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last updated: Tue, 16 Sep 2014 04:37:20 GMT

 Mon, 15 Sep 2014 12:00:00 GMT 'Rebooted' stem cells may lead to new treatments

"Scientists have managed to 'reset' human stem cells," the Mail Online reports. It is hoped studying these cells will provide more information about the mechanics of early human development.

This headline comes from a laboratory study that reports to have found a way to turn the clock back on human stem cells so they exhibit characteristics more similar to seven- to nine-day-old embryonic cells.

These more primitive cells are, in theory, capable of making all and any type of cell or tissue in the human body, and are very valuable for researching human development and disease.

Previous research efforts have successfully engineered early-stage stem cells capable of making several cell and tissue types, called pluripotent stem cells.

However, pluripotent stem cells engineered in the laboratory are not perfect and display subtle differences to natural stem cells.

This study involved using biochemical techniques to return pluripotent human stems cells to a more primitive "ground-state" stem cell.

If this technique is confirmed as reliable and can be replicated in other studies, it could ultimately lead to new treatments, although this possibility is uncertain.

While the immediate impact is probably minimal, it's hoped this research may lead to advances in the years to come.

 

Where did the story come from?

The study was carried out by researchers from the University of Cambridge, the University of London and the Babraham Institute.

It was funded by the UK Medical Research Council, the Japan Science and Technology Agency, the Genome Biology Unit of the European Molecular Biology Laboratory, European Commission projects PluriMes, BetaCellTherapy, EpiGeneSys and Blueprint, and the Wellcome Trust.

The study was published in the peer-reviewed journal Cell as an open access article, so it's available to read online for free.

The Mail Online's coverage was accurate and reflected many of the facts summarised in the press release issued by the Medical Research Council. Interviews with the research's authors and other scientists in the field added useful extra insight to interpret and contextualise the findings.

 

What kind of research was this?

This was a laboratory study to develop and test a new technique to return pluripotent human stem cells to an earlier, more pristine developmental state.

Pluripotent stem cells are early developmental cells capable of becoming several different cell types. Some stem cells are said to be totipotent (capable of becoming all types of cell), such as early embryonic stem cells shortly after fertilisation.

These types of cells are very valuable in developmental science research as they allow the study of developmental processes in the laboratory that aren't possible to study in a foetus shortly after conception.

As the MRC press release explains: "Capturing embryonic stem cells is like stopping the developmental clock at the precise moment before they begin to turn into distinct cells and tissues.

"Scientists have perfected a reliable way of doing this with mouse cells, but human cells have proved more difficult to arrest and show subtle differences between the individual cells. It's as if the developmental clock has not stopped at the same time and some cells are a few minutes ahead of others."

The aim of this study was therefore to devise and test a way of turning back the clock in human pluripotent stem cells so they exhibit more totipotent characteristics. This was also termed as returning the pluripotent cells to a "ground-state" pluripotency.

 

What did the research involve?

This research took existing human pluripotent stem cells and subjected them to a battery of laboratory-based experiments in an effort to produce stable stem cells showing a more ground-state pluripotency.

This chiefly involved culturing the human stem cells in a range of biological growth factors and other chemical stimuli designed to coax them into earlier phases of development. Extensive monitoring of the cell characteristics, such as self-replication, gene and protein activity (expression), occurred along the way.

 

What were the basic results?

The main findings include:

  • Short-term expression of proteins NANOG and KLF2 was able to put into action a biological pathway leading to the "reset" of pluripotent stems cells to an earlier state. The MRC press release indicated this was equivalent to resetting the cells to those found in an embryo before it implants in the womb at around seven to nine days old.
  • Inhibiting well-established biochemical signalling pathways involving extracellular signal-regulated kinases (ERK) and protein Kinase C (both of which are proteins involved in cell regulation) sustained the "rewired state", allowing cells to stay in the arrested development state.
  • The reset cells could self-renew – a key feature of stem cells – without biochemical ERK signalling, and their observable characteristics and genetics remained stable.
  • DNA methylation – a naturally occurring way of regulating gene expression associated with cellular differentiation – was also dramatically reduced, suggesting a more primitive state.

These features, the authors commented, distinguished these reset cells from other types of embryo-derived or induced pluripotent stem cell, and aligns them closer to the ground-state embryonic stem cell (totipotent) in mice.

 

How did the researchers interpret the results?

The researchers indicate their findings demonstrate the "feasibility of installing and propagating functional control circuitry for ground-state pluripotency in human cells". They added the reset can be achieved without permanent genetic modification.

