Using reservoir sediment deposits to determine the longer-term fate of chernobyl-derived 137Cs fallout in the fluvial system.

Vast areas of Europe were contaminated by the fallout of 137Cs and other radionuclides, as a result of the Chernobyl accident in 1986. The post-fallout redistribution of Chernobyl-derived 137Cs was associated with erosion and sediment transport processes within the fluvial system. Bottom sediments from lakes and reservoirs can provide a valuable source of information regarding the post-fallout redistribution and fate of 137Cs released by the Chernobyl accident. A detailed investigation of sediment-associated 137Cs in the bottom sediments of a reservoir in a Chernobyl-affected area in Central Russia has been undertaken. A new approach, based on the vertical distribution of 137Cs activity concentrations in the reservoir bottom sediment makes it possible to separate the initially deposited bottom sediment, where the 137Cs activity reflects the direct fallout of Chernobyl-derived 137Cs to the reservoir surface and its subsequent incorporation into sediment deposited immediately after the accident, from the sediment mobilized from the catchment deposited subsequently. The deposits representing direct fallout from the atmosphere was termed the "Chernobyl peak". Its shape can be described by a diffusion equation and it can be distinguished from the remaining catchment-derived 137Cs associated with sediment accumulated with sediments during the post-Chernobyl period. The 137Cs depth distribution above the "Chernobyl peak" was used to provide a record of changes in the concentration of sediment-associated 137Cs transported from the upstream catchment during the post-Chernobyl period. It was found that the 137Cs activity concentration in the sediment deposited in the reservoir progressively decreased during the 30-year period after the accident due to a reduction in the contribution of sediment eroded from the arable land in the catchment. This reflects a reduction in both the area of cultivated land area and the reduced incidence of surface runoff from the slopes during spring snowmelt due to climate warming.

[Are hybrid technologies appropriate for revascularization of aortoiliac-femoral segment?] / Opravdano li primenenie gibridnykh tekhnologii pri revaskulyarizatsii aorto-podvzdoshno-bedrennogo segmenta.

OBJECTIVE: To compare various approaches to revascularization of aortoiliac-femoral segment. MATERIAL AND METHODS: Data were collected prospectively for retrospective analysis. There were 192 patients with atherosclerotic lesion of the aortoiliac-femoral segment who underwent reconstructive surgeries. All patients were divided into 3 groups depending on the type of reconstruction: 85 patients underwent open surgical interventions, 63 patients - endovascular interventions, 44 patients - hybrid techniques. Between-group differences were considered significant at p-value <0.05. RESULTS: Hybrid revascularization is characterized by less duration of surgery, blood loss and morbidity. Hybrid interventions ensured favorable primary patency compared to open surgery within the follow-up period. CONCLUSION: Hybrid revascularization of aortoiliac-femoral segment is characterized by less duration of surgery, blood loss and morbidity.

[Choice of the revascularization method for patients of elderly age with infraeinguvinal arterial disease.]

The aim of the study was to perform a comparative evaluation of the use of various methods of reconstructive assistance in the defeat of the femoral-tibial segment in elderly patients with peripheral arterial disease. 253 patients over 60 years old (60-74 years and more than 75 years) with atherosclerotic lesions of arteries below the inguinal ligament were examined and revascularized. According to the type of reconstruction performed, the patients were divided into 3 groups: 98 patients underwent open surgical interventions; 116 patients underwent endovascular interventions; 39 people performed hybrid reconstructions. The shorter duration of each stage of hybrid interventions, minor blood loss, and stability of hemodynamics during the perioperative period positively characterize hybrid effects. It was found that there was a shorter stay in the intensive care unit and shorter hospitalization of patients after hybrid revascularization methods compared to open methods. The absence of dangerous complications and the primary patency of the operated segment in the early postoperative period, approaching 100%, characterize hybrid techniques as an effective method of treating patients with infraganginal arterial disease. Conclusion: Hybrid reconstructions are promising in elderly patients who have severe comorbidity due to less operational blood loss, shorter duration of intervention and the minimum number of postoperative complications.

