Intense solar activity reduces urinary 6-sulfatoxymelatonin in patients with COPD.

BACKGROUND: Little is known about the link between solar activity and variations in melatonin. In this study, we investigated if melatonin's major urinary metabolite, urinary 6-sulfatoxymelatonin (aMT6s), is lowest under periods of intense solar activity. METHODS: We investigated associations between high-energy solar particle events [Coronal Mass Ejection (CME) mass, speed and energy] on creatinine-adjusted aMT6s (aMT6sr) concentrations in 140 patients with chronic obstructive pulmonary disease (COPD) using up to four seasonal urine samples (n = 440). Mixed effect models with a random intercept for each subject were used to estimate associations, including effect modification attributable to diabetes, obesity, and reduced pulmonary function. RESULTS: Higher values of CME were associated with reduced aMT6sr concentrations, with stronger associations in patients with diabetes. An interquartile range (IQR) increase in natural log CMEspeed averaged through two days before urine collection was associated with a reduction of 9.3% aMT6sr (95%CI: - 17.1%, - 0.8%) in aMT6sr. There was a greater reduction in aMT6sr in patients with diabetes (- 24.5%; 95%CI: - 35.9%, - 11.6%). In patients without diabetes there was no meaningful association (- 2.2%; 95%CI: - 12%, 8.4%). There were similar associations with CMEenergy and CMEmass. There was no effect modification attributable to reduced pulmonary function or obesity. CONCLUSIONS: This is the first study in patients with COPD to demonstrate strong detrimental impact of high-energy solar particle events on aMT6sr, with greater associations in patients with diabetes. Since melatonin is an anti-oxidant, it is possible that adverse effects of intense solar activity may be attributable to a reduction in circulating melatonin and that patients with both COPD and diabetes may be more susceptible.

Association between urine 6-sulfatoxy-melatonin level and intravesical Bacillus Calmette-Guerin treatment-induced sleep quality deterioration in patients with non-muscle invasive bladder cancer.

PURPOSE: The level of 6-sulfatoxy-melatonin (SaMT), a metabolite of melatonin, in first-void morning urine reflects blood melatonin levels from the previous night. We investigated the association between urine SaMT and sleep quality deterioration in patients with non-muscle invasive bladder cancer (NMIBC) treated with intravesical Bacillus Calmette-Guerin induction therapy (iBCG). METHODS: We enrolled 51 patients who received iBCG once weekly for 6 or 8 weeks. Patient-reported outcomes were assessed with questionnaires including the International Prostate Symptom Score (IPSS) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQC30). Questionnaires were completed before (baseline), during, at completion, and 1 and 3 months after iBCG. Melatonin and SaMT levels at baseline were measured in serum and first-void morning urine samples, respectively. RESULTS: Based on changes in the QLQC30 insomnia subscale, 28 (55%) patients experienced sleep quality deterioration (deterioration group). Urine SaMT values in the deterioration group were lower than those in the non-deterioration group (P = 0.0015; 7.5 vs 15.4 ng/mg creatinine, respectively). Nocturia scores in the non-deterioration group decreased over time, while those of the deterioration group remained high after completion of iBCG. A binary logistic regression analysis revealed that low urine SaMT levels (≤ 9.6 ng/mg creatinine), high IPSS nocturia scores at baseline, and high IPSS storage subscores at baseline were associated with BCG-induced sleep quality deterioration. CONCLUSIONS: This study confirmed the association among urine SaMT levels, nocturia, and sleep disturbance in patients with NMIBC who receive iBCG. We should be aware of treatment-induced impairments to aid in appropriate decision-making.

The role of serotonin in pathogenesis of unclassified irritable bowel syndrome.

