Biomedical subjects
Publications and source records attributed to S Velasco.
In this Brief Report we show that the inhomogeneous density obtained from a density-functional theory of classical fluids in the canonical ensemble (CE), recently presented by White et al. [Phys. Rev. Lett. 84, 1220 (2000)], is equivalent to first order to the result of the series expansion of the CE inhomogeneous density introduced by Gonzalez et al. [Phys. Rev. Lett. 79, 2466 (1997)].
A recent study has shown that losartan, an AT(1)-receptor antagonist, interacts with thromboxane A(2) (TxA(2))/prostaglandin H(2) (PGH(2)) receptors in human platelets. The aim of the present study was to analyse the ability of different angiotensin II (Ang II) AT(1)-receptor antagonists to inhibit TxA(2)-dependent human platelet activation. Platelets were obtained from healthy volunteers and were stimulated with the thromboxane A(2) analogue, U46619 (10(-6) mol/L). U46619-stimulated platelet activation was significantly reduced by losartan in a dose-dependent manner. Only maximal doses of valsartan (5x10(-6) mol/L), reduced U46619-induced platelet activation. The active form of candesartan cilexetil, candesartan (CV-11974), failed to modify platelet activation. Losartan reduced the binding of [(3)H]-U46619 to platelets, an effect that was observed to a lesser extent with valsartan but not with CV-11974. These results suggest that, whilst some AT(1)-receptor antagonists reduce TxA(2)-dependent human platelet activation, it is not a feature common to all AT(1) antagonists.
BACKGROUND: Recent studies suggest that polymorphisms associated to the aldose reductase gene could be related to early retinopathy in noninsulin dependent diabetics (NIDDM). There is also new interest on the genetic modulation of coagulation factors in relation to this complication. AIM: To look for a possible relationship between the rate of appearance of retinopathy and the genotype of (AC)n polymorphic marker associated to aldose reductase gene. PATIENTS AND METHODS: A random sample of 27 NIDDM, aged 68.1 +/- 10.6 years, with a mean diabetes duration of 20.7 +/- 4.8 years and a mean glycosilated hemoglobin of 10.6 +/- 1.6%, was studied. The genotype of the (AC)n, polymorphic marker associated to the 5' end of the aldose reductase (ALR2) gene was determined by 32P-PCR plus sequenciation. Mutations of the factor XIII-A gene were studied by single stranded conformational polymorphism, sequenciation and restriction fragment length polymorphism. RESULTS: Four patients lacked the (AC)24 and had a higher rate of appearance of retinopathy than patients with the (AC)24 allele (0.0167 and 0.0907 score points per year respectively, p = 0.047). Both groups had similar glycosilated hemoglobin (11.7 +/- 0.2 and 10.5 +/- 1.6% respectively). Factor XIII gene mutations were not related to the rate of appearance of retinopathy. CONCLUSIONS: Our data suggest that the absence of the (AC)24 allele of the (AC)n polymorphic marker associated to the 5' end of the aldose reductase gene, is associated to a five fold reduction of retinopathy appearance rate.
In a previous work we have analysed a family of antibody and B-cell network models (basic AB models) of the immune system. This analysis focused principally on the physiological interpretation of their parameters. Our approach consisted in building a detailed and general mathematical model (referred to as the GIB model) and then simplifying it formally to a version (named the RIB model) that belongs to the family of AB models, but which is more general than the basic AB models. From that study it was clear that some of the assumptions necessary to simplify the GIB model into the RIB one, as well as to recover the basic AB models from the RIB one, are quite unrealistic from a physiological point of view. All this raised the issue of the reliability, or even the heuristic value, of theoretical studies based on current network models for experimental immunologists. One approach to clarify this issue is to ask whether the unrealism of the assumptions implicit in the RIB and AB models entails qualitatively different behaviours between them compared to the GIB one. We initiate here such a work by performing a comparative study of a two-clone system of the AB and RIB models, and a variant of the GIB model in which the different molecular compartments were merged into a single one (labelled IGB model). Because all those models rely critically on certain B-cell activation functions, which constitute the core of an implicit model of individual B-cell reactivity or "local rules", we focused the present numerical study, to a great extent, on two parameters determining those activation functions (Hill coefficient and thresholds). Our results indicate that: (1) the RIB and IGB models display in general a much larger diversity of steady states than the AB models; (2) only under a very restricted parameter regime did all studied models behave similarly; (3) the parameter regime under which the AB and IGB models, but not the RIB one, behave similarly is still rather restricted through not as much as in (2); and (4) even relatively small quantitative changes (within reasonable values) in the postulated "local rules" can induce very large quantitative changes in the behaviour of the AB and RIB models but not the IGB model. In the light of the present results, we discuss the need of postulating a set of "local rules" solidly based on experimental evidence as a necessary condition for the reliability of current network models.
