Connexin 43 Regulates Intercellular Mitochondrial Transfer from Human Mesenchymal Stromal Cells to Chondrocytes.

Background: The phenomenon of intercellular mitochondrial transfer from mesenchymal stromal cells (MSCs) has shown promise for improving tissue healing after injury and has potential for treating degenerative diseases like osteoarthritis (OA). Recently MSC to chondrocyte mitochondrial transfer has been documented, but the mechanism of transfer is unknown. Full-length connexin43 (Cx43, encoded by GJA1 ) and the truncated internally translated isoform GJA1-20k have been implicated in mitochondrial transfer between highly oxidative cells, but have not been explored in orthopaedic tissues. Here, our goal was to investigate the role of Cx43 in MSC to chondrocyte mitochondrial transfer. In this study, we tested the hypotheses that (a) mitochondrial transfer from MSCs to chondrocytes is increased when chondrocytes are under oxidative stress and (b) MSC Cx43 expression mediates mitochondrial transfer to chondrocytes. Methods: Oxidative stress was induced in immortalized human chondrocytes using tert-Butyl hydroperoxide (t-BHP) and cells were evaluated for mitochondrial membrane depolarization and reactive oxygen species (ROS) production. Human bone-marrow derived MSCs were transduced for mitochondrial fluorescence using lentiviral vectors. MSC Cx43 expression was knocked down using siRNA or overexpressed (GJA1+ and GJA1-20k+) using lentiviral transduction. Chondrocytes and MSCs were co-cultured for 24 hrs in direct contact or separated using transwells. Mitochondrial transfer was quantified using flow cytometry. Co-cultures were fixed and stained for actin and Cx43 to visualize cell-cell interactions during transfer. Results: Mitochondrial transfer was significantly higher in t-BHP-stressed chondrocytes. Contact co-cultures had significantly higher mitochondrial transfer compared to transwell co-cultures. Confocal images showed direct cell contacts between MSCs and chondrocytes where Cx43 staining was enriched at the terminal ends of actin cellular extensions containing mitochondria in MSCs. MSC Cx43 expression was associated with the magnitude of mitochondrial transfer to chondrocytes; knocking down Cx43 significantly decreased transfer while Cx43 overexpression significantly increased transfer. Interestingly, GJA1-20k expression was highly correlated with incidence of mitochondrial transfer from MSCs to chondrocytes. Conclusions: Overexpression of GJA1-20k in MSCs increases mitochondrial transfer to chondrocytes, highlighting GJA1-20k as a potential target for promoting mitochondrial transfer from MSCs as a regenerative therapy for cartilage tissue repair in OA.

Predicting the net administered activity in 90 Y-radioembolization patients from post-procedure 90 Y-SPECT/CT.

BACKGROUND: The calculation of the net administered activity (Aadmin ) in patients undergoing 90 Y-radioembolization is essential for dosimetry and radiation safety, yet current methods for measuring residual 90 Y activity are often associated with high uncertainty. Therefore, an accurate, robust, and clinically viable method for the determination of Aadmin across approved 90 Y microsphere devices is desirable. PURPOSE: We report on a novel method to determine Aadmin by leveraging the quantitative capabilities of SPECT/CT to measure 90 Y-emission in vivo from patients following 90 Y-radioembolization with glass or resin microspheres. METHODS: 90 Y-SPECT/CT attenuation-corrected count data from 147 sequential 90 Y-radioembolization patients was used for this analysis. Aadmin was calculated as part of routine clinical practice via the exposure rate differences between the initial 90 Y-vial and the 90 Y-residual jar. This served as our gold standard measure of Aadmin . Patient data for each microsphere device were separated into training and testing cohorts to first develop regression models and then to independently assess model performance. The training cohorts were divided into four groups: first, based on the microsphere device (glass or resin), and second, based on the SPECT volume used to calculate counts (the full SPECT field of view (FOV) or liver only (VOIliver )). Univariate linear regression models were generated for each group to predict Aadmin based on 90 Y-SPECT data from the training cohorts. Leave-one-out cross validation was implemented to estimate variability in model parameters. To assess performance, linear models derived from the training cohort were applied to 90 Y-SPECT data from the testing cohort. A comparison of the models between microspheres devices was also performed. RESULTS: Linear models derived from the glass and resin training cohorts demonstrated a strong, positive correlation between 90 Y-SPECT image counts and Aadmin for VOIliver and FOV with R2  > 0.98 in all cases. In the glass training cohort, model accuracy (100%-absolute mean prediction error) and precision (95% prediction intervals of mean prediction error) were 99.0% and 15.4% for the VOIliver and 99.7% and 17.5% for the FOV models, respectively. In the resin training cohort, the corresponding values were 98.6% and 16.7% for VOIliver and > 99.9% and 11.4% for the FOV models, respectively. The application of these linear models to 90 Y-SPECT data from the testing cohort showed Aadmin prediction errors to have high accuracy and precision for both microsphere devices. For the glass testing cohort, accuracy (precision) was 96.9% (19.6%) and 98.8% (21.1%) for the VOIliver and FOV models, respectively. The corresponding values for the resin training cohort were 97.3% (26.2%) and 98.5% (25.7%) for the VOIliver and FOV models, respectively. The slope of the linear models between the two microsphere devices was observed to be significantly different with resin microspheres generating 48%-49% more SPECT counts for equivalent 90 Y activity based on each device manufacturer's activity calibration process. CONCLUSION: 90 Y-SPECT image counts can reliably predict (accuracy > 95% and precision < 18%) Aadmin after 90 Y-radioembolization, with performance characteristics essentially equivalent for both glass and resin microspheres. There is a clear indication that activity calibrations are fundamentally different between the two microsphere devices.

