Rationale

“EFFICACY EVALUATION OF INTERNAL INTAKE OF DRINKING WATERS OF EXPLORING AND OPERATIONAL CLEFT BQ 10 (ROGATETS-SOBONKI, THE CZECH REPUBLIC) FOR TREATMENT AND PREVENTION OF DISEASES OF GENITOURINARY SYSTEM” “Pyatigorsk State Scientific Research Institute of Balneology” of the Federal Medical-Biological Agency, Pyatigorsk, Russia

Scientific supervisors of the study:

Doctor of Medicine, Professor N.V. Efimenko

Deputy director for medical work, Doctor of Medicine A.S. Kaisinova

Department supervisor of action mechanisms studying of physical factors, Candidate of pharmaceutical sciences, associate professor V.V. Kozlova

Pyatigorsk, 2015

Reasoning

High prevalence rate of socially significant diseases such as chronic pyelonephritis, urolithiasis, chronic prostatitis. Side effects, complications and allergization in the course of use of drug therapy. The necessity to develop new and optimization of the existing treatment methods. The need in in-depth study of action mechanisms of drinking mineral waters and their rational use.

References

In the present document there are references to the following normative documents:

  • GOST 1.5-2001 (edition of 2005). Interstate system of standardization. Interstate standards, rules and recommendations about interstate standardization. General requirements to construction, contents and designation;
  • GOST 7.32-2001 System of standard documents on information, library and publishing. The report on research work. General requirements and rules of registration;
  • GOST 15.101-98 (edition of 2003). System of development and production engineering. The order of research works.
  • System of standardization in health care of the Russian Federation. Group 15. Requirements to documentation in health care, confirmed on 24.10.2010.

Terms, definitions, designations and abbreviations

ACTH – adrenocorticotropic hormone

IL – interleukin

LH – luteinizing hormone

MW – mineral water

MDA – malondialdehyde

USD – urinary stone disease

PG – prostate gland

PO – peroxidase

FSH – follicle-stimulating hormone

PF – physical factor

CP – chronic prostatitis

CD3 (Т-cells) – T-lymphocytes

CD4 – T-helpers

CD8 (T-cytotox) – T cytotoxic cells cytotoxic ( suppressors)

CD45 (В-cells)

coli – Escherichia coli

IRI – immunoregulatory index

IL – interleukin

Significance

The tasks of preservation and promotion of health of the population have set the rehabilitation problems on one of the leading places in health system [16, 22, 24, 35]. Medical rehabilitation allows to use medical natural factors (climate, mineral waters and peloids) to increase medical, social and economic efficiency of restorative treatment and successfully to carry out primary and secondary prevention of socially significant diseases [7, 18, 20, 40, 44].

The share of chronic pyelonephritis among all kidney diseases reaches 60% [26, 36, 37]. However, its social and hygienic importance is defined not only by high frequency and    prevalence rates, this illness has a chronic course, badly responds to treatment and quite often is complicated by the development of nephrogenic hypertensia, urosepsis, chronic kidney disease [5, 16]. In pathogenesis of chronic pyelonephritis weakening of organism protective functions plays an important role, in particular, the suppression of cellular component of immune system, abnormalities in coagulation system, clot lysis and microcirculation which are closely connected [23, 34]. These data are the background to carry out a complex treatment of patients with chronic pyelonephritis.

Chronic prostatitis (CP) appears in 35-45% of cases of urological pathology [15, 17]. Inefficiency of arterial circulation, amplitude of anastomosis between blood vessels of prostate gland (PG) and low tension circulation of pelvis [4] play an important role in the development of chronic prostatitis. Innervation abnormalities, hormonal shifts, immunological disorders, anatomic features of vascular system, tissue compression of prostate gland and other factors are also very important in the development of chronic prostatitis. Haemodynamics dysregulation of prostate gland promotes abnormalities of antioxidant protection, secretory, incretory and motor functions [2] which leads to the increase in volume of PG, deepens stasis in the microcirculator course, introduces hypostasis, exudation and migration of blood corpuscle through the vessel wall [4, 34]. Difficulties in treatment of chronic prostatitis are caused by the existence of haemoprostatic barrier that doesn’t allow antibacterial preparations to get into prostate parenchyma [14]. Besides, complex anatomy of the urinary tract, the ascending infection from which is a frequent reason of chronic prostatitis,  serves as a common cause of the disease recurrence and treatment inefficiency due to the formation of closed cavities with microorganisms isolated in them [4, 15].

Kidney stone disease (KSD) is high on the list among urological diseases, 34,2% in average across Russia, and not less than 3% of the population suffer from it [16, 26, 49]. KSD is educed with most patients at the productive age, and the indicator of the registered patients increases every year. Modern methods of treatment (a remote lithotripsy, etc.) don’t relieve the patient of possible recurrent lithiasis: without treatment, during 1 year after removal of a stone, the recurrence of KSD arises with 10% of the patients [40].

The main objective of medical rehabilitation of patients with urological pathology is restoration of system functions and organs suffered from an illness or a trauma by complex use of modern medical and health-improving technologies [16]. Recently, considering nonspecific increase of general organism resistance to the action of pathological and other unfauvorable factors of the environment and human activity, the usage of drinking mineral waters at various somatic diseases has been significantly expanded [30, 38, 42].

It is well-known that patients suffering from chronic pyelonephritis, chronic prostatitis, kidney stone disease if they want to achieve a lasting therapeutic effect, have to use medically induced preparations longtime which reception quite often is followed by formation of allergic reactions, polyorgan and system complications as well as the resistance to drug therapy. Considering this important fact, the search of highly effective non-drug methods of treatment and rehabilitation which causes the necessity of research of other remedies is still actual. Drinking mineral waters [18] can be such remedies.

The mankind possesses a long-term experience of usage of physical factors (PF) with prevention and treatment purposes in medicine. Positive clinical effects of these factors were famous long ago. They are anaesthetizing and anti-inflammatory, trophic and reparative, regulatory and normalizing cell functions, organs and tissues.

There has been proved a positive action of medical physical factors on main types of metabolism, oxidation-reduction reactions in cells and tissues, improvement of neuro and humoral regulatory processes in an organism, nervous and humoral (blood, lymph) trophism of internals and activation of organism protective forces under their influence [11, 55, 58].

It is necessary to correlate the properties of these factors (the environment) and an organism (the influence target) to gain an idea about action mechanisms of physical factors on a human body.

Such natural factors as hydrotherapeutic (influence by water), balneal (influence by mineral water), peloids (therapeutic muds, clays) natural thermotherapeutic (wax influence, paraffin), radiotherapeutic (radonotherapy), climatic treatment methods (temperature, humidity, air movement), including factors of the seaside (thalassotherapy) are successfully applied in medical-and-preventive purposes [19].

The impact on an organism of the majority of natural and preformed physical factors can be regarded as weak comparable to the corresponding parameters of the organism itself or the environment habitual for it [30, 54, 55, 57]. For example, mineralization of many drinking and balneological mineral waters applied in the preventive and medical purposes (1-20 g/dm3, it is in average close to a mineralization of organism fluid media (8,9 g/dm3).  Natural medical resources depending on the structure have a  corpuscular or (and) energetic effect on a human body. Physical factors cause irritation of receptor zones in skin, mucous membranes of digestive and respiratory channels, in separate organs. In response to this irritation there are  complex neuro and reflex phenomena of local, segmentary (a vegetative nervous system) and central (with participation of the central nervous system) character  that change the balance of nervous device activity and organism functions regulated by it. Later it became clear that humoral factors – hormonal (a big endocrine ring: hypophysis – adrenal glands, thyroid, parathyroid and sexual glands, organs of gastroenteropancreatic system), immunological (interleukins and other cytokines, immunoglobulins, leukotriens, some mediators (histamine, serotonin, melatonin, etc.) play an important role in reactions to a physical factor. Every year new parties of mechanisms and action levels of physical factors on a human body are explained. But creation of a consistent approach to mechanisms of this action became possible after the development of the theory of functional systems (U.R. Eshbi, P. K. Anokhin).

Functional system is a set of cells, organs and tissues forming an organism response to the influence. Thus the after-effect of PF can significantly exceed its action in time, and the volume of this after-effect can be beyond of local reciprocal changes. The main thing in operation of functional system is the achievement of its purpose. The main objective of functional systems arising in response to the action of PF is an adequate adaptation of the organism to this action and its consequences. As a result of the communication of central bodies operating regulatory processes in an organism (nervous, endocrine, immune), with afferent (ascending) reception, analyzers of these bodies constantly estimate the result of adaptation and aptitude of its ultimate goal. If the objective hasn’t been achieved, the system conducts further search of necessary reactions leading to changes of organism physiological status for the most adequate adaptation to an ecological factor.

Thus, adaptation and homeostatic physiological system is a certain sequence of inclusion of separate organs and tissues, biochemical and physiological reactions in response to external influence directed on preservation of constancy of the internal environment within its optimum performance and adaptation to this influence. After mild exposure of physical factors, the reaction to them quite often demands high energetic expenses than the energy received directly from the factor [10, 12]. It can mean only one thing that is the reaction of an organism to PF is, as a rule, energy consuming and the factor initiating it has an information component of its influence. This component starts a certain order of organism reactions finally providing adaptation to this factor.

The human body has a certain “biological portrait” including chemical composition, features of cell, tissue and organs construction as well as energetic component that is inseparably linked with corpuscular component. The work of the above described adaptive and homeostatic systems, first of all, the immune system is directed on the maintenance of the constancy of this “portrait”. Their main task is to save the permanence of organism “information frame” and protection of the latter from heterogenes information and its carriers [10, 25].

