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At least 253 records · Page 14

Effects of inspired CO2, hyperventilation, and time on VA/Q inequality in the dog

In a recent study by Tsukimoto et al. (J. Appl. Physiol. 68: 2488-2493, 1990), CO2 inhalation appeared to reduce the size of the high ventilation-perfusion ratio (VA/Q) mode commonly observed in anesthetized mechanically air-ventilated dogs. In that study, large tidal volumes (VT) were used during CO2 inhalation to preserve normocapnia. To separate the influences of CO2 and high VT on the VA/Q distribution in the present study, we examined the effect of inspired CO2 on the high VA/Q mode using eight mechanically ventilated dogs (4 given CO2, 4 controls). The VA/Q distribution was measured first with normal VT and then with increased VT. In the CO2 group at high VT, data were collected before, during, and after CO2 inhalation. With normal VT, there was no difference in the size of the high VA/Q mode between groups [10.5 +/- 3.5% (SE) of ventilation in the CO2 group, 11.8 +/- 5.2% in the control group]. Unexpectedly, the size of the high VA/Q mode decreased similarly in both groups over time, independently of the inspired PCO2, at a rate similar to the fall in cardiac output over time. The reduction in the high VA/Q mode together with a simultaneous increase in alveolar dead space (estimated by the difference between inert gas dead space and Fowler dead space) suggests that poorly perfused high VA/Q areas became unperfused over time. A possible mechanism is that elevated alveolar pressure and decreased cardiac output eliminate blood flow from corner vessels in nondependent high VA/Q regions.

NASA Discipline Cardiopulmonary↗

Vasopressin responses to unloading arterial baroreceptors during cardiac nerve blockade in conscious dogs

We examined the relative contributions of afferent input from the heart and from arterial baroreceptors in the stimulation of arginine vasopressin (AVP) secretion in response to hypotension caused by thoracic inferior vena caval constriction (TIVCC). Afferent input from cardiac receptors was reversibly blocked by infusing 2% procaine into the pericardial space to anesthetize the cardiac nerves. Acute cardiac nerve blockade (CNB) alone caused a rise in mean arterial pressure (MAP) of 24 +/- 3 mmHg but no change in plasma AVP. If the rise in MAP was prevented by TIVCC, plasma AVP increased by 39 +/- 15 pg/ml, and if MAP was allowed to increase and then was forced back to control by TIVCC, plasma AVP increased by 34 +/- 15 pg/ml. Thus the rise in MAP during CNB stimulated arterial baroreceptors, which in turn compensated for the loss of inhibitory input from cardiac receptors on AVP secretion. These results indicate that the maximum secretory response resulting from complete unloading of cardiac receptors at a normal MAP results in a mean increase in plasma AVP of 39 pg/ml in this group of dogs. When MAP was reduced 25% below control levels (from 95 +/- 5 to 69 +/- 3 mmHg) by TIVCC during pericardial saline infusion, plasma AVP increased by 79 +/- 42 pg/ml. However, the same degree of hypotension during CNB (MAP was reduced from 120 +/- 5 to 71 +/- 3 mmHg) led to a greater (P less than 0.05) increase in plasma AVP of 130 +/- 33 pg/ml. Because completely unloading cardiac receptors can account for an increase of only 39 pg/ml on average in this group of dogs, the remainder of the increase in plasma AVP must be due to other sources of stimulation. We suggest that the principal stimulus to AVP secretion after acute CNB in these studies arises from unloading the arterial baroreceptors.

NASA Center ARC↗

Caffeine potentiates the enhancement by choline of striatal acetylcholine release

We investigated the effect of peripherally administered caffeine (50 mg/kg), choline (30, 60, or 120 mg/kg) or combinations of both drugs on the spontaneous release of acetylcholine (ACh) from the corpus striatum of anesthetized rats using in vivo microdialysis. Caffeine alone or choline in the 30 or 60 mg/kg dose failed to increase ACh in microdialysis samples; the 120 mg/kg choline dose significantly enhanced ACh during the 80 min following drug administration. Coadministration of caffeine with choline significantly increased ACh release after each of the choline doses tested. Peak microdialysate levels with the 120 mg/kg dose were increased 112% when caffeine was additionally administered, as compared with 54% without caffeine. These results indicate that choline administration can enhance spontaneous ACh release from neurons, and that caffeine, a drug known to block adenosine receptors on these neurons, can amplify the choline effect.

