Preparation of drug nanocrystals embedded in mannitol microcrystals via liquid antisolvent precipitation followed by immediate (on-line) spray drying

The aim of this study is to investigate the feasibility of producing pharmaceutical nanoformulations for enhanced oral or pulmonary delivery of poorly water-soluble drugs via liquid antisolvent precipitation followed by immediate (on-line) spray drying. A poorly water-soluble corticosteroid, budesonide, was chosen as the model drug. Budesonide nanoparticles were prepared through liquid antisolvent precipitation, and then processed into a powdered nanoformulation which consists of budesonide nanoparticles embedded in mannitol microcrystals by immediate (on-line) spray drying. The size of the freshly precipitated and the reconstituted budesonide particles was analyzed by dynamic light scattering (DLS). The spray-dried nanoformulation, together with budesonide and mannitol raw materials, their physical mixture and the spray-dried mannitol, were characterized by field emission scanning electron microscopy (FESEM), differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). In vitro dissolution test and aerosol deposition study were conducted on the spray-dried nanoformulation and the physical mixture of budesonide and mannitol raw materials. It was found that the spray-dried nanoformulation, consisting of mannitol microcrystals comprising budesonide nanocrystals with z-average mean size of 520?±?11.4?nm, exhibited enhanced drug dissolution rate and higher fine particle fraction (FPF). The results of this study indicated the potential of the combined process of liquid antisolvent precipitation followed by immediate (on-line) spray drying to be used as a direct and continuous formulation process to produce powdered nanoformulations to achieve enhanced oral or pulmonary delivery of poorly water-soluble drugs.     

Goat farm variability affects milk Fourier-transform infrared spectra used for predicting coagulation properties

Driven by the large amount of goat milk destined for cheese production, and to pioneer the goat cheese industry, the objective of this study was to assess the effect of farm in predicting goat milk-coagulation and curd-firmness traits via Fourier-transform infrared spectroscopy. Spectra from 452 Sarda goats belonging to 14 farms in central and southeast Sardinia (Italy) were collected. A Bayesian linear regression model was used, estimating all spectral wavelengths' effects simultaneously. Three traditional milk-coagulation properties [rennet coagulation time (min), time to curd firmness of 20 mm (min), and curd firmness 30 min after rennet addition (mm)] and 3 curd-firmness measures modeled over time [rennet coagulation time estimated according to curd firmness change over time (RCT_eq), instant curd-firming rate constant, and asymptotical curd firmness] were considered. A stratified cross validation (SCV) was assigned, evaluating each farm separately (validation set; VAL) and keeping the remaining farms to train (calibration set) the statistical model. Moreover, a SCV, where 20% of the goats randomly taken (10 replicates per farm) from the VAL farm entered the calibration set, was also considered (SCV₈₀). To assess model performance, coefficient of determination (R²_VAL) and the root mean squared error of validation were recorded. The R²_VAL varied between 0.14 and 0.45 (instant curd-firming rate constant and RCT_eq, respectively), albeit the standard deviation was approximating half of the mean for all the traits. Although average results of the 2 SCV procedures were similar, in SCV₈₀, the maximum R²_VAL increased at about 15% across traits, with the highest observed for time to curd firmness of 20 mm (20%) and the lowest for RCT_eq (6%). Further investigation evidenced important variability among farms, with R²_VAL for some of them being close to 0. Our work outlined the importance of considering the effect of farm when developing Fourier-transform infrared spectroscopy prediction equations for coagulation and curd-firmness traits in goats.     

Label-free probing of G-quadruplex formation by surface-enhanced Raman scattering

In this work, we establish the use of surface-enhanced Raman scattering (SERS) as a label-free analytical technique for the direct detection of G-quadruplex formation. In particular, we demonstrate that SERS analysis allows the evaluation of the relative stability of G quadruplexes that differ for the number of G tetrads and investigate several structural features of quadruplexes, such as the orientation of glycosidic bonds, the identification of distortions in the sugar-phosphate backbone, and the degree of hydrogen-bond solvation. Herein, the fluctuation of the SERS spectra, due to the specific interaction of vibrational modes with the SERS-active substrate, is quantitatively analyzed before and after quadruplex formation. The results of this study suggest a perpendicular orientation of the quadruplexes (with or without the 3'-tetra end linker) with respect to the silver colloidal surface, which opens new perspectives for the use of SERS as a label-free analytical tool for the study of the binding mode between quadruplexes and their ligands.     

Assessment of subjective and hemodynamic tolerance of different high‐ and low‐flux dialysis membranes in patients undergoing chronic intermittent hemodialysis: A randomized controlled trial

