A per-cent-level determination of the nucleon axial coupling from quantum chromodynamics.

The axial coupling of the nucleon, gA, is the strength of its coupling to the weak axial current of the standard model of particle physics, in much the same way as the electric charge is the strength of the coupling to the electromagnetic current. This axial coupling dictates the rate at which neutrons decay to protons, the strength of the attractive long-range force between nucleons and other features of nuclear physics. Precision tests of the standard model in nuclear environments require a quantitative understanding of nuclear physics that is rooted in quantum chromodynamics, a pillar of the standard model. The importance of gA makes it a benchmark quantity to determine theoretically-a difficult task because quantum chromodynamics is non-perturbative, precluding known analytical methods. Lattice quantum chromodynamics provides a rigorous, non-perturbative definition of quantum chromodynamics that can be implemented numerically. It has been estimated that a precision of two per cent would be possible by 2020 if two challenges are overcome1,2: contamination of gA from excited states must be controlled in the calculations and statistical precision must be improved markedly2-10. Here we use an unconventional method 11 inspired by the Feynman-Hellmann theorem that overcomes these challenges. We calculate a gA value of 1.271 ± 0.013, which has a precision of about one per cent.

Duration of activity and mode of action of modafinil: Studies on sleep and wakefulness in humans.

The duration of activity of modafinil was investigated in healthy male volunteers in two double-blind crossover studies. Mode of action was explored using a statistical model concerned with the relationship between total sleep duration and that of rapid eye movement (REM) sleep. Nocturnal sleep (23:00-07:00) followed by next-day performance (09:00-17:00) was studied in 12 subjects administered 100, 200, 300 mg modafinil and placebo, 0.5 h before bedtime. Performance overnight (19:00-08:45) followed by sleep (09:15-15:15) was studied in nine subjects administered 100, 200, 300, 400 mg modafinil, 300 mg caffeine and placebo at 22:15. Modafinil dose-dependently reduced sleep duration (nocturnal: 200 mg, p<0.05; 300 mg, p<0.001; morning: 300 and 400 mg, p<0.05) and REM sleep (nocturnal: 300 mg; morning: 400 mg; p<0.05). The statistical model revealed that reduced REM sleep was due to alerting activity, with no evidence of direct suppression of REM sleep, suggesting dopaminergic activity. Enhanced performance with modafinil during overnight work varied with dose (200 mg>100 mg; 300, 400 mg>200, 100 mg, caffeine). However, in the study of next-day performance, the enhancement was attenuated at the highest dose (300 mg) by the greater disturbance of prior sleep. These findings indicate that modafinil has a long duration of action, with alerting properties arising predominantly from dopaminergic activity.

Antihypertensive therapy in critical occupations: studies with an angiotensin II antagonist.

OBJECTIVE: This study was performed to establish whether an angiotensin II antagonist modulates daytime sleepiness or performance. METHODS: The central effects of losartan (50 and 100 mg), as well as amlodipine (5 and 10 mg) and promethazine (10 mg), were studied in six healthy volunteers (aged between 20 and 27 (mean 24) yr). Digit symbol substitution, tracking, vigilance, immediate and short-term memory recall, complex reaction time, together with objective (daytime sleep latencies) and subjective measures of sleepiness, were measured 1.0 h before and 0.5, 2.0, 3.5, 5.0, 6.5, and 8.0 h after ingestion. The study was placebo-controlled and double-blind with a six-way crossover design. RESULTS: No changes in performance or in measurements related to sleepiness were observed with losartan (50 and 100 mg). Amlodipine (10 mg) impaired immediate memory and increased subjective sleepiness at 8.0 h (p < 0.05). Promethazine (10 mg) impaired vigilance and immediate memory recall and increased reaction time (basic and complex) from 2.0 to 6.5 h after ingestion, impaired tracking from 3.5 to 6.5 h and increased subjective sleepiness from 2.0 to 8.0 h (p < 0.05). CONCLUSION: The study suggests that an angiotensin II antagonist could prove useful for the treatment of hypertension in aircrew.

Hypnotic activity of melatonin.

