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Purpose: To use an automated morphometric analysis system of in vivo confocal microscopy (IVCM) images for evaluating reinnervation occurring at the subbasal nerve plexus (SNP) after direct corneal neurotization (DCN) and to further report neurophysiological and histopathological findings., Methods: Prospective interventional case series including 3 eyes with neurotrophic keratitis that underwent DCN. Deep anterior lamellar keratoplasty was performed 18 months after DCN in patient 1. The following evaluations were performed before and at 3, 6, and 12 months after DCN: clinical evolution of keratitis; corneal sensitivity; IVCM images of the SNP analyzed with "ACCMetrics;" neurophysiological study of corneal reflex. Protein gene product 9.5 immunofluorescence staining assay and transmission electron microscopy were conducted on the neurotized button excised during deep anterior lamellar keratoplasty., Results: Complete healing was obtained in all patients by 3 months postoperatively. Corneal sensitivity was absent preoperatively in all eyes and improved after surgery, reaching an average value of 30 mm 1 year postoperatively. The corneal SNP was not visible at IVCM in any of the cases preoperatively and became visible by 3 months postoperatively, showing IVCM metrics comparable to normal contralateral eyes at 1 year. In all cases, neurophysiological evaluation showed a partial recovery of the electrical activity of the cornea. In patient 1, protein gene product (PGP) 9.5 staining of neurotized cornea showed nerve fascicles at the SNP, whereas transmission electron microscopy showed amyelinic nerve axons and nerve endings., Conclusions: The corneal SNP exhibited IVCM metrics comparable to the normal contralateral eye 1 year after DCN. Ex vivo histopathological assessment of neurotized corneas confirmed the presence of nerves with normal ultrastructure.

Purpose: To investigate the comparative effect of allogeneic peripheral blood serum (allo-PBS) and cord blood serum (CBS) eye drops on the status of the corneal subbasal nerve plexus in patients with dry eye disease by using an automated analysis system of in vivo confocal microscopy images., Methods: This prospective, randomized, double-blind study included 30 patients with severe dry eye disease assigned to receive allo-PBS (group 1) or CBS (group 2) eye drops 8 times a day for 30 days. The following in vivo confocal microscopy parameters were calculated with ACCMetrics before (visit 1 [V1]) and after treatment (visit 2 [V2]): corneal nerve fiber density, corneal nerve branch density, corneal nerve fiber length, corneal nerve total branch density, corneal nerve fiber area, corneal nerve fiber width, and corneal nerve fractal dimension (CNFrD)., Results: In overall patients, the values of corneal nerve fiber density, corneal nerve fiber length, and CNFrD significantly increased, whereas the value of corneal nerve fiber width significantly decreased at V2 compared with V1 (respectively, 20.4 ± 7.9 vs. 17.4 ± 10.1 n/mm; 13.5 ± 4.0 vs. 12.0 ± 5.1 mm/mm; 1.466 ± 0.046 vs. 1.475 ± 0.033; and 0.022 ± 0.002 vs. 0.023 ± 0.002; all P < 0.05). In the subanalysis according to the treatment type, the increase of CNFrD value from V1 to V2 was higher in group 2 compared with group 1 (respectively, from 1.455 ± 0.041 to 1.471 ± 0.030 and from 1.479 ± 0.050 to 1.481 ± 0.035; P = 0.030)., Conclusions: Overall, both treatments significantly improved corneal subbasal nerve plexus parameters, and in particular, nerve density, length, width, and fractal dimension. Treatment with CBS eye drops was associated with a higher increase of CNFrD compared with allo-PBS.

Purpose: To assess whether omega-3 fatty acid (FA) supplementation is more efficacious than placebo in amelioration of signs and symptoms of dry eye disease., Methods: We performed a systematic literature search in PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials databases. We included randomized clinical trials comparing omega-3 FA supplementation with placebo in patients with dry eye disease. The outcome measures were dry eye symptoms, breakup time (BUT), Schirmer test, and corneal fluorescein staining. The pooled effect sizes were estimated using a random-effects model. Heterogeneity was evaluated using the Q and I tests. Sensitivity analysis and assessment of publication bias were performed. Meta-regression was performed to evaluate the source of heterogeneity., Results: Seventeen randomized clinical trials involving 3363 patients were included. Compared with placebo, omega-3 FA supplementation decreased dry eye symptoms [standardized difference in mean values (SDM) = 0.968; 95% confidence interval (CI) 0.554-1.383; P < 0.001] and corneal fluorescein staining (SDM = 0.517; 95% CI, 0.043-0.991; P = 0.032), whereas it increased the BUT (SDM = 0.905; 95% CI, 0.564-1.246; P < 0.001) and Schirmer test values (SDM = 0.905; 95% CI, 0.564-1.246; P < 0.001). No evidence of publication bias was observed, and sensitivity analyses indicated the robustness of results obtained. Meta-regression analysis showed a higher improvement of dry eye symptoms and BUT in studies conducted in India., Conclusions: This meta-analysis provides evidence that omega-3 FA supplementation significantly improves dry eye symptoms and signs in patients with dry eye disease. Therefore, our findings indicate that omega-3 FA supplementation may be an effective treatment for dry eye disease.

