Analysis of relative telomere length and apoptosis in humans exposed to ionising radiation

Background: Ionizing radiation could modify lymphocyte function via oxidative damage, DNA breaks, and resulting changes of proliferation, apoptosis and cellular senescence, where telomeres may play a critical role. Aim: To study the effect of low-dose irradiation on the telomere length and apoptosis rates in peripheral blood lymphocytes of irradiated persons. Patients and Methods: A study was performed on 83 peripheral blood samples from the Chornobyl clean-up workers, radiation workers exposed under the professional limits at construction works at the “Shelter” object and healthy controls. Bone marrow leukocyte telomere length was estimated in 15 patients with myelodysplastic syndrome secondary to low-dose radiation exposure and 12 age-standardized healthy donors. Relative telomere length was studied by the combination of a fluorescence hybridization in situ with PNA probe and flow cytometry, apoptosis — by Annexin-V test. Results: A significant relative telomere length decrease has been demonstrated in Chornobyl clean-up workers compared to healthy donors (13.2 ± 0.69 and 18.6 ± 0.73 respectively, p < 0.05), and a tendency (p < 0.1) in radiation workers. At doses over professional limits an inverse dependency is demonstrated between the relative telomere length and a number of lymphocytes in early stage of apoptosis. In MDS group a tendency of telomere elongation was demonstrated in bone marrow granulocytes in RAEB-t and RAEB as comparing with RA. Conclusion: This study shows telomere shortening after low-dose irradiation and preservation of these changes even 20 years after exposure. Apoptosis induction is possible by the telomere region changes at least in individuals with shorter telomeres. Apoptosis decrease in MDS clonal transformation is associated with a substantially longer telomeres

IGHV3-21 gene expression in patients with b-cell chronic lymphocytic leukemia in Ukraine

The aim of the study was to evaluate the frequency of IGHV3-21 gene usage and its clinical significance for patients with B-cell chronic lymphocytic leukemia (CLL) in Ukraine. Patients and Methods: Immunoglobulin variable heavy chain (IGHV) gene repertoire was studied in 189 CLL patients using reverse transcribed polymerase chain reaction and direct sequence of amplified products. Results: IGHV3-21 gene expression was found in 11 cases (5.8%), and its frequency was intermediate between Scandinavian (11.7%) and Mediterranean CLL (2.9%) cohorts. The most of cases (9 of 11) belonged to subset with heterogeneous HCDR3 (heteroHCDR3 subset), and only 2 cases – to subset with classical short ARDANGMDV motif (homHCDR3 subset). Six IGHV3-21 cases were mutated and 5 cases were unmutated. All unmutated cases (all were from heteroHCDR3 subset) had similarity of their HCDR3s with previously published sequences. The differences in overall (OS), progression-free (PFS) and treatment-free survival (TFS) for IGHV3-21 positive patients in comparison with CLL patients expressing the other IGHV genes were statistically insignificant. These survival parameters were comparable also for CLL patients with mutated IGHV3-21 gene usage and expression the others