Effect of (R)-2-Amino-6-(1R,2S)-1,2-Dihydroxypropyl)-5,6,7,8-Tetrahydropterin-4(3H)-One and Its Structural Analogues on the Temperature Stability of Tryptophan Hydroxylase 2 with the P447R Mutation.

The enzyme tryptophan hydroxylase 2 (TPH2) catalyzes the hydroxylation of L-tryptophan to L-5-hydroxytryptophan (5-HTP), the first and the key step in 5-HT synthesis in the mammalian brain. Mutations in the human Tph2 gene reducing enzyme activity increase the risk of psychopathology. Pharmacological chaperones are small molecules that can specifically bind to mutant protein molecules, restore their disturbed 3D structure to the native state, and increase their stability and functional activity. The chaperone activity of (R)-2-amino-6-(1R,2S)-1,2-dihydroxypropyl)-5,6,7,8-tetrahydropterin-4(3H)-one (BH4) is expressed by increasing the in vitro thermal stability of mutant tyrosine hydroxylase and phenylalanine hydroxylase molecules which are similar to TPH2 in their structure and characteristics. The P447R substitution in the mouse TPH2 molecule results in a 2-fold decrease in enzyme activity in their brains. We studied the effect of this mutation on the TPH2 thermal stability, as well as on the ability of BH4 and its 8 structural analogues to increase the thermal stability of the mutant TPH2 from midbrain extracts of BALB/C mice. Temperature stability was studied by the decrease in enzyme activity during its heating for 2 min at increasing temperatures and was evaluated by the T50 value that is the temperature at which the enzyme activity decreased by half. For the mutant TPH2, the T50 value was decreased compared to the wild type enzyme. BH4 and its closest structural analogue, 6-methyl-5,6,7,8-tetrahydropterin, increased the T50 value, i.e., exhibited chaperone activity. Other close BH4 analogs, 6,7-dimethyl-5,6,7,8-tetrahydropterin and folic acid, were not effective. It can be assumed that BH4 can be effective in the treatment of mental disorders caused by mutations in the Tph2 gene.

[Effectiveness and safety of brolucizumab in the treatment of neovascular age-related macular degeneration]. / Effektivnost' i bezopasnost' brolutsizumaba v lechenii neovaskulyarnoi vozrastnoi makulyarnoi degeneratsii.

PURPOSE: This study analyzes the effectiveness and safety of brolucizumab in the treatment of neovascular age-related macular degeneration (nAMD) in real clinical practice. MATERIAL AND METHODS: The study included patients with nAMD who received brolucizumab treatment and evaluated the changes in best-corrected visual acuity (BCVA), central retinal thickness (CRT), macular volume, as well as the number of injections and adverse events. RESULT: The group of previously treated patients included 28 subjects (28 eyes) that were switched to brolucizumab with a loading phase. By 12 months, BCVA changed from 0.43±0.29 to 0.33±0.27 LogMAR (p=0.11), CRT decreased from 281.5±58.2 to 239.9±45.6 µm (p=0.02). The group of previously untreated patients included 29 subjects (29 eyes). By 12 months, BCVA changed from 0.47±0.32 to 0.40±0.30 LogMAR (p=0.09), CRT decreased from 333.2±77.3 to 226.2±49.6 µm (p<0.001). Patients received 6.3±0.7 injections. In this group, baseline choroidal thickness showed a statistically significant correlation with final visual acuity (r=0.54; p<0.05) and CRT (r= -0.5; p<0.05). The group of previously treated patients switched without a loading phase included 18 patients (18 eyes). By 6 months, BCVA changed from 0.42±0.2 to 0.37±0.26 LogMAR (p=0.42). CRT remained stable at 285.6±56.9 µm (p=0.97). No adverse events related to intraocular inflammation were reported during the course of 385 injections. CONCLUSION: Brolucizumab therapy helps achieve significant anatomical and functional improvements in real clinical practice both in patients switched from previous treatments and in treatment-naïve patients. Greater baseline choroidal thickness may be associated with better anatomical and functional outcomes with brolucizumab treatment.

