3r? 3534. 3r3-31. Researchers tend to pay more and more attention to inflammatory processes in the brain in degenerative diseases, both in the role of the root cause and in the role of a secondary factor caused by damage to the nervous tissue. Neuro-inflammation can be central to the aging process of the body. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. It is very difficult to determine neuroinflammation in the context of neurodegenerative diseases, although, for example, in multiple sclerosis (an autoimmune disease, it has nothing to do with sclerosis in the common sense) it is not a problem. In the latter case, the lymphocytes and monocytes in excess penetrate the barrier separating the nervous tissue from the bloodstream, causing impaired function. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. With pathologies that include Alzheimer's disease, which you probably know from the state of the writer Terry Pratchett before his death, Parkinson's disease, from which the artist Salvador Dali suffered in the last years of his life, amyotrophic lateral sclerosis, which became known due to the state of physicist Steven Hawking, the description is based on the reaction, expressed in changing the shape and structure of glial cells - astrocytes and microglia. Many of these diseases manifest themselves in older age, they are associated with aging and possibly caused by them. Understanding of neuro-inflammation, its causes and consequences, can potentially improve the treatment of many diseases, some of which are now treated only symptomatically. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. In order to understand the phenomenon of neuro-inflammation, it is first necessary to understand what inflammation is. The proposed issue is more than 2000 years old, but the definition of inflammation, which would lead scientists and doctors all over the world to a consensus, has not yet been proposed. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. What is inflammation? 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. www.ncbi.nlm.nih.gov/pmc/articles/PMC4089888 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Astrocytes do not lag behind their glial counterparts. Being represented by the most numerous class of cells in the central nervous system, they occupy a strategic position between vascular endothelial cells and neurons, regulating the work of the barrier between the blood and the brain. After injury, they react either to danger signals that originate from neurons, or to substances secreted by activated microglia. Then astrocytes increase in size, hypertrophying, releasing neuroregulatory peptides, for example, BDNF (brain-derived neurotrophic factor) or neurotrophic factor of the brain, which contributes to the survival of damaged neurons. They also produce and secrete fibrillar proteins that regenerate the extracellular matrix and form a glial scar. On the one hand, this is a good thing, since the injury site is isolated, on the other hand, regeneration of neurons will be difficult in this area. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Nerve cells are not restored? 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. As Santiago Ramon y Kahal postulated, the founder of modern neuroscience, at the beginning of the 20th century, nerve cells in an adult organism are not restored. You must have heard this statement more than once in the form of the phrase "lost nerves are not restored." However, in the 60s of the last century, Joseph Altman announced the discovery of neuron division in the hippocampus of mature guinea pigs. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. 3r3r1616. www.nature.com/articles/2141098a0
3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. These evidence of adult neurogenesis were not taken seriously until the 90s of the last century. The accumulated data on the neurogenesis of various species, including primates, has led to a paradigm shift. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. 3r3176. www.ncbi.nlm.nih.gov/pubmed/10521353 3r353519. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Researchers confirmed that neurogenesis actually occurs in the brain of various adult animals, and eventually found traces of newly formed neurons in the brain of an adult. It is assumed that hundreds of such cells are produced every day in the hippocampus, where they help shape memory and new skills. This concept is widely accepted by scientists, and you can even find diets and special exercises that supposedly enhance it. Predictably, you can even find TED talk about this phenomenon. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. That's just the problem: this update neurons may actually not be. Studies that disprove the existence of adult neurogenesis continue to appear until today. The last such large study was published on March 15 of this year in the journal Nature. In it, scientists from the California Institute of San Francisco conclude that they could not find any traces in a few dozen hippocampi, derived from the brains of adults who bequeathed their bodies to science. According to the researchers, they did not find any signs even in the best-preserved specimens. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. 3r3190. www.nature.com/articles/nature25975.epdf
3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. As usual, it is very difficult to prove that something is really not there, and many scientists are skeptical about the results of their work. Many indicate that the calculation was carried out indirectly - by the presence of proteins, which are usually produced by young, recently divided cells. These proteins could easily degrade shortly after the death of the organism. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. It is very likely that the debate will continue further, and the last word on this issue will be put only when techniques for observing neurons in the brain of living people are developed. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. In the brain of zebrafish, the neurons of the lateral wall of the ventricles are able to divide, and then move into the affected area, forming young neurons to replace the dead. The corresponding cells of the mice closer to us are no longer capable of such a focus, although being placed in a test tube in vitro, the ability is restored. It is believed that the microenvironment in the place of injury in such highly developed animals hinders the development of new neurons. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. 3r3208. www.sciencedirect.com/science/article/pii/S0962892413001372
