[The eye and circadian rhythms].
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Animals↗
Biomedical subjects
B Claustrat
Publications and source records attributed to B Claustrat.
[Adrenal vein catheterization in primary hyperaldosteronism: aid in surgical decision making?].
UNLABELLED: The localisation of aldosterone-producing adenomas (APA's) remains difficult. Indeed, CT scan may not detect small APA's while CT detected tumours do not necessarily produce aldosterone. OBJECTIVE: To evaluate the value of adrenal vein catheterization (AVC) for the diagnosis of APA's and also the rates of unsuccessful procedures and complications. PATIENTS: One-hundred-and-nine hypertensives with biological features of primary hyperaldosteronism were included. Plasma sodium, potassium, aldosterone and renin levels were obtained after one night in lying position. Aldosterone and renin levels were also measured after a one-hour walking period and after a sodium expansion with saline. All patients underwent a CT scan and AVC. For adrenal samples, the ratio of aldosterone to cortisol concentrations was calculated for both sides. Both ratios were divided by the opposite one and the higher was retained as an index of laterization (IL). For lack of a golden standard variable, we have taken as a working hypothesis that operated patients had an APA (n = 38) and the non operated ones bilateral hypereplasia (n = 71). RESULTS: Operated patients had a shorter history of hypertension, more frequently a left ventricular hypertrophy on ECG, and lower serum creatinine and potassium levels, along with a higher sodium level. None of these features appeared discriminant, however. Presence of a 10-mm tumour on CT scan was not significantly different between the 2 groups. Operated patients had more than a five-fold higher IL compared with that of non-operated patients. Analysis using a ROC curve showed that the value of 12 for "IL" was an acceptable operational criterium of lateralization, producing a specificity of 90%, while maintaining a sensitivity of 62%. AVC appeared most useful in case of middle-range pre-test probability of an APA being present, that is when when clinical, biological, or radiological features are not fully concordant. The rate of unsuccessful procedure and the rate of complications were low (1.8% and 3.6%, respectively). CONCLUSION: With a low iatrogenicity, AVC appears helpful in indicating surgery mostly when clinical, biological, and CT scan features are not fully concordant. A value of 12 for IL appears to allow a high specificity while retaining an acceptable sensitivity.
Adenoma↗
[Melatonin and circadian rhythm].
Melatonin is an indole hormone that is produced by the pineal gland, mainly at night, with a peak around 3.00 a.m. under normal environmental conditions. This endogenic secretion cycle is generated by the suprachiasmatic nuclei in response to the day/night alternation. Light either suppresses or entrains melatonin production according to the time of light exposure. Melatonin can be viewed as the "hand" of the internal clock and is regulated via the central nervous and sympathetic systems. Melatonin synchronizes biological cycles, particularly the temperature and sleep/wake cycles. Exogenous melatonin can influence the endogenous secretion of melatonin according to a phase response curve, an effect that provides a rationale for the use of melatonin to treat disorders of biological rhythms (rapid time-zone change syndrome, delayed sleep phase syndrome, desynchronization in blind subjects or shift workers, insomnia in the elderly).
Circadian Rhythm↗
Longitudinal study of bone loss in pre- and perimenopausal women: evidence for bone loss in perimenopausal women.
Bone loss before and around the time of menopause is not well characterized by longitudinal studies. We measured bone mineral density at various skeletal sites--total body, femoral neck, trochanter, anteroposterior (AP) and lateral spine, and forearm--with dual-energy X-ray absorptiometry in a large prospective cohort of 272 untreated pre- and perimenopausal women aged 31-59 years, at 1 year intervals for 3 years. Sex steroids and the following markers of bone remodeling were measured: serum osteocalcin (OC), procollagen I carboxyterminal extension peptide, bone alkaline phosphatase (BAP) and urinary crosslinks (CTX and NTX). Seventy-six women were classified as perimenopausal and 196 as premenopausal. Over the 3 years, premenopausal women had no significant bone loss at any site and a small but significant increase in bone mineral density at the trochanter, total hip, AP spine and radius. Perimenopausal women significantly lost bone from cancellous and cortical sites, i.e., the femoral neck, trochanter and lumbar spine. In perimenopausal women with increased follicle stimulating hormone, the rate of bone loss at the femoral neck correlated negatively with OC and BAP. In perimenopausal women, serum estradiol levels decreased during the 3 years of follow-up and bone loss from the trochanter and the AP spine was correlated with serum estradiol after 3 years. In conclusion, among premenopausal women there is no bone loss. In contrast, there is a rapid and diffuse bone loss in perimenopausal women, related to decreased estrogen secretion. Bone markers may be useful to identify these women losing bone.
