Methods to match high-intensity interval exercise intensity in hypoxia and normoxia - A pilot study.

The aim of this study was to compare high-intensity interval exercise (HIIE) sessions prescribed on the basis of a maximal value (peak power output, PPO) and a submaximal value (lactate threshold, LT) derived from graded exercise tests (GXTs) in normoxia and hypoxia. METHODS: A total of ten males (aged 18-37) volunteered to participate in this study. The experimental protocol consisted of a familiarization procedure, two GXTs under normoxia (FiO2 = 0.209) and two GXTs under normobaric hypoxia (FiO2 = 0.140), and three HIIE sessions performed in a random order. The HIIE sessions included one at hypoxia (HY) and two at normoxia (one matched for the absolute intensity in hypoxia, designated as NA, and one matched for the relative intensity in hypoxia, designated as NR). RESULTS: The data demonstrated that there was significant lower peak oxygen uptake (V̇O2peak), peak heart rate (HRpeak), PPO, and LT derived from GXTs in hypoxia, with higher respiratory exchange ratio (RER), when compared to those from GXTs performed in normoxia (p < 0.001). Among the three HIIE sessions, the NA session resulted in lower percentage of HRpeak (85.0 ± 7.5% vs 94.4 ± 5.0%; p = 0.002) and V̇O2peak (74.1 ± 9.1% vs 88.7 ± 7.7%; p = 0.005), when compared to the NR session. HIIE sessions in HY and NR resulted in similar percentage of HRpeak and V̇O2peak, as well as similar rating of perceived exertion and RER. The blood lactate level increased immediately after all the three HIIE sessions (p < 0.001), while higher blood lactate concentrations were observed immediately after the HY (p = 0.0003) and NR (p = 0.014) sessions when compared with NA. CONCLUSION: Combining of PPO and LT derived from GXTs can be used to prescribe exercise intensity of HIIE in hypoxia.

Fifteen days of moderate normobaric hypoxia does not affect mitochondrial function, and related genes and proteins, in healthy men.

PURPOSE: To investigate within the one study potential molecular and cellular changes associated with mitochondrial biogenesis following 15 days of exposure to moderate hypoxia. METHODS: Eight males underwent a muscle biopsy before and after 15 days of hypoxia exposure (FiO2 = 0.140-0.154; ~ 2500-3200 m) in a hypoxic hotel. Mitochondrial respiration, citrate synthase (CS) activity, and the content of genes and proteins associated with mitochondrial biogenesis were investigated. RESULTS: Our main findings were the absence of significant changes in the mean values of CS activity, mitochondrial respiration in permeabilised fibers, or the content of genes and proteins associated with mitochondrial biogenesis, after 15 days of moderate normobaric hypoxia. CONCLUSION: Our data provide evidence that 15 days of moderate normobaric hypoxia have negligible influence on skeletal muscle mitochondrial content and function, or genes and proteins content associated with mitochondrial biogenesis, in young recreationally active males. However, the increase in mitochondrial protease LON content after hypoxia exposure suggests the possibility of adaptations to optimise respiratory chain function under conditions of reduced O2 availability.

Targeting the DNA Damage Response to Overcome Cancer Drug Resistance in Glioblastoma.

Glioblastoma multiforme (GBM) is a severe brain tumor whose ability to mutate and adapt to therapies is at the base for the extremely poor survival rate of patients. Despite multiple efforts to develop alternative forms of treatment, advances have been disappointing and GBM remains an arduous tumor to treat. One of the leading causes for its strong resistance is the innate upregulation of DNA repair mechanisms. Since standard therapy consists of a combinatory use of ionizing radiation and alkylating drugs, which both damage DNA, targeting the DNA damage response (DDR) is proving to be a beneficial strategy to sensitize tumor cells to treatment. In this review, we will discuss how recent progress in the availability of the DDR kinase inhibitors will be key for future therapy development. Further, we will examine the principal existing DDR inhibitors, with special focus on those currently in use for GBM clinical trials.

