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The biocompatibility and effects on cells' bioactivity of developed pharmaceuticals are crucial properties, required to permit their safe delivery. Nanogel matrices offer a promising role in emerging pharmaceutics; however, it is crucial that they and their excipients do not demonstrate detrimental effects on the cells to which they interact. This study investigated the use of Teflon and the secondary bile acid deoxycholic acid in the formation of novel nanogel matrices. Each has properties which may be of benefit for the nanogels created and their use in the pharmaceutical industry. Rheological parameters and scanning electron microscopy studies were conducted. In order to assess the developed nanogels' impacts on cellular bioactivity, studies using Seahorse assays were conducted on three cell types, hepatic, muscle and pancreatic beta cells. Results demonstrated the addition of Teflon did not alter the morphological characteristics of resulting nanogels or the metabolic profiles of the cell lines. Interestingly, pancreatic beta cells highlighted the potential of Teflon to exert a protective profile from mitochondrial damage. Overall, the developed nanogels showed potentially promising profiles in certain studies conducted which may lead to future research.

Bile acids (BAs) are amphiphilic compounds and of recently have demonstrated wide range of formulation stabilizing effects. A recent study showed that primary un-metabolised bile acids (PUBAs) have β-cell protective effects, and synergistic antidiabetic effects when combined with antioxidant and anti-inflammatory drugs, such as probucol (PB). Thus, this study aimed to design and test microcapsules containing a PUBA incorporated with PB and an alginate-Eudragit matrix.Six types of microcapsules were developed without (control) or with (test) PUBA, and tested for internal and external features and β-cell protective effects.The incorporation of PB-alginate-Eudragit with PUBA produced stable microcapsules but did not exert consistent positive effects on cell viability in the hyperglycaemic state, which suggests that PUBA in alginate-Eudragit matrices did not exhibit synergistic effects with PB nor exerted antidiabetic effects. Keywords: Probucol, Microencapsulation, Eudragit, Alginate, Oral delivery, Diabetes mellitus

The paper describes an experimental, mechanically simple, tactile sensing solution in the form of a sensing chair for discriminating human motion in a reaching task. This cost-efficient technical approach was employed for the assessment of selective arm movements in stroke survivors. The sensing system classifies trunk motion in a seated stroke survivor during a goal-directed task where there is direct correlation with the level of severity of arm movement. The system interprets motion mechanically from coupled sensory data transients using artificial neural networks and shows tolerance to patients’ sitting posture and performance variability. The accuracy of classification was typically greater than 94% across three categories when applied to a group of stroke survivors of wide-ranging motor abilities. The mechanical simplicity, versatility of approach for use in other classes of movement, and potential low cost of manufacturing provides opportunity to employ the system at clinics and homes for assessment and training.

In order to investigate potential therapeutically agents, novel products of Biginelli reaction (4a-l) were synthesized and exposed to cytotoxic and caspase activities, angiogenesis, cell cycle distribution, gene and microRNA expression levels, lipophilicity assessment and docking study. Among the twelve novel compounds (4a-l) evaluated for the cytotoxic activity, five of them (4c,4d,4f,4kand4l) that showed excellent activity on the tested cell lines (HeLa, LS174 and A549) were selected for further evaluation. Interestingly, compound4fhas up to three times higher selectivity index (SI) towards cancer cells than cisplatin (on HeLa, LS174 and A549 SI = 18.2, 13.5 and 11.2, respectively). The obtained results from cell cycle distribution and caspase activity indicate that tested compounds (4c,4d,4f,4kand4l) promoted caspase-9 activation, implicated in the intrinsic pathway of apoptosis. Lipophilicity of4a-lwas determinate by using reversed-phase high-performance liquid chromatography. Graphical abstract https://ars.els-cdn.com/content/image/1-s2.0-S0045206818312598-ga1_lrg.jpg

Transportable normothermic kidney perfusion for 24 hours or longer could enable viability assessment of marginal grafts, increased organ use, and improved transplant logistics. Eleven clinically declined kidneys were perfused normothermically, with 6 being from donors after brain death (median cold ischemia time 33 ± 36.9 hours) and 5 being from donors after circulatory death (36.2 ± 38.3 hours). Three kidneys were perfused using Ringer’s lactate to replace excreted urine volume, and 8 kidneys were perfused using urine recirculation to maintain perfusate volume without fluid replenishment. In all cases, normothermic perfusion either maintained or slightly improved the histopathologically assessed tubular condition, and there was effective urine production in kidneys from both donors after brain death and donors after circulatory death (2367 ± 1798 mL vs 744.4 ± 198.4 mL, respectively; P = .44). Biomarkers, neutrophil gelatinase–associated lipocalin, and kidney injury molecule‐1 were successfully detected and quantified in the perfusate. All kidneys with urine recirculation were readily perfused for 24 hours (n = 8) and exhibited physiological perfusate sodium levels (140.7 ± 1.2 mmol/L), while kidneys without urine recirculation (n = 3) achieved a reduced normothermic perfusion time of 7.7 ± 1.5 hours and significantly higher perfusate sodium levels (159.6 ± 4.63 mmol/:, P, Normothermic machine perfusion of human kidneys for 24 hours is feasible, and urine recirculation facilitates maintenance of perfusate volume and homeostasis.

