COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models.

One year into the Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), effective treatments are still needed 1-3 . Monoclonal antibodies, given alone or as part of a therapeutic cocktail, have shown promising results in patients, raising the hope that they could play an important role in preventing clinical deterioration in severely ill or in exposed, high risk individuals 4-6 . Here, we evaluated the prophylactic and therapeutic effect of COVA1-18 in vivo , a neutralizing antibody isolated from a convalescent patient 7 and highly potent against the B.1.1.7. isolate 8,9 . In both prophylactic and therapeutic settings, SARS-CoV-2 remained undetectable in the lungs of COVA1-18 treated hACE2 mice. Therapeutic treatment also caused a dramatic reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg - 1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 had a very strong antiviral activity in the upper respiratory compartments with an estimated reduction in viral infectivity of more than 95%, and prevented lymphopenia and extensive lung lesions. Modelling and experimental findings demonstrate that COVA1-18 has a strong antiviral activity in three different preclinical models and could be a valuable candidate for further clinical evaluation.

Adherence to Medical Treatment in Patients who Have Experienced Acute Coronary Syndrome and Percutaneous Coronary Intervention.

PURPOSE: to study adherence to therapy after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). We analyzed retrospectively 127 case histories of patients who underwent PCI for ACS in 2015 (in Udmurtia at that time PCIs were mostly carried out later than 6 hours after onset of symptoms). INCLUSION CRITERIA: age 25-75 years; confirmed ACS; stenting of coronary arteries for the first time. EXCLUSION CRITERIA: pregnancy; prisoners; incompetent persons; history of PCI or coronary artery bypass grafting. In two years after the PCI 95 patients were questioned concerning use of statins (including their doses) and dual antiplatelet therapy (DAPT). RESULTS: In 2 years after index PCI 83% of patients took statins regularly. DAPT for 1 year or more after PCI received 85% of patients. CONCLUSION: Adherence to therapy with statins and antiplatelet therapy was found to be high. PCI in patients with ACS was mainly delayed (more than 6 hours from the onset of symptoms). It is necessary to further improve the routing of patients to PCI performing centers from Udmurtia regions for the timely myocardial revascularization.

A hypothetical hierarchical mechanism of the self-assembly of the Escherichia coli RNA polymerase σ(70) subunit.

Diverse morphology of aggregates of amyloidogenic proteins has been attracting much attention in the last few years, and there is still no complete understanding of the relationships between various types of aggregates. In this work, we propose the model, which universally explains the formation of morphologically different (wormlike and rodlike) aggregates on the example of a σ(70) subunit of RNA polymerase, which has been recently shown to form amyloid fibrils. Aggregates were studied using AFM in solution and depolarized dynamic light scattering. The obtained results demonstrate comparably low Young's moduli of the wormlike structures (7.8-12.3 MPa) indicating less structured aggregation of monomeric proteins than that typical for ß-sheet formation. To shed light on the molecular interaction of the protein during the aggregation, early stages of fibrillization of the σ(70) subunit were modeled using all-atom molecular dynamics. Simulations have shown that the σ(70) subunit is able to form quasi-symmetric extended dimers, which may further interact with each other and grow linearly. The proposed general model explains different pathways of σ(70) subunit aggregation and may be valid for other amyloid proteins.

Lanthanide complexes with 2-(tosylamino)benzylidene-N-benzoylhydrazone, which exhibit high NIR emission.

New NIR emitting materials were found among the lanthanide complexes with 2-(tosylamino)benzylidene-N-benzoylhydrazone. Complexes of Nd(3+), Er(3+) and Yb(3+), as well as Eu(3+), Gd(3+) and Lu(3+), were synthesized for the first time. Owing to the absence of vibration quenching the ytterbium complex was found to exhibit a photoluminescence quantum yield of 1.4%. Since the sensitization efficiency was calculated to be 55%, the losses in the quantum yield are probably due to Yb-Yb resonant energy transfer.

