Article

Oral melatonin reduces blood coagulation activity: A placebo-controlled study in healthy young men

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Abstract

Melatonin has previously been suggested to affect hemostatic function but studies on the issue are scant. We hypothesized that, in humans, oral administration of melatonin is associated with decreased plasma levels of procoagulant hemostatic measures compared with placebo medication and that plasma melatonin concentration shows an inverse association with procoagulant measures. Forty-six healthy men (mean age 25 +/- 4 yr) were randomized, single-blinded, to either 3 mg of oral melatonin (n = 25) or placebo medication (n = 21). One hour thereafter, levels of melatonin, fibrinogen, and D-dimer as well as activities of coagulation factor VII (FVII:C) and VIII (FVIII:C) were measured in plasma. Multivariate analysis of covariance and regression analysis controlled for age, body mass index, mean arterial blood pressure, heart rate, and norepinephrine plasma level. Subjects on melatonin had significantly lower mean levels of FVIII:C (81%, 95% CI 71-92 versus 103%, 95% CI 90-119; P = 0.018) and of fibrinogen (1.92 g/L, 95% CI 1.76-2.08 versus 2.26 g/L, 95% CI 2.09-2.43; P = 0.007) than those on placebo explaining 14 and 17% of the respective variance. In all subjects, increased plasma melatonin concentration independently predicted lower levels of FVIII:C (P = 0.037) and fibrinogen (P = 0.022) explaining 9 and 11% of the respective variance. Melatonin medication and plasma concentration were not significantly associated with FVII:C and D-dimer levels. A single dose of oral melatonin was associated with lower plasma levels of procoagulant factors 60 min later. There might be a dose-response relationship between the plasma concentration of melatonin and coagulation activity.

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... Oxidative stress, chronic systemic inflammation and coagulation activation are accepted fundamental conditions to initiate and to progress of atherothrombotic disease such as coronary artery disease (Levi et al. 2004, Libby and Theroux 2005, Förstermann and Münzel 2006, Wirtz et al. 2008). Melatonin as a free radical scavenger, antioxidant, anti-inflammatuar, antiaggregatory is reported that it might be useful in suppression disorders of coagulation, procoagulant processes, inflammation and disseminated intravascular thrombosis (Bekyarova et al. 2010). ...
... Melatonin as a free radical scavenger, antioxidant, anti-inflammatuar, antiaggregatory is reported that it might be useful in suppression disorders of coagulation, procoagulant processes, inflammation and disseminated intravascular thrombosis (Bekyarova et al. 2010). It was reported that melatonin has pleiotropic action and could favorably influence the course of coronary artery disease (Carrillo-Vico et al. 2005, Claustrat et al. 2005, Dahm et al. 2006, Wirtz et al. 2008). Based on this acknowledgement, we used melatonin to investigate the effect on blood coagulation parameters in rats with cerulein induced acute pancreatitis. ...
... Tunali et al. (2005) reported that melatonin normalized shortened prothrombin time and elevated levels of fibrin degradation products in rats. Wirtz et al. (2008) found that plasma Fac-torVIII and fibrinogen are lower in young men received melatonin than received placebo. It was suggested that melatonin could exert an indirect effect on plasma coagulation activities by its anti-inflammatory and antioxidative properties (Claustrat et al. 2005, Viles-Gonzalez et al. 2006, Muller et al. 2007, Wirtz et al. 2008). ...
... The coagulation activation and platelet aggregability have a diurnal maximum early in the morning, when melatonin reaches its minimal diurnal values in blood [19][20][21]. Inhibitory effects of exogenous MLT on plasma coagulation and platelet aggregation have already been observed in vivo and in vitro under normal conditions [22][23][24][25][26]. In healthy young men, the administration of MLT has resulted in diminished blood coagulation activity through the reduction of the mean values of coagulation factor VIII and fibrinogen [22]. ...
... Inhibitory effects of exogenous MLT on plasma coagulation and platelet aggregation have already been observed in vivo and in vitro under normal conditions [22][23][24][25][26]. In healthy young men, the administration of MLT has resulted in diminished blood coagulation activity through the reduction of the mean values of coagulation factor VIII and fibrinogen [22]. In vitro, inhibition of arachidonic acid-, adenosine diphoshate-and collagen-induced platelet aggregation and delta-granule secretion, thromboxan A 2 production, and serotonin uptake in platelets by high exogenous doses of MLT have been observed [23][24][25][26]. ...
... In consequence, the administration of MLT does not prevent the LPS-induced activation of coagulation and resulting consumption coagulopathy (DIC). In some contrast to our results, the oral administration of 3 mg MLT has shown an inhibitory effect on plasmatic coagulation in healthy young men [22]. A possible explanation for this discrepancy could be the strong activation of coagulation through LPS, which can apparently not be prevented by the intravenous administration of even higher cumulative MLT dose (3 x 3mg/kg). ...
Article
Introduction: Inhibitory effects of exogenous melatonin (MLT) on plasma coagulation and platelet aggregation have already been observed in vivo and in vitro under normal conditions. Here, we studied whether MLT also diminishes the lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC) during subacute endotoxaemia. Materials and methods: Subacute endotoxaemia was induced in male Wistar rats by an intravenous infusion of LPS over a period of 300min (0.5mg LPS/kg×h). MLT was administered intravenously 15min before and 120min and 240min after starting of the LPS infusion (3×3mg MLT/kg×15min). The kinetic of clot formation was analysed by thromboelastometry. Results: Infusion of LPS led initially to a significant reduction of clotting time (120min, LPS: 150±21s vs. SHAM: 292±36s), and finally a significant increase of clotting time (300min, LPS: 2768±853s vs. SHAM: 299±67s) and a slight increase of clot formation time (300min, LPS: 1038±657s vs. SHAM: 98±14s) as well as a significant decrease of alpha-angle (300min, LPS: 35±15° vs. SHAM: 72±3°), maximum clot firmness (300min, LPS: 22±6mm vs. SHAM: 68±3mm), and area under the curve (300min, LPS: 1657±552mm×100 vs. SHAM: 6849±307mm×100). Simultaneously, a decrease of platelet count (300min, LPS: 55±8 vs. SHAM: 180±55) and a release of cell-free haemoglobin (240min, LPS: 46±5μmol/L vs. SHAM: 16±2μmol/L) could be observed in the course of subacute endotoxaemia. The additional administration of MLT did not reduce the LPS-induced alterations in parameters of thromboelastometry, but significantly reduced the LPS-induced decrease of platelet count (300min, LPS+MLT: 130±10) and release of cell-free haemoglobin (240min, LPS+MLT: 29±3μmol/L). Conclusion: Melatonin does not affect DIC but diminishes thrombocytopenia and haemolysis during endotoxaemia.
... Nocturnal secretion of melatonin is reduced in subjects with coronary artery disease, and especially those with acute coronary syndrome (ACS), compared to healthy individuals, and in patients with unstable compared to stable angina. 29,30,168,[171][172][173] Impaired circadian biological rhythmicity and the lack of the blunting effect of melatonin on sympathetic activity lead to sympathetic activation, contributing to endothelial injury, platelet activation and predisposing vulnerable plaques to rupture. 29,113 Increased sympathetic activity and activation of the coagulation cascade in the early morning might contribute to the well-described morning peaks in cardiovascular events in patients with coronary artery disease (CAD). ...
... 29,113 Increased sympathetic activity and activation of the coagulation cascade in the early morning might contribute to the well-described morning peaks in cardiovascular events in patients with coronary artery disease (CAD). 28,173,174 In addition, increased sympathetic activity might affect production of a key inhibitor of fibrinolysis, PAI-1, thus contributing to hypofibrinolysis and increasing the risk of vascular events. 175 Urinary 6-sulfatoxymelatonin excretion, a urinary metabolite of melatonin serving as an index of its secretion, is inversely associated with arterial stiffness after adjusting for diabetes and hypertension. ...
... [181][182][183] In healthy young men, the administration of melatonin was associated with a significant reduction in FVIII:c and fibrinogen levels, whereas levels of FVII:c and D-dimer showed no change. 173 On the contrary, melatonin could attenuate elevations in d-dimer, suggesting limited thrombus formation and providing support for melatonin potential in reducing atherothrombotic risk. 172,183 In addition to the protein arm of coagulation, melatonin is thought to influence circadian variation in platelet activity and several studies have suggested melatonin having direct effects on platelet function. ...
Article
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Obesity-related euglycaemic insulin resistance clusters with cardiometabolic risk factors, contributing to the development of both type 2 diabetes and cardiovascular disease. An increased thrombotic tendency in diabetes stems from platelet hyperactivity, enhanced activity of prothrombotic coagulation factors and impaired fibrinolysis. Furthermore, a low-grade inflammatory response and increased oxidative stress accelerate the atherosclerotic process and, together with an enhanced thrombotic environment, result in premature and more severe cardiovascular disease. The disruption of circadian cycles in man secondary to chronic obesity and loss of circadian cues is implicated in the increased risk of developing diabetes and cardiovascular disease. Levels of melatonin, the endogenous synchronizer of circadian rhythm, are reduced in individuals with vascular disease and those with deranged glucose metabolism. The anti-inflammatory, antihypertensive, antioxidative and antithrombotic activities of melatonin make it a potential therapeutic agent to reduce the risk of vascular occlusive disease in diabetes. The mechanisms behind melatonin-associated reduction in procoagulant response are not fully known. Current evidence suggests that melatonin inhibits platelet aggregation and might affect the coagulation cascade, altering fibrin clot structure and/or resistance to fibrinolysis. Large-scale clinical trials are warranted to investigate the effects of modulating the circadian clock on insulin resistance, glycaemia and cardiovascular outcome.
... It was reported that beer containing melatonin contributes to the total antioxidative capability of human serum, therefore protects the organism from oxidative stress (Maldonado et al., 2009). In a placebo-controlled human study, it was found that oral melatonin resulted in lower plasma concentrations of procoagulant factors (Wirtz, Spillmann, Bärtschi, Ehlert, & Von Känel, 2008). According to a study, repeated melatonin intake decreased the blood pressure in patients with hypertension (Scheer, Van Montfrans, van Someren, Mairuhu, & Buijs, 2004). ...
... Protection of the organism from oxidative stress (Maldonado et al., 2009). Lower plasma concentrations of procoagulant factors (Wirtz et al., 2008) Decreasing of the blood pressure in patients with hypertension (Scheer et al., 2004) Decreasing of the glucose tolerance and insulin sensitivity (Cagnacci et al., 2001) Positive effects on jet lag and sleep problems (Garzón et al., 2009) Reduction in the toxicity of chemotherapeutic agents and treatment-related negative effects in cancer patients Usage in treatment of Parkinson's disease (Ovallath & Sulthana, 2017) ...
... In a randomized, single-blinded study on 46 healthy young men, a single dose of oral melatonin was associated with lower plasma levels of procoagulant factors 60 min later [23]. In another case-study, also in a young man, melatonin (single 3 mg oral doses) attenuated the stress-induced elevation in the sensitive coagulation activation marker D-dimer, without affecting catecholamine activity. ...
... The hypnotic properties of melatonin are circadianphase-dependant. This conclusion is the result of a doubleblind, placebo-controlled, parallel-group trial performed on 36 healthy persons (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) year-old), placed in isolated rooms, and subjected to a 27-day forced desynchrony paradigm with a 20-hour scheduled sleep-wake cycle. Melatonin (0.3 mg or 5.0 mg) or placebo was administered 30 minutes prior to each 6.67-hour sleep episode during forced desynchrony. ...
Article
Full-text available
During the last 20 years, numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. The objective of this article is to review, in depth, the science regarding clinical trials performed to date. The efficacy of melatonin has been assessed as a treatment of ocular diseases, blood diseases, gastrointestinal tract diseases, cardiovascular diseases, diabetes, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome, infectious diseases, neurological diseases, sleep disturbances, aging and depression. Melatonin has been also used as a complementary treatment in anaesthesia, hemodialysis, in vitro fertilization and neonatal care. The conclusion of the current review is that the use of melatonin as an adjuvant therapy seems to be well funded for macular degeneration, glaucoma, protection of the gastric mucosa, irritable bowel syndrome, arterial hypertension, diabetes, side effects of chemotherapy and radiation in cancer patients or hemodialysis in patients with renal insufficiency and, especially, for sleep disorders of circadian etiology (jet lag, delayed sleep phase syndrome, sleep deterioration associated with aging, etc.) as well as in those related with neurological degenerative diseases (Alzheimer, etc.,) or Smith-Magenis syndrome. The utility of melatonin in anesthetic procedures has been also confirmed. More clinical studies are required to clarify whether, as the preliminary data suggest, melatonin is useful for treatment of fibromyalgia, chronic fatigue syndrome, infectious diseases, neoplasias or neonatal care. Preliminary data regarding the utility of melatonin in the treatment of ulcerative colitis, Crohn's disease, rheumatoid arthritis are either ambiguous or negative. Although in a few cases melatonin seems to aggravate some conditions, the vast majority of studies document the very low toxicity of melatonin over a wide range of doses.
