Procalcitonin and proinflammatory cytokine interactions in sepsis.

Immunoneutralization of procalcitonin (ProCT), a putative mediator of sepsis, has been shown to increase survival in an animal model of sepsis. To better understand the role that ProCT plays in the sepsis cascade, we studied the relationship of this hormone to the proximal proinflammatory mediators, IL-1beta and TNFalpha. Hamsters were made septic by i.p. implantation of Escherichia coli-impregnated agar pellets. A time line study of serum IL-beta, TNFalpha, and ProCT levels showed that the increase in the cytokines was transient and less than 2-fold over baseline, whereas ProCT increased >100-fold by 12 h and remains elevated through 24 h. TNFalpha (400 microg/kg) was injected into healthy animals, inducing an elevation in ProCT that was 25-fold greater than controls. ProCT (30 microg/kg) was given to healthy and septic animals. In healthy animals, there was no significant elevation in serum IL-1beta or TNFalpha levels. In septic animals, IL-1beta was modestly blunted at 3 h but not at 12 h, and there was no change in TNFalpha levels. ProCT did not initiate or enhance IL-1beta or TNFalpha expression; however, the massive and sustained elevation of this hormone seen in sepsis can be induced by the proximal cytokine, TNFalpha. This study suggests that ProCT is a secondary mediator that might augment and amplify but does not initiate the septic response. Immunoneutralization of ProCT may prove to be an important clinical strategy, in view of its sustained elevation and the difficulty in initiating therapy for sepsis during the early phases of illness.

Serum endostatin levels are elevated and correlate with serum vascular endothelial growth factor levels in patients with stage IV clear cell renal cancer.

Clear cell renal carcinoma (CCRC) is a highly angiogenic tumor known to secrete vascular endothelial cell growth factor (VEGF). Endostatin is an endogenous antiangiogenic agent with antitumor activity in mice. The purpose of this study was to evaluate serum levels of endostatin in normal subjects and in patients with CCRC and to examine the relationship of these levels to circulating VEGF levels. Fifteen patients (mean age, 48 years) on a clinical protocol for stage IV CCRC at the National Cancer Institute were included in the study. Archived prenephrectomy serum samples were analyzed for endostatin and VEGF concentrations. Endostatin and VEGF levels were compared with those of an age-matched group of volunteer blood donors (n = 18) using a competitive enzyme immunoassay. Data were analyzed using the Mann-Whitney U test and the Spearman rank correlation. Median serum endostatin levels were 24.6 ng/ml (range, 15.1-54.0 ng/ml) in CCRC patients versus 14.1 ng/ml (range, 1.0-19.3 ng/ml) in healthy controls (P < 0.0001). Median VEGF levels were 3.4 ng/ml (range, 0.1-11.2 ng/ml) and 2.5 ng/ml (range, 0.1-4.2 ng/ml), respectively (P = 0.065). A highly significant correlation was observed between endostatin and VEGF levels among the CCRC patients (r = 0.81, P = 0.0003) but not among controls (r = -0.22, P = 0.37). Endostatin levels are detectable in serum from healthy subjects as well as from CCRC patients. Levels are significantly elevated and correlate with VEGF levels in CCRC patients. Elucidating the nature of this correlation may lend insight into the regulation of tumor angiogenesis in patients with renal cancer.

Procalcitonin and proinflammatory cytokine in interactions in sepsis.

Immunoneutralization of procalcitonin (ProCT), a putative mediator of sepsis, has been shown to increase survival in an animal model of sepsis. To better understand the role that ProCT plays in the sepsis cascade, we studied the relationship of this hormone to the proximal proinflammatory mediators, IL-1beta and TNFalpha. Hamsters were made septic by i.p. implantation of Escherichia coli-impregnated agar pellets. A time line study of serum IL-beta, TNFalpha, and ProCT levels showed that the increase in the cytokines was transient and less than 2-fold over baseline, whereas ProCT increased >100-fold by 12 h and remains elevated through 24 h. TNFalpha (400 microg/kg) was injected into healthy animals, inducing an elevation in ProCT that was 25-fold greater than controls. ProCT (30 microg/kg) was given to healthy and septic animals. In healthy animals, there was no significant elevation in serum IL-1beta or TNFalpha levels. In septic animals, IL-1beta was modestly blunted at 3 h but not at 12 h, and there was no change in TNFalpha levels. ProCT did not initiate or enhance IL-1beta or TNFalpha expression; however, the massive and sustained elevation of this hormone seen in sepsis can be induced by the proximal cytokine, TNFalpha. This study suggests that ProCT is a secondary mediator that might augment and amplify but does not initiate the septic response. Immunoneutralization of ProCT may prove to be an important clinical strategy, in view of its sustained elevation and the difficulty in initiating therapy for sepsis during the early phases of illness.

