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Hypoxia is increasingly recognized as an important physiological driving force. A specific transcriptional program, induced by a decrease in oxygen (O2) availability, for example, inspiratory hypoxia at high altitude, allows cells to adapt to lower O2 and limited energy metabolism. This transcriptional program is partly controlled by and partly independent of hypoxia‐inducible factors. Remarkably, this same transcriptional program is stimulated in the brain by extensive motor‐cognitive exercise, leading to a relative decrease in O2 supply, compared to the acutely augmented O2 requirement. We have coined the term “functional hypoxia” for this important demand‐responsive, relative reduction in O2 availability. Functional hypoxia seems to be critical for enduring adaptation to higher physiological challenge that includes substantial “brain hardware upgrade,” underlying advanced performance. Hypoxia‐induced erythropoietin expression in the brain likely plays a decisive role in these processes, which can be imitated by recombinant human erythropoietin treatment. This article review presents hints of how inspiratory O2 manipulations can potentially contribute to enhanced brain function. It thereby provides the ground for exploiting moderate inspiratory plus functional hypoxia to treat individuals with brain disease. Finally, it sketches a planned multistep pilot study in healthy volunteers and first patients, about to start, aiming at improved performance upon motor‐cognitive training under inspiratory hypoxia. This article review presents hints of how inspiratory O2 manipulations can potentially contribute to enhanced brain function. It thereby provides the ground for exploiting moderate inspiratory plus functional hypoxia to treat individuals with brain disease. Finally, it sketches a planned multistep pilot study in healthy volunteers and first patients, about to start, aiming at improved performance upon motor‐cognitive training under inspiratory hypoxia. Highlights This review focuses on the brain and sketches hypoxia as a physiological driving force, inducing specific transcriptional programs. Moderate inspiratory hypoxia may improve brain function and performance. Our concept of “functional hypoxia” is introduced as a demand‐responsive mediator of “brain hardware upgrade” on extensive motor‐cognitive exercise. Hypoxia‐induced erythropoietin (EPO) expression in the brain plays a decisive role in these processes, constituting what we coined the “brain EPO circle.” The brain EPO circle underlies the adaptation to challenge, that is, enhanced brain function including cognition and accomplishment on demand: “Brain doping.” Recombinant human EPO imitates the effects of brain‐expressed EPO, explaining the strong neuroprotective and procognitive impact of this treatment. A pilot study in healthy volunteers and first patients is outlined, exploiting moderate inspiratory plus functional hypoxia in humans for improving cognition.

Hypoxia is more and more perceived as pivotal physiological driving force, allowing cells in the brain and elsewhere to acclimate to lowered oxygen (O2), and abridged metabolism. The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor‐cognitive tasks, provoking a relative decrease in O2 in relation to the acutely augmented requirement. We termed this fundamental, demand‐dependent drop in O2 availability “functional hypoxia.” Major players in the hypoxia response are hypoxia‐inducible factors (HIFs) and associated prolyl‐hydroxylases. HIFs are transcription factors, stabilized by low O2 accessibility, and control expression of a multitude of genes. Changes in oxygen, however, can also be sensed via other pathways, among them the thiol‐oxidase (2‐aminoethanethiol) dioxygenase. Considering the far‐reaching biological response to hypoxia, hitherto mostly observed in rodents, we initiated a translational project, combining mild to moderate inspiratory with functional hypoxia. We had identified this combination earlier to benefit motor‐cognitive attainment in mice. A total of 20 subjects were included: 13 healthy individuals and 7 patients with depression and/or autism spectrum disorder. Here, we show that motor‐cognitive training under inspiratory hypoxia (12% O2) for 3.5 h daily over 3 weeks is optimally tolerated. We present first signals of beneficial effects on general well‐being, cognitive performance, physical fitness and psychopathology. Erythropoietin in serum increases under hypoxia and flow cytometry analysis of blood reveals several immune cell types to be mildly modulated by hypoxia. To obtain reliable information regarding the “add‐on” value of inspiratory on top of functional hypoxia, induced by motor‐cognitive training, a single‐blind study—with versus without inspiratory hypoxia—is essential and outlined here. Highlights Motor‐cognitive training under inspiratory hypoxia (12% O2) for 3.5 h daily over 3 weeks is very well tolerated by healthy individuals as well as by patients with depression and/or autism spectrum disorder. We find first promising signals of beneficial effects on general well‐being, cognitive performance, physical fitness, and psychopathology. Our protocol of motor‐cognitive training under inspiratory hypoxia does not adversely affect the mononuclear cell composition in the blood of adults. To obtain reliable information regarding the “add‐on” value of mild to moderate inspiratory on top of functional hypoxia, induced by motor‐cognitive training, the planned single‐blind study—with versus without inspiratory hypoxia—is required.

