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The COMPASS Collaboration performed measurements of the Drell-Yan process in 2015 and 2018 using a 190  GeV/c π^{-} beam impinging on a transversely polarized ammonia target. Combining the data of both years, we present final results on the amplitudes of five azimuthal modulations, which correspond to transverse-spin-dependent azimuthal asymmetries (TSAs) in the dimuon production cross section. Three of them probe the nucleon leading-twist Sivers, transversity, and pretzelosity transverse-momentum dependent (TMD) parton distribution functions (PDFs). The other two are induced by subleading effects. These TSAs provide unique new inputs for the study of the nucleon TMD PDFs and their universality properties. In particular, the Sivers TSA observed in this measurement is consistent with the fundamental QCD prediction of a sign change of naive time-reversal-odd TMD PDFs when comparing the Drell-Yan process with deep inelastic scattering. Also, within the context of model predictions, the observed transversity TSA is consistent with the expectation of a sign change for the Boer-Mulders function.

It is widely postulated that the majority of pathologically elevated extracellular or cell-free DNA (cfDNA) in cancer originates from tumor cells; however, evidence has emerged regarding the significant contributions of other cells from the tumor microenvironment. Here, the effect of cfDNA originating from murine B16 melanoma cells and L929 fibroblasts on B16 cells was investigated. It was found that cfDNAL929 increased the viability and migration properties of B16 cells in vitro and their invasiveness in vivo. In contrast, cfDNAB16 exhibited a negative effect on B16 cells, reducing their viability and migration in vitro, which in vivo led to decreased tumor size and metastasis number. It was shown that cell treatment with both cfDNAs resulted in an increase in the expression of genes encoding DNases and the oncogenes Braf , Kras , and Myc. cfDNAL929-treated cells were shown to experience oxidative stress. Gene expression changes in the case of cfDNAB16 treatment are well correlated with the observed decrease in proliferation and migration of B16 cells. The obtained data may indicate the possible involvement of fibroblast DNA in the tumor microenvironment in tumor progression and, potentially, in the formation of new tumor foci due to the transformation of normal cells., Competing Interests: The authors declare no conflicts of interest.

Small interfering RNA (siRNA) holds significant therapeutic potential by silencing target genes through RNA interference. Current clinical applications of siRNA have been primarily limited to liver diseases, while achievements in delivery methods are expanding their applications to various organs, including the lungs. Cholesterol-conjugated siRNA emerges as a promising delivery approach due to its low toxicity and high efficiency. This study focuses on developing a cholesterol-conjugated anti- Il6 siRNA and the evaluation of its potency for the potential treatment of inflammatory diseases using the example of acute lung injury (ALI). The biological activities of different Il6 -targeted siRNAs containing chemical modifications were evaluated in J774 cells in vitro. The lead cholesterol-conjugated anti- Il6 siRNA after intranasal instillation demonstrated dose-dependent therapeutic effects in a mouse model of ALI induced by lipopolysaccharide (LPS). The treatment significantly reduced Il6 mRNA levels, inflammatory cell infiltration, and the severity of lung inflammation. IL6 silencing by cholesterol-conjugated siRNA proves to be a promising strategy for treating inflammatory diseases, with potential applications beyond the lungs.

Acute lung injury (ALI) is a specific form of lung inflammation characterized by diffuse alveolar damage, noncardiogenic pulmonary edema, as well as a pulmonary and systemic inflammation. The pathogenesis of ALI involves a cascade inflammatory response accompanied by an increase in the local and systemic levels of proinflammatory cytokines and chemokines. The development of molecular tools targeting key components of cytokine signaling appears to be a promising approach in ALI treatment. The development of lipopolysaccharide (LPS)-induced ALI, as well as the feasibility of suppressing it by an aptamer targeting the proinflammatory cytokine TNF-α, was studied in a mouse model. The TNF-α level was shown to increase significantly and remain steadily high during the development of ALI. LPS-induced morphological signs of inflammation in the respiratory system become most pronounced 24 h after induction. Intranasal administration of TNF-α-targeting aptamers conjugated with polyethylene glycol (PEG-aptTNF-α) to mice with ALI reduced the intensity of inflammatory changes in lung tissue. Assessment of the levels of potential TNF-α target genes ( Usp18 , Traf1 , and Tnfaip3 ) showed that their expression levels in the lungs increase during ALI development, while declining after the application of PEG-aptTNF-α. Therefore, topical use of TNF-α- targeting aptamers may be an efficient tool for treating ALI and other inflammatory lung diseases., (Copyright ® 2024 National Research University Higher School of Economics.)

Objective: Traumatic brain injury (TBI) is an independent risk factor for venous thromboembolism (VTE). This study aimed to determine the optimal timing for initiating pharmacological thromboprophylaxis for VTE in patients with isolated severe TBI using rotational thromboelastometry (ROTEM)., Methods: This single-center observational study enrolled 115 patients aged 18-59 years with isolated severe TBI within the first 48 hours after injury., Results: Using ROTEM data, we identified hypercoagulation due to an increase in clot density (MCF EXTEM >72), which was attributed to fibrinogen (MCF FIBTEM >25). From day 4, hypercoagulation occurred in 14.8% of the patients. By day 7, these changes were observed in 85.2% of patients. According to brain computed tomography findings, patients who received early VTE chemoprophylaxis on days 3-4 after severe TBI did not experience progression of hemorrhagic foci., Conclusion: Our results emphasize the clinical significance of thromboelastometry in patients with isolated severe traumatic TBI. Anticoagulant prophylaxis started on 3-4 days after severe TBI was relatively safe, and most patients did not experience hemorrhagic foci progression. The data acquired in this study may enable the optimization of VTE chemoprophylactic approaches, thereby reducing the associated risks to patients., Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest., (Copyright © 2024 Korean Neurotraumatology Society.)

Background: Treatment of patients with prolonged and permanent disturbance of consciousness is still an extremely difficult problem. Nowadays, management is based on pathophysiological and molecular mechanisms of impaired consciousness. Several electrophysiological and pharmacological methods were proposed to restore consciousness in appropriate patients., Objective: We present recovery of clear consciousness under therapy with phenazepam and literature review devoted to therapy of these disorders., Results and Conclusion: This case confirms available data on drug neuromodulation in complex treatment of patients with prolonged impairment of consciousness and substantiates the need for individual multimodal assessment of structural and functional disorders in prolonged and chronic impairment of consciousness for adequate therapy.

Neurosurgical interventions within the ventral surface of the clivus and upper cervical vertebrae in childhood are sometimes carried out through transoral approach. In this situation, tracheostomy is safer for airway protection and mechanical ventilation compared to prolonged intubation. The world experience of percutaneous dilation tracheostomy in pediatric patients is limited due to anatomical and physiological features, such as difficult orientation in anatomical landmarks, high mobility of the trachea and small tracheal lumen. Also, the trachea easily collapses when pressed in pediatric patients that complicates safe puncture of anterior wall and can lead to perforation of posterior tracheal wall., Objective: To describe a modified technique of video-assisted percutaneous dilation tracheostomy using additional thin guide and dilator in children of primary school age., Material and Methods: We considered 11 patients aged 6-12 years who underwent video-assisted percutaneous dilation tracheostomy., Results: There were no perioperative complications (bleeding, false course, perforation of posterior tracheal wall). Infection of tracheostomy, fistulas or tracheal stenosis was absent., Conclusion: Percutaneous dilation tracheostomy may be alternative to classical surgical tracheostomy for pediatric patients. Endoscopic control and certain technical changes of percutaneous tracheostomy are necessary and provide safe manipulation. Surgery time, less trauma and minimal cosmetic defect after tracheostomy are significant advantages of this technique compared to surgical tracheostomy.