Rhinovirus infection induces mucus hypersecretion.

Rhinorrhea is a prominent symptom of the common cold. Although increases in vascular permeability and serous cell secretion have been demonstrated in human nasal mucus during active rhinovirus infections, changes in mucin constituents have not been quantified. Nonallergic (n = 48) and asymptomatic allergic rhinitis (n = 32) subjects were inoculated with rhinovirus type hanks before the spring allergy season. Nasal lavages were performed before inoculation (day 0), then daily for 5 days afterward. The subjects were divided into infected and noninfected groups on the basis of evidence of successful rhinovirus infection (nasal shedding of virus or fourfold increases in specific serum antibodies). Concentrations of interleukin (IL)-8, markers of vascular leak (IgG), seromucous cells (lysozyme), and mucoglycoprotein exocytosis [7F10-immunoreactive mucin (7F10-irm) and Alcian blue staining of acidic mucoglycoproteins] were measured in lavage fluids. The infected subgroup had maximal increases in nasal lavage fluid concentrations of IL-8 (sevenfold), IgG (fourfold), total protein (twofold), and gel-phase 7F10-irm (twofold) on day 3. There were no differences between infected allergic and nonallergic subjects. IL-8 and gel-phase 7F10-irm were significantly higher in infected than in noninfected subjects. In addition to promoting plasma exudation, rhinovirus hanks infection increases IL-8 and gel-phase mucin secretion. These processes may contribute to a progression from watery rhinorrhea to mucoid discharge, with mild neutrophilic infiltration during the common cold.

CSF IL-1 and IL-2 in medicated schizophrenic patients and normal volunteers.

It is clear that cytokines exert a variety of modulatory actions on the central nervous system. As part of our work exploring the relationship between immune activation and psychosis, we measured cerebrospinal fluid (CSF) IL-1 alpha and IL-2 levels in 60 medicated schizophrenic patients and in 21 normal volunteers using a competitive enzyme immunoassay. The two groups did not differ significantly in their mean cytokine levels: 1.01 (0.149) ng/ml (patients) vs. 1.28 (0.150) ng/ml (controls) for IL-1 alpha and 0.970 (0.038) ng/ml (patients) vs. 1.25 (0.086) ng/ml (controls) for IL-2. There was a significant positive correlation between CSF IL-1 alpha and IL-2 levels for all subjects (r = 0.50, n = 44, p = 0.0001).

Learned immunosuppression is associated with an increased risk of chemically-induced tumors.

Based on the hypothesis that certain aspects of the CNS and immune system interact and that altered immune function affects carcinogenesis, an animal model was developed to examine the effects of learned immunosuppression on the development of a chemically induced tumor. In two experiments, we evaluated whether mice, for which immunosuppression was associated with a neutral (conditioned) stimulus, would exhibit an increased susceptibility to tumor development upon reexposure to the conditioned stimulus, as compared to nonconditioned and control animals. A taste aversion conditioning paradigm, based on classical conditioning techniques, was employed to suppress immune function using the cytotoxic and immunosuppressive drug cyclophosphamide (CY) as the unconditioned stimulus and consequently increase the risk of chemically induced tumorigenesis. CY (100 mg/kg, intraperitoneal) was paired with saccharin in the drinking water (0.1%) of adult female mice (CF-1). Conditioned mice were exposed to saccharin twice in the absence of CY, on days 4 and 7 after the first exposure (day 1). All mice were injected with the chemical carcinogen 9,10-dimethylbenzanthracene (DMBA, 50 mg/kg, subcutaneous) on day 4 of conditioning. Two subsequent exposures to saccharin alone substantially increased the risk of developing DMBA-induced tumors (ranging from 83-91%), as compared to control animals (36%) that had not received this pairing. Mice that received all agents (i.e., CY, DMBA, and saccharin) in a slightly different order did not display elevated tumor incidence. Three separate exposures to CY also significantly increased the number of animals developing tumors in response to the carcinogen (75%). Mice were observed for at least 8 weeks after conditioning.(ABSTRACT TRUNCATED AT 250 WORDS)

Estradiol and androgen modulate chicken luteinizing hormone-releasing hormone-I release in vitro.

