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In order to study the adaptation scope of the fish respiratory organ and the O2 metabolism due to endurance training, we subjected adult zebrafish (Danio rerio) to endurance exercise for 5 weeks. After the training period, the swimmer group showed a significant increase in swimming performance, body weight and length. In scanning electron microscopy of the gills, the average length of centrally located primary filaments appeared significantly longer in the swimmer than in the non-trained control group (+6.1%, 1639 μm vs. 1545 μm, p = 0.00043) and the average number of secondary filaments increased significantly (+7.7%, 49.27 vs. 45.73, p = 9e-09). Micro-computed tomography indicated a significant increase in the gill volume (p = 0.048) by 11.8% from 0.490 mm3 to 0.549 mm3. The space-filling complexity dropped significantly (p = 0.0088) by 8.2% from 38.8% to 35.9%., i.e. making the gills of the swimmers less compact. Respirometry after 5 weeks showed a significantly higher oxygen consumption (+30.4%, p = 0.0081) of trained fish during exercise compared to controls. Scanning electron microscopy revealed different stages of new secondary filament budding, which happened at the tip of the primary lamellae. Using BrdU we could confirm that the growth of the secondary filaments took place mainly in the distal half and the tip and for primary filaments mainly at the tip. We conclude that the zebrafish respiratory organ-unlike the mammalian lung-has a high plasticity, and after endurance training increases its volume and changes its structure in order to facilitate O2 uptake.

Aquatic ecosystems play an important role in global methane cycling and many field studies have reported methane supersaturation in the oxic surface mixed layer (SML) of the ocean and in the epilimnion of lakes. The origin of methane formed under oxic condition is hotly debated and several pathways have recently been offered to explain the “methane paradox.” In this context, stable isotope measurements have been applied to constrain methane sources in supersaturated oxygenated waters. Here we present stable carbon isotope signatures for six widespread marine phytoplankton species, three haptophyte algae and three cyanobacteria, incubated under laboratory conditions. The observed isotopic patterns implicate that methane formed by phytoplankton might be clearly distinguished from methane produced by methanogenic archaea. Comparing results from phytoplankton experiments with isotopic data from field measurements, suggests that algal and cyanobacterial populations may contribute substantially to methane formation observed in the SML of oceans and lakes. Plain Language Summary Methane plays an important role in atmospheric chemistry and physics as it contributes to global warming and to the destruction of ozone in the stratosphere. Knowing the sources and sinks of methane in the environment is a prerequisite for understanding the global atmospheric methane cycle but also to better predict future climate change. Measurements of the stable carbon isotope composition of carbon—the ratio between the heavy and light stable isotope of carbon—help to identify methane sources in the environment and to distinguish them from other formation processes. We identified the carbon isotope fingerprint of methane released from phytoplankton including algal and cyanobacterial species. The observed isotope signature improves our understanding of methane cycling in the surface layers of aquatic environments helping us to better estimate methane emissions to the atmosphere. Key Points Stable carbon isotope values of methane emitted from six phytoplankton cultures incubated in the laboratory Isotope fractionation between methane source signature and biomass of widespread algal and cyanobacterial species Isotopic patterns of methane released by phytoplankton may be clearly distinguished from methane formed by methanogenic archaea

