Article abstract Interferon beta (IFNβ) reduces the relapse rate, disease activity as measured by serial MRI scanning, and disease progression of MS. Therapy with IFNβ may be associated with a number of adverse reactions. Relatively frequent side effects include flu-like symptoms, transient laboratory abnormalities, menstrual disorders, and increased spasticity. Dermal injection site reactions occur after subcutaneous application of IFNβ-1b and IFNβ-1a. Possible side effects of IFNβ include various autoimmune reactions, capillary leak syndrome, anaphylactic shock, thrombotic-thrombocytopenic purpura, insomnia, headache, alopecia, and depression. We discuss the mechanisms and management of the different side effects of IFNβ.

Multiple sclerosis: Side effects of interferon beta therapy and their management

Magnetocardiography is a noninvasive contactless method to measure the magnetic field generated by the same ionic currents that create the electrocardiogram. The time course of magnetocardiographic and electrocardiographic signals are similar. However, compared with surface potential recordings, multichannel magnetocardiographic mapping (MMCG) is a faster and contactless method for 3D imaging and localization of cardiac electrophysiologic phenomena with higher spatial and temporal resolution. For more than a decade, MMCG has been mostly confined to magnetically shielded rooms and considered to be at most an interesting matter for research activity. Nevertheless, an increasing number of papers have documented that magnetocardiography can also be useful to improve diagnostic accuracy. Most recently, the development of standardized instrumentations for unshielded MMCG, and its ease of use and reliability even in emergency rooms has triggered a new interest from clinicians for magnetocardiography, leading to several new installations of unshielded systems worldwide. In this review, clinical applications of magnetocardiography are summarized, focusing on major milestones, recent results of multicenter clinical trials and indicators of future developments.

Clinical application of magnetocardiography

Expression profiling promises to provide insight into normal biological and pathological processes (Alizadeh et al. 2000; Shaffer et al. 2001; van't Veer et al. 2002). The hope is that knowledge obtained from gene expression patterns will predict disease outcome or indicate individualized courses of therapy. The two technologies that have emerged as the most promising gene expression tools are hybridization-based microarrays and quantitative real-time RT-PCR (QPCR)analysis (Duggan et al. 1999; Lockhart and Winzeler 2000; Giulietti et al. 2001; Green et al. 2001). Microarrays permit the simultaneous analysis of a large number of genes, but extensive replicate sampling can be labor-intensive. Additionally, samples with limiting RNA (such as mouse peripheral blood or laser-capture microdissection samples)can only be used following cDNA amplification (Wang et al. 2000), which adds another processing step that could introduce bias. This makes longitudinal microarray analysis of peripheral blood samples from an experimental cohort technically challenging.

QPCR platforms using gene-specific primers provide highly sensitive and reproducible expression quantification from small amounts of starting material (Gibson et al. 1996; Heid et al. 1996; Schmittgen et al. 2000), but have been limited in the number of genes analyzed practically. Therefore, we combined the multiple gene approach of microarrays with the sensitivity of QPCR to produce a high-throughput customized “ImmunoQuantArray” (IQA), the first generation of which consists of 96 gene-specific QPCRs designed to monitor genes associated with immune processes.

QPCR instruments monitor gene-specific amplicons with fluorescent dye chemistry. The amplification curves typically have a sigmoidal shape in which the exponential amplification phase reveals the number of PCR cycles required to achieve a certain fluorescence intensity. A cycle threshold or Ct value for each reaction is the number of cycles at which the reaction crosses the fluorescence threshold. The fewer cycles required to reach a certain fluorescence intensity, the lower the Ct value and the greater the initial amount of input target cDNA. Genes that do not amplify during the 40-cycle PCR are considered “off” and are given a Ct value of 40 (Heid et al. 1996).

QPCR data are usually interpreted as fold changes in gene expression. Changes in gene expression are derived by normalizing the expression of a gene to that of an appropriate “housekeeping” gene (assumed to be invariant; Livak and Schmittgen 2001). This relative normalization procedure is presently regarded to be the only practical option available for interpreting QPCR data. An alternative, accurate quantification of input RNA/cDNA is challenging when input RNA is of limiting quantities and impractical for scale-up (Morrison et al. 1998).

To more reliably evaluate expression changes in QPCR data, we developed a novel statistical algorithm—Global Pattern Recognition (GPR)—to reveal significant changes in gene expression patterns. Inspired by triangulation techniques to determine positional information in cartography and astronomy, GPR goes through several iterations to compare the change of expression of a gene normalized to every other gene in the IQA. By comparing the expression of each gene to every other gene in the array, a global pattern is established, and significant changes are identified and ranked. Importantly, GPR takes advantage of biological replicates to extract significant changes in gene expression, thus providing a novel alternative to the use of relative normalization in QPCR experiments.

We show here that the IQA/GPR approach is a reliable analytical tool that can be used to establish immunological gene expression profiles of normal mice and in mice developing rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and graft versus host disease (GVHD). Moreover, we show that one can obtain temporal expression profiles from unamplified blood cDNA samples from individual mice, thus making it possible to establish the relationship between gene expression pattern and individual disease severity.

