[Study of maternal nutrition and genetic on the foetal adiposity programming (The PREOBE study)]. / Estudio de la influencia de la nutrición y genética maternas sobre la programación del desarrollo del tejido adiposo fetal (Estudio PREOBE).

BACKGROUND: Maternal genetics and feeding before and during pregnancy, different maternal metabolic pathologies, as well as nutrient intakes of newborns in their first months of life may be involved in the obesity aetiology and its long-term consequences. The possible role of these and others factors, the mechanisms and the effects on the metabolism, and the development of this disease need further research. OBJECTIVE: To acquire more knowledge about foetal adipose tissue development and the influence of genetic, dietetic and environmental factors on the risk to suffer from obesity. METHODOLOGY: Four study groups have been established with 30 pregnant women in each one: 1) control group; 2) mothers with glucose intolerance/gestational diabetes; 3) women with low weight gain during pregnancy, and 4) women with overweight/obesity at the beginning of the pregnancy. The magnitudes to be studied are: 1) dietary intake; 2) life-style habits; 3) physical activity; 4) anthropometry and body composition; 5) haematological study; 6) biochemical study (lipid and metabolic biomarkers); 7) immune function profile related to nutritional status; 8) psychological profile; 9) genetic biomarkers, and 10) microbiological markers; all of them in relation to the development of the foetal adipose tissue in the first stages of life and the risk of suffering from obesity in the future. CONCLUSION: This project, coordinated by the Department of Paediatrics of the School of Medicine in the University of Granada, and with the collaboration of well-known and expert research groups, tries to contribute to the knowledge about the obesity aetiology in infancy and its subsequent development in later periods of life.

Effects of metabolic control on vitamin E nutritional status in children with type 1 diabetes mellitus.

OBJECTIVE: To evaluate the effects of the metabolic control of the insulin-dependent diabetes mellitus (IDDM) on the nutritional status of vitamin E. METHODS: A total of 47 children with IDDM and a mean age of 11.91+/-1.60 (mean+/-SD) years were studied, matched for age and sex with 16 healthy children (11.75+/-1.83 years). Following the American and British Associations for IDDM, we used a classification of "good", "moderate" or "poor" control of the illness: (a) good control [glycosilated haemoglobin (HbAlc) < or =7%]; (b) moderate control (7%< HbAlc < or =8%); and (c) poor control (HbAlc>8%). Serum concentrations of total cholesterol (CHOL), triglycerides (TG), high-density lipoproteins-cholesterol (HDLc), very low- and low-density lipoproteins cholesterol (VLDLc and LDLc), plasma and erythrocyte vitamin E (Vit Ep and Vit Ee) and plasma vitamin A (Vit Ap) were measured in all children. RESULTS: The children with "poor" metabolic control of the illness presented significantly higher plasma concentrations of CHOL, LDLc, VLDLc, LDLc/HDLc, (VLDL+LDL)c/HDLc, TG and Vit Ep; higher indices Vit Ep/Vit Ee and Vit Ep/Vit Ap relative to those with a "good" control of the illness. Direct-linear correlations were found between Vit Ep and the percentage of HbAlc and with the markers of atherogenic risk in the IDDM children. CONCLUSION: There is a significant rise in Vit Ep concentrations as metabolic control of the illness worsens, whereas Vit Ee remained unchanged. These results suggest that vitamin E maintains its nutritional status despite a poor control of the IDDM during childhood.

Vitamin A, retinol binding protein and lipids in type 1 diabetes mellitus.

