Physicochemical properties of aqueous core hydrogel capsules.

Capsules having a thin alginate hydrogel membrane and an aqueous core can be obtained by a process that involves a co-extrusion step in air followed by a sol-gel transition of the shell after immersion into a gelling bath. The possibility to encapsulate cells that further grow in these biocompatible compartments, and thus offer a versatile tool for cell culture, led us to investigate the physicochemical properties of the capsules. A cut-off pore size of the semi-permeable membrane is extrapolated from the release of polymers out of the capsule. When polymers cannot diffuse through the membrane, the osmotic pressure mismatch between the core and the surrounding medium triggers an inflation of the capsule. The swelling may reach a steady state that allows the determination of the elastic features of the hydrogel shell. On the other hand, the capsule membrane may rupture and then contract. From this stress-relaxation process, a critical deformation of the hydrogel shell above which plasticity occurs can be deduced. Finally, thanks to the physical nature of the hydrogel, the core content can be released by dissolving the membrane with the help of small electrolytes. The shell life is shown to vary inversely with the ionic strength of the solution.

Anxiodepressive disorders and chronic psychological stress are associated with Tako-Tsubo cardiomyopathy- New Physiopathological Hypothesis.

BACKGROUND: Recent retrospective studies suggest that psychiatric disorders could be a predisposing risk factor for Tako-tsubo cardiomyopathy (TTC). The aim of the present study was to characterize the prevalence of anxiodepressive disorders (ADD) and chronic psychological stress (CPS) in patients with TTC or acute coronary syndrome (ACS). METHODS AND RESULTS: Between January 2010 and December 2011, 45 consecutive patients with TTC were prospectively screened by systematic interview with the Mini International Neuropsychiatric Interview. CPS was systematically recorded. During the same period, 50 patients admitted for ACS with troponin elevation and matched for age and sex were prospectively included as a control group. An acute stressful event within 72 h before presentation was identified in 35 patients (78%) with TTC vs. 9 (18%) with ACS (P<0.001). Thirty-five patients (78%) and 13 (26%) had ADD in the TTC and ACS groups, respectively (P<0.001). CPS was found in 20 patients (44%) and in 9 (18%) with TTC and ACS, respectively (P=0.005). CPS and/or ADD were found in 35 patients (78%) and in 18 (36%) with TTC and ACS, respectively (P<0.001). CONCLUSIONS: ADD and CPS are common in patients with TTC and more frequent than in patients with ACS. This finding suggests that systemic effects of ADD and CPS could participate in the pathophysiology of TTC.

Non-traumatic Acute Subdural Hematoma in a Patient With Scleroderma Complicated by Pulmonary Arterial Hypertension: A Case Report.

Non-traumatic acute subdural hematoma (SDH) in patients with scleroderma is infrequently described in literature reviewing the neurologic disorders in scleroderma. We report a case of a patient with scleroderma complicated by severe pulmonary arterial hypertension (PAH), and a history of pulmonary embolism on warfarin who developed an SDH, requiring hemicraniectomy after initiating therapy with IV epoprostenol. The proposed mechanisms for SDH development and management strategy are discussed.

An association between occupancy rates in the emergency department and rates of violence toward staff.

BACKGROUND: Studies have explored possible causes of violent acts in the emergency department (ED), however, the association of violence with ED crowding has not been studied. Although the total number of violent acts would be expected to increase, it is not clear if the rate of violent acts also increases as occupancy levels rise. OBJECTIVE: The purpose of this study was to determine if there is an association between occupancy rates in the ED and rates of violence toward staff. METHODS: This was a retrospective chart review study. Violent incidents in a community, Level I trauma center ED were identified from review of orders of emergency detainment, adverse event forms, physical restraint logs, and pharmacy records from January 1, 2005 to June 1, 2008. Occupancy rates for all days were calculated and violent vs. non-violent days were compared using a standard two-sample t-test. Logistic regression analysis was then used to investigate other factors associated with violent incidents. RESULTS: A rate of violence of 1.3 incidents per 1000 patients was found. When comparing the occupancy rates of violent days (mean 95%, SD 26%) with non-violent days (mean 86%, SD 24%), a statistically significant association was found (p<0.0001). Multivariate logistic regression confirmed a significant association between crowding and violence toward staff (odds ratio 4.290, 95% confidence interval 2.137-8.612). CONCLUSION: These results suggest another possible negative effect that crowding has on ED staff and physicians. Policies and recommendations regarding ED operating procedures and staff safety during times of higher occupancy levels should be discussed.

