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Biomedical subjects

E Alberdi

Publications and source records attributed to E Alberdi.

At least 19 recordsLinked to original sources
PubMed2002

Eliciting a terminology for mammographic calcifications.

AIM: Two studies were carried out to establish, validate and assess descriptors for use in the differential diagnosis for mammographic calcifications. METHODS: In Study 1, eleven radiologists were asked to 'think out loud' as they interpreted 20 sets of calcifications. Participants used 159 terms to describe calcifications. We used this data to design a scheme with 50 descriptors. In Study 2, ten radiologists used the scheme to describe 40 sets of calcifications. We assessed the capacity of the terms to discriminate between benign and malignant calcifications, testing them against radiologists' assessments of malignancy and follow-up data. RESULTS: All descriptors were used by at least 5 radiologists. Five additional descriptors were required. With some exceptions, properties that discriminated between benign and malignant outcomes were highly correlated with radiologists' assessment of risk. Many descriptors have a fairly low sensitivity but high specificity. CONCLUSIONS: Our data suggest that radiologists consider a wide range of features than is included in existing reporting schemes. Our scheme allows a richer characterization of calcifications, potentially improving the reporting and understanding of these abnormalities.

Breast Diseases↗
PubMed2001

The link between excitotoxic oligodendroglial death and demyelinating diseases.

Oligodendrocytes, the myelinating cells of CNS axons, are highly vulnerable to excitotoxic signals mediated by glutamate receptors of the AMPA and kainate classes. Receptors in these cells are commonly activated by glutamate that is released from axons and glial cells. In addition, oligodendrocytes contribute to the control of extracellular glutamate levels by means of their own transporters. However, acute and chronic alterations in glutamate homeostasis can result in overactivation of AMPA and kainate receptors and subsequent excitotoxic oligodendroglial death. Furthermore, demyelinating lesions caused by excitotoxins can be similar to those observed in multiple sclerosis. This, together with the effect of AMPA and kainate receptor antagonists in ameliorating the neurological score of animals with experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis), indicates that oligodendrocyte excitotoxicity could be involved in the pathogenesis of demyelinating disorders.

Animals↗
PubMed2001

Combining decision support and image processing: a PROforma model.

This paper addresses two important problems in medical image interpretation:(1) integration of numeric and symbolic information, (2) access to external sources of medical knowledge. We have developed a prototype in which image processing algorithms are combined with symbolic representations for reasoning, decision making and task management in an integrated, platform-independent system for the differential diagnosis of abnormalities in mammograms. The prototype is based on PROforma, a generic technology for building decision support systems based on clinical guidelines. The PROforma language defines a set of tasks, one of which, the enquiry, is used as means of interaction with the outside world. However, the current enquiry model has proved to be too limited for our purposes. In this paper we outline a more general model, which can be used as an interface between symbolic functions and image or other signal data.

Algorithms↗
PubMed2000

Computerisation and decision making in neonatal intensive care: a cognitive engineering investigation.

This paper reports results from a cognitive engineering study that looked at the role of computerised monitoring in neonatal intensive care. A range of methodologies was used: interviews with neonatal staff, ward observations, and experimental techniques. The purpose was to investigate the sources of information used by clinicians when making decisions in the neonatal ICU. It was found that, although it was welcomed by staff, computerised monitoring played a secondary role in the clinicians' decision making (especially for junior and nursing staff) and that staff used the computer less often than indicated by self-reports. Factors that seemed to affect staff use of the computer were the lack (or shortage) of training on the system, the specific clinical conditions involved, and the availability of alternative sources of information. These findings have relevant repercussions for the design of computerised decision support in intensive care and suggest ways in which computerised monitoring can be enhanced, namely: by systematic staff training, by making available online certain types of clinical information, by adapting the user interface, and by developing intelligent algorithms.

Attitude to Computers↗
PubMed2000

CADMIUM II: acquisition and representation of radiological knowledge for computerized decision support in mammography.

