Search PubMed⌕ Search

Biomedical subjects

P Mendes

Publications and source records attributed to P Mendes.

At least 19 recordsLinked to original sources
PubMed2005

Modelling and simulation for metabolomics data analysis.

The advent of large data sets, such as those produced in metabolomics, presents a considerable challenge in terms of their interpretation. Several mathematical and statistical methods have been proposed to analyse these data, and new ones continue to appear. However, these methods often disagree in their analyses, and their results are hard to interpret. A major contributing factor for the difficulties in interpreting these data lies in the data analysis methods themselves, which have not been thoroughly studied under controlled conditions. We have been producing synthetic data sets by simulation of realistic biochemical network models with the purpose of comparing data analysis methods. Because we have full knowledge of the underlying 'biochemistry' of these models, we are better able to judge how well the analyses reflect true knowledge about the system. Another advantage is that the level of noise in these data is under our control and this allows for studying how the inferences are degraded by noise. Using such a framework, we have studied the extent to which correlation analysis of metabolomics data sets is capable of recovering features of the biochemical system. We were able to identify four major metabolic regulatory configurations that result in strong metabolite correlations. This example demonstrates the utility of biochemical simulation in the analysis of metabolomics data.

Algorithms↗
PubMed2005

Effect of a very late antigen-4 receptor antagonist on allergen-induced airway responses and inflammation in asthma.

BACKGROUND: Very late antigen-4 (VLA(4)) plays a key role in the recruitment of eosinophils in allergic responses in animal studies. OBJECTIVE: We investigated whether pretreatment with multiple doses of a VLA(4) receptor antagonist, HMR 1031, protects against allergen-induced airway responses and airway inflammation in humans. METHODS: Fourteen asthmatics (7F/7M), 18-49 years, PC(20) forced expiratory volume in 1 s (FEV(1)) methacholine (M) (<8 mg/mL; FEV(1) 82.3-116.1% predicted) with dual responses to inhaled allergen participated in a double-blind, placebo-controlled, cross-over study. Each treatment period consisted of 9 days, separated by >or=2 weeks. Exhaled nitric oxide (eNO), PC(20)FEV(1)(M) and hypertonic saline-induced sputum was obtained on Days 1, 7 and 9. Subjects inhaled HMR 1031 (20 mg b.i.d.) or placebo (P) on Days 1--8. On Day 8, an allergen bronchoprovocation test was performed, the airway response was measured by FEV(1), and expressed as %fall from baseline. Data from 12 evaluable subjects are presented here. RESULTS: Both treatments were well tolerated. There was no significant difference between HMR 1031 and P in the early asthamatic response: mean AUC (0-3 h)+/-SEM (%fall h): 26.01+/-4.26 and 17.41+/-4.26, respectively (P=0.18), nor in the late response: mean AUC (3-9 h)+/-SEM (%fall h): 97.09+/-8.63 and 97.61+/-8.63, respectively, P=0.97. This corresponded to the absence of significant allergen-induced changes in PC(20)FEV(1)(M), eNO, sputum eosinophils and soluble inflammation markers between both treatment periods. CONCLUSIONS: Treatment with multiple inhaled doses of the VLA(4) antagonist, HMR 1031, did not result in detectable protection against allergen-induced airway responses or airway inflammation in asthma.

Administration, Inhalation↗
PubMed2003

The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models.

MOTIVATION: Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. RESULTS: We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others. AVAILABILITY: The specification of SBML Level 1 is freely available from http://www.sbml.org/

Database Management Systems↗
PubMed2002

[Dog bite in a splenectomized patient].

We present a case of Capnocytophaga canimorsus fulminant infection linked to a dog bite in a splenectomized patient. Capnocytophaga canimorsus is a gram-negative rod that typically causes septicaemia with disseminated intravascular coagulation in both immunocompromised and immunocompetent hosts. It is associated with high mortality. We also reviewed the literature and provide some recommendations on the management of bite wound as well as on both prevention and treatment of infection in asplenic state.