Non-NASA Center↗

Response properties of gerbil otolith afferents to small angle pitch and roll tilts

The responses from isolated single otolith afferent fibers were obtained to small angle sinusoidal pitch and roll tilts in anesthetized gerbils. The stimulus directions that produced the maximum (response vector) and minimum response sensitivities were determined for each otolith afferent, with response vectors for the units being spread throughout the horizontal plane, similar to those reported for other species. A breadth of tuning measure was derived, with narrowly tuned neurons responding maximally to stimulation in one direction and minimally along an orthogonal ('null') direction. Most (approximately 80%) otolith afferents are narrowly tuned, however, some fibers were broadly tuned responding significantly to stimulations in any direction in the horizontal plane. The number of broadly tuned otolith afferents (approximately 20%) differs significantly from the more substantial number of broadly tuned vestibular nuclei neurons (88%) recently reported in rats.

NASA Discipline Neuroscience↗

Enhanced vasomotion of cerebral arterioles in spontaneously hypertensive rats

Intrinsic rhythmic changes in the diameter of pial cerebral arterioles (30-70 microns) in anesthetized normotensive and hypertensive rats were assessed in vivo to determine if any significant differences exist between the two strains. All diameter measurements were analyzed using a traditional graphic analysis technique and a new frequency spectrum analysis technique known as the Prony Spectral Line Estimator. Graphic analysis of the data revealed that spontaneously hypertensive rats (SHR) possess a significantly greater fundamental frequency (5.57 +/- 0.28 cycles/min) of vasomotion compared to the control Wistar-Kyoto normotensive rats (WKY) (1.95 +/- 0.37 cycles/min). Furthermore, the SHR cerebral arterioles exhibited a significantly greater amplitude of vasomotion (10.07 +/- 0.70 microns) when compared to the WKY cerebral arterioles of the same diameter (8.10 +/- 0.70 microns). Diameter measurements processed with the Prony technique revealed that the fundamental frequency of vasomotion in SHR cerebral arterioles (6.14 +/- 0.39 cycles/min) was also significantly greater than that of the WKY cerebral arterioles (2.99 +/- 0.42 cycles/min). The mean amplitudes of vasomotion in the SHR and WKY strains obtained by the Prony analysis were found not to be statistically significant in contrast to the graphic analysis of the vasomotion amplitude of the arterioles. In addition, the Prony system was able to consistently uncover a very low frequency of vasomotion in both strains of rats that was typically less than 1 cycle/min and was not significantly different between the two strains. The amplitude of this slow frequency was also not significantly different between the two strains. The amplitude of the slow frequency of vasomotion (less than 1 cycle/min) was not different from the amplitude of the higher frequency (2-6 cycles/min) vasomotion by Prony or graphic analysis. These data suggest that a fundamental intrinsic defect exists in the spontaneously hypertensive rat that may contribute to the pathogenesis of hypertension in these animals.

NASA Discipline Cardiopulmonary↗

Cardiopulmonary Resuscitation in Microgravity: Efficacy in the Swine During Parabolic Flight

INTRODUCTION: The International Space Station will need to be as capable as possible in providing Advanced Cardiac Life Support (ACLS) and cardiopulmonary resuscitation (CPR). Previous studies with manikins in parabolic microgravity (0 G) have shown that delivering CPR in microgravity is difficult. End tidal carbon dioxide (PetCO2) has been previously shown to be an effective non-invasive tool for estimating cardiac output during cardiopulmonary resuscitation. Animal models have shown that this diagnostic adjunct can be used as a predictor of survival when PetCO2 values are maintained above 25% of pre-arrest values. METHODS: Eleven anesthetized Yorkshire swine were flown in microgravity during parabolic flight. Physiologic parameters, including PetCO2, were monitored. Standard ACLS protocols were used to resuscitate these models after chemical induction of cardiac arrest. Chest compressions were administered using conventional body positioning with waist restraint and unconventional vertical-inverted body positioning. RESULTS: PetCO2 values were maintained above 25% of both 1-G and O-G pre-arrest values in the microgravity environment (33% +/- 3 and 41 +/- 3). No significant difference between 1-G CPR and O-G CPR was found in these animal models. Effective CPR was delivered in both body positions although conventional body positioning was found to be quickly fatiguing as compared with the vertical-inverted. CONCLUSIONS: Cardiopulmonary resuscitation can be effectively administered in microgravity (0 G). Validation of this model has demonstrated that PetCO2 levels were maintained above a level previously reported to be predictive of survival. The unconventional vertical-inverted position provided effective CPR and was less fatiguing as compared with the conventional body position with waist restraints.

