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Background/ObjectiveCompelling evidence indicates that myokines act in an autocrine, paracrine and endocrine manner to alter metabolic homeostasis. The mechanisms underlying exercise-induced changes in myokine secretion remain to be elucidated. Since exercise acutely decreases oxygen partial pressure (pO(2)) in skeletal muscle (SM), the present study was designed to test the hypothesis that (1) hypoxia exposure impacts myokine secretion in primary human myotubes and (2) exposure to mild hypoxia in vivo alters fasting and postprandial plasma myokine concentrations in humans.MethodsDifferentiated primary human myotubes were exposed to different physiological pO(2) levels for 24 h, and cell culture medium was harvested to determine myokine secretion. Furthermore, we performed a randomized single-blind crossover trial to investigate the impact of mild intermittent hypoxia exposure (MIH: 7-day exposure to 15% O-2, 3x2h/day vs. normoxia: 21% O-2) on in vivo SM pO(2) and plasma myokine concentrations in 12 individuals with overweight and obesity (body-mass index >= 28 kg/m(2)).ResultsHypoxia exposure (1% O-2) increased secreted protein acidic and rich in cysteine (SPARC, p = 0.043) and follistatin like 1 (FSTL1, p = 0.021), and reduced leukemia inhibitory factor (LIF) secretion (p = 0.009) compared to 3% O-2 in primary human myotubes. In addition, 1% O-2 exposure increased interleukin-6 (IL-6, p = 0.004) and SPARC secretion (p = 0.021), whilst reducing fatty acid binding protein 3 (FABP3) secretion (p = 0.021) compared to 21% O-2. MIH exposure in vivo markedly decreased SM pO(2) (approximate to 40%, p = 0.002) but did not alter plasma myokine concentrations.ConclusionsHypoxia exposure altered the secretion of several myokines in primary human myotubes, revealing hypoxia as a novel modulator of myokine secretion. However, both acute and 7-day MIH exposure did not induce alterations in plasma myokine concentrations in individuals with overweight and obesity.

AIM: Hypoxic exercise (HE) may have more pronounced effects on glucose homeostasis than exercise under normoxic conditions (NE), but effects on 24-h glucose profile and substrate utilization remain unclear. We investigated the effects of moderate-intensity HE compared to NE on 24-h glucose profile and substrate metabolism in overweight/obese individuals.METHODS: Ten overweight/obese men with impaired glucose homeostasis participated in a randomized, single-blind, crossover trial. Participants performed moderate-intensity cycling exercise for 4 consecutive days under mild normobaric hypoxic (FiO2: 15%) or normoxic (FiO2: 21%) conditions at similar relative exercise intensity (2x30 min/d at 50% of maximal heart rate, with a ~4 week washout period. 24-h glucose levels and systemic oxygen saturation (SpO2) were monitored throughout the study. At day 5, plasma metabolites and substrate oxidation were determined during a mixed-meal test under normoxic conditions.RESULTS: SpO2 and absolute workload were lower (both PCONCLUSION: HE at similar relative exercise intensity reduces SpO2 and has comparable effects on mean 24-h glucose concentration and glycemic variability than NE in overweight/obese men with impaired glucose metabolism. Nevertheless, a more pronounced reduction in SpO2 during HE was associated with lower 24-h glucose concentrations, suggesting that a marked hypoxic stimulus is needed to improve glucose homeostasis.

Humans living at a higher altitude are less prone to suffer from impaired glucose homeostasis and type 2 diabetes mellitus (T2DM), which might at least partly be explained by lower oxygen availability at higher altitudes. The present systematic review aimed to provide an overview of the current literature on the effects of hypoxia exposure on glucose homeostasis in metabolically compromised humans. Several databases were searched up to August 10th, 2020. The search strategy identified 368 unique records. Following assessment for eligibility based on the selection criteria, 16 studies were included in this review. Six studies (2 controlled studies; 4 uncontrolled studies) demonstrated beneficial effects of hypoxia exposure on glucose homeostasis, while 10 studies (8 controlled studies; 2 uncontrolled studies) reported no improvement in glucose homeostasis following hypoxia exposure. Notably, passive hypoxia exposure seemed to improve glucose homeostasis, whereas hypoxic exercise training (2–8 weeks) appeared to have no additional/synergistic effects on glucose homeostasis compared to normoxia exposure. Due to the heterogeneity in study populations and intervention duration (acute studies / 2–8 wks training), it is difficult to indicate which factors may explain conflicting study outcomes. Moreover, these results should be interpreted with some caution, as several studies did not include a control group. Taken together, hypoxia exposure under resting and exercise conditions might provide a novel therapeutic strategy to improve glucose homeostasis in metabolically compromised individuals, but more randomized controlled trials are warranted before strong conclusions on the effects of hypoxia exposure on glucose homeostasis can be drawn.

