Erythropoietin regulates hypoxic ventilation in mice by interacting with brainstem and carotid bodies.
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Apart from its role in elevating red blood cell number, erythropoietin (Epo) exerts protective functions in brain, retina and heart upon ischaemic injury. However, the physiological non-erythroid functions of Epo remain unclear. Here we use a transgenic mouse line (Tg21) constitutively overexpressing human Epo in brain to investigate Epo's impact on ventilation upon hypoxic exposure. Tg21 mice showed improved ventilatory response to severe acute hypoxia and moreover improved ventilatory acclimatization to chronic hypoxic exposure. Furthermore, following bilateral transection of carotid sinus nerves that uncouples the brain from the carotid body, Tg21 mice adapted their ventilation to acute severe hypoxia while chemodenervated wild-type (WT) animals developed a life-threatening apnoea. These results imply that Epo in brain modulates ventilation. Additional analysis revealed that the Epo receptor (EpoR) is expressed in the main brainstem respiratory centres and suggested that Epo stimulates breathing control by alteration of catecholaminergic metabolism in brainstem. The modulation of hypoxic pattern of ventilation after i.v. injection of recombinant human Epo in WT mice and the dense EpoR immunosignal observed in carotid bodies showed that these chemoreceptors are sensitive to plasma levels of Epo. In summary, our results suggest that Epo controls ventilation at the central (brainstem) and peripheral (carotid body) levels. These novel findings are relevant to understanding better respiratory disorders including those occurring at high altitude. (+info)
Predicting hypoxia in cystic fibrosis patients during exposure to high altitudes.
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BACKGROUND: For patients with cystic fibrosis (CF)-related partial respiratory insufficiency and reduced arterial oxygen tension at ground level, the mild hypobaric environment on commercial jet aircraft poses the risk of severe hypoxemia. Thus, physicians should be able to estimate the extent of in-flight hypoxia. OBJECTIVES: To derive tools for estimating the expected drop in arterial oxygen partial pressure (paO(2)) and oxygen saturation (saO(2)) in young adult CF patients with mild to moderate airway obstruction during exposure to the hypobaric conditions aboard commercial aircraft and to test the predictive power of a hypobaric chamber simulation. METHODS: Blood gases of 12 CF patients were measured at ground level, at two altitudes in a hypobaric chamber (2000 and 3000 m) and during two 3.5-h flights at cabin altitudes of 1855 m and 1700 m. The altitude dependence of paO(2) and saO(2) in the chamber and during the flights was calculated and results were used to derive estimation equations for in-flight values. RESULTS: In the chamber, saO(2) decreased by 0.33% per 100 m vertical ascent, and this rate increased significantly at altitudes >2000 m. Predicted saO(2) differed from in-flight value by <5%, and agreement between in-flight saO(2) decrease rate and chamber data was good. paO(2) decreased at a rate of 0.99 mm Hg/100 m in the chamber and by 1.33 mm Hg/100 m during flights. None of the subjects showed any clinical symptoms during the flights and the chamber simulation. CONCLUSION: During our worst-case scenario, i.e. the hypobaric chamber simulation at 3000 m, 90% of patients tolerated paO(2) values below the commonly recommended threshold of 50 mm Hg, probably due to adaptation to chronic hypoxemia and lung function impairment. We propose the following equations for an estimation of the expected extent of in-flight hypoxemia in CF patients with mild to moderate airway obstruction and a flight duration of up to 3.5 h: -paO2[Alt]=paO2[ground] -1.33 x Alt[mm Hg], and -saO2[Alt]=saO2[ground] -0.33 x Alt [%], with Alt=altitude in 100 m. In addition to the overall clinical situation of a patient, these equations will serve as a practical supportive tool for the assessment of the fitness to fly in the primary care setting. (+info)
A method for recording single unit activity in lumbar spinal cord in rats anesthetized with nitrous oxide in a hyperbaric chamber.
