A new potential treatment for Retinitis Pigmentosa & Macular Degeneration

A team of researchers from the University of California, Berkeley, in collaboration with researchers at University of Munich and University of Washington in Seattle have found a chemical that can temporarily restore some amount of vision in blind mice.

This compound could eventually help those with Retinitis Pigmentosa, a common genetic disease that leads to blindness, as well as Age-related Macular Degeneration.

The chemical, referred to as AAQ, acts on the remaining cells in the retina, which are normally "blind" cells, sensitive to light. AAQ is a photoswitch that binds to protein ion channels on the surface of retinal cells; when switched on by light, it alters the flow of ions through the channels and activates these neurons similar to the way rods and cones are activated by light.

This chemical has been shown to eventually wear off, and hence may offer a safer alternative to other approaches that restore sight, such as gene or stem cell therapies, which may permanently change the retina. It is also less invasive than implanting light-sensitive chips in the eye.

Considering that it is a simple chemical, it will be easy to change the dosage, use it in combination with other therapies, or discontinue the therapy if the need be. This would allow new and improved chemicals that may become available in time to be offered to the same patients.

The blind mice in the experiment had genetic mutations that made their rods and cones die within months of birth and inactivated other photopigments in the eye. After injecting very small amounts of AAQ into the eyes of the blind mice, the researchers confirmed that they had restored light sensitivity because the mice's pupils contracted in bright light. The mice also demonstrated light avoidance, a typical rodent behavior impossible without the animals being able to see some light. The researchers are hoping to conduct more sophisticated vision tests in rodents injected with the next generation of the compound.

It will be a while before this compound will find its way in humans. The researchers have to show that these compounds are safe and will work in patients the way they work in mice. BUt these preliminary results demonstrate that this class of compound restores light sensitivity to retinas blind from genetic disease.

The current technologies being evaluated for restoring sight to people whose rods and cones have died include injection of stem cells to regenerate the rods and cones; "optogenetics," a type of gene therapy where a photoreceptor gene is inserted into blind neurons to make them sensitive to light; and installation of electronic prosthetic devices, such as a small light-sensitive retinal chip with electrodes that stimulate blind neurons.

Eight years ago, Kramer, Trauner, a former UC Berkeley chemist now at the University of Munich, and their colleagues developed an optogenetic technique to chemically alter potassium ion channels in blind neurons so that a photoswitch could latch on. Potassium channels normally open to turn a cell off, but with the attached photoswitch, they were opened when hit by ultraviolet light and closed when hit by green light, thereby activating and deactivating the neurons.

Subsequently, Trauner synthesized AAQ (acrylamide-azobenzene-quaternary ammonium), a photoswitch that attaches to potassium channels without the need to genetically modify the channel.

Newer versions of AAQ now being tested have demonstrated better results, as per the researchers. They activate neurons for days rather than hours using blue-green light of moderate intensity, and these photoswitches naturally deactivate in darkness, so that a second color of light is not needed to switch them off.

Source

Musings over a cup of sambar

It's not just the sight, but smells and sounds have the ability to transport someone to a different place, a different time. It happens too often for someone who suffered progressive vision loss. Here's the experience of one of them.

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In spite of the clattering of plates and the high-decibel noise, the restaurant seemed more appealing. It doesn't require a genius to figure out why? The smell of coffee lured us from quite a distance, and as we wade through the crowd milling around the tables, we were assailed bythe smell of sambar.

The aroma transported me to a different place, to a different time.

Friday evening at our home town of Viruddachalam (better known these days as the former constituency of actor-politician Vijayakant). The bazaar road would be chaotic with fast moving 'town buses' and trucks carrying loads of sugarcanes and groundnuts. Roadside tea stalls did brisk business, and the police station that sat at the corner of the Double street looked more magical as the lone tube light inside flickered and flashed at regular intervals.

Having spent a full day playing cricket on the dry riverbank, myself and my brother would feel hardly tired as we looked forward to the prospect of eating the evening snack outside. We invariably went to the thatched roof stall of Adai Rayar, whose serves special 'onion adai' with tasty 'Milagai podi' (chilli powder) and gingili oil.

That was, of course, the popular choice. The thick dosa like dish would arrive the moment Rayar Mama saw uncle cycling with a nephew each on the front and back of the saddle. While everyone preferred to eat the crisp and wonderfully fried Adai with chilli powder, my choice was the other

one: vegetable sambar and coconut chatni. Rayar was too happy to serve the sambar several times, especially to me since I never used to waste even a drop. How can I? It was one of the best thing I had ever tasted.

It was harder to say what made the sambar tasty. It could be the dal or the native tamarind and vegetable. My guess was the proportion and the blend, which needed immense skill to reproduce without any change on a daily basis.

With the red mark on his forehead and customary dhoti-towel, not to mention the trademark smile, Rayar offered the best food in the town. The Adai, made with red gram-rice-red chilli paste, topped the billing.

The sambar we tasted at the restaurant didn't live up to the sweetness of its smell. But thoughts of Adai Rayar and the tasty sambar at his modest stall seemed to have done the trick. There was only the smile and no complaints of the tanginess due to excess tamarind juice. Oh yes, the mind often crawls through scenes of the past, morphing the unpleasantness of the present with fond memories.

- Learner

Tripping and falling isn’t a blindness problem

It was a warm March Sunday evening as I stepped out of my front door to alight a flight of steps for dinner at my sister’s place. Everything appeared usual: I was humming a favourite song, my daughter ran in the front toward the gate downstairs and I was cautious as I possibly can as I descended down the first step.

I don’t know about other blind persons, but for me walking on long stairways is fun. Be it walking up or getting down, I enjoy it because stairways are one place where we don’t need anyone’s help. The moment I hit the stairway, I ask, “Where’s the railing?” and follow it without expecting assistance. Believe me, walking alone with absolutely nothing to interrupt you, is a particularly liberating feeling for a blind man. So, I usually take brisk steps and even run if I am confident that the stairway is obstacle free.

