[Therapeutic approaches for sleep and rhythms disorders in children with ASD]. / Approches thérapeutiques des troubles du sommeil et des rythmes chez l'enfant avec TSA.

Sleep disturbances are extremely common (40-86%) in children and adolescents, especially those with autism spectrum disorders (ASD) and are often among the first symptoms identified by parents at a very early stage of their child's development. These abnormalities are among the main parental concerns when having a child with ASD and have a significant impact on the quality of life of patients, their parents, and more broadly their siblings. Sleep disorders are essentially abnormalities of the sleep-wake rhythm - primarily sleep onset insomnia or nocturnal awakenings (with difficulty falling back to sleep). These disturbances can be accompanied by other sleep disorders, requiring notably a systematic elimination of the presence of a sleep apnea or restless legs syndrome - to ensure a personalized and efficient therapeutic approach. Physiologically, the determinants of these sleep disorders are poorly understood, even though several studies point to a significant decrease in melatonin synthesis in people with ASD. Melatonin is a hormone that facilitates falling asleep and maintaining sleep and is also involved in the endogenous synchronization of internal biological clocks. However, the causal factors of this decrease in melatonin synthesis are largely unknown, involving to a small extent the genes involved in melatonin synthesis pathway. The treatment of sleep disorders is relatively systematic: after eliminating other specific sleep disorders associated with the complaint of insomnia, as well as other possible associated comorbidities (such as seizures), a global and graduated therapeutic approach must be put in place. This treatment will be non-pharmacological as a first line, then pharmacological as a second line. A number of non-pharmacological treatment strategies for sleep disorders in typically developing children and adolescents, as well as those with ASD, have been shown to be effective. This treatment requires a combination of: 1) parental education to promote sleep development; 2) setting up bedtime rituals adapted to the child's age and particularities; 3) specific behavioral strategies including bedtime fading, gradual extinction and positive reinforcement of adapted behaviors. It is very essential that the parents are accompanied throughout this therapy. Sleep hygiene and behavioral care must also take into consideration the important role of the zeitgebers of sleep-wake rhythms, i.e. the external environmental factors involved in the synchronization of the biological clocks: regular exposure to light at adapted times, regular meal and wake-up times, social activities and times for going to school. The evidence for the effectiveness of behavioral interventions in the treatment of behavioral insomnia in the typical developmental child is strong, since 94% of children show clinically significant improvements in nighttime sleepiness and waking. By contrast, only about 25% of children with ASD are improved by an approach combining sleep hygiene and behavioral therapy. Melatonin has a special and prominent place in the drug management of sleep disorders associated with ASD. Several clinical trials have shown that melatonin is effective in treating sleep disorders in patients with ASD. This work led to the European Medicines Agency (EMA) granting marketing authorization in September 2018 for a sustained-release paediatric melatonin molecule (Slenyto®). This synthetic molecule is a prolonged release melatonin (PRM) which mimics the physiological pharmacokinetic and secretory characteristics of endogenous melatonin, having a very short blood half-life and prolonged secretion for several hours during the night. A recent study evaluated the efficacy and safety of pediatric PRM (mini-tablets) in 125 children, aged 2 to 17.5 years with mainly ASD. After 15 days on placebo, the children were randomized into two parallel groups, PRM or placebo in a double-blind design for 13 weeks. At endpoint, total sleep time was increased by an average of 57.5 minutes on PRM and only 9.14 minutes on placebo (P=0.034). This difference between the two groups was already significant after three weeks of treatment (P=0.006). Sleep latency was also improved in the PRM group (-39.6 minutes) compared to placebo (-12.51 minutes) (P=0.01). Consolidated sleep duration (uninterrupted by awakenings) was improved by 77.9 minutes for the PRM group and only 25.4 minutes for the placebo group (P<0.001). PRM was well tolerated, the most frequent side effects being headache and daytime drowsiness at the same level with PRM or placebo. In addition, the acceptability by the children for swallowing the mini-tablets was excellent (100% compliance). The efficacy and tolerability of PRM was maintained over the medium and long term in the open phase, over a total study duration of 2 years.

[Melatonin: Physiological and pharmacological aspects related to sleep: The interest of a prolonged-release formulation (Circadin®) in insomnia]. / Mélatonine : aspects physiologiques et pharmacologiques en relation avec le sommeil, intérêt d'une forme galénique à libération prolongée (Circadin®) dans l'insomnie.

Melatonin is a hormone secreted by the pineal gland. It displays a very marked nycthohemeral rhythm, which is entrained to the light dark cycle. The secretion spreads over 8-10 hours, with a maximum around 3-4 a.m. Melatonin plays the role of an endogenous synchronizer which regulates circadian rhythms, especially the sleep/wake and temperature rhythms. Acute melatonin administration reduces sleep latency, increases theta/alpha power and spindle activity (soporific activity). Fast-release melatonin preparations showed inconstant effects in insomnia. Melatonin displays a short blood half-life, a fast turn over and undergoes a high first-pass hepatic metabolism. More than 80% is excreted exclusively in the urine as 6-sulfatoxymelatonin. The individual's capacity to produce the endogenous hormone, the decline in circadian clock output and the increase in complaints of poor sleep quality at older age led to develop a prolonged-release melatonin preparation to mimic the endogenous secretion in patients. This reviews provides data on physiological and pharmacological melatonin effects related to sleep and summarizes trials published about Circadin® efficacy and tolerance in insomnia. Preliminary therapeutic data on other indications are given. The main clinically relevant benefits are improvements in sleep quality and latency, next-day morning alertness and quality of life. The response develops over several days. An oral 2-mg dose once daily, for 3 months, is generally well tolerated with no rebound, withdrawal or 'hangover' effects and no safety concerns on concomitant therapy with antihypertensive, antidiabetic, lipid-lowering or anti-inflammatory drugs. Untoward effects of hypnotics on cognition, memory, postural stability and sleep structure are not seen with Circadin®. Given as a first-line prescription, with 13 weeks' posology and the lack of rebound effects, Circadin® has the potential to improve quality of life in insomnia patients aged 55 years and older and avoid long-term use of hypnotics.

Melatonin: Physiological effects in humans.

Melatonin is a methoxyindole synthesized and secreted principally by the pineal gland at night under normal light/dark conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained to the light/dark cycle. Light is able to either suppress or synchronize melatonin production according to the light schedule. The nycthohemeral rhythm of this hormone can be evaluated by repeated measurement of plasma or saliva melatonin or urine sulfatoxymelatonin, the main hepatic metabolite. The primary physiological function of melatonin, whose secretion adjusts to night length, is to convey information concerning the daily cycle of light and darkness to body structures. This information is used for the organisation of functions, which respond to changes in the photoperiod such as the seasonal rhythms. Seasonal rhythmicity of physiological functions in humans related to possible alteration of the melatonin message remains, however, of limited evidence in temperate areas under field conditions. Also, the daily melatonin secretion, which is a very robust biochemical signal of night, can be used for the organisation of circadian rhythms. Although functions of this hormone in humans are mainly based on correlations between clinical observations and melatonin secretion, there is some evidence that melatonin stabilises and strengthens coupling of circadian rhythms, especially of core temperature and sleep-wake rhythms. The circadian organisation of other physiological functions depend also on the melatonin signal, for instance immune, antioxidant defences, haemostasis and glucose regulation. The difference between physiological and pharmacological effects of melatonin is not always clear but is based upon consideration of dose and not of duration of the hormone message. It is admitted that a "physiological" dose provides plasma melatonin levels in the same order of magnitude as a nocturnal peak. Since the regulating system of melatonin secretion is complex, following central and autonomic pathways, there are many pathophysiological situations where melatonin secretion can be disturbed. The resulting alteration could increase the predisposition to disease, add to the severity of symptoms or modify the course and outcome of the disorder. Since melatonin receptors display a very wide distribution in the body, putative therapeutic indications of this compound are multiple. Great advances in this field could be achieved by developing multicentre trials in a large series of patients, in order to establish efficacy of melatonin and absence of long-term toxicity.

Is pineal melatonin released in the third ventricle in humans? A study in movement disorders.