[N6-dipeptide derivatives of the N12-ribosyl-indolo[2,3-a]carbazole].

N6-derivatives of N12-ribosyl-indolo[2,3-a]pirrolo[3,4-c]carbazole-5,7-dione are synthesized as potential antitumor agents, in which an atom of N6-pyrrole part of heterocycle is included into the dipeptide residual of the general formula >N6-(CH2)n-CO-Ala/ßAla-OMe (n = 2 or 3). These compounds are derived by reacting of 13-methyl-12-(2,3,4-three-O-acetyl-ß-D-ribopyranosyl)indolo[2,3-a]furano[3,4-c] carbazole-5,7-dione with dipeptides, having an unreplaced N-amino end-group, in DMF at 130°C, wherein the nitrogen atom of peptide amino group replaces oxygen O6 in furan ring of heterocycle and is embedded in imide nitrogen atom of pyrrole N6. The ability of the obtained compounds to inhibit growth of SKOV3 human ovarian carcinoma cells was studied, only derivative with radical >N6-(CH2)3-CO-L-Ala-OMe showed cytotoxic activity with an inhibitory concentration of IC50 = 8 µM.

Multidisciplinary approach to epizootiology and pathogenesis of bat rabies viruses in the United States.

Zoonotic disease surveillance is typically initiated after an animal pathogen has caused disease in humans. Early detection of potentially high-risk pathogens within animal hosts may facilitate medical interventions to cope with an emerging disease. To effectively spillover to a novel host, a pathogen may undergo genetic changes resulting in varying transmission potential in the new host and potentially to humans. Rabies virus (RABV) is one model pathogen to consider for studying the dynamics of emerging infectious diseases under both laboratory and field conditions. The evolutionary history of RABV is characterized by regularly documented spillover infections and a series of notable host shifts. Within this context, enhanced field surveillance to improve detection of spillover infections will require validated techniques to non-invasively differentiate infected from non-infected individuals. In this study, we evaluate the use of infrared thermography to detect thermal changes associated with experimental RABV infection in big brown bats (Eptesicus fuscus) in a captive colony. Our results indicated that 62% of rabid bats had detectable facial temperature decreases (-4.6°C, SD ± 2.5) compared with pre-inoculation baseline values. These data suggest potential utility for discriminating rabid bats in natural field settings. In addition, focusing upon RABV circulating in the United States between 2008 and 2011, we confirmed spillover events of bat RABV among carnivores and identified cross-species transmission events caused by four lineages of RABV associated with insectivorous bats. Additionally, our analysis of RABV glycoprotein sequences identified substitutions in antigenic sites that may affect neutralizing activity associated with monoclonal antibodies proposed for use in human post-exposure prophylaxis. This study provides a glimpse into RABV pathobiology and spillover dynamics among and between bats and a variety of mesocarnivores.

Monoclonal-based enzyme-linked immunosorbent assay for the detection of zearalenone in cereals.

A monoclonal antibody against zearalenone (ZEA) was produced and used successfully to develop a direct competitive enzyme-linked immunosorbent assay (DC-ELISA) for the analysis of ZEA in cereals. This DC-ELISA had a limit of detection of 0.15 +/- 0.02 microg l(-1) and an IC50 value of 1.13 +/- 0.16 microg l(-1). Matrix interference was minimized by dilution of the sample extract before ELISA assays. Aqueous methanol (80%) gave good extraction efficiencies, and the recovery from spiked rice, barley, and corn samples averaged between 87 and 112%. Although ZEA was detected in seven (9%) of 80 rice samples and in eight (16%) of 50 barley samples, the concentration of ZEA in samples was around or below the limit of detection of DC-ELISA. Among 38 corn samples, ZEA was detected in nine (24%) samples in the range 41.0-909.8 microg kg(-1). Re-analysis of the ELISA-positive corn samples by high-performance liquid chromatography (HPLC) confirmed that seven (18%) corn samples were positive. The ZEA results for corn showed very good agreement between DC-ELISA and a commercial AgraQant zearalenone kit (r2 = 0.98). Thus, the monoclonal antibody-based DC-ELISA could be applied to the preliminary screening of ZEA contamination when analysis of a large sample number is needed.