The two-floor ascent at office is something I enjoy since they are familiar, and I use my break to walk down to have water. For someone confined to the chair throughout the working hours, this is a welcome relief. But imagine my shock when I was very close one day to kicking a bucket heavy with water!! (It was apparently kept by house keeping person for mopping the stairway.)

I thanked my stars for not falling over the bucket, and plunging seven or eight steps down, which would have surely broken my ankle or knee. People around me started cautioning me almost immediately about how I should be careful – putting out my hand and walking one step at a time and so on. “Do you walk like that?” I asked obviously exasperated by the way people treat me because of my blindness.

The funny thing is that stairways are supposed to be obstacle-free and no one expects a bucketful of water on the middle of the climb. And no one either questioned or instructed the house keeping person not to do it again. “It’s too early to kick the bucket” I joked with a colleague and explained the housekeeper about the dangers of keeping things like buckets on the way.

Back on that Sunday at home, I was getting down the steps and tripped suddenly. I lost control and went on a free fall and dashed my head against a wall in the front of the landing. This was far costlier than the near miss of ‘kicking the bucket’ as I felt lingering pain in my right temple and broke a half-grown wisdom tooth which made me sit through an agonizing dental surgery.

No one can predict accidents and probably that’s why it is accident. I also understand the concerns of people and feel touched when they take a moment to enquire about my condition and offer their genuine support in so many little ways. In fact, that is the best thing about being blind: you are always loved, supported and protected by people you barely know. The condition of blindness in a person evokes kindness in others and so they respond to our situation as if it were something that hurts them.

But when people somehow presume that I am sloppy or must act differently in this situation because of my blindness, I tend not to agree with that. As people without a vital sense, our body has various defense mechanisms to protect us (this is something purely instinctual and reflex) so usually you don’t find a blind person falling over something despite worries of people around him/her. By law of average, even that is bound to fail once in a way, not because the mechanism is faulty, but because our environment is full of unpredictabilities.

Should my blindness be blamed for this? I don’t know. Probably those who read and analyze this may have better answers.

- L Subramani, Bangalore

The journey continues...

Retina India congratulates Mr Avneesh Singh from New Delhi for his completion of the Executive MBA program from the Indian Institute of Management (IIM), Kozhikode. (Ed: For those not in the know, Kozhikode is situated in the State of Kerala, on the south-west coastal border of India.)

Since Mr Avneesh Singh's MBA journey, as much as others like Mr Pranav Lal from New Delhi, and Mr Vishal Jain, who is currently studying at IIM Lucknow, are inspiring to others, we thought we should share this story with you. Below is Mr Singh's story, in his own words. Enjoy, and get inspired!

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"Dear all, I will like to share  the journey of the last 13 years, which has many transitional stages, but it has led to a satisfactory life so far.

I always had a passion for mechanical engineering. I could never imagine a life without machines, especially when machines create speed. This keen interest in speed & engineering made me specialize in thermal sciences in my mechanical engineering course.

When I came to know about the progress of my retinal degeneration, this keenness suffered a big blow. It was shocking to know that I will have to give up my ardent desire for speed & machines. Leave aside driving, I will not even be able to walk well with reduced vision.

Many suggested to me to leave the field of engineering, and switch to a safer profession like management or bank officer, but it was an excruciating idea for me. I realized that mechanical engineering was not practical now, but it was very difficult to abandon my passion. Moreover, the alternatives, such as becoming a bank officer, were something that my mind could just not accept.

To go on with my zest for engineering, I finally decided to pursue my career in computers that looked more viable, due to availability of assistive technologies like magnifiers, high contrast mode etc.

It was initially hard to create interest in computer engineering, which I always considered to be inferior to mechanical, because it lacked high speed adventure that is integral part of thermal sciences. But since it was the only practicable path at that time, I pushed through it.

Vision loss was even rapid in last few semesters of my degree. I was able to complete computer engineering but future looked quite uncertain.

I used to ask the ophthalmologists I consulted about the rate of degeneration, and the amount of time I had before I loose my useful vision, but all of them gave me hope instead of stating facts. I knew that macula in my left eye was degenerating very rapidly, and right eye would be following the degeneration in the same pattern. So one day, I bluntly asked an ophthalmologist that I know that I am loosing reading capability, and whether it was time for me to start learning Braille and similar skills. He replied with hesitation that I should start some practice of Braille.

This thought of learning Braille was not tolerable for my parents because I could still somehow read, but I was stubborn on this issue and made my way to the AICB- New Delhi, where I started learning all the skills that were now a must for self subsistence.

Accepting blindness was very tough for both me and my parents, but this step became one of the turning stones in my life. It helped me overcome fear of the approaching blindness, preparing me for the worst-case scenario, and actually made me more efficient in performing day-to-day activities.

But at the same time, it also made me realize that rehabilitation centres are overlooking the new generation enabler, the technological advancements that information technology is presenting, and are actually underestimating the potential of visually impaired.

I continued working as freelance programmer and kept on refining my potency in JAWS scripting and using programming platforms with the help of JAWS.

Some months later, I visited NAB Delhi and met Mr. Dipendra Manocha. After getting to know of my engineering & programming skills, he suggested me to start contributing to accessibility related projects. He encouraged me by stating that I am a rare combination who knows the needs (as I myself suffer from vision loss), and also have the capability to develop access technology. I came to know about DAISY books then, while Mr. Manocha also introduced me to the field of accessible digital publishing. Finally, I ended up working with the DAISY Consortium as a software developer.

A couple of years later, I got the responsibility of leading the Obi project – the audio NCX book production tool. The success of Obi was a benchmark in my career that helped me gain the trust of my seniors that resulted in attaining the responsibility of the Obi-Tobi project, formerly known as the Urakawa project. Now, I was not only leading the cutting edge project, but was also involved in research of upcoming technology along with experienced minds from different parts of the world.

Along with the professional development, my academic life also took on a new dimension. After 5 years of experience in technology development, I thought of going for management education because now my ambition of becoming a self dependent engineer was fulfilled and I was leading software development projects.

