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PubMed1965

The electrical conductance of semipermeable membranes. I. A formal analysis.

A kinetic analysis of membrane conductance under conditions of stationary flow is presented. The semipermeable membrane is idealized as a homogeneous laminar phase separating ionic solutions on either side. It is assumed, without consideration of the mechanisms involved, that some ion species permeate the membrane while others do not. The flux of a given species is taken to be linearly related to the gradient of its concentration and to the electric field. The resulting flow equations, when combined with Poisson's equation, permit the formulation of the conductance problem in terms of a set of non-linear differential equations. They describe the spatial variation of the electric displacement and contain the ion current densities as parameters. Their integration, subject to appropriate boundary conditions, fixes the values of these parameters and of the corresponding transmembrane potential. The solution of the conductance problem cannot, however, be carried through in analytic form. The numerical analysis of a number of special cases will be presented in subsequent publications.

Cell Membrane↗
PubMed1985

Strong electrolyte continuum theory solution for equilibrium profiles, diffusion limitation, and conductance in charged ion channels.

The solution for the ion flux through a membrane channel that incorporates the electrolyte nature of the aqueous solution is a difficult theoretical problem that, until now, has not been properly formulated. The difficulty arises from the complicated electrostatic problem presented by a high dielectric aqueous channel piercing a low dielectric lipid membrane. The problem is greatly simplified by assuming that the ratio of the dielectric constant of the water to that of the lipid is infinite. It is shown that this is a good approximation for most channels of biological interest. This assumption allows one to derive simple analytical expressions for the Born image potential and the potential from a fixed charge in the channel, and it leads to a differential equation for the potential from the background electrolyte. This leads to a rigorous solution for the ion flux or the equilibrium potential based on a combination of the Nernst-Planck equation and strong electrolyte theory (i.e., Gouy-Chapman or Debye-Huckel). This approach is illustrated by solving the system of equations for the specific case of a large channel containing fixed negative charges. The following characteristics of this channels are discussed: anion and mono- and divalent cation conductance, saturation of current with increasing concentration, current-voltage relationship, influence of location and valence of fixed charge, and interaction between ions. The qualitative behavior of this channel is similar to that of the acetylcholine receptor channel.

Animals↗
PubMed2002

Receptor modeling application framework for particle source apportionment.

Receptor models infer contributions from particulate matter (PM) source types using multivariate measurements of particle chemical and physical properties. Receptor models complement source models that estimate concentrations from emissions inventories and transport meteorology. Enrichment factor, chemical mass balance, multiple linear regression, eigenvector. edge detection, neural network, aerosol evolution, and aerosol equilibrium models have all been used to solve particulate air quality problems, and more than 500 citations of their theory and application document these uses. While elements, ions, and carbons were often used to apportion TSP, PM10, and PM2.5 among many source types, many of these components have been reduced in source emissions such that more complex measurements of carbon fractions, specific organic compounds, single particle characteristics, and isotopic abundances now need to be measured in source and receptor samples. Compliance monitoring networks are not usually designed to obtain data for the observables, locations, and time periods that allow receptor models to be applied. Measurements from existing networks can be used to form conceptual models that allow the needed monitoring network to be optimized. The framework for using receptor models to solve air quality problems consists of: (1) formulating a conceptual model; (2) identifying potential sources; (3) characterizing source emissions; (4) obtaining and analyzing ambient PM samples for major components and source markers; (5) confirming source types with multivariate receptor models; (6) quantifying source contributions with the chemical mass balance; (7) estimating profile changes and the limiting precursor gases for secondary aerosols; and (8) reconciling receptor modeling results with source models, emissions inventories, and receptor data analyses.

Air Pollutants↗
PubMedDate not supplied

[Research and the recent evolution of primary health care].

