D.m.n. T.B. Of semenova, k.m.n. V.B. Stoyanov

Moscow urban protivogerpeticheskiy center


The uncontrollable general increase in the morbidity by genital herpes (GG) places the problem of gerpesvirusnoy infection (GI) in one row with the most urgent socially significant problems of public health. Morbidity GG in the countries of West Europe exceeds 80 cases to 100 thousand populations. At present, according to the data OF B Halioua et al. (1999), in the world are counted 86 mln. people, infected with the viruses of 2 types herpes simplex (VPG-.II), traditionally associating with GG, although it is proven that GG can be caused by 1 types VPG. The data analysis of official statistics carry ouied by us showed that the morbidity GG in Russia in 19931999 yr. grew from 8,5 before 16,3 cases to 100 thousand populations, and in Moscow from 11,0 to 74,8. Bulk of patients in Russia is turned to the doctors independently: 70-94% of registered patients. The specific weight of active development sick GG by the doctors OF LPU of the first component in all forms of preventive is inspection in Russia it composed 22,7-27,8%, in Moscow - 5,4-7,2%. With this akusheryginekologi reveal 45,154,8%, dermatovenerologists 39,843,8% of the total number actively revealed sick GG, but in the portion of urologists it is fallen not more than 512%. If to the study of herpes of external genitalia to the unfavorable influence GI on the genital function of women is given close attention, then the information about VPG as the etiological factor of the diseases of the organs of urino-genital system (MPS), in men are very limited. One should say that to estimate true role VPG in the development of the pathology of the organs OF MPS in men, taking into account the frequent low- or asymptomatic flow of infection, frequently occurs very difficult task. Herpes is called?mnogolikim? and?kovarnym?, keeping in mind the variety of the manifestations of disease and associated symptoms, caused by the special features of pathogenesis GI. The basic links of the pathogenesis of herpetic infection are: 1. infection of the sensory ganglia of vegetative nervous system and lifelong persistentsiya VPG in them. 2. defeat of immunocompetent cells, which leads to the second immunodeficiency, which creates conditions for the relapses of disease. 3. tropism VPG to the epithelial and nerve cells, the causing polymorphism of the clinical manifestations of herpetic infection. Infection genitalia occurs with the close physical contact with the patient or the virus carrier with the genital, orogenital'nom, genitorektal'nom and oral'noanal'nom contacts. Only clinical symptoms primary GG are developed in 10% of those infected. Virus begins to be multiplied in the place for the inoculation, where typical bubble precipitations appear, and it penetrates the bloodstream and the lymphatic system. In the early stages GI virus particles take root also in the nerve ends of the skin or the mucous membrane, move centripetally on the axoplasm, they reach the peripheral, then segmental and regional sensitive ganglia of the central nervous system, where they for life remain in the latent state in the nerve cells. The infection of sensory ganglia is one of the important stages in the pathogenesis GI. With herpes genitalia these are the sensitive ganglia of the lyumbosakral'nogo division of spine, which serve as the reservoir of virus for its sexual transfer. Propagation VPG in the centrifugal direction during the relapse determines the anatomical fixation of stricken areas with the relapses. VPG can strike any nervous formations, which will be clinically manifested by different neurologic symptoms depending on the properties of the nervous formations, implicated in the infectious process. With the defeat of sympathetic it is main and peripheral nerves in patients are noted the symptoms of ganglionevrita; the sochetannoye defeat of ganglia and segmental rootlets of spinal cord causes the clinical manifestations of ganglioradikulonevrita. The irritation of parasympathetic fibers causes in patients subjective sensations in the form of burning. The special feature of painful syndrome with recurrent herpes (RG) consists in the fact that it periodically can appear independent of skin manifestations, which to a considerable extent hampers its treatment. The neurologic symptomatology, which complicates the course of disease and which worsens forecast, is encountered in each ego of patient, which suffers recurrent genital herpes (RGG). In the literature are described the cases of sharp retention of urine, reason for which was sacral it miyeloradikulit (syndrome Of elsberga), meningitis also of radikulomiyelopatiya, reason for which was VPG. In 25% sick RGG appears the increased traumatism, dryness and formation with the mechanical irritation of the small unhealthy bleeding small cracks on the mucous membranes of external sex organs. Clinical manifestations GG in the men Herpes of external the genitalia In the majority of the cases primary infection genitalia flows asymptomatically, with