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Customized Molecular Phenotyping by Quantitative Gene Expression and Pattern Recognition Analysis

https://www.internationaljournalofcardiology.com/article/S0167-5273(12)01685-3/pdf

Diagnostic value of magnetocardiography in coronary artery disease and cardiac arrhythmias: A review of clinical data

Biological signal and image processing (BSIP) constitutes a major field of interest in both educational aspects and research environments in biomedical engineering. In fact, the physiological knowledge improvement in a wide variety of innovative research as well as the implementation in many clinical procedures extensively makes use of these concepts in more or less sophisticated medical applications. In this article, the important links between BSIP and physiological modeling and their important derived synergies are particularly stressed. In support of this aim, examples have been provided in the areas of cardiovascular system studies, as well as in neurosciences and functional imaging, by using different modalities. Along this direction, the integration operation of the detected information between multiple signals, organs, modalities, and across multiple scales (from gene/protein levels up to cell and organ levels) seems to be extremely promising. Further, advanced methods in the area of information treatment, such as time-frequency and time-variant approaches, have been investigated in the biomedical field together with the complexity measurements, most often carried out through nonlinear dynamical approaches where, also in this context, the integration between modeling and information processing plays a fundamental role. Finally, a few examples have been described in which the study of EMFs, in the form of signals and images properly detected, have a relevant impact on various biomedical applications.

Biomedical Signal and Image Processing

Non-invasive imaging of arrhythmogenic left-ventricular myocardium after infarction

https://www.internationaljournalofcardiology.com/article/S0167-5273(97)00326-4/pdf

Noninvasive biomagnetic imaging in coronary artery disease based on individual current density maps of the heart

In magnetocardiography, averaging of QRS complexes is often used to improve the signal-to-noise ratio. However, averaging of QRS complexes ignores the variation in amplitude and shape of the signals caused, for example, by respiration. This may lead to suppression of signal portions within the QRS complexes. Furthermore, for inverse source, reconstructions of dipoles and of current density distributions errors in the spacial arrangement may occur. To overcome these problems we developed a method for separating and selective averaging QRS complexes with different shapes and amplitudes. The method is based on a spline interpolation of the QRS complex averaged by a standard procedure. This spline function then is fitted to each QRS complex in the raw data by means of nonlinear regression (Levenberg-Marquardt method). Five regression parameters are applied: a linear amplitude scaling, two parameters describing the baseline drift, a time scaling parameter, and a time shift parameter. We found that both amplitude and shape of the QRS complex are influenced by respiration. The baseline shows a weaker influence of the respiration. The regression parameters of two neighboring measurement channels correlate linearly. Thus, selective averaging of a larger number of sensors can be performed simultaneously.

QRS Amplitude and Shape Variability in Magnetocardiograms

The inverse solution of the single equivalent current dipole model obviously fails in the explanation of more complex source structures like a distributed myocardial activation wavefront For this reason we applied depth normalized minimum norm estimation with anatomical constraints in patients with myocardial infarction and known regions of large myocardial damage Current density was calculated for several hundred myocardial support points using lead field normalized minimum norm least square estimates and overlayed with 3D-MR-images as color coded surfaces In 55% of 40 patients/normals investigated, MCI had complete correspondence with the other cardiological findings, in 27% we found partly correspondence and 18% MCI failed to provide correct diagnosis Myocardial current imaging (MCI) is a new and promising method for assessing of myocardial viability

Application of anatomically constrained minimum norm solution in coronary artery disease (myocardial current imaging)

Late field detection for cardiac biomagnetic signals is difficult. One reason is the low signal to noise ratio. The Simson algorithm is a standard procedure to detect and quantify late fields in the terminal portion of the QRS complex using a bidirectional Butterworth filter (p=4, 40-250 Hz). The signal output includes frequencies ranging from 30 to 250 Hz. In our datasets it was difficult to detect late fields with frequency rage above 100 Hz. With the discrete wavelet transformation (DWT) using Daubechies wavelets we divided the signal in different frequency intervals with sufficient time localization. For these signal outputs we calculated the parameter RMS/sub 40/ QRS/sub DUR/ and LAS/sub DUR/ and compared it with the parameter extracted using Butterworth filtered signal. The parameters of the Simson-method and of the wavelet output with frequency 50/spl plusmn/30 Hz correlate linearly. This correlation vanished for wavelet outputs with higher frequency content.

M. Huck

Papers

Non-invasive imaging of arrhythmogenic left-ventricular myocardium after infarction

Noninvasive biomagnetic imaging in coronary artery disease based on individual current density maps of the heart

QRS Amplitude and Shape Variability in Magnetocardiograms

Application of anatomically constrained minimum norm solution in coronary artery disease (myocardial current imaging)

Comparison of Simson-method and Daubechies wavelet method in the detection of late fields