Neuroactive steroids in depression and anxiety disorders: Clinical studies

Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3 alpha-reduced pregnane steroids are potent positive allosteric modulators of the gamma-aminobutyric acid type A (GABA(A)) receptor. During major depression, there is a disequilibrium of 3 alpha-reduced neuroactive steroids, which is corrected by clinically effective pharmacological treatment. To investigate whether these alterations are a general principle of successful antidepressant treatment, we studied the impact of nonpharmacological treatment options on neuroactive steroid concentrations during major depression. Neither partial sleep deprivation, transcranial magnetic stimulation, nor electroconvulsive therapy affected neuroactive steroid levels irrespectively of the response to these treatments. These studies suggest that the changes in neuroactive steroid concentrations observed after antidepressant pharmacotherapy more likely reflect distinct pharmacological properties of antidepressants rather than the clinical response. In patients with panic disorder, changes in neuroactive steroid composition have been observed opposite to those seen in depression. However, during experimentally induced panic induction either with cholecystokinine-tetrapeptide or sodium lactate, there was a pronounced decline in the concentrations of 3 alpha-reduced neuroactive steroids in patients with panic disorder, which might result in a decreased GABAergic tone. In contrast, no changes in neuroactive steroid concentrations could be observed in healthy controls with the exception of 3 alpha,5 alpha-tetrahydrodeoxycorticosterone. The modulation of GABA(A) receptors by neuroactive steroids might contribute to the pathophysiology of depression and anxiety disorders and might offer new targets for the development of novel anxiolytic compounds. Copyright (c) 2006 S. Karger AG, Basel

An assessment of validity and responsiveness of generic measures of health-related quality of life in hearing impairment

This article is made available through the Brunel Open Access Publishing Fund. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.Purpose: This review examines psychometric performance of three widely used generic preference-based measures, that is, EuroQol 5 dimensions (EQ-5D), Health Utility Index 3 (HUI3) and Short-form 6 dimensions (SF-6D) in patients with hearing impairments. Methods: A systematic search was undertaken to identify studies of patients with hearing impairments where health state utility values were measured and reported. Data were extracted and analysed to assess the reliability, validity (known group differences and convergent validity) and responsiveness of the measures across hearing impairments. Results: Fourteen studies (18 papers) were included in the review. HUI3 was the most commonly used utility measures in hearing impairment. In all six studies, the HUI3 detected difference between groups defined by the severity of impairment, and four out of five studies detected statistically significant changes as a result of intervention. The only study available suggested that EQ-5D only had weak ability to discriminate difference between severity groups, and in four out of five studies, EQ-5D failed to detected changes. Only one study involved the SF-6D; thus, the information is too limited to conclude on its performance. Also evidence for the reliability of these measures was not found. Conclusion: Overall, the validity and responsiveness of the HUI3 in hearing impairment was good. The responsiveness of EQ-5D was relatively poor and weak validity was suggested by limited evidence. The evidence on SF-6D was too limited to make any judgment. More head-to-head comparisons of these and other preference measures of health are required.Medical Research Counci

Citizenship Norms in Eastern Europe

Research on Eastern Europe stresses the weakness of its civil society and the lack of political and social involvement, neglecting the question: What do people themselves think it means to be a good citizen? This study looks at citizens’ definitions of good citizenship in Poland, Slovenia, the Czech Republic and Hungary, using 2002 European Social Survey data. We investigate mean levels of civic mindedness in these countries and perform regression analyses to investigate whether factors traditionally associated with civic and political participation are also correlated with citizenship norms across Eastern Europe. We show that mean levels of civic mindedness differ significantly across the four Eastern European countries. We find some support for theories on civic and political participation when explaining norms of citizenship, but also demonstrate that individual-level characteristics are differently related to citizenship norms across the countries of our study. Hence, our findings show that Eastern Europe is not a monolithic and homogeneous bloc, underscoring the importance of taking the specificities of countries into account

“Avoiding or approaching eyes”? Introversion/extraversion affects the gaze-cueing effect

