Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men

Interleukin-6 (IL-6) is a proinflammatory cytokine that has been shown to mediate, in addition to immune reactions, various endocrine and central nervous components of the acute phase response. In this context, the present study aimed to specify the contributions of IL-6 to the regulation of pituitary-adrenal secretory activity and GH and TSH secretion, as well as to the regulation of central nervous sleep and mood in healthy men. Effects of a low dose of IL-6 (0.5 microgram/kg body weight) were assessed, inducing plasma IL-6 concentrations closely comparable with those typically observed after infectious challenge. Each of the 16 male subjects participated in two 14-h sessions (between 1800 and 0800 h), receiving either placebo or human recombinant IL-6 sc at 1900 h. Blood was collected repeatedly to determine plasma hormone levels, serum concentrations of cytokines, and C-reactive protein. Moreover, mood was assessed, and sleep recordings were obtained between 2300 and 0700 h. The cytokine induced a prolonged increased in plasma concentrations of ACTH and cortisol (P < 0.001), but led to a decrease in TSH concentrations (P < 0.01). In response to IL-6, subjects reported fatigue and felt more inactive and less capable of concentrating than after placebo. Sleep architecture was altered significantly by the cytokine. Slow-wave sleep was decreased during the first half and increased during the second half of sleep. Rapid eye movement sleep during the entire nocturnal sleep time was significantly decreased. After IL-6, body temperature rose slightly. C-reactive protein concentrations were dramatically increased 12.5 h after substance administration (P < 0.001). IL-6 did not affect serum concentrations of IL-2, IL-8, interferon-alpha, and interferon-gamma. The results underscore the importance of IL-6 in the cascade of cytokines for the neuroendocrine response during the acute phase reaction. In addition, IL-6 appears to be involved in changes of sleep and behavior accompanying infection and inflammatory disorders.     

Increasing required neural response to expose abnormal brain function in mild versus moderate or severe Alzheimer''s disease: PET study using parametric visual stimulation

OBJECTIVES: Glycaemic control often deteriorates during puberty in girls with insulin dependent diabetes mellitus (IDDM). This may be due in part to the normal psychosocial changes associated with adolescence. Puberty is, however, also characterized by rapid somatic development, orchestrated by hormonal changes. Some of these hormones play a major role in glucose homeostasis. We have examined the insulin-GH-IGF-I axis in 11 adolescent girls with poorly controlled insulin dependent diabetes and compared the data with those of 10 non-diabetic girls matched for age, pubertal stage and body mass index (BMI). METHODS: Serum profiles of glucose, insulin, GH and IGF binding protein 1 (IGFBP1) were analysed in addition to IGF-I in serum and nocturnal urinary excretion of GH. MEASUREMENTS: Serum glucose, insulin and IGFBP1 were measured every hour for 24 h, whereas GH in serum was measured every 30 minutes during the same period. Nocturnal urinary GH was analysed as a mean of three consecutive nights. RESULTS: The insulin profiles of the IDDM patients were flat with low post-prandial peaks, corresponding to only one-third of the peaks of the non-diabetic girls. The integrated insulin levels, both during 24-h sampling and during daytime, were significantly lower in the diabetic group. There were no differences during night-time. The diabetic patients had elevated mean baseline levels of serum GH (IDDM 2.8 +/- 0.5 mU/l, controls 0.7 +/- 0.2; P < 0.001), a higher 24-h mean serum GH level (9.8 +/- 1.7 mU/l vs. 4.4 +/- 0.7; P < 0.001), significantly more peaks and a urinary GH excretion twice as high as in the non-diabetic group. An interesting observation was the finding of marked differences in daytime GH concentrations between the groups, both regarding overall integrated levels (GH AUC 103 +/- 15.8 and 35.9 +/- 7.1 mU/l x 12 h, respectively; P < 0.005) as well as baseline levels (3.8 +/- 0.6 mU/l vs. 0.7 +/- 0.2; P < 0.001). In contrast, during night-time only the mean basal levels of GH differed. The level of IGF-I was reduced in the diabetic group compared with the healthy controls (IDDM 233 +/- 19 micrograms/l vs. controls 327 +/- 21; P < 0.005). In addition, the IDDM patients had significantly increased concentrations of IGFBP 1, but kept a normal diurnal rhythm with a pronounced night peak. CONCLUSION: Hypoinsulinaemia in adolescent IDDM patients, particularly in the portal hepatic circulation, results in decreased IGF-I and increased IGFBP 1 production in the liver. High levels of IGFBP 1 may, in turn, reduce the bioactivity of IGF-I even further. Low levels of IGF-I will lead to increased GH secretion. Earlier studies on the relationship between GH and diabetic control have focused on elevated GH levels during the night. In this study we have observed markedly elevated levels of GH also during daytime in adolescent IDDM patients. This indicates increased insulin resistance and insulin demand also during the day in diabetic subjects. The increased insulin resistance may result in hyperglycaemia leading to additional insulin resistance. A vicious circle may thus be induced, accelerating metabolic impairment in poorly controlled adolescent IDDM girls.     

