Spectrum of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies.

Distribution of cancer-predisposing mutations demonstrates significant interethnic variations. This study aimed to evaluate patterns of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies. APC gene defects were identified in 26/38 (68%) subjects with colon polyposis; 8/26 (31%) APC mutations were associated with 2 known mutational hotspots (p.E1309Dfs*4 [n = 5] and p.Q1062fs* [n = 3]), while 6/26 (23%) mutations were novel (p.K73Nfs*6, p.S254Hfs*12, p.S1072Kfs*9, p.E1547Kfs*11, p.L1564X and p.C1263Wfs*22). Biallelic mutations in MUTYH gene were detected in 3/12 (25%) remaining subjects with polyposis and in 6/90 (6.7%) patients with colorectal cancer (CRC) carrying KRAS p.G12C substitution, but not in 231 early-onset CRC cases negative for KRAS p.G12C allele. In addition to known European founder alleles p.Y179C and p.G396D, this study revealed a recurrent character of MUTYH p.R245H germ-line mutation. Besides that, 3 novel pathogenic MUTYH alleles (p.L111P, p.R245S and p.Q293X) were found. Targeted next-generation sequencing of 7 APC/MUTYH mutation-negative DNA samples identified novel potentially pathogenic POLD1 variant (p.L460R) in 1 patient and known low-penetrant cancer-associated allele CHEK2 p.I157T in 3 patients. The analysis of 1120 healthy subjects revealed 15 heterozygous carriers of recurrent MUTYH mutations, thus the expected incidence of MUTYH-associated polyposis in Russia is likely to be 1:23 000.

[Pharmacological correction of experimental chronic limb ischemia].

In tests on a group of 250 rats, we studied (i) the level of microcirculation in the muscles of a healthy limb in the norm and (ii) the dynamics of microcirculation for 6 h after treatment with pentoxifylline in a dose of 60 mg/kg dose and L-arginine in a dose of 30 and 200 mg/kg. The chronic ischemia was modeled by excision of basic femoral artery. There was no significant difference in pentoxyfilline-treated animals in comparison to the control. In the group treated with L-arginine in a dose of 30 mg/kg, a significant increase in microcirculation was observed on the 28-th day of experiment. In the group treated with L-arginine in a dose of 200 mg/kg, there was an increase of microcirculation in all terms of the experiment in comparison to the control. The results of laser doppler flow measurements are correlated with the results of morphological investigation.

[Experimental and clinical grounds of revascularizing osteomyoplasty for treatment of critical ischemia of the lower extremities].

In an experimental work it was found that under conditions of muscle ischemia the revascularizing osteomyoplasty was better than revascularizing osteotrepanation: it resulted in 1.4 times greater diameter of muscle fibers and 1.3 times larger size of the capillary network. An analysis of treatment of 30 patients was made who had critical ischemia of the extremities against the background of a diffuse lesion of the arteries below the inguinal ligament. In the first group consisting of 15 patients standard revascularizing osteotrepanation of the femur and shin was performed, in the second group (15 patients) revascularizing osteomyoplasty on the shin was added to the revascularizing osteotrepanation on the femur. In the second group the percentage of "mild improvement" of the clinical status of the patients was 10 times greater, and the number of patients with "minimal improvement" was 3.7 times less.

[Pharmacokinetics, biological availability and residues of sulfadoxine and trimethoprim when used jointly on calves]. / Farmakokinetika, biologichna nalichnost i ostatuchni veshtestva na sulfadoksin i trimetoprim pri suvmestno prilagane na teleta.

In calves (cross-breds--Bulgarian Brown Cattle breed and Black Spot Cattle bred) weighing about 189 kg pharmacokinetics of sulphadoxine (SD) and trimethoprim (TMP) was studied. The two substances were administered in combination (5 + 1) as a dosage form Tridoxin (Pharmachim, Bulgaria; 24% injectable solution) (TD) at a dose 15 mg/kg m. The results show that after intramuscular administration TD is absorbed relatively rapidly. SD and TMP have systemic availability 94.1 +/- 18.1% and 52.5 +/- 6.2% and produce blood levels, after a single dose of TD, higher than potentiated minimum inhibitory concentrations for 24-48 h and 5(4-8) h, respectively. Upon intravenous administration the two-compartmental model is applicable for the distribution and elimination of SD and TMP (for TMP in part of the animals one-compartmental model is applicable). The two substances are distributed relatively widely in organs and tissues. The biological half-life of TD--t1/2 beta for SD is 14.36 +/- 1.40 h and for TMP--2.40 +/- 0.31 (for one-compartmental model--1.92 +/- 0.26) h, Vd--429.9 +/- 16.9 ml/kg and for TMP in part of the animals one-compartmental model is applicable). The two substances are distributed relatively widely in organs and tissues. The biological half-life of TD--t1/2 beta for SD is 14.36 +/- 1.40 h and for TMP--2.40 +/- 0.31 (for one-compartmental model--1.92 +/- 0.26) h, Vd--429.9 +/- 16.9 ml/kg and for TMP in part of the animals one-compartmental model is applicable). The two substances are distributed relatively widely in organs and tissues. The biological half-life of TD--t1/2 beta for SD is 14.36 +/- 1.40 h and for TMP--2.40 +/- 0.31 (for one-compartmental model--1.92 +/- 0.26) h, Vd--429.9 +/- 16.9 ml/kg and 655.8 +/- 77.6 (for one-compartmental model--671.7 +/- 40.0) ml/kg, ClB--0.35 +/- 0.02 ml/kg/min and 2.87 +/- 0.35 (for one-compartmental model--4.15 +/- 0.80) ml/kg/min, respectively. After intramuscular injection at the dose used a suitable withdrawal time for meat and internal organs is 5 days and for milk--2 days.