Evidence-based guidelines for drug dosing in intravitreal injections in silicone oil-filled eyes: Pharmacokinetics, safety, and optimal dosage.

We evaluate the pharmacokinetics, safety, and optimal dosages of intravitreal agents in silicone oil (SO)-filled eyes, addressing challenges in administering such therapies. We assessed the pharmacological properties and safety profiles of intravitreal drugs in SO-filled eyes, deriving conclusions and guidance from available literature and expert consensus. Preclinical data suggest comparable half-lives of anti-vascular endothelial growth factoragents in SO-filled eyes, but clinical evidence is mainly from case reports and small series. Available research prioritizes standard dosages, particularly for bevacizumab (1.25 mg), supported by stronger evidence than aflibercept (2 mg) or ranibizumab (0.5 mg). Intravitreal steroids, especially dexamethasone at 0.7 mg, show efficacy and safety, while evidence for fluocinolone acetonide at 0.19 mg is limited. Intravitreal methotrexate has been reported at the dosage of 250-400 µg, with keratitis as the primary expected side effect. Case reports indicate tolerability of standard dosages of antivirals (foscarnet 1.2-2.4 mg/0.1 mL, ganciclovir 4 mg/0.1 mL) and the antibiotic combination piperacillin/tazobactam (250 µg/0.1 mL). We offer guidance based on current, but limited, literature. Standard dosage of intravitreal agents should be carefully considered, along with close monitoring for potential side effects, which should be discussed with patients.

Store-Operated Calcium Entry Inhibition and Plasma Membrane Calcium Pump Upregulation Contribute to the Maintenance of Resting Cytosolic Calcium Concentration in A1-like Astrocytes.

Highly neurotoxic A1-reactive astrocytes have been associated with several human neurodegenerative diseases. Complement protein C3 expression is strongly upregulated in A1 astrocytes, and this protein has been shown to be a specific biomarker of these astrocytes. Several cytokines released in neurodegenerative diseases have been shown to upregulate the production of amyloid ß protein precursor (APP) and neurotoxic amyloid ß (Aß) peptides in reactive astrocytes. Also, aberrant Ca2+ signals have been proposed as a hallmark of astrocyte functional remodeling in Alzheimer's disease mouse models. In this work, we induced the generation of A1-like reactive astrocytes after the co-treatment of U251 human astroglioma cells with a cocktail of the cytokines TNF-α, IL1-α and C1q. These A1-like astrocytes show increased production of APP and Aß peptides compared to untreated U251 cells. Additionally, A1-like astrocytes show a (75 ± 10)% decrease in the Ca2+ stored in the endoplasmic reticulum (ER), (85 ± 10)% attenuation of Ca2+ entry after complete Ca2+ depletion of the ER, and three-fold upregulation of plasma membrane calcium pump expression, with respect to non-treated Control astrocytes. These altered intracellular Ca2+ dynamics allow A1-like astrocytes to efficiently counterbalance the enhanced release of Ca2+ from the ER, preventing a rise in the resting cytosolic Ca2+ concentration.

The Plasma Membrane Ca2+-ATPase, a Molecular Target for Tau-induced Cytosolic Calcium Dysregulation.

Disruption of calcium (Ca2+) homeostasis is emerging as a prevalent feature of aging and aging-associated neurodegenerative diseases, including Alzheimer's disease (AD), the most common type of tauopathy. This disease is characterized by the combined presence of extracellular neuritic plaques composed by amyloid ß-peptides (Aß) and neurofibrillary tangles of tau. The association of calcium dyshomeostasis with Aß has been extensively studied, however its link with tau has been less investigated. Thus, this review will concentrate on the functional link between tau and the plasma membrane Ca2+ pump (PMCA) and other membrane proteins involved in the regulation of intracellular calcium and/or its association with neurodegeneration.

Inhibition of SERCA and PMCA Ca2+-ATPase activities by polyoxotungstates.