Clinical experience and experimental data suggest that intradialytic hemodynamic profiles could be influenced by the characteristics of the dialysis membranes. Even within the worldwide used polysulfone family, intolerance to specific membranes was occasionally evoked. The aim of this study was to compare hemodynamically some of the commonly used polysulfone dialyzers in Switzerland. We performed an open‐label, randomized, cross‐over trial, including 25 hemodialysis patients. Four polysulfone dialyzers, A (Revaclear high‐flux, Gambro, Stockholm, Sweden), B (Helixone high‐flux, Fresenius), C (Xevonta high‐flux, BBraun, Melsungen, Germany), and D (Helixone low‐flux, Fresenius, Bad Homburg vor der Höhe, Germany), were compared. The hemodynamic profile was assessed and patients were asked to provide tolerance feedback. The mean score (±SD) subjectively assigned to dialysis quality on a 1–10 scale was A 8.4 ± 1.3, B 8.6 ± 1.3, C 8.5 ± 1.6, D 8.5 ± 1.5. Kt/V was A 1.58 ± 0.30, B 1.67 ± 0.33, C 1.62 ± 0.32, D 1.45 ± 0.31. The low‐ compared with the high‐flux membranes, correlated to higher systolic (128.1 ± 13.1 vs. 125.6 ± 12.1 mmHg, P < 0.01) and diastolic (76.8 ± 8.7 vs. 75.3 ± 9.0 mmHg; P < 0.05) pressures, higher peripheral resistance (1.44 ± 0.19 vs. 1.40 ± 0.18 s × mmHg/mL; P < 0.05) and lower cardiac output (3.76 ± 0.62 vs. 3.82 ± 0.59 L/min; P < 0.05). Hypotension events (decrease in systolic blood pressure by >20 mmHg) were 70 with A, 87 with B, 73 with C, and 75 with D (P < 0.01 B vs. A, 0.05 B vs. C and 0.07 B vs. D). The low‐flux membrane correlated to higher blood pressure levels compared with the high‐flux ones. The Helixone high‐flux membrane ensured the best efficiency. Unfortunately, the very same dialyzer correlated to a higher incidence of hypotensive episodes.     

Lactobacillus pentosus dominates spontaneous fermentation of Italian table olives

Culture-dependent and -independent approaches were applied to identify the bacterial species involved in Italian table olive fermentation. Bacterial identification showed that Lactobacillus pentosus was the dominant species although the presence of Lactobacillus plantarum, Lactobacillus casei, Enterococcus durans, Lactobacillus fermentum and Lactobacillus helveticus was observed. Rep-PCR allowed to obtain strain-specific profiles and to establish a correlation with table olive environment. PCR-DGGE (Denaturing Gradient Gel Electrophoresis) confirmed the heterogeneity of bacterial community structure in fermented table olives as well as the prevalence of L. pentosus. The strains were characterized on the basis of technological properties (NaCl tolerance, β-glucosidase activity and the ability to grow in synthetic brine and in presence of 1 g/100 mL oleuropein). L. pentosus showed a high capacity of adaptation to the different conditions characterizing the olive ecosystem. This species showed the highest percentage of strains able to grow in presence of 10 g/100 mL NaCl, oleuropein and in the synthetic brine. Moreover, all the strains belonging to L. pentosus and L. plantarum species showed a β-glucosidase activity. This study allowed both to identify the main species and strains associated to Italian table olives and to obtain a lactic acid bacteria collection to apply as starter culture in the process of olive fermentation.     

Tetrabromocinnamic acid (TBCA) and related compounds represent a new class of specific protein kinase CK2 inhibitors

Abnormally high constitutive activity of protein kinase CK2, levels of which are elevated in a variety of tumours, is suspected to underlie its pathogenic potential. The most widely employed CK2 inhibitor is 4,5,6,7-tetrabromobenzotriazole (TBB), which exhibits a comparable efficacy toward another kinase, DYRK1 a. Here we describe the development of a new class of CK2 inhibitors, conceptually derived from TBB, which have lost their potency toward DYRK1 a. In particular, tetrabromocinnamic acid (TBCA) inhibits CK2 five times more efficiently than TBB (IC50 values 0.11 and 0.56 microM, respectively), without having any comparable effect on DYRK1 a (IC50 24.5 microM) or on a panel of 28 protein kinases. The usefulness of TBCA for cellular studies has been validated by showing that it reduces the viability of Jurkat cells more efficiently than TBB through enhancement of apoptosis. Collectively taken, the reported data support the view that suitably derivatized tetrabromobenzene molecules may provide powerful reagents for dissecting the cellular functions of CK2 and counteracting its pathogenic potentials.     

Textile Reinforced Concrete: experimental investigation on design parameters

Textile Reinforced Concrete (TRC) is an advanced cement-based material in which fabrics used as reinforcement can bring significant loads in tension, allowing architects and engineers to use thin cross-sections. Previous research projects, developed during the last 10 years mainly in Germany, Israel and the USA, have shown the capabilities of such a material. In this paper an extensive experimental investigation of TRC is presented: tensile tests were carried out to obtain a complete mechanical characterization of the composite material under standard conditions, considering the influence of different variables such as reinforcement ratio, fabric geometry, curing conditions, displacement rate and specimen size.     

Oxidative Folding of Proteins: The “Smoking Gun” of Glutathione

Glutathione has long been suspected to be the primary low molecular weight compound present in all cells promoting the oxidative protein folding, but twenty years ago it was found “not guilty”. Now, new surprising evidence repeats its request to be the “smoking gun” which reopens the criminal trial revealing the crucial involvement of this tripeptide.     

Integrated analysis of cooling water systems: Modeling and experimental validation

Cooling towers are widely used in many industrial and utility plants as a cooling medium, whose thermal performance is of vital importance. Despite the wide interest in cooling tower design, rating and its importance in energy conservation, there are few investigations concerning the integrated analysis of cooling systems. This work presents an approach for the systemic performance analysis of a cooling water system. The approach combines experimental design with mathematical modeling. An experimental investigation was carried out to characterize the mass transfer in the packing of the cooling tower as a function of the liquid and gas flow rates, whose results were within the range of the measurement accuracy. Then, an integrated model was developed that relies on the mass and heat transfer of the cooling tower, as well as on the hydraulic and thermal interactions with a heat exchanger network. The integrated model for the cooling water system was simulated and the temperature results agree with the experimental data of the real operation of the pilot plant. A case study illustrates the interaction in the system and the need for a systemic analysis of cooling water system. The proposed mathematical and experimental analysis should be useful for performance analysis of real-world cooling water systems.