Conjugation of small interfering RNA (siRNA) with lipophilic molecules is one of the most promising approaches for delivering siRNA in vivo . The rate of molecular weight-dependent siRNA renal clearance is critical for the efficiency of this process. In this study, we prepared cholesterol-containing supramolecular complexes containing from three to eight antisense strands and examined their accumulation and silencing activity in vitro and in vivo . We have shown for the first time that such complexes with 2'F, 2'OMe, and LNA modifications exhibit interfering activity both in carrier-mediated and carrier-free modes. Silencing data from a xenograft tumor model show that 4 days after intravenous injection of cholesterol-containing monomers and supramolecular trimers, the levels of MDR1 mRNA in the tumor decreased by 85% and 68%, respectively. The in vivo accumulation data demonstrated that the formation of supramolecular structures with three or four antisense strands enhanced their accumulation in the liver. After addition of two PS modifications at the ends of antisense strands, 47% and 67% reductions of Ttr mRNA levels in the liver tissue were detected 7 days after administration of monomers and supramolecular trimers, respectively. Thus, we have obtained a new type of RNAi inducer that is convenient for synthesis and provides opportunities for modifications.

Bronchial asthma is a heterogeneous disease characterized by persistent respiratory system inflammation, airway hyperreactivity, and airflow obstruction. Airway remodeling, defined as changes in airway wall structure such as extensive epithelial damage, airway smooth muscle hypertrophy, collagen deposition, and subepithelial fibrosis, is a key feature of asthma. Lung fibrosis is a common occurrence in the pathogenesis of fatal and long-term asthma, and it is associated with disease severity and resistance to therapy. It can thus be regarded as an irreversible consequence of asthma-induced airway inflammation and remodeling. Asthma heterogeneity presents several diagnostic challenges, particularly in distinguishing between chronic asthma and other pulmonary diseases characterized by disruption of normal lung architecture and functions, such as chronic obstructive pulmonary disease. The search for instruments that can predict the development of irreversible structural changes in the lungs, such as chronic components of airway remodeling and fibrosis, is particularly difficult. To overcome these challenges, significant efforts are being directed toward the discovery and investigation of molecular characteristics and biomarkers capable of distinguishing between different types of asthma as well as between asthma and other pulmonary disorders with similar structural characteristics. The main features of bronchial asthma etiology, pathogenesis, and morphological characteristics as well as asthma-associated airway remodeling and lung fibrosis as successive stages of one process will be discussed in this review. The most common murine models and biomarkers of asthma progression and post-asthmatic fibrosis will also be covered. The molecular mechanisms and key cellular players of the asthmatic process described and systematized in this review are intended to help in the search for new molecular markers and promising therapeutic targets for asthma prediction and therapy.

In this study, the impact of different delivery systems on the cytokine-inducing, antiproliferative, and antitumor activities of short immunostimulatory double-stranded RNA (isRNA) was investigated. The delivery systems, consisting of the polycationic amphiphile 1,26-bis(cholest-5-en-3-yloxycarbonylamino)-7,11,16,20 tetraazahexacosan tetrahydrochloride (2X3), and the lipid-helper dioleoylphosphatidylethanolamine (DOPE), were equipped with polyethylene glycol lipoconjugates differing in molecular weight and structure. The main findings of this work are as follows: (i) significant activation of MCP-1 and INF-α, β, and γ production in CBA mice occurs under the action of isRNA complexes with liposomes containing lipoconjugates with long PEG chains, while activation of MCP-1 and INF-γ, but not INF-α or β, was observed under the action of isRNA lipoplexes containing lipoconjugates with short PEG chains; (ii) a pronounced antiproliferative effect on B16 melanoma cells in vitro, as well as an antitumor and hepatoprotective effect in vivo, was induced by isRNA pre-complexes with non-pegylated liposomes, while complexes containing lipoconjugates with long-chain liposomes were inactive; (iii) the antitumor activity of isRNA correlated with the efficiency of its accumulation in the cells and did not explicitly depend on the activation of cytokine and interferon production. Thus, the structure of the delivery system plays a vital role in determining the response to isRNA and allows for the choice of a delivery system depending on the desired effect.

Acinetobacter baumannii is one of the significant healthcare-associated meningitis agents characterized by multidrug resistance and a high mortality risk. Thirty-seven A. baumannii strains were isolated from thirty-seven patients of Moscow neuro-ICU with meningitis in 2013-2020. The death rate was 37.8%. Strain susceptibility to antimicrobials was determined on the Vitek-2 instrument. Whole-genome sequencing was conducted using Illumina technology; the sequence types (ST), capsular types (KL), lipooligosaccharide outer core locus (OCL), antimicrobial resistance genes, and virulence genes were identified. The prevalent ST was ST2, belonging to the international clone IC2, and rarer, ST1, ST19, ST45, ST78, ST106, and ST400, with prevalence of KL9 and OCL1. Twenty-nine strains belonged to multidrug-resistant (MDR) and eight extensively drug-resistant (XDR) categories. Genes conferring resistance to beta-lactams ( bla PER , bla GES , bla ADC , bla CARB , bla CTX-M , bla TEM , and bla OXA -types), aminoglycosides ( aac , aad , ant , aph , and arm ), tetracyclines ( tet ), macrolides ( msr and mph ), phenicols ( cml , cat , and flo ), sulfonamides ( dfr and sul ), rifampin ( arr ), and antiseptics ( qac ) were identified. Virulence genes of nine groups (Adherence, Biofilm formation, Enzymes, Immune evasion, Iron uptake, Regulation, Serum resistance, Stress adaptation, and Antiphagocytosis) were detected. The study highlights the heterogeneity in genetic clones, antimicrobial resistance, and virulence genes variability among the agents of A. baumannii meningitis, with the prevalence of the dominant international clone IC2.

Currently, a significant increase in the levels of circulating cell-free DNA (cfDNA) in the blood of patients is considered as a generally recognized marker of the development of oncological diseases. Although the tumor-associated cfDNA has been well studied, its biological functions remain unclear. In this work, we investigated the effect of cfDNA isolated from the blood serum of the mice with B16-F10 metastatic melanoma on the properties of the B16-F10 melanoma cells in vitro. It was found that the profile of cfDNA isolated from the blood serum of mice with melanoma differs significantly from the cfDNA isolated from the blood serum of healthy mice, and is similar to the genomic DNA of B16 cells with regards to abundance of oncogenes and mobile genetic elements (MGE). It was shown that the cfDNA of mice with melanoma penetrated into B16 cells, resulting in the increase in abundance of oncogenes and MGE fragments, and caused 5-fold increase of the mRNA level of the secreted DNase Dnase1l3 and a slight increase of the mRNA level of the Jun, Fos, Ras, and Myc oncogenes. cfDNA of the healthy mice caused increase of the mRNA level of intracellular regulatory DNase EndoG and 4-fold increase of the mRNA level of Fos and Ras oncogenes, which are well-known triggers of a large number of signal cascades, from apoptosis inhibition to increased tumor cell proliferation. Thus, it is obvious that the circulating cfDNA of tumor origin is able to penetrate into the cells and, despite the fact that no changes were found in the level of viability and migration activity of the tumor cells, cfDNA, even with a single exposure, can cause changes at the cellular level that increase oncogenicity of the recipient cells.

