Melatonin Release Research Articles

Сравнительный анализ качества сна здоровых девушек и женщин в период гестации

Background: Sleep disorders during pregnancy pose a real threat to the mother and fetus due to a violation of the physiological course of the gestation process, the release of melatonin (central and peripheral). The aim of the study:Comparative evaluation of sleep and chronotype indicators in healthy pregnant and healthy non-pregnant women. Materials and methods: There was conducted a voluntary survey of 210 relatively healthy non-pregnant girls (medical students), the average age was 20±3.5 years, and 69 women with physiological pregnancy (the average age was 29.69±5.03 years) according to the Russian version of the Munich Chronotype Questionnaire in the conditions of Vladikavkaz without a block of subjective self-assessment of the chronotype. 100 people were randomly selected from a group of healthy girls –group 1; pregnant women were divided by trimesters: group 2 (I trimester, 10 women), group 3 (II trimester, 20 women), group 4 – (III trimester, 39 women). Integral indicators were calculated on weekends and working days: the middle and duration of sleep, wake-up time, "jetlag" (desynchronosis), and the chronotype was estimated. Statistical processing was carried out by methods of variational statistics IBM SPSS 23 and Statistica 10.0. Results: Physiological pregnancy is characterized by a statistically significant improvement in sleep indicators, a shift in the middle of sleep to the period of maximum melatonin concentration, a decrease in sleep deficit on working days, and a reduction in jet lag. The increase in sleep duration noted in pregnant women prevents a number of physical and mental health disorders associated with the secretion of melatonin and the restructuring of the NEIM system. In all trimesters of pregnancy, an intermediate chronotype (ImCht) was determined – a "medium" chronotype, in non-pregnant women – a slightly late chronotype (SLCht) – a "slightly late" chronotype, which also speaks in favor of greater sleep stability during the physiological course of pregnancy. Conclusion: The use of the Munich Chronotype Questionnaire (MCTQ) in pregnant women allowed us to determine the trends of physiological changes in normal sleep indicators.

Chronopharmacology : The right timing can be crucial

Chronopharmacology takes into account, among other things, the circadian rhythm, arecurring, daily rhythm of biological functions that is significantly influenced by the day-night rhythm. Daily rhythm, diseases, and therapies influence each other: the circadian rhythm, among other factors, could influence the effect of pharmacological and nonpharmacological therapies, especially in urological oncology. This article focuses on the question of the optimal time for therapeutic interventions and considers relevant basics of chronobiological principles depending on possible biomarkers that could be targets of afuture therapeutic approach. With chronomodulated chemotherapy, cancer therapies are not only more tolerable, but also more effective. Effects and side effects of an active substance can change according to the circadian rhythm. Due to the introduction of particularly targeted, oral tumor therapies, adaily application would be organizationally possible, but further clinical studies are necessary for this. The internal clock could play an unexpected role, especially in hormone-dependent prostate cancer: the amount of the circadian factor Cry1 not only seems to increase in the advanced stage, but is also closely associated with apoorer prognosis. Epidemiological studies also show aconnection between hormone-dependent tumors and the disruption of the rhythmic release of melatonin. Melatonin appears to be able to improve therapy as an adjunct to cancer therapy in some urological tumor entities.

The Effects of Different Density Microneedles on Melatonin Release

The Effects of Different Density Microneedles on Melatonin Release

Circadian molecular clock disruption in chronic pulmonary diseases.

The circadian clock is the biochemical oscillator with a near 24-h period that is responsible for generating the circadian rhythms in peripheral organs including the lung. Mounting evidence suggests that circadian clock disruption during chronic lung diseases plays an essential role in augmented oxidative stress, inflammatory response, metabolic imbalances, hypoxia/hyperoxia, mucus secretion, dysregulated autophagy, and alters pulmonary function. Here, we review circadian clock disruption and discuss candidate clock genes that are altered at the transcriptional or translational level in chronic pulmonary diseases. This review aims to provide the current knowledge and understanding of the circadian molecular clock disruption in chronic pulmonary diseases which will further advance the development of novel clock-based therapeutics in the future.