We investigated whether the extra-/introversion personality dimension can influence processing of others’ eye gaze direction and emotional facial expression during a target detection task. On the basis of previous evidence showing that self-reported trait anxiety can affect gaze-cueing with emotional faces, we also verified whether trait anxiety can modulate the influence of intro-/extraversion on behavioral performance. Fearful, happy, angry or neutral faces, with either direct or averted gaze, were presented before the target appeared in spatial locations congruent or incongruent with stimuli’s eye gaze direction. Results showed a significant influence of intra-/extraversion dimension on gaze-cueing effect for angry, happy, and neutral faces with averted gaze. Introverts did not show the gaze congruency effect when viewing angry expressions, but did so with happy and neutral faces; extraverts showed the opposite pattern. Importantly, the influence of intro-/extraversion on gaze-cueing was not mediated by trait anxiety. These findings demonstrated that personality differences can shape processing of interactions between relevant social signals

The 2dF Galaxy Redshift Survey: correlation functions, peculiar velocities and the matter density of the Universe

We present a detailed analysis of the two-point correlation function, ξ(σ, π), from the 2dF Galaxy Redshift Survey (2dFGRS). The large size of the catalogue, which contains ∼220 000 redshifts, allows us to make high-precision measurements of various properties of the galaxy clustering pattern. The effective redshift at which our estimates are made is zs≈ 0.15, and similarly the effective luminosity, Ls≈ 1.4L*. We estimate the redshift-space correlation function, ξ(s), from which we measure the redshift-space clustering length, s0= 6.82 ± 0.28 h−1 Mpc. We also estimate the projected correlation function, Ξ(σ), and the real-space correlation function, ξ(r), which can be fit by a power law (r/r0), with r0= 5.05 ± 0.26 h−1 Mpc, γr= 1.67 ± 0.03. For r≳ 20 h−1 Mpc, ξ drops below a power law as, for instance, is expected in the popular Λ cold dark matter model. The ratio of amplitudes of the real- and redshift-space correlation functions on scales of 8–30 h−1 Mpc gives an estimate of the redshift-space distortion parameter β. The quadrupole moment of ξ(σ, π) on scales 30–40 h−1 Mpc provides another estimate of β. We also estimate the distribution function of pairwise peculiar velocities, ƒ(v), including rigorously the significant effect due to the infall velocities, and we find that the distribution is well fit by an exponential form. The accuracy of our ξ(σ, π) measurement is sufficient to constrain a model, which simultaneously fits the shape and amplitude of ξ(r) and the two redshift-space distortion effects parametrized by β and velocity dispersion, a. We find β= 0.49 ± 0.09 and a= 506 ± 52 km s−1, although the best-fitting values are strongly correlated. We measure the variation of the peculiar velocity dispersion with projected separation, a(σ), and find that the shape is consistent with models and simulations. This is the first time that β and ƒ(v) have been estimated from a self-consistent model of galaxy velocities. Using the constraints on bias from recent estimates, and taking account of redshift evolution, we conclude that β (L=L*, z= 0) = 0.47 ± 0.08, and that the present-day matter density of the Universe, Ωm≈ 0.3, consistent with other 2dFGRS estimates and independent analyses