Absorptiometry, Photon↗
Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study.
The mechanisms leading to increased bone loss and skeletal fragility in women with postmenopausal osteoporosis are still poorly understood. Increased bone resorption, low serum estradiol and high serum sex-hormone-binding globulin (SHBG) recently have been reported as predictors of vertebral and hip fractures in elderly women. In a cohort of healthy untreated younger postmenopausal women aged 50-89 years (mean, 64 years), we compared baseline levels of bone markers and endogenous hormones in 55 women who subsequently had a fracture (20 vertebral and 35 peripheral fractures) with levels in the 380 women who did not fracture during a mean 5 years of follow-up. Women with levels in the highest quartile of four bone resorption markers including urinary-free deoxypyridinoline (D-Pyr), urinary type I collagen N-telopeptides (NTX), and urinary and serum type I collagen C-telopeptides (CTX) had about a 2-fold increased risk of fractures compared with women with levels in the three lowest quartiles with relative risk (RR) and 95% CI of 1.8 (1.0-3.4) for free D-Pyr, 1.7 (0.9-3.2) for urinary NTX, 2.3 (1.3-4.1) for urinary CTX, and 2.1 (1.2-3.8) for serum CTX. Serum levels of bone alkaline phosphatase (BAP) in the highest quartile were associated with an RR of fracture of 2.4 (1.3-4.2). Women with serum levels of estradiol and dehydroepiandrosterone (DHEA) sulfate in the lowest quartile had an RR of fracture of 2.2 (1.2-4.0) and 2.1 (1.2-3.8), respectively. Increased levels of SHBG and intact parathyroid hormone (PTH) were moderately associated with an increased risk of fracture. Similar results were obtained when the analysis was restricted to symptomatic vertebral and nonvertebral fractures. Adjustment of biochemical markers by hormone levels did not significantly alter the results. Women with both high bone resorption markers and low estradiol (or low DHEA sulfate) had a higher risk of fracture with RRs of 3.0-3.3 (p < 0.001). After adjustment for bone mineral density (BMD) of the hip, spine, radius, or total body, bone markers and hormones were still predictive of fracture risk with similar RRs. We conclude that high levels of some biochemical markers of bone turnover, low serum estradiol, low DHEA sulfate, high SHBG, and high PTH are associated with increased risk of osteoporotic fracture in postmenopausal women, independently of each other and of BMD. The mechanism by which some postmenopausal women have an increased rate of bone turnover leading to an increased risk of fracture remains to be elucidated.
Alkaline Phosphatase↗
Hypoprolactinemic rats under conditions of constant darkness or constant light. Effects on the sleep-wake cycle, cerebral temperature and sulfatoxymelatonin levels.
In genetic hypoprolactinemic rats under light-dark (LD) conditions, the circadian rhythms of slow-wave (SWS) and paradoxical (PS) sleep display an alteration of their phase relationship. The aim of our study was to investigate the effects of constant darkness (DD) or constant light (LL) on the daily distribution and amounts of sleep-wake stages, cerebral temperature and concentrations of the urinary melatonin metabolite, 6-sulfatoxymelatonin, in prolactin-deficient rats. After 3 weeks of DD, the SWS period was 24 h 8+/-6 min and the acrophase occurred at 15:44+/-1:35, while for PS, the period was more stable than during LD (24 h 10+/-8 min vs. 24 h 55+/-43 min) and the acrophase occurred at 16:44+/-1:54. Under LL conditions, circadian sleep rhythms persisted during the first 3 days, then completely disappeared during the third week, to be replaced by ultradian rhythms (period of 4-6 h). Time-series analysis showed that the two sleep states became synchronous as early as the second day under constant conditions. The total amount of PS was increased under both conditions (LL and DD) at the expense of duration of waking. Under LD and constant conditions, the pattern of changes in cerebral temperature was similar to that for wakefulness (W). Sulfatoxymelatonin was rhythmically secreted under both LD and DD conditions, whereas, under LL conditions, its rhythm was abolished. The results show that, in IPL rats in the absence of a zeitgeber, the PS and SWS rhythms recover a synchronous phase relationship and PS amounts are increased.
