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At least 397 records · Page 22

Epstein-Barr virus DNA loads in adult human immunodeficiency virus type 1-infected patients receiving highly active antiretroviral therapy

Patients with human immunodeficiency virus type 1 (HIV-1) infection are at high risk of developing Epstein-Barr virus (EBV)-associated lymphoma. However, little is known of the EBV DNA loads in patients receiving highly active antiretroviral therapy (HAART). Using a real-time quantitative polymerase chain reaction assay, we demonstrated that significantly more HIV-1-infected patients receiving HAART than HIV-1-uninfected volunteers had detectable EBV DNA in blood (57 [81%] of 70 vs. 11 [16%] of 68 patients; P=.001) and saliva (55 [79%] of 68 vs. 37 [54%] of 68 patients; P=.002). The mean EBV loads in blood and saliva samples were also higher in HIV-1-infected patients than in HIV-1-uninfected volunteers (P=.001). The frequency of EBV detection in blood was associated with lower CD4+ cell counts (P=.03) among HIV-1-infected individuals, although no differences were observed in the EBV DNA loads in blood or saliva samples in the HIV-1-infected group. Additional studies are needed to determine whether EBV-specific CD4+ and CD8+ cells play a role in the pathogenesis of EBV in HIV-1-infected patients receiving HAART.

NASA Discipline Regulatory Physiology↗

Aerosols and Particulates Workshop Sampling Procedures and Venues Working Group Summary

The Sampling Procedures and Venues Workgroup discussed the potential venues available and issues associated with obtaining measurements. Some of the issues included Incoming Air Quality, Sampling Locations, Probes and Sample Systems. The following is a summary of the discussion of the issues and venues. The influence of inlet air to the measurement of exhaust species, especially trace chemical species, must be considered. Analysis procedures for current engine exhaust emissions regulatory measurements require adjustments for air inlet humidity. As a matter of course in scientific investigations, it is recommended that "background" measurements for any species, particulate or chemical, be performed during inlet air flow before initiation of combustion, if possible, and during the engine test period as feasible and practical. For current regulatory measurements, this would be equivalent to setting the "zero" level for conventional gas analyzers. As a minimum, it is recommended that measurements of the humidity and particulates in the incoming air be taken at the start and end of each test run. Additional measurement points taken during the run are desirable if they can be practically obtained. It was felt that the presence of trace gases in the incoming air is not a significant problem. However, investigators should consider the ambient levels and influences of local air pollution for species of interest. Desired measurement locations depend upon the investigation requirements. A complete investigation of phenomenology of particulate formation and growth requires measurements at a number of locations both within the engine and in the exhaust field downstream of the nozzle exit plane. Desirable locations for both extractive and in situ measurements include: (1) Combustion Zone (Multiple axial locations); (2) Combustor Exit (Multiple radial locations for annular combustors); (3) Turbine Stage (Inlet and exit of the stage); (4) Exit Nozzle (Multiple axial locations downstream of the nozzle). Actual locations with potential for extractive or non-intrusive measurements depend upon the test article and test configuration. Committee members expressed the importance of making investigators aware of various ports that could allow access to various stages of the existing engines. Port locations are engine si)ecific and might allow extractive sampling or innovative hybrid optical-probe access. The turbine stage region was one the most desirable locations for obtaining samples and might be accessed through boroscope ports available in some engine designs. Discussions of probes and sampling systems quickly identified issues dependent on particular measurement quantities. With general consensus, the group recommends SAE procedures for measurements and data analyses of currently regulated exhaust species (CO2, CO, THC, NO(x),) using conventional gas sampling techniques. Special procedures following sound scientific practices must be developed as required for species and/or measurement conditions not covered by SAE standards. Several issues arose concerning short lived radicals and highly reactive species. For conventional sampling, there are concerns of perturbing the sample during extraction, line losses, line-wall reactions, and chemical reactions during the sample transport to the analyzers. Sample lines coated with quartz.or other materials should be investigated for minimization of such effects. The group advocates the development of innovative probe techniques and non-intrusive optical techniques for measurement of short lived radicals and highly reactive species that cannot be sampled accurately otherwise. Two innovative probe concepts were discussed. One concept uses specially designed probes to transfer optical beams to and from a region of flow inaccessible by traditional ports or windows. The probe can perturb the flow field but must have a negligible impact on the region to be optically sampled. Such probes are referred to as hybrid probes and are under development at AEDC for measurement in the high pressure, high temperature of a combustor under development for power generation. The other concept consists of coupling an instrument directly to the probe. The probe would isolate a representative sample stream, freeze chemical reactions and direct the sample into the analyzer portion of the probe. Thus, the measurement would be performed in situ without sample line losses due either to reactions or binding at the wall surfaces. This concept was used to develop a fast, in situ, time-of-flight mass spectrometer measurement system for temporal quantification of NO in the IMPULSE facility at AEDC. Additional work is required in this area to determine the best probe and sampling technique for each species measurement requirement identified by the Trace Chemistry Working Group. A partial list of Venues was used as a baseline for discussion. Additional venues were added to the list and the list was broken out into the following categories: (1)Engines (a) Sea Level Test Stands (b) Altitude Chambers; (2) Annular Combustor Test Stands, (3) Sector Flametube Test Stands, (4) Fundamentals Rigs/Experiments.

