Клиническая значимость вирусологических методов верификации этиологии инфекционного мононуклеоза

Purpose: to justify the need to use at least two methods (direct and indirect) for reliable laboratory decoding of infectious mononucleosis. Materials and methods. We observed 107 children with infectious mononucleosis. Deciphering the etiology was carried out using ELISA (We determined IgM VCA-EBV, IgG EA-EBV, IgG EBNA-EBV, IgM CMV, IgG CMV in serum) and PCR (We determined investigated viral DNA (EBV, CMV, HHV 6) in peripheral blood mononuclear cells). Results: In the structure of infectious mononucleosis, EBV remains the leading infection: 82 children (76.6%). In case of reactivated EBV infection, the isolated use of the ELISA method does not limit the possibility of interpreting the results without additional evaluation of the test results by PCR. A significantly level of viral DNA concentration in the examined children has not been established. The detection frequencies of EBV DNA and HHV 6 DNA by PCR are not mutually independent (p < 0.001). Detection of one of the viruses reduces the chance of detecting another virus (OR = 0.133; 95% CI from 0.0537 to 0.3273, p < 0.0001).Цель исследования: обоснование необходимости применения, как минимум, двух методов (прямых и непрямых) для надежной лабораторной расшифровки инфекционного мононуклеоза (ИМ). Материалы и методы: нами было обследовано 107 детей с ИМ. Расшифровка этиологии проводилась методами ИФА (определялись IgM VCA-EBV, IgG EA-EBV, IgG EBNA-EBV, IgM CMV, IgG CMV в сыворотке крови) и ПЦР (исследовалась вирусная ДНК (ВЭБ, ЦМВ, ВГЧ 6) в мононуклеарах периферической крови). Результаты: В структуре инфекционного мононуклеоза ВЭБ остается лидирующей инфекцией: 82 ребенка (76,6%). При реактивированной ВЭБ-инфекции изолированное применение метода ИФА ограничивает возможность интерпретации результатов без дополнительной оценки результатов тестов методом ПЦР. Достоверно значимого уровня вирусной нагрузки у обследованных детей установлено не было. Частоты выявления ДНК ВЭБ и ДНК ВГЧ 6 методом ПЦР не являются взаимно независимыми (p < 0,001). Выявление одного из вирусов уменьшает шанс выявить другой вирус (ОШ = 0,133; 95% ДИ от 0,0537 до 0,3273, p < 0,0001)

Распространенность и особенности течения ВИЧ/ВГС ко-инфекции у беременных

The aim of the work is to improve the algorithm of management of pregnant women with HIV/HCV co-infection. The study was conducted on the basis of the Moscow City Center for AIDS Prevention and Control of the Moscow Department of Health from 2020 to 2022. 80 women diagnosed with HIV/HCV coinfection were under observation. The patients underwent a general examination and evaluation of anamnesis data, laboratory tests. The article presents statistical data on HIV/HCV-infected women who have been registered at the Moscow City Center for the Prevention and Control of AIDS for the past three years. The social characteristics of pregnant women with HIV/HCV co-infection are given and the clinical and immunological features of the course of the disease are presented.Целью работы является усовершенствование алгоритма ведения беременных с ВИЧ/ВГС ко-инфекцией. Исследование проводилось на базе Московского городского центра профилактики и борьбы со СПИДом Департамента здравоохранения г. Москвы с 2020 года по 2022 год. Под наблюдением находилось 80 женщин с диагнозом ВИЧ/ВГС ко-инфекция. Пациентам проводились общий осмотр и оценка данных анамнеза, лабораторные исследования. В статье представлены статистические данные по ВИЧ/ВГС-инфицированным женщинам, состоявшим на учете в МГЦ СПИД за последние три года. Дана социальная характеристика беременных с ко-инфекциией ВИЧ/ВГС и представлены клинико-иммунологические особенности течения заболевания

