Cataract is the leading cause of vision loss worldwide but early noninvasive detection of the condition has, until now, remained elusive. However, a compact fiber optic probe developed for the space program is set to change this.
Researchers at the National Eye Institute (NEI; MD, USA), aimed to develop a simple, safe test for measuring a protein related to cataract development. The hope is that early detection of protein changes may allow individuals to make lifestyle changes, such as decreasing sun exposure, quitting smoking and controlling diabetes, to reduce their risk of cataracts progressing.
Manuel Datiles 3rd, lead author of the study, explains: “By the time the eye’s lens appears cloudy from a cataract, it is too late to reverse or medically treat this process. This technology can detect the earliest damage to lens proteins, triggering an early warning for cataract formation and blindness.”
The new device utilizes a laser light technique called dynamic light scattering that was originally developed to analyze the growth of protein crystals in a zero-gravity space environment. NEI vision researchers were made aware of the technology by NASA researcher Rafat R Ansari, after he discovered that his father’s cataracts were the result of changes in lens proteins.
Although a number of proteins are involved in cataract formation, one known as α-crystalline, which binds damaged proteins to stop them from agglomerating to form a cataract, acts as the eye’s anti-cataract molecule. However, humans are born with a fixed amount of α-crystalline and so, a cataract can form if the supply is depleted by factors such as diabetes and smoking.
The recent NEI–NASA clinical trial examined 380 eyes of people aged from 7 to 86 years who had lenses ranging from clear to severely cloudy as a result of cataracts. The dynamic light-scattering device was used to shine a low-power laser light through the lenses. α-crystallin’s light-scattering ability, which had been determined previously, was then used to detect and measure the amount of α-crystallin in the lenses. They found that as cloudiness increased, α-crystallin in the lenses decreased and that α-crystallin amounts also decreased as the participants’ ages increased, even when lenses were transparent. These age-related, pre-cataract changes would remain undetected by currently available imaging tools.
“We have shown that this noninvasive technology that was developed for the space program can now be used to look at the early signs of protein damage due to oxidative stress, a key process involved in many medical conditions, including age-related cataract and diabetes, as well as neurodegenerative diseases such as Alzheimer’s and Parkinson’s,” said Ansari. “By understanding the role of protein changes in cataract formation, we can use the lens not just to look at eye disease, but also as a window into the whole body.”
Source: Datiles MB 3rd, Ansari RR, Suh KI et al. Clinical detection of precataractous lens protein changes using dynamic light scattering. Arch. Ophthalmol. 126(12) 1687–1693 (2008).
Research sheds light on role of melanopsin retinal ganglion cells
Melanopsin retinal ganglion cells require bright light for activation, but produce a large signal that is transmitted directly to the brain, activating the pupillary reflex.
A team of researchers from Johns Hopkins University, MD, USA has shed light on how melanopsin retinal ganglion cells detect light and control the pupillary light reflex.
The team initially flashed light at individual photoreceptors from mice and recorded the electrical response to determine their sensitivity. They found melanopsin retinal ganglion cells to be less sensitive than cones.
“The next question was, what makes them so insensitive to light? Perhaps each photon they capture elicits a tiny electrical signal. Then there would have to be bright light – giving lots of captured photons – for a signal large enough to influence the brain. Another possibility is that these cells capture photons poorly,” said Michael Do, first author of the study.
In an effort to distinguish between these possibilities, the team flashed dim light at the cells. The light was so dim that, on average, only a single melanopsin molecule in each cell was activated by capturing a photon. The researchers found that each activated melanopsin molecule triggered a large electrical signal and, moreover, that this single-photon signal was transmitted all the way to the brain. The paradox that the cells tended to need very bright light for activation, but generated a very large signal was resolved when the team calculated the density of melanopsin molecules in the cells, finding them to be 5000 times sparser than other light-capturing molecules used for image-forming vision.