The pathogenesis of irritable bowel syndrome (IBS) has not been clearly understood. Numerous factors, including neurotransmitters, can interfere with the functions of the digestive tract. AIM: The aim of present study was to determine the secretion and metabolism of serotonin in patients with unclassified irritable bowel syndrome (IBS-U). MATERIALS AND METHODS: The study included 50 healthy subjects (Controls) and 50 patients with IBS-U, diagnosed according to Rome IV Criteria of functional gastrointestinal disorders. The severity of gastrointestinal symptoms was assessed using the Gastrointestinal Symptom Rating Scale (GSRS- IBS). The quality of sleep was estimated by Insomnia Severity Index (ISI). The serum serotonin and melatonin levels and 5-hydroxyindoleacetic acid (5-HIAA) and 6-sulfatoxymelatonin (aMT6s) concentration in urine were determined with ELISA method. RESULTS: Compared to control group, patients with IBS-U had a higher serum levels (201.3 ± 37.8 vs 145.4 ± 36.9 ng/ml, p < 0.001) and lower levels of melatonin (5.86 ± 1,16 vs9.11 ±2.43 pg/ml, p < 0.001). Likewise, in IBS-U patients urinary excretion of 5-HIAA was greater, while aMT6s excretion was lower. Due to the above changes cyproheptadine (6 mg daily) or melatonin (7 mg daily) was recommended to be taken. After 12 weeks of taking cyproheptadine, the IBS symptoms disappeared in 86.6% patients, and in 20.0% of those taking melatonin. Both drugs improved sleep in equal measure. CONCLUSIONS: Increased serotonin secretion may be the cause of abdominal complaints in unclassified irritable bowel syndrome, what should be considered in its treatment.

Exploratory assessment of pineal gland volume, composition, and urinary 6-sulfatoxymelatonin levels on prostate cancer risk.

INTRODUCTION: Melatonin levels are partially driven by the parenchyma volume of the pineal gland. Low urinary levels of 6-sulfatoxymelatonin have been associated with increased risk of advanced prostate cancer, but the relationship between pineal gland volume and composition and prostate cancer risk has not been examined. MATERIALS AND METHODS: We utilized data from 864 men from the AGES-Reykjavik Study with complete pineal gland volumes and urinary 6-sulfatoxymelatonin measurements. Pineal parenchyma, calcification, and cyst volumes were calculated from brain magnetic resonance imaging. Levels of 6-sulfatoxymelatonin were assayed from prediagnostic urine samples. We calculated Pearson correlation coefficients between parenchyma volume and urinary 6-sulfatoxymelatonin levels. We used Cox proportional hazards regression to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) comparing prostate cancer risk across parenchyma volume tertiles and across categories factoring in parenchyma volume, gland composition, and urinary 6-sulfatoxymelatonin level. RESULTS: Parenchyma volume was moderately correlated with urinary 6-sulfatoxymelatonin level (r = .24; p < .01). There was no statistically significant association between parenchyma volume tertile and prostate cancer risk. Men with high parenchyma volume, pineal cysts and calcifications, and low urinary 6-sulfatoxymelatonin levels had almost twice the risk of total prostate cancer as men with low parenchyma volume, no pineal calcifications or cysts, and low urinary 6-sulfatoxymelatonin levels (HR: 1.98; 95% CI: 1.02, 3.84; p: .04). CONCLUSIONS: Although parenchyma volume is not associated with prostate cancer risk, pineal gland composition and other circadian dynamics may influence risk for prostate cancer. Additional studies are needed to examine the interplay of pineal gland volume, composition, and melatonin levels on prostate cancer risk.

Loading-induced antitumor capability of murine and human urine.

While urine has been considered as a useful bio-fluid for health monitoring, its dynamic changes to physical activity are not well understood. We examined urine's possible antitumor capability in response to medium-level, loading-driven physical activity. Urine was collected from mice subjected to 5-minute skeletal loading and human individuals before and after 30-minute step aerobics. Six cancer cell lines (breast, prostate, and pancreas) and a mouse model of the mammary tumor were employed to evaluate the effect of urine. Compared to urine collected prior to loading, urine collected post-activity decreased the cellular viability, proliferation, migration, and invasion of tumor cells, as well as tumor weight in the mammary fat pad. Detection of urinary volatile organic compounds and ELISA assays showed that the loading-conditioned urine reduced cholesterol and elevated dopamine and melatonin. Immunohistochemical fluorescent images presented upregulation of the rate-limiting enzymes for the production of dopamine and melatonin in the brain. Molecular analysis revealed that the antitumor effect was linked to the reduction in molecular vinculin-linked molecular force as well as the downregulation of the Lrp5-CSF1-CD105 regulatory axis. Notably, the survival rate for the high expression levels of Lrp5, CSF1, and CD105 in tumor tissues was significantly lowered in the Cancer Genome Atlas database. Collectively, this study revealed that 5- or 10-minute loading-driven physical activity was sufficient to induce the striking antitumor effect by activating the neuronal signaling and repressing cholesterol synthesis. The result supported the dual role of loading-conditioned urine as a potential tumor suppressor and a source of diagnostic biomarkers.