the formation subsequently of latent carriage VPG or relapsing form of genital herpes. With the clinically expressed cases primary genital herpes usually is manifested after 110 days of incubative period and is differed from the subsequent relapses in terms of the heavier and more prolonged (to 3 weeks) flow (Fig. 1). The probability of the formation of the relapsing form GG depends on serological type VPG: with the infection the genitalia VPG of 1 types relapse during the year appears in 25% of those, who had primary episode GG, with GG, 2 types caused VPG, relapses appear in 89%. Clinically herpes of external sex organs can flow in the typical, atypical and subclinical (low-symptom) forms. In men the precipitations are located usually in the region of the external and internal leaves of extreme flesh, rim fissure, navicular fossa. More rarely is surprised head and body of sexual term, the skin of scrotum. Typical form RGG is characterized by classical dynamics of defeats (erythema - vesicula - the erozivnoyazvennye elements - formation of crusts) and by local subjective sensations in the form of itch, burning, sickliness. Stricken areas usually bear the limited, more rarely extended nature and are localized in one and the same section of the skin or the mucous membrane. Frequent aggravations RGG are frequently accompanied by worsening in the general state of patients, the symptoms of intoxication, caused by viremia (headache, a chill, indisposition, subfebrile temperature), appear, inguinal lymph nodes can increase and become unhealthy. Atypical forms RGG, which to a considerable extent complicate the formulation of diagnosis, can be caused: 1) by a change of the cycle of the development of herpetic elements in the stricken area; 2) by uncommon localization of center and by the anatomical special features of the subjects of cloths. With the atypical forms RGG predominates one of the stages of the development of inflammatory process in the center (erythema, the formation of bubbles) or one of the components of inflammation (edema, hemorrhage, necrosis). Over the intensity of clinical manifestations atypical forms can flow stormily with the demonstration (bullous, ulceronecrotic) or subclinically (microscopic crack), see Fig. 2-4. Subclinical form RGG is revealed predominantly with the virusological inspection of the sexual partners of patients with any illness, transferred through sex, or with the inspection of conjugal pairs with the disturbance of fertility. Herpetic infection of the organs of the small basin Multi-focality is special feature GG. Into the pathologic process frequently are implicated the lower division of urethra, the mucous membrane of the anus and the rectums, that can occur for a second time, following the appearance of herpes of external genitalia, and it can flow as the isolated defeat. On the special features of clinical manifestations the herpetic defeats of the organs of small basin in men it is expedient to divide into: herpes of the lower division of urogenital'nogo circuit, anal region and ampulla of rectum; herpes of the upper division of sexual circuit (table 1). Herpes of the lower division of urogenital'nogo circuit, anal region and ampulla of rectum is manifested in two clinical forms: focus, that is characterized by the appearance of mucous membranes of vesicular- erosive elements typical for herpes simplex, and diffuse, with which pathologic process proceeds over the type of unspecific inflammation. Herpes of the urethra In the conventional classification of urethritis are distinguished virus urethritis, caused BY VPG and virus of papillomy of man (HPV). VPG is more frequently the reason for tightened torpidly elapsing urethritis and recurrent cystitis, and also aggravation of chronic prostatites. The frequency of herpetic urethritis (GU) kolebletsya from 0,3 to 2,9% of all recorded negonokokovykh urethritis (Il'in I.I., 1977; Nahmias A Et Al, 1976), which allowed researchers 70x it was annual to carry GU to the rare forms of urethritis. The works of the last years showed that GU is revealed into 42,446,6 % the cases in men, who suffer RGG (Baluyants E.R., 1991; Semenova T.B., 2000). is subjectively gu manifested by pains in the form of burning, sensation of heat, hyperesthesias on the motion of urethra in the state of rest and with the urination, by sharp pains in the beginning of urination. Incubative period in the development GU remains obscure, but, probably, it composes several months, it is thinner than weeks or days. With the clinical inspection hyperemia and swelling of the sponges of urethra is determined, scant mucous discharge from the external opening of urethra periodically appears. Flow GU is subacute or is sluggish with the periodic remissions and the relapses. In the discharge of urethra epithelial cells and mucus usually predominate, leukocytosis periodically appears. With the mixed infection the discharge of urethra becomes more abundant more opaque. With the two-glass test the urine in the first portion transparent, but contains