It was time to look for proper management education and with God’s grace, I got admission in Indian Institute of Management – Kozhikode in year 2008. Now I was again a student, completely dependent on screen readers, and the problems of accessible books rose up again. But there was no effective solution available.

The administration of the institute told me that none of them had any experience of having a visually impaired student. It took some months to get the minimum facilities required for visually impaired. In first 2 terms, I could not even get extra time for giving exam through scribe. But gradually, the guidelines were formed, and most of the things were sorted out as the course progressed. This was a learning experience for the institute also, so such of the problems were, in a way, expected. IIM-K also tried to contact publishers for electronic copies of books for me, but publishers were not able to provide any of them.

I graduated from IIM-Kozhikode in early 2010. But it was not the end of my academics. My vision loss had moulded my fascination for machines into a quest for understanding war strategies, and the study of human mind. So I decided to go further for advanced specialization in strategy.

It was a challenging year, full of excitement, stress & many amazing experiences that tested me and also helped me develop me into a mature person.

On March 17, 2012, I graduated from Indian Institute of Management – Kozhikode in Executive MBA specialized in strategy. It was satisfactory to successfully complete one of the most rigorous management programs in India, but I will say that it is just a milestone.

A long journey still lies ahead. Now, along with project management responsibilities, I am also part of strategy formulation management team of DAISY Consortium.

And the journey continues...

With regards,
Avneesh Singh

New animal model may help develop new treatments for RP

Developing new treatments for diseases such as RP have been difficult for many reasons. Apart from the fact that it was difficult to pinpoint the genetic defect in the disease, lack of an adequate animal model that could be used to test any new treatment to study its effect and follow the effect for a few months has been an underlying problem for many years now.   

Hence the recent publication in IOVS of success in creating a genetically modified mini-pig may help in the development of newer and improved treatment paradigms, and may eventually help lead us to a cure diseases such as retinitis pigmentosa (RP), which is the most common inherited retinal disease in India. The researchers used miniature pigs, weighing about 150 pounds at full growth, instead of the larger pig, since managing the smaller pigs was much more easier. 

This model has been developed by researchers in the Department of Ophthalmology & Visual Sciences at the University of Louisville, along with researchers from the National Swine Resource and Research Center, University of Missouri.

For those from the scientific background, here's the abstract from IOVS. " ... describes the creation of an inbred, transgenic mini-pig that carries a mutant human rhodopsin gene which is expressed in the retina and is associated with progressive loss of light-evoked ERG responses. This is a significant achievement of considerable practical value in an era in which translational activity for retinal diseases is burgeoning. The rationale for generating this pig is laid out well, and the design appears to have multiple advantages over the existing retinal dystrophic pig. There are many rodent models of retinitis pigmentosa (RP) and conditions resembling RP, but what has been lacking is a large animal model that more accurately mimics the situations encountered when treating human patients. One potential animal model is the pig. There is an existing pig model of retinal degeneration (RD); however, a number of factors have made this model difficult to use, including the large size of the animals at the time of degeneration as well as molecular genetic considerations. The article describes the successful development of a genetically accurate RP-like condition in a mini-pig.

This model should prove quite valuable to people working on treatment of RD, including traditional pharmacologic approaches and regenerative strategies, such as stem cell transplantation. The authors evaluated six transgenic founders whose retinal function was studied with full-field electroretinography from three months through two years. Progeny from one founder were generated and genotyped to determine the transgene inheritance pattern. Retinal mRNA was isolated and the ratio of P23H to wild-type pig RHO measured. The result is a powerful new tool for retinal degeneration research that should be of interest to a wide range of workers in that field."

The Pro23His (P23H) rhodopsin (RHO) mutation is the cause for the most common form of human autosomal dominant retinitis pigmentosa (adRP), with a high propensity for disease characteristics to pass to the next generation. This study was focused on establishing a transgenic miniature swine model of RP using this human P23H RHO gene. 

Animal models are used to screen for safety and efficacy of new treatment paradigms for diseases such as RP, which includes newer treatment modalities such as medications, stem cell therapies, gene therapy, and the artificial retinal prosthesis.

The prevalence of RP in India is considered to be significantly higher compared to other nations. With some small sample studies indicating that RP may affect about 1 in 1000 in some areas, to almost 1 in 500 in some rural areas in India, we potentially have a population of about a million RP patients. 

Sources: 1 2

App turns tablet into math aid for visually impaired students

From www.physorg.com: Article link here.

For the video, please click here.

Without looking down, Kira runs her index finger across the screen of an Android tablet that she is holding in her lap. For the occasion, she has painted her fingernails bright pink. When her finger touches a line drawn on the screen, the tablet vibrates quietly. Scanning her finger back and forth and feeling the vibration come and go allows her to trace the line's path. When her finger reaches a pink dot, the tablet gives off an electronic tone and she grins delightedly.

Kira is one of two visually impaired high school students who are testing a new Android app, one designed to assist students like her in mastering algebra, geometry, graphing and other subjects that are particularly hard to comprehend without the aid of normal vision.

The app is the brainstorm of Jenna Gorlewicz, a graduate student in the Medical and Electromechanical Design Laboratory (MED Lab) at Vanderbilt University, and her advisor Robert Webster, an assistant professor of mechanical engineering, who directs the lab. Given the enthusiastic reaction of Kira, her classmate Quinn and their teacher, her innovation could have a major impact on how science, technology, engineering and math – the critical STEM subjects – are taught to the visually impaired.

A major change in direction

The project is a considerable change from the research projects that Gorlewicz pursued during her first two years in the MED Lab. Supported by a fellowship from the National Science Foundation, she worked on improving cochlear implant surgery and miniaturizing endoscopic robotic capsules. But she wasn't completely satisfied: "I'm a real people person," she explained. "So I wanted a project that would let me interact directly with the people it was helping."

