Diagnostic criteria for persistent postural-perceptual dizziness (PPPD): Consensus document of the committee for the Classification of Vestibular Disorders of the Barany Society

This paper presents diagnostic criteria for persistent postural-perceptual dizziness (PPPD) to be included in the International Classification of Vestibular Disorders (ICVD). The term PPPD is new, but the disorder is not. Its diagnostic criteria were derived by expert consensus from an exhaustive review of 30 years of research on phobic postural vertigo, space-motion discomfort, visual vertigo, and chronic subjective dizziness. PPPD manifests with one or more symptoms of dizziness, unsteadiness, or non-spinning vertigo that are present on most days for three months or more and are exacerbated by upright posture, active or passive movement, and exposure to moving or complex visual stimuli. PPPD may be precipitated by conditions that disrupt balance or cause vertigo, unsteadiness, or dizziness, including peripheral or central vestibular disorders, other medical illnesses, or psychological distress. PPPD may be present alone or co-exist with other conditions. Possible subtypes await future identification and validation. The pathophysiologic processes underlying PPPD are not fully known. Emerging research suggests that it may arise from functional changes in postural control mechanisms, multi-sensory information processing, or cortical integration of spatial orientation and threat assessment. Thus, PPPD is classified as a chronic functional vestibular disorder. It is not a structural or psychiatric condition

Subcellular distribution of terminal α-D- and β-D-galactosyl residues in Ehrlich tumour cells studied by lectin-gold techniques

We have studied by high resolution in situ light and electron microscopic lectin-gold techniques the subcellular distribution of α- d -Gal residues using the Griffonia simplicifolia I-B 4 isolectin and compared it with that of β- d -Gal residues as detected with the Datura stramonium lectin in Ehrlich tumour cells grown as ascites or monolayer. The microvillar but not the smooth plasma membrane regions were labelled with the Griffonia simplicifolia I-B 4 isolectin whereas both plasma membrane regions were equally well labelled with the Datura stramonium lectin. Elements of the endocytotic/lysosomal system such as coated membrane invaginations and vesicles, early and late endosomes and secondary lysosomes were positive for both α- d -Gal and β- d -Gal residues. A particular feature of Ehrlich tumour cells is an elaborate tubular membrane system located in the pericentriolar region which is labelled throughout by both lectins and represents part of the endosomal system. In the Golgi apparatus labelling with both lectins was observed to commence in trans cisternae which is indirect evidence for a joint distribution of the sequentially acting β1,4 and α1,3-galactosyl-transferases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45677/1/10719_2004_Article_BF00731358.pd

Potential climatic transitions with profound impact on Europe

We discuss potential transitions of six climatic subsystems with large-scale impact on Europe, sometimes denoted as tipping elements. These are the ice sheets on Greenland and West Antarctica, the Atlantic thermohaline circulation, Arctic sea ice, Alpine glaciers and northern hemisphere stratospheric ozone. Each system is represented by co-authors actively publishing in the corresponding field. For each subsystem we summarize the mechanism of a potential transition in a warmer climate along with its impact on Europe and assess the likelihood for such a transition based on published scientific literature. As a summary, the ‘tipping’ potential for each system is provided as a function of global mean temperature increase which required some subjective interpretation of scientific facts by the authors and should be considered as a snapshot of our current understanding. <br/

Dental methacrylates may exert genotoxic effects via the oxidative induction of DNA double strand breaks and the inhibition of their repair

Methacrylate monomers used in dentistry have been shown to induce DNA double strand breaks (DSBs), one of the most serious DNA damage. In the present work we show that a model dental adhesive consisting of 45% 2-hydroxyethyl methacrylate (HEMA) and 55% bisphenol A-diglycidyl dimethacrylate (Bis-GMA) at concentrations up to 0.25 mM Bis-GMA induced oxidative DNA in cultured primary human gingival fibroblasts (HGFs) as evaluated by the comet assay and probed with human 8-hydroxyguanine DNA-glycosylase 1. HEMA/Bis-GMA induced DSBs in HGFs as assessed by the neutral comet assay and phosphorylation of the H2AX histone and sodium ascorbate or melatonin (5-methoxy-N-acetyltryptamine) both at 50 μM reduced the DSBs, they also inhibited apoptosis induced by HEMA/Bis-GMA. The adhesive slowed the kinetics of the repair of DNA damage induced by hydrogen peroxide in HGFs, while sodium ascorbate or melatonin improved the efficacy of H2O2-induced damage in the presence of the methacrylates. The adhesive induced a rise in the G2/M cell population, accompanied by a reduction in the S cell population and an increase in G0/G1 cell population. Sodium ascorbate or melatonin elevated the S population and reduced the G2/M population. In conclusion, HEMA/Bis-GMA induce DSBs through, at least in part, oxidative mechanisms, and these compounds may interfere with DSBs repair. Vitamin C or melatonin may reduce the detrimental effects induced by methacrylates applied in dentistry

