Hello, friends. very important in the first days of life. Consider the main points of caring for newborn puppies. Here you have puppies. Their bunch is growing in size right before our eyes. The puppies have become active, crawling around the box and actively sucking their mother. Their coat has become shiny, they have grown stronger and grow rapidly. But inexperienced owners along the way can have a lot of questions and worries. Today I will try to cover the main points of caring for newborn puppies.

(The photo of the puppy is 5 days old. compare with the photo in the article about childbirth and pregnancy. how has he changed)

In the last article, we talked about dog pregnancy and how to take. Let's be consistent and today we'll talk about what should be the care of newborn puppies and their mother.
We will consider the main points on the example of Yorkshire Terrier puppies. Since I am engaged in this particular breed, it will be much easier to explain what is what with this particular breed.
In the first week, your addition grows literally by leaps and bounds. A puppy gains about 100 grams of weight in the first 7 days of life. In general, normal daily weight gain should be 15 grams on average. To do this, you need to weigh each puppy immediately after birth, and then every day, once a day, weigh each puppy. This is necessary for control - if the puppy is gaining less than 10 grams per day, you need to pay special attention to him. Perhaps this puppy is weaker and less nimble than his brothers and sisters, and he simply does not have enough milk. Such a puppy should be hung separately on the boobs several times a day and make sure that other puppies do not push him away from the chest. If all the puppies are not gaining weight well, the problem may lie in the lack of milk from the mother. Strengthen the nutrition of the bitch, add calories to her diet. For the first 10 days after giving birth, I do not recommend giving the bitch meat, in order to avoid postpartum complications. Well-soaked dry food, which the bitch ate during pregnancy, is best suited. You can also add buckwheat porridge with milk, a little non-fat cottage cheese or a boiled egg to the diet. I do not advise giving rice porridge - puppies can get tummy ache and problems with defecation can begin.

- be careful!

When your puppies squeak for the first few days, this is normal. However, you need to feel the difference between a child's squeak and a squeak of pain. If the puppies (and especially one of them) squeak for a long time and persistently, this is a signal that something is wrong with him. It usually happens at night. The puppy squeaks, crawls on the box, does not cling to the boob and is very worried. So he's in pain. Usually at such an early age, it is due to the fact that he cannot go to the toilet. Puppies at this age still cannot pee or poop themselves, the bitch must lick the puppy's tummy and under his tail, so that the reflex works and defecation occurs. However, the dog sometimes forgets or simply does not want to lick the puppy in the right place. Then you need to help her. You can spread a little bit of butter under the puppy's tail. Then the dog will begin to lick the puppy and he will poop. Or take a wet cotton swab yourself and massage the puppy's tummy and under the tail. If this does not help, the puppy needs to be given an enema. To do this, take an ordinary 2-cc syringe, draw warm boiled water, grease the nose with baby cream and gently insert the syringe into the puppy's anus. After such an enema in 2 ml of warm water, the puppy will definitely poop and should calm down after a while.

In all my practice, I have not seen other problems with puppies of a week of age. It was just poor weight gain and a stomach ache and constipation. Which basically happened after the bitch ate just rice porridge. Therefore, I recommend not to experiment with dog food while feeding puppies.

Farther. Puppies are 5 days old. According to the breed standard, a Yorkie should have 4 toes on its hind legs. But many Yorkie puppies are born with what are called dewclaws. This is the 5th toe on the inside of the foot. Sometimes they are even doubled. They must be removed. In the article, of course, it is impossible to show how to do it correctly. But the bottom line is this - you need to take sharp scissors, preferably clerical, pull the skin on the paw a little in the opposite direction and quickly cut off the puppy's finger. After that, the wound must be cauterized with potassium permanganate to stop the bleeding. I usually do this procedure in 5 days. Puppies at this age do not yet feel pain as much, and if this procedure is performed correctly, many of them will not even utter a peep.
Your dog needs to eat properly and well while feeding newborn puppies. Add calcium to her diet. I recommend giving the dog an injection of calcium glucanate 2 ml subcutaneously every night for the first 5 days. Again, if you get used to it, the dog does not even feel this injection. It's all about technique and practice.
So today we talked about the main points caring for newborn puppies. Let's recap the main points.
1. Don't Experiment with dog food during the feeding period. Give her her usual food. I do not recommend giving rice porridge. Give your dog milk.
2. Listen for the squeak puppies. A prolonged strained squeak indicates a problem. Help him go to the toilet, if necessary, put an enema.
3. Control your weight gain each puppy daily, the first 7 days. Puppies that are not gaining weight should be hooked separately to the chest.
4. At the age of 5 days, dewclaws should be removed in puppies. For the first time, it is better to invite an experienced person for this case.
5. To avoid complications after childbirth- eclampsia, do not give the bitch the first 10 days after giving birth to meat, and give an injection of calcium gluconate for several days in a row.

In the following articles, I will cover issues related to the growth and development of puppies along the way. If someone still has questions on today's topic - ask them through the feedback form or in the comments to the article. I will definitely answer you.
Health to you and your pets.

Want more interesting articles? We have them! Subscribe to updates and you will be happy :) You can also tell about us in social networks using the appropriate buttons, and you will be doubly happy :)

As a result of such unpleasant difficulties in the large intestine, there is an accumulation of feces and subsequent hardening. In the latrine masses, the presence of sharp objects, for example, bone fragments, is not excluded. When defecating, objects cause damage to the walls of the intestine. What to do is a question that worries the owner, who is watching the torment of the animal. Let us consider what means will benefit the poor fellow and alleviate the painful condition.

Constipation is common in dogs

The dog is deprived of speech functions, the dog is unable to describe the state. By external signs, an observant owner will guess that the four-legged pet is experiencing pain and discomfort during bowel movements. The prerogative of tracking the dog's health remains with the owner of the dog. It is better to show a sick animal to a veterinarian.

The fact is that constipation in a dog can be provoked by various factors. Common - the wrong diet of a pet.

Unwritten rules for keeping dogs should begin with care and feeding. It is unacceptable to feed the dog with treats and sweets, to throw food from the table. Often, owners are mistaken in believing that natural dog food is bones of various sizes, tubular and boiled.

The age of the animal affects the course of constipation in dogs. The disease is typical for older individuals leading a sedentary sofa lifestyle. Dogs with severe constipation are caused by a number of reasons:

• Feeding bones;
• Feeding with steep broth;
• Overfeeding;
• Improper feeding with dry food.

The most dangerous manifestations of constipation, as a consequence of the development of diseases:

1. Prostate (males suffer);
2. Paraanal glands;
3. Internal organs (gastrointestinal tract, liver, kidneys, pancreas);
4. Anus, perineum and intestines;
5. neurological pathologies;
6. Orthopedic diseases.

The elimination of the causes can be achieved through a revision of the diet and proper construction. For example, if a dog is constipated after bones, the cure for the disease lies in the full monitoring of the processes of nutrition and urination of the animal.

Diseases can be diagnosed by an experienced veterinarian already during the initial examination, it is not worth delaying. It is important to consult a veterinarian at the slightest manifestation of difficulty with defecation. Only a full examination will help identify the cause, and the doctor will make an accurate diagnosis and indicate how to treat the dog for constipation.

Constipation caused by improperly organized feeding can be treated at home. Vegetable oil is simply added to food for a four-legged pet, in small quantities. Make sure your pet has fresh water at all times. An enema will help a dog with constipation, but the procedure is highly undesirable. Firstly, experience and knowledge are required (for example, calculating the volume of water depending on the weight of the dog), and secondly, the body is supposed to be given a chance to cope without medications and enemas.

Symptoms

A healthy dog ​​with a healthy intestine and stomach will empty its bowels twice a day. If the procedure occurs once a day or does not occur at all, you should worry about the health of the pet, what is happening symbolizes constipation.

The manifestation of constipation is characterized by the dog making significant efforts to empty the intestines, unsuccessful attempts and pain as a result of these actions. The dog may try to go to the toilet several times during the day without success. The condition can last for several days.

