Rare presentation of BRASH syndrome with hypoglycemia and altered mental status.

BACKGROUND: BRASH syndrome (bradycardia, renal failure, atrioventricular nodal blockade, shock, and hyperkalemia) is a rare clinical condition with potentially severe outcomes. Patients with BRASH syndrome can present with diverse signs and symptoms and are usually in critical condition, but if recognized early, the syndrome is treatable and may have a favorable prognosis. CASE PRESENTATION: This case study presents a 74-year-old patient with a history of multiple chronic conditions who was brought to the emergency department with a suspected cerebrovascular accident, altered mental status, and bradycardia. A head computed tomography scan was unremarkable but laboratory results showed hyperkalemia, acidosis, and renal failure with concomitant progressive hypoglycemia. The patient was diagnosed with a BRASH syndrome characterized by a vicious cycle of atrioventricular nodal blockade induced by the potentiated effect of beta-blockers or calcium channel blockers, in combination with progressive hypoglycemia due to the suspected accumulation of anti-diabetic medications, which influenced the presentation and initial triage in the emergency department. She was admitted to the intensive care unit for further management, where she continued to improve and was ultimately discharged in a relatively stable condition. CONCLUSION: This case study highlights the importance of considering rare and atypical presentations of medical conditions, particularly in elderly patients who may have multiple comorbidities. Early recognition and prompt management of such cases are crucial for improving patient outcomes.

Cutaneous Impact Location Predicts Intracranial Injury Among the Elderly Population with Traumatic Brain Injury.

Background: Traumatic brain injury (TBI) is one of the most common trauma-related diagnoses among the elderly population treated in emergency departments (ED). Identification of patients with increased or decreased risk of intracranial bleeding is of clinical importance. The objective of this study was to evaluate the implication of cutaneous impact location (CIL) on the prevalence of intracranial injury after suspected or confirmed TBI irrespective of its severity. Methods: This was a retrospective, single-center, descriptive observational study of geriatric patients aged 65 years and older treated for suspected or confirmed TBI in a trauma surgery ED. The primary outcome of the study was the assessment of a CIL of the injury and its association with the prevalence of intracranial lesions found on a head computed tomography scan. Results: Among 381 patients included in the analysis, the CIL of interest (temporo-parietal and occipital impacts) was present among 178 (46.7%) cases. Thirty-six (9.5%) patients were diagnosed with intracranial bleeding. The prevalence of intracranial bleeding was higher in the CIL of interest group compared with other locations outside (12.9% vs 6.4%; p = 0.030). CIL of interest was a predictor of intracranial bleeding (p = 0.033; OR: 2.17; 95% CI: 1.06 to 4.42). Conclusion: The CIL of head injury is a predictor of intracranial lesions among geriatric patients with traumatic brain injury. Physicians should be aware of this association when assessing elderly patients with head injuries. More studies are needed to develop a clinical management tool incorporating CIL to guide the diagnosis of TBI in this population.

Solvophobicity-Driven Mesoscale Structures: Stabilizer-Free Nanodispersions.

Solvophobicity-driven mesoscale structures that lack any stabilizers are perhaps the most common spontaneously formed stable colloidal objects (particles, droplets). In spite of this, they have been significantly overlooked for a long time and the knowledge on solvophobicity-driven mesoscale structures (SDMSs) is rather limited. Here, we follow up on our previous work on mesoscale solubility [Rak, D.; Sedlák, M. On the Mesoscale Solubility in Liquid Solutions and Mixtures. J. Phys. Chem. B 2019, 123, 1365-1374. 10.1021/acs.jpcb.8b10638] and aim at providing a fully consistent picture of the nature, formation, and stability of SDMSs. We investigate both aqueous and nonaqueous mixtures, showing that this phenomenon is universal and not limited to aqueous systems. An experimental regime diagram is constructed as a function of the concentration of the solvophobic component and the solvophobicity strength given by mixtures of various organic solvents. Aqueous mixtures are investigated using well-defined ternary systems comprising water, ethanol (or other organic solvents), and a series of linear alkanes serving as hydrophobes. This investigation covers unique long-time monitoring of SDMS stability (up to three years). Another parameter studied in detail is the temperature of the mixture. SDMSs are characterized in terms of their shape and size distributions obtained using orthogonal techniques. Last but not least, we bring some insights into the SDMS surface zeta potential─the key quantity behind the stability of SDMSs. We investigate zeta potential as a function of the mixture composition, pH, and temperature.

