Brain-Derived neurotrophic factor and inflammatory biomarkers are unaffected by acute and chronic intermittent hypoxic-hyperoxic exposure in geriatric patients: a randomized controlled trial.

BACKGROUND: Animal and human studies have shown that exposure to hypoxia can increase brain-derived neurotrophic factor (BDNF) protein transcription and reduce systematic inflammatory cytokine response. Therefore, the aim of this study was to investigate the acute and chronic effects of intermittent hypoxic-hyperoxic exposure (IHHE) prior to aerobic exercise on BDNF, interleukin-6 (IL-6), and C-reactive protein (CRP) blood levels in geriatric patients. PATIENTS AND METHODS: Twenty-five geriatric patients (83.1 ± 5.0 yrs, 71.1 ± 10.0 kg, 1.8 ± 0.9 m) participated in a placebo-controlled, single-blinded trial and were randomly assigned to either an intervention (IG) or control group (CG) performing an aerobic cycling training (17 sessions, 20 min·session-1, 3 sessions·week-1). Prior to aerobic cycling exercise, the IG was additionally exposed to IHHE for 30 min, whereas the CG received continuous normoxic air. Blood samples were taken immediately before (pre-exercise) and 10 min (post-exercise) after the first session as well as 48 h (post-training) after the last session to determine serum (BDNFS) and plasma BDNF (BDNFP), IL-6, and CRP levels. Intervention effects were analyzed using a 2 x 2 analysis of covariance with repeated measures. Results were interpreted based on effect sizes with a medium effect considered as meaningful (ηp2 ≥ 0.06, d ≥ 0.5). RESULTS: CRP was moderately higher (d = 0.51) in the CG compared to the IG at baseline. IHHE had no acute effect on BDNFS (ηp2 = 0.01), BDNFP (ηp2 < 0.01), BDNF serum/plasma-ratio (ηp2 < 0.01), IL-6 (ηp2 < 0.01), or CRP (ηp2 = 0.04). After the 6-week intervention, an interaction was found for BDNF serum/plasma-ratio (ηp2 = 0.06) but not for BDNFS (ηp2 = 0.04), BDNFP (ηp2 < 0.01), IL-6 (ηp2 < 0.01), or CRP (ηp2 < 0.01). BDNF serum/plasma-ratio increased from pre-exercise to post-training (d = 0.67) in the CG compared to the IG (d = 0.51). A main effect of time was found for BDNFP (ηp2 = 0.09) but not for BDNFS (ηp2 = 0.02). Within-group post-hoc analyses revealed a training-related reduction in BDNFP in the IG and CG by 46.1% (d = 0.73) and 24.7% (d = 0.57), respectively. CONCLUSION: The addition of 30 min IHHE prior to 20 min aerobic cycling seems not to be effective to increase BDNFS and BDNFP or to reduce IL-6 and CRP levels in geriatric patients after a 6-week intervention.The study was retrospectively registered at drks.de (DRKS-ID: DRKS00025130).

Breast Cancer-related Lymphedema: Recent Updates on Clinical Efficacy of Therapies and Bioengineering Approaches for a Personalized Therapy.

BACKGROUND: Post-mastectomy lymphedema is a chronic progressive disease characterized by a significant reduction in quality of life and a range of complications. AIM: To this date, no single treatment method provides pathological correction of the mechanisms associated with tissue reorganization observed in later-stage breast cancer-related lymphedema (BCRL). METHODS: To define a personalized approach to the management of patients with iatrogenic lymphedema, we performed a systematic review of literature without a comprehensive meta-analysis to outline existing molecular- genetic patterns, overview current treatment methods and their efficacy, and highlight the specific tissue-associated changes in BCRL conditions and other bio-engineering approaches to develop personalized therapy. RESULTS: Our results show that several tissue-specific and pathological molecular markers may be found, yet current research does not aim to define them. CONCLUSION: As such, currently, a strong foundation for further research into molecular-genetic changes in lymphedema tissue exists, and further research should focus on finding specific targets for personalized treatment through bio-engineering approaches.

Influence of acute and chronic intermittent hypoxic-hyperoxic exposure prior to aerobic exercise on cardiovascular risk factors in geriatric patients-a randomized controlled trial.

