Vol 79, No 7 (2004)


"Plasticity" of bone marrow stem cells

Chertkov I.L., Drize N.I.
Terapevticheskii arkhiv. 2004;79(7):5-11
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Preliminary results of a multicenter randomized study on the treatment of acute promyelocytic leukemias

Parovichnikova E.N., Savchenko V.G., Demidova I.A., Isaev V.G., Shuravina E.N., Ustinova E.N., Gribanova E.O., Alexanyan M.Z., Misyurin A.V., Domracheva E.V., Olshanskaya Y.V., Khoroshko N.D., Kravchenko S.K., Konstantinova T.S., Anchukova L.V., Kaplanov K., Zagoskina T.P., Volkova S.A., Filatov L.В., Rekhtman G.В., Sokolova I., Mashuk V.N., Milyulina G.I., Lapin V.A., Perekatova T.N., Sviridova E.I., Pristupa A.S., Zyuzgin I.S.


Aim. To study efficacy of maintenance therapy of patients with acute promyelocyte leukemia (APL) in the APL treatment Russian multicenter trial. Material and methods. The trial was made with participation of 18 hematological departments of clinics in Russia. A total of 68 APL patients entered the trial. The maintenance therapy consisted of 5day courses of cytostatic drugs which alternated or did not altenate with 5-day courses of ATRA. Cytogenetic tests were made in 31 patients, t(15;17) was detected in 26 of them. Molecular examination conducted in 28 patients discovered chimeric transcript PML/RARa in 26 of them. Of 20 patients examined in Hematological Research Center, 7 (35%) had a bcr 1/2 variant of the transcript PML/RARa, 13 (657c) - bcr 3 variant. Results. 65 patients were eligible for assessment. A complete remission was achieved in 90% cases. No resistance was observed. In follow-up within 30 months the recurrence rate was similar on both treatments. The results of the induction therapy and survival in patients with different variants of the transcripts were also simitar. Overall 2.5 year survival for all the patients was 77%, recurrence-free 80%. The survival analysis in patients with leukocytosis higher and lower 10 lO9/! found no statistical differences by the survival. Patients with hyperleukocytosis had higher early lethality than patients with leukocytes under 10 Iff/I (25% vs 5.3%, p = 0.03). Conclusion. The APL 06.01 protocol showed high efficacy of the relevant maintenance which provides a complete molecular remission in the majority of patients with probable recurrence-free 2.5 year survival 80%.
Terapevticheskii arkhiv. 2004;79(7):11-18
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Transplantation of allogenic bone marrow in chronic myeloid leukemias

Lyubimova L.S., Savchenko V.G., Mendeleeva L.P., Kuzmina L.A., Anukhina M.V., Gribanova E.O., Demidova I.A., Misyurin A.V., Vinogradova О.A., Domracheva E.V., Poreshina L.P., Kutyina R.M., Shpakova A.P., Matveenko A.A., Kalinin N.N., Gemdzhyan E.G.


Aim. To assess the role of allogenic bone marrow (ABM) transplantation in chronic myeloid leukemia (CML). Material and methods. 44 ABM transplantations were performed in 37 CML patients in the chronic phase and 7 patients in acceleration or blast crisis. Results. A complete molecular remission was achieved in 26 (59%) patients: 67.6% after ABM transplantation in the chronic phase and only 14.3% after myelotransplantation in non-chronic phase. Follow-up was 8-150 months (median - 59 months). Early lethality after ABM transplantation in the chronic phase was under 14%. A phase of the disease plays a key role in ABM transplantation. If it is made in a chronic phase, CML recurrence rate is low (in our series it was 14%), efficacy of donor's bone marrow lymphocyte transfusions is high. The second complete molecular remission was achieved in 3 of 4 cases of posttransplantation recurrences. Probability of maintenance of a complete remission after ABM transplantation in a chronic phase was 75%, recurrence-free survival - 64%), uneventful survival 55% for 90 months. Conclusion. The experience of many years demonstrates high efficacy of ABM transplantation in the treatment of chronic myeloid leukemia. It promotes long-term molecular remission the maintenance of which did not require therapy in 65% patients.
Terapevticheskii arkhiv. 2004;79(7):18-24
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Somatic masks of depressions in leukemias

Vybornykh D.E., Savchenko V.G., Isaev V.G.