Background Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by mutations in the TSC1 or TSC2 gene. More than 90% of patients with TSC develop neurological and/or neuropsychiatric manifestations. The aim of the present study was to determine the developmental and cognitive long-term outcomes of pediatric TSC patients. Methods This cross-sectional, monocenter study included pediatric TSC patients who received multidisciplinary long-term care with a last visit between 2005 and 2019. Neurological manifestations and cognitive development (BSID, K-ABC) were analyzed in relation to age and type of mutation. Results Thirty-five patients aged 13.5 ± 7.8 years were included in the study. Diagnosis was confirmed genetically in 65.7% of patients (TSC1, 26.1%; TSC2, 65.2%; NMI, 8.7%). Mean age at diagnosis was 1.3 ± 3.5 years; 74.3% of the patients had been diagnosed within the first year of life due to seizures (62.9%) or/and cardiac rhabdomyomas (28.6%). The most common TSC manifestations included structural brain lesions (cortical tubers, 91.4%; subependymal nodules, 82.9%), epilepsy (85.7%), and cardiac rhabdomyomas (62.9%). Mean age at seizure onset was 1.5 ± 2.3 years, with onset in 80.0% of patients within the first two years of life. Infantile spasms, which were the first seizure type in 23.3% of the patients, developed earlier (0.6 ± 0.4 years) than focal seizures (1.8 ± 2.5 years). Refractory epilepsy was present in 21 (70.0%) patients, mild or severe intellectual impairment in 66.6%, and autism spectrum disorders in 11.4%. Severe cognitive impairment (33.3%) was significantly associated with epilepsy type and age at seizure onset ( p  < 0.05). Conclusions The results emphasized the phenotypic variability of pediatric-onset TSC and the high rate of neurological and neuropsychiatric morbidity. Early-onset refractory epilepsy was associated with impaired cognitive development. Children of all ages with TSC require multidisciplinary long-term care and individual early-intervention programs.

In quantitative susceptibility mapping (QSM), reconstructed results can be critically biased by misinterpreted or missing phase data near the edges of the brain support originating from the non-local relationship between field and susceptibility. These data either have to be excluded or corrected before further processing can take place. To address this, our iterative restoration of the fringe phase (REFRASE) approach simultaneously enhances the accuracy of multi-echo phase data QSM maps and the extent of the area available for evaluation. Data loss caused by strong local phase gradients near the surface of the brain support is recovered within the original phase data using harmonic and dipole-based fields extrapolated from a robust support region toward an extended brain mask. Over several iterations, phase data are rectified prior to the application of further QSM processing steps. The concept is successfully validated on numerical phantoms and brain scans from a cohort of volunteers. The increased extent of the mask and improved numerical stability within the segmented globus pallidus confirm the efficacy of the presented method in comparison to traditional evaluation.

Key Points Osteoarthritis (OA) is a painful, complex disease that affects millions of people worldwide. There is currently no disease-modifying therapy for OA, and existing drugs to treat symptoms of OA are largely ineffective. The lack of a validated animal model and the multifactorial nature of the disease make the discovery and development of new drugs even more challenging. OA is a disease of the whole joint that involves many pathophysiological processes that arise from a dysregulation in the function of cytokines and growth factors, prostaglandins, cartilage matrix fragments, neuropeptides, reactive oxygen intermediates, proteolytic enzymes and protease inhibitors. Dysregulation of these factors sets in motion a cycle of degeneration of cartilage, bone, ligaments and synovium that coincides with an inflammatory response and peripheral and central nervous system sensitization. Current treatments for OA include acetaminophen, non-steroidal anti-inflammatories, cyclooxygenase 2 (COX2) inhibitors, and intra-articular hyaluronic acid or steroid injections. However, disease-modifying efficacy has not been demonstrated for any of these drugs. These drugs are only moderately effective, leaving the patients with a substantial pain burden and often gastrointestinal side effects after chronic administration. Disease-modifying drugs currently in various stages of clinical development include inhibitors against matrix metalloproteinases, interleukin-1β-convertase (ICE) and cathepsin K, and the nutraceutical glucosamine. Inhibitors against lipoxygenase and COX2, as well as nitric oxide analgesics and novel NSAIDS, are being tested in the clinic for the symptomatic treatment of OA. The complex pathology of OA calls for a systems biology approach to dissecting the molecular pathways of disease initiation and progression, and to this end much effort is now focused on identifying and validating biomarkers and disease models for OA. Osteoarthritis is a painful and disabling disease that affects millions of patients. Its aetiology is largely unknown, but is most likely multi-factorial. Osteoarthritis poses a dilemma: it often begins attacking different joint tissues long before middle age, but cannot be diagnosed until it becomes symptomatic decades later, at which point structural alterations are already quite advanced. In this review, osteoarthritis is considered as a disease of the whole joint that may result from multiple pathophysiological mechanisms, one of which is the dysregulation of lipid homeostasis. No proven disease-modifying therapy exists for osteoarthritis and current treatment options for chronic osteoarthritic pain are insufficient, but new pharmacotherapeutic options are emerging.