Background: Intermittent hypoxic-hyperoxic exposure (IHHE) and aerobic training have been proposed as non-pharmacological interventions to reduce age-related risk factors. However, no study has yet examined the effects of IHHE before aerobic exercise on cardiovascular risk factors in the elderly. Therefore, the aim of this study was to investigate the acute and chronic effects of IHHE prior to aerobic cycling exercise on blood lipid and lipoprotein concentrations as well as blood pressure in geriatric patients. Methods: In a randomized, controlled, and single-blinded trial, thirty geriatric patients (72-94 years) were assigned to two groups: intervention (IG; n = 16) and sham control group (CG; n = 14). Both groups completed 6 weeks of aerobic cycling training, 3 times a week for 20 min per day. The IG and CG were additionally exposed to IHHE or sham IHHE (i.e., normoxia) for 30 min prior to aerobic cycling. Blood samples were taken on three occasions: immediately before the first, ∼10 min after the first, and immediately before the last session. Blood samples were analyzed for total (tCh), high-density (HDL-C), and low-density lipoprotein cholesterol (LDL-C), and triglyceride (Tgl) serum concentration. Resting systolic (SBP) and diastolic blood pressure (DBP) was assessed within 1 week before, during (i.e., at week two and four), and after the interventions. Results: The baseline-adjusted ANCOVA revealed a higher LDL-C concentration in the IG compared to the CG after the first intervention session (ηp 2 = 0.12). For tCh, HDL-C, Tgl, and tCh/HDL-C ratio there were no differences in acute changes between the IG and the CG (ηp 2 ≤ 0.01). With regard to the chronic effects on lipids and lipoproteins, data analysis indicated no differences between groups (ηp 2 ≤ 0.03). The repeated measures ANOVA revealed an interaction effect for SBP (ηp 2 = 0.06) but not for DBP (ηp 2 ≤ 0.01). Within-group post-hoc analysis for the IG indicated a reduction in SBP at post-test (d = 0.05). Conclusion: Applying IHHE prior to aerobic cycling seems to be effective to reduce SBP in geriatric patients after 6 weeks of training. The present study suggests that IHHE prior to aerobic cycling can influence the acute exercise-related responses in LDL-C concentration but did not induce chronic changes in basal lipid or lipoprotein concentrations.

Effects of Intermittent Hypoxia-Hyperoxia Exposure Prior to Aerobic Cycling Exercise on Physical and Cognitive Performance in Geriatric Patients-A Randomized Controlled Trial.

Background: It was recently shown that intermittent hypoxic-hyperoxic exposure (IHHE) applied prior to a multimodal training program promoted additional improvements in cognitive and physical performance in geriatric patients compared to physical training only. However, there is a gap in the literature to which extent the addition of IHHE can enhance the effects of an aerobic training. Therefore, the aim of this study was to investigate the efficacy of IHHE applied prior to aerobic cycling exercise on cognitive and physical performance in geriatric patients. Methods: In a randomized, two-armed, controlled, and single-blinded trial, 25 geriatric patients (77-94 years) were assigned to two groups: intervention group (IG) and sham control group (CG). Both groups completed 6 weeks of aerobic training using a motorized cycle ergometer, three times a week for 20 min per day. The IG was additionally exposed to intermittent hypoxic and hyperoxic periods for 30 min prior to exercise. The CG followed the similar procedure breathing sham hypoxia and hyperoxia (i.e., normoxia). Within 1 week before and after the interventions, cognitive performance was assessed with the Dementia-Detection Test (DemTect) and the Clock Drawing Test (CDT), while physical performance was measured using the Timed "Up and Go" Test (TUG) and the Short-Physical-Performance-Battery (SPPB). Results: No interaction effect was found with respect to the DemTect (η p 2 = 0.02). An interaction effect with medium effect size (η p 2 = 0.08) was found for CDT performance with a higher change over time for IG (d = 0.57) compared to CG (d = 0.05). The ANCOVA with baseline-adjustment indicated between-group differences with a large and medium effect size at post-test for the TUG (η p 2 = 0.29) and SPPB (η p 2 = 0.06) performance, respectively, in favour of the IG. Within-group post-hoc analysis showed that the TUG performance was worsened in the CG (d = 0.65) and remained unchanged in the IG (d = 0.19). Furthermore, SPPB performance was increased (d = 0.58) in IG, but no relevant change over time was found for CG (d = 0.00). Conclusion: The current study suggests that an additional IHHE prior to aerobic cycling exercise seems to be more effective to increase global cognitive functions as well as physical performance and to preserve functional mobility in geriatric patients in comparison to aerobic exercise alone after a 6-week intervention period.