Hypothalamic slices (1 mm) including medial basal hypothalamus and preoptic areas (MBH-POA) were taken from adult male Japanese quail, placed in a short-term perifusion system, and exposed to estradiol or androgen. Release of chicken LHRH-I (cLHRH-I) was measured by an enzyme immunoassay specific for cLHRH-I. In separate experiments, MBH-POA slices were exposed short-term to 5 alpha-dihydrotestosterone (5 alpha-DHT, 10(-7) M) and testosterone (T, 10(-7) M), and short- or long-term to 17 beta estradiol (E2, 10(-9) M). Release of both basal and stimulated cLHRH-I (15-min exposure to 10(-6) M norepinephrine [NE]) was monitored. Basal cLHRH-I release during perfusion was episodic throughout the experimental periods. During no treatment, there was a mean (+/- SEM) pulse interval of 21.27 +/- 1.03 min, pulse duration of 13.98 +/- 0.59 min, pulse duration of 13.98 +/- 0.59 min, pulse amplitude of 4.12 +/- 0.13 pg/5 min, and pulse frequency of 2.93 +/- 0.12/h. Mean cLHRH-I pulse amplitude significantly (p < 0.05) increased with challenge by NE to 25.03 +/- 3.09 pg/5 min. Short-term E2 exposure significantly (p < 0.01) potentiated NE-induced cLHRH-I release. Neither T nor 5 alpha-DHT affected baseline or NE-stimulated cLHRH-1 release. Pretreatment with E2 (10(-9) M) for 14 h in static culture before perifusion significantly (p < 0.05) reduced the NE-induced cLHRH-I release. These results suggest that a hypothalamic LHRH-I pulse-generating mechanism is located within the MBH-POA. Further, these data provide evidence for E2 modulation of cLHRH-I release, which varies with exposure.

Pulsatility of 24-hour concentrations of circulating interleukin-1-alpha in healthy women: analysis of integrated basal levels, discrete pulse properties, and correlation with simultaneous interleukin-2 concentrations.

Even though it is widely known that interleukin (IL)-1 alpha acts at the local level, it is still uncertain whether IL-1 alpha is secreted into the circulation and acts at distant sites. We have tried to elucidate this by measuring 24-hour levels of total IL-1 alpha in six healthy female volunteers. Subjects had detectable and pulsatile levels of IL-1 alpha throughout the 24-hour period. The integrated 24-hour IL-1 alpha concentration was 2,367 +/- 753 min x micrograms/l (mean +/- SD), and the integrated pulsatile IL-1 alpha concentration was 553 +/- 260 (25 +/- 10% ot total integrated IL-1 alpha). The mean IL-1 alpha concentration was 1.63 +/- 0.53 micrograms/l, mean pulse frequency/24 h was 12.8 +/- 0.8, mean pulse height was 2.31 +/- 0.52 micrograms/l; mean pulse width was 80.4 +/- 2.3 min, and mean interpulse interval was 105.3 +/- 2.8 min. Total IL-1 alpha levels significantly correlated with those previously reported for IL-2 in the same samples, and IL-1 alpha pulse parameters which are concentration independent were significantly similar to those of IL-2. Furthermore, cross-correlation analysis indicated that in 83% of our subjects (5/6) there was synchronicity of IL-1 alpha and IL-2 levels. IL-1 alpha pulse parameters were in the range reported for hormones which have well-characterized pulsatility, such as growth hormone, luteinizing hormone, follicle-stimulating hormone, cortisol, beta-endorphin, and progesterone. Based on these data we speculate that a pulsatile cytokine cascade may exist in the systemic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

LHRH-I release from quail hypothalamic slices measured by specific EIA.

A competitive enzyme immunoassay (EIA) was developed for luteinizing hormone-releasing hormone (LHRH), which measures either mammalian luteinizing hormone-releasing hormone or chicken LHRH-I (cLHRH-I). There is negligible cross-reactivity with chicken LHRH-II. Assay sensitivity is 1 pg/ml and the intra- and interassay variation are 3.4 and 10.0%, respectively. The assay was validated for measuring cLHRH-I by parallelism and quantitative recovery. Using this EIA, cLHRH-I content was measured in microdissected samples of median eminence from mature quail and chickens. Mean cLHRH-I concentrations were 1.25 +/- 0.35 and 2.10 +/- 0.25 ng/mg protein in quail and chickens, respectively. In vitro release of cLHRH-I was studied by perifusion of quail medial basal hypothalamus-preoptic area (MBH-POA) slices. Challenge with increasing concentrations of K+ resulted in significant (P < 0.05) release of cLHRH-I. The release of cLHRH-I from MBH-POA slices was also measured in response to norepinephrine (NE), epinephrine (E), and isoproterenol (ISO). Chicken LHRH-I was released in a dose-dependent manner; maximal release occurred with 10(-7) M NE, 10(-8) M E, and 10(-7) M ISO. Tissue response was optimal for experimental manipulation 6-25 hr postcollection; thereafter, the response deteriorated until 60 hr postcollection. These data extend previous studies in birds by detailed characterization of responses to neurochemical challenge and description of optimal parameters for tissue response during perifusion.

