Ophthalmology Clinic

Cystoid macular edema (CME) is a well-known endpoint of various ocular diseases, but the relative pathogenic impact of extra- and intracellular fluid accumulation within the retinal tissue still remains uncertain. While most authors favor an extracellular fluid accumulation as the main causative factor of cyst formation, there are indications that Müller cell swelling may also contribute to CME development (particularly in cases without significant angiographic vascular leakage). Vascular leakage occurs after a breakdown of the blood-retinal barrier during traumatic, vascular, and inflammatory ocular diseases, and allows the serum to get into the retinal interstitium. Since intraretinal fluid distribution is restricted by two diffusion barriers, the inner and outer plexiform layers, serum leakage from intraretinal vessels causes cysts mainly in the inner nuclear layer while leakage from choroid/pigment epithelium generates (in addition to subretinal fluid accumulation) cyst formation in the Henle fiber layer. In the normal healthy retina, the transretinal water fluxes are mediated by glial and pigment epithelial cells. These water fluxes are inevitably coupled to fluxes of osmolytes; in the case of glial (Müller) cells, to K(+) clearance currents. For this purpose, the cells express a complex, microtopographically optimized pattern of transporters and channels for osmolytes and water in their plasma membrane. Ischemic/hypoxic alterations of the retinal microvasculature result in gliotic responses which involve down-regulation of K(+) channels in the perivascular Müller cell end-feet. This means a closure of the main pathway which normally generates the osmotic drive for the redistribution of water from the inner retina into the blood. The result is an intracellular K(+) accumulation which, then, osmotically drives water from the blood into the glial cells (i.e., in the opposite direction) and causes glial cell swelling, edema, and cyst formation. While the underlying mechanisms await further research, it is expected that their improved knowledge will stimulate the development of novel therapeutic approaches to resolve edema in retinal tissue.

BACKGROUND: The impact on the endothelial glycocalyx for the extravasation of colloidal infusion solutions has not been investigated sufficiently. METHODS: Isolated guinea pig hearts were perfused with Krebs-Henseleit buffer in a Langendorff mode. Solutions of 0.9% saline, 5% albumin (70 kd), or 6% hydroxyethyl starch (200 kd) were infused into the coronary system for 20 min at a rate of one third of the coronary flow, also during reperfusion after 15 min of ischemia, and after enzymatic digestion of the endothelial glycocalyx by heparinase. Net coronary fluid filtration was assessed directly by measuring the formation of transudate on the epicardial surface, and solute extravasation was assessed by measuring albumin and hydroxyethyl starch in the coronary effluent and transudate. Hearts were perfusion fixed to visualize the endothelial glycocalyx using transmission electron microscopy. RESULTS: Only infusion of hydroxyethyl starch, not infusion of albumin, significantly decreased net coronary fluid filtration. Heparinase application without ischemia increased coronary leak by 25% but did not accelerate the passage of colloids. Ischemia alone did not alter permeability. However, there was a large (approximately +200%), transient (approximately 4 min) increase in permeability for water, albumin, and hydroxyethyl starch after ischemia with heparinase application. Also, histamine (10 m) only increased permeability after pretreatment of the hearts with heparinase. The thickness of the glycocalyx after colloid administration was 0.2-0.3 microm. No glycocalyx could be detected after application of heparinase. CONCLUSION: The endothelial glycocalyx acts as a competent barrier for water and colloids. Only after its destruction do changes in endothelial morphology (postischemic reperfusion or histamine application) become effective determinants of coronary extravasation.

In Brief Purpose: To determine if reducing the area of internal limiting membrane (ILM) peeling in the inverted ILM flap technique results in satisfactory outcomes for the repair of large Stage IV idiopathic macular holes. Methods: Prospective comparative interventional study of 87 consecutive eyes. Participants were randomized into two treatment groups. In Group A, the classic inverted ILM flap technique was performed. In Group B, a modification of this procedure, the temporal inverted ILM flap technique, was performed. In the modified inverted ILM flap technique, peeling of the ILM was restricted to the temporal side of the fovea only—the macular hole was then covered with the temporal ILM flap. Results: There was no significant difference in initial and final visual acuities between Groups A and B. In both groups, defects in photoreceptors and the external limiting membrane decreased with time. Successive postoperative examinations revealed an increasing number of patients with the dissociated optic nerve fiber layer appearance, although this was less frequent in Group B (modified ILM flap) than in Group A. Conclusion: The study results indicate that the temporal inverted ILM flap technique is as effective as the classic inverted ILM flap technique for the repair of large Stage IV macular holes. Temporal inverted internal limiting membrane flap technique for large macular holes enables achieving similar results as in the inverted internal limiting membrane flap technique. Additionally, temporal inverted internal limiting membrane technique tends to cause less retinal nerve fiber layer defects.

