Right ventricular dysfunction in children and adolescents conceived by assisted reproductive technologies.

Assisted reproductive technologies (ART) predispose the offspring to vascular dysfunction, arterial hypertension, and hypoxic pulmonary hypertension. Recently, cardiac remodeling and dysfunction during fetal and early postnatal life have been reported in offspring of ART, but it is not known whether these cardiac alterations persist later in life and whether confounding factors contribute to this problem. We, therefore, assessed cardiac function and pulmonary artery pressure by echocardiography in 54 healthy children conceived by ART (mean age 11.5 ± 2.4 yr) and 54 age-matched (12.2 ± 2.3 yr) and sex-matched control children. Because ART is often associated with low birth weight and prematurity, two potential confounders associated with cardiac dysfunction, only singletons born with normal birth weight at term were studied. Moreover, because cardiac remodeling in infants conceived by ART was observed in utero, a situation associated with increased right heart load, we also assessed cardiac function during high-altitude exposure, a condition associated with hypoxic pulmonary hypertension-induced right ventricular overload. We found that, while at low altitude cardiac morphometry and function was not different between children conceived by ART and control children, under the stressful conditions of high-altitude-induced pressure overload and hypoxia, larger right ventricular end-diastolic area and diastolic dysfunction (evidenced by lower E-wave tissue Doppler velocity and A-wave tissue Doppler velocity of the lateral tricuspid annulus) were detectable in children and adolescents conceived by ART. In conclusion, right ventricular dysfunction persists in children and adolescents conceived by ART. These cardiac alterations appear to be related to ART per se rather than to low birth weight or prematurity.

Prooxidant/Antioxidant Balance in Hypoxia: A Cross-Over Study on Normobaric vs. Hypobaric "Live High-Train Low".

"Live High-Train Low" (LHTL) training can alter oxidative status of athletes. This study compared prooxidant/antioxidant balance responses following two LHTL protocols of the same duration and at the same living altitude of 2250 m in either normobaric (NH) or hypobaric (HH) hypoxia. Twenty-four well-trained triathletes underwent the following two 18-day LHTL protocols in a cross-over and randomized manner: Living altitude (PIO2 = 111.9 ± 0.6 vs. 111.6 ± 0.6 mmHg in NH and HH, respectively); training "natural" altitude (~1000-1100 m) and training loads were precisely matched between both LHTL protocols. Plasma levels of oxidative stress [advanced oxidation protein products (AOPP) and nitrotyrosine] and antioxidant markers [ferric-reducing antioxidant power (FRAP), superoxide dismutase (SOD) and catalase], NO metabolism end-products (NOx) and uric acid (UA) were determined before (Pre) and after (Post) the LHTL. Cumulative hypoxic exposure was lower during the NH (229 ± 6 hrs.) compared to the HH (310 ± 4 hrs.; P<0.01) protocol. Following the LHTL, the concentration of AOPP decreased (-27%; P<0.01) and nitrotyrosine increased (+67%; P<0.05) in HH only. FRAP was decreased (-27%; P<0.05) after the NH while was SOD and UA were only increased following the HH (SOD: +54%; P<0.01 and UA: +15%; P<0.01). Catalase activity was increased in the NH only (+20%; P<0.05). These data suggest that 18-days of LHTL performed in either NH or HH differentially affect oxidative status of athletes. Higher oxidative stress levels following the HH LHTL might be explained by the higher overall hypoxic dose and different physiological responses between the NH and HH.

Neuronal death after perinatal cerebral hypoxia-ischemia: Focus on autophagy-mediated cell death.

Neonatal hypoxic-ischemic encephalopathy is a critical cerebral event occurring around birth with high mortality and neurological morbidity associated with long-term invalidating sequelae. In view of the great clinical importance of this condition and the lack of very efficacious neuroprotective strategies, it is urgent to better understand the different cell death mechanisms involved with the ultimate aim of developing new therapeutic approaches. The morphological features of three different cell death types can be observed in models of perinatal cerebral hypoxia-ischemia: necrotic, apoptotic and autophagic cell death. They may be combined in the same dying neuron. In the present review, we discuss the different cell death mechanisms involved in neonatal cerebral hypoxia-ischemia with a special focus on how autophagy may be involved in neuronal death, based: (1) on experimental models of perinatal hypoxia-ischemia and stroke, and (2) on the brains of human neonates who suffered from neonatal hypoxia-ischemia.

