Macular atrophy development in neovascular age-related macular degeneration during first year of treatment: Incidence and risk factors.

PURPOSE: To assess the development of macular atrophy, according to the new Classification of Atrophy Meetings criteria, in patients with treatment-naïve neovascular age-related macular degeneration during the first year of treatment with ranibizumab or aflibercept, and to determine baseline factors predictive of atrophy development. METHODS: Retrospective subanalysis of three prospective clinical trials that included eyes with treatment-naïve neovascular age-related macular degeneration. Multimodal evaluation was performed with spectral-domain optical coherence tomography, fluorescein angiography, fundus autofluorescence and color fundus photography at baseline and after 12 months of treatment. The main outcome was the macular atrophy type, classified according to Classification of Atrophy Meeting criteria. Logistic regression models were built to test predictors of macular atrophy development. RESULTS: A total of 85 eyes of 85 patients (63% female; mean age: 78.5 ± 6.3 years old) were included. After 12 months of antiangiogenic therapy, all four Classification of Atrophy Meeting types of macular atrophy developed de novo. The atrophy type with highest incidence at end of follow-up was incomplete retinal pigment epithelium and outer retinal atrophy (63.6%; 95% confidence interval: 45.9%-86.0%). A significant association was observed between development at 12 months and the presence of incomplete retinal pigment epithelium and outer retinal atrophy at baseline (odds ratio (95% confidence interval): 22.4 (1.6, 323.5)). The number of injections was predictive of complete outer retinal atrophy development at end of follow-up (odds ratio (95% confidence interval) 1.5 (1.1, 2.1), p = 0.011). CONCLUSION: Predictors of atrophy development have the potential to change treatment practices. Further research is warranted.

Challenges of BDNF-based therapies: From common to rare diseases.

Neurotrophins are a well-known family of neurotrophic factors that play an important role both in the central and peripheral nervous systems, where they modulate neuronal survival, development, function and plasticity. Brain-derived neurotrophic factor (BDNF) possesses diverse biological functions which are mediated by the activation of two main classes of receptors, the tropomyosin-related kinase (Trk) B and the p75 neurotrophin receptor (p75NTR). The therapeutic potential of BDNF has drawn attention since dysregulation of its signalling cascades has been suggested to underlie the pathogenesis of both common and rare diseases. Multiple strategies targeting this neurotrophin have been tested; most have found obstacles that ultimately hampered their effectiveness. This review focuses on the involvement of BDNF and its receptors in the pathophysiology of Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Rett Syndrome (RTT). We describe the known mechanisms leading to the impairment of BDNF/TrkB signalling in these disorders. Such mechanistic insight highlights how BDNF signalling compromise can take various shapes, nearly disease-specific. Therefore, BDNF-based therapeutic strategies must be specifically tailored and are more likely to succeed if a combination of resources is employed.

Impairment of adenosinergic system in Rett syndrome: Novel therapeutic target to boost BDNF signalling.

Rett syndrome (RTT; OMIM#312750) is mainly caused by mutations in the X-linked MECP2 gene (methyl-CpG-binding protein 2 gene; OMIM*300005), which leads to impairments in the brain-derived neurotrophic factor (BDNF) signalling. The boost of BDNF mediated effects would be a significant breakthrough but it has been hampered by the difficulty to administer BDNF to the central nervous system. Adenosine, an endogenous neuromodulator, may accomplish that role since through A2AR it potentiates BDNF synaptic actions in healthy animals. We thus characterized several hallmarks of the adenosinergic and BDNF signalling in RTT and explored whether A2AR activation could boost BDNF actions. For this study, the RTT animal model, the Mecp2 knockout (Mecp2-/y) (B6.129P2 (C)-Mecp2tm1.1Bird/J) mouse was used. Whenever possible, parallel data was also obtained from post-mortem brain samples from one RTT patient. Ex vivo extracellular recordings of field excitatory post-synaptic potentials in CA1 hippocampal area were performed to evaluate synaptic transmission and long-term potentiation (LTP). RT-PCR was used to assess mRNA levels and Western Blot or radioligand binding assays were performed to evaluate protein levels. Changes in cortical and hippocampal adenosine content were assessed by liquid chromatography with diode array detection (LC/DAD). Hippocampal ex vivo experiments revealed that the facilitatory actions of BDNF upon LTP is absent in Mecp2-/y mice and that TrkB full-length (TrkB-FL) receptor levels are significantly decreased. Extracts of the hippocampus and cortex of Mecp2-/y mice revealed less adenosine amount as well as less A2AR protein levels when compared to WT littermates, which may partially explain the deficits in adenosinergic tonus in these animals. Remarkably, the lack of BDNF effect on hippocampal LTP in Mecp2-/y mice was overcome by selective activation of A2AR with CGS21680. Overall, in Mecp2-/y mice there is an impairment on adenosinergic system and BDNF signalling. These findings set the stage for adenosine-based pharmacological therapeutic strategies for RTT, highlighting A2AR as a therapeutic target in this devastating pathology.

