Multidimensional sleep health and diabetic retinopathy: Systematic review and meta-analysis.

Diabetic retinopathy (DR) is one of the most prevalent microvascular diabetic complications. Poor sleep health and obstructive sleep apnea (OSA) are risk factors for diabetes and poor glycemic control. Recent studies have suggested associations between poor sleep health/OSA and DR. Furthermore, there have been suggestions of melatonin dysregulation in the context of DR. We conducted a systematic review and meta-analysis exploring the associations between multidimensional sleep health (duration, satisfaction, efficiency, timing/regularity and alertness), OSA and melatonin with DR. Forty-two studies were included. Long, but not short sleep, was significantly associated with DR, OR 1.41 (95%CI 1.21, 1.64). Poor sleep satisfaction was also significantly associated with DR, OR 2.04 (1.41, 2.94). Sleep efficiency and alertness were not associated with DR, while the evidence on timing/regularity was scant. Having OSA was significantly associated with having DR, OR 1.34 (1.07, 1.69). Further, those with DR had significantly lower melatonin/melatonin metabolite levels than those without DR, standardized mean difference -0.94 (-1.44, -0.44). We explored whether treating OSA with continuous positive airway pressure (CPAP) led to improvement in DR (five studies). The results were mixed among studies, but potential benefits were observed in some. This review highlights the association between poor multidimensional sleep health and DR.

Disruption of the circadian rhythm of melatonin: A biomarker of critical illness severity.

Circadian dysrhythmias occur commonly in critically ill patients reflecting variable effects of underlying illness, ICU environment, and treatments. We retrospectively analyzed the relationship between clinical outcomes and 24-h urinary 6-sulfatoxymelatonin (aMT6s) excretion profiles in 37 critically ill patients with shock and/or respiratory failure. Nonlinear regression was used to fit a 24-h cosine curve to each patient's aMT6s profile, with rhythmicity determined by the zero-amplitude test. From these curves we determined acrophase, amplitude, phase, and night/day ratio. After assessing unadjusted relationships, we identified the optimal multivariate models for hospital survival and for discharge to home (vs. death or transfer to another facility). Normalized aMT6s rhythm amplitude was greater (p = 0.005) in patients discharged home than in those who were not, while both groups exhibited a phase delay. Patients with rhythmic aMT6s excretion were more likely to survive (OR 5.25) and be discharged home (OR 8.89; p < 0.05 for both) than patients with arrhythmic profiles, associations that persisted in multivariate modelling. In critically ill patients with shock and/or respiratory failure, arrhythmic and/or low amplitude 24-h aMT6s rhythms were associated with worse clinical outcomes, suggesting a role for the melatonin-based rhythm as a novel biomarker of critical illness severity.

Acute effects of fresh versus dried Hayward green kiwifruit on sleep quality, mood, and sleep-related urinary metabolites in healthy young men with good and poor sleep quality.

