Biomedical subjects

M Serra

Publications and source records attributed to M Serra.

At least 37 records · Page 2Linked to original sources

PubMed2002

Exacerbated chronic obstructive pulmonary disease: a frequently unrecognized condition.

OBJECTIVES: To assess to which extent exacerbated chronic obstructive pulmonary disease (COPD) remains unrecognized in the emergency department, which factors account for misdiagnosis and which are the effects of misdiagnosis on patient's management. DESIGN: Retrospective study and stratified random sampling method as selection criterion. SETTING: University Hospital. SUBJECTS: Eighty patients representative of those discharged from the wards of medicine with a diagnosis of exacerbated COPD and 72 having a discharge diagnosis of coronary artery disease (CAD) were studied. MAIN OUTCOME MEASURES: Degree of concordance between admission and discharge diagnosis; presenting symptoms and signs of patients correctly or incorrectly classified on admission; impact of diagnostic procedures carried out by the physician on call on patient's management. RESULTS: The correct diagnosis was missed on admission in 13/80 COPD and 3/72 CAD patients (chi(2): 5.87, P=0.015). The prevalence of the following presenting features distinguished the 67 COPD patients who were correctly classified on admission from the remaining 13: severe weakness (21 vs. 10, chi(2): 9.53, P=0.002), dyspnea (60 vs. 3, chi(2): 28.75, P < 0.001), and limb oedema (14 vs. 6, chi(2): 3.70, P=0.054). Critical hypoxemia was diagnosed and treated only after admission in 19 COPD patients. CONCLUSIONS: Exacerbated COPD frequently escapes recognition in the emergency room, mainly if severe weakness and limb oedema are its presenting features. Arterial blood gas analysis is not systematically performed in the emergency room and, consequently, oxygen therapy is either not administered or given to selected COPD patients on an empirical basis.

Coronary Disease↗

PubMed2002

Theory of mind in children with 'lesser variants' of autism: a longitudinal study.

BACKGROUND: The study investigated the development of theory-of-mind (ToM) knowledge in children with lesser variants' of autism (PDD-NOS) over a period thought to be critical for ToM development (i.e., 3 to 5 years of age). METHOD: The sample included 11 children with PDD-NOS; 23 normally developing children were included for cross-sectional comparison and 13 normally developing children for longitudinal comparison. The groups were comparable in verbal and non-verbal mental age. Two storybooks were used for repeated assessment of various aspects of the children's theory of mind: emotion recognition, the distinction between physical and mental entities, prediction of behaviour and emotions on the basis of desires and prediction of behaviour and emotions on the basis of beliefs. RESULTS: The results showed that the children with PDD-NOS had specific difficulties in understanding and predicting other people's emotions on the basis of situational cues, desires and beliefs. However, their ability to predict actions from beliefs and desires were relatively intact. Compared to the normally developing children, these children achieved lower levels of theory-of-mind knowledge, both at time of initial assessment and approximately 6 months later. CONCLUSIONS: The data suggest that the theory-of-mind development of children with PDD-NOS is both delayed and deviant. The growth pattem of theory-of-mind skills in children with PDD-NOS seemed to be qualitatively different from the growth pattern found in the group of normally developing children.

Child Development Disorders, Pervasive↗

PubMed2001

Binding of [3H]CB 34, a selective ligand for peripheral benzodiazepine receptors, to rat brain membranes.

The 2-phenyl-imidazo[1,2-a]pyridine derivative CB 34 is a ligand for peripheral benzodiazepine receptors. The binding of [3H]CB 34 to rat cerebrocortical membranes was characterized. Specific binding was rapid, reversible, saturable and of high affinity. Kinetic analysis yielded association and dissociation rate constants of 0.2x10(8) M(-1) min(-1) and 0.29 min(-1), respectively. Saturation binding experiments revealed a single class of binding sites with a total binding capacity of 188+/-8 fmol/mg protein and an apparent dissociation constant of 0.19+/-0.02 nM. Specific [3H]CB 34 binding was inhibited by ligands selective for peripheral benzodiazepine receptors, whereas, with the exception of flunitrazepam and diazepam, ligands for central benzodiazepine receptors were inactive. Of the brain regions examined, the density of the [3H]CB 34-binding sites was greatest in the hypothalamus and lowest in the cerebral cortex. [3H]CB 34 is thus a potent and selective ligand for peripheral benzodiazepine receptors and should be proven useful for studies of the roles of these receptors.

