Raoziegler1193
The mean contribution of identified mitochondrial sites to this extracellular hydrogen peroxide signal was 30 ± 7% SD; the mean contribution of NADPH oxidases was 60 ± 14%. The relative contributions of different sites in the mitochondrial electron transport chain were broadly similar in all seven cell types (and similar to published results for C2C12 cells). 70 ± 4% of identified superoxide/hydrogen peroxide generation in the mitochondrial matrix was from site IQ; 30 ± 4% was from site IIIQo. We conclude that although absolute rates vary considerably, the relative contributions of different sources of hydrogen peroxide production are similar in nine diverse cell types under unstressed conditions in vitro. Identified mitochondrial sites account for one third of total cellular hydrogen peroxide production (half each from sites IQ and IIIQo); in the mitochondrial matrix the majority (two thirds) of superoxide/hydrogen peroxide is from site IQ.S-glutathionylation of reactive protein cysteines is a post-translational event that plays a critical role in transducing signals from oxidants into biological responses. S-glutathionylation can be reversed by the deglutathionylating enzyme glutaredoxin (GLRX). We have previously demonstrated that ablation of Glrx sensitizes mice to the development of parenchymal lung fibrosis(1). It remains unclear whether GLRX also controls airway fibrosis, a clinical feature relevant to asthma and chronic obstructive pulmonary disease, and whether GLRX controls the biology of airway epithelial cells, which have been implicated in the pathophysiology of these diseases. In the present study we utilized a house dust mite (HDM) model of allergic airway disease in wild type (WT) and Glrx-/- mice on a C57BL/6 background prone to develop airway fibrosis, and tracheal basal stem cells derived from WT mice, global Glrx-/- mice, or bi-transgenic mice allowing conditional ablation of the Glrx gene. Herein we show that absence of Glrx led to enhanced HDM-induced collagen deposition, elevated levels of transforming growth factor beta 1 (TGFB1) in the bronchoalveolar lavage, and resulted in increases in airway hyperresponsiveness. Airway epithelial cells isolated from Glrx-/- mice or following conditional ablation of Glrx showed spontaneous increases in secretion of TGFB1. Glrx-/- basal cells also showed spontaneous TGFB pathway activation, in association with increased expression of mesenchymal genes, including collagen 1a1 and fibronectin. Overall, these findings suggest that GLRX regulates airway fibrosis via a mechanism(s) that involve the plasticity of basal cells, the stem cells of the airways.Human MIA40, an intermembrane space (IMS) import receptor of mitochondria harbors twin CX9C motifs for stability while its CPC motif is known to facilitate the import of IMS bound proteins. Site-directed mutagenesis complemented by MALDI on in vivo hMIA40 protein shows that a portion of MIA40 undergoes reversible S-glutathionylation at three cysteines in the twin CX9C motifs and the lone cysteine 4 residue. We find that HEK293T cells expressing hMIA40 mutant defective for glutathionylation are compromised in the activities of complexes III and IV of the Electron Transport Chain (ETC) and enhance Reactive Oxygen Species (ROS) levels. Immunocapture studies show MIA40 interacting with complex III. Interestingly, glutathionylated MIA40 can transfer electrons to cytochrome C directly. RMC-7977 inhibitor However, Fe-S clusters associated with the CPC motif are essential to facilitate the two-electron to one-electron transfer for reducing cytochrome C. These results suggest that hMIA40 undergoes glutathionylation to maintain ROS levels and for optimum function of complexes III and IV of ETC. Our studies shed light on a novel post-translational modification of hMIA40 and its ability to act as a redox switch to regulate the ETC and cellular redox homeostasis.
There are chronic forms of hypersensitivity pneumonitis (cHP) that can progress to pulmonary fibrosis. There is no recommended treatment for patients whose respiratory condition continues to deteriorate in spite of antigen avoidance. Whether rituximab may be beneficial to patients with cHP is unknown. The aim of this study was to describe the course of 20 patients with cHP under rituximab therapy.
This retrospective study was conducted from November 2018 to July 2019 in 7 French university hospitals. Forced Vital Capacity (FVC) was measured 6 months before rituximab therapy onset (M-6), at rituximab onset (M0), and 6 months later (M+6).
FVC decreased significantly in the 6 months preceding the introduction of rituximab (65% [44; 112%] at M-6 versus 59% [39; 102%] at M0; p=0.0001), but it did not differ significantly from that at 6 months after the introduction of rituximab (61% [38; 99%]). The decline in FVC between M0 and M+6 (-3% [-15; +19%]) was significantly less than between M-6 and M0 (-8% [-21; 0%]) (p=0.0002). Between M0 (37% [16; 73%]) and M+6 (45% [15; 70%]), the median DLCO remained stable (p=0.12). DLCO improved at M+6 in 5 of the 8 patients (63%) for whom a DLCO value was available at M+6 improved their DLCO.
Rituximab seems well tolerated, and may lead to stabilization or improvement of lung function in some patients.
