Unified representation of high- and low-resolution spectra to facilitate application of mass spectrometric techniques in clinical practice.

The majority of research in the biomedical sciences is carried out with the highest resolution accessible to the scientist, but, in the clinic, cost constraints necessitate the use of low-resolution devices. Here, we compare high- and low-resolution direct mass spectrometry profiling data and propose a simple pre-processing technique that makes high-resolution data suitable for the development of classification and regression techniques applicable to low-resolution data, while retaining high accuracy of analysis. This work demonstrates an approach to de-noising spectra to make the same representation for both high- and low-resolution spectra. This approach uses noise threshold detection based on the Tversky index, which compares spectra with different resolutions, and minimizes the percentage of resolution-specific peaks. The presented method provides an avenue for the development of analytical algorithms using high-resolution mass spectrometry data, while applying these algorithms in the clinic using low-resolution mass spectrometers.

[The comprehensive evaluation of the age-specific changes in the skin]. / Kompleksnaia otsenka vozrastnykh izmenenii kozhi.

The objective of the present study was to evaluate the age-specific changes in the skin at the anterior forearm surface of the men based on the results of the examination of 100 masculine corpses at the age varying from 18 to 80 years with the application of the low invasive techniques. The ultrasonograms were used to identify the qualitative characteristics of each skin layer being visualized with special reference to the thickness and echogenic properties of dermis and epidermis. The following parameters of the age-related changes in the skin microrelief were considered to be of particular interest: Volume (the volume of skin irregularities), SR (skin roughness), SW (skin wrinkling), and SS (skin smoothness). The qualitative characteristics of the age-specific changes in the skin as well as the parameters of its relief recorded during the ultrasound scanning can be used to comprehensively evaluate its age-related condition for the purpose of determination of the biological age of non-identified individuals. The calculation of the squared coefficient of correlation between the age-specific parameters of the skin and their changes taking into consideration the autosolvability requirements made it possible to predict the subject's age with a mean error of around 2.22 years.

High strength, biodegradable and cytocompatible alpha tricalcium phosphate-iron composites for temporal reduction of bone fractures.

In this work alpha tricalcium phosphate (α-TCP)/iron (Fe) composites were developed as a new family of biodegradable, load-bearing and cytocompatible materials. The composites with composition from pure ceramic to pure metallic samples were consolidated by pulsed electric current assisted sintering to minimise processing time and temperature while improving their mechanical performance. The mechanical strength of the composites was increased and controlled with the Fe content, passing from brittle to ductile failure. In particular, the addition of 25 vol% of Fe produced a ceramic matrix composite with elastic modulus much closer to cortical bone than that of titanium or biodegradable magnesium alloys and specific compressive strength above that of stainless steel, chromium-cobalt alloys and pure titanium, currently used in clinic for internal fracture fixation. All the composites studied exhibited higher degradation rate than their individual components, presenting values around 200 µm/year, but also their compressive strength did not show a significant reduction in the period required for bone fracture consolidation. Composites showed preferential degradation of α-TCP areas rather than ß-TCP areas, suggesting that α-TCP can produce composites with higher degradation rate. The composites were cytocompatible both in indirect and direct contact with bone cells. Osteoblast-like cells attached and spread on the surface of the composites, presenting proliferation rate similar to cells on tissue culture-grade polystyrene and they showed alkaline phosphatase activity. Therefore, this new family of composites is a potential alternative to produce implants for temporal reduction of bone fractures. STATEMENT OF SIGNIFICANCE: Biodegradable alpha-tricalcium phosphate/iron (α-TCP/Fe) composites are promising candidates for the fabrication of temporal osteosynthesis devices. Similar to biodegradable metals, these composites can avoid implant removal after bone fracture healing, particularly in young patients. In this work, α-TCP/Fe composites are studied for the first time in a wide range of compositions, showing not only higher degradation rate in vitro than pure components, but also good cytocompatibility and mechanical properties controllable with the Fe content. Ceramic matrix composites show high specific strength and low elastic modulus, thus better fulfilling the requirements for bone fractures fixation. A significant advance over previous works on the topic is the use of pulsed electric current assisted sintering together with α-TCP, convenient to improve the mechanical performance and degradation rate, respectively.

