Microencapsulation of alcohol solvents and high-content actives for efficient transdermal delivery.

The barrier function of the skin in effectively protecting the underlying tissue from the surrounding environment makes it challenging to achieve the efficient transdermal delivery of actives. Herein, we report on alcohol-solvent-encapsulated microcapsules to achieve enhanced skin efficacy. We show that using palm oil as the shell material allows for the microencapsulation of a broad range of alcohol solvents, including ethanol and dipropylene glycol (DPG), as well as on-demand release. Moreover, clinical trials reveal that the high-content actives in microcapsules result in enhanced skin efficacy, and the presence of DPG effectively mediates the transdermal delivery of these actives without causing any skin irritation. We envision that the alcohol-solvent microencapsulation strategy outlined in this work offers new possibilities in cosmetics, food, and drug delivery systems.

Effect of physical activity on the change in carotid intima-media thickness: An 8-year prospective cohort study.

BACKGROUND AND AIMS: There is a demand for longitudinal studies that use both objective and subjective measures of physical activity to investigate the association of physical activity with the change in carotid intima-media thickness (CIMT). In order to investigate such association, we conducted an 8-year follow-up study that used both objective and subjective measures of physical activity. METHODS: This cohort study used subsamples of the ongoing Korean Genome and Epidemiology Study (KoGES). Included participants were between 49 to 79 years of age at baseline. Exclusion criteria included incomplete assessments of pedometer/accelerometer, international physical activity questionnaire (IPAQ), and baseline CIMT. Participants with a history of cardiovascular diseases were further excluded. Linear regression models were used for the main analysis. Age differences were assessed by stratifying the participants into < 60 years and ≥ 60 years. RESULTS: After removing excluded participants, 835 participants were included in the final analysis (age, 59.84 ± 6.53 years; 326 (39.04%) males). 453 participants were < 60 years and 382 participants were ≥ 60 years. The daily total step count was inversely associated with the percent change in overall CIMT over 8-years (ß = -0.015, standard error = 0.007, P = 0.034). This association was present among participants in the < 60-year-old group (ß = -0.026, standard error = 0.010, P = 0.006), but not among participants in the ≥ 60-year-old group (ß = -0.010, standard error = 0.011, P = 0.38). CONCLUSIONS: The findings suggest that taking preemptive actions of increasing physical activity may prevent the incidence of atherosclerosis.

Skin Penetration Enhancer-Incorporated Lipid Nanovesicles (SPE-LNV) for Skin Brightening and Wrinkle Treatment.

In this work, we utilize skin penetration enhancers (SPEs) such as ceramide and fatty acids in lipid nanovesicles to promote the transdermal delivery of active ingredients. These SPE-incorporated lipid nanovesicles (SPE-LNV) interact with the constituents of skin's outermost stratum corneum (SC) layer, enabling even niacinamide and adenosine with high water solubility to effectively permeate through, leading to enhanced skin efficacy. We demonstrate by both in vitro and in vivo skin permeation studies that the SPE-LNV formulation containing both ceramide and fatty acids (LNV-CF) exhibits deeper penetration depth and faster permeation rate compared to conventional lipid nanovesicles (LNV) without SPE as well as LNV-C with only ceramide. Moreover, in vivo clinical trials were also performed to confirm that LNV-CF most effectively mediates the delivery of niacinamide and adenosine, resulting in a substantial decrease in melanin index as well as skin wrinkle compared to the control groups. We envision that the strategy of incorporating both ceramide and fatty acids in lipid nanovesicles offers a simple and convenient route for the rapid and effective delivery of water-soluble active ingredients across the skin barrier layer.

Altered small-world property of a dynamic metabolic network in murine left hippocampus after exposure to acute stress.

