Репозиторий Университета

© 2019 John Wiley  &  Sons Ltd Aim: To develop a quantitative drug-disease systems model to investigate the paradox that sodium-glucose co-transporter (SGLT)2 is responsible for >80% of proximal tubule glucose reabsorption, yet SGLT2 inhibitor treatment results in only 30% to 50% less reabsorption in patients with type 2 diabetes mellitus (T2DM). Materials and methods: A physiologically based four-compartment model of renal glucose filtration, reabsorption and excretion via SGLT1 and SGLT2 was developed as a system of ordinary differential equations using R/IQRtools. SGLT2 inhibitor pharmacokinetics and pharmacodynamics were estimated from published concentration-time profiles in plasma and urine and from urinary glucose excretion (UGE) in healthy people and people with T2DM. Results: The final model showed that higher renal glucose reabsorption in people with T2DM versus healthy people was associated with 54% and 28% greater transporter capacity for SGLT1 and SGLT2, respectively. Additionally, the analysis showed that UGE is highly dependent on mean plasma glucose and estimated glomerular filtration rate (eGFR) and that their consideration is critical for interpreting clinical UGE findings. Conclusions: Quantitative drug-disease system modelling revealed mechanistic differences in renal glucose reabsorption and UGE between healthy people and those with T2DM, and clearly showed that SGLT2 inhibition significantly increased glucose available to SGLT1 downstream in the tubule. Importantly, we found that the findings of lower than expected UGE with SGLT2 inhibition are explained by the shift to SGLT1, which recovered additional glucose (~30% of total).

© 2019, The Author(s).  Objectives: Glioblastoma (GB) contains diverse histologic regions. Apparent diffusion coefficient (ADC) values are surrogates for the degree of number of cells within the tumour regions. Because an assessment of ADC values and volumes within tumour sub-compartments of GB is missing in the literature, we aimed to evaluate these associations. Methods: A retrospective cohort of 48 patients with GB underwent segmentation to calculate tumour region volumes (in cubic centimetre) and ADC values in tumour regions: normal tissue, enhancing tumour, proximal oedema, distal oedema, and necrosis. Correlation, Kaplan-Meier, and Cox hazard regression analyses were performed. Results: We found a statistically significant difference among ADC values for tumour regions: F (4, 220) = 166.71 and p ≤.001 and tumour region volumes (necrosis, enhancing tumour, peritumoural oedema): F (2, 141) = 136.3 and p ≤.001. Post hoc comparisons indicated that the only significantly different mean score was the peritumoural volume in oedema region (p <.001). We observed a positive significant correlation between ADC of distal oedema and peritumoural volume, r =.418, df = 34, and p =.011. Cox proportional hazards regression analysis considering only tumour region volumes provided an almost significant model: − 2 log-likelihood = 146.066, χ 2 (4) = 9.303, and p =.054 with a trend towards significance of the hazard function: p =.067 and HR = 1.077 for the non-enhancing tumour volume. Conclusions: ADC values together with volumes of oedema region might have a role as predictors of progression-free survival (PFS) in patients with GB; we recommend a routine MRI assessment with the calculation of these biomarkers in GB.

© 2018 Elsevier Ltd An excessive inflammatory response is frequently associated with cellular dysfunction and cell death. The latter may cause single and multiple organ failure. The most susceptible organs are liver, lung, kidney, heart and intestine. This review will focus on the liver as a target organ for an excessive inflammatory response. It is commonly accepted that organ failure is caused by the action of inflammatory cytokines released in excess during the inflammatory response. It has been suggested that inflammation mediated liver failure is not due to an increased death rate of parenchymal cells, but due to an intracellular metabolic disorder. This metabolic disorder is associated with mitochondrial and endoplasmic reticulum (ER) dysfunction during the acute phase response elicited by systemic inflammation. An overproduction of acute phase proteins in the liver as well as elevated reactive oxygen species (ROS) generation induce ER stress, triggering the unfolded protein response (UPR), which may initiate or aggravate inflammation. It is known that certain inflammatory mediators, such as the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α induce ER stress. These findings suggest that ER stress and the subsequent UPR on the one hand, and the inflammatory response on the other create a kind of feed forward loop, which can be either beneficial (e.g., elimination of the pathogen and restoration of tissue homeostasis) or deleterious (e.g., excessive cell dysfunction and cell death). This review aims to unfurl the different pathways contributing to this loop and to highlight the relevance of UPR signaling (IRE1α, ATF6, and PERK) and mediators of the inflammatory response (NF-κB, STAT3, IL-1β, IL-6, TLR) which have a particular role as pathophysiological triggers in the liver.

