TELOMERE LENGTH, TELOMERASE ACTIVITY, HEART RATE VARIABILITY, OR OXIDATIVE STRESS: WHICH ONE IS MOST ASSOCIATED WITH THE ATHEROTHROMBOTIC STROKE IN THE ELDERLY?

The objective of this study - to evaluate the impact of the markers of oxidative stress and HRV to stroke. The comprehensive clinical and instrumental study involved 84 patients with the diagnosis "Cerebral Atherosclerosis" (CA). Study design: simple, prospective, non-randomized, with sequential inclusion of patients. All patients underwent generally accepted clinical, laboratory and instrumental examination. All patients received antihypertensive drugs and metformin if they had DM and didn't receive any statins. Patients were divided into the 2 groups: I - those who underwent ischemic stroke (IS), II - with CA of 1-2 degrees. Mean age was 65.5±10.2 and 66.0±9.3 years, respectively. The number of patients with type 2 diabetes and the average fasting glucose was comparable in both groups. The LF/HF indicator reflects the state of the sympatho-parasympathetic balance of the ANS. Large values of this indicator indicate the predominance of the tone of the sympathetic ANS, which was observed (p <0.05) in patients of the 2nd group, while HF, LF and VLF were also higher (p>0.05) in the group of patients with cerebral atherosclerosis of 1-2 stages and above normal international values. Both groups were comparable in terms of telomere length and telomerase activity, as well as markers of oxidative stress, with the exception of GSH, which was higher in post-stroke patients (p>0.05). Our findings show that markers of oxidative stress together with HRV indices are useful for the atherothrombotic stroke risk assessment in the elderly. Future longitudinal study with bigger sample size and, probably wide panel of markers required for clarifying links between oxidative stress, HRV and stroke.

Differentiated thyroid carcinomas associated with chronic thyroiditis: biological and clinical properties.

AIM: To determine biological and clinical features of papillary and follicular thyroid carcinomas associated or not associated with chronic thyroiditis. MATERIALS AND METHODS: The study was conducted by retrospective analysis of medical histories of 2,459 patients with thyroid cancer. Tumor size, its category according to the TNM system, multi-focal properties of tumor growth, carcinoma invasiveness, as well as disease stage, rates of relapses and metastasis, and also cumulative survival rates were analyzed. RESULTS: The tumor size in patients with papillary or follicular carcinoma associated with thyroiditis was smaller compared to the patients without thyroiditis. In the first case, the invasion frequency into extrathyroid structure and into the capsule was also lower. Multi-focal growth of both carcinoma types was registered more frequently in the presence of thyroiditis. The frequency of papillary carcinoma metastasis to lateral cervical lymph nodes was lower in the presence of thyroiditis, the frequency being equal for metastasis into lymph nodes of the VI lymph outflow zone in both groups of patients (with and without thyroiditis). In the presence of thyroiditis, the frequency of distant papillary carcinoma metastasis was decreased, no metastases were detected in patients with follicular carcinoma. In the group of patients with papillary carcinoma there was found no relation between the presence of thyroiditis and disease stage, relapse rates, and mortality levels; however, the risk of follicular carcinoma relapse was significantly lower in patients with thyroiditis. CONCLUSIONS: The presence of chronic thyroiditis in papillary carcinoma patients showed a certain positive impact on the course of the disease, in particular, primary tumor growth, invasion, and metastasis. Such effect is even more expressed in the patients with follicular thyroid carcinoma.

30 years of the Chernobyl accident. Molecular genetic mechanisms of carcinogenesis of thyroid gland.

The review presents data on the basic molecular ge-netic mechanisms of formation of papillary thyroid carcinoma. The participation of ionizing radiation in the cancer pathogenesis was analyzed. The role of tu-mor microenvironment, inflammation and nuclear trans-cription factor NF-κB in the initiation and development of papillary thyroid carcinoma was shown.

BIOCHEMICAL EFFECTS OF ESTROGENS IN NON-REPRODUCTIVE ORGANS.

Biochemical processes initiated by estrogenic hormones in the organs which are not directly related to reproduction were described in the survey on the basis of literature and the authors' own studies. The importance of these compounds in the regulation of fundamental biological processes has been established in the last decades. The biochemical mechanisms of realization of estrogen effects may be considered as potential links of pathogenesis for a number of diseases and as targets of their therapy.