Causative Pathogens of Endophthalmitis after Intravitreal Anti-VEGF Injection: An International Multicenter Study.

PURPOSE: The main objective of this study was to investigate the microbiological spectrum of endophthalmitis after anti-VEGF injections and to compare streptococcal with non-streptococcus-associated cases with regard to baseline characteristics and injection procedure. METHODS: Retrospective, international multicenter study of patients with culture-positive endophthalmitis after intravitreal anti-VEGF injection at 17 different retina referral centers. RESULTS: Eighty-three cases with 87 identified pathogens were included. Coagulase-negative staphylococci (59%) and viridans streptococci (15%) were the most frequent pathogens found. The use of postoperative antibiotics and performance of injections in an operating room setting significantly reduced the rate of streptococcus-induced endophthalmitis cases (p = 0.01 for both). CONCLUSION: We found a statistically significant lower rate of postinjectional local antibiotic therapy and operating room-based procedures among the streptococcus-induced cases compared to cases caused by other organisms.

Real-World Results of Aflibercept versus Ranibizumab for the Treatment of Exudative AMD Using a Fixed Regimen.

Intravitreal injections of antivascular endothelial growth factors have been considered a milestone in the treatment of neovascular age-related macular degeneration (nAMD). However, the increasing incidence of AMD and the burden of visits and injections overcharge both the patient and the healthcare systems. Real-world solutions depend on treatment protocols aimed at optimizing the number of clinical visits while guaranteeing good functional outcomes. We performed a retrospective analysis of 72 eyes from 63 naïve patients diagnosed with nAMD that underwent a fixed intravitreal protocol consisting of bimonthly injections after a three-month loading dose, with either Aflibercept or Ranibizumab (no predefined criteria for treatment selection). Best corrected visual acuity (BCVA) and optical coherence tomography were analyzed at baseline and during follow-up clinical visits (months 3, 6, 12, and 18). From the included participants, 42 followed a fixed regimen with Aflibercept and 30 with Ranibizumab. At the 12-month visit, there was not a statistically significant difference in the mean change of BCVA between the two groups (p=0.121); however, the mean difference in the central retinal thickness was significantly superior in the Aflibercept group (-142.2 versus -51.5, p=0.011). The described fixed regimen seems to be efficient in the treatment of nAMD in a clinical practice setting.

Erythropoietin Induces Homeostatic Plasticity at Hippocampal Synapses.

The cytokine erythropoietin (EPO) is the master regulator of erythropoiesis. Intriguingly, many studies have shown that the cognitive performance of patients receiving EPO for its hematopoietic effects is enhanced, which prompted the growing interest in the use of EPO-based strategies to treat neuropsychiatric disorders. EPO plays key roles in brain development and maturation, but also modulates synaptic transmission. However, the mechanisms underlying the latter have remained elusive. Here, we show that acute (40-60 min) exposure to EPO presynaptically downregulates spontaneous and afferent-evoked excitatory transmission, without affecting basal firing of action potentials. Conversely, prolonged (3 h) exposure to EPO, if followed by a recovery period (1 h), is able to elicit a homeostatic increase in excitatory spontaneous, but not in evoked, synaptic transmission. These data lend support to the emerging view that segregated pathways underlie spontaneous and evoked neurotransmitter release. Furthermore, we show that prolonged exposure to EPO facilitates a form of hippocampal long-term potentiation that requires noncanonical recruitment of calcium-permeable AMPA receptors for its maintenance. These findings provide important new insight into the mechanisms by which EPO enhances neuronal function, learning, and memory.

