EFFECT OF IRON ON BONE TISSUE METABOLISM AND THYROID FUNCTION IN CHILDREN LIVING ON RADIOLOGICALLY CONTAMINATED TERRITORIES SINCE THE ChNPP ACCIDENT. / ВПЛИВ ЗАЛІЗА НА ПРОЦЕСИ МЕТАБОЛІЗМУ В КІСТКОВІЙ ТКАНИНІ ТА ФУНКЦІЮ ЩИТОПОДІБНОЇ ЗАЛОЗИ УДІТЕЙ, ЯКІ ЖИВУТЬ НА РАДІОАКТИВНО ЗАБРУДНЕНИХ ТЕРИТОРІЯХ ПІСЛЯ АВАРІЇ НА ЧАЕС.

OBJECTIVE: identification of clinical and metabolic characteristics of osteogenesis and factors affecting bone mineral density (BMD) in children living in radioactively contaminated territories (RCT) after the ChNPP accident for the use of therapeutic and preventive measures aiming to reduce the incidence of disorders. MATERIALS AND METHODS: Children aged 4 to 18 years old (n = 539) were involved in the study within 4 age groups, namely under 7 years old, 7-10 years old, 10-14 years old, older than 14 years old. Studied parameters in children with a reduced BMD (85-65 relative units and under 65 relative units) were estimated vs. the normative BMD (100-85 relative units) cases. Diagnosis of osteopenia and osteoporosis in children was established according to the BMD T-index. Family history of the relatives of children was studied. Body weight at birth, fractures of the long bones, complaints of osalgia, jaw anomalies, dental caries, presence of obesity, and hypermobility syndrome (HMS) were assessed. Peripheral blood biochemical tests were performed featuring the serum total protein, alkaline phosphatase (APh), calcium, vitamin D, creatinine, serum iron (SI), ferritin, cortisol, pituitary thyroid-stimulating hormone (TSH), and free thyroxine (FT4) assay. BMD was measured and radiation doses in children were reconstructed. RESULTS: BMD depended on the age of children. A direct correlation was established between the cholelithiasis and urolithiasis incidence (р < 0.01), cancer and endocrine diseases (р < 0.05) in the relatives of children that had BMD under 65 relative units. Dental caries developed more often (р < 0.05), while obesity was less frequent (р < 0.05) in the subjects with BMD < 65 relative units. A direct correlation was established between the level of serum creatinine and BMD (р < 0.01), and there was an inverse correlation between the serum APh level and BMD (р < 0.001).Every third child had a vitamin D deficiency. Fractures of long bones and increased content of SI and TSH were characteristic for the children having got osteopenia (BMD within 85-65 relative units), while besides a predisposition to bone fractures the higher levels of SI, APh, cortisol both with calcium deficiency were found in children with osteoporosis (BMD < 65 relative units) compared to the general group with a similar BMD. An increased incidence of HMS was characteristic too. Radiation doses in children with osteopenia were higher than in those with osteoporosis: (1.17 ± 0.09) mSv and (0.92 ± 0.06) mSv respectively (р < 0.05). No correlation was found between the radiation doses and clinical signs, blood biochemistry or BMD. CONCLUSIONS: Study of the functional mechanisms of bone structures in children, depending on their metabolism, had made it possible to reveal the factors that affect bone formation in children living in RCT after the ChNPP accident, and to form the population groups for the timely application of therapeutic and preventive measures aiming to reduce the incidence of disorders of musculoskeletal system.

DRIVERS OF HYPERFERREMIA IN CHILDREN LIVING ON RADIOLOGICALLY CONTAMINATED TERRITORIES AFTER THE CHNPP ACCIDENT IN UKRAINE. / ЧИННИКИ, ЯКІ ВПЛИВАЮТЬ НА МЕХАНІЗМИ ФОРМУВАННЯ ПІДВИЩЕНОЇ ЩІЛЬНОСТІ КІСТКОВОЇ ТКАНИНИ У ДІТЕЙ, ЖИТЕЛІВ РАДІОАКТИВНО ЗАБРУДНЕНИХ ТЕРИТОРІЙ, ПІСЛЯ АВАРІЇ НА ЧАЕС.

OBJECTIVE: assessment of clinical-hematological and metabolic-biochemical parameters of the of bone tissue and hormonal regulation depending on the serum iron content and radiation dose values in children living on radiologically contaminated territories after the ChNPP accident in Ukraine. MATERIALS AND METHODS: Children (n = 271) living on radiologically contaminated territories (RCT) of Ukraine were involved in the study. Three study groups were formed according to the serum iron level (SIL), namely group I with SIL 10.0-22.0 µmol/l (n = 92), group II with SIL 23.0-34.0 µmol/l (n = 144), and group III with SIL above 35.0 µmol/l (n = 35). Diseases in the family tree, bodyweight at birth, complaints on osalgia, bone fractures, jaw anomalies, dental caries, and obesity were accounted. Morphometric parameters of erythrocytes and hemogram elements were analyzed. Creatinine, alkaline phosphatase, calcium, total protein, iron, cholesterol, bilirubin, and transaminases were assayed in blood serum. The urine content of the 19 free amino acids, serum content of the free thyroxine (FT4), pituitary thyroid-stimulating hormone (TSH), and cortisol were assayed both with bone tissue density. Individual radiation doses were calculated. RESULTS: In 12.9 % of cases the SIL was > 35.0 µmol/l. Relatives with endocrine diseases were often present in the family tree of children with SIL > 23.0 µmol/l. There were increased urine content of the free amino acids (p < 0.05) and signs of protein degradation under high SIL. Contents of amino acids involved in collagen synthesis and antioxidant status (alanine, serine, glutamine, aspartic acid) and iron metabolism (arginine, leucine) were assayed at the highest levels (p < 0.05). Urinary levels of valine, lysine, and methionine, which are associated with iron metabolism, were decreased (p < 0.05). An inverse correlation (rs = -0.58; p < 0.01) was established between the serum TSH and cortisol levels regardless of the SIL. Serum TSH level directly correlated with urine content of amino acids involved in collagen synthesis. An inverse correlation (rs = -0.55; p < 0.001) was established between the serum TSH level and urine content of tyrosine that is essential for the thyroid hormone (triiodothyronine and thyroxine) synthesis.Cortisol was found having a negative effect on protein synthesis. Inverse correlation was established between the serum cortisol level and urine content of the free amino acids essential for collagen synthesis. There was no dependence of the average radiation dose values on the SIL. An inverse correlation was determined between the patient's radiation dose and SIL > 35.0 µmol/l (rs = -0.29; p < 0.05). CONCLUSIONS: The increased SIL in children living on RCT may occur due to both a genetic predisposition and the acquired factors driving protein and mineral metabolism of bone and their hormonal regulation.

