[Combination therapy at an early stage of the novel coronavirus infection (COVID-19). Case series and design of the clinical trial "BromhexIne and Spironolactone for CoronаvirUs Infection requiring hospiTalization (BISCUIT)"].

The article focuses on effective treatment of the novel coronavirus infection (COVID-19) at early stages and substantiates the requirement for antiviral therapy and for decreasing the viral load to prevent the infection progression. The absence of a specific antiviral therapy for the SARS-CoV-2 virus is stated. The authors analyzed results of early randomized studies using lopinavir/ritonavir, remdesivir, and favipiravir in COVID-19 and their potential for the treatment of novel coronavirus infection. Among the drugs blocking the virus entry into cells, the greatest attention was paid to the antimalaria drugs, chloroquine and hydroxychloroquine. The article addresses in detail ineffectiveness and potential danger of hydroxychloroquine, which demonstrated neither a decrease in the time of clinical recovery nor any improvement of prognosis for patients with COVID-19. The major objective was substantiating a possible use of bromhexine, a mucolytic and anticough drug, which can inhibit transmembrane serin protease 2 required for entry of the SARS-CoV-2 virus into cells. Spironolactone may have a similar feature. Due to its antiandrogenic effects, spironolactone can inhibit X-chromosome-related synthesis of ACE-2 receptors and activation of transmembrane serin protease 2. In addition to slowing the virus entry into cells, spironolactone decreases severity of fibrosis in different organs, including the lungs. The major part of the article addresses clinical examples of managing patients with COVID-19 at the University Clinic of the Medical Research and Educational Centre of the M. V. Lomonosov Moscow State University, including successful treatment with schemes containing bromhexine and spironolactone. In conclusion, the authors described the design of a randomized, prospective BISCUIT study performed at the University Clinic of the M. V. Lomonosov Moscow State University with an objective of evaluating the efficacy of this scheme.

The alternative complement pathway in ANCA-associated vasculitis: further evidence and a meta-analysis.

We compared the common pathway components C3a, C5a and membrane attack complex (MAC), also known as C5b-9, and the alternative pathway components factor B and properdin in patients with ANCA-associated vasculitis (AAV) and healthy controls, and conducted a meta-analysis of the available clinical evidence for the role of complement activation in the pathogenesis of AAV. Complement components were evaluated in 59 patients with newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis and 36 healthy volunteers. In 28 patients, testing was repeated in remission. Next, we performed a meta-analysis by searching databases to identify studies comparing complement levels in AAV patients and controls. A random-effects model was used for statistical analyses. The median concentrations of MAC, C5a, C3a and factor B were higher in active AAV patients (P < 0·001). Achievement of remission was associated with reductions in C3a (P = 0·005), C5a (P = 0·035) and factor B levels (P = 0·045), whereas MAC and properdin levels did not change. In active AAV, there were no effects of ANCA specificity, disease phenotype, previous immunosuppression or disease severity on complement levels. A total of 1122 articles were screened, and five studies, including this report, were entered into the meta-analysis. Plasma MAC, C5a and factor B in patients with active AAV were increased compared to patients in remission (excluding factor B) and controls. Changes in C3a were of borderline significance. Our findings and the results of the meta-analysis support activation of the complement system predominantly via the alternative pathway in AAV patients.

[Results of Open-Label non-Randomized Comparative Clinical Trial: "BromhexIne and Spironolactone for CoronаvirUs Infection requiring hospiTalization (BISCUIT)].