Longtime administration of growth hormone-releasing hormone (GHRH) does not restore the reduced efficiency of GHRH on sleep endocrine activity in 2 old-aged subjects--a preliminary study

Aging results in a more shallow sleep accompanied by a blunted growth hormone (GH) secretion. In young male normal controls repetitive administration of GH-releasing hormone (GHRH) at the beginning of the night results in an increased secretion of GH, a blunting of cortisol and a stimulation of slow-wave sleep (SWS). In healthy elderly men and women, however, GHRH exerts only weak effects on sleep-endocrine activity. In a previous report continuous treatment of healthy elderly males by repetitive administration of GHRH (during 12 days administration with 100 micrograms GHRH i.v. at 9.00 h every second day, "priming") enhanced GHRH stimulated GH secretion at daytime markedly. We tested if priming with GHRH results in a more distinct modulation of the nocturnal hormone secretion and of the sleep EEG than acute administration of the peptide. Two elderly male controls spent first three consecutive nights in the sleep laboratory, the first of which served for adaptation to laboratory conditions. During the two other nights (at days 1 and 2) sleep EEG was recorded and blood was sampled for determining the secretion of GH, cortisol and ACTH. In one of the nights the subjects received 50 micrograms GHRH hourly between 22.00 h and 1.00 h (4 x 50 micrograms) or placebo. The next examination followed after the priming period at day 14 and the last was performed two weeks after treatment at day 28. After the baseline administration of 4 x 50 micrograms GHRH before priming no clear changes of sleep EEG towards improved sleep were detectable, whereas GH secretion was increased. After priming sleep period time and SWS time were lower compared to the baseline night with GHRH administration, whereas REM time duration increased. GHRH induced GH secretion was not enhanced after priming. ACTH secretion was markedly enhanced compared to baseline stimulation. We conclude that priming with GHRH has no sleep improving effect and does not change hormone secretion in elderly normal subjects. Hence in the elderly priming with GHRH is not capable to induce a rejuvenation of sleep endocrine activity.     

Restitutive effect of sleep on chronic performance stress

During a polysomnographic (2 nights) sleep registration of 5 chronically stressed compared to 5 control persons 24 h blood cortisol values and salivary cortisol at daytime were measured and compared with measured stress vulnerability. While daytime cortisol levels were reduced under stress conditions, during night sleep combined with a significant change in sleep architecture cortisol excretion raised markedly compared to controls, and the cortisol response to CRF provocation is no more blunted but activated beyond controls, demonstrating the restitutive and protective effect of sleep.     

Interrelations between sleep and the somatotropic axis

In the human as in other mammals, growth hormone (GH) is secreted as a series of pulses. In normal young adults, a major secretory episode occurs shortly after sleep onset, in temporal association with the first period of slow-wave (SW) sleep. In men, approximately 70% of the daily GH output occurs during early sleep throughout adulthood. In women, the contribution of sleep-dependent GH release to the daily output is lower and more variable. Studies involving shifts of the sleep-wake cycle have consistently shown that sleep-wake homeostasis is the primary determinant of the temporal organization of human GH release. Effects of circadian rhythmicity may occasionally be detected. During nocturnal sleep, the sleep-onset GH pulse is caused by a surge of hypothalamic GHRH release which coincides with a circadian-dependent period of relative somatostatin disinhibition. Extensive evidence indicates the existence of a consistent relationship between SW sleep and increased GH secretion and, conversely, between awakenings and decreased GH release. There is a linear relationship between amounts of SW sleep--whether measured by visual scoring or by delta activity--and amounts of concomitant GH secretion, although dissociations may occur, most likely because of variable levels of somatostatin inhibition. Pharmacological stimulation of SW sleep results in increased GH release, and compounds which increase SW sleep may therefore represent a novel class of GH secretagogues. During aging, SW sleep and GH secretion decrease with the same chronology, raising the possibility that the peripheral effects of the hyposomatotropism of the elderly may partially reflect age-related alterations in sleep-wake homeostasis. While the association between sleep and GH release has been well documented, there is also evidence indicating that components of the somatotropic axis are involved in regulating sleep. The studies are most consistent in indicating a role for GHRH in promoting NREM and/or SW sleep via central, rather than peripheral, mechanisms. A role for GH in sleep regulation is less well-documented but seems to involve REM, rather than NREM, sleep. It has been proposed that the stimulation of GH release and the promotion of NREM sleep by GHRH are two separate processes which involve GHRH neurons located in two distinct areas of the hypothalamus. Somatostatinergic control of GH release appears to be weaker during sleep than during wake, suggesting that somatostatinergic tone is lower in the hypothalamic area(s) involved in sleep regulation and sleep-related GH release than in the area controlling daytime GH secretion. While the concept of a dual control of daytime and sleep-related GH secretion remains to be directly demonstrated, it allows for the reconciliation of a number of experimental observations.     

