Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future.

PURPOSE: Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. DESIGN: Meta-analysis of prevalence data. PARTICIPANTS: A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. METHODS: AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). MAIN OUTCOME MEASURES: Prevalence of early and late AMD, BCVA, and number of AMD cases. RESULTS: Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%-5.0%) in those aged 55-59 years to 17.6% (95% CI 13.6%-21.5%) in those aged ≥85 years; for late AMD these figures were 0.1% (95% CI 0.04%-0.3%) and 9.8% (95% CI 6.3%-13.3%), respectively. We observed a decreasing prevalence of late AMD after 2006, which became most prominent after age 70. Prevalences were similar for gender across all age groups except for late AMD in the oldest age category, and a trend was found showing a higher prevalence of CNV in Northern Europe. After 2006, fewer eyes and fewer ≥80-year-old subjects with CNV were visually impaired (P = 0.016). Projections of AMD showed an almost doubling of affected persons despite a decreasing prevalence. By 2040, the number of individuals in Europe with early AMD will range between 14.9 and 21.5 million, and for late AMD between 3.9 and 4.8 million. CONCLUSION: We observed a decreasing prevalence of AMD and an improvement in visual acuity in CNV occuring over the past 2 decades in Europe. Healthier lifestyles and implementation of anti-vascular endothelial growth factor treatment are the most likely explanations. Nevertheless, the numbers of affected subjects will increase considerably in the next 2 decades. AMD continues to remain a significant public health problem among Europeans

Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future

Purpose Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. Design Meta-analysis of prevalence data. Participants A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. Methods AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). Main Outcome Measures Prevalence of early and late AMD, BCVA, and number of AMD cases. Results Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%–5.0%) in those aged 55–59 years to 17.6% (95%

Ophthalmology

PURPOSE: To investigate systemic and ocular determinants of peripapillary retinal nerve fiber layer thickness (pRNFLT) in the European population. DESIGN: Cross-sectional meta-analysis. PARTICIPANTS: A total of 16 084 European adults from 8 cohort studies (mean age range, 56.9+/-12.3-82.1+/-4.2 years) of the European Eye Epidemiology (E3) consortium. METHODS: We examined associations with pRNFLT measured by spectral-domain OCT in each study using multivariable linear regression and pooled results using random effects meta-analysis. MAIN OUTCOME MEASURES: Determinants of pRNFLT. RESULTS: Mean pRNFLT ranged from 86.8+/-21.4 mum in the Rotterdam Study I to 104.7+/-12.5 mum in the Rotterdam Study III. We found the following factors to be associated with reduced pRNFLT: Older age (beta = -0.38 mum/year; 95% confidence interval [CI], -0.57 to -0.18), higher intraocular pressure (IOP) (beta = -0.36 mum/mmHg; 95% CI, -0.56 to -0.15), visual impairment (beta = -5.50 mum; 95% CI, -9.37 to -1.64), and history of systemic hypertension (beta = -0.54 mum; 95% CI, -1.01 to -0.07) and stroke (beta = -1.94 mum; 95% CI, -3.17 to -0.72). A suggestive, albeit nonsignificant, association was observed for dementia (beta = -3.11 mum; 95% CI, -6.22 to 0.01). Higher pRNFLT was associated with more hyperopic spherical equivalent (beta = 1.39 mum/diopter; 95% CI, 1.19-1.59) and smoking (beta = 1.53 mum; 95% CI, 1.00-2.06 for current smokers compared with never-smokers). CONCLUSIONS: In addition to previously described determinants such as age and refraction, we found that systemic vascular and neurovascular diseases were associated with reduced pRNFLT. These may be of clinical relevance, especially in glaucoma monitoring of patients with newly occurring vascular comorbidities

Evolutionary conservation of mechanosensitive cues involved in endomesoderm formation in Bilaterians and Cnidarians

