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Extreme value theory is concerned with the stochastic modeling of rare and extreme events. While fundamental theories of classical stochastics - such as the laws of small numbers or the central limit theorem - are used to investigate the asymptotic behavior of the sum of random variables, extreme value theory focuses on the maximum or minimum of a set of observations. The limit distribution of the normalized sample maximum among a sequence of independent and identically distributed random variables can be characterized by means of so-called max-stable distributions.
This dissertation concerns with different aspects of the theory of max-stable random vectors and stochastic processes. In particular, the concept of 'differentiability in distribution' of a max-stable process is introduced and investigated. Moreover, 'generalized max-linear models' are introduced in order to interpolate a known max-stable random vector by a max-stable process. Further, the connection between extreme value theory and multivariate records is established. In particular, so-called 'complete' and 'simple' records are introduced as well as it is examined their asymptotic behavior.
Despite available diagnostic tests and recent advances, diagnosis of pulmonary invasive aspergillosis (IPA) remains challenging. We performed a longitudinal case-control pilot study to identify host-specific, novel, and immune-relevant molecular candidates indicating IPA in patients post allogeneic stem cell transplantation (alloSCT). Supported by differential gene expression analysis of six relevant in vitro studies, we conducted RNA sequencing of three alloSCT patients categorized as probable IPA cases and their matched controls without Aspergillus infection (66 samples in total). We additionally performed immunoassay analysis for all patient samples to gain a multi-omics perspective. Profiling analysis suggested LGALS2, MMP1, IL-8, and caspase-3 as potential host molecular candidates indicating IPA in investigated alloSCT patients. MMP1, IL-8, and caspase-3 were evaluated further in alloSCT patients for their potential to differentiate possible IPA cases and patients suffering from COVID-19-associated pulmonary aspergillosis (CAPA) and appropriate control patients. Possible IPA cases showed differences in IL-8 and caspase-3 serum levels compared with matched controls. Furthermore, we observed significant differences in IL-8 and caspase-3 levels among CAPA patients compared with control patients. With our conceptual work, we demonstrate the potential value of considering the human immune response during Aspergillus infection to identify immune-relevant molecular candidates indicating IPA in alloSCT patients. These human host candidates together with already established fungal biomarkers might improve the accuracy of IPA diagnostic tools.
Although the field of fungal infections advanced tremendously, diagnosis of invasive pulmonary aspergillosis (IPA) in immunocompromised patients continues to be a challenge. Since IPA is a multifactorial disease, investigation from different aspects may provide new insights, helpful for improving IPA diagnosis. This work aimed to characterize the human immune response to Aspergillus fumigatus in a multilevel manner to identify characteristic molecular candidates and risk factors indicating IPA, which may in the future support already established diagnostic assays. We combined in vitro studies using myeloid cells infected with A. fumigatus and longitudinal case-control studies investigating patients post allogeneic stem cell transplantation (alloSCT) suffering from IPA and their match controls.
Characteristic miRNA and mRNA signatures indicating A. fumigatus-infected monocyte-derived dendritic cells (moDCs) demonstrated the potential to differentiate between A. fumigatus and Escherichia coli infection. Transcriptome and protein profiling of alloSCT patients suffering from IPA and their matched controls revealed a distinctive IPA signature consisting of MMP1 induction and LGAL2 repression in combination with elevated IL-8 and caspase-3 levels. Both, in vitro and case-control studies, suggested cytokines, matrix-metallopeptidases and galectins are important in the immune response to A. fumigatus. Identified IPA characteristic molecular candidates are involved in numerous processes, thus a combination of these in a distinctive signature may increase the specificity. Finally, low monocyte counts, severe GvHD of the gut (grade ≥ 2) and etanercept administration were significantly associated with IPA diagnosis post alloSCT. Etanercept in monocyte-derived macrophages (MDM) infected with A. fumigatus downregulates genes involved in the NF-κB and TNF-α pathway and affects the secretion of CXCL10.