[THE CONTENTS OF FORMATION OF THE ELECTRIC WELDING ANASTOMOSIS OF STOMACH AND SMALL INTESTINE].

The character and sequence of changes in the tissues structure of the gastrointestinal walls under the impact of the impulse and constant delivery of electric pressure with frequency 440 kHz were studied. The investigation object was squeezed, using the force, measured from 2 to 6 N/mm2. The ЕКВЗ-300 «Patonmed¼ apparatus was used as a source of supply. Еlectric parameters of the process was fixed, using the analogue-numerical digital converter LCard E20-10 and laboratory oscilloscope Tektronix TDS 3014C. There was established, that electric conjunction of stomach and small intestine include three elements: destroying and disappearance of mucosa, connective tissue and membranes; fusion of the collagen fascicles and the smooth muscle cells; the loss of the collagen fascicles and the smooth muscle structure and creation of homogenous еlectric welding suture. The first two elements of the electric welding anastomosis are occurring simultaneously, but not dependent one from the other. At the welding suture completion the nondestructive changes of the tissues are spreading on a distance not more than 1 mm beyond the borders of the electrods apposition.

[Immunohistochemical study of the specific features of expression of matrix metalloproteinases 1, 9 in the photoaged skin, the foci of actinic keratosis and basal cell carcinoma]. / Immunogistokhimicheskoe issledovanie osobennostei ekspressii matriksnykh metalloproteinaz 1, 9 v kozhe s dermatogeliozom, ochagakh aktinicheskogo keratoza i bazal'no-kletochnogo raka kozhi.

Matrix metalloproteinases (MMPs) mediate the degradation of all types of collagens and other extracellular matrix components (elastin, proteoglycans, and laminin), their synthesis and accumulation play a key role in the hydrolysis of basement membrane. MMPs are involved in a wide range of proteolytic processes in the presence of different physiological and pathological changes, including inflammation, wound healing, angiogenesis, and carcinogenesis. AIM: to study the specific features of MMP-1 and MMP-9 expression in different stages of skin photoaging, in the foci of actinic keratosis and basal cell carcinoma by immunohistochemical examination. MATERIAL AND METHODS: 12 samples of the healthy skin (6 samples of the eyelid skin with Glogau grade II photoaging; 6 ones of eyelid skin with Glogau grades III-IV photoaging) and biopsies from 8 foci of actinic keratosis and from 8 ones of basal cell carcinoma were examined. A positive reaction to MMPs was shown as different brown staining intensity in the cytoplasm of keratinocytes/tumor cells. RESULTS: MMP-1 and MMP-9 expression was recorded in 67% of the histological specimens of the Glogau grade III photoaged skin and in 100% of those of Glogau grade IV. In the foci of actinic keratosis, the expression of MMP-1 was observed in 62.5% of cases and that of MMP-9 was seen in 87.5%. In basal cell carcinoma, the expression of MMP-1 and MMP-9 was detected in all investigated samples. CONCLUSION: The immunomorphological findings are indicative of the important role of the level of MMP-1 and MMP-9 expression that is associated with the degree of progression of skin photoaging processes. Minimal MMP-1 and MMP-9 expression was recorded even in grades III-IV photoaging and in the foci of actinic keratosis. Intense MMP-1 and MMP-9 expression was detected in malignant skin epithelial neoplasms as different clinicomorphological types of basal cell carcinoma.

[Assessment of skin photoaging in middle-aged and elder patients with non-melanoma skin cancers].

The development of methods of early detection of non-melanoma skin cancers, assessment of risk factors, including photoaging, by means of non-invasive techniques are the main research interests of modern dermato-oncology and gerontology. In our study we aim to investigate the range of clinical features of photoaging in 92 patients older than 50 years (50 patients had malignant epithelial skin tumors (actinic keratosis, basal cell carcinoma), to reveal risk factors for basal-cell carcinoma using adapted SCINEXA scale and to assess of the pathomorphological features of dermathoheliosis using reflectance confocal microscopy. The assessment of photoaging by means of SCINEXA with subsequent non-invasive evaluation using reflectance confocal microscopy allows to evaluate the cumulative effect of the ultraviolet irradiation on the skin with objective criteria. That algorithm is perspective in terms of early detection of the risk factors of non-melanoma skin cancers.

