Island, 0.91 PRU/ml; p < 0.001), which resulted in the ratio of specific to total IgE being nine times higher than in the nonatopic mainland subjects. These differences were maintained even when the children were matched on the basis of infection intensity, thus indicating that the atopic children have an intrinsic propensity to favor specific over polyclonal IgE responses to the parasite. CONCLUSIONS: The children with a strong atopic background demonstrated IgE responses concordant with an enhanced protective response against helminthic parasites and had significantly lower intensities of infection than their nonatopic counterparts. These observations support the concept that the atopic state has conferred a selective evolutionary advantage that could compensate for its involvement in allergic disease.

Animals↗
PubMed1998

The importance of family functioning to caregiver adaptation in mothers of child cancer patients: testing a social ecological model.

This study was designed to investigate associations between family relationships, personal-psychological caregiver adaptation (ie, depressive symptomatology, sense of burden), and ability to function within the health care system (perceived doctor-parent relationship) in mothers of child cancer patients. Data were collected through a survey of a sample of 29 mothers whose children were diagnosed with some form of childhood cancer, mainly leukemia. Family functioning was positively related to both caregiver adaptation and doctor-parent relationship. Mothers who reported decreased maternal depression and burden were significantly more likely to report respectively improved spousal relationships and improved spousal communication. Mothers reporting more positive doctor-parent relationships also described themselves as having improved relationships with spouse and child, and improved spousal communication. Maternal well-being and doctor-parent relationship were not directly related. By suggesting that both intrapsychic and instrumental maternal adaptation are influenced by positive relationships in the family, this study provides support for the social ecological model of stress. The possibility that family factors exert a direct influence on both caregiver intrapsychic well-being and instrumental skills argues for the importance of their being carefully considered in any models evaluating caregiver adaptation.

Adaptation, Psychological↗
PubMed1997

5-HT1B receptor antagonist properties of novel arylpiperazide derivatives of 1-naphthylpiperazine.

A new series of arylpiperazide derivatives of 1-naphthylpiperazine of general formula 4 has been prepared and evaluated as 5-HT1B antagonists. Binding experiments at cloned human 5-HT1A, 5-HT1B, and 5-HT1D receptors show that these derivatives are potent and selective ligands for 5-HT1B/1D subtypes with increased binding selectivity versus the 5-HT1A receptor when compared to 1-naphthylpiperazine (1-NP). Studies of inhibition of the forskolin-stimulated cAMP formation mediated by the human 5-HT1B receptor demonstrate that the nature of the arylpiperazide substituent modulates the intrinsic activity of these 1-NP derivatives. Among them, 2-[[8-(4-methylpiperazin-1-yl)naphthalen-2-yl]oxy] -1-(4-o-tolylpiperazin-1-yl)ethanone (4a) was identified as a potent neutral 5-HT1B antagonist able to antagonize the inhibition of 5-HT release induced by 5-CT (5-carbamoyltryptamine) in guinea pig hypothalamus slices. Moreover, 4a was found to potently antagonize the hypothermia induced by a selective 5-HT1B/1D agonist in vivo in the guinea pig following oral administration (ED50 = 0.13 mg/kg).

Animals↗
PubMed1997

Synthesis of a new zinc finger peptide; comparison of its 'code' deduced and 'CASTing' derived binding sites.

Using two synthetic oligonucleotides, we have constructed a new gene containing three zinc finger motifs of the Cys2-His2 type. We named this artificial gene 'Mago'. The Mago nucleotide triplets encoding the amino acid positions, described to be crucial for DNA binding specificity, have been chosen on the basis of the proposed recognition 'code' that relates the zinc finger's primary structure to the DNA binding target. Here we demonstrate that Mago protein specifically binds the 'code' DNA target, with a dissociation constant (Kd) comparable to the Kd of the well known Zif268 protein with its binding site. Moreover, we show that the deduced Mago 'code' and the 'experimental' selected DNA binding sites are almost identical, differing only in two nucleotides at the side positions.

Amino Acid Sequence↗
PubMed1997

Membrane permeability changes induced in Escherichia coli by the SH protein of human respiratory syncytial virus.