Rituximab seems well tolerated, and may lead to stabilization or improvement of lung function in some patients.The aim of this study was to determine whether the driving-related cognitive performance differs among adults with schizophrenia taking different types of antipsychotics. Neurocognitive performance was assessed using the Cognitive Perceptual Assessment for Driving (CPAD), a computerized battery of tests of visual perception, attention, working memory, reaction time, and inhibitory control for driving ability. One hundred and two adults with schizophrenia who were on antipsychotic monotherapy participated in the study. Of these, 15 were on haloperidol, 28 on risperidone, 14 on olanzapine, 28 on aripiprazole, and 17 on paliperidone. Sixty-four (63%) of the 102 subjects were regarded as competent to drive. Of the subjects taking haloperidol, 33% passed the CPAD, while the passing rates of subjects taking risperidone, olanzapine, aripiprazole, and paliperidone were 57%, 57%, 75%, and 82%, respectively, with a significant difference between the haloperidol and aripiprazole groups (p = 0.005) and between the haloperidol and paliperidone groups (p = 0.001). Additionally, scores on CPAD depth perception (number of correct responses), divided attention, digit span test, and trail-making test B subtests were significantly better for the aripiprazole and paliperidone groups than for the haloperidol and risperidone groups. In this cross-sectional design study, adults with schizophrenia treated with aripiprazole or paliperidone antipsychotic monotherapy demonstrated superior driving-related cognitive performance than those treated with haloperidol or risperidone antipsychotic monotherapy.
Behavioral observations support clinical in-depth phenotyping but phenotyping and pattern recognition are affected by training background. As Attention Deficit Hyperactivity Disorder, Restless Legs syndrome/Willis Ekbom disease and medication induced activation syndromes (including increased irritability and/or akathisia), present with hyperactive-behaviors with hyper-arousability and/or hypermotor-restlessness (H-behaviors), we first developed a non-interpretative, neutral pictogram-guided phenotyping language (PG-PL) for describing body-segment movements during sitting.
The PG-PL was applied for annotating 12 1-min sitting-videos (inter-observer agreements >85%->97%) and these manual annotations were used as a ground truth to develop an automated algorithm using OpenPose, which locates skeletal landmarks in 2D video. We evaluated the algorithm's performance against the ground truth by computing the area under the receiver operator curve (>0.79 for the legs, arms, and feet, but 0.65 for the head). While our pixel displacement algorithm performed well for the legs, arms, and feet, it predicted head motion less well, indicating the need for further investigations.
This first automated analysis algorithm allows to start the discussion about distinct phenotypical characteristics of H-behaviors during structured behavioral observations and may support differential diagnostic considerations via in-depth phenotyping of sitting behaviors and, in consequence, of better treatment concepts.
This first automated analysis algorithm allows to start the discussion about distinct phenotypical characteristics of H-behaviors during structured behavioral observations and may support differential diagnostic considerations via in-depth phenotyping of sitting behaviors and, in consequence, of better treatment concepts.
In the 2000s, the Baltic countries experienced unprecedented economic growth followed by a deep recession. This study aimed to examine changes and educational inequalities in suicide mortality among working-age men in the Baltic countries and Finland in relation to macroeconomic fluctuations.
We analysed changes in overall suicide mortality and by educational level between the 2000-2003, 2004-2007, 2008-2011 and 2012-2015 periods among men aged 30-64 years using census-linked longitudinal mortality data. We estimated age-standardised mortality rates, mortality rate ratios (Poisson regression), the relative index of inequality and slope index of inequality.
Overall suicide mortality fell markedly from 2000-2003 to 2004-2007. The decline was largest among high educated men in the Baltic countries and among middle and low educated men in Finland. From 2004-2007 to 2008-2011, the positive trend slowed and while suicide mortality continued to fall among middle and low educated men, it increased somewhat among high educated men in all Baltic countries. In Finland, suicide mortality decreased among the high educated and increased slightly among low educated men.
In the Baltic countries, lower educated men had a smaller decline in suicide mortality than higher educated men during a period of rapid economic expansion, however, they were not more disadvantaged during the recession, possibly because of being less exposed to financial loss. Consequently, relative inequalities in suicide mortality may increase during economic booms and decrease during recessions.
In the Baltic countries, lower educated men had a smaller decline in suicide mortality than higher educated men during a period of rapid economic expansion, however, they were not more disadvantaged during the recession, possibly because of being less exposed to financial loss. Consequently, relative inequalities in suicide mortality may increase during economic booms and decrease during recessions.
Health care workers, especially frontline nurses, faced great challenges during the coronavirus disease 2019 (COVID-19) outbreak.
To assess the magnitude of the psychological status and associated risk factors among nurses in the pandemic center in Wuhan, China.
In this study, we enrolled nurses from Renmin Hospital of Wuhan University. The questionnaire was designed to obtain basic information of the participants, and included four psychological assessment scales. We issued the questionnaires at two different points of time. We conducted the first survey on January 29 to February 2 (outbreak period) with 709 eligible responses, and the second survey on February 26 to February 28 (stable period) with 621 eligible responses. The nurses from Wuchang Fangcang shelter hospital were also enrolled in the second survey.
During the pandemic, over one-third of nurses suffered from depression, anxiety, and insomnia. In the outbreak period, the nurses showed significantly higher risks for depression, anxiety, and posttraumatic stress disorder (PTSD) symptoms than those in the stable period (P<0.