Background and aims: Daily kiwifruit (KF) consumption has been associated with improved sleep quality, but underlying physiological mechanisms are unknown. This study examined acute effects of fresh and dried green KF, compared with a water control, on sleep quality, mood, and urinary serotonin and melatonin metabolite concentrations. Methods: 24 men (age: 29 ± 1 years, body mass index: 24 ± 1 kg/m2) with poor (n = 12) or good (n = 12) sleep quality participated in a randomized, single-blind crossover study. One of three treatments was consumed with a standardized evening meal; (1) the flesh of two fresh green KF, (2) dried green KF powder (including skin; equivalent to dry matter of two fresh KF) mixed with water, or (3) a water control, in their own home. Subjective and objective sleep quality, mood, waking urinary 5-hydroxyindoleacetic acid (5-HIAA), 6-sulfatoxymelatonin (aMT6s), vitamin C and B-vitamin concentrations were determined. Results: Regardless of sleep quality group, compared to control, morning sleepiness, alertness upon awakening, and vigor were improved (p < 0.05) after dried KF consumption. Compared to control, both fresh and dried KF treatments tended (p < 0.1) toward improved esteem and total mood disturbance. Both KF treatments increased (fresh +1.56 ± 0.4 ng/g, p = 0.001; dried: +1.30 ± 0.4 ng/g, p = 0.004) urinary concentration of the serotonin metabolite 5-HIAA compared to the control (4.32 ± 0.4 ng/g). In poor sleepers, ease of awakening improved by 24% after dried KF consumption (p = 0.005) and tended to improve by 13% after fresh KF intake (p = 0.052) compared to the control. Good sleepers tended toward 9% improved ratings of getting to sleep with fresh KF (p = 0.053) compared to the control. Poor sleepers had lower amounts of some B-vitamins compared to good sleepers (p < 0.05). Conclusion: Consumption of dried or fresh KF with a standard evening meal, was associated with improved aspects of sleep quality and mood, possibly mediated through changes in serotonin metabolism. Clinical trial registration: [www.anzctr.org.au], identifier [ACTRN12621000046808]. Graphical Abstract.

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.

Subchronic Low-Dose Methylmercury Exposure Accelerated Cerebral Telomere Shortening in Relevant with Declined Urinary aMT6s Level in Rats.

Methylmercury (MeHg) is a global pollutant with established toxic effects on the central nervous system (CNS). However, early events and early-warning biomarkers of CNS damage following exposure to low-dose MeHg are still lacking. This study aimed to investigate whether subchronic low-dose MeHg exposure had adverse effects on the cerebral telomere length, as well as serum melatonin and its urinary metabolite 6-sulfatoxymelatonin (aMT6s) in rats. Sixteen male Sprague Dawley rats were divided into two groups. Group I was the control group. In group II, rats were exposed to MeHg by gavage at a dose of 0.1 mg/kg/day for 3 months. This study revealed that MeHg exposure resulted in impairment of learning and memory ability, a slightly reduced number of neurons and an irregular arrangement of neurons in the hippocampus. It also significantly accelerated telomere shortening in the cerebral cortex, hippocampus and hypothalamus. Moreover, MeHg exposure decreased the levels of melatonin in serum and aMT6s in urine, partly by suppressing the synthesis of 5-hydroxytryptamine (5-HT) in the brain but promoted the expression of melatonin-catalyzing AANAT and ASMT. Importantly, cerebral telomere length was positively correlated with MT and aMT6s after MeHg exposure. These results suggested that the shortened telomere length in the brain may be an early event in MeHg-induced CNS toxicity, and the level of aMT6s in urine may serve as an early-warning biomarker for MeHg-induced CNS damage.

Chronobiological parameters as predictors of early treatment response in major depression.

BACKGROUND: Alterations in circadian system organization have been related to major depressive disorder manifestations. This study aimed to evaluate chronobiological parameters, such as sleep, levels of 6-sulfatoxymelatonin, and others derived from actimetry as potential predictors of adequate treatment response in MDD. METHODS: 98 adult women with confirmed diagnosis of MDD were included. Participants completed standard questionnaires (Hamilton Depression Rating Scale - HAM-D; Munich Chronotype Questionnaire - MCTQ) at baseline and after 4 weeks of treatment. Urinary samples for assessing 6-sulfatoxymelatonin were collected on the day before and immediately after pharmacological treatment administration, and 28 continuous days of actigraphy data were collected during the protocol. Participants were classified into Responder (R) or Non-responder (NR) to antidepressant treatment in 4 weeks (early responder), which was characterized by a ≥50 % decrease in the HAM-D score. RESULTS: The following biological rhythms variables significantly predicted a better treatment response in a model controlling for age, sex, and previous treatments: higher levels of activity (M10 - average activity in the 10 most active hours within the 24 h-day) and an earlier center of the 10 most active hours (M10c), as well as lower intradaily variability (IV) of light exposure. Sleep parameters and 6-sulfatoxymelatonin levels did not associate with treatment response prediction. LIMITATION: Actimetry data were not assessed before changing in the treatment plan. CONCLUSION: Different patterns in activity and light exposure might be linked to early antidepressant response.