Effect of oral nitrate supplementation on pulmonary hemodynamics during exercise and time trial performance in normoxia and hypoxia: a randomized controlled trial.

BACKGROUND: Hypoxia-induced pulmonary vasoconstriction increases pulmonary arterial pressure (PAP) and may impede right heart function and exercise performance. This study examined the effects of oral nitrate supplementation on right heart function and performance during exercise in normoxia and hypoxia. We tested the hypothesis that nitrate supplementation would attenuate the increase in PAP at rest and during exercise in hypoxia, thereby improving exercise performance. METHODS: Twelve trained male cyclists [age: 31 ± 7 year (mean ± SD)] performed 15 km time-trial cycling (TT) and steady-state submaximal cycling (50, 100, and 150 W) in normoxia and hypoxia (11% inspired O2) following 3-day oral supplementation with either placebo or sodium nitrate (0.1 mmol/kg/day). We measured TT time-to-completion, muscle tissue oxygenation during TT and systolic right ventricle to right atrium pressure gradient (RV-RA gradient: index of PAP) during steady state cycling. RESULTS: During steady state exercise, hypoxia elevated RV-RA gradient (p > 0.05), while oral nitrate supplementation did not alter RV-RA gradient (p > 0.05). During 15 km TT, hypoxia lowered muscle tissue oxygenation (p < 0.05). Nitrate supplementation further decreased muscle tissue oxygenation during 15 km TT in hypoxia (p < 0.05). Hypoxia impaired time-to-completion during TT (p < 0.05), while no improvements were observed with nitrate supplementation in normoxia or hypoxia (p > 0.05). CONCLUSION: Our findings indicate that oral nitrate supplementation does not attenuate acute hypoxic pulmonary vasoconstriction nor improve performance during time trial cycling in normoxia and hypoxia.

Is altitude training an efficient treatment for obesity?

Worldwide, about half the adult population is considered overweight as defined by a body mass index (BMI - calculated by body weight divided by height squared) ratio in excess of 25 kg.m-2. Of these individuals, half are clinically obese (with a BMI in excess of 30) and these numbers are still increasing, notably in developing countries such as those of the Middle East region. Obesity is a disorder characterised by increased mass of adipose tissue (excessive fat accumulation) that is the result of a systemic imbalance between food intake and energy expenditure. Although factors such as family history, sedentary lifestyle, urbanisation, income and family diet patterns determine obesity prevalence, the main underlying causes are poor knowledge about food choice and lack of physical activity3. Current obesity treatments include dietary restriction, pharmacological interventions and ultimately, bariatric surgery. The beneficial effects of physical activity on weight loss through increased energy expenditure and appetite modulation are also firmly established. Another viable option to induce a negative energy balance, is to incorporate hypoxia per se or combine it with exercise in an individual's daily schedule. This article will present recent evidence suggesting that combining hypoxic exposure and exercise training might provide a cost-effective strategy for reducing body weight and improving cardio-metabolic health in obese individuals. The efficacy of this approach is further reinforced by epidemiological studies using large-scale databases, which evidence a negative relationship between altitude of habitation and obesity. In the United States, for instance, obesity prevalence is inversely associated with altitude of residence and urbanisation, after adjusting for temperature, diet, physical activity, smoking and demographic factors.

Comparison of Griffiths-II and Bayley-II tests for the developmental assessment of high-risk infants.