mutated IGHV genes. But remarkable feature of IGHV3-21 expressing patients was high incidence of solid tumors. They have developed in 4 IGHV3-21 positive cases (36.4%) and in 10 cases with expression of the others IGHV genes (5.6%, p = 0.0002). Furthermore, in small group of 6 patients with mutated IGHV3-21 gene expression, 3 patients had solid tumors and one underwent Richter transformation. Unmutated IGHV3-21 gene expressed patients had worse OS and PFS in comparison with CLL patients that expressed the others unmutated IGHV genes. Conclusion: Presented data are in agrement with the opinion about negative prognostic significance of IGHV3-21 gene expression regardless its mutation status. IGHV3-21 expression was associated with development of secondary solid tumors. Revealed high level of homology in heteroHDR3s subset might suggest about possible antigenic influence also, in addition to homHCDR3 subset that was proposed earlier.Цель: оценить частоту использования гена IGHV3-21 и его клиническое значение для больных B-клеточным хроническим лимфолейкозом (ХЛЛ) в Украине. Больные и методы исследования: репертуар генов вариабельных участков тяжелых цепей иммуноглобулинов (IGHV) изучали у 189 больных с ХЛЛ с помощью полимеразной цепной реакции на базе обратной транскрипции и прямого сиквенса амплифицированных продуктов. Результаты: экспрессия гена IGHV3-21 выявлена у 11 пациентов (5,8%), что занимает промежуточное положение между Скандинавской (11,7%) и Средиземноморской (2,9%) когортами. Большинство случаев (9 из 11) относились к подгруппе с гетерогенным третьим комплементарнымрегионом (heteroHCDR3 подгуппа) и только 2 случая — к подгруппе с коротким классическим ARDANGMDV мотивом (homHCDR уппа). есть IGHV3-21-позитивных случаев были мутированными и 5 — немутированными. Все немутированные случаи (все из heteroHCDR уппы) имели сходство HCDR3 с анее описанными последовательностями. Различия в общей выживаемости (OS), длительности периода до прогрессии заболевания (PFS) и начала лечения (TFS) для IGHV3-21-позитивных больных были статистически незначимы по сравнению с пациентами с ХЛЛ с экспрессией других IGHV-генов. Указанные параметры также сравнивали между больными ХЛЛ с экспрессией мутированных IGHV3-21- и других IGHV-генов. Отличительной чертой пациентов с экспрессией IGHV3-гена была высокая встречаемость солидных опухолей. Они развились в 4 IGHV3-21-позитивных случаях (36,4%) и в 10 случаях с экспрессией других IGHV-генов (5,6%, p = 0,0002). Кроме того, в небольшой группе больных (6) с экспрессией мутированного IGHV3-21-гена у 3 возникли солидные опухоли и 1 пациента — синдром Рихтера. У больных с экспрессией немутированного IGHV3-21-гена определяли худшие показатели OS и PFS по савнению с пациентами с экспрессией других немутированных IGHV-генов. Выводы: представленные данные согласуются с мнением о самостоятельном негативном прогностическом значении для больных с ХЛЛ экспрессии IGHV3-21-гена вне зависимости от его мутационного статуса. IGHV3-21-экспрессия была ассоциирована с развитием вторичных солидных опухолей. Выявленный высокий уровень гомологии в heteroHDR3s-подгруппе может свидетельствовать о возможном антигенном влиянии в дополнение к антигенному влиянию в homHCDR уппе, что было установлено ране

