Asunto(s)
Mycobacterium/aislamiento & purificación , Esputo/microbiología , Tuberculosis/diagnóstico , Animales , Antituberculosos/farmacología , Técnicas Bacteriológicas , Técnicas de Laboratorio Clínico , Femenino , Humanos , Masculino , Microscopía/métodos , Manejo de Especímenes/métodos , Tuberculosis/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Tuberculosis Resistente a Múltiples Medicamentos/microbiologíaRESUMEN
The concept of elementary vector is generalised to the case where the steady-state space of the metabolic network is not a flux cone but is a general polyhedron due to further inhomogeneous constraints on the flows through some of the reactions. On one hand, this allows to selectively enumerate elementary modes which satisfy certain optimality criteria and this can yield a large computational gain compared with full enumeration. On the other hand, in contrast to the single optimum found by executing a linear program, this enables a comprehensive description of the set of alternate optima often encountered in flux balance analysis. The concepts are illustrated on a metabolic network model of human cardiac mitochondria.
Asunto(s)
Algoritmos , Modelos Biológicos , Proteoma/metabolismo , Transducción de Señal/fisiología , Animales , Simulación por Computador , Metabolismo Energético/fisiología , Humanos , Análisis Numérico Asistido por ComputadorRESUMEN
Current international tuberculosis (TB) guidelines recommend the microscopic examination of three sputum specimens for acid-fast bacilli in the evaluation of persons suspected of having pulmonary TB. We conducted a systematic review of studies that quantified the diagnostic yield of each of three sputum specimens. By searching multiple databases and sources, we identified a total of 37 eligible studies. The incremental yield in smear-positive results (in studies using all smear-positive cases as the denominator) and the increase in sensitivity (in studies that used all culture-positive cases as the denominator) of the third specimen were the main outcomes of interest. Although heterogeneity in study methods and results presented challenges for data synthesis, subgroup analyses suggest that the average incremental yield and/or the increase in sensitivity of examining a third specimen ranged between 2% and 5%. Reducing the recommended number of specimens examined from three to two (particularly to two specimens collected on the same day) could benefit TB control programs, and potentially increase case detection for several reasons. A number of operational research issues need to be addressed. Studies examining the most effective and efficient means to utilize current technologies for microscopic examination of sputum would be most useful if they followed an internationally coordinated and standardized approach, both to strengthen the country-specific evidence base and to permit comparison among studies.
Asunto(s)
Esputo/microbiología , Tuberculosis Pulmonar/diagnóstico , Humanos , Sensibilidad y Especificidad , Manejo de EspecímenesRESUMEN
MOTIVATION: An important tool in Systems Biology is the stoichiometric modeling of metabolic networks, where the stationary states of the network are described by a high-dimensional polyhedral cone, the so-called flux cone. Exhaustive descriptions of the metabolism can be obtained by computing the elementary vectors of this cone but, owing to a combinatorial explosion of the number of elementary vectors, this approach becomes computationally intractable for genome scale networks. RESULT: Hence, we propose to instead focus on the conversion cone, a projection of the flux cone, which describes the interaction of the metabolism with its external chemical environment. We present a direct method for calculating the elementary vectors of this cone and, by studying the metabolism of Saccharomyces cerevisiae, we demonstrate that such an analysis is computationally feasible even for genome scale networks.
Asunto(s)
Biología Computacional/métodos , Regulación Fúngica de la Expresión Génica , Metabolismo , Mapeo de Interacción de Proteínas/métodos , Biología de Sistemas/métodos , Algoritmos , Simulación por Computador , Proteínas Fúngicas/química , Genes Fúngicos , Vectores Genéticos , Saccharomyces cerevisiae/fisiología , Programas InformáticosRESUMEN
MOTIVATION: Genome scale analysis of the metabolic network of a microorganism is a major challenge in bioinformatics. The combinatorial explosion, which occurs during the construction of elementary fluxes (non-redundant pathways) requires sophisticated and efficient algorithms to tackle the problem. RESULTS: Mathematically, the calculation of elementary fluxes amounts to characterizing the space of solutions to a mixed system of linear equalities, given by the stoichiometry matrix, and linear inequalities, arising from the irreversibility of some or all of the reactions in the network. Previous approaches to this problem have iteratively solved for the equalities while satisfying the inequalities throughout the process. In an extension of previous work, here we consider the complementary approach and derive an algorithm which satisfies the inequalities one by one while staying in the space of solution of the equality constraints. Benchmarks on different subnetworks of the central carbon metabolism of Escherichia coli show that this new approach yields a significant reduction in the execution time of the calculation. This reduction arises since the odds that an intermediate elementary flux already fulfills an additional inequality are larger than when having to satisfy an additional equality constraint.