[The modern non-invasive methods for the evaluation of the age-specific changes in the skin].

The present review article is designed to analyse the current state-of-the-art in the field of diagnostics of the main morphological and functional parameters characterizing the involutional processes in the facial skin. The possibilities of the practical application of the available non-invasive methods for the evaluation of the age of the living people in the framework of the forensic medical identification expertise are considered. The main problems and vectors of the further development of methodological approaches to the determination of the biological age based on the results of the studies of skin and its appendages are discussed.

[BIOELECTRIC ACTIVITY OF INTERNEURONES OF SPINAL CORD IN THE EXPERIMENTAL MENOPAUSE IN FEMAL RATS].

We analyzed the amplitude-time characteristics of the components of the potential dorsal surface of the spinal cord (PDS SC) in experimental menopause. The excitation threshold increased at 102.14% and the latent period at 94.12% in animals with experimental menopause. In the context of supramaximal stimulation of dorsal root L5 identified N1 amplitude growth at 10.14%, N2 at 11.82%, N3 at 48.28%, and P-wave 31.58% and to increase component N3 26.54% in the experimental group. At condition of paired stimulation pulses on the time interval from 2 to 3 ms there was a significant increase, and from 6 to 30 ms--a depression of N1-component of the second PDS SC in the group of animals with experimental menopause. Thus, our results suggest the presence of changes in nerve structures of the posterior horn of the spinal cord at conditions of estrogen deficiency.

Mechanical and tribological behavior of silicon nitride and silicon carbon nitride coatings for total joint replacements.

Total joint replacements currently have relatively high success rates at 10-15 years; however, increasing ageing and an active population places higher demands on the longevity of the implants. A wear resistant configuration with wear particles that resorb in vivo can potentially increase the lifetime of an implant. In this study, silicon nitride (SixNy) and silicon carbon nitride (SixCyNz) coatings were produced for this purpose using reactive high power impulse magnetron sputtering (HiPIMS). The coatings are intended for hard bearing surfaces on implants. Hardness and elastic modulus of the coatings were evaluated by nanoindentation, cohesive, and adhesive properties were assessed by micro-scratching and the tribological performance was investigated in a ball-on-disc setup run in a serum solution. The majority of the SixNy coatings showed a hardness close to that of sintered silicon nitride (~18 GPa), and an elastic modulus close to that of cobalt chromium (~200 GPa). Furthermore, all except one of the SixNy coatings offered a wear resistance similar to that of bulk silicon nitride and significantly higher than that of cobalt chromium. In contrast, the SixCyNz coatings did not show as high level of wear resistance.

Measurement of the neutron F2 structure function via spectator tagging with CLAS.

We report on the first measurement of the F(2) structure function of the neutron from the semi-inclusive scattering of electrons from deuterium, with low-momentum protons detected in the backward hemisphere. Restricting the momentum of the spectator protons to ≲100 MeV/c and their angles to ≳100° relative to the momentum transfer allows an interpretation of the process in terms of scattering from nearly on-shell neutrons. The F(2)(n) data collected cover the nucleon-resonance and deep-inelastic regions over a wide range of Bjorken x for 0.65

Effects of expression of transcriptional factor AP-1 FOSL1 gene on psoriatic process.

We performed quantitative analysis of FOSL1 gene expression in lesional psoriatic skin. The expression of this gene in lesional psoriatic skin was significantly increased compared to that in unaffected areas. Enhanced FOSL1 expression significantly correlated with high psoriasis area and severity index (PASI). High level of FOSL1 gene expression was proposed to be a marker of pathological process activity in psoriasis.

[Correction of the antioxidative system during ozone therapy in peritonitis].