Tissue specificity of mitochondrial adaptations in rats after 4 weeks of normobaric hypoxia.

PURPOSE: Exposure to hypoxia has been suggested to activate multiple adaptive pathways so that muscles are better able to maintain cellular energy homeostasis. However, there is limited research regarding the tissue specificity of this response. The aim of this study was to investigate the influence of tissue specificity on mitochondrial adaptations of rat skeletal and heart muscles after 4 weeks of normobaric hypoxia (FiO2: 0.10). METHODS: Twenty male Wistar rats were randomly assigned to either normobaric hypoxia or normoxia. Mitochondrial respiration was determined in permeabilised muscle fibres from left and right ventricles, soleus and extensorum digitorum longus (EDL). Citrate synthase activity and the relative abundance of proteins associated with mitochondrial biogenesis were also analysed. RESULTS: After hypoxia exposure, only the soleus and left ventricle (both predominantly oxidative) presented a greater maximal mass-specific respiration (+48 and +25%, p < 0.05) and mitochondrial-specific respiration (+75 and +28%, p < 0.05). Citrate synthase activity was higher in the EDL (0.63 ± 0.08 vs 0.41 ± 0.10 µmol min- 1 µg- 1) and lower in the soleus (0.65 ± 0.17 vs 0.87 ± 0.20 µmol min- 1 µg- 1) in hypoxia with respect to normoxia. There was a lower relative protein abundance of PGC-1α (-25%, p < 0.05) in the right ventricle and a higher relative protein abundance of PGC-1ß (+43%, p < 0.05) in the left ventricle of rats exposed to hypoxia, with few differences for protein abundance in the other muscles. CONCLUSION: Our results show a muscle-specific response to 4 weeks of normobaric hypoxia. Depending on fibre type, and the presence of ventricular hypertrophy, muscles respond differently to the same degree of environmental hypoxia.

Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma.

Caspase-8 was originally identified as a central player of programmed cell death triggered by death receptor stimulation. In that context, its activity is tightly regulated through several mechanisms, with the best established being the expression of FLICE-like inhibitory protein (FLIP) family proteins and the Src-dependent phosphorylation of Caspase-8 on Tyr380. Loss of apoptotic signaling is a hallmark of cancer and indeed Caspase-8 expression is often lost in tumors. This event may account not only for cancer progression but also for cancer resistance to radiotherapy and chemotherapy. Intriguingly, other tumors, such as glioblastoma, preferentially retain Caspase-8 expression, and high levels of Caspase-8 expression may correlate with a worse prognosis, suggesting that in this context this protease loses its apoptotic activity and gains additional functions. Using different cellular systems, it has been clearly shown that in cancer Caspase-8 can exhibit non-canonical functions, including promotion of cell adhesion, migration, and DNA repair. Intriguingly, in glioblastoma models, Caspase-8 can promote NF-κB-dependent expression of several cytokines, angiogenesis, and in vitro and in vivo tumorigenesis. Overall, these observations suggest that some cancer cells may hijack Caspase-8 function which in turn promote cancer progression and resistance to therapy. Here we aim to highlight the multiple functions of Caspase-8 and to discuss whether the molecular mechanisms that modulate the balance between those functions may be targeted to dismantle the aberrant activity of Caspase-8 and to restore its canonical apoptotic functionality.

Platelet aggregation values in patients with cardiovascular risk factors are reduced by verbascoside treatment. A randomized study.

