Репозиторий Университета

© 2019 The Journal of Rheumatology. All rights reserved. Objective. To determine whether neutropenia is associated with increased risk for infection in patients with systemic juvenile idiopathic arthritis (sJIA) and polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with tocilizumab (TCZ). Methods. Data up to Week 104 from 2 phase III trials of intravenous TCZ in sJIA (n = 112; ClinicalTrials.gov, NCT00642460) and pcJIA (n = 188; ClinicalTrials.gov, NCT00988221) were pooled. Worst common toxicity criteria grade and lowest observed absolute neutrophil count (ANC) were identified for each patient. Associations between patient characteristics and lowest observed ANC were tested using univariate regression analysis. Infection and serious infection rates per 100 patient-years (PY) in periods associated with grades 1/2 and 3/4 neutrophil counts were compared with rates associated with normal neutrophil counts. Results.ANC decreased to grade ≥ 3 in 25.0% and 5.9% of sJIA and pcJIA patients, respectively, and decreases were transient. Young age (p = 0.047) and methotrexate use (p = 0.012) were positively associated with neutropenia in patients with sJIA but not in patients with pcJIA. The rate of serious infections in patients with sJIA (10.9/100 PY; 95% CI 6.8-16.5) tended to be higher than in patients with pcJIA (5.2/100 PY; 95% CI 3-8.5). No increase in rates of serious or nonserious infections was observed during periods of neutropenia in either trial. Conclusion. Patients with JIA treated with TCZ experienced transient neutropenia that was not associated with an increased number of infections.

© 2019, Springer Nature B.V. The objective of this study was to determine the impact of polymorphism of CYP3A subfamily isoenzymes (allelic variants of CYP3A4*22 and CYP3A5*3) on the efficacy clopidogrel in patients with an acute coronary syndrome (ACS), who have undergone percutaneous coronary intervention (PCI). Platelet activity was determined on a VerifyNow P2Y12 test system in 81 patients with ACS aged 37–91 who had PCI. The activity of CYP3A4/5 was expressed as the ratio of the concentrations of cortisol and 6β-hydroxycortisol was performed by using high performance liquid chromatography. Genotyping was performed by using real-time polymerase real-time chain reaction. The frequencies for the CYP3A5 gene, rs 776746, were identified as follows: 77 (95.1%)—CC, 4 (4.9%)—CT; the allele frequencies by loci for the CYP3A4, rs rs35599367, were as follows: 78 (96.3%)—GG, 3 (3.7%)—AG. There was no statistically significant genotype-dependent difference between the presence of a minor T and G alleles and the presence of clopidogrel resistance (OR 3.53; 95% CI 0.46–26.94; p = 0.233 and p = 0.443, respectively). The average level of the metabolic relationship (6β-hydroxycortisol/cortisol) between the clopidogrel-resistant group and the normal platelet reactivity group was not statistically significantly different: 3.3 ± 2.8 versus 3.2 ± 3.2; p = 0.947. So, the activity of CYP3A4/5 was not related to platelet aggregation rates in this model. Genotyping and phenotyping CYP3A4\CYP3A5 does not predict the antiplatelet effect of clopidogrel. More extensive research is required to establish their clinical relevance.

© 2019 by the authors. Real-time molecular navigation of tissue surgeries is an important goal at present. Combination of electrosurgical units and mass spectrometry (MS) to perform accurate molecular visualization of biological tissues has been pursued by many research groups. Determination of molecular tissue composition at a particular location by surgical smoke analysis is now of increasing interest for clinical use. However, molecular analysis of surgical smoke is commonly lacking molecular specificity and is associated with significant carbonization and chemical contamination, which are mainly related to the high temperature of smoke at which many molecules become unstable. Unlike traditional electrosurgical tools, low-temperature electrosurgical units allow tissue dissection without substantial heating. Here, we show that low-temperature electrosurgical units can be used for desorption of molecules from biological tissues without thermal degradation. The use of extractive electrospray ionization technique for the ionization of desorbed molecules allowed us to obtain mass spectra of healthy and pathological tissues with high degree of differentiation. Overall, the data indicate that the described approach has potential for intraoperative use.