[Hybrid surgical treatment of a multilevel lesion of lower-limb arteries]. / Gibridnoe khirurgicheskoe lechenie mnogourovnevogo porazheniia arterii nizhnikh konechnostei.

The study was aimed at assessing immediate postoperative and remote results of hybrid surgical treatment of patients with a multilevel lesion of lower-limb arteries. Described herein is the authors' experience with simultaneous hybrid surgical management of 48 patients, including 43 subjects with a multilevel lesion of arteries of the lower extremities. There were 40 men and 8 women, with the average age amounting to 65.8±7.9 years. Of these, 30 patients suffered from stage II-b chronic arterial insufficiency (CAI), 11 had stage III CAI and 7 had stage IV CAI according to A.V. Pokrovsky classification. While planning the hybrid operation on the arteries of lower limbs we assessed the type of the lesion to the aortofemoral and femoropopliteal segments according to TASC II. All patients were subdivided into 3 groups, depending on the type of hybrid operations: Group I (n=17) - aortofemoral segment, Group II (n=5) - femoropopliteal segment, and Group III (n=26) reconstruction of both above-mentioned segments. The technical success amounted to 93.7% in revascularization of all types of lesions of the arteries of lower limbs with the use of hybrid vascular reconstructions. The mean duration of the operation was 231.8±90.7 min, including that of the open stage amounting to 126.4±72.8 min and that of the endovascular stage to 105.4±62.9 min. In the immediate postoperative period there were 2 complications requiring repeat reconstructive operation. The ankle-brachial index (ABI) after the intervention increased from 0.43±0.17 to 0.85±0.12. The duration of follow-up averaged 23.4±15.1 months (range 1.9-45.2 mos). Primary patency at 6 months was 94%, at 12 months 94%, at 24 months - 85% and at 36 months - 79% in all groups studied. Four patients during the follow-up period were subjected to amputation. The limb salvage rates were as follows: during 36 months in all patients - 91.6%, in those with stage II-b CAI - 93.3% and in those with critical lower-limb ischaemia - 88.8%. The overall survival rate was 95.8%. The use of a hybrid method in treatment of a multilevel lesion of lower-limb arteries with revascularization of the aortofemoral and femoropopliteal segments proved efficient both in the immediate and remote periods.

[Bicyclic furano[2,3-D] derivatives of pyrimidine nucleosides--synthesis and antiviral properties].

The methods of synthesis of furano- and pyrrolo[2,3-dlpyrimidine nucleosides as well as structure activity relationship of obtained compounds towards viruses of varicella zoster, hepatitis C, bovine viral diarrhea and some others are reviewed.

[Synthesis and biological properties of α-thymidine 5'-aryl phosphonates].

The interaction of CDI-activated diethyl phosphonoacetate with methyl 4-aminobenzoat or 3,5-difluoromethylphenylamine followed by treatment with Me3SiBr in DMF led to N-aryl aminocarbonylmethyl phosphonates and their ethyl esters. Their coupling with 3'-acetyl-α-thymidine followed by removal of the acetyl groups gave (α-D-thymidine-5'-il) N-[4-(methoxycarbonyl-, aminocarbonyl- and carboxy)phenyl]-aminocarbonylmethyl phosphonates, (α-D-thymidine-5'-il)-[3,5-bis(trifluoromethyl)phenylaminocarbonyl]methyl phosphonate and their ethyl esters. The phosphonates were stable in different conditions, low cytotoxic (in Vero and K562 cells) and were able to penetrate into K562 cells. The only ethyl ester of (α-D-thymidine-5'-il) N-[4-(methoxycarbonyl)phenyl]-aminocarbonylmethyl phosphonate in high concentration (200 µg/mL) inhibited in vitro the growth of laboratory sensitive strain of Mycobacterium tuberculosis H37Rv.

Topical hindpaw application of L-menthol decreases responsiveness to heat with biphasic effects on cold sensitivity of rat lumbar dorsal horn neurons.