Aim. To specify types of depressive conditions in a sample of leukemia patients. Material and methods. The study included 71 leukemia patients with depressions in the structure of which somatized disorders are an obligatory component of the depressive syndrome and determine clinical picture of the condition. This is the form of masking affective disorders. Results. The patients had the following types of depression: somatized, hypochondriac, asthenic, depressive-delirium, hysteric depression. How to manage depression in leukemia patients is described.
Terapevticheskii arkhiv. 2004;79(7):24-28
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Leukemic transformation of donor cells: is it possible?

Vinogradova O.A., Savchenko V.G., Domracheva E.V., Parovichnikova E.N., Dyachenko L.V., Alimova G.A., Mendeleeva L.P., Lyubimova L.S., Sokolov A.N., Zhelnova E.I., Pokrovskaya O.S.


Aim. To genotype tumor cells in the recurrence of leukemia after allogenic transplantation of bone marrow (TBM). Material and methods. Standard cytogenetics and fluorescent hybridization in situ (FISH) with a probe to the centrometic sites of X/Y chromosomes were used in examination of 2 patients with acute promyelocyte and acute non-differentiated leukemia after allogenic TBM from donors of the opposite gender. Bone marrow was studied 1, 2, 3, 6, 9, 12, 15, 17, 18 months after the transplantation. Results. One of the patient in leukemia recurrence there were 72% cells with one X chromosome with unknown origin 28% donor cells were with genotype XX. The primary archival cytological sample of the recipients bone marrow 68% cells did not contain Ychromosome. Thus, the clone with Yloss is the recipient's clone and leukemia after transplantation developed from the recipient's cells The other patient had only 8% dividing cells with her karyotype XX with translocation t(10; 11) while 92% metaphases were donor's ones; the interphase cells ratio was 75% of host cells and 25% donor cells. This confirms leukemia origin from the recipient's cells. Conclusion. High sensitive quantitative method FISH indicates a true correlation between the host and donor cells and is a method of choice for genotyping leukemic cells in recurrence after transplantation of bone marrow. While standard caryotyping depends on mytotic activity of donor and host cell populations, use of only one cytogenetic test for determination of leukemia origin after ТВМ may provoke diagnostic errors.
Terapevticheskii arkhiv. 2004;79(7):28-34
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Damage to vascular endothelium in the treatment of acute leukemia: in vitro study

Romanov Y.A., Chervontseva A.M., Savchenko V.G.


Aim. Cytostatic drugs used in the treatment of hemopoietic malignancies affect cells of other organs and systems, vascular endothelium, in particular. This leads to cardiovascular complications. We studied effects of some drugs and their combinations on cultured human endothelial cells (EC). Material and methods. Primary culture of umbilical human vein EC was used in the study. Cytosinearabinoside (cytozar, alexan, cytarabin) and daunorubicin were added in concentration from 1 ng/ml to 1 mg/ml; the action of the drugs was assessed by morphology of the cells, their viability, inclusion of bromodesoxyuridine by means of cloning, immunohistochemistry and flow cytofluorimetry. Results. It is shown that in a wide range of concentrations cytosinearabinoside and daunorubicine cause specific structural-functional changes in the cells related to cytostatic and cytotoxic effects. Conclusion. The data of the study confirm that cardiovascular complications in the course of acute leukemia treatment are resultant from systemic damage to vascular endothelium.
Terapevticheskii arkhiv. 2004;79(7):34-40
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Molecular-cytogenetic monitoring of different regimens of treatment

Dyachenko L.V., Zakharova A.V., Aseeva E.A., Turkina A.G., Khoroshko N.D., Vodinskaya L.A., Udovichenko A.I., Domracheva E.V.