OBJECTIVE: A case-control study was conducted to evaluate the effects of type 1 diabetes mellitus (IDDM) on plasma levels of vitamin A (retinol) and serum levels of retinol-binding protein (RBP) and their relationship with the atherogenic indicators. SUBJECTS: A total of 47 randomised IDDM children were recruited from those treated at the Endocrinology Unit of the University Hospital of Granada (Spain). They were matched for age and sex with 16 healthy children. METHODS: The following parameters were measured in all patients: serum concentrations of total cholesterol, triglycerides, high (HDL, spectrophotometry), very low (VLDL) and low (LDL) density lipoprotein cholesterol (Friedewald's formula); serum levels of RBP (kinetic nephelometry); plasma vitamin A and glycosilated haemoglobin (HbA1c; high performance chromatography). RESULTS: Higher RBP concentrations in IDDM children (P=0.05), lower retinol levels (P=0.05) and lower vitamin A/cholesterol ratio (P=0.02) than in the control group were found; no differences in the atherogenic indicators were observed. There was a correlation between RBP and vitamin A (P=0.0001). Relationships between retinol, RBP and atherogenic indicators were demonstrated in the IDDM group (A-LDLc/HDLc (P=0.01); A-(VLDL+LDL)c/HDLc (P=0.007); RBP-LDLc/HDLc (P=0.05); RBP-(VLDL+LDL)c/HDLc (P=0.02)), and an inverse relationship was found between the vitamin A/TG ratio and HbA1c (P=0.004). The children with HbA1c>8% showed increased atherogenic indicators and lower vitamin A/CHOL and vitamin A/TG ratios than those with good control of the illness. CONCLUSIONS: The IDDM children with poor metabolic control face a higher atherogenic risk and vitamin A 'relative deficiency' risk than those with good metabolic control of their illness. Relationships between retinol and RBP with atherogenic indicators were found. The results suggest that vitamin A therapeutic supplements in IDDM children may reduce or prevent atherogenic risk.

Role of intrapartum hypoxia in carnitine nutritional status during the early neonatal period.

We analyze markers of carnitine insufficiency and deficiency, lysine (LYS) and methionine (MET), in 39 neonates with intrapartum hypoxia (selection criteria: umbilical artery pH <7.20, lactate >1.8 mmol/l and PaO2 <25 mm Hg), and in 35 healthy newborn infants (control group) in the early neonatal period (1-7 days of life). Free (FC), total (TC) carnitine and acylcarnitines (AC=short-chain+long-chain acylcarnitines) were measured using a radioisotopic micromethod; LYS and MET were determined by high-pressure liquid chromatography. AC and TC plasma concentrations and AC/FC ratio were higher while FC/TC ratio was lower in the hypoxic neonates than in the control group. Hypoxic newborn infants (59%) presented "carnitine deficiency" (FC/TC <0.7) and 60% of them "carnitine insufficiency" (AC/FC ratio >0.4) vs. 31% and 28%, respectively, for the neonates of the control group (p<0.05). In the healthy neonates group, MET correlated with FC/TC and the AC/FC ratio. FC, TC, AC, AC/FC and umbilical artery pH (pHua) were inversely correlated. FC/TC and MET correlated with pHua. We conclude that: (1) an important percentage of newborn infants with intrapartum hypoxia suffer carnitine deficiency and carnitine insufficiency in the early neonatal period, related to MET plasma levels; (2) the carnitine deficiency or insufficiency in the neonate is determined by the degree of intrapartum acidosis.

Analysis of organochlorine pesticides in human milk: preliminary results.

In the face of evidence of human milk contamination by organochlorine pesticides, an analysis was performed on samples of milk obtained from healthy lactating women in the provinces of Granada and Almeria in Southern Spain. The samples were obtained by the Neonate Section of the Department of Pediatrics of Granada University Hospital (Neonatology Division) and by the Neonatal Service of Poniente Hospital in El Ejido, Almería. A liquid-liquid extraction procedure was performed. The cleaning of the sample before gas chromatography-mass spectrometry (GC-MS) used silica Sep-Pak. Among other pesticides, aldrin, dieldrin, DDT and its metabolites, lindane, methoxychlor and endosulfan were identified. The presence of these products was confirmed by mass spectrometry. The identification and quantification of these organochlorine molecules is important because they have estrogenic effects.

Melatonin's role as an anticonvulsant and neuronal protector: experimental and clinical evidence.

The pineal gland classically has been considered as a vestigial and mystic organ. In the last decades, and with the incorporation of new methodologic procedures, it could be proved that it also has physiologic actions that vary depending on the level of the phylogenetic scale. Its best-known secretion, melatonin, has been related to many different actions, such as sleep promotion, control of biologic rhythms, hormonal inhibition, and an inhibiting action on central nervous system regulation mechanisms. In animal experimentation, there are papers even accepting an anticonvulsant effect. In humans, evidence is reduced to few experiences. In addition to this clinical experience, there is other evidence that clearly relates melatonin to convulsive phenomena. This relationship must be mediated by the following mechanisms attributed to melatonin: altered brain GABAergic neurotransmission, its known interaction with benzodiazepinic brain receptors, through tryptophan metabolite activity (kynurenine, kynurenic acid), or even by its efficacy as a free-radical scavenger.

