Delayed treatment of traumatic eyeball dislocation into the maxillary sinus and treatment algorithm: a case report and literature review.

Orbital floor fractures are commonly encountered, but the dislocation of the eyeball into the maxillary sinus is relatively rare. When it does occur, globe dislocation can have serious consequences, including vision loss, enucleation, and orbito-ocular deformity. Immediate surgical intervention is typically attempted when possible. However, severe comorbidities and poor general health can delay necessary surgery. In this report, we present the surgical outcomes of a 70-year-old woman who received delayed treatment for traumatic eyeball dislocation into the maxillary sinus due to a subarachnoid hemorrhage and hemopneumothorax. Additionally, we propose a treatment algorithm based on our clinical experience and a review of the literature.

Epstein-Barr Virus Positive Diffuse Large B-Cell Lymphoma with Epidermotropism.

Primary cutaneous B-cell lymphomas are rare diseases comprising nodular to diffuse lymphoid cell infiltration with an overlying grenz zone and no epidermal involvement upon histological analysis. Diagnostics can become challenging when lymphomas exhibit the characteristics of both B and T-cells. Differential diagnoses may include reactive proliferations, cutaneous composite lymphomas, and transformed mycosis fungoides. Immunohistochemistry and gene arrangement tests may be beneficial to clarify the diagnosis. Herein, we report a rare case of epidermotropic EBV-positive cutaneous B-cell lymphoma along with a literature review.

Nickel, cobalt, and chromium in nail sticker and tip products in Korea.

BACKGROUND: Nail stickers and nail tips are increasingly used nail products in Korea, and the rest of the world. However, no studies have examined if these specific consumer products might contain nickel, cobalt, and/or chromium, that is, metals known to provoke contact allergy. OBJECTIVE: We aimed to assess the release and content of nickel, cobalt, and chromium in nail stickers and tips by performing qualitative and quantitative analyses, respectively, of 50 convenience samples purchased in Korea. METHODS: Eighty-six qualitative spot tests were performed to determine the release of nickel, cobalt, and chromium on 35 nail stickers and 15 nail tips across five brands. Subsequently, the metal contents were quantified using inductively coupled plasma-optical mass spectrometry (ICP-MS). RESULTS: According to the spot tests, nickel was released in 7/86 (8.1%) tests before and 10/86 (11.6%) tests after exposure to artificial sweat. Cobalt and chromium (VI) spot test results were negative. However, ICP-MS detected nickel, cobalt, and chromium in 11%, 6.3%, and 16.7% of the samples, respectively. Detection rates were higher in nail tips than in stickers and were most common in rhinestones. CONCLUSION: Nail stickers and tips may contain nickel, cobalt, and/or chromium.

Glioma progression is shaped by genetic evolution and microenvironment interactions.

The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

Facile nanostructured zinc oxide coating technique for antibacterial and antifouling air filters with low pressure drop.

Air filters effectively filtrate external contaminants including pathogenic bioaerosols; however, they also act as culture sites for the pathogenic bacteria captured in nutrient organic pollutants. Although many researchers have applied various antibacterial coatings to filters, the coating application inevitably increased the pressure drop, leading to the low efficiency and high energy consumption of the purification system. Herein, we report a simple nanostructured zinc oxide (ZnO) coating technique to confer a polypropylene nonwoven filter with superior antibacterial, antifouling and anti-biofilm properties without an additional pressure drop. For aerodynamic coating designs, filters were directly immersed into low concentration precursor solutions to enable the sedimentation of the ZnO sol-gel particles on the filter fibers according to fluid dynamic. The precursor concentration affected the surface topology and so properties of the as-fabricated coating. 0.07 M precursor solution produced a rose-like nanostructured coating exhibiting no pressure-drop increase. The large specific surface area and hydrophobic surface killed and then repelled the attached bacteria effectively. As a result, the bare filter promoted the growth and consequent biofilm formation of the surface bacteria in a favorable environment for the growth of microorganisms, while the coated filter successfully suppressed biofilm development.

Strong and Selective Inhibitory Effects of the Biflavonoid Selamariscina A against CYP2C8 and CYP2C9 Enzyme Activities in Human Liver Microsomes.

