Pharmacological sequestration of mitochondrial calcium uptake protects against dementia and β-amyloid neurotoxicity

All forms of dementia including Alzheimer's disease are currently incurable. Mitochondrial dysfunction and calcium alterations are shown to be involved in the mechanism of neurodegeneration in Alzheimer's disease. Previously we have described the ability of compound Tg-2112x to protect neurons via sequestration of mitochondrial calcium uptake and we suggest that it can also be protective against neurodegeneration and development of dementia. Using primary co-culture neurons and astrocytes we studied the effect of Tg-2112x and its derivative Tg-2113x on β-amyloid-induced changes in calcium signal, mitochondrial membrane potential, mitochondrial calcium, and cell death. We have found that both compounds had no effect on β-amyloid or acetylcholine-induced calcium changes in the cytosol although Tg2113x, but not Tg2112x reduced glutamate-induced calcium signal. Both compounds were able to reduce mitochondrial calcium uptake and protected cells against β-amyloid-induced mitochondrial depolarization and cell death. Behavioral effects of Tg-2113x on learning and memory in fear conditioning were also studied in 3 mouse models of neurodegeneration: aged (16-month-old) C57Bl/6j mice, scopolamine-induced amnesia (3-month-old mice), and 9-month-old 5xFAD mice. It was found that Tg-2113x prevented age-, scopolamine- and cerebral amyloidosis-induced decrease in fear conditioning. In addition, Tg-2113x restored fear extinction of aged mice. Thus, reduction of the mitochondrial calcium uptake protects neurons and astrocytes against β-amyloid-induced cell death and contributes to protection against dementia of different ethology. These compounds could be used as background for the developing of a novel generation of disease-modifying neuroprotective agents

Pediatric bacteremia and CNS infections associated with <i>klebsiella pneumoniae</i>: molecular genetic characteristics and clinical features

Klebsiella pneumoniae is one of the most significant and life-threatening pathogen of nosocomial infections. This opportunistic microorganism can cause infections of the bloodstream, respiratory tract, urinary tract, skin and soft tissues, inflammation of meninges of the brain and spinal cord, leading to elevated hospital mortality. The purpose of our study was a retrospective analysis of molecular genetic characteristics of K. pneumoniae isolated from blood and liquor samples as well as to describe clinical features in bacteremia and CNS infections. According to the results of assessed clinical data, K. pneumoniae isolates were selected from 64 children suffered from surgical pathology (congenital heart defects — 30%, abdominal pathology — 39%, severe combined trauma — 12%) and somatic diseases accompanied by antibacterial and/or glucocorticosteroid therapy — 14%. The minimum suppressive concentrations of antibiotics were determined by the broth micro-dilution method. Carbapenemases were detected by real time polymerase chain reaction. Virulence genes and capsule serotypes K1/K2 were assessed by multiplex PCR. Biofilms were grown using flat-bottomed polystyrene plates, followed by coloring, fixation, elution and data detection. The population diversity was assessed by multilocus sequence typing. Bacteremia and CNS infections associated with K. pneumoniae were fatal in 25% of cases. A substantial portion of the isolates demonstrated the phenotype of extremely drug resistance (XDR) — 43%, the phenotype of multidrug resistance (MDR) was shown in 16% of the isolates. The blaCTX-M cephalosporinase gene was found in 85% of the strains. The main determinant of resistance to carbapenems was the blaOXA-48 gene (33%); the blaNDM gene was detected in 9% of strains. The combination of blaOXA-48 and blaNDM was found in 7% of isolates. The study of biofilm production showed that moderate ability to form biofilms was shown in 61%, strong — 21%, and weak — 15% isolates. Two isolates (3%) did not form biofilms. The virulence genes entB and mrkD were detected in 100% of isolates, ybtS — in 78%. The iutA gene was found in 18% of the strains. Two isolates showed the presence of the kfu gene. Seven isolates belonged to the K2 serotype. 27 different genotypes were found in K. pneumoniae isolates examined. The most common were: ST307 — 21%, ST395 — 12%, ST48 — 7%, ST39 — 6% and ST29 — 6%. Infections of the bloodstream and central nervous system associated with K. pneumoniae have great importance in clinical practice. This microorganism is able to long persist on biotic and abiotic surfaces, has a wide natural and acquired resistance to antibiotics