Introduction The aim of this study was to assess the efficacy and safety of a combination of bromhexine at a dose of 8 mg 4 times a day and spironolactone 50 mg per day in patients with mild and moderate COVID 19.Material and methods It was an open, prospective comparative non-randomized study. 103 patients were included (33 in the bromhexine and spironolactone group and 70 in the control group). All patients had a confirmed 2019 novel coronavirus infection (COVID 19) based on a positive polymerase chain reaction (PCR) for SARS-CoV-2 virus RNA and/or a typical pattern of viral pneumonia on multispiral computed tomography. The severity of lung damage was limited to stage I-II, the level of CRP should not exceed 60 mg / dL and SO2 in the air within 92-98%. The duration of treatment is 10 days.Results The decrease in scores on the SHOKS-COVID scale, which, in addition to assessing the clinical status, the dynamics of CRP (a marker of inflammation), D-dimer (a marker of thrombus formation), and the degree of lung damage on CT (primary endpoint) was statistically significant in both groups and differences between them was not identified. Analysis for the group as a whole revealed a statistically significant reduction in hospitalization time from 10.4 to 9.0 days (by 1.5 days, p=0.033) and fever time from 6.5 to 3.9 days (by 2.5 days, p<0.001). Given the incomplete balance of the groups, the main analysis included 66 patients who were match with using propensity score matching. In matched patients, temperature normalization in the bromhexine/spironolactone group occurred 2 days faster than in the control group (p=0.008). Virus elimination by the 10th day was recorded in all patients in the bromhexine/spironolactone group; the control group viremia continued in 23.3% (p=0.077). The number of patients who had a positive PCR to the SARS-CoV-2 virus on the 10th day of hospitalization or longer (≥10 days) hospitalization in the control group was 20/21 (95.2%), and in the group with bromhexine /spironolactone -14/24 (58.3%), p=0.012. The odds ratio of having a positive PCR or more than ten days of hospitalization was 0.07 (95% CI: 0.008 - 0.61, p=0.0161) with bromhexine and spironolactone versus controls. No side effects were reported in the study group.Conclusion The combination of bromhexine with spironolactone appeared effective in treating a new coronavirus infection by achieving a faster normalization of the clinical condition, lowering the temperature one and a half times faster, and reducing explanatory combine endpoint the viral load or long duration of hospitalization (≥ 10 days).

Atypical Goodpasture's disease: a clinical case report and literature review.

Goodpasture's disease (anti-GBM disease) is a rare small vessels vasculitis characterized by the presence of autoantibodies directed against the glomerular basement membrane (GBM) and alveolar basement membrane. Common feature of anti-GBM disease is a combination of rapidly progressive glomerulonephritis and alveolar hemorrhage (pulmonary-renal syndrome). We present a case of atypical disease course in a young male patient who developed alveolar hemorrhage without renal failure. The only symptom of renal involvement was isolated hematuria. Plasmapheresis combined with immunosuppression (cyclophosphamide and corticosteroids) was effective. We present a review of state-of-art data on the pathogenesis and disease course of anti-GBM disease.

[Kidney injury molecules (KIM-1, MCP-1) and type IV collagen in the assessment of activity of antineutrophil cytoplasmic antibody-associated glomerulonephritis]. / Molekuly povrezhdeniia pochechnoi tkani (KIM-1, MCP-1) i kollagen IV tipa v otsenke aktivnosti assotsiirovannogo s antineitrofil'nymi tsitoplazmaticheskimi antitelami glomerulonefrita.

AIM: To assess the significance of determining the serum and urinary concentrations of monocyte chemotactic protein-1 (MCP-1), kidney injury molecule-1 (KIM-1), and type IV collagen in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) to estimate the activity of renal involvement in AAV. SUBJECTS AND METHODS: 78 patients (32 men and 46 women) (median age 55 (45; 61) years) with AAV were examined. The patients were divided into 3 groups according to the AAV activity estimated using the Birmingham vasculitis activity Score (BVAS): 1) 25 patients with active ANCA-associated glomerulonephritis (GN); 2) 26 patients with active AAV without renal involvement; 3) 27 patients in sustained AAV remission. The serum and urinary concentrations of the markers were measured by enzyme immunoassay. RESULTS: The urinary concentration of all 3 biomarkers was higher in patients with renal involvement (Group 1); the differences in the levels of MCP-1 and type IV collagen were statistically significant as compared to Groups 2 and 3 (p<0.01), while that in KIM-1 level was only in Group 2. There were statistically significant correlations between the urinary concentration of these biomarkers and the traditional GN activity indices (erythrocyturia, daily proteinuria (DPU), total BVAS scores that reflect renal involvement, as well as serum creatinine levels and estimated glomerular filtration rate (p<0.05). ROC curve analysis showed that the urinary MCP-1 excretion of ≥159 pg/ml had the highest (92%) sensitivity and urinary type IV collagen excretion of ≥3.09 µg/l had the highest (86%) specificity in assessing the activity of ANCA-associated GN. At the same time, their diagnostic value increased in terms of a combination of DPU and ESR (96% sensitivity, 84.9% specificity). CONCLUSION: The urinary excretion of MCP-1, KIM-1, and type IV collagen reflects the severity of local renal inflammation in AAV patients and a study of these indicators is a promising diagnostic tool for assessing the activity of ANCA-associated GN.

