Lanosterol revealed clues for cataract prevention and treatment

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Posted on 10th August 2015 by Pacific ClearVision Institute in Cataracts |General

On July 30, 2015, researchers from Sichuan University, Sun Yat-sen University, University of California, BGI, etc, reported the latest study on congenitalcataracts. The finding, published on Nature, identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.

Cataracts are the most common cause of blindness worldwide, accounting for over half of all cases of blindness worldwide. Currently the only treatment is surgical removal of cataractous lenses. High concentrations of crystallin proteins in lens fibers contribute to lens transparency and refractive properties. Protein aggregation is the single most important factor in cataract formation. Factors that lead to protein aggregation include mutations in crystallin proteins, which are known to cause congenital cataracts, or oxidative stress, which in turn contributes to age-related cataracts. However, the precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown.

Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cycliza¬tion reaction of a cholesterol synthesis pathway. Previous study showed that the specific combination of hypomorphic mutations on LSS could decrease cholesterol levels in the lens and result in cataracts in rats.

In the study, researchers identified novel homozygous mutations in the LSS gene in two consanguineous families and investigate the ability of lanosterol to alleviate protein aggregation and cataract formation. They found that, treatment by lanosterol significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. They further show that lanosterol treatment could reduce cataract severity and increase transparency in animal models.

Dr. Xin Jin, Project Leader of BGI, stated, “This project is aimed to discover casual genes for congenital cataracts. Then we uncovered that gene LSS responsible for two affected families involved in the study. This is extremely exciting when we noticed that the discovery might lead to a novel and simple strategy for the prevention and treatment of cataracts. It encourages us to have more efforts from bench to bed-side.”

Cataract culprits: Genes linked to cataract formation identified

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Posted on 10th August 2015 by Pacific ClearVision Institute in Cataracts |General

When cataracts encroach on the eyes, the only effective remedy is to surgically replace the eyes’ lenses with synthetic substitutes.

But what if scientists found a way to delay or prevent cataracts from forming in the first place?

Researchers at the University of Delaware may have found such an opportunity by identifying the prime suspects in the formation of cataracts — deficiency of two genes that encode regulatory proteins.

When those two genes are unable to do their work, the lenses of the eyes become cloudy and develop cataracts, no aging process or damaging exposure to radiation required.

Cataracts, the leading cause of blindness, can have a genetic basis.

The discoveries emerged in the laboratory of UD biologist Salil Lachke, assistant professor of biological sciences and a Pew Scholar in biomedical sciences.

Lachke and graduate students Smriti Agrawal, Archana Siddam and post-doctoral fellow Deepti Anand study lens development in mice to better understand the genetic mechanisms that lead to cataracts in humans.

Their findings, published in the journal Human Genetics, could contribute to interventions that one day delay or prevent cataract formation, which now afflicts more than half of the U.S. population over 80 years old and costs Medicare an estimated $3 billion in treatment every year.

The study was supported by a grant from the National Institutes of Health (NIH) and a Fight For Sight grant-in-aid award to Lachke.

Lachke compares the lens of the eye to the lens of a camera. A clear lens, free of internal scratches and other damage, transmits a clear image to the retina. Vision is impaired and can be lost completely when lens deterioration is unaddressed.

Lachke and his students wanted to understand the genetic factors involved in keeping the lens transparent and whether disrupting their function allowed cataracts to form.

They found answers in the proteins that regulate expression of genes necessary for transparency, demonstrating that deficiency of two regulatory proteins — called Mafg and Mafk — led to formation of cataracts.

The lens of the eye is made up of several kinds of proteins, Lachke said. Some are essential to transcribing genetic information and promoting healthy development.

To zero in on the genes essential to lens transparency — distinguishing them from normal day-to-day genetic function — Lachke’s lab used the integrated Systems Tool for Eye Gene Discovery (iSyTE), a web-based bioinformatics tool initiated by Lachke during his post-doctoral work at Harvard Medical School and now hosted at UD’s Center for Bioinformatics and Computational Biology.

With iSyTE, Lachke and his fellow researchers were able to identify the genes critical to lens formation and develop a detailed roadmap of the network controlled by the Mafg and Mafk proteins.

