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Cataract surgery outcomes in centenarian patients have not previously been explored. This study aimed to examine characteristics and report clinical results of people aged ≥100 years undergoing cataract surgery. This was a retrospective observational study, including patients aged ≥100 years who underwent cataract surgery between 2003 and 2021 at Miyata Eye Hospital in Japan. Medical charts were reviewed for information on cataract severity, surgery type, anesthesia, as well as ocular and medical comorbidities. Using Mann-Whitney test, visual acuity, intraocular pressure, and corneal endothelial cell density were compared before and after surgery. Eight eyes of 5 patients were included in the study (mean age, 101.5 ± 1.2 years). Seven of these eyes (87.5%) belonged to women. All surgeries were performed under topical anesthesia using phacoemulsification and insertion of the intraocular lens fixed in the bag. All patients had multiple preoperative medical comorbidities; however, there were no intraoperative, postoperative ocular, or general complications. The postoperative best-corrected visual acuity was significantly improved compared to that before surgery (1.18 ± 0.74 and 0.29 ± 0.52, respectively, P = .004). Neither intraocular pressure nor corneal endothelial cell density demonstrated a significant difference postoperatively. Cataract surgery can be safely performed under topical anesthesia in centenarians without complications using proper perioperative medical control and preparation., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The ability to predict secondary cardiovascular events could improve health of patients undergoing statin treatment. Circulating ANGPTL8 (angiopoietin-like protein 8) levels, which positively correlate with proatherosclerotic lipid profiles, activate the pivotal proatherosclerotic factor ANGPTL3. Here, we assessed potential association between circulating ANGPTL8 levels and risk of secondary cardiovascular events in statin-treated patients., Methods: We conducted a biomarker study with a case-cohort design, using samples from a 2018 randomized control trial known as randomized evaluation of high-dose (4 mg/day) or low-dose (1 mg/day) lipid-lowering therapy with pitavastatin in coronary artery disease (REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease])." From that study's full analysis set (n=12 413), we selected 2250 patients with stable coronary artery disease (582 with the primary outcome, 1745 randomly chosen, and 77 overlapping subjects). A composite end point including cardiovascular-related death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergent admission was set as a primary end point. Circulating ANGPTL8 levels were measured at baseline and 6 months after randomization., Results: Over a 6-month period, ANGPTL8 level changes significantly decreased in the high-dose pitavastatin group, which showed 19% risk reduction of secondary cardiovascular events compared with the low-dose group in the REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease] study. In the highest quartiles, relative increases in ANGPTL8 levels were significantly associated with increased risk for secondary cardiovascular events, after adjustment for several cardiovascular disease risk factors and pitavastatin treatment (hazard ratio in Q4, 1.67 [95% CI, 1.17-2.39). Subgroup analyses showed relatively strong relationships between relative ANGPTL8 increases and secondary cardiovascular events in the high-dose pitavastatin group (hazard ratio in Q4, 2.07 [95% CI, 1.21-3.55]) and in the low ANGPTL8 group at baseline (166

Purpose: This study aimed to present a case of transient corneal damage after exposure to the effluent squirting from a sea anemone, Anthopleura uchidai, and to experimentally confirm the presence of toxic substances from an A. uchidai in the tissue culture., Methods: We reviewed the clinical course of a 51-year-old man who complained of decreased vision in his left eye after the stinging of a sea anemone, A. uchidai. The toxicity of the effluents from an A. uchidai in immortalized human corneal endothelial cells (HCEnC-21T) and human corneal epithelial cells in vitro were evaluated., Results: Corneal edema was observed, and his best-corrected visual acuity was 0.2. Corneal endothelial cell density decreased to 1435 cells/mm2. Although his corneal edema and visual acuity recovered after topical instillation with a topical steroid and 5% NaCl, corneal endothelial cell density did not recover for 3 years after the injury. The in vitro study revealed fractioned effluence from the sea anemone, by size-exclusion chromatography, containing a substance toxic to HCEnC-21T with cytoplasmic swelling and nuclear dislocation., Conclusions: It is necessary to be cautious of effluents from sea anemones along the coast, and ophthalmologists should be aware that sea anemones can cause corneal endothelial dysfunction., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Understanding the clinical course and short-term outcomes of suspected myocarditis after the coronavirus disease 2019 (COVID-19) vaccination has important public health implications in the decision to vaccinate youth., Methods: We retrospectively collected data on patients <21 years old presenting before July 4, 2021, with suspected myocarditis within 30 days of COVID-19 vaccination. Lake Louise criteria were used for cardiac MRI findings. Myocarditis cases were classified as confirmed or probable on the basis of the Centers for Disease Control and Prevention definitions., Results: We report on 139 adolescents and young adults with 140 episodes of suspected myocarditis (49 confirmed, 91 probable) at 26 centers. Most patients were male (n=126, 90.6%) and White (n=92, 66.2%); 29 (20.9%) were Hispanic; and the median age was 15.8 years (range, 12.1-20.3; interquartile range [IQR], 14.5-17.0). Suspected myocarditis occurred in 136 patients (97.8%) after the mRNA vaccine, with 131 (94.2%) after the Pfizer-BioNTech vaccine; 128 (91.4%) occurred after the second dose. Symptoms started at a median of 2 days (range, 0-22; IQR, 1-3) after vaccination. The most common symptom was chest pain (99.3%). Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%), or no anti-inflammatory therapies (8.6%). Twenty-six patients (18.7%) were in the intensive care unit, 2 were treated with inotropic/vasoactive support, and none required extracorporeal membrane oxygenation or died. Median hospital stay was 2 days (range, 0-10; IQR, 2-3). All patients had elevated troponin I (n=111, 8.12 ng/mL; IQR, 3.50-15.90) or T (n=28, 0.61 ng/mL; IQR, 0.25-1.30); 69.8% had abnormal ECGs and arrhythmias (7 with nonsustained ventricular tachycardia); and 18.7% had left ventricular ejection fraction <55% on echocardiogram. Of 97 patients who underwent cardiac MRI at a median 5 days (range, 0-88; IQR, 3-17) from symptom onset, 75 (77.3%) had abnormal findings: 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria. Among 26 patients with left ventricular ejection fraction <55% on echocardiogram, all with follow-up had normalized function (n=25)., Conclusions: Most cases of suspected COVID-19 vaccine myocarditis occurring in persons <21 years have a mild clinical course with rapid resolution of symptoms. Abnormal findings on cardiac MRI were frequent. Future studies should evaluate risk factors, mechanisms, and long-term outcomes.