Area of the plateau depression and higher age predict post-operative subsidence in split-depression lateral tibial fracture.

INTRODUCTION: The aim of this study was to determine factors that affect post-operative subsidence in split-depression lateral plateau tibial fracture (OTA/AO 41B3.1) which was treated with raft construct through a locking plate. PATIENTS AND METHODS: The retrospective study evaluated all split-depression lateral plateau tibial fracture cases treated with raft construct through a locking plate between 01/2015 and 04/2020 with a minimum of 12-month follow-up. Data on the patients' age, sex, time from injury to surgery, type of plate, and use of subchondral bone defect filler were retrieved from the hospital database. The measurements of total plateau area (TPA), depressed lateral plateau area (DPA), and maximal plateau depression (MPD) were performed on the patients' pre-operative CT scans. The percentage of DPA to TPA (%DPA) was calculated. Post-operative radiographs were used for the evaluation of plateau subsidence. A subsidence greater than 2 mm was considered a failure. RESULTS: There were 41 consecutive cases of split-depression lateral plateau tibial fracture in the reviewed period. Five cases were excluded, three of them were lost to follow up, 1 patient had no pre-operative CT scan and 1 had a history of cancer. A failure was identified in 11 (31%) cases. Patients in the failure group were older (61.0 vs 50.7 years, p = 0.01), and had a higher incidence of fractures extending into intercondylar eminence (100% vs 56%, p = 0.02). Multiple logistic regression identified DPA (OR = 3.6; 95%CI 1.4-9.5, p < 0.01) and age (OR = 1.2; 95% CI 1.0-1.4, p = 0.02) as predictive factors for plateau subsidence. DPA cut-off value for predicting subsidence greater than 2 mm was 5.8 cm2 [Area Under the ROC Curve 0.89 (95% CI 0.74-0.97), sensitivity 91%, specificity 80%, p < 0.01)]. CONCLUSION: Age and depressed lateral plateau area (DPA) in split-depression lateral plateau tibial fracture treated with raft construct through a locking plate are risk factors for post-operative subsidence greater than 2 mm.

Small Extracellular Vesicles Derived from Human Chorionic MSCs as Modern Perspective towards Cell-Free Therapy.

Mesenchymal stem cells (MSCs) are of great interest to scientists due to their application in cell therapy of many diseases, as well as regenerative medicine and tissue engineering. Recently, there has been growing evidence surrounding the research based on extracellular vesicles (EVs), especially small EVs (sEVs)/exosomes derived from MSCs. EVs/exosomes can be secreted by almost all cell types and various types of EVs show multiple functions. In addition, MSCs-derived exosomes have similar characteristics and biological activities to MSCs and their therapeutic applications are considered as a safe strategy in cell-free therapy. The aim of this study was the characterization of MSCs isolated from the chorion (CHo-MSCs) of human full-term placenta, as well as the isolation and analysis of small EVs obtained from these cells. Accordingly, in this study, the ability of small EVs' uptake is indicated by synovial fibroblasts, osteoblasts and periosteum-derived MSCs. Improvement in the understanding of the structure, characteristics, mechanism of action and potential application of MSCs-derived small EVs can provide new insight into improved therapeutic strategies.

Comment on "Bulk Nanobubbles or Not Nanobubbles: That is the Question".

In a recent article, Jadhav and Barigou ( Langmuir 2020, 36 (7), 1699-1708) investigated the question of the existence of stable bulk nanobubbles in water generated by hydrodynamic cavitation, ultrasound cavitation, and the addition of an organic compound (namely, ethanol) to water. They firmly conclude that these procedures result in stable bulk nanobubbles. However, a number of previous works documented that the nanoentities observed in water upon such procedures are not nanobubbles. Here, we analyze work of Jadhav and Barigou and show that conclusions regarding the nanobubble nature of the nanoentities are incorrect and are due to the choice of experimental techniques with weak sensitivity, methodical issues in the use of otherwise proper experimental techniques, and ambiguous outcomes of the rest of experiments.