When these regulatory proteins were compromised, several genes responsible for lens transparency were “turned down” and cataracts formed about four months after birth.

“The lens pathology in the compound mutants is severe,” said Agrawal, now studying human genetics in a doctoral program at the Baylor College of Medicine in Texas. “The lens appears to be completely opaque and the fiber cells that comprise the tissue lose their structural organization.”

Using a microarray — a collection of thousands of DNA probes on a small chip — researchers can look at the expression of all the genes in the lens, Agrawal said, and bioinformatics allows them to identify the specific targets of regulatory proteins such as Mafg and Mafk.

The discoveries were exciting to be part of, she said.

“When I first found out that the mutant mice exhibited cataract, I ran to Dr. Lachke,” she said.

It was a “eureka!” moment, she said.

The iSyTE tool has many other uses, Lachke said, and it is available to other researchers and to the public.

“In just four years, application of the iSyTE tool has significantly expedited eye disease gene discovery, having led to identification of several new — and often unexpected — genes linked to cataracts,” he said.

The list of iSyTE-identified genes includes a novel post-transcriptional regulator called TDRD7, commonly involved in germ cell development across various animal species, he said. TDRD7 was shown by Lachke to be linked to human cataract in a research article published in Science.

“There are 22,000 protein-coding genes in our genome — and far less than half are characterized,” Lachke said. “Extending the iSyTE approach to other components of the eye and other tissues or organs will greatly expedite disease gene discovery and advance our understanding of the human genome.”

Working with Lachke has been an outstanding experience, his three co-authors said.

“He gives us intellectual freedom,” Siddam said. “We always go back and run our ideas through him, but he will challenge you and make you think outside the box.”

“He likes to include state-of-the-art approaches,” Anand said. “He never says ‘No’ — he tries to understand our ideas.”

“And even if they are almost technically impossible, he would never just say ‘No,’” Siddam said. “He would appreciate the thought process.”

Innovation and discovery happens more freely in such an environment, they said.

“If you want to make breakthroughs, you need to take risks,” Anand said.

Agrawal said working with Lachke on cataract research at UD inspired her to pursue her doctorate research on understanding the genetic basis of other eye diseases. Her research now focuses on retinal diseases.

Siddam said top researchers from around the world approached them at a recent conference to discuss the work of the Lachke Lab.

“The credibility of the research here drives us to do more,” she said.

Americans rate losing eyesight as having greatest impact on their lives

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Posted on 11th October 2014 by Pacific ClearVision Institute in Cataracts |General

Many Americans across racial and ethnic groups describe losing eyesight as potentially having the greatest impact on their day-to-day life, more so than other conditions including: loss of limb, memory, hearing and speech (57% of African-Americans, 49% of non-Hispanic whites, 43% of Asians and 38% of Hispanics). When asked which disease or ailment is the worst that could happen to them, blindness ranked first among African-Americans followed by AIDS/HIV. Hispanics and Asians ranked cancer first and blindness second, while Alzheimer’s disease ranked first among non-Hispanic whites followed by blindness.

When asked about various possible consequences of vision loss, “quality of life” ranked as the top concern by non-Hispanic whites (73%) and Asians (68%) while African-Americans (66%) and Hispanics (63%) ranked “loss of independence” as number one. These and other findings from a new national public opinion poll commissioned by Research!America and the Alliance for Eye and Vision Research (AEVR) point to various perspectives among racial and ethnic groups regarding eye and vision health.

“Every segment of the population has major concerns about the impact of eye disorders on quality of life,” said Mary Woolley, president and CEO of Research!America. “Individuals realize the importance of good eye health in maintaining productive lives and fear its loss. But the reality is that advances in the prevention and treatment of eye disorders will not be possible without stronger investments in research.”

National support of research that focuses on improving the prevention and treatment of eye and vision disorders is considered a priority among a strong majority of respondents (83% of African-Americans and non-Hispanic whites, 80% of Asians and 79% of Hispanics). When told that the federal government spends on average $2.10 per person each year on such research, half of African-Americans (51%) and Hispanics (50%) say this is not enough followed by non-Hispanic whites (47%) and Asians (35%). About half of all groups believe that non-governmental sectors — industry, patient groups and philanthropies — should also increase funding for eye and vision research (57% of Hispanics, 51% of African-Americans, 49% of Asians and 47% of non-Hispanic whites).