Addition of gangliosides to an adapted milk formula modifies levels of fecal Escherichia coli in preterm newborn infants.

Because some gangliosides bind bacteria, we tested the influence of supplementating an adapted milk formula with gangliosides, at a total concentration of 1.43 mg/100 kcal, on the fecal microflora of preterm infants. At all sampling times, feces from infants fed with ganglioside-supplemented formula had significantly lower relative content of Escherichia coli than feces from infants fed with control milk formula: the difference was especially significant at age 7 days postnatal < .001). At age 30 days postnatal, fecal bifidobacterial counts were higher in infants fed with ganglioside-supplemented formula (P < .05). We conclude that gangliosides at concentrations present in human milk significantly modify the fecal flora.

Some current controversies on nutritional requirements of full-term and pre-term newborn infants.

Many controversial topics have still to be resolved regarding the nutritional requirements of the newborn, and in particular of the pre-term infant. The term 'controversy' bears the connotation of prolonged dispute and such a situation has arisen for various reasons: (a) from inadequate research methodologies; (b) from the misinterpretation of, or bias within, the results of studies undertaken; (c) from not taking into account the multifactorial etiology of physiopathological situations or illnesses suffered by suckling neonates and newborn infants. Nevertheless, controversy as such is not always a negative factor, as investigation and discussion enable advances in therapeutic methods.

Nutrition and fetal growth.

Essential factors for normal fetal growth include the correct utilization by the fetus of a suitable supply of energy and plastic nutrients, together with the adequate genic expression of the factors promoting tissue growth and an optimal hormonal framework. The nutritional state and welfare of the mother, the endocrine changes experienced and the uteroplacental function have all been related to the health of the fetus and the newborn infant, premature births, fetal nutritional disorders, certain diseases and even death.

Evaluation of carnitine nutritional status in full-term newborn infants.

Carnitine supplements may be advisable not only in premature but also in artificially-fed full-term babies. The acyl-carnitine/free carnitine (AC/FC) and FC/total carnitine (FC/TC) ratios have been considered markers of "carnitine insufficiency" and "carnitine deficiency", respectively. Values of AC/FC>0.40 are considered abnormal and mean that FC has a low bioavailability to the cells and so reflects a "carnitine insufficiency". Values of FC/TC<0.7 indicate "carnitine deficiency". We analyze the validity of such ratios and the limits for them in three groups of full-term neonates (n=66): 22 breast-fed (BF), 22 with formula (F); and 22 fed with carnitine-supplemented formula. Several studies have shown the need to give supplements of carnitine to the neonate because of its "essentiality", but no one has demonstrated the adequate dosages. We therefore propose to establish new limit levels for these ratios to control carnitine nutritional status in neonates, based on the control of percentile ranges for normal BF infants (in this study: 97th percentile of AC/FC>0.83; 3rd percentile of FC/TC<0.54) and on evaluating the needs of neonates and dosages required to supplement F. The supplement of 2.2 mg of L-carnitine/100 ml in the cow's milk formula used in the present study produces a similar biochemical pattern of plasma carnitine and ACs to that observed in BF infants, together with a lower risk of developing "carnitine deficiency" or "carnitine insufficiency" than those babies fed with nonenriched F. Considering that human milk is the best source of nutrition for full-term infants, the limit established for AC/FC and FC/TC ratios at other ages of life seems to be "inadequate" for neonates.

Utility of high doses of melatonin as adjunctive anticonvulsant therapy in a child with severe myoclonic epilepsy: two years' experience.