Adult↗
PubMed2001

Bioinformatics for rice resources.

The distinguishing feature of the 'new biology' is that it is information intensive. Not only does it demand access to and assimilation of vast data sets accumulated by engineered laboratory processes, but it also demands a previously unimaginable level of data integration across data types and sources. There are various information resources available for rice. In addition, there are various information resources that are not focused on rice but that contain rice data. The challenge for rice researchers and breeders is to access this wealth of data meaningfully. This challenge will grow significantly as international efforts aimed at sequencing the entire rice genome come into full swing. Only through concerted efforts in bioinformatics will the power of these public data be brought to bear on the needs of rice researchers and breeders worldwide. These efforts will need to focus on two large but distinct areas: (1) development of an effective bioinformatics infrastructure (hardware systems, software systems, and software engineers and support staff) and (2) computational biology research in visualization and analysis of very large, complex data sets, such as those that will be developed using high-throughput expression technologies, large-scale insertional mutagenesis, and biochemical profiling of various types. In the midst of the large flow of high-throughput data that the international rice genome sequencing efforts will produce, it is also imperative that integration of those data with unique germplasm data held in trust by the CGIAR be a part of the informatics infrastructure. This paper will focus on the state of rice information resources, the needs of the rice community, and some proposed bioinformatics activities to support these needs.

Algorithms↗
PubMed2001

In situ kinetic analysis of glyoxalase I and glyoxalase II in Saccharomyces cerevisiae.

The kinetics of glyoxalase I [(R)-S-lactoylglutathione methylglyoxal-lyase; EC 4.4.1.5] and glyoxalase II (S-2-hydroxyacylglutathione hydrolase; EC 3.1.2.6) from Saccharomyces cerevisiae was studied in situ, in digitonin permeabilized cells, using two different approaches: initial rate analysis and progress curves analysis. Initial rate analysis was performed by hyperbolic regression of initial rates using the program HYPERFIT. Glyoxalase I exhibited saturation kinetics on 0.05-2.5 mM hemithioacetal concentration range, with kinetic parameters Km 0.53 +/- 0.07 mM and V (3.18 +/- 0.16) x 10(-2) mM.min(-1). Glyoxalase II also showed saturation kinetics in the SD-lactoylglutathione concentration range of 0.15-3 mM and Km 0.32 +/- 0.13 mM and V (1.03 +/- 0.10) x 10(-3) mM.min(-1) were obtained. The kinetic parameters of both enzymes were also estimated by nonlinear regression of progress curves using the raw absorbance data and integrated differential rate equations with the program GEPASI. Several optimization methods were used to minimize the sum of squares of residuals. The best parameter fit for the glyoxalase I reaction was obtained with a single curve analysis, using the irreversible Michaelis-Menten model. The kinetic parameters obtained, Km 0.62 +/- 0.18 mM and V (2.86 +/- 0.01) x 10(-2) mM.min(-1), were in agreement with those obtained by initial rate analysis. The results obtained for glyoxalase II, using either the irreversible Michaelis-Menten model or a phenomenological reversible hyperbolic model, showed a high correlation of residuals with time and/or high values of standard deviation associated with Km. The possible causes for the discrepancy between data obtained from initial rate analysis and progress curve analysis, for glyoxalase II, are discussed.

Cell Membrane Permeability↗
PubMed2001

ISYS: a decentralized, component-based approach to the integration of heterogeneous bioinformatics resources.

MOTIVATION: Heterogeneity of databases and software resources continues to hamper the integration of biological information. Top-down solutions are not feasible for the full-scale problem of integration across biological species and data types. Bottom-up solutions so far have not integrated, in a maximally flexible way, dynamic and interactive graphical-user-interface components with data repositories and analysis tools. RESULTS: We present a component-based approach that relies on a generalized platform for component integration. The platform enables independently-developed components to synchronize their behavior and exchange services, without direct knowledge of one another. An interface-based data model allows the exchange of information with minimal component interdependency. From these interactions an integrated system results, which we call ISYSf1.gif" BORDER="0">. By allowing services to be discovered dynamically based on selected objects, ISYS encourages a kind of exploratory navigation that we believe to be well-suited for applications in genomic research.