Reference intervals for 6-sulfatoxymelatonin in urine: A meta-analysis.

Despite the essential functions of melatonin in the human body, until now no norms of the amount of melatonin produced overnight have been established. Measuring the amount of the main urinary melatonin metabolite 6-sulfatoxymelatonin (aMT6s), corrected for creatinine, in the first morning void is the most simple as well as reliable method to evaluate the total amount of melatonin produced at night. We performed a meta-analysis to provide reference estimates and intervals by consolidating data from multiple studies. A total of 68 studies, representing 17,847 subjects, were retained for the analysis. No gender differences could be found in aMT6s values in this meta-review. aMT6s excretion is very high during the first 5 years of life, flattens out in adolescence with gradual decline continuing to 50-60 years, after which the decline stagnates and a limited increase occurs around about 60 years of age. This late increase may suggest the premature death of individuals with low aMT6s levels, as lower aMT6s levels are found in various disorders, such as cardiovascular diseases, cancer and neurodegenerative disorders. Our aMT6s values can be used to identify individuals with a possible melatonin deficiency.

Evaluation of multiple reaction monitoring cubed performed by a quadrupole-linear ion trap mass spectrometer for quantitative determination of 6-sulfatoxymelatonin in urine.

Liquid chromatography (LC) - mass spectrometry quantitative analysis of substances in biological samples is usually performed in the multiple reaction monitoring (MRM) variant. In complex biological matrices, strong interferences can be observed when using the LC-MRM method. Interference levels can be significantly reduced by using LC - multiple reaction monitoring cubed (MRM3). 6-sulfatoxymelatonin (6-SM) is a metabolite of melatonin, an important regulator of many biological processes. The quantitative analysis of 6-SM in urine allows monitoring of the melatonin level in the blood. The aim of the present work was to evaluate the LC-MRM3 method for the quantitative determination of 6-SM in urine. We found that for 6-SM in aqueous solutions, under some parameters of the MRM3 experiment, the effect of degradation of the MRM3 signal is observed. When analyzing 6-SM in urine, this signal degradation effect was significantly reduced. We have shown that optimization of such parameters of the MRM3 method as the linear ion trap fill time, the number of scans to sum, and the range of triple-stage scan allows obtaining the LC-MRM3 method, which is comparable to the LC-MRM in sensitivity and significantly exceeds it in selectivity.

Relationship among melatonin, postoperative delirium, and postoperative cognitive dysfunction.

BACKGROUND: Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are the most common central nervous system dysfunctions during the perioperative period. Melatonin protects nerve cells and impacts cognitive functioning in patients after surgery. METHODS: A total of 120 patients undergoing elective non-cardiac surgery were evaluated with the confusion assessment method (CAM) for diagnosis of POD on the day before and the 1st, 2nd, 3rd, and 7th day after surgery. Also, a neuropsychological test for the diagnosis of POCD was performed on the day before and 1 week after surgery. Patients' urine was collected to examine the concentration of 6-sulfatoxymelatonin (6-SMT), the metabolite of melatonin, with the enzyme-linked immunosorbent assay method. Meanwhile, urine creatinine values were examined to calculate the 6-SMT/creatinine ratio (M/C). RESULTS: The incidence rates of POD and POCD were 7% and 44%, respectively. There were no statistically differences for the M/C on the 1st, 2nd, 3rd, and 7th day after surgery between the POD and the non-POD groups (P>0.05). However, there were statistically significant differences (P<0.05) in the rates of M/C change [(preoperative value-postoperative value)/(postoperative value) ×100%] on the 1st and 7th day after surgery between both groups. Patients were divided into Group I1 (≥100%) and Group II1 (<100%) based on the M/C rate changes on the 1st day, Group I7 (≥200%) and Group II7 (<200%) based on the M/C rate changes on the 7th day, and Group Iw (≥100%) and Group IIw (<100%) based on the M/C rate changes during the 1st week after surgery. The incidence rates of POD for Group I1 and Group II1 were 21.1% and 3.7%, respectively; for Group I7 and Group II7 were 50% and 1.1%, respectively; for Group Iw and Group IIw were 17.2% and 2.8%, respectively. For 7 patients with POD had POCD, the occurrence of POCD was related to POD (P<0.05). CONCLUSIONS: Increased melatonin after surgery may be a risk factor for POD. There may be no correlation between melatonin and POCD. POD may be a risk factor of POCD.

