Lower plasma melatonin levels in non-hypoxic premature newborns associated with neonatal pain.

We analyzed plasma melatonin levels in different groups of preterm newborns without hypoxia and their relationship with several perinatal variables like gestational age or neonatal pain. Prospective cohort study of preterm newborns (PTNB) without perinatal hypoxia, Apgar > 6 at 5 min, and oxygen needs on the third day of life. We compared melatonin levels at day 3 of life in different groups of non-hypoxic preterm infants (Student's t-tests, Mann-Whitney U, and chi2) and analyzed the relationship of melatonin with GA, birth weight, neonatal pain (Premature Infant Pain Profile (PIPP) scale), caffeine treatment, parenteral nutrition, or the development of free radical diseases (correlation study, linear regression) and factors associated with moderate/intense pain and free radical diseases (logistic regression analysis). Sixty-one preterm infants with gestational age (GA) of 30.7 ± 2.0 weeks with no oxygen requirements at day 3 of life were studied with plasma melatonin levels of 33.8 ± 12.01 pg/ml. Preterm infants weighing < 1250 g at birth had lower plasma melatonin levels (p = 0.05). Preterm infants with moderate or severe pain (PPIPP > 5) have lower melatonin levels (p = 0.01), and being preterm with PIPP > 5 is associated with lower plasma melatonin levels (p = 0.03). Being very preterm (GA < 32 GS), having low weight for gestational age (LWGA), receiving caffeine treatment, or requiring parenteral nutrition did not modify melatonin levels in non-hypoxic preterm infants (p = NS). Melatonin on day 3 of life in non-hypoxic preterm infants is not associated with later development of free radical diseases (BPD, sepsis, ROP, HIV, NEC). CONCLUSION: We observed that preterm infants with moderate to severe pain have lower melatonin levels. These findings are relevant because they reinforce the findings of other authors that melatonin supplementation decreases pain and oxidative stress in painful procedures in premature infants. Further studies are needed to evaluate whether melatonin could be used as an analgesic in painful procedures in preterm infants. TRIAL REGISTRATION: Trial registration was not required since this was an observational study. WHAT IS KNOWN: • Melatonin is a potent antioxidant and free radical scavenger in newborns under stress conditions: hypoxia, acidosis, hypotension, painful procedures, or parenteral nutrition. • Pain stimulates the production of melatonin. • Various studies conclude that melatonin administration decreases pain during the neonatal period. WHAT IS NEW: • Non-hypoxic preterm infants with moderate to severe pain (PIPP>5) have lower levels of melatonin. • Administration of caffeine and treatment with parenteral nutrition do not modify melatonin levels in non-hypoxic preterm infants.

Interstitial Cells of Cajal and Enteric Nervous System in Gastrointestinal and Neurological Pathology, Relation to Oxidative Stress.

The enteric nervous system (ENS) is organized into two plexuses-submucosal and myenteric-which regulate smooth muscle contraction, secretion, and blood flow along the gastrointestinal tract under the influence of the rest of the autonomic nervous system (ANS). Interstitial cells of Cajal (ICCs) are mainly located in the submucosa between the two muscle layers and at the intramuscular level. They communicate with neurons of the enteric nerve plexuses and smooth muscle fibers and generate slow waves that contribute to the control of gastrointestinal motility. They are also involved in enteric neurotransmission and exhibit mechanoreceptor activity. A close relationship appears to exist between oxidative stress and gastrointestinal diseases, in which ICCs can play a prominent role. Thus, gastrointestinal motility disorders in patients with neurological diseases may have a common ENS and central nervous system (CNS) nexus. In fact, the deleterious effects of free radicals could affect the fine interactions between ICCs and the ENS, as well as between the ENS and the CNS. In this review, we discuss possible disturbances in enteric neurotransmission and ICC function that may cause anomalous motility in the gut.

Early-life fecal microbiome and metabolome dynamics in response to an intervention with infant formula containing specific prebiotics and postbiotics.

