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Biomedical subjects

M Serra

Publications and source records attributed to M Serra.

At least 127 records · Page 7Linked to original sources
PubMed1995

An exploration of person perception abilities in children with a pervasive developmental disorder not otherwise specified.

This explorative study investigates differences in person perception abilities between a group of children diagnosed as having a Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS) and a group of normal children of the same age and sex. Person perception, a social-cognitive skill, concerns the way in which children conceptualise other people, their intentions, attitudes, traits and emotions (central), as well as their overt behaviour and their physical characteristics (peripheral). Person perception was investigated by means of a free-person description, in which the child was asked to describe another person. Children with a PDDNOS used more peripheral and less central statements than the control group to describe another person. However, these differences seemed to reflect differences in intelligence between the two groups, rather than differences in a specific social-cognitive skill. The results need to be replicated, but seem to be in line with other studies that suggest that there may be subgroups of the autistic spectrum that show severe social impairment but have good social-cognitive abilities.

Child↗
PubMed1995

Enhancement of acetylcholine release by flumazenil in the hippocampus of rats chronically treated with diazepam but not with imidazenil or abecarnil.

The effects of long-term treatment (three times a day for 3 weeks) with pharmacologically active doses of the novel anxiolytics and anticovulsants abecarnil (0.5 mg/kg, IP) and imidazenil (0.5 mg/kg, IP) on basal hippocampal acetylcholine release in freely moving rats were compared with those of diazepam (3 mg/kg, IP). Challenge doses of diazepam, abecarnil, and imidazenil decreased the extracellular acetyl-choline concentration in the hippocampus by the same extent in animals chronically treated with the respective drug or vehicle. Moreover, the abrupt discontinuation of long-term treatment with diazepam, abecarnil, or imidazenil failed to affect hippocampal acetylcholine release during the first 5 days of withdrawal. In contrast, the acute administration of the benzodiazepine receptor antagonist flumazenil (1 mg/kg, IP) 2 days after diazepam withdrawal elicited a marked increase (65%) in acetylcholine release in the hippocampus. Flumazenil failed to induce the same effect 5 days after diazepam withdrawal or 2 or 5 days after discontinuation of long-term treatment with abecarnil or imidazenil. These results indicate that (i) the inhibitory effects of full (diazepam), partial (imidazenil), and selective (abecarnil) benzodiazepine receptor agonists on acetylcholine output in rat hippocampus are not affected by repeated drug administration; (ii) discontinuation of long-term treatment with each type of agonist does not affect hippocampal cholinergic mechanisms; and (iii) flumazenil increases acetylcholine release only in the hippocampus of rats chronically treated with diazepam. Together, these data further differentiate the pharmacology of benzodiazepine receptor full agonists from that of partial and selective agonists.

Acetylcholine↗
PubMed1995

Antagonism of isoniazid-induced convulsions by abecarnil in mice tolerant to diazepam.

The ability of the benzodiazepine receptor full agonist diazepam, the selective agonist abecarnil, and the partial agonist imidazenil to antagonize convulsions induced by isoniazid (200 mg/kg, S.C.) was studied in mice chronically treated with diazepam (3 mg/kg, i.p., three times daily) or abecarnil (0.1 or 1 mg/kg, i.p., three times daily or 6 mg/kg, S.C., daily). Diazepam induced tolerance to its own anticonvulsant effect. In contrast, chronic treatment with abecarnil failed to induce tolerance to its own anticonvulsant activity. Animals treated with abecarnil at 0.1 mg/kg developed cross-tolerance to imidazenil, whereas those treated with 1 mg/kg became less sensitive to diazepam. Mice chronically treated with abecarnil at 6 mg/kg showed almost complete tolerance to diazepam. Abecarnil was able to antagonize the convulsions elicited by isoniazid in diazepam-tolerant mice. These data indicate that chronic administration of abecarnil, unlike that of classical benzodiazepines, does not induce tolerance to its anticonvulsant effect, and that abecarnil overcomes tolerance induced by long-term treatment with the full agonist diazepam.

