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AimsCardiomyopathy in Fabry disease (FD) is a major determinant of morbidity and mortality. This study investigates the effects of FD-specific treatment using enzyme replacement therapy (ERT) and chaperone therapy on left atrial (LA) function using two-dimensional speckle tracking echocardiography (2DSTE).Methods and resultsIn this prospective observational single-center study, 20 FD patients [10 (50%) females] treated with migalastat, 48 FD patients [24 (50%) females] treated with ERT (agalsidase-alfa and agalsidase-beta), and 30 untreated FD patients (all females) as controls were analyzed. The mean follow-up time ranged from 26 to 81 months. 2DSTE was performed for left ventricle strain, right ventricle strain, and LA strain (LAS). FD-specific treated patients presented with increased left ventricular mass index (LVMi) and higher frequency of left ventricular hypertrophy at baseline, whereas untreated control patients showed normal baseline values. FD-specific treated (including migalastat and ERT) patients showed stabilization of LAS over time (p > 0.05). LVMi was also stable in treated FD patients during observation (p > 0.05).ConclusionIn patients with FD, treated with either ERT or chaperone therapy, LAS values measured by echocardiographic speckle tracking were stable over time, pointing toward disease stabilization.

Polyethylene glycol (PEG)ylated drugs are used for medical treatment, since PEGylation either decreases drug clearance or/and shields the protein from undesirable immunogenicity. PEGylation was implemented in a new enzyme replacement therapy for Fabry disease (FD), pegunigalsidase-alfa (PRX-102). However, exposure to PEG via life-style products and vaccination can result in the formation of anti-PEG antibodies. We demonstrate the de novo formation of functional anti-PEG antibodies in a healthy male after the second mRNA-based vaccination against SARS-CoV-2. Consequently, we analyzed the frequency and inhibitory function of anti-PEG and anti-α-Galactosidase A (AGAL) antibodies in 102 FD patients (46.9% males). We identified 29 out of 87 (33.3%) patients with low anti-PEG titers. Sera from patients without anti-AGAL antibodies [n=70] showed a higher rescued AGAL activity of agalsidase-beta and PRX-102 [both p

Restoration of the degraded rangelands in Jordan using mechanized water harvesting and native species planting has become key to enhancing and maintaining the productivity and resilience of fragile ecosystems. A balanced interaction between the rangeland's hydrology and vegetation states is vital for achieving long-term sustainability. To gain a better insight into the impact of restoration on surface runoff and erosion and its role in recovering the ecosystem functions, we used the Rangeland Hydrological and Erosion Model (RHEM) to simulate various vegetation scenarios. Our research aims to understand the rangelands' water and sediment dynamics and the vegetation transition states of the ecosystem through evaluating the current (degraded) situation, assess the restoration approach on improving the degraded status (restored), and investigate the long-term sustainability of the restoration approach compared with historical rangeland conditions (baseline). Several scenarios were developed with rangeland experts, local community representatives, and measurements at protected and restored areas to represent the rangeland conditions. We found that restoration of the degraded Badia areas will decrease annual surface runoff from an average of 23.5 to 19.1 mm/year and soil erosion rate from 3.3 to 1.3 tons/ha. With time, restoration can bring back rangeland water and sediment dynamics closer towards the baseline conditions, which were 16.9 mm/year runoff rates and 0.85 ton/ha/year soil loss. The results indicate that restoration is a promising methodology to restore the degraded ecosystem and approximate the environment's historical hydrological regime.