γ-Butyrolactone Copolymerization with the Well-Documented Polymer Drug Carrier Poly(ethylene oxide)-block-poly(ε-caprolactone) to Fine-Tune Its Biorelevant Properties.

Polymeric drug carriers exhibit excellent properties that advance drug delivery systems. In particular, carriers based on poly(ethylene oxide)-block-poly(ε-caprolactone) are very useful in pharmacokinetics. In addition to their proven biocompatibility, there are several requirements for the efficacy of the polymeric drug carriers after internalization, e.g., nanoparticle behavior, cellular uptake, the rate of degradation, and cellular localization. The introduction of γ-butyrolactone units into the hydrophobic block enables the tuning of the abovementioned properties over a wide range. In this study, a relatively high content of γ-butyrolactone units with a reasonable yield of ≈60% is achieved by anionic ring-opening copolymerization using 1,5,7-triazabicyclo[4.4.0]dec-5-ene as a very efficient catalyst in the nonpolar environment of toluene with an incorporated γ-butyrolactone content of ≈30%. The content of γ-butyrolactone units can be easily modulated according to the feed ratio of the monomers. This method enables control over the rate of degradation so that when the content of γ-butyrolactone increases, the rate of degradation increases. These findings broaden the application possibilities of polyester-polyether-based nanoparticles for biomedical applications, such as drug delivery systems.

(Non)Existence of Bulk Nanobubbles: The Role of Ultrasonic Cavitation and Organic Solutes in Water.

A drawback of studies on bulk nanobubbles is the absence of direct proof that the nano-objects reported are really nanobubbles. The aim of our work was to provide such a proof or disproof. We focused on two effects (processes) commonly considered in research on nanobubbles: ultrasonic cavitation and addition of organic compounds to water, which could create in principle a barrier at the gas/water interface contributing to the stability of nanobubbles. We found that both of these processes lead to the generation of nano-objects, which are, however, not bulk nanobubbles. Ultrasonication leads to the formation of fine metal nanoparticles originating from the disintegration of the surface of the metal ultrasonic probe. Addition of organic solutes to water leads to the formation of a population of nanoparticles/nanodroplets originating from the so-called mesoscale solubilization of hydrophobic compounds present in the added solute as molecularly dissolved impurities. Subsequent ultrasonication of such mixtures adds metal nanoparticles and only slightly modifies the size distribution of mesoscale particles. While our results do not dismiss existence of nanobubbles in general, described effects must be seriously taken into account, especially in the case of biomedical applications where they can result in serious side effects.

Rifampicin Nanoformulation Enhances Treatment of Tuberculosis in Zebrafish.

Mycobacterium tuberculosis, the etiologic agent of tuberculosis, is an intracellular pathogen of alveolar macrophages. These cells avidly take up nanoparticles, even without the use of specific targeting ligands, making the use of nanotherapeutics ideal for the treatment of such infections. Methoxy poly(ethylene oxide)- block-poly(ε-caprolactone) nanoparticles of several different polymer blocks' molecular weights and sizes (20-110 nm) were developed and critically compared as carriers for rifampicin, a cornerstone in tuberculosis therapy. The polymeric nanoparticles' uptake, consequent organelle targeting and intracellular degradation were shown to be highly dependent on the nanoparticles' physicochemical properties (the cell uptake half-lives 2.4-21 min, the degradation half-lives 51.6 min-ca. 20 h after the internalization). We show that the nanoparticles are efficiently taken up by macrophages and are able to effectively neutralize the persisting bacilli. Finally, we demonstrate, using a zebrafish model of tuberculosis, that the nanoparticles are well tolerated, have a curative effect, and are significantly more efficient compared to a free form of rifampicin. Hence, these findings demonstrate that this system shows great promise, both in vitro and in vivo, for the treatment of tuberculosis.

On the Mesoscale Solubility in Liquid Solutions and Mixtures.

