The neuronal circuits mediating the sedative action of diazepam are unknown. Although the motor-depressant action of diazepam
is suppressed in α1(H101R) homozygous knockin mice expressing ...diazepam-insensitive α1-GABA A receptors, global α1-knockout mice show greater motor sedation with diazepam. To clarify this paradox, attributed to compensatory
up-regulation of the α2 and α3 subunits, and to further identify the neuronal circuits supporting diazepam-induced sedation,
we generated Emx1-cre-recombinase-mediated conditional mutant mice, selectively lacking the α1 subunit (forebrain-specific
α1 -/- ) or expressing either a single wild-type (H) or a single point-mutated (R) α1 allele (forebrain-specific α1 -/H and α1 -/R mice, respectively) in forebrain glutamatergic neurons. In the rest of the brain, α1 -/R mutants are heterozygous α1(H101R) mice. Forebrain-specific α1 -/- mice showed enhanced diazepam-induced motor depression and increased expression of the α2 and α3 subunits in the neocortex
and hippocampus, in comparison with their pseudo-wild-type littermates. Forebrain-specific α1 -/R mice were less sensitive than α1 -/H mice to the motor-depressing action of diazepam, but each of these conditional mutants had a similar behavioral response
as their corresponding control littermates. Unexpectedly, expression of the α1 subunit was reduced in forebrain, notably in
α1 -/R mice, and the α3 subunit was up-regulated in neocortex, indicating that proper α1 subunit expression requires both alleles.
In conclusion, conditional manipulation of GABA A receptor α1 subunit expression can induce compensatory changes in the affected areas. Specifically, alterations in GABA A receptor expression restricted to forebrain glutamatergic neurons reproduce the behavioral effects seen after a global alteration,
thereby implicating these neurons in the motor-sedative effect of diazepam.
Induction of erythropoietin (Epo) expression under hypoxic conditions is mediated by the heterodimeric hypoxia-inducible factor (HIF)-1. Following binding to the 3′ hypoxia-response element (HRE) of ...the Epo gene, HIF-1 markedly enhances Epo transcription. To facilitate the search for HIF-1 (ant)agonists, a hypoxia-reporter cell line (termed HRCHO5) was constructed containing a stably integrated luciferase gene under the control of triplicated heterologous HREs. Among various agents tested, we identified a class of substances called epolones, which induced HRE-dependent reporter gene activity in HRCHO5 cells. Epolones are fungal products known to induce Epo expression in hepatoma cells. We found that epolones (optimal concentration 4-8 μmol/L) potently induce HIF-1α protein accumulation and nuclear translocation as well as HIF-1 DNA binding and reporter gene transactivation. Interestingly, the activity of a compound related to the fungal epolones, ciclopirox olamine (CPX), was blocked after addition of ferrous iron. This suggests that CPX might interfere with the putative heme oxygen sensor, as has been proposed for the iron chelator deferoxamine mesylate (DFX). However, about 10-fold higher concentrations of DFX (50-100 μmol/L) than CPX were required to maximally induce reporter gene activity in HRCHO5 cells. Moreover, structural, functional, and spectrophotometric data imply a chelator:iron stoichiometry of 1:1 for DFX but 3:1 for CPX. Because the iron concentration in the cell culture medium was determined to be 16 μmol/L, DFX but not CPX function can be explained by complete chelation of medium iron. These results suggest that the lipophilic epolones might induce HIF-1α by intracellular iron chelation.
Fetal skin wounds heal scarlessly while adult wounds scar. Fetal wound healing occurs in a physiologically hypoxic environment whereas in adult wound healing, cells have to acutely adapt to hypoxia ...caused by locally impaired blood supply. We examined the expression of hypoxia-inducible factor 1 (HIF-1), a potent transcriptional regulator of oxygen-dependent genes such as vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-beta), a potentially HIF-1-regulated scarring cytokine, on fetal and adult responses to wounding. Incisional skin wounds were created in four sheep fetuses (twins served as controls) and two ewes at 100 days of gestation (term = 150 days). Fetal and adult wounds as well as non-wounded control tissues were harvested 2 days post-wounding. Intraoperative arterial blood gas analyses and invasive subcutaneous pO2 measurements revealed that the fetuses were indeed hypoxic while the mothers were normoxic. Expression patterns of HIF-1alpha were investigated by Western blot analyses. HIF-1alpha expression in fetal wounds and fetal control skin was similar, whereas HIF-1alpha was only detected in adult wounds but not in adult control skin. Exposure of cultured fetal and adult dermal fibroblasts to hypoxia (1% O2) showed a marked induction of VEGF mRNA. In contrast, exposure of these cell types to hypoxia did not significantly affect TGF-beta1 mRNA expression in comparison to their normoxic controls. The presence of HIF-1alpha in fetal but not in adult normal skin indicates that HIF-1alpha might be involved in fetal skin development. Conversely, the upregulation of HIF-1alpha in adult but not early fetal wound repair might represent a pathway in the pathogenesis of scarring, since several growth factors overexpressed in, and associated, with scarring are hypoxia-inducible. Further studies need to be performed in order to identify hypoxia-regulated HIF-1alpha target genes involved in the pathogenesis of scarring.