L'émergence du mésoderme est une transition évolutive importante mais encore mal comprise. Précédemment, l’équipe a identifié une voie mécanosensible induisant la différenciation du mésoderme chez des embryons bilatériens. Les contraintes mécaniques des premiers mouvements morphogénétiques induisent la phosphorylation de la ßcat jonctionnelle et l’activation de la voie. Pour en tester les origines évolutives, nous avons travaillé sur le cnidaire, Nematostella vectensis, dont le dernier ancêtre commun avec les bilatériens remonte à plus de 600 millions d'années. Nous avons testé l'activation de la voie mécanosensible ßcat suite à la gastrulation. En réalisant des immunofluorescences, nous avons montré que la ßcat est phosphorylée (p-ßcat) dans les cellules constrictées du futur endomésoderme en début de gastrulation. Nous avons observé que l'inhibition de la densification du réseau d'actine - par injections de morpholinos de Strabismus (StbmMO) - inhibe la p-ßcat. Cette phosphorylation est mécanosensible puisque nous avons ramené les niveaux de p-ßcat à la normale en comprimant les embryons inhibés. Grâce à une analyse informatisée, nous avons révélé que les signaux d'actine jonctionnelle et de p-ßcat sont positivement corrélés. Nous postulons que les tensions induites par le réseau d’actomyosine, nécessaires à l'invagination du blastopore, déclenchent la voie ßcat. Nous avons commencé à tester la fonctionnalité de cette voie en identifiant des gènes dont l'expression est modifiée par injections de StbmMO. Ces résultats indiquent que la voie mécanosensible ßcat est conservée et remonte donc à plus de 600 millions d'années.The emergence of the mesoderm is an important -but still poorly understood- evolutionary transition. Previously, the team identified a mechanosensitive pathway inducing mesoderm specification in bilaterian embryos. The mechanical constraints of the first morphogenetic movements induce the phosphorylation of the junctional ßcat and the activation of the pathway. To test its evolutionary origins, we worked on the cnidarian Nematostella vectensis, who diverged from bilaterians more than 600 million years ago. We tested the activation of the ßcat mechanosensitive pathway by mechanical cues and its role in endomesoderm specification. By carrying out immunofluorescence imaging at the gastrulation stage, we showed that the ßcat is phosphorylated (p-ßcat) in the constricted cells of the future endomesoderm. We observed that the inhibition of the actin network densification - upon morpholinos injections (StbmMO) - inhibits the p-ßcat. This phosphorylation is mechanosensitive since we rescued p-ßcat levels to normal by compressing inhibited embryos. Through computer analysis, we found that the junctional actin signals and the p-ßcat signals are positively correlated. We postulate that the tensions induced by the actomyosin network, necessary for blastopore invagination, trigger the ßcat pathway. We also identified genes whose expression is altered by StbmMO injections and so maybe by mechanical constraint inhibition. These results indicate that the ßcat mechanosensitive pathway is conserved in a cnidarian and therefore dates back more than 600 million years

Conservation entre Cnidaires et Bilatériens d’une voie mécanosensible induisant la formation de l’endomésoderme