In order to determine sources and metabolism of melatonin in human cerebrospinal fluid (CSF), melatonin and 6-sulfatoxymelatonin (aMT6S) concentrations were measured in CSF sampled during neurosurgery in both lateral and third ventricles in patients displaying movement disorder (Parkinson's disease, essential tremor, dystonia or dyskinesia) and compared with their plasma levels. Previous determinations in nocturnal urine had showed that the patients displayed melatonin excretion in the normal range, compared with healthy controls matched according to age. A significant difference in melatonin concentration was observed between lateral and third ventricles, with the highest levels in the third ventricle (8.75±2.75pg/mL vs. 3.20±0.33pg/mL, P=0.01). CSF aMT6s levels were similar in both ventricles and of low magnitude, less than 5pg/mL. They were not correlated with melatonin levels or influenced by the area of sampling. Melatonin levels were significantly higher in third ventricle than in the plasma, whereas there was no difference between plasma and lateral ventricle levels. These findings show that melatonin may enter directly the CSF through the pineal recess in humans. The physiological meaning of these data remains to be elucidated.

Effect of constant light on prolactin and corticosterone rhythms evaluated using a noninvasive urine sampling protocol in the rat.

Circadian prolactin and corticosterone rhythms are usually investigated in the rat by analysis of plasma hormone profiles. In order to develop a nonstressful methodology for long-term studies, we validated prolactin and corticosterone radioimmunoassays in rat urine samples. Among the criteria of validation, prolactin was identified in urine by Western blot whereas both prolactin and corticosterone levels were undetectable in the urine of hypophysectomized rats. The determination of prolactin and corticosterone levels on serial urine samples showed daily variations in male rats entrained by the light-dark cycle. The acrophases of the 24-hour prolactin and corticosterone profiles were located at 03:26 h and 23:32 h respectively, a delay of 3-4 hours compared with the values of the 24-hour plasma profiles reported in the literature. Corticosterone and prolactin rhythms were abolished or dramatically delayed after 3 weeks of constant illumination. As expected, constant light suppressed the rhythm of 6-sulfatoxymelatonin, the major hepatic metabolite of melatonin. The noninvasive and nonstressful methodology we developed could be of interest for studying the regulation of hormone rhythms and their mutual endocrine interactions in physiological conditions, especially their evolution in the aging process.

Histological features and expression of enzymes implicated in melatonin synthesis in pineal parenchymal tumours and in cultured tumoural pineal cells.

Pineal parenchymal tumours (PPT) are rare neoplasms and there have been few in vitro studies. Their capacity for synthesizing and secreting melatonin has been only partially examined. We investigated the presence of messenger RNA (mRNA) encoding tryptophan hydroxylase (TPH), arylalkylamine N-acetyltransferase (AANAT), hydroxyindol-O-methyltransferase (HIOMT), three enzymes involved in melatonin synthesis, and c-myc, a tumoural marker, in 10 PPT, one papillary tumour of the pineal region (PTPR), cell cultures derived from four PPTs and from three other tumours of the pineal region, and in normal pineal gland. Moreover, protein expression of TPH was investigated in three PPT and PTPR. Quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry were used and the melatonin production by tumoural cells in vitro was analysed by radioimmunoassay. We showed that all the tumoural tissues and cells contained c-myc mRNA. mRNAs encoding TPH, AANAT and HIOMT were detected in all PPT, suggesting that tumour cells can synthesize melatonin. Only PPT expressed TPH protein. Cultured cells lost expression of transcripts throughout passages even if ultrastructural study revealed the presence of characteristic organelles in these tumoural cells. Nevertheless, the basal secretion of melatonin observed in one PPT culture is in favour of a maintained melatonin production and secretion by tumoural pinealocytes, but melatonin production was not stimulated by a beta noradrenergic agonist. Moreover, PTPR never expressed mRNA encoding TPH, AANAT and HIOMT. Our results may contribute to a better understanding of the biology of PTT and PTPR and may help to the diagnosis of these rare tumours.

[Circadian clock gene expression in human peripheral blood mononuclear cells]. / Expression des gènes de l'horloge circadienne dans les cellules sanguines mononuclées humaines.

