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The purpose of this report is to comment the results from long-term growth hormone (GH) treatment of Bulgarian patients suffering from rare genetic disease-Prader-Willi syndrome (PWS) with reference to the age, body composition, complications and genetic etiology. Statistical analysis was performed by ANOVA with post hoc Kruskal-Wallis test and Dunn's multiple comparison tests. In 90% of the patients maternal uniparental disomy (mUPD) was found to be the cause of the disease. No cases due to imprinting defects are found. The BMI data shows no statistically significant difference between BMI at diagnosis (21.850), at the beginning of the GH therapy (21.852) and current BMI (24.09) - measured under the GH background. Early GH treatment allows to overcome arising obstacles in time and to improve the quality of life for PWS children and their families. During the fourteen years study period only ten patients were diagnosed with the disease. Ninety percent (n=9) of the children were found to be with maternal UPD (mUPD) and only one case was due to deletion in 15q11-13. These results are in agreement with other studies in the field which shows the need for reassessment and new robust statistical analysis of the frequency of genetic mechanisms for PWS.

The article is devoted to the peculiarities of autonomous sensory meridional response technologies application in marketing and advertising communication. In the context of the modern information oversaturation of a person, it is a promising technology of advertising due to its anti-stress orientation and indirect influence on the subconscious of recipients, which helps to create a favourable perception of an advertised product by the audience.

Coronary heart disease (CHD) is a major cause of mortality and morbidity in Europe. CHD is usually caused by atherosclerosis. Despite extensive studies that have identified a large number of genetic variants, strong evidence of association with CHD are not easily replicable in different populations. Two DNA pools were constructed: one with 32 Bulgarian centenarians and one with 61 young healthy Bulgarian individuals. The pools were whole-exome sequenced and variants were annotated and quality filtered (89,810 filtered variants). Allele frequencies were estimated and Fisher’s exact test was used to evaluate the significance of allele frequency differences between the two pools. Two publicly available databases, Ensembl and DisGeNET, were used as a source of 2025 CHD-associated variants (CHD-AVs). These single nucleotide polymorphisms were screened in our data and 158 variants in 133 genes were found. ToppGene pathways analysis of genes called in both pools discovered participation of 37 genes in 9 significantly over-represented pathways. Eight variants in these 37 genes have significantly higher frequency in young individuals, and are nominated for CHD association. Variants called only in the young individuals pool (13 variants) are also nominated for association with CHD. Based on sufficiently unambiguous literature data, from the nominated variants, we prioritize five as associated with CHD in the studied Bulgarian sample. Centenarian genomes can be used to provide additional information regarding the clinical relevance of genetic variants reported as associated with CHD.

The article discusses the problems of the innovative activity of managers in Russian enterprises as one of the conditions for the development of the labour potential of a region. The paper shows the main reasons for the low innovative activity of Russian enterprises. The systems of labour relations that have developed, as a rule, generate labour and innovative passivity as well as the opportunistic behaviour of managers. Most Russian enterprises lack incentive schemes for managers’ innovative activity. We propose a systematic approach to stimulating the innovative activity of managers, relying on the authors’ experience of researching the innovative activity of managers in a number of enterprises. The authors’ system «Innovation», which is a Russian version of the Japanese lean manufacturing system, stimulates the innovative activity of personnel. Implementing this system in the enterprises of the Ural Federal District has convincingly shown that in modern conditions, a radical increase in the innovative activity of business managers is possible. It, therefore, stimulates the development of regional labour potential. Our hypothesis is that a high innovative activity of managers in Russian enterprises is possible by developing and implementing a two-sided incentive system for stimulating managers’ innovative activity. Such a system should provide not only incentives for innovative activity but also managers’ responsibility for their innovative passivity. We suggest a system of concepts of the innovative activity of personnel, which is necessary when organizing work to stimulate the innovative activity of enterprise managers. For the first time in the theory of incentives for staff and practical activities of enterprises, we propose to introduce a semi-annual assessment of the innovative activity of managers. The assessment of managers’ innovative activity is an instrument for incentives for an enterprise. Moreover, for managers, it becomes one of the motivational factors for the manifestation of innovation activity. The research results were applied in the development of the System of Innovative Activity of Managers in OAO Uralelectromed and OAO Shadrinsky Auto Aggregate Plant. The results of the research can be applied in industrial enterprises of different legal status and forms of ownership.

