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Biomedical subjects

Fernando Ortega

Publications and source records attributed to Fernando Ortega.

At least 19 recordsLinked to original sources
PubMed2007

Modular metabolic control analysis of large responses.

Deciphering the laws that govern metabolic responses of complex systems is essential to understand physiological functioning, pathological conditions and the outcome of experimental manipulations of intact cells. To this aim, a theoretical and experimental sensitivity analysis, called modular metabolic control analysis (MMCA), was proposed. This field was previously developed under the assumptions of infinitesimal changes and/or proportionality between parameters and rates, which are usually not fulfilled in vivo. Here we develop a general MMCA for two modules, not relying on those assumptions. Control coefficients and elasticity coefficients for large changes are defined. These are subject to constraints: summation and response theorems, and relationships that allow calculating control from elasticity coefficients. We show how to determine the coefficients from top-down experiments, measuring the rates of the isolated modules as a function of the linking intermediate (there is no need to change parameters inside the modules). The novel formalism is applied to data of two experimental studies from the literature. In one of these, 40% increase in the activity of the supply module results in less than 4% increase in flux, while infinitesimal MMCA predicts more than 30% increase in flux. In addition, it is not possible to increase the flux by manipulating the activity of demand. The impossibility of increasing the flux by changing the activity of a single module is due to an abrupt decrease of the control of the modules when their corresponding activities are increased. In these cases, the infinitesimal approach can give highly erroneous predictions.

Algorithms↗
PubMed2006

The association of increased p14ARF/p16INK4a and p15INK4a gene expression with proliferative activity and the clinical course of multiple myeloma.

p14/p16 and p15 gene expression was assessed by quantitative polymerase chain reaction in purified plasma cells (PC) from 52 patients with symptomatic multiple myeloma (MM) and seven with smoldering MM in order to clarify the impact of these genes on the proliferative activity of tumor cells and patients' outcome. p15 expression was lower in symptomatic MM than in smoldering SMM (-1.80 vs.1.51,p=0.026); similar results were observed for p14/p16. MM patients whose PC displayed high p15 and/or p14/p16 expression had a lower percentage of S-phase PC than the remaining cases (1.79%+/-1.35 vs. 3.04%+/-1.42, p=0.028), favorable prognostic factors and longer survival (100% vs. 49%at 2.5 years; p=0.007).

Cell Proliferation↗
PubMed2006

Bistability from double phosphorylation in signal transduction. Kinetic and structural requirements.

Previous studies have suggested that positive feedback loops and ultrasensitivity are prerequisites for bistability in covalent modification cascades. However, it was recently shown that bistability and hysteresis can also arise solely from multisite phosphorylation. Here we analytically demonstrate that double phosphorylation of a protein (or other covalent modification) generates bistability only if: (a) the two phosphorylation (or the two dephosphorylation) reactions are catalyzed by the same enzyme; (b) the kinetics operate at least partly in the zero-order region; and (c) the ratio of the catalytic constants of the phosphorylation and dephosphorylation steps in the first modification cycle is less than this ratio in the second cycle. We also show that multisite phosphorylation enlarges the region of kinetic parameter values in which bistability appears, but does not generate multistability. In addition, we conclude that a cascade of phosphorylation/dephosphorylation cycles generates multiple steady states in the absence of feedback or feedforward loops. Our results show that bistable behavior in covalent modification cascades relies not only on the structure and regulatory pattern of feedback/feedforward loops, but also on the kinetic characteristics of their component proteins.

Animals↗
PubMed2006

Integrated telemedicine applications and services for oncological positron emission tomography.