"Jenna kept saying that she wanted to work more with people, so we began exploring other possible projects," said Webster. "Fortunately, her fellowship and my NSF CAREER Award gave us enough flexibility to think outside the box and explore a wide variety of thesis topics for her."
One of the ideas they came up with was a study of the effectiveness of haptic technology: technology that takes advantage of a user's sense of touch by applying forces, vibrations or motions to enhance remote control of machines, devices or virtual objects. The lab was experimenting with haptic interfaces to control some of their biomedical robots.

Matching haptics with visually impaired

"When I began reading articles about haptic technology being incorporated into these new touch screen devices, I realized that the people who really need haptics are people with impaired vision because they heavily rely on their sense of touch to 'see' the world around them." Gorlewicz said. "I love math and I love teaching, so I immediately thought of using them for math education, because it has such a strong visual component." After she did some research into the methods that are currently used to teach mathematics to the visually impaired, she became even more enthusiastic about her idea.

When she started the new project 18 months ago, the only off-the-shelf tablet that Gorlewicz could find that included tactile feedback was a $2,500 model produced for industrial and commercial applications. Since then haptic feedback has been added in a number of consumer tablets that sell for as little as $300.

The grad student has programmed these tablets so they vibrate or generate a specific tone when the student's fingertip touches a line, curve or shape displayed on the screen. The devices can generate vibrations with a number of different frequencies and hundreds of different sounds. This allows Gorlewicz to assign different tactile or audio signals to different features. For example, in an exercise that includes an X-Y grid, she can set the horizontal and vertical lines to vibrate at different frequencies and set points to make a certain tone. In this way, it's easier for the students to distinguish between the gridlines and the points on the grid.

"If one of these tablets were networked wirelessly to the teacher's computer, then, when he or she projects a graph or equation on the screen at the front of the class, the same graph would appear on the student's tablet. They could then use their senses of touch and hearing to follow the content the teacher is discussing," Gorlewicz said.

"When Jenna first approached me with the idea, I thought it would be interesting and might be some small help," said Ann Smith, the teacher of the visually impaired who works with Kira and Quinn at Hillsboro High School in Nashville. "The more experience I have with it, the more valuable I think it could be. It makes the work more accessible. The students are really interested and they talk about it even when Jenna isn't here."

Hillsboro High follows the approach of including students with special needs in classes with their sighted peers as much as possible. That means Kira and Quinn attend general education classes. Smith sits with them during their math classes and uses various methods to ensure that they can follow the teacher's presentation. With Quinn, who can read Braille and see large print, this involves duplicating the shapes and figures the teacher is using on a small white board that he can hold close enough to see. In Kira's case Smith must use tactile aids like pins and pipe-cleaners on a bulletin board with raised graphing lines to reproduce complex mathematical shapes that Kira can feel with her fingers.

"Because this takes a certain amount of time, we are always one or two steps behind the teacher," Smith said. "One of these haptic tablets would allow them to keep up much better. If I didn't have to attend class with them, it would also make them feel more independent."

Smith also pointed out that such a tablet can be used by students with widely differing degrees of impairment because it combines visual, tactile and audio capabilities.

Some learning required

According to Kira and Quinn, there is a little bit of a learning curve with the new device. "At first, I didn't think this would help me," Quinn said. "But after I started using it I found that it can be very helpful." According to Kira, "The biggest obstacle was getting the correct mental images. However, once you get the knack, it gets fairly easy."

"It was amazing how quickly they caught on and how good they have become," Gorlewicz said.
According to the graduate student, every time she meets with the students, they come up with new features that they would like her to add. The configuration that they think would be the most useful is a touch-sensitive version of the graphing calculators that are widely used by their sighted classmates.
"It would really help to have something like this because it makes us equal to everyone else," Kira said.

Provided by Vanderbilt University

POSITIVE PRELIMINARY RESULTS FROM PHASE 1b TRIAL OF QLT091001 IN SUBJECTS WITH RETINITIS PIGMENTOSA DUE TO RPE65 AND LRAT MUTATIONS

QLT Inc. has announced positive preliminary results from its international multi-center Phase 1b proof-of-concept clinical trial of QLT091001 for the treatment of Retinitis Pigmentosa (RP) due to inherited genetic mutations in retinal pigment epithelium protein 65 (RPE65) or lecithin:retinol acyltransferase (LRAT) (also known as early-onset RP). 

The Phase 1b study showed rapid, statistically significant and clinically meaningful changes in visual fields (VF) from baseline values, as well as improvements in visual acuity (VA), in the study of 17 RP subjects. In addition, small subsets of RP subjects were investigated for secondary effects on other key vision parameters impacted by RP, such as decreased retinal sensitivity, and the data available in these subsets showed notable and promising increases in average sensitivity levels. The single-course treatment data with QLT091001 represents the first stage of dose regimen testing as the basis for a longer term multiple course regimen in RP due to mutations in RPE65 and LRAT. 

RP is a disabling group of genetic eye diseases associated with progressive loss of vision including night blindness, constricted peripheral vision resulting in difficulties with daily activities, and in later life, reduced central vision, inability to read, and in many cases progression to severe blindness. RP can be caused by many different gene defects and symptoms can start at varying ages; patients with mutations in the RPE65 and LRAT genes tend to show vision loss very early in life (this type of RP is also known as early-onset RP).

In the open-label, multi-center Phase 1b clinical study, 17 subjects (ranging in age from 6 to 55 years, mean 29 years) with either RPE65 (12 subjects) or LRAT (5 subjects) mutations received a 40 mg/m2/day dose of QLT091001 once daily for seven days with post-treatment follow-up at 7, 14, and 30 days. Visual fields and visual acuity are key measures of clinically relevant visual function. VF was assessed using Goldmann Visual Fields (GVF) and VA was assessed using best-corrected visual acuity (BCVA, ETDRS letters); GVF maps were converted to assess the remaining functional retinal area for analysis. After a single 7-day course of treatment with QLT091001, the average retinal areas from baseline showed statistically significant improvements of 34% at day 7 (p=0.005), 29% at day 14 (p=0.02) and trended towards a statistically significant improvement of 23% at day 30 (p=0.07) in the evaluable subjects meeting GVF test criteria (n=14 subset). In the intent-to-treat (ITT; all subjects enrolled) analysis (n=17), the average retinal area from baseline improved by 22% at day 7 (p=0.03, statistically significant), 16% at day 14 (p=0.13) and 18% at day 30 (p=0.096). The evaluable subset of 14 subjects excludes three patients in the VF analysis because they did not meet criteria as determined by a third-party reader. Nine of 17 subjects (53%) showed an improvement in VA over baseline in at least one eye by greater than or equal to five ETDRS letters. 