Animals↗
The tumor promoting effect of constant light exposure on diethylnitrosamine-induced hepatocarcinogenesis in rats.
The hypothesis that light-induced circadian clock suppression exerts a promoting effect on liver carcinogenesis was investigated in rats. Sixty-five male Wistar rats were given diethylnitrosamine (DEN, 10 mg/kg/day p.o.) for 6 weeks and were randomized into 3 groups. Rats from group 1 (N=20) received DEN only. Rats from group 2 (N=22) also received phenobarbital (pheno, 30 mg/rat/day p.o.) for 4 weeks as a promoting agent and rats from group 3 (N=23) were exposed to continuous light. Three months after starting DEN treatment, urinary 6-sulfatoxymelatonin (alphaMT6s) excretion, a marker of circadian clock function, had lost its circadian rhythmicity in the LL group, with a 4-fold lower 24 h mean than that found in the LDpheno and LD groups (8.0 +/- 3.2 ng/ml, 33.6 +/- 3.1 ng/ml and 34.3 +/- 2.4 ng/ml respectively; p from ANOVA <0.001). Laparotomy was then performed. The proportion of rats with macroscopic nodules on liver surface was 72% (LD group), 89% (LDpheno group) and 95% (LL group) (p from chi2 = 0.1). Nodules were more numerous and larger both in the LL group and in the LDpheno one as compared to the LD group (p from chi2 <0.05). All the rats died with hepatocellular carcinomas, with a median survival of 5 months, similar in all 3 groups. Light-induced circadian clock suppression exerted a promoting effect similar to that caused by phenobarbital in this model, yet through different effects on circadian system function.
Animals↗
Dietary docosahexaenoic acid-enriched phospholipids normalize urinary melatonin excretion in adult (n-3) polyunsaturated fatty acid-deficient rats.
Melatonin (MEL) plays an essential role in physiologic functions associated with darkness. We examined the effects of docosahexaenoic acid (DHA)-enriched phospholipids from pig brains (BPL) or hen eggs (EPL), as sources of DHA, on lipid FA composition of pineal membranes and daytime and nighttime concentrations of 6-sulfatoxymelatonin (aMT6) in adult male control and (n-3)-deficient rats fed BPL and EPL diets for 5 wk. In two experiments, at 3 wk of age, rats were divided into subgroups and fed semipurified diets containing either peanut oil [(n-3)-deficient group] or peanut plus rapeseed oil (control group) and two dietary formulas containing either 3.5 g/100 g diet of BPL (Experiment 1) or 5.0 g/100 g diet of EPL (Experiment 2). BPL and EPL diets provided approximately 200 mg of DHA/100 g diet. During the daytime, aMT6 concentrations were not significantly different among groups. Conversely, the (n-3)-deficient rats had significantly lower nighttime aMT6 concentrations than the control rats. BPL and EPL did not affect urinary nighttime aMT6 concentration in the control group, whereas (n-3)-deficient + BPL or EPL groups exhibited significantly higher nighttime aMT6 concentrations than the (n-3)-deficient group (76 and 110%, respectively). The level of DHA was significantly higher in the pineal glands of control rats than in (n-3)-deficient rats. In rats fed EPL and BPL, the level of DHA reached a plateau, between 10 and 11 mg/100 mg total fatty acids in control + BPL or EPL and (n-3)-deficient + BPL or EPL groups. These findings suggest that new DHA-enriched formulas may be used as an efficient alternative source of (n-3) polyunsaturated fatty acids to normalize MEL secretion.
Animals↗
Estimation of frequently sampled nocturnal melatonin production in humans by deconvolution analysis: evidence for episodic or ultradian secretion.
