Controlled release by permeability alteration of cationic ammonio methacrylate copolymers using ionic interactions.

A multiparticulate drug delivery system was studied in which the drug release of a model drug theophylline could be modulated by interactions of ammonio methacrylate polymer and anions. The system consisted of a EUDRAGIT NE coated anionic core, layered with drug and further layered with EUDRAGIT RS. The effects of different anions like chloride, succinate, citrate, and acetate as well as the thickness of the polymer layers on the in vitro drug release were studied. It was seen that succinate and acetate anions had permeability enhancing effects and citrate and chloride anions had permeability retarding effects on the polymer. The results indicate that changing these variables would enable us to get a desired release profile and hence the proposed system could be a viable alternative to existing technologies for the development of a controlled drug delivery system.

Nocturnal aircraft noise effects.

Noise protection associated with the construction and extension of airports in the Federal Republic of Germany has been regulated by the law for protection against aircraft noise since 1971. This legislation is due for revision because of different aspects. One aspect is the growth of air traffic which has led many airports to the limits of their capacity and in search of new ways of adaptation to the increasing demand for flight services. Another aspect is the increasing concern of the population about noise effects which has to be addressed by better protection against the effects of aircraft noise. The framework conditions of policy in terms of society as a whole, its health and economic environment need to be put into effect by political action. Science can contribute to this goal by performing noise effects research and by providing recommendations to the political body. However, it remains controversial, what measures are necessary or adequate to assure effective protection of the population against aircraft noise. This is particularly true for the protection of rest and sleep at night. The problem of finding a common basis for adequate recommendations is associated with (1) the low number of primary studies, which also exhibited highly variable results and assessments, (2) the handling of acoustic or psycho-acoustic dimensions for quantifying psychological or physiological reactions, and (3) the conception of how far preventive measures have to go to prove effective. With this in mind, the DLR Institute for Aerospace Medicine is conducting a large-scale, multi-stage study for investigating the acute effects of nocturnal aircraft noise on human sleep. This enterprise is implemented in the framework of the HGF/DLR project "Quiet Air Traffic" for developing sustainable assessment criteria for human-specific effects of aircraft noise at night.

Hodgkin's lymphoma of T-cell type: clonal association with a CD30+ cutaneous lymphoma.

The derivation of Reed-Sternberg cells in Hodgkin's lymphoma has been a subject of great interest. In most cases, Reed-Sternberg cells seem to be derived from germinal center B cells. In few sporadic cases, a T-cell origin has been shown. This article supports the concept of a T-cell derivation for rare cases of Hodgkin's lymphoma and provides evidence of a novel mechanism of pathogenesis from chronic inflammation in the skin.

Lymphomatoid papulosis and anaplastic large cell lymphomas of the skin.

It is now generally accepted that primary CD30+ cutaneous lymphomas comprise a clinical and morphologic spectrum in which a clear distinction between lymphomatoid papulosis (LyP) and lymphoma cannot always be made. Management varies from observation in patients who have relatively asymptomatic, spontaneously remitting disease (as in LyP) to multiagent chemotherapy regimens with or without autologous stem cell transplantation in patients whose disease has spread to involve extracutaneous sites other than regional lymph nodes (as in disseminated CD30+ lymphoma). Choosing an appropriate management strategy requires correlation of the patient's clinical history (including symptoms) with physical exam and pathologic findings. The importance of clinicopathologic correlation cannot be overemphasized, because lesions with clinically "benign" behavior may appear "malignant" by pathology, and failure to interpret pathologic findings in accordance with the patient's clinical history and physical exam can result in unnecessary, overly aggressive, and potentially harmful treatments. This review highlights integration of clinical and pathologic features of these primary cutaneous CD30+ lymphoproliferative disorders.

Melatonin and jet-lag.