It is interesting that at supervision over the development of general pathology (for example, a serious chronic illness) one can note a direct connection of the speed of this development, clinical and para-clinical shifts from the condition of adaptive and homeostatic systems. For any chronic disease the same scheme of its development is characteristic: in the beginning – abnormalities of adaptation processes to extreme loadings, then – to daily and, at last, to any. The person lives in the disease as if within prison with gradually moving walls. Thus, the condition of adaptation and homeostatic systems defines projected growth of any chronic pathology as well as the result of acute distress. Therefore, the training impact of PF on this state is one of the main mechanism parts of sanogenetic action of PF [10, 25, 56].

Long-term researches of scientists of Pyatigorsk state scientific research institute of Resort study of FMBA of Russia [8, 21, 28, 32, 39] showed that drinking mineral waters have an expressed favourable effect not only at already existing diseases of the person, but they are also effective remedies of promotion of health reserves and prevention of diseases. Therapeutic effect of mineral waters depends on gas and chemical structures and a temperature factor, however, in this case it is defined not by borium and silicon, namely salt composition and other biologically active components. In the basis of the action mechanism of mineral waters at internal application there are polymodal organism responses to the influence which are initially developed in proximal parts of alimentary tube and then irradiate on the system level realizing its biological potential far beyond the primary contact [21, 33, 45].

Drinking mineral waters universally influence secretory and motor functions of gastrointestinal tract both directly (contact and quickly) and indirectly due to the stimulation of the development of gastrointestinal hormones, information influence on target organs, central nervous system, hormonal blocks of high level of biological integration (hypothalamus-pituitary paranephric, thyroid, etc.) [22, 46]. As a result, there is a formation of not only and not just short-term but long-term adaptation reactions that bring organs of gastrointestinal tract to the new level of functioning close to physiological with the maximum use of biological reserves and resulting effect in the form of increase of organ and organismal resistance.

At reception of drinking MW there is an improvement of incretory function of the insular device of pancreas which is shown in optimization of the yield producing power of β-клеток at the expense of the increase in labile and main insulin pools, efficiency of its action in tissues. There is a restoration of disturbed correlation of insulin and glucagon. There is also an activation of intestinal and  pancreatic and neuroendocrine interrelations, gastrin secretion, secretin and other  intestinal hormones which actively influence the function of β-cells. Counterinsular influences that remove the intense stimulation of β-cells are inhibited and lead to the increase of their functional reserves [39, 46]. The interest in achievements of endocrinology in this case is connected with the thing that at the basis of all regulation and management processes there is information that can be better transferred by hormones which are some kind of information biopolymers [11, 47]. This system of chemical information acts, in addition, as the integrator controlling coordinate activity of internals.

In recent years the theory of adaptation action of physical factors is gaining popularity [10, 22]. Adaptation is nearly the most important thing in modern medicine since the normal course of physiological reactions (i.e. health) depends on the ability of an organism to adaptation and its disorders make an illness [24, 25, 30]. The concept of adaptation is connected with concept of stress. Stress predetermines adaptation. “Soft” and short stresses (so-called physiological stresses) are training factors that significantly increase the resistance of an organism to action of damage factors. Numerous researches [6, 8, 20, 31, 41] allowed to study rather well the features of hormonal shifts at a stress (hormones of hypothalamus-pituitary paranephric, thyroid, gastroenteropancreatic systems, endogenous opiates, etc.). However, it is enough to determine the content of adrenocorticotrophin and/or cortisol in blood. Its increase for this season and day testifies to the condition of stress. For pathological stress (i.e. at action of an irritator excessive in force) it is characteristic to have an early rise of ACT and cortisol in blood by 5-10 times over the limit proceeding till 2-3 weeks and at the same time the decrease in insulin secretion within 2-5 days. On the contrary, at physiological stress, for example, at single influence (reception) of mineral water there is a short-term increase (for 30 minutes) in cortisol level and an early (on the 30th minute) increase in insulin level. The given data allow to draw a conclusion that one of the main action mechanisms of drinking mineral waters is formation of adaptation reactions in hormonal systems of various regulation levels. Their “start” requires the development of the condition of physiological stress in the organism. The integral indicators of this physiological stress-reaction can be cortisol and insulin contents in blood which researches give the chance to define, in conditions of a single reception of mineral waters of various structure, the extent of their medical-and-preventive action [31, 45].

The administration course of MW within 18-21 days promotes the  improvement of functioning of hormonal organism blocks and, according to it, leads to optimization of carbohydrate and fat metabolism, activation of enzymes, increase of tissue sensitivity to the hormone action at the expense of increase in number of free receptors on the cell membrane of target organs. Besides, mineral water slows down absorption of nutrients in intestine which is especially important at such widespread diseases of the modern person as diabetes and obesity.

Experimental and clinical studies conducted by the staff of Pyatigorsk state scientific research institute of Resort study of FMBA of Russia [10, 22] showed that mineral waters with the contents of hydrogen sulfide of 10 mg/l possess, in comparison with non-hydrogen sulfide waters, the expressed antioxidant action that promotes normalization of peroxide homeostasis. Lipid peroxidation disorder, as we know, is one of pathogenetic bases of bad state of many diseases, in particular, digestive organs.

It has been proved that waters containing ions of sodium and chlorine have a stimulating effect on hormone secretion of hypophysis and suprarenal cortex which are main regulators of general organism resistance, that is resistance to the action of damage factors of various character (irritants, alcohol, high-rise hypoxia, radiation, etc.) [10, 22]. These results have been received not only on models of experimental pathology with animals, but they have also been approved in clinic with patients suffering from ventricle diseases, hepatic disorders and diseases of bile passages, pancreas and intestine. In recent years it has been revealed that administration course of MW with high contents of sodium and chlorine ions promotes the increase of serotonin in blood, it is the hormone that has a direct connection with the increase in life expectancy.

The existence of hydrocarbonate and sodium ions in mineral waters provides a great impact on organs of digestive system [10, 22]. Mineral water when it is in stomach has an alkalifying effect which depending on the functional activity of parietal cells of mucous membrane remains from several to 20 minutes. Along with alkalization of the gastric contents one can observe the increase of gastrin secretion, the hormone that has the expressed acidstimulating and trophic effect. The cooperative ion influence of hydrocarbonate and gastrin promotes the increase of motor evacuation ventricle functions which leads to the accelerated dumping of stomach contents in duodenum and small bowel. This, in its turn, is a motivation to increase secretion of the whole scale of intestinal hormones that provide not only optimization of the actual digestion process but promotes the increase in adaptive capacity and resistance of digestive system to the action of unfavourable factors. The course reception of mineral water causes a long hormone-stimulating effect that lasts from 2-3 weeks to several months providing a beneficial effect of the drinking treatment on metabolism, trophism state and resistance both digestive organs and other organism systems.

Rapid development of resort study and experimental medicine allowed to develop experimental models and treatment methods of prevention of various diseases that include a number of inflammatory diseases of organs of urogenital system. In Pyatigorsk scientific research institute of resort study there has been studied and described a medical effect of drinking mineral waters of various mineralization which substantially is defined by their chemical composition [10, 22, 43]. Ions of magnesium, calcium, hydrocarbonate, chlorine and sulfate have the greatest value. Sulphatic water strengthens biliation and biliary excretion, promotes the removal of cholesterol and bilirubin with bile, and also improves the depletion of intestine which leads to the reduction of infectious and toxic agents in liver through enterogenous way. Medical action of sulfide water is generally connected with free hydrogen sulfide in water that possesses active chemical properties. In the mechanism of therapeutic action of sulfide water hormonal shifts, changes of sympathetic-adrenal system function,  condition of immunological reactivity play a great role. At a drinking method of application, hydrogen sulfide gets into an organism from water through mucous membranes and airways. Bile-expelling effect of hydrocarbonate and chloride water is expressed more weakly but nevertheless it is rather distinct. Magnesium ions possess considerable bile-expelling action, reduce spasms of bilious ways, stimulate intestinal motility. Calcium ions strengthen anti-inflammatory effect. Carbon dioxide of drinking mineral waters is an active irritant of mucous membrane receptors, blood vessels, it activates regional blood circulation, metabolic processes in tissues, secretory and fermentative activity of digestive glands. Hydrogen sulfide increases the contents of sulfhydryl groups in liver tissue, improves the trophism, especially, at the protein synthesis level.

Historically mineral waters rich in soluble silicon compounds have been applied in resort practice. This water possesses the expressed diuretic action, makes mainly stimulating impact on secretory and acid-forming ventricle functions, oppresses its motor and evacuatory functions, strengthens bile production and biliation.

Humic substances [1, 13, 27, 29] belong to the most important components of mineral water defining its medicinal properties. Humic acid is a big, long chain of molecules that can be marked in the form of humate from coal or soil layer. Its integral component is fulvic acid which properties can be sometimes considered separately.

A complex of humic and fulvic acids is extremely powerful combination for improvement of an organism. It possesses high bioavailability. Its structure contains a full range of minerals, amino acids and microcells. Among them there are natural polysaccharides, peptides, to 20 amino acids, vitamins, minerals, sterols, hormones, fatty acids, polyphenols and ketones with subgroups including flavonoids, flavones, flavins, catechins, tannins, quinones, isoflavon, tocopherols and others. In total there are about 70 useful components. Such saturated polymorphic structure causes a variety of positive biological effects of humic acids.