In healthy individuals, increasing cognitive load induces an asymmetric deployment of visuospatial attention, which favors the right visual space. To date, the neural mechanisms of this left/right attentional asymmetry are poorly understood. The aim of the present study was thus to investigate whether a left/right asymmetry under high cognitive load is due to a shift in the interhemispheric balance between the left and right posterior parietal cortices (PPCs), favoring the left PPC. To this end, healthy participants completed a visuospatial attention detection task under low and high cognitive load, whilst undergoing biparietal transcranial direct current stimulation (tDCS). Three different tDCS conditions were applied in a within-subjects design: sham, anodal left/cathodal right, and cathodal left/anodal right stimulation. The results revealed a left/right attentional asymmetry under high cognitive load in the sham condition. This asymmetry disappeared during cathodal left/anodal right tDCS, yet was not influenced by anodal left/cathodal right tDCS. There were no left/right asymmetries under low cognitive load in any of the conditions. Overall, these findings demonstrate that attentional asymmetries under high cognitive load can be modulated in a polarity-specific fashion by means of tDCS. They thus support the assumption that load-related asymmetries in visuospatial attention are influenced by interhemispheric balance mechanisms between the left and right PPCs.

Purpose: A large body of literature has indicated vowel space area expansion in infant-directed (ID) speech compared with adult-directed (AD) speech, which may promote language acquisition. The current study tested whether this expansion occurs in storybook speech read to infants at various points during their first 2 years of life. Method: In 2 studies, mothers read a storybook containing target vowels in ID and AD speech conditions. Study 1 was longitudinal, with 11 mothers recorded when their infants were 3, 6, and 9 months old. Study 2 was cross-sectional, with 48 mothers recorded when their infants were 3, 9, 13, or 20 months old (n = 12 per group). The 1st and 2nd formants of vowels /i/, /?/, and /u/ were measured, and vowel space area and dispersion were calculated. Results: Across both studies, 1st and/or 2nd formant frequencies shifted systematically for /i/ and /u/ vowels in ID compared with AD speech. No difference in vowel space area or dispersion was found. Conclusions: The results suggest that a variety of communication and situational factors may affect phonetic modifications in ID speech, but that vowel space characteristics in speech to infants stay consistent across the first 2 years of life.

PurposePositron emission tomography (PET) using O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) improves the diagnostics of cerebral gliomas compared with conventional magnetic resonance imaging (MRI). Sodium MRI is an evolving method to assess tumor metabolism. In this pilot study, we explored the relationship of [18F]FET-PET and sodium MRI in patients with cerebral gliomas in relation to the mutational status of the enzyme isocitrate dehydrogenase (IDH).ProceduresTen patients with untreated cerebral gliomas and one patient with a recurrent glioblastoma (GBM) were investigated by dynamic [18F]FET-PET and sodium MRI using an enhanced simultaneous single-quantum- and triple-quantum-filtered imaging of 23Na (SISTINA) sequence to estimate total (NaT), weighted non-restricted (NaNR, mainly extracellular), and restricted (NaR, mainly intracellular) sodium in tumors and normal brain tissue. [18F]FET uptake and sodium parameters in tumors with a different IDH mutational status were compared. After biopsy or resection, histology and the IDH mutational status were determined neuropathologically.ResultsNaT (p = 0.05), tumor-to-brain ratios (TBR) of NaT (p = 0.02), NaNR (p = 0.003), and the ratio of NaT/NaR (p < 0.001) were significantly higher in IDH-mutated than in IDH-wild-type gliomas (n = 5 patients each) while NaR was significantly lower in IDH-mutated gliomas (p = 0.01). [18F]FET parameters (TBR, time-to-peak) were not predictive of IDH status in this small cohort of patients. There was no obvious relationship between sodium distribution and [18F]FET uptake. The patient with a recurrent GBM exhibited an additional radiation injury with strong abnormalities in sodium MRI.ConclusionsSodium MRI appears to be more strongly related to the IDH mutational status than are [18F]FET-PET parameters. A further evaluation of the combination of the two methods in a larger group of high- and low-grade gliomas seems promising.