Taken together, identified characteristic molecular signatures and risk factors indicating IPA may in the future in combination with established fungal biomarkers overcome current diagnostic challenges and help to establish tailored antifungal therapy. Therefore, further multicentre studies are encouraged to evaluate reported findings.
Context: Patients with primary adrenal insufficiency (PAI) or congenital adrenal hyperplasia (CAH) are at a high risk of adrenal crisis (AC). Glucocorticoid sensitivity is at least partially genetically determined by polymorphisms of the glucocorticoid receptor (GR).
Objectives: To determine if a number of intercurrent illnesses and AC are associated with the GR gene polymorphism \(Bcl\)I in patients with PAI and CAH.
Design and patients: This prospective, longitudinal study over 37.7 ± 10.1 months included 47 PAI and 25 CAH patients. During the study period, intercurrent illness episodes and AC were documented.
Results: The study period covered 223 patient years in which 21 AC occurred (9.4 AC/100 pat years). There were no significant differences between \(Bcl\)I polymorphisms (CC (n=29), CG (n=34) and GG (n=9)) regarding BMI, hydrocortisone equivalent daily dose and blood pressure. We did not find a difference in the number of intercurrent illnesses/patient year among \(Bcl\)I polymorphisms (CC (1.5±1.4/pat year), CG (1.2±1.2/pat year) and GG (1.6±2.2/pat year)). The occurrence of AC was not significantly different among the homozygous (GG) genotype (32.5 AC/100 pat years), the CC genotype (6.7 AC/100 pat years) and the CG genotype (4.9 AC/100 pat years). Concomitant hypothyroidism was the highest in the GG genotype group (5/9), compared to others (CC (11/29) and CG (11/34)).
Conclusions: Although sample sizes were relatively small and results should be interpreted with caution, this study suggests that the GR gene polymorphism \(Bcl\)I may not be associated with the frequencies of intercurrent illnesses and AC.
Besides external characteristics and reading a piece of DNA (barcode), the DNA weight per nucleus (genome size) via flow cytometry is a key value to detect species and hybrids and determine ploidy. In addition, the DNA weight appears to be related to various properties, such as the size of the cell and the nucleus, the duration of mitosis and meiosis and the generation time. Sometimes it is even possible to distinguish between groups or sections, which can lead to new classification of the genera. The variation in DNA weight is also useful to analyze biodiversity, genome evolution and relationships between related taxa. Moreover, it is important to know how large a genome is before one determines the base sequence of the DNA of a plant. Flow cytometry is also important for understanding fundamental processes in plants such as growth and development and recognizing chimeras. In the literature, DNA weight measurements are usually limited to one genus and often only locally (Siljak et al. 2010; Bai et al. 2012). In this study, however, it was decided to investigate all vascular plants from one country. This can also contribute to the protection of rare plants. This study is the first flora in the world whose weight of DNA per nucleus and peak patterns has been determined. More than 6400 plants, representing more than 2350 (sub)species (more than 90%) have been collected, thanks to the help of almost 100 volunteers of Floristisch Onderzoek Nederland (Floron). Multiple specimens of many species have therefore been measured, preferably from different populations, in some cases more than fifty. For 1370 species, these values were not previously published. Moreover, a good number of the remaining 45% are new for The Netherlands. In principle, each species has a fixed weight of DNA per nucleus. It has also been found that, especially between the genera, there are strong differences in the number of peaks that determine the DNA weight, from one to five peaks. This indicates that in a plant or organ there are sometimes nuclei with multiples of its standard DNA weight (multiple ploidy levels). It is impossible to show graphs of more than 2350 species. Therefore, we have chosen to show the peak pattern in a new way in a short formula. Within most genera there are clear differences in the DNA weights per nucleus between the species, in some other genera the DNA weight is hardly variable. Based on about twenty genera that were previously measured completely in most cases (‘t Hart et al. 2003: Veldkamp and Zonneveld 2011; Soes et al. 2012; Dirkse et al. 2014, 2015; Verloove et al. 2017; Zonneveld [et al.] 2000−2018), it can be noted that even if all species of a genus have the same number of chromosomes, there can still be a difference of up to three times in the weight of the DNA. Therefore, a twice larger DNA weight does not have to indicate four sets of chromosomes. Finally, this research has also found clues to examine further the current taxonomy of a number of species or genera.
