Signalling mechanisms of long term facilitation of breathing with intermittent hypoxia.

Intermittent hypoxia causes long-term facilitation (LTF) of respiratory motor nerve activity and ventilation, which manifests as a persistent increase over the normoxic baseline for an hour or more after the acute hypoxic ventilatory response. LTF is likely involved in sleep apnea, but its exact role is uncertain. Previously, LTF was defined as a serotonergic mechanism, but new evidence shows that multiple signaling pathways can elicit LTF. This raises new questions about the interactions between signaling pathways in different time domains of the hypoxic ventilatory response, which can no longer be defined simply in terms of neurochemical mechanisms

The effect of combined glutamate receptor blockade in the NTS on the hypoxic ventilatory response in awake rats differs from the effect of individual glutamate receptor blockade.

Ventilatory acclimatization to hypoxia (VAH) increases the hypoxic ventilatory response (HVR) and causes persistent hyperventilation when normoxia is restored, which is consistent with the occurrence of synaptic plasticity in acclimatized animals. Recently, we demonstrated that antagonism of individual glutamate receptor types (GluRs) within the nucleus tractus solitarii (NTS) modifies this plasticity and VAH (J. Physiol. 592(8):1839-1856); however, the effects of combined GluR antagonism remain unknown in awake rats. To evaluate this, we exposed rats to room air or chronic sustained hypobaric hypoxia (CSH, PiO2 = 70 Torr) for 7-9 days. On the experimental day, we microinjected artificial cerebrospinal fluid (ACSF: sham) and then a "cocktail" of the GluR antagonists MK-801 and DNQX into the NTS. The location of injection sites in the NTS was confirmed by glutamate injections on a day before the experiment and with histology following the experiment. Ventilation was measured in awake, unrestrained rats breathing normoxia or acute hypoxia (10% O2) in 15-min intervals using barometric pressure plethysmography. In control (CON) rats, acute hypoxia increased ventilation; NTS microinjections of GluR antagonists, but not ACSF, significantly decreased ventilation and breathing frequency in acute hypoxia but not normoxia (P < 0.05). CSH increased ventilation in hypoxia and acute normoxia. In CSH-conditioned rats, GluR antagonists in the NTS significantly decreased ventilation in normoxia and breathing frequency in hypoxia. A persistent HVR after combined GluR blockade in the NTS contrasts with the effect of individual GluR blockade and also with results in anesthetized rats. Our findings support the hypotheses that GluRs in the NTS contribute to, but cannot completely explain, VAH in awake rats

A strategy for determining arterial blood gases on the summit of Mt. Everest

BACKGROUND: Climbers on the summit of Mt. Everest are exposed to extreme hypoxia, and the physiological implications are of great interest. Inferences have been made from alveolar gas samples collected on the summit, but arterial blood samples would give critical information. We propose a plan to insert an arterial catheter at an altitude of 8000 m, take blood samples above this using an automatic sampler, store the samples in glass syringes in an ice-water slurry, and analyze them lower on the mountain 4 to 6 hours later. RESULTS: A preliminary design of the automatic sampler was successfully tested at the White Mountain Research Station (altitude 3800 m – 4300 m). To determine how much the blood gases changed over a long period, rabbit blood was tonometered to give a gas composition close to that expected on the summit (PO(2 )4.0 kPa (30 mmHg), PCO(2 )1.3 kPa (10 mmHg), pH 7.7) and the blood gases were measured every 2 hours for 8 hours both at sea level and 3800 m. The mean changes were PO(2 )+0.3 to +0.4 kPa (+2 to +3 mmHg), PCO(2 )0 to +0.13 kPa (+1 mmHg), pH -0.02 to -0.04, base excess -0.7 to -1.2 mM. In practice the delay before analysis should not exceed 4 to 6 hours. The small paradoxical rise in PO(2 )is presumably caused mainly by contamination of the blood with air. CONCLUSION: We conclude that automatic arterial blood sampling at high altitude is technically feasible and that the changes in the blood gases over a period of several hours are acceptably small

Ibuprofen Blunts Ventilatory Acclimatization to Sustained Hypoxia in Humans.