In order to investigate nocturnal melatonin production and clearance rates, we applied deconvolution analysis to plasma melatonin concentration time series obtained every 20 min for 12 hr from 20:00 h to 08:00 h in two groups of healthy subjects at rest (group 1, 12 male subjects, 22-26 yr; group 2, ten female subjects, 31-42 yr). The estimated melatonin production rate from group 1 (0.55 +/- 0.21 microg/kg/night) was significantly higher than that of group 2 (0.26 +/- 0.19 microg/kg/night), as well as the mass of melatonin released per burst (275 +/- 110 vs. 145 +/- 130 pg/mL for groups 1 and 2, respectively), the amplitude of secretory bursts (7.8 +/- 3.2 vs. 4.7 +/- 3.5 pg/mL/min), and the pulsatile melatonin production rate (2.76 +/- 1.14 vs. 1.27 +/- 0.97 ng/mL/night). These differences could reflect alterations related to age and or gender. No differences were observed between the two groups in the secretory burst half-duration and frequency and the interburst interval. Melatonin production rates, as estimated by deconvolution analysis, are in agreement with other independent estimates, especially the isotopic method, and disclose an ultradian rhythmicity.
Adult↗
Occurrence of hyperhomocysteinemia 1 year after gastroplasty for severe obesity.
Severe obesity exposes one to an increased risk of cardiovascular mortality. Gastroplasty has been shown to induce substantial weight loss and to improve the atherogenic profile of severely obese subjects. However, vitamin deficiencies after gastroplasty have been reported. Because hyperhomocysteinemia, an independent risk factor for cardiovascular disease, is influenced by nutritional status (and especially by folate intake), we hypothesized that a marginal folate deficiency induced by gastroplasty could promote hyperhomocysteinemia. Thus, plasma homocysteine concentrations were measured by high-performance liquid chromatography in 53 severely obese patients (body mass index = 42 +/- 1), before and 1 yr after vertical gastroplasty. Plasma homocysteine concentrations increased, on an average, from 9.9 +/- 0.4 to 12.8 +/- 0.6 micromol/L (P < 0.0001). This increase in homocysteine levels was observed in two thirds of the subjects, leading to clear-cut hyperhomocysteinemia (>15 micromol/L) in 32%. The changes in homocysteine concentrations were correlated to weight loss (P < 0.001) and to decrease in plasma folate concentrations (P < 0.01). Whereas gastroplasty induced a mean 32-kg weight loss and a striking improvement in conventional risk factors, the occurrence of iatrogenic hyperhomocysteinemia might hamper the benefit of surgery on cardiovascular risk in most of the patients. Our results further support use of a systematic efficient folate supplementation after gastroplasty.
Adult↗
African trypanosomiasis in the rat alters melatonin secretion and melatonin receptor binding in the suprachiasmatic nucleus.
Rats infected with Trypanosoma brucei brucei, a subspecies of the extracellular parasites that cause African sleeping sickness, were examined for disturbances in the circadian rhythms of melatonin secretion (evaluated by determination of the excretion of melatonin in the urine) and the binding of melatonin to its receptor in the suprachiasmatic nuclei of the anterior hypothalamus. In normal and infected rats, Cosinor analysis showed a significant nocturnal peak. The amplitude of this peak was, however, significantly decreased in the infected rats. The peak of melatonin receptor binding in the suprachiasmatic nuclei showed a 4-h phase advance in the infected rats, compared with the controls (0400 and 0800, respectively). These data point to a disturbance in the circadian rhythm of the melatonin-generating systems in the pathogenesis of African sleeping sickness.
Animals↗
Effect of modafinil on plasma melatonin, cortisol and growth hormone rhythms, rectal temperature and performance in healthy subjects during a 36 h sleep deprivation.
Modafinil is an alerting substance which has been used successfully to treat narcolepsy. Nothing is known about its effect on hormone secretions. For this purpose, eight healthy young men were enrolled in a double blind trial to test the effects of modafinil on daily plasma melatonin, cortisol and growth hormone (GH) rhythms. Blood was sampled for hormone assays, every hour during the daytime and every 30 min during the nighttime. In addition, rectal temperature and mental performances were determined during the study which comprised 3 sessions, two weeks apart: a 24 h control session including a night with sleep (S1) and two 48 h sessions S2 and S3 with a sleep-deprived night (N1) followed by a recovery night (N2). Modafinil (300 mg x 2) or placebo were randomly attributed during N1 at 22 h and 8 h. As expected, performance was improved after modafinil administration and body temperature was maintained or increased. Plasma melatonin and cortisol profiles were similar after modafinil and placebo administration. The levels observed during the recovery and the control nights (N2) displayed no difference. For GH, during both sleep deprived nights, secretion was dramatically reduced compared with the control one, although the number of secretory episodes was unchanged. These data show that the alerting property of modafinil is not related to an alteration of hormone profiles and suggest that the acute modafinil administration is devoid of short-term side-effects.