“It appears that these cells capture very little light. However, once captured, the light is very effective in producing a signal large enough to go straight to the brain,” said King-Wai Yau, a member of the research team. “The signal is also very slow, so it is not intended for detecting very brief changes in ambient light, but slow changes over time instead.”
To explore how melanopsin retinal ganglion cells affect behavior, the researchers examined pupil constriction in mice that had been genetically altered to be free of rod and cone function, allowing the researchers to record activity resulting only from melanopsin retinal ganglion cells. The degree of pupil constriction of mice that experienced flashes of light while in darkness was measured. On average, approximately 500 light-activated melanopsin molecules were enough to elicit a pupil response. “But it takes a lot of light to activate 500 molecules of melanopsin, thus the pupils close maximally only in bright light.” said Yau. “In terms of controlling the pupils and the body clock, it makes sense to have a sensor that responds slowly and only to large light changes – you wouldn’t want your body to think every cloud passing through the sky is nightfall.”
The team now intends to discover more about how information from melanopsin retinal ganglion cell is used by the brain: “These melanopsin-containing cells signal light to many different parts of the brain to drive different behaviors, from setting the circadian clock to affecting mood and movement,” says Do. “I want to know how these signals are processed and whether they are abnormal in disorders like seasonal affective disorder and jetlag.”
Source: Do MT, Kang SH, Xue T et al. Photon capture and signaling by melanopsin retinal ganglion cells. Nature 457, 281–287 (2008).
Link between statin therapy and eye disorders examined
Statin therapy aimed at reducing cholesterol and, thus, the incidence of adverse cardiovascular outcomes is linked to certain eye disorders in approximately 0.1% of patients. FW Fraunfelder of Oregon Health and Sciences University, OR, USA, and colleagues have explored this relationship for the first time, examining statin-associated reports of diplopia (double vision), ptosis (drooping upper eyelids) and ophthalmoplegia (weakened eyes muscles) in the databases of the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization, and the US FDA. A total of 256 patients with an average age of 64.5 years were involved.
In total, 23 cases of loss of eye range of motion, eight cases of ptosis, and 18 cases of ptosis in conjunction with diplopia occurred. Although disorders in all patients appeared to resolve completely when statins were discontinued, researchers could not determine which eye muscles were involved or the time needed to fully recover after statin discontinuation for individual cases. The average statin dose of patients with one or more eye disorder was within ranges recommended by drug manufacturers and the average time from beginning of therapy to developing an adverse drug reaction was 8.3 months.
“We advise physicians prescribing statins to be aware that these eye disorders may result and that medications should be discontinued, if so. When a patient has one of these eye disorders, he should be rigorously evaluated to determine the cause, and statin use should be taken into account,” Fraunfelder concluded.
Source: Fraunfelder FW, Richards AB. Diplopia, blepharoptis and ophthalmoplegia and 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor use. Ophthalmology 115(12), 2282–2285 (2008).
Mammalian retinal nerve cells will regrow in vivo
Research carried out at the University of Washington, WA, USA has demonstrated for the first time that the damaged mammalian retina is capable of regrowing inner nerve cells in vivo.
Tom Reh and colleagues studied a particular type of retinal cell called Müller glia. “This type of cell exists in all the retinas of all vertebrates, so the cellular source for regeneration is present in the human retina,” said Reh.
Müller glia generally stop dividing after a certain developmental stage. In both fish and birds, however, damage to retinal cells prompts Müller glia to begin dividing again and become progenitor cells. These progenitor cells are capable of generating several types of specialized nerve cells. However, this response is very limited in mammals. In an injured mouse or rat retina, cells may react and become larger, but few recommence division.
Researchers have tried to stimulate Müller glia to grow in vitro and in vivoby injecting cell growth factors or factors capable of reactivating certain genes that were silenced. Such studies demonstrated the ability of Müller glia to start dividing again and in some experiments, light-detecting receptors were generated. However, these studies were unable to detect any regenerated inner retinal nerve cells, except when the Müller glia were genetically modified with genes to specifically promote the formation of amacrine cells.