3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. When tissue is damaged, the microenvironment is formed by the breakdown products of proteins and other macromolecules of which it consists, as well as of substances secreted by the surrounding cells. The specific actions of glial cells and their role in the recovery strongly depend on the nature of the injury. When microglia are excessively and continuously activated, the substances secreted by it in high concentration become toxic to the surrounding cells, the produced cytokines disrupt the functioning of neurons; fibrillar proteins secreted by astrocytes prevent the formation of functional bonds. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. A high amount of interleukin ? one of the major mediators of inflammation, especially its beta form, in combination with tumor necrosis factor, interleukins 6 and 1? produced in the CNS in case of damage, can lead to headaches and migraines. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. It should be remembered that these pro-inflammatory cytokines are necessary to restore the affected tissue, despite the fact that they in turn can cause cell death and cause secondary damage to the tissue. For example, tumor necrosis factor alpha is toxic to neurons in the early stages of inflammation, but it promotes regeneration in the later stages. 3r? 3522.  
3r? 3522.  3r? 3534. Neuroinflammation in Alzheimer's disease 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. As evident from the definition given above, neuroinflammation is a frequent companion of neurodegenerative diseases. Such diseases are characterized by loss of structure, function and number of neurons. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. The disease, first described by the German psychiatrist Alois Alzheimer, usually affects people over 6? although other forms are sometimes found. With the development of the disease, patients lose the ability to memorize information, and in extreme cases lose their long-term memory, the ability to speak, orient themselves in the setting and look after themselves. The cause of many cognitive impairments in this pathology is the degeneration of neurons and synapses, leading to atrophy of the cerebral cortex. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Microglia in the role of one of the main participants of neuroinflammation becomes active after exposure to one of the many stimuli, namely hypoxia, trauma, stroke, along with such factors as viruses, bacteria and toxins. Cells are also activated when amyloid plaques and accumulations of tau proteins appear. It is these two factors — neurofibrillary tau tang protein and neuroinflammation — that are key signs of Alzheimer's disease. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. www.ncbi.nlm.nih.gov/pmc/articles/PMC4805095 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Activated microglia is observed in excess in the patient's brain when examined by a post-mortem pathologist. Apparently, in the presence of pro-inflammatory cytokines, macrophages of the brain lose the ability to phagocytize extracellular accumulations of beta-amyloid, a group of peptides forming a characteristic plaque. In addition, an increased concentration of cytokines, such as interleukin 1 beta, prevents the formation of synapses, which explains their loss in the pathological process. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Considering the enormous damage inflicted on the brain by chronic inflammation, it was suggested that substances that suppress inflammation can cure the disease or at least reduce the likelihood of its development. There is evidence that nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, can reduce the inflammation caused by amyloid plaques, but clinical trials have not been completed due to the high risk of side effects. Currently, NSAIDs are not considered useful in the treatment of Alzheimer's disease, and none of the clinical trials to prove the ability of NSAIDs to prevent or reduce the risk of developing the disease has not been completed. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. The results of recent studies in general cast doubt on the benefits of taking daily low doses of aspirin and potentially other NSAIDs. The study, published in one of the most influential medical peer-reviewed scientific journals Lancet, where doctors and scientists monitored more than 1?000 patients with a moderate risk of developing heart disease, did not confirm any benefit in taking this medication. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. www.thelancet.com/journals/lancet/article/PIIS0140-6736 (18) 31924-X /fulltext 3r33535.  3r? 3534. 3r? 3522.  3r? 3534. Neurospiolitis in Parkinson's disease 3r3493. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. But what about the other neurodegenerative diseases? In Parkinson's disease, which is characterized by the massive death of dopamine-secreting neurons in the basal ganglia, neuroinflammation is almost the main component of the disease. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. People with Parkinson lose control of their movements, their hands begin to shake, their handwriting worsens. Patients begin to walk more slowly, they have trouble walking. These are all early manifestations of the disease. Over time, abstract thinking and attention control worsens and hallucinations appear. The latter have almost 50% of those diagnosed. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Early post mortem brain tests reveal the entire repertoire of proinflammatory cytokines, including interleukins ? ? ? interferon gamma, tumor necrosis factor alpha, and others. The same set is observed in the cerebrospinal fluid of patients. High concentrations of nitric oxide and superoxide, which can directly and indirectly cause neuronal death, are also detected. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. www.ncbi.nlm.nih.gov/pmc/articles/PMC5926497 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. However, despite the great success in studying the presented pathology, researchers find it difficult to say for sure whether neuroinflammation is the cause or consequence of the disease. One thing is certain: as soon as inflammation is drawn into the game, it becomes a key player. This is confirmed by epidemiological studies. Unlike Alzheimer's disease, NSAIDs, with the exception of aspirin, can reduce the risk of developing Parkinson's disease according to a meta-analysis conducted in 2010. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. 3r3305. www.ncbi.nlm.nih.gov/pubmed/20308684 3r3ir3519. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. A characteristic feature of many neurodegenerative diseases is that their risk of development increases with age. From this we can assume that neuroinflammation and aging are also somehow connected. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. [b] Neuroinflammation during aging 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Brain cells live and die, this is the normal life cycle. Neurons are gradually replaced by astrocytes, and cytokines released during their death control inflammation and recovery. Thus, at any given point in time, a certain level of pro-inflammatory cytokines is present in the brain. However, with age, the markers of inflammation in glia become larger, and in addition, they contribute to an excessive immune response during stimulation. Microglia becomes hyperactive. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. With aging, there are also disorders of cognitive functions — memory, speech, and abstract thinking — albeit to a lesser extent than with neurodegenerative diseases. In general, aging can be considered the main risk of mild cognitive disorders. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Older people often show signs of cognitive impairment during or after infection or stress. These observations are confirmed in laboratory experiments on mice, whose cognitive disorders can be caused by the administration of a lipopolysaccharide (a component of the bacterial wall, to which an immune response is developed), but which can be eased using resveratrol, a strong anti-inflammatory agent. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. 3r33333. onlinelibrary.wiley.com/doi/???/9781118732748.ch6
3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Aging of the hippocampus 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Any description of aging of the central nervous system invariably begins with the hippocampus, the brain area responsible for the formation of memories. It is affected by both normal aging and Alzheimer's disease. In addition to memory, the hippocampus intrigues researchers with the effects of stress. Since the hippocampus is an important feedback element responsible for stopping the production of glucocorticoids, the effect of chronic stress on aging is under scrutiny. 3r? 3522.  3r? 3534. In early studies on the aging of the hippocampus, it was shown that the elderly have a significant loss in the number of neurons. However, in later studies using exact techniques, physiologists found minimal differences between the number of neurons in the hippocampi of young and old people. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. A very similar situation exists with the volume of the hippocampus, as measured by magnetic resonance imaging. It is authentically known that the smaller the volume of the hippocampus, the worse the memory of an elderly person will be. Fortunately, there are studies that show that moderate aerobic workouts help preserve the volume of the hippocampus. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. 3r33333. 3r? 3522.  3r? 3534. 3r33358. Effects of cortisol on the brain during stress 3r33359. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Since hippocampal neurons have a significant amount of glucocorticoid receptors, they are vulnerable to long-term stress. In people who suffer from severe and long-term traumatic stress, the hippocampus atrophies faster than the rest of the brain. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Similar effects are observed in post-traumatic stress disorder, schizophrenia and depression. Interestingly, atrophy in depression can be slowed down by taking antidepressants even if they do not help to cope with other symptoms. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Neuroinflammation in mental disorders 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. In general, an interesting picture is formed around depression. The reasons for it are still unknown; The most popular serotonin theory is constantly criticized. At the same time, patients with chronic inflammation often show signs and symptoms of depression. This year a paper was published, where scientists determined that psychological stress, including social factors, increases the level of inflammation in the brain of mice. Mice periodically met with an aggressive male for 10 days. Such stress caused an increase in the amount of interleukin 1 and tumor necrosis factor secreted by activated microglia in the prefrontal cortex, a region of the brain that is responsible for making decisions. Such a violation eventually led to episodes of severe depression, which could be cured by neutralizing inflammation. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Sleep disturbance, described in experimental conditions, causes activation of the same innate immunity receptors as social stress. 3r33382. www.ncbi.nlm.nih.gov/pmc/articles/PMC3548567