OBJECTIVE: To establish the effect of melatonin upon nocturnal and evening sleep. METHODS: Experiment I: The effect of melatonin (0.1, 0.5, 1.0, 5.0, and 10 mg), ingested at 23:30, was studied on nocturnal sleep (23:30-07:30) and core body temperature in 8 healthy volunteers. Performance was measured 8.5 h post-ingestion. On completion of the experiment dim light melatonin onsets (DLMO) were determined. Experiment II: The effect of melatonin (0.5, 1.0, 5.0, and 10 mg), ingested at 18:00, was studied on evening sleep (18:00-24:00) and core body temperature in 6 healthy volunteers. Performance was measured 6.5 h post-ingestion. Each experiment was placebo-controlled and double-blind with a cross-over design with temazepam (20 mg) as an active control. RESULTS: Experiment I: Melatonin (5 mg) reduced the duration of stage 3 in the first 100 min of sleep. Melatonin (0.1 mg) reduced body temperature 6.5 to 7 h post-ingestion. Temazepam increased stage 2, reduced wakefulness and stage 1, and increased the latency to REM sleep. Temazepam reduced body temperature 4.5 to 6.5 h post-ingestion. There were no changes in performance compared with placebo. DLMO occurred between 20:40 and 23:15. Experiment II: Melatonin (all doses) increased total sleep time (TST), sleep efficiency index (SEI) and stage 2, and reduced wakefulness. Temazepam increased TST, SEI, stage 2 and slow-wave sleep, and reduced wakefulness. There were no changes in body temperature or performance compared with placebo. CONCLUSION: Melatonin given at 23:30 has no significant clinical effect on nocturnal sleep in healthy individuals. Hypnotic activity of melatonin when given in the early evening (presumably in the absence of endogenous melatonin) is similar to 20 mg temazepam.

Antihistamines and aircrew: usefulness of fexofenadine.

INTRODUCTION: The aim of this study was to establish whether fexofenadine hydrochloride, an antihistamine, modulates daytime sleepiness or performance. METHODS: The effects of fexofenadine (120, 180, and 240 mg) on digit symbol substitution, tracking, and vigilance tasks, and on objective (multiple sleep latency test) and subjective sleepiness, were studied in six healthy volunteers (two males, four females, aged 20-34 [mean 26.5] yr) from 1 h pre-ingestion to 8 h post-ingestion. The study was placebo-controlled and double-blind with a six-way cross-over design. The centrally acting antihistamine, promethazine (10 mg), was used as an active control to confirm the sensitivity of the experimental procedures. RESULTS: There were no changes in performance or sleepiness with any dose of fexofenadine at any time, compared with placebo. Promethazine, compared with both placebo and fexofenadine, impaired performance on the digit symbol substitution task (2.5 h post-ingestion), vigilance task (2.5-5h post-ingestion) and tracking task (2.5-3.5 h post-ingestion), increased objective sleepiness (1.5-2.5 h post-ingestion) and subjective sleepiness (1.5-8h post-ingestion). CONCLUSION: Consideration may be given to the clinical use of currently licensed doses of fexofenadine (120-180 mg) by individuals involved in skilled activity. Fexofenadine may be potentially useful for aircrew.

Intensive and sustained air operations: potential use of the stimulant, pemoline.

BACKGROUND: Intensive and sustained military operations involve long periods of overnight work and the occasional use of a stimulant to maintain performance may be beneficial. In this context a dose response study was carried out to investigate the effects of pemoline, a dopamimetic agent, on overnight work and to assess potential residual effects on subsequent sleep. METHODS: Six healthy volunteers participated in a placebo-controlled, double-blind, cross-over trial involving a 12-h period of work during which subjective alertness and performance on a range of tasks were assessed at 1.5 h intervals following ingestion at 2000 hours of pemoline (10, 20, 30 and 40 mg) and, on two occasions, placebo. The work period was preceded by a 6-h sleep period with temazepam 20 mg, and followed by a 4-h recovery sleep with no medication. All sleep periods were recorded electroencephalographically. RESULTS: There was no difference between sleep periods preceding the work period. Subjective alertness and performance on all tasks deteriorated significantly during the work period, with the earliest impairments in performance observed at 0200 hours. Pemoline increased subjective alertness and performance on all but two tasks, compared with placebo. The onset of activity was seen 4.5 h after drug ingestion and alerting effects of 30 and 40 mg pemoline persisted beyond the work period, disturbing morning recovery sleep. Doses of 10 and 20 mg pemoline had no effect on recovery sleep. CONCLUSION: The present studies indicate that a 20 mg dose of pemoline may be suitable for maintaining nocturnal performance without having adverse effects on recovery sleep.

