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Early diagnostic technique for chronic prostatitis by detecting regional microvascular endothelium dysfunction

IPC classes for russian patent Early diagnostic technique for chronic prostatitis by detecting regional microvascular endothelium dysfunction (RU 2540495):
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FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to a diagnostic technique for chronic prostatitis by detecting a regional microvascular endothelium dysfunction. Substance of the invention consists in conducting an ionophoretic assay with underlying laser doppler flowmetry, measuring a capillary blood flow reserve with an acetyl choline and sodium nitroprusside ionophoresis on the belly skin above a pubis in a projection point of the prostate, calculating an endothelial function coefficient (EFC), and if the derived EFC is less than 1.0, chronic prostatitis is diagnosed.

EFFECT: using the declared technique enables simplifying the early diagnosis of chronic prostatitis by assessing the functional state of the regional microvascular endothelium.

2 ex

 

The invention relates to medicine, namely to urology, and can be used for the diagnosis of chronic prostatitis.

The success of the practice of medicine, specifically urology and andrology, currently determined by the possibility of early detection of violations of the functional state of the microvascular endothelium. Studies of foreign and domestic authors conclusively proven that vasoregulatory endothelial dysfunction detected even before its organic damage and in the absence of clinical and instrumental signs of violation of a flow in the pelvis (C. A. Burmistrov. The prevalence of erectile dysfunction in patients with diabetes mellitus type 2. // The dissertation on competition of a scientific degree of candidate of medical Sciences. - 2004. - 23 S., I. C. Chaliapin. The value of hemorheological and hemostatic disorders in the pathogenesis of chronic prostatitis. // The dissertation on competition of a scientific degree of candidate of medical Sciences. - 2001. - 24 S.).

Thus, early detection of microvascular pathology at the stage of functional disorders is an important biomedical problem.

In recent years, new data on the role of violations of the functional activity of the endothelium in the pathogenesis of many urological diseases. Thus, the author of Cask is he A. L. (2009) using modern microrheological methods of research have studied the structural and functional characteristics of the skin microcirculation of the penis in humans and found its regulatory performance. For the first time the author has studied disorders of the skin microcirculation in the penis in chronic abacterial prostatitis and showed that underlying pathophysiological mechanism disorders are suppressed vasumati and structural deformation microvascular venous Department that leads to the progression of venous congestion in the tissues of the penis.

It is obvious that the most feasible way to prevent the formation of irreversible vascular complications is the timely identification of functional disorders of the vascular endothelium.

The interest of the vascular endothelium in the pathogenesis of vascular disease was considered from the time Virchow, however, more accurate scientific understanding of the true role of the vascular wall in the pathogenesis of many disease processes, and can check the functional state of the vascular endothelium has emerged only recently, largely as a result of the use of modern molecular biology, laboratory and instrumental methods.

Existing methods for detection of endothelial dysfunction (ED) is Astelit on two areas: the detection of circulating markers of ED in serum and assessment of endothelium-dependent vasodilation.

The author of Krainichenko S. C. (2009) identified key indicators of basal blood flow and the amplitude-frequency spectrum in the system microvasculature of the prostate by laser Doppler flowmetry in healthy men without diseases of the genitourinary system. Found that for healthy men characteristic sredneimportnye pulse vibrations, slow oscillations normal amplitude preserving vasomotor activity. Chronic abacterial prostatitis, complicated sexual disorders, the author establishes the presence of intravascular violations of microcirculatory, which is manifested by the decrease of peak linear, diastolic, and mean velocities in the Central and peripheral zones of the prostate gland, and decreased basal tone, increased shunting and reduced performance index of microcirculation. The author concludes that all this testifies to the intravascular disorders of microcirculation.

Common drawbacks of these methods for detection of endothelial dysfunction are:

- the need for invasive procedures (blood);

- the inability to perform in routine clinical laboratories;

- the complexity of technical performance;

- the need to use expensive reaction is ivov;

- the complexity of the interpretation of the obtained results.

For example, elevated levels of von Willebrand factor may indicate increased activation of endothelial cells (i.e., about changing the functions of the vascular endothelium), and may be due to endothelial damage. The most reliable sign of ED is the reduction of NO synthesis, to measure the content of which is difficult due to the instability and short life span of the molecule. The NO production was estimated by the content in plasma and in urine end products of NO metabolism (nitrite, nitrate). The concentration of these substances are extremely small and have a high dependence on other sources of nitrite and nitrate, why the clinical application of this method is limited.