The emergence of the mesoderm is an important -but still poorly understood- evolutionary transition. Previously, the team identified a mechanosensitive pathway inducing mesoderm specification in bilaterian embryos. The mechanical constraints of the first morphogenetic movements induce the phosphorylation of the junctional ßcat and the activation of the pathway. To test its evolutionary origins, we worked on the cnidarian Nematostella vectensis, who diverged from bilaterians more than 600 million years ago. We tested the activation of the ßcat mechanosensitive pathway by mechanical cues and its role in endomesoderm specification. By carrying out immunofluorescence imaging at the gastrulation stage, we showed that the ßcat is phosphorylated (p-ßcat) in the constricted cells of the future endomesoderm. We observed that the inhibition of the actin network densification - upon morpholinos injections (StbmMO) - inhibits the p-ßcat. This phosphorylation is mechanosensitive since we rescued p-ßcat levels to normal by compressing inhibited embryos. Through computer analysis, we found that the junctional actin signals and the p-ßcat signals are positively correlated. We postulate that the tensions induced by the actomyosin network, necessary for blastopore invagination, trigger the ßcat pathway. We also identified genes whose expression is altered by StbmMO injections and so maybe by mechanical constraint inhibition. These results indicate that the ßcat mechanosensitive pathway is conserved in a cnidarian and therefore dates back more than 600 million years.L'émergence du mésoderme est une transition évolutive importante mais encore mal comprise. Précédemment, l’équipe a identifié une voie mécanosensible induisant la différenciation du mésoderme chez des embryons bilatériens. Les contraintes mécaniques des premiers mouvements morphogénétiques induisent la phosphorylation de la ßcat jonctionnelle et l’activation de la voie. Pour en tester les origines évolutives, nous avons travaillé sur le cnidaire, Nematostella vectensis, dont le dernier ancêtre commun avec les bilatériens remonte à plus de 600 millions d'années. Nous avons testé l'activation de la voie mécanosensible ßcat suite à la gastrulation. En réalisant des immunofluorescences, nous avons montré que la ßcat est phosphorylée (p-ßcat) dans les cellules constrictées du futur endomésoderme en début de gastrulation. Nous avons observé que l'inhibition de la densification du réseau d'actine - par injections de morpholinos de Strabismus (StbmMO) - inhibe la p-ßcat. Cette phosphorylation est mécanosensible puisque nous avons ramené les niveaux de p-ßcat à la normale en comprimant les embryons inhibés. Grâce à une analyse informatisée, nous avons révélé que les signaux d'actine jonctionnelle et de p-ßcat sont positivement corrélés. Nous postulons que les tensions induites par le réseau d’actomyosine, nécessaires à l'invagination du blastopore, déclenchent la voie ßcat. Nous avons commencé à tester la fonctionnalité de cette voie en identifiant des gènes dont l'expression est modifiée par injections de StbmMO. Ces résultats indiquent que la voie mécanosensible ßcat est conservée et remonte donc à plus de 600 millions d'années

Trans-scale mechanotransductive cascade of biochemical and biomechanical patterning in embryonic development: the light side of the force

International audienceEmbryonic development is made of complex tissue shape changes and cell differentiation tissue patterning. Both types of morphogenetic processes, respectively biomechanical and biochemical in nature, were historically long considered as disconnected. Evidences of the biochemical patterning control of morphogenesis accumulated during the last 3 decades. Recently, new data revealed reversal mechanotransductive feedback demonstrating the strong coupling between embryonic biomechanical and biochemical patterning. Here we will review the findings of the emerging field of mechanotransduction in animal developmental biology and its most recent advancements. We will see how such mechanotransductive cascade of biochemical and mechanical patterning events ensures trans-scale direct cues of co-regulation of the microscopic biomolecular activities with the macroscopic morphological patterning. Mechanotransduction regulates many aspects of embryonic development including efficient collective cell behaviour, distant tissues morphogenesis coordination, and the robust coordination of tissue shape morphogenesis with differentiation

Achievement of insulin independence in three consecutive type-1 diabetic patients via pancreatic islet transplantation using islets isolated at a remote islet isolation center