Impedance Measures for Detecting Electrical Responses during Acute Injury and Exposure of Compounds to Roots of Plants.

Electrical activity is widely used for assessing a plant's response to an injury or environmental stimulus. Commonly, a differential electrode recording between silver wire leads with the reference wire connected to the soil, or a part of the plant, is used. One method uses KCl-filled glass electrodes placed into the plant, similar to recording membrane/cell potentials in animal tissues. This method is more susceptible to artifacts of equipment noise and photoelectric effects than an impedance measure. An impedance measure using stainless steel wires is not as susceptible to electrically induced noises. Impedance measurements are able to detect injury in plants as well as exposure of the roots to environmental compounds (glutamate). The impedance measures were performed in 5 different plants (tomato, eggplant, pepper, liverwort, and Coleus scutellarioides), and responses to mechanical movement of the plant, as well as injury, were recorded. Monitoring electrical activity in a plant that arises in a distant plant was also demonstrated using the impedance method. The purpose of this report is to illustrate the ease in using impedance measures for monitoring electrical signals from individual plants or aggregates of plants for potentially scaling for high throughput and monitoring controlled culturing and outdoor field environments.

Measuring Electrical Responses during Acute Exposure of Roots and Rhizoids of Plants to Compounds Using a Flow-Through System.

Monitoring electrical signals in plants allows the examination of their acute and chronic physiological changes and responses to stimuli. Understanding how plant roots/rhizoids respond to chemical cues in their environment will provide insight into how these structures acquire resources. Chronic exposure to L-glutamate alters root growth and is known to alter Ca2+ flux inside roots. The ionic flux can be detected by electrical changes. A rapid and relatively easy approach is presented to screen the electrical sensitivity of roots/rhizoids to compounds such as amino acids and known agonists/antagonists to receptors and ion channels. The approach uses a background-flow system of basal salt or water; then, the administered compounds are added to the roots/rhizoids while monitoring their electrical responses. As a proof of concept, the response to flow-through of glutamate (1 mM) was targeted at the root/rhizoids of three plants (Arabidopsis thaliana, Pisum sativum and Marchantia inflexa). Both Arabidopsis thaliana and Pisum sativum produced rapid depolarization upon exposure to glutamate, while M. inflexa did not show an electrical response. In some experiments, simultaneous recordings with impedance measures for acute changes and glass electrodes for chronic electrical potential changes were used. The effect of potassium chloride (300 mM) as a depolarizing stimulus produced responses in both P. sativum and M. inflexa. The protocol presented can be used to screen various compounds in a relatively rapid manner for responsiveness by the roots/rhizoids of plants.

Human mesenchymal stromal cells release functional mitochondria in extracellular vesicles.