INTRODUCTION: Two important risk factors for abnormal neurodevelopment are preterm birth and neonatal hypoxic ischemic encephalopathy. The new revisions of Griffiths Mental Development Scale (Griffiths-II, [1996]) and the Bayley Scales of Infant Development (BSID-II, [1993]) are two of the most frequently used developmental diagnostics tests. The Griffiths-II is divided into five subscales and a global development quotient (QD), and the BSID-II is divided into two scales, the Mental scale (MDI) and the Psychomotor scale (PDI). The main objective of this research was to establish the extent to which developmental diagnoses obtained using the new revisions of these two tests are comparable for a given child. MATERIAL AND METHODS: Retrospective study of 18-months-old high-risk children examined with both tests in the follow-up Unit of the Clinic of Neonatology of our tertiary care university Hospital between 2011 and 2012. To determine the concurrent validity of the two tests paired t-tests and Pearson product-moment correlation coefficients were computed. Using the BSID-II as a gold standard, the performance of the Griffiths-II was analyzed with receiver operating curves. RESULTS: 61 patients (80.3% preterm, 14.7% neonatal asphyxia) were examined. For the BSID-II the MDI mean was 96.21 (range 67-133) and the PDI mean was 87.72 (range 49-114). For the Griffiths-II, the QD mean was 96.95 (range 60-124), the locomotors subscale mean was 92.57 (range 49-119). The score of the Griffiths locomotors subscale was significantly higher than the PDI (p<0.001). Between the Griffiths-II QD and the BSID-II MDI no significant difference was found, and the area under the curve was 0.93, showing good validity. All correlations were high and significant with a Pearson product-moment correlation coefficient >0.8. CONCLUSIONS: The meaning of the results for a given child was the same for the two tests. Two scores were interchangeable, the Griffiths-II QD and the BSID-II MDI.

Corticosteroids and the retina: a role for the mineralocorticoid receptor.

PURPOSE OF REVIEW: Long-lasting devices releasing steroids have been approved recently for macular edema of various origins. Identification of the retina as a novel mineralo-sensitive tissue also raises new therapeutic options. RECENT FINDINGS: Recently, the over activation of the mineralocorticoid receptor (MR) pathway has been shown to cause fluid accumulation in the retina, choroidal vasodilation, and to promote retinal neovascularization in hypoxic conditions. These findings indicate that MR antagonists could have beneficial effects in the treatment of retinal diseases. Central serous chorioretinopathy is a retinal disease associated with choroidal vasodilation and subretinal fluid that affects mostly men with type A personality and occurrence has been associated with steroid intake. In several independent studies, MR antagonists have shown beneficial effects, significantly reducing subretinal fluid in eyes of chronic central serous chorioretinopathy patients. SUMMARY: The role of MR in retinal disorder is emerging and the potential association with psychological traits is considered. The place of MR antagonists for retinal diseases treatment is discussed.

Additive effects of rapamycin and aspirin on dendritic cell allostimulatory capacity.

Acting as antigen presenting cells, mature dendritic cells (DCs) initiate both innate and adaptive alloimmune responses. However, immature DCs are weak immunostimulators and mediate tolerogenic effects under certain conditions. Tolerogenic activities of immature DCs can be enhanced by pharmacological agents. Here, we compared pharmacological DC preconditioning with rapamycin and aspirin, applied alone or in combination, on LPS-induced DC maturation and T-cell allostimulatory capacity. Preconditioning with aspirin but not rapamycin tended to reduce the number of mouse bone marrow-derived immature DCs expressing CD40 and major histocompatibility complex class II molecules upon LPS stimulation. Conversely, DC preconditioning with rapamycin, but not aspirin, reduced T-cell alloproliferative responses. A combination of rapamycin and aspirin was more effective than either drug applied alone with respect to inhibition of T-cell alloproliferation. The two agents in combination reduced numbers of CD4(+)IFN-γ(+) Th1 and CD4(+)IL-17(+) Th17 effector cells while maintaining Foxp3(+) regulatory T cells. These results suggest aspirin may moderately enhance rapamycin-mediated inhibition of DC allostimulatory capacity.

