The involvement of central corticotropin-releasing hormone and its receptors in sleep-wake regulation of mice

The corticotropin-releasing hormone (CRH) is widely recognised as the major activator of the hypothalamic-pituitary-adrenocortical (HPA) axis, thereby mediating neuroendocrine, autonomic, and behavioural responses to stress. Dysregulation of the release of stress hormones, caused by excessive CRH secretion from the hypothalamus, is frequently observed in patients with affective disorders such as depression. One of the cardinal symptoms of major depression is a severe impairment of sleep (e.g. reduced sleep intensity, disinhibition of rapid eye movement sleep (REMS), and early morning awakenings). Consequently, besides a role of CRH in stress-induced arousal, its additional contribution to spontaneous sleep-wake regulation was suggested in literature. Due to the lack of highly specific CRH receptor antagonists and adequate CRH receptor knockout animal models, the mechanism and pathways by which CRH communicates its arousal function remained indistinct. Up to now it is unclear whether CRH interferes with sleep by a direct central action, or if the activation of the HPA axis and the subsequent release of peripheral stress hormones are mandatory. The present study with conditional CNS-specific CRH receptor type 1 (CRH-R1 CKO) and conventional CRH receptor type 2 knockout mice (CRH-R2 KO), allows assessment of CRH effects on wakefulness and sleep separately from a functional HPA axis together with various levels of CRH receptor system functionality. In addition, challenging sleep homeostasis in these mouse lines by sleep deprivation allows investigating the involvement of CRH and its receptor system in basic sleep-wake regulatory processes. Besides slight dissimilarities between the baseline sleep profiles in the various genotypes, CRH-R1 CKO displayed a markedly different response to intracerebroventricular (i.c.v.) CRH injections. The dose-dependent increases in wakefulness and decreases in non-REM sleep (NREMS), which could be observed in all other mouse lines, were almost totally absent in CRH-R1 CKO. The dose-dependent REMS suppression on the other hand persisted in all, even CRH-R1 CKO, animals. This suggests that the centrally expressed CRH receptor type 1 (CRH-R1) but not the CRH receptor type 2 (CRH-R2), mediates the crucial effects of CRH on wake induction and NREMS suppression. Since REMS inhibition by CRH still occurred in CRH-R1 CKO animals pretreated with a highly specific CRH-R2 antagonist, the clear role of central CRH and both receptors in REMS suppression remains elusive. Sleep deprivation induced significant increases in plasma corticosterone levels in all mouse lines, demonstrating HPA axis activation and suggesting that all mice perceived sleep loss as a stressor. After termination of sleep deprivation, all animals responded with a significant increase of slow wave activity (SWA), an indicator of sleep intensity, followed by a rebound of NREMS. With the exception of CRH-R1 CKO mice, all mice furthermore similarly displayed REMS rebound. Another difference in response to sleep deprivation constitutes the course of SWA in CRH-R1 CKO which was significantly increased over baseline levels for a longer period as compared to all other mouse lines. Accordingly CRH-R1 CKO animals presumably sleep more intensely or efficiently than mice of the other breeding lines. These results suggest that CRH mediates the effects, at least the stressful component, of sleep loss, and moreover that CRH-R1 is essentially involved in sleep homeostasis. This study is the first to show considerable evidence for a crucial involvement of central CRH and CRH-R1 in arousal and the suppression of NREMS. It could further be shown that activation of the HPA axis is not a prerequisite of these effects. Additionally, the action of central CRH, mediated by CRH-R1 seems to influence sleep quality. The role of CRH-R2 has to be regarded as of a minor nature. The impact of CRH on REMS regulation demands further investigation

Low grade glioma: An Update for Radiologists

With the recent publication of a new World Health Organization (WHO) brain tumour classification that reflects increased understanding of glioma tumour genetics there is a need for radiologists to understand the changes and their implications for patient management. There has also been an increasing trend for adopting earlier, more aggressive surgical approaches to low grade glioma treatment. We will summarise these changes, give some context to the increased role of tumour genetics and discuss the associated implications for radiologists of their adoption. We will discuss the earlier and more radical surgical resection of low grade gliomas and what it means for imaging patients

Rapid eye movements during sleep in mice: High trait-like stability qualifies rapid eye movement density for characterization of phenotypic variation in sleep patterns of rodents

