Coronary Microcirculatory Dysfunction and Acute Cellular Rejection After Heart Transplantation.

BACKGROUND: Acute cellular rejection is a major determinant of mortality and retransplantation after heart transplantation. We sought to evaluate the prognostic implications of coronary microcirculatory dysfunction assessed by index of microcirculatory resistance (IMR) for the risk of acute cellular rejection after heart transplantation. METHODS: The present study prospectively enrolled 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiological assessment 1 month after transplantation. IMR is microcirculatory resistance under maximal hyperemia. By measuring hyperemic mean transit time using 3 injections (4 mL each) of room-temperature saline under maximal hyperemia, IMR was calculated as hyperemic distal coronary pressure×hyperemic mean transit time. The primary end point was biopsy-proven acute cellular rejection of grade ≥2R during 2 years of follow-up after transplantation and was compared by using multivariable Cox proportional hazards regression according to IMR. The incremental prognostic value of IMR, in addition to the model with clinical factors, was evaluated by comparison of C-index, net reclassification index, and integrated discrimination index. RESULTS: The mean age of recipients was 51.2±13.1 years (81.2% male), and the cumulative incidence of acute cellular rejection was 19.0% at 2 years. Patients with acute cellular rejection had significantly higher IMR values at 1 month than those without acute cellular rejection (23.1±8.6 versus 16.8±11.1, P=0.002). IMR was significantly associated with the risk of acute cellular rejection (per 5-U increase: adjusted hazard ratio, 1.18 [95% CI, 1.04-1.34], P=0.011) and the optimal cutoff value of IMR to predict acute cellular rejection was 15. Patients with IMR≥15 showed significantly higher risk of acute cellular rejection than those with IMR<15 (34.4% versus 3.8%; adjusted hazard ratio, 15.3 [95% CI 3.6-65.7], P<0.001). Addition of IMR to clinical variables showed significantly higher discriminant and reclassification ability for risk of acute cellular rejection (C-index 0.87 versus 0.74, P<0.001; net reclassification index 1.05, P<0.001; integrated discrimination index 0.20, P<0.001). CONCLUSIONS: Coronary microcirculatory dysfunction assessed by IMR measured early after heart transplantation showed significant association with the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02798731.

Effect of Cholesterol on Nano-Structural Alteration of Light-Activatable Liposomes via Laser Irradiation: Small Angle Neutron Scattering Study.

Although the light-activated liposomes have been extensively studied for drug delivery applications, the fundamental mechanism of the drug release based on lipid compositions has not been fully understood. Especially, despite the extensive use of cholesterol in the lipid composition, the role of cholesterol in the light-activated drug release has not been studied. In this study, the influence of cholesterol on drug release from light-responsive drug-encapsulated liposomes after activated by near infrared (NIR) laser was investigated. We prepared methotrexate (MTX)-encapsulated DSPC liposomes consisting of 0 mol% (-Chol) or 35 mol% cholesterol (+Chol), with (+Au) or without gold nanorods (-Au) on the lipid bilayer to compare drug release, morphological changes, and nanostructures after laser irradiations. Transmission electron microscopy (TEM) and small angel neutron scattering (SANS) data revealed that only +Chol +Au liposomes showed partial aggregation of the liposomes after laser irradiation. Similar trends on the drug release and structural change were observed when the liposomes were heated to above chain-transition temperature. Overall, we have found that (1) inclusion of 35 mol% cholesterol enhanced the permeability of lipid bilayers above Tc; (2) the mechanism of laser-activated liposomal drug delivery is disrupting lipid bilayer membranes by the photothermal effect in the presence of plasmonic materials. By understanding the fundamentals of the technology, precise controlled drug release at a targeted site with great stability and repeatability is anticipated.

Repetitive drug releases from light-activatable micron-sized liposomes.