The research group explained the theory that a "self-renewing ground state similar to rodent ESC [embryonic stem cells] may pertain to primates is contentious", but "our findings indicate that anticipated ground state properties may be instated in human cells following short-term expression of NANOG and KLF2 transgenes. The resulting cells can be perpetuated in defined medium lacking serum products or growth factors."

 

Conclusion

This laboratory study showed human pluripotent stem cells could be coaxed into a seemingly more primitive developmental state, exhibiting some of the key features of an equivalently primitive embryonic stem cell in mice. Namely, this is the ability to stably self-renew and be able to develop into a range of other types of cell.

If replicated and confirmed by other research groups, this finding may be useful to developmental biologists in their efforts to better understand human development and what happens when it goes wrong and causes disease. But this is the hope and expectation for the future, rather than an achievement that has been realised using this new technique.

Sounding a note of caution, Yasuhiro Takashima of the Japan Science and Technology Agency and one of the authors of the study, commented on the Mail Online website: "We don't yet know whether these will be a better starting point than existing stem cells for therapies, but being able to start entirely from scratch could prove beneficial."

This is the start rather than the end of the journey for this new technique and the cells derived from it. The technique will need to be replicated by other research groups in other conditions to ensure its reliability and validity.

The cells themselves will also need to be studied further to see if they do really have the stability and versatility of true primitive stem cells expected under different conditions and time horizons. This will include looking for any subtle or unusual behaviour further down the development line, as has been found to be the case with other types of stem cell thought to be primitive.

Overall, this study is important to biologists and medical researchers as it potentially gives them new tools to investigate human development and associated diseases. For the average person the immediate impact is minimal, but may be felt in the future if new treatments arise.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Links To The Headlines

British scientists 'reset' human stem cells to their earliest state: 'Major step forward' could lead to development of life-saving medicines. Mail Online, September 11 2014

Ultimate human stem cells created in the lab. New Scientist, September 12 2014

Links To Science

Takashima Y, Guo G, Loos R et al. Resetting Transcription Factor Control Circuitry toward Ground-State Pluripotency in Human. Cell. Published online September 11 2014

 Mon, 15 Sep 2014 11:00:00 GMT Could meditation help combat migraines?

“Daily meditation may be the most effective way of tackling migraine,” the Daily Express reports.

This headline is not justified, as it was based on a small pilot study involving just 19 people.

It showed that an eight week "mindfulness-based stress reduction course" (a combination of mediation and yoga-based practices) led to benefits in measures of headache duration and subsequent disability in 10 adult migraine sufferers, compared to nine in a control group who received usual care.

There were no statistically significant differences found for the arguably more important measures of migraine frequency (migraines per month) and severity. However, the study may have been too small to reliably detect any differences in these outcomes. Both groups continued to take any migraine medication (preventative or for treatment during a headache) they were already taking before the trial.

Overall, this trial showed weak and tentative signs that mindfulness-based stress reduction might be beneficial in a very small group of highly select adults with migraines. However, we will only be able to say it works with any confidence after much larger studies have been carried out.

 

Where did the story come from?

The study was carried out by researchers from Wake Forest School of Medicine, North Carolina (US) and Harvard Medical School, Boston. It was funded by the American Headache Society Fellowship and the Headache Research Fund of the John Graham Headache Center, Brigham and Women’s Faulkner Hospital.

The study was published in the peer-reviewed journal Headache.

One of the study authors reported receiving research support from GlaxoSmithKline, Merck and Depomed. All other authors report no conflicts of interest.

The Daily Express’ coverage of this small study arguably gave too much prominence and validity to the findings, indicating they were reliable: “The ancient yoga-style technique lowers the number of attacks and reduces the agonising symptoms without any nasty side effects”.

Many of the limitations associated with the study were not discussed, including the fact that some of the findings may have been chance, due to the small sample size.

To be fair, the researchers themselves were forthright in highlighting the limitations of their research.

 

What kind of research was this?

This was a small randomised controlled trial (RCT) investigating the effects of a standardised eight week mindfulness-based stress reduction course in adults with migraines.

Stress is known to be associated with headaches and migraines, but the research group said solid evidence on whether stress-reducing activities might reduce the occurrence or severity of migraines was lacking. Because of this, they designed a small RCT to test one such activity – an eight-week mindfulness-based stress reduction course.