Circadian clock genes have been identified in humans but information regarding their expression has remained very limited. However from a basic point as well as in a diagnostic and therapeutic perspective, it is important to evaluate molecular clock gene expression. Peripheral blood mononuclear cells represent an ideal material to investigate non-invasively the human clock at the molecular level. Several studies including ours reported rhythmic expression of clock genes in these cells, with significant intersubject variability of expression. In addition, our results reveal the existence of different chronotypes of clock gene expression patterns and suggest specific regulatory mechanisms in these human cells as compared to other peripheral tissues.

[Interactions between clock gene mutation, circadian phenotype and tumor growth in mice]. / Interactions entre mutation des gènes horloge, phénotype circadien et croissance tumorale chez la Souris.

The relation between circadian physiology (rest-activity and body temperature) and the growth of a grafted tumor (Glasgow osteosarcoma-GOS) was investigated in the mice with mutation of clock gene (ClockDelta19(-)) or gene controlled by the clock (Vpac(-/-)). Circadian rhythms in temperature and activity were stable, with an approximately 24-h period in all the mice synchronized by the alternation of 12 h of light and 12 h of darkness (LD 12:12). Following exposure to constant darkness (DD), both rhythms persisted in ClockDelta19(-), yet with a lengthening of the period by 4.5 h compared to wild type. In DD, the amplitude increased by 45.9% for the temperature rhythm (p<0.001) and by 17.4% for the activity one (p=0.08) as compared to LD 12:12 in ClockDelta19(-). The improvement of circadian coordination and/or the lengthening of the circadian period observed in ClockDelta19(-) kept in DD was associated with a moderate slowing down of tumor growth. Although the exposure to DD ablated the activity and temperature rhythms in Vpac(-/-), no modification in tumor growth was observed as compared to wide type or Vpac(-/-) in LD 12:12. Major alternations of circadian physiology can result from interactions between photoperiodic environment and mutation of clock gene or gene controlled by the clock. In these conditions, we have shown that the alternation of the circadian phenotype does not seem to constitute an essential determinant of the growth of a grafted tumor.

[Aging and circadian clock gene expression in peripheral tissues in rats]. / Vieillissement et expression des gènes de l'horloge circadienne dans les tissus périphériques chez le rat.

Aging is associated with alterations of the circadian rhythms (shortened amplitude and phase-advance). We studied by quantitative RT-PCR the influence of aging on the expression of circadian clock genes (Clock, Bmal1, Cry1,2, Per1-3) in peripheral tissues (liver and heart) of middle-aged (13 months) and old (27 months) rats of the Wag/Rij strain exposed to a 12 hours light/12 hours dark cycle. Rats were killed at the light-dark transition (8 am and 8 pm). In the liver, Per, Cry et Bmal1 genes showed a morning/evening difference of expression; in addition, old rats exhibited a significant decrease of Per gene expression in the evening vs middle-aged rats. The heart showed similar profiles with only a tendency toward a decrease of Per expression and an increased Bmal1 expression in the evening in old rats. These results show that aging is associated with circadian gene expression changes.

[Complementary methodological steps in the analysis of rhythms: search of periods, modelling. Examples of plasma melatonin and temperature curves]. / Eléments méthodologiques complémentaires dans l'analyse des rythmes: recherche de périodes, modélisation. Exemples de la Mélatonine plasmatique et de courbes de températures.

The choice of the period is a problematic in the field of the analysis of rhythms which is not yet sufficiently formalized in the sense that it was often postulated that the period is known and more precisely in the case of the circadian rhythms. We propose some methods which have a great reliability in the determination of the period and consequently can allow to characterize the parameters of the rhythmic phenomena (amplitude, phase, rhythmic level) with more precision. Traditional "cosine" modeling is always an unquestionable interest in the sense that it is a good reflect of the behavior of a biological periodic phenomenon in the course of time. However its employment requires to check complementary assumptions of validity in front of a statistical expertise. We will show the main ones. On the other hand it seems that this model requires a certain adaptation as it shows for example in the variabilities of the phase that one can notice in the behaviour of the biological rhythmic phenomena.

Dissociation in circadian rhythms in a pseudohypersomnia form of fatal familial insomnia.

The authors present clinical, sleep, and neuroendocrine features of a patient with genetically confirmed fatal familial insomnia (D178N mutation with heterozygosity at codon 129 of the prion protein gene). The patient exhibited pseudohypersomnia behavior instead of insomnia. There was profound alteration in the sleep-wake cycle with a clear dissociation in the disappearance of circadian and neuroendocrine rhythms, findings unrelated to abnormalities in the hypocretinergic system.

Role of sex steroids in the regulation of bone morphology in men. The MINOS study.

In ageing men, skeletal fragility is associated with reduced cortical thickness and decreased bone density. To better understand the role of testosterone and 17beta-estradiol regarding these characteristics of skeletal fragility, we correlated their circulating levels with the estimates of mechanical bone properties derived from areal bone mineral density (aBMD) measured by DXA. External diameter and BMD were used to estimate cortical thickness, cross-sectional area (CSA), section modulus, buckling ratio and strength index of the femoral neck and distal radius on 760 men aged 40-85 years. The 17beta-estradiol level was an independent positive determinant of CSA, aBMD and estimated cortical thickness of both bones. In multivariate models adjusted for age, body weight, height, lean body mass and testosterone concentration, men in the lowest quartile of 17beta-estradiol had lower CSA at the femoral neck (4.8%, P<0.001) and distal radius (3.6%, P<0.01) compared with men in the highest quartile. They had also thinner cortical bone at the femoral neck and distal radius (4.8%, P<0.001 and 4.6%, P<0.001, respectively). Furthermore 17beta-estradiol had a negative association with indices of cortical instability (buckling ratio) and a positive association with bending strength (section modulus, strength index) both at femoral neck and radius. Men in the lowest quartile of 17beta-estradiol had higher buckling ratios (femoral neck 4.8%, P<0.002; radius 5.1%, P<0.005), lower strength index (femoral neck 8.5%, P<0.001, radius 6.1%, P<0.01) and greater section modulus at the femoral neck. However, there were no between-quartile differences in external diameter in any bone sites. Similar, even though somewhat smaller, between-quartile differences were found for bioavailable 17beta-estradiol. Neither total testosterone nor apparent free testosterone concentration was associated with any bone variables after adjusting for age, body weight, body height, and lean body mass and 17beta-estradiol level. In conclusion, in elderly men, low concentration of 17beta-estradiol (total and bioavailable) was associated with a decreased cortical thickness and with a deterioration of biomechanical parameters of long bones (lower section modulus and strength index, higher buckling ratio).

Interest of Chromogranin A for diagnosis and follow-up of endocrine tumours.

OBJECTIVE: To determine the interest of Chromogranin A (CgA) determination for diagnosis and follow-up in patients with gastroenteropancreatic endocrine tumours (GEP-ET) and multiple endocrine neoplasia type 1 (MEN-1). PATIENTS AND METHODS: CgA levels were measured with an immunoradiometric assay in 124 sporadic GEP-ET, 34 MEN-1 and 127 controls. Serial determinations were performed in 56 patients (212 visits). Changes in CgA levels over 25% were considered as significant. RESULTS: Using a cut-off value of 130 micro g/l, established from a receiver-operating characteristic curve, the specificity of CgA was 98.4%, with a sensitivity of 62.9%, higher in secreting than in nonsecreting tumours (73%vs. 45%; P < 0.003) and related to the extent of metastatic spreading (P < 0.001). In nonsecreting tumours, the positive predictive value (PPV) of CgA for the presence of metastases was 100% but the negative predictive value (NPV) was only 50%. In MEN-1, high CgA levels indicated a pancreatic tumour with a 100% specificity but the sensitivity was 59%. During the follow-up, the concordance between CgA and tumour evolution was 80%, whatever the secretory status. In patients with carcinoid tumours, the concordance was higher for CgA than for serotonin (81%vs. 54%; P < 0.001). CONCLUSION: Due to its high specificity, CgA determination may help to discriminate the endocrine character of a GEP tumour and to indicate a pancreatic tumour in MEN-1. However, its low NPV in nonsecreting tumours limits its interest for diagnosis and staging. By contrast, serial evaluation of CgA seems of particular interest for the follow-up of GEP-ET tumours.

Melatonin secretion is supersensitive to light in migraine.

The present study examined the sensitivity to light of melatonin (MLT) secretion in familial migraine during a headache-free interval. Twelve female patients and 12 healthy controls were included in the trial. All subjects were studied twice. In each session, light exposure (300 lx) or placebo was randomly administered for 30 min between 00.30 and 01.00 h. Blood was sampled hourly between 20.00 and 24.00 h, and 02.00 and 04.00 h and every 15 min between 00.30 and 01.30 h. Plasma MLT levels were determined by radioimmunoassay. MLT suppression was more marked in the migraine group than in the control group [difference of area under curve (DeltaAUC)=-53.8 +/- 16.2 vs. 18.5 +/- 12.7 pg/h/ml, P<0.005; maximum of MLT suppression (Delta)=-35.7 +/- 10.2 vs. - 6.7 +/- 5.8 pg/ml, P<0.05]. These findings show a clear hypersensitivity to light in young female migraineurs during the headache-free period.

[Inversion of the circadian melatonin rhythm in Smith-Magenis syndrome]. / Inversion du rythme circadien de la mélatonine dans le syndrome de Smith-Magenis.

Smith-Magenis syndrome (SMS) is a genetic disease ascribed to an interstitial deletion on chromosome 17 (del 17p11); the prevalence is 1/25,000 births. The diagnosis is made on high-resolution karyotype confirmed by FISH. Clinical features include mild dysmorphism, short stature, other malformations (heart, renal, neurologic diseases). Mental retardation is constant; there are major behavioral disturbances and severe sleep disorders. We studied sleep disorders and melatonin secretion in SMS children and we have shown inversion of the circadian rhythm of melatonin, abnormally secreted during the day. This is the first biological model of behavioral and sleep disorder in a genetic disease. Therapeutic approach using beta-blockers in the morning and melatonin in the evening, reset circadian rhythm of melatonin, improve behavior and restore sleep.

Increased risk of falls and increased bone resorption in elderly men with partial androgen deficiency: the MINOS study.

The goal of this study was to identify the clinical and biological patterns of hypogonadism in a cohort of 1040 elderly men. Residual androgenic activity was estimated by total testosterone as well as the apparent free testosterone concentration (AFTC) and free testosterone index (FTI) calculated on the basis of concentrations of SHBG and total testosterone using appropriate formulae. The lower limit of the normal range defined by 2 SD below the mean in 150 healthy, nonobese, and nonsmoking men, aged 19-40 yr, was calculated for total testosterone (9.26 nmol/liter), AFTC (146 pmol/liter), and FTI (0.14 nmol/nmol). The prevalence of hypogonadism increased with ageing. Hypogonadal men were older and heavier (due to a higher fat body mass) and had lower concentrations of 17 beta-estradiol and androstenedione than men with normal androgenic activity. Men with decreased AFTC had a slightly lower bone mineral density (BMD) at certain sites. Men with decreased FTI had lower appendicular skeletal muscle mass and relative skeletal muscle index. For all three measures of androgenic activity, hypogonadal men had increased levels of the markers of bone resorption. In the multiple regression models including both 17 beta-estradiol and testosterone (total, AFTC, or FTI), 17 beta-estradiol was the only significant determinant of BMD. In the multiple regression models including 17 beta-estradiol and AFTC or FTI, only testosterone was a significant determinant of the variability in bone formation markers, whereas both 17 beta-estradiol and testosterone were significant determinants of the variability of the markers of bone resorption. Hypogonadism was associated with an increase in the risk of falls, an impairment of static and dynamic balance, as well as the inability to stand up from a chair and to perform the tandem walk. Decreased AFTC (<146 pmol/liter) discriminated best men with functional disabilities (odds ratio, 1.54-7.95; P < 0.05-0.0001). Hypogonadal elderly men had increased bone resorption that was not adequately matched by an increase in bone formation, lower muscle strength, impaired static and dynamic balance, a higher risk of falls, and, in men with low AFTC, a slightly lower BMD. Low AFTC seems to have the best discriminative power for densitometric, biochemical, and functional parameters, followed by FTI, whereas total testosterone was the least discriminative. In multiple regression models, 17 beta-estradiol was the strongest determinant of BMD, and AFTC and FTI were significant determinants of the variability in bone formation markers, whereas both 17 beta-estradiol and testosterone determined the variability in bone resorption markers.

Melatonin and methimazole mimic short-day-induced fattening in gray mouse lemurs.

Short-day-induced fattening was investigated in the small nocturnal primate Microcebus murinus. Animals were either transferred from long photoperiod (LP) to short photoperiod (SP) or maintained in LP and submitted to various treatments. Animals fed daily on 40 microg of melatonin (MEL) at two different times showed a significant increase in body mass compared to LP-exposed animals. This weight gain was more marked in animals fed with MEL 2 h before night onset, suggesting a critical period around the first hours of the night. The MEL-induced fattening was associated with an increase in food intake and a decrease in plasma thyroxin (T4) levels. On the other hand, a decrease in T4 plasma levels induced by two doses of methimazole (MET) led to either an increase (3 mg/day) or a decrease (10 mg/day) of body mass, suggesting a role of thyroid hormones in the photoperiodic regulation of body mass. The MET-induced fattening did not involve any change in food intake. These findings suggest that autumn fattening in the gray mouse lemur proceeds from two distinct mechanisms. First, an increase of food intake may result in the SP-induced increase in MEL secretion. Second, a decrease of energy expenditure may be due to the MEL-induced hypothyroidism.

[Video screen exposure and 6-sulfatoxymelatonin urinary excretion in women]. / Travail sur écran d'ordinateur et excrétion urinaire de la 6-sulfatoxymélatonine chez la femme.

A study in blind conditions was conducted on 13 women (mean age < 30 years). Six women worked at least four hours per day, five days a week, since more than one month, in front of a video screen constituted the exposed group. Radioimmunoassay of 6-sulfatoxymelatonin was done on urine collected during night. Results were analysed by a non parametric rank-test (Mann-Withney). It was observed an important (- 54%) and significant lower level (p < 0.01) of 6-sulfatoxymelatonin in urine of women exposed to video screen.

Increased bone resorption in moderate smokers with low body weight: the Minos study.

Tobacco was found to be a risk factor for osteoporosis, mainly in postmenopausal women. We studied the effect of smoking on bone mineral density (BMD) and bone turnover in a cohort of 719 men, aged 51-85 yr, composed of 83 current smokers, 405 former smokers, and 231 men who never smoked. Most current and former smokers were moderate smokers (median, 10 cigarettes/d). Current smokers were younger, thinner, and drank more coffee and more alcoholic beverages. After adjustment for age, body weight, alcohol intake, and caffeine intake, current and former smokers had similar BMD, except at the forearm. Former smokers had lower BMD compared with never-smokers at most skeletal sites. Men who had smoked more than 7120 packs (third quartile) had lower BMD of total hip (P < 0.01) and distal forearm (P = 0.03) compared with men in the 2 lower tertiles. In the 3 groups, levels of bone formation markers did not differ. After adjustment for confounding variables, levels of urinary markers of bone resorption (beta-isomerized C-terminal telopeptide, free and total deoxypyridinoline) were higher in the current smokers than in former smokers and never-smokers. Concentrations of T, total 17beta-E2, and androstenedione were higher, whereas that of 25-hydroxyvitamin D was lower, in current smokers. When men were divided according to tertiles of body weight, increased bone resorption, decreased BMD and biochemical indexes of secondary hyperparathyroidism were observed in current smokers in the lowest tertile of body weight (<75 kg) compared with the never-smokers, but not in men in the two highest tertiles of body weight. Current smokers had a higher prevalence of vertebral deformities after adjustment for age and body weight (13% vs. 5%; P < 0.005). In summary, in moderate smokers with low body weight (<75 kg), increased bone resorption, not matched by increased bone formation, results in decreased BMD and an increased prevalence of vertebral deformities. In this group, low serum 25-hydroxyvitamin D and secondary hyperparathyroidism may explain, at least partly, the effect of tobacco on bone turnover. In former smokers, bone resorption is not increased, but BMD remains lower compared with that in never-smokers.