How to prepare and stabilize very small nanoemulsions.

Practical and theoretical considerations that apply when aiming to formulate by ultrasonication very small nanoemulsions (particle diameter up to 150 nm) with very high stability are presented and discussed. The droplet size evolution during sonication can be described by a monoexponential function of the sonication time, the characteristic time scale depending essentially on the applied power. A unique master curve is obtained when plotting the mean diameter size evolution as a function of sonication energy. We then show that Ostwald ripening remains the main destabilization mechanism whereas coalescence can be easily prevented due to the nanometric size of droplets. The incorporation of "trapped species" within the droplet interior is able to counteract Ostwald ripening, and this concept can be extended to the membrane compartment. We finally clarify that nanoemulsions are not thermodynamically stable systems, even in the case where their composition lies very close to the demixing line of a thermodynamically stable microemulsion domain. However, as exemplified in the present work, nanoemulsion systems can present very long-term kinetic stability.

Sepsis as the primary admitting diagnosis of transferred patients who died within 48 hours of arrival at a Central Texas hospital.

Interhospital transfers are independently associated with inpatient mortality, and transferred patients have worse outcomes. The aim of this study was to retrospectively assess the 48-hour mortality rate in interhospital transfer cohorts of all transfers to a Central Texas teaching hospital and to identify a primary admitting diagnosis for potential intervention. A total of 15,435 patients with 19,161 transfers over the course of the study were retrospectively reviewed and placed in 18 different categories based upon the primary admitting diagnosis. There were about 5000 transfer patients yearly with ∼1.4% deaths within 48 hours of arrival. The three leading categories for transferred patients were cardiovascular, neurologic, and psychiatric. In this group, 268 of 19,161 transfers died within 48 hours of arrival. Despite being the 10th leading category for transfer, sepsis was the leading primary admitting diagnosis of patients who died within 48 hours of arrival, accounting for nearly 22% of those patients. Given the significant association found between sepsis and 48-hour mortality after transfer, we devised a novel interhospital transfer checklist based upon the Surviving Sepsis guidelines in an attempt to decrease mortality associated with these transfers.

Evaluation of transdermal delivery of nanoemulsions in ex vivo porcine skin using two-photon microscopy and confocal laser-scanning microscopy.

This study experimentally evaluates the self-targeting ability of asiaticoside-loaded nanoemulsions compared with nontargeted nanoemulsions in ex vivo experiments with porcine skin samples. Homebuilt two-photon and confocal laser-scanning microscopes were employed to noninvasively examine the transdermal delivery of two distinct nanoemulsions. Prior to the application of nanoemulsions, we noninvasively observed the morphology of porcine skin using two-photon microscopy. We have successfully visualized the distributions of the targeted and nontargeted nanoemulsions absorbed into the porcine skin samples. Asiaticoside-loaded nanoemulsions showed an improved ex vivo transdermal delivery through the stratum corneum compared with nonloaded nanoemulsions. As a secondary measure, nanoemulsions-applied samples were sliced in the depth direction with a surgical knife in order to obtain the complete depth-direction distribution profile of Nile red fluorescence. XZ images demonstrated that asiaticoside-loaded nanoemulsion penetrated deeper into the skin compared with nontargeted nanoemulsions. The basal layer boundary is clearly visible in the case of the asiaticoside-loaded skin sample. These results reaffirm the feasibility of using self-targeting ligands to improve permeation through the skin barrier for cosmetics and topical drug applications.

Quantitative analysis of ligand effects on bioefficacy of nanoemulsion encapsulating depigmenting active.