Clinical studies revealed correlation of changes in anti-oxidative system and lipid peroxidation with peritonitis phases. The assessment of anti-oxidative system was used as an additional diagnostic and prognostic criterion for the disease. Data are presented in proof of efficiency of an ozone physiological solution included in combined treatment of acute peritonitis. Ozone therapy helped to normalize functioning of the anti-oxidative defensive system and thereby decrease the incidence of severe complications and fatal cases among patients with peritonitis.

[Evaluation of fludarabine-containing regimens versus immunochemotherapy for chronic lymphocytic leukemia].

AIM: to analyze the efficacy of RFC (rituximab, fludarabine, and cyclophosphan), FCM (fludarabine, cyclophosphan, and mitoxantrone), and FC (fludarabine and cyclophosphan) treatment programs in patients with chronic lymphocytic leukemia (CLL) in an open-labeled comparative controlled investigation. MATERIALS AND METHODS: The paper presents the authors' results of treatment in patients with progressive CLL in 2002 to 2007. The study included 229 patients, of them 78 patients received the RFC program, 72 had the FCM program, and 79 had the FC one. RESULTS: With the use of RFC, a clinically significant therapeutic effect was obtained in 96% of the patients, a complete remission (CR) was in 80% of the primary patients and in 53% of the pretreated patients. When the FCM program was applied, a positive response was noted in 93% of the patients, CR was seen in 75 and 42% of the primary and pretreated patients, respectively. In the treatment of FC, the total effect was 80%, CR was in 41 and 14% of the primary and pretreated patients, respectively. CONCLUSION: Comparative analysis of an objective response to therapy has indicated that the effectiveness of the RFC significantly exceeds that of the FCM and FC programs, without enhancing toxicity, which allows he RFC regimen to be regarded as the program of choice in therapy for CLL.

From anti-allergic to anti-Alzheimer's: Molecular pharmacology of Dimebon.

Dimebon, originally developed as an anti-histamine drug, is being re-purposed for new indications as an effective treatment for patients suffering from Alzheimer's and Huntington's diseases, albeit with an as-yet unknown mechanism of action. We have performed molecular pharmacology profiling of this drug on a panel of 70 targets to characterize the spectrum of its activity, with the goal to possibly elucidate a potential molecular mechanism for the re-purposing of this drug candidate. We show that in addition to histaminergic receptors, Dimebon exhibits high affinity to a constellation of other receptors; specifically serotonergic, alpha-adrenergic and dopaminergic receptors. Good correlations with published literature were obtained for the affinity of Dimebon to inhibit butyrylcholinesterase, interact with H1and H2 receptors (Ki = 2 nM and 232 nM), and to block histamine-induced calcium fluxes in cells. Within serotonergic receptor subtypes, Dimebon shows highest affinity for 5-HT7 (Ki=8 nM) and 5-HT6 (Ki=34 nM) receptors, with the relative affinity rank-order of 5-HT7 > 5-HT6 > or = 5-HT2A = 5-HT2C > 5-HT1A = 5-HT1B > 5-HT2B=5-HT3. Dimebon also interacts with adrenergic receptor subtypes (rank-order: alpha1A (Ki = 55 nM)= alpha1B > or = alpha2A (Ki = 120 nM) = alpha1D), and dopaminergic receptor subtypes (rank-order: D1=D2S=D2L (Ki approximately 600 nM) >D3> or =D4.2>D4.4> or =D4.7). These results demonstrate a molecular pharmacological basis for re-purposing of this drug to new therapeutic areas. The informed targeting of the combined molecular target activities may provide additional advantages for patients suffering from similar diseases syndromes. Understanding the role that different pathways play in diseases with complex etiologies may allow for the rational design of multi-target drugs.

New approaches to the treatment of inflammatory disease : focus on small-molecule inhibitors of signal transduction pathways.