Cartilage and other skeletal soft tissues heal poorly after injury, in part due to their lack of vascularity and low metabolic rate. No pharmacologic approaches have proven effective in preventing chronic degenerative disease after joint injury. Mesenchymal stromal cells (MSCs) have been investigated for their ability to treat pain associated with osteoarthritis (OA) and preserve articular cartilage. Limitations of MSCs include variability in cell phenotype, low engraftment and retention rates, and inconsistent clinical outcomes. Therefore, acellular biologic therapies such as extracellular vesicles (EVs) are currently being investigated. MSC-derived EVs have been found to replicate many of the therapeutic effects of their cells of origin, but the mechanisms driving this remain unclear. Recent evidence in non-orthopedic tissues suggests MSCs can rescue injured cells by donating mitochondria, restoring mitochondrial function in recipient cells, preserving cell viability, and promoting tissue repair. Our group hypothesized that MSCs package mitochondria for export into EVs, and that these so-called "mitoEVs" could provide a delivery strategy for cell-free mitochondria-targeted therapy. Therefore, the goals of this study were to: 1) characterize the vesicle fractions of the MSCs secretome with respect to mitochondrial cargoes, 2) determine if MSC-EVs contain functional mitochondria, and 3) determine if chondrocytes can take up MSC-derived mitoEVs. We isolated exosome, microvesicle, and vesicle-free fractions from MSC-conditioned media. Using a combination of dynamic light scattering and nanoparticle tracking, we determined that MSC-EV populations fall within the three size categories typically used to classify EVs (exosomes, microvesicles, apoptotic bodies). Fluorescent nanoparticle tracking, immunoblotting, and flow cytometry revealed that mitochondrial cargoes are abundant across all EV size populations, and mitoEVs are nearly ubiquitous among the largest EVs. Polarization staining indicated a subset of mitoEVs contain functional mitochondria. Finally, flow cytometry and fluorescent imaging confirmed uptake of mitoEVs by chondrocytes undergoing rotenone/antimycin-induced mitochondrial dysfunction. These data indicate that MSCs package intact, functional mitochondria into EVs, which can be transferred to chondrocytes in the absence of direct cell-cell interactions. This work suggests intercellular transfer of healthy MT to chondrocytes could represent a new, acellular approach to augment mitochondrial content and function in poorly-healing avascular skeletal soft tissues.

Surgical outcome of scleral buckling compared with scleral buckling with vitrectomy for treatment of macula-off retinal detachment.

BACKGROUND AND OBJECTIVE: To compare the surgical outcome of scleral buckling (group 1) versus scleral buckling with pars plana vitrectomy (group 2) for the repair of macula-off rhegmatogenous retinal detachment without proliferative vitreoretinopathy. PATIENTS AND METHODS: A retrospective chart review was performed. RESULTS: Eighty-three patients were identified in group 1 and 63 patients in group 2. Presenting visual acuity was 4/200 in group 1 and 3/200 in group 2. Median duration of detachment prior to surgery was 5 days in group 1 and 6 days in group 2. There was no statistical difference in best-corrected (P = .59) or most recent (P = .75) visual acuity between groups. Median best-corrected visual acuity was 20/30 and median most recent visual acuity was 20/40 in both groups. Significantly more additional procedures were performed in group 1 than in group 2 (21.7% vs 7.9%, respectively; P = .024). The final reattachment rate was 96.4% in group 1 and 98.4% in group 2. Proliferative vitreoretinopathy developed in 15.7% of patients in group 1 and 4.8% in group 2 (P= .037). CONCLUSION: Visual outcome of scleral buckling is similar to scleral buckling with pars plana vitrectomy for the treatment of macula-off rhegmatogenous retinal detachment in patients without proliferative vitreoretinopathy. Patients undergoing scleral buckling only are at an increased risk of developing proliferative vitreoretinopathy and requiring additional procedures.

Long-term follow-up of surgical removal of extensive peripapillary choroidal neovascularization in presumed ocular histoplasmosis syndrome.

PURPOSE: To report the long-term visual outcomes of surgical removal of extensive peripapillary choroidal neovascularization associated with presumed ocular histoplasmosis syndrome (POHS). DESIGN: Long-term retrospective review. Follow-up ranged from 14 to 139 months (mean, 68). PARTICIPANTS: Forty consecutive eyes (in 35 patients) undergoing surgical removal of extensive peripapillary choroidal neovascularization associated with POHS at the Barnes Retina Institute between May 1992 and December 2003 were included in this review. Patient age ranged from 5 to 73 years (median, 34.5). All eyes were ineligible for laser treatment by Macular Photocoagulation Study criteria. INTERVENTION: Pars plana vitrectomy and surgical removal of choroidal neovascularization were performed. MAIN OUTCOME MEASURES: Determination of Snellen best-corrected visual acuity (BCVA), funduscopic examination, and intravenous fluorescein angiography were done before surgery and at regular intervals after surgery. RESULTS: In the 23 eyes with subfoveal extension of peripapillary choroidal neovascularization, preoperative BCVA ranged from 20/25 to counting fingers (CF) at 2 feet (median, 20/200). Final postoperative BCVA ranged from 20/15 to CF at 2 feet (median, 20/50). Of 23 eyes, 18 achieved stable or improved BCVA from the preoperative to the final postoperative examination; only 5 eyes had > or =2 lines of decreased BCVA. Overall, 11 of 23 eyes achieved > or =20/40 BCVA at the final postoperative examination. In the 17 eyes in which choroidal neovascularization remained extrafoveal, preoperative BCVA ranged from 20/20 to 20/400 (median, 20/60). Final BCVA ranged from 20/20 to 20/200 (median, 20/20). Of 17 eyes, 15 achieved stable or improved BCVA from preoperative to final postoperative examination; only 2 eyes had > or =2 lines of decreased BCVA. Overall, 14 of 17 eyes achieved > or =20/40 BCVA at the final postoperative examination. CONCLUSIONS: The data from this small retrospective study suggest that surgical removal may provide visual benefit in selected cases of extensive peripapillary choroidal neovascularization associated with POHS. Surgical removal of extensive peripapillary choroidal neovascularization does appear preferable to photoablation. Given the likelihood of multiple treatments with photodynamic therapy or anti-vascular endothelial growth factor therapies, surgical removal provides a potentially efficacious treatment with low recurrence rates and good visual results.