As a result of advances in both immunosuppressive protocols and pancreatic islet isolation techniques, insulin independence has recently been achieved in several patients with type 1 diabetes mellitus via pancreatic islet transplantation (PIT). Although the dissemination of immunosuppressive protocols is quite easy, transferring the knowledge and expertise required to isolate a large number of quality human islets for transplantation is a far greater challenge. Therefore, in an attempt to centralize the critical islet processing needed for islet transplantation and to avoid the development of another islet processing center, we have established a collaborative islet transplant program between two geographically distant transplant centers. Three consecutive patients with type 1 diabetes mellitus with a history of severe hypoglycemia and metabolic instability underwent PIT at the Methodist Hospital (TMH), Houston, Texas, using pancreatic islets. All pancreatic islets were isolated from pancreata procured in Houston and subsequently transported for isolation to the Human Islet Cell Processing Facility of the Diabetes Research Institute (DRI) at the University of Miami, Miami, Florida. Pancreatic islets were isolated at DRI after enzymatic ductal perfusion (Liberase-HI) by the automated method (Ricordi Chamber) using endotoxin-free and xenoprotein-free media. After purification, the islets were immediately transported back to TMH and transplanted via percutaneous transhepatic portal embolization. Immunosuppression consisted of sirolimus, tacrolimus, and daclizumab. After donor cross-clamp in Houston, donor pancreata arrived at DRI and the isolation process began within 6.5 hr in all cases (median, 5.4 hr; range, 4.8-6.5 hr). At the completion of the isolation process, the islets were immediately transported back to TMH and transplanted. All three patients attained sustained insulin independence after transplantation of 395,567, 394,381, and 563,206 pancreatic islet equivalents (IEQ), respectively. Despite insulin independence, the first two patients received less than 10,000 IEQ/kg; therefore, to increase their functional pancreatic islet reserve, they underwent a second islet transplant with 326,720 and 768,132 IEQ, respectively. Posttransplantation follow-up for these three patients is 4, 3, and 0.5 months, respectively. The mean glycosylated hemoglobin values have been dramatically reduced in the first two patients. In addition, the mean amplitude of glycemic excursions have also been reduced in all three recipients (patient 1: before transplantation 197 mg/dL vs. after transplantation 61 mg/dL; patient 2: before transplantation 202 mg/dL vs. after transplantation 52 mg/dL; patient 3: before transplantation 245 mg/dL vs. after transplantation 58 mg/dL) after PIT. All pancreatic islet allografts demonstrated the ability to respond to an in vitro glucose stimulus at the DRI before shipment and at TMH after shipment and final processing with a median stimulation index of 2.1 and 2.2, respectively. None of the transplant recipients have had a hyper- or hypoglycemic episode since PIT and no complications have occurred. These early data demonstrate that (1) pancreatic islets remain viable after shipment to remote transplant sites; (2) pancreatic islet isolation techniques and experience can be concentrated at a small number of regional facilities that could supply islets to remote transplant centers; and (3) insulin independence via PIT can be achieved using a remote pancreatic islet isolation center

Mechano-biochemical marine stimulation of inversion, gastrulation, and endomesoderm specification in multicellular Eukaryota

International audienceThe evolutionary emergence of the primitive gut in Metazoa is one of the decisive events that conditioned the major evolutionary transition, leading to the origin of animal development. It is thought to have been induced by the specification of the endomesoderm (EM) into the multicellular tissue and its invagination (i.e., gastrulation). However, the biochemical signals underlying the evolutionary emergence of EM specification and gastrulation remain unknown. Herein, we find that hydrodynamic mechanical strains, reminiscent of soft marine flow, trigger active tissue invagination/gastrulation or curvature reversal via a Myo-II-dependent mechanotransductive process in both the metazoan Nematostella vectensis ( cnidaria ) and the multicellular choanoflagellate Choanoeca flexa. In the latter, our data suggest that the curvature reversal is associated with a sensory-behavioral feeding response. Additionally, like in bilaterian animals, gastrulation in the cnidarian Nematostella vectensis is shown to participate in the biochemical specification of the EM through mechanical activation of the β-catenin pathway via the phosphorylation of Y654-βcatenin. Choanoflagellates are considered the closest living relative to metazoans, and the common ancestor of choanoflagellates and metazoans dates back at least 700 million years. Therefore, the present findings using these evolutionarily distant species suggest that the primitive emergence of the gut in Metazoa may have been initiated in response to marine mechanical stress already in multicellular pre-Metazoa. Then, the evolutionary transition may have been achieved by specifying the EM via a mechanosensitive Y654-βcatenin dependent mechanism, which appeared during early Metazoa evolution and is specifically conserved in all animals