Weightlessness↗

Aerospace Toxicology and Microbiology

Toxicology dates to the very earliest history of humanity with various poisons and venom being recognized as a method of hunting or waging war with the earliest documentation in the Evers papyrus (circa 1500 BCE). The Greeks identified specific poisons such as hemlock, a method of state execution, and the Greek word toxos (arrow) became the root of our modern science. The first scientific approach to the understanding of poisons and toxicology was the work during the late middle ages of Paracelsus. He formulated what were then revolutionary views that a specific toxic agent or "toxicon" caused specific dose-related effects. His principles have established the basis of modern pharmacology and toxicology. In 1700, Bernardo Ramazzini published the book De Morbis Artificum Diatriba (The Diseases of Workers) describing specific illnesses associated with certain labor, particularly metal workers exposed to mercury, lead, arsenic, and rock dust. Modern toxicology dates from development of the modern industrial chemical processes, the earliest involving an analytical method for arsenic by Marsh in 1836. Industrial organic chemicals were synthesized in the late 1800 s along with anesthetics and disinfectants. In 1908, Hamilton began the long study of occupational toxicology issues, and by WW I the scientific use of toxicants saw Haber creating war gases and defining time-dosage relationships that are used even today.

James, John T.↗

Ultrasound Evaluation of the Magnitude of Pneumothorax: A New Concept

Pneumothorax is commonly seen in trauma patients; the diagnosis is usually confirmed by radiography. Use of ultrasound for this purpose, in environments such as space flight and remote terrestrial areas where radiographic capabilities are absent, is being investigated by NASA. In this study, the ability of ultrasound to assess the magnitude of pneumothorax in a porcine model was evaluated. Sonography was performed on anesthetized pigs (avg. wt. 50 kg) in both ground-based laboratory (n = 5) and micro gravity conditions (0 g) aboard the KC-135 aircraft during parabolic flight (n = 4). Aliquots of air (50-1 OOcc) were introduced into the chest through a catheter to simulate pneumothorax. Results were video-recorded and digitized for later interpretation by radiologists. Several distinct sonographic patterns of partial lung sliding were noted, including the combination of a sliding zone with a still zone, and a "segmented" sliding zone. These "partial lung sliding" patterns exclude massive pneumothorax manifested by a complete separation of the lung from the parietal pleura. In 0 g, the sonographic picture was more diverse; 1 g differences between posterior and anterior aspects were diminished. CONCLUSIONS: Modest pneumothorax can be inferred by the ultrasound sign of "partial lung sliding". This finding, which increases the negative predictive value of thoracic ultrasound, may be attributed to intermittent pleural contact, small air spaces, or alterations in pleural lubricant. Further studies of these phenomena are warranted.