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. The aim of the present study was to compare the cardiodynamic parameters in the isolated rat heart in animals chronically treated with cisplatin, platinum(IV) complex and its diamine ligand. Sixty Wistar albino rats (8 weeks old) were divided into five groups: three experimental and two control groups. Animals in all groups were treated with a dose of 4 mg/kg body weight once a week for 4 weeks with different substances; experimental groups received cisplatin, ligand and octahedral platinum(IV) complex, and control groups received saline and dimethyl sulfoxide. After sacrificing the animals, hearts were isolated and perfused according to the Langendorff technique at gradually increased coronary perfusion pressures (40–120 cmH2O). The following parameters of cardiac function were continuously recorded: maximum and minimum rate of change of pressure in the left ventricle, systolic and diastolic left ventricular pressure, heart rate and coronary flow. The results showed statistically significant differences between all experimental groups in maximum and minimum rate of pressure development as well as in systolic pressure of the left ventricle, whereas cisplatin, ligand and the platinum(IV) complex had effects on heart contractility without significant influences on coronary circulation. The findings of the present study could be important for a better understanding of anticancer drug cardiac side effects. Our results indicate that compared to cisplatin as a “gold standard”, novel platinum complexes and ligands do not possess fewer negative effects on the heart, indicating insufficient safety for their usage in terms of affecting cardiac function, a result that can be of great interest for further investigations.

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. The superficial femoral artery (SFA) is a typical atherosclerosis-prone site. We aimed to explore whether the tortuosity of the SFA associates with the occurrence of atherosclerosis and investigate how vascular tortuosity influences the characteristics of blood flow. Ten patients diagnosed with atherosclerotic disease in their SFAs while free of systemic atherosclerosis risk factors were enrolled together with ten atherosclerosis-free patients. The tortuosity of each SFA was quantitatively evaluated by calculating the averaged curvature (AC), maximum curvature (MC) and fraction of high curvature (FC) based on the geometrical model reconstructed from medical images. Hemodynamic studies were performed using both geometrically simplified and anatomically realistic models of the SFA to systematically address the hemodynamic effects of vascular tortuosity. Morphological analyses revealed that all curvature indices of the SFA were significantly larger in patients with atherosclerosis than in atherosclerosis-free patients (AC [mm−1]: 0.034 ± 0.016 vs. 0.018 ± 0.006; MC [mm−1]: 0.055 ± 0.023 vs. 0.034 ± 0.008; FC [%]: 22.77 ± 10.22 vs. 11.39 ± 6.82; p < 0.001). Simulations of blood flows in the geometrically simplified SFAs showed that increasing vascular curvature caused a progressive increase in the area ratios of low wall shear stress (LWSA) and high oscillatory shear index (HOSA). Hemodynamic studies on the anatomically realistic SFAs further demonstrated that high-curvature SFAs (n = 10) had overall larger LWSA and HOSA compared with low-curvature SFAs (n = 10) (LWSA [%]: 4.13 ± 1.91 vs. 1.79 ± 1.13, p = 0.009; HOSA [%]: 4.95 ± 1.92 vs. 2.37 ± 1.51, p = 0.007). These results suggest that increased vascular tortuosity augments the severity and distribution of atherosclerosis-promoting flow disturbances in the SFA and may be an independent risk factor for atherosclerosis.