Pachlhofer, Peter↗

Nutrition and renal stone disease in space

There is a growing body of evidence from the National Aeronautics and Space Administration and the Russian space program showing that humans exposed to the microgravity environment of space have a greater risk for developing renal stones. Increased bone resorption and the attendant hypercalciuria and hyperphosphaturia contribute significantly to raising the urinary state of saturation with respect to the calcium salts, namely calcium oxalate and calcium phosphate. In addition, other environmental and dietary factors may adversely affect urine composition and increase stone formation risk during space flight. For example, reductions in urinary volume, pH, and citrate contribute to raising stone formation risk. In addition to raising the risk for calcium stone formation, this metabolic profile is conducive to the formation of uric acid stones. Although observations to date have suggested that there may actually be a reduced food intake during the early phase of flight, crew members on longer-duration flights may increase food intake and be at increased risk for stone formation. Taken together, these findings support the use of nutritional recommendations for crew members that would serve to reduce the stone-forming propensity of the urinary environment. Pharmacologic intervention should be directed at raising urinary volumes, diminishing bone losses, and preventing reductions in urinary pH and citrate. Success in reducing the risk for stone formation in astronauts would also be of potential major benefit to the estimated 20 million Americans with nephrolithiasis.

Review↗

Physiological effects of light on the human circadian pacemaker

The physiology of the human circadian pacemaker and its influence and on the daily organization of sleep, endocrine and behavioral processes is an emerging interest in science and medicine. Understanding the development, organization and fundamental properties underlying the circadian timing system may provide insight for the application of circadian principles to the practice of clinical medicine, both diagnostically (interpretation of certain clinical tests are dependent on time of day) and therapeutically (certain pharmacological responses vary with the time of day). The light-dark cycle is the most powerful external influence acting upon the human circadian pacemaker. It has been shown that timed exposure to light can both synchronize and reset the phase of the circadian pacemaker in a predictable manner. The emergence of detectable circadian rhythmicity in the neonatal period is under investigation (as described elsewhere in this issue). Therefore, the pattern of light exposure provided in the neonatal intensive care setting has implications. One recent study identified differences in both amount of sleep time and weight gain in infants maintained in a neonatal intensive care environment that controlled the light-dark cycle. Unfortunately, neither circadian phase nor the time of day has been considered in most clinical investigations. Further studies with knowledge of principles characterizing the human circadian timing system, which governs a wide array of physiological processes, are required to integrate these findings with the practice of clinical medicine.

