[Morphological aspects of atherosclerosis lesion: past and present]. / Aspetti morfologici della lesione ateromasica tra passato e presente.

Atherosclerosis is an inflammatory process disease that involves the artery wall and that is characterized by the progressive accumulation of lipids. The term arteriosclerosis has been created by Lobstein in 1833. Subsequently, during the 19th century, the contribution of Rokitansky and Virchow was important to elucidate the pathogenesis of arteriosclerosis and the morphologic aspects of the plaque. In the beginning of the 20th century, Aschoff was a leading proponent who regarded the morphologically different intimal lipid deposits of children and adults as early and late stages of one disease and he called them atherosis and atherosclerosis, respectively. The first classification of atherosclerosis was made by the World Health Organization (WHO) in 1958 and it consisted of the following sequence: fatty streak, atheroma, fibrous plaque and complicated lesions. In 1990s, thanks to much more sensitive techniques, the American Heart Association (AHA) proposed a new morphological classification based on eight lesion types designated by Roman numerals which indicate the usual sequence of lesion progression. Finally, Virmani et al. (2000) described a classification with the add of a specific plaque type, not recognized by the AHA classification, called "thin fibrous cap atheroma" which is more likely to rupture. The atherosclerotic process is characterized by typical ultrastructural changes that mainly involve the endothelial and smooth muscle cells. The morphological alterations of the endothelium are associated with dysfunctions leading to a proinflammatory and prothrombotic phenotype. This process seems to be due to turbulent blood flow and low fluid shear stress that normally occurs in particular regions of the vascular tree. Inflammation has a key role in the pathogenesis of atherosclerosis and it is supported by numerous factors such as modified LDL, hypertension, diabetes mellitus, free radicals and, in particular, by infectious agents such as Chlamydia pneumoniae.

Efficacy, safety and tolerability of combined low-dose simvastatin-fenofibrate treatment in primary mixed hyperlipidaemia.

OBJECTIVE: In order to assess the long-term (12 months) efficacy and safety of fenofibrate administered with simvastatin in the treatment of primary mixed hyperlipidaemia, we conducted a study that compared increasing dosages of these drugs in subgroups of men and women belonging to a clinical sample of out-patients. DESIGN: This was an open study carried out in patients with primary mixed hyperlipidaemia (lipoprotein phenotype IIb) who needed a combined therapeutic approach because of their poor response to a single-drug regimen with an HMG-CoA reductase inhibitor (simvastatin). Thus, a fibrate (fenofibrate) was added to the therapy. The study lasted 12 months. PATIENTS: Forty-five patients (mean age: 58.9 +/- 11.3 years) with primary mixed hyperlipidaemia who showed a poor response to the single-drug hypolipidaemic treatment were enrolled. Their average plasma triglyceride level was consistently above 300 mg/dL and low-density lipoprotein cholesterol (LDL-C) was over 160 mg/dL after at least 6 months of a single hypolipidaemic drug (simvastatin) regimen plus antiatherogenic dietary treatment. INTERVENTIONS: Five patients received simvastatin 10mg once daily in addition to fenofibrate 200mg; 26 patients received simvastatin 20mg once daily plus fenofibrate 200mg; 11 patients received simvastatin 20mg once daily plus fenofibrate 300mg; and three patients received simvastatin 30mg once daily plus fenofibrate 200mg. The patients were allocated to treatment groups on the basis of their relative response to the therapy. Those making up the progressively higher agent/dose groups were the individuals at higher cardiovascular risk according to the total cholesterol and non-high-density lipoprotein cholesterol (HDL-C) values. RESULTS: The double-drug regimen given for 12 months to four different groups, according to the different combined dosages of simvastatin and fenofibrate, resulted in a reduction in total cholesterol of 18% (p

Immunoadsorption apheresis (Selesorb) in the treatment of chronic hepatitis C virus-related type 2 mixed cryoglobulinemia.

In this short-term open label clinical pilot study, conducted at one center, the immune complex dextran sulphate adsorber (Selesorb) was used to treat four female patients aged 59-69 with HCV-related cryoglobulinaemia, vasculitis and/or neuropathy. The primary trial objective was to assess the clinical efficacy of the immunoadsorber. The secondary objective of the trial was to determine the safety of the adsorber and to investigate the adsorption capacity, measured as the adsorption of cryoglobulin-related immune complexes and the resulting influence on plasma components of the immune system. The patients have been submitted to treatment with the immunoadsorber, at approximately 1-3 days intervals, completing six sessions. The follow-up was one month. In the patients treated with Selesorb, we observed a statistically significant decrease in plasma of all classes of immunoglobulins (IgA: 5-28%; IgG: 14-44%; IgM: 8-38%). In two patients with peripheral neuropathy secondary to cryoglobulinemia, the symptomatology was improved. In a third patient the neurological involvement was substantially unchanged, and the same unsuccessful outcome was observed for Sjögren syndrome is concerned. Nevertheless, the two patients with lower extremity vasculitis showed an appreciable improvement. We failed to observe significant side effects directly related to the use of this immunoadsorbent.

Prevalence and clinical features of skin diseases in chronic HCV infection. A prospective study in 96 patients.

BACKGROUND: Between extra-hepatic manifestations of hepatitis C virus (HCV) infection particular interest is focused on some dermatological diseases such as: leukocytoclastic vasculitis, oral lichen planus, pruritus-urticaria, psoriasis, etc. The aim of this study was to determine the prevalence of some dermatoses in our population of patients with HCV infection and describe the more characteristics clinical pictures. METHODS: Ninety-six patients (36 men and 60 women) aged from 35 to 74 years with HCV documented by 3rd generation ELISA and RIBA tests were prospectively examined for 3 years to determine the prevalence of some skin disorders, reported as associated with HCV infection. All patients were also studied for presence and quantification of HCV-RNA by polymerase chain reaction and genotyping when possible. Eighty-one underwent a liver biopsy. Routine laboratory tests and some immunological investigations (ANA, AMA, SMA, LKM, ANCA, ICC, crioglobulins) were performed using standard procedures and indirect immunofluorescence, nephelometric, RIA methods. RESULTS: Twelve of 96 patients (12.5%) presented skin disorders in progress of chronic virus C hepatitis: 5 cases of leukocytoclastic vasculitis (LCV) by mixed cryoglobulinemia, 1 case of pruritus, 2 cases of oral lichen planus (OLP), 2 cases of alopecia areata, 1 case of urticaria, 1 case of psoriasis. CONCLUSIONS: Our findings show a calculated prevalence of clinical dermatoses in HCV infected patients around 12.5%. These findings confirm however the importance of liver examination in presence of skin diseases not related to other pathogenetic mechanisms.

Effects of mud-pack treatment on plasma cytokine and soluble adhesion molecule levels in healthy volunteers.

BACKGROUND: The suggested hypothesis of a direct anti-inflammatory property of mud-pack treatment has led us to speculate that its action on the cytokine network might counteract the heat-stress-related effects on platelet and endothelial cell function often reported following hot-spring baths. Therefore, the present study was designed to investigate the effects of a cycle of 12 daily mud-pack treatments on bio-humoral markers of inflammation, as well as on markers of in vivo platelet and/or endothelial cell activation, in plasma samples obtained from healthy volunteers. METHODS: Blood samples were obtained before (T(0)), at the end of the first treatment (T(1)) and after a cycle of 12 daily mud-pack treatments (T(2)). Plasma cytokines (TNF-alpha IL-1beta, and IL-6) and adhesion molecules (sP-selectin, sE-selectin and sVCAM) levels, as well as hematocrit and complete and differential blood cell counts were determined at every time point. RESULTS: Plasma sP-selectin levels were not modified during treatment, as were not sE-selectin or sVCAM. Similarly, IL-1beta and TNF-alpha levels were unchanged through a 12 daily mud-pack treatment. Conversely, plasma IL-6 levels were significantly lowered at the end of a 20-min 47 degrees C mud-pack treatment (p<0.01). CONCLUSIONS: The lack of effects on in vivo platelet and/or endothelial cell activation suggests that hot mud-pack treatment might be used as a relatively safe procedure in patients with atherothrombotic disorders.

Increased soluble P-selectin levels in hepatitis C virus-related chronic hepatitis: correlation with viral load.

BACKGROUND: Platelet functional abnormalities are commonly found in patients with chronic liver disease; however, their nature and clinical significance are still a matter of discussion. METHODS: Soluble P-selectin (sP-selectin, a marker of in vivo platelet activation) levels, lipid pattern, and clotting activity were investigated in 39 patients with histologically confirmed chronic C hepatitis. RESULTS: Serum factor VIIc (P < 0.01), total cholesterol (P < 0.005), high density lipoprotein (P < 0.001), and low density lipoprotein (P<0.05) levels were lower in patients compared with healthy subjects, whereas triglyceride and fibrinogen levels were similar in both groups. Platelet counts were lower in chronic hepatitis patients compared with controls (P < 0.0001), and approximately 20% of patients had thrombocytopenia (platelet counts < 110 x 10(3)/microL). Platelet-associated immunoglobulin G (PAIgG) was present in 30.8% of patients. Plasma sP-selectin levels were higher in hepatitis C patients compared with controls (P < 0.0001), and significant differences were observed with respect to the Scheuer score (P < 0.01). The analysis of the distribution of plasma sP-selectin showed the presence of higher levels in patients with low platelet counts compared with patients with normal platelet counts and controls (P < 0.0001); moreover, sP-selectin levels did not correlate with the presence of PAIgG. On the other hand, sP-selectin levels directly correlated with serum hepatitis C virus (HCV)-RNA (P < 0.05) and inversely correlated with platelet count, blood lipids, and factor VIIc. CONCLUSIONS: The results obtained in this study support the hypothesis that HCV infection might be directly responsible for a condition of in vivo platelet activation in patients with chronic C hepatitis.

Hashimoto's disease during interferon-alpha therapy in a patient with pre-treatment negative anti-thyroid autoantibodies and with the specific genetic susceptibility to the thyroid disease.

OBJECTIVES: The authors described a case of Hashimoto's disease during interferon-alpha (IFN-alpha) treatment for chronic viral C hepatitis in a patient with the specific genetic susceptibility associated with the thyroid disease. RESULTS: A 60-year-old woman with chronic active viral C hepatitis (HCV genotype = 3a) started IFN-alpha therapy in November '96. Before treatment thyroid function tests were normal and anti-thyroid (anti-thyroglobulin and anti-thyroid peroxidase) Abs were negative. During IFN therapy, serum aminotransferases fell within the normal range and viremia (serum HCV-RNA) became negative after one year. After 20 months, the patient presented clinical features of primary hypothyroidism. Anti-thyroid Abs were found positive. Hormonal, ultrasonographic, radioiodine scanning and fine needle aspiration findings were consistent with the diagnosis of Hashimoto's thyroiditis. The tissutal typing of the patient showed the presence of Human Leukocyte Antigen (HLA) DRB1*11 gene (corresponding to DR5 antigen). IFN-alpha therapy was suspended and a treatment with l-T4 started. Chronic viral infection relapsed after the suspension of the IFN-alpha therapy. CONCLUSIONS: This case report showed that the clinical appearance of Hashimoto's disease after IFN-alpha therapy for chronic C hepatitis in our patient was associated with a specific genetic predisposition (DR5) for this pathology. Further studies are necessary to evaluate whether the study of HLA antigens may be a very useful tool to detect the patients with a predisposition to develop autoimmune thyroiditis, in order to make a early diagnosis of thyroid disorders during the IFN-alpha treatment.

DALI low-density lipoprotein apheresis in homozygous and heterozygous familial hypercholesterolemic patients using low-dose citrate anticoagulation.

The purpose of this study was to clarify the efficacy and safety of direct adsorption of lipoprotein low-density lipoprotein apheresis (DALI LDL apheresis) in patients with severe homozygous and heterozygous familial hypercholesterolemia who showed minor adverse effects during treatment with the usual DALI configuration (AC 1:20) through the use of a new system with low-dose citrate anticoagulation (AC 1:40) developed in order to minimize citrate-related adverse effects. Serum total cholesterol and LDL-cholesterol (LDL-C) showed a decrease of 57% to 61%, and 62% to 67%, respectively, in the 2 patients. Serum lipoprotein (a) (Lp[a]) was higher in the homozygous patient (Patient 1: MD) and within the normal range in the heterozygous patient (Patient 2: ES). In the former, Lp(a) was reduced by 52%. Serum high-density lipoprotein cholesterol (HDL-C) showed a statistically insignificant acute reduction: 15% to 19%. The observed reduction is mainly related to the well-known effect of hemodilution. The cardiovascular risk (total cholesterol/HDL-C) was reduced in both patients (46% to 54%) as expected. Serum triglycerides were reduced by 33% to 49%. The mean blood volume processed per session was 7,600 ml. Fifteen treatments for each patient have successfully been completed without the appearance of any clinically significant subjective and objective symptoms related to treatment with the new system.

Persistent hepatitis G virus (HGV) infection in chronic hemodialysis patients and non-B, non-C chronic hepatitis.

Three groups of patients have been studied longitudinally for 24 months to analyze the role of hepatitis G virus (HGV) in hepatic disease. Group 1 consisted of 50 patients with non-B, non-C chronic hepatitis, group 2 consisted of 44 hemodialyzed patients, and group 3 consisted of 50 healthy blood donors. The presence of HGV RNA was detected by both reverse transcription-polymerase chain reaction (RT-PCR) and capillary zone electrophoresis (CZE). At the baseline visit the HGV RNA was detected in seven out of 50 patients with non-B, non-C chronic hepatitis, in two out of 44 hemodialyzed patients, and in three out of 50 healthy blood donors. HGV-infected hemodialyzed patients and HGV viremic blood donors had serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels within normal limits. During the follow-up period the two HGV-positive hemodialyzed patients and the three infected healthy blood donors did not show any sign of hepatic disease. There were no significant differences between HGV-positive patients in the three groups at the beginning and at the end of the follow-up. No considerable deterioration of general health conditions was observed on the basis of clinical and laboratory data in HGV-positive chronic hepatitis patients. Finally, HGV does not seem to be responsible for hepatic disease.

Evaluation of myocardial involvement in systemic lupus erythematosus by signal-averaged electrocardiography and echocardiography.

OBJECTIVE: The myocardial involvement in systemic lupus erythematosus (SLE) patients, frequently found at autopsy or at endomyocardial biopsy, is less easily detected clinically. The myocardial lesions are characterized by an increase in interstitial connective tissue and myocardial scarring. Signal-averaged electrocardiography (ECG-SA) is currently used for recording ventricular late potentials which are the expression of slowed and disorganized conduction through zones of myocardial scarring. M-mode, two-dimensional and Doppler echocardiography (ECHO) represent relatively simple methods for evaluating the left ventricular function. This study was aimed to evaluate by ECG-SA and ECHO the myocardial involvement of SLE patients without clinical and electrocardiographic evidence of cardiac disease. METHODS AND RESULTS: Twenty outpatients with SLE were studied and compared with 18 normal controls. Late potentials were recorded in 20% of SLE patients and in 5.5% of controls. A significant increase of abnormal left ventricular diastolic filling was found in the SLE patients, characterized by reduced E/A (p = 0.018), a lower deceleration rate of early diastolic flow velocity (p = 0.048) and a prolonged isovolumic relaxation time (p = 0.001). SLE patients had diastolic dysfunction of various degrees although the depolarization abnormalities detected by ECG-SA were found only in a few subjects. CONCLUSIONS: The depolarization abnormalities, revealed by ECG-SA, probably reflect a longer extent of myocardial fibrosis in SLE patients with ECHO evidence of abnormal left ventricular filling. The simultaneous occurrence of ECHO and ECG-SA alterations could be a marker of subclinical myocardial involvement.

Diastolic function abnormalities in rheumatoid arthritis. Evaluation By echo Doppler transmitral flow and pulmonary venous flow: relation with duration of disease.

OBJECTIVE: The aim of this study was to evaluate left ventricular filling in patients with rheumatoid arthritis (RA), analysing transmitral flow and pulmonary venous flow, with special regard to age and disease duration. METHODS: 32 patients affected by RA according to ARA criteria were selected, without evidence of cardiac disease, and compared with matched control subjects. All patients and the control group were submitted to M-mode, two dimensional, Doppler and colour Doppler (continuous and pulsed wave) echocardiography. The following diastolic parameters were evaluated: transmitralic flow (E/A ratio), pulmonary venous flow (S/D ratio), a-Pw, IVRT and DT. RESULTS: In RA patients left ventricular filling abnormalities were found characterised by a reduced E/A ratio (mean (SD) 1.16 (0.31) v. controls 1.37 (0.32); p = 0.02) and an increased S/D ratio (1.43 (0.40) v. controls 1.22 (0.29); p = 0.017). In the group of patients a relation was found between E/A ratio and disease duration (r= 0.40, p = 0.01 Spearman rank correlation). CONCLUSIONS: At present, it is concluded that RA patients, in absence of clinical evidence of heart disease, show diastolic dysfunction characterised by impaired E/A and S/D ratio. The relation between transmitral flow alteration and disease duration suggests a sub-clinical myocardial involvement.

Natural history of cardiac involvement in myotonic dystrophy (Steinert's disease): a 13-year follow-up study.

Myotonic dystrophy (MD) is associated with a wide spectrum of cardiac abnormalities, but only a few longitudinal studies have investigated the natural course of heart disease in MD. To assess whether neuromuscular involvement significantly predicts cardiac disorders in MD, 83 patients with various grades of disease severity were enrolled in a 13-year follow-up study (mean, 60.6 +/- 37.8 months) that included periodic physical and instrumental cardiac examinations (standard and Holter electrocardiography, echocardiography). During follow-up, muscular disease worsened clinically in 9 patients (11%) whose baseline severity grade changed accordingly; only 3 of them demonstrated parallel worsening of cardiac disturbance, however, compared with a large number of patients who showed additional cardiac abnormalities. These included further worsening of pre-existing pathologic features (19/83) and the appearance de novo of serious arrhythmias and/or conduction defects (23/83). Pacemaker implantation was necessary in 11 of 83 patients (13.2%) who had symptomatic bradyarrhythmias, bifascicular block, and P-R prolongation with a His-to-ventricle interval exceeding 55 ms, as documented by electrophysiologic study. Eight (9.6%) patients died: 2 from noncardiac and 1 from unknown causes, 1 from heart failure, and 4 from sudden death closely related to documented ventricular tachycardia. The incidence and seriousness of arrhythmic and conduction disturbances correlated with the severity of the muscular involvement. Nevertheless, cardiac and muscular disease did not show a linear progression. Cardiac involvement generally worsened more rapidly than did skeletal muscle disease.

[Harmonic echocardiography of tissue in the diagnosis of aneurysms of the interatrial septum. Study of 550 consecutive ambulatory patients]. / Ecocardiografia in armonica tissutale nella diagnosi dell'aneurisma del setto interatriale. Studio su 550 pazienti ambulatoriali consecutivi.

BACKGROUND: It has been assessed whether echocardiographic harmonic imaging improves the detection of atrial septal aneurysm (ASA) compared with fundamental imaging. METHODS: We studied consecutively, using fundamental and harmonic imaging, 550 patients (with or without cardiopathy; 300 females and 250 males) in an outpatients' department (age 23-76 years, mean 50 years). We used a multifrequency transthoracic probe transmitting at 2 Mhz and receiving at 4 Mhz. The ASA was classified in three types according to Hanley et al. Type 1A, protruding into the right atrium without oscillation; Type 1B protruding into the right atrium with oscillation, and Type 2, protruding into the left atrium with oscillation. We compared atrial septal aneurysm definition in fundamental and harmonic mode, and assessed the interobserver agreement in the diagnosis of ASA. The echocardiographic images were recorded on magneto-optical disk and analysed by two blinded observer. With Pearson test we assessed the interobserver concordance in the ASA study; so we quantified the advantage of harmonic imaging as reduction of the inter-observer variability. RESULTS: Among 550 consecutive subjects in the echocardiographic study population, ASA was diagnosed in 8 (1.45%) and 15 (2.72%) patients using fundamental and harmonic methods respectively. A significant reduction of the inter-observer variability in the ASA diagnosis was found with harmonic imaging (harmonic imaging: r = 0.96; fundamental imaging: r = 0.70). CONCLUSIONS: The harmonic methods drastically improves echocardiographic imaging of ASA, it may be used routinely and reduces the need for more invasive technique such as transesophageal echocardiography.

Peripheral neuropathy without cryoglobulinemia in patients with hepatitis C virus infection.

