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Introduction. Over the past 5 years, signifi cant progress has been achieved in the treatment of patients with Ph-negative acute lymphoblastic leukemia (ALL). Treatment results were compared between two protocols of the Russian multicenter studies «ALL-2009» and «ALL-2016», in which multicomponent high-dose consolidation was not used. The principle of continuity of treatment was observed with modifi cation of doses of cytostatic drugs depending on the depth of cytopenia.Aim – to compare the 5-year results of two studies and to determine the factors of unfavorable prognosis in the treatment of patients with ALL.Materials and methods. The studies were performed from April 2009 to April 2016 (ALL-2009) and from April 2016 to September 2021 (ALL-2016), and 596 patients were included: 330 in ALL-2009 and 266 in ALL-2016. The analysis was performed in March 2022. The median age of patients in ALL-2009 was 28 years (15–55), in ALL-2016 – 32.5 years (18–55). Cytogenetic studies were performed in 242 patients in ALL-2009 (73.3 %) and 236 patients in ALL-2016 (88.7 %). Patients in the ALL-2016 protocol underwent a centralized assessment of minimal residual disease (MRD) by fl ow cytometry on protocol +70 day (after completion of two induction phases), +133 and +190 days. Transplantation of allogeneic stem hematopoietic cells was performed in 7 % of patients in ALL-2009 and in 9 % in ALL-2016.Results. Overall, relapse-free survival (OS, RFS) and the probability of relapse for a period of 3 years from the moment of inclusion of patients in a particular study were 59 %, 63 % and 23 % for ALL-2009, and for ALL-2016 – 64 %, 59 % and 22 %, respectively. For patients with B-cell precursor ALL, two cytogenetic risk groups were formed, in which long-term survival rates differed signifi cantly: the standard group (hyperploid set of chromosomes and normal karyotype) – OS 63 %, RFS 70 %, and high cytogenetic risk (any abnormal karyotype, except for hyperploidy) – OS 49 %, RFS 52 % (р = 0.001, р = 0.0014). In T-ALL, cytogenetic markers had no prognostic value, but the immunophenotype of early T-cell precursor turned out to be an important predictor of poor prognosis (the probability of relapse was 52 % compared with 15 % for all other immunophenotypic variants). According to the results of centralized monitoring of MRD, it was determined that for B-cell precursor ALL, the signifi cant negative factors are the high cytogenetic risk group and positive MRD status at +70 day, and for T-cells, the early immunophenotype and positive MRD status at +133 day.

This study uses the electron paramagnetic resonance (EPR) method to study changes in the relative nitric oxygen content in the cortex of a rat brain in conditions of acute ischemia. Laser-induced vascular thrombosis is used as the model of ischemia. Rose bengal is administered into the bloodstream beforehand. In response to laser beaming, it generates reactive oxygen species, which induces protein coagulation, vascular wall damage, and, as a consequence, the formation of thrombus. It is shown histologically that the acute ischemic process ends a day after the laser surgery, and active remission, with the corresponding morphological changes in the area of the lesion, starts within three days. The relative nitric oxide content is determined 1 and 3 days after the brain vascular photothrombosis using the NO–Fe–DETC paramagnetic complex as a spin trap. The nitric oxide content is estimated by the extreme lower field of the EPR spectrum of this complex. It is shown that a significant increase in the relative nitric oxide (NO) content occurs on the third day after laser surgery and coincides with the beginning of remission after the acute ischemia. A possible role of nitric oxide in the remission is discussed in the study.

Treatment ofprognostically unfavorable forms ofacute leukemia isaserious problem ofhematology, since their frequency inthe group ofadult patients reaches 60%, and inelderly patients- 80-90%.Aim: toanalyze the case ofdiagnostics and treatment ofacute myelomonoblastic leukemia with anunfavorable genetic prognosis inayoung adult female using double haploidentical bone marrow transplantation.Samples ofbone marrow and peripheral blood ofpatient K., 35years old, who recived program chemotherapy and double haploidentical bone marrow transplantation inthe Sverdlovsk Regional Hematological Centre were examined.Atthe onset ofdisease was noted hyperleukocytosis, blastaemia and infiltration ofleukemic cells inthe bone marrow. Cytochemical reactions tolipids were positive in7,0% ofblasts, small-granular and large-granular glycogen was detected in24,0% ofblast cells, and diffuse- in22,0%. Immunophenotypically, 28,0% ofblast cells were characterized byexpression ofHLA-DR, CD13, CD33, CD34, CD38, CD117, MPO-cyt, 13,0%- CD33, CD11cyt, CD64, CD14. The cytogenetic study determined the karyotype 48, XX, +4, +21[2]/ 47, XX, +4[3]/ 46, XX[2]. Non-synonymous transversions с. 2447A>Тinс-KIT gene, с.215С>GinТР53, and transition с. 2644С>ТinDNMT3A were detected using direct sequencing method. Despite the detection ofoncogenic mutations, the tumor was chemosensitive topolychemotherapy (including anthracyclines with cytarabine). However, given the unfavorable genetic prognosis, itwas decided toperform abone marrow transplantation. Due tothe lack ofanHLA-matched unrelated donor, the first haploidentical transplantation was performed from the patient'seldest daughter. At+51day, transfusion ofdonor white blood cells with correction ofthe immunosuppression scheme was performed tocorrect persistent pancytopenia. At+ 71day after the first transplantation, taking into account the remaining pancytopenia, asecond haploidentic transplantation from the patient'syounger daughter was performed. The total duration ofhematological remission was 48months, including 36months after the second haploidentical bone marrow transplantation.