The small hydrophobic (SH) protein of human respiratory syncytial virus (HRSV) has been efficiently expressed in Escherichia coli. In analogy to small hydrophobic proteins encoded by other RNA viruses, membrane permeability changes to low-molecular-weight compounds were detected in bacteria expressing HRSV SH protein. These changes implied, at least, the entry of both the protein synthesis inhibitor hygromycin B and the beta-galactoside substrate o-nitrophenyl-beta-d-galactopyranoside and the exit of preloaded [3H]uridine from bacterial cells. Site-directed mutagenesis indicated that the C-terminal end of SH is needed for induction of membrane permeability changes. In addition, amino acid substitution at residue 32 (Ile to Lys) abolished that activity. This was correlated with a drastic increase in SH electrophoretic mobility and a decrease of the predicted values of alpha-helix for all residues of the SH transmembrane domain. Other sequence changes have either partial effect or no effect on the membrane permeability changes induced by the SH protein. However, none of the mutations abrogated the association of SH protein with bacterial membranes, indicating that incorporation of SH protein to membranes is not sufficient to induce the observed changes. Membrane permeability changes then might provide a useful test for the identification of key amino acid residues in this unique HRSV gene product.

Amino Acid Sequence↗
PubMed1997

Loss of low-affinity nerve growth factor receptor during malignant transformation of the human prostate.

BACKGROUND: The low-affinity nerve growth factor receptor (LNGFR) exhibits an inverse association of epithelial expression with the degree of differentiation of prostate adenocarcinoma tissue. However, the stage at which loss of LNGFR expression is first manifested in the malignant prostate has not been determined. METHODS: In order to characterize loss of LNGFR expression in the clinically localized malignant prostate of untreated patients, the pattern of expression of the LNGFR was examined in nonmalignant tissues, consisting of normal and prostatic intraepithelial neoplastic tissues, and in malignant tissues that had been graded by Gleason's scores and categorized into well, moderately, and poorly differentiated adenocarcinomas. In order to determine whether there was an inverse correlation between LNGFR expression and prostate-specific antigen (PSA) secretion, preoperative concentrations of PSA in the serum were also analyzed in relation to the differentiative state of the adenocarcinomas. RESULTS: Premalignant prostate tissues exhibited expression of the LNGFR on all epithelia, whereas in malignant prostate tissues a proportion of epithelia exhibited loss of expression of the LNGFR. An increase in Gleason score of the adenocarcinoma tissue was associated with an increase in the proportion of epithelia that exhibited loss of expression of the LNGFR. Moreover, the proportion of epithelia expressing the LNGFR was inversely correlated with an increase in the concentration of serum PSA. The loss of LNGFR expression was first manifested in epithelia that occurred toward the center of adenocarcinoma tissue. Furthermore, extensive loss of expression of the LNGFR of approximately 63% occurred in well-differentiated adenocarcinomas. CONCLUSIONS: These observations demonstrate that loss of LNGFR expression is first observed in well-differentiated malignant epithelia. Hence, loss of the LNGFR may be indicative of the initial stages of malignant transformation of prostate epithelia, as well as all subsequent stages of prostate adenocarcinomas.

Adenocarcinoma↗
PubMed1997

Short-term effects of prone position in critically ill patients with acute respiratory distress syndrome.

