Scoliosis linked to disruptions in spinal fluid flow

A new study in zebrafish by researchers at Princeton University and the University of Toronto suggests that irregular fluid flow through the spinal column brought on by gene mutations is linked to a type of scoliosis that can affect humans during adolescence. Also found in people, these genes damage the hair-like projections called motile cilia that move fluid through the spinal canal and lead to a curvature of the spine. The researchers used a temperature-sensitive mutation in the gene c21orf59 to induce scoliosis in adolescent zebrafish. The fish develop a normal spine when the mutation is turned off (top panel) but a curved spine when the mutation is on (bottom panel)

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A new study in zebrafish suggests that irregular fluid flow through the spinal column brought on by gene mutations is linked to a type of scoliosis that can affect humans during adolescence. Found in humans and zebrafish, these mutated genes damage the cilia—tiny hair-like projections that line the spinal canal and help move the fluid—and lead to a curvature of the spine.

The researchers found that when they repaired the mutated cilia genes, they restored cerebrospinal fluid flow and could prevent spinal curves from developing. If translatable to humans, the study could lead to a non-surgical approach for treating the condition known as idiopathic scoliosis, which has no known cause and affects roughly three out of every 100 adolescents. The research was published June 10 by the journal Science by researchers at Princeton University and the University of Toronto.

"This is the first hint of a biological mechanism for idiopathic scoliosis," said Rebecca Burdine, associate professor of molecular biology at Princeton, and a senior author of the study. "We hope this research will open up new areas of inquiry as to how the disruptions to normal cerebrospinal fluid flow can lead to spinal curvature."

Burdine's lab conducted the study in collaboration with a team led by senior author Brian Ciruna, an associate professor of molecular genetics at the University of Toronto and a senior scientist at the Hospital for Sick Children in Toronto.

"Traditionally, theories regarding the biology behind idiopathic scoliosis have revolved around defects in the bone, cartilage or neuromuscular activity," Ciruna said. "The finding that defects in cerebrospinal fluid flow may be contributing to scoliosis came as a surprise. It is not a theory that had been put out there previously."

The study is the first to link spinal curvature to mutations in genes that govern motile cilia, which stick out from cells and make synchronous whip-like motions to push fluid through narrow passages such as the spinal column.

Hazel Sive, a professor in biology at the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology who was not involved in the study, is an expert in the use of zebrafish to study vertebrate development.

"This study is an important step forward in understanding events underlying spinal curvature," Sive said. "In an elegant set of experiments, the authors take advantage of the outstanding zebrafish system to define that cilia function and perhaps cerebrospinal fluid flow is required for normal spinal cord development."

Researchers in the Burdine laboratory had observed that mutant genes that disrupt cilia motility produce spinal curves in zebrafish as adults, although the work had not been published. "I've presented this finding for years, but didn't have a way to link this work to human disease," Burdine said. "Collaborating with Brian's group helped us make this link."

Previous research by Ciruna's lab revealed that mutations in a gene found in zebrafish and humans called protein tyrosine kinase-7 (ptk7) causes spinal curvature during a period of rapid growth that corresponds to adolescence in zebrafish. Published in the journal Nature Communications in 2014, the findings, suggested that the mutant fish could serve as a model for studying the condition. The researchers knew that the ptk7 gene plays a role in helping cells orient in the correct direction during embryonic development, but they didn't know that it also governed the formation of motile cilia.

Researchers studied the flow of cerebrospinal fluid in zebrafish brain regions located at the entrance to the spinal cord using fluorescently tagged beads. In zebrafish with mutations in genes that control the function of motile cilia, the …more

To explore how ptk7 mutations lead to spine curvature in zebrafish, Curtis Boswell, a graduate student at the University of Toronto, examined the brains and spinal cords of fish with mutated ptk7. In brain regions known as ventricles, which sit at the top of the spinal cord, the motile cilia were sparse and malformed and the fish developed a brain-swelling condition called hydrocephalus, which is associated with loss of cilia function. Using fluorescent dyes to track the flow of cerebrospinal fluid through the ventricles, the researchers saw that the flow was irregular and slower than normal.

When the researchers introduced a non-mutated version of the ptk7 gene specifically into tissues harboring motile cilia, the hydrocephalus disappeared, the cerebrospinal fluid began to flow normally and the spine straightened.