This study examined fecal metabolome dynamics to gain greater functional insights into the interactions between nutrition and the activity of the developing gut microbiota in healthy term-born infants. The fecal samples used here originate from a randomized, controlled, double-blind clinical study that assessed the efficacy of infant formula with prebiotics and postbiotics (experimental arm) compared with a standard infant formula (control arm). A group of exclusively breast-fed term infants was used as a reference arm. First, conventional targeted physiological and microbial measurements were performed, which showed differences in fecal Bifidobacterium levels and corresponding activity (e.g., lactate levels). Next, the overall fecal microbiota composition was determined by 16S rRNA gene amplicon sequencing. The microbiota composition profiles showed several bacterial groups in the experimental arm to be significantly different from the control arm and mostly closer to the levels observed in the reference arm. Finally, we applied an untargeted UPLC-MS/MS approach to examine changes in the fecal metabolome. Fecal metabolome profiles showed the most distinct separation, up to 404 significantly different metabolites, between the study arms. Our data reveal that infant formula with specific prebiotics and postbiotics may trigger responses in the intestinal microbiota composition that brings the ensuing fecal metabolite profile of formula-fed infants closer toward those observed in breast-fed infants. Furthermore, our results demonstrate a clear need for establishing an infant gut metabolome reference database to translate these metabolite profile dynamics into functional and physiologically relevant responses.NEW & NOTEWORTHY Untargeted metabolomics techniques can provide a "snapshot" of an ecosystem in response to environmental stimuli, such as nutritional interventions. Our analyses of fecal samples from infants demonstrate the potential of phenotyping by metabolomics while deciphering the complex interactions of early-life nutrition and gut microbiome development.

Protective Effect of Melatonin Administration against SARS-CoV-2 Infection: A Systematic Review.

INTRODUCTION: according to the World Health Organization (WHO), COVID-19 is an infectious disease caused by the SARS-CoV-2 virus, responsible for an increasing number of cases and deaths. From a preventive and therapeutic point of view, there are two concerns that affect institutions and healthcare professionals: global immunization (which is still far from being achieved) and the availability of drugs capable of preventing its consequences in the infected patient. In this sense, the role that melatonin can play is has been assessed in the recent literature. Justification and Objectives: the serious health, social and economic consequences of COVID-19 have forced an urgent search for preventive methods, such as vaccines, among others, and therapeutic methods that could be alternatives to the drugs currently used. In this sense, it must be accepted that one of the most recommended has been the administration of melatonin. The present study proposes to carry out a systematic review of its possible role in the treatment and/or prevention of COVID-19. Material and methods: a systematic review of the literature related to the prevention of COVID-19 through the administration of melatonin was carried out, following the sequence proposed by the Prisma Declaration regarding the identification and selection of documents, using the specialized health databases Trip Medical Database, Cochrane Library, PubMed, Medline Plus, BVS, Cuiden and generic databases such as Dialnet, Web of Science and Google Scholar for their retrieval. Appropriate inclusion and exclusion criteria are described for the articles assessed. The main limitation of the study has been the scarcity of works and the lack of defining a specific protocol in terms of dosage and administration schedule. Results: once the selection process was completed, and after an in-depth critical analysis, 197 papers were selected, and 40 of them were finally used. The most relevant results were: (1) melatonin prevents SARS-CoV-2 infection, (2) although much remains to be clarified, at high doses, it seems to have a coadjuvant therapeutic effect in the treatment of SARS-CoV-2 infection and (3) melatonin is effective against SARS-CoV-2 infection. Discussion: until group immunization is achieved in the population, it seems clear that we must continue to treat patients with SARS-CoV-2 infection, and, in the absence of a specific and effective antiviral therapy, it is advisable to continue researching and providing drugs that demonstrate validity based on the scientific evidence. In this regard, we believe that the available studies recommend the administration of melatonin for its anti-inflammatory, antioxidant, immunomodulatory, sleep-inducing, CD147, Mpro, p65 and MMP9 protein suppressing, nephrotoxicity-reducing and highly effective and safe effects. Conclusions: (1) melatonin has anti-inflammatory, antioxidant, immunomodulatory, and Mpro and MMP9 protein-inhibitory activity. (2) It has been shown to have a wide margin of safety. (3) The contributions reviewed make it an effective therapeutic alternative in the treatment of SARS-CoV-2 infection. (4) Further clinical trials are recommended to clearly define the administration protocol.

Hypothermia Plus Melatonin in Asphyctic Newborns: A Randomized-Controlled Pilot Study.

