Cardiopulmonary haemodynamics in Tibetans and Han Chinese during rest and exercise.

During sea-level exercise, blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) in humans without a patent foramen ovale (PFO) is negatively correlated with pulmonary pressure. Yet, it is unknown whether the superior exercise capacity of Tibetans well adapted to living at high altitude is the result of lower pulmonary pressure during exercise in hypoxia, and whether their cardiopulmonary characteristics are significantly different from lowland natives of comparable ancestry (e.g. Han Chinese). We found a 47% PFO prevalence in male Tibetans (n = 19) and Han Chinese (n = 19) participants. In participants without a PFO (n = 10 each group), we measured heart structure and function at rest and peak oxygen uptake ( V ̇ O 2 peak ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ ), peak power output ( W ̇ p e a k ${{\dot{W}}_{peak}}$ ), pulmonary artery systolic pressure (PASP), blood flow through IPAVA and cardiac output ( Q ̇ T ${{\dot{Q}}_{\mathrm{T}}} $ ) at rest and during recumbent cycle ergometer exercise at 760 Torr (SL) and at 410 Torr (ALT) barometric pressure in a pressure chamber. Tibetans achieved a higher W peak ${W}_{\textit{peak}}$ than Han, and a higher V ̇ O 2 peak ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ at ALT without differences in heart rate, stroke volume or Q ̇ T ${{\dot{Q}}_{\mathrm{T}}} $ . Blood flow through IPAVA was generally similar between groups. Increases in PASP and total pulmonary resistance at ALT were comparable between the groups. There were no differences in the slopes of PASP plotted as a function of Q ̇ T ${{\dot{Q}}_{\mathrm{T}}} $ during exercise. In those without PFO, our data indicate that the superior aerobic exercise capacity of Tibetans over Han Chinese is independent of cardiopulmonary features and more probably linked to differences in local muscular oxygen extraction. KEY POINTS: Patent foramen ovale (PFO) prevalence was 47% in Tibetans and Han Chinese living at 2 275 m. Subjects with PFO were excluded from exercise studies. Compared to Han Chinese, Tibetans had a higher peak workload with acute compression to sea level barometric pressure (SL) and acute decompression to 5000 m altitude (ALT). Comprehensive cardiac structure and function at rest were not significantly different between Han Chinese and Tibetans. Tibetans and Han had similar blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) during exercise at SL. Peak pulmonary artery systolic pressure (PASP) and total pulmonary resistance were different between SL and ALT, with significantly increased PASP for Han compared to Tibetans at ALT. No differences were observed between groups at acute SL and ALT.

Exercise-Related Effects on Executive Functions During a Simulated Underwater Extravehicular Activity.

OBJECTIVE: Investigation of cognitive performance during extravehicular activities (EVAs) in a space-analog setting. BACKGROUND: EVAs performed by humans in microgravity on the International Space Station (ISS) call for high cognitive performance during upper-body workload. Higher cardiovascular demands interact with cognitive performance, but no knowledge exists about EVA's special requirements. This study simulates EVA-training underwater to investigate its effects on the executive functions inhibition and switching. METHOD: In a counterbalanced crossover design, 16 divers (age: 28 ± 2.4 years; eight females) performed two conditions (i.e., EVA vs. Inactivity [INACT]) in 3-5 m submersion (diving gear; not in a space-suit). EVA included 30 min of moderate-, followed by 30 min of high-intensity upper-body exercise intervals, paired with EVA-specific cognitive-motor tasks. INACT included no exercise in submersion and neutral buoyancy. Both conditions included cognitive testing at pre, mid (after the first 30 min), and post (after the second 30 min) on a tablet computer. Reaction times (RTs) and response accuracy (ACC) were calculated for both tasks. RESULTS: ACC was significantly lower during EVA compared with INACT for inhibition (post: p = .009) and switching (mid: p = .019) at post (p = .005). RTs for inhibition were significantly faster during EVA (p = .022; ηp2 = 0.320). CONCLUSION: Specific physical exercise, intensity, duration, and tasks performed during the EVA might differently affect the exercise-cognition interaction and need further investigation, especially for future long-term space travel. APPLICATION: Future research might serve to improve mission success and safety for EVAs and long-term space travel.