[Cytogenetic effect of thaliblastine in a culture of human peripheral blood lymphocytes]. / Tsitogenetichekii éffekt taliblastina v kul'ture limfotsitov perifericheskoi krovi cheloveka.

The mutagenicity of thaliblastine (Bulgarian potential antitumor drug) was investigated in vitro in lymphocytes from healthy donors, and in vivo in lymphocytes of oncological patients after thaliblastine administration. No increase in the rate of chromosome aberrations was noted with increasing thaliblastine concentrations in vitro and in the course of therapy in vivo. Some polyploid metaphases were found in the lymphocytes of the patients treated with thaliblastine, as a result of the statmokinetic effect of the drug. Thaliblastine exerts extraordinarily slight mutagenic effect, as compared with other cytostatics.

[Effect of charged particles of relativistic energy on the number of chromosome aberrations in human blood lymphocytes. Dose-response relationship and the RBE of protons, deuterons and helium ions]. / Vliianie zariazhennykh chastits reliativistskikh énergii na chastoty khromosomnykh aberratsii v limfotsitakh krovi cheloveka. Zavisimost' doza-éffekt i OBE protonov, deitonov i ionov geliia.

In experiments with human blood lymphocyte culture exposed to fast protons, deuterons and helium ions the frequency and types of chromosome aberrations have been studied. Fast charged particles of a relativistic energy are shown to have a pronounced harmful effect resulting in a sharply increased formation of exchange chromosome aberrations as compared to that produced by gamma-radiation. The RBE coefficients of the particles under study have been determined: their values vary depending on the type of radiation and the tests used.

[Effect of a constant magnetic field and gamma radiation on the hereditary structure of somatic cells. Effect of the combination of a constant magnetic field and ionizing radiation on human lymphocytes in vitro]. / Vliianie postoiannogo magnitnogo polia i gamma-radiatsii na nasledstvennuiu strukturu somaticheskikh kletok. Vozdeistvie sochetaniia postoiannogo magnitnogo polia i ioniziruiushchei radiatsii na limfotsity krovi cheloveka in vitro.

Samples of human whole blood were exposed in CMF (field induction, 0.3 T) for 15, 30, 45, 60, 75, 90, 120, 150, 180, 240, 300 or 360 min. 15 min following exposure, the samples were gamma-irradiated in a dose of 0.0516 C/kg (137Cs) at a dose rate of 1.95 A/kg. The following chromosome aberrations were scored: deletions dicentrics, rings, and symmetrical exchanges. Exposure of the blood in CMF for 15 to 360 min decreased radiation damage to cells as compared with unexposed irradiated samples. The extention of time from 15 to 180 min increases the effect the smallest amount of chromosome damages being scored at 150-180 min. A 2.8 - fold, 3 - fold and 3.5 - fold decrease was registered in the number of aberrant cells, deletions and dicentrics, respectively. With increasing time of exposure (240 min), the radiomodifying effect started decreasing, and with 300-360 min exposure it was the same as that observed at 15-45 min.

[Frequency of chromosome disorders occurring in human lymphocytes in the in vitro exposure to different doses of deuterons as protected by adeturon]. / Issledovanie chastoty vozniknoveniia khromosomnykh narushenii v limfotsitakh cheloveka pri vozdeistvii in vitro razlichnykh doz deitronov pod zashchitoi adeturona.

Peripheral blood of 4 healthy donors was exposed to deutrons with the energy 4,2 GeV/nuclone and the intensivity of 4 to 6.10(10) particles per impulse, the capacity of the dose being 0,008 Gr/sec. The LPE of deutrons was 2,14 MeV sm2/g. Irradiation doses were 0,26; 0,49; 0,97; 2,02; 3,80 Gr. 15-20 min prior to irradiation, the protector adeturone was added at a concentration of 550 micrograms/ml of blood. Chromosome aberrations were analyzed in protected and unprotected blood samples. The results were treated using the method of variance and regression analysis. The correlative correspondence between the number of chromosome aberrations and an approximate dose of actual irradiation was established as Y = 0,13 d + 6,55.10(-4) D2 for dicentrics and as 0,26 D + 12,6.10(-4) D2 + 4,5 for the total percentage of aberrations. The pattern of the dose - effect dependence was retained in protected samples. The calculated values of the factor of dose decrease confirmed antiirradiation properties of adeturone.