© 2019, © 2019 Informa UK Limited, trading as Taylor  &  Francis Group. Introduction: Due to the polymorphic clinical presentations and manifestations of systemic lupus erythematosus (SLE), biomarkers with enough diagnostic and prognostic value are of paramount importance. Recently, anti-double stranded DNA (anti-dsDNA) auto-antibodies have been proposed to monitor the response to different therapies. It has also been suggested that they should be employed as entry markers in trial studies. However, their clinical use remains still debated and, sometimes, controversial, due to conflicting findings reported. Areas covered: Through an extensive literature review, we evaluated changes in anti-dsDNA auto-antibodies levels before and after the administration of the treatment (either biological or non-biological). Expert opinion: Anti-dsDNA auto-antibodies related findings are still difficult to compare mainly because of the different detecting methods employed, even though in most studies included in this review a consistent decreasing pattern after the treatment seems to emerge. Hence, if properly standardized, anti-dsDNA auto-antibody profile may be a reliable biomarker to monitor the effectiveness of biologics as well as of non-biological drugs, especially if grouped in composite outcomes scores, such as the ‘Lupus Multivariable Outcome Score’ (LUMOS) or measured with other biomarkers, such as anti-nucleosome auto-antibodies. We recommend the assessment of anti-dsDNA auto-antibodies levels in both daily practice and research settings.

© 2019 Elsevier Inc. Background: Low anterior resections are increasingly performed laparoscopically for rectal cancer. Recently, natural orifice specimen extraction surgery (NOSES) has been reported as an alternative approach without additional incisions or extensions. In this study, we aimed to evaluate the safety and feasibility of NOSES by comparing the short-term outcomes with those of conventional laparoscopic resection (CLR) in a multicenter retrospective study from China and Russia. Methods: The retrospective multicenter study was conducted at three centers between January 2015 and December 2017. Relevant collected data included patient demographics, operative parameters, and postoperative complications. All procedures were performed using either a NOSES or a CLR approach. Results: The data of a total of 768 consecutive patients with rectal cancer were retrospectively analyzed, including 412 CLR and 356 NOSES cases. The two groups were comparable for all demographics and characteristics except for the median tumor size (P = 0.038). No difference was found in the operative time and number of retrieved lymph nodes. Intraoperative complications and positive resection margins were nil in both groups. No difference was found in the time to first flatus (P = 0.150), time to first defecation (P = 0.084), length of postoperative hospital stay (P = 0.152), anastomotic leakage (P = 0.377), and intra-abdominal abscess (P = NA). The CLR group but not the NOSES group had incisional hernia or wound infection events, although the difference between groups was not significant (P = 0.253). Conclusions: The NOSES procedure is a well-established strategy and may be considered as an alternative procedure to CLR for rectal cancer. However, the long-term benefits of this approach require further evaluation.