In this work, a novel light activatable micron-sized liposomal drug carrier that has a unique capability to release drug repetitively in proportion to the cycle number of short irradiation (5 s) of near-infrared (NIR) pulsed laser is reported. We synthesized methotrexate (MTX)-loaded liposomes based on a modified reverse-phase evaporation method. Gold nanorods (AuNR) were attached to the liposomal surfaces, enabling the liposomes to release drug under short NIR irradiation via the photothermal effect. The concentrations of methotrexate (MTX) released from the liposomes were 10.6, 29.8, 43.7 and 65.9 µg/mL after one, two, three or four NIR laser cycles (1.1 W at 1064 nm, 5 s per cycle), respectively. The current finding will provide possible solution to the previously reported inconsistency in drug release from light activatable liposomal drug carriers at each activation cycle. The repeatability of drug release described in this work is believed to be due to reversible nature of the liposomes. The liposomes release drug via lipid bilayer melting when irradiated by laser due to gold nanorods' plasmonic heat on the lipid bilayer surface and quickly regain their original structure once the laser source is removed. We provided evidence of the reversible liposomal structures by monitoring the change of number densities of liposomes using a microelectrode sensor with different laser irradiation durations and powers. We also assessed the micron-sized liposome with respect to long-term stability, drug encapsulation efficiency, and drug-releasing efficiency, demonstrating the possibility of utilizing these liposomes as long-term drug delivery vehicles for various drugs.

Impact of Sleep-Disordered Breathing on Functional Outcomes in Ischemic Stroke: A Cardiopulmonary Coupling Analysis.

BACKGROUND AND PURPOSE: Cardiopulmonary coupling (CPC) analysis is an easily assessable method to evaluate sleep-disordered breathing (SDB); however, its prognostic impact in patients with acute ischemic stroke needs to be investigated. We performed a CPC analysis using Holter monitoring at the early stage of noncardioembolic ischemic stroke to investigate the prognostic effect of SDB on functional impairment at the 3-month follow-up. METHODS: A total 615 patients with acute noncardioembolic ischemic stroke who underwent Holter monitoring within 30 days of stroke onset were enrolled from a multicenter, prospective, all-comer cohort. CPC analysis was conducted, and SDB was defined by the presence of narrow-band coupling during sleep time. We investigated the association between SDB and functional impairment at 3 months as measured by the modified Rankin Scale. RESULT: Narrow-band coupling was present in 191 (31.1%) of 615 patients (mean age 64.5±12.6 years). The narrow-band group showed a significantly higher rate of severe functional impairment (modified Rankin Scale score >2; 45.5% versus 12.9%, P<0.001) and persistent disability (Δmodified Rankin Scale score ≤0; 53.9% versus 39.8%, P<0.001) at the 3-month follow-up. In multivariate analysis, narrow-band coupling was an independent predictor of higher risk of severe and persistent functional impairment at 3 months (odds ratio, 3.98 [95% CI, 2.34-6.78]; P<0.001; and odds ratio, 1.81 [95% CI, 1.23-2.66]; P<0.001, respectively). The results remained consistent after propensity-score matched analysis with 157 patient pairs (C-statistic=0.770). CONCLUSIONS: SDB assessed by CPC analysis at the early stage of ischemic stroke could predict severe and prolonged functional impairment at 3 months. CPC analysis using Holter monitoring can help predicting functional impairment in acute ischemic stroke.

Effect of Surfactant-Keratin Hydrolysate Interactions on the Hydration Properties of a Stratum Corneum Substitute.

A novel stratum corneum substitute (SCS) has been developed, and the fundamental mechanism of the dehydration process has been studied using the SCS. After washing with cleansers which contain surfactants, our skin "feels" dehydrated (or hydrated). Although many studies have focused on the effect of surfactants on the regulation of the water loss by the lipid bilayers in the stratum corneum (SC) for a long timescale or at equilibrium, only few studies have focused on the acute effect of the surfactant interaction on dehydration. In addition, the interaction between the surfactant and keratin has been often underappreciated compared to lipid bilayers although keratin is the major nonaqueous component of the SC. Here, we have developed novel SCS models, nonkeratinized (lipid only) and keratinized, to study the effect of keratin hydrolysates on the dehydration rate. We have confirmed that the lipid organizational structure of the SCS was similar to that of the human SC using X-ray scattering. We have revealed that keratin hydrolysates play a significant role in the dehydration rate, accelerating the rate for the short term. We have also demonstrated that the effect of surfactants on dehydration is more pronounced for keratinized samples than that for the nonkeratinized sample. However, the dehydration rate for the nonkeratinized SCS with the surfactant became faster than the that for the keratinized SCS after the 20 min evaporation process, suggesting that the water binding sites of keratin hydrolysates slowed down evaporation, while the surfactant interacting with the lipids accelerated the water loss. Lastly, the study demonstrated that the SCS model can be a great platform to test macroscopic properties and analyze the underlying mechanism at the molecular level for various chemicals.

