A relationship between plasma renin activity and the rapid eye movement phase of sleep in man.

The possible influence of the central nervous system on renin release was investigated by simultaneously monitoring the PRA and the changes of the sleep-wake cycle. Nine normal volunteers were studied, 2 of whom were subjected to an acute sleep reversal procedure. PRA exhibited marked intra- and intersubject variability. No consistent diurnal or ultradian rhythm was observed. The nocturnal variation in PRA, however, was associated with changes in the stage of sleep. The rapid eye movement (REM) phase correlated with a decrease in PRA. In the 9 subjects, 26 measurements were made during REM, all but 2 of which showed a drop compared to the level obtained in the immediately preceding sleep stage (P less than 0.001), by two-tailed t test). The mean decrease in PRA accompanying REM was 407 pg/ml.h, and the mean time for PRA to decrease by half after REM onset was 33 min, with a SE of 8 min. The sleep reversal procedure confirmed that REM was associated with decreased PRA even when sleep occurred at an unaccustomed time. REM is demonstrated by these findings to be temporally associated with a suppression of PRA. The rate of decrease of PRA after REM onset closely approximates the most recent estimations of PRA half-life, which suggests that REM onset is associated with a virtual cessation in renin production.

Circadian rhythms of epinephrine and norepinephrine in man.

The diurnal rhythms of plasma epinephrine and norepinephrine were investigated in a group of normal young men. Sleep, posture, illumination, and food intake were monitored. Plasma epinephrine demonstrated a statistically significant diurnal rhythm, with a mean amplitude of 14 +/- 1.6 (+/- SE) pg/ml superimposed on a mean level of 43 +/- 5.3 pg/ml. The trough occurred at 03.20 h +/- 35 min. Plasma norepinephrine had a significant diurnal rhythm, with a mean amplitude of 111 +/- 19 pg/ml superimposed on a mean level of 413 +/- 25 pg/ml, with the trough occurring at 02.20 h +/- 30 min. There was a significant correlation between the two rhythms at zero phase shift, with a pooled value for the group of r = 0.49. Epinephrine levels had no direct relationship to sleep or posture, whereas norepinephrine levels were significantly higher with upright posture and higher when the men were awake than when asleep. Our results indicate that circadian variations in the sympathetic-adrenal medullary system are not explained by a single controlling influence and that the norepinephrine rhythm can be accounted for as a direct response to changes in posture and sleep, whereas the epinephrine rhythm is probably controlled by a circadian oscillator.

Postmenopausal flashes: studies of chronological organisation.

The times of occurrence of climacteric flashes were recorded by three women over a period of one month. The mean intervals between flashes were 130 +/- 5, 142 +/- 6 and 67 +/- 3 min (mean +/- S.E.) for the three women. The flashes did not occur simply randomly in time. Following a flash, a period of suppression of the ability to flash again was apparent. No mathematical model was derived which satisfactorily described the incidence of flashing in all three women. However, models assuming suppression of the ability to flash immediately following a flash gave the best fits to our data. This suggest that there is an inhibitory feedback mechanism mediating partial suppression of flashing for at least 30 min after a flash.

Liver cell cancer--intervention studies.

The field studies leading to possible intervention procedures are reviewed. Currently the most promising form of intervention is the prevention of aflatoxin contamination of foodstuffs. It is essential that these are monitored and their efficacy in lowering the incidence of liver cancer measured. The association of liver cancer with hepatitis B infection may be a confounding factor and the impact of this on the study population must also be considered. The imminent production of vaccines for hepatitis B infection may provide an alternative or additional mode of intervention. The possibilities for intervention in liver cell cancer appear one of the brighter prospects for primary prevention of a cancer.

A study of 24-hour profiles of plasma met-enkephalin in man.

Met-enkephalin has recently been demonstrated to circulate in human plasma and using this highly specific extracted radioimmunoassay the fluctuations of plasma Met-enkephalin in man were studied over 24 h. The subjects were 6 healthy volunteers. Following a 24 h adaptation period in the metabolic ward and sleep laboratory, an i.v. catheter was inserted. Blood samples were taken at hourly intervals through the day and at 30 min intervals between 23.00 h and 07.00 h. Sleep was monitored polygraphically. There was no regular rhythm discernible in plasma Met-enkephalin levels throughout the 24 h, nor was there any relationship with sleep or food intake. In a further 3 subjects beta-LPH and beta-endorphin levels as estimated by N- and C-terminal beta-LPH radioimmunoassay were elevated on waking compared with 01.00 h, suggesting a nyctohemeral rhythm. In contrast to the correlated circadian fluctuations in beta-LPH, ACTH and beta-endorphin levels therefore, the lack of circadian rhythmicity and dissociation of plasma Met-enkephalin from plasma levels of the former group of peptides suggests control mechanisms for the secretion of Met-enkephalin are quite different and adds support to the concept of separate Met-enkephalin precursors.

Environmental chemical carcinogens and liver cancer.

An appraisal is made of these chemical carcinogens available in the human environment that have been implicated in the etiology of liver cancer. The possible role of mycotoxins is discussed in detail, in particular the association between the aflatoxins and liver cancer in Africa and the Far East.