Currently, the main pathogenetic method for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) is the treatment with recombinant monoclonal antibodies that block the C5 component of the complement system. Eculizumab is the first biotechnological drug, which is a monoclonal antibody, with proven clinical efficacy and safety for the treatment of patients with PNH, which is used in world clinical practice. In Russia, in the framework of the state program Development of the pharmaceutical and medical industry for 20132020 was developed Elizaria (JSC GENERIUM) the first biosimilar of the original drug eculizumab.To evaluate the pharmacokinetic and pharmacodynamic parameters, as well as safety and immunogenicity parameters of the drug Elizara in the induction phase of therapy in previously untreated patients with PNH.The study included 11 patients with PNH aged 26 to 75 years who had not previously received eculizumab. Each of the study participants was injected with the studied drug Elizaria at a dose of 600 mg intravenously once a week for 4 weeks.During the clinical study, it was noted that the concentration of the studied drug significantly increased by the time the infusion was completed and then gradually decreased to a minimum at the end of the dosing interval. The average concentration of eculizumab 5 minutes before the administration of the study drug at all visits exceeded 35 g/ml, the minimum concentration sufficient to completely inhibit intravascular hemolysis in patients with PNH. The pharmacodynamic efficacy of the drug Elizaria was confirmed by a decrease in the concentration of the membrane-attack complex (MAC) after the first infusion of the drug was maintained at stable levels until visit 5. A persistent decrease in the level of MAC and a four-fold decrease in the average values of lactate dehydrogenase to visit 5 from 1286.4 to 280.9 U/l demonstrated a marked decrease in activity and stabilization of the hemolytic process against the background of the induction of therapy with Elizaria at a dose of 600 mg once a week and confirmed the effecacy of the study drug. Among the 9 adverse events, only 5 had a relationship with the studied drug, including one serious adverse event in the form of an allergic reaction, which, according to the researcher, had a possible cause-effect relationship with the infusion of the studied drug. In 2 patients, low-titer binding anti-drug antibodies were detected without neutralizing activity during treatment with the studied drug, which may indicate its low immunogenicity.The study evaluated the pharmacokinetic and pharmacodynamic properties of the drug Elizaria in the regimen of induction therapy in previously untreated patients with PNH, confirming its efficacy. The study demonstrated the safety and low immunogenicity of the study drug.В настоящее время основным патогенетическим методом лечения пароксизмальной ночной гемоглобинурии (ПНГ) является терапия рекомбинантными моноклональными антителами, блокирующими С5-компонент системы комплемента. Экулизумаб первый биотехнологический лекарственный препарат, являющийся моноклональным антителом, с доказанной клинической эффективностью и безопасностью для лечения больных ПНГ, который используется в мировой клинической практике. В России в рамках реализации государственной программы Развитие фармацевтической и медицинской промышленности на 20132020 гг. разработан препарат Элизария (АО ГЕНЕРИУМ) первый биоаналог оригинального препарата экулизумаб. Цель. Изучение фармакокинетических и фармакодинамических показателей, а также параметров безопасности и иммуногенности препарата Элизария в фазе индукции терапии у ранее не леченных больных ПНГ. Материалы и методы. В исследование включены 11 пациентов с ПНГ в возрасте от 26 до 75 лет, ранее не получавших экулизумаб. Каждому из участников исследования вводили исследуемый препарат Элизария в дозе 600 мг внутривенно капельно один раз в неделю в течение 4 нед. Результаты. В ходе клинического исследования отмечено, что концентрация исследуемого препарата значительно увеличивается к моменту окончания инфузии и далее постепенно снижается до минимума в конце интервала дозирования. Средние значения концентрации экулизумаба за 5 мин до введения исследуемого препарата на всех визитах превышали 35 мкг/мл, минимальную концентрацию, достаточную для полного ингибирования внутрисосудистого гемолиза у больных ПНГ. Фармакодинамическая эффективность препарата Элизария подтверждалась снижением концентрации мембраноатакующего комплекса (МАК) после окончания первой инфузии препарата с поддержанием ее на стабильных уровнях до визита 5. Стойкое снижение концентрации МАК и четырехкратное снижение средних значений лактатдегидрогеназы к визиту 5 с 1286,4 до 280,9 Ед/л демонстрировало выраженное снижение активности и стабилизацию гемолитического процесса в результате индукции терапии препаратом Элизария в дозе 600 мг один раз в неделю и подтверждало эффективность исследуемого препарата. Из 9 нежелательных явлений только 5 имели связь с применением исследуемого препарата, включая одно серьезное в виде аллергической реакции, имевшее, по мнению исследователя, возможную причинно-следственную связь с инфузией исследуемого препарата. У 2 больных выявлены связывающие антилекарственные антитела в низком титре без нейтрализующей активности во время лечения исследуемым препаратом, что может свидетельствовать о его низкой иммуногенности. Заключение. В ходе исследования оценены фармакокинетические и фармакодинамические свойства препарата Элизария в режиме индукции терапии у ранее не леченных больных ПНГ, подтверждающие его эффективность. В исследовании продемонстрированы безопасность и низкая иммуногенность исследуемого препарата.