Plasma membrane calcium ATPases (PMCA) and sarco(endo) reticulum calcium ATPases (SERCA) are key proteins in the maintenance of calcium homeostasis. Herein, we compare for the first time the inhibition of SERCA and PMCA calcium pumps by several polyoxotungstates (POTs), namely by Wells-Dawson phosphotungstate anions [P2W18O62]6- (intact, {P2W18}), [P2W17O61]10- (monolacunary, {P2W17}), [P2W15O56]12- (trilacunary, {P2W15}), [H2P2W12O48]12- (hexalacunary, {P2W12}), [H3P2W15V3O62]6- (trivanadium-substituted, {P2W15V3}) and by Preyssler-type anion [NaP5W30O110]14- ({P5W30}). The speciation in the solutions of tested POTs was investigated by 31P and 51V NMR spectroscopy. The tested POTs inhibited SERCA Ca2+-ATPase activity, whereby the Preyssler POT showed the strongest effect, with an IC50 value of 0.37 µM. For {P2W17} and {P2W15V3} higher IC50 values were determined: 0.72 and 0.95 µM, respectively. The studied POTs showed to be more potent inhibitors of PMCA Ca2+-ATPase activity, with lower IC50 values for {P2W17}, {P5W30} and {P2W15V3}.

Vitrectomy versus Vitrectomy with Scleral Buckling in the Treatment of Giant Retinal Tear Related Retinal Detachments: An International Multicenter Study.

PURPOSE: To determine the practice pattern for treating giant retinal tear (GRT) related detachments, and their anatomic and visual outcomes with pars plana vitrectomy (PPV) with or without scleral buckling (SB). DESIGN: Retrospective cohort study. SUBJECTS: Eyes with GRT detachments repaired from 2008 to 2020 with at least 6 months of follow-up from 7 institutions in North and South America, Europe, and Asia. METHODS: Eyes repaired using PPV versus PPV/SB were compared. MAIN OUTCOME MEASURES: Anatomic and functional outcomes. RESULTS: A comparable number of eyes underwent PPV (n = 101) and PPV/SB (n = 99). Except for history of developmental abnormalities, prior intraocular surgery, and lens status, no differences in baseline demographics, ocular characteristics, or intraoperative surgical adjuncts were observed. The overall single surgery anatomic success (SSAS) at 6 months and 1 year were similar between the groups (82.2% and 77.2% of PPV, and 87.9% and 85.7% of PPV/SB). When stratified by age, the 1-year SSAS rate was higher for PPV/SB (88.5%) than PPV (56.3%) (P = 0.03) for children <18 years. For both children and adults, the mean best-corrected visual acuity (BCVA) at baseline did not differ between the PPV and PPV/SB groups. However, for children, mean BCVA at 1 year was better in the PPV/SB than PPV groups (P = 0.001) while for adults, no difference was found between the 2 groups. The mean time to the first redetachment was 7.9 months in the PPV group and 5.5 months in the PPV/SB group (P = 0.8). Proliferative vitreoretinopathy was the most common cause for redetachment (70.4% of PPV and 93.8% of PPV/SB in redetached eyes; P = 0.1). Postoperative complications were also similar between the 2 groups, including ocular hypertension, epiretinal membrane, and cataract formation. CONCLUSIONS: PPV and PPV/SB are equally popular among surgeons globally for managing GRT detachments and have comparable anatomic and visual outcomes in adults. In children, PPV/SB is superior to PPV for anatomic and functional success at 1 year. In adults, the relief of traction by the GRT may reduce peripheral traction and obviate the need for an SB. However, in children, a supplemental SB can be beneficial as complete vitreous shaving and posterior hyaloid detachment, and postoperative positioning, are difficult in this group.

Five-year outcomes after intravitreal bevacizumab of treatment-naive eyes with macular edema secondary to CRVO in routine clinical practice: Results of the Pan-American Collaborative Retina Study (PACORES) group.

PURPOSE: The purpose of this study was to report the 5-year outcomes of treatment-naive eyes with cystoid macular edema secondary to central retinal vein occlusion treated with intravitreal bevacizumab in routine clinical practice. METHODS: We conducted multicenter retrospective non-comparative case series of 102 eyes. The main outcome measured was the change in best-corrected visual acuity (BCVA) at 5 years. Secondary outcomes included the number of injections and the change in CMT at 5 years. RESULTS: At 5 years, the mean BCVA improved from 1.22 ± 0.58 (Snellen 20/428) at baseline to 1.00 ± 0.68 logMAR (Snellen 20/200; p < 0.0001). At 5 years, 48 (47%) eyes had a gain of ≥ 3 lines, 41 (40.2%) eyes remained within 3 lines and 13 (12.7%) eyes had a loss of ≥ 3 lines of BCVA. The CMT improved from 740 ± 243 to 322 ± 179 µm (p < 0.0001). At 5 years, 59 (57.8%) eyes had a completely dry SD-OCT. Patients received a total of 10.6 ± 6.1 (range 6-27) injections. Baseline BCVA (p < 0.0001) and the duration of symptoms prior to initial anti-VEGF injection (p = 0.0274) were the only predictive factors for BCVA at 5 years. CONCLUSIONS: After 5 years with an average of 10.6 injections, there was a mean gain of 0.22 logMAR. In addition, more eyes achieved a BCVA of ≥ 20/40, gained ≥ 3 lines and less patients had a BCVA ≤ 20/200. Eyes with a better baseline BCVA and a shorter duration of symptoms were more likely to achieve better BCVA at 5 years.