Conditions underlying balance impairment should be identified to improve knowledge regarding clinical interventions for frail older adults. This study aims to explore the relationship between balance functions and frailty by using the brief balance evaluation systems test (BESTest), which can assess biomechanical constraints, stability limits/verticality, anticipatory postural adjustments (APAs), reactive postural responses, sensory orientation and stability in gait. A total of 75 community-dwelling older women were included in this cross-sectional study. We evaluated frailty by using the Kihon checklist and assessed the participants' balance functions by using the Brief BESTest. We performed the Mann-Whitney U test and receiver operating characteristic curve analysis to compare each balance function between frail and nonfrail participants. Twenty-two of the 75 (29.3%) participants were included in the frailty group. We noted significant differences between the frailty and nonfrailty groups with regard to stability limit, APAs, sensory orientation, and stability in gait (P = 0.010, 0.001, 0.008 and <0.001, respectively). In terms of determining frailty and nonfrailty, APAs and stability in gait were moderately accurate (the area under the curve = 0.730 and 0.713, respectively). APAs showed the highest sensitivity (0.864), whereas stability limits, sensory orientation, and stability in gait showed the highest specificity (0.943, 0.849 and 0.868, respectively). Thus, frail and nonfrail older adults showed significantly different balance functions, such as stability limits, APAs, sensory orientation and stability in gait. The Brief BESTest is useful for evaluating balance functions in relation to frailty., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Coronary artery abnormalities (CAAs) still occur in patients with Kawasaki disease receiving intensified treatment with corticosteroids. We aimed to determine the risk factors of CAA development and resistance to intensified treatment in Post RAISE (Prospective Observational Study on Stratified Treatment With Immunoglobulin Plus Steroid Efficacy for Kawasaki Disease)-the largest prospective cohort of Kawasaki disease patients to date., Methods: In Post RAISE, 2648 consecutive patients with Kawasaki disease were enrolled. The present study analyzed 724 patients predicted to be intravenous immunoglobulin (IVIG) nonresponders (Kobayashi score ≥5) who received intensified treatment consisting of IVIG plus prednisolone. The association between the baseline characteristics and CAA at 1 month after disease onset was examined. The association between the baseline characteristics and treatment resistance was also investigated., Results: Maximum Z score at baseline ≥2.5 (odds ratio, 3.4 [95% CI, 1.5-7.8]), age at fever onset <1 year (odds ratio, 3.4 [95% CI, 1.6-7.4]), and nonresponsiveness to IVIG plus prednisolone treatment (odds ratio, 6.8 [95% CI, 3.3-14.0]) were independent predictors of CAA development. Nonresponsiveness to IVIG plus prednisolone was significantly associated with 8 baseline variables. Baseline total bilirubin (odds ratio, 1.4 [95% CI, 1.2-1.7]) was the only significant independent predictor other than the variables included in the Kobayashi score, enabling treatment resistance to be identified at diagnosis. The area under the ROC curve was 0.74 (95% CI, 0.69-0.79). At a cutoff point of 1.0, the sensitivity and specificity for predicting treatment resistance were 71% and 65%, respectively., Conclusions: In Post RAISE, younger age at fever onset, a larger maximum Z score at baseline, and nonresponsiveness to IVIG plus prednisolone were risk factors significantly associated with CAA development. Nonresponders were able to be identified at diagnosis based on the total bilirubin value. To prevent CAA, more intensified or adjunctive therapies using other agents, such as pulsed methylprednisolone, ciclosporin, infliximab, and Anakinra, should be considered for patients with these risk factors. Registration: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000007133.

Keratoprosthesis is used for corneal transplantation in high-risk patients who require penetrating keratoplasty (PKP). Boston keratoprosthesis (BKpro) is a representative type of keratoprosthesis used worldwide. In Japan, the first BKpro was implanted in an eye after multiple corneal graft failures in 2008, but its use remains limited. A recent patient survey revealed that among the Japanese patients who had previously undergone multiple PKPs, the retention rate of BKpro was significantly higher than that of PKP at 5 years postoperatively (100% vs. 26%; P < 0.01). Patients with implanted BKpro also had better best corrected visual acuity of 20/200 or higher than those with PKP at 5 years postoperatively (80.0% vs. 17.6%; P = 0.03). Regarding the postoperative complications, retroprosthetic membrane formation was observed in 88.9%, infectious keratitis in 33.3%, and glaucoma progression in 11.1% of cases. Another retrospective analysis showed that fungal keratitis occurred in 0.09 patients per year and severely affected visual acuity. Furthermore, because it is difficult to accurately examine intraocular pressure after BKpro implantation, the intraocular pressure of patients with implanted BKpro was prospectively estimated using a transpalpebral tonometer (Diaton). In conclusion, BKpro implantation is effective and safe for Japanese patients, given the reported improvements in visual acuity and low rates of complications.

Objectives: To investigate the effectiveness of presbyopia correction using multifocal soft contact lenses (MF SCLs) for pseudophakic subjects with monofocal intraocular lenses (IOLs)., Methods: In 11 subjects, after monofocal IOL implantation, disposable MF SCLs (Dailies Total 1 Multifocal, Alcon) were daily used for 3 months. Binocular visual acuity between 0.3 and 5 m was measured using an all-distance vision tester (AS-15, Kowa) at 1 and 3 months and compared before and during MF SCL wear. Binocular contrast sensitivity testing was conducted under mesopic and photopic illuminations at 1 month., Results: The mean manifest refraction spherical equivalent before MF SCL wear was -0.36 D. The add powers of used MF SCLs were +1.25, +2.00, and +2.50 D in 1, 16, and 5 eyes, respectively. The mean binocular visual acuities during MF SCL wear were 20/20 or better between 0.5 and 5 m and significantly improved at 0.7 m or less (P<0.025). There was no change in the mesopic contrast sensitivity, whereas the photopic contrast sensitivity at 18 cycles per degree was degraded during MF SCL wear., Conclusions: The use of MF SCL was effective for presbyopia correction in pseudophakic subjects with monofocal IOL, and favorable binocular vision would be obtained in a range from distance to intermediate.

Purpose: The prospective case series aimed to examine the agreement between the use of a slit-scanning contact specular microscope and a noncontact specular microscope in corneal endothelial cell (CEC) analysis and to evaluate the differences between the central and peripheral regions in normal corneas., Methods: After confirming normal corneal endothelium with slit-lamp microscopy, CEC images of 56 eyes of 56 cataractous patients were analyzed in the central and 4 peripheral regions using a slit-scanning contact specular microscope. A noncontact specular microscope was used for the analysis in the central region. The endothelial cell density (ECD), the percentage of hexagonal shape cells (HEX), and the coefficient of variation (CV) in the central region were compared. Differences between central and peripheral CECs were also evaluated., Results: The mean ECD was 2778 cell/mm and was not different from the results using the noncontact specular microscope (2736 cell/mm, P = 0.051). There was a significant correlation (P < 0.001, R = 0.72). The analysis of HEX resulted in larger values with the slit-scanning contact microscope (53.13% vs. 48.89%, P < 0.001), whereas there was no difference in the CV (38.48 vs. 38.04, P = 0.56). On comparing the central and peripheral regions, there was no significant difference in the ECD, whereas significant differences were found in the superior region in the HEX and CV (P < 0.001) and in the nasal region in CV (P = 0.023)., Conclusions: The analysis of ECD with the use of the slit-scanning contact specular microscope did not differ from the noncontact specular microscope, and the results demonstrated no difference between the central and peripheral ECD.

Interleukin (IL)-27, one of cytokines in the IL-12 family, is considered to have both pro- and anti-inflammatory properties. However, blood IL-27 levels in coronary artery disease (CAD) have not been fully elucidated yet. This cross-sectional study was done to elucidate the association between blood IL-27 levels and CAD.We investigated plasma IL-27 and high-sensitivity C-reactive protein (hsCRP) levels in 274 consecutive patients who underwent elective coronary angiography for suspected CAD. CAD was present in 177 patients [30 acute coronary syndrome (ACS) and 147 stable CAD]. Compared with 97 patients without CAD, 177 patients with CAD had higher IL-27 (median 0.26 vs 0.22 ng/mL, P < .05) and higher hsCRP (0.98 vs 0.41 mg/L, P < .001) levels. However, there was no significant difference in IL-27 levels among 3 groups of ACS, stable CAD, and CAD(-) (0.26, 0.25, and 0.22 ng/mL), whereas hsCRP levels were significantly higher in ACS and stable CAD than in CAD(-) (2.09, 0.91 vs 0.41 mg/L, P < .001) and were highest in ACS. IL-27 levels tended to increase with the number of >50% stenotic coronary vessels: 0.22 in CAD(-), 0.22 in 1-vessel disease, 0.31 in 2-vessel disease, and 0.27 ng/mL in 3-vessel disease (P < .05). A stepwise increase in hsCRP levels was also found: 0.41 in CAD(-), 0.75 in 1-vessel, 1.05 in 2-vessel, and 1.85 mg/L in 3-vessel disease (P < .001). Plasma hsCRP levels significantly (r = 0.35), but IL-27 levels weakly (r = 0.15), correlated with the number of stenotic coronary segments. In multivariate analysis, both IL-27 and hsCRP levels were independent factors associated with CAD. However, hsCRP, but not IL-27, was also a factor for ACS.While plasma IL-27 levels were high in patients with CAD, these levels were an independent factor for only CAD, not ACS, and weakly correlated with the severity of CAD. Our results suggest that IL-27 is unlikely to be a good biomarker reflecting the severity of CAD or the presence of ACS, or to play a major role in the progression of CAD.

Purpose: To propose a grading system of pterygium severity based on corneal higher-order irregularity (HOI) and to evaluate postoperative changes in corneal irregularity of the graded pterygia., Methods: In 268 eyes of 226 patients undergoing excision surgery of primary nasal pterygium, Placido corneal topography images were taken before and until 6 months after surgery. The best-corrected visual acuity (BCVA) and pterygium size with respect to the corneal diameter were also measured. HOI components within 1.0-, 3.0-, and 5.0-mm diameters were obtained using Fourier harmonic analysis of corneal topography data. With threshold levels when the HOIs for 3 diameters steeply increased, 4 levels of grading from 0 (mild) to 3 (severe) were determined. Associations of the grades with the preoperative surface regularity index (SRI), irregular components (IRRs) obtained from the 3.0-mm diameter Fourier analysis, and BCVA were examined. Time-course changes in the indexes after surgery were evaluated for each grade., Results: There were 62, 65, 41, and 100 eyes in grades 0 to 3, respectively. Preoperatively, the SRI in grade 3 was significantly higher than in the other grades (P < 0.001), and the IRR and BCVA varied with the grade (P < 0.001). Between 1 and 6 months postoperatively, grade 3 pterygia showed significant changes in the SRI and IRR (P = 0.013 and 0.017, respectively), whereas there was no change after 3 months postoperatively in the SRI, IRR, and BCVA for all other grades., Conclusions: The proposed grading effectively classified the severity of pterygia and evaluated postoperative restoration of corneal irregularity. Using corneal topographic data allowed for objective evaluation of pterygium severity.

Rationale: There are roughly 5 to 10 million persons infected with human T-lymphotropic virus type 1 (HTLV-1) worldwide, and the safety of treating this population with biologics remains poorly understood., Patient Concerns and Diagnosis: An HTLV-1-infected 66-year-old female with HTLV-1 uveitis (HU) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Her HU had been in remission and her HAM/TSP symptoms had been managed effectively with oral steroids for years. However, she developed severe rheumatoid arthritis (RA) after failing to respond well to conventional anti-rheumatic agents., Interventions: She was administered two intravenous 8mg/kg doses of the biologic tocilizumab., Outcomes: Subsequently, her RA symptoms resolved, but she suffered a recurrence of HU and exacerbation of HAM/TSP symptoms. When she was switched back to steroid-based treatment, HU and HAM symptoms both improved, but RA symptoms again worsened. Finally, an attempt to substitute the biologic abatacept and reduce the steroids failed when HAM/TSP symptoms again became aggravated., Lessons: To the best of our knowledge, this represents the first report worldwide of a biologic aggravating HTLV-1-associated conditions. This report suggests that caution is advised when using biologics to treat HTLV-1-infected patients, though further research is required to clarify the situation.

Objectives: We sought to investigate whether treatment with ezetimibe in combination with statins improves coronary endothelial function in target vessels in coronary artery disease patients after coronary stenting., Approach and Results: We conducted a multicenter, prospective, randomized, open-label, blinded-end point trial among 11 cardiovascular treatment centers. From 2011 to 2013, 260 coronary artery disease patients who underwent coronary stenting were randomly allocated to 2 arms (statin monotherapy, S versus ezetimibe [10 mg/d]+statin combinational therapy, E+S). We defined target vessel dysfunction as the primary composite outcome, which comprised target vessel failure during treatment and at the 6- to 8-month follow-up coronary angiography and coronary endothelial dysfunction determined via intracoronary acetylcholine testing performed in cases without target vessel failure at the follow-up coronary angiography. Coadministration of ezetimibe with statins further lowered low-density lipoprotein cholesterol levels (83±23 mg/dL in S versus 67±23 mg/dL in E+S; P<0.0001), with significant decreases in oxidized low-density lipoprotein and oxysterol levels. Among patients without target vessel failure, 46 out of 89 patients (52%) in the S arm and 34 out of 96 patients (35%) in the E+S arm were found to have coronary endothelial dysfunction (P=0.0256), and the incidence of target vessel dysfunction at follow-up was significantly decreased in the E+S arm (69/112 (62%) in S versus 47/109 (43%) in E+S; P=0.0059). A post hoc analysis of post-treatment low-density lipoprotein cholesterol-matched subgroups revealed that the incidence of both target vessel dysfunction and coronary endothelial dysfunction significantly decreased in the E+S arm, with significant reductions in oxysterol levels., Conclusions: The CuVIC trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction after Coronary Stenting) has shown that ezetimibe with statins, compared with statin monotherapy, improves functional prognoses, ameliorating endothelial dysfunction in stented coronary arteries, and was associated with larger decreases in oxysterol levels., (© 2016 American Heart Association, Inc.)

Objective: Transforming growth factor-β inhibits migration and proliferation of endothelial and smooth muscle cells. Endoglin is a transmembrane receptor for transforming growth factor-β1 and transforming growth factor-β3. Endoglin is released into blood as a soluble form (soluble endoglin [sEng]), but plasma sEng levels in patients with coronary artery disease (CAD) have not been elucidated., Approach and Results: We measured plasma sEng levels in 244 patients undergoing coronary angiography. The severity of coronary atherosclerosis was evaluated as the numbers of >50% stenotic vessels and segments. CAD was found in 147 patients, of whom 55 had 1-vessel, 42 had 2-vessel, and 50 had 3-vessel disease. Compared with 97 patients without CAD, 147 with CAD had lower sEng levels (median 4.04 versus 4.37 ng/mL; P<0.005). A stepwise decrease in sEng levels was found based on the number of stenotic vessels: 4.37 in CAD(-), 4.23 in 1-vessel, 4.13 in 2-vessel, and 3.74 ng/mL in 3-vessel disease (P<0.005). sEng levels inversely correlated with the number of stenotic segments (r=-0.25; P<0.001). In multivariate analysis, sEng was an independent factor for 3-vessel disease and CAD. Odds ratios for CAD and 3-vessel disease were 0.97 (95% confidence interval, 0.95-0.99; P<0.02) and 0.96 (95% confidence interval, 0.93-0.99; P<0.01) for a 0.1 ng/mL increase in sEng levels, respectively., Conclusions: Plasma sEng levels were low in patients with CAD, especially 3-vessel disease, and were inversely associated with the severity of coronary atherosclerosis., (© 2016 American Heart Association, Inc.)

Purpose: To compare the long-term outcomes of visual function and endothelial cell survival after Descemet stripping automated endothelial keratoplasty (DSAEK) and penetrating keratoplasty (PK)., Methods: The cohort included 108 eyes from 97 patients who underwent primary PK and 85 eyes from 78 patients who underwent primary DSAEK at Miyata Eye Hospital in Japan. Uncorrected visual acuity, best spectacle-corrected visual acuity (BSCVA), endothelial cell density, and four components from Fourier harmonic analysis of topography data (spherical component, regular astigmatism component, asymmetry component, and higher-order irregularity component) were retrospectively compared between PK and DSAEK at each time point for 5 years using mixed-effects models. Subgroup analyses were performed to compare the effect of PK and DSAEK on visual acuity., Results: Average BSCVA was significantly better in the DSAEK group compared with that in the PK group both preoperatively and postoperatively. Subgroup analyses revealed that average changes in BSCVA from preoperative baseline in eyes with preoperative logarithm of the minimum angle of resolution BSCVA between 0.39 and 1.0 and between 1.3 and 2.0 were not significantly different between the PK and DSAEK groups at all postoperative time points. All components from Fourier harmonic analysis were significantly higher after PK than DSAEK at almost all postoperative time points. There were no significant differences in endothelial cell density between PK and DSAEK after 3 years., Conclusions: PK and DSAEK provide similar recovery of BSCVA and endothelial cell survival at 5 years after surgery.

Background: There are several treatments for wrinkles and depressed areas of the face, hands, and body. Hyaluronic acid is effective, but only for 6 months to 1 year. Autologous fat grafting may cause damage during tissue harvest., Methods: In this study, patients were injected with platelet-rich plasma plus basic fibroblast growth factor (bFGF). Platelet-rich plasma was prepared by collecting blood and extracting platelets using double centrifugation. Basic fibroblast growth factor diluted with normal saline was added to platelet-rich plasma. There were 2005 patients who received platelet-rich plasma plus bFGF therapy., Results: Of the 2005 patients treated, 1889 were female and 116 were male patients; patients had a mean age of 48.2 years. Treated areas inlcuded 1461 nasolabial folds, 437 marionette lines, 1413 nasojugal grooves, 148 supraorbital grooves, 253 midcheek grooves, 304 foreheads, 49 temples, and 282 glabellae. Results on the Global Aesthetic Improvement Scale indicated that the level of patient satisfaction was 97.3 percent and the level of investigator satisfaction was 98.4 percent. The period for the therapy's effectiveness to become apparent was an average of 65.4 days. Platelet-rich plasma plus bFGF therapy resulted in an improved grade on the Wrinkle Severity Rating Scale. Improvement was 0.55 for a Wrinkle Severity Rating Scale grade of 2, 1.13 for a Wrinkle Severity Rating Scale grade of 3, 1.82 for a Wrinkle Severity Rating Scale grade of 4, and 2.23 for a Wrinkle Severity Rating Scale grade of 5., Conclusions: Platelet-rich plasma plus bFGF is effective in treating wrinkles and depressed areas of the skin of the face and body. The study revealed that platelet-rich plasma plus bFGF is an innovative therapy that causes minimal complications., Clincal Question/level of Evidence: Therapeutic, IV.

Objective: To assess the effect of pterygium size on time-course change of corneal topography after excision surgery of primary pterygium., Methods: Retrospective case series included eyes that underwent excisions of primary pterygium. Pterygium size was graded according to the advancing edge position: less than one third of corneal diameter (grade 1), outside the pupil (grade 2), and within the pupillary area (grade 3). Time-course changes in corneal refractive power, astigmatism, and irregularity (surface regularity and asymmetry indices) in corneal topographies over 12 months postoperatively were compared between the pterygium size grades., Results: Pterygium excision was performed on 562 eyes, consisting of 119, 338, and 105 eyes with grades 1 to 3, respectively. Grade 1 did not change in corneal irregularity, and there was no difference between grades 1 and 2, except for corneal astigmatism at 6 months. Grade 3 showed significantly higher corneal refractive power and irregularity than grade 1 until 3 and 6 months, respectively, whereas corneal astigmatism was higher over 12 months., Conclusions: Topographic changes after primary pterygium excision were associated with pterygium size. Pterygium advancing over the pupillary area required 6 to 12 months for corneal topography restoration, resulting in slow recovery of visual acuity.

Purpose: To evaluate the effect of diquafosol tetrasodium (DQS) for the treatment of persistent dry eye after laser in situ keratomileusis (LASIK)., Setting: Miyata Eye Hospital, Miyazaki, Japan., Design: Noncomparative case series., Methods: This prospective study included 30 eyes of 15 patients in whom dry eye had persisted for over 12 months after LASIK, and the symptoms had not improved with artificial tears and sodium hyaluronate treatment. In addition, treatment with DQS 3% eye drops, 6 times a day, was performed for 12 weeks. Best-corrected visual acuity, tear secretion with the Schirmer test, tear break-up time, and fluorescein and lissamine green staining scores on the cornea and conjunctiva were examined before and at 1, 4, and 12 weeks after the addition. A subjective questionnaire of 14 symptoms was also assessed before and 12 weeks after treatment., Results: The fluorescein and lissamine green staining scores significantly improved over 12 weeks; however, the best-corrected visual acuity and tear secretion did not change. The symptoms of fatigue, dryness, grittiness, discomfort, difficulty in reading, and discomfort within the area of dryness improved after the additional DQS treatment., Conclusions: The DQS treatment improved the subjective and objective symptoms of persistent dry eye after LASIK. Increased mucin production because of the addition of DQS probably improved the tear film stability and reduced the symptoms of dry eye in patients who had persistent dry eye after LASIK.

Objective: Cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression. Nonetheless, molecular mechanisms underlying this activity remain unclear. Here, we ask whether angiopoietin-like protein 2 (Angptl2), a proinflammatory protein, contributes to vascular inflammation that promotes atherosclerosis progression., Approach and Results: Histological analysis revealed abundant Angptl2 expression in endothelial cells and macrophages infiltrating atheromatous plaques in patients with cardiovascular disease. Angptl2 knockout in apolipoprotein E-deficient mice (ApoE(-/-)/Angptl2(-/-)) attenuated atherosclerosis progression by decreasing the number of macrophages infiltrating atheromatous plaques, reducing vascular inflammation. Bone marrow transplantation experiments showed that Angptl2 deficiency in endothelial cells attenuated atherosclerosis development. Conversely, ApoE(-/-) mice crossed with transgenic mice expressing Angptl2 driven by the Tie2 promoter (ApoE(-/-)/Tie2-Angptl2 Tg), which drives Angptl2 expression in endothelial cells but not monocytes/macrophages, showed accelerated plaque formation and vascular inflammation because of increased numbers of infiltrated macrophages in atheromatous plaques. Tie2-Angptl2 Tg mice alone did not develop plaques but exhibited endothelium-dependent vasodilatory dysfunction, likely because of decreased production of endothelial cell-derived nitric oxide. Conversely, Angptl2(-/-) mice exhibited less severe endothelial dysfunction than did wild-type mice when fed a high-fat diet. In vitro, Angptl2 activated proinflammatory nuclear factor-κB signaling in endothelial cells and increased monocyte/macrophage chemotaxis., Conclusions: Endothelial cell-derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression.

