Young Hyo Lim

Preparation and in Vitro Antimicrobial Activity of Silver-Bearing Degradable Polymeric Nanoparticles of Polyphosphoester-block-Poly(l-lactide)

The development of well-defined polymeric nanoparticles (NPs) as delivery carriers for antimicrobials targeting human infectious diseases requires rational design of the polymer template, an efficient synthetic approach, and fundamental understanding of the developed NPs, e.g., drug loading/release, particle stability, and other characteristics. Herein, we developed and evaluated the in vitro antimicrobial activity of silver-bearing, fully biodegradable and functional polymeric NPs. A series of degradable polymeric nanoparticles (dNPs), composed of phosphoester and L-lactide and designed specifically for silver loading into the hydrophilic shell and/or the hydrophobic core, were prepared as potential delivery carriers for three different types of silver-based antimicrobials-silver acetate or one of two silver carbene complexes (SCCs). Silver-loading capacities of the dNPs were not influenced by the hydrophilic block chain length, loading site (i.e., core or shell), or type of silver compound, but optimization of the silver feed ratio was crucial to maximize the silver loading capacity of dNPs, up to ca. 12% (w/w). The release kinetics of silver-bearing dNPs revealed 50% release at ca. 2.5-5.5 h depending on the type of silver compound. In addition, we undertook a comprehensive evaluation of the rates of hydrolytic or enzymatic degradability and performed structural characterization of the degradation products. Interestingly, packaging of the SCCs in the dNP-based delivery system improved minimum inhibitory concentrations up to 70%, compared with the SCCs alone, as measured in vitro against 10 contemporary epidemic strains of Staphylococcus aureus and eight uropathogenic strains of Escherichia coli. We conclude that these dNP-based delivery systems may be beneficial for direct epithelial treatment and/or prevention of ubiquitous bacterial infections, including those of the skin and urinary tract.

Development of a Vinyl Ether-Functionalized Polyphosphoester as a Template for Multiple Postpolymerization Conjugation Chemistries and Study of Core Degradable Polymeric Nanoparticles

A novel polyphosphoester (PPE) with vinyl ether side chain functionality was developed as a versatile template for postpolymerization modifications, and its degradability and biocompatibility were evaluated. An organocatalyzed ring-opening polymerization of ethylene glycol vinyl ether-pendant cyclic phosphotriester monomer allowed for construction of poly(ethylene glycol vinyl ether phosphotriester) (PEVEP). This vinyl ether-functionalized PPE scaffold was coupled with hydroxyl- or thiol-containing model small molecules via three different types of conjugation chemistries—thiol–ene “click” reaction, acetalization, or thio-acetalization reaction—to afford modified polymers that accommodated either stable thio–ether or hydrolytically labile acetal or thio–acetal linkages. Amphiphilic diblock copolymers of poly(ethylene glycol) and PEVEP formed well-defined micelles with a narrow and monomodal size distribution in water, as confirmed by dynamic light scattering (DLS), transmission electron microscopy, and atomic force microscopy. The stability of the micelles and the hydrolytic degradability of the backbone and side chains of the PEVEP block segment were assessed by DLS and nuclear magnetic resonance spectroscopy (1H and 31P), respectively, in aqueous buffer solutions at pH values of 5.0 and 7.4 and at temperatures of 25 and 37 °C. The hydrolytic degradation products of the PEVEP segments of the block copolymers were then identified by electrospray ionization, gas chromatography, and matrix-assisted laser desorption/ionization mass spectrometry. The parent micelles and their degradation products were found to be non-cytotoxic at concentrations up to 3 mg/mL, when evaluated with RAW 264.7 mouse macrophages and OVCAR-3 human ovarian adenocarcinoma cells.

Surface Charges and Shell Crosslinks Each Play Significant Roles in Mediating Degradation, Biofouling, Cytotoxicity and Immunotoxicity for Polyphosphoester-based Nanoparticles

The construction of nanostructures from biodegradable precursors and shell/core crosslinking have been pursued as strategies to solve the problems of toxicity and limited stability, respectively. Polyphosphoester (PPE)-based micelles and crosslinked nanoparticles with non-ionic, anionic, cationic, and zwitterionic surface characteristics for potential packaging and delivery of therapeutic and diagnostic agents, were constructed using a quick and efficient synthetic strategy, and importantly, demonstrated remarkable differences in terms of cytotoxicity, immunotoxicity, and biofouling properties, as a function of their surface characteristics and also with dependence on crosslinking throughout the shell layers. For instance, crosslinking of zwitterionic micelles significantly reduced the immunotoxicity, as evidenced from the absence of secretions of any of the 23 measured cytokines from RAW 264.7 mouse macrophages treated with the nanoparticles. The micelles and their crosslinked analogs demonstrated lower cytotoxicity than several commercially-available vehicles, and their degradation products were not cytotoxic to cells at the range of the tested concentrations. PPE-nanoparticles are expected to have broad implications in clinical nanomedicine as alternative vehicles to those involved in several of the currently available medications.