Asunto(s)
Algoritmos , Proteínas de Escherichia coli/metabolismo , Escherichia coli/fisiología , Perfilación de la Expresión Génica/métodos , Regulación Bacteriana de la Expresión Génica/fisiología , Modelos Biológicos , Mapeo de Interacción de Proteínas/métodos , Transducción de Señal/fisiología , Técnicas Químicas Combinatorias , Simulación por Computador , Bases de Datos Factuales , Metabolismo Energético/fisiología , Factores de Transcripción/metabolismoAsunto(s)
Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/aislamiento & purificación , Esputo/microbiología , Tuberculosis Pulmonar/tratamiento farmacológico , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Mycobacterium tuberculosis/efectos de los fármacos , Medición de Riesgo , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Factores de Tiempo , Tuberculosis Pulmonar/diagnósticoRESUMEN
An unsupervised learning procedure based on maximizing the mutual information between the outputs of two networks receiving different but statistically dependent inputs is analyzed [S. Becker and G. Hinton, Nature (London) 355, 161 (1992)]. For a generic data model, I show that in the large sample limit the structure in the data is recognized by mutual information maximization. For a more restricted model, where the networks are similar to perceptrons, I calculate the learning curves for zero-temperature Gibbs learning. These show that convergence can be rather slow, and a way of regularizing the procedure is considered.
RESUMEN
Using methods of statistical physics, we investigate the role of model complexity in learning with support vector machines (SVMs), which are an important alternative to neural networks. We show the advantages of using SVMs with kernels of infinite complexity on noisy target rules, which, in contrast to common theoretical beliefs, are found to achieve optimal generalization error although the training error does not converge to the generalization error. Moreover, we find a universal asymptotics of the learning curves which depend only on the target rule but not on the SVM kernel.
RESUMEN
A learning algorithm for multilayer perceptrons is presented which is based on finding the principal components of a correlation matrix computed from the example inputs and their target outputs. For large networks our procedure needs far fewer examples to achieve good generalization than traditional on-line algorithms.
Asunto(s)
Aprendizaje , Redes Neurales de la Computación , AlgoritmosRESUMEN
Supervised online learning with an ensemble of students randomized by the choice of initial conditions is analyzed. For the case of the perceptron learning rule, asymptotically the same improvement in the generalization error of the ensemble compared to the performance of a single student is found as in Gibbs learning. For more optimized learning rules, however, using an ensemble yields no improvement. This is explained by showing that for any learning rule f a transform f exists, such that a single student using f has the same generalization behavior as an ensemble of f students.