Like flavonoids, biflavonoids, dimeric flavonoids, and polyphenolic plant secondary metabolites have antioxidant, antibacterial, antiviral, anti-inflammatory, and anti-cancer properties. However, there is limited data on their effects on cytochrome P450 (P450) and uridine 5'-diphosphoglucuronosyl transferase (UGT) enzyme activities. In this study we evaluate the inhibitory potential of five biflavonoids against nine P450 activities (P450s1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) in human liver microsomes (HLMs) using cocktail incubation and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The most strongly inhibited P450 activity was CYP2C8-mediated amodiaquine N-dealkylation with IC50 ranges of 0.019~0.123 µM. In addition, the biflavonoids-selamariscina A, amentoflavone, robustaflavone, cupressuflavone, and taiwaniaflavone-noncompetitively inhibited CYP2C8 activity with respective Ki values of 0.018, 0.083, 0.084, 0.103, and 0.142 µM. As selamariscina A showed the strongest effects, we then evaluated it against six UGT isoforms, where it showed weaker inhibition (UGTs1A1, 1A3, 1A4, 1A6, 1A9, and 2B7, IC50 1.7 µM). Returning to the P450 activities, selamariscina A inhibited CYP2C9-mediated diclofenac hydroxylation and tolbutamide hydroxylation with respective Ki values of 0.032 and 0.065 µM in a competitive and noncompetitive manner. However, it only weakly inhibited CYP1A2, CYP2B6, and CYP3A with respective Ki values of 3.1, 7.9, and 4.5 µM. We conclude that selamariscina A has selective and strong inhibitory effects on the CYP2C8 and CYP2C9 isoforms. This information might be useful in predicting herb-drug interaction potential between biflavonoids and co-administered drugs mainly metabolized by CYP2C8 and CYP2C9. In addition, selamariscina A might be used as a strong CYP2C8 and CYP2C9 inhibitor in P450 reaction-phenotyping studies to identify drug-metabolizing enzymes responsible for the metabolism of new chemicals.

Discovery of Novel Pyruvate Dehydrogenase Kinase 4 Inhibitors for Potential Oral Treatment of Metabolic Diseases.

Pyruvate dehydrogenase kinase 4 (PDK4) activation is associated with metabolic diseases including hyperglycemia, insulin resistance, allergies, and cancer. Structural modifications of hit anthraquinone led to the identification of a new series of allosteric PDK4 inhibitors. Among this series, compound 8c showed promising in vitro activity with an IC50 value of 84 nM. Good metabolic stability, pharmacokinetic profiles, and possible metabolites were suggested. Compound 8c improved glucose tolerance in diet-induced obese mice and ameliorated allergic reactions in a passive cutaneous anaphylaxis mouse model. Additionally, compound 8c exhibited anticancer activity by controlling cell proliferation, transformation, and apoptosis. From the molecular docking studies, compound 8c displayed optimal fitting in the lipoamide binding site (allosteric) with a full fitness, providing a new scaffold for drug development toward PDK4 inhibitors.

Simultaneous Determination of Five Cytochrome P450 Probe Substrates and Their Metabolites and Organic Anion Transporting Polypeptide Probe Substrate in Human Plasma Using Liquid Chromatography-Tandem Mass Spectrometry.

A rapid and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of organic anion transporting polypeptide 1B1 (OATP1B1) and cytochrome P450 (P450) probe substrates and their phase I metabolites in human plasma was developed. The OATP1B1 (pitavastatin) and five P450 probe substrates, caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A) and their metabolites were extracted from human plasma (50 µL) using methanol. Analytes were separated on a C18 column followed by selected reaction monitoring detection using MS/MS. All analytes were separated simultaneously within a 9 min run time. The developed method was fully validated over the expected clinical concentration range for all analytes tested. The intra- and inter-day precisions for all analytes were lower than 11.3% and 8.82%, respectively, and accuracy was 88.5⁻117.3% and 96.1⁻109.2%, respectively. The lower limit of quantitation was 0.05 ng/mL for dextromethorphan, dextrorphan, midazolam, and 1'-hydroxymidazolam; 0.5 ng/mL for losartan, EXP-3174, omeprazole, 5'-hydroxyomeprazole, and pitavastatin; and 5 ng/mL for caffeine and paraxanthine. The method was successfully used in a pharmacokinetic study in healthy subjects after oral doses of five P450 and OATP1B1 probes. This analytical method provides a simple, sensitive, and accurate tool for the determination of OATP1B1 and five major P450 activities in vivo drug interaction studies.