Risk of Posterior Capsular Rupture during Phacoemulsification in Patients with the History of Anti-VEGF Intravitreal Injections: Results from the Pan-American Collaborative Retina Study (PACORES) Group.

PURPOSE: To assess the risk for capsular rupture during routine phacoemulsification in patients with a history of anti-VEGF injections and other possible risk modifiers such as treatment patterns, type of anti-VEGF agent, and experience of the surgeon, among others. METHODS: This study reviewed the medical records of 11,129 patients from 7 different hospitals in 5 countries. The study included 939 patients that underwent routine phacoemulsification and had a history of anti-VEGF therapy. We excluded patients with known risk factors for capsular rupture, as well as patients with a history of other retinal procedures. The study extracted data regarding general demographics, the number of previous injections, type of anti-VEGF agent, details of cataract surgery, and anti-VEGF treatment patterns. RESULTS: Overall prevalence of posterior capsular rupture: 7.45% (95% CI: 5.9-9.32%). The mean number of injections per patient was 3.37 ± 2.8. More than 50% of the patients received their last anti-VEGF injection within three months before cataract surgery. The complication rate during intravitreal injections was 1.07%. In the univariate analysis, the experience of the cataract surgeon (inexperience surgeons; OR: 2.93) and the history of prior anti-VEGF therapy (OR: 1.77) were significant risk indicators for PCR (p < 0.05). However, after controlling for age in the multivariate analysis, the trend did not reach a statistical significance. CONCLUSION: The risk for capsular rupture is higher in patients with a history of intravitreal anti-VEGF injections.

Sorcin Activates the Brain PMCA and Blocks the Inhibitory Effects of Molecular Markers of Alzheimer's Disease on the Pump Activity.

Since dysregulation of intracellular calcium (Ca2+) levels is a common occurrence in neurodegenerative diseases, including Alzheimer's disease (AD), the study of proteins that can correct neuronal Ca2+ dysregulation is of great interest. In previous work, we have shown that plasma membrane Ca2+-ATPase (PMCA), a high-affinity Ca2+ pump, is functionally impaired in AD and is inhibited by amyloid-ß peptide (Aß) and tau, two key components of pathological AD hallmarks. On the other hand, sorcin is a Ca2+-binding protein highly expressed in the brain, although its mechanism of action is far from being clear. Sorcin has been shown to interact with the intracellular sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), and other modulators of intracellular Ca2+ signaling, such as the ryanodine receptor or presenilin 2, which is closely associated with AD. The present work focuses on sorcin in search of new regulators of PMCA and antagonists of Aß and tau toxicity. Results show sorcin as an activator of PMCA, which also prevents the inhibitory effects of Aß and tau on the pump, and counteracts the neurotoxicity of Aß and tau by interacting with them.

Early pars plana vitrectomy for proliferative diabetic retinopathy: update and review of current literature.

PURPOSE OF REVIEW: Diabetic retinopathy (DR) is one of the leading causes of preventable vision loss in the world and its prevalence continues to increase worldwide. One of the ultimate and visually impairing complications of DR is proliferative diabetic retinopathy (PDR) and subsequent tractional retinal detachment. Treatment modalities, surgical techniques, and a better understanding of the pathophysiology of DR and PDR continue to change the way we approach the disease. The goal of this review is to provide an update on recent treatment modalities and outcomes of proliferative diabetic retinopathy and its complications including tractional retinal detachment. RECENT FINDINGS: Panretinal photocoagulation (PRP), anti-vascular endothelial growth factor (anti-VEGF), and pars plana vitrectomy are the mainstay of PDR treatment. However, PRP and anti-VEGF are associated with significant treatment burden and multiple subsequent treatments. Early vitrectomy is associated with vision preservation, less treatment burden, and less subsequent treatments than therapy with PRP and anti-VEGF. SUMMARY: Concerning costs, high rates of noncompliance in the diabetic population and significant rates of subsequent treatments with initial PRP and anti-VEGF, early vitrectomy for diabetic retinopathy in patients at risk of PDR is a cost-effective long-term stabilizing treatment for diabetics with advanced disease.