OBJECTIVES: To investigate the effect of adding melatonin to hypothermia treatment on neurodevelopmental outcomes in asphyctic newborns. DESIGN: Pilot multicenter, randomized, controlled, double-blind clinical trial. Statistical comparison of results obtained in two intervention arms: hypothermia plus placebo and hypothermia plus melatonin. SETTING: Level 3 neonatal ICU. PATIENTS: Twenty-five newborns were recruited. INTERVENTIONS: The hypothermia plus melatonin patients received a daily dose of IV melatonin, 5 mg per kg body weight, for 3 days. General laboratory variables were measured both at neonatal ICU admission and after intervention. All infants were studied with amplitude-integrated electroencephalography and brain MRI within the first week of life. The neurodevelopmental Bayley III test, the Gross Motor Function Classification System, and the Tardieu scale were applied at the ages of 6 and 18 months. MEASUREMENTS AND MAIN RESULTS: Clinical characteristics, laboratory evaluations, MRI findings, and amplitude-integrated electroencephalography background did not differ between the treatment groups. The newborns in the hypothermia plus melatonin group achieved a significantly higher composite score for the cognitive section of the Bayley III test at 18 months old, with respect to the hypothermia plus placebo group (p = 0.05). There were no differences between the groups according to the Gross Motor Function Classification System and Tardieu motor assessment scales. CONCLUSIONS: The early addition of IV melatonin to asphyctic neonates is feasible and may improve long-term neurodevelopment. To our knowledge, this is the first clinical trial to analyze the administration of IV melatonin as an adjuvant therapy to therapeutic hypothermia.

Accommodative response in children with attention deficit hyperactivity disorder (ADHD): the influence of accommodation stimulus and medication.

BACKGROUND: There are claims that ocular accommodation differs in children with attention deficit hyperactivity disorder (ADHD) compared to typically developing children. We examined whether the accommodation response in ADHD children is influenced by changing the stimulus to accommodation in an attempt modify the level of attentional engagement or by medication for the condition. METHODS: We measured the accommodative response and pupil diameter using a binocular, open-field autorefractor in non-medicated and medicated children with ADHD (n = 22, mean age = 10.1 ± 2.4 years; n = 19; mean age = 11.0 ± 3.8 years; respectively) and in an age-matched control group (n = 22; mean age = 10.6 ± 1.9 years) while participants were asked to maintain focus on (i) a high-contrast Maltese cross, (ii) a frame of a cartoon movie (picture) and (iii) a cartoon movie chosen by the participant. Each stimulus was viewed for 180 s from a distance of 25 cm, and the order of presentation was randomised. RESULTS: Greater lags of accommodation were present in the non-medicated ADHD in comparison to controls (p = 0.023, lags of 1.10 ± 0.56 D and 0.72 ± 0.57 D, respectively). No statistically significant difference in the mean accommodative lag was observed between medicated ADHD children (lag of 1.00 ± 0.44D) and controls (p = 0.104) or between medicated and non-medicated children with ADHD (p = 0.504). The visual stimulus did not influence the lag of accommodation (p = 0.491), and there were no significant group-by-stimulus interactions (p = 0.935). The variability of accommodation differed depending on the visual stimulus, with higher variability for the picture condition compared to the cartoon-movie (p < 0.001) and the Maltese cross (p = 0.006). In addition, the variability yielded statistically significant difference for the main effect of time-on-task (p = 0.027), exhibiting a higher variability over time. However, no group differences in accommodation variability were observed (p = 0.935). CONCLUSIONS: Children with ADHD have a reduced accommodative response, which is not influenced by the stimulus to accommodation. There is no marked effect of medication for ADHD on accommodation accuracy.

Children with Attention-deficit/Hyperactivity Disorder Show an Altered Eye Movement Pattern during Reading.