Animals↗

PubMed2001

Dissolution properties and anticonvulsant activity of phenytoin-polyethylene glycol 6000 and -polyvinylpyrrolidone K-30 solid dispersions.

Solid dispersions of phenytoin in polyethylene glycol 6000 and polyvinylpyrrolidone K-30 with different drug-to-carrier ratios were prepared by the solvent method with the aim of increasing dissolution rate and bioavailability of the drug. These new formulations were characterized in the solid state by FT-IR spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. Drug solubility and dissolution rate are improved by these formulations, particularly with SDPEG 1/20 and SDPVP 1/20 systems. Storage was found to influence the stability of the solid dispersions. By maximal electroshock test, it was found that the intraperitoneal administration in mice of the SDPEG 1/20 and SDPVP 1/20 systems exhibited anticonvulsant activity similar to diphenylhydantoin sodium salt.

Animals↗

PubMed2001

Opposite effects of short- versus long-term administration of fluoxetine on the concentrations of neuroactive steroids in rat plasma and brain.

RATIONALE: Recent preclinical and clinical studies have shown that selective serotonin re-uptake inhibitors modulate neurosteroid synthesis in an opposite manner. OBJECTIVES: The action of long-term administration of fluoxetine was investigated on the peripheral and central concentrations of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-TH PROG) and 3alpha,5alpha-tetrahydrodeoxycorticosterone (of 3alpha,5alpha-TH DOC), progesterone, and pregnenolone in rats. We also investigated the effect of chronic treatment with fluoxetine on the foot-shock stress-induced increase in the plasma and brain concentrations of these steroids. METHODS: Fluoxetine was administered acutely (20 mg/kg) or chronically (10 mg/kg, once daily for 15 days). Steroids were extracted from plasma and brain, separated and purified by means of high-performance liquid chromatography, and quantified by means of radioimmunoassay. RESULTS: A single dose of fluoxetine (20 mg/kg, i.p.) induced in 20 min significant increases in the cerebral cortical and plasma concentrations of 3alpha,5alpha-TH PROG (+96% and +13%, respectively), 3alpha,5alpha-TH DOC (+129 and +31%, respectively), progesterone (+111 and +58%, respectively), and pregnenolone (+151 and +59%, respectively). In addition, the plasma concentration of corticosterone was also significantly increased (+24%) after acute administration of fluoxetine. In contrast, long-term administration of fluoxetine reduced the basal concentrations of these various steroids (ranging from -22 to -43%), measured 48 h after the last drug injection, in both brain and plasma. A challenge injection of fluoxetine (20 mg/kg, i.p.), however, was still able to increase the concentrations of steroids in both the brain and plasma of rats chronically treated with this drug. Acute foot-shock stress increased the cortical and plasma concentrations of steroids in rats chronically treated with fluoxetine to extents similar to those apparent in control rats. CONCLUSIONS: A repetitive increase in the brain concentrations of neuroactive steroids may contribute to the therapeutic action of fluoxetine.

Animals↗

PubMed2001

Long-term treatment with antidepressant drugs reduces the sensitivity of cortical cholinergic neurons to the activating actions of stress and the anxiogenic drug FG 7142.

Certain antidepressant drugs exert an anxiolytic action in both humans and rodents. The effects of long-term treatment with imipramine or mirtazapine, two antidepressant drugs with different mechanisms of action, on the response of cortical cholinergic neurons to foot-shock stress or to the anxiogenic drug FG 7142 were investigated in freely moving rats. Chronic treatment with imipramine or mirtazapine reduced the increase in cortical acetylcholine output induced by foot-shock stress by approximately 50%. The same treatment also reduced the sensitivity of cortical cholinergic neurons to the stimulatory effect of acute administration of FG 7142. In contrast, the administration of a single dose of either antidepressant 40 min before foot shock or FG 7142 injection failed to increase the threshold of excitability of cortical cholinergic neurons. These results demonstrate that long-term treatment with either imipramine or mirtazapine reduces the sensitivity of cortical cholinergic neurons to stress or to an anxiogenic drug with an efficacy similar to that of acute administration of benzodiazepines. The neurochemical mechanism responsible for regulation of cholinergic neuron sensitivity might contribute to the modulation of cognitive function associated with emotional and affective disorders.