Recent data indicate that melatonin inhibits brain glutamate receptors and nitric oxide production, thus suggesting that it may exert a neuroprotective and antiexcitotoxic effect. Melatonin has been seen to prevent seizures in several animal models and to decrease epileptic manifestations in humans. The lack of response to conventional anticonvulsants in an epileptic child led us to use melatonin in this case. A female child who began to have convulsive seizures at the age of 1.5 months and was diagnosed as having severe myoclonic epilepsy was unsuccessfully treated with different combinations of anticonvulsants, including valproic acid, phenobarbital, clonazepam, vigabatrin, lamotrigin, and clobazam. Melatonin was thus added to the treatment. Imaging studies (CT, SPECT, and MNR), EEG recordings, blood biochemical, and hematological analyses, including measures of the circadian rhythm of melatonin, were made. The child was initially treated with various anticonvulsants. Severe neurological and psychomotor deterioration combined with increased seizure activity showed a lack of response to the treatment. At the age of 29 mon the patient was in a pre-comatose stage at which time melatonin was added to treatment. After 1 month of melatonin plus phenobarbital therapy and for a year thereafter, the child's seizures were under control. On reducing the melatonin dose after this time, however, seizures resumed and the patient's condition was re-stabilized after restoring melatonin. Prior to our attempts to reduce melatonin, all analyses, including EEG recordings and SPECT, were normal. As far as the results of neurological examination are concerned, only mild hypotony without focalization remained. Changes in the therapeutic schedules during the second year of melatonin treatment, including the withdrawal of phenobarbital, did not result in the same degree of seizure control, although progressively the child became satisfactorily controlled. At the present moment the child continues to have mild hypotony and shows attention disorder and irritability. Melatonin has proven to be useful as adjunctive therapy in the clinical control of this case of severe infantile myoclonic epilepsy. The results suggest that melatonin may have a useful role in mechanisms of neuroprotection and also indicate its use in other cases of untreatable epilepsy. Further studies using more patients and placebo-treatment would be beneficial in understanding the potential use of melatonin as a co-therapy in some cases of seizures.

[The effect of melatonin as anti-convulsant and neuron protector]. / Efeto de la melatonina como anticonvulsivante y protector neuronal.

INTRODUCTION: Melatonin is the principal hormone secreted by the pineal gland. In human beings the pineal gland is found on the posterior aspect of the midbrain. Melatonin is synthesized from tryptophan following a circadian rhythm, with low levels during the day and high levels during the night. It regulates many biological processes in relation to the cycles of light and darkness. DEVELOPMENT: Its first known function was that of inducing sleep. In experimental animals its effect as a depressor of the central nervous system and its anti-convulsive action have been shown. Few studies have been done in human beings, although there is some evidence of its beneficial effect in epileptic patients, improving both the frequency of the crises and the EEG tracing. In our experience we gave melatonin to a girl with severe myoclonic epilepsy which did not respond to usual treatment, obtaining improvement in both the number of crises daily and in psycho-motor development. Several possible modes of action have been described for melatonin; increase in Gabaergic transmission at a cerebral level, where GABA is the main inhibitory neurotransmitter; interaction with benzodiazepinic cerebral receptors; it may owe its effect to the activity of its metabolites, particularly kinurenic and kinurenic acid; it may induce hormone changes in the organism. Recent studies show the marked anti-oxidant activity of melatonin. Its considerable capacity to accept free radicles resulting from biological processes has been shown and it thus acts as a cell protector. CONCLUSIONS: It seems reasonable to assume that melatonin has anticonvulsant and neuroprotector properties. Further study may define its pharmacological usefulness in these disorders.

[Pineal functioning (melatonin levels) in healthy children of different ages. An update and the value of pineal gland study in pediatrics]. / Funcionalismo pineal (tasas de melatonina) en niños sanos de diferentes edades. Actualidad e interés del estudio de la glándula pineal en pediatría.

BACKGROUND: Classically, the function of the pineal gland involved the regulation of several endocrine and non-endocrine functions, such as seasonal breeding, biological rhythm synchronization and the sleep/wake cycle. The study of the pineal gland has not a new increasing interest due to the recent discovery that melatonin is the most potent antioxidant compound known to date. MATERIAL AND METHODS: We present here the data of aMT levels (mean +/- SD, pg/ml) measured by RIA in healthy children grouped by age and time of sample extraction. The group differences are evaluated by a mean comparison test. RESULTS: The results showed that plasma levels of aMT in cord blood reflect both the aMT levels and their circadian rhythm seen in the mother, without significant differences between umbilical artery and vein. In children between 18 months and 6 years of age, aMT concentrations at 09.00 reaches a maximum of 60.8 +/- 100.58. This value significantly decreased in children between 6-8 years old (35.54 +/- 9.17, p < 0.001), with a more significant decrease in children 8-13 years old (25.28 +/- 7.16, p < 0.01). However, in children 13-15 years of age, aMT concentrations increased to 31.14 +/- 8.29 pg/ml (p < 0.01). CONCLUSION: Our data support the existence of a functional pineal gland during the neonatal period, although it lacks the rhythmic secretion of aMT. From the preschool stage, children show a significant decrease in aMT concentration, except during the pubertal period when there is a small increase in aMT levels. In this paper we also review the available information about pineal function, specifically in regards to the relationship between pineal-melatonin and CURRENT PEDIATRICS in order to better understand the infant physiology and physiopathology related to this area.