CADMIUM II is a system for the interpretation of mammograms. A novel aspect of the system is that it combines symbolic reasoning with image processing, in contrast with most other approaches, which use only image processing and rely on artificial neural networks (ANNs) to classify mammograms. A problem of ANNs is that the advice they give cannot be traced back to communicable diagnostic inferences. Our approach is to provide advice based on explicit knowledge about the diagnostic process. To this end, we have conducted a knowledge elicitation study which looked at the descriptors used by expert radiologists when making diagnostic decisions about mammograms. The analysis of the radiologists' reports yielded a set of salient diagnostic features. These were used to inform the advice provided by the symbolic decision making component of CADMIUM II.

Breast Diseases↗
PubMed1999

Contribution of phosphodiesterase isoenzymes and cyclic nucleotide efflux to the regulation of cyclic GMP levels in aortic smooth muscle cells.

Involvement of phosphodiesterase isoenzymes (PDEs) in guanosine-3',5'-cyclic monophosphate (cGMP) hydrolysis was analyzed in aortic smooth muscle cells. Four families of PDEs were separated from pig aorta: PDE1 (calcium-calmodulin-activated), PDE3 (cGMP-inhibited), PDE4 (adenosine 3',5'-cyclic monophosphate [cAMP]-specific), and PDE5 (cGMP-specific). Within this PDE complement, PDE1 and PDE5 mostly contributed to the hydrolysis of cGMP both in the presence and absence of calcium-calmodulin. The role of these isoenzymes in cGMP degradation was analyzed in primary cultures of porcine aortic smooth muscle cells after stimulation with sodium nitroprusside (SNP) or atrial natriuretic factor (ANF). Pretreatment with 10 microM zaprinast, a concentration that selectively inhibits PDE5, did not potentiate the SNP- or ANF-induced rise of cGMP, questioning the widespread opinion that only PDE5 accounts for cGMP hydrolysis in this tissue. Further evidence came from experiments assessing the effect of zaprinast or 3-isobutyl-1-methylxanthine at concentrations inhibiting both type 1 and type 5 isoenzymes, in which this potentiation was clearly seen. Contribution of cGMP egression to the control of intracellular cGMP levels after SNP or ANF stimulation was also investigated. Shortly after guanylate cyclase activation, extracellular cGMP levels surpassed intracellular levels. However, comparison of the amounts of cGMP extruded to the extracellular medium with those degraded by PDEs leads to the conclusion that efflux is of relatively minor importance in regulating intracellular cGMP levels. In cells made tolerant to SNP, selective PDE5 inhibition synergistically increased intra- and extracellular cGMP amounts after SNP stimulation. These results indicate a previously undescribed greater relevance of PDE5 after tolerance development in aortic smooth muscle cells.

Animals↗
PubMed1999

Binding of pigment epithelium-derived factor (PEDF) to retinoblastoma cells and cerebellar granule neurons. Evidence for a PEDF receptor.

Pigment epithelium-derived factor (PEDF) has neuronal differentiation and survival activity on retinoblastoma and cerebellar granule (CG) cells. Here, we investigated the presence of PEDF receptors on retinoblastoma Y-79 and CG cells. PEDF radiolabeled with (l25)I remained biologically active and was used for radioligand binding analysis. The binding was saturable and specific to a single class of receptors on both cells and with similar affinities (K(d) = 1.7-3.6 nM, B(max) = 0.5-2.7 x 10(5) sites/Y-79 cell; and K(d) = 3.2 nM, B(max) = 1.1 x 10(3) sites/CG cell). A polyclonal antiserum to PEDF, previously shown to block the PEDF neurotrophic activity, prevented the (125)I-PEDF binding. We designed two peptides from a region previously shown to confer the neurotrophic property to human PEDF, synthetic peptides 34-mer (positions 44-77) and 44-mer (positions 78-121). Only peptide 44-mer competed for the binding to Y-79 cell receptors (EC(50) = 5 nM) and exhibited neuronal differentiating activity. PEDF affinity column chromatography of membrane proteins from both cell types revealed a PEDF-binding protein of approximately 80 kDa. These results are the first demonstration of a PEDF-binding protein with characteristics of a PEDF receptor and suggest that the region comprising amino acid positions 78-121 of PEDF might be involved in ligand-receptor interactions.

Animals↗
PubMed1999

Pigment epithelium-derived factor promotes the survival and differentiation of developing spinal motor neurons.

Pigment epithelium-derived factor (PEDF) is a member of the serine protease inhibitor (serpin) superfamily that has been shown previously to promote the survival and/or differentiation of rat cerebellar granule neurons and human retinoblastoma cells in vitro. However, in contrast to most serpins, PEDF has no inhibitory activity against any known proteases, and its described biological activities do not appear to require the serpin-reactive loop located toward the carboxy end of the polypeptide. Because another serpin, protease nexin-1, has been shown to promote the in vivo survival and growth of motor neurons, the authors investigated the potential neurotrophic effects of PEDF on spinal cord motor neurons in highly enriched cultures and in vivo after injury. Here, it is shown that native bovine and recombinant human PEDF promoted the survival and differentiation (neurite outgrowth) of embryonic chick spinal cord motor neurons in vitro in a dose-dependent manner. A truncated form of PEDF that lacks approximately 62% of the carboxy end of the polypeptide comprising the homologous serpin-reactive loop also exhibited neurotrophic activities similar to those of the full-length protein. Furthermore, the data here showed that PEDF was transported retrogradely and prevented the death and atrophy of spinal motor neurons in the developing neonatal mouse after axotomy. These results indicate that PEDF exerts trophic effects on motor neurons, and, together with previous reports, these findings suggest that this protein may be useful as a pharmacologic agent to promote the development and maintenance of motor neurons. J. Comp. Neurol. 412:506-514, 1999. Published 1999 Wiley-Liss, Inc.

Animals↗
PubMed1999

Synthesis and anti-HIV-1 activities of new pyrimido[5,4-b]indoles.

A set of new pyrimido[5,4-b]indole derivatives that are structurally related to some non-nucleside HIV-1 reverse transcriptase inhibitors were synthesized and biologically evaluated for their activity as inhibitors of wild and mutant HIV-1 RT types in an 'in vitro' recombinant HIV-1 RT screening assay, as well as anti-infectives in HLT4lacZ-1IIIB cells. Preliminary structure-activity relationships suggest that activity is promoted by simultaneous substitution in positions 2 and 4, especially when chains of alkyldiamine type are present, and by electron-releasing substituents (methoxy) in positions 7 and 8. The inactivity or the very low activity of title derivatives does not suggest interest in AIDS therapy.

Anti-HIV Agents↗
PubMed1998

Pigment epithelium-derived factor (PEDF) binds to glycosaminoglycans: analysis of the binding site.

Pigment epithelium-derived factor (PEDF), a neurotrophic protein, is a secreted serpin identified in extracellular matrixes. We show that PEDF extractions from the interphotoreceptor matrix are more efficient with increasing NaCl concentrations, indicating that ionic interactions mediate its association with this polyanionic matrix. We have used affinity chromatography and ultrafiltration to probe for direct binding of PEDF to glycosaminoglycans/polyanions. Correctly folded PEDF bound to immobilized heparin, chondroitin sulfate-A, -B, -C, and dextran sulfate columns and eluted from each with an increase in NaCl concentration. However, in the presence of urea, the protein lost its affinity for heparin. Binding of PEDF to heparan sulfate proteoglycan in solution was in a concentration-dependent fashion (half-maximal specific binding EC50 = 40 micrograms/mL) and was sensitive to increasing NaCl concentrations. The glycosaminoglycan-binding region was analyzed using chemical modification and limited proteolysis. PEDF chemically modified on lysine residues by biotinylation lost its capacity for interacting with heparin, implicating the involvement of PEDF lysine residues in heparin binding. Cleavage of the serpin-exposed loop with chymotrypsin did not affect the heparin-binding property. A limited proteolysis product containing residues 21-approximately 260 bound to heparin with similar affinity as the intact PEDF. Homology modeling of PEDF based on the X-ray crystal structures of antithrombin III and ovalbumin shows a region at the center of beta-sheet A-strands 2 and 3- and helix F that has a basic electrostatic surface potential and is densely populated with lysines exposed to the surface (K134, K137, K189, K191, H212, and K214) that are available to interact with various glycosaminoglycans/polyanions. This region represents a novel site for glycosaminoglycan binding in a serpin, which in PEDF, is distinct and nonoverlapping from the PEDF neurotrophic active region.

