Search

Daniel P Cardinali,1 Gregory M Brown,2 Seithikurippu R Pandi-Perumal3 1Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina; 2Molecular Brain Science Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; 3Department of Psychiatry, University of Toronto, Toronto, Ontario, CanadaCorrespondence: Seithikurippu R Pandi-Perumal, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India, Email Pandiperumal2022@gmail.comAbstract: Aging is accompanied by circadian changes, including disruptive alterations in the sleep/wake cycle, as well as the beginning of low-degree inflammation (“inflammaging”), a scenario that leads to several chronic illnesses, including cancer, and metabolic, cardiovascular, and neurological dysfunctions. As a result, any effective approach to healthy aging must consider both the correction of circadian disturbance and the control of low-grade inflammation. One of the most important prerequisites for healthy aging is the preservation of robust circadian rhythmicity (particularly of the sleep/wake cycle). Sleep disturbance disrupts various activities in the central nervous system, including waste molecule elimination. Melatonin is a chemical with extraordinary phylogenetic conservation found in all known aerobic creatures whose alteration plays an important role in sleep changes with aging. Every day, the late afternoon/nocturnal surge in pineal melatonin helps to synchronize both the central circadian pacemaker found in the hypothalamic suprachiasmatic nuclei (SCN) and a plethora of peripheral cellular circadian clocks. Melatonin is an example of an endogenous chronobiotic substance that can influence the timing and amplitude of circadian rhythms. Moreover, melatonin is also an excellent anti-inflammatory agent, buffering free radicals, down-regulating proinflammatory cytokines, and reducing insulin resistance, among other things. We present both scientific and clinical evidence that melatonin is a safe drug for treating sleep disturbances in the elderly.Keywords: melatonin, sleep, elderly, safety, neurodegeneration

Ramanujam Karthikeyan,1 Ganapathy Marimuthu,1 Chellamuthu Ramasubramanian,2 Gautham Arunachal,2 Ahmed S BaHammam,3 David Warren Spence,4 Daniel P Cardinali,5 Gregory M Brown,6 Seithikurippu R Pandi-Perumal7 1Department of Animal Behaviour and Physiology, School of Biological Sciences, Madurai Kamaraj University, Madurai, India; 2MS Chellamuthu Trust and Research Foundation, KK Nagar, Madurai, India; 3University Sleep Disorders Center, College of Medicine, National Plan for Science and Technology, King Saud University, Riyadh, Saudi Arabia; 4Independent researcher, Toronto, Ontario, Canada; 5Department of Teaching and Research, Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina; 6Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; 7Center for Healthful Behavior Change (CHBC), Division of Health and Behavior, Department of Population Health, NYU Langone Medical Center, Clinical and Translational Research Institute, New York, New York, USA Background: Sleep–wake disturbances have frequently been reported in bipolar disorder and schizophrenia, and are considered to be caused by an underlying circadian rhythm disorder. The study presented here was designed to investigate the existence of Per3 polymorphism in bipolar disorder type I (BD-I) and schizophrenic patients in South India.Methods: Blood samples were collected from 311 BD-I patients, 293 schizophrenia patients, and 346 age- and sex-matched normal controls. Per3 genotyping was performed on DNA by polymerase chain reaction using specific primers.Results: An increased prevalence of five repeat homozygotes was seen in BD-I patients as compared with healthy controls (odds ratio =1.72 [95% confidence interval: 1.08–2.76, P=0.02]). In BD-I patients, the frequency of the five repeat allele was higher (allele frequency =0.41), and that of the four repeat allele lower (allele frequency =0.36) (χ2=4.634; P

Scher J, Wankiewicz E, Brown GM, Fujieda H. Invest Ophthalmol Vis Sci 2002;43:889-897. PURPOSE. Melatonin's function in human vision is far from understood, in part because of the lack of [...]

Sleep is a behavioral process that is governed by both homeostatic and circadian processes. While the intensity and duration of sleep is governed mainly by the homeostatic process (sleep debt), the timing of sleep is orchestrated by the anterior hypothalamic suprachiasmatic nuclei (SCN). Disturbances in the organization of the sleep/wake cycle as well as circadian (approximately 24-hour periodicity) dysregulation are often noted in mental illness. The circadian rhythm of pineal melatonin secretion, which is controlled by the SCN, is reflective of mechanisms that are involved in the control of the sleep/wake cycle. Melatonin influences sleep-promoting and sleep/wake rhythm-regulating actions through the specific activation of melatonin (MT)[1] and MT2 receptors, highly concentrated in the SCN. In healthy humans, melatonin induces sleep by a process influenced by the circadian phase. The hypnotic and rhythm-regulating properties of metatonin and its agonists (ramelteon, agomelatine) make them an important addition to the armamentarium of drugs for treating sleep disturbances and circadian rhythm steep disorders associated with mental illness. [ABSTRACT FROM AUTHOR]

Two different heavy ion reactions were used to produce 43 Sc (t 12 = 3.891 h), 44g Sc (t 12 = 4.042 h), and 44m Sc (t 12 = 58.61 h) among other stable or long-lived chemically separable products. Production cross sections for 19 F + 27 Al and the reverse kinematic reaction 35 Cl + nat B were measured using an MC-SNICS ion source and the Notre Dame FN Tandem Accelerator. 19 F beams from 35 to 60 MeV were produced with beam currents between 40-80 pnA and 35 Cl beams were produced at six entrance energies with comparable beam currents. This work reports nuclear reaction cross sections 27 Al ( 19 F, x) 43 Sc, 27 Al ( 19 F, pn) 44g Sc, and 27 Al ( 19 F, pn) 44m Sc at six energies between 35 and 60 MeV lab energy. Cross sections within the same energy range were measured for 27 Al ( 19 F, 3pn) 42 K and 27 Al ( 19 F, 3p) 43 K. Comparative measurements were performed for the same compound nucleus produced from nat B( 35 Cl, x) 43 Sc, nat B( 35 Cl, pn) 44g Sc, and nat B( 35 Cl, pn) 44m Sc. The measured thin target cross sections show an overestimation by several statistical models for the scandium radioisotopes. This is corroborated by the measured thick target production rates for both entrance channels. This may be due to angular momentum effects of a heavy ion entrance channel compared to light-ion production, but additional work is required to understand this discrepancy. These measurements demonstrate that the medically useful 43 Sc, 44g Sc, and 44m Sc radioisotopes can be free of the long-lived contaminant 46 Sc without the use of enriched targets, using heavy ion beams and robust target materials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A circadian disruption, manifested by disturbed sleep and low-grade inflammation, is commonly seen in noncommunicable diseases (NCDs). Cardiovascular, respiratory and renal disorders, diabetes and the metabolic syndrome, cancer, and neurodegenerative diseases are among the most common NCDs prevalent in today's 24-h/7 days Society. The decline in plasma melatonin, which is a conserved phylogenetic molecule across all known aerobic creatures, is a constant feature in NCDs. The daily evening melatonin surge synchronizes both the central pacemaker located in the hypothalamic suprachiasmatic nuclei (SCN) and myriads of cellular clocks in the periphery ("chronobiotic effect"). Melatonin is the prototypical endogenous chronobiotic agent. Several meta-analyses and consensus studies support the use of melatonin to treat sleep/wake cycle disturbances associated with NCDs. Melatonin also has cytoprotective properties, acting primarily not only as an antioxidant by buffering free radicals, but also by regulating inflammation, down-regulating pro-inflammatory cytokines, suppressing low-grade inflammation, and preventing insulin resistance, among other effects. Melatonin's phylogenetic conservation is explained by its versatility of effects. In animal models of NCDs, melatonin treatment prevents a wide range of low-inflammation-linked alterations. As a result, the therapeutic efficacy of melatonin as a chronobiotic/cytoprotective drug has been proposed. Sirtuins 1 and 3 are at the heart of melatonin's chronobiotic and cytoprotective function, acting as accessory components or downstream elements of circadian oscillators and exhibiting properties such as mitochondrial protection. Allometric calculations based on animal research show that melatonin's cytoprotective benefits may require high doses in humans (in the 100 mg/day range). If melatonin is expected to improve health in NCDs, the low doses currently used in clinical trials (i.e., 2-10 mg) are unlikely to be beneficial. Multicentre double-blind studies are required to determine the potential utility of melatonin in health promotion. Moreover, melatonin dosage and levels used should be re-evaluated based on preclinical research information., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Purpose: Eccentric viewing training for macular disease has been performed for > 40 years, but no large studies including control groups have assessed the benefits of this training. The EFFECT (Eccentric Fixation From Enhanced Clinical Training) study is a large randomized controlled trial of 2 types of eccentric viewing training., Design: Randomized controlled trial., Participants: Two hundred adults with age-related macular disease., Methods: Participants were randomized to either of the following: (1) a control group; (2) a group receiving supervised reading support; (3) a group receiving 3 sessions of training to optimize the use of their own preferred retinal locus; or (4) a group receiving 3 sessions of biofeedback training of a theoretically optimal trained retinal locus. All participants received standard low-vision rehabilitation., Main Outcome Measures: The primary outcome was patient-reported visual task ability measured on the Activity Inventory instrument at goal level. Secondary outcomes included reading performance and fixation stability., Results: There was no difference between groups on change in task ability ( F (3,174)  = 1.48, P  = 0.22) or on any of the secondary outcome measures. Visual acuity and contrast sensitivity fell in all groups, suggesting that disease progression outweighed any benefit of training., Conclusions: Eccentric viewing training did not systematically improve task ability, reading performance, or fixation stability in this study. Our results do not support the routine use of eccentric viewing training for people with progressing age-related macular disease, although this training may help people with end-stage disease. Rehabilitation of an inherently progressive condition is challenging., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2023 by the American Academy of Ophthalmology.)