Background: This retrospective analysis assessed all recorded malaria cases in Bulgaria after 1965, when the country was certified as malaria-free by the World Health Organization (WHO), and evaluated the readiness of the public health system to interrupt an outbreak of local transmission in case of infection importation. Methods: The cases were analyzed according to causative species; geographic origin of the imported case; and the citizenship, age, and gender of the infected individuals. Results: In the 50-year study period (1966–2015), there were a total of 3011 cases of malaria imported to Bulgaria from different regions of the world. The majority of the cases originating in Africa were caused by Plasmodium falciparum (65.5%), while most of these originating in Asia were caused by P. vivax (80.9%). The potential season for malaria transmission in Bulgaria is from April to October, and 58.5% of the malaria cases were imported during that time of the year. Conclusions: The increasing movement of people to and from areas endemic for malaria requires the health authorities of countries with appropriate conditions for reintroduction to conduct enhanced measures for surveillance and control of this potentially deadly disease. Keywords: Local transmission, Reintroduction, Surveillance, Control

Increased antimicrobial resistance together with the lack of new antimicrobial drugs suggest on an urgent need for new therapeutics in this field. Vanilidene derivatives of Meldrum’s acid present one of the possible approaches. In this work lipophilicity of 13 vanilidene derivatives of Meldrum’s acid as well as their predicted antimicrobial activity towards several characteristic species has been evaluated. 10 vanilidene derivatives have been previously synthesized and 3 new compounds are synthetized afterwards following the same procedure. These selected 13 candidates were examined using thin layer chromatography in two different solvent systems. Gained retention parameters were a starting point for further Quantitative Structure Property Relationships (QSRR) studies in which minimum inhibitory concentration (MIC) for Candida albicans, Trichoderma viride, Penicillium italicum, Fuscarium oxysporum, Pseudomonas aeruginosa and Escherichia coli were determined. Statistically significant QSRR models were established and clustering of the compounds was performed with the help of principal component analysis (PCA) and hierarchical cluster analysis (HCA). Absorption, Distribution, Metabolism, and Excretion (ADME) properties of investigated molecules were subjected to sum of ranking differences (SRD) analysis in order to explore their pharmacokinetic properties. SRD analysis was also performed for the ranking of the established QSRR models. It was shown that compounds 6, 8 and 9 possess a significant antimicrobial activity, satisfied ADME properties and these candidates should be further optimized in order to utilize unexplored potential of Meldrum's acid in synthesis of novel antifungal compounds.

Purpose: The study aimed to explore the relationship of different exposure measures with 131I therapy response in patients with benign thyroid disease, estimate the variability in the response, investigate possible covariates, and discuss dosing implications of the results. Methods: A population exposure-response analysis was performed using nonlinear mixed-effects modelling. Data from 95 adult patients with benign thyroid disease were analysed. Evaluated exposure parameters were: administered radioactivity dose (Aa) [MBq], total absorbed dose (ABD) [Gy], maximum of absorbed dose-rate (MXR) [Gy/h] and biologically effective dose (BED) [Gy]. The response was modelled as ordered categorical data: hyper-, eu- and hypothyroidism. The final model performance was evaluated by a visual predictive check. Results: The probability of the outcome following 131I therapy was best described by a proportional-odds model, including the log-linear model of 131I effect and the exponential model of the response-time relationship. All exposure measures were statistically significant with p

Context The bile acid taurocholic acid (TCA) is endogenously produced, and has shown formulation-stabilising effects when incorporated into microcapsules containing potential antidiabetic drugs. This study aimed to develop and characterise TCA-microcapsules, and test their antidiabetic effects, in an animal model of Type 1 diabetes (T1D). Methods Using the polymer sodium alginate (SA), SA-microcapsules (control) and TCA-microcapsules (test) were prepared, and assessed for morphology, surface composition, chemical and thermal stability, swelling, buoyancy, mechanical, release and rheological properties. TCA-microcapsules were gavaged as a single dose (1.2 mg/300 g) to alloxan-induced diabetic rats, and blood glucose and TCA concentrations in serum, tissues (ileum, liver and pancreas) and faeces, were measured. One healthy and one diabetic group were used as control and gavaged SA-microcapsules. Results TCA-microcapsules showed consistent size, TCA presence on surface and all layers of microcapsules, chemical and thermal stability, enhanced swelling, buoyancy and targeted-release properties and rheological analysis showed Non-Newtonian flow properties. TCA serum concentrations were lower in the healthy group, compared with the diabetic and diabetic-treated groups, but there was no significant difference between diabetic control and diabetic treated groups, in terms of TCA levels, and blood glucose concentrations. Conclusions The developed TCA-microcapsules showed good stability and release properties, but did not lower blood glucose levels in T1D, which suggests absence of insulin-mimetic effects, when using a single 1.2 mg/rat oral dose.

