Superhelical Duplex Destabilization and the Recombination Position Effect

The susceptibility to recombination of a plasmid inserted into a chromosome varies with its genomic position. This recombination position effect is known to correlate with the average G+C content of the flanking sequences. Here we propose that this effect could be mediated by changes in the susceptibility to superhelical duplex destabilization that would occur. We use standard nonparametric statistical tests, regression analysis and principal component analysis to identify statistically significant differences in the destabilization profiles calculated for the plasmid in different contexts, and correlate the results with their measured recombination rates. We show that the flanking sequences significantly affect the free energy of denaturation at specific sites interior to the plasmid. These changes correlate well with experimentally measured variations of the recombination rates within the plasmid. This correlation of recombination rate with superhelical destabilization properties of the inserted plasmid DNA is stronger than that with average G+C content of the flanking sequences. This model suggests a possible mechanism by which flanking sequence base composition, which is not itself a context-dependent attribute, can affect recombination rates at positions within the plasmid

Theoretical Analysis of the Stress Induced B-Z Transition in Superhelical DNA

We present a method to calculate the propensities of regions within a DNA molecule to transition from B-form to Z-form under negative superhelical stresses. We use statistical mechanics to analyze the competition that occurs among all susceptible Z-forming regions at thermodynamic equilibrium in a superhelically stressed DNA of specified sequence. This method, which we call SIBZ, is similar to the SIDD algorithm that was previously developed to analyze superhelical duplex destabilization. A state of the system is determined by assigning to each base pair either the B- or the Z-conformation, accounting for the dinucleotide repeat unit of Z-DNA. The free energy of a state is comprised of the nucleation energy, the sequence-dependent B-Z transition energy, and the energy associated with the residual superhelicity remaining after the change of twist due to transition. Using this information, SIBZ calculates the equilibrium B-Z transition probability of each base pair in the sequence. This can be done at any physiologically reasonable level of negative superhelicity. We use SIBZ to analyze a variety of representative genomic DNA sequences. We show that the dominant Z-DNA forming regions in a sequence can compete in highly complex ways as the superhelicity level changes. Despite having no tunable parameters, the predictions of SIBZ agree precisely with experimental results, both for the onset of transition in plasmids containing introduced Z-forming sequences and for the locations of Z-forming regions in genomic sequences. We calculate the transition profiles of 5 kb regions taken from each of 12,841 mouse genes and centered on the transcription start site (TSS). We find a substantial increase in the frequency of Z-forming regions immediately upstream from the TSS. The approach developed here has the potential to illuminate the occurrence of Z-form regions in vivo, and the possible roles this transition may play in biological processes

Фармакоэпидемиология использования оригинального дротаверина при дисменорее: результаты международного многоцентрового исследования

