̽��ֱ�� of Cambridge - spine

‘Wraparound’ implants represent new approach to treating spinal cord injuries

sc604 — Wed, 08 May 2024 18:01:25 +0000

A team of engineers, neuroscientists and surgeons from the ̽��ֱ�� of Cambridge developed the devices and used them to record the nerve signals going back and forth between the brain and the spinal cord. Unlike current approaches, the Cambridge devices can record 360-degree information, giving a complete picture of spinal cord activity.

Tests in live animal and human cadaver models showed the devices could also stimulate limb movement and bypass complete spinal cord injuries where communication between the brain and spinal cord had been completely interrupted.

Most current approaches to treating spinal injuries involve both piercing the spinal cord with electrodes and placing implants in the brain, which are both high-risk surgeries. ̽��ֱ��Cambridge-developed devices could lead to treatments for spinal injuries without the need for brain surgery, which would be far safer for patients.

While such treatments are still at least several years away, the researchers say the devices could be useful in the near-term for monitoring spinal cord activity during surgery. Better understanding of the spinal cord, which is difficult to study, could lead to improved treatments for a range of conditions, including chronic pain, inflammation and hypertension. ̽��ֱ��results are reported in the journal Science Advances.

“ ̽��ֱ��spinal cord is like a highway, carrying information in the form of nerve impulses to and from the brain,” said Professor George Malliaras from the Department of Engineering, who co-led the research. “Damage to the spinal cord causes that traffic to be interrupted, resulting in profound disability, including irreversible loss of sensory and motor functions.”

̽��ֱ��ability to monitor signals going to and from the spinal cord could dramatically aid in the development of treatments for spinal injuries, and could also be useful in the nearer term for better monitoring of the spinal cord during surgery.

“Most technologies for monitoring or stimulating the spinal cord only interact with motor neurons along the back, or dorsal, part of the spinal cord,” said Dr Damiano Barone from the Department of Clinical Neurosciences, who co-led the research. “These approaches can only reach between 20 and 30 percent of the spine, so you’re getting an incomplete picture.”

By taking their inspiration from microelectronics, the researchers developed a way to gain information from the whole spine, by wrapping very thin, high-resolution implants around the spinal cord’s circumference. This is the first time that safe 360-degree recording of the spinal cord has been possible – earlier approaches for 360-degree monitoring use electrodes that pierce the spine, which can cause spinal injury.

̽��ֱ��Cambridge-developed biocompatible devices – just a few millionths of a metre thick – are made using advanced photolithography and thin film deposition techniques, and require minimal power to function.

̽��ֱ��devices intercept the signals travelling on the axons, or nerve fibres, of the spinal cord, allowing the signals to be recorded. ̽��ֱ��thinness of the devices means they can record the signals without causing any damage to the nerves, since they do not penetrate the spinal cord itself.

“It was a difficult process, because we haven’t made spinal implants in this way before, and it wasn’t clear that we could safely and successfully place them around the spine,” said Malliaras. “But because of recent advances in both engineering and neurosurgery, the planets have aligned and we’ve made major progress in this important area.”

̽��ֱ��devices were implanted using an adaptation to routine surgical procedure so they could be slid under the spinal cord without damaging it. In tests using rat models, the researchers successfully used the devices to stimulate limb movement. ̽��ֱ��devices showed very low latency – that is, their reaction time was close to human reflexive movement. Further tests in human cadaver models showed that the devices can be successfully placed in humans.

̽��ֱ��researchers say their approach could change how spinal injuries are treated in future. Current attempts to treat spinal injuries involve both brain and spinal implants, but the Cambridge researchers say the brain implants may not be necessary.

“If someone has a spinal injury, their brain is fine, but it’s the connection that’s been interrupted,” said Barone. “As a surgeon, you want to go where the problem is, so adding brain surgery on top of spinal surgery just increases the risk to the patient. We can collect all the information we need from the spinal cord in a far less invasive way, so this would be a much safer approach for treating spinal injuries.”

While a treatment for spinal injuries is still years away, in the nearer term, the devices could be useful for researchers and surgeons to learn more about this vital, but understudied, part of human anatomy in a non-invasive way. ̽��ֱ��Cambridge researchers are currently planning to use the devices to monitor nerve activity in the spinal cord during surgery.

“It’s been almost impossible to study the whole of the spinal cord directly in a human, because it’s so delicate and complex,” said Barone. “Monitoring during surgery will help us to understand the spinal cord better without damaging it, which in turn will help us develop better therapies for conditions like chronic pain, hypertension or inflammation. This approach shows enormous potential for helping patients.”