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In bacterial sepsis and meningitis, large concentrations of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) correlate directly with morbidity and mortality. This laboratory has reported previously that elevated temperature in the physiologic range is associated with down regulation of IL-1 beta and TNF alpha expression in cultured astroglia after lipopolysaccharide (LPS) stimulation. To further investigate the role of elevated temperature in the CNS inflammatory response, the effects of LPS and elevated temperature on the expression of genes that participate in the inflammatory response were determined in cultured transformed human fetal astrocytes and in an astrocytoma cell line. The effect of physiologic temperature elevation on cytokine concentrations in cerebrospinal fluid (CSF) was also investigated in a rabbit meningitis model. The findings indicate that astrocytes express a wide variety of cytokines, growth factors, growth factor receptors, and other genes that could play important roles in CNS inflammation. Furthermore, temperature elevation in the febrile range can lead to alterations in the patterns of expression of many genes involved in the inflammatory response of these cells.
B-cell activation driven by ligand-induced crosslinking of membrane immunoglobulin (mIg) is one of the most important processes in experimental and theoretical immunology. Although the activation of B cells through mIgs involves a complex series of intracellular processes, in immune network models it is usually assumed that there is a correlation between the degree of mIg crosslinking and the probability of B-cell activation. We explore the implications of this hypothesis by studying a model of ligand-induced B-cell receptor clustering proposed by Bell and further elaborated by Delisi and Perelson (BDP model). In this model, a critical time (tc) is defined at which the probability of infinite size complex formation (i.e., percolation) becomes non-zero. We use this variable, tc, as a means to characterize the degree of mIg crosslinking. To study the dependence of tc with respect to ligand valence, kinetic constants and ligand-receptor affinity x ligand concentration (K x C), we perform a systematic numerical study of the BDP model for parameter ranges including current empirical estimates for the kinetic constants. Concerning tc, we find that, for ranges of immunological interest (namely, those including current estimates of dissociation and receptor crosslinking rate constants), the curves obtained by plotting 1/tc vs. log(K x C) shift sensibly towards higher values of log(K x C), broadening and increasing its maximum amplitude, as the dissociation rate constant increases. As this finding suggests important consequences for immune network models, we further study the BDP model in an extended version for the case of two different ligands interacting simultaneously with a given B cell.3+
Endoscopic ultrasound has not yet become a routine procedure for the diagnosis and therapy planning of malignant lymphomas, and it was always restricted to patients with gastric or bowel involvement. From 1990 to 1992, 33 endoscopic ultrasound investigations have been performed in 25 patients with malignant lymphomas at the Cologne University Hospital. In addition, 21 of these patients had other (conventional) diagnostic procedures at the same time serving as reference. Endoscopic ultrasound showed lymphomas in 16/21 patients, and no evidence of lymphomas in 5/21 patients. The referencial investigations together showed lymphomas in 17/21 patients, and no evidence of lymphomas in 4/21 patients. Therefore, sensitivity was 94%. 5 of the patients in addition had involvement of the upper gastrointestinal tract's wall, proven by referencial investigations, which was diagnosed correctly in all cases. The pathological lymph nodes appeared mostly as echopoor, rather sharply demarcated and homogeneous. Their size was 7 mm to 55 mm in diameter, median 11 mm. The different histological types of lymphomas could not be distinguished by means of these criteria. Endoscopic ultrasound allows a detailed view at the mediastinal and epigastrical lymph node stations and may give important informations for the staging of malignant lymphomas.
In immune network models it is assumed that membrane immunoglobulin (mIg) crosslinking leads to B-cell activation. To analyse further the implications of this idea, a model of B-cell activation by ligand-induced mIg crosslinking in the absence of cell-to-cell interactions is proposed. The present model, based on a simple crosslinking mechanism previously proposed by other authors, assumes that activation of B-cells is possible once crosslinks of mIgs percolate and that percolation of crosslinks can only happen within a relatively short time tau. Given a lattice (regular or not), a molecular cluster is said to percolate or to become a percolating cluster if it spans the whole lattice (this is the case, for instance, of a polymer in a gel phase). From this model of B-cell activation we define the activation function fa (LK) as the fraction of B-cells activated after tau minutes of interaction with a ligand at concentration L and with affinity K. Numerical calculations show that, for current estimates of kinetic constants involved in the interaction of a given ligand with a B-cell clone, the activation function fa shifts when k-, the dissociation rate constant, is varied below 10(-3) s-1, this shift being linearly proportional to the variation of k-. This result contradicts and, therefore, challenges the assumption in immune network models that the activation function is identical for all ligands. This is important because the behaviour of at least some of those immune network models is quite sensitive to the relative values of the activation function thresholds.
