Scleral-fixated intraocular lens implants-evolution of surgical techniques and future developments.

Varied options are available for the implantation of secondary intraocular lens implants in the absence of zonular or capsular support. Loss of the capsule can occur in the context of complicated cataract surgery, trauma or inherited conditions such as Marfan syndrome or pseudoexfoliation. Approaches to overcome this include optical measures such as the use of spectacles or contact lenses, and surgical therapy incorporating the use of anterior chamber, iris-fixated or scleral-fixated lenses. Surgical techniques to implant scleral-fixated lenses have undergone various modifications, since the first publication of sutured intrascleral fixation described in the 1980s. However, despite the advances in surgical techniques, studies are limited either by their retrospective nature, small sample size and most importantly small duration of follow-up. This comprehensive review aims to amalgamate the evolution of various surgical techniques with regards to intrascleral lens fixation and suggests areas for future development.

Ranibizumab pretreatment in diabetic vitrectomy: a pilot randomised controlled trial (the RaDiVit study).

PurposeOur aim was to evaluate the impact of intravitreal ranibizumab pretreatment on the outcome of vitrectomy surgery for advanced proliferative diabetic retinopathy. The objective was to determine the feasibility of a subsequent definitive trial and estimate the effect size and variability of the outcome measure.Patients and methodsWe performed a pilot randomised double-masked single-centre clinical trial in 30 participants with tractional retinal detachment associated with proliferative diabetic retinopathy. Seven days prior to vitrectomy surgery, participants were randomly allocated to receive either intravitreal ranibizumab (Lucentis, Novartis Pharmaceuticals UK Ltd, Frimley, UK) or subconjunctival saline (control). The primary outcome was best-corrected visual acuity 12 weeks following surgery.ResultsAt 12 weeks, the mean (SD) visual acuity was 46.7 (25) ETDRS letters in the control group and 52.6 (21) letters in the ranibizumab group. Mean visual acuity improved by 14 (31) letters in the control group and by 24 (27) letters in the ranibizumab group. We found no difference in the progression of tractional retinal detachment prior to surgery, the duration of surgery, or its technical difficulty. Vitreous cavity haemorrhage persisted at 12 weeks in two of the control group but none of the ranibizumab group.ConclusionRanibizumab pretreatment may improve the outcome of vitrectomy surgery for advanced proliferative diabetic retinopathy by reducing the extent of post-operative vitreous cavity haemorrhage. However, the effect size appears to be modest; we calculate that a definitive study to establish a minimally important difference of 5.9 letters at a significance level of P<0.05 would require 348 subjects in each arm.

Ethnic variation in primary idiopathic macular hole surgery.

PurposeThe purpose of the study was to investigate the role of ethnicity on idiopathic macular holes (IMH) structure and surgical outcome. This was a retrospective review.Patients and methodsConsecutive patients undergoing primary IMH surgery at two surgical sites of Moorfields Eye Hospital (London, UK) between April 2012 and June 2013. The main outcome measure was post surgical anatomical closure of IMH.ResultsTwo hundred and twenty two primary IMH surgeries were undertaken. A standard procedure including pars plana vitrectomy, internal limiting membrane peeling, and gas tamponade was undertaken for all cases. 61.3% of patients were Caucasian, 21.2% were South Asian, and 16% were Afro-Caribbean. The mean minimum linear diameter (MLD) for our cohort was 434.6 mcm. Mean MLD was 395.3 mcm in Caucasian patients, 490.0 mcm in South Asians (P=0.006), and 491.4 mcm in Afro-Caribbeans (P=0.007). Regression analysis demonstrated that MLD and Afro-Caribbean ethnicity were independent significant risk factors for surgical failure (OR: 1.01, P<0.001 and OR: 5.73, P=0.008, respectively).ConclusionSouth Asian and Afro-Caribbean patients present with larger IMH than Caucasians. In addition to IMH diameter, Afro-Caribbean ethnicity is an independent risk factor for surgical failure.