Effect of Laser Irradiation on Reversibility and Drug Release of Light-Activatable Drug-Encapsulated Liposomes.

Although several studies have demonstrated repetitive drug release using light-activatable liposomes, inconsistent drug release at each activation limits widespread usage. Here, we report reversible plasmonic material-coated encapsulated liposomes for proportional controlled delivery of methotrexate (MTX), which is a common drug for cancer and autoimmune diseases, using repetitive laser irradiation. Our results suggest a proportional increase in total drug release after repetitive laser irradiation. We hypothesize that the drug is released via "melted" lipid bilayers when the plasmonic materials on the liposome surface are heated by laser irradiation followed by reversible formation of the liposome. To evaluate our hypothesis, the number density of liposomes after laser irradiation was measured using single-particle (liposome) collision experiments at an ultramicroelectrode. Collisional frequency data suggest that the number density of liposomes remains unaltered even after 60 s of laser irradiation at 1.1 and 1.8 W, indicating that the liposome structure is reversible. The results were further compared with gold nanorod-coated nanodroplets where drug is released via irreversible phase transition. In contrast to what was observed with the liposome particles, the number density of the nanodroplets decreased with increasing laser irradiation duration. The structure reversibility of our liposome particles may be responsible for repetitive drug release with laser heating. We also studied the temperature rise in the lipid bilayer by incorporating polymerized 10,12-pentacosadiynoic acid (PCDA) in the lipid composition. The red shift in the UV-vis spectrum due to the structural change in PCDA lipids after laser irradiation indicates a rise in temperature above 75 °C, which is also above the chain-melting temperature of the main lipid used in the liposomes. All these results indicate that drug is released from the light-activatable liposomes due to reversible nanostructural alteration in the lipid bilayer by plasmonic resonance heating. The liposomes have potential to be a drug carrier for dose-controlled repetitive drug delivery.

Cilostazol-based triple versus potent P2Y12 inhibitor-based dual antiplatelet therapy in patients with acute myocardial infarction undergoing percutaneous coronary intervention.

Although potent P2Y12 inhibitor-based dual antiplatelet therapy (DAPT) has replaced clopidogrel-based therapy as the standard treatment in patients with acute myocardial infarction (AMI), there is a concern about the risk of bleeding in East Asian patients. We compared the efficacy and safety of cilostazol-based triple antiplatelet therapy (TAT) with potent P2Y12 inhibitor-based DAPT in Korean patients. A total of 4152 AMI patients who underwent percutaneous coronary intervention (PCI) in the Korea Acute Myocardial Infarction Registry were analyzed retrospectively. Patients were divided into two groups: the TAT group (aspirin + clopidogrel + cilostazol, n = 3161) and the potent DAPT group (aspirin + potent P2Y12 inhibitors [ticagrelor or prasugrel], n = 991). Major clinical outcomes at 30 days and 2 years were compared between the two groups using propensity score matching (PSM) analysis. After PSM (869 pairs), there were no significant differences between the two groups in the incidence of total death, cardiac death, myocardial infarction (MI), target vessel revascularization, stent thrombosis, and stroke at 30 days and 2 years. However, the Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding rates were significantly lower in the TAT group compared with the potent DAPT group at 2 years (6.4% vs. 3.6%, p = 0.006). In Korean AMI patients undergoing PCI, TAT with cilostazol was associated with lower bleeding than the potent P2Y12 inhibitor-based DAPT without increased ischemic risk. These results could provide a rationale for the use of TAT in East Asian AMI patients.