РАДИОЛОГИЧЕСКИЕ И МЕДИЦИНСКИЕ ПОСЛЕДСТВИЯ ЧЕРНОБЫЛЬСКОЙ КАТАСТРОФЫ

From the position of a 25-years’ experience to overcome the health effects of Chernobyl the dynamics of the radiation environment, the first summarizing at the international level (1988), the results of completed research and practical monitoring are analyzed. Cohort of acute radiation syndrome (ARS) survivors under medical observation at the S.I. "Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine" is the largest. Within the 25 years the functional state of the major organs and body systems, and metabolic homeostasis for this category of persons were studied, a comprehensive assessment of their health, mental and physical performance were given, and risk factors and peculiarities of stochastic and non-stochastic pathology courses were identified, as well as a system of rehabilitation patients after ARS was developed. ARS survivors are suffering from chronic diseases of internal organs and systems (from 5-7 to 10-12 diagnoses at the same time). A correlation between acute radiation effects and specific HLA phenotypes were revealed. The dynamics of the immune system recovery after irradiation was studied. The role and prognostic value of telomere length and programmed cell death of lymphocytes in the formation of the cellular effects of ionizing radiation were determined for the first time. Differences between spontaneous and radiation-induced acute myeloid leukemias were found. Dose-dependent neuropsychiatric, neurophysiological, neuropsychological and neuroimaging deviations were identified after irradiation at doses above 0.3 Sv. It was shown that the lymphocytes of Chernobyl clean-up workers with doses 350 – 690 mGy can induce "the bystander effect" in the non-irradiated cells even after 19 years after exposure. The rates of cancer incidence and mortality of victims, the lessons and key problems to be solved in the third decade after the Chernobyl accident are considered.С позиций 25-летнего опыта преодоления медицинских последствий аварии на Чернобыльской АЭС проанализирована динамика радиационной обстановки, первые обобщения на международном уровне (1988 г.), итоги выполненных научных исследований и практического мониторинга. Когорта больных, перенесших ОЛБ и находящихся под диспансерным наблюдением в ГУ «Научный центр радиационной медицины НАМН Украины», в Украине остается самой многочисленной. За 25 лет изучено функциональное состояние основных органов и систем организма, метаболических процессов и гомеостаза у данной категории лиц; дана комплексная оценка состояния их здоровья, умственной и физической работоспособности, а также определены факторы риска развития и особенности течения стохастической и нестохастической патологии, разработана система реабилитации больных, перенесших острую лучевую болезнь (ОЛБ). Перенесшие ОЛБ и оставшиеся живыми страдают хроническими заболеваниями внутренних органов и систем (от 5–7 до 10–12 диагнозов одновременно). Выявлены коррелятивные связи между острым радиационным эффектом и определенными HLAфенотипами. Исследована динамика восстановления иммунной системы после облучения. Впервые установлены роль и прогностическое значение длины теломер и запрограммированной клеточной гибели лимфоцитов в формировании клеточных эффектов ионизирующего облучения. Найдены различия между спонтанными и радиационно-индуцированными острыми миелоидными лейкемиями. Дозозависимые нейропсихиатрические, нейрофизиологические, нейропсихологические и нейровизуализационные отклонения выявлены после облучения в дозах свыше 0,3 Зв. Показано, что лимфоциты участников ликвидации последствий аварии на ЧАЭС с дозами облучения 350–690 мГр способны индуцировать «эффект свидетеля» в необлученных клетках даже через 19 лет после воздействия радиации. Рассмотрены показатели онкологической заболеваемости, смертности пострадавших, уроки и основные проблемы для решения в третьем десятилетии после Чернобыльской катастрофы

Incidence of multiple myeloma among cleanup workers of the chornobyl accident and their survival

The study presents the updated data on the multiple myeloma (MM) incidence in Ukrainian cleanup workers after the Chornobyl accident and their survival. The epidemiological analysis is based on the extended follow-up period to identify new MM cases for higher statistical power and to collect additional data on the disease course and outcome for the survival analysis. The objective of the study was to analyze the MM incidence and survival in Chornobyl cleanup workers in 1996–2013 in comparison with the national MM statistical data. Materials and Methods: A study cohort consisted of 152,520 male cleanup workers resided in one of 6 regions of Ukraine or Kyiv city and registered in the Ukrainian State Chornobyl Registry (SChR). The Cohort Database was linked to the Ukrainian National Cancer Registry (NCR) Database to identify MM cases and to analyze MM incidence in 1996– 2013. Standardized incidence ratios (SIR) for MM over the period 1996–2013 were calculated as compared to the general population of Ukraine. A 10-year lag period (when incident cases are not considered radiation-related) was applied. One-year and 5-year cause-specific survival of MM cases were calculated as percentage of those who were alive correspondingly for 1 or 5 years after diagnosis among overall diagnosed. By the moment, the 5-year survival rate either for the sub-period 2008–2013 or for the whole study period 1996–2013 cannot be determined. Vital status data were updated according to the recent SChR and NCR information. Results: 75 MM cases diagnosed in 1986–2013 were identified in the studied cohort. 69 of them were included to the incidence analysis considering a 10-year lag period. While the incidence over 15 years after the accident did not differ significantly from the corresponding rate in general population of Ukraine, a tendency to increase was seen in the period from 16 to 21 years after the accident, and significantly increased SIR estimate was revealed for 2008–2013 (SIR 1.86, 95% confidence interval (CI) 1.27–2.44). The highest incidence was detected in 2008–2013 among cohort members diagnosed over the age of 50 years mostly due to the significant excess among those aged 60–69 (SIR 2.46, 95% CI 1.32–3.59). Survival rates in cleanup workers were shown to be higher than in the general population of Ukraine (73.9% and up to 65.0%, respectively). Conclusions: SIR for the 2008– 2013 period, 22–27 years after the accident, demonstrated the significant excess of MM incidence among male cleanup workers. Survival of MM cases is higher in cleanup workers in comparison with that in general population. This article is a part of a Special Issue entitled “The Chornobyl Nuclear Accident: Thirty Years After”