Measurement of Goldmann Visual Field Improvement from Baseline
GVF analysis – retinal area	Day 7	Day 14	Day 30
Avg. increase from baseline – evaluable subjects (n=14) Avg. increase from baseline – ITT (n=17)	34% (p=0.005)* 22% (p=0.03)*	29% (p=0.02)* 16% (p=0.13)	23% (p=0.07) 18% (p=0.096)

(*statistically significant)

Following single-course treatment with QLT091001, the Retinitis Pigmentosa patients in the clinical trial experienced a rapid and significant improvement in certain visual function parameters, as per Dr. Hendrik Scholl of the Wilmer Eye Institute at Johns Hopkins University. He also added that the discovery of the genetic cause of retinal degeneration has revolutionized insight into disease processes at a molecular level and has given the physicians encouragement for potential therapeutic approaches.  

Baseline values in subjects showed a broad range of moderately to severely reduced visual acuities and visual fields. All subjects reported early onset of night blindness as one of the hallmarks of disease.

Additional tests included spectral-domain optical coherence tomography (OCT), full-field electroretinography (ERG), and quality of life assessments. Also, in small subsets of subjects, the effects of QLT091001 on several parameters of light sensitivity in dim light (night vision), pupillary reflexes, and responses of the visual cortex to potential changes in visual stimuli (functional magnetic resonance imaging, fMRI) were measured.

The fMRI substudy (n=2) showed activation of several previously quiet areas of the visual and parietal cerebral cortex after treatment. In addition, the substudy in dark adapted visual fields (n=2) showed a 16- fold average increase in sensitivity at 10%-50% of locations tested in each eye within days of the first dose. With longer dark adaptation, light sensitivity increases averaged 40-80-fold greater than baseline at 40%- 83% of the locations tested. Full-field sensitivity (FST) and pupillometry results supported the large increases in sensitivity in both eyes.

The additional secondary endpoints evaluated to date in this study support and are consistent with the changes in VF and VA observed following single course treatment with QLT091001.

Ongoing analysis of the safety profile of QLT091001 demonstrates a safety profile consistent with the Company’s Phase 1b study in patients with Leber Congenital Amaurosis (LCA). A retreatment study for the RP cohort has been initiated to assess the effects of repeat QLT091001 therapy in these patients. The database on this study remains open and further analyses of additional anatomic tests (OCT) and retinal sensitivity tests (ERG) are also ongoing to further explore the optimal baseline characteristics of responders for clinical development purposes.

The RP (early-onset RP) Phase 1b clinical study is being conducted at seven leading centers for the treatment of inherited retinal diseases in the U.S., Europe and Canada.

About Synthetic Retinoid Drugs
Genetic diseases in the eye such as Leber Congenital Amaurosis (LCA) and Retinitis Pigmentosa (RP) arise from gene mutations of enzymes or proteins required in the biochemistry of vision. QLT091001 is a replacement for 11-cis-retinal, which is an essential component of the retinoid-rhodopsin cycle and visual function, and is under investigation for the treatment of LCA and RP. QLT091001 has received orphan drug designations for the treatment of LCA and RP by the European Medicines Agency, and for the treatment of LCA and RP due to inherited mutations in the LRAT and RPE65 genes by the U.S. Food and Drug Administration (FDA). The drug has also been granted two Fast Track designations by the FDA for the treatment of the LRAT and RPE65 genetic mutations in both LCA and RP.

About Leber Congenital Amaurosis (LCA)
LCA is an inherited degenerative retinal disease characterized by abnormalities such as roving eye movements and sensitivity to light, and manifesting in severe vision loss from birth. Both rod and cone photoreceptors are affected in LCA. Eye examinations of infants with LCA reveal normal appearing retinas. However, a low level of retinal activity, measured by electroretinography, indicates very little visual function. According to current epidemiological estimates, LCA affects approximately one in 81,000 newborns worldwide, of which approximately 10% carry the inherited deficiencies of either RPE65 or LRAT.

About Retinitis Pigmentosa (RP) Due to RPE65 and LRAT Mutations
RP is a set of hereditary retinal diseases demonstrating clinical features similar to LCA. RP is also characterized by degeneration of rod and cone photoreceptors, but it presents with a more variable loss of vision in late childhood to adulthood. Deficits in dark adaptation and peripheral vision are particular hallmarks of RP. RP is currently estimated to affect at least 300,000 individuals worldwide, of which approximately 20%–30% are autosomal recessive (arRP). It is currently estimated that less than 3% of autosomal recessive RP patients carry the inherited deficiencies of either RPE65 or LRAT.

About QLT
QLT is a biotechnology company dedicated to the development and commercialization of innovative ocular products that address the unmet medical needs of patients and clinicians worldwide. We are focused on developing our synthetic retinoid program for the treatment of certain inherited retinal diseases, developing our proprietary punctal plug delivery system, as well as U.S. marketing of the commercial product Visudyne® for the treatment of wet age-related macular degeneration.

Derived from the press release from QLT Inc.

Understanding pictures and drawing by the visually challenged

Richard Baldwin is a Professor of Computer Information Technology at Austin Community College in Austin, Texas, USA.

Prof Baldwin first became involved in the issues confronting blind students when a blind-from-birth student named Amanda Lacy enrolled in an object-oriented programming course that he taught. Ms. Lacy successfully completed that course and two others that he taught. Knowing that she was a very good student, he became concerned upon learning that she was having difficulty in a physics course. Being an engineer by training, he volunteered to tutor her in the physics course. This led to the two of them spending about four hours per week in tutoring sessions for the past couple of years.