̽��ֱ��research was supported in part by the Royal College of Surgeons, the Academy of Medical Sciences, Health Education England, the National Institute for Health Research, MRC Confidence in Concept, and the Engineering and Physical Sciences Research Council (EPSRC), part of UK Research and Innovation (UKRI).

Reference:
Ben J Woodington, Jiang Lei et al. ‘Flexible Circumferential Bioelectronics to Enable 360-degree Recording and Stimulation of the Spinal Cord.’ Science Advances (2024). DOI: 10.1126/sciadv.adl1230

A tiny, flexible electronic device that wraps around the spinal cord could represent a new approach to the treatment of spinal injuries, which can cause profound disability and paralysis.

Because of recent advances in both engineering and neurosurgery, the planets have aligned and we’ve made major progress in this important area

George Malliaras

SEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY

Illustration of spinal cord

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Inflatable, shape-changing spinal implants could help treat severe pain

sc604 — Fri, 25 Jun 2021 17:14:34 +0000

A team of engineers and clinicians has developed an ultra-thin, inflatable device that can be used to treat the most severe forms of pain without the need for invasive surgery.

Cambridge researchers launch charity to tackle ‘slow motion spinal cord injury’ affecting up to a million UK adults

cjb250 — Mon, 06 May 2019 23:13:22 +0000

Myelopathy is caused by arthritic changes affecting the spinal column of the neck. Because of the close proximity, these can exert pressure on the spinal cord and trigger a "slow motion spinal cord injury".

“If you haven’t heard of myelopathy, you are probably in good company,” said Dr Kotter. “Myelopathy is likely the most under-diagnosed neurological condition, yet it affects as many as a million adults in the UK.”

̽��ֱ��onset of myelopathy is often subtle: symptoms include numb and clumsy hands, imbalance, and urinary problems. When left unattended, it can progress with patients losing control of their hands and bladder, and becoming unable to walk. Myelopathy is now recognised as having one of the worst impacts on quality of life.

̽��ֱ��actual number of patients who suffer from this condition remain unclear. Recent research by Dr Kotter's team who analysed existing spinal MRI studies, indicates that as many as one in 50 adults may be affected.

Treatment options for myelopathy are limited. ̽��ֱ��only form of treatment that is effective consists of surgical decompression of the spinal cord. Despite this single option, the management of myelopathy patients remains highly divergent across the globe.

To raise awareness of myelopathy and to address gaps in our knowledge of the condition and how best to treat it, Dr Kotter and colleague Ben Davies, together with Iwan Sadler, a myelopathy-sufferer, have launched Myelopathy.org, a charity that aims to give patients a voice and effect change.

̽��ֱ��charity has grown out of an information website created by Dr Kotter and Mr Davies. Today, Myelopathy.org celebrates its official launch as the first charity dedicated to the condition at an event in the House of Lords hosted by Lord and Lady Carter of Coles. ̽��ֱ��launch will gather together top representatives from the NHS, politics, research councils, charities, and health care providers.

“Today’s event shows how research can impact not only academia and industry, but inspire grassroots initiatives that bring together individuals in order to tackle important issues,” said Dr Kotter. “It is also a clear demonstration of the difference that the ̽��ֱ�� of Cambridge can make to the lives of millions of patients worldwide.”

Previously, Dr Kotter and colleagues from the Spinal Cord Injury Knowledge Forum in the AOSpine, the world-largest spine surgeon network, brought together patients, health professionals including physicians, surgeons, physiotherapists, allied health professionals, and researchers to develop the first clinical guidelines for the treatment of myelopathy. ̽��ֱ��guidelines recommend monitoring the condition at early stages, but for moderate or severe forms, as well as any signs of deterioration, considering urgent surgical attention.

̽��ֱ��guidelines have been welcome by health care professional and sufferers around the globe, recognised by multiple national and international bodies, and are being implemented on a world-wide scale. As the guidelines also determine in which cases surgery is not appropriate, they are expected to benefit not only those that require treatment but also protect individuals from unnecessary surgery. This is a prime example of how research can translate rapidly and have positive impact on a global scale.

In the largest ever survey of myelopathy patients world-wide, carried out on the Myelopathy.org website, Dr Kotter's team asked sufferers questions, including: how long have they suffered from myelopathy? How long did it take to be diagnosed? Did they undergo surgery? At what stage is their disease? And, how does it affect their quality of life? Would they be interested in participating in research? And what would be their number one research priority?