Background and Objectives: Abdominal trauma among severely injured patients with an injury severity score (ISS) of 16 and above can lead to potentially life-threatening injuries that might need immediate surgical intervention. Traumatic injuries to the diaphragm (TID) are a challenging condition often accompanied by other injuries in the thoracoabdominal region. Materials and Methods: We retrospectively analyzed the occurrence and clinical course of TID among severely injured patients treated at our center between 2008 and 2019 and compared them to other groups of severely injured patients without TID. Results: Thirty-five patients with TID and a median ISS of 41 were treated in the period mentioned above. They were predominantly middle-aged men and mostly victims of blunt trauma as a consequence of motor vehicle accidents. A total of 70.6% had left-sided TID, and in 69.6%, the size of defect was larger than 10 cm. The diagnosis was made with computed tomography (CT) in 68.6% of the cases, while in 25.8%, it was made intraoperatively or delayed by a false-negative initial CT scan, and in 5.7%, an intraoperative diagnosis was made without preoperative CT imaging. Surgical repair was mostly conducted via laparotomy, performing a direct closure with continuous suture. A comparison to 191 patients that required laparotomy for abdominal injuries other than TID revealed significantly higher rates of concomitant injuries to several abdominal organs among patients suffering from TID. Compared to all other severely injured patients treated in the same period (n = 1377), patients suffering from TID had a significantly higher median ISS and a longer mean duration of hospital stay. Conclusions: Our findings show that TID can be seen as an indicator of particularly severe thoracoabdominal trauma that requires increased attention from the treatment team so as not to miss relevant concomitant injuries that require immediate intervention.

Nitriding of Fe-1 wt.% Cu and Fe-5 wt.% Cu alloys at 813 K leads to the formation of predominantly the γ′-iron nitride phase (γ′-Fe4N) when using nitriding conditions, which lead to pronounced formation of ε-iron nitride phase (ε-Fe3N1+x) upon nitriding of pure α-Fe. Energy dispersive X-ray analysis reveals that the developing γ′ can attain a Cu content corresponding to that of the base material. In contrast, tiny amounts of ε-nitride that eventually develop contain considerably less Cu. The microstructure implies that the formation of the ε-nitride requires long-range substitutional interdiffusion to achieve the Cu partitioning. These observations were interpreted in terms of a significantly higher solubility of Cu in the γ′ phase than in the ε phase, which is explainable by the phases’ crystal structures. The observations were rationalized in terms of schematic Fe–Cu–N phase diagrams valid for 813 K.

Background: High-intensity interval training (HIIT) is a well-established training modality to improve aerobic and anaerobic capacity. However, sex-specific aspects of different HIIT protocols are incompletely understood. This study aimed to compare two HIIT protocols with different recovery periods in moderately trained females and males and to investigate whether sex affects high-intensity running speed and speed decrement.Methods: Fifty moderately trained participants (30 females and 20 males) performed an exercise field test and were randomized by lactate threshold (LT) to one of two time- and workload-matched training groups. Participants performed a 4-week HIIT intervention with two exercise sessions/week: Group 1 (4 × 30,180 HIIT), 30-s all-out runs, 180-s active recovery and Group 2 (4 × 30,30 HIIT), 30-s all-out runs, 30-s active recovery. High-intensity runs were recorded, and speed per running bout, average speed per session, and speed decrement were determined. Blood lactate measurements were performed at baseline and follow-up at rest and immediately post-exercise.Results: Females and males differed in running speed at LT and maximal running speed determined during exercise field test (speed at LT, females: 10.65 ± 0.84 km h−1, males: 12.41 ± 0.98 km h−1, p < 0.0001; maximal speed, females: 14.55 ± 1.05 km h−1, males: 17.41 ± 0.68 km h−1, p < 0.0001). Estimated maximal oxygen uptake was ~52.5 ml kg−1 min−1 for females and 62.6 ml kg−1 min−1 for males (p < 0.0001). Analysis of HIIT protocols revealed an effect of sex on change in speed decrement (baseline vs. follow-up) in that females showed significant improvements only in the 4 × 30:30 HIIT group (p = 0.0038). Moreover, females performing the 4 × 30:30 protocol presented increased speed per bout and average speed per session at follow-up (all p ≤ 0.0204), while no effect was detected for females performing the 4 × 30:180 protocol. Peak blood lactate levels increased in all HIIT groups (all p < 0.05, baseline vs. follow-up), but males performing the 4 × 30:180 protocol showed no difference in lactate levels.Conclusions: If not matched for physical performance, females, but not males, performing a 4 × 30 HIIT protocol with shorter recovery periods (30 s) present increased average high-intensity running speed and reduced speed decrement compared to longer recovery periods (180 s). We conclude that female- and male-specific HIIT protocols should be established since anthropometric and physiological differences across sexes may affect training performance in real-world settings.