[Rehabilitation of patients after spinal surgery: effectiveness of nonthermal techniques of peloidotherapy]. / Reabilitatsiya patsientov posle operatsii na pozvonochnike: effektivnost' neteplovykh metodik peloidoterapii.

The problem of patients' rehabilitation after spinal surgery remains relevant. The use of therapeutic physical factors, both preformed and natural, including pelotherapy, is very important. The application of the latter requires to develop new techniques in this pathology, one of which is low temperature exposure. OBJECTIVE: To study the possibility and to assess the effectiveness of resource-saving nonthermal pelotherapy techniques in patients' rehabilitation, who underwent surgeries for intervertebral discs' herniation. MATERIAL AND METHODS: The number of patients equal 88, including 39 males and 49 females, after lumbar microdiscectomy, was examined in this study. The patients were divided into 3 groups. Control group (28 patients) received a basic rehabilitation complex (therapeutic gymnastics, massage, low-frequency magnetotherapy); the 1st study group (30 patients) - basic complex and procedures of thin layer applications with peat muds preparation (Tomed-applikat) at 20-24 °C; the 2nd study group (30 patients) - basic complex and procedures of fluctuoresis of 2% solution of peat mud Tomed-aqua preparation. RESULTS: There was a significant reduction of pain syndrome, recovery of sensitivity and motor activity, decrease of Oswestry index, characterizing the degree of vital activity disturbance, in patients of the study group compared to the control group after treatment. CONCLUSION: The inclusion of nonthermal resource-saving techniques of pelotherapy in rehabilitation complex of patients who underwent spinal surgery is effective and pathogenetically justified.

[Prospects for the use of ozone therapy and low-intensity laser therapy in the treatment of atrophic pharyngitis]. / Perspektivy primeneniya ozonoterapii i nizkointensivnoi lazeroterapii pri lechenii atroficheskogo faringita.

Chronic pharyngitis (CP) is one of the most common diseases of the oropharynx. The number of referrals from patients with CP reaches 70% of the total number of referrals to an otorhinolaryngologist. The development of this disease is facilitated by the neuro-reflex factor and a violation of trophic and metabolic processes. It should be noted that of all forms of CP, the greatest impact on the quality of life is noted precisely in atrophic pharyngitis (AP), due to the presence of pronounced subjective sensations from the oropharynx. Many of the modern methods of treatment do not provide a lasting effect due only to the application, superficial local effect on the altered mucous membrane of the posterior pharyngeal wall, without taking into account the changes caused by a violation of trophic processes in the tissue. A promising direction in the treatment of atrophic pharyngitis is the use of a combined technique - ozone therapy and low-intensity laser therapy. The article presents the results of the application of fine-drip irrigation of the mucous membrane of the posterior pharyngeal wall with Ozonide oil in combination with low-intensity laser radiation on the projection of vessels supplying blood to the middle parts of the oropharynx. OBJECTIVE: Improving the effectiveness of treatment of patients with atrophic pharyngitis through the use of ozone therapy and low-intensity laser therapy. MATERIAL AND METHODS: A single-center experimental controlled randomized open-label study of 90 patients with AP aged 18 and over was conducted. All patients were randomly divided into three groups depending on the treatment performed: group I - traditional treatment method (rinsing the oropharynx with antiseptic solutions, the use of tablets for resorption), group II - treatment with ozone therapy (fine drip irrigation of the mucous membrane of the posterior pharyngeal wall with Ozonide oil), group III - treatment with ozone therapy and laser therapy. During the examination of patients, anamnesis collection, examination of ENT organs, cytological and microbiological examination of the mucous membrane of the posterior pharyngeal wall, contact endoscopy of the mucous membrane of the posterior pharyngeal wall were performed. 5-point visual analogue scales (VAS) were used to assess complaints and pharyngoscopic signs. RESULTS: Our results showed a statistically significant improvement in the quality of life of patients with AP (p=0.012), an improvement in the pharyngoscopic picture (p=0.003). The results obtained by us indicate an improvement in microcirculation under the influence of ozone therapy and low-intensity laser radiation. The technique using ozone therapy and low-intensity laser therapy is characterized by a bactericidal and fungicidal effect. There is a decrease in the total contamination of the posterior wall of the oropharynx with pathogenic and saprophytic microflora (there is a decrease in the contamination of the posterior wall of the pharynx with saprophytic and pathogenic microflora (p≤0.05), the differences are statistically significant). The technique using ozone therapy and low-intensity laser therapy has a pronounced anti-inflammatory effect, which was expressed in a decrease in the severity of dyskeratosis and hyperkeratosis. Thus, the use of ozone therapy in combination with laser therapy opens up new prospects for pathogenetically sound and effective treatment of AP.