“ ̽��ֱ��results of our survey were shocking: on average it takes more than two and a half years to be diagnosed,” said Mr Davies. “As many as a third of patients have to wait more than five years. These delays can result in increased disability and suffering on an individual level, and most likely also to heavy financial burden on health care systems.

“We need to look at why the condition is not recognised earlier and how this situation can be changed. Are there gaps in knowledge amongst health professionals, or in the health care system?”

̽��ֱ��bulk of clinical research so far has been conducted on surgical approaches to myelopathy, but this research did not provide any firm conclusions. One of the reasons is that the primary outcomes of studies in myelopathy vary considerably. This renders studies difficult to compare.

In addition, researchers often fail to take into account the patient perspective. For example, patients responded to the survey that pain is their number one priority; however, only a fraction of studies measure pain and very few have asked how this can be addressed.

As well as celebrating the launch of Myelopathy.org, today's event also announces RECEDE (REgeneration in CErvical DEgenerative) Myelopathy, the first regenerative medicine trial for the condition. ̽��ֱ��clinical trial is sponsored by the National Institute for Health Research and is being carried out as a joint UK-collaboration. It is expected to begin later this year.

Today sees the official launch of Myelopathy.org, a charity dedicated to one of the most common, yet under-diagnosed neurological conditions. ̽��ֱ��charity is the brainchild of Dr Mark Kotter, neurosurgeon and clinician scientist at the ̽��ֱ�� of Cambridge, who works on a disorder known officially as Degenerative Cervical Myelopathy.

If you haven’t heard of myelopathy, you are probably in good company. Myelopathy is likely the most under-diagnosed neurological condition, yet it affects as many as a million adults in the UK.

Mark Kotter

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Spinal injury and ‘biorobotic control’ of the bladder

cjb250 — Tue, 16 Feb 2016 13:27:49 +0000

Spinal cord injury is, in many respects, a testosterone disease, says Professor James Fawcett.

What he means by this is that four out of five spinal cord injuries happen to men, and the most common age group is early adulthood. “Men are not good at assessing risk at that age,” he says. “Females are much more sensible.”

It is perhaps not surprising, then, that when asked about their priorities, most quadriplegic people will select a return of sexual function as second after the use of arms and hands. Third on the list, above being able to walk, is a return of bladder and bowel control. “Way down the list is walking, because wheelchairs work reasonably well and patients can get used to using them,” says Fawcett, who heads the John van Geest Centre for Brain Repair at Cambridge.

Restoring bladder and bowel control is a particular challenge, however. Currently, patients have to fill their bladder with botulinum toxin (botox) to paralyse it and catheterise themselves several times a day. This may be the simplest method, but catheterisation can cause infection and scarring in the urethra.

Instead, Fawcett is developing a device based on the ‘Brindley device’, named after physiologist Giles Brindley, who trained at Cambridge after the Second World War. ̽��ֱ��Brindley device is an implant to which an external stimulator is applied manually, causing the bladder to contract and empty itself. It has been used in thousands of patients, but it, too, is not without problems: it necessitates severing sensory nerves from the pelvis into the spinal cord, causing weakening of the pelvic muscles – and loss of sexual function. (For most male patients, Viagra can at least help them maintain an erection, but this is only half the problem. ‘Well OK, doc,’ they say, ‘you’ve given me an erection, but what’s the use if I can’t feel it?’”)

Fawcett and colleagues are developing a ‘biorobotic’ version of the Brindley device that can read signals from the sensory nerves in the pelvis, rather than requiring them to be cut. These signals would stop the bladder emptying itself at embarrassing times, tell the patient how full the bladder is, and allow them to use the electronics to empty it.

̽��ֱ��ability to record signals from individual nerves has applications beyond just bladder control: Fawcett envisioned the technology as enabling patients who had lost a limb – such as soldiers losing arms or legs – to control robotic limbs. “ ̽��ֱ��limbs themselves are quite sophisticated,” he says, “but what doesn’t work at all well is their interface with the nervous system.” ̽��ֱ��technology required for recording signals for a whole limb has proven to be extremely complicated, so the team is looking at the bladder-control device as a simpler demonstration of a proof of concept.

Biorobotics will be one focus of a proposed new Spinal Injury Research Centre to be based at Addenbrooke’s Hospital. Although still at the very early planning stages, the Centre will capitalise on Cambridge’s position as the regional trauma centre for the East of England (even though a lack of facilities means spinal injury patients have to be sent to Stoke Mandeville near Oxford for rehabilitation).

A simplified version of the adapted Brindley device has so far been trialled in around 50 dogs, in whom spinal cord injury is surprisingly common, particularly in dogs with longer spines, such as dachshunds. Many owners of injured dogs want to keep their pets but, as Fawcett explains, “the dogs are perfectly happy to paddle around with wheels under their back legs, but they do so dribbling urine around your house.”

