A protein long thought to be one of the body's supporting players has quietly been taking a lead role in healthy eyesight, a discovery that could rapidly lead to treatments for babies born with retinopathy of prematurity, say University of Florida and Harvard Medical School researchers.

The finding, described in separate papers published in the June 19 Proceedings of the National Academy of Sciences, offers a new target for ROP therapies. In newborns with the disease, oxygen-starved areas of the retina compensate by quickly growing new blood vessels. But these new vessels are fragile and leaky.

"We've identified a protein that is part of the body's natural defenses in oxygen-deprived conditions," said Maria B. Grant, MD, a professor of pharmacology and therapeutics at UF's College of Medicine. "When babies are born before levels of this protein are normal, blood vessels spread abnormally throughout the retina. But if we can increase the protein to more normal levels in premature babies, it should result in healthier blood vessel growth."

The protein—insulin-like growth factor binding protein-3, or IGFBP-3—was thought to exist exclusively to regulate insulin-like growth factor-1, a molecular growth factor that is necessary for the development of nerve, muscle, bone, liver, kidney, lung, eye and other body tissues.

But in studies of mice and of human cells in cultures, scientists from the Program in Stem Cell Biology and Regenerative Medicine at UF's McKnight Brain Institute found that IGFBP-3 activates stem cells and other reparative cells of the bone marrow and the lining of blood vessels.

Researchers from Harvard Medical School and the University of Goteborg in Sweden arrive at essentially the same conclusion in  the same issue of PNAS, identifying the protein IGFBP-3 as a promising therapeutic agent after analyzing data from mouse and human studies.

"This discovery has a big future in helping premature babies," said Alexander V. Ljubimov, PhD, a professor of medicine at UCLA and director of Ophthalmology Research Laboratories at Cedars-Sinai Medical Center. "The idea is to administer this already clinically available protein to premature babies to stabilize the existing vessels in the retina, prevent their loss and block the compensatory growth of new, aberrant vessels. Finding the right dose may enable babies to cope with the first phases of their life without becoming blind."

Treatments based on IGFBP-3 could advance relatively quickly because it is a natural protein and presumably safe, said Dr. Ljubimov, who was not involved in the research. "The discovery has added credibility because independent research groups took different approaches to show essentially the same thing. There is independent confirmation from totally different research teams within the same journal."

UF researchers infused IGFBP-3 into one eye of each of nine mice before placing the animals into a high-oxygen chamber for five days. When scientists compared vascular growth within the retinas, they found blood vessels were closer to normal in eyes treated with IGFBP-3.

When UF scientists repeated the experiment in 18 mice treated with bone marrow stem cells expressing IGFBP-3, they found the treated eyes developed normally.

In addition to studies in mice, Harvard research collaborators in Sweden examined infants with retinopathy of prematurity in a prospective clinical study and found that the IGFBP-3 levels were lower than those of healthy infants, further suggesting that the protein helps prevent oxygen-induced blood vessel loss and promotes healthy vascular regrowth.

"The implications for retinopathy are that IGFBP-3 appears to have benefit in preventing vessel loss independent of insulin-like growth factor-1 in both the mouse model of oxygen-induced retinopathy and in infants with retinopathy of prematurity," said Lois E.H. Smith, MD, PhD, an associate professor of ophthalmology at Harvard Medical School and senior author of the Harvard study. "Supplementation to increase IGFBP-3 in premature infants at risk for ROP to normal levels in utero may prove beneficial in this disease.

"Harvard Medical School researchers and collaborators at the University of Goteborg are currently conducting a Phase 1 clinical study to evaluate the use of IGFBP-3 in combination with IGF-1 to examine the effects on prevention of retinopathy in premature infants, based on the clinical findings in our study," Dr. Smith said. "This work suggests that both IGF-1 and IGFBP-3 acting independently help prevent retinopathy."

 

Can Caffeine Treat Blepharospasm?

Drinking coffee may protect against blepharospasm, an Italian study suggests. Researchers at the University of Bari, Italy, looked at the coffee-drinking and smoking habits of 166 people with blepharospasm. One or two cups of coffee a day seemed to reduce the risk of the condition, the team reported in the Journal of Neurology, Neurosurgery and Psychiatry.

Professor Giovanni Defazio and colleagues from the Department of Neurological and Psychiatric Sciences at the university said a previous study had suggested that smoking had a protective effect on the condition. They compared smoking and drinking habits in patients with the condition with patients with hemifacial spasm and people who were relatives of patients.

In the current study there was no significant association found with smoking but those who drank coffee were less likely to develop the condition. The effect was proportional to the amount of coffee drunk and the age of onset of the spasm was also found to be greater in patients who drank more coffee—1.7 years for each additional cup per day.

Professor Defazio said, "Our findings raise doubt about the association of smoking and blepharospasm but strongly suggest coffee as a protective factor. The most obvious candidate for the protective effect is caffeine, but the low frequency of decaffeinated coffee intake in Italy prevented us from examining the effects of caffeine on blepharospasm."

He suggested that caffeine may block receptors in the brain that are associated with the tremor; a similar mechanism had been proposed for the protective effects of caffeine in Parkinson's disease.

Tom Warner, MD, a medical adviser to the Dystonia Society, said a much larger study was needed to confirm the findings. "Whilst the data is fascinating and offers new areas of research, it should not be accepted as a proven association and certainly does not mean we should be addressing our coffee intake," he said.

ASCRS Task Force Addresses Acanthamoeba and Lens Care

Following the May voluntary recall by Advanced Medical Optics of its Complete MoisturePlus contact lens solution, a task force of the American Society of Cataract and Refractive Surgery has issued guidelines regarding contact lens care and Acanthamoeba keratitis. The full report is available at ascrs.org. Among the recommendations of the ASCRS Infectious Disease Task Force:

 • Remove and return any AMO Complete MoisturePlus Solution from offices/places of work.

 • Advise all patients, and especially contact lens wearers, of the association of Acanthamoeba with AMO Complete MoisturePlus Solution so they may dispose of the solutions.

 •Recommend that all contact lens wearers rub their lenses with an alternate cleaning solution and avoid the "no rub" technique advocated by manufacturers.

 • Although suspicion should be kept high due to the increased risk of Acanthamoeba, bacterial infectious keratitis is still the most common etiology and should remain on top of the list of differential diagnoses.

 • Watch for the early signs of Acanthamoeba keratitis and use vital dyes to help differentiate these lesions from those caused by herpes simplex keratitis.

 • With cases of acute keratitis, unless it is of an abnormal appearance, larger than 2 mm in size, moderate to deep stromal melting, or is central or paracentral, begin treatment with intensive application of a topical broad spectrum antibiotic(s).

 • If the keratitis does not respond, or has any of the above unusual characteristics, obtain corneal scrapings and cultures to identify the pathogen. Confocal microscopy can aid in the diagnosis of Acanthamoeba.

 • For any contact lens patient with a suspected infection, contact lenses, cases, and cleaning solutions should be collected for culturing.

 • Steroids should be used with caution in the above concerning situations, and preferably only if the organism has been identified, and the patient is clinically responding to the treatment.

 • Early diagnosis is the key to improved outcomes so consider earlier referral to a specialist than usual.

 • Treatment involves extended and frequent dosing of at least one of the cystocidal biguanides (PHMB 0.02% and/or chlorhexidine 0.02%), and at least one other agent—neomycin, propamidine and/or clotrimazole, for weeks to months. In addition, the treating clinician may consider judicious use of oral itraconazole as an adjunct to topical therapy.