Reh et al. specifically eliminated ganglion cells and amacrine cells in the mouse retina with intraocular NMDA injections, and then, by injecting the eye with EGF, FGF1 or a combination of FGF1 and insulin, they were able to stimulate the Müller glia to recommence division and proliferate across the retina. The presence of markers of progenitor cells indicated that glia had transformed to this cell type and, subsequently, the presence of markers of amacrine cells suggested that some of these cells in turn had then become amacrine cells. Although many of the progenitor cells arising from the dividing Müller glia died within the first week after their production, those that managed to turn into amacrine cells survived for at least 30 days, thus demonstrating for the first time that the mammalian retina has the potential to regenerate inner retinal neurons in vivo.
Source: Karl MO, Hayes S, Nelson BR, Tan K, Buckingham B, Reh TA. Stimulation of neural regeneration in the mouse retina. Proc. Natl Acad. Sci. USA 105(49), 19508–19513 (2008).
Genetic cause of uveal melonoma discovered
Catherine Van Raamsdonk and colleagues from the University of British Columbia, Canada, have discovered a mutation in the GNAQ gene that may be responsible for nearly 45% of cases of uveal melanoma.
“We discovered that GNAQ regulates melanocyte survival,” says Van Raamsdonk. “When the GNAQ gene is mutated it leads to unregulated growth of melanocytes. Since cancer is a disease of unregulated cell growth, our findings led us to the discovery that a genetic mutation of the GNAQ gene causes uveal melanoma.”
Uveal melanoma arises from melanocytes located in the uveal tract, which is one of the three layers that make up the wall of the eye. The mutation in GNAQ leads to the activation of a signaling pathway that has previously been implicated in many other types of melanoma. The team also discovered that the mutation is instrumental in the development of a type of benign skin mole – blue nevi.
“Prior to our work, the mutations responsible for uveal melanoma were completely unknown,” says Van Raamsdonk. “No other research looked at mutations in GNAQ. The next step is to develop an effective treatment by targeting the specific biological processes that this mutated gene controls.”
Source: Van Raamsdonk CD, Bezrookove V, Green G et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature (2008) (Epub ahead of print).
Visual awareness unnecessary for navigation
Research published recently in Current Biology is the first evidence that people are able to successfully navigate an obstacle course even if brain damage has left them unaware of the ability to see and with no activity in the visual cortex.
The research was carried out in a patient known as TN, who was left blind by two consecutive strokes that damaged his visual cortices in both hemispheres. TN has an ability termed blindsight; although he is unaware of seeing, he still has the ability to detect objects in his environment. For example, he responds to the facial expressions of others, as indicated by activity in brain regions consistent with emotional expressions of fear, anger and joy. Despite this, he still navigates his environment like blind person, using a cane to negotiate obstacles.
To test his navigational ability, researchers constructed an obstacle course, consisting of randomly arranged boxes and chairs, and asked him to cross it without the aid of a cane or person. TN negotiated the course perfectly on every trial, never once colliding with any obstacle.
The experiment shows that alternative visual paths available in the brain can allow people to orientate themselves and rapidly detect obstacles in the environment without any conscious attention or experience of seeing them. “It’s a part of our vision that’s for orienting and doing in the world rather than for understanding,” said researcher Beatrice de Gelder of Tilburg University, The Netherlands. “All the time, we are using hidden resources of our brain and doing things we think we are unable to do.’’
Source: de Gelder B, Tamietto M, van Boxtel G et al. Intact navigation skills after bilateral loss of striate cortex. Curr. Biol. 18(24), R1128–R1129 (2008).
Study on retinal prostheses increases patient enrollment
Promising early results of the Argus™ II Retinal Implant study give hope to those suffering from autoretinal degeneration diseases.