The anti-inflammatory potential of three cyanoenone-containing triterpenoids, including soloxolone methyl (SM), soloxolone (S) and its novel derivative bearing at the C-30 amidoxime moiety (SAO), was studied in murine models of acute inflammation. It was found that the compounds effectively suppressed the development of carrageenan-induced paw edema and peritonitis as well as lipopolysaccharide (LPS)-driven acute lung injury (ALI) with therapeutic outcomes comparable with that of the reference drugs indomethacin and dexamethasone. Non-immunogenic carrageenan-stimulated inflammation was more sensitive to the transformation of C-30 of SM compared with immunogenic LPS-induced inflammation: the anti-inflammatory properties of the studied compounds against carrageenan-induced paw edema and peritonitis decreased in the order of SAO > S > > SM, whereas the efficiency of these triterpenoids against LPS-driven ALI was similar (SAO ≈ S ≈ SM). Further studies demonstrated that soloxolone derivatives significantly inhibited a range of immune-related processes, including granulocyte influx and the expression of key pro-inflammatory cytokines and chemokines in the inflamed sites as well as the functional activity of macrophages. Moreover, SM was found to prevent inflammation-associated apoptosis of A549 pneumocytes and effectively inhibited the protease activity of thrombin (IC 50 = 10.3 µM) tightly associated with rodent inflammatome. Taken together, our findings demonstrate that soloxolone derivatives can be considered as novel promising anti-inflammatory drug candidates with multi-targeted mechanism of action., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Inflammatory bowel disease (IBD) is a complex and multifactorial systemic disorder of the gastrointestinal tract and is strongly associated with the development of colorectal cancer. Despite extensive studies of IBD pathogenesis, the molecular mechanism of colitis-driven tumorigenesis is not yet fully understood. In the current animal-based study, we report a comprehensive bioinformatics analysis of multiple transcriptomics datasets from the colon tissue of mice with acute colitis and colitis-associated cancer (CAC). We performed intersection of differentially expressed genes (DEGs), their functional annotation, reconstruction, and topology analysis of gene association networks, which, when combined with the text mining approach, revealed that a set of key overexpressed genes involved in the regulation of colitis ( C3 , Tyrobp , Mmp3 , Mmp9 , Timp1 ) and CAC ( Timp1 , Adam8 , Mmp7 , Mmp13 ) occupied hub positions within explored colitis- and CAC-related regulomes. Further validation of obtained data in murine models of dextran sulfate sodium (DSS)-induced colitis and azoxymethane/DSS-stimulated CAC fully confirmed the association of revealed hub genes with inflammatory and malignant lesions of colon tissue and demonstrated that genes encoding matrix metalloproteinases (acute colitis: Mmp3 , Mmp9 ; CAC: Mmp7 , Mmp13 ) can be used as a novel prognostic signature for colorectal neoplasia in IBD. Finally, using publicly available transcriptomics data, translational bridge interconnecting of listed colitis/CAC-associated core genes with the pathogenesis of ulcerative colitis, Crohn's disease, and colorectal cancer in humans was identified. Taken together, a set of key genes playing a core function in colon inflammation and CAC was revealed, which can serve both as promising molecular markers and therapeutic targets to control IBD and IBD-associated colorectal neoplasia.

Background: Klebsiella pneumoniae, a member of the ESKAPE group of bacterial pathogens, has developed multi-antimicrobial resistance (AMR), including resistance to carbapenems, which has increased alarmingly due to the acquisition of carbapenemase genes located on specific plasmids., Methods: Four clinical K. pneumoniae isolates were collected from four patients of a neuro-intensive care unit in Moscow, Russia, during the point prevalence survey. The AMR phenotype was estimated using the Vitec-2 instrument, and whole genome sequencing (WGS) was done using Illumina and Nanopore technologies., Results: All strains were resistant to beta-lactams, nitrofurans, fluoroquinolones, sulfonamides, aminoglycosides, and tetracyclines. WGS analysis revealed that all strains were closely related to K. pneumoniae ST39, capsular type K-23, with 99.99% chromosome identity. The novelty of the study is the description of the strains carrying simultaneously three large plasmids of the IncHI1B, IncC, and IncFIB groups carrying the carbapenemase genes of three types, bla OXA-48 , bla NDM-1 , and bla KPC-2 , respectively. The first of them, highly identical in all strains, was a hybrid plasmid that combined two regions of the resistance genes ( bla OXA-48 and bla TEM-1 + bla CTX-M-15 + bla OXA-1 + catB + qnrS1 + int1 ) and a region of the virulence genes ( iucABCD , iutA , terC , and rmpA2 :: IS110 )., Conclusion: The spread of K. pneumoniae strains carrying multiple plasmids conferring resistance even to last-resort antibiotics is of great clinical concern.

Acute lung injury is a complex cascade process that develops in response to various damaging factors, which can lead to acute respiratory distress syndrome. Within this study, based on bioinformatics reanalysis of available full-transcriptome data of acute lung injury induced in mice and humans by various factors, we selected a set of genes that could serve as good targets for suppressing inflammation in the lung tissue, evaluated their expression in the cells of different origins during LPS-induced inflammation, and chose the tissue inhibitor of metalloproteinase Timp1 as a promising target for suppressing inflammation. We designed an effective chemically modified anti-TIMP1 siRNA and showed that Timp1 silencing correlates with a decrease in the pro-inflammatory cytokine IL6 secretion in cultured macrophage cells and reduces the severity of LPS-induced acute lung injury in a mouse model.

Background: Status epilepticus (SE) is characterized by continuous course of clinical and/or electrographic epileptic seizures. There are little data on the course and outcomes of SE after resection of brain tumors., Objective: To analyze clinical and electrographic manifestations of SE, its course and outcomes in short-term period after resection of brain tumors., Material and Methods: We analyzed medical records of 18 patients over 18 years old between 2012 and 2019. All patients underwent resection of brain tumor and developed SE after surgery. Clinical criteria were repeated epileptic seizures without interictal recovery of consciousness, stereotypical motor phenomena, impaired consciousness with continued epileptic activity according to video-EEG data. We analyzed EEG data, neurological status, CT and laboratory data., Results: Metastases (33%) and meningiomas (16%) prevailed. Supratentorial tumors were observed in 61% of patients. Two patients had preoperative seizures. Non-convulsive SE was diagnosed in 62% of patients. SE was successfully treated in 77% of cases. Mortality rate in patients with SE was 44%., Conclusion: Early postoperative SE is rare after brain tumor surgery (about 0.09%). Nevertheless, this complication is associated with high mortality. Non-convulsive SE is common (62%) that should be considered in postoperative management.