We report on a mesoscale solubility reflecting the fact that solubility is achieved not only by the well-known "like likes like" or "like dissolves like" based on molecular solvation but also on mesoscale solubilization of dislike compounds characterized in that the solubility (homogeneous distribution over the whole volume of the system) is achieved on a mesoscale level ranging from tens to hundreds of nanometers. It is shown that mesoscale solubility is a spontaneously occurring, literally everywhere present phenomenon, which was hidden and overlooked for a long time. This paper reveals the physical mechanism of mesoscale solubilization comprising nucleation and aggregation accompanied by the development of significant surface zeta potentials on nanoprecipitates, giving them a long-term stability. We show that mesoscale solubilization is common for aqueous as well as nonaqueous systems. Experiments with organic solvents not capable of self-ionization (self-dissociation) instead of water also shed light on the mechanism of the generation of surface zeta potentials at hydrophobic interfaces. We identified the key parameters enabling the mesoscale solubilization and mapped its occurrence as their function. Mesoscale structures including their formation kinetics, long-term stability, and different types of solubilization procedures were characterized by scattering and ultramicroscopic visualization comprising sizing and counting.

A novel approach to controlled self-assembly of pH-responsive thermosensitive homopolymer polyelectrolytes into stable nanoparticles.

This review addresses the recent research progress in introducing and elaborating a novel approach to controlled polymer self-assembly into stable nanoparticles using pH-responsive thermosensitive homopolymer polyelectrolytes. Interesting aspect of this approach is that stable polymeric nanoparticles are formed from homopolymers of one type only and without any assembly-triggering additives. The process of their formation can be monitored online e.g. by light scattering and particle size can be finely custom tuned. Obtained nanoparticles have interesting properties and are very stable over long periods of time and over a broad range of salt concentrations including physiological conditions. Much effort was devoted not only to finding optimum experimental protocols and to characterizing resulting nanoparticles in detail, but also to understanding physical processes behind these successful protocols.

Self-assembly thermodynamics of pH-responsive amino-acid-based polymers with a nonionic surfactant.

The behavior of pH-responsive polymers poly(N-methacryloyl-l-valine) (P1), poly(N-methacryloyl-l-phenylalanine) (P2), and poly(N-methacryloylglycyne-l-leucine) (P3) has been studied in the presence of the nonionic surfactant Brij98. The pure polymers phase-separate in an acidic medium with critical pHtr values of 3.7, 5.5, and 3.4, respectively. The addition of the surfactant prevents phase separation and promotes reorganization of polymer molecules. The nature of the interaction between polymer and surfactant depends on the amino acid structure in the side chain of the polymer. This effect was investigated by dynamic light scattering, isothermal titration calorimetry, electrophoretic measurements, small-angle neutron scattering, and infrared spectroscopy. Thermodynamic analysis revealed an endothermic association reaction in P1/Brij98 mixture, whereas a strong exothermic effect was observed for P2/Brij98 and P3/Brij98. Application of regular solution theory for the analysis of experimental enthalpograms indicated dominant hydrophobic interactions between P1 and Brij98 and specific interactions for the P2/Brij98 system. Electrophoretic and dynamic light scattering measurements support the applicability of the theory to these cases. The specific interactions can be ascribed to hydrogen bonds formed between the carboxylic groups of the polymer and the oligo(ethylene oxide) head groups of the surfactant. Thus, differences in polymer-surfactant interactions between P1 and P2 polymers result in different structures of polymer-surfactant complexes. Specifically, small-angle neutron scattering revealed pearl-necklace complexes and "core-shell" structures for P1/Brij98 and P2/Brij98 systems, respectively. These results may help in the design of new pH-responsive site-specific micellar drug delivery systems or pH-responsive membrane-disrupting agents.

On the origin of mesoscale structures in aqueous solutions of tertiary butyl alcohol: the mystery resolved.