Disrupted nocturnal melatonin in autism: Association with tumor necrosis factor and sleep disturbances.

Sleep disturbances, abnormal melatonin secretion, and increased inflammation are aspects of autism spectrum disorder (ASD) pathophysiology. The present study evaluated the daily urinary 6-sulfatoxymelatonin (aMT6s) excretion profile and the salivary levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) in 20 controls and 20 ASD participants, as well as correlating these measures with sleep disturbances. Although 60% of ASD participants showed a significant night-time rise in aMT6s excretion, this rise was significantly attenuated, compared to controls (P < .05). The remaining 40% of ASD individuals showed no significant increase in nocturnal aMT6s. ASD individuals showed higher nocturnal levels of saliva TNF, but not IL-6. Dysfunction in the initiation and maintenance of sleep, as indicated by the Sleep Disturbance Scale for Children, correlated with night-time aMT6s excretion (r = -.28, P < .05). Dysfunction in sleep breathing was inversely correlated with aMT6s (r = -.31, P < .05) and positively associated with TNF level (r = .42, P < .01). Overall such data indicate immune-pineal axis activation, with elevated TNF but not IL-6 levels associated with disrupted pineal melatonin release and sleep dysfunction in ASD. It is proposed that circadian dysregulation in ASD is intimately linked to heightened immune-inflammatory activity. Such two-way interactions of the immune-pineal axis may underpin many aspects of ASD pathophysiology, including sleep disturbances, as well as cognitive and behavioral alterations.

Sleep variability, 6-sulfatoxymelatonin, and diabetic retinopathy.

PURPOSE: Recent evidence suggests that diabetic retinopathy (DR) is associated with abnormal melatonin regulation, possibly related to dysfunction of the melanopsin-expressing intrinsically photosensitive retinal ganglion cells. This study explored melatonin regulation in type 2 diabetes (T2D) patients with DR and its relation to sleep and circadian functioning. METHODS: Thirty-five participants (10 non-diabetic controls, 10 T2D without DR, and 15 T2D with DR) were recruited. Overnight urine 6-sulfatoxymelatonin (aMT6s) and objective sleep and wrist activity (7-day actigraphy) were obtained. RESULTS: After adjusting for covariates, having T2D with DR was significantly associated with lower urinary aMT6s (ß = - 1.369, p = 0.004) compared with controls, while having T2D without DR was not (p = 0.418). T2D patients with DR reported poorer sleep quality (p = 0.014) and had greater variability of sleep duration (p = 0.017) than others, while no differences were found in sleep duration, efficiency, and rest-activity rhythm. After adjusting for covariates, lower nocturnal aMT6s was significantly associated with greater sleep variability. CONCLUSION: T2D patients with DR exhibited low overnight production of aMT6s which likely contributed to sleep irregularities possibly due to weak circadian signaling. Whether or not melatonin supplementation could improve health in T2D patients with DR remains to be explored.

Nail Melatonin Content: A Suitable Non-Invasive Marker of Melatonin Production.