Illiterately organized feeding is the main factor that provokes constipation in a dog. Symptoms of the disease are characterized by:

1. Multiple attempts of the animal to defecate and the inability to do so, the defecation process is delayed.
2. The animal experiences pain in the process of emptying the intestines.
3. The dog is tormented by vomiting (an extremely dangerous symptom that signals the presence of another disease).

Prevention

To avoid annoying canine malaise, feeding is adjusted:

1. Dog food must be balanced. Special feeds are preferred.
2. The dog should not receive handouts from the table.
3. Boiled tubular bones should not be present in the dog's diet (it is not uncommon for undigested bone fragments to accumulate in the animal's intestines, only surgery helps).

In the most severe cases, the dog simply removes part of the intestine clogged with hardened feces.

The following dog nutrition mistakes often include:

1. Feeding the dog steep broth,
2. The presence in the diet of foods overloaded with fiber (foods are difficult to digest) or foods poor in fiber,
3. Overfeeding or underfeeding an animal.
4. Lack of fluid in the dog's body.

Water enemas are just a way to help a dog with constipation. The purpose of the enema is to clear the overcrowded intestines of hardened feces. The procedure, although it alleviates the condition of a sick animal, does not mean the end of torment if the diet is not adjusted in the right direction. Fresh drinking water, a varied diet, meat with the addition of vegetables, raw and boiled (pumpkin, celery), unprocessed bran, beets and fresh carrot juice will improve intestinal motility.

You should remain aware of the peculiarities of the digestive system of a four-legged friend in order to avoid annoying mistakes in feeding and caring for a pet. Preventive measures taken in advance by forward-thinking owners stop constipation in dogs:

• Balanced food containing essential vitamins and minerals.
• "Sprinkling" portions of food with a small amount of vegetable oil once or twice a week.
• Availability of sufficient water.
• Walks, outdoor games, physical exercises designed to keep the four-legged pet in shape.

Particular attention should be paid to adequate physical activity. The dog was created for hunting, running, active games and fun fussing with a ball and rubber ducks. Tune in to an active life, full of not only worries, but also the joy that the disinterested friendship of a four-legged creature gives.

Coprostasis

Improper feeding of a pet leads to the development of the disease coprostasis. It occurs as a result of feeding the dog with bones or eating large portions. It is worth noting that in a dog, constipation from the bones occurs extremely often. In addition, the disease pursues males suffering from an enlarged prostate gland. The last factor is directly related to the formation of constipation, as a result of the increase, the intestines are squeezed, feces cannot come out.

An additional reason for the difficulty in the exit of feces is the presence of damage to the pelvic region, the factor strongly affects the state of the intestine. In such cases, pets need to take laxatives. Dogs suffering from coprostasis are easy to identify, dogs are always restless, periodically run to defecate to no avail. The belly of such dogs is in a somewhat swollen state.

With suspicion of a disease, dogs are sent to a hospital for an X-ray examination with contrasting of the intestinal region. Light conditions are cured in the simplest ways, for example, with the help of antispasmodics.

Another effective medicine is considered to be a combination of vaseline (20) and castor oils (1). Severe cases require surgical intervention. An enema for a dog with constipation is performed under general anesthesia, and the procedure is supplemented by the removal of feces using obstetric forceps. In order to avoid complicating the situation, it is not allowed to feed the dog with an overflowing intestine.

MEMBRANE MECHANISMS OF PHOTOBIOLOGICAL ACTION
LOW-INTENSITY LASER RADIATION

G.I. Klebanov

Department of Biophysics
Russian State Medical University, Moscow

Low-intensity laser radiation (LILR), which has been widely used in clinical practice in the last decade, is used in medicine in two main areas:

1) in photodynamic therapy (PDT) of tumors, where the damaging effect of LILI is manifested

,

2) in the treatment of a wide range of various inflammatory diseases with laser therapy (LT), where the stimulating effect of LILI is manifested

.

The mechanism of the damaging effect of LILI in PDT of tumors is based on the initiation of photosensitized free radical reactions (SRR)

, resulting from the interaction of laser radiation quanta with photosensitizer molecules in the presence of oxygen. As for laser therapy, despite the widespread use of this laser technology in clinics in Russia, the CIS countries, Israel, China, Japan, Latin America, etc., the mechanism or mechanisms of the stimulating effect of LILI are far from being understood and are considered in the literature only on hypothesis level , many of which are contradictory and speculative, do not have experimental evidence for the presence of a specific chromophore, primary reactions that ultimately lead to the formation of a physiological response of the body.

It has already been noted earlier that LILI is very successfully used in the treatment of many diseases.

. It would be logical to assume that there is some common link in the pathogenesis of all nosological forms of diseases, in the therapy of which LT is beneficially manifested. This implies the existence of a single general mechanism of action of LILI in relation to all pathologies, and not a multitude of various individual reactions for each specific disease. It is most likely that such a link is a universal pathological process, namely inflammation, which occurs in all the above examples of the use of LT and either plays the role of a leading pathogenetic link or is reactive.

One of the essential stages in the pathogenesis of the inflammatory process is a microcirculation disorder, including a violation of blood rheology. The inflammatory process in its development passes through a phase change in the cycle(s) of ischemia-reperfusion

with impaired microcirculation. Any action that can shorten the duration of the ischemic stage will have a beneficial effect on the subsequent development of the disease.

It should be taken into account that the introduction of LILI into clinical practice is predominantly empirical. One of the most insidious properties of LILI is a sharp dependence of the magnitude and even the sign of the effect on the radiation dose and the functional state of a biological object. A positive, stimulating effect is manifested, as a rule, in a narrow range of radiation doses, and then disappears or even is replaced by a depressing effect [

21–23]. Since the mechanisms of the therapeutic effect of LILI on the human body have not yet been explained and the nature of the endogenous chromophore of laser radiation has not been determined., there is still no scientifically based method for selecting radiation doses for LLLT.

The molecular and cellular mechanisms of the therapeutic effect of LILI are now discussed in the literature only at the level of hypotheses. The main point of any hypothesis of the photobiological effect of laser radiation on the body is the establishment of the primary chromophore-acceptor of the energy of the absorbed photon LO and the target cell of the action of LILI. The fact is that the interaction of laser energy with a chromophore is based on the first law of photochemistry: only the quantum that is absorbed is effective. This means that in order to trigger all subsequent biochemical and physiological responses of the body during RT, a chromophore is required that is capable of absorbing strictly defined laser energy quanta, i.e. having the coincidence of the absorption spectrum with the wavelength of the laser source.

The most widely used in medicine and biology is currently a helium-neon laser (GNL), whose radiation wavelength is 632.8 nm. With regard to this source of laser energy, it is suggested in the literature that chromophores in the red region of the spectrum can be:

• porphyrins and its derivatives

,

antioxidant enzyme molecules: superoxide dismutase (SOD), catalase, ceruloplasmin

,

components of the mitochondrial respiratory chain: flavoproteins and cytochromes

,

molecular oxygen

.

As for hypotheses

about the photobiological effect of LILR, several assumptions about the mechanism of action of laser radiation are considered in the literature:

1) reactivation of metal-containing antioxidant enzymes

,

2) hypothesis about the interaction of LILI with the components of the electron transport chain in mitochondria

,

3) non-specific effect on biopolymers

,

4) photoexcited formation of singlet oxygen

,

5) non-specific effect on the structure of water

.

Many of the existing hypotheses about the mechanisms of therapeutic action of LILI have shortcomings, which can be divided into two groups. First, some authors consider the effects of LILI without taking into account the presence of a chromophore. It is obvious that the search for the LI acceptor is the most important in the problem of the action of LILI. Secondly, some assumptions about the mechanisms of action of laser radiation are speculative; are not confirmed by experimental data, or these data are contradictory.

The essence of the hypothesis proposed by T. Y. Karu about the interaction of laser radiation with the components of electron transport chains [

13, 24 ] is reduced to the fact that LILI acceptors in the human body can be cytochromes a and a 3 , cytochrome oxidase. The mechanism of action of laser radiation within the framework of this hypothesis implies the following sequence of events:

1. During hypoxia under conditions of oxygen deficiency, there is a restoration of carrier enzymes in the respiratory chain and a drop in the transmembrane potential of mitochondria.

