PGE2 contributes to in vitro MSC-mediated inhibition of non-specific and antigen-specific T cell proliferation in MS patients.

Current theories of multiple sclerosis (MS) induction and progression place autoreactive T cells in the focus of the pathogenesis. Mesenchymal/stromal stem cells (MSC) have become a promising alternative approach for pathogenic therapy of MS due to their immunomodulatory properties, underlying mechanisms of which are intensive study. The objective of the research was to investigate the contribution of PGE2 to MSC-mediated suppression in patients with MS using in vitro model of mitogen- and myelin-stimulated T cell cocultivation with autologous/allogeneic MSC. We have showed that PGE2 production depends on cell-to-cell contact of MSC and lymphocytes. The antigenic stimulation did not affect PGE2 production following cocultivation of MSC and PBMC, and it is the presence of MSC in cell culture that significantly increases PGE2 production irrespective of antigenic cultivation conditions. Simultaneously, PGE2 synthesis correlated with indexes of MSC-mediated suppression of mitogen- and myelin-stimulated T cell proliferation in patients with MS. No significant differences in PGE2 production by autologous and allogeneic MSC have been established. These results have demonstrated that in patients with MS, PGE2 is one of the possible factors of MSC immunosuppression. The interrelation between PGE2 concentrations and T cell proliferation suppression mediated by MSC may explain one of the immune mechanisms of cell therapy, which is crucial for the further proper use of MSC in MS research and pathogenic treatment.

Thyroid cancer in infants and adolescents after Chernobyl.

Studies in children medically exposed to external irradiation more than 50 years ago revealed a considerably increased risk for thyroid cancer. Similarly, a strongly age-dependent risk for thyroid cancer was observed in the Japanese population after the atomic bomb explosions with the highest risk in the group of children below age of 10. After the Chernobyl accident, children from Belarus living in highly exposed regions received mean thyroid doses by radioactive fallout higher by a factor of approximately 2 as compared to the survivors of the atomic bomb explosions. This lead to a radiation related increase of thyroid cancer incidence in children and adolescents with the highest incidence in age group 0-4 years up to now totally amounting to approximately 5 000 cases. For screening of thyroid cancer in children, high resolution ultrasound is the method of choice which has to be complemented by fine-needle aspiration biopsy in suspicious cases. Diagnostic criteria for malignancy in childhood thyroid cancer by ultrasound are hypoechogenicity and irregularity of the outline, subcapsular location of lesions and increased peri-intranodular vascularisation. The treatment strategy for thyroid cancer in children does not differ substantially from the approach used in adults. Primary treatment consists of thyroidectomy and lymph node dissection. Careful and complete removal of the lymph nodes is of great clinical relevance in children because of very frequent node involvement (between 40% and 90%). Because of the high prevalence of lymph node metastases, ablation of thyroid remnants is mostly indicated in children with thyroid cancer. Distant metastases which need higher activities of radioiodine are less frequent with 10-20%. Even in advanced cases of childhood thyroid cancer, long-lasting remissions can be achieved. A specific finding in children is disseminated, milliary lung metastases with intense radioiodine uptake. In this situation, pulmonary fibrosis may be a severe side-effect so that the indication for repeated courses of radioiodine therapy has to be decided thoroughly. With respect to side-effects of radioiodine therapy, the risk of developing breast cancer has to be taken into account seriously since especially the female breast is exposed to a relatively high radiation dose. Generally, young patients treated with high activities of radioiodine should be carefully followed up during their whole lifespan.

Thyroid cancer risk in areas of Ukraine and Belarus affected by the Chernobyl accident.

The purpose of the present study was to analyze the thyroid cancer incidence risk after the Chernobyl accident and its degree of dependence on time and age. Data were analyzed for 1034 settlements in Ukraine and Belarus, in which more than 10 measurements of the (131)I content in human thyroids had been performed in May/June 1986. Thyroid doses due to the Chernobyl accident were assessed for the birth years 1968-1985 and related to thyroid cancers that were surgically removed during the period 1990-2001. The central estimate for the linear coefficient of the EAR dose response was 2.66 (95% CI: 2.19; 3.13) cases per 10(4) PY-Gy; for the quadratic coefficient, it was -0.145 (95% CI: -0.171; -0.119) cases per 10(4) PY-Gy(2). The EAR was found to be higher for females than for males by a factor of 1.4. It decreased with age at exposure and increased with age attained. The central estimate for the linear coefficient of the ERR dose response was 18.9 (95% CI: 11.1; 26.7) Gy(-1); for the quadratic coefficient, it was -1.03 (95% CI: -1.46; -0.60) Gy(-2). The ERR was found to be smaller for females than for males by a factor of 3.8 and decreased strongly with age at exposure. Both EAR and ERR were higher in the Belarusian settlements than in the Ukrainian settlements. In contrast to ERR, EAR increases with time after exposure. At the end of the observation period, excess risk estimates were found to be close to those observed in a major pooled analysis of seven studies of childhood thyroid cancer after external exposures.

