Bulletin of RSMU

ISSN Print 2500–1094 ISSN Online 2542–1204

Bulletin of RSMU

BIOMEDICAL JOURNAL OF PIROGOV UNIVERSITY (MOSCOW, RUSSIA)

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Popov NS, Terekhov VM, Baranov MS, Balabanyan VYu, Kaurova DE, Myasnyanko IN, Terekhova EA

Assessment of pharmacologically active molecule biotransformation represents the most important phase of drug development, the results of which make it possible to identify active and toxic metabolites and provide a fundamental basis for the targeted design of new candidate drug molecules. The liver is the main organ involved in biotransformation of drugs. The currently widely used in vitro metabolism assessment methods do not allow one to identify products of extrahepatic drug molecule biotransformation. The study aimed to develop an in vivo approach to determination of the role of the liver in biotransformation of candidate drug molecules. The approach proposed is based on the vascular liver isolation performed surgically in laboratory rats. The organ involvement in biotransformation of pharmacologically active molecules is exemplified by the leader compound of the sydnone imine group possessing vasodilatory activity. It has been shown that elimination of the liver from systemic blood flow does not result in generation of the test compound metabolites identified by chromatography–mass spectrometry. The findings can provide the basis for prediction of drug pharmacokinetics, efficacy, and safety.

Received: 2025-04-16

Published online: 2025-05-15

DOI: 10.24075/brsmu.2025.026

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VIEWS 1904

Rebrikov DV, Degtyareva AV, Yanushevich YuG, Gautier MS, Gorodnicheva TV, Bavykin AS, Ushakova LV, Filippova EA, Degtyarev DN, Sukhikh GT

Crigler–Najjar syndrome type I, an orphan UTG1A1 enzyme deficiency, manifests at birth with severe unconjugated hyperbilirubinemia. Here we describe sustained clinical response in a pediatric patient with Crigler–Najjar syndrome type I treated with two consecutive doses of AAV8 delivering the UTG1A1 coding sequence. Infusion I (6 × 1012 vg/kg) afforded sustained decrease in serum bilirubin, allowing substantial relaxation of the phototherapy from 12 h to 4 h daily. Infusion II at a double dose was made in 6 months; the decision was intended at complete elimination of phototherapy. However, the elimination led to a sharp increase in bilirubin levels necessitating resumption of phototherapy. The patient is currently stable on 4 h daily phototherapy for 80 weeks since the resumption and 107 weeks since the AAV8 therapy initiation. No toxic side effects were encountered. A slow incremental dynamics in serum bilirubin opens the issue of clinical advisability for subsequent infusions of the drug.

Received: 2025-04-25

Published online: 2025-04-30

DOI: 10.24075/brsmu.2025.025

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VIEWS 2189

Minasov BSh, Yakupov RR, Akbashev VN, Shchekin VS, Vlasova AO, Minasov TB, Karimov KK, Akhmeldinova AA

Morphological subchondral bone tissue alterations associated with knee osteoarthritis represent a key pathogenesis link and can precede articular cartilage destruction. The study aimed to identify typical morphological and morphometric signs of osteosclerosis and osteoporosis in the subchondral zone of the femur and tibia. Analysis of 40 bone tissue fragments collected when performing knee replacement surgery in 20 patients (12 females and 8 males) aged 58–75 years with stage III–IV osteoarthritis was performed. Histological and morphometric assessment involving the use of light microscopy and microfracture index (MFI) calculation revealed significant differences in trabecular thickness, intertrabecular distance, and the degree of microdamage between the sites of sclerosis and osteoporosis. High MFI values in the zones of osteoporosis can reflect reduced subchondral bone strength. The findings confirm the diagnostic value of the subchondral zone morphometry and the prospects of using MFI as a quantitative risk criterion when planning orthopedic treatment.