Menthol is used in pharmaceutical applications because of its desired cooling and analgesic properties. The neural mechanism by which topical application of menthol decreases heat pain is not fully understood. We investigated the effects of topical menthol application on lumbar dorsal horn wide dynamic range and nociceptive-specific neuronal responses to noxious heat and cooling of glabrous hindpaw cutaneous receptive fields. Menthol increased thresholds for responses to noxious heat in a concentration-dependent manner. Menthol had a biphasic effect on cold-evoked responses, reducing the threshold (to warmer temperatures) at a low (1%) concentration and increasing threshold and reducing response magnitude at high (10%, 40%) concentrations. Menthol had little effect on responses to innocuous or noxious mechanical stimuli, ruling out a local anesthetic action. Application of 40% menthol to the contralateral hindpaw tended to reduce responses to cooling and noxious heat, suggesting a weak heterosegmental inhibitory effect. These results indicate that menthol has an analgesic effect on heat sensitivity of nociceptive dorsal horn neurons, as well as biphasic effects on cold sensitivity, consistent with previous behavioral observations.

Nanostructure of vortex during explosion welding.

The microstructure of a bimetallic joint made by explosion welding of orthorhombic titanium aluminide (Ti-30Al-16Nb-1Zr-1Mo) with commercially pure titanium is studied. It is found that the welded joint has a multilayered structure including a severely deformed zone observed in both materials, a recrystallized zone of titanium, and a transition zone near the interface. Typical elements of the transition zone-a wavy interface, macrorotations of the lattice, vortices and tracks of fragments of the initial materials-are determined. It is shown that the observed vortices are formed most probably due to local melting of the material near the contact surface. Evidence for this assumption is deduced from the presence of dipoles, which consist of two vortices of different helicity and an ultrafine duplex structure of the vortex. Also, high mixing of the material near the vortex is only possible by the turbulent transport whose coefficient is several orders of magnitude larger than the coefficient of atomic diffusion in liquids. The role played by fragmentation in both the formation of lattice macrorotations and the passage of coarse particles of one material through the bulk of the other is determined.

[Synthesis and biological properties of pyrimidine 4'-fluoro nucleosides and 4'-fluoro uridine 5'-O-triphospate].

4'- Fluoro-2',3'-O-isopropylidenecytidine was synthesized via interaction of 5'-O-acetyl-4'-fluoro-2',3'-O-isopropylideneuridine with triazole and 4-chlorophenyl dichlorophosphate followed by ammonolysis. Treatment of 5'-O-acetyl-4'-fluoro-2',3'-O-isopropylidenecytidine with hydroxylamine resulted in 5'-O-acetyl-4'-fluoro-2',3'-O-isopropylidene-N(4)-hydroxycytidine. Subsequent removal of 2',3'-O-isopropylidene groups gave 5'-O-acetyl derivatives of 4'-fluorouridine, 4'-fluorocytidine and 4'-fluoro-N(4)-hydroxycytidine. 5'-O-Triphosphate of 4'-fluorouridine was obtained in three steps starting from 4'-fluoro-2',3'-O-isopropylideneuridine. The 4'-fluoro uridine 5'-O-triphospate was found to be an effective inhibitor of HCV RNA-dependent RNA polymerase, substrate for NTPase reaction, catalyzed by protein NS3 HCV (a rate of the analogue hydrolysis was similar to that of ATP) and an activator for helicase reaction (with an efficacy only three fold lower than that of ATP).

[New furano- and pyrrolo[2,3-d]pyrimidine nucleosides and their 5'-triphosphates: synthesis and biological properties].

Bicyclic furano[2,3-d]pyrimidine ribonucleosides were synthesized by Pd(0)- and CuI-catalyzed coupling of 5-iodouridine with terminal alkynes. The treatment of the resulting nucleosides with ammonia or methylamine solution in aqueous alcohol resulted in pyrrolo- and N(7)-methylpyrrolo[2,3-d]pyrimidine nucleosides. 5'-O-Triphosphates of bicyclic nucleosides were obtained by the treatment of the nucleosides with POCl3 in the presence of a "proton sponge." The 5'-O-triphosphates are not substrates for HCV RNA-dependent RNA polymerase, but are effective substrates for HCV RNA helicase/NTPase and did not inhibit ATP hydrolysis. Only 3-(beta-D-ribofuranosyl)-6-decyl-2,3-dihydrofuro-[2,3-d]pyrimidin-2-one showed a moderate anti-HCV activity in the HCV replicon system and efficiently inhibited replication of bovine viral diarrhea virus (BVDV) in KCT-cells, other compounds being inactive. None of the compounds were cytotoxic within the tested range of concentrations.