"We demonstrated that if we could restore gene function in the motile ciliated tissues, we could restore cerebrospinal fluid flow, and we could actually prevent scoliosis in these mutants," Ciruna said.

The researchers also tested other motile-cilia gene mutations to see whether they disrupt cerebrospinal fluid flow and cause spine curvature. Daniel Grimes, a postdoctoral research associate, and Nicholas Morante, a graduate student, both in the Burdine lab in Princeton's Department of Molecular Biology, studied four such mutations in genes called ccdc40, ccdc151, dyx1c1 and c21orf59. They found that all four gene mutations led to curvature of the spine in zebrafish.

The researchers found that the damage to motile cilia function occurs and leads to the onset of scoliosis during adolescence for zebrafish, a period of rapid growth. They took advantage of the temperature-sensitivity of the mutant c21orf59 gene, which can be switched on or off by controlling temperature. They kept zebrafish embryos at 25 degrees Celsius (77 degrees Fahrenheit), which switches the mutation off, so that the fish didn't develop embryonic defects.

The researchers then moved groups of fish aged 19-, 24-, 29- or 34-days-old to a tank set at 30 degrees Celsius (86 degreees Fahrenheit), which turned the mutation on and stopped cilia-driven spinal fluid flow. The fish that were switched to the warmer tank at 19 days, which corresponds to adolescence, formed spinal curves. However, fish that were shifted to the warmer tank at ages 24 and 29 days respectively developed milder curves, and fish shifted at age 34 days did not develop curves.

"Together with the Burdine group we defined a critical window for motile cilia function and cerebrospinal fluid flow in normal spine development," Ciruna said. "This window appears to be not during embryogenesis and not in adulthood, but specifically when fish are growing rapidly, in other words, fish adolescence."

Additionally, the development of spinal curves in these adolescent fish could be blocked by switching the fish back to the cooler tank. "This provides proof-of-principle that the development of severe idiopathic scoliosis spinal curvatures can be managed without invasive surgical manipulation," the authors wrote in Science.

Several additional lines of evidence point to links between motile cilia dysfunction, cerebrospinal fluid flow disruption and idiopathic scoliosis, Burdine said. For example, individuals with primary ciliary dyskinesia, a rare genetic disorder that causes defects in the movement of cilia lining the respiratory tract, have an elevated risk for scoliosis. Also, scoliosis is prevalent in humans with conditions such as tumors that obstruct cerebrospinal fluid flow.

The next step will be to understand the mechanisms by which disrupted cerebrospinal fluid flow causes the spine to curve, Burdine said.

"Now that we can study idiopathic scoliosis in zebrafish," she said, "we can begin to identify molecular pathways that are involved in spine curvature, and hopefully, find therapeutic targets to address this condition."

Source : Medical Express , 10th June 2016 

Tyrone baby Charlie on road to recovery after treatment for curved spine in US

Charlie Ferris with his mum Donna after treatment in America to help heal his bones

The family of an 11-month-old baby boy living with a spinal condition have spoken of their joy after he underwent successful treatment in the US to straighten his curved bones.

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Donna Ferris (35) and her husband Jody, from Ballinderry, Co Tyrone, were told that if their little boy, Charlie, did not have treatment for his infantile scoliosis, his spine could become severely twisted, leading to breathing problems and even decreased life expectancy.

After being given the devastating news, the couple and their local community set about raising the necessary money to send Charlie to the Shriners Hospital in Philadelphia for specialist treatment.

When first X-rayed on April 4, the little boy had a 42 degree curve of the spine.

After a special cast was applied in America, this was reduced to between 15 and 20 degrees.

And in a post on Facebook, Charlie's mum revealed there had been even more progress.

"The third X-ray shows Charlie in cast today... they managed to get his curve down to 10 degrees," Donna wrote.

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"We were so emotional when we saw the X-rays, and overwhelmed beyond belief.

"We are so thankful to the Shriners Hospital, Philadelphia, the staff, and to Charlie's doctor, for everything they have done.

"When we see the X-rays, we are so relieved and proud of the decision we made to take Charlie to Philadelphia.

"It wasn't the easiest route to choose, but it certainly was the best route. We want to thank you all for your support, kind words, messages and generous donations, which have helped us on this journey.

"Charlie still has a way to go, but we are determined we will see it through."