Brain Radiation Information Data Exchange (BRIDE): Integration of experimental data from low-dose ionising radiation research for pathway discovery

Background: The underlying molecular processes representing stress responses to low-dose ionising radiation (LDIR) in mammals are just beginning to be understood. In particular, LDIR effects on the brain and their possible association with neurodegenerative disease are currently being explored using omics technologies. Results: We describe a light-weight approach for the storage, analysis and distribution of relevant LDIR omics datasets. The data integration platform, called BRIDE, contains information from the literature as well as experimental information from transcriptomics and proteomics studies. It deploys a hybrid, distributed solution using both local storage and cloud technology. Conclusions: BRIDE can act as a knowledge broker for LDIR researchers, to facilitate molecular research on the systems biology of LDIR response in mammals. Its flexible design can capture a range of experimental information for genomics, epigenomics, transcriptomics, and proteomics. The data collection is available at:

Radiation and the Risk of Chronic Lymphocytic and Other Leukemias among Chornobyl Cleanup Workers

Background: Risks of most types of leukemia from exposure to acute high doses of ionizing radiation are well known, but risks associated with protracted exposures, as well as associations between radiation and chronic lymphocytic leukemia (CLL), are not clear.
 Objectives: We estimated relative risks of CLL and non-CLL from protracted exposures to low-dose ionizing radiation.
 Methods: A nested case–control study was conducted in a cohort of 110,645 Ukrainian cleanup workers of the 1986 Chornobyl nuclear power plant accident. Cases of incident leukemia diagnosed in 1986–2006 were confirmed by a panel of expert hematologists/hematopathologists. Controls were matched to cases on place of residence and year of birth. We estimated individual bone marrow radiation doses by the Realistic Analytical Dose Reconstruction with Uncertainty Estimation (RADRUE) method. We then used a conditional logistic regression model to estimate excess relative risk of leukemia per gray (ERR/Gy) of radiation dose.
 Results: We found a significant linear dose response for all leukemia [137 cases, ERR/Gy = 1.26 (95% CI: 0.03, 3.58]. There were nonsignificant positive dose responses for both CLL and non-CLL (ERR/Gy = 0.76 and 1.87, respectively). In our primary analysis excluding 20 cases with direct in-person interviews less than 2 years from start of chemotherapy with an anomalous finding of ERR/Gy = –0.47 (95% CI: less than –0.47, 1.02), the ERR/Gy for the remaining 117 cases was 2.38 (95% CI: 0.49, 5.87). For CLL, the ERR/Gy was 2.58 (95% CI: 0.02, 8.43), and for non-CLL, ERR/Gy was 2.21 (95% CI: 0.05, 7.61). Altogether, 16% of leukemia cases (18% of CLL, 15% of non-CLL) were attributed to radiation exposure.
 Conclusions: Exposure to low doses and to low dose-rates of radiation from post-Chornobyl cleanup work was associated with a significant increase in risk of leukemia, which was statistically consistent with estimates for the Japanese atomic bomb survivors. Based on the primary analysis, we conclude that CLL and non-CLL are both radiosensitive.

A qualitative examination of the perceived impact of bureaucratic managerialism on evidence-based practice implementation in Nigeria: a collective case study

BackgroundEvidence-based practice (EBP) is widely recognised as an essential aspect of contemporary healthcare delivery. However, the rise in cost containment and quest for profitability in healthcare management is found to be compromising implementation of evidence-based initiatives aimed at improving care quality.AimsThe aim of this work was to examine perspectives of nurses regarding the impact of bureaucratic managerialism on EBP implementation in the Nigerian acute care setting.MethodsA qualitative case study methodology was utilised to gather data from two large acute care settings. Drawing on semi-structured interviews, 12 staff nurses, 21 ward managers and 2 nurse managers were interviewed. Data were inductively analysed and themes generated.ResultsThe managerial practice in this context is founded on bureaucratic managerialism, which in turn generated hierarchical constraints that denied nurses the opportunity to self-govern. Implementation of evidence-based initiatives was consequently opposed by the managerial desire to maximise throughput.ConclusionsThere is need for nurse managers to have greater managerial influence, which would allow opportunities for implementing EBPs to be created. Managerial autonomy for nurse managers would allow them to create enabling environments capable of facilitating successful implementation

