Activity patterns as a correlate for sleep-wake behaviour in mice

Sleep-wake behaviour in mice is known to interact with various behavioural dimensions. Therefore, it is necessary to control for such dimensions when evaluating sleep in mice. The characterisation of sleep in rodents usually is based on EEG signals. Since this method demands the invasive implantation of electrodes, it cannot be integrated into general behavioural phenotyping procedures. Thus, non- or minimum-invasive methods are needed for the analysis of sleep-wake behaviour. Although physiological parameters, like for instance general locomotor activity, allow for the assessment of sleep-wake behaviour in mice, existing methods lack reliability especially in measuring stationary and three-dimensional activities. In this study, a small magnet was implanted subcutaneously near the neck muscles of mice and each movement of the magnet was registered via a sensor plate. For validation of the described method, the effects of sleep deprivation were evaluated by both the magnet and the EEG in parallel. Our results show that the data obtained via the subcutaneously implanted magnet represent a reliable and sensitive measurement of quantitative aspects of sleep-wake behaviour: spatial variation as well as stationary activities could be dissociated from sleep. Qualitative sleep characteristics were not detected. In summary, this minimum invasive method allows for the detection of quantitative alterations in sleep-wake behaviour in mice, thus, offering a useful, rapid pre-screen in animal sleep research.     

Early course of illness in first episode schizophrenia with long duration of untreated illness - a comparative study

When a long duration of untreated illness (DUI) is correlated with an unfavourable progression of schizophrenia in the same way as that of a long duration of untreated psychosis (DUP), the characteristics of patients with a long DUI are of particular interest for early recognition and early intervention programmes. With this background, demographic data and early symptoms were collected from 82 first time in-patients with schizophrenia using the IRAOS (Interview for the Retrospective Assessment of the Onset of Schizophrenia). In the total sample, the average DUI was almost 5.9 years. On the basis of the DUI median (5.2 yrs), the random sample was divided into two groups: one with long (n = 41) and one with short (n = 41) DUI. When comparing both groups in terms of socio-demographic data, no significant differences could be found (with the exception of age at first admission: 28 - 32 yrs). On a psychopathological level, patients with long DUI were prone to depressive moods, anxiety, compulsive symptoms and showed early signs of disturbances in bodily perception. An educational campaign should sensitize both employees working in primary care and experts who diagnose and treat psychological illnesses, to the fact that these symptoms could point to a prodrome even when the patient has passed the typical age of being at risk from schizophrenia.     

Pathways to care: help-seeking behavior in first-episode psychosis

Several studies on first episode schizophrenia suggest that a longer duration of untreated psychosis (DUP) results in poorer clinical outcome. The same is expected for the duration of untreated illness (DUI). It is therefore important to expose people at risk of schizophrenia to adequate treatment early on. The improvement of pathways to adequate treatment within the health care system might well be helpful. Therefore, an analysis of the pathways to care is necessary. Thus, in this present study 80 in-patients with first episode psychosis were investigated using the semi-structured interview IRAOS ("Interview for the Retrospective Assessment of the Onset of Schizophrenia") and data about the pathways to care before psychiatric admission were collected. The results indicate that patients contact on average three carers. Contact to a psychiatrist or a psychotherapist was only made two and a half years after onset of illness; general practitioners were only contacted after more than five years. However, there was a significant time lapse between first contact to psychiatrist/ psychotherapist and psychiatric admission. Only 31 % of patients sought help in the prodromal phase of the illness. Two strategies for a public campaign can be derived from these results: firstly, a public awareness campaign has to be implemented to shorten the interval from onset of illness to first help-seeking behaviour and secondly, professionals need to have more knowledge and better awareness of prodromal signs in order to reduce the time between diagnosis and adequate treatment.     

Tissue-specific response to interstitial angiotensin II in humans

Angiotensin II is synthesized locally in various tissues; however, the role of interstitial angiotensin II in the regulation of regional metabolism and tissue perfusion is not clear. We characterized the effect of interstially applied angiotensin II in skeletal muscle and subcutaneous adipose tissue of young, normal-weight, healthy subjects by using the microdialysis technique. Furthermore, we tested the hypothesis that the effect of interstitial angiotensin II is modulated by nitric oxide. Tissues were perfused with 0.01, 0.1, and 1 micro mol/L angiotensin II in the presence of the L- or D-isomer of N(G)-nitro-arginine-methyl ester (L- or D-NAME), the effective and noneffective isomer, respectively, for blocking nitric oxide synthase. Dialysate ethanol, glycerol, glucose, lactate, and pyruvate concentrations were measured to assess changes in blood flow (ethanol dilution technique), lipolysis, and glycolysis, respectively. Baseline blood flow and dialysate concentrations of the metabolites were similar with L- and D-NAME in both tissues. Blood flow and dialysate glucose and lactate did not change significantly in both tissues during perfusion with angiotensin II. Dialysate glycerol dose-dependently increased in adipose tissue (P<0.0438) but decreased in muscle (P<0.007). In muscle, dialysate pyruvate increased (P<0.0002), whereas lactate/pyruvate ratio decreased (P<0.001), both dose-dependently. All effects were similar with L- and D-NAME and could be reversed by nitroprusside. We conclude that in contrast to the profound hemodynamic effect of intravascular angiotensin II, interstitial angiotensin II has a minimal acute effect on blood flow in both tissues. However, interstitial angiotensin II modulates lipid and carbohydrate metabolism in a tissue specific fashion. Thus, the physiology of interstitial angiotensin II cannot be predicted from intravascular studies.     

C5a anaphylatoxin as a product of complement activation up-regulates the complement inhibitory factor H in rat Kupffer cells

The 155-kDa complement regulator factor H (FH) is the predominant soluble regulatory protein of the complement system. It acts as a cofactor for the factor I-mediated conversion of the component C3b to iC3b, competes with factor B for a binding site on C3b and C3(H2O) and promotes the dissociation of the C3bBb complex. The primary site of synthesis is the liver, i.e. FH-specific mRNA and protein were identified in both hepatocytes (HC) and Kupffer cells (KC). Previous studies in rat primary HC and KC had shown that the proinflammatory cytokine IFN-gamma influences the balance between activation and inhibition of the complement system through up-regulation of the inhibitory FH. In this study we show that C5a, as a product of complement activation, stimulates the expression of FH-specific mRNA and protein in KC and thus induces a negative feedback. Quantitative-competitive RT-PCR showed an approximate threefold C5a-induced up-regulation of FH. ELISA analyses revealed a corresponding increase in FH protein in the supernatants of KC. The up-regulation of FH was completely inhibited by the C5a-blocking monoclonal antibody 6-9F. Furthermore, an involvement of LPS and IFN-gamma was excluded, which strongly indicates a direct effect of C5a on the expression of FH in KC.     

Aversive Learning in Adolescents: Modulation by Amygdala–Prefrontal and Amygdala–Hippocampal Connectivity and Neuroticism

Neuroticism involves a tendency for enhanced emotional and cognitive processing of negative affective stimuli and a propensity to worry and be anxious. It is known that this trait modulates fear learning and the activation of brain regions involved in it such as the amygdala, hippocampus, and prefrontal cortex and their connectivity. Thirty-nine (21 female) 14-year-old healthy adolescents participated in functional magnetic resonance imaging (fMRI) of aversive pavlovian differential delay conditioning. An unpleasant sound served as unconditioned stimulus (US) and pictures of neutral male faces as conditioned stimuli (CS+ followed by the US in 50% of the cases; CS− never followed by the US). During acquisition (CS+/− differentiation), higher levels of neuroticism were associated with a stronger interaction between the right amygdala and the right hippocampus as well as the right amygdala and prefrontal cortical regions, specifically ventromedial prefrontal cortex, dorsolateral prefrontal cortex, and anterior cingulate cortex. The association of stronger conditionability of fear and connectivity of brain regions related to consolidation of fear associations and neuroticism points to underlying mechanisms of the enhanced propensity for anxiety disorders in highly neurotic participants. This is especially important in adolescence, a vulnerable time for the onset of mental disorders such as anxiety disorders.     

Air Pollution and Polyclonal Elevation of Serum Free Light Chains: An Assessment of Adaptive Immune Responses in the Prospective Heinz Nixdorf Recall Study

