Molecular Epidemiology of Adenoviral Keratoconjunctivitis in Korea.

Human adenoviruses (HAdVs) are a major cause of epidemic keratoconjunctivitis. We investigated the types of adenoviruses responsible for the recent epidemic of keratoconjunctivitis in Korea. From January to November 2019, 218 conjunctival swab samples were collected from patients clinically suspected as having adenoviral keratoconjunctivitis. Genotyping targeting of adenovirus capsid hexon genes was performed using PCR and sequencing. Of the 218 samples collected, 128 (58.7%) were positive for the adenovirus genes by PCR, and 126 samples were successfully genotyped. Adenovirus type 8 (HAdV-D8) was the most common type (67.5%), followed by HAdV-D64 (11.1%), HAdV-D37 (9.5%), HAdV-B3 (5.6%), HAdV-D53 (4.0%), HAdV-E4 (1.6%), and HAdV-D56 (0.8%). Adenoviral keratoconjunctivitis cases were the most frequent in July and August 2019, which were mainly caused by type 8. Phylogenetic analyses revealed little genetic distance among adenoviruses of the same type detected in our study. Our results provide basic data for further studies of adenoviral keratoconjunctivitis.

Cystargamides C and D, New Cyclic Lipopeptides From a Tidal Mudflat-Derived Streptomyces sp. JMS132.

Cystargamides C and D (2 and 3) were isolated from a marine actinomycete strain collected at Beolgyo, South Korea. The planar structures of the cystargamides were elucidated by 1/2D NMR, UV, and MS spectroscopic analyses. The absolute configurations of 2 and 3 were determined based on ROESY correlations and the advanced Marfey's methods. The structures of the compounds were elucidated as new lipodepsipeptides bearing six amino acids with an epoxy fatty acid side chain. For the first time, the nonribosomal peptide synthetase biosynthetic pathway of the cystargamides has been proposed using whole genome sequence analysis. The cystargamides displayed antioxidant effect in the DPPH and ABTS assay. The discovery of new cyclic lipopeptides, cystargamides C and D, from a tidal mudflat-derived Streptomyces sp. supported that marine bacteria have potential as source of bioactive natural products.

Alginate and fucoidan changes the bacterial community in different directions and the alginate or fucoidan degrading bacteria isolated from paddy soil promotes the plant growth.

Seaweed and its extracts have been developed as fertilizers because they possess plant-growth-promoting and antibacterial compounds. For use as fertilizers, the major carbohydrates in seaweed, including fucoidan and alginate, need to be efficiently digested in the soil. We isolated fucoidan/alginate degrading bacteria from paddy soil and verified its use as a biofertilizer. Results show that Stenotrophomonas pavanii has a high alginate degrading activity, and also stimulating melon, pepper, and tomato growth. The growth stimulation effect of the bacteria was enhanced by alginate treatment. Bacillus sp. was isolated as a fucoidan degrading bacterium and this bacterium was also able to stimulate melon growth. Using 16S ribosomal DNA analysis, fucoidan/alginate resistant or susceptible bacteria were successively selected. Bacteria with increased population due to fucoidan and alginate had specificity to each carbohydrate, whereas those with decreased population showed susceptibility to both carbohydrates. This report demonstrates some bacteria for their use as biofertilizers with seaweed and demonstrated that a high throughput method is efficient in identifying bacteria with specific properties.

Traffic-related particulate matter aggravates ocular allergic inflammation by mediating dendritic cell maturation.

The aim of this study was to determine the effects of traffic-related particulate matter (PM) on allergic inflammation of ocular surfaces. BALB/c mice were sensitized with ovalbumin (OVA) and aluminum hydroxide via intraperitoneal injection. Two weeks later, mice were challenged with eye drops containing OVA concomitant with either traffic-related PM2.5 or vehicle eye drops. Topical OVA challenges were administered following unilateral subconjunctival injection of magnetic-bead-sorted CD11c+ dendritic cells (DC). The following were assessed: (1) clinical signs, (2) infiltration of inflammatory cells into conjunctiva, (3) serum levels of OVA-specific IgE production, and (4) T-cell cytokine secretion with topical application of PM2.5, compared to saline vehicle. PM2.5 was found to increase production of OVA-specific IgE in serum and Th2 immune response-related cytokines including interleukin (IL)-4, IL-17A, and IL-13 compared to vehicle control. It is of interest that PM2.5 treatment also elevated the population of mature DCs in draining lymph nodes (LNs). Exposure with PM2.5 was associated with a significant rise in conjunctival expression of IL-1ß, IL-6, IL-17, and TNF. After subconjunctival injection of CD11c+DCs from PM2.5-treated allergic conjunctivitis (AC) mice into naïve mice, T cell responses and OVA-specific IgE were also enhanced. Data suggest that traffic-related PM2.5 exacerbated allergic conjunctivitis as evidenced by increased infiltration of inflammatory cells into the conjunctiva and Th2 responses in the draining LNs associated with enhanced maturation of DCs. Our findings provide new insight into the hazardous potential of traffic-related PM2.5 on allergic diseases, such as asthma or atopic dermatitis.