Non-contact wide-angled visualization with chandelier-assisted scleral buckling for primary uncomplicated rhegmatogenous retinal detachment.

PURPOSE: To report our experience in non-contact wide-angled visualization with chandelier-assisted scleral buckling (SB) in uncomplicated primary rhegmatogenous retinal detachments (RRD). METHODS: Retrospective case series of 282 eyes that underwent non-contact wide-angled visualization with chandelier-assisted SB and were followed for a mean of 13.5 months. RESULTS: There were 160 male patients. The average age was 42.6 years old. There were 262 eyes that were phakic, 18 pseudophakic, and 2 aphakic. Two-thirds of eyes presented with the macula detached. Eyes had an average of 1.6 breaks. The single operation anatomic success rate was 85.1% (240/282). The pre-op visual acuity improved from 1.21 to 0.76 logMAR at 6 months (p < 0.0001). Complications included a case of scleral laceration, choroidal hemorrhage, 3 epiretinal membranes, 1 macular fold, and 4 eyes with buckle exposure. CONCLUSION: Non-contact wide-angled visualization with chandelier-assisted SB compares favorably with conventional SB for primary uncomplicated primary RRD.

Clinical comparison of 27-gauge and 23-gauge instruments on the outcomes of pars plana vitrectomy surgery for the treatment of vitreoretinal diseases.

PURPOSE OF REVIEW: To compare outcomes of 27-gauge and 23-gauge pars plana vitrectomy (PPV) for treatment of vitreoretinal diseases. RECENT FINDINGS: Sixty-eight patients undergoing microincisional PPV for treatment of vitreoretinal diseases were randomized 1 : 1 to 27-gauge or 23-gauge surgery with a 7500 cuts-per-minute vitrectomy probe. The most common reasons for vitrectomy were epiretinal membrane (49%) and vitreous hemorrhage (24%). Mean ±â€Šstandard deviation (SD) changes from immediate preoperative to immediate postoperative intraocular pressure were -0.40 ±â€Š6.60 mmHg in the 27-gauge and -3.05 ±â€Š7.64 mmHg in the 23-gauge group (adjusted mean difference 2.42 mmHg, 95% lower confidence limit 0.64, P = 0.013), but these changes were not associated with primary reason for vitrectomy (P = 0.065). Mean ±â€ŠSD conjunctival edema grades in the 27-gauge and 23-gauge groups 1 week after surgery were 0.02 ±â€Š0.124 and 0.10 ±â€Š0.246, respectively (least squares mean difference -0.09, 95% upper confidence limit -0.03, P = 0.004), and were 0.01 ±â€Š0.122 and 0.12 ±â€Š0.338, respectively, at the probe incision site. Conjunctival edema grades were similar in both groups at 1 and 3 months. Mean ±â€ŠSD pain ratings on postoperative day 1 - an indicator of patient comfort - were similar in the two groups. SUMMARY: Smaller diameter vitrectomy instruments are associated with smaller reductions in immediate postoperative intraocular pressure.

Surgical Innovations in the Treatment of Diabetic Macular Edema and Diabetic Retinopathy.

PURPOSE OF REVIEW: Diabetic macular edema (DME) and complications of proliferative diabetic retinopathy (PDR) are the primary causes of vision loss in patients with diabetic retinopathy. As the incidence of diabetes increases worldwide, new, cost-effective treatments for DME and PDR will become paramount. Currently, anti-vascular endothelial growth factor (anti-VEGF) medications are considered first-line treatment. However, multiple visits for injections and the economic and time burden they entail make this treatment modality less than ideal. Early vitrectomy as well as depot delivery systems for medications could potentially reduce the treatment burden of patients with diabetes, prevent visual loss, and provide long-term stabilization of retinopathy in patients with diabetes. Newer port delivery systems for anti-VEGF medications could one day make this treatment modality better suited for patients across the globe. RECENT FINDINGS: Real-world data shows poor compliance with treatment among patients with diabetes. Recent publications show catastrophic results when anti-VEGF treatments are stopped abruptly. The port delivery system for ranibizumab shows maintenance of adequate anti-VEGF levels in the vitreous cavity for many months. Early vitrectomy can provide cost-effective long-term stabilization in eyes with diabetic retinopathy. Microincisional vitrectomy as a treatment for DME and PDR remains controversial and larger trials are needed to definitively prove its superiority over other modalities; however, small-scale data point towards its usefulness in specific populations. Newer port delivery systems of anti-VEGF show promise in decreasing the number of office visits in patients with diabetic retinopathy.