[Changes in erythrocyte rigidity and neonatal relative viscosity during the adaptation of the newborn to extrauterine life. Observations on term and premature newborns]. / Modificaciones de la rigidez eritrocitaria y viscosidad relativa neonatal durante la adaptación del recién nacido a la vida extrauterina. Consideraciones en recién nacidos a término y pretérmino.

BACKGROUND: The deformability of the red blood cell is a important factor in the blood viscosity and it is related with the blood viscosity and it is modified by the plasma biochemical characteristics and the composition of hemoglobin in the red blood cell. In this study, we want to compare the rheologic characteristics in the blood of cord umbilical in term and preterm newborns during the first 24 hours of life and we want to evaluate that hemorheologic modifications are explained because of the different gestational age. METHODS: We studied 191 newborns in our maternity from 1989 until 1990. We analyzed four groups: In the first group (n = 40) of preterm newborn (gestational age < 37 weeks); in the second group (n = 72) of term newborns (gestational age > 37 weeks); the samples were obtained from umbilical artery immediately after the umbilical cord clamp; in the third group (n = 38) of preterm newborn and the fourth group of term newborns (n = 41) was studied during 24 hours after delivery. We analyzed the plasma viscosity, the viscosity of red blood cell (RBC) content and the RBC rigidity calculated by Taylor's coefficient. RESULTS: The RBC rigidity is greater during the post-delivery period, which could be in relation with the greater values of plasma viscosity and the RBC content during the postnatal period. The comparisons between umbilical cord of term and preterm newborn they did not show differences for the RBC content viscosity and the relative viscosity. The plasma viscosity of the umbilical cord was discretely greater in the term newborn though in meaning limits statistics. In umbilical cord the hematocrit does not defer significantly between term and preterm newborns. CONCLUSIONS: Following our data we can make firm that the RBC rigidity is increased after the delivery in term and preterm newborns and the greater relative viscosity observed in newborn to term during the first life extrauterine days in related fundamentally to the corporal liquids readjustment that occurs after of delivery.

Prenatal care and prevention of preterm birth. A case-control study in southern Spain.

The value of prenatal care is controversial and difficult to establish. A national policy for improving perinatal outcomes was proposed and applied throughout Andalusia (Southern Spain) in 1984. Here we report the results of an evaluation of this health care program as regards the prevention of preterm delivery. Effectiveness of prenatal care was assessed on the basis of two case-control studies in a hospital setting: one performed before the program was implemented (1981-1982) and the second one six years after the program began (1990-1993). A total of 229 cases and 395 controls for the period 1981-1982, and 207 cases and 381 controls for 1990-1993 were selected. Prenatal care was assessed based on the number of prenatal care visits, the date of the first visit, and an American composite index adjusting for gestational age. Multiple-factor adjusted odds ratios and their 95% confidence intervals (CI) were estimated using unconditional logistic regression analysis. The use of prenatal care significantly improved across time: the proportion of women receiving no prenatal care decreased from over 30% to less than 5%, and the proportion of women starting prenatal care in the first trimester for 1990-1993 was three times greater than the figure for 1981-1982. In the 1981-1982 case-control study, the date of first visit and the composite index were shown to be unrelated to preterm birth risk; and the number of visits yielded a significant association, although no definite trend could be established. In the 1990-1993 case-control study, a clear and significant relationship was observed between the number of prenatal care visits, the trimester of the first visit, and the adequacy of care according to the composite index. This latter variable, reflecting a more stringent standard of prenatal care, was selected by a stepwise logistic regression analysis as the best predictor for preterm birth risk. The results suggest that the present Andalusian program helps prevent preterm delivery. Nonetheless, its minimum standards should be raised to further decrease preterm birth risk.

Lipoproteins in pregnant women before and during delivery: influence on neonatal haemorheology.