Relevance. COVID-19 pandemic currently has a significant negative impact on the treatment of patients with oncological pathology, including patients with classic Hodgkin lymphoma. Generalized data on publications on the impact of concomitant pathology on the severity of infection show a significant increase in the risk of death from infection in male patients, aged 60 years, with the presence of 3 concomitant diseases, among which particularly negative role is played by diseases of the cardiovascular system, diabetes, oncology, chronic lung disease, immunodeficiency conditions. Particularly dangerous is the development of COVID-19 infection in an interval of less than 14 days from the course of antitumor therapy. At the same time, patients with Hodgkin lymphoma require immediate treatment, often associated with toxic, immunosuppressive therapy, frequent visits to the clinic, hospitalizations. International communities have not yet developed clear guidelines for the management of patients with Hodgkins lymphoma. Taking into account the understanding that the circulation of coronoviral infection will continue in the population, the Advisory board on the Problems of Hodgkin Lymphoma Therapy in the COVID-19 Pandemic is highly relevant. Aim. To change and adapt current treatment approaches in the current epidemiological environment. Results. The main directions of the impact of the COVID-19 pandemic on the treatment of patients with cancer pathology, including patients with classical Hodgkin lymphoma, were determined, key problems in the treatment of LC during the COVID-19 pandemic were identified, and measures aimed at reducing the risk for patients were developed. Existing approaches to first-line, relapse/refracturing cHL therapy, including salvage therapy, and auto/allo SCT during the COVID-19 pandemic, have been adapted.

The plasma coagulation factor XIII (рFXIII) is a key protein of the blood coagulation systems, the main function of which consists of the enzymatic covalent stabilization of the polymeric structure of fibrin. The protein has a heterotetrameric structure consisting of two catalytic (FXIII-A2) and two regulatory (FXIII-В2) subunits. Using a high resolution mass spectrometry, hypochlorite-induced oxidation of рFXIII molecules and its enzymatic form (FXIIIa) is studied for the first time. It is demonstrated that sulfur and aromatic amino acid residues are the most vulnerable residues to oxidative attack. The mass spectrometry data indicate that oxidized amino acid residues are found in all structural elements of the FXIII-A catalytic subunit in the protein we are studying (except for the activation peptide), while a number of domains remain in native form in the FXIII-В regulatory subunit. When treated FXIIIa with hypochlorite, additional modification sites both in the FXIII- $${\text{A}}_{{\text{2}}}^{*}$$ and in the FXIII-В2 subunits are detected. The data obtained allowed us to postulate that in the process of converting the proenzyme into FXIIIa, new amino acid residues (previously inaccessible to oxidizers) migrate to the surface of the protein globule and become vulnerable targets for oxidizer molecules, while some of the initially surface-exposed amino acid residues move inside the protein, losing their ability to participate in the oxidative modifications. Electrophoresis of reduced samples of covalently cross-linked fibrin detected a decrease in transglutaminase activity of oxidized FXIIIa manifested in the inhibition of the reaction of the formation of γ–γ-dimers. The ability of the рFXIII molecule to resist the oxidative attack due to its antioxidant structural adaptation to the effect of reactive oxygen species is discussed.

It is believed that one of the causes of photodamage to the retina is the accumulation of all-trans-retinal (ATR) in the visual cells. However, the ATR is formed during photolysis inside the disk of the photoreceptor cell and transferred to the cytoplasm of the cell, where it is converted with a high yield to retinol, a nonphototoxic compound. Inside the disk, where ATR can accumulate, it can form Schiff bases, which are also not phototoxic compounds, with the amino groups of proteins and lipids. In addition, the resulting free retinal (R) isomers bind to specific retinal-binding proteins that can shield them from oxygen. Thus, the question on the concentrations in which free ATR can accumulate inside a cell is ambiguous. In this study, it is proposed to evaluate the concentration of free ATR in a cell by the yield of the excited triplet state, since neither the Schiff bases of ATR nor retinol are transformed into an excited triplet state. It is shown that 70% of ATR form Schiff bases in the equilibrium state in the native cell. This significantly reduces the likelihood that ATR is the main inducer of photodamage. Moreover, it is shown that the quantum yield of the formation reaction of an excited triplet state of R when it is bound to interfotoreceptor proteins is significantly reduced.

Relevance. Cutaneous T-cell lymphomas (CTCL) are not common diseases which are associated with a decrease in quality of life. Currently available systemic therapy rarely provides a stable and long-termed response. In Russia, current CTCL therapy is a big issue due to the limited access to modern targeted therapy, an absence of a National CTCL registry, and the difficulties in morphological diagnosis of these rare diseases. Since June 17, 2019, a new indication of brentuximab vedotin as a new treatment option for patients with CD30+ CTCL after at least one line of previous systemic therapy was registered. Brentuximab vedotin is a conjugate of a CD30 directed monoclonal antibody and an antitumor agent. Brentuximab vedotin is a CD30-directed monoclonal antibody conjugated to an antitumor agent. Aim. To identify the unresolved issues of current clinical practice and to adapt available approaches to the treatment and diagnosis of CD30 + CTCL given new therapeutic opportunities. Results. The available approaches to the systemic CTCL therapy in Russia routine clinical practice have been discussed, the unresolved issues of therapy and diagnosis have been identified, the routing of patients with CD30 + CTCL in Russia has been discussed, the importance of CD30 testing has been established, the profiles of patients with CTCL for treatment with brentuximab vedotin have been determined.