FACTORS AFFECTING MECHANISMS OF INCREASED BONE DENSITY FORMATION IN CHILDREN LIVING ON RADIOLOGICALLY CONTAMINATED TERRITORIES AFTER THE ChNPP ACCIDENT. / ChYNNYKY, IaKI VPLYVAIuT' NA MEKhANIZMY FORMUVANNIa PIDVYShchENOÏ ShchIL'NOSTI KISTKOVOÏ TKANYNY U DITEI, ZhYTELIV RADIOAKTYVNO ZABRUDNENYKh TERYTORII, PISLIa AVARIÏ NA ChAES.

OBJECTIVE: to determine the causes of increased bone mineral density (BMD) based on case history, clinical and laboratory data, including the assay of hormones involved in ossification processes in children, living on radiologically contaminated territories (RCT) after the accident at the ChNPP, compared to the normative BMD patterns. MATERIALS AND METHODS: There were 289 children involved in the study. The 1st group included persons with a BMD above 100 IU, 2nd group - with normative BMD (100-85 IU). Family history of diseases was assessed featuring cancer and endocrine diseases, cholelithiasis, and urolithiasis. Weight of the child at birth, frequency of bone fractures, complaints about osalgia, jaw abnormalities, dental caries, presence or absence of obesity, peripheral blood count, blood biochemical parameters (total protein, creatinine, iron, alkaline phosphatase, calcium), serum pituitary thyroid-stimulating hormone and cortisol were accounted. Children's radiation doses were calculated according to the materials of the «General dosimetric certification of settlements of Ukraine that were exposed to radioactive contamination after the Chornobyl accident¼. RESULTS: Higher than normative BMD values were found in children after puberty, while normative ones - in puberty (р < 0.001), regardless of gender. A direct correlation between the bone fractures frequency was established in children with increased BMD (р < 0.01). Jaw anomalies and dental caries occurred at that significantly less often than in normative BMD (р > 0.05). A direct correlation was established between the obesity and BMD (р < 0.001).Increased alkaline phosphatase activity was inversely correlated with BMD (rs = -0.21; р < 0.05). In children with elevated BMD a direct correlation was established between the level of iron and endocrine disorders in the family history (р > 0.001). Serum level of cortisol was directly correlated with dental caries (р < 0.05). In children, regardless of BMD value, a direct correlation was established between the radiation dose, age and obesity (р < 0.001). CONCLUSIONS: Higher than normative BMD is accompanied by an increased frequency of bone fractures, jaw abnormalities, metabolic changes in bone tissue and bone tissue hormonal regulation in children, which requires application of pathogenetic therapy for the osteogenesis.

EFFECT OF IRON ON BONE TISSUE METABOLISM AND THYROID FUNCTION IN CHILDREN LIVING ON RADIOLOGICALLY CONTAMINATED TERRITORIES SINCE THE ChNPP ACCIDENT. / VPLYV ZALIZA NA PROTsESY METABOLIZMU V KISTKOVII TKANYNI TA FUNKTsIIu ShchYTOPODIBNOÏ ZALOZY UDITEI, IaKI ZhYVUT' NA RADIOAKTYVNO ZABRUDNENYKh TERYTORIIaKh PISLIa AVARIÏ NA ChAES.

OBJECTIVE: To assess the metabolic processes in bone tissue and state of thyroid gland depending on iron metabolism parameters in children of pre-pubertal, pubertal and post-pubertal age, living on radiologically contaminated territories after the ChNPP accident. MATERIALS AND METHODS: Children (n = 119) aged 6 to 18 years were examined and the 4 study groups were formed, featuring the childhood, pre-pubertal, pubertal and post-pubertal life periods. Clinical symptoms, iron metabolism parameters (serum iron (SI) and ferritin (SF) content, transferrin saturation coefficient), parameters of bone tissue metabolism (serum creatinine and alkaline phosphatase (APh)), and amino acid content in urine were taken into account. Functional state of thyroid, titers of antibodies to thyroperoxidase (TPOAb) and thyroglobulin (TgAb) were assayed. Results and their discussion are presented depending on the age of children, biochemical parameters of blood, iron metabolism findings, thyroid gland function and individualized radiation doses. RESULTS: In 13.4 % of pubertal and post-pubertal children an elevated content of SI and SF was observed. APh levels were increased in 20.2 % of children (758.9 ± 16.3 U/l) being directly correlated with SI levels (rs = 0.50; р < 0.01). In 16.3 % of children of pubertal and post-pubertal age, in whom the level of SI was above 27 µmol/l, a direct correlation with serum thyroid-stimulating hormone (TSH) level was established in case of the hormone content above 2.5 mU/l (rs = 0.50; р < 0.05). Serum creatinine level directly correlated with glycine content in urine (rs = 0.70), which is a part of collagen, and inversely correlated with serum APh (rs = -0.47), (р < 0.05). Under the levels of SI higher than (15.1 ± 1.2) µmol/l and SF higher than (87.5 ± 6.4) ng/ml, the TPOAb titer was higher than at lower iron concentrations (U-test = 64.5, р < 0.05). The TgAb titer directly correlated with SI (rs = 0.39) and TSH (rs = 0.81) levels (р < 0.01). The average effective radiation dose in children was (0.75 ± 0.10) mSv. A direct correlation was established between the child's radiation dose and age (rs = 0.33; р < 0.05). CONCLUSIONS: Bone metabolism depends on the age of children, characteristics of pubertal period, excess of iron in the body, and functional state of thyroid system, which is involved in collagen formation and protein metabolism.