© 2019 The Author(s). Background: Spontaneous pregnancy loss and implantation failure after assisted reproductive technologies (ART) are very common occurrences. Although 50-60% of all cases remains unexplained, various predisposing factors, including thrombophilias, have been identified. Thus, the potential benefit of a prophylaxis with low-molecular-weight heparins in improving outcomes has been often investigated over the years. However, the majority of studies are observational and results from randomized clinical trials (RCTs) are inconclusive, probably due to heterogeneity and limited sample size. To cover these unmet needs and to have further data mainly based on the real-life clinical management, we designed these multicenter registries. Methods: OTTILIA (Observational sTudy on antiThrombotic prevention in thrombophILIA and pregnancy loss) and FIRST (recurrent Failures in assIsted Reproductive Techniques) registries are two prospective, multicenter, observational studies to evaluate pregnancy or ART outcomes in consecutive women with previous reproductive failures after spontaneous or assisted conception, respectively. All enrolled women are observed from their first visit after positive pregnancy test (OTTILIA) or before commencing a new ART cycle (FIRST) until the end of pregnancy or ART procedure (negative pregnancy test/end of pregnancy, if successful cycle), respectively. Data are collected by means of questionnaires and recorded in a central database. Follow-up investigations are performed during hospital stay, routine clinical follow-up visits or telephone interviews. Primary outcome is live birth rate in the OTTILIA register and clinical pregnancy rate in the FIRST. Discussion: Although RCTs are the 'gold standard' for evaluating treatment outcomes, we believe that our registries represent a valid alternative in improving knowledge on mechanisms involved in reproductive failures and supporting future clinical decisions. Trial registration: NCT 02385461, retrospectively registered 5 March 2015 (OTTILIA); NCT 02685800, registered 10 February 2016 (FIRST).

© 2018, SICOT aisbl. Objective: To investigate the effect of knee arthroscopic synovectomy (AS) on the disease activity, quality-of-life (QoL), and the functional status of patients with rheumatoid arthritis (RA). Materials and methods: A retrospective analysis was conducted on the outcomes of AS performed on 138 RA patients; pre-surgery assessments were done using Disease Activity score (DAS 28) and Routine Assessment of Patient Index Data З (RAPID-3) on а multidimensional health-assessment questionnaire for disease activity, EuroQol-5D (EQ-5D) and the Short-Form Medical Outcomes Study (SF-36) for quality of life, and the Health Assessment Questionnaire (HAQ) for functional status. The pain response to SA was measured by а visual analogue score (VAS) and the Knee Society Score (KSS). Results: All parameters assessed in the study showed significant positive changes: the activity of the disease decreased, and patients’ functional status and QoL improved. Conclusion: AS is effective treatment for recurrent synovitis of the knee in RA patients. This technique improves the functional status of patients and their quality of life and reduces the activity of the disease.

© 2019, The Author(s). Introduction: This study examined the dynamics of 24-h electrocardiogram (ECG) monitoring parameters (Holter monitoring) in patients with ischemic heart disease (IHD) before and after conservative or surgical treatment of patients with voiding and storage lower urinary tract symptoms (LTS) due to benign prostatic hyperplasia (BPH). Methods: A total of eighty-three 57 to 81-year-old (mean age 70.4 ± 5.75 years) patients with LUTS/BPH and accompanying IHD were examined and treated at the Institute of Urology and Human Reproductive Health and Clinic of Cardiology of Sechenov University. All patients received recommended cardiac therapy at least 6 months before inclusion in the study. Results: Our study demonstrated that there is correlation between voiding and storage LUTS/BPH and Holter-detected cardiac impairments in patients with IHD/BPH. These data make it possible to consider LUTS/BPH (voiding and storage) as a factor in the additional functional and psychological load on the activity of patients with ischemic heart disease. Improvement of voiding and storage LUTS due to BPH and objective parameters of urination (Qmax) in patients treated with alpha-1 adrenoceptor blocker tamsulosin correlated with improvement of 24-h ECG monitoring parameters (Holter monitoring) in 72% of patients. Improvement of 24-h ECG monitoring parameters (Holter monitoring) 1 month after transurethral resection of the prostate (TURP) in IHD/BPH patients and indications for surgical treatment was observed in 65.7%. Negative dynamics of the Holter-based ECG was not registered in patients who were operated on. Conclusion: Holter monitoring helps to identify groups of patients in whom urinary impairments caused by prostatic hyperplasia negatively affect the course of IHD. Restored urination (either conservatively or operatively) in patients with BPH in 72% of cases decreased the number of fits of angina, thus influencing favourably the course of IHD. Trial Registration: ClinicalTrials.gov Identifier: NCT03856242.

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. A total of 100 women with early pregnancy loss were recruited and further classified into two subgroups: sporadic pregnancy loss and recurrent pregnancy loss; each subgroup consisted of 50 women. The control group included 56 women with normal pregnancies. Genotyping was performed by PCR with restriction fragment length polymorphism analysis. A statistically significant increase in the frequencies of TT genotype and T allele for DNMT3B rs2424913 polymorphism was found in the total patient group and in both patient subgroups in comparison with the control. Moreover, homozygous TT genotype was associated with increased risk of early pregnancy loss (both sporadic and recurrent). DNMT3B rs2424913 gene polymorphism in women can be used a marker of predisposition to early pregnancy loss and recurrent pregnancy loss.

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. A model of moderate hyperhomocysteinemia associated with mechanical injury of the musculoskeletal system was developed and experimentally substantiated. The adequacy of this model for studies of morphological and functional regularities is verified. This model can be used for the development of a new concept of evaluation of thrombotic complications of mechanical injury.

© 2019 Wiley Periodicals, Inc. Introduction: Sarcomas of the mandible are extremely rare tumors, with osteosarcoma being the most common, followed by Ewing's sarcoma. Materials and methods: A retrospective review of the clinical records, imaging studies, and pathology slides of patients with sarcoma of the mandible at a Tertiary Care Cancer Center from 1998 to 2014 was undertaken. The impact of neoadjuvant chemotherapy and postoperative radiotherapy with or without chemotherapy was studied, and factors impacting upon local control and disease-specific survival were analyzed. Results: Twenty-two patients were treated over the study period, comprising of 15 males and seven females. External swelling, intraoral growth, or facial numbness were the presenting symptoms. Eighteen patients had osteosarcoma and four had the Ewing's sarcoma. Nine patients received neoadjuvant chemotherapy. All but one patient underwent surgery. Eleven had negative margins, with 90% recurrence-free survival at 3 years, compared to 10 with positive or close margins, leading to 67% recurrence-free survival. None of the patients receiving neoadjuvant chemotherapy developed recurrence and all were alive at 3 years. The impact of postoperative radiotherapy or adjuvant chemotherapy was not statistically significant. Conclusions: Wide surgical resection with negative margins remains the hallmark of surgical treatment.

© 2019 Background and aim: The increase of the carbohydrate-deficient transferrin (CDT) as results of an heavy intake of alcohol for at least two weeks, is a well-known biochemical modification since the middle ‘70s. Notwithstanding the first commercial kit for the diagnosis of chronic alcohol abuse based on this biomarker was commercially accessible already thirty years ago, only expensive analytical methods are currently available for its determination. The present paper shows a new approach intrinsically sensitive and specific, based on a specific derivatization of transferrin, and not requiring sophisticated instrumentation. Methods: The proposed procedure is based on a selective chelation of terbium (III) by transferrin followed by detection using an characteristic Fluorescence Resonance Transfer Energy (FRET) phenomenon (ex 298 nm - em 550 nm). Results: The proposed procedure showed a limit of detection of 2.5 pmol/mL and a reproducibility intra-day and inter-days <15% and 20%, respectively. The results obtained analyzing 40 serum samples using the developed method, were compared with those obtained with HPLC-Vis and an R2 = 0.8854 was found. Conclusions: Considering its main features (low-cost, ease of operation, minimum need of instrumentation) the present method is suitable for application in screening contexts and in non-strictly regulated environments (e.g. clinical diagnosis) as well as in developing countries or remote areas.