Factors affecting the nocturnal decrease in blood pressure: a community-based study in Ohasama

OBJECTIVE: To investigate factors affecting the nocturnal decrease in blood pressure. DESIGN: A cross-sectional study of 823 community-based untreated subjects aged > 20 years. Screening and ambulatory blood pressures were measured and the effects of age and the ambulatory blood pressure on the nocturnal decrease were examined. RESULTS: The magnitude of the decrease and the percentage decrease in the nocturnal blood pressure increased with increasing daytime ambulatory blood pressure and decreased with increasing night-time ambulatory blood pressure. Although the magnitude of the nocturnal decrease in blood pressure increased with increasing daytime blood pressure, the nocturnal blood pressure levels in hypertensives were still higher than those in normotensive subjects. The magnitude decreased with increasing age for men but not for women, whereas the percentage decrease decreased with increasing age both for men and for women. The SD of the 24 h blood pressure correlated strongly to the magnitude of the nocturnal decrease (systolic blood pressure r = 0.62, P < 0.0001; diastolic blood pressure r = 0.52, P < 0.0001), suggesting that the SD of the 24 h blood pressure is representative of the nocturnal decrease. A minimal nocturnal decrease was observed frequently in elderly normotensive men but infrequently in hypertensive individuals from the general population. A marked nocturnal decrease was observed frequently in hypertensive women aged > 70 years. CONCLUSION: Although the magnitude of the nocturnal decrease in blood pressure increased with increasing daytime blood pressure, the nocturnal blood pressure levels increased with increasing daytime ambulatory blood pressure. Therefore, the blood pressure in hypertensive subjects should essentially be lowered throughout the 24 h period. A marked nocturnal decrease in blood pressure in some elderly hypertensive women was observed without treatment. The nocturnal blood pressure levels of such subjects should be considered during treatment.     

Medication use patterns among demented, cognitively impaired and cognitively intact community-dwelling elderly people

OBJECTIVE: The present study was conducted in order to describe human hypothalamo-pituitary adrenal (HPA) axis adaptation in a model of repeated physical stress (endurance training) that causes a moderate increase in cortisol levels. SUBJECTS: We performed the same stimulation tests (adrenal stimulation with ACTH or pituitary stimulation with combined CRH/LVP) in a population of 8 endurance-trained athletes in two distinct situations: resting (baseline cortisol values) and 2 h after the end of strenuous exercise (increased cortisol values) to evaluate the HPA axis sensitivity to endogenous sustained increases in cortisol concentrations. MEASUREMENTS: During these tests, saliva and plasma cortisol (Fs and Fp, respectively) were assessed and compared. RESULT: Cortisol values in both plasma and saliva at the end of 2 h of exercise were significantly higher than in rested controls: Fs 11.5 +/- 1.3 vs 6.5 +/- 0.8 nmol.l-1 and Fp 428 +/- 36 vs 279 +/- 27 nmol.l-1 (post exercise vs post rest sessions, respectively, P < 0.001 for both). After either hormone test (CRH/LVP or ACTH), cortisol levels in plasma and saliva increased similarly when rest was compared to post exercise. Saliva variations (delta %) under exogenous hormone stimulation were dramatically greater than plasma variations. For example, under ACTH stimulation, the relative increments in cortisol were on control day: delta Fs 980 +/- 139 vs delta Fp 218 +/- 43% (saliva vs plasma, respectively, P < 0.05) and on exercise day: delta Fs 605 +/- 89 vs delta Fp 102 +/- 14% (saliva vs plasma, respectively, P < 0.05). CONCLUSIONS: In endurance-trained athletes, displaying a moderate but sustained endogenous cortisol increase: (1) ACTH responses following pituitary stimulation are not blunted, (2) cortisol responses following maximal adrenal stimulation are not blunted. Our results favour the hypothesis of a decreased pituitary sensitivity to cortisol negative feedback whereas the hypothesis of a major decreased adrenal sensitivity to ACTH was discarded. The greater ability of saliva assays to detect a cortisol increase strongly supports its use in the study of HPA physiology, whether under basal or dynamic conditions.     