Sargsyan, Ashot E.↗

Radiation Exposure Alters Expression of Metabolic Enzyme Genes In Mice

Most pharmaceuticals are metabolized by the liver. The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Because of the importance of the liver in drug metabolism it is important to understand the effects of spaceflight on the enzymes of the liver. Exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments. This study is an effort to examine the effects of adaptive mechanisms that may be triggered by early exposure to low radiation doses. Using procedures approved by the JSC Animal Care & Use Committee, C57 male mice were exposed to Cs-137 in groups: controls, low dose (50 mGy), high dose (6Gy) and a fourth group that received both radiation doses separated by 24 hours. Animals were anesthetized and sacrificed 4 hours after their last radiation exposure. Livers were removed immediately and flash-frozen in liquid nitrogen. Tissue was homogenized, RNA extracted and purified (Absolutely RNA, Agilent). Quality of RNA samples was evaluated (Agilent Bioanalyzer 2100). Complementary DNA was prepared from high-quality RNA samples, and used to run RT-qPCR screening arrays for DNA Repair and Drug Metabolism (SuperArray, SABiosciences/Qiagen; BioRad Cfx96 qPCR System). Of 91 drug metabolism genes examined, expression of 7 was altered by at least one treatment condition. Genes that had elevated expression include those that metabolize promethazine and steroids (4-8-fold), many that reduce oxidation products, and one that reduces heavy metal exposure (greater than 200-fold). Of the 91 DNA repair and general metabolism genes examined, expression of 14 was altered by at least one treatment condition. These gene expression changes are likely homeostatic and could lead to development of new radioprotective countermeasures.

Wotring, Virginia E.↗

Real-Time Teleguidance of a Non-Surgeon Crew Medical Officer Performing Orthopedic Surgery at the Amundsen-Scott South Pole Station During Winter-Over

The Amundsen-Scott South Pole Research station located at the geographic South Pole, is the most isolated, permanently inhabited human outpost on Earth. Medical care is provided to station personnel by a non-surgeon crew medical officer (CMO). During the winter-over period from February to October, the station is isolated, with no incoming or outgoing flights due to severe weather conditions. In late June, four months after the station had closed for the austral winter, a 31 year old meteorologist suffered a complete rupture of his patellar tendon while sliding done an embankment. An evacuation was deemed to be too risky to aircrews due to the extreme cold and darkness. A panel of physicians from Massachusetts General Hospital, Johns Hopkins University and the University of Texas Medical Branch were able to assess the patient remotely via telemedicine and agreed that surgery was the only means to restore mobility and prevent long term disability. The lack of a surgical facility and a trained surgical team were overcome by conversion of the clinic treatment area, and intensive preparation of medical laypersons as surgical assistants. The non-surgeon CMO and CMO assistant at South Pole, were guided through the administration of spinal anesthetic, and the two-hour operative repair by medical consultants at Massachusetts General Hospital. Real-time video of the operative field, directions from the remote consultants and audio communication were provided by videoconferencing equipment, operative cameras, and high bandwidth satellite communications. In real-time, opening incision/exposure, tendon relocation, hemostatsis, and operative closure by the CMO was closely monitored and guided and by the remote consultants. The patient s subsequent physical rehabilitation over the ensuing months of isolation was also monitored remotely via telemedicine. This was the first time in South Pole s history that remote teleguidance had been used for surgery and represents a model for real-time guidance of CMO s working at remote duty stations.

Otto, Christian↗

Expression of Enzymes that Metabolize Medications

INTRODUCTION: Increased exposure to radiation is one physiological stressor associated with spaceflight and it is feasible to conduct ground experiments using known radiation exposures. The health of the liver, especially the activity rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. While radiation is known to alter normal physiological function, how radiation affects liver metabolism of administered medications is unclear. Crew health could be affected if the actions of medications used in spaceflight deviated from expectations formed during terrestrial medication use. This study is an effort to identify liver metabolic enzymes whose expression is altered by spaceflight or by radiation exposures that mimic features of the spaceflight environment. METHODS: Using procedures approved by the Animal Care and Use Committee, mice were exposed to either 137Cs (controls, 50 mGy, 6Gy, or 50 mGy + 6Gy separated by 24 hours) or 13 days of spaceflight on STS 135. Animals were anesthetized and sacrificed at several time points (4 hours, 24 hours or 7 days) after their last radiation exposure, or within 6 hours of return to Earth for the STS 135 animals. Livers were removed immediately and flash-frozen in liquid nitrogen. Tissue was homogenized, RNA extracted, purified and quality-tested. Complementary DNA was prepared from high-quality RNA samples, and used in RT-qPCR experiments to determine relative expression of a wide variety of genes involved in general metabolism and drug metabolism. RESULTS: Results of the ground radiation exposure experiments indicated ~65 genes of the 190 tested were significantly affected by at least one of the radiation doses. Many of the affected genes are involved in the metabolism of drugs with hydrophobic or steroid-like structures, maintenance of redox homeostasis and repair of DNA damage. Most affected genes returned to near control expression levels by 7 days post-treatment. Not all recovered completely by the final time point tested: with 6 Gy exposure, metallothionein expression was 132-fold more than control at the 4 hr time point, and fell at each later time point (11-fold at 24 hrs, and 8-fold at 7 days). In contrast, there were other genes whose expression was altered and remained relatively constant through the 7 day period we tested. One examples is Cyp17a1, which showed a 4-fold elevation at 4 hrs after exposure and remained constant for 7 days after the last treatment. Spaceflight samples evaluated with similar methods and comparisons will be made between the radiation-treated groups and the spaceflight samples. CONCLUSION It seems likely that radiation exposure triggers homeostatic mechanisms, which could include alterations of gene expression. Better understanding of these pathways could aid in optimizing medications doses given to crewmembers who require treatment and eventually, to development of new countermeasures to ameliorate or prevent radiation-induced damage to cells and tissues.