Decision on the control of a dietary carcinogen -- aflatoxin.

The sequence of events is described whereby decisions are made by the scientific community and national or international legislative bodies in evaluating a dietary carcinogen. This is proposed on the basis of experience gained from the aflatoxins. Suspicion arose first after the deaths of large numbers of poultry and fish; the agent was soon identified as aflatoxins. This was followed by laboratory investigations of their toxic and carcinogenic effects in experimental animals, which showed them to be the most potent liver carcinogen known to experimentalists. Field studies were established to assess a possible association with liver-cell cancer in humans, and a significant correlation was found. An intervention programme was therefore set up to lower exposure and to observe the trend of cancer incidence. Aflatoxins are found in many cereals and nuts exposed to humidity; thus, the staple foods of most of the developing world are at risk. The severity of the economic problem for some countries if prejudice should continue to develop against peanuts as a basis for animal feeds is illustrated. Decisions about control of aflatoxins thus fall into two groups: control measures to prevent contaminated foods from reaching the populations of industrialized countries, and primary prevention for the millions in the developing world. Regulatory actions have been taken in various industrialized countries, but their effect is to make developing countries safeguard exports and still to ignore the hazard within the country. The main problem is thus protection of food supplies, for the indigenous populations of those countries that grow and consume the bulk of the susceptible cereals, by improved husbandry.

The mycotoxins and human health hazards.

The general background of the role of mycotoxins in human disease is briefly reviewed. The acute effects of the ingestion of the aflatoxins and the role that long term exposure may play in human disease are examined in detail. The necessity for co-operation between chemists, veterinarians, physicians and mycologists in the elucidation of the role of the mycotoxins in human disease is stressed.

Dietary aflatoxins and human primary liver cancer.

The results of the dietary aflatoxin-liver cancer study carried out in the Murang'a district of Kenya have been reassessed in relation to disease incidence rates based on a total of seven years of cancer registration and related to the Population Census carried out during the course of the initial study. These newly derived data have been combined with the results of a second similar dietary aflatoxin-liver cancer study which was later carried out in Swaziland. Separate treatment of the male and female data has been considered necessary due to the variation of the sex ratio of the disease incidence in the two areas. The combined results of the two studies show a high degree of positive correlation between the calculated ingestion levels of aflatoxin, expressed as ng/kg bodyweight/day (x) and the adult incidence rates of hepatocellular carcinoma expressed as cases/10(5) adults/year (y) within the two study populations and this is true for both males and females. Based upon an assumed 2 kg/day intake of wet diet and a mean bodyweight of 70 kg, the calculated relationship for adult females is: y = 4.14 log10 x--0.80 (0.05 greater than P4 greater than 0.02, tor = +/- 2.90). With the added assumption of a daily intake of native beer of two liters/day the regression equation for adult males is: y = 21.96 log10 x--11.17 (P5 less than 0.001, tor = +/- 3.42). The regression data are found to be essentially compatible with comparable data recorded by independent workers in Thailand and Mozambique; the latter being the region where the highest rates of liver cancer and of aflatoxin ingestion levels have so far been recorded. A highly significant regression line has also been calculated using crude disease incidence data and aflatoxin exposure levels from all available studies: y = 7.60 log10 x--3.60 (P8 less than 0.001, tor = +/- 3.10).

Influence of sleep disruption and calorie restriction on biological markers for depression.

The hypothesis that the dexamethasone suppression test (DST) and rapid-eye-movement (REM) latency test are not biological markers for depressive illness but artifacts arising from dietary and sleep disturbances that accompany depression was examined in 28 normal volunteers. The restriction of calorie intake with moderate weight loss reproduced a pattern of response to dexamethasone closely resembling that claimed to be diagnostic of depressive illness. The shortened REM latencies claimed as a diagnostic marker were replicated in volunteers by mimicking the sleep pattern commonly found in depression. These changes could not be explained by the induction of mood disorder in the subjects. The results put in question the diagnostic value of the DST and REM latency tests in clinical practice, where sleep disorder and poor appetite, with reduced calorie intake, are the common accompaniments of depressive illness.

A focus of rumenal cancer in Kenyan cattle.

A minimal incidence rate of 2·5% of rumenal cancer of cattle in the Nasampolai valley of Kenya Masailand has been established.Carcinoma of the oesophagus and oesophageal region of the stomach in two free-living giant forest hogs from the same area is reported.The high incidence of the bovine disease is thought to be associated with the abnormal forest grazing of the cattle.The possible aetiology of the disease is discussed.

Dietary aflatoxins and human liver cancer. A study in Swaziland.

A study in Swaziland to assess the possible relationship of aflatoxin contamination and the incidence of primary liver cancer is reported. Aflatoxin ingestion levels have been determined in "food from the plate" samples collected over a 1-year period. A significant correlation between the calculated ingested daily dose and the adult male incidence of primary liver cancer in different parts of Swaziland has been established. Samples of foodstuffs other than the plate samples also reflected the correlation of aflatoxin contamination and liver cancer. This study extends and amplifies the findings of an earlier study in the Murang'a district of Kenya and supports the hypothesis that aflatoxin ingestion is a factor in the genesis of primary liver cancer in Africa.