Asunto(s)
Aprendizaje , Redes Neurales de la Computación , Sistemas en Línea , Humanos , Distribución Aleatoria , EstudiantesRESUMEN
Following the historical introduction (the review by Schlossberger, 1928) the evolution of individual chemotherapy phases is briefly discussed. Then after following points are discussed. 1) The usual controlled clinical trials for evaluation of new drugs must be replaced (perhaps by estimates of the "early bactericidal activity" and of the 2 months' sputum conversion rates). 2) Interesting and of importance are research activities connected with the reasons for properties of TB bacilli in the persistence state, and of drugs capable to combat such bacilli (metronidazole?). 3) Since the human immunity against TB normally operates well (from 100 infected approximately 10 will get a clinically manifest disease), it is necessary to investigate possible combinations of chemo- and immunotherapy, either of combinations of antituberculous and immunomodulating drugs (eg. TNF alpha-antagonists), or of chemotherapy combined with vaccination (eg. M. vaccae). 4) There are still unsolved problems in formulations of drugs (particularly R in fixed combinations) and of drug resorption (in HIV-pos. patients). 5) Other points of research interest could be the adsorption of TB bacilli on the surface of mammalian cells (1st step in pathogenesis), drugs other than antituberculotics (eg. amoxycillin + clavulanic acid), or even drugs used for completely other diseases (eg. antidepressive). 6) All these attempts should serve primarily the purpose of further reduction of the necessary therapy duration (M+ pulmonary TB) to 1 - 2 months in total.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Antituberculosos/uso terapéutico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Tuberculosis Pulmonar/tratamiento farmacológico , Antituberculosos/efectos adversos , Quimioterapia Combinada , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacosAsunto(s)
Biología Molecular/tendencias , Infección por Mycobacterium avium-intracellulare/diagnóstico , Tuberculosis Pulmonar/diagnóstico , Predicción , Humanos , Complejo Mycobacterium avium/genética , Infección por Mycobacterium avium-intracellulare/microbiología , Mycobacterium tuberculosis/genética , Micobacterias no Tuberculosas/genética , Tuberculosis Pulmonar/microbiologíaRESUMEN
Microscopy remains, for various reasons, even today the most important diagnostic tool for pulmonary TB. Because of the need to monitor drug resistance rates (pulmonary TB) and with other forms of TB or other mycobacterioses radiometric culture techniques, particularly if combined with conventional egg media cultures and with identification of grown bacilli using genetic probes are required on a broad scale; the speed of complete investigation is of utmost importance. Thus, even susceptibility testing should be performed with the radiometric technique. Serology, so far, is unfortunately still incapable of clear-cut answers. This applies also--for the time being--to polymerase chain reaction and other techniques in the field of molecular biology: the sensitivity, specificity and predictive values of such techniques are still not sufficiently high to warrant unequivocal results. This applies also to novel drug resistance tests e.g. luciferase techniques or genetic probes for resistance genes.
Asunto(s)
Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Tuberculosis Pulmonar/diagnóstico , Antituberculosos/uso terapéutico , Técnicas Bacteriológicas , Humanos , Pruebas de Sensibilidad Microbiana , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Reacción en Cadena de la Polimerasa , Pruebas Serológicas , Tuberculosis Pulmonar/tratamiento farmacológicoRESUMEN
A tuberculosis caused by resistant or even multidrug-resistant TB bacilli seems to be of increasing importance in some parts of the world. An exact investigation of rates of initial and acquired drug resistance of tubercle bacilli for the whole state of Germany is--considering the corresponding technical, logistic and economic necessities--rather demanding. The "Arbeitskreis Mykobakterien" performed therefore, as a first step, an estimation of global resistance rates of tubercle bacilli in Germany based on questionnaires sent to TB laboratories throughout the country: only the first strain isolated in a patient in 1991 and 1992 should have been considered. The results are presented in Table 1.
Asunto(s)
Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis Pulmonar/tratamiento farmacológico , Farmacorresistencia Microbiana , Quimioterapia Combinada , Alemania , Humanos , Tuberculosis Pulmonar/microbiologíaRESUMEN
Treatment of NMRI mice with isoniazid (INH; 25 mg/kg) intraperitoneally induced significant protection when it was injected before or after a lethal intravenous challenge with endotoxin. The INH preparation used was not contaminated with endotoxin. Tumor necrosis factor (TNF) was not elevated in sera from NMRI mice 2 h after the injection of INH. INH did not influence TNF synthesis or release determined in human monocytes in vitro. Therefore, it is concluded that the protective effect of INH against lethal endotoxin is not due to a suppressive effect of INH on TNF production.
Asunto(s)
Endotoxinas/toxicidad , Isoniazida/farmacología , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Células Cultivadas , Femenino , Humanos , Ratones , Monocitos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Microscopy is, for various reasons, even today the most important diagnostic measure for pulmonary Tb. With other forms of Tb and with other mycobacterioses there is a considerable increase in importance of the radiometric culture techniques, particularly if these are combined with serologic (ELISA and its variants) or molecular-genetic assays for the presence of mycobacteria. The latter, especially the so called genetic probes combined with the polymerase chain reaction, represent probably the assay of the future for mycobacteria; however, a stern warning must be sounded against the use of such techniques without previous experience in the field of the "classic" mycobacteriology. Serology is, inspite of recent enormous advances, still not capable of producing unequivocal results.