Caused by time shift, a desynchronisation of the body clock from external zeitgebers occurs after transmeridian flight which leads to disturbances of sleep and circadian rhythms. These disturbances are not pathological and diminish within days. To achieve a faster resynchronisation than naturally, the hormone melatonin is often taken by business people and travelers, and--to some extent--by aircrew. The usefulness of the melatonin intake for alleviation of jet-lag is intensively discussed. Most field studies reporting about a favourable influence of melatonin on jet-lag, have been performed using questionnaires; few studies monitoring physiological circadian functions have found a better adjustment under melatonin treatment. However, from laboratory experiments is known that external melatonin is indeed capable to influence the circadian system. With respect to the efficacy of melatonin on better sleep and performance, there is a lack of information from field studies, and laboratory studies do not provide consistent results. Unequivocal estimations of the dosage of melatonin for best efficacy are not yet performed, although a range of different dosages have been tested. Recommendations about dosage, duration of medication and time of intake (which is of major importance for efficacy) do not rely on systematic examinations of the drug. Adverse effects of melatonin on sleepiness and impaired performance directly after intake of the drug are known. From studies is also derived that an inappropriate timing of intake causes sleep disturbances and unfavourable shifts of the circadian system. The administration of melatonin for influencing sleep and circadian rhythms cannot be recommended for aircrew. Flight physicians should refer to adverse and side effects of the hormone melatonin. Before any general recommendations for the use of melatonin can be presented, genuine clinical studies following good clinical practice should be performed.

Culturing and bioassay testing of Daphnia magna using Elendt M4, Elendt M7, and COMBO media.

A performance-based, tiered approach was used to evaluate survival, growth, and reproduction of Daphnia magna in three selected synthetic media: Elendt M4, Elendt M7, and COMBO. Both Elendt M4 and Elendt M7 are high-hardness media currently recommended for Organization for Economic Cooperation and Development (OECD) testing. COMBO is a softer medium similar in total hardness to natural water found in the environment. Tier I consistent of an acclimation phase; Tier II involved a 21-day evaluation of survival, growth, and reproduction; and Tier III used each medium in a 21-day chronic study using a reference toxicant, 3,4-dichloroaniline (3,4-DCA). The evaluation of the performance of each medium was based on acceptance criteria similar to those used by the U.S. Environmental Protection Agency and the European Commission. Tests were run concurrently at three laboratories to assess interlaboratory variability. Daphnids were acclimated to the media for less than 1 month. Daphnid performance in all media exceeded the European Economic Community (EEC) validity criteria; however, reproductive performance and growth were significantly greater in the Elendt media than in COMBO. 3,4-DCA exerted more toxicity to daphnids in COMBO medium [no-observed-effect concentration (NOEC), <3.1microg/liter] compared with those in the Elendt media (NOEC,

Joint NASA-ESA-DARA Study. Part three: circadian rhythms and activity-rest cycle under different CO2 concentrations.

BACKGROUND: During manned space missions, the actual concentration of carbon dioxide (CO2) is frequently elevated to a degree that may affect human functioning and productivity. Therefore, a ground-based international study was performed that tested various psychological and physiological functions under the condition of two different levels of CO2. Thus, a specific experiment aimed at the influence of enhanced CO2-concentrations on the sleep-wake cycle and the circadian system. METHODS: Four volunteers were subjected to a CO2 concentration of 0.7% and 1.2%, respectively, for 24 consecutive days under each condition. Before they were exposed to these elevated levels, baseline measurements were conducted during 5 d under ambient CO2 concentrations (<0.1%). Circadian parameters were assessed by continuous recording of body temperature and by the determination of excretion rates of cortisol, 6-hydroximelatoninsulfate and catecholamines at 3-h intervals during wake. These measurements were conducted on 3 consecutive days 4 times during the two campaigns. Nondominant wrist activity and subjective fatigue was monitored throughout both study phases. RESULTS: Daily means of activity showed significant differences between the two study conditions (with lower values during the 1.2% condition), but these differences only occurred during day-time, whereas during sleep activity levels remained the same. Diurnal mean and circadian amplitude of the temperature rhythm was also significantly lower during the 1.2% condition. CONCLUSIONS: The lower daily mean and circadian amplitudes of temperature during the higher CO2 level can be explained by lower physical activity that was monitored under this level, i.e., a masking effect. We hesitate to explain the lower activity (and hence temperature) as a response to the changed CO2 concentration. More probably, subjects became so acquainted with the procedures of the study protocol during the second study phase (1.2% CO2) that they did not need similar effort to conduct the tasks as during the first phase. The activity level during sleep which was the same during the two phases may support this conclusions. Thus, we conclude that CO2 levels up to 1.2% do not impair the circadian rhythm of healthy men.

Two-crew operations: stress and fatigue during long-haul night flights.