Review, Tutorial↗

Urban Air Mobility (UAM) Market Study

The Booz Allen Team explored market size and potential barriers to Urban Air Mobility (UAM) by focusing on three potential markets – Airport Shuttle, Air Taxi, and Air Ambulance. We found that the Airport Shuttle and Air Taxi markets are viable, with a significant total available market value in the U.S. of $500 billion, for a fully unconstrained scenario. In this unconstrained best-case scenario, passengers would have the ability to access and fly a UAM at any time, from any location to any destination, without being hindered by constraints such as weather, infrastructure, or traffic volume. Significant legal and regulatory, weather, certification, public perception, and infrastructure constraints exist, which reduce the market potential for these applications to only about 0.5% of the total available market, or $2.5 billion, in the near term. However, we determined that these constraints can be addressed through ongoing intra-governmental partnerships, government and industry collaboration, strong industry commitment, and existing legal and regulatory enablers. We found that the Air Ambulance market is not a viable market if served by electric vertical takeoff and landing (eVTOL) vehicles due to technology constraints but may potentially be viable if a hybrid VTOL aircraft are utilized. The barriers and challenges we characterized in this study can be stratified according to their applicability or potential mitigation through technology as well as market maturity (Figure 1). In the near term, high cost of service will be a key economic challenge. We found potential for significant reduction in service cost through increased vehicle and component efficiency, and automation in a more mature market scenario. Weather conditions also pose a challenge to the UAM market, though there is potential for mitigation of some of these impacts through technology such as sensors enabling operations in low visibility. However, even in a mature market with advanced technology, disruptions are still likely to occur due to weather events such as thunderstorms and strong winds. High density operations will likely stress the current Air Traffic Management (ATM) system in the near term, but technology and new initiatives such as the Air Traffic Management -eXploration project (ATM-X) will enable safe and efficient integration of UAM into the National Airspace System (NAS). Current battery technology creates a barrier in the near term, especially for the Air Ambulance market, as battery weight and extensive recharging times would be needed for these operations. Advancements in battery technology, as well as use of hybrid VTOLs, could significantly reduce this barrier in the longer term. As UAM emerges as a viable mode of transportation in the near term, adverse energy and environmental impacts, particularly noise, may impact community acceptance and potentially persist as the market matures into larger-scale operations. For non-technology related challenges, we found that infrastructure constraints will create a significant barrier to UAM in the near term but could be addressed in the longer term through development and expansion of vertiports. Competition from existing modes of transportation such as ride-sharing (e.g., Lyft, Uber) and ground taxi’s pose a key barrier to UAM in the short term, which will likely evolve into competition from other emerging technologies such as autonomous cars and electric trains in the longer term. Weather events will influence other components of the operation such as passenger comfort (e.g., extreme temperatures, turbulence) and infrastructure (e.g., winter weather causing cracks and degradation in vertiports). There is also potential for these impacts to be heightened in the longer term from the increased frequency of adverse weather such as thunderstorms due to changing climatic conditions. We also found that the public has strong concerns about safety as a passenger in a piloted UAM, including “lasing” of pilots, unruly passengers, and sabotage. They would prefer that all passengers pass through a security screening process before boarding a vehicle. They would also prefer to use UAM for longer regional trips, such as flying from Washington, DC to Baltimore, MD or San Diego, CA to Los Angeles, CA. A longer term automated UAM vehicle market will face challenges due to public apprehension about automation and unmanned operations, and a preference to fly with passengers they know in an autonomous (unmanned) operational scenario.

Rohit Goyal↗

Mass balance approaches for estimating the intestinal absorption and metabolism of peptides and analogues: theoretical development and applications

A theoretical analysis for estimating the extent of intestinal peptide and peptide analogue absorption was developed on the basis of a mass balance approach that incorporates convection, permeability, and reaction. The macroscopic mass balance analysis (MMBA) was extended to include chemical and enzymatic degradation. A microscopic mass balance analysis, a numerical approach, was also developed and the results compared to the MMBA. The mass balance equations for the fraction of a drug absorbed and reacted in the tube were derived from the general steady state mass balance in a tube: [formula: see text] where M is mass, z is the length of the tube, R is the tube radius, Pw is the intestinal wall permeability, kr is the reaction rate constant, C is the concentration of drug in the volume element over which the mass balance is taken, VL is the volume of the tube, and vz is the axial velocity of drug. The theory was first applied to the oral absorption of two tripeptide analogues, cefaclor (CCL) and cefatrizine (CZN), which degrade and dimerize in the intestine. Simulations using the mass balance equations, the experimental absorption parameters, and the literature stability rate constants yielded a mean estimated extent of CCL (250-mg dose) and CZN (1000-mg dose) absorption of 89 and 51%, respectively, which was similar to the mean extent of absorption reported in humans (90 and 50%). It was proposed previously that 15% of the CCL dose spontaneously degraded systematically; however, our simulations suggest that significant CCL degradation occurs (8 to 17%) presystemically in the intestinal lumen.(ABSTRACT TRUNCATED AT 250 WORDS).

Non-NASA Center↗

Nutritional status assessment in semiclosed environments: ground-based and space flight studies in humans

Adequate nutrition is critical during long-term spaceflight, as is the ability to easily monitor dietary intake. A comprehensive nutritional status assessment profile was designed for use before, during and after flight. It included assessment of both dietary intake and biochemical markers of nutritional status. A spaceflight food-frequency questionnaire (FFQ) was developed to evaluate intake of key nutrients during spaceflight. The nutritional status assessment protocol was evaluated during two ground-based closed-chamber studies (60 and 91 d; n = 4/study), and was implemented for two astronauts during 4-mo stays on the Mir space station. Ground-based studies indicated that the FFQ, administered daily or weekly, adequately estimated intake of key nutrients. Chamber subjects maintained prechamber energy intake and body weight. Astronauts tended to eat 40--50% of WHO-predicted energy requirements, and lost >10% of preflight body mass. Serum ferritin levels were lower after the chamber stays, despite adequate iron intake. Red blood cell folate concentrations were increased after the chamber studies. Vitamin D stores were decreased by > 40% on chamber egress and after spaceflight. Mir crew members had decreased levels of most nutritional indices, but these are difficult to interpret given the insufficient energy intake and loss of body mass. Spaceflight food systems can provide adequate intake of macronutrients, although, as expected, micronutrient intake is a concern for any closed or semiclosed food system. These data demonstrate the utility and importance of nutritional status assessment during spaceflight and of the FFQ during extended-duration spaceflight.