[On the Draft Regulations on Districts of Sanitary (Mountain Sanitary) Protection of Natural Medicinal Resources: Comments, Suggestions]. / O proekte Polozheniya ob okrugakh sanitarnoi (gorno-sanitarnoi) okhrany prirodnykh lechebnykh resursov: zamechaniya, predlozheniya.

The purpose of the article is to attract the attention of specialists in the resort business in the document being developed - the Decree of the Government of the Russian Federation «On Approval of the Regulations on the Districts of Sanitary (Mining and Sanitary) Protection of Natural Medicinal Resources¼, the draft of which is proposed for discussion. The article presents all the comments on the discussed draft Regulation and proposals for making appropriate changes with their reasoned justification. The proposals put forward to change the wording of specific paragraphs of the Regulation are aimed at protecting and preserving the wealth of our country - natural healing factors that form the basis of sanatorium treatment. The proposals made to edit the paragraphs of the Regulation will undoubtedly guarantee the preservation of Russia's natural healing resources in order to use them for the prevention, treatment and rehabilitation of the population of our country and the successful development of the resort industry.

[Effects of thymus tissue transplantation on the survival of mice exposed to a lethal X-Ray dose.]

During the radiation exposure of the body, processes similar to those characteristic of the natural aging of mammals occur. This phenomenon is most often referred to as accelerated aging. By transplanting the thymus tissue, it is possible to achieve a normalization of food and water consumption, a stabilization of weight gain, and a significant increase in the life expectancy of experimental animals, even after their lethal irradiation.

[Alterations in the Level of mRNA of TPH1, TPH2 Genes, Tryptophan Hydroxylase Activity and Serotonin Metabolism in Mouse Brain Five Days after Lipopolysaccharide Administration].

Tryptophan hydroxylases 1 and 2 (TPH1 and TPH2) play a key role in the synthesis of serotonin (5-HT), a hormone and neurotransmitter, in the peripheral organs and brain, respectively. The main aim of this study was to clarify the distribution of mRNA of the Tph1 and Tph2 genes in brain structures under normal conditions and after inflammation. The experiments were carried out on young (4 weeks old) male C57BL/6 mice. The animals were divided into three groups: intact, control, injected ip with saline, and injected ip with 2 mg/kg of bacterial lipopolysaccharide (LPS). Markers of inflammation, spleen mass and thymus mass were assayed 5 days after the saline or LPS administration. In the frontal cortex, hippocampus, striatum, hypothalamus, and midbrain the concentrations of 5-HT and its main metabolite, 5-hydroxyindole acetic acid (5-HIAA), and TPH activity were assayed using HPLC, while Tph1 and Tph2 mRNA were quantified using quantitative real-time RT-PCR. A dramatic increase of spleen mass and decrease of thymus mass 5 days after LPS administration was shown. A significant increase of 5-HT and 5-HIAA levels in the midbrain as well as decrease of 5-HIAA concentration and TPH activity in hypothalamus in mice treated with LPS and saline compared with intact animals was revealed. The highest concentration of Tph2 gene mRNA was observed in the midbrain in 5-HT neuron bodies, while this gene mRNA level was lower in 5-HT endings (cortex, hippocampus, striatum, and hypothalamus). Trace amounts of Tph1 mRNA was found in all studied brain structures in mice of the three groups. Thus, Tph1 gene expression in the mouse brain is too low to significantly affect 5-HT synthesis in normal conditions and during inflammation.