Objective: To date no research has examined the potential influence of acute stress symptoms (ASD) on subsequent development of post-traumatic stress disorder (PTSD) symptoms in stroke survivors. Our objective was to examine whether acute stress symptoms measured 1-2 weeks post-stroke predicted the presence of post-traumatic stress symptoms measured 6-12 weeks later., Design: Prospective within-groups study., Methods: Fifty four participants who completed a measure of acute stress disorder at 1-2 weeks following stroke (time 1) and 31 of these participants completed a measure of posttraumatic stress disorder 6-12 weeks later (time 2). Participants also completed measures of stroke severity, functional impairment, cognitive impairment, depression, anxiety, pre-morbid intelligence and pain across both time points., Results: Some 22% met the criteria for ASD at baseline and of those, 62.5% went on to meet the criteria for PTSD at follow-up. Meanwhile two of the seven participants (28.6%) who met the criteria for PTSD at Time 2, did not meet the ASD criteria at Time 1 (so that PTSD developed subsequently). A hierarchical multiple regression analysis indicated that the presence of acute stress symptoms at baseline was predictive of post-traumatic stress symptoms at follow-up (R2 = .26, p < .01). Less severe stroke was correlated with higher levels of post-traumatic stress symptoms at Time 2 (rho = .42, p < .01)., Conclusions: The results highlight the importance of early assessment and identification of acute stress symptoms in stroke survivors as a risk factor for subsequent PTSD. Both ASD and PTSD were prevalent and the presence of both disorders should be assessed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Feely et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Black Americans with multiple sclerosis (MS) experience higher levels of disease-related disability compared to White Americans (Marrie et al., 2006). Comorbidities such as depression and anxiety, which are underdiagnosed and undertreated in this population, negatively impact quality of life and treatment outcomes for people living with multiple sclerosis (plwMS) (D'Alisa et al., 2006; Marrie et al., 2009; Stepleman et al., 2014). Acts of discrimination toward Black Americans is associated with stress, which is a contributing factor for depression (Carter, 2017; Nadimpalli, 2015; Williams and Mohammed, 2009). This study compared the severity of multiple sclerosis symptoms amongst Black Americans and White Americans, and whether worsened MS symptoms in Black Americans are associated with increased experiences of discrimination. Data was analyzed from 143 plwMS in the Stress Indicators in Minorities with Multiple Sclerosis (SiMMS) study. Using the Mann-Whitney U test, significant differences were found on the NIH Emotional Distress - Anxiety measure (U = 1466.500, p = 0.045) and NIH Sleep Disturbance measure (U = 1467.000, p = 0.044) between the Black participant and the White participant groups. Discrimination was significantly correlated with both NIH Emotional Distress - Anxiety (r = 0.677, p < .001) and NIH Sleep Disturbance (r = 0.446, p = .007) in Black MS individuals. Additionally, several physiological condition and psychological outcome measures were correlated with the NIH Emotional Distress - Anxiety and NIH Sleep Disturbance measures. This study contributes to literature highlighting the negative impacts of discrimination and race related stress on the physical and mental health of Black Americans., Competing Interests: Declaration of Competing Interest There are no financial or personal interests (across any/all authors) that would affect author objectivity regarding this manuscript., (Copyright © 2023. Published by Elsevier B.V.)