<p>Abstract</p> <p>Background</p> <p>In humans, rapid eye movements (REM) density during REM sleep plays a prominent role in psychiatric diseases. Especially in depression, an increased REM density is a vulnerability marker for depression. In clinical practice and research measurement of REM density is highly standardized. In basic animal research, almost no tools are available to obtain and systematically evaluate eye movement data, although, this would create increased comparability between human and animal sleep studies.</p> <p>Methods</p> <p>We obtained standardized electroencephalographic (EEG), electromyographic (EMG) and electrooculographic (EOG) signals from freely behaving mice. EOG electrodes were bilaterally and chronically implanted with placement of the electrodes directly between the musculus rectus superior and musculus rectus lateralis. After recovery, EEG, EMG and EOG signals were obtained for four days. Subsequent to the implantation process, we developed and validated an Eye Movement scoring in Mice Algorithm (EMMA) to detect REM as singularities of the EOG signal, based on wavelet methodology.</p> <p>Results</p> <p>The distribution of wakefulness, non-REM (NREM) sleep and rapid eye movement (REM) sleep was typical of nocturnal rodents with small amounts of wakefulness and large amounts of NREM sleep during the light period and reversed proportions during the dark period. REM sleep was distributed correspondingly. REM density was significantly higher during REM sleep than NREM sleep. REM bursts were detected more often at the end of the dark period than the beginning of the light period. During REM sleep REM density showed an ultradian course, and during NREM sleep REM density peaked at the beginning of the dark period. Concerning individual eye movements, REM duration was longer and amplitude was lower during REM sleep than NREM sleep. The majority of single REM and REM bursts were associated with micro-arousals during NREM sleep, but not during REM sleep.</p> <p>Conclusions</p> <p>Sleep-stage specific distributions of REM in mice correspond to human REM density during sleep. REM density, now also assessable in animal models through our approach, is increased in humans after acute stress, during PTSD and in depression. This relationship can now be exploited to match animal models more closely to clinical situations, especially in animal models of depression.</p

Agrammatic but numerate

A central question in cognitive neuroscience concerns the extent to which language enables other higher cognitive functions. In the case of mathematics, the resources of the language faculty, both lexical and syntactic, have been claimed to be important for exact calculation, and some functional brain imaging studies have shown that calculation is associated with activation of a network of left-hemisphere language regions, such as the angular gyrus and the banks of the intraparietal sulcus. We investigate the integrity of mathematical calculations in three men with large left-hemisphere perisylvian lesions. Despite severe grammatical impairment and some difficulty in processing phonological and orthographic number words, all basic computational procedures were intact across patients. All three patients solved mathematical problems involving recursiveness and structure-dependent operations (for example, in generating solutions to bracket equations). To our knowledge, these results demonstrate for the first time the remarkable independence of mathematical calculations from language grammar in the mature cognitive system

Prevention of siderophore- mediated gut-derived sepsis due to P. aeruginosa can be achieved without iron provision by maintaining local phosphate abundance: role of pH

<p>Abstract</p> <p>Background</p> <p>During extreme physiological stress, the intestinal tract can be transformed into a harsh environment characterized by regio- spatial alterations in oxygen, pH, and phosphate concentration. When the human intestine is exposed to extreme medical interventions, the normal flora becomes replaced by pathogenic species whose virulence can be triggered by various physico-chemical cues leading to lethal sepsis. We previously demonstrated that phosphate depletion develops in the mouse intestine following surgical injury and triggers intestinal <it>P. aeruginosa </it>to express a lethal phenotype that can be prevented by oral phosphate ([Pi]) supplementation.</p> <p>Results</p> <p>In this study we examined the role of pH in the protective effect of [Pi] supplementation as it has been shown to be increased in the distal gut following surgical injury. Surgically injured mice drinking 25 mM [Pi] at pH 7.5 and intestinally inoculated with <it>P. aeruginosa </it>had increased mortality compared to mice drinking 25 mM [Pi] at pH 6.0 (p < 0.05). This finding was confirmed in <it>C. elegans</it>. Transcriptional analysis of <it>P. aeruginosa </it>demonstrated enhanced expression of various genes involved in media alkalization at pH 6.0 and a global increase in the expression of all iron-related genes at pH 7.5. Maintaining the pH at 6.0 via phosphate supplementation led to significant attenuation of iron-related genes as demonstrated by microarray and confirmed by QRT-PCR analyses.</p> <p>Conclusion</p> <p>Taken together, these data demonstrate that increase in pH in distal intestine of physiologically stressed host colonized by <it>P. aeruginosa </it>can lead to the expression of siderophore-related virulence in bacteria that can be prevented without providing iron by maintaining local phosphate abundance at pH 6.0. This finding is particularly important as provision of exogenous iron has been shown to have untoward effects when administered to critically ill and septic patients. Given that phosphate, pH, and iron are near universal cues that dictate the virulence status of a broad range of microorganisms relevant to serious gut origin infection and sepsis in critically ill patients, the maintenance of phosphate and pH at appropriate physiologic levels to prevent virulence activation in a site specific manner can be considered as a novel anti-infective therapy in at risk patients.</p