Comparison of Fluorometric and Chromatographic Methods of In Vitro Assay of Tryptophan Hydroxylase 2, the Key Enzyme of Serotonin Synthesis in the Brain.

We present rapid and sensitive assay of tryptophan hydroxylase 2 enzyme activity based on the fluorescence of the complex of 5-hydroxytryptophan (5-HTP) with o-phthalic aldehyde. This method was compared with the standard method based on chromatographic isolation of 5-HTP followed by its quantification using an electrochemical detector. High sensitivity of the developed fluorometric method and similarity of the results obtained by fluorometric and chromatographic methods were demonstrated. The use of this rapid, cheap, and effective fluorometric method can simplify and facilitate measurements of tryptophan hydroxylase 2 activity and can make this assay available for a wide range of neurochemical and pharmacological laboratories.

Long-Term Continuous Computer Registration and Analysis of Motor Activity of a Group of Zebrafish Danio rerio.

A new algorithm for long-term continuous computer recording and analysis of motor activity of a group of zebrafish in the home tank has been developed. The movements of a group of Danio rerio during the entire light period and for several days are recorded at a frequency of 1 frame/sec in the form of short (15 min) files. Then these files are analyzed by the unique DanioStudo software, which, using a threshold algorithm and appropriate masks, calculates for each frame the sum of pixels associated with fish (the sum of fish silhouettes), and for two consecutive frames, the sum of altered pixels (the sum of altered fish silhouettes). The following indexes are calculated: the rate of sum of silhouettes alteration as the ratio of the sum of altered silhouettes to the sum of silhouettes (1) and the time spent in the selected area of the home tank as the ratio of the sum of silhouettes in this area to the sum of silhouettes in the entire tank (2). The mean rate of silhouette alteration correlates to the length of the path travelled by the fish and, therefore, serves as a correct measure of the motor activity of a group of fish. Using these algorithms, completely new data were obtained: it was shown that the motor activity of fish remains constant throughout the entire light period, but depends on the size of the home tank. The proposed approach, together with the DanioStudio software, can be effective in studying the dynamics of changes in the behavior of fish under long-term exposure to short daylight, drugs and toxic substances.

Effect of Prolonged Exposure to Short Daylight and a Tryptophan Hydroxylase Inhibitor on the Behavior and Brain Serotonin System in Danio rerio.

We studied the effect of reduced tryptophan hydroxylase (TPH) activity and short daylight exposure on the behavior and the 5-HT system of the brain in D. rerio. Male and female D. rerio were exposed for 30 days to standard (12:12 h light:dark) and short (4:20 h light:dark) photoperiods in the presence or absence of TPH inhibitor (p-chlorophenylalanine, pCPA, 5 mg/liter). On day 31, the fish behavior in the "novel tank diving" test, their sex and body weight were determined, and the levels of pCPA, 5-HT, and its metabolite 5-HIAA were measured by HPLC; the levels of the key genes encoding metabolism enzymes (Tph1a, Tph1b, Tph2, and Mao) and receptors of 5-HT (Htr1aa, Htr2aa) were assessed by real-time PCR with reverse transcription. The short daylight exposure caused masculinization of females, reduced body weight, and motor activity in the "novel tank diving" test, but did not affect the 5-HT system of the brain. Long-term pCPA treatment had no effect on sex and body weight, significantly reduced the 5-HIAA level, but increased Tph1a and Tph2 gene expression in the brain. No effects of the interaction of short daylight and pCPA exposure on the sex, body weight, behavior, and 5-HT system of the brain were found. Thus, a moderate decrease in TPH activity cannot potentiate the negative effects of short daylight exposure on the sex, body weight, behavior, and 5-HT system of D. rerio.