Complex circadian regulation of pineal melatonin and wheel-running in Syrian hamsters.

Circadian regulation of pineal melatonin content was studied in Syrian hamsters (Mesocricetus auratus), especially melatonin peak width and the temporal correlation to wheel-running activity. Melatonin was measured by radioimmunoassay in glands removed at different circadian times with respect to activity onset (= CT 12). Pineal melatonin peak width (h; for mean > or = 125 pg/gland) and activity duration (alpha) were both 4-5 h longer after 12 or 27 weeks than after 5 or 6 days in continuous darkness (DD). Increased peak width was associated with a delay in the morning decline (M) of melatonin to baseline, correlated with a similar delay in wheel-running offset. In contrast, the evening rise (E) in melatonin occurred at approximately the same circadian phase regardless of the length of DD. Fifteen min light pulses produced similar phase-shifts in melatonin and activity. In a phase advance shift, M advanced at once, while E advanced only after several days of adjustment. Independent timing of shifts in the E and M components of the melatonin rhythm suggest that these events are controlled separately by at least two circadian oscillators whose mutual phase relationship determines melatonin peak width. This two-oscillator control of melatonin peak width is integral to the circadian mechanism of hamster photoperiodic time measurement.

Sequential cerebrospinal fluid and plasma sampling in humans: 24-hour melatonin measurements in normal subjects and after peripheral sympathectomy.

Simultaneous measurements of plasma and cerebrospinal fluid (CSF) melatonin and urinary excretion of 6-hydroxymelatonin were performed in four normal volunteers and one patient before and after upper thoracic sympathectomy for the control of essential hyperhidrosis. For normal individuals, hourly 24-h melatonin concentrations in plasma and CSF exhibited similar profiles, with low levels during the day and high levels at night. Peak plasma levels varied from 122-660 pmol/L, and the peak CSF levels from 94-355 pmol/L. The onset of the nocturnal increase in melatonin did not occur at the same time for each individual. Urinary 6-hydroxymelatonin levels also exhibited a daily rhythm, with peak excretion at night. The individual with the lowest nocturnal levels of circulating melatonin also had the lowest excretion of 6-hydroxymelatonin. In the patient with hyperhidrosis, a prominent melatonin rhythm was observed preoperatively in the CSF and plasma. After bilateral T1-T2 ganglionectomy, however, melatonin levels were markedly reduced, and the diurnal rhythm was abolished. These results provide direct evidence in humans for a diurnal melatonin rhythm in CSF and plasma as well as regulation of this rhythm by sympathetic innervation.

Immunological correlates of seasonal fluctuations in mood and behavior and their relationship to phototherapy.

Immunological parameters were studied before and after phototherapy, with bright and dim light, in 38 individuals with a range of retrospectively reported seasonal changes in mood and behavior. There was a significant negative correlation between the degree of mood and behavioral difficulties in fall and winter (seasonality) and the total number of circulating natural killer cells. Changes in the numbers of circulating helper T cells correlated significantly with changes in mood following phototherapy. Moreover, mitogen-induced lymphocyte blastogenesis increased significantly after phototherapy, but there was no significant difference between the bright and dim light treatments. The results suggest that cellular immune function is associated with both seasonality and response to phototherapy.

Interleukin-1 alpha differentially synchronizes estrogen-dependent and estrogen-independent human breast cancer cells in the G0/G1 phase of the cell cycle.