SIGNIFICANCE: Attention-deficit/hyperactivity disorder (ADHD) is characterized by oculomotor abnormalities. However, the eye movement pattern of children with ADHD during reading has yet to be fully determined. This investigation provides novel insights into the altered eye movement pattern during oral reading of nonmedicated children with pure ADHD in comparison with age-matched controls. PURPOSE: The purpose of this study was to objectively compare the eye movement pattern during oral reading in a group of nonmedicated children with pure ADHD and an age-matched control group. METHODS: Forty-one children, 21 children with pure ADHD (9.3 ± 2.2 years, 15 boys) and 20 control children (9.3 ± 2.5 years, 10 boys), orally read a standardized text according to their age while the eye movement pattern was objectively recorded using the Visagraph Eye Movement recording system. RESULTS: The Bayesian statistical analyses revealed that children with ADHD exhibited a significantly higher number of fixations (Bayes factor 10 [BF10] = 3.39), regressions (BF10 = 9.97), saccades in return sweeps (BF10 = 4.63), and anomalies of fixations and regressions (BF10 = 3.66) compared with controls. In addition, children with ADHD significantly showed longer reading times (BF10 = 31.29), as well as lower reading rate (BF10 = 156.74) and grade-level equivalent (BF10 = 168.24) in comparison with controls. CONCLUSIONS: Our data showed that the nonmedicated children with pure ADHD have an altered eye movement pattern during oral reading when compared with controls, which cannot be attributable to any comorbid condition. The present outcomes may help to understand the link between ADHD and reading performance and design the most pertinent strategies to enhance the reading skills of this population.

Visual Perceptual Skills in Attention-deficit/Hyperactivity Disorder Children: The Mediating Role of Comorbidities.

SIGNIFICANCE: Attention-deficit/hyperactivity disorder (ADHD) has been commonly associated with alterations in visual perception. However, the individual behavior of visual perceptual skills and its relationship with different comorbidities remain unknown. PURPOSE: The purpose of this study was to examine whether visual perceptual skills are impaired in children with ADHD, as well as to test the possible mediating role of comorbidities. METHODS: Thirty-five nonmedicated ADHD (20 pure and 15 with comorbidities) and 35 age-matched controls completed the performance-based Test of Visual Perceptual Skills. RESULTS: The analysis between total ADHD and controls favored the alternative hypothesis (greater values for children with ADHD) for visual memory, spatial relationships, sequential memory, and all the composite measures (Bayes factor [BF] range, 4.26 to 366.85). The analysis between pure ADHD and controls showed that data are more likely under the alternative hypothesis for spatial relationships, sequential memory, overall, basic, and sequencing (BF range, 3.82 to 21.71), whereas the comparison between ADHD with comorbidities and controls additionally favored the alternative hypothesis for visual discrimination (BF = 5.37). Lastly, data from the comparison between pure ADHD and ADHD with comorbidities were insensitive for favoring the null or alternative hypotheses in any subtest or composite scaled score (BF range, 0.33 to 0.66). CONCLUSIONS: Our results suggest that some specific patterns of visual perception are altered in ADHD, especially for the total ADHD group. The current findings also evidence that comorbidities play an important role in the association between ADHD and visual perceptual skills. Future studies should address the mediating role of each specific type of comorbidity.

Early monitoring of fatty acid profile in children with attention deficit and/or hyperactivity disorder under treatment with omega-3 polyunsaturated fatty acids.

BACKGROUND: Cognitive effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) might make them helpful in attention deficit/hyperactivity disorder (ADHD). However, the results derived from supplementation studies in children depend on the respective combinations and the study period. We aimed to investigate the serum fatty acid profile, attention scores and the tolerability in a group of ADHD children after receiving methylphenidate (MPH) and ω-3 PUFAs for 1 month. METHODS: A combination of MPH (1 mg/kg/day) and eicosapentaenoic (EPA, 70 mg/day) + docosahexaenoic acids (DHA, 250 mg/day) was administered to 40 ADHD children (7-15 years). An analysis of serum fatty acids by gas chromatography and an assessment of attention by using the Magallanes Scale of Visual Attention (MSVA) were carried out before and after 1 month of treatment. RESULTS: Our data revealed significant decreases of several ω-6 PUFAs, like arachidonic acid (P<0.0259). EPA and DHA concentrations increased by 27% and 3% respectively, and the ω-6/ω-3 index slightly decreased. The quality of attention significantly increased (P<0.026) and an improvement of ADHD core symptoms was reported both by parents and by teachers. No severe side effects occurred. CONCLUSIONS: Results demonstrate that the combination of MPH and EPA+DHA at the tested doses has positive clinical effects and an adequate safety profile. Therefore, our study suggests that ω-3 PUFAs may represent a feasible and a safe adjuvant therapy in children with ADHD and might enhance the effects of MPH. Further long-term follow-up studies are required to confirm these initial findings.