The acute stress response is a natural and fundamental reaction that balances the physiological conditions of the brain. To maintain homeostasis in the brain, the response is based on changes over time in hormones and neurotransmitters, which are related to resilience and can adapt successfully to acute stress. This increases the need for dynamic analysis over time, and new approaches to examine the relationship between metabolites have emerged. This study investigates whether the constructed metabolic network is a realistic or a random network and is affected by acute stress. While the metabolic network in the control group met the criteria for small-worldness at all time points, the metabolic network in the stress group did not at some time points, and the small-worldness had resilience after the fifth time point. The backbone metabolic network only met the criteria for small-worldness in the control group. Additionally, creatine had lower local efficiency in the stress group than the control group, and for the backbone metabolic network, creatine and glutamate were lower and higher in the stress group than the control group, respectively. These findings provide evidence of metabolic imbalance that may be a pre-stage of alterations to brain structure due to acute stress.

Biocompatible amphiphilic Janus nanoparticles with enhanced interfacial properties for colloidal surfactants.

Emulsions in which water droplets are dispersed in fluorocarbon oil phase (W/F emulsions) serve as effective means to encapsulate bioactives and precisely execute reactions in confined space due to the gas permeability, chemical inertness, and biocompatibility offered by the continuous phase. While molecular surfactants consisting of perfluorinated polyether (PFPE) and polyethylene glycol (PEG) have been used to stabilize these emulsions, these surfactants cannot effectively prevent coalescence and cross-contamination between the neighboring droplets. Herein, we present Janus nanoparticles (F-SiO2-PEG) as biocompatible colloidal surfactants to achieve excellent stability in W/F emulsions. By utilizing monolayered wax colloidosomes as templates, we show that Janus silica nanoparticles with two distinctive surface wetting properties can be synthesized in high purity. Moreover, we demonstrate that additional PEGylation of these Janus particles allows these colloidal surfactants to strongly adhere at the W/F interface, granting excellent emulsion stability compared to the equivalent randomly functionalized nanoparticles and prevent non-specific adsorption of proteins. As the strategy outlined in this work is general, we anticipate that it can be further extended to prepare Janus particles with tailored interfacial properties for biomedical, cosmetics, and pharmaceutical applications involving emulsions.

Biocompatible Wax-Based Microcapsules with Hermetic Sealing for Thermally Triggered Release of Actives.

We present a microfluidic approach that utilizes temperature-responsive and biocompatible palm oil as the shell material in microcapsules to simultaneously achieve hermetic sealing as well as on-demand temperature-triggered release of the encapsulated actives. Unlike common paraffin waxes (e.g., eicosane), microcapsule shells comprising palm oil do not form pores or cracks during freezing and provide a hermetic seal, a nearly perfect seal that separates the core containing the actives from the surrounding environment over a prolonged period of time. This allows effective isolation and protection of complex cargoes such as small molecules with high diffusivity, strong acids, and cosmetic actives including niacinamide. Moreover, the palm oil shell melts above the defined melting temperature, allowing the on-demand release of the encapsulated actives. Furthermore, palm oil is biocompatible, is edible, and leaves a minimal footprint when used in personal care and cosmetic products, offering new perspectives in the design of microcapsules for cosmetic applications.

Temperature-Responsive Janus Particles as Microsurfactants for On-Demand Coalescence of Emulsions.

A new strategy that utilizes temperature-responsive wax-based Janus particles as microsurfactants to simultaneously achieve enhanced emulsion stability, as well as, on-demand coalescence of emulsion droplets is presented. The dumbbell structure with different surface wetting properties on each side of the Janus particle enables the particles to strongly adsorb at the liquid-liquid interface, leading to excellent stability against coalescence for both water-in-oil (W/O) and oil-in-water (O/W) emulsions. Moreover, these Janus microparticles are composed of a hydrophilic acrylate resin and a hydrophobic wax compartment which transitions from a frozen to an oil-soluble molten state above the melting point. This allows the particle-adsorbed droplets to coalesce above a designated temperature, depending on the type of wax material used. It is envisioned that the excellent emulsion stability and the tunable and rapid response to local temperature enabled by the wax-based Janus particle offers new and exciting opportunities in the advancing technologies including micro-reactors and drug delivery systems to name a few.