We analyzed literature data on the most common drug interactions in neurosurgical patients. Drug interactions are a potential cause of adverse and dangerous clinical events and outcomes. Awareness of nature of drug interactions is valuable to avoid negative consequences when using combination of several drugs. Polypharmacy in neurosurgical patients is caused by treatment of intracranial lesions (hormonal therapy, antiepileptic drugs, etc.) and concomitant somatic diseases that increases the risk of drug interactions.

Pulmonary embolism (PE) is a serious problem for neurosurgical patients because of high risk of mortality and the need to choose effective and safe anticoagulation., Objective: To analyze the patients with PE after neurosurgical interventions., Material and Methods: A prospective study was performed at the Burdenko Neurosurgical Center between January 2021 and December 2022. Inclusion criteria were neurosurgical disease and PE., Results: In accordance with inclusion criteria, we analyzed 14 patients. Mean age was 63 [45.8; 70.0] years. Four patients died. PE was a direct cause of death in 1 case. PE occurred in 5.14±3.68 days after surgery. Anticoagulation was safely implemented in 3 patients with PE on the first day after craniotomy. In a patient with massive PE several hours after craniotomy, anticoagulation resulted hematoma with brain dislocation and death. Thromboextraction and thrombodestruction were used in 2 patients with massive PE and high risk of mortality., Conclusion: Despite low incidence (0.1%), PE is a serious problem in neurosurgical patients due to the risk of intracranial hematoma under effective anticoagulant therapy. In our opinion, endovascular interventions with thromboextraction, thrombodestruction or local fibrinolysis are the safest in the treatment of PE after neurosurgery. Individual approach considering clinical, laboratory data, advantages and disadvantages of a particular anticoagulant drug is required when choosing the tactics of anticoagulation. Further analysis of a larger number of clinical cases is needed to develop the guidelines for the management of neurosurgical patients with PE.

Patients with traumatic brain injury (TBI) are at high risk of infection., Objective: To delineate infections in acute period of TBI, association between intracranial lesion type and risk of infection, as well as to estimate treatment outcomes in these patients depending on infection., Material and Methods: This study included 104 patients with TBI (80 men and 24 women) aged 33.01±14.35 years. All patients met the inclusion criteria: admission within 72 hours after TBI, age 18-75 years, ICU-stay >48 hours, available brain MRI data. Mild, moderate and severe TBI were diagnosed in 7%, 11% and 82% of patients, respectively. Analysis of infections was performed in accordance with the definitions of the Centers for Disease Control/National Healthcare Safety Network (CDC/NHSN)., Results: Acute period of TBI is associated with high incidence of infection (73%), and prevalent infection is pneumonia (58.7%). Severe intracranial damage in acute period of TBI (grade 4-8 according to MR-based classification by A.A. Potapov and N.E. Zakharova) is associated with higher incidence of infection. Infectious complications more than twice increase duration of mechanical ventilation, ICU- and hospital-stay., Conclusion: Infectious complications significantly affect treatment outcomes in acute period of TBI increasing duration of mechanical ventilation, ICU- and hospital-stay.

Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to lung architecture disruption and respiratory failure. The development of pulmonary fibrosis is mostly the result of previous acute lung inflammation, caused by a wide variety of etiological factors, not resolved over time and causing the deposition of fibrotic tissue in the lungs. Despite a long history of study and good coverage of the problem in the scientific literature, the effective therapeutic approaches for pulmonary fibrosis treatment are currently lacking. Thus, the study of the molecular mechanisms underlying the transition from acute lung inflammation to pulmonary fibrosis, and the search for new molecular markers and promising therapeutic targets to prevent pulmonary fibrosis development, remain highly relevant tasks. This review focuses on the etiology, pathogenesis, morphological characteristics and outcomes of acute lung inflammation as a precursor of pulmonary fibrosis; the pathomorphological changes in the lungs during fibrosis development; the known molecular mechanisms and key players of the signaling pathways mediating acute lung inflammation and pulmonary fibrosis, as well as the characteristics of the most common in vivo models of these processes. Moreover, the prognostic markers of acute lung injury severity and pulmonary fibrosis development as well as approved and potential therapeutic approaches suppressing the transition from acute lung inflammation to fibrosis are discussed.

The spread of multidrug-resistant Gram-negative bacteria, which is associated with the distribution of beta-lactamase genes and class 1 and 2 integrons, is a global problem. In this study, in the Moscow neurosurgery intensive care unit (neuro-ICU), the high prevalence of the above-stated genes was found to be associated with intestinal and tracheal carriage. Seven-point prevalence surveys, which included 60 patients in the neuro-ICU, were conducted weekly in the period from Oct. to Nov. 2019. A total of 293 clinical samples were analyzed, including 146 rectal and 147 tracheal swabs; 344 Gram-negative bacteria isolates were collected. Beta-lactamase genes (n = 837) were detected in the isolates, including beta-lactamase bla TEM (n = 162), bla SHV (n = 145), cephalosporinase bla CTX-M (n = 228), carbapenemase bla NDM (n = 44), bla KPC (n = 25), bla OXA-48 (n = 126), bla OXA-51-like (n = 54), bla OXA-40-like (n = 43), bla OXA-23-like (n = 8), and bla VIM (n = 2), as well as class 1 (n = 189) and class 2 (n = 12) integrons. One extensively drug-resistant Klebsiella pneumoniae strain (sequence type ST39 and capsular type K23), simultaneously carried beta-lactamase genes, bla SHV-40 and bla TEM-1B , three carbapenemase genes, bla NDM , bla KPC , and bla OXA-48 , the cephalosporinase gene bla CTX-M , and two class 1 integrons. Before this study, such heavily armed strains have not been reported, suggesting the ongoing evolution of antibiotic resistance.

It is known that epoxide-bearing compounds display pronounced pharmacological activities, and the epoxidation of natural metabolites can be a promising strategy to improve their bioactivity. Here, we report the design, synthesis and evaluation of biological properties of αO-SM and βO-SM , novel epoxides of soloxolone methyl ( SM ), a cyanoenone-bearing derivative of 18βH-glycyrrhetinic acid. We demonstrated that the replacement of a double-bound within the cyanoenone pharmacophore group of SM with α- and β-epoxide moieties did not abrogate the high antitumor and anti-inflammatory potentials of the triterpenoid. It was found that novel SM epoxides induced the death of tumor cells at low micromolar concentrations (IC 50 (24h) = 0.7-4.1 µM) via the induction of mitochondrial-mediated apoptosis, reinforced intracellular accumulation of doxorubicin in B16 melanoma cells, probably by direct interaction with key drug efflux pumps (P-glycoprotein, MRP1, MXR1), and the suppressed pro-metastatic phenotype of B16 cells, effectively inhibiting their metastasis in a murine model. Moreover, αO-SM and βO-SM hampered macrophage functionality in vitro (motility, NO production) and significantly suppressed carrageenan-induced peritonitis in vivo. Furthermore, the effect of the stereoisomerism of SM epoxides on the mentioned bioactivities and toxic profiles of these compounds in vivo were evaluated. Considering the comparable antitumor and anti-inflammatory effects of SM epoxides with SM and reference drugs (dacarbazine, dexamethasone), αO-SM and βO-SM can be considered novel promising antitumor and anti-inflammatory drug candidates.

In this investigation, we extensively studied the mechanism of antitumor activity of bovine pancreatic RNase A. Using confocal microscopy, we show that after RNase A penetration into HeLa and B16 cells, a part of the enzyme remains unbound with the ribonuclease inhibitor (RI), resulting in the decrease in cytosolic RNAs in both types of cells and rRNAs in the nucleoli of HeLa cells. Molecular docking indicates the ability of RNase A to form a complex with Ku70/Ku80 heterodimer, and microscopy data confirm its localization mostly inside the nucleus, which may underlie the mechanism of RNase A penetration into cells and its intracellular traffic. RNase A reduced migration and invasion of tumor cells in vitro. In vivo, in the metastatic model of melanoma, RNase A suppressed metastases in the lungs and changed the expression of EMT markers in the tissue adjacent to metastatic foci; this increased Cdh1 and decreased Tjp1, Fn and Vim, disrupting the favorable tumor microenvironment. A similar pattern was observed for all genes except for Fn in metastatic foci, indicating a decrease in the invasive potential of tumor cells. Bioinformatic analysis of RNase-A-susceptible miRNAs and their regulatory networks showed that the main processes modulated by RNase A in the tumor microenvironment are the regulation of cell adhesion and junction, cell cycle regulation and pathways associated with EMT and tumor progression.

Asthma is a heterogeneous pulmonary disorder, the progression and chronization of which leads to airway remodeling and fibrogenesis. To understand the molecular mechanisms of pulmonary fibrosis development, key genes forming the asthma-specific regulome and involved in lung fibrosis formation were revealed using a comprehensive bioinformatics analysis. The bioinformatics data were validated using a murine model of ovalbumin (OVA)-induced asthma and post-asthmatic fibrosis. The performed analysis revealed a range of well-known pro-fibrotic markers ( Cat , Ccl2 , Ccl4 , Ccr2 , Col1a1 , Cxcl12 , Igf1 , Muc5ac/Muc5b , Spp1 , Timp1 ) and a set of novel genes ( C3 , C3ar1 , Col4a1 , Col4a2 , Cyp2e1 , Fn1 , Thbs1 , Tyrobp ) mediating fibrotic changes in lungs already at the stage of acute/subacute asthma-driven inflammation. The validation of genes related to non-allergic bleomycin-induced pulmonary fibrosis on asthmatic/fibrotic lungs allowed us to identify new universal genes ( Col4a1 and Col4a2 ) associated with the development of lung fibrosis regardless of its etiology. The similarities revealed in the expression profiles of nodal fibrotic genes between asthma-driven fibrosis in mice and nascent idiopathic pulmonary fibrosis in humans suggest a tight association of identified genes with the early stages of airway remodeling and can be considered as promising predictors and early markers of pulmonary fibrosis., Competing Interests: The authors declare no conflicts of interest.

Transoral or combined transnasal-transoral approach is sometimes used for tumor resection in patients with skull base and vertebral neoplasms. In such cases, percutaneous tracheostomy before surgical intervention is advisable. Tracheostomy facilitates surgical access, eliminates intraoperative risk of endotracheal tube kinking and provides airway protection from aspiration in early postoperative period in case of bulbar disorders, hypopharynx and tongue edema. The authors present two patients with massive proliferation of pathological tissue in nasopharynx and oropharynx that excluded tracheal intubation before tracheostomy. These patients underwent awake percutaneous tracheostomy.

Posterior cranial fossa (PCF) surgery is associated with the risk of increased intracranial pressure ( ICP) under tentorium. The last one can lead to severe brainstem syndromes and postoperative complications. The currently recommended method for ICP control with a supratentorial parenchymal sensor or CSF pressure measurement through an external ventricular drainage is ineffective. Indeed, these methods do not show the true situation in the PCF., Objective: To determine the feasibility of ICP sensor insertion into cerebellar parenchyma for PCF edema after neurosurgery., Material and Methods: We retrospectively analyzed literature data (15 references) and 3 patients after ICP sensor insertion into cerebellar parenchyma for ICP control in PCF., Conclusion: ICP sensor insertion into cerebellar parenchyma is indicated for infratentorial postoperative edema.

Background: For patients with primary brain injury, septic shock is especially dangerous due to the possibility of secondary cerebral damage. The key factor of sepsis-associated brain injury is inflammatory mediators, pathogen and damage-associated molecular patterns (PAMPs, DAMPs) release. Theoretically, blood purification may be beneficial for patients with primary brain injury due to its possibility for fast removal of inflammatory mediators., Case Presentation: We report on six post-neurosurgery septic shock patients treated with combined blood purification (CBP), which included CRRT with high adsorption capacity membrane in combination with CytoSorb adsorber. Clinical improvement in the course of CBP was registered in all patients. Three patients had a stable clinical improvement; the other three patients had only a transient improvement due to underlying neurological and cardiac deficits aggravation. We observed septic shock reversal in four patients. The key observations of the case series are a significant decrease in MOF severity (measured by SOFA score) and in catecholamine need (not statistically significant). By the end of CBP we observed a significant decrease in blood lactate, PCT and IL-6 levels. Two patients demonstrated level of consciousness increase in the setting of CBP therapy measured by GCS and FOUR score., Conclusion: This case series demonstrates that CBP therapy may have a role for septic shock patients with primary brain injury., (© 2021. The Author(s).)

Acute lung injury (ALI) is a specific form of lung damage caused by different infectious and non-infectious agents, including SARS-CoV-2, leading to severe respiratory and systemic inflammation. To gain deeper insight into the molecular mechanisms behind ALI and to identify core elements of the regulatory network associated with this pathology, key genes involved in the regulation of the acute lung inflammatory response (Il6, Ccl2, Cat, Serpine1, Eln, Timp1, Ptx3, Socs3) were revealed using comprehensive bioinformatics analysis of whole-genome microarray datasets, functional annotation of differentially expressed genes (DEGs), reconstruction of protein-protein interaction networks and text mining. The bioinformatics data were validated using a murine model of LPS-induced ALI; changes in the gene expression patterns were assessed during ALI progression and prevention by anti-inflammatory therapy with dexamethasone and the semisynthetic triterpenoid soloxolone methyl (SM), two agents with different mechanisms of action. Analysis showed that 7 of 8 revealed ALI-related genes were susceptible to LPS challenge (up-regulation: Il6, Ccl2, Cat, Serpine1, Eln, Timp1, Socs3; down-regulation: Cat) and their expression was reversed by the pre-treatment of mice with both anti-inflammatory agents. Furthermore, ALI-associated nodal genes were analysed with respect to SARS-CoV-2 infection and lung cancers. The overlap with DEGs identified in postmortem lung tissues from COVID-19 patients revealed genes (Saa1, Rsad2, Ifi44, Rtp4, Mmp8) that (a) showed a high degree centrality in the COVID-19-related regulatory network, (b) were up-regulated in murine lungs after LPS administration, and (c) were susceptible to anti-inflammatory therapy. Analysis of ALI-associated key genes using The Cancer Genome Atlas showed their correlation with poor survival in patients with lung neoplasias (Ptx3, Timp1, Serpine1, Plaur). Taken together, a number of key genes playing a core function in the regulation of lung inflammation were found, which can serve both as promising therapeutic targets and molecular markers to control lung ailments, including COVID-19-associated ALI., Competing Interests: The authors declare no conflicts of interest.