© 2019, The Author(s). Abstract: In 2014 the International Endohernia Society (IEHS) published the first international “Guidelines for laparoscopic treatment of ventral and incisional abdominal wall hernias”. Guidelines reflect the currently best available evidence in diagnostics and therapy and give recommendations to help surgeons to standardize their techniques and to improve their results. However, science is a dynamic field which is continuously developing. Therefore, guidelines require regular updates to keep pace with the evolving literature. Methods: For the development of the original guidelines all relevant literature published up to year 2012 was analyzed using the ranking of the Oxford Centre for Evidence-Based-Medicine. For the present update all of the previous authors were asked to evaluate the literature published during the recent years from 2012 to 2017 and revise their statements and recommendations given in the initial guidelines accordingly. In two Consensus Conferences (October 2017 Beijing, March 2018 Cologne) the updates were presented, discussed, and confirmed. To avoid redundancy, only new statements or recommendations are included in this paper. Therefore, for full understanding both of the guidelines, the original and the current, must be read. In addition, the new developments in repair of abdominal wall hernias like surgical techniques within the abdominal wall, release operations (transversus muscle release, component separation), Botox application, and robot-assisted repair methods were included. Results: Due to an increase of the number of patients and further development of surgical techniques, repair of primary and secondary abdominal wall hernias attracts increasing interests of many surgeons. Whereas up to three decades ago hernia-related publications did not exceed 20 per year, currently this number is about 10-fold higher. Recent years are characterized by the advent of new techniques—minimal invasive techniques using robotics and laparoscopy, totally extraperitoneal repairs, novel myofascial release techniques for optimal closure of large defects, and Botox for relaxing the abdominal wall. Furthermore, a concomitant rectus diastasis was recognized as a significant risk factor for recurrence. Despite still insufficient evidence with respect to these new techniques it seemed to us necessary to include them in the update to stimulate surgeons to do research in these fields. Conclusion: Guidelines are recommendations based on best available evidence intended to help the surgeon to improve the quality of his daily work. However, science is a continuously evolving process, and as such guidelines should be updated about every 3 years. For a comprehensive reference, however, it is suggested to read both the initially guidelines published in 2014 together with the update. Moreover, the presented update includes also techniques which were not known 3 years before.

© 2019, The Author(s). Abstract: In 2014, the International Endohernia Society (IEHS) published the first international “Guidelines for laparoscopic treatment of ventral and incisional abdominal wall hernias.” Guidelines reflect the currently best available evidence in diagnostics and therapy and give recommendations to help surgeons to standardize their techniques and to improve their results. However, science is a dynamic field which is continuously developing. Therefore, guidelines require regular updates to keep pace with the evolving literature. Methods: For the development of the original guidelines, all relevant literature published up to year 2012 was analyzed using the ranking of the Oxford Centre for Evidence-Based Medicine. For the present update, all of the previous authors were asked to evaluate the literature published during the recent years from 2012 to 2017 and revise their statements and recommendations given in the initial guidelines accordingly. In two Consensus Conferences (October 2017 Beijing, March 2018 Cologne), the updates were presented, discussed, and confirmed. To avoid redundancy, only new statements or recommendations are included in this paper. Therefore, for full understanding both of the guidelines, the original and the current, must be read. In addition, the new developments in repair of abdominal wall hernias like surgical techniques within the abdominal wall, release operations (transversus muscle release, component separation), Botox application, and robot-assisted repair methods were included. Results: Due to an increase of the number of patients and further development of surgical techniques, repair of primary and secondary abdominal wall hernias attracts increasing interests of many surgeons. Whereas up to three decades ago hernia-related publications did not exceed 20 per year, currently this number is about 10-fold higher. Recent years are characterized by the advent of new techniques—minimal invasive techniques using robotics and laparoscopy, totally extraperitoneal repairs, novel myofascial release techniques for optimal closure of large defects, and Botox for relaxing the abdominal wall. Furthermore, a concomitant rectus diastasis was recognized as a significant risk factor for recurrence. Despite insufficient evidence with respect to these new techniques, it seemed to us necessary to include them in the update to stimulate surgeons to do research in these fields. Conclusion: Guidelines are recommendations based on best available evidence intended to help the surgeon to improve the quality of his daily work. However, science is a continuously evolving process, and as such guidelines should be updated about every 3 years. For a comprehensive reference, however, it is suggested to read both the initial guidelines published in 2014 together with the update. Moreover, the presented update includes also techniques which were not known 3 years before.

© 2019 The Authors This article is essentially a dataset necessary for analysing the taxation. The data analysis has allowed to determine the optimal taxation model, when the criteria of economic efficiency and equity are incompatible. The dataset has allowed the use of the method of successive concessions in tax optimization. The practical significance of the dataset lies in the ability to simultaneously improve the efficiency and equity in taxation. The dataset was obtained by using the method of expert estimates. A group of experts was asked to rank the taxes established by the Tax Code of the Russian Federation, in descending order of importance. Only strict rankings were allowed. The consistency of expert opinion was evaluated using the Kendall coefficient of concordance. The data set was supplemented with the expert ranking data of the basic principles of taxation, such as the principle of equity; the principle of certainty and accuracy of taxes; the principle of ease of tax collection for taxpayers; the principle of efficiency; the principle of commitment. The dataset can be used in the future to determine a rational amount of taxation depending on the established criteria.