Circadian and ultradian variations of leptin in normal man under continuous enteral nutrition: relationship to sleep and body temperature

To determine the influence of circadian rhythmicity and sleep on the 24-h leptin diurnal variations, plasma leptin levels were measured at 10-min intervals over 24 h in seven normal subjects, once during nocturnal sleep, and once after an 8-h shift of sleep. The subjects were submitted to constant conditions (continuous enteral nutrition and bed rest in controlled chambers). Body temperature and plasma glucose and insulin levels were measured simultaneously. During nighttime sleep, leptin levels increased to a maximum (109.9 +/- 2.5% of the 24-h mean) and then decreased to reach a nadir in the late afternoon. The mean diurnal variation was 18.0 +/- 3.8% of the 24-h mean. In the daytime sleep condition, leptin levels rose during the night of deprivation to a maximum of 104.7 +/- 2.3% of the 24-h mean, decreased to a minimum around 0700 h, and then rose again during diurnal sleep (108.4 +/- 3.1% of the 24-h mean); the mean diurnal variation was 13.4 +/- 3.6% of the 24-h mean. ANOVA revealed a significant interaction between time of day and sleep effects (P < 0.05). The diurnal and the sleep-related variations of plasma leptin mirrored those of body temperature and roughly paralleled those of plasma glucose and insulin; the amplitudes of the diurnal leptin variations were significantly correlated with the amplitudes of the diurnal body temperature variations (P < 0.05). Plasma leptin levels also displayed irregular pulses of low amplitude (mean duration, 70 min) that were not affected by sleep, but were associated with a significant decrease in glucose and insulin levels (P < 0.01). These results demonstrate that under continuous enteral nutrition, plasma leptin levels are modulated by both a slight circadian component and sleep, which interact under normal conditions, and suggest that leptin is implicated in circadian thermoregulatory adjustments.     

Cardiovascular effects of mibefradil in hypertensive patients with obstructive sleep apnea

OBJECTIVE: Hypertension is often seen in obstructive sleep apnea (OSA) and is characterized by increased sympathetic activity, depressed baroreflex and accentuated vascular responsiveness. The objective of this study was to investigate the effects of the new T-selective calcium channel blocker mibefradil on invasively measured blood pressure (BP) and heart rate in hypertensive patients with OSA. METHODS: The present study was a double-blind, randomized and placebo-controlled before and after trial in two parallel groups. Fifty-three men aged 23 69 years with systemic hypertension and OSA were recruited from the Outpatient Department of the Marburg University Sleep Laboratory and hospitalized for 10 days. Mibefradil (50 mg) or placebo were given orally in the morning for 8 days. The main outcome measure was the mean arterial (radial) BP monitored continuously during nocturnal sleep and during standardized daytime physical and psychological performance testing. RESULTS: Mibefradil lowered mean arterial BP and heart rate with (SD) during the entire measurement period compared with placebo: -7.25 (9.59) vs -2.11 (8.43) mmHg (P=0.039) and -4.83 (5.94) vs -1.34 (4.13) bpm (P=0.022), respectively. Both effects were observed during nocturnal sleep and performance testing, including graded exercise. Adverse events did not differ compared with placebo. CONCLUSION: Mibefradil is an effective but well-tolerated antihypertensive that also lowers heart rate over 24 h in OSA, in conditions known to increase BP.     

Salivary alpha-amylase as a measure of endogenous adrenergic activity

This investigation was designed to evaluate the production rates and concentrations of salivary alpha-amylase as a measure of adrenergic activity under several conditions of stress in human subjects. Saliva and blood samples were simultaneously collected from men at four 15 min intervals both before and after regimens for exercise, a written examination, or a rest period. The regressions of salivary alpha-amylase on plasma norepinephrine (NE) concentrations were significant for both exercise (P < 0.001) and examination (P < 0.01) protocols. Aerobic exercise induced a 3-fold mean increase in alpha-amylase; both NE and epinephrine (EP) increased approximately 5-fold over control levels. Levels of alpha-amylase and NE returned to control levels within 30-45 min after exercise, but EP remained elevated by approximately 2-fold during the remaining hour of observation. During the written examination, alpha-amylase and NE, but not EP, concentrations increased in parallel. In further studies the effects of exercise and exposure to heat and cold on the relationship of salivary alpha-amylase to heart rate and body temperature were investigated. Greater intensities of exercise were associated with greater increases in alpha-amylase concentrations. During heat exposure in a sauna (66 degrees C for 40 min) amylase, heart rate and body temperature all increased progressively. However, during exposure to cold (4 degrees C for 40 min) amylase increased rapidly, though heart rate and body temperature remained unchanged. Salivary cortisol concentrations were unchanged during exposure to heat or cold. We conclude that salivary alpha-amylase concentrations are predictive of plasma catecholamine levels, particularly NE, under a variety of stressful conditions, and may be a more direct and simple end point of catecholamine activity than are changes in heart rate.     

Effects of hormones on sleep

Administration of hormones to humans and animals results in specific effects on the sleep electroencephalogram (EEG) and nocturnal hormone secretion. Studies with pulsatile administration of various neuropeptides in young and old normal controls and in patients with depression suggest they play a key role in sleep-endocrine regulation. Growth hormone (GH)-releasing hormone (GHRH) stimulates GH and slow wave sleep (SWS) and inhibits cortisol, whereas corticotropin-releasing hormone (CRH) exerts opposite effects. Changes in the GHRH:CRH ratio contribute to sleep-endocrine aberrations during normal ageing and acute depression. In addition, galanin and neuropeptide Y promote sleep, whereas, in the elderly, somatostatin impairs sleep. The rapid eye movement (REM)-nonREM cycle is modulated by vasoactive intestinal polypeptide. Cortisol stimulates SWS and GH, probably by feedback inhibition of CRH. Neuroactive steroids exert specific effects on the sleep EEG, which can be explained by gamma-aminobutyric acid(A) receptor modulation.     

Twenty-four-hour ambulatory oxygen desaturation and electrocardiographic recording in obstructive sleep apnea syndrome

BACKGROUND: Although nocturnal pulseoximetry is routinely performed in obstructive sleep apnea syndrome (OSAS), pulseoximetry over a 24-h period has not been studied. HYPOTHESIS: The purpose of the study was to determine whether simultaneous 24-h oxygen desaturation and electrocardiographic (ECG) recording might be used to screen for daytime sleep sequelae in patients with OSAS. METHODS: Simultaneous recording of arterial oxygen saturation (SpO2) and ECG was conducted over a 24-h period in 18 male patients with OSAS (mean age 51.3 years) who were diagnosed by standard polysomnography (PSG), and in 15 age-matched healthy subjects (mean age 52.7 years) as controls to evaluate circadian variation of these parameters. The measures of heart rate variability (HRV) were calculated from 24-h ambulatory ECGs. Seventeen patients with OSAS showed excessive daytime sleepiness (EDS). We calculated the duration in which SpO2 decreased to < 90% (duration of SpO2 < 90%). The number of apnea/hypopneas per hour (AHI) during sleep was investigated with Apnomonitors (Chest MI, Co., Tokyo) on the same day as the SpO2 recordings. RESULTS: Controls showed no episodes of oxygen desaturation. In patients with OSAS, driving (33.3% of patients with OSAS) was the most common activity in which SpO2 decreased to < 90%, followed by daytime napping (27.8%) and resting after meals (22.2%). The duration of SpO2 < 90% over a 24-h period correlated significantly with the duration levels recorded during sleep (r = 0.99, p < 0.05) and in the afternoon (r = 0.62, p < 0.05), and with the AHI (r = 0.55, p < 0.05), but not with the duration of SpO2 < 90% in the morning. The number of ventricular premature beats correlated significantly with the duration of SpO2 < 90% for a 24-h period, but not with measures of HRV. Ventricular tachycardia was found in two (11.1%) and ST-T depression in three patients (16.6%) with underlying cardiac diseases. CONCLUSION: Our results suggest that daytime sleep attacks accompanied by oxygen desaturation in patients with moderate to severe OSAS may contribute to the occurrence of traffic or cardiovascular accidents. We conclude that 24-h ambulatory recordings of SpO2 and ECG are useful for screening for daytime sleep sequelae associated with the potential risk of this pathology in OSAS during social activities.     

The effect of growth hormone replacement on cortisol metabolism and glucocorticoid sensitivity in hypopituitary adults