Integrating quantitative proteomics and metabolomics in a cellular model of diabetic retinopathy

Diabetic retinopathy is the leading cause of visual loss in individuals under the age of 55. Most investigations into the pathogenesis of diabetic retinopathy have been concentrated on the neural retina since this is where clinical lesions are manifested. Recently, however, various abnormalities in the structural and secretory functions of retinal pigment epithelium that are essential for neuroretina survival, have been found in diabetic retinopathy. In this context, here we study the effect of hyperglycemic and hypoxic conditions on the metabolism of a human retinal pigment epithelial cell line (ARPE-19) by integrating quantitative proteomics using tandem mass tagging (TMT), untargeted metabolomics using MS and NMR, and 13C-glucose isotopic labeling for metabolic tracking. We observed a remarkable metabolic diversification under our simulated in vitro hyperglycemic conditions of diabetes, characterized increased flux through polyol pathways and inhibition of the Krebs cycle and oxidative phosphorylation. Importantly, under low oxygen supply RPE cells seem to consume rapidly glycogen storages and stimulate anaerobic glycolysis. Our results therefore pave the way to future scenarios involving new therapeutic strategies addressed to modulating RPE metabolic impairment, with the aim of regulating structural and secretory alterations of RPE. Finally, this study shows the importance of tackling biomedical problems by integrating metabolomic and proteomics results.

Coma post-anoxique après arrêt cardiaque et hypothermie, peut-on encore prédire le pronostic en 2014 ?

L'encéphalopathie post-anoxique après arrêt cardiaque (AC) est une cause féquente d'admission pour coma en réanimation. Depuis les recommandations de 2003, l'hypothermie thérapeutique (HT) est devenue un standard de traitement après AC et est à l'origine de l'amélioration du pronostic au cours de cette derniere décennie. Les élements prédicteurs de pronostic validés par l'Académie Américaine de Neurologie avant l'ère de l'HT sont devenus moins précis. En effet, l'HT et la sédation retardent la reprise de la réponse motrice et peuvent altérer la valeur prédictive des réflexes du tronc cérébral. Une nouvelle approche est nécessaire pour établir un pronostic après AC et HT. L'enregistrement (pendant l'HTou peu après) d'une activité électroencéphalographique réactive et/ou continue est un bon prédicteur de récupération neurologique favorable après AC. Au contraire, la présence d'un tracé non réactif ou discontinu de type burst-suppression, avec une réponse N20 absente bilatérale aux potentiels évoqués somatosensoriels, sont presqu'à 100 % prédictifs d'un coma irréversible déjà à 48 heures après AC. L'HT modifie aussi la valeur prédictive de l'énolase neuronale spécifique (NSE), principal biomarqueur sérique de la lésion cérébrale post-anoxique. Un réveil avec bonne récupération neurologique a été récemment observé par plusieurs groupes chez des patients présentant des valeurs de NSE>33 μg/L à 48-72 heures : ce seuil ne doit pas être utilisé seul pour guider le traitement. L'imagerie par résonance magnétique de diffusion peut aider à prédire les séquelles neurologiques à long terme. Un réveil chez les patients en coma post-anoxique est de plus en plus observé, malgré l'absence précoce de signes moteurs et une élévation franche des biomarqueurs neuronaux. En 2014, une nouvelle approche multimodale du pronostic est donc nécessaire, pour optimiser la prédiction d'une évolution clinique favorable après AC. Hypoxic-ischemic encephalopathy after cardiac arrest (CA) is a frequent cause of intensive care unit (ICU) admission. Incorporated in all recent guidelines, therapeutic hypothermia (TH) has become a standard of care and has contributed to improve prognosis after CA during the past decade. The accuracy of prognostic predictors validated in 2006 by the American Academy of Neurology before the era of TH is less accurate. Indeed, TH and sedation may delay the recovery of motor response and alter the predictive value of brainstem reflexes. A new approach is needed to accurately establish prognosis after CA and TH. A reactive and/or continuous electroencephalogram background (during TH or shortly thereafter) strongly predicts good outcome. On the contrary, unreactive/spontaneous burst-suppression electroencephalogram pattern, together with absent N20 on somatosensory evoked potentials, is almost 100% predictive of irreversible coma. TH also affects the predictive value of neuronspecific enolase (NSE), the main serum biomarker of postanoxic injury. A good outcome can occur despite NSE levels >33 μg/L, so this cutoff value should not be used alone to guide treatment. Diffusion magnetic resonance imagery may help predict long-term neurological sequelae. Awakening from postanoxic coma is increasingly observed, despite the absence of early motor signs and pathological elevation of NSE. In 2014, a multimodal approach to prognosis is recommended to optimize the prediction of outcome after CA.