the products of inflammation in the form of the floating threads and flakes. Diagnosis GU is made on the basis of isolation VPG from the material, undertaken from the discharge of urethra in the culture of cells or development of antigen VPG by the method PTSR. The organs OF MPS in men are located in the close anatomical and physiological interrelation, that it does not make it possible mechanical to approach the estimation of the results of laboratory investigation. Thus, development VPG in urine or discharge of urethra makes it possible to suspect the possibility of involvement in the infectious process of prostate gland, even if VPG in the juice of prostate is not discovered, but there are clinical data about torpidly elapsing prostatitis. With dry uretroskopii on the mucous membrane of urethra usually is revealed the soft infiltration (thinner transitional) with the fragments of mucosa of red color, with the expressed large folds and the disappearing small. Herpetic centers are small single or confluent erosions with the polycyclic edges against the background of local vasodilation (focus form GI), or expressed focus hyperemia of mucosa (diffuse form GI). More frequent into the process are implicated front and middle third of urethra. Contra-evidence to conducting of uretroskopii are the aggravation of urethritis and the presence of herpetic precipitations in the region of head, navicular fossa and the internal leaf of the extreme flesh of sexual term. Conducting uretroskopii rekomendovano with the calming of the external manifestations of herpes, with the retention of complaints from the side of urethra, the presence in sick chronic recurrent urethritis of obscure etiology, with the preliminary exception of other urogenital'nykh infections. Herpes of the bladder The leading symptoms of herpetic cystitis are appearance be ill at the end of the urination, dysuric phenomena; hematuria is its characteristic manifestation. In patients the disorder of the urination is noted: change frequency, nature of jet, quantity of urine. Herpetic cystitis in men, as a rule, is second and is developed as complication with the aggravation of chronic herpetic urethritis or prostatitis. With cystoscopy it is observed catarrhal inflammation, single erosions. Herpes of anal region and rectum The herpetic defeat of anal region and ampulla of rectum is encountered both in the heterosexual men and in homosexuals. Anal region can be struck primarily or for a second time (with the propagation of infection in patient with GI of external genitalia). Stricken area is usually the relapsing crack that it is frequently occasion for the diagnostic errors. Such patients with the erroneous diagnosis of?treshchina of rear passage? they reach the surgeons. With the defeat of sphincter and mucous membrane of the ampulla of the rectum (herpetic proctitis) of patients they disturb itch, feeling of burning and sickliness in the stricken area, appear the small erosions in the form of surface cracks with the fixed localization, which bleed with the defecation. The appearance of precipitations can be accompanied by the sharp bursting open pains in the region of sigma, meteorism and tenesmuses, what is the symptoms of the irritation of pelvic nervous interlacement. With rectoscopy is determined catarrhal inflammation, sometimes erosion. To place the diagnosis of herpetic proctitis is possible only on the basis of the results of the virusological inspection of patient. Herpes of the upper division of sexual circuit is manifested by the symptoms of unspecific inflammation. The typical clinical picture of the herpetic defeats of the organs of the upper division of urino-genital circuit is manifested by the symptoms of unspecific inflammation. To establish the real frequency of the defeat of internal sex organs in men is very complicated, since in 4060% of cases disease flows without the subjective sensations. Genitalia of complaint in patient they be absent with the subclinical form of herpes of internal; with the clinical inspection the symptoms of inflammation are not revealed with the dynamic laboratory investigation of the smears of the discharge of urethra in the secret of prostate periodically it is revealed the increased quantity of leukocytes (to 3040 and above in the field of sight), which testifies about the presence of inflammatory process. The asymptomatic form of herpes of internal genitalia (asymptomatic virusovydeleniye) is characterized, by absence in any sick complaints and objective clinical symptoms of inflammation. With the laboratory investigation of the discharge of urogenital'nogo circuit it is allotted BY VPG, while in the smears it is indicative there is no inflammation (leukocytosis). Herpes of the prostate In the contemporary etiopathogenetic classification of prostatites virus prostatites estimate as the infectious kanalikulyarnye complications of virus urethritis. According to classification Mears (1992) this variety of prostatites carries to the doubtful or unproven type, on Blumensaat (1961) to the