OBJECTIVE: Growth hormone (GH) replacement therapy in hypopituitary adults is associated with sodium and water retention. The underlying mechanisms are incompletely understood and a possible contribution of altered cortisol metabolism or action has not been evaluated. We have investigated the effect of GH replacement therapy on cortisol metabolism, cortisol binding globulin and in-vitro glucocorticoid sensitivity in a group of adult hypopituitary patients. DESIGN AND PATIENTS: We studied 19 adult hypopituitary patients (18 adult onset, M:F, 6:13), who were receiving conventional hydrocortisone (16 patients), thyroxine (14 patients), triiodothyronine (1 patient), sex steroid (9 patients), human chorionic gonadotrophin (1 patient) or desmopressin (6 patients) replacement during a 6-month, double blind controlled trial of GH therapy (active:placebo, 8:11) followed by a 6-month open phase of GH (mean dose: 0.2 IU/kg/week, range 0.051-0.27) and after a 6-week washout phase following discontinuation of GH therapy. MEASUREMENTS: Twenty-four-hour urine free cortisol, cortisol metabolites (CoM), ratio 11-hydroxy/11-oxo CoM (F/E) and ratio 5 alpha/beta tetrahydrocortisol were measured at 6 months, 12 months and after the 6 week washout phase. Serum cortisol binding globulin was measured basally, at 6 months, 12 months and after washout. Glucocorticoid sensitivity was determined in lymphocyte preparations from 8 patients, during GH therapy and after washout, using an in-vitro technique dependent on dexamethasone suppression of phytohaemagglutinin-stimulated thymidine incorporation into DNA. Plasma renin activity and aldosterone were measured after 6-12 months GH therapy and after washout. RESULTS: After 6 months of GH, in patients on hydrocortisone (n = 9), there were significant decreases in CoM (mean decrement 21%, P < 0.01), F/E (mean decreased from 1.27 to 1.0, P = 0.04; reference range 0.33-1.29) and 5 alpha/5 beta tetrahydrocortisol (mean decreased from 0.67 to 0.48, P = 0.01) and a subsequent increase after washout. Patients not on hydrocortisone (n = 2) demonstrated a normal basal F/E falling by 25% on GH therapy but no change in CoM. During 12 months of GH therapy, patients on hydrocortisone (n = 7) demonstrated a further trend to decrement in CoM (P = 0.09) which reversed after washout (P = 0.04). Urine free cortisol tended to fall during GH therapy and increased significantly following washout after 12 months treatment (P < 0.02). Serum cortisol binding globulin decreased by 20% (P < 0.05) during 12 months GH treatment but remained within the reference range. In-vitro studies demonstrated a trend to reduced glucocorticoid sensitivity on GH therapy; the maximum inhibition of phytohaemagglutinin by dexamethasone tended to be less on GH therapy (P = 0.052) and was also lower than in 29 normal volunteers (P < 0.05). There were no significant changes in plasma renin but there was a small increment in aldosterone in recumbent patients (P = 0.04) during the open phase of GH therapy in the placebo arm. CONCLUSIONS: GH therapy in hypopituitary adults is associated with an apparent reduction in availability of administered hydrocortisone as measured by urine cortisol metabolites and urine free cortisol. This effect is unlikely to be clinically significant except possibly in ACTH deficient subjects on suboptimal hydrocortisone replacement. The changes in F/E suggest that GH may directly or indirectly modulate the activity of 11 beta-hydroxysteroid dehydrogenase. The apparent decrease in glucocorticoid sensitivity during GH therapy, demonstrated in vitro, merits further investigation.     

Cortisol secretion is related to electroencephalographic alertness in human subjects during daytime wakefulness

To determine whether human hypothalamo-pituitary-adrenal axis activity is related to the alertness level during wakefulness, 10 healthy young men were studied under resting conditions in the daytime (0900-1800 h) after an 8-h nighttime sleep (2300-0700 h). A serial 70-sec gaze fixation task was required every 10 min throughout the daytime experimental session. The corresponding waking electroencephalographic (EEG) segments were submitted to quantitative spectral analysis, from which EEG beta activity (absolute power density in the 13-35 Hz frequency band), an index of central alertness, was computed. Blood was collected continuously through an indwelling venous catheter and sampled at 10-min intervals. Plasma cortisol concentrations were measured by RIA, and the corresponding secretory rates were determined by a deconvolution procedure. Analysis of individual profiles demonstrated a declining tendency for EEG beta activity and cortisol secretory rate, with an overall temporal relationship indicated by positive and significant cross-correlation coefficients between the two variables in all subjects (average r=0.565, P < 0.001). Changes in cortisol secretion lagged behind fluctuations in EEG beta activity, with an average delay of 10 min for all the subjects. On the average, 4.6+/-0.4 cortisol secretory pulses and 4.9+/-0.5 peaks in EEG beta activity were identified by a detection algorithm. A significant, although not systematic, association between the episodes in the two variables was found: 44% of the peaks in EEG beta activity (relative amplitude, near 125%; P < 0.001) occurred during an ascending phase of cortisol secretion, cortisol secretory rates increasing by 40% (P < 0.01) 10-min after peaks in EEG beta activity. However, no significant change in EEG beta activity was observed during the period from 50 min before to 50 min after pulses in cortisol secretion. In conclusion, the present study describes a temporal coupling between cortisol release and central alertness, as reflected in the waking EEG beta activity. These findings suggest the existence of connections between the mechanisms involved in the control of hypothalamo-pituitary-adrenal activity and the activation processes of the brain, which undergoes varying degrees of alertness throughout daytime wakefulness.     