Evaluation of the effects of topical clobetasol propionate by visual score, electrical impedance and laser Doppler flowmetry.

BACKGROUND/PURPOSE: The intensity of steroid-induced skin blanching is usually evaluated subjectively by a trained observer using a visual score although a few methods have been described for doing this objectively. In this study we wished to establish whether the effects of topical steroids can be detected by measuring the electrical impedance of the skin. METHODS: Ten healthy volunteers were treated with three concentrations of clobetasol propionate (0.005, 0.05, and 0.5 mg/mL) on the forearm covered by a dressing overnight. On the following morning, we assessed dermal blanching using a visual score, laser Doppler flowmetry and electrical impedance. RESULTS: Using the visual score, we found dose-response blanching at all concentrations of clobetasol propionate. The laser Doppler flow values declined significantly after the application of clobetasol propionate (0.005 mg/mL (P<0.01) and 0.5 mg/mL (P<0.05)), as compared with the test site treated with the vehicle alone. Electrical impedance showed a significant increase in phase index after the application of 0.05 mg (P<0.01) and 0.5 mg (P<0.01) of clobetasol propionate, and a significant reduction in real part index after of 0.05 mg/mL (P<0.05) and 0.5 mg/mL (P<0.05) compared with the test site treated with the vehicle alone. The magnitude index and imaginary part index were not affected by this steroid. CONCLUSION: Our findings indicate that the dermal blanching induced by topical corticosteroids can be evaluated with a skin impedance spectrometer.

Molecular structures of tris(dipivaloylmethanato) complexes of the lanthanide metals, Ln(dpm)3, studied by gas electron diffraction and density functional theory calculations: a comparison of the Ln-O Bond distances and enthalpies in Ln(dpm)3 complexes and the cubic sesquioxides, Ln2O3.

The molecular structures of tris(dipivaloylmethanato)neodymium(III), Nd(dpm)3, and tris(dipivaloylmethanato)ytterbium(III), Yb(dpm)3, have been determined by gas electron diffraction (GED) and structure optimizations through density functional theory (DFT) calculations. Both molecules were found to have D3 molecular symmetry. The most important structure parameters (r(a) structure) are as follows (GED/DFT): Nd-O = 2.322(5)/2.383 A, Yb-O = 2.208(5)/2.243 A, O-Nb-O = 72.1(3)/71.3 degrees , and O-Yb-O = 75.3(2)/75.8 degrees . The twist angles of the LnO6 coordination polyhedron, defined as zero for prismatic and 30 degrees for antiprismatic coordination, were theta = 19.1(3)/14.2 degrees for Nd and 20.4(2)/19.2 degrees for Yb. Structure optimizations of La(dpm)3, Gd(dpm)3 Er(dpm)3, and Lu(dpm)3 by DFT also yielded equilibrium structures of D3 symmetry with bond distances of La-O = 2.438 A, Gd-O = 2.322 A, Er-O = 2.267 A, and Lu-O = 2.232 A. The Ln-O bond distances in 12 Ln(dpm)3 complexes studied by GED decrease in a nearly linear manner with the increasing atomic number (Z) of the metal atom, as do the Ln-O bond distances in the cubic modifications of 14 sesquioxides, Ln2O3. The bond distances in the dpm complexes are, however, about 2% shorter. The mean Ln-O bond rupture enthalpies of the cubic sesquioxides calculated from thermodynamic data in the literature vary in an irregular manner with the atomic number; the La-O, Gd-O, Tb-O, and Lu-O bonds are nearly equally strong, and the remaining bonds are significantly weaker. The Ln-O bond rupture enthalpies previously reported for 11 Ln(dpm)3 complexes are on the average 13 kJ mol(-1) or about 5% smaller than in the sesquioxides, but they vary in a similar manner along the series: it is suggested that the pattern reflects variations in the absolute enthalpies of the gaseous Ln atoms.