Plasminogen being a precursor of plasmin, a serine protease which plays a fundamental role in the intravascular thrombolysis. For the first time, by using high-resolution mass spectrometry, data were obtained of oxidative modifications of the plasminogen molecule under induced oxidation. The FTIR data show that under oxidation on the protein, its secondary structure also undergoes the rearrangements. The high tolerance of plasminogen to oxidation can be due to both the closed conformation and the ability of some Met residues to serve as ROS trap.

Plasminogen, the precursor of plasmin, is a serine protease that plays a fundamental role in the intravascular thrombolysis. For the first time, by using high-resolution mass spectrometry, data on the oxidative modifications of the plasminogen molecule under induced oxidation were obtained. The FTIR data show that, under oxidation on the protein, its secondary structure also undergoes the rearrangements. The high tolerance of plasminogen to oxidation can be due to both the closed conformation and the ability of some Met residues to serve as ROS trap.

The 57Fe hyperfine interactions are the useful source of information about the finest structural peculiarities in various iron-containing proteins which can be essential in the natural variety of structure and function relationship in normal biomolecules as well as in its changes in the case of molecular pathology. Mossbauer spectroscopy with a high velocity resolution as the most sensitive probe for the 57Fe hyperfine interactions demonstrates some advances in the study of various hemoglobins, ferritins and pharmaceutical products that can bring new information for the life sciences.

In this overview, we present the results of the study of spleen and liver tissues taken from healthy donors in comparison with those from patients with (i) non-Hodgkin B-cell lymphomas, namely, mantle cell lymphoma and marginal zone B-cell lymphoma, (ii) acute myeloid leukemia, and (iii) primary myelofibrosis. The study was carried out using Mossbauer spectroscopy and magnetization measurements for the analysis of ferritin-like iron in spleen and liver tissues. Magnetization measurements demonstrated small differences in the saturation magnetic moments and revealed additional paramagnetic components. Two liver samples demonstrated unusual behavior of the magnetic moment when the zero-field-cooled curve was over the field-cooled curve in the temperature range between ~40 and ~70 K. Relative iron content variations in the tissue cells as well as small variations in the 57Fe hyperfine parameters were demonstrated for healthy and patients’ spleen and liver tissues on the base of measured Mossbauer spectra. The results obtained permit us to suggest small differences in the ferritin iron core structure in spleen and liver tissues from healthy donors and patients with hematological malignancies.

Study of human spleen and liver tissues from healthy persons and two patients with mantle cell lymphoma and acute myeloid leukemia was carried out using Mossbauer spectroscopy with a high velocity resolution. Small variations in the 57Fe hyperfine parameters for normal and patient’s tissues were detected and related to small variations in the 57Fe local microenvironment in ferrihydrite cores. The differences in the relative parts of more crystalline and more amorphous core regions were also supposed for iron storage proteins in normal and patients’ spleen and liver tissues.

Spleen tissues from five patients with two types of non-Hodgkin B-cells lymphomas, namely, mantle cell lymphoma and marginal zone B-cell lymphoma, and one sample of healthy human spleen tissue were studied using Mossbauer spectroscopy and magnetization measurements. Magnetization measurements demonstrated small differences in the saturation magnetic moments and the presence of paramagnetic components. Mossbauer spectra of spleen tissues demonstrated some variations in the relative content of ferritin-like iron in tissues as well as small variation in the hyperfine parameters for normal and patients’ spleen tissues. Some changes in the ferritin iron core structure in patients’ spleen were suggested in comparison with normal subject.

It was shown that retinal ischemia entailed apoptosis in the inner layers of the retina. Administration of an NO-synthase inhibitor suppressed the development of ischemic apoptosis. To ascertain whether nitric oxide could induce the retinal apoptosis by itself, a nontoxic NO donor—dinitrosyl iron complex (DNIC) with glutathione—was injected into the vitreous body. DNIC at low concentrations induced apoptosis in the same retinal layers as in ischemia. However, with increasing DNIC doses, the number of apoptotic nuclei decreased markedly. Simultaneous administration of excess glutathione prevented apoptosis at any DNIC dose. The obtained data demonstrate the neurotoxic properties of the excess of nitric oxide in the retina.

Aim. To review results of 2-year experience in execution of the protocol on the treatment of adult acute Ph-negative lymphoblastic leukemia ALL-2009. Material and methods. Of 111 patients registered in the study from November 2008 to December 2010 the analysis covered 96 patients from 23 hematological centers in 18 towns of the RF. Results. Treatment according to the Protocol ALL-2009 resulted in achievement of a complete remission in 91.2% patients with low early lethality of 5.5%. Postremission lethality fell to 3.7% versus previous studies (22%). Overall 2-year survival and recurrence-free survival reached 77.6 and 78.4%, respectively. Detection of any chromosomic aberrations significantly affected recurrence-free survival: 74 vs 100% in patients with normal karyotype. Conclusion. Protocol All-2009 demonstrates high efficacy in moderate toxicity and good reproducibility in any hematologic center.