Reduction of low- and high-grade cervical abnormalities associated with high uptake of the HPV bivalent vaccine in Scotland

In Scotland, a national HPV immunisation programme began in 2008 for 12-13 year olds, with a catch-up campaign from 2008-2011 for those under the age of 18. To monitor the impact of HPV immunisation on cervical disease at the population level, a programme of national surveillance was established.  We analysed colposcopy data from a cohort of women born between 1988-1992 who entered the Scottish Cervical Screening Programme (SCSP) and were aged 20-21 in 2008-2012.  By linking datasets from the SCSP and colposcopy services, we observed a significant reduction in diagnoses of cervical intraepithelial neoplasia 1 (CIN 1) (RR 0.71, 95% CI 0.58 to 0.87, p=0.0008), CIN 2 (RR 0.5, 95% CI 0.4, 0.63, p<0.0001) and CIN 3 (RR 0.45, 95% CI 0.35 to 0.58, p< 0.0001) for women who received 3 doses of vaccine compared with unvaccinated women.  To our knowledge, this is one of the first studies to show a reduction of low and high grade cervical intraepithelial neoplasia associated with high uptake of the HPV bivalent vaccine at the population level. These data are very encouraging for countries that have achieved high HPV vaccine uptake

Teacher training for professional and technological education

As pesquisas e discussões em formação de professores assumem importância por se constituírem preocupação constante das políticas públicas, programas, planos de Governo e reformas educacionais. O reconhecimento de que a formação de professores se articula com o desenvolvimento profissional e favorece a melhoria da educação é proclamado por inúmeros pesquisadores, o que exige a permanente reflexão e divulgação das pesquisas realizadas. Esse dossiê ao eleger como tema “A formação de professores para a educação profissional e tecnológica” se soma ao movimento de debates, análises e ponderações e possibilidades da formação docente para essa modalidade educativa. A proposta desse Dossiê é gerada diante da expansão da oferta de Educação Profissional e Tecnológica - EPT, especialmente a partir da implantação dos Institutos Federais, que ampliaram a oferta de cursos desde a formação inicial até a pós- graduação. Com efeito, a preocupação com a formação dos professores para atuar em EPT é uma questão central no exame de sua configuração pedagógica.info:eu-repo/semantics/publishedVersio

MR-guided cholecystostomy: Assessment of biplanar, real-time needle tracking in three pigs

Purpose: To demonstrate the feasibility of magnetic resonance (MR)-guided cholecystostomy using active, real-time, biplanar MR tracking in animal experiments. Methods: Experiments were performed on three fully anesthetized pigs in an interventional MR system (GE open). The gallbladder was displayed in two orthogonal planes using a heavily T2-weighted fast spin-echo sequence. These "cholangio roadmaps” were displayed on LCD monitors positioned in front of the interventionalist. A special coaxial MR-tracking needle, equipped with a small receive-only coil at its tip, was inserted percutaneously into the gallbladder under continuous, biplanar MR guidance. The MR-tracking sequence allowed sampling of the coil (needle tip) position every 120 msec. The position of the coil was projected onto the two orthogonal "cholangio roadmap” images. Results: Successful insertion of the needle was confirmed by aspiration of bile from the gallbladder. The process of aspiration and subsequent instillation of Gd-DTPA into the gallbladder was documented with fast gradient-recalled echo imaging. Conclusion: Biplanar, active, real-time MR tracking in combination with "cholangio roadmaps” allows for cholecystostomies in an interventional MRI environmen