BACKGROUND: As part of a research program concerning legal aspects of two-pilot operations on long-haul routes, the purpose of the study was to investigate two-crew extended range operations during a flight roster with two consecutive night flights and a short layover. HYPOTHESIS: Present flight time regulations may not be adequate for two-crew minimum operations. METHODS: The study was conducted in cooperation with a German airline company on the route Frankfurt (FRA)-Mahe (SEZ). There were 11 rotations (22 flights) that were investigated by pre-, in- and post-flight data collection each time from the two pilots. Recordings included sleep, taskload, fatigue and stress by measurement of EEG, ECG, motor activity, and subjective ratings. The average actual flight times were 9:15 h (FRA-SEZ) and 9:53 h (SEZ-FRA). All flights took place at night. The layover duration in Mahe was 13:30 h during day-time. RESULTS: During layover, sleep was shortened by 2 h on average compared with 8-h baseline sleep. The two consecutive night duties resulted in a sleep loss of 9.3 h upon return to home base. Inflight ratings of taskload showed moderate grades, but for fatigue ratings an increasing level was observed. Fatigue was more pronounced during the return flight and several pilots scored their fatigue at a critical level. Motor activity, brainwave activity (occurrences of micro-events) and heart rate indicated drowsiness and a low state of vigilance and alertness during both night flights, but these effects were more pronounced during the second flight. CONCLUSIONS: From the findings it is concluded that a duty roster, as conducted in this study, may impose excessive demands on mental and physiological capacity.

Aircrew fatigue in long-haul operations.

The studies were conducted on the transmeridian routes Düsseldorf (DUS)-Atlanta (ATL) and Hamburg (HAM)-Los Angeles (LAX), and on the north-south route Frankfurt (FRA)-Mahe (SEZ). Scheduled flight duration was between 8:50 hours (ATL-DUS) and 11:50 hours (HAM-LAX). In total, 25 rotations (50 flights) have been investigated by pre-, in- and post-flight data collection of sleep, taskload, fatigue and stress by electroencephalogram and electrocardiogram measurements and subjective ratings. Inflight ratings of taskload showed low perceived exertion during the Atlantic flights, and were moderate during the north-south transitions. Fatigue ratings increased with progressing flight duration. Towards the end of long U.S.-westcoast flights performed at day-time, and in all night flights, fatigue was elevated compared to the 'baseline' ratings collected during the day-time DUS-ATL flights. Fatigue was rated as being 'critical' by several pilots, particularly during the return flight SEZ-FRA when fatigue was severely pronounced. From the findings it is concluded that duty schedules, as performed on the route HAM-LAX (because of long duty hours), and particularly on the route FRA-SEZ (because of consecutive night work), may place excessive demands on mental and physiological capacity. With respect to legal aspects, the results are significant and should promote further deliberations for advanced schemes of flight duty time limitations and rest requirements.

Bright light: a countermeasure for jet lag?

After time-zone flights, the environmental time is shifted abruptly. The sleep-wake cycle and the circadian system cannot follow this sudden phase shift. Therefore, some or several days are necessary to achieve complete adjustment to a new time zone. The effects resulting from the displacement between internal and external time are well known as jet lag. In principle, timed bright light is able to enhance the resynchronization process of the circadian system after advance or delay shifts. In this report, the effects of bright light exposure on circadian phases and amplitudes after real or simulated time zone transitions are reviewed from the accessible literature and are critically discussed. It can be concluded that laboratory studies have not been unequivocally successful to support the hypothesis that bright light alleviates jet lag. The sparse number of field studies do not yet allow a clear judgment on the beneficial effect of bright light treatment on jet lag.

[Stress and fatigue in long distance 2-man cockpit crew]. / Stress und Ermüdung im Zwei-Mann-Cockpit auf Langstrecken.