Attention-deficit/hyperactivity disorder children exhibit an impaired accommodative response.

PURPOSE: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common paediatric neurobehavioural disorders causing multiple functional impairments in children. Based on the relationship between the neural system that controls attention and ocular dynamics, the present study compares the magnitude and variability of accommodation between a group of non-medicated ADHD children and an age-matched control group. METHODS: The magnitude and variability of the accommodative response were objectively measured in 36 children using the WAM-5500 autorefractometer for 90 consecutive seconds at three static viewing distances (500, 40, and 20 cm). Participants were divided into ADHD (n = 18) or control (n = 18) groups based on clinically validated criteria. RESULTS: Children with ADHD exhibited higher lags of accommodation (p = 0.024), increasing at closer viewing distances, in comparison to the control group. Marginal statistical differences were found for the variability of accommodation (p = 0.066), with the ADHD group showing a trend towards higher variability. Our analysis showed that the magnitude and variability of accommodation did not vary over time between groups (p > 0.05). CONCLUSIONS: Our data suggest that children with ADHD have a less accurate accommodative response. These results provide a new ocular index that could help to clarify the relationship between accommodative response and attentional deficits, which could have a direct impact on the academic, cognitive, and visual performance of ADHD children.

Prevention of syncytial respiratory virus infection with palivizumab: descriptive and comparative analysis after 12 years of use.

BACKGROUND: The use of palivizumab has been recommended to prevent syncytial respiratory virus (SRV) infection in vulnerable children. METHODS: We performed a retrospective study of hospital admissions for bronchiolitis from 2000 to 2012 in the context of a prevention study with palivizumab in at-risk newborns. RESULTS: A total of 952 children (59.5% males) were admitted due to bronchiolitis. Admissions occurred in younger children in the SRV+ cases compared to the SRV- cases (P<0.001). Additionally, 641 children were treated with Palivizumab at our service. Sixty of these children (9.8%) were admitted due to bronchiolitis and SRV was detected in 22 of them (3.4%). Fifty (7.8%) had underlying diseases, 6 (0.9%) presented with a history of perinatal infection and 20 (3.12%) had been part of a multiple birth. The treated children with some additional risk factor presented a greater risk of admission due to bronchiolitis (OR=1.99, P=0.045); however, this was not observed for admissions due to SRV (P=0.945). CONCLUSIONS: Children treated with Palivizumab showed a lower rate of SRV infection, despite having more risk factors associated with a higher risk of infection or complications.

Melatonin Treatment Reduces Oxidative Damage and Normalizes Plasma Pro-Inflammatory Cytokines in Patients Suffering from Charcot-Marie-Tooth Neuropathy: A Pilot Study in Three Children.

Charcot-Marie-Tooth neuropathy (CMT) is a motor and sensory neuropathy comprising a heterogeneous group of inherited diseases. The CMT1A phenotype is predominant in the 70% of CMT patients, with nerve conduction velocity reduction and hypertrophic demyelination. These patients have elevated oxidative stress and chronic inflammation. Currently, there is no effective cure for CMT; herein, we investigated whether melatonin treatment may reduce the inflammatory and oxidative damage in CMT1A patients. Three patients, aged 8-10 years, were treated with melatonin (60 mg at 21:00 h plus 10 mg at 09:00 h), and plasma levels of lipid peroxidation (LPO), nitrites (NOx), IL-1ß, IL-2, IL-6, TNF-α, INF-γ, oxidized to reduced glutathione (GSSG/GSH) ratio, and the activities of superoxide dismutase (SOD), glutathione-S transferase (GST), glutathione peroxidase (GPx), and reductase (GRd), were determined in erythrocytes at 3 and 6 months of treatment. Healthy age- and sex-matched subjects were used as controls. The results showed increased activities of SOD, GST, GPx, and GRd in CMT1A patients, which were reduced at 3 and 6 months of treatment. The GSSG/GSH ratio significantly increased in the patients, returning to control values after melatonin treatment. The inflammatory process was confirmed by the elevation of all proinflammatory cytokines measured, which were also normalized by melatonin. LPO and NOx, which also were elevated in the patients, were normalized by melatonin. The results document beneficial effects of the use of melatonin in CMT1A patients to reduce the hyperoxidative and inflammatory condition, which may correlate with a reduction of the degenerative process.