This was a small pilot RCT. These are usually designed to provide proof of concept that something might work and is safe before moving on to larger trials involving more people. The larger trials are designed to reliably and robustly prove effectiveness and safety. Hence, on their own, pilot RCTs rarely provide reliable evidence of effectiveness.

 

What did the research involve?

Researchers took a group of 19 adults who had been diagnosed with migraines (with or without aura) and randomly divided then into two groups. One group (n=10) received an eight-week mindfulness-based stress reduction course, while the others (n=9) received “usual care” – they were asked to continue taking any migraine medication they had, and not to change the dose during the eight-week trial.

During the mindfulness trial, participants were also allowed to continue to take any medication they usually would. The main outcome of interest was change in migraine frequency from the start of the trial to eight weeks. Secondary measures included change in headache severity, duration, self-efficacy, perceived stress, migraine-related disability/impact, anxiety, depression, mindfulness and quality of life from the start to the end of the eight-week trial period. 

The standardised mindfulness-based stress reduction course class met for eight weekly, two-hour sessions, plus one “mindfulness retreat day”, which comprised six hours led by a trained instructor and followed a method created by Dr Jon Kabat-Zinn. The intervention is based on systematic and intensive training in mindfulness meditation and mindful hatha yoga in the context of mind/body medicine. Participants were encouraged to practice at home to build their daily mindfulness practice for 45 minutes per day, on at least five additional days per week. Compliance was monitored through class attendance and by daily logs of home practice.

To be included in the trial, participants had to have reported between 4 and 14 migraine days per month, more than a year of migraine history, be over 18, in good general health and be able and willing to attend weekly sessions of mindfulness and to practice every day at home for up to 45 minutes. Excluding criteria included participating in yoga/meditation practice and having a major illness (physical or mental).

All participants in both groups were taking medications for their headaches.

At the end of the eight-week period, the control group were offered the mindfulness course as a courtesy for their participation in the trial. In an attempt to blind the control group to treatment allocation,they were told there were two start periods for the eight-week trial and they were merely on the second, continuing usual care in the interim.

For all final analyses, migraines were more precisely defined as those headaches that were more than 4 hours long with a severity of 6 to 10, based on patient diary information.

The study aimed to recruit 34 people, but only recruited 19, so was underpowered to detect statistically significant differences in the outcomes assessed.

All participants kept a daily headache diary for 28 days before the study began.

What were the basic results?

All nine people completed the eight-week stress reducing course, averaging 34 minutes of daily meditation. In both groups, more than 80% took daily prophylactic migraine medication, such as Propranolol and 100% used abortive medication, such as Triptans, when a migraine struck. There were no adverse events recorded, suggesting the intervention was safe, at least in the short term.

The main findings were:

Primary outcome

Mindfulness participants had 1.4 fewer migraines per month compared to controls (intervention 3.5 migraines during 28-day run-in, reduced to 1.0 migraines per month during the eight-week study, vs. control: 1.2 to 0 migraines per month, 95% confidence interval (CI) [−4.6, 1.8], an effect that did not reach statistical significance in this pilot sample. The lack of statistical significance means the result could be due to chance alone.

Secondary outcomes

Headaches were less severe (−1.3 points/headache on 0-10 scale, [−2.3, 0.09], on the borderline of statistical significance) and shorter (−2.9 hours/headache, [−4.6, −0.02], statistically significant) in the intervention group compared to the controls

Migraine Disability Assessment and Headache Impact Test-6 (a widely used test that assesses the impact of migraines on quality of life and day to day function) dropped in intervention group compared with the control group (−12.6, [−22.0, −1.0] and −4.8, [−11.0, −1.0], respectively), both of which were statistically significant. Self-efficacy and mindfulness improved in the intervention group compared with control (13.2 [1.0, 30.0] and 13.1 [3.0, 26.0]) and was also a statistically significant finding.

 

How did the researchers interpret the results?

The researchers indicated the mindfulness-based stress reduction course was “safe and feasible for adults with migraines. Although the small sample size of this pilot trial did not provide power to detect statistically significant changes in migraine frequency or severity, secondary outcomes demonstrated this intervention had a beneficial effect on headache duration, disability, self-efficacy and mindfulness. Future studies with larger sample sizes are warranted to further evaluate this intervention for adults with migraines”.

 

Conclusion

This pilot RCT, based on just 19 adult migraine sufferers, showed an eight-week mindfulness-based stress reduction course led to benefits for headache duration, disability, self-efficacy and mindfulness measures, compared to a control group who received usual care. There were non-significant benefits observed for measures of migraine frequency and severity. Both groups continued to take any migraine medication (prophylactic or for treatment during a headache) they were already taking before the trial.