The possibility and the mechanism of the reduction of nitrites in retinal vessels under acute hypoxia in vivo have been investigated. An experimental model of rat retinal ischemia was elaborated using laser coagulation of retinal vessels. It was demonstrated that vessel thrombosis does not occur if the nitrite concentration in the vessels is increased. It was proposed that, under acute hypoxia, nitrites are reduced to NO, which results in drastic vasodilatation. Considering that the effect takes less than a minute, this reduction cannot be due to hypoxic acidosis but is more likely associated with NO reduction by heme proteins. It was found that increased concentration of nitrites protects the retina from the development of ischemia progress and that preliminary administration of nitrites prevents apoptosis in the retina and a decrease in its photoelectric activity.

A comparative study of normal human, rabbit and pig oxyhemoglobins and oxyhemoglobin from patients with chronic myeloleukemia and multiple myeloma using Mossbauer spectroscopy with a high velocity resolution demonstrated small variations of the 57Fe quadrupole splitting and isomer shift. These variations may be a result of small structural differences in the heme iron stereochemistry of various hemoglobins.

The blazar AO 0235+164 was claimed to show a quasi-periodic behaviour in the radio and optical bands. Moreover, an extra emission component contributing to the UV and soft X-ray flux was detected, whose nature is not yet clear. A predicted optical outburst was observed in late 2006/early 2007. We here present the radio-to-optical WEBT light curves during the outburst, together with UV data acquired by Swift in the same period. We found the optical outburst to be as strong as the big outbursts of the past: starting from late September 2006, a brightness increase of 5 mag led to the outburst peak in February 19-21, 2007. We also observed an outburst at mm and then at cm wavelengths, with an increasing time delay going toward lower frequencies during the rising phase. Cross-correlation analysis indicates that the 1 mm and 37 GHz flux variations lagged behind the R-band ones by about 3 weeks and 2 months, respectively. These short time delays suggest that the corresponding jet emitting regions are only slightly separated and/or misaligned. In contrast, during the outburst decreasing phase the flux faded contemporaneously at all cm wavelengths. This abrupt change in the emission behaviour may suggest the presence of some shutdown mechanism of intrinsic or geometric nature. The behaviour of the UV flux closely follows the optical and near-IR one. By separating the synchrotron and extra component contributions to the UV flux, we found that they correlate, which suggests that the two emissions have a common origin., Comment: 9 pages, 7 figures, in press for Astronomy and Astrophysics

Nitric oxide is a universal molecule that regulates many different functions in an organism. In the eye retina nitric oxide plays both a regulatory role by modulation of the synaptic transmission between photoreceptors and bipolar cells and a toxic role in apoptosis induction in the outer nuclear layer and in the layer of ganglion cells. In this paper there has been made the first attempt to estimate the endogenous NO concentration in retina layers in vivo. The concentration of the nitric oxide was determined by two indepen- dent techniques: ESR spectrometry using spin trap for in vivo determination and NO-sensitive microelectrode for in situ determination in the survival isolated frog retina. The distinct NO con- centration was detected only in the ganglion cells layer (~0.25 μM) and in the inner segments layer of the photoreceptors (~0.6 μM). The activity and the kinetic characteristic of the NO-synthase localized in the same layers were also determined. Key words: retina cells layers, nitric oxide, ESR, NO-sensitive microelectrodes.

Mrk 501 is one of the brightest blazars at TeV energies and has been extensively studied since its first VHE detection in 1996. Our goal is to characterize in detail the source gamma-ray emission, together with the radio-to-X-ray emission, during the non-flaring (low) activity, which is less often studied than the occasional flaring (high) activity. We organized a multiwavelength (MW) campaign on Mrk 501 between March and May 2008. This multi-instrument effort included the most sensitive VHE gamma-ray instruments in the northern hemisphere, namely the imaging atmospheric Cherenkov telescopes MAGIC and VERITAS, as well as Swift, RXTE, the F-GAMMA, GASP-WEBT, and other collaborations and instruments. Mrk 501 was found to be in a low state of activity during the campaign, with a VHE flux in the range of 10%-20% of the Crab nebula flux. Nevertheless, significant flux variations were detected with various instruments, with a trend of increasing variability with energy. The broadband spectral energy distribution during the two different emission states of the campaign can be adequately described within the homogeneous one-zone synchrotron self-Compton model, with the (slightly) higher state described by an increase in the electron number density. This agrees with previous studies of the broadband emission of this source during flaring and non-flaring states. We report for the first time a tentative X-ray-to-VHE correlation during a low VHE activity. Although marginally significant, this positive correlation between X-ray and VHE, which has been reported many times during flaring activity, suggests that the mechanisms that dominate the X-ray/VHE emission during non-flaring-activity are not substantially different from those that are responsible for the emission during flaring activity., Comment: Accepted for publication in A&A