Background: Residential exposure to air pollution (AP) has been shown to activate the immune system (IS). Although innate immune responses to AP have been studied extensively, investigations on the adaptive IS are scarce.Objectives: The aim of this study was to investigate the association between short- to long-term AP exposure and polyclonal free light chains (FLC) produced by plasma cells.Methods: We used repeated data from three examinations (t0: 2000–2003; t1: 2006–2008; and t2: 2011–2015) of the population-based German Heinz Nixdorf Recall cohort of initially 4,814 participants (45–75 y old). Residential exposure to total and source-specific particulate matter (PM) with an aerodynamic diameter of 10 or 2.5μm (PM10 and PM2.5 respectively), nitrogen dioxide (NO2), and particle number concentrations (accumulation mode; PNAM) was estimated using a chemistry transport model with different time windows (1- to 365-d mean ± standard deviation) before blood draw. We applied linear mixed models with a random participant intercept to estimate associations between total, traffic- and industry-related AP exposures and log-transformed FLC, controlling for examination time, sociodemographic and lifestyle variables, estimated glomerular filtration rate and season.Results: Analyzing 9,933 observations from 4,455 participants, we observed generally positive associations between AP exposures and FLC. We observed strongest associations with middle-term exposures, e.g., 3.0% increase in FLC (95% confidence interval: 1.8%, 4.3%) per interquartile range increase in 91-d mean of NO2 (14.1μg/m³). Across the different pollutants, NO2 showed strongest associations with FLC, followed by PM10 and PNAM. Effect estimates for traffic-related exposures were mostly higher compared with total exposures. Although NO2 and PNAM estimates remained stable upon adjustment for PM, PM estimates decreased considerably upon adjustment for NO2 and PNAM.Discussion: Our results suggest that middle-term AP exposures in particular might be positively associated with activation of the adaptive IS. Traffic-related PM, PNAM, and NO2 showed strongest associations. https://doi.org/10.1289/EHP7164     

Effect of Surface Energy on Powder Compactibility

Purpose  The influence of surface energy on the compactibility of lactose particles has been investigated. Materials and Methods  Three powders were prepared by spray drying lactose solutions without or with low proportions of the surfactant polysorbate 80. Various powder and tablet characterisation procedures were applied. The surface energy of the powders was characterized by Inverse Gas Chromatography and the compressibility of the powders was described by the relationship between tablet porosity and compression pressure. The compactibility of the powders was analyzed by studying the evolution of tablet tensile strength with increasing compaction pressure and porosity. Results  All powders were amorphous and similar in particle size, shape, and surface area. The compressibility of the powders and the microstructure of the formed tablets were equal. However, the compactibility and dispersive surface energy was dependent of the composition of the powders. Conclusion  The decrease in tablet strength correlated to the decrease in powder surface energy at constant tablet porosities. This supports the idea that tablet strength is controlled by formation of intermolecular forces over the areas of contact between the particles and that the strength of these bonding forces is controlled by surface energy which, in turn, can be altered by the presence of surfactants.     

Effects of short-term exposure to fine and ultrafine particles from indoor sources on arterial stiffness – A randomized sham-controlled exposure study

ObjectivesParticulate air pollution is linked to adverse cardiovascular effects, including arterial stiffness. The aim of the study was to investigate the effect of short-term exposure to indoor fine and ultrafine particles on augmentation index (AIx), augmentation pressure (AP), and pulse wave velocity (PWV), early signs of vascular damage.MethodsWe analyzed the association of particle emissions from typical indoor sources (candle burning - CB, toasting bread - TB, and frying sausages - FS) with changes in pulse wave analysis indices in 55 healthy adults in a randomized cross-over controlled exposure study. Particle mass concentration (PMC), size-specific particle number concentration (PNC) and lung-deposited particle surface area concentration (PSC) were measured during the 2 h exposure. AIx and AP were measured before, directly, 2, 4 and 24 h after exposure. PWV was measured directly and 24 h after exposure. We performed multiple mixed linear regression analyses of different particle metrics and AIx, AP and PWV.ResultsThe highest mean PMC was observed during FS reaching a maximum of 210 μg/m³ PM₁₀. The maximal PNC for UFP <100 nm was reached during CB with 2.3 million particles/cm³. PSC was similar across all three exposures (about 3000 μm²/cm³). Strongest associations between different particles metrics and arterial stiffness indices could be observed for UFP from CB and FS and for PMC from TB. The highest mean increase could be observed for the UFP fraction <10 nm, measured during CB, and AIx with an increase of 9.5%-points (95%-CI: 3.1; 15.9). PSC seemed to follow the pattern of PNC. PM₁₀ and PM_2.5 from TB led to clear changes in AIx with biggest increases for PM₁₀ of 5.8%-points (95%-CI: 3.2; 8.4) 2 h after exposure and for PM_2.5 of 8.1%-points (95%-CI: 2.5; 13.7) directly after exposure.ConclusionsOur study indicates effects of indoor exposure to fine and ultrafine particles on systemic arterial stiffness indices that depend on the indoor source as well as on particle metric. Differences in size-specific physical characteristics of source-specific particles might account for these differential effects. We did not observe clear and stable associations of indoor particle exposure and PWV.