Melatonin and its usefulness in sleep disorders

Melatonin is a hormone produced by the pineal gland. At nightfall, the neuronal signals that connect the retina and the central nervous system with the gland produce a release of noradrenaline that induces the transformation of serotonin into melatonin, which is secreted into the blood and cerebrospinal fluid. Being very fat-soluble, it easily crosses the blood-brain barrier. Most of the circulating melatonin is metabolized in the liver by cytochrome P450 enzymes. It is mainly eliminated by urine in the form of inactive metabolites. In humans, receptors have been identified in the membrane and in the cell nucleus of multiple tissues and systems in which melatonin exerts various actions, including the regulation of circadian rhythms. The rhythmic pattern of melatonin secretion is important because it provides organisms with time information that allows them to adopt some of their physiological functions to daily and seasonal variations.

Melatonin exerts its pharmacological actions through two receptors mainly: MT1 and MT2. The first one is distinguished by being a high-affinity receptor, and the MT2 is of low affinity. Both receptors are found in the suprachiasmatic nucleus of the hypothalamus, although they are also found in certain tissues, such as the intestine, the endothelium of blood vessels and the ovaries. Both are part of the family of receptors coupled to G proteins that inhibit adenylate cyclase. The action in the MT1 receptor generates the sleep-promoting effect. On the other hand, the action in MT2 receptors is attributed to chronobiotic properties, that is, the ability to modify the phase or period of the circadian cycle. Based on this chronobiotic property, the usefulness of melatonin in the treatment of various conditions has been studied, such as the delayed sleep phase syndrome, the decompensation syndrome and the shift disorder in the work shift.

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Other physiological actions of melatonin as totipotent molecule include:
• Facilitation of the release of free radicals
• Antioxidant action
• Bone protection
• Regulation of bicarbonate secretion by the gastrointestinal tract
• Facilitation of immunity regulation. It collaborates in the control of tumor growth
• It has a regulating action of blood pressure (The MT1 receptor has vasoconstrictive action and the vasodilating MT2).
• It can modify the function of the CNS neurotransmitters. The levels of serotonin and gamma-aminobutyric acid (GABA) are increased in the brain after administration of the same.
• Action on nutritional status.
• Action on the temperature.
• Action on the reproductive system.

As mentioned above, melatonin acts as a chronobiological agent (internal synchronizer) stabilizing and reinforcing biological rhythms (sleep-wake rhythm) rather than as a hypnotic. Because the half-life of melatonin in plasma is short, about 30 minutes, and variable from one subject to another, between 20-40 minutes, the metabolization of melatonin is a factor to be taken into account when evaluating the hypnotic effects of its exogenous administration. One of the advantages of melatonin treatment is that the administration of exogenous melatonin does not inhibit its endogenous production. The chronobiological effect that propitiates the reorganization of the sleep phases depends to a great extent on the moment of its administration. When it is administered in the afternoon and the first part of the night, it advances the sleep phase, while the administration in the second part of the night or the morning delays the sleep phase.

The effects of melatonin administration depend on whether or not there is a prior sleep disturbance. If so, a reduction in sleep latency is consistently produced, a reduction in the number and duration of alert periods during the night, and an improvement in the subjective quality of sleep. In short, endogenous melatonin plays an important role in the circadian regulation of sleep, while exogenous melatonin influences aspects of sleep such as its latency and quality.

The endogenous production of melatonin and the amplitude of its nocturnal peak decrease with age, which is associated with fragmentation of sleep in small periods over 24 hours. This is a natural process of aging. However, this process is reversible and the administration of melatonin periodically every 24 hours (5-10 mg) can resynchronize the rhythm of the altered sleep, improving not only the quality of sleep but also the activity during the vigil, which results in a substantial improvement in the quality of life of the individual.

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The irregular sleep/wake rhythm presents an undefined pattern of sleep and vigil throughout the 24 hours. This sleep pattern is observed mainly in elderly people (due to the decrease in the production of melatonin), but it is also associated with neurological diseases such as dementia and in children with intellectual deficits. The administration of melatonin is very useful in children and also in older subjects. Even in the alteration of sleep/wake rhythm in Alzheimer's disease, melatonin has a remarkable effect.

There is an alteration of the sleep/wake rhythm that affects the whole population and age. It is the alteration secondary to a rapid change of time zone (jet-lag). It is due to a desynchronization between the sleep/wake cycle and the cycle generated by the biological clock that is observed from two time zones of change. The symptomatology, which disappears by itself at 5-7 days, is accompanied by sleep disturbance, decreased alertness, alteration of cognitive functions, discomfort and gastrointestinal symptoms. There is abundant evidence that treatment with melatonin (2-5 mg) just before sleeping during the first nights at the destination is completely effective to eliminate jet-lag.

