Circadian variations in plasma osmolality, electrolytes, glucose, and cortisol in carp (Cyprinus carpio)

Male carps (Cyprinus carpio) of about 1.5 kg were used in all experiments performed in December and February. Blood was taken by heart-puncture within 1 min or less every 4 hr from different fishes during a 24-hr period to establish circadian rhythmicities of all parameters. The water temperature was 11-12 degrees. In December circadian variations could be calculated for cortisol, Na+ and plasma osmolality in partly fed carps and for cortisol, Ca2+, glucose, and plasma osmolality in food deprived animals. No difference in cortisol level, amplitude, or acrophase was present between both experiments but plasma Na+ and osmolality was more elevated when feeding. Also the acrophase of the osmolality rhythm differed between both groups. In February carps, cortisol levels were still comparable to December ones, but a 4 hr shift in acrophase had occurred (from +/- 02 hr to 06 hr). Levels of all other parameters also were comparable to December, except for glucose with only 1/5th of the December values. There was also a shift in acrophase present from the morning to around midnight. The level of cortisol in February carps acclimated to 18 degrees for 1 week was twice the one found in the 11 degrees group. At the same time a significant increase in amplitude and shift in acrophase to 22 hr was seen. Other parameters, except for glucose of which the level was significantly lower than in the 11 degrees group, remained unchanged. Also no correlation between the individual 24-hr data of all parameters could be found. It is therefore concluded that cortisol is not responsible for the observed circadian rhythmicities of Na+, Ca2+, glucose, or plasma osmolality.     

Urinary melatonin: a noninvasive method to follow human pineal function as studied in three experimental conditions

Abstract:  The aim of this study was to examine whether urinary melatonin, rather than urinary 6-sulfatoxymelatonin (aMT6s), can be used as an indicator of diurnally and seasonally changing melatonin secretion. The subjects (n = 15) spent three separate 24-hr periods in a climatic chamber during winter (n = 7) and summer (n = 8). Blood and urine samples were obtained during each period at 2- to 5-hr intervals. Serum melatonin and urinary melatonin and aMT6s were assayed by radioimmunoassay. The serum melatonin levels increased nearly 10-fold from low daytime to high nocturnal values. The mean nocturnal increase of urinary melatonin was 1.7-fold and that of urinary aMT6s was 4.6-fold. Both urinary melatonin and aMT6s correlated significantly with area under the curve melatonin in serum during the night, during the day and throughout the entire 24-hr observation period in all cases. The ratio between urinary melatonin and aMT6s excretion showed significant diurnal variation, being ninefold higher at 16:00 hr than at 07:00 or at 09:00 hr. The ninefold decrease in the urinary melatonin/aMT6s excretion ratio between the evening and the morning may reflect increased liver metabolism of melatonin during the night. Both urinary melatonin and aMT6s are good indicators of melatonin secretion, but the variation is significantly smaller for the former molecule.     

A multifactorial approach employing melatonin to accelerate resynchronization of sleep-wake cycle after a 12 time-zone westerly transmeridian flight in elite soccer athletes

Rapid transmeridian translocation through multiple time zones has a negative impact on athletic performance. The aim of the present study was to test the timely use of three factors (melatonin treatment, exposure to light, physical exercise) to hasten the resynchronization of a group of elite sports competitors and their coaches to a westerly transmeridian flight comprising of 12 time-zones. Twenty-two male subjects were included in the study. They were professional soccer players and their coaches who travelled to Tokyo to play the final game of the Intercontinental Coup. The day prior to departure, urine was collected from each subject from 18:00 to 06:00 hrs to measure the melatonin metabolite 6-sulphatoxymelatonin. Participants were asked to complete sleep log diaries from day 0 (preflight) to the day before returning to Buenos Aires (day 8). All subjects received 3 mg of melatonin p.o. daily at expected bedtime at Tokyo immediately after leaving Buenos Aires. Upon arrival at Tokyo the subjects performed a daily physical exercise routine outdoors at two restricted times of the day (from 08:00 to 11:00 hrs in the morning and from 13:00 to 16:00 hrs in the afternoon). Exposure to sunlight or physical exercise at other times of the day was avoided. Except for the number of awakenings (which increased on days 1 and 3) and sleep latency (which decreased on days 2, 6 and 8), there was an absence of significant changes in subjective sleep parameters as compared with preflight assessment. Sleep quality and morning alertness at Tokyo correlated significantly with preflight 6-sulphatoxymelatonin excretion. Mean resynchronization rate of sleep-wake cycle to the 12 hr-time shift was 2.13 +/- 0.88 days, significantly different from the minimal resynchronization rate of 6 days expected after a 12-time-zones flight. The results indicate that the combination of melatonin treatment, an appropriate environmental light schedule and timely applied physical exercise can be useful to help elite athletes to overcome the consequences of jet lag.     

