Abstract Background Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system (mast cells and microglia). Study AB09004 evaluated masitinib as an adjunct to cholinesterase inhibitor and/or memantine in patients with mild-to-moderate dementia due to probable Alzheimer’s disease (AD). Methods Study AB09004 was a randomized, double-blind, two parallel-group (four-arm), placebo-controlled trial. Patients aged ≥50 years, with clinical diagnosis of mild-to-moderate probable AD and a Mini-Mental State Examination (MMSE) score of 12–25 were randomized (1:1) to receive masitinib 4.5 mg/kg/day (administered orally as two intakes) or placebo. A second, independent parallel group (distinct for statistical analysis and control arm), randomized patients (2:1) to masitinib at an initial dose of 4.5 mg/kg/day for 12 weeks that was then titrated to 6.0 mg/kg/day, or equivalent placebo. Multiple primary outcomes (each tested at a significance level of 2.5%) were least-squares mean change from baseline to week 24 in the Alzheimer’s Disease Assessment Scale - cognitive subscale (ADAS-cog), or the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL). Safety for each masitinib dose level was compared against a pooled placebo population. Results Masitinib (4.5 mg/kg/day) (n=182) showed significant benefit over placebo (n=176) according to the primary endpoint of ADAS-cog, −1.46 (95% CI [−2.46, −0.45]) (representing an overall improvement in cognition) versus 0.69 (95% CI [−0.36, 1.75]) (representing increased cognitive deterioration), respectively, with a significant between-group difference of −2.15 (97.5% CI [−3.48, −0.81]); p
Introduction: Excessive lipoperoxidation is accompanied by accumulation of peroxidation products and depletion of antioxidant re-serves, which cause hyperenzymemia and the accumulation of toxic substances. The level of endotoxicosis is determined by the content of hydrophilic and hydrophobic products in the blood. Aim: To define the pathogenetic role of endogenous intoxication in the dynamics of development of experimental periodontitis of bacterial-immune genesis. Materials and methods: The experiment was conducted on rats. The animals were divided into three groups: group 1 - control group/intact; group 2 - model periodontitis at 7 days; group 3 - model periodontitis at 30 days. The experimental bacterial-immune periodon-titis was induced by injection into the tissue of the periodontal complex of the microorganisms' mixture diluted with egg's albumin. For the study, we selected the blood serum in which the content of middle molecular weight molecules and erythrocyte intoxication index were determined. The results were statistically analyzed by means of non-parametric indices methods. Results: The development of generalized periodontitis is characterized by the occurrence of oxidative stress, which leads to violation of the metabolism in the mucous membrane of the oral cavity resulting in the accumulation of toxic products and the development of endogenous intoxication. The results show that the content of middle molecular weight molecules (aromatic amino and chain amino acids) determined on day 7 of the experiment was 1.11 times higher than that of the control group (p<0.01) and by 1.16 times (p<0.01), respectively. Comparing the levels of the above hydrophilic components of endogenous intoxication at 30 days of experimental peri-odontitis, we found a probable increase in these indicators compared with those at 7 days of the experiment. Studying the level of eryth-rocyte intoxication index, we found that at 7 days of experimental periodontitis this index was 1.28 times higher (p<0.01) than that of the intact group and continued to increase at 30 days. Conclusions: The dynamics of experimental periodontitis of bacterial-immune genesis show that the highest rates of endogenous intoxication are found in the late stages of the dynamics of the inflammatory process in the periodontium, namely at 30 days of the experiment, which may indicate chronic inflammation.