Received: 2025-04-06

Published online: 2025-04-30

DOI: 10.24075/brsmu.2025.024

Comments 0

VIEWS 2112

Kildyushevsky AV, Kotov SV, Sidorova OP, Borodin AV, Bunak MS

Multiple sclerosis is an autoimmune disorder, the development of which involves humoral and cellular immunity. The disease-modifying drugs (DMDs) for multiple sclerosis slow down the disease progression, but the therapy prescribed is not always well tolerated by patients; allergy and other side effects are possible. In this regard, the development of new methods, including non-pharmacological ones, is relevant. These methods include extracorporeal photopheresis involving UV exposure of peripheral blood lymphocytes and its modification — transimmunization (involving incubation of lymphocytes after UV exposure). The study aimed to compare and within a year assess the transimmunization and glatiramer acetate efficacy in patients with relapsing-remitting multiple sclerosis. A total of 19 adult patients with relapsing-remitting multiple sclerosis, who had been prescribed transimmunization, were assessed. Patients over the age of 18, who did not receive treatment by other methods (DMDs for multiple sclerosis, etc.), were included in the study. The comparison group consisted of 48 adult patients with relapsing-remitting multiple sclerosis, who were prescribed subcutaneous glatiramer acetate 20 mg daily. Clinical assessment was performed using EDSS. Brain and spinal cord MRI was performed in the 3.0 and 1.5 T scanners. When performing transimmunization, the decrease in the median overall EDSS score from 2 to 1.5 points was reported. In the comparison group of patients receiving glatiramer acetate, the median EDSS score changed from 1.75 to 2 points. Therefore, transimmunization is comparable with first-line DMDs for multiple sclerosis and can be used to stabilize the disease course.

Received: 2025-04-02

Published online: 2025-04-29

DOI: 10.24075/brsmu.2025.023

Comments 0

VIEWS 2018

Ivanenko AV, Starodubova VD, Shokhina AG

Wilson’s disease is a rare hereditary disorder caused by the ATP7B gene mutations that leads to copper metabolism disturbances and toxic copper accumulation in the liver, brain, and other organs. The main manifestations include liver damage, neurological and psychiatric symptoms. The use of advanced treatment methods (D-penicillamine, trientine, zinc salts) improves the outcome, but is limited by side effects and complexity of adherence to therapy. Liver transplantation is used in severe forms, but it is limited by the donor shortage and the need for immunosuppression. In our opinion, promising areas include gene therapy involving the use of AAV vectors and CRISPR/Cas9, mRNA platforms, and cell technologies. However, these approaches require further research for the efficacy, safety, and accessibility improvement.

Received: 2025-04-02

Published online: 2025-04-28

DOI: 10.24075/brsmu.2025.022

Comments 0

VIEWS 1979

Nikishina VB, Petrash EA, Chausov AS, Kanimetov KK

The relevance of the study provided results from the need to search for the objectifying methods to assess self-identification phenomenon in early childhood. The study aimed to evaluate the diagnostic potential of the software-hardware complex for analysis of self-identification phenomenon in young children. The sample consisted of 136 subjects of early age (12–36 months): 57 boys and 79 girls. Assessment methods: functional neuropsychological tests for evaluation of facial and optical-spatial gnosis; test 22 — mirror image series of the Bayley-III cognitive scale; self-recognition mirror test; the developed software-hardware complex for analysis of self-identification phenomenon in early childhood (SHC). The study conducted has shown that self-identification emerges at the age of 18 months, which has been also confirmed by the earlier research. However, the response to one’s own reflection in the mirror as one sign of self-identification manifests itself in children at an earlier age and in some children turns out to be shaped by the age of 12 months, which is suggested by the facts of successful test execution in the group aged 12–17 months and low specificity of the method for self-identification. Thus, high SHC specificity for self-identification in early childhood is reported based on the findings.

