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Concept: Hypoxia

171

The incidence of Alzheimer’s disease increases in people who have had an ischemic episode. Furthermore, APP expression is increased following ischemic or hypoxic conditions, as is the production of the Aβ peptide. To address the question of why APP and Aβ are increased in hypoxic and ischemic conditions we induced an ischemic episode in APP knockout mice (APP-/-) and BACE1 knockout mice (BACE-/-). We find that both APP-/- and BACE-/- mice have a dramatically increased risk of mortality as a result of cerebral ischemia. Furthermore, APP knockout mice have reduced cerebral blood flow in response to hypoxia, while wild-type mice maintain or increase cerebral blood flow to the same conditions. The transcription factor, serum response factor (SRF), and calcium-binding molecule, calsequestrin, both involved in vascular regulation, are significantly altered in the brains of APP-/- mice compared to wild type controls. These results show that APP regulates cerebral blood flow in response to hypoxia, and that it, and its cleavage fragments, are crucial for rapid adaptation to ischemic conditions.

Concepts: Alzheimer's disease, Gene, Gene expression, Stroke, Traumatic brain injury, Transcription factor, Ischemia, Hypoxia

164

The mortality after aneurysmal subarachnoid hemorrhage (SAH) is 50%, and most survivors suffer severe functional and cognitive deficits. Half of SAH patients deteriorate 5 to 14 days after the initial bleeding, so-called delayed cerebral ischemia (DCI). Although often attributed to vasospasms, DCI may develop in the absence of angiographic vasospasms, and therapeutic reversal of angiographic vasospasms fails to improve patient outcome. The etiology of chronic neurodegenerative changes after SAH remains poorly understood. Brain oxygenation depends on both cerebral blood flow (CBF) and its microscopic distribution, the so-called capillary transit time heterogeneity (CTH). In theory, increased CTH can therefore lead to tissue hypoxia in the absence of severe CBF reductions, whereas reductions in CBF, paradoxically, improve brain oxygenation if CTH is critically elevated. We review potential sources of elevated CTH after SAH. Pericyte constrictions in relation to the initial ischemic episode and subsequent oxidative stress, nitric oxide depletion during the pericapillary clearance of oxyhemoglobin, vasogenic edema, leukocytosis, and astrocytic endfeet swelling are identified as potential sources of elevated CTH, and hence of metabolic derangement, after SAH. Irreversible changes in capillary morphology and function are predicted to contribute to long-term relative tissue hypoxia, inflammation, and neurodegeneration. We discuss diagnostic and therapeutic implications of these predictions.Journal of Cerebral Blood Flow & Metabolism advance online publication, 25 September 2013; doi:10.1038/jcbfm.2013.173.

Concepts: Blood, Blood vessel, Stroke, Traumatic brain injury, Ischemia, Reperfusion injury, Subarachnoid hemorrhage, Hypoxia

140

Acute exercise has been demonstrated to improve cognitive function. In contrast, severe hypoxia can impair cognitive function. Hence, cognitive function during exercise under severe hypoxia may be determined by the balance between the beneficial effects of exercise and the detrimental effects of severe hypoxia. However, the physiological factors that determine cognitive function during exercise under hypoxia remain unclear. Here, we examined the combined effects of acute exercise and severe hypoxia on cognitive function and identified physiological factors that determine cognitive function during exercise under severe hypoxia. The participants completed cognitive tasks at rest and during moderate exercise under either normoxic or severe hypoxic conditions. Peripheral oxygen saturation, cerebral oxygenation, and middle cerebral artery velocity were continuously monitored. Cerebral oxygen delivery was calculated as the product of estimated arterial oxygen content and cerebral blood flow. On average, cognitive performance improved during exercise under both normoxia and hypoxia, without sacrificing accuracy. However, under hypoxia, cognitive improvements were attenuated for individuals exhibiting a greater decrease in peripheral oxygen saturation. Cognitive performance was not associated with other physiological parameters. Taken together, the present results suggest that arterial desaturation attenuates cognitive improvements during exercise under hypoxia.