Abstract Background KIBRA has been suggested as a key regulator of the Hippo signaling pathway, regulating organ size, cell contact inhibition, tissue regeneration as well as tumorigenesis and cystogenesis. We recently reported that human KIBRA expression depends on a complex alternative CpG-rich promoter system. Our current study aimed at the identification of epigenetic mechanisms associated with alterations in KIBRA expression regulation. Results We identified two separated methylation-sensitive CpG islands located to independent KIBRA promoter regions. In vitro promoter methylation analysis using human neuroblastoma (SH-SY5Y) and immortalized kidney cells (IHKE) revealed that total promoter methylation by CpG methyltransferase SssI resulted in complete abrogation of transcriptional activity (p

The diagnosis and prognosis of patients with severe chronic disorders of consciousness are still challenging issues and a high rate of misdiagnosis is evident. Hence, new tools are needed for an accurate diagnosis, which will also have an impact on the prognosis. In recent years, functional Magnetic Resonance Imaging (fMRI) has been gaining more and more importance when diagnosing this patient group. Especially resting state scans, i.e., an examination when the patient does not perform any task in particular, seems to be promising for these patient groups. After preprocessing the resting state fMRI data with a standard pipeline, we extracted the correlation matrices of 132 regions of interest. The aim was to find the regions of interest which contributed most to the distinction between the different patient groups and healthy controls. We performed feature selection using a genetic algorithm and a support vector machine. Moreover, we show by using only those regions of interest for classification that are most often selected by our algorithm, we get a much better performance of the classifier.

Optical coherence tomography angiography (OCT-A) represents the most recent modality in retinal imaging for non-invasive and depth-selective visualization of blood flow in retinal vessels. With regard to quantitative OCTA measurements for early detection of subclinical alterations, it is of great interest, which intra- and extra-ocular factors affect the results of OCTA measurements. Here, we performed OCTA imaging of the central retina in 65 eyes of 65 young healthy female and male participants and evaluated individual physical fitness levels by standard lactate diagnostic using an incremental maximal performance running test. The main finding was that OCTA measurements of the foveal avascular zone (FAZ) area were associated with physical fitness. Using multivariate regression analysis, we found that running speed at the individual lactate threshold, a marker strongly associated with aerobic performance capacity, significantly contributed to differences in FAZ area (β = 0.111, p = 0.032). The data indicates that smaller FAZ areas are likely observed in individuals with higher aerobic exercise capacity. Our findings are also of interest with respect to the potential use of retinal OCTA imaging to detect exercise-induced microvascular adaptations in future studies.

The ability to fabricate complex graded structures would be a significant step towards the manufacturing of material systems with properties tailored to individual applications. While powder metallurgy has had some success in this regard, it requires that the semi-finished products be exactly similar to the final component. However, it is significantly cheaper to produce simple, semi-finished products and then join them to form complex components with the desired graded structure through powder forging and simultaneous compaction. It is also essential that the graded structure of the semi-finished products is retained during the forming process. In this study, pre-sintered cylindrical semi-finished products consisting of identical homogeneous layers as well as graded components consisting of non-identical homogeneous layers were joined using powder forging at 1100 °C. The microstructures and densities as well as the mechanical properties of the final components were investigated. It was observed that, upon compaction, the components formed solid structures, in which the reinforcing ZrO2 particles were completely integrated within the transformation-induced plasticity steel matrix. Finally, it was confirmed that the graded structure of the semi-finished products was retained in the final components.