Amino Acid Sequence↗
PubMed1997

Synthesis and evaluation of new Reissert analogs as HIV-1 reverse transcriptase inhibitors. 1. Quinoline and quinoxaline derivatives.

The synthesis and preliminary evaluation of new quinoline and quinoxaline derivatives (obtained by applying the original Reissert method, conveniently modified) as HIV-1 Reverse Transcriptase (RT) inhibitors are presented in this paper; likewise, the first structure-activity relationships are also proposed. Propyl 2-cyano-1(2H)-quinolin-carboxylate 2e, isopropyl 2-cyano-1 (2H)-quinolincarboxylate 2f, butyl 2-cyano-1 (2H)-quinolincarboxylate 2g and isobutyl 2-cyano-1 (2H)-quinolincarboxylate 2h have been selected as lead compounds. These compounds are active against the HIV-1 RT mutant type P236L (2f, IC50 = 1.2 microM) and present activity as anti-infective agents in HLT41acZ-1IIIB cells, showing no cytotoxicity at the active concentrations.

Anti-HIV Agents↗
PubMed1996

A checkerboard method to evaluate interactions between drugs.

A method to evaluate interactions between biologically active agents is presented. Synergism, zero interaction, and antagonism were easily detected with the three-dimensional approach proposed herein. This method is compatible with a checkerboard design to diagnose the interaction between agents and obviate the need to test their mixtures in a fixed concentration ratio as proposed by Chou and Talalay. Dose-response curves for individual agents were obtained, and experimental data fitted to appropriate equations by nonlinear regression. If zero interaction was present, the predicted effect could be calculated for each combination using the classical isobole equation with any spreadsheet having a command to solve mathematical equations by iteration. This allowed the selection of appropriate concentrations for the combination of two or more agents. Interaction between agents could be assessed in two ways: by comparing experimental with expected effects, if zero interaction is present; or by analyzing the reduction or increase in total dose found as a consequence of the interaction. The applicability of both approaches is discussed and, for purposes of comparison with other methods, examples based on published data are analyzed and commented upon.

Alcohol Dehydrogenase↗
PubMed1996

Recombinant human pigment epithelium-derived factor (PEDF): characterization of PEDF overexpressed and secreted by eukaryotic cells.

Pigment epithelium-derived factor (PEDF) is a serpin found in the interphotoreceptor matrix of the eye, which, although not a proteinase inhibitor, possesses a number of important biological properties, including promotion of neurite outgrowth and differential expression in quiescent versus senescent states of certain cell types. The low amounts present in the eye, together with the impracticality of using the eye as a source for isolation of the human protein, make it important to establish a system for overexpression of the recombinant protein for biochemical and biological studies. We describe here the expression and secretion of full-length glycosylated human recombinant PEDF at high levels (> 20 micrograms/ mL) into the growth medium of baby hamster kidney cells and characterization of the purified rPEDF by circular dichroism and fluorescence spectroscopies and neurite outgrowth assay. By these assays, the recombinant protein behaves as expected for a correctly folded full-length human PEDF. The availability of milligram amounts of PEDF has permitted quantitation of its heparin binding properties and of the effect of reactive center cleavage on the stability of PEDF towards thermal and guanidine hydrochloride denaturation.

Animals↗
PubMed1995

New indole and pyridazinoindole analogs--synthesis and study as inhibitors of phosphodiesterases and as inhibitors of blood platelet aggregation.

