[Historical aspects of the formation and development of children's health resort medicine in the Samara region]. / Istoricheskie aspekty formirovaniya i razvitiya detskoi kurortnoi meditsiny v Samarskom regione.

Archive documents and sources in scientific electronic databases were analyzed in order to study the historical origins of the health resort business in terms of children's health resort medicine in the Samara government. It has been established that the period of origin and intensive development of balneology for children in the Samara region occurred at the beginning of the 20th century and the first children's sanatoriums began to function thanks to the initiative of the Society of Governmental Physicians for charitable funds of the Samara nobility and merchantry in territories with natural and climatic therapeutic factors, namely Sernovodsky resort, Barboshina glade and Postnikov ravine. A comparative analysis of the dynamics of morbidity structure of children admitted for sanatorium treatment, as well as general education institutions, from which information on the health of school pupils is received, has been conducted over a period of 120 years. Despite the change of years and generations, there is a general concept of sanatorium health improvement of school pupils as a future social and economic pillar of society, with the formation of a healthy generation for both the region and the country in general.

Targosomes: Anti-HER2 PLGA nanocarriers for bioimaging, chemotherapy and local photothermal treatment of tumors and remote metastases.

Developing combined cancer therapy strategies is of utmost importance as it can enhance treatment efficacy, overcome drug resistance, and ultimately improve patient outcomes by targeting multiple pathways and mechanisms involved in cancer growth and progression. Specifically, the potential of developing a combination chemo&photothermal therapy using targeted polymer nanoparticles as nanocarriers offers a promising approach for synergistic cancer treatment by combining the benefits of both therapies, such as targeted drug delivery and localized hyperthermia. Here, we report the first targeted anti-HER2 PLGA nanocarriers, called targosomes, that simultaneously possess photothermal, chemotherapeutic and diagnostic properties using only molecular payloads. Biocompatible poly(lactic-co-glycolic acid), PLGA, nanoparticles were loaded with photosensitizer phthalocyanine, diagnostic dye Nile Blue, and chemotherapeutic drug irinotecan, which was chosen as a result of screening a panel of theragnostic nanoparticles. The targeted delivery to cell surface oncomarker HER2 was ensured by nanoparticle modification with the anti-HER2 monoclonal antibody, trastuzumab, using the one-pot synthesis method without chemical conjugation. The irradiation tests revealed prominent photothermal properties of nanoparticles, namely heating by 35 °C in 10 min. Nanoparticles exhibited a 7-fold increase in binding and nearly an 18-fold increase in cytotoxicity for HER2-overexpressing cells compared to cells lacking HER2 expression. This enhancement of cytotoxicity was further amplified by >20-fold under NIR light irradiation. In vivo studies proved the efficacy of nanoparticles for bioimaging of primary tumor and metastasis sites and demonstrated 93% tumor growth inhibition, making these nanoparticles excellent candidates for translation into theragnostic applications.

Phage-mimicking nanoagents for rapid depolymerase specificity screening against multidrug resistant bacteria.

With the rise of drug resistance, bacteriophages and bacteriophage-derived proteins may become an efficient successor to traditional antibiotics. While the enormous natural diversity of the phages allows matching virtually any bacteria, identification of the potentially life-saving phage is currently a tedious and time-consuming challenge that often cannot be performed within a reasonable time. Here we show a rapid 1-min bacteriophage screening assay based on specially constructed phage-mimicking nanoagents and surface plasmon resonance effect. Within the assay, a panel of phage-mimicking gold nanoparticles, possessing the specificity and enzymatic activity of a particular phage, is mixed with a suspension of the bacteria of interest. The spectral behaviour of the assay mix allows measurement of two critical parameters of the nanoagents and the corresponding bacteriophages: 1) direct assessment of their specificity due to convergence of the particles on the cell walls, and more importantly, 2) real-time evaluation of their enzymatic activity for the destruction of the cell capsule via detection of nanoagent detachment from the surface of bacteria. The proposed assay overcomes the current time limitations of the phage-bacteria matching procedures and thereby can facilitate faster development and adoption of phage-based therapies as a much-needed alternative to traditional antibiotics.