OBJECTIVE: Changing the position from supine to prone is an emerging strategy to improve gas exchange in patients with the acute respiratory distress syndrome (ARDS). The aim of this study was to evaluate the acute effects on gas exchange, hemodynamics, and respiratory system mechanics of turning critically ill patients with ARDS from supine to prone. DESIGN: Open, prospective study. SETTING: General intensive care units. PATIENTS: 23 patients [mean age 56 +/- 17 (SD) years] who met ARDS criteria and had a Lung Injury Score > 2.5 (mean 3.25 +/- 0.3). INTERVENTIONS: The decision to turn a patient was made using a protocol based on impaired oxygenation despite the use of positive end-expiratory pressure and a fractional inspired oxygen (FIO2) of 1. MEASUREMENTS AND RESULTS: We measured gas exchange and hemodynamic variables in all patients and in 16 patients calculated respiratory system compliance when they were supine and 60 to 90 min after turning them to a prone position. This latter position was remarkably well tolerated and no clinically relevant complications or events were detected either during turning or while prone. The partial pressure of oxygen in arterial blood (PaO2)/FIO2 ratio improved from 78 +/- 37 mm Hg supine to 115 +/- 31 mm Hg prone (p < 0.001), and intrapulmonary shunt decreased from 43 +/- 11 to 34 +/- 8% (p < 0.001). Cardiac output and other hemodynamic parameters were not affected. Respiratory system compliance slightly improved from 24.7 +/- 10.2 ml/cmH20 supine to 27.8 +/- 13.2 ml/cmH20 prone (p < 0.05). An improvement in PaO2/FIO2 of more than 15% from changing from supine to prone was found in 16 patients (responders). Responders had more hypoxemia (PaO2/FIO2 70 +/- 23 vs 99 +/- 53 mm Hg in non-responders, p < 0.01), more hypercapnia (partial pressure of carbon dioxide in arterial blood (70 +/- 27 vs 64 +/- 9 mm Hg, p < 0.01) and a shorter elapsed time to the onset of ARDS and turning to the prone position (11.8 +/- 16 vs 32.8 +/- 42 days, p < 0.01). CONCLUSIONS: Turning critically ill, severely hypoxemic patients from the supine to the prone position is a safe and useful therapeutic intervention. Our data suggest that prone positioning should be carried out early in the course of ARDS.

Adult↗
PubMed1997

Advances in dermatologic surgery.

The major advances in dermatologic surgery for this period reside in the areas of diagnosis and management of cutaneous melanoma, laser surgery, tumescent liposuction, and tumorigenesis. A closer look at these advances is presented.

Forecasting↗
PubMed1997

Thyrotropin (TSH) receptor autoantibodies do not appear to bind to the TSH receptor produced in an in vitro transcription/translation system.

An in vitro transcription/translation (TnT) system was used to produce 35S-labeled full-length TSH receptor (TSHR) and TSHR extracellular domain (TSHRex). The interaction of the labeled proteins with TSHR autoantibodies in Graves' sera was then studied using an immunoprecipitation assay. In the assay, 35S-labeled TSHR or TSHRex were incubated with test sera, and any immune complexes formed were precipitated with protein A-Sepharose (in the case of mouse monoclonal antibodies, antimouse IgG-agarose was used). Rabbit antibodies to the TSHR and a mouse monoclonal antibody precipitated as much as 50% of the 35S-labeled TSHR preparations compared with about 2% for normal rabbit serum and 4% for a control monoclonal antibody. However, none of 34 Graves' sera (TSHR autoantibody levels ranging from 14-95% inhibition of [125I]TSH binding) were able specifically to immunoprecipitate 35S-labeled TSHR or TSHRex. These negative findings were confirmed by analysis of the immunoprecipitates on SDS-PAGE followed by autoradiography. Our results indicate that the TnT system is not useful for producing labeled TSHR preparations that can bind TSHR autoantibodies well. This is in contrast to TnT produced 35S-labeled glutamic acid decarboxylase, thyroid peroxidase, and 21-hydroxylase, which react well with their respective autoantibodies. One main difference between these 3 autoantigens and the TSHR is that the receptor is highly glycosylated, and this extensive glycosylation may be of critical importance for correct folding of the receptor. Consequently, the inability of the TnT system to glycosylate proteins could explain in part why TnT-produced 35S-labeled TSHR and TSHRex do not bind TSHR autoantibodies.

Animals↗
PubMed1997

The toxic and accumulative effects of short-term exposure to cadmium in rainbow trout (Oncorhynchus mykiss).

Groups of 20 trout (Oncorynchus mykiss) were exposed for 3-w periods to different subacute oral doses of Cl2Cd (0.01, 0.025 or 0.05 microgram Cd/mL). Cadmium toxicity and accumulation were studied in kidney, liver, gills, muscle and brain weekly. Cadmium determination was carried out using atomic absorption spectrocopy (AAS) with graphite furnace. After 21 d exposure, cadmium concentrations increased significantly. In all tissues studied except muscle and brain. Cadmium storage presented the following sequence: kidney > liver > gills. At the beginning, cadmium accumulation was linearly dose dependent (r = 0.999). Then, at the highest dose (0.05 microgram Cd/mL) accumulation increased rapidly during the second week of exposure until equilibrium was reached. In contrast, liver did not accumulate cadmium selectively, suggesting that liver is able to eliminate cadmium, perhaps through metallothionein formation. Cadmium levels in gills were higher than controls (P < 0.05) and showed signs of equilibrium after the first week. According to organ weight/body weight ratios, there was similar accumulation behavior. Liver and kidney ratios increased dose dependently, but gills and brain did not have significant differences.