Poly(A)-binding proteins (PABPs) regulate mRNA fate by controlling stability and translation through interactions with both the poly(A) tail and eIF4F complex. Many organisms have several paralogs of PABPs and eIF4F complex components and it is likely that different eIF4F/PABP complex combinations regulate distinct sets of mRNAs. Trypanosomes have five eIF4G paralogs, six of eIF4E and two PABPs, PABP1 and PABP2. Under starvation, polysomes dissociate and the majority of mRNAs, most translation initiation factors and PABP2 reversibly localise to starvation stress granules. To understand this more broadly we identified a protein interaction cohort for both T. brucei PABPs by cryo-mill/affinity purification-mass spectrometry. PABP1 very specifically interacts with the previously identified interactors eIF4E4 and eIF4G3 and few others. In contrast PABP2 is promiscuous, with a larger set of interactors including most translation initiation factors and most prominently eIF4G1, with its two partners TbG1-IP and TbG1-IP2. Only RBP23 was specific to PABP1, whilst 14 RNA-binding proteins were exclusively immunoprecipitated with PABP2. Significantly, PABP1 and associated proteins are largely excluded from starvation stress granules, but PABP2 and most interactors translocate to granules on starvation. We suggest that PABP1 regulates a small subpopulation of mainly small-sized mRNAs, as it interacts with a small and distinct set of proteins unable to enter the dominant pathway into starvation stress granules and localises preferentially to a subfraction of small polysomes. By contrast PABP2 likely regulates bulk mRNA translation, as it interacts with a wide range of proteins, enters stress granules and distributes over the full range of polysomes.
The larvae of the cabbage root fly induce serious damage to cultivated crops of the family Brassicaceae. We here report the biochemical characterisation of neuropeptides from the central nervous system and neurohemal organs, as well as regulatory peptides from enteroendocrine midgut cells of the cabbage maggot. By LC-MALDI-TOF/TOF and chemical labelling with 4-sulfophenyl isothiocyanate, 38 peptides could be identified, representing major insect peptide families: allatostatin A, allatostatin C, FMRFamide-like peptides, kinin, CAPA peptides, pyrokinins, sNPF, myosuppressin, corazonin, SIFamide, sulfakinins, tachykinins, NPLP1-peptides, adipokinetic hormone and CCHamide 1. We also report a new peptide (Yamide) which appears to be homolog to an amidated eclosion hormone-associated peptide in several Drosophila species. Immunocytochemical characterisation of the distribution of several classes of peptide-immunoreactive neurons and enteroendocrine cells shows a very similar but not identical peptide distribution to Drosophila. Since peptides regulate many vital physiological and behavioural processes such as moulting or feeding, our data may initiate the pharmacological testing and development of new specific peptide-based protection methods against the cabbage root fly and its larva.
Background
Homeostatic mechanisms to maintain the T cell compartment diversity indicate an ongoing process of thymic activity and peripheral T cell renewal during human life. These processes are expected to be accelerated after childhood thymectomy and by the influence of cytomegalovirus (CMV) inducing a prematurely aged immune system.
The study aimed to investigate proportional changes and replicative history of CD8+ T cells, of recent thymic emigrants (RTEs) and CD103+ T cells (mostly gut-experienced) and the role of Interleukin-(IL)-7 and IL-7 receptor (CD127)-expressing T cells in thymectomized patients compared to young and old healthy controls.
Results
Decreased proportions of naive and CD31 + CD8+ T cells were demonstrated after thymectomy, with higher proliferative activity of CD127-expressing T cells and significantly shorter relative telomere lengths (RTLs) and lower T cell receptor excision circles (TRECs). Increased circulating CD103+ T cells and a skewed T cell receptor (TCR) repertoire were found after thymectomy similar to elderly persons. Naive T cells were influenced by age at thymectomy and further decreased by CMV.