[Aerobic exercise and fatigue indices in rheumatoid arthritis patients in the health resort care setting]. / Aerobnye uprazhneniya i pokazateli ustalosti u bol'nykh revmatoidnym artritom v usloviyakh sanatorno-kurortnogo lecheniya.

Fatigue is one of the most common symptoms of rheumatoid arthritis (RA). There is strong evidence that physical activity is an effective way to reduce fatigue. OBJECTIVE: To evaluate the effectiveness of aerobic exercise (walking) to reduce fatigue in RA patients in the health resort setting. MATERIAL AND METHODS: The study involved 102 female patients with RA (age 54.38±11.3 years, body mass index 20-29 kg/m2, DAS28-ESR ≤3.2, with severe fatigue of VAS ≥50) who received 21 days of health resort treatment. The health-improving and therapeutic complex includes dosed physical activity, aerobic exercises (walking). Visual analog scale (VAS0-100) and Bristol Rheumatoid Arthritis Fatigue Scale-Numerical Rating Scale (BRAF-NRS V2) were used to assess fatigue, and the 50-meter walking test was used to evaluate the functional status of patients. RESULTS: A correlation between walking duration and the number of steps at a distance of 50 m (p<0.001) as well as between these indices and fatigue (p<0.001) was shown. A positive effect of a standard three-week medical rehabilitation program for patients with RA on fatigue NRS severity (p=0.003) and NRS effect (p=0.037), as well as on patients' functional status (reduced time spent on the 50-meter test, p=0.01) was demonstrated. When comparing groups of RA patients with low (group 1, <5000-6000 steps per day) and optimal (group 2, ≥7000-8000 steps per day) aerobic exercise, positive results were noted in the short term (at 3 weeks) (p<0.001). CONCLUSION: Aerobic exercise is a promising intervention for treating fatigue in rheumatoid arthritis patients. Medical rehabilitation in a resort setting is the best starting point to encourage performing regular physical activity, as well as the best way to develop exercise programs tailored to rheumatoid arthritis patients.

[State policy of development of resort business in Russia: legal and organizational aspects, including those in an emergency]. / Gosudarstvennaya politika razvitiya kurortnogo dela v Rossii: pravovye i organizatsionnye aspekty realizatsii, v tom chisle v ekstremal'noi situatsii.

OBJECTIVE: To analyze the normative and regulatory support of the state policy of development of health resort business in Russia and organizational and methodological aspects of its implementation, including those in emergency and coronavirus pandemic. MATERIAL AND METHODS: The following current methods of community hygienic and medical-organizational research were applied: analytical, statistical, best practice study, monographic, etc. Data from state and departmental official sources, statistical books, scientific publications, and other sources were studied. RESULTS: The main normative, regulatory, organizational and methodological aspects of the strategy implementation, developed in accordance with the order of the Government of the Russian Federation «On approval of the development strategy of the health-resort complex of the Russian Federation¼ dated 26.11.18 №2581-p were analyzed. Some discrepancies in the state and departmental statistics of health-resort organizations were found. The nomenclature of the health-resort area was reviewed, and the used term «health-resort treatment¼ was criticized, which does not correspond to the parts of this type of daily practice medical care, unlike the concepts «health-resort care¼ or «health-resort business¼. The article presents the author's vision of the issue of normative and organizational support of health-resort organizations in an emergency such as COVID-19 pandemic since 2020. CONCLUSIONS: It is shown that the national and local experience of coronavirus infection control contributed to the development of a considerable number of federal regulatory documents in a short time frame. The publication describes an analysis and systematic review of the most important documents, including those related to the spa resorts. Addressing the demanding challenges of further development of the country's health-resort complex largely relies on the state of its facilities and resources. However, its objective analysis is hindered by the identified significant discrepancies in the state and departmental statistic data concerning the number of functioning health-resort organizations and its change over time. As opposed to the concept of «health-resort treatment¼, the term «health-resort care¼ most accurately describes its complexity.

[Traditional nutrition and demography in the Arctic zone of Western Siberia].