Due to the fact that neuroinflammation can play a key role in psychiatric diseases - depression, schizophrenia, bipolar disorder - this phenomenon becomes extremely curious, because the results of these experiments imply the conclusion that these diseases can be prevented long before their appearance by correcting lifestyle, diet and sleep patterns. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. 3r33333. bmcmedicine.biomedcentral.com/articles/???/1741-7015-11-200
3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Aging of the hypothalamus 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Unlike the hippocampus, whose changes explain the occurrence of cognitive impairment with age, the hypothalamus probably controls aging. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. This structure in the brain, similar to the tonsil, is a bridge between the nervous and endocrine systems of the human body. It helps regulate behavior and many basic needs, such as hunger, sleep, fear, and aggression. Accordingly, with age, the homeostasis of the secreting nerve cells that make up the hypothalamus is disturbed, and manifestations associated with aging manifest. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. The first searches in this direction concerned the establishment of feedback chains of various hormones, often sex hormones. However, feedback disorders and the emergence of resistance to estrogen, insulin, growth hormone and other regulatory molecules are a consequence, not a cause. The cellular and molecular mechanisms explaining the loss of homeostasis have not yet been studied thoroughly. 3r? 3522.  3r? 3534. Over the past few years, several molecular paths and genes associated with the onset and progression of age-dependent degenerative processes have been considered. Among them were now very popular among researchers sirtuins, SIRT, mammalian target mammalian rapamycin protein, mTOR, NF-kB transcription factor, and others. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. mTOR is an enzyme belonging to the family of protein kinases, which is the target of the anticancer drug rapamycin. As a result of research on yeasts, worms, flies and some mammals, rapamycin has been shown to prolong the life of these model organisms. So mTOR has earned a reputation as the central, evolutionarily conservative determinant of life expectancy. 3r? 3522.  3r? 3534. mTOR is very sensitive to insulin and growth factors; it controls the metabolism of the cell, its growth and survival. However, with chronic high stimulation, excessive work of mTOR leads to oxidative stress, accumulation of damage and cell aging — all signs of the inflammatory response of the cell. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Activation of the transcription factor NF-kB contributes to the further development of the inflammatory response, since it controls the genes responsible for maintaining it. In a recent research paper, it has been shown that a constant excess of calories in food can contribute to the development of inflammatory responses in the hypothalamus. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Neuroinflammation with excess nutrition 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Excess nutrients have a domino effect. First of all, it suffers from endoplasmic reticulum - an extensive network of cavities, vesicles and tubules, associated with a large number of metabolic functions: transport of proteins and lipids, accumulation of calcium, and so on. When this important organoid experiences stress in the hypothalamic microglia, NF-kB is activated in these cells. Microglial cells are in continuous communication with neurons through pro-inflammatory cytokines, such as tumor necrosis factor alpha and interleukin 1 beta. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Increasing their expression activates NF-kB in secreting neurons, suppressing the production of GnRH, a hormone that controls the production of pituitary gonadotropic hormones, and promoting insulin resistance and leptin. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Over time, this does not weaken the hypothalamus homeostasis. This dysregulation is associated with systemic aging and the development of age-related pathologies - diabetes, obesity, cardiovascular diseases, dementias, and reproductive dysfunction. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. 3r3442. www.ncbi.nlm.nih.gov/pmc/articles/PMC2586330
3r? 3522.  3r? 3534. www.ncbi.nlm.nih.gov/pmc/articles/PMC3756938 3r? 3522.  3r? 3534. 3r33450. www.ncbi.nlm.nih.gov/pubmed/23636330 3r353519. 3r? 3522.  3r? 3534. www.ncbi.nlm.nih.gov/pmc/articles/PMC4313775 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Stem cells and neuroinflammation 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. In 201? researchers from the Albert Einstein Medical College discovered hypothalamus stem cells, which they also think are capable of controlling aging. They report that the number of stem cells in the hypothalamus decreases over time in mice that have been the target of research. By the age of two - the age of old mice - most of these cells do not remain with them. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. The experimenters transplanted stem cells to normal mice, as well as mice, to which they had previously destroyed the hypothalamic stem cells. Both groups showed signs of delayed aging. It turned out that specific miRNAs were the key effector in this phenomenon. This group of molecules differs from ordinary RNAs in that they are not involved in the process of protein synthesis, but instead are involved in regulating the expression of other genes in cells. The cell can secrete miRNAs in special containers - exosomes. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. To confirm their hypothesis, experimenters isolated the exosomes of the hypothalamus stem cells and injected spinal fluid into normal mice and mice that had their hypothalamus stem cells destroyed. The result exceeded all expectations: again, both groups of mice grew older more slowly - their muscle strength, motor coordination, social behavior and cognitive abilities were evaluated.
