Kooperation der Lernorte in der beruflichen Bildung (KOLIBRI). Abschlussbericht des Programmträgers zum BLK-Programm

Der Abschlussbericht stellt den (vorläufigen) Endpunkt intensiver Forschungen zum Thema "Lernortkooperation" dar. Im Zeitraum von Oktober 1999 bis Dezember 2003 wurden 28 Modellversuche, die zum Thema Lernortkooperation arbeiteten, im Programm KOLIBRI ("Kooperation der Lernorte in der beruflichen Bildung") zusammengefasst. Die einzelnen Forschungsvorhaben untersuchten die verschiedenen Facetten von Lernortkooperation und konzipierten praktische Lösungen für die unterschiedlichsten Probleme. (DIPF/Orig.

Transferring clinically established immune inflammation markers into exercise physiology

Over the last decades the cellular immune inflammation markers neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII = NLR × platelets) have emerged in clinical context as markers of disease-related inflammation and are now widely appreciated due to their integrative character. Transferring these clinically established inflammation markers into exercise physiology seems highly beneficial, especially due to the low temporal, financial and infrastructural resources needed for assessment and calculation. Therefore, the aim of this review is to summarize evidence on the value of the integrative inflammation markers NLR, PLR and SII for depiction of exercise-induced inflammation and highlight potential applications in exercise settings. Despite sparse evidence, multiple investigations revealed responsiveness of the markers to acute and chronic exercise, thereby opening promising avenues in the field of exercise physiology. In performance settings, they might help to infer information for exercise programming by reflecting exercise strain and recovery status or periods of overtraining and increased infection risk. In health settings, application involves the depiction of anti-inflammatory effects of chronic exercise in patients exhibiting chronic inflammation. Further research should, therefore, focus on establishing reference values for these integrative markers in athletes at rest, assess the kinetics and reliability in response to different exercise modalities and implement the markers into clinical exercise trials to depict anti-inflammatory effects of chronic exercise in different patient collectives

Fitness, physical activity, and exercise in multiple sclerosis

Background A moderate to high level of physical activity, including regular exercise, represents an established behavioral and rehabilitative approach for persons with multiple sclerosis (pwMS). Although being increasingly proposed to limit disease activity and progression, high-quality evidence is lacking. Objective The objective of the study is to provide valuable information for MS clinicians and researchers by systematically evaluating the current state of evidence (i) whether exercise interventions affect established clinical measures of disease activity and progression in pwMS (i.e., EDSS, relapse rate, lesion load, brain volume, MSFC) and (ii) how the physical activity and fitness level interact with these measures. Methods Literature search was conducted in MEDLINE, EMBASE, CINAHL, and SPORTDiscus. Evaluation of evidence quality was done based on standards published by The American Academy of Neurology. Results It is likely that exercise improves the MSFC score, whereas the EDSS score, lesion load, and brain volume are likely to remain unchanged over the intervention period. It is possible that exercise decreases the relapse rate. Results from cross-sectional studies indicate beneficial effects of a high physical activity or fitness level on clinical measures which, however, is not corroborated by high evidence quality. Conclusions A (supportive) disease-modifying effect of exercise in pwMS cannot be concluded. The rather low evidence quality of existing RCTs underlines the need to conduct more well-designed studies assessing different measures of disease activity or progression as primary end points. A major limitation is the short intervention duration of existing studies which limits meaningful exercise-induced effects on most disability measures. Findings from cross-sectional studies are difficult to contextualize regarding clinical importance due to their solely associative character and low evidence quality

Acute exercise impacts AhR and PD-1 levels of CD8+ T-cells

Purpose: The programmed cell death protein 1 (PD-1) has become a promising target in cancer immunotherapy. PD-1 expression of CD8+ T-cells may be increased via the exploitation of aryl hydrocarbon receptor (AhR) signaling with kynurenine (KYN) as a ligand. Since exercise affects KYN metabolism, we exploratory investigated the influence of acute exercise bouts on AhR and PD-1 levels of CD8+ T-cells. Method: In this study, 24 healthy males (age: 24.6 ± 3.9 years; weight 83.9 ± 10.5 kg; height: 182.4 ± 6.2 cm) completed a single bout of endurance (EE) and resistance exercise (RE) in a randomly assigned order on separate days. Blood samples were drawn before (t0), after (t1), and 1 h after (t2) both conditions. T-cell populations, the level of cytoplasmic AhR, and surface PD-1 were assessed by flow cytometry. Results: T-cell populations changed over time, indicated by an increase in the absolute numbers of CD3+ lymphocytes after EE (p < .001) and RE (p = .036) and in PD-1+ CD8+ T-cells after EE (p = .021). Proportions of T-cell populations changed only after EE (t0–t2: p = .029; t1-t2: p = .006). The level of cytoplasmic AhR decreased immediately after exercise in both exercise conditions (EE: p = .009; RE: p = .036). The level of surface PD-1 decreased 1 h after EE (p = .005). Conclusion: We analyzed the level of surface PD-1 and cytoplasmic AhR following acute physical exercise for the first time. Especially EE was observed to impact both AhR and PD-1 levels, undermining its role as the AhR-PD-1 axis modulator. These results provide new insights into the impact of exercise on AhR-signaling, which could potentially be relevant for various chronic diseases