specific, on The the o.L.Tiktinskomu and THE EXPLOSIVE Mikhaylechenko (1999) to the infectious. In the development of virus prostatites more frequently is observed the uretrogennyy way of transfer, and the descending (urogennyy) way is encountered rarely with the penetration of viruses from the infected urine with cystitis through the excretory ducts of prostate gland (PZH). According to the estimations of the different authors, prostatitis is caused or are supported BY VPG into 2,9 21,8% of cases (Weidner et al, 1981). Most frequently chronic prostatitis with herpetic urethritis and RGG is manifested in the catarrhal form, in this case the course of disease is characterized by the frequent and upornoretsidiviruyushchim nature (O.B. Kapralov, 1988; Bennett et al, 1993). In the clinical practice the diagnosis of chronic herpetic prostatitis is made by urologists rarely. Reason, apparently in the fact that the virusological methods of diagnostics do not enter into the standard of the inspection of patients with chronic prostatitis. The stereotype of thinking doctor operates, and to patients traditionally is conducted inspection on ZPPP of nevirusnoy nature. Meanwhile with effaced abacterial prostatites it is possible to assume that the virus is pathogenic agent. In the clinical course of prostatites are noted functional shifts reproductive changes, painful (with the irradiation into the external sex organs, the perineum, the back) and dysuric syndromes. In the majority of the cases the aggravation of chronic prostatites precedes the appearance of herpetic precipitations in the region genitalia. The appearance of vezikuleznoerozivnykh elements can coincide with the advent of complaints from the side PZH. Frequently prostatitis flows subclinically in sick RGG: in these patients the diagnosis of prostatitis is made on the basis of the appearance of leukocytosis in the secret of prostate and decrease of the number of lecithin grains. It is necessary to remember that herpetic prostatitis can exist as the isolated form GI. In this case there are no symptoms RGG and VPG is not determined in the discharge of urethra. Etiological diagnosis is based on the detection VPG in the secret PZH, in this case pathogenic flora in the secret and in the third portion of urine is absent. With an ultrasonic study of prostate gland in the region of the parauretral'nykh zones of prostate are determined hyper-Echogenetic fibrous centers by the size of 39 mm. in patients with herpetic prostatitis in comparison with abacterial prostatites of obscure etiology it is noted the large manifestation of fibrous divisions in the region of peripheral zones. At the same time the expansion of seed phials occurs, their indicating disturbance drainages into the rear urethra, which makes it possible to assume the defeat of prostate matochki. The variety of the clinical manifestations of herpes simplex, the presence of the atypical, subclinical and asymptomatic forms of disease, involvement in the infectious process of many systems of organism frequently hamper diagnostics of this illness. Diagnostics of herpes The diagnosis of recurrent genital herpes with the typical clinical manifestations of the disease of difficulties does not represent and it can be set visually with the inspection of patient. Significant complexities appear with the atypical forms GG or with the herpetic defeat OMT. Important significance in these cases has thoroughly assembled anamnesis. To assume herpetic nature of the defeat of urogenital'nogo circuit in the absence of typical manifestations on the skin and mucous membranes are allowed complaints of the itch, burning, scant mucous isolations from the urethra, sanious isolations from the rectum, indications of painful syndrome, relapsing nature of the disease OMT, and also to the resistance of disease to the previously conducted antibiotic therapy. Furthermore, patients frequently note tendency toward the catarrhal diseases, fear of drafts, which periodically appears general weakness, indisposition, subfebrile temperature, depressions. In sick GG frequently are encountered the pains, which patients do not always connect with the aggravations of herpes. For recurrent herpes, independent of the place of the manifestation of pathologic process, the characteristically undulating flow, when unhealthy states are changed by the periods of prosperity, even without the specific therapy. The formulation of the diagnosis Of vPGinfektsii complicates the fact that VPG frequently find in the association with other microorganisms: by khlamidiyami, strepto and by staphylococci, fungus flora, etc. did not exclude the mixed infection VPG with gonococcus, pale treponemoy, VICH, which indicates the need of the thorough inspection of patients. The existing methods of laboratory diagnostics of herpes simplex principally are divided into two groups: 1) isolation and identification VPG in the culture of cells or the development of the antigen of agent from the infected material with cytological, immunofluorescent studies, immunoenzyme