Intravitreal bevacizumab for choroidal neovascularization in ocular histoplasmosis.

PURPOSE: To define the role of intravitreal bevacizumab in individuals with choroidal neovascularization (CNV) resulting from Ocular Histoplasmosis syndrome (OHS). DESIGN: Retrospective chart review of a surgical therapy. METHODS: We reviewed the course of 28 eyes of 28 patients who underwent intravitreal injection of bevacizumab for treatment of CNV secondary to OHS. Outcome was measured by pretreatment and posttreatment visual acuity (VA). RESULTS: The average pretreatment logarithm of the minimum angle of resolution (logMAR) VA was 0.65 (Snellen equivalent of 20/88). Mean follow-up was 22.43 weeks with an average of 1.8 intravitreal injections. Average final logMAR VA was 0.43 (Snellen equivalent of 20/54). Twenty eyes (71%) experienced an increase in central VA, whereas four eyes (14%) were unchanged and four eyes (14%) experienced a decrease in vision. CONCLUSIONS: Intravitreal bevacizumab may improve or stabilize VA in a significant majority of patients with neovascular complications of OHS (24 eyes [85.7%] in our study population).

Penetration pharmacokinetics of topically administered 0.5% moxifloxacin ophthalmic solution in human aqueous and vitreous.

OBJECTIVE: To investigate the penetration of 0.5% moxifloxacin hydrochloride into the aqueous and vitreous after topical administration in humans. METHODS: A prospective, nonrandomized study of 20 patients scheduled for vitrectomy surgery between September 1 and December 31, 2003. Aqueous and vitreous samples were obtained and analyzed after topical administration of 0.5% moxifloxacin hydrochloride, every 2 hours (q2h) or every 6 hours (q6h), for 3 days before surgery. Assays were performed using high-performance liquid chromatography. RESULTS: Mean +/- SD moxifloxacin concentrations in the q2h group for the aqueous (n = 9) and vitreous (n = 10) were 2.28 +/- 1.23 and 0.11 +/- 0.05 microg/mL, respectively. Mean +/- SD moxifloxacin concentrations in the q6h group for the aqueous (n = 10) and vitreous (n = 9) were 0.88 +/- 0.88 and 0.06 +/- 0.06 microg/mL, respectively. The minimum inhibitory concentration for 90% of isolates (MIC(90)) was far exceeded in the aqueous for a wide spectrum of key pathogens, whereas it was not exceeded in the vitreous for several organisms. However, the minimum inhibitory concentration for 50% of the isolates was exceeded in the q2h vitreous group for Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Bacillus cereus, and other gram-negative pathogens. CONCLUSIONS: The Endophthalmitis Vitrectomy Study revealed that 94.2% of isolates from postoperative endophthalmitis are gram-positive pathogens. Moxifloxacin has a spectrum of coverage that appropriately encompasses the most common organisms in endophthalmitis. The pharmacokinetic findings of this investigation show that relatively high aqueous levels can be achieved after topical administration. Further studies will help define the precise role of 0.5% moxifloxacin ophthalmic solution in the treatment of or prophylaxis against intraocular infections.

The safety profile of long-term, high-dose intraocular corticosteroid delivery.