The Argus™ II Retinal Implant study on retinal prostheses will increase patient enrollment, following positive results from the first 17 participants in the study so far. Second Sight Medical Products, Inc. announced that this increase in patient enrollment in the 3-year feasibility study, currently underway in the USA, Europe and Mexico, will take place in clinical sites in Europe for patients blinded by the genetic eye disease retinitis pigmentosa. “We are encouraged by the results we have seen in the seventeen individuals that have participated in the study so far,” reports Robert Greenberg, President and CEO of Second Sight. “We are now expanding our trial enrollment in order to strengthen our data, further demonstrate clinically meaningful performance and begin the process of seeking market approval.”
Currently, retinal prostheses are the only option for blind people suffering from outer retinal degeneration diseases, such as retinitis pigmentosa. The Argus II consists of a 60 electrode grid that is implanted into the retina. These electrodes send signals to the brain that are collected from a video camera, worn by implanted persons in a pair of eye glasses. The implant is supposed to last a lifetime, although a safe removal is possible. The 17 individuals so far implanted have been enrolled in the study for an average of 14 months. The reports on the orientation and mobility of the implanted subjects were promising. Implanted people could locate a door up to 20 ft away and walk to the end of a 20 ft line drawn on the floor. Mark Humayun from the Doheny Eye Institute in Los Angeles, CA, USA reported no device failures and few serious adverse effects in the 17 transplanted individuals, the most serious resulting in safe removal of the device.
“These first results hold a novel and quite unprecedented promise for blind subjects as well as the physicians and researchers that have the opportunity to participate in this pioneering endeavor … We now have a strong incentive for continuing and expanding the efforts in testing this new technology.” commented Jose-Alain Sahel from the Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, Paris, France. In Europe, the Moorfields Eye Hospital in London, UK, the Hôpital Cantonal Universitaire de Genève in Geneva, Switzerland and the Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts in Paris, France are taking part in this feasibility study. Support of the new technology was announced by the British Retinitis Pigmentosa Society, Retina France, the Fédération des Aveugles de France and the Fondation Ophtalmologique Rothschild. Christina Fasser, President of Retina International and CEO of Retina Switzerland, added “Retina International and its members in more than 40 countries are excited that this innovative research is now in critical clinical trials and that it is bringing hope to thousands of people with advanced retinal disease.”
Source: www.2-sight.com/News.htm
New intraocular lens for cataracts gains US FDA approval
Device: +3.0 D add power AcrySof® IQ ReSTOR® intraocular lens
Manufacturer: Alcon Inc.
Indication: Presbyopia in cataract patients
Eye care company Alcon Inc. have announced that the US FDA has approved its +3.0 D add power AcrySof® IQ ReSTOR® intraocular lens (IOL) for the correction of presbyopia in cataract patients. This IOL is a new addition to the AcrySof IQ ReSTOR platform in the USA, having been released in several other major markets early in 2008. Clinical trials in the USA included a 3-month follow-up examination of the patients’ visual acuities at near, intermediate and far distances.
The number of trial participants achieving 20/20 visual acuity or better at all three of the distances was four times greater in the +3.0 D AcrySof IQ ReSTOR IOL group compared with the trial group that received a control lens. The results of the clinical studies also showed that 95% of patients who received the +3.0 D IOL were satisfied with the lens and would have the same IOL implanted again. Kelly Solomon, Professor of Ophthalmology, Medical University of South Carolina (SC, USA) and Medical Director at the Storm Eye Institute, one of the study investigators, described the benefits of the new lens. “The introduction of this lens allows me to deliver a full range of quality vision for my patients’ needs, lifestyles and personal preferences. In my experience, the AcrySof IQ ReSTOR +3.0 D IOL gives my patients a more comfortable reading distance, improved intermediate vision for tasks such as computer work and excellent distance vision.” Alcon are optimistic that the introduction of the new IOL in the USA will allow a large number of cataracts patients to not wear spectacles following cataract surgery.
Source: Alcon Inc. www.alcon.com/en/index.asp