spasmodic abdominal pain is a common complaint. Dysmenorrhea is one of the most important problems not only from medical, but also social point of view. Drotaverine hydrochloride is a potent smooth muscle spasmolytic agent. Objective: To evaluate the effectiveness of drotaverine in the daily practice management of spasmodic abdominal pain due to gastrointestinal, biliary, urological tract conditions and dysmenorrhea. Material and Methods: a multicenter, prospective, cross-sectional and longitudinal product registry (3 visits), non-interventional on the therapeutic strategy was conducted in Mexico, Kazakhstan, and Russia. Each investigator contributed at the 2 sequences: one cross-sectional, assessing physicians' interest for and knowledge of spasmodic abdominal pain management [Prescription Registry, PR] and longitudinal registry [LREG]: data on 25 consecutive eligible patients with spasmodic pain were recorded in the PR, and 5-day (+3) follow-up on the first 5 consecutive eligible patients receiving NOSPA ® . Pain was evaluated asking patients to rate the worst abdominal pain over the past 12 hours (11-point Numerical Pain Rating Scale, NPRS) and a Visual Analogue Scale (VAS) to evaluate the drotaverine onset of action. Only spontaneous adverse events reports were collected. Results: 208 physicians participated and included 5507 patients. 75% of them received drotaverine. Treatment was mostly prescribed in monotherapy (72%). From these patients, 1116 were included in the Longitudinal Registry (881 in the PP population) with a mean age of 34.2 ± 12.5 years. 86 % were females. Most suffered from dysmenorrhea (53%). They received drotaverine for 5.7±4 days. 89% were responders. Compared to the first evaluation, a statistical difference was observed in patients suffering from dysmenorrhea (p<0.0001). Conclusion: Results show that pain rapidly improves in patients suffering from spasmodic abdo minal pain when taking drotaverine in this open product registry conducted under conditions of real life. It is possible to discuss introduction of drotaverine in national guidelines for management of dysmenorrhea patients.обусловленная спазмом абдоминальная боль широко распространена. Дисменорея является одной из наиболее важных проблем не только с медицинской, но и с социальной точки зрения. Дротаверина гидрохлорид является эффективным спазмолитиком, действующим на гладкую мускулатуру. Цель исследования: оценить эффективность дротаверина в повседневной практике лечения спастической боли в животе, обусловленной заболеваниями желудочно-кишечного тракта (ЖКТ), желчевыводящих путей и урологического тракта, а также дисменореей. Материалы и методы: многоцентровое, проспективное, перекрестное и долговременное неинтервенционное регистровое исследование препарата (три визита) проводилось в Мексике, Казахстане и России. Исследование включало перекрестную (предписываемая регистрация, PR) и пролонгированную (долговременная регистрация, LREG) фазы. Данные 25 последовательных пациентов со спастической болью в животе, подходящих для участия в исследовании, документировали в предписываемой регистрации и в ходе последующего наблюдения через 5 дней (+3) в отношении первых пяти последовательных, подходящих для участия в исследовании пациентов, принимающих оригинальный дротаверин – в долговременной регистрации. Боль оценивали по цифровой рейтинговой шкале боли NPRS и визуальной аналоговой шкале (ВАШ). Регистрировали только спонтанные сообщения о нежелательных явлениях. Результаты: в исследовании участвовали 208 врачей и 5507 пациентов. 75% пациентов получали дротаверин. Лечение назначалось преимущественно в виде монотерапии (72%). 1116 пациентов были включены в долговременную регистрацию (881 – в популяцию в соответствии с протоколом). Средний возраст составлял 34,2±12,5 года, 86% пациентов были женщинами. Большинство страдали от дисменореи (53%). Они получали дротаверин перорально в течение 5,7±4 дней. 89% пациентов ответили на терапию. У пациенток с дисменореей по сравнению с первой оценкой результаты были статистически достоверны (p<0,0001). Заключение: результаты данного открытого наблюдательного исследования показали быстрое облегчение состояния у пациентов со спастической абдоминальной болью при использовании дротаверина в условиях реальной клинической практики. Полученные результаты позволяют поднять вопрос о включении дротаверина в национальные руководства по ведению пациенток с дисменорее

Theoretical Analysis of Competing Conformational Transitions in Superhelical DNA

We develop a statistical mechanical model to analyze the competitive behavior of transitions to multiple alternate conformations in a negatively supercoiled DNA molecule of kilobase length and specified base sequence. Since DNA superhelicity topologically couples together the transition behaviors of all base pairs, a unified model is required to analyze all the transitions to which the DNA sequence is susceptible. Here we present a first model of this type. Our numerical approach generalizes the strategy of previously developed algorithms, which studied superhelical transitions to a single alternate conformation. We apply our multi-state model to study the competition between strand separation and B-Z transitions in superhelical DNA. We show this competition to be highly sensitive to temperature and to the imposed level of supercoiling. Comparison of our results with experimental data shows that, when the energetics appropriate to the experimental conditions are used, the competition between these two transitions is accurately captured by our algorithm. We analyze the superhelical competition between B-Z transitions and denaturation around the c-myc oncogene, where both transitions are known to occur when this gene is transcribing. We apply our model to explore the correlation between stress-induced transitions and transcriptional activity in various organisms. In higher eukaryotes we find a strong enhancement of Z-forming regions immediately 5′ to their transcription start sites (TSS), and a depletion of strand separating sites in a broad region around the TSS. The opposite patterns occur around transcript end locations. We also show that susceptibility to each type of transition is different in eukaryotes and prokaryotes. By analyzing a set of untranscribed pseudogenes we show that the Z-susceptibility just downstream of the TSS is not preserved, suggesting it may be under selection pressure

Specificity of hand-foot skin reaction induced by multikinase inhibitors: clinical, histological and ultrasound characteristics

Background. Multikinase inhibitors of angiogenesis are currently the most effective group of drugs in target therapy for cancer. They are associated with a high prevalence of a specific cutaneous adverse reaction, which manifests as a hand-foot skin reaction (HFSR). This side effect is quite prominent in the majority of patients, usually graded as II–III degree, which leads to the dose reduction and even discontinuation of the drug. The study objective is to evaluate clinical, histological and ultrasound characteristics of a HFSR associated with MKI treatment, and to assess the influence of a HFSR on patient’s quality of life. Materials and methods. The study included 46 patients with HFSR, who were previously treated with sorafenib or lenvatinib. Clinical characteristics of HFSR, including severity grading, were evaluated. We also performed ultrasound and histological examinations and assess the Dermatology Life Quality Index. Results. Grade III HFSR was in 5 (10.86 %) patients, grade II – in 25 (54.35 %), and grade I – in 16 (34.79 %). Dermatology Life Quality Index depended on the HFSR severity, with the mean value 24.5 ± 2.4. Pathomorphological examination revealed irregular epidermal proliferation with hypertrophic psoriasiform acanthosis, minimal keratinocyte vacuolization, few apoptotic figures, dyskeratosis, hyperkeratosis and microvessel dilation in the papillary dermis. Ultrasound examination showed increased vascularization in papillary and reticular dermis in affected skin areas, which was more prominent in patients with severe degrees of HFSR. The pronounced enhancement of vascularization was detected in fragmented hypoechogenic sites along the border of papillary and reticular dermis and in similar sites along the border of dermis and hypodermis. Conclusion. The use of multikinase inhibitors leads to pronounced changes not only in the surface layers of the skin, but also in the dermis and subcutaneous fat, which significantly worsens the quality of life of patients. This indicates the need to search for pathogenetically based methods of treatment of HFSR and create practical guidelines for supportive treatment of patients with HFSR taking multikinase inhibitors

Smoking and its association with socio-economic and cardiometabolic risk factors in the population 25–45 years of Novosibirsk. the problem of female smoking (2013–2014)

The article presents the results of population-based study of a representative sample of the population of one of the districts of Novosibirsk, conducted in 2013–2014. A total of 749 people of both sexes (43 % men) aged 25–45 years were examined. The response rate was 38 %. The program included a survey questionnaire on smoking and socio-economic factors (education, marital status, employment). Measurement of blood pressure, anthropometric parameters, serum cotinine, total cholesterol and its fractions, blood glucose were conducted. The high prevalence of smoking among men (46 %) and women (24 %) revealed. Associations of smoking with cardiometabolic risk factors such as hypertension, hyperglycemia and hypo-HDL-C were received. On the subsample (273 people) using the verification of the questionnaire on smoking by serum cotinine 4–6 % false answers were found. Marked increasing in female smoking and decreasing in male smoking in the past 20 years in Novosibirsk were revealed

АSSOCIATION BETWEEN OXIDATIVE-ANTIOXIDANT MODIFICATIONS OF LOW-DENSITY LIPOPROTEINS AND CORONARY HEART DISEASE IN A MALE POPULATION OF NOVOSIBIRSK