Central effects of the H1-antihistamine, cetirizine.

BACKGROUND: Effects of the H1-antihistamine, cetirizine, were studied on daytime alertness and performance to establish whether the drug would be suitable for use by air personnel and others involved in skilled activity. METHODS: The investigation was carried out in six healthy volunteers, and the effects of the drug (5, 10, and 15 mg) were studied on sleep latency, subjective sleepiness, digit symbol substitution, tracking and vigilance from 0.5 h to 7.5 h after ingestion. The study was placebo-controlled and double-blind with a six-way cross-over design. Promethazine (10 mg) was used as an active control to establish the sensitivity of the experimental procedures. RESULTS: Promethazine (10 mg) decreased the mean level of vigilance over the day, increased objective and subjective sleepiness from 1.5 to 5.5 h, and impaired tracking 5.5 h after ingestion. Cetirizine (10 and 15 mg) led to shortened sleep latencies over the day, and at 7.5 h sleep latencies were shorter with 10 mg cetirizine than with placebo. Subjective sleepiness with cetirizine was increased compared with placebo after 5 mg at 1.5 h, 10 mg at 7.5 h, and 15 mg at 5.5 h and when meaned over the day. Tracking was impaired with 5 and 15 mg cetirizine 0.5 h after ingestion. CONCLUSION: The study failed to establish dose-response effects of cetirizine, but it is evident that cetirizine is not free of central activity over the therapeutic range, and so its use by air personnel is not recommended.

Central effects of the diuretic, bendrofluazide.

1. Central effects of the diuretic, bendrofluazide (2.5, 5 and 10 mg) were studied in 12 healthy volunteers. Two placebos and an active control drug, oxazepam (15 mg), were included. Single doses were administered double-blind at 10.00 h. The effects of drugs on performance and subjective feelings were assessed before and from 1.5-2.5 and 3.5-4.5 h after ingestion, and recording of the electrical activity of the brain (EEG) and body sway carried out. 2. Performance was assessed using digit symbol substitution, continuous attention, letter cancellation, choice reaction time, finger tapping, immediate and short-term memory, together with critical flicker fusion and two flash fusion. Subjects assessed their mood and well-being on a series of 12 visual analogue scales. The EEG was recorded with eyes open while the subjects carried out a mental arithmetic task, and with eyes closed, when they were required to relax. Body sway was recorded with eyes open and with eyes closed. 3. Bendrofluazide (10 mg) increased the number of errors at letter cancellation and reduced the rate of finger tapping (P < 0.05), while oxazepam increased the number of errors and reduced accuracy at continuous attention (P < 0.01), and increased the number of involuntary rest pauses during tapping (P < 0.05). 4. There were no effects of drugs on subjective assessment of mood. 5. No changes in the electrical activity of the brain were observed with bendrofluazide. In recordings with eyes open, oxazepam reduced delta (0.5-3 Hz), theta (3.5-7 Hz) and alpha 2 (10.5-13 Hz) while increasing beta 1 (13.5-21 Hz) activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Central effects of repeated administration of atenolol and captopril in healthy volunteers.

The central effects of atenolol (50 mg tds) and captopril (50 mg tds) ingested for a period of seven days were studied in ten healthy volunteers. A placebo and two active control drugs, methyldopa (250 mg tds) and oxazepam (10 mg), were included in the design. Oxazepam was ingested on the seventh day only, with a placebo being taken on the preceding six days. On the seventh day, central effects of the drugs were tested at 10.00-11.00 h (session 1), immediately before the subjects' last dose of each drug and at 2.5-3.5 h after the final dose of each drug (1330-1430 h, session 2). Performance was assessed using digit symbol substitution, continuous attention, letter cancellation, choice reaction time, finger tapping, immediate and short-term memory, critical flicker fusion and two flash fusion. Subjects assessed their mood and well-being on a series of 12 visual analogue scales. Recordings of the EEG and body sway were carried out. Neither atenolol nor captopril altered performance at any of the skills tested. There were no effects on subjectively assessed alertness or mood with captopril, while atenolol significantly increased wakefulness in session 2 and when the two sessions were meaned. Similarly, captopril did not modify body sway, while with atenolol there was a significant decrease in activity in the frequency range 1.0-2.75 Hz from session 1 to session 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of polar route schedules on the duty and rest patterns of aircrew.