ASSESSMENT OF QUALITATIVE CHANGES IN PERIPHERAL BLOOD CELLS IN CHILDREN - RESIDENTS OF RADIOLOGICALLY CONTAMINATED TERRITORIES IN THE LATE PERIOD AFTER THE ChNPP ACCIDENT. / OTsINKA IaKISNYKh ZMIN V ELEMENTAKh PERYFERYChNOÏ KROVI U DITEI ­ MEShKANTsIV RADIOAKTYVNO ZABRUDNENYKh TERYTORII U VIDDALENYI PERIOD PISLIa AVARIÏ NA ChAES.

OBJECTIVE: to establish the relationship between quantitative and qualitative parameters of peripheral blood cells(lymphocytes, neutrophilic granulocytes, monocytes, platelets) depending on the type of somatic diseases andannual internal radiation doses from 137Cs in children - residents of radiologically contaminated territories in thelate period after the Chornobyl Nuclear Power Plant (ChNPP) accident. MATERIALS AND METHODS: There were 175 children included in the study comprising residents of radiologically con-taminated territories (n = 79) aged from 4 to 18 years. Annual internal radiation doses in children from 137Cs rangedfrom 0.004 to 0.067 mSv. Certain blood parameters were assessed in a comparative mode in children having got theradiation doses up to 0.01 mSv and higher. The comparison group (n = 96) included children living in settlementsnot attributed to the radiologically contaminated ones. Incidence and type of somatic diseases and its impact onquantitative and qualitative changes in blood parameters (i.e. lymphocyte, neutrophilic granulocyte, monocyte, andplatelet count) were studied. The cell size, state of nucleus, membranes and cytoplasm, signs of proliferative anddegenerative processes were taken into account. RESULTS: Incidence and type of somatic diseases in children did not depend on the annual internal radiation dose.Number of cases of monocytosis was significantly higher among the children exposed to ionizing radiation than inthe comparison group (16.6 % vs. 7.3 %). There were, however, no correlation between these changes and radiationdoses. Number of activated blood monocytes with cytoplasmic basophilia and residues of nucleoli in nuclei washigher in individuals with internal radiation doses > 0.01 mSv. A direct correlation between the qualitative param-eters of monocytes and internal radiation doses was established (rs = 0.60; р < 0.001), as well as a direct correlationof different strength between qualitative parameters of blood cells, indicating their unidirectional pattern depend-ing on the somatic morbid conditions. Regardless of annual internal radiation dose, there was an increase in thenumber of degenerative and aberrant cells vs. the comparison group (р < 0.05), which could be due to the role ofnon-radiation factors. CONCLUSIONS: Results of the assessment of quantitative and qualitative parameters of peripheral blood cells reflect-ed the state of morbid conditions in children and are of a diagnostic value. The identified dose-dependent changesin monocyte lineage of hematopoiesis may be the markers of impact of long-term radionuclide incorporation withfood in children living in environmentally unfavorable conditions after the ChNPP accident.

THYROID DISEASE IN THE LATE OBSERVATION PERIOD UPON CHEMO AND RADIOTHERAPY IN CHILDREN/SURVIVORS OF ACUTE LYMPHOBLASTIC LEUKEMIA. / KhVOROBY ShchYTOPODIBNOÏ ZALOZY PISLIa KhIMIO TA PROMENEVOÏ TERAPIÏ U DITEI, IaKI PERENESLY GOSTRU LIMFOBLASTNU LEIKEMIIu, U VIDDALENOMU PERIODI SPOSTEREZhENNIa.

OBJECTIVE: to assess the thyroid disease in the late observation period in children who had received chemo- andradiotherapy for the acute lymphoblastic leukemia (ALL) taking into account gender, age period and disease sub-type. MATERIALS AND METHODS: The incidence and nature of thyroid disease (hypothyroidism, thyroiditis, and thyroid can-cer) were studied in children-survivors of acute lymphoblastic leukemia (ALL) being in remission from 6 to 25 years.The distribution of patients by leukemia subtypes was as follows: «common¼ - 67.4 %, pre-B - 23.9 %, pro-B andT-cell - 4.3 %. Children had been receiving chemo- and radiotherapy according to the protocol. Regarding the ageof patients at the time of ALL diagnosis the prepubertal, pubertal and postpubertal periods were taken into account.The endocrine diseases in family history, body weight at birth, serum content of free thyroxine, pituitary thyroid-stimulating hormone, cortisol, iron, ferritin and thyroperoxidase antibodies were evaluated and assayed. RESULTS: Thyroid disease in children was emerging in the first 2-3 years after the ALL treatment with an incidenceof 22.8 % (hypothyroidism - 14.1 %, autoimmune thyroiditis - 7.6 %, papillary cancer - 1.1 %). Seven children inthis group had received radiotherapy (12-18 Gy doses) on the central nervous system (CNS). No correlation wasfound between the radiation exposure event itself, radiation dose to the CNS and thyroid disease in the long-termfollow-up period. Thyroid cancer had developed in a child 11 years upon chemo- and radiotherapy. Hypothyroidismwas more often diagnosed in the patients of prepubertal age (rs = 0.49). There were endocrine diseases in thefamily history in about a half of children, being significantly higher than in the general sample (р < 0.05). The bodyweight at birth of a child who had later developed hypothyroidism was less than in children having got thyroiditis(rs = 0.57). CONCLUSIONS: Disorders in endocrine regulation and of thyroid in particular can affect the prognosis of blood can-cer course in the long-term follow-up in children, especially in prepubertal age, which requires systematic supervi-sion by hematologist and endocrinologist.