The little boy was only three months old when Jody and Donna became first noticed and became concerned about a bump on their son's back. In the beginning, they dismissed it, putting it down to the way he was sitting.

However, in November, the couple's fears were realised when their son was diagnosed with infantile scoliosis.

Not wanting him to have to undergo an invasive operation, they searched for an alternative treatment and found the hospital in America. Luckily, the family were able to stay with Charlie's aunt, who lives close to Philadelphia.

However, doctors said they could not be sure how long the little boy's treatment programme would last.

As a result, the family faces having to fly to America every eight weeks.

Despite the strain, Donna and Jody said they had been overwhelmed by how many people had offered help with travel and treatment costs.

Among those who gave support to Charlie was tragic road racer Malachi Mitchell-Thomas, who died in a crash at the North West 200 in May.

The Ferris family praised the 20-year-old sportsman as "kind-hearted" after he posed with Charlie's mascot, Big Ted, just 48 hours before he lost his life on the race track.

Source : Belfast Telegraph , 09.06.2016 

New 3D imaging reduces radiation dose for scoliosis patients

Stollery’s diagnostic technology gives more accurate view of musculoskeletal system

Children with spinal deformities like scoliosis or other skeletal conditions are now receiving reduced radiation doses thanks to new diagnostic imaging technology at the Stollery Children’s Hospital.

Edmonton is now home to a low-dose, 3D imaging system that captures whole body images of a standing patient in a single scan, eliminating the need for traditional X-rays for most scoliosis patients. More than 600 pediatric patients have benefited since the system’s launch last Nov. 19.

The EOS Imaging System exposes children to seven to nine times less radiation than standard X-ray machines as it creates a high-quality image by scanning the spine of a patient in approximately seven seconds. The refined images are used for initial diagnosis and assessment.

The system also boasts a micro-dose setting which exposes patients to 50 times less radiation than a standard X-ray. While a micro-dose image may not be as clear as the traditional image, it’s sufficient to monitor disease progression for scoliosis patients who require follow-up imaging.

“X-rays and scans can be helpful, even life-saving, but increased exposure to radiation can lead to an increased incidence of cancer,” says Dr. Marc Moreau, a pediatric orthopedic surgeon at the Stollery. “It's important to use the lowest dose possible when scanning a child; this technology allows us to obtain the best quality imaging without compromising the safety of our patients.”

Scoliosis, defined as a spinal curvature of more than 10 degrees to the right or left, impacts three to five per cent of children, and typically affects girls more frequently and more severely than boys. The scoliosis clinic at the Stollery sees about 1,800 patient visits per year, with patients who often require scans every six months.

“Scoliosis is a three-dimensional deviation of the spine, but traditional X-rays only give us a two-dimensional view,” says Dr. Moreau. “This new device uses an ultra-low dose of radiation to provide extremely detailed, high-quality images. Using the EOS machine makes imaging safer for our pediatric patients and gives a more accurate perspective for diagnosis, surgical treatment and follow-up of the spine.”

Philippa Madill, 13, of Drayton Valley, was five years old the first time her spine was X-rayed. Her older sister Hannah, who was also diagnosed with scoliosis, received as many as four X-rays per year to monitor her spine as she grew up.

“Every time they X-rayed the girls I would cringe,” says their mother Sue Madill. “Knowing they were constantly being exposed to radiation always bothered me.”

In May, Philippa had her first scan using the new EOS Imaging System.

“As a parent, it is such a relief that this machine is available now,” she adds, “and that Philippa will be receiving substantially less radiation as she continues to grow.”

The Stollery Children’s Hospital Foundation contributed $750,000 towards the machine and an additional $27,500 for the micro-dose software.

“The EOS imaging system is a prime example of why the foundation funds excellence at the Stollery,” says Mike House, President and CEO of the Stollery Children’s Hospital Foundation.

“This advanced equipment improves the health and safety of children by reducing their exposure to radiation during diagnostic testing. Thanks to our generous donors, the Stollery is the only hospital in Alberta, and just one of two in western Canada, using the EOS system on a clinical basis.”

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The Stollery Children’s Hospital Foundation is committed to transforming children’s health care by funding excellence at the Stollery Children’s Hospital. Excellence comes in many forms: specialized equipment; sub-specialty education to train the brightest medical minds; research to discover new treatments and cures; and specialized pediatric programs that enhance family centred care, and patient and family outcomes at the Stollery.