BACKGROUND: Hydrocortisone protects against ischemia-reperfusion injury, reduces paracellular permeability for macromolecules, and is routinely applied in the prevention of interstitial edema. Healthy vascular endothelium is coated by the endothelial glycocalyx, diminution of which increases capillary permeability, suggesting that the glycocalyx is a target for hydrocortisone action. METHODS: Isolated guinea pig hearts were perfused with Krebs-Henseleit buffer. Hydrocortisone was applied in a stress dose (10 microg/ml) before inducing 20 min of ischemia (37 degrees C). Hearts were reperfused for 20 min at constant flow (baseline perfusion pressure, 70 cm H2O) with Krebs-Henseleit buffer or Krebs-Henseleit buffer plus 2 g% hydroxyethyl starch (130 kd). Coronary net fluid filtration was assessed directly by measuring transudate formation on the epicardial surface. Hearts were perfusion fixed to visualize the glycocalyx. RESULTS: Ischemia-induced degradation of the glycocalyx enhanced coronary perfusion pressure (118.8 +/- 17.3 cm H2O) and increased vascular permeability (8 +/- 0.2 microl x min(-1) x cm H2O(-1) at baseline vs. 34 +/- 3.3 microl x min(-1) x cm H2O(-1) after reperfusion). Enzymatic digestion of the glycocalyx (heparinase) elicited similar effects. Hydrocortisone reduced postischemic oxidative stress, perfusion pressure (86.3 +/- 6.4 cm H2O), and transudate formation (11 +/- 0.6 microl x min(-1) x cm H2O(-1)). Applying colloid augmented this (70.6 +/- 5.6 cm H2O and 9 +/- 0.5 microl x min(-1) x cm H2O(-1)). Postischemic shedding of syndecan-1, heparan sulfate, and hyaluronan was inhibited by hydrocortisone, as was release of histamine from resident mast cells. Electron microscopy revealed a mostly intact glycocalyx after hydrocortisone treatment, but not after heparinase treatment. CONCLUSIONS: Hydrocortisone preserves the endothelial glycocalyx, sustaining the vascular barrier and reducing interstitial edema. The effect of colloids suggests that prevention of postischemic rise in coronary resistance by hydrocortisone could also be based on alleviation of endothelial swelling. Stabilization of myocardial mast cells by hydrocortisone may account for the mitigated inflammatory affect of ischemia-reperfusion.

BACKGROUND: A European (EU) and a North American (NA) placebo-controlled study with interferon beta-1b (IFNB-1b) in secondary progressive multiple sclerosis (SPMS) showed divergent results with regard to their primary outcome of sustained Expanded Disability Status Scale (EDSS) progression, while effects were similar on relapse and MRI-related endpoints. Reasons for this discrepancy were explored in the combined dataset. METHODS: Baseline characteristics and variability in EDSS assessments were compared. Retrospective combined analyses for time to confirmed progression were performed to assess treatment effects overall and in subgroups defined by pre-study disease activity criteria and other key baseline variables. RESULTS: The variance of EDSS measurements was 6.5% higher in the NA-SPMS study. The EU study included patients in an earlier phase of SPMS and with more active disease both pre-study (relapses, MRI) as well as on study (EDSS, relapses, and MRI variables as assessed in the placebo groups). The pooled analysis showed an overall risk reduction by about 20% in patients treated with 8 MIU (250 mcg) IFNB-1b for EDSS progression confirmed at 6 months (p = 0.008). Risk reduction by 30% to 40% was found for patients with at least one relapse or change in EDSS by >1 in the 2 years prior to study entry. No other consistent across-studies relation of clinical and MRI variables at baseline to potential treatment response was found. CONCLUSIONS: Although post hoc, this combined analysis of the two large studies with IFNB-1b in secondary progressive multiple sclerosis suggests that both pronounced disability progression and continuing relapse activity might help in identifying those patients in the secondary progressive phase of the disease who are more likely to benefit from treatment.