Mineral water of low mineralization of various chemical composition are useful in treatment of renal diseases. Drinking mineral water promotes strengthening of intraorganic blood flow, glomerular filtration, normalizes urodynamics, increases diuresis, possesses anti-inflammatory, stimulating action [16, 18]. If  mineral water is prescribed to the patients of urological profile, it’s necessary to consider water parameters (acidity, mineralization degree, ionic and gas structures, presence of organic substances, etc.) and application conditions (for example, cold mineral water has good diuretic effect, and warm water promotes elimination of inflammatory processes, removes spasms and stimulates bile outflow). Diuretic property of mineral water means not only the removal of water from an organism, but it’s also the removal of useless mineral substances and products of nitrogenous exchange together with water.

The most known mineral waters at diseases of urinogenital system are “Slavyanovskaya” and “Smirnovskaya” (Russia, Zheleznovodsk), “Krainskaya” and “Demidovskaya” (Russia, Tula), “Fyudzhi” (Italy, Fyudzhi), “Naftusya” (Ukraine, Truskavets).

The drinking mineral waters applied to prevent and treat patients with diseases of urinogenital system must [10, 16, 18, 22]:

have the expressed diuretic effect;

  • strengthen a kidney plasmotoc and urine filtration in malpighian tufts;
  • have the anti-inflammatory and mucolytic effect;
  • possess relaxing effect at pathological spasm of smooth muscles of urinoexcretory system;
  • have a toning effect on smooth muscles of the top of urinary tracts;
  • have an analgesic end point.

Clinical supervision of the scientists working in the field of resort study, there has been established a beneficial effect of low-mineralized mineral waters (MW) while treating urological and some other diseases [10, 18, 22]. According to its chemical composition, the given MW belongs to hydrocarbonate-calcium-magnesium mineral water (salt concentration is no more than 0,8 g/l, colourless, even very transparent, cold (8-10 degrees Celsius) with a light smell of hydrogen sulfide and oil flavor) which distinctive property is the existence of small amounts of difficult complex of organic substances. They are organic acids, amines, phenolic derivatives and dozens of group microorganism that according to a number of researchers and have an influence of its medical action. Interesting data were obtained when studying mineral water of “Naftusya” (Ukraine). “Naftusya” is a famous medicinal mineral water from Truskavets. Thanks to this medicinal water Truskavets got glory of the global resort. According to its chemical composition, this MW belongs to hydrocarbonate-calcium-magnesium mineral water (salt concentration is no more than 0,8 g/l, colourless, even transparent, cold (8-10 degrees Celsius) with a light smell of hydrogen sulfide and flavour of oil), its distinctive property is that it contains small amounts of complex aggregate of organic substances – organic acids, amines, phenolic derivatives and dozens of microorganism groups that according to a number of researchers have impact on its medical action.

Mineral water «Naftusya» has impact not only on hepatobiliarny system and kidneys, but on other bodies and systems of a human body too [9]. One of the mechanisms that provide analgetic effect is an interaction of the components which are a part of MW «Naftusya» with receptors of parasympathetic and sympathetic departments of vegetative nervous system which have an essential impact on a tonicity of unstriated muscles of ventricle, bilious and urinary tracts, blood vessels. There has been noticed positive dynamics of exocrinous function of pancreatic gland and improvement of its incretory function after the course of «Naftusya» is noted. Unique properties of the given MW are caused by its high ferrous ion contents that are a specific blood regenerator, accelerate the formation of erythrocytes and serve as a peculiar construction material for hemoglobin. Such water like «Naftusya» increases ventricle acidity, influences blood acidity, normalizes digestion with the patients who have disorders of gastrointestinal tract.

MW of «Naftusya» eliminates inflammatory processes in an organism, stimulates kidney activity, extrusion of small kidney stones and sand, reduces danger of reaquisition of lithiasis. Besides, it normalizes metabolism, work of gastrointestinal tract, pancreas, bilious and urinary tracts, blood vessels. Physiologists are sure in direct influence of some components of MW «Naftusya» on metabolic processes in hepatocyte. There has been noticed an improvement of anomalous gland activity, restoration of liver cells, kidney cells and cells of urinary tract, excretion of radionuclides and toxins from an organism. There has also been marked an expressed immunomodulatory effect this MW.

Under the influence of MW “Naftusya” we can observe the increase in diuresis and removal of nitrogenous substances (in particular urea), inorganic phosphorus, chlorides, calcium salts from an organism of nitrogenous substances (in particular urea), inorganic phosphorus, chlorides, calcium salts and along with the general increase in removal of chlorides, one can notice the increase in their concentration in urine. In his works M. B. Plastunov notes a diuretic effect of MW Naftusya, specifying the fact that under its influence, the removal of phosphates, urea and chlorides increases not only in proportion to increase in amount of urine, but also due to the increase of concentration of these substances in it. The same author observed antispastic and analgesic influence of MW Naftusya which favors to kidney stones extrusion.

The resort of Fyudzhi is the only urological resort of Italy. Cold  mineral water Fyudzhi (temperature in the spring is 12,440С), there are no analogues in chemical composition in the world, it is oligomineral water with low content of calcium and possesses a pronounced diuretic action due to the minimum total salt content. The unique composition of water Fyudzhi is caused by hydrogeological features of Antikolana area where there are water springs. It is a tuffaceous field where water flows down to the course at rather low depth (between 8 and 20 meters), in the area covered with chestnut trees, oaks and pines. As a result of molecule influence with a rather low molecular weight causing degradation of such biopolymers as proteins, polysaccharides, cellulose,  lignin, tannins, pigments, such compositions as and fulvic organic compounds are formed that are engaged in chemical interaction with ions of metals and especially calcium – one of the main minerals participating in formation of nephroliths and interferes with formation and growth of crystal lattice of nephrolith. The medical action of MW «Fyudzhi» consisting in prevention of lithiasis in urinary tract isn’t subject to any doubt. The relative risk of nephrolith formationis is low with people approximately by 30% at daily consumption of liquid more than 2,5 liters in comparison with those who consume half of this volume or less. The simple biochemical and physiological program is realized: prevention of formation of new concrements – removal of small concrements – growth blocking of the available concrements. In case of application of MW “Fyudzhi” the program is more difficult and more effective: there is a prevention of formation of concrements; removal of small concrements; growth blocking of the available concrements; destruction of the available concrements; removal of the small concrements formed owing to destruction [3]. The major stage is the destruction of the available concrements. It is explained by the existence of specific organic molecules belonging to fulvic and humic acids capable to attack the crystal lattice of oxalate nephrolith structure and to destroy it. As for nephrolith fracture speed of calcium oxalate in the experiment, then in the first days of the influence of mineral water Fyudzhi, a stone starts collapsing with formation of single small fragments and loses in weight to 5%, in two weeks the loss of weight makes more than 30%, by the end of the first month – more than 50%, by the end of the second month – more than 60% with final destruction in small fragments, at last on the sixty third day the stone is destroyed completely. Fyudzhi mineral water effectively influences all types of nephroliths, and also cystine stones with children.

Mineral water «Leonardiya» is very close to the chemical composition to mineral water «Naftusya» and «Fyyudzhi». It is cold fresh underground water from BQ 2 deposit (Rogatets-Sobonki, the Czech Republic). The analysis of fractional organic structure and qualification assessment of the water chemical composition has been carried out in the laboratory of physical and chemical mineral waters and therapeutic muds of PSSRIRS FMBA of Russia (protocol №  1/OKR from 11.01.2013). The water from an artesian well of BQ 2 belongs to cold fresh underground water (depth of 82 m, temperature 12,20С, an output of 120 l/min). As the mining level, the well captured terrigenous deposits (clays, sand, condensed silt) with inclusion of brown-coaly facies (lignites). Possible additional application of the water spring is a commercial bottling of drinking and mineral natural table water according to the specifications and technical documentation.

As the conducted researches showed water from well BQ 2 “Leonardiya” belongs to mineral natural table water and is according to  mineralization and main ionic structure fresh (“ultrafresh”), hydrocarbonate calcium-sodium (or magnesium-calcium-sodium) without specific components and properties, weakly alkaline reaction of the environment. According to the temperature, the water belongs to the group of cold waters. According to organoleptic properties, the water of the spring represents transparent colourless liquid with slight hydrocarbonic smell, fresh on taste; without deposit.

The composition of the dissolved gases is characterized as nitrogen-metane, the contents of the free dissolved carbon dioxide (CO2) doesn’t exceed 9 mg/l. The water of well BQ2 (“Leonardiya”) doesn’t possess radioactivity. It doesn’t contain other microcells including ions of heavy and non-ferrous metals that exceed the norms of biologically active without exceeding concentration, admissible by GOST P 54316-2011, SanPiN 2.3.2.1078-01 and to other norms and rules.

The total content of organic substances in the water spring is low and makes 2,34 mgS/l according to carbon of non-volatile organic compounds which is less the confirmed balneological norm of  water reference to medical and table based on this indicator. The fractional structure is presented by humic substances, neutral and acid bitumens (fraction sum is to 4,0 mg/l).  Thus, phenols, aromatic hydrocarbons and other compounds on which prohibitive criteria are extended, haven’t been found  in the group structure.