ENDOCRINE REGULATION OF ERYTHROID LINEAGE OF HEMATOPOIESIS IN CHILDREN LIVING UNDER A LOW-DOSE RADIATION EXPOSURE AFTER THE CHORNOBYL NPP ACCIDENT. / ENDOKRYNNA REGULIaTsIIa ERYTROTsYTARNOÏ LANKY GEMOPOEZU V DITEI, IaKI ZhYVUT' NA RADIOAKTYVNO ZABRUDNENYKh TERYTORIIaKh PISLIa AVARIÏ NA ChAES.

OBJECTIVE: Elucidation of relationship between the levels of thyroid-stimulating hormone (TSH), free serum thyroxine, serum and urine cortisol and parameters of erythroid lineage of hematopoiesis to estimate the thyroid functionin children of prepubertal, pubertal, and postpubertal age permanently residing under a low-dose radiation exposureto determine the premorbid state of thyroid function. MATERIALS AND METHODS: Children aged 3 to 18 years old (n = 203) living in the most intensively radionuclide-contaminated regions of Kyiv, Zhytomyr and Chornihiv oblasts of Ukraine after the Chornobyl NPP accident wereenrolled. Complaints of ossalgia, arthralgia, fatigue, bone fractures in the history, bone dysembryogenetic stigmata,hypermobility syndrome degree, and types of somatic diseases were taken into account. Peripheral blood countparameters, biochemical indices of blood serum were studied, namely the levels of total protein, cholesterol, creatinine and alkaline phosphatase activity. Levels of the free thyroxine, pituitary TSH, serum and daily urine cortisol, anddoses of radiation exposure were determined. RESULTS: The radiation dose values in children ranged from (0.35 ± 0.09) mSv to (0.54 ± 0.12) mSv. There was nodifference between the parameters of erythroid lineage of hematopoiesis depending on radiation dose. At the levels of serum TSH up to 1.0 µIU/ml no correlation was found with cortisol levels; at TSH levels of 1.0-3.0 µIU/ml thecorrelation coefficient was r = 0.31; at TSH levels higher than 3.0 µIU/ml the correlation coefficient was r = 0.61probably indicating a compensatory role of adrenal cortex in children at risk of thyroid disease development. In children with joint hypermobility grade II there was a higher incidence of dentofacial anomalies (χ2 = 6.9), deformitiesof lower extremities (χ2 = 6.9), and dental caries (χ2 = 4.3) (p < 0.05). There was a direct correlation between theserum TSH level (over 3 µIU/ml) and micrognathia (brachygnathia) (r = 0.62) indicating the impact of thyroid disease on dentofacial development. The TSH at a level of upper limit of the reference range values may contribute toa decreased RBC count in peripheral blood, increased average volume and hemoglobin content in erythrocyte beingassociated with the initial manifestations of thyroid dysfunction. CONCLUSIONS: Abnormal endocrine regulation of hematopoiesis affects the connective tissue, stromal microenvironment of bone marrow, and accordingly the erythroid branch of hematopoiesis in children, which may be relevant inthe development and course of oncohematological diseases.

PROGNOSIS OF ACUTE LEUKEMIA DEPENDING ON THE IRON METABOLISM PARAMETERS IN CHILDREN AFTER CHORNOBYL NUCLEAR POWER PLANT ACCIDENT. / PROGNOZ PEREBIGU GOSTRYKh LEIKEMII U DITEI PISLIa AVARIÏ NA ChAES ZALEZhNO VID OBMINU ZALIZA.

OBJECTIVE: To determine the influence of iron metabolism on the prognosis of acute lymphoblastic (ALL) and (AML)myeloblastic leukemia at the different phases of chemotherapy in children after Chоrnobyl accident. MATERIALS AND METHODS: 333 children (295 - ALL, 38 - AML) were examined at the stages of chemotherapy. Thecomparison group included 93 children without leukemia. Acute leukemia variants, patients survival, relapses, thenature of disease (live child or died), iron methabolism (morphometric parameters of erythrocytes, SI, SF, STf, TS),manifestations of dyserythropoiesis, bone marrow sideroblast and patients radiation dose were taken into account. RESULTS: In 295 patients with ALL the following variants of leukemia were established: pro-B-ALL in 23, «common¼type of ALL in 224, pre-B-ALL in 29, T-ALL in 19. Thirty eight patients were diagnosed with AML (11 - M1, 19 - M2,8 - M4). Doses of radiation in patients with AL were (2.78 ± 0.10) mSv and they did not correlate with clinical andhematological parameters, disease variant. Relapse rates and shorter survival were in patients with T-ALL, pro-B-ALLand AML with SF levels > 500 ng/ml (p < 0.05). The amount of children with normochromic-normocytic anemias andmanifestations of dysplasia of erythroid lineage elements was greater in the AML than in ALL. SF content in patientswas elevated during chemotherapy and was lower than the initial one only in the remission period. Transferrin wasreliably overloaded with iron: TS (70.2 ± 2.3) % compared with the control group (32.7 ± 2.1) %. Correlationbetween TS and survival of patients was detected (rs = -0.45). Direct correlation between the number of iron granules in erythrocariocytes and SF level (rs = 0.43) was established, indicating the phenomena of ineffective erythropoiesis. CONCLUSIONS: The negative influence of iron excess in the patients body on the hemopoiesis function, manifestations of ineffective erythropoiesis and the course of acute leukemia in children have been established. Changes inferrokinetic processes in children can be the basis of leukemоgenesis development.

FEATURES OF CLINICAL SYMPTOMS AND SIGNS, HEMATOLOGICAL AND BIOCHEMICAL PARAMETERS IN CHILDREN WITH JOINT HYPERMOBILITY IN A LATE PERIOD UPON THE CHORNOBYL NPP ACCIDENT. / OSOBLYVOSTI KLINIChNOÏ SYMPTOMATYKY, GEMATOLOGIChNYKh TA BIOKhIMIChNYKh POKAZNYKIV U DITEY̆ Z GIPERMOBIL'NISTIu SUGLOBIV U VIDDALENYY̆ PERIOD PISLIa AVARIÏ NA ChORNOBYL'S'KIY̆ AES.