The aim of the work was to create an approach for the development of HPLC methods for the determination of meldonium in dosage forms with the usage of salts of chaotropic anions in mobile phases. Material and methods. Analytical equipment: Shimadzu UPLC system LC-40 PDA; Shimadzu Nexera-i LC-2040C 3D-Plus, controlled by software Lab Solution version 5.97, electronic laboratory balance RAD WAG AS 200/C, pH-meter I-160MI. Meldonium dihydrate (purity 99.3 %) was purchased from Sigma-Aldrich (Switzerland), and Vasopro capsules 500 mg were purchased from a local pharmacy. Chromatographic conditions: Agilent Zorbax C-18 SB 150 mm x 4.6 mm 3.5 μm column was used (Agilent Technologies, USA). Mobile phases: 1) 0.25 % KPF6 w/v – 0.1 % v/v 85 %H3PO4 95 % – 5 % ACN, 2) 0.3 % bis-(trifluoromethane)sulfonimide lithium salt 97 % w/v – 0.1 %v/v 85 % H3PO4 80 % – 20 % acetonitrile. Flow rate - 1mL/min, T=32 °C, detection UV=at 4 channels - 190 nm, 195 nm, 200 nm, 205 nm. Results and discussion. We have proposed two approaches using two different salts of chaotropic anions - potassium hexafluorophosphate and bis-(trifluoromethane)sulfonimide lithium salt – for the HPLC method development. The chaotropic effects of these anions toward meldonium strongly influenced the analyte migratory behaviour. Both mobile phases involved, in addition to the use of a chaotrope, also the use of acetonitrile and pH adjustment with 0.1 % v/v 85 % H3PO4 solution. The detection wavelength (190 nm, 195 nm, 200 nm, 205 nm) was selected experimentally. The results were obtained for 8 concepts. Parameters of the chromatographic system confirm the conclusions and results of this investigation for the influence of chaotropic salts on N-containing molecules in an acidic pH medium, by increasing their retentivity and improving peak shape and uniformity homogeneity, even on the column without end-capping and base-deactivating. Validation of the analytical method was carried out following the requirements of SPhU. Conclusions. HPLC methods for the determination of meldonium in dosage forms have been developed, using positive impacts of chaotropic salts on the molecules containing N-atoms in their molecule on their retentions and peak symmetries on the chromatogram. The validation of the analytical methods showed their suitability for pharmaceutical analysis
Autoimmune disorders and some types of blood cancer originate when B lymphocytes malfunction. In particular, when B cells produce antibodies recognizing the body’s proteins, it leads to various autoimmune disorders. Additionally, when B cells of various developmental stages transform into cancer cells, it results in blood cancers, including multiple myeloma, lymphoma, and leukemia. Thus, new methods of targeting B cells are required for various patient groups. Here, we used protein kinase inhibitors alectinib, brigatinib, ceritinib, crizotinib, entrectinib, and lorlatinib previously approved as drugs treating anaplastic lymphoma kinase (ALK)-positive lung cancer cells. We hypothesized that the same inhibitors will efficiently target leukocyte tyrosine kinase (LTK)-positive, actively protein-secreting mature B lymphocytes, including plasma cells. We isolated CD19-positive human B cells from the blood of healthy donors and used two alternative methods to stimulate cell maturation toward plasma cells. Using cell proliferation and flow cytometry assays, we found that ceritinib and entrectinib eliminate plasma cells from B cell populations. Alectinib, brigatinib, and crizotinib also inhibited B cell proliferation, while lorlatinib had no or limited effect on B cells. More generally, we concluded that several drugs previously developed to treat ALK-positive malignant cells can be also used to treat LTK-positive B cells.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive inborn error of immunity (IEI), which is accompanied by immune dysregulation. Hypoparathyroidism, adrenocortical failure and candidiasis are its typical manifestations. Here we report about recurrent COVID-19 in a 3-year-old boy with APECED, who developed retinopathy with macular atrophy and autoimmune hepatitis after the first episode of SARS-CoV-2 infection. Primary Epstein-Barr virus infection and a new episode of SARS-CoV-2 infection with COVID pneumonia triggered the development of severe hyperinflammation with signs of hemophagocytic lymphohistiocytosis (HLH): progressive cytopenia (thrombocytopenia, anemia, lymphopenia), hypoproteinemia, hypoalbuminemia, high levels of liver enzymes, hyperferritinemia, increased triglycerides levels; and coagulopathy with a low level of fibrinogen. Treatment with corticosteroids and intravenous immunoglobulins did not lead to a significant improvement. The progression of HLH and COVID-pneumonia resulted in a fatal outcome. The rarity and varied presentation of the HLH symptoms led to diagnostic difficulties and diagnosis delay. HLH should be suspected in a patient with immune dysregulation and impaired viral response. Treatment of infection-HLH is a major challenge due to the difficulties in balancing immunosuppression and management of underlying/triggering infection.