Melatonin plays multiple physiological roles in the human body. Evaluation of melatonin production by the determination of urinary 6-sulfatoxymelatonin in 24-h samples has important drawbacks which hinder the successful evaluation of melatonin production in large cohorts. Here, we evaluated the potential of nail analysis for estimating melatonin production. Firstly, mass spectrometry methodology for the determination of melatonin in nails was optimized and successfully validated. The method was found to be linear in the range 6.5-830 fg/mg with intraday and interday accuracy in the range 100-104 %, precision below 15 % and a LOD of 3.5 fg/mg. Secondly, nail melatonin concentrations from 84 volunteers (age 5-96) were determined. The expected correlation between melatonin and age was obtained (correlation coefficient -0.615; p < 0.001). Additionally, we showed that fingernails are preferable to toenails to determine nail melatonin content. Finally, fingernails collected for 180 days after melatonin administration (two volunteers, 1.9 mg/night during 5 days) were analyzed. Nail melatonin concentrations immediately rose after administration and went back to pre-administration values after ≈100 days in both volunteers. Our results suggest that melatonin determination in nails is a suitable non-invasive tool for the estimation of global melatonin production. Due to the easy collection and storage of nails, the long-term information obtained and the multiple functions of melatonin, nail melatonin content might complement dim light melatonin onset, which is commonly measured from plasma/saliva samples, paving the way for melatonin research.

Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Decreased melatonin secretion in patients with glaucoma: Quantitative association with glaucoma severity in the LIGHT study.

Glaucoma may be associated with circadian disruption due to its association with a loss of intrinsically photosensitive retinal ganglion cells. Clinical evidence demonstrating an association between glaucoma and circadian disruption is limited, and no large-scale studies have been performed. The purpose of this cross-sectional study was to determine whether the presence and severity of glaucoma is correlated with the urinary 6-sulfatoxymelatonin levels as a circadian rhythm parameter. We measured the level of urinary 6-sulfatoxymelatonin excretion (UME) in 118 glaucoma patients and 395 control participants without glaucoma. The UME in the glaucoma group was significantly lower than that of the control group without glaucoma (3.05 and 3.24 log ng/mg creatinine, respectively; P = .010). Next, we examined association of the severity of glaucoma and melatonin levels. In stratification analysis of the glaucoma groups, multivariable linear regression analyses adjusted for potential confounders indicated significantly lower UME by 0.30 log ng/mg creatinine in patients with functional severe glaucoma (visual field mean deviation ≤ -6 dB) compared with mild glaucoma (mean deviation > -6 dB; P = .040) and lower UME by 0.05 log ng/mg creatinine with each 10 µm thinning of the circumpapillary retinal nerve fiber layer thickness as the index of structural severity of glaucoma (P = .011). In conclusion, significant association between glaucoma and lower urinary 6-sulfatoxymelatonin was found. In addition, patients with functional and structural severe glaucoma were significantly associated with lower urinary 6-sulfatoxymelatonin levels. Our results indicate the possibility of a circadian disruption in patients with glaucoma.

Endogenous Melatonin Levels and Therapeutic Use of Exogenous Melatonin in Migraine: Systematic Review and Meta-Analysis.

