Genetic screening of an endemic mutation in the DYSF gene in an isolated, mountainous population in the Republic of Dagestan.

BACKGROUND: Dysferlinopathy has a high prevalence in relatively isolated ethnic groups where consanguineous marriages are characteristic and/or the founder effect exists. However, the frequency of endemic mutations in most isolates has not been investigated. METHODS: The prevalence of the pathological DYSF gene variant (NM_003494.4); c.200_201delinsAT, p. Val67Asp (rs121908957) was investigated in an isolated Avar population in the Republic of Dagestan. Genetic screenings were conducted in a remote mountainous region characterized by a high level of consanguinity among its inhabitants. In total, 746 individuals were included in the screenings. RESULTS: This pathological DYSF gene variant causes two primary phenotypes of dysferlinopathy: limb-girdle muscular dystrophy (LGMD) type R2 and Miyoshi muscular dystrophy type 1. Results indicated a high prevalence of the allele at 14% (95% confidence interval [CI]: 12-17; 138 out of 1518 alleles), while the allele in the homozygous state was detected in 29 cases-3.8% (CI: 2.6-5.4). The population load for dysferlinopathy was 832.3 ± 153.9 per 100,000 with an average prevalence of limb-girdle muscular dystrophies ranging from 0.38 ± 0.38 to 5.93 ± 1.44 per 100,000. CONCLUSION: A significant burden of the allele was due to inbreeding, as evidenced by a deficiency of heterozygotes and the Wright fixation index equal to 0.14 (CI 0.06-0.23).

Comparative efficacy evaluation of catheter intraperitoneal chemotherapy, normothermic and hyperthermic chemoperfusion in a rat model of ascitic ovarian cancer.

OBJECTIVES: The choice of an optimal administration route for intraperitoneal (IP) chemotherapy and a suitable chemotherapeutic regime in the treatment of ovarian cancer remains a controversy. We investigated survival outcomes according to catheter intraperitoneal chemotherapy (CIPC), normothermic and hyperthermic chemoperfusion (NIPEC and HIPEC) with cytostatic drugs dioxadet and cisplatin in rats with transplantable ascitic ovarian cancer. METHODS: Ascitic liquid containing 1 × 107 tumour cells was inoculated to female Wistar rats and 48 hours after rats received dioxadet and cisplatin at the maximum tolerated doses. Dioxadet at doses 1.5, 30 and 15 mg/kg and cisplatin at doses 4, 40 and 20 mg/kg body weight were administered for CIPC, NIPEC and HIPEC, respectively. Rats in the control groups received physiological saline and CIPC with physiological saline was regarded as the untreated control. The antitumor activity of the drugs was evaluated as an increase in average life expectancy (ALE). Analysis of the data was based primarily on Bayesian statistics and included Kaplan-Meier method, log-rank test and hazard ratio (HR) estimation. RESULTS: Compared to the untreated control CIPC, NIPEC and HIPEC with dioxadet significantly increased ALE by 101316, 61524 and 1.71735 days, whereas with cisplatin by 61013, 122437 and -13523 days, respectively. CONCLUSIONS: Dioxadet and cisplatin show similar efficacy in the CIPC route. Compared with CIPC IP chemotherapy by chemoperfusions is more effective for both the drugs. Dioxadet in HIPEC showed highest survival benefit whereas largest effect during NIPEC is achieved with cisplatin.

Polymorphism of LDLR, GYPA, HBGG, D7S8, GC, HLA-DQA1, Ig-JH, D17S30, ApoB and D1S80 loci in northwestern Russians.

Allele frequencies for polymarker, HLA-DQA1, Ig-JH, D17S30, ApoB and D1S80 loci and population genetic parameters were obtained from a sample of 501 unrelated individuals born in the northwestern Federal Region of Russia.

Differential mutagenic, antimutagenic and cytotoxic responses induced by apomorphine and its oxidation product, 8-oxo-apomorphine-semiquinone, in bacteria and yeast.

Apomorphine (APO) is considered to be a classical mixed type dopamine D(1) and D(2) receptor agonist. It has been used in the therapy of Parkinson's disease and, more recently, for the treatment of erectile dysfunction. Like other catechols (e.g. dopamine), APO easily autoxidizes, producing quinone and semiquinone derivatives that may lead to the formation of reactive oxygen species and induce neurotoxicity. We assayed mutagenicity, antimutagenicity, and cytotoxicity of these compounds by means of the Salmonella/microsome assay, WP2 Mutoxitest and sensitivity assay in Saccharomyces cerevisiae yeast strains lacking antioxidant defenses. In the absence of S9 mix both compounds Apomorphine and its oxidation derivative, 8-oxo-apomorphine-semiquinone (8-OASQ), both at doses ranging from 20 to 80 microg per plate, induced frameshift mutations in TA98 and TA97 S. typhimurium strains, with 8-OASQ being up to two times more mutagenic. However, for strains which detect oxidative mutagens, 8-OASQ acted as a mutagen while APO was an antimutagen, inhibiting H(2)O(2) and t-BOOH-induced mutagenicity in TA102 S. typhimurium and WP2-derived E. coli strains. The S9 mix inhibited all mutagenic effects, probably either by conjugation of APO and 8-OASQ to proteins or by quenching reactive oxygen species. In sensitivity assays with S. cerevisiae, APO was only clearly cytotoxic to some strains at higher doses (200 and 400 microg/ml), whereas 8-OASQ dose-dependently sensitized all the strains, mainly the mutants lacking catalase (deltactt1), superoxide dismutase (deltasod1) and Yap1 transcription factor (deltayap1), suggesting that 8-OASQ cytotoxicity towards S. cerevisiae results from its pro-oxidant properties. APO also tended to protect S. cerevisiae strains against oxidative damage induced by high concentrations of H(2)O(2) and t-BOOH, while 8-OASQ enhanced pro-oxidant effects and induced adaptation responses to these agents. These results suggest that the 8-OASQ oxidation product of APO might induce cytotoxic and genotoxic effects.