Knowledge about specific eye disorders was uneven among populations. More than half of all groups have heard of cataracts and glaucoma but fewer were aware of age-related macular degeneration (AMD) and diabetic eye disease. Hispanics (35%) and Asians (31%) are more likely to say they have not heard of these conditions compared to 22% of non-Hispanic whites and African-Americans.

As for causes of eye disorders, a majority of all respondents (80% of non-Hispanic whites, 77% of Hispanics, 76% of Asians and 70% of African-Americans) believe that excessive sunlight or ultraviolet radiation is a risk factor for eye disease along with ethnic heritage (64% of Asians, 60% of non-Hispanic whites, 59% of Hispanics and 52% of African-Americans). Chronic exposure of eyes to sunlight can cause cataracts and macular degeneration as well as eye irritation. Minority groups are often at a higher risk for vision impairment and blindness due to higher rates of certain eye conditions such as glaucoma, cataract and diabetic retinopathy.

More than half of Asians (57%), Hispanics and non-Hispanic whites (52%) and a plurality of African-Americans (42%) agree that obesity is also associated with greater risk for eye disease, and 62% of Hispanics, 60% of Asians, 54% of non-Hispanic whites and 48% of African-Americans agree smoking is a risk factor. Research has shown the risks of AMD, diabetic retinopathy, cataract and glaucoma increase with obesity-related systemic diseases such as diabetes or a high body mass index (BMI), abdominal circumference or waist-hip ratio. Smoking also increases the risk of AMD, cataracts, glaucoma, diabetic retinopathy and chronic dry eye.

Looking ahead, many respondents believe health care costs from eye disorders will increase by the year 2050 (62% of non-Hispanic whites, 58% of Asians, 54% of Hispanics and 50% of African-Americans). A June 2014 report by Prevent Blindness estimates that the total cost of vision disorders is expected to reach $717 billion in 2050 compared to the current annual cost of $145 billion.

New DNA test for diagnosing diseases linked to childhood blindness

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Posted on 11th October 2014 by Pacific ClearVision Institute in Cataracts |General

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.[i] 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.

“There are many diseases that involve congenital cataracts but finding the exact reason was always difficult,” said Graeme Black, DPhil., professor of genetics and ophthalmology at the University of Manchester and strategic director of the Manchester Centre for Genomic Medicine. “Even with a family history, diagnosing these rare diseases was always a bit of a shot in the dark.”

In the course of their work, done in collaboration with Manchester Royal Eye Hospital, researchers also found previously undescribed mutations linked to cataract formation. “There is hope that our work may one day provide more insight into the development and treatment of age-related cataracts, a leading cause of blindness worldwide,” said Rachel Gillespie, MSc, lead author of the study who designed and developed the test.

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. For more information, please see the Academy’s recommendations on genetic testing for inherited eye diseases.

High-precision software developed for diagnosing eye sensitivity

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Posted on 11th October 2014 by Pacific ClearVision Institute in Cataracts |General

Researchers at the University of Alicante have developed high-precision software for diagnosing eye sensitivity. This is a new technology that allows to quantify the degree of opacity in the posterior capsule of the eye caused by the growth of cells in the intraocular lens.

The opacity of the posterior capsule is currently the most important aspect of cataract surgery in modern times, and is the postoperative complication that can still occur months or years after cataract surgery. This is reported to occur between 20% and up to 50% of patients in the period of five years after surgery, and is associated with the decreased of visual acuity, impaired contrast sensitivity and glare problems that involve significant social, medical and economic impact.

According to Dr. Daniel Ruiz Fern√°ndez, main researcher and member of the research group in Bioinspired Engineering and Computer Science for Health (IBIS), the problem of quantification of posterior capsule opacity has been addressed in different works and business solutions using different computational techniques. However, these processes entail some drawbacks because they require interaction with experts for them to detect the zones of opacification, with the risk of losing objectivity in the quantification. On the other hand, some of the systems are automated but focused on detecting the lens opacity (cataract origin) and not specifically on the growth of cells in intraocular lens.

The technology developed by the researchers at the UA provides a fully automatic and objective quantification from a digital image of the magnification of the ocular fundus. The process does not require any intervention by specialists, becoming an important tool for diagnosis. Thus, the use of this technology can avoid unnecessary interventions as well as improving diagnostic in those necessary.

This is a high-precision process since it directly analyses the origin of the opacity in the intraocular lens, ie, cells that grow on the lens.

The IBIS group has developed the first prototype of the implementation that has been tested successfully. The group also continues to work on continuous improvement and optimization of the software for better detection of artifacts and cells as well as in reducing the processing time.

Vitamin E, selenium supplements unlikely to affect age-related cataracts in men

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Posted on 11th October 2014 by Pacific ClearVision Institute in Cataracts |General

Taking daily supplements of selenium and/or vitamin E appears to have no significant effect on the development of age-related cataracts in men, writes Author William G. Christen, Sc.D., of Brigham & Women’s Hospital and Harvard Medical School, Boston, and colleagues.

Some research, including animal studies, has suggested that dietary nutrients can have an effect on the onset and progression of cataracts. Vitamin E and selenium are of particular interest.

The authors report the findings for cataracts from the Selenium and Vitamin E Cancer Prevention Trial (SELECT) Eye Endpoints (SEE) Study. The SEE study was an ancillary study of SELECT, a randomized placebo-controlled trial of selenium, vitamin E and a combination of the two in prostate cancer prevention among 35,533 men (50 years and older for black men and 55 years and older for all other men). Men were asked to report cataract diagnosis or removal since entering the SELECT trial. A total of 11,267 SELECT participants took part in the SEE study.

During an average of 5.6 years of treatment and follow-up, there were 389 cases of cataracts. There were 185 cases of cataracts in the selenium group and 204 in the group that didn’t take selenium. There were 197 cases of cataracts in the vitamin E group and 192 in the group without vitamin E. Results were similar for cataract removal.

“These randomized trial data from a large cohort of apparently healthy men indicate that long-term daily supplemental use of vitamin E has no material impact on cataract incidence. The data also exclude any large beneficial effect on cataract for long-term supplemental use of selenium, with or without vitamin E, although a smaller but potentially important beneficial effect could not be ruled out.”

Cataract may Occur in Children Too, Say Doctors

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Posted on 8th January 2014 by Pacific ClearVision Institute in Cataracts |General

Cataract might strike kids and require a far more complicated treatment, say doctors.

“A malformed lens in a developing foetus is the cause of cataract in infants. It is relatively rare, but I receive about 10 to 15 cases a year,” said Sanjay Dhawan, director ophthalmology at the Fortis Hospital.

According to doctors, it was very important to detect paediatric cataract at an early stage, as the retinal image becomes so distorted that a permanent loss of vision might occur without early treatment.

Dhawan said: “Children with cataract might eventually need eye muscle surgery for crossed eyes. In cases of congenital cataract, we do not expect the baby to have 100 percent vision, they have to be satisfied with 70 to 80 percent vision.”

However, cataract surgery in children was not very painful, said the doctor.

“As a precautionary measure, parents must get neonatal eye examination of their children done,” adds Dhawan.

Eyes may Now be Immune to Cataract

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Posted on 8th January 2014 by Pacific ClearVision Institute in Cataracts |General

Cataract may now be prevented by detecting the activation mechanism of a protective protein that prevents diseases of the human eye, thanks to researchers.

The lens of the human eye is made up of a highly concentrated protein solution that imparts the eye its high refractive power. Yet, despite this high protein content the ocular lens must remain clear and transparent.

To this end ocular lens cells have developed a remarkable strategy: They have thrown overboard the complex machinery present in all other cells of the human body for building up and breaking down proteins. Instead, lens proteins are created only once in a lifetime – during embryonic development.

In 2009, Johannes Buchner, professor for biotechnology at the Technische Universitaet Muenchen collaborated with Sevil Weinkauf, professor for electron microscopy at the Technische Universitaet Muenchen, and helped the first part of the aB-crystallin puzzle fall into place.

The team successfully deciphered the molecular structure of the most important form of this versatile protein – a molecule comprising 24 subunits. Under normal conditions, i.e. when the cell is not exposed to stress, this complex is the most common variant.

However, it is merely an idle form that contributes little to the prevention of clumping in other proteins. It was clear that there must be another molecular switch that triggers the protective protein.

It is this trigger mechanism that the team headed by Buchner and Weinkauf uncovered now. When a cell is exposed to stress, for instance when subjected to heat, phosphate groups are attached to a specific region of the protein.

The negative charges of these phosphates break the links between the subunits and the large complexes consequently disintegrate into numerous smaller ones of only six or twelve subunits each.

As a result of this breakup, the regions at the ends of the complexes become more flexible allowing the molecules to dock up with different partners, thereby preventing them from clumping – the protective protein is now active.

The study has been published in Proceedings of the National Academy of Sciences.

Study Finds Medicare Patients Are Increasingly Conducting Consultations Before Cataract Surgery

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Posted on 8th January 2014 by Pacific ClearVision Institute in Cataracts |General

A study finds preoperative consultations before cataract surgery became more common for Medicare patients despite no clear guidelines about when to require such a service, hinting at unnecessary use of health care resources. The study was published by JAMA Internal Medicine, a JAMA Network publication.

Preoperative medical consultation is a common health care service that can be billed separately to Medicare. There is little information about how often preoperative consultation is performed among the large numbers of patients in the United States who undergo elective, low-risk surgical procedures that may not require routine consultation, and how the referral for such consultation varies by patient, facility and geographic region, according to the study background.

Stephan R. Thilen, M.D., M.S., of the University of Washington, Seattle, and colleagues measured consultations performed by family practitioners, general internists, pulmonologists, endocrinologists, nurse practitioners or anesthesiologists as early as 42 days before cataract surgery.
Study Finds Medicare Patients Are Increasingly Conducting Consultations Before Cataract Surgery

Researchers analyzed a 5 percent sample of Medicare part B claims, which included 556,637 patients 66 years or older who had cataract surgery from 1995 to 2006.

The study findings indicate preoperative consultations became more common, increasing from 11.3 percent in 1998 to 18.4 percent in 2006. Older patients (age 75 to 84 years) were more likely to have a consultation than patients between age 66 to 74 years, while patients who were black or lived in a rural area were less likely to receive a consultation. Those patients who had their cataract surgery in an inpatient or outpatient hospital had higher odds of having a consultation than those whose surgery was performed in an office.

Patients who had an anesthesiologist involved with their care (either personally administering it or medically directing or supervising certified registered nurse anesthesists) also had higher odds of having a preoperative consultation. Living in the northeast also meant higher odds that a patient would have a consultation compared with patients living in the South or West.

“This large retrospective study suggests that there was substantial use of preoperative medical consultation for cataract surgery and that referrals for consultation had increased during the study period. With the exception of age, referral for preoperative consultation seems driven primarily by nonmedical factors including practice setting, type of anesthesia provider and geographical region,” the authors conclude. “These data highlight an area of opportunity for interventions aimed at reducing unwanted practice variability in a process that has the potential to consume vast amounts of health care resources.”

Scientists Explore Link Between Cataract Surgery and Longer Life

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Posted on 8th January 2014 by Pacific ClearVision Institute in Cataracts |General

A recent study finds that people who have had cataract surgery live longer than those who choose not to undergo the procedure.

The research is drawn from data gathered in the Blue Mountains Eye Study, a population-based cohort study of vision and common eye diseases in an older Australian population.

A total of 354 persons aged 49 years and older and diagnosed with cataract-related vision impairment – some of whom had undergone surgery and others who had not – were assessed between 1992 and 2007.

Adjustments were made for age and gender as well as a number of mortality risk factors, including hypertension, diabetes, smoking, cardiovascular disease, body mass index and measures of frailty and comorbid disease. Follow-up visits took place after five and ten years since the baseline exam.

Jie Jin Wang, Ph.D., of the Westmead Millennium Institute and one of lead researchers of the study, said that their findings suggested that correcting cataract patients’ visual impairment in their daily practice results in improved outcomes beyond that of the eye and vision, and has important impacts on general health.

Wang noted one limitation of the study is that participants with cataract-related visual impairment who did not have cataract surgery could have had other health problems that prevented them from undergoing surgery, and that these other health problems could partly explain the poorer survival among non-surgical participants.

The study has been published in the journal of the American Academy of Ophthalmology.