According to the certificate issued by MH of the Czech Republic to the company “Bohemia Beverage Industry Group s.r.o.” about the spring of the natural mineral water BQ – 2 (from July 9, 2015. Reference number: MZDR 24698/2015-5/OZD-ČIL-Pr *MZDRX00Q8X3O* Identification number: 27746470), the mineral water spring received from BQ-2 well, located on site № 3256/1 in the cadastral Rogatets area (system coordinates are S-JTSK Y – 557 295,83; X – 1 198 605,29; Z – 168,17 m – an entrance to the well; the depth is 82 m) is a source of natural mineral water with mineralization of 270-300 mg/l, pH 8.2. – Mineral water low-mineralized, geochemical HCO3-Na-Ca type, cold, hypotonic.

In the certificate there was an expert’s opinion on usefulness of mineral water springs BQ-2 according to §6 paragraph 2 subparagraph d) the Law on resorts for production of bottled natural mineral water that was prepared in May, 2015 by the candidate of natural sciences Tomash Vylita, the doctor of philosophy, and the doctor of medicine Ladislav Shpishak, the candidate of science.

The presented results of hydrogeological researches, quantitative and qualitative supervisions show that mineral water of BQ-2 well has a stable structure and is microbiologically safe. Protection of the spring is provided with security zones I and II degrees established by the resolution of Ministry of Health.

Ministry of Health of the Czech Republic came to the conclusion that according to the provided information contained in technical statement made by the doctor of medicine Ladislav Shpishak it is possible to draw a conclusion that physiological value of mineral water for food is based, first of all, on combination of two important chemical characteristics of the option, i.e. at the expense of low mineralization in combination with antioxidant properties that are provided by negative oxidation-reduction potential (ORPAgCl =-206 mV) with the content of fulvic acid 1mgl, silicon acid 17 mg/l.

The comparison of the results reflected in balneological conclusions of PSSRIRS FMBA of Russia (protocol № 1/OKR from 11.01.2013) and the laboratory protocol of 19.03.2014 № RL 030-14 “The complex analysis of BQ-2 Rogatets – Sobonki” allows to draw a conclusion on stability of macroionic and microcomponent composition of underground water of BQ 2 deposit  (Rogatets-Sobonki, the Czech Republic) and its high quality.

The fulvic acids that are contained in NMW “Leonardiya” belong to more aggressive fraction of humic substances. They have a specific element structure (SES). Fulvic acid  contains 74 organic minerals, 10 vitamins, and 18 amino acids. Fulvic acid has low molecular weight, it is capable to make active the “sleeping” neutrons in an organism by an intensification of cell respiration. “Having woken up” these neutrophils are capable to awake all immune system. The given data that fulvic acid actively catches free radicals, oxygen and hydroxyl radicals, inhibit cytotoxic activity which causes the decrease in metastatic potential of cancer cells. Fulvic acids are capable to absorb toxins (radionucleids, oil carbons, heavy metals, chlorinated hydrocarbons, pesticides, polycyclic aromatic hydrocarbons, metallorganic connections). In the world balneological practice mineral water containing fulvic acid (“Sergiev Posad”, “Bern”, “Fyudzhi”) is very popular.

The research objective

is to study the efficiency of drinking mineral water «Leonardiya» (the Czech Republic) at treatment and prevention of diseases of genitourinary system (chronic pyelonephritis, prostatitis) in comparative aspect with mineral water «Naftusya» (Ukraine) and «Fyudzhi» (Italy).

Basic research tasks:

  1. To study hormonal, immune status, carbohydrate and lipidic exchange with animals in various terms after modeling of chronic pyelonephritis and chronic prostatitis in the experiment.
  2. To study the efficiency of the course reception of mineral water «Leonardiya» in comparison with mineral water of similar structure, «Naftusya» and «Fyudzhi» with animals with the model of chronic pyelonephritis and prostatitis and to analyse the dependence of these disorders on the condition of hormonal security, immune status, lipidic and carbohydrate exchange with animals before and after animals watering by the mineral water.
  3. To study the condition of hormonal regulation blocks, immune status, lipidic and carbohydrate exchange, the influence of the course of drinking treatment with mineral water «Leonardiya» on these indicators and the interrelations between the studied indicators with animals that have a model of chronic pyelonephritis and chronic prostatitis.
  4. To study the duration of preservation of the course effect of mineral water «Leonardiya» at experimental forms of pathology (chronic pyelonephritis, chronic prostatitis).
Materials and methods

There have been carried out some researches on 122 rat-males Vistar line with a body weight of 240-260 grams.

The studies on animals have been conducted according to “Rules of work with use of experimental animals” (the order of Ministry of Health of the USSR 755 from 12.08.77) and the Federal law of the Russian Federation “About protection of animals against ill treatment” from 01.01.97.

A suspension of E. coli is usually used as a bacillary agent to model a lemic prostatitis which is inserted in an experimental animal by various ways [17]. So, there has been described a model of infectious prostatitis in which the bacterial suspension of E.coli was inserted in one of prostatic rami, i.e. angiogenic. In her work M. I. Kaplun and her co-authors (1976) recommend a direct introduction of bacterial E. coli suspension to parenchyma of prostate gland of previously castrated male-rats [22]. Quite good results of reproduction of an infectious prostatitis model can be observed at the transurethral insertion of E. coli bacteria for the first time described in the work by V. P. Chernyshev.

All the described ways of modeling have a low reproducibility connected with impossibility of exact model replica on other individuals. Insertion of E. coli bacteria is made by carrying out surgeries, stress, anesthesia, operation differently influence the natural protection of an organism of experimental animals due to their identity.

Chronic pyelonephritis is a frequent disease that accompanies various urological pathologies (urolithiasis, arctation of ureteropelvic junction or transureteral-cyctic segment, kidney and urinary tract abnomal development, etc.), and also meeting independently (primary chronic pyelonephritis) [5, 11, 16].

Long and relapsing course of this disease can lead to the  development of renal disease. Therapy efficiency of chronic pyelonephritis is usually low and leads only to more or less long remission without relieving the patient from the illness and danger of kidney loop of function. Even at elimination of the factor inducing the development of chronic pyelonephritis (kidney stones, development of urina transit) this disease can progress despite the carried-out anti-inflammatory therapy and becomes the main pathological process that  causes kidney loop of function. In this regard searches of new more effective ways of chronic pyelonephritis are actual [16, 18].

In genesis of the development of chronic pyelonephritis special significance is paid to haemo dynamics changes in kidneys that are shown in a spasm the intraorganic, mainly cortical arteries, and a sharp decrease in vein tonicity [37]. A number of authors developed some ways of modeling to study pyelonephritis pathogenesis and to carry out preclinical researches of efficiency of new treatment methods of infectious and inflammatory pathology of urinary organs. They are orally infection – triple introduction of Escherichia coli suspension to intestines of outbred rats with a break in 3 days (A.V. Lukyanov, V. T. Dolgikh, etc.) as one of the ways of hematogenic infection along with inhalation introduction of colibacillus suspension to animals; injection of pathogenic microorganisms cultures to the area of nephros projection (E.M. Parmon, B.S. Kamyshnikov, etc.). When carrying out morphological researches at this way of nephros infection of experimental animals there is a formation of the drain purulent centers testifying to the development of a special form of apostematous pyelonephritis which is seldom found in clinic. In the experiment it is shown that a stressful impact on an organism causes a dissemination of intestinal flora to the blood course (B. A. Berdichevsky and co-authors, 1993). In this regard the development of a model of hematogenic pyelonephritis that is developed against the impaired intestinal microbiocenosis and stressful influence has a special relevance.

To carry out experimental studies we have chosen some qualitative models of chronic pyelonephritis and chronic prostatitis possessing high reproducibility. To model chronic prostatitis we used a mixture on the basis of 10% of dimexidum solution in water and turpentine in a volume ratio 4:1. The irritant was inserted into the top department of a rat rectum on the depth of 25 mm in number of 1 ml by means of the device for rectal injections (batcher) that provides a noninvasive procedure. Before the introduction the mixture was shaken up before receiving finely-divided emulsion.

The model of chronic pyelonephritis was created by triple introduction to a rats’ tail vein of a suspension of Escherichia coli in a caption of 108 in 1 ml with a break in 3 days with simultaneous cryogenic influence at the temperature of -20С within 2,5 hours till the achievement of rectal (in a rectum) temperature +320С (the norm is +37-380С) every other day within 12 days. The animals were fixed in a horizontal position. The suspension of germ culture of Escherichia coli was entered in a caption of 105, previously determined by  turbidimetric method on photoelectrophotometer KFK-3, (the optical density of bacterial suspension in plain broth was in limits D=0,012, the wave length λ 540 nanometers, the cuvet – 1,060 mm).

To assess the efficiency of prostatitis modeling in 28 days after the rectal injections, there has been made a fragment withdrawal of prostata and acinotubular  glands, and also a part of straight intestine adjacent to prostate gland with rats after decapitation and there has been also conducted a histological examination. For morphological examination there have been made histologic sections of biopsy materials that were painted with hematoxylin, eosin and according to Van-Gizon.

To study the changes after the modeling of chronic pyelonephritis, kidney bioptatas and the kidney received after the decapitation of animals have been subjected to morphological research. Renal tissue sections were painted with hematoxylin and eosin, picrofuchsin according to Van-Gizon, fuchselin according to Veygert, isocarmine according to Geydengain, sudan according to Goldman. The revealed changes were estimated according to morphological classification by V.V. Serov and T.N. Ganzen. Ultrathin cuts were painted with uranyl acetate and lead citrate according to Reynolds and studied in electronic microscope EVM-100L.

The population and subpopulation structure of lymphocytes in blood was determined by the method of two-coloured flowing cytofluorometry on the apparatus Cytomics FC-500 with application of software CXP 2.0 (“Beckman Coulter”, the USA) using the following panel of monoclonal antibodies: CD3-FITC, CD4-PE,  CD8α-PE, CD45R-PE, immunoregulatory index — (CD4/CD8) [48].