BACKGROUND: Sleep disorders and circadian dysregulation appear to be associated with primary headache disorders. OBJECTIVE: The aim of this study was to review the existing evidence for the deployment of melatonin in migraine prophylaxis. Initially, case-control studies investigating nocturnal melatonin and 6-sulphatoxymelatonin (aMT6s, melatonin metabolite discarded by the urine) levels in patients with migraine and healthy controls (HC) would be reviewed and meta-analyzed. Second, results from randomized controlled trials (RCTs) and non-randomized studies evaluating the use of melatonin in migraine would be synthesized. METHODS: MEDLINE EMBASE, CENTRAL, PsycINFO, trial registries, Google Scholar, and OpenGrey were comprehensively searched. The quality of studies was assessed according to the Newcastle-Ottawa Scale (case-control studies) and the Risk-of-Bias Cochrane tool (RCTs). Random-effects (RE) or fixed-effects (FE) model was used based on heterogeneity among studies (homogeneity assumed when PQ > 0.1 and I2  < 30%). Publication bias was assessed by funnel plots. RESULTS: Literature search provided 11 case-control studies. Evidence was compatible with lower nocturnal serum [5 of 6 studies were synthesized due to deficient reporting of 1 abstract, migraine n = 197, HC n = 132, RE MD = -12.29 pg/ml, 95%CI = (-21.10, -3.49)] and urinary melatonin [3 studies, migraine n = 30, HC n = 29, RE MD = -0.12 nmol/nocturnal (12 hours) urinary collection, 95%CI = (-0.22, -0.03)], as well as urine aMT6s levels [1 study, migraine n = 146, HC n = 74, MD = -11.90 µg/nocturnal (12 hours) urine collection, 95%CI = (-19.23, -4.57)] in adult migraine patients compared to HC [1 study involving children did not reveal any difference regarding nocturnal urine aMT6s, n = 18 per group, MD = -6.00 µg/nocturnal (12 hours) urine collection, 95%CI = (-21.19, 9.19)]. Regarding the treatment-prevention of migraine, 7 RCTs and 9 non-randomized studies were retrieved. Data synthesis was not feasible for the comparison of melatonin and placebo due to the existing clinical and methodological heterogeneity of the 5 relevant RCTs. Overall, melatonin was more efficacious and equally safe with placebo in the prevention of migraine in adults (3 of 4 RCTs provided superior efficacy results for melatonin, 1 RCT revealed no difference regarding Headache Frequency -HF-), while there are limited data for children (1 RCT revealed no difference against placebo regarding HF). Additionally, no difference was revealed between melatonin and amitriptyline (1 RCT), sodium valproate (1 RCT) or propranolol (1 non-randomized study) with respect to their efficacy in adults with migraine, while melatonin was more effective than pizotifen (1 RCT). In children with migraine, amitriptyline is more efficacious regarding most assessed parameters (2 studies, n = 85 per group, HF: RE MD = 4.03, 95%CI = (2.64, 5.42), Headache Duration: RE MD = 0.72, 95%CI = (0.41, 1.03), Headache Severity: FE MD = 1.57, 95%CI = (1.13, 2.00), Response to Treatment: FE MD = 0.33, 95%CI = (0.16, 0.69), Headache Induced Disability Severity: RE MD = 6.07, 95%CI = (-11.87, 24.01 ), Analgesic Consumption - assessed in 1 study, n = 40 per group - MD = 1.11, 95%CI = (-0.10, 2.32)), although melatonin presents a superior safety profile than amitriptyline both in adults and in children. CONCLUSIONS: Melatonin may be of potential benefit in the treatment-prevention of migraine in adults, but complementary evidence from high-quality RCTs is required.

Mass spectrometric quantification of urinary 6-sulfatoxymelatonin: age-dependent excretion and biological variation.

Objectives: Regulators of circadian rhythm, including melatonin, influence fundamental biological processes. Measuring the melatonin metabolite 6-sulfatoxymelatonin in urine can estimate melatonin production. 6-sulfatoxymelatonin is mainly analyzed by immunoassays, but these methods are hampered by cross-reactivity and poor reproducibility when used to analyze small molecules. Therefore, we validated a high-throughput liquid chromatography with tandem mass spectrometry (LC-MS/MS) method to quantify 6-sulfatoxymelatonin in urine. We evaluated age-dependent 24-h excretion of 6-sulfatoxymelatonin into urine and the biological variation of urinary excretion in healthy individuals. Methods: The online solid phase extraction method combined with LC-MS/MS was validated according to international guidelines, and used to measure the excretion of 6-sulfatoxymelatonin into urine of 240 healthy individuals. Biological variation of 6-sulfatoxymelatonin excretion was examined in 10 healthy individuals. Results: Urinary 6-sulfatoxymelatonin results were well within the validation criteria (interassay coefficient of variation: <5.4%, quantification limit: 0.2 nmol/L). There was an age-related decrease in 6-sulfatoxymelatonin excretion into 24-h urine [F(5, 234)=13.9; p<0.001]. Within-subject variation of 6-sulfatoxymelatonin was 39.2% in day urine, 15.1% in night urine, and 12.2% in 24-h urine. Between-subject variation was 39.1% in day urine, 37.9% in night urine, and 36.8% in 24-h urine. Conclusions: This MS-based method enables straightforward, reproducible, and sensitive quantification of 6-sulfatoxymelatonin in urine. Urinary 6-sulfatoxymelatonin levels decreased with age. Biological variation of 6-sulfatoxymelatonin excretion into urine was high between subjects and lower within subjects, indicating that repeated measurements of 6-sulfatoxymelatonin in 24-h urine are needed in future studies.