Objective Recent studies suggest that hypoxia exposure may improve glucose homeostasis, but well-controlled human studies are lacking. We hypothesized that mild intermittent hypoxia (MIH) exposure decreases tissue oxygen partial pressure (pO2) and induces metabolic improvements in people who are overweight/obese. Methods In a randomized, controlled, single-blind crossover study, 12 men who were overweight/obese were exposed to MIH (15 % O2, 3 × 2 h/day) or normoxia (21 % O2) for 7 consecutive days. Adipose tissue (AT) and skeletal muscle (SM) pO2, fasting/postprandial substrate metabolism, tissue-specific insulin sensitivity, SM oxidative capacity, and AT and SM gene/protein expression were determined. Furthermore, primary human myotubes and adipocytes were exposed to oxygen levels mimicking the hypoxic and normoxic AT and SM microenvironments. Results MIH decreased systemic oxygen saturation (92.0 ± 0.5 % vs 97.1 ± 0.3, p, Highlights • MIH exposure decreases oxygen partial pressure in human adipose tissue and skeletal muscle. • MIH exposure induces a shift in substrate utilization toward glycolytic metabolism. • Hypoxia exposure increases insulin-independent glucose uptake in primary human myotubes, at least in part through AMPK. • MIH does not alter adipose tissue, hepatic and peripheral insulin sensitivity.

Obesity is a complex disorder of excessive adiposity, and is associated with adverse health effects such as cardiometabolic complications, which are to a large extent attributable to dysfunctional white adipose tissue. Adipose tissue dysfunction is characterized by adipocyte hypertrophy, impaired adipokine secretion, a chronic low‐grade inflammatory status, hormonal resistance and altered metabolic responses, together contributing to insulin resistance and related chronic diseases. Adipose tissue hypoxia, defined as a relative oxygen deficit, in obesity has been proposed as a potential contributor to adipose tissue dysfunction, but studies in humans have yielded conflicting results. Here, we will review the role of adipose tissue oxygenation in the pathophysiology of obesity‐related complications, with a specific focus on human studies. We will provide an overview of the determinants of adipose tissue oxygenation, as well as the role of adipose tissue oxygenation in glucose homeostasis, lipid metabolism and inflammation. Finally, we will discuss the putative effects of physiological and experimental hypoxia on adipose tissue biology and whole‐body metabolism in humans. We conclude that several lines of evidence suggest that alteration of adipose tissue oxygenation may impact metabolic homeostasis, thereby providing a novel strategy to combat chronic metabolic diseases in obese humans.

Adipose tissue is a highly dynamic, metabolically active organ involved in a multitude of physiological processes. The expansion of adipose tissue during the development of obesity is often accompanied by adipose tissue dysfunction, which in turn contributes to metabolic and endocrine derangements. Indeed, adipose tissue dysfunction, which is characterized by adipocyte hypertrophy, impaired lipid metabolism, inflammation, a disproportionate deposition of extracellular matrix components, and inadequate vascularization, seems to play a prominent role in insulin resistance and systemic low-grade inflammation. In this chapter, the metabolic and immunological consequences of adipose tissue dysfunction in obesity are discussed. Moreover, we will elaborate on the possible link between adipose tissue dysfunction and lung diseases. Targeting adipose tissue dysfunction may provide a valuable strategy to improve cardiometabolic health and pulmonary function in obese individuals and individuals with sarcopenia, who are characterized by a relative excess of adipose tissue.

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A patient with valproic acid induced hyperammonaemic encephalopathy is presented. During chronic treatment with valproic acid this patient developed a potentially life-threatening encephalopathy without signs of liver failure. After discontinuing the valproic acid the patient recovered completely. In the case of a patient presenting with hyperammonaemic encephalopathy, the possibility of the use of valproic acid should not be overlooked.

The effect of the observational frequency upon the Conduction Electron Spin Resonance recorded from silver foils and sodium in quartz tubes is reported. For both materials an increase in frequency results in an increase in linewidth, a linear relationship being indicated for silver. We interpret some features of the results as being due to surface effects, additional evidence for the influence of the surface on CESR coming from surface treatment of copper foils.