2. LO leads to the reactivation of these enzymes (for example, cytochrome oxidase), which restores the flow of electrons in the respiratory chain and forms the transmembrane potential of mitochondria, i.e., the transmembrane potential in mitochondria increases, ATP production in cells increases, Ca transport is activated

2+ . Increase in ATP production and Ca ion concentration 2+ in the cell leads to stimulation of intracellular processes .

This hypothesis about the mechanism of action of LILI suggests a thoughtful and well-founded chain of events, which may be real. The authors rely on data on an increase in the proliferation of various cells, on a laser-induced respiratory burst of phagocytes observed

in vitro etc., that is, on the facts that can be a consequence, and not the cause of the effects of LILI. In addition, using this hypothesis, it is difficult to explain the remoteness and prolongation of the effects of LILI observed in the clinic.

Earlier, the concept of the membrane mechanism of the stimulating action of LILI was formulated at the Department of Biophysics of the Russian State Medical University

. Its main provisions can be summarized as follows:

1. The chromophores of laser radiation in the red region of the spectrum are endogenous porphyrins, which are capable of absorbing light in this region of the spectrum and are well known as photosensitizers. The content of porphyrins in the body increases in many diseases and pathological conditions of a person. The targets of laser energy are cells, in particular leukocytes, and blood lipoproteins containing porphyrins.

2. Porphyrins, absorbing LILI light energy, induce photosensitized free radical reactions leading to the initiation of lipid peroxidation (LPO) in leukocyte membranes and lipoproteins with the formation of primary and secondary LPO products. The accumulation of lipid peroxidation products in membranes, in particular hydroperoxides, contributes to an increase in ion permeability, including for Ca ions.

2+ .

3. Increase in the content of Ca ions

2+ in the cytosol of leukocytes triggers Ca 2+ - dependent processes leading to cell priming, which is expressed in an increase in the level of functional activity of the cell, to increased production of various biologically active compounds (nitric oxide, superoxide anion- radical oxygen, hypochlorite anion, etc.). Some of them have a bactericidal effect, others can affect blood microcirculation.. For example, nitric oxide is a precursor to the so-called Endothelium Derived Relaxing Factor (EDRF) – a factor that relaxes the vascular endothelium, which leads to vasodilation of the latter and to an improvement in microcirculation, which is the basis for most of the beneficial clinical effects of RT [ 5–8].

MECHANISMS OF BIOLOGICAL EFFECTS OF LOW-INTENSITY LASER RADIATION

The biological (therapeutic) effect of low-intensity laser radiation (coherent, monochromatic and polarized light) can be divided into three main categories:

1) primary effects(changes in the energy of the electronic levels of molecules of living matter, stereochemical rearrangement of molecules, local thermodynamic disturbances, the emergence of concentration gradients of intracellular ions in the cytosol);

2) secondary effects(photoreactivation, stimulation or inhibition of bioprocesses, changes in the functional state of both individual systems of a biological cell and the organism as a whole);

3) aftereffects(cytopathic effect, formation of toxic products of tissue metabolism, response effects of the neurohumoral regulation system, etc.).

All this variety of effects in tissues determines the widest range of adaptive and sanogenetic reactions of the body to laser exposure. It was previously shown that the initial starting moment of the biological action of LILR is not a photobiological reaction as such, but local heating (more correctly, a local thermodynamic disturbance), and in this case we are dealing with a thermodynamic rather than a photobiological effect. This explains many, if not all, of the well-known phenomena in this field of biology and medicine.

Violation of thermodynamic equilibrium causes the release of calcium ions from the intracellular depot, the propagation of a wave of increased Ca2+ concentration in the cytosol of the cell, which triggers calcium-dependent processes. After that, secondary effects develop, which are complex of adaptive and compensatory reactions arising in tissues, organs and a whole living organism, among which the following are distinguished:

1) activation of cell metabolism and increase in their functional activity;

2) stimulation of reparative processes;

3) anti-inflammatory action;

4) activation of blood microcirculation and an increase in the level of trophic provision of tissues;

5) analgesic action;

6) immunostimulating effect;

7) reflexogenic effect on the functional activity of various organs and systems.

It is necessary to pay attention to two important points. First, in each of the listed items, the unidirectionality of the influence of LILI (stimulation, activation, etc.) is a priori set. As will be shown below, this is not entirely true, and laser radiation can cause exactly the opposite effects, which is well known from clinical practice. Secondly, all these processes are calcium-dependent. Let us now consider exactly how the presented physiological changes occur, giving as an example only a small part of the known ways of their regulation.

Activation of cell metabolism and an increase in their functional activity occur primarily due to a calcium-dependent increase in the redox potential of mitochondria, their functional activity, and ATP synthesis.

Stimulation of reparative processes depends on Ca2+ at various levels. In addition to activating the work of mitochondria, with an increase in the concentration of free intracellular calcium, protein kinases are activated, which take part in the formation of mRNA. Also, calcium ions are allosteric inhibitors of membrane-bound thioredoxin reductase, an enzyme that controls the complex process of synthesis of purine disoxyribonucleotides during active DNA synthesis and cell division. In addition, the basic fibroblast growth factor (bFGF) is actively involved in the physiology of the wound process, the synthesis of which and activity depend on the concentration of Ca2+.

Anti-inflammatory effect of LILI and his influence on microcirculation are caused, in particular, by calcium-dependent release of inflammatory mediators such as cytokines, as well as calcium-dependent release by endothelial cells of the vasodilator nitric oxide (NO), a precursor of endothelial vascular wall relaxation factor (EDRF).

Since exocytosis is calcium-dependent, in particular, the release of neurotransmitters from synaptic vesicles, the process of neurohumoral regulation is completely controlled by the Ca2+ concentration, and, therefore, is also subject to the influence of LILI. In addition, it is known that Ca2+ is an intracellular mediator of the action of a number of hormones, primarily CNS and ANS mediators, which also suggests the participation of effects caused by laser radiation in neurohumoral regulation.

The interaction of the neuroendocrine and immune systems has been little studied, but it has been established that cytokines, in particular IL-1 and IL-2, act in both directions, playing the role of modulators of the interaction of these two systems. LILI can affect immunity both indirectly through neuroendocrine regulation and directly through immunocompetent cells (which has been proven in in vitro experiments). Among the early triggers of lymphocyte blast transformation is a short-term increase in the concentration of free intracellular calcium, which activates protein kinase involved in the formation of mRNA in T-lymphocytes, which, in turn, is the key moment of laser stimulation of T-lymphocytes. The impact of LILI on fibroblast cells in vitro also leads to increased generation of intracellular endogenous g-interferon.

In addition to the physiological reactions described above, to understand the whole picture, it is also necessary to know how laser radiation can affect the mechanisms neurohumoral regulation. LILI is considered as a non-specific factor, the action of which is not directed against the pathogen or symptoms of the disease, but to increase the body's resistance (vitality). It is a bioregulator of both cellular biochemical activity and the physiological functions of the body as a whole - neuroendocrine, endocrine, vascular and immune systems.

Scientific research data allow us to say with full confidence that laser radiation is not the main therapeutic agent at the level of the organism as a whole, but, as it were, eliminates obstacles, imbalances in the central nervous system that interfere with the sanogenetic function of the brain. This is carried out by a possible change under the influence of LILI in the physiology of tissues both in the direction of strengthening and in the direction of suppressing their metabolism, depending on the initial state of the body and the dose of exposure, which leads to the attenuation of pathological processes, the normalization of physiological reactions and the restoration of the regulatory functions of the nervous system. Laser therapy, when used correctly, allows the body to restore disturbed systemic balance.

Consideration of the CNS and ANS as independent regulatory systems has ceased to suit many researchers in recent years. There are more and more facts confirming their closest interaction. Based on the analysis of numerous scientific research data, a model of a single system regulating and maintaining homeostasis, called the neurodynamic generator (NDG), was proposed.

The main idea of ​​the NDG model is that the dopaminergic department of the CNS and the sympathetic department of the ANS, combined into a single structure, named by V.V. Skupchenko (1991) phasic motor-vegetative (FMV) system complex closely interacts with another, mirror-cooperative structure - tonic motor-vegetative (TMV) system complex. The presented mechanism functions not so much as a reflex response system, but as a spontaneous neurodynamic generator that restructures its work according to the principle of self-organizing systems.