Impact of Dim Light at Night on Urinary 6-Sulphatoxymelatonin Concentrations and Sleep in Healthy Humans.

Artificial light at night can have negative effects on human wellbeing and health. It can disrupt circadian rhythms, interfere with sleep, and participate in the progress of civilisation diseases. The aim of the present study was to explore if dim artificial light during the entire night (ALAN) can affect melatonin production and sleep quality in young volunteers. We performed two experiments in real-life home-based conditions. Young volunteers (n = 33) were exposed to four nights of one lux ALAN or two nights of five lux ALAN. Melatonin production, based on 6-sulphatoxymelatonin/creatinine concentrations in urine, and sleep quality, based on actimetry, were evaluated. Exposure to ALAN one lux during the entire night did not suppress aMT6s/creatinine concentrations but did aggravate sleep quality by increasing sleep fragmentation and one-minute immobility. ALAN up to five lux reduced melatonin biosynthesis significantly and interfered with sleep quality, as evidenced by an increased percentage of one-minute immobility and a tendency of increased fragmentation index. Our results show that people are more sensitive to low illuminance during the entire night, as previously expected. ALAN can interfere with melatonin production and sleep quality in young, healthy individuals, and both processes have different sensitivities to light.

Healthier rhythm, healthier brain? Integrity of circadian melatonin and temperature rhythms relates to the clinical state of brain-injured patients.

BACKGROUND: Healthy circadian rhythmicity has been suggested to relate to a better state of brain-injured patients and to support the emergence of consciousness in patient groups characterized by a relative instability thereof such as patients with disorders of consciousness (DOC). METHODS: Going beyond earlier studies, a systems-level perspective was adopted and, using multilevel modelling, the joint predictive value of three indices of circadian rhythm integrity derived from skin temperature variations, melatoninsulfate secretion, and physical activity (wrist actigraphy) patterns was evaluated for the behaviourally assessed state [Coma Recovery Scale - Revised (CRS-R) score] of DOC patients [13 unresponsive wakefulness syndrome; seven minimally conscious (exit) state]. Additionally, it was assessed in a subset of 16 patients whether patients' behavioural repertoire (CRS-R score) varied (i) with time of day or (ii) offset from the body temperature maximum (BTmax ), i.e. when cognitive performance is expected to peak. RESULTS: The results reveal that better integrity of circadian melatoninsulfate and temperature rhythms relate to a richer behavioural repertoire. Moreover, higher CRS-R scores are, by trend, related to assessments taking place at a later daytime or deviating less from the pre-specified time of occurrence of BTmax . CONCLUSIONS: In conclusion, the results suggest that therapeutic approaches aimed at improving circadian rhythms in brain-injured patients are promising and should be implemented in hospitals or nursing homes. Beyond this, it might be helpful to schedule diagnostic procedures and therapies around the (pre-assessed) BTmax (≈4 pm in healthy individuals) as this is when patients should be most responsive.

Is circadian rhythmicity a prerequisite to coma recovery? Circadian recovery concomitant to cognitive improvement in two comatose patients.

Circadian rhythmicity (CR) is involved in the regulation of all integrated functions, from sleep-wake cycle regulation to metabolic function, mood and cognition. However, the interdependence of CR, cognition and consciousness has been poorly addressed. To clarify the state of CR in coma and to determine the chronological relationship between its recovery and consciousness after brain lesions, we conducted a longitudinal observational study investigating how the state of CR was chronologically related with the recovery of behavioural wakefulness, cognition and/or awareness. Among 16 acute comatose patients, we recruited two 37-year-old patients with a persistent disorder of consciousness, presenting diencephalic lesions caused by severe traumatic brain injuries. Two biological urinary markers of CR were explored every 2 hours during 24 hours (6-sulfatoxymelatonin, free cortisol) with a dedicated methodology to extract the endogenous component of rhythmicity (environmental light recording, near-constant-routine protocol, control of beta-blockers). They presented an initial absence of rhythmic secretions and a recovered CR 7-8 months later. This recovery was not associated with the restoration of behavioural wakefulness, but with an improvement of cognition and awareness (up to the minimally conscious state). MRI showed a lesion pattern compatible with the interruption of either the main hypothalamic-sympathetic pathway or the accessory habenular pathway. These results suggest that CR may be a prerequisite for coma recovery with a potential but still unproven favourable effect on brain function of the resorted circadian melatonin secretion and/or the functional recovery of the suprachiasmatic nucleus (SCN). Assessing circadian functions by urinary melatonin should be further explored as a biomarker of cognition reappearance and investigated to prognosticate functional recovery.

Preliminary Evidence that Melatonin Is not a Biomarker in Children and Adolescents With Episodic Migraine.

BACKGROUND: To date, there have not been reliable biomarkers to identify impending migraine episodes. A prior study in adults with migraine demonstrated a reduction in the urinary metabolic substrate of melatonin (urinary 6-sulfatoxymelatonin; aMT6s) during a migraine. The aim of this study was to examine whether evening urinary melatonin metabolite levels could predict migraine the next day in children and adolescents with migraine. METHODS: Twenty-one children and adolescents with migraine (aged 5-17 years) were recruited to this observational study conducted at UC San Francisco to provide urine samples for 10 days and maintain a prospective headache diary during the same period. Nightly melatonin metabolite 6-sulfatoxymelatonin in urine was assayed and results from nights preceding migraine were compared to nights preceding a non-headache day. RESULTS: Mean (±SD) aMT6s levels the night prior to a migraine attack were 56.2 ± 39.0 vs 55.4 ± 46.6 ng/mL (P = .915), and mean melatonin metabolite levels the night following migraine were 55.5 ± 46.9 vs 57.0 ± 37.7 ng/mL (P = .841). However, in post hoc exploratory analyses, aMT6s levels were lower the night before a migraine in those who experienced aura or premonitory symptoms. CONCLUSION: While urinary melatonin metabolites do not predict migraine attacks in children and adolescents overall, they may be predictive in those who experience premonitory phase symptoms as part of their migraine attacks.

Association of functioning and quality of life with objective and subjective measures of sleep and biological rhythms in major depressive and bipolar disorder.

OBJECTIVE: Disruptions in biological rhythms and sleep are a core aspect of mood disorders, with sleep and rhythm changes frequently occurring prior to and during mood episodes. Wrist-worn actigraphs are increasingly utilized to measure ambulatory activity rhythm and sleep patterns. METHODS: A comprehensive study using subjective and objective measures of sleep and biological rhythms was conducted in 111 participants (40 healthy volunteers [HC], 38 with major depressive disorder [MDD] and 33 with bipolar disorder [BD]). Participants completed 15-day actigraphy and first-morning urine samples to measure 6-sulfatoxymelatonin levels. Sleep and biological rhythm questionnaires were administered: Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN), Munich Chronotype Questionnaire (MCTQ), Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Actigraph data were analyzed for sleep and daily activity rhythms, light exposure and likelihood of transitioning between rest and activity states. RESULTS: Mood groups had worse subjective sleep quality (PSQI) and biological rhythm disruption (BRIAN) and higher objective mean nighttime activity than controls. Participants with BD had longer total sleep time, higher circadian quotient and lower 6-sulfatoxymelatonin levels than HC group. The MDD group had longer sleep onset latency and higher daytime probability of transitioning from rest to activity than HCs. Mood groups displayed later mean timing of light exposure. Multiple linear regression analysis with BRIAN scores, circadian quotient, mean nighttime activity during rest and daytime probability of transitioning from activity to rest explained 43% of variance in quality-of-life scores. BRIAN scores, total sleep time and probability of transitioning from activity to rest explained 52% of variance in functioning (all p < 0.05). CONCLUSIONS: Disruption in biological rhythms is associated with poorer functioning and quality of life in bipolar and MDD. Investigating biological rhythms and sleep using actigraphy variables, urinary 6-sulfatoxymelatonin and subjective measures provide evidence of widespread sleep and circadian system disruptions in mood disorders.