Concepts: Better, Oxygen, Improve, Blood, Heart, Middle cerebral artery, Hypoxia, Pulse oximetry

137

The decline of oxygen tension in the tissues below the physiological demand leads to the hypoxic adaptive response. This physiological consequence enables cells to recover from this cellular insult. Understanding the cellular pathways that mediate recovery from hypoxia is therefore critical for developing novel therapeutic approaches for cardiovascular diseases and cancer. The master regulators of oxygen homeostasis that control angiogenesis during hypoxia are hypoxia-inducible factors (HIFs). HIF-1 and HIF-2 function as transcriptional regulators and have both unique and overlapping target genes, whereas the role of HIF-3 is less clear. HIF-1 governs the acute adaptation to hypoxia, whereas HIF-2 and HIF-3 expressions begin during chronic hypoxia in human endothelium. When HIF-1 levels decline, HIF-2 and HIF-3 increase. This switch from HIF-1 to HIF-2 and HIF-3 signaling is required in order to adapt the endothelium to prolonged hypoxia. During prolonged hypoxia, the HIF-1 levels and activity are reduced, despite the lack of oxygen-dependent protein degradation. Although numerous protein factors have been proposed to modulate the HIF pathways, their application for HIF-targeted therapy is rather limited. Recently, the miRNAs that endogenously regulate gene expression via the RNA interference (RNAi) pathway have been shown to play critical roles in the hypoxia response pathways. Furthermore, these classes of RNAs provide therapeutic possibilities to selectively target HIFs and thus modulate the HIF switch. Here, we review the significance of the microRNAs on the relationship between the HIFs under both physiological and pathophysiological conditions.

Concepts: DNA, Gene, Gene expression, Transcription, Virus, RNA, RNA interference, Hypoxia

136

Intermittent hypoxia (IH) has been shown to exert preconditioning-like cardioprotective effects. It also has been reported that IH preserves intracellular pH (pHi) during ischemia and protects cardiomyocytes against ischemic reperfusion injury. However, the exact mechanism is still unclear.

Concepts: Ischemia, Reperfusion injury, Ischemic cascade, Hypoxia, Reperfusion

121

Background Whether noninvasive ventilation should be administered in patients with acute hypoxemic respiratory failure is debated. Therapy with high-flow oxygen through a nasal cannula may offer an alternative in patients with hypoxemia. Methods We performed a multicenter, open-label trial in which we randomly assigned patients without hypercapnia who had acute hypoxemic respiratory failure and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 300 mm Hg or less to high-flow oxygen therapy, standard oxygen therapy delivered through a face mask, or noninvasive positive-pressure ventilation. The primary outcome was the proportion of patients intubated at day 28; secondary outcomes included all-cause mortality in the intensive care unit and at 90 days and the number of ventilator-free days at day 28. Results A total of 310 patients were included in the analyses. The intubation rate (primary outcome) was 38% (40 of 106 patients) in the high-flow-oxygen group, 47% (44 of 94) in the standard group, and 50% (55 of 110) in the noninvasive-ventilation group (P=0.18 for all comparisons). The number of ventilator-free days at day 28 was significantly higher in the high-flow-oxygen group (24±8 days, vs. 22±10 in the standard-oxygen group and 19±12 in the noninvasive-ventilation group; P=0.02 for all comparisons). The hazard ratio for death at 90 days was 2.01 (95% confidence interval [CI], 1.01 to 3.99) with standard oxygen versus high-flow oxygen (P=0.046) and 2.50 (95% CI, 1.31 to 4.78) with noninvasive ventilation versus high-flow oxygen (P=0.006). Conclusions In patients with nonhypercapnic acute hypoxemic respiratory failure, treatment with high-flow oxygen, standard oxygen, or noninvasive ventilation did not result in significantly different intubation rates. There was a significant difference in favor of high-flow oxygen in 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique Interrégional 2010 of the French Ministry of Health; FLORALI ClinicalTrials.gov number, NCT01320384 .).

Concepts: Oxygen, Intensive care medicine, Hypoxia, Partial pressure, Oxygen therapy, Breathing gas, Nasal cannula, Hypoxemia

66

Systemic vascular pressure in vertebrates is regulated by a range of factors: one key element of control is peripheral resistance in tissue capillary beds. Many aspects of the relationship between central control of vascular flow and peripheral resistance are unclear. An important example of this is the relationship between hypoxic response in individual tissues, and the effect that response has on systemic cardiovascular adaptation to oxygen deprivation. We show here how hypoxic response via the HIF transcription factors in one large vascular bed, that underlying the skin, influences cardiovascular response to hypoxia in mice. We show that the response of the skin to hypoxia feeds back on a wide range of cardiovascular parameters, including heart rate, arterial pressures, and body temperature. These data represent the first demonstration of a dynamic role for oxygen sensing in a peripheral tissue directly modifying cardiovascular response to the challenge of hypoxia.

