Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease.

Disruption of the physiologic sleep-wake cycle and low melatonin levels frequently accompany cardiac disease, yet the underlying mechanism has remained enigmatic. Immunostaining of sympathetic axons in optically cleared pineal glands from humans and mice with cardiac disease revealed their substantial denervation compared with controls. Spatial, single-cell, nuclear, and bulk RNA sequencing traced this defect back to the superior cervical ganglia (SCG), which responded to cardiac disease with accumulation of inflammatory macrophages, fibrosis, and the selective loss of pineal gland-innervating neurons. Depletion of macrophages in the SCG prevented disease-associated denervation of the pineal gland and restored physiological melatonin secretion. Our data identify the mechanism by which diurnal rhythmicity in cardiac disease is disturbed and suggest a target for therapeutic intervention.

MiR-375-3p mediates reduced pineal function in hypoxia-ischemia brain damage.

The functional roles of microRNAs (miRNAs) have been studied in various diseases, including hypoxic-ischemic brain damage (HIBD). However, changes in the expression of miRNAs and the underlying mechanisms in the pineal gland during HIBD remain unknown. Based on the previous study by microRNA array, hundreds of miRNAs showed altered expression patterns in the pineal gland in a rat model of HIBD. MiR-375-3p was found to be significantly upregulated and abundant in the pineal gland. Further investigation in an in vitro HI model of pinealocytes showed that miRNA-375 exacerbated the damage to pineal function. After oxygen-glucose deprivation / reoxygenation (OGD/R), miR-375-3p expression increased, while aralkylamine N-acetyltransferase (AANAT) expression and melatonin (MT) secretion decreased. Overexpression of miRNA-375 in pinealocytes aggravated the influence of OGD/R on AANAT expression and MT secretion. Because miRNA-375 overexpression in pinealocytes induced decreased rasd1 mRNA and protein expression, rasd1 may mediate the effect of miR-375-3p on pineal function. Furthermore, miR-375-3p aggravated the cognitive impairment caused by HIBD in rats, as observed by Morris water maze test, and also affected emotion and circadian rhythm in HIBD-treated rats. Thus, miR-375-3p may be a key regulatory molecule in the pineal gland following HIBD, and targeting of miR-375-3p may represent a new strategy for the treatment of HIBD.

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.

Mass-spectrometry analysis of the human pineal proteome during night and day and in autism.

The human pineal gland regulates day-night dynamics of multiple physiological processes, especially through the secretion of melatonin. Using mass-spectrometry-based proteomics and dedicated analysis tools, we identify proteins in the human pineal gland and analyze systematically their variation throughout the day and compare these changes in the pineal proteome between control specimens and donors diagnosed with autism. Results reveal diverse regulated clusters of proteins with, among others, catabolic carbohydrate process and cytoplasmic membrane-bounded vesicle-related proteins differing between day and night and/or control versus autism pineal glands. These data show novel and unexpected processes happening in the human pineal gland during the day/night rhythm as well as specific differences between autism donor pineal glands and those from controls.

Isolated convergence-retraction nystagmus secondary to intralesional haemorrhage of a pineal cyst: an easily missed neurological finding with potentially life-threatening consequences.

This case report describes a patient who presented to the emergency department with intermittent visual disturbance and was found to have convergence-retraction nystagmus. This occurred in the setting of supratherapeutic anticoagulation on warfarin for an aortic dissection graft repair. Urgent imaging demonstrated haemorrhagic transformation of a previously identified incidental pineal cyst. After close monitoring given the risk of secondary hydrocephalus, the patient was discharged in stable condition with symptom resolution and without any further significant complications. This case report highlights the importance of identifying subtle clinical findings and the risk of secondary haemorrhage of pineal cysts when on anticoagulation. While the risk of secondary hydrocephalus is a significant concern, clinically stable patients can be followed without need for neurosurgical intervention.

Arecoline inhibits pineal-testis function in experimentally induced hypothyroid rats.