Wotring, V. E.↗

Ultramicro to mesopore frameworks for selective separation and storage of noble gases

Methods and materials for the selective capture and storage of preselected materials from gas streams using metal organic framework (MOF) materials are described. In various embodiments preselected target material gases could include noble gasses such as Kr, Xe, Rn, Arultramicro to mesopore frameworks for selective separation and storage of noble gases, other gasses such as I2 or other particular isotopes either naturally occurring or man-made, or another preselected gas capture material such as a target material for legal, regulatory or treaty compliance, or a preselected material from a particular process such as a cleaning or etching agent from semiconducting or microelectronic manufacture, or a portion of an anesthetic gas such as nitrous oxide, isoflurane, sevoflurane or a fluorinated ethers.

Thallapally, Praveen K.↗

Carotid Artery Stenosis at MSCT: Is there a Threshold in Millimeters that Determines Clinical Significance?

Purpose: The purpose of this work was to determine whether it is possible to identify a reliable carotid stenosis threshold-measured in millimeters (mm)-that is associated with cerebrovascular symptoms. Methods: Written, informed consent was obtained for each patient; 149 consecutive patients (98 men; median age, 68 years) were studied for suspected pathology of the carotid arteries by using MDCTA. In each patient, carotid artery stenosis was quantified using the mm-method. Continuous data were described as the mean value {+-} standard deviation (SD), and they were compared by using the Student's t test. A ROC curve was calculated to test the study hypothesis and identify a specific mm-stenosis threshold. Logistic regression analysis was performed to include other MDCTA findings, such as plaque type and ulcerations. A P value < 0.05 was considered to indicate statistical significance. Results: Twenty-six patients were excluded. Of those remaining, 75 patients suffered cerebrovascular symptoms (61%). There was a statistically significant difference (P = 0.0046) in the mm-carotid stenosis between patients with symptoms (1.31 {+-} 0.64 mm SD) and without symptoms (1.68 {+-} 0.79 mm SD). Multiple logistic regression analysis confirmed that symptoms were associated with increased luminal stenosis (P = 0.013) and with the presence of fatty plaques (P = 0.0491). Moreover, the ROC curve (Az = 0.669; {+-}0.051 SD; P = 0.0009) indicated that a threshold of 1.6 mm stenosis was associated with a sensitivity to symptoms of 76%. Conclusions: The results of our study suggest an association between luminal stenosis (measure in mm) and the presence of cerebrovascular symptoms. Luminal stenosis of 1.6 mm is associated, with a sensitivity of 76%, with cerebrovascular symptoms.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

A possible mechanism for the decrease in serum thyroxine level by phenobarbital in rodents