... Melatonin, a versatile and pluripotent molecule, has been shown to have several beneficial effects above and beyond its highly celebrated property of sleep promotion (Figure 2). While melatonin has been shown to exhibit protective effects against certain neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease [3,41,42] and sundowning syndrome [43,44], perhaps the most exciting of these pleotropic effects include anti-inflammatory, antioxidant, anticoagulopathic as well as endothelial-protective properties [45][46][47][48]. This has led to an exciting hypothesis by Dun-Xian Tan, et al. from the University of Texas in a recently published article highlighting these various beneficial effects of melatonin and proposing it as potential treatment for Ebola [49], a highly dreaded modern-day epidemic that has claimed over 4,500 lives thus far without a glimpse of hope for an effective therapeutic strategy in sight. ...
... While melatonin possesses pro-and anti-inflammatory properties, these contradictory characteristics reflect more anti-inflammatory benefits in advanced stages of inflammation [46]. Melatonin also has a favorable effect on coagulopathy, as demonstrated in a placebocontrolled study where a single dose of oral melatonin lowered plasma levels of procoagulant factors 60 minutes post-administration [48]. Accumulating evidence also indicates that melatonin ameliorates vascular endothelial dysfunction in several conditions such as hypertension, atherosclerosis, diabetes, reperfusion injury and nicotine-induced vasculopathy [47]. ...
Article
Full-text available
Melatonin is a hormone secreted by the enigmatic pineal gland in response to darkness, hence the name hormone of darkness. It has generated a great deal of interest as a therapeutic modality for various diseases particularly sleep disorders. This pleiotropic molecule has anti-inflammatory, antioxidant and anticoagulopathic properties in addition to its endothelial protective effects. In this article we discuss melatonin secretion and mechanisms of action as well as therapeutic rationale. We also highlight the potential utility of melatonin in the deadly modern-day Ebola epidemic.
... Melatonin, a versatile and pluripotent molecule, has been shown to have several beneficial effects above and beyond its highly celebrated property of sleep promotion (Figure 2). While melatonin has been shown to exhibit protective effects against certain neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease [3,41,42] and sundowning syndrome [43,44], perhaps the most exciting of these pleotropic effects include anti-inflammatory, antioxidant, anticoagulopathic as well as endothelial-protective properties [45][46][47][48]. This has led to an exciting hypothesis by Dun-Xian Tan, et al. from the University of Texas in a recently published article highlighting these various beneficial effects of melatonin and proposing it as potential treatment for Ebola [49], a highly dreaded modern-day epidemic that has claimed over 4,500 lives thus far without a glimpse of hope for an effective therapeutic strategy in sight. ...
... While melatonin possesses proand anti-inflammatory properties, these contradictory characteristics reflect more antiinflammatory benefits in advanced stages of inflammation [46]. Melatonin also has a favorable effect on coagulopathy, as demonstrated in a placebo-controlled study where a single dose of oral melatonin lowered plasma levels of procoagulant factors 60 minutes postadministration [48]. Accumulating evidence also indicates that melatonin ameliorates vascular endothelial dysfunction in several conditions such as hypertension, atherosclerosis, diabetes, reperfusion injury and nicotine-induced vasculopathy [47]. ...
Article
Full-text available
Melatonin is a hormone secreted by the enigmatic pineal gland in response to darkness, hence the name hormone of darkness. It has generated a great deal of interest as a therapeutic modality for various diseases particularly sleep disorders. This pleiotropic molecule has anti-inflammatory, antioxidant and anticoagulopathic properties in addition to its endothelial protective effects. In this article we discuss melatonin secretion and mechanisms of action as well as therapeutic rationale. We also highlight the potential utility of melatonin in the deadly modern-day Ebola epidemic.
... Melatonin is also known to possess few adverse effects such as headache, somnolence, palpitations, abdominal pain, dizziness, nausea, vomiting, and nightmares [12]. Melatonin should be avoided in a few cases such as renal impairment, alcohol addiction, high lipid levels, pregnancy, and blood coagulation dysfunction [13]. ...
... In the present study, melatonin, a powerful antioxidant, was used to attenuate SOS. However, melatonin reduced the platelet count, thereby altering blood coagulation hemostasis, leading to elevated hepatic hemorrhage [13]. In response to injury to hepatic sinusoids, platelets migrate to the injured site to aid in healing the injury, mainly in the central and portal veins, leading to platelet aggregation (thrombosis). ...
... Catecholamine levels were not significantly different between the two medication groups and showed no significant correlation with melatonin levels. As previously reported [36], resting FVIII:C levels were significantly lower in subjects who had received melatonin than in those who had received placebo (82.1 ± 32.8% vs. 101.1 ± 42.0%; P = 0.048). There was also a trend towards statistical significance for lower resting fibrinogen levels in the melatonin group compared with the placebo group (1.98 ± 0.29 g/L vs. 2.20 ± 0.50 g/L; P < 0.08). ...
Article
Acute mental stress is a potent trigger of acute coronary syndromes. Catecholamine-induced hypercoagulability with acute stress contributes to thrombus growth after coronary plaque rupture. Melatonin may diminish catecholamine activity. We hypothesized that melatonin mitigates the acute procoagulant stress response and that this effect is accompanied by a decrease in the stress-induced catecholamine surge. Forty-five healthy young men received a single oral dose of either 3 mg melatonin (n = 24) or placebo medication (n = 21). One hour thereafter, they underwent a standardized short-term psychosocial stressor. Plasma levels of clotting factor VII activity (FVII:C), FVIII:C, fibrinogen, D-dimer, and catecholamines were measured at rest, immediately after stress, and 20 min and 60 min post-stress. The integrated change in D-dimer levels from rest to 60 min post-stress differed between medication groups controlling for demographic and metabolic factors (P = 0.047, eta(p)(2) = 0.195). Compared with the melatonin group, the placebo group showed a greater increase in absolute D-dimer levels from rest to immediately post-stress (P = 0.13; eta(p)(2) = 0.060) and significant recovery of D-dimer levels from immediately post-stress to 60 min thereafter (P = 0.007; eta(p)(2) = 0.174). Stress-induced changes in FVII:C, FVIII:C, fibrinogen, and catecholamines did not significantly differ between groups. Oral melatonin attenuated the stress-induced elevation in the sensitive coagulation activation marker D-dimer without affecting catecholamine activity. The finding provides preliminary support for a protective effect of melatonin in reducing the atherothrombotic risk with acute mental stress.
... It is anticipated that the literature related to this subject will continue to experience the explosive growth it has witnessed over the last decade. Furthermore , in addition to these basic research investigations it is almost assured that clinical trials with melatonin will continue and expand in scope (Gitto et al 2001; Simko and Paulis, 2007; Dominguez-Rodriguez et al., 2008; Wasdell et al., 2008; Wirtz et al., 2008). ...
Article
Full-text available
N-acetyl-5-methoxytryptamine (melatonin) is an endogenous indoleamine produced by all vertebrate organisms. Its production in the pineal gland has been extensively investigated but other organs also synthesize this important amine. Melatonin's functions in organisms are diverse. The actions considered in the current review relate to its ability to function in the reduction of oxidative stress, i.e., molecular damage produced by reactive oxygen and reactive nitrogen species. Numerous publications have now shown that not only is melatonin itself an efficient scavenger of free radicals and related reactants, but so are its by-products cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, and others. These derivatives are produced sequentially when each functions in the capacity of a free radical scavenger. These successive reactions are referred to as the antioxidant cascade of melatonin. That melatonin has this function within cells has been observed in studies employing time lapse conventional, confocal and multiphoton fluorescent microscopy coupled with the use of appropriate mitochondrial-targeted fluorescent probes. The benefits of melatonin and its metabolites have been described in the brain where they are found to be protective in models of Parkinson's disease, Alzheimer's disease and spinal cord injury. The reader is reminded, however, that data not covered in this review has documented beneficial actions of these amines in every organ where they have been tested. The outlook for the use of melatonin in clinical trials looks encouraging given its low toxicity and high efficacy.
... At recommended doses, melatonin is regarded as safe for short-term use (Buscemi et al., 2005), although large doses have been used for longer periods of time. Side effects may include headaches, nausea, and dizziness; melatonin use may also decrease prothrombin time and has been implicated in seizures in children, although conflicting data have been reported (Sheldon, 1998;Wirtz, Spillmann, Bärtschi, Ehlert, & von Känel, 2008). Melatonin has been used orally as a supplement during cancer treatment as well as topically in studies on melanoma (Slominski et al., 2005). ...
Article
Herbs, vitamins, and other natural health products are being used by cancer patients and survivors with increasing prevalence in the United States. These complementary and alternative medicine (CAM) products, which are also referred to as natural health products in Canada and abroad, are used during cancer treatment and the survivorship period to ease the burden of symptoms such as pain, fatigue, insomnia, anxiety, and depression and hence improve overall quality of life. Data indicate that while patients choose these products for self-treatment, they often do not inform their health-care providers, thereby presenting the potential for negative interactions. This article gives an overview of CAM natural health products, including discussion of herbs, vitamins, and other supplements such as minerals, enzymes, and more. Related research is presented, and implications for advanced practitioners are discussed. Insights into guiding safe and effective use among patients as well as appropriate decision-making strategies are explored.
... These modest results obtained could be enhanced by the use of combination therapies. Other anti-coagulants such as melatonin have been tested in rats and humans [97][98][99]. According to Tan et al. [100], melatonin is a potent free radical scavenger and an antiinflammatory agent. ...
... 338,339 Whereas the evidence may be somewhat less compelling, melatonin's favorable effects on coagulopathy also have been described. 340 The rationale for the use of melatonin as a potential treatment voiced by Anderson et al. 331 was similar to that proposed by Tan et al. 330 Anderson et al. 331 also noted that melatonin upregulates heme oxygenase, which inhibits the replication of the Ebola virus. ...
Article
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Melatonin is uncommonly effective in reducing oxidative stress under a remarkably large number of circumstances. It achieves this action via a variety of means: direct detoxification of reactive oxygen and reactive nitrogen species and indirectly by stimulating antioxidant enzymes while suppressing the activity of pro-oxidant enzymes. In addition to these well-described actions, melatonin also reportedly chelates transition metals which are involved in the Fenton/Haber-Weiss reactions; in doing so, melatonin reduces the formation of the devastatingly toxic hydroxyl radical resulting in the reduction of oxidative stress. Melatonin's ubiquitous but unequal intracellular distribution, including its high concentrations in mitochondria, likely aid in its capacity to resist oxidative stress and cellular apoptosis. There is credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant. Melatonin's capacity to prevent oxidative damage and the associated physiological debilitation is well documented in numerous experimental ischemia/reperfusion (hypoxia/reoxygenation) studies especially in the brain (stroke) and in the heart (heart attack). Melatonin, via its anti-radical mechanisms, also reduces the toxicity of noxious prescription drugs and of methamphetamine, a drug of abuse. Experimental findings also indicate that melatonin renders treatment-resistant cancers sensitive to various therapeutic agents and may be useful, due to its multiple antioxidant actions, in especially delaying and perhaps treating a variety of age-related diseases and dehumanizing conditions. Melatonin has been effectively used to combat oxidative stress, inflammation and cellular apoptosis and to restore tissue function in a number of human trials; its efficacy supports its more extensive use in a wider variety of human studies. The uncommonly high safety profile of melatonin also bolsters this conclusion. It is the current feeling of the authors that, in view of the widely-diverse beneficial functions that have been reported for melatonin, these may be merely epiphenomena of the more fundamental, yet-to-be identified basic action(s) of this ancient molecule. This article is protected by copyright. All rights reserved.
... There was no study evaluating the direct effect of melatonin on D-Dimer in COVID-19 patients except one study which compared the effect of single dose melatonin (3 mg) on D-dimer level induced by exercise only which showed an attenuated increase in D-dimer in response to exercise but was not statistically significant. 24 This apparent discrepancy may be due to a small single dose of melatonin used and the fact that this increase in D-dimer was a normal physiological response rather than a pathological one. However, melatonin and several of its metabolites have antioxidant effect and the capacity to regulate the vascular tone. ...
... Another benefit of melatonin is an antioxidant [3], to prevent kidney damage which is caused by smoking [4], to address the myocardial damage due to nicotine [5], preventing cerebral hemorrhage [6], inhibits neurotoxic of arsenic [7], as an anti-mouth cancer [8], and anti-hypertension [9]. Due to the importance of the function phytomelatonin compounds, therefore the study of compounds phytomelatonin needs to be conducted [10]. ...