In fact, a randomised controlled trial in 2013 showed that injured dogs may even be able to do away with their wheels. Professor Robin Franklin from the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute showed that transplanting cells found in the nasal cavity, known as olfactory ensheathing cells, into the injured spine could help restore movement to the previously paralysed limbs. Although the cell transplant did not restore bowel or bladder control, it was, says Franklin, “a landmark study” that offers the promise of translation into humans. Franklin’s colleague Dr Mark Kotter is currently seeking funding to carry out a trial in humans.

But as Fawcett says, the priority among injured patients is to recover use of their upper limbs. Spinal cord injury causes damage to motor nerve fibres travelling from the brain and to sensory nerve fibres travelling to the brain. Both are structurally different and need to be coaxed to regenerate across the site of the injury – but even getting the nerve fibres to span these couple of centimetres is a challenge.

“ ̽��ֱ��problem is scar tissue,” says Fawcett. “It’s very difficult for nerve fibres to grow through this tissue.” He has identified an enzyme, chondroitinase, which can dissolve scar tissue. ̽��ֱ��enzyme works in rats and is in preclinical development for use in humans by the US biotech company Acorda Therapeutics.

Once the scar tissue has been dissolved, the nerve fibres need to regenerate and make new connections. Although restoring motor nerve fibres is proving a challenge, Fawcett has managed to restore sensory nerve fibres in rats, which is an important start. “Patients need to be able to feel what they’re doing and to sense pain. If they turn on a hot tap, they can easily scald themselves if they can’t feel the heat. And of course, they want sensation back in their genitalia.”

In most spinal cord injuries, some nerve fibres will always survive, and Fawcett believes we may be able to harness these to bypass nerve damage if we can harness a remarkable property of the young brain known as plasticity, which enables new connections to be made as we learn new skills. If a young child receives a spinal injury, their chances of recovery are much better than for an adult as their brain can adapt, but as we age, a cartilage-like coating wraps around nerve fibres, cementing the connections in place. These molecules make it difficult for the brain of an injured adult to find a way to bypass the injury.

“Interestingly,” explains Fawcett, “one of the main constituents of this cartilage is the same as that which blocks nerve growth in scar tissue – and we know we can dissolve this using chondroitinase. This should make rehabilitation – teaching the brain to do useful things again – dramatically more successful.”

Inset image: Credit ̽��ֱ��District.

There are many challenges facing people with spinal cord injury – and walking again is often the least of their problems. Cambridge research could help patients take control of their lives once more.

This should make rehabilitation – teaching the brain to do useful things again – dramatically more successfull.

James Fawcett

Zeevveez

Wheelchair

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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What is so unusual about a sloth’s neck?

amb206 — Wed, 11 Nov 2015 09:58:52 +0000

Scroll to the end of the article to listen to the podcast.

Xenarthra is an order of primarily South American mammals that includes sloths, ant-eaters and armadillos. Several are sufficiently endangered to be on the IUCN ‘red list’. In previous millenia, the group was far bigger. It covered many other creatures, now extinct, such as giant ground sloths estimated to have exceeded the size of a male African elephant.

As ‘exotic’ animals, xenarthrans have long fascinated westerners and became a must-have item in ‘cabinets of curiosities’ – collections gathered from a world that was opening up to exploration from the 15th century onwards. In the mid-17th century, the naturalist-physician, Georg Marcgrave, stationed in Dutch Brazil, described the armadillos that he encountered:

" ̽��ֱ��Tatu or Tatu-peba in Brazilian, Armadillo in Spanish, Encuberto in Portuguese, we Belgians call Armoured-piglet. It is a most powerful animal that lives in the ground, though also in water and soggy places. It is found in various sizes."

As a consequence of the blossoming of scientific enquiry in the 19th century, many leading zoology museums have examples of xenarthrans in their collections. Cambridge’s Museum of Zoology, for example, has a fine collection of specimens collected on expeditions to South America, from the diminutive Pink Fairy Armadillo (Chlamyphorus truncatus) to the towering giant ground sloth (Megatherium americanum) which became extinct some 10,000 years ago.

̽��ֱ��ground sloth is one of a number of relatively recently extinct large sloths, one of which Charles Darwin himself helped discover on the voyage of the Beagle. On September 18, 1832, Darwin noted in his dairy that he had dined on “Ostrich dumpling & Armadillos”. ̽��ֱ��‘ostrich’ he ate was, in fact, rhea; the abundant armadillos were a staple diet of the local gauchos.