Background: The global pandemic of coronavirus disease 2019 (COVID-19) continues to affect people around the world, with one of the most frequent comorbidities being Type 2 Diabetes (T2D). Studies have suggested a link between disbalances in gut microbiota and these diseases, as well as with COVID-19, potentially due to inflammatory dysfunction. This study aims to analyze the changes in gut microbiota in COVID-19 patients with T2D using a culture-based method. Methods: The stool samples were taken from 128 patients with confirmed COVID-19. Changes in the composition of gut microbiota were analyzed by culture-based method. The study used chi-squared and t-test to find significant differences in gut bacteria between samples and non-parametric correlation analysis to examine relationship between gut bacteria abundance, C‐reactive protein (CRP) levels and length of stay (LoS) in COVID-19 patients without T2D. Results: The gut microbiota of T2D patients with COVID-19 showed increased Clostridium spp., Candida spp., and decreased Bifidobacterium spp., Lactobacillus spp. Metformin-treated patients with T2D and COVID-19 without antibiotic treatment showed increased Bacteroides spp., Lactobacillus spp., and decreased Enterococcus, Clostridium compared to the same group with antibiotic treatment. The study also found a positive correlation between the abundance of certain gut microbiota genera, such as Klebsiella spp. and Enterococcus spp., and CRP levels and LoS in COVID-19 patients without and with T2D, while the abundance of other genera, such as Bifidobacterium spp. and Lactobacillus spp., was found to have a negative correlation. Conclusion: In conclusion, this study provides important insights into the gut microbiota composition of SARS-CoV-2-infected individuals with T2D and its potential impact on the course of the disease. The findings suggest that certain gut microbiota genera may be associated with increased CRP levels and longer hospital stays. The significance of this study lies in the fact that it highlights the potential role of gut microbiota in the progression of COVID-19 in patients with T2D, and may inform future research and treatment strategies for this patient population. The future impact of this study could include the development of targeted interventions to modulate gut microbiota in order to improve outcomes for COVID-19 patients with T2D.
Objective. The hallmarks of type 2 diabetes mellitus (T2DM) are insulin resistance (IR) and insulin receptor substrate (IRS) proteins essential for the insulin signaling. IRS-1 gene has not only been shown to be associated with T2DM, but also has indicated that it may significantly correlate with diabetic complications, such as coronary heart disease and obesity. The aim of this study was to evaluate changes of the lipid panel data in T2DM patients with comorbid obesity and/or essential hypertension in connection with the IRS-1 (rs2943640) polymorphism. Methods. The study involved 33 T2DM patients and 10 healthy individuals. The IRS-1 (rs2943640) polymorphism was genotyped using a TaqMan real-time polymerase chain reaction method. Blood serum lipid panel data were determined with commercially available kits using a Cobas 6000 analyzer. Results. Analysis of the serum lipid panel data depending on the presence of the C/A alleles of IRS-1 (rs2943640) polymorphism in T2DM patients, regardless of the presence/absence of comorbidities, showed significantly lower level of high-density lipoprotein cholesterol (HDL-C) and significantly higher level of non-HDL-C in the carriers of C allele vs. carriers of A allele. In T2DM patients with comorbid obesity and essential hypertension, proatherogenic lipid changes were found in both C and A alleles carriers. Analysis of the effect of IRS-1 (rs2943640) genotypes on serum lipid panel data in T2DM patients, regardless of the presence/absence of comorbidities, showed that the CC genotype carriers had more pronounced pro-atherogenic changes vs. carriers of СА and АА genotypes. In the comorbid course of T2DM (both in combination with obesity and obesity and essential hypertension), pro-atherogenic changes were found in the carriers of the CA genotype of IRS-1 (rs2943640) polymorphism. Conclusions. The presence of the C allele of IRS-1 (rs2943640) polymorphism in both homo-zygous and heterozygous states indicates increased risk of pro-atherogenic changes in T2DM patients with comorbid obesity and/or essential hypertension.