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The limited potency of nitrous oxide mandates the use of a hyperbaric chamber to produce anesthesia. Use of a hyperbaric chamber complicates anesthetic delivery, ventilation, and electrophysiological recording. We constructed a hyperbaric acrylic-aluminum chamber allowing recording of single unit activity in spinal cord of rats anesthetized only with N(2)O. Large aluminum plates secured to each other by rods that span the length of the chamber close each end of the chamber. The 122 cm long, 33 cm wide chamber housed ventilator, intravenous infusion pumps, recording headstage, including hydraulic microdrive and stepper motors (controlled by external computers). Electrical pass-throughs in the plates permitted electrical current or signals to enter or leave the chamber. In rats anesthetized only with N(2)O we recorded extracellular action potentials with a high signal-to-noise ratio. We also recorded electroencephalographic activity. This technique is well-suited to study actions of weak anesthetics such as N(2)O and Xe at working pressures of 4-5 atm or greater. The safety of such pressures depends on the wall thickness and chamber diameter. (+info)
Use of hydrogen peroxide vapor for deactivation of Mycobacterium tuberculosis in a biological safety cabinet and a room.
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Mycobacterium tuberculosis is an important human pathogen that is routinely cultured in clinical and research laboratories. M. tuberculosis can contaminate surfaces and is highly resistant to disinfection. We investigated whether hydrogen peroxide vapor (HPV) is effective for the deactivation of M. tuberculosis on experimentally contaminated surfaces in a biological safety cabinet (BSC) and a room. Biological indicators (BIs) consisting of an approximately 3-log(10) inoculum of M. tuberculosis on stainless steel discs and a 6-log(10) inoculum of Geobacillus stearothermophilus were exposed to HPV in BSC time course experiments and at 10 locations during room experiments. In three separate BSC experiments, M. tuberculosis BIs were transferred to growth media at 15-min intervals during a 180-min HPV exposure period. No M. tuberculosis BIs grew following 30 min of HPV exposure. In three separate room experiments, M. tuberculosis and G. stearothermophilus BIs were exposed to HPV for 90, 120, and 150 min, respectively. BIs for both microorganisms were deactivated in all 10 locations following 90 min of HPV exposure. HPV provides an alternative to traditional decontamination methods, such as formaldehyde fumigation, for laboratories and other areas contaminated with M. tuberculosis. (+info)
Behavior of rock wool in rat lungs after exposure by nasal inhalation.
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To evaluate the safety of rock wool (RW) fibers, we examined the biopersistence of RW fibers in the lungs of rats, based on the changes of fiber number and fiber size in the length and width, in a nose-only inhalation exposure study. Twenty male Fischer 344 rats (6 to 10 wk old) were exposed to RW fibers at a fiber concentration of 70.6 (20.4) fiber/m(3) and a dispersion density of 30.4 (6.6) mg/m(3) [arithmetic mean (SD)] continuously for 3 h daily for 5 consecutive days. Five rats each were sacrificed shortly after exposure ended (baseline group) and at 1, 2, and 4 wk after exposure, and their lung tissues were ashed by a low temperature plasma-asher. The numbers and sizes of fibers in the ash samples were determined using a phase contrast microscope and a computed image analyzer. The fiber numbers in the lungs at 4 wk after exposure had significantly decreased from the baseline value, i. e. shortly after exposure (p<0.05). The half-lives of RW fibers calculated using the one-compartment model were 32 d for total fibers and 10 d for fibers longer than 20 microm in length. Fiber number was 53.6% of the baseline at 4 wk after exposure (baseline group=100%). Likewise, fiber sizes had significantly decreased at 4 wk after exposure (p<0.05), probably because fibers had been dissolved in body fluid, phagocytosed by alveolar macrophages or discharged from the body by mucociliary movement. In future studies, it will be necessary to examine the carcinogenicity of RW fibers through long-term inhalation studies. (+info)
Effects of inhalation exposure to propylene oxide on respiratory tract, reproduction and development in rats.
