Pharmacoeconomical assessement of syphyllus primary and specialized health care

The article deals the results of pharmacoeconomical analysis of the syphilis in various forms drug supply. To assess the economic effect, the «budget impact analysis» (BIA) method was used. Significant economies of scale have been identified: savings from additional costs for pharmacotherapy of patients with syphilis, taking into account the low cost of this pathology.В статье описаны результаты организационно-фармацевтического и фармакоэкономического анализа лекарственного обеспечения различных форм сифилиса. Для оценки экономического эффекта применялся метод анализа «влияния на бюджет» (BIA). Выявлен значительный эффект масштаба экономии от добавочных затрат на фармакотерапию больных сифилисом с учетом низкой затратности данной патологии

Deep Learning in Processing Medical Images and Calculating the Orbit Volume

A software tool for calculating the volume of a soft-tissue eye orbit using the deep learning of neural network Mask R-CNN has been developed and tested. The result of the development will be in demand when evaluating the results of surgical intervention for the reconstruction of the thin bones of the orbit. It was established that the inaccuracy in constructing the contour of a soft-tissue orbit is 4–8%

Directional Sensitivity of the NEWSdm Experiment to Cosmic Ray Boosted Dark Matter

We present a study of a directional search for Dark Matter boosted forward when scattered by cosmic-ray nuclei, using a module of the NEWSdm experiment. The boosted Dark Matter flux at the edge of the Earth's atmosphere is expected to be pointing to the Galactic Center, with a flux 15 to 20 times larger than in the transverse direction. The module of the NEWSdm experiment consists of a 10 kg stack of Nano Imaging Trackers, i.e.~newly developed nuclear emulsions with AgBr crystal sizes down to a few tens of nanometers. The module is installed on an equatorial telescope. The relatively long recoil tracks induced by boosted Dark Matter, combined with the nanometric granularity of the emulsion, result in an extremely low background. This makes an installation at the INFN Gran Sasso laboratory, both on the surface and underground, viable. A comparison between the two locations is made. The angular distribution of nuclear recoils induced by boosted Dark Matter in the emulsion films at the surface laboratory is expected to show an excess with a factor of 3.5 in the direction of the Galactic Center. This excess allows for a Dark Matter search with directional sensitivity. The surface laboratory configuration prevents the deterioration of the signal in the rock overburden and it emerges as the most powerful approach for a directional observation of boosted Dark Matter with high sensitivity. We show that, with this approach, a 10 kg module of the NEWSdm experiment exposed for one year at the Gran Sasso surface laboratory can probe Dark Matter masses between 1 keV/c$^2$ and 1 GeV/c$^2$ and cross-section values down to $10^{-30}$~cm$^2$ with a directional sensitive search.Comment: 15 pages, 14 figures, updated references, clarified discussion in intro section. Submitted to JCA

КОМПЬЮТЕРНОЕ МОДЕЛИРОВАНИЕ ИНДИВИДУАЛЬНЫХ ЛИЦЕВЫХ ИМПЛАНТОВ

The possibilities of the spiral computed tomography to eliminate post-traumatic defects and deformations of the linear and geometric parameters of individual implants are studied. Set of criteria for assessing the orbital data is determined. Criteria allow to determine spatial dimensions of the defect and to build 3D model based on data.Изучены возможности применения спиральной компьютерной томографии для 3D моделирования и быстрого прототипирования индивидуальных размерно-геометрических параметров имплантатов при устранении посттравматических дефектов и деформаций глазницы и глазничного органокомплекса. Определен комплекс критериев оценки данных глазницы, позволяющие наиболее точно определять пространственные размеры дефекта и на основе полученных данных строить 3D модель

Disruption of Higher Order DNA Structures in Friedreich's Ataxia (GAA)n Repeats by PNA or LNA Targeting

Expansion of (GAA)n repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich’s ataxia. (GAA)n expansions form non-canonical structures, including intramolecular triplex (H-DNA), and R-loops and are associated with epigenetic modifications. With the aim of interfering with higher order H-DNA (like) DNA structures within pathological (GAA)n expansions, we examined sequence-specific interaction of peptide nucleic acid (PNA) with (GAA)n repeats of different lengths (short: n=9, medium: n=75 or long: n=115) by chemical probing of triple helical and single stranded regions. We found that a triplex structure (H-DNA) forms at GAA repeats of different lengths; however, single stranded regions were not detected within the medium size pathological repeat, suggesting the presence of a more complex structure. Furthermore, (GAA)4-PNA binding of the repeat abolished all detectable triplex DNA structures, whereas (CTT)5-PNA did not. We present evidence that (GAA)4-PNA can invade the DNA at the repeat region by binding the DNA CTT strand, thereby preventing non-canonical-DNA formation, and that triplex invasion complexes by (CTT)5-PNA form at the GAA repeats. Locked nucleic acid (LNA) oligonucleotides also inhibited triplex formation at GAA repeat expansions, and atomic force microscopy analysis showed significant relaxation of plasmid morphology in the presence of GAA-LNA. Thus, by inhibiting disease related higher order DNA structures in the Frataxin gene, such PNA and LNA oligomers may have potential for discovery of drugs aiming at recovering Frataxin expression