Animals↗
PubMed1995

Analysis of P-glycoprotein expression in osteosarcoma.

Current treatment of high-grade osteosarcoma combines surgical removal of the lesion with chemotherapy. In this study we evaluated whether the expression of P-glycoprotein, a protein closely associated with multidrug resistance, may be helpful in identifying the patients whose tumours will be further resistant to specific agents. By using multidrug-resistant osteosarcoma cell lines as standards, the expression of P-glycoprotein was evaluated in 105 cases of primary and metastatic osteosarcoma by semiquantitative immunofluorescence. Overexpression of the protein was shown in 23% of primary and in 50% of metastatic lesions. In 38 cases, homogeneously treated and followed-up for at least 24 months, overexpression of P-glycoprotein appeared to be associated with a higher relapse rate and with a trend toward a worse outcome. These data support the role of P-glycoprotein in the response to chemotherapy and its involvement in the determination of the outcome of osteosarcoma patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Emotional role-taking abilities of children with a pervasive developmental disorder not otherwise specified.

Seven to 12-year-old children with a Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS) were compared with normal, healthy children of the same age and sex on three different emotional role-taking tasks. In these tasks, children had to use person-specific information to make an inference about another child's emotional reaction and behaviour, Significant differences were found between the PDDNOS group and control group: PDDNOS children performed worse on all three role-taking tasks. However, the differences on one of these tasks could be completely explained by intelligence differences between the two groups. On the other tasks, differences could not or be partially explained by intelligence differences. The results of this study led to the formulation of a more specific hypothesis, namely that PDDNOS children might have problems interpreting social information when affectively charged background information has to be used.

Aptitude↗
PubMed1995

Modulation of basal and stress-induced release of acetylcholine and dopamine in rat brain by abecarnil and imidazenil, two anxioselective gamma-aminobutyric acidA receptor modulators.

The effects of imidazenil (6-(2-bromophenyl)-8-fluoro-4-H-imidazo[1-5-a][1-4]benzodiazepine-3- carboxamide) and abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate), new partial and selective benzodiazepine recognition site agonists, respectively, on basal and stress-induced hippocampal acetylcholine and cortical dopamine release were determined with the microdialysis technique in freely moving rats. The actions of these new anxioselective and anticonvulsant drugs were compared with those of diazepam and midazolam, two classical benzodiazepine full agonists. Abecarnil (0.05-1 mg/kg i.p.), imidazenil (0.05-1 mg/kg i.p.), diazepam (2.5-10 mg/kg i.p.) and midazolam (2.5-10 mg/kg i.p.) inhibited basal hippocampal acetylcholine release in a dose-dependent manner. In contrast, whereas diazepam and midazolam significantly decreased dopamine release in the prefrontal cortex, abecarnil and imidazenil had no effect on basal dopamine output. The effects of these drugs on both acetylcholine and dopamine release were antagonized by the benzodiazepine receptor antagonist flumazenil (1 mg/kg i.p.). Foot-shock stress (0.2 mA for 500 msec/sec) delivered for 8 min induced a rapid and marked (+75%) increase in hippocampal acetylcholine output that persisted for approximately 40 min. Foot-shock stress also increased dopamine release in the cerebral cortex; the effect was maximal (+90%) after 20 min and persisted for approximately 30 min. Prior administration of abecarnil or imidazenil at a dose (0.05 mg/kg) that did not significantly affect the basal release of either acetylcholine or dopamine completely prevented the effect of stress on the output of these neurotransmitters, an effect mimicked by higher doses of diazepam (2.5 mg/kg) and midazolam (2.5 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1995

Nuclear immunolocalization of P-glycoprotein in multidrug-resistant cell lines showing similar mechanisms of doxorubicin distribution.