OBJECTIVE: establishing the types and frequency of disembriogenetic stigma in children with joint hypermobility given the clinical and laboratory features, genetic component and endocrine regulation of these disorders in a late period upon the accident. MATERIALS AND METHODS: Children (n = 109) inhabiting the radiologically contaminated territories and having the connective tissue dysplasia (CTD) signs were involved in the study. Diseases in family history, ossalgia complaints, fractures in a personal history, bone disembriogenetic stigma, joint hypermobility, type of somatic diseases, blood serum biochemical parameters (namely calcium, alkaline phosphatase, total protein, cholesterol, creatinine, iron, ferritin content), serum cortisol, free thyroxine, pituitary thyroid-stimulating hormone (TSH) levels, free amino acid composition in urine and radiation dose were considered. RESULTS: Radiation doses in children having the CTD ranged from (0.37 ± 0.11) mSv to (0.56 ± 0.10) mSv with no difference from that in those without CTD. Joint hypermobility (JHM) correlated with cancer in family history (rs = 0.53) and lower extremity varicose vein disease (rs = 0.40) (p < 0.05). Incidence of ossalgia, easy fatigability, and bone fractures was higher in children with CTD. Anomalies of the dentofacial system were first in line (38.5 %) in these children. Proportion of children with grade II JHM and platypodia was lower (rs = 0.42), but with lower extremity deformations was higher (rs = 0.68) (p < 0.05) vs. in the control group. Iron and ferritin deficiencies both with lymphocytosis were more common in children with CTD than in the comparison group (p < 0.05). The increased content of oxyproline, lysine, proline both with glycine deficiency were detected in children having the CTD, i.e. an imbalance of amino acids from the collagen content was observed featuring a predominance of catabolic processes over anabolic ones. There was a direct correlation between the TSH level and the JHM grade (rs = 0.49), although the values of hormone concentration in these children did not exceed the reference range (maximum values were 3.3 µIU/ml). CONCLUSIONS: The revealed abnormalities in amino acid content, ferrokinetics, and thyroid function indices can affect the collagen formation, organic matrix structure of bone tissue and significantly deregulate the hemato- poiesis. The later can underlie the pathways of haematologic malignancy development.

PROGNOSIS OF THE COURSE OF CHORNOBYL-ORIGINATED ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN IN UKRAINE DEPENDING ON THE REASON OF STANDARD CHEMOTHERAPY INTERRUPTION. / PROGNOZ PEREBIGU GOSTRYKh LIMFOBLASTNYKh LEY̆KEMIY̆ ChORNOBYL'S'KOGO POKhODZhENNIa U DITEY̆ UKRAÏNY ZALEZhNO VID PRYChYN PERERV PRY PROVEDENNI STANDARTNOÏ KhIMIOTERAPIÏ.

OBJECTIVE: Estimation of the bone marrow haemopoietic status depending on the reasons and duration of breaks in a standard chemotherapy (BFM-ALL protocol) to predict the course of acute lymphoblastic leukemia (ALL) in chil- dren exposed to low doses of ionizing radiation after the Chornobyl accident. MATERIALS AND METHODS: The ALL patients (n = 34) were examined within 5 stages of a program chemotherapy. The clinical symptoms, hemogram and myelogram data were analyzed. The radiation dose on bone marrow, initial leuko- cyte count, variants and prognosis of ALL course were accounted. Days of the stopped chemotherapy, type and fre- quency of complications (septic processes, febrile neutropenia, toxic hepatitis, granulocytopenia degree), and the prognosis of disease course (child living status, i.e. alive or died) were estimated. RESULTS: There were abnormal differentiation processes and high percentage of lymphoblasts (86.2 ± 3.3) % in bone marrow in the 1st acute period. Hematological remission was established in all patients on the 33rd day of chemothe- rapy. In a half of cases the haematopoietic recovery occurred by a granulocyte-monocyte type. One third of patients presenting an erythroid type of haemopoiesis died later. The inverse correlation was found between the number of myelocaryocytes and disease prognosis (rs = -0.49). Breaks in chemotherapy for various reasons were recorded. The number of patients with granulocytopenia was greater at the phase 1 and 2 of protocol I and protocol M application, coinciding with a higher incidence of complications. An inverse correlations between the prediction of ALL course and sum of days of breaks between the protocol M and phase 1 of protocol II (rs = -0.56), as well as the duration of the phase 2 of protocol II (rs = -0.62) were found. The radiation dose on bone marrow was (5.37 ± 1.23) mSv. No relationship was found between the radiation doses, ALL variants and disease course. CONCLUSIONS: Prognosis of ALL course in children depends on the type of haemopoietic recovery and reasons of breaks in a standard chemotherapy. Interaction between the haemopoiesis functioning and microenvironment and that of their regulation are the key mechanisms of above-mentioned abnormalities, which is the basis for further research.

Childhood leukemia in Ukraine after the Chornobyl accident.