© 2019 WILEY-VCH Verlag GmbH  &  Co. KGaA, Weinheim Polydimethylsiloxane (PDMS) is a long-standing material of significant interest in microfluidics due to its unique features. As such, rapid prototyping of PDMS-based microchannels is of great interest. The most prevalent and conventional method for fabrication of PDMS-based microchips relies on softlithography, the main drawback of which is the preparation of a master mold, which is costly and time-consuming. To prevent the attachment of PDMS to the master mold, silanization is necessary, which can be detrimental for cellular studies. Additionally, using coating the mold with a cell-compatible surfactant adds extra preprocessing time. Recent advances in 3D printing have shown great promise in expediting microfabrication. Nevertheless, current 3D printing techniques are sub-optimal for PDMS softlithography. The feasibility of producing master molds suitable for rapid softlithography is demonstrated using a newly developed 3D-printing resin. Moreover, the utility of this technique is showcased for a number of widely used applications, such as concentration gradient generation, particle separation, cell culture (to show biocompatibility of the process), and fluid mixing. This can open new opportunities for biologists and scientists with minimum knowledge of microfabrication to build functional microfluidic devices for their basic and applied research.

© 2019 The Authors. Alcoholism: Clinical  &  Experimental Research published by Wiley Periodicals, Inc. on behalf of Research Society on Alcoholism Background: The Alcohol Use Disorders Identification Test (AUDIT) was developed for use in primary health care settings to identify hazardous and harmful patterns of alcohol consumption, and is often used to screen for alcohol use disorders (AUDs). This study examined the AUDIT as a screening tool for AUDs. Methods: A systematic literature search was performed of electronic bibliographic databases (CINAHL, Embase, ERIC, MEDLINE, PsycINFO, Scopus, and Web of Science) without language or geographic restrictions for original quantitative studies published before September 1, 2018, that assess the AUDIT's ability to screen for AUDs. Random-effects meta-regression models were constructed by sex to assess the potential determinants of the AUDIT's specificity and sensitivity. From these models and ecological data from the Global Information System on Alcohol and Health, the true- and false-positive and true- and false-negative proportions were determined. The number of people needed to be screened to treat 1 individual with an AUD was estimated for all countries globally where AUD data exist, using a specificity of 0.95. Results: A total of 36 studies met inclusion criteria for the meta-regression. The AUDIT score cut-point was significantly associated with sensitivity and specificity. Standard drink size was found to affect the sensitivity and specificity of the AUDIT for men, but not among women. The AUDIT performs less well in identifying women compared to men, and countries with a low prevalence of AUDs have higher false-positive rates compared to countries with a higher AUD prevalence. Conclusions: The AUDIT does not perform well as a screening tool for identifying individuals with an AUD, especially in countries and among populations with a low AUD prevalence (e.g., among women), and thus should not be used for this purpose.

© 2019 IAP and EPC Background: Pancreatic calcifications is a common finding in patients with chronic pancreatitis (CP), but the underlying pathophysiology is incompletely understood. Past studies for risk factors of calcifications have generally been focused on single parameters or limited by small sample sizes. The aim of this study was to explore several patient and disease characteristics and their associations with pancreatic calcifications in a large cohort of CP patients with diverse aetiological risk factors. Methods: This was a multicentre, cross-sectional study including 1509 patients with CP. Patient and disease characteristics were compared for patients with calcifications (n = 912) vs. without calcifications (n = 597). Multivariable logistic regression was performed to assess the parameters independently associated with calcifications. Results: The mean age of patients was 53.9 ± 14.5 years and 1006 (67%) were men. The prevalence of calcifications was 60.4% in the overall patient cohort, but highly variable between patients with different aetiological risk factors (range: 2–69%). On multivariate analysis, alcoholic aetiology (OR 1.76 [95% CI, 1.39–2.24]; p < 0.001) and smoking aetiology (OR 1.77 [95% CI, 1.39–2.26], p < 0.001) were positively associated with the presence of calcifications, while an autoimmune aetiology was negatively associated with calcifications (OR 0.15 [95% CI, 0.08–0.27], p < 0.001). Patients with pancreatic calcifications were more likely to have undergone pancreatic duct stenting (OR 1.59 [95%CI, 1.16–2.19], p = 0.004). Conclusion: The presence of pancreatic calcifications is associated with diverse aetiological risk factors in patients with CP. This observation attest to the understanding of CP as a complex disease and may have implications for disease classification.

© 2019 Walter de Gruyter GmbH, Berlin/Boston. Altered cardiac geometry affects a proportion of fetuses with growth restriction (FGR). The aim of this study was to explore the hemodynamic factors associated with cardiac remodeling in late FGR. This was a prospective study of singleton pregnancies complicated by late-onset FGR undergoing assessment of left (LV) and right (RV) ventricular sphericity-index (SI). The study population was divided in two groups according to the presence of cardiac remodelling, defined as LVSI <5th centile. The following outcomes were explored: Gestational age at birth, birthweight, caesarean section (CS) for fetal distress, umbilical artery (UA) pH and neonatal admission to special care unit. The differences between the 2 groups in UA pulsatility index (PI), middle cerebral artery (MCA) PI, uterine artery PI, cerebroplacental ratio (CPR) and umbilical vein (UV) flow corrected for fetal abdominal circumference (UVBF/AC) were tested. In total, 212 pregnancies with late FGR were enrolled in the study. An abnormal LV SI was detected in 119 fetuses (56.1%). Late FGR fetuses with cardiac remodeling had a lower birthweight (2390 g vs. 2490; P = 0.04) and umbilical artery pH (7.21 vs. 7.24; P = 0.04) and were more likely to have emergency CS (42.8% vs. 26.9%; P = 0.023) and admission to special care unit (13.4% vs. 4.3%; P = 0.03) compared to those with normal LVSI. No difference in either UA PI (p = 0.904), MCA PI (P = 0.575), CPR (P = 0.607) and mean uterine artery PI (P = 0.756) were present between fetuses with or without an abnormal LV SI. Conversely, UVBF/AC z-score was lower (-1.84 vs.-0.99; P ≤ 0.001) in fetuses with cardiac remodeling and correlated with LV (P ≤ 0.01) and RV SI (P ≤ 0.02). Fetal cardiac remodelling occurs in a significant proportion of pregnancies complicated by late FGR and is affected by a high burden of short-term perinatal compromise. The occurrence of LV SI is independent from fetal arterial Dopplers while it is positively associated with umbilical vein blood flow.

© 2019, European Society of Radiology. Objectives: Invasive treatment of tumors adjacent to large hepatic vessels is a continuous clinical challenge. The primary aim of this study was to examine the feasibility of ablating liver tissue adjacent to large hepatic and portal veins with magnetic resonance imaging–guided high-intensity focused ultrasound (MRgHIFU). The secondary aim was to compare sonication data for ablations performed adjacent to hepatic veins (HV) versus portal veins (PV). Materials and methods: MRgHIFU ablations were performed in six male land swine under general anesthesia. Ablation cells of either 4 or 8 mm diameter were planned in clusters (two/animal) adjacent either to HV (n = 6) or to PV (n = 6), with diameter ≥ 5 mm. Ablations were made using 200 W and 1.2 MHz. Post-procedure evaluation was made on contrast-enhanced MRI (T1w CE-MRI), histopathology, and ablation data from the HIFU system. Results: A total of 153 ablations in 81 cells and 12 clusters were performed. There were visible lesions with non-perfused volumes in all animals on T1w CE-MRI images. Histopathology showed hemorrhage and necrosis in all 12 clusters, with a median shortest distance to vessel wall of 0.4 mm (range 0–2.7 mm). Edema and endothelial swelling were observed without vessel wall rupture. In 8-mm ablations (n = 125), heat sink was detected more often for HV (43%) than for PV (19%; p = 0.04). Conclusions: Ablations yielding coagulative necrosis of liver tissue can be performed adjacent to large hepatic vessels while keeping the vessel walls intact. This indicates that perivascular tumor ablation in the liver is feasible using MRgHIFU. Key Points: • High-intensity focused ultrasound ablation is a non-invasive treatment modality that can be used for treatment of liver tumors. • This study shows that ablations of liver tissue can be performed adjacent to large hepatic vessels in an experimental setting. • Liver tumors close to large vessels can potentially be treated using this modality.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Anorexia nervosa (AN) is an eating disorder often occurring in adolescence. AN has one of the highest mortality rates amongst psychiatric illnesses and is associated with medical complications and high risk for psychiatric comorbidities, persisting after treatment. Remission rates range from 23% to 33%. Moreover, weight recovery does not necessarily reflect cognitive recovery. This issue is of particular interest in adolescence, characterized by progressive changes in brain structure and functional circuitries, and fast cognitive development. We reviewed existing literature on fMRI studies in adolescents diagnosed with AN, following PRISMA guidelines. Eligible studies had to: (1) be written in English; (2) include only adolescent participants; and (3) use block-design fMRI. We propose a pathogenic model based on normal and AN-related neural and cognitive maturation during adolescence. We propose that underweight and delayed puberty—caused by genetic, environmental, and neurobehavioral factors—can affect brain and cognitive development and lead to impaired cognitive flexibility, which in turn sustains the perpetuation of aberrant behaviors in a vicious cycle. Moreover, greater punishment sensitivity causes a shift toward punishment-based learning, leading to greater anxiety and ultimately to excessive reappraisal over emotions. Treatments combining physiological and neurobehavioral rationales must be adopted to improve outcomes and prevent relapses.