The MDR1 gene product P-glycoprotein is a plasma membrane efflux pump which is responsible for multiple drug resistance of cancer cells. Although the ability of multidrug-resistant cells to exclude drugs from the nucleus is a distinctive and possibly the main mechanism for resistance against a number of drugs, including doxorubicin, this phenomenon is not entirely understood. In this paper, the relationship between doxorubicin subcellular distribution and P-glycoprotein activity at different cell sites has been investigated by different techniques. Cytofluorometry and confocal microscopy were used to study doxorubicin subcellular distribution in U-2 OS human osteosarcoma cells and in the multidrug-resistant variant U-2 OS/DX580. Stable levels of doxorubicin accumulation were found in the nuclei of sensitive cells, whereas the absence of detectable levels of drug in the nuclei of resistant cells could be attributed to an energy-dependent mechanism. Moreover, in resistant cells, inhibition of P-glycoprotein activity was able to induce drug accumulation in the nuclei of resistant cells and to achieve cytotoxic effects comparable to those observed in sensitive cells. Similar results were also found in isolated nuclei from U-2 OS/DX580 cells. The expression of P-glycoprotein in U-2 OS/DX580 and in two other multidrug-resistant cell lines (SW948-R-300 and LoVo-R-100) was investigated by confocal microscopy and immunoelectron microscopy, by using a panel of monoclonal antibodies directed against this protein. Higher levels of P-glycoprotein expression, not only in the plasma membrane and inside the cytoplasm, but also in the nucleus, were found in U-2 OS/DX580 and in LoVo-R-100 multidrug-resistant cells compared to their corresponding sensitive cells. SW948-R-300 cells, featuring increased amounts of MDR1 mRNA but lacking P-glycoprotein expression at the cell surface, showed a higher P-glycoprotein immunolabeling only in the nucleus and in the cytoplasm. The localization of P-glycoprotein in the nucleus of multidrug-resistant cells was confirmed also by studies on isolated nuclei and nuclear matrices, and by Western blot analysis on total cell and isolated nuclear extracts. These findings, suggesting the possible involvement of nuclear P-glycoprotein in the regulation of subcellular doxorubicin distribution in multidrug-resistant cells, open new insights on the mechanisms of P-glycoprotein-mediated resistance to anticancer drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Felbamate antagonizes isoniazid- and FG 7142-induced reduction of GABAA receptor function in mouse brain.

Injection of the antiepileptic drug, felbamate (2-phenyl-1,3-propanediol dicarbamate), into mice reduced in a dose-dependent manner (150-300 mg/kg i.p.) the isoniazid (200 mg/kg s.c.)-induced increase in ex vivo binding of t-[35S]butylbicyclophosphorothionate ([35S]TBPS) to cerebral cortical and hippocampal membranes. The same doses of felbamate reduced significantly the number of mice exhibiting isoniazid-induced seizures. A dose of felbamate (50 mg/kg) ineffective in isoniazid-treated mice completely antagonized the increase of [35S]TBPS binding elicited by FG 7142 (N-methyl-beta-carboline-3-carboxamide), a benzodiazepine receptor inverse agonist. The above effects of felbamate resembled those of diazepam. Accordingly, the combination of ineffective doses of felbamate (50 mg/kg) and diazepam (0.2 mg/kg) elicited a marked decrease of [35S]TBPS binding. The results indicate that facilitation of gamma-aminobutyric acid type A (GABAA) receptor function may play a role in the anticonvulsant action of felbamate.

Animals↗
PubMed1994

Differential effects of abecarnil on basal release of acetylcholine and dopamine in the rat brain.

Abecarnil (0.1-1 mg/kg i.p.), a new anxioselective and anticonvulsant ligand of benzodiazepine receptors, like diazepam (2.5-10 mg/kg i.p.) inhibited in a dose-dependent manner the basal release of acetylcholine in the hippocampus of freely moving rats. In contrast, whereas diazepam inhibited the basal output of dopamine in the prefrontal cortex, abecarnil had no such effect. The effects of both abecarnil and diazepam were antagonized by prior treatment with flumazenil at a dose (1 mg/kg i.p.) that per se had no effect on acetylcholine or dopamine release. The results suggest that abecarnil has different intrinsic efficacies at gamma-aminobutyric acid type A (GABAA) receptors involved in the regulation of acetylcholine release in the hippocampus and dopamine release in the prefrontal cortex, two brain areas important in cognitive function and emotional state, respectively.