Conclusions
After childhood thymectomy, the immune system demonstrated constant efforts of the peripheral CD8+ T cell compartment to maintain homeostasis. Supposedly it tries to fill the void of RTEs by peripheral T cell proliferation, by at least partly IL-7-mediated mechanisms and by proportional increase of circulating CD103+ T cells, reminiscent of immune aging in elderly. Although other findings were less significant compared to healthy elderly, early thymectomy demonstrated immunological alterations of CD8+ T cells which mimic features of premature immunosenescence in humans.
BACKGROUND: In the face of growing resistance in malaria parasites to drugs, pharmacological combination therapies are important. There is accumulating evidence that methylene blue (MB) is an effective drug against malaria. Here we explore the biological effects of both MB alone and in combination therapy using modeling and experimental data.
RESULTS: We built a model of the central metabolic pathways in P. falciparum. Metabolic flux modes and their changes under MB were calculated by integrating experimental data (RT-PCR data on mRNAs for redox enzymes) as constraints and results from the YANA software package for metabolic pathway calculations. Several different lines of MB attack on Plasmodium redox defense were identified by analysis of the network effects. Next, chloroquine resistance based on pfmdr/and pfcrt transporters, as well as pyrimethamine/sulfadoxine resistance (by mutations in DHF/DHPS), were modeled in silico. Further modeling shows that MB has a favorable synergism on antimalarial network effects with these commonly used antimalarial drugs.
CONCLUSIONS: Theoretical and experimental results support that methylene blue should, because of its resistance-breaking potential, be further tested as a key component in drug combination therapy efforts in holoendemic areas.
B cells and DCs are suspected to play an important role in the pathogenesis of cGvHD, which is a serious complication of HSCT with high morbidity. It is characterized by immune responses of donor immune cells against recipient-derived antigens. athogenesis is not yet fully understood, however reconstitution of B cells after HSCT has similarities to physiologic ontogeny. Immunophenotyping and co-cultivation-experiments of B cells and DCs from pediatric patients with cGvHD as well as healthy donors were conducted. Significant differences between patients and healthy donors were observed with increased memory, transitional, CD69+ and CD86+ phenotype and lower levels of naïve B cells due to apoptosis. Co-cultivation revealed this to be primarily B cell-dependent without major effects of and with DCs. There was a decreased CD11c- phenotype in patients and less apoptosis of DCs. Our data suggest a disturbed homeostasis in B cells with increased memory phenotype in patients, whereas DCs could not influence these differences, therefore DCs are not imposing as promising targets. B cell-dependent approaches should be further investigated.
Limiting bone resorption and regenerating bone tissue are treatment goals in myeloma bone disease (MMBD). Physical stimuli such as mechanical loading prevent bone destruction and enhance bone mass in the MOPC315.BM.Luc model of MMBD. It is unknown whether treatment with the Bruton's tyrosine kinase inhibitor CC-292 (spebrutinib), which regulates osteoclast differentiation and function, augments the anabolic effect of mechanical loading. CC-292 was administered alone and in combination with axial compressive tibial loading in the MOPC315.BM.Luc model for three weeks. However, neither CC-292 alone nor its use in combination with mechanical loading was more effective in reducing osteolytic bone disease or rescuing bone mass than mechanical stimuli alone, as evidenced by microcomputed tomography (microCT) and histomorphometric analysis. Further studies are needed to investigate novel anti-myeloma and anti-resorptive strategies in combination with physical stimuli to improve treatment of MMBD.