Aim. To conduct molecular-cytogenetic monitoring of bone marrow cells in different regimens of chronic myeloid leukemia (CML) treatment. Material and methods. A total of 651 samples of bone marrow from 319 CML patients were studied. 229patients receivedpolychemotherapy and 90patients - interferon-alpha. Primary examination and monitoring of the treatment efficacy were performed using G-differential chromosome staining. Fluorescent in situ hybridization (FISH) was made in 75% cases. Results. Interferon therapy resulted in a significant increase in the number of complete and significant cytogenetic responses. With aggravation of the disease the above responses occurred less frequently while minor and no response are encountered more often. Treatment with interferon-alpha in combination with chemotherapy is much more effective than monotherapy with interferon. Conclusion. G-differential chromosome staining karyotypes metaphases and detects clonal chromosome restructuring. Molecular-cytogenetic methods study chromosome restructuring at DNA level. FISH detects chimeric gene bcr/abl in cases when Ph-chromosome is not detectable by standard cytogenetic methods.
Terapevticheskii arkhiv. 2004;79(7):41-44
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Prediction of interferon therapy efficacy in chronic myeloid leukemia according to histomorphological evidence

Khoroshko N.D., Turkina A.G., Kumas S.M., Zhurarlev V.S., Kuznetsov S.V., Sokolova M.A., Semenova E.A., Kaplanskaya I.В., Frank G.A., Korolev А.V., Scherbinina L.A., Zakharova A.V., Domracheva E.V., Zingermam B.V.


Aim. To investigate factors determining prognosis and efficacy of induction therapy including interferon-alpha-2b (intron-A, Schehng Plough) in patients at an early chronic stage of Ph-positive chronic myeloid leukemia (CML) as shown by histomorphological examination. Material and methods. The analysis covered 52 CML patients treated at an early chronic phase with intron-A in a standard daily dose 5 IU/m2 in combination with low-dose cytosinearabinoside (10 mg/m2, s.c. , daily for 10 days of each month). The treatment efficacy was assessed by the international criteria of complete and partial hematological remission and cytogenetic response. The cytogenetic study employed the direct method, even and G-differential staining, fluorescent hybridization in situ (FISH). The sections were stained with hematoxilin-eosine by Gomori, van Gieson. Histological samples were examined with histomorphometry. Immunohistochemical examination was made on paraffin sections using a panel of monoclonal antibodies CD3, CD4, CDS, CD20, NK, PCNA, Ki-67 (Dako, Denmark). Results. Repeated assessment of histomorphological parameters such as erythroid lineage, degree of myelofibrosis and reduction of leukemic population indicate the treatment efficacy. Estimation of the level of leukemic population proliferation in trephine biopsies from CML patients with monoclonal antibodies PCNA and Ki-67 before the treatment is prognostically significant as it further correlates with the cytogenetic response (r = 0.821, p = 0.000000). Conclusion. It is valid to study histomorphological picture of CML to prognosticate and assess treatment efficacy with standard doses of interferon-alpha with high probability.
Terapevticheskii arkhiv. 2004;79(7):44-50
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Possibility of diagnosis and treatment of thrombotic complications in primary mediastinal B-cell lymphoma

Dzhumabaeva В.Т., Kremenetskaya A.M., Vasilyev S.A., Shulutko E.M., Kravchenko S.K., Shevelev A.A., Sergeeva E.V., Sakhibov Y.D., Orel E.В., Romanova E.A., Frank G.A.