[A case of arrhythmogenic right ventricular cardiomyo-pathy associated with myocardial inflammation].

Recent years have been marked by a number of published reports that have shown a high frequency of signs of myocardial inflammation in patients with confirmed arrhythmogenic right ventricular cardiomyopathy (ARVC). This article presents a clinical case of typical phenotypic manifestations of ARVC associated with morphometric signs of subacute myocarditis. A 66-year-old man presented to the emergency department with signs of arrhythmogenic shock caused by ventricular tachycardia. Examination detected electrocardiographic signs of (ARVC), visualized signs of right ventricular dilatation, increased trabeculation, and wall fibrosis. Endomyocardial biopsy of the right ventricular wall showed degenerative alterations of cardiomyocytes with perivascular lymphocytic infiltration and areas of granulation tissue. New facts that evidence inflammatory alterations of the myocardium will still require specifying and reconsidering positions of expert consensuses on diagnostics and treatment of ARVC.

[Ocular complications in intense pulsed light therapy (case study)]. / Glaznye oslozhneniya intensivnoi fototerapii (klinicheskoe nablyudenie).

A 24-year-old female patient with photophobia, discoria, redness and dryness in her right eye after intense pulsed light (IPL) therapy applied for posttraumatic subcutaneous hemorrhage received a comprehensive ophthalmic examination including optical coherence tomography (OCT) and OCT angiography of the anterior eye segment. Her best corrected visual acuity was 20/20 in both eyes. Medically induced mydriasis revealed discoria with paresis of pupil dilatator in the left eye (pupil size 4.2 mm and 6.6 mm in the right and left eye, respectively). Anterior segment OCT showed anterior chamber cytosis and increased iris vascularity. The patient was prescribed topical 1.0% tropicamide 2 times per day and 1.0% dexamethasone 4 times per day for two weeks. Examination performed after 3 months showed no restoration of pupil dilatator function in the left eye. The case demonstrates potential ocular complications of IPL therapy, which may include iris burn with iritis and persistent pupil dilatator dysfunction.

[Analysis of intraocular lens displacement relative to the haptic plane by ultrasound biomicroscopy data]. / Analiz smeshchenii opticheskoi chasti intraokulyarnoi linzy otnositel'no ploskosti gapticheskikh elementov po dannym ul'trazvukovoi biomikroskopii.

PURPOSE: This study analyzed cases with postoperative displacement of intraocular lens (IOL) relative to the haptic plane using ultrasound biomicroscopy (UBM). MATERIAL AND METHODS: The study analyzed biometry data of 231 patients (277 eyes) aged 72.39±7.77 years, among them 43.25% were males. IOL position and refraction were analyzed at 1, 3 and 6 months after standard phacoemulsification. RESULTS AND DISCUSSION: UBM was performed to analyze the position of the IOL. Stabilization of lens position was observed by the 3rd month of observation. Among the cases with displacement of the optical part relative to the haptic plane, the forward shift was determined in 24.85%, backward - in 16.67% of cases. Eyes with opposite IOL displacements differed significantly in lens diameter, ciliary sulcus diameter and the power of implanted IOL. IOL shift towards the retina produced significant hyperopic refractive error. A discriminant function was compiled using preoperative biometry data comprising the model for predicting backward IOL displacement with high probability. However, we failed to obtain a qualitative model for forward IOL displacements. CONCLUSION: Calculation error in modern formulas could occur because of IOL displacement, including the shift of the optical part relative to the haptic plane in postoperative period. Analysis of biometry data allows calculating IOL displacement towards the retina with a high probability, which could help avoid hyperopic refraction error postoperatively.

[The first application of intraoperative mri for analysis of cerebral perfusion in surgical brain revascularization]. / Pervoe primenenie intraoperatsionnoi MRT dlya issledovaniya tserebral'noi perfuzii pri khirurgicheskoi revaskulyarizatsii golovnogo mozga.