Arabidopsis↗
PubMed1998

Non-linear optimization of biochemical pathways: applications to metabolic engineering and parameter estimation.

MOTIVATION: The simulation of biochemical kinetic systems is a powerful approach that can be used for: (i) checking the consistency of a postulated model with a set of experimental measurements, (ii) answering 'what if?' questions and (iii) exploring possible behaviours of a model. Here we describe a generic approach to combine numerical optimization methods with biochemical kinetic simulations, which is suitable for use in the rational design of improved metabolic pathways with industrial significance (metabolic engineering) and for solving the inverse problem of metabolic pathways, i.e. the estimation of parameters from measured variables. RESULTS: We discuss the suitability of various optimization methods, focusing especially on their ability or otherwise to find global optima. We recommend that a suite of diverse optimization methods should be available in simulation software as no single one performs best for all problems. We describe how we have implemented such a simulation-optimization strategy in the biochemical kinetics simulator Gepasi and present examples of its application. AVAILABILITY: The new version of Gepasi (3.20), incorporating the methodology described here, is available on the Internet at http://gepasi.dbs.aber.ac.uk/softw/Gepasi. html. CONTACT: prm@aber.ac.uk

Biochemistry↗
PubMed1998

[Remuneration and productivity: the case of the Minas Gerais Hospital Foundation, Brazil, 1992-1995].

This article presents an analysis of the Minas Gerais State Hospital Foundation immediately after the introduction in its health services units in early 1993 of a new system of rewards for good performance and productivity, as a complement to salaried remuneration. Analysis was based on a cross-sectional study of changes in indicators of production and productivity in the Foundation during the 1992-1995 period. Data were obtained from hospitalization authorization forms, payment authorization guides, and bulletins from the Human Resource Administration. The strategy of conditional remuneration and incentives was adopted not only to step up production and productivity, but also to increase the employees' commitment to the institution. Analysis of the selected indicators appears to confirm other study results in that remuneration based on results (conditional incentives) leads to a positive change in the production level of services and productivity, even if it does not last for the long term. Study results also support the notion that such alternatives may be deliberately used as part of a more general strategy of organizational development and not only as an isolated element for concrete improvements in productivity.

Awards and Prizes↗
PubMed1996

High neuron specific enolase levels in bronchoalveolar lavage fluid of patients with lung carcinoma: diagnostic value, relation to serum neuron specific enolase, and staging.

BACKGROUND: High levels of neuron specific enolase (NSE) have recently been described in the bronchoalveolar lavage (BAL) fluid of patients with lung carcinoma. Although its value in serum has been extensively studied, its diagnostic value in BAL fluid in terms of sensitivity, specificity, and predictive value have not been evaluated. In addition, its value in staging and relation to serum NSE are yet unknown. METHODS: NSE levels were determined on the same day in the BAL fluid and the sera of two groups of patients: those with newly diagnosed lung carcinoma and those with smoking related chronic obstructive pulmonary disease (COPD). Clinical TNM staging was also performed. Levels of NSE in BAL fluid were expressed as nanograms per 100 international units of lactate dehydrogenase. BAL fluid NSE levels of the two groups were compared with staging and serum NSE. RESULTS: A highly significant difference exists in BAL NSE in the two groups. For diagnostic purposes, the simultaneous measurements of serum NSE increases its sensitivity, but specificity remains unchanged. No correlation exists between BAL NSE and serum NSE, tumor size, nodal status, or the presence of metastases. BAL NSE is a better predictor of malignancy than serum NSE. CONCLUSION: BAL fluid measurements of NSE may have diagnostic value, specially if it is simultaneously measured in the serum. However, our study does not show any value for this technique in staging of lung carcinoma. Also it has no correlation with serum NSE. Studies will have to be performed to determine if BAL NSE can predict chemotherapeutic sensitivity.