Aim. Efficacy of the treatment of primary mediastinal B-cell lymphosarcoma depends to a great extent on early diagnosis and treatment policy. In this study we evaluated possibilities of diagnosis and treatment of thrombotic complications of primary mediastinal B-cell lymphosarcoma (PMBL). Material and methods. 61 patients were examined using roentgenography, computed tomography, chest ultrasound investigation,coagulogram, allelle specific polymerase chain reaction, ultrasound investigation of the jugular, subclavian, brachial veins, vena cava superior to detect mutation of genes II, Vfactors and methylentetrahydrofolatereductase. Results. In 7 cases prechemotherapy examination detected thrombosis of the internal jugular and subclavian veins. In 4 of 7 cases there was a combined thrombosis of the left internal jugular and subclavian veins, in 3 cases one the vessels was affected with thrombosis. In 2 cases, in the course of polychemotherapy, there was recurrent thrombosis and development of pulmonary artery thromboembolism (PATE). In progression of the disease there was thrombosis of the left subclavian vein (1 case) and PA ТЕ (a case). Coagulologically, hypercoagulation syndrome signs were registered. 5 patients with PMBL complicated by thromboses showed gene mutations. Conclusion. In PMBL there is a tendency to formation of venous thrombosis and development of PATE. This is explained by tumor process and hereditary factors of thrombogenicity. Therefore, specific antitumor treatment should include anticoagulation theerapy.
Terapevticheskii arkhiv. 2004;79(7):50-54
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Wilson's disease and secondary copper hemochromatoses in hematological practice

Vorobyev A.I., Lukina E.A., Sysoeva E.P., Levina A.A., Solovyeva T.I.


Aim. To characterize clinical, diagnostic and therapeutic syndromes of copper overloading in patients with hepatic lesion in combination with hemopoietic disorder. Material and methods. Treatment results and diagnostic findings are presented for patients with clinical picture of liver cirrhosis, cytopenia and copper overloading. The examination included standard clinical and specific tests, morphological investigation of the bone marrow, copper metabolism in dynamics. Results. A case of a patient is reported in whom Wilson's disease presented in debut with a picture of decompensated liver cirrhosis and immune thrombocytopania complicated by recurrent hemorrhagic syndrome. D-penicillomine treatment initiated ex juvantibus allowed verification of the diagnosis of Wilson's disease and achievement of marked clinical response. In another case laboratory signs of copper overloading were revealed in a patient with liver cirrhosis of viral etiology (HBsAg+) and deep cytopenia associated with unejfective hemopoiesis. Chelator therapy with D-penicillamine regressed cytopenic syndrome and improved functional capacity of the liver. Conclusion. Primary or secondary nature of copper overloading in patients with hepatic cirrhosis and critical cytopenia, pathogenesis of cytopenic syndrome, practical significance of copper hemochromatoses diagnosis are discussed.
Terapevticheskii arkhiv. 2004;79(7):55-59
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Prognostic implication of a focal lesion of bone marrow in diffuse large В cell lymphosarcoma

Magomedova A.U., Kremenetskaya A.M., Vorobyev I.A., Kravchenko S.K., Kaplanskaya I.В., Samoilova R.S., Gemdzhyan E.G., Vorobyev A.I.


Aim. To study prognostic implications of a focal mature cell lesion of the bone marrow (BM) in patients with diffuse large В cell lymphosarcoma (DBLCL). Material and methods. 54 patients with histologically confirmed DBLCL were given first-line CHOP and CHOP-like courses from 1996 to 2003. B-cell nature of the tumor was confirmed immunohistochemically, immunophenotypically and with flow fluorimetry. Results. In debute of the disease 16 patients had local involvement of the lymph organs (stage I-II by Enn-Arbor), 21 patients - generalized disease (stage III-IV) and 17 patients - involvement of nonlymphatic organs. Overall 3-year survival in first-line therapy in mature cell lesion of BM was 23%, without it - 0%. One-year event-free survival was 34 and 0%, respectively. Conclusion. The presence of a focal mature cell lesion of BM in DBLCL patients influences the prognosis. Regarding high frequency of transformation of mature cell lymphoproliferative diseases in DBLCL . focal lesion of BM is an indirect sign of a secondary nature of the disease.
Terapevticheskii arkhiv. 2004;79(7):60-63
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The results of histological and immunohistological studies of primary biopsies from 400 cases of nonHodgkin's lymphoma according to WHO classification in the North-West region of Russia

Krivolapov Y.A.