Disparity in hospice use threatens optimal quality of life during the final stage of life while American Indians/Alaska Natives may not be aware of hospice benefits. Our established Blackfeet members and Montana State University collaborative team conducted a modified Duke End-of-Life Care Survey (8 sections with 60 questions) to assess a baseline end-of-life values, beliefs, and attitudes of Blackfeet individuals. In this manuscript, we present the results of 3 sections with 28 questions: Preference of Care; Beliefs About Dying, Truth Telling, and Advance Care Planning; and Hospice Care by examining overall and generational differences. Most participants (n = 92) chose quality of life over quantity of life with using various devices if they had an incurable disease (54-82%), would want to know if they were dying (92%) or had cancer (89%), but had not thought or talked about their preference of end-of-life care (30% and 35% respectively). The results portray understandable cultural context as well as generational differences with personal variability. While an affirmative shift towards hospice was emerging, dissemination of accurate hospice information would benefit people in the partner community. In conclusion, an individual-centered approach-understanding individual need first-may be the most appropriate and effective strategy to promote hospice information and its use.

Taboo perception on talking about death and dying among American Indians/Alaska Natives is prevalent. This suppressive value makes hospice introduction difficult, leading hospice disparity. Working together by using a community-based participatory research approach over a decade, we conducted a 6-hour workshop including information sharing and group activities. The purpose of the study was to investigate the community readiness for end-of-life knowledge by conducting a public workshop. We used pre- and post-workshop surveys with Likert-type responses to five questions to assess the effect of workshop in end-of-life knowledge. Thirty individuals participated the workshop; 80% of them reported their knowledge increase on at least one question. While the survey had concerns, positive participant responses indicated readiness and appropriateness to use workshops to increase end-of-life knowledge.

Clinical sequelae and symptoms for a considerable number of COVID-19 patients can linger for months beyond the acute stage of SARS-CoV-2 infection, "long COVID". Among the long-term consequences of SARS-CoV-2 infection, cognitive issues (especially memory loss or "brain fog"), chronic fatigue, myalgia, and muscular weakness resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are of importance. Melatonin may be particularly effective at reducing the signs and symptoms of SARS-CoV-2 infection due to its functions as an antioxidant, anti-inflammatory, and immuno-modulatory agent. Melatonin is also a chronobiotic medication effective in treating delirium and restoring the circadian imbalance seen in COVID patients in the intensive care unit. Additionally, as a cytoprotector, melatonin aids in the prevention of several COVID-19 comorbidities, including diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases. This narrative review discusses the application of melatonin as a neuroprotective agent to control cognitive deterioration ("brain fog") and pain in the ME/CFS syndrome-like documented in long COVID. Further studies on the therapeutic use of melatonin in the neurological sequelae of SARS-CoV-2 infection are warranted.

In this paper I explore what it means to encounter the symbol as a meaningful object, or process, within the environment of the other-than-human. Using Jung's account in 'The spirit mercurius' of an enlisted Indigenous soldier who attempts to desert his barracks on hearing a native Oji tree calling him, I compare the evolving stages of consciousness theorised by Jung to explain this phenomenon with the progression discussed by him in his commentary on Dorn's coniunctio. My aim is to clarify Jung's understanding of the symbolically constellated and 'undifferentiated' worldview of what Jung calls the 'primitive'. I also draw on the work of Spitzform, Searles, Roszak, Fisher, Chalquist, Prentice and Rust in relation to the emerging field of ecopsychology, where consideration of a fundamental link between psychological and material existence - between psyche and ecos - has been proposed as an essential component of psychological theory, and in which our alienation from our natural surroundings has been identified as pathological. I include observations from my own experience of working therapeutically with clients in outdoor settings and I ask how a more ecosystemically integrated sense of self might be sought for a psyche that encounters symbolic material within its containing environment., (© 2022 The Authors. Journal of Analytical Psychology published by John Wiley & Sons Ltd on behalf of The Society of Analytical Psychology.)