Phase-Transition Temperature of Gold-Nanorod-Coated Nanodroplets to Microbubbles by Pulsed Laser.

Previously, gold-nanorod-coated perfluorocarbon nanodroplets have been developed as light-activated on-demand drug delivery carriers. When gold nanorods on the perfluorocarbon nanodroplets resonate with a laser wavelength, plasmonic heat is generated and vaporizes the nanodroplets to gas bubbles. Optimal laser parameters such as pulse duration, pulse repetition frequency, and average power are critical to effectively trigger the phase transition of nanodroplets and allow for drug release. This study focused on determining the temperature of a gold-nanorod-coated perfluorocarbon nanodroplet during phase transition to a gas bubble using a femtosecond laser. Two integrated experimental and theoretical methods were explored. First, the theoretical temperature was determined by the Arrhenius equation and the time it took for the phase transition to occur, assuming the phase-transition process followed a first-order kinetic model. The activation energy and Arrhenius constant of the phase-transition process were obtained via light transmittance through a nanodroplet suspension at different temperatures. The time required for phase transition by a femtosecond laser was measured using an optical microscope. The second approach used a classical heat diffusion model. When the pulse peak energy was considered in the model, the temperature predicted matched the experimental observation of phase-transition temperature threshold, while the total energy value failed to predict the temperature threshold. The results suggest that the phase-transition mechanism is triggered by the vaporization of the nanodroplets via photothermal heating, which is influenced by the peak energy of the laser. It also indicates that optimal laser parameters can be determined by a simple calculation using the classical heat diffusion model and peak energy to control phase transition.

Selective ß1-Blockers Are Not Associated With New-onset Diabetes Mellitus in Hypertensive Patients.

BACKGROUND: Although ß-blockers are known to increase new-onset diabetes mellitus (DM), previous evidence have been controversial. It has been suggested that newer vasodilatory ß-blockers yield better glycemic control than older nonselective agents. The aim of this study was to evaluate the diabetogenicity of currently used newer ß-blockers based on ß1 receptor selectivity in a series of Asian population. METHODS: We investigated a total of 65,686 hypertensive patients without DM from 2004 to 2014. Patients with hemoglobin (Hb) A1c ≤6.0%, fasting blood glucose ≤110 mg/dL, and no history of diabetes or diabetic treatment were enrolled for analysis. Patients were divided into the ß-blockers group and non-ß-blockers group. Propensity score matching (PSM) analysis using a logistic regression model was performed to adjust for potential confounders. The primary end point was the cumulative incidence of new-onset DM, defined as a fasting blood glucose ≥126 mg/dL or HbA1c ≥6.5%, and major adverse cardiac and cerebral events (MACCE), defined as a composite of total death, nonfatal myocardial infarction, and cerebrovascular accidents. We investigated predictors of new-onset DM and MACCE based on 2 models, including clinical risk factors and co-medications, respectively. RESULTS: Mean follow-up duration was 30.91 ± 23.14 months in the entire group before adjustment. The ß-blockers group had a significantly higher incidence of new-onset DM and MACCE than the non-ß-blockers group. After PSM, analysis of a total of 2284 patients (1142 pairs, C-statistic = 0.752) showed no difference between the 2 groups in new-onset DM or MACCE. In multivariate analysis after PSM, baseline HbA1c, stroke, heart failure, nonselective ß-blockers, and age were independent predictors of new-onset DM. Selective ß1-blockers did not increase new-onset DM after adjustment for other antihypertensive medication and statins. CONCLUSIONS: In the era of newer ß-blockers, selective ß1-blockers were not associated with new-onset DM. More evidence is needed to verify this relationship and the underlying mechanisms.

Hyperuricaemia and development of type 2 diabetes mellitus in Asian population.