TENPET (Trans European Network for Positron Emission Tomography) aims to evaluate the provision of integrated teleconsultation and intelligent computer supported cooperative work services for clinical positron emission tomography (PET) in Europe at its current stage, as it is a multi-centre project financially supported by the European Commission (Information Society, eTEN Program). It addresses technological challenges by linking PET centres and developing supporting services that permit remote consultation between professionals in the field. The technological platform (CE-marked) runs on Win2000/NT/XP systems and incorporates advanced techniques for image visualization, analysis and fusion, as well as for interactive communication and message handling for off-line communications. Four PET Centres from Spain, France and Germany participate to the pilot system trials. The performance evaluation of the system is carried out via log files and user-filled questionnaires on the frequency of the teleconsultations, their duration and efficacy, quality of the images received, user satisfaction, as well as on privacy, ethical and security issues. TENPET promotes the co-operation and improved communication between PET practitioners that are miles away from their peers or on mobile units, offering options for second opinion and training and permitting physicians to remotely consult patient data if they are away from their centre. It is expected that TENPET will have a significant impact in the development of new skills by PET professionals and will support the establishment of peripheral PET units. To our knowledge, TENPET is the first telemedicine service specifically designed for oncological PET. This report presents the technical innovations incorporated in the TENPET platform and the initial pilot studies at real and diverse clinical environments in the field of oncology.

Artificial Intelligence↗
PubMed2005

Morphological and secretory characterization of extrafloral nectaries in plants of coastal Veracruz, Mexico.

BACKGROUND AND AIMS: Morphological descriptions of the extrafloral nectaries (EFNs) of certain plant species are common in the literature, but they rarely relate morphology with histology, gland distribution and secretory attributes. In this study a morphological/secretory characterization of EFNs occurring on several plant species in a tropical coastal community is made and the implications of gland attributes discussed from a functional perspective. METHODS: The morphology and nectar secretion of the EFNs of 20 plant species are characterized through scanning electron microscopy, histochemical detection of reducing sugars (Fehling's reagent) and nectar volume/concentration estimates. KEY RESULTS: Sixty-five per cent of plant species in coastal communities had EFNs on vegetative structures and 35 % of species had glands on reproductive and vegetative organs. The Fabaceae is the plant family with the most species with EFNs and most diversity of gland morphologies. Four types of vascularized nectaries and four of glandular trichomes are described; sugar-secreting trichomes are characterized using Fehling's technique, and the first descriptions of unicellular and peltate trichomes functioning as EFNs are provided. Glands of ten plant species and six genera are described for the first time. Four plant species possess more than one morphological type of EFN. Eleven species have EFNs in more than one location or organ. More complex glands secrete more nectar, but are functionally homologous to the aggregations of numerous secretory trichomes on specific and valuable plant organs. CONCLUSION: Important diversity of EFN morphology was foundin the coastal plant community studied. Both vascularized and non-vascularized EFNs are observed in plants and, for the latter, previously non-existent morpho-secretory characterizations are provided with a methodological approach to study them. It is recommended that studies relating EFN attributes (i.e. morphology, distribution) with their differential visitation by insects (i.e. ants) and the cost of maintenance to the plants are carried out to understand the evolution of these glands.

Acacia↗
PubMed2005

[Contribution of positron emission tomography to the detection and staging of breast cancer].

INTRODUCTION: 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a diagnostic imaging tool with multiple applications in oncology. One of the more promising applications in breast cancer is noninvasive lymph node staging and detection of distant metastases, which may provide useful information about prognosis and treatment response. MATERIAL AND METHOD: Published studies on FDG-PET applications in breast cancer detection and staging were reviewed. We also present our own experience in patients referred for preoperative staging of breast cancer. RESULTS: FDG-PET is very useful in evaluating dense breasts, multicentric disease and breast prostheses. The sensitivity of FDG-PET for nodal staging is low, and consequently it cannot replace either sentinel lymph node biopsy or histologic examination. However, it is more accurate than another noninvasive techniques and is very useful in internal mammary node chain evaluation. FDG-PET can improve and maybe replace conventional imaging in detecting metastatic disease, especially in high risk patients with locoregionally advanced recurrent breast cancer or increased serum tumor markers, and helps to characterize unclear findings of anatomic imaging techniques or scintigraphy. CONCLUSIONS: FDG-PET is useful in breast cancer staging. It complements and even improves information from other diagnostic techniques and changes therapeutic management in a high proportion of patients.

Breast Neoplasms↗
PubMed2005

Neurocognitive impairment in lead-exposed children of Andean lead-glazing workers.