Acetylcholine↗

PubMed2001

Stress and neuroactive steroids.

The discovery that the endogenous steroid derivatives 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone, or 3 alpha,5 alpha-TH PROG) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone, or 3 alpha,5 alpha-TH DOC) elicit marked anxiolytic and anti-stress effects and selectively facilitate gamma-aminobutyric acid (GABA)-mediated neurotransmission in the central nervous system (see Chapter 3) has provided new perspectives for our understanding of the physiology and neurobiology of stress and anxiety. Evidence indicating that various stressful conditions that downregulate GABAergic transmission and induce anxiety-like states (Biggio et al., 1990) also induce marked increases in the plasma and brain concentrations of these neuroactive steroids (Biggio et al., 1996, 2000) has led to the view that stress, neurosteroids, and the function of GABAA receptors are intimately related. Changes in the brain concentrations of neurosteroids may play an important role in the modulation of emotional state as well as in the homeostatic mechanisms that counteract the neuronal overexcitation elicited by acute stress. Indeed, neurosteroids not only interact directly with GABAA receptors but also regulate the expression of genes that encode subunits of this receptor complex. This chapter summarizes observations from our laboratories and others, suggesting that neurosteroids and GABAergic transmission are important contributors to the changes in emotional state induced by environmental stress.

Animals↗

PubMed2001

Role of allopregnanolone in regulation of GABA(A) receptor plasticity during long-term exposure to and withdrawal from progesterone.

Here we summarize recent data from our laboratory pertaining to the effects of fluctuations in the brain concentrations of the progesterone (PROG) metabolite allopregnanolone (3alpha,5alpha-TH PROG) on the expression and function of gamma-aminobutyric acid type A (GABA(A)) receptors. The effects of long-term exposure to progesterone and of its sudden withdrawal on the activity of GABA(A) receptors and on the abundance of receptor subunit mRNAs were examined in cultured rat cerebellar granule cells and cortical neurons. The effects of a persistent reduction in the brain concentration of 3alpha,5alpha-TH PROG on GABA(A) receptor function and gene expression were examined in vivo in rats subjected to long-term administration of oral contraceptives. Our results demonstrate that long-lasting changes in the exposure of GABA(A) receptors to this PROG metabolite induce marked effects on receptor structure and function. These effects of 3alpha,5alpha-TH PROG appear to be mediated through modulation of GABA(A) receptor signaling mechanisms that control the expression of specific receptor subunit genes. Furthermore, the specific outcomes of such signaling appear to differ among neurons derived from different regions of the brain. Neuroactive steroids such as 3alpha,5alpha-TH PROG might thus exert differential actions on GABA(A) receptor plasticity in distinct neuronal cell populations, likely accounting for some of the physiological effects induced by these compounds.

Animals↗

PubMed2001

Prevention of the stress-induced increase in frontal cortical dopamine efflux of freely moving rats by long-term treatment with antidepressant drugs.

Use of antidepressant drugs in the treatment of anxiety disorders has recently increased due to the anxiolytic effect of some of these agents. Because dopaminergic transmission in the prefrontal cortex is sensitive to anxiogenic or stressful stimuli, the effects of two antidepressant drugs with different mechanisms of action, imipramine and mirtazapine, on the response of rat cortical dopaminergic neurons to stress were investigated. A 2-week (but not single dose) administration of imipramine (10 mg/kg, i.p., twice daily) or mirtazapine (10 mg/kg, i.p., once daily) reduced and completely antagonized, respectively, the increase in dopamine release in the prefrontal cortex elicited by footshock stress. Long-term administration of imipramine or mirtazapine had no marked effect on the stress-induced increases in the brain or plasma concentrations of neuroactive steroids or corticosterone. An attenuation of the response of mesocortical dopaminergic neurons to stress induced by long-term treatment with antidepressants might contribute to the anxiolytic effects of such drugs.