Verbascoside, a phenolic compound, showed several favorable biological activities, including an antiplatelet activity. No in vivo studies tested its efficacy and safety in subjects with cardiovascular (CV) factors. The aim of this randomized, single-center, double-blind, phase II study was to assess the efficacy and tolerability of verbascoside intake for the modulation of platelet aggregation (PA) values in subjects with cardiovascular (CV) risk factors. One-hundred subjects with at least one CV risk factor (age >65 years, diabetes mellitus, hypertension, current cigarettes use, hyperlidemia, waist circumference >102 cm in male or >88 cm in female) were enrolled and randomly assigned to receive placebo or verbascoside 50mg or verbascoside 100mg. PA was measured at baseline and after 2 weeks of study drug assumption, with light transmittance aggregometry (arachidonic acid, AA, 1 µM and adenosine diphosphate, ADP, 5 µM). Two weeks of treatment with placebo or verbascoside 50mg did not modify PA values (both after AA and ADP stimuli). On the contrary, after 2 weeks of verbascoside 100mg, PA values decreased significantly (from 51 ± 13% to 39 ± 15%, p<0.01 after AA; from 60 ± 12% to 49 ± 15%, p = 0.01 after ADP). No serious adverse events were reported during the study, and no subjects discontinued the study because of adverse events. We conclude that long-term intake of verbascoside 100mg significantly reduces PA values in subjects with CV risk factors.

Delineating the contribution of ageing and physical activity to changes in mitochondrial characteristics across the lifespan.

Ageing is associated with widespread physiological changes prominent within all tissues, including skeletal muscle and the brain, which lead to a decline in physical function. To tackle the growing health and economic burdens associated with an ageing population, the concept of healthy ageing has become a major research priority. Changes in skeletal muscle mitochondrial characteristics have been suggested to make an important contribution to the reductions in skeletal muscle function with age, and age-related changes in mitochondrial content, respiratory function, morphology, and mitochondrial DNA have previously been reported. However, not all studies report changes in mitochondrial characteristics with ageing, and there is increasing evidence to suggest that physical activity (or inactivity) throughout life is a confounding factor when interpreting age-associated changes. Given that physical activity is a potent stimulus for inducing beneficial adaptations to mitochondrial characteristics, delineating the influence of physical activity on the changes in skeletal muscle that occur with age is complicated. This review aims to summarise our current understanding and knowledge gaps regarding age-related changes to mitochondrial characteristics within skeletal muscle, as well as to provide some novel insights into brain mitochondria, and to propose avenues of future research and targeted interventions. Furthermore, where possible, we incorporate discussions of the modifying effects of physical activity, exercise, and training status, to purported age-related changes in mitochondrial characteristics.

FBXO32-mediated degradation of PTEN promotes lung adenocarcinoma progression.

FBXO32, a member of the F-box protein family, is known to play both oncogenic and tumor-suppressive roles in different cancers. However, the functions and the molecular mechanisms regulated by FBXO32 in lung adenocarcinoma (LUAD) remain unclear. Here, we report that FBXO32 is overexpressed in LUAD compared with normal lung tissues, and high expression of FBXO32 correlates with poor prognosis in LUAD patients. Firstly, we observed with a series of functional experiments that FBXO32 alters the cell cycle and promotes the invasion and metastasis of LUAD cells. We further corroborate our findings using in vivo mouse models of metastasis and confirmed that FBXO32 positively regulates LUAD tumor metastasis. Using a proteomic-based approach combined with computational analyses, we found a positive correlation between FBXO32 and the PI3K/AKT/mTOR pathway, and identified PTEN as a FBXO32 interactor. More important, FBXO32 binds PTEN via its C-terminal substrate binding domain and we also validated PTEN as a bona fide FBXO32 substrate. Finally, we demonstrated that FBXO32 promotes EMT and regulates the cell cycle by targeting PTEN for proteasomal-dependent degradation. In summary, our study highlights the role of FBXO32 in promoting the PI3K/AKT/mTOR pathway via PTEN degradation, thereby fostering lung adenocarcinoma progression.

Caspase-8 and Tyrosine Kinases: A Dangerous Liaison in Cancer.