The appearance of facts indicating the simultaneous participation of the same brain structures in providing both somatic and autonomic regulation is difficult to perceive, since they do not fit into known theoretical constructions. However, we cannot ignore what is confirmed by everyday clinical practice. Such a mechanism, having a certain neurodynamic mobility, is not only able to provide a continuously changing adaptive adjustment of the regulation of the entire range of energy, plastic and metabolic processes, but controls, in fact, the entire hierarchy of regulatory systems from the cellular level to the central nervous system, including endocrine and immunological changes. In clinical practice, the first positive results of this approach to the mechanism of neurohumoral regulation were obtained in neurology and in the treatment of keloid scars.

Normally, there are constant transitions from the phasic state to the tonic state and vice versa. Stress causes the inclusion of phasic (adrenergic) mechanisms of regulation, as a general adaptation syndrome. At the same time, as a response to the prevalence of dopaminergic influence, tonic (GABAergic and cholinergic) regulatory mechanisms are launched. The last circumstance remained outside the scope of G. Selye's research, but is, in fact, the most important point explaining the principle of the self-regulatory role of the GND. Normally, two systems, interacting, restore the disturbed balance.

Many diseases appear to us to be associated with the prevalence of one of the states of a given regulatory system. With a long-term, uncompensated influence of a stress factor, a malfunction occurs in the work of the NDG and its pathological fixation in one of the states, in the phasic, which happens more often, or in the tonic phase, as if moving into a mode of constant readiness to respond to irritation. Thus, stress or constant nervous tension can shift homeostasis and fix it pathologically either in a phasic or tonic state, which causes the development of the corresponding diseases, the treatment of which should be primarily aimed at correcting neurodynamic homeostasis.

A combination of various causes (hereditary predisposition, a certain constitutional type, various exogenous and endogenous factors, etc.) leads to the onset of the development of any particular pathology in a particular individual, but the cause of the disease is common - the steady prevalence of one of the conditions of NDH.

Once again, we draw attention to the most important fact that not only the CNS and ANS regulate various processes at all levels, but, conversely, a locally acting external factor, such as LILI, can lead to systemic shifts, eliminating the true cause of the disease - an imbalance of NDG, and when local action of LILI to eliminate the generalized form of the disease. This must be taken into account when developing laser therapy techniques.

Now it becomes clear that LILI can have a multidirectional effect depending on the exposure dose – stimulation of physiological processes or their suppression. The versatility of the action of LILI is due, among other things, to the fact that, depending on the dose, laser exposure both stimulates and suppresses proliferation and the wound process.

Most often, the methods use the minimum, generally accepted doses of laser exposure (1–3 J/cm2 for continuous radiation), but sometimes in clinical practice, it is the conditionally NON-stimulating effect of LILI that is required. The conclusions drawn from the previously proposed model were brilliantly confirmed in practice in substantiating effective methods for the treatment of vitiligo and Peyronie's disease.

So, in the biological effects of LILI, local thermodynamic disturbances act as the primary acting factor, causing a chain of changes in calcium-dependent physiological reactions of the body. Moreover, the direction of these reactions can be different, which is determined by the dose and localization of exposure, as well as the initial state of the organism itself.

The developed concept allows not only to explain almost all the facts already available, but also to draw conclusions on the basis of these ideas both about predicting the results of the influence of LILI on physiological processes and about the possibility of increasing the effectiveness of laser therapy.

Indications and contraindications for the use of LILI

The main indication is the feasibility of using, in particular:

Pain syndromes of a neurogenic and organic nature;

Violation of microcirculation;

Violation of the immune status;

Sensitization of the body to drugs, allergic manifestations;

Inflammatory diseases;

The need to stimulate reparative and regenerative processes in tissues;

The need to stimulate homeostasis regulation systems (reflexology).

Contraindications:

Cardiovascular diseases in the phase of decompensation;

Violation of cerebral circulation II degree;

Pulmonary and pulmonary heart failure in the phase of decompensation;

Malignant neoplasms;

Benign formations with a tendency to progression;

Diseases of the nervous system with a sharply increased excitability;

Fever of unknown etiology;

Diseases of the hematopoietic system;

Liver and kidney failure in the stage of decompensation;

Diabetes mellitus in the stage of decompensation;

Hyperthyroidism;

Pregnancy in all terms;

Mental illness in the acute stage;

Hypersensitivity to phototherapy (photodermatitis and photodermatosis, porphyrin disease, discoid and systemic lupus erythematosus).

It should be noted that There are no absolute specific contraindications for laser therapy.. However, depending on the patient's condition, the phase of the course of the disease, etc., restrictions on the use of LILI are possible. In some areas of medicine - oncology, psychiatry, endocrinology, phthisiology and pediatrics - it is strictly necessary that laser therapy be prescribed and carried out by a specialist or with his direct participation.

Moskvin Sergey Vladimirovich - Doctor of Biological Sciences, Candidate of Technical Sciences, Leading Researcher, State Scientific Center for Laser Medicine named after I.I. OK. Skobelkin FMBA of Russia”, Moscow, author of more than 550 scientific publications, including more than 50 monographs, and 35 copyright certificates and patents; email mail: [email protected] website: www.lazmik.ru

A more detailed description of the primary mechanism of the biological, or, as it is now customary to say, biomodulating action (BD) of LILI, as well as the proof of the model we proposed, can be found in the first two volumes of the series of books "Effective Laser Therapy" [Moskvin S.V., 2014, 2016], which are best downloaded for free on the website http://lazmik.ru.

In this chapter, as well as in some other sections of the book, material is also presented on the secondary processes that occur during the absorption of laser light by living cells and biological tissues, the knowledge of which is extremely important for the clinical application and understanding of the LT methodology as applied to the problem of pain and trophic disorders.

To study the mechanisms of DB LILI, we have chosen a systematic approach to data analysis, for which some part is conditionally distinguished from the whole organism, united by the type of anatomical structure or type of functioning, but each part is considered exclusively in terms of interaction as a single system. The key point of this approach is the determination of the backbone factor [Anokhin PK, 1973]. The scientific literature was analyzed, primarily related to the study of the mechanisms of the BD, the practice of using LILI in clinical medicine, as well as modern ideas about the biochemistry and physiology of both a living cell and at the level of organizing the regulation of human homeostasis in general. Based on the data obtained, some fundamentally important conclusions were made, which were confirmed in the course of numerous experimental and clinical studies [Moskvin S.V., 2008, 2008(1), 2014].

It is shown that as a result of the absorption of LILI energy, it is transformed into biological reactions at all levels of the organization of a living organism, the regulation of which, in turn, is realized in many ways - this is the reason for the extraordinary versatility of the effects that appear as a result of such an impact. In this case, we are dealing only with the external triggering of the processes of self-regulation and self-recovery of disturbed homeostasis. Therefore, there is nothing surprising in the universality of laser therapy: it is only the result of the elimination of pathological fixation of the body outside the boundaries of normal physiological regulation. Photobiological processes can be schematically represented as the following sequence: after the absorption of photons by acceptors, the absorption spectrum of which coincides with the wavelength of the incident light, biochemical or physiological reactions are triggered that are characteristic (specific) for these absorbing elements. But for laser-induced bioeffects, everything looks as if there are no specific acceptors and responses of biological systems (cells, organs, organisms), the interaction is absolutely non-specific. This is confirmed by the relative non-specificity of the "wavelength - effect" dependence, the response of a living organism to one degree or another takes place in the entire studied spectral range, from the ultraviolet (325 nm) to the far IR region (10,600 nm) [Moskvin S. IN 2014; Moskvin S.V., 2017].

The absence of a specific spectrum of action can only be explained by the thermodynamic nature of the interaction of LILI with a living cell, when the temperature gradient that occurs at the absorbing centers triggers the launch of various physiological regulation systems. As the primary link, as we assume, are intracellular calcium depots, capable of releasing Ca2+ under the influence of many external factors. There are enough arguments to confirm this theory, however, due to the limitation of the size of the book, we will give only one: all known effects of laser-induced biomodulation are secondary and Ca2+-dependent [Moskvin S.V., 2003, 2008, 2008(1)]!