Methylene Blue Blocks and Reverses the Inhibitory Effect of Tau on PMCA Function.

Methylene blue (MB) is a synthetic phenothiazine dye that, in the last years, has generated much debate about whether it could be a useful therapeutic drug for tau-related pathologies, such as Alzheimer's disease (AD). However, the molecular mechanism of action is far from clear. Recently we reported that MB activates the plasma membrane Ca2+-ATPase (PMCA) in membranes from human and pig tissues and from cells cultures, and that it could protect against inactivation of PMCA by amyloid ß-peptide (Aß). The purpose of the present study is to further examine whether the MB could also modulate the inhibitory effect of tau, another key molecular marker of AD, on PMCA activity. By using kinetic assays in membranes from several tissues and cell cultures, we found that this phenothiazine was able to block and even to completely reverse the inhibitory effect of tau on PMCA. The results of this work point out that MB could mediate the toxic effect of tau related to the deregulation of calcium homeostasis by blocking the impairment of PMCA activity by tau. We then could conclude that MB could interfere with the toxic effects of tau by restoring the function of PMCA pump as a fine tuner of calcium homeostasis.

Preoperative Bevacizumab for Tractional Retinal Detachment in Proliferative Diabetic Retinopathy: A Prospective Randomized Clinical Trial.

PURPOSE: To assess the effectiveness and safety of an intravitreal injection of 1.25 mg bevacizumab (IVB) as a preoperative adjunct to small-gauge pars plana vitrectomy (PPV) compared with PPV alone in eyes with tractional retinal detachment secondary to proliferative diabetic retinopathy. METHODS: This prospective, double-masked, randomized, multicenter, active-controlled clinical trial enrolled 224 eyes of 224 patients between November 2013 and July 2015. All eyes underwent a baseline examination including best-corrected visual acuity, color photos, optical coherence tomography, and fluorescein angiography. Data were collected on intraoperative bleeding, total surgical time, early (<1 month) postoperative vitreous hemorrhage, and mean change in best-corrected visual acuity at 12 months. P < .05 was considered statistically significant. RESULTS: A total of 214 patients (214 eyes) were randomized in a 1:1 ratio to PPV plus IVB ([study group] 102 eyes) or PPV plus sham ([control] 112 eyes). Iatrogenic retinal breaks were noted intraoperatively in 35 eyes (34.3%) in the study group, and 66 eyes (58.9%) in the control group (P = .001). Grade 2 intraoperative bleeding was noted in 32 (31.3%) eyes in the study group and 58 (51.7 %) eyes in the control group (P = .001). Endodiathermy was necessary in 28 (27.4 %) eyes in the study group, compared with 75 (66.9%) eyes in the control group (P = .0001). Mean surgical time was 71.3 ± 32.1 minutes in the study group and 83.6 ± 38.7 minutes in the control group (P = .061). CONCLUSION: Preoperative IVB seems to reduce intraoperative bleeding, improving surgical field visualization, and reducing intraoperative and postoperative complications. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

SURGICAL OUTCOMES AFTER INVERTED INTERNAL LIMITING MEMBRANE FLAP VERSUS CONVENTIONAL PEELING FOR VERY LARGE MACULAR HOLES.

PURPOSE: To evaluate the anatomical and visual outcomes of inverted flap technique of peeling of internal limiting membrane (ILM) versus standard peeling of ILM for macular holes of basal diameter more than 800 µm. METHODS: Patients with very large idiopathic macular holes more than 800 µm in basal diameter (ranging from 243 µm to 840 µm in minimum diameter) were retrospectively included in the study. In Group A, 18 eyes of 18 patients underwent ILM peeling using the inverted flap technique. In Group B, 18 eyes of 18 patients underwent conventional ILM peeling. The primary endpoint was the rate of hole closure at 6 months after surgery. The secondary outcome measure was the change in best-corrected visual acuity at 6 months after surgery. RESULTS: There were no significant differences in ocular characteristics of the study groups at baseline except for the age distribution. Mean macular hole diameter was 1,162.8 ± 206.0 µm and 1,229.6 ± 228.1 µm in Group A and Group B, respectively. The hole closure rate was 88.9% (16/18) in Group A and 77.8% (14/18) in Group B (P = 0.66). The mean gain in best-corrected visual acuity was higher in Group A than in Group B (P = 0.12) at 6 months, but this was not statistically significant. There were no severe ocular adverse events in either group. CONCLUSION: In this multicenter series, inverted ILM flap technique did not lead to significantly higher anatomical closure rates than conventional ILM peeling in large macular holes more than 800 µm in diameter.