© 2019 Elsevier Ltd Objective: Polymorphous adenocarcinoma of salivary gland (PAC) is rare. Despite being described as a low risk histology, some patients develop regional and distant metastasis. More aggressive behavior has been attributed to a PAC subcategory called cribriform adenocarcinoma of minor salivary glands (CAMSG). We examined oncological outcomes of PAC. Patients and methods: Fifty-seven patients with PAC were identified from an institutional database of 884 patients surgically treated for salivary gland malignancies from 1985 to 2015. Detailed histopathological analysis was performed. Survival outcomes were calculated using the Kaplan-Meier method. Factors predictive of recurrence were identified using the Cox proportional hazard method. Results: Fifty-four (95%) had tumors of minor salivary gland origin; the most frequent location was the oral cavity in 41 (76%), specifically the hard palate in 32 (55%). Forty-six patients (81%) were clinical T1-T2; 3 (5%) had a clinically positive neck. Thirty-two patients (56%) were classified as PAC and 14 (25%) as CAMSG. Forty-four patients (77%) had surgery alone; 13 (23%) had surgery and postoperative radiotherapy. The 5- and 10-year overall survival and disease-specific survival were 88% and 79% and 98% and 94%, respectively (median follow up 84 [1–159] months); 5- and 10-year recurrence-free survival were 93% and 88%, respectively. Univariate analysis showed male sex, III/IV stage, and CASMG variant had increased incidence of recurrence but were not statistically significant. Conclusion: PAC of the salivary glands is an indolent disease with good survival outcomes. Recurrence is uncommon and tends to occur late. Long-term follow-up is indicated in patients with this disease.

© 2019 Elsevier Inc. Asialo-human transferrin (asialo-hTf) is a glycoform of the human serum protein transferrin characterized by the lack of the sialic acid (SA) terminal unit. It is known that glycosylation micro-heterogeneity and the presence of SA are strongly involved in protein functioning and pathophysiological activities. Some hTf glycoforms are valuable biomarkers for the detection of both genetic defects of glycosylation and/or sialoform distribution changes. The detection of the carbohydrate deficient transferrin (CDT) glycoforms is currently a widely employed method for the diagnosis of chronic alcohol abuse. The physiological significance of asialo-hTf is still unclear, despite its important biological implications. The current knowledge suggests that asialo-hTf may be involved in regulation of iron transport and release at the hepatic level, which, consequently, could strongly be affected by alcohol consumption. For these reasons, a deeper understanding of asialo-hTf structure and its physiological role is required, and an improved method of its analysis would favor the detection of both chronic abuse and other habits of alcohol intake and/or misuse. Thus, suitable analytical methods possessing higher sensitivity and specificity in comparison with the currently available techniques are certainly recommended. The present review summarizes the studies on asialo-hTf structure, roles, and detection techniques mainly in relation to its possible use as a potentially additional useful biomarker of alcohol abuse, and underlines its prospective value as a forensic and diagnostic tool.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Human serum albumin nanoparticles (HSA-NPs) have been widely used as drug delivery systems. In most cases, HSA-NPs are formed by the method of desolvation in the presence of glutaraldehyde as a crosslinking agent. In the present study, we showed the possibility of crosslinking human serum albumin (HSA) molecules with natural agents, urea, and cysteine at the nanoparticle level under mild conditions (at room temperature of 20–25 °C). Optimal concentrations of the interacting components (HSA, urea, and cysteine) were found to produce nanoparticles with optimal physico-chemical parameters (particle size, polydispersity, zeta potential, yield, etc.) for application as drug carriers. We used hydroxyurea (HU), a simple organic compound currently used as a cancer chemotherapeutic agent. The results indicated sizes of 196 ± 5 nm and 288 ± 10 nm with a surface charge of −22 ± 3.4 mV and −17.4 ± 0.5 mV for HSA-NPs (20 mg/mL of HSA, 0.01 mg/mL of cysteine, and 10 mg/mL of urea) and HSA–HU-NPs (2 mg/mL of HU), respectively. The yield of the HSA–HU-NPs was ~93% with an encapsulation efficiency of ~77%. Thus, the particles created (immobilized with HU) were stable over time and able to prolong the effect of the drug.