We present optical, X-ray, high energy ($\lessapprox 30$ GeV) and very high energy ($\gtrapprox 100$ GeV; VHE) observations of the high-frequency peaked blazar Mrk 421 taken between 2008 May 24 and June 23. A high energy $\gamma$-ray signal was detected by AGILE with \sqrt{TS}=4.5 on June 9--15, with $F(E>100 \mathrm{MeV})= 42^{+14}_{-12}\times 10^{-8}$ photons cm$^{-2}$ s$^{-1}$. This flaring state is brighter than the average flux observed by EGRET by a factor of $\sim$3, but still consistent with the highest EGRET flux. In hard X-rays (20-60 keV) SuperAGILE resolved a 5-day flare (June 9-15) peaking at $\sim$ 55 mCrab. SuperAGILE, RXTE/ASM and Swift/BAT data show a correlated flaring structure between soft and hard X-rays. Hints of the same flaring behavior are also detected in the simultaneous optical data provided by the GASP-WEBT. A Swift/XRT observation near the flaring maximum revealed the highest 2-10 keV flux ever observed from this source, of 2.6 $\times 10^{-9}$ erg cm$^{-2}$ s$^{-1}$ (i.e. > 100 mCrab). A peak synchrotron energy of $\sim$3 keV was derived, higher than typical values of $\sim$0.5-1 keV. VHE observations with MAGIC and VERITAS on June 6-8 show the flux peaking in a bright state, well correlated with the X-rays. This extraordinary set of simultaneous data, covering a twelve-decade spectral range, allowed for a deep analysis of the spectral energy distribution as well as of correlated light curves. The $\gamma$-ray flare can be interpreted within the framework of the synchrotron self-Compton model in terms of a rapid acceleration of leptons in the jet., Comment: accepted for publication in ApJL, 7 pages, 2 figures, 1 table

Cartographic approaches to studying the spatial distribution of the biological efficiency of Moldova's climate are presented and investigated. In particular, a Climate Biological Efficiency Index (CBEI) was calculated from data gathered from 17 meteorological stations in the republic for the period 1961–1992. The CBEI for this period is compared with one characterizing a “normal” climate (up to 1980) and the period of “global warming” (after 1980) to determine the extent to which recent trends have altered the republic's climate in terms of its suitability for agriculture. Translated by Edward Torrey, Alexandria, Virginia from: Izvestiya Akademii Nauk, seriya geograficheskaya, 1999, No 3, pp. 86-92.

To study the experience in managing patients with acute promyelocytic leukemia (APL) diagnosed in different periods of pregnancy.Nine women with APL were treated in 1998-2013. When APL was diagnosed in the first trimester of pregnancy, the latter was terminated (n = 1); when its diagnosis was made in the second trimester, chemotherapy (CT) followed by delivery (D) was performed (n = 3); when it was done in the third trimester, D followed by CT was done in relation to gestational age (n = 2) or these were performed at a later gestational age (n = 1). APL was treated in 5 and 1 patients according to the AIDA protocol and the 7+3 plus ATRA one, respectively.All the patients with APL achieved remission after the first cycle of induction CT; 5 of the 6 patients did at the moment of delivery; one patient underwent emergency delivery during cytopenia after the cycle. The gestational age at delivery after CT was 34 (34-40) weeks. Spontaneous term labor occurred in 2 patients at an obstetric hospital. Cesarean section was made in 4 of the 6 patients. All babies were born alive, healthy, and without developmental abnormalities. Their age at the time of analyzing the results was 2.5 months to 15 years. Four of the 9 patients are presently alive. Late recurrences occurred in 3 (33%) patients. The median overall survival is 26 (0.25-128) months; the median relapse-free survival is 17.5 (0-127) months.APL treatment in pregnant women, which is aimed at saving two lives, is effective and reasonable.

Study of oxyhemoglobin in red blood cells and spleen tissues from normal human and patient with primary myelofibrosis was carried out using Mössbauer spectroscopy with a high velocity resolution. The 57Fe hyperfine parameters were evaluated and small variations in quadrupole splitting were revealed for both normal human and patient's oxyhemoglobin and both normal human and patient's spleen. © 2012 Springer Science+Business Media Dordrecht.

Comparative study of human liver ferritin and spleen tissues from healthy human and patient with primary myelofibrosis was carried out using Mössbauer spectroscopy with a high velocity resolution at 295 and 90 K and with a low velocity resolution at 20 K. The results obtained demonstrated that the iron content in patient's spleen in the form of iron storage proteins was about ten times larger than that in normal tissue. However, in the case of patient with primary myelofibrosis the magnetic anisotropy energy barrier differed from that in normal case and, probably, the iron core size was supposed to be slightly larger than that in both normal spleen tissue and normal human liver ferritin in contrast to well-known data for iron overload in patients with thalassemia accompanied by the iron-core size increase. Therefore, the iron overload in the case of patient with primary myelofibrosis may be related to increase in the ferritin content mainly. It was also found that Mössbauer hyperfine parameters for normal and patient's spleen and normal human liver ferritin demonstrated some small differences related, probably, to some small structural variations in the ferritin iron cores of patient's spleen. © 2013 Springer Science+Business Media New York.