analysis (IFA), PTSR; 2) the development of virus-specific antibodies in the blood serum. The frequency of isolation VPG from different biological media varies. With the inspection it is more than of 200 patients with the established diagnosis RGG, which suffer the chronic diseases OMT, VPG was possible to isolate from the discharge of urethra in 22% of cases, juice of prostate - 23%, the sperm - 15%, the urine - 26%. VPG can be revealed not in each, but into 12 of 34 biological materials, obtained from the patient. Therefore for decreasing the probability of pseudonegative diagnosis it is necessary to investigate the maximum number of models from one patient. The negative result of a single virusological study cannot exclude completely the diagnosis of genital herpes. With the suspicion to VPGinfektsiyu it is necessary to conduct a repeated virusological study of the discharge of urino-genital system (1 time in 7 days of 24 times in the course of the month), and in a number of cases - to use several methods of inspection. Diagnostic value with primary GI has development IgM and/or fourfold increase in the captions of the specific immunoglobulins G (IgG) in the paired blood serum, obtained from the patient with the interval of 1012 days. Recurrent herpes usually flows against the background of the high indices IgG, which testify about a constant antigenic stimulation of the organism of patient. Appearance IgM in patient, who suffers RGG, he speaks about the aggravation of disease. Treatment of genital herpes General principles of the treatment of herpes simplex Contemporary medicine does not have available the methods of treatment, which make it possible to eliminate VPG from the organism. Therefore the purpose of treatment is the suppression of reproduction VPG in the period of aggravation, shaping of the adequate immune response and its prolonged retention for the purpose of the blocking of reactivation VPG in the centers of persistentsii. At present there are two basic directions in the treatment of herpes simplex: 1. antiviral therapy, basic place in which is assigned to the preparations of atsiklovira (ATSV), which are used for stopping the relapses of herpes, preventive maintenance and treatment of the complications Of vPGinfektsii. 2. complex method of the treatment, purpose of which is an increase in the mezhretsidivnykh periods, includes immunotherapy (specific and unspecific) in combination with the antiviral treatment. The correction of the disturbances of unspecific and specific it is sectional immunity one of the basic directions in the complex therapy of herpes simplex. The expressed immunomodulating effect in treatment and preventive maintenance of the complications of herpes simplex possess the synthetic inductors of interferon (IFN). Among them the domestic preparation Of poludan. Are at the present time acquired convincing clinical data about the high efficiency Of poludana for treating various clinical forms of recurrent herpes. Poludan possesses the general immunostimulating action, which makes it possible to use it with the second immunodeficient states, caused not only by gerpesvirusnymi infections. In these cases of poludan it is introduced hypodermically in the forearm: 200 g (1 bottle) they dissolve ex tempore in 1 ml of the distilled water, introduce daily, to the course of 10 injections. One of the advantages of the inductor IFN of tilorona (Amiksina) is the oral method of application, which makes possible for patients to independently carry out courses of antirelapse therapy recommended by doctor the preventive. The mechanism of the action Of amiksina is switched on: the induction of interferons of types a, b, g, immunocorrection and direct antiviral action. Amiksin possesses the soft immunomodulating effect, it stimulates stem cells of bone marrow, strengthens antibody formation, decreases the degree of immunodepression. Amiksin is included in complex treatment RGG according to the diagram: 250 mg of 1 times in a 24 hour period of 2 days, then on 125 mg in a day during 34 weeks. According to the same diagram Of amiksin it is possible to recommend by patient between the courses of vaccinotherapy for the prolongation of the effect reached. The antiviral activity of the inductor IFN Of arbidola is caused by its immunomodulating and antioxidant properties. Arbidol can be included in complex treatment RGG (on 0.2 g of 2 times in the day during the food during 1014 days) and used between the courses of vaccinotherapy for the preventive maintenance of the relapses of herpes (0.2 g of 1 times in the day during the food during 23 weeks). For the stimulation T and Vzven'ev of cellular immunity for the patients with recurrent herpes it is possible to use Taktivin, Timalin, Timogen, Miyelopid and other immunomodulators. Specific immunotherapy consists of the application of a domestic herpetic vaccine (polyvalent, woven, killed). The therapeutic effect of vaccine is connected with the stimulation of the specific reactions of antiviral immunity, the restoration of the functional