Aim. To determine relative frequency of non-Hodgkin's lymphoma (NHL) variants according to WHO classification categories in the North-West of Russia by the data of the local pathomorphological department. Material and methods. Four hundred consecutive untreated patients with NHL were diagnosed according to the WHO classification between January 2000 and October 2003 in the Regional Bureau of Pathology, St-Petersburg. The patients' age, gender, location of the biopsied tumor focus were considered. The immunohistochemical study was performed by the paraffin section-immunoperoxidase method. Cases of plasma cell myeloma and bone marrow trephine biopsy diagnosed neoplasms were excluded, the rest series of 377 cases was compared to other regional world series. Results. B-cell lymphomas accounted for 79.6% and T-cell type for 20.4% of 377 NHL cases. 33.2% cases were different histological variants of diffuse large B-cell lymphoma, 17.0% were B-cell small lymphocytic lymphomas, 11.0% -follicular lymphomas, 4.5% - mantle cell lymphomas, 2.1% - extranodal marginal zone B-cell lymphomas (MALT-type), 1.9% - primary B-cell mediastinal lymphomas. Peripheral T-cell lymphomas, unspecified and anaplastic large T/null cell lymphomas were diagnosed in 6.4 and 4.2% of 377cases, respectively. Other lymphoma diagnoses comprised 19.7%. Conclusion. Diffuse large B-cell lymphomas and B-cell small lymphocytic lymphomas are prevalent among B-cell neoplasms. Follicular lymphomas and mantle cell lymphomas are less common in the North-West of Russia compared to Europe and USA. The relative frequency of extranodal marginal zone B-cell lymphomas (MAL T-type) is lower and anaplastic large T/null cell lymphomas is higher than these in International Lymphoma Study Group, Taiwan and Japan series. This study provides evidence that the distribution pattern ofnon-Hodgkin 's lymphoma subtypes in the North-West of Russia shows significant differences with those from the rest of the world.
Terapevticheskii arkhiv. 2004;79(7):64-70
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Cytogenetics of mantle cell lymphoma

Obukhova T.N., Lorie Y.Y., Vodinskaya L.A., Alimova G.A., Nikitin E.A., Samoilova R.S., Kaplanskaya I.В., Domracheva E.V.


Aim. To determine the type and rate of secondary chromosomal aberrations and role in pathogenesis of mantle cell lymphoma (MCL). Material and methods. Standard cytogenetic examination (SCE) and fluorescent in situ hybridization (FISH) with tests for Uq22/ATM, 13ql4, 17pl3/p53, 9p 21/p 16 and chromosome 12 centromere were made in 28 patients. Results. Secondary chromosomal aberrations were detected in 22 patients. Chromosomal abnormalities occurring in more than 2 cases include deletions 6ql5-q23 (53% cases); 1Ц22/АТМ (50%); 9p21 (36%, in half the cases deletion 9p21 was biallele); 13ql4 (32%); trisomy 3/3q, monosomy 20 and deletions/translocations Iq and Ip (27% and 20%) and deletion 17pl3/p53 (18%). Trisomies 12/12q, 6 and 18/18q, monosomies 2 and 16, deletions/translocations 2p and 16p were found in 2 cases each. The FISH technique identified 9 chromosomal anomalies missed at SCE. Deletions 6ql5q23 were seen in patients with privalent lesions of lymph nodes. Deletions llq, 13ql4, 9p21 and 17pl3 occur more frequently in transformation and the blastoid variant. Monosomy 20 was found only in patients with large cell transformations. This was the only cytogenetic defect characteristic for transformed cases, in contrast to denovoblastoid ones. Thus, deletions 6q, Uq23, 13ql4 and 9p21 are typical for MCL. Deletions 9p2I and 17pl3 are more characteristic for large cell variants of the tumor. Deletion 17pl3 occurs at the terminal stage of the disease in rapidly growing tumor mass and resistance to chemotherapy. FISH technique is effective in detection of submicroscopic rearrangements especially small deletions. No significant differences were found between transformed and de novo blastoid cases. This shows that the blastoid variant is not a specific biological form, it is rather a less typical manifestation of the disease due to some preclinical cytogenetic disorders. Conclusion. Progression and transformation of MCL are related to mutation of proapoptotic genes and genes proteins of which are inhibitors of active complexes of Dl cycline. Specification of these mechanisms requires further investigations in patients with different clinicomorphological forms of the disease at various stages of the disease.
Terapevticheskii arkhiv. 2004;79(7):70-77
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Expression of PRAME gene in multiple myeloma

Abramenko I.В., Belous N.I., Kryachok I.A., Chumak A.A., Aksenova E.V., Lisovskaya E.V., Misyurin A.V.