© 2019 American Pharmacists Association® Various drug delivery systems (DDSs) are often used in modern medicine to achieve controlled and targeted drug release. Diffusional release of drugs from DDSs is often the main mechanism, especially at early times. Generally, average dimensions of DDS are used to model the drug release, but our recent work on drug release from fibers demonstrated that taking into account diameter distribution is essential. This work systematically investigated the effect of size distribution on diffusional drug release from DDSs of various geometric forms such as membranes, fibers, and spherical particles. The investigation clearly demonstrated that the size distribution has the largest effect on the drug release profiles from spherical particles compared to other geometric forms. Published experimental data for drug release from polymer microparticles and nanoparticles were fitted, and the diffusion coefficients were determined assuming reported radius distributions. Assuming the average radius when fitting the data leads to up to 5 times underestimation of the diffusion coefficient of drug in the polymer.

Тhe rapid increase in the frequency of сesarian section (CS) observed in recent years (up to 60% in some countries) is alarming and reduces the reproductive potential of the population. The operated uterus remains the main indication for CS (up to 40%). This is the factor which may allow reducing the frequency of the CS by subsequent delivering through the birth canal. A comparative analysis of maternal and neonatal outcomes enabled the authors to develop a two-stage delivery technology for patients with a caesarean scar, including the usage of the programmed delivery method. The presented algorithm confirmed the validity of vaginal delivery in such patients, and reduced the number of complications up to 4 times. Neonatal morbidity in children born through the birth canal in such patients was comparable to physiological birth.

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Near-IR spectroscopy is a promising analytical method in pharmacy. It was shown that it can be used as a rapid method for confirming the identity and analyzing the purity of kemantane (5-hydroxyadamantan-2-one) drug substance.

© 2019, Mary Ann Liebert, Inc., publishers 2019. The purpose of our work was to study late cardiac complications after treatment for Hodgkin's lymphoma (HL) in children and adolescents. Methods: Sixty-seven patients were examined in the long term (>5 years) after chemoradiotherapy for HL according to two different programs of treatment (groups I and II). Mean total doses of radiotherapy (RT) to the mediastinum were 37.2 and 28.9 Gy, respectively. The status of the heart was assessed at the mean age of 22.7 years with electrocardiography (ECG) and echocardiography (EchoCG). Mean terms of follow-up were 16.4 and 9.5 years for group I and group II, respectively. Results: Incidence of ECG changes was equal between the groups (88% and 90%). The prevalence of signs of valvular calcifications and fibrosis was 70.9% after mediastinal doses ≥30 Gy, and 16.6% after lower doses (p = 0.002). Those changes led to considerable valvular dysfunction in four patients. EchoCG signs of pulmonary hypertension were seen in 33.3% patients of group I versus 4.8% in group II (p = 0.047). Pericardial effusion was observed in 7.4% and 5.1%, respectively (p = 1.0). Left ventricular ejection fraction decreased slightly only in two patients (one in each group). Conclusions: The RT mediastinal dose level is the important risk factor of late heart complications. Nevertheless, the differences in the rate and severity of those complications between the groups should be viewed with caution because of differences in the age at baseline and in follow-up terms. The survivors of HL should undergo life-long regular examinations of the heart status.

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. Purpose of review More than 30 years ago, the first molecular structures of allergens were elucidated and defined recombinant allergens became available. We review the state of the art regarding molecular AIT with the goal to understand why progress in this field has been slow, although there is huge potential for treatment and allergen-specific prevention. Recent findings On the basis of allergen structures, several AIT strategies have been developed and were advanced into clinical evaluation. In clinical AIT trials, promising results were obtained with recombinant and synthetic allergen derivatives inducing allergen-specific IgG antibodies, which interfered with allergen recognition by IgE whereas clinical efficacy could not yet be demonstrated for approaches targeting only allergen-specific T-cell responses. Available data suggest that molecular AIT strategies have many advantages over allergen extract-based AIT. Summary Clinical studies indicate that recombinant allergen-based AIT vaccines, which are superior to existing allergen extract-based AIT can be developed for respiratory, food and venom allergy. Allergen-specific preventive strategies based on recombinant allergen-based vaccine approaches and induction of T-cell tolerance are on the horizon and hold promise that allergy can be prevented. However, progress is limited by lack of resources needed for clinical studies, which are necessary for the development of these innovative strategies.