In animals’ blood on the 30th, 55th and 60th days of the modeling there was noticed the content of aspartate transaminase (АСТ) and glutamyl pyruvic transaminase (ALT) in (u/l), cholesterol (Ch) in (mmol/l), cholesterol of lipoprotein of high density (CLHD) and cholesterol lipoprotein of low density (CLLD) in (mmol/l), triglycerids (TC) in (mmol/l), creatinine (CT) in (mcmol/l) and alkaline phosphatase (AP) in (IU/l), cortisol (nmol/l), insulin (ng/ml), aldosterone (pg/ml) in blood serum. The level of malondialdehyde (MDA; according to I.D. Stalnoy and T.G. Garishvilly) and peroxidase (PO; according to V.S. Asatiany).

The studying of  biological properties of MW was carried out on healthy animals and on CP models. The studied water was inserted in animals orally in a dose of 1,5-2 ml on 100 grams of body weight within 21 days, similarly experimentally calculated volume for rats at reception of mineral waters. After the termination of the treatment course (including control group of intact rats, and the animals with models of prostatitis and pyelonephritis, models without influence), all the animals were decapitated. Then laboratory researches were conducted.

The rats were distributed by the method of a simple selection in 11 groups:

  • the 1st group, intact – 12 animals, received tap water;
  • the 2nd group – 10 animals with CP model, received tap water;
  • the 3rd group – 10 animals with CP model, received a course of MW “Leonardiya”;
  • the 4th group – 10 animals with CP model, received a course of MW “Naftusya”;
  • the 5th group – 10 animals with CP model, received a course of MW “Fyudzhi”

the 6th group – 10 animals with the model of chronic pyelonephritis, received tap water;

the 7th group – 10 animals with the model of chronic pyelonephritis, received a course of MW “Leonardiya”

the 8th group – 10 animals with the model of chronic pyelonephritis, received a course of MW “Naftusya”

the 9th group – 10 animals with the model of chronic pyelonephritis, received a course MW “Fyudzhi”

the 10th group – 15 healthy animals received MW “Leonardiya” within 25 days

the 11th group (control) – 15 healthy animals received tap water within 25 days

Statistical processing methods

The data obtained as a result of the researches were statistically processed on the PC IBM PC/AT with application of a package of statistical programs with application of various methods of parametrical and nonparametric statistics, variation methods and methods of correlation analysis. Arithmetic average value (M), standard deviation (m), correlation coefficient by Pearson (r ) have been calculated. The reliability of distinctions (р) was determined by t- criterion Styudent-Fischer. The results were presented in form of М±m. The statistical significance value when checking statistical hypotheses was accepted equal to 0,05.

The received results and their discussion.
Structure of mineral water «Leonardiya», «Naftusya» and «Fyudzhi» (comparative analysis)

The essential characteristics of mineral water is its ionic structure. So, in the comparative analysis it has been revealed that MW “Naftusya” contains more quantity of such inorganic components as ions of calcium, magnesium, sulfates and hydrocarbonates, and in MW “Leonardiya” and “Fyudzhi” there is a less number of these components. Quite a high content of silicon – in MW “Leonardiya” – 17 mg/dm3, in MW “Fyudzhi” – 18,3 mg/ dm3 (for ground water it is characteristic 10 mg/dm3) allows to assume their beneficial effect on the immune system of an organism.

Medical effects of the examined drinking MW are caused, generally, by organic components. It is possible to judge about the high concentration of organic components in the contents of MW in terms of permanganate oxygen consumed: so in MW “Leonardiya” it makes 1,8 mg of oxygen in 1 dm3, in “Fyudzhi” – 0,4 mg/dm3, in “Naftusya” – 3,7 mg/ dm3 (for ground water 0,01-0,1 mg of oxygen in 1 dm3 is characteristic: GOST 13273-88 and SanPiN 2.1.4.1116-02).

There are more important components of mineral waters «Leonardiya» and «Fyudzhi» that distinguish them from other known mineral water and define their medicinal properties. They are humic substances. According to I.V. Perminova’s data (2000) [29] humic substances:

  • form water-soluble complexes with metal ions including heavy metals, bringing them out of the organism;
  • accelerate transformation of microcells (in particular, iron, zinc, silicon) and vitamins in forms available to assimilation;
  • increase permeability of the cell membranes (work as specific sensibilizing agents);
  • assume that they are organic accelerants.

Humic substances are divided into some fractions [27, 29]: humin (non-recoverable residue, soluble neither in alkalis nor in acids), humic acids (humic acids – soluble only in alkalis and fulvic acids – soluble both in alkalis and in acids) and bitumens (natural oil derivatives). Mineral water «Naftusya» contains bitumens [9], «Fyudzhi» mineral water has only humic and fulvic acids, and «Leonardiya» has both bitumens and humins (fulvic acids) [52]. Due to the irregular structure of humic substances, it is possible to derive only their general structures [29], these are low-condensate aromatic organic compounds of uncertain structure. Humic acids contain a lot of active functional groups on the periphery that are responsible for sorption of heavy metals and complex formation with ions of calcium and magnesium, the latter can be the reason of prevention of lithiasis [27]. Fulvic acids represent a simplified type of humic acids as their structure is close to the structure of their nucleus. Reactivity of the humic acids consisting of chains low-condensate aromatic rings that are connected between themselves by not aromatic chains is connected with the existence of spirit, phenolic, carboxyl and carbonyl functional groups in them. It is considered that these are humic acids that reduce the activity of formation of calcium calculi [52].

Table 1. Chemical composition of mineral waters (comparative characteristics)

IndicatorMineral water
«Leonardiya»«Naftusya»«Fyudzhi»
Степень минерализации (г/дм3)0,290,80,15-0,20
Реакция среды (рН)87,0-7,27,5
Температура (Т (0С)12,21012,4
Перманганатная окисляемость

 

(мг/дм3)

1,763,70,4
Ионный состав (мг/дм3)Calcium ions Са2+20104-11015-25
Magnesium ions Mg2+1635-455-10
Na+, K+613-6< 10
Sulfates SO42< 357-58< 5
Chloride ions Cl315-207-10
Hydrocarbonate HCO396440-45090-110
Silicon salts171018,3
Organic component (mg/l)Organic carbon2,344,9less than 1,0
Amount of organic substances4,0Minimum 15 
Bitumens0,6Minimum 10
Humins – fulvic acid3,4Minimum 5 

The carried-out comparative analysis of fractional organic structure and qualification assessment of the chemical composition of mineral water of low-mineralization «Leonardiya» testifies that this water belongs to the XVII-th group of medical table water and is an analogue of MW of low mineralization «Naftusya» and «Fyudzhi» and it is reasonable to use it in clinical practice at recovery treatment of diseases of the genitourinary system.

Medical effects of the mineral waters «Leonardiya», «Naftusya» and «Fyudzhi» at experimental prostatitis

We have proved that modeling of chronic prostatitis after the rectal introduction of 10% of solution of  dimexidum in water and terebenthen leads to considerable activity disorders of various functional systems of the organism which is confirmed by histologic researches, and is fixed, after the change of leukogram with prevalence of inflammatory and immunomodulatory components.

The researches have been conducted in the experiment on 49 animals – Vistar rat-males with body weight of 240-260 g. In a week after the prostatitis modeling, a course of treatment by mineral water «Leonardiya», «Naftusya» and «Fyudzhi» was carried out. The animals received mineral water in a dose of 1,5-2 ml on 100 grams of body weight within 23-24 days. After the termination of the treatment course, all the animals (including control group of intact rats and animals with a prostatitis model without influence) were decapitated. The animals’ blood contained some content of cortisol, insulin, testosterone, follicle-stimulating (FSH) and luteinized hormones (LH) and prolactin hormone. On the biochemical polyanalyzer by means of standard test-sets, we defined the content of the total cholesterol, lipoprotein of high density and glucose in blood. The level of malondialdehyde (MDA; according to I.D. Stalnaya and T.G. Garishvily) and peroxidase (PO; according to V.S. Asatiani) has been studied.

Experimental reproduction of chronic prostatitis with animals is followed by essential changes in indicators of fluid homeostasis.

The analysis of the received material showed that even 5 weeks later after the prostatitis modeling, the whole range of changes of the hormonal status and metabolism can be observed besides prostate morphofunctional changes which testifies to the system nature of the process. So, all the animals had an increase in prostate gland mass by 2,5 times, acute oedemata and hyperimia, the content of fructose in the tissue increased twice. Along with it, the expressed decrease in testosterone level in blood (twice) and prolactin (for 21,2%), the increase in the content of FSH (for 32%) and LH was observed (twice). Besides, even 5 weeks after modeling of pathology, the glucose level (for 25,4%) and the total cholesterol (21,2%) was still increased. The content of insulin in blood was not changed, and  it was possible to state only the tendency of cortisol to increase (for 6,8%) which is not statistically confirmed.