Aim. To determine clinical significance of PRAME gene expression in multiple myeloma (MM) and feasibility of its use as a marker of residual tumor clone. Material and methods. 35 MM patients, of them 15 were newly diagnosed and 20 had resistance to previous therapy. PRAME was made if the patients received programmed therapy with high-dose chemotherapy (VD) and autologous transplantation of peripheral cell stem cells. 12 PRAME-positive patients were examined on the day +100, 5 patients ~ a year later. Monoclonal paraprotein was detected by electrophoresis and radial immunodiffusion of blood serum. Bone marrow affection was assessed at roentgenography and/or MRI. PRAME gene expression in bone marrow biopsy was measured by reverse transcription and PCR amplification. Results. Activation of expression of PRAME gene in MM was found in 68.57% patients. It was higher in patients with MM duration more than 1 year and if they were treated before (85%) than in new cases (46.67%). Expression of PRAME tended to associate with activity of LDP of blood serum. After the above chemotherapy and autotransplantation transcript PRAME did not disappear in 8 of 12 cases. One year after the treatment, of 5 PRAME-positive patients 2 died, 1 had recurrence, 2 are in a compete clinicohematologica/ remission. Conclusion. Frequent activation of transcription of the gene FRAME in MM, its assay can be used for monitoring of the disease course, assessment of remission completeness, detection of tumor cell contamination of preparations of autologous stem cells of peripheral blood.
Terapevticheskii arkhiv. 2004;79(7):77-81
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Features of a clinical course of immune cytopenias with a high titer of autoantibodies to the thyroid

Vinogradova Y.E., Shinkarkina A.P., Vinogradov D.L., Poverenny A.M.


Aim. To ascertain the role of high antibodies (Ab) titers to microsomal antigen (MA) of the thyroid in clinical manifestations of cytopenic syndromes. Material and methods. Clinical data are presented on 144 patients with depressed hemopoiesis having different levels of thyroid Aab. Results. When the titer was significantly elevated (41% patients with immune cytopenias), hematological malignancies run with recurrences, remission is rare. Treatment of the thyroid pathology improves hematological indices in some cases though does not reduce titers of Ab thyroid MA. Conclusion. Detection of autoimmune pathology of the thyroid is necessary not only for specification of the concurrent process diagnosis but also for initiation of adequate combined treatment.
Terapevticheskii arkhiv. 2004;79(7):81-85
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Secondary myelodysplastic syndrome in patients with multiple myeloma

Abdulkadyrov К.М., Gritsaev S.V., Bessmeltsev S.S., Matynkevich I.S., Tiranova S.A., Blinov M.N., Stelmashenko L.V., Pesterova V.V.


secondary myelodysplastic syndrome, multiple myeloma, complex karyotype impairments, treatment
Terapevticheskii arkhiv. 2004;79(7):85-87
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Glivek in therapy of some forms of Ph- and bcr/abl-negative myeloproliferative diseases and a myeloproliferative variant of idiopathic hypereosinophilic syndrome

Nemchenko I.S., Khoroshko N.D., Turkina A.G., Vinogradova O.Y., Sokolova M.A., Abakumov E.M., Semenova E.A., Zakharova A.V., Domracheva E.V.
Terapevticheskii arkhiv. 2004;79(7):87-90
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Primary diffuse large B-cell lymphosarcoma of the stomach and renal cell carcinoma of the right kidney (a case report)

Kulkova D.M., Zvonkov E.E., Makhinya V.A., Grimov S.В., Kaplanskaya I.В., Varlamova E.Y., Krasilnikova В.В., Kravchenko S.K., Egorova E.K., Iskhakov E.D.
Terapevticheskii arkhiv. 2004;79(7):90-91
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