RAS activation is implicated in physiologic and pathologic cardiac hypertrophy. Cross-talk between the Ras and calcineurin pathways, the latter also having been implicated in cardiac hypertrophy, has been suspected for pathologic hypertrophy. Our recent discovery that germ-line mutations in RAF1, which encodes a downstream RAS effector, cause Noonan and LEOPARD syndromes with a high prevalence of hypertrophic cardiomyopathy provided an opportunity to elaborate the role of RAF1 in cardiomyocyte biology. Here, we characterize the role of RAF1 signaling in cardiomyocyte hypertrophy with an aim of identifying potential therapeutic targets. We modeled hypertrophic cardiomyopathy by infecting neonatal and adult rat cardiomyocytes (NRCMs and ARCMs, respectively) with adenoviruses encoding wild-type RAF1 and three Noonan/LEOPARD syndrome-associated RAF1 mutants (S257L, D486N or L613V). These RAF1 proteins, except D486N, engendered cardiomyocyte hypertrophy. Surprisingly, these effects were independent and dependent of mitogen activated protein kinases in NRCMs and ARCMs, respectively. Inhibiting Mek1/2 in RAF1 overexpressing cells blocked hypertrophy in ARCMs but not in NRCMs. Further, we found that endogenous and heterologously expressed RAF1 complexed with calcineurin, and RAF1 mutants causing hypertrophy signaled via nuclear factor of activated T cells (Nfat) in both cell types. The involvement of calcineurin was also reflected by down regulation of Serca2a and dysregulation of calcium signaling in NRCMs. Furthermore, treatment with the calcineurin inhibitor cyclosporine blocked hypertrophy in NRCMs and ARCMs overexpressing RAF1. Thus, we have identified calcineurin as a novel interaction partner for RAF1 and established a mechanistic link and possible therapeutic target for pathological cardiomyocyte hypertrophy induced by mutant RAF1.

Purpose of reviewThere is a rising interest in the impact of diet on the pathogenesis of common ophthalmic conditions. The purpose of this review is to summarize the potential preventive and therapeutic power of dietary interventions described in recent basic science and epidemiological literature. Recent findingsBasic science investigations have elucidated a variety of mechanisms by which diet may impact ophthalmic disease, particularly through its action on chronic oxidative stress, inflammation and macular pigmentation. Epidemiologic investigations have shown the real-world influence of diet on the incidence and progression of a number of ophthalmic diseases, particularly cataract, age-related macular degeneration (AMD) and diabetic retinopathy. A large observational cohort study found a 20% reduction in the incidence of cataract among vegetarians compared with nonvegetarians. Two recent systematic reviews found that higher adherence to Mediterranean dietary patterns was associated with a decreased risk of progression of AMD to later stages. Finally, large meta-analyses found that patients following plant-based and Mediterranean diets had significant reductions of mean haemoglobin A1c scores and incidence of diabetic retinopathy as compared with controls. SummaryThere is a significant and growing body of evidence that Mediterranean diet and plant-based diets --those that maximize fruits, vegetables, legumes, whole grains and nuts; and that minimize animal products and processed foods --help prevent vision loss from cataract, AMD and diabetic retinopathy. These diets may hold benefits for other ophthalmic conditions, as well. Nevertheless, there is a need for further randomized, controlled and longitudinal studies in this area.

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Purpose: To characterize retinal neurovasculature changes after small-incision lenticule extraction (SMILE) in myopic patients. Setting: Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University, China. Design: Prospective interventional study. Methods: The corrected distance visual acuity/uncorrected distance visual acuity, corrected intraocular pressure (CIOP), and corneal tomography were evaluated at baseline (PRE), postoperative day (POD) 1, and POD 7. Ganglion cell-inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thicknesses were measured. The vessel area densities (VADs, %), vessel skeleton densities (VSDs, %), vessel diameter index (VDI), and fractal dimensions (Dbox) of the superficial vascular plexus (SVP) and deep vascular plexus (DVP) were measured in a circular area (ϕ 2.5 mm) centered on the fovea. Results: A total of 38 myopic patients were recruited. The GCIPL thickness was increased after SMILE at POD 1 and POD 7 (P < .01) but no significant changes in the pRNFL thickness. The VAD, VSD, and Dbox of the SVP were decreased at POD 1 (P < .01), but not at POD 7. The VDI in small vessels of the SVP and DVP was decreased at POD 1 (P < .05) and increased at POD 7 (P < .05). Changes in CIOP were positively correlated with changes in the GCIPL thickness. Changes in CIOP were negatively correlated with changes in the VAD of small vessels and the Dbox of total vessels in the DVP. Changes in CIOP were negatively correlated with the VSD and VDI of small vessels in the DVP and changes in the VDI of big vessels in the SVP. Conclusions: The transient fluctuations in the retinal neurovasculature after SMILE may represent a characteristic homeostasis pattern in patients after refractive surgery.

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