Effect of melatonin treatment on 24-hour rhythms of serum ACTH, growth hormone, prolactin, luteinizing hormone and insulin in rats injected with Freund''s adjuvant

The effect of melatonin injection on Freund's adjuvant-induced changes in levels and 24-hr rhythms of circulating ACTH, growth hormone (GH), prolactin (PRL), luteinizing hormone (LH), and insulin was assessed in rats. Animals received subcutaneous (s.c.) injections of melatonin (30 microg) or vehicle, 1 hr before lights off for 12 days. Ten days after melatonin treatment, they were injected with Freund's complete adjuvant or its vehicle s.c., and after 3 days, rats were killed at six different time intervals throughout a 24-hr cycle to measure the different hormones by radioimmunoassay (RIA). Following Freund's adjuvant injection, an increase in serum ACTH, with maintenance of ACTH diurnal rhythm was found. Acrophases of the ACTH rhythm varied from 13:39 to 17:12 hr and the amplitude of rhythm was augmented after immunization. In immunized rats, melatonin treatment increased the amplitude of serum ACTH rhythm. For GH, a depressive effect of immunization on circulating levels, together with absence of diurnal rhythmicity were found. Immunization augmented circulating PRL, while conserving its diurnal rhythmicity. Melatonin-injected rats showed significant diurnal variations of serum PRL after immunization only. Acrophases of the serum PRL rhythm varied from 19:37 to 22:04 hr. Immunization decreased circulating LH and suppressed its 24-hr rhythmicity pattern. The effect of immunization on LH was counteracted by melatonin injection. Acrophases of serum LH rhythm varied from 00:44 to 03:53 hr. Significant effects of immunization and time of day on circulating insulin were detected; immunization increased serum insulin levels with a shift in acrophase from early afternoon to midnight. The data indicate that several early changes in levels and 24-hr rhythms of circulating ACTH, PRL, and LH in Freund's adjuvant-injected rats were sensitive to treatment with pharmacological amounts of melatonin.     

Cushing's syndrome due to adrenal adenoma with persistent diurnal cortisol secretory rhythm.

A 41-yr-old female with presumed Cushing's syndrome was found to have a diurnal cortisol rhythm characterized by low values of 8:00 a.m. and consistently high values at 4:00 p.m. and midnight. Hourly sampling of plasma cortisol over 24 hr confirmed this rhythm, as did measurement of urinary free cortisols in samples collected every 6 hr over 24 hr. Hypercortisolemia was not suppressed by 2 mg of dexamethasone given every 6 hr for 24 hr. The adrenal tissue was responsive to ACTH. Iodocholesterol scanning revealed unilateral activity, and the patient's syndrome was cured by resection of an adrenal adenoma. In this patient a diurnal cortisol secretory pattern was present due to the secretory activity of the adenoma. The cause of the abnormal but persistent diurnal pattern is unknown.     

Hypoxic depression of melatonin secretion after simulated long duration flights in man

Fatigue is often reported after long duration flights. Mild hypobaric hypoxia caused by pressurization may be involved in this effect through disruption of circadian rhythms, independent of the number of time zones crossed. In this controlled crossover study we assessed the effects of two levels of hypoxia equivalent to 8000 and 12,000 ft on the rhythm of plasma melatonin concentrations, a marker of circadian rhythmicity. Sixteen healthy young male volunteers (23-39 years) were exposed in a hypobaric chamber for 8 hr (08:00-16:00 hours) to 8000 ft, followed 4 wk later by 12,000 ft. Plasma melatonin was assayed over two 24-hr cycles (control and hypoxic exposure) every 2 hr in all subjects. We found a significant decrease in the nocturnal melatonin peak after hypoxic exposure at both altitudes, and we found that this effect was age dependent for the 12,000-ft exposure: the decrease was only seen in the younger subjects (23-28 years). Analysis of heart rate variability allowed us to demonstrate that the older and less trained subjects (29-39 yr) in our study exhibited a far greater increase in sympathetic tone than the younger subjects during the 12,000-ft exposure. These results show that hypoxic depression of melatonin secretion may be influenced by individual factors such as age, physical fitness and sympathetic reactivity to hypoxia. Our findings suggest that hypoxia may by itself contribute at least in part to postflight fatigue after long duration flights, and to the clinical disorders of jet lag in transmeridian flights through its effects on the circadian system.     