Biophysical assessment of atopic dermatitis skin and effects of a moisturizer.

BACKGROUND: The mechanisms of the skin barrier impairment in patients with atopic dermatitis (AD) are still unknown and need further studying. OBJECTIVE: We evaluated the skin of healthy subjects and of patients having atopic dermatitis with an instrument measuring electrical impedance and other noninvasive methods (transepidermal water loss, capacitance) and studied the effects of a new emollient [Proderm (Pro-Q in the USA)]. METHODS: After a 2-week washout period, we treated clinically noneczematous skin on the forearm of 24 patients with AD and assessed the effects with the noninvasive methods. 22 healthy subjects were used as controls. RESULTS: The findings indicate that barrier function and hydration, and certain patterns of electrical impedance of AD skin are abnormal compared with normal skin. Moreover, there was an increase in hydration in patients' skin after treatment and a reversal of certain impedance indices towards normal. CONCLUSIONS: Our findings demonstrate that the moisturizer we used changes some biophysical parameters when applied to atopic skin. In addition, a technique based on electrical impedance seems to give valuable information in atopic skin studies, especially the effects of moisturizers.

Magnetically isolated Cu(II)Gd(III) pairs in the series [Cu(acacen)Gd(pta)(3)], [Cu(acacen)Gd(hfa)(3)], [Cu(salen)Gd(pta)(3)], and [Cu(salen)Gd(hfa)(3)], [acacen = N,N'-ethylenebis(acetylacetoniminate(-)), salen = N,N'-ethylenebis(salicylideniminate(-)), hfa = 1,1,1,5,5,5-hexafluoropentane-2,4-dionate(-), pta = 1,1,1-trifluoro-5,5-dimethylhexane-2,4-dionate(-)].

[Cu(salen)Gd(pta)(3)] (1), [Cu(acacen)Gd(pta)(3)] (2), and [Cu(acacen)Gd(hfa)(3)] (3) are three heterobimetallic [Cu(II)Gd(III)] complexes of general formula [Cu(SB)Gd(beta-dik)(3)], in which a N,N',O,O' Schiff base (SB) ligand [acacen = N,N'-ethylenebis(acetylacetoniminate(-)), salen = N,N'-ethylenebis(salicylideneiminate(-))] tetracoordinates Cu(II) and chelates Gd(III) as a tris(beta-diketonate) complex [hfa = 1,1,1,5,5,5-hexafluoropentane-2,4-dionate(-); pta = 1,1,1-trifluoro-5,5-dimethylhexane-2,4-dionate(-)]. They crystallize as a triclinic structure (space group P). The cell parameters are a = 9.8616(10) A, b = 12.1976(13) A, c = 18.4187(22) A, alpha = 90.671(14) degrees, beta = 100.588(13) degrees, gamma = 103.684(12) degrees, V = 2113 A(3), and Z = 2 for 1; a = 9.7560(11) A, b = 12.2924(13) A, c = 18.9368(22) A, alpha = 88.449(14) degrees, beta = 87.269(14) degrees, gamma = 67.629(12) degrees, V = 2098 A(3), and Z = 2 for 2; and a = 12.5726(15) A, b = 15.5985(18) A, c = 18.3724(21) A, alpha = 85.963(13) degrees, beta = 85.411(14) degrees, gamma = 80.766(14) degrees, V = 3539 A(3), and Z = 4 for 3. The Cu(O,O')Gd bridging cores show folding angles about O,O' in the range 139 degrees -147 degrees and intramolecular Cu small middle dot small middle dot small middle dotGd distances of about 3.3 A. In the solid state, the molecules form centrosymmetric pseudodimers [Cu(SB)Gd(beta-dik)(3)](2), through the overlap of the Cu(SB) entities. Resulting intradimer Cu...Cu distances are 5.941(1) A for 1, 4.831(1) A for 2, and 4.511(1) and 3.868(1) A for 3 which comprises two symmetrically independent dimers. The temperature dependence of complexes 1-3 was investigated in the range 1.8-300 K and revealed weak ferromagnetic interactions. Results are discussed in light of the structural features and of available magnetostructural data for other heterobimetallic [Cu(II)Gd(III)] complexes, including [Cu(salen)Gd(hfa)(3)] (4) (Ramade, I.; Kahn, O.; Jeannin, Y.; Robert, F. Inorg. Chem. 1997, 36, 930-936).