Article
p>Green Algae, an organism with active substance such as phytomelatonin, has potential to be developed as Indonesian traditional medicine. As the long term addition of Green Algae ethanol extract ( Ekstrak etanol ganggang hijau , EEGH) influences the hematology system, in this paper, the safety test was done to ensure the safety of its use through subchronic toxicity test of EEGH on the hematology parameters of Wistar rats. The test group consisted of three groups treated with EEGH 100 mg/kg, 200 mg/kg, and 400 mg/kg, while the control group was given by 0.5% CMC-Na, with 8 rats each respectively. By using blood samples taken from orbital sinus on the 29<sup>th</sup> day, common hematologic parameters (erythrocytes, leukocytes, and hemoglobin level), the parameters of hemostasis (platelets, pT, aPTT, BT) and immune parameters (Differential Leukocytes Counts include neutrophils segment, lymphocytes, monocytes, and eosinophils) were finally observed and showed that the 28 days-addition of EEGH increase the hematological parameters of Wistar rats.</p
... Brown et al. suggested three reasons that reduced melatonin level can increase the risk of stroke [7]. Lack of melatonin can i) increase the risk of atherosclerosis, since atherosclerosis is mainly due to ROS, and melatonin is an antioxidant [7,32], ii) contribute to hypercoagulability [7,33], and iii) reduce blood pressure [7,34]. These protective roles of melatonin cannot be fully exerted if workers are constantly exposed to nighttime work, as melatonin synthesis will be reduced. ...
Article
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A large number of people in highly industrialized society are employed in night-shift work. Night-shift work interrupts the 24-hour daily cycle known as the circadian rhythm, as well as melatonin synthesis. These disruptions can make the body susceptible to oxidative stress and neural damage. In this regard, it is recommended that employees avoid long-term exposure to night-shift work.
... For example, melatonin might have anticoagulant effects, so it might increase the risk of bleeding if used with anticoagulants. It also might reduce the effects of both anticonvulsants and immunosuppressants [132][133][134]. ...
Article
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COVID-19, the disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in 2019 and has infected over 230 million people worldwide as of October 1, 2021. Common initial signs and symptoms include cough, fever, fatigue, headache, muscle aches and pain, and diarrhea [2]. Some individuals with COVID-19 become severely ill, usually starting about 1 week after symptom onset; severe COVID-19 often involves progressive respiratory failure and may also result in life-threatening pneumonia, multiorgan failure, and death. In addition, thousands of individuals-possibly 10% to 75%-who have had COVID-19 report symptoms of “long COVID” (including fatigue, muscle weakness, sleep difficulties, and cognitive dysfunction) for several months after the acute stage of illness has passed. Currently, data are insufficient to support recommendations for or against the use of any vitamin, mineral, herb or other botanical, fatty acid, or other dietary supplement ingredient to prevent or treat COVID-19. And by law, dietary supplements are not allowed to be marketed as a treatment, prevention, or cure for any disease; only drugs can legally make such claims. Nevertheless, sales of dietary supplements marketed for immune health increased after the emergence of COVID-19 because many people hoped that these products might provide some protection from SARS-CoV-2 infection and, for those who develop COVID-19, help reduce disease severity. The immune system defends the body against pathogens that cause disease and is comprised of innate responses, which are the first line of defense, and adaptive responses, which become engaged later.
... Oral melatonin reduces blood coagulation activity with a dose-response relationship [189]. It has been reported that the evening administration of melatonin in hypertensive patients taking the calcium antagonist nifedipine, interfered with the mechanism of cardiovascular regulation, inducing an increase in blood pressure [190]. ...
Article
At the moment, little treatment options are available for Duchenne muscular dystrophy (DMD). The absence of the dystrophin protein leads to a complex cascade of pathogenic events in myofibres, including chronic inflammation and oxidative stress as well as altered metabolism. The attention towards dietary supplements in DMD is rapidly increasing, with the aim to counteract pathology-related alteration in nutrient intake, the consequences of catabolic distress or to enhance the immunological response of patients as nowadays for the COVID-19 pandemic emergency. By definition, supplements do not exert therapeutic actions, although a great confusion may arise in daily life by the improper distinction between supplements and therapeutic compounds. For most supplements, little research has been done and little evidence is available concerning their effects in DMD as well as their preventing actions against infections. Often these are not prescribed by clinicians and patients/caregivers do not discuss the use with their clinical team. Then, little is known about the real extent of supplement use in DMD patients. It is mistakenly assumed that, since compounds are of natural origin, if a supplement is not effective, it will also do no harm. However, supplements can have serious side effects and also have harmful interactions, in terms of reducing efficacy or leading to toxicity, with other therapies. It is therefore pivotal to shed light on this unclear scenario for the sake of patients. This review discusses the supplements mostly used by DMD patients, focusing on their potential toxicity, due to a variety of mechanisms including pharmacodynamic or pharmacokinetic interactions and contaminations, as well as on reports of adverse events. This overview underlines the need for caution in uncontrolled use of dietary supplements in fragile populations such as DMD patients. A culture of appropriate use has to be implemented between clinicians and patients’ groups.
... The reduction in vascular permeability was likely mediated through the inhibition of endothelial cell hyper-adhesiveness by melatonin (181). In humans, oral melatonin administration (3 mg) resulted in an inverse relationship with procoagulant measures in 46 healthy young men, where increased plasma melatonin predicted lower levels of FVIII:C (P = 0.037) and fibrinogen (P = 0.022) (182). Hypercoagulability and thrombotic complications are frequently observed in patients with hemolytic anemia (183). ...
Article
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The rapid escalation of pandemic health threats associated with the novel, pathogenic SARS-CoV-2 coronavirus poses unprecedented challenges as proven effective vaccines and drugs have yet to be produced. Refractory hypoxemia and myocardial injury have been observed as two of the major causes of fatality in COVID-19 patients. SARS-CoV-2 spike (S) protein binding to broadly expressed CD147 receptors on erythrocytes causes oxidative hemolysis that may result in refractory hypoxemia and myocardial injury. Both of these life-threatening conditions are further exacerbated by imbalance in ACE2 from spike (S) protein receptor binding. Dysregulation in the CD147-cyclophilin A signaling pathway, together with altered calcium signaling from SARS-CoV-2 ion channel activities, may contribute to hypercoagulation, thrombosis, and cardiac remodeling resulting in heart failure. Melatonin is an ancient pleiotropic molecule with recognized antioxidant properties that is essential for the protection of erythrocytes from oxidative hemolysis. Found in erythrocytes, melatonin can reverse hemolytic anemia, normalize heme synthesis, restore lymphocytes and platelet counts, and reduce vessel permeability during an acute hemolytic crisis by maintaining intracellular calcium homeostasis and reduction of oxidative stress. In acute hypoxic conditions, melatonin is cardioprotective via blunting of cardiopulmonary response to hypoxia and suppressing hypoxia pathways. Melatonin normalizes endothelial-dependent nitric oxide production to prevent multiple organ damage from hypercoagulability, thrombosis, and hypertension associated with oxidative hemolysis and ACE2 deficiency, protecting cardiomyocytes from hypertrophy. This review discusses the full potential of melatonin as a safe and effective therapeutic intervention for the prevention and attenuation of hemoglobinopathies, refractory hypoxemia and myocardial injury during critical COVID-19 infections.
... Notably, melatonin has anticoagulant properties as reported by Petra and co-workers. Their findings demonstrated that, after administration of 3 mg melatonin in healthy men, plasma levels of procoagulant factors were reduced compared to the placebo group [142]. ...
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Cardiovascular diseases (CVDs) are the leading global cause of mortality and disability, tending to happen in younger individuals in developed countries. Despite improvements in medical treatments, the therapy and long-term prognosis of CVDs such as myocardial ischemia-reperfusion, atherosclerosis, heart failure, cardiac hypertrophy and remodeling, cardiomyopathy, coronary artery disease, myocardial infarction, and other CVDs threatening human life are not satisfactory enough. Therefore, many researchers are attempting to identify novel potential therapeutic methods for the treatment of CVDs. Melatonin is an anti-inflammatory and antioxidant agent with a wide range of therapeutic properties. Recently, several investigations have been carried out to evaluate its effectiveness and efficiency in CVDs therapy, focusing on mechanistic pathways. Herein, this review aims to summarize current findings of melatonin treatment for CVDs.
... Strength of evidence Conditional Risk of harm [86][87][88][89][90][91][92][93][94] Mimimal Vitamin A Vitamin A is a micronutrient that is crucial for maintaining vision, promoting growth and development, and protecting epithelium and mucus integrity in the body. Vitamin A is known as an anti-inflammation vitamin because of its critical role in enhancing immune function. ...
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As the novel infection with SARS-CoV-2 emerges, objective assessment of the scientific plausibility of nutraceutical and botanical interventions for prevention and treatment is important. We evaluate twelve such interventions with mechanisms of action that modulate the immune system, impair viral replication, and/or have been demonstrated to reduce severity of illness. These are examples of interventions that, mechanistically, can help protect patients in the presence of the prevalent and infectious SARS-CoV-2 virus. While there are limited studies to validate these agents to specifically prevent COVID-19, they have been chosen based upon their level of evidence for effectiveness and safety profiles, in the context of other viral infections. These agents are to be used in a patient-specific manner in concert with lifestyle interventions known to strengthen immune response (see related article in this issue of IMCJ).
... It is often the direct cause of death. Considering the evidence that melatonin affects the coagulation processes [76], it can be expected to have a beneficial effect in this area. ...
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Melatonin is registered to treat circadian rhythm sleep-wake disorders and insomnia in patients aged 55 years and over. The essential role of the circadian sleep rhythm in the deterioration of sleep quality during COVID-19 confinement and the lack of an adverse effect of melatonin on respiratory drive indicate that melatonin has the potential to be a recommended treatment for sleep disturbances related to COVID-19. This review article describes the effects of melatonin additional to its sleep-related effects, which make this drug an attractive therapeutic option for treating patients with COVID-19. The preclinical data suggest that melatonin may inhibit COVID-19 progression. It may lower the risk of the entrance of the SARS-CoV-2 virus into cells, reduce uncontrolled hyper-inflammation and the activation of immune cells, limit the damage of tissues and multiorgan failure due to the action of free radicals, and reduce ventilator-induced lung injury and the risk of disability resulting from fibrotic changes within the lungs. Melatonin may also increase the efficacy of COVID-19 vaccination. The high safety profile of melatonin and its potential anti-SARS-CoV-2 effects make this molecule a preferable drug for treating sleep disturbances in COVID-19 patients. However, randomized clinical trials are needed to verify the clinical usefulness of melatonin in the treatment of COVID-19.
... Another benefit of melatonin is an antioxidant [3], to prevent kidney damage which is caused by smoking [4], to address the myocardial damage due to nicotine [5], preventing cerebral hemorrhage [6], inhibits neurotoxic of arsenic [7], as an anti-mouth cancer [8], and anti-hypertension [9]. Due to the importance of the function phytomelatonin compounds, therefore the study of compounds phytomelatonin needs to be conducted [10]. ...
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p>Green Algae, an organism with active substance such as phytomelatonin, has potential to be developed as Indonesian traditional medicine. As the long term addition of Green Algae ethanol extract ( Ekstrak etanol ganggang hijau , EEGH) influences the hematology system, in this paper, the safety test was done to ensure the safety of its use through subchronic toxicity test of EEGH on the hematology parameters of Wistar rats. The test group consisted of three groups treated with EEGH 100 mg/kg, 200 mg/kg, and 400 mg/kg, while the control group was given by 0.5% CMC-Na, with 8 rats each respectively. By using blood samples taken from orbital sinus on the 29<sup>th</sup> day, common hematologic parameters (erythrocytes, leukocytes, and hemoglobin level), the parameters of hemostasis (platelets, pT, aPTT, BT) and immune parameters (Differential Leukocytes Counts include neutrophils segment, lymphocytes, monocytes, and eosinophils) were finally observed and showed that the 28 days-addition of EEGH increase the hematological parameters of Wistar rats.</p
... 23 Likewise, reduced blood coagulation activity was reported in young adults previously. 24 Herein, patients without any comorbidity including old age, hypertension, obesity, and diabetes have entered the study to evaluate the effectiveness and safety of 6mg melatonin. Previous studies positively demonstrated the effect of melatonin in modulating inflammation in obesity, hypertension, and diabetes. ...
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No effective antiviral drugs and vaccines are available for the treatment of patients with severe coronavirus 2019 (COVID-19). Therefore, available, safe, and inexpensive drugs and supplements such as melatonin are among the proposed options for controlling inflammation. We did a randomized, single-blind study in Imam Khomeini Hospital between June 30, 2020, and August 5, 2020. Mild to moderate COVID-19 patients aged 25-65 years were eligible to enter the study based on chest CT scan, clinical symptoms, and physician diagnosis. The intervention group was prescribed 6 mg of oral melatonin for 2 weeks, which consumed half an hour before bedtime every night in low light conditions. Clinical symptoms and C-reactive protein (CRP) were measured before and after treatment in the melatonin received and control (regular medications) groups. Among screened patients with COVID-19, 14 patients were assigned to receive melatonin, and 17 patients were considered as controls. A significant difference (p=0.005) between CRP 1 and CRP 2 levels (before and after using melatonin) was found in the melatonin group while this difference (p=0.069) was not significant in the control group. Also, the percentage of recovery (based on symptoms) in patients who took melatonin was higher than that of patients in the control group (85.7% VS 47.1%). The result of this study confirmed the effectiveness of melatonin in mild to moderate outpatients with COVID-19. More clinical trials on elderly, diabetic, obese patients and severe cases are suggested in future studies.