Cycling Time Trial Is More Altered in Hypobaric than Normobaric Hypoxia

PURPOSE: Slight physiological differences between acute exposure in normobaric hypoxia (NH) and hypobaric hypoxia (HH) have been reported. Taken together, these differences suggest different physiological responses to hypoxic exposure to a simulated altitude (NH) versus a terrestrial altitude (HH). For this purpose, in the present study, we aimed to directly compare the time-trial performance after acute hypoxia exposure (26 h, 3450 min) by the same subjects under three different conditions: NH, HH, and normobaric normoxia (NN). Based on all of the preceding studies examining the differences among these hypoxic conditions, we hypothesized greater performance impairment in HH than in NH. METHODS: The experimental design consisted of three sessions: NN (Sion: FiO2, 20.93), NH (Sion, hypoxic room: FiO2, 13.6%; barometric pressure, 716 mm Hg), and HH (Jungfraujoch: FiO2, 20.93; barometric pressure, 481 mm Hg). The performance was evaluated at the end of each session with a cycle time trial of 250 kJ. RESULTS: The mean time trial duration in NN was significantly shorter than under the two hypoxic conditions (P < 0.001). In addition, the mean duration in NH was significantly shorter than that in HH (P < 0.01). The mean pulse oxygen saturation during the time trial was significantly lower for HH than for NH (P < 0.05), and it was significantly higher in NN than for the two other sessions (P < 0.001). CONCLUSION: As previously suggested, HH seems to be a more stressful stimulus, and NH and HH should not be used interchangeability when endurance performance is the main objective. The principal factor in this performance difference between hypoxic conditions seemed to be the lower peripheral oxygen saturation in HH at rest, as well as during exercise.

Same Performance Changes after Live High-Train Low in Normobaric vs. Hypobaric Hypoxia.

PURPOSE: We investigated the changes in physiological and performance parameters after a Live High-Train Low (LHTL) altitude camp in normobaric (NH) or hypobaric hypoxia (HH) to reproduce the actual training practices of endurance athletes using a crossover-designed study. METHODS: Well-trained triathletes (n = 16) were split into two groups and completed two 18-day LTHL camps during which they trained at 1100-1200 m and lived at 2250 m (P i O2 = 111.9 ± 0.6 vs. 111.6 ± 0.6 mmHg) under NH (hypoxic chamber; FiO2 18.05 ± 0.03%) or HH (real altitude; barometric pressure 580.2 ± 2.9 mmHg) conditions. The subjects completed the NH and HH camps with a 1-year washout period. Measurements and protocol were identical for both phases of the crossover study. Oxygen saturation (S p O2) was constantly recorded nightly. P i O2 and training loads were matched daily. Blood samples and VO2max were measured before (Pre-) and 1 day after (Post-1) LHTL. A 3-km running-test was performed near sea level before and 1, 7, and 21 days after training camps. RESULTS: Total hypoxic exposure was lower for NH than for HH during LHTL (230 vs. 310 h; P < 0.001). Nocturnal S p O2 was higher in NH than in HH (92.4 ± 1.2 vs. 91.3 ± 1.0%, P < 0.001). VO2max increased to the same extent for NH and HH (4.9 ± 5.6 vs. 3.2 ± 5.1%). No difference was found in hematological parameters. The 3-km run time was significantly faster in both conditions 21 days after LHTL (4.5 ± 5.0 vs. 6.2 ± 6.4% for NH and HH), and no difference between conditions was found at any time. CONCLUSION: Increases in VO2max and performance enhancement were similar between NH and HH conditions.

FemHab: The effects of bed rest and hypoxia on oxidative stress in healthy women.