PURPOSE: To report the feasibility and safety profile of 2-mg and 6-mg fluocinolone acetonide implants after long-term follow-up in eyes with choroidal neovascularization (CNV). DESIGN: Prospective, noncomparative, interventional case series of patients with non-age-related subfoveal choroidal neovascularization enrolled in a compassionate use protocol. METHODS: Sustained drug delivery devices containing either 2 mg (eight eyes) or 6 mg (six eyes) of fluocinolone acetonide were implanted through the pars plana into the vitreous cavity of 14 patients with predominantly classic, subfoveal CNV. The main outcome measures were complications related to the device. Secondary outcome measures were involution of established CNV, inhibition of recurrent CNV, and visual acuity. RESULTS: Patients had a diagnosis of ocular histoplasmosis (seven), myopic degeneration (four), angioid streaks (two), and punctate inner choroidopathy (one). Patients were followed for an average of 33 months (range, 16 to 40 months). All 14 eyes developed elevated intraocular pressure and cataract. Four eyes developed nonischemic central retinal vein occlusion. Complications required implant removal in 8 eyes. Ten of 14 eyes demonstrated involution of CNV or inhibition of recurrent CNV. Ten eyes had stable or improved visual acuity. Median initial visual acuity was 20/64. Median final visual acuity was 20/40. CONCLUSIONS: Long-term follow-up demonstrates a significant complication rate with the sustained release of high-dose intraocular corticosteroids. The complications are treatable, and eyes can retain good vision. This therapeutic approach warrants further study to identify if lower doses of corticosteroids may reduce the complication rate yet still be effective in treating ocular disease.

Surgical removal of peripapillary choroidal neovascularization associated with age-related macular degeneration.

BACKGROUND AND OBJECTIVE: To describe the results of surgical treatment of peripapillary choroidal neovascularization in age-related macular degeneration as an option to both laser photocoagulation and photodynamic therapy. PATIENTS AND METHODS: Retrospective review of patients with peripapillary choroidal neovascularization secondary to age-related macular degeneration who were not eligible for or refused laser photocoagulation. Patients without the diagnosis of age-related macular degeneration and those who had extension of their neovascularization subfoveally were excluded from the review. RESULTS: Eleven patients total were identified who met the specified inclusion criteria. The male to female ratio was 4:7, with an age range of 63 to 94 years (mean = 78 years). The mean area of involved retina temporal to the optic disc was 5 clock hours, with the distance of the temporal edge of the lesion from the fovea ranging from 100 to 2,000 microm. The mean duration of follow-up was 23 months, with 27% (3 of 11) experiencing recurrent choroidal neovascularization. The preoperative and postoperative visual acuity ranges were both 20/25 to counting fingers. Sixty-four percent (7 of 11) of patients had stable or improved visual acuity postoperatively, with a mean visual acuity change of 1 line visual improvement. CONCLUSION: In cases where photodynamic therapy and laser photocoagulation are not indicated, the surgical treatment of peripapillary choroidal neovascularization secondary to age-related macular degeneration may prove beneficial.

Intravitreal Aflibercept for Neovascular AMD: Short-Term Clinical Effects of Intravitreal Aflibercept Injection as a Predictor of Long-Term Results.

BACKGROUND AND OBJECTIVE: To study the relationship between early response to intravitreal aflibercept injection (IAI) for neovascular age-related macular degeneration (nAMD) and long-term visual outcomes PATIENTS AND METHODS: Seventeen patients with nAMD participated in this prospective clinical trial. All patients received three initial monthly IAIs, followed by IAIs at 8-week intervals. Study visits were scheduled at 1 week, followed by every 2 weeks for the first 3 months and then every 4 weeks until the conclusion of the study at 48 weeks. RESULTS: Eight eyes (47%) were dry on spectral-domain optical coherence tomography by week 2 (early responders), and the remaining nine eyes took an average of 7.5 weeks for fluid resolution (late responders). The mean change in best-corrected visual acuity (BCVA) at the final visit was +11.9 letters from baseline (P = .002). Average BCVA gain in early responders was +11.6 letters compared to +12.2 letters in late responders (P = .7). CONCLUSIONS: Although there was not a statistically significant correlation between early response to IAI and better long-term outcomes, both early and late responders maintained excellent visual outcomes at 48 weeks.

Surgery for subfoveal choroidal neovascularization in age-related macular degeneration: ophthalmic findings: SST report no. 11.