Safety and Efficacy of Intermittent Hypoxia Conditioning as a New Rehabilitation/ Secondary Prevention Strategy for Patients with Cardiovascular Diseases: A Systematic Review and Meta-analysis.

BACKGROUND: Once used by mountaineers to facilitate rapid adaptations to altitude and by athletes to improve their aerobic capacity, exposure to hypoxia has been proven to affect various physiological, clinically relevant parameters. A form of conditioning known as Intermittent Hypoxia Conditioning (IHC) consists of repeated exposures to intermittent hypoxia, combined with normoxia and hyperoxia, which has been shown to have potential as a treatment to improve cardio- metabolic risks profile in cardiac patients but results across studies are inconsistent. This systematic review and meta-analysis aimed to evaluate the clinical effectiveness of IHC. METHODS: Four electronic databases (PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials) were searched (from inception to December 2019) to retrieve all studies focused on IHC in elderly patients with cardiovascular disease. A meta-analysis of functional, efficacy and safety outcomes in cardiac patients was completed to compare IHC to sham treatments. RESULTS: Fourteen studies with 320 patients in the Interval Hypoxia-normoxia Group (IHNG) or Interval Hypoxia-hyperoxia training Group (IHHG) and 111 patients in the control group were included in our meta-analysis. IHNT and IHHT were associated with significant reduction in heart rate, SBP, and DBP at rest after treatment [MD= -5.35 beat/min, 95% CI (-9.19 to -1.50), p=0.006], [MD= -13.72 mmHg, 95% CI (-18.31 to -9.132), p<0.001], and [MD= -7.882 mmHg, 95% CI (-13.163 to -2.601), p=0.003], respectively. There were no significant complications or serious adverse events related to IHNT/IHHT. CONCLUSION: The current evidence suggested that the use of the IHNT/IHHT program in elderly patients with CVDs can be safe and effective in terms of heart rate and elevated blood pressure. However, currently, there is no supporting evidence that IHNT/IHHT can significantly improve hematological parameters or lipid profile. Exercise tolerance increased at the end of the course of hypoxic conditioning within IHC group, but did not differ from controls. Further research is needed.

Is fighting against COVID-19 enough?

Tools of empirical epidemiology have been and are indispensable to focus political power on blocking the spreading of coronavirus disease 2019 (COVID-19) by stopping transmission. The present paper is a comment on E. Gibney's article 'Whose coronavirus strategy worked best?' (Nature 2020;581:15-6). The strategy for phase 2 should be more complex and interdisciplinary than described in the paper in Nature, especially in the period before a vaccine and specific treatments are available. The focus on reducing the mortality of COVID-19 will have side effects, including excess mortality from other causes. A part of this excess mortality will be based on the reduction of health-care offers as a consequence of the pandemic, and on structural limitations of the health-care system. A special challenge is to understand the relationship between death from and death with COVID-19, and therefore the relevance of severe acute respiratory syndrome coronavirus 2 infection in people with pre-existing burdens, for example coronary heart disease, cancer or older age. There is a need to extend the recently used tools to all available instruments, including physiological principles of prevention and promotion. The way to integrate global solidarity into the strategies of the different countries is critical not only for global health but also for the peace and long-term success for each individual country. The consequences of efforts against COVID-19 and the impact on reduced air pollution and climate change are also important to analyse from a global health perspective.

Intermittent systemic hypoxic-hyperoxic training for myocardial protection in patients undergoing coronary artery bypass surgery: first results from a single-centre, randomised controlled trial.

Background: Although remote ischaemic preconditioning (RIP) provides protection against myocardial ischaemia and reperfusion injury during cardiac surgery, it is not widely used. Systemic intermittent hypoxic-hyperoxic training (IHHT) may be a suitable alternative. Methods: This is a prospective, single-centre, randomised controlled trial. 127 patients with ischaemic heart disease and indication for coronary artery bypass graft (CABG) surgery from the Cardiology Clinic IM Sechenov First Moscow State Medical University were randomly assigned to IHHT, IHHT-control or RIP. Primary endpoint was serum concentration of troponin I and lactate 2 and 24 hours after surgery. Results: Median value for troponin I 24 hours after surgery was 1.068 (0.388-1.397) ng/mL in the IHHT group and was significantly lower compared with IHHT-controls with 1.980 (1.068-3.239) ng/mL (p=0.012) and to the RIP group with 1.762 (1.288-2.186) ng/mL (p=0.029), while there was no significant difference between RIP and the IHHT-control. Serum lactate after surgery was 1.74 (1.23-2.04) mmol/L in the IHHT group and was also significantly lower compared with IHHT-controls with 2.10 (1.80-2.29) mmol/L (p=0.045) and RIP with 2.12 (1.91-2.33) mmol/L (p=0.032). No significant complications or serious adverse events were observed during IHHT. Intraoperative and early postoperative complications did not differ significantly between groups. Conclusions: The results of this first trial using IHHT for myocardial protection against perioperative ischaemic myocardial injury in patients undergoing CABG surgery are promising and further larger trials should be done with adequate power to detect clinical rather than surrogate marker benefits.