Paradigms in multiple sclerosis: time for a change, time for a unifying concept

It has recently been suggested that, rather than being an autoimmune disease, multiple sclerosis (MS) is an example of a neurocristopathy, a pathological process resulting from a faulty development of the neural crest. Whilst several characteristics of the disease suggest a neurocristopathy, other aetiological factors require consideration, including hygiene-related factors that alter the immune responses to common pathogens resulting in an eclipse of immune reactivity that could protect against MS, the possible role of human endogenous retroviruses (HERVs) in pathogenesis and autoimmune phenomena, HLA polymorphism, vitamin D levels before and after birth and immune repair mechanisms. A postulated aetiological factor in MS, associated with altered vitamin D metabolism and abnormal HERV expression, is a long-lasting disturbed redox regulation in the biosynthesis of a melanoma-like melanin pigment. Although intensive further studies on melanin pigments in nerve tissue in MS are required, the known properties of a pathological form of such pigments in melanoma could explain a number of observations in MS, including the impact of light, UV-light, and vitamin D, and could explain the clinical manifestations of MS on the basis of an oscillating process of oxidative charge and discharge of the pigments and a threshold phenomenon with a change of the quasi-catalytic function of the pigment from destroying reactive oxygen radicals or species to transforming them to more harmful long-persisting highly reactive species. Taken together with the consequences of an adaptive process in partly demyelinated neurons, resulting in an increase in number of mitochondria, and the impact of stressful life events, these conditions are necessary and sufficient to explain the disease process of MS with its spatial (plaques) and temporal (attacks and remissions) characteristics. This suggested unifying concept of the pathogenesis of MS may open perspectives for prevention, diagnosis and therapy. In particular, prevention may be achieved by vaccinating against Epstein-Barr virus in early childhood

γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor

Reactive oxygen species regulate redox-signaling processes, but in excess they can cause cell damage, hence underlying the aetiology of several neurological diseases. Through its ability to down modulate reactive oxygen species, glutathione is considered an essential thiol-antioxidant derivative, yet under certain circumstances it is dispensable for cell growth and redox control. Here we show, by directing the biosynthesis of γ-glutamylcysteine—the immediate glutathione precursor—to mitochondria, that it efficiently detoxifies hydrogen peroxide and superoxide anion, regardless of cellular glutathione concentrations. Knocking down glutathione peroxidase-1 drastically increases superoxide anion in cells synthesizing mitochondrial γ-glutamylcysteine. In vitro, γ-glutamylcysteine is as efficient as glutathione in disposing of hydrogen peroxide by glutathione peroxidase-1. In primary neurons, endogenously synthesized γ-glutamylcysteine fully prevents apoptotic death in several neurotoxic paradigms and, in an in vivo mouse model of neurodegeneration, γ-glutamylcysteine protects against neuronal loss and motor impairment. Thus, γ-glutamylcysteine takes over the antioxidant and neuroprotective functions of glutathione by acting as glutathione peroxidase-1 cofactor

Hearing Ability with Age in Northern European Women: A New Web-Based Approach to Genetic Studies

Age-related hearing impairment (ARHI) affects 25–40% of individuals over the age of 65. Despite the high prevalence of this complex trait, ARHI is still poorly understood. We hypothesized that variance in hearing ability with age is largely determined by genetic factors. We collected audiologic data on females of Northern European ancestry and compared different audiogram representations. A web-based speech-to-noise ratio (SNR) hearing test was compared with pure-tone thresholds to see if we could determine accurately hearing ability on people at home and the genetic contribution to each trait compared. Volunteers were recruited from the TwinsUK cohort. Hearing ability was determined using pure-tone audiometry and a web-based hearing test. Different audiogram presentations were compared for age-correlation and reflection of audiogram shape. Using structural equation modelling based on the classical twin model the heritability of ARHI, as measured by the different phenotypes, was estimated and shared variance between the web-based SNR test and pure-tone audiometry determined using bivariate modelling. Pure-tone audiometric data was collected on 1033 older females (age: 41–86). 1970 volunteers (males and females, age: 18–85) participated in the SNR. In the comparison between different ARHI phenotypes the difference between the first two principle components (PC1–PC2) best represented ARHI. The SNR test showed a sensitivity and specificity of 89% and 80%, respectively, in comparison with pure-tone audiogram data. Univariate heritability estimates ranged from 0.70 (95% CI: 0.63–0.76) for (PC1–PC2) to 0.56 (95% CI: 0.48–0.63) for PC2. The genetic correlation of PC1–PC2 and SNR was −0.67 showing that the 2 traits share variances attributed to additive genetic factors. Hearing ability showed considerable heritability in our sample. We have shown that the SNR test provides a useful surrogate marker of hearing. This will enable a much larger sample to be collected at a fraction of the cost, facilitating future genetic association studies