The physiological significance of p-Aminobenzoic Acid

Thesis submitted for the Degree of Doctor of Medicine in the University of the Witwatersrand, JohannesburgThe interest of the biochemist in para-aminobenzoic acid is very recent and, indeed, only goes back about five years, but in this time quite a voluminous literature has accumulated on the biological aspects and importance of this aniline derivative. Attention was originally focussed on it indirectly as a result of the intensive research devoted to the understanding of the mode of action of the various sulphonamides, which were shown during the last decade to be very powerful chemothera-peutic agents against many bacteria. Fildes (1940, propounded the hypothesis that p-aminobenzoic acid was an essential meta-bolite for bacteria, that it was normally associated with an enzyme system in the bacterial cell, and that sulphanilamide, being structurally similar to p-aminobenzoic acid, was capable in sufficient concentration of displacing p-aminobenzoic acid from its enzyme and stopping this essential line of metabolism. Fildes further suggested that a substance which was found to be an essential metabolite for bacteria would also be essential in the animal kingdom, so that such a substance might be found to act as a vitamin in the higher animals and even in man. In 19U1 interest in p-aminobenzoic acid was intensified with the announcement by Ansbacher (19U1J that p-eminobenzoic acid was actually a vitamin and should be included in the vita¬min B complex. In this thesis, studies on the absorption and excretion of p-aminobenzoic acid are reported, the estimation of p-amino- bensoic acid being based on its property of antagonising the Bulphonamides. Evidence is presented that p-arainobenzoic acid la excreted ae p-acetylaminobenzoic acid, and that its conjuga- tion with the acetyl radical probably takeB place in the liver. Further it is suggested that the experiments performed do not lend support to the view that p-aminobenzolc acid is a vitamin for man. Finally the various physiological effects of p-aminobenzoic acid are discussed and an attempt is made to gauge its function in the living organism. Preliminary experiments indicating a new, hitherto unreported, role of p-aminobenzoic acid are re¬corded, namely its ability in large doses to increase the re¬sistance of animals to disease.IT201

Spaceflight-Induced Cardiovascular Changes and Recovery During NASA's Functional Task Test

Microgravity-induced physiological changes could impair a crewmember s performance upon return to a gravity environment. The Functional Task Test (FTT) is designed to correlate these physiological changes to performance in mission-critical tasks. The Recovery from Fall/Stand Test (RFST) simulates one such task, measuring the ability to recover from a prone position and the cardiovascular response to orthostasis. The purpose of this study was to evaluate spaceflight-induced cardiovascular changes during the FTT. METHODS: Five astronauts participated in the FTT before 10-15 day missions, on landing day (R+0), and one (R+1), six (R+6) and thirty (R+30) days after landing. The RFST consisted of a 2-minute prone rest followed by a 3-minute stand during which heart rate (HR, Holter) and continuous blood pressure (BP, Finometer) were measured. Spectral heart rate variability (HRV) was calculated during the RFST to approximate autonomic function. Statistical analysis was performed with two-factor repeated measures ANOVA. RESULTS: During RFST, HR was higher on R+0 than preflight (p<0.004). This increase in HR persisted on R+1 and R+6 during the stand portion of RFST (p<0.026). BP was well-regulated on all test days. Parasympathetic activity was diminished on R+0 (p=0.035). Sympathovagal balance tended to be affected by spaceflight (main effect, p=0.072), appearing to be slightly elevated during postflight RFST except on R+30. Additionally, analysis of HR during the functional tasks yielded a higher HR on R+0 than preflight during 8 of 11 tasks analyzed, where all tasks had HR return to preflight values by R+30 (p<0.05). CONCLUSION: Spaceflight causes an increase in HR, decrease in parasympathetic activity, and increase in sympathovagal balance, which we confirmed during RFST. These spaceflight-induced changes seen in the RFST, along with the increased postflight HR in most functional tasks, can be used to assess functional performance after short-duration spaceflight

First principles numerical model of avalanche-induced arc discharges in electron-irradiated dielectrics

The model consists of four phases: single electron dynamics, single electron avalanche, negative streamer development, and tree formation. Numerical algorithms and computer code implementations are presented for the first three phases. An approach to developing a code description of fourth phase is discussed. Numerical results are presented for a crude material model of Teflon

Sex differences in functional limitations and the role of socioeconomic factors: a multi-cohort analysis