High requirements for macro- and micronutrients of the organism of a pregnant woman living in the Far North are associated with the influence of extreme factors of high latitudes, and the needs of the mother and the growing fetus. Only the products of the unique food culture of the Arctic people - the Nenets, make it possible to meet the emerging needs. The aim of the work was to study the impact of traditional nutrition on the reproductive health of Nenets women living in the Arctic zone of Western Siberia. Material and methods. 619 indigenous inhabitants (Nenets) of the Yamal, Nadym and Taz districts of the Yamal-Nenets Autonomous Okrug at the age of 18-65 years were examined. The influence of the type of nutrition (traditional or imported products) on reproductive health indicators (the number of pregnancies, the number of children, the number of spontaneous abortions, frequency of gestosis, threats of termination of pregnancy, operative deliveries) for the period 2013-2018 was studied by analyzing official statistics and by questioning of the female population in own research. Results. The consumption of traditional products (venison, local fishery products, at least 3 times a week) by Nenets women was more often accompanied by a normal physiological course of pregnancy and childbirth (75.2 versus 64.2%, χ2=8.7; p=0.003). It led to a 1.5-fold decrease in the frequency of complications during pregnancy (gestosis, the threat of abortion) (χ2=5.8; p=0.01) and a 20% decrease in the frequency of delivery by cesarean section (χ2=16.6; p<0.001). As a result, a family whose diet was dominated by traditional products had a statistically significantly larger number of children (per child). Conclusion. The preservation of the consumption of reindeer and river fishery products by indigenous women will contribute to the sufficient intake of macro- and micronutrients, that will make it possible to gestate and give birth to a healthier generation of the Nenets society.

GLAD-PCR Assay of R(5mC)GY Sites in the Regulatory Region of Tumor-Suppressor Genes Associated with Gastric Cancer.

At early stages of carcinogenesis, the regulatory regions of some tumor suppressor genes become aberrantly methylated at RCGY sites, which are substrates of DNA methyltransferase Dnmt3. Identification of aberrantly methylated sites in tumor DNA is considered to be the first step in the development of epigenetic PCR test systems for early diagnosis of cancer. Recently, we have developed a GLAD-PCR assay, a method for detecting the R(5mC)GY site in the genome position of interest even at significant excess of DNA molecules with a non-methylated RCGY site in this location. The aim of the present work is to use the GLAD-PCR assay to detect the aberrantly methylated R(5mC)GY sites in the regulatory regions of tumor suppressor genes (brinp1, bves, cacna2d3, cdh11, cpeb1, epha7, fgf2, galr1, gata4, hopx, hs3st2, irx1, lrrc3b, pcdh10, rprm, runx3, sfrp2, sox17, tcf21, tfpi2, wnt5a, zfp82, and znf331) in DNA samples obtained from gastric cancer (GC) tissues. The study of the DNA samples derived from 29 tumor and 25 normal gastric tissue samples demonstrated a high diagnostic potential of the selected RCGY sites in the regulatory regions of the irx1, cacna2d3, and epha7 genes; the total indices of sensitivity and specificity for GC detection being 96.6% and 100%, respectively.

[The effectiveness of combined laser therapy in patients with trophic leg ulcer and chronic venous insufficiency]. / Effektivnost' kombinirovannoi lazernoi terapii patsientov s troficheskimi yazvami nizhnikh konechnostei na fone khronicheskoi venoznoi nedostatochnosti.

New prospects associated with the use of laser radiation of different wavelengths in the ultraviolet (365 nm) and the green emission spectrum (525 nm) have appeared in recent years. The high prevalence of the trophic leg ulcers necessitates the search for more effective methods of conservative treatment. PURPOSE OF THE STUDY: Development and scientific justification for the low-intensity laser radiation of different wavelengths combined use in patients with trophic leg ulcers and chronic venous insufficiency (CVI). MATERIAL AND METHODS: 102 patients with trophic leg ulcers and CVI were examined. They were divided into 3 equal groups using simple randomization. Patients in the control group received only traditional conservative therapy; comparison group - traditional conservative therapy and an intravenous laser blood irradiation (ILBI) (λ - 635 nm); the main group - traditional conservative therapy and different wavelengths laser therapy (LT) course. RESULTS AND CONCLUSION: A more significant improvement in the clinical condition occurred under the influence of the course application of combined different wavelengths laser therapy in patients with trophic venous leg ulcers. Compared to patients who received traditional conservative therapy and in combination with ILBI 635 nm, the speed of reparative regeneration of trophic ulcers increased, the time for cleansing trophic ulcers from devitalized tissues was reduced. Computer capillaroscopy data showed that the positive effect of laser exposure on all parts of the microcirculation underlies its therapeutic efficacy.