Audit to Assess Melatonin Prescribing in Community CAMHS

AimsDisordered sleep is common, affecting 20–30%of children aged 1–5 years and often continues later into childhood. Neurodevelopmental disorders and psychiatric comorbidities pose a greater risk. The audit aimed to determine whether clinical prescribing practice of melatonin in Burlington House, Sefton CAMHS reflected current NICE recommendations. NICE suggest that first-line treatments for children with sleep problems include good sleep hygiene and behavioural therapy (including sleep diary).MethodsNice guideline CG170 provides guidance on Autism management. BNFC states that melatonin therapy should be reviewed every 6 months. Records of children currently prescribed modified release melatonin were checked to see if they met the inclusion criteria. Data were collected retrospectively from clinical case files and pharmacy records (December 2020- February 2021).ResultsThe results showed 18 young persons received melatonin for insomnia with ASD, 26 for insomnia without ASD, 3 for likely ASD and none for Smith Magenis syndrome. 36 received Specialist CAMHS review, 9 received Community Pediatrics review and 2 GP review. All patients received melatonin as per dose recommendations with 6 monthly reviews. Documentation on sleep hygiene was unclear.ConclusionWe concluded that Melatonin prescribing in community CAMHS tends to be high and discussion on sleep hygiene measures must be given importance.

0813 Post-Pinealectomy Insomnia and Melatonin Therapy

Abstract Introduction Melatonin is a hormone produced in the pineal gland that has an important role in sleep; immune, neurologic, psychiatric, metabolic, and endocrinologic function; cardiac-autonomic regulation and even cancer risk. We present a case of insomnia, somnambulism, dream enactment, and periodic limb movements of sleep (PLMS) after a pinealectomy. Report of Cases: A 40-year-old woman with a history of a complete pinealectomy due to a pineal cyst presented to the sleep medicine clinic. Shortly after the pinealectomy, she developed sleep onset and maintenance insomnia. Two years later she developed somnambulism, and four years later she developed dream enactment and PLMS. She reported no prior treatments for her sleep issues, including no history of melatonin use. On average, her total sleep time (TST) was 2-8 hours/night with awakenings every 2 hours. Sleep latency was 10-45 minutes. Polysomnograghy demonstrated an apnea-hypopnea index of 0.6/hr, PLM index of 68.1/hr, normal REM atonia, and no complex behaviors. The patient started 1mg immediate release (IR) melatonin, which did not help her insomnia, but parasomnias resolved. She had improvement in her PLMS with iron supplementation and melatonin. The melatonin dose was increased to 3mg IR which helped increase her TST to 4-8 hours. She was switched to 3mg extended release (ER) melatonin, and then increased to 4mg ER. She obtained the most benefit for her insomnia with 1mg IR plus 4mg ER with sleep latency reduced to 5-10 minutes and TST improved up to 7.5 hours with rare awakenings. Conclusion Pinealectomy in humans is rarely reported. Most data about the consequences of pinealectomy and pathophysiology of melatonin come from animal research. Melatonin level after pinealectomy is often undetectable or severely diminished. Current limited literature on patients with pinealectomy consists of case reports about patients who experienced insomnia, non-24-hour sleep-wake rhythm disorder [SSM1] and mood disorders. Melatonin doses ranging from 0.5mg to 14mg IR and up to 5mg ER have been trialed with most patients having symptomatic improvement with doses above 3mg. We found that a combination of 1mg immediate and 4mg extended release melatonin was the most beneficial for our patient. Support (If Any)