Spot the clot

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Twenty-four-year-old Spanish skateboarding star Danny Leon got made up to look like a not-so-steady-on-his-feet 80-year-old man. His goal: To see if teens at a local skate park would teach him the sport. They obliged, but when Danny started speeding down the half pipe and doing aerial spins, well, the kids were blown away.

Being a force of nature disguised as a harmless old guy -- that's a pretty good metaphor for the way a blood clot can disguise itself as a simple bruise. Don't you fall for it.

Bruises can be painful and turn shades of black and blue, but generally they're not harmful. One caveat: Easy or spontaneous bruising can indicate underlying disease and a need to see your doc.

A blood clot, on the other hand, is a concentrated aggregation of blood. It forms from an external injury to blood vessels or internal injury to the lining of a blood vessel from plaque, or because of dysfunction in your blood's flow-and-clot chemistry. Clots can obstruct blood flow or dislodge and travel through your bloodstream, triggering heart attack, stroke, deep vein thrombosis (DVT) or pulmonary embolism (PE). So if you spot a clot, see your doc.

Some tips:

Near your skin's surface, clots can appear bruise-like, but are generally redder and the underlying vein may be hard to the touch.

A clot that's moved and is causing trouble may trigger swelling and pain in an extremity (DVT); slurred speech and vision problems (stroke); chest pain or upper body discomfort, shortness of breath and a rapid heart rate (PE or heart attack).

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(c) 2018 Michael Roizen, M.D. and Mehmet Oz, M.D. Distributed by King Features Syndicate, Inc.

How to Prevent the Widowmaker – the Worst Cardiac Attack

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The Widowmaker is a heart attack that is frequently fatal since it affects the left anterior descending artery (LAD). The LAD provides blood and oxygen to the entire frontal region of the heart, irrigating a more extensive area than other coronary arteries. The obstruction of the left anterior descending artery interrupts 40 percent of the blood that nourishes the heart, which leads to an increased risk of complications. The most common complications are irregular heartbeat, heart failure, and less frequently, sudden death.

A feature that makes the Widowmaker more fearsome is that it attacks silently. Most men who suffered sudden death due to coronary heart disease had no previous symptoms. Men 30 to 50 years old have a greater risk of death from coronary heart disease than women; this is because estrogen exerts protection against cardiovascular diseases.

Thanks to advances in medicine, an obstructed artery can be rapidly permeabilized with timely treatment. These procedures take place in a catheterization laboratory where the interventional cardiologist performs an angioplasty by threading a thin tube (catheter) in the blocked coronary artery expanding the diameter of the vessel and restoring blood flow.

How to prevent a heart attack from a widowmaker

Understand what happens in your body

A heart attack is caused by a blockage in an artery due to atherosclerosis (a process in which the fat called plaque adheres to the inside of blood vessels). However, to be at imminent risk of a sudden heart attack, there must be a blockage greater than 60% of the blood flow. A 90% blockage can cause a life-threatening heart attack. Plaque is often formed as a soft, unstable reservoir instead of a hard, stable reservoir. As it is soft, a fragment of the plaque often breaks off, and the fatty material flows into the bloodstream until it clogs a smaller artery.

Risk factors such as smoking, eating fatty foods, obesity, and having high cholesterol make the rupture of the atheromatous plaque more likely.

Calculate your risk of heart attack

Through the ASCVD Risk Estimator Plus of the American College of Cardiology, you can obtain an approximate risk of developing atherosclerosis in the next ten years. You simply need to enter your age, your cholesterol values (HDL and LDL), blood pressure, and answer questions regarding your lifestyle. If you get a score higher than 7.5 percent, you should consult your doctor for a full evaluation and establish therapeutic behavior.

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Adopt a healthy diet

Various studies in different populations have linked the consumption of high-quality, healthy foods with a lower risk of heart disease compared to the consumption of unhealthy foods of low quality, independent of other risks such as sedentary lifestyle, obesity, and smoking. To maintain a healthy diet, you must prioritize the consumption of vegetable proteins and reduce the consumption of red and processed meats. Foods such as vegetables, fruits, whole grains, nuts, legumes, fish, and yogurt also have a beneficial effect on your health.

Exercise

The adult population should avoid a sedentary lifestyle. Performing any type of physical activity will provide great health benefits. To obtain recognizable benefits, you should get at least 2.5 hours of moderate physical activity a week or 75 minutes of intense physical activity. To obtain an additional benefit, physical activity should include 5 hours of moderate-intensity aerobic exercise or 2.5 hours of high-intensity aerobic exercise. Exercising has very positive effects on emotional health. When exercising, the body releases endorphins; metabolites that make the person feel more calm and happy. Also, physical exercise helps some people sleep better. It can also be of great help in some psychological problems such as mild depression.

