Misaligned foveal morphology and sector retinal dysfunction in AKT1-mosaic Proteus syndrome.

PURPOSE: Proteus syndrome arises as a result of a post-zygotic mosaic activating mutation in the AKT1 oncogene, causing a disproportionate overgrowth of affected tissues. A small number of ocular complications have been reported. We present the unique findings in a patient who had molecular confirmation of AKT1 mosaicism alongside fulfilling the clinical criteria for Proteus syndrome. METHODS: Pattern electroretinography, visual evoked potentials and multifocal electroretinography testing were performed alongside detailed retinal imaging and clinical examination to detail the ophthalmic characteristics. RESULTS: Electrophysiological findings characterised unilateral macular dysfunction alongside sector retinal dysfunction of the right eye. This was demonstrated through optical coherence tomography and ultra-wide-field imaging to be associated with a misaligned foveal morphology and sector retinal dysfunction extending into the temporal retina. CONCLUSION: We propose this patient has asymmetric foveal development and concomitant sector retinal dysfunction as the result of the mosaic AKT1 mutation, either through disruption in the retinal PI3K-AKT1 signalling pathway or through mechanical distortion of ocular growth, resulting in disproportionate inner retinal development. The findings expand the ocular phenotype of Proteus syndrome and encourage early assessment to identify any incipient ocular abnormalities.

Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction.

Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16INK4A during human skin ageing. Aged melanocytes also display additional markers of senescence such as reduced HMGB1 and dysfunctional telomeres, without detectable telomere shortening. Additionally, senescent melanocyte SASP induces telomere dysfunction in paracrine manner and limits proliferation of surrounding cells via activation of CXCR3-dependent mitochondrial ROS. Finally, senescent melanocytes impair basal keratinocyte proliferation and contribute to epidermal atrophy in vitro using 3D human epidermal equivalents. Crucially, clearance of senescent melanocytes using the senolytic drug ABT737 or treatment with mitochondria-targeted antioxidant MitoQ suppressed this effect. In conclusion, our study provides proof-of-concept evidence that senescent melanocytes affect keratinocyte function and act as drivers of human skin ageing.

Kaempferol ameliorates hyperglycemia through suppressing hepatic gluconeogenesis and enhancing hepatic insulin sensitivity in diet-induced obese mice.

Obesity-associated insulin resistance (IR) is a major risk factor for developing type 2 diabetes and an array of other metabolic disorders. In particular, hepatic IR contributes to the increase in hepatic glucose production and consequently the development of fasting hyperglycemia. In this study, we explored whether kaempferol, a flavonoid isolated from Gink go biloba, is able to regulate hepatic gluconeogenesis and blood glucose homeostasis in high-fat diet-fed obese mice and further explored the underlying mechanism by which it elicits such effects. Oral administration of kaempferol (50 mg/kg/day), which is the human equivalent dose of 240 mg/day for an average 60 kg human, significantly improved blood glucose control in obese mice, which was associated with reduced hepatic glucose production and improved whole-body insulin sensitivity without altering body weight gain, food consumption or adiposity. In addition, kaempferol treatment increased Akt and hexokinase activity, but decreased pyruvate carboxylase (PC) and glucose-6 phosphatase activity in the liver without altering their protein expression. Consistently, kaempferol decreased PC activity and suppressed gluconeogenesis in HepG2 cells as well as primary hepatocytes isolated from the livers of obese mice. Furthermore, we found that kaempferol is a direct inhibitor of PC. These findings suggest that kaempferol may be a naturally occurring antidiabetic compound that acts by suppressing glucose production and improving insulin sensitivity. Kaempferol suppression of hepatic gluconeogenesis is due to its direct inhibitory action on the enzymatic activity of PC.

Evaluation of whether intracameral dexamethasone predisposes to glaucoma after pediatric cataract surgery.

PURPOSE: To evaluate the effect of intracameral dexamethasone during pediatric cataract surgery on the incidence of postoperative glaucoma. SETTING: Clinical and Academic Department of Ophthalmology, Great Ormond Street Hospital, London, United Kingdom. DESIGN: Retrospective case series. METHODS: This case-note review comprised all infants who had cataract surgery with intraocular lenses between January 1, 2007, and December 31, 2008, and were given preservative-free intracameral dexamethasone intraoperatively. The definition of glaucoma was an intraocular pressure (IOP) of 21 mm Hg or greater on more than 2 occasions or moderate or firm digital IOP with 1 of the following: myopic shift, increased cup-to-disc ratio, increased horizontal corneal diameter, or corneal edema. RESULTS: Eighteen patients (24 eyes) were included. The median age at surgery was 3 months (mean 4 months ± 3 (SD); range 1 to 11 months). The median follow-up was 38 months (mean 34 ± 10 months; range 20 to 48 months). In 4 eyes, transient postoperative antihypertensive medication was used; however, no eye developed glaucoma during the follow-up period. Fifteen eyes had a second procedure to clear the visual axis due to posterior visual axis opacification a mean of 6.4 ± 3.5 months postoperatively (median 4.8 months; range 3.5 to 14.5 months); however, no eye developed anterior membranes. CONCLUSION: Intracameral preservative-free dexamethasone in infantile cataract surgery did not seem to cause an increased risk for glaucoma and appeared to protect against anterior membrane formation.

On the measurement of human osteosarcoma cell elastic modulus using shear assay experiments.

This paper presents a method for determining the elastic modulus of human osteosarcoma (HOS) cells. The method involves a combination of shear assay experiments and finite element analysis. Following in-situ observations of cell deformation during shear assay experiments, a digital image correlation (DIC) technique was used to determine the local displacement and strain fields. Finite element analysis was then used to determine the Young's moduli of HOS cells. This involved a match of the maximum shear stresses estimated from the experimental shear assay measurements and those calculated from finite element simulations.