Prof. Baldwin quickly learned that neither the physics lectures nor the physics textbook were accessible to Ms. Lacy. She had stopped attending lectures because she was unable to follow along. The electronic copy of the textbook that she had been provided contained hundreds of equations and pictures that were incompatible with her assistive tools: a screen reader and a Braille pad.

Prof. Baldwin began by authoring an online physics tutorial titled “Accessible Physics Concepts for Blind Students” (available here) to help Ms. Lacy through the first semester physics course. Although it took more than one semester for her to complete the course, she did complete it and made an A in the course.

While authoring the online physics tutorial, Prof. Baldwin came to realize that unlike sighted students, blind students were unable to draw and submit graphical homework assignments, such as vector diagrams with any accuracy. Although there are several outstanding free drawing programs available on the web, all or at least most of them require the user to manipulate a mouse. Therefore, they are not accessible to blind students. As a result, Prof. Baldwin wrote a drawing program named SVGDraw01 that is fully accessible for blind students. The theme for this program is “if you can imagine it, you can draw it.” The program is freely available for downloading here.

Later, Prof. Baldwin decided to tackle the inaccessible pictures and diagrams in textbooks. One technique that blind students can use to understand the content of diagrams and pictures is to emboss them using any of several available embossing techniques. Basically, embossing an image means to create a tactile document containing raised lines or raised dots that describe the salient features of the image.

Originally, Prof. Baldwin hoped to make it possible for blind students to emboss their own textbook images. So far, that is still a dream for several reasons. The most common format of electronic textbook is the Adobe pdf format. Without the purchase of expensive software (and probably not even then), it is impossible for a blind student to successfully extract most of the images in a pdf file intact. While there are numerous programs available that claim to extract the images from pdf files, in most cases each image ends up in several different files that must be reassembled for embossing.

After coming to that realization, Prof. Baldwin decided to direct his attention to the many technical issues that make it very difficult for even a sighted person to convert a typical bitmap file into an embossed image that is meaningful to a blind student.

There are about 16-million good reasons why the embossed version of a full-color bitmap image often fails to produce satisfactory tactile results. Begin with the fact that the embossing process often discards the information content from more than 16-million colors ending up with what is effectively black and white, or possibly black and white with two or three shades of gray in between, depending on the embossing method.

Follow the loss of color information with the fact that, unless the original image is very small, the spatial sampling is probably reduced by a factor of 5 to 10 in the embossed image with little or no consideration being given to frequency aliasing that occurs in a brute-force spatial re-sampling process.

The bottom line is that it is very difficult to emboss full-color bitmap images and end up with high-quality tactile images.

Different embossing methods produce different physical outputs. Many of the older Braille printers have a graphics mode that allows pictures to be displayed by raising a subset of individual Braille dots to a standard height. The dot separation on those printers ranges from ten dots per inch to perhaps 17 dots per inch. Compare this with the typical 96 dots per inch of an image on a computer monitor and you will understand the issues regarding spatial sampling mentioned above. When the image is re-sampled down to a level that is consistent with the number of dots in an embossed image, much of the detail simply disappears.

Newer Braille printers have dot resolutions of up to 25 dots per inch, which is still very low in comparison with onscreen images. Some of them can also raise dots to variable heights to simulate gray scale imaging. Although there is no published information as to how many “gray levels” can be understood by an experienced blind user of an embosser with variable dot height. Prof. Baldwin estimates that such a user can probably recognize black, white, and perhaps three gray levels in between.

Typical embossing techniques either convert the 16 million colors in a bitmap image to black and white through the application of a single intensity threshold, or convert the 16 million colors to black, white, and several shades of gray through the application of several intensity thresholds. The result is that many colored pixels that are clearly distinguishable in the original image become indistinguishable in a four or five-level gray scale version of the image. Detail that depends on the recognition of different colors simply disappears. Therefore, many of the salient features of the image are often lost in the embossing process.

Prof. Baldwin has developed a mathematical image processing algorithm which, in many cases, preserves much more detail than the typical intensity-based gray scale approach. This algorithm converts the original image to either black and white or black and white plus three levels of gray, based not on absolute colors, but rather based on changes in color. The result is that images processed using this algorithm tend to have black outlines that define the salient features of the original image. In many cases, this produces more meaningful embossed images than the typical approach based on the direct conversion of color intensity to gray scale.

Prof. Baldwin’s solution to the spatial sampling issue is to make it possible in his programs to subdivide an enhanced image into panels, which can be individually embossed and then assembled into a poster-size tactile image. While not an ideal solution, short of developing an embossing method with an improved dot resolution, that is the best he has to offer.

Prof. Baldwin and Ms. Lacy have packaged the image enhancement algorithm in a free computer program designed specifically for use with embossers that support a single dot height and accept Duxbury graphics files in the .sig format as input. This program is named JpgToSig-A-01. It accepts any of several different bitmap image files as input and writes the enhanced version of the image into an output sig file. While it is possible for blind students to use the program, it is primarily targeted for use by teachers and others who assist blind students.

Prof. Baldwin has also packaged the algorithm in a free computer program named ShapeExtractor02 that is designed for use with any embossing method that can accept jpeg image files as input. This program accepts any of several different bitmap image files as input and writes the enhanced version of the image into an output jpeg file. Both of these programs can also be freely downloaded here along with the program named SvgDraw01. Note that all three of these programs require the Windows operating system.

These programs can be used with bitmap images from any source. However, in the world of education for blind students, the images that need to be embossed are often contained in electronic pdf versions of course textbooks. Prof. Baldwin uses the following procedure to assist Ms. Lacy in embossing images from her physics textbook.

1. Open the pdf file in the free version of Adobe Acrobat and locate the image of interest.
2. Use the zoom capability of Acrobat to make the image as large as possible while still fitting on the screen.
3. Hold down the shift key and press the Print Screen key. This saves the current screen image on the clipboard.
4. Open any of many available image editing programs such as the program named Lview Pro.
5. Paste the clipboard into the image editor.
6. Crop the image out of the surrounding material retaining only the material necessary to contain the image.
7. Save the cropped image.
8. Open either JpgToSig-A-01 or ShapeExtractor02 and follow the usage instructions to convert the image to the desired black and white or black, white, and gray format.
9. Save the enhanced image in an output file and emboss it using the embossing method of choice.