Holistic assessment of covalently labeled core-shell polymeric nanoparticles with fluorescent contrast agents for theranostic applications.

The successful development of degradable polymeric nanostructures as optical probes for use in nanotheranostic applications requires the intelligent design of materials such that their surface response, degradation, drug delivery, and imaging properties are all optimized. In the case of imaging, optimization must result in materials that allow differentiation between unbound optical contrast agents and labeled polymeric materials as they undergo degradation. In this study, we have shown that use of traditional electrophoretic gel-plate assays for the determination of the purity of dye-conjugated degradable nanoparticles is limited by polymer degradation characteristics. To overcome these limitations, we have outlined a holistic approach to evaluating dye and peptide-polymer nanoparticle conjugation by utilizing steady-state fluorescence, anisotropy, and emission and anisotropy lifetime decay profiles, through which nanoparticle-dye binding can be assessed independently of perturbations, such as those presented during the execution of electrolyte gel-based assays. This approach has been demonstrated to provide an overall understanding of the spectral signature-structure-function relationship, ascertaining key information on interactions between the fluorophore, polymer, and solvent components that have a direct and measurable impact on the emissive properties of the optical probe. The use of these powerful techniques provides feedback that can be utilized to improve nanotheranostics by evaluating dye emissivity in degradable nanotheranostic systems, which has become increasingly important as modern platforms transition to architectures intentionally reliant on degradation and built-in environmental responses.

Relationship between sodium intake and blood pressure according to metabolic syndrome status in the Korean National Health and Nutrition Examination Survey.

ObjectivesThe relationship between sodium intake and blood pressure (BP) in population studies varies depending on the dietary habit and the characteristics of the population studied. Asian dietary patterns and salt sensitivity have been suggested to explain this association. Aging and metabolic syndrome (MS) are the most common reasons for salt sensitivity in populations. Participants and methodsWe therefore examined the dietary patterns in the Korean National Health and Nutrition Examination Survey. ResultsIn a multiple regression model for 3757 patients, age, antihypertensive medication, BMI, family history of hypertension, and MS were positively associated with systolic BP, whereas female sex, income, educational status, and fruit intake were negatively associated with systolic BP. Fruit intake was the only dietary factor that was negatively associated with systolic BP (P=0.017). In MS (n=712), sodium and fruit intake was independently positively and negatively associated with systolic BP, respectively, discounting age and medication. In contrast, in normal individuals (n=3045), diet was not related to systolic BP. The relationship between diet and systolic BP is more clear-cut in MS. ConclusionDietary pattern and salt sensitivity at the population level could be a cause of the relationship between sodium intake and BP.

The Relationship Between Ambulatory Arterial Stiffness Index and Blood Pressure Variability in Hypertensive Patients

Background and Objectives Ambulatory arterial stiffness index (AASI) is well known as a predictor of cardiovascular mortality in hypertensive patients. Mathematically, AASI reflect the standard deviation (SD) of blood pressure (BP) variation. AASI is measured higher levels in non-dipper than dipper. Thus, AASI has a possibility of not only reflecting arterial stiffness but also BP variability and/or autonomic nervous dysfunction. Subjects and Methods Consecutive data from 418 untreated hypertensive patients were analyzed retrospectively. We examined the association between the 24-hour ambulatory BP monitoring (ABPM) parameters and AASI. Results AASI had a simple correlation with age (R=0.189, p<0.001), relative wall thickness (RWT) (R=0.115, p=0.019), left ventricular mass index (LVMI) (R=0.192, p<0.001), average systolic BP (SBP) (R=0.232, p<0.001), average pulse pressure (PP) (R=0.363, p<0.001), SD of diastolic BP (DBP) (R=-0.352, p<0.001), SD of PP (R=0.330, p<0.001), SD of heart rate (HR) (R=-0.268, p<0.001), and nocturnal dipping (R=-0.137, p=0.005). In multiple linear regression analysis model including clinical parameters and 24 hour-ABPM parameters, independent predictors of AASI were SD of PP (β=1.246, p<0.001), SD of DBP (β=-1.067, p<0.001), SD of SBP (β=-0.197, p<0.001), and non-dipper (β=0.054, p=0.033). Conclusion AASI is closely correlated with BP variability. The result of this study shows that AASI is not only a parameter for arterial stiffness, but also a parameter for BP variability.