An evaluation of indirubin analogues as phosphorylase kinase inhibitors

Phosphorylase kinase (PhK) has been linked with a number of conditions such as glycogen storage diseases, psoriasis, type 2 diabetes and more recently, cancer (Camus S. et al., Oncogene 2012, 31, 4333). However, with few reported structural studies on PhK inhibitors, this hinders a structure based drug design approach. In this study, the inhibitory potential of 38 indirubin analogues have been investigated. 11 of these ligands had IC50 values in the range 0.170 – 0.360 µM, with indirubin-3’-acetoxime (1c) the most potent. 7-bromoindirubin-3’-oxime (13b), an antitumor compound which induces caspase-independent cell-death (Ribas J. et al., Oncogene, 2006, 25, 6304) is revealed as a specific inhibitor of PhK (IC50 = 1.8 µM). Binding assay experiments performed using both PhK-holo and PhK-γtrnc confirmed the inhibitory effects to arise from binding at the kinase domain (γ subunit). High level computations using QM/MM-PBSA binding free energy calculations were in good agreement with experimental binding data, as determined using statistical analysis, and support binding at the ATP-binding site. The value of a QM description for the binding of halogenated ligands exhibiting -hole effects is highlighted. A new statistical metric, the ‘sum of the modified logarithm of ranks’ (SMLR), has been defined which measures performance of a model for both the “early recognition” (ranking earlier/higher) of active compounds and their relative ordering by potency. Through a detailed structure activity relationship analysis considering other kinases (CDK2, CDK5 and GSK-3α/β), 6’(Z) and 7(L) indirubin substitutions have been identified to achieve selective PhK inhibition. The key PhK binding site residues involved can also be targeted using other ligand scaffolds in future work

Swimming Exercise Prevents Fibrogenesis in Chronic Kidney Disease by Inhibiting the Myofibroblast Transdifferentiation

BACKGROUND: The renal function of chronic kidney disease (CKD) patients may be improved by a number of rehabilitative mechanisms. Swimming exercise training was supposed to be beneficial to its recovery. METHODOLOGY/PRINCIPAL FINDINGS: Doxorubicin-induced CKD (DRCKD) rat model was performed. Swimming training was programmed three days per week, 30 or 60 min per day for a total period of 11 weeks. Serum biochemical and pathological parameters were examined. In DRCKD, hyperlipidemia was observed. Active mesangial cell activation was evidenced by overexpression of PDGFR, P-PDGFR, MMP-2, MMP-9, α-SMA, and CD34 with a huge amount collagen deposition. Apparent myofibroblast transdifferentiation implicating fibrogenesis in the glomerular mesangium, glomerulonephritis and glomeruloscelorosis was observed with highly elevated proteinuria and urinary BUN excretion. The 60-min swimming exercise but not the 30 min equivalent rescued most of the symptoms. To quantify the effectiveness of exercise training, a physical parameter, i.e. "the strenuosity coefficient" or "the myokine releasing coefficient", was estimated to be 7.154 × 10(-3) pg/mL-J. CONCLUSIONS: The 60-min swimming exercise may ameliorate DRCKD by inhibiting the transdifferentiation of myofibroblasts in the glomerular mesangium. Moreover, rehabilitative exercise training to rescue CKD is a personalized remedy. Benefits depend on the duration and strength of exercise, and more importantly, on the individual physiological condition

The Stability and Formation of Native Proteins from Unfolded Monomers Is Increased through Interactions with Unrelated Proteins