Adult↗
The physiology and pharmacology of melatonin in humans.
Melatonin (MLT) is a methoxyindole secreted principally by the pineal gland. It is synthesized at night under normal environmental conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained by the light/dark cycle. Light is able to both suppress or entrain MLT production on light schedule. The nyctohemeral rhythm of this hormone can be determined by repeated measurement of plasma or saliva MLT or urine sulfatoxy-MLT, the main hepatic metabolite. MLT can be considered as the output (the hand) of the endogenous clock. Since the regulating system follows a central and sympathetic nervous pathway, an abnormality at any level could unspecifically modify the MLT secretion, especially in patients with sympathalgia or dysautonomia. MLT plays the role of an endogenous zeitgeber on core temperature or sleep-wake cycle. Exogenous MLT is able to influence the endogenous secretion of the hormone according to a phase-response curve. There are practical implications for this property in situations when biological rhythms are disturbed (jet-lag syndrome, delayed sleep phase syndrome, insomnia in blind people, shift-work, insomnia in elderly people). Improvement of pharmaceutical forms (controlled release preparations) or development of MLT analogs could lead to decisive progress.
Adenylyl Cyclases↗
Plasma melatonin rhythm is maintained in human African trypanosomiasis.
In human African trypanosomiasis (sleeping sickness), sleep and wake episodes are sporadically distributed throughout the day and the night. Plasma melatonin, sleep-wakefulness and rectal temperature rhythms were studied in 9 Congolese patients suffering from sleeping sickness compared to 6 healthy controls submitted to the same light/dark regime. The circadian distribution of the sleep-wake cycle was disturbed in relation to the severity of the disease. As controls, patients maintained a very distinct plasma melatonin nyctohemeral rhythm which displayed a significant phase advance (1:08 +/- 0:43 and 2:34 +/- 0:31 mean +/- SD, in patients and controls respectively; p < 0.01, U test), as well as a persistent rectal temperature rhythm (mesor 36.67 +/- 0.29 and 36.74 +/- 0.13 degrees C, amplitude 0.29 +/- 0.16 and 0.32 +/- 0.13 degrees C, acrophase 13:53 +/- 2:47 and 15:32 +/- 0:36 for patients and controls respectively). No alteration of these rhythms was observed after treatment. In African controls we observed plasma melatonin characteristics similar to those of European controls, especially for the onset and the duration of the secretion and the stability of the rhythm, despite a different light/dark regime. The dissociation observed between the 3 rhythms (melatonin, temperature and sleep-wake cycle) is discussed, taking into consideration a functional compartmentalization of the suprachiasmatic nuclei or more likely a disruption of the neural pathway between the circadian clock and structures involved in the regulation of the sleep-wake cycle, related to the activity of compounds released by the parasites or host cells.
Adolescent↗
Melatonin: from the hormone to the drug?
Melatonin (MLT) is a methoxyindole secreted principally by the pineal gland. It is synthesized at night under normal environmental conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained by the light/dark cycle. Light is able to both suppress or synchronize melatonin production according to the light schedule. The nycthohemeral rhythm of this hormone is determined by repeated measurement of plasma of saliva MLT or urine sulfatoxymelatonin, the main hepatic metabolite. Melatonin can be considered as the output (the hand) of the endogenous clock. Since the regulating system follows central and sympathetic nervous pathways, an abnormality at any level unspecifically modifies the melatonin secretion, especially in patients with sympathalgia or dysautonomia. Melatonin plays the role of an endogenous zeitgeber on sleep-wake cycle or core temperature. Exogenous melatonin is able to influence the endogenous secretion of the hormone according to a phase response curve. There are therapeutic implications for this property in situations when biological rhythms are disturbed (jet-lag syndrome, delayed sleep phase syndrome, insomnia in blind or elderly people, shift-work). Improvement of pharmaceutical forms studied in controlled trials under the responsibility of the medical community or development of melatonin analogs could lead to decisive progress in this field.