This population-based ecological study analyzes the prevalence of childhood leukemia in Ukraine before and after the Chornobyl nuclear power plant accident, based on the contamination status of the territory, time period, gender, and age. Three regions-Zhytomyr, Kyiv (except Kyiv city), and Chernihiv were included as areas contaminated by radioactive 137Cs from 1 to 15 Ci/km2 with annual effective doses exceeding 1.0 mSv, and Sumy region as the control (non-contaminated) area with 137Cs contamination less than 1 Ci/km2 and effective doses less than 0.5 mSv per year. The integrated database of the National Research Centre for Radiation Medicine used in the present study included 1085 childhood leukemia cases. Two aggregated periods were used for analysis: 1980-1986 (pre-accident) and 1987-2000 (post-accident). ICD-9 codes for leukemia (204-208.9) were used to perform analyses according to the extent of leukemic cells maturity (acute, chronic, and maturity unspecified leukemia), leukemic cell lineage (lymphoid, myeloid and lineage unspecified leukemia) and all leukemia cases in different age subgroups (1-4, 5-9, 10-14, and 15-19 years). Standard methods of descriptive epidemiology were used to calculate the prevalence of disease and frequency ratio in regression models. A statistically significant increase in frequency ratio for acute leukemia (1.44; 95% confidence interval (CI), 1.22-1.71), myeloid leukemia (2.93; 95% CI, 1.71-5.40), cell lineage unspecified leukemia (II) (1.48; 95% CI, 1.18-1.87) and all forms of leukemia (1.59; 95% CI, 1.36-1.86) was found for the post-accident period in highly contaminated areas. The results indicate that the frequency of childhood leukemia (and of some of its types) increased in contaminated areas during the post-accident period, suggesting that radiation exposure after the Chornobyl accident might be the cause of the increase. However, further analytical studies, with individual or at least group dose estimates, are needed to confirm a link between childhood leukemia and the Chornobyl accident.

EFFECT OF SOMEUNFAVORABLE FACTORS OF ENVIRONMENT ON THE SURVIVAL OF CHILDREN WITH ACUTE LEUKEMIA IN A LONG6TERM PERIOD AFTER ACCIDENT ON THE CHORNOBYL NPP. / VPLYV DEIaKYKh NESPRYIaTLYVYKh ChYNNYKIV DOVKILLIa NA VYZhYVANIST' DITEI Z GOSTRYMY LEIKEMIIaMY U VIDDALENYI PERIOD PISLIa AVARIÏ NA ChORNOBYL'S'KII AES.

OBJECTIVE: Determine of the influence of adverse environmental factors, including irradiation, on the survival ofchildren with acute leukemia in the long-term period after the Chornobyl accident (2008-2017). MATERIALS AND METHODS: Examined 74 children with acute leukemia (АL): 64 with acute lymphoblastic leukemia(ALL); 10 - acute myeloblastic leukemia (AML). The influence of negative environmental factors was assessed bythe degree of integrated pollution of the atmospheric air, surface waters and soils with pesticides, heavy metals (Pb,Cu, Ni, Cr, Mn, Zn, Fe) and cesium isotope 137Cs. These regions were ranked on a moderately polluted (1), polluted (2),very (3) and extremely (4) polluted territories. Took into account the age of children, blood test, immunophenotyp-ic of variant the acute leukemia, survival of patients and place of residence (city / village), serum ferritin level (SF). RESULTS: Exposure doses of children were in the range from 0.4 mSv to 35.0 mSv (average values were (4.25 ± 0.63 mSv)and did not affect the prognosis and variants of AL. 52 children lived in moderately and polluted territories (30 wereresidents of cities, 22 - villages). 22 patients were lived in very and extremely polluted territories (4 were residentsof cities, 18 - villages). Of 74 patients with ALL and AML 24 children died (32.4 %). The smallest number ofchildren, who died, were patients with «general type¼ В-ALL (18.7 %), most of all children with pro-В-ALL (8 out of10) and Т-ALL (3 of 4). Of the 52 patients, the inhabitants of moderately and polluted regions, 13 patients died (25%), while out of 22 patients, who lived in very and extremely polluted areas, 11 children died (50 % share)(rs = 0.39; p < 0.05). Of the 10 patients with AML, 4 children died. Most often, children died, who were residents ofvillages. Moreover, the level of SF was significantly higher in children over 6 years, the inhabitants of villages -(406.8 ± 40.6) ng/ml, compared to younger patients - (211.2 ± 32.1) ng/ml) and residents of of cities: up to 6years - (297.4 ± 52.3) ng/ml; over 6 years - (275.6 ± 29.8) ng/ml. CONCLUSIONS: The obtained data testify to the negative influence of environmental factors, including iron, and canbe the basis for understanding the mechanisms of potentiating influence of metals and their compounds on thedevelopment of malignant diseases of the blood system in children.

Cortisol level as risk factor for malignant hematologic pathology in children exposed to ionizing radiation after Chornobyl accident. / STAN ERYTROÏDNOÏ, GRANULOTsYTARNOÏ TA TROMBOTsYTARNOÏ LANOK GEMOPOEZU NA ETAPAKh KhIMIOTERAPIÏ U DITEY̆ Z GOSTRYMY LIMFOBLASTNYMY LEY̆KEMIIaMY, IaKI ZAZNALY VPLYVU IONIZUIuChOGO VYPROMINIuVANNIa VNASLIDOK AVARIÏ NA ChAES.

OBJECTIVE: Determination of serum cortisol level in the initial period of acute leukemia in children, who exposed to ion izing radiation and other factors of Chornobyl accident, depending on their age and prognosis of disease. MATERIALS AND METHODS: The study involved 283 children residents of Kyiv, Zhytomyr and Chernihiv regions. There were 90 acute leukemia patients(AL) (ALL - 56, AML - 34), and 193 people of comparison group with anemia, leukemoid reactions and lymphadenopathy. We analyzed the type of comorbid somatic pathology, diseases in the genealogy, hematological parameters, cortisol levels in blood serum and irradiation doses in all children. In patients with AL expected median survival was calculated. RESULTS: In 28.9 % of AL children the initial cortisol content was below 200 nmol/l, in 7.8 % - higher than 500 nmol/l (in the comparison group 10.4 % and 17.1 % respectively). Among AL patients with cortisol levels below 200 nmol/l were significantly less amount of persons with chronic bacterial infections and persistent viral infections (CMV, EBV) and in the genealogy of these children allergic reactions, endocrine pathology diagnosed more often compared with patients, whose hormone levels was higher than 200 nmol/l (p < 0.05). Distribution of children from control group by gradations of cortisol, age groups, defined somatic pathology and diseases in genealogy had no difference. It is shown, that lower initial blood serum cortisol level in ALL children correlates to a greater probability of relapse (Rs = -0,67). In patients with AML a direct correlation between cortisol level and median survival was detected (Rs = 0,79). Children radiation doses were ranging from 0.08 mSv to 14.9 mSv, and there were slightly higher among residents of Zhytomyr region (8.4 ± 1.2 mSv) compared to other regions. However, these doses did not affect blood serum cortisol levels in children and the course of AL. CONCLUSIONS: These data suggest the need for correction and individualization of corticosteroid doses for optimization of AL patients treatment. Children, who have lower than normative serum cortisol levels are at increased risk of hema tologic pathology and they need for hematologic monitoring.