In addition to the laboratory techniques described methods of estimation of the functional state of the vascular endothelium, based on the study of endothelium-dependent vasodilation in vivo.

Thus, the known method consists in the estimation of change of the diameter of the main artery or the blood flow through it or in small resistance vessels of the body part in response to pharmacological or mechanical stimulation of the endothelium (G. I. Martsinkevich et al. Comparing the results of the functional tests used in the noninvasive assessment of endothelial function // Therapeutic archive. - 2002. No. 4. - S. 16-18. Of the pharmacological stimuli typically use the endothelium-dependent vasodilator - acetylcholine, less serotonin. Increasing the speed of the current in the main artery is achieved with the introduction of endothelium-independent vasodilators in the distal direction or mechanical stimulus by temporary occlusion of a vessel by measuring the response of large vessel on reactive hyperemia (A. A. Popov et al. Evaluation of vasomotor function of vascular endothelial dysfunction in young patients with arterial hypertension // Russian family doctor. - 2006. No. 1. - S. 31-32). Incentives studied during direct angiographic (mostly coronary) rendering.

However, this method has significant drawbacks:

- the need for appropriate equipment for diagnostic procedures and conditions for conducting research;

- the complexity of technical performance;

- the need for special facilities and trained personnel;

- invasiveness and high cost koronaroangiografiulad research;

- the inability to perform koronaroangiografii in the dynamics (for monitoring changes of endothelial function under the influence of the treatment).

So become more and more widespread non-invasive methods. In 1992, D. Celermajer et al. developed a non-invasive Ultrazvuk the Oh Doppler method for determining the functional state of the endothelium of peripheral vessels, uses mechanical stimulation of blood flow synthesis and excretion endothelium relaxing factor produced. Increase blood flow was achieved by temporary occlusion of the brachial artery pneumatic cuff pressure above systolic 50 mm RT.article then suddenly her "deflation". In the works of D. Celermajer et al. the location of the artery was performed above the place of occlusion (D. S Celermajer. Noninvasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis // Lancet. - 1992. - Vol.340, No. 8828. - P. 1111-1115). At the same time in the Department of new methods of research and diagnostics Russian cardiology research industrial complex Ministry of health in conducting this research uses the classic breakout with reactive hyperemia, in which the artery scan below the occlusion. According to D. A. Staikova and B. A. Sidorenko, this methodology allows to identify the endothelial dysfunction in patients with arterial hypertension and ischemic heart disease (B. A. Sidorenko, D. A. Staikov. Endothelial dysfunction in the pathogenesis of atherosclerosis and its complications / // Kremlin medicine. Clinical journal. - 1999. No. 2. - S. 7-12).

Currently have the opportunity to assess the state of the vascular endothelial function using laser Doppler flowmetry (LDF), based on optical sensing of tissues helium-neon laser (Century. And. To the units et al. The method of laser Doppler flowmetry: a Manual for physicians. - M., 2000. - 35 C.). The advantage of this method is its non invasiveness, the possibility of long-term monitoring, the absence of contraindications. To assess vasomotor endothelial function are ionophoretically samples with the introduction of endothelium-independent and endothelium-dependent vasodilators (I.e. Konyayeva et al. Conditions ionophoretically samples with acetylcholine and nitroprusside for assessment of microvascular endothelium of human skin // Bulletin of new medical technologies. - 2004. - T. XI, No. 1-2. - S. 68-70).

The closest to our proposed method is the diagnosis of endothelial dysfunction in patients with bronchial asthma using laser Doppler flowmetry with a calculation of the coefficient of endothelial function (EFC) by the ratio of the allowance of capillary blood flow in the sample with acetylcholine to the provision of capillary blood flow in the sample with sodium nitroprusside (I. C. Nurzhanova et al. Pat. 2436091 OF THE RUSSIAN FEDERATION, IPC G01N 33/483. The method of assessing the functional state of the microvascular endothelium in patients with bronchial asthma / (RF, GOU VPO ASMA University). No. 2010124218/15 Announced. 11.06.10; Publ. 10.12.11. Bull. "Of the invention. Utility models", No. 34).

The disadvantages of this method are:

- described practical application only in pain who's bronchial asthma;

- evaluation of the functional state of the vascular bed as a whole (i.e., detection of disorders systemic) without detail and without taking into account regional blood flow, in particular blood flow in the prostate gland.

The invention is aimed at facilitating the early diagnosis of chronic prostatitis by evaluating the functional status of regional microvascular endothelium.

This technical result is achieved by measuring the performance reserve capillary blood flow during iontophoresis of acetylcholine and sodium nitroprusside on the skin of the abdomen above the fold at the point of projection of the prostate, calculate the ratio of endothelial function (EFC) and the EFC value below 1.0 diagnosed with chronic prostatitis.

For the clinical assessment of vasomotor endothelial function during LDF testing we conducted pharmacological tests using specific agents causing endothelium-independent (ENVD) and endothelium-dependent (EDVD) vasodilatation. Namely, using local iontophoresis we carried out sequential introduction of two solutions: the endothelium-independent vasodilator - sodium nitroprusside (5%) and the endothelium-dependent vasodilator, acetylcholine was used (5%).

The study was conducted at the point of projection of prestate Inoi glands on the skin of the abdomen above the fold. The choice of this region is due to the fact that it reflects the blood flow in the prostate gland.

During each ionophoretically samples in addition to temporal parameters, we estimated RCM-reserve capillary blood flow (degree of growth of the microcirculation in response to iontophoresis of the drug).

As is known, the estimate of the degree of endothelial dysfunction based on a comparison of vascular response in response to the introduction of endothelium-dependent and endothelium-independent vasodilators. The response to sodium nitroprusside (NN) reflects the relaxation of blood vessels, caused by the direct action of nitric oxide on smooth muscles. The acetylcholine (ach) is used to demonstrate vasodilatation, mediated by endothelium that allows you to use this test to assess the functional state of the endothelium (specifically the ability to synthesize the factors relaxation). Endothelial dysfunction is manifested in the reduction of the severity of the reaction to acetylcholine: the maximum value of the index of microcirculation (PM) in this case is less than in the case of response to sodium nitroprusside, and in proportion to the degree of dysfunction.

To detect dysfunction of regional microvascular endothelium by undertaking a comparative analysis of endothelium-dependent and endothelium-independent vasodilation, according to the recommendations of the Institute. Organovo et al., we calculated the ratio of endothelial function - the EFC as the ratio of the RCM AH / ALAC NN (%) [degree of growth of the microcirculation during the iontophoresis of acetylcholine to the degree of increase in GR, during iontophoresis of sodium nitroprusside].

According to the LDF testing at the point of projection of the prostate gland on the skin of the abdomen above the fold of the patients in the control group (i.e., men without prostate) is the EFC was 1,08±0,06% EFC Is greater than 1.0 indicates the absence of regional dysfunction of the endothelium: the response of the vascular bed (in the form of growth of microcirculation) on endothelium-dependent stimulation prevail over those of the endothelium-independent stimulation. In the control group, the presence of prostatitis were excluded according to common urological procedures: complaints, and rectal ultrasound of the prostate, smear discharge from the urethra, microscopy of prostate secretion.

Men suffering from prostatitis, LDF-testing the skin of the abdomen above the fold at the point of projection of the prostate was diagnosed dysfunction of regional microvascular endothelium, namely, the value of the EFC is less than 1.0. While 36% of patients did not show any specific complaints, the diagnosis of "Chronic prostatitis" was exhibited for the first time according to further examination almarine is passed urological techniques.

Another interesting fact that with the proven diagnosis of "Chronic prostatitis" and the value of the EFC at the point of projection of the prostate is less than 1.0, the ratio, calculated at the point characterizing the systemic circulation (on the skin of the left forearm in the midline at 4 cm above the base of the styloid processes of the ulnar and radial bones), in 62% of patients exceeds 1.0.

Thus was established the relationship: dysfunction of regional microvascular endothelium (i.e., the EFC at the point of projection of the prostate less than 1.0) - the presence of chronic prostatitis.

The study was carried out calculation of diagnostic sensitivity (DF) method by the formula:

QH=a/(a+C), where a is the number of matches on the presence of the disease (true positive results); - the number of false-negative results (β-error).

Also calculated diagnostic specificity (DS) method by the formula:

DS=d/(d+b), where d is the coincidence conclusions about the absence of disease (true negative); b - false-positive result (α-error).

Was calculated diagnostic efficiency (DE) of the method according to the formula TE=(DF+DS)/2 is the average between DF and DS.

Was calculated also:

- predictive value of a positive result (PZPR) according to the formula: PCP=a/(a+b) is the probability of the presence of the disease with a positive test result.

- prognostic valuable the th negative result (PCOR) according to the formula: PCOR=C/(C+d) - the probability of the absence of the disease with a negative test result.

Thus, the diagnostic sensitivity of the test was 96%, and its diagnostic specificity of 95%. The overall diagnostic efficacy of the test was also relatively high with 95.5%, and predictive value of a positive result is 93%.

All this allows to recommend this method for the diagnosis of chronic prostatitis. A positive result makes it likely to assume the examined patient of chronic prostatitis.

We offer to evaluate the functional status of regional microvascular endothelium by LDF-test on the skin of the abdomen above the fold at the point of projection of the prostate with the calculation of the EFC expands the Arsenal of diagnostic tools and facilitates early detection of chronic prostatitis.

This method was successfully tested on the clinical basis of the Department of urology and Nephrology state budgetary educational institution of higher professional education "Astrakhan state medical Academy" of the Ministry of health of Russia - in the urology Department and clinic of the establishment of health care JSC Alexander-Mariinsky regional clinical hospital, also in terms of outpatient departments the establishment of health care JSC "Regional dermatovenerologic dispensary, Astrakhan in 2011-2012

Surveyed 226 men Astrakhan region, of whom 97 Dunn is m LDF-test was diagnosed dysfunction of regional microvascular endothelium (EFC< 1) and was suspected chronic prostatitis, later confirmed by clinical and ultrasound examination by 90 people. Among 129 patients with normal regional microvascular endothelial chronic prostatitis was diagnosed in only 4 people, and 125 patients this diagnosis was excluded, which allowed to form from among the control group. The age of examined patients was - 34 [22; 43]. The median duration of disease was 12 [2; 34] years. Persons in the control group were comparable in age with the examined patients with chronic prostatitis.

Below are the results of testing.

In the group of men without prostate, recognized control were conducted by conventional methods of diagnosis of prostatitis, and advanced LDF was carried out testing of regional dermal microvessels in the coupe with ionophoretically samples. The value of the EFC on the skin of the abdomen above the fold in men with prostatitis, made up 1.08±0,06%

Example 1

Patient K., 37 years (medical outpatient map No. 2124), appealed to the Regional dermatovenerologic dispensary 08.08.2011. Complained of pain in the perineum, inguinal region, erection and orgasm, decreased libido, frequent urge for urination, pollakiuria, sluggish stream of urine. Marked is l also fatigue, weakness, irritability.

Ill for about 7 years. The beginning of the disease was burning in the urethra, which appeared after hypothermia. Was diagnosed with Chronic bacterial prostatitis. About this diagnosis are often treated on an outpatient basis, receiving in each case, antibacterial drugs, massage of the prostate, physiotherapy.

Objectively. Build giperstenichesky. From internal organs pathology it is not revealed. Adult male of a male. External genitals are developed correctly.

Rectal examination. The prostate gland is enlarged, swollen, smooth, painful, smooth midlevel furrow.

Ultrasound examination. Kidney is normal in size, contours smooth. Cup-pelvis system is not changed, pathological processes it is not revealed. The prostate gland is visualized in size of 4.8×5,5×5 cm, with fuzzy and jagged contours. After voiding residual urine volume 30 ml. Marked diffuse decrease in echogenicity of the prostate gland, dilatation paraproctitis venous plexus, cystic inclusions.

After provocation gonococcal vaccine (under the scheme) held smear discharge from the urethra, as well as the microscopy of prostate secretion. Detected leukocytes 11-15-22 in the field of view. Les is siminovich beans a little. Protein content in prostate secretion were: LF-157 mg/l, FSC-3315 mg/l, DOG-2221 mg/L. Wasserman negative. Analysis of HIV - negative result.

Microscopic examination of smears from prostate secretion in the color of Gram-detected gram-positive cocci: diplococci, streptococci, cocci in clusters; on the enzymatic activity were determined following types of staphylococci: S. aureus, S. epidermidis, Str. agalactiae, Str. faecalis., E. coli.

In General, the analysis of blood (09.08.11): erythrocytes - 4,63×1012/l, hemoglobin - 129 g/l, leucocytes - 5,9×109/l; eosinophils - 2%, stab neutrophils - 2%, segmented neutrophils - 63%, lymphocytes 25%, monocytes - 4%; ESR - 23 mm/hour.

Urinalysis (09.08.11) no pathological features.

ECG (08.08.11): sinus tachycardia, electrical axis of the heart is not rejected.