The role of membrane-inner retina adherence in predicting simultaneous internal limiting membrane peeling during idiopathic epiretinal membrane surgery.

PurposeTo correlate the frequency and extent of simultaneous inadvertent internal limiting membrane (ILM) peeling during idiopathic epiretinal membrane (ERM) removal with characteristics of ERM adherence demonstrated on pre-operative spectral domain optical coherence tomography (SD-OCT).Patients and methodsThis is a prospective, observational, case series of patients undergoing pars plana vitrectomy for idiopathic ERM. Inner retina-ERM adhesion was categorized as focal, broad or complete in five anatomic locations at macular area based on preoperative SD-OCT findings. The extent of spontaneous ILM peeling was quantified on a scale 0-100% in each of the aforementioned anatomic locations by the operating surgeons who were masked to the OCT characteristics. All operations were recorded with a high definition recording system and the area of simultaneous ILM peel was quantified by a second masked observer. The final extent of spontaneous ILM peel was calculated as the average of the two scores.ResultsThirty consecutive subjects who underwent surgery for idiopathic ERM were included in the study. Evidence of simultaneous ILM peeling was identified in 80.3% of individuals. With regards to the type of ERM-macula adhesion, inadvertent ILM peel was observed in 70% of the patients who pre-operatively showed complete adhesion, in 43% with broad adhesion and in only 21% with focal adhesion (P<0.001). The extent of the spontaneous ILM peel during removal of ERM was also significantly dependent on the type of ERM-inner retina adhesion. Total simultaneous ILM peel was observed in 59% of locations with complete ERM-macula adhesion but only in 22% and 7% of locations with broad and focal adhesion respectively (P<0.001).ConclusionsSimultaneous ILM peel is a frequent occurrence during ERM surgery, especially when there is complete or broad ERM adherence to the macula. The type of ERM-inner retina adhesion represents a valid predictor of the extent of simultaneous ILM peel during removal of ERM. Thorough evaluation of preoperative OCT may be a useful tool in determining a safer, more simplistic strategy in ERM surgery.

Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder.

Although the physiologic role of muscarinic receptors in bladder function and the therapeutic efficacy of muscarinic antagonists for the treatment of overactive bladder are well established, the role of ß3-adrenergic receptors (ß3ARs) and their potential as therapeutics is just emerging. In this manuscript, we characterized the pharmacology of a novel ß3AR agonist vibegron (MK-4618, KRP-114V) and explored mechanistic interactions of ß3AR agonism and muscarinic antagonism in urinary bladder function. Vibegron is a potent, selective full ß3AR agonist across species, and it dose dependently increased bladder capacity, decreased micturition pressure, and increased bladder compliance in rhesus monkeys. The relaxation effect of vibegron was enhanced when combined with muscarinic antagonists, but differentially influenced by muscarinic receptor subtype selectivity. The effect was greater when vibegron was co-administered with tolterodine, a nonselective antagonist, compared with coadministration with darifenacin, a selective M3 antagonist. Furthermore, a synergistic effect for bladder strip relaxation was observed with the combination of a ß3AR agonist and tolterodine in contrast to simple additivity with darifenacin. To determine expression in rhesus bladder, we employed a novel ß3AR agonist probe, [3H]MRL-037, that selectively labels ß3 receptors in both urothelium and detrusor smooth muscle. Vibegron administration caused a dose-dependent increase in circulating glycerol and fatty acid levels in rhesus and rat in vivo, suggesting these circulating lipids can be surrogate biomarkers. The translation of our observation to the clinic has yet to be determined, but the combination of ß3AR agonists with M2/M3 antimuscarinics has the potential to redefine the standard of care for the pharmacological treatment of overactive bladder.

Differential anti-thrombotic benefit and bleeding risk profiles of antagonists of protease-activated receptor 1 and 4 in Cynomolgus Macaques.

Platelet activation plays a crucial role in hemostasis and thrombosis. Thrombin, the most potent stimulus of platelet activation, mediates platelet activation via the protease activated receptors (PARs). The platelet PAR repertoire in mediating thrombin's action differs across species. Only nonhuman primate (NHP) platelet activation is known to be similar to humans, mediated by PAR1 and PAR4, hence limiting translational in vivo studies of PAR's role in thrombosis and hemostasis to NHPs. Earlier studies have demonstrated a range of distinct in vitro activities of PAR1 and 4 in platelet activation yet the implications of these events in vivo is unclear. The objective of this study is to investigate and compare the roles of PAR1 and PAR4 in hemostasis and thrombosis in a relevant animal species. NHP models for pharmacokinetic, ex vivo platelet aggregation responses, FeCI3 injury-mediated arterial thrombosis and template bleeding were developed in Cynomolgus Macaques. Potent and selective small molecule antagonists of PAR1 and PAR4 were characterized in an array of in vitro assays, and subsequently examined head-to-head in the NHP models. Treatment of NHPs with antagonists of PAR1 or PAR4 both resulted in strong inhibition of ex vivo platelet aggregation. At doses that led to similar inhibition of platelet aggregation, animals treated with the PAR4 antagonist showed similar levels of anti-thrombotic efficacy, but longer bleeding times, compared to animals treated with the PAR1 antagonist. These findings suggest that PAR1 antagonism will likely produce a larger therapeutic index (ie. a larger anti-thrombotic efficacy over bleeding risk margin) than PAR4 antagonism.

The design and validation of an optical coherence tomography-based classification system for focal vitreomacular traction.

PURPOSE: To develop and validate a classification system for focal vitreomacular traction (VMT) with and without macular hole based on spectral domain optical coherence tomography (SD-OCT), intended to aid in decision-making and prognostication. METHODS: A panel of retinal specialists convened to develop this system. A literature review followed by discussion on a wide range of cases formed the basis for the proposed classification. Key features on OCT were identified and analysed for their utility in clinical practice. A final classification was devised based on two sequential, independent validation exercises to improve interobserver variability. RESULTS: This classification tool pertains to idiopathic focal VMT assessed by a horizontal line scan using SD-OCT. The system uses width (W), interface features (I), foveal shape (S), retinal pigment epithelial changes (P), elevation of vitreous attachment (E), and inner and outer retinal changes (R) to give the acronym WISPERR. Each category is scored hierarchically. Results from the second independent validation exercise indicated a high level of agreement between graders: intraclass correlation ranged from 0.84 to 0.99 for continuous variables and Fleiss' kappa values ranged from 0.76 to 0.95 for categorical variables. CONCLUSIONS: We present an OCT-based classification system for focal VMT that allows anatomical detail to be scrutinised and scored qualitatively and quantitatively using a simple, pragmatic algorithm, which may be of value in clinical practice as well as in future research studies.

Platelet transfusion reverses bleeding evoked by triple anti-platelet therapy including vorapaxar, a novel platelet thrombin receptor antagonist.

Vorapaxar is a novel protease-activated receptor-1 (PAR-1) antagonist recently approved for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Patients who received vorapaxar in addition to standard of care antiplatelet therapy had an increased incidence of major bleeding events compared with placebo. To assess whether platelet transfusion can restore hemostasis in primates on triple antiplatelet therapy, template bleeding times were assessed concurrently in the buccal mucosa, finger pad, and distolateral tail of anesthetized cynomolgus macaques to evaluate bleeding with vorapaxar as either monotherapy or in combination with aspirin or aspirin and clopidogrel. Aspirin (5mg/kg, IV) or vorapaxar (1mg/kg, PO) alone had no significant effect on bleeding times in the three vascular beds examined. A modest (<2-fold) increase in bleeding time was achieved in the three beds with the dual combination of aspirin and vorapaxar. Major increases in bleeding time were achieved in the three beds with the triple combination of aspirin (5mg/kg, IV), vorapaxar (1mg/kg, PO), and clopidogrel (1mg/kg, PO). Transfusion of fresh human platelet rich plasma, but not platelet poor plasma, reversed the increase in bleeding time in the triple therapy group. Transfusion of human platelets may be a viable approach in situations requiring a rapid reversal of platelet function in individuals treated with triple anti-platelet therapy that includes vorapaxar.