Not long afterwards, Darwin saw for the first time fossils of shells and other animals, embedded in soft sea cliffs, including a specimen of giant ground sloth which was to be named Mylodon darwinii in his honour.

Xenarthans have been a source of fascination to Dr Robert Asher, an evolutionary biologist in the Department of Zoology, ever since he first began studying mammalian diversity as a graduate student some 20 years ago. He’s particularly interested in the evolutionary stories told by the structure of their skeletons – and the ways in which their bones act as clues to their relative position within the tree of life.

Natural history museums in Berlin, Paris and London have in their collections examples of three-toed sloths, including embryos and foetuses. These specimens enabled Dr Robert Asher and his colleague Dr Lionel Hautier (formerly a Cambridge postdoctoral fellow and now at the ̽��ֱ�� of Montpellier) to publish research on an aspect of the anatomy of sloths which sets them apart from almost every other mammal on earth.

̽��ֱ��difference lies in the arrangement of vertebrae in sloths’ spinal columns – which can be seen as clues to xenarthrans’ divergent evolutionary pathways over the past few million years.

You might think that animals with long necks would have more neck vertebrae than those with short necks. This is certainly true of some birds and reptiles. But almost every placental mammal on earth (some 5,000 species in total) has seven ‘ribless’ vertebrae in the neck – even creatures with long necks such as giraffes. ̽��ֱ��three-toed sloth deviates from this rule: many of these tree-living creatures have eight, nine or even ten cervical vertebrae.

This remarkable diversity was noticed in the 18th century and scientists continue to tease apart the mechanisms by which mammals deviate from the “rule of seven”. In 2009, Asher and colleagues set out to learn more about this intriguing quirk. Neck vertebrae are known as cervicals and the rib-bearing vertebrae below them are known as thoracics. Thoracic vertebrae have facets which allow articulation with the ribs.

Asher and colleagues looked at patterns of bone formation in mammals as they developed. They found that, in all mammals, the centrum (or middle part) of the first thoracic (number eight, counting down from the skull) turns from cartilage to bone earlier than the centra of the posterior-most cervicals. In sloths, too, the eighth vertebrae begins to develop early – but, in their case, this ribless vertebra is located in the neck and generally considered to be ‘cervical’.

“ ̽��ֱ��‘extra’ vertebrae in sloths’ necks have the same developmental characteristics as thoracic vertebrae. They are, in effect, ribcage vertebrae, masquerading as neck vertebrae. In sloths, the position of the shoulders, pelvis and ribcage are linked with one another, and compared to their common ancestor shared with other mammals, have shifted down the vertebral column to make the neck longer,” explains Asher.

“Even in sloths, the mammalian ‘rule of seven’ applies to the vertebral centra. ̽��ֱ��ossification of the centra in a long-necked sloth resembles ossification in other mammals. However, sloths can deviate from the “rule” by shifting the embryonic tissues that give rise to the limb girdles and rib cage relative to the vertebrae, adding what are essentially one or more ribcage vertebrae into the caudal end of their neck. ̽��ֱ��next question to address is why and how sloths managed this shift.”

Xenarthrans also pack some intriguing surprises when it comes to teeth. Anteaters have no teeth. Sloths have just one set of teeth to see them through life – as do all but one genus of armadillo. Armadillos in the genus Dasypus (including seven- and nine-banded species) are unlike other armadillos in having two sets of teeth during their lifespan: deciduous (or ‘milk’) teeth and permanent teeth.

Most mammals, including humans, shed their baby teeth while they are growing. Recent research by Asher and colleagues from the ̽��ֱ�� of La Plata, Argentina, into the dentition of Dasypus revealed that its permanent teeth erupt long after the animal reaches its full size. “ ̽��ֱ��equivalent scenario in a human would be losing your milk teeth, and gaining all your permanent ones, once you were fully grown and well into your 20s,” says Asher.

In this regard, Dasypus is similar to most species of endemic African mammals (Afrotheria) – a group of animals that includes elephants, manatees, tenrecs, golden moles and sengis. “Eruption of adult teeth after the attainment of full body size and sexual maturity is not unheard of in other mammals,” says Asher. “Some people reading this won’t yet have erupted their ‘wisdom’ teeth or third molars. But few groups do this as pervasively as Afrotherians and Dasypus.“

With gratitude to PhD candidate Natalie Lawrence (Department of History and Philosophy of Science) for her input on early western encounters with ‘exotic’ animals.

Next in the Cambridge Animal Alphabet: Y is for an animal that is an integral part of high-altitude livelihoods throughout the Himalayas, Tibet and Central Asia.

Have you missed the series so far? Catch up on Medium here.

Inset images: Illustration of an armadillo from Historiae Naturalis Brasilae Tatu by Georg Marcgrave; Skeleton of a giant land sloth (Museum of Zoology); Three-toed sloth - Bradypodidae - Luiaard (Martha de Jong-Lantink); Lateral view of 3D reconstruction of computerized tomography (CT) scans of skeleton in the three-toed sloth Bradypus (Hautier et al).

̽��ֱ��Cambridge Animal Alphabet series celebrates Cambridge’s connections with animals through literature, art, science and society. Here, X is for Xenarthran. A must-have item for 15th-century collectors of 'curiosities' and a source of fascination for evolutionary biologist Dr Robert Asher.

It is a most powerful animal that lives in the ground, though also in water and soggy places

Georg Marcgrave

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Folic acid deficiency can affect the health of great, great grandchildren

gm349 — Thu, 26 Sep 2013 00:07:14 +0000

Folic acid deficiency can cause severe health problems in offspring, including spina bifida, heart defects and placental abnormalities. A study out today reveals that a mutation in a gene necessary for the metabolism of folic acid not only impacts the immediate offspring but can also have detrimental health effects on the next several generations. ̽��ֱ��new research, which also sheds light on the molecular mechanism of folic acid (also known as folate) during development, was published today in the journal Cell.

“Although our research focused on genetic mutations which disrupts the break down and metabolism of folic acid, we believe that folic acid deficiency in the diet would have a similar multi-generational impact on health,” said Dr Erica Watson from the Centre for Trophoblast Research at the ̽��ֱ�� of Cambridge, who led the study.

̽��ֱ��detrimental effects of folic acid deficiency on development are quite well known. As a result, many countries, to include Canada and the US, have implemented folate fortification programmes which require folic acid to be added to cereal products. However, until now, very little was known about how folic acid deficiency caused the diverse range of health problems in offspring.

“Fortification programmes have reduced the risk of health effects but not eliminated them completely,” said Dr Watson. “Based on our research, we now believe that it may take more than one generation to eliminate the health problems caused by folate deficiency.”

̽��ֱ��researchers, from the Universities of Cambridge and Calgary, used mice for the study as they metabolize folic acid very similarly to humans and because folic acid deficiency or mutations in the same genes required to break down folic acid in humans result in similar developmental abnormalities and diseases in mice. This enabled the researchers to explore how the molecular mechanism of folic acid deficiency impacted development, thereby causing health problems.

For the study, the scientists used mice in which a gene called Mtrr was specifically mutated. ̽��ֱ��gene is key to the normal progression of the folic acid cycle and, when mutated, it results in abnormal folic acid metabolism causing similar effects to dietary folic acid deficiency. ̽��ֱ��researchers found that when either the maternal grandmother or the maternal grandfather had this Mtrr mutation, their genetically normal grandchildren were at risk of a wide spectrum of developmental abnormalities. These developmental abnormalities were also seen in the fourth and fifth generations of mice.

Through another experiment which involved transferring the embryo from the third generation into a normal healthy female mouse, they discovered that these developmental abnormalities were not passed down genetically. Instead, the serious defects were the result of epigenetic changes which had been inherited.

Epigenetics is a system which turns genes on and off. It occurs when chemicals, such as methyl groups, bind to the DNA at specific locations to control which genes are expressed and when they are expressed. (Interestingly, the folic acid cycle is required to make sure that the cell has enough methyl groups for normal gene expression.) Epigenetic inheritance refers to the passing of these epigenetic marks from one generation to the next – despite the epigenome, for the most part, being ‘wiped clean’ after each generation.

̽��ֱ��researchers hypothesize that, for a yet unknown reason, some of these abnormal epigenetic marks caused by the Mtrr mutation may escape this normal erasure and are inherited by the next generation. If these abnormal epigenetic marks that regulate genes important for development are inherited, then these generations may develop abnormalities as a result of the wrong genes being turned on or off.

“It surprised us to find that the great, great grandchildren of a parent who has had a folic acid deficiency could have health problems as a result - suggesting that the ‘sins of your maternal grandparents’ can have an effect on your development and your risk for disease,” said Dr Watson.

“More importantly, our research shows that disease in general can be inherited through epigenetic means rather than genetic means, which has huge implications for human health. Environmental factors that influence epigenetic patterns - e.g., diet, epigenetic disruptors in the environment such as chemicals, etc. - may also have long term, multigenerational effects.”