Turning to energy regularities, even more surprising than spectral ones, let us repeat some basic concepts and foundations, the axioms of laser therapy. The most famous of them is the presence of an optimum dependence "energy density (ED) - effect", which is sometimes called "biphasic", i.e. the desired result is achieved only with the optimal ED of exposure. A decrease or increase in this value in a very narrow range leads to a decrease in the effect, its complete disappearance, or even an inverse response.

This is the fundamental difference between DB LILI and photobiological phenomena, where the dependence on EF has a linearly increasing character over a wide range. For example, the more sunlight, the more intense photosynthesis and increase in plant mass. Does the biphasic nature of the biological action of LILI contradict the laws of photobiology? Not at all! This is only a special case of the manifestation of the physiological law of the dependence of the response on the strength of the current stimulus. In the “optimum” phase, after reaching the threshold level, as the stimulus strength increases, an increase in the response of cells and tissues and a gradual achievement of the reaction maximum are observed. A further increase in the strength of the stimulus leads to inhibition of the reactions of cells and the body, inhibition of reactions or a state of parabiosis develops in the tissues [Nasonov D.N., 1962].

For effective exposure to LILR, it is necessary to provide both optimal power and power density (PM), i.e., the distribution of light energy over the area of ​​cells in vitro and the area and/or volume of biological tissues in animal experiments and in clinical practice is important.

The exposure (exposure time) for one zone is extremely important, which should not exceed 300 s (5 min), except for some variants of the method of intravenous laser illumination of blood (up to 20 min).

By multiplying the exposure by the PM, you get the power density per unit time, or EF. This is a derivative value that does not play any role, but is often and erroneously used in the special literature under the name "dose", which is absolutely unacceptable.

For pulsed lasers (pulse power is most often in the range of 10-100 W, the duration of the light pulse is 100-150 ns), with an increase in the pulse repetition rate, the average power increases proportionally, i.e., the EF of the effect.

Interestingly, the EF for pulsed lasers (0.1 J/cm2) is ten times less than for continuous LILI (1-20 J/cm2) for similar experimental models [Zharov V.P. et al., 1987; Nussbaum E.L. et al., 2002; Karu T. et al., 1994], which indicates a greater efficiency of the pulse mode. There is no analogue of such regularity in photobiology.

We would like to note one more interesting fact - the non-linear dependence of the LILI DB on the exposure time, which is easily explained by the periodicity of waves of increased Ca2+ concentration propagating in the cytosol after activation of intracellular calcium depots by laser light. Moreover, for completely different types of cells, these periods are completely identical and are strictly 100 and 300 s (Table 1). There are hundreds of times more clinical studies confirming the effectiveness of LT techniques using such an exposure. We also draw attention to the fact that the effect is observed in a very wide range of wavelengths, therefore, intracellular calcium depots localized in different parts of the cell have a different structure.

Table 1

Optimal exposure 100 or 300 s for maximum in vitro effect

cell type	Result	LILI wavelength, nm	Link
E. coli, S. aureus	Proliferation	467	Podshibyakin D.V., 2010
hippocampus	epileptiform activity	488	Walker J.B. et al., 2005
fibroblasts	Proliferation	633	Rigau J. et al., 1996
fibroblasts	Increasing the concentration of Ca2+	633	Lubart R. et al., 1997(1); 2005
Keratinocytes	Increase in IL-1α and IL-8 mRNA production and expression	633	Yu H.S. et al., 1996
macrophages	Proliferation	633	Hemvani N. et al., 1998
Fibroblasts, E. coli	Proliferation	660	Ribeiro M.S. et al., 2010
Human neutrophils	Increased Ca2+ concentration in the cytosol	812	Løvschall H. et al., 1994
Human buccal epithelial cells	Proliferation	812	Løvschall H., Arenholt-Bindslev D., 1994
E. coli	Proliferation	890	Zharov V.P. et al., 1987
Myoblasts C2C12	Proliferation, viability	660, 780	Ferreira M.P.P. et al., 2009
HeLa	Mitotic activity	633, 658, 785	Yang H.Q. et al., 2012
E. coli	Proliferation	633, 1064, 1286	Karu T. et al., 1994

To illustrate and demonstrate that the activation of mitochondria is a secondary process, only a consequence of an increase in the concentration of Ca2+ in the cytosol, we present the corresponding graphs from only one study (Fig. 1) .

Rice. 1. Change in Ca2+ concentration (1) in the cytosol and redox potential of mitochondria ΔΨm (2) under the action of laser radiation (wavelength 647 nm, 0.1 mW/cm2, exposure 15 s) on human foreskin fibroblasts (Alexandratou E. et al., 2002)

The most important fact is the increase in Ca2+ concentration solely due to intracellular depots (where calcium ions are re-injected after the end of the physiological cycle after 5-6 minutes), and not as a result of the intake of ions from the outside, as many believe. Firstly, there is no correlation between the level of ATP in cells and the transport of Ca2+ into the cell from outside, the activation of mitochondria is carried out only by increasing the concentration of Ca2+ from intracellular depots. Secondly, the removal of calcium ions from the serum does not delay the increase in the Ca2+ concentration in the anaphase of the cell cycle, i.e., the activation of cell proliferation under the action of LILI is in no way associated with extracellular calcium, membranes, specifically dependent pumps, etc. These processes are only important when exposed to cells that are in the whole body, and are secondary.

The regularities shown above can be easily explained if the mechanisms of the LILR database are arranged in the following sequence: as a result of illumination of the LILR, a thermodynamic disturbance occurs inside the cell (“temperature gradient”), as a result of which the intracellular depot is activated, they release calcium ions (Ca2+) with a short-term (up to 300 c) an increase in their concentration with the subsequent development of a cascade of responses at all levels, from cells to the body as a whole: activation of mitochondria, metabolic processes and proliferation, normalization of the immune and vascular systems, inclusion in the ANS and CNS process, analgesic effect, etc. ( Fig. 2) [Moskvin S.V., 2003, 2008, 2014, 2016].

Rice. 2. The sequence of development of biological effects after exposure to LILI (mechanisms of biological and therapeutic action)

This approach makes it possible to explain the non-linear nature of the dependences "EP-effect" and "exposure-effect" by the peculiarities of the work of intracellular calcium depots, and the absence of an action spectrum - by the nonspecificity of their inclusion. We repeat that what was said above refers to “laser-” and not “photo-” (biomodulation), i.e. only for monochromatic light and in the absence of a specific effect (for example, bactericidal action).

The most important thing in knowing and correctly understanding the mechanisms of DL LILI is the ability to develop and optimize laser therapy techniques, understand the principles and conditions for effective application of the method.

The dependence of the effect on the modulation frequency, monochromaticity, polarization, etc. forces us to consider these regularities also not entirely from the standpoint of classical photobiology. Here, in our opinion, to characterize the supporters of the “acceptor”, static approach to the study of the mechanisms of the DB LILI, it is appropriate to quote the words of the American writer G. Garrison: “They sorted out the facts. Whereas they analyzed the most complex closed system with such elements as positive and negative feedback, or variable switching. Yes, and the whole system is in a dynamic state due to continuous homeostatic correction. No wonder they didn't get anything." So photobiologists with a similar approach to research did not understand anything about the mechanisms of the LILI database.

So how do biological processes induced by laser light develop? Is it possible to trace the entire chain, from the absorption of photons to the patient's recovery, to fully and reliably explain the available scientific facts and, on their basis, develop the most effective treatment methods? In our opinion, there is every reason for an affirmative answer to these questions, of course, within the framework of limited general knowledge in the field of biology and physiology.

The mechanisms of the biological (therapeutic) action of low-intensity laser light on any living organism must be considered only from the standpoint of the general nature of both the acting light energy and the organization of living matter. On fig. Figure 2 shows the main sequence of reactions, starting from the primary act of absorbing a photon and ending with the reaction of various body systems. This scheme can only be supplemented with details of the pathogenesis of a particular disease.