Exhibited clinical diagnosis of Chronic bacterial prostatitis in the acute phase.

According to LDF-test ionophoretically samples when applying the ratio of endothelial function (EFC) on the skin of the abdomen above the fold at the point of projection of the prostate, the patient was 0,79 (ALAC AH=169,6%, ALAC, NN=214,7%). Additionally was calculated EFC at LCF testing at the point characterizing the systemic microcirculation (on the skin of the left forearm in the midline at 4 cm above the base of the styloid processes of the elbow and the beam is howling bones), amounting to 1.1. Thus, was diagnosed dysfunction of regional microvascular endothelium at the point of projection of the prostate on the skin of the abdomen above the fold.

Example # 2

Patient K., 35 years (medical outpatient map No. 1139), turned to the clinic and was admitted to the urology Department of the establishment of health care JSC Alexander-Mariinsky regional clinical hospital" , Astrakhan 15.04.2012. Complained of pain in the perineum, scrotum, inguinal region, erection, decreased libido. Also noted fatigue, weakness, irritability, poor sleep.

Sick for about 9 years. Repeatedly outpatients receiving in each case, the massage of the prostate, physiotherapy, physiotherapy and anti-inflammatory drugs. The effect of therapy was short, so repeatedly observed recurrences of the disease. From the anamnesis of life: the patient leads a sedentary lifestyle, sex single in the course of the year.

Objectively. Build giperstenichesky. From internal organs pathology it is not revealed. Adult male of a male. External genitals are developed correctly.

Rectal examination. The prostate gland is enlarged, swollen, painful, smooth midlevel furrow.

Ultrasound is the surveys. Kidney is normal in size, contours smooth. Cup-pelvis system is not changed, pathological processes it is not revealed. The prostate gland is visualized in size of 6.8×6,5×7 cm, with fuzzy and jagged contours. After voiding residual urine volume 20 ml.

Microscopic examination of smears from prostate secretion in the color of Gram-detected isolated gram-positive cocci: diplococci, cocci.

In General, the analysis of blood (16.04.12): erythrocytes - 4,63×1012/l, hemoglobin - 129 g/l, leucocytes - 4,9×109/l; eosinophils - 6%, stab neutrophils - 2%, segmented neutrophils - 63%, lymphocytes 25%, monocytes - 4%; ESR - 15 mm/hour.

Urinalysis (16.04.12) no pathological features.

ECG (15.04.12): sinus rhythm, electrical axis of the heart is not rejected.

After provocation gonococcal vaccine (under the scheme) held smear discharge from the urethra, as well as the microscopy of prostate secretion. Detected leukocytes 1-2-4 in the field of view. Lacitignola grains are rare. The Wasserman negative. Analysis of HIV - negative result.

Based on the above data was put the final diagnosis: Chronic congestive prostatitis in the acute phase. The patient was treated by standard baseline therapy.

According to LDF-test ionophoretically samples the ri receiving the coefficient of endothelial function (EFC) on the skin of the abdomen above the fold at the point of projection of the prostate in patients was 0.69 (ALAC AH=118,1%, ALAC NN=171%). Additionally was calculated EFC at LCF testing at the point characterizing the systemic microcirculation (on the skin of the left forearm in the midline at 4 cm above the base of the styloid processes of the ulnar and radial bones), amounting to 0,9.

The specified value of the EFC at the point of projection of the prostate confirms the presence of dysfunction of regional microvascular endothelium in patients with chronic prostatitis.

The proposed way of detecting dysfunction of regional microvascular endothelium is achieved simplification of early diagnosis of chronic prostatitis. To evaluate the functional status of the microvascular endothelium in the level of the EFC allows to reliably determine the presence of endothelial dysfunction. The method of laser Doppler flowmetry meets the requirements of modern, non-invasive, has no contraindications, simple in execution and can be used for dynamic monitoring. When production samples are not used expensive or toxic reagents.

In addition, the important point is the fact that the results of laser Doppler test can be mapped to common in urological practice methods.

The method of early diagnosis of chronic prostatitis by identifying dysfunction regional microvascular endothelium by holding ionophoretic the definition of the sample during laser Doppler flowmetry, characterized in that the measuring indicators of reserve capillary blood flow during iontophoresis of acetylcholine and sodium nitroprusside on the skin of the abdomen above the fold at the point of projection of the prostate, calculate the ratio of endothelial function (EFC) and the EFC value below 1.0 diagnosed with chronic prostatitis.

 

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