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In this review we summarized the actual clinical data for a cardioprotective therapeutic role of melatonin, listed melatonin and its agonists in different stages of development, and evaluated the melatonin cardiovascular target tractability and prediction using machine learning on ChEMBL. To date, most clinical trials investigating a cardioprotective therapeutic role of melatonin are in phase 2a. Selective melatonin receptor agonists Tasimelteon, Ramelteon, and combined melatonergic-serotonin Agomelatine, and other agonists with registered structures in CHEMBL were not yet investigated as cardioprotective or cardiovascular drugs. As drug-able for these therapeutic targets, melatonin receptor agonists have the benefit over melatonin of well-characterized pharmacologic profiles and extensive safety data. Recent reports of the X-ray crystal structures of MT1 and MT2 receptors shall lead to the development of highly selective melatonin receptor agonists. Predictive models using machine learning could help to identify cardiovascular targets for melatonin. Selecting ChEMBL scores > 4.5 in cardiovascular assays, and melatonin scores > 4, we obtained 284 records from 162 cardiovascular assays carried out with 80 molecules with predicted or measured melatonin activity. Melatonin activities (agonistic or antagonistic) found in these experimental cardiovascular assays and models include arrhythmias, coronary and large vessel contractility, and hypertension. Preclinical proof-of-concept and early clinical studies (phase 2a) suggest a cardioprotective benefit from melatonin in various heart diseases. However, larger phase 3 randomized interventional studies are necessary to establish melatonin and its agonists’ actions as cardioprotective therapeutic agents.
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Ebola Virus Disease (EVD), formerly known as Ebola hemorrhagic fever (EHF), is caused by a genus of viruses called Ebolavirus first found in 1976 near the Ebola River in the Democratic Republic of Congo (then Zaire), and the current outbreak concentrated in West Africa is now the largest outbreak in history, exhibiting rapid human-to-human progression and high lethality requiring new and bolder international collaborative initiatives for management and treatment. Without any licensed therapy at this time, informed efforts must be directed towards a new understanding of its nature, transmission dynamics, and pathology, correcting much casual and misguided information in both the popular and even regulatory media. We therefore review the state-of-the-art in Ebola information, primarily towards the goal of founding and elucidating our review of new experimental treatments for prevention or therapeutics, including several using natural agents that have supporting data beyond the in vitro level. It will be only through an expansive view of both potential experimental and alternative treatment modalities that we may arrive at more effective interventions for achieving superior outcomes in the management of this Public Health Emergency of International concern (PHEIC).
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Rotating night shift work disrupts circadian rhythms and is associated with coronary heart disease. The relation between rotating night shift work and ischemic stroke is unclear. The Nurses’ Health Study, an ongoing cohort study of registered female nurses, assessed in 1988 the total number of years the nurses had worked rotating night shifts. The majority (69%) of stroke outcomes from 1988 to 2004 were confirmed by physician chart review. The authors used Cox proportional hazards models to assess the relation between years of rotating night shift work and ischemic stroke, adjusting for multiple vascular risk factors. Of 80,108 subjects available for analysis, 60% reported at least 1 year of rotating night shift work. There were 1,660 ischemic strokes. Rotating night shift work was associated with a 4% increased risk of ischemic stroke for every 5 years (hazard ratio = 1.04, 95% confidence interval: 1.01, 1.07; Ptrend = 0.01). This increase in risk was similar when limited to the 1,152 confirmed ischemic strokes (hazard ratio = 1.03, 95% confidence interval: 0.99, 1.07; Ptrend = 0.10) and may be confined to women with a history of 15 or more years of rotating shift work. Women appear to have a modestly increased risk of stroke after extended periods of rotating night shift work.
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Thesis (M.F.A., English)--University of California, Irvine, 1975.
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The purpose of this study is to determine the effect of melatonin on thrombosis, sepsis, and mortality rate in adult patients with severe coronavirus infection (COVID-19). Methods: This single-center, prospective, randomized clinical trial was conducted from 1 December 2020 to 1 June 2021 at Al-Shifaa hospital in Mosul, Iraq. There were 158 patients with severe COVID-19 included in the study, 82 in the melatonin group (who received 10 mg melatonin in addition to standard therapeutic care), and 76 in the control group (given standard therapeutic care only). Patients were chosen by blocked randomization design. The physician then evaluated and recorded the incidence of thrombosis, sepsis, and mortality rate on days 5, 11, and 17 of symptoms. Results: The intervention group consisted of 82 patients, while the control group consisted of 76 patients. In comparison to the control group, thrombosis and sepsis developed significantly less frequently (P < 0.05) in the melatonin group during the second week of infection, while mortality was significantly higher in the control group (P < 0.05). Conclusions: Adjuvant use of Melatonin may help reduce thrombosis, sepsis, and mortality in COVID-19 patients.
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Metabolic syndrome (MS) patients exhibit sleep/wake disturbances and other circadian abnormalities, and these may be associated with more rapid weight increase and development of diabetes and atherosclerotic disease. On this basis, the successful management of MS may require an ideal drug that besides antagonizing the trigger factors of MS could also correct the disturbed sleep-wake rhythm. Melatonin is an effective chronobiotic agent able to change the phase and amplitude of circadian rhythms. Melatonin has also significant cytoprotective properties preventing a number of MS sequelae in animal models of diabetes and obesity. A small number of controlled trials indicate that melatonin is useful to treat the metabolic and cardiovascular comorbidities of MS. Whether the recently introduced melatonergic agents (ramelteon, agomelatine, tasimelteon) have the potential for treating sleep disorders in MS patients and, more generally, for arresting the progression of disease, merits further investigation.
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From a physiological perspective the sleep-wake cycle can be envisioned as a sequence of three physiological states (wakefulness, non-rapid eye movement, NREM, sleep and REM sleep) which are defined by a particular neuroendocrine-immune profile regulating the metabolic balance, body weight and inflammatory responses. Sleep deprivation and circadian disruption in contemporary "24/7 Society" lead to the predominance of pro-orexic and proinflammatory mechanisms that contribute to a pandemic metabolic syndrome (MS) including obesity, diabetes and atherosclerotic disease. Thus, a successful management of MS may require a drug that besides antagonizing the trigger factors of MS could also correct a disturbed sleep-wake rhythm. This review deals with the analysis of the therapeutic validity of melatonin in MS. Melatonin is an effective chronobiotic agent changing the phase and amplitude of the sleep/wake rhythm and having cytoprotective and immunomodulatory properties useful to prevent a number of MS sequels. Several studies support that melatonin can prevent hyperadiposity in animal models of obesity. Melatonin at a low dose (2-5 mg/day) has been used for improving sleep in patients with insomnia and circadian rhythm sleep disorders. More recently, attention has been focused on the development of potent melatonin analogs with prolonged effects (ramelteon, agomelatine, tasimelteon, TK 301). In clinical trials these analogs were employed in doses considerably higher than those usually employed for melatonin. In view that the relative potencies of the analogs are higher than that of the natural compound, clinical trials employing melatonin doses in the range of 50-100 mg/day are needed to assess its therapeutic value in MS.
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The purpose of this report is to emphasize the potential utility for the use of melatonin in the treatment of individuals who are infected with the Ebola virus. The pathological changes associated with an Ebola infection include, most notably, endothelial disruption, dissiminated intravascular coagulation and multiple organ hemorrhage. Melatonin has been shown to target these alterations. Numerous similarities between Ebola virus infection and septic shock have recognized for more than a decade. Moreover, melatonin has been successfully employed for the treatment of sepsis in many experimental and clinical studies. Based on these factors, since the number of treatments currently available is limited and the useable products are not abundant, the use of melatonin for the treatment of Ebola virus infection is encouraged. Additionally, melatonin has a high safety profile, is readily-available and can be orally-self administered; thus, the use of melatonin is compatible with the large scale of this serious outbreak. This article is protected by copyright. All rights reserved.
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Tetraplegic patients have increased risk of venous thrombosis despite anti-thrombotic prophylaxis. Moreover, they have blunted plasma variations in melatonin and altered diurnal variation of several haemostatic markers, compared with able-bodied. However, whether healthy individuals and tetraplegic patients, with or without melatonin, display abnormalities in thrombin generation during a 24-hour (h) cycle, is unknown. We therefore used the Calibrated Automated Thrombogram (CAT) assay to examine diurnal variations and the possible role of melatonin in thrombin generation. Six men with long-standing complete tetraplegia were included in a randomised placebo-controlled cross-over study with melatonin supplementation (2 mg, 4 consecutive nights), whereas six healthy, able-bodied men served as controls. Ten plasma samples were collected frequently during a 24-h awake/sleep cycle. No significant diurnal variation of any of the measured CAT indices was detected in the three study groups. Whereas endogenous thrombin potential (ETP) was independent (p > 0.05) of whether the tetraplegic men received melatonin or placebo, melatonin decreased (p = 0.005). Peak values in tetraplegia compared with those given placebo. Able-bodied men had lower (p = 0.019) ETP and Lag-Time (p = 0.018) compared with tetraplegics receiving placebo. Neither the Time-to-Peak nor the Start-Tail was affected (p > 0.05) by melatonin in tetraplegia. In conclusion, indices of thrombin generation are not subjected to diurnal variation in healthy able-bodied or tetraplegia, but peak thrombin generation is reduced in tetraplegic men receiving oral melatonin.
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This study was designed to determine the effects of physical activity on thrombin time and coagulation time in epiphysectomized rats. Male Wistar rats (n = 60) weighing 90 to 100 g were divided into 2 groups; control group (without epiphysectomy) and experimental group (epiphysectomy). In each group, animals were divided into three subgroups: control (without physical activity), short-time (5 min physical activity) and long-time (with 20 min physical activity). Blood samples were collected from rat tail tip in several stages as before and after epiphysectomy and physical activity from experimental group, to determine coagulation time. Exercise programs were performed including; swimming on water pool until 5 min (short-time) and 20 min (long-time) in experimental and control groups. Autopsy was done on all the rats. Thrombin time was measured for each tissue. Our data showed that physical activity significantly decreased thrombin time on tissues of rats as compared to baseline values in control group (P < 0.001). In contrast, physical activity significantly increased thrombin time on different tissues in epiphysectomy rats (P < 0.001). Also, our results showed that in epiphysectomized rats after long-time physical activity, coagulation time increased but after short-time it decreased. In conclusion, these results suggest that there is a functional relationship between the pineal gland and the exercise on changes of hemostatic parameters in blood via its hormone melatonin.
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Background: Age-related macular degeneration (AMD) is the leading cause of blindness. Shift work has well-known adverse effects on health. However, few studies have investigated the relationship between shift work and AMD. This study was conducted to investigate the relationship between shift work and AMD. Methods: This study used aggregated data from the 2010-2012 cycles of the Korea National Health and Nutrition Examination Survey. The work schedules were classified into 2 types: day work and shift work. AMD was determined using fundus photographs. The χ2 test and multiple logistic regression analysis were used to assess sex-stratified relationship between shift work and AMD. Results: The odds ratio (OR) of AMD in male shift workers was higher (1.54 [95% confidence interval, CI: 1.01-2.36]) than that in male day workers after adjusting for covariates. After dividing into subgroups of the shift work pattern, the OR of AMD in male night shift workers was higher (1.75 [95% CI: 1.07-2.85]) than that in male day workers after adjusting for covariates. However, results of the female worker group were not significant. Conclusions: The results of this study provide limited support for the hypothesis that shift work is related to AMD. Further prospective studies are needed to define the relationship between shift work and AMD.
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Microorganisms have showed the ability to produce biologically active compounds associated with neurotransmission in higher organisms. In particular, serotonin‐ and melatonin‐producing microbes are valuable sources for the development of eco‐friendly bioproducts. Serotonin and melatonin are indoleamines that have received special attention due to their positive effects on human health. These biomolecules exert a critical role in several physiological or pathological processes, including some mental and neurological disorders. This article includes a review of the microbial production of serotonin and melatonin, their functions in microorganisms, and their potential uses as therapeutic and/or preventive agents to improve human health. A description of the quantification methods employed to detect indoleamines and the evidence found concerning their microbial production at lab and industrial scale ‐for application in biotechnological products‐ is also provided. The microbial ability to synthesize beneficial indoleamines should be further studied and harnessed, in order to allow the development of sustainable bioprocesses to produce foods and pharmaceuticals for human health.
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There are insufficient data about the effects of melatonin on hemostasis. The purpose of the study is to investigate the effect of melatonin and of luzindole, an inhibitor of melatonin receptors MT 1 and MT 2, on the count and functional activity of thrombocytes, as estimated according to the changes in the plasma levels of beta-thromboglobulin (β-TG) and platelet factor 4 (PF 4). The study included 52 white male Wistar rats weighing 200-220 g on a 12/12 h light/dark regimen. Daily doses of melatonin of 0.2 mg/kg b.m. and luzindole of 0.4 mg/kg b.m. were applied. Melatonin was administered s.c. twice daily at intervals of 12 h, for three consecutive days. The animals were divided into 4 equal groups (n = 13) and injected as follows: group one-with saline, group two-with melatonin, group three -with luzindole, and group four-with luzindole and 1 h later-with melatonin. The results demonstrated that melatonin significantly increased the thrombocyte count (p < 0.001) and plasma levels of β-TG (p < 0.001) and PF 4 (p < 0.001) known as markers of platelet functional activity. When applied independently, luzindole significantly reduced (p < 0.001) thrombocyte count, β-TG and PF 4, which allowed for the assumption that it probably inhibited the effect of endogenous melatonin to a significant extent. Luzindole pretreatment suppressed the effects of both endogenous and exogenous melatonin. Melatonin represents an important non-specific regulator of platelet homeostasis. It significantly increases the count and functional activity of thrombocytes, as estimated by means of the plasma concentrations of β-TG and PF 4.