BACKGROUND: Effectiveness of surgical revascularization in patients with chronic cerebral ischemia depends on restoration of circulation in the damaged artery. Modern methods do not take into account dynamic changes in cerebral perfusion after extra-intracranial microvascular anastomosis (EICMA) and do not allow timely localizing the areas of persistent perfusion deficit. We propose a new method for determining the tactics of surgical cerebral revascularization based on intraoperative MRI (iMRI) perfusion data. This method provides the earliest information on intraoperative brain reperfusion. OBJECTIVE: To develop the principles of dynamic assessment of cerebral blood flow using intraoperative ASL perfusion during surgical revascularization in patients with chronic cerebral ischemia and to determine the indications for additional anastomoses. MATERIAL AND METHODS: Surgical revascularization with intraoperative MRI perfusion was performed in 27 patients between March 2022 and April 2023. There were 10 patients with post-thrombotic occlusion of internal carotid artery, 4 patients with occlusion of middle cerebral artery and 13 patients with moyamoya disease. All patients underwent MRI before surgery. After imposing the first EICMA, all patients underwent ASL perfusion for analysis of residual hypoperfusion zones, signs of local hyperperfusion and indications or contraindications for additional revascularization with the second donor branch. RESULTS: In all cases, iMRI made it possible to determine the tactics of brain revascularization using one or two EICMA. In 17 cases, ASL perfusion confirmed the targeted improvement of cerebral blood flow (CBF) in the entire hemisphere or middle cerebral artery basin. Only one EICMA was imposed in these cases. In 10 cases, a single anastomosis was insufficient for restoration of blood flow. These patients underwent additional revascularization with the second donor branch (35.7%). In all cases, we achieved significant quantitative improvement in CBF and volume of brain tissue with restored blood flow (ASPECTS scale). A single EICMA was followed by increase in CBF and areas of restored blood flow by almost 2 times (22.7±9.6 ml/100 g/min and 4.7±1.8 scores (ASPECTS) before surgery vs. 39.4±16.4 ml/100 g/min and 4.7±1.8 scores after EICMA). In the double EICMA group, these parameters increased by almost 3 times (18±3.1 ml/100 g/min and 3.8±0.9 scores before surgery vs. 57±11.4 ml/100 g/min and 7.7±1.5 scores after double EICMA). All patients had no complications. Neurological status improved immediately after surgery in 9 patients (33.3%), stable postoperative period was observed in 12 cases (44.4%). Six (22.2%) patients had transient neurological deficit associated with hyperperfusion syndrome that regressed within a few days after surgery. There were no persistent ischemic complications. CONCLUSION: Intraoperative ASL perfusion is an effective and informative tool for determining the degree of restoration of blood flow. We can timely adjust surgical strategy, determine the indications or contraindications for additional revascularization and exclude early ischemic complications using this method.

[Short-term experience of intravitreal brolucizumab in treatment of diabetic macular edema]. / Kratkosrochnyi opyt primeneniya brolutsizumaba v lechenii diabeticheskogo makulyarnogo oteka.

PURPOSE: This study examines the efficacy and safety of brolucizumab in the treatment of diabetic macular edema (DME) in real clinical practice in the Russian Federation. MATERIAL AND METHODS: The study included 14 consecutive treatment-naïve DME patients, among them 7 males and 7 females (21 eyes in total) with mean age of 65.1±8.0 years. Patients underwent standard ophthalmological examination and multimodal imaging, including optical coherence tomography. All patients received intravitreal injections of brolucizumab every 6 weeks. A total of 73 injections were performed. A data analysis was performed for 10 eyes of 10 patients 6 months after initiation of the treatment. RESULTS: After 4 injections of brolucizumab, best-corrected visual acuity (BCVA) increased statistically significantly from 35.8±13.7 to 41.5±11.9 ETDRS letters (p=0.03), central retinal thickness (CRT) and macular volume (MV) decreased from 411.5±107.4 to 280.2±64.6 microns (p=0.014) and from 7.39±0.92 to 6.16±7.37 mm3 (p=0.0006), respectively. The average gain of visual acuity was 5.7±7.0 letters, average decrease of CRT was -131.3±91.2, and average decrease of MV was -1.21±0.75 mm3. There were no adverse events associated with intraocular inflammation. CONCLUSION: Intravitreal injections of brolucizumab provide significant anatomical and functional improvement to DME patients in real clinical practice with results comparable to that of randomized clinical trials.