Purpose: To evaluate the rate and outcomes of immunologic stromal rejection occurring after large deep anterior lamellar keratoplasty (DALK) and the effect of the underlying disease on the cumulative probability of rejection., Methods: This was a retrospective chart review of all eyes that underwent a 9-mm DALK at Ospedali Privati Forlì (Forlì, Italy). On the basis of preoperative diagnosis, eyes were assigned to group 1: keratoconus, group 2: stromal disease with a low risk for rejection, or group 3: stromal disease with a high risk for rejection. The cumulative probability of experiencing a rejection episode over time was assessed by Kaplan-Meier analysis and was compared among the 3 groups using the log-rank test. Values of corrected distance visual acuity, central corneal thickness, and endothelial cell density before and 6 months after rejection were compared., Results: Twenty of 377 eyes (5.3%) experienced an episode of stromal rejection [17/265 (6.4%) in group 1, 2/71 (2.8%) in group 2, and 1/41 (2.4%) in group 3]. The mean time interval between DALK and the rejection onset was 11.8 months (range 1-24). The cumulative probability of rejection episodes did not differ significantly among the 3 groups. All episodes resolved within 6 months after the onset, with no significant differences between prerejection and 6-month postrejection values of corrected distance visual acuity, central corneal thickness, and endothelial cell density., Conclusions: The rate of immunologic stromal rejection after large 9-mm DALK is within the range reported in the literature for conventional DALK, regardless of the indication for surgery.

Purpose: To measure the corneal temperature in patients with dry eye (DE) and to correlate the values with subjective discomfort symptoms., Methods: Twenty-four patients with DE (scored as DEWS severity grade 2 to 3) and 15 age-matched normal control subjects were enrolled. Subjective symptoms of discomfort were scored with an Ocular Surface Disease Index questionnaire, and a 100-mm horizontal visual analog scale (VAS) technique was used to measure symptom intensity. Schirmer I test, tear film breakup time (TFBUT), and Oxford grade scoring were performed in all subjects. Dynamic infrared noncontact thermal imaging (Tomey TG 1000) was used to measure the central corneal temperature (CCT). After training, subjects were asked to maintain their eyes forcedly open and to signal the discomfort onset time (DOT). The temperature was measured at eye opening (T0) and every second during 10 seconds of sustained eye opening (T10). The first discomfort sensation onset time (DOT) was also recorded. Temperature values were correlated with the clinical tests, Ocular Surface Disease Index, VAS, and DOT, and data were statistically evaluated (significance P < 0.05)., Results: The corneal temperature immediately after eye opening was significantly lower in patients with DE than in controls, in correlation to the subject age, VAS, and TFBUT. A 3-phase cooling profile in patients with DE and a point of highest decrease (HD) in both groups were identified. DOT occurred earlier in patients with DE than in controls (5.9 vs. 15.9 seconds) and was strongly correlated to the VAS, TFBUT, and CCT-HD., Conclusions: Subjective sensation of discomfort occurred earlier in patients with DE than in controls, in correlation to low corneal temperatures and enhanced tear evaporation.

Purpose: The aim of this study was to assess corneal hysteresis (CH) and corneal resistance factor (CRF) in healthy subjects, to evaluate the relationship with age, and to investigate possible associations with other ocular factors., Methods: Four hundred Italian subjects (male-to-female ratio, 168:232; mean age, 58.8 ± 17.2 years) were included and divided into 5 subgroups based on age. CH, CRF, and central corneal thickness (CCT) were measured by using the Ocular Response Analyzer and the integrated handheld pachymeter, and their relationship with gender, age, and ocular factors was evaluated., Results: The mean CH, CRF, and CCT values were 10 ± 1.6 mm Hg, 10.5 ± 1.7 mm Hg, and 532.2 μm, respectively. Women had a lower mean CH (9.9 vs. 10.2 mm Hg; P = 0.04) and CRF (10.3 vs. 10.8 mm Hg; P = 0.03) than did men. The youngest subjects had the highest CH (11.2 ± 1.5 mm Hg), whereas the oldest patients had the lowest CH values (9 ± 1.1 mm Hg). No significant differences in CRF were observed between age groups. CH and CRF showed a positive correlation (r = 0.58; P < 0.001), and both had a positive association with CCT (r = 0.27; P < 0.001 and r = 0.57; P < 0.001, respectively). The strongest correlations were observed between Goldmann-correlated intraocular pressure (IOP) and corneal-compensated IOP (r = 0.68; P < 0.001) and between Goldmann-correlated IOP and Goldmann applanation tonometry (r = 0.88; P < 0.001)., Conclusions: Gender and advancing age may influence corneal biomechanical properties. In our population, CH decreased with aging, and men demonstrated a higher CH and CRF than women did. Further, CH, CRF, and CCT were significantly related.