Received: 2025-03-28

Published online: 2025-04-25

DOI: 10.24075/brsmu.2025.021

Comments 0

VIEWS 1970

Nuralieva NF, Yukina MYu, Bykova SV, Savvateeva EN, Nikankina LV, Kulagina EV, Shaskolskiy BL, Gryadunov DA, Troshina EA

The search for concomitant autoimmune disorders (ADs) in patients with celiac disease is a pressing issue. The study aimed to determine the rate of the carrier state for antibodies (Abs) being the markers of AD development in patients with celiac disease using various immunological approaches. Enzyme-linked immunoassay and hydrogel microarray-based multiplex immunoassay (MI) were used to determine Abs against thyroid peroxidase (TPO), thyroglobulin (TG), glutamate decarboxylase (GAD), pancreatic islet cells (ICA), tyrosine phosphatase (IA2), 21-hydroxylase (P450c21), Castle's intrinsic factor, tissue transglutaminase (TGM2) in blood serum of patients with celiac disease (group 1, n = 27) and healthy individuals (group 2, n = 16). The microarray also enables testing of Abs against interferons (IFN) alpha and omega, interleukin 22. In group 1, Abs against IA2 (30%), TPO (22%), TG (19%), GAD (19%) were detected by the enzyme-linked immunoassay, and in group 2 Abs against IA2 (38%), TPO (19%), GAD (19%) were detected. In group 1, Abs against TPO (11%), TG (11%), P450c21 (4%), IFN-alpha (4%), ICA (4%) were detected using the microarray, and in group 2 Abs against TPO (13%), ICA (13%), TG (6%), IFN-alpha (6%) were identified. No significant differences in the rate of elevated Abs in the groups were revealed (p > 0.05). Patients, in whom the Ab carrier state was established using microarrays, with negative results enzyme-linked immunoassay can develop the delayed ADs, which suggests prognostic value of MI. The lack of significant differences in the rate of elevated Abs in patients with celiac disease and healthy individuals can result from small size of the studied groups and can suggest high prevalence of potential AD forms in these cohorts.

Received: 2025-04-02

Published online: 2025-04-23

DOI: 10.24075/brsmu.2025.020

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VIEWS 1917

Buzenkova AV, Grigoryeva ES, Alifanov VV, Tashireva LA, Savelieva OE, Pudova ES, Zavyalova MV, Cherdyntseva NV, Perelmuter VM

It is difficult to detect the circulating tumor cells (CTCs) being through the epithelial–mesenchymal transition (EMT) terminal phase, since these do not express epithelial markers or show weak expression of those. This hampers assessment of the CTC prognostic potential. It has been shown that the circulating cells (CCs) with the CD45–EpCAM–CK7/8–CD24+N-cadherin‒ phenotype are associated with the risk of metastasis in breast cancer (BC). The study aimed to test CCs based on the side scatter parameters considering the expression of epithelial cell markers and CD11b. CC phenotypes were assessed by flow cytometry within the regions with low (SSClow) and high (SSChigh) side scatter in 11 donors and 20 female patients with BC. All the CD45–EpCAM–CK7/8–CD24+N-cadherin– CCs were represented by the CD11b– and CD11b+ phenotypes found in both SSClow and SSChigh regions. Among eight CD45–mEpCAM–CK7/8–CD24+N-cadherin– CC phenotypes with different variants of co-expression of epithelial markers (E-cadherin, panCK, and icEpCAM) and CD11b found in patients, six showed signs of epithelial nature based on one of the markers, while another two showed no epithelial traits and predominated over other phenotypes (only these two phenotypes were found in donors). The differences in light scattering parameters of the CCs with the same phenotype is one more characteristic, the prognostic value of which remains to be uncovered. The E-cadherin and panCK expression in the absence of mEpCAM and presence of icEpCAM suggest that some CCs are tumor cells in the state of pronounced EMT. CCs showing co-expression of CD11b and epithelial markers can emerge due to hybridization with myeloid cells.

Received: 2025-03-11

Published online: 2025-04-18

DOI: 10.24075/brsmu.2025.019

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VIEWS 1898