State of erythroid, granulocyte and platelet branches of hematopoiesis on stages of chemotherapy in children with acute lymphoblastic leukemia, who were exposed to ionizing radiation after the Chornobyl NPP accident. / STAN ERYTROÏDNOÏ, GRANULOTsYTARNOÏ I TROMBOTsYTARNOÏ LANOK GEMOPOEZU NA ETAPAKh KhIMIOTERAPIÏ U DITEY̆ Z GOSTRYMY LIMFOBLASTNYMY LEY̆KEMIIaMY, IaKI ZAZNALY VPLYVU IONIZUIuChOGO VYPROMINIuVANNIa VNASLIDOK AVARIÏ NA ChAES.

OBJECTIVE: Evaluation of proliferation and differentiation processes of progenitor cells in bone marrow by the com position of elements of erythroid, granulocyte and platelet branches of hematopoiesis on the treatment stages in children with acute lymphoblastic leukemia (ALL), who were exposed to radiation from the Chornobyl NPP accident. MATERIALS AND METHODS: The 46 children with ALL were studied, who lived in Kyiv, Zhytomyr and Chernihiv regions. Studies were conducted before the start of chemotherapy (ChT), on the 33 day of ChT (phase I), and after the com pletion of ChT (phase II). Exposure doses of patients, hemogram and myelogram parameters both with indices of mat uration of progenitor cells were evaluated. Signs of dysplasia of hematopoietic branch elements were revewed. RESULTS: The 46 patients were studied. They have had the B ALL, namely pro B ALL (n=5), «common type¼ (n=36), pre B ALL (n=3), and T ALL in 2 other cases. In a debut of ALL the bone marrow was represented by lymphoblasts. Along with ChT conduction the bone marrow hematopoiesis recovered by such types, as erythroid, granulocyte, gran ulocyte whith monocytes, and uniform, when the cells number of all branches was within a normal quantity. At the phase ІІ of ChT the number of patients with hematopoiesis recovery by erythroid type decreased and number of chil dren with activation of granulocyte branch of hematopoiesis increased. In children with pro B ALL the number of erythroid elements was higher than normative at both ChT phases. A direct correlation was established between the number of myelokaryocytes (Mkc) and megakaryocytes (Mgkc) in both phase І and phase ІІ of treatment (Rs = +0.72; Rs = +0.56, respectively). There was no correlation between the radiation dose in patients (3.73 ± 0.12 mSv) and studied parameters. CONCLUSIONS: Types of bone marrow recovery were established in ALL patients after the ChT indicating to the differ ent kinetic pathways of hematopoietic progenitor cells. Evaluation of reasons of prevalence of some hematopoietic branches will allow to reveal their role in leukemogenesis and to correct the treatment programs.

Effect of radiation and non radiation environmental factors on children hematopoietic system. / VPLYV RADIATsIY̆NYKh TA NERADIATsIY̆NYKh FAKTORIV DOVKILLIa NA STAN SYSTEMY KROVOTVORENNIa DITEY̆.

OBJECTIVE: Identification of impact of radiation and non radiation environmental factors on development of hematopoi etic abnormalities in children and justification of criteria for the increased risk groups of hematologic diseases. MATERIALS AND METHODS: The results of clinical and hematological survey of 1465 children living in Kyiv, Zhytomyr and Chernihiv regions for the period from 2008 to 2014 were presented. There were 777 children with anemia, 466 with changes in hemogram, 191 with acute leukemia. The irradiation doses, correlation of integrated pollution degree of territories with hematopoietic parameters and course hematologic diseases were estimated. Metal con tent in hair, nails, and blood was determined in 121 children. RESULTS: We have found the most common cause of anemia in children and peculiarities of acute leukemia depend ing on the area integrated contamination. Number of children living in contaminated areas with pro B ALL and T ALL having an initial leukocytosis and unfavorable course of the disease was higher compared to the number of patients from moderately polluted regions (r = 0.47). There is a direct correlation between percentage of children with monocytosis and degree of territory contamination: the 20.2 % of such children lived in the intensively polluted areas and 10,3 % in moderately contaminated ones (p < 0.05). Content of Pb, Cu, Cr, Mn, Zn in biological tissues did not exceed the permissible MAC. Level of Zn in all children was at the lower normal threshold. Individual levels of metals in hair, nails and blood did not depend on gender of patients and their radiation doses. Criteria of increased risk of hematologic diseases in children living in ecologically unfavorable regions were grounded. CONCLUSIONS: Radiation and non radiation environmental factors influencing the development of changes in hematopoiesis and characteristics of the blood system diseases in children play a role in leukeima development processes. These findings are the basis for a further research in the field of radiobiology and ecology.

Evaluation of median survival patients with acute lymphoblastic leukemia exposed to ionizing radiation by the Chornobyl accident, depending on the aminoacid composition of stromal fibroblasts bone marrow and indicators of myelogram. / OTsINKA MEDIANY VYZhYVANOSTI KhVORYKh NA GOSTRI LIMFOBLASTNI LEYKEMII, IaKI ZAZNALY VPLYVU IONIZUIu ChOGO VYPROMINENNIa VNASLIDOK AVARII NA ChAES, ZALEZh NO VID AMINOKYSLOTNOGO SKLADU STROMAL'NYKh FIBROBLASTIV KISTKOVOGO MOZKU TA POKAZNYKIV MIIeLOGRAMY.