Intermittent Hypoxia-Hyperoxia Conditioning Improves Cardiorespiratory Fitness in Older Comorbid Cardiac Outpatients Without Hematological Changes: A Randomized Controlled Trial.

AIM: To compare a program based on intermittent hypoxia-hyperoxia training (IHHT) consisting of breathing hypoxic-hyperoxic gas mixtures while resting to a standard exercise-based rehabilitation program with respect to cardiorespiratory fitness (CRF) in older, comorbid cardiac outpatients. MATERIALS AND METHODS: Thirty-two cardiac patients with comorbidities were randomly allocated to IHHT and control (CTRL) groups. IHHT completed a 5-week program of exposure to hypoxia-hyperoxia while resting, CTRL completed an 8-week tailored exercise program, and participants in the CTRL were also exposed to sham hypoxia exposure. CRF and relevant hematological biomarkers were measured at baseline and after treatment in both groups. RESULTS: After intervention, CRF in the IHHT group was not significantly different (n = 15, 19.9 ± 6.1 mlO2 minutes-1 kg-1) compared with the CTRL group (n = 14, 20.6 ± 4.9 mlO2 minutes-1 kg-1). CRF in IHHT increased significantly from baseline (6.05 ± 1.6 mlO2 minutes-1 kg-1), while no difference was found in CTRL. Systolic and diastolic blood pressures were not significantly different between groups after treatment. Hemoglobin content was not significantly different between groups. Erythrocytes and reticulocytes did not change pre/post interventions in both experimental groups. CONCLUSIONS: IHHT is safe in patients with cardiac conditions and common comorbidities and it might be a suitable option for older patients who cannot exercise. A 5-week IHHT is as effective as an 8-week exercise program in improving CRF, without hematological changes. Further studies are needed to clarify the nonhematological adaptations to short, repeated exposure to normobaric hypoxia-hyperoxia.

A programme based on repeated hypoxia-hyperoxia exposure and light exercise enhances performance in athletes with overtraining syndrome: a pilot study.

Overtraining syndrome (OTS) is a major concern among endurance athletes and is a leading cause in preventing them to perform for long periods. Intermittent exposure to hypoxia has been shown to be an effective way of improving performance without exercising. Aim of this pilot study was to evaluate intermittent hypoxia-hyperoxia training combined with light exercise as an intervention to facilitate athletes with OTS to restore their usual performance level. Thirty-four track and field athletes were recruited: 15 athletes with OTS volunteered to participate and undertook a conditioning programme consisting of repeated exposures to hypoxia (O2 at 10%) and hyperoxia (O2 at 30%) (6-8 cycles, total time 45 min-1 h), three times a week, delivered 1·5-2 h after a low-intensity exercise session (2 bouts of 30 min, running at 50% of VO2max with 10 min rest between bouts) over 4 weeks. Nineteen healthy track and field athletes volunteered to participate as a control group and followed their usual training schedule. Measurements before and after the intervention included exercise capacity, analysis of heart rate variability and hematological parameters. In athletes with OTS, a 4-week light exercise combined with intermittent hypoxia-hyperoxia training improved exercise performance (191·9 ± 26·9 W versus 170·8 ± 44·8 W in exercise capacity test, P = 0·01). Heart rate variability analysis revealed an improved sympatho-parasympathetic index (low frequency/high frequency ratio, 8·01 ± 7·51 before and 1·45 ± 1·71 after, P = 0·007). Hematological parameters were unchanged. Our pilot study showed that intermittent hypoxia-hyperoxia training and low-intensity exercise can facilitate functional recovery among athletes with OTS in a relatively short time.