Ventilatory acclimatization to hypoxia is a time-dependent increase in ventilation and the hypoxic ventilatory response (HVR) that involves neural plasticity in both carotid body chemoreceptors and brainstem respiratory centers. The mechanisms of such plasticity are not completely understood but recent animal studies show it can be blocked by administering ibuprofen, a nonsteroidal anti-inflammatory drug, during chronic hypoxia. We tested the hypothesis that ibuprofen would also block the increase in HVR with chronic hypoxia in humans in 15 healthy men and women using a double-blind, placebo controlled, cross-over trial. The isocapnic HVR was measured with standard methods in subjects treated with ibuprofen (400 mg every 8 hrs) or placebo for 48 hours at sea level and 48 hours at high altitude (3,800 m). Subjects returned to sea level for at least 30 days prior to repeating the protocol with the opposite treatment. Ibuprofen significantly decreased the HVR after acclimatization to high altitude compared to placebo but it did not affect ventilation or arterial O2 saturation breathing ambient air at high altitude. Hence, compensatory responses prevent hypoventilation with decreased isocapnic ventilatory O2-sensitivity from ibuprofen at this altitude. The effect of ibuprofen to decrease the HVR in humans provides the first experimental evidence that a signaling mechanism described for ventilatory acclimatization to hypoxia in animal models also occurs in people. This establishes a foundation for the future experiments to test the potential role of different mechanisms for neural plasticity and ventilatory acclimatization in humans with chronic hypoxemia from lung disease

Cognitive function and mood at high altitude following acclimatization and use of supplemental oxygen and adaptive servoventilation sleep treatments.

Impairments in cognitive function, mood, and sleep quality occur following ascent to high altitude. Low oxygen (hypoxia) and poor sleep quality are both linked to impaired cognitive performance, but their independent contributions at high altitude remain unknown. Adaptive servoventilation (ASV) improves sleep quality by stabilizing breathing and preventing central apneas without supplemental oxygen. We compared the efficacy of ASV and supplemental oxygen sleep treatments for improving daytime cognitive function and mood in high-altitude visitors (N = 18) during acclimatization to 3,800 m. Each night, subjects were randomly provided with ASV, supplemental oxygen (SpO2 > 95%), or no treatment. Each morning subjects completed a series of cognitive function tests and questionnaires to assess mood and multiple aspects of cognitive performance. We found that both ASV and supplemental oxygen (O2) improved daytime feelings of confusion (ASV: p < 0.01; O2: p < 0.05) and fatigue (ASV: p < 0.01; O2: p < 0.01) but did not improve other measures of cognitive performance at high altitude. However, performance improved on the trail making tests (TMT) A and B (p < 0.001), the balloon analog risk test (p < 0.0001), and the psychomotor vigilance test (p < 0.01) over the course of three days at altitude after controlling for effects of sleep treatments. Compared to sea level, subjects reported higher levels of confusion (p < 0.01) and performed worse on the TMT A (p < 0.05) and the emotion recognition test (p < 0.05) on nights when they received no treatment at high altitude. These results suggest that stabilizing breathing (ASV) or increasing oxygenation (supplemental oxygen) during sleep can reduce feelings of fatigue and confusion, but that daytime hypoxia may play a larger role in other cognitive impairments reported at high altitude. Furthermore, this study provides evidence that some aspects of cognition (executive control, risk inhibition, sustained attention) improve with acclimatization

The use of intravascular ultrasound imaging to improve use of inferior vena cava filters in a high-risk bariatric population