Staphylococcus aureus is an important pathogen in cystic fibrosis (CF). However, it is not clear which factors are associated with worse lung function in patients with persistent S. aureus airway cultures. Our main hypothesis was that patients with high S. aureus density in their respiratory specimens would more likely experience worsening of their lung disease than patients with low bacterial loads. Therefore, we conducted an observational prospective longitudinal multi-center study and assessed the association between lung function and S. aureus bacterial density in respiratory samples, co-infection with other CF-pathogens, nasal S. aureus carriage, clinical status, antibiotic therapy, IL-6- and IgG-levels against S. aureus virulence factors. 195 patients from 17 centers were followed; each patient had an average of 7 visits. Data were analyzed using descriptive statistics and generalized linear mixed models. Our main hypothesis was only supported for patients providing throat specimens indicating that patients with higher density experienced a steeper lung function decline (p<0.001). Patients with exacerbations (n = 60), S. aureus small-colony variants (SCVs, n = 84) and co-infection with Stenotrophomonas maltophilia (n = 44) had worse lung function (p = 0.0068; p = 0.0011; p = 0.0103). Patients with SCVs were older (p = 0.0066) and more often treated with trimethoprim/sulfamethoxazole (p = 0.0078). IL-6 levels positively correlated with decreased lung function (p<0.001), S. aureus density in sputa (p = 0.0016), SCVs (p = 0.0209), exacerbations (p = 0.0041) and co-infections with S. maltophilia (p = 0.0195) or A. fumigatus (p = 0.0496). In CF-patients with chronic S. aureus cultures, independent risk factors for worse lung function are high bacterial density in throat cultures, exacerbations, elevated IL-6 levels, presence of S. aureus SCVs and co-infection with S. maltophilia. ClinicalTrials.gov NCT00669760.

Abstract Rationale Glutathione is the major antioxidant in the extracellular lining fluid of the lungs and depleted in patients with cystic fibrosis (CF). Objectives We aimed to assess glutathione delivered by inhalation as a potential treatment for CF lung disease. Methods This randomized, double-blind, placebo-controlled trial evaluated inhaled glutathione in subjects with CF 8 years of age and older and FEV1 of 40–90% of predicted. Subjects were randomized to receive 646 mg glutathione in 4 ml (n = 73) or placebo (n = 80) via an investigational eFlow nebulizer every 12 hours for 6 months. Measurements and Main Results FEV1 (absolute values), both as pre–post differences (P = 0.180) and as area under the curves (P = 0.205), were the primary efficacy endpoints, and were not different between the glutathione group and the placebo group over the 6-month treatment period. Exploratory analysis showed an increase of FEV1 from baseline over placebo of 100 ml or 2.2% predicted; this was significant at 3 months, but not later. Subjects receiving glutathione had neither fewer pulmonary exacerbations, nor better scores for quality of life. Whereas increased glutathione and metabolites in sputum demonstrated significant delivery to the lungs, there was no indication of diminished oxidative stress to proteins or lipids, and no evidence for anti-inflammatory or antiproteolytic actions of glutathione supplemented to the airways. The adverse event incidence was similar between glutathione and placebo. Conclusions Inhaled glutathione in the dose administered did not demonstrate clinically relevant improvements in lung function, pulmonary exacerbation frequency, or patient-reported outcomes. Glutathione delivery to the airways was not associated with changes in markers of oxidation, proteolysis, or inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT00506688) and https://eudract.ema.europa.eu/index.html (EudraCT 2005-003870-88).

Zymogen granule glycoprotein 2 (GP2) was demonstrated as first autoimmune mucosal target in primary sclerosing cholangitis (PSC) associated with disease severity. Autoantibodies to four GP2 isoforms (aGP2 ) were found in patients with inflammatory bowel diseases but reactivity against specific GP2 epitopes has not been investigated in PSC yet. Hence, the prevalence of aGP2 and their association with the PSC phenotype for risk prediction were examined. GP2 isoforms were stably expressed as glycosylphosphatidyl - inositol-anchored molecules in the membrane of HEp-2 cells and used as autoantigenic targets in indirect immunofluorescence assay (IFA). aGP2 IgA and IgG were detected by IFA in 212 PSC patients of four European university hospitals and 145 controls comprising 95 patients with cystic fibrosis and 50 healthy subjects. Combined aGP2 and aGP2 IgA testing with a sensitivity of 66.0% and a specificity of 97.9% resulted in the best diagnostic performance (Youden index: 0.64) regarding all aGP2 and combinations thereof. aGP2 IgA positivity is significantly associated with the presence of cirrhosis in PSC ( = 0.0056). Logistic regression revealed the occurrence of aGP2 IgA (odds ratio [OR] 1.38, 95% confidence interval [CI]: 1.03-1.86) and aGP2 IgA (OR 1.52, 95%CI: 1.07-2.15) along with male gender (OR 0.51, 95%CI: 0.27-0.97) and older age (OR 1.03 95%CI: 1.01-1.05) as significant risks for the concomitant presence of cirrhosis in PSC. Combined aGP2 and aGP2 IgA analysis is preferred to single aGP2 isoform analysis for sensitive PSC autoantibody testing. Positivity for aGP2 and aGP2 IgA is associated with cirrhosis in PSC and could be used for risk stratification.