Gender-related differences in urinary 6-sulfatoxymelatonin levels in obese pubertal individuals

The objective of this study was to measure the urinary excretion of the main melatonin metabolite 6-sulfatoxymelatonin in obese and normal weight (wt) boys and girls. The study included 94 subjects, aged 4-15.7 yr (50 obese and 44 normal wt; 48 boys) classified as: mid-childhood (4-7.99 yr), late-childhood (8-12 yr) and pubertal (10.1-15.7 yr, Tanner II-IV). Normal wt subjects were children with a body mass index (BMI) between the 25th and 75th percentiles, and the group of obese subjects included children whose BMI was above the 97th percentile. A 24-hr urine sample was collected during two intervals: (i) 18:00-08:00 hr, and (ii) 08:00-18:00 hr. Analysis of urinary 6-sulfatoxymelatonin levels was performed by radioimmunoassay. Excretion of 6-sulfatoxymelatonin was expressed as: (i) total amount excreted (microg); (ii) mug excreted per time interval, nocturnal or diurnal; and (iii) the difference between nocturnal and diurnal samples (microg, estimated amplitude). A factorial analysis of variance indicated that nocturnal 6-sulfatoxymelatonin excretion and amplitude were significantly higher in the obese individuals. A significant interaction 'BMI x age' was detected, i.e. the effect of BMI was significant in the pubertal group only. Total, nocturnal and diurnal 6-sulfatoxymelatonin excretion was significantly higher in girls. The increase in 6-sulfatoxymelatonin excretion found in obesity occurred only in boys and at the pubertal age. To what extent this increase in melatonin production contributes to a delayed puberty in some pubertal obese males remains to be established.     

Impact of sleep and circadian disturbances in urinary 6-sulphatoxymelatonin levels, on cognitive function after major surgery

Sleep and circadian disturbances may underlie cognitive dysfunction after major surgery. The aim of this study was to examine the association between sleep and circadian disturbances (as assessed by changes in the melatonin rhythm) and postoperative cognitive dysfunction (POCD). We measured subjective and objective sleep quality, excretion of the major metabolite of melatonin, 6-sulphatoxymelatonin (aMT6s) in urine and cognitive function before and 4 days after major abdominal surgery in 36 patients. Subjective sleep quality was measured by visual analogue scale, objective sleep quality was measured by actigraphy, and cognitive function was assessed by neuropsychological testing. Eighteen patients (50%) had POCD on day 4 after surgery. At that time, the excretion of aMT6s was disturbed with significantly higher daytime excretion and a reduced night/day ratio compared with the preoperative measure (P = 0.05). Patients with POCD had significantly worse sleep quality and more night awakenings (P < 0.05) but we found no significant differences in day time (06:00-22:00 hr), night-time (22:00-06:00 hr) or total aMT6s excretion (mug/24 hr). A significant correlation was found between the total excretion of aMT6s and actigraphically measured sleep efficiency (r(s) = 0.45, P = 0.03) and wakefulness after sleep onset (r(s) = -0.44, P = 0.04). In conclusion, POCD was associated with worse subjective sleep quality and more awakenings. Circadian rhythmicity as assessed by aMT6s excretion was disturbed after surgery but we were unable to show an association with POCD. Strategies to improve postoperative sleep quality should be investigated in the future.     