The influence of ion implantation of 56Fe and 63Cu on the bulk properties of the conduction electrons in aluminium has been investigated with the reflection conduction electron spin resonance (CESR) technique at 21 GHz. The doses were kept low and varied from 3*1013 to 5.4*1014 atoms cm-2. Below 25K, large line broadening and an unexpected g rise has been found in the nonannealed Fe implanted samples, which indicate the existence of surface spins. From the similarity between pure and ion implanted Al it is concluded that surface spins may be important in the so called pure Al too.

EPR spectra at 35 and 60 GHz of Gd3+ diluted (∼1%) in powdered SnMo6S8 and PbMo6S8 are presented and interpreted. The crystal field is found to be axial, with D = b20=-760 gauss and -740 Gauss for the tin and lead compounds respectively. Values are obtained for and J(q = 0). Below Tc the impurity to conduction electron relaxation rate is no longer proportional to temperature but decreases more rapidly. From this temperature dependence we extract a value for 2Δ kT c of roughly 5 for both compounds.

A simple theory is developed for the interaction of conduction electron spins with local moments in the bulk or at the surface of the metal, with emphasis on the conduction electron system, which is considered most important. When considering a local moment system with a distribution in g-values and introducing an interaction strength in the electron system, this can give rise to extra linewidth terms, depending on the coupling strengths between the d-s, d-d, and s-s subsystems, as compared to the width of the g-distribution in the d-system. Une theorie simple a ete construite pour expliquer l'interaction des electrons de conduction avec des moments magnetiques locaux situes dans le metal ou sur la surface. On accepte que le systeme des electrons de conduction est le plus important. En considerant un systeme compose de moments locaux avec une distribution des facteurs g et en introduisant une certaine force d'interaction dans le systeme des electrons, on arrive a des largeurs de raie des spectres affectuees par la distribution des facteurs g. Cet elargissement depend evidemment des forces d'interaction entre les systemes d-s, d-d et s-s.

Conduction-electron spin resonance in thin aluminium platelets, coated with a plastic surface layer, has been studied in a reflection spectrometer at 60 GHz. It is shown that the data on linewidth and g -factor fall in line with recent measurements at 21 GHz by the present authors and partly also with earlier measurements at 1.27 GHz 9.27 GHz, 35 GHz and 79 GHz by others.

The construction of a simple high-frequency (100 kHz) modulation technique for conduction-electron spin resonance cavities is described. In K-band cavities, modulation field amplitudes of more than 7 mT can easily be obtained without introducing any noticeable modulation-induced microphonics.

The rise in g factor and linewidth with decreasing temperature below 30 K usually observed in CESR of aluminium samples, is almost absent in samples coated with a plastic layer. The properties of untreated samples are slowly restored after removal of the plastic layer. These observations, together with previous results on ion implanted samples, point towards interactions of the conduction electrons with a layer of localized moments on the surface.

A simple reflection-cavity spectrometer at V-band is described. It consists of a klystron with reflector-modulation stabiliser, a directional coupler, a variable-coupling device, a cavity with high-frequency field modulation and a crystal detector. Its sensitivity is very high, as shown by the detection of conduction-electron spin resonance in aluminium.

Thirty-five patients with severe chronic congestive heart failure that was refractory to conventional therapy were given high dosages of furosemide (250 to 4000 mg/d) because of significantly reduced renal function (mean endogenous creatinine clearance, 0.53 mL/s/1.73 m2 [32 mL/min/1.73 m2]). Natriuresis, weight reduction (mean, 11 kg), and relief of symptoms were achieved in all patients. The mean survival after the start of the high-dose furosemide therapy was 11.3 months (range, 0.5 to 36 months) (n = 35). When this therapy eventually failed, long-term intermittent hemofiltration was performed in eight selected cases, further prolonging survival (mean, 3.0 months). High-dose furosemide therapy and hemofiltration improved the quality of life and prolonged survival. The use of diuretics in congestive heart failure should therefore include treatment with high-dose furosemide, which is effective and can be given over a long period without serious side effects.

A variable coupling to a microwave cavity, achieved by rotating the waveguide with respect to the cavity, is described. The coupling device is sufficiently solid to avoid microphonics, it is easily remotely controlled and has a large tuning range.