Prediction Model for Dry Eye Syndrome Incidence Rate Using Air Pollutants and Meteorological Factors in South Korea: Analysis of Sub-Region Deviations.

Here, we develop a dry eye syndrome (DES) incidence rate prediction model using air pollutants (PM10, NO2, SO2, O3, and CO), meteorological factors (temperature, humidity, and wind speed), population rate, and clinical data for South Korea. The prediction model is well fitted to the incidence rate (R2 = 0.9443 and 0.9388, p < 2.2 × 10-16). To analyze regional deviations, we classify outpatient data, air pollutant, and meteorological factors in 16 administrative districts (seven metropolitan areas and nine states). Our results confirm NO2 and relative humidity are the factors impacting regional deviations in the prediction model.

Exposure to Traffic-Related Particulate Matter 2.5 Triggers Th2-Dominant Ocular Immune Response in a Murine Model.

Ambient particulate matter (PM), a major component of air pollution, aggravates ocular discomfort and inflammation, similarly to dry eye disease (DED) or allergies. However, the mechanism(s) by which PM induces the ocular inflammatory response is unknown. This study investigated the immunological response of traffic-related fine particulate matter (PM2.5) on the ocular surface in a murine model. C57BL/6 mice were exposed by topical application to PM2.5 or vehicle for 14 days to induce experimental environmental ocular disease. Corneal fluorescein staining and the number of ocular inflammatory cells were assessed in both groups. The expression of IL-1ß, IL-6, tumor necrosis factor (TNF)-α, and mucin 5AC (MUC5AC) in the ocular surface were evaluated by real-time PCR. An immunohistochemical assay evaluated apoptosis and goblet cell density. ELISA was used to determine the levels of serum IgE and cytokines of Type 1 helper (Th1) and Type 2 helper (Th2) cells after in vitro stimulation of T cells in the draining lymph nodes (LNs). Exposure to traffic-related PM2.5 significantly increased corneal fluorescein staining and cellular toxicity in the corneal epithelium compared with the vehicle control. A significant increase in the number of CD11b+ cells on the central cornea and mast cells in the conjunctiva was observed in the PM2.5 group. Exposure to PM2.5 was associated with a significant increase in the corneal or conjunctival expression of IL-1ß, IL-6, TNF, and MUC5AC compared to the vehicle, and increased maturation of dendric cells (DCs) (MHC-IIhighCD11c+) in draining LNs. In addition, PM2.5 exposure increased the level of serum IgE and Th2 cytokine production in draining LNs on day 14. In conclusion, exposure to traffic-related PM2.5 caused ocular surface damage and inflammation, which induced DC maturation and the Th2-cell-dominant allergic immune response in draining LNs.

Characteristics of nanoparticle formation and hazardous air pollutants emitted by 3D printer operations: from emission to inhalation.

This study examined the emissions of nanoparticles and hazardous air pollutants (HAPs) by 3D printer operations and evaluated nanoparticle deposition behavior using a prediction model. Nanoparticles and HAPs were sampled at the Inha University 3D printing center with five fused filament fabrication (FFF)-type 3D printers. The number size distribution of the nanoparticles exhibited a bimodal distribution with dominant peaks over a large size range between 70 and 100 nm and a smaller size range between 10 and 20 nm. With increasing 3D printer operation, the number concentration of 10 nm particles increased, and the final number concentration was 3.6 times higher than that of the background concentration. Nanoparticle formation and agglomeration were characterized by transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Model calculations revealed that a large number of nanoparticles between 10 and 30 nm in size are deposited in the lower human respiratory tract (generation number: 16-22). A total of 14 HAPs species were detected, among which hexane, acrylonitrile, and benzene concentrations were the highest.

Development of a Conjunctivitis Outpatient Rate Prediction Model Incorporating Ambient Ozone and Meteorological Factors in South Korea.