Caspase-8 is a cysteine-aspartic acid protease that has been identified as an initiator caspase that plays an essential role in the extrinsic apoptotic pathway. Evasion of apoptosis is a hallmark of cancer and Caspase-8 expression is silenced in some tumors, consistent with its central role in apoptosis. However, in the past years, several studies reported an increased expression of Caspase-8 levels in many tumors and consistently identified novel "non-canonical" non-apoptotic functions of Caspase-8 that overall promote cancer progression and sustain therapy resistance. These reports point to the ability of cancer cells to rewire Caspase-8 function in cancer and raise the question of which are the signaling pathways aberrantly activated in cancer that may contribute to the hijack of Caspase-8 activity. In this regard, tyrosine kinases are among the first oncogenes ever identified and genomic, transcriptomic and proteomic studies indeed show that they represent a class of signaling molecules constitutively activated in most of the tumors. Here, we aim to review and discuss the role of Caspase-8 in cancer and its interplay with Src and other tyrosine kinases.

Caspase-8 as a novel mediator linking Src kinase signaling to enhanced glioblastoma malignancy.

Caspase-8 is a cysteine protease that plays an essential role in apoptosis. Consistently with its canonical proapoptotic function, cancer cells may genetically or epigenetically downregulate its expression. Unexpectedly, Caspase-8 is often retained in cancer, suggesting the presence of alternative mechanisms that may be exploited by cancer cells to their own benefit. In this regard, we reported that Src tyrosine kinase, which is aberrantly activated in many tumors, promotes Caspase-8 phosphorylation on Tyrosine 380 (Y380) preventing its full activation. Here, we investigated the significance of Caspase-8 expression and of its phosphorylation on Y380 in glioblastoma, a brain tumor where both Caspase-8 expression and Src activity are often aberrantly upregulated. Transcriptomic analyses identified inflammatory response as a major target of Caspase-8, and in particular, NFκB signaling as one of the most affected pathways. More importantly, we could show that Src-dependent phosphorylation of Caspase-8 on Y380 drives the assembly of a multiprotein complex that triggers NFκB activation, thereby inducing the expression of inflammatory and pro-angiogenic factors. Remarkably, phosphorylation on Y380 sustains neoangiogenesis and resistance to radiotherapy. In summary, our work identifies a novel interplay between Src kinase and Caspase-8 that allows cancer cells to hijack Caspase-8 to sustain tumor growth.

Determinants of performance in 1,500-m runners.

Our aim was to investigate the relationship between physiological variables (not previously studied) and performance in elite 1,500-m runners. We assessed eight male athletes with an average personal best time of 233.3 ± 6.9 s (110% of the world record) for the 1,500-m race. Ventilatory measurements, maximal oxygen consumption VO2max maximal vastus lateralis muscle deoxygenation (∆[deoxy(Hb+Mb)])max via near-infrared spectroscopy (NIRS), and maximal velocity (V (max)) were obtained during an incremental treadmill test. During subsequent constant-speed exercise at Vmax, we determined the time to exhaustion (Tlim), end-exercise blood lactate concentration ([La]b(max)), VO2 and ∆[deoxy(Hb+Mb)] kinetics parameters. The mean VO2max, [La]b(max) and Vmax were 70.2 ± 3.9 mL kg(-1) min(-1), 12.7 ± 2.4 mmol L(-1), 21.5 ± 0.5 km h(-1), respectively. VO2 at Vmax showed a significant negative correlation with Tlim, whereas [La]b(max) was positively correlated with Tlim. Race speed was found to significantly correlate with ∆[deoxy(Hb+Mb)](max) (79% of maximal value obtained during a transient limb ischemia), ∆[deoxy(Hb+Mb)] slow component (22.9 ± 9.3% of total amplitude) and [La]b(max) at Vmax. [La]b(max) at Vmax was also significantly correlated with ∆[deoxy(Hb+Mb)] slow component, suggesting a greater release of oxygen from the hemoglobin due to the Bohr effect. We conclude that both the maximal capacity of muscle to extract O2 from the blood and the end-exercise blood lactate accumulation are important predictors of best performance in 1,500-m runners.

The Impact of a Precision-Based Exercise Intervention in Childhood Hematological Malignancies Evaluated by an Adapted Yo-Yo Intermittent Recovery Test.