Long intronic GAA•TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia

Friedreich ataxia (FRDA) is caused by hyperexpansion of GAA•TTC repeats located in the first intron of the FXN gene, which inhibits transcription leading to the deficiency of frataxin. The FXN gene is an excellent target for therapeutic intervention since (i) 98% of patients carry the same type of mutation, (ii) the mutation is intronic, thus leaving the FXN coding sequence unaffected and (iii) heterozygous GAA•TTC expansion carriers with ∼50% decrease of the frataxin are asymptomatic. The discovery of therapeutic strategies for FRDA is hampered by a lack of appropriate molecular models of the disease. Herein, we present the development of a new cell line as a molecular model of FRDA by inserting 560 GAA•TTC repeats into an intron of a GFP reporter minigene. The GFP_(GAA•TTC)560 minigene recapitulates the molecular hallmarks of the mutated FXN gene, i.e. inhibition of transcription of the reporter gene, decreased levels of the reporter protein and hypoacetylation and hypermethylation of histones in the vicinity of the repeats. Additionally, selected histone deacetylase inhibitors, known to stimulate the FXN gene expression, increase the expression of the GFP_(GAA•TTC)560 reporter. This FRDA model can be adapted to high-throughput analyses in a search for new therapeutics for the disease

Friedreich's Ataxia (GAA)n•(TTC)n Repeats Strongly Stimulate Mitotic Crossovers in Saccharomyces cerevisae

Expansions of trinucleotide GAA•TTC tracts are associated with the human disease Friedreich's ataxia, and long GAA•TTC tracts elevate genome instability in yeast. We show that tracts of (GAA)230•(TTC)230 stimulate mitotic crossovers in yeast about 10,000-fold relative to a “normal” DNA sequence; (GAA)n•(TTC)n tracts, however, do not significantly elevate meiotic recombination. Most of the mitotic crossovers are associated with a region of non-reciprocal transfer of information (gene conversion). The major class of recombination events stimulated by (GAA)n•(TTC)n tracts is a tract-associated double-strand break (DSB) that occurs in unreplicated chromosomes, likely in G1 of the cell cycle. These findings indicate that (GAA)n•(TTC)n tracts can be a potent source of loss of heterozygosity in yeast

Progressive GAA·TTC Repeat Expansion in Human Cell Lines

Trinucleotide repeat expansion is the genetic basis for a sizeable group of inherited neurological and neuromuscular disorders. Friedreich ataxia (FRDA) is a relentlessly progressive neurodegenerative disorder caused by GAA·TTC repeat expansion in the first intron of the FXN gene. The expanded repeat reduces FXN mRNA expression and the length of the repeat tract is proportional to disease severity. Somatic expansion of the GAA·TTC repeat sequence in disease-relevant tissues is thought to contribute to the progression of disease severity during patient aging. Previous models of GAA·TTC instability have not been able to produce substantial levels of expansion within an experimentally useful time frame, which has limited our understanding of the molecular basis for this expansion. Here, we present a novel model for studying GAA·TTC expansion in human cells. In our model system, uninterrupted GAA·TTC repeat sequences display high levels of genomic instability, with an overall tendency towards progressive expansion. Using this model, we characterize the relationship between repeat length and expansion. We identify the interval between 88 and 176 repeats as being an important length threshold where expansion rates dramatically increase. We show that expansion levels are affected by both the purity and orientation of the repeat tract within the genomic context. We further demonstrate that GAA·TTC expansion in our model is independent of cell division. Using unique reporter constructs, we identify transcription through the repeat tract as a major contributor to GAA·TTC expansion. Our findings provide novel insight into the mechanisms responsible for GAA·TTC expansion in human cells

Molecular Characterization of Podoviral Bacteriophages Virulent for Clostridium perfringens and Their Comparison with Members of the Picovirinae

Clostridium perfringens is a Gram-positive, spore-forming anaerobic bacterium responsible for human food-borne disease as well as non-food-borne human, animal and poultry diseases. Because bacteriophages or their gene products could be applied to control bacterial diseases in a species-specific manner, they are potential important alternatives to antibiotics. Consequently, poultry intestinal material, soil, sewage and poultry processing drainage water were screened for virulent bacteriophages that lysed C. perfringens. Two bacteriophages, designated ΦCPV4 and ΦZP2, were isolated in the Moscow Region of the Russian Federation while another closely related virus, named ΦCP7R, was isolated in the southeastern USA. The viruses were identified as members of the order Caudovirales in the family Podoviridae with short, non-contractile tails of the C1 morphotype. The genomes of the three bacteriophages were 17.972, 18.078 and 18.397 kbp respectively; encoding twenty-six to twenty-eight ORF's with inverted terminal repeats and an average GC content of 34.6%. Structural proteins identified by mass spectrometry in the purified ΦCP7R virion included a pre-neck/appendage with putative lyase activity, major head, tail, connector/upper collar, lower collar and a structural protein with putative lysozyme-peptidase activity. All three podoviral bacteriophage genomes encoded a predicted N-acetylmuramoyl-L-alanine amidase and a putative stage V sporulation protein. Each putative amidase contained a predicted bacterial SH3 domain at the C-terminal end of the protein, presumably involved with binding the C. perfringens cell wall. The predicted DNA polymerase type B protein sequences were closely related to other members of the Podoviridae including Bacillus phage Φ29. Whole-genome comparisons supported this relationship, but also indicated that the Russian and USA viruses may be unique members of the sub-family Picovirinae