© 2018 UICC The selective MEK1/2 inhibitor pimasertib has shown anti-tumour activity in a pancreatic tumour model. This phase I/II, two-part trial was conducted in patients with metastatic pancreatic adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m2) in 28-day cycles to identify the recommended phase II dose (RP2D) of pimasertib. In the phase II part, patients were randomised to pimasertib (RP2D) or placebo plus weekly gemcitabine (n = 88) to investigate progression-free survival (PFS), overall survival (OS) and safety. The RP2D was determined to be 60 mg BID. PFS and OS outcomes did not indicate any treatment benefit for pimasertib over placebo in combination with gemcitabine (median PFS 3.7 and 2.8 months, respectively, HR = 0.91, 95% CI: 0.58–1.42: median OS 7.3 vs. 7.6 months, respectively). KRAS status did not influence PFS or OS. The incidence of grade ≥3 adverse events was 91.1% and 85.7% for pimasertib/gemcitabine and placebo/gemcitabine respectively, but there was a higher incidence of ocular events with pimasertib/gemcitabine (28.9% vs. 4.8% for placebo/gemcitabine). In conclusion, no clinical benefit was observed with first-line pimasertib plus gemcitabine compared with gemcitabine alone in patients with mPaCa.

© 2018 American Association of Endodontists Introduction: The aim of the study was to determine long-term tooth survival after endodontic retreatment and whether the presence of intraradicular posts influences the outcome. Methods: Ninety-five teeth were randomly assigned to surgical or nonsurgical endodontic retreatment. Forty-seven teeth in 45 patients were treated by conventional endodontic surgery and 48 teeth (47 patients) by nonsurgical retreatment, including the removal of intraradicular posts in 37 (77%). The outcome was tooth survival; follow-up continued until the tooth had been extracted, at least 10 years had elapsed since retreatment, the patient declined further follow-up, or the patient died. The Fisher exact test was used to analyze differences between the groups. Results: The median follow-up time was 10.1 years (range, 0.0–15.6 years). The overall survival rate was 76%, with no significant differences in long-term tooth survival between retreatment methods or the presence of an intraradicular post. The reasons for tooth extraction were related to the retreatment method. Vertical root fractures were significantly more frequent in the nonsurgical group when retreatment included post removal (P =.036). Conclusions: There was no significant difference in long-term tooth survival after surgical or nonsurgical retreatment. The presence of intraradicular posts did not affect long-term tooth survival, but for teeth with posts, those retreated nonsurgically were more frequently extracted because of vertical root fractures than those retreated surgically (P =.036). The major limitations of the study were a smaller sample size and the use of outmoded retreatment techniques.

© 2018 2018 Walter de Gruyter GmbH, Berlin/Boston. Calcium drugs are analogs of endogenous substances. The baseline concentration of endogenous substances in the body and homeostasis mechanisms of regulation make the bioavailability and bioequivalence (BE) evaluation of these drugs very difficult. The aim of the study was to assess the pharmacokinetic parameters of calcium in the studies of comparative bioavailability combined with the assessment of homeostatic regulation mechanisms. The study included 42 healthy male volunteers. We studied the composition of 1000 and 1200 mg of calcium, and 800 and 1000 IU of cholecalciferol. Blood sampling was carried out at 8 a.m. and 0.5, 1, 2, 3, 4, 6, 8 h after administering the drugs. Calcium pharmacokinetic parameters were measured: the area under the curve (AUC) "concentration-time", and maximum concentration (Cmax) in volunteers. The excretion of calcium in urine in terms of creatinine clearance and parathyroid hormone (PTH) levels was assessed. The maximum excretion of calcium was converted to creatinine (calcium/creatinine). Enzyme-linked immunosorbent assay (ELISA) was used to determine the PTH and the o-cresolphthalein method to quantitatively measure the total calcium serum and urine. Results indicated that both the AUC and the excretion of calcium are comparable, and the differences are not statistically significant, p>0.05 (the ratio of calcium and creatinine in the urine maintained within physiological levels). The comparable dynamics of PTH concentration is an indirect measure of the amount of absorbed calcium. The study demonstrates that, along with the standard way of calculating the area under the curve "concentration-time" (total calcium in serum), it is important to assess the calcium excretion in urine in terms of creatinine excretion, as well as focusing on the changes in the PTH levels in volunteers, which could be considered as a marker of the calcium level in the blood.

© 2018 IEEE. Authors describe new effect of laser radiation in endoscopic urological surgery (BPH enucleation, en-bloc removal of bladder cancer, stricture endotomy): two-phase jet - a result of superintensive boiling in the area of laser radiation absorption and consisting of steam-gas microbubbles and hot water. In this case, the area of thermal influence appears significantly more, than thickness of a layer in which laser radiation is absorbed. Cutting soft tissue, the jet coagulates section walls due to heat generated at steam condensation. The same jet is formed behind the macrobubble, which is formed in liquid (Moses effect), because of boiling.

© 2018 Zlobin, Mokrushina, Terekhov, Zalevsky, Bobik, Stepanova, Aliseychik, Kartseva, Panteleev, Golovin, Belogurov, Gabibov and Smirnov. Butyrylcholinesterase (BChE) is considered as an efficient stoichiometric antidote against organophosphorus (OP) poisons. Recently we utilized combination of calculations and ultrahigh-throughput screening (uHTS) to select BChE variants capable of catalytic destruction of OP pesticide paraoxon. The purpose of this study was to elucidate the molecular mechanism underlying enzymatic hydrolysis of paraoxon by BChE variants using hybrid quantum mechanical/molecular mechanical (QM/MM) calculations. Detailed analysis of accomplished QM/MM runs revealed that histidine residues introduced into the acyl-binding loop are always located in close proximity with aspartate residue at position 70. Histidine residue acts as general base thus leading to attacking water molecule activation and subsequent SN2 inline hydrolysis resulting in BChE reactivation. This combination resembles canonical catalytic triad found in active centers of various proteases. Carboxyl group activates histidine residue by altering its pKa, which in turn promotes the activation of water molecule in terms of its nucleophilicity. Observed re-protonation of catalytic serine residue at position 198 from histidine residue at position 438 recovers initial configuration of the enzyme's active center, facilitating next catalytic cycle. We therefore suggest that utilization of uHTS platform in combination with deciphering of molecular mechanisms by QM/MM calculations may significantly improve our knowledge of enzyme function, propose new strategies for enzyme design and open new horizons in generation of catalytic bioscavengers against OP poisons.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Issues pertaining to determination of the pharmacokinetic parameters of calcium preparations are examined using their comparative bioavailability as an example. Pharmacokinetic parameters of calcium such as area under the concentration—time curve (AUC) and maximum concentration (Cmax) are calculated considering the background calcium contents in volunteers. Calcium excretion with urine is assessed as clearance of creatinine, a calcium elimination factor. The dynamics of the content of parathormone (PTH), the main hormone regulating calcium homeostasis, are studied. The results can be used to plan clinical trials for assessing the pharmacokinetics of drug analogs of endogenous compounds.