Background: Women are more likely to have functional limitations than are men, partly because of greater socioeconomic disadvantage. However, how sex differences vary by severity of functional limitations remains unclear. We examined sex differences in functional limitations, with attention to socioeconomic factors and severity of limitations. Methods: Longitudinal data on limitations in basic activities of daily living (ADL) and instrumental activities of daily living (IADL) and mobility activities were drawn from 62 375 participants from 14 countries. For ADL, IADL, and mobility, participants were categorised based on number of limited activities (0, 1, 2, or ≥3). Sex differences in limitations in four birth cohorts (1895–1929, 1930–38, 1939–45, and 1946–60) were analysed before and after adjustment for socioeconomic factors (education and labour force status). Findings: The prevalence of IADL and ADL limitations was higher in women than in men. After adjustment for socioeconomic factors, this sex difference was attenuated. The sex difference in IADL limitations at age 75 years (in the 1895–1929 cohort) was 3·7% before adjustment for socioeconomic factors (95% CI 2·6–4·7) and 1·7% (1·1–2·2) after adjustment. For ADL, the sex difference in limitations at age 75 years (in the 1895–1929 cohort) was 3·2% (2·3–4·1) before adjustment for socioeconomic factors and 1·4% (0·9–1·8) after adjustment. Sex differences in mobility limitations (16·1%, 95% CI 14·4–17·7) remained after adjustment for socioeconomic factors (14·3%, 12·7–15·9). After age 85 years, women were more likely to have three or more IADL or mobility limitations and men were more likely to have one or two limitations. Interpretation: Socioeconomic factors largely explain sex differences in IADL and ADL limitations but not mobility. Sex differences in mobility limitations in midlife are important targets for future research and interventions. Funding: National Institute on Aging, UK National Institute for Health Research, European Commission, and US Social Security Administration

Heart Rate Response During Mission-Critical Tasks After Space Flight

Adaptation to microgravity could impair crewmembers? ability to perform required tasks upon entry into a gravity environment, such as return to Earth, or during extraterrestrial exploration. Historically, data have been collected in a controlled testing environment, but it is unclear whether these physiologic measures result in changes in functional performance. NASA?s Functional Task Test (FTT) aims to investigate whether adaptation to microgravity increases physiologic stress and impairs performance during mission-critical tasks. PURPOSE: To determine whether the well-accepted postflight tachycardia observed during standard laboratory tests also would be observed during simulations of mission-critical tasks during and after recovery from short-duration spaceflight. METHODS: Five astronauts participated in the FTT 30 days before launch, on landing day, and 1, 6, and 30 days after landing. Mean heart rate (HR) was measured during 5 simulations of mission-critical tasks: rising from (1) a chair or (2) recumbent seated position followed by walking through an obstacle course (egress from a space vehicle), (3) translating graduated masses from one location to another (geological sample collection), (4) walking on a treadmill at 6.4 km/h (ambulation on planetary surface), and (5) climbing 40 steps on a passive treadmill ladder (ingress to lander). For tasks 1, 2, 3, and 5, astronauts were encouraged to complete the task as quickly as possible. Time to complete tasks and mean HR during each task were analyzed using repeated measures ANOVA and ANCOVA respectively, in which task duration was a covariate. RESULTS: Landing day HR was higher (P < 0.05) than preflight during the upright seat egress (7%+/-3), treadmill walk (13%+/-3) and ladder climb (10%+/-4), and HR remained elevated during the treadmill walk 1 day after landing. During tasks in which HR was not elevated on landing day, task duration was significantly greater on landing day (recumbent seat egress: 25%+/-14 and mass translation: 26%+/-12; P < 0.05). CONCLUSION: Elevated HR and increased task duration during postflight simulations of mission-critical tasks is suggestive of spaceflight-induced deconditioning. Following short-duration microgravity missions (< 16 d), work performance may be transiently impaired, but recovery is rapid

Identification of physical activity and sedentary behaviour dimensions that predict mortality risk in older adults: Development of a machine learning model in the Whitehall II accelerometer sub-study and external validation in the CoLaus study.

Identification of new physical activity (PA) and sedentary behaviour (SB) features relevant for health at older age is important to diversify PA targets in guidelines, as older adults rarely adhere to current recommendations focusing on total duration. We aimed to identify accelerometer-derived dimensions of movement behaviours that predict mortality risk in older populations. We used data on 21 accelerometer-derived features of daily movement behaviours in 3991 participants of the UK-based Whitehall II accelerometer sub-study (25.8% women, 60-83 years, follow-up: 2012-2013 to 2021, mean = 8.3 years). A machine-learning procedure was used to identify core PA and SB features predicting mortality risk and derive a composite score. We estimated the added predictive value of the score compared to traditional sociodemographic, behavioural, and health-related risk factors. External validation in the Switzerland-based CoLaus study (N = 1329, 56.7% women, 60-86 years, follow-up: 2014-2017 to 2021, mean = 3.8 years) was conducted. In total, 11 features related to overall activity level, intensity distribution, bouts duration, frequency, and total duration of PA and SB, were identified as predictors of mortality in older adults and included in a composite score. Both in the derivation and validation cohorts, the score was associated with mortality (hazard ratio = 1.10 (95% confidence interval = 1.05-1.15) and 1.18 (1.10-1.26), respectively) and improved the predictive value of a model including traditional risk factors (increase in C-index = 0.007 (0.002-0.014) and 0.029 (0.002-0.055), respectively). The identified accelerometer-derived PA and SB features, beyond the currently recommended total duration, might be useful for screening of older adults at higher mortality risk and for diversifying PA and SB targets in older populations whose adherence to current guidelines is low. National Institute on Aging; UK Medical Research Council; British Heart Foundation; Wellcome Trust; French National Research Agency; GlaxoSmithKline; Lausanne Faculty of Biology and Medicine; Swiss National Science Foundation