NASA Center JSC↗

Regulatory and Technical Issues Concerning the Detection and Treatment of NDMA-Contaminated Groundwater at NASA WSTF

The National Aeronautics and Space Administration (NASA) White Sands Test Facility (WSTF) was established in 1963 primarily to provide rocket engine testing services for several NASA programs. The groundwater underlying the site has been contaminated as a result of historical operations. Groundwater contaminants include several volatile organic compounds (VOCs) and two semi-volatile compounds: N-nitrosodimethylamine (NDMA) and N-nitrodimethylamine (DMN). This paper discusses some of the technical, analytical, regulatory, and health risk issues associated with the contaminant plume. The plume has moved approximately 2.5 miles downgradient of the facility industrial boundary, with evidence of continued migration. As a result, NASA has proposed a pump and treat system using air strippers and ultraviolet (UV) oxidation to stabilize future movement of the contaminant plume. The system has been designed to treat 1,076 gallons (4,073 liters) per minute, with provisions for future expansion. The UV oxidation process was selected to treat NDMA-contaminated groundwater based on successes at other NDMA-contaminated sites. Bench- and pilot-scale testing of WSTF groundwater confirmed the ability of UV oxidation to destroy NDMA and generated sufficient data to design the proposed full-scale treatment system. NDMA is acutely toxic and is a probable human carcinogen. EPA-recommended health risk criteria for the residential consumption of NDMA/DMN-contaminated groundwater was used to determine that a 1.0 x 10(exp -6) excess cancer risk corresponds to 1.7 parts per trillion (ppt). EPA analytical methods are unable to detect NDMA and DMN in the low ppt range. EPA's current Appendix IX analytical method used to screen for NDMA, Method 8270, can detect NDMA only at levels that are orders of magnitude greater than the recommended health risk level. Additionally, EPA Method 607, the most sensitive EPA approved method, has a detection limit of 150 ppt. This corresponds to an excess cancer risk of 9.0 x 10(exp -5), which exceeds the State of New Mexico's water quality standard of a cancer risk less than 1 x 10(exp -5). The treatment system has been engineered to treat contaminated groundwater to levels significantly below the New Mexico standard. However, the inability of EPA-approved analytical methods to detect NDMA and DMN at low ppt levels, and to provide verification of compliance with the 1 x 10(exp -5) cancer risk, introduces a notable risk to the long-term operation of the system. WSTF has been working with Southwest Research Institute to develop a non-EPA analytical method that can achieve a reporting limit of 1 ppt, which corresponds to an excess cancer risk of 7.6 x 10(exp -7). WSTF is currently developing a proposal to obtain approval from the New Mexico Environment Department (NMED) of this non-EPA method.

Wiebe, D. T.↗

Estimation of the oxalate content of foods and daily oxalate intake

BACKGROUND: The amount of oxalate ingested may be an important risk factor in the development of idiopathic calcium oxalate nephrolithiasis. Reliable food tables listing the oxalate content of foods are currently not available. The aim of this research was to develop an accurate and reliable method to measure the food content of oxalate. METHODS: Capillary electrophoresis (CE) and ion chromatography (IC) were compared as direct techniques for the estimation of the oxalate content of foods. Foods were thoroughly homogenized in acid, heat extracted, and clarified by centrifugation and filtration before dilution in water for analysis. Five individuals consuming self-selected diets maintained food records for three days to determine their mean daily oxalate intakes. RESULTS: Both techniques were capable of adequately measuring the oxalate in foods with a significant oxalate content. With foods of very low oxalate content (<1.8 mg/100 g), IC was more reliable than CE. The mean daily intake of oxalate by the five individuals tested was 152 +/- 83 mg, ranging from 44 to 352 mg/day. CONCLUSIONS: CE appears to be the method of choice over IC for estimating the oxalate content of foods with a medium (>10 mg/100 g) to high oxalate content due to a faster analysis time and lower running costs, whereas IC may be better suited for the analysis of foods with a low oxalate content. Accurate estimates of the oxalate content of foods should permit the role of dietary oxalate in urinary oxalate excretion and stone formation to be clarified. Other factors, apart from the amount of oxalate ingested, appear to exert a major influence over the amount of oxalate excreted in the urine.

