Salivary gland immunohistochemistry vs substantia nigra sonography: comparative analysis of diagnostic significance

Introduction. Parkinson's disease (PD) urges for new instrumental methods of diagnosis. Transcranial sonography of the substantia nigra (SN TCS) is an established method for early PD diagnosis but its application is limited. Recently, biopsies (primarily that of salivary gland) and test for abnormal -synuclein are suggested to verify PD. Materials and methods. We assessed 12 individuals with PD, HoehnYahr 2.3 0.4. The assessments included: UPDRS, NMSQ, NMSS, RBDSQ, PDQ-8, MoCA, and HADS scoring; SN TCS; and sublingual gland immunohistochemistry for phosphorylated -synuclein (PS-129) with automated morphometric analysis. Results. Substantia nigra hyperechogenicity was shown in 75% of patients whereas biopsy revealed PS-129 in 100% of patients. Echogenic area of the substantia nigra was 0.24 [0.21; 0.3] cm2. PS-129 inclusion area varied from 28.47 [27.55; 96.26] to 238.77 [234.13; 272.49] m2, and PS-129 proportion varied from 13.4% to 93.4% of the nervous fiber area across the patients. We found relations between PS-129 and NMSQ (r = 0.8; p 0.001), NMSS (r = 0.9; p 0.001), PDQ-8 (r = 0.7; p = 0.003), UPDRS-I (r = 0.7; p = 0.009), UPDRS-II (r = 0.6; p = 0.03), and HADS (anxiety r = 0.8; p = 0.002; depression r = 0.6; p = 0.04) scores. Conclusion. The results demonstrate a higher biopsy sensitivity as compared to SN TCS. Automated morphometric analysis has been newly applied to assess PS-129 occurrence. Immunohistochemistry results are directly related to non-motor symptom severity, which may indicate high probability of PS-129 presence and diagnosis confirmation in early disease

Morphological Changes in Neural Progenitors Derived from Human Induced Pluripotent Stem Cells and Transplanted into the Striatum of a Parkinson's Disease Rat Model

Introduction. Development of cell therapy for Parkinson's disease (PD) requires protocols based on transplantation of neurons derived from human induced pluripotent stem cells (hiPSCs) into the damaged area of the brain. Objective: to characterize neurons transplanted into a rat brain and evaluate neural transplantation efficacy using a PD animal model. Materials and methods. Neurons derived from hiPSCs (IPSRG4S line) were transplanted into the striatum of rats after intranigral injection of 6-hydroxydopamine (6-OHDA). Immunostaining was performed to identify expression of glial and neuronal markers in the transplanted cells within 224 weeks posttransplant. Results. 4 weeks posttransplant we observed increased expression of mature neuron markers, decreased expression of neural progenitor markers, and primary pro-inflammatory response of glial cells in the graft. Differentiation and maturation of neuronal cells in the graft lasted over 3 months. At 3 and 6 months we detected 2 graft zones: one mainly contained the transplanted neurons and the other human astrocytes. We detected human neurites in the corpus callosum and surrounding striatal tissue and large human tyrosine hydroxylase-expressing neurons in the graft. Conclusion. With graft's morphological characteristics identified at different periods we can better understand pathophysiology and temporal patterns of new dopaminergic neurons integration and striatal reinnervation in a rat PD model in the long-term postoperative period

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Investigation and development of a rational method and conditions of loading of charge materials into blast furnace

The work is aimed at development of the technique of calculating radionuclide precipitation in reactor facilities with different heat carriers. A physical model of precipitation is developed, conditions of precipitation simulation are determined; calculated dependences are received for radionuclide concentration fields and precipitation coefficients. A technique of calculating radionuclide precipitation is developed, RADON computation program is created. Radionuclide precipitation is calculated for reactor plant AST-200 using RADON program. An increase of APP radiation sefety was observed. The field of application covers design and use of APP with different heat carriersAvailable from VNTIC / VNTIC - Scientific & Technical Information Centre of RussiaSIGLERURussian Federatio

Neuroprotective Effect of L-carnitine. Focus on Changing Mitochondrial Function

Introduction: In this study, the neuroprotective effect of L-carnitine administered per os in a dose of 25 mg/kg – 800 mg/kg was evaluated. The effects of L-carnitine on changes in mitochondrial function were also studied. Materials and Methods: The neuroprotective effect and mitochondrial function were evaluated in a model of permanent focal ischemia in Wistar-line rats. L-carnitine was administered to rats orally for 72 hours from the moment of modeling ischemia. On the 4th day after the ischemia simulation, the change in the respiratory function of the mitochondria, the opening time of the mitochondrial permeability transition pore, the mitochondrial membrane potential, the concentration of intracellular calcium and the size of the cerebral necrosis zone were determined in rats’ brain supernatant. Results: As a result, it was found that the administration of L-carnitine contributed to the restoration of mitochondrial function and a decrease in the size of the brain necrosis zone. At the same time, the administration of L-carnitine in low doses (25 mg/kg – 100 mg/kg) did not have a significant effect on the change in the concentration of intracellular calcium. It should be noted that an increase in the dose of L-carnitine from 200 mg/kg to 800 mg/kg was not accompanied by a significant increase in the therapeutic effect. Discussion: L-carnitine is one of the key biomolecules that directly affect metabolic processes. It is known that L-carnitine acts as a ”shuttle” for long-chain fatty acids and thus can affect the alteration of mitochondrial function. However, the detailed nature of the mitochondriotropic action of L-carnitine has not been yet established. This was the focus of this study, which showed that the mitochondrion-oriented effect of L-carnitine is dose-dependent and expressed in the form of restoring the respiratory function of mitochondria, restoring the mitochondrial potential and increasing the latent opening time of the mitochondrial permeability transition pore, reducing the level of intracellular calcium. Conclusion: The study allowed us to expand our understanding of the L-carnitine neuroprotective effect and the effect of this compound on changes in mitochondrial function. Graphical abstrac

Neuroprotective Effect of L-carnitine. Focus on Changing Mitochondrial Function

Introduction: In this study, the neuroprotective effect of L-carnitine administered per os in a dose of 25 mg/kg – 800 mg/kg was evaluated. The effects of L-carnitine on changes in mitochondrial function were also studied. Materials and Methods: The neuroprotective effect and mitochondrial function were evaluated in a model of permanent focal ischemia in Wistar-line rats. L-carnitine was administered to rats orally for 72 hours from the moment of modeling ischemia. On the 4th day after the ischemia simulation, the change in the respiratory function of the mitochondria, the opening time of the mitochondrial permeability transition pore, the mitochondrial membrane potential, the concentration of intracellular calcium and the size of the cerebral necrosis zone were determined in rats’ brain supernatant. Results: As a result, it was found that the administration of L-carnitine contributed to the restoration of mitochondrial function and a decrease in the size of the brain necrosis zone. At the same time, the administration of L-carnitine in low doses (25 mg/kg – 100 mg/kg) did not have a significant effect on the change in the concentration of intracellular calcium. It should be noted that an increase in the dose of L-carnitine from 200 mg/kg to 800 mg/kg was not accompanied by a significant increase in the therapeutic effect. Discussion: L-carnitine is one of the key biomolecules that directly affect metabolic processes. It is known that L-carnitine acts as a ”shuttle” for long-chain fatty acids and thus can affect the alteration of mitochondrial function. However, the detailed nature of the mitochondriotropic action of L-carnitine has not been yet established. This was the focus of this study, which showed that the mitochondrion-oriented effect of L-carnitine is dose-dependent and expressed in the form of restoring the respiratory function of mitochondria, restoring the mitochondrial potential and increasing the latent opening time of the mitochondrial permeability transition pore, reducing the level of intracellular calcium. Conclusion: The study allowed us to expand our understanding of the L-carnitine neuroprotective effect and the effect of this compound on changes in mitochondrial function. Graphical abstrac

