Influence of induced decentered orthokeratology lens on ocular higher-order wavefront aberrations and contrast sensitivity function.

PURPOSE: To quantitatively evaluate the effect of overnight orthokeratology lenses intentionally left decentered after 3 months of wear and assess the influence on clinical outcomes such as ocular higher-order wavefront aberrations and contrast sensitivity function. SETTING: Department of Ophthalmology, Tsukuba University Hospital, Ibaraki, Japan. METHODS: This prospective study assessed refraction, visual acuity, corneal topography, wavefront aberration, and contrast sensitivity function before and 3 months after overnight orthokeratology treatment. Decentration of the treatment zone from the center of the entrance pupil was determined using computerized videokeratography (TMS-4) and data-analysis software (MatLab). The relationship between decentration and the clinical parameters was analyzed. RESULTS: The mean age of the 23 patients (46 eyes) was 24.2 years+/-3.3 (SD) and the mean spherical equivalent refraction before treatment, -2.38+/-0.98 diopters. The mean magnitude of decentration (0.85+/-0.51 mm) was statistically significantly correlated with the amount of myopic correction (P<.05), increases in coma-like aberration (P<.01), increases in spherical-like aberration (P<.01), and reductions in contrast sensitivity function (P<.0001). Changes in contrast sensitivity function were also statistically significantly correlated with the amount of myopic correction (P<.05), changes in coma-like aberration (P<.01), and changes in spherical-like aberration (P<.01). Stepwise multiple regression analysis showed that the magnitude of decentration was the only explanatory variable related to contrast sensitivity function (P<.0001). CONCLUSION: Decentered treatment of orthokeratology resulted in decreased contrast sensitivity after treatment, showing that centration of the procedure is crucial to good outcomes.

Patient satisfaction and clinical outcomes after overnight orthokeratology.

PURPOSE: To assess patient satisfaction following overnight orthokeratology using a visual analogue scale and to find clinical factors that influence patient satisfaction. METHODS: In this prospective study, subjective patient satisfaction with visual outcomes was measured using a visual analogue scale, ranging from 0 (very dissatisfied) to 10 (very satisfied) in 17 patients who completed 1-year follow-up examinations after commencement of orthokeratology. Spherical equivalent refraction at baseline was 2.17 +/- 0.84 diopter (mean +/- SD). Various clinical parameters including refraction, visual acuity, ocular higher-order aberrations, and photopic and mesopic contrast sensitivity function were examined before and after the procedure. The influence of these parameters on patient satisfaction was evaluated using Spearman rank correlation test. RESULTS: The overall satisfaction with visual outcomes was scored 7.8 +/- 1.8 (range, 3.5 to 10). The level of satisfaction showed significant correlation (Spearman rank correlation coefficient; r = -0.599, p = 0.017) with posttreatment uncorrected visual acuity and pretreatment myopic error (r = 0.500, p = 0.045). CONCLUSIONS: This study demonstrated a relatively high level of patient satisfaction following overnight orthokeratology. Posttreatment uncorrected visual acuity is associated with patient satisfaction, and patients with higher myopia are predisposed to lower levels of subjective satisfaction.

Mesopic contrast sensitivity and ocular higher-order aberrations in eyes with conventional spherical intraocular lenses.

PURPOSE: To investigate relationship between mesopic contrast sensitivity (CS) function and ocular higher-order aberrations in eyes implanted with conventional spherical intraocular lenses (IOL). DESIGN: Prospective, nonrandomized case series. METHODS: Sixty-eight eyes of 48 patients who attained best spectacle-corrected visual acuity (BSCVA) of 20/20 or better after phacoemulsification and spherical IOL implantation were included in the study. At 2 months postoperatively, mesopic CS was measured with the Mesotest II (Oculus; Wetsler, Germany), and ocular higher-order aberrations for a 4-mm pupil were measured with the Hartmann-Shack aberrometer. CS and letter CS under photopic conditions were recorded with the CSV-1000 charts (Vector Vision Co, Greenville, Ohio, USA). RESULTS: There was significant correlation between mesopic CS and ocular fourth-order root mean square (RMS) of wavefront aberration (Spearman r(s) = -0.293; P = .017), but no correlation was found between mesopic CS and ocular third-order RMS (r(s) = 0.196; P = .189). Ocular third- and fourth-order RMS did not correlate with other parameters, including BSCVA, and CS and letter CS under photopic conditions. CONCLUSIONS: Mesopic CS is significantly associated with ocular fourth-order RMS of wavefront aberrations in eyes implanted with conventional spherical IOLs.