Assessment of Intestinal Permeability with a Two-Hour Urine Collection

The differential urinary excretion of orally administered lactulose and mannitol is used to evaluate intestinal permeability. This test usually involves a 5- to 6-hr urine collection. We hypothesized that a shorter collection time would give an equivalent result. Forty-three patients with a variety of gastrointestinal symptoms and diagnoses (group 1) and 42 patients with Crohn's disease (group 2) had a standard lactulose/mannitol permeability test. The lactulose and mannitol urinary excretion was calculated using the first urine (group 1) or the 1-hr and 2-hr urine (group 2) and was compared to the values calculated from the routine 5- or 6-hr collection. Lactulose excretion kinetics, expressed as the percent of the total urinary excretion within a given time period, were as follows: 21% in first hour (group 2), 29% in second hour (group 2), and 46% in first 2.5 hr (group 1). Mannitol urinary excretion kinetics were 16%, 31%, and 44%, respectively. The lactulose/mannitol ratio based on a standard urine collection correlated well with the ratio based on just the first urine produced by the patient (R² = 0.94; P < 0.001; group 1) and the 2-hr urine (R² = 0.464; P < 0.001; group 2). Future use of the lactulose/mannitol ratio to assess intestinal permeability may be able to be simplified by shortening the urine collection time.     

Daytime 50 Hz magnetic field exposure and plasma melatonin and urinary 6-sulfatoxymelatonin concentration profiles in humans

Concern about the health effects of extremely low frequency (ELF) magnetic fields (MF) has been raised by epidemiological studies indicating an association between certain cancers and living near power lines or working in high electric field environments. Alterations in pineal function have been proposed as a mechanism through which power-frequency MFs may interact with living organisms. A double blind laboratory study was performed to evaluate daytime exposure effects of 100 microT root mean square (rms) 50 Hz MF. Three head exposure sessions of 30 min each were performed: sham, continuous, and intermittent (15 s on/off cycles) MFs were presented to each subject in early or late afternoon (13:30 or 16:30 hr). Twenty-one healthy male volunteers (20-27 yr old) participated in these 3-weekly experimental conditions. Blood samples were drawn for serum melatonin measurement, hourly at night (from 20:00 to 07:00 hr) under controlled environmental conditions. Urinary excretion of 6-sulfatoxymelatonin (aMT6s), the main melatonin metabolite, was measured for a 17 hr period, by means of urine samples taken at 19:00 hr (14:00-19:00 hr "afternoon period"), 23:00 hr (19:00-23:00 hr "evening period"), and 07:00 hr, day 2 (23:00-07:00 hr day 2 "night-time period"). There were no significant differences in either plasma melatonin or in aMT6s excretion profiles in the three experimental conditions. However, a tendency for a smaller increase of night-time urinary aMT6s after continuous MF exposure was found (P=0.08) particularly in men with the lower excretion rate of aMT6s ("Low Group") (P=0.07). We conclude that this study does not indicate that daytime acute MF exposure influences either melatonin secretion or aMT6s excretion. Inter-individual differences in pineal production of melatonin, however, have to be taken into account in further studies.     

Cortisol metabolism in glucose-6-phosphate dehydrogenase deficiency

Ten subjects with glucose-6-phosphate dehydrogenase deficiency (G6PD Canton) and ten G6PD normal subjects matched for sex and age distribution were studied with respect to their plasma cortisol levels and 24-hr urinary total 17-oxogenic steroids excretion before and after maximal stimulation with B^1–24 corticotrophin (Synacthen depot). In five patients and five controls, the study included the metabolic clearance rate of cortisol which increased twofold after B^1–24 corticotrophin administration. No significant differences were found in these two groups of individuals. This indicates that in G6PD-deficient subjects, under basal conditions and with maximal stimulation, both cortisol production and metabolism proceed at a normal rate.     

Melatonin excretion is not related to sleep in the elderly

Abstract: We examined the association between 6-sulphatoxymelatonin (6-SMT) excretion and sleep in 68 volunteers 60–79 years of age who complained of insomnia or depression. An Actillume wrist monitor was worn for 5–7 consecutive days and nights in home-living conditions. Activity was used to estimate total sleep time (TST) and wake after sleep onset (WASO). Throughout two 24 hr periods, urine was collected approximately every 2 hr during the day and after any voidings during the sleep period. During the next week, subjects spent 5 nights and 4 days in the laboratory. Sleep was measured and scored with standard polysomnographic techniques. Urine was collected, as for home recording, on days 1 and 4. Urinary concentrations of 6-SMT were assayed. Cosine- fitting of urine data across both days at home and both laboratory collections established the mesors and amplitudes of 24 hr 6-SMT excretion rhythms, but neither was significantly correlated with sleep. Mean and peak 6-SMT excretion during the sleep period was also determined. Significant correlations were found between mean 6-SMT during the laboratory sleep period and TST and WASO. However, these associations were not independent of circadian timing: sleep was better when sleep occurred near the circadian acrophase of 6-SMT excretion. These data indicate that low melatonin production may not be an important factor in insomnia among the elderly.     

