Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial

The orexin system is a key regulator of sleep and wakefulness. In a multicenter, double-blind, randomized, placebo-controlled, two-way crossover study, 161 primary insomnia patients received either the dual orexin receptor antagonist almorexant, at 400, 200, 100, or 50 mg in consecutive stages, or placebo on treatment nights at 1-week intervals. The primary end point was sleep efficiency (SE) measured by polysomnography; secondary end points were objective latency to persistent sleep (LPS), wake after sleep onset (WASO), safety, and tolerability. Dose-dependent almorexant effects were observed on SE , LPS , and WASO . SE improved significantly after almorexant 400 mg vs. placebo (mean treatment effect 14.4%; P < 0.001). LPS (–18 min (P = 0.02)) and WASO (–54 min (P < 0.001)) decreased significantly at 400 mg vs. placebo. Adverse-event incidence was dose-related. Almorexant consistently and dose-dependently improved sleep variables. The orexin system may offer a new treatment approach for primary insomnia.

Cascading climate effects and related ecological consequences during past centuries

The interface between climate and ecosystem structure and function is incompletely understood, partly because few ecological records start before the recent warming phase. Here, we analyse an exceptional 100-yr long record of the great tit (Parus major) population in Switzerland in relation to climate and habitat phenology. Using structural equation analysis, we demonstrate an uninterrupted cascade of significant influences of the large-scale atmospheric circulation (North-Atlantic Oscillation, NAO, and North-sea – Caspian Pattern, NCP) on habitat and breeding phenology, and further on fitness-relevant life history traits within great tit populations. We then apply the relationships of this analysis to reconstruct the circulation-driven component of fluctuations in great tit breeding phenology and productivity on the basis of new seasonal NAO and NCP indices back to 1500 AD. According to the structural equation model, the multi-decadal oscillation of the atmospheric circulation likely led to substantial variation in habitat phenology, productivity and consequently, tit population fluctuations with minima during the "Maunder Minimum" (∼ 1650–1720) and the Little Ice Age Type Event I (1810–1850). The warming since 1975 was not only related with a quick shift towards earlier breeding, but also with the highest productivity since 1500, and thus, the impact of the NAO and NCP has contributed to an unprecedented increase of the population. A verification of the structural equation model against two independent data series (1970–2000 and 1750–1900) corroborates that the retrospective model reliably depicts the major long-term NAO/NCP impact on ecosystem parameters. The results suggest a complex cascade of climate effects beginning at a global scale and ending at the level of individual life histories. This sheds light on how large-scale climate conditions substantially affect major life history parameters within a population, and thus influence key ecosystem parameters at the scale of centuries.

A paradigm shift in mechanical biofilm management? Subgingival air polishing: a new way to improve mechanical biofilm management in the dental practice

In the past few years indications for the use of the air polishing technology have been expanded from supragingival use (airflow) to subgingival air polishing (perioflow) by the development of new low-abrasive glycine-based powders and devices with a subgingival nozzle. Several studies on the subgingival use of air polishing have been completed. On 7 June 2012, during the Europerio 7 Congress in Vienna, a consensus conference on mechanical biofilm management took place aiming to review the current evidence from the literature on the clinical relevance of the subgingival use of air polishing and to make practical recommendations for the clinician. Bernita Bush (Bern), Prof Johannes Einwag (Stuttgart), Prof Thomas Flemmig (Seattle), Carmen Lanoway (Munich), Prof Ursula Platzer (Hamburg), Prof Petra Schmage (Hamburg), Brigitte Schoeneich (Zurich), Prof Anton Sculean (Bern), Dr Clemens Walter (Basel), and Prof Jan Wennström (Gothenburg) discussed under the moderation of Klaus-Dieter Bastendorf and Christian Becker (both ADIC Association for Dental Infection Control) the available clinical studies to reach a consensus on available clinical evidence. This paper summarizes the main conclusions of the consensus conference and points to the clinical relevance of the findings for the dental practitioner.