Pilot randomised controlled trial of face-down positioning following macular hole surgery.

OBJECTIVE: This was a pilot randomised controlled trial (RCT) to investigate the effect of post-operative face-down positioning on the outcome of macular hole surgery and to inform the design of a larger definitive study. METHODS: In all, 30 phakic eyes of 30 subjects with idiopathic full-thickness macular holes underwent vitrectomy with dye-assisted peeling of the ILM and 14% perfluoropropane gas. Subjects were randomly allocated to posture face down for 10 days (posturing group) or to avoid a face-up position only (non-posturing group). The primary outcome was anatomical hole closure. RESULTS: Macular holes closed in 14 of 15 eyes (93.3%; 95% confidence interval (CI) 68-100%) in the posturing group and in 9 of 15 (60%; 95% CI 32-84%) in the non-posturing group. In a subgroup analysis of outcome according to macular hole size, all holes smaller than 400 µm closed regardless of posturing (100%). In contrast, holes larger than 400 µm closed in 10 of 11 eyes (91%; 95% CI 58-99%) in the posturing group and in only 4 of 10 eyes (40%; 95% CI 12-74%) in the non-posturing group (Fisher's exact test P=0.02). CONCLUSION: Post-operative face-down positioning may improve the likelihood of macular hole closure, particularly for holes larger than 400 µm. These results support the case for a RCT.

Plasma lipid profiling across species for the identification of optimal animal models of human dyslipidemia.

In an attempt to understand the applicability of various animal models to dyslipidemia in humans and to identify improved preclinical models for target discovery and validation for dyslipidemia, we measured comprehensive plasma lipid profiles in 24 models. These included five mouse strains, six other nonprimate species, and four nonhuman primate (NHP) species, and both healthy animals and animals with metabolic disorders. Dyslipidemic humans were assessed by the same measures. Plasma lipoprotein profiles, eight major plasma lipid fractions, and FA compositions within these lipid fractions were compared both qualitatively and quantitatively across the species. Given the importance of statins in decreasing plasma low-density lipoprotein cholesterol for treatment of dyslipidemia in humans, the responses of these measures to simvastatin treatment were also assessed for each species and compared with dyslipidemic humans. NHPs, followed by dog, were the models that demonstrated closest overall match to dyslipidemic humans. For the subset of the dyslipidemic population with high plasma triglyceride levels, the data also pointed to hamster and db/db mouse as representative models for practical use in target validation. Most traditional models, including rabbit, Zucker diabetic fatty rat, and the majority of mouse models, did not demonstrate overall similarity to dyslipidemic humans in this study.

Transurethral bladder catheterization of male rhesus macaques: a refinement of approach.

BACKGROUND: Successful transurethral bladder catheterization in male non-human primates can be challenging. An optimized approach for consistent and reproducible catheterization using a refined technique is described. METHODS: Under sedated and non-sedated conditions, transurethral bladder catheterization was performed on 25 male rhesus macaques of varying ages and body weights over time. A refined technique ensuring optimal lubrication of the urethral canal prior to catheter insertion was utilized along with various single and multiple lumen catheters. RESULTS: All animals were successfully catheterized. Sixty-five catheterization sessions were conducted with a high overall success rate (100%). The incidence of catheter (10%) and post-catheterization (2%) complications was low. CONCLUSIONS: The urinary bladder of male rhesus can be reliably and reproducibly catheterized with minimal complication using this approach. Successful catheterization was facilitated by thorough urethral lubrication and using suitable catheters. In addition, this approach may be performed without sedation on thoroughly conditioned animals.

Comparative analysis of the effects of antimuscarinic agents on bladder functions in both nonhuman primates and rodents.