A case of primary plasmacytoma of lymph nodes.

Extramedullary plasmacytoma may originate in any organ, either as a primary tumor or as a facet of systemic multiple myeloma. These solid lesions most commonly affect the upper respiratory tract, gastrointestinal and urogenital tract, skin, and lung. Primary plasmacytoma of the lymph node is a rare hematologic neoplasm, which usually manifests as an enlargement of the cervical lymph nodes with no evidence of any other plasma cell dyscrasia. A 56-year-old man was admitted, due to the presence of multiple palpable masses in the right cervical and submandibular areas. Surgical resection revealed plasmacytoma of the lymph nodes. According to our full work-up, no evidence of the systemic involvement of plasma cell dyscrasia was discovered and thus, the diagnosis of primary plasmacytoma of the lymph node was made. Radiotherapy was administered, and the remnant mass was reduced substantially, to 1×2 cm in size. The patient was scheduled to be monitored by a PET CT scan, as well as by a neck CT scan.

Erratum to: Relationship between nocturnal blood pressure and 24-h urinary sodium excretion in a rural population in Korea

Background The relationship between sodium intake and blood pressure (BP) is affected by many factors such as absolute level of sodium intake, salt sensitivity, and the accuracy or the timing of the BP measurement. There is no epidemiologic study using both ambulatory BP monitoring (ABPM) and 24-h urine sample in a middle-aged general population.

Effects of genetic variants on platelet reactivity and one-year clinical outcomes after percutaneous coronary intervention: A prospective multicentre registry study

Clopidogrel is the mainstay for antiplatelet treatment after percutaneous coronary intervention (PCI). The relationship of platelet reactivity and genetic polymorphism with clinical outcomes with newer-generation drug-eluting stents is unclear. We analysed 4,587 patients for the most powerful single-nucleotide polymorphisms (CYP2C19, CYP2C9, ABCB1, PON1, and P2Y12) related to on-treatment platelet reactivity (OPR). The optimal cut-off value of high OPR for major adverse thrombotic events was 266. CYP2C19 was significantly associated with high OPR and the number of CYP2C19*R (*2 or *3) alleles was proportional to the increased risk of high OPR. Death, myocardial infarction (MI), stroke, stent thrombosis, and bleeding events were assessed during a 1-year follow-up period. Primary endpoints were death and non-fatal MI. The cumulative 1-year incidence of death and stent thrombosis was significantly higher in patients with CYP2C19*2/*2, CYP2C19*2/*3, and CYP2C19*3/*3 (Group 3) than in patients with CYP2C19*1/*1 (Group 1). Multivariate Cox proportional hazard model showed that cardiac death risk was significantly higher in Group 3 than in Group 1 (hazard ratio 2.69, 95% confidence interval 1.154–6.263, p = 0.022). No association was reported between bleeding and OPR. Thus, CYP2C19 may exert a significant impact on the prognosis of PCI patients even in the era of newer-generation drug-eluting stents.

Mediating effects of nocturnal blood pressure and morning surge on the contributions of arterial stiffness and sodium intake to morning blood pressure: A path analysis.

Abstract Background. The aim of this study was to evaluate the mediating effects of nocturnal blood pressure (BP) and morning surge on the contribution of arterial stiffness and sodium intake to morning BP in a middle-aged general population. Methods. The study included 124 subjects aged 30–59 years, from rural Yeoju County, Gyeonggi Province, South Korea. Ambulatory BP monitoring, 24 h urinary sodium excretion (24 h UNa) and brachial–ankle pulse wave velocity (baPWV) measurements were performed in all subjects. Results. The mean ± SD age was 48.1 ± 8.2 years and the proportion of male subjects was 41.1%. After adjusting for covariates, morning systolic blood pressure (SBP) was significantly correlated with morning surge [coefficient = 0.761, 95% confidence interval (CI) 0.651–0.872, p < 0.001], nocturnal SBP (coefficient = 0.576, 95% CI 0.454–0.698, p < 0.001) and baPWV (coefficient = 3.550, 95% CI 1.447–5.653, p = 0.001). Path analysis modeling revealed that baPWV had significant direct (0.035, p = 0.013) and indirect effects (0.042, p = 0.012) on morning SBP. The indirect effect mediated by nocturnal SBP was statistically significant (0.054, p = 0.005), but the indirect effect mediated by the morning surge was not significant. The 24 h UNa had no significant direct or indirect effects on morning SBP. Conclusion. baPWV had significant direct and indirect effects on morning SBP. The indirect effect was mediated by nocturnal SBP, but not by morning surge. The 24 h UNa had neither significant direct nor indirect effects on morning SBP.