Aim: To conduct a comparative analysis of the dynamics of heart rate variability parameters in CP patients with autonomic dysfunction under the influence of the proposed complex treatment programs with the additional inclusion of the vegetative stabilizing agent memoplant and a combination of complex bioregulatory drugs. Materials and Methods: Statistical and spectral parameters of heart rate variability were analyzed in 69 patients with CP before and after outpatient treatment. Patients were divided into 3 groups of 23 patients with CP: group 1 – received conventional treatment (CT) according to the clinical diagnosis and the protocol proposed by the Ministry of Health of Ukraine (Order No. 638 of 10.09.2014); group 2 – CT enhanced with a course of the vegetative-stabilizing drug ginkgo biloba (memoplant); 3 group – CT with a course of memoplant and complex bioregulatory therapy (BRT): momordica compositum, traumeel S and neurexan according to the proposed scheme. Results: In group 1, the stress index (SI) decreased by 18.49%, p<0.05, vegetative reactivity (VR) increased by 21.31%, p<0.05, IARS decreased by 25.79%, p<0.01. In group 2, a more significant decrease in sympathicotonia was observed: SI decreased by 38.17% (p<0.01), mode amplitude (АМо) by 14.57% (p<0.05), the range of variation (X) increased by 12.78% (p<0.05); IARS decreased by 44.55 % (p<0.01) to moderate tension. There was an increase in the total spectrum power (TP) (by 29.21%, p<0.01) and components: LF increased by 37.03% (p<0.01) relative to the initial level, HF by 64.01% (p<0.01), VLF by 8.75% (p<0.05). In patients of group 3, normalization of SI and АМо was observed (indicators decreased by 48.42% and 19.98%, p<0.01), X increased by 17.35%, p<0.01; The VR level did not differ significantly from the control (1.16±0.06 and 1.25±0.10, respectively). IARS decreased by 56.18% (p<0.01); TP increased by 49.61% (p<0.01), LF by 76.78% (p<0.01), HF by 117.67% (p<0.01), VLF by 8.41% (p<0.05). Conclusions: In patients with CP, a higher efficiency of treatment programs with the inclusion of ginkgo biloba and complex bioregulatory therapy on the state of autonomic regulation was established compared to the generally accepted program in terms of spectral and statistical parameters of heart rate variability.
The obesity pandemic is one of society's most urgent public health concerns. A third of the global adult population may fall under obese or overweight by 2025, suggesting a rising demand for medical care and an exorbitant cost of healthcare expenditure in the coming years. Generally, the treatment strategy for obese patients is largely patient-centric and needs dietary, behavioral, pharmacological, and sometimes even surgical interventions. Given that obesity cases are rising in adults and children and lifestyle modifications have failed to produce desired results, so the need for medical therapy adjunct to lifestyle modifications is vital for better managing of obesity. Most existing or past drugs for obesity treatment target satiety or monoamine pathways and induce a feeling of fullness in patients, while drugs like orlistat are targeted against intestinal lipases. However, many medications targeted against neurotransmitters showed adverse events in patients, thus being withdrawn from the market. Alternatively, the combination of some drugs has been successfully tested in obesity management. However, the demand for novel, safer, and more efficacious pharmaceutical drugs for weight management does exist. The present review elucidates the current understanding of the available anti-obesity medicines of synthetic and natural origin, their main mechanisms of action, and the shortcomings associated with current weight-management drugs.
