РОЛЬ ИНФЕКЦИОННОГО И ВОЗРАСТНОГО ФАКТОРА В РАЗВИТИИ ЛЕЙКОЭНЦЕФАЛИТОВ У ДЕТЕЙ

We have performed a clinical and cerebral MRI study of among 145 children with leukoencephalitis aged from 6 months to 18 years. The group of herpes viruses (i.e., herpes virus 1–2 and 6 types, virus Epstein – Barr, varicellazoster and cytomegalovirus) has been found to play the main role in etiology of leukoencephalitises with children; these viruses are detected in patients with mixed infections as well as in patients with mono infections. We defined clinical and MRI patterns, characteristic of leukoencephalitis and caused by different pathogens. The etiology of leukoencephalitis has been found to determine the course and outcome of the disease. Patient`s age (> 10 years) is associated with chronical leukoencephalitis.Проведен анализ клинической картины и данных МРТ головного и спинного мозга у 145 детей с лейкоэнцефалитами в возрасте от 6 мес. до 18 лет. Установлено, что в этиологии лейкоэнцефалитов у детей ведущее значение имеют группа вирусов герпеса: вирус герпеса 1–2-го и 6-го типов, вирус Эпштейна – Барр, варицелла-зостер и цитомегаловирус, в виде как моно-, так и микст-инфекций. Определены клинические и лучевые паттерны, характерные для различной этиологии и варианта течения заболевания. Выявлена зависимость этиологических агентов на течение и исходы лейкоэнцефалитов у детей. Установлено, что для ЛЭ с хроническим течением преобладал в 79,5% случаев возраст детей старше 10 лет

ПАРВОВИРУСНАЯ (B19V) ИНФЕКЦИЯ У БЕРЕМЕННЫХ И ДЕТЕЙ РАННЕГО ВОЗРАСТА

The modern detailed data about different aspects of parvovirus infection presented in this review. Based on the analysis of literature, the ethiology epidemiology, clinical manifestations of this disease described. The special attention pays to mechanisms of virus’s pathologic impact to fetus. The authors widely take up the possibilities to estimate risks of congenital parvovirus infection, antenatal diagnostics measures, interpretation of the lab and instrumental results. Therapeutic approaches in different clinical situations described, possibilities of prophylaxis discussed.В обзоре представлены современные подробные сведения о различных аспектах проблемы парвовирусной инфекции. На основании анализа данных литературы описаны этиология, эпидемиология заболевания, его клинические проявления. Особое внимание обращено на механизмы патологического воздействия парвовируса на плод. Широко освещены возможности оценки риска врожденной парвовирусной инфекции, антенатальной диагностики, интерпретации результатов различных лабораторных и инструментальных методов исследований. Описаны терапевтические подходы в различных клинических ситуациях, обсуждаются возможности профилактики заболевания

Target protection as a key antibiotic resistance mechanism

Antibiotic resistance is mediated through several distinct mechanisms, most of which are relatively well understood and the clinical importance of which has long been recognized. Until very recently, neither of these statements was readily applicable to the class of resistance mechanism known as target protection, a phenomenon whereby a resistance protein physically associates with an antibiotic target to rescue it from antibiotic-mediated inhibition. In this Review, we summarize recent progress in understanding the nature and importance of target protection. In particular, we describe the molecular basis of the known target protection systems, emphasizing that target protection does not involve a single, uniform mechanism but is instead brought about in several mechanistically distinct ways

Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens

he antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F-subtype (ARE-ABCFs), which are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition from antibiotics that target the large ribosomal subunit. Here, we present single-particle cryo-EM structures of ARE-ABCF-ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaALC and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a general model for antibiotic resistance mediated by these ARE-ABCFs to be proposed. In this model, ABCF binding to the antibiotic-stalled ribosome mediates antibiotic release via mechanistically diverse long-range conformational relays that converge on a few conserved ribosomal RNA nucleotides located at the peptidyltransferase center. These insights are important for the future development of antibiotics that overcome such target protection resistance mechanisms

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease