Clinical signs, duodenal histopathological grades, and serum high-mobility group box 1 concentrations in dogs with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) commonly occurs in dogs, but there is lack of information about potential biomarkers of clinical and histopathologic severity. OBJECTIVE: To examine the role of serum C-reactive protein (CRP) and high-mobility group box 1 (HMGB1) concentrations in dogs with IBD. ANIMALS: Seventeen dogs with IBD and 25 healthy dogs. METHODS: In this prospective study, duodenal histopathologic severity was graded, and the clinical severity of IBD was assessed by the canine IBD assessment index (CIBDAI) score in dogs with IBD. Serum CRP and HMGB1 concentrations were compared between IBD and healthy dogs and analyzed according to histopathologic grade in dogs with IBD. The correlations between serum CRP and HMGB1 concentrations and the CIBDAI score were evaluated. RESULTS: Dogs with IBD had higher serum CRP (median [range] = 20.39 [1.53-67.69] µg/mL vs 2.31 [0.17-11.49] µg/mL; P < .001) and HMGB1 concentrations (0.44 [0.07-1.58] ng/mL vs 0.05 [0.01-0.25] ng/mL; P < .001) than healthy dogs. The serum HMGB1 concentration was higher in IBD dogs with a moderate to severe histopathologic grade (0.51 [0.30-1.58] ng/mL, P = .03) than in those with a mild histopathologic grade (0.17 [0.07-0.75] ng/mL). Serum CRP concentrations and CIBDAI score were positively correlated in dogs with IBD (rs  = .49, P = .05). CONCLUSIONS AND CLINICAL IMPORTANCE: Serum HMGB1 could be a potential biomarker for diagnosing IBD and might be indicative of histopathologic severity in dogs, whereas serum CRP might be an indicator of clinical severity.

Radioisotope identification using an energy-weighted algorithm with a proof-of-principle radiation portal monitor based on plastic scintillators.

In this study, we validated the feasibility of an energy weighted algorithm that highlights a characteristic area including the Compton edge as a single peak in a proof-of-principle radiation portal monitor system with a plastic scintillator measuring 50 × 100 × 5 cm3. We measured the energy weighted spectra with steel shielding and the dynamic movements of the 137Cs and 60Co sources. The results showed that the peak locations of each source could be identified under shielded or dynamic motion conditions, each within a maximum difference of 0.08 MeV.

On-screen fingerprint sensor with optically and electrically tailored transparent electrode patterns for use on high-resolution mobile displays.

In this study, a mutual capacitive-type on-screen fingerprint sensor, which can recognize fingerprints on a display screen to provide smartphones with full-screen displays with a minimal bezel area, is fabricated. On-screen fingerprint sensors are fabricated using an indium tin oxide transparent conductor with a sheet resistance of ~10 Ω/sq. and a transmittance of ~94% (~86% with the substrate effect) in the visible wavelength range, and assembled onto a display panel. Even at this high transmittance, the electrodes can degrade the display quality when they are placed on the display. The interference between periodic display pixel arrays and sensor patterns can lead to the Moiré phenomenon. It is necessary to find an appropriate sensor pattern that minimizes the Moiré pattern, while maintaining the signal sensitivity. To search for appropriate patterns, a numerical calculation is carried out over wide ranges of pitches and rotation angles. The range is narrowed for an experimental evaluation, which is used to finally determine the sensor design. As the selected sensor pitches are too small to detect capacitance variations, three unit patterns are electrically connected to obtain a unit block generating a larger signal. By applying the selected sensor pattern and circuit driving by block, fingerprint sensing on a display is demonstrated with a prototype built on a commercial smartphone.

Moiré-free fingerprint sensors based on multilayer oxide-metal-oxide electrodes.