Absorption↗
PubMed1996

Serotonin dimers: application of the bivalent ligand approach to the design of new potent and selective 5-HT(1B/1D) agonists.

A series of serotonin dimers of formula 4 in which two serotonin moeities are linked together through their 5-hydroxyl residue has been prepared and evaluated as 5-HT(1B/1D) receptor agonists. Binding experiments at cloned human 5-HT(1B), 5-HT(1D), and 5-HT(1A) receptors show that all of these dimers are very potent ligands at 5-HT(1B/1D) receptors with increased binding selectivity vs the 5-HT(1A) receptor when compared to serotonin. Studies of inhibition of the forskolin-stimulated c-AMP formation mediated by the human 5-HT(1B) receptor (formerly the 5-HT(1Dbeta) receptor) demonstrate that all of these serotonin dimers behave as full agonists. Among them, the piperazide derivatives of bis-serotonin, 4g,j, were also identified as very potent agonists in contracting the New Zealand white rabbit saphenous vein (pD2 = 7.6 in each case compared to 5.8 for sumatriptan). Results analysis supports the hypothesis that the important increase in potency of the serotonin dimers can be attributed to the presence of two serotonin pharmacophores in the same molecule, while the enhanced selectivity for 5-HT(1B/1D) receptor subtypes may be due to the position of the spacer attachment to serotonin.

Animals↗
PubMed1996

Regulation of epidermal growth factor receptor activity by crotoxin, a snake venom phospholipase A2 toxin. A novel growth inhibitory mechanism.

Crotoxin (CT), a phospholipase A2 (PLA2) derived from the venom of Crotalus durissus terrificus, is a heterodimeric protein composed of subunit B with enzymatic activity and a binding regulatory subunit (A) without enzyme activity. Although the PLA2 activity of CT may be important in its anti-proliferative activity, its cytostatic mechanism is unknown. In this study, we examined the cytostatic effect of PLA2-associated CT activity on squamous carcinoma cells expressing distinct levels of epidermal growth factor receptor (EGFr). CT was most effective in suppressing growth on cells expressing high intrinsic levels of EGFr. Cardiotoxin, another membrane active toxin with no intrinsic PLA2 activity, had no differential anti-proliferative activity on cells expressing high EGFr levels, suggesting a correlation between EGFr expression and CT-directed anti-proliferative activity. Both chemically modified CT (MCT) devoid of PLA2 activity and covalently cross-linked CT (CCT), which is functionally unable to utilize cellular membranes as PLA2 substrate, were also without growth inhibitory activity. No evidence for direct binding of CT to EGFr was found, although pretreatment with EGF was able to partially suppress the anti-proliferative activity of CT. Tyrosine phosphorylation of EGFr, however, was stimulated by CT in intact A431 cells. Tyrosine phosphorylation of EGFr was concentration-dependently stimulated (3- to 8-fold) in cellular membranes of A431 cells treated in vitro with CT but not with anti-proliferatively inactive MCT or CCT. The data provide evidence for transmembrane receptors involved in growth signaling (namely EGFr) as cellular targets and potential effectors of PLA2-mediated anti-proliferative activity of snake venom.

Animals↗
PubMed1996

Zfp60, a mouse zinc finger gene expressed transiently during in vitro muscle differentiation.

The complete cDNA coding sequence of the zinc finger gene Zfp60 is reported. The predicted amino acid sequence of the Zfp60 protein has been found to contain 19 zinc finger motives clustered at the C-terminus. At its N-terminus, Zfp60 shares with other members of the zinc finger gene family two additional conserved amino acid modules named Kruppel Associated Boxes (KRAB). The expression patterns of Zfp60, MyoD and MHC mRNAs have been followed during in vitro myogenic differentiation of C2 cells. We show that the bacterial produced Zfp60 protein binds DNA only in presence of zinc ions. Zfp60 locus has been mapped in chromosome 7, where other Zfp loci are localised.