Methylphenidate ameliorates depressive comorbidity in ADHD children without any modification on differences in serum melatonin concentration between ADHD subtypes.

UNLABELLED: The vast majority of Attention-deficit/hyperactivity disorder (ADHD) patients have other associated pathologies, with depressive symptoms as one of the most prevalent. Among the mediators that may participate in ADHD, melatonin is thought to regulate circadian rhythms, neurological function and stress response. To determine (1) the serum baseline daily variations and nocturnal excretion of melatonin in ADHD subtypes and (2) the effect of chronic administration of methylphenidate, as well as the effects on symptomatology, 136 children with ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision: DSM-IV-TR criteria) were divided into subgroups using the "Children's Depression Inventory" (CDI). Blood samples were drawn at 20:00 and 09:00 h, and urine was collected between 21:00 and 09:00 h, at inclusion and after 4.61 ± 2.29 months of treatment. Melatonin and its urine metabolite were measured by radioimmunoassay RIA. Factorial analysis was performed using STATA 12.0. Melatonin was higher predominantly in hyperactive-impulsive/conduct disordered children (PHI/CD) of the ADHD subtype, without the influence of comorbid depressive symptoms. Methylphenidate ameliorated this comorbidity without induction of any changes in the serum melatonin profile, but treatment with it was associated with a decrease in 6-s-melatonin excretion in both ADHD subtypes. CONCLUSIONS: In untreated children, partial homeostatic restoration of disrupted neuroendocrine equilibrium most likely led to an increased serum melatonin in PHI/CD children. A differential cerebral melatonin metabolization after methylphenidate may underlie some of the clinical benefit.

Is S100B Involved in Attention-Deficit/Hyperactivity Disorder (ADHD)? Comparisons with Controls and Changes Following a Triple Therapy Containing Methylphenidate, Melatonin and ω-3 PUFAs.

BACKGROUND: Increasing evidence supports a neuroinflammatory basis in ADHD damaging glial function and thereby altering dopaminergic (DA) neurotransmission. Previous studies focusing on the S100B protein as a marker of glial function have shown contradictory results. We conducted a clinical trial to investigate differences in S100B levels between ADHD patients and controls, as well as observe gradual changes in S100B concentrations after a triple therapy (TT) containing methylphenidate (MPH), melatonin (aMT) and omega-3 fatty acids (ω-3 PUFAs). METHODS: 62 medication-naïve children with ADHD (ADHD-G) and 65 healthy controls (C-G) were recruited. Serum S100B was measured at baseline (T0) in ADHD-G/C-G, and three (T3) and six months (T6) after starting TT in the ADHD-G, together with attention scores. RESULTS: A significant increase in S100B was observed in the ADHD-G vs. C-G. In the ADHD-G, significantly higher S100B values were observed for comparisons between T0-T3 and between T0-T6, accompanied by a significant improvement in attention scores for the same timepoint comparisons. No significant differences were found for S100B between T3-T6. CONCLUSION: Our results agree with the hypothesis of glial damage in ADHD. Further studies on the link between DA and S100B are required to explain the transient increase in S100B following TT.

Low Doses of Melatonin to Improve Sleep in Children with ADHD: An Open-Label Trial.

OBJECTIVE: Only a few studies assessing the sleep effects of low doses of melatonin (aMT) have been performed in the past, most of them in adults, and only one in subjects with attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to provide evidence of the changes induced by aMT doses as low as 1 mg in the sleep pattern of pediatric patients with ADHD under treatment with methylphenidate (MPH). METHODS: Children and adolescents (7-15 years) with ADHD who were receiving extended-release MPH were recruited. A seven-week sleep diary was collected prior to starting a four-week treatment with 1 mg of aMT (30 min before bedtime). Seven-day actigraphic assessments of sleep were performed before and after treatment. RESULTS: Twenty-seven patients (17 males, 62.96%) participated in the study, who had been receiving MPH for 1.57 (1.11) months. A significant increase in sleep duration (TST) was observed after one month of treatment (463 (49) min to 485 (41) min; p < 0.040), with nonsignificant improvements in sleep-onset latency (SOL), nocturnal awakenings, or sleep efficiency. Only minor adverse effects were reported. CONCLUSION: Low doses of melatonin (1 mg) are able to increase TST in children and adolescents with ADHD receiving treatment with psychostimulants, with an adequate tolerability profile. Further placebo-controlled trials adjusting the time of aMT administration to the individual circadian profile should explore the effects of low doses of this hormone to shorten SOL in this population of patients.