Ms. Lacy is now enrolled in her second physics course and plans to complete several more.

- As told by Prof Baldwin

A Tale of One Aim

It began at the age of four when my teacher, Mrs. Ireland noticed that I bend too much over books and copies to read and write. My parents were advised to have my eyes tested, and it was then told to us that I had an incurable genetic disorder called Retinitis Pigmentosa, which could lead me to total blindness.

My sight deteriorated fast. After failing in the half yearly exams of class seven, I had to leave my beloved school – La Martiniere Boys. That place is so dear to me even today, that I still feel a sweet pain for leaving it. I used to cry to get back to that school, and often had dreams of continuing to study there. I terribly missed my teachers, my friends, the atmosphere and the building.

Living at home was not so easy. I used to hide from my neighbors because everyone kept asking if I had decided to leave school and studies. I was filled with shame. If I was caught at home during the school hours, I made all kinds of pretexts. But even though I tried my best, my neighbors eventually got to know the truth. I was considered a liar, a spoilt chap, a bad influence, and an ignorant. I was strictly chastised that quitting studies was bad, but no one ever told me how I could study with low vision.

I felt so shamed for having left school that I started avoiding relatives and neighbours, and confined myself at home. When I was forced to meet a relative, I went in front of him with an artificial smile and empty confidence, all the while fearing that my ignorance and sightlessness could soon be caught.

Music enters my life

It was then that we discovered Mr. Tej Singh Tak, who was blind and taught vocal music at Bhatkhande Music Institute (Deemed University). We talked with him, and it was decided that I would learn singing. It wasn't that I was good at singing. I liked listening to songs, but making a career in that field seemed a horrible idea to me.

I started learning vocal music, though I kind of despised it. Mr. Tak indicated, and another blind teacher advised me with good intentions, that singing would be a difficult task for me. People tried to tell me that such a talent is God’s gift, and that I should try to learn instrumental music instead. But surprisingly, in spite of the negative vibes, I had started to enjoy singing. I made up my mind to practice and be a good singer.

In pravashika (the first class), I was the only one to pass with third division; some got the second division, but most students got the first.

At this time, I also started playing the harmonium and the Spanish guitar. Saving from money meant for buying clothes for Eid, I bought a tampura and practiced singing. My teachers started feeling that I was showing some improvement, and in prathama, I got the second division. For a few months, I learnt guitar from a teacher, and then started teaching it back to him. I was hugely intoxicated with light music, and made up my mind to become a playback singer. My aim was Bollywood.

Mr. Tak made me recognize the six Braille dots, and embossed English letters so that I could learn Braille. My private education went on, but I focused mainly on becoming a Bollywood singer. My first opportunity of singing on stage was at a marriage party. The orchestra director told me that my singing was horrific. Later, I participated in a singing competition held in Lucknow. That too was termed horrific, though much better than the previous performance.

My singing practice continued. My family members and neighbors were troubled by my practicing before sunrise. I kept changing my place of practice, but the complaints kept flowing. A boy once told me that as he was going out during the wee hours, he had heard my riaz and had run away with fright, thinking that someone had got murdered!

The sound of success

After a few months, I took part in another singing competition, and this time, I was selected for the final round. It was a huge achievement for me; the person who read my name from the list even mocked at my blindness, but I just patted him and jumped with joy. As I got on to the stage in the final round and sang the first line, the audience started clapping, which continued to cheer me throughout the song. I received a medal in that competition!

I participated in several singing competitions after that, and received prizes. My name started featuring in the newspapers. In madhyama, I scored 80 per cent in the practical, which were the highest in Bhatkhande. Mr. Tak was proud of me, and another teacher actually started sending students to me so that I could teach them singing.

Once, a neighbour of mine whom I call Baba since my childhood, asked me to sing at a function. I went with my guitar and karaoke cassette. I entered the auditorium, but had to come out because of the hall, because of the loud noise. Loud noise has always troubled me. Sometimes, I had to jab cotton pieces in my ears when I sang on stage.

Observing me step out of the auditorium, Baba got worried. He had spoken very highly of me to everyone. He thought that I was nervous about singing in front of the audience. I assured him, “Do not worry. The moment they announce my name, I will be on the stage. And I will certainly give my best performance.”

I sang on the music of karaoke cassette. Baba’s wife wept with joy to see the audience uncontrollably cheering. One of the directors of Lucknow Durdarshan (local TV station) told Baba that she wanted me to sing songs of sugam sangeet on television. I could not meet her and some others because I had left for home since I felt unwell. Excessive noise had again worked cruelly on my ears.

The Rise and the fall

People told my parents that I was an ‘out-of-control’ boy. I too felt that I was moving faster than I had expected, and that that day was not far when I would win a Filmfare Award for singing! I turned my attention to locating people who could help me release an audio album. Those days, I was so happy that my dream appeared to be unfolding into reality in a dreamlike manner! When you get the feeling of rushing towards success, the pressure of excitement and joy becomes really difficult to handle.

My father felt that I would destroy myself, so deep was I involved in reaching to my goal. I had bitter arguments with him several times, which I deeply regret now, but then, I had fancied that music for me was what water is to fish, or the soul is to the body. If you had ever seen the manner I argued with my father those days, you would have certainly hated me. He was only telling me to reduce the time I gave to singing, and devote more time to studies. But I did not realize that I had become selfish for my aim. If I had not been drunk in the passion of ‘success’, I would have certainly obeyed him for my own good. I had become a selfish and helpless slave to the passion for singing.

Before getting on the stage, I used to bombard my brain with all the negativity that I had faced. That was my way of bringing out the best in me. The overflowing enthusiasm and sullen pride triggered by this bombardment used to merge with the intoxication of music, making it a fantastic combination, making me feel like the ‘King of Kings’. Stage-fright only pepped up my adrenaline! I knew how difficult it is to make a single person clap on your singing ability – and here I was, with hundreds adoring my singing talent. I was able to make them dance; I was able to make them cry.