Effects and Moderators of Acute Aerobic Exercise on Subsequent Interference Control: A Systematic Review and Meta-Analysis

Background: Acute aerobic exercise leads to positive physiological adaptations within the central nervous system. These findings inspired research on potential cognitive benefits following acute aerobic exercise. The effects of acute aerobic exercise on subsequent cognitive performance, by far, have been the most researched for interference control, a subcomponent of executive function. The results of primary studies on the effects of acute aerobic exercise on subsequent interference control performance are inconsistent. Therefore, we used meta-analytic methods to pool available effect sizes, and to identify covariates that determine the magnitude of exercise-induced interference control benefits. Methods: Medline, PsycINFO, and SPORTDiscus were searched for eligible records. Hedges' g corrected standardized mean difference values (SMDs) were used for analyses. Random-effects weights were used to pool effect sizes. Moderator analyses were conducted using meta-regressions and subgroups analyses. Covariates that were here tested for moderation included parameters of the applied exercise regimen (exercise intensity and exercise duration), characteristics of examined participants (age and fitness), and methodological features of existing research (type of control group, familiarization with test procedure, type of test variable, delay between exercise cessation, and testing). Results: Fifty studies, with data from 2,366 participants, were included in qualitative and quantitative synthesis. A small, significant beneficial effect of acute aerobic exercise on time-dependent measures of interference control was revealed (k = 49, Hedges' g = −0.26, 95%CI: −34 to −0.18). Effect sizes from time-dependent measures of interference control varied widely and heterogeneity reached statistical significance (T2 = 0.0557, I2 = 28.8%). Moderator analyses revealed that higher exercise intensities (vigorous intensity and high-intensity interval training), also participants at younger or older age, and participants who are familiar with the testing procedure prior to the experiment, benefitted most from acute aerobic exercise. However, noticeable heterogeneity remained unexplained within specific subgroups (high-intensity interval training, preadolescent children, and active and supervised control group). Conclusion: Acute aerobic exercise improves subsequent interference control performance. However, the covariates exercise intensity, participants' age, and familiarization with testing procedure determine the magnitude of that effect. Methodological features were not found to influence the magnitude of effects. This dismisses some doubts that exercise induced benefits for interference control performance are scientific artifacts. The fact that large heterogeneity remained unexplained in some subgroups indicates the need for further research on covariates within these subgroups. It should be noted that effect sizes for all analyses were small. © Copyright © 2019 Oberste, Javelle, Sharma, Joisten, Walzik, Bloch and Zimmer

Acute hypertrophic but not maximal strength loading transiently enhances the kynurenine pathway towards kynurenic acid

Purpose Due to distinct immuno- and neuro-modulatory properties, growing research interest focuses on exercise-induced alterations of the kynurenine (KYN) pathway in healthy and clinical populations. To date, knowledge about the impact of different acute strength exercise modalities on the KYN pathway is scarce. Therefore, we investigated the acute effects of hypertrophic (HYP) compared to maximal (MAX) strength loadings on the KYN pathway regulation. Methods Blood samples of twelve healthy males (mean age and weight: 23.5 ± 3.2 years; 77.5 ± 7.5 kg) were collected before (T0), immediately after (T1), and 1 h after completion (T2) of HYP (5 sets with 10 repetitions at 80% of 1RM) and MAX (15 sets with 1RM) loadings performed in a randomized cross-over design. Serum concentrations of tryptophan (TRP), KYN, kynurenic acid (KA), and quinolinic acid (QA) were assessed using high-performance liquid chromatography. Results The KA/KYN ratio increased from T0 to T1 (p = 0.01) and decreased from T1 to T2 (p = 0.011) in HYP, while it was maintained within MAX. Compared to MAX, serum concentrations of KA were greater in HYP at T1 (p = 0.014). Moreover, the QA/KA ratio was significantly lower in HYP than in MAX at T1 (p = 0.002). Conclusion Acute HYP loading led to increases in the metabolic flux yielding KA, thereby possibly promoting immunosuppression and neuroprotection. Our findings emphasize the potential of acute HYP exercise as short-term modulator of KYN pathway downstream to KA in healthy males and need to be proven in other samples

Cellular immune response to acute exercise

Objectives: Exercise‐induced cellular mobilization might play a role in treatment and prevention of several diseases. However, little is known about the impact of different exercise modalities on immune cell mobilization and clinical cellular inflammation markers. Therefore, the present study aimed to investigate differences between acute endurance exercise (EE) and resistance exercise (RE) on cellular immune alterations. Methods: Twenty‐four healthy men conducted an acute EE (cycling at 60% of peak power output) and RE (five exercise machines at 70% of the one‐repetition maximum) session lasting 50 minutes in randomized order. Blood samples were collected before, after and one hour after exercise cessation. Outcomes included counts and proportions of leukocytes, neutrophils (NEUT), lymphocytes (LYM), LYM subsets, CD4/CD8 ratio, and the clinical cellular inflammation markers NEUT/LYM ratio (NLR), platelets/LYM ratio (PLR), and systemic immune inflammation index (SII). Results: Alterations in all outcomes were revealed except for CD8+ T cells, CD4/CD8 ratio, NLR, and PLR. EE induced a stronger cellular immune response and provoked alterations in more immune cell populations than RE. SII was altered only after EE. Conclusion: An acute EE session causes a stronger mobilization of immune cells than RE. Additionally, SII represents an integrative marker to depict immunological alterations