Integrated reconstruction of Holocene millennial-scale environmental changes in Tierra del Fuego, southernmost South America

This study presents new paleoenvironmental data obtained from sedimentary cores from Lago Fagnano, an elon- gated lake located at 54°S in southernmost South America. Data from palynomorphs (pollen, spores and algae) and associated palynofacies as well as from diatom taxa retrieved from these cores compared with other regional proxies contribute to evaluate the similarities and differences in the climate patterns based on different proxies from southernmost Patagonia. The pollen analysis reveals that a grass steppe environment existed during the early Holocene (11,300–~8000 cal a BP) followed by a major vegetation change characterized by development of forest-steppe ecotone communities between ~8000 and ~6500 cal a BP, under more humid conditions. Between ~ 6500 and ~ 4000 cal a BP, expansion and colonization by Nothofagus forests reflect an increase in effec- tive moisture levels, while openness in the forest communities characterizes the region after ~ 1100 cal a BP. The palynological organic matter combined with the algal content reflects hydrological changes occurring in the lake and its nutrient status, probably in close relation with past climate oscillations. All these past ecological changes are closely related to oscillations in precipitation and temperature as a response to the variations in the latitudinal position and/or strength of the Southern Westerlies wind belt during the Holocene.

Humane Orientation as a New Cultural Dimension of the GLOBE Project: A Validation Study of the GLOBE Scale and Out-Group Humane Orientation in 25 Countries

We validate, extend, and empirically and theoretically criticize the cultural dimension of humane orientation of the project GLOBE (Global Leadership and Organizational Behavior Effectiveness Research Program). Theoretically, humane orientation is not just a one-dimensionally positive concept about being caring, altruistic, and kind to others as discussed by Kabasakal and Bodur (2004), but there is also a certain ambivalence to this concept. We suggest differentiating humane orientation toward in-group members from humane orientation toward out-group members. A multicountry construct validation study used student samples from 25 countries that were either high or low in humane orientation (N = 876) and studied their relation to the traditional GLOBE scale and other cultural-level measures (agreeableness, religiosity, authoritarianism, and welfare state score). Findings revealed a strong correlation between humane orientation and agreeableness, welfare state score, and religiosity. Out-group humane orientation proved to be the more relevant subfacet of the original humane orientation construct, suggesting that future research on humane orientation should make use of this measure instead of the vague original scale. The ambivalent character of out-group humane orientation is displayed in its positive correlation to high authoritarianism. Patriotism was used as a control variable for noncritical acceptance of one’s society but did not change the correlations. Our findings are discussed as an example of how rigid expectations and a lack of tolerance for diversity may help explain the ambivalent nature of humane orientation

The dementia cognitive fluctuation scale, a new psychometric test for clinicians to identify cognitive fluctuations in people with dementia.

OBJECTIVES Cognitive fluctuation (CF) is a common feature of dementia and a core diagnostic symptom for dementia with Lewy bodies (DLB). CF remains difficult to accurately and reliably detect clinically. This study aimed to develop a psychometric test that could be used by clinicians to facilitate the identification of CF and improve the recognition and diagnosis of DLB and Parkinson disease, and to improve differential diagnosis of other dementias. METHODS We compiled a 17-item psychometric test for identifying CF and applied this measure in a cross-sectional design. Participants were recruited from the North East of England, and assessments were made in individuals' homes. We recruited people with four subtypes of dementia and a healthy comparison group, and all subjects were administered this pilot scale together with other standard ratings. The psychometric properties of the scale were examined with exploratory factor analysis. We also examined the ability of individual items to identify CF to discriminate between dementia subtypes. The sensitivity and specificity of discriminating items were explored along with validity and reliability analyses. RESULTS Participants comprised 32 comparison subjects, 30 people with Alzheimer disease, 30 with vascular dementia, 29 with DLB, and 32 with dementia associated with Parkinson disease. Four items significantly discriminated between dementia groups and showed good levels of sensitivity (range: 78.6%-80.3%) and specificity (range: 73.9%-79.3%). The scale had very good levels of test-retest (Cronbach's alpha: 0.82) and interrater (0.81) reliabilities. The four items loaded onto three different factors. These items were: 1) marked differences in functioning during the daytime; 2) daytime somnolence; 3) daytime drowsiness; and 4) altered levels of consciousness during the day. CONCLUSIONS We identified four items that provide valid, sensitive, and specific questions for reliably identifying CF and distinguishing the Lewy body dementias from other major causes of dementia (Alzheimer disease and vascular dementia).