NASA Discipline Regulatory Physiology↗

Sustained Partial Sleep Deprivation: Effects on Immune Modulation and Growth Factors

The vulnerability to medical emergencies is greatest in space where there are real limits to the availability or effectiveness of ground based assistance. Moreover, astronaut safety and health maintenance will be of increasing importance as we venture out into space for extended periods of time. It is therefore critical to understand the mechanisms of the regulatory physiology of homeostatic systems (sleep, circadian, neuroendocrine, fluid and nutritional balance) and the key roles played in adaptation. This synergy project has combined aims of the "Human Performance Factors, Sleep and Chronobiology Team"; the "Immunology, Infection and Hematology Team"; and the "Muscle Alterations and Atrophy Team", to broadly address the effects of long term sleep reduction, as is frequently encountered in space exploration, on neuroendocrine, neuroimmune and circulating growth factors. Astronaut sleep is frequently curtailed to averages of between 4- 6.5 hours per night. There is evidence that this amount of sleep is inadequate for maintaining optimal daytime functioning. However, there is a lack of information concerning the effects of chronic sleep restriction, or reduction, on regulatory physiology in general, and there have been no controlled studies of the cumulative effects of chronic sleep reduction on neuroendocrine and neuroimmune parameters. This synergy project represents a pilot study designed to characterize the effects of chronic partial sleep deprivation (PSD) on neuroendocrine, neuroimmune and growth factors. This project draws its subjects from two (of 18) conditions of the larger NSBRI project, "Countermeasures to Neurobehavioral Deficits from Cumulative Partial Sleep Deprivation During Space Flight", one of the projects on the "Human Performance Factors, Sleep and Chronobiology Team ". For the purposes of this study, to investigate the effects of chronic sleep loss on neuroendocrine and neuroimmune function, we have focused on the two extreme sleep conditions from this larger study: a 4.2 hour per night condition, and a 8.2 hour per night condition. During space flight, muscle mass and bone density are reduced, apparently due to loss of GH and IGF-I, associated with microgravity. Since >70% of growth hormone (GH) is secreted at night in normal adults, we hypothesized that the chronic sleep restriction to 4 hours per night would reduce GH levels as measured in the periphery. In this synergy project, in collaboration with the "Muscle Alterations and Atrophy Team ", we are measuring insulin-like growth factor-I (IGF-I) in peripheral circulation to test the prediction that it will be reduced by chronic sleep restriction. In addition to stress modulation of immune function, recent research suggests that sleep is also involved. While we all have the common experience of being sleepy when suffering from infection, and being susceptible to infection when not getting enough sleep, the mechanisms involved in this process are not understood and until recently have gone largely overlooked. We believe that the immune function changes seen in spaceflight may also be related to the cumulative effects of sleep loss. Moreover, in space flight, the possibility of compromised immune function or of the reactivation of latent viruses are serious potential hazards for the success of long term missions. Confined living conditions, reduced sleep, altered diet and stress are all factors that may compromise immune function, thereby increasing the risks of developing and transmitting disease. Medical complications, which would not pose serious problems on earth, may be disastrous if they emerged in space.

Mullington, Janet M.↗

Sucrose regulation of ADP-glucose pyrophosphorylase subunit genes transcript levels in leaves and fruits

ADP-glucose pyrophosphorylase (AGPase, EC2.7.7.27) is a key regulatory enzyme in starch biosynthesis. The enzyme is a heterotetramer with two S and two B subunits. In tomato, there are three multiple forms of the S subunit gene. Agp S1, S2 and B are highly expressed in fruit from 10 to 25 days after anthesis. Agp S3 is only weakly expressed in fruit. Sucrose significantly elevates expression of Agp S1, S2 and B in both leaves and fruits. Agp S1 exhibits the highest degree of regulation by sucrose. In fact, sucrose may be required for Agp S1 expression. For excised leaves incubated in water, no transcripts for Agp S1 could be detected in the absence of sucrose, whereas it took up to 16 h in water before transcripts were no longer detectable for Agp S2 and B. Neither Agp S3 nor the tubulin gene is affected by sucrose, demonstrating that this response is specifically regulated by a carbohydrate metabolic signal, and is not due to a general increase in metabolism caused by sucrose treatment. Truncated versions of the promoter for Agp S1 indicate that a specific region 1.3-3.0 kb upstream from the transcription site is responsible for sucrose sensitivity. This region of the S1 promoter contains several cis-acting elements present in the promoters of other genes that are also regulated by sucrose. c2002 Elsevier Science Ireland Ltd. All rights reserved.