Mutations in the receptor of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) are used as biomarkers for predicting the response of treatment with EGFR tyrosine kinase inhibitors (EGFR TKIs). Non-small cell lung cancer patients usually have activating EGFR mutations that leads to a very good response when they are treated with EGFR TKIs. Our tumor samples were examined for the presence of sensitive mutations in the EGFR gene, resistant mutations or the absence of mutations. To identify the types of the mutation, we used a real-time polymerase chain reaction (RT-PCR) method. Additionally, we evaluated the frequency of EGFR mutations and their association with smoking status, gender and histology. The tumor samples (n = 551) were tested for 29 somatic mutations in the EGFR gene. Sensitive mutations in the EGFR genes were found in 55 NSCLC samples (10.0%). The prevalence of EGFR mutations was much higher for females than for males (27.1 vs. 3.9%, p EGFR mutations was greater in subjects who had never smoked than in smokers (15.0 vs. 6.08%, p EGFR mutations was higher in adenocarcinomas than in other histological types (14.9 vs. 5.1%; p EGFR gene are more frequent in females than in males, in adenocarcinoma than other histological types and in non smokers than smokers.

Most of the principles related to top managers work incentives were inherited from the planned economy that produces demotivation and opportunistic behaviour. Remuneration is a commercial secret and shall not be disclosed. The system of top managers’ stimulation is unbalanced and does not motivate them to achieve medium- and long-term goals of the company. The study pays great attention to the development of managers’ stimulation policies, the transparency of remuneration, correlation between pay and performance. We provide practical examples of foreign and national experience, showing the ability to ensure the transparency of remuneration of managers, and the relation between compensation and performance. These examples show that managers’ remuneration amount does not always correspond to the efficiency of enterprises and return on capital. To solve these problems, we offer to develop philosophy and policy for the stimulation of managers in enterprises. It will allow to find a balance between the interests of shareholders and managers. Furthermore, this philosophy will have a positive impact on the competitiveness of enterprises in a region. The policy of stimulating managers should include certain key areas. Firstly, it should ensure the competitiveness of managers’ remuneration. Secondly, it implies studying the motives of managers’ work and the integration of these motives in the development of incentive system for the managers. Thirdly, it should include an optimal combination of elements to stimulate labour: base salary, material and social remuneration, short and long-term remuneration, etc. And last, it should consider the indicators and norms of enterprise’s effectiveness as well as the assessment of working results of managers. The results of this research can be used for further study of the stimulation of managers’ work in Russian companies. They can also be used in practice for the analysis of labour incentives of managers and their impact on the development of enterprises.

Objective. Ultrasound stimulation is an emerging neuromodulation technique, for which the exact mechanism of action is still unknown. Despite the number of hypotheses such as mechanosensitive ion channels and intermembrane cavitation, they fail to explain all of the observed experimental effects. Here we are investigating the ionic concentration change as a prime mechanism for the neurostimulation by the ultrasound. Approach. We derive the direct analytical relationship between the mechanical deformations in the tissue and the electric boundary conditions for the cable theory equations and solve them for two types of neuronal axon models: Hodgkin–Huxley and C-fibre. We detect the activation thresholds for a variety of ultrasound stimulation cases including continuous and pulsed ultrasound and estimate the mechanical deformations required for reaching the thresholds and generating action potentials (APs). Main results. We note that the proposed mechanism strongly depends on the mechanical properties of the neural tissues, which at the moment cannot be located in literature with the required certainty. We conclude that given certain common linear assumptions, this mechanism alone cannot cause significant effects and be responsible for neurostimulation. However, we also conclude that if the lower estimation of mechanical properties of neural tissues in literature is true, or if the normal cavitation occurs during the ultrasound stimulation, the proposed mechanism can be a prime cause for the generation of APs. Significance. The approach allows prediction and modelling of most observed experimental effects, including the probabilistic ones, without the need for any extra physical effects or additional parameters.

Celiac disease, or extreme gluten intolerance, is an autoimmune disease that primarily causes damage to the small intestine. It is caused by dietary intake of gluten in genetically predisposed individuals. The presentation of celiac disease consists of digestive tract symptoms, mainly diarrhea and subsequent weight loss. Other related symptoms and findings are iron deficiency anemia, decreased bone density, and some nonspecific neurological symptoms. In the recent past, the diagnosis of celiac disease was made based on specific serological tests, small intestinal mucosa biopsy results, and fading away of symptoms after gluten-free diet is applied. After the identification of the disease-specific genes HLA-DQ2 and DQ8 , genetic testing was considered the gold standard for the diagnosis of celiac disease, because the presence of a specific genotype is a prerequisite for the development of this disease. Risk variants of HLA-DQ2 and DQ8 are found in about 30% of the general European population. Determining the genetic status allows adequate subsequent clinical decisions. The lack of genetic variants predisposing to celiac disease leads to the exclusion of the diagnosis, while the detection of high-risk variant(s) in an individual prompts additional diagnostic steps through a number of serological and invasive tests. The introduction of genetic analysis has led to a significant reduction in the number of invasive intestinal tests (biopsies). The purpose of this article is to present the current practical approach in the diagnosis of celiac disease, which includes mandatory genetic analysis, and to explain the nature of this autoimmune disease from a genetic point of view.