[The effect of long-term beta-blockers on melatonin secretion, sleep quality, and vascular brain damage]. / Vliyanie dlitel'nogo priema beta-adrenoblokatorov na sekretsiyu melatonina, kachestvo sna i sosudistoe porazhenie golovnogo mozga.

Circadian rhythm of pineal melatonin production is paced by the thalamus suprachiasmatic nucleus (SCN) depending on the lighting conditions via signal transduction to pinealocytes beta-receptors. Melatonin is a natural regulator of many physiological processes, and the decrease of its synthesis leads to various diseases, in particular, insomnia and metabolic disorders. It is known that administration of beta-blockers reduces melatonin production, but the data showing clinical significance of melatonin reduction associated with beta-blockers administration are still contradictory. OBJECTIVE: The influence of long-term administration of beta-blockers to melatonin synthesis, sleep quality and vascular brain damage. MATERIALS AND METHODS: The main study group included 114 patients, aged 47-83, with cardiovascular diseases, who were under a complex therapy with long-term administration of beta-blockers. The comparison group included 110 patients with cardiovascular diseases, similar in age and sex, who did not receive beta-blockers in their complex therapy. The circadian dynamics of melatonin synthesis was observed by excretion of 6-sulfatoxymelatonin (6-SM), the major metabolite of melatonin, in three urinary samples (day, evening, night). All the patients underwent night polysomnography to assess the severity of sleep disorders. The severity of vascular brain damage was assessed using magnetic resonance imaging. RESULTS: The analyses showed large variability in individual values of 6-SM circadian excretion of patients with cardiovascular diseases (from 0.9 to 133 µg/24h with a mid-point 16.8 µg/24h). A considerable decrease of 6-SM circadian excretion is detected in the group of patients taking beta-blockers comparing to those not Me [q 25; q 75]: 12.8 [6.2; 21.1] and 24.0 [12.5; 41.5] µg/24h, respectively (p<0.001), with no differences in sleep values and severity of vascular brain damage. Comparing subgroups of patients with 6-SM circadian excretion lower and higher than 16.8 µg/24h showed a significant increase of sleep latency, decrease of rapid eye movement sleep (REM sleep), increasing number of gliosis foci in white matter of the brain with higher values of leptin, leptin/adiponectin ratio and glycohemoglobin in the group of patients with 6-SM circadian excretion ≤16.8 µg/24h. CONCLUSION: A low level of endogenous melatonin is a risk factor for development of sleep structure and quality disorders, vascular white matter brain damages with a higher risk for metabolic disorders. Long-term beta-blockers administration decrease endogenous melatonin synthesis to 50% increasing the risk for insomnia and vascular brain damage, mostly in patients with lower initial level of 6-SM circadian excretion.: melatonin, 6-sulfatoxymelatonin, beta-blockers, insomnia, vascular white matter brain damage, leptin, adiponectin.

Physiological rhythms are influenced by photophase wavelength in a nocturnal and a diurnal rodent species from South Africa.