Recently, meta-analysis studies reported that hyperuricaemia is associated with higher incidence of type 2 diabetes mellitus (T2DM), however, there are limited data on the Asian population. The aim of this observational study is to estimate the long-term impact of hyperuricaemia on the new-onset T2DM and cardiovascular events. This study is based on a single-centre, all-comers, and large retrospective cohort. Subjects that visited from January 2004 to February 2014 were enrolled using the electronic database of Korea University Guro Hospital. A total of 10 505 patients without a history of T2DM were analyzed for uric acid, fasting glucose and haemoglobin (Hb) A1c level. Inclusion criteria included both Hb A1c <5.7% and fasting glucose level <100 mg/dL without T2DM. Hyperuricaemia was defined as a uric acid level ≥7.0 mg/dL in men, and ≥6.5 mg/dL in women. To adjust baseline confounders, a propensity score matching (PSM) analysis was performed. The impact of hyperuricaemia on the new-onset T2DM and cardiovascular events were compared with the non-hyperuricaemia during the 5-year clinical follow-up. After PSM, baseline characteristics of both groups were balanced. In a 5-year follow-up, the hyperuricaemia itself was a strong independent predictor of the incidence of new-onset T2DM (HR, 1.78; 95% CI, 1.12 to 2.8). Hyperuricaemia was a strong independent predictor of new-onset T2DM, which suggests a substantial implication for a correlation between uric acid concentration and insulin resistance (or insulin sensitivity). Also, hyperuricaemia is substantially implicated in cardiovascular risks and the further long-term cardiovascular events in the crude population, but it is not an independent predictor of long-term cardiovascular mortality in the matched population.

Monodisperse Micro-Oil Droplets Stabilized by Polymerizable Phospholipid Coatings as Potential Drug Carriers.

There is a critical need to formulate stable micron-sized oil droplets as hydrophobic drug carriers for efficient drug encapsulation, long-term storage, and sustained drug release. Microfluidic methods were developed to maximize the stability of micron-sized, oil-in-water (o/w) emulsions for potential use in drug delivery, using doxorubicin-loaded triacetin oil as a model hydrophobic drug formulation. Initial experiments examined multiple flow conditions for the dispersed (oil) and continuous (liposome aqueous) phases in a microfluidic device to establish the parameters that influenced droplet size. These data were fit to a mathematical model from the literature and indicate that the droplet sizes formed are controlled by the ratio of flow rates and the height of the device channel, rather than the orifice size. Next, we investigated effects of o/w emulsion production methods on the stability of the droplets. The stability of o/w emulsion produced by microfluidic flow-focusing techniques was found to be much greater (5 h vs 1 h) than for emulsions produced by mechanical agitation (vortexing). The increased droplet stability was attributed to the uniform size and lipid distribution of droplets generated by flow-focusing. In contrast, vortexed populations consisted of a wide size distribution that resulted in a higher prevalence of Ostwald ripening. Finally, the effects of shell polymerization on stability were investigated by comparing oil droplets encapsulated by a photopolymerizable diacetylene lipid shell to those with a nonpolymerizable lipid shell. Shell polymerization was found to significantly enhance stability against dissolution for flow-focused oil droplets but did not significantly affect the stability of vortexed droplets. Overall, results of these experiments show that flow-focusing is a promising technique for generating tunable, stable, monodisperse oil droplet emulsions, with potential applications for controlled delivery of hydrophobic drug formulations.

Adsorption of superparamagnetic iron oxide nanoparticles on silica and calcium carbonate sand.