Primary care in Spain has undergone a burgeoning phase in the 80's, followed by a decade of stagnation in the 90's, with little creativity, a routinisation of tasks, and the set up of service port-folios and program-contracts. On the other hand, the recent changes in the orientation of the research promoted by the health administration, in favor of basic research, at the expense of health services research and clinical epidemiology, are in contrast with the importance of primary care as a natural setting for the management of many causal agents and risk factors for health. Despite such limitations, the culture of research has become present in many primary care centres and pharmacies, and primary care research is increasingly present in scientific journals. Nevertheless, it is necessary, also for the case of primary care, to manage research, in differentiated and specific ways, favoring priorization, evaluation and responsibility through flexible organisational formulas and information systems. This should include contracting procedures allowing for at least part-time research, as well as professional career models acknowledging research and teaching activities. Scientific and professional associations in primary care face the challenge of maintaning research projects, of increasing their presence among professionals, of formulating opinions regarding the problems of their sector, as well as of reinforcing their organizational and communication capabilities.

Biomedical Research↗
PubMed2002

Synthesis, beta-adrenoceptor pharmacology and toxicology of S-(-)-1-(4-(2-ethoxyethoxy)phenoxy)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethylamino)propane hydrochloride, a short acting beta(1)-specific antagonist.

The synthesis of S-(-)-1-(4-(2-ethoxyethoxy)phenoxy)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethylamino)propane hydrochloride (D140S.HCl 6), a novel short acting beta(1)-specific adrenoceptor antagonist, has been described. The antagonist potency for D140S.HCl 6 has been compared with esmolol, another short acting agent, and other well known beta-adrenoceptor antagonists in isolated rat tissue preparations. The pharmacokinetics of D140S.HCl 6 in 7 day continuous intravenous infusions and 4 weeks intravenous bolus injection studies in conscious rats and dogs have been examined in toxicology studies. The effect on the isoprenaline-induced heart rate increase and the pharmacodynamic half-life of D140S.HCl 6 has been compared with esmolol in a conscious rat model. In addition, the results of a range of toxicological studies are presented. The results indicate that D140S.HCl 6 is a highly specific beta(1)-adrenoceptor antagonist (pA(2) = 8.15+/-0.22, beta(1)/beta(2) selectivity > 4400). The in vitro studies suggest D140S.HCl is ca. ten times more potent and 60 times more beta(1)-specific than racemic esmolol. Pharmacokinetic non-linearity was seen when given as a 7 day intravenous infusion at toxicological doses above 10 mg kg(-1) h(-1) in the rat and 2.5 mg kg(-1) h(-1) in the dog. Both D140S.HCl 6 and esmolol have very short durations of action after intravenous infusion in the rat (pharmacodynamic half-life is < 15 min for D140S.HCl and 10 min for esmolol). The toxicological tests indicate that D140S.HCl 6 shows no unexpected toxicity and none of the tissue irritancy problems reported for esmolol formulations.

Adrenergic beta-1 Receptor Agonists↗
PubMed2000

Purification and characterization of Streptococcus pneumoniae palmitoylated pneumococcal surface adhesin A expressed in Escherichia coli.

All Streptococcus pneumoniae isolates tested to date express a species-common lipoprotein designated as pneumococcal surface adhesin A (PsaA). This protein is cell-associated, hydrophobic, immunogenic, and genetically conserved. It is currently under investigation as a potential component in third-generation pneumococcal vaccine formulations. To overcome the problem of low-level expression of native hydrophobic PsaA in S. pneumoniae, and also of the recombinant PsaA (rPsaA) in Escherichia coli, we generated a stable E. coli construct expressing functional palmitoylated rPsaA ( approximately 10 mg/l of fermentation culture) using Borrelia burgdorferi outer surface protein A (OspA, a hydrophobic lipoprotein) signal peptide. By Western blot analysis, the chimeric rPsaA ( approximately 34 kDa) was detected in the cell lysate using anti-PsaA antibodies. It was partially purified by extracting the cell pellet with PBS/Triton X(R)-114 buffers, followed by anion exchange filter chromatography. A trypsin digestion profile of rPsaA closely resembled that of the native protein, as revealed by SDS-PAGE/silver staining. Lipidation of rPsaA was confirmed by labeling recombinant E. coli cells with [(3)H] palmitic acid and analyzing the labeled E. coli cells by Western blotting coupled with autoradiography. Further, analysis of purified rPsaA by mass spectrometry (MALDI-TOF) revealed a heterogenous spectrum with a major peak (M+H)(+1) of mass 33,384 Da (theoretical mass of palmitoylated rPsaA=33,361 Da). Purified rPsaA was immunogenic in CBA/NCAHN-XID female mice following intranasal immunization with or without adjuvant, as determined by measurement of anti-PsaA serum IgG levels. These anti-PsaA antibodies reacted with both native and rPsaA polypeptides. Our data strongly suggest that E. coli-expressed rPsaA is palmitoylated and closely resembles the native protein in structure and immunogenicity. It was also observed to elicit measurable protection against nasopharyngeal carriage with S. pneumoniae.