Establishment of Novel Limbus-Derived, Highly Proliferative ABCG2+/ABCB5+ Limbal Epithelial Stem Cell Cultures.

Homeostasis and regeneration of corneal epithelia are sustained by limbal epithelial stem cells (LESCs); thus, an LESC deficiency is a major cause of blindness worldwide. Despite the generally promising results of cultivated LESC transplantation, it has been limited by variations in long-term success rates, the use of xenogeneic and undefined culture components, and a scarcity of donor tissues. In this study, we identified the culture conditions required to expand LESCs in vitro and established human limbus-derived highly proliferative ABCG2+/ABCB5+ double-positive LESCs. These LESCs exhibited the LESC marker profile and differentiated into corneal epithelial cells. In addition, cultured LESCs expressed high levels of the stem cell markers Sox2, Oct4, c-Myc, and Klf4, had high telomerase activity, and had stable, normal genomes. These results suggest that our novel cultivation protocol affects the phenotype and differentiation capacity of LESCs. From the limbus, which contains a heterogenous cell population, we have derived highly proliferative ABCG2+/ABCB5+ double-positive cells with the ability to differentiate into corneal epithelial cells. This study opens a new avenue for investigation of the molecular mechanism of LESC maintenance and expansion in vitro and may impact the treatment of corneal disease, particularly corneal blindness due to an LESC deficiency.

Role of TGFBIp in Wound Healing and Mucin Expression in Corneal Epithelial Cells.

PURPOSE: Transforming growth factor-ß-induced protein (TGFBIp) is highly expressed in the cornea, and mutant TGFBIp induces corneal diseases. However, the function of TGFBIp in cornea epithelium is not fully investigated. Here, we tested the importance of TGFBIp in regulation of gene expression and corneal epithelial cell (CEC) activity. MATERIALS AND METHODS: The effect of TGFBIp on CEC activity was analyzed by cell migration, adhesion, proliferation and wound healing assay. Analysis of gene expression was examined by western blot and quantitative reverse transcription PCR. RESULTS: The results demonstrated that TGFBIp increased adhesion, migration, proliferation, and wound healing of CECs. Analysis of gene expression presented that TGFBIp-stimulated CECs exhibited increased expression of mucin family genes, such as MUC1, -4, -5AC, and -16. Furthermore, TGFBIp treatment increased the expression of MUC1, -4, -5AC, -7, and -16 in conjunctival epithelial cells. TGFBIp also increased the activity of intracellular signaling molecules ERK and AKT in CECs. Using pharmacologic inhibitors of ERK and AKT, we showed that the expression of mucin genes by TGFBIp is mediated by the activation of ERK and AKT signaling. CONCLUSION: Our findings demonstrate that the locally generated TGFBIp in the cornea may contribute to wound healing of CECs by enhancing the migration, adhesion, and proliferation of CECs. In addition, our results suggest that TGFBIp has a protective effect on ocular surfaces by inducing the expression of mucin genes in corneal and conjunctival epithelial cells. These data suggest that TGFBIp is a useful therapeutic target for patients with corneal wounds.

Determination of volatile organic compounds, catechins, caffeine and theanine in Jukro tea at three growth stages by chromatographic and spectrometric methods.

Tea contains characteristic volatile organic compounds, polyphenols, caffeine and catechins, and is therefore among the most widely consumed beverages all over the world. In this study, fresh Jukro tea leaves collected from Damyang-gun (Jeollanam-do) at 40, 60 and 90day growth stages, were semi-fermented. The volatile organic compounds (VOCs) were extracted by simultaneous distillation-solvent extraction (SDE) and analyzed by gas chromatography/mass spectrometry (GC/MS). Catechins, caffeine and theanine were analyzed by high performance liquid chromatography (HPLC). A total of 159 VOCs were identified in the analyzed Jukro tea leaves. Comparatively, the increase in the concentrations of VOCs was high in 60day leaves. The content of catechins increased along the three growth stages, whereas caffeine, compared to 90day leaves, was higher for 40 and 60day leaves. Based on the results, the 60day leaves were found to be the most suitable and useful for making semi-fermented Jukro tea.

Development of a novel microbubble-liposome complex conjugated with peptide ligands targeting IL4R on brain tumor cells.