Dose-Dependent Effect of Melatonin on BAT Thermogenesis in Zücker Diabetic Fatty Rat: Future Clinical Implications for Obesity.

Experimental data have revealed that melatonin at high doses reduced obesity and improved metabolic outcomes in experimental models of obesity, mainly by enhancing brown adipose tissue (BAT) thermogenesis. A potential dose-response relationship has yet to be performed to translate these promising findings into potential clinical therapy. This study aimed to assess the effects of different doses of melatonin on interscapular BAT (iBAT) thermogenic capacity in Zücker diabetic fatty (ZDF) rats. At 6 wk of age, male ZDF rats were divided into four groups (n = 4 per group): control and those treated with different doses of melatonin (0.1, 1, and 10 mg/kg of body weight) in their drinking water for 6 wk. Body weight (BW) was significantly decreased at doses of 1 and 10 mg/kg of melatonin, but not at 0.1 mg/kg compared with the control, with a similar rate of BW decrease being reached at the dose of 1 mg/kg (by ~11%) and 10 mg/kg (by ~12%). This effect was associated with a dose-dependent increase in the thermal response to the baseline condition or acute cold challenge in the interscapular area measurable by infrared thermography, with the highest thermal response being recorded at the 10 mg/kg dose. Upon histology, melatonin treatment markedly restored the typical brownish appearance of the tissue and promoted a shift in size distribution toward smaller adipocytes in a dose-dependent fashion, with the most pronounced brownish phenotype being observed at 10 mg/kg of melatonin. As a hallmark of thermogenesis, the protein level of uncoupled protein 1 (UCP1) from immunofluorescence and Western blot analysis increased significantly and dose-dependently at all three doses of melatonin, reaching the highest level at the dose of 10 mg/kg. Likewise, all three doses of melatonin modulated iBAT mitochondrial dynamics by increasing protein expression of the optic atrophy protein type 1 (OPA1) fusion marker and decreasing that of the dynamin-related protein1 (DRP1) fission marker, again dose-dependently, with the highest and lowest expression levels, respectively, being reached at the 10 mg/kg dose. These findings highlight for the first time the relevance of the dose-dependency of melatonin toward BW control and BAT thermogenic activation, which may have potential therapeutic implications for the treatment of obesity. To clinically apply the potential therapeutic of melatonin for obesity, we consider that the effective animal doses that should be extrapolated to obese individuals may be within the dose range of 1 to 10 mg/kg.

Melatonin induces fat browning by transdifferentiation of white adipocytes and de novo differentiation of mesenchymal stem cells.

The role of melatonin in obesity control is extensively accepted, but its mechanism of action is still unclear. Previously we demonstrated that chronic oral melatonin acts as a brown-fat inducer, driving subcutaneous white adipose tissue (sWAT) into a brown-fat-like function (beige) in obese diabetic rats. However, immunofluorescence characterization of beige depots in sWAT and whether melatonin is a beige-fat inducer by de novo differentiation and/or transdifferentiation of white adipocytes are still undefined. Lean (ZL) and diabetic fatty (ZDF) Zücker rats were subdivided into two groups, control (C) and oral melatonin-supplemented (M, 10 mg kg-1 day-1) for 6 weeks. Mesenchymal stem cells (MSCs) were isolated from both rat inguinal fat and human lipoaspirates followed by adipogenesis assays with or without melatonin (50 nM for 12 h in a 24 h period, 12 h+/12 h-) mimicking the light/dark cycle. Immunofluorescence and western-blot assays showed the partial transdifferentiation of white adipocytes in both ZL and ZDF rats, with increasing thermogenic and beige markers, UCP1 and CITED1 and decreasing white adipocyte marker ASC-1 expression. In addition, melatonin increased UCP1, CITED1, and PGC1-α expression in differentiated adipocytes in both rats and humans. These results demonstrate that melatonin increases brown fat in obese diabetic rats by both adipocyte transdifferentiation and de novo differentiation. Furthermore, it promotes beige MSC adipogenesis in humans. This may contribute to the control of body weight attributed to melatonin and its metabolic benefits in human diabesity.