Common rules on flight-duty times and rest requirements within the European Union are under intense discussion. In the deliberations, results from scientific investigations should be considered. As part of a research programme concerning legal aspects of two-pilot operations on long-haul routes, the purpose of the studies was to investigate two-crew extended range operations during transmeridian and transequatorial flight schedules. The studies were conducted with two German charter airlines on the transmeridian routes Düsseldorf (DUS)-Atlanta (ATL) and Hamburg (HAM)-Los Angeles (LAX), and on the north-south route Frankfurt (FRA)-Mahe (SEZ) including two consecutive night flights with a short layover. In total, 25 rotations (50 flights) have been investigated by pre-, in-, and post-flight data collection from the two pilots being the minimum required crew. Recordings included sleep, taskload, fatigue and stress by measurements of EEG, ECG, motor activity and subjective ratings. During the transmeridian schedules, pilots lost one night of sleep because of the return flights which were conducted at night. The resulting sleep deficit was 8.2 h. During the layover of the SEZ-rotation with a duration of 14 h on average, sleep was shortened by 2 h compared with baseline sleep. The two consecutive night flights resulted in a sleep loss of 9.3 h upon return to home base. Inflight ratings of taskload showed low levels during the atlantic flights, and moderate grades during the north-south transitions. Fatigue ratings exhibited an increasing level with progressing flight duration. Towards the end of long US-westcoast flights performed at day-time, and in all night flights, fatigue was enhanced compared to the "baseline" ratings collected during the DUS-ATL flights. Fatigue was scored at a critical level by several pilots, particularly during the return flight SEZ-FRA when fatigue was severely pronounced. The subjective fatigue ratings were confirmed by the objective measurements of motor activity, brain-wave activity (occurrences of micro-sleep) and heart rate which indicated drowsiness and a low state of vigilance and alertness during all night flights under study. From the findings it is concluded that duty schedules, as conducted on the route HAM-LAX (because of long duty hours), and particularly on the route FRA-SEZ, (because of consecutive night duties) are coming close to the limits of mental and physiological capacity. With respect to legal aspects, the results have significance and should promote further deliberations for advanced schemes of flight duty time limitations and rest requirements.

Jet lag and sleepiness in aircrew.

Jet-lag and day-time sleepiness cannot be avoided in transmeridian operations, because work hours of aircrews interfere with the circadian system through irregular work-rest schedules and rapid time-zone transitions. Although the primary cause of accidents is usually the human factor, jet lag and sleepiness have seldom been officially identified as causes of inadequate functioning in the cockpit. However, research clearly indicates that flights at night and/or across time zones will impair performance and reduce safety. Research on countermeasures have focused on on-board napping, crew augmentation, behavioural strategies against jet-lag, light treatment and melatonin administration. Regrettably, scientific knowledge has been successfully transmitted to only a very few national authorities responsible for work hours of aircrews.

Bright light as a chronobiological countermeasure for shiftwork in space.

Work-rest schedules during long duration space missions involve several factors which could disrupt sleep and circadian temporal organisation: (1) displacement of sleep due to two-shift operations; (2) planned or unplanned schedule changes due to operational requirements; (3) social and light zeitgebers different from those on earth; (4) changes in the gravitational exposure. Timed bright light treatment has the potential to accelerating adaptation to schedule changes. Four male subjects were exposed to two sessions of 11 d of simulated microgravity (6 degrees head down tilt bedrest) with 6-h extensions of the wake period on 2 days (12-h phase delay). In a blind crossover design, subjects were exposed to bright light (>3500 lux) for 5 h on each of the 2 shift days and the following day, at times either expected to accelerate the adjustment to the phase delay (experimental condition) or to have no phase shifting effect (control condition). Sleep was recorded polygraphically, the circadian system was monitored by recordings of heart rate and body temperature, and by collection of urine (electrolyte and hormone excretion). Only the rhythms of 6-hydroxymelatoninsulphate and potassium excretions showed significantly enhanced adjustment under the experimental condition. Different rhythms adapted to the 12-h delay at different rates, comparable to those observed after time zone shifts. Sleep was shorter in simulated weightlessness than in normal ambulatory age-matched subjects, consistent with the shorter sleep durations characteristic of space flight. These results confirm the disruptive effects of wake-rest schedule shifts on sleep and circadian rhythms. Contrary to our initial hypothesis, 5-h exposures to bright light finishing at the time of the circadian temperature minimum were not more effective at accelerating adjustment to a 12-h schedule delay than exposures coinciding with the temperature maximum. We conclude that, while bright light may accelerate adjustment to work-rest schedule delays, any such effect seems to be largely independent from the timing of the light exposure.

Sleepiness of civil airline pilots during two consecutive night flights of extended duration.