Animals↗

PubMed2001

Complexation of phenytoin with some hydrophilic cyclodextrins: effect on aqueous solubility, dissolution rate, and anticonvulsant activity in mice.

The main objective of this study was to evaluate the influence of hydroxypropylated beta- and gamma-cyclodextrins and Me-beta-cyclodextrin (HP-beta-CD, HP-gamma-CD, and Me-beta-CD, respectively) on the dissolution rate and bioavailability of the antiepileptic agent, phenytoin (DPH). The corresponding solid complexes were prepared by a freeze-drying method and characterized by infrared spectroscopy, X-ray powder diffraction, and differential scanning calorimetry studies. Evidence of inclusion complex formation in the case of HP-beta-CD was obtained by (1)H- and (13)C-nuclear magnetic resonance spectroscopy. Drug solubility and dissolution rate in 0.05 M potassium phosphate buffer (pH 6) were notably improved by employing the beta-CDs. Thus a 45% w/v HP-beta-CD or Me-beta-CD solution gave rise to an increase of dissolved drug of 420- and 578-fold, respectively. The Q(10) (i.e. percentage of dissolved DPH at 10 min) was 5.2% for the pure drug and 93, 98, and 96% for DPH/HP-beta-CD, DPH/HP-gamma-CD, and DPH/Me-beta-CD complexes, respectively. Moreover, it was found that in the maximal electroshock seizure test in mice the DPH/Me-beta-CD complex exhibited anticonvulsant activity similar to DPH sodium salt (NaDPH).

Animals↗

PubMed2001

High affinity central benzodiazepine receptor ligands. Part 2: quantitative structure-activity relationships and comparative molecular field analysis of pyrazolo[4,3-c]quinolin-3-ones.

A large series of 2-aryl(heteroaryl)-2,5-dihydropyrazolo[4,3-c]quinolin-3(3H)-ones (PQ, 106 compounds), carrying appropriate substituents at the quinoline and N2-phenyl rings, were designed, prepared and tested as central benzodiazepine receptor ligands. Compounds with an affinity significantly higher than the parent compound CGS-8216 were obtained, the most active ligand showing a pIC50 = 10.35. Hansch and comparative molecular field analyses gave coherent results suggesting the main structural requirements of high receptor binding affinity. The possible formation of a three-centred hydrogen bond (HB) at the HB donor site H2, as a key interaction for high receptor binding affinity, was assessed by the calculation and comparison of the molecular electrostatic potentials of a series of selected ligands.

Animals↗

PubMed2001

Simultaneous paired analysis of numerical chromosomal aberrations and DNA content in osteosarcoma.

Relatively little is known about the biologic relevance of numerical chromosomal changes in relation to DNA content in osteosarcoma. In this study, by using a series of human osteosarcoma cell lines, we standardized a method for the assessment, on the same nuclei specimen, of both specific chromosome copy numbers by fluorescence in situ hybridization (FISH) and the DNA content by static cytofluorometry or image cytometry. On the same cell lines, we also evaluated the DNA content by using flow cytometry and the chromosome number distribution by metaphase analysis. Comparison between these different methods showed that DNA ploidy level as determined by FISH or metaphase analysis is frequently lower than the ploidy pattern as defined by cytometric methods. By using comparative genomic hybridization, we were able to demonstrate that these discrepancies were due to the presence of several unbalanced chromosome aberrations, specifically gains and high-level amplifications, which affect the total DNA content with less effect on the total chromosome number. Thus, evaluation of DNA ploidy in osteosarcoma cells is needed for a correct interpretation of FISH or cytogenetic data concerning numerical chromosomal changes. Evaluation of tumor ploidy in a series of clinical samples demonstrated that in high-grade osteosarcoma, flow cytometry sometimes may give false results because of the presence of high proportions of contaminating, nonneoplastic cells that cannot be excluded from the flow cytometric assessment but that do not interfere with the evaluation of DNA ploidy by static cytofluorometry or image cytometry, in which only tumor cells are selected for the analysis. The possibility of using this method to evaluate, on the same nuclei sample, both specific chromosomal aberrations and DNA ploidy may allow a better determination of numerical chromosomal changes that may be relevant for the biologic behavior of osteosarcoma.