Oxygen-enriched Air Decreases Ventilation during High-intensity Fin-swimming Underwater.

Oxygen-enriched air is commonly used in the sport of SCUBA-diving and might affect ventilation and heart rate, but little work exists for applied diving settings. We hypothesized that ventilation is decreased especially during strenuous underwater fin-swimming when using oxygen-enriched air as breathing gas. Ten physically-fit divers (age: 25±4; 5 females; 67±113 open-water dives) performed incremental underwater fin-swimming until exhaustion at 4 m water depth with either normal air or oxygen-enriched air (40% O2) in a double-blind, randomized within-subject design. Heart rate and ventilation were measured throughout the dive and maximum whole blood lactate samples were determined post-exercise. ANOVAs showed a significant effect for the factor breathing gas (F(1, 9)=7.52; P=0.023; η2 p=0.455), with a lower ventilation for oxygen-enriched air during fin-swimming velocities of 0.6 m·s-1 (P=0.032) and 0.8 m·s-1 (P=0.037). Heart rate, lactate, and time to exhaustion showed no significant differences. These findings indicate decreased ventilation by an elevated oxygen fraction in the breathing gas when fin-swimming in shallow-water submersion with high velocity (>0.5 m·s-1). Applications are within involuntary underwater exercise or rescue scenarios for all dives with limited gas supply.

Physical Exercise Intensity During Submersion Selectively Affects Executive Functions.

OBJECTIVE: The intact cognitive processing capacity in highly demanding and dynamically changing situations (e.g., in extreme environmental conditions) is of central relevance for personal safety. This study therefore investigated whether underwater physical exercise (PE) affected cognitive performance by comparing these effects during underwater fin-swimming as opposed to inactivity under normal environmental conditions. BACKGROUND: Although acute bouts of PE can modulate cognitive performance under highly controlled and standardized laboratory conditions, no previous study has determined whether PE acutely modulates cognitive performance in non-laboratory testing conditions involving extreme environments (e.g., underwater). METHOD: A total of 27 healthy volunteers (16 males and 11 females; 28.9 ± 7.4 years of age) participated in two experiments involving either moderate or high PE intensity. A PRE/POST crossover design was employed among participants while performing cognitive tests in a counterbalanced order (i.e., before and after 20 min of PE in submersion [WET] and once before and after inactivity [DRY] while in the laboratory). Cognitive performance was measured as a combination of executive functions through the Eriksen Flanker (inhibition) and Two-Back (working memory) Tasks using an underwater tablet computer. RESULTS: ANOVAs revealed enhanced reaction times only in the Flanker test after moderate PE for the WET condition. No other effects were detected. CONCLUSION: These findings indicate that cognitive performance is exercise-intensity-dependent with enhanced effects during moderate PE, even in extreme environments (i.e., underwater). APPLICATION: These results should be relevant in recreational and occupational contexts involving underwater activity and may also apply to microgravity (e.g., during extra-vehicular activities). DESCRIPTION: This study compared the acute effects of physical exercise (PE) on cognitive performance in an underwater environment while participants fin-swam with SCUBA (self-contained underwater breathing apparatus) gear. Findings revealed that 20 min of moderate PE positively affected cognitive performance (i.e., inhibitory control ability). However, no changes were observed after high-intensity exercise.

Translational read-through as an alternative approach for ocular gene therapy of retinal dystrophies caused by in-frame nonsense mutations.