Binding of plasminogen to hepatocytes isolated from injured mouse liver and nonparenchymal-cell-dependent proliferation of hepatocytes.

Plasmin is an essential enzyme located in the pericellular microenvironment of liver cells during liver regeneration. Previously, we reported that liver regeneration ability was significantly increased in alpha2-antiplasmin gene knockout mice as compared to wild-type mice, but it was significantly decreased in plasminogen knockout mice, or Plg/alpha2-antiplasmin gene knockout mice. The present study aimed to demonstrate direct interaction between plasminogen and mouse hepatocytes in the process of liver regeneration. Using the isolated hepatocytes from mice we analyzed following subjects: binding capacity of plasminogen to hepatocytes, plasminogen activation in the presence of hepatocytes, and proliferation ability of hepatocytes cocultured with liver nonparenchymal cells. The isolated hepatocytes from plasminogen wild-type mice bound to immobilized plasminogen. The mouse hepatocytes enhanced plasminogen activation, and impaired the inhibitory effect of alpha2-antiplasmin. The proliferation ability of hepatocytes after liver injury was studied. In plasminogen wild-type and plasminogen knockout mice, the hepatocytes cocultured with nonparenchymal cells, which were obtained from mice without CCl4 injection, showed similar proliferation abilities. On the contrary, the proliferation ability of hepatocytes cocultured with nonparenchymal cells, which were obtained from CCl4-treated plasminogen knockout mice, was significantly impaired as compared to wild-type mice. These results indicate that the plasminogen-plasmin system on the surface of mouse hepatocytes plays an important role in liver regeneration.

Time course of changes in ocular higher-order aberrations and contrast sensitivity after overnight orthokeratology.

PURPOSE: To investigate prospectively the time course of changes in ocular higher-order aberration and contrast sensitivity after overnight orthokeratology. METHODS: Data from 34 eyes of 17 patients who completed 1-year follow-up examinations were analyzed. The manifest refraction was -2.17 +/- 0.86 D at baseline. Ocular higher-order aberrations for a 4-mm pupil were measured, and the root-mean-square (RMS) of the third-, fourth-, and total higher-order aberrations were determined. Contrast sensitivity was assessed at four spatial frequencies, and the area under the log contrast sensitivity function (AULCSF) was calculated. These examinations were performed before and 1, 2, 3, 6, and 12 months after commencement of the procedure. RESULTS: The treatment significantly increased third-, fourth-, and total higher-order RMS (all P < 0.0001, paired t-test). Log contrast sensitivity significantly decreased at all four spatial frequencies, and AULCSF was also significantly reduced after the treatment (P < 0.0001). To assess the time course of changes in these parameters, posttreatment data were analyzed by using repeated-measures analysis of variance. There were no significant fluctuations in manifest refraction; uncorrected visual acuity; third-, fourth-, and total higher-order RMS; and AULCSF (all P > 0.05). In addition, there was no significant variance in log contrast sensitivity at each spatial frequency during the 1-year follow-up period (all P > 0.05). CONCLUSIONS: The initial reduction in optical quality of the eye and quality of vision after the procedure is stable during the treatment period of at least 1 year, and the reduction does not worsen further after 1 month. Orthokeratology candidates should be fully informed of these changes.

Alpha2-antiplasmin is a critical regulator of angiotensin II-mediated vascular remodeling.

OBJECTIVE: Alpha2-antiplasmin (alpha2-AP) is the major circulating inhibitor of plasmin, which plays a determining role in the regulation of intravascular fibrinolysis. We investigated the role of alpha(2)-AP on vascular remodeling in response to angiotensin II (Ang II). METHODS AND RESULTS: alpha2-AP-deficient mice were performed. Ang II and N(omega)-nitro- L-arginine methyl ester (L-NAME)-induced perivascular fibrosis was significantly decreased in alpha2-AP-/- mice compared with wild-type mice. In situ gelatinolytic activity analysis shows that perivascular gelatinolytic activity was increased in alpha2-AP-/- mice, which was responsible for decreased perivascular fibrosis in response to Ang II and L-NAME. Ang II-induced arterial wall thickening, vascular cell proliferation, apoptosis, c-Myc, and collagen I expression were significantly decreased in alpha2-AP-/- mice compared with wild-type mice. Further analysis shows that increased p53 and p21 expression were responsible for inhibition of Ang II-induced vascular remodeling in alpha2-AP-/- mice. CONCLUSIONS: The results show that alpha2-AP is a critical regulator for vascular remodeling by inhibiting p53/p21 pathway, suggesting that alpha2-AP is proposed to be a potential therapeutic target for vascular remodeling.

Mesopic contrast sensitivity and ocular higher-order aberrations after overnight orthokeratology.

PURPOSE: To investigate mesopic contrast sensitivity and night driving ability in eyes undergoing overnight orthokeratology, and to analyze the relationship among mesopic contrast sensitivity, ocular higher-order aberrations, and myopic correction. DESIGN: Prospective, noncomparative, consecutive case series. METHODS: In 44 eyes of 22 subjects (mean age +/- standard deviation [SD], 24.0 +/- 3.2 years) with orthokeratology, ocular aberrations and mesopic contrast sensitivity were determined before and three months after commencement of the procedure. Mean spherical equivalent refraction +/- SD was -2.34 +/- 0.99 diopters at baseline. Mesopic contrast sensitivity with and without glare was assessed using the Mesotest II (Oculus, Wetzlar, Germany). RESULTS: Orthokeratology significantly reduced the log mesopic contrast sensitivity from 0.25 +/- 0.08 to 0.08 +/- 0.10 without glare (P < .0001, Wilcoxon) and from 0.21 +/- 0.11 to 0.07 +/- 0.10 with glare (P < .0001). The proportion of eyes that fulfilled the German standard recommendation level for night driving was 36%. The induced changes in log mesopic contrast sensitivity showed significant negative correlation with the changes in third-order (r = -0.490, P = .0013 without glare; r = -0.362, P = .0177 with glare; Spearman rank correlation coefficient) and fourth-order root mean square (r = -0.586, P = .0001 and r = -0.306, P = .0450, respectively). Furthermore, significant correlation was found between the amount of myopic correction and the induced changes in log mesopic contrast sensitivity (r = -0.442, P = .0038 without glare; r = -0.464, P = .0024 with glare). The induced changes in higher-order aberrations significantly correlated with the amount of myopic correction (P < .0001, Pearson correlation coefficient). CONCLUSIONS: Mesopic contrast sensitivity after overnight orthokeratology is deteriorated significantly as ocular higher-order aberrations increase, and these changes depend on the amount of myopic correction.

Effect of staphylokinase-derived nonadecapeptide on the activation of plasminogen.

Staphylokinase (SAK) expresses plasminogen activator (PA) activity by forming a complex with plasmin. The interaction between the plasmin-SAK complex and plasminogen was investigated using synthesized peptides, which were constructed according to the amino acid sequence of the SAK molecule. A synthetic nonadecapeptide (SAK22-40) corresponding to Glu22-Leu40 by the SAK molecule enhanced the activation of Glu-plasminogen by the plasmin-SAK complex. Analysis of IAsys resonant mirror biosensor showed that SAK22-40 bound to Glu-plasminogen. This binding was completely inhibited by IgG against the B-chain in the plasminogen molecule. But, this binding was not inhibited by IgG against lysine-binding sites (LBS) of the A-chain in the plasminogen molecule. The substitution of Lys35 with Ala in SAK22-40 did not enhance the activation of Glu-plasminogen by the plasmin-SAK complex. When SAK22-40 was administrated in a mouse thrombosis model, earlier recanalization was observed than in mice with vehicle administration. Thus, a newly synthesized peptide, SAK22-40 enhanced Glu-plasminogen activation and induced effective thrombolysis.

Plasmin decreases the BH3-only protein BimEL via the ERK1/2 signaling pathway in hepatocytes.

Since the signal transduction mechanisms responsible for liver regeneration mediated by the plasminogen/plasmin system remain largely undetermined, we have investigated whether plasmin regulates the pro-apoptotic protein Bim(EL) in primary hepatocytes. Plasmin bound to hepatocytes in part via its lysine binding sites (LBS). Plasmin also triggered phosphorylation of ERK1/2 without cell detachment. The plasmin-induced phosphorylation of ERK1/2 was inhibited by the LBS inhibitor epsilon-aminocaproic acid (EACA), the serine protease inhibitor aprotinin, and the MEK inhibitor PD98059. DFP-inactivated plasmin failed to phosphorylate ERK1/2. Plasmin temporally decreased the starvation-induced expression of Bim(EL) and activation of caspase-3 via the ERK1/2 signaling pathway, resulting in an enhancement of cell survival. The amount of mRNA for Bim increased 1 day after the injection of CCl(4) in livers of plasminogen knockout (Plg-KO) and the wild-type (WT) mice. The increase in Bim(EL) protein persisted for at least 7 days post-injection in livers of Plg-KO mice, whereas WT mice showed an increase in Bim(EL) protein 1 day after the injection. Plg-KO and WT mice showed notable phosphorylation of ERK1/2 7 and 3 days after the injection of CCl(4), respectively. Our data suggest that the plasminogen/plasmin system could decrease Bim(EL) expression via the ERK1/2 signaling pathway during liver regeneration.

c-Myc is essential for urokinase plasminogen activator expression on hypoxia-induced vascular smooth muscle cells.

OBJECTIVES: The purpose of this study was to investigate whether c-Myc regulates expression of urokinase plasminogen activator (uPA) on hypoxia-induced vascular smooth muscle cells (VSMCs). METHODS: VSMCs were isolated from thoracic aorta of wild-type (WT), tissue plasminogen activator (tPA) and uPA-deficient mice. Gene and protein expression levels were examined by reverse-transcription PCR and Western blotting, respectively. c-Myc and uPA transcriptional activity were determined by luciferase analysis. Zymography analysis was used to test the activity of matrix metalloproteinases (MMPs), tPA, and uPA. RESULTS: Hypoxia significantly promoted WT and tPA-/- VSMC migration and invasion. However, uPA-/- severely decreased hypoxia-induced VSMC migration and invasion. Hypoxia increased uPA and MMP-2 activity, while uPA-/- decreased hypoxia-induced MMP-2 activity. c-Myc expression and transcriptional activity were increased in response to hypoxia, and silenced c-Myc abolished hypoxia-induced uPA and MMP-2 activity. In addition, hypoxia-induced Bcl2 expression and Bcl2 binding to c-Myc led to enhanced c-Myc-mediated uPA and MMP-2 activity in response to hypoxia. CONCLUSIONS: The results show that c-Myc was essential for hypoxia-induced uPA expression and activity, resulting in VSMC migration and invasion. In addition, Bcl2 enhanced the c-Myc-mediated uPA/MMP-2 pathway.

Contrast sensitivity function and ocular higher-order aberrations following overnight orthokeratology.

PURPOSE: To evaluate relationships among contrast sensitivity function, ocular higher-order aberration, and myopic correction in eyes undergoing overnight orthokeratology for myopia. METHODS: A prospective study was conducted in 46 eyes of 23 patients undergoing orthokeratology. Inclusion criteria were spherical equivalent refraction between -1.00 and -4.00 diopters (D), refractive astigmatism up to 1.00 D, and best-corrected visual acuity of 20/20 or better. Ocular higher-order aberrations and contrast sensitivity function were determined before and 3 months after initiation of the procedure. We measured three indices of contrast sensitivity function: contrast sensitivity, low-contrast visual acuity, and letter contrast sensitivity with the CSV-1000 charts (Vector Vision Co., Greenville, OH). Area under the log contrast sensitivity function (AULCSF) was calculated from the contrast sensitivity data. RESULTS: Orthokeratology significantly improved logMAR uncorrected visual acuity (P < 0.0001; paired t-test) but significantly increased ocular higher-order aberrations (P < 0.0001) and decreased contrast sensitivity function, including AULCSF (P < 0.0001), low-contrast visual acuity (P = 0.0025), and letter contrast sensitivity (P < 0.0001; Wilcoxon signed-rank test). The induced changes in AULCSF, low-contrast visual acuity, and letter contrast sensitivity by orthokeratology showed significant correlation with changes in third-order (Pearson r = -0.430, P = 0.0026; r = 0.423, P = 0.0031; and Spearman r(s) = -0.351, P = 0.0186, respectively), fourth-order (r = -0.418, P = 0.0035; r = 0.425, P = 0.0029; and r(s) = -0.566, P = 0.0001, respectively), and total higher-order (r = -0.460, P = 0.0011; r = 0.471, P = 0.0008; and r(s) = -0.434, P = 0.0036, respectively) aberrations. The induced changes in contrast sensitivity function and higher-order aberrations significantly correlated with the amount of myopic correction (P < 0.01). CONCLUSIONS: Orthokeratology significantly increases ocular higher-order aberrations and compromises contrast sensitivity function, depending on the amount of myopic correction.