Efficient skin delivery of active molecules is the main challenge to overcome in order to achieve significant therapeutic efficiency of cosmetics or dermo-pharmaceutical products. Nanocarriers such as nanoemulsions have been envisaged to overcome main challenges of active solubilization, protection and transport to their site of biological action. Nonetheless, their skin permeation is still limited and a new approach is required to significantly improve bioavailability. We here explored the possibility of increasing the whitening activity of a model active, licorice, by implementing a targeting approach of nanoemulsions to melanocyte cells. Targeting requires particle surface modification with specific molecules favoring nanoemulsion/cells contact through ligand-receptor interactions. The uniqueness of our strategy is that unlike classical covalent chemical grafting, we propose a self-assembled strategy based on a selection of amphiphilic ligands able to localize at nanoemulsion droplets interface. Four ligand candidates were thus assayed in terms of formulation and in vitro biological evaluation: a palmitoyl-peptide (palmitoyl-GQPR), a lipidized hyaluronic acid (caproyl-HA) and two amphiphilic actives (polydatin and isopilosine). A functional analysis based on a cellular assay of melanin inhibition was realized. The intrinsic properties of ligand candidates were first evaluated. Then, nanoemulsions encapsulating a drug model, licorice, and targeted with the different ligand candidates were assayed. The use of caproyl-HA significantly improved bioefficacy of the encapsulated licorice, suggesting a better interaction with the cells. The improved value observed was not attributed to a synergetic action as caproyl-HA did not evidence intrinsic melanogenesis modulation activity. In this study, we demonstrated the feasibility of targeting nanoemulsion droplets without chemical covalent modification of nanoemulsion droplets to increase bioefficacy of encapsulated drugs in vitro.

Lipidots: competitive organic alternative to quantum dots for in vivo fluorescence imaging.

The use of fluorescent nanostructures can bring several benefits on the signal to background ratio for in vitro microscopy, in vivo small animal imaging, and image-guided surgery. Fluorescent quantum dots (QDs) display outstanding optical properties, with high brightness and low photobleaching rate. However, because of their toxic element core composition and their potential long term retention in reticulo-endothelial organs such as liver, their in vivo human applications seem compromised. The development of new dye-loaded (DiO, DiI, DiD, DiR, and Indocyanine Green (ICG)) lipid nanoparticles for fluorescence imaging (lipidots) is described here. Lipidot optical properties quantitatively compete with those of commercial QDs (QTracker(®)705). Multichannel in vivo imaging of lymph nodes in mice is demonstrated for doses as low as 2 pmols of particles. Along with their optical properties, fluorescent lipidots display very low cytotoxicity (IC(50) > 75 nM), which make them suitable tools for in vitro, and especially in vivo, fluorescence imaging applications.

Preparation and characterization of highly stable lipid nanoparticles with amorphous core of tuneable viscosity.

Lipid nanoparticles (LNP) have been designed based on low cost and human-use approved excipients, and manufactured by an easy, robust, and up-scalable process. Fluid colloidal dispersions or gel viscous formulations of highly stable nanoparticles (more than 12 month stability is achieved for some formulations) can be obtained. Their physicochemical properties are studied by Dynamic Light Scattering, Differential Scanning Calorimetry, and NMR. The results picture nanoparticles with a non-crystalline core, which viscosity can be finely tuned by the lipid composition and the temperature. A design of experiments has been used to investigate the limits of the system colloidal stability. The impact of core and surfactant weight fractions have been explored both experimentally and using the design of experiments. The versatility of this physicochemical system could open the way to a wide range of future pharmaceutical applications.

Cyclosporine A--protection against microvascular hyperpermeability is calcineurin independent.

BACKGROUND: Mitochondria-mediated apoptotic signaling contributes to microvascular hyperpermeability. We hypothesized that cyclosporine A (CsA), which protects mitochondrial transition pores, would attenuate hyperpermeability independent of its calcineurin inhibitory property. METHODS: Hyperpermeability was induced in microvascular endothelial cell monolayers using proapoptotic BAK or active caspase-3 after CsA or a specific calcineurin inhibitor, calcineurin autoinhibitory peptide (CIP), treatment. Permeability was measured based on fluorescein isothiocyanate-albumin flux across the monolayers. Mitochondrial transmembrane potential (MTP) was determined using 5,5',6,6'-tetrachoro-1,1',3,3'-tetraethylbenzimidazolyl carbocyanine iodide. Mitochondrial release of cytochrome c was measured using an enzyme-linked immunosorbent assay and caspase-3 activity fluorometrically. RESULTS: CsA-attenuated (10 nmol/L) but not CIP-attenuated (100 mumol/L) BAK induced hyperpermeability (P < .05), CsA- but not CIP-attenuated BAK induced a decrease in MTP and an increase in cytochrome c levels and caspase-3 activity (P < .05). CsA and CIP were ineffective against caspase-3-induced hyperpermeability. CONCLUSIONS: CsA attenuated hyperpermeability by protecting MTP, thus preventing mitochondria-mediated apoptotic signaling. The protective effect of CsA is independent of calcineurin inhibition.