Periprostatic innervation: New issues based on segmental analysis of 10 human cadaver pelvic blocs.

BACKGROUND: The exact paths of periprostatic nerves have been under debate over the last decades. In the present study, the topographic distribution of nerves around the prostate and their relative distances from the prostatic capsule were analyzed in male cadaver visceral blocs. METHODS: The pelvic organs from ten fresh male cadavers were removed and serial sectioned en bloc for histological investigation. The macroslices was divided into four sectors. Each sector was centrally covered with a raster dividing each sector in three subsectors numbered clockwise. The prostatic capsule was identified, and distances of 2.5 and 5 mm from the prostate were demarked with lines. We quantified the number of nerve fibers present in each subsector of each slide and recorded their position relative to the prostatic capsule. RESULTS: In general, the topographic analysis revealed that the majority of nerves were identified in sectors 4 through 9, corresponding to the posterolateral and posterior surfaces of the prostate gland. At the prostate base, the majority of nerves were found at the posterolateral and posterior surfaces of the gland. Within the mid-region of the prostate, the same topographic distribution pattern was observed, but the nerve fibers were closer to the prostatic capsule. At the apical region, the percentage of nerve fibers identified in the anterior region was higher, despite their major concetration in the posterior surface. The nerves identified at the apex were mainly located up to 2.5 mm from the prostate. This proximity to the prostate was specifically observed in the anterolateral and anterior sectors. In the craniocaudal sense, the percentage of nerves identified between 2.5 and 5 mm from the prostatic capsule remained constant. CONCLUSIONS: A significant number of nerve fibers were present in the anterior and anterolateral positions, especially at the apex. The anterior nerves were closer to the prostate. This proximity suggests that the anterior nerves may participate in local physiology and that the cavernous nerves are probably formed by the posterior nerve fibers. It is likely that the safe distance of 2.5 mm from all surfaces of the prostate may be related to cavernous fiber preservation.

Adenosine A(2A) Receptors as novel upstream regulators of BDNF-mediated attenuation of hippocampal Long-Term Depression (LTD).

Hippocampal Long-Term Potentiation (LTP) is facilitated by BDNF, through the activation of tropomyosin-related kinase B (TrkB) receptors. However, an influence of BDNF upon Long-Term Depression (LTD) was also shown. The present work aimed to further evaluate the effect of BDNF and TrkB receptors upon CA1 hippocampal LTD and to elucidate whether this effect is under the upstream control of other signalling processes, such as the adenosine A(2A)Receptors (A(2A)Rs). LTD, induced by a Low-Frequency Stimulation (LFS, 900 pulses, 1 Hz) in the CA1 area of rat hippocampal slices, was significantly attenuated when these slices were exposed to BDNF (60-100 ng/mL). A lower BDNF concentration (20 ng/ml) was only effective to inhibit LTD if A(2A)Rs were activated by a selective agonist, CGS 21680 (10 nM), or if the extracellular adenosine level was increased by 5-iodotubercidin (100 nM). BDNF (100 ng/ml) effect upon LTD was prevented by K252a (200 nM), which is known to prevent TrkB transphosphorylation, hence suggesting that this action requires TrkB receptor activation. BDNF (100 ng/ml) lacked effect on an adenosine-depleted background (adenosine deaminase, 2 U/ml) or under selective A(2A)R blockade (SCH 58261, 100 nM), indicating that it relies on tonic A(2A)R activation. Forskolin (10 µM), a cell-permeable activator of adenylate cyclase, rescued BDNF (100 ng/ml) effect in slices where A(2A)Rs were blocked with SCH 58261 (100 nM), whereas a PKA inhibitor, H-89 (1 µM), prevented LTD attenuation by BDNF (100 ng/ml). We conclude that the influence of BDNF TrkB receptors upon LTD is under the strict control of A(2A)Rs activation, through a mechanism that requires the cAMP/PKA transducing system.