Superparamagnetic iron oxide (SPIO) nanoparticles have the potential to be used in the characterization of porous rock formations in oil fields as a contrast agent for NMR logging because they are small enough to traverse through nanopores and enhance contrast by shortening NMR T2 relaxation time. However, successful development and application require detailed knowledge of particle stability and mobility in reservoir rocks. Because nanoparticle adsorption to sand (SiO2) and rock (often CaCO3) affects their mobility, we investigated the thermodynamic equilibrium adsorption behavior of citric acid-coated SPIO nanoparticles (CA SPIO NPs) and poly(ethylene glycol)-grafted SPIO nanoparticles (PEG SPIO NPs) on SiO2 (silica) and CaCO3 (calcium carbonate). Adsorption behavior was determined at various pH and salt conditions via chemical analysis and NMR, and the results were compared with molecular theory predictions. Most of the NPs were recovered from silica, whereas far fewer NPs were recovered from calcium carbonate because of differences in the mineral surface properties. NP adsorption increased with increasing salt concentration: this trend was qualitatively explained by molecular theory, as was the role of the PEG grafting in preventing NPs adsorption. Quantitative disagreement between the theoretical predictions and the data was due to NP aggregation, especially at high salt concentration and in the presence of calcium carbonate. Upon aggregation, NP concentrations as determined by NMR T2 were initially overestimated and subsequently corrected using the relaxation rate 1/T2, which is a function of aggregate size and fractal dimension of the aggregate. Our experimental validation of the theoretical predictions of NP adsorption to minerals in the absence of aggregation at various pH and salt conditions demonstrates that molecular theory can be used to determine interactions between NPs and relevant reservoir surfaces. Importantly, this integrated experimental and theoretical approach can be used to gain insight into NP mobility in the reservoir.

Drug delivery systems for wound healing treatment of upper airway injury.

INTRODUCTION: Endotracheal intubation is a common procedure to maintain an open airway with risks for traumatic injury. Pathological changes resulting from intubation can cause upper airway complications, including vocal fold scarring, laryngotracheal stenosis, and granulomas and present with symptoms such as dysphonia, dysphagia, and dyspnea. Current intubation-related laryngotracheal injury treatment approaches lack standardized guidelines, relying on individual clinician experience, and surgical and medical interventions have limitations and carry risks. AREAS COVERED: The clinical and preclinical therapeutics for wound healing in the upper airway are described. This review discusses the current developments on local drug delivery systems in the upper airway utilizing particle-based delivery systems, including nanoparticles and microparticles, and bulk-based delivery systems, encompassing hydrogels and polymer-based approaches. EXPERT OPINION: Complex laryngotracheal diseases pose challenges for effective treatment, struggling due to the intricate anatomy, limited access, and recurrence. Symptomatic management often requires invasive surgical procedures or medications that are unable to achieve lasting effects. Recent advances in nanotechnology and biocompatible materials provide potential solutions, enabling precise drug delivery, personalization, and extended treatment efficacy. Combining these technologies could lead to groundbreaking treatments for upper airways diseases, significantly improving patients' quality of life. Research and innovation in this field are crucial for further advancements.

Adsorption of acid and polymer coated nanoparticles: a statistical thermodynamics approach.

A molecular theoretical description is developed to describe the adsorption of nanoparticles (NPs) that are coated with polymers and functionalized with (surface) acid groups. Results are presented for the adsorption onto both negatively and positively charged surfaces as a function of pH and salt concentration, polymer coating, and NP size. An important finding is that nanoparticles that are coated with weak charge regulating acid molecules such as citric acid develop an asymmetric charge distribution close to a charged surface, due to their finite size. Depending on the sign of the surface charge of the adsorbing surface, a nanoparticle close to the surface either gains more charge or loses charge compared to its "bulk" degree of charge. This in turn influences the amount of NPs that adsorb. The effect of adsorption of negatively charged NPs onto a positively charged surface shows a nonmonotonical variation with pH. The described charging mechanism reveals that details such as size of the NP and acid distribution on the NP need to be considered to provide an accurate understanding of the adsorption process.

The Effects of ROCK Inhibitor on Prevention of Dexamethasone-Induced Glaucoma Phenotype in Human Trabecular Meshwork Cells.