The duty and rest periods of aircrew operating the polar route from London via Anchorage were recorded during five schedules which involved 1-, 2- or 3-day sojourns in Japan. Sleep throughout each schedule was fragmented, with naps before duty and short sleeps after arrival at a new location. Sleep disturbance rather than cumulative sleep loss appeared to be the overriding problem, and the shorter schedules had the most marked disturbances in sleep during the trip and during the immediate recovery period. Electroencephalographic studies are necessary to confirm these observations, and information on circadian rhythmicity is needed to define the circumstances which lead to persistence of sleep disturbance on return to Europe.

Jet lag and motion sickness.

Jet lag. Present day aircraft operating round northern and southern latitudes cross time zones at almost the same rate as the earth rotates, and it is these rapid transmeridian transitions that lead to the syndrome commonly referred to as jet lag. On arrival at their destination, individuals find themselves out of synchrony with the social and time cues of their new environment and, until they adapt, may experience symptoms such as malaise, gastrointestinal disturbance, loss of appetite, tiredness during the day and poor sleep. The severity and exact nature of the problems vary with the direction of travel and the number of time zones crossed, and some people react more unfavourably to intercontinental travel than others. Clearly, with increasing numbers of passengers undertaking such journeys, there is considerable interest in strategies to reduce the immediate effects of jet lag or to facilitate acclimatisation. Motion sickness is a generic term which embraces seasickness, airsickness, carsickness, space sickness etc, names that identify the provocative environment or vehicle. It is a normal reaction of humans to exposure to certain motion stimuli that occur during passive transportation.

Central effects of the calcium antagonist, nifedipine.

1. Central effects of the calcium antagonist, nifedipine retard (10, 20 and 40 mg) and nifedipine capsules (10 mg) were studied in 14 healthy male subjects. Two placebos and an active control drug, oxazepam (15 mg), were included. Medication was administered double-blind at 10.00 h. The effects of drugs on performance and subjective feelings were assessed before and from 1.5-2.5 h and 3.5-4.5 h after ingestion, and recordings of the electrical activity of the brain (EEG) and body sway carried out. 2. Performance was assessed using digit symbol substitution, continuous attention, letter cancellation, choice reaction time, finger tapping, immediate and short-term memory, together with critical flicker fusion and two flash fusion. The EEG was recorded with eyes open while the subjects carried out a mental arithmetic task, and with eyes closed, when they were required to relax. Body sway was recorded with eyes open and with eyes closed. Subjects assessed their mood and well-being on a series of 12 visual analogue scales. 3. Nifedipine did not alter performance levels on any of the skills tested, while oxazepam (15 mg) increased the number of errors (P less than 0.01) and reduced accuracy at continuous attention (P less than 0.01). 4. Nifedipine (10 mg) reduced total power of the EEG in the frequency range (0.5-30 Hz), and nifedipine (20 mg) increased total alpha power (7.5-13 Hz) (P less than 0.05). Oxazepam reduced alpha and increased beta 1 power (13.5-21 Hz).(ABSTRACT TRUNCATED AT 250 WORDS)

Sedation and histamine H1-receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene.

1. The effects of 10 mg (+)- and (-)-chlorpheniramine and 5 mg (+)- and (-)-dimethindene on daytime sleep latencies, digit symbol substitution and subjective assessments of mood and well-being were studied in 6 healthy young adult humans. Each subject also took 5 mg triprolidine hydrochloride as an active control and two placebos. 2. Daytime sleep latencies were reduced with triprolidine, (+)-chlorpheniramine and (-)-dimethindene, and subjects also reported that they felt more sleepy after (+)-chlorpheniramine and (-)-dimethindene. Performance on digit symbol substitution was impaired with (+)-chlorpheniramine. 3. Changes in measures with (-)-chlorpheniramine and (+)-dimethindene were not different from changes with placebo. 4. In the present study, changes in measures of drowsiness and performance were limited to the enantiomers with high affinity for the histamine H1-receptor. These findings strongly suggest that sedation can arise from H1-receptor antagonism alone, and provide further support for the belief that the histaminergic system is concerned with the regulation of alertness in man.

Presynaptic alpha 2-adrenoceptor function and sleep in man: studies with clonidine and idazoxan.