The Russian version of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ).

We report herein the results of the cross-cultural adaptation and validation into the Russian language of the parent's version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. The Russian CHAQ CHQ were fully validated with 3 forward and 3 backward translations. A total of 146 subjects were enrolled: 86 patients with JIA (23% systemic onset, 39% polyarticular onset, 15% extended oligoarticular subtype, and 23% persistent oligoarticular subtype) and 60 healthy children. The CHAQ clinically discriminated between healthy subjects and JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and a lower overall well-being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the systemic onset, polyarticular onset and extended oligoarticular subtypes having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the Russian version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.

[Hemostasis in pregnancy and antenatal fetal distress]. / Sistema gemostaza beremennoi i antenatalnyi distress ploda.

Study of the hemostasis system of pregnant women at risk of developing fetal distress in the third gestation trimester showed the prognostic significance of platelet aggregation test as an additional method of diagnosis of placental insufficiency. If platelet aggregation index is more than 70%, a woman should be included in the group at risk of developing ante- or intranatal fetal distress.

Comparative efficacy and safety of advanced drug therapy in children with juvenile rheumatoid arthritis.

Results from three randomized placebo-controlled trials were combined in a meta-analysis to compare the clinical utility of four advanced drug therapy agents used to treat juvenile rheumatoid arthritis (JRA): D-penicillamine (10 mg/kg/d), hydroxychloroquine (6 mg/kg/d), auranofin (oral gold, 0.15 to 0.20 mg/kg/d), and two low dose levels of methotrexate [5MTX, 5 mg/M2/wk; 10MTX, 10 mg/M2/wk]. A total of 520 children with JRA were enrolled into these trials. Only 10MTX resulted in significantly greater improvement than placebo in variables that assess effectiveness: physician's global assessment, a composite index, and erythrocyte sedimentation rate. Treatment effect sizes were the largest in the 10MTX group for all articular disease indices. The short-term safety profiles were similar across all treatment groups. It is concluded that the current trend among pediatric rheumatologists to use oral methotrexate as the first advanced drug therapy in JRA is appropriate and that the minimum effective dose is 10 mg/M2/wk.

Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and The Cooperative Children's Study Group.

BACKGROUND: The antimetabolite methotrexate has been shown in placebo-controlled trials to be effective in adults with rheumatoid arthritis. Methotrexate may also be effective in children with resistant juvenile rheumatoid arthritis, but the supporting data are from uncontrolled trials. METHODS: Centers in the United States and the Soviet Union participated in this randomized, controlled, double-blind trial designed to evaluate the effectiveness and safety of orally administered methotrexate. Patients received one of the following treatments each week for six months: 10 mg of methotrexate per square meter of body-surface area (low dose), 5 mg of methotrexate per square meter (very low dose), or placebo. The use of prednisone (less than or equal to 10 mg per day) and two nonsteroidal antiinflammatory drugs was also allowed. RESULTS: The 127 children (mean age, 10.1 years) had a mean duration of disease of 5.1 years; 114 qualified for the analysis of efficacy. According to a composite index of several response variables, 63 percent of the children who received low-dose methotrexate improved, as compared with 32 percent of those in the very-low-dose group and 36 percent of those in the placebo group (P = 0.013). As compared with the placebo group, the low-dose group also had significantly larger mean reductions from base line in the number of joints with pain on motion (-11.0 vs. -7.1), the pain-severity score (-19 vs. -11.5), the number of joints with limited motion (-5.4 vs. -0.7), and the erythrocyte sedimentation rate (-19.0 vs. -6 mm per hour). In the methotrexate groups only three children had the drug discontinued because of mild-to-moderate side effects; none had severe toxicity. CONCLUSIONS: Methotrexate given weekly in low doses is an effective treatment for children with resistant juvenile rheumatoid arthritis, and at least in the short term this regimen is safe.