BACKGROUND: Fluid extravasation may lead to myocardial edema and consequent reduction in ventricular function. Albumin is presumed to interact with the endothelial glycocalyx. The authors' objective was to compare the impact of different resuscitation fluids (human albumin, hydroxyethyl starch, saline) on vascular integrity. METHODS: In an isolated perfused heart model (guinea pig), Krebs-Henseleit buffer was augmented with colloids (one third volume 5% albumin or 6% hydroxyethyl starch 130/0.4) or crystalloid (0.9% saline). Perfusion pressure and vascular fluid filtration (epicardial transudate formation) were assessed at different flow rates. After global, stopped-flow ischemia (37 degrees C, 20 min), hearts were reperfused with the same resuscitation fluid additives. In a second series, the authors applied the respective perfusates after enzymatic digestion of the endothelial glycocalyx (heparinase, 10 U over 15 min). RESULTS: Both 5% albumin and 6% hydroxyethyl starch decreased fluid extravasation versus saline (68.4 +/- 5.9, 134.8 +/- 20.5, and 436.8 +/- 14.7 microl/min, respectively, at 60 cm H(2)O perfusion pressure; P < 0.05), the corresponding colloid osmotic pressures being 2.95, 5.45, and 0.00 mmHg. Digestion of the endothelial glycocalyx decreased coronary integrity in both colloid groups. After ischemia, a transient increase in vascular leak occurred with Krebs-Henseleit buffer containing hydroxyethyl starch and saline, but not with albumin. The authors observed no difference between intravascular and bulk interstitial colloid concentration in the steady state. Notwithstanding, electron microscopy revealed an intact endothelial glycocalyx and no interstitial edema in the albumin group. CONCLUSION: Ex vivo, albumin more effectively prevented fluid extravasation in the heart than crystalloid or artificial colloid. This effect was partly independent of colloid osmotic pressure and may be attributable to an interaction of albumin with the endothelial glycocalyx.

The aim of this study was to assess the efficacy of BioPlus 2B, a probiotic containing Bacillus licheniformis and Bacillus subtilis spores, on the health status and productivity of sows and their litters. A total of 109 gilts and sows were allocated into two experimental groups, as follows: untreated controls (UC) and BioPlus 2B (same feeding as the UC group plus BioPlus 2B) at a dose of 400 g/ton of feed (equal to 1.28 x 10(6) viable spores/g of feed). Treatment started from the day of allocation (14 days prior to the expected farrowing) up to the weaning day. Homogeneity of the groups was satisfied with regard to the parity. From the results it was evident that BioPlus 2B supplementation of the feed improved gilt/sow performance as shown by: (i) the increase of sow feed consumption during the first 14 days postpartum and (ii) the decrease of sow weight loss during the suckling period. Certain blood and milk parameters were significantly improved, as shown by higher serum cholesterol and total lipids concentrations and higher milk fat and protein content at mid-suckling period. As a consequence, a positive effect was also noticed as regard litter health and performance characteristics in terms of: (i) decrease in piglet diarrhoea score, (ii) decrease in pre-weaning mortality thus leading to increase in the number of weaned piglets per litter and (iii) increase in piglet body weight at weaning. Moreover, BioPlus 2B tended to improve the health status and fertility of sows demonstrating: (i) tendency to a lower proportion of sows with Mastitis-Metritus-Agalactia (MMA) problems and (ii) lower proportion of sows returning to oestrus.

Background. Highly pathogenic avian H5N1 influenza viruses preferentially infect alveolar type II pneumocytes in human lung. However, it is unknown whether this cellular tropism contributes to high viral virulence because the primary target cells of other influenza viruses have not been systematically studied.

PURPOSE: To present the anatomical and functional results of vitrectomy with the "inverted internal limiting membrane flap technique" in myopic macular holes without retinal detachment. METHODS: A prospective interventional study of 19 myopic eyes with a spherical equivalent >-6 diopters with macular holes in 18 consecutive patients. Preoperative and postoperative visual acuity and spectral domain optical coherence tomography images were evaluated. The main outcome measure was visual outcome and macular hole closure rate. RESULTS: Mean visual acuity improved from 1.2 logMAR to 0.56 logMAR. We confirmed the closure of the macular hole with spectral domain optical coherence tomography in all cases. The closure of the macular hole began in the inner retinal layers, and the architecture gradually filled with tissue. Photoreceptor and external limiting membrane defects improved during the first 12 months after surgery. CONCLUSION: Vitrectomy with the inverted internal limiting membrane flap technique may be an effective addition to surgical options for treating myopic macular holes. Spectral domain optical coherence tomography images confirm that the process of foveal architectural repair after this surgery continues over at least a 12-month period.