Amino Acid Sequence↗
PubMed1996

Total body calcium and bone mineral content: comparison of dual-energy X-ray absorptiometry with neutron activation analysis.

The aim of this study was to compare the dual-energy X-ray absorptiometry (DXA) measurement of bone mass with an independent measure of body calcium obtained by neutron activation analysis (NAA). Total body bone mineral content (BMC) was measured using DXA in 46 subjects in the age range 5-47 years (17 children, 28 young women, and 1 adult male). Total body calcium (TBCa) was measured in the same subjects by in vivo NAA. The correlation between the two measures of bone mass was highly significant (BMC[g] = 3.22 x TBCa[g] - 51.4, r > 0.98, p < 0.0001, SEEBMC = 122.7 g). When BMC was the independent parameter, the SEETBCa was 37.5 g. Bland-Altman analysis indicated a mean difference of 2.8 g with a standard error +/- 4.7 g for TBCaNAA versus TBCaDXA when the BMC values were converted to TBCa. The relative change in bone mass (delta TBCa/delta BMC) for DXA was higher than that reported for dual-photon absorptiometry versus NAA. The findings presented in this study provide translational equations among the DXA and NAA measurements and for the conversion of total body BMC to TBCa in children and young adults.

Absorptiometry, Photon↗
PubMed1996

The behavioral treatment of auditory hallucinatory responding of a schizophrenic patient.

This study assessed the efficacy of a behaviorally based treatment package to decrease the frequency of verbal responding to auditory hallucinations and to increase attention to important external stimuli, rather than to the hallucinations. The subject, a 49-year-old male, with a 20-year history of auditory hallucinatory responding (AHR), laughing and talking to himself, was seen in an outpatient clinic. Observations were made during management skill training, given usually twice a week. Observation sessions were divided into 15-minute intervals. The intervention package included reinforcement in the form of praise, pats on the back, and token reinforcement contingent on the absence of auditory hallucinations. Cancellation tests were given to measure his ability to attend to external tasks. Using an ABCAD design, it was seen that the data indicated that the intervention resulted in both a sharp decrease in auditory hallucinations and an increase in the subject's ability to attend to external tasks.

Attention↗
PubMed1996

Activation of epidermal growth factor receptor tyrosine phosphorylation by tumor necrosis factor correlates with loss of cytotoxic activity.

TNF induces cytotoxicity in human tumor cells through a receptor-mediated process with unknown signaling characteristics. Evidence suggests that overexpression of transmembrane growth factor receptors with intrinsic tyrosine kinase activity may suppress the antiproliferative or cytotoxic activity of TNF, suggesting antagonism between these two signaling pathways in tumor cells. To investigate TNF cytotoxic signal transduction, ME-180 cervical carcinoma cell variants were isolated that expressed complete cytotoxic sensitivity (ME-180S) or resistance (ME-180R) to TNF but identical levels of p55 TNF receptor expression. ME-180R cells expressed threefold higher EGFR than the ME-180S cell line and TNF treatment stimulated EGFR tyrosine phosphorylation only in resistant cells. Activation of tyrosine phosphorylation in ME-180R cells was TNF concentration dependent and maximally stimulated (three- to-five-fold) after 10-15 minutes of treatment. Other tyrosine phosphoproteins were not affected by TNF incubation demonstrating specific TNF-stimulated tyrosine phosphomodulation of EGFR. Pretreatment with the tyrosine kinase inhibitor tryphostin before incubation with TNF resulted in partial reversal of TNF cytotoxic resistance in ME-180R cells and enhanced TNF responsiveness in ME-180S cells, suggesting a "protective" role for tyrosine phosphorylation in TNF-induced cytotoxicity. Together these results demonstrate that TNF-mediated tyrosine phosphorylation is differentially regulated in sensitive and resistant tumor cells and may play a critical role in the cytotoxic signaling process through differential expression or regulation of tyrosine protein kinases and phosphatases.

Cell Survival↗