AIMS: To investigate whether the lipid profile of pregnant women during parturition differs from the profile at previous stages of pregnancy and to determine the effects of maternal lipid changes on fetal or neonatal haemorheology. METHODS: Sixty pregnant women were studied, divided into two groups. Group 1 contained 30 women of mean age of 27 (SD 3) years and gestational age > 38 weeks in whom delivery had not yet begun; all these pregnancies followed an uncomplicated course and there was no evidence of any fetal pathology from previous obstetric examinations. All the women reached term and birth weight was 3340 (350) g. Group 2 contained women of mean age 26 (4) years, in whom delivery was ongoing, all of whose pregnancies reached term. The following variables were determined in all cases: total cholesterol, triglycerides, high density lipoproteins (HDL), low density lipoproteins (LDL), free fatty acids and phospholipids, and apoprotein A (apo-A) and apoprotein B (apo-B). Serum and plasma viscosity was measured with a capillary viscosimeter. RESULTS: The apo-B/apo-A and HDL/apo-A ratios increased during delivery, indicating that in pregnant women these atherogenic indices are raised during delivery compared with previous gestational stages. Significant correlation coefficients were obtained between maternal lipids (triglycerides, total cholesterol, LDL, total cholesterol/HDL, and LDL/HDL) and plasma viscosity in the neonate. CONCLUSIONS: Plasma atherogenic indices increase progressively until birth. These changes have implications for neonatal haemorheology because they cause an increase in plasma viscosity.

Relationship of blood rheology to lipoprotein profile during normal pregnancies and those with intrauterine growth retardation.

AIMS: The effects on fetal growth of hyperlipidaemia in pregnancy are not well understood at present. In this study the different lipid fractions in normal pregnancies and pregnancies complicated by intrauterine growth retardation (IUGR) were determined and related to changes in plasma and serum viscosity. METHODS: Two groups of pregnant women were studied. Group 1 consisted of 35 healthy pregnant women aged between 21 and 38 years with no previous pathology and a normal pregnancy to term. Group 1 patients were studied at four periods defined at the start of the study: (1) < or = 17 weeks; (2) 18-24 weeks; (3) 25-32 weeks, (4) > or = 33 weeks. Group 2 consisted of 24 pregnant women aged between 16 and 34 years with ultrasound diagnosed IUGR confirmed after birth. Plasma lipids and plasma and serum viscosity were measured. RESULTS: Plasma triglycerides, low density lipoprotein cholesterol, and total cholesterol increased progressively throughout pregnancy, with significantly higher values after week 25. Apolipoprotein A (ApoA) and triglyceride concentrations were significantly lower in the IUGR group than in the normal group. The HDL/ApoA ratio was greater in the IUGR group than in the control group, as was the ApoB/ApoA ratio. There were no differences in the other lipids. Plasma and serum viscosity was higher in the IUGR group than in the normal group. CONCLUSIONS: Haemorheological modifications in the IUGR group are partly secondary to changes in high density lipoprotein metabolism and the competitive inhibition of fibrinolysis by ApoB, which is increased in pregnancies with IUGR. Changes in ApoA, and more specifically in the ApoB/ApoA ratio, could be good markers for the early detection of IUGR.

Light deprivation increases plasma levels of melatonin during the first 72 h of life in human infants.

The development of rhythmic melatonin secretion in full-term neonates seems to occur at about 12 weeks of age, but activity of the pineal gland from 1 to 12 weeks of age is not well documented. To determine whether the pineal gland actively secretes melatonin and reacts to photoperiodic information during this period, we analyzed 45 full-term infants exposed to continuous artificial light during 24, 48 and 72 h after birth for treatment of hyperbilirubinemia. During this light treatment, the eyes of the neonates were completely covered to avoid damage, thus the infants were under continuous light deprivation. Phototherapy significantly decreased plasma bilirubin during treatment. With regard to pineal gland activity, the shortest period of light deprivation tested, 24 h, significantly increased plasma melatonin levels from 152.66 +/- 11.57 to 244.86 +/- 19.49 ng/l (mean +/- SEM; p < 0.001). The other periods tested, 48 and 72 h of light deprivation, led to similar percentages of melatonin stimulation. These results suggest that the pineal gland of neonates, before displaying rhythmic metabolic activity, is sensitive to changes in environmental illumination, indicating maturity of some features of suprachiasmatic nuclei function.