ObjectivePulmonary embolism is the leading cause of death after gastric bypass procedures for obesity, approximating 0.5% to 4%. All bariatric patients, but especially the super-obese, which have a body mass index (BMI) >50 kg/m2, are at significant risk for postoperative venous thromboembolism (VTE). Visualization and weight limitations of fluoroscopy tables exclude most bariatric and all super-obese patients from inferior vena cava (IVC) filter placement using fluoroscopy. Intravascular ultrasound (IVUS)-guided IVC filter placement is the only modality that allows these high-risk patients to have an IVC filter placed.MethodsHospital and outpatient records of the 494 patients who underwent gastric bypass procedures from January 1, 2004, to May 31, 2006, were reviewed. All patients who had concurrent IVC filter placement with the use of IVUS guidance were selected. Comorbidities, outcomes, and complications were recorded.ResultsWe identified 27 patients with mean BMI of 70 ± 3 kg/m2; of these, 25 were super-obese (BMI >50 kg/m2). Procedures included five laparoscopic and 22 open gastric bypass operations. All patients underwent concurrent IVC filter placement using IVUS guidance. In addition to super-obesity, indications for IVC filter placement included history of VTE (n = 4), known hypercoagulable state (n = 2), and profound immobility (n = 21). Mean follow up was 293 ± 40 days. Technical success rate was 96.3%. There were no catheter site complications. In one surviving patient, a nonfatal pulmonary embolism was detected by computed tomography 2 months postoperatively. Two patients died, and autopsy excluded VTE as the cause of death in both.ConclusionThis study suggests efficacy of IVUS-guided IVC filter placement in preventing mortality from pulmonary embolism in high-risk bariatric patients, including the super-obese. IVUS-guided IVC filter placement can be safely performed with an excellent success rate in all bariatric patients, including the super-obese, who otherwise would not be candidates for IVC filter placement due to the limitations imposed by their large body habitus

Relationships Between Chemoreflex Responses, Sleep Quality, and Hematocrit in Andean Men and Women.

Andean highlanders are challenged by chronic hypoxia and many exhibit elevated hematocrit (Hct) and blunted ventilation compared to other high-altitude populations. While many Andeans develop Chronic Mountain Sickness (CMS) and excessive erythrocytosis, Hct varies markedly within Andean men and women and may be driven by individual differences in ventilatory control and/or sleep events which exacerbate hypoxemia. To test this hypothesis, we quantified relationships between resting ventilation and ventilatory chemoreflexes, sleep desaturation, breathing disturbance, and Hct in Andean men and women. Ventilatory measures were made in 109 individuals (n = 63 men; n = 46 women), and sleep measures in 45 of these participants (n = 22 men; n = 23 women). In both men and women, high Hct was associated with low daytime SpO2 (p < 0.001 and p < 0.002, respectively) and decreased sleep SpO2 (mean, nadir, and time <80%; all p < 0.02). In men, high Hct was also associated with increased end-tidal PCO2 (p < 0.009). While ventilatory responses to hypoxia and hypercapnia did not predict Hct, decreased hypoxic ventilatory responses were associated with lower daytime SpO2 in men (p < 0.01) and women (p < 0.009) and with lower nadir sleep SpO2 in women (p < 0.02). Decreased ventilatory responses to CO2 were associated with more time below 80% SpO2 during sleep in men (p < 0.05). The obstructive apnea index and apnea-hypopnea index also predicted Hct and CMS scores in men after accounting for age, BMI, and SpO2 during sleep. Finally, heart rate response to hypoxia was lower in men with higher Hct (p < 0.0001). These data support the idea that hypoventilation and decreased ventilatory sensitivity to hypoxia are associated with decreased day time and nighttime SpO2 levels that may exacerbate the stimulus for erythropoiesis in Andean men and women. However, interventional and longitudinal studies are required to establish the causal relationships between these associations

Percolation with excluded small clusters and Coulomb blockade in a granular system

We consider dc-conductivity $\sigma$ of a mixture of small conducting and insulating grains slightly below the percolation threshold, where finite clusters of conducting grains are characterized by a wide spectrum of sizes. The charge transport is controlled by tunneling of carriers between neighboring conducting clusters via short ``links'' consisting of one insulating grain. Upon lowering temperature small clusters (up to some $T$-dependent size) become Coulomb blockaded, and are avoided, if possible, by relevant hopping paths. We introduce a relevant percolational problem of next-nearest-neighbors (NNN) conductivity with excluded small clusters and demonstrate (both numerically and analytically) that $\sigma$ decreases as power law of the size of excluded clusters. As a physical consequence, the conductivity is a power-law function of temperature in a wide intermediate temperature range. We express the corresponding index through known critical indices of the percolation theory and confirm this relation numerically.Comment: 7 pages, 6 figure

Polar cap size during 14–16 July 2000 (Bastille Day) solar coronal mass ejection event: MHD modeling and satellite imager observations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94904/1/jgra17603.pd