activity of immunocompetent cells and the specific desensitization of organism. Takeing into account the special features of the pathogenesis of herpes simplex, most expedient for achievement of therapeutic effect is the kombinirovannoye use of preparations with different mechanism of antiviral action, which prevents the appearance of resistance strains VPG. The application of interferons and their inductors in combination with the herpetic vaccine and the immunomodulators makes it possible to complexly solve the problems of the therapy of herpes simplex. Local treatment GI of the organs OF MPS in the men The achievement of therapeutic effect with the treatment of the herpetic defeats of the organs OF MPS in men is impossible without conducting of local treatment. With the presence of precipitations on the skin and the mucous membranes with RGG by patient locally are assigned antiviral preparations for the external application: Zoviraks (cream), Atsiklovirakri (ointment), Gevizosh (ointment), Virumerts (gel), Epigen (aerosol), etc. Important significance in the treatment GG has the local immunostimulating therapy. For this purpose it is possible to use Poludan. Poludan with RGG they use in the form of applications to the stricken area for which 200 g of preparation (1 bottle) they dissolve in 4 ml of water, wet wadded tampon and on 57 min apply to the center of porazhenniya. Procedure repeats 23 times a day during 24 days. With the treatment of herpetic urethritis Of poludan they use in the form of instillyatsiiy into the urethra (400 g they separate in 10 ml of water). Procedure repeats 1 time in the day daily during 57 days. It is possible to use a liniment of tsikloferona (according to the same diagram). With herpetic proctitis the expressed therapeutic effect is observed with the designation by the patient of the solution Of poludana in the form of the micro-enemas (400 g they separate in 10 ml of water, 10 micro-enemas to the course of treatment). Together with the medicinal local treatment to patients with the chronic herpetic diseases OMT are conducted the traditional local manipulations: bougienage of urethra, the massage of prostate with the subsequent total instillation of the solution Of poludana or liniment of tsikloferona. For achievement of the more expressed antipyretic, resorbing and analgesic effect by such patient in the course of treatment it is expedient to include low-frequency laser-therapy. In this case the intracavitary introduction of fiber light guide into the urethra or into the rectum into the region of projection PZH is desirable to combine with laser reflexotherapy. The complex treatment of men, who suffer herpes OF MPS, that includes the general antiviral and immunostimulating therapy in combination with the local treatment, leads to the regress of clinical it is indicative chronic urethritis and prostatitis (to decrease or to the permission of painful and dysuric syndromes), the normalization of laboratory indices, to the steadfast positive dynamics of flow RGG in 8590% of cases. Conclusion Among the virus diseases herpetic infection occupies one of the key places, which is determined by general propagation VPG, by 90%nym infection by them human population, by the lifelong persistentsiyey of virus in the organism, by the polymorphism of the clinical manifestations of herpes, by torpidity to the existing methods of treatment. At present pathogenic influence VPG on the development of the chronic diseases of urino-genital sphere in women, the flow of pregnancy it is ancestral, the status of the health of fruit and newly born does not undergo doubt. Role VPG in the development of pathologic processes in the man organism clearly is underestimated. At the same time, according to the data of domestic and foreign researchers, in men, who suffer the chronic inflammatory diseases of the organs of small basin, it is possible to reveal VPG in the discharge of urino-genital system in 5060% of cases. It is proven that VPG is the agent, which disrupts spermatogenesis and which possesses the ability to infect spermatozoids. This has special importance in the men of reproductive age and are opened new aspects in treatment and solution of the problem of barren marriages. Literature: 1. Barinskiy I.F., To shubladze A.K., The Caspar A.A., Grebenyuk V.N. Herpes. Etiology, diagnostics, treatment// by M. 1986. 272 s. 2. Borisenko SPACECRAFT// genital herpes. In the book unknown epidemic: genital herpes. Farmagrafiks. 1997. s. 7583. 3. Bragina YE.E.// of laws governing the disturbances of spermatogenesis of man with some genetic and infectious illnesses. Author's Abst. dissertation... of d.b.n. M. 2001. 54 s. 4. genital infection, caused by the virus of herpes simplex (survey informatsiya).// Zh zppp. 1994. є 3. s. 58. 5. Semenova T.B. herpes simplex. Clinic, diagnostics, treatment, preventive maintenance// the Author's Abst. dissertation... of d.m.n. 2000. M. 48 s. It is published by authorization of the administration of Russian medical periodical. Note: Source: www.medlinks.ru