Background: Although Yo-Yo intermittent tests are frequently used in a variety of sports and research studies to determine physical fitness, no structured reference exists for comparison and rating of test results. This systematic review of the most common Yo-Yo tests aimed to provide reference values for test results by statistical aggregation of published data.Methods: A systematic literature search for articles published until August 2017 was performed in MEDLINE, Web of Science, SPORTDiscus and Google Scholar. Original reports on healthy females and males ≥16 years were eligible for the analysis. Sub-maximal test versions and the Yo-Yo Intermittent Recovery Level 1 Children's test (YYIR1C) were not included.Results: 248 studies with 9,440 participants were included in the structured analysis. The Yo-Yo test types most frequently used were the Yo-Yo Intermittent Recovery Level 1 (YYIR1, 57.7%), the Yo-Yo Intermittent Recovery Level 2 (YYIR2, 28.0%), the Yo-Yo Intermittent Endurance Level 2 (YYIE2, 11.4%), and the Yo-Yo Intermittent Endurance Level 1 (YYIE1, 2.9%) test. For each separate test, reference values (global means and percentiles) for sports at different levels and both genders were calculated.Conclusions: Our analysis provides evidence that Yo-Yo intermittent tests reference values differ with respect to the type and level of sport performed.The presented results may be used by practitioners, trainers and athletes to rate Yo-Yo intermittent test performance levels and monitor training effects.

Aim: MicroRNA-222 (miR-222) and miR-29c have been identified as important modulators of cardiac growth and may protect against pathological cardiac remodeling. miR-222 and -29c may thus serve as functional biomarkers for exercise-induced cardiac adaptations. This investigation compared the effect of two workload-matched high-intensity interval training (HIIT) protocols with different recovery periods on miR-222 and -29c levels.Methods: Sixty-three moderately trained females and males (22.0 ± 1.7 years) fulfilled the eligibility criteria and were randomized into two HIIT groups using sex and exercise capacity. During a controlled 4-week intervention (two sessions/week) a 4 × 30 HIIT group performed 4 × 30 s runs (all-out, 30 s active recovery) and a 8 × 15 HIIT group performed 8 × 15 s runs (all-out, 15 s active recovery). miR-222 and -29c as well as transforming growth factor-beta1 (TGF-beta1) mRNA levels were determined during high-intensity running as well as aerobic exercise using capillary blood from earlobes. Performance parameters were assessed using an incremental continuous running test (ICRT) protocol with blood lactate diagnostic and heart rate (HR) monitoring to determine HR recovery and power output at individual anaerobic threshold (IAT).Results: At baseline, acute exercise miR-222 and -29c levels were increased only in the 4 × 30 HIIT group (both p < 0.01, pre- vs. post-exercise). After the intervention, acute exercise miR-222 levels were still increased in the 4 × 30 HIIT group (p < 0.01, pre- vs. post-exercise) while in the 8 × 15 HIIT group again no acute effect was observed. However, both HIIT interventions resulted in elevated resting miR-222 and -29c levels (all p < 0.001, pre- vs. post-intervention). Neither of the two miRNAs were elevated at any ICRT speed level at baseline nor follow-up. While HR recovery was improved by >24% in both HIIT groups (both p ≤ 0.0002) speed at IAT was improved by 3.6% only in the 4 × 30 HIIT group (p < 0.0132). Correlation analysis suggested an association between both miRNAs and TGF-beta1 mRNA (all p ≤ 0.006, r ≥ 0.74) as well as change in speed at IAT and change in miR-222 levels (p = 0.024, r = 0.46).Conclusions: HIIT can induce increased circulating levels of cardiac growth-associated miR-222 and -29c. miR-222 and miR-29c could be useful markers to monitor HIIT response in general and to identify optimal work/rest combinations.