In the article, the ways of influence of corporate culture on innovative activity of staff of enterprises are considered. The authors understand the corporate culture of the enterprise as the system of cultural, moral, esthetic and other wealth, which is used and introduced in labor life of employees by employers and CEO. On the basis of this system, the enterprise norms and rules of the relations of workers, customs, traditions etc. are developed. The corporate culture of the enterprise is connected with the general culture of the people of the country, it reflects on this or that form, to some extent, but it can contradict it. In this case, the conflict of cultural values of the enterprise and workers is possible. In the article, much attention is paid to influence of corporate culture of Japanese corporations on innovative activity of their workers. It is shown that high innovative activity of the personnel is provided not with separate systems of material and moral incentive, but with all system of the labor relations built on the basis of corporate culture. In the center of corporate culture, there is a person, instead of goods and services. It can be found in such systems of work with staff as “lifelong hiring†, account system in a salary of “vital peaks†of employees, staff turnover, training at the workplace etc. The corporate culture of Toyota corporation is based on the business philosophy, according to which, the main socio-economic purpose is the ensuring the welfare of its employees and improvement of life of the population of the whole world. In the article is shown that in the conditions of transition of the Russian Federation to the market economy, there were basic changes in corporate culture of the enterprises. Market business-culture according to which the main thing for the enterprise is profit, and workers are only one of means of production, was included in a contradiction with a mentality of the Russian people, its cultural and moral wealth that caused mass opportunistic behavior of workers including their innovative passivity. At the same time, in the article is shown that in these conditions, the high innovative activity of employees of the Russian enterprises on the basis of introduction of stimulation system of innovative activity of employees “Innovation†is possible. In the article, the mechanism of the increase of innovative activity of staff of the enterprises on the basis of corporate culture is offered.

Ендометриозата е хронично естроген-зависимо заболяване, което се характеризира с развитие на ендометриална тъкан извън маточната кухина. В световен мащаб засяга около 10% от жените. Заболяването може да причини дисменорея, хронична тазова болка, диспареуния и инфертилитет. Медикаментозното лечение играе ключова роля в контрола на заболяването. В повечето случаи е наложително лекарствената терапия да бъде комбинирана с хирургична, за да бъде постигнато пълно излекуване. Подходът при избор на подходящо медикаментозно лечение трябва да бъде индивидуализиран, като бъде съобразен с тежестта на ендометриозата, ефикасността на лекарството, страничните му ефекти, желанието на пациентката, възрастта ѝ и репродуктивните ѝ планове. Голяма част от използваните днес лекарства за лечение на ендометриоза целят потискане на овариалната функция. Най-често прилаганите и показващи най-добри резултати са комбинираните орални контрацептиви, аналозите на гонадотропин-освобождаващия хормон и прогестините. Освен тези утвърдени терапии, съвременното лечение включва и нови хормонално и нехормонално-базирани терапевтични подходи, които модулират различни патогенетични механизми. В този обзор ще бъдат разгледани настоящите терапевтични опции - както класическите, така и по-новите, все още неодобрени медикаменти за лечение на ендометриоза.

Етиологията, патогенезата и лечението на злокачествените новообразувания на пикочния мехур все още пораждат редица въпроси. Установени са биомаркери, показващи разлики в молекулния образ на инвазивния и неинвазивния уроепителен карцином, които са част от факторите, отговорни за големите вариации в лечението дори и при тумори с еднакъв хистологичен резултат. В момента стандартно прилаганата системна терапия включва различни цитотоксични химиотерапевтични схеми и се основава главно на хистологичната оценка и стадирането на тумора. От май 2016 г. за първи път се разреши прилагането на прицелна терапия при лечение на онкологични зболявания на пикочен мехур. Прицелната терапия се използва за спиране на растежа и разпространението на раковите клетки, посредством потискане на активирани сигнални пътища - най-често на фибробластния, епидермалния и ендотелния растежен фактор. Изборът на „правилното` лекарство се базира до голяма степен върху молекулно-генетичната диагноза на тумора и наличие на специфични биомаркери, показващи възможността за прилагане на едно или друго лекарство. През последните години е постигнат значителен напредък в ерата на молекулната диагностика и прицелната терапия, което неминуемо води до удължаване на преживяемостта на онкопоциентите и подобряване качеството им на живот. В тази статия ние разглеждаме потенциалните и съществуващите възможности за приложение на прецизирана терапия при пациенти с уроепителни тумори.