Bone Neoplasms↗

PubMed2001

Prevention of adjuvant arthritis by the W3/25 anti-CD4 monoclonal antibody is associated with a decrease of blood CD4(+)CD45RC(high) T cells.

Imbalance between Th1 and Th2 functions is considered to play a key role in the induction and development of several autoimmune diseases, and the correction of that imbalance has led to effective therapies of some experimental pathologies. To examine whether CD4(+)CD45RC(high) (Th1-like) and CD4(+)CD45RC(low) (Th2-like) lymphocytes play a role in the pathogenesis of adjuvant arthritis (AA) and in its prevention by anti-CD4 antibody, CD45RC expression on CD4(+) T cells was determined in arthritic rats and in animals treated with an anti-CD4 MoAb (W3/25) during the latency period of AA. The phenotype of regional lymph node lymphocytes from arthritic rats in the active phase of the disease was determined by flow cytometry. Peripheral blood lymphocytes from rats treated with W3/25 MoAb were also analysed for 2 weeks after immunotherapy finished. IgG2a and IgG1 isotypes of sera antibodies against the AA-inducing mycobacteria, considered to be associated with Th1 and Th2 responses, respectively, were also determined by ELISA techniques. Fourteen days after arthritis induction, regional lymph nodes presented an increase in CD4+CD45RC(high) T cell proportion. Preventive immunotherapy with W3/25 MoAb inhibited the external signs of arthritis and produced a specific decrease in blood CD4(+)CD45RC(high) T cells and a diminution of antibodies against mycobacteria, more marked for IgG2a than for IgG1 isotype. These results indicate a possible role of CD4(+)CD45RC(high) T lymphocytes in the pathogenesis of AA, and suggest that the success of anti-CD4 treatment is due to a specific effect on CD4(+)CD45RC(high) T subset that could be associated with a decrease in Th1 activity.

Animals↗

PubMed2001

Increased expression of the neuropeptide Y receptor Y(1) gene in the medial amygdala of transgenic mice induced by long-term treatment with progesterone or allopregnanolone.

The neurosteroid allopregnanolone, a reduced metabolite of progesterone, induces anxiolytic effects by enhancing GABA(A) receptor function. Neuropeptide Y (NPY) and GABA are thought to interact functionally in the amygdala, and this interaction may be important in the regulation of anxiety. By using Y(1)R/LacZ transgenic mice, which harbour a fusion construct comprising the promoter of the mouse gene for the Y(1) receptor for NPY linked to the lacZ gene, we previously showed that long-term treatment with benzodiazepine receptor ligands modulates Y(1) receptor gene expression in the medial amygdala. We have now investigated the effects of prolonged treatment with progesterone or allopregnanolone on Y(1)R/LacZ transgene expression, as determined by quantitative histochemical analysis of beta-galactosidase activity. Progesterone increased both the cerebrocortical concentration of allopregnanolone and beta-galactosidase expression in the medial amygdala. Finasteride, a 5alpha-reductase inhibitor, prevented both of these effects. Long-term administration of allopregnanolone also increased both the cortical concentration of this neurosteroid and transgene expression in the medial amygdala. Treatment with neither progesterone nor allopregnanolone affected beta-galactosidase activity in the medial habenula. These data suggest that allopregnanolone regulates Y(1) receptor gene expression through modulation of GABA(A) receptor function, and they provide further support for a functional interaction between GABA and neuropeptide Y in the amygdala.

Amygdala↗

PubMed2001

Neuroactive steroid-serotonergic interaction: responses to an intravenous L-tryptophan challenge in women with premenstrual syndrome.