Sleep and the circadian clock are intertwined and have persisted throughout history. The suprachiasmatic nucleus (SCN) orchestrates sleep by controlling circadian (Process C) and homeostatic (Process S) activities. As a "hand" on the endogenous circadian clock, melatonin is critical for sleep regulation. Light serves as a cue for sleep/wake control by activating retino-recipient cells in the SCN and subsequently suppressing melatonin. Clock genes are the molecular timekeepers that keep the 24 h cycle in place. Two main sleep and behavioural disorder diagnostic manuals have now officially recognised the importance of these processes for human health and well-being. The body's ability to respond to daily demands with the least amount of effort is maximised by carefully timing and integrating all components of sleep and waking. In the brain, the organization of timing is essential for optimal brain physiology., (Copyright © 2022. Published by Elsevier Inc.)

Exposure to an adequate light-dark cycle is important for the speedy recovery of hospitalized and institutionalized patients. Light exposure, including natural light, offers several health benefits to both patients and nursing staff. This includes physical (e.g., decreased confusion and disorientation) and mental health benefits (e.g., prevention of depression) and a reduction in the hospital stay. Improved alertness and performance can also be noted among hospital staff. In this commentary, we discuss disrupting factors that include light during the nighttime along with noise and physical procedures on the patient and others. We then address some of the important steps that can be undertaken to restore a more normal environment for patients in the intensive care unit, which can be particularly important for COVID-19 patients.

Objective: The prevalence of sleep disorders during the perinatal period is high and large health administrative database surveys have shown that the use of exogenous melatonin in pregnant populations is quite common, about 4%. Much of the concern about using melatonin during pregnancy and breastfeeding stems from animal research. Thus, the objective of this article is to provide a critical review of human studies related to exogenous melatonin use during pregnancy and breastfeeding., Methods: The electronic databases Ovid, MEDLINE, Embase, and the Cochrane Library were searched using terms and keywords related to melatonin, pregnancy, and breastfeeding., Results: Fifteen studies were included in this review. Eight focused on melatonin use during pregnancy and seven focused on melatonin use during breastfeeding. There was a variety of study designs, including case reports, cohort studies, and clinical trials. There is a lack of randomized, controlled trials examining the efficacy and safety of melatonin as a treatment for sleep disorders during pregnancy or breastfeeding and, notably, insomnia was not the primary outcome measure in any of the studies included in this review. Clinical trials that used exogenous melatonin during pregnancy and breastfeeding for other clinical conditions have not suggested major safety concerns or adverse events., Conclusion: Contrary to what animal studies have suggested, evidence from clinical studies to date suggests that melatonin use during pregnancy and breastfeeding is probably safe in humans. This review further emphasizes the need for clinical studies on sleep disorders, including exogenous melatonin, during pregnancy and lactation.

Aims: The objective of the present study was to investigate the effect of melatonin and L-thyroxine (T4) on the expression of various receptors, and some metabolic, reproductive, and gonadotropic hormones in letrozole-induced polycystic ovary syndrome (PCOS) in rats., Material and Methods: Assessment of gravimetric, hormonal profile and thyroid histology and relative expression of melatonin receptors (MT1, MT2) and estrogen receptor α (Erα) in thyroid and ovary, and type II iodothyronine deiodinase (Dio2) and thyroid hormone receptor α (TRα) in the ovary were performed using standard protocols., Key Findings: A significant increase in thyroid follicles numbers was noted in the hyperthyroid rat. T4 treatment to PCOS showed the expected increment in the circulating level of triiodothyronine (T 3 ) and T 4 . Melatonin and T4 treatment of PCOS rats resulted in a significant decrease in the circulating level of T 3 and T 4 . Hyperthyroid rats showed a decrement in plasma melatonin levels. However, T4 treatment to PCOS rats showed increased circulating melatonin levels, and a decrease in the circulating level of gonadotropins (LH and FSH), and testosterone. Melatonin treatment to PCOS-hyperthyroid rats resulted in the normal expression of ovarian and thyroid MT1 and ERα, receptors, which had been altered in PCOS and hyperthyroid rats, without any significant change in the MT2 receptor., Significance: The present findings suggest a fine interplay and cross-talk via melatonin and its two receptors with ERα, TRα, and Dio 2 in thyroid and ovarian tissue during PCOS and hyperthyroidism pathogenicity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives/methods: The biology underlying sleep is not yet fully elucidated, but it is known to be complex and largely influenced by circadian rhythms. Compelling evidence supports of a link among circadian rhythms, sleep and metabolism, which suggests a role for mitochondria. These organelles play a significant role in energy metabolism via oxidative phosphorylation (OXPHOS) and several mitochondrial enzymes display circadian oscillations. However, the interplay between mitochondria and sleep is not as well-known. This review summarises human and animal studies that have examined the role of mitochondria in sleep. Literature searches were conducted using PubMed and Google Scholar., Results: Using various models of sleep deprivation, animal studies support the involvement of mitochondria in sleep via differential gene and protein expression patterns, OXPHOS enzyme activity, and morphology changes. Human studies are more limited but also show differences in OXPHOS enzyme activity and protein levels among individuals who have undergone sleep deprivation or suffer from different forms of insomnia., Conclusions: Taken altogether, both types of study provide evidence for mitochondria's involvement in the sleep-wake cycle. We briefly discuss the potential clinical implications of these studies.