Нутригеномиката и нутригенетиката са нови направления в медицинските науки. Те се за­нимават с изучаването на молекулните механизми, чрез които обикновените химически веще­ства в диетата оказват влияние върху здравето и могат да модулират риска от развитие на заболяване при определен генетичен терен, включващ комбинации от вариации в няколко гена. През последните две десетилетия тези две дисциплини набират скорост, като в момента най-много резултати са получени чрез изследване на определени генетични вариации – еднонуклео­тидни полиморфизми (ЕНП), които са подходящ молекулярен инструмент за изследване на ро­лята на храненето в човешкото здраве, болестите и идентифицирането на оптимална диета. Хранителните вещества и геномът взаимодействат чрез потискане / индуциране на генната експресия или чрез разликите в активността на рецептори, ензими и пр., участващи във важни метаболитни пътища, като по този начин повлияват концентрацията на циркулиращите ве­щества и техните метаболити, както и способността на нутриентите да взаимодействат с отделните гени. Изясняването на тези механизми е от съществено значение за извършването на адекватна профилактика и повишаване ефективността от лечението при редица социално-значими заболявания като диабет тип 2, затлъстяване, сърдечно-съдови заболявания и някои видове рак.

Ракът на пикочния мехур е най-честото онкологично заболяване на отделителната система, като основната причина за появата му са инфекциите на уринарния тракт и ариламините в урината, които са в пряк досег със стената на мехура. Лечението на рака на пикочния мехур зависи главно от хистологичната характеристика на тумора, дълбочина на инвазия в мехурната стена и наличието на рецидиви. То бива оперативно отстраняване на тумора или хирургично лечение, съчетано с лъчелечение, химиотерапия или имунотерапия. При лечението на повърхностния неинвазивен рак на пикочния мехур, химиотерапията се използва с профилактична цел като интравезикална адювантна терапия след ендоскопска резекция. Най-често използваните химиотерапевтици са митомицин, епирубицин, доксорубицин и тиотепа. При инвазивният рак на пикочния мехур над половината от пациентите загиват в резултат от далечни метастази, произлезли от микрометастази в началото на туморната инвазия. За редуциране на броя и дълбочината на прорастване на микрометастазите се прилага комбинация от локално лечение и системна химиотерапия, a намаляване на размерите на първичния тумор се постига чрез неоадювантна химиотерапия с метотрексат, винбластин, адриамицин и цисплатина. При пациентите с напреднал метастатичен рак на пикочен мехур основен метод за лечение е химиотерапията. Прилагат се два режима на химиотерапия: M-VAC (метотрексат, винбластин, адриамицин, цисплатина) и CMV (цисплатина, метотрексат, винбластин). Друг подход използван при лечението за рак на пикочния мехур е имунотерапията, която използва собствените сили на организма в борбата с рака. Така при Carcinoma in situ (CIS), избор за лечение е интравезикално приложение на BCG (Bacillus Calmette-Guerin), което намалява инвалидизацията в следствие на терапевтичната цистектомия.

Background Balkan endemic nephropathy (BEN) represents a chronic progressive interstitial nephritis in striking correlation with uroepithelial tumours of the upper urinary tract. The disease has endemic distribution in the Danube river regions in several Balkan countries. DNA methylation is a primary epigenetic modification that is involved in major processes such as cancer, genomic imprinting, gene silencing, etc. The significance of CpG island methylation status in normal development, cell differentiation and gene expression is widely recognized, although still stays poorly understood. Methods We performed whole genome DNA methylation array analysis on DNA pool samples from peripheral blood from 159 affected individuals and 170 healthy individuals. This technique allowed us to determine the methylation status of 27 627 CpG islands throughout the whole genome in healthy controls and BEN patients. Thus we obtained the methylation profile of BEN patients from Bulgarian and Serbian endemic regions. Results Using specifically developed software we compared the methylation profiles of BEN patients and corresponding controls and revealed the differently methylated regions. We then compared the DMRs between all patient-control pairs to determine common changes in the epigenetic profiles. SEC61G, IL17RA, HDAC11 proved to be differently methylated throughout all patient-control pairs. The CpG islands of all 3 genes were hypomethylated compared to controls. This suggests that dysregulation of these genes involved in immunological response could be a common mechanism in BEN pathogenesis in both endemic regions and in both genders. Conclusion Our data propose a new hypothesis that immunologic dysregulation has a place in BEN etiopathogenesis.