O-(2-[18F]fluoroethyl)-L-tyrosine (FET) is a widely used amino acid tracer for positron emission tomography (PET) imaging of brain tumours. This retrospective study and survey aimed to analyse our extensive database regarding the development of FET PET investigations, indications, and the referring physicians’ rating concerning the role of FET PET in the clinical decision-making process. Between 2006 and 2019, we performed 6534 FET PET scans on 3928 different patients against a backdrop of growing demand for FET PET. In 2019, indications for the use of FET PET were as follows: suspected recurrent glioma (46%), unclear brain lesions (20%), treatment monitoring (19%), and suspected recurrent brain metastasis (13%). The referring physicians were neurosurgeons (60%), neurologists (19%), radiation oncologists (11%), general oncologists (3%), and other physicians (7%). Most patients travelled 50 to 75 km, but 9% travelled more than 200 km. The role of FET PET in decision-making in clinical practice was evaluated by a questionnaire consisting of 30 questions, which was filled out by 23 referring physicians with long experience in FET PET. Fifty to seventy per cent rated FET PET as being important for different aspects of the assessment of newly diagnosed gliomas, including differential diagnosis, delineation of tumour extent for biopsy guidance, and treatment planning such as surgery or radiotherapy, 95% for the diagnosis of recurrent glioma, and 68% for the diagnosis of recurrent brain metastases. Approximately 50% of the referring physicians rated FET PET as necessary for treatment monitoring in patients with glioma or brain metastases. All referring physicians stated that the availability of FET PET is essential and that it should be approved for routine use. Although the present analysis is limited by the fact that only physicians who frequently referred patients for FET PET participated in the survey, the results confirm the high relevance of FET PET in the clinical diagnosis of brain tumours and support the need for its approval for routine use.

Background: Lateral sliding calcaneus osteotomies are common procedures to correct hindfoot varus deformities. Shifting the calcaneal tuberosity laterally (lateralization) can lead to tarsal tunnel pressure increase and tibial nerve palsy. The purpose of this cadaveric biomechanical study was to investigate the correlation of lateralization and pressure increase underneath the flexor retinaculum. Methods: The pressure in the tarsal tunnel of 12 Thiel-fixated human cadaveric lower legs was measured in different foot positions and varying degrees of calcaneal lateralization. Results: The mean pressure increased from plantarflexion (PF) to neutral position (NP) and from NP to hindfoot dorsiflexion (DF), and with increasing amounts of lateralization of the calcaneal tuberosity. The mean baseline pressure in PF was 1.5, in NP 2.2, and in DF 6.5 mmHg and increased to 8.1 in PF, 18.4 in NP, and 33.1 mmHg with 12 mm of lateralization. The release of the flexor retinaculum significantly lowered the pressure. Conclusion: Increasing pressures were found in the tarsal tunnel with increasing lateralization of the tuberosity and with both dorsiflexion and plantarflexion of the ankle. Clinical Relevance: A pre-emptive release of the flexor retinaculum for a lateralization of the calcaneal tuberosity of more than 8 mm should be considered, especially if specific patient risk factors are present. No tibial nerve palsy should be expected with 4 mm of lateralization.