Ozone (O3) is a commonly known air pollutant that causes adverse health effects. This study developed a multi-level prediction model for conjunctivitis in outpatients due to exposure to O3 by using 3 years of ambient O3 data, meteorological data, and hospital data in Seoul, South Korea. We confirmed that the rate of conjunctivitis in outpatients (conjunctivitis outpatient rate) was highly correlated with O3 (R 2 = 0.49), temperature (R 2 = 0.72), and relative humidity (R 2 = 0.29). A multi-level regression model for the conjunctivitis outpatient rate was well-developed, on the basis of sex and age, by adding statistical factors. This model will contribute to the prediction of conjunctivitis outpatient rate for each sex and age, using O3 and meteorological data.

Development of a population pharmacokinetic model to describe olmesartan medoxomil/ hydrochlorothiazide (20/12.5 mg) FDC tablet in male healthy South Korean subjects.

AIM: The objective of the present study was to develop population pharmacokinetic models for olmesartan medoxomil and hydrochlorothiazide and to investigate the influence of demographic factors on these population pharmacokinetics. METHODS: Plasma concentrations of olmesartan medoxomil and hydrochlorothiazide were measured in 41 healthy volunteers enrolled in our bioequivalence study by LC-MS/MS following oral administration of an olmesartan medoxomil/hydrochlorothiazide (20/12.5 mg) fixed-dose combination tablet. This data and covariates were subjected to nonlinear mixed-effect modeling analysis using the NONMEM software. Evaluation featured a visual predicted check and bootstrapping. RESULTS: The distributions of olmesartan medoxomil and hydrochlorothiazide were best fitted using a two-compartment model with no lag time and first-order elimination. When analyzing hydrochlorothiazide kinetics, we found that TCHO and CL/F were correlated, while. HB and Ka influenced olmesartan medoxomil modeling. All evaluations indicated that the pharmacokinetic profiles of olmesartan medoxomil and hydrochlorothiazide were adequately described using our PPK model. CONCLUSIONS: This study indicates that demographic factors influence the inter-individual variability in the disposition of the combination drug, and it might be more useful to apply it to the PK of olmesartan medoxomil/hydrochlorothiazide (20/12.5 mg) FDC tablets administered to patients with hypertension. *These two authors contributed equally to this work.

A simple pharmacokinetic model of alendronate developed using plasma concentration and urine excretion data from healthy men.

The study of pharmacokinetics of alendronate has been hampered by difficulties in accurately and reproducibly determining their concentrations in serum and urine. Thus, pharmacokinetic characteristics of alendronate have been described in many reports based on urinary excretion data; and plasma pharmacokinetics and the simultaneous pharmacokinetic models of alendronate in plasma and urine are not available. The aims of this study were to measure alendronate concentration in plasma and excretion in urine concurrently and to develop compartmental pharmacokinetic model using urine data. In open-label, single-dose pharmacokinetic study, 10 healthy male volunteers received oral dose of alendronate (70 mg tablet). Blood and urine alendronate concentrations were determined using validated high-performance liquid chromatography method. Non-compartmental analysis was performed using WinNonlin program (Pharsight Inc., Apex, NC). A one-compartment pharmacokinetic model was applied to describe pharmacokinetics of alendronate. A peak plasma alendronate concentration of 33.10 ± 14.32 ng/mL was attained after 1.00 ± 0.16 h. The cumulative amount of alendronate excreted in urine and peak excretion rate were 731.28 ± 654.57 µg and 314.68 ± 395.43 µg/h, respectively. The model, which included first-order absorption rate for oral dosing, showed good fit to alendronate data obtained from plasma and urine. The absorption rate constant was 2.68 ± 0.95 h(-1). The elimination rate constants Kurine and Knon-ur were 0.005 ± 0.004 h(-1) and 0.42 ± 0.08 h(-1), respectively. The pharmacokinetics of alendronate in plasma and urine of healthy men can be predicted using one-compartment model, and thus the behavior of drug in plasma can be estimated from urinary excretion data.

Preclinical pharmacokinetics of PDE-310, a novel PDE4 inhibitor.