Alberta Health Services is the provincial health authority responsible for planning and delivering health supports and services for more than four million adults and children living in Alberta. Its mission is to provide a patient-focused, quality health system that is accessible and sustainable for all Albertans.

Source : Albert Health Services , 8th June 2016

Predictive Technology Group, Inc. (PRED) Announces Key Patent Issuance by US Patent and Trademark Office for Treating Patients With Genetic Spinal Deformities and Syndromes Award Provides Patent Protection for Multiple Therapeutic and Companion Diagnostic Products

Predictive Technology Group, Inc. (OTC PINK: PRED), a life sciences technology holding company, announced today that the United States Patent and Trademark Office (USPTO) has granted a fundamental patent (US Patent 9,370,431) that covers the practice of administering ANY spine deformation therapeutics to a patient having a spine deformation altered risk associated biomarker

"We are pleased to see this latest patent issuance that supports PRED's novel approach to diagnosing spinal disorders and syndromes," said Mike Schramm, PRED's Director of Intellectual Property. "This issued US patent supports the commercial use of both our diagnostic and next-generation companion treatment products." The claims of the '431 application build on previously issued US patents 8,123,787 and 8,641,738 to which '431 claims priority and further bolster PRED's Intellectually Property position.

"We are gratified to see this latest patent issuance, which covers the core technology underlying the Company's first available molecular diagnostic test," said Bradley Robinson, President and Chief Executive Officer of Predictive Technology Group, Inc. "Furthermore, this fundamental patent covers not only spinal applications of our technology but establishes a precedent for the other patent applications that have been submitted on the Company's portfolio of next-generation diagnostic and companion treatment products."

The patent establishes the foundation of key intellectual property (IP) covering ANY treatment options (drug, surgery, bracing, etc.) for patients having a specific spine deformity biomarker. This newly issued patent is additive to previously announced patents. Furthermore, the Company has additional US and International patent applications pending and will pursue such applications with the objective of receiving additional issued patents in several other disease states.

The issuance of this new patent is a significant milestone for PRED

For information about this release, contact Rich Kaiser, Investor Relations, YES INTERNATIONAL, 757-306-6090,

yes@yesinterntional.com, and

info@predictivetechnologygroup.com.

About Predictive Technology Group, Inc.

Predictive Technology Group, Inc. (PRED), through its wholly owned subsidiaries, revolutionizes the treatment of serious and debilitating diseases through the commercialization of novel therapeutics leveraged by proprietary gene-based companion diagnostics. The Company develops and/or acquires proprietary technologies that open windows into the origin of human disease and the role that genes and their related proteins play in diseases' onsets and progressions. PRED's subsidiaries use gene-based information as cornerstones in the development of new diagnostics that assess a person's risk of disease and therapeutic products designed to prevent effectively and/or treat disease

Forward-Looking Statements

To the extent any statements made in this release contain information that is not historical, these statements are essentially forward-looking and are subject to risks and uncertainties, including the difficulty of predicting FDA approvals, acceptance and demand for new vaccines and other pharmaceutical products, the impact of competitive products and pricing, new product development and launch, reliance on key strategic alliances, availability of raw materials, availability of additional intellectual property rights, availability of future financing sources, the regulatory environment, and other risks the Company may identify from time to time in the future.

Source : Market Wired , 21st June 2016

European spine surgery devices market to grow at CAGR of 6.1% to 2020: 5 takeaways

The European spine surgery devices market is anticipated to hit $2.37 billion by 2020, acoording to a Market Reports World report.

Here are five key takeaways:

1. The market is anticipated to grow at a compound annual growth rate of 6.1 percent between 2015 and 2020.

2. A rising number of spine deformity cases and increasing popularity of non-fusion devices will spur market growth.  

3. Additionally, a growing geriatric population and increasing advancements in minimally invasive techniques and biologics will boost market growth.

4. In 2014, the spinal fusion devices segment accounted for the largest market share.

5. Key market players include Stryker, DePuy Synthes, Zimmer Biomet, Medtronic, Alphatec Spine, NuVasive, Integra LifeSciences, Orthofix International, Globus Medical, LDR, K2M and B. Braun Melsungen.

