August 2014

August brings some basic science, genetics and optometry research to the eye blog. If you have any comments of suggestions please do contact me, I would love to hear from you.

 

Elewys Hearne

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Cholecystokinin octapeptide antagonizes apoptosis in retinal pigment epithelial cells

 

Oxidative stress can cause retinal pigment epithelial (RPE) cell apoptosis. Nitric oxide and superoxide react to produce peroxynitrite, which, along with its derivatives, are strong oxidants. Cholecystokinin octapeptide-8 (CCK-8) can protect cholinergic neurons against basal forebrain lesions caused by brain injury.

Dr. Yuan Liu research team in China treated human RPE cells with the oxidative stress inducer peroxynitrite, and evaluated the neuroprotective effects of CCK-8. Peroxynitrite triggered apoptosis in these cells, and increased the expression of Fas-associated death domain, Bax, caspa-se-8 and Bcl-2.

These changes were suppressed by treatment with CCK-8. These results suggest that cholecystokinin octapeptide-8 can protect human retinal pigment epithelial cells against apoptosis induced by peroxynitrite.

References:

 

Liu Y, Zhang YL, Gu ZH, Hao LN, Du J, Yang Q, Li SP, Wang LY, Gong SL. Cholecystokinin octapeptide antagonizes apoptosis in human retinal pigment epithelial cells. Neural Regen Res. 2014;9(14):1402-1408.

 

Inhibiting FGF pathways in the eye may help patients with age-related macular degeneration or diabetic retinopathy

 

Mice missing two important receptor proteins of the vascular system (FGFR1 and FGFR2) develop normally and appear healthy in adulthood, as long as they don't become injured. If they do become injured, their wounds don't heal properly. This may have implications for treating diseases involving abnormal blood vessel growth, such as the impaired wound healing often seen in diabetes mellitus and the loss of vision caused by macular degeneration.

FGF proteins are signaling molecules that play broad roles in embryonic development, tissue maintenance, and wound healing. They interact with specific receptor molecules, FGF receptors (FGFRs), located on the surface of many types of cells in the body.

When an organ is injured, the healing process involves the growth of new blood vessels. Since the cells lining the interior of blood vessels and blood cells themselves are important for developing new vasculature, the authors asked what would happen if they turned off signaling of the FGFR1 and FGFR2 proteins, two major mediators of the FGF signal that are present in the cells that line blood vessels. Their strategy differed from past studies, which shut down this signaling more broadly.

 The mutant mice appeared normal; running around and lived to an average age. Genetic tests were performed to confirm the mutant mice actually lacked these proteins, which they did. When the authors challenged these mice, they saw that they healed from a skin injury more slowly than their normal littermates, and that the density of blood vessels surrounding the injury site was significantly decreased.

The investigators also looked at the eyes. Like any other organ, new blood vessels grow in the eye in response to disease or injury. However, unlike the rest of the body, new blood vessels are not desired here, since they bleed, cause scar tissue formation and block light to the retina, causing vision loss.

The paper suggests that increasing FGF signaling in the body might help improve wound healing by increasing new blood vessel growth following an injury. This particularly applies to those who have trouble healing, such as patients with diabetes-related foot ulcers. Human FGF2 is already in clinical use as a topical spray in Japan for foot ulcers and similar wound healing purposes.

Conversely, inhibiting these pathways in the eye might help patients with age-related macular degeneration or diabetic retinopathy. Such patients grow new blood vessels in response to these diseased or injured states, but the new vessels only serve to obscure vision, not help heal an abnormal eye. As this research suggests these FGF pathways are not involved with normal development and tissue maintenance, any treatments boosting or inhibiting these signals would likely not effect healthy tissue.

 

References:

 

Oladipupo S, Smith C, Santeford A, Park C, Sene A, Wiley LA, Osei-Owusu P, Hsu J, Zapata N, Liu F, Nakamura R, Lavine KJ, Blumer KJ, Choi K, Apte RS, Ornitz DM. Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis. PNAS Early Edition. Aug. 18, 2014.

 

http://www.medicalnewstoday.com/releases/281263.php accessed August 26th 2014

 

 

DNA test for congenital cataracts leads to faster, more accurate diagnoses of rare diseases linked to childhood blindness

 

Researchers in the United Kingdom have demonstrated that advanced DNA testing for congenital cataracts can quickly and accurately diagnose a number of rare diseases marked by childhood blindness, according to a study published online in Ophthalmology, the journal of the American Academy of Ophthalmology. Using a single test, doctors were able to tailor care specifically to a child's condition based on their mutations reducing the time and money spent on diagnosis and enabling earlier treatment and genetic counseling.