The display quality of touchscreen devices with on-screen fingerprint sensors is reduced by moiré patterns, interference phenomena caused by an overlap between the pixel pattern of the display, and the electrode pattern of the fingerprint sensor. A promising strategy for resolving this issue is to reduce the visibility of the moiré pattern, by including a filling layer with a transmittance similar to that of the electrodes, between the different patterns. We propose a moiré-free fingerprint sensor that uses an oxide-metal-oxide (IZO/Ag/IZO) multilayer as a highly transparent electrode. To verify the moiré reduction effect, we conducted a two-dimensional spectral analysis to calculate the spatial frequencies of the superimposed image of the display and the sensor patterns, and demonstrated experimentally that the proposed electrode greatly reduces the undesirable moiré phenomenon.

Scopoletin downregulates MMP­1 expression in human fibroblasts via inhibition of p38 phosphorylation.

Irradiation of keratinocytes by ultraviolet B induces cytokine production, which in turn activates fibroblasts to produce cytokines and increase matrix metallopeptidase (MMP)­1 protein expression. The present study investigated the effect and potential mechanisms of scopoletin on the regulation of MMP­1 expression in fibroblasts. Scopoletin was isolated from Artemisia capillaris crude extract. Treatment of fibroblasts with scopoletin resulted in a decrease in the protein expression of MMP­1 following stimulation with human keratinocyte (HaCaT) conditioned medium. To further explore the mechanism underlying this effect, the expression levels of proteins in the mitogen­activated protein kinase (MAPK) and nuclear factor­κB (NF­κB) signaling pathways were evaluated via western blot analysis. The mRNA expression levels of interleukin (IL)­1α and tumor necrosis factor (TNF) α were evaluated via reverse transcription­quantitative polymerase chain reaction. The effect of scopoletin on cell viability was assessed with the MTT assay. The results demonstrated that scopoletin treatment markedly decreased MMP­1, IL­1α and TNFα mRNA expression in fibroblasts stimulated with HaCaT conditioned medium (40 mJ/cm2), without any apparent cell cytotoxicity, and in a dose­dependent manner. In addition, western blot analysis demonstrated that scopoletin reduced the phosphorylation of p38 MAPK in fibroblasts. In summary, the present study demonstrated that scopoletin inhibited MMP­1 and proinflammatory cytokine expression by inhibiting p38 MAPK phosphorylation. These findings suggest that scopoletin may have potential as a therapeutic agent to prevent and treat photoaging of the skin.

Soyasaponin Ag inhibits α­MSH­induced melanogenesis in B16F10 melanoma cells via the downregulation of TRP­2.

Saponins, which are glycosylated, represent a diverse group of biologically functional products in plants. In the present study, we investigated the effects of soyasaponin Ag, a secondary metabolite extracted from soybean, on α­melanocyte-stimulating hormone (α­MSH)­induced melanin synthesis in B16F10 mouse melanoma cells and the underlying molecular mechanisms. To elucidate the mechanisms through which soyasaponin Ag inhibits melanin synthesis, we performed cellular tyrosinase activity assays and analyzed the expression of the melanogenesis­related genes, tyrosinase, tyrosinase­related protein (TRP)­1 and TRP­2. We demonstrated that soyasaponin Ag inhibited α­MSH­induced melanin synthesis in melanoma cells. Of note, soyasaponin Ag had no inhibitory effect on intracellular tyrosinase activity. However, soyasaponin Ag inhibited TRP­2 expression in a dose­dependent manner. Therefore, the depigmenting effect of soyasaponin Ag may be due to the inhibition of tyrosinase expression or the enhancement of tyrosinase degradation. Moreover, soyasaponin Ag did not exert any toxic on B16F10 mouse melanoma cells, suggesting that soyasaponin is a safe component for use in skin care cosmetic formulations that are used for skin whitening.

Protective effects of a polymethoxy flavonoids-rich Citrus aurantium peel extract on liver fibrosis induced by bile duct ligation in mice.

OBJECTIVE: To evaluate the possible protective effect of Citrus aurantium peel extract (CAE) against apoptosis in cholestatic liver fibrosis induced by bile duct ligation in mice. METHODS: Male ICR mice were divided to 5 groups: 1) Control group (Sham-operated mice), 2) Cholestatic liver injury group induced by bile duct ligation (BDL), 3) BDL mice treated with silymarin (200 mg/kg) for 4 weeks, 4) BDL mice treated with 50 mg/kg CAE for 4 weeks, 5) BDL mice treated with 200 mg/kg CAE for 4 weeks. Mice were sacrificed and liver fibrosis was evaluated by serum and hepatic tissue biochemistry tests and liver histopathological examination. Effects of CAE on inflammation and apoptosis gene regulation were investigated through real-time PCR. CAE effect on lipid metabolism related signaling was determined by western blot analysis. RESULTS: In BDL mice, administration of CAE for 4 weeks markedly attenuated liver fibrosis based on histopathological alteration. Serum and hepatic tissue biochemistry results revealed that CAE (50 and 200 mg/kg) decreased the levels of alanine transaminase, aspartate transaminase, gamma-glutamyl transferase, total bilirubin, nitric oxide, and thiobarbituric acid reactive substances. Real-time PCR and western blot analysis showed that CAE regulated inflammation, apoptosis, and lipid metabolism factors increased by BDL. Interleukin family, tumor necrosis factor α, and related apoptosis factors mRNA levels were increased by BDL treatment. However, these increases were suppressed by CAE administration. In addition, CAE effectively increased phosphorylation of AMP-activated protein kinase, nuclear factor E2-related factor 2, and related cytoprotective proteins. CONCLUSIONS: CAE can efficiently regulate BDL-induced liver injury with antioxidant, anti-inflammatory, and anti-apoptotic activities.

Is a Price Increase Policy Enough for Adolescent Smokers?: Factors Affecting the Effectiveness of Increasing Cigarette Prices Among Korean Adolescent Smokers.

BACKGROUND: Cigarette pricing policy is one tool for controlling smoking behavior on a national scale. It is unclear, however, what effects such policy has on adolescents and which characteristic subgroups of adolescents are more or less sensitive to cigarette pricing policy. MATERIALS AND METHODS: Our data came from the 2013 Korea Youth Risk Behavior Web-based Survey. The dependent variable was whether or not a participant was classified as a "persistent smokers," defined as a smoker who would continue smoking despite any price increase. Other variables of interest were smoking days (quantity), previous attempts to stop smoking, and previous education on smoking cessation. The statistical analysis was performed using weighted data and the SURVEYFREQ and SURVEYLOGISTIC procedures in SAS 9.3. RESULTS: Among 7094 adolescent smokers (5349 males and 1745 females), 19.9% of males and 25.1% of females reported as persistent smokers. Compared with light smokers, heavy smokers are more likely to be persistent smokers (male: odds ratio [OR] = 2.45, 95% confidence interval [CI] = 2.04-2.95, P value < .001; female: OR = 3.23, 95% CI = 2.44-4.27, P value < .001). When we stratified the data by household income, previous attempts to stop smoking, and previous education on smoking cessation, that trend remained statistically significant. CONCLUSIONS: Because heavier smokers with higher risk of health-related consequences were less sensitive to pricing policy than mild smokers, pricing policy alone is not enough to reduce the societal burden caused by smoking. We suggest that additional cessation policy is needed along with pricing policy for adolescents with heavier smoking behavior in Korea. IMPLICATION: This study shows that heavy smokers are more likely to be persistent smokers despite the cigarette price increase policy, compared with light smokers in Korean adolescents. Because heavier smokers were less sensitive to pricing policy than mild smokers, pricing policy alone is not enough to reduce the societal burden caused by smoking. We suggest that additional tobacco control policies should be evaluated and effective ones implemented in addition to cigarette prices to reduce smoking among regular adolescent smokers.

Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives.