The COMPASS Collaboration experiment recently discovered a new isovector resonancelike signal with axial-vector quantum numbers, the a_{1}(1420), decaying to f_{0}(980)π. With a mass too close to and a width smaller than the axial-vector ground state a_{1}(1260), it was immediately interpreted as a new light exotic meson, similar to the X, Y, Z states in the hidden-charm sector. We show that a resonancelike signal fully matching the experimental data is produced by the decay of the a_{1}(1260) resonance into K^{*}(→Kπ)K[over ¯] and subsequent rescattering through a triangle singularity into the coupled f_{0}(980)π channel. The amplitude for this process is calculated using a new approach based on dispersion relations. The triangle-singularity model is fitted to the partial-wave data of the COMPASS experiment. Despite having fewer parameters, this fit shows a slightly better quality than the one using a resonance hypothesis and thus eliminates the need for an additional resonance in order to describe the data. We thereby demonstrate for the first time in the light-meson sector that a resonancelike structure in the experimental data can be described by rescattering through a triangle singularity, providing evidence for a genuine three-body effect.

The purpose of this study was the identification of genetic lineages and antimicrobial resistance (AMR) and virulence genes in Klebsiella pneumoniae isolates associated with severe infections in the neuro-ICU. Susceptibility to antimicrobials was determined using the Vitek-2 instrument. AMR and virulence genes, sequence types (STs), and capsular types were identified by PCR. Whole-genome sequencing was conducted on the Illumina MiSeq platform. It was shown that K. pneumoniae isolates of ST14 K2 , ST23 K57 , ST39 K23 , ST76 K23 , ST86 K2 , ST218 K57 , ST219 KL125/114 , ST268 K20 , and ST2674 K47 caused severe systemic infections, including ST14 K2 , ST39 K23 , and ST268 K20 that were associated with fatal incomes. Moreover, eight isolates of ST395 K2 and ST307 KL102/149/155 were associated with manifestations of vasculitis and microcirculation disorders. Another 12 K. pneumoniae isolates of ST395 K2,KL39 , ST307 KL102/149/155 , and ST147 K14/64 were collected from patients without severe systemic infections. Major isolates ( n = 38) were XDR and MDR. Beta-lactamase genes were identified: bla SHV ( n = 41), bla CTX-M ( n = 28), bla TEM ( n = 21), bla OXA-48 ( n = 21), bla NDM ( n = 1), and bla KPC ( n = 1). The prevalent virulence genes were wabG ( n = 41), fimH ( n = 41), allS ( n = 41), and uge ( n = 34), and rarer, detected only in the genomes of the isolates causing severe systemic infections- rmpA ( n = 8), kfu ( n = 6), iroN ( n = 5), and iroD ( n = 5) indicating high potential of the isolates for hypervirulence.

This review is devoted to the modern method of monitoring of pupil diameter and reactivity in patients with acute brain injury. The authors present complete data on diagnostic and prognostic capabilities of automated infrared pupillometry, which should take its rightful place in comprehensive assessment of functional brain state in ICU patients. In authors' opinion, clinical introduction of pupillometry will improve prediction of outcomes following acute brain injury and quality of neurological monitoring in patients with cerebral edema and intracranial hypertension.

Background. Hyperthermia is a common symptom in ICU patients with brain injury., Objective: To study the effect of hyperthermia on intracranial pressure (ICP) and cerebral autoregulation (Prx)., Material and Methods: There were 8 patients with acute brain injury, signs of brain edema and intracranial hypertension. Cerebral autoregulation was assessed by using of PRx. ICP, CPP, BP, PRx were measured before and during hyperthermia. We have analyzed 33 episodes of cerebral hyperthermia over 38.30 C. Statistica 10.0 (StatSoft) was used for statistical analysis., Results: Only ICP was significantly increased by 6 [3; 11] mm Hg ( p <0.01). In patients with initially normal ICP, hyperthermia resulted increase of ICP in 48% of cases (median 24 [22; 28] mm Hg). In patients with baseline intracranial hypertension, progression of hypertension was noted in 100% cases (median 31 [27; 32] mm Hg) ( p <0.01). Hyperthermia resulted intracranial hypertension regardless brain autoregulation status., Conclusion: Cerebral hyperthermia in patients with initially normal ICP results intracranial hypertension in 48% of cases. In case of elevated ICP, further progression of intracranial hypertension occurs in 100% of cases. Cerebral hyperthermia is followed by ICP elevation in both intact and impaired cerebral autoregulation.

Nosocomial meningitis (NM) is a serious complication in neurosurgery. Understanding the risk factors of nosocomial meningitis is important for their prevention., Objective: To determine the main risk factors of NM in neurological intensive care unit., Material and Methods: A prospective study included all patients ( n =2140) treated at the neurological intensive care unit for more than 48 hours between October 1, 2010 and October 31, 2015. Cases of nosocomial meningitis were registered. We analyzed risk factors in 2 groups of patients (with and without NM)., Results and Discussion: The incidence of NM in neurological intensive care unit was 8.4% (95% CI 6.8-10.0) ( n =180). Relative risk of NM under external ventricular drainage was 3.98 (99 cases of NM, p <0.05). Relative risk of NM in patients with CSF leakage (including nasal CSF leakage after transsphenoidal surgery) was 5.2 (49 cases of NM, p <0.05). The incidence of nosocomial meningitis was significantly higher among patients with surgery time ≥8 hours (17.68%, p <0.01). Nosocomial meningitis was also significantly more common after redo surgery (13.07%, p <0.05). Insertion of intracranial pressure sensor was not a significant risk factor of NM. The risk of meningitis was 2.67% if the above-mentioned factors were absent. Extracranial factors are not specific for NM. No significant relationship between certain neurosurgical disease and NM was found., Conclusion: We found higher risk of NM in ICU patients with the following factors: external ventricular drainage, CSF leakage, redo surgery and surgery time.

The design of modified oligonucleotides that combine in one molecule several therapeutically beneficial properties still poses a major challenge. Recently a new type of modified mesyl phosphoramidate (or µ-) oligonucleotide was described that demonstrates high affinity to RNA, exceptional nuclease resistance, efficient recruitment of RNase H, and potent inhibition of key carcinogenesis processes in vitro. Herein, using a xenograft mouse tumor model, it was demonstrated that microRNA miR-21-targeted µ-oligonucleotides administered in complex with folate-containing liposomes dramatically inhibit primary tumor growth via long-term down-regulation of miR-21 in tumors and increase in biosynthesis of miR-21-regulated tumor suppressor proteins. This antitumoral effect is superior to the effect of the corresponding phosphorothioate. Peritumoral administration of µ-oligonucleotide results in its rapid distribution and efficient accumulation in the tumor. Blood biochemistry and morphometric studies of internal organs revealed no pronounced toxicity of µ-oligonucleotides. This new oligonucleotide class provides a powerful tool for antisense technology., Competing Interests: The authors declare no competing interest.