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Recently multiple pleiotropic effects on various tissues have been attributed to the hormone melatonin. However, data about the effects of the hormone on blood coagulation system are rather scarce and controversial. This study was aimed to investigate melatonin influence on antigen concentration and plasma activities of vitamin K-dependent plasma clotting factors (F II, F VII, F IX and F X). The study was performed on 52 male Wistar rats, kept at 12/12 h natural regimen dark/light. The rats were distributed into four equal groups and were treated as follows: the first group (control group) by saline; the second group by melatonin; the third group by luzindole; and the fourth group by luzindole and an hour later by melatonin. The daily doses of melatonin 0.2 mg/kg b.m. and luzindole 0.4 mg/kg b.m. were applied twice daily subcutaneously for three consecutive days. Plasma clotting factor concentrations were measured by an ELISA method. Clotting factor activities were estimated by a kinetic coagulation method. Melatonin significantly elevated the levels of antigen concentrations of F VII: Ag (p < 0.01), F IX: Ag (p < 0.01), F X: Ag (p < 0.01), and F II: Ag (p < 0.001).The activities of all the vitamin K-dependent clotting factors studied were significantly raised (p < 0.01) by melatonin too. Luzindole applied alone lowered (p < 0.001) plasma concentrations of F VII: Ag, F IX: Ag, F X: Ag, and F II: Ag, as well as activities F II, F VII and F IX (p < 0.001); and F X (p < 0.05). Melatonin injected one hour after luzindole pretreatment decreased the antigen concentrations of the four clotting factors studied (p < 0.001), and reduced the activities of F II and F IX (p < 0.001); and F VII and F X (p < 0.01). The results of the study indicate a tendency of hypercoagulability after melatonin application. Blockade of MT1 and MT2 melatonin receptors after separate luzindole application, as well as luzindole pretreatment followed by melatonin, reveal a definite tendency of hypocoagulability.
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Recently melatonin has been established as a hormone with multiple biological effects. Nevertheless, the data about its effects on haemocoagulation are relatively limited. The present study was aimed to investigate melatonin effect(s) on the activity of plasma clotting factors V, XI, XII and XIII. The study included 52 white male Wistar rats weighing 200-220 g on a 12/12 h light/dark regimen. Daily doses of melatonin of 0.2 mg/kg b.m. and luzindole of 0.4 mg/kg b.m. were used. Melatonin was administered s.c. twice daily at intervals of 12 h, for three consecutive days. The animals were divided into four equal groups (n = 13) and injected as follows: group one - with saline, group two - with melatonin, group three - with luzindole, and group four - with luzindole and one hour later - with melatonin. The necessary blood volume was obtained by a cardiac puncture under urethane narcosis. Plasma clotting factor activities were determined by Diagnostica Stago (France) enzyme tests, while aPTT was estimated by a routine coagulation method. Melatonin increased significantly (p < 0.001) factors V, XII and XIII, shortened aPTT (p < 0.001) and did not affect F XI. Luzindole applied both separately and in combination with melatonin lengthened aPTT (p < 0.001) and suppressed the activities of all clotting factors studied (p < 0.001). In conclusion, the data of this study provide evidence to assume that melatonin application is accompanied by a tendency to hypercoagulability. The decreased activity of the four clotting factors by luzindole, a nonselective inhibitor of melatonin receptors MT 1 and MT 2, may be evidence of their direct involvement in the expression of melatonin effects. Their blockade leads to a demonstrated tendency to hypocoagulability.
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The role of melatonin in haemostasis is insufficiently determined. The study is aimed to investigate the effects of melatonin and luzindole (MT1 and MT2 melatonin receptor inhibitor) on integral haemocoagulation parameters. The study was performed on 52 male Wistar rats, kept at 12/12 h natural regi- men dark/light. The daily doses of melatonin 0.2 mg/kg b.m. and luzindole 0.4 mg/kg b.m. were applied twice daily subcutaneously for three consecutive days. The rats were distributed into four equal groups (n = 13) and were treated as follows: the first group (control group) – by saline; the second group – by mela- tonin; the third group – by luzindole; and the fourth group – by luzindole and an hour later by melatonin. The results indicate that melatonin significantly shortens the activated partial thromboplastin time (aPTT), prothrombin time (PT) and thrombin time (TT) (p < 0.001). Luzindole applied alone elongates aPTT, PT and TT (p < 0.001), which probably is a result of a suppressed endogenous melatonin secretion. Melatonin applied after luzindole pretreat- ment to a great extent repeats the effect of separate luzindole application. The results of the study suggest melatonin is significantly involved in haemoco- agulation regulation leading to a tendency of hypercoagulability. The effects observed are accomplished both by modulation of the intrinsic and the extrin- sic coagulation pathways, as well as by influence on conversion of fibrinogen to fibrin.
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Melatonin has been shown to reduce oxidative stress and mitigate hypercoagulability. We hypothesized that maternally administered melatonin may reduce placental oxidative stress and hypercoagulability associated with exposure to intrauterine inflammation (IUI) and consequently improve fetoplacental blood flow and fetal sequelae. Mice were randomized to the following groups: control (C), melatonin (M), lipopolysaccharide (LPS; a model of IUI) (L), and LPS with melatonin (ML). The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro-inflammatory mediators was significantly increased in L compared to C and ML. The systolic/diastolic ratio, resistance index, and pulsatility index in uterine artery (UtA) and umbilical artery (UA) were significantly increased in L compared with other groups when analyzed by Doppler ultrasonography. The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro-inflammatory mediators was significantly increased in L compared to C and ML. Vascular endothelial damage and thrombi formation, as evidenced by fibrin deposits, were similarly increased in L compared to other groups. Maternal pretreatment with melatonin appears to modulate maternal placental malperfusion, fetal cardiovascular compromise, and fetal neuroinflammation induced by IUI through its antioxidant properties.
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Introduction: Melatonin produced in the pineal gland plays a key role in regulating sleep and wake hours. Synthetic melatonin is used as an adjunct to treat sleep disorders, regulate the sleep-wake rhythm and prevent ailments related to changing time zones or shift work. Its other applications are more widely described, including antioxidant and immunomodulatory properties – therefore melatonin supplementation may be beneficial in alleviating symptoms associated with the occurrence of COVID-19. However, reports on the influence of exogenous melatonin on the platelet, plasma and vascular hemostasis are ambiguous. Aim: The aim of the study was to evaluate the in vitro influence of melatonin on spontaneous and ADP-induced adhesion of platelets to fibrinogen, kinetic parameters of ADP-induced aggregation and selected elements of plasma haemostasis: general potential for clot formation and fibrinolysis, as well as kinetic parameters of the clot formation process, its stabilization and fibrinolysis. Material and methods: The study were performed with the use of the previously described research model, which includes the method of assessing platelet adhesion, a multi-parameter test for assessing platelets aggregation and a test that enables kinetic assessment of the clot formation process, the period of fibrin stabilization and its lysis. Results: Our preliminary studies indicated that melatonin at concentrations: 0.2-10 nmol/L does not show a significant and direct impact on the assessed kinetic parameters of the studied processes, important for platelet and plasma hemostasis. Conclusions: The pleiotropic effects of melatonin are increasingly applied, especially its antioxidant and immunomodulating properties, therefore further and in-depth in vitro as well as in vivo hemostasis studies followed by clinical observations of patients using melatonin are needed.
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In this article, we attempt to distinguish between the properties of moderator and mediator variables at a number of levels. First, we seek to make theorists and researchers aware of the importance of not using the terms moderator and mediator interchangeably by carefully elaborating, both conceptually and strategically, the many ways in which moderators and mediators differ. We then go beyond this largely pedagogical function and delineate the conceptual and strategic implications of making use of such distinctions with regard to a wide range of phenomena, including control and stress, attitudes, and personality traits. We also provide a specific compendium of analytic procedures appropriate for making the most effective use of the moderator and mediator distinction, both separately and in terms of a broader causal system that includes both moderators and mediators.
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We derived and tested a short form of the Center for Epidemiologic Studies Depression Scale (CES-D) for reliability and validity among a sample of well older adults in a large Health Maintenance Organization. The 10-item screening questionnaire, the CESD-10, showed good predictive accuracy when compared to the full-length 20-item version of the CES-D (kappa = .97, P < .001). Cutoff scores for depressive symptoms were > or = 16 for the full-length questionnaire and > or = 10 for the 10-item version. We discuss other potential cutoff values. The CESD-10 showed an expected positive correlation with poorer health status scores (r = .37) and a strong negative correlation with positive affect (r = -.63). Retest correlations for the CESD-10 were comparable to those in other studies (r = .71). We administered the CESD-10 again after 12 months, and scores were stable with strong correlation of r = .59.
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The cardiovascular effects induced by the daytime administration of melatonin (1 mg) were compared with those of placebo in 17 young, healthy, early follicular-phase women. Compared with placebo, the administration of melatonin modified, within 90 min, the pulsatility index (PI), evaluated by color Doppler ultrasound, of the internal carotid artery, abdominal aorta, and axillary artery. The effect was linearly related to baseline PI, higher baseline PI being associated with greater PI declines. Melatonin administration significantly decreased mean PI of internal carotid artery (P < 0.02), systolic and diastolic blood pressure (P < 0.01), and norepinephrine levels evaluated after 5 min of standing position (P < 0.02). Heart rate and supine catecholamine levels were not modified. These data indicate that in young, healthy women the administration of 1 mg of melatonin greatly influences artery blood flow, decreases blood pressure, and blunts noradrenergic activation. Clinical implications of present data are worthy to be fully explored.
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A common problem faced by industrial hygienists is the selection of a valid way of dealing with those samples reported to contain nondetectable values of the contaminant. In 1990, Hornung and Reed compared a maximum likelihood estimation (MLE) statistical method and two methods involving the limit of detection, L. The MLE method was shown to produce unbiased estimates of both the mean and standard deviation under a variety of conditions. That method, however, was complicated, requiring difficult mathematical calculations. Two simpler alternatives involved the substitution of L/2 or L/square root of 2 for each nondetectable value. The L/square root of 2 method was recommended when the data were not highly skewed. Although the MLE method produces the best estimates of the mean and standard deviation of an industrial hygiene data set containing values below the detection limit, it was not practical to recommend this method in 1990. However, with advances in desktop computing in the past decade the MLE method is now easily implemented in commonly available spreadsheet software. This article demonstrates how this method may be implemented using spreadsheet software.
Article
Inflammation and immune activation are crucially involved in the pathogenesis of atherosclerosis and cardiovascular disease. Accordingly, markers of inflammation such as fibrinogen, ferritin, C-reactive protein or neopterin are found in patients with vascular diseases, correlating strongly with the extent of disease and predicting disease progression. Neopterin formation by human monocyte-derived macrophages and dendritic cells is induced by the pro-inflammatory cytokine interferon-γ, which is released by activated T-lymphocytes. Human macrophages are centrally involved in plaque formation, and interferon-γ and macrophages are also of importance in the development of oxidative stress for antimicrobial and antitumoural defence within the cell-mediated immune response. Interferon-γ also stimulates the enzyme indoleamine-2,3-dioxygenase, which degrades tryptophan to kynurenine. Again, macrophages are the most important cell type executing this enzyme reaction, but also other cells like dendritic cells, endothelial cells or fibroblasts can contribute to the depletion of tryptophan. Likewise, enhanced tryptophan degradation was reported in patients with coronary heart disease and was found to correlate with enhanced neopterin formation. In chronic diseases such as in cardiovascular disease, biochemical reactions induced by interferon-γ may have detrimental consequences for host cells. In concert with other pro-inflammatory cytokines, interferon-γ is the most important trigger for the formation and release of reactive oxygen species (ROS). Chronic ROS-production leads to the depletion of antioxidants like vitamin C and E and glutathione, with a consequence that oxidative stress develope. Oxidative stress plays a major role in the atherogenesis and progression of cardiovascular disease, and it may also account for the irreversible oxidation of other oxidation-sensitive substances like B-vitamins (e.g. folic acid and B12). They are essential cofactors in homocysteine-methionine metabolism. Associations between moderate hyperhomocysteinaemia and cellular immune activation are found in several diseases including coronary heart disease, and data indicate that hyperhomocysteinaemia may develop as a consequence of immune activation. Homocysteine accumulation in the blood is established as an independent risk factor for cardiovascular disease. Homocysteine itself has the capacity to further enhance oxidative stress. Interferon-γ appears to be a central player in atherogenesis and in the development and progression of cardiovascular disease. Anti-inflammatory and immunosuppressive treatment (e.g. with non-steroidal anti-inflammatory drugs or statins) may among other consequences, also contribute to a slow-down of the adverse effects of interferon-γ.