Acetylcholine↗
PubMed1994

Pre-treatment of human osteosarcoma cells with N-methylformamide enhances P-glycoprotein expression and resistance to doxorubicin.

N-methylformamide (NMF), a powerful differentiating agent, has been extensively used in experimental and preclinical cancer chemotherapy studies, alone or in association with conventional anti-cancer drugs. To evaluate the use of this molecule in the treatment of osteosarcoma (OS), we have analyzed the effects of NMF and doxorubicin (DXR) on DXR-sensitive and -resistant human OS cell lines. Our study shows that NMF exerts remarkable effects on cell proliferation and, in Saos-2 and SARG cells, also induces differentiation, as shown by increasing alkaline phosphatase activity. Moreover, NMF increases the cytotoxic activity of DXR when administered after the drug, in both DXR-sensitive and -resistant cells. However, when this agent is given before DXR, it enhances P-glycoprotein expression in U-2 OS cell lines. This over-expression is associated with reduced DXR accumulation within cells and with significant enhancement of resistance to DXR.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Long-term treatment with abecarnil fails to induce tolerance in mice.

The effects of long-term treatment (3 times a day for 4 weeks) with a pharmacologically active dose (0.1 mg/kg i.p.) of the novel anxiolytic, abecarnil, on exploratory behaviour and [35S]TBPS (t-butylbicyclophosphorothionate) binding were compared to those of diazepam (1 mg/kg i.p.) in mice. A challenge dose (0.1 mg/kg) of abecarnil given 12 h after the last administration of the treatment protocol markedly inhibited exploratory behaviour in animals treated chronically with abecarnil (-62%) or vehicle (-87%). Consistent with this behavioural effect, the same challenge dose of abecarnil significantly reduced [35S]TBPS binding to unwashed cerebral cortical membranes from mice treated chronically with abecarnil (-28%) or vehicle (-30%). In contrast, a challenge dose (1 mg/kg) of diazepam failed to affect motor behaviour and [35S]TBPS binding in mice chronically exposed to diazepam; in animals chronically treated with vehicle, diazepam markedly inhibited both exploratory behaviour (-55%) and [35S]TBPS binding (-21%). These results indicate that long-term treatment with abecarnil failed to induce tolerance to the effect of this drug on gamma-aminobutyric acid type A (GABAA) receptor function. Accordingly, [35S]TBPS binding was increased (+15-26%) 12 and 48 h after discontinuation of long-term diazepam administration while no such increase in [35S]TBPS binding was observed for mice chronically treated with abecarnil. Moreover, whereas a significant decrease (-15%) in [35S]TBPS binding was observed 96 h after discontinuation of long-term diazepam treatment, chronic treatment with abecarnil did not modify this parameter. Together, these data indicate that long-term treatment with a pharmacologically effective dose of abecarnil did not induce tolerance or the discontinuation syndrome in mice.

Animals↗
PubMed1994

Chronic administration of an anticonvulsant dose of imidazenil fails to induce tolerance of GABAA receptor function in mice.

The ability of an anticonvulsant dose (0.1 mg/kg i.p.) of imidazenil, a new partial agonist of benzodiazepine receptors, to antagonize the convulsions and the increase in t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to the gamma-aminobutyric acid type A (GABAA) receptor elicited by isoniazid, an inhibitor of central GABAergic function, was evaluated in mice chronically treated (3 times daily for 30 days) with the same dose of imidazenil. The challenge dose of imidazenil, administered 36 h after the last injection of the chronic treatment protocol, reduced both isoniazid-induced convulsions and the isoniazid-induced increase in [35S]TBPS binding to the same marked extent as in control mice. These results indicate that long-term treatment with a pharmacologically effective dose of imidazenil failed to induce tolerance to both the anticonvulsant effect and the positive modulatory action on GABAA receptor function of this drug in mouse brain.