The eye has become an excellent target for gene therapy, and gene augmentation therapy of inherited retinal disorders has made major progress in recent years. Nevertheless, a recent study indicated that gene augmentation intervention might not stop the progression of retinal degeneration in patients. In addition, for many genes, viral-mediated gene augmentation is currently not feasible due to gene size and limited packaging capacity of viral vectors as well as expression of various heterogeneous isoforms of the target gene. Thus, alternative gene-based strategies to stop or delay the retinal degeneration are necessary. This review focuses on an alternative pharmacologic treatment strategy based on the usage of translational read-through inducing drugs (TRIDs) such as PTC124, aminoglycoside antibiotics, and designer aminoglycosides for overreading in-frame nonsense mutations. This strategy has emerged as an option for up to 30-50% of all cases of recessive hereditary retinal dystrophies. In-frame nonsense mutations are single-nucleotide alterations within the gene coding sequence resulting in a premature stop codon. Consequently, translation of such mutated genes leads to the synthesis of truncated proteins, which are unable to fulfill their physiologic functions. In this context, application of TRIDs facilitates the recoding of the premature termination codon into a sense codon, thus restoring syntheses of full-length proteins. So far, clinical trials for non-ocular diseases have been initiated for diverse TRIDs. Although the clinical outcome is not analyzed in detail, an excellent safety profile, namely for PTC124, was clearly demonstrated. Moreover, recent data demonstrated sustained read-through efficacies of nonsense mutations causing retinal degeneration, as manifested in the human Usher syndrome. In addition, a strong retinal biocompatibility for PTC124 and designer aminoglycosides has been demonstrated. In conclusion, recent progress emphasizes the potential of TRIDs as an alternative pharmacologic treatment strategy for treating nonsense mutation-based retinal disorders.

The neurological syndrome in adults during the 2011 northern German E. coli serotype O104:H4 outbreak.

The aim of this study was to describe the neurological syndrome in the largest cohort of adult patients with a complicated Shiga toxin-producing Escherichia coli infection. The recent outbreak of Shiga toxin-producing E. coli serotype O104:H4 in northern Germany affected more than 3842 patients, 22% of whom developed haemolytic uraemic syndrome. The proportion of adult patients was unusually high, and neurological complications were frequent and severe. In three hospitals, population-based evaluation of 217 patients with complicated Shiga toxin-producing E. coli infection was carried out, including neurological, neuroradiological, neurophysiological, cerebrospinal fluid and neuropathological analyses. Of the 217 patients with complicated Shiga toxin-producing E. coli infection, 104 (48%) developed neurological symptoms. Neurological symptoms occurred 5.3 days (mean) after first diarrhoea and 4 days after onset of haemolytic uraemic syndrome. Of the infected patients with neurological symptoms, 67.3% presented with cognitive impairment or aphasia. During the course of the disease, 20% of the patients developed epileptic seizures. The onset of neurological symptoms was paralleled by increases in blood urea nitrogen and serum creatinine. In 70 patients with cerebral magnetic resonance imaging, the most common findings were symmetrical hyperintensities in the region of abducens nucleus and lateral thalamus. On follow-up scans, these abnormalities were resolved. Neuropathological analysis revealed regionally accentuated astrogliosis and microgliosis, more predominant in the thalamus and brainstem than in the cortex, and neuronal expression of globotriaosylceramide. There were no signs of microbleeds, thrombotic vessel occlusion or ischaemic infarction. The neurological syndrome in adult patients with complicated Shiga toxin-producing E. coli infection is a rapidly progressive and potentially life-threatening disease necessitating intensive care unit treatment and intubation in >30% of cases. The outcome of neurological patients in the 2011 northern German Shiga toxin-producing E. coli O104:H4 outbreak was surprisingly good. Magnetic resonance imaging and neuropathological findings point to a mixed toxic and inflammatory pathomechanism leading to largely reversible damage of neuronal function.

Physiological and cognitive responses to hyperoxic exercise in full water submersion.