Contrast sensitivity function and ocular higher-order wavefront aberrations in normal human eyes.

PURPOSE: To investigate the relation between contrast sensitivity function and ocular higher-order wavefront aberrations in normal human eyes. STUDY DESIGN: Prospective observational case series. PARTICIPANTS: Three hundred seven eyes of 161 normal subjects, ranging in age from 15 to 60 years (30.9+/-8.0 [mean +/- standard deviation]). METHODS: Ocular higher-order aberrations were measured for a 4-mm pupil using the Hartmann-Shack wavefront analyzer. The root-mean-square of the third- and fourth-order Zernike coefficients was used to represent comalike and spherical-like aberrations, respectively. We measured contrast sensitivity, low-contrast visual acuity (VA), and letter contrast sensitivity. From the contrast sensitivity data, the area under the log contrast sensitivity function (AULCSF) was calculated. Pupil diameter in a photopic condition was recorded using a digital camera. RESULTS: Multiple linear regression analysis revealed that comalike aberration (P = 0.002) was significantly associated with AULCSF, but spherical-like aberration (P = 0.200), age (P = 0.185), and photopic pupil diameter (P=0.252) were not. Comalike aberration showed a significant correlation with low-contrast VA (P<0.001), but spherical-like aberration (P = 0.293), age (P = 0.266), and pupil diameter (P = 0.756) did not. Comalike aberration was found to be significantly associated with letter contrast sensitivity (P<0.001), but spherical-like aberration (P=0.082), age (P = 0.370), and pupil diameter (P = 0.160) were not. CONCLUSIONS: In normal human eyes, comalike aberration of the eye significantly influences contrast sensitivity function.

Ultrasound biomicroscopic findings in aniridia.

PURPOSE: To describe the ultrasound biomicroscopic features of eyes with aniridia. DESIGN: Observational case series. METHODS: Nineteen eyes of 10 patients with aniridia (six males and four females) ranging in age from 3 months to 53 years (21.0 +/- 16.4, mean +/- SD), and 50 normal subjects (30 men and 20 women) ranging from 16 to 56 years (31.1 +/- 13.2) were evaluated. Ultrasound biomicroscopic findings were recorded in the 3-, 6-, 9-, and 12-o'clock directions. Adult patients (aged 16 years or older) with aniridia were compared with the age-matched controls. RESULTS: Ultrasound biomicroscopy (UBM) detected extremely tiny irises in all eyes with aniridia. The eyes with aniridia showed significantly smaller values than the controls in ciliary body length (4.49 +/- 0.63 versus 5.79 +/- 0.44 mm, P <.001, unpaired Student t test), ciliary body thickness (0.75 +/- 0.17 versus 1.24 +/- 0.22 mm, P <.001), iris root thickness (0.47 +/- 0.14 versus 0.61 +/- 0.07 mm, P <.001), scleral-ciliary process angle (31.7 +/- 3.26 versus 43.1 +/- 4.48 degree, P <.001), and anterior chamber depth (1.99 +/- 0.43 versus 2.94 +/- 0.34 mm, P <.001). In the aniridia eyes, there was a significantly positive correlation between iris thickness and ciliary body thickness (Pearson r = 0.829, P =.001). CONCLUSION: Ultrasound biomicroscopic imaging demonstrated that not only iris hypoplasia but also ciliary body hypoplasia exist in aniridia. Anterior inclination of the ciliary process was also found, which was thought to be at least partly responsible for the shallow anterior chamber.