Restoration Of Circadian Rhythm Research Articles

Lessons Learned from Telemonitoring in an Outpatient Bariatric Surgery Pathway—Secondary Outcomes of a Patient Preference Clinical Trial

BackgroundRemote monitoring is increasingly used to support postoperative care. This study aimed to describe the lessons learned from the use of telemonitoring in an outpatient bariatric surgery pathway.Materials and MethodsPatients were assigned based on their preference to an intervention cohort of same-day discharge after bariatric surgery. In total, 102 patients were monitored continuously for 7 days using a wearable monitoring device with a Continuous and Remote Early Warning Score–based notification protocol (CREWS). Outcome measures included missing data, course of postoperative heart and respiration rate, false positive notification and specificity analysis, and vital sign assessment during teleconsultation.ResultsIn 14.7% of the patients, data for heart rate was missing for > 8 h. A day-night-rhythm of heart rate and respiration rate reappeared on average on postoperative day 2 with heart rate amplitude increasing after day 3. CREWS notification had a specificity of 98%. Of the 17 notifications, 70% was false positive. Half of them occurred between day 4 and 7 and were accompanied with surrounding reassuring values. Comparable postoperative complaints were encountered between patients with normal and deviated data.ConclusionTelemonitoring after outpatient bariatric surgery is feasible. It supports clinical decisions, however does not replace nurse or physician care. Although infrequent, the false notification rate was high. We suggested additional contact may not be necessary when notifications occur after restoration of circadian rhythm or when surrounding reassuring vital signs are present. CREWS supports ruling out serious complications, what may reduce in-hospital re-evaluations. Following these lessons learned, increased patients’ comfort and decreased clinical workload could be expected.Trial RegistrationClinicalTrials.gov. Identifier: NCT04754893.Graphical

Rescue of Comorbid Behavioral and Metabolic Phenotypes of Arrhythmic Mice by Restoring Circadian Cry1/2 Expression in the Suprachiasmatic Nucleus

BackgroundPsychiatric and metabolic disorders occur disproportionately often comorbidly, which poses particular hurdles for patients and therapists. However, the mechanisms that promote such comorbidities are largely unknown and therefore cannot yet be therapeutically targeted for the simultaneous treatment of both conditions. Because circadian clocks regulate most physiological processes and their disruption is a risk factor for both psychiatric and metabolic disorders, they may be considered as a potential mechanism for the development of comorbidities and a therapeutic target. In the current study, we investigated the latter assumption in Cry1/2−/− mice, which exhibit substantially disrupted endogenous circadian rhythms and marked metabolic and behavioral deficits. MethodsBy targeted virus-induced restoration of circadian rhythms in their suprachiasmatic nucleus, we can restore behavioral as well as several metabolic processes of these animals to near-normal circadian rhythmicity. ResultsImportantly, by rescuing suprachiasmatic nucleus rhythms, several of their anxiety-like behavioral as well as diabetes- and energy homeostasis–related deficits were significantly improved. Interestingly, however, this did not affect all deficits typical of Cry1/2−/− mice; for example, restlessness and body weight remained unaffected. ConclusionsTaken together, the results of this study demonstrate, on the one hand, that restoration of disturbed circadian rhythms can be used to simultaneously treat psychiatric and metabolic deficits. On the other hand, the results also allow us to distinguish processes that depend more on local canonical clocks from those that depend more on suprachiasmatic nucleus rhythms.

Pleiotropic effect of sodium-glucose cotransporter 2 inhibitors on blood pressure.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been incorporated as guideline-directed medical therapy for heart failure with reduced ejection fraction. Recent trials clearly established the efficacy of SGLT2 inhibitors on cardiac remodeling while preventing renal function decline in patients with or without diabetes mellitus. Blood pressure reduction during SGLT2 inhibitors use has been proposed through pleiotropic pathways and as a potential contributor that translates to cardiovascular benefits. The mechanisms underlying this decrease in blood pressure are not simply glycemic control. Orchestrating fluid status, modulation of sodium content and renin-angiotensin-activation system, anti-fibrosis and anti-inflammatory effect, ameliorating the characteristics of metabolic syndrome, as well as restoration of circadian rhythm all contributed to the BP lowering effect by SGLT2 inhibitors. Although SGLT2 inhibitors has not been demonstrated as anti-hypertensive agents thus far, their effects on BP alteration are clinically significant. In this review, we revisited the evidence correlating SGLT2 inhibitor use with blood pressure level. Future research directions will focus on the signaling pathway of SGLT2 inhibitors for fluid removal, atherosclerosis, vasoconstriction, and eventually hypertension.

Long-term environmental exposure of darkness induces hyperandrogenism in PCOS via melatonin receptor 1A and aromatase reduction.

Polycystic ovary syndrome (PCOS) is a common and complex disorder impairing female fertility, yet its etiology remains elusive. It is reported that circadian rhythm disruption might play a crucial role in PCOS pathologic progression. Here, in this research, we investigated the effect of environmental long-term circadian rhythm dysfunction and clarified its pathogenic mechanism in the development of PCOS, which might provide the targeted clinical strategies to patients with PCOS. Female SD rats were used to construct a circadian rhythm misalignment model with constant darkness (12/12-h dark/dark cycle), and the control group was kept under normal circadian rhythm exposure (12/12-h light/dark cycle) for 8 weeks. We measured their reproductive, endocrinal, and metabolic profiles at different zeitgeber times (ZTs). Different rescue methods, including melatonin receptor agonist and normal circadian rhythm restoration, and in vitro experiments on the KGN cell line were performed. We found that long-term darkness caused PCOS-like reproductive abnormalities, including estrous cycle disorder, polycystic ovaries, LH elevation, hyperandrogenism, and glucose intolerance. In addition, the expression of melatonin receptor 1A (Mtnr1a) in ovarian granulosa cells significantly decreased in the darkness group. Normal light/dark cycle and melatonin receptor agonist application relieved hyperandrogenism of darkness-treated rats. In vitro experiments demonstrated that decreased MTNR1A inhibited androgen receptor (AR) and CYP19A1 expression, and AR acted as an essential downstream factor of MTNR1A in modulating aromatase abundance. Overall, our finding demonstrates the significant influence of circadian rhythms on PCOS occurrence, suggests that MTNR1A and AR play vital roles in pathological progression of hyperandrogenism, and broadens current treatment strategies for PCOS in clinical practice.

Beneficial effects of melatonin on liver fibrosis: A systematic review of current biological evidence.

Hepatic fibrosis is a reversible response to either acute or chronic cellular injury from a wide variety of etiologies, characterized by excessive deposition of extracellular matrix resulting in liver dysfunction and cirrhosis. Melatonin (N‐acetyl‐5‐methoxytryptamine), the main product secreted by the pineal gland, is a multitasking indolamine with important physiological functions such as anti‐inflammatory and antioxidant actions, modulation of circadian rhythms, and immune system enhancement. Among the numerous biological activities of melatonin, its antifibrotic effects have received increasingly more attention. In this study, we performed a systematic review of publications of the last 10 years evaluating the mechanisms of action of melatonin against liver fibrosis. The study protocol was registered at PROSPERO (CRD42022304744). Literature research was performed employing PubMed, Scopus, and Web of Science (WOS) databases, and after screening, 29 articles were included. Results from the selected studies provided denoted the useful actions of melatonin on the development, progression, and evolution of liver fibrosis. Melatonin antifibrotic effects in the liver involved the reduction of profibrogenic markers and modulation of several cellular processes and molecular pathways, mainly acting as an antioxidant and anti‐inflammatory agent. In addition, the indolamine influenced different molecular processes, such as hepatocyte apoptosis, modulation of autophagy and mitophagy, restoration of circadian rhythms, and modulation of microRNAs, among others. Although some limitations have been found regarding variability in the study design, the findings here summarized display the potential role of melatonin in ameliorating the development of liver fibrosis and its possible progression to liver cirrhosis and hepatocarcinoma.

CHRONOBIOLOGICAL ASPECTS OF MELATONIN INFLUENCE ON THE SEVERAL COMPONENTS OF THE METABOLIC SYNDROME IN HYPOPINEALISM

It was studied the effects of melatonin administration (2,5 mg/kg b. w. intramuscularly for 10 days) on circadian rhythms of the metabolic syndrome main components parameters on young adult rabbits with metabolic syndrome on the background of hypopinealism induced by long (for 5 months) day and night lighting. It was established that chronic treatment with this indolamine induced restoration of circadian rhythms of insulin and glucose levels in serum, decrease of insulin resistance manifestations, reduce abdominal-visceral fat weight, lowering the concentration and recovery leptin circadian rhythms in the serum. It was also revealed, that melatonin administration demonstrate antihypertensive effect, but don’t restore systolic blood pressure circadian rhythm in studied rabbits.

YOGA as a Potential Mind-Body Medicine for Circadian Rhythm Restoration for Cancer Patients

YOGA as a Potential Mind-Body Medicine for Circadian Rhythm Restoration for Cancer Patients

Log files analysis and evaluation of circadian patterns for the early diagnosis of pump thrombosis with a centrifugal continuous-flow left ventricular assist device

No clinical standardized methods exist to identify the early stage of the development of pump thrombosis in the setting of HVAD (Medtronic Inc., USA) implantation. We aimed at developing a clinically relevant tool to evaluate HVAD operation during long-term support and at identifying a new reliable marker for the early diagnosis of pump thrombosis reflecting altered patient-pump physiological interplay. We developed a novel algorithm based on time-frequency analysis of the HVAD log files allowing the detection of the intrinsic circadian rhythmicity of the pump power consumption. With this tool, we retrospectively evaluated (1) post-operative restoration of circadian rhythm (n = 14 patients), (2) long-term stability of circadian rhythmicity in patients with no reported adverse events (n = 12), and (3) alteration of circadian fluctuations in patients who suffered from pump thrombosis (n = 19). We demonstrate (1) progressive development of circadian rhythm following post-operative recovery (93% of the patients, 23 ± 15 days after implantation), (2) long-term stability of circadian rhythmicity in patients with no thrombotic complications (92% of the patients; 962 (445-1447) days of support), and (3) severe instability and loss of circadian fluctuations before the thrombotic event (89% of the patients, 12 ± 6 days ahead of the clinical manifestation of overt pump thrombosis). Furthermore, we provide the first clinical evidence of recovery of circadian rhythmicity following non-surgical resolution of pump thrombosis. Time-frequency analysis of the HVAD log files provides a new tool for the early diagnosis of pump thrombosis. Loss of circadian rhythmicity might trigger medical evaluation, improving the results of medical management of pump thrombosis, and decreasing the need for pump exchange.

Eplerenone restores 24-h blood pressure circadian rhythm and reduces advanced glycation end-products in rhesus macaques with spontaneous hypertensive metabolic syndrome

Hypertension is often associated with metabolic syndrome (MetS), and serves as a risk factor of MetS and its complications. Blood pressure circadian rhythm in hypertensive patients has been suggested to contribute to cardiovascular consequences and organ damage of hypertension. But circadian changes of BP and their response to drugs have not been clearly investigated in non-human primates (NHPs) of MetS with hypertension. Here, we identified 16 elderly, hypertensive MetS rhesus monkeys from our in-house cohort. With implanted telemetry, we investigate BP changes and its circadian rhythm, together with the effect of antihypertensive drugs on BP and its diurnal fluctuation. MetS hypertensive monkeys displayed higher BP, obesity, glucose intolerance, and dyslipidemia. We also confirmed impaired 24-h BP circadian rhythm in MetS hypertensive monkeys. Importantly, Eplerenone, a mineralocorticoid receptor blocker, exerts multiple beneficial effects in MetS hypertensive monkeys, including BP reduction, 24-h BP circadian rhythm restoration, and decreased plasma concentration of inflammation factors and advanced glycation end-products. In summary, we identified a naturally-developed hypertensive MetS NHP model, which is of great value in the studies on pathogenesis of MetS-associated hypertension and development of novel therapeutic strategies. We also provided multiple novel mechanistic insights of the beneficial effect of Eplerenone on MetS with hypertension.

Switching from serotonin reuptake inhibitors to agomelatine in patients with refractory obsessive-compulsive disorder: a 3 month follow-up case series

BackgroundSerotonin reuptake inhibitors (SRIs) currently represent the cornerstone of obsessive-compulsive disorder (OCD) pharmacotherapy. However, OCD is characterized by high rates of partial and/or absent response to standard, recommended treatments, often prompting pharmacological and non-pharmacological augmentation or switching of strategies. Agomelatine, a novel melatonin agonist and selective serotonin antagonist (MASSA) antidepressant approved for major depressive disorder (MDD) has recently been additionally proposed as a treatment for anxiety disorders such as social anxiety disorder (SAD) and panic disorder (PD), but not yet OCD. Nonetheless, agomelatine may have a role in the management of OCD, essentially due to its anxiolytic 5-hydroxytryptamine (HT)2C blockade action, while melatonin (MT)1 and MT2 modulation might contribute to circadian rhythm restoration if impaired.MethodsThis case series reports the outcome of six patients with or without comorbid mood and/or other anxiety disorders who were treated with SRIs at adequate doses for at least 8 weeks, showing partial or no response. Patients were then switched to agomelatine 50 mg/day, and followed up for 12 weeks.ResultsThree out of six patients, in particular those with relevant circadian rhythm subjective impairment, showed a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score reduction of ≥35%. No relevant side effects were observed, but initial, transient, self-remitting dizziness in one patient and weight gain in another were seen.ConclusionsAlthough clinical confounding factors (subthreshold bipolarity and eventually the presence of impaired circadian rhythms) and methodological boundaries (lack of control and neurophysiological recording, tiny sample size and short follow-up) limit the validity of this preliminary observation, it does indicate agomelatine may have a role in some SRI-refractory OCD cases, thus prompting the validity of investigation by further controlled studies, even for drug-naïve OCD patients.

▼Agomelatine for major depressive episodes

▼Agomelatine (Valdoxan - Servier) is an antidepressant licensed for treating patients with major depressive episodes. The drug company's website for agomelatine states that the drug acts simultaneously as a melatonin...

Phase tracking and restoration of circadian rhythms by model-based optimal control

Periodic cellular processes and especially circadian rhythms governed by the oscillating expression of a set of genes based on feedback regulation by their products have become an important issue in biology and medicine. The central circadian clock is an autonomous biochemical oscillator with a period close to 24 h. Research in chronobiology demonstrated that light stimuli can be used to delay or advance the phase of the oscillator, allowing it to influence the underlying physiological processes. Phase shifting and restoration of altered rhythms can generally be viewed as open-loop control problems that may be used for therapeutic purposes in diseases. A circadian oscillator model of the central clock mechanism is studied for the fruit fly Drosophila and show how model-based mixed-integer optimal control allows for the design of chronomodulated pulse-stimuli schemes achieving circadian rhythm restoration in mutants and optimal phase synchronisation between the clock and its environment.

Flatness-Based Control of PER Protein Oscillations in a Drosophila Model

Rhythms, and specially circadian rhythms governed by an oscillating set of genes called the central clock, and their incidence on therapeutics, have become an important concern in biology and medicine. Restoration of altered rhythms for therapeutic purpose can be viewed as an open-loop control problem. We study in this paper a nonlinear oscillator modeling the central clock mechanism through the synthesis cycle of PER protein for fruit fly Drosophila. Its particularly robust bifurcation structure makes it representative for a wide number of oscillating biological systems. We show how classical flatness-based motion planning techniques allow for fast design of chronomodulated injection schemes achieving circadian rhythm restoration.

Neurotransplantation of the Biological Clock in Mammals, Importance and Perspectives

The tool of neurotransplantation has been successfully introduced in the chronobiology of mammals. Grafting of the foetal suprachiasmatic nucleus (SCN) in the IIIrd ventricle of the brain of SCN-lesioned arhythmic rodents restored free-running circadian activity patterns. This ultimately proves the SCN to be the central circadian pacemaker system. However, recovery is not seen in all animals with a surviving SCN implant and the rhythm is usually not as robust as seen for the intact system. Moreover, the grafted foetal SCN has a partially deviant development, whereas the structure-function relationship after restoration of circadian rhythm was reported to differ in the various studies. This has led to two possible mechanisms of graft action: the one a circadian humoral signal diffusing into the SCN-lesioned host brain, and the other a neuritic afferent outgrowth into the brain. There is, moreover, doubt about the integration of the ‘new’ SCN in terms of afferent input. Given the fact that the in situ SCN has an extensive efferent and afferent system in the intact brain, the SCN grafting experiments seem to indicate that only limited aspects of the SCN can drive circadian physiological rhythms. However, on the basis of current knowledge on grafting results the present paper recommends performing more sophisticated SCN grafting experiments to contribute to the knowledge on the SCN clock system.

Loss of circadian rhythm in luminal acidity of canine stomach by implantation of a gastric fistula.

One to four months after implantation of a gastric fistula, a circadian rhythm in gastric acidity could be demonstrated by use of the intragastric 24-hour pH-metry in dogs with the gastric fistula protruding on the left side of the upper abdomen. This circadian rhythm was found to be fully developed within 3 years, and it remained unchanged up to 5 years after implantation. It is characterized by a daytime intragastric median pH of about 2 and a nocturnal intragastric median pH of about 7. In contrast, a circadian rhythm did not develop within 5 months after instrumentation of the dogs with a gastric fistula protruding on the right side of the upper abdomen. Only 2 years after implantation of the fistula, an intragastric daytime median pH of about 2 and a nocturnal median pH of about 4 appeared. Four years after implantation, the circadian rhythm had evolved. The results show a delayed postoperative restoration of circadian rhythm in canine gastric acidity if a gastropexy occurs at an untolerated position. This may lead to unphysiological distensions in the gastric wall with subsequent continuous stimulation of acid secretion.

Morphological Correlates of Circadian Rhythm Restoration Induced by Transplantation of the Suprachiasmatic Nucleus in Hamsters

A compelling body of evidence indicates that the suprachiasmatic nucleus (SCN) of the hypothalamus is a pacemaker in the rodent circadian timing system. Two important components of this evidence are studies showing that SCN lesions abolish circadian rhythms and others demonstrating restoration of circadian activity rhythms after transplantation of fetal SCN into the brains of arrhythmic hosts. In the present study, we evaluated what has remained a persisting issue in this transplant literature, the extent to which the exact localization and organization of the transplants is critical to their capacity to restore circadian function in the hamster. The data obtained indicate that the location of the graft in the ventricular system is not crucial to outcome. Grafts in the lateral ventricle, dorsal third ventricle, interventricular foramen, and caudal third ventricle are as capable of restoring circadian function as ones placed in the ventral third ventricle in the vicinity of the lesion. Restoration of rhythmicity does require that the grafts contain a minimum volume of SCN-like tissue as defined by cytoarchitecture and the presence of vasopressin—and vasoactive intestinal polypeptide (VIP)— immunoreactive cells and fibers. There is also an indication that VIP-immunoreactive elements are the component critical to functional recovery. Connections between graft and host are evident in the immunohistochemical material but are quite variable in extent and often very limited. Thus, the data obtained in this study are consistent with the view that restoration of circadian function by fetal grafts requires the presence of SCN, and probably VIP-containing neurons, but does not depend upon the exact location of the graft or the presence of specific connections between graft and host.

Location of the suprachiasmatic nucleus grafts in rats which restored circadian rhythmicity after transplantation

In Wistar male rats whose circadian wheel running activity rhythms were disrupted by bilateral suprachiasmatic nuclei (SCN) lesions, transplantation of neonatal rat SCN into the 3rd ventricle was performed. Out of 49 rats from which adequate wheel running activity records were obtained, 15 rats showed restoration of circadian rhythm starting 2 to 13 weeks (average 1 month) after transplantation. The existence of active SCN neurons in the graft was shown by immunocytochemical reactivity to vasopressin- and VIP-like substances. In all rats, effective grafts were found in the diencephalon, mostly on the wall of the 3rd ventricle.