A carbon paste electrode modified with Al2O3-supported palladium nanoparticles for simultaneous voltammetric determination of melatonin, dopamine, and acetaminophen.

The authors have modified a carbon paste electrode with Al2O3-supported palladium nanoparticles (PdNP@Al2O3) to obtain a sensor for simultaneous voltammetric determination of melatonin (MT), dopamine (DA) and acetaminophen (AC). The PdNP@Al2O3 was characterized by scanning electron microscopy and energy-dispersive X-ray spectra. The sensor can detect DA, AC, MT and their mixtures by giving distinct signals at working voltages of typically 236, 480 and 650 mV (vs. Ag/AgCl), respectively. Differential pulse voltammetric peak currents of DA, AC and MT increase linearly in the 50 nmol L-1 - 1.45 mmol L-1, 40 nmol L-1 -1.4 mmol L-1, and 6.0 nmol L-1 - 1.4 mmol L-1 concentration ranges. The limits of detection are 36.5 nmol L-1 for DA, 36.5 nmol L-1 for AC, and 21.6 nmol L-1 for MT. The sensor was successfully used to detect the analytes in (spiked) human serum and drug samples. Graphical abstract Schematic presentation of Al2O3-supported palladium nanoparticles (PdNP@Al2O3) for modification of a carbon paste electrode (CPE) to develop a voltammetric sensor for the simultaneous determination of dopamine (DA), acetaminophen (AC) and melatonin (MT).

The effects of a sleep/recovery supplement: 'Night Time Recharge' on sleep parameters in young adults.

BACKGROUND: Concentrated cherry juice reportedly contains melatonin which, in turn, has been highlighted as an important regulator in initiating sleep. AIM: The present investigation aims to clarify whether Night Time Recharge (NTR), a marketed sleep aid containing cherry extract, improves key sleep parameters in young, active adults with mildly poor sleep. METHODS: A double-blind, randomized, placebo-controlled, cross-over study design was employed. Twenty participants (nine female) consumed either NTR or a placebo for seven days. Accelerometers were used to assess sleep quality and physical activity levels. Urinary levels of 6-sulphatoxymelatonin (6-SMT), a marker of melatonin synthesis, was assessed via enzyme-linked immunosorbent assay. RESULTS: 6-SMT levels increased following NTR treatment (28.95 ng/ml) compared with placebo (4.0 ng/ml) (p < 0.001). There was also a significant difference (p = 0.047) in dietary tryptophan consumption during the NTR treatment (1236 mg) versus placebo (1149 mg). No trace of melatonin was detected from our analysis of the supplement. NTR had no significant effect on any sleep parameters with the exception of sleep latency (p = 0.001). CONCLUSIONS: As chemical analysis of NTR by liquid-chromatography mass-spectrometry identified no detectable melatonin, the tryptophan content of the supplement is a likely reason for improvement in sleep latency. These results are in contrast to previous studies which have found a positive effect on sleep following cherry supplementation. Future work should focus on sleep latency and investigating whether cherry juice is effective in participants with problems in initiating sleep.

[Perimenopausal melatonin deficiency syndrome in system of personalized management of quality of life of women with climacteric syndrome.]

The aim of our study is to search diagnostic tools for early detection of prenosological melatonin deficiency in postmenopausal women and women in menopausal transition with climacteric syndrome for establishment effective personalized prevention and treatment programs. In this study 221 women were enrolled. They were divided into four groups: the 1st group - 39 women in menopausal transition with climacteric syndrome, the 2nd group - 104 menopausal women with climacteric syndrome, the 3rd group - 41 women with physiological menopause, the 4th group - 37 healthy women in reproductive-age. The study was conducted using the test for detecting melatonin deficiency, women's health questionnaire (WHQ), and morning level detection of 6-sulfatoxymelatonin in urine. A new prenosological state - perimenopausal melatonin deficiency syndrome was build on the data obtained. It is appropriate to evaluate prognosis of melatonin treatment in women with climacteric syndrome during the planning of personalized prevention and treatment programs. The assessment of prognosis is carried out with the help of the discriminant mathematical model, which is the basis of personalized management of quality of life in women with climacteric syndrome. This system is based on participatory principles.