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“Disabled people could soon re-grow damaged or diseased limb joints,” said the Daily Mirror. The newspaper said that the prospect of a new technique, using people’s own stem cells rather than transplanted ones “offers hope to millions suffering crippling pain”.

The study behind this news attempted to grow new cartilage in rabbits by drawing the rabbits’ own circulating stem cells to a scaffolding of bone-like substances implanted into their shoulder joints. To assess the technique the researchers then observed the rabbits’ movement and took samples from the joint to see if new cartilage had formed. The rabbits regenerated cartilage and were soon able to bear weight.

The real test of this technology will come if it is eventually applied to humans. While the researchers have tried growing cartilage to attach to artificial joints they say that regeneration of other tissues may also be possible with their technique. However, this type of research proceeds in small steps and so it is too soon to say if this could ever be a reliable alternative to a simple artificial hip replacement in humans.

 

Where did the story come from?

The study was carried out by researchers from Columbia University Medical Center, the University of Missouri and Clemson University in the US. It was funded by the New York State Stem Cell Science programme and the US National Institutes of Health. The study was published in the peer-reviewed medical journal The Lancet.

Several newspapers have accurately reported this research, with some pointing out that experts have said that even if the technique is successful in eventual human trials, a conventional hip replacement might still be the best option. The Daily Mirror goes further, claiming that this early animal research offers “new hope for millions”.

 

What kind of research was this?

The researchers explain that they wanted to test a new approach to generating new tissues. In this case, they wanted to test whether they could grow new sections of the cartilage naturally found on the surface of joints. Rather than directly transplanting stem cells from an external source, which some experiments have attempted, they instead wanted to provide an artificial surface that could attract the body’s own circulating stem cells and encourage them to deposit and grow on this artificial scaffolding.

The study was well conducted, and the research paper features cautious reminders that this is very preliminary work that still needs much more research to assess the feasibility of applying this technology to humans.

 

What did the research involve?

The researchers designed a ‘proof of concept’ study to see if it was technically possible to grow new cartilage in rabbits by attracting their circulating stem cells to a new form of scaffolding.

They compared two ‘bioscaffolds’ in an experiment on 23 rabbits. Ten scaffolds were covered in a growth factor called TGF?3 and implanted into the rabbits, while ten rabbits were implanted with scaffolds lacking the growth factor chemical. Three rabbits also had operations to remove the joint without a bioscaffold replacement (the ‘defect only’ rabbits).

To produce these bioscaffolds, the researchers first used a computer to trace the surface shape and size of a rabbit shoulder joint. They then made a bioscaffold out of a composite of a biodegradable polymer, a polyester and a substance called hydroxyapatite, a mineral that forms a large part of normal bone.

The whole joint surface of the shoulder in the rabbits was then surgically removed and replaced with these bioscaffolds that either lacked or contained the transforming growth factor. The researchers then assessed the movement of the joints and ability of the rabbits’ shoulders to bear weight at 1–2, 3–4 and 5–8 weeks after surgery. At four months they took a sample of bone and cartilage from the live rabbits and checked them for things such as cracks, thickness, density, cell numbers and mechanical properties.

 

What were the basic results?

All the animals in the group given the scaffolds infused with growth factor fully resumed weight bearing and movement 3–4 weeks after surgery. The rabbits that had received the bioscaffolds infused with growth factor showed more consistent improvement than the rabbits that had received the bioscaffolds lacking the growth factor. Defect-only rabbits limped at all times.

When the sample of scaffolding and cartilage was removed at four months after surgery, joint-facing surfaces of the TGF?3-infused bioscaffolds were fully covered with hyaline cartilage, a pad of tough but flexible cartilage that naturally lines joints. There was only isolated cartilage formation in the other implant group and no cartilage formation in the defect-only rabbits.

 

How did the researchers interpret the results?

The researchers say that their findings suggest that the cartilage layer across the entire surface of synovial joints (lubricated, freely moving joints) “can regenerate without cell transplantation”.

They go on to call for further investigation into the technique, saying that the regeneration of complex tissues seems probable when using ‘homing’ (having a surface or environment that attracts the body’s circulating cells) in tissues that need repair.

 

Conclusion

This interesting study has demonstrated the potential of a new technique. The researchers point out the areas that need further investigation:

• They do not yet know where the stem cells (or progenitor early cartilage cells) came from. Although they think that some of these cells are derived from stem or progenitor cells of synovium, bone marrow, fat cells and perhaps blood vessels, more research will be needed to find out exactly where they came from.
• They suspect that if TGF?3 can attract multiple cell types then more research will be needed to find out how to target the specific cell populations needed for the regeneration of more complex tissues.
• They say that it is good news that the regenerated cartilage is strong enough for weight bearing in rabbits.

The real test of this technology will come if it is eventually applied to humans. The researchers were not just thinking of growing cartilage to attach to artificial joints, and explain that regeneration of other tissues may also be possible with their technique. However, this type of research proceeds in small steps and so it is too soon to say if this could ever be a reliable alternative to a simple artificial hip replacement in humans.

Links To The Headlines

Hip hope from stem cell technique. BBC News, July 29 2010

The ‘grow your own’ hip and knee replacements with full range of movement. Daily Mail, July 29 2010

Regrowing limb joints. Daily Mirror, July 29 2010

Links To Science

Lee CH, Cook JL, Mendelson A et al. Regeneration of the articular surface of the rabbit synovial joint by cell homing: a proof of concept study. The Lancet, Early Online Publication, July 29 2010

“Kicking and lashing out while asleep could mean you’re more likely to develop dementia or Parkinson’s disease,” reported the Daily Mail. It said a study has found a link between a sleep disorder and a higher risk of certain types of dementia up to 50 years later.