Where does it all begin? Based on the fact that low-intensity laser light causes the corresponding effects in vitro in a single cell, it can be assumed that the initial starting point when exposed to biological tissues is the absorption of LILI by intracellular components. Let's try to figure out which ones.

The facts presented above and obtained by T. Karu et al. (1994), the data convincingly prove that such regularities can only be the result of thermodynamic processes that occur when laser light is absorbed by any, i.e., any, intracellular components. Theoretical estimates show that under the action of LILR, local "heating" of acceptors by tens of degrees is possible. Although the process lasts a very short period of time - less than 10-12 s, this is quite enough for very significant thermodynamic changes both in the group of chromophores directly and in the surrounding areas, which leads to significant changes in the properties of molecules and is the starting point of the reaction induced by laser radiation. We emphasize once again that any intracellular component that absorbs at a given wavelength, including water, which has a continuous absorption spectrum, can act as an acceptor, i.e. local temperature gradient, and we are dealing with a thermodynamic rather than a photobiological effect (in the classical sense of the term), as previously thought. This is a fundamentally important point.

At the same time, it should be understood that the “temperature gradient” does not mean a change in temperature in the generally accepted, “everyday” sense, we are talking about a thermodynamic process and terminology from the corresponding section of physics - thermodynamics, which characterizes the change in the state of the vibrational levels of macromolecules and describes exclusively energy processes [Moskvin S.V., 2014, 2016]. This "temperature" cannot be measured with a thermometer.

However, it is the “lack of direct experimental evidence of a local intracellular temperature increase” that is the main argument in criticizing our theory [Ulashchik V.S., 2016]. The remark of V.S. Ulaschik (2016) regarding the fact that the result of this process cannot be only the release of calcium ions, should be recognized as fair. Indeed, there is, albeit a very limited, list of identified patterns that are difficult to explain only by Ca2+-dependent processes, this remains to be studied.

Nevertheless, the conclusions from our theory have already made it possible to qualitatively improve the efficiency of laser therapy methods, their stability and reproducibility, which is already quite enough for its recognition (although it does not reject the need for further development). And it is absolutely impossible to agree with the opinion of a highly respected specialist [Ulashchik V.S., 2016], that “theories” have the right to exist only if there are some “experimental data”, often very doubtful and misinterpreted, the conclusions from which are detrimental to clinical practice. For example, the consequence of all such hypotheses is the impossibility of using LILI with a wavelength in the range of 890-904 nm for laser therapy. And what would you order tens of thousands of specialists to do when they have been successfully using just such laser light for more than 30 years, consider it the most effective and get excellent treatment results? Abandon reality in favor of the ambitions of units?

There are no reasonable arguments against the thermodynamic nature of the LILI interaction at the cellular level, otherwise it is simply impossible to explain the incredibly wide and almost continuous spectrum of action (from 235 to 10600 nm), so we will continue to adhere to our concept in terms of the primary process.

With minor local thermodynamic perturbations that are insufficient to transfer the molecule to a new conformational state, however, the geometry and configuration of the molecules can change relatively strongly. The structure of the molecule is, as it were, "leaded", which is facilitated by the possibility of rotations around the single bonds of the main chain, not very strict requirements for the linearity of hydrogen bonds, etc. This property of macromolecules decisively affects their functioning. For efficient energy conversion, it is sufficient to excite such degrees of freedom of the system that slowly exchange energy with thermal degrees of freedom [Goodwin B., 1966].

Presumably, the ability to direct conformational changes, i.e. to their movement under the influence of local gradients, is a distinctive feature of protein macromolecules, and the required relaxation changes may well be caused by laser light of “low” or “therapeutic” intensity (power, energy) [Moskvin S.V., 2003(2)].

The functioning of most intracellular components is closely related not only to the nature of their conformations, but most importantly, to their conformational mobility, which depends on the presence of water. Due to hydrophobic interactions, water exists not only in the form of a bulk phase of a free solvent (cytosol), but also in the form of bound water (cytogel), the state of which depends on the nature and localization of the protein groups with which it interacts. The lifetime of weakly bound water molecules in such a hydration shell is short (t ~ 10-12 ÷ 10-11 s), but near the center it is much longer (t ~ 10-6 s). In general, several layers of water can be held stably near the surface of the protein. Small changes in the quantity and state of a relatively small fraction of water molecules that form the hydration layer of a macromolecule lead to sharp changes in the thermodynamic and relaxation parameters of the entire solution as a whole [Rubin A.B., 1987].

Explanation of the mechanisms of DB LILI from the thermodynamic standpoint makes it possible to understand why the effect is achieved when exposed to laser light, and its most important property is its monochromaticity. If the width of the spectral line is significant (20-30 nm or more), i.e., commensurate with the absorption band of the macromolecule, then such light initiates the oscillation of all energy levels and only a slight, by hundredths of degrees, “heating” of the entire molecule will occur. Whereas light with a minimum spectral line width characteristic of LILR (less than 3 nm) will cause a temperature gradient of tens of degrees, so necessary for a full-fledged effect. In this case, all the light energy of the laser will be released (relatively speaking) in a small local area of ​​the macromolecule, causing thermodynamic changes, an increase in the number of vibrational levels with a higher energy, sufficient to trigger a further physiological response. Drawing a conditional analogy, the process can be represented as follows: when a magnifying glass concentrates sunlight on a point, paper can be set on fire, while when scattered light illuminates its entire area, only a slight heating of the surface occurs.

The consequence of the photoinduced “behavior” of macromolecules is the release of calcium ions from the calcium depot into the cytosol and the propagation of waves of increased Ca2+ concentration through and between cells. And this is the main, key point of the primary stage in the development of the laser-induced process. Together with the act of photon absorption, the appearance and propagation of waves of increased concentration of calcium ions can be defined precisely as the primary mechanism of DL LILI.

The possible participation of calcium ions in laser-induced effects was first suggested by N.F. Gamaleya (1972). Later it was confirmed that the intracellular concentration of calcium ions in the cytosol under the influence of LILI increases many times [Smolyaninova N.K. et al., 1990; Tolstykh P.I. et al., 2002; Alexandratou E. et al., 2002]. However, in all studies, these changes were noted only in conjunction with other processes, they were not distinguished in any special way, and only we first suggested that an increase in the Ca2+ concentration in the cytosol is precisely the main mechanism that subsequently triggers secondary laser-induced processes, and it has also been observed that all the physiological changes that occur as a result of this at the most diverse levels, calcium dependent [Moskvin S.V., 2003].

Why do we pay attention to calcium ions? There are several reasons for this.