Using model elaborated it was shown that the retinal ischemia initiated the development of the apoptosis in the inner layers of the retina. Administration of NOS inhibitor prevented the development of the apoptosis in the retina. To ascertain if nitric oxide could induce the retinal apoptosis by itself the nontoxic donor of nitric oxide (dinitrosyl iron complex) was injected intravitreally. Administration of DNIC in low concentrations induced the development of the apoptosis in the same retinal layers as in ischemia. The injection of dinitrosyl iron complex at the higher concentration resulted in the decrease of the apoptosis level. Administration of dinitrosyl iron complex with excess of glutathione didn't lead to the development of the retinal apoptosis. The obtained data demonstrates the neurotoxic properties of the excess of nitric oxide in the retina.

To review results of 2-year experience in execution of the protocol on the treatment of adult acute Ph-negative lymphoblastic leukemia ALL-2009.Of 111 patients registered in the study from November 2008 to December 2010 the analysis covered 96 patients from 23 hematological centers in 18 towns of the RF.Treatment according to the Protocol ALL-2009 resulted in achievement of a complete remission in 91.2% patients with low early lethality of 5.5%. Postremission lethality fell to 3.7% versus previous studies (22%). Overall 2-year survival and recurrence-free survival reached 77.6 and 78.4%, respectively. Detection of any chromosomic aberrations significantly affected recurrence-free survival: 74 vs 100% in patients with normal karyotype.Protocol All-2009 demonstrates high efficacy in moderate toxicity and good reproducibility in any hematologic center.

We present multiwavelength observations of 3C 454.3 from April 2008 to March 2010. The radio to optical data are mostly from the GASP-WEBT, UV and X-ray data from Swift, and gamma-ray data from the AGILE and Fermi satellites. We improved the calibration of optical-UV data from the UVOT and OM instruments and estimated the Lyalpha flux to disentangle the contributions from different components in this spectral region. The observations reveal prominent variability above 8 GHz. In the optical-UV band, the variability amplitude decreases with increasing frequency due to a steadier radiation from both a broad line region and an accretion disc. The optical flux reaches nearly the same levels in the 2008-2009 and 2009-2010 observing seasons; the mm one shows similar behaviour, whereas the gamma and X-ray flux levels rise in the second period. Two prominent gamma-ray flares in mid 2008 and late 2009 show a double-peaked structure, with a variable gamma/optical flux ratio. The X-ray flux variations seem to follow the gamma-ray and optical ones by about 0.5 and 1 d, respectively. We interpret the multifrequency behaviour in terms of an inhomogeneous curved jet, where synchrotron radiation of increasing wavelength is produced in progressively outer and wider jet regions, which can change their orientation in time. In particular, we assume that the long-term variability is due to this geometrical effect. By combining the optical and mm light curves to fit the gamma and X-ray ones, we find that the gamma (X-ray) emission may be explained by inverse-Comptonisation of synchrotron optical (IR) photons by their parent relativistic electrons (SSC process). A slight, variable misalignment between the synchrotron and Comptonisation zones would explain the increased gamma and X-ray flux levels in 2009-2010, as well as the change in the gamma/optical flux ratio during the outbursts peaks., 17 pages, 9 figures, accepted for publication in A&A

A comparative study of oxyhemoglobins from pig, rabbit, normal human and patients with blood system malignant diseases was performed using Mossbauer spectroscopy with a high velocity resolution at 90 K. Mossbauer spectra were fitted with the help of two models: using one quadrupole doublet (model of equivalent iron electronic structure in α- and β-subunits of hemoglobins) and superposition of two quadrupole doublets (model of non-equivalent iron electronic structure in α- and β-subunits of hemoglobins). The results obtained using both models demonstrated small variations of hyperfine parameters that were related to the heme iron state variation in different hemoglobins. These results were compared with structural and functional differences of the hemoglobins investigated.

The possibility and the mechanism of the reduction of nitrites in retinal vessels under the acute hypoxia in vivo have been investigated. An experimental model of the rat retina ischemia was elaborated using the laser coagulation of retinal vessels. It was demonstrated that the vessel thrombosis does not occur if the nitrite concentration in the vessels is increased. It was proposed that, under acute hypoxia, nitrites are reduced to NO, which results in a drastic vasodilatation. Considering that the effect takes less than a minute, this reduction cannot be due to hypoxic acidosis but is more likely associated with NO reduction by heme proteins. It was found that the increased concentration of nitrites protects the retina from the development of ischemia progress and that the preliminary administration of nitrites prevents apoptosis in the retina and a decrease in its photoelectric activity.

In 2007-2008 we carried out a new multiwavelength campaign of the Whole Earth Blazar Telescope (WEBT) on BL Lacertae, involving three pointings by the XMM-Newton satellite, to study its emission properties. The source was monitored in the optical-to-radio bands by 37 telescopes. The brightness level was relatively low. Some episodes of very fast variability were detected in the optical bands. The X-ray spectra are well fitted by a power law with photon index of about 2 and photoelectric absorption exceeding the Galactic value. However, when taking into account the presence of a molecular cloud on the line of sight, the data are best fitted by a double power law, implying a concave X-ray spectrum. The spectral energy distributions (SEDs) built with simultaneous radio-to-X-ray data at the epochs of the XMM-Newton observations suggest that the peak of the synchrotron emission lies in the near-IR band, and show a prominent UV excess, besides a slight soft-X-ray excess. A comparison with the SEDs corresponding to previous observations with X-ray satellites shows that the X-ray spectrum is extremely variable. We ascribe the UV excess to thermal emission from the accretion disc, and the other broad-band spectral features to the presence of two synchrotron components, with their related SSC emission. We fit the thermal emission with a black body law and the non-thermal components by means of a helical jet model. The fit indicates a disc temperature greater than 20000 K and a luminosity greater than 6 x 10^44 erg/s., 11 pages, 7 figures, accepted for publication in A&A

Since 2001, the radio quasar 3C 454.3 has undergone a period of high optical activity, culminating in the brightest optical state ever observed, during the 2004-2005 outburst. The Whole Earth Blazar Telescope (WEBT) consortium has carried out several multifrequency campaigns to follow the source behaviour. The GLAST-AGILE Support Program (GASP) was born from the WEBT to provide long-term continuous optical-to-radio monitoring of a sample of gamma-loud blazars, during the operation of the AGILE and GLAST (now known as Fermi GST) gamma-ray satellites. The main aim is to shed light on the mechanisms producing the high-energy radiation, through correlation analysis with the low-energy emission. Thus, since 2008 the monitoring task on 3C 454.3 passed from the WEBT to the GASP, while both AGILE and Fermi detected strong gamma-ray emission from the source. We present the main results obtained by the GASP at optical, mm, and radio frequencies in the 2008-2009 season, and compare them with the WEBT results from previous years. An optical outburst was observed to peak in mid July 2008, when Fermi detected the brightest gamma-ray levels. A contemporaneous mm outburst maintained its brightness for a longer time, until the cm emission also reached the maximum levels. The behaviour compared in the three bands suggests that the variable relative brightness of the different-frequency outbursts may be due to the changing orientation of a curved inhomogeneous jet. The optical light curve is very well sampled during the entire season, which is also well covered by the various AGILE and Fermi observing periods. The relevant cross-correlation studies will be very important in constraining high-energy emission models., Comment: 5 pages, 5 figures, to be published in A&A (Letters)

Since 1997, BL Lacertae has undergone a phase of high optical activity, with the occurrence of several prominent outbursts. Starting from 1999, the Whole Earth Blazar Telescope (WEBT) consortium has organized various multifrequency campaigns on this blazar, collecting tens of thousands of data points. One of the main issues in the study of this huge dataset has been the search for correlations between the optical and radio flux variations, and for possible periodicities in the light curves. The analysis of the data assembled during the first four campaigns (comprising also archival data to cover the period 1968-2003) revealed a fair optical-radio correlation in 1994-2003, with a delay of the hard radio events of ~100 days. Moreover, various statistical methods suggested the existence of a radio periodicity of ~8 years. In 2004 the WEBT started a new campaign to extend the dataset to the most recent observing seasons, in order to possibly confirm and better understand the previous results. In this campaign we have collected and assembled about 11000 new optical observations from twenty telescopes, plus near-IR and radio data at various frequencies. Here, we perform a correlation analysis on the long-term R-band and radio light curves. In general, we confirm the ~100-day delay of the hard radio events with respect to the optical ones, even if longer (~200-300 days) time lags are also found in particular periods. The radio quasi-periodicity is confirmed too, but the "period" seems to progressively lengthen from 7.4 to 9.3 years in the last three cycles. The optical and radio behaviour in the last forty years suggests a scenario where geometric effects play a major role. In particular, the alternation of enhanced and suppressed optical activity (accompanied by hard and soft radio events, respectively) can, Comment: 6 pages, 4 figures

We studied the development of retinal ischemia in rat eye after laser coagulation of blood vessels. Typical signs of ischemia manifested in the retina after 24 h: development of stable retinal edema, decrease in the b/a index (ratio of the electroretinogram b and a-wave amplitudes) to 1-2 units, pronounced disorders in the retinal microcirculation system, leading to ischemia of the inner layers of the retina. The proposed model is convenient for studies of the development of acute retinal ischemia, is easily realized, and reproduces some acute ischemic diseases of the retina.

We present radio-to-optical data taken by the WEBT, supplemented by VLBA and RXTE observations, of 3C 279. Our goal is to use this extensive database to draw inferences regarding the physics of the relativistic jet. We assemble multifrequency light curves with data from 30 ground-based observatories and the space-based instruments, along with linear polarization vs. time in the optical R band. In addition, we present a sequence of 22 images (with polarization vectors) at 43 GHz at resolution 0.15 milliarcsec, obtained with the VLBA. We analyse the light curves and polarization, as well as the spectral energy distributions at different epochs, corresponding to different brightness states. The IR-optical-UV continuum spectrum of the variable component corresponds to a power law with a constant slope of -1.6, while in the 2.4-10 keV X-ray band it varies in slope from -1.1 to -1.6. The steepest X-ray spectrum occurs at a flux minimum. During a decline in flux from maximum in late 2006, the optical and 43 GHz core polarization vectors rotate by ~300 degrees. The continuum spectrum agrees with steady injection of relativistic electrons with a power-law energy distribution of slope -3.2 that is steepened to -4.2 at high energies by radiative losses. The X-ray emission at flux minimum comes most likely from a new component that starts in an upstream section of the jet where inverse Compton scattering of seed photons from outside the jet is important. The rotation of the polarization vector implies that the jet contains a helical magnetic field that extends ~20 pc past the 43 GHz core., 12 pages, aa.cls style; accepted for publication in A&A