OBJECTIVE: The level of lead (Pb) exposure necessary to induce intellectual impairment has not been firmly established. Some studies using conventional language-based intelligence tests have reported that pediatric blood lead (PbB) levels lower than 10 microg/dL (0.483 micromol/L) are associated with neurocognitive impairment. However, these tests may introduce cultural biases in the assessment of intellectual functioning. The objective of this study was to assess the effects of PbB concentration on nonverbal intelligence in Andean children with chronic environmental Pb exposure using a nonlanguage-based test of cognitive functioning. METHODS: Using Raven Colored Progressive Matrices (RCPM) as a measure of nonverbal intelligence, this study investigated the effects of Pb exposure (biomarker: PbB levels) on intellectual functioning in 188 chronically Pb-exposed children (age range: 5.33-11.67 years) of Ecuadorian Andean Pb-glazing workers. RESULTS: The mean PbB level of the 188 children was 29.3 microg/dL (range: 3.5-94.3 microg/dL). Forty-seven children had PbB levels <10 microg/dL (Centers for Disease Control and Prevention [CDC] I classification), of which 30 had abnormal (ie, < or =25th percentile) RCPM standard scores. Of the 141 children with PbB levels > or =10 microg/dL, 97 had abnormal RCPM scores. A regression analysis revealed a statistically significant negative association (r = -0.331, P < 0.0001) between PbB level and RCPM standard score. Conversion of RCPM standard scores to estimated IQ scores showed an approximate two-point decrease in IQ for each 10-microg/dL increment in PbB level from 10 to >70 microg/dL. CONCLUSIONS: Performance on a test of nonverbal intelligence was inversely associated with chronic Pb exposure in Andean children with PbB levels below and above the CDC risk management level of 10 microg/dL, with the decline in test scores suggesting a dose-response relationship.

Adult↗
PubMed2004

Current pediatric and maternal lead levels in blood and breast milk in Andean inhabitants of a lead-glazing enclave.

Prenatal and postnatal lead (Pb) exposure may induce neurodevelopmental disabilities in children. As part of an ongoing health-monitoring study, blood lead (PbB) levels were compared in 90 children tested in 2003 (current group) and 166 children tested between 1996 and 2000 (reference group) in Ecuadorian Andean villages with high Pb contamination. The mean PbB level for children in the reference group was 40 microg/dL (range, 6.2-119.1), and significantly higher than the mean PbB level of 25.5 microg/dL (range, 2.1-94.3) for the current group (t test, P = 0.0001). An analysis of variance revealed no significant main effects for age and gender and no significant interaction between age and gender for the current group but a significant age by gender interaction for the reference group (F = 5.96, P = 0.01). Regression analysis revealed a significant correlation (r = 0.258, P = 0.01) between PbB level and age for males but not for females in the reference group. The Pb levels in breast milk from nursing mothers ranged from 0.4-20.5 microg/L (mean, 4.6), and the PbB levels in the breastfeeding mothers ranged from 4.5-35.2 microg/dL (mean, 17.1). The PbB levels of mother-infant pairs ranged from 4.6-27.4 microg/dL for mothers and 3.9-33.5 microg/dL for infants. The results showed significantly reduced PbB levels in children in the study area and suggest that a Pb education and prevention program contributed to the current reduction in Pb intoxication.

Adolescent↗
PubMed2003

Glucose conversion by multiple pathways in brain extract: theoretical and experimental analysis.

Experimental and model studies were performed to characterize the flux of glucose metabolism and the sharing of glucose-6-phosphate (Glu6P) by the upper parts of glycolytic and pentosephosphate pathways in the brain extract. A mathematical model based upon the kinetic equations of the individual enzymes was evaluated to fit the experimental data. Glucose is converted to glucose-6-phosphate by hexokinase that controls almost exclusively the glucose metabolism. Experiments showed that this crossroad-metabolite was shared between glycolysis and pentosephosphate pathway in the brain extract in a ratio of 1.5:1. This ratio was favorable to the pentosephosphate pathway by the addition of high excess of exogenous glucose-6-phosphate dehydrogenase, standardly used for the activity assay of hexokinase, but still a significant part (17+/-3%) of the common intermediate was converted into the direction of glycolysis. Stimulation of glucose-6-phosphate formation via moderate (30-50%) increase of hexokinase activity by adding exogenous hexokinase or tubulin resulted in the slight increase of the relative flux into direction of glycolysis. The model correctly described all of these observations. However, when the activity of hexokinase was doubled with exogenous enzyme, significantly less glucose-6-phosphate was converted into direction of glycolysis than predicted. This discrepancy shows that the system did not behave in this case as an ideal one, which could be due to the formation of distinct pools for the intermediate.

Animals↗
PubMed2003

Mathematical modelling of the urea cycle. A numerical investigation into substrate channelling.

Metabolite channelling, the process in which consecutive enzymes have confined substrate transfer in metabolic pathways, has been proposed as a biochemical mechanism that has evolved because it enhances catalytic rates and protects unstable intermediates. Results from experiments on the synthesis of radioactive urea [Cheung, C., Cohen, N.S. & Raijman, L (1989) J. Biol. Chem.264, 4038-4044] have been interpreted as implying channelling of arginine between argininosuccinate lyase and arginase in permeabilized hepatocytes. To investigate this interpretation further, a mathematical model of the urea cycle was written, using Mathematica it simulates time courses of the reactions. The model includes all relevant intermediates, peripheral metabolites, and subcellular compartmentalization. Analysis of the output from the simulations supports the argument for a high degree of, but not absolute, channelling and offers insights for future experiments that could shed more light on the quantitative aspects of this phenomenon in the urea cycle and other pathways.

Arginase↗
PubMed2003

Analysis of genetic diversity in red clover (Trifolium pratense L.) breeding populations as revealed by RAPD genetic markers.

Red clover is an important forage legume species for temperate regions and very little is known about the genetic organization of its breeding populations. We used random amplified polymorphic DNA (RAPD) genetic markers to address the genetic diversity and the distribution of variation in 20 breeding populations and cultivars from Chile, Argentina, Uruguay, and Switzerland. Genetic distances were calculated for all possible pairwise combinations. A high level of polymorphism was found and the proportion of polymorphic loci across populations was 74.2%. A population derived from a non-certified seedlot displayed a higher proportion of polymorphic loci than its respective certified seedlot. Gene diversity values and population genetics parameters suggest that the populations analyzed are diverse. An analysis of molecular variance (AMOVA) revealed that the largest proportion of variation (80.4%) resides at the within population level. RAPD markers are a useful tool for red clover breeding programs. A dendrogram based on genetic distances divided the breeding populations analyzed into three distinct groups. The amount and partition of diversity observed can be of value in identifying the populations that parents of synthetic cultivars are derived from and to exploit the variation available in the populations analyzed.

Analysis of Variance↗
PubMed2002

Elasticity analysis and design for large metabolic responses produced by changes in enzyme activities.

Metabolic control analysis has been extensively used to describe how the sensitivity properties of the component enzymes in a metabolic pathway (represented by the elasticity coefficients) determine the way in which metabolic variables respond (described by the control coefficients). Similarly, metabolic control design addresses the inverse problem of obtaining the sensitivity properties of the component enzymes that are required for the system to show a pre-established pattern of responses. These formalisms, including what is called elasticity analysis and design, were developed for small, strictly speaking infinitesimal, changes. Here we extend them to large metabolic responses. The new approach can be applied to simple two-step pathways or to any arbitrary metabolic system divided into two groups linked by one intermediate. General expressions that relate control and elasticity coefficients for large changes are derived. Concentration and flux connectivity relationships are obtained. The relationships for large changes indicate that the pattern of responses is not necessarily the same as the one obtained with the traditional infinitesimal approach, in some cases the patterns being qualitatively different. The general analysis is used to study the control of ketogenesis in rat liver mitochondria, starting from data available in the literature. The control profile of the pathway subject to large changes shows both quantitative and qualitative differences from the one obtained from an analysis that is performed with infinitesimal coefficients. This exemplifies the type of errors that may be introduced when drawing conclusions about large metabolic responses from results obtained with an infinitesimal treatment.

Animals↗
PubMed2002

Product dependence and bifunctionality compromise the ultrasensitivity of signal transduction cascades.