After carrying out the multiple correlation analysis, the interrelations between all the studied indicators were revealed that are worth, in our opinion, special consideration. Between the values of LH and cortisol at prostatitis model,  a close (almost functional) inverse relationship r=-0,96±0,001 (р<0,0001) was observed which proves the existence of a distinct tendency of cortisolemia to decrease as the level of LH at the model sharply increases. The return correlation communication between the FSH level and cortisol testifies the same, it is as close as with LH and cortisol (r=-0,91±0,001; р<0,0001). One more proof of the activity decrease of suprarenal cortex when modeling prostatitis is a highly reliable direct link between the level of cortisol and testosterone (r=0,85±0,019; р<0,0001) in blood. Testosterone as we noted, decreases at this pathology twice. Additional oppression of testosterone secretion at experimental prostatitis can be also connected with direct impact of the infectious agent on prostate gland tissue. To compensate this, the activity of LH increases widely which stimulates the production of testosterone. Such a scheme quite corresponds to the opinion of physiologists conventional nowadays that “hormones change their activity not because and in order that”. In other words, hormonal regulatory blocks accurately correspond to the principle of usefulness of the system analysis and therefore behave as regulators of adaptation processes to the changed environmental conditions. When modeling experimental prostatitis the level of prolactin in blood decreases which causes the removal of antigonadotropic effect and the increase of FSH level. The correlation coefficient between the values of hormones in group of intact animals is reliable (r=-0,57±0,161; р<0,01), but breaks during the experimental pathology. In our researches the decrease in level of testosterone in blood at prostatitis coincided with the decrease in PRL level, and between these indicators there was a reliable direct dependence (r=0,49±0,230; р<0,05), absent with intact animals.

At discussion of the received results special attention is given to the data on metabolism disorders with animals that are remained for quite a long time. It is as it has already been noted, the increase of glucose level in blood and total cholesterol.

It is possible to believe that  hyperglycemia and hypercholesterolemia are not only the consequence of the stress after the operation, but it is also the reflection of the general situation at prostatitis that as we know, occurs considerably more often with people of the senior age groups when carbohydrate and lipidic exchange disorders are almost a natural phenomenon.

The scientists of Pyatigorsk state scientific-research institute of resort study of FMBA of Russia [32, 39, 45] proved the ability of drinking mineral waters significantly to optimize carbohydrate and lipidic exchange at various forms of experimental and clinical pathology which was confirmed in our research too (tab. 2).

The course of animal watering by MW «Naftusya» led to the essential increase of insulin in blood level (for 66,4%), normalization of glucose level and cholesterol in blood. However we received a new fact – after the MW in animals’ blood with experimental prostatitis not only cortisol content increased (for 69,5%), but also testosterone (for 18,5%), and between the levels of these hormones it was revealed statistically reliable direct dependence (0,80±0,019; р<0,001). Therefore, the more the function of suprarenal cortex is activated, the more the production of testosterone activates that was lowered at prostatitis. The conducted researches give the chance to draw a conclusion on disorders consistency at experimental prostatitis and high efficiency of application of drinking mineral waters that have a positive impact on hormonal regulation of metabolism. One more circumstance should be noted. The animals that have a prostatitis model, the content of fructose increased in prostate gland tissue authentically (for 95,7%). After the course of MW «Naftusya» there was a reliable decrease in this indicator (for 31,1%). As the condition of fructoliz is an indirect indicator of androgen metabolism in prostate gland, these data are the proof of normalization of the hormonal status after the course MW not only at the system, but also at tissue level.

Table 2 – The influence of course reception of mineral water «Leonardiya», «Naftusya» and «Fyudzhi» on hormonal and metabolic indicators with animals with experimental prostatitis

IndicatorIntact animals

 

1 group

(n=12)

Model

 

2 group

(n=10)

 

Model and course of mineral water   
«Leonardiya»

 

3 group (n=10)

«Naftusya»

 

4 group (n=10)

«Fyudzhi»

 

5 group (n=10)

Cortisol, nmol/l328±17,5298±21,4319±20,6*^312±19,5*^315±17,8*^
Insulin, pmol/l18,8±2,4619,2±3,3919,0±2,77*^18,9±4,55*^18,8±3,56*^
LH, mIU/ml0,19±0,0130,37±0,0320,27±0,014*^0,29±0,02*^0,28±0,06*^
FSH, mIU/ml0,25±0,0130,33±0,0240,29±0,012*^0,30±0,06*^0,29±0,01*^
Prolactin, mIU/ml0,19±0,0090,15±0,0090,16±0,09*^0,18±0,08*^0,17±0,08*^
Testosterone, nmol/l4,18±0,362,68±0,2113,25±0,18*^3,35±0,25*^3,26±0,21*^
Total Cholesterol, mmol/l2,59±0,1013,14±0,1042,76±0,09*^2,68±0,11*^2,75±0,07*^
Glucose, mmol/l4,57±0,3005,13±0,3404,94±0,28*^4,61±0,22*^4,90±0,20*^
LPHD, mmol/l1,05±0,0691,01±0,1551,02±0,06*^1,04±0,07*^1,03±0,07*^
Fructose, mmol/l0,23±0,0200,45±0,0380,28±0,02*^0,31±0,02*^0,26±0,01*^
MDA, mmol/l0,39±0,110,76±0,120,48±0,09**^0,41±0,10**^0,52±0,13**^
Peroxidase, mcAB/l8,08±1,145,48±1,147,92±0,30**^7,98±0,52**^7,99±0,45**^
         

Note: * – reliable deviations in comparison with prostatitis model without the influence of MW р <0,05, ** – р <0,01; ^ – р >0,05 the data of group distinctions (reliability of deviation between the 3rd, 4th and 5th groups); n — the number of animals.

It should be noted that the use of MW «Leonardiya» (the 3rd group) was followed by statistically significant normalization of indicators of antioxidant blood capacity (р<0,05-0,01), which is explained by enough number of humic substances, neutral and acid bitumens (the sum of fractions is to 4,0 mg/l) in this water that possess anti-inflammatory action. There have been obtained some data that prove that the course application of drinking MW «Leonardiya» possesses antioxidant properties which are provided by negative oxidation-reduction potential (ORPAgCl =-206 mV), with the content of fulvic acid of 1 mg/l, silicon acid of 17 mg/l.

In general, positive dynamics of metabolic and hormonal indicators under the influence of MW «Leonardiya» and «Fyudzhi» was lower only than for 4-6% which testifies that these low-mineralized MW also possess hormone-modulating action and are capable to optimize significantly carbohydrate and lipidic exchange, peroxide homeostasis.

Thus, the results of experimental studies testify that when modeling experimental prostatitis, the expressed changes of animals’ hormonal status are observed. They consist of the expressed reduction of the testosterone level, cortisol and prolactin in blood and the increase in FSH and LH. Besides the changes of hormonal balance at the level of systemic blood, the animals have a change of hormonal security of prostate gland tissue. The data on metabolism disorders with animals that remain quite for a long time are especially important. As we have already noted, it is the increase of glucose level and total cholesterol, MDA and PO – even in 5 weeks after the pathology modeling.

Such indicators of peripheral blood as T-help and T-cytotox have considerably changed against chronic prostatitis: the contents of helper-cells authentically decreased in 28,8% (р<0,001), and the contents of cytotoxic cells raised by 2,5 times (р<0,001). Substantial increase in population of T-lymphocytes (T-cells) by 2,2 times testifies to the decrease in immunoregulatory function which is confirmed by reduction of IRI index by 3 times. The observed shifts in indicators accurately reflect the relation between chronic prostatitis and change of the main structure of subbpopulation of T-lymphocytes in rats’ blood. The raised contents in subpopulation of B-cells (B-cells) for 38% remained almost invariable even on the 21st day after the modeling of chronic pyelonephritis. Thus, the pathological model of chronic prostatitis reproduces the model of secondary immunodeficiency CD4 of positive lymphocytes in conditions that are defined by the formation of reversible destructive and degenerate changes in bodies and tissues. In immunological system of rats, there have been diagnosed some disorders of cell link of the immune response. It has been established that the course reception of «Leonardiya» mineral water (the 3rd group) has more beneficial effect on the studied immunological parameters with rats with chronic prostatitis (tab. 3). In the assessment of population and subpopulation structure of lymphocytes directly after the course of MW «Naftusya», it has been proved that the contents of T-cells active (CD3) authentically became close to the values of intact animals (р<0,01), at reception of MW «Leonardiya», indicators dynamics was lower in 7,8% р3-4>0,05), and MW «Fyyudzhi» – in 10,1% (р3-5>0,05). Under the influence of the given MW there was a reliable decrease in quantity T-helpers (CD4+) and cytotoxic T-cells (CD8+). Thus dynamics of these indicators at application of MW «Leonardiya» was lower only for 3% (р3-4>0,05), MW «Fyudzhi» – for 5% (р3-4>0,05). The decrease in immune-regulatory IRI index with healthy animals for 28,5% confirms the magnitude of immune response to the course reception of MW. Besides, we observed the decrease in 36,6% of subpopulation of B-cells (B-cells). At application of MW «Leonardiya» (the 3rd group) and «Fyudzhi» (the 5th group) all absolute values of population structure of T-lymphocytes also became close to the values of intact animals, reliable advantage of MW «Naftusya» wasn’t noted, i.e. according to the dynamics of immunological indicators, the efficiency between the studied waters was doubtful. The expressed immune-modulatory effect of the studied MW can be explained, in our opinion, with enough organic compounds – derivative bitumens and humins, and also silicon salts that have an immune-modulatory effect [10, 16, 18, 22].

Table 3. The influence of the course reception of «Leonardiya»«Naftusya» and «Fyudzhi» mineral waters on immunological indicators with animals with experimental prostatitis

IndicatorIntact animals

 

1 group

(n=12)

 

Model

 

2 group

(n=10)

 

Model and course of mineral water  
«Leonardiya»

 

3 group (n=10)

«Naftusya»

 

4 group (n=10)

«Fyudzhi»

 

5 group (n=10)

CD3+cells

 

(T-cells active (in %)

0,46±0,050,89±0,09

 

р12<0,01

0,57±0,04**

 

р3-4>0,05

0,50±0,03**

 

р2-3<0,01

0,59±0,05**

 

р3-5>0,05

CD45+cells

 

(В-cells (in %)

27,1±2,0117,2±1,79

 

р12<0,01

25,3±2,37

 

р3-4>0,05

26,3±1,46

 

р2-3<0,01

24,1±1,46

 

р3-5>0,05

CD4+cells

 

(T-helpers (in %)

21,2±2,6227,4±2,19

 

р12<0,01

23,1±2,36**

 

р3-4>0,05

22,3±2,29**

 

р2-3<0,01

23,6±2,09**

 

р3-5>0,05

CD8+cells

 

(T-cytotox (in %)

6,23±0,7111,41±0,68

 

р12<0,01

6,35±0,62**

 

р3-4>0,05

6,29±0,58**

 

р2-3<0,01

6,43±0,58**

 

р3-5>0,05

IRI (in %)3,40±0,392,40±0,15

 

р12<0,01

3,64±0,27**

 

р3-4>0,05

3,54±0,36**

 

р2-3<0,01

3,67±0,66**

 

р3-5>0,05

        

Note: ** – data of group distinctions – р <0,01 in relation to indicators of the 2nd group (model of chronic prostatitis); IRI – an immune-regulatory index.

The experimental data testify to beneficial effect of drinking MW «Leonardiya» on the course of experimental prostatitis which is shown in normalization of hormonal, immunological and metabolic indicators, and in general about the expediency of its use in clinical practice at rehabilitation treatment of diseases of urogenital system.

Medical effects of mineral water «Leonardiya», «Naftusya» and «Fyudzhi» at experimental pyelonephritis

Modeling of chronic pyelonephritis leads to considerable activity disorders of various functional systems of the organism which is confirmed by histologic researches.

When carrying out morphological researches of nephritic bioptat, the animals with chronic pyelonephritis have stromal edema, pericanalicular clumps of lymphohisticitharids elements. In nephrocytes there was granulose and hyaline and drop dystrophy. Separate tubules were expanded with nidal epithelium preatrophy. Besides, periglomerul sclerosis, some glomerul atrophy and existence of small centers of focal sclerosis in stroma were observed. The revealed changes testify to the development of chronic pyelonephritis with animals. In 3 days after the modeling of chronic pyelonephritis in peripheral blood it was revealed a reliable increase in leucocytes with neutrophilous shift to the left and eosonophilia that are remained until the animal exclusion from the experiment. The observed shifts in indicators of the main structure of subpopulations of T and B-lymphocytes in rats’ blood after the modeling of chronic pyelonephritis testify to disorders of cell link of the immune response with rats, the result of which is the secondary immunodeficiency of CD4 of positive lymphocytes and reversible destructive and degenerate changes in bodies and tissues. All this testified to preservation of post-stressful recombination of humoral regulatory mechanisms.

To study the medical effect of MW «Leonardiya», «Naftusya» and «Fyudzhi» after the modeling of chronic pyelonephritis, we carried out clinical blood and urine tests, cytochemical research of differentiation of lymphoid rat cells by method of flow cytometry.

The analysis of indicators dynamics of clinical and biochemical blood test reflected favorable shifts caused by carrying out drinking balneotherapy (tab. 4). So, the medical course by MW «Leonardiya» promoted some reduction of pathologic features at chronic pyelonephritis, and this phenomenon was shown in various functional systems. First, blood leucogram changed authentically and to the best: leukocyte concentration decreased by 1,49 times (р<0,01), segmented neutrophils – by 1,09 times (р<0,01), stab – by 1,81 times (р<0,01), at simultaneous increase of lymphocyte level by 1,57 times (р<0,01). Thus the comparative analysis of MW influence on indicators of peripheral blood testified to the decrease in the activity of inflammation processes under the influence of all studied waters («Leonardiya», «Naftusya» and «Fyyudzhi»), reliable advantage between them hasn’t been revealed.

Secondly, under the influence of MW «Leonardiya» the correction of metabolic disorders was noted that is shown in normalization of indicators of compensatory and adaptation opportunities: insulin concentration decreased by 1,17 times (р<0,01), and cortisol – raised by 1,08 times (р<0,01). It is well known that cortisol is the main adaptation hormone [11, 47, 50, 51, 53] and the increase of its contents in blood at the course application of drinking mineral water can be considered a favorable sign.

The increase of degree of inflammatory intoxication is followed by the increase in blood toxicity: progressive increase in the level of creatinine and urea. Under the influence of the studied drinking MW, a reliable decrease in these indicators was noted.

Aldosteron is a highly active hormone; it is developed in cells of zona glomerulosa, regulates potassium homeostasis and is a powerful stimulator of potassium secretion by collector tubules. The bigeminal correlation analysis showed that the decrease in the level of aldosteron was followed by hyperkalemia (r=-0,66; р<0,001) in our research. At application of drinking MW, we observed the increase of aldosteron concentration.

Table 4 – The influence of the course reception of «Leonardiya»«Naftusya» and «Fyudzhi» mineral water on clinical and biochemical indicators of blood with animals with experimental pyelonephritis

IndicatorIntact animals

 

1 group

(n=12)

 

Model

 

6 group

(n=10)

 

Model and course of mineral water  
«Leonardiya»

 

7 group (n=10)

«Naftusya»

 

8 group (n=10)

«Fyudzhi»

 

9 group (n=10)

LK of blood, abs.х109/l7,78 ±0,5212,8±1,488,6±1,61**^8,4±1,59**^8,7±0,57**^
Stab cell, %2,33±0,467,72±0,394,25±0,57**^4,53±0,55**^4,36±0,56**^
Segmental LK, %54,2±3,2464,5±3,2259,2±4,18**^58,8±4,32**^59,8±4,28**^
Lymphocytes, %34,4±4,2919,5±4,3229,6±3,29**^30,1±3,34**^28,7±3,38**^
Creatinine,Mkmol/l94,1±7,699,6±8,296,0±8,1*^95,3±7,5*^96,2±7,2*^
Urea,8,33±0,7610,98±1,129,23±0,81*^9,16±0,75*^9,32±0,73*^
Cortisol, nmol/l328±17,5276±13,9298±16,4**^306±14,2**^291±15,8**^
Insulin, ng/ml18,8±2,1623,8±2,1520,4±2,18*^20,6±2,14*^20,8±2,12*^
Aldosteron, pg/ml788±51,9557±52,8705±55,2**^724±53,2**^698±54,6**^
        

Note: * – reliable deviations in comparison with pyelonephritis model without the influence of MW р <0,05, ** – р <0,01; ^ – р >0,05 data of group distinctions (reliability of deviation between the 7th, 8th and 9th groups); n – number of animals; LK – leukocytes.

Dynamics of urine indicators at reception of drinking MW «Leonardiya», «Naftusya» and «Fyudzhi» was unidirectional (tab. 5). The level of proteinuria decreased by 4,7 times (р<0,01) at application of MW «Leonardiya», «Naftusya» – by 6,2 times (р<0,01),  «Fyudzhi» – by 3,1 times (р<0,01). The decrease in leukocyturia happened by 2,83 (р<0,01), 2,86 (р<0,01) and 2,81 times (р<0,01) respectively. The quantity of erythrocytes in urinary sediment decreased by 1,62 (р<0,01), 1,65 (р<0,01), 1,53 times (р<0,01) respectively.

Table 5 – The influence of the course reception of «Leonardiya»«Naftusya» and «Fyudzhi» mineral water on urine indicators with animals with experimental pyelonephritis

IndicatorIntact animals

 

1 group

(n=12)

 

Model

 

6 group

(n=10)

 

Model and course of mineral water  
«Leonardiya»

 

7 group (n=10)

«Naftusya»

 

8 group (n=10)

«Fyudzhi»

 

9 group (n=10)

рН6,68±0,246,27±0,226,56±0,31*^6,59±0,29*^6,47±0,27*^
Leukocytes, abs.х109/l3,02±0,4115,72±1,395,54±0,38**^5,48±0,36**^5,59±0,33**^
Erythrocytes, abs.х109/l0,81±0,061,52±0,130,94±0,08*^0,92±0,06*^0,99±0,03*^
Total protein, g/l0,04±0,0020,56±0,070,12±0,04**^0,09±0,005**^0,18±0,08**^
        

Note: * – reliable deviations in comparison with pyelonephritis model without MW influence р <0,05, ** – р <0,01; ^ – р >0,05 data of group distinctions (reliability of deviation between the 7th, 8th and 9th groups); n – number of animals.

Dynamics of indicators of the cytokine status (tab. 7) also testifies to favorable effects of drinking balneotherapy. The animals that received MW had the normalization of such dynamic factors as pro- and anti-inflammatory interleukins that were initially raised in several times. So, at application of MW «Leonardiya» IL-1β level decreased by the end of the treatment by 1,80 times (р<0,01)  at simultaneous increase of anti-inflammatory level of IL-8 by 1,06 times (р<0,05). The decrease in concentration of tumor necrosis factor by 1,12 times (р<0,05) was noted at the same time. The dynamics of these indicators at application of MW «Naftusya» was higher only for 4-5%, and at application of MW «Fyudzhi» – lower for 4-6% (р8-7-9>0,05). Normalization of IL under the influence of drinking balneotherapy testified to the reduction of inflammatory evidence, and, therefore, the subsiding of acute pyelonephritis with experimental animals.