Introduction: The present study was designed to evaluate the therapeutic efficacy of melatonin and insulin coadministration in diabetes-induced renal injury in rats., Research Design and Methods: Diabetes was achieved by giving streptozotocin (15 mg/kg) for 6 consecutive days. The diabetic condition was confirmed by assessing the blood glucose level; animals having blood glucose levels above 250 mg were considered as diabetic. Following the confirmation, animals were randomly divided into different experimental groups, viz group I served as the control (CON), group II diabetic (D), group III D+melatonin (MEL), group IV D+insulin (INS), group V D+MEL+INS, group VI D+glibenclamide (GB), group VII CON+MEL, group VIII CON+INS, and group IX CON+GB. Following the completion of the experimental period, animals were sacrificed, blood was collected via a retro-orbital puncture, and kidneys were harvested. Diabetic rats exhibited a significant increment in blood glucose and biochemical indexes of renal injury (tubular disruption, swollen glomeruli with loss of glomerular spaces, and distortion of the endothelial lining) including augmented levels of serum creatinine, urea, uric acid, Na+, and K+, and inhibition/suppression of the activity of glutathione (GSH) peroxidase, GSH reductase, glucose-6-phosphate dehydrogenase, and GSH-S-transferase in the renal cortex., Results: By examining thiobarbiturate reactive substances, reduced GSH, superoxide dismutase activity, and catalase activity in the renal cortex of control and diabetic rats, it was documented that treatment with melatonin or insulin alone or in combination showed a significant ad integrum recovery of GSH-dependent antioxidative enzymatic activities. Melatonin and insulin coadministration caused greater reductions in circulating tumor necrosis factor-α, tumor growth factor-β1, interleukin (IL)-1β, and IL-6 levels in diabetic rats, whereas IL-10 levels increased, as compared to each treatment alone. Diabetic rats showed a significant increase in the expression of both MT1 and MT2 melatonin receptor genes. Melatonin or insulin treatment alone or in combination resulted in significant restoration of the relative expression of both melatonin receptors in the renal cortex., Conclusion: The coadministration of exogenous melatonin and insulin abolished many of the deleterious effects of type 1 diabetes on rat renal function., (© 2021 S. Karger AG, Basel.)

Background: The prevalence of insomnia and hypersomnia in depressed individuals is substantially higher than that found in the general population. Unfortunately, these concurrent sleep problems can have profound effects on the disease course. Although the full biology of sleep remains to be elucidated, a recent genome-wide association (GWAS) of insomnia, and other sleep traits in over 1 million individuals was recently published and provides many promising hits for genetics of insomnia in a population-based sample. Methods: Using data from the largest available GWAS of insomnia and other sleep traits, we sought to test if sleep variable PRS scores derived from population-based studies predicted sleep variables in samples of depressed cases [Psychiatric Genomics Consortium - Major Depressive Disorder subjects (PGC MDD)]. A leave-one-out analysis was performed to determine the effects that each individual study had on our results. Results: The only significant finding was for insomnia, where p -value threshold, p = 0.05 was associated with insomnia in our PGC MDD sample ( R 2 = 1.75 -3 , p = 0.006). Conclusion: Our results reveal that <1% of variance is explained by the variants that cover the two significant p -value thresholds, which is in line with the fact that depression and insomnia are both polygenic disorders. To the best of our knowledge, this is the first study to investigate genetic overlap between the general population and a depression sample for insomnia, which has important treatment implications, such as leading to novel drug targets in future research efforts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Melhuish Beaupre, Tiwari, Gonçalves, Zai, Marshe, Lewis, Martin, McIntosh, Adams, Baune, Levinson, Boomsma, Penninx, Breen, Hamilton, Awasthi, Ripke, Jones, Jones, Byrne, Hickie, Potash, Shi, Weissman, Milaneschi, Shyn, Geus, Willemsen, Brown, Kennedy and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.)