Abnormalities of apoptosis of the thyroid gland cells from extratumoral microfollicular tissue.

AIM: The aim of this study was to evaluate the frequency of existence of thyroid extratumoral normo- and microfollicular tissue in patients with thyroid carcinoma and peculiarities of apoptosis in mentioned tissue. MATERIALS AND METHODS: Using samples of normo- and microfollicular thyroid tissue it was determined the content of fragmented DNA and intensity of stimulated internucleosomal DNA fragmentation; activities of caspase-3 and cysteine lysosomal cathepsins. RESULTS: It was found that normofollicular tissue is observed more often in patients with nodal euthyroid goiter but microfollicular tissue is more common for patients with carcinoma. Extratumoral microfollicular tissue was found in the thyroid of patients above 50 years old mostly, and more rarely in young ones. The fragmented DNA concentration in microfollicular tissue was lower by a factor of 3.5 and intensity of stimulated internucleosomal DNA fragmentation was also decreased. Activity both of cathepsin B in lisosomes and caspase-3 in lysates of such tissue was also decreased. CONCLUSIONS: The decrease of intensity of spontaneous apoptosis and the absence of its modulation/induction following proapoptotic factors in extratumoral microfollicular thyroid tissue may be considered as a respond of the thyroid gland tissue to an existence of carcinoma.

[DNA fragmentation rate in human thyroid tissue and carcinomas and its change under the influence of a-tocopherol and iodine ions in vitro].

The rate of DNA fragmentation was studied in intact thyroid tissue and thyroid carcinoma tissue. The determination of low molecular-weight DNA concentrations and the electrophoretic analysis of DNA isolated from the thyroid tissues and tumors, followed by the calculation of the content of oligonucleosome fractions, indicated a drastic reduction in the DNA fragmentation rate in papillary carcinomas and no its significant changes in follicular carcinomas. In the intact thyroid tissue, α-tocopherol and potassium iodide at a concentration of 10-7 M inhibited the rate of stimulated DNA fragmentation in vitro. The agents showed no effect in the papillary carcinoma tissue and their effect was similar in the follicular carcinoma tissue, but it was less pronounced in intact thyroid tissue.

Effect of o,p'-DDD and Li+ on apoptotic DNA fragmentation in conventionally normal and tumour tissues of human adrenal cortex.

The actions of 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane (o,p'-DDD), potassium and lithium ions upon apoptotic processes in conventionally normal and tumour tissues of human adrenal cortex were studied. There was no effect of K+ on the apoptosis in tumour tissue. o,p'-DDD--the specific drug for conservative therapy of adrenocortical cancer--enhanced the apoptotic DNA fragmentation in all tested tissues. The conclusion was made that apoptosis may be involved in curative effect of o,p'-DDD in adrenal cortex. Lithium ions, which are used in clinic as antidepressant, inhibited the apoptosis in conventionally normal tissue and in most tumours. On the other hand, lithium enhanced the DNA fragmentation in the postoperative tissue of patients with Cushing disease. The possible mechanisms mediating lithium effects on the adrenal cortex are discussed.

Post-Chernobyl thyroid cancers in Ukraine. Report 2: risk analysis.

On April 26, 1986, the worst nuclear reactor accident to date occurred at the Chornobyl (Chernobyl) power plant in Ukraine. Millions of people in Ukraine, Belarus and Russia were exposed to radioactive nuclides, especially (131)I. Since then, research has been conducted on various subgroups of the exposed population, and it has been demonstrated that the large increase in thyroid cancer is related to the (131)I exposure. However, because of study limitations, quantified risk estimates are limited, and there remains a need for additional information. We conducted an ecological study to investigate the relationship between (131)I thyroid dose and the diagnosis of thyroid cancer in three highly contaminated oblasts in Northern Ukraine. The study population is comprised of 301,907 persons who were between the ages of 1 and 18 at the time of the Chornobyl accident and were living in 1,293 rural settlements in the three study oblasts. Twenty-four percent of the study population had individual thyroid dose estimates and the other 76% had "individualized" estimates of thyroid dose based on direct thyroid measurements taken from a person of the same age and gender living in the same or nearby settlement. Cases include 232 thyroid cancers diagnosed from January 1990 through December 2001, and all were confirmed histologically. Dose-response analyses took into account differences in the rate of ultrasound examinations conducted in the three study oblasts. The estimated excess relative risk per gray was 8.0 (95% CI = 4.6-15) and the excess absolute risk per 10,000 person-year gray was estimated to be 1.5 (95% CI = 1.2-1.9). In broad terms, these estimates are compatible with results of other studies from the contaminated areas, as well as studies of external radiation exposure.