During cancer treatments in childhood hematological malignancies, reduced exercise tolerance is one of the main hardships. Precision-based training programs help children, adolescents, and young adults and their families to resume regular physical activity, exercise, and sports once they return to their communities after the intensive phases spent in hospital. This study was aimed at verifying whether an intermittent recovery test, the Yo-Yo AD, could provide a simple and valid way to evaluate an individual's capacity to perform repeated intense exercise and to follow up on the impact of tailored exercise in children, adolescents, and young adults with hematological malignancies. The Yo-Yo AD involved the repetition of several shuttles to muscle exhaustion, at pre-established speeds (walking and slow running). The heart rate (HR) and oxygen saturation (SaO2) were monitored during the test. The total distance and the walking/running ability, measured as the slope of the HR vs. distance correlation, were investigated before (T0) and after 11 weeks (T1) of precision exercise intervention. The Yo-Yo AD was also performed by healthy children (CTRL). Ninety-seven patients (10.58 ± 4.5 years, 46% female) were enrolled. The Yo-Yo AD showed the positive impact of the exercise intervention by increasing the distance covered by the individuals (T0 = 946.6 ± 438.2 vs. T1 = 1352.3 ± 600.6 m, p < 0.001) with a more efficient walking/running ability (T0 = 2.17 ± 0.84 vs. T1 = 1.73 ± 0.89 slope, p < 0.0164). CTRLs performed better (1754.0 ± 444.0 m, p = 0.010). They were equally skillful (1.71 ± 0.27 slope) when compared to the patients after they received the precision-based intervention. No adverse events occurred during the Yo-Yo AD and it proved to be an accurate way of correctly depicting the changes in performance in childhood hematological malignancies.

ATM Kinase-Dependent Regulation of Autophagy: A Key Player in Senescence?

Increasing evidence suggests a strong interplay between autophagy and genomic stability. Recently, several papers have demonstrated a molecular connection between the DNA Damage Response (DDR) and autophagy and have explored how this link influences cell fate and the choice between apoptosis and senescence in response to different stimuli. The aberrant deregulation of this interplay is linked to the development of pathologies, including cancer and neurodegeneration. Ataxia-telangiectasia mutated kinase (ATM) is the product of a gene that is lost in Ataxia-Telangiectasia (A-T), a rare genetic disorder characterized by ataxia and cerebellar neurodegeneration, defects in the immune response, higher incidence of lymphoma development, and premature aging. Importantly, ATM kinase plays a central role in the DDR, and it can finely tune the balance between senescence and apoptosis: activated ATM promotes autophagy and in particular sustains the lysosomal-mitochondrial axis, which in turn promotes senescence and inhibits apoptosis. Therefore, ATM is the key factor that enables cells to escape apoptosis by entering senescence through modulation of autophagy. Importantly, unlike apoptotic cells, senescent cells are viable and have the ability to secrete proinflammatory and mitogenic factors, thus influencing the cellular environment. In this review we aim to summarize recent advances in the understanding of molecular mechanisms linking DDR and autophagy to senescence, pointing out the role of ATM kinase in these cellular responses. The significance of this regulation in the pathogenesis of Ataxia-Telangiectasia will be discussed.