Independently, both inactivity and hypoxia augment oxidative stress. This study, part of the FemHab project, investigated the combined effects of bed rest-induced unloading and hypoxic exposure on oxidative stress and antioxidant status. Healthy, eumenorrheic women were randomly assigned to the following three 10-day experimental interventions: normoxic bed rest (NBR;n= 11; PiO2 = 133 mmHg), normobaric hypoxic bed rest (HBR;n= 12; PiO2 = 90 mmHg), and ambulatory hypoxic confinement (HAMB;n= 8: PiO2 = 90 mmHg). Plasma samples, obtained before (Pre), during (D2, D6), immediately after (Post) and 24 h after (Post+1) each intervention, were analyzed for oxidative stress markers [advanced oxidation protein products (AOPP), malondialdehyde (MDA), and nitrotyrosine], antioxidant status [superoxide dismutase (SOD), catalase, ferric-reducing antioxidant power (FRAP), glutathione peroxidase (GPX), and uric acid (UA)], NO metabolism end-products (NOx), and nitrites. Compared with baseline, AOPP increased in NBR and HBR on D2 (+14%; +12%;P< 0.05), D6 (+19%; +15%;P< 0.05), and Post (+22%; +21%;P< 0.05), respectively. MDA increased at Post+1 in NBR (+116%;P< 0.01) and D2 in HBR (+114%;P< 0.01) and HAMB (+95%;P< 0.05). Nitrotyrosine decreased (-45%;P< 0.05) and nitrites increased (+46%;P< 0.05) at Post+1 in HAMB only. Whereas SOD was higher at D6 (+82%) and Post+1 (+67%) in HAMB only, the catalase activity increased on D6 (128%) and Post (146%) in HBR and HAMB, respectively (P< 0.05). GPX was only reduced on D6 (-20%;P< 0.01) and Post (-18%;P< 0.05) in HBR. No differences were observed in FRAP and NOx. UA was higher at Post in HBR compared with HAMB (P< 0.05). These data indicate that exposure to combined inactivity and hypoxia impairs prooxidant/antioxidant balance in healthy women. Moreover, habitual activity levels, as opposed to inactivity, seem to blunt hypoxia-related oxidative stress via antioxidant system upregulation.

Similar Hemoglobin Mass Response in Hypobaric and Normobaric Hypoxia in Athletes

PURPOSE: To compare hemoglobin mass (Hbmass) changes during an 18-d live high-train low (LHTL) altitude training camp in normobaric hypoxia (NH) and hypobaric hypoxia (HH). METHODS: Twenty-eight well-trained male triathletes were split into three groups (NH: n = 10, HH: n = 11, control [CON]: n = 7) and participated in an 18-d LHTL camp. NH and HH slept at 2250 m, whereas CON slept, and all groups trained at altitudes <1200 m. Hbmass was measured in duplicate with the optimized carbon monoxide rebreathing method before (pre-), immediately after (post-) (hypoxic dose: 316 vs 238 h for HH and NH), and at day 13 in HH (230 h, hypoxic dose matched to 18-d NH). Running (3-km run) and cycling (incremental cycling test) performances were measured pre and post. RESULTS: Hbmass increased similar in HH (+4.4%, P < 0.001 at day 13; +4.5%, P < 0.001 at day 18) and NH (+4.1%, P < 0.001) compared with CON (+1.9%, P = 0.08). There was a wide variability in individual Hbmass responses in HH (-0.1% to +10.6%) and NH (-1.4% to +7.7%). Postrunning time decreased in HH (-3.9%, P < 0.001), NH (-3.3%, P < 0.001), and CON (-2.1%, P = 0.03), whereas cycling performance changed nonsignificantly in HH and NH (+2.4%, P > 0.08) and remained unchanged in CON (+0.2%, P = 0.89). CONCLUSION: HH and NH evoked similar Hbmass increases for the same hypoxic dose and after 18-d LHTL. The wide variability in individual Hbmass responses in HH and NH emphasizes the importance of individual Hbmass evaluation of altitude training.

Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury.

Perinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy.