[Primary vasculitis of internal carotid and vertebral arteries: a role of cytokines, transforming growth factor beta 1 and basic fibroblast growth factor]. / Pervichnyi vaskulit vnutrennei sonnoi i pozvonochnoi arterii: rol' tsitokinov, transformiruyushchego faktora rosta ß1 i osnovnogo faktora rosta fibroblastov.

OBJECTIVE: To study clinical/laboratory signs of primary vasculitis (PV) of the internal carotid artery (ICA) and vertebral artery (VA). MATERIAL AND METHODS: We examined 31 patients (23 men, 74%, mean age - 36.2±5.7 years) with ICA/VA PV verified by vessel wall contrast enhancement on black blood MRI (T1-weighted fat and blood suppressed sequences with- and without contrast injection) at the Research Center of Neurology (Moscow) from January 2012 to September 2019. Systemic vasculitis was excluded in all cases. Interleukins (IL-1ß, IL-2, IL-6, IL-17), TNF-a, transforming growth factor beta 1 (TGF-ß1) and basic fibroblast growth factor (bFGF) were analyzed by ELISA in 25 patients. Control group consisted of 21 healthy volunteers (12 men, 57%; mean age - 35.3±10.2 years). RESULTS: Clinical manifestations of ICA/VA PV included: ischemic stroke (IS) (94%), which combined with transient ischemic attacks (TIA) in 35%; isolated TIA (3%); Tolosa-Hunt syndrome (3%). Recurrent strokes were observed in 41% of patients on average in 5.3±2.1 months. Carotid artery was involved in 77%, VA - in 16%, both arteries - in 7%. Concomitant involvement of ICA/VA branches was in 19% patients. The level of arterial damage was follows: Intracranial part of arteries involved in 55%, intra-extracranial - in 35%, extracranial - in 10%. Bilateral involvement was found in 26%. Headache/neck pain in the acute IS period was observed in 21%. IS severity (NIHSS) was as follows: moderate (59%), mild (34%), moderately severe (7%). Disability after 3 months according to mRankin scale was as follows: mild (72%) moderate (21%), none (7%). The laboratory study revealed an increased levels of IL-6 (8.19±3.89 pg/ml vs 4.7±1.48 in control, p=0.000), IL-2 (5.64±1.82 pg/ml vs 4.30±1.65, p=0.013), TNF-a (36.9±33.66 pg/ml vs 12.68±5.93, p=0.000), TGF ß1 (2.77±1.60 pg/ml vs 1.63±0.64, p=0.006) and bFGF (417.67±132.68 pg/ml vs 335.71±105.08, p=0.018). The levels of IL-1ß and IL-17 did not differ significantly from the control. CONCLUSION: ICA/VA PV has a number of clinical peculiarities. Proinflammatory cytokines produced by Th17 and Th1 CD4+ lymphocytes as well as bFGF and TGR-ß1 play a role in its pathogenesis. Normal levels of IL-1ß and IL-17 suggest that they are not significant in the development of isolated inflammation in ICA/PA, in contrast to systemic inflammation in giant cell arteritis, in which, according to literature data, their level increases. Isolated ICA/PA inflammation seems to be caused by transaxonal (trigeminal nerve, upper-cervical roots, autonomic nerves) spread of pathogens that initiate immune inflammation in the ICA/PA wall.

[Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids]. / Khronicheskoe limfotsitarnoe vospalenie s perivaskulyarnym nakopleniem kontrastnogo veshchestva v mostu golovnogo mozga, otvechayushchee na lechenie steroidami.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disease of the central nervous system, mainly affecting the brain stem, cerebellum and spinal cord. The clinical picture includes gradually developing ataxia, double vision, dysarthria, pyramidal and cognitive impairment. Morphological examination reveals T-cell perivascular lymphocytic infiltration with CD4 lymphocytes predominance over CD8 lymphocytes. The cause of the disease is unknown. The article describes two patients (a 18-year-old woman and a 40-year-old man) with typical clinical and MRI manifestations of CLIPPERS, which was confirmed by brain biopsy in the female patient. The duration of follow-up was 3 and 7 years, respectively. Both patients survived an infection 2-3 weeks before the onset of disease that allows one to discuss its role in CLIPPERS pathogenesis. Both patients had a clear clinical and MRI responsiveness to steroids. In the female patient, steroids were replaced by intramuscular administration of the TNF-α blocker adalimumab. During 1,5 years of its use, there were no clinical relapses and pathological brain changes on MRI.

Neovascularization of Carotid Atherosclerotic Plaque and Quantitative Methods of Its Dynamic Assessment in Vivo.

The study demonstrates significant variety of neovascularization degree and vessel diameter in the carotid atherosclerotic plaque. It is suggested that the increase in the number of vessels with a diameter <20 µ can be indicative of increased atherosclerosis activity, while the increase in the number of vessels with a diameter ≥40 µ indicates "reparative potential" of plaques. Duplex contrast-enhanced ultrasound scanning allows characterization of the localization and number of vessels with a diameter of ≥30 µ in the plaque, while even slight elevation of plasma concentration of basic fibroblast growth factor attests, first of all, to increased content of small vessels <30 µ in the plaque. The level of fibroblast growth factor >1.5 pg/ml is a reliable marker of increased number of both small and large vessels in the plaque.

[Indicators of homeostasis, inflammation and homocysteine in ischemic stroke in the young age]. / Pokazateli gemostaza, vospaleniia i gomotsistein pri ishemicheskom insul'te v molodom vozraste.

AIM: To determine indicators of homeostasis, inflammation and homocysteine in the young-aged patients with ischemic stroke (IS) of different genesis in the subacute and chronic stages. MATERIAL AND METHODS: Out of 218 patients with IS (mean age 34.7±8.7 years), 55 had stroke due to dissection of the inner carotid or the spinal artery, 28 due to cardioembolia, 38 due to antiphospholipid syndrome (APS), 16 due to cerebral arteritis; 85 patients were classified as having cryptogenic stroke, including 23 with noncerebral thrombosis (coagulopathy of unknown etiology) and 62 with no thrombosis. The control group included 28 healthy people matched for age and sex. RESULTS: There were 1) an increase in von Willebrand factor and coagulation factor VIII as well as a decrease in plasminogen and an increase in plasmin-inhibitor in IS caused by thrombosis (APS, cardioembolia, coagulopathy of unknown etiology); 2) alterations in erythrocyte aggregation and deformity in cryptogenic stroke; 3) mild or moderate hyperhomocysteinemia, with the exception of patients with APS and arteritis. Linear regression analysis confirmed these relationships. Discriminant analysis identified the clusters of parameters characteristic of APS (an increase in (aPTT), plasminogen, blood sedimentation rate, C-reactive protein) and cardioembolia (decreased protein C and increased hematocrit). CONCLUSION: The laboratory markers associated with cerebral thrombosis can be used for identification of a prothrombotic state as a cause of IS in the young age. Moderate hyperhomocysteinemia is a risk factor but not a cause of IS. The increase of inflammatory markers in APS suggests a role of infection in its development.

Estimation of Functional Activity of Ionized Calcium for Complement System Reactivity Assessment.

We proposed a new indicator for evaluation of functional activity of Ca(2+) in human blood serum based on lysis of sheep erythrocytes with 10% human blood serum in the presence of 0.55 mM ethylene glycol tetraacetic acid at 37°C for 10 min. After incubation, the degree of sheep erythrocytes lysis inhibition is estimated: inhibition of complement hemolytic activity <30% is considered as high functional Са(2+) activity, inhibition by 31-70% corresponds to normal activity, and >71% indicates low activity. The comparative studies of complement activating function of heterophilic antibodies, complement system reactivity in the presence of 0.29 M NaCl, and functional activity of ionized Ca(2+) make possible estimation of the individual's immune status.

[In vitro lipid-lowering and fibrinolytic effects of regulatory leucine-containing glyprolines in human blood].

The lipid-lowering, fibrinolytic, and anticoagulant effects of leucine-containing glyprolines, Pro-Gly-Pro-Leu and Leu-Pro-Gly-Pro, were studied in vitro in the blood of patients with disorders of lipid metabolism. The lipid-lowering impact of glyprolines and their ability to reduce the polymerization and to increase the depolymerization of fibrin in human blood were found. Possible mechanisms of lipolytic action of peptides by means of modulation of the lipid-dependent phospholipase A2 were proposed.

[Estimation of atherogenic immune complexes containing modified lipoproteins in complement fixation tests].

A method for determining atherogenicity of the immune complexes containing multiple modified low-density lipoprotein (mmLDL) in complement fixation test has been found. In the proposed method, the precipitate immune complexes containing mmLDL (IC mmLDL) was prepared from human serum by treating it with buffer (8.3% of th PEG 3350 and 3.3% PVP 12600 th in the ratio 1: 1.2) for 10 min at 23 °C. IC mmLDL aggregates were separated by centrifugation at 3100g for 10 min at 23 °C. The precipitate IC mmLDL was dissolved in buffer without PEG and PVP, cholesterol content and the degree of binding of guinea pig complement were measured. Atherogenicity of the IC mmLDL was registered as the ratio of the degree of complement binding to cholesterol in the the immune complexes.

[Mitochondrial arteriopathy as a cause of spontaneous dissection of cerebral arteries].

The vascular wall weakness caused by dysplastic alterations predisposes to the spontaneous dissection of cerebral arteries. The authors hypothesized for the first time that dysplasia might be the result of mitochondrial cytopathy. To test this hypothesis, the muscle biopsy was conducted in 3 male patients, aged 30-38 years, with the spontaneous dissection of the internal carotid (2) and posterior cerebral (1) arteries. Clinically dissections manifested by ischemic stroke (2) or the peripheral paresis of the hypoglossal nerve (1). The morphological study of fresh frozen sections of muscle by modified Gomori trichrome method revealed ragged-red fibers The histochemical study showed the severe decrease of the stain on succinate dehydrogenase and cytochrome-c-oxidase as well as the focal intensive staining of peripheral regions of muscle fibers. The complex of found changes is characteristic for a mitochondrial pathology. No patients had A3243G tRNA gene mutation, the most common mutation for MELAS. The serum lactate level was elevated only in one patient. We suggest that the mitochondrial disorder occurs not only in muscle, but also in cerebral artery wall--mitochondrial arteriopathy, which predisposes to spontaneous cerebral artery dissection.

[Chronic cerebrovascular diseases, metabolic syndrome and the status of hemorrheological and hemostatic systems].

AIM: to study an association between metabolic syndrome and endothelial dysfunction as a regulator of hemorrheological and hemostatic processes in patients with chronic forms of cerebral circulatory insufficiency. SUBJECTS AND METHODS: Forty-six patients with chronic cerebrovascular diseases (CCVD) were examined; of them 23 patients were diagnosed as having metabolic syndrome (MS). Clinical manifestations and major hemorrheological and hemostatic parameters, such as platelet and erythrocyte aggregation, fibrinogen, hematocrit, von Willebrand factor, antithrombin III, intercellular adhesion molecules (IAM), etc., were estimated. Endothelial dysfunction was studied from the data of cuff test (CT). RESULTS: MS promotes a higher degree of clinical symptomatology in patients with CCVD and more significant impairments in the hemorrheological and hemostatic systems. CT has shown that all the patients have an inadequate endothelial reaction - the antiaggregatory, fibrinolytic, and anticoagulant activities of the endothelium are lowered. There was endothelium-dependent hyperproduction of IAM. CONCLUSION: The found changes suggest that MS has a considerable impact on the formation of a significant procoagulant state of the hemorrheological and hemostatic systems in patients with CCVD.

[Hemorheology and hemostasis in patients suffering from ischemic cerebral stroke and metabolic syndrome].

A high level of mortality and disability makes study of various aspects of ischemic cerebral stroke (ICS) an extremely important problem. Presently, combination of various cardiovascular risk factors significantly increases the probability of such life-threatening conditions as ICS. Such risk factors as arterial hypertension, dyslipoproteinemia, excessive body weight, glucose intolerance or diabetes are often combined, which led to a suggestion to consider them together as one symptom complex, metabolic syndrome (MS). It is evident that MS affects the functioning of different organs and systems, including the systems of hemorheology and hemostasis. These are changes in hemorheological and hemostatic parameters that play a leading (in some cases decisive) role in the development of ICS. The present study found that the presence of MS in ICS patients hindered improvement in hemorheological and hemostatic parameters in the course of the disease. This was manifested by the absence of positive changes in thrombocyte aggregation, as well as fibrinogen level elevation in patients with MS in the course of treatment. Elevated blood level of D-dimers within the whole acute period in most MS patients also reflected more active thrombus formation. The development of ICS is very unfavorable to the condition of vascular wall athrombogenic activity in all patients. At the same time, worsening in all the chains of endothelial wall athrombogenic ability was more prominent in MS patients. Significant influence of MS on the forming of prothrombotic condition, which determines unfavorable clinical course of ICS, was demonstrated.