PURPOSE: The proteolytic activity of matrix metalloproteinases (MMPs) is involved in pathologic angiogenesis in the eye. However, it is unknown whether MMPs may stimulate the production of the major angiogenic factor, vascular endothelial growth factor (VEGF). The authors investigated whether MMP-2 and MMP-9 alter the expression of VEGF by retinal pigment epithelial (RPE) cells. They also sought to determine the effects of MMPs on cellular proliferation and migration and the effect of triamcinolone acetonide on MMP-9-evoked cellular responses. METHODS: Human RPE cell cultures were stimulated with MMP-2 or MMP-9. The gene expression and secretion of MMP-9 and VEGF were determined by real-time RT-PCR and ELISA, respectively. Cellular proliferation was investigated with a bromodeoxyuridine immunoassay, and chemotaxis was examined with a Boyden chamber assay. RESULTS: Under control conditions, RPE cells in vitro expressed a significantly higher amount of mRNA for MMP-2 than for MMP-9. Chemical hypoxia caused upregulation of the gene expression of both MMPs, whereas VEGF increased the gene expression and secretion of MMP-9. The hypoxic expression of MMP-9 was mediated by autocrine VEGF signaling. Exogenous MMP-9 increased the gene expression and secretion of VEGF, whereas MMP-2 reduced the secretion of VEGF. MMP-2 and MMP-9 did not alter the proliferation but stimulated the migration of RPE cells. Triamcinolone fully inhibited the stimulatory effect of MMP-9 on the expression of VEGF and the VEGF-evoked increase in the expression of MMP-9. However, triamcinolone had no effect on the motogenic effect of MMP-9. CONCLUSIONS: There is a positive feedback regulation between MMP-9 and VEGF in RPE cells. The hypoxic expression of MMP-9 may stimulate the production and secretion of VEGF under pathologic conditions. Triamcinolone inhibits the positive feedback regulation between MMP-9 and VEGF under hypoxic conditions through inhibition of the gene expression of MMP-9 and the secretion of VEGF.

OBJECTIVES: To define minimum standards for provision of services and clinical practice in the investigation of anal cancer precursors. METHODS: After initial face to face meetings of experts at the International Papillomavirus meeting in Lisbon, September 17 to 21, 2015, a first version was drafted and sent to key stakeholders. A complete draft was reviewed by the Board of the International Anal Neoplasia Society (IANS) and uploaded to the IANS Web site for all members to provide comments. The final draft was ratified by the IANS Board on June 22, 2016. RESULTS: The essential components of a satisfactory high-resolution anoscopy (HRA) were defined. Minimum standards of service provision, basic competencies for clinicians, and standardized descriptors were established. Quality assurance metrics proposed for practitioners included a minimum of 50 HRAs per year and identifying 20 cases or more of anal high-grade squamous intraepithelial lesions (HSILs). Technically unsatisfactory anal cytological samples at first attempt in high-risk populations should occur in less than 5% of cases. Where cytological HSIL has been found, histological HSIL should be identified in ≥ 90% of cases. Duration of HRA should be less than 15 minutes in greater than 90% of cases. Problematic pain or bleeding should be systematically collected and reported by 10% or lesser of patients. CONCLUSIONS: These guidelines propose initial minimum competencies for the clinical practice of HRA, against which professionals can judge themselves and providers can evaluate the effectiveness of training. Once standards have been agreed upon and validated, it may be possible to develop certification methods for individual practitioners and accreditation of sites.

PURPOSE: To evaluate refractive and visual parameters related to distance, intermediate, and near vision after cataract surgery and the optical quality of a new diffractive trifocal intraocular lens (IOL). SETTING: Vissum Instituto Oftalmologico de Alicante, Alicante, Spain. DESIGN: Case series. METHODS: Patients had bilateral refractive lens exchange and multifocal diffractive IOL (AT Lisa tri 839 MP) implantation. A complete ophthalmology examination was performed preoperatively and postoperatively. The follow-up was 6 months. The main outcome measures were uncorrected distance (UDVA) and corrected distance (CDVA), intermediate, and near visual acuities; keratometry; manifest refraction; and aberrations (total, corneal, internal). RESULTS: The study comprised 60 eyes of 30 patients (mean age 57.9 years ± 7.8 [SD]; range 42 to 76 years). There was significant improvement in UDVA, uncorrected intermediate visual acuity, uncorrected near visual acuity, CDVA, and distance-corrected intermediate and near visual acuity. The postoperative refractive status was within the range of +1.00 to -1.00 diopter. Total internal aberrations decreased significantly (P<.001). CONCLUSIONS: The trifocal IOL improved near, intermediate, and distance vision in presbyopic patients. The use of 3 foci provided significant intermediate visual results without sacrificing near or distance vision.

BACKGROUND: Little is known about how chronic conditions other than prematurity, heart disease, and Down syndrome affect the risk and severity of hospitalization for respiratory syncytial virus (RSV). We assess the risk and severity of RSV hospitalization in children with chronic conditions in this register-based, population-based cohort study. METHODS: Data on RSV tests, maternal smoking, siblings, single parenthood, mode of delivery, gestational age at birth, major surgery, asthma diagnosis, chronic conditions, and hospitalization and discharge dates were obtained from the Danish RSV database, the National Patient and Birth Registries, and the Civil Registration System. STATISTICS: Cox regression models were used to estimate incidence rate ratios (IRRs) for RSV hospitalization between groups stratified by sex and date of birth. Duration of RSV hospitalization was analyzed in a linear regression and reported as geometric mean ratios. RESULTS: A total of 391 983 children aged 0-23 months were included in the analysis. A total of 10,616 (2.7%) had a diagnosis for chronic disease. IRRs (95% confidence intervals) for RSV hospitalization in children with any congenital or acquired chronic condition were 2.18 (2.01-2.36) and 2.25 (1.94-2.61), respectively. Several new risk factors for RSV hospitalization, including malformations, interstitial lung disease, neuromuscular disease, liver disease, chromosomal abnormalities, congenital immunodeficiencies, and inborn errors of metabolism, were identified. Duration of RSV hospitalization was increased in many chronic conditions. CONCLUSIONS: Chronic disease per se is an important risk factor for RSV hospitalization.

PURPOSE: To evaluate the efficacy of a marrow-stimulating technique with microfractures of the greater tuberosity during arthroscopic rotator cuff repair. METHODS: Eighty patients with a full-thickness rotator cuff tear underwent an arthroscopic single-row repair. Patients were divided into 2 groups of 40 cases each. In group 1, standard repair was performed; in group 2, microfractures of the greater tuberosity were performed to enhance tendon repair. Clinical outcome was assessed with the Disabilities of the Arm, Shoulder and Hand (DASH) score and normalized Constant score. Tendon integrity was assessed with magnetic resonance imaging. Multivariate analysis was performed to determine which predictors were independently associated with the outcome. Significance was set at P < .05. RESULTS: The mean follow-up was 28.1 ± 3 months. Seven patients were lost to follow-up (2 in group 1 and 5 in group 2). Comparison between groups did not show significant differences for baseline characteristics. The mean DASH score was 28.6 ± 21.3 points in group 1 and 23.3 ± 20.1 points in group 2. Although the difference was not statistically significant, the confidence interval included a 10-point value (minimal clinically important difference) in favor of the microfracture group. The difference in the Constant score between groups was not significant. The tendon healing rate was 52.6% in group 1 and 65.7% in group 2, without a significant difference between groups. Subgroup analysis for tear size showed that group 2 had a significantly greater healing rate than group 1 for large tears (P = .040). Multivariate analysis showed that age, timing of symptoms, tear location, tendon retraction, and fatty infiltration significantly affected the outcomes. CONCLUSIONS: Postoperative magnetic resonance imaging did not show any significant difference between groups in structural integrity. However, subgroup analysis showed a significantly greater healing rate in the microfracture group for large tears involving the supraspinatus and infraspinatus. LEVEL OF EVIDENCE: Level I, high-quality randomized controlled trial with no statistically significant difference but narrow confidence intervals.