The same dynamics was observed in the comparative analysis of other indicators of immune-resistance (tab. 7). The medical course of drinking MW at chronic pyelonephritis has a favourable effect on lymphocyte subpopulations, changing the main structure of subpopulations of T-lymphocytes with immunodeficiency of T-helpers (CD4+). The increase of value of IRI index after the medical course of drinking balneotherapy («Leonardiya») testifies to the increase of compensatory activation mechanisms of sanogenesis at restoration of immune system.

Totally analyzing the effect of drinking MW, it is possible to regard it as inhibitory in the relation the phagocytic and humoral indicators of immunity.

The carried-out matrix correlation analysis showed the direct link between the decrease in MDA level and pro-inflammatory cytokine IL-1β (r=+0,66; р<0,001) and the feedback – between these indicators and catalase level (r=-0,62; р<0,001). The decrease in contents of IL-1β was followed by the increase in number of T-helpers (r=-0,64; р<0,001) and directly correlated with the reduction of immune-regulatory index (r=+0,62; р<0,001). The improvement of condition of antioxidant system, the increase of immune-reactivity and the decrease in lipid peroxidation processes, cytokine activity when using drinking MW led to regress of inflammatory process in kidneys.

Thus, the received results of indicator dynamics of immune-resistance with animals with the model of chronic pyelonephritis indicate the expressed sanogenetic influence of drinking balneotherapy that is shown in considerable improvement of qualitative and quantitative condition of immune system, therefore, «Leonardiya», «Naftusya» and «Fyyudzhi» mineral waters have an obvious immune-modulatory effect. In general, indicators of immune-resistance testify to the available deviations in the condition of the immune status of experimental animals and to their correction as the result of the treatment.

Table 7 – The influence of the course reception of «Leonardiya», «Naftusya» and «Fyudzhi» mineral waters on indicators of the immune status with animals with experimental pyelonephritis

IndicatorIntact animals

 

1 group

(n=12)

 

Model

 

6 group

(n=10)

 

Model and course of mineral water  
«Leonardiya»

 

7 group (n=10)

«Naftusya»

 

8 group (n=10)

«Fyudzhi»

 

9 group (n=10)

IL-1β, pg/ml41,4±4,2113±6,5462,5±5,2**^59,4±5,6**^64,1±5,5**^
IL-8, pg/ml159±8,6125±9,3149±8,2**^151±8,0**^144±7,9**^
TNF-α, pg/ml35,6±3,865,4±4,640,2±4,3**^39,4±3,9**^43,2±4,4**^
CD3+cells

 

(T-cells active (in %)

0,46±0,050,98±0,08

 

 

0,64±0,07**

 

 

0,60±0,04**^0,72±0,06**^

 

 

CD45+cells

 

(В-cells (in %)

27,1±2,0114,6±1,65

 

 

23,3±2,11**^

 

 

24,0±1,76**^

 

 

22,4±2,38**^

 

 

CD4+cells

 

(T-helpers (in %)

21,2±2,6229,7±2,22

 

 

24,4±2,24**^

 

 

23,8±2,29**^

 

 

25,2±2,34**^

 

 

CD8+cells

 

(T-cytotox (in %)

6,23±0,7112,48±0,73

 

 

7,92±0,66**^

 

 

7,18±0,56**^8,01±0,68**^

 

 

IRI (in %)3,40±0,392,64±0,282,95±0,37**^3,03±0,36**^2,90±0,40**^
        

Note: * – reliable deviations in comparison with pyelonephritis model without MW influence р <0,05, ** – р <0,01; ^ – р >0,05 data of group distinctions (deviation reliability between the 7th, 8th and 9th groups); n – number of animals; IL – interleukin; TNF-α –  tumor necrosis factor –alpha; IRI – immune-regulatory index

The obtained experimental data allow to assume that the medical course by mineral water from BQ2 deposit «Leonardiya» (Rogatets-Sobonki, the Czech Republic) has a sanogenetic impact on different levels of bioregulatory organism systems and allows to expand possibilities of non-drug correction of metabolic disorders at chronic pyelonephritis.

The duration of the course effect of «Leonardiya» drinking mineral water at experimental pathology forms (chronic pyelonephritis, chronic prostatitis)

There have been conducted special studies to specify the identity of reactions nature in hormonal systems of various regulation levels at action of MW with animals, where we compared the dynamics of hormone contents in blood with intact animals in the conditions of a single reception of «Leonardiya» drinking mineral water.

In the real researches we studied the hormone random level in 3, 7, 10, 14, 17, 21 and 25 days after the beginning of the course of watering of some animals (15 rats, the 10th group). The control group included the animals (15 rats, the 11th group) that received tap water.

In our researches in 17-25 days there was a process of steady increase of gastrin, glucagon, insulin, cortisol and aldosteron in blood, though the latter still remained statistically and authentically below the initial level.

In the dynamics of hormonal systems activity of various levels (gastro-entero-pancreatic hypothalamo-pituitary adrenal axis) it is possible to note both lines of similarity and distinction. The majority of hormones had the increase of their content in blood after the course of MW «Leonardiya». Gastrin made 68,8% (from 35,5±0,58 to 60,0±1,73 pg/ml; р<0,05), insulin – 34% (from 18,8±2,46 to 28,3±2,89 pmol/l; р<0,05), glucagon – 83,7% (from 136,6±3,87 to 273,0±20,41 pg/ml; р<0,05), cortisol – 11,6% (from 328±17,5 to 338±16,4 nmol/ml; р<0,05). The dynamics of a triiodothyronine, thyroxine and aldosteron which random level decreased respectively in 25; 26,5 and 33,8% was antithetic.

The factorial analysis showed that dynamics of random level of the majority of hormones was defined only by watering duration factor. So, its influence for insulin and glucagon made 0,28 (F = 18,9; р<0,01) and 0,49 (F = 56,3; р<0,001) respectively, and for triiodothyronine – 0,62 (F = 83,3; р<0,0001) and tyroxine – 0,51 (F = 72,4; р<0,0001).

«Leonardiya» drinking mineral water causes reliable changes of functional hormonal activity of regulatory systems (gastro-entero-pancreatic hypothalamo-pituitary adrenal axis) which is defined by the duration of animals watering with mineral water.

In early terms of the course watering of animals with MW (the 3rd and the 7th days), the nature of dynamics of hormone random level reminds stressory which can be connected not only with the action of MW but also with the situational stress with animals. In later terms of watering with MW (the 17th day) the stress of the situation is caused already by the reception of mineral water. It is possible to believe that formation of hormonal reactions to single reception of water characterizes urgent adaptation reactions in systems at the first meeting of drinking irritant agent whereas at the action renewal of MW we notice the development of long-term adaptation reactions.

CONCLUSIONS

  1. The carried-out comparative analysis of fractional organic structure and qualification assessment of physical and chemical structure of mineral water of low-mineralization «Leonardiya» testifies that this water is the analogue of such mineral waters of low-mineralization as «Naftusya» (Ukraine) and «Fyudzhi» (Italy) and it is expedient to use it in rehabilitation treatment of diseases of genitourinary system.
  2. «Leonardiya» drinking mineral water possesses hormone-modulating action, its course application significantly optimizes carbohydrate and lipid exchange.
  3. «Leonardiya» drinking mineral water possesses antioxidant properties that are provided with negative oxidation-reduction potential (ORPAgCl =-206 mV), with the content of fulvic acid of 1 mg/l, silicon acid of 17 mg/l which promotes normalization of peroxide homeostasis.
  4. The dynamics of indicators of immune-resistance with animals with the model of chronic pyelonephritis indicates the expressed sanogenetic effect of drinking mineral water «Leonardiya» that is shown in considerable improvement of qualitative and quantitative condition of immune system which testifies to its immune-modulatory effect.
  5. Drinking mineral water «Leonardiya» has a regulating impact on water and electrolytic exchange. Thus rather high content of fulvic acid and its ability to reduce formation activity of calcium calculi provides a considerable decrease in oxalatury level which causes the expediency of its application at recovery treatment and medical rehabilitation of urolithiasis.
  6. In early terms of the watering course of animals with mineral water «Leonardiya» (the 3rd and the 7th days) the dynamics nature of random hormone level reminds stressory which can be connected not only with the effect of the mineral water, but also with the situational stress with the animals. In later terms of watering with mineral water (the 17th day) the stressor situation is already caused by the reception of mineral water. It is possible to believe that the formation of hormonal reactions to a single reception of mineral water characterizes urgent adaptation reactions whereas the result of the watering course with mineral water is long-term adaptation reactions.
  7. «Leonardiya» drinking mineral water causes reliable changes of functional activity of hormonal regulatory systems (gastro-entero-pancreatic, hypothalamic-pituitary-adrenal) which authentically correlates with the duration of animals’ watering with mineral water. The treatment course has to make not less than 17 days.
  8. The experimental data testify to a beneficial effect of «Leonardiya» drinking mineral water on the course of experimental prostatitis and pyelonephritis that is shown in normalization of hormonal, immunological and metabolic indicators which is the basis for its further use in clinical practice.
  9. The obtained experimental data give the grounds to believe that the medical course of mineral water from BQ2 deposit «Leonardiya» (Rogatets-Sobonki, the Czech Republic) has the expressed sanogenetic impact on regulatory systems of various level of biological integration which allows to use it in the medical and rehabilitation purposes at diseases of genitourinary system (chronic prostatitis and chronic pyelonephritis).

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