Journal Article↗
Tryptophan hydroxylase mRNAs analysis by RT-PCR: preliminary report on the effect of noradrenaline in the neonatal rat pineal gland.
The levels of mRNAs coding for tryptophan hydroxylase (TPOH), the first enzyme in melatonin synthesis, have been investigated by quantitative reverse transcription of RNA, followed by polymerase chain reaction (RT-PCR), after stimulation of neonatal pineal organ cultures with Noradrenaline (NA). TPOH mRNAs were specifically amplified from various adult tissues, namely the pineal gland, raphe, retina, and kidney, but not the lung. PCR signals for TPOH were detected in the neonatal pineal gland in the absence of stimulation. Stimulation of neonatal pineal organ culture with 0.1 microM NA resulted in a significant increase (x2.5) in expression of TPOH mRNAs, whereas higher doses (1 and 10 microM) had no effect. All concentrations of NA enhanced melatonin secretion. Our results suggest that the level of TPOH mRNAs can be controlled by NA and that this effect might be implicated in the gene level regulation of the daily enzyme rhythm in the rat pineal gland.
Animals↗
Evidence for tryptophan hydroxylase and hydroxy-indol-O-methyl-transferase mRNAs in human blood platelets.
Human blood platelets were tested for the presence of mRNAs coding for tryptophan hydroxylase (TPOH) and hydroxy-indol-o-methyl-transferase (HIOMT). Total RNA was extracted from platelets (12.9 +/- 3.3 mg RNA/100 ml blood, mean +/- SEM of 6 preparations) and cDNA synthesized by reverse transcription using random hexamers, oligo-dT or TPOH- or HIOMT-specific primers, designed to amplify a 254 bp fragment for TPOH and a 301 bp fragment for HIOMT. Positive controls were performed using RNA extracted from human normal or tumoral pineal glands. The PCR products were analyzed by gel electrophoresis, transferred to a nylon membrane and hybridized with a 32P-labeled internal probe. When random hexamers, oligo-dT or specific primers were used for reverse transcription, amplification products of the predicted sizes were detectable following electrophoresis in the case of pineal glands and following transfer and hybridization in the case of platelets. These results show TPOH and HIOMT mRNAs to be present in human blood and support the hypothesis that serotonin and melatonin may be synthesized in blood and, more particularly, in platelets.
Acetylserotonin O-Methyltransferase↗
Transmucosal, oral controlled-release, and transdermal drug administration in human subjects: a crossover study with melatonin.
The effect of oral controlled-release (CR), oral transmucosal (buccal; TMD) and transdermal (TDD) drug delivery systems on plasma concentrations of melatonin (MT) and its principal metabolite in human subjects using a crossover, single dose design was evaluated. Twelve adult male volunteers participated in the study and received all three dosage forms on three separate occasions. All patch dosage forms were removed after 10 h of wear. Plasma concentrations of the parent drug and its metabolite, 6-sulfatoxymelatonin (MT6s) were measured by radioimmunoassay. Between-subject plasma concentrations of MT were very variable following both oral CR and TDD. Use of the oral CR system gave plasma MT profiles in some subjects that were initially similar to physiological levels, but then differed substantially from physiological in the rate of MT offset; in a few subjects, plasma MT levels remained consistently much below normal nocturnal physiological levels. Also, the ratio of metabolite to parent drug by the oral CR route was many times greater than physiological. TDD resulted in a significant delay in systemic drug levels and a gradual decline in drug delivery after patch removal, possibly due to deposition of melatonin in the skin. TDD failed to simulate the physiological plasma profile of MT (rapid achievement of steady-state blood levels and rapid decline after removal of the patch; i.e., so-called "square-wave" profile). TMD provided prompt systemic drug levels with less variability than oral CR or TDD delivery. Also, plasma MT levels fell promptly and rapidly after removal of the patch. No indication of mucosal deposition was observed. TMD was able to mimic the physiological plasma profiles of both MT and its principal metabolite.
Administration, Buccal↗