Covalent modification cycles are ubiquitous. Theoretical studies have suggested that they serve to increase sensitivity. However, this suggestion has not been corroborated experimentally in vivo. Here, we demonstrate that the assumptions of the theoretical studies, i.e., irreversibility and absence of product inhibition, were not trivial: when the conversion reactions are close to equilibrium or saturated by their product, "zero-order" ultrasensitivity disappears. For high sensitivities to arise, not only substrate saturation (zero-order) but also high equilibrium constants and low product saturation are required. Many covalent modification cycles are catalyzed by one bifunctional 'ambiguous' enzyme rather than by two independent proteins. This makes high substrate concentration and low product concentration for both reactions of the cycle inconsistent; such modification cycles cannot have high responses. Defining signal strength as ratios of modified (e.g., phosphorylated) over unmodified protein, signal-to-signal response sensitivity equals 1: signal strength should remain constant along a cascade of ambiguous modification cycles. We also show that the total concentration of a signalling effector protein cannot affect the signal emanating from a modification cycle catalyzed by an ambiguous enzyme if the ratio of the two forms of the effector protein is not altered. This finding may explain the experimental result that the pivotal signal transduction protein PII plus its paralogue GlnK do not control steady-state N-signal transduction in Escherichia coli. It also rationalizes the absence of strong phenotypes for many signal-transduction proteins. Emphasis on extent of modification of these proteins is perhaps more urgent than transcriptome analysis.

Enzymes↗
PubMed2002

Elevated blood mercury and neuro-otological observations in children of the Ecuadorian gold mines.

The prevalence of mercury (Hg) intoxication was investigated in 114 Andean Saraguro and non-Saraguro (Mestizo) children living in remote gold-mining settlements in Nambija and Portovelo, Ecuador. Venous blood samples showed a mean total blood mercury (B-Hg) level of 18.2 microg/L (SD 15.5; range 2-89.) for 77 Saraguro and non-Saraguro children in the Nambija settlement, which was significantly higher than that of children in the Portovelo and reference groups. Comparison of groups showed mean B-Hg levels of 26.4 microg/L (range 4-89 microg/L) for 32 indigenous/Saraguro children; 12.3 microg/L (range 2-33 microg/L) for 45 non-Saraguro children; 4.9 microg/L (range 1-10 microg/L) for 37 children in Portovelo; and 2.4 microg/L (range 1-6 microg/L) for a reference group of 15 children. Fisher's post hoc analysis revealed significant differences among groups, except between the Portovelo and the reference groups. Neuro-otological symptoms and abnormalities were observed in Saraguro, non-Saraguro, and Portovelo children. Samples of soil collected at sites near the local school were found to contain Hg levels ranging from 0. 1 to 38 ppm, cadmium (Cd) levels from 0.07 to 0.82 ppm and arsenic (As) levels from < 1 to 3.9 ppm. in conclusion, the children of Nambija, particularly the Saraguro "Amer-Indians," exhibited elevated B-Hg levels from exposure to Hg used in the gold-mining process, and are at risk for neurological impairment. The children of Portovelo who reported neuro-otological symptoms but had low B-Hg levels (<10 microg/L) may be affected by exposure to sodium cyanide, which is used extensively in the local gold-mining operations.

Adolescent↗
PubMed2002

Sensitivity analysis of metabolic cascades catalyzed by bifunctional enzymes.

Covalent modification/demodification cycles are common in metabolism. When the modification and demodification steps are carried out by two independent enzymes, the degree of modification can be ultrasensitive to the total concentration of either catalyst. We recently showed that the degree of modification of a target molecule cannot exhibit ultrasensitivity to the free concentrations of effectors that decide whether a bifunctional enzyme acts as modifier or demodifier. However, here we can now demonstrate that the degree of modification of a target molecule can display ultrasensitivity to the total, rather than free, concentrations of such effectors. Our results clarify some general aspects of ultrasensitive responses to effectors, including competitive inhibitors, in mono-cyclic cascades.

Catalysis↗
PubMed2002

Modulation of metabolite concentrations with no net effect on fluxes.

The concentration of a metabolite in a metabolic system can be varied without affecting any other concentrations or any fluxes by varying the concentrations of two inhibitors, one a competitive inhibitor of the enzyme that produces the metabolite, the other a competitive inhibitor of the enzyme that consumes it. The two concentrations need to be varied in opposite directions in such a way that the they add up to 100% when each is expressed as a percentage of the concentration that gives the desired flux in the absence of the other. The general approach can be extended to systems in which the inhibited enzymes do not catalyse consecutive reactions.

Enzyme Inhibitors↗