Adhesins, Bacterial↗
PubMed1997

[Evidence-based medicine].

This paper presents the origins and the concepts in which the paradigm of a new line of clinical reasoning "Evidence Based Medicine", is based. We describe its basic components such as: problem-oriented clinical policy formulation; information retrieval distillation and synthesis of the medical literature; critical appraisal of the evidence and clinical application. Additionally, we describe them already well established, for promoting and Evidence Based Clinical Practice. We particularly focus on the so called "Cochrane Collaboration", an international initiative whose mission is to prepare, maintain and disseminate systematic and updated reviews of the effects of health care.

Controlled Clinical Trials as Topic↗
PubMed2003

Flexible ligand docking using evolutionary algorithms: investigating the effects of variation operators and local search hybrids.

The docking of ligands to proteins can be formulated as a computational problem where the task is to find the most favorable energetic conformation among the large space of possible protein-ligand complexes. Stochastic search methods such as evolutionary algorithms (EAs) can be used to sample large search spaces effectively and is one of the commonly used methods for flexible ligand docking. During the last decade, several EAs using different variation operators have been introduced, such as the ones provided with the AutoDock program. In this paper we evaluate the performance of different EA settings such as choice of variation operators, population size, and usage of local search. The comparison is performed on a suite of six docking problems previously used to evaluate the performance of search algorithms provided with the AutoDock program package. The results from our investigation confirm that the choice of variation operators has an impact on the search-capabilities of EAs. The introduced DockEA using the best settings found obtained the overall best docking solutions compared to the Lamarckian GA (LGA) provided with AutoDock. Furthermore, the DockEA proved to be more robust than the LGA (in terms of reproducing the results in several runs) on the more difficult problems with a high number of flexible torsion angles.

Algorithms↗
PubMedDate not supplied

Sexual adjustment of male alcoholics: changes from before to after receiving alcoholism counseling with and without marital therapy.

Married male alcoholics (N = 36), who had recently begun individual outpatient alcoholism counseling, were randomly assigned to a no-marital-treatment control group or to 10 weekly sessions of either a behavioral marital therapy (BMT) or an interactional couples therapy group. Impotence decreased from before to after counseling irrespective of whether the alcoholic patients received additional marital therapy. Husbands who received BMT reported increased frequency of wives' orgasm during intercourse and greater increases in satisfaction with the privacy and context of their sexual activities than did couples in the other two treatment groups. These findings support a biopsychosocial formulation of alcoholics' sexual problems that implicates the physical effects of acute and chronic alcohol intake as most relevant to the elevated rates of impotence and marital conflict as a major contributing factor to most sexual problems of alcoholics. The improvement observed in sexual adjustment was rather limited. Despite the improvements in impotence, the alcoholics still experienced over twice the rate of impotence reported by demographically similar nonalcoholics. In terms of sexual satisfaction, BMT produced only modest gains as viewed by husbands and no gains from the wives' perspective. Perhaps sexual adjustment is one of the last areas of the alcoholic's marriage to improve after treatment. The limited time frame of the present study may have precluded observing further improvements in sexual adjustment that would emerge later after a longer period of recovery.

Adult↗
PubMed1999

Improved RPLC determination of acyclovir using hexylamine as silanol masking agent.