The effects of an alpha 2-adrenoceptor agonist, clonidine and an antagonist, idazoxan, were studied on nocturnal sleep in man. Clonidine increased non-rapid eye movement sleep and idazoxan reduced slow wave sleep and increased awake activity. Changes in the continuity of sleep with clonidine were similar to, and those with idazoxan opposite to, the effects of maprotiline, an inhibitor of the uptake of noradrenaline, used as an active control. These findings support the previous conclusion that raised levels of noradrenaline in the synapse, after inhibition of uptake, lead to increased presynaptic inhibition of release of transmitter in man. However, all three drugs decreased rapid eye movement (REM) sleep and the ratio of REM to nonREM sleep and this is believed to be due to a non-specific upset of the balance of influences which control the appearance of REM sleep.

Circadian rhythmicity and sleep of aircrew during polar schedules.

Sleep and circadian rhythms of aircrew were studied during a 7-d polar schedule operated between London and Tokyo. Sleep, rectal temperature, and subjective alertness were recorded for 2 d before departure during the schedule, and for 10 d after the return. Changes in sleep during the early part of the trip were due to sleep loss on the outward journey, but later these changes were related to the displacement of the circadian rhythm. The acrophases of the circadian rhythms of temperature were delayed by the outward journey, and amplitudes were reduced throughout the trip. During the return, aircrew reported high levels of tiredness which persisted until the second recovery night. Though the amounts of sleep obtained during the schedule were satisfactory for the aircrew as a group, some crewmembers experienced difficulties. Realignment of circadian rhythms was attained by an advance of the circadian phase in eight aircrew and by a delay in three, and resynchronization was achieved in all cases within 6 d.

Central effects of the angiotensin-converting enzyme inhibitor, captopril. I. Performance and subjective assessments of mood.

1. Central effects of single doses of captopril (12.5, 25 and 50 mg) were studied in fourteen healthy male subjects. Two placebos and an active control drug, oxazepam (15 mg), were included, together with a single dose of atenolol (100 mg). The drugs were administered double-blind at 11.00 h, and performance and subjective feelings were assessed before and from 1.5-2.5 h and 3.5-4.5 h after ingestion. 2. Performance was assessed using digit symbol substitution, continuous attention, letter cancellation, choice reaction time, finger tapping, immediate and short-term memory, together with critical flicker fusion and two flash fusion. Subjects assessed their mood and well-being on a series of 12 visual analogue scales. 3. Captopril did not impair performance on any of the tests, but improved short-term memory (P less than 0.05) and increased the number of letters cancelled (P less than 0.05). Oxazepam reduced the number of substitutions completed in the digit symbol test (P less than 0.01), accuracy on continuous attention (P less than 0.05), number of letters cancelled (P less than 0.05), and rate of finger tapping (P less than 0.05), and increased choice reaction time (P less than 0.001). Atenolol reduced the rate of finger tapping (P less than 0.05), but increased the number of letters cancelled (P less than 0.05). 4. No effects on mood or on subjective feelings were evident with captopril. Oxazepam reduced subjective alertness (P less than 0.05), and atenolol increased feelings of sleepiness (P less than 0.05). 5. Although these observations suggest that central effects may exist with captopril, no adverse consequences have been established on performance or on subjective assessment of mood. Captopril may, therefore, be an appropriate drug for hypertensive patients engaged in skilled activity.

Central effects of the angiotensin-converting enzyme inhibitor, captopril. II. Electroencephalogram and body sway.

1. Effects of single doses of captopril (12.5, 25 and 50 mg) on the electroencephalogram (EEG) and on body sway were studied in fourteen healthy male subjects. Oxazepam (15 mg), as an active control, and two placebos were included in the study, together with a single dose of atenolol (100 mg). Medication was administered double-blind at 11.00 h, and assessments made before and at 2 and 4 h after drug ingestion. 2. There were no changes in the EEG with captopril. Oxazepam reduced the circadian rise in alpha activity, while atenolol decreased beta power. Delta activity was modified by both oxazepam and atenolol. 3. A reduction in lower frequencies of body sway (0.05-1 Hz) occurred with captopril, while the spectra were unaffected by oxazepam. Atenolol increased (P less than 0.05) activity in the frequency range 0.75-2.75 Hz. 4. These observations suggest that captopril is free of central effects such as sedation that may occur with beta-adrenoceptor antagonists. Reduced body sway with captopril could reflect improved integration of central and peripheral control of posture.