We have performed a detailed experimental study on aqueous solutions of tertiary butyl alcohol which were a subject of long-standing controversies regarding the puzzling presence of virtually infinitely stable large-scale structures in such solutions occurring at length scales exceeding appreciably dimensions of individual molecules, referred to also as mesoscale structures. A combination of static and dynamic light scattering yielding information on solution structure and dynamics and gas chromatography coupled with mass spectrometry yielding information on chemical composition was used. We show that tertiary butyl alcohol clearly exhibiting such structures upon mixing with water does not contain any propylene oxide, which was previously considered as a source of these structures (an impurity expected to be present in all commercial samples of TBA). More importantly, we show that no mesoscale structures are generated upon addition of propylene oxide to aqueous solutions of TBA. The ternary system TBA/water/propylene oxide exhibits homogeneous mixing of the components on mesoscales. We show that the source of the mesoscale structures is a mesophase separation of appreciably more hydrophobic compounds than propylene oxide. These substances are explicitly analytically identified as well as their disappearance upon filtering out the mesoscale structures by nanopore filtration. We clearly show which substances are disappearing upon filtration and which are not. This enables us to estimate with rather high probability the chemical composition of the mesoscale structures. Visualization of large-scale structures via nanoparticle tracking analysis is also presented. Video capturing the mesoscale particles as well as their Brownian motion can be found in the Supporting Information .

Large-scale inhomogeneities in solutions of low molar mass compounds and mixtures of liquids: supramolecular structures or nanobubbles?

In textbooks, undersaturated solutions of low molar mass compounds and mixtures of freely miscible liquids are considered as homogeneous at larger length scales exceeding appreciably dimensions of individual molecules. However, growing experimental evidence reveals that it is not the case. Large-scale structures with sizes on the order of 100 nm are present in solutions and mixtures used in everyday life and research practice, especially in aqueous systems. These mesoscale inhomogeneities are long-lived, and (relatively slow) kinetics of their formation can be monitored upon mixing the components. Nevertheless, the nature of these structures and mechanisms behind their formation are not clear yet. Since it was previously suggested that these can be nanobubbles stabilized by adsorbed solute at the gas/solvent interface, we devote the current study to addressing this question. Static and dynamic light scattering was used to investigate solutions and mixtures prepared at ordinary conditions (equilibrated with air at 1 atm), prepared with degassed solvent, and solutions and mixtures degassed after formation of large structures. The behavior of large structures in strong gravitational centrifugal fields was also investigated. Systems from various categories were chosen for this study: aqueous solutions of an inorganic ionic compound (MgSO4), organic ionic compound (citric acid), uncharged organic compound (urea), and a mixture of water with organic solvent freely miscible with water (tert-butyl alcohol). Obtained results show that these structures are not nanobubbles in all cases. Visualization of large-scale structures via nanoparticle tracking analysis is presented. NTA results confirm conclusions from our previous light scattering work.

Homopolymer self-assembly into stable nanoparticles: concerted action of hydrophobic association and hydrogen bonding in thermoresponsive poly(alkylacrylic acid)s.

A new approach to polymer self-assembly was presented recently [M. Sedlák, C. Konák, J. Dybal, Macromolecules 2009, 2, 7430-7438 and 7439-7446.] (1, 2) where stable polymeric nanoparticles were formed from poly(ethylacrylic acid) homopolymers without any assembly triggering additives, simply by heating polymer solution under conditions of thermosensitivity to certain temperature. In the current Article, we present successful results on poly(propylacrylic acid), which is a more hydrophobic polymer. We also present results on a less hydrophobic polymer from this series, poly(methacrylic acid), from which nanoparticles cannot be formed. Comparison of results on all three polymers gives a solid physicochemical insight and supports the molecular mechanism of the self-assembly previously suggested: The solvent quality gradually worsens upon heating of a thermosensitive polymer solution, and polymer-polymer contacts are preferred over polymer-solvent contacts, which leads to the formation of polymer assemblies. The presence of a significant amount of charge on chains prevents macroscopic phase separation. Upon subsequent cooling to laboratory temperature, the assemblies (nanoparticles) should eventually dissolve; however, this is not the case due to the fact that polymer chains brought to a close proximity at elevated temperatures become hydrogen-bonded. In addition, hydrogen bonds strengthen upon cooling. Mainly carboxylic-carboxylate hydrogen bonds (COOH····COO(-)) are responsible for the irreversibility of the process and the stability of nanoparticles. Conclusions are supported by results from static and dynamic light scattering, FTIR spectroscopy, and cryo-TEM microscopy. Size of nanoparticles can be monitored during the growth and custom-tailored by tuning critical parameters, especially the degree of ionization, temperature, and time of heating. Nanoparticles are stable over long periods of time. They are stable in a broad range of salt concentrations, including physiological conditions, and possess a mild acceptable degree of polydispersity.

Large-scale supramolecular structure in solutions of low molar mass compounds and mixtures of liquids. III. Correlation with molecular properties and interactions.

The presence of a large-scale supramolecular structure is evidenced in a large variety of electrolyte solutions, nonelectrolyte solutions, and mixtures of liquids. This structure comprises submicron-sized domains with different solute concentration from that in the rest of solution. While the first paper of this series [J. Phys. Chem. B 2006, 110 (9), 4329-4338] dealt with a detailed characterization of the supramolecular structure and the second paper [J. Phys. Chem. B 2006, 110 (9), 4339-4345] dealt with the kinetics of the formation of this structure and its long-time stability, the present work contains a detailed classification of systems with respect to the capability of formation of the supramolecular organization. Around 100 different solute-solvent pairs were investigated in total, covering most common inorganic and organic electrolytes, nonionic solid compounds, and a large variety of liquids. The main experimental techniques used were static and dynamic light scattering, which are very effective techniques in observing and characterizing association. Light scattering data were complemented by osmotic pressure data obtained by vapor pressure osmometry, which reflects association on a different principle. The presence and intensity of the supramolecular domain organization was correlated with properties and interactions between constituent molecules and ions. The most plausible explanation of the observed effect of the large-scale supramolecular structure at this stage of our knowledge is that domains form due to directional attractive interactions between solute molecules via hydrogen bond bridges formed by one or several solvent molecules, which are themselves hydrogen bonded.

Large-scale supramolecular structure in solutions of low molar mass compounds and mixtures of liquids: I. Light scattering characterization.

Static and dynamic laser light scattering were used to bring evidence of large-scale supramolecular structure in solutions of low molar mass electrolytes, nonelectrolytes, and mixtures of liquids. It was shown that solutes are distributed inhomogeneously on large length scales. Regions of higher and lower solute concentration exist in solution and give sufficient scattering contrast for experimental observation. A detailed light scattering study showed that these regions can be characterized as close-to-spherical discrete domains of higher solute density in a less dense rest of solution. These domains do contain solvent inside and can be therefore characterized as loose associates (giant clusters, aggregates). Their size distributions are significantly broad, ranging up to several hundreds of nanometers. Characteristic sizes of these inhomogenities thus exceed angstrom dimensions of individual molecules by several orders of magnitude. The number of solute molecules per domain varies approximately in the range 10(3)-10(8). Phenomena described were observed in a very broad range of solutes and solvents. Among others, selected data on most common substances of great chemical and biological importance such as sodium chloride, citric acid, glucose, urea, acetic acid, and ethanol are presented.

Large-scale supramolecular structure in solutions of low molar mass compounds and mixtures of liquids: II. Kinetics of the formation and long-time stability.

Kinetics of the formation of large-scale supramolecular structure and its long-time stability were investigated in detail in solutions of electrolytes, nonelectrolytes, and mixtures of liquids. This structure comprises submicron-sized domains (large clusters) with higher solute concentration than in the rest of solution. In the case of mixtures of liquids, a complete real-time monitoring of the structure formation was possible in all cases. In the case of solutions of solid samples, the observation was possible in cases when the structure formation was significantly slower than the dissolution process. The time scale on which the supramolecular structure develops varies from minutes to weeks, depending on the concrete system. The long-time stability of the developed structure was investigated in time intervals ranging up to 15 months. In some systems the resulting domain structure appears stable, in others a very slow ceasing of domains is observed over very long time intervals. In all cases, however, slow kinetic effects are present in the systems investigated. Among others, data on some common substances of great chemical and biological importance such as sodium chloride, acetic acid, glucose, and ethanol, are presented.

Real-time monitoring of the origination of multimacroion domains in a polyelectrolyte solution.

First real-time monitoring of the origination of multimacroion domains in an initially homogeneous polyelectrolyte solution was performed. Domains were generated by pH-induced increase of macroion charge in solution of poly(methacrylic acid). Monitoring was performed by static and dynamic light scatterings, in which scattering contributions from individual polyions and growing multimacroion domains were separated, such that amplitudes of both modes were expressed in absolute units. Kinetic results also yield new information regarding the nature of multimacroion domains.