The important role of miRNA in cell proliferation and differentiation has raised interest in exogenous ribonucleases (RNases) as tools to control tumour-associated intracellular and extracellular miRNAs. In this work, we evaluated the effects of the RNase binase from Bacillus pumilus on small non-coding regulatory RNAs in the context of mouse RLS 40 lymphosarcoma inhibition. In vitro binase exhibited cytotoxicity towards RLS 40 cells via apoptosis induction through caspase-3/caspase-7 activation and decreased the levels of miR-21a, let-7g, miR-31 and miR-155. Intraperitoneal injections of binase in RLS 40 -bearing mice resulted in the retardation of primary tumour growth by up to 60% and inhibition of metastasis in the liver by up to 86%, with a decrease in reactive inflammatory infiltration and mitosis in tumour tissue. In the blood serum of binase-treated mice, decreases in the levels of most studied miRNAs were observed, excluding let-7g, while in tumour tissue, the levels of oncomirs miR-21, miR-10b, miR-31 and miR-155, and the oncosuppressor let-7g, were upregulated. Analysis of binase-susceptible miRNAs and their regulatory networks showed that the main modulated events were transcription and translation control, the cell cycle, cell proliferation, adhesion and invasion, apoptosis and autophagy, as well as some other tumour-related cascades, with an impact on the observed antitumour effects.

The emergence of highly pathogenic viruses and a high speed of infection spread put forward the problem of the development of novel antivirals and their delivery vehicles. In this study, we investigated the antiviral effect of the previously identified immunostimulatory 19-bp dsRNA (isRNA) with 3'-nucleotide overhangs, which stimulates interferon α synthesis when delivered using cationic liposomes consisting of 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosan tetrahydrochloride and lipid-helper dioleoylphosphatidylethanolamine and its PEGylated formulation P1500 in vitro and in vivo. In vitro data showed that isRNA/2X3-DOPE complexes protected L929 cells from encephalomyocarditis virus infection, while isRNA/P1500 complexes were not active, which correlates with their lower transfection activity in cell culture. Comparison of the interferon-inducing activity of isRNA in BALB/c, CBA and C57Bl/6 mice showed that PEGylated liposomes significantly enhance the interferon-inducing activity of isRNA in vivo. The antiviral efficacy of the isRNA in vivo was considerably affected by the delivery system. The cationic liposomes 2X3-DOPE did not enhance the antiviral properties of isRNA in vivo. Similar liposomes equipped with a PEGylated lipoconjugate provided a pronounced anti-influenza effect of the isRNA in vivo. Administration of isRNA to C57Bl/6 led to a decrease in virus titers in the lungs and a significant decrease in the severity of the infection. Administration of a similar formulation to BALB/c mice caused only a mild antiviral effect at the initial stages of the infection. The data show that isRNA in combination with the PEGylated delivery system can be considered an effective means of suppressing influenza A infection.

Melanoma is one of the most aggressive tumors and is accompanied by the induction of local and systemic inflammatory responses. Combinations of chemotherapeutic agents with immunotherapy are therefore commonly used for melanoma treatment. A B16 melanoma model was used to study the tumor suppressive, immunostimulating, and hepatotoxic effects of a combination of a small double-stranded immunostimulatory RNA (isRNA) with 3'-trinucleotide overhangs and the cytotoxic drug dacarbazine compared with respective monotherapies. The drugs efficiently suppressed the tumor growth and acted synergistically. Histological and immunohistochemical examinations of tumor nodes showed that the combination of isRNA and dacarbazine significantly decreased mitotic activity and more efficiently increased apoptosis in tumor tissue as compared with either monotherapy. Regardless of the treatment regimen, signs of immune activation were observed in the spleen, including an increase in the number and diameter of lymphoid follicles and the volume density of the white pulp. Destructive changes were detected in the livers of nontreated animals with B16 melanoma. Administration of isRNA in combination with dacarbazine did not cause any additional damage to liver parenchyma, while stimulating regenerative processes in hepatic tissue of tumor-bearing animals.

Introduction: Paradoxical air embolism (PAE) is a rare potentially fatal complication followed by entering of air emboli from the right cardiac chambers and pulmonary artery to large circulation circle., Objective: To analyze five patients who underwent neurosurgical intervention complicated by PAE and early postoperative convulsive syndrome., Material and Methods: There were five patients who developed early postoperative convulsive syndrome after previous neurosurgery in sitting position complicated by PAE. Convulsive syndrome required intensive care at the ICU. MRI confirmed ischemic foci de novo outside the zone of surgical intervention in all cases. All patients underwent video-EEG monitoring in order to select anticonvulsant therapy and evaluate its effectiveness. The authors were able to match the epileptogenic focus in the cerebral cortex with MRI data. Available literature data devoted to the problem of convulsive syndrome after neurosurgery complicated by PAE were analyzed., Results: The focus of epileptiform activity coincided with one of the foci of hyperintense MR signal in all cases., Conclusion: Video-EEG monitoring is advisable in patients with impaired consciousness who underwent neurosurgery complicated by PAE.

Subarachnoid hemorrhage after cerebral aneurysm rupture (aSAH) leads to delayed cerebral ischemia (DCI) in 25-35% of surviving patients. It is believed that DCI has a multifactorial etiology, including vasospasm. Furthermore, aSAH is associated with the development of hypercoagulation and microthrombosis; thus, its pharmacological correction may help to prevent DCI. We encountered a case where hypercoagulation was detected using rotational thromboelastometry (ROTEM), although the standard coagulation test results were within the normal ranges. Based on reviews of viscoelastic tests in cases of aSAH, ROTEM could be more sensitive to hypercoagulation after aSAH, compared to standard coagulation testing.

Objective: This research is aimed to study the clinical and MRI predictors of coma duration, the intensity of critical care, and outcome of traumatic brain injury (TBI)., Material and Methods: The data from 309 patients with TBI of varying severity were included in the analysis, of whom 257 (86.7%) were treated in the intensive care unit (ICU), including 196 (63.4%) patients admitted in a comatose state lasting longer than 1 day. All patients underwent brain MRI within 21 days after the injury. MRI findings were classified according to MRI grading scale of brain damage level and localization proposed previously., Results: The proposed MRI grading significantly correlated with the Glasgow coma (GCS, r=-0.67; p<0.0001) and Glasgow outcome (0.69; p<0.001) scores in the entire group. In a subgroup of comatose patients (GCS<9) it correlated with coma duration (r=0.52; p<0.0001). Spearman correlation analysis showed a significant relationship between the MRI classification and a number of parameters: ICU length of stay (r=0.62; p<0.0001), the duration of artificial ventilation (r=0.47; p<0.0001), the rate of artificial ventilation, sedatives, analgesics, mannitol, hypertonic saline and vasopressors usage (p<0.01). These data confirm the relationship between higher grades of MRI classification (deep brain damage) and the need for the escalation of intensive care main components., Conclusion: Our results support the hypothesis that the levels and localization of brain damage, estimated by the proposed MRI grading scale, might be predictors of coma duration, intensity and duration of intensive care, and TBI outcomes. A prognosis based on clinical and neuroimaging data comparison can be valuable for planning and efficient use of the hospital beds and ICU resources, for optimizing the patient flow and timing of patient transfer to neurorehabilitation facilities.

