Retinitis pigmentosa (RP) is an inherited blinding disease characterized by progressive loss of retinal photoreceptors. There are numerous rodent models of retinal degeneration, but most are poor platforms for interventions that will translate into clinical practice. The rabbit possesses a number of desirable qualities for a model of retinal disease including a large eye and an existing and substantial knowledge base in retinal circuitry, anatomy, and ophthalmology. We have analyzed degeneration, remodeling, and reprogramming in a rabbit model of retinal degeneration, expressing a rhodopsin proline 347 to leucine transgene in a TgP347L rabbit as a powerful model to study the pathophysiology and treatment of retinal degeneration. We show that disease progression in the TgP347L rabbit closely tracks human cone-sparing RP, including the cone-associated preservation of bipolar cell signaling and triggering of reprogramming. The relatively fast disease progression makes the TgP347L rabbit an excellent model for gene therapy, cell biological intervention, progenitor cell transplantation, surgical interventions, and bionic prosthetic studies.

OFF-center retinal ganglion cells (RGCs) occupy a smaller proportion than ON RGCs when RGCs regenerate axons into a transplanted peripheral nerve. We examined whether the regeneration ability of OFF RGCs in adult cats was promoted when the numbers of regenerating RGCs were increased with brain-derived neurotrophic factor (BDNF)+ciliary neurotrophic factor (CNTF)+forskolin (BCF) or 3,4-dihydro-8-(2-hydroxy-3-isopropylamino)-propoxy-3-nitroxy-2H-1-benzopyran (nipradilol), an anti-glaucoma drug. ON or OFF RGCs were morphologically determined on the basis of their dendritic ramification in the inner plexiform layer using computational analysis. In the normal intact retina the ratio of ON and OFF RGCs (ON/OFF ratio) was 1.25 (55%/44%); whereas, it was 2.61 in regenerating RGCs with saline injection (control) 6 weeks after peripheral nerve transplantation. Estimated numbers of regenerating ON and OFF RGCs were 2149 and 895, respectively. An injection of BCF increased only numbers of ON RGCs into 5766 (2.7-fold to control) but not that of OFF RGCs, n=858. Nipradilol increased both estimated numbers of ON (11,518, 5.4-fold to control) and OFF RGCs (7330, 8.2-fold to control). In the retinas with optic nerve (OpN) transection and intravitreal saline-, BCF- or nipradilol-injection, numbers of ON and OFF RGCs surviving axotomy showed similar trend to that in regenerating RGCs. Thus, nipradilol promoted the survival and regeneration abilities of both of ON and OFF RGCs whereas BCF only did the abilities of ON RGCs. The distribution of tropo-myosin-related kinase B, BDNF receptor, was sparser in the outer two thirds of inner plexiform layer. The lower surviving ability of OFF-RGCs may be attributed in part to the distribution.

Detachment of photoreceptors from the retinal pigment epithelium is seen in various retinal disorders, resulting in photoreceptor death and subsequent vision loss. Cell death results in the release of endogenous molecules that activate molecular platforms containing caspase-1, termed inflammasomes. Inflammasome activation in retinal diseases has been reported in some cases to be protective and in others to be detrimental, causing neuronal cell death. Moreover, the cellular source of inflammasomes in retinal disorders is not clear. Here, we demonstrate that patients with photoreceptor injury by retinal detachment (RD) have increased levels of cleaved IL-1β, an end product of inflammasome activation. In an animal model of RD, photoreceptor cell death led to activation of endogenous inflammasomes, and this activation was diminished by Rip3 deletion. The major source of Il1b expression was found to be infiltrating macrophages in the subretinal space, rather than dying photoreceptors. Inflammasome inhibition attenuated photoreceptor death after RD. Our data implicate the infiltrating macrophages as a source of damaging inflammasomes after photoreceptor detachment in a RIP3-dependent manner and suggest a novel therapeutic target for treatment of retinal diseases.

We investigated the relation of overweight and obesity with cancer in a population-based cohort of more than 145 000 Austrian adults over an average of 9.9 years. Incident cancers (n=6241) were identified through the state cancer registry. Using Cox proportional-hazards models adjusted for smoking and occupation, increases in relative body weight in men were associated with colon cancer (hazard rate (HR) ratio 2.48; 95% confidence interval (CI): 1.15, 5.39 for body mass index (BMI) > or =35 kg m(-2)) and pancreatic cancer (HR 2.34, 95% CI: 1.17, 4.66 for BMI>30 kg m(-2)) compared to participants with normal weight (BMI 18.5-24.9 kg m(-2)). In women, there was a weak positive association between increasing BMI and all cancers combined, and strong associations with non-Hodgkin's lymphomas (HR 2.86, 95% CI: 1.49, 5.49 for BMI> or =30 kg m(-2)) and cancers of the uterine corpus (HR 3.93, 95% CI: 2.35, 6.56 for BMI> or =35 kg m(-2)). Incidence of breast cancer was positively associated with high BMI only after age 65 years. These findings provide further evidence that overweight is associated with the incidence of several types of cancer.