Article
In the attempt to estimate the average concentration of a particular contaminant during some period of time, a certain proportion of the collected samples is often reported to be below the limit of detection. The statistical terminology for these results is known as censored data, i.e., nonzero values which cannot be measured but are known to be below some threshold.Samples taken over time are assumed to follow a lognormal distribution. Given this assumption, several techniques are presented for estimation of the average concentration from data containing nondetectable values. The techniques proposed include three methods of estimation with a left-censored lognormal distribution: a maximum likelihood statistical method and two methods involving the limit of detection. Each method is evaluated using computer simulation with respect to the bias associated with estimation of the mean and standard deviation. The maximum likelihood method was shown to produce unbiased estimates of both the mean and standard deviation under a variety of conditions. However, this method is somewhat complex and involves laborious calculations and use of tables. Two simpler alternatives involve the substitution of L/2 and a new proposal of L/2 for each nondetectable value, where L = the limit of detection. The new method was shown to provide more accurate estimation of the mean and standard deviation than the L/2 method when the data are not highly skewed. The L/2 method should be used when the data are highly skewed (geometric standard deviation [GSD] approximately 3.0 or greater)
Derived and tested a short form of the Center for Epidemiologic Studies Depression Scale (CES-D) for reliability and validity among 1,206 well older adults (aged 65–98 yrs). The 10-item screening questionnaire, the CESD-10, showed good predictive accuracy when compared to the full-length 20-item version of the CES-D. The CESD-10 showed an expected positive correlation with poorer health status scores and a strong negative correlation with positive affect. Retest correlations for the CESD-10 were comparable to those in other studies. The CESD-10 was administered again after 12 mo. Data were based on 80% of the original sample. Scores were stable with strong correlation. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
Current views regard atherosclerosis as a dynamic and progressive disease arising from the combination of endothelial dysfunction and inflammation.1–6 The vascular endothelium, located at the interface of blood and tissue, is able to sense changes in hemodynamic forces and bloodborne signals and react by synthesizing and releasing vasoactive substances. Vascular homeostasis is maintained by a balance between endothelium-derived relaxing and contracting factors. With disruption of this balance, mediated by inflammatory and traditional cardiovascular risk factors, the vasculature becomes susceptible to atheroma formation. Inflammatory mediators appear to play a fundamental role in the initiation, progression, and eventual rupture of atherosclerotic plaques. As evidence accumulates linking inflammatory processes to atherogenesis, markers of inflammation and endothelial activation may become useful by providing additional information about a patient’s risk of developing cardiovascular disease, as well as providing new targets for treatment.7,8 This review article is the first part of a two-article series examining emerging markers of inflammation and cardiovascular disease. Part 1 will provide a brief overview of the link between inflammation, endothelial dysfunction, and atherosclerosis and will begin highlighting emerging inflammatory mediators of endothelial cell (EC) activation, a discussion that will be continued in Part 2. Endothelial dysfunction is a broad term that implies diminished production or availability of nitric oxide (NO) and/or an imbalance in the relative contribution of endothelium-derived relaxing and contracting factors, such as endothelin-1 (ET-1), angiotensin, and oxidants.1 NO, generated by the conversion of the amino acid l-arginine to NO and l-citrulline by the enzyme NO synthase, is the key endothelium-derived relaxing factor that plays a pivotal role in the regulation of vascular tone and vasomotor function.9 Impaired endothelium-dependent vasodilation in coronary arteries with established atherosclerosis results in paradoxical vasoconstriction, which may result in reduced myocardial perfusion and myocardial ischemia. However, endothelial dysfunction, …
Article
A rapid and sensitive method for the routine quantitative determination of melatonin in pineal and plasma is described. The assay used reversed-phase high-performance liquid chromatography (RP-HPLC) separation combined with either amperometric (system A) or coulometric (system B) detection. The method gave satisfactory reproducibility and accuracy, and detection limits for melatonin were as low as 8.5 pg (system A) and 1 pg (system B). This high sensitivity, together with the short analysis time (less than 10 min), and the simplicity of sample procedure make the present RP-HPLC method suitable for a wide range of studies concerning melatonin measurements. Melatonin values obtained in this study from both rat pineal and human plasma agree with those reported previously, and clearly determined a circadian pattern.
Article
Atherosclerosis is no longer considered a disorder of lipid accumulation, but a disease process characterized by the dynamic interaction between endothelial dysfunction, subendothelial inflammation and the 'wound healing response' of the vascular smooth muscle cells. Prospective epidemiological studies have unequivocally demonstrated increased vascular risk in individuals with elevated levels of (i) cytokines such as interleukin-6 and tumour necrosis factor-alpha, (ii) cell adhesion molecules such as intercellular adhesion molecule-1 and P-selectin, and (iii) acute-phase proteins such as C-reactive protein, fibrinogen and serum amyloid A. Furthermore, evidence from clinical trials have demonstrated that risk reduction achieved with anti-inflammatory agents such as statins is significantly greater in patients with evidence of inflammation. A number of risk factors for atherogenesis, including infectious agents, have been shown to exert their influence via inflammatory mechanisms. However, despite compelling experimental evidence, clinical studies looking at the role of infection in atherogenesis have lacked consistency. The clinical product of this dynamic process is variable and unpredictable between individuals, even those with apparently similar risk profiles.
Article
When more than one statistical test is performed in analysing the data from a clinical study, some statisticians and journal editors demand that a more stringent criterion be used for “statistical significance” than the conventional P<0.05.1 Many well meaning researchers, eager for methodological rigour, comply without fully grasping what is at stake. Recently, adjustments for multiple tests (or Bonferroni adjustments) have found their way into introductory texts on medical statistics, which has increased their apparent legitimacy. This paper advances the view, widely held by epidemiologists, that Bonferroni adjustments are, at best, unnecessary and, at worst, deleterious to sound statistical inference. #### Summary points Adjusting statistical significance for the number of tests that have been performed on study data—the Bonferroni method—creates more problems than it solves The Bonferroni method is concerned with the general null hypothesis (that all null hypotheses are true simultaneously), which is rarely of interest or use to researchers The main weakness is that the interpretation of a finding depends on the number of other tests performed The likelihood of type II errors is also increased, so that truly important differences are deemed non-significant Simply describing what tests of significance have been performed, and why, is generally the best way of dealing with multiple comparisons Bonferroni adjustments are based on the following reasoning.1-3 If a null hypothesis is true (for instance, two treatment groups in a randomised trial do not differ in terms of cure rates), a significant difference (P<0.05) will be observed by chance once in 20 trials. This is the type I error, or α. When 20 independent tests are performed (for example, study groups are compared with regard to 20 unrelated variables) and the null hypothesis holds for all 20 comparisons, the chance of at least one test being significant is no longer 0.05, but 0.64. …
Article
Introducation Factor VIII and von Willebrand factor are plasma glycoproteins whose deficiency or structural defects cause hemophilia A and von Willebrand disease, respectively (1). These diseases are the most common inherited bleeding disorders of man. Factor VIII and vWF are synthesized by different cell types and circulate in plasma as a tightly bound complex. Factor VIII is synthesized in the liver (2), and functions as a cofactor for activated factor IX in the intrinsic activation of factor X on a membrane surface (3). vWF is synthesized in endothelial cells (4, 5) and megakaryocytes (6). vWF has a dual role in hemostasis: it promotes platelet adhesion to subendothelium after vessel injury (7, 8) and it acts as a carrier protein of factor VIII (1). The distinction between factor VIII and vWF was unclear for many years, because severe Von Willebrand disease is associated with factor VIII deficiency and because early preparations of factor VIII concentrates contained vWF and were therefore effective in correcting the platelet adhesion defects in patients with von Willebrand disease (9). Since factor VIII and vWF form a tightly bound non-covalent complex in plasma, both proteins are copurified when isolated from plasma, unless special measures are taken (1). The stoichiometry of factor VIII and vWF in plasma is approximately 1:50 and factor VIII and monomeric vWF have similar molecular weights of approximately 240 kDa. Therefore, vWF represents 98% of the molecular mass of the factor VIII-vWF complex (10) and almost all the antibodies raised against the complex react to vWF. In the 1980’s, factor VIII and vWF have each been purified to homogeneity and the genes for these proteins have been cloned. This set the stage for studies with purified proteins which have elucidated structure-function relationships for both proteins. Also, the interaction between both proteins could be studied using proteolytic fragments, small peptides, and monoclonal antibodies. In the last few years, the construction of recombinant mutants and fragments of both factor VIII (11-13) and vWF (14-16) has proven to be a powerful tool in the elucidation of the structure and function of both proteins. Binding of factor VIII to vWF is essential for the survival of factor VIII in vivo (17, 18). The underlying mechanism is probably that factor VIII bound to vWF is protected from phospholipid dependent proteolysis by activated protein C and factor Xa (19, 20). The binding site for factor VIII has been located at the amino terminus of vWF (21, 22). A tryptic fragment containing this binding site was not sufficient to protect factor VIII against activated protein C-mediated degradation according to some groups (23, 24). In contrast, a recent study using comparable vWF fragments showed protection of factor VIII equivalent to mature vWF (16). In 1989, a new variant of von Willebrand disease was discerned (type Normandy or 2N), distinct from the more than 20 subtypes known, characterized by a mutant vWF that is structurally and functionally normal, except that it does not bind to and stabilize factor VIII (25, 26). Since then, several mutations in the factor VIII binding site on vWF have been found (27). A number of reports have shown that factor VIII binds vWF via a high affinity binding site on its light chain (28-30). Two recent studies suggest that this binding site consists of two separate binding sites (31, 32). This review summarizes current knowledge on the interaction between factor VIII and vWF. Emphasis will be laid on the biological importance of, and the domains involved in binding, and on the stoichiometry and kinetics of complex formation.
Article
Early investigations have suggested a relationship between hypertension and melatonin, a pineal hormone. The aims of this study were to evaluate the implication of the sympathetic nervous system in the acute effect of melatonin on blood pressure in conscious 12-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY), and to determine whether the hypotensive effect of melatonin is associated with alterations in pre- or postsynaptic mechanisms. Melatonin, 10 mg/kg, produced a sustained time-dependent decrease of mean arterial pressure only in SHR without changes in heart rate in both groups. Until 20 min after melatonin administration, plasma epinephrine (EPI) levels were reduced by about 60% in both groups, but norepinephrine (NE) levels were decreased only in SHR by about 30%. The nitroprusside-induced hypotension responses and the associated increases in heart rate were similar in both groups before or after administration of melatonin. Unexpectedly, the sympathetic reactivity to nitroprusside, evaluated by the increases in NE and EPI, was markedly enhanced after melatonin treatment in both WKY and SHR. The stimulation induced [3H]-norepinephrine release from isolated atria was not altered by melatonin in SHR. In cultured aortic vascular smooth muscle cells, the basal and phenylephrine induced inositol phosphate formations were greater in SHR, and the melatonin pretreatment dose dependently attenuated the phenylephrine responses in cells from both WKY and SHR. Therefore the hypotensive action of melatonin appears to be associated with an inhibition of basal sympathoadrenal tone and could also be mediated partly by the blockade of postsynaptic alpha1-adrenergic receptor-induced inositol phosphate formation.
Article
CONTEXT: Plasma fibrinogen levels may be associated with the risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationships of fibrinogen levels with risk of major vascular and with risk of nonvascular outcomes based on individual participant data. DATA SOURCES: Relevant studies were identified by computer-assisted searches, hand searches of reference lists, and personal communication with relevant investigators. STUDY SELECTION: All identified prospective studies were included with information available on baseline fibrinogen levels and details of subsequent major vascular morbidity and/or cause-specific mortality during at least 1 year of follow-up. Studies were excluded if they recruited participants on the basis of having had a previous history of cardiovascular disease; participants with known preexisting CHD or stroke were excluded. DATA EXTRACTION: Individual records were provided on each of 154,211 participants in 31 prospective studies. During 1.38 million person-years of follow-up, there were 6944 first nonfatal myocardial infarctions or stroke events and 13,210 deaths. Cause-specific mortality was generally available. Analyses involved proportional hazards modeling with adjustment for confounding by known cardiovascular risk factors and for regression dilution bias. DATA SYNTHESIS: Within each age group considered (40-59, 60-69, and > or =70 years), there was an approximately log-linear association with usual fibrinogen level for the risk of any CHD, any stroke, other vascular (eg, non-CHD, nonstroke) mortality, and nonvascular mortality. There was no evidence of a threshold within the range of usual fibrinogen level studied at any age. The age- and sex- adjusted hazard ratio per 1-g/L increase in usual fibrinogen level for CHD was 2.42 (95% confidence interval [CI], 2.24-2.60); stroke, 2.06 (95% CI, 1.83-2.33); other vascular mortality, 2.76 (95% CI, 2.28-3.35); and nonvascular mortality, 2.03 (95% CI, 1.90-2.18). The hazard ratios for CHD and stroke were reduced to about 1.8 after further adjustment for measured values of several established vascular risk factors. In a subset of 7011 participants with available C-reactive protein values, the findings for CHD were essentially unchanged following additional adjustment for C-reactive protein. The associations of fibrinogen level with CHD or stroke did not differ substantially according to sex, smoking, blood pressure, blood lipid levels, or several features of study design. CONCLUSIONS: In this large individual participant meta-analysis, moderately strong associations were found between usual plasma fibrinogen level and the risks of CHD, stroke, other vascular mortality, and nonvascular mortality in a wide range of circumstances in healthy middle-aged adults. Assessment of any causal relevance of elevated fibrinogen levels to disease requires additional research.