Take the medications recommended by your cardiologist

One of the most commonly prescribed drugs is the statin. This drug is to reduce cholesterol levels even if you have not been diagnosed with heart disease. Statins have been shown to reduce the risk of heart attack by 25 to 33 percent by limiting unstable plaque deposits and reducing inflammation.

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Prediabetes – the Silent Enemy

[Image 1] With the growth of the population, changes in lifestyle, obesity, and other risk factors, diseases such as diabetes mellitus type 2 (DM2) and cardiovascular events have increased in parallel; both entities can occur independently or interrelated. DM2 is considered a public health problem, given its high prevalence and its accelerated increase in the last 20 years. The World Health Organization (WHO) has indicated that this increase can be up to 160% in the next 25 years. The support of epidemiological studies and the knowledge that it is possible to identify DM2 in an asymptomatic stage has allowed the development of early detection strategies with economic, simple, and sensitive diagnostic procedures, allowing timely prevention measures.

Prediabetes is a condition that precedes the diagnosis of type 2 diabetes and is characterized by an elevation in the concentration of sugar (glucose) in blood beyond normal levels without reaching the diagnostic values of diabetes. It is identified by evidencing alterations in the oral glucose tolerance test (140-199 mg/dl) and the change in fasting blood glucose values (100-125 mg/dl).

The evolution of prediabetes to type 2 diabetes can be avoided. Consuming healthy foods, incorporating physical activity into your daily routine, and maintaining a healthy weight can help you regulate your blood sugar level.

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Symptoms of prediabetes

Prediabetes is a condition that often goes unnoticed because it usually does not present evident symptoms. However, the main symptoms in people with prediabetes are found below.

Blurred vision: Sudden rises and falls in blood sugar levels (common in people with pre-diabetes) can affect the ability of the eye to focus, which results in blurred vision. Once the sugar levels are regulated, this symptom should disappear.

Excessive thirst: When there is excess sugar in the blood, the body eliminates it through urine, which prompts the need to go to the bathroom more than usual. That, in turn, causes dehydration which produces excessive thirst.

Wounds or infections that take a long time to heal: High levels of blood sugar slow down circulation, so the skin needs more time to heal itself. Therefore, small bruises and cuts take longer than normal to heal. Pre-diabetes can also promote the growth of bacteria and fungi, which lead to recurrent infections in the skin, vagina and or urinary tract.

Fatigue: Your body uses sugar in the blood as fuel, but prediabetes causes insulin resistance, which makes your body unable to convert glucose into energy efficiently. Consequently, you feel fatigue and excessive fatigue.

Skin areas darken: Some people with prediabetes may show signs of insulin resistance. High insulin accelerates the speed of reproduction of skin cells, resulting in pigmentary acanthosis. This happens when the skin of the neck, under the arm, or in the folds of the elbows begins to darken.

Unexplained weight gain or loss: When the body cannot get the energy it needs from blood glucose, it starts burning other things for energy which can cause sudden weight loss even if you do not diet or exercise. However, insulin resistance can also make the patient hungry and gain weight.

Treatment

Several clinical trials have been published regarding the treatment of prediabetes to investigate the effectiveness of these treatments in delaying or abrogating the progression of prediabetes to diabetes. In general, the studies provide optimistic data and establish that: 1) lifestyle changes are highly effective in slowing the progression of prediabetes to diabetes, and 2) pharmacological agents that increase insulin sensitivity (metformin, glitazones) or prevent the absorption of carbohydrates (Acarbose) also confer a delay effect in the progression of prediabetes to diabetes.

In a simplified form, the treatment of individuals with prediabetes primarily includes the change in lifestyle, with the goal of weight loss and increasing daily physical exercise. If these measures do not have the desired effect in a reasonable time, then medication treatment should be supplemented. This treatment scheme is fluid, especially taking into account the recent data obtained in the treatment with pioglitazone, where there is evidence of an 82% decrease in the incidence of diabetes in individuals treated with this drug.

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Vitamin D, an Ally in the Treatment of Asthma

Vitamin D exerts various functions throughout the body including the immune system. This vitamin is synthesized in the skin when exposed to sunlight. The wide use of sunscreen, a characteristic of modern life, would partly explain the increase in the prevalence of vitamin D insufficiency.

Multiple epidemiological studies have shown strong associations between asthma and reduced serum levels of 25-hydroxyvitamin D (25 [OH] D), the main precursor in the circulation of vitamin D.

More severe asthma has been observed in patients with low vitamin D levels, but it is unknown at this time whether the linkages express causality or inverse causality. It is possible that the association between asthma and vitamin D is complex. The information as a whole supports the therapeutic role of vitamin D in reducing the risk of asthma exacerbations.

In the Childhood Asthma Management Program, an association was observed between baseline vitamin D insufficiency (<30 ng / ml) and the risk of severe exacerbations over four years.