Internet applications are becoming more and more flexible to support diverge user demands and network conditions. This is reflected by technical concepts, which provide new adaptation mechanisms to allow fine grained adjustment of the application quality and the corresponding bandwidth requirements. For the case of video streaming, the scalable video codec H.264/SVC allows the flexible adaptation of frame rate, video resolution and image quality with respect to the available network resources. In order to guarantee a good user-perceived quality (Quality of Experience, QoE) it is necessary to adjust and optimize the video quality accurately. But not only have the applications of the current Internet changed. Within network and transport, new technologies evolved during the last years providing a more flexible and efficient usage of data transport and network resources. One of the most promising technologies is Network Virtualization (NV) which is seen as an enabler to overcome the ossification of the Internet stack. It provides means to simultaneously operate multiple logical networks which allow for example application-specific addressing, naming and routing, or their individual resource management. New transport mechanisms like multipath transmission on the network and transport layer aim at an efficient usage of available transport resources. However, the simultaneous transmission of data via heterogeneous transport paths and communication technologies inevitably introduces packet reordering. Additional mechanisms and buffers are required to restore the correct packet order and thus to prevent a disturbance of the data transport. A proper buffer dimensioning as well as the classification of the impact of varying path characteristics like bandwidth and delay require appropriate evaluation methods. Additionally, for a path selection mechanism real time evaluation mechanisms are needed. A better application-network interaction and the corresponding exchange of information enable an efficient adaptation of the application to the network conditions and vice versa. This PhD thesis analyzes a video streaming architecture utilizing multipath transmission and scalable video coding and develops the following optimization possibilities and results: Analysis and dimensioning methods for multipath transmission, quantification of the adaptation possibilities to the current network conditions with respect to the QoE for H.264/SVC, and evaluation and optimization of a future video streaming architecture, which allows a better interaction of application and network.
Incremental exercise testing is frequently used as a tool for evaluating determinants of endurance performance. The available reference values for the peak oxygen uptake \((VO_{2peak})\), % of \(VO_{2peak}\) , running speed at the lactate threshold \((v_{LT})\), running economy (RE), and maximal running speed \((v_{peak})\) for different age, gender, and disciplines are not sufficient for the elite athletic population. The key variables of 491 young athletes (age range 12–21 years; 250 males, 241 females) assessed during a running step test protocol \((2.4 m s^{−1} ; increase 0.4 m s^{−1} 5 min^{−1})\) were analysed in five subgroups, which were related to combat-, team-, endurance-, sprint- and power-, and racquet-related disciplines. Compared with female athletes, male athletes achieved a higher \(v_{peak}\) (P = 0.004). The body mass, lean body mass, height, abs. \(VO_{2peak} (ml min^{−1})\), rel. \(VO_{2peak} (ml kg^{−1} min^{−1})\), rel. \(VO_{2peak} (ml min^{−1} kg^{−0.75})\), and RE were higher in the male participants compared with the females (P < 0.01). The % of \(VO_2\) at \(v_{LT}\) was lower in the males compared with the females (P < 0.01). No differences between gender were detected for the \(v_{LT}\) (P = 0.17) and % of \(VO_2\) at \(v_{LT}\) (P = 0.42). This study is one of the first to provide a broad spectrum of data to classify nearly 500 elite athletes aged 12–21 years of both gender and different disciplines.
The purpose of this study was threefold: 1) to assess the eggbeater kick and throwing performance using a number of water polo specific tests, 2) to explore the relation between the eggbeater kick and throwing performance, and 3) to investigate the relation between the eggbeater kick in the water and strength tests performed in a controlled laboratory setting in elite water polo players. Fifteen male water polo players of the German National Team completed dynamic and isometric strength tests for muscle groups (adductor, abductor, abdominal, pectoralis) frequently used during water polo. After these laboratory strength tests, six water polo specific in-water tests were conducted. The eggbeater kick assessed leg endurance and agility, maximal throwing velocity and jump height. A 400 m test and a sprint test examined aerobic and anaerobic performance. The strongest correlation was found between jump height and arm length (p < 0.001, r = 0.89). The laboratory diagnostics of important muscles showed positive correlations with the results of the in-water tests (p < 0.05, r = 0.52-0.70). Muscular strength of the adductor, abdominal and pectoralis muscles was positively related to in-water endurance agility as assessed by the eggbeater kick (p < 0.05; r = 0.53-0.66). Findings from the current study emphasize the need to assess indices of water polo performance both in and out of the water as well as the relation among these parameters to best assess the complex profile of water polo players.