Article
To assess the magnitude and direction of associations of depression with C-reactive protein (CRP), interleukin (IL)-1, and IL-6 in community and clinical samples. Systematic review of articles published between January 1967 and January 2008 in the PubMed and PsycINFO electronic databases was performed. Effect sizes were calculated as stat d and meta-analyzed, using random-effects models. Each inflammatory marker was positively associated with depression; CRP, d = 0.15 (95% CI = 0.10, 0.21), p < .001; IL-6, d = 0.25 (95% CI = 0.18, 0.31), p < .001; IL-1, d = 0.35 (95% CI = 0.03, 0.67), p = .03; IL-1ra, d = 0.25 (95% CI = 0.04, 0.46), p = .02. Associations were strongest in clinically depressed patient samples--but were also significant in community-based samples--and when clinical interviews were used. Studies adjusting for body mass index (BMI) had smaller associations, albeit significant. Relationships were inconsistent with respect to age, medication, and sex. Depression was related to CRP and IL-6 among patients with cardiac disease or cancer. Depression and CRP, IL-1, and IL-6 are positively associated in clinical and community samples and BMI is implicated as a mediating/moderating factor. Continuity in clinic- and community-based samples suggests there is a dose-response relationship between depression and these inflammatory markers, lending strength to the contention that the cardiac (or cancer) risk conferred by depression is not exclusive to patient populations. Available evidence is consistent with three causal pathways: depression to inflammation, inflammation to depression, and bidirectional relationships.
Article
Previous studies have shown a low rate of engagement in pleasant activities to be a concomitant of depression. The crucial question addressed by the Hammen and Glass study is whether an increase in pleasant activity level will produce a decrease in depression level. Positive results would constitute strong evidence that low rate of engagement in pleasant activities is an antecedent of depression. The results of the Hammen and Glass study should not be considered conclusive because neither an initial low pleasant activities level nor a significant association between mood and pleasant activity level was demonstrated for the subjects prior to the introduction of the experimental treatment.
Article
Results from a 2-year (4 waves) longitudinal study show strong evidence for patient decline and high levels of depressive symptomatology among caregivers. Female caregivers reported high, stable rates of depressive symptomatology throughout the study, whereas male caregivers exhibited significant increases in depression over time. Cross-sectional multivariate analyses revealed significant positive relationships between depression and number of patient problem behaviors, negative social support, and concern about financial resources; negative relationships were found between depression and social support, quality of prior relationship, and satisfaction with social contacts. Three significant independent predictors of change in depression were found: Lower depression scores at Time 1 were related to increases in depression over time; men were more likely than women to experience increases; and a decline in social support resulted in increased depression.
Article
Subjective sleep quality deteriorates with aging, but the extent to which this is a product of age itself, as opposed to the medical or psychiatric problems associated with aging, has not been carefully studied. To investigate this issue, we examined the subjective sleep quality of 44 healthy subjects over 80 years of age (20 men, 24 women), and 35 healthy subjects [corrected] between the ages of 20 and 30 (23 men, 12 women) using the Pittsburgh Sleep Quality Index (PSQI). All subjects underwent rigorous medical and psychiatric evaluations to verify that they were in excellent physical and psychological health. Significant age effects were noted for the global PSQI score and several PSQI component scores, but overall sleep quality for the majority (68.1%) of 80-yr-olds fell within a categorically defined range for "good" sleepers. Measures of habitual sleep quality did not correlate strongly with most polysomnographic sleep measures, number of medications used or circadian measures in elderly subjects. These results show that subjective sleep quality does deteriorate in the healthy elderly, but not to the level seen in patients with sleep disorders. Extremely healthy elderly subjects appear to adapt in their perception of objectively disturbed sleep.
Article
Case reports have prompted concern that the use of bromocriptine mesylate to prevent lactation in the puerperium increases the risk of postpartum seizure. We conducted a record-based case-control study of postpartum seizures in three data bases to evaluate this relation. We identified 43 women who had a postpartum seizure, and we matched 319 controls individually by hospital of delivery, quinquenium of age, and time of delivery. Overall, women taking bromocriptine had a 22% lower risk for seizures, that is, the relative risk estimate was 0.78, with a 90% confidence interval of 0.29 to 1.87. A reduction in seizure risk is consistent with reports of antiseizure activity for bromocriptine in various species, including humans. We found a small positive association between bromocriptine use and seizures occurring more than 72 hours after delivery, with a relative risk estimate of 1.6 after controlling for seizure history. This association was offset by a strong negative association between bromocriptine use and early-occurring seizures. The pattern of an initial reduced risk followed by an increase to normal or above-normal levels of risk could result from an antiseizure activity of bromocriptine, with a rebound in risk when bromocriptine is withdrawn.
Article
Adjustments for making multiple comparisons in large bodies of data are recommended to avoid rejecting the null hypothesis too readily. Unfortunately, reducing the type I error for null associations increases the type II error for those associations that are not null. The theoretical basis for advocating a routine adjustment for multiple comparisons is the "universal null hypothesis" that "chance" serves as the first-order explanation for observed phenomena. This hypothesis undermines the basic premises of empirical research, which holds that nature follows regular laws that may be studied through observations. A policy of not making adjustments for multiple comparisons is preferable because it will lead to fewer errors of interpretation when the data under evaluation are not random numbers but actual observations on nature. Furthermore, scientists should not be so reluctant to explore leads that may turn out to be wrong that they penalize themselves by missing possibly important findings.
Article
This paper views caregiver stress as a consequence of a process comprising a number of interrelated conditions, including the socioeconomic characteristics and resources of caregivers and the primary and secondary stressors to which they are exposed. Primary stressors are hardships and problems anchored directly in caregiving. Secondary stressors fall into two categories: the strains experienced in roles and activities outside of caregiving, and intrapsychic strains, involving the diminishment of self-concepts. Coping and social support can potentially intervene at multiple points along the stress process.
Article
The effects of melatonin on platelet aggregation and thromboxane-B2 (TxB2) production induced by 1-4 x 10(-6) M adenosine diphosphate (ADP) or 0.6 x 10(-3) M arachidonic acid (AA) were assessed in platelet-rich plasma (PRP). Micromolar concentrations of melatonin inhibited in a dose-dependent way ADP-induced platelet aggregation with individual inhibitions 40% or more at 10(-6)-10(-5) M. A significant depression of AA-induced platelet aggregation was observed only at 10(-5)-10(-4) M melatonin. Morning (0830 h)-evening (1800 h) studies of ADP-induced platelet aggregation in seven normal men showed a higher sensitivity at 1800 h when analyzed as a global inhibitory effect of melatonin (P less than 0.01). Moreover, only during the evening hours did melatonin induce reversible aggregation, an index of inhibition of the platelet secretory process elicited by ADP exposure. No diurnal variability in melatonin inhibition of AA-induced aggregation was detected. TxB2 production elicited by AA in the evening was inhibited significantly in a concentration-related manner by a 2-min preincubation with 10(-9)-10(-5) M melatonin, while during the morning hours the inhibition was significant only at 10(-6) M or higher melatonin concentrations. In the case of ADP, the inhibition of TxB2 release attained significance at 10(-5)-M (0830 h) or 10(-6)-M concentrations (1800 h). In the presence of either stimulatory agent, melatonin depression of TxB2 generation was about 2-fold greater at 1800 h than at 0830 h. The diurnal changes in melatonin effect on TxB2 production were also observed in thrombin-stimulated washed platelets. The present data indicate the existence of circadian variations in platelet responsiveness to melatonin in humans.
Article
During the tenth biennial examination of the Framingham Study, 1315 participants who were free of cardiovascular disease had fibrinogen levels measured. During the ensuing 12 years, cardiovascular disease developed in 165 men and 147 women. For both sexes, the risk of cardiovascular disease was correlated positively to antecedent fibrinogen values higher than the 1.3 to 7.0 g/L (126 to 696 mg/dL) range. The magnitude of the risk diminished with advancing age in women but not in men. Risk for coronary heart disease also was significantly related to fibrinogen level. Here, the magnitude of risk displayed diminishing impact with age, again only in women. Risk of stroke increased progressively with fibrinogen level in men but not in women. The impact of fibrinogen value, considered as a separate variable, on cardiovascular disease was comparable with the major risk factors, such as blood pressure, hematocrit, adiposity, cigarette smoking, and diabetes. Fibrinogen values were also significantly related to these risk factors. Taking all these into account in a multivariate analysis, fibrinogen level was still significantly related to the incidence of cardiovascular disease in men and marginally significant in women. For coronary heart disease, the fibrinogen level was significant for both men and women. Elevated fibrinogen level is a predictor of cardiovascular disease that should be added to the cardiovascular risk factor profile.
Article
To study the possible risk factors for cardiovascular disease, we collected data on plasma levels of coagulation factors, blood pressure, serum cholesterol, and smoking in a random sample of 792 men 54 years of age. During 13.5 years of follow-up, myocardial infarction occurred in 92 men, stroke in 37, and death from causes other than myocardial infarction or stroke in 60. The blood pressure, degree of smoking, serum cholesterol, and fibrinogen level measured at the base-line examination proved to be significant risk factors for infarction by univariate analyses during follow-up, and blood pressure and fibrinogen were risk factors for stroke. Fibrinogen and smoking were strongly related to each other. The relation between fibrinogen and infarction, and between fibrinogen and stroke, became weaker when blood pressure, serum cholesterol, and smoking habits were taken into account, but was still significant for stroke. Although causality cannot be inferred from these data, it is possible that the fibrinogen level plays an important part in the development of stroke and myocardial infarction.
Article
Patients with coronary heart disease have increased nocturnal urinary noradrenaline. Because melatonin suppresses sympathetic activity, we measured serum melatonin concentrations at night (0200 h) in 15 patients with coronary heart disease. Melatonin was significantly lower in the patients than in 10 healthy controls (median 7.8 [interquartile range 6.5-11.8] vs 36.2 [32.2-42.5] pg/mL, p<0.0001). Thus, impaired nocturnal secretion of melatonin is associated with coronary heart disease. Patients disease nocturnal noradrenaline.
Article
Relations of factor VIII activity, FVIIIC, and von Willebrand factor antigen (vWFAg), with ischaemic heart disease (IHD) were examined in 1393 men aged between 40 and 64 years at entry to the Northwick Park Heart Study (NPHS) who experienced 178 first major episodes of IHD during an average follow-up period of 16.1 years. After allowing for the large factor VIII differences between the main ABO blood groups, FVIIIC was probably associated with IHD incidence, possibly more strongly with fatal than non-fatal episodes. Thus, an increase of 1 standard deviation in FVIIIC raised the risk of fatal IHD by about 28%. vWFAg was also significantly associated with fatal events. The observed relation of FVIIIC with IHD incidence probably underestimates the true strength of the association because of the considerable within-person and laboratory variability in factor VIII measurements. FVIIIC and vWFAg were strongly correlated (r = 0.57) and in statistical terms there may be little to choose between them in long-term studies of IHD. Taking account of evidence that haemophiliacs seem to experience less IHD than expected, high factor VIII levels may contribute to the incidence of IHD by increasing thrombogenic potential. The incidence of IHD was significantly higher in those of blood group AB than in those of groups O, A or B, particularly for fatal events. There was no evidence that the FVIIIC and vWFAg associations with IHD are determined by ABO group. The factor VIII and ABO blood group effects therefore appeared to be independent. Group AB may be a genetic marker of characteristics influencing other indices of IHD risk such as short stature, NPHS men (though not women) of group AB being about 2 cm shorter than those of other groups.
Article
Melatonin, an indolamine synthesized in the pineal gland, is known to have antiprostanoid activity. The inhibition of platelet aggregation induced by melatonin has been proposed to take place through the cyclooxygenase pathway. In the present study, we found that melatonin has a marked inhibitory effect on collagen, arachidonic acid (AA), adenosine diphosphate (ADP), epinephrine, and A23187-induced aggregation in platelet-rich plasma. On the other hand, using metrizamide-filtered platelets resuspended in Tyrode's buffer, melatonin fails to suppress AA-induced platelet aggregation and 14C-5-HT release. Under the same conditions, melatonin inhibits collagen-induced platelet activation; however, the addition of threshold doses of AA (0.3 mM) abrogates this effect. These studies suggest that melatonin also inhibits platelet function at a stage preceding the cyclooxygenase-dependent pathway.