The intracellular concentration of protein may be as high as 400 mg per ml; thus it seems inevitable that within the cell, numerous protein-protein contacts are constantly occurring. A basic biochemical principle states that the equilibrium of an association reaction can be shifted by ligand binding. This indicates that if within the cell many protein-protein interactions are indeed taking place, some fundamental characteristics of proteins would necessarily differ from those observed in traditional biochemical systems. Accordingly, we measured the effect of eight different proteins on the formation of homodimeric triosephosphate isomerase from Trypanosoma brucei (TbTIM) from guanidinium chloride unfolded monomers. The eight proteins at concentrations of micrograms per ml induced an important increase on active dimer formation. Studies on the mechanism of this phenomenon showed that the proteins stabilize the dimeric structure of TbTIM, and that this is the driving force that promotes the formation of active dimers. Similar data were obtained with TIM from three other species. The heat changes that occur when TbTIM is mixed with lysozyme were determined by isothermal titration calorimetry; the results provided direct evidence of the weak interaction between apparently unrelated proteins. The data, therefore, are strongly suggestive that the numerous protein-protein interactions that occur in the intracellular space are an additional control factor in the formation and stability of proteins

Quantifying the Effects of Elastic Collisions and Non-Covalent Binding on Glutamate Receptor Trafficking in the Post-Synaptic Density

One mechanism of information storage in neurons is believed to be determined by the strength of synaptic contacts. The strength of an excitatory synapse is partially due to the concentration of a particular type of ionotropic glutamate receptor (AMPAR) in the post-synaptic density (PSD). AMPAR concentration in the PSD has to be plastic, to allow the storage of new memories; but it also has to be stable to preserve important information. Although much is known about the molecular identity of synapses, the biophysical mechanisms by which AMPAR can enter, leave and remain in the synapse are unclear. We used Monte Carlo simulations to determine the influence of PSD structure and activity in maintaining homeostatic concentrations of AMPARs in the synapse. We found that, the high concentration and excluded volume caused by PSD molecules result in molecular crowding. Diffusion of AMPAR in the PSD under such conditions is anomalous. Anomalous diffusion of AMPAR results in retention of these receptors inside the PSD for periods ranging from minutes to several hours in the absence of strong binding of receptors to PSD molecules. Trapping of receptors in the PSD by crowding effects was very sensitive to the concentration of PSD molecules, showing a switch-like behavior for retention of receptors. Non-covalent binding of AMPAR to anchored PSD molecules allowed the synapse to become well-mixed, resulting in normal diffusion of AMPAR. Binding also allowed the exchange of receptors in and out of the PSD. We propose that molecular crowding is an important biophysical mechanism to maintain homeostatic synaptic concentrations of AMPARs in the PSD without the need of energetically expensive biochemical reactions. In this context, binding of AMPAR with PSD molecules could collaborate with crowding to maintain synaptic homeostasis but could also allow synaptic plasticity by increasing the exchange of these receptors with the surrounding extra-synaptic membrane

A Protein Aggregation Based Test for Screening of the Agents Affecting Thermostability of Proteins

To search for agents affecting thermal stability of proteins, a test based on the registration of protein aggregation in the regime of heating with a constant rate was used. The initial parts of the dependences of the light scattering intensity (I) on temperature (T) were analyzed using the following empiric equation: I = Kagg(T−T0)2, where Kagg is the parameter characterizing the initial rate of aggregation and T0 is a temperature at which the initial increase in the light scattering intensity is registered. The aggregation data are interpreted in the frame of the model assuming the formation of the start aggregates at the initial stages of the aggregation process. Parameter T0 corresponds to the moment of the origination of the start aggregates. The applicability of the proposed approach was demonstrated on the examples of thermal aggregation of glycogen phosphorylase b from rabbit skeletal muscles and bovine liver glutamate dehydrogenase studied in the presence of agents of different chemical nature. The elaborated approach to the study of protein aggregation may be used for rapid identification of small molecules that interact with protein targets

Influenza vaccination for immunocompromised patients: systematic review and meta-analysis from a public health policy perspective.

Immunocompromised patients are vulnerable to severe or complicated influenza infection. Vaccination is widely recommended for this group. This systematic review and meta-analysis assesses influenza vaccination for immunocompromised patients in terms of preventing influenza-like illness and laboratory confirmed influenza, serological response and adverse events