Objectives: We have established rat models of pancreatic ductal adenocarcinoma (PDAC) in which expression of a human H-ras(G12V) or K-ras(G12V) oncogene regulated by the Cre/lox system drives pancreatic carcinogenesis. Pancreatic ductal adenocarcinoma which develops in H-ras(G12V) and K-ras(G12V) transgenic rats is cytogenetically and histopathologically similar to human PDAC. The present study was designed to determine the feasibility of using the commercially available H-ras(G12V) transgenic rat to find diagnostic protein biomarkers for human pancreatic cancer., Methods: For an animal model to be useful for searching for protein biomarkers for a disease, it is essential that proteins that are up-regulated in the model are also up-regulated in humans. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to compare H-ras(G12V) transgenic rat PDAC with surrounding normal pancreas tissue., Results: We identified 30 up-regulated proteins in the H-ras(G12V) transgenic rat PDAC lesions; importantly, 21 human homologs of these 30 rat proteins are up-regulated in human pancreatic cancer patients., Conclusions: These results indicate that numerous proteins that are up-regulated in H-ras(G12V) transgenic rat PDAC are also up-regulated in human pancreatic cancer; therefore, this rat model can be used to search for diagnostic biomarkers for this disease.

Objective: Recently, we reported that angiopoietin-like protein 2 (Angptl2) functions in various chronic inflammatory diseases. In the present study, we asked whether Angptl2 and its associated chronic inflammation contribute to abdominal aortic aneurysm (AAA)., Methods and Results: Immunohistochemistry revealed that Angptl2 is abundantly expressed in infiltrating macrophages within the vessel wall of patients with AAA and in a CaCl(2)-induced AAA mouse model. When Angptl2-deficient mice were used in the mouse model, they showed decreased AAA development compared with wild-type mice, as evidenced by reduction in aneurysmal size, less severe destruction of vessel structure, and lower expression of proinflammatory cytokines and matrix metalloproteinase-9. However, no difference in the number of infiltrating macrophages within the aortic aneurysmal vessel wall was observed between genotypes. AAA development was also significantly suppressed in wild-type mice that underwent Angptl2-deficient bone marrow transplantation. Expression levels of proinflammatory cytokines and metalloproteinase-9 in Angptl2-deficient macrophages were significantly decreased, and those decreases were rescued by treatment of Angptl2 deficient macrophages with exogenous Angptl2., Conclusions: Macrophage-derived Angptl2 contributes to AAA development by inducing inflammation and degradation of extracellular matrix in the vessel wall, suggesting that targeting the Angptl2-induced inflammatory axis in macrophages could represent a new strategy for AAA therapy.

Purpose: The efficacy of gene therapy using nonviral vector based on polyplex micelle has been studied against corneal neovascularization in mice., Methods: A block copolymer, poly(ethylene glycol) (PEG)-block-polycation carrying ethylenediamine units in the side chain (PEG-b-P[Asp(DET)]), was prepared. PEG-b-P[Asp(DET)] formed a polyplex micelle through the polyion complex formation with plasmid DNA. To evaluate in vivo gene transfer efficiency, PEG-b-P[Asp(DET)] micelle was injected into the subconjunctival space of mice, and the expression of the reporter gene was assessed. Furthermore, mouse corneal neovascularization models were treated with the PEG-b-P[Asp(DET)] polyplex micelle containing expression plasmid vector of soluble vascular endothelial growth factor receptor 1 (sflt-1)., Results: Subconjunctival injection of the PEG-b-P[Asp(DET)] polyplex micelle containing a reporter gene showed prolonged gene expression with low cytotoxicity. Also, gene transfer into subconjunctival space by the polyplex micelle containing sflt-1 plasmid showed significant inhibition of corneal neovascularization in mice., Conclusions: Nonviral gene therapy using PEG-b-P[Asp(DET)] polyplex micelle may have potential for safe and effective therapeutic treatment of corneal neovascularization.

Objective: To elucidate whether and how the endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP) pathway in macrophages is involved in the rupture of atherosclerotic plaques., Methods and Results: Increases in macrophage-derived foam cell death in coronary atherosclerotic plaques cause the plaque to become vulnerable, thus resulting in acute coronary syndrome. The ER stress-CHOP/growth arrest and DNA damage-inducible gene-153 (GADD153) pathway is induced in the macrophage-derived cells in atherosclerotic lesions and is involved in plaque formation. However, the role of CHOP in the final stage of atherosclerosis has not been fully elucidated. Many CHOP-expressing macrophages showed apoptosis in advanced ruptured atherosclerotic lesions in wild-type mice, whereas few apoptotic cells were observed in Chop(-/-) mice. The rupture of atherosclerotic plaques was significantly reduced in high cholesterol-fed Chop(-/-)/Apoe(-/-) mice compared with Chop(+/+)/Apoe(-/-) mice. Furthermore, using mice that underwent bone marrow transplantation, we showed that expression of CHOP in macrophages significantly contributes to the formation of ruptures. By using primary cultured macrophages, we further showed that unesterified free cholesterol derived from incorporated denatured low-density lipoprotein was accumulated in the ER and induced ER stress-mediated apoptosis in a CHOP-Bcl2-associated X protein (Bax) pathway-dependent manner., Conclusions: The ER stress-CHOP-Bax-mediated apoptosis in macrophages contributes to the instability of atherosclerotic plaques.

Study Design: This prospective study analyzed preoperative and postoperative dynamic changes of the spinal cord in patients with cervical spondylotic myelopathy., Objective: (1) To study preoperative kinematic characteristics of the spinal cord in patients with cervical spondylotic myelopathy and compare results with healthy individuals, (2) to understand the dynamic changes of the spinal cord after posterior decompression, and (3) to discover whether the degree of posterior shifting is correlated with surgical outcomes using kinematic magnetic resonance imaging (MRI)., Summary of Background Data: Laminoplasty for cervical myelopathy increases the space occupied by the spinal cord leading to a decompressive effect on the cord. However, no consecutive studies have reported the kinematic characteristics of the cervical spine in patients with cervical spondylotic myelopathy both preoperatively and postoperatively. Additionally, there have been no reports investigating the effects of posterior cord shifting in the neutral and maximum flexion and extension positions on surgical outcomes after cervical laminoplasty., Methods: Twenty cervical spondylotic myelopathy patients who underwent extensive laminoplasty and 20 healthy individuals were examined. Preoperative and postoperative MRI records were available in all cases. The cervical spines of the subjects were examined in the neutral and maximum flexion and extension positions using an MRI scanner. Sagittal T1-weighted images were obtained at 12 different angles. Images were analyzed for the distance between the dorsal edge of the vertebral column and the center of the cord at each disc level using NIH image software., Results: Average cord distances (L value) in the neutral position and maximum extension position at C4/5 was significantly smaller than those at the other disc levels. The spinal cords of the patients after laminoplasty moved dorsally in the enlarged spinal canal in the neutral position, and in the maximum flexion and extension position. However, the degree of posterior spinal cord shifting was not correlated with surgical outcomes., Conclusions: Cord distances are relatively smaller at C4/5 and C5/6 levels, resulting in a narrowing of the posterior subarachnoid space with posterior cord compression in patients with cervical spondylotic myelopathy. The outcome of surgery was not correlated with the magnitude of postoperative backward shifting of the spinal cord, although the spinal cord of patients after posterior decompression moved significantly dorsally at any of the flexed, neutral, or extended spinal positions. Thus numerous factors might affect the postoperative outcomes.

Objective: Transgenic mice overexpressing angiopoietin-related growth factor (AGF) exhibit enhanced angiogenesis, suggesting that AGF may be a useful drug target in ischemic disease. Our goal was to determine whether AGF enhances blood flow in a mouse hind-limb ischemia model and to define molecular mechanisms underlying AGF signaling in endothelial cells., Methods and Results: Intramuscular injection of adenovirus harboring AGF into the ischemic limb increased AGF production, which increased blood flow through induction of angiogenesis and arteriogenesis, thereby reducing the necessity for limb amputation. In vitro analysis showed that exposing human umbilical venous endothelial cells to AGF increased nitric oxide (NO) production through activation of an ERK1/2-endothelial NO synthetase (eNOS) signaling pathway. AGF-stimulated eNOS phosphorylation, NO production, and endothelial cell migration were all abolished by specific MEK1/2 inhibitors. Moreover, AGF did not restore blood flow to ischemic hind-limbs of either mice receiving NOS inhibitor L-NAME or eNOS knockout mice., Conclusions: Activation of an ERK1/2-eNOS-NO pathway is a crucial signaling mechanism by which AGF increases blood flow through induction of angiogenesis and arteriogenesis. Further investigation of the regulation underlying AGF signaling pathway may contribute to develop a new clinical strategy for ischemic vascular diseases.

Purpose: Investigation of a positive polymerase chain reaction (PCR) for Streptococcus species from an excised cornea of a patient with infectious crystalline keratopathy., Methods: Samples microdissected from corneal intrastromal aggregates present in infectious crystalline keratopathy were subjected to PCR for 3 primer pairs respectively specific for Streptococcus, Staphylococcus, and several kinds of fungi., Results: The PCR detected DNA from Streptococcus but not from Staphylococcus or fungi. Direct sequencing of the PCR products showed that the PCR products had the highest identity (99.8%) with Streptococcus mitis and Streptococcus gordoni, indicating that these species were the most probable causes of infectious crystalline keratopathy in this patient., Conclusion: Our findings suggest that PCR provides a good adjunct technique in the diagnosis of corneal infection.

Study Design: An in vivo flexion-extension magnetic resonance imaging study., Objective: To evaluate the kinetic changes of the cervical spinal cord after laminoplasty in patients with cervical myelopathy., Summary of Background Data: Laminoplasty for cervical myelopathy increases the space occupied by the spinal cord, leading to a decompressive effect on the cord. However, there are few reports on kinetic changes of the spinal cord following this surgical procedure, by which it may contribute to an improvement of clinical symptoms., Methods: Patients who underwent spinous process-splitting laminoplasty (n = 40) and control group (n = 20) were enrolled in the study. Cervical spines of the subjects were examined from maximum extension to maximum flexion using a magnetic resonance imaging scanner. Sagittal T1-weighted images were obtained at 12 different angle positions. Images were analyzed with respect to the distance and alignment disparity between the dorsal edge of the vertebral column and the center of the cord at each disc level using National Institutes of Health Image software., Results: Spinal cords of patients after laminoplasty were dorsally shifted in the enlarged spinal canal at neutral, extension, and flexion positions. Alignment changes of the cord during flexion-extension movements of the cervical spine were dissociated from those of the vertebral column because of smaller changes in the cord alignment., Conclusions: Spinous process-splitting laminoplasty increases the degree of freedom of the spinal cord.

Purpose: To evaluate the efficacy and safety of atelocollagen punctal occlusion for dry eye patients., Design: Prospective noncomparative interventional case series., Methods: Atelocollagen was injected into the superior and inferior canaliculi of 52 eyes of 28 dry eye patients. Vital staining of the ocular surface, breakup time of tears (BUT), tear volume, and corneal epithelial permeability to fluorescein were examined before and 1, 2, 4, and 8 weeks after treatment., Results: Rose bengal stain, fluorescein stain, BUT, and corneal epithelial permeability to fluorescence were significantly improved 1 week after atelocollagen punctal occlusion, and the improvement was maintained for up to 8 weeks after treatment., Conclusions: Atelocollagen punctal occlusion effectively improves ocular surface disorders in dry eye patients.

Purpose: To compare corneal thickness measurements using Orbscan II scanning slit topography, Topcon SP-2000P noncontact specular microscopy, and ultrasonic pachymetry in eyes with keratoconus., Methods: Central corneal thickness was measured in 22 eyes with keratoconus. Eyes with apparent corneal opacity were excluded. Scanning slit topography, noncontact specular microscopy, and ultrasonic pachymetry were used in this sequence. The acoustic equivalent correlation factor (0.92) was used for Orbscan readings., Results: Three devices gave significantly different corneal thickness readings (P < 0.001, repeated-measure analysis of variance). Measurements with Orbscan scanning slit topography (449.5 +/- 43.2 [SD] mum) were significantly smaller than those of ultrasonic pachymetry (485.0 +/- 29.3 microm; P < 0.001, Tukey multiple comparison) and SP-2000P noncontact specular microscopy (476.7 +/- 28.3 microm; P = 0.002). There were significant linear correlations between ultrasonic pachymetry and scanning slit topography (Pearson correlation coefficient r = 0.741, P < 0.001), between scanning slit topography and noncontact specular microscopy (r = 0.880, P < 0.001), and between noncontact specular microscopy and ultrasonic pachymetry (r = 0.811, P < 0.001)., Conclusion: In eyes with keratoconus, Orbscan II scanning slit topography system gave significantly smaller corneal thickness readings than the other 2 devices. Measurements taken by noncontact specular microscopy and ultrasonic pachymetry were comparable. Three devices showed significant linear correlations with one another.

Purpose: To determine the influence of dispersive ophthalmic viscosurgical products (OVPs) on corneal endothelial cell (CEC) density during penetrating keratoplasty (PKP) and on the postoperative intraocular pressure (IOP)., Methods: In 117 eyes of 113 patients, PKP was performed by a single surgeon from April 1, 1998 to April 30, 2002. Loss of CECs and postoperative IOP were evaluated retrospectively after use of Viscoat (sodium hyaluronate 3.0%, chondroitin sulfate 4.0%) plus Healon (sodium hyaluronate 1.0%) (Viscoat/Healon group) or Healon alone (Healon group) during surgery., Results: The average CEC loss was 14.6 +/- 15.5% and 9.0 +/- 10.5% at 1 month, 18.1 +/- 14.6% and 10.1 +/- 7.3% at 3 months, 20.1 +/- 16.3% and 12.2 +/- 10.9% at 6 months, and 31.7 +/- 21.4% and 18.1 +/- 15.5% at 12 months in the Healon (n = 74) and Viscoat/Healon (n = 43) groups, respectively. Patients were stratified into groups with corneal leukoma (n = 61) or bullous keratopathy (n = 56). Loss of CECs was significantly smaller in the Viscoat/Healon group compared with the Healon group irrespective of whether patients had corneal leukoma or bullous keratopathy at 3, 6, and 12 months postoperatively. There was no significant difference of postoperative IOP between the Healon and Viscoat/Healon groups over 12 months of follow-up., Conclusion: These results suggest that the addition of Viscoat to Healon decreases CEC loss during PKP and does not affect postoperative IOP.

The binding affinities of YM598, a novel endothelin-A (ETA) receptor antagonist, for native human ETA receptors expressed in human coronary artery smooth muscle cells and endothelin-B (ETB) subtypes in the human melanoma cell line SKMel- 28 were compared with those of atrasentan and bosentan. The in vivo ETA receptor antagonist activities of YM598 and atrasentan were also evaluated in pithed rats. The inhibitory dissociation constant values of YM598, atrasentan and bosentan were 0.772, 0.0551 and 4.75 nM, respectively, for native human ETA receptors, and 143, 4.80 and 40.9 nM, respectively, for native human ETB subtypes. The calculated selectivity ratios of YM598, atrasentan and bosentan for ETA versus ETB receptors were 222, 136 and 13.0, respectively. In pithed rats, YM598 and atrasentan inhibited the big endothelin-1 (1 nmol/kg)-induced pressor response in a dose-dependent manner, after both intravenous and oral administration. The inhibitory effect of YM598 was less potent than that of atrasentan when these agents were intravenously administered, but those of both agents were comparable when orally administered. These results suggest that YM598 has a high selectivity for native human ETA receptors against ETB receptors, and that YM598 is superior to atrasentan as an ETA receptor antagonist, with regard to pharmacological bioavailability in rats.

In some diseases in which endothelin-1 (ET-1) production increases (e.g. prostate cancer), ET-1 is considered to be involved in the generation of pain. In the present study, we investigated the effects of a selective endothelin-A receptor antagonist, YM598, on the nociception potentiated by ET-1 in formalin-induced and cancer inoculation-induced pain models in mice. The formalin-induced pain model was prepared by intraplantar injection of 0.7% formalin into the hind paws of ICR mice, and the cancer pain model was prepared by inoculation of the human prostate cancer cell line PPC-1 into the hind paws of severe combined immunodeficiency mice. Formalin caused a biphasic pain response and paw edema in the mouse hind paw. ET-1 (10 pmol/paw) potentiated these responses, and single oral administration of YM598 (0.3-3 mg/kg) significantly inhibited this ET-1-induced potentiation of nociception and paw edema. ET-1 (10 pmol/paw) also potentiated the pain response in prostate cancer-inoculated mice. Both YM598 and atrasentan (0.3-3 mg/kg) significantly inhibited the ET-1-induced potentiation of nociception. These results suggest that selective endothelin-A receptor antagonists relieve pain in patients with various diseases in which ET-1 production increases (e.g. prostate cancer).

Purpose: To review the time course of corneal anteroposterior shift and refractive stability after myopic excimer laser keratorefractive surgery., Methods: We examined 65 eyes undergoing photorefractive keratectomy (PRK) and 45 eyes undergoing laser in situ keratomileusis (LASIK). Corneal elevation maps and pachymetry were obtained by scanning-slit corneal topography before; 1 week; and 1, 3, 6, and 12 months after surgery., Results: Both PRK and LASIK induced significant forward shifts of the cornea. Corneal forward shift was progressive up to 6 months after PRK, but no progression was seen after LASIK. Progressive thinning and expansion of the cornea were not observed after either procedure. The amount of corneal forward shift showed a significant negative correlation with preoperative corneal thickness (r = -0.586; P < 0.01) and a significant positive correlation with the amount of myopic correction (r = 0.504; P < 0.01). A significant correlation was found between the amount of forward shift and the degree of myopic regression after surgery (r = -0.347; P < 0.05)., Conclusion: Myopic PRK and LASIK induce significant forward shifts of the cornea, which are not true corneal ectasia. Eyes with thinner corneas and higher myopia requiring greater ablation are more predisposed to anterior protrusion of the cornea. Corneal forward shift was progressive up to 6 months after PRK but not progressive after LASIK. Forward shift of the cornea can be one of the factors responsible for myopic regression after surgery.

Purpose: To evaluate the corneal epithelial barrier function in diabetic patients., Methods: In 29 eyes of 29 diabetic patients and 55 eyes of 55 nondiabetic controls, corneal epithelial permeability to fluorescein was measured using an anterior fluorophotometer. The average fluorescein concentration in the central cornea was compared between diabetic patients and controls. Multiple regression analysis was used to assess the factors that affect corneal epithelial barrier function in diabetic patients., Results: The average fluorescein concentrations in diabetic patients and nondiabetic controls were 44.1 +/- 25.3 ng/mL and 29.9 +/- 19.8 ng/mL (mean +/- SD), respectively (P = 0.0057, unpaired t test). An explanatory variable relevant to the impaired corneal epithelial barrier function was the serum hemoglobin A1c (HbA1c) concentration (standardized partial regression coefficient = 0.466, P = 0.0163)., Conclusions: The corneal epithelial barrier function is impaired in diabetic patients. Diabetic patients with higher serum HbA1c levels are more predisposed to impaired barrier function in the corneal epithelium.

Objective: We have recently demonstrated that protein kinase C (PKC) and Rho-kinase play important roles in coronary vasospasm in a porcine model. However, it remains to be examined whether there is an interaction between the two molecules to cause the spasm., Methods and Results: A segment of left porcine coronary artery was chronically treated with IL-1beta-bound microbeads in vivo. Two weeks after the operation, phorbol ester caused coronary spasm in vivo and coronary hypercontractions in vitro at the IL-1beta-treated segment; both were significantly inhibited by hydroxyfasudil, a specific Rho-kinase inhibitor. Guanosine 5'-[gamma-thio]triphosphate (GTPgammaS), which activates Rho with a resultant activation of Rho-kinase, enhanced Ca2+ sensitization of permeabilized vascular smooth muscle cells, which were resistant to the blockade of PKC by calphostin C. The GTPgammaS-induced Ca2+ sensitization was greater in the spastic segment than in the control segment. Western blot analysis revealed that only PKCdelta isoform was activated during the hypercontraction., Conclusions: These results demonstrate that PKC and Rho-kinase coexist on the same intracellular signaling pathway, with PKC located upstream on Rho-kinase, and that among the PKC isoforms, only PKCdelta may be involved. Thus, the strategy to inhibit Rho-kinase rather than PKC may be a more specific and useful treatment for coronary spasm.

Although the importance of monocytes/macrophages in the pathogenesis of arteriosclerosis is widely accepted, effective and safe treatment to inhibit those inflammatory cells remains to be developed. It was recently found that propagermanium, which is clinically used for the treatment of chronic hepatitis type B in Japan, markedly suppresses monocyte chemotaxis in response to macrophage chemoattractant protein-1 (MCP-1) through inhibition of its receptor, C-C chemokine receptor 2, in vitro. This prompted examination of whether propagermanium suppresses the macrophage-mediated formation of coronary arteriosclerotic lesions in our porcine model in vivo. It was first confirmed that propagermanium inhibited the migration of porcine monocytes in response to MCP-1 at therapeutic concentrations in vitro. Pigs were randomly divided into two groups; one group was orally treated with propagermanium (1 mg/kg, three times/day) and another group served as a control (n = 6 each). Porcine coronary segment was treated from the adventitia with MCP-1 and oxidized low-density lipoprotein for 2 weeks. In the control group, this treatment resulted in the development of stenotic coronary lesions with hyperconstrictive responses to serotonin where arteriosclerotic lesions (neointimal formation and constrictive remodeling) were developed. Immunohistochemical analysis demonstrated the macrophage accumulation in the adventitia and the media. By contrast, in the propagermanium group, angiographic coronary stenosis, hyperconstrictive responses, histologic changes, and macrophage accumulation were all significantly suppressed. These results indicate that propagermanium suppresses macrophage-mediated formation of coronary arteriosclerotic lesions in vivo, suggesting its potential usefulness for the treatment of arteriosclerotic vascular diseases.

Objective: The transmembrane ligand ephrin-B2 and its receptor tyrosine kinase EphB4 are specifically expressed on arterial and venous endothelial cells, respectively, and bidirectional signals mediated by both proteins play an important role in vascular development. However, how such bidirectional signals are required for cell-cell adhesion or repulsion remains unclear., Methods and Results: Using a cell line and sorted primary endothelial cells, we show that ephrin-B2 forward signaling through the EphB4 receptor inhibits cell adhesion, whereas EphB4 reverse signaling by the transmembrane ephrin-B2 ligand does not. Cell migration is also inhibited on immobilized ephrin-B2-Fc but not on EphB4-Fc protein., Conclusions: Ephrin-B2 forward signaling and EphB4 reverse signaling differentially affect cell adhesion and migration between arterial and venous endothelial cells.

Study Design: A case of Horner's syndrome caused by a thoracic dumbbell-shaped schwannoma is reported., Objectives: To report a rare case of a mediastinal dumbbell-shaped schwannoma as a cause of Horner's syndrome and to show the result of intercostal nerve grafting for sympathetic chain reconstruction after resection of the sympathetic nerve., Summary of Background Data: It has been reported that approximately 10% of neurogenic mediastinal tumors extend through the neural foramen into the spinal canal, creating a dumbbell shape. Although the most frequent causes of Horner's syndrome are tumors, a dumbbell-shaped schwannoma has rarely been described as a cause of the syndrome. Moreover, there have been no previous reports that primary sympathetic chain reconstruction has been performed with an intercostal nerve graft after resection of the sympathetic nerve with the tumor., Methods: A 48-year-old woman was diagnosed with a mediastinal tumor by routine chest radiography. The patient had right-sided Horner's syndrome, the signs of which she had not noticed. Surgical resection of the dumbbell-shaped tumor was performed in a one-stage combined resection of both the intraspinal and the mediastinal component of the tumor. Primary sympathetic chain reconstruction was also performed with an intercostal nerve graft., Results: The tumor was resected completely, and no recurrence of the tumor was observed 1 year after the operation. Blepharoptosis and anhidrosis on the right side of her face and upper limb gradually improved after surgery, and compensatory oversweating on the left side eventually improved. In bright illumination, the right pupil diameter was 3.5 mm and the left was 5 mm after surgery; the right pupil measured 4 mm and the left measured 5 mm 1 year after the operation., Conclusions: A mediastinal dumbbell-shaped schwannoma has rarely been described as a cause of Horner's syndrome. Primary sympathetic nerve reconstruction with an intercostal nerve was shown to be useful after resection of the sympathetic nerve involved in the tumor.

Objective: To disclose imaging features of air-containing spaces other than air bronchograms in lung adenocarcinoma on high-resolution computed tomography (HRCT)., Materials and Methods: We retrospectively reviewed HRCT scans of 42 consecutive patients with surgically proved lung adenocarcinoma correlating with pathologic specimens., Results: Air-containing spaces were seen in 17 (40%) of cases on HRCT. The air-containing spaces appeared as multiple air densities (16 cases [94%]) with variable shapes and had a relatively larger size than that of air bronchograms. Internal septi were often noted (11 cases [65%])., Conclusion: Our results demonstrate that multiplicity, larger diameter, and internal septi are the features of air-containing spaces. These findings could be a key to the definitive diagnosis of lung adenocarcinoma, distinguishing it from the mimics such as organizing pneumonia, tuberculoma, or malignant lymphoma.

Small GTPase Rho and its target Rho-kinase/ROK/ROCK play an important role in various cellular functions, including smooth muscle contraction, actin cytoskeleton organization, and cell adhesion and migration, all of which may be involved in the pathogenesis of arteriosclerosis. Here, we show that adenovirus-mediated transfer of dominant-negative Rho-kinase (DNRhoK) induces a marked regression of coronary constrictive remodeling and abolishes coronary vasospastic activity in vivo. Porcine coronary segments were chronically treated with interleukin-1beta, which resulted in the development of constrictive remodeling and vasospastic responses to serotonin, as previously reported. Adenovirus-mediated transfer of DNRhoK, but not that of beta-galactosidase, into the interleukin-1beta-treated coronary segment caused a marked regression of the constrictive remodeling and abolished the vasospastic activity in 3 weeks. Western blot analysis showed that the phosphorylation of adducin and the ezrin/radixin/moesin family, the target proteins of Rho-kinase, were upregulated at the coronary lesions and were significantly suppressed by the transfer of DNRHOK: These results indicate that Rho-kinase is substantially involved in coronary constrictive remodeling and vasospastic responses, both of which can be reversed by the selective inhibition of the molecule in our porcine model in vivo.

The effects of alteplase (tissue plasminogen activator, t-PA) and pamiteplase (a modified t-PA with longer half-life and increased potency) were compared in a clinically relevant model of embolic stroke. Rats were treated with pamiteplase (0.5 mg/kg or 1 mg/kg bolus), alteplase (10 mg/kg infusion) or normal saline. Pamiteplase (1 mg/kg) was as effective as alteplase in reducing 24 h brain infarct volumes, neurological deficit scores and residual clot grades. Cerebral blood flow recovery at 30 min after thrombolytic treatment was partial and did not correlate with 24 h infarct volumes or neurological deficits. However, there was good correlation between 24 h residual clot grades and infarct volumes, suggesting a delayed timeframe for pamiteplase- and alteplase-induced reperfusion.

Purpose: To examine the effect of donor age on the morphologic variation of cultured human corneal endothelial cells (HCEC)., Methods: HCEC were obtained from the remaining corneoscleral rims of seven human corneas used for penetrating keratoplasty. The donor age ranged from 2 to 75 years. Primary cultures were established from explants of the endothelial cell layer, including the Descemet's membrane, and were propagated on culture dishes coated with bovine corneal endothelial extracellular matrix. At the fourth passage, frequency distribution of cell area in the confluent monolayer was calculated and the effect of donor age on cell area was analyzed., Results: The percentage of HCEC with cell area over 2000 microm2 significantly increased with donor age (r = 0.935, p = 0.0007)., Conclusion: Cultured HCEC established from older donor tissue display greater heterogeneity. The use of HCEC from younger donors may be preferable to maximize the benefits of HCEC transplantation.