Article
The Pleasant Events Schedule-AD (PES-AD) has been described as a useful tool for identifying pleasant activities for Alzheimer's disease patients. The current investigation provides psychometric data on the PES-AD, introduces a shortened, 20-item version, and examines the relationship between pleasant events, cognitive functioning, and depression. Both versions of PES-AD had good reliability and were significantly correlated with each other and with other relevant measures. As hypothesized, both depression and decreased cognitive functioning were associated with reduced frequency of enjoyable activity, and the reduction was significantly greater in AD patients who were depressed than in those who were not depressed, regardless of cognitive level.
Article
In alcoholics, disturbances of the autonomic nervous system as well as of the hypothalamic-pituitary-adrenal axis (HPA) are known. However, these two systems have never been analyzed, under stimulated conditions, in parallel in the same patients. Moreover, studies using intravenous (i.v.) corticotropin releasing factor (CRF) to assess neuroendocrine function bypass the hypothalamic component of the HPA axis. Therefore, i.v. human (h) CRF (pituitary stimulation/exogenous CRF) and a multifaceted stress test (hypothalamic activation/endogenous CRF) were compared with respect to their effects on hemodynamics as well as plasma norepinephrine (NE), epinephrine (E), ACTH, and cortisol in abstinent alcoholics (n = 11) versus healthy men (n = 10). Each stimulus was tested twice, 12 weeks apart, in two separate experimental blocks (I and II). Alcoholics entered block 18 days after the last ethanol ingestion and were controlled for abstinence up to block II. hCRF caused a fall in mean arterial pressure (MAP), most pronounced in alcoholics, particularly in block II. In contrast, stress testing raised MAP in both groups and blocks. A sustained increase in ACTH, cortisol, and NE occurred after hCRF, although the ACTH response in alcoholics was blunted in both blocks. Stress testing elevated NE in both groups and blocks, while raising plasma ACTH and cortisol during block I only in controls. However, unlike the persistently blunted ACTH response to i.v. CRF, a normalization of the stress-induced ACTH output occurred in alcoholics after 12 weeks of abstinence. During block I, basal E levels were elevated in alcoholics whereas NE levels tended to be lower than in controls, resulting in a significantly decreased NE/E ratio that returned to near control values in block II. Neither CRF nor stress had any effect on circulating E in either group or block. To conclude: (1) Normalization of the ACTH response to stress, but not to i.v. CRF, after 12 weeks of abstinence, suggests that other ACTH secretagogues may be compensating for CRF dysfunction in alcoholics. (2) Despite the dramatically lowered plasma NE/E ratio in alcoholics, the NE response to stimuli was unaffected. (3) The exaggerated hypotensive reaction and blunted ACTH response to i.v. CRF may reveal a long-term dissociative dysregulation of CRF actions in alcoholics.
Article
Cardiac arrhythmias during ischemia/reperfusion are believed to be related to free radicals generated in the heart especially during the period of reperfusion. Since melatonin functions as a free radical scavenger and antioxidant, the ability of this molecule to influence cardiac arrhythmias was investigated. The pineal secretory product, melatonin, reduced the incidence and severity of arrhythmias induced by ischemia/reperfusion due to ligation of the anterior descending coronary artery in the isolated rat heart. Melatonin was either infused during both the ischemia and reperfusion periods or only late in the ischemia period and throughout reperfusion. The percentage of hearts that developed cardiac arrhythmias during reperfusion as indicated by the incidence of premature ventricular contraction (PVC) and ventricular fibrillation (VF) were recorded. Melatonin either infused during both the ischemia and reperfusion periods or during essentially the period of reperfusion greatly reduced PVC and VF due to occlusion and reopening the anterior descending coronary artery. Presumably melatonin's beneficial effect in reducing cardiac arrhythmias was due in part to its free radical scavenging activity, which is greatly assisted by the rapidity with which it is taken up into cells. Previous studies have shown that vitamin C is effective in reducing the severity of cardiac arrhythmias induced by ischemia/reperfusion; thus, we also compared the efficacy of melatonin with this well-known antioxidant. Melatonin was more potent than vitamin C in protecting against arrhythmias induced by ischemia/reperfusion. Besides melatonin's function as a broad spectrum free radical scavenger, melatonin may have also reduced cardiac arrhythmias due to its regulation of intracellular calcium levels, i.e., by preventing calcium overloading, or due to its ability to suppress sympathetic nerve function and reduce adrenergic receptor function in the myocardium. Additional studies into the mechanisms of melatonin's action in reducing cardiac arrhythmias due to ischemia/reperfusion or other causes are warranted because of the possible application of this information to humans with heart disease.
Article
In this study it was investigated whether the oral administration of melatonin (1 mg) in comparison to placebo was able to reduce blood pressure, vascular reactivity, and catecholamines in men, as previously reported in young women. The administration of melatonin significantly reduced blood pressure, the pulsatility index in the internal carotid artery, and catecholamines levels within 90 minutes. The effect of melatonin on the artery pulsatility index was related to baseline values, being greater in men with higher baseline values. The present data indicate that melatonin may blunt the activity of the cardiovascular system and may have both physiopathologic and clinical implications.
Article
Aims: Decreased night-time plasma levels of melatonin were recently reported in patients with coronary artery disease, and it was postulated that melatonin production may be impaired, due to a lack of synthesizing enzymes. However, since artefacts possibly influencing the release pattern were not taken into account, this interpretation was strongly criticized. We therefore carefully investigated night-time melatonin production in patients with coronary artery disease using an appropriate experimental approach. Furthermore, we examined the effect of beta-blockers, a frequently used drug in coronary artery disease therapy. Methods and results: Forty-eight male patients with angiographically documented severe coronary artery disease, 24 of them taking beta-blockers daily in therapeutic dosages, were included. Eighteen age-matched men, with no evidence of coronary sclerosis, served as controls. To determine melatonin production, 6-sulfatoxymelatonin (aMT6s) was measured radioimmunologically from overnight urine. Urinary aMT6s concentration was significantly decreased in patients, and beta-blocker treatment did not further suppress melatonin production. Conclusions: The data obtained using this investigative approach provide clearcut evidence that melatonin production in patients with coronary artery disease is decreased. Whether a decreased melatonin level may be a predisposing factor for coronary artery disease, or whether the occurrence of coronary artery disease decreases melatonin synthesis remains to be determined.
Article
A decrease in nocturnal serum melatonin levels was reported in patients with clinically uncharacterized coronary artery disease. To assess whether there was a correlation between melatonin production and disease stage, we measured the nocturnal urinary excretion of 6-sulphatoxymelatonin (an index of blood melatonin concentration) in patients with chronic stable or unstable coronary disease and in a group of age-matched controls. Three groups of individuals were studied: a) 24 healthy subjects (mean age: 63 +/- 13 yr); b) 32 patients with chronic, stable, coronary disease (62 +/- 11 yr); and c) 27 patients with unstable angina (62 +/- 12 yr). For 6-sulphatoxymelatonin measurement, urine was collected from 18:00 to 06:00 hr, within 48 hr of hospitalization in the case of unstable angina. 6-Sulphatoxymelatonin was measured by a specific radioimmunoassay. Urinary 6-sulphatoxymelatonin excretion was significantly lower in unstable angina patients than in healthy subjects or in patients with stable angina. 6-Sulphatoxymelatonin correlated negatively with age in healthy subjects, but not in coronary patients. 6-Sulphatoxymelatonin excretion in patients treated with beta-adrenoceptor blockers did not differ significantly from coronary patients not receiving beta-blockers. The results indicate that patients with coronary disease have a low melatonin production rate, with greater decreases in those with higher risk of cardiac infarction and/or death.
Article
Overactivity of the sympathetic nervous system (SNS) has been related to increased cardiovascular morbidity. Historical reports suggest hastening of blood coagulation following intravenous administration of epinephrine. Given the important role of the hemostatic system in atherosclerosis and thrombosis, it is surprising that short-term adrenergic effects on blood coagulation, fibrinolysis and platelet activity have not been scrutinized closely. To elucidate such effects in vivo, this paper reviews human studies in which alpha- and beta-sympathomimetic agents had been infused. The literature suggests a dose-dependent stimulation of factor VIII clotting activity, von Willebrand factor antigen, tissue-type plasminogen activator, and platelets within a 15- to 40-min infusion of epinephrine. Precise mechanisms underlying hemostatic changes with sympathetic activation remain to some extent speculative. However, there is evidence from adrenoreceptor blockade studies that coagulation and fibrinolysis molecules are released into circulation by stimulation of vascular endothelial beta-adrenoreceptors (most likely beta2-receptors). Combined alpha2- and beta2-adrenoreceptor-related mechanism(s) are responsible for platelet activation. Short-term activation of the SNS effects regular hemostatic activity. While in healthy individuals the hemostatic balance between coagulation and fibrinolysis may be preserved, catecholamine surge may trigger a hypercoagulable state and enhance the odds of overt thrombosis in patients with atherosclerotic disease.
Article
Previous studies have suggested that melatonin, a major pineal hormone, possibly modulates the autonomic nervous system in animals. The aim of this study was to examine the effects of melatonin administration on heart rate variability (HRV) in human beings. In 26 healthy men, melatonin (2 mg) or placebo was randomly administered. Power spectral analysis of HRV and blood pressure monitoring were performed in the supine position before and 60 minutes after administration and in the standing position 60 minutes after administration. Plasma catecholamine levels were also assessed. No differences in any baseline parameters were found between the two groups. Compared with placebo, melatonin administration within 60 minutes increased R-R interval, the square root of the mean of the squared differences between adjacent normal R-R intervals, high-frequency power, and low-frequency power of HRV and decreased the low-frequency to high-frequency ratio and blood pressure in the supine position (all P <.01). Plasma norepinephrine and dopamine levels in the supine position 60 minutes after melatonin administration were lower compared with placebo (P <.05 and P <.01, respectively). Standing up resulted in the decrease of HRV and the increase of blood pressure and plasma catecholamine levels in both administration groups, and the differences between the groups found in the supine position disappeared. These findings indicate that melatonin administration increased cardiac vagal tone in the supine position in awake men. Melatonin administration also may exert suppressive effects on sympathetic tone.
Article
It is unknown whether modest increases of fibrin D-dimer, a circulating marker of fibrin turnover, are relevant to coronary heart disease (CHD) in the general population. Methods and We measured serum concentrations of D-dimer antigen in the stored baseline blood samples of 630 CHD cases and 1269 controls "nested" in a prospective cohort of 5661 men who were monitored for 16 years, and we conducted a meta-analysis of previous relevant studies to place our findings in context. In a comparison of men in the top third compared with those in the bottom third of baseline fibrin D-dimer values (tertile cutoffs, >94 versus <49 ng/mL), the odds ratio for CHD was 1.67 (95% CI, 1.31 to 2.13; P<0.0001) after adjustments for age and town. The odds ratio increased slightly after further adjustment for smoking, other classic risk factors, and indicators of socioeconomic status (1.79; 95% CI, 1.36 to 2.36). Strong correlations were observed of fibrin D-dimer values with circulating concentrations of C-reactive protein and serum amyloid A protein but not with smoking, blood lipids, blood pressure, and other risk factors. Although there may be an association between circulating D-dimer values and CHD, further studies are needed to determine the extent to which this is causal.
Article
Inflammatory processes play a pivotal role in the pathogenesis of atherosclerosis and mediate many of the stages of atheroma development from initial leukocyte recruitment to eventual rupture of the unstable atherosclerotic plaque. Elevated plasma levels of several markers of the inflammatory cascade have been shown to predict future risk of plaque rupture. These markers include P-selectin, interleukin-6, tumor necrosis factor-alpha, soluble intercellular adhesion molecule-1, and C-reactive protein (CRP). Produced in the liver in response to interleukin-6, CRP has emerged as the most powerful inflammatory marker of future cardiovascular risk. Initially considered an innocent bystander in the atherosclerotic process, recent evidence suggests that CRP may have direct proinflammatory effects. Numerous large-scale, prospective studies have found that elevated baseline levels of CRP are a strong independent predictor of future vascular risk. Furthermore, aspirin and statin therapy appear to be particularly effective among individuals with high CRP levels. The addition of CRP screening to traditional lipid testing has the potential to identify individuals at high risk for future cardiovascular events who may benefit from targeted preventive interventions.
Article
The hormone melatonin produced by the pineal gland during the daily dark phase regulates a variety of biological processes in mammals. The aim of this study was to determine the effect of melatonin and its precursor N-acetylserotonin on the microcirculation during acute inflammation. Arteriolar diameter, blood flow rate, leukocyte rolling and adhesion were measured in the rat microcirculation in situ by intravital microscopy. Melatonin alone or together with noradrenaline did not affect the arteriolar diameter or blood flow rate. Melatonin inhibited both leukocyte rolling and leukotriene B(4) induced adhesion while its precursor N-acetylserotonin inhibits only leukocyte adhesion. The rank order of potency of agonists and antagonist receptor selective ligands suggested that the activation of MT(2) and MT(3) melatonin binding sites receptors modulate leukocyte rolling and adhesion, respectively. The effect of melatonin and N-acetylserotonin herein described were observed with concentrations in the range of the nocturnal surge, providing the first evidence for a possible physiological role of these hormones in acute inflammation.