Single dipole localization: Some numerical aspects and a practical rejection criterion for the fitted parameters

Summary There have been a number of attempts in the last years to localize the generators of brain electromagnetic activity, considering one current dipole as the source model. Single Dipole Localization (SDL) requires the selection of an optimization algorithm (OA). General aspects related with the selection, implementation and evaluation of some of the OA employed for SDL are discussed in this paper. Specifically the performance of two algorithms, those of Hooke-Jeeves and Levenberg-Marquardt, are tested by simulations. Suggestions for including restrictions to the dipole position and comments about some commonly used measures of the goodness of fit are given. Examples of erroneous implementations of these algorithms are also illustrated. A simple graphic rejection criterion, which can be easily used by inexperienced researchers, is introduced and tested in noisy and noise free simulations.The authors are grateful to Roberto D. Pascual Marqui for programming the Hooke-Jeeves algorithm.     

Peroxisome proliferator-activated receptor-α and liver cancer: where do we stand?

The peroxisome proliferator-activated receptor- (PPAR), first identified in 1990 as a member of the nuclear receptor superfamily, has a central role in the regulation of numerous target genes encoding proteins that modulate fatty acid transport and catabolism. PPAR is the molecular target for the widely prescribed lipid-lowering fibrate drugs and the diverse class of chemicals collectively referred to as peroxisome proliferators. The lipid-lowering function of PPAR occurs across a number of mammalian species, thus demonstrating the essential role of this nuclear receptor in lipid homeostasis. In contrast, prolonged administration of PPAR agonists causes hepatocarcinogenesis, specifically in rats and mice, indicating that PPAR also mediates this effect. There is no strong evidence that the low-affinity fibrate ligands are associated with cancer in humans, but it still remains a possibility that chronic activation with high-affinity ligands could be carcinogenic in humans. It is now established that the species difference between rodents and humans in response to peroxisome proliferators is due in part to PPAR. The cascade of molecular events leading to liver cancer in rodents involves hepatocyte proliferation and oxidative stress, but the PPAR target genes that mediate this response are unknown. This review focuses on the current understanding of the role of PPAR in hepatocarcinogenesis and identifies future research directions that should be taken to delineate the mechanisms underlying PPAR agonist-induced hepatocarcinogenesis.     

Distinct reovirus-like agents associated with acute infantile gastroenteritis.

Human reovirus-like particles were found by electron microscopy in the stools of 25% of 71 infants and young children hospitalized with acute gastroenteritis in Mexico between December 1976 and April 1977. The virus was also identified by the electrophoresis patterns of its ribonucleic acid upon disruption of partially purified particles. This technique is as reliable as electron microscopy but less laborious, and could become a routine diagnostic procedure. The electrophoretic patterns of viral ribonucleic acid from different cases suggest that there are at least two different reovirus-like agents associated with infantile gastroenteritis.     

Emergence of resistance of Candida albicans to clotrimazole in human immunodeficiency virus-infected children: in vitro and clinical correlations

Oropharyngeal candidiasis (OPC) is a common opportunistic infection in human immunodeficiency virus (HIV)-infected patients and other immunocompromised hosts. Clotrimazole troches are widely used in the treatment of mucosal candidiasis. However, little is known about the potential contribution of clotrimazole resistance to the development of refractory mucosal candidiasis. We therefore investigated the potential emergence of resistance to clotrimazole in a prospectively monitored HIV-infected pediatric population receiving this azole. Adapting the National Committee for Clinical Laboratory Standards M27-A reference method for broth antifungal susceptibility testing of yeasts to clotrimazole, we compared MICs in macrodilution and microdilution assays. We further analyzed the correlation between these in vitro findings and the clinical response to antifungal therapy. One isolate from each of 87 HIV-infected children was studied by the macrodilution and microdilution methods. Two inoculum sizes were tested by the macrodilution method (10(3) and 10(4) CFU/ml) in order to assess the effect of inoculum size on clotrimazole MICs. The same isolates also were tested using a noncolorimetric microdilution method. Clotrimazole concentrations ranged from 0.03 to 16 microg/ml. Readings were performed after incubation for 24 and 48 h at 35 degrees C. For 62 (71.2%) of 87 clinical isolates, the MICs were low (< or =0.06 microg/ml). The MIC for 90% of the strains tested was 0.5 microg/ml, and the highest MIC was 8 microg/ml. There was no significant difference between MICs at the two inoculum sizes. There was 89% agreement (+/-1 tube) between the microdilution method at 24 h and the macrodilution method at 48 h. If the MIC of clotrimazole for an isolate of C. albicans was > or =0.5 microg/ml, there was a significant risk (P < 0.001) of cross-resistance to other azoles: fluconazole, > or = 8 microg/ml (relative risk [RR] = 8.9); itraconazole, > or =1 microg/ml (RR = 10). Resistance to clotrimazole was highly associated with clinically overt failure of antifungal azole therapy. Six (40%) of 15 patients for whom the clotrimazole MIC was > or =0.5 microg/ml required amphotericin B for refractory mucosal candidiasis versus 4 (5.5%) of 72 for whom the MIC was <0.5 microg/ml (P = 0.001; 95% confidence interval = 2.3 to 22; RR = 7.2). These findings suggest that an interpretive breakpoint of 0.5 microg/ml may be useful in defining clotrimazole resistance in C. albicans. The clinical laboratory's ability to determine MICs of clotrimazole may help to distinguish microbiologic resistance from the other causes of refractory OPC, possibly reducing the usage of systemic antifungal agents. We conclude that resistance to clotrimazole develops in isolates of C. albicans from HIV-infected children, that cross-resistance to other azoles may develop concomitantly, and that this resistance correlates with refractory mucosal candidiasis.     