Gas (SF6)-filled microbubbles (MBs) were prepared by emulsion and solvent-evaporation method. The prepared MBs were further conjugated with doxorubicin (Dox)-loaded nano-sized liposome and peptide ligands to interleukin-4 receptor (IL4R) for targeting brain tumor cells. The final MB-liposome (Dox)-IL4R targeting peptide ligand [MB-Lipo (Dox)-IL4RTP] had a spherical structure with the mean size of 1,500 nm. The MB-Lipo (Dox)­IL4RTP exhibited cellular uptake in U87MG brain tumor cells (a brain tumor cell line expressing strongly IL4R) with frequency ultrasound energy suggesting that MB-Lipo (Dox)­IL4RTP provided effective targeting ability for brain tumor cells. In addition, WST-1 assay results showed that MB-Lipo (Dox)­IL4RTP inhibited the proliferation of U87MG cells IL4R­dependently. This was confirmed by western blotting of γH2AX, phospho (Ser15)-p53, p53 and p21 which are signal transduction proteins involved in DNA damage response and cell cycle arrest. Taken together, these results indicate that MB-Lipo (Dox)-IL4RTP represents a promising ultrasonic contrast agent for tumor-targeting ultrasonic imaging.

Antioxidative and antiinflammatory activities of quercetin-loaded silica nanoparticles.

Utilizing the biological activities of compounds by encapsulating natural components in stable nanoparticles is an important strategy for a variety of biomedical and healthcare applications. In this study, quercetin-loaded silica nanoparticles were synthesized using an oil-in-water microemulsion method, which is a suitable system for producing functional nanoparticles of controlled size and shape. The resulting quercetin-loaded silica nanoparticles were spherical, highly monodispersed, and stable in an aqueous system. Superoxide radical scavenging effects were found for the quercetin-loaded silica nanoparticles as well as free quercetin. The quercetin-loaded silica nanoparticles showed cell viability comparable to that of the controls. The amounts of proinflammatory cytokines produced by macrophages, such as interleukin 1 beta, interleukin 6, and tumor necrosis factor alpha, were reduced significantly for the quercetin-loaded silica nanoparticles. These results suggest that the antioxidative and antiinflammatory activities of quercetin are maintained after encapsulation in silica. Silica nanoparticles can be used for the effective and stable incorporation of biologically active natural components into composite biomaterials.

Effects of multipurpose solutions on the adhesion of Acanthamoeba to rigid gas permeable contact lenses.

PURPOSE: To evaluate the effect of multipurpose contact lens care solutions (MPSs) on the adhesion of Acanthamoeba to rigid gas permeable (RGP) contact lenses. METHODS: Acanthamoeba castellanii (AC) trophozoites were inoculated onto untreated RGP contact lenses (FP, Extra, or Menicon Z), and numbers of trophozoites adhering to lenses were counted under a phase contrast microscope at 18 h post-inoculation (controls). Similarly, adhering trophozoites were counted at 6 h post-inoculation on each of the three RGP lens types with one of three MPSs (Boston Simplus, Menicare Plus, and O2 Care). Scanning electron microscopic examinations were performed to compare lens surfaces. RESULTS: Adhesion of AC trophozoites to untreated FP was greater than to untreated Extra or Menicon Z. Surfaces of Extra and Menicon Z lenses were waxier, smoother, and more homogeneous than those of FP lenses. After treatment with Boston Simplus, adhesion of AC trophozoites was significantly reduced for all lens types as compared with controls (p < 0.0001). Treatments with Menicare Plus or O2 Care reduced the number of adherent AC trophozoites significantly on FP lenses only as compared with controls (p < 0.0001). CONCLUSIONS: The adhesion rates of AC trophozoites to RGP lenses depended on lens surfaces. Boston Simplus reduced the adhesion rate of AC trophozoites more than Menicare Plus or O2 Care. Appropriate RGP lens and MPS selection could decrease the prevalence of Acanthamoeba keratitis.

Cytochrome b5 reductase, a plasma membrane redox enzyme, protects neuronal cells against metabolic and oxidative stress through maintaining redox state and bioenergetics.

The plasma membrane redox system (PMRS) containing NADH-dependent reductases is known to be involved in the maintenance of redox state and bioenergetics. Neuronal cells are very vulnerable to oxidative stress and altered energy metabolism linked to mitochondrial dysfunction. However, the role of the PMRS in these pathways is far from clear. In this study, in order to investigate how cytochrome b5 reductase (b5R), one of the PM redox enzymes, regulates cellular response under stressed conditions, human neuroblastoma cells transfected with b5R were used for viability and mitochondrial functional assays. Cells transfected with b5R exhibited significantly higher levels of the NAD(+)/NADH ratio, consistent with increased levels of b5R activity. Overexpression of b5R made cells more resistant to H2O2 (oxidative stress), 2-deoxyglucose (metabolic stress), rotenone and antimycin A (energetic stress), and lactacystin (proteotoxic stress), but did not protect cells against H2O2 and serum withdrawal. Overexpression of b5R induced higher mitochondrial functions such as ATP production rate, oxygen consumption rate, and activities of complexes I and II, without formation of further reactive oxygen species, consistent with lower levels of oxidative/nitrative damage and resistance to apoptotic cell death. In conclusion, higher NAD(+)/NADH ratio and consequent more efficient mitochondrial functions are induced by the PMRS, enabling them to maintain redox state and energy metabolism under conditions of some energetic stresses. This suggests that b5R can be a target for therapeutic intervention for aging and neurodegenerative diseases.

Histone methylation levels correlate with TGFBIp and extracellular matrix gene expression in normal and granular corneal dystrophy type 2 corneal fibroblasts.

BACKGROUND: TGFß1-induced expression of transforming growth factor ß-induced protein (TGFBIp) and extracellular matrix (ECM) genes plays a major role in the development of granular corneal dystrophy type 2 (GCD2: also called Avellino corneal dystrophy). Although some key transcription factors are known, the epigenetic mechanisms modulating TGFBIp and ECM expression remain unclear. We examined the role of chromatin markers such as histone H3 lysine methylation (H3Kme) in TGFß1-induced TGFBIp and ECM gene expression in normal and GCD2-derived human corneal fibroblasts. METHODS: Wild-type (n = 3), GCD2-heterozygous (n = 1), and GCD2-homozygous (n = 3) primary human corneal fibroblasts were harvested from human donors and patients prepared. Microarray and gene-expression profiling, Chromatin immunoprecipitation microarray analysis, and Methylated DNA isolation assay-assisted CpG microarrays was performed in Wild-type and GCD2-homozygous human cells. RESULTS: Transcription and extracellular-secretion levels of TGFBIp were high in normal cells compared with those in GCD2-derived cells and were related to H3K4me3 levels but not to DNA methylation over the TGFBI locus. TGFß1 increased the expression of TGFBIp and the ECM-associated genes connective tissue growth factor, collagen-α2[Ι], and plasminogen activator inhibitor-1 in normal corneal fibroblasts. Increased levels of gene-activating markers (H3K4me1/3) and decreased levels of repressive markers (H3K27me3) at the promoters of those gene accompanied the changes in expression. TGFß1 also increased recruitment of the H3K4 methyltransferase MLL1 and of SET7/9 and also the binding of Smad3 to the promoters. Knockdown of both MLL1 and SET7/9 significantly blocked the TGFß1-induced gene expression and inhibited TGFß1-induced changes in promoter H3K4me1/3 levels. Those effects were very weak, however, in GCD2-derived corneal fibroblasts. CONCLUSIONS: Taken together, the results show the functional role of H3K4me in TGFß1-mediated TGFBIp and ECM gene expression in corneal fibroblasts. Pharmacologic and other therapies that regulate these modifications could have potential cornea-protective effects for granular corneal dystrophy.

Alginate-based composite sponge containing silver nanoparticles synthesized in situ.

Silver-based biomaterials have been developed in a variety of bactericidal applications, especially for wound dressings. In this study, silver nanoparticles (AgNPs) were synthesized in a sodium alginate solution and then the composite sponge containing AgNPs was prepared from the nanocolloid solution. The alginate-stabilized AgNPs had the mean negative zeta potential of -52.5mV, suggesting that the surface charge prevents the nanoparticles from aggregating through electrostatic repulsion. The alginate-AgNPs composite sponge had a highly enhanced antimicrobial activity compared to the alginate sponge. In spite of excellent cytocompatibility of the alginate sponge, the viability of the cell treated with the alginate-AgNPs composite sponge extract decreased to 86% of the control. The amount of proinflammatory cytokines released from macrophages treated with the alginate-AgNPs composite sponge was reduced. For the preparation of AgNPs-embedded composites, alginate can be a potential candidate stabilizing AgNPs and providing synergistic antimicrobial and antiinflammatory activities with AgNPs.