Direct in vitro effects of IL-1 alpha on cell cycle progression of the estrogen-responsive, MCF-7, and estrogen-unresponsive, MDA-231, human breast cancer cells were investigated by flow cytometry. IL-1 alpha, at nanomolar concentrations, caused the synchronization of MCF-7, but not MDA-231, cells in the G0/G1 phase of the cell cycle. The S phase of IL-1 treated MCF-7 cells was correspondingly decreased. The IL-1 induced synchronization of MCF-7 cells was observed in the dose range of 10(-11) M to 10(-7) M and was seen as early as 6 h after the start of treatment. Furthermore, these effects were shown to be sensitive to the weak estrogen, phenol red, since the IL-1-induced shifts in G0/G1 and S phases were markedly blunted in its presence. In cell proliferation experiments, the IL-1-induced synchronization of MCF-7 cells increased the cytotoxic efficacy of the chemotherapeutic drug, 5-fluorodeoxyuracil. These data demonstrate that IL-1 by arresting the estrogen-responsive human breast cancer cells, MCF-7, in the G0/G1-phase of the cell cycle can not only directly inhibit the growth of MCF-7 cells, but also increase the efficacy of FUDR.

Ethanol enhancement of isoproterenol-stimulated melatonin and cyclic AMP release from cultured pineal glands.

Norepinephrine stimulates the synthesis of melatonin in the pineal gland. The action of norepinephrine is believed to be mediated primarily by beta adrenergic receptors, and involves activation of adenylate cyclase. Ethanol, 25 to 50 mM, added to cultured pineal glands in vitro, enhanced isoproterenol-induced stimulation of cyclic AMP and melatonin production. The action of ethanol was observed only at doses of isoproterenol that produced a submaximal effect, and ethanol alone had no effect on cyclic AMP or melatonin release. Butanol, at a concentration of 2 mM, was as effective as 50 mM ethanol in increasing isoproterenol-stimulated cyclic AMP and melatonin release, indicating that the response to alcohols was not due simply to changes in osmolarity, and may reflect a hydrophobic interaction of the alcohols with the cell membrane. The effects of ethanol on pineal cyclic AMP and melatonin release were reversible after a 15-min preincubation, but not after a 2-hr preincubation, suggesting that, over a long incubation period, ethanol may sensitize the pineal beta adrenergic receptor-coupled adenylate cyclase system to isoproterenol. The findings in this study are consistent with earlier work showing that ethanol increases cerebral cortical beta adrenergic receptor-coupled adenylate cyclase activity, and demonstrate that the effect of ethanol on the receptor-effector system can result in an endocrinological response.

Issues in psychoneuroimmunology research.

Careful design of studies is crucial for meaningful progress in this area of inquiry. Along with systematic evaluation of immunologic factors, clear understanding of antecedent factors is also important. Age, sex, and other sociodemographic factors might play a major role in how an individual reacts to a given situation when compared with another individual. Assessment of the impact of these factors on the immune system might be further complicated by immunosuppressive viruses like HIV or by the use of many common medications such as beta-blockers for hypertension (Kiecolt-Glaser & Glaser, 1988). Longitudinal studies are needed to understand the process of change and the dynamic patterning of psychosocial and immunologic relationships over time. Additionally, use of multimodal measures to assess psychological events such as stress is imperative (Baum, Grunberg, & Singer, 1982). It will not serve our understanding of psychological influences on the immune system to jump to the conclusion that an event is "stressful" because it seems as if it should be. Finally, establishing a "core" battery of widely accepted immune tests will be important in establishing comparability across studies. The standardization and acceptance of specific biochemical measures will facilitate the infusion of talented clinical and basic scientists into the area of psychoneuroimmunology.

Melatonin profile in marmots: the influence of catecholamines, hibernation, and light.

The aim of this study was to determine the effects of circulating catecholamines and light on the daily melatonin rhythm in the marmot. Endogenous levels of circulating catecholamines and plasma melatonin were measured during arousal from hibernation in light and studies were performed on the circadian melatonin rhythm in two photoperiods (LD 4:20 and LD 8:16). In addition, studies were done on the capacity of broad-band white light at normal room intensities (32 muW/cm2 or 108 Ix) and of low-intensity monochromatic green light (500 nm; 1.4muW/cm2 or 3.1 Ix) to suppress high nocturnal melatonin levels. We conclude that high levels of plasma catecholamines that occur during arousal from hibernation do not influence the production and secretion of pineal melatonin. During the nocturnal portion of its light/dark cycle, the marmot plasma melatonin rhythm is suppressed by both white light and low-intensity green light.

Effects of serotonergic agonists and antagonists on corticotropin-releasing hormone secretion by explanted rat hypothalami.