Antigenic comparison of different foot-and-mouth disease virus types using monoclonal antibodies defining multiple neutralizing epitopes on FMDV A5 subtypes

Thirteen monoclonal antibodies (MAbs) were elicited with A5 Spain-86 virus, the cause of the most recent foot-and-mouth disease virus (FMDV) outbreak in Spain. The MAbs were tested for ability to bind 140S virions and 12S protein subunits by liquid-phase radioimmunoassay (RIA), and to bind VP1 capsid protein by Western immunoblot assay. One of the thirteen MAb was virion (140S) specific, seven recognized 140S and 12S subunits, one bound to 140S, 12S and VP1 and four were 12S specific. These MAbs presented varying binding patterns when tested against different FMDV subtypes and serotypes, indicating the presence of conserved and non-conserved epitopes among FMDV serotypes and subtypes. Neutralization assays, in vivo and in vitro, showed that none of the 140S specific MAbs or 12S specific MAbs were neutralizing, but notably several of the 12S specific MAbs bound to all the different FMDV serotypes and can be useful diagnostic reagent for the detection of FMDV. The remaining MAbs showed varying behavior with the different types tested: not all types to which the MAbs bound were neutralized, demonstrating that the presence of an epitope and subsequent neutralization of infectivity are not necessarily correlated. Five type A12 neutralizing MAbs, previously characterized, have been used in this work. Four bound to A5 Spain-86 virus, but only one neutralized viral infectivity. On the basis of differential reactivity and neutralization among various FMDV subtypes and serotypes, and cross-inhibition binding assays between these MAbs, seven neutralization related epitopes have been defined on A5 Spain-86 virus.     

Novel KChIP2 isoforms increase functional diversity of transient outward potassium currents

Kv4.3 channels conduct transient outward K⁺ currents in the human heart and brain where they mediate the early phase of action potential repolarization. KChIP2 proteins are members of a new class of calcium sensors that modulate the surface expression and biophysical properties of Kv4 K⁺ channels. Here we describe three novel isoforms of KChIP2 with an alternatively spliced C-terminus (KChIP2e, KChIP2f) or N-terminus (KChIP2g). KChIP2e and KChIP2f are expressed in the human atrium, whereas KChIP2g is predominantly expressed in the brain. The KChIP2 isoforms were coexpressed with Kv4.3 channels in Xenopus oocytes and currents recorded with two-microelectrode voltage-clamp techniques. KChIP2e caused a reduction in current amplitude, an acceleration of inactivation and a slowing of the recovery from inactivation of Kv4.3 currents. KChIP2f increased the current amplitude and slowed the rate of inactivation, but did not alter the recovery from inactivation or the voltage of half-maximal inactivation of Kv4.3 channels. KChIP2g increased current amplitudes, slowed the rate of inactivation and shifted the voltage of half-maximal inactivation to more negative potentials. The biophysical changes induced by these alternatively spliced KChIP2 proteins differ markedly from previously described KChIP2 proteins and would be expected to increase the diversity of native transient outward K⁺ currents.     

Color modulation of Doppler spectra with the use of a personal computer.

This paper describes a method for the use of a personal computer in developing color modulated spectral maps of blood flow echoes from a Doppler flowmeter. The acoustical signal from a Doppler flowmeter is digitized and transformed into the frequency domain with a fast Fourier technique with the use of an Apple IIe microcomputer in conjunction with a Motorola 68000 co-processor. The resultant transform is displayed as a pseudo three-dimensional, color modulated spectral map by way of a color monitor, or a television projector onto the meeting room screen. We have found this technique to be useful in appreciating differences in blood flow from different hydraulic conditions, as well as in helping the medical students appreciate these differences in pulsatile flow in various arteries.     

An improved method for isolating type II cells in high yield and purity

A method has been developed for isolating alveolar type II cells by digesting lung tissue with elastase and "panning" the resultant cell suspension on plates coated with IgG. This method provides both high yield and purity of type II cells. In 50 experiments with rats, we obtained 35 +/- 11 X 10(6) cells/rat, 89 +/- 4% of which were type II cells (mean +/- SD). Type II cells isolated by "panning" adhered more rapidly and completely in tissue culture than did cells isolated by centrifugation over discontinuous density gradients of metrizamide. The "panning" method is superior to other methods for isolating type II cells in that it provides a population of type II cells of both high yield and high purity. The method is fast, reproducible, and easily adaptable to isolating type II cells from species other than rats.     

An outbreak of Plasmodium vivax malaria among heroin users in Spain

We report the first outbreak of induced malaria among heroin users in Spain, and the first one caused by Plasmodium vivax in Europe. Five drug addicts from Madrid, who had never travelled to endemic areas, were admitted to hospital with fever and splenomegaly. Four had P. vivax malaria with low parasitaemia, ranging from 1 to 3% red blood cells. The fifth case was considered a "seropositive contact" because he had fever and positive malaria indirect fluorescent antibody test but negative blood smear. The source of infection was a young drug addict, who had often travelled to Equatorial Guinea. Another heroin user with a diagnosis of malaria refused to be admitted to our hospital for further study. All had shared contaminated injection equipment. Treatment with chloroquine was effective and none had recrudescence of malaria during a mean follow-up of six months. Drug addicts with unexplained fever may have been infected by malaria transmitted by sharing injections.