Quantitative analysis of electroencephalograms: is there chaos in the future?

The history of quantitative, computerized electroencephalogram (EEG) analysis is reviewed. It is shown that, until very recently, the basic approach to EEG analysis involved the assumption that the EEG is stochastic. Consequently, statistical pattern recognition techniques, segmentation procedures, syntactic methods, knowledge-based approaches, and even artificial neural network methods have been developed with different levels of success. A fundamentally different approach to computerized EEG analysis, however, is making its way into the laboratories. The basic idea, inspired by recent advances in the area of non-linear dynamics, and especially the theory of chaos, is to view an EEG as the output of a deterministic system of relatively simple complexity, but containing non-linearities. This suggests that studying the geometrical dynamics of EEGs, and the development of neurophysiologically realistic models of EEG generation may produce more successful automated EEG analysis techniques than the classical, stochastic methods. Evidence supporting the non-linear dynamics paradigm is reviewed, and possible research paths are indicated.     

Quasi-linkage: a confounding factor in linkage analysis of complex diseases?

Human linkage analysis is based on the assumption that unlinked genomic loci, particularly loci located on non-homologous chromosomes, segregate independently during meiosis. An exception to this rule is the phenomenon of quasi-linkage (QL) that describes the non-random segregation of non-homologous chromosomes, which can undermine the basic concept of linkage. Molecular mechanisms of QL are not clear; however, observations in mice and plants suggest a possible affinity between non-homologous chromosomal regions containing repetitive or like sequences. QL has not been investigated in humans. As QL may generate false linkages in genome scans of complex diseases, we sought to determine whether genomic loci detected in such genome scans exhibit QL. A number of individual markers showing linkage to schizophrenia, asthma, multiple sclerosis, inflammatory bowel disease and type-1 diabetes were tested for QL in a pairwise linkage analysis against all other markers exhibiting evidence for linkage in each specific study. The Marshfield genotype dataset of eight CEPH families was used for this purpose. The best QL lod scores generated from the analysis were within the range of the lukewarm lod scores reported in the majority of linkage studies for complex disorders. In addition, we performed a genome-wide QL analysis on the Marshfield family database which detected eight QL lod scores >6. The replication of the best Marshfield QL scores was performed using the deCODE families and although none of the eight pairs demonstrated independent evidence for QL, three pairs generated maximal lod scores of 0.11, 0.3, and 1.51. In conclusion, although complex disease relevant markers did not produce high QL lod scores, the general phenomenon of QL in humans cannot be excluded and potentially can be a confounding factor in genetic studies of complex traits.     

Paraoxonase 1 and atherosclerosis: is the gene or the protein more important?

The oxidation of low-density lipoprotein (LDL) is centrally involved in the initiation and progression of atherosclerosis. High-density lipoprotein (HDL) paraoxonase 1 (PON1) retards the oxidation of LDL and is a major antiatherosclerotic component of HDL. The PON1 gene contains a number of functional polymorphisms in both the coding and the promoter regions, which affect either the level or the substrate specificity of PON1. Genetic case-control and prospective studies conducted to date have produced confusing results. Meta-analysis of these studies indicates no simple relationship between the PON1 polymorphisms and the presence of coronary heart disease (CHD). However, at the present moment in time, it seems that PON1 status, i.e., activity and/or concentration, is more closely related to CHD, and indeed, PON1 has shown to be an independent risk factor for CHD in a prospective study, compared to the genetic polymorphisms. PON1 levels can also be modulated by environmental\lifestyle and possibly pharmaceutical factors. Larger, better designed, preferably prospective studies are needed to determine further the association of PON1 genetic polymorphisms and status with CHD.     

Interactions of quinone with the iron-sulfur protein of the bc(1) complex: is the mechanism spring-loaded?