Clinical testing of the hypothalamic-pituitary-adrenocortical system in states of hypo- and hypercortisolism.

Cortisol production is appropriately maintained by a complex control system which involves primarily the hypothalamus, the pituitary, and the adrenal cortices. Very small quantities of ACTH stimulate cortisol production, and maximum stimulation occurs with serum concentrations of only 3 mU/100 ML. Under normal circumstances, cortisol is secreted in bursts about ten times each day and circulates predominately bound to a specific binding protein which is rather completely saturated. Radioimmunoassay of plasma cortisol is now generally available and is the assay method of choice, but because of the episodic nature of its secretion, random values of plasma cortisol must be interpreted with great reservation, and even the comparison of morning and evening values in assessing circadian rhythmicity is not often helpful. Urinary free cortisol determinations provide excellent discrimination between normal function and all forms of hypercortisolism. Although the response of the adrenal cortices to ACTH may be evaluated in a number of different ways, the simplest but most definitive procedure involves continuous intravenous administration over a 48-hr period. Of the various tests which indirectly assess the potential for ACTH secretion, the use of metyrapone is most helpful. In the test of greatest utility, plasma cortisol and 11-desoxycortisol are determined the morning after a single midnight oral dose of 30 mg/kg. The detection of all forms of pathologic hypercortisolism is still best accomplished by the oral administration of dexamethasone. Plasma cortisol can be determined the morning after a single midnight dose of 1 mg, or urinary 17-hydroxycorticosteroids can be determined after 2 days in which 0.5 mg is given at 6-hr intervals. Patients with hypercortisolism of hypothalamic-pituitary origin usually evidence appropriate suppression of urinary steroids if the dose is increased to 2.0 mg every 6 hr for another 48 hr. In patients who do not suppress on this or even higher doses of dexamethasone, the distinction between those with adrenal tumor and those with the ectopic ACTH syndrome can be accomplished most definitively by the assay of plasma ACTH where this determination is available.     

Timing of initiation of the preovulatory luteinizing hormone surge and its relationship with the circadian cortisol rhythm in the human

The relationship between the hypothalamo-pituitary-gonadal (HPG) axis and the hypothalamo-pituitary-adrenal (HPA) axis has been well documented in the rat. In most cases, a negative coupling was observed and an inhibitory effect of the HPA axis upon the HPG was shown. In the female rat, a marked circadian rhythm of corticosterone plasma values is observed during each day of the estrous cycle, with maximal values around 08:00 p.m. The preovulatory luteinizing hormone (LH) surge also occurs at 08:00 p.m. on the day of proestrus. Here we measured circadian variations of plasma cortisol in humans in relation with the time of initiation of the preovulatory LH surge. Blood samples were taken at 08:00 a.m., 12:00 a.m., 04:00 p.m., 08:00 p.m., 12:00 p.m., and 04:00 a.m. from 19 subjects for 4 consecutive days, once 17beta-estradiol (E(2)) values reached 125 pg/ml (days 7-10 of the menstrual cycle). Serum E(2) and LH determinations were performed by microparticle enzyme immunoassays. Serum progesterone and plasma cortisol determinations were made using RIA methods. For plasma cortisol values, a marked circadian rhythm, with 2- to 3-fold higher values during the morning than during the afternoon, was almost identical before, during and after the LH surge. However, values were generally higher during the follicular phase than during the luteal phase. Maximum cortisol values occurred between 04:00 and 08:00 a.m. and minimal cortisol values between 04:00 and 08:00 p.m. Initiation of the LH surge (50% over the mean of previous values) occurred at 04:00 a.m. (20% of the cases) or at 08:00 a.m. (80% of the cases). There was a strong coupling between the onset of the surge and the acrophase of the cortisol circadian rhythm: maximal cortisol plasma values were seen at 04:00 a.m. when the LH preovulatory surge started at 04:00 a.m. and 08:00 a.m. when it started at 08:00 a.m. The present results show that the positive coupling documented in the female rat between the HPA and the HPG axis at the time of preovulatory LH surge is also present during the menstrual cycle in the human.     