The positive effects of combined hyperoxia and physical exercise on physiological parameters and cognitive functioning are established for normobaric laboratory contexts. Still, increased practicability exists in hyperbaric settings like underwater activities and SCUBA diving, where environmental and sport-specific factors might moderate effects. Improved cognition, reduced ventilation (V̇E), and lower blood lactate concentrations [Lac-] are highly relevant, especially during high-stress and rescue scenarios. Fifteen participants performed 3 × 8 min of continuous underwater fin-swimming at 25 % (low), 45 % (moderate), and 75 % (vigorous) heart rate reserve (HRR) in each test. Three separate test days differed solely by the inspiratory oxygen partial pressure (PIO2: 29 kPa, 56 kPa, and 140 kPa). V̇E was measured continuously, whereas breathing gas analysis, blood sampling, and Eriksen Flanker tasks for inhibitory control (100 stimuli) were performed post-exercise. Two-way ANOVAs with repeated measures on the factors PIO2 and exercise intensity analyzed physiological outcome variables and reactions times (RT) and accuracy (ACC) of inhibitory control. V̇E was significantly reduced for 140 kPa during moderate and vigorous and for 56 kPa during vigorous compared to 29 kPa. 56 kPa and 140 kPa showed no differences. [Lac-], post-exercise V̇CO2, and velocity were unaffected by PIO2. Faster RTs but lower ACC of inhibitory control were observed following exercise at 75 % HRR compared to rest, 25 %, and 45 % HRR, while PIO2 produced no effects. Underwater performance in hyperoxia presents reduced V̇E, possible by dampened chemoreceptor sensitivity, and effects on cognition that differ from laboratory results and emphasise the moderating role of sport-specific factors.

Hyperoxia-induced reductions in V̇_E with 56 and 140 kPa P_IO₂ during constant submaximal fin-swimming intensity compared to air might be prominently caused by peripheral chemoreceptor suppression.No difference between 56 and 140 kPa was detected, indicating a P_IO₂ threshold limiting further hyperoxic influence on V̇_E. O₂ supply might sufficiently cover metabolic demands of submaximal exercise with 56 kPa, while further reductions in V̇_E could be observed only by severely higher P_IO₂.Cognitive performance by inhibitory control was unaffected by P_IO₂. Faster RTs but lower ACC were observed following vigorous exercise (75 % HRR) compared to rest, low, and moderate exercise.

Targeting Nonsense Mutations in Diseases with Translational Read-Through-Inducing Drugs (TRIDs).

In recent years, remarkable advances in the ability to diagnose genetic disorders have been made. The identification of disease-causing genes allows the development of gene-specific therapies with the ultimate goal to develop personalized medicines for each patient according to their own specific genetic defect. In-depth genotyping of many different genes has revealed that ~12% of inherited genetic disorders are caused by in-frame nonsense mutations. Nonsense (non-coding) mutations are caused by point mutations, which generate premature termination codons (PTCs) that cause premature translational termination of the mRNA, and subsequently inhibit normal full-length protein expression. Recently, a gene-based therapeutic approach for genetic diseases caused by nonsense mutations has emerged, namely the so-called translational read-through (TR) therapy. Read-through therapy is based on the discovery that small molecules, known as TR-inducing drugs (TRIDs), allow the translation machinery to suppress a nonsense codon, elongate the nascent peptide chain, and consequently result in the synthesis of full-length protein. Several TRIDs are currently under investigation and research has been performed on several genetic disorders caused by nonsense mutations over the years. These findings have raised hope for the usage of TR therapy as a gene-based pharmacogenetic therapy for nonsense mutations in various genes responsible for a variety of genetic diseases.

A comparative evaluation of NB30, NB54 and PTC124 in translational read-through efficacy for treatment of an USH1C nonsense mutation.

Translational read-through-inducing drugs (TRIDs) promote read-through of nonsense mutations, placing them in the spotlight of current gene-based therapeutic research. Here, we compare for the first time the relative efficacies of new-generation aminoglycosides NB30, NB54 and the chemical compound PTC124 on retinal toxicity and read-through efficacy of a nonsense mutation in the USH1C gene, which encodes the scaffold protein harmonin. This mutation causes the human Usher syndrome, the most common form of inherited deaf-blindness. We quantify read-through efficacy of the TRIDs in cell culture and show the restoration of harmonin function. We do not observe significant differences in the read-through efficacy of the TRIDs in retinal cultures; however, we show an excellent biocompatibility in retinal cultures with read-through versus toxicity evidently superior for NB54 and PTC124. In addition, in vivo administration of NB54 and PTC124 induced recovery of the full-length harmonin a1 with the same efficacy. The high biocompatibilities combined with the sustained read-through efficacies of these drugs emphasize the potential of NB54 and PTC124 in treating nonsense mutation-based retinal disorders.