The quality and quantity of light changes significantly over the course of the day. The effect of light intensity on physiological and behavioural responses of animals has been well documented, particularly during the scotophase, but the effect of the wavelength of light, particularly during the photophase, less so. We assessed the daily responses in urine production, urinary 6-sulfatoxymelatonin (6-SMT) and glucocorticoid metabolite (uGCM) concentrations in the nocturnal Namaqua rock mouse (Micaelamys namaquensis) and diurnal four striped field mouse (Rhabdomys pumilio) under varying wavelengths of near monochromatic photophase (daytime) lighting. Animals were exposed to a short-wavelength light cycle (SWLC; ∼465-470 nm), a medium-wavelength light cycle (MWLC; ∼515-520 nm) and a long-wavelength light cycle (LWLC; ∼625-630 nm). The SWLC significantly attenuated mean daily urine production rates and the mean daily levels of urinary 6-SMT and of uGCM were inversely correlated with wavelength in both species. The presence of the SWLC greatly augmented overall daily 6-SMT levels, and simultaneously led to the highest uGCM concentrations in both species. In M. namaquensis, the urine production rate and urinary 6-SMT concentrations were significantly higher during the scotophase compared to the photophase under the SWLC and MWLC, whereas the uGCM concentrations were significantly higher during the scotophase under all WLCs. In R. pumilio, the urine production rate and uGCM were significantly higher during the scotophase of the SWLC, not the MWLC and LWLC. Our results illustrate that wavelength in the photophase plays a central role in the entrainment of rhythms in diurnal and nocturnal African rodent species.

Melatonin and Depression: A Translational Perspective From Animal Models to Clinical Studies.

Daily rhythm of melatonin synchronizes the body to the light/dark environmental cycle. Several hypotheses have been raised to understand the intersections between melatonin and depression, in which changes in rest-activity and sleep patterns are prominent. This review describes key experimental and clinical evidence that link melatonin with the etiopathology and symptomatology of depressive states, its role in the follow up of therapeutic response to antidepressants, as well as the clinical evidence of melatonin as MDD treatment. Melatonin, as an internal temporal cue contributing to circadian organization and best studied in the context of circadian misalignment, is also implicated in neuroplasticity. The monoaminergic systems that underly MDD and melatonin production overlap. In addition, the urinary metabolite 6-sulfatoxymelatonin (aMT6) has been proposed as biomarker for antidepressant responders, by revealing whether the blockage of noradrenaline uptake has taken place within 24 h from the first antidepressant dose. Even though animal models show benefits from melatonin supplementation on depressive-like behavior, clinical evidence is inconsistent vis-à-vis prophylactic or therapeutic benefits of melatonin or melatonin agonists in depression. We argue that the study of melatonin in MDD or other psychiatric disorders must take into account the specificities of melatonin as an integrating molecule, inextricably linked to entrainment, metabolism, immunity, neurotransmission, and cell homeostasis.

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.

Association between night-shift work and level of melatonin: systematic review and meta-analysis.

BACKGROUNDS: Night-shift workers are exposed to nocturnal light and are more prone to circadian rhythm disorders. Although night-shift work is thought to be associated with the decrease in melatonin secretion, studies have shown inconsistent results. METHODS: This systematic review and meta-analysis studied the association between night-shift work and melatonin levels. Pubmed and Embase databases were used for literature searching. The pooled standardized mean differences (SMDs) and 95% confidence intervals (CIs) were used to compare the differences between night-shift workers and the controls. RESULTS: Thirty-three studies reported in 25 articles (1845 night-shift workers and 3414 controls, mean age 45.12 years) were included after a systematic literature review. Data of circulating melatonin levels and its metabolites, 6-sulfatoxymelatonin (aMT6s) in urine were collected for meta-analysis. The results showed that the first morning-void aMT6s level in night-shift workers was significantly lower than in day workers (SMD = -0.101, 95% CI = -0.179 to -0.022, P = 0.012). The level of mean 24-h urinary aMT6s was lower in night-shift workers than day workers (SMD: -0.264, 95% CI: -0.473 to -0.056, P = 0.013). Among fixed night-shift workers, the level of circulating melatonin, as well as first morning-void aMT6s was lower than that of day workers. CONCLUSION: Our findings indicate that experience of night-shift work is associated with suppression of melatonin production, especially among fixed night-shift workers.