RET rearrangements in post-Chernobyl papillary thyroid carcinomas with a short latency analysed by interphase FISH.

Tissue samples from 13 post-Chernobyl childhood thyroid tumours that occurred within a short period of time (4-8 years) after the Chernobyl accident have been investigated by interphase FISH analysis for rearrangements of RET. In all, 77% of cases showed RET/PTC rearrangements and a distinct intratumoural genetic heterogeneity. The data were compared to findings on 32 post-Chernobyl PTCs that occurred after a longer period of time (9-12 years) after the accident. In none of the cases from either group were 100% of cells positive for RET rearrangement. In addition, the pattern of RET-positive cells was different in the two groups (short vs longer latency). A significant clustering of aberrant cells could be detected in the long-latency subgroup, whereas the aberrant cells were more homogeneously distributed among the short-latency tumours. The findings suggest that oligoclonal tumour development occurs in post-Chernobyl PTCs. This pattern of different clones within the tumour appears to become more discrete in cases with longer latencies, suggesting either outgrowth of individual clones or development of later subclones with time.

Time trends of thyroid cancer incidence in Ukraine after the Chernobyl accident.

The rate of childhood thyroid cancer incidence observed in northern Ukraine during the period 1986-1998 is described as a function of time-since-exposure, age-at-exposure, and sex. Conclusions are drawn for the excess absolute risk per dose: after a minimal latency period of about three years it shows a linear increase with time-since-exposure for at least nine years. It is roughly constant in age-at-exposure, up to 15 years. For girls exposed very young it is about a factor 2 larger than for boys. For children exposed at age 16-18 this ratio increases to about 5. The thyroids of young children are not more sensitive to radiation dose than those of older ones in absolute risk in northern Ukraine in the currently used data set. As the background is increasing with age, a constant absolute risk gives a decreasing relative risk.

Thyroid cancer in children of Ukraine after the Chernobyl accident.

The results of treatment of 330 children (< 14 years) and adolescents (15-18 years) with thyroid cancer who were operated on at the Institute of Endocrinology after the Chernobyl accident in 1986 were analyzed. The number of young patients increased after 1986 (1981-1985, 9 cases; 1986-1990, 37 cases; 1991-1995, 177 cases; 1996-1998, 116 cases). Most of these children and adolescents were younger than 8 years at the time of the accident (84.2%). More than half of the children (58.1%) lived in areas receiving the highest radiation exposure. These thyroid cancers developed after a short latent period, were more aggressive at presentation, and expressed regional (57.3%) or distant (14.5%) metastasis. Solid papillary cancers were present in 93.1%. Coexisting thyroid conditions were common (thyroid hyperplasia, 25.1%; nodular goiter, 18.8%; chronic thyroiditis, 10.2%). Most patients were treated by total thyroidectomy with intraoperative visualization of recurrent laryngeal nerves and parathyroid glands. When lymph node metastases were identified, a modified neck dissection was performed. Such operations were done in 277 (84.1%) patients. Postoperatively, the patients were treated with radioiodine and thyroid-stimulating hormone suppressive therapy. Postoperative complications included recurrent nerve palsy in 12.3% and permanent hypoparathyroidism in 6%. Operations for local recurrence of cancer were performed in 2.8% cases and for regional metastasis in 4%. The general mortality was 1. 8%. We anticipate that there will be more patients with thyroid cancer during the next few years. Therefore this high risk population for thyroid cancer must be carefully monitored and evaluated during the next several decades.

Gene rearrangement and Chernobyl related thyroid cancers.