 3r? 3534. 3r? 3522.  3r? 3534. 3r33478. www.nature.com/articles/nature23282
3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Although several miRNAs are already known that play an important role in inflammation, such as miR-10? miR-155 and miR-22? it was not studied in this work which specific miRNA was responsible for slowing aging. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Research miRNAs are still only at the beginning, and insights on how they can be used to increase the duration of healthy life may be waiting for us in the near future. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Conclusion 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. As you can see now, neuro-inflammation is an extremely complex process. When it is not observed classical manifestations of inflammation described by Celsus, namely redness, swelling with fever and pain. However, during neuroinflammation, the molecular and cellular mechanisms are partially the same as in inflammation. In either case, signaling molecules or cytokines, such as interleukins, chemokines, and tumor necrosis factor, are involved. Both processes have positive and negative sides. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. The key to these processes is the body's attempt to repair damaged tissue in the ways that are available to it. There are differences. Microglial cells are the resident macrophages in the brain tissue. They are not detected in other tissues of the body. Instead of the usual scar in the nervous tissue, glial is formed due to the activation of astrocytes. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. It is not surprising that inflammation in the nervous tissue, especially the central nervous system, has far-reaching consequences. Neuro-inflammation is involved in aging, age-related pathologies, obesity, and some types of dementia. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Despite the fact that much in health depends on genetics, our behavior also partly determines how we will live and grow old. Moderate exercise and, again, a moderate, healthy and varied diet, healthy sleep can reduce neuroinflammation, as well as prolong the health of the brain and body. It is also necessary to seek the help of doctors in time, even if it is “some kind of depression” and will pass by itself. And also you should not get involved in self-medication, and reading on pubs, which came to our society to replace the diagnosis of Google. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. 3r???. www.ncbi.nlm.nih.gov/pmc/articles/PMC4588685
3r? 3522.  3r? 3534. 3r33518. www.ncbi.nlm.nih.gov/pubmed/25527485 3r33535. 3r? 3522.  3r? 3534. 3r? 3522.  3r? 3534. Author Vasily Tsvetkov. 3r? 3530. 3r? 3534. 3r? 3534. 3r33535. ! function (e) {function t (t, n) {if (! (n in e)) {for (var r, a = e.document, i = a.scripts, o = i.length; o-- ;) if (-1! == i[o].src.indexOf (t)) {r = i[o]; break} if (! r) {r = a.createElement ("script"), r.type = "text /jаvascript", r.async =! ? r.defer =! ? r.src = t, r.charset = "UTF-8"; var d = function () {var e = a.getElementsByTagName ("script")[0]; e.parentNode.insertBefore (r, e)}; "[object Opera]" == e.opera? a.addEventListener? a.addEventListener ("DOMContentLoaded", d,! 1): e.attachEvent ("onload", d ): d ()}}} t ("//mediator.mail.ru/script/2820404/"""_mediator") () (); 3r33528. 3r? 3534. 3r? 3530. 3r? 3534. 3r? 3534. 3r? 3534. 3r? 3534.