RADIOLOGICAL AND MEDICAL CONSEQUENCES OF THE CHERNOBYL ACCIDENT

From the position of a 25-years’ experience to overcome the health effects of Chernobyl the dynamics of the radiation environment, the first summarizing at the international level (1988), the results of completed research and practical monitoring are analyzed. Cohort of acute radiation syndrome (ARS) survivors under medical observation at the S.I. "Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine" is the largest. Within the 25 years the functional state of the major organs and body systems, and metabolic homeostasis for this category of persons were studied, a comprehensive assessment of their health, mental and physical performance were given, and risk factors and peculiarities of stochastic and non-stochastic pathology courses were identified, as well as a system of rehabilitation patients after ARS was developed. ARS survivors are suffering from chronic diseases of internal organs and systems (from 5-7 to 10-12 diagnoses at the same time). A correlation between acute radiation effects and specific HLA phenotypes were revealed. The dynamics of the immune system recovery after irradiation was studied. The role and prognostic value of telomere length and programmed cell death of lymphocytes in the formation of the cellular effects of ionizing radiation were determined for the first time. Differences between spontaneous and radiation-induced acute myeloid leukemias were found. Dose-dependent neuropsychiatric, neurophysiological, neuropsychological and neuroimaging deviations were identified after irradiation at doses above 0.3 Sv. It was shown that the lymphocytes of Chernobyl clean-up workers with doses 350 – 690 mGy can induce "the bystander effect" in the non-irradiated cells even after 19 years after exposure. The rates of cancer incidence and mortality of victims, the lessons and key problems to be solved in the third decade after the Chernobyl accident are considered

Delayed Immunological Effects of the Acute Radiation Syndrome

Objective. From 237 cases of ARS registered after Chornobyl 134 diagnoses were confirmed. The rest of 103 exposed were regarded as non-confirmed ARS (ARS-0) due to the absence of supportive diagnostic materials or other reasons. Long-term follow-up was performed of 192 survivors who are citizens of Ukraine. Methods. Delayed immunologic effects were studied in 57 ARS grade 0-III survivors 20 years after exposure. Cellular immunity was studied by peripheral blood mononuclear cells and early progenitors subset analysis, p53, bcl2, Bax, CD95 expression, spontaneous and verapamil-induced apoptosis, proliferation tests with Con A, microbial and tissue antigens; oxidative status was studied by MDA, catalase, SOD, β-glucosidase, β-galactosidase activity, antioxidant factor, lipid peroxidation, GSH and ceruloplasmin concentration. Results. Combined radiation induced immune deficiency was demonstrated as the early changes with a period of recovery of 7 to 20 years depending of the exposure dose. In ARS-0 and 1 wavy variations of basic immunity parameters were shown with the tendency to normalization. In ARS-1 and 2 (group doses: 1,34; 1,75 Sv) we registered normal mean parameters of T- and B-cell subsets and oxidative status except of ceruloplasmin. Low expression was shown for CD123w antigen. Immune function deviations were demonstrated in activation tests and induced apoptosis. In ARS-3 (mean dose: 5,6 Sv) a marked immune system deficiency was demonstrated at the group levels (low CD4+, NK-cell counts, high CD8+ with significantly smaller cytotoxic T-cell subset) accompanied with low oxidative stress markers and significantly higher MDA and GSH. Analysis of confounding factors such as endocrine and nervous systems influence and blood viral infections carriage showed a prevalent role of the radiation exposurel a marked dose-effect dependency remained at the late period at individual and group levels. Number of TCR-variant cells correlated with the decreased immune function. Radiation-induced depression of immunity was characterized by the non-stability of CD34+ cells with presence of committed primitive early progenitors not capable for terminal differentiation and apoptosis. High proliferative activity and accumulation of CD34+ cells as an adaptive reaction to radiation exposure in combination with the decreased apoptosis, cytotoxic and NK-cell activity could be the basis for radiation-induced oncologic effects