Aim. To investigate the association between potentially atherogenic oxidativeantioxidant modifications of low-density lipoproteins (LDL) and coronary heart disease (CHD) in a male population. Material and methods. A population-based survey included 1024 male residents ofNovosibirskCity, aged 47–73 years. The participants underwent a questionnaire survey, a standard cardiologic survey, anthropometry, blood pressure measurement, and electrocardiography. “Definite CHD” (Functional Class II–IV stable effort angina) was registered in 223 men (21,8%), according to validated epidemiologic, clinical, and functional criteria. Blood biochemistry analyses focused on the levels of total cholesterol (TCH), triglycerides (TG), high-density lipoprotein cholesterol (HDL–CH), high-sensitivity C-reactive protein (hsCRP), glucose, baseline levels of lipid peroxidation (LPO) products and fat-soluble antioxidants (alpha-tocopherol, retinol, beta-carotene, and xanthines) in LDL, LDL oxidation resistance in vitro, and an concentration of autoantibodies to oxidised LDL (oxLDL). Results. There were positive correlations and independent associations between the oxidative LDL modifications, in particular between reduced LDL oxidation resistance and CHD. On the other hand, there were negative correlations between the antioxidant LDL modifications (such as reduced alpha-tocopherol levels in LDL) and CHD. The prevalence of CHD was higher in participants with baseline levels of LPO products in LDL >0,8 nM MDA/mg LDL protein and with reduced LDL oxidation resistance (baseline levels >5,4 nM MDA/mg LDL protein vs. levels >13,2 nM MDA/mg LDL protein at later stages of LDL oxidation). However, the prevalence of CHD was lower in individuals with LDL levels of alpha-tocopherol >1,06 mg/mg LDL protein. Conclusion. These findings agree with the previously obtained data on the key role of oxidative LDL modifications in the pathogenesis of atherosclerosis and CHD

Detection of kidney dysfunction potential biomarkers with hypertension in the persons of 25–45 years

Aim.To assess the significance of symmetrical dimethylarginine (SDMA), uromodulin, retinol-binding protein 4 (RSB-4), transforming growth factorb1 (TGF-b1), plasminogen activator inhibitor 1 (PAI-1) as kidney dysfunction potential biomarkers persons with hypertension in persons 2545 years old. Materials and methods.The study included 147 people. Hypertension was recorded with blood pressure (BP)140/90 mm Hg, renal dysfunction with GFRCKD-EPI90 ml/min/1.73 cm2. Four groups were formed: 1 individuals with hypertension and GFR90 ml/min/1.73 cm2; 2 with hypertension and GFR90 ml/min/1.73 cm2; 3 with BP140/90 mm Hg and GFR90 ml/min/1.73 cm2; 4 with BP140/90 mm Hg and GFR90 ml/min/1.73 cm2. The groups were comparable by gender, age, and number of respondents. Creatinine, SDMA, uromodulin, RSB-4, TGF-b1, PAI-1 levels were examined in all individuals in the serum. Results.The maximum values of SDMA were determined in the 1st and 3rd groups (1.30 and 1.36 mol/l). In the 1st group, an association was found between SDMA and GFR (r=-0.324;p=0.048). In the 1st group, the minimum values of uromodulin were recorded, in the 4th group the maximum values (164.86 and 188.90 ng/ml; at the same timeр=0.921). The level of RSB-4 was the highest in the 1st group, the lowest in the 4th group (88.64 and 80.05 g/ml;p=0.011). The association of RSB-4 with SDMA in the 3rd group (r=0.400;p=0.017), the 4th group (r=0.403;p=0.018) was detected. The level of TGF-b1 was 1.5 times higher in the 1st group than in the 3rd (23.16 and 15.99 g/ml;p=0.026), the association of TGF-b1 with GFR in the 1st group had the opposite direction (r=-0.452;p=0.005). The study of similar indicators of PAI-1 did not reveal its relationship with renal dysfunction in hypertension. Conclusion.The results of the study made it possible to consider SDMA, RSB-4, TGF-b1 as potential biomarkers of renal dysfunction in hypertension in persons 2545 years old

Chronic cervicitis and chronic endometritis: general aspects of pathogenesis and pathogenetic therapy

Inflammatory diseases occupy leading positions in the list of gynaecological pathology. Inflammatory diseases of the pelvic organs (PID) recorded in 60-65% of women of reproductive age have a very negative impact on the female reproductive function, and cause chronic pelvic pain syndrome in 24% cases, infertility in 40%, miscarriage in 45%, and ectopic pregnancy in 3% of cases [1-3, 5, 7-9, 12, 13, 15-17, 20, 23]. Among inflammatory diseases in gynecology, endometritis and cervicitis account for about 70-80% of cases; however, the asymptomatic nature of the majority of endometritis and cervicitis cases (chronicity of the inflammatory process) and the fact of their being diagnosed only at routine gynecological exams, lead us to suggest that their incidence is much higher [4, 6, 10, 11, 14, 18, 19, 21, 22]