The cheers of the audience robbed me of my peace and bliss. I do not know when I actually slipped into the dark pool of arrogance. The seed of arrogance was sown, and a nasty plant had started to sprout. My friends tried to tell me about my arrogant ways, but I was beyond all that. I was rendered ignorant and blind not by Retinitis Pigmentosa, but by an inflamed ego.The deceptive feeling of being “the King of Kings” was like the effect of a dreadful drug.

The new bright change

Luckily, I managed to grasp the seriousness of the situation. I realized that I was hurting people who loved me, who cared for me. I had rebelled against my own father, who had nothing but the best intentions for me in his advice, and was arrogant to my sweet companions who truly wished me well.

I decided to quit singing, faster than what it takes for an eye to blink. It was a cold evening and the spring of my life when I was coming out of Bhatkhande, knowing well that I would never return to it. The setting of the sun seemed to raise fresh energy into my life. I knew nothing about my future, but I felt the tides of joy that one feels when he stops being susceptible to negative emotions.

A stream, when gushing forth from within a mountain, does not seem to know its path. It just knows that it will carve a path for itself.

Now, as the burden of ambition and the darkness of ego had vanished, everything was new and clear to me. I was sure that life had not stopped for me; rather, it was at the edge of a new, bright change. What that change was and what I will do was hidden by time. I had entered adulthood, but I enjoyed the bliss of childhood. I was free; my mind was clear, I could see the world with open eyes and I could feel that my heart wished to tell me something sweet.

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Shadab Husain, Lucknow, India, with a little editorial help from Ms Hema Vijay, Chennai, India.

The Hero

That Monday morning, we were going for an interview in a multinational company. You probably know how excited, happy and nervous freshers are on their first interview.

Our batch consisted of five students, and almost all of us were quite bright and sharp. We had demonstrated remarkably well at computers and had sharpened our soft skills in the personality development course which was designed for us. Our teachers at the Indian Confederation for the Blind used to say that our batch is the best; we all have extraordinary talents and skills.

I was confident that I will give my best performance. The same spirit was in Alice, Meena and Ritu. But Vibhore did not seem to have this feeling. He was the only student in our batch who had only studied up to matriculation, otherwise we all were graduates. More to it, his English communication too was not so good.

We reached the interview venue a little before time. The human resources person, who arrived late in the interview room, greeted us warmly. He humoured with us to make us feel comfortable, and it did alleviate our nervousness to a certain extent. He inquired our names, and then asked whether we wanted to be interviewed in a group or separately. We decided to have a group interview.

Alice was the first one to be asked the typical interview question: “Tell me something about yourself.” She stammered in the beginning, but once she got into the flow, she went on to tell about her education, hobbies and achievements, which were pretty impressive.

Meena was asked to tell her achievement. “I feel that the greatest achievement of my life is that I am happy and undeterred despite my visual impairment. I have learnt how to work against odds, and this makes me feel that I can achieve a lot in life.”

This answer of Meena earned praises from the HR and we too appreciated it.

Ritu, on being asked her weakness, said that “I feel that I am unduly passionate about work. Sometimes this passion compels me to do more than I feel I have the stamina of doing.”

It impressed the HR probably due to the genuine spirit with which it was spoken.

Now it was my turn. “How do you pronounce it {Ghazenfar}?” inquired the HR, trying to take my name looking at my CV. I pronounced my name and tried to clearly emphasize each syllable and vowel. “G-H-A-Z-E-N-F-A-R.” The HR was still unable to pronounce my name, and preferred to address me by my second name, Khan.

I was asked to tell about any unusual event of the recent past. I told how we celebrated the birthday of one of our friends. “We did not wish him for the entire day because we had planned to cut the cake on his bike. That poor guy was worried to think that we don’t remember his birthday. But we wanted to give him a surprise, and that could have only happened after our classes, so we waited till the evening.” “A creative idea – cutting the birthday cake on a bike!” said the HR, appreciably.

Vibhore’s turn came. He too was asked to tell about an unusual incident. Instead of his cheerful expressions, which had impressed many, his face wore a dull look due to nervousness. He tried to speak, but neither his grammar nor his pronunciation were good at all. He stammered, and abruptly halted in the middle – probably feeling how poor his performance is. The HR, who had a remark for all of us, seemed to feel it unnecessary to say anything for Vibhore. I felt sorry for him, and could not properly enjoy the high appreciation I had received by the HR. 

All of us were offered jobs. Well, everyone, except Vibhore.

As we came out, I was thinking hard how to encourage Vibhore, when I heard a cheerful voice calling my name from behind, “Ghazenfar! You have cracked the thing!”

It was Vibhore. He had brought refreshments for all of us to celebrate our victory. I knew that his joy was caused neither due to frustration, nor was it to kill the sadness of his failure. The life in his heart had caused it. His never-give-up spirit had made him so happy. And I must confess here that I felt jealous to see his happy state of mind, despite his failure at the interview. I was able to sense the same jealousy in the shocked expressions of all the job-getters. I got highly inspired by him and craved to get his positive energy.

Vibhore had an uncommonly courageous heart throbbing in his chest. Such people never give up, because they focus on the real, larger picture of life. Failing in interviews or examinations are small matters for them. They know that this world offers so many more opportunities that failing in a few fields would not be able to deter them. Getting sad over a failure is pretty natural. But such people soon overcome their sadness, and keep going ahead.

Now Vibhore runs two booming petrol pumps, has three cabs running in a company and few of the employees under him earn quite like us. But he could never clear an interview.

Tell me who is the hero?

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Shadab Husain works in the front office at Chhatrapati Shahuji Maharaj Medical University, Lucknow. He has an MA in English literature, and has pursued a diploma in computer applications as well as a personality development course. He also writes a blog on personality development and improving English at PersonalityAndEnglish.blogspot.com.