To elucidate the mechanisms underlying the differences in adaptation of arm and leg muscles to sprint training, over a period of 11 days 16 untrained men performed six sessions of 4–6 × 30-s all-out sprints (SIT) with the legs and arms, separately, with a 1-h interval of recovery. Limb-specific VO2peak, sprint performance (two 30-s Wingate tests with 4-min recovery), muscle efficiency and time-trial performance (TT, 5-min all-out) were assessed and biopsies from the m. vastus lateralis and m. triceps brachii taken before and after training. VO2peak and Wmax increased 3–11% after training, with a more pronounced change in the arms (P < 0.05). Gross efficiency improved for the arms (+8.8%, P < 0.05), but not the legs (−0.6%). Wingate peak and mean power outputs improved similarly for the arms and legs, as did TT performance. After training, VO2 during the two Wingate tests was increased by 52 and 6% for the arms and legs, respectively (P < 0.001). In the case of the arms, VO2 was higher during the first than second Wingate test (64 vs. 44%, P < 0.05). During the TT, relative exercise intensity, HR, VO2, VCO2, VE, and Vt were all lower during arm-cranking than leg-pedaling, and oxidation of fat was minimal, remaining so after training. Despite the higher relative intensity, fat oxidation was 70% greater during leg-pedaling (P = 0.017). The aerobic energy contribution in the legs was larger than for the arms during the Wingate tests, although VO2 for the arms was enhanced more by training, reducing the O2 deficit after SIT. The levels of muscle glycogen, as well as the myosin heavy chain composition were unchanged in both cases, while the activities of 3-hydroxyacyl-CoA-dehydrogenase and citrate synthase were elevated only in the legs and capillarization enhanced in both limbs. Multiple regression analysis demonstrated that the variables that predict TT performance differ for the arms and legs. The primary mechanism of adaptation to SIT by both the arms and legs is enhancement of aerobic energy production. However, with their higher proportion of fast muscle fibers, the arms exhibit greater plasticity.
Here, we evaluated the influence of breathing oxygen at different partial pressures during recovery from exercise on performance at sea-level and a simulated altitude of 1800 m, as reflected in activation of different upper body muscles, and oxygenation of the m. triceps brachii. Ten well-trained, male endurance athletes (25.3±4.1 yrs; 179.2±4.5 cm; 74.2±3.4 kg) performed four test trials, each involving three 3-min sessions on a double-poling ergometer with 3-min intervals of recovery. One trial was conducted entirely under normoxic (No) and another under hypoxic conditions \((Ho; F_iO_2 = 0.165)\). In the third and fourth trials, the exercise was performed in normoxia and hypoxia, respectively, with hyperoxic recovery \((HOX; F_iO_2 = 1.00)\) in both cases. Arterial hemoglobin saturation was higher under the two HOX conditions than without HOX (p<0.05). Integrated muscle electrical activity was not influenced by the oxygen content (best d = 0.51). Furthermore, the only difference in tissue saturation index measured via near-infrared spectroscopy observed was between the recovery periods during the NoNo and HoHOX interventions (P<0.05, d = 0.93). In the case of HoHo the athletes’ \(P_{mean}\) declined from the first to the third interval (P < 0.05), whereas Pmean was unaltered under the HoHOX, NoHOX and NoNo conditions. We conclude that the less pronounced decline in \(P_{mean}\) during 3 x 3-min double-poling sprints in normoxia and hypoxia with hyperoxic recovery is not related to changes in muscle activity or oxygenation. Moreover, we conclude that hyperoxia \((F_iO_2 = 1.00)\) used in conjunction with hypoxic or normoxic work intervals may serve as an effective aid when inhaled during the subsequent recovery intervals.
Purpose: Research dealing with ischemic preconditioning (IPC) has primarily focused on variables associated to endurance performance with little research about the acute responses of IPC on repeated multidirectional running sprint performance. Here we aimed to investigate the effects of IPC of the arms and the legs on repeated running sprint performance with changes-of-direction (COD) movements.