Simultaneous Monitoring of Temperature and Ca2+ Concentration Variation by Fluorescent Polymer during Intracellular Heat Production.

The relationship between calcium ion (Ca2+) concentration and temperature variation during the oxidative phosphorylation (OXPHOS) process has become an essential focus for exploration of signaling pathways and neurodegenerative disease. However, there have been limited reports of fluorescent probes for simultaneous Ca2+ detection and temperature sensing. Herein, a new water-soluble fluorescent probe that combines a thermoresponsive polymer, curcumin and Fluo-4 AM for intracelllar temperature and Ca2+ sensing is described. Furthermore, this fluorescent polymer was successfully applied for intracelluar temperature and Ca2+ gradient monitoring generated by exogenous heating in HeLa cells. It was discovered that within 10 min after the OXPHOS process was induced by an inhibitor, the temperature increased 0.5-1.0 °C and the Ca2+ level decreased by about 5.7 µM. These results confirmed that the fluorescent polymer enabled investigation of the relationship between intracelluar temperature and Ca2+-induced neurotransmitter release.

Altered structural brain network resulting from white matter injury in obstructive sleep apnea.

STUDY OBJECTIVES: To assess, using fractional anisotropy (FA) analysis, alterations of brain network connectivity in adults with obstructive sleep apnea (OSA). Abnormal networks could mediate clinical functional deficits and reflect brain tissue injury. METHODS: Structural brain networks were constructed using diffusion tensor imaging (DTI) from 165 healthy (age 57.99 ± 6.02 years, male 27.9%) and 135 OSA participants (age 59.01 ± 5.91 years, male 28.9%) and global network properties (strength, global efficiency, and local efficiency) and regional efficiency were compared between groups. We examined MRI biomarkers of brain tissue injury using FA analysis and its effect on the network properties. RESULTS: Differences between groups of interest were noted in global network properties (p-value < 0.05, corrected), and regional efficiency (p-value < 0.05, corrected) in the left middle cingulate and paracingulate gyri, right posterior cingulate gyrus, and amygdala. In FA analysis, OSA participants showed lower FA values in white matter (WM) of the right transverse temporal, anterior cingulate and paracingulate gyri, and left postcentral, middle frontal and medial frontal gyri, and the putamen. After culling fiber tracts through WM which showed significant differences in FA, we observed no group difference in network properties. CONCLUSIONS: Changes in WM integrity and structural connectivity are present in OSA participants. We found that the integrity of WM affected brain network properties. Brain network analysis may improve understanding of neurocognitive deficits in OSA, enable longitudinal tracking, and provides explanations for specific symptoms and recovery kinetics.

Synthesis of ficin-protected AuNCs in a droplet-based microreactor for sensing serum ferric ions.

A droplet-based microfluidic synthesis approach for preparation of ficin capped gold nano clusters (AuNCs) was developed. Well dispersed AuNCs could be procured within 8 min. Upon excitation wavelength at 340 nm, the resultant AuNCs exhibited a strong blue fluorescence with the maximum emission at 450 nm. Due to the aggregation-induced "turn-off" fluorescence mechanism, the synthesized AuNCs as a fluorescent probe displayed high sensitivity and good selectivity for sensing ferric ions. The relative fluorescence intensity versus ferric ions concentration yielded a good linear calibration in the range of 10.0-1000.0 µM (R2 = 0.998) and the limit of detection was 4.1 µM. Moreover, the possible mechanism for abated fluorescence intensity of AuNCs by adding ferric ions was discussed briefly. Further, the as-prepared fluorescent AuNCs was successfully applied for the detection of serum ferric ions. The results indicated that the droplet-based microfluidic synthesis system could provide a new way for the rapid preparation of AuNCs with good polydispersity and have potential as the sensing probes for the analysis of ferric ions in real biological samples.