Non-NASA Center↗

Dahl salt-sensitive rats develop hypovitaminosis D and hyperparathyroidism when fed a standard diet

The Dahl salt-sensitive rat (S), a model for salt-sensitive hypertension, excretes protein-bound 25-hydroxyvitamin D (25-OHD) into urine when fed a low salt diet. Urinary 25-OHD increases during high salt intake. We tested the hypothesis that continuous loss of 25-OHD into urine would result in low plasma 25-OHD concentration in mature S rats raised on a standard diet. Dahl S and salt-resistant (R) male rats were raised to maturity (12-month-old) on a commercial rat diet (1% salt) and switched to 0.3% (low) or 2% (high) salt diets 3 weeks before euthanasia. Urine (24 h) was collected at the end of the dietary treatments. Urinary 25-OHD and urinary 25-OHD binding activity of S rats were three times that of R rats, resulting in lower plasma 25-OHD and 24,25-dihydroxyvitamin D concentrations in S rats than in R rats (P < 0.001). Plasma parathyroid hormone concentrations of S rats were twice that of R rats. S rats fed 2% salt had higher plasma 1,25-dihydroxyvitamin D concentrations than those fed 0.3% salt (P = 0.002). S rats excreted more calcium into urine than R rats (P < 0.001) and did not exhibit the expected calciuric response to salt. Proteinuria of the S rats was three times that of the R rats, suggesting kidney damage in the S rats. Low plasma 25-OHD and 24,25-dihydroxyvitamin D and high plasma 1,25-dihydroxyvitamin D and PTH concentrations seen in the mature S rats have also been reported for elderly patients with low-renin (salt-induced) hypertension. An implication of this study is that low vitamin D status may occur with age in salt-sensitive individuals, even when salt intake is normal.

NASA Discipline Regulatory Physiology↗

The relationship between lifestyle regularity and subjective sleep quality

In previous work we have developed a diary instrument-the Social Rhythm Metric (SRM), which allows the assessment of lifestyle regularity-and a questionnaire instrument--the Pittsburgh Sleep Quality Index (PSQI), which allows the assessment of subjective sleep quality. The aim of the present study was to explore the relationship between lifestyle regularity and subjective sleep quality. Lifestyle regularity was assessed by both standard (SRM-17) and shortened (SRM-5) metrics; subjective sleep quality was assessed by the PSQI. We hypothesized that high lifestyle regularity would be conducive to better sleep. Both instruments were given to a sample of 100 healthy subjects who were studied as part of a variety of different experiments spanning a 9-yr time frame. Ages ranged from 19 to 49 yr (mean age: 31.2 yr, s.d.: 7.8 yr); there were 48 women and 52 men. SRM scores were derived from a two-week diary. The hypothesis was confirmed. There was a significant (rho = -0.4, p < 0.001) correlation between SRM (both metrics) and PSQI, indicating that subjects with higher levels of lifestyle regularity reported fewer sleep problems. This relationship was also supported by a categorical analysis, where the proportion of "poor sleepers" was doubled in the "irregular types" group as compared with the "non-irregular types" group. Thus, there appears to be an association between lifestyle regularity and good sleep, though the direction of causality remains to be tested.

NASA Program Biomedical Research and Countermeasur↗

Time-dependent oral absorption models

The plasma concentration-time profiles following oral administration of drugs are often irregular and cannot be interpreted easily with conventional models based on first- or zero-order absorption kinetics and lag time. Six new models were developed using a time-dependent absorption rate coefficient, ka(t), wherein the time dependency was varied to account for the dynamic processes such as changes in fluid absorption or secretion, in absorption surface area, and in motility with time, in the gastrointestinal tract. In the present study, the plasma concentration profiles of propranolol obtained in human subjects following oral dosing were analyzed using the newly derived models based on mass balance and compared with the conventional models. Nonlinear regression analysis indicated that the conventional compartment model including lag time (CLAG model) could not predict the rapid initial increase in plasma concentration after dosing and the predicted Cmax values were much lower than that observed. On the other hand, all models with the time-dependent absorption rate coefficient, ka(t), were superior to the CLAG model in predicting plasma concentration profiles. Based on Akaike's Information Criterion (AIC), the fluid absorption model without lag time (FA model) exhibited the best overall fit to the data. The two-phase model including lag time, TPLAG model was also found to be a good model judging from the values of sum of squares. This model also described the irregular profiles of plasma concentration with time and frequently predicted Cmax values satisfactorily. A comparison of the absorption rate profiles also suggested that the TPLAG model is better at prediction of irregular absorption kinetics than the FA model. In conclusion, the incorporation of a time-dependent absorption rate coefficient ka(t) allows the prediction of nonlinear absorption characteristics in a more reliable manner.