Insulin-like growth factors (IGF) I and II and IGF binding proteins 1, 2 and 3 during low-dose growth hormone (GH) infusion and sequential euglycemic and hypoglycemic glucose clamps: studies in GH-deficient patients

To evaluate the short-term effects of growth hormone (GH), insulin and different levels of glycemia on insulin-like growth factors (IGF) I and II and IGF binding proteins (IGFBP) 1, 2 and 3, we studied six GH-deficient adolescents during a night and the following day in the postabsorptive (basal) state followed by sequential euglycemic (5 mmol/l) and hypoglycemic (3 mmol/l) glucose clamps concomitant with an intravenous infusion (starting at 24.00 h) of GH (35 micrograms/h) or saline. Current GH therapy was withdrawn 24 h prior to each study. Nocturnal levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 remained stable during both studies. Nocturnal serum IGFBP-1 increased and correlated inversely with insulin in both studies. Regression analysis revealed a significant inverse correlation between mean nocturnal IGFBP-2 and IGFBP-3 levels. During the daytime, serum IGF-I declined slowly during saline infusion, whereas serum IGF-II remained stable in both studies. Serum IGFBP-1 displayed a gradual significant decline during the basal state and the euglycemic and hypoglycemic clamps seemed to be unaffected by GH levels. By contrast, serum IGFBP-2 remained stable during the same period in both the GH and the saline study. Serum IGFBP-3 declined insignificantly during the daytime in the saline study.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of sleep and circadian rhythm on human circulating immune cells

The role of nocturnal sleep for normal immune regulation and its relation to circadian rhythm was examined in 10 men participating in two 51-h sessions. One session included two regular wake-sleep cycles; the other included a night of sustained wakefulness followed by a night of recovery sleep. Blood was collected every 3 h to determine PBMC counts, including the enumeration of monocytes, NK cells, and lymphocyte subsets (CD19+, CD3+, CD4+, CD8+, HLA-DR+). Production of IL-1beta, TNF-alpha, IL-2, and IFN-gamma was determined after stimulation of whole blood samples with LPS and PHA, respectively. Concentrations of IL-6 and cortisol were assessed in plasma. Enumeration of cells indicated significant circadian rhythms for all PBMC subsets under conditions of sustained wakefulness. Compared with sustained wakefulness, nocturnal sleep acutely reduced the numbers of monocytes, NK cells, and counts of all lymphocyte subsets. However, in the afternoon and evening of the day following sleep, counts of NK cells and lymphocytes were significantly higher than after nocturnal wakefulness, indicating that effects of sleep interacted with those of the circadian pacemaker. Sleep markedly enhanced production of IL-2 by T cells (CD3+) but did not influence production of IL-1beta and TNF-alpha, or IL-6 concentrations. Effects of sleep were not mediated by changes in cortisol. The decrease in monocytes, NK cells, and lymphocytes, together with an increased production of IL-2 during sleep, may serve to support ongoing immune defense in extravascular lymphoid tissue during a time of diminished acute Ag challenge.     

Assessment of family carers

Thirty-four patients who presented with excessive daytime sleepiness (EDS) and who showed an elevated number of periodic leg movements during sleep (PLMS) were studied. None of these patients reported other symptoms or presented sleep laboratory manifestations of narcolepsy or of breathing disorders during sleep. A diagnosis of restless leg syndrome, head trauma or a past history of psychopathology or infectious diseases known to cause EDS were also ruled out. In addition, none of the patients reported a history of drug or alcohol abuse, chronic sleep deprivation or irregular sleep-wake schedule and none were taking medications known to influence sleep at the time of the study. Results of the present study showed no correlation between PLMS index and poor sleep efficiency or daytime sleepiness as measured by the multiple sleep latency test (MSLT). However, a significant negative correlation was found between sleep efficiency at night and the mean sleep latency on the MSLT. These results suggest not only that PLMS and nocturnal sleep disruption are not the primary cause of EDS, but that these sleepy patients have a high propensity to sleep both at night and during the daytime. Therefore, the presence of PLMS during nocturnal sleep recording should not preclude the diagnosis of idiopathic hypersomnia.     