The aim of the present work is to improve the sensitivity in the RPLC determination of acyclovir [9-(2-hydroxy ethoxymethyl) guanine] (ACV) and guanine, the major impurity of the drug synthesis and one of the compounds found in the chemical degradation process of ACV. The method was applied to the quantification of drug in liposomal formulations. The most important problem for RPLC analysis of both compounds are their high pKa values, mainly guanine, and the interaction with reactive silanol groups in the stationary phase. In order to avoid these problems there are four basic strategies: (i) ionic pair reagents, (ii) deactivated silica columns, (iii) polymeric based columns and (iv) silanol masking agents. A validation protocol was followed to develop the analytical method, using a Spherisorb ODS (250 x 4.6 mm i.d.) analytical column, with a mobile phase of 95% aqueous phosphate buffer (pH 3.0) and 5% HPLC methanol pumped isocratically at 1.3 ml/min(-1), with ultraviolet detection at 254 nm. The results showed a high reproducibility in retention time value, with R.S.D. of 2.37% for ACV and 0.32% for guanine. The lowest concentration levels assayed, 0.15 microg/ml(-1) for guanine and 1 microg/ml(-1) for ACV, showed good R.S.D. in the quantification parameter (peak area) 11.0% (guanine) and 9.64% (ACV)

Acyclovir↗
PubMed1999

Enteric polymers as binders and coating materials in multiple-unit site-specific drug delivery systems.

The aim of this study was to develop a multiple-unit, site-specific drug formulation allowing targeting of drug release in the colon. Initially, characteristics of matrix pellets containing various enteric polymers as binders were tested. An enteric coating was then added to the formulations. Ibuprofen and furosemide were used as model drugs. The former is absorbed throughout the gastrointestinal tract, the latter only from upper parts. Methacrylate copolymers, hydroxypropyl methylcellulose acetate succinates and cellulose acetate phthalate were used as enteric polymers. The properties of the products were initially tested via dissolution studies at different pHs, then via bioavailability studies in healthy volunteers. The main conclusion was that drug release can be targeted on the distal part of the small intestine and the colon by preparing film-coated matrix pellets in which enteric polymers dissolving at pH approximately 7 have been used both as binders in the pellets and as coating material. This conclusion is based on the finding that absorption of ibuprofen from the formulations developed was adequate, with a lag-time of about 2 h and tmax values at 4-5 h, where as absorption of furosemide from the analogous products was negligible. It was also found that uncoated pellets as such could represent a slow-release formulation for furosemide, a problem drug as far as modified-release products are concerned.

Adult↗
PubMedDate not supplied

Bispectral de-noising of the compound action potential for estimation of the nerve conduction velocity distribution.

The distribution of the conduction velocities (DCV) of a peripheral nerve is a powerful diagnostic tool for the assessment of neuromuscular disorders. Its efficient calculation depends on the signal-to-noise ratio (SNR) of the acquired electroneurograms (ENGs), thus, time averaging is solely used. An alternative way of improving the SNR is based on averaging in the bispectrum domain and it is proposed in this work. The compound action potential (CAP) is a linear summation of the single fiber action potentials (SFAPs) propagating along the nerve fibers and can be expressed, in the discrete time, as the circular convolution of a delay sequence (DS) and the sampled SFAP. In the proposed method, averaging of low SNR CAP measurements is done in third order spectrum domain so no time alignment is required. Averaged bispectra are introduced in modified Hirose's method, to estimate the delay sequence for a conduction distance l1. The lost linear phase is recovered by using the delay phase cepstrum. Finally, the DCV can be calculated from the estimated DS, according to the formulation of the forward problem. Comparison between time and bispectrum averaging is performed using simulated data, proving the more efficient performance of the proposed method, especially in the case of noisy ENGs.

Action Potentials↗
PubMed2004

Statistical models for protein validation using tandem mass spectral data and protein amino acid sequence databases.