Since available structures of native bc(1) complexes show a vacant Q(o)-site, occupancy by substrate and product must be investigated by kinetic and spectroscopic approaches. In this brief review, we discuss recent advances using these approaches that throw new light on the mechanism. The rate-limiting reaction is the first electron transfer after formation of the enzyme-substrate complex at the Q(o)-site. This is formed by binding of both ubiquinol (QH(2)) and the dissociated oxidized iron-sulfur protein (ISP(ox)). A binding constant of approximately 14 can be estimated from the displacement of E(m) or pK for quinone or ISP(ox), respectively. The binding likely involves a hydrogen bond, through which a proton-coupled electron transfer occurs. An enzyme-product complex is also formed at the Q(o)-site, in which ubiquinone (Q) hydrogen bonds with the reduced ISP (ISPH). The complex has been characterized in ESEEM experiments, which detect a histidine ligand, likely His-161 of ISP (in mitochondrial numbering), with a configuration similar to that in the complex of ISPH with stigmatellin. This special configuration is lost on binding of myxothiazol. Formation of the H-bond has been explored through the redox dependence of cytochrome c oxidation. We confirm previous reports of a decrease in E(m) of ISP on addition of myxothiazol, and show that this change can be detected kinetically. We suggest that the myxothiazol-induced change reflects loss of the interaction of ISPH with Q, and that the change in E(m) reflects a binding constant of approximately 4. We discuss previous data in the light of this new hypothesis, and suggest that the native structure might involve a less than optimal configuration that lowers the binding energy of complexes formed at the Q(o)-site so as to favor dissociation. We also discuss recent results from studies of the bypass reactions at the site, which lead to superoxide (SO) production under aerobic conditions, and provide additional information about intermediate states.     

What is the future of CCR5 antagonists in rheumatoid arthritis?

A clinical trial of lupus patients with nephritis was established to determine any possible role for Atacicept, a biologic drug that blocks two B-cell-activating factors (BLyS and APRIL). The trial was stopped after just six patients had been enrolled because three patients developed serious infections. Initial concerns that the biologic was the main cause of the increased susceptibility to these infections have had to be revised on close inspection of the data. The evidence clearly points to a previously unrecognised capacity for mycophenolate to cause notable drops in immunoglobulin levels as the prime suspect.     

African trypanosomes in the 21st century: what is their future in science and in health?

The African trypanosomes remain well recognised for their role as an interesting model eukaryote for basic science, but are loosing ground in their ability to contribute to understanding common cellular mechanisms. At the same time, the diseases they cause remain as prevalent as ever, but appear increasingly irrelevant in their wider medical, social, economic and political context. What can be done to keep trypanosome biology relevant and vigorous in the 21st century?     

Why is epigenetics important in understanding the pathogenesis of inflammatory musculoskeletal diseases?

In its widest sense, the term epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. These mechanisms comprise DNA and chromatin modifications and their associated systems, as well as the noncoding RNA machinery. The epigenetic apparatus is essential for controlling normal development and homeostasis, and also provides a means for the organism to integrate and react upon environmental cues. A multitude of functional studies as well as systematic genome-wide mapping of epigenetic marks and chromatin modifiers reveal the importance of epigenomic mechanisms in human pathologies, including inflammatory conditions and musculoskeletal disease such as rheumatoid arthritis. Collectively, these studies pave the way to identify possible novel therapeutic intervention points and to investigate the utility of drugs that interfere with epigenetic signalling not only in cancer, but possibly also in inflammatory and autoimmune diseases.     

Hepatic PPARγ and LXRα independently regulate lipid accumulation in the livers of genetically obese mice

The nuclear hormone receptors liver X receptor α (LXRα) and peroxisome proliferator-activated receptor γ (PPARγ) play key roles in the development of fatty liver. To determine the link between hepatic PPARγ and LXRα signaling and the development of fatty liver, a LXRα-specific ligand, T0901317, was administered to normal OB/OB and genetically obese (ob/ob) mice lacking hepatic PPARγ (Pparγ^ΔH). In ob/ob-Pparγ^ΔH and OB/OB-Pparγ^ΔH mice, as well as ob/ob-Pparγ^WT and OB/OB-Pparγ^WT mice, the liver weights and hepatic triglyceride levels were markedly increased in response to T0901317 treatment. These results suggest that hepatic PPARγ and LXRα signals independently contribute to the development of fatty liver.     

PVCs with multiple exits and single site of origin in the outflow tract: What is the mechanism?