Introduction IFN-α intervention may block SARS-CoV-2 replication and normalize the deregulated innate immunity of COVID-19. Aim This meta-analysis aimed to investigate the efficacy of interferon IFN-α–containing regimens when treating patients with moderate-to-severe COVID-19. Material and methods PubMed, SCOPUS, and ClinicalTrials.gov were searched from inception to 15 January 2022. A systematic literature search was conducted by applying relevant terms for ‘COVID-19’ and ‘interferon-α’. The primary outcome enclosed the all-cause hospital mortality. The secondary outcomes constituted the length of hospital stay; hospital discharge; nucleic acid negative conversion. Results Eleven studies are enclosed in the meta-analysis. No significant difference in the all-cause mortality rate was found between the study and control groups (OR 0.2; 95% CI 0.05-1.2; I ² = 96%). The implementation of interferon did not influence such outcomes as the length of hospital stay (OR 0.9; 95% CІ, 0.3-2.6; I 2 = 91%), nucleic acid negative conversion (OR 0.8; 95% CI, 0.04-17.2; I 2 = 94%). Nevertheless, IFN-α treatment resulted in a higher number of patients discharged from the hospital (OR 26.6; 95% CІ, 2.7-254.3; I ² = 95%). Conclusions Thus, IFN-α does not benefit the survival of hospitalized COVID-19 patients but may increase the number of patients discharged from the hospital. Systematic review registration www.crd.york.ac.uk/prospero , identifier (CRD42022374589).
Background : Antiphospholipid syndrome is an autoimmune disease of multiple venous and/or arterial thrombosis and/or pregnancy loss. Oxidative stress only enhances the body’s immune response. In pathological conditions, the formation of nitric oxide is disrupted, which can be manifested by vasoconstriction, increased coagulation, and endothelial dysfunction. Objective : The aim of the research was to study the level of immunoglobulins and circulating immune complexes (CICs) in experimental antiphospholipid syndrome and its correction with L-arginine and aminoguanidine. Materials and methods : Antiphospholipid syndrome was modeled on white female BALB/c mice. L-arginine (25 mg/kg) and aminoguanidine (10 mg/kg) were used for its correction. The content of immunoglobulins and CICs was studied. Results : It was established that the level of immunoglobulins (Ig) and circulating immune complexes increased in the group of animals with antiphospholipid syndrome compare to the control. The levels of IgA and CICs decreased significantly, and the levels of IgM and IgG did not change in the mice with antiphospholipid syndrome and L-arginine correction. In cases of aminoguanidine administration, decreased IgM and IgG levels and no significant decrease in IgA and CICs was evidenced compare to the animals with antiphospholipid syndrome. In cases of using a combination of L-arginine and aminoguanidine agents, only IgM did not change, all other parameters decreased compare to the animals with APS. Conclusion : The parameters of the humoral immunity in female mice with experimental antiphospholipid syndrome increase. The level of immunoglobulins and circulating immune complexes decrease depending on the chosen correction agents or their complex administration. Thus, L-arginine and aminoguanidine has a positive effect on various immunity responses by decreasing the negative impact of pathobiochemical alterations.
The paper explored the problem of automatic diagnosis based on immunohistochemical image analysis. The issue of automated diagnosis is a preliminary and advisory statement for a diagnostician. The authors studied breast cancer histological and immunohistochemical images using the following biomarkers progesterone, estrogen, oncoprotein, and a cell proliferation biomarker. The authors developed a breast cancer diagnosis method based on immunohistochemical image analysis. The proposed method consists of algorithms for image preprocessing, segmentation, and the determination of informative indicators (relative area and intensity of cells) and an algorithm for determining the molecular genetic breast cancer subtype. An adaptive algorithm for image preprocessing was developed to improve the quality of the images. It includes median filtering and image brightness equalization techniques. In addition, the authors developed a software module part of the HIAMS software package based on the Java programming language and the OpenCV computer vision library. Four molecular genetic breast cancer subtypes could be identified using this solution: subtype Luminal A, subtype Luminal B, subtype HER2/neu amplified, and basalt-like subtype. The developed algorithm for the quantitative characteristics of the immunohistochemical images showed sufficient accuracy in determining the cancer subtype “Luminal A”. It was experimentally established that the relative area of the nuclei of cells covered with biomarkers of progesterone, estrogen, and oncoprotein was more than 85%. The given approach allows for automating and accelerating the process of diagnosis. Developed algorithms for calculating the quantitative characteristics of cells on immunohistochemical images can increase the accuracy of diagnosis.