Pheochromocytoma: a long-term follow-up of 24 patients undergoing laparoscopic adrenalectomy.

PURPOSE: Pheochromocytomas are tumors derived from chromaffin cells that often secrete catecholamines and cause hypertension. The clinical diagnosis of pheochromocytoma depends on the presence of excessive production of catecholamines. Conventional imaging modalities that have been used in the preoperative evaluation include CT, MRI, and 131I-MIBG scintigraphy. Surgical resection is the definitive treatment for patients with pheochromocytoma. The goal of this study was to evaluate the long-term follow-up of 24 patients undergoing laparoscopic adrenalectomy for pheochromocytoma. MATERIALS AND METHODS: From January 1995 to September 2006, 24 patients underwent laparoscopic adrenalectomy for adrenal pheochromocytoma. Twenty (83.3%) patients had arterial hypertension. The inclusion criteria of patients in this retrospective study were laparoscopic approach, unilateral or bilateral adrenal tumor, pathological diagnosis of pheochromocytoma and a minimum follow-up of 18 months. RESULTS: Intra-operative complications occurred in 4 (16.7%) patients. Two (8.3%) patients had postoperative complications. Two patients (8.3%) had blood transfusion. The mean postoperative hospital stay was 3.8 days (range 1 to 11). Eighteen (90%) of the twenty patients who had symptomatic hypertension, returned to normal blood pressure immediately after surgery, during the hospital stay. In one patient, the high blood pressure levels remained unchanged. Another patient persisted with mild hypertension, well controlled by a single antihypertensive drug. CONCLUSIONS: Our results confirmed that laparoscopic adrenalectomy for pheochromocytoma is a safe and effective procedure, providing the benefits of a minimally invasive approach. In our study, the initial positive results obtained in the treatment of 24 patients were confirmed after a mean follow-up of 74 months.

Pheochromocytoma: a long-term follow-up of 24 patients undergoing laparoscopic adrenalectomy

Purpose: Pheochromocytomas are tumors derived from chromaffin cells that often secrete catecholamines and cause hypertension. The clinical diagnosis of pheochromocytoma depends on the presence of excessive production of catecholamines. Conventional imaging modalities that have been used in the preoperative evaluation include CT, MRI, and 131I-MIBG scintigraphy. Surgical resection is the definitive treatment for patients with pheochromocytoma. The goal of this study was to evaluate the long-term follow-up of 24 patients undergoing laparoscopic adrenalectomy for pheochromocytoma. Materials and Methods: From January 1995 to September 2006, 24 patients underwent laparoscopic adrenalectomy for adrenal pheochromocytoma. Twenty (83.3 percent) patients had arterial hypertension. The inclusion criteria of patients in this retrospective study were laparoscopic approach, unilateral or bilateral adrenal tumor, pathological diagnosis of pheochromocytoma and a minimum follow-up of 18 months. Results: Intra-operative complications occurred in 4 (16.7 percent) patients. Two (8.3 percent) patients had postoperative complications. Two patients (8.3 percent) had blood transfusion. The mean postoperative hospital stay was 3.8 days (range 1 to 11). Eighteen (90 percent) of the twenty patients who had symptomatic hypertension, returned to normal blood pressure immediately after surgery, during the hospital stay. In one patient, the high blood pressure levels remained unchanged. Another patient persisted with mild hypertension, well controlled by a single antihypertensive drug. Conclusions: Our results confirmed that laparoscopic adrenalectomy for pheochromocytoma is a safe and effective procedure, providing the benefits of a minimally invasive approach. In our study, the initial positive results obtained in the treatment of 24 patients were confirmed after a mean follow-up of 74 months.