Deficiencies associated with spina bifida, heart defects and placental abnormalities.

It surprised us to find that the great, great grandchildren of a parent who has had a folic acid deficiency could have health problems as a result.

Dr Erica Watson

Folic acid deficiency can affect the health of great, great grandchildren

Dr Erica Watson

Mouse embryos half-way through gestation (embryonic day 10.5). From left to right: normal size, growth restricted and growth enhanced.

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First randomised controlled trial to show spinal cord regeneration in dogs

fpjl2 — Mon, 19 Nov 2012 14:54:25 +0000

In a collaboration between the ̽��ֱ��’s Veterinary School and MRC’s Regenerative Medicine Centre, scientists used a unique type of cell to regenerate the damaged part of the dogs’ spines. ̽��ֱ��researchers are cautiously optimistic that the work could have a future role in the treatment of human patients with similar injuries if used alongside other treatments.

Scientists have been aware for over a decade that olfactory ensheathing cells (OEC) might be useful in treating the damaged spinal cord because of their unique properties. ̽��ֱ��cells have the ability to support nerve fibre growth that maintains a pathway between the nose and the brain.

Previous research using laboratory animals has already revealed that OECs can aid regeneration of the parts of nerve cells that transmit signals (axons) so as to form a ‘bridge’ between damaged and undamaged spinal cord tissue. A Phase 1 trial in human patients with SCI established that the procedure is safe.

̽��ֱ��study, published in the latest issue of the neurology journal Brain, is the first double-blinded randomised controlled trial to test the effectiveness of these transplants to improve function in ‘real-life’ spinal cord injury. ̽��ֱ��trial was performed on animals that had spontaneous and accidental injury rather than in the controlled environment of a laboratory, and some time after the injury occurred. This far more closely resembles the way in which the procedure might be used in human patients.

̽��ֱ��34 pet dogs had all suffered severe spinal cord injury. Twelve months or more after the injury, they were unable to use their back legs to walk and unable to feel pain in their hindquarters. Many of the dogs were dachshunds which are particularly prone to this type of injury. Dogs are also more likely to suffer from SCIs because the spinal cord may be damaged as a result of what in humans is the relatively minor condition of a slipped disc.

In the study, funded by the MRC, one group of dogs had olfactory ensheathing cells from the lining of their own nose injected into the injury site. ̽��ֱ��other group of dogs was injected with just the liquid in which the cells were transplanted. Neither the researchers nor the owners (nor the dogs!) knew which injection they were receiving.

̽��ֱ��dogs were observed for adverse reactions for 24 hours before being returned to their owners. From then on, they were tested at one month intervals for neurological function and to have their gait analysed on a treadmill while being supported in a harness. In particular, the researchers analysed the dogs’ ability to co-ordinate movement of their front and back limbs.

̽��ֱ��group of dogs that had received the OEC injection showed considerable improvement that was not seen in the other group. These animals moved previously paralysed hind limbs and co-ordinated the movement with their front legs. This means that in these dogs neuronal messages were being conducted across the previously damaged part of the spinal cord. However, the researchers established that the new nerve connections accounting for this recovery were occurring over short distances within the spinal cord and not over the longer distances required to connect the brain with the spinal cord.

Professor Robin Franklin, a co-author of the study from the Wellcome Trust-MRC Cambridge Stem Cell Institute, ̽��ֱ�� of Cambridge, said: “Our findings are extremely exciting because they show for the first time that transplanting these types of cell into a severely damaged spinal cord can bring about significant improvement. We’re confident that the technique might be able to restore at least a small amount of movement in human patients with spinal cord injuries but that’s a long way from saying they might be able to regain all lost function. It’s more likely that this procedure might one day be used as part of a combination of treatments, alongside drug and physical therapies, for example.”

Dr Rob Buckle, Head of Regenerative Medicine at the MRC, commented: “This proof of concept study on pet dogs with the type of injury sustained by human spinal patients is tremendously important and an excellent basis for further research in an area where options for treatment are extremely limited. It’s a great example of collaboration between veterinary and regenerative medicine researchers that has had an excellent outcome for the pet participants and potentially for human patients.”

̽��ֱ��researchers stress that human patients with a spinal injury rate a return in sexual function and continence far higher than improved mobility. Some of the dogs in the study did regain bowel and bladder control but the number of these was not statistically significant.

Mrs May Hay, owner of Jasper who took part in the trail (and can be seen in the video), said: “Before the trial, Jasper was unable to walk at all. When we took him out we used a sling for his back legs so that he could exercise the front ones. It was heartbreaking. But now we can’t stop him whizzing round the house and he can even keep up with the two other dogs we own. It’s utterly magic.”