Non-NASA Center↗

A liposomal model that mimics the cutaneous production of vitamin D3. Studies of the mechanism of the membrane-enhanced thermal isomerization of previtamin D3 to vitamin D3

We reported previously that the rate of previtamin D3 (preD3) <==> vitamin D3 isomerization was enhanced by about 10 times in the skin compared with that in organic solvents. To elucidate the mechanism by which the rate of this reaction is enhanced in the skin, we developed a liposomal model that mimicked the enhanced isomerization of preD3 to vitamin D3 that was described in human skin. Using this model we studied the effect of changing the polarity of preD3 as well as changing the chain length and the degree of saturation of liposomal phospholipids on the kinetics of preD3 <==> vitamin D3 isomerization. We found that a decrease in the hydrophilic interaction of the preD3 with liposomal phospholipids by an esterification of the 3beta-hydroxy of preD3 (previtamin D3-3beta-acetate) reduced the rate of the isomerization by 67%. The addition of a hydroxyl on C-25 of the hydrophobic side chain (25-hydroxyprevitamin D3), which decreased the hydrophobic interaction of preD3 with the phospholipids, reduced the rate by 87%. In contrast, in an isotropic n-hexane solution, there was little difference among the rates of the conversion of preD3, its 3beta-acetate, and 25-hydroxy derivatives to their corresponding vitamin D3 compounds. We also determined rate constants (k) of preD3 <==> vitamin D3 isomerization in liposomes containing phosphatidylcholines with different carbon chain lengths. The rates of the reaction were found to be enhanced as the number of carbons (Cn) in the hydrocarbon chain of the phospholipids increased from 10 to 18. In conclusion, these results support our hypothesis that amphipathic interactions between preD3 and membrane phospholipids stabilize preD3 in its "cholesterol like" cZc-conformer, the only conformer of preD3 that can convert to vitamin D3. The stronger these interactions were, the more preD3 was likely in its cZc conformation at any moment and the faster was the rate of its conversion to vitamin D3.

NASA Discipline Regulatory Physiology↗

Alkali absorption and citrate excretion in calcium nephrolithiasis

The role of net gastrointestinal (GI) alkali absorption in the development of hypocitraturia was investigated. The net GI absorption of alkali was estimated from the difference between simple urinary cations (Ca, Mg, Na, and K) and anions (Cl and P). In 131 normal subjects, the 24 h urinary citrate was positively correlated with the net GI absorption of alkali (r = 0.49, p < 0.001). In 11 patients with distal renal tubular acidosis (RTA), urinary citrate excretion was subnormal relative to net GI alkali absorption, with data from most patients residing outside the 95% confidence ellipse described for normal subjects. However, the normal relationship between urinary citrate and net absorbed alkali was maintained in 11 patients with chronic diarrheal syndrome (CDS) and in 124 stone-forming patients devoid of RTA or CDS, half of whom had "idiopathic" hypocitraturia. The 18 stone-forming patients without RTA or CDS received potassium citrate (30-60 mEq/day). Both urinary citrate and net GI alkali absorption increased, yielding a significantly positive correlation (r = 0.62, p < 0.0001), with the slope indistinguishable from that of normal subjects. Thus, urinary citrate was normally dependent on the net GI absorption of alkali. This dependence was less marked in RTA, confirming the renal origin of hypocitraturia. However, the normal dependence was maintained in CDS and in idiopathic hypocitraturia, suggesting that reduced citrate excretion was largely dietary in origin as a result of low net alkali absorption (from a probable relative deficiency of vegetables and fruits or a relative excess of animal proteins).