Aberrant DNA Methylation Is Associated with Disease Progression, Resistance to Imatinib and Shortened Survival in Chronic Myelogenous Leukemia

The epigenetic impact of DNA methylation in chronic myelogenous leukemia (CML) is not completely understood. To elucidate its role we analyzed 120 patients with CML for methylation of promoter-associated CpG islands of 10 genes. Five genes were identified by DNA methylation screening in the K562 cell line and 3 genes in patients with myeloproliferative neoplasms. The CDKN2B gene was selected for its frequent methylation in myeloid malignancies and ABL1 as the target of BCR-ABL translocation. Thirty patients were imatinib-naïve (mostly treated by interferon-alpha before the imatinib era), 30 were imatinib-responsive, 50 were imatinib-resistant, and 10 were imatinib-intolerant. We quantified DNA methylation by bisulfite pyrosequencing. The average number of methylated genes was 4.5 per patient in the chronic phase, increasing significantly to 6.2 in the accelerated and 6.4 in the blastic phase. Higher numbers of methylated genes were also observed in patients resistant or intolerant to imatinib. These patients also showed almost exclusive methylation of a putative transporter OSCP1. Abnormal methylation of a Src suppressor gene PDLIM4 was associated with shortened survival independently of CML stage and imatinib responsiveness. We conclude that aberrant DNA methylation is associated with CML progression and that DNA methylation could be a marker associated with imatinib resistance. Finally, DNA methylation of PDLIM4 may help identify a subset of CML patients that would benefit from treatment with Src/Abl inhibitors

Analysis of Clonal Type-Specific Antibody Reactions in Toxoplasma gondii Seropositive Humans from Germany by Peptide-Microarray

BACKGROUND: Different clonal types of Toxoplasma gondii are thought to be associated with distinct clinical manifestations of infections. Serotyping is a novel technique which may allow to determine the clonal type of T. gondii humans are infected with and to extend typing studies to larger populations which include infected but non-diseased individuals. METHODOLOGY: A peptide-microarray test for T. gondii serotyping was established with 54 previously published synthetic peptides, which mimic clonal type-specific epitopes. The test was applied to human sera (n = 174) collected from individuals with an acute T. gondii infection (n = 21), a latent T. gondii infection (n = 53) and from T. gondii-seropositive forest workers (n = 100). FINDINGS: The majority (n = 124; 71%) of all T. gondii seropositive human sera showed reactions against synthetic peptides with sequences specific for clonal type II (type II peptides). Type I and type III peptides were recognized by 42% (n = 73) or 16% (n = 28) of the human sera, respectively, while type II-III, type I-III or type I-II peptides were recognized by 49% (n = 85), 36% (n = 62) or 14% (n = 25) of the sera, respectively. Highest reaction intensities were observed with synthetic peptides mimicking type II-specific epitopes. A proportion of the sera (n = 22; 13%) showed no reaction with type-specific peptides. Individuals with acute toxoplasmosis reacted with a statistically significantly higher number of peptides as compared to individuals with latent T. gondii infection or seropositive forest workers. CONCLUSIONS: Type II-specific reactions were overrepresented and higher in intensity in the study population, which was in accord with genotyping studies on T. gondii oocysts previously conducted in the same area. There were also individuals with type I- or type III-specific reactions. Well-characterized reference sera and further specific peptide markers are needed to establish and to perform future serotyping approaches with higher resolution

2-Hydroxylethyl methacrylate (HEMA), a tooth restoration component, exerts its genotoxic effects in human gingival fibroblasts trough methacrylic acid, an immediate product of its degradation

HEMA (2-hydroxyethyl methacrylate), a methacrylate commonly used in dentistry, was reported to induce genotoxic effects, but their mechanism is not fully understood. HEMA may be degraded by the oral cavity esterases or through mechanical stress following the chewing process. Methacrylic acid (MAA) is the primary product of HEMA degradation. In the present work we compared cytotoxic and genotoxic effects induced by HEMA and MAA in human gingival fibroblasts (HGFs). A 6-h exposure to HEMA or MAA induced a weak decrease in the viability of HGFs. Neither HEMA nor MAA induced strand breaks in the isolated plasmid DNA, but both compounds evoked DNA damage in HGFs, as evaluated by the alkaline comet assay. Oxidative modifications to the DNA bases were monitored by the DNA repair enzymes Endo III and Fpg. DNA damage induced by HEMA and MAA was not persistent and was removed during a 120 min repair incubation. Results from the neutral comet assay indicated that both compounds induced DNA double strand breaks (DSBs) and they were confirmed by the γ-H2AX assay. Both compounds induced apoptosis and perturbed the cell cycle. Therefore, methacrylic acid, a product of HEMA degradation, may be involved in its cytotoxic and genotoxic action