Impact of parathyroid status and Ca and vitamin-D supplementation on bone mass and muscle-bone relationships in 208 Belarussian children after thyroidectomy because of thyroid carcinoma.

This observational study analyzes Ca-P metabolism and its impact on bone mass accrual and density and the muscle-bone mass/mass relationships in male and female children and adolescents who were parathyroidectomized because of thyroid carcinoma. Two hundred and eight children and adolescents (119 girls and 89 boys) from Gomel city (Belarus) and its rural surroundings were referred to our institution after having undergone total thyroidectomy for the treatment of advanced papillary thyroid cancer. A subgroup of children with demonstrated primary hypoparathyroidism received dihydrotachysterol (AT-10) and/or Ca supplementation. Among routine procedures over a maximum follow-up period of 5 years (average 3.7 years, maximum 8 visits), whole-body scans were taken using dual energy X-ray absorptiometry (DXA) at each visit in order to determine whole-body bone mineral content (TBMC), projected "areal" bone mineral density (TBMD), total lean mass (TLM) and total fat mass (TFM). The average serum Ca, P and AP concentrations over the whole observation period were significantly different between the groups; however, TBMC z-scores for all studied children were statistically similar in all visits. In girls, no between-group differences in height- and weight-controlled TBMC and TBMD or the TBMC/TLM ratio were observed (ANCOVA) and supplementation exerted no effect on these data, suggesting that the total bone mass accrual was not impaired by PTH deficiency in the studied conditions. However, non-supplemented boys showed lower values of the TBMC/TLM ratio than girls, and supplementation normalized these values in direct correlation with the induced improvement in serum P availability to bone. Results indicate that the primary impairment in parathyroid function and bone metabolism indicators in the thyroidectomized children was unrelated to any measurable change in crude bone mass values. However, in boys this condition impaired the TBMC/TLM ratio in such a way that the administered supplementation could normalize it as a function of improved P availability. Girls' skeleton seemed to have been naturally protected against the negative metabolic effect of the studied condition. An estrogen-induced enhancement of the biomechanical impact of muscle contractions on bone mass and structure could not be excluded in this group.

Systematic ultrasound screening as a significant tool for early detection of thyroid carcinoma in Belarus.

We report the results of ultrasound screening of the thyroid gland in 3,051 Belarus children 4-14 years of age exposed to radioactive fallout due to the Chernobyl accident. Screening was performed in 1990, 1993 and 1998. The study demonstrated that with time the prevalence of thyroid nodules in this contaminated region increased from 1.2% to 3.5%, mostly due to pathologically verified nodular goiter and non-verified small solid nodules and cysts. In contrast, the prevalence of thyroid carcinoma decreased from 0.6% in 1990 to 0.3% in 1993. We found 15 patients with carcinoma. On analysis of the ultrasound pattern of all carcinomas, we observed nodular and diffuse variants. Thus, we can conclude that systematic ultrasound screening is useful for the early detection of thyroid carcinoma in the population of Belarus exposed to radiation due to the Chernobyl accident.

Thyroid cancer among Ukrainians and Belarusians who were children or adolescents at the time of the Chernobyl accident.

Our objective is to assess the regional and temporal dependences of the baseline cases contributing to thyroid cancer incidence among those exposed in childhood or during adolescence in Belarus and Ukraine after the Chernobyl accident. Data are analysed for Kyiv and Sevastopol City and the 25 oblasts (regions) in Ukraine, and for Minsk and Gomel City and the 6 oblasts in Belarus. Average thyroid doses due to the Chernobyl accident were assessed for every birth year in the period from 1968 to 1985. Case data pertain to people who underwent surgical removal of thyroid cancers during the period 1986 to 2001 and who were allocated to their place of residence at the time of the accident. The 35 oblasts/cities were subdivided into an upper, middle and lower group of baseline thyroid cancer incidence. Poisson regressions were performed to estimate age, time and gender dependences of the baseline incidence rates in the three groups. The majority of oblasts/cities with high average doses and the majority of Belarusian oblasts/cities belong to the upper group of baseline thyroid cancer incidence. The baseline in the upper group is estimated to be larger than in the middle group by a factor of 2.3, and by a factor of 4.0 when compared to the lower group. The baseline incidence increases with age and with time since exposure. Estimated baseline incidence rates were found to increase from 1988 to 1999 by factors of three and two for the upper and the two lower groups respectively. The estimated thyroid cancer incidence rates in Belarus and Ukraine, and their dependences on gender and age, are consistent with observed rates found in the larger cancer registries of other countries. In conclusion, the baseline cases are found to contribute about 70% to the thyroid cancer incidence in Ukraine, and about 40% to the incidence in Belarus.