Aim: MicroRNA-126 (miR-126) exerts beneficial effects on vascular integrity, angiogenesis, and atherosclerotic plaque stability. The purpose of this investigation was to analyze the dose-response relationship of high-intensity interval training (HIIT) on miR-126-3p and -5p levels.Methods: Sixty-one moderately trained individuals (females = 31 [50.8%]; 22.0 ± 1.84 years) were consecutively recruited and allocated into three matched groups using exercise capacity. During a 4-week intervention a HIIT group performed three exercise sessions/week of 4 × 30 s at maximum speed (all-out), a progressive HIIT (proHIIT) group performed three exercise sessions/week of 4 × 30 s at maximum speed (all-out) with one extra session every week (up to 7 × 30 s) and a low-intensity training (LIT) control group performed three exercise sessions/week for 25 min

Abstract Fabry disease (FD) is a rare X-linked disorder caused by a deficiency of lysosomal α-galactosidase A activity. Treatment with recombinant enzyme replacement therapy is available since 2001 and the effects of anti-drug antibodies (ADA) on therapy efficacy and disease outcome in affected patients have been controversially reported. In this letter we discuss the importance of adequate measurements of neutralizing ADAs and appropriate longitudinal analysis to determine therapy efficiency and clinical outcome in patients with FD.

The peroxisome proliferator-activated receptor γ (PPARγ) Pro12Ala polymorphism affects plasma lipids, but to what extent alcohol intake interferes with this association remains unknown. We randomly recruited 251 nuclear families (433 parents and 493 offspring) in the framework of the European Project on Genes in Hypertension study and genotyped 926 participants in whom all serum lipid variables and information on alcohol consumption were available for PPARγ2 Pro12Ala. Genotype-phenotype relations were assessed using generalized estimating equations (GEE) and a quantitative transmission disequilibrium test (QTDT). The Ala12 allele was more frequent in Novosibirsk (0.17) than in Cracow (0.12) and Mirano (0.11) (P < 0.01). Using GEE (P = 0.03) or QTDT (P = 0.007), Italian offspring carrying the Ala12 allele had higher serum HDL cholesterol than noncarriers. HDL cholesterol levels were on average 0.086 mmol/l (P = 0.001) higher in drinkers than in nondrinkers. Compared with Pro12 homozygotes, Ala12 allele carriers consuming alcohol had higher serum total and HDL cholesterol, with the opposite trend occurring in nondrinkers. This genotype-alcohol interaction was independent of the type of alcoholic beverage and more pronounced in moderate than in heavy drinkers.We conclude that alcohol intake modulates the relation between the PPARγ2 Pro12Ala and HDL cholesterol level and that, therefore, the Pro12Ala polymorphism, pending confirmation of our findings, might affect cardiovascular prognosis.

The microsomal triglyceride transfer protein (MTP) catalyzes the transfer of triglyceride, cholesteryl ester, and phosphatidylcholine between phospholipid surfaces. The 97-kD subunit imparts lipid transfer activity and thus plays a role in the assembly of apolipoprotein B (apoB)-containing lipoproteins. We tested whether polymorphisms in the promoter region of the large subunit of the MTP gene might be related to different plasma lipid variables, atherosclerosis, and the risk of myocardial infarction (MI). We screened 838 bp in the promoter region of the MTP gene by PCR-SSCP and identified two polymorphisms at positions −400 (MTP/−400 (A→t)) and −164 (MTP/−164 (T→c)), the latter being situated on a putative sterol responsive element (SRE) consensus sequence. The two polymorphisms, investigated in 622 male patients with MI and in 728 age-matched controls participating in the ECTIM Study, were in nearly complete linkage disequilibrium (|D′| = ′0.98, less frequent alleles being preferentially associated, P < 0.001). There were no significant differences in genotype or allele frequencies between patients with MI and controls. Moreover, no significant associations between the two promoter polymorphisms and several lipid variables measured in the control groups of the ECTIM Study or coronary artery stenosis, angiographically assessed in patients with MI, were detected. We conclude that these MTP polymorphisms are unrelated to lipid variables or coronary heart disease in this study.—Herrmann, S-M., O. Poirier, V. Nicaud, A. Evans, J-B. Ruidavets, G. Luc, D. Arveiler, C. Bao-Sheng, and F. Cambien. Identification of two polymorphisms in the promoter of the microsomal triglyceride transfer protein (MTP) gene: lack of association with lipoprotein profiles. J. Lipid Res. 1998. 39: 2432–2435.