Tailored Exercise Training Counteracts Muscle Disuse and Attenuates Reductions in Physical Function in Individuals With Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterized by the progressive loss of motor neurons, which leads to a reduction in strength and exercise capacity. Although the concept of "Exercise is Medicine" is accepted for many diseases, the role of exercise in individuals with ALS is still debated. The aim of this study was to propose a tailored exercise training program that was both safe and effective for individuals with ALS, and to evaluate the effects of this combined, moderate-intensity, aerobic and strength training program on aerobic capacities, strength, and physical function. Sixteen individuals with ALS were randomly assigned to either a training (three times a week for 12 weeks; TRAIN, n = 8) or usual care (continued their usual standard of care and served as control; UC, n = 8) group. Peak power, peak oxygen uptake, as well as the gas exchange threshold (GET) during a cardiopulmonary exercise test (CPET) on a cycle ergometer, and the maximal strength (1RM) of the knee extensor muscles, were evaluated before and after 12 weeks. Participants also performed the "Timed Up and Go" (TUG) and the "6-min walking" (6MWT) tests. The ALS Functional Rating Scale revisited (ALSFRS-R), the ALS Severity Scale (ALS-SS), and the McGill quality of life (QoL) questionnaire were also measured. The GET increased from 0.94 ± 0.08 to 1.06 ± 0.10 L min-1 in TRAIN (p = 0.009) and decreased from 0.79 ± 0.17 to 0.72 ± 0.17 L min-1 in UC (p = 0.001). There was a significant difference between groups for changes in TUG (9.1 ± 5.5% improvement in TRAIN and 56.8 ± 18.5% worsening in UC, p = 0.002), ALSFRS-R (4.7 ± 2.6% decrease in TRAIN and 23.0 ± 5.6% decrease in UC, p = 0.007), and for the ALS-SS (2.2 ± 2.1% decrease in TRAIN and 12.4 ± 4.4% decrease in UC, p = 0.04). Even if the 1RM of the knee-extensor muscles showed a tendency to increase in TRAIN (70.1 ± 30.0%, p = 0.07), there was not a statistically significant difference (p = 0.57) with respect to the changes in the UC group (44.9 ± 20.7% increase, p = 0.11). This study showed that a combined moderate-intensity aerobic and strength training program, tailored to the physical capacities of each individual, can improve aerobic fitness and maintain physical function in individuals with ALS.

p16Ink4a Prevents the Activation of Aged Quiescent Dentate Gyrus Stem Cells by Physical Exercise.

In the neurogenic niches-the dentate gyrus of the hippocampus and the subventricular zone (SVZ) adjacent to lateral ventricles-stem cells continue to divide during adulthood, generating progenitor cells and new neurons, and to self-renew, thus maintaining the stem cell pool. During aging, the numbers of stem/progenitor cells in the neurogenic niches are reduced. The preservation of the neurogenic pool is committed to a number of antiproliferative genes, with the role of maintaining the quiescence of neural cells. The cyclin-dependent kinase inhibitor p16Ink4a, whose expression increases with age, controls the expansion of SVZ aging stem cells, since in mice its deficiency prevents the decline of neurogenesis in SVZ. No change of neurogenesis is however observed in the p16Ink4a-null dentate gyrus. Here, we hypothesized that p16Ink4a plays a role as a regulator of the self-renewal of the stem cell pool also in the dentate gyrus, and to test this possibility we stimulated the dentate gyrus neural cells of p16Ink4a-null aging mice with physical exercise, a powerful neurogenic activator. We observed that running highly induced the generation of new stem cells in the p16Ink4a-null dentate gyrus, forcing them to exit from quiescence. Stem cells, notably, are not induced to proliferate by running in wild-type (WT) mice. Moreover, p16Ink4a-null progenitor cells were increased by running significantly above the number observed in WT mice. The new stem and progenitor cells generated new neurons, and continued to actively proliferate in p16Ink4a-null mice longer than in the WT after cessation of exercise. Thus, p16Ink4a prevents aging dentate gyrus stem cells from being activated by exercise. Therefore, p16Ink4a may play a role in the maintenance of dentate gyrus stem cells after stimulus, by keeping a reserve of their self-renewal capacity during aging.

Impact of Hanging Motionless in Harness on Respiratory and Blood Pressure Reflex Modulation in Mountain Climbers.