Each year, between 20,000 and 40,000 children worldwide are born with congenital cataracts, a disease that clouds the lens of the eye and often requires surgery and treatment to prevent blindness(1). The disease can arise following a maternal infection or be inherited as an isolated abnormality. Congenital cataracts can also appear as a symptom of more than 100 rare diseases, making mutations in the 115 genes associated with congenital cataracts useful as diagnostic markers for the illnesses.

Diagnosing these rare diseases previously proved a lengthy, costly and inconclusive process involving numerous clinical assessments and taking a detailed family history. DNA testing, one gene at a time, would have taken years to complete. Employing new DNA sequencing technology, called targeted next-generation sequencing, researchers at the University of Manchester sped up diagnosis to a matter of weeks by testing for mutations in all 115 known congenital cataracts genes at one time.

In 75 percent of the 36 cases tested, the DNA test determined the exact genetic cause of congenital cataracts. In one case, the DNA test helped diagnose a patient with Warburg Micro syndrome, an extremely rare disease that is marked by an abnormally small head and the development of severe epilepsy, among other medical issues. Having a clear diagnosis allowed for genetic counseling and appropriate care to be delivered quicker than previously possible without the test. The researchers also found previously undescribed mutations linked to cataract formation.

The test was made available to U.K. patients through the country's National Health Service in December 2013. Infants and children who have congenital cataracts can be tested as well as prospective parents with a history of the condition who wish to evaluate the risk to their child. Results generally take about two months. While only available in the U.K., the congenital cataract DNA test can be requested by registered medical facilities through international referral.

As with all genetic testing, the American Academy of Ophthalmology encourages clinicians and patients to consider the benefits as well as the risks. Ophthalmologists who order genetic tests either should provide genetic counseling to their patients themselves, if qualified to do so, or should ensure that counseling is provided by a trained individual, such as a board-certified medical geneticist or genetic counselor.

 

References

(1) Epidemiology of cataract in childhood: a global perspective, J Cataract Refract Surg. 1997;23 Suppl 1:601-4.

Personalized Diagnosis and Management of Congenital Cataract by Next-Generation Sequencing, Rachel L. Gillespie, MSc, James O’Sullivan, BSc, Jane Ashworth, FRCOphth, SanjeevBhaskar, MSc, Simon Williams, PhD, SusmitoBiswas, FRCOphth, Elias Kehdi, FRANZCO, Simon C. Ramsden, FRCPath, Jill Clayton-Smith, FRCP, Graeme C. Black, DPhil, FRCOphth, I. Christopher Lloyd, FRCOphth, Ophthalmology, DOI: 10.1016/j.ophtha.2014.06.006, published online 19 August 2014.

http://www.medicalnewstoday.com/releases/281442.php accessed 26th August 2014

Increased macular pigment may improve outdoor vision

Individuals with greater amounts of yellow pigment in the eye may be better able to see distant objects in hazy conditions. Increased macular pigment (MP) may help in filtering out "blue haze," thus making distant objects more visible.

The researchers tested the effects of MP on the ability to see distant objects through "atmospheric scattering," or haze. "All human eyes, and many animal eyes, contain an inert yellow pigment that is reported to be both protective and also slightly enhance vision, particularly in short wavelength (blue light) settings," Dr Adams explains. Some people have more MP than others.

The researchers designed an experiment to simulate hazy conditions to see if individuals with higher levels of MP can better see distant targets. Laboratory studies were performed using xenon light, paired with a specialized glass filter, to closely approximate the effects of atmospheric haze. The subjects varied widely in the density of MP present in the eye.

At increasing levels of simulated blue haze background, the visibility of distant objects decreased significantly. However, individuals with higher levels of MP required more stimulated haze before they could no longer see the distant target.

For subjects with the highest versus lowest levels of MP, there was about a twofold difference in the amount of haze required to lose sight of the distant object. The researchers write, "An individual with high MP optical density would be able to detect a target at a much greater distance (ie, more atmospheric haze between them and the target) than an individual with lower MP optical density."

The presence of yellow pigment in the macula represents accumulations of the nutrients lutein and zeaxanthin. By filtering out short-wave light, MP may protect long-term damage to the eye.

But from an evolutionary standpoint, it's much more likely that accumulations of MP could develop as a result of favorable effects on vision. The new findings support the "visibility hypothesis" of MP accumulation: by absorbing atmospheric haze, which is predominantly short-wavelength light, the presence of MP may extend visual range outdoors.

In this experiment, the effect seems large enough to provide a visual advantage of higher levels of MP for people who rely heavily on outdoor vision - for example, pilots. According to the authors, the next step in research would be to test the effects of different levels of MP on visibility in outdoor settings.

 References:

Visibility through Atmospheric Haze and Its Relation to Macular Pigment. Optometry & Vision Science: September 2014 - Volume 91 - Issue 9 - p 1089-1096