The Escherichia coli AcrAB-TolC efflux pump is the archetype of the resistance nodulation cell division (RND) exporters from Gram-negative bacteria. Overexpression of RND-type efflux pumps is a major factor in multidrug resistance (MDR), which makes these pumps important antibacterial drug discovery targets. We have recently developed novel pyranopyridine-based inhibitors of AcrB, which are orders of magnitude more powerful than the previously known inhibitors. However, further development of such inhibitors has been hindered by the lack of structural information for rational drug design. Although only the soluble, periplasmic part of AcrB binds and exports the ligands, the presence of the membrane-embedded domain in AcrB and its polyspecific binding behavior have made cocrystallization with drugs challenging. To overcome this obstacle, we have engineered and produced a soluble version of AcrB [AcrB periplasmic domain (AcrBper)], which is highly congruent in structure with the periplasmic part of the full-length protein, and is capable of binding substrates and potent inhibitors. Here, we describe the molecular basis for pyranopyridine-based inhibition of AcrB using a combination of cellular, X-ray crystallographic, and molecular dynamics (MD) simulations studies. The pyranopyridines bind within a phenylalanine-rich cage that branches from the deep binding pocket of AcrB, where they form extensive hydrophobic interactions. Moreover, the increasing potency of improved inhibitors correlates with the formation of a delicate protein- and water-mediated hydrogen bond network. These detailed insights provide a molecular platform for the development of novel combinational therapies using efflux pump inhibitors for combating multidrug resistant Gram-negative pathogens.

Validation of energy-weighted algorithm for radiation portal monitor using plastic scintillator.

To prevent illicit tracking of radionuclides, radiation portal monitor (RPM) systems employing plastic scintillators have been used in ports and airports. However, their poor energy resolution makes the discrimination of radioactive material inaccurate. In this study, an energy weight algorithm was validated to determine (133)Ba, (22)Na, (137)Cs, and (60)Co by using a plastic scintillator. The Compton edges of energy spectra were converted to peaks based on the algorithm. The peaks have a maximum error of 6% towards the theoretical Compton edge.

Creating Anti-icing Surfaces via the Direct Immobilization of Antifreeze Proteins on Aluminum.

Cryoprotectants such as antifreeze proteins (AFPs) and sugar molecules may provide a solution for icing problems. These anti-icing substances protect cells and tissues from freezing by inhibiting ice formation. In this study, we developed a method for coating an industrial metal material (aluminum, Al) with AFP from the Antarctic marine diatom, Chaetoceros neogracile (Cn-AFP), to prevent or delay ice formation. To coat Al with Cn-AFP, we used an Al-binding peptide (ABP) as a conjugator and fused it with Cn-AFP. The ABP bound well to the Al and did not considerably change the functional properties of AFP. Cn-AFP-coated Al (Cn-AFP-Al) showed a sufficiently low supercooling point. Additional trehalose coating of Cn-AFP-Al considerably delayed AFP denaturation on the Al without affecting its antifreeze activity. This metal surface-coating method using trehalose-fortified AFP can be applied to other metals important in the aircraft and cold storage fields where anti-icing materials are critical.

A Monte Carlo study of an energy-weighted algorithm for radionuclide analysis with a plastic scintillation detector.

Nuisance and false alarms due to naturally occurring radioactive material (NORM) are major problems facing radiation portal monitors (RPMs) for the screening of illicit radioactive materials in airports and ports. Based on energy-weighted counts, we suggest an algorithm that distinguishes radioactive nuclides with a plastic scintillation detector that has poor energy resolution. Our simulation study, using a Monte Carlo method, demonstrated that man-made radionuclides can be separated from NORM by using a conventional RPM.

Structure-activity relationships of a novel pyranopyridine series of Gram-negative bacterial efflux pump inhibitors.

Recently we described a novel pyranopyridine inhibitor (MBX2319) of RND-type efflux pumps of the Enterobacteriaceae. MBX2319 (3,3-dimethyl-5-cyano-8-morpholino-6-(phenethylthio)-3,4-dihydro-1H-pyrano[3,4-c]pyridine) is structurally distinct from other known Gram-negative efflux pump inhibitors (EPIs), such as 1-(1-naphthylmethyl)-piperazine (NMP), phenylalanylarginine-ß-naphthylamide (PAßN), D13-9001, and the pyridopyrimidine derivatives. Here, we report the synthesis and biological evaluation of 60 new analogs of MBX2319 that were designed to probe the structure activity relationships (SARs) of the pyranopyridine scaffold. The results of these studies produced a molecular activity map of the scaffold, which identifies regions that are critical to efflux inhibitory activities and those that can be modified to improve potency, metabolic stability and solubility. Several compounds, such as 22d-f, 22i and 22k, are significantly more effective than MBX2319 at potentiating the antibacterial activity of levofloxacin and piperacillin against Escherichia coli.