Study of dose-dependent actoprotective effect of ATACL on physical performancend psychoemotional status of animals under exhausting exercise

Introduction: The aim of the study was to investigate the dose-dependent actoprotective effect of ATACL on physical performance and psychoemotional status of animals under conditions of exhausting exercise. Materials and methods: Outbred male mice (23–25 g) were used in the experiment. The test compound in various dosages, as well as the reference drug, were administered intragastrically 60 minutes before the forced swimming test for 10 days of the experiment. At the end of the physical activity, the psychoemotional status of the animals was assessed in the Open Field (OF) and Elevated plus maze (EPM) tests. Results and discussion: In the course of the experiment, it was found that under conditions of exhausting physical execise, a smooth increase in performance was observed in the group that had received the test compound 4-hydroxy-3,5-di-tert butyl cinnamic acid (ATACL) at a dosage of 100 mg/kg for 10 days. The peak of performance was recorded on the 8th day, which was 47.3% (p<0.05) higher than the physical activity of the mice treated with the reference drug ethylthiobenzimidazole hydrobromide (EBH). When assessing changes in the Open Field test, it was found that the test compound ATACL at a dosage of 100 mg/kg is also a leader in stabilizing the psychoemotional status of the animals, which is reflected in the improvement of the motor activity (the number of sectors crossed by 4.7 times (p< 0.05)), exploratory activity (an increase in the number of «peeps» and rearings by 8.5 times (p<0.05) and 12.7 times (p<0.05), respectively) and changes in the level of anxiety (a 2.5-time decrease in the number of short-term grooming acts (p<0.05)) in comparison with the negative control (NC) group. The results obtained in the EPM test are completely consistent with the results of the OF test; the most pronounced activity was observed for the ATACL compound at a dosage of 100 mg/kg. Conclusion: Based on the combination of reproducible methods, it can be concluded that the most pronounced actоprotective effect is exerted by the compound at a dosage of 100 mg/kg, not inferior, at the same time, to the reference drug EBН. Graphical abstract

Study of dose-dependent actoprotective effect of ATACL on physical performancend psychoemotional status of animals under exhausting exercise

Introduction: The aim of the study was to investigate the dose-dependent actoprotective effect of ATACL on physical performance and psychoemotional status of animals under conditions of exhausting exercise. Materials and methods: Outbred male mice (23–25 g) were used in the experiment. The test compound in various dosages, as well as the reference drug, were administered intragastrically 60 minutes before the forced swimming test for 10 days of the experiment. At the end of the physical activity, the psychoemotional status of the animals was assessed in the Open Field (OF) and Elevated plus maze (EPM) tests. Results and discussion: In the course of the experiment, it was found that under conditions of exhausting physical execise, a smooth increase in performance was observed in the group that had received the test compound 4-hydroxy-3,5-di-tert butyl cinnamic acid (ATACL) at a dosage of 100 mg/kg for 10 days. The peak of performance was recorded on the 8th day, which was 47.3% (p<0.05) higher than the physical activity of the mice treated with the reference drug ethylthiobenzimidazole hydrobromide (EBH). When assessing changes in the Open Field test, it was found that the test compound ATACL at a dosage of 100 mg/kg is also a leader in stabilizing the psychoemotional status of the animals, which is reflected in the improvement of the motor activity (the number of sectors crossed by 4.7 times (p< 0.05)), exploratory activity (an increase in the number of «peeps» and rearings by 8.5 times (p<0.05) and 12.7 times (p<0.05), respectively) and changes in the level of anxiety (a 2.5-time decrease in the number of short-term grooming acts (p<0.05)) in comparison with the negative control (NC) group. The results obtained in the EPM test are completely consistent with the results of the OF test; the most pronounced activity was observed for the ATACL compound at a dosage of 100 mg/kg. Conclusion: Based on the combination of reproducible methods, it can be concluded that the most pronounced actоprotective effect is exerted by the compound at a dosage of 100 mg/kg, not inferior, at the same time, to the reference drug EBН. Graphical abstract