Chiral recognition in dimerization of adsorbed cysteine observed by scanning tunnelling microscopy

Kühnle A, Linderoth TR, Hammer B, Besenbacher F. Chiral recognition in dimerization of adsorbed cysteine observed by scanning tunnelling microscopy. Nature. 2002;415(6874):891-893.Stereochemistry plays a central role in controlling molecular recognition and interaction: the chemical and biological properties of molecules depend not only on the nature of their constituent atoms but also on how these atoms are positioned in space. Chiral specificity is consequently fundamental in chemical biology and pharmacology(1,2) and has accordingly been widely studied. Advances in scanning probe microscopies now make it possible to probe chiral phenomena at surfaces at the molecular level. These methods have been used to determine the chirality of adsorbed molecules(3-5), and to provide direct evidence for chiral discrimination in molecular interactions(6) and the spontaneous resolution of adsorbates into extended enantiomerically pure overlayers(3,7-9). Here we report scanning tunnelling microscopy studies of cysteine adsorbed to a (110) gold surface, which show that molecular pairs formed from a racemic mixture of this naturally occurring amino acid are exclusively homochiral, and that their binding to the gold surface is associated with local surface restructuring. Density-functional theory(10) calculations indicate that the chiral specificity of the dimer formation process is driven by the optimization of three bonds on each cysteine molecule. These findings thus provide a clear molecular-level illustration of the well known three-point contact model(11,12) for chiral recognition in a simple bimolecular system

Resonances in a chaotic attractor crisis of the Lorenz Flow

Local bifurcations of stationary points and limit cycles have successfully been characterized in terms of the critical exponents of these solutions. Lyapunov exponents and their associated covariant Lyapunov vectors have been proposed as tools for supporting the understanding of critical transitions in chaotic dynamical systems. However, it is in general not clear how the statistical properties of dynamical systems change across a boundary crisis during which a chaotic attractor collides with a saddle. This behavior is investigated here for a boundary crisis in the Lorenz flow, for which neither the Lyapunov exponents nor the covariant Lyapunov vectors provide a criterion for the crisis. Instead, the convergence of the time evolution of probability densities to the invariant measure, governed by the semigroup of transfer operators, is expected to slow down at the approach of the crisis. Such convergence is described by the eigenvalues of the generator of this semigroup, which can be divided into two families, referred to as the stable and unstable Ruelle--Pollicott resonances, respectively. The former describes the convergence of densities to the attractor (or escape from a repeller) and is estimated from many short time series sampling the state space. The latter is responsible for the decay of correlations, or mixing, and can be estimated from a long times series, invoking ergodicity. It is found numerically for the Lorenz flow that the stable resonances do approach the imaginary axis during the crisis, as is indicative of the loss of global stability of the attractor. On the other hand, the unstable resonances, and a fortiori the decay of correlations, do not flag the proximity of the crisis, thus questioning the usual design of early warning indicators of boundary crises of chaotic attractors and the applicability of response theory close to such crises

A Genome-Wide Study of DNA Methylation Patterns and Gene Expression Levels in Multiple Human and Chimpanzee Tissues

The modification of DNA by methylation is an important epigenetic mechanism that affects the spatial and temporal regulation of gene expression. Methylation patterns have been described in many contexts within and across a range of species. However, the extent to which changes in methylation might underlie inter-species differences in gene regulation, in particular between humans and other primates, has not yet been studied. To this end, we studied DNA methylation patterns in livers, hearts, and kidneys from multiple humans and chimpanzees, using tissue samples for which genome-wide gene expression data were also available. Using the multi-species gene expression and methylation data for 7,723 genes, we were able to study the role of promoter DNA methylation in the evolution of gene regulation across tissues and species. We found that inter-tissue methylation patterns are often conserved between humans and chimpanzees. However, we also found a large number of gene expression differences between species that might be explained, at least in part, by corresponding differences in methylation levels. In particular, we estimate that, in the tissues we studied, inter-species differences in promoter methylation might underlie as much as 12%–18% of differences in gene expression levels between humans and chimpanzees