Flow-Assisted Switchable Catalysis of Metal Ions in a Microenvelope System Embedded with Core-Shell Polymers.

Many efforts have been made on stimuli-responsive switchable catalysis to trigger catalytic activity over various chemical reactions. However, the reported light-, pH- or chemically responsive organocatalysts are mostly incomplete in the aspects of shielding efficiency and long-term performance. Here, we advance the flow-assisted switchable catalysis of metal ions in a microenvelope system that allows  the on-off catalysis mode on demand for long-lasting catalytic activity. Various metal-ion catalysts can be selectively embedded in a novel polymeric core-shell of the heteroarm star copolymer of poly(styrene) and poly(4-vinylpyridine) emanated from a polyhedral oligomeric silsesquioxane center. The immobilized core-shell polymer on the inner wall of a poly(dimethylsiloxane) envelope microreactor shows on-off switching catalysis between the expanded active mode and contracted protective mode under continuous flow of solvents or subsequent dry conditions. In particular, the preserved catalytic activity of toxic Hg2+ for oxymercuration was demonstrated even for 2 weeks without leaching, whereas the activity of moisture-sensitive Ru3+ ions for polymerization of methyl methacrylate was maintained even after 5 days from an open atmosphere. It is practical that the tight environment of the enveloped microfluidic system facilitates cyclic switching between the reaction-"on" and -"off" modes of such toxic, sensitive/expensive catalysts for long-term prevention and preservation.

Integrated CO2 capture-fixation chemistry via interfacial ionic liquid catalyst in laminar gas/liquid flow.

Simultaneous capture of carbon dioxide (CO2) and its utilization with subsequent work-up would significantly enhance the competitiveness of CO2-based sustainable chemistry over petroleum-based chemistry. Here we report an interfacial catalytic reaction platform for an integrated autonomous process of simultaneously capturing/fixing CO2 in gas-liquid laminar flow with subsequently providing a work-up step. The continuous-flow microreactor has built-in silicon nanowires (SiNWs) with immobilized ionic liquid catalysts on tips of cone-shaped nanowire bundles. Because of the superamphiphobic SiNWs, a stable gas-liquid interface maintains between liquid flow of organoamines in upper part and gas flow of CO2 in bottom part of channel. The intimate and direct contact of the binary reagents leads to enhanced mass transfer and facilitating reactions. The autonomous integrated platform produces and isolates 2-oxazolidinones and quinazolines-2,4(1H,3H)-diones with 81-97% yields under mild conditions. The platform would enable direct CO2 utilization to produce high-valued specialty chemicals from flue gases without pre-separation and work-up steps.

Impact of sleep restriction on the structural brain network.

Sleep restriction (SR) is defined as the condition of not having enough sleep, and it can cause brain injury. In this study, we examined the impact of SR on the structural brain network. We obtained diffusion MRI (dMRI) data for the SR group of fourteen participants who got less than or equal to 5.5 h of sleep for the last 1 month and normal group of the same number of participants who got 7 h of sleep. We constructed the structural brain networks from the dMRI data and analyzed them using graph theoretical approaches. In comparison with the normal group, the SR group showed higher vulnerability to the targeted node attack and alterations of regional efficiency in the brain regions such as the bilateral orbital part of the frontal gyri, superior occipital gyri, left insula, fusiform, right supplementary motor area, and cingulate gyrus. These findings indicate that SR may cause the reduction of the potential alternative neuronal pathways in the brain and rewiring of neuronal fibers in the structural brain networks, which may result in potential functional impairments, as well as alterations of the structural brain connectivity. Therefore, investigating the structural brain network offers new insight into how SR influences the human brain.

Ratiometric Fluorescent Polymeric Thermometer for Thermogenesis Investigation in Living Cells.