Endogenous melatonin mediation of systemic inflammatory responses to ozone exposure in healthy adults.

BACKGROUND/AIM: Melatonin is a free radical scavenger and an anti-inflammatory biomolecule. Air pollution exposure has been associated with increased inflammatory responses. We hypothesize that endogenous melatonin plays a role in inflammatory responses to air pollution exposure. METHODS: We tested this hypothesis in a cohort of 53 healthy adults (22-52 years old, 16 women), none of whom were on melatonin supplementation. Early morning urine and fasting blood were collected from each participant longitudinally up to three times. We analyzed urinary 6-sulfatoxymelatonin (aMT6s), as a surrogate of circulating melatonin, and pro- and anti-inflammatory cytokines in the plasma samples. Indoor and outdoor air pollutants were measured and combined with participants' time-activity patterns to calculate personal exposure to O3, PM2.5, NO2, and SO2 averaged over 12-hour, 24-hour, 1-week, and 2-week periods prior to biospecimen collection, respectively. Linear mixed-effects models were used to examine the relationships among urinary aMT6s, personal pollutant exposure, and plasma cytokines. A mediation analysis was conducted to examine the role of aMT6s in the relationships between pollutant exposures and inflammatory cytokines. RESULTS: One interquartile range (4.2 ppb) increase in 2-week O3 exposure was associated with a -26.2% (95% CI: -43.9% to -2.8%) decrease in aMT6s. Within the range of endogenous aMT6s concentrations (0.5-53.0 ng/ng creatinine) across the participants, increased aMT6s was associated with decreased pro-inflammatory cytokines including IL-1ß, IL-8, IL-17A, IFN-γ, and TNF-α. These cytokines were significantly and positively associated with 2-week average O3 exposure. Furthermore, 7.4% to 17.4% of the O3-cytokine associations were mediated by aMT6s. We did not find similar effects for the other pollutants. CONCLUSIONS: Pro-inflammatory responses to O3 exposure in the preceding 2 weeks partly resulted from the depletion of endogenous melatonin by O3.

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.

Meta-analysis of melatonin levels in cluster headache-Review of clinical implications.

Cluster headache (CH) has been associated with circadian disturbances. The present systematic review examined available evidence for the utilization of melatonin (MT) in CH prophylaxis. First, case-control studies assessing nocturnal MT or its urine-expelled metabolite 6-sulfatoxymelatonin (aMT6s) in CH individuals and healthy controls (HC) were reviewed and meta-analyzed. Secondly, the results from randomized controlled trials (RCTs) and non-randomized studies evaluating MT's use in the prevention of CH were discussed. Literature search included MEDLINE, EMBASE, CENTRAL, PsycINFO, trial registries, Google Scholar, and OpenGrey. Bouts and remissions were assessed separately. Ten case-control studies (adult participants) were retrieved. Seven evaluated serum MT; meta-analysis involved only three of them (due to deficient reporting, n: bout = 31, remission = 38, HC = 31). Results were compatible with lower nocturnal serum MT levels during bouts [bout-HC; FE-MD = -29.89 pg/mL, 95% CI = (-46.00, -13.78), remission-HC; FE-MD = -2.40 pg/mL, 95% CI = (-16.57, 21.38), bout-remission; RE-MD = -32.10 pg/mL, 95% CI = (-56.78, -7.42)]. Nocturnal urinary melatonin was appraised in two studies, but reporting issues impeded the capitalization of the results. Nocturnal urine aMT6s was evaluated by two studies (n: bout = 29, remission = 22, HC = 20), and pooled results were indicative of lower aMT6s concentration in CH individuals during both active and inactive periods [bout-HC; FE-MD = -9.63 µg/nocturnal urine collection, 95% CI = (-14.40, -4.85), remission-HC; FE-MD = -9.12 µg/nocturnal urine collection, 95% CI = (-14.63,-3.62), bout-remission; FE-MD = -0.58 µg/nocturnal urine collection, 95% CI = (-4.58, 3.42)]. Regarding CH prophylaxis, one RCT and two non-randomized trials were retrieved, involving a total of 41 adult CH individuals (11-episodic, 31-chronic) and rendering the deduction of any conclusions precarious. Overall, available data for the role use of MT in CH are insufficient and inconclusive. Complementary studies evaluating endogenous MT concentrations and MT administration to patients with CH are warranted.