Base-modified ribonucleosides as potential anti-hepatitis C virus agents.

Four novel series of base modified ribonucleoside analogues were synthesized and evaluated as potential anti-HCV agents. For two compounds notable anti-HCV activity was observed The triphosphates of bicyclic pyrimidine ribonucleosides were studied as substrates/inhibitors of HCV RNA-dependent RNA polymerase (RdRp, NS5B protein) and RNA helicase/NTPase (NS3 protein).

Furano- and pyrrolo [2,3-d] pyrimidine nucleosides and their 5'-O-triphospates: synthesis and enzymatic activity.

A series of bicyclic [2,3-d]furano- and pyrrolopyrimidine ribonucleosides were synthesized and converted chemically into corresponding 5'-O-triphosphates. Substrate properties of the triphosphates toward some RNA and DNA polymerases are reported.

[Inactivation and sensitization of the tumor cells by the gene Bax transfection].

After the transfection of the gene Bax into the cultured tumor cells of human ovary adenocarcinoma SKOV3 and uterus carcinoma HeLa in vitro the high sensitivity of the cells SKOV3 to the protein Bax produced after the gene Bax transfection was found. The sensitivity of the cells HeLa to the gene Bax transfection was much smaller. The hyperexpression of gene Bax and hypersensitivity to doxorubicin were seen in HeLa cells received as a result of the gene Bax transfection and subsequent selection. All cells of the line SKOV3 with the increased expression of the transfected gene Bax died. In the cell line SKOV3 the mutation in a gene Bax was found which has a genotype G7/G9 against a native type of a gene Bax--G8/G8. It was concluded that the found in the exone 3 of the gene Bax mutation G7/G9 in cells SKOV3 results in an inactivation of proapoptotic activity of the protein Bax.

TNR/11q#1 trinucleotide (GCC)n repeat alleles and predisposition to acute and chronic leukemia.

TNR/11q#1 is a polymorphic trinucleotide (GCC)n repeat located within the minimal region of the 11q deletion in chronic lymphocytic leukemia (CLL). It was recently shown that certain alleles of this repeat are associated with a worse prognosis in CLL patients. To investigate the role of TNR/11q#1 variants as risk-modifying factors in leukemogenesis, we conducted a case-control study on 113 acute lymphotic leukemia (ALL) patients, 82 CLL patients and 146 healthy controls of Russian origin. Comparison of allele and genotype distributions in the control, ALL and CLL groups, performed by Fisher's exact test with two-sized P-value, showed significant decrease in the presence of the GCC(6) allele in the ALL and CLL groups compared to controls. Moreover, 'rare' alleles GCC(7-8) and GCC(13-14) were significantly overrepresented in the ALL group versus controls. We found that CLL risk genotypes were those with both alleles containing more than 6 GCC repeats (P = 0,0212, odds ratio = 1,68 (95% CI, 1,121...2,531)). ALL risk genotypes include three allele combination variants: 1) both alleles containing more than 6 GCC repeats (P = 0,0019, odds ratio = 1,756 (95% CI 1,223...2,502)); 2) one of the alleles containing 7 or 8 repeats (P = 0,0155, odds ratio = 18,22 (95% CI 1,93...136.37)); 3) one of the alleles containing more than 12 repeats (P = 0,0209, Odds ratio = 2,599 (95% CI 1,161...5,815)). Association of certain alleles and genotypes of the TNR/11q#1 repeat with both acute and chronic lymphocytic leukemia suggests the presence of a cancer related gene, involved in a wide spectrum of neoplasia, in the vicinity of this repeat.

Controlled transgene expression by E1-E4-defective adenovirus vectors harbouring a "tet-on" switch system.

BACKGROUND: The "tet switch system" was originally described under the tet-off configuration with its components encoded by two separate plasmids. Since then, many virus vectors harbouring tet-off components have been designed and their regulation by tetracycline is widely reported. On the contrary, tet-on regulation by viral vectors is poorly documented. METHODS: E1-E4-defective adenoviruses harbouring either rtTA or the luciferase gene under a minimal inducible promoter (TK* or CMV*) or both components in a single genome were produced. Using either a double or a single virus strategy, induction of luciferase expression was investigated in various cell lines, in mice muscle and in rat brain. RESULTS: Over 400-fold induction can be reached with PC12 and NHA cells using a double virus strategy. Comparison of the background activity of different minimal inducible promoters revealed a significant difference between TK* and CMV* promoters both with the cell culture and the in vivo experiments. Interestingly, a single virus strategy permitted an induction exceeding 600-fold with human astrocyte primary cells. Moreover, the E1-E4-defective adenovirus-mediated tet-on system can be quickly switched off and turned back on again. Depending on the cell line, the level of rtTA derived by the single virus strategy differed, resulting in different efficiencies. Experiments performed in rat striatum and mouse muscle confirmed the importance of rtTA expression and minimal promoter used on both doxycycline-independent expression and induction efficiency. Under appropriated rtTA expression, a 32-fold induction is observed in mouse muscle. CONCLUSIONS: In the recombinant adenovirus context, the CMV* but not the TK* promoter is sensitive to transcriptional interference resulting in high doxycycline-independent expression. By paying attention to the rtTA expression, moderate and high induction can be obtained in vivo and in vitro accordingly.

Antisense MBD2 gene therapy inhibits tumorigenesis.

BACKGROUND: Aberration in the pattern of DNA methylation is one of the hallmarks of cancer. We present data suggesting that dysregulation of MBD2, a recently characterized member of a novel family of methylated DNA binding proteins, is involved in tumorigenesis. Two functions were ascribed to MBD2, DNA demethylase activity and repression of methylated genes. METHODS: Multiple antisense expression and delivery systems, transfection, electrotransfer and adenoviral were employed to demonstrate that MBD2 is essential in tumorigenesis, both ex vivo and in vivo. RESULTS: Inhibition of MBD2 by antisense expression resulted in inhibition of anchorage-independent growth of antisense transfected cancer cells or cells infected with an adenoviral vector expressing MBD2 antisense. Xenograft tumors treated with an adenoviral vector expressing MBD2 antisense or xenografts treated with electrotransferred plasmids expressing MBD2 antisense showed reduced growth. CONCLUSIONS: These results support the hypothesis that one or both of the functions described for MBD2 are critical in tumorigenesis and that MBD2 is a potential anticancer target.

Efficient DNA electrotransfer into tumors.

DNA transfer to tumor cells of antiproliferative genes or of genes coding for immunomodulatory or antiangiogenic products is a promising approach for cancer therapy. However, intratumoral injection of plasmid DNA either naked or associated to chemical vectors results in a low level of gene expression. Recently, electrically mediated gene transfer has been described to strongly increase foreign gene expression in various tissues. We confirm and extend these observations using long duration electric pulses for several murine and human tumor models, using a reporter gene encoding for luciferase. After plasmid intratumoral injection, eight electric pulses of 20-ms duration were delivered at a frequency of 1 Hz through two flat parallel stainless steel electrodes placed at each side of the tumor. Optimal gene transfer was obtained using a voltage-to-distance ratio comprising between 400 and 600 V/cm. Two days after electrotransfer, we obtained a 10- to 1200-fold increase in gene expression over the naked DNA injection alone, leading to the expression of 0.6 to 300 ng luciferase per tumor. Moreover, histological results using beta-Gal reporter gene injected in H1299 tumor indicate that electrotransfer leads to a substantial increase in the percentage of beta-Gal positive cells. These results confirm the wide potential of electrotransfer for gene therapy in cancer.