PURPOSE: To establish a time-proven "gold standard" in modified osteoodontokeratoprosthesis (OOKP) surgery. METHODS: The OOKP is the procedure of choice for restoring sight in patients with corneal blindness caused by end-stage ocular surface disease not amenable to penetrating keratoplasty. Members of the OOKP Study Group met in Rome, Italy in 2001 and Vienna, Austria in 2002 to discuss indications and contraindications, patient selection, surgical technique, postoperative care, and recognition and management of complications of OOKP surgery according to Strampelli and modified by Falcinelli. RESULTS: Falcinelli's modification of Strampelli's technique of OOKP surgery remains the gold standard as far as visual and keratoprosthesis-retention results are concerned. The agreement on indications and contraindications, patient selection, surgical technique, postoperative care, and recognition and management of complications of this technique of OOKP surgery is summarized in the text of this manuscript. CONCLUSION: This standard technique of modified OOKP surgery, where adequately performed, is capable of providing excellent anatomic and functional results even in the long term. In patients with corneal blindness untreatable by other approaches, we strongly recommend this technique for visual rehabilitation. Students of OOKP surgery should become familiar with the protocol described in this paper before subjecting the technique to further modifications.

The anatomy of urinary incontinence and the underlying pathology is still under discussion. We examined 24 stress incontinent patients and 6 healthy volunteers. Magnetic resonance imaging (MRI) clearly shows that the urethra is not connected to the levator ani. The urethra is not fixed to deep perineal muscle layers. In stress incontinence the sharp angulation of the levator ani of healthy volunteers is lost in 65%. MRI shows degeneration of the levator ani muscle in 45% of stress incontinent patients. The extent of damage to the levator can clearly be identified with the aid of MRI.

PURPOSE: To evaluate the safety and efficacy of the iStent Trabecular Micro-bypass Stent in patients undergoing concurrent cataract and glaucoma surgery. METHODS: Prospective, 24-month, uncontrolled, multicenter, multicountry evaluation of 58 patients with uncontrolled primary open-angle glaucoma (including pseudoexfoliation and pigmentary) and cataract. Patients underwent clear cornea phacoemulsification followed by ab interno gonioscopically guided implantation of the iStent. Of the 48 per protocol population, 42 patients completed 12 months of the 24-month study, and their data are included in this interim analysis. RESULTS: At baseline, mean (+/-SD) intraocular pressure (IOP) was 21.7+/-3.98 mmHg. At 12 months, mean IOP was reduced to 17.4+/-2.99 mmHg, a mean IOP reduction of 4.4+/-4.54 mmHg (p<0.001, 18.3%). At baseline, patients were taking a mean 1.6+/-0.8 medications. By 12 months, the mean number of medications was reduced to 0.4+/-0.62 (p<0.001). Half the patients achieved an IOP < or =18 mmHg and were able to discontinue hypotensive medication by the 12-month visit. The most commonly reported device-related adverse events were the appearance of stent lumen obstruction (7 eyes) and stent malposition (6 eyes). None of the adverse events were deemed serious. CONCLUSIONS: In patients undergoing concurrent cataract and glaucoma surgery, the iStent was safe and efficacious for the reduction of IOP and medication therapy.