Dynamic light scattering biosensing based on analyte-induced inhibition of nanoparticle aggregation.

A new approach to direct quantitative detection of small molecules (haptens) by dynamic light scattering biosensing is presented. The proposed technique implements a homogeneous competitive immunoassay and is based on optical detection of specific inhibition of nanoparticle aggregation induced by the analyte in a sample. The technique performance was tested both in buffer and milk for detection of chloramphenicol - antibiotic relevant to food safety diagnostics. Good specificity, sensitivity (LOD in milk is 2.4 ng/ml), precision (4.0 ± 1.2%), ruggedness (8.3%), and 96% recovery in conjunction with a record wide dynamic range (3 orders of magnitude) of the nanosensing technique were demonstrated. Such characteristics complemented by the assay simplicity (no washing step) and a short assay time make the approach attractive for application as an analytical platform for point-of-care and field-oriented diagnostics. Graphical abstract.

[Application of GLAD-PCR Assay for Study on DNA Methylation in Regulatory Regions of Some Tumor-Suppressor Genes in Lung Cancer].

Hypermethylation of the gene regulatory regions are common for many cancer diseases. In this work we applied GLAD-PCR assay for identificating of the aberrantly methylated RCGY sites in the regulatory regions of some downregulated genes in tissue samples of lung cancer (LC). This list includes EFEMP1, EPHA5, HOXA5, HOXA9, LHX1, MYF6, NID2, OTX1, PAX9, RARB, RASSF1A, RXRG, SIX6, SKOR1 and TERT genes. The results of DNA samples from 40 cancer and 25 normal lung tissues showed a good diagnostic potential of selected RCGY sites in regulatory regions of MYF6, SIX6, RXRG, LHX1, RASSF1A and TERT genes with relatively high sensitivity (80.0 %) and specificity (88.0 %) of LC detection in tumor DNA.

First Measurement of a Long-Lived π

The adapted DIRAC experiment at the CERN PS accelerator observed for the first time long-lived hydrogenlike π^{+}π^{-} atoms, produced by protons hitting a beryllium target. A part of these atoms crossed the gap of 96 mm between the target and a 2.1 µm thick platinum foil, in which most of them dissociated. Analyzing the observed number of atomic pairs, n_{A}^{L}=436_{-61}^{+157}|_{tot}, the lifetime of the 2p state is found to be τ_{2p}=(0.45_{-0.30}^{+1.08}|_{tot})×10^{-11} s, not contradicting the corresponding QED 2p state lifetime τ_{2p}^{QED}=1.17×10^{-11} s. This lifetime value is three orders of magnitude larger than our previously measured value of the π^{+}π^{-} atom ground state lifetime τ=(3.15_{-0.26}^{+0.28}|_{tot})×10^{-15} s. Further studies of long-lived π^{+}π^{-} atoms will allow us to measure energy differences between p and s atomic states and so to discriminate between the isoscalar and isotensor ππ scattering lengths with the aim to check QCD predictions.

Nanoparticle-based drug delivery via RBC-hitchhiking for the inhibition of lung metastases growth.

Delivery of particle-based theranostic agents via their transportation on the surfaces of red blood cells, commonly referred to as RBC-hitchhiking, has historically been developed as a promising strategy for increasing the extremely poor blood circulation lifetime, primarily, of the large-sized sub-micron agents. Here, we show for the first time that RBC-hitchhiking can be extremely efficient for nanoparticle delivery and tumor treatment even in those cases when no circulation prolongation is observed. Specifically, we demonstrate that RBC-hitchhiking of certain small 100 nm particles, unlike that of the conventional sub-micron ones, can boost the delivery of non-targeted particles to lungs up to a record high value of 120-fold (and up to 40% of the injected dose). To achieve this remarkable result, we screened sub-200 nm nanoparticles of different sizes, polymer coatings and ζ-potentials and identified particles with the optimal RBC adsorption/desorption behavior. Furthermore, we demonstrated that such RBC-mediated rerouting of particles to lungs can be used to fight pulmonary metastases of aggressive melanoma B16-F1. Our findings could change the general paradigm of drug delivery for cancer treatment with RBC-hitchhiking. It is not the blood circulation lifetime that is the key factor for nanoparticle efficiency, but rather the complexation of nanoparticles with the RBC. The demonstrated technology could become a valuable tool for development of new strategies based on small nanoparticles for the treatment of aggressive and small-cell types of cancer as well as other lung diseases.

Magnetometry based method for investigation of nanoparticle clearance from circulation in a liver perfusion model.

Nanoparticles (NPs) are among the most promising agents for advanced theranostics. However, their functioning in vivo is severely inhibited by the mononuclear phagocyte system (MPS), which rapidly removes all foreign entities from blood circulation. Little is known about the sequestration mechanisms and the ways to counteract them. New methods are highly demanded for investigation with high scrutiny of each aspect of NP clearance from blood. For example, while liver macrophages capture the majority of the administered particles, reliable investigation of this process in absence of other MPS components is hard to implement in vivo. Here, we demonstrate a novel method for real-time investigation hepatic uptake of NPs in an isolated perfused liver based on an extremely accurate magnetometric registration technique. The signal is obtained solely from the magnetic NPs without any 'background' from blood or tissues, which is a significant advantage over other techniques, e.g. optical ones. We illustrate the method capacity by investigation of behavior of different particles and show good correlation with in vivo studies. We also demonstrate notable suitability of the method for studying the NP clearance from the flow in the user-defined mediums, e.g. those containing specific serum components. Finally, the method was applied to reveal an interesting effect of short-term decrease of liver macrophage activity after the first interaction with small amounts of NPs. The developed perfusion model based on the high-performance magnetometry can be used for finding new mechanisms of NP sequestration and for development of novel 'stealth' nanoagents.

Data on characterization and validation of assays for ultrasensitive quantitative detection of small molecules: Determination of free thyroxine with magnetic and interferometric methods.

The presented data refer to optimization and quantitative characterization of a rapid lateral flow assay based on high-affinity bifunctional ligand and magnetic nanolabels, which was developed for detection of small molecules of thyroid hormones. The results were obtained by several techniques, including the magnetic particle quantification method, spectral-correlation interferometry and spectral-phase interferometry, dynamic light scattering, enzyme linked immunosorbent assay. The long-term stability of "antibody - magnetic nanoparticle" conjugates is shown. The assay specificity is confirmed, and verification of successful combination of magnetic particles and antibodies is demonstrated. The kinetic and equilibrium dissociation constants are determined for interactions between thyroxine and monoclonal antibodies. The obtained data could be used for design of other platforms for detection of small molecules.

Synthesis of Magnetic Nanoparticles Stabilized by Magnetite-Binding Protein for Targeted Delivery to Cancer Cells.

A new method for obtaining biomodified magnetite nanoparticles for targeted delivery to cells was developed. The method is based on the use of the C-terminal fragment of the Mms6 protein, which is involved in the magnetite biomineralization during the synthesis of magnetosomes in magnetotactic bacteria Magnetospirillum magneticum AMB-1, and the barnase*barstar high-affinity protein pair. The Mms6 protein fragment is required for stabilizing magnetite, and the barnase*barstar pair mediates the interaction between nanoparticles and the component for modification. The efficiency of this method was confirmed in the synthesis of magnetite nanoparticles recognizing the HER2/neu tumor marker and in the selective labeling of HER2/neu with these nanoparticles on the surface of cancer cells.

Ultrasensitive detection enabled by nonlinear magnetization of nanomagnetic labels.

Geometrically confined magnetic particles due to their unique response to external magnetic fields find a variety of applications, including magnetic guidance, heat and drug delivery, magneto-mechanical actuation, and contrast enhancement. Highly sensitive detection and imaging techniques based on the nonlinear properties of nanomagnets were recently proposed as innovative strong-translational potential methods applicable in complex, often opaque, biological systems. Here we report on the significant enhancement of the detection capability using optical-lithography-defined, ferromagnetic iron-nickel alloy disk-shaped particles. We show that an irreversible transition between strongly non-collinear (vortex) and single domain states, driven by an alternating magnetic field, translates into a nonlinear magnetic response that enables ultrasensitive detection of these particles. The record sensitivity of ∼3.5 × 10-9 emu, which is equivalent to ∼39 pg of magnetic material is demonstrated at room temperature for arrays of patterned disks. We also show that unbound disks suspended in the aqueous buffer can be successfully detected and quantified in real-time when administered into a live animal allowing for tracing of their biodistribution. The use of nanoscale ferromagnetic particles with engineered nonlinear properties opens prospects for further enhancing the sensitivity, scalability, and tunability of noise-free magnetic tag detection in high-background environments for various applications spanning from biosensing and medical imaging to anti-counterfeiting technologies.