STIM1 deficiency is linked to Alzheimer's disease and triggers cell death in SH-SY5Y cells by upregulation of L-type voltage-operated Ca2+ entry.

STIM1 is an endoplasmic reticulum protein with a role in Ca2+ mobilization and signaling. As a sensor of intraluminal Ca2+ levels, STIM1 modulates plasma membrane Ca2+ channels to regulate Ca2+ entry. In neuroblastoma SH-SY5Y cells and in familial Alzheimer's disease patient skin fibroblasts, STIM1 is cleaved at the transmembrane domain by the presenilin-1-associated γ-secretase, leading to dysregulation of Ca2+ homeostasis. In this report, we investigated expression levels of STIM1 in brain tissues (medium frontal gyrus) of pathologically confirmed Alzheimer's disease patients, and observed that STIM1 protein expression level decreased with the progression of neurodegeneration. To study the role of STIM1 in neurodegeneration, a strategy was designed to knock-out the expression of STIM1 gene in the SH-SY5Y neuroblastoma cell line by CRISPR/Cas9-mediated genome editing, as an in vitro model to examine the phenotype of STIM1-deficient neuronal cells. It was proved that, while STIM1 is not required for the differentiation of SH-SY5Y cells, it is absolutely essential for cell survival in differentiating cells. Differentiated STIM1-KO cells showed a significant decrease of mitochondrial respiratory chain complex I activity, mitochondrial inner membrane depolarization, reduced mitochondrial free Ca2+ concentration, and higher levels of senescence as compared with wild-type cells. In parallel, STIM1-KO cells showed a potentiated Ca2+ entry in response to depolarization, which was sensitive to nifedipine, pointing to L-type voltage-operated Ca2+ channels as mediators of the upregulated Ca2+ entry. The stable knocking-down of CACNA1C transcripts restored mitochondrial function, increased mitochondrial Ca2+ levels, and dropped senescence to basal levels, demonstrating the essential role of the upregulation of voltage-operated Ca2+ entry through Cav1.2 channels in STIM1-deficient SH-SY5Y cell death. KEY MESSAGES: STIM1 protein expression decreases with the progression of neurodegeneration in Alzheimer's disease. STIM1 is essential for cell viability in differentiated SH-SY5Y cells. STIM1 deficiency triggers voltage-regulated Ca2+ entry-dependent cell death. Mitochondrial dysfunction and senescence are features of STIM1-deficient differentiated cells.

Methylene blue activates the PMCA activity and cross-interacts with amyloid ß-peptide, blocking Aß-mediated PMCA inhibition.

The phenothiazine methylene blue (MB) is attracting increasing attention because it seems to have beneficial effects in the pathogenesis of Alzheimer's disease (AD). Among other factors, the presence of neuritic plaques of amyloid-ß peptide (Aß) aggregates, neurofibrilar tangles of tau and perturbation of cytosolic Ca2+ are important players of the disease. It has been proposed that MB decreases the formation of neuritic plaques due to Aß aggregation. However, the molecular mechanism underlying this effect is far from clear. In this work, we show that MB stimulates the Ca2+-ATPase activity of the plasma membrane Ca2+-ATPase (PMCA) in human tissues from AD-affected brain and age-matched controls and also from pig brain and cell cultures. In addition, MB prevents and even blocks the inhibitory effect of Aß on PMCA activity. Functional analysis with mutants and fluorescence experiments strongly suggest that MB binds to PMCA, at the C-terminal tail, in a site located close to the last transmembrane helix and also that MB binds to the peptide. Besides, Aß increases PMCA affinity for MB. These results point out a novel molecular basis of MB action on Aß and PMCA as mediator of its beneficial effect on AD.