Both the physiological role of muscarinic receptors for bladder function and the therapeutic efficacy of antimuscarinic agents for overactive bladder syndrome are well documented. We investigated the effect of antimuscarinic agents with different subtype selectivity on urodynamic parameters in nonhuman primates and rodents and compared plasma levels of these agents between species. Anesthetized rhesus monkeys were transurethrally catheterized, and the bladder was infused with saline. Urodynamic parameters were measured before and after intravenous drug administration. Tolterodine (nonselective) and oxybutynin (moderately M(3)-selective) increased bladder capacity at lower doses than those required to decrease micturition pressure. However, higher doses of darifenacin (M(3)-selective) were needed to increase the bladder capacity than those needed to decrease the micturition pressure. In rats, tolterodine had no effect on the bladder capacity but decreased the micturition pressure at all of the doses administered. Oxybutynin also decreased micturition pressure and increased bladder capacity at the highest dose. Plasma levels of these drugs overlap in both species. These results suggest that, in addition to the M(3) receptor, other muscarinic receptor subtypes contribute to regulate bladder storage function in nonhuman primates, since less subtype-selective tolterodine and oxybutynin showed higher specificity to the bladder capacity effect than the effect on micturition pressure compared with M(3)-selective darifenacin. In addition, the role of muscarinic receptors in bladder storage function varies between primates and rodents. Compared with rodents, muscarinic receptors may play a more active role during the storage phase to regulate the functional bladder capacity in primates.

Retinal detachment repair by vitrectomy: simplified formulae to estimate the risk of failure.

AIM: Devise simplified formulae, using preoperative clinical data, to give risk estimates of (1) failure and (2) proliferative vitreoretinpathy (PVR) following primary retinal detachment repair by vitrectomy. METHODS: 641 patients were analysed as part of an RCT investigating use of 5-fluorouracil and low-molecular-weight heparin. Treatment status had no effect on success rates and did not therefore form part of the analyses. Preoperative risk factors for surgical failure and for PVR within 6 months of retinal detachment surgery were identified, and a multiple variable logistic regression model developed. Further analyses were performed to devise a simple points system to produce risk estimates of failure. RESULTS: Three risk factors were related to failure-previous lens extraction (p=0.046), grade C PVR (p=0.039) and extent of detachment (p<0.001). Three risk factors were also related to failure due to PVR-vitreous haemorrhage (p=0.088), grade C PVR (p=0.044) and extent of detachment (p<0.001). There was good agreement between risk estimates produced by the points system and those calculated directly using a multivariate regression model. The points-system model gave an area under the receiver operating characteristic curve of 0.658. The receiver operating characteristic curve for the PVR model gave an area under the curve of 0.8399 suggesting greater diagnostic value. CONCLUSIONS: A simple points system may be used as a clinical guide to identify patients at higher risk of failure following retinal detachment repair by vitrectomy. This may help clinicians select appropriate surgical approaches and stratify cases in research and surgical training.

A pilot randomised controlled trial comparing the post-operative pain experience following vitrectomy with a 20-gauge system and the 25-gauge transconjunctival system.

AIMS: To compare post-operative pain following 25-gauge (25G) and 20-gauge (20G) vitrectomy in the first week following surgery. METHODS: The study was a pilot randomised controlled trial with patients masked to the treatment allocation. Post-operative pain was assessed using both a visual scale and verbal pain scores for 1 week following surgery. Additional data collected included intraocular pressure (IOP), time taken to perform the surgical procedure, per-operative and post-operative complications, and dropout rates. RESULTS: Forty patients were recruited for the study: 21 randomised to 20G vitrectomy and 19 to 25G. In the first 12 h following surgery, presence of significant post-operative pain (defined as >1 cm on a visual analogue scale) was similar in both 20G (50%) and 25G (53%) patients. In the first week following surgery, 38 of the 527 scores (7.2%) were >1 (median 2.1, IQR 1.3-3) cm; however, there was evidence that "significant pain" was experienced more commonly in the 20G group. There was no statistical difference in the time taken to complete the surgical procedure, although in the 25G group the time from first incision to the start of vitrectomy was significantly shorter (p = 0.043) and in the 20G group the time taken to complete the vitrectomy was less (p = 0.047). Post-operative hypotony (IOP <6 mmHg) was observed in 25% of patients in the 25G group. No patients required additional surgery for hypotony. CONCLUSION: There was evidence that 25G resulted in less patient discomfort. However, pain was not a prominent feature in either group. We failed to find a significant advantage in 25G for patients or surgeons.

Use of a rigid endoscope to teach urethral catheterization of the female dog.

Urethral catheterization of the female dog is known to be a challenging procedure. The authors describe a catheterization technique in which they use a rigid endoscope to visualize the canine urogenital vestibule during the procedure. The technique is particularly helpful as a training tool for students who are not yet experienced with the canine anatomy. The endoscope is attached to a video camera and monitor, allowing others to observe and learn the procedure.

Histological analysis of retinas sampled during translocation surgery: a comparison with normal and transplantation retinas.

AIMS: To carry out a histopathological analysis of retinal specimens of patients undergoing translocation surgery for age-related macular degeneration (ARMD). METHODS: A histopathological analysis, using confocal microscopy, was performed on six retinal specimens. Results were compared with those from two further retinal specimens, collected during RPE transplantation, to control for the effects of vitrectomy and ARMD. In addition, a third control specimen from a cadaver with no history of ophthalmic disease was also analysed. RESULTS: In the translocation specimens, rods and cones were relatively well preserved but showed reduced density and outer segment length. In four specimens, there were focal areas of rod opsin redistribution to the inner segment, but this was not observed in the controls. Staining with calbindin was decreased in cones compared with controls but normal in horizontal and amacrine cells. Rod bipolar cells were mildly disorganised, and in one there was evidence of neurite sprouting. Glial fibrillar acidic protein was raised in both translocation and transplantation retinae but not in the cadaver control. CONCLUSIONS: In this study, there was little evidence of cellular injury following iatrogenic detachment; however, the rate of PVR following translocation surgery infers that cellular events set in motion may continue despite early reattachment.

Predictive clinical features and outcomes of vitrectomy for proliferative diabetic retinopathy.

OBJECTIVE: To study the preoperative characteristics, complications and outcomes of vitrectomy for proliferative diabetic retinopathy and to identify any factors that may predict visual outcome. METHODS: Prospective study of 174 consecutive vitrectomies in 148 patients, with a minimum follow-up of 4 months. RESULTS: 41 (27.7%) patients had a vision of <6/60 in their better eye at presentation. Posterior retinal breaks occurred in 47 (27.0%) eyes. Postoperative complications included vitreous cavity haemorrhage in 37 (22.0%) eyes, retinal detachment in five eyes (3.0%), and rubeotic glaucoma in five eyes (3.0%). 124 (74.7%) eyes improved by at least 0.3 LogMAR units, and 15 (9.0%) worsened by at least 0.3 LogMAR units. 119 (71.7%) eyes had a visual acuity of 6/60 or better, and 27 (16.3%) were counting fingers or worse. Only 16 (11.1%) patients had a vision of <6/60 in both eyes at latest follow-up. Preoperative vision in both the operated eye and the contralateral eye, macular detachment, and long-acting intraocular tamponade were independent predictors of poor postoperative vision, but this model accounted for only a small proportion of the observed variation in outcomes. CONCLUSIONS: Major complications are rare after vitrectomy for proliferative diabetic retinopathy, and >70% of eyes will regain vision of 6/60 or better. Visual outcomes remain unpredictable.

Randomized controlled trial of combined 5-Fluorouracil and low-molecular-weight heparin in the management of unselected rhegmatogenous retinal detachments undergoing primary vitrectomy.