PURPOSE: To present visual acuity (VA) and related findings from patients enrolled in one of the Submacular Surgery Trials (SST) evaluating surgical removal versus observation of subfoveal choroidal neovascularization secondary to age-related macular degeneration (SST Group N Trial). DESIGN: Randomized clinical trial. PARTICIPANTS: Eligible patients had age-related macular degeneration with subfoveal choroidal neovascularization, some with a classic pattern on fluorescein angiography, and best-corrected VA (BCVA) of 20/100 to 20/800 in one eye (study eye) that had received no treatment in the macula. Any contiguous blood had to account for <50% of the total area occupied by the subfoveal lesion (maximum size, 9.0 disc areas [22.9 mm2]). METHODS: Randomization was stratified by VA and by clinical center. All patients were scheduled for study examinations at 3, 6, 12, and 24 months after enrollment for assessment of study outcomes. MAIN OUTCOME MEASURE: A successful outcome was defined a priori to be either improvement of BCVA or VA no more than 1 line (7 letters) worse than baseline at the 24-month examination. RESULTS: Of 454 patients enrolled, 228 study eyes were assigned to observation and 226 to surgery. The percentages of eyes that had successful outcomes were similar in the 2 arms: 44% assigned to observation and 41% assigned to surgery. Median VA losses from baseline to the 24-month examination were 2.1 lines (10.5 letters) in the observation arm and 2.0 lines (10 letters) in the surgery arm. Median VA declined from 20/100 at baseline to 20/400 at 24 months in both arms. No subgroup of patients was identified in which submacular surgery led to better VA outcomes. In the surgery arm, 55 (39%) of 142 initially phakic eyes had cataract surgery by the 24-month examination, compared with 6 (5%) of 133 eyes in the observation arm. Rhegmatogenous retinal detachment occurred in 12 surgery eyes (5%) and 1 observation eye. CONCLUSIONS: Submacular surgery, as performed in this clinical trial, did not improve or preserve VA for 24 months in more eyes than observation and is not recommended for patients with similar lesions. This article contains additional online-only material available at http://www.ophsource.com/periodicals/ophtha.

Surgery for hemorrhagic choroidal neovascular lesions of age-related macular degeneration: ophthalmic findings: SST report no. 13.

PURPOSE: To present best-corrected visual acuity (BCVA) findings and other clinical outcomes from eyes of patients enrolled in one of the Submacular Surgery Trials (SST) evaluating surgical removal versus observation of predominantly hemorrhagic subfoveal choroidal neovascularization (CNV) associated with age-related macular degeneration. DESIGN: Randomized clinical trial (SST Group B Trial). PARTICIPANTS: Eligible patients had subfoveal choroidal neovascular lesions greater than 3.5 disk areas (8.9 mm2) composed of at least 50% blood (either blood or CNV underlying the center of the foveal avascular zone) and BCVA of 20/100 to light perception in the study eye. INTERVENTION: Patients were assigned randomly at time of enrollment to observation or surgical removal of blood and any associated CNV. MAIN OUTCOME MEASURE: A successful outcome was defined a priori as either improvement in visual acuity (VA), no change in VA, or a decline in VA of no more than 1 line (7 letters) from baseline to the 24-month examination based on an intent-to-treat analysis. RESULTS: Of 336 patients enrolled, 168 were assigned to each treatment arm; treatment arms were balanced by baseline characteristics. Of 1501 expected examinations 3 months through 36 months after baseline, 1370 (91%) were performed. Loss of > or =2 lines (> or =8 letters) of VA occurred in 56% of surgery eyes, versus 59% of observation eyes examined at 24 months. Although severe loss of VA was not the primary outcome of interest, surgery more often prevented such loss: 36% in the observation arm versus 21% in the surgery arm at the 24-month examination (chi2 P = 0.004). Of initially phakic eyes, the cumulative percentage that had undergone cataract surgery by 24 months was 44% in the surgery arm, compared with 6% in the observation arm. Twenty-seven eyes (16%) in the surgical arm, compared with 3 eyes (2%) in the observation arm, had a rhegmatogenous retinal detachment (RD). CONCLUSIONS: Submacular surgery as performed in the SST Group B Trial did not increase the chance of stable or improved VA (the primary outcome of interest) and was associated with a high risk of rhegmatogenous RD, but did reduce the risk of severe VA loss in comparison with observation. This article contains additional online-only material available at http://www.ophsource.com/periodicals/ophtha.

Surgical removal vs observation for subfoveal choroidal neovascularization, either associated with the ocular histoplasmosis syndrome or idiopathic: I. Ophthalmic findings from a randomized clinical trial: Submacular Surgery Trials (SST) Group H Trial: SST Report No. 9.