The study looked at people diagnosed with one of several related neurological conditions and analysed their history of a severe form of REM sleep behaviour disorder (RBD), a condition in which people can act out recurrent dreams and move excessively while asleep.

The study was not designed to look at the strength of the link between RBD and dementias, as patients in the study were selected because they were known to have had both of these conditions. Therefore, it is not possible to say from this study whether restless sleep is a predictor of future dementia as is implied in the newspaper headline. More research into whether RBD could be an early sign of the brain changes that lead to dementia later on would be useful.

 

Where did the story come from?

The study was carried out by researchers from the Department of Neurology at the Mayo Clinic in the US. The researchers received several individual grants and awards. The study was published in the peer-reviewed medical journal Neurology.

The Daily Mail has concentrated on the theoretical link between a group of neurological conditions and this sleep disorder. Previous research has indicated that there is some association between the two, but the strength of this relationship is unclear and, at this stage, RBD cannot be used to predict later disease.

 

What kind of research was this?

The stage of sleep in which your brain activity increases and when dreaming may occur is known as rapid eye movement (REM) sleep because, during this phase, your eyes start to move quickly and flicker.

This research looked at the association between a sleep disorder called REM sleep behaviour disorder (RBD) and a group of neurological conditions including Parkinson’s disease, multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). RBD is a sleep disorder where people act out recurrent dreams and move excessively while asleep, and in this study injured themselves or their partners as a result.

To investigate this, the researchers used the records from a specialist neurological clinic of 27 patients who had been diagnosed with RBD and then went on to develop degenerative neurological symptoms at least 15 years later.

The researchers confirmed the diagnoses of RBD and analysed the records to define the types and timing of diseases and symptoms the patient developed. They used these data to calculate the length of time between the first sign of restless sleep and the diagnosis of a range of dementias.

This was a case series analysis in which all the participants were selected because they had both conditions. As such, it cannot demonstrate a link between the conditions as there was no comparison group. However, the researchers refer to previous research that they say has demonstrated this link. They say that the first study to document this relationship reported that nearly 40% of patients with isolated, idiopathic RBD developed a parkinsonian disorder an average of 12.7 years later. This current study was mainly interested in the question of whether the length of time between RBD and dementia could be even longer than 12.7 years.

 

What did the research involve?

Some patients with these neurological disorders have reported that their first experience of restless sleep happened many years previously. The aim of this study was to explore a theory based on this anecdotal evidence that RBD symptoms can predate Parkinson’s disease by several decades.

The researchers were interested in a range of conditions thought to be caused by abnormal deposition of a protein called alpha-synuclein in the brain. These diseases included Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy, which are all neurodegenerative diseases that appear later in life.

The researchers used the Mayo Clinic’s records to identify all patients who had been evaluated for these diseases between 2002 and 2006. They then selected all those who had a history of RBD and for whom there was at least 15 years between onset of RBD and their neurodegenerative symptoms. To be eligible, patients also had to have been assessed by a specialist in a sleep lab and by at least one other neurological specialist in the Mayo Clinic’s behavioural neurology or movement disorders sections.

RBD was diagnosed if abnormal flailing movements occurred during sleep, with sleep-related injuries or movements that were potentially injurious or disruptive. Symptoms of physical activity during sleep were provided by the patient and bed partner. Patients were then divided into probable and definite RBD. The numbers of patients with the different disorders were counted, and the interval between RBD and symptom onset for the neurological disorder recorded.

 

What were the basic results?

The researchers identified 550 patients with RBD and one of the three neurodegenerative disorders of interest.

Of the 550 patients, 27 (4.9%) had first started experiencing RBD more than 15 years before the onset of neurodegenerative disease symptoms. Of these, 13 had developed Parkinson’s disease, Parkinson’s with mild cognitive impairment or Parkinson disease dementia. Another 13 had developed probable dementia with Lewy bodies and one had developed parkinsonism-predominant MSA.

Most of the patients were male (24 [89%]). The average (median) interval between RBD symptoms and neurodegenerative syndrome symptom onset was 25 years (range 15–50 years), and the median age at onset of restless sleep was 49 years.

 

How did the researchers interpret the results?

The researchers say that their cases add a new time dimension to theories on the evolution of neurodegenerative syndromes characterised by alpha-synuclein deposition. They say that, until now, the estimated interval between changes in the brain and disease onset had been about 5-6 years, but this study suggests that it may be longer.

 

Conclusion

These findings suggest that the brain changes associated with certain neurodegenerative diseases could begin many years before the symptoms start to show.

There are a few points to note about this study:

• This study was not set up to evaluate the strength of the association between RBD and neurodegenerative disease, and it does not shed any light on how many people with restless sleep go on to develop neurological conditions.
• The study only looked at a few specific types of dementia and not the more common Alzheimer’s or vascular type of dementia. As such, these findings are even less applicable to people concerned about the more common dementias.
• These participants had a very specific form of severe sleep disturbance, involving lashing out and characteristic brain wave patterns during their sleep. Many people will have the occasional restless night of sleep, but most are unlikely to have RBD. The results of this study are unlikely to apply to them.

In general, this study provides some insight into these rare conditions and will be of interest to doctors, scientists and the public. The results should not be interpreted to mean that restless sleep can be used to predict future dementias or neurological diseases.

Links To The Headlines

Kicking and lashing during sleep ‘could signal dementia or Parkinson’s disease’. Daily Mail, July 29 2010

Links To Science

Claassen DO, Josephs KA, Ahlskog JE, et al. REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century. Neurology 2010, [Published online before print] July 28, 2010