Sleepiness of civil airline pilots was studied in a two-crew cockpit during two consecutive night flights of about 10 h duration each. Sleepiness was assessed by EEG recordings and subjective ratings during hourly recurrent short experimental phases. On the second night flight, the alertness component that is related to the preceding sleep showed a modification due to reduced quality and quantity of sleep between flights. The daytime sleep during layover was not sufficient to maintain the same alertness level as observed during the initial flight. This result is in coincidence with investigations in shift workers starting a period of night shifts. It is concluded that improvements such as the introduction of a nap schedule should be considered to alleviate spontaneous sleepiness in the cockpit.

[Therapy of jet lag]. / Therapie des Jet-Lag.

After transmeridian flights, disturbances of the circadian rhythm and sleep occur due to the desynchronization between the body clock and external zeitgebers. Under normal circumstances, these disturbances are not pathological and disappear within a few days. However, they impair well-being and lead to significant changes in performance and vigilance. These effects are of particular importance for tasks and operations which require enhanced attention and alertness. Some of the acute symptoms of jet-lag can be reduced and shortened by appropriate countermeasures. The application of these therapies is practicable and has been successfully incorporated in clinical measures.

Pre-adaptation to shiftwork in space.

Astronauts are often required to work in shift schedules. To test pre-mission adaptation strategies and effects on the circadian system, a study was performed using microgravity simulation by head-down bedrest. Eight male subjects were studied over 4 control days, and 7 days each for pre-mission adaptation, bedrest, and readjustment. The circadian system was assessed by monitoring ECG and temperature, and by collecting urine for determination of hormones and electrolytes. Rhythms did not achieve complete adjustment within the adaptation period when the sleep-wake cycle was shortened by 1 h/day, but resynchronization continued during bedrest. After the bedrest period when the time shift was reversed by a 7-h delay within 2 days, resynchronization was achieved satisfactorily only within 7 days. From the results it is concluded that a sleep-wake cycle advance as used in this study is insufficient to keep the circadian system in pace. Under operational conditions the circadian system of astronauts may become longer and more destabilized than under controlled laboratory conditions.

Response of the circadian system to 6 degrees head-down tilt bed rest.

The influence of simulated microgravity and reduced zeitgebers on the circadian system was examined in eight subjects. The 12-d study included a 3-d period for baseline measurements, 7 d of 6 degrees head-down bed rest, and 2 d for recovery. The sleep-wake cycle was kept constant during the study. The state of the circadian system was assessed from continuous measurements of temperature and ECG, and collections of urine at 3-h intervals for the determination of hormone and electrolyte excretions. Results indicate that only minor changes occurred in rhythm acrophases, whereas daily means for several physiological functions and their circadian amplitudes were significantly altered during the bed-rest phase. These studies using head-down tilt confirm previous findings with horizontal bed rest and indicate that rhythm disturbances can occur without change in the sleep-wake cycle. To the degree that bed-rest studies simulate manned spaceflights, results indicate that variations in circadian cycles can occur even during short-term missions and must be taken into account when interpreting subsequently obtained physiological data.

Sleep patterns in aircrew operating on the polar route between Germany and east Asia.

The study was performed as the second part of an investigation to assess sleep behavior and circadian rhythmicity in aircrew operating regular passenger flights between Germany and East Asia via Anchorage (ANC). Continuous records of sleep and ratings of sleep quality were obtained by sleep logs from 101 B747-cockpit crewmembers, starting at least 3 d before commencing flight duty, continuing during days on duty (the duration depending on the flight schedule) and finishing 4 d after return, at the earliest. Regardless of the specific duty roster, sleep deficit occurred mainly after the first flight leg to ANC, presumably due to the 10-h time zone difference and the short layover time. During the layover in the Far East, the sleep deficit diminished partly because of additional naps. Sleep was often disturbed and scattered over days and nights. Another pronounced sleep deficit occurred after the first return flight from South Korea or Japan to ANC. Compared to the outgoing layover period in ANC, the number and duration of naps increased during this layover and, additionally, on the first 2 d after returning home. Poorer sleep quality ratings were associated with accumulated sleep deficit and increased napping, but significant decrements in sleep quality were seen only during two out of the six different duty rosters. All six of the polar route duty rosters may lead to significant sleep disturbances. During some flight schedules the sleep deficit is large enough to raise operational implications.