OBJECTIVE: To present visual acuity findings and related outcomes from eyes of patients enrolled in a randomized trial conducted by the Submacular Surgery Trials (SST) Research Group (SST Group H Trial) to compare surgical removal vs observation of subfoveal choroidal neovascular lesions that were either idiopathic or associated with ocular histoplasmosis. METHODS: Eligible patients 18 years or older had subfoveal choroidal neovascularization (new or recurrent) that included a classic component on fluorescein angiography and best-corrected visual acuity of 20/50 to 20/800 in 1 eye ("study eye"). Patients were examined 3, 6, 12, and 24 months after enrollment to assess study outcomes and adverse events. Best-corrected visual acuity was measured by a masked examiner at the 24-month examination. A successful outcome was defined a priori as 24-month visual acuity better or no more than 1 line (7 letters) worse than at baseline. RESULTS: Among 225 patients enrolled (median visual acuity 20/100), 113 study eyes were assigned to observation and 112 to surgery. Forty-six percent of the eyes in the observation arm and 55% in the surgery arm had a successful outcome (success ratio, 1.18; 95% confidence interval, 0.89-1.56). Median visual acuity at the 24-month examination was 20/250 among eyes in the observation arm and 20/160 for eyes in the surgery arm. The prespecified subgroup of eyes with visual acuity worse than 20/100 at baseline (n = 92) had more successes with surgery; 31 (76%) of 41 eyes in the surgery arm vs 20 (50%) of 40 eyes in the observation arm examined at 24 months (success ratio, 1.53; 95% confidence interval, 1.08-2.16). Five (4%) of 111 eyes in the surgery arm subsequently had a rhegmatogenous retinal detachment. Twenty-seven (24%) of 112 initially phakic eyes in the surgery arm (none in the observation arm) had cataract surgery during follow-up, all among patients older than 50 years. Recurrent choroidal neovascularization developed by the 24-month examination in 58% of surgically treated eyes. CONCLUSIONS: Overall, findings supported no benefit or a smaller benefit to surgery than the trial was designed to detect. Findings support consideration of surgery for eyes with subfoveal choroidal neovascularization and best-corrected visual acuity worse than 20/100 that meet other eligibility criteria for the SST Group H Trial. Other factors that may influence the treatment decision include the risks of retinal detachment, cataract among older patients, and recurrent choroidal neovascularization and the possibility that additional treatment will be required after submacular surgery.

Pars plana vitrectomy in eyes containing a treated posterior uveal melanoma.

PURPOSE: To determine the safety of pars plana vitrectomy in eyes containing a treated posterior uveal melanoma. DESIGN: Interventional case series. METHODS: Retrospective case series of patients with posterior uveal melanoma who underwent pars plana vitrectomy. Complications, vitreous cytology, local tumor control, and metastasis were assessed. RESULTS: Nine patients met study criteria. Tumors were treated with (125)I plaque radiotherapy (seven patients) or transpupillary thermotherapy (two patients). Vitrectomy was performed for vitreous hemorrhage (five patients), macular pucker (two patients), macular hole (one patient), and rhegmatogenous retinal detachment (one patient). Vitrectomy was performed at a mean of 24.7 months (range, 7-47 months) after melanoma treatment. Dispersion of tumor cells at vitrectomy was not observed in any patients. Melanoma cells were detected in the vitreous aspirate in one of seven cases examined cytologically. This patient had intratumoral and vitreous hemorrhage before plaque radiotherapy, underwent combined vitrectomy/cataract extraction, and developed intraocular tumor dissemination 56 months after vitrectomy. No other patients developed intraocular tumor dissemination. At mean follow-up of 24 months (range, 3-63 months) after vitrectomy, none of the nine patients developed systemic metastasis. CONCLUSIONS: Pars plana vitrectomy rarely may lead to intraocular tumor dissemination, although the risk of this complication is probably low if the tumor has been treated and has responded to therapy before vitrectomy. Vitrectomy should be approached with caution if a vitreous hemorrhage is present, especially if the hemorrhage occurred before tumor treatment, as this may seed tumor cells into the vitreous cavity.

Human intraocular penetration pharmacokinetics of moxifloxacin 0.5% via topical and collagen shield routes of administration.