Intracellular temperature has a fundamental effect on cellular events. Herein, a novel fluorescent polymer ratiometric nanothermometer has been developed based on transferrin protein-stabilized gold nanoclusters as the targeting and fluorescent ratiometric unit and the thermosensitve polymer as the temperature sensing unit. The resultant nanothermometer could feature a high and spontaneous uptake into the HeLa cells and the ratiometric temperature sensing over the physiological temperature range. Moreover, the precise temperature sensing for intracellular heat generation in HeLa cells following calcium ions stress has been achieved. This practical intracellular thermometry could eliminate the interference of the intracellular surrounding environment in cancer cells without a microinjection procedure, which is user-friendly. The prepared new nanothermometer can provide tools for unveiling the intrinsic relationship between the intracellular temperature and ion channel function.

Primary surgical closure should be considered in premature neonates with large patent ductus arteriosus.

BACKGROUND: Treatment for patent ductus arteriosus (PDA) in premature infants can consist of medical or surgical approaches. The appropriate therapeutic regimen remains contentious. This study evaluated the role of surgery in improving the survival of premature neonates weighing less than 1,500 g with PDA. MATERIALS AND METHODS: From January 2008 to June 2011, 68 patients weighing less than 1,500 g with PDA were enrolled. The patients were divided into three groups: a group managed only by medical treatment (group I), a group requiring surgery after medical treatment (group II), and a group requiring primary surgical treatment (group III). RESULTS: The rate of conversion to surgical methods due to failed medical treatment was 67.6% (25/37) in the patients with large PDA (≥2 mm in diameter). The number of patients who could be managed with medical treatment was nine which was only 20.5% (9/44) of the patients with large PDA. There was no surgery-related mortality. Group III displayed a statistically significantly low rate of development of bronchopulmonary dysplasia (BPD) (p=0.008). The mechanical ventilation time was significantly longer in group II (p=0.002). CONCLUSION: Medical treatment has a high failure rate in infants weighing less than 1,500 g with PDA exceeding 2.0 mm. Surgical closure following medical treatment requires a longer mechanical ventilation time and increases the incidence of BPD. Primary surgical closure of PDA exceeding 2.0 mm in the infants weighing less than 1,500 g should be considered to reduce mortality and long-term morbidity events including BPD.

Bax predicts outcome in gastric cancer patients treated with 5-fluorouracil, leucovorin, and oxaliplatin palliative chemotherapy.

BACKGROUND: Platinum and 5-fluorouracil (5-FU)-based regimens have been used the most frequently in palliative chemotherapy for gastric cancer. The present study evaluated the prognostic significance of Bax, excision repair cross-complementation group 1 (ERCC1), and thymidylate synthase (TS) in advanced gastric cancer patients treated with 5-FU, leucovorin, and oxaliplatin (FOLFOX) palliative chemotherapy. METHODS: Seventy-two patients with metastatic or recurrent gastric cancer were treated with FOLFOX regimen. Pretreatment tumor biopsy specimens were analyzed for Bax, ERCC1, and TS expression by immunohistochemistry. RESULTS: High expression of Bax, ERCC1, and TS was observed in 31 (43%), 33 (46%), and 35 (49%) patients, respectively. The median overall survival (OS) of patients was 12 months. Low expression of Bax was associated with poor OS (median, 9 months vs. 18 months; 2-year, 10% vs. 48%; p=0.0005) in univariate analysis, while expression of ERCC1 and TS was not correlated with patient outcome. In multivariate analysis, low expression of Bax was a significant independent predictor of poor OS (p=0.028). Low expression of Bax was significantly associated with poor survival of patients with metastatic or recurrent gastric cancer treated with FOLFOX chemotherapy. CONCLUSIONS: Immunohistochemical staining for Bax with pretreatment biopsy specimen may be useful in selecting FOLFOX regimen as a treatment option for advanced gastric cancer patients.

High expression of excision repair cross-complementation group 1 protein predicts poor outcome in patients with nasopharyngeal cancer.