0799 Precipitation of Dream Enactment Behavior in the setting of β -Blocker therapy

Abstract Introduction REM sleep behavior disorder (RBD) is defined by dream enactment behavior (DEB) and REM sleep without muscle atonia (RWA). It is proposed that in both isolated and secondary RBD, the loss of REM sleep atonia is related to a failure of spinal motoneuron inhibition in the rostral pons. RBD is most commonly isolated, although it has been attributed to serotonergic antidepressant medication. This is the first report of metoprolol succinate (MS) provoking DEB in patients with RWA which helps shed more light on the mechanism of DEB in RBD. Report of Cases: A 51-year-old male with a new diagnosis of atrial fibrillation (AF) was referred for evaluation of snoring and hypersomnolence. Polysomnography (PSG) revealed obstructive sleep apnea and RWA. DEB was not observed. Compliance with PAP therapy improved his symptoms. Persistent AF required the use of Metoprolol Succinate (MS), which precipitated aggressive DEB. Discontinuation of MS resulted in clinical resolution of DEB. Conclusion The data sheds more light on the potential role of β- blockers, in general, and MS, in particular, in precipitating DEB in susceptible individuals with RWA. While MS is an uncommon cause of visual hallucinations, the data here indicates that it might increase susceptibility to DEB in those who are at risk (RWA). Potential mechanisms include the following: β-blockers bind to serotonin receptors and precipitate DEB in the setting of RWA. β-blockers may also precipitate DEB by suppressing melatonin release via specific inhibition of central beta-adrenoreceptors culminating in sleep instability and DEB as a consequence. This case illustrates a clinically important role of the β-blocker MS, in precipitating DEB, and the need to avoid these agents in the setting of injurious parasomnias. We recommend that clinicians keep a vigilant eye for the exacerbation of DEB in people with RBD who are prescribed β-blockers. Support (If Any)

Effects of Modified Melatonin Release on Human Colostrum Neutrophils to Induce Death in the MCF-7 Cell Line.

Cancer is one of the diseases with the highest mortality rate today, with breast cancer being the second most common type among the Brazilian population. Due to its etiological complexity and inefficiency of treatments, studies have focused on new forms of treatment. Among these forms of treatment, hormonal therapy seems to be an excellent auxiliary mechanism in tumoricidal activity, and melatonin has great potential as a modulator of the immune system. Thus, the present study is aimed at evaluating the effect of the hormone melatonin on the coculture of colostrum polymorphonuclear cells and MCF-7 cancer cells and evaluates the effect of this hormone using a modified transport system. A feasibility analysis was performed by fluorescence microscopy at three cell incubation times, 2 hours, 24 hours, and 72 hours. The measurement of cytokines in the cell supernatant occurred in 24 hours, and the apoptosis assay was performed in 72 hours using flow cytometry. The results showed higher levels of cell viability in groups treated with melatonin and less viability in groups containing a coculture of polymorphonuclear cells and MCF-7 after 72 hours of incubation. Furthermore, the apoptosis and necrosis rates were higher in coculture polymorphonuclear and MCF-7 cells, especially in groups containing microemulsion as a modified release agent. These data suggest that melatonin, especially if associated with a modified release system, has immunomodulatory effects on human colostrum polymorphonuclear cells. These cells can play a crucial role in the resolution of the tumor through their mediation and inflammatory action.

Melatonin-Eluting Contact Lenses Effect on Tear Volume: In Vitro and In Vivo Experiments.

(1) Background: The purpose of this study was to synthesize melatonin-eluting contact lenses (CLs) and evaluate both the ocular kinetics of the released melatonin and its effect on tear volume and intraocular pressure. (2) Methods: In vitro, melatonin-eluting CLs were synthesized by using non-functionalized (HEMA) and functionalized (HEMA/APMA) monomers. In vivo, a short-term prospective and randomized study was performed on 15 rabbits divided into two groups: 12 rabbits wearing functionalized CLs and 3 rabbits without CLs as a control. The melatonin levels in tears, aqueous humor, vitreous body and retina, tear volume, and intraocular pressure were measured for 8 h. (3) Results: In vitro, both monomers did not show differences in terms of melatonin loading and release (p ≥ 0.05). In vivo, the melatonin concentration was elevated in tears and aqueous humor after 2 and 4 h of wearing CLs, respectively (p < 0.05). Additionally, the CLs increased tear volume for 2 h (p < 0.05). (4) Conclusions: The melatonin-eluting CLs released their content over the ocular surface for at least 2 h, which was associated with a secretagogue effect on tear volume. However, the increased amount of melatonin found in the aqueous humor had no effect on intraocular pressure.

Impact of melatonin on periodontal ligament fibroblasts during mechanical strain.

The endogenous hormone melatonin regulates the circadian rhythm and impacts on bone metabolism. As patient compliance to wear removable orthodontic appliances is generally higher at night, when melatonin release is increased, a boosting effect on tooth movement would be favourable for therapy, whereas an inhibiting effect would indicate daytime wear to be more therapy-effective. We hypothesize that melatonin has either a stimulating or impeding effect on the expression profile of periodontal ligament fibroblasts (PDLF) during simulated orthodontic compressive and tensile strain, which would suggest either an accelerating or inhibiting impact on orthodontic tooth movement in vivo. PDLF were preincubated with melatonin for 24h and then subjected to tensile or compressive strain to mimic tension and pressure sides in PDL. In addition, the selective melatonin MTNR1B-receptor antagonist 4P-PDOT was used. We investigated melatonin effects on collagen synthesis, expression of inflammatory and bone-remodelling genes/proteins by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assays, and total collagen assays. PDLF-induced osteoclastogenesis was analysed in a coculture model by tartrate-resistant acid phosphatise (TRAP) staining. Expression of melatonin receptors in PDLF was not affected by compressive strain. Melatonin increased expression of inflammatory factors and elevated collagen synthesis during mechanical strain. Melatonin showed no effects on OPG or RANKL expression without mechanical strain, but increased RANKL gene expression during compression. Expression of melatonin receptors by PDLF enable them to detect fluctuating melatonin concentrations in the periodontal ligament. Melatonin increased collagen synthesis and expression of inflammatory mediators, but had no effect on genes involved in bone remodelling. Therefore, we suggest that melatonin has no accelerating effect on PDLF-induced osteoclastogenesis.

Modified Release of the Pineal Hormone Melatonin from Matrix Tablets Containing Poly(L-lactic Acid) and Its PLA-co-PEAd and PLA-co-PBAd Copolymers.

In terms of drug delivery, the attractive properties of poly(L-lactic acid) (PLA) and its aliphatic polyesters, poly(ethylene adipate) (PEAd) and poly(butylene adipate) (PBAd), render them ideal co-formulants for the preparation of modified-release pharmaceutical formulations. Furthermore, we have previously demonstrated that by adding a “softer” aliphatic polyester onto the macromolecular chain of PLA, i.e., PEAd or PBAd, resulting in the formation of the PLA’s copolymers (PLA-co-PEAd and PLA-co-PBAd, in 95/5, 90/10, 75/25 and 50/50 weight ratios), the hydrolysis rate is also severely affected, leading to improved dissolution rates of the active pharmaceutical ingredients (API). In the present report, we communicate our findings on the in vitro modified release of the chronobiotic hormone melatonin (MLT), in aqueous media (pH 1.2 and 6.8), from poly(L-lactic acid) and the aforementioned copolymer matrix tablets, enriched with commonly used biopolymers, such as hydroxypropylmethylcellulose (HPMC K15), lactose monohydrate, and sodium alginate. It was found that, depending on the composition and the relevant content of these excipients in the matrix tablets, the release of MLT satisfied the sought targets for fast sleep onset and sleep maintenance. These findings constitute a useful background for pursuing relevant in vivo studies on melatonin in the future.

Circadian Rhythms and Melatonin Metabolism in Patients With Disorders of Gut-Brain Interactions.

Circadian rhythms are cyclic patterns of physiological, behavioural and molecular events that occur over a 24-h period. They are controlled by the suprachiasmatic nucleus (SCN), the brain’s master pacemaker which governs peripheral clocks and melatonin release. While circadian systems are endogenous, there are external factors that synchronise the SCN to the ambient environment including light/dark cycles, fasting/fed state, temperature and physical activity. Circadian rhythms also provide internal temporal organisation which ensures that any internal changes that take place are centrally coordinated. Melatonin synchronises peripheral clocks to the external time and circadian rhythms are regulated by gene expression to control physiological function. Synchronisation of the circadian system with the external environment is vital for the health and survival of an organism and as circadian rhythms play a pivotal role in regulating GI physiology, disruption may lead to gastrointestinal (GI) dysfunction. Disorders of gut-brain interactions (DGBIs), also known as functional gastrointestinal disorders (FGIDs), are a group of diseases where patients experience reoccurring gastrointestinal symptoms which cannot be explained by obvious structural abnormalities and include functional dyspepsia (FD) and irritable bowel syndrome (IBS). Food timing impacts on the production of melatonin and given the correlation between food intake and symptom onset reported by patients with DGBIs, chronodisruption may be a feature of these conditions. Recent advances in immunology implicate circadian rhythms in the regulation of immune responses, and DGBI patients report fatigue and disordered sleep, suggesting circadian disruption. Further, melatonin treatment has been demonstrated to improve symptom burden in IBS patients, however, the mechanisms underlying this efficacy are unclear. Given the influence of circadian rhythms on gastrointestinal physiology and the immune system, modulation of these rhythms may be a potential therapeutic option for reducing symptom burden in these patients.

PEGylated Nanoencapsulate of Melatonin-Rich Supercritical CO2 Extract of Yellow Mustard Seeds is an Authentic Lead for Type 2 Diabetes and Cholesterol Management

This study aimed to formulate melatonin (MT)-rich nanocapsulates from natural sources for mitigating hypercholesterolemia and type 2 diabetes. The in vivo hypocholesterolemic and antidiabetic efficacies of the MT-rich extract of yellow mustard (YM) seeds has already been established in our previous investigation. This outcome prompted us to formulate nanoliposomes of the aforesaid extract to enhance the said therapeutic efficacies. YM extract has been encapsulated in the form of nanoliposomes (YM-PN) and subjected to detailed functional characterization. YM-PN has been administered orally (550 mg/kg b.w. for 28 days) in Wistar albino rats and, post-sacrification their plasma MT level, fasting blood glucose (FBG) level, serum lipid profile and activities of key enzymes of glucose and cholesterol metabolic pathways were assayed. Functional characterization of YM-PN revealed PEGylated-o/w type-hydrophilic nanoliposomes which demonstrated prolonged and sustained release of MT (63.32% after 8 h). A synergistic consortium of antioxidants conferred strong antioxidant activity to YM-PN. Oral administration of YM-PN to diabetic and hypercholesterolemic rats restored their normal FBG and total cholesterol (TC) levels, respectively, with desirable up-down regulations of key enzymes of glucose and cholesterol homeostasis. Plasma MT levels also improved in these animals. The in vitro non-invasive model of iHOMA2 predicted that YM-PN increased hepatic insulin sensitivity and/ or glucose uptake in the gut in diabetic rats. The synergistic consortium of bioactives (including melatonin) in YM-PN is an authentic lead for natural product-based medicines in redressing hypercholesterolemia and type 2 diabetes.

Melanopsin elevates locomotor activity during the wake state of the diurnal zebrafish

Mammalian and fish pineals play a key role in adapting behaviour to the ambient light conditions through the release of melatonin. In mice, light inhibits nocturnal locomotor activity via the non‐visual photoreceptor Melanopsin. In contrast to the extensively studied function of Melanopsin in the indirect regulation of the rodent pineal, its role in the intrinsically photosensitive zebrafish pineal has not been elucidated. Therefore, it is not evident if the light signalling mechanism is conserved between distant vertebrates, and how Melanopsin could affect diurnal behaviour. A double knockout of melanopsins (opn4.1‐opn4xb) was generated in the diurnal zebrafish, which manifests attenuated locomotor activity during the wake state. Transcriptome sequencing gave insight into pathways downstream of Melanopsin, implying that sustained repression of the melatonin pathway is required to elevate locomotor activity during the diurnal wake state. Moreover, we show that light induces locomotor activity during the diurnal wake state in an intensity‐dependent manner. These observations suggest a common Melanopsin‐driven mechanism between zebrafish and mammals, while the diurnal and nocturnal chronotypes are inversely regulated downstream of melatonin.

Approches thérapeutiques des troubles du sommeil et des rythmes chez l’enfant avec TSA

Sleep disturbances are extremely common (40–86%) in children and adolescents, especially those with autism spectrum disorders (ASD) and are often among the first symptoms identified by parents at a very early stage of their child's development. These abnormalities are among the main parental concerns when having a child with ASD and have a significant impact on the quality of life of patients, their parents, and more broadly their siblings. Sleep disorders are essentially abnormalities of the sleep-wake rhythm – primarily sleep onset insomnia or nocturnal awakenings (with difficulty falling back to sleep). These disturbances can be accompanied by other sleep disorders, requiring notably a systematic elimination of the presence of a sleep apnea or restless legs syndrome – to ensure a personalized and efficient therapeutic approach. Physiologically, the determinants of these sleep disorders are poorly understood, even though several studies point to a significant decrease in melatonin synthesis in people with ASD. Melatonin is a hormone that facilitates falling asleep and maintaining sleep and is also involved in the endogenous synchronization of internal biological clocks. However, the causal factors of this decrease in melatonin synthesis are largely unknown, involving to a small extent the genes involved in melatonin synthesis pathway. The treatment of sleep disorders is relatively systematic: after eliminating other specific sleep disorders associated with the complaint of insomnia, as well as other possible associated comorbidities (such as seizures), a global and graduated therapeutic approach must be put in place. This treatment will be non-pharmacological as a first line, then pharmacological as a second line. A number of non-pharmacological treatment strategies for sleep disorders in typically developing children and adolescents, as well as those with ASD, have been shown to be effective. This treatment requires a combination of: 1) parental education to promote sleep development; 2) setting up bedtime rituals adapted to the child's age and particularities; 3) specific behavioral strategies including bedtime fading, gradual extinction and positive reinforcement of adapted behaviors. It is very essential that the parents are accompanied throughout this therapy. Sleep hygiene and behavioral care must also take into consideration the important role of the zeitgebers of sleep-wake rhythms, i.e. the external environmental factors involved in the synchronization of the biological clocks: regular exposure to light at adapted times, regular meal and wake-up times, social activities and times for going to school. The evidence for the effectiveness of behavioral interventions in the treatment of behavioral insomnia in the typical developmental child is strong, since 94% of children show clinically significant improvements in nighttime sleepiness and waking. By contrast, only about 25% of children with ASD are improved by an approach combining sleep hygiene and behavioral therapy. Melatonin has a special and prominent place in the drug management of sleep disorders associated with ASD. Several clinical trials have shown that melatonin is effective in treating sleep disorders in patients with ASD. This work led to the European Medicines Agency (EMA) granting marketing authorization in September 2018 for a sustained-release paediatric melatonin molecule (Slenyto®). This synthetic molecule is a prolonged release melatonin (PRM) which mimics the physiological pharmacokinetic and secretory characteristics of endogenous melatonin, having a very short blood half-life and prolonged secretion for several hours during the night. A recent study evaluated the efficacy and safety of pediatric PRM (mini-tablets) in 125 children, aged 2 to 17.5 years with mainly ASD. After 15 days on placebo, the children were randomized into two parallel groups, PRM or placebo in a double-blind design for 13 weeks. At endpoint, total sleep time was increased by an average of 57.5 minutes on PRM and only 9.14 minutes on placebo (P=0.034). This difference between the two groups was already significant after three weeks of treatment (P=0.006). Sleep latency was also improved in the PRM group (−39.6 minutes) compared to placebo (−12.51 minutes) (P=0.01). Consolidated sleep duration (uninterrupted by awakenings) was improved by 77.9 minutes for the PRM group and only 25.4 minutes for the placebo group (P<0.001). PRM was well tolerated, the most frequent side effects being headache and daytime drowsiness at the same level with PRM or placebo. In addition, the acceptability by the children for swallowing the mini-tablets was excellent (100% compliance). The efficacy and tolerability of PRM was maintained over the medium and long term in the open phase, over a total study duration of 2 years.

Melatonin/nanoclay hybrids for skin delivery

Melatonin is a hormone used for treating several disorders. However, its oral administration is problematic due to the variable absorption and extensive first-pass metabolism. The topical application of this drug does not present these disadvantages and can be used for therapeutic and skin protection purposes. The adsorption and release of melatonin in the montmorillonite clay were investigated experimentally and theoretically. The drug-clay interaction products were prepared and characterized, showing a modified and improved release of melatonin. The crystal structure and spectroscopic properties of the crystal of melatonin and melatonin-water-mineral materials were studied by molecular modeling, finding that the adsorption of this drug is energetically favourable, and the results were consistent with the experimental data. Ab initio molecular dynamics simulations with the metadynamics methodology showed the release of melatonin from the confined interlayer nanospace of montmorillonite to the liquid bulk water with a 20 kcal/mol free energy barrier.

Non-24-Hour Sleep–Wake Disorder and Tasimelteon: A Review for Practitioners Who Work With Blind People

Introduction This narrative review summarizes the biology of human circadian rhythms; details the epidemiology, clinical manifestation, and diagnosis of non-24-hour sleep–wake disorder (N24SWD); and reviews the efficacy of possible treatments. Methods Searches of targeted phrases, such as “non-24-hour sleep–wake disorder” and “tasimelteon,” were conducted on PubMed between December 2016 and March 2020. Results As the world’s population ages, health practitioners frequently work with people who are blind. Damage to the retinal ganglion cells that signal environmental irradiance levels to the suprachiasmatic nucleus prevents many of these individuals from synchronizing their internal clocks to the 24-hour day. As a result, they experience a condition called N24SWD, where the body’s circadian rhythms fall in and out of phase with the solar cycle. The ability to fall asleep and remain asleep is a complex process that depends on many variables, including the release of the neurohormone melatonin. Melatonin is produced at night and is a key regulator of regular sleep cycles. Periods of interrupted sleep, increased sleep latency, and reduced total sleep time occur when melatonin production peaks during daytime. Thus, many persons with N24SWD have difficulty maintaining normal schedules due in part to the mistimed release of melatonin. Randomized clinical trials have shown that melatonin receptor agonist tasimelteon is an effective therapy for individuals with N24SWD. Other treatments have varying efficacy profiles. Conclusions Although rare, N24SWD is a serious condition that can impair quality of life for blind persons. Tasimelteon appears to be a safe and efficacious treatment option. Implications for Practitioners Practitioners can use this information to better understand why blind persons often report difficulties sleeping and to realize that therapeutic options are available to these individuals.

Reduced melatonin levels may facilitate glioblastoma initiation in the subventricular zone.

There is increasing evidence that glioblastoma, a highly aggressive brain tumour, originates from a neural stem cell (NSC) located in the subventricular zone (SVZ) of the lateral cerebral ventricle. Using the most advanced in vivo imaging techniques, Gengatharan and colleagues recently identified a day/night difference in the adult SVZ-NSC division. They reported that the circadian melatonin rhythm and its receptor control the day/night difference in NSC division with high mitotic activity during the day and low activity at night. Expression of melatonin and its receptor diminishes during ageing, which eliminates the regulatory effect of melatonin on NSC mitosis. Moreover, the circadian melatonin rhythm is dampened by light-at-night with the potential of altering the circadian mitotic cycle of NSC in the SVZ. Also, men with a lower melatonin amplitude than women exhibit a 60% higher rate of glioblastoma incidence. Given that ageing contributes significantly to glioblastoma initiation and progression, we suggest that the decline in circadian melatonin synthesis and release as well as its receptors in the SVZ, which also diminish with an ageing act in concert with other factors to facilitate glioblastoma initiation and growth.

Fast delivery of melatonin from electrospun blend polyvinyl alcohol and polyethylene oxide (PVA/PEO) fibers

&lt;abstract&gt; &lt;p&gt;Water-soluble polymers possess great advantages in current drug delivery systems, such as fast delivery through polymer matrix dissolution as well as promoting solid dispersion of poorly water-soluble drugs. In this work, water-soluble polyvinyl alcohol (PVA) and polyethylene oxide (PEO) were blended (50/50) to electrospin with and without the incorporation of a model drug, melatonin (MLT), at various blend polymer concentrations. Results suggested that increasing blend PVA/PEO solution concentrations, up to 7 wt%, promoted the formation of smooth and defect-free drug-incorporating fibers with an average fiber diameter ranged from 300 to 700 nm. Mechanical properties of the blank and MLT-loaded PVA/PEO fibers showed dependence on fiber morphologies and fiber mat structures, due to polymer concentrations for electrospinning. Furthermore, the surface wettability of the blend PVA/PEO fibers were investigated and further correlated with the MLT release profile of the fibers. Results suggested that fiber mats with a more well-defined fiber structure promoted a linear release behavior within 10 minutes in vitro. These drug-incorporated fibers were compatible to human umbilical vein endothelial cells (HUVECs) up to 24 hours. In general, this work demonstrated the structure-property correlations of electrospun PVA/PEO fibers and their potential biomedical applications in fast delivery of small molecule drugs.&lt;/p&gt; &lt;/abstract&gt;

Dysfunctional Learning and Verbal Memory in Patients with Elevated Tau Protein Levels and Serum Recoverin Autoantibodies-Case Series and Review.

Recoverin-antibody-related disease is currently restricted to late-onset ataxia and autoimmune retinopathy, which can be paraneoplastic or not. However, cognitive dysfunction associated with recoverin antibodies has not been reported so far in a homogeneous patient group. Our case series is dedicated to describing the novel phenotype of cognitive impairment associated with recoverin antibodies. We included five patients with cognitive impairment who presented serum recoverin autoantibodies detected by immunoblots in our case series investigation. We also analyzed their psychopathology, clinical data, cerebrospinal fluid (CSF), and neuroimaging data. Five patients with cognitive impairment associated with serum recoverin antibodies exhibited profound dysfunctional learning and verbal memory. In the CSF of 40% of them, we also diagnosed axonal neurodegeneration entailing elevated tau and phosphorylated tau protein levels. Psychopathologies such as affective symptoms (restlessness, depressive mood, anxiety, complaintiveness) and formal thought disorder, such as rumination, were detected in 25–75% of the patients. We hypothesized a role of recoverin autoimmunity in the pineal gland involving consecutive modulation of hippocampus-based memory caused by an altered release of melatonin. We describe a novel phenotype of possible recoverin autoimmunity in patients with cognitive impairment. However, no clear diagnostic clues can be extracted because of the low diagnostic validity of the testing strategies applied. The possibility of recoverin antibody autoimmunity in the pineal gland correlating with a modulation of hippocampus-based memory should be further investigated.