The purpose of this work is to develop and verify statistical models for protein identification using peptide identifications derived from the results of tandem mass spectral database searches. Recently we have presented a probabilistic model for peptide identification that uses hypergeometric distribution to approximate fragment ion matches of database peptide sequences to experimental tandem mass spectra. Here we apply statistical models to the database search results to validate protein identifications. For this we formulate the protein identification problem in terms of two independent models, two-hypothesis binomial and multinomial models, which use the hypergeometric probabilities and cross-correlation scores, respectively. Each database search result is assumed to be a probabilistic event. The Bernoulli event has two outcomes: a protein is either identified or not. The probability of identifying a protein at each Bernoulli event is determined from relative length of the protein in the database (the null hypothesis) or the hypergeometric probability scores of the protein's peptides (the alternative hypothesis). We then calculate the binomial probability that the protein will be observed a certain number of times (number of database matches to its peptides) given the size of the data set (number of spectra) and the probability of protein identification at each Bernoulli event. The ratio of the probabilities from these two hypotheses (maximum likelihood ratio) is used as a test statistic to discriminate between true and false identifications. The significance and confidence levels of protein identifications are calculated from the model distributions. The multinomial model combines the database search results and generates an observed frequency distribution of cross-correlation scores (grouped into bins) between experimental spectra and identified amino acid sequences. The frequency distribution is used to generate p-value probabilities of each score bin. The probabilities are then normalized with respect to score bins to generate normalized probabilities of all score bins. A protein identification probability is the multinomial probability of observing the given set of peptide scores. To reduce the effect of random matches, we employ a marginalized multinomial model for small values of cross-correlation scores. We demonstrate that the combination of the two independent methods provides a useful tool for protein identification from results of database search using tandem mass spectra. A receiver operating characteristic curve demonstrates the sensitivity and accuracy level of the approach. The shortcomings of the models are related to the cases when protein assignment is based on unusual peptide fragmentation patterns that dominate over the model encoded in the peptide identification process. We have implemented the approach in a program called PROT_PROBE.

Amino Acid Sequence↗
PubMedDate not supplied

Parametrization strategy for the MolFESD concept: quantitative surface representation of local hydrophobicity.

We derive a new model for the established concept of the molecular free energy surface density (MolFESD) yielding a more rigorous representation of local surface contributions to the overall hydrophobicity of a molecule. The model parametrization makes efficient use of both local and global information about solvation thermodynamics, as formulated earlier for the problem of predicting free energies of hydration. The free energy of transfer is separated into an interaction contribution and a term related to the cavity formation. Interaction and cavity components are obtained from the statistical three-dimensional (3D) free energy density and a linear combination of surface and volume terms, respectively. An appropriate molecular interaction field generated by the program Grid is used as an approximate representation of the interaction part of the 3D free energy density. We further compress the 3D density by means of a linear combination of localized surface functions allowing for the derivation of local hydrophobic contributions in the form of a free energy surface density. For a set of 400 compounds our model yields significant correlation (R(2) = 0.95, sigma = 0.57) between experimental and calculated log P values. The final model is applied to establish a correlation between partial free energies of transfer for a series of sucrose derivatives and their relative sweetness, as studied earlier in the group of the authors. We find considerable improvement regarding the rms error of the regression thus validating the presented approach.

Journal Article↗
PubMed2003

Determination of phthalate ester congeners and mixtures by LC/ESI-MS in sediments and biota of an urbanized marine inlet.

Phthalate esters (PEs) are a group of widely used commercial chemicals consisting of many different congeners. Concentrations of di(2-ethylhexyl) phthalate ester in the parts per million range have been observed in sediments from locations in North America and Europe. However, sediment and biota concentrations of other widely used PEs (i.e., dibutyl phthalate, diisononyl phthalate, and diisodecyl phthalate) are rare and often in doubt because of analytical difficulties. One of the problems is that commercial formulations predominantly consist of PEs with a specific molecular weight but include many isomers within each molecular weight class. Currently there are no analytical methods or required standards to fully separate PEs into the different molecular weight classes corresponding to the formulations from which they originate. Hence, ambient total and mixture-specific PE concentrations do not exist. This study presents a new method based on reversed-phase liquid chromatography/ electrospray ionization mass spectrometry (LC/ESI-MS) for the quantitative determination of individual PEs, including six congeners on the U.S. EPA Priority pollutant list and several commercial PE isomeric mixtures, in complex environmental matrixes. The method is applied to determine the composition of PE concentrations in sediments and fish in an urbanized marine ecosystem. PE fingerprints in sediments show a predominance of high molecular weight PEs and match per capita consumption levels of PEs. Fingerprints in fish tissue show a predominance of low molecular weight PEs and do not match per capita consumption levels. The findings indicate that the higher molecular weight PEs are less biologically available than the lower molecular weight ones.