Psychosocial dwarfism: psychopathological aspects and putative neuroendocrine markers.

There exists an extensive terminology for defining the situation of children who, in varying circumstances, suffer from affective deprivation (AD), within an unsatisfactory family situation or in institutions. Nevertheless, the neuroendocrine mechanisms (if they exist) determining it have yet to be identified. Our objective was to determine if specific neuroendocrine markers, all of them previously implicated in affective disorders, could be modified, and in which sense, in affective deprivation syndrome of the child. For this purpose, we studied three separate groups of children: (1) control group (CG); (2) children suffering from AD; and (3) children with non-organic failure to thrive (NOFT). In every case, we studied the serum levels of melatonin, serotonin, ß-endorphins and adrenocorticotropic hormone (ACTH); and kynurenine pathway tryptophan metabolites (both during the day and at night). Significantly, there was a conspicuous reduction in the levels of each of the neuroendocrine markers (melatonin, serotonin, ß-endorphins and ACTH) in the group suffering from affective deficiency, a diminution which was even more noticeable in the group of patients presenting delayed growth. Furthermore, as also occurs in other affective disorders, there were corresponding modifications in the metabolisation of tryptophan. We report the existence of neuroendocrine mechanisms that are associated with the above-mentioned clinical manifestations in these patients, mechanisms that may underlie the close connection existing between AD syndrome and the cause of NOFT. These data suggest that the AD syndrome and NOFT comprise a single process, but one with a different evolutionary continuum of psychosocial dwarfism.

Current Evidence on the Role of the Gut Microbiome in ADHD Pathophysiology and Therapeutic Implications.

Studies suggest that the bidirectional relationship existent between the gut microbiome (GM) and the central nervous system (CNS), or so-called the microbiome-gut-brain axis (MGBA), is involved in diverse neuropsychiatric diseases in children and adults. In pediatric age, most studies have focused on patients with autism. However, evidence of the role played by the MGBA in attention deficit/hyperactivity disorder (ADHD), the most common neurodevelopmental disorder in childhood, is still scanty and heterogeneous. This review aims to provide the current evidence on the functioning of the MGBA in pediatric patients with ADHD and the specific role of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in this interaction, as well as the potential of the GM as a therapeutic target for ADHD. We will explore: (1) the diverse communication pathways between the GM and the CNS; (2) changes in the GM composition in children and adolescents with ADHD and association with ADHD pathophysiology; (3) influence of the GM on the ω-3 PUFA imbalance characteristically found in ADHD; (4) interaction between the GM and circadian rhythm regulation, as sleep disorders are frequently comorbid with ADHD; (5) finally, we will evaluate the most recent studies on the use of probiotics in pediatric patients with ADHD.

Capturing attention improves accommodation: An experimental study in children with ADHD using multiple object tracking.

The present study was aimed at assessing the impact of manipulating the attentional load using a multiple object tracking (MOT) task on the dynamics of the accommodative response in children with attention deficit hyperactivity disorder (ADHD). The pupil size was recorded to assess the effectiveness of the experimental manipulation, and the role of ADHD medication was also explored. The accommodative and pupil dynamics (magnitude and variability) were monitored with an open-field autorefractometer (WAM-5500) in 41 children with ADHD (24 non-medicated and 17 medicated) and 21 non-ADHD controls, while they performed the MOT task with four different levels of complexity (i.e., tracking zero, one, two, or three targets). We found that increasing the attentional load caused a heightened accommodative response, showing a negative association between MOT complexity and accommodative lag in children with ADHD and non-ADHD controls. Complementarily, the pupil size increased as a function of task complexity, confirming a successful experimental manipulation. The stability of accommodation was insensitive to the attentional manipulation, but it differed between groups. Specifically, non-medicated children with ADHD exhibited a greater variability of accommodation in comparison to controls. Increasing the attentional load is associated with a reduction in the accommodative lag in children with ADHD and controls. Our findings show that the allocation of attention plays an important role in the dynamics of the accommodative response, which may be of relevance in the diagnosis and treatment of accommodative deficits in children with and without ADHD.