Matrix approach to the simultaneous detection of multiple potato pathogens by real-time PCR.

AIM: Create a method for highly sensitive, selective, rapid and easy-to-use detection and identification of economically significant potato pathogens, including viruses, bacteria and oomycetes, be it single pathogen, or a range of various pathogens occurring simultaneously. METHODS AND RESULTS: Test-systems for real-time PCR, operating in the unified amplification regime, have been developed for Phytophthora infestans, Pectobacterium atrosepticum, Dickeya dianthicola, Dickeya solani, Ralstonia solanacearum, Pectobacterium carotovorum, Clavibacter michiganensis subsp. sepedonicus, potato viruses Y (ordinary and necrotic forms as well as indiscriminative test system, detecting all forms), A, X, S, M, potato leaf roll virus, potato mop top virus and potato spindle tuber viroid. The test-systems (including polymerase and revertase) were immobilized and lyophilized in miniature microreactors (1·2 µl) on silicon DNA/RNA microarrays (micromatrices) to be used with a mobile AriaDNA® amplifier. CONCLUSIONS: Preloaded 30-reaction micromatrices having shelf life of 3 and 6 months (for RNA- and DNA-based pathogens, respectively) at room temperature with no special conditions were successfully tested on both reference and field samples in comparison with traditional ELISA and microbiological methods, showing perfect performance and sensitivity (1 pg). SIGNIFICANCE AND IMPACT OF THE STUDY: The accurate, rapid and user-friendly diagnostic system in a micromatrix format may significantly contribute to pathogen screening and phytopathological studies.

Synthesis and Characterization of Hybrid Core-Shell Fe3O4/SiO2 Nanoparticles for Biomedical Applications.

The creation of markers that provide both visual and quantitative information is of considerable importance for the mapping of tissue macrophages and other cells. We synthesized magnetic and magneto-fluorescent nanomarkers for the labeling of cells which can be detected with high sensitivity by the magnetic particle quantification (MPQ) technique. For stabilization under physiological conditions, the markers were coated with a dense silica shell. In this case, the size and zeta-potential of nanoparticles were controlled by a modified Stober reaction. Also, we developed a novel facile two-step synthesis of carboxylic acid-functionalized magnetic SiO2 nanoparticles, with a carboxyl polymer shell forming on the nanoparticles before the initiation of the Stober reaction. We extensively characterized the nanomarkers by transmission electron microscopy, electron microdiffraction, and dynamic and electrophoretic light scattering. We also studied the nanoparticle cellular uptake by various eukaryotic cell lines.

Synthesis of magnetic silica nanomarkers with controlled physicochemical properties.

Magnetic markers which can be detected with an extremely high sensitivity with the method of magnetic particle quantification (MPQ) were synthesized. Using a controlled Stober reaction, a set of magnetic silica markers of different sizes and zeta potentials was obtained. The use of a carboxymethyl dextran polymer to stabilize the magnetite particles during the synthesis made it possible to substantially reduce the detection limit of the obtained construct, which opens up new opportunities for creating effective diagnostic nanoagents.

Observation of π

The observation of hydrogenlike πK atoms, consisting of π^{-}K^{+} or π^{+}K^{-} mesons, is presented. The atoms are produced by 24 GeV/c protons from the CERN PS accelerator, interacting with platinum or nickel foil targets. The breakup (ionization) of πK atoms in the same targets yields characteristic πK pairs, called "atomic pairs," with small relative momenta Q in the pair center-of-mass system. The upgraded DIRAC experiment observed 349±62 such atomic πK pairs, corresponding to a signal of 5.6 standard deviations. This is the first statistically significant observation of the strange dimesonic πK atom.