Animals↗
PubMed2006

Evidence for Efimov quantum states in an ultracold gas of caesium atoms.

Systems of three interacting particles are notorious for their complex physical behaviour. A landmark theoretical result in few-body quantum physics is Efimov's prediction of a universal set of bound trimer states appearing for three identical bosons with a resonant two-body interaction. Counterintuitively, these states even exist in the absence of a corresponding two-body bound state. Since the formulation of Efimov's problem in the context of nuclear physics 35 years ago, it has attracted great interest in many areas of physics. However, the observation of Efimov quantum states has remained an elusive goal. Here we report the observation of an Efimov resonance in an ultracold gas of caesium atoms. The resonance occurs in the range of large negative two-body scattering lengths, arising from the coupling of three free atoms to an Efimov trimer. Experimentally, we observe its signature as a giant three-body recombination loss when the strength of the two-body interaction is varied. We also detect a minimum in the recombination loss for positive scattering lengths, indicating destructive interference of decay pathways. Our results confirm central theoretical predictions of Efimov physics and represent a starting point with which to explore the universal properties of resonantly interacting few-body systems. While Feshbach resonances have provided the key to control quantum-mechanical interactions on the two-body level, Efimov resonances connect ultracold matter to the world of few-body quantum phenomena.

Journal Article↗
PubMed2001

Genesis of the T wave as based on an equivalent surface source model.

This article shows the use of the equivalent surface source model in its application to the genesis of the surface ECG in which the sources are of the double layer type. This model has previously been shown to yield an accurate description of body surface potentials during the QRS interval. Its application to the genesis of the T wave is now worked out in greater detail. In this source model, the full spatio-temporal character of the cardiac electric generator is expressed by means of an equivalent double layer situated at the boundary of ventricular tissue. The timing of local depolarization and of repolarization of the cells near this boundary is used to simulate the surface ECG. The background of this source model is discussed, as well as its validity. A matrix formulation is presented of the forward problem of computing the resulting body surface potentials. Based on this forward formulation, an inverse computation of the timing of the repolarization process was performed. Simulated T waves, based on this timing, showed a close correspondence with measured body surface potentials. By taking the inversely computed timing of repolarization as representing the true situation, the model can be used to study in which way perturbations in the timing of local repolarization effect the shape of T waves. An analysis based on this model indicates that the amplitude of the T wave is proportional to the dispersion of the repolarization times at the ventricular surface. The model is also shown to be capable of simulating the ECG changes during local ischemia.

Body Surface Potential Mapping↗
PubMed2006

[Not significant--what now?].

In a statistical significance test a scientific problem is expressed by formulating a null hypothesis and an opposite alternative. Construction of an empirical decision rule usually focuses on control of the alpha-error, i.e. the probability of erroneously refusing the null hypothesis. Contrary to the alpha-error, the beta-error is not controlled and in general is of unknown size. Thus in case of a non-significant result the validity of the null hypothesis still may be highly questionable. Such an unwanted outcome of an applied test the researcher should try to avoid by choosing an appropriate study design. In case it occurs nevertheless, it is advised to further evaluate the (non-significant) result. This can be done by calculating confidence intervals of the tested effects. Furthermore the p-value can be interpreted as a metric measure of evidence against the null hypothesis. By means of a posterior power analysis the probability of a significant test result is estimated under the given circumstances. Thus possibly the applied test--under the assumption of actual validity of the alternative--turns out to have had hardly a chance of rejecting the null hypothesis. In this case the non-significant result (pointing towards the null hypothesis) is relativized substantially. On the other hand a large power points to a small probability of a beta-error.

Probability↗