Effect of Short Photoperiod on the Behavior and Brain Serotonin System in Zebrafish Danio rerio.

Reduced daylight duration causes the development of seasonal affective disorder (SAD; depression-like disorders characterized by depressed mood, apathy, bulimia, and weight gain) in sensitive individuals. Neurotransmitter serotonin (5-HT) is involved in the mechanism of SAD. Zebrafish (D. rerio) is a promising model for translational studies. We studied changes in the behavior, content of 5-HT and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the expression of genes encoding the key enzymes of 5-HT metabolism, tryptophan hydroxylases TPH1A, TPH1B, TPH2, monoamine oxidase (MAO), 5-HT transporter, and 5-HT1A and 5-HT2A receptors in the brain of zebrafish reared for 60 days under short (04:20 h) compared to those reared at normal (12:12 h) photoperiod. Exposure to short photoperiod decreased locomotor activity in the novel tank diving test, increased the level 5-HIAA, and reduced the level of Mao gene mRNA, but did not affect the level of 5-HT and expression of Tph1a, Tph1b, Tph2, Slc6a4a (transporter), Htr1aa, and Htr2aa (receptors) genes. Thus, zebrafish can be used as a promising model to study the involvement of 5-HT in the SAD mechanism.

C1473G Polymorphism in Tph2 Gene Affects Activation of Serotonin Metabolism in Mouse Brain 24 h after LPS Administration.

We studied the effect of the C1473G polymorphism in the Tph2 gene that reduces the activity of the tryptophan hydroxylase 2 in the brain on the severity of changes in motor activity (23 h after intraperitoneal administration of 0.8 mg/kg LPS or saline) and on the level of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the endings of 5-HT neurons in the cortex, hippocampus, and striatum (24 h after administration) of mature male mice of congenic lines B6-1473CC (high activity) and B6-1473GG (low activity). The state of the immune system in these structures was assessed by the expression of genes for proinflammatory cytokines IL-1ß and TNF. LPS caused a decrease in motor and exploratory activities and increased the expression of the Il1b and Tnf genes in the studied brain structures in mice of both genotypes. LPS did not affect the level of 5-HT in any of the studied brain structures, but dramatically increased the level of 5-HIAA in these structures. The influence of the C1473G polymorphism on the intensity of the LPS-dependent increase in the level of 5-HIAA in the cortex and striatum was shown: in B6-1473CC mice this increase was more pronounced than in B6-1473GG mice. Demonstration of the influence of this polymorphism on the response of the 5-HT system after stimulation of the innate immunity is important for understanding of the role of tryptophan hydroxylase 2 in the mechanism of adaptation of the nervous system during infections and for predicting and reducing the risks of mental disorders.

The Influence of Spatial Effects on the Dynamics of Solutions in Keynes' Mathematical Model of the Business Cycle.

We consider the special case of the mathematical model of Keynes' business cycle with the spatial interaction. In this model we assume that macroeconomic factors affect a certain geographical region and economic indicators. The dependence occurs on the spatial (geographical) coordinates in addition to the dependence on the temporal evolution, even if the economic subject is externally homogeneous in space. Spatial interaction led us to analyze a system of two differential equations of the 'reaction-diffusion' type, which replaces a system of two ordinary differential equations. This method is often used to analyze the dynamics of complex nonlinear systems and macroeconomic entities. An analysis of such a mathematical model is based on the use of modern methods of the theory of dynamical systems indicate the presence of new nonlinear effects in addition to those used in the traditional version of the Keynes model. We encountered the loss of stability of the homogeneous economic equilibrium state and the occurrence of economic cycles for some values of the parameters while investigating the characteristics of such a system. Meanwhile, another version of instability of a homogeneous economic equilibrium state with a different choice of parameters occurs, which in many cases leads to the appearance of a spatially non-homogeneous equilibrium state, which is characterized by the dependence of the corresponding economic indicators on the spatial (geographical) coordinates of the area in which the assigned macroeconomic entity is located.