This 'state-of-the-art' review specifically focuses on alternative signalling pathways deeply involved in acute and chronic inflammatory responses initiated by various pathological stimuli. The accumulated scientific knowledge has already revealed key biological targets, such as COX-2, and related pro-inflammatory mediators (cytokines and chemokines, interleukins [ILs], tumour necrosis factor [TNF]-alpha, migration inhibition factor [MIF], interferon [IFN]-gamma and matrix metalloproteinases [MMPs]) implicated in uncontrolled, destructive inflammatory reaction. A number of physiologically active agents are currently approved for market or are under active investigation in different clinical trials. However, recent findings have exposed the fatal adverse effects directly associated with drug therapy based on COX-2 inhibition. Given these possible harmful outcomes, a range of novel therapeutically relevant biological targets that include nuclear transcription factor (NF-kappaB), p38 mitogen-activated protein kinases (MAPK) and Janus protein tyrosine kinases and signal transducers and activators of transcription (JAK/STAT) signalling pathways has received growing attention. Here we discuss recent progress in the identification and development of novel, clinically approved or evaluated small-molecule regulators of these signalling cascades as promising anti-inflammatory drugs.

Redox status of rats during treatment by ozonated saline according to different protocols.

Repeated daily injections of ozonated saline to intact rats significantly modified their redox status. Intensification of free-radical processes paralleled by suppression of the antioxidant system creates prerequisites for failure of adaptation and compensation mechanisms of homeostasis.

[Contractile capacity of fibroblasts from different sources in the model of living skin equivalent].

Human fibroblasts contract collagen gel in vitro and produce a connective tissue-like structure termed the living skin equivalent. In this study, the contractile capacity of postnatal dermal fibroblasts, bone marrow mesenchymal cells and mesenchymal cells derived from the fat tissue has been compared to that of fetal dermal fibroblasts in the model of living skin equivalent. The results show that fetal fibroblasts contract the collagen gel approximately six times stronger than do all other fibroblast cell types, with the numbers of all these cells being equal. A deeper insight into the behavior of fibroblasts differing in their origin will help to develop new approaches to the treatment and regulation of wound healing and fibrosis formation.

[Apoptosis and micro- and macroelement composition of lymphocytes in patients with pulmonary tuberculosis].

The paper describes the results of comparatively analyzing the parameters of apoptosis, micro- and macroelement spectrum of peripheral blood lymphocytes in healthy donors and in patients with chronic obstructive pulmonary disease (COPD) and pulmonary tuberculosis. In drug-responsive and drug-resistant pulmonary tuberculosis, unidirectional pretreatment changes were generally recorded in the activity of apoptosis and the spectrum of chemical elements of peripheral blood lymphocytes, which were most pronounced after completion of a phase of intensive antituberculosis chemotherapy. After termination of a complete course of the therapy, apoptotic activity lowered with the cationic composition of cells being normalized. The parameters differentiating pulmonary tuberculosis from COPD were ascertained, these included increases in the count of apoptotic cells and the cell concentrations of Ca2+, Zn2+, and Mg2+.

[Polymorphism of glutathion-S-transferase genes in patients with prostatic cancer].

The study of polymorphic variants of GSTT1, GSTM1 and GSTP1 genes from 61 patients with prostatic cancer (PC) has shown that incidence of 0/0 genotype GSTT1 and GSTM1 in PC patients was significantly higher of that in healthy men (n = 100) (34.4 and 15% in p = 0.007 and 60.7 and 43% in p = 0.04, respectively). PC risk in carriers of a GSTT1 deletion form was 2.97, CI95%--1.3-6.84, GSTM1--2.04 in CI95% 1.02-4.1. The analysis of combinations of pathological genotypes of xenobiotic biotransformation enzymes has demonstrated that 89.8% PC patients have a mutation in one of the genes GSTT1, GSTM1 or GSTP1.

[Mechanisms underlying changes in functional properties of red cells in acute action of carbon monoxide].

It has been experimentally established that a single impact of carbon mono-oxide in concentration 4000 mg/m3 during 75 minutes (CL50) in rats is accompanied with disturbance of functional activities of blood red cells in the form of a decrease of deformability and an increase of aggregative capacity of erythrocytes which are most evident to the end of the first day after carbon mono-oxide administration. These changes are combined with structural modification and changes in metabolism of erythrocytic membrane. The signs of structural modification of erythrocytic membrane in rats exposed to acute effect of carbon mono-oxide in a mean lethal concentration stay long remaining during elimination of carboxyhemoglobinemia (up to 14-21 days).