This brief review was written to provide a perspective on the flurry of reports suggesting that melatonin can be an important add-on therapy for COVID-19. Despite the passage of more than 60 years since its discovery and much evidence representing the contrary, there has been great reluctance to conceive melatonin as anything other than a hormone. Many other body chemicals are known to have multiple roles. Melatonin was first shown to be a hormone derived from the pineal gland, to be actively synthesized there only at night, and to act on targets directly or via the G-protein-coupled receptors (GPCRs) superfamily. It is of note that over 40 years ago, it was also established that melatonin is present, synthesized locally, and acts within the gastrointestinal tract. A wider distribution was then found, including the retina and multiple body tissues. In addition, melatonin is now known to have non-hormonal actions, acting as a free radical scavenger, an antioxidant, and as modulating immunity, dampening down innate tissue responses to invaders while boosting the production of antibodies against them. These actions make it a potentially excellent weapon against infection by the SARS-CoV-2 virus. Early published results support that thesis. Recently, a randomized controlled study reported that low doses of melatonin significantly improved symptoms in hospitalized COVID-19 patients, leading to more rapid discharge with no side effects, while significantly decreasing levels of CRP, proinflammatory cytokines, and modulating dysregulated genes governing cellular and humoral immunity. It is now critical that these trials be repeated, with dose-response studies conducted and safety proven. Numerous randomized controlled trials are ongoing, which should complete those objectives while also allowing for a more thorough evaluation of the mechanisms of action and possible applications to other severe diseases.

Melatonin is an ancient molecule that is evident in high concentrations in various tissues throughout the body. It can be separated into two pools; one of which is synthesized by the pineal and can be found in blood, and the second by various tissues and is present in these tissues. Pineal melatonin levels display a circadian rhythm while tissue melatonin does not. For decades now, melatonin has been implicated in promoting and maintaining sleep. More recently, evidence indicates that it also plays an important role in neuroprotection. The beginning of our review will summarize this literature. As an amphiphilic, pleiotropic indoleamine, melatonin has both direct actions and receptor-mediated effects. For example, melatonin has established effects as an antioxidant and free radical scavenger both in vitro and in animal models. This is also evident in melatonin's prominent role in mitochondria, which is reviewed in the next section. Melatonin is synthesized in, taken up by, and concentrated in mitochondria, the powerhouse of the cell. Mitochondria are also the major source of reactive oxygen species as a byproduct of mitochondrial oxidative metabolism. The final section of our review summarizes melatonin's potential role in aging and psychiatric disorders. Pineal and tissue melatonin levels both decline with age. Pineal melatonin declines in individuals suffering from psychiatric disorders. Melatonin's ability to act as a neuroprotectant opens new avenues of exploration for the molecule as it may be a potential treatment for cases with neurodegenerative disease.

Patients with Autism Spectrum Disorder (ASD) may be particularly prone to develop COVID-19. An unusual extended course of COVID-19 disease illness has been reported in one ASD patient and a group of patients have COVID-19 disease in a neurodevelopmental facility. It has been widely reported that many of those with ASD have substantial sleep disorders with low levels of melatonin and various genetic alterations related to melatonin production have been found. Several lines of evidence point to a substantial role of melatonin in the body's innate defense system including acting as a scavenger, an antioxidant and modulating the immune system. We therefore hypothesize that melatonin deficiency may predispose those ASD patients who have low melatonin output to COVID-19 disease. Potential implications for treatment are discussed., (Copyright © 2021. Published by Elsevier Ltd.)