Effects of phenobarbital (PB) on the levels of serum thyroid hormones such as total thyroxine (T{sub 4}) and triiodothyronine were examined in male mice, hamsters, rats, and guinea pigs. One day after the final administration of PB (80 mg/kg, intraperitoneal, once daily for 4 days), significant decreases in the levels of the serum total T{sub 4} and free T{sub 4} occurred in mice, hamsters, and rats, while a significant decrease in the level of serum triiodothyronine was observed in hamsters and rats among the animals examined. In addition, a significant decrease in the level of serum thyroid-stimulating hormone was observed in only hamsters among the rodents examined. Significant increases in the level and activity of hepatic T{sub 4}-UDP-glucuronosyltransferase (UGT1A) after the PB administration occurred in mice, hamsters, and rats, while the increase in the amount of biliary [{sup 125}I]T{sub 4}-glucuronide after an intravenous injection of [{sup 125}I]T{sub 4} to the PB-pretreated animals occurred only in rats. In mice, rats, and hamsters, but not guinea pigs, PB pretreatment promoted the clearance of [{sup 125}I]T{sub 4} from the serum, led to a significant increase in the steady-state distribution volumes of [{sup 125}I]T{sub 4}, and raised the concentration ratio (Kp value) of the liver to serum and the liver distribution of [{sup 125}I]T{sub 4}. The present findings indicate that the PB-mediated decreases in the serum T{sub 4} level in mice, hamsters, and rats, but not guinea pigs, occur mainly through an increase in the accumulation level of T{sub 4} in the liver.

60 APPLIED LIFE SCIENCES↗

Physiologically-based pharmacokinetic model for Fentanyl in support of the development of Provisional Advisory Levels

Provisional Advisory Levels (PALs) are tiered exposure limits for toxic chemicals in air and drinking water that are developed to assist in emergency responses. Physiologically-based pharmacokinetic (PBPK) modeling can support this process by enabling extrapolations across doses, and exposure routes, thereby addressing gaps in the available toxicity data. Here, we describe the development of a PBPK model for Fentanyl – a synthetic opioid used clinically for pain management – to support the establishment of PALs. Starting from an existing model for intravenous Fentanyl, we first optimized distribution and clearance parameters using several additional IV datasets. We then calibrated the model using pharmacokinetic data for various formulations, and determined the absorbed fraction, F, and time taken for the absorbed amount to reach 90% of its final value, t90. For aerosolized pulmonary Fentanyl, F = 1 and t90 < 1 min indicating complete and rapid absorption. The F value ranged from 0.35 to 0.74 for oral and various transmucosal routes. Oral Fentanyl was absorbed the slowest (t90 ∼ 300 min); the absorption of intranasal Fentanyl was relatively rapid (t90 ∼ 20–40 min); and the various oral transmucosal routes had intermediate absorption rates (t90 ∼ 160–300 min). Based on these results, for inhalation exposures, we assumed that all of the Fentanyl inhaled from the air during each breath directly, and instantaneously enters the arterial circulation. We present model predictions of Fentanyl blood concentrations in oral and inhalation scenarios relevant for PAL development, and provide an analytical expression that can be used to extrapolate between oral and inhalation routes for the derivation of PALs. - Highlights: • We develop a Fentanyl PBPK model for relating external dose to internal levels. • We calibrate the model to oral and inhalation exposures using > 50 human datasets. • Model predictions are in good agreement with the available pharmacokinetic data. • The model can be used for extrapolating across routes, doses and exposure durations. • We illustrate how the model can be used for developing Provisional Advisory Levels.

60 APPLIED LIFE SCIENCES↗

Different behavioral effect dose–response profiles in mice exposed to two-carbon chlorinated hydrocarbons: Influence of structural and physical properties

The present study aimed to clarify whether dose–response profiles of acute behavioral effects of 1,2-dichloroethane (DCE), 1,1,1-trichloroethane (TCE), trichloroethylene (TRIC), and tetrachloroethylene (PERC) differ. A test battery involving 6 behavioral endpoints was applied to evaluate the effects of DCE, TCE, TRIC, and PERC in male ICR strain mice under the same experimental conditions. The behavioral effect dose–response profiles of these compounds differed. Regression analysis was used to evaluate the relationship between the dose–response profiles and structural and physical properties of the compounds. Dose–response profile differences correlated significantly with differences in specific structural and physical properties. These results suggest that differences in specific structural and physical properties of DCE, TCE, TRIC, and PERC are responsible for differences in behavioral effects that lead to a variety of dose–response profiles. - Highlights: • We examine effects of 4 chlorinated hydrocarbons on 6 behavioral endpoints in mice. • The behavioral effect dose–response profiles for the 4 compounds are different. • We utilize regression analysis to clarify probable causes of the different profiles. • The compound's physicochemical properties probably produce the different profiles.

60 APPLIED LIFE SCIENCES↗