Micronutrients availability, immune response, and COVID-19

Vaccination and hygiene are currently the main strategies for helping limit the spread and impact of acute respiratory infections. However, the pandemic of SARS-CoV-2 infection and its severe consequences require the search for additional measures for reducing the morbidity and mortality from coronavirus infection. One of these additional prevention strategies is micronutrient status optimization, which is safe and cost-effective. Vitamins and minerals are important components of the immune response. The effect of micronutrients such as vitamin D, ascorbic acid, zinc, omega-3 polyunsaturated fatty acids on the immune response has been studied for several decades. As a result, significant shreds of evidence have been accumulated regarding the importance of provision immuno-nutrients on the adequate immune response. This implies in both contexts: the prevention of infectious diseases and their course. At the same time, the problem of insufficient supply with various micronutrients is gaining global significance, affecting every country and every socio-economic class of people. This review contains data on the state of micronutrient status of the global and Russian population, discussion of the role of key immunonutrients in the prevention and treatment of respiratory infections, and results of recent meta-analyses. It will also provide recommendations of experts in the field of nutrition, developed in 2020 with regard to the COVID-19 pandemic

Signatures of Dermal Fibroblasts from RDEB Pediatric Patients

The recessive form of dystrophic epidermolysis bullosa (RDEB) is a debilitating disease caused by impairments in the junctions of the dermis and the basement membrane of the epidermis. Mutations in the COL7A1 gene induce multiple abnormalities, including chronic inflammation and profibrotic changes in the skin. However, the correlations between the specific mutations in COL7A1 and their phenotypic output remain largely unexplored. The mutations in the COL7A1 gene, described here, were found in the DEB register. Among them, two homozygous mutations and two cases of compound heterozygous mutations were identified. We created the panel of primary patient-specific RDEB fibroblast lines (FEB) and compared it with control fibroblasts from healthy donors (FHC). The set of morphological features and the contraction capacity of the cells distinguished FEB from FHC. We also report the relationships between the mutations and several phenotypic traits of the FEB. Based on the analysis of the available RNA-seq data of RDEB fibroblasts, we performed an RT-qPCR gene expression analysis of our cell lines, confirming the differential status of multiple genes while uncovering the new ones. We anticipate that our panels of cell lines will be useful not only for studying RDEB signatures but also for investigating the overall mechanisms involved in disease progression

Clinical Features and Management of the Disease Caused by New Coronaviral Infection (COVID-19) in Children. Version 2

The Ministry of Health of the Russian Federation jointly with professional association and experts in the field of pediatrics, infectious diseases and resuscitation has revised guidelines “Clinical Features and Management of the Disease Caused by New Coronaviral Infection (COVID-19) in Children” in order to provide the child population with effective medical care during the pandemic of the new coronaviral infection. The practical experience of specialists from various countries was considered during the development of this document. Special attention should be given to the evidence base of the presented data, as well as to the efficiency and safety issues of medications used in treatment of coronaviral infection and its complications. The authors highlight the problems of prevention, diagnostics and management of pathological conditions caused by COVID-19 in the article according to the presented guidelines. Patient’s management is presented depending on the age and severity of the disease itself. The therapy is considered with regard to etiological, pathogenetic and symptom focus

Особенности клинических проявлений и лечения заболевания, вызванного новой коронавирусной инфекцией (COVID-19), у детей. Версия 2

The Ministry of Health of the Russian Federation jointly with professional association and experts in the field of pediatrics, infectious diseases and resuscitation has revised guidelines “Clinical Features and Management of the Disease Caused by New Coronaviral Infection (COVID-19) in Children” in order to provide the child population with effective medical care during the pandemic of the new coronaviral infection. The practical experience of specialists from various countries was considered during the development of this document. Special attention should be given to the evidence base of the presented data, as well as to the efficiency and safety issues of medications used in treatment of coronaviral infection and its complications. The authors highlight the problems of prevention, diagnostics and management of pathological conditions caused by COVID-19 in the article according to the presented guidelines. Patient’s management is presented depending on the age and severity of the disease itself. The therapy is considered with regard to etiological, pathogenetic and symptom focus.С целью обеспечения детского населения эффективной медицинской помощью в условиях пандемии новой коронавирусной инфекции Минздравом России совместно с профессиональными ассоциациями и экспертами в области педиатрии, инфекционных болезней и реанимации были переработаны методические рекомендации «Особенности клинических проявлений и лечения заболевания, вызванного новой коронавирусной инфекцией (COVID-19), у детей». При разработке документа был учтен практический опыт не только специалистов нашей страны, но и зарубежных коллег. Особое внимание уделено доказательной базе представленных данных, а также вопросам эффективности и безопасности лекарственных препаратов, применяемых при лечении данной инфекции и ее осложнений. В статье на основании указанных методических рекомендаций авторы освещают вопросы профилактики, диагностики, лечения патологических состояний, обусловленных COVID-19. Тактика ведения пациента представлена в зависимости от возраста и степени тяжести течения болезни, терапия рассмотрена с позиций этиологической, патогенетической и симптоматической направленности