BACKGROUND: An association between essential mixed cryoglobulinemia and hepatitis C virus infection has been documented by many reports. Some clinical manifestations such as purpura, arthralgia, vascular lesions and peripheral neuropathies are also connected with the presence of detectable cryoglobulins. The association between HCV infection, the presence of mixed cryoglobulinemia and peripheral neuropathy is well documented. The aim of this study was to define the possible presence of peripheral neuropathy in HCV patients without detectable cryoglobulins and the possible association with the different genotypes. METHODS: Twenty patients (11 females, 9 males) with chronic HCV hepatitis and without detectable cryoglobulins were submitted to neurological and electrophysiological studies to detect a possible peripheral neurological involvement. In all patients the HCV infection was assumed by the presence of antibodies to HCV with ELISA assay and then confirmed with recombinant immunoblot assay. HCV genotyping was obtained by INNO LIPA in 15 out of 20 patients. In 4 patients a sural nerve biopsy was possible. RESULTS: Genotype 1b was present in 80% of patients, while 1a in 13.3% and 4 in 6.6%. Thirteen patients had positive neurological anamnesis (65%), while neurological examination was positive in 40% of the cases. Electromyographic study was positive in 50% of subjects. The sural nerve biopsies agreed with axonal degeneration in amyelinated fibres. CONCLUSIONS: Our results suggest a possible peripheral neurological system involvement in patients with HCV infection without cryoglobulins.

Adrenomedullin assay and its clinical significance.

Adrenomedullin (Am) is a recently discovered peptide, first purified from pheochromocytoma specimens, with a chemical structure similar to that of CGRP and amylin. Adrenomedullin is present in numerous human body tissues and its powerful vasodilatatory activity is thought to play an essential role in cardiovascular and renal homeostasis.

CGRP and ET-1 plasma levels in normal subjects.

OBJECTIVE: Calcitonin gene-related peptide (CGRP) is a 37 amino acid peptide displaying about 50% homology with amylin which is secreted from the pancreatic islets of Langerhans. The main form, the beta-CGRP, is produced by the enteric nervous system and perivascular nerves of the vasa-vasorum. It represents one of the most powerful vasodilator yet discovered but its role is not yet completely clarified. High levels of this peptide have been shown in patients affected with thyroid medullary carcinoma, phaemocromocytoma and lung carcinoma. Recently circulating levels of CGRP have been found in normal subjects. Endothelin-1 (ET-1), a potent vasoconstrictor peptide, isolated from porcine endothelial cells, is an important regulator of the vascular tone acting in physiological antagonism with atrial natriuretic hormone (ANH). With this study we intended to investigate the presence of any correlation between CGRP and ET-1 in normal subjects. PATIENTS: For the study we considered 20 normal subjects (11 males and 9 females) aged 23 to 50. MEASURES: Plasma levels of CGRP and ET-1 were measured by radioimmunological Kit. RESULTS: A positive and significant correlation between calcitonin gene-related peptide and endothelin-1 was found. CONCLUSIONS: Our results confirms that CGRP and ET-1 have opposing actions on vessels and that they can act together in haemodinamic regulation.

[Descriptive analysis of measles epidemic in Palermo, from September 1996 to June 1997. Failure of a vaccination campaign]. / Analisi descrittiva di un'epidemia di morbillo a Palermo dal settembre 1996 al giugno 1997. Insuccesso di una campagna vaccinale.

BACKGROUND: The authors report 1642 measles cases observed from September 1996 to June 1997 at the "G. Di Cristina" Children's Hospital. 34% of patients were hospitalized at the Division of Infectious Diseases. METHODS: The records of children admitted with measles to emergency area were retrospectively collected. The medical records (anamnestic, clinical and laboratory findings) of hospitalized children were obtained from schedules which since 1993 were performed to perspectively collect the exanthematous diseases. International criteria for the definition of measles case were applied. The variables considered were: background, demographic data, seasonal distribution, clinical presentation, complications and days of hospital stay. RESULTS: The results of this research showed that the outbreak involved predominantly infants. The complications accounted for 72% of measles hospitalized cases. Four cases of encephalitis were observed. A total of 1692 days of hospital stay was reported. CONCLUSIONS: These data show the failure in measles control adopted by the Sicilian Region and confirm the difficulties to achieve high percentage of parents participation to the infant recommended vaccination program.

[Drug-induced hepatobiliary damage]. / Danni epato-biliari da farmaci.

Setting out from the high prevalence of iatrogenic toxic effects on the liver and biliary system, the authors examine the pathophysiological mechanisms underlying and suggest an updated classification. The clinical models of the action of main drugs responsible are discussed.