ObjectiveEye drops of aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, inhibited corneal neovascularization in a previous dose-finding phase II study. We aimed to confirm these results in a phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL), and need for transplantation.DesignMulticenter, double-masked, randomized, placebo-controlled phase III study.ParticipantsAnalysis of 69 patients with keratitis-related progressive corneal neovascularization randomized to aganirsen (34 patients) or placebo (35 patients). Patients applied aganirsen eye drops (86 μg/day/eye) or placebo twice daily for 90 days and were followed up to day 180.Main Outcome MeasuresThe primary end point was VA. Secondary end points included area of pathologic corneal neovascularization, need for transplantation, risk of graft rejection, and QoL.ResultsAlthough no significant differences in VA scores between groups were observed, aganirsen significantly reduced the relative corneal neovascularization area after 90 days by 26.20% (P = 0.014). This improvement persisted after 180 days (26.67%, P = 0.012). Aganirsen tended to lower the transplantation need in the intent-to-treat (ITT) population at day 180 (P = 0.087). In patients with viral keratitis and central neovascularization, a significant reduction in transplantation need was achieved (P = 0.048). No significant differences between groups were observed in the risk of graft rejection. However, aganirsen tended to decrease this risk in patients with traumatic/viral keratitis (P = 0.162) at day 90. The QoL analyses revealed a significant improvement with aganirsen in composite and near activity subscores (P = 0.039 and 0.026, respectively) at day 90 in the per protocol population. Ocular and treatment-related treatment-emergent adverse events (TEAEs) were reported in a lower percentage with aganirsen compared with placebo. Only 3 serious TEAEs (2 with aganirsen and 1 with placebo) were considered treatment-related.ConclusionsThis first phase III study on a topical inhibitor of corneal angiogenesis showed that aganirsen eye drops significantly inhibited corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well tolerated. Eye drops of aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, inhibited corneal neovascularization in a previous dose-finding phase II study. We aimed to confirm these results in a phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL), and need for transplantation. Multicenter, double-masked, randomized, placebo-controlled phase III study. Analysis of 69 patients with keratitis-related progressive corneal neovascularization randomized to aganirsen (34 patients) or placebo (35 patients). Patients applied aganirsen eye drops (86 μg/day/eye) or placebo twice daily for 90 days and were followed up to day 180. The primary end point was VA. Secondary end points included area of pathologic corneal neovascularization, need for transplantation, risk of graft rejection, and QoL. Although no significant differences in VA scores between groups were observed, aganirsen significantly reduced the relative corneal neovascularization area after 90 days by 26.20% (P = 0.014). This improvement persisted after 180 days (26.67%, P = 0.012). Aganirsen tended to lower the transplantation need in the intent-to-treat (ITT) population at day 180 (P = 0.087). In patients with viral keratitis and central neovascularization, a significant reduction in transplantation need was achieved (P = 0.048). No significant differences between groups were observed in the risk of graft rejection. However, aganirsen tended to decrease this risk in patients with traumatic/viral keratitis (P = 0.162) at day 90. The QoL analyses revealed a significant improvement with aganirsen in composite and near activity subscores (P = 0.039 and 0.026, respectively) at day 90 in the per protocol population. Ocular and treatment-related treatment-emergent adverse events (TEAEs) were reported in a lower percentage with aganirsen compared with placebo. Only 3 serious TEAEs (2 with aganirsen and 1 with placebo) were considered treatment-related. This first phase III study on a topical inhibitor of corneal angiogenesis showed that aganirsen eye drops significantly inhibited corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well tolerated.

The Cerebral Palsy Register in eastern Denmark has collected cases using a uniform data sampling procedure since birth year 1979. We have investigated changes in the rate of cerebral palsy, related to gestational age, mortality and perinatal risk factors in children born 1983--90. The total cerebral palsy birth prevalence decreased from 3.0 in the birth year period 1983--86 to 2.4 per 1000 live births (P < 0.01) in 1987--90, owing to a decrease among all preterm infants (29--19 per 1000, P < 0.001). The perinatal and early neonatal mortality in preterm infants was unchanged from 1983--86 to 1987--90. The rate of cerebral palsy in term infants was 1.5 per 1000 in all birth-year periods from 1979--90. Among the cerebral palsy infants, the proportion of very preterm babies treated with mechanical ventilation in the neonatal period decreased from 95% in 1983--86 to 61% in 1987--90 (P < 0.001), while the group treated with CPAP among the moderately preterm babies increased from 61% to 78% (P < 0.05). The significant decline in cerebral palsy rate in preterm infants born 1987--90 may be due to a change in treatment at the neonatal intensive care units using less mechanical ventilation, a hypothesis which needs further investigation.

Sport has been known to be one of the most important factors in preventing cardiovascular disorders; some studies suggest its role in preventing neurodegenerative diseases. This review discusses the results of various studies regarding the effects of physical exercises on intraocular pressure (IOP), myopia, certain physical parameters of the eye, ocular blood flow, and retinal electrical function. Although dynamic exercises are known to reduce IOP from 1.2 to 5.9 mm Hg only for a short period of time, uncertainty persists about whether isometric exercises or activities such as yoga can increase IOP up to 16.7 mm Hg. There has been an established connection between the time being spent outdoor and reduction in the odds of myopia-2% less odds for every hour spent outdoor. Physical activity and the level of physical fitness have an impact on the changes of b-wave electroretinogram and P100. Physical exercises increase perfusion pressure up to 190% baseline and also increase choroidal blood flow up to 140%, thus providing more blood to retina. Sport-induced change on visual field is a subject of controversy. Majority of patients show a better ocular physiological function due to sports and sports are thus considered essential for preventing common ocular diseases. Further research should focus more on long-term effects of sport-induced changes in ocular physiology and newly discovered techniques may be utilized for such purposes.