It is argued that the realism of computer simulations of network models of the immune system depends basically on the coherence of these models with the essentials of the known physiology of the cells and molecules selected to be modelled and on the incorporation in them of the different compartments of activated B cells. Focusing on these two aspects, here we analyse the simplifications and assumptions that go implicit in the formulation of a recently developed new class of network models that distinguish between immunoglobulins and B cells. This is approached by first building a general model which incorporates explicitly the kinetics of different B-cell compartments as well as a splenic compartment and a peripheric one for immunoglobulins, and then formally studying the simplifications on this model that are necessary to recover the initial simpler models. Following this procedure, it is shown that the effective coefficients of the different rate terms in the simpler models are particular combinations of the elementary rates obtained empirically. These relations reflect the particular assumptions associated with each simplification step. Also, it is shown that the usual biological interpretation of some of the coefficients in the ordinary differential equations of the simpler models is inconsistent with the more exact general model, unless one makes certain unreasonable assumptions about B-cell physiology. The relevance of this approach in providing variables with a biologically identifiable reality and for realistic, testable, computer simulations is discussed.
We developed a Wilms' tumor-cell culture system to investigate the molecular basis of nephrogenesis and oncogenesis. Several distinct fractions of cells were isolated and characterized from the same tumor specimen. The cells exhibited striking differences in morphology, immunocytochemical staining profiles and cytogenetics. One fraction contained cells with features of epithelium; other cell fractions resembled partially differentiated mesenchyme (blastema or stroma). While the Wilms' tumor-suppressor gene WT1 was not altered, loss of heterozygosity (LOH) and an insertion in intron I of the p53 tumor-suppressor gene occurred in the tumor and the cultured cell types. LOH for RB was detected only in the cultured cells. These findings are consistent with a model of tumor initiation in a pluripotent cell that is able to undergo subsequent differentiation along multiple different lines and which mimics normal nephrogenesis.
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BACKGROUND: Congenital mesoblastic nephroma (CMN) is a rare tumor of the neonatal kidney. It was once thought to be a variant of Wilms tumor that also arises from primitive renal cells. METHODS: Molecular characteristics of two CMN were studied to clarify their potential relationship to Wilms tumors. Patterns of gene expression were assayed by Northern blot hybridization analysis. Tumors were tested for loss of heterozygosity (LOH) at chromosomes 11p13 and 11p15 using Southern blot analysis. RESULTS: The CMN, like Wilms tumors, demonstrated high-level expression of insulin-like growth factor II. Unlike Wilms tumors, however, the CMN expressed neither the N-myc oncogene nor the putative Wilms tumor suppressor gene, WT1. Using a panel of probes spanning 11p13 and 11p15, no LOH was detected in the CMN, nor was there evidence of deletion or rearrangements of WT1. CONCLUSIONS: Although Wilms tumor and CMN both arise from the developing kidney, molecular characterization suggests that different factors are involved in the pathogenesis of these two tumors.
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In bacterial meningitis, LPS induces production in cerebrospinal fluid of the cytokines IL-1 beta and tumor necrosis factor alpha (TNF alpha), which are the principle mediators of meningeal inflammation. IL-1 beta and TNF alpha induce fever, and elevated temperature may affect cytokine expression. Dexamethasone treatment improves outcome in bacterial meningitis possibly by inhibiting IL-1 beta and TNF alpha. In this report, the effects of elevated temperature and dexamethasone on LPS-stimulated IL-1 beta and TNF alpha mRNA gene expression and protein synthesis were studied in human astrocytoma cell lines and primary cultures of human fetal astrocytes. Cells cultured at 40 degrees C exhibited smaller peaks of IL-1 beta and TNF alpha transcription and protein synthesis compared with cells cultured at 37 degrees C. The addition of dexamethasone before, during, or after exposure of the cells to LPS resulted in temperature-dependent inhibition of IL-1 beta transcription and protein synthesis. The most extensive inhibition occurred in pretreated cells cultured at 37 degrees C. Cotreatment with LPS and dexamethasone also inhibited TNF alpha mRNA transcription at both temperatures. The effects of another antiinflammatory agent, indomethacin, on LPS induction of IL-1 beta and TNF alpha mRNA were temperature and cell line dependent. These findings provide a possible explanation for the efficacy of dexamethasone treatment of bacterial meningitis and support the proposal that fever may be beneficial to the host in this disease.