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Nasal, respiratory, reproductive and developmental toxicities of propylene oxide (PO) were examined by exposing male and female Sprague-Dawley rats to PO vapor by inhalation at a concentration of 0 (control), 125, 250, 500 or 1,000 ppm for 6 h/d, 7 d/wk, during a 5- to 6-wk period, including premating, mating and postmating or gestation. The inhalation exposure to 1,000 ppm PO seriously affected parental survival, the upper and lower respiratory tract, male and female reproductive systems, motor function, and fetal survival and development, whereas the exposure to 500 ppm or less primarily caused nasal lesions without any sign of reproductive or developmental toxicity. Because atrophy of the olfactory epithelium in the male rats exposed to 250 ppm was the most sensitive endpoint for PO toxicity, the NOAEL was determined to be 125 ppm for the nasal endpoint. An additional inhalation experiment was carried out to further examine developmental toxicity by exposing pregnant rats to 0, 125, 250, 500, 750 or 1,000 ppm PO during a 2-wk period of gestation, Day 6 through Day 19. The 2-wk inhalation experiment revealed that reduced fetal body weights and delayed ossification occurred in association with significantly reduced body weights of the dams exposed to 750 and 1,000 ppm, whereas neither fetal death nor teratogenicity occurred at those two exposure levels. It was concluded that the developmental toxicity of fetal death was manifested at parentally toxic exposure levels above 500 ppm, a level which seriously affected parental survival, the upper and lower respiratory tracts and reproductive system. (+info)
Chronic high-inspired CO2 decreases excitability of mouse hippocampal neurons.
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To examine the effect of chronically elevated CO(2) on excitability and function of neurons, we exposed mice to 8 and 12% CO(2) for 4 wk (starting at 2 days of age), and examined the properties of freshly dissociated hippocampal neurons obtained from slices. Chronic CO(2)-treated neurons (CC) had a similar input resistance (R(m)) and resting membrane potential (V(m)) as control (CON). Although treatment with 8% CO(2) did not change the rheobase (64 +/- 11 pA, n = 9 vs. 47 +/- 12 pA, n = 8 for CC 8% vs. CON; means +/- SE), 12% CO(2) treatment increased it significantly (73 +/- 8 pA, n = 9, P = 0.05). Furthermore, the 12% CO(2) but not the 8% CO(2) treatment decreased the Na(+) channel current density (244 +/- 36 pA/pF, n = 17, vs. 436 +/- 56 pA/pF, n = 18, for CC vs. CON, P = 0.005). Recovery from inactivation was also lowered by 12% but not 8% CO(2). Other gating properties of Na(+) current, such as voltage-conductance curve, steady-state inactivation, and time constant for deactivation, were not modified by either treatment. Western blot analysis showed that the expression of Na(+) channel types I-III was not changed by 8% CO(2) treatment, but their expression was significantly decreased by 20-30% (P = 0.03) by the 12% treatment. We conclude from these data and others that neuronal excitability and Na(+) channel expression depend on the duration and level of CO(2) exposure and maturational changes occur in early life regarding neuronal responsiveness to CO(2). (+info)
Effect of aircraft-cabin altitude on passenger discomfort.
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BACKGROUND: Acute mountain sickness occurs in some unacclimatized persons who travel to terrestrial altitudes at which barometric pressures are the same as those in commercial aircraft during flight. Whether the effects are similar in air travelers is unknown. METHODS: We conducted a prospective, single-blind, controlled hypobaric-chamber study of adult volunteers to determine the effect of barometric pressures equivalent to terrestrial altitudes of 650, 4000, 6000, 7000, and 8000 ft (198, 1219, 1829, 2134, and 2438 m, respectively) above sea level on arterial oxygen saturation and the occurrence of acute mountain sickness and discomfort as measured by responses to the Environmental Symptoms Questionnaire IV during a 20-hour simulated flight. RESULTS: Among the 502 study participants, the mean oxygen saturation decreased with increasing altitude, with a maximum decrease of 4.4 percentage points (95% confidence interval, 3.9 to 4.9) at 8000 ft. Overall, acute mountain sickness occurred in 7.4% of the participants, but its frequency did not vary significantly among the altitudes studied. The frequency of reported discomfort increased with increasing altitude and decreasing oxygen saturation and was greater at 7000 to 8000 ft than at all the lower altitudes combined. Differences became apparent after 3 to 9 hours of exposure. Persons older than 60 years of age were less likely than younger persons and men were less likely than women to report discomfort. Four serious adverse events, 1 of which may have been related to the study exposures, and 15 adverse events, 9 of which were related to study exposures, were reported. CONCLUSIONS: Ascent from ground level to the conditions of 7000 to 8000 ft lowered oxygen saturation by approximately 4 percentage points. This level of hypoxemia was insufficient to affect the occurrence of acute mountain sickness but did contribute to the increased frequency of reports of discomfort in unacclimatized participants after 3 to 9 hours. (ClinicalTrials.gov number, NCT00326703 [ClinicalTrials.gov].). (+info)