Feasibility and suitability of a graded exercise test in patients with aggressive hemato-oncological disease

Purpose Physical activity promises to reduce disease-related symptoms and therapy-related side effects in patients suffering from aggressive lymphoma (L) or acute leukemia (AL). For an efficient training program, determination of patients’ physical capacity with a purposive exercise test is crucial. Here, we evaluated the feasibility and suitability of a graded exercise test (GXT) frequently applied in patients suffering from solid tumors by assessing whether patients achieved criteria for maximal exercise testing according to the American College of Sports Medicine (ACSM). Methods The GXT was performed by 51 patients with an aggressive L or AL prior to the start or in the earliest possible phase of high-dose chemotherapy, following a recommended protocol for cancer patients, starting at 20 Watts (W), with an increase of 10 W/min until volitional exhaustion. Subsequently, we investigated whether the following ACSM criteria were fulfilled: (1) failure of heart rate to increase despite increasing workload, (2) post-exercise capillary lactate concentration ≥ 8.0 mmol L−1, (3) rating of perceived exertion at exercise cessation > 17 on the 6–20 Borg Scale. Results Out of 51 patients, two, six, and 35 participants met the first, second, and third criterion, respectively. No relevant relationships between the completion of the criteria and patients’ characteristics (e.g., gender, age) were found. Conclusion Although results of this study suggest a general feasibility of the applied GXT, the ACSM criteria were not met by the majority of the participants. Therefore, this study raises doubts about the suitability of the GXT protocol and the ACSM criteria for this group of patients

Influence of combined functional resistance and endurance exercise over 12 weeks on matrix metalloproteinase-2 serum concentration in persons with relapsing-remitting multiple sclerosis-a community-based randomized controlled trial

Background: The relevance of regular moderate to intense exercise for ameliorating psychomotor symptoms in persons with multiple sclerosis (pwMS) is becoming increasingly evident. Over the last two decades, emerging evidence from clinical studies and animal models indicate immune regulatory mechanisms in both periphery and the central nervous system that may underlie these beneficial effects. The integrity of the blood-brain barrier as the main structural interface between periphery and brain seems to play an important role in MS. Reducing the secretion of proteolytic matrix metalloproteinases (MMP), i.e. MMP-2, as disruptors of blood-brain barrier integrity could have profound implications for MS. Methods: In this two-Armed randomized controlled trial 64 participants with relapsing-remitting MS (RRMS) (EDSS 0-4.0) will be allocated to either an intervention group or a passive wait list control group. The intervention group will perform 60 min of combined functional resistance and endurance exercises 3x per week over a period of 12 weeks in a community-based and publicly available setting. Changes in serum concentration of MMP-2 will be the primary outcome. Secondary outcomes are numbers of immune cell subsets, soluble (anti-) inflammatory factors, physical capacity, cognitive performance, physical activity behavior, gait performance, and patient-reported outcomes. All outcome measures will be assessed at baseline and after week 12 with an additional blood sampling before, during and immediately after a single training session in week 6. Discussion: To our knowledge, this will be the first RCT to investigate both the acute and chronic effects of a community-based intense functional resistance and endurance exercise regimen in persons with RRMS. Combining analysis of biological and cognitive or psychological outcomes may provide a better understanding of the MS-specific symptomology. Trial registration: DRKS00017091; 05th of April, 2019; International Clinical Trials Registry Platform

The OTUD6B-LIN28B-MYC axis determines the proliferative state in multiple myeloma

Deubiquitylases (DUBs) are therapeutically amenable components of the ubiquitin machinery that stabilize substrate proteins. Their inhibition can destabilize oncoproteins that may otherwise be undruggable. Here, we screened for DUB vulnerabilities in multiple myeloma, an incurable malignancy with dependency on the ubiquitin proteasome system and identified OTUD6B as an oncogene that drives the G1/S-transition. LIN28B, a suppressor of microRNA biogenesis, is specified as a bona fide cell cycle-specific substrate of OTUD6B. Stabilization of LIN28B drives MYC expression at G1/S, which in turn allows for rapid S-phase entry. Silencing OTUD6B or LIN28B inhibits multiple myeloma outgrowth in vivo and high OTUD6B expression evolves in patients that progress to symptomatic multiple myeloma and results in an adverse outcome of the disease. Thus, we link proteolytic ubiquitylation with post-transcriptional regulation and nominate OTUD6B as a potential mediator of the MGUS-multiple myeloma transition, a central regulator of MYC, and an actionable vulnerability in multiple myeloma and other tumors with an activated OTUD6B-LIN28B axis.</p