PTEN is a tumour suppressor gene involved in cell cycle control, apoptosis and mediation of adhesion and migration signalling. Germline mutations of PTEN in humans are associated with familial tumour ...syndromes, among them Cowden disease. Glioblastomas, highly malignant glial tumours of the central nervous system frequently show loss of PTEN . Recent reports have outlined some aspects of PTEN function in central nervous system development. Using a conditional gene disruption approach, we inactivated Pten in mice early during embryogenesis locally in a region specific fashion and later during postnatal development in a cell-specific manner, to study the role of PTEN in differentiation, migration and neoplastic transformation. We show that PTEN is required for the realisation of normal cerebellar architecture, for regulation of cell and organ size, and for proper neuronal and glial migration. However, PTEN is not required for cell differentiation and lack of PTEN is not sufficient to induce neoplastic transformation of neuronal or glial cells
Drawing on ethnographic research, this article explores the multifaceted, situational and shifting social boundaries in the translocational positionalities of middle-class Swiss migrants in China. ...The analysis unpacks the central role of whiteness and Western ethnicity under the ‘Chinese gaze’, intersected by nationality. However, while they are marked by continuities of white privilege, the resulting racialised positionalities of the foreign white ‘others’ are characterised by a simultaneous elevation and subjugation, equally shaped by a ‘Chinese ascendancy’. European migrants’ self-positionings meander between this ambiguous ‘outsiderness’ and a propensity for integration as they navigate the multifaceted middle positions they occupy. Contextualising the findings in research on white migration movements from the West, the conclusion suggests that the class-based notion of middling migration should be refined by including economic, social and cultural ways of being ‘of the middle’.
OBJECTIVES:Data show that family members of ICU patients may have high levels of anxiety, depression, posttraumatic stress disorders, and/or complicated grief. This was previously referred to as ...post-intensive care syndrome-family. We systematically review randomized controlled trials for post-intensive care syndrome-family.
DATA SOURCES:Systematic research in databases (Pubmed, EMBASE, PsycINFO, CINHAL for articles published between January 2000 and October 2019).
STUDY SELECTION:Interventions in randomized controlled trials for post-intensive care syndrome-family in relatives of adult ICU patients.
DATA EXTRACTION:Review, quality assessment, and risk assessment for bias of eligible publications were performed along recommended guidelines for each investigation. Quality assessment graded studies into “strong” (n = 5), “moderate” (n = 4), and “weak” (n = 2).
DATA SYNTHESIS:Out of 2,399 publications, 11 investigations were found eligible (3,183 relatives of ICU patients). Studies addressed interventions during ICU stay (n = 6), during the post-ICU period (n = 4), or both (n = 1). Two studies included relatives of dying/deceased patients. One study implemented end-of-life conferences and showed reduced prevalence of posttraumatic stress disorder (45% vs 69%; p = 0.01), anxiety (45% vs 67%; p = 0.02), and depression (29% vs 56%; p = 0.003). Family conferences with a physician and proactive participation of a nurse reduced anxiety-scores (p = 0.01) without reducing anxiety prevalence (33.3% vs 52.3%; p = 0.08). Other studies failed to improve symptoms or reduce prevalence of post-intensive care syndrome-family. Interestingly, condolence letters may even increase prevalence of posttraumatic stress disorder (52.4% vs 37.1%; p = 0.03). Meetings without the presence of ICU physicians were shown to increase Impact of Event Scale-Revised scores (25.9 vs 21.3; p = 0.0495).
CONCLUSIONS:Only few data are available on interventions for post-intensive care syndrome-family. It appears that proactive communication and provision of information seems pivotal for post-intensive care syndrome-family treatment. Interestingly, some interventions may even worsen post-intensive care syndrome-family. In the light of the relevance of post-intensive care syndrome-family in daily ICU care, more high-quality data seems urgently needed.
BDDCS, ECCS and ECCCS are compound disposition classification concepts that aim to streamline, de-risk and speed-up drug development. Although all three systems have the same purpose and are based on ...classifying drugs into four main categories, they have different backgrounds and contrast in their criteria. Here the details, differences and most important applications of the three systems are reviewed with particular emphasis of their roles for drug discovery and development.
This paper applies the methods of historical climatology to present a climate reconstruction for the area of the Burgundian Low Countries during the 15th century. The results are based on documentary ...evidence that has been handled very carefully, especially with regard to the distinction between contemporary and non-contemporary sources. Approximately 3000 written records derived from about 100 different sources were examined and converted into seasonal seven-degree indices for temperature and precipitation. For the Late Middle Ages only a few climate reconstructions exist. There are even fewer reconstructions which include spring and autumn temperature or any precipitation information at all. This paper therefore constitutes a useful contribution to the understanding of climate and weather conditions in the less well researched but highly interesting 15th century. The extremely cold winter temperatures during the 1430s and an extremely cold winter in 1407/1408 are striking. Moreover, no other year in this century was as hot and dry as 1473. At the beginning and the end of the 1480s and at the beginning of the 1490s summers were considerably wetter than average.
This article investigates how white European (mostly Swiss) foreigners living in Beijing, Shanghai, and various cities in the Pearl River Delta have negotiated their social and legal positions during ...the early Covid-19 pandemic. Their transnational citizenship constellation spans two political systems that are commonly thought of as incommensurable and whose legitimacy is mutually contested by opponents of either model of governance. My research illustrates how this polarization was exacerbated during the Covid-19 pandemic. The research participants noted how the position of white, Western foreigners in China was shifting as they became exposed to suspicion of being potential carriers of the virus and to a related uptick in xenophobia. They felt that the Chinese authorities and media externalized and racialized the new corona virus to enhance the legitimacy of the authoritarian regime vis-à-vis the domestic population; but they also considered the Chinese response to the outbreak of Covid-19 at the time a success overall and praised people in China for their compliance with state measures. How these white European foreigners in China navigated the early Covid-19 era is thus mediated by the larger geopolitical polarization between China and "the West" inherent in their citizenship constellation, racialized social hierarchies among foreigners in China, and an ambiguity between the experience of being othered and their identification with the Chinese approach to containing Covid-19.
Abstract
Background
During the COVID-19 pandemic, suspension of visits by next of kin to patients in intensive care units (ICU), to prevent spread of the SARS-CoV-2 virus, has been a common practice. ...This could impede established family-centered care and may affect the mental health of the next of kin. The aim of this study was to explore symptoms of post-traumatic stress syndrome (PTSD) in the next of kin of ICU patients.
Methods
In this prospective observational single-center study, next of kin of ICU patients were interviewed by telephone, using the Impact of Event Scale-Revised (IES-R), to assess symptoms of acute stress disorder during the ICU stay and PTSD symptoms at 3 months after the ICU stay. The primary outcome was the prevalence of severe PTSD symptoms (IES-R score ≥ 33) at 3 months. The secondary outcomes comprised the IES-R scores during the ICU stay, at 3 months, and the prevalence of severe symptoms of acute stress disorder during ICU stay. An inductive content analysis was performed of the next of kin’s comments regarding satisfaction with patient care and the information they were given.
Results
Of the 411 ICU patients admitted during the study period, 62 patients were included together with their next of kin. An IES-R score
>
33 was observed in 90.3% (56/62) of next of kin during the ICU stay and in 69.4% (43/62) 3 months later. The median IES-R score was 49 (IQR 40–61) during the ICU stay and 41 (IQR 30–55) at 3 months. The inductive content analysis showed that communication/information (55%), support (40%), distressing emotions (32%), and suspension of ICU visits (24%) were mentioned as relevant aspects by the next of kin.
Conclusions
During the suspension of ICU visits in the COVID-19 pandemic, high prevalence and severity of both symptoms of acute stress disorder during the ICU stay and PTSD symptoms 3 months later were observed in the next of kin of ICU patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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