Methods: Thirteen moderately-to-well-trained team-sport athletes (7 males; 6 females; age: 24 ± 2 years, size: 175 ± 8 cm, body mass: 67.9 ± 8.1 kg) performed 16 × 30 m all-out sprints (15 s rest) with multidirectional COD movements on a Speedcourt\(^{©}\) with IPC (3 × 5 min) of the legs (IPC\(_{leg}\); 240 mm Hg) or of the arms (remote IPC: IPC\(_{remote}\); 180–190 mm Hg) 45 min before the sprints and a control trial (CON; 20 mm Hg).
Results: The mean (±SD) time for the 16 × 30 m multidirectional COD sprints was similar between IPC\(_{leg}\) (Mean t: 16.0 ± 1.8 s), IPC\(_{remote}\) (16.2 ± 1.7 s), and CON (16.0 ± 1.6 s; p = 0.50). No statistical differences in oxygen uptake (mean difference: 0%), heart rate (1.1%) nor muscle oxygen saturation of the vastus lateralis (4.7%) and biceps brachii (7.8%) between the three conditions were evident (all p > 0.05).
Conclusions: IPC (3 × 5 min) of the legs (220 mm Hg) or arms (180–190 mm Hg; remote IPC) applied 45 min before 16 × 30 m repeated multidirectional running sprint exercise does not improve sprint performance, oxygen uptake, heart rate nor muscle oxygen saturation of the vastus lateralis muscle when compared to a control trial.
In this study, we tested the hypothesis that breathing hyperoxic air (F\(_{in}\)O\(_2\) = 0.40) while exercising in a hot environment exerts negative effects on the total tissue level of haemoglobin concentration (tHb); core (T\(_{core}\)) and skin (T\(_{skin}\)) temperatures; muscle activity; heart rate; blood concentration of lactate; pH; partial pressure of oxygen (P\(_a\)O\(_2\)) and carbon dioxide; arterial oxygen saturation (S\(_a\)O\(_2\)); and perceptual responses. Ten well-trained male athletes cycled at submaximal intensity at 21°C or 33°C in randomized order: first for 20 min while breathing normal air (FinO\(_2\) = 0.21) and then 10 min with F\(_{in}\)O\(_2\) = 0.40 (HOX). At both temperatures, S\(_a\)O\(_2\) and P\(_a\)O\(_2\), but not tHb, were increased by HOX. Tskin and perception of exertion and thermal discomfort were higher at 33°C than 21°C (p < 0.01), but independent of F\(_{in}\)O\(_2\). T\(_{core}\) and muscle activity were the same under all conditions (p > 0.07). Blood lactate and heart rate were higher at 33°C than 21°C. In conclusion, during 30 min of submaximal cycling at 21°C or 33°C, T\(_{core}\), T\(_{skin}\) and T\(_{body}\), tHb, muscle activity and ratings of perceived exertion and thermal discomfort were the same under normoxic and hyperoxic conditions. Accordingly, breathing hyperoxic air (F\(_{in}\)O\(_2\) = 0.40) did not affect thermoregulation under these conditions.
Background: Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME (TM) trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes.
Methods: Patients who were drug naive (HbA(1c) >= 7.0% and <= 9.0%), or on background glucose-lowering therapy (HbA(1c) >= 7.0% and <= 10.0%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until >= 691 confirmed primary outcome events have occurred, providing a power of 90% to yield an upper limit of the adjusted 95% CI for a hazard ratio of <1.3 with a one-sided a of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved.
Results: Between Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41% from Europe, 20% from North America, and 19% from Asia). At baseline, the mean age was 63 +/- 9 years, BMI 30.6 +/- 5.3 kg/m(2), HbA1c 8.1 +/- 0.8%, and eGFR 74 +/- 21 ml/min/1.73 m(2). The study is expected to report in 2015.
Discussion: EMPA REG OUTCOME (TM) will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection.