The pattern of basal and stimulated insulin responses to intravenous glucose in first degree relatives of Type 1 (insulin-dependent) diabetic children and unrelated adults aged 5 to 50 years

Summary The pattern of insulin secretion was studied in 107 normal individuals aged 5 to 50 years. Intravenous glucose tolerance tests were performed on 64 islet-cell antibody negative siblings of diabetic children and on 43 normal adults. Puberty was staged using Tanner's criteria and subjects were grouped as follows: I — stage 1 (n=22), II — stages 2 and 3 (n=18), III — stages 4 and 5 (n=20), IV — adults >17 years (n=47). Basal and stimulated (incremental 0–10 and 10–60 min areas) insulin responses rose throughout puberty (Groups I–III), declined following puberty until the third decade (Groups III and IV) and then appeared constant thereafter. Insulin levels in the 17.6–22.5 year group were lower than in the 12.6–15 year group (p<0.01). Fasting insulin to glucose ratios and incremental 0–60 min insulin to glucose area ratios produced a similar age-related pattern indicating that changes in insulin levels were independent of glucose concentrations. Gender did not affect these changes and multiple regression analysis showed that HLA haplotype sharing did not influence insulin responses in siblings of diabetic patients. Age and pubertal status must be carefully considered when interpreting intravenous glucose tolerance tests from patients suspected of having early abnormalities of carbohydrate metabolism.     

Clinical trials of controlled-release melatonin in children with sleep-wake cycle disorders

This is the first study to examine effective doses of controlled-release (CR) melatonin in children with chronic sleep wake cycle disorders. All 42 subjects had severe neurodevelopmental difficulties. Initially, a randomized double-blinded cross-over design was used in 16 children, comparing the effectiveness of fast-release (FR) and CR melatonin. In the remainder of the patients, the CR melatonin was studied on a clinical basis. The effectiveness of treatment was assessed by sleep charts and clinical follow-up. Emphasis was placed on the judgement of the parents, who had guidance from the physicians. The average final CR melatonin dose in the 42 patients was 5.7 mg (2-12 mg). The studies showed that the FR melatonin was most effective when there was only delayed sleep onset, but CR formulations were more useful for sleep maintenance. Children appeared to require higher doses than adults.     

Thrombopoietic properties of 5-methoxytryptamine plus melatonin versus melatonin alone in the treatment of cancer-related thrombocytopenia

Recent studies have shown that the hematopoietic system is under neuroendocrine control. In particular, thrombopoiesis has been proven to be stimulated by melatonin, and the pineal indole has been shown to be effective in the treatment of thrombocytopenia resulting from different causes. At present, however, there are no data concerning the possible thrombopoietic activity of pineal indoles other than melatonin. The present study was carried out to evaluate the effect of a concomitant administration of the pineal indole 5-methoxytryptamine in patients with cancer-related thrombocytopenia who did not respond to melatonin alone. The present study included 30 patients, who were randomized to receive melatonin alone (20 mg/day orally in the evening) or melatonin plus 5-methoxytryptamine (1 mg/day orally in the early afternoon). A normalization of platelet count was achieved in 5/14 (36%) patients treated with melatonin plus 5-methoxytryptamine and in none of the patients treated with melatonin alone (P < 0.05). Moreover, mean platelet number significantly increased only in the patients treated with melatonin plus 5-methoxytryptamine. This preliminary clinical study would suggest that 5-methoxytryptamine, a pineal indole, may also exert thrombopoietic activity. Further studies, however, will be required to establish whether 5-methoxytryptamine may play a direct thrombopoietic activity, or whether it may act by improving melatonin's efficacy.     