White matter lesions (WML) are clinically relevant since they are associated with strokes, cognitive decline, depression, or epilepsy, but the underlying etiology in young adults without classical risk factors still remains elusive. Our aim was to elucidate the possible clinical diagnosis and mechanisms leading to WML in patients carrying the D313Y mutation in the α-galactosidase A (GLA) gene, a mutation that was formerly described as nonpathogenic. Pathogenic GLA mutations cause Fabry disease, a vascular endothelial glycosphingolipid storage disease typically presenting with a symptom complex of renal, cardiac, and cerebrovascular manifestations. We performed in-depths clinical, biochemical and genetic examinations as well as advanced magnetic resonance imaging analyses in a pedigree with the genetically determined GLA mutation D313Y. We detected exclusive neurologic manifestations of the central nervous system of the "pseudo"-deficient D313Y mutation leading to manifest WML in 7 affected adult family members. Furthermore, two family members that do not carry the mutation showed no WML. The D313Y mutation resulted in a normal GLA enzyme activity in leukocytes and severely decreased activities in plasma. In conclusion, our results provide evidence that GLA D313Y is potentially involved in neural damage with significant WML, demonstrating the necessity of evaluating patients carrying D313Y more thoroughly. D313Y might broaden the spectrum of hereditary small artery diseases of the brain, which preferably occur in young adults without classical risk factors. In view of the existing causal therapy regime, D313Y should be more specifically taken into account in these patients.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are effective in treating malignant disorders and were lately suggested to have an impact on non-malignant diseases. However, in some inflammatory conditions like rheumatoid arthritis (RA) the in vivo effect seemed to be moderate. As most TKIs are taken up actively into cells by cell membrane transporters, this study aimed to evaluate the role of such transporters for the accumulation of the TKI Imatinib mesylates in RA synovial fibroblasts as well as their regulation under inflammatory conditions. METHODOLOGY/PRINCIPAL FINDINGS: The transport and accumulation of Imatinib was investigated in transporter-transfected HEK293 cells and human RA synovial fibroblasts (hRASF). Transporter expression was quantified by qRT-PCR. In transfection experiments, hMATE1 showed the highest apparent affinity for Imatinib among all known Imatinib transporters. Experiments quantifying the Imatinib uptake in the presence of specific transporter inhibitors and after siRNA knockdown of hMATE1 indeed identified hMATE1 to mediate Imatinib transport in hRASF. The anti-proliferative effect of Imatinib on PDGF stimulated hRASF was quantified by cell counting and directly correlated with the uptake activity of hMATE1. Expression of hMATE1 was investigated by Western blot and immuno-fluorescence. Imatinib transport under disease-relevant conditions, such as an altered pH and following stimulation with different cytokines, was also investigated by HPLC. The uptake was significantly reduced by an acidic extracellular pH as well as by the cytokines TNFα, IL-1β and IL-6, which all decreased the expression of hMATE1-mRNA and protein. CONCLUSION/SIGNIFICANCE: The regulation of Imatinib uptake via hMATE1 in hRASF and resulting effects on their proliferation may explain moderate in vivo effects on RA. Moreover, our results suggest that investigating transporter mediated drug processing under normal and pathological conditions is important for developing intracellular acting drugs used in inflammatory diseases.

Lightweight linear cellular composite materials on basis of austenite stainless TRIP- (TRansformation Induced Plasticity-) steel as matrix with reinforcements of MgO partially stabilized zirconia (Mg-PSZ) are described. Two-dimensional cellular materials for structural applications are conventionally produced by sheet expansion or corrugation processes. The presented composites are fabricated by a modified ceramic extrusion powder technology. Characterization of the microstructure in as-received and deformed conditions was carried out by optical and scanning electron microscopy. Magnetic balance measurements and electron backscatter diffraction (EBSD) were used to identify the deformation-induced martensite evolution in the cell wall material. The honeycomb composite samples exhibit an increased strain hardening up to a certain engineering compressive strain and an extraordinary high specific energy absorption per unit mass and unit volume, respectively. Based on improved property-to-weight ratio such linear cellular structures will be of interest as crash absorbers or stiffened core materials for aerospace, railway, or automotive applications.