OBJECTIVE: To investigate the aminoacid composition in the stromal fibroblasts of bone marrow and indexes of hemogram in children with acute lymphoblastic leukemias, which exposed to radiation from the Chornobyl accident, for evaluation of the median survival. MATERIALS AND METHODS: In the study 54 patients with acute lymphoblastic leukemia, residents of Kyiv, Zhytomyr and Chernihiv regions of Ukraine were involved. Effectiveness of stromal fibroblasts colony forming units of bone marrow and aminoacid composition of fibroblasts were studied. Bone marrow examination was conducted on day33 and after stop of chemotherapy, the median survival of patients and exposure dose were evaluated. RESULTS: In children with acute leukemias effectiveness of stromal fibroblasts of bone marrow was 2-2,3 times lower than normative. Correlation (rs = +0,83) between the number of erythroid progenitor cells in the bone marrow and proline content in stromal fibroblasts established . The correlation between patients median survival and number of granulocytes in myelogram (rs = + 0,82) was proven. Mean exposure doses in patients was (5,86 ± 1,11) mSv and it did not correlate with myelogram results, effectiveness of stromal fibroblasts of bone marrow and median survival. CONCLUSIONS: The median survival of patients with acute leukemias depends on the content of amino acids in stro mal fibroblasts of bone marrow and recover of hematopoiesis after chemotherapy.

Rationale treatment and preventive measures for correction of bone structure in children with acute leukemia, exposed to ionizing radiation due to the Chornobyl accident. / Ocinka likuval''no-profilaktychnyh zahodiv dlja korekcii' struktury kistkovoi' tkanyny u ditej z gostrymy lejkemijamy, jaki zaznaly vplyvu ionizujuchogo vyprominennja vnaslidok avarii' na ChAES.

Objective. To justify and evaluate the effectiveness of treatment and preventive measures taken to correct the bio-chemical and biophysical changes in the structure of bone in children exposed to ionizing radiation due to Chornobyl accident in the dynamics of leukemic process. Materials and methods. The study involved 144 patients with acute lymphoid and myeloid leukemia. Serum calcium, total protein, alkaline phosphatase, cortisol and thyroid-stimulating hormone were investigated, as well as calcium and phosphate excretion, amino acids composition in the urine, acid-base balance and buffer systems of blood, bone density. Results. A reduction of bone densitometry, calcium and cortisol levels and increase of serum alkaline phosphatase and urine oxyproline were found in children with acute leukemia in acute I phase and during the chemotherapy. In the period of remission the majority of patients did not differ from the comparison group. The signs of osteopenic syndrome that require monitoring of the bone structure status were revealed in 10.0 % of children of the comparison group. Radiation doses of leukemia patients were 3.66 ± 0.11 mSv. No relationship between radiation dose and indicators that reflect the state of the bone tissue structures has been established. The use of complex health care measures in children with acute leukemia in remission, contributed to the positive effect of 62.0 %. Worser effect was observed in patients with an unfavorable course of the disease. Conclusions. Results of the study of bone tissue metabolism prove fore a change in the organic and mineral matrix in patients with acute leukemia exposed to ionizing radiation as a result of the Chonobyl NPP accident, and persons without hematologic diseases, and the need for treatment and prevention.

Lymphocytosis in children after the Chornobyl NPP accident.

OBJECTIVE: To establish the sources of lymphocytosis in children living in ecologically unfavorable conditions after the Chornobyl Nuclear Power Plant accident aiming the high risk group formation for oncohematological diseases among the children's population. MATERIALS AND METHODS: The 226 children with lymphocytosis were surveyed. The of child's life history and kind of somatic morbidity were considered. Quantitative and qualitative parameters of blood cells, biochemical indices including immunoglobulins (A, M, G), circulating immune complexes, phagocytosis indices were assayed. RESULTS: Children with lymphocytosis were more often born with a high bodyweight, they demonstrated manifestations of constitutional lymphatism, lymphadenopathy and more often had respiratory infections. Quantitative and qualitative changes of hemopoietic elements depended on a type of a disease. Activation of lipid peroxidation, dysimmunoglobulinemia and increased level of circulating immune complexes were revealed. Treatment and preventive actions promoted normalization of hemogram indices in 58% of children surveyed. CONCLUSIONS: The abnormalities in immune indices, activated lipid peroxidation in membranes of hemopoietic elements, and manifestations of granulocytopoietic disorders were established it children with lymphocytosis. Therefore these children can be attributed tot the group of increased risk on oncohematological disease.

[The role of radiation and non-radiation factors in the development and progression of acute leukemia in children].

At 278 ALL and AML patients the kind of hereditary pathology in the family; clinikal-laboratory features and a course of acute leukemia and terms of longevity of children were studied. Degree of integrated pollution of territory (air, water, soil) by heavy metals and radionuclides and also the irradiation doses have been considered. Results which have been received testify about the certain contribution of genetic components and adverse factors of environment in of development of acute leukemia and their course at children. The definition of different leukemogenic factors action on the condition of hemopoietic system gives the chance to generate the abnormally high risk groups of oncological hematological pathologies among the children's population and to improve the diagnostic and treatment-and-prophylactic actions.

[State of bone structures in children with acute leukemia, experiencing unfavorable factors from Chernobyl accident].

The authors present an assessment of bone structure condition in children with acute leukemia. The changes in the collagen molecule, amino acid composition of urine and proteins reparation processes were revealed. Calcium phosphate excretion in the patients urine were increased. The serum osteocalcin level and colony formation efficiency of bone marrow fibroblasts in acute leukemia patients are lower than in control group. In the initial period of the disease 32% of patients have disturbancies in their endocrine status. The bone structure violation is combined with unfavorable disease outcome. The effectiveness of the treatment and prevention steps in acute leukemia patients depends on the leukemic process stage.