Characterization of a novel pyranopyridine inhibitor of the AcrAB efflux pump of Escherichia coli.

Members of the resistance-nodulation-division (RND) family of efflux pumps, such as AcrAB-TolC of Escherichia coli, play major roles in multidrug resistance (MDR) in Gram-negative bacteria. A strategy for combating MDR is to develop efflux pump inhibitors (EPIs) for use in combination with an antibacterial agent. Here, we describe MBX2319, a novel pyranopyridine EPI with potent activity against RND efflux pumps of the Enterobacteriaceae. MBX2319 decreased the MICs of ciprofloxacin (CIP), levofloxacin, and piperacillin versus E. coli AB1157 by 2-, 4-, and 8-fold, respectively, but did not exhibit antibacterial activity alone and was not active against AcrAB-TolC-deficient strains. MBX2319 (3.13 µM) in combination with 0.016 µg/ml CIP (minimally bactericidal) decreased the viability (CFU/ml) of E. coli AB1157 by 10,000-fold after 4 h of exposure, in comparison with 0.016 µg/ml CIP alone. In contrast, phenyl-arginine-ß-naphthylamide (PAßN), a known EPI, did not increase the bactericidal activity of 0.016 µg/ml CIP at concentrations as high as 100 µM. MBX2319 increased intracellular accumulation of the fluorescent dye Hoechst 33342 in wild-type but not AcrAB-TolC-deficient strains and did not perturb the transmembrane proton gradient. MBX2319 was broadly active against Enterobacteriaceae species and Pseudomonas aeruginosa. MBX2319 is a potent EPI with possible utility as an adjunctive therapeutic agent for the treatment of infections caused by Gram-negative pathogens.

Different functions of MdtB and MdtC subunits in the heterotrimeric efflux transporter MdtB(2)C complex of Escherichia coli.

In contrast to homotrimeric transporters of the RND (resistance-nodulation-division) superfamily, which often conduct efflux transport of a wide range of substrates by the functionally rotating mechanism, the mechanism utilized by the heterotrimeric members of this family, which also perform multidrug efflux, is unclear. We examined one heterotrimeric transporter, the MdtB(2)C complex of Escherichia coli, by an extensive cysteine scanning mutagenesis of residues likely involved in ligand transport. Many such mutations in MdtC strongly decreased the level of cloxacillin transport, whereas mutations of corresponding residues in MdtB did not affect transport. Furthermore, many such residues in MdtC were covalently modified by fluorescein maleimide, which acted as a substrate and presumably produced labeling of the residues in the substrate path. In contrast, few residues in MdtB were labeled. Together with the previous data showing that the inactivation of proton translocation channel in MdtC has an only modest effect on transport yet in MdtB totally inactivated the activity, these results suggest that the two subunits, MdtB and MdtC, play very different roles, MdtC likely involved in substrate binding and transport and MdtB presumably inducing the conformational change needed for transport through proton translocation. Three-dimensional models of MdtB and MdtC, based on sequence homology with the AcrB transporter, also support this interpretation.

Experience of 100 laparoscopic radical prostatectomies performed by a single surgeon: an analysis of surgical and functional outcomes.

PURPOSE: We analyzed the surgical and functional outcomes of 100 consecutive laparo-scopic radical prostatectomies (LRP) performed by a single surgeon. MATERIALS AND METHODS: Between October 2007 and May 2010, a total of 100 consecutive patients underwent LRP for prostate cancer at our institution. We retrospectively reviewed the medical records of these patients to determine surgical and functional results. We compared surgical and functional outcomes between three groups divided on the basis of operation period (Group 1; first 40 cases; Group 2; next 30 cases; Group 3; last 30 cases). RESULTS: The operative time decreased significantly as the surgeon's experience increased over time (P<0.01). The learning curve for operative time was surpassed after approximately 40 cases. The overall positive surgical margin (PSM) rate was 17.5% in Group 1, 16.7% in Group 2, and 10% in Group 3. For organ-confined disease, the PSM rate was 2.5%, 6.7%, and 3.3% in Groups 1, 2, and 3, respectively. The continence rate (absence of a pad) was 73.2% and the social continence rate was 94.7% at 12 months after surgery. There was a significant difference in continence (absence of pad) between the early (Group 1) and late group (Group 3) at 1, 3, and 6 months (P<0.0001). The continence rate was not affected by whether the pubic bone-anchoring procedure or the Rocco suture method was used. The overall potency rate was 16.7% and 48.6% at 6 and 12 months, respectively. For bilateral nerve-sparing cases, the potency rate was 20% and 57.1% at 6 and 12 months, respectively. CONCLUSIONS: Our surgical and functional outcomes indicate that even in this 'robotic era', LRP is still an attractive treatment option for patients with localized prostate cancer, especially in areas with limited access to surgical robots.

Multidrug efflux pump MdtBC of Escherichia coli is active only as a B2C heterotrimer.

RND (resistance-nodulation-division) family transporters in Gram-negative bacteria frequently pump out a wide range of inhibitors and often contribute to multidrug resistance to antibiotics and biocides. An archetypal RND pump of Escherichia coli, AcrB, is known to exist as a homotrimer, and this construction is essential for drug pumping through the functionally rotating mechanism. MdtBC, however, appears different because two pump genes coexist within a single operon, and genetic deletion data suggest that both pumps must be expressed in order for the drug efflux to occur. We have expressed the corresponding genes, with one of them in a His-tagged form. Copurification of MdtB and MdtC under these conditions showed that they form a complex, with an average stoichiometry of 2:1. Unequivocal evidence that only the trimer containing two B protomers and one C protomer is active was obtained by expressing all possible combinations of B and C in covalently linked forms. Finally, conversion into alanine of the residues, known to form a proton translocation pathway in AcrB, inactivated transport only when made in MdtB, not when made in MdtC, a result suggesting that MdtC plays a different role not directly involved in drug binding and extrusion.

New empirical formula for neutron dose level at the maze entrance of 15 MV medical accelerator facilities.

An easily applicable empirical formula was derived for use in the assessment of the photoneutron dose at the maze entrance of a 15 MV medical accelerator treatment room. The neutron dose equivalent rates around the Varian medical accelerator head calculated with the Monte Carlo code MCNPX were used as the source term in producing the base data. The dose equivalents were validated by measurements with bubble detectors. Irradiation geometry conditions expected to yield higher neutron dose rates in the maze were selected: a 20 x 20 cm2 irradiation field, gantry rotation plane parallel to the maze walls, and the photon beams directed to the opposite wall to the maze entrance. The neutron dose equivalents at the maze entrance were computed for 697 arbitrary single-bend maze configurations by extending the Monte Carlo calculations down to the maze entrance. Then, the empirical formula was derived by a multiple regression fit to the neutron dose equivalents at the maze entrance for all the different maze configurations. The goodness of the empirical formula was evaluated by applying it to seven operating medical accelerators of different makes. When the source terms were fixed, the neutron doses estimated from the authors' formula agreed better with the corresponding MCNPX simulations than the results of the Kersey method. In addition, compared with the Wu-McGinley formula, the authors' formula provided better estimates for the mazes with length longer than 8.5 m. There are, however, discrepancies between the measured dose rates and the estimated values from the authors' formula, particularly for the machines other than a Varian model. Further efforts are needed to characterize the neutron field at the maze entrance to reduce the discrepancies. Furthermore, neutron source terms for the machines other than a Varian model should be simulated or measured and incorporated into the formula for accurate extended application to a variety of models.

Concentration of cytokines in the aqueous humor of patients with naive, recurrent and regressed CNV associated with amd after bevacizumab treatment.

PURPOSE: : To evaluate the concentration of various cytokines in the aqueous humor of patients with naive, recurrent, and regressed choroidal neovascularization (CNV) of age-related macular degeneration after bevacizumab treatment. METHODS: : Aqueous humor samples were collected from 36 eyes with age-related macular degeneration and 10 controls during cataract surgery. Of 36 patients with age-related macular degeneration, 5 eyes were naïve to bevacizumab injection, 14 eyes had recurrent CNV after bevacizumab treatment, and 17 eyes had regressed CNV after bevacizumab treatment. Cytokines were measured by an immunoassay using multianalyte biochip array technology (Evidence investigator cytokine and growth factor biochip array, RANDOX laboratories Ltd., Crumlin, UK). RESULTS: : No significant difference in the cytokine levels was noted between the control group and the naïve CNV group (all P > 0.05). Vascular endothelial growth factor in both naive (66.8 +/- 35.1 pg/mL) and recurrent CNV groups (55.7 +/- 63.0 pg/mL) was significantly higher compared with regressed CNV group (9.8 +/- 12.8 pg/mL, P = 0.025 and P = 0.004, respectively) but was not statistically different from the control group (81.8 +/- 43.7 pg/mL, P = 0.310 and P = 0.212, respectively). The aqueous humor level of tumor necrosis factor-alpha and interleukin (IL)-2 was significantly lower in recurrent CNV group (P = 0.036 and P = 0.019) compared with the control group. In the active CNV patients (recurrent and naïve CNV groups), the aqueous humor levels of IL-6 and IL-8 significantly correlated with the size of CNV (rho = 0.692, P = 0.001 and rho = 0.745, P < 0.001, respectively). CONCLUSION: : Levels of Vascular endothelial growth factor measured in the aqueous humor were significantly related to the disease activity of CNV in age-related macular degeneration. Moreover, IL-2, IL-6, IL-8, and tumor necrosis factor-alpha may be related to the activity of CNV.

Effect of intravitreal bevacizumab injection on aqueous humor cytokine levels in clinically significant macular edema.

PURPOSE: To determine the effect of intravitreal bevacizumab (Avastin, Genentech, Inc., San Francisco, CA) injection on aqueous humor cytokine levels in clinically significant macular edema (CSME). DESIGN: Retrospective, comparative study. PARTICIPANTS: Seventeen eyes undergoing intravitreal injection for CSME and 11 eyes undergoing cataract surgery as negative controls. Nine patients with CSME were naïve to intravitreal bevacizumab injection (CSME group 1), and 8 patients previously received 1 intravitreal bevacizumab injection at a mean of 9.6+/-1.4 weeks earlier (CSME group 2). METHODS: Aqueous humor samples were collected before performing intravitreal injection in the CSME group and during cataract surgery in the control group. Aqueous cytokine levels were determined by immunoassay using multianalyte biochip array technology. MAIN OUTCOME MEASURES: The concentration of cytokines in the aqueous humor was recorded as a mean (+/- standard deviation) in CSME groups 1 and 2 and the control group. Correlations of aqueous humor cytokine levels were evaluated. RESULTS: Significantly higher levels of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1 were noted in patients with CSME compared with controls. Although higher vascular endothelial growth factor (VEGF) levels were noted in CSME group 1 (P = 0.001), a lower level of VEGF was noted after intravitreal bevacizumab injection in CSME group 2 (P = 0.004) compared with the control group. VEGF levels were also lower in CSME group 2 compared with CSME group 1 (P = 0.001). In CSME group 2, a significant negative correlation was observed between VEGF and IL-6 (rho = -0.833, P = 0.01) and VEGF and MCP-1 (rho = -0.736, P = 0.037). CONCLUSIONS: Significantly higher levels of IL-6, IL-8, VEGF, and MCP-1 were noted in the aqueous humor of CSME. However, recurrence of macular edema was noted with significantly lower concentrations of VEGF after a single intravitreal injection of bevacizumab. This suggests the potential importance of IL-6 and MCP-1 in the pathogenesis of CSME. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.