Comprehensive characterization of important parameters of biopolymer polyhydroxyalkanoates (PHAs) was performed. Biodegradable PHA polymer material was applied for fabrication of components using for cost effective xurography method.Inductor-capacitor structure was fabricated on PHA, sensor characteristics were determined in air, saliva and gastric fluid. This is the peer-reviewed version of the article: Goran M. Stojanović, Jasmina Nikodinović-Runić, Stefan Švenderman, Tijana Kojić, Milan Radovanović, Momir Mikovc, Danijela Randjelović, Comprehensive characterization of elastomeric polyhydroxyalkanoate and its sensor applications, Materials Science & Engineering C, 2020, 115, 111091, [https://doi.org/10.1016/j.msec.2020.111091] Published version: [http://cer.ihtm.bg.ac.rs/handle/123456789/3578]

Background Adverse neurologic outcome in preterm infants could be associated with abnormal heart rate (HR) characteristics as well as with abnormal general movements (GMs) in the 1st month of life. Aims To demonstrate to what extent GMs assessment can predict neurological outcome in preterm infants in our clinical setting; and to assess the clinical usefulness of time-domain indices of heart rate variability (HRV) in improving predictive value of poor repertoire (PR) GMs in writhing period. Study design Qualitative assessment of GMs at 1 and 3 months corrected age; 24 h electrocardiography (ECG) recordings and analyzing HRV at 1 month corrected age. Subjects Seventy nine premature infants at risk of neurodevelopmental impairments were included prospectively. Outcome measures Neurodevelopmental outcome was assessed at the age of 2 years corrected. Children were classified as having normal neurodevelopmental status, minor neurologic dysfunction (MND), or cerebral palsy (CP). Results We found that GMs in writhing period (1 month corrected age) predicted CP at 2 years with sensitivity of 100%, and specificity of 72.1%. Our results demonstrated the excellent predictive value of cramped synchronized (CS) GMs, but not of PR pattern. Analyzing separately a group of infants with PR GMs we found significantly lower values of HRV parameters in infants who later developed CP or MND vs. infants with PR GMs who had normal outcome. Conclusions The quality of GMs was predictive for neurodevelopmental outcome at 2 years. Prediction of PR GMs was significantly enhanced with analyzing HRV parameters.

Bile acids are endogenous emulsifiers synthesized from cholesterol having a peculiar amphiphilic structure. Appreciation of their beneficial effects on human health, recognized since ancient times, has expanded enormously since the discovery of their role as signaling molecules. Activation of farnesoid X receptor (FXR) and Takeda G-protein receptor-5 (TGR5) signaling pathways by bile acids, regulating glucose, lipid and energy metabolism, have become attractive avenue for metabolic syndrome treatment. Therefore, extensive effort has been directed into the research and synthesis of bile acid derivatives with improved pharmacokinetic properties and high potency and selectivity for these receptors. Minor modifications in the structure of bile acids and their derivatives may result in fine-tuning modulation of their biological functions, and most importantly, in an evasion of undesired effect. A great number of semisynthetic bile acid analogues have been designed and put in preclinical and clinical settings. Obeticholic acid (INT-747) has achieved the biggest clinical success so far being in use for the treatment of primary biliary cholangitis. This review summarizes and critically evaluates the key chemical modifications of bile acids resulting in development of novel semisynthetic derivatives as well as the current status of their preclinical and clinical evaluation in the treatment of metabolic syndrome, an aspect that is so far lacking in the scientific literature. Taking into account the balance between therapeutic benefits and potential adverse effects associated with specific structure and mechanism of action, recommendations for future studies are proposed.

The knowledge of the process of formation of molecular aggregates of bile acids in aqueous media and of the corresponding critical micellar concentrations (CMCs) is of great significance because of the biological importance of these compounds and their pharmacological applications. In view of this, the present study is concerned with the determination of CMCs of cholic and chenodeoxycholic acids and their keto derivatives at different temperatures with the aim to calculate the standard thermodynamic functions of micelle formation. Based on the molecular descriptors for tested compounds and entropy of micelle formation, the method of principal component analysis (PCA) allowed grouping of the behavior of tested molecules at 30, 50 and 70 degrees C. To one group belong cholic acid and its keto derivatives, the other group consisting of chenodeoxycholic and deoxycholic acids and their keto derivatives. For each group, the derived multiple linear regression equations of the entropy dependence on temperature contains different independent variables. A main difference between the two groups of tested bile acids is in the energy of dipole-dipole interaction, which appears to be temperature dependent, and in the case of the latter group comes into play as an independent variable already in the regression equation derived for 30 degrees C. The most remarkable changes of the descriptors with temperature were observed in the group of cholic acid and its derivatives.