The first results of intracisternal administration of verapamil for the prevention and treatment of cerebral vasospasm (CVS) in patients in the acute period of subarachnoid hemorrhage (SAH) after microsurgical clipping of cerebral aneurysms are presented., Objective: Safety assessment of the method of prolonged intracisternal infusion (PII) of verapamil., Material and Methods: Over the period from May 2017 to December 2018, 42 patients were included in the study, who underwent clipping of aneurysm of the anterior segments of the Willis circle. Most patients (78.6%) were operated during the first 6 days after SAH. For each patient, a thin silicone catheter was installed, through which verapamil was infused. A prerequisite was the installation of external ventricular drainage and opening of the lamina terminalis. The daily dosage of verapamil varied from 25 to 50 mg of the drug diluted in 200-400 ml of isotonic sodium chloride solution. The indication for the use of the PII method was the presence of one of the following factors: a score on the Hunt-Hess scale from III to V, 3 or 4 points on the Fisher scale, confirmed angiographically by the CVS before the operation., Results: The PII procedure was performed from 2 to 5 days. The average dose of verapamil was 143.5±41.2 mg additionally, in the presence of an angiographically confirmed CVS accompanied by clinical manifestations, 14 (33.4%) patients received intra-arterial injection of verapamil in several stages, with individual selection of the drug dose. The formation of new cerebral ischemic foci of vasospastic genesis was observed in only 1 (2.4%) patient. No infectious intracranial complications were noted. The average follow-up period was 297.6±156.1 days. Long-term treatment outcomes, assessed by a modified Rankin scale from 0 to 2 points, were observed in 83.3% of patients. There were no outcomes such as vegetative status and no deaths. The frequency of liquorodynamic disorders, as well as epileptic syndrome did not exceed that among patients with SAH according to the literature., Conclusion: The study has confirmed the safety of prolonged PII. The efficacy of the method, compared with other methods for CVS treatment requires further investigation. The first results look quite promising: the observation shows a low percentage of new foci of cerebral ischemia and the absence of deaths associated with it. In patients with severe CVS, the efficacy of the PII method is increased when combined with intra-arterial administration of verapamil.

Objective: The aim of this study was to estimate the prognostic value of magnetic resonance imaging (MRI) classification of traumatic brain lesion localization and levels in patients with a brain injury of various severity in a few days to three weeks after the injury., Material and Methods: The cohort of 278 patients with traumatic brain injury (TBI) of various severity aged 8-74 y.o. (average -31.4±13.8, median - 29 (21.3; 37.0) was included in the analysis. The severity of TBI at admission varied from 3 to 15 Glasgow coma scores (GCS) (average - 8±4, median - 7 (5; 12). The main indications and conditions for MRI were: inconsistency between computed tomography (CT) data and neurological status, the necessity to clarify the location and type of brain damage, the absence of metal implants, the stabilization of the patient's vital functions, etc. MRI was performed during the first three weeks after the injury using T1, T2, T2-FLAIR, DWI, T2*GRE, SWAN sequences. The damage to the brain was classified according to 8 grades depending on the lesion levels (cortical-subcortical level, corpus callosum, basal ganglia and/or thalamus, and/or internal, and/or external capsules, uni- or bilateral brain stem injury at a different level). Outcomes were assessed by the Glasgow outcome scale (GOS) 6 months after injury., Results: The significant correlations were found for the entire cohort between MRI grading and TBI severity (by GCS) and outcome (by GOS) of the injury (R=-0.66; p<0.0001; R=-0.69; p<0.0001, respectively). A high accuracy (77%), sensitivity (77%) and specificity (76%) of the proposed MRI classification in predicting injury outcomes (AUC=0.85) were confirmed using the logistic regression and ROC analysis. The assessment of MRI-classification prognostic value in subgroups of patients examined during the first, second, and third weeks after injury showed significant correlations between the GCS and the GOS as well as between MRI-grading and GCS, and GOS in all three subgroups. In the subgroup of patients examined during the first 14 days after the injury, the correlation coefficients were higher compared with those obtained in a subgroup examined 15-21 days after the injury. The highest correlations between MRI grading, TBI severity, and the outcome were found in the subgroup of patients who underwent MRI in the first three days after the injury (n=58)., Conclusion: The proposed MRI classification of traumatic brain lesion levels and localization based on the use of different MR sequences reliably correlated with the clinical estimate of TBI severity by GCS and the outcomes by GOS in patients examined during the first three weeks after injury. The strongest correlation was observed for patients examined during the first three days after the injury.

Management of the healthcare quality and safety is one of the priorities of state policy for protecting health of Russian citizens. We describe modern technologies for managing the quality of medical care and patient safety based on a systematic approach. Potential applications of these technologies in neurosurgical practice are defined. Quantitative, qualitative, and basic indicators are proposed for evaluation of outcomes (results) as part of implementation of an integrated quality management system in neurosurgical practice.

Treatment of children in the acute stage of hemorrhage from cerebral aneurysms is based on clinical cases reported in the literature and descriptions of small series of observations. There are no studies that enable the development of evidence-based approaches to intensive care in treatment of children with aSAH. We present a clinical case with a favorable outcome of complex treatment in a child admitted to the Burdenko Neurosurgical Institute at an extremely severe condition. The efficacy of treatment was based on a timely urgent neurosurgical intervention and adequate intensive therapy in the form of extended neuromonitoring with continuous measurement of intracranial pressure, which enabled using the whole complex of measures for timely management of intracranial hypertension. A favorable outcome (a GOS score IV) after this severe aneurysmal SAH indicates that there are no absolute contraindications for neurosurgical treatment of children with cerebral aneurysms.

The use of endoscopic technique has significantly extended the indications for surgery using the transsphenoidal approach. Currently, more than 90% of pituitary adenomas are operated on transsphenoidally. Transnasal removal of giant pituitary adenomas has become possible. Transition to the endoscopic endonasal approach in removal of pituitary adenomas changed the rate and structure of postoperative complications. We analyzed potential complications after endoscopic endonasal transsphenoidal removal of pituitary adenomas. These include complications of the approach itself (nasal bleeding, perforation of the nasal septum, impaired olfactory function, atrophic rhinitis, synechiae, mucoperiosteal flap necrosis, and external nasal deformities), infectious complications (meningitis, intracranial abscesses), cerebral circulation disorder (subarachnoid hemorrhage, cerebral vasospasm, injury to large vessels, intracranial hematomas), neuro-ophthalmological complications (visual and oculomotor disorders), endocrine (hypopituitarism, diabetes insipidus, hyponatremia) and somatic complications, and nasal liquorrhea. In conclusion, it should be noted that despite continuous improvement of the technique for endoscopic endonasal removal of pituitary adenomas, there is a risk of serious complications, which necessitates the development of techniques for prevention of these complications.

Subarachnoid hemorrhages due to rupture of cerebral aneurysms are characterized by high mortality. More than 25% of patients who have survived the first hours after aneurysmal SAH (aSAH) develop delayed cerebral ischemia that is one of the main causes of disability. The mechanisms underlying delayed ischemia have not yet been fully understood. Previously, the development of vasospasm was believed to be the only cause for development of delayed ischemia. In recent years, there has been evidence that hemostatic system disorders typical of this category of patients are the cause of cerebral artery thrombosis, which is one of the main pathophysiological mechanisms for the development of delayed cerebral ischemia. This review presents an analysis of published papers on hemostasis disturbances in patients with aSAH, their pathophysiological mechanisms, and their role in the development of cerebral ischemia.