"Seat of the soul"? The structure and function of the pineal gland in women with alleged spirit possession-Results of two experimental studies.

BACKGROUND: Cultural traditions attribute to pineal gland an important role for spiritual experiences. Mediumship and spirit possession are cultural phenomena found worldwide which have been described as having dissociative and psychotic-like characteristics, but with nonpathological aspects. A sympathetic activation pattern in response to spirit possession has been reported in some studies, but empirical data on pineal gland is scarce in this context. METHODS: We aimed to investigate pineal gland and pituitary volumes, as well as urinary 6-sulfatoxymelatonin levels in 16 alleged mediums (Medium Group-MG) compared with 16 healthy nonmedium controls (Control Group) (Experiment 1). Furthermore, we aimed to evaluate urinary 6-sulfatoxymelatonin and stress reactivity in GM (n = 10) under different physiological conditions (Experiment 2). RESULTS: In Experiment 1, MG presented higher scores of anomalous experiences, but there were no between-group differences regarding mental health or subjective sleep quality. Similar pineal gland and pituitary volumes were observed between groups. There were no between-group differences in urinary 6-sulfatoxymelatonin collected under equivalent baseline conditions. In Experiment 2, the rise of anxiety and heart rate in response to mediumistic experience was intermediate between a nonstressful control task (reading) and a stressful control task (Trier Social Stress Test-TSST). No significant differences were observed in 6-sulfatoxymelatonin urinary levels between the three conditions. The pattern of stress reactivity during the TSST was normal, but with an attenuated salivary cortisol response. CONCLUSION: The normal neuroimaging and stress reactivity findings in MG contrast with the abnormal results usually observed in subjects with psychotic and dissociative disorders.

Urinary Excretion of 6-Sulfatoxymelatonin, the Main Metabolite of Melatonin, and Mortality in Stable Outpatient Renal Transplant Recipients.

Melatonin is a multifaceted hormone which rises upon the onset of darkness. Pineal synthesis of melatonin is known to be disturbed in patients with end-stage renal disease, but it is not known if its production is restored to normal after successful renal transplantation. We hypothesized that urinary excretion of 6-sulfatoxymelatonin, the major metabolite of melatonin, is lower in renal transplant recipients (RTRs) compared to healthy controls and that this is associated with excess mortality. Urinary 6-sulfatoxymelatonin was measured via LC-MS/MS in 701 stable outpatient RTRs and 285 healthy controls. Median urinary 6-sulfatoxymelatonin in RTR was 13.2 nmol/24h, which was 47% lower than in healthy controls. Urinary 6-sufatoxymelatonin appeared undetectable in the majority of 36 RTRs with diabetic nephropathy as primary renal disease. Therefore, this subgroup was excluded from further analyses. Of the remaining 665 RTRs, during 5.4 years of follow-up, 110 RTRs died, of whom 38 died due to a cardiovascular cause. In Cox-regression analyses, urinary 6-sulfatoxymelatonin was significantly associated with all-cause mortality (0.60 (0.44-0.81), p = 0.001) and cardiovascular mortality (0.49 (0.29-0.84), p = 0.009), independent of conventional risk factors and kidney function parameters. Based on these results, evaluation and management of melatonin metabolism could be considered for improvement of long-term outcomes in RTRs.