A 40 year old man with frequent PVCs with two different morphologies was referred for catheter ablation. Although initial mapping in the RVOT revealed fragmented potentials 20ms earlier than PVC2 onset with a good pace map score, ablation at this site was unsuccessful. Subsequent mapping in the LCC/NCC junction revealed that local ventricular activation preceded QRS onset by 30 and 28 ms for PVC1 and PVC2, respectively. Altering the pacing output at this site produced QRS morphologies similar to PVC1(low output,6mA) and PVC2(high output,15mA) with better pace map scores compared to RVOT. During high-output pacing, there was an increase in stim-QRS latency with decremental conduction. Ablation at this site was successful and suppressed both PVCs.     

Impact of global warming on viral diseases: what is the evidence?

Global warming is believed to induce a gradual climate change. Hence, it was predicted that tropical insects might expand their habitats thereby transmitting pathogens to humans. Although this concept is a conclusive presumption, clear evidence is still lacking--at least for viral diseases. Epidemiological data indicate that seasonality of many diseases is further influenced by strong single weather events, interannual climate phenomena, and anthropogenic factors. So far, emergence of new diseases was unlinked to global warming. Re-emergence and dispersion of diseases was correlated with translocation of pathogen-infected vectors or hosts. Coupled ocean/atmosphere circulations and 'global change' that also includes shifting of demographic, social, and economical conditions are important drivers of viral disease variability whereas global warming at best contributes.     

Modulating co-stimulation: a rational strategy in the treatment of rheumatoid arthritis?

Rheumatoid arthritis (RA) is a common destructive inflammatory disease that affects 0.5-1% of the population in many countries. Even though several new treatments have been introduced for patients with RA, a considerable proportion of patients do not benefit from these, and the need for alternative treatment strategies is clear. This review explores the potential for a therapy targeting the adaptive immune system by modulating co-stimulation of T cells with a CTLA4-Ig fusion protein (abatacept).     

Modelling tissues in 3D: the next future of pharmaco-toxicology and food research?

The development and validation of reliable in vitro methods alternative to conventional in vivo studies in experimental animals is a well-recognised priority in the fields of pharmaco-toxicology and food research. Conventional studies based on two-dimensional (2-D) cell monolayers have demonstrated their significant limitations: the chemically and spatially defined three-dimensional (3-D) network of extracellular matrix components, cell-to-cell and cell-to-matrix interactions that governs differentiation, proliferation and function of cells in vivo is, in fact, lost under the simplified 2-D condition. Being able to reproduce specific tissue-like structures and to mimic functions and responses of real tissues in a way that is more physiologically relevant than what can be achieved through traditional 2-D cell monolayers, 3-D cell culture represents a potential bridge to cover the gap between animal models and human studies. This article addresses the significance and the potential of 3-D in vitro systems to improve the predictive value of cell-based assays for safety and risk assessment studies and for new drugs development and testing. The crucial role of tissue engineering and of the new microscale technologies for improving and optimising these models, as well as the necessity of developing new protocols and analytical methods for their full exploitation, will be also discussed.     

Phylogeography of the capercaillie in Eurasia: what is the conservation status in the Pyrenees and Cantabrian Mounts?

The Western capercaillie (Tetrao urogallus) is a keystone species of Palearctic boreal and altitude coniferous forests. With the increase of mountain leisure activities and habitat loss, populations are declining in most mountain ranges in Western Europe. Recent work has shown that the populations from the Pyrenees and Cantabrian Mountains survived a severe bottleneck during the 19th century, and are still considered as threatened due to habitat fragmentation and isolation with other populations. We present an extensive phylogeographic study based on mitochondrial DNA sequence (control region) extracted non-invasively from faeces collected throughout the species range (from western European mountains to central and eastern Europe, Fenno-Scandia, Russia and Siberia). We also compared our results with DNA sequences of closely related black-billed capercaillie (T. parvirostris). We found that populations from Pyrenees and Cantabrians are closely related but are different from all other capercaillie populations that form a homogenous clade. Therefore, we consider that these South-Western populations should be considered as forming an Evolutionary Significant Unit that needs an appropriate management at a local scale. We also discuss the possible locations of glacial refugia and subsequent colonisation routes in Eurasia, with a Western “aquitanus” lineage from Iberia and Balkans, and an Eastern “urogallus” lineage from Southern Asia. This work might have important implication for capercaillie conservation strategies to define important areas for conservation, and to prevent possible exchange or introductions of individuals originated from other lineages. Electronic Supplementary Material The online version of this article (doi: ) contains supplementary material, which is available to authorized users.