[Cytogenetic and hormonal studies of persons occupationally irradiated with ionizing radiation]. / Tsitogenetichni i khormonalni prouchvaniia na profesionalno oblucheni litsa s ionizirashta radiatsiia.

Cytogenetic investigations were carried out on 23 subjects and hormonal -- on 18 of them, working in the sphere of ionizing radiation at medical institutions. After the quantitative processing of the results from the cytogenetic investigations, statistically significant differences were established to exist in cell obtaining with aberations, chromozome and chromatide fragments as compared with the spontaneous frequency of healthy subjects. Statistically significant differences were observed also in the group with length of service over 10 years as regards the dicentrics obtaining as well. With the follow-up of hormone concentrations in blood plasma a statistical decrease was found in the level of sex hormones -- testosterone in males and progesterone in females, accompanied by increased level of FSH, suggesting a primarily damage of gonads (testis and ovaries). Plasma cortisol level is statistically significant increased in all subjects examined whereas aldosterone level is normal in subjects with a length of service to 10 years and statistically significant decrease with a length of service over 10 years.

Spontaneous chromosomal aberration levels in human peripheral lymphocytes.

Spontaneous levels of structural chromosomal aberrations in human peripheral lymphocytes were studied cytogenetically in 49 female and 56 male subjects. With a total of 16 267 metaphase spreads examined, 191 cells were found to contain chromosomal aberrations, giving a rate of 1.17%. The rates of individual aberration types were as follows: chromatid fragments, 0.39%; chromosome fragments, 0.71% dicentrics, 0.06%; symmetrical and asymmetrical chromatid exchanges, 0.01%; and rings, 0.006%. There were significant differences in aberration yields between females aged 20--29 yr. and 60--70 yr., whereas males aged 20--50 yr. showed no difference. The two sexes differed significantly in chromatid fragments, chromosome fragments and aberrants cells.

[Chromosome aberrations in human lymphocytes induced by exposure to different doses of chronic gamma irradiation in vitro]. / Khromosomnye aberratsii v limfotsitakh cheloveka, vyzvannye vozdeistviem razlichnykh doz khronicheskogo gamma-oblucheniia in vitro.

Non-stimulated with phytohemagglutinin human blood was chronically gamma-irradiated (226Ra, 99 mg) in vitro at 37 derees C. The dose rates were 8.2 (irradiation doses 8.2, 16.4, 41 and 162.2 rads) and 25.3 (irradiation doses 8.4, 16.9, 42.2, 168.2, 337.3 and 506 rads) rads/hour. Quantitative analysis of different types of structural chromosome aberrations was carried out. The data on aberrant cells and dicentrics were statistically interpreted. The frequency of aberrant cells, observed at both dose rates, was statistically described by the equation y = a + bD, where y = 7.11 (+/- 0.56) + 11.38 (+/- 2.32) . 10(-2) D, and y = 5.23 (+/- 0.23 + 13.20 (+/- 1.11) . 10(-2) D at dose rates 8.2 and 25.3 rads respectively. The dicentrics yield was described by the equation y = alphaD + betaD2 + C, where y = 3.19 (+/- 0.22) . 10(-2) D + 7.0 (+/- 0.46) . 10(-5) D2 + 0.42, and y = 5.05 (+/- 0.38) . 10(-2) D + 7.1 (+/- 0.41) . 10(-5) D2 + 0.42 at 8.2 and 25.3 dose rates. Statistically reliable differences in the dicentric yield in lymphocytes irradiated with different dose rates are observed. The results obtained show that the increase in the dose rate results in the increase of the dicentric yield, originated in one-track process, while the dicentric yield from two-track process remains constant.

[Spontaneous chromosome aberrations in the lymphocytes of human peripheral blood]. / Spontanni khromozomni aberatsii v limfotsiti ot choveshka periferna kruv.

The authors carried out cytogenetic studies on lymphocytes from human peripheral blood of 105 persons--49 women and 56 men in order to examine spontaneous frequency of the structural chromosomal abberations in the somatic cells. There were 191 cells with abberations (1,17%), out of 16,267 analyzed metaphasic plates. They found 0,39% of chromatid fragments, 0,71% of chromosomal fragments, 0,06% dicentricets, 0,01% of symetric and asymetric chromatid exchanges and 0,006% of rings. There were no statistically significant differences in the discovery of the spontaneous abberations in the examined persons at various age and sex.