We evaluated the prognostic significance of excision repair cross-complementation group 1 protein (ERCC1) and thymidylate synthase (TS) in patients with nasopharyngeal cancer (NPC) treated with concurrent chemoradiotherapy (CCRT). Pre-treatment tumor biopsy specimens from 41 patients with locally advanced NPC (stage I: 1, II: 10, III: 9, IV: 21 patients) were analyzed for ERCC1 and TS expression by immunohistochemistry. All patients were treated with one cycle of induction chemotherapy (5-fluorouracil 1000 mg/m(2)/day and cisplatin 20mg/m(2)/day, days 1-4) followed by CCRT starting on day 22. CCRT consisted of radiotherapy (70 Gy/35 fractions for 7 weeks) with cisplatin 20mg/m(2)/day for 4 days on weeks 1, 4, and 7 of radiotherapy. High expression of ERCC1 and TS was observed in 25 (60%) and 21 (51%) patients, respectively. High expression of ERCC1 was associated with WHO type 1 or 2 histology (p=0.045). With a median follow-up duration of 106 months (32-152 months) in survivors, the 5-year overall survival (OS) of all patients was 53%. In univariate analysis, 5-year OS (73% versus 39%, p=0.005) was significantly inferior in patients with high expression of ERCC1, while high expression of TS was not correlated with patient outcome. In multivariate analysis, high expression of ERCC1 was a significant independent prognostic factor for poor OS (p=0.029) along with WHO type 1 or 2 histology. High expression of ERCC1 protein may be a useful prognostic factor for poor outcome in patients with locally advanced NPC treated with CCRT.

Expression of Bcl-2 predicts outcome in locally advanced non-small cell lung cancer patients treated with cisplatin-based concurrent chemoradiotherapy.

BACKGROUND: Platinum-based concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced unresectable non-small cell lung cancer (NSCLC). The determination of parameters that may predict the result of the treatment has strong clinical implications. PATIENTS AND METHODS: Pretreatment tumor biopsy specimens from 39 patients with locally advanced NSCLC (stage IIIA: 5, stage IIIB: 34) were analyzed for p53, Bcl-2, Bax and ERCC1 expression by immunohistochemistry. All patients were treated with cisplatin-based CCRT. Twenty-four patients received induction chemotherapy followed by CCRT (60Gy/30 fractions, 6mg/m(2) of cisplatin daily). The most commonly administered induction chemotherapy regimen was VIP (etoposide, ifosfamide, cisplatin; 20 patients). Fifteen patients received the same CCRT without induction chemotherapy. RESULTS: High expression of p53, Bcl-2, Bax and ERCC1 was observed in 15 (38%), 19 (49%), 17 (44%) and 12 (31%) patients, respectively. High expression of Bcl-2 was significantly associated with longer survival duration (20 months vs. 9 months, P=0.008) and better response to the treatment (74% vs. 30%, P=0.01). In multivariate analysis, Bcl-2 expression was the only significant independent prognostic factor of overall survival (P=0.007) among the pretreatment patients characteristics. CONCLUSIONS: High expression of Bcl-2 may be a useful prognostic factor in locally advanced NSCLC patients treated with cisplatin-based CCRT.

Acute Mitral Regurgitation due to Spontaneous Chordal Rupture in a Patient With Obstructive Hypertrophic Cardiomyopathy.

A 69-year-old male presented with obstructive hypertrophic cardiomyopathy, mitral valve regurgitation, and myxomatous mitral valve prolapse. A spontaneous chordal rupture and acute severe mitral regurgitation resulted in abrupt clinical deterioration despite complete relief of severe left ventricular outflow tract obstruction and systolic anterior motion of the anterior mitral leaflet. The patient underwent extensive cardiac surgery due to intractable heart failure. Surgical procedures included a mitral valve replacement, a septal myectomy, and the Maze procedure.