Purpose: This study investigated the effects of dexamethasone (Dex) on human trabecular meshwork (TM) cells, a model of glucocorticoid-induced glaucoma, and evaluated the impact of ripasudil (Rip) as a co-delivery or sequential dosing strategy. Methods: In vitro experiments were conducted to assess the effects of Dex and Rip on TM cells. Confocal microscopy was used to evaluate the impact of Dex and Rip on F-actin staining signals. Contractility of the TM cells upon Dex and Rip treatment mimicking co-delivery and sequential delivery was quantified using collagen gel contraction assay. Transepithelial electrical resistance (TEER) values and fluorescein isothiocyanate (FITC)-dextran permeability were also measured to assess the impact of Dex and Rip on TM cells. Results: Dex and Rip did not exhibit cytotoxicity at the maximum tested concentration (20 µM). Dex-treated TM cells exhibited higher F-actin staining signals compared to controls, which were reduced when co-treated with Rip. Rip inhibited Dex-induced collagen gel contraction activity in both co-delivery and sequential treatments. Dex resulted in increased TEER values as the dose increased, whereas TEER values were maintained when co-treated with Rip. Conclusions: Co-delivery of Rip has the potential to prevent glaucoma symptoms when patients are treated with Dex. This study highlights the importance of identifying strategies to reduce the side effects of prolonged use of glucocorticoids, such as Dex, in the treatment of various diseases. Translational Relevance: This study demonstrates the potential of co-delivering ripasudil with dexamethasone to mitigate glucocorticoid-induced ocular hypertension and a secondary glaucoma that resembles primary open-angle glaucoma, providing insights for the development of novel preventive strategies in clinical care.

Stability of superparamagnetic iron oxide nanoparticles at different pH values: experimental and theoretical analysis.

The detection of superparamagnetic nanoparticles using NMR logging has the potential to provide enhanced contrast in oil reservoir rock formations. The stability of the nanoparticles is critical because the NMR relaxivity (R(2) ≡ 1/T(2)) is dependent on the particle size. Here we use a molecular theory to predict and validate experimentally the stability of citric acid-coated/PEGylated iron oxide nanoparticles under different pH conditions (pH 5, 7, 9, 11). The predicted value for the critical surface coverage required to produce a steric barrier of 5k(B)T for PEGylated nanoparticles (MW 2000) was 0.078 nm(-2), which is less than the experimental value of 0.143 nm(-2), implying that the nanoparticles should be stable at all pH values. Dynamic light scattering (DLS) measurements showed that the effective diameter did not increase at pH 7 or 9 after 30 days but increased at pH 11. The shifts in NMR relaxivity (from R(2) data) at 2 MHz agreed well with the changes in hydrodynamic diameter obtained from DLS data, indicating that the aggregation behavior of the nanoparticles can be easily and quantitatively detected by NMR. The unexpected aggregation at pH 11 is due to the desorption of the surface coating (citric acid or PEG) from the nanoparticle surface not accounted for in the theory. This study shows that the stability of the nanoparticles can be predicted by the theory and detected by NMR quantitatively, which suggests the nanoparticles to be a possible oil-field nanosensor.

Tunable diacetylene polymerized shell microbubbles as ultrasound contrast agents.

Monodisperse gas microbubbles, encapsulated with a shell of photopolymerizable diacetylene lipids and phospholipids, were produced by microfluidic flow focusing, for use as ultrasound contrast agents. The stability of the polymerized shell microbubbles against both aggregation and gas dissolution under physiological conditions was studied. Polyethylene glycol (PEG) 5000, which was attached to the diacetylene lipids, was predicted by molecular theory to provide more steric hindrance against aggregation than PEG 2000, and this was confirmed experimentally. The polymerized shell microbubbles were found to have higher shell-resistance than nonpolymerizable shell microbubbles and commercially available microbubbles (Vevo MicroMarker). The acoustic stability under 7.5 MHz ultrasound insonation was significantly greater than that for the two comparison microbubbles. The acoustic stability was tunable by varying the amount of diacetylene lipid. Thus, our polymerized shell microbubbles are a promising platform for ultrasound contrast agents.

Application of Nanoparticles: Diagnosis, Therapeutics, and Delivery of Insulin/Anti-Diabetic Drugs to Enhance the Therapeutic Efficacy of Diabetes Mellitus.