Animals↗
PubMed1994

New model for bone resorption study in vitro: human osteoclast-like cells from giant cell tumors of bone.

Cells harvested from 12 human giant cell tumors of bone and kept in culture for several passages were characterized for bone-resorbing capability, total and tartrate-resistant acid phosphatase activity, response to the calciotropic hormone calcitonin, cell proliferation, multinucleation after passages, and presence of calcium sensing. Cells obtained from three tumors presented a complete panel of osteoclast characteristics and maintained their multinuclearity after several passages. Cells from four other tumors increased their cAMP levels after treatment with calcitonin, and the other five apparently consisted of cells of stromal origin. These human cell populations with osteoclast characteristics may provide valid in vitro models for the investigation of osteoclastic differentiation and activity.

Acid Phosphatase↗
PubMed1994

Adhesion properties and integrin expression of cultured human osteoclast-like cells.

Osteoclast interaction with extracellular matrix drives the sequential events that end with bone resorption. However, the role of matrix proteins is not yet fully understood. We studied this problem on human osteoclast-like cells derived from giant cell tumors of bone (GCT cells). On GCT cells we considered cytoskeletal organization, adhesion properties, and integrin expression upon plating in serum-free medium onto fibronectin (FN), collagen (COL), thrombospondin (TSP), bone sialoprotein (BSPII), and osteopontin (OPN). GCT cells promptly adhered and spread on FN, BSPII, and OPN, while only 50% adhered on COL and none on TSP. The integrin beta 1 chain was always associated to focal adhesions, while the alpha v beta 3 heterodimer was detected in focal contacts only upon plating on BSPII, OPN, and FN. The focal clustering of beta 1 was impaired by monensin treatment, indicating that endogenous FN secretion was required to drive beta 1 into focal contacts. Conversely, alpha v beta 3 clustering was also not affected by monensin when cells were plated onto plasma FN. Immunoprecipitation of metabolically labeled GCT cell lysates showed that three different heterodimers (alpha v beta 3, alpha 3 beta 1, and alpha 5 beta 1) were assembled. Adhesion to FN was completely inhibited by beta 1 antibodies at dilutions up to 1:400, while beta 3 antibodies, at similar dilutions, impaired spreading but not adhesion. We conclude that alpha v beta 3 is the main integrin used by GCT cells in bone recognition. We also suggest that selected substrata may induce the release and the organization of endogenous FN that eventually drives the recruitment of a beta 1 integrin receptor into focal contacts.

Amino Acid Sequence↗
PubMed1994

The effect of cyclopyrrolones on GABAA receptor function is different from that of benzodiazepines.

The effects of the cyclopyrrolones zopiclone and suriclone on the function of the central gamma-amino-butyric acid type A (GABAA) receptor complex in mouse brain were evaluated both in vitro and in vivo. Added in vitro to mouse cerebral cortical membranes, these compounds potently inhibited [3H]flumazenil binding with IC50 (50% inhibitory concentration) values of 35.8 nM (zopiclone) and 1.1 nM (suriclone). Similar results were obtained with cerebellar membranes, indicating that these drugs do not discriminate between putative type I and type II benzodiazepine receptors. The interaction of cyclopyrrolones with recognition sites present at the level of the GABA receptor complex appears to be competitive, because zopiclone decreased the affinity of the receptors for [3H]flumazenil without affecting the maximal number of binding sites. Moreover, zopiclone and suriclone did not affect the rate of dissociation of [3H]flumazenil from benzodiazepine receptors. The in vitro efficacy of zopiclone appeared different from that of suriclone and the benzodiazepines diazepam and flunitrazepam. Thus, zopiclone failed to affect muscimol-stimulated 36Cl- uptake and only slightly inhibited t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding. In contrast, like diazepam and flunitrazepam, suriclone increased muscimol-stimulated 36Cl- uptake and markedly inhibited [35S]TBPS binding. In contrast, like diazepam and flunitrazepam, suriclone increased muscimol-stimulated 36Cl- uptake and markedly inhibited [35S]TBPS binding. On the other hand, suriclone, like zopiclone, did not modify [3H]muscimol binding to mouse cerebral cortical membranes. Moreover, zopiclone antagonized the reduction in [35S]TBPS binding elicited by the benzodiazepine receptor full of agonist diazepam. Consistent with its low efficacy in vitro, oral administration of zopiclone (2.5 to 100 mg/kg, p.o.) in mice failed to modify [35S]TBPS binding subsequently measured in cerebral cortical membranes "ex vitro".(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