Incidence of air travel-related pulmonary embolism at the Madrid-Barajas airport

BACKGROUND: Prolonged air travel and the associated immobilization are risk factors for venous thromboembolism. The occurrence of pulmonary thromboembolism (PTE) under these circumstances is referred to as economy class syndrome. We assessed the incidence of symptomatic PTE in passengers on long-haul flights arriving at Madrid-Barajas Airport, Madrid, Spain, and the association with the number of flight hours. METHODS: We retrospectively reviewed cases of PTE among international travelers arriving at Madrid-Barajas Airport between January 1995 and December 2000. Patients presenting with symptoms of deep venous thrombosis but without symptoms of PTE were excluded. Pulmonary thromboembolism was identified using an algorithm of diagnostic tests. The incidence of PTE and the association with flight duration was assessed. RESULTS: The average number of passengers per year who arrived at the airport on flights originating abroad in the period analyzed was 6 839 222. Sixteen cases of PTE were detected over the 6-year period. All patients with travel-associated PTE had flight durations of greater than 6 hours. The overall incidence of PTE was 0.39 per 1 million passengers (95% confidence interval [CI], 0.20-0.58). On flights that lasted between 6 and 8 hours, the incidence was 0.25 per 1 million passengers (95% CI, 0-0.75), while on flights longer than 8 hours, the incidence was 1.65 per 1 million passengers (95% CI, 0.81-2.49) (P<.001). CONCLUSIONS: Air travel is a risk factor for PTE, and the incidence of PTE increases with the duration of the air travel. However, the low incidence of PTE among long-distance passengers, similar to that observed in other international airports, does not justify social alarm.     

A test of the coincidence and duration models of melatonin action in Siberian hamsters. II. The effects of 4- and 8-hr melatonin infusions on testicular development of pinealectomized juvenile Siberian hamsters (Phodopus sungorus)

In a previous paper we demonstrated that properly timed 1-hr infusions of 50 ng melatonin effectively suppressed testicular development in juvenile Siberian hamsters. Only melatonin infused between 20:00 and 21:00 hr was effective in animals exposed to 16L (lights off 20:00 hr). In this paper we further investigate the importance of the coincidence and duration hypotheses of daily exposure of melatonin. Prepubertal Siberian hamsters received either 4- or 8-hr melatonin infusions at various times either on long photoperiod (LD 16:8 = 16L) or on short photoperiod (LD 10:14 = 10L). Daily 8-hr melatonin infusions suppressed testicular development in both photoperiods. Daily 4-hr, 50 ng/hr, melatonin infusions at 17:00-21:00 hr inhibited testicular growth in 16L and daily 4-hr melatonin infusions (either 50 ng/h or 50 ng/day) inhibited testicular growth at 17:00-21:00 hr in 10L. We also tested the efficacy of an interrupted melatonin infusion of long duration (8 hr). Pinealectomized prepubertal male Siberian hamsters, born on 16L, were infused with two signals of 4 hr separated by an interval of 2 hr. Melatonin-infused groups had significantly inhibited testicular growth compared to vehicle-infused animals. Testicular development was maximally inhibited only in those groups in which the period of melatonin sensitivity identified in the previous paper (20:00-21:00 hr) overlapped or immediately followed a period of melatonin infusion. Considering the restrictions of the experimental design employed in these studies, the results are best explained by the hypothesis that the photoperiodic gonadal response in juvenile Siberian hamsters is regulated by the coincidence in time of exogenously administered melatonin with an intrinsic rhythm of sensitivity to melatonin, which occurred at 20:00-21:00 hr. The duration of the melatonin signal alone can not explain the results.     

Value of urinary copper excretion after penicillamine challenge in the diagnosis of Wilson's disease.

To investigate the diagnostic value of 24-hr urinary copper excretion testing after penicillamine challenge in the diagnosis of Wilson's disease, 75 consecutive children referred for a variety of liver problems and in whom parameters of copper metabolism had been investigated were analyzed retrospectively. Seventeen had Wilson's disease, 22 had autoimmune chronic active hepatitis, 6 had primary sclerosing cholangitis, 12 had chronic liver disease of various etiologies, 4 had cryptogenic acute liver failure, 6 had acute hepatitic illnesses and 8 had a variety of disorders featuring normal liver histological appearance. Serum ceruloplasmin and total copper levels were significantly lower in Wilson's disease patients compared with all other groups, but three children with Wilson's disease had normal ceruloplasmin levels and seven had normal total copper levels. No significant difference was found for free serum copper levels and liver copper content between Wilson's disease patients and the other groups. Baseline 24-hr urinary copper excretion was significantly higher in Wilson's disease patients compared with that of the other patients, but six children with Wilson's disease had levels just above the upper limit of normal, overlapping with values obtained in three children with liver failure, two with acute hepatitis, two with autoimmune chronic active hepatitis and three with primary sclerosing cholangitis. The 24-hr urinary copper excretion after penicillamine challenge proved the most accurate single diagnostic test; levels more than 25 mumol/24 hr were present in 15 of 17 patients with Wilson's disease, but in only 1 child with liver failure of the 58 with other disorders.(ABSTRACT TRUNCATED AT 250 WORDS)     