Text courtesy of the Medical Research Council

Researchers have shown it is possible to restore co-ordinated limb movement in dogs with severe spinal cord injury (SCI).

Our findings are extremely exciting because they show for the first time that transplanting these types of cell into a severely damaged spinal cord can bring about significant improvement.

Robin Franklin

Cambridge Veterinary School

A dog called Jasper during the trial

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Back ache: it’s been a pain for millions of years

ns480 — Mon, 21 Mar 2011 09:40:28 +0000

̽��ֱ��high incidence of back pain apparent today is often blamed on our lazy lifestyles: we sit at computers, watch television, travel by car and eat too much. But debilitating back ache is nothing new: it dates back millions of years to an era long before screens and sofas, according to a Cambridge ̽��ֱ�� researcher who is looking at the fossil record of human bones.

In a talk called "Four Million Years of Back Pain" on 25 February, Dr Asier Gomez-Olivencia will present the latest results of his research on the damaged spine of an early hominin called Homo heidelbergensis. He will set this in the context of the diseases evident in the fossil record of the hominin spine from australopithecines to Neanderthals - a time span stretching from 4.4 million to 30,000 years ago.

Gomez-Olivencia will also discuss the possibility that disabled members of early human communities may have been looked after by the rest of the group for significant periods of time, confounding popular stereotypes of these societies as brutal and uncaring.

Found among the bones of around 28 individuals at a site called Sima de los Huesos (pit of bones) in northern Spain, the almost-complete lumbar spine caused huge excitement when it was carefully reconstructed from fragments discovered during different field seasons by a team of scientists from the Centro Mixto de Evolución Humana in Burgos.

̽��ֱ��spine comes from the same individual as a pelvis found back in 1994, two years after the site yielded three complete crania. These finds merited the front cover of the prestigious scientific journal Nature as they pushed back the Neanderthal lineage into the Middle Pleistocene (around 500,000 years ago) and helped to clarify human evolution in that period.

While the tough bone material of human teeth and long bones is more likely to survive, human vertebrae are more fragile and prone to break and finally disappear, making them tantalisingly rare in the fossil record. ̽��ֱ��lumbar spine found in Sima de los Huesos, known as SH1, is more or less intact.

Examination of the morphology of the pubis symphysis shows that the bones come from a man of around 45 years (distinctly elderly for the time) who lived more than half a million years ago. ̽��ֱ��way in which the bones developed (their morphology) and the way they changed due to wear and tear (their pathology) show that this individual is likely to have suffered severe back pain.

Back problems - which today account for almost half of absences from work and exert a heavy toll on the economy - are often considered to be a side effect of an "unnatural" life style. But the SH1 spine adds to other fossil evidence that vertebral pathologies have been present in our history for millions of years. Living very differently to us, our ancestors suffered from back problems comparable to the conditions that cause us so much misery.

Dr Gomez-Olivencia is matching the morphology and pathology of the SH1spine to modern spines showing similar lesions. "It appears that we are looking at the spine of a man who had several different problems, including the inversion of the curvature of the back, spondylolisthesis, and Baastrup disease - which are associated with pain today," he said.

Homo heidelbergensis were nomadic hunter gatherers, relying on animals such as red deer and horses for food, and a damaged spine would have made hunting impossible. ̽��ֱ��survival of a man with limited mobility suggests that some individuals may have been looked after by others, or have found alternative roles in the community.

"It's likely that communities differed in their responses to disabilities so we can't say for certain that the SH1 individual was cared for by the group or that this was typical - but it's interesting to note that this is not the only individual that suffered pathologies in this site," said Dr Gomez-Olivencia.

Not only are Homo heidelbergensis likely, like us, to have suffered back pain. ̽��ֱ��results of a study published by Spanish scientists suggest that our female ancestors experienced another health hazard often regarded as relatively modern - difficult and painful births.

When the human pelvis adapted to an upright position, its modified configuration "competed" with the need to give birth to infants with large heads. A comparison of the shape of the SH1 pelvis with human fossil pelvises known to be female from around the world reveals that the difference between sexes of the fossil specimens parallels those of modern males and females. This discovery suggests that our female ancestors had tricky and life-threatening deliveries.

Research by a Cambridge archaeologist shows that back pain caused untold misery long before we started staring into screens and slumping on sofas.

It's likely that communities differed in their responses to disabilities so we can't say for certain that the SH1 individual was cared for by the group or that this was typical.

Dr Asier Gomez-Olivencia

ksmithdc from Flickr

backache

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