Asthma triggered by allergens

The asthmatic inflammation was essentially due to immunological reactions in response to aeroallergens. In this situation, T-helper lymphocytes phenotype 2 (Th2), B lymphocytes (producers of antibodies) and mast cells have a fundamental role.

Th2 lymphocytes synthesize various interleukins (IL), such as IL-4, IL-5, and IL-13, involved in the etiopathogenesis of asthma. IL-4, in particular, induces the synthesis of immunoglobulin (Ig) E by B lymphocytes.

IgE binds to mast cells, and cross-linking induces rapid release of proinflammatory mediators such as leukotrienes and histamine, which cause bronchial obstruction and mucus production.

Adaptive immune responses are regulated by various classes of regulatory T lymphocytes (Treg), for example, Foxp3 positive Treg lymphocytes and Treg lymphocytes that synthesize IL-10. In healthy subjects, both lymphocyte subpopulations participate in the emergence of tolerance towards non-harmful antigens.

Vitamin D plays a decisive role in the function of responses mediated by Treg lymphocytes. In several studies, it has been observed that vitamin D is favorably associated with the frequency of Foxp3 positive Treg lymphocytes and with the levels of IL-10 in the airways of patients with asthma.

Likewise, the stimulation and the signals derived from dendritic cells (DC) determine the induction of tolerance or the appearance of inflammatory responses; Vitamin D regulates multiple functions of DC.

In vitro, vitamin D suppresses the synthesis of IgE by B lymphocytes and increases the synthesis of IL-10 with induction of a regulatory B phenotype. In children, vitamin D deficiency is associated with increased levels of specific IgE against aeroallergens.

Vitamin D inhibits the activation of mast cells so that it reduces the synthesis of histamine and tumor necrosis factor alpha; it can also increase the production of IL-10 with anti-inflammatory properties.

Epithelial damage and asthmatic inflammation mediated by cytokines

The epithelial damage is accompanied by the release of IL-25, IL-33, and thymic stromal lymphopoietin, which directly stimulate various cell subtypes, including innate lymphoid cells type 2 (ILC2) and mast cells. ILC2 synthesize Th2-type cytokines, for example, IL-5, which induce eosinophilic inflammation.

Vitamin D modulates the epithelial response, especially by inducing synthesis in bronchial epithelial cells of soluble ST2, a suppressor of IL-33, associated with proinflammatory effects on effector cells, such as mast cells.

Viral infections induce the epithelial release of IL-33; in asthma, the mechanisms dependent on the Th2 phenotype alter the antiviral responses. Vitamin D is associated with increased immunological antimicrobial responses, through various mechanisms, including the increased production of antimicrobial peptides, such as cathelicidin, and autophagy, an important mechanism in viral and bacterial infections.

In a meta-analysis, the intake of vitamin D reduced the incidence of acute respiratory tract infections in selected patients with asthma.

Asthma resistant to steroids and IL-17

The physiopathological mechanisms involved in corticosteroid-resistant asthma would be somewhat different. The colonization of the airways with proinflammatory bacteria such as Haemophilusinfluenzae, oxidative stress (associated with air pollution) and vitamin D deficiency would play an important role in this type of asthma. Vitamin D increases the antimicrobial pathways and induces antioxidant responses.

Patients with asthma resistant to corticosteroids synthesize less IL-10. In these patients, the contribution of calcitriol is associated with the recovery of the clinical and immunological response of IL-10. Likewise, in patients with asthma resistant to corticosteroids, IL-17 would induce pathological neutrophilic inflammation, a phenomenon that reverts after the administration of vitamin D.

Vitamin D and remodeling of the airways

The final result of the abnormal immunological responses in asthma is the remodeling of the airways, associated with smooth muscle contraction and mucus secretion in the short term, and with remodeling and fibrosis in the long term. Vitamin D prevents the proliferation of smooth muscle cells in the airways.

Clinical data on the use of vitamin D for the treatment of asthma

In the study, Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma (VIDA), showed that for every 10 ng / ml increase in serum levels of 25 (OH) D, the rate of therapeutic failures and exacerbations was reduced in a meaningful way.

Although the rate of asthma exacerbations did not decrease significantly in the total group assigned to vitamin D therapy, the exploratory analysis revealed a significant decrease in the frequency of exacerbations in the group of patients who reached levels of 25 (OH ) D3 ≥ 30 ng/ml.

In multiple investigations and Meta-analyses, it was observed that vitamin D supplements substantially decreased the rate of severe asthmatic exacerbations in patients with asthma.

With the exception of asthma resistant to corticosteroids, the different asthma endotypes have not been studied in detail in controlled clinical studies. Although more work will undoubtedly be required to answer these questions, the information as a whole suggests that the optimal state of vitamin D is important regarding the appearance and clinical evolution of asthma.

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