OBJECTIVE: To evaluate the circulating concentrations of the neuroactive steroids in response to an i.v. L-tryptophan (L-TP) challenge across the menstrual cycle in women with premenstrual syndrome (PMS) and in controls. METHOD: An i.v. L-TP challenge was administered eight times during 1 month to five women with prospectively documented PMS and five age- and body mass-matched controls. Progesterone, allopregnanolone pregnenolone and 3alpha-5alpha-tetrahydrocorticosterone were assessed 15 and 0 min before, and at 30, 60 and 90 min after the challenge, across the menstrual cycle. RESULTS: In response to L-TP challenge, only allopregnanolone concentrations were significantly increased across the cycle and this increase was of a greater magnitude in women with PMS. Pregnenolone and 3alpha-5alpha-tetrahydrocorticosterone concentrations were not affected in women with PMS or controls after L-TP challenge. CONCLUSIONS: The data provide evidence for possible interaction between the serotonergic system and the neuroactive steroid, allopregnanolone. Women with PMS demonstrated a more significant increase in allopregnanolone concentrations in response to L-TP challenge, which could be due to an initial low basal serotonergic tone in the luteal phase in the PMS group.

Adult↗

PubMed2000

CD99 engagement: an effective therapeutic strategy for Ewing tumors.

CD99 is a Mr 32,000 transmembrane molecule that shows a high level of expression on cells of the hemopoietic system as well as on Ewing tumor cells. Within the hematopoietic system, CD99 has been implicated in cell adhesion and cell death, participating in this way in the differentiation of T-cell precursors. In this study, we demonstrate that engagement of CD99 significantly inhibits the in vitro and in vivo growth ability of Ewing tumor cells by delivering an apoptotic stimulus and reducing the malignant potential of these cells. Moreover, we show that anti-CD99 monoclonal antibodies may be advantageously used in association with conventional anticancer agents. These results provide a novel entry site for therapeutic intervention, which may have application in the care of patients with Ewing tumor, and warrant additional studies to clarify the molecular mechanisms activated by CD99 engagement.

12E7 Antigen↗

PubMed2000

Identification of EWS/FLI-1 transcripts in giant-cell tumor of bone.

The EWS/FLI-1 fusion gene, resulting from a t(11;22) translocation, plays a key role in the pathogenesis of Ewing's sarcoma. We demonstrate the presence of EWS/FLI-1 hybrid transcripts also in giant-cell tumor, a bone neoplasm featuring intermediate characteristics between benign and malignant lesions. Chimeric products were detected by semi-nested PCR after 2 cycles of amplification in 13/15 cases of giant-cell tumor, and their presence was confirmed by Southern and Western blots and fluorescence in situ hybridization. Moreover, 3/8 primary cultures of giant-cell tumor showed the same type of hybrid transcript observed in the original tumor sample. Sequencing of PCR products confirmed the presence of EWS and FLI-1 sequences in these products. Detection of EWS/FLI-1 fusion transcripts in giant-cell tumor of bone provides a model for the study of the transforming mechanisms of the EWS/FLI-1 fusion gene in mesenchymal tumors.

Adolescent↗

PubMed2000

Murine model for skeletal metastases of Ewing's sarcoma.

Ewing's sarcoma shows a strong tendency to metastasize to the lungs or the skeleton, or both. A peculiar feature of the secondary involvement of bone with this tumor is that it may also appear in the absence of clinically evident lung metastases, both at clinical presentation and during the course of the disease. Although osseous metastases are critically relevant for prognosis, the pathogenesis of this peculiar feature of Ewing's sarcoma is poorly understood, partly due to the lack of appropriate experimental in vivo models. We show that the intravenous injection of TC-71 Ewing's sarcoma cells into athymic 4-5-week-old Crl/nu/nu (CD1) BR mice reproducibly colonizes specific sites of the skeleton in addition to the lungs and lymph nodes. The distribution and the morphologic appearance of these experimental bone metastases mimic the pattern of skeletal involvement observed in humans. This experimental model of bone metastasis of Ewing's sarcoma may be the basis for future studies aimed at understanding the pathophysiology and treatment of Ewing's sarcoma.

12E7 Antigen↗