Experimental evidence suggests that serotonin (5HT) is excitatory to the hypothalamic-pituitary-adrenal axis and that this effect involves activation of both hypothalamic corticotropin-releasing hormone (CRH) and pituitary ACTH secretion. The present study was undertaken to examine the mechanism by which 5HT stimulates the central component of the HPA axis. To accomplish this we employed an in vitro rat hypothalamic organ culture system in which CRH secretion from single explanted hypothalami was measured by specific radioimmunoassay (IR-rCRH). All experiments were performed after an overnight (15-18 hr) preincubation. Serotonin stimulated IR-rCRH secretion in a dose-dependent fashion. The response was bell-shaped and the peak effect was observed at the concentration of 10(-9) M. The stimulatory effect of 10(-9) M 5HT was antagonized by the 5HT1 and 5HT2 receptor metergoline and by the selective 5HT2 receptor antagonists ketanserin and ritanserin. The muscarinic antagonist atropine, the nicotinic antagonist hexamethonium and the alpha-adrenergic receptor antagonist phentolamine, on the other hand, did not inhibit 5HT-induced IR-rCRH secretion. The specific 5HT2 receptor agonist 1-(2,5-dimethoxy-4-iodo-phenyl)-2-aminopropane (DOI) stimulated IR-rCRH secretion in a dose-dependent fashion. The response was bell-shaped with peak of effect reached at the concentration of 10(-9) M. We also tested the ability of the 5HT agonist meta-chlorophenylpiperazine (m-CPP) and of the selective 5HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) to cause CRH secretion. Although both m-CPP and 8-OH-DPAT stimulated IR-rCRH secretion in a dose-dependent fashion, several differences were observed when their effect was compared to that of 5HT. These included a different shape of the dose-response curve, a lower maximal stimulatory effect and a different maximal stimulatory concentration. These findings suggest that serotonin stimulates CRH secretion by explanted rat hypothalami and that this effect appears to be mediated mainly through a 5HT2 receptor mechanism.

Interleukin-2 differentially affects the proliferation of a hormone-dependent and a hormone-independent human breast cancer cell line in vitro and in vivo.

Direct in vitro and in vivo effects of the lymphokine, interleukin-2 (IL-2), on hormone-dependent (MCF-7) and- independent (MDA-231) human breast cancer cell proliferation were investigated. In vitro, picomolar concentrations of IL-2 directly inhibited MCF-7 cell proliferation after 12 days of culture, while nanomolar doses of IL-2 significantly stimulated MCF-7 cell growth over the same time period. In addition, micromolar concentrations of IL-2 had virtually no effect on the in vitro proliferation of MCF-7 cells. In parallel in vitro growth experiments, the hormone-independent cells, MDA-231, were not affected by IL-2 regardless of concentration. IL-2 treatment of overiectomized, estrogen-treated nude mice, burdened with MCF-7 or MDA-231 tumors, inhibited MCF-7 tumor growth, but had no effect on MDA-231 tumors. Examination of T, B and natural killer (NK) cell function in these animals indicated that the interleukin-2-mediated effect on MCF-7 cell growth in vivo is independent of the proliferative abilities of these lymphoid cells, suggesting that IL-2 may directly affect the growth of these hormone-dependent human breast cancer cells.

Supersensitivity to melatonin suppression by light in young people at high risk for affective disorder. A preliminary report.

Affective illness aggregates in families and appears to be heritable. Bipolar affective patients have been found to be supersensitive to the suppressive effect of light on the nocturnal secretion of melatonin, both in ill and well states. We tested young people aged 15 to 25 years with one manic-depressive parent (n = 18), major affective disorder on both sides of the family (n = 7), and age-matched controls (n = 20). The subjects in the high-risk groups were more likely to show supersensitivity in melatonin response to light at night than controls. Follow-up studies are necessary to assess the predictive value of this response.

The effect of total sleep deprivation on plasma melatonin and cortisol in healthy human volunteers.

Twelve healthy volunteers were included in this study. Baseline curves for melatonin and cortisol were obtained after one night of adaptation to laboratory conditions. From 10:00 p.m. to 6:00 a.m., blood samples were drawn every hour. On the third night, the subjects were kept awake at the sleep unit. Curves for the two hormones were then obtained after 36 h of total sleep deprivation (SD). The levels of these hormones were evaluated by calculating the area under the curve at each hour in both situations (basal and after sleep deprivation). It was found that the melatonin levels were increased after sleep deprivation, whereas the cortisol levels remained the same. These results suggest a mechanism by which a reset of abnormal rhythms can occur in depression.