Harness hang syncope (HHS) is a risk that specifically affects safety of harness users in mountain climbing. Aims: To evaluate individual patterns of breathing resulting from deranged cardiovascular reflexes triggering a syncopal event when a mismatch between cerebral O2 demand and supply is present. Results: Forty healthy participants [aged 39.1 (8.2) years] were enrolled in a motionless suspension test while hanging in harness. Respiratory gas exchange values were analyzed to assess the pattern of breathing (EpInWel, respiratory elastic power) and cardiovascular parameters were monitored (BP, blood pressure). Four participants experienced HHS after 30.0 (7.6) minutes, with an early manifestation of loss of control of both a sustainable EpInWel and BP, starting after 10-12 minutes. Among the other participants, two different reactions were observed during suspension: (1) group G1 tolerated 32.7 (11.4) minutes of suspension by a favorable adaptation of the EpInWel and BP parameters and (2) group G2 showed significantly shorter time of suspension 24.0 (10.4) minutes with unfavorable increase in EpInWel and BP. Conclusions: Greater resistance to HHS occurs in people developing less marked fluctuations of both respiratory and cardiovascular reflex responses. Conversely, wider fluctuations both in control of EpInWel and BP were observed in the event of decreased suspension tolerance or in syncopal events.

The Elusive Path of Brain Tissue Oxygenation and Cerebral Perfusion in Harness Hang Syncope in Mountain Climbers.

Lanfranconi, Francesca, Luca Pollastri, Giovanni Corna, Manuela Bartesaghi, Massimiliano Novarina, Alessandra Ferri, and Giuseppe Andrea Miserocchi. The elusive path of brain tissue oxygenation and cerebral perfusion in harness hang syncope in mountain climbers. High Alt Med Biol. 18:363-371, 2017. AIM: Harness hang syncope (HHS) is a risk that specifically affects wide ranges of situations requiring safety harnesses in mountains. An irreversible orthostatic stasis could lead to death if a prompt rescue is not performed. We aimed at evaluating the risk of developing HHS and at identifying the characteristics related to the pathogenesis of HHS. RESULTS: Forty adults (aged 39.1 [8.2] years) were enrolled in a suspension test lasting about 28.7 (11.4) minutes. We measured cardiovascular parameters, and near infrared spectroscopy (NIRS) was used to assess cerebral hypoxia by changes in the concentration of oxyhemoglobin (Δ[HbO2]) and de-oxyhemoglobin (Δ[HHb]). In the four participants who developed HHS: (1) systolic and diastolic blood pressure showed ample oscillations with a final abrupt drop (∼30 mmHg); (2) Δ[HbO2] increased after 8-12 minutes of suspension and reached a plateau before HHS; and (3) Δ[HHb] decreased with a final abrupt increase before syncope. CONCLUSIONS: Participants who developed HHS failed to activate cardiovascular reflexes that usually safeguard O2 availability to match the metabolic needs of the brain tissue. Since cerebral hypoxia was detected as an early phenomenon by Δ[HbO2] and Δ[HHb] changes, NIRS measurement appears to be the most important parameter to monitor the onset of HHS.

Noninvasive evaluation of skeletal muscle oxidative metabolism after heart transplant.