Ca2+-dependent repair of pneumolysin pores: A new paradigm for host cellular defense against bacterial pore-forming toxins

Pneumolysin (PLY), a key virulence factor of Streptococcus pneumoniae, permeabilizes eukaryotic cells by forming large trans-membrane pores. PLY imposes a puzzling multitude of diverse, often mutually excluding actions on eukaryotic cells. Whereas cytotoxicity of PLY can be directly attributed to the pore-mediated effects, mechanisms that are responsible for the PLY-induced activation of host cells are poorly understood. We show that PLY pores can be repaired and thereby PLY-induced cell death can be prevented. Pore-induced Ca2+ entry from the extracellular milieu is of paramount importance for the initiation of plasmalemmal repair. Nevertheless, active Ca2+ sequestration that prevents excessive Ca2+ elevation during the execution phase of plasmalemmal repair is of no less importance. The efficacy of plasmalemmal repair does not only define the fate of targeted cells but also intensity, duration and repetitiveness of PLY-induced Ca2+ signals in cells that were able to survive after PLY attack. Intracellular Ca2+ dynamics evoked by the combined action of pore formation and their elimination mimic the pattern of receptor-mediated Ca2+ signaling, which is responsible for the activation of host immune responses. Therefore, we postulate that plasmalemmal repair of PLY pores might provoke cellular responses that are similar to those currently ascribed to the receptor-mediated PLY effects. Our data provide new insights into the understanding of the complexity of cellular non-immune defense responses to a major pneumococcal toxin that plays a critical role in the establishment and the progression of life-threatening diseases. Therapies boosting plasmalemmal repair of host cells and their metabolic fitness might prove beneficial for the treatment of pneumococcal infections.

Religious Diversity and Religious Vitality: New Measuring Strategies and Empirical Evidence

Quantitative studies of the conditions and consequences of religious diversity are based mostly on indices that measure the variety of religious membership in a particular region. However, this line of research has become stagnant, and the question of whether diversity affects religious vitality remains unanswered. This article attempts to shed new light on the discussion by measuring religious diversity differently and capturing religious vitality independently of membership figures. In particular, it contrasts the Herfindahl-Hirschman Index based on membership proportions with a second measure of diversity: an index of organizational diversity. Conversely, the dependent variable religious vitality is measured not by using rates of participation in religious organizations but via the Centrality of Religion Scale. Based on ecological and individual level data of forty-three local regions in Finland, Germany, and Slovenia and using multilevel analysis, our results suggest that religious diversity is related to religious vitality. However, the nature of this association differs across subgroups.

More adaptive versus less maladaptive coping: What is more predictive of symptom severity? Development of a new scale to investigate coping profiles across different psychopathological syndromes

BACKGROUND: Lack of adaptive and enhanced maladaptive coping with stress and negative emotions are implicated in many psychopathological disorders. We describe the development of a new scale to investigate the relative contribution of different coping styles to psychopathology in a large population sample. We hypothesized that the magnitude of the supposed positive correlation between maladaptive coping and psychopathology would be stronger than the supposed negative correlation between adaptive coping and psychopathology. We also examined whether distinct coping style patterns emerge for different psychopathological syndromes. METHODS: A total of 2200 individuals from the general population participated in an online survey. The Patient Health Questionnaire-9 (PHQ-9), the Obsessive-Compulsive Inventory revised (OCI-R) and the Paranoia Checklist were administered along with a novel instrument called Maladaptive and Adaptive Coping Styles (MAX) questionnaire. Participants were reassessed six months later. RESULTS: MAX consists of three dimensions representing adaptive coping, maladaptive coping and avoidance. Across all psychopathological syndromes, similar response patterns emerged. Maladaptive coping was more strongly related to psychopathology than adaptive coping both cross-sectionally and longitudinally. The overall number of coping styles adopted by an individual predicted greater psychopathology. Mediation analysis suggests that a mild positive relationship between adaptive and certain maladaptive styles (emotional suppression) partially accounts for the attenuated relationship between adaptive coping and depressive symptoms. LIMITATIONS: Results should be replicated in a clinical population. CONCLUSIONS: Results suggest that maladaptive and adaptive coping styles are not reciprocal. Reducing maladaptive coping seems to be more important for outcome than enhancing adaptive coping. The study supports transdiagnostic approaches advocating that maladaptive coping is a common factor across different psychopathologies.