Concepts: Blood, Heart, Blood vessel, Blood pressure, Cardiovascular system, Hypoxia, Ibn al-Nafis, Pulmonary vein

56

Ocean models predict a decline in the dissolved oxygen inventory of the global ocean of one to seven per cent by the year 2100, caused by a combination of a warming-induced decline in oxygen solubility and reduced ventilation of the deep ocean. It is thought that such a decline in the oceanic oxygen content could affect ocean nutrient cycles and the marine habitat, with potentially detrimental consequences for fisheries and coastal economies. Regional observational data indicate a continuous decrease in oceanic dissolved oxygen concentrations in most regions of the global ocean, with an increase reported in a few limited areas, varying by study. Prior work attempting to resolve variations in dissolved oxygen concentrations at the global scale reported a global oxygen loss of 550 ± 130 teramoles (10(12) mol) per decade between 100 and 1,000 metres depth based on a comparison of data from the 1970s and 1990s. Here we provide a quantitative assessment of the entire ocean oxygen inventory by analysing dissolved oxygen and supporting data for the complete oceanic water column over the past 50 years. We find that the global oceanic oxygen content of 227.4 ± 1.1 petamoles (10(15) mol) has decreased by more than two per cent (4.8 ± 2.1 petamoles) since 1960, with large variations in oxygen loss in different ocean basins and at different depths. We suggest that changes in the upper water column are mostly due to a warming-induced decrease in solubility and biological consumption. Changes in the deeper ocean may have their origin in basin-scale multi-decadal variability, oceanic overturning slow-down and a potential increase in biological consumption.

Concepts: Scientific method, Oxygen, Water, Hypoxia, Quantitative research, Ocean, Decade, Deep sea

42

Although hypoxia is a major stress on physiological processes, several human populations have survived for millennia at high altitudes, suggesting that they have adapted to hypoxic conditions. This hypothesis was recently corroborated by studies of Tibetan highlanders, which showed that polymorphisms in candidate genes show signatures of natural selection as well as well-replicated association signals for variation in hemoglobin levels. We extended genomic analysis to two Ethiopian ethnic groups: Amhara and Oromo. For each ethnic group, we sampled low and high altitude residents, thus allowing genetic and phenotypic comparisons across altitudes and across ethnic groups. Genome-wide SNP genotype data were collected in these samples by using Illumina arrays. We find that variants associated with hemoglobin variation among Tibetans or other variants at the same loci do not influence the trait in Ethiopians. However, in the Amhara, SNP rs10803083 is associated with hemoglobin levels at genome-wide levels of significance. No significant genotype association was observed for oxygen saturation levels in either ethnic group. Approaches based on allele frequency divergence did not detect outliers in candidate hypoxia genes, but the most differentiated variants between high- and lowlanders have a clear role in pathogen defense. Interestingly, a significant excess of allele frequency divergence was consistently detected for genes involved in cell cycle control and DNA damage and repair, thus pointing to new pathways for high altitude adaptations. Finally, a comparison of CpG methylation levels between high- and lowlanders found several significant signals at individual genes in the Oromo.

Concepts: DNA, Gene, Genetics, Natural selection, Genotype, Evolution, Ethiopia, Hypoxia

41

Hypoxic ischemic brain injury (HIBI) after cardiac arrest (CA) is a leading cause of mortality and long-term neurologic disability in survivors. The pathophysiology of HIBI encompasses a heterogeneous cascade that culminates in secondary brain injury and neuronal cell death. This begins with primary injury to the brain caused by the immediate cessation of cerebral blood flow following CA. Thereafter, the secondary injury of HIBI takes place in the hours and days following the initial CA and reperfusion. Among factors that may be implicated in this secondary injury include reperfusion injury, microcirculatory dysfunction, impaired cerebral autoregulation, hypoxemia, hyperoxia, hyperthermia, fluctuations in arterial carbon dioxide, and concomitant anemia.Clarifying the underlying pathophysiology of HIBI is imperative and has been the focus of considerable research to identify therapeutic targets. Most notably, targeted temperature management has been studied rigorously in preventing secondary injury after HIBI and is associated with improved outcome compared with hyperthermia. Recent advances point to important roles of anemia, carbon dioxide perturbations, hypoxemia, hyperoxia, and cerebral edema as contributing to secondary injury after HIBI and adverse outcomes. Furthermore, breakthroughs in the individualization of perfusion targets for patients with HIBI using cerebral autoregulation monitoring represent an attractive area of future work with therapeutic implications.We provide an in-depth review of the pathophysiology of HIBI to critically evaluate current approaches for the early treatment of HIBI secondary to CA. Potential therapeutic targets and future research directions are summarized.

Concepts: Neuron, Blood, Physiology, Traumatic brain injury, Neurology, Ischemia, Hypoxia, Neurotrauma