Non-NASA Center↗

Validation of Spectral Analysis as a Noninvasive Tool to Assess Autonomic Regulation of Cardiovascular Function

A major focus of our program has been to develop a sensitive noninvasive procedure to quantify early weightlessness-induced changes in cardiovascular function or potential dysfunction. Forty studies of healthy young volunteers (10 men and 10 women, each studied twice) were conducted to determine changes in the sympatho-vagal balance of autonomic control of cardiovascular regulation during graded headward and footward blood volume shifts. Changes in sympatho-vagal balance were classified by changes in the mean levels and spectral content of cardiovascular variables and verified by changes in circulating levels of catecholamines and pancreatic polypeptide. Possible shifts in intra/extravascular fluid were assessed from changes in hematocrit and plasma mass density while changes in the stimulus to regulate plasma volume were determined from Plasma Renin Activity (PRA). Autonomic blockade was used to unmask the relative contribution of sympathetic and parasympathetic efferent influences in response to 10 min each of 0, 20 and 40 mmHg Lower Body Negative Pressure (LBNP) and 15 and 30 mmHg Positive Pressure (LBPP). The combination of muscarinic blockade with graded LBNP and LBPP was used to evoke graded increases and decreases in sympathetic activity without parasympathetic contributions. The combination of beta blockade with graded LBNP and LBPP was used to produce graded increases and decreases in parasympathetic activity without beta sympathetic contributions. Finally, a combination of both beta and muscarinic blockades with LBNP and LBPP was used to determine the contribution from other, primarily alpha adrenergic, sources. Mean values, spectral analyses and time frequency analysis of R-R interval (HR), Arterial Pressure (AP), peripheral blood flow (RF), Stroke Volume (SV) and peripheral resistance (TPR) were performed for all phases of the study. Skin blood Flow (SF) was also measured in other studies and similarly analyzed. Spectra were examined for changes in three frequency regions (low 0.006 - 0.005 Hz (LF), mid 0.05 - 0.15 Hz (W), and high 0.15 - 0.45 Hz (EF)). The primary objective of the study was to indicate which changes in the mean values and/or spectra of cardiovascular variables consistently correlated with changes in sympatho-vagal balance in response to headward and footward fluid shifts. A secondaey objective was to quantify the vascular and extravascular fluid shifts evoked by LBNP and LBPP. The principal hypothesis being tested was that headward fluid shifts would evoke an increase in parasympathetic activity and footward fluid shifts would evoke an increase in sympathetic activity both of which would be detected by spectral analysis and verified by circulating hormones. Hematocrit (HCT), plasma mass density and plasma renin activity increased with muscarinic blockade and with LBNP, a response indicative of a plasma shift to extravascular spaces. Beta blockade alone or after muscarinic blockade had no effect on HCT or plasma mass density. With respect to intravascular fluid volume distribution, LBNP and LBPP produced sufficient upper body vascular fluid shifts to evoke appropriate autonomic regulatory responses.

Knapp, Charles F.↗

Cell shape, cytoskeletal mechanics, and cell cycle control in angiogenesis

Capillary endothelial cells can be switched between growth and differentiation by altering cell-extracellular matrix interactions and thereby, modulating cell shape. Studies were carried out to determine when cell shape exerts its growth-regulatory influence during cell cycle progression and to explore the role of cytoskeletal structure and mechanics in this control mechanism. When G0-synchronized cells were cultured in basic fibroblast growth factor (FGF)-containing defined medium on dishes coated with increasing densities of fibronectin or a synthetic integrin ligand (RGD-containing peptide), cell spreading, nuclear extension, and DNA synthesis all increased in parallel. To determine the minimum time cells must be adherent and spread on extracellular matrix (ECM) to gain entry into S phase, cells were removed with trypsin or induced to retract using cytochalasin D at different times after plating. Both approaches revealed that cells must remain extended for approximately 12-15 h and hence, most of G1, in order to enter S phase. After this restriction point was passed, normally 'anchorage-dependent' endothelial cells turned on DNA synthesis even when round and in suspension. The importance of actin-containing microfilaments in shape-dependent growth control was confirmed by culturing cells in the presence of cytochalasin D (25-1000 ng ml-1): dose-dependent inhibition of cell spreading, nuclear extension, and DNA synthesis resulted. In contrast, induction of microtubule disassembly using nocodazole had little effect on cell or nuclear spreading and only partially inhibited DNA synthesis. Interestingly, combination of nocodazole with a suboptimal dose of cytochalasin D (100 ng ml-1) resulted in potent inhibition of both spreading and growth, suggesting that microtubules are redundant structural elements which can provide critical load-bearing functions when microfilaments are partially compromised. Similar synergism between nocodazole and cytochalasin D was observed when cytoskeletal stiffness was measured directly in living cells using magnetic twisting cytometry. These results emphasize the importance of matrix-dependent changes in cell and nuclear shape as well as higher order structural interactions between different cytoskeletal filament systems for control of capillary cell growth during angiogenesis.

Non-NASA Center↗