OBJECTIVE: To determine the efficacy of a combination of 5-fluorouracil (5FU) and low-molecular-weight heparin (LMWH) in the treatment of unselected rhegmatogenous retinal detachment (RRD) undergoing primary vitrectomy. DESIGN: Double-masked, prospective, randomized, placebo-controlled clinical trial. PARTICIPANTS: Six hundred forty-one patients presenting with primary RRD were recruited from 2 specialized vitreoretinal units-Moorfields Eye Hospital, London (n = 553) and St. Pauls Eye Unit, Liverpool (n = 88). INTERVENTION: All patients underwent primary vitrectomy and gas endotamponade. Adjuvant therapy in the treatment group consisted of 5 IU/ml LMWH and 200 mug/ml 5FU added to the perioperative infusion fluid. MAIN OUTCOME MEASURES: The primary outcome measure was retinal reattachment after primary vitrectomy without any reoperations at 6 months. Secondary outcome measures recorded at 6 months were the occurrence and grade of proliferative vitreoretinopathy (PVR), best-corrected visual acuity in logarithm of the minimum angle of resolution, intraocular pressure (mmHg), corneal clarity, and complications. RESULTS: The overall primary success rate was 84.4%; in the treatment group, the primary success rate was 82.3% compared with 86.8% in the placebo group (P = 0.12). At 6 months, the final complete anatomical reattachment rate was 97.9% in both treatment and placebo groups. The number of patients who failed due to the development of PVR was not statistically significant, 23 in the treatment group (7.0%) and 14 in the placebo group (4.9%) (P = 0.309). There was no significant difference in the mean visual acuity at 6 months in the placebo group (0.48) versus the treatment group (0.53; P = 0.072). The visual acuity at 6 months of patients presenting with a macula-sparing retinal detachment was significantly worse in the treatment group (P = 0.0091). There was no significant difference between the 2 groups in patients who presented with a macula involving retinal detachment (P = 0.896). CONCLUSIONS: Primary vitrectomy has a high anatomic and visual success rate for RRD. Adjuvant therapy with 5FU and LMWH does not improve the anatomic or visual success rate of unselected primary retinal detachments undergoing vitrectomy. After adjuvant therapy, a worse visual outcome was observed in patients presenting with macula-sparing retinal detachments. A combination of 5FU and LMWH should not be used routinely for primary RRD surgery.

Sphingosine-1-phosphate agonists increase macrophage homing, lymphocyte contacts, and endothelial junctional complex formation in murine lymph nodes.

The sphingosine-1-phosphate (S1P) receptor agonist, phosphorylated FTY720 (FTY-P), causes lymphopenia, lymphocyte sequestration in mesenteric lymph nodes (MLNs), and immunosuppression. Using multiple techniques to analyze MLN cells harvested from mice treated with S1P receptor agonists, we saw a redistribution of lymphocytes out of nodal sinuses and an expansion of follicles. Although changes in circulating monocytes were not observed with overnight exposure to FTY720, we saw a significant increase in S1P receptor 1 (S1P1)-expressing CD68+ macrophages in subcapsular sinuses of FTY-P-treated MLNs. This was confirmed by quantitative analysis of F4/80+ cells in MLN suspensions. The sinus volume and number of S1P1-positive cells within sinuses were also increased by FTY-P. High endothelial venules and lymphatic endothelium expressed high levels of S1P1, and treatment with FTY-P resulted in intense staining and colocalization of CD31, beta-catenin, and zona occludens 1 in junctions between sinus cells. Transmission electron microscopy showed that FTY-P greatly reduced lymphocyte microvilli and increased cell-cell contacts in the parenchyma. Immunoelectron microscopy revealed that intranodal lymphocytes lacked surface expression of S1P1, whereas S1P1 was evident on the surface and within the cytoplasm of macrophages, endothelial cells, and stromal cells. This subcellular pattern of intranodal receptor distribution was unchanged by treatment with FTY-P. We conclude that S1P1 agonists have profound effects on macrophages and endothelial cells, in addition to inducing lymphopenia.