A novel phosphodiesterase-4 inhibitor, 2-aryl-7(3',4'-dialkoxyphenyl)-pyrazolo[1,5-alpha] pyrimidine (PDE-310), has been synthesized for the treatment of respiratory diseases. We conducted in vitro and in vivo studies to characterize the pharmacokinetics of PDE-310. The high liver microsomal stability and low inhibitory potency against CYP isoforms of PDE-310 suggested a low first-pass effect and high bioavailability. PDE-310 exhibited high Caco-2 cell permeability in the absorptive direction (apparent permeability coefficients, ∼20 × 10(-6) cm/s), with higher transport in the secretory direction, giving efflux ratios of 3.9 and 2.6 at 5 and 10 µM, respectively. In addition, the high efflux ratio and improved absorption on treatment with efflux transporter inhibitors such as verapamil and MK-571 indicated the involvement of P-gp, BCRP and MRP2 in intestinal transport. PDE-310 bound strongly to human plasma proteins, whereas significantly more PDE-310 (27-34%) was free in rat plasma. Following intravenous administration, nonlinear elimination of PDE-310 was observed at the tested dose ranges (K(m), 0.87 µg/mL; V(max), 0.3 mg·h(-1)·kg(-1)). Following oral PDE-310 administration, dose-normalized AUC and T(max) increased significantly in a dose-dependent manner. PDE-310 exhibited high oral bioavailability (>70%) and was distributed well to various tissues except brain and testis.

Antiemetic effects of midazolam added to fentanyl-ropivacaine patient-controlled epidural analgesia after subtotal gastrectomy: A prospective, randomized, double-blind, controlled trial.

BACKGROUND: Nausea and vomiting are frequent adverse effects of patient-controlled epidural analgesia (PCEA) with opioids. OBJECTIVE: This study was designed to assess the antiemetic effect of midazolam added to fentanyl-ropivacaine PCEA. METHODS: In a prospective, randomized, double-blind, controlled trial, smoking patients with gastric cancer undergoing elective subtotal gastrectomy were evenly allocated to 1 of 2 treatment groups to manage postoperative pain: 0.2% ropivacaine mixed with fentanyl 4 µg/mL and midazolam 0.2 mg/mL (test group) or 0.2% ropivacaine mixed with fentanyl 4 µg/mL (control group). The PCEA infusion was set to deliver 4 µL/h of the study solution, with a bolus of 2 mL per demand and a 15-minute lockout time. The incidence of postoperative nausea and vomiting (PONV), pain intensity, sedation score, usage of rescue analgesia and rescue antiemetic, respiratory depression, urinary retention, and pruritus were recorded at 2, 6, 12, 24, 48, and 72 hours after surgery. Total infused volume of PCEA at 72 hours after surgery was measured. RESULTS: A total of 60 patients were approached and randomized to treatment. No patients were excluded by exclusion criteria and all enrolled patients completed this study. Incidence of nausea (7% vs 33%; P = 0.02) in the test group was significantly lower than in the control group. The overall frequency of PONV in the test group was significantly less than that of the control group (7% vs 40%; P = 0.006). In addition, the mean (SD) infused volume of PCEA in the test group was significantly lower than that in the control group (392.3 [68.9] vs 351.2 [49.8] mL; P = 0.01). However, there were no significant differences in pain intensity, usage of rescue antiemetics and rescue analgesics, and mild pruritus between groups. No patient reported moderate or severe sedation, respiratory depression, or hypoxemia. In addition, there were no severe adverse events. CONCLUSIONS: Midazolam added to fentanyl-ropivacaine PCEA was associated with a significant reduction in the incidence of PONV compared with fentanyl-ropivacaine alone, and a significant decrease in the amount of PCEA administered without a significant increase in adverse events in these patients who underwent subtotal gastrectomy.

Effects of smoking on the pharmacokinetics and pharmacodynamics of a nicotine patch.

The effect of smoking on the pharmacokinetics and pharmacodynamics of a nicotine transdermal delivery system, administered as a single dose or multiple doses, was examined in smokers (n=12) and nonsmokers (n=12). The study was a two-period, parallel trial. In the first period, a single dose of the Nicotinell TTS 20 patch was administered, followed by a 1-week washout period. Then, in the second period, multiple doses of the Nicotinell TTS 20 patch were administered over 4 days. Regarding the pharmacokinetics of nicotine, the AUC(36 h) and AUC(tau) of smokers were about 20% and 40% greater, respectively, than those of nonsmokers. Significant differences in heart rate were observed between smokers and nonsmokers at 10, 12, 16 and 24 h, and significant differences in systolic blood pressure were seen between smokers and nonsmokers at 12, 30 and 36 h in the single-dose study. With multiple doses, significant differences in systolic and diastolic blood pressures were detected between smokers and nonsmokers only at 72.5 and 82 h. Here, it is demonstrated for the first time that the pharmacokinetic and hemodynamic effects of a nicotine patch are significantly different between smokers and nonsmokers.