NMDA receptor function is enhanced in the hippocampus of aged rats.

The density and functional activity of the N-methyl-D-aspartate (NMDA)-sensitive glutamate receptor was examined in various brain areas of 3-, 18- and 24-month-old rats. The total numbers of binding sites for the NMDA receptor antagonists [3H]CGP 39653 and [3H]MK 801 binding sites were decreased in the hippocampus, cerebral cortex and striatum of 18- and 24-month-old rats, relative to 3-month-old animals. In the hippocampus of 18-month-old rats, the reduced number of NMDA receptors was associated with an increased sensitivity of [3H]MK 801 binding to the stimulatory action of glycine and glutamate. Thus, 10 microM glycine and 10 microM glutamate increased [3H]MK 801 binding in the hippocampus of 18-month-old rats by 75 and 160%, respectively; in 3-month-old animals, the same concentration of these amino acids increased binding by 37 and 95%, respectively. The sensitivity of [3H]MK 801 binding to glycine and glutamate was not increased in the cerebral cortex and striatum of aged rats. Moreover, an increased efficacy of glycine and glutamate in stimulating the binding of [3H]MK 801 in the hippocampus was no longer apparent in the 24-month-old rats. The increased sensitivity of [3H]MK 801 binding to glycine and glutamate in the hippocampus of 18-month-old rats may reflect an increase in NMDA receptor activity to compensate for the decrease in receptor number.

2-Amino-5-phosphonovalerate↗
PubMed1994

Multivariate analysis of determinants of fetal growth retardation.

OBJECTIVE: To analyse the relative effect of the risk factors related to fetal growth retardation (FGR) in the central area of Spain. STUDY DESIGN: This is a case-control survey of 370 full-term gestations. Of the 370 women, 185 were diagnosed with intrauterine growth retardation, and 185 were in the normal group. All came from a central region of Spain. We took into account 25 possible risk factors. RESULTS: In the FGR group we found 12 risk factors with statistical significance in the univariate analysis (tobacco, drugs, low pre-pregnancy weight, low maternal height, little gestational weight gain, excessive physical activity during pregnancy, low socioeconomic status, low educational level, unmarried, urinary infection, mother's haematological changes, and previous infertility). After the multiple logistic regression analysis, five factors were shown to exist as independent risks (tobacco: OR, 23.50; 95% CI, 3.01-183.18; P < 0.01; low pre-pregnancy weight: OR, 4.01; 95% CI, 2.14-7.51; P < 0.001; low socioeconomic status: OR, 2.91; 95% CI, 1.72-4.90; P < 0.001; little gestational weight gain: OR, 2.52; 95% CI, 1.21-5.22; P < 0.05; and urinary infection: OR, 3.83; 95% CI, 1.49-9.87; P < 0.01). CONCLUSIONS: (i) Tobacco, low pre-pregnancy weight and low socioeconomic status are the three main cause-effect factors of relative importance in our sanitary zone for FGR. (ii) Disproportionate FGR is related more to older mothers and maternal previous illness than to the proportionate FRG.

Body Weight↗