Purpose: We standardized quality-controlled cord blood serum (CBS)-based eye drops and evaluated the efficacy of 1-month CBS treatment in the healing of diseased corneal epithelium in severe dry eye (DE) patients., Methods: Seventeen graft-versus-host disease (GVHD) and 13 Sjogren syndrome patients with severe persistent corneal defects were enrolled in the framework of a registered clinical trial (ClinicalTrials.gov NCT01234623). Sterile CBS eye drops were prepared to supply 0.15 ng per eye per day epithelial growth factor and administered for 1 month in a 1-day dose dispensing. The extent of epithelial defect was evaluated in square millimeters area, and subjective symptom score (Ocular Surface Disease Index score), Schirmer test I, break-up time, tear osmolarity, corneal esthesiometry (Cochet-Bonnet esthesiometer), conjunctival scraping, and imprint cytology with goblet cell count were performed at baseline (V0) and after 15 (V1) and 30 (V2, endpoint) days of treatment. Satisfaction and tolerability questionnaires were evaluated at V1 and V2., Results: A significant reduction was shown at the endpoint versus baseline in corneal epithelial damage (mean ± SD, 16.1 ± 13.7 vs. 40.9 ± 30 mm²/area, respectively), discomfort symptoms (Ocular Surface Disease Index score, 22.3 ± 10.3 vs. 39.3 ± 16.9), scraping cytology score (3.8 ± 1.2 vs. 6.6 ± 2.1), and tear osmolarity (312.5 ± 7 vs. 322 ± 9.1 mOsm/L), whereas a significant improvement was shown in corneal esthesiometry (48.2 ± 2.1 vs. 49.7 ± 2.1 nylon/mm/length, P < 0.05). All patients reported a high degree of satisfaction upon drop instillation., Conclusions: Heterologous CBS-based eye drops represent a promising therapeutic approach in the healing of severely injured corneal epithelium and in subjective symptom relief. These drops can be obtained as readily available and quality-controlled blood derivative from cord blood banks on a routine basis.

Purpose of Review: The purpose of the present review is to describe recent insights into the pathomechanism of ocular surface impairment in the course of thyroid dysfunctions. The review focuses in particular on Graves' ophthalmopathy as the majority of the literature is published on this topic., Recent Findings: Mechanical factors were thought, until now, to be the indirect causes of ocular surface function failure. In particular, eyeglobe bulging and upper eyelid retraction with consequent eyelid fissure width increase were mainly considered responsible for increased exposed area and ocular surface impairment. Recent evidence demonstrated that ocular surface tissues are direct targets for autoantibodies in either hypothyroid or hyperthyroid states. A set of tear protein biomarkers were identified and shown to have high diagnostic performance., Summary: New horizons can be displayed on the basis of these new findings, in particular, as referred earlier, Graves' ophthalmopathy diagnosis. A detailed slit-lamp examination and a careful medical history by validated questionnaires in patients with ocular surface discomfort symptoms are now recommended to investigate early manifestations of an underlying thyroid dysfunction. Ocular surface signs should also be included in professional guidelines. Autoantibody assays in tears and proteomic analysis of tear protein expression could be important further steps in early diagnosis and posttherapy control of thyroid dysfunction.

This study describes increased sarcolemmal permeability and myofilamentar damage that occur together with lipid peroxidation and protein nitration in the myocardium in severe sepsis induced by cecal ligation and puncture. Male C57BL/6 mice were submitted to moderate and severe septic injury and sham operation. Using light and laser confocal microscopy, diffuse foci of myocytolysis associated with focal disruption of the actin/myosin contractile apparatus could be seen in hearts with severe septic injury. The myocardial expressions of the sarcomeric proteins myosin and actin were downregulated by both severe and moderate injuries. The detection of albumin staining in the cytoplasm of myocytes to evaluate sarcolemmal permeability provided evidence of severe and mild injury of the plasma membrane in hearts with severe and moderate septic injury, respectively. The administration of a superoxide scavenger caused marked reduction of sarcolemmal permeability, indicating the involvement of free radicals in its genesis. On electron microscopy, these changes were seen to correspond to spread blocks of a few myocytes with fragmentation and dissolution of myofibrils, intracellular edema, and, occasionally, rupture of the sarcolemma. In addition, oxidative damage to lipids, using anti-4-hydroxynonenal, an indicator of oxidative stress and disruption of plasma membrane lipids, and to proteins, using antinitrotyrosine, a stable biomarker of peroxynitrite-mediated protein nitration, was demonstrated. These findings make plausible the hypothesis that increased sarcolemmal permeability might be a primary event in myocardial injury in severe sepsis possibly due to oxidative damage to lipids and proteins that could precede phenotypic changes that characterize a septic cardiomyopathy.