Diabetes mellitus (DM) is a chronic metabolic disorder of carbohydrates, lipids, and proteins due to a deficiency of insulin secretion or failure to respond to insulin secreted from pancreatic cells, which leads to high blood glucose levels. DM is one of the top four noncommunicable diseases and causes of death worldwide. Even though great achievements were made in the management and treatment of DM, there are still certain limitations, mainly related to the early diagnosis, and lack of appropriate delivery of insulin and other anti-diabetic agents. Nanotechnology is an emerging field in the area of nanomedicine and NP based anti-diabetic agent delivery is reported to enhance efficacy by increasing bioavailability and target site accumulation. Moreover, theranostic NPs can be used as diagnostic tools for the early detection and prevention of diseases owing to their unique biological, physiochemical, and magnetic properties. NPs have been synthesized from a variety of organic and inorganic materials including polysaccharides, dendrimers, proteins, lipids, DNA, carbon nanotubes, quantum dots, and mesoporous materials within the nanoscale size. This review focuses on the role of NPs, derived from organic and inorganic materials, in the diagnosis and treatment of DM.

Repetitive drug delivery using Light-Activated liposomes for potential antimicrobial therapies.

Overuse or misuse of antibiotics and their residues in the environment results in the emergence and prevalence of drug-resistant bacteria and leads to serious health problems. Notable progress in liposome research has been made in drug delivery and several liposomal drugs have been approved for clinical use owing to its biocompatibility and improved efficacy. Recently, liposomes have been engineered further to release encapsulated drugs on the target of interest in a dose-controlled fashion in response to external stimuli such as light, pH, and heat. Among those, light-activated liposomal drug delivery gained a lot of attention because drug release at the targeted sites can be precisely controlled by varying laser/light duration, energy and beam area. We envision potential applications of the light-activated liposomal delivery systems for effective drug-resistant antimicrobial therapies. The use of light-activated liposomes will be widely spread in antimicrobial therapies if the amount of drug is precisely controlled for a prolonged time at a target location. In this review, we discussed the breadth and depth of various light-activated liposomal drug delivery technology. Emphasis was given to repetitive release mechanism and applications of light-activated liposomes because the repeatability provides stability and precise control of the drug delivery system to prevent overdose of antimicrobials and treat with minimal doses. We described limitations on translation from pre-clinical to clinical settings and strategies to overcome the limitations. Careful consideration of light-responsive materials, lipid composition, laser parameters and laser safety is important when selecting and designing the drug delivery system for successful applications.

Increased Cardiac Arrhythmia After Pregnancy-Induced Hypertension: A South Korean Nationwide Database Study.

Background Although pregnancy-induced hypertension (PIH) is associated with an elevated cardiovascular risk, long-term studies or prepregnancy baseline data are scarce. Therefore, using a large nationwide cohort with prepregnancy periodic health screening data, we investigated whether clinically significant arrhythmia incidence increases after PIH. Methods and Results Data were extracted from the Korea National Health Insurance database and combined with the National Health Screening Examination database; women who gave birth between 2007 and 2015 and underwent the national health screening test within a year before pregnancy were followed up until 2016. We excluded women who had a diagnosis of arrhythmia within 1 year before pregnancy. The primary outcome was significant arrhythmia during the year after delivery. Secondary analysis included only specific diagnostic codes of arrhythmia with clinical significance. Additionally, the risk of arrhythmia was stratified by the use of magnesium sulfate. Of 2 035 684 women (PIH; n=37 297 versus normotensive pregnancy; n=1 998 387), the PIH group had a higher prepregnancy risk profile and showed a higher incidence of arrhythmia than women with normotensive pregnancies within 1 year. Women with PIH had a significantly higher risk of atrial flutter/fibrillation and atrioventricular block, but not lethal arrhythmias. Other predictors of arrhythmia development included advanced maternal age and cesarean section. Stratified analysis showed a higher risk of arrhythmia with magnesium sulfate use. Conclusions PIH was significantly associated with the development of arrhythmia within 1 year after delivery. Nevertheless, the incidence of lethal arrhythmias was not increased by PIH. Arrhythmia, especially atrial fibrillation, may largely contribute to increasing the future cardiovascular risk in women with a PIH history.