Aged↗
PubMed1996

Why and when channelling can decrease pool size at constant net flux in a simple dynamic channel.

Cornish-Bowden and Cárdenas (Cornish-Bowden, A. and Cárdenas M.L. (1993) Eur. J. Biochem. 213, 87-92) have suggested that simulation results peviously published by us (Mendes, P., Kell, D.B. and Westerhoff, H.V. (1992) Eur. J. Biochem. 204, 255-266) which had demonstrated that large reductions of intermediate pool sizes could be accompanied by increasing channel flux in a model metabolic pathway, were an artefact of changes in the pathway's overall flux of the order of 0.0075%, or of inappropriate alterations of enzyme activities. They also asserted to prove that the "channelling of an intermediate cannot affect its free concentration at constant net flux". We consider the co-response of the intermediate metabolite concentration ('pool') and the channel flux to changes in kinetic (or thermodynamic) parameters. Both by analytical proofs and by numerical examples we show that this co-response can be positive, negative or null, depending on the parameter change. In particular, we prove that there is always a number of ways of changing parameters such that the intermediate metabolite concentration decreases with increasing channel flux, whether the total flux varies or is constant. We also show that increased stability of the (dynamic) enzyme-intermediate-enzyme complex, as well as a single parameter change that similarly displays no cross-over effects, can lead to decreased intermediate metabolite concentration and increased channel flux at constant total flux. In general, a non-zero co-response of the intermediate metabolite concentration ('pool') and the channel flux to changes in kinetic (or other) parameters is the rule rather than the exception. More specifically: (i) The algebraic analysis ('general proof') given in Cornish-Bowden and Cárdenas (1993) contains the constraint that the elasticities of various steps to the modulation parameters which were used to vary the channel flux at constant net flux were unity. This is an unfortunate and unnecessary constraint which, when lifted, means that the concentration of the pool in the general case can indeed change at constant net flux. A 'simplified proof' given in Cornish-Bowden and Cárdenas (1993) also fails, due in addition to the consequent failure to include mass conservation relations for some of the enzymes. (ii) In the systems studied by Cornish-Bowden and Cárdenas (1993), flux is properly to be considered as a variable (since it varies during the transition to the steady state), and not a parameter, and as such cannot per se affect the magnitude of other variables in the steady state. (iii) By relaxing the constraint referred to in (i), above, and by making dual modulations (i.e., of more than one parameter at once) which are different from those carried out in Cornish-Bowden and Cárdenas (1993) we find many instances in which channelling (described by a parameter p) does significantly affect the concentration of the pool intermediate C at constant total flux. (iv) In the same pathways, but in which the flux is held constant by setting it via a zero-order flux-generating reaction, the addition of a channel is also able to significantly to modulate the size of the pool at constant total flux. Our results show that the effectiveness of channelling in decreasing a pool, even at constant flux, is very much a reality.

Animals↗
PubMed1996

On the analysis of the inverse problem of metabolic pathways using artificial neural networks.