Auranofin in the treatment of juvenile rheumatoid arthritis. Results of the USA-USSR double-blind, placebo-controlled trial. The USA Pediatric Rheumatology Collaborative Study Group. The USSR Cooperative Children's Study Group.

A 6-month double-blind, parallel, randomized, placebo-controlled multicenter trial of auranofin (0.15-0.20 mg/kg/day) was conducted in 231 children with juvenile rheumatoid arthritis (JRA) in the United States and in the Union of Soviet Socialist Republics. Approximately 80% of the children had polyarticular disease. The auranofin-treated patients showed greater mean decreases from baseline in 11 of the 12 articular disease indices measured than did the placebo-treated subjects after 3 months of therapy, and in 9 of the 12 indices after 6 months. However, the actual intergroup mean differences were relatively small and were not statistically significant. According to the physician's global assessment, 69% of the auranofin-treated patients and 61% of the placebo-treated patients demonstrated clinically significant improvement from baseline after 6 months (P = 0.24). Children whose disease onset occurred less than 2 years prior to entry improved more than did those who had arthritis for a longer period. In addition, those with polyarticular involvement at baseline improved more than did patients with mild disease. However, these relationships were observed in both the auranofin- and placebo-treated groups, and again, there were no significant intergroup differences. Diarrhea was the most common adverse effect of auranofin. We conclude that the clinical efficacy of auranofin is modestly higher than that of placebo in the treatment of JRA, as evidenced by the consistent trends observed in the data. However, the magnitude of the individual intergroup differences is not statistically significant. Auranofin appears to be very safe in children with JRA.

Characteristics of responders and nonresponders to slow-acting antirheumatic drugs in juvenile rheumatoid arthritis.

A 12-month double-blind, parallel, randomized, placebo-controlled multicenter trial of D-penicillamine and hydroxychloroquine was conducted in 162 children with juvenile rheumatoid arthritis in the United States and in the Union of Soviet Socialist Republics. No statistically significant intergroup differences were detected in primary outcome variables. We investigated the possible existence of select subgroups of patients who have a higher likelihood of response to active drugs than to placebo. Using previously published criteria, each patient was classified as a responder or nonresponder, and their demographic and disease characteristics at baseline were compared. We were unable to identify a subgroup of individuals who were more likely to respond to D-penicillamine or hydroxychloroquine than to placebo.

Penicillamine and hydroxychloroquine in the treatment of severe juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind placebo-controlled trial.

One hundred sixty-two children with severe juvenile rheumatoid arthritis were entered in a randomized, double-blind, placebo-controlled 12-month clinical trial designed to establish the efficacy and safety of two slower-acting antirheumatic drugs, penicillamine and hydroxychloroquine. The study was a cooperative effort of the United States and the Soviet Union. One group of subjects received 10 mg of penicillamine per kilogram of body weight per day, another group received 6 mg of hydroxychloroquine per kilogram daily, and a third group received placebo. All three groups were allowed a single concurrent nonsteroidal antiinflammatory drug, but no other antirheumatic medications, including corticosteroids. All three groups had dramatic improvement in many of the clinical and laboratory outcome variables after one year of study. There were no significant differences in efficacy between the penicillamine and placebo groups. Pain on movement was the only index of articular disease that was alleviated more by hydroxychloroquine than by placebo. Serious adverse drug reactions attributable to the active agents were rare. We were unable to demonstrate that, in the presence of a nonsteroidal antiinflammatory drug, either penicillamine or hydroxychloroquine is superior to placebo in the treatment of children with juvenile rheumatoid arthritis.