1. Calcium is in the greatest degree in a specifically and non-specifically bound state both in cells (99.9%) and in the blood (70%) [Murry R. et al., 2009], i.e., in principle, there is the possibility of a significant increase in concentration free calcium ions, and this process is provided by more than a dozen mechanisms. Moreover, in all living cells there are specialized intracellular depots (sarco- or endoplasmic reticulum) for storing only calcium in a bound state. The intracellular concentration of other ions and ionic complexes is regulated exclusively by transmembrane ion currents.
2. The extraordinary versatility of the Ca2 + regulation mechanisms of many physiological processes, in particular: neuromuscular excitation, blood coagulation, secretion processes, maintaining the integrity and deformability of membranes, transmembrane transport, numerous enzymatic reactions, the release of hormones and neurotransmitters, the intracellular action of a number of hormones, etc. [Grenner D. , 1993(1)].
3. The intracellular concentration of Ca2+ is extremely low - 0.1-10 μm/l, therefore, the release of even a small absolute amount of these ions from the bound state leads to a significant relative increase in the concentration of Ca2+ in the cytosol [Smolyaninova N.K. et al., 1990; Alexandratou E. et al., 2002].
4. More and more is known about the role of calcium in maintaining homeostasis every day. For example, a Ca2+-induced change in the mitochondrial membrane potential and an increase in intracellular pH lead to an increase in ATP production and ultimately stimulate proliferation [Karu T.Y., 2000; Schaffer M. et al., 1997]. Stimulation with visible light leads to an increase in the level of intracellular cAMP almost simultaneously with a change in the concentration of intracellular Ca2+ in the first minutes after exposure, thus contributing to the regulation carried out by calcium pumps.
5. It is important to note that the organization of the cell itself ensures its homeostasis, in most cases, precisely through the influence of calcium ions on energy processes. In this case, the general cellular oscillatory circuit acts as a specific coordinating mechanism: Ca2+ of the cytosol - calmodulin (CaM) - a system of cyclic nucleotides [Meerson FZ, 1984]. Another mechanism is also involved through Ca2+-binding proteins: calbindin, calretinin, parvalbumin and effectors such as troponin C, CaM, synaptotagmin, S100 proteins and annexins, which are responsible for the activation of Ca2+-sensitive processes in cells.
6. The presence of various oscillatory contours of changes in the concentrations of active intracellular substances is closely related to the dynamics of the release and regulation of the content of calcium ions. The fact is that a local increase in Ca2+ concentration does not end with a uniform diffuse distribution of ions in the cytosol or the activation of mechanisms for pumping excess into intracellular depots, but is accompanied by the propagation of waves of increased Ca2+ concentration inside the cell, causing numerous calcium-dependent processes. Calcium ions released by one cluster of specialized tubules diffuse to neighboring ones and activate them. This hopping mechanism allows the initial local signal to trigger global waves and fluctuations in Ca2+ concentrations.
7. Sometimes the Ca2+ waves are very limited in space, for example, in amacrine cells of the retina, in which local signals from the dendrites are used to calculate the direction of movement. In addition to such intracellular waves, information can be propagated from cell to cell via intercellular waves, as has been described for endocrine cells, vertebrate gastrula, and intact perfused liver. In some cases, intercellular waves can move from one cell type to another, as happens in endothelial cells and smooth muscle cells. The fact of such propagation of Ca2+ waves is very important, for example, for explaining the mechanism of generalization of laser exposure during the healing of a significant wound (for example, a burn) under local action of LILI.

So, what happens after the waves of increased Ca2+ concentration began to propagate under the influence of LILI in the cytosol of the cell and between groups of cells at the tissue level? To answer this question, it is necessary to consider what changes LILI causes at the level of the organism. Laser therapy has become widespread in almost all areas of medicine due to the fact that LILI initiates a wide variety of biochemical and physiological responses, which are a set of adaptive and compensatory reactions resulting from the implementation of primary effects in tissues, organs and the whole living organism and aimed at its recovery:

• activation of cell metabolism and increase in their functional activity;
• stimulation of reparative processes;
• anti-inflammatory action;
• activation of blood microcirculation and an increase in the level of trophic provision of tissues;
• anesthesia;
• immunomodulatory action;
• reflexogenic effect on the functional activity of various organs and systems.

Two important points should be noted here. Firstly, in almost each of the listed points, the unidirectional influence of LILI (stimulation, activation, etc.) is a priori set. As will be shown below, this is not entirely true, and laser light can cause exactly the opposite effects, which is well known from clinical practice. Secondly, all these processes are Ca2+-dependent! This is really something no one has paid attention to before. Let us now consider exactly how the presented physiological changes occur, giving as an example only a small part of the known ways of their regulation.

Activation of cell metabolism and an increase in their functional activity occur primarily due to a calcium-dependent increase in the redox potential of mitochondria, their functional activity and ATP synthesis [Karu T.Y., 2000; Philippine L. et al., 2003; Schaffer M. et al., 1997].

Stimulation of reparative processes depends on Ca2+ at various levels. In addition to activating the work of mitochondria, with an increase in the concentration of calcium ions, protein kinases are activated, which take part in the formation of mRNA. Calcium ions are also allosteric inhibitors of membrane-bound thioredoxin reductase, an enzyme that controls the complex process of synthesis of purine deoxyribonucleotides during active DNA synthesis and cell division [Rodwell V., 1993]. In addition, the main fibroblast growth factor (bFGF) is actively involved in the physiology of the wound process, the synthesis of which and activity depend on the Ca2+ concentration.

The anti-inflammatory effect of LILI and its effect on microcirculation are due, in particular, to Ca2+-dependent release of inflammatory mediators, such as cytokines, as well as Ca2+-dependent release by endothelial cells of a vasodilator - nitric oxide (NO) - a precursor of endothelial vascular wall relaxation factor (EDRF) .

Since exocytosis is calcium-dependent, in particular, the release of neurotransmitters from synaptic vesicles, the process of neurohumoral regulation is completely controlled by Ca2+ concentration, therefore, it is also subject to the influence of LILI. In addition, it is known that Ca2+ is an intracellular mediator of the action of a number of hormones, primarily mediators of the CNS and ANS [Grenner D., 1993], which also suggests the involvement of laser-induced effects in neurohumoral regulation.

The interaction of the neuroendocrine and immune systems has not been studied enough, but it has been established that cytokines, in particular IL-1 and IL-6, act in both directions, playing the role of modulators of the interaction of these two systems [Royt A. et al., 2000]. LILI can affect immunity both indirectly through neuroendocrine regulation and directly through immunocompetent cells (which has been proven in in vitro experiments). Among the early starting points of blast transformation of lymphocytes is a short-term increase in the intracellular concentration of calcium ions, which activates protein kinase, which is involved in the formation of mRNA in T-lymphocytes, which, in turn, is the key moment of laser stimulation of T-lymphocytes [Manteifel V.M., Karu T.J., 1999]. The impact of LILI on fibroblast cells in vitro also leads to increased generation of intracellular endogenous γ-interferon.

In addition to the physiological reactions described above, to understand the picture as a whole, it is also necessary to know how laser light can affect the mechanisms of neurohumoral regulation. LILI is considered as a non-specific factor, the action of which is not directed against the pathogen or symptoms of the disease, but to increase the body's resistance (vitality). It is a bioregulator of both cellular biochemical activity and the physiological functions of the body as a whole - neuroendocrine, endocrine, vascular and immune systems.

Scientific research data allow us to say with full confidence that laser light is not the main therapeutic agent at the level of the organism as a whole, but, as it were, eliminates obstacles, imbalances in the central nervous system (CNS), which interferes with the sanogenetic function of the brain. This is carried out by a possible change under the action of laser light in the physiology of tissues both in the direction of strengthening and in the direction of suppressing their metabolism, depending mainly on the initial state of the body and the energy density of LILI, which leads to the attenuation of pathological processes, the normalization of physiological reactions and restoration of the regulatory functions of the nervous system. Laser therapy, when used correctly, allows you to restore the disturbed systemic balance [Moskvin S.V., 2003(2); Skupchenko V.V., 1991].

Consideration of the CNS and the autonomic nervous system (ANS) as independent structures has ceased to suit many researchers in recent years. There are more and more facts confirming their closest interaction and mutual influence. Based on the analysis of numerous scientific research data, a model of a single system that regulates and maintains homeostasis, called the neurodynamic generator (NDG) [Moskvin S.V., 2003(2)], was proposed.

The main idea of ​​the NDG model is that the dopaminergic department of the CNS and the sympathetic department of the ANS, combined into a single structure, named by V.V. Skupchenko (1991) phasic motor-vegetative (FMV) system complex, are closely related to another, mirror-cooperative (P.K. Anokhin's term) structure - tonic motor-vegetative (TMV) system complex. The presented mechanism functions not so much as a reflex response system, but as a spontaneous neurodynamic generator that restructures its work according to the principle of self-organizing systems.

The appearance of facts indicating the simultaneous participation of the same brain structures in providing both somatic and autonomic regulation is difficult to perceive, since they do not fit into known theoretical constructions. However, we cannot ignore what is confirmed by everyday clinical practice. Such a mechanism, having a certain neurodynamic mobility, is not only able to provide a continuously changing adaptive adjustment of the regulation of the entire range of energy, plastic and metabolic processes, which was first suggested and brilliantly proved by V.V. Skupchenko (1991), but manages, in fact, the entire hierarchy of regulatory systems from the cellular level to the central nervous system, including endocrine and immunological changes [Moskvin S.V., 2003(2)]. In clinical practice, the first positive results of this approach to the mechanism of neurohumoral regulation were obtained in neurology [Skupchenko V.V., Makhovskaya T.G., 1993] and in the removal of keloid scars [Skupchenko V.V., Milyudin E.S., 1994 ].