Pituitary and plasma levels of growth hormone in Booroola sheep that are either homozygous carriers or non-carriers of the FecBB fecundity gene

The aim of this study was to examine the effect of the FecBB fecundity gene on plasma concentrations and pituitary content of growth hormone (GH) in sheep. No differences were found between homozygous carriers (BB) and non carriers (++) of the FecBB gene with regard to pituitary GH contents in both ovariectomized and intact ewes. However, ovariectomized ewes had higher levels of pituitary GH than intact ewes (P < 0.01). There were no differences between FecBB genotypes with respect to plasma concentrations of GH in 6-year-old ovariectomized ewes bled every 10 min for 12 h or in ram lambs bled weekly during their first year of life. GH levels in the rams decreased until week 27, increased to a peak at week 31 then decreased before increasing again at week 43. Mean plasma GH concentrations in the ewe lambs bled weekly for a year decreased until week 19 then remained at approximately this level for the remainder of the year. Mean GH plasma concentrations in the ram lambs were higher than in the ewe lambs (P < 0.001). Ewe lambs that were homozygous for the FecBB gene had lower body weights (P < 0.05) and had higher levels of GH (P < 0.01) than non carrier ewe lambs during their first year. Before the average age of first behavioural oestrus (36 weeks) GH levels in the ewe lambs were negatively correlated with body weights (r = -0.69, P < 0.001, n = 22). When body weight was included as a covariate in analysis of variance the genotype difference in ewe lamb plasma GH concentrations was no longer significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuropsychological functioning and determinants of morning alertness in patients with obstructive sleep apnea syndrome

Neuropsychological functioning is reported to be impaired in patients suffering from obstructive sleep apnea syndrome (OSAS). This syndrome is characterized by nocturnal respiratory disturbances, blood oxygen desaturations, sleep fragmentation, and excessive daytime sleepiness. Opinions are divided concerning the exact relationship between the observed cognitive deficits, nocturnal hypoxia, sleep disruption, and impaired daytime alertness. In the present study, morning neuropsychological function of 26 moderate to severe middle-aged sleep apneics is compared to that of 22 primary insomniacs. There were no performance differences on a range of neuropsychological tests among the two patient groups. In addition, the data suggest that morning alertness impairment, which is closely associated with a lack of slow wave sleep (SWS) and rapid eye movement (REM) sleep, is of major importance in inducing poorer cognitive performance in patients with moderate to severe sleep apnea.     

The influence of sleep breathing disorder on growth hormone secretion in children with tonsil hypertrophy

INTRODUCTION: Recently it has been revealed that Obstructive Sleep Apnea Syndrome has an influence on the endocrine system, especially to the secretion of growth hormone (GH). It was previously reported that secretion of GH has a circadian rhythm along with a correlation with slow wave sleep. Normally in a pediatric patient, after 90 min of sleep the brain wave shows patterns of deep sleep, and a matching peak in GH secretion is observed. We have studied the effect of GH secretion in sleep breathing disorder of pediatric patients by observing the pre- and post-operative difference in GH secretion in children with tonsillar hypertrophy who had tonsillectomies. MATERIAL AND METHODS: Ten pediatric patients who complained of sleep apnea or hypopnea, and were highly suspected of having sleep breathing disorders due to tonsil hypertrophy and underwent surgery were chosen. Pre and post-operative blood somatomedin C and urinary growth hormone levels were measured. In 6 of the 10 patients blood GH levels were measured after overnight collection of blood every 30 min through a catheter placed in the vein. METHOD OF ANALYSIS: Integral blood GH calculated from GH levels of the blood samples taken every 30 min was used to express the efficacy of GH secretion during sleep, and was compared with blood somatomedin C and urinary GH levels. Pre- and post-operative somatomedin C and urinary GH measurements were compared. RESULT: 1) In 6 of the 10 patients, there was a positive correlation with integral GH and urinary GH, and no correlation with integral GH or somatomedin C. 2) Post-operatively, 7 of the 10 patients had increased urinary GH levels, 1 showed no change and 2 had decreased levels. There was a significant increase in the mean urinary GH levels from 18.6 +/- 16.1 pg/ml pre-operatively to 35.8 +/- 19.6 pg/ml post-operatively (P < 0.05). 3) Eight of the 10 patients had a post-operative increase in somatomedin C levels, 1 showed no change and the other patient had a decreased level. There was a significant increase in mean somatomedin C levels from 175.9 +/- 124.8 ng/ml pre-operatively to 226.6 +/- 134.3 ng/ml post-operatively (P < 0.01). CASE: An 8-year-old-boy was diagnosed as having habitual tonsillitis and suspected sleep breathing disorder, and was admitted to our hospital for a tonsillectomy. Apnea and hypopnea were observed during sleep in the hospital. After receiving his parents' consent, GH secretion was evaluated before and after the tonsillectomy. Integrated GH measurements, somatomedin C and urinary GH increased significantly after the operation. CONCLUSION: In this study, the improvement of sleep breathing disorder by surgery was associated with a positive effect to the GH secretion. GH secretion is important for growth of a child. Wen the cause of sleep breathing disorder is evident in the upper airway system, active treatment and cure by surgery is advised. Measurement of urinary GH in the morning is useful and simple for evaluating the ability to secrete GH.