Arecoline is known to cause endocrine dysfunction. In the current article role of arecoline on pineal-testis activity was investigated in hypothyroid rats induced by propylthiouracil (PTU). PTU treatment caused thyroid dysfunction ultrastructurally with a fall in T3 and T4 levels followed by a rise of thyroid stimulating hormone (TSH) level. Pineal activity was impaired by PTU treatment, as evident from degenerated synaptic ribbons and mitochondria of the pinealocytes with depletion of pineal and serum N-acetyl serotonin and melatonin levels. Leydig cell function was suppressed, evident from reduced smooth endoplasmic reticulum and depletion of testosterone level. Sex accessories function was impaired by showing scanty rough endoplasmic reticulum with depletion of fructose and sialic acid levels. Arecoline treatment that caused pineal dysfunction and testicular stimulation in control rats, suppressed both pineal and testis functions after PTU treatment. The findings suggest that arecoline inhibits pineal-testis function in experimentally induced hypothyroid rats.

Current understanding of pineal gland structure and function in headache.

PURPOSE: The pineal gland plays an important role in biological rhythms, circadian and circannual variations, which are key aspects in several headache disorders. OVERVIEW: Melatonin, the main pineal secreting hormone, has been extensively studied in primary and secondary headache disorders. Altered melatonin secretion occurs in many headache syndromes. Experimental data show pineal gland and melatonin both interfere in headache animal models, decreasing trigeminal activation. Melatonin has been shown to regulate CGRP and control its release. DISCUSSION: Melatonin has been used successfully as a treatment for migraine, cluster headaches and other headaches. There is a rationale for including the pineal gland as a relevant brain structure in the mechanisms of headache pathophysiology, and melatonin as a treatment option in primary headache.

Pineal gland dysfunction in Alzheimer's disease: relationship with the immune-pineal axis, sleep disturbance, and neurogenesis.

Alzheimer's disease (AD) is a globally common neurodegenerative disease, which is accompanied by alterations to various lifestyle patterns, such as sleep disturbance. The pineal gland is the primary endocrine organ that secretes hormones, such as melatonin, and controls the circadian rhythms. The decrease in pineal gland volume and pineal calcification leads to the reduction of melatonin production. Melatonin has been reported to have multiple roles in the central nervous system (CNS), including improving neurogenesis and synaptic plasticity, suppressing neuroinflammation, enhancing memory function, and protecting against oxidative stress. Recently, reduced pineal gland volume and pineal calcification, accompanied by cognitive decline and sleep disturbances have been observed in AD patients. Here, I review current significant evidence of the contribution of pineal dysfunction in AD to the progress of AD neuropathology. I suggest new insights to understanding the relationship between AD pathogenesis and pineal gland function.

A Case Report of Adult Pineoblastoma Occurring in a Pregnant Woman.

BACKGROUND/AIM: Pineoblastoma of the adult age is an uncommon tumor with only 200 cases reported. A standardized approach for an optimal adjuvant strategy is currently lacking. The case presented herein also deals with the issue of central nervous system tumors in pregnancy. CASE REPORT: A 21-year-old pregnant woman presented with massive hydrocephalus due to a mass in the pineal region detected with MRI. After positioning an urgent ventricular derivation, a cesarean section was performed. During a third ventriculocisternostomy, a biopsy revealed a pineoblastoma. After a maximal safe resection, postoperative craniospinal irradiation for a total dose of 36 Gy plus a sequential boost to the tumor bed to 54 Gy, and adjuvant chemotherapy with CDDP plus CCNU plus vincristine were performed. After one year, the patient is alive with no evidence of disease. CONCLUSION: The use of adjuvant radio-chemotherapy provided excellent outcomes in our case. The advanced gestational age facilitated the choice of the therapeutic strategy.

The absence of maternal pineal melatonin rhythm during pregnancy and lactation impairs offspring physical growth, neurodevelopment, and behavior.

Maternal melatonin provides photoperiodic information to the fetus and thus influences the regulation and timing of the offspring's internal rhythms and preparation for extra-uterine development. There is clinical evidence that melatonin deprivation of both mother and fetus during pregnancy, and of the neonate during lactation, results in negative long-term health outcomes. As a consequence, we hypothesized that the absence of maternal pineal melatonin might determine abnormal brain programming in the offspring, which would lead to long-lasting implications for behavior and brain function. To test our hypothesis, we investigated in rats the effects of maternal melatonin deprivation during gestation and lactation (MMD) to the offspring and the effects of its therapeutic replacement. The parameters evaluated were: (1) somatic, physical growth and neurobehavioral development of pups of both sexes; (2) hippocampal-dependent spatial learning and memory of the male offspring; (3) adult hippocampal neurogenesis of the male offspring. Our findings show that MMD significantly delayed male offspring's onset of fur development, pinna detachment, eyes opening, eruption of superior incisor teeth, testis descent and the time of maturation of palmar grasp, righting reflex, free-fall righting and walking. Conversely, female offspring neurodevelopment was not affected. Later on, male offspring show that MMD was able to disrupt both spatial reference and working memory in the Morris Water Maze paradigm and these deficits correlate with changes in the number of proliferative cells in the hippocampus. Importantly, all the observed impairments were reversed by maternal melatonin replacement therapy. In summary, we demonstrate that MMD delays the appearance of physical features, neurodevelopment and cognition in the male offspring, and points to putative public health implications for night shift working mothers.

[CME: Jet Lag Jetlag]. / CME: Jetlag CME-Fragen.

CME: Jet Lag Jetlag Abstract. Crossing several time zones by air travel leads to a temporary desynchronization of the internal clock with the external light/dark cycle. In the following jet lag occurs typically including difficulties falling asleep or waking up early as well as day-time sleepiness and significant reduction of wellbeing and fitness. To provide optimal medical advice, it is necessary to understand the human circadian rhythm and sleep-wake regulation. In consideration with additional information on travel plans, an approach to alleviate jet lag symptoms can be developed. This article addresses different supportive measures and advice on how to adjust to a new time zone and reduce jet lag symptoms.

Peripheral Precocious Puberty Caused by Human Chorionic Gonadotropin Producing Pineal Gland Tumor.

BACKGROUND: Pineal gland lesions usually present with central precocious puberty. CASE CHARACTERISTICS: A 3½-yr-old boy presented with precocious puberty. Clinically and biochemically, it was gonadotropin releasing hormone (GnRH) independent. Serum and CSF beta-hCG levels were increased. Thin section magnetic resonance imaging of brain revealed a pineal gland tumor. OUTCOME: He received chemotherapy followed by radiotherapy and responded well. MESSAGE: CSF beta-hCG should be measured in all cases of peripheral precocity, and if CSF beta-hCG is elevated, thin section magnetic resonance imaging of brain should be considered.

Arecoline cannot alter testicular dysfunction and pineal activation caused by noise in wistar rat.

Millions of people consume betel nut for increased capacity to work and for stress reduction. The nut contains arecoline, which has multiple side effects on endocrine functions. Objective of the work is to investigate pineal-testicular responses to noise and after arecoline treatment in noise in rats. Noise exposure (100 dB, 6 h daily, 10 days) caused pineal stimulation ultrastructurally and at indoleamines level. Leydig cell dysfunction with fall of testosterone level and suppression of sex accessories were noticed. In contrast, pineal activity was inhibited and reproductive functions were stimulated after arecoline administration, confirmed from reversed changes to those of noise. Arecoline treatment in noise exposure showed same results as in noise both in pineal and in reproductive functions. It is concluded that noise causes testicular dysfunction probably by gonadotropin suppression induced by pineal melatonin in noise. Furthermore, arecoline cannot prevent it in noise in rats.

Peculiairities of the influence nitrogen monoxide synthesis blockade on circadian organization of kidney acid-regulating function under conditions of pineal gland hyperfunction.

OBJECTIVE: Introduction: In recent decades chronobiology - a science that studies the regularities of the functioning of the organism, especially biological rhythms is developing rapidly. Biorhythms are stable nonstopper lifetime fluctuations with individual amplitude-frequency characteristics. Kidneys are characterized by a clear time organization of functions too, however, the peculiarities of circadian organization and the mechanisms of the participation of intracellular messengers in particular nitrogen monoxide (NО) in biorhythmic regulation of renal functions, remain insufficiently studied The aim of our work was to investigate the peculiairities of the influence nitrogen monoxide synthesis blockade on circadian organization of kidney acid-regulating function under conditions of pineal gland hyperfunction. PATIENTS AND METHODS: Materials and methods: The experiments were conducted on 72 mature non-linear albino male rats with their body mass 0,15-0,18 kg. The animals were kept under vivarium conditions at a stable temperature and air humidity fed on a standard dietary intake. The control group included animals (n=36) kept under conditions of usual light regimen (12.00L:12.00D) during 7 days. The experimental group included animals (n=36) injected with N-nitro-L-arginine (L-NNA) in the dose of 20 mg/kg during 7 days under conditions of continuous absolute darkness (12.00D:12.00D). On the 8th day the animals were exposed to 5& water load with heated to room temperature water supplied and the parameters of the kidney acid-regulating function under conditions of forced diuresis were investigated. RESULTS: Results: The inhibition of the monoxide synthesis (NО) in conditions of pineal gland (PG) hyperfunction violated the structures of chronorhythms acid-regulating function of the kidneys. The decrease in urine pH at daytime intervals was due to a decrease in the level of hydrogen ion excretion during this period of the day. The introduction of the NО blocker against the background of the PG hyperfunction violated the structure of the acid esterification chronorhythms that are titrated. The maximum level of this indicator was recorded at 20.00 a.m. a day. The blockade of the synthesis NО on the background of the PG hyperfunction significantly reduced the level of excretion of ammonia. CONCLUSION: Conclusions: The maximum level of excretion was 12.00 a.m., bathyphase - at 24.00 a.m. The average daily level was 1.5 mcmol/100 mcl GF and was lower relative to the control animals and animals that were in the conditions of PG hyperfunction.

PECULIAIRITIES OF MELATONIN EFFECT ON CHONORHYTMIC ORGANIZATION OF KIDNEY ACID-REGULATING FUNCTION INFLUENCED BY NITROGEN MONOXIDE SYNTHESIS BLOCKADE UNDER CONDITIONS OF PINEAL GLAND HYPOFUNCTION.

The objective of research is to study the peculiarities of melatonin effect on chronorhythmic organization of the kidney acid-regulating function influenced by nitrogen monoxide (NO) synthesis blockade under conditions of pineal gland (PG) hypofunction. The experiments were conducted on 72 mature non-linear albino male rats with their body mass 0,15-0,18 kg. The animals were kept under vivarium conditions at a stable temperature and air humidity fed on a standard dietary intake. The control group included animals (n=36) kept under conditions of usual light regimen (12.00С:12.00Т) during 7 days. The experimental group included animals (n=36) injected with N-nitro-L-arginine (L-NNA) in the dose of 20 mg/kg during 7 days under conditions of continuous light (12.00С:12.00С) and melatonin in the dose of 0,5 mg/kg during 7 days simultaneously. On the 8th day the animals were exposed to 5% water load with heated to room temperature water supplied and the parameters of the kidney acid-regulating function under conditions of forced diuresis were investigated. Kidney functions in the control animals are subordinated to accurate circadian organization. Daily rhythms of the parameters of kidney acid-regulating functions reflect similar changes of the renal processes. Chronorhythmic transformations of the kidney acid-regulating functions in animals with blocked NO synthesis against continuous light and parallel injection of melatonin enable to suggest that NO synthesis blockade under conditions of melatonin correction reduces daily mean pH level as compared to the control. Although, it was higher than that in the animals with blocked NO synthesis against the ground of physiological function of the pineal gland, and animals with PG hypofunction under conditions of NO synthesis blockadeю Therefore, under conditions of L-NNA blockade of NO synthesis and injection of melatonin influenced by PG hypofunction chronorhythmic transformations of architectonics and phase structure of rhythms of the majority of parameters of the kidney acid-regulating function were found, which is an important diagnostic sign of exertion of adaptive possibilities on the border of transmission of adaptation into disadaptation, were detected.

Non-24-Hour Sleep-Wake Rhythm Disorder and Melatonin Secretion Impairment in a Patient With Pineal Cyst.

ABSTRACT: We report the case of a 14-year-old girl with a wide non-compressive pineal cyst, associated with the inability to control her sleep-wake schedule. Actigraphic monitoring showed a 24-hour free-running disorder (tau 26.96 hours). A 24-hour serum melatonin curve assay, with concomitant video-polysomnographic and body-core temperature monitoring, was performed. Melatonin curve showed a blunted nocturnal peak, lower total quantity of melatonin, and prolonged melatonin secretion in the morning, with normal temperature profile and sleep parameters. Treatment with melatonin up to 14 mg at bedtime was initiated with complete realignment of the sleep-wake rhythm (tau 23.93 hours). The role of the pineal cyst in the aforementioned alteration of melatonin secretion and free-running disorder remains controversial, but our case supports the utility of monitoring sleep/wake, temperature, and melatonin rhythms in the diagnostic work-up of pineal cysts associated with free-running disorder.

The association of pineal gland volume and body mass in obese and normal weight individuals: a pilot study.

BACKGROUND: In obese individuals impaired sleep and neuroendocrine alterations such as melatonin deficits are associated with circadian rhythm disruption, altered circadian clock gene expression, and bright light at night. While the relation of pineal gland volume (PGV) and melatonin levels has recently been documented in humans, surprisingly little is known about the possible interference of the PGV and the pathophysiology of obesity in humans. SUBJECTS AND METHODS: We therefore compared the PGV of obese with non-obese individuals; both groups were matched by age and gender. Volumetric analyses were performed on the basis of 3 Tesla high resolution Magnetic Resonance Imaging (MRI). RESULTS: We found, that the PGV was significantly smaller in obese individuals than in lean controls (P=0.036). Moreover, PGV and waist-hip ratio showed a significant negative association in controls (P=0.018, rs=-0.602) whereas no association of both variables was found in obese individuals (P=0.856, rs=-0.051). CONCLUSIONS: Thus, the current pilot investigation suggests that pineal gland function, reflected by PGV might be involved in the energy homeostasis and pathophysiological mechanisms that contribute to the development and the maintenance of obesity in humans. Moreover, our data supports the notion that the replacement of melatonin deficits might be a novel strategy in the treatment of obesity.

SPECIFIC FEATURES OF CHRONORHYTH- MOLOGIC CHANGES OF THE ION-REGU- LATING FUNCTION OF THE KIDNEYS UN- DER THE HYPOFUNCTION OF THE PINEAL GLAND.

The paper investigates the specific features of chronorhythmologic changes of the ion-regulating function of the kidneys under the hypofunction of the pineal gland. For the study of hypofunction of the pineal gland, animals were maintained under constant light stimulation during 7 days. It has been established that the hypofunction epiphysis point out disturbances of the phasic structure of the ion-regulating function in relation to chronograms of the intact group of rats. In terms of physiological pinealectomy observed in- crease in the excretion of sodium ions (6,11±0,81 mmol/h) and the concentration of this cation in the blood plasma remained elevated around the clock. The obtained results indicate significant changes of integral characteristics of the rhythms of electrolyte metabolism and the important role of the pineal gland in ensuring physiological homeostasis.

[Reproductive health disorders in night shift workers (review of literature)].

The review considers problems of reproductive health disorders in night shift workers. In materials of national and foreign authors, ambiguous opinions are presented on the influence, such as on reproductive sphere malignancies development in shift workers. Data of experimental and clnical laboratory studies are presented, that support reproductive pathologies connected with night shift work. The authors tackle a problem on role of epiphysis and circadian rhythms, that influence physiologic biologic rhythms.