PURPOSE: The main aim of the present study was to investigate skeletal muscle oxidative metabolism in heart transplant recipients (HTR) by noninvasive tools. METHODS: Twenty male HTR (age 50.4 +/- 2.6 yr; mean +/- SE) and 17 healthy untrained age-matched controls (CTRL) performed an incremental exercise (IE) and a series of constant-load (CLE) moderate-intensity exercise tests on a cycloergometer. The following variables were determined: heart rate (HR); breath-by-breath pulmonary O2 uptake (VO2); and skeletal muscle (vastus lateralis) oxygenation indices by continuous-wave near-infrared spectroscopy. Changes in concentration of deoxygenated hemoglobin (Hb) and myoglobin (Mb) (Delta[deoxy(Hb + Mb)]), expressed as a fraction of values obtained during a transient limb ischemia, were taken as an index of skeletal muscle O2 extraction. "Peak" values were determined at exhaustion during IE. Kinetics of adjustment of variables were determined during CLE. RESULTS: VO2peak, HRpeak, and Delta[deoxy(Hb + Mb)] peak were significantly lower in HTR than in CTRL (17.1 +/- 0.7 vs 34.0 +/- 1.9 mL.kg(-1).min(-1), 133.8 +/- 3.8 vs 173.0 +/- 4.8 bpm, and 0.42 +/- 0.03 vs 0.58 +/- 0.04, respectively). In HTR, Delta[deoxy(Hb + Mb)] increase at submaximal workloads was steeper than in CTRL, suggesting an impaired O2 delivery to skeletal muscles, whereas the lower Delta[deoxy(Hb + Mb)] peak values suggest an impaired capacity of O2 extraction at peak exercise. VO2 and HR kinetics during CLE were significantly slower in HTR than in CTRL, whereas, unexpectedly, no significant differences were found for Delta[deoxy(Hb+Mb)] kinetics (mean response time: 21.3 +/- 1.1 vs 20.2 +/- 1.2 s). CONCLUSION: The findings confirm the presence of both "central" (cardiovascular) and "peripheral" (at the skeletal muscle level) impairments to oxidative metabolism in HTR. The noninvasiveness of the measurements will allow for serial evaluation of the patients, in the presence and/or absence of rehabilitation programs.

Implantable cardioverter defibrillator management: an update.

Implantable cardioverter defibrillator (ICD) is the cornerstone of primary and secondary prevention of sudden cardiac death. In 35 years of technologic improvement and clinical trials, there has been a continuous increase in implantation rate. Purpose of this review is to point out and discuss every aspect related to actual ICD management, investigating implantation procedure and predischarge care, office and remote monitoring follow-up, diagnostic evaluations, management of patients with suspected therapies or malfunctions, heart failure, surgery, radiotherapy and endoscopic procedures. Also, ICD backface such as infections and other complications will be discussed. Finally, we will focus on interesting future perspectives for this setting of patients.

Fifteen days of 3,200 m simulated hypoxia marginally regulates markers for protein synthesis and degradation in human skeletal muscle.

Chronic hypoxia leads to muscle atrophy. The molecular mechanisms responsible for this phenomenon are not well defined in vivo. We sought to determine how chronic hypoxia regulates molecular markers of protein synthesis and degradation in human skeletal muscle and whether these regulations were related to the regulation of the hypoxia-inducible factor (HIF) pathway. Eight young male subjects lived in a normobaric hypoxic hotel (FiO2 14.1%, 3,200 m) for 15 days in well-controlled conditions for nutrition and physical activity. Skeletal muscle biopsies were obtained in the musculus vastus lateralis before (PRE) and immediately after (POST) hypoxic exposure. Intramuscular hypoxia-inducible factor-1 alpha (HIF-1α) protein expression decreased (-49%, P=0.03), whereas hypoxia-inducible factor-2 alpha (HIF-2α) remained unaffected from PRE to POST hypoxic exposure. Also, downstream HIF-1α target genes VEGF-A (-66%, P=0.006) and BNIP3 (-24%, P=0.002) were downregulated, and a tendency was measured for neural precursor cell expressed, developmentally Nedd4 (-47%, P=0.07), suggesting lowered HIF-1α transcriptional activity after 15 days of exposure to environmental hypoxia. No difference was found on microtubule-associated protein 1 light chain 3 type II/I (LC3b-II/I) ratio, and P62 protein expression tended to increase (+45%, P=0.07) compared to PRE exposure levels, suggesting that autophagy was not modulated after chronic hypoxia. The mammalian target of rapamycin complex 1 pathway was not altered as Akt, mammalian target of rapamycin, S6 kinase 1, and 4E-binding protein 1 phosphorylation did not change between PRE and POST. Finally, myofiber cross-sectional area was unchanged between PRE and POST. In summary, our data indicate that moderate chronic hypoxia differentially regulates HIF-1α and HIF-2α, marginally affects markers of protein degradation, and does not modify markers of protein synthesis or myofiber cross-sectional area in human skeletal muscle.