Objective: The study aimed to compare vitamin D levels between children and adolescents with vasovagal syncope, syncope due to orthostatic hypotension, cardiac syncope, and healthy individuals and to investigate the correlations of 25(OH)D with main clinical parameters of syncope. Materials and methods: This study involved 83 children aged 8-17 years with syncope: 40 with vasovagal syncope, 24 with syncope due to orthostatic hypotension, and 19 with cardiac syncope. There were 24 healthy volunteers in the control group. Data concerning active standing test, electrocardiography, echocardiography, electroencephalography, and 24-hour Holter monitoring findings were collected. Serum vitamin D was evaluated by an enzyme-linked immunoassay technique test. Results: The mean levels of serum 25(OH)D were decreased in children with vasovagal syncope (18.8 ± 5.9 ng/mL), syncope due to orthostatic hypotension (19.9 ± 6.7 ng/mL), and cardiac syncope (20.6 ± 7.3 ng/mL) in comparing with the control group (30.9 ± 5.9 ng/mL; P < .001). In patients with syncope due to orthostatic hypotension, vitamin D deficiency was associated with a reduction in systolic blood pressure (r = 0.43) and diastolic blood pressure (r = 0.38) within the first minute, lower systolic blood pressure (r = 0.44) within the third minute of active orthostasis (P < .05). There were significant correlations of vitamin D deficiency with parameters of cardiac autonomic activity pNN50 (r = 0.49), total power (r = 0.39), and low frequency index (r = 0.35) in children with cardiac syncope (P < .05), while heart rate variability was not affected in patients with vasovagal syncope and syncope due to orthostatic hypotension (P > .05). Conclusion: Children and adolescents with vasovagal syncope, syncope due to orthostatic hypotension, as well as cardiac syncope had higher frequency of vitamin D deficiency than healthy pediatric controls. This provides a new approach to syncope management in pediatric population, requiring further studies.
Dental implants to replace lost teeth are a common dentistry practice nowadays. Titanium dental implants display a high success rate and improved safety profile. Nevertheless, there is an increasing peri-implantitis (PI), an inflammatory disease associated with polymicrobial infection that adversely affects the hard and soft tissues around the implant. The present review highlights the contribution of different metabolic conditions to PI. The considerations of both local and systemic metabolic conditions are crucial for planning successful dental implant procedures and during the treatment course of PI. Un- or undertreated PI can lead to permanent jaw bone suffering and dental implant losses. The common mediators of PI are inflammation and oxidative stress, which are also the key mediators of most systemic metabolic disorders. Chronic periodontitis, low-grade tissue inflammation, and increased oxidative stress raise the incidence of PI and the underlying systemic metabolic conditions, such as obesity, diabetes mellitus, or harmful lifestyle factors (cigarette smoking, etc.). Using dental biomaterials with antimicrobial effects could partly solve the problem of pathogenic microbial contamination and local inflammation. With local dentistry considering factors, including oral microbiota and implant quality control, the inclusion of the underlying systemic metabolic conditions into the pre-procedure planning and during the treatment course should improve the chances of successful outcomes.
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m.Voli, 1, 46001, Ternopil, Ternopil, Ukraine
Head of institution
MD, PhD, DSci, Mykhaylo Korda
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