PURPOSE: To determine penetration of moxifloxacin 0.5% into human aqueous and vitreous via topical and collagen shield routes of administration. METHODS: Moxifloxacin 0.5% was administered prior to vitrectomy surgery through one of three routes: topical drops every 2 hours for 3 days, versus topical drops every 6 hours for 3 days, versus delivery using a 24-hour dissolvable cross-linked corneal collagen shield. Aqueous and vitreous moxifloxacin concentrations were assayed using high-performance liquid chromatography. RESULTS: Mean moxifloxacin concentrations in the every-2-hour group for aqueous (n = 9) and vitreous (n = 10) were 2.28 +/- 1.23 microg/mL and 0.11 +/- 0.05 microg/mL, respectively. Mean moxifloxacin concentrations in the every-6-hour group for aqueous (n = 10) and vitreous (n = 9) were 0.88 +/- 0.88 microg/mL and 0.06 +/- 0.06 microg/mL, respectively. Levels of minimum inhibitory concentration at which 90% of isolates are inhibited (MIC90) were far exceeded in the aqueous for a wide spectrum of pathogens that most commonly cause postoperative endophthalmitis. Moxifloxacin concentration in the vitreous did not exceed the MIC90 for several key organisms. Delivery of moxifloxacin via a collagen shield revealed a mean aqueous concentration of 0.30 +/- 0.17 microg/mL 4 hours after placement (n = 5). Vitreous levels at 4 hours, as well as aqueous and vitreous levels at 24 hours, were negligible using this route of administration. CONCLUSIONS: The findings of this investigation reveal that topically administered moxifloxacin 0.5% can achieve relatively high aqueous concentrations. Although aqueous moxifloxacin levels achieved through the use of a collagen shield delivery device are lower, there are several advantages to this route of delivery that make it appealing in the immediate postoperative period. Future studies will be needed to precisely define the role of fourth-generation fluoroquinolones and presoaked collagen shields in the prophylaxis or management of intraocular infections.

Attentional control and asymmetric associative priming.

Participants completed a battery of 3 attentional control (AC) tasks (OSPAN, antisaccade, and Stroop, as in Hutchison, 2007) and performed a lexical decision task with symmetrically associated (e.g., sister-brother) and asymmetrically related primes and targets presented in both the forward (e.g., atom-bomb) and backward (e.g., fire-blaze) directions at either a 250- or 1,250-ms stimulus onset asynchrony (SOA). As predicted, high-AC individuals showed greater forward priming than low-AC individuals. There was also some evidence that low-AC individuals exhibited greater backward priming than high-AC individuals, and this difference was most pronounced in the later portions of the reaction time distribution. These results suggest that high-AC individuals are more likely to prospectively generate and maintain expected targets in working memory, whereas low-AC individuals are more likely to rely on a retrospective semantic matching or integration processes. These findings support the distinction between proactive and reactive forms of cognitive control embodied in Braver, Gray, and Burgess's (2007) dual-mechanism model of cognitive control.

Type IIb bony mallet finger: is anatomical reduction of the fracture necessary?

One-third of all mallet fingers are associated with a fracture. Many different management strategies have been described. Some authors recommend nonsurgical management for all mallet fractures. In contrast, others suggest mandatory open reduction and internal fixation for bony mallet injuries with a large displaced dorsal fragment and associated distal interphalangeal (DIP) joint subluxation. We retrospectively studied 3 cases of a mallet fracture with a large displaced dorsal fragment and subsequent DIP joint subluxation managed with closed reduction using only percutaneous pinning of the DIP joint. All 3 patients had satisfactory pain-free and functional clinical outcomes at their particular follow-up (4, 6, or 19 months). Closed reduction and internal fixation of the subluxated joint using only Kirschner wires produced satisfactory outcomes for the 3 type IIb bony mallet fingers. Anatomical reduction of the fracture may be unnecessary in patients such as those in our case series. One aim of this pilot study is to justify larger, prospective studies.

Alloplastic augmentation of the facial skeleton: an occasional adjunct or alternative to orthognathic surgery.

BACKGROUND: Alloplastic implants can be adjunctive to orthognathic surgery by correcting contour irregularities or disharmonies after skeletal movements. Implant augmentation can also simulate the visual effect of osteotomies in patients with skeletal deficiencies whose occlusion is normal or has been corrected. Although sometimes it is an adjunct or an alternative to facial skeletal rearrangements, facial skeleton augmentation is not a substitute for orthognathic surgery. METHODS: Alloplastic implants designed specifically to augment the infraorbital rim can correct the residual upper midface deficiency remaining after Le Fort I maxillary advancement. When used with paranasal and malar implants, they can simulate the visual effect of the Le Fort III osteotomy with advancement. Paranasal implants can simulate the appearance after Le Fort I advancement. Mandible and extended chin implants can correct skeletal irregularities and deficiencies after sagittal and horizontal osteotomies. They can also simulate the visual effect of these osteotomies. RESULTS: The application of these concepts has been effective, with low morbidity, in 294 patients. No implants extruded or migrated. Eight patients (3 percent) had early postoperative infections. There were no late infections. Ten of 108 patients (9 percent) with midface implants had implant visibility with time. CONCLUSION: Alloplastic augmentation of the facial skeleton can be a useful adjunct or an alternative to orthognathic surgical procedures in situations when the occlusion is normal or has been corrected.