The increase in thyroid carcinoma post-Chernobyl has been largely confined to a specific subtype of papillary carcinoma (solid/follicular). This subtype is observed predominantly in children under 10 in unirradiated populations, but maintains a high frequency in those aged 10-15 from those areas exposed to fallout from the Chernobyl accident. The aim of this study was to link morphology with molecular biology. We examined 106 papillary carcinomas from children under the age of 15 at operation. All were examined for rearrangements of the RET oncogene by reverse transcription polymerase chain reaction (RT-PCR); a subset of these cases were also examined for mutations of the three ras oncogenes, exon 10 of the thyroid stimulating hormone receptor, associated more usually with a follicular rather than papillary morphology, and exons 5, 6, 7 and 8 of the p53 gene, commonly involved in undifferentiated thyroid carcinoma. Rearrangements of the REToncogene were found in 44% of papillary carcinomas in which we studied fresh material; none of the tumours examined showed mutation in any of the other genes. The two rearrangements resulting from inversion of part of chromosome 10 (PTC1 and PTC3) accounted for the majority of RET rearrangements identified, with PTC1 being associated with papillary carcinomas of the classic and diffuse sclerosing variants and PTC3 with the solid/follicular variant.

Xenotransplantation of cultured newborn pig thyroid tissue for the treatment of post-radioiodine hypothyroidism in rats.

The aim of the present study was to develop atransplantation technique for restoration of thyroidfunction in rats with radioiodine-inducedhypothyroidism. Each Wistar rat received the dose of75.0 muCi of 131-iodine by intraperitonealinjection. The serum thyroxine and triiodothyroninevalues in all rats fell to low levels by 2.5 weeksafter radioiodine administration. Thexenotransplantation of 3-day-old newborn pig thyroidorgan culture was performed on day 18 afterradioactive ablation by injection into the fat tissueof anterior abdominal wall. Epithelial cell swarmswith follicular formation manifested themselves amongadipose tissue on day 7 as well as day 17 afterxenotransplantation. The serum thyroxine andtriiodothyronine values in the rats were generallywithin the euthyroid range by day 7-17 afterxenotransplantation. The thyroid gland of ratsreverted to the norm in morphofunctional appearance.These results indicated that the xenografted newbornpig thyroid organ culture allowed a restoration of thyroid function in Wistar rats with post-radioiodine hypothyroidism.

High prevalence of RET/PTC rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between RET/PTC3 and the solid-follicular variant.

A sharp increase in the incidence of pediatric thyroid papillary cancer was documented after the Chernobyl power plant explosion. An increased prevalence of rearrangements of the RET protooncogene (RET/PTC rearrangements) has been reported in Belarussian post-Chernobyl papillary carcinomas arising between 1990 and 1995. We analyzed 67 post-Chernobyl pediatric papillary carcinomas arising in 1995-1997 for RET/PTC activation: 28 were from Ukraine and 39 were from Belarus. The study, conducted by a combined immunohistochemistry and RT-PCR approach, demonstrated a high frequency (60.7% of the Ukrainian and 51.3% of the Belarussian cases) of RET/PTC activation. A strong correlation was observed between the solid-follicular subtype of papillary carcinoma and the RET/PTC3 isoform: 19 of the 24 RET/PTC-positive solid-follicular carcinomas harbored a RET/PTC3 rearrangement, whereas only 5 had a RET/PTC1 rearrangement. Taken together these results support the concept that RET/PTC activation plays a central role in the pathogenesis of thyroid papillary carcinomas in both Ukraine and Belarus after the Chernobyl accident.

Prevalence of diabetes mellitus and its complications in the Ukraine.

Analysis of the prevalence of insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) in various climato-geographic and administrative regions of the Ukraine was performed. The prevalence of diabetes mellitus (DM) complication in the west and north zones of the Ukraine was studied. The role of prophylactic measures in decreasing the number of complications was elucidated. The statistical reports from the specialized endocrinologic institutions of the Ukraine were analysed in the Laboratory of Epidemiology of Endocrine disease of Institute and results from 3450 and 673 diabetic patients in the west and north zone of the Ukraine were used, respectively. In various administrative regions of the Ukraine the prevalence of IDDM significantly varied from 1740 to 3813 patients per 1 million population. Significant differences in the prevalence of NIDDM were found. Generally in the west zone of the Ukraine the prevalence of DM was less than that of average in the Ukraine. Angiopathy of the lower extremities, neuropathy and retinopathy were registered in 92, 24, and 21% of diabetes cases in the west zone, respectively. Prophylactic measures directed at a decrease in patient weight, the normalization of metabolism, arterial pressure and the elimination of pernicious habits promoted a decrease in the number of complications.