Here we develop the use of artificial neural networks for solving the inverse metabolic problem, in other words, given a set of steady-state metabolite levels and fluxes in a pathway of known structure to obtain the parameters of the system, in this case the enzymatic limiting rate and Michaelis constants. This requires two main procedures: first the development of a computer program with which one can model metabolism in the forward direction (i.e. given the internal and parameters to determine the steady-state fluxes and metabolite concentrations), and second, given arrays of associated parameters and variables thereby obtained, to exploit artificial neural networks to form a model capable of obtaining the parameters from the variables. We studied 2-step pathways exhibiting first-order kinetics, 2-step pathways exhibiting reversible Michaelis-Menten kinetics and then 3-step pathways (again exhibiting reversible Michaelis-Menten kinetics), modelled using the program Gepasi. Whilst it was fairly easy for the networks to learn most of the parameters in the 2-step pathway, it was found helpful for the Michaelis-Menten case to vary the concentration of the starting pathway substrate for each set of internal parameters, and to train separate networks for each parameter. Some parameters were much easier to learn than others, reverse K(m) and V(max) values normally being the most difficult. For the 3-step pathway learning sometimes required as much as 3 days, and occasionally convergence was not obtained. Overall, neural networks of the present type, with fully interconnected feedforward architectures and trained according to the backpropagation algorithm, scaled poorly as the problem size was increased.

Algorithms↗
PubMed1996

Gastrin levels in serum and bronchoalveolar lavage fluid of patients with lung cancer: comparison with patients with chronic obstructive pulmonary disease.

BACKGROUND: The gastrin gene is known to be expressed in all classes of bronchogenic carcinomas. Furthermore, high levels of gastrin have been reported in both the bronchoalveolar lavage (BAL) fluid and serum of patients with lung cancer. Based on these preliminary data a study was conducted to evaluate the usefulness of gastrin measurements in the diagnosis and staging of lung cancer. METHODS: Thirty-five patients with lung cancer (26 non-small cell (NSCLC) and nine small cell (SCLC)) and 25 patients with chronic obstructive pulmonary disease underwent fibreoptic bronchoscopy and BAL. Gastrin levels were determined in both BAL fluid and the serum and compared with each other and with staging. RESULTS: No difference was found between the gastrin levels in the BAL fluid or serum of the study groups. There was no correlation with the stage in NSCLC and no correlation was found between the gastrin levels in the serum and the BAL fluid. A significant difference was seen in gastrin levels in BAL fluid between extensive and limited SCLC (p < 0.05). CONCLUSION: There is no evidence of clinical usefulness for gastrin measurements in lung cancer.

Adult↗
PubMed1995

NONMEM analysis in determining the tri-exponential disposition of cefotaxime: a method of evaluating serum and urinary phase I data.

The time above the minimum inhibitory concentration (MIC) is an important surrogate parameter for the efficacy of cephalosporines. In clinical practice cefotaxime (CTX) is usually administered every 8 h or 12 h. Unfortunately the limit of quantification (LOQ) of the available assay is not low enough to detect CTX concentrations in serum later than 6 h after a 2 g i.v. dose. Consequently the time above MIC has to be estimated by extrapolation of the available serum data. Due to the concentrating properties of the kidney, concentrations in urine following a 2 g dose however remain above the LOQ for up to 16 h. It is therefore possible to follow the pharmacokinetics of CTX in urine within a 12 h dosing interval. Due to the linear pharmacokinetics of CTX, serum concentrations, and accordingly the time above MIC, can be estimated by using the measured urinary excretion and the calculated renal clearance. The pharmacokinetics of cefotaxime were studied in 12 healthy subjects who received a single 2 g i.v. dose administered as a short infusion. Blood and fractional urine were collected up to 24 h after dosing. For the characterization of the true terminal half-life only sparse and unbalanced serum and urinary data was available. In such situations, the population approach is the method of choice for estimating the kinetic parameters. The combined analysis of serum and urinary data using NONMEM shows the superiority of a tri-exponential compared to a bi-exponential pharmacokinetics model. As a result, the predicted serum trough levels of cefotaxime following twice daily dosing are about 30-fold higher than those extrapolated from the bi-exponential model. Consequently, the concentrations of CTX- and its metabolite desacetyl-CTX--are above the MIC of many therapeutically relevant pathogens for a longer period of time than previously assumed. In conclusion, a twice daily dosing regimen for cefotaxime is adequate for a number of clinically relevant pathogens. This is supported by the positive outcome in previous clinical trials following this dosing regimen.

Body Weight↗