5-Methoxypsoralen enhances plasma melatonin concentrations in the male rat: Non-noradrenergic-mediated stimulation and lack of effect in pinealectomized animals

Previous studies have shown that 8-methoxypsoralen (8-MOP) is able to enhance melatonin secretion from rat pineal glands. The effect of another psoralen, 5-methoxypsoralen (5-MOP) on plasma melatonin concentrations alone or in combination with isoproterenol (Iso, 10 mg/kg BW, i.p.) or propranolol (Prop, 20 mg/kg BW, s.c.) was studied in the rat. An increase in plasma melatonin concentrations was observed 1 h after psoralen administration and lasted 8 h. The stimulatory effect of 5-MOP on circulating melatonin concentrations was dose dependent above 5-mg/kg, BW. 5-MOP also potentiated the Iso-induced rise in plasma melatonin levels. Furthermore, Prop did not block the effect of 5-MOP, indicating that the psoralen acts independently of the noradrenergic system controlling pineal melatonin synthesis. No increase in plasma melatonin levels was observed in pinealectomized (Px) animals after injection of 5-MOP (20 mg/kg BW) or 8-MOP (20 mg/kg BW). This demonstrates that the rise in plasma melatonin concentrations observed after treatment requires the presence of the pineal gland, and that neither 5-MOP nor 8-MOP stimulates melatonin release from other structures such as the retina or Harderian gland.     

Mechanisms underlying the effects of estrogen on nocturnal melatonin synthesis in peripubertal female rats: relation to norepinephrine and adenylate cyclase

We previously reported that estrogen modulates the nocturnal synthesis of melatonin in the pineal gland of peripubertal female rats. These effects appeared to be mediated by the modulation of N-acetyltransferase (NAT) activity. The present study assessed the mechanism underlying the effects of estrogen deficiency and stimulation on pineal melatonin synthesis in peripubertal female rats. We measured the norepinephrine levels and adenylate cyclase activity in pineal gland homogenates obtained from 4-10-wk-of-age female Sprague Dawley rats at mid-dark during the daily light/dark cycle. The animals were ovariectomized and daily s.c. administration of estradiol benzoate (E2B, 1.0 microgram/d) was initiated at 4 wk of age. Pineal norepinephrine levels increased significantly from Week 3 to 4 (P < 0.0001), and remained unchanged thereafter. Neither ovariectomy nor E2B administration significantly affected norepinephrine levels. Adenylate cyclase activity in the pineal gland peaked at 4 wk in untreated (control) rats. Ovariectomy at Week 4 led to a significant increase in adenylate cyclase activity at Week 8. At Week 10, adenylate cyclase activity returned to control levels. S.c. injection of E2B suppressed the ovariectomy-induced increase in adenylate cyclase activity to the level seen in control rats. These changes in mid-dark adenylate cyclase activity resembled those previously observed with NAT activity. The results suggest that estrogen modulates adenylate cyclase activity in the pineal gland of peripubertal female rats. The inhibitory effect of estrogen on melatonin synthesis appeared to be mediated in part, by changes in the norepinephrine-induced stimulation of pineal adenylate cyclase activity.     

The seasonal interrelationship between melatonin, vasopressin, and serum osmolality in elderly subjects

Abstract: Plasma concentration of arginine vasopressin (AVP) and melatonin and serum osmolality were measured at noon and at midnight in individuals living in the northern hemisphere on March 22–23, June 13–14, September 26–27, and December 12–13 in 35 healthy volunteers (15 men and 20 women) aged 60–74 years. The nocturnal increase in melatonin was highest in the autumn and lowest in the winter in both sexes. The midnight serum osmolality level was lower in the autumn than in any other time of the year. In both the men and the women the AVP level was higher in winter than in any other season ( P < 0.01 and P < 0.0001, respectively). In men, the AVP level was higher at noon than at midnight in 49% of the investigated 24 hr periods, at the same level in 15% and lower in 36% (NS). The corresponding figures for women were 55%, 25%, and 20%, respectively ( P < 0.05). This study suggests a possible relationship between melatonin and serum osmolality.     

Controlled-release melatonin implants delay puberty in rats without altering melatonin rhythmicity

ABSTRACT: There is increasing evidence that continuous availability of melatonin via implants can produce the same physiological changes in animals as timed administration of the hormone. The mechanisms underlying this apparent contradiction are not known. In an attempt to gain further understanding of the way continuous melatonin administration affects reproductive activity, the effects of melatonin implants on gonadal development and melatonin production were investigated in rats treated neonatally with testosterone. Five-day-old male rats maintained on a 12L: 12D photoperiod were injected with 1 mg testosterone propionate to induce photo-responsiveness and implanted at 21 days of age with novel melatonin implants designed to raise the daytime blood melatonin concentration into the nighttime range, i.e., from less than 60 pM in the controls during the day to 380 ± 33 pM in the implanted rats. Following 21 days treatment, seminal vesicle and ventral prostate weights of implanted rats were significantly less than the controls (27.0 ± 1.9 vs. 18.5 ± 1.5 mg/ 100g BW (P= 0.003) and 33.8 ± 2.1 vs. 26.7 ± 2.2 mg/100g BW (P= 0.02), respectively). To determine the effect of the implants upon melatonin production, urine was collected at hourly intervals during the last four days of the experiment and the hourly 6-sulphatoxymelatonin (aMT.6S) excretion rate was determined. Rats bearing melatonin implants maintained a rhythm of aMT.6S excretion in 12L:12D, which was indistinguishable from that in the control animals except for a raised daytime excretion of the metabolite. Following one cycle of urinary aMT.6S measurements in the light/dark cycle, the animals were released into constant darkness, with the implants still in place or after their removal four hours before darkness to evaluate the characteristics of the melatonin rhythm in the absence of masking effects of the light/dark cycle. The melatonin rhythm persisted in both control and implanted rats and no differences in the onset, offset, or amplitude could be determined. The results of this study indicate that, like many other mammals, for laboratory rats controlled continuous release of melatonin can mimic the effects of short daylength or timed melatonin administration. Despite the reproductive consequences of continuous melatonin delivery, the timing of endogenous melatonin production is unaffected.     

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.     

Effect of propranolol plus exercise on melatonin and growth hormone levels in children with growth delay

The pineal gland in humans is under both alpha- and beta-adrenergic control, although it seems that beta1-adrenoceptors are mainly implicated in melatonin secretion. In the present study, we evaluated the role of beta-adrenergic innervation on melatonin production and its relation with the production of growth hormone (GH). Thirty-four children (15 males and 19 females, mean age 10.5 +/- 0.8 years) from the University of Granada Hospital were studied. The children were included in a protocol for the evaluation of growth delay using the propranolol + exercise test. This standardized test allowed us to study simultaneously the role of an unspecific beta-adrenergic blocker such as propranolol and of an adrenergic stimulus such as exercise on the pineal production of melatonin. Changes in plasma levels of melatonin and GH were determined at basal, 120 and 140 min after the test was applied. Hormonal determinations were carried out by commercial radioimmunoassay kits previously standardized in our laboratory. The results show a significant decrease in plasma melatonin levels at 120 and 140 min after the test (P < 0.05), whereas GH levels increased significantly at 140 min (P < 0.001). The decrease of melatonin levels was a consequence of the test, since in a control group, the circadian decay of melatonin was significantly less pronounced (P < 0.05). These data suggest an inverse relationship between melatonin and GH after the propranolol + exercise test, and the reduction in melatonin may be related to its depletion by exercise-induced oxidative stress.     

Long-term effectiveness outcome of melatonin therapy in children with treatment-resistant circadian rhythm sleep disorders

Abstract:  To date, there have been no prospective long-term studies of melatonin therapy in children. We report here data from a prospective follow-up study of 44 children with neurodevelopmental disabilities and treatment-resistant circadian rhythm sleep disorders (CRSD) who had participated in a placebo controlled, double blind cross-over trial of sustained-release melatonin. The follow-up study involved a structured telephone interview of caregivers every 3 months for upto 3.8 yr. The caregivers provided ratings of satisfaction, adverse effects, benefits, persistence with treatment and additional medications. Changes in melatonin dose were recorded. Open ended questions were included to capture caregivers' impressions and comments concerning melatonin therapy. Adverse reaction to melatonin therapy and development of tolerance were not evident. Better sleep was associated with reported improvement in health, behavior and learning. At the end of the study, the parental comments regarding the effectiveness of long-term melatonin therapy were highly positive. Parents whose children had sleep maintenance difficulties expressed a wish to have a commercially available controlled-release melatonin product which would promote sleep for 8–10 hr. Hypnotics for children with CRSD should be considered a second line of treatment for those who fail to respond to sleep hygiene and/or melatonin.     

Effect of clonidine on plasma ACTH, cortisol and melatonin in children

An interaction between melatonin and adrenocorticotropin (ACTH) seems to occur in humans and both hormones respond to beta-adrenergic stimulation. As in lower animal species, human pineal gland also contains alpha2-adrenergic receptors as does the hypothalamus-pituitary axis. In this study the response of the pineal gland and of the hypothalamus-pituitary-adrenal axis to alpha2-adrenergic stimulation was assessed. Twenty-nine children (21 males, mean age 11.2 +/- 0.6 yr and eight females, mean age 9.1 +/- 1.1 yr) from the University of Granada Hospital were studied. The children were diagnosed as having growth problems but with a normal response of growth hormone (GH) to clonidine test. Changes in plasma levels of ACTH, cortisol and melatonin were evaluated in these children after oral administration of the alpha2-adrenoceptor agonist clonidine (100 microg/m2) or a placebo. Plasma ACTH, cortisol and melatonin were measured before (basal) and at 30, 60 and 90 min after oral clonidine or placebo administration. Hormonal determinations were carried out by commercial radioimmunoassay kits, previously standardised in our laboratory. The results show a significant decrease in plasma ACTH, cortisol and melatonin 30 min after clonidine administration (P < 0.001), reaching lowest values at 90 min after the drug was administered. The reduction in the levels of these hormones is independent of their normal circadian decay since the control group showed a significantly different pattern of behaviour. These data support the existence of an inhibitory alpha2-adrenergic influence on both the pineal gland and the hypothalamus-pituitary-adrenal in children and further support the presence of alpha2-adrenoceptors in the human pineal gland.     

上海市区学龄儿童尿碘水平调查

应用温和酸消化法对上海市区１４２７名五年级学生进行了尿碘测定。结果显示，尿碘中位数为７１．２７μｇ／Ｌ尿碘值〉１００μｇ／Ｌ者所占比例为３１．８９％。男女学生的尿碘中位数分别为７８．４１μｇ／Ｌ和６３．８７Ｌ，有非常的差异。１０个市区学龄儿童尿碘中位数范围为６０．８９－１０．１５μｇ／Ｌ；按ＷＨＯ／ＵＮＩＣＥＦ／ＩＣＣＩＤＤ的判别标准评估本市有９／１０的区为轻度缺碘地区。此外，午后收集尿样的碘浓度     

Melatonin biosynthesis in plants: multiple pathways catalyze tryptophan to melatonin in the cytoplasm or chloroplasts

Melatonin is an animal hormone as well as a signaling molecule in plants. It was first identified in plants in 1995, and almost all enzymes responsible for melatonin biosynthesis had already been characterized in these species. Melatonin biosynthesis from tryptophan requires four‐step reactions. However, six genes, that is, TDC, TPH, T5H, SNAT, ASMT, and COMT, have been implicated in the synthesis of melatonin in plants, suggesting the presence of multiple pathways. Two major pathways have been proposed based on the enzyme kinetics: One is the tryptophan/tryptamine/serotonin/N‐acetylserotonin/melatonin pathway, which may occur under normal growth conditions; the other is the tryptophan/tryptamine/serotonin/5‐methoxytryptamine/melatonin pathway, which may occur when plants produce large amounts of serotonin, for example, upon senescence. The melatonin biosynthetic capacity associated with conversion of tryptophan to serotonin is much higher than that associated with conversion of serotonin to melatonin, which yields a low level of melatonin synthesis in plants. Many melatonin intermediates are produced in various subcellular compartments, such as the cytoplasm, endoplasmic reticulum, and chloroplasts, which either facilitates or impedes the subsequent enzymatic steps. Depending on the pathways, the final subcellular sites of melatonin synthesis vary at either the cytoplasm or chloroplasts, which may differentially affect the mode of action of melatonin in plants.     

我国中小学生风湿热流行状况的调查

目的确立我国中小学生初发风湿热（ＡＲＦ）系列发病率及流行特点。方法用发病监测方法，于１９９２～１９９５年监测我国东、南、西、北、中五省易感人群２２万５～１８岁中小学生ＡＲＦ发病状况。结果我国ＡＲＦ年发病率为２００５／１０万，复发率与死亡率均为零。ＡＲＦ以９～１７岁多见；秋冬春季较多；地区差异大，四川最高，广东最低，南方高于北方；农村多于城市。结论我国风湿热发病率仍较高，个别地区为高发区。控制我国风湿热根本途径是开展群体性风湿热一级预防。防治重点是农村。     

Endoscopic findings in children with obstructive sleep apnea: effects of age and hypotonia

Obstructive sleep apnea (OSA) syndrome is a common disorder among children and is often associated with significant morbidity. The causes of OSA are related to either fixed upper airway abnormalities such as adenotonsillar hypertrophy, or dynamic airway abnormalities such as laryngomalacia and pharyngeal wall collapse. The aim of the present study was to determine the prevalence of dynamic upper airway abnormalities, based on endoscopic findings, in normotonic and hypotonic children with polysomnographically documented OSA. The records of 39 consecutive children with OSA who underwent bronchoscopy (22 with normal tone, and 17 with hypotonia) were reviewed. The prevalence of dynamic defects among children with normal tone decreased with age. All 7 patients less than 1 year old had dynamic abnormalities (isolated or combined fixed/dynamic), compared to only 66% (6/9) of patients between 1-2 years old, and 17% (1/6) of children more than 2 years old. In contrast, dynamic abnormalities were very common among hypotonic children, independent of age. Since children with dynamic defects are less likely to respond to surgical treatments, it would be appropriate to identify these children prior to any intervention. Due to the higher frequency of dynamic defects in both infants (< 1 year) and hypotonic children, it may be appropriate to include endoscopy as part of the diagnostic evaluation of OSA in these subgroups.     

A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities

The purpose of this study was to determine the efficacy of controlled-release (CR) melatonin in the treatment of delayed sleep phase syndrome and impaired sleep maintenance of children with neurodevelopmental disabilities including autistic spectrum disorders. A randomized double-blind, placebo-controlled crossover trial of CR melatonin (5 mg) followed by a 3-month open-label study was conducted during which the dose was gradually increased until the therapy showed optimal beneficial effects. Sleep characteristics were measured by caregiver who completed somnologs and wrist actigraphs. Clinician rating of severity of the sleep disorder and improvement from baseline, along with caregiver ratings of global functioning and family stress were also obtained. Fifty-one children (age range 2-18 years) who did not respond to sleep hygiene intervention were enrolled. Fifty patients completed the crossover trial and 47 completed the open-label phase. Recordings of total night-time sleep and sleep latency showed significant improvement of approximately 30 min. Similarly, significant improvement was observed in clinician and parent ratings. There was additional improvement in the open-label somnolog measures of sleep efficiency and the longest sleep episode in the open-label phase. Overall, the therapy improved the sleep of 47 children and was effective in reducing family stress. Children with neurodevelopmental disabilities, who had treatment resistant chronic delayed sleep phase syndrome and impaired sleep maintenance, showed improvement in melatonin therapy.     

老年人血清褪黑素水平变化的探讨

目的　探讨老年人血清褪黑素 (松果腺主要在夜间分泌的一种吲哚胺类激素 )水平变化。方法　用放射免疫法检测了 14 4例济南市人 (31～ 110岁 )夜间 (0 2 :0 0 )及白天 (0 8:0 0 )血清褪黑素水平。结果　夜间血清褪黑素水平随着年龄增长呈下降趋势 ,与成年人组比较 70岁组和 >80岁组的褪黑素水平明显降低 (P <0 .0 1) ;女性的褪黑素水平略高于男性 (P <0 .0 5 ) ;健康老年人与老年患者 (主要为心血管系统疾病 )比较褪黑素水平差异无显著性意义(P >0 .0 5 ) ,年龄、性别和健康状况对白天血清褪黑素水平无明显影响。结论　年龄与性别是影响老年人夜间血清褪黑素水平的主要因素 ,研究结果未能显示健康状况对老年人血清褪黑素水平的影响。