This paper presents the synthesis of new indole, pyridazino[4,5-b]-indole, and pyridazino[4,5-a]indole analogs as well as a study of their "in vitro" activity as inhibitors of different phosphodiesterases isolated from dog cardiac tissue, dog aorta, and bovine platelets; the study of their activity as inhibitors of platelet aggregation in guinea pig whole blood, with ADP and arachidonic acid (AA) as pro-aggregants, is also included. The selected compounds 8-benzyloxy-3,4-dihydro-1-(3,4,5-trimethoxy)benzylideneaminopyridazin o[4,5- b]indole 14g, and 8-benzyloxy-4-[(3,4-dimethyl)pyrazolyl]pyridazino[4,5-b]indo le 20 present an interesting profile as potential inodilators, with a complementary, beneficial activity as inhibitors of the aggregation, activities which could possibly be related to the inhibition of the PDE's. Among the other compounds studied, 8-benzyloxy-3,4-dihydro-1-[4-(methyl)piperazino]acetamidopyrida zino[4,5- b]indol-4-one 16c and 8-benzyloxy-3,4-dihydro-1-[4-(2- methoxyphenyl)piperazino]acetamidopyridazino[4,5-b]indol-4-o ne 16f stood out as inhibitors of platelet aggregation, with a mechanism that could possibly be related to the AA cascade.

Animals↗
PubMed1995

Inotropic and chronotropic effects of 4-(4'-n-butylaniline)-7,8- dimethoxy-5H-pyrimido[5,4-b]indole in guinea-pig atria.

Cardiotonic effect of 4-(4'-n-butylaniline)-7,8-dimethoxy- 5H-pyrimido[5,4-b]indole (B11) was investigated in isolated cardiac tissue preparations. The action of this agent on force of contraction, beating frequency and cyclic nucleotide phosphodiesterase (PDE) activity was studied. Amrinone was used for comparison. B11 produced concentration-dependent (5 x 10(6)-1 x 10(-4)M) positive inotropic and positive chronotropic responses in guinea-pig atrial tissues. The potency of B11 was greater than that of amrinone. The cardiotonic effects of B11 were not modified by beta-adrenoceptor blockade. Carbachol inhibited the positive inotropic effect of B11. The activity of B11 was increased in desensitized left atrial tissues. B11 inhibited the activities of PDE isoenzymes (type I, II, IV and V) from dog heart ventricle and PDE type IV from guinea-pig heart ventricle nonselectively. It is concluded that B11 possesses potent positive inotropic activity in guinea-pig atria, and the effect is probably mediated by a non-selective inhibition of PDE activity.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1993

New 4-amino-7,8-dimethoxy-5H-pyrimido[5,4-b]indole derivatives: synthesis and studies as inhibitors of phosphodiesterases.

A series of 4-amino-7,8-dimethoxy-5H-pyrimido[5,4-b]indole derivatives has been synthesized. These compounds resemble carbazeram and other pyridazino compounds with activity in the cardiovascular system. Some of these new compounds possess inotropic activity (Table 2), with a complementary effect on the inhibition of different CGI-PDE (Table 3). The most active compounds 5, 6d, and 7 also possess activity as vasodilators (Table 4). Some of these new compounds inhibit blood platelet aggregation induced by ADP and AA and are active as inhibitors of human platelet PDEs (Tables 5 and 6).

Animals↗
PubMed1993

A novel class of cardiotonic agents: synthesis and biological evaluation of pyridazino[4,5-b]indoles with cyclic AMP phosphodiesterases inhibiting properties.

Some fused pyridazino[4,5-b]indoles (7) were synthesized. These new compounds present a planar topography and some resemblance to carbazeram, imadozan, and other pyridazino agents with cardiotonic activity. These compounds also possess a complementary effect as inhibitors of platelet aggregation. 6-(3,5-Dimethylpyrazolyl)-1,2,4-triazolo[4,3-b]pyridazino[4, 5-b]indole (7a) has a good profile as an inodilatador with antiaggregate activity due to the inhibition of phosphodiesterase.

3',5'-Cyclic-AMP Phosphodiesterases↗