Yellow (577 nm) micropulse laser versus half-dose verteporfin photodynamic therapy in eyes with chronic central serous chorioretinopathy: results of the Pan-American Collaborative Retina Study (PACORES) Group.

PURPOSE: To compare the functional and anatomical outcomes of eyes with chronic central serous chorioretinopathy treated with yellow micropulse (MP) laser versus half-dose verteporfin photodynamic therapy (PDT). METHODS: This is a multicentre, retrospective comparative study of 92 eyes treated with yellow MP laser (duty cycle of 5%, zero spacing between spots, spot size varied from 100 to 200 µm, power varied from 320 to 660 mW, and the pulse burst duration was 200 ms) and 67 eyes treated with PDT (half-dose verteporfin (3 mg/m2) infused over 10 min), followed by laser activation for 83 s. Spot sizes varied from 400 to 2000 µm. RESULTS: In the MP group, at 12 months of follow-up, the mean best corrected visual acuity (BCVA) improved from the logarithm of the minimum angle of resolution (logMAR) of 0.41±0.27 at baseline to 0.21±0.26 (P<0.0001), 48.9% (45/92) of eyes had an improvement of ≥3 lines of BCVA from baseline, 48.9% (45/92) of eyes remained within 2 lines of baseline BCVA, and only 2.2% (2/92) of eyes lost ≥3 lines of BCVA from baseline. In the PDT group, at 12 months of follow-up, the mean BCVA changed from logMAR of 0.50±0.34 at baseline to 0.47±0.34 (P=0.89), 19% (13/67) of eyes had an improvement of ≥3 lines of BCVA from baseline, 73% (49/67) of eyes remained within 2 lines of baseline BCVA, and 7% (5/67) of eyes lost ≥3 lines of BCVA from baseline. There were no adverse events attributable to the yellow MP laser treatment. One eye in the PDT group developed choroidal neovascularisation, which was treated with three intravitreal bevacizumab injections. CONCLUSIONS: Both PDT and MP are effective in restoring the macular anatomy. In places where PDT is not available, yellow MP laser may be an adequate treatment alternative.

Long-Term Visual Outcomes and Safety Profile of 27-Gauge Pars Plana Vitrectomy for Posterior Segment Disease.

PURPOSE: To report longer-term outcomes of 27-gauge pars plana vitrectomy (PPV) in eyes with posterior segment disease. DESIGN: Multicenter, retrospective, interventional case series. PARTICIPANTS: A total of 390 eyes of 360 patients undergoing 27-gauge PPV for a vitreoretinal surgery indication. INTERVENTION: Three-port, transconjunctival, 27-gauge PPV. MAIN OUTCOME MEASURES: Change in visual acuity (VA) and occurrence of intraoperative and postoperative complications with a minimum follow-up of 365 days. RESULTS: Mean follow-up was 715±332 days (median, 514; range, 365-1440 days). Surgical indications included epiretinal membrane (ERM) (n = 121), vitreous floaters (n = 69), diabetic tractional retinal detachment (n = 49), vitreous hemorrhage (n = 40), full-thickness macular hole (n = 33), recurrent proliferative vitreoretinopathy (PVR)-related retinal detachment (n = 18), primary rhegmatogenous retinal detachment (RRD) (n = 17), silicone oil removal (n = 16), dislocated intraocular lens (n = 10), submacular hemorrhage (n = 7), endophthalmitis (n = 6), and retained lens material (n = 4). Mean logarithm of the minimum angle of resolution (logMAR) VA improved from 0.72±0.62 (20/105 Snellen equivalent) preoperatively to 0.40±0.55 (20/50 Snellen equivalent) postoperatively (P < 0.001). No case required conversion to 23- or 25-gauge instrumentation. Postoperative complications included transient ocular hypertension in 44 eyes (11.3%), vitreous hemorrhage in 31 eyes (7.9%), and transient hypotony in 22 eyes (5.6%). Acute postoperative endophthalmitis occurred in 1 case (0.26%). Overall, 82 of 390 eyes (21.0%) underwent at least 1 additional intraocular surgery in the follow-up period, most commonly for cataract extraction (n = 40/82 eyes, 48.8%). Of the 18 eyes undergoing surgery for primary RRD, recurrent detachment due to PVR occurred in 2 eyes (11.1%). CONCLUSIONS: At a minimum follow-up of 1 year, 27-gauge PPV was well tolerated with low rates of postoperative complications across varied surgical indications, including primary and complex retinal detachment.