[Informativeness estimation for the main clinical and laboratory parameters in patients with severe COVID-19].

AIM: To conduct a retrospective assessment of the clinical and laboratory data of patients with severe forms of COVID-19 hospitalized in the intensive care and intensive care unit, in order to assess the contribution of various indicators to the likelihood of death. MATERIALS AND METHODS: A retrospective assessment of data on 224 patients with severe COVID-19 admitted to the intensive care unit was carried out. The analysis included the data of biochemical, clinical blood tests, coagulograms, indicators of the inflammatory response. When transferring to the intensive care units (ICU), the indicators of the formalized SOFA and APACHE scales were recorded. Anthropometric and demographic data were downloaded separately. RESULTS: Analysis of obtained data, showed that only one demographic feature (age) and a fairly large number of laboratory parameters can serve as possible markers of an unfavorable prognosis. We identified 12 laboratory features the best in terms of prediction: procalcitonin, lymphocytes (absolute value), sodium (ABS), creatinine, lactate (ABS), D-dimer, oxygenation index, direct bilirubin, urea, hemoglobin, C-reactive protein, age, LDH. The combination of these features allows to provide the quality of the forecast at the level of AUC=0.85, while the known scales provided less efficiency (APACHE: AUC=0.78, SOFA: AUC=0.74). CONCLUSION: Forecasting the outcome of the course of COVID-19 in patients in ICU is relevant not only from the position of adequate distribution of treatment measures, but also from the point of view of understanding the pathogenetic mechanisms of the development of the disease.

[Short-term efficacy and safety of Brolucizumab for neovascular age-related macular degeneration in the Russian Federation]. / Kratkosrochnye dannye effektivnosti i bezopasnosti primeneniya preparata «Brolutsizumab¼ pri lechenii neovaskulyarnoi vozrastnoi makulyarnoi degeneratsii na territorii Rossiiskoi Federatsii.

PURPOSE: To analyze the short-term efficacy and safety of Brolucizumab in the treatment of patients with neovascular age-related macular degeneration (nAMD). MATERIAL AND METHODS: This retrospective pilot study included 154 patients (51 males and 103 females, mean age 73.9±8.1 years). Among the 154 patients, 97 (63.0%) had previously been treated with anti-VEGF drugs and were included in this study due to continuing disease activity. All study patients underwent standard ophthalmological examination and optical coherence tomography at the initial visit as well as at each monthly visit. RESULTS: A total of 283 Brolucizumab injections were performed in two ophthalmic care centers. In total, 49.4%, 24.0%, 20.1%, 6.5% of patients received 1, 2, 3 and 4 injections, respectively. Central retinal thickness has significantly decreased from 301±79 to 230±41 µm (p<0.05) in the ophthalmic center of the Military Medical Academy (site 1), and from 418±102 to 217±50 µm (p<0.05) in the ophthalmic center of the Institute of the Human Brain (site 2). The prevalence of subretinal and sub-RPE fluid has decreased statistically significantly (p<0.05) in patients of both sites. Visual acuity has not changed significantly (p>0.05) in patients of both sites. One case of mild vitreitis was registered, it was successfully treated with topical steroids. CONCLUSIONS: Both treatment-naive nAMD patients and those with the disease remaining active despite anti-VEGF therapy showed a significant decrease in disease activity. In this short-term study, the cumulative risk of intraocular inflammation associated with brolucizumab therapy amounted to 0.65%.