The terms "tonic" and "phasic" were originally formulated by the names of the corresponding types of muscle fibers, since the mechanism of interaction between the two types of nervous systems, presented for the first time, was proposed to explain movement disorders (dyskinesias). Despite the fact that this terminology does not reflect the full significance of NDG, we decided to keep it in memory of the discoverer of such a mechanism for regulating physiological processes - prof. V.V. Skupchenko.

On fig. Figure 3 shows a general scheme demonstrating the concept of GND as a universal regulator of homeostasis, of course, in a “static” state, so to speak. The main idea of ​​such a systematization is to show the unity of all regulatory systems. This is a kind of fulcrum around which the methodology of therapy is built under the motto: “The impact of unidirectional therapeutic factors” [Moskvin S.V., 2003(2)].

The scheme is rather conditional, which is emphasized by the presentation of LILI as the only method for regulating the neurodynamic state. In this case, we only demonstrate the ability of the same therapeutic effect, depending on the EP for the selected wavelength of LILI, to cause multidirectional effects, which is a characteristic property of, if not all, then most non-specific methods of biologically significant influence. However, laser light seems to us to be the most universal therapeutic physical factor, far beyond the scope of just one of the physiotherapeutic methods. And there is every reason for such a conclusion.

The proposed neurodynamic model for maintaining homeostasis allows a new assessment of the systemic mechanisms of mediator and autonomic regulation. The whole set of neurodynamic, neurotransmitter, immunological, neuroendocrine, metabolic, etc. processes reacts as a whole. When the vegetative balance changes at the organismic level, this means that at the same time neurodynamic restructuring covers the entire complex of a hierarchically organized system of internal regulation. Even more impressive is the fact that a local change in homeostasis at the cellular level also causes a reaction of the entire neurodynamic generator, to a greater or lesser extent involving its various levels [Moskvin S.V., 2003(2)]. The details of the functioning of such a mechanism are not yet fully understood, however, over the past few years, the number of publications devoted to the study of this issue has increased like an avalanche in foreign neurological journals. Still, it is more important for us to analyze the general patterns associated with the body's response to external influences, some of them are already known and are actively used to improve the efficiency of predicting the results of laser therapy.

First of all, we draw attention to the need to use the terms “regulation” and “modulation”, and not “activation” or “stimulation” in relation to the LILI database, since now it is completely clear that laser light is not a unidirectional influence factor, but, as shown us, depending on the EP impact, a shift of homeostasis in one direction or another is possible. This is extremely important when choosing the energy parameters of the therapeutic effect, while simultaneously correctly assessing the initial state of the body and for the etiopathogenetic substantiation of LT methods based on the proposed concept of the neurodynamic model of disease pathogenesis.

Normally, there are constant transitions from the phasic state to the tonic state and vice versa. Stress causes the inclusion of phasic (adrenergic) mechanisms of regulation, which is described in detail in the works of G. Selye (1960) as a general adaptation syndrome. At the same time, in response to the prevalence of dopaminergic influence, tonic (GABAergic and cholinergic) regulatory mechanisms are launched. The last circumstance remained outside the scope of G. Selye's research, but is, in fact, the most important point explaining the principle of the self-regulatory role of the GND. Normally, two systems, interacting, themselves restore the disturbed balance.

Many diseases appear to us to be associated with the prevalence of one of the states of a given regulatory system. With a long, uncompensated influence of a stress factor, a malfunction occurs in the work of the NDG and its pathological fixation in one of the states: in the phasic, which happens more often, or in the tonic phase, as if moving into a mode of constant readiness to respond to irritation, affecting almost all regulatory physiological processes, in particular metabolic ones. Thus, stress, or constant nervous tension, can shift homeostasis and fix it pathologically either in a phasic or tonic state, which causes the development of the corresponding diseases, the treatment of which should be primarily aimed at correcting neurodynamic homeostasis. The combination of several circumstances - a hereditary predisposition, a certain constitutional type, various exogenous and endogenous factors, etc. - causes the development of any particular pathology in a particular individual, but the true cause of the disease is common - the steady prevalence of one of the conditions of NDG.

Rice. 3. Schematic representation of the concept of neurodynamic regulation of homeostasis by low-intensity laser light

Once again, we draw attention to the most important fact that not only the CNS and ANS regulate various processes at all levels, but, on the contrary, a locally acting external factor, for example, laser light, can lead to systemic shifts, eliminating the true cause of the disease - an imbalance of NDG, and with local illumination to eliminate the generalized form of the disease. This must be taken into account when developing laser therapy techniques.

Now it becomes clear the possibility of multidirectional influence depending on the energy and spectral parameters of the acting laser light - stimulation of physiological processes or their inhibition. The universality of bioeffects is due, among other things, to the fact that, depending on the EP, LILI both stimulates and suppresses proliferation and the wound process [Kryuk A.S. et al., 1986; Al-Watban F.A.N., Zhang X.Y., 1995; Friedmann H. et al., 1991; Friedmann H., Lubart R., 1992].

Most often, the methods use the minimum, generally accepted EF of laser exposure (1-3 J/cm2 for continuous operation of a laser with a wavelength of 635 nm), but sometimes in clinical practice, it is the conditionally NOT stimulating effect of LILI that is required. For example, in psoriasis, the proliferation of keratinocytes is greatly increased; this disease is typical of a tonic state in which plastic processes are activated. It is clear that minimal EP LILI that stimulates proliferation is inappropriate in this case. It is necessary to act with super-high power at small areas of the illumination zone in order to suppress excessive cell division. The conclusions made on the basis of this model were brilliantly confirmed in practice in the development of effective methods for the treatment of patients with psoriasis [Pat. 2562316 RU], atopic dermatitis [Pat. 2562317 RU], vitiligo [Adasheva O.V., Moskvin S.V., 2003; Moskvin S.V., 2003], Peyronie's disease [Ivanchenko L.P. et al., 2003].

Now that we have a fairly complete picture of the mechanisms of action of LILI, it is easy to get an answer to some well-known questions. For example, how to explain the biphasic character of the LILI database? With an increase in absorbed energy, the temperature gradient also increases, which causes the release of a larger number of calcium ions, but as soon as their concentration in the cytosol begins to exceed the physiologically permissible maximum level, the mechanisms of Ca2+ pumping into calcium depots are activated, and the effect disappears.

Why is the effect higher in the pulse mode at an average power, 100-1000 times less than in the continuous mode of radiation? Because the time of thermodynamic relaxation of macromolecules (10-12 s) is much shorter than the duration of the light pulse (10-7 s) and a very short, in our understanding, watt pulse has a much greater effect on the state of local thermodynamic equilibrium than continuous radiation in units milliwatt.

Is it effective to use laser sources with two different wavelengths? Absolutely yes! Different wavelengths cause the release of Ca2+ from different intracellular stores, potentially providing a higher concentration of ions, hence a higher effect. It is only important to understand that simultaneous illumination with laser light with different wavelengths is NOT ALLOWED, it must be separated in time or space.

Other ways to increase the effectiveness of laser therapy, known and developed by us on the basis of the proposed concept of the mechanisms of the DL LILI, can be found in the 2nd volume of the series of books "Effective Laser Therapy" [Moskvin S.V., 2014].

Thus, the application of system analysis made it possible to develop a universal, unified theory of the mechanisms of the biomodulating action of low-intensity laser light. The primary acting factor is local thermodynamic shifts that cause a chain of changes in Ca2+-dependent physiological reactions, both at the cellular level and the organism as a whole. Moreover, the direction of these reactions can be different, which is determined by the energy density, the wavelength of laser light and the localization of the impact, as well as the initial state of the organism itself (biological system).

The concept developed by us allows not only to explain almost all the existing scientific facts, but also to draw conclusions both about predicting the results of the influence of LILI on physiological processes, and about possible ways to increase the effectiveness of laser therapy.

Source: Moskvin S.V., Fedorova T.A., Foteeva T.S. Plasmapheresis and laser illumination of blood. - M.-Tver: Triada Publishing House LLC, 2018. - P. 7-23.