Persistence of a circadian rhythmicity of glucocorticoid secretion in a patient with Cushing's syndrome: study before and after unilateral adrenalectomy

A 47-year-old woman affected by Cushing's syndrome due to an adrenal adenoma is described. An altered but rhythmometrically apparent cortisol secretory rhythm was detected using the single-cosinor computation. In fact serum cortisol levels and urinary excretion of 17-OHCS were elevated in the PM hours, particularly between 14:00-18.00 h and 18:00-22:00 h, and normal between 02:00-10:00 h. The patient was cured by unilateral adrenalectomy and one year later the circadian rhythm of corticosteroids secretion was investigated again. A normal rhythm of cortisol secretion and of 17-OHCS urinary excretion was found. Though it may be hypothesized that factors intrinsic to the tumoral adrenal cells were responsible for the rhythmic, but phase-shifted, hormonal release, the cause of the persistent and abnormal cortisol secretory rhythm is unknown.     

Venous thromboembolism from air travel: the LONFLIT study.

The LONFLIT study was planned to evaluate the incidence of deep venous thrombosis (DVT) occurring as a consequence of long flights. In the Lonflit study 355 subjects at low-risk for DVT and 389 at high-risk were studied. Low-risk subjects had no cardiovascular disease and used no drugs. All flights were in economy class. The average flight duration was 12.4 hours (range, 10-15 hr). The mean age of the studied subjects was 46 years (range 20-80 yr, SD 11; 56% males). DVT diagnosis was made by ultrasound scans after the flights (within 24 hours). In low-risk subjects no events were recorded while in high-risk subjects 11 had DVT (2.8%) with 13 thromboses in 11 subjects and 6 superficial thromboses (total of 19 thrombotic events in 389 patients [4.9%]). In the Lonflit2 study the authors studied 833 subjects (randomized into 422 control subjects and 411 using below-knee stockings). Mean age was 44.8 years (range, 20-80 yr, SD 12; 57% males). The average flight duration was 12.4 hours. Scans were made before and after the flights. In the control group there were 4.5% of subjects with DVT while only 0.24% of subjects had DVT in the stockings group. The difference was significant. The incidence of DVT observed when subjects were wearing stockings was 18.75 times lower than in controls. Long-haul flights are associated to DVT in some 4-5% of high-risk subjects. Below-knee stockings are beneficial in reducing the incidence of DVT.     

Normalization of the sleep-wake pattern and melatonin and 6-sulphatoxy-melatonin levels after a therapeutic trial with melatonin in children with severe epilepsy

Abstract: This study evaluated the sleep–wake pattern, plasma melatonin levels and the urinary excretion of its metabolite, 6‐sulphatoxy‐melatonin among children with severe epileptic disorders, before and after a therapeutic trial with melatonin. Ten paediatric patients, suffering from severe epileptic disorders, were selected and given a nightly dose of 3 mg of a placebo, for 1 wk; for the next 3 months, the placebo was replaced with a nightly dose of 3 mg of melatonin. At the end of each treatment period, the urinary excretion of 6‐sulphatoxy‐melatonin (for the intervals 09.00 – 21:00 hr or 21:00–09:00 hr) and plasma levels of melatonin (recorded at 01:00, 05:00, 09:00, 13:00, 17:00 and 21:00 hr) were recorded, over a period of 24 hr; an actigraph record was also kept. Sleep efficiency among patients who received melatonin was significantly higher than among those given the placebo, with fewer night‐time awakenings. Periodic plasma melatonin levels were regained and a better control gained of convulsive episodes, in that the number of seizures decreased. We conclude that melatonin is a good regulator of the sleep–wake cycle for paediatric patients suffering from severe epilepsy, moreover, it to a better control of convulsive episodes.