Postural Responses Following Space Flight and Ground Based Analogs

With the transition from the Shuttle program to the International Space Station (ISS), the opportunity to fly sensorimotor experiments in a weightless environment has become increasingly more difficult to obtain. As a result, more investigations have turned to ground-based analogs as a way of evaluating an experiment's viability. The two primary analogs available to most investigators are 6deg head down bed rest (HDBR) and dry immersion (DI). For the time being, HDBR investigations have been associated with studies conducted in the United States while the Russians and several other European Union states have concentrated their efforts on using DI as the space flight analog of choice. While either model may be viable for cardiovascular, bone and other system changes, vestibular and sensorimotor investigators have retained serious reservations of either analog's potential to serve as a replacement for a true weightless environment. These reservations have merit, but it is worthwhile to consider that not all changes associated with sensorimotor function during space flight are the result of top-down modifications, but may also be due to the lack, or change, of appropriate support surfaces applying force to the bottom of the feet. To this end we have compared quiet stance postural responses between short duration Space Shuttle flights, long duration ISS flights and HDBR of varying duration. Using these three platforms, representing different modifications of support we investigated postural ataxia using a quiet stance model. Quiet stance was obtained by asking the subjects to stand upright on a force plate, eyes open, arms at the side of the body for three min. From the force plate we obtained average sway velocity in two axes as well as length of line (stabilogram). These parameters were then related to EMG activity recorded from the medial gastrocnemius and lateral tibialis. It is significant to note that postural ataxia measured as quiet stance shows analogous changes between HDBR and space flight. Primary differences across short duration, long duration space flight and HDBR are related to the length of exposure associated with both space flight and HDBR

Walk on Floor Eyes Closed Test as a Measure of Postflight Ataxia

INTRODUCTION: Astronauts returning from space flight universally exhibit impaired posture and locomotion. Measurement of this impairment is an evolving process. The walk on the floor line test with the eyes closed (WOFEC) provides a unique procedure for quantifying postflight ataxia. Data from a modified WOFEC were obtained as part of an ongoing NASA interdisciplinary pre- and postflight study (Functional Task Test, FTT) designed to evaluate astronaut postflight functional performance. METHODS: Seven astronauts (5 short duration with flights of 12-16 days; 2 long duration crewmembers with flights of 6 months) were tested twice before flight, on landing day (short duration only), and 1, 6, and 30 days after flight. The WOFEC consisted of walking for 10 steps (repeated twice) with the feet heel to toe in tandem, arms folded across the chest and the eyes closed. The performance metric (scored by three examiners from video) was the percentage of correct steps completed over the three trials. A step was not counted as correct if the crewmember sidestepped, opened their eyes, or paused for more than three seconds between steps. RESULTS/ CONCLUSIONS: There was a significant decrease in percentage of correct steps on landing day (short duration crew) and on first day following landing (long duration) with partial recovery the following day, and full recovery beginning on day sixth after flight. Both short and long duration fliers appeared to be unaware of foot position relative to their bodies or the floor. Postflight, deviation from a straight path was common, and the test for two crewmembers elicited motion sickness symptoms. These data clearly demonstrate the sensorimotor challenges facing crewmembers after returning from spaceflight. The WOFEC test has value providing the investigator or crew surgeon with a simple method to quantify vestibular ataxia, as well as providing instant feedback of postural ataxia without the use of complex test equipment

Enhancing Functional Performance using Sensorimotor Adaptability Training Programs

During the acute phase of adaptation to novel gravitational environments, sensorimotor disturbances have the potential to disrupt the ability of astronauts to perform functional tasks. The goal of this project is to develop a sensorimotor adaptability (SA) training program designed to facilitate recovery of functional capabilities when astronauts transition to different gravitational environments. The project conducted a series of studies that investigated the efficacy of treadmill training combined with a variety of sensory challenges designed to increase adaptability including alterations in visual flow, body loading, and support surface stability