Source : Beckers Spine , 24th June 2016 

A 3D-Printed Solution to Scoliosis

One of the prices of increased wisdom seems to be a general increase in aches and pains. For adults, the sensation of waking with sore back or neck after a fitful night’s sleep isn’t particularly noteworthy. For children and young adults, this can be a sign of more serious health problems, including scoliosis.

The NIH defines scoliosis as “a musculoskeletal disorder in which there is a sideways curvature of the spine or backbone.” In some cases, scoliosis requires bracing or monitoring by a physician to ensure the curvature doesn’t increase. The worst cases require surgery using rods to straighten the spine. A new option has been developed by Medicrea, based on the flexibility offered by 3D printing. The company uses the technology to produce patient-specific fusion implants, helping prepare the patient for surgery. 

Dr. King demonstrates the difficulty of bending a spinal rod by hand. Image courtesy of Medicrea.

Traditionally, when surgery is required to fix severe cases of scoliosis, doctors are required to bend the rods by hand and fit them in place as best they can. This can be a difficult procedure, even for the most experienced doctors.

“I personally have been bending those rods for 34 years,” said Dr. Andrew G. King, Children’s Hospital orthopedic surgeon. “I’ve been underwhelmed by my ability to bend a rod so that it matches the perfect numbers. The surgical rods which we put in to fix the scoliosis are specific to each particular patient.”

With recent FDA approval, Medicrea’s UNiD system allows doctors to build spinal rods specific to each patient before surgery even begins with precision contouring. Patients are measured for the rods, which are then implanted along with 3D-printed interbody fusion devices — such as osteosynthesis cages and vertebral body replacements.  In the short time since approval was granted, more than 700 patients have benefited from the UNiD system.

Along with a surety that a treatment will correctly adjust a patient’s spine, recovery time has also been reduced as a result of UNiD.

“If I slept a certain way or just sat certain ways it would cause pain,” said Karly, a 14-year old patient. “I was worried that I wouldn’t be able to play softball or do cheer. It’s been almost four months. I started playing softball again and made the team.

Source : Rapid Ready , 23rd June 2016

Brave battle to heal a body

JUNE is Scoliosis Awareness Month, so for Inverell’s Lauren Mangano and her mother Kym, it was a perfect time to tell their story of Lauren’s experience with the disorder, and of her terror when, six ago months today, surgeons prepared to straighten her spine.

Lauren just after surgery with her brother Chris while being taken back to the ward.

Scoliosis is a progressive, lateral curvature of the spine affecting both children and adults. In children the condition can rapidly progress as the child grows.

For 14-year-old Lauren, the first sign of scoliosis was detected in x-rays for a suspected shoulder injury following a fall at age 10. Kym actually asked the radiologist if Lauren had moved while the x-ray was being taken.

“He said no, but that we would have to go and see about it, and from that we noticed that the top of her spine had curved,” she said. In 2011, Lauren was referred to a specialist at John Hunter Hospital who diagnosed scoliosis. She had with a 17 degree curve. Lauren said the first thing they did was Google scoliosis.

“It looked scary and painful,” Lauren said.

And she did suffer pain that greatly restricted her sport as the curve in her spine increased. 

Surgeons decided to operate in 2015 to realign her hips and straighten her shoulders after the curve in her spine reached 77 degrees. Lauren said when that day arrived on December 14, she was terrified by the risks. 

“I didn’t know what was going to happen afterwards,” she said.

“I kept thinking ‘what happens if something goes wrong? What happens if they hit a nerve in my back? I could be paralysed’.”

It looked scary and painful.

- Lauren Mangano

Surgeons untwisted Lauren’s spine as much as they could, inserted two titanium rods into her back, pinned them in place and fused parts of her spinal column.

But nothing went wrong and Lauren’s fears never eventuated; and Kym said her daughter grew six-and-a-half centimetres overnight.

“One of the first things she said afterwards was ‘I’ve got a waist’, because of how she was she never had one before,” Kym said.

Although Lauren still suffers with muscular tearing as her body adjusts to its new position and the rods dig into her back when she sits at school, Kym said she is a great deal better than before.

“When I leave school I want to go to university and become a nurse, or go into the scoliosis clinic and help kids that have the same problem as me because I know about it and have been through it,” Lauren said.

Source : The Inverell Times , 14th June 2016