The research group themselves were very reasonable in their conclusions and called for larger trials to be done to investigate this issue further. As they acknowledge, relatively little can be said with reliability based on this small pilot study alone. This is because small studies van often not be generalised to the wider population.

For example, what are the chances the experience of a group of nine people will represent the experiences of the UK population as a whole who could be different ages, have different attitudes and expectations of meditation and have different medical backgrounds? 

Also, larger trials are able to more accurately estimate the magnitude of any effect, whereas small studies may be more volatile to change or extreme findings. Taken together, a pilot study of this size cannot and does not prove that "mindfulness-based stress reduction" is beneficial for migraine sufferers. This point may have been missed by those reading The Daily Express’ coverage, which appeared to accept some of the positive findings at face value and assume widespread effectiveness, without considering the limitations inherent in a pilot RCT of this size.

It is also worth noting that the participants were recruited if they suffered between 4 and 14 migraines per month, but the actual frequency of headache was much smaller for all participants during the run-in period and the eight-week study period. Indeed, some participants in each group had no headaches during each period. This further reduces the ability of this study to show any significant difference between the groups.

Overall, the eight-week mindfulness-based stress reduction course showed tentative signs that it might be beneficial in a very small group of highly select adults with migraines. However, we will only be able to say it is beneficial with any confidence after much larger studies have been carried out. Until then, we simply don’t know if this type of course will help migraine sufferers, hence the Daily Express’ headline is premature.

That said, adopting a psychological approach to chronic pain conditions, rather than relying on medication alone, can help improve symptoms in some people. Read more about coping with chronic pain.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Links To The Headlines

Daily meditation could help 8m conquer pain of migraines. Daily Express, September 13 2014

How To Cure A Migraine? Study Says Meditation Might Be The Answer. Huffington Post, September 12 2014

Links To Science

Wells RE, Burch R, Paulsen RH, et al. Meditation for Migraines: A Pilot Randomized Controlled Trial. Headache – the Journal of Head and Face Pain. Published online July 18 2014

 Fri, 12 Sep 2014 10:29:00 GMT Pregnant drink binges harm kids' mental health

“Binge drinking ONCE during pregnancy can damage your child's mental health and school results,” says the Mail Online. 

The headline follows an analysis of results from a study including thousands of women and their children. In analyses of up to 7,000 children, researchers found that children of women who engaged in binge drinking at least once in pregnancy, but did not drink daily, had slightly higher levels of hyperactivity and inattention problems. These children also scored on average about one point lower in exams.

The results appear to suggest potential for some links, particularly in the area of hyperactivity/inattention. However, the differences identified were generally small, and weren’t always statistically significant after taking into account potential confounders. The links also weren’t always found across both boys and girls, or across both teachers’ and parents’ assessment of the child.

It’s already official advice for women to avoid binge drinking or getting drunk when pregnant. Pregnant women should avoid alcohol in the first three months of pregnancy, especially. If women choose to drink alcohol, officials say to stick to, at most, two units (preferably one) and no more than twice a week (preferably once).

 

Where did the story come from?

The study was carried out by researchers from the University of Nottingham and other research centres in the UK and Australia. The ongoing study is funded by the Medical Research Council, the Wellcome Trust and the University of Bristol. The study was published in the peer-reviewed European Journal of Child and Adolescent Psychiatry.

The media covers the research reasonably, although they sometimes refer generally to the effect on children’s mental health, which may make readers think they are referring to diagnoses of mental health conditions, which is not the case.

The study looked at teacher- and parent-rated levels of problems in areas such as “hyperactivity” and conduct, but did not assess whether the children had psychiatric diagnoses, such as ADHD.

 

What kind of research was this?

This research was part of a cohort study. The current analysis looked at the effect of binge drinking in pregnancy on mental health and school achievement when the children were aged 11. ALSPAC researchers recruited 85% of the pregnant women in the Avon region due to give birth between 1991 and 1992. Researchers have been assessing these women and their children regularly.

The researchers reported that previous analyses of this study have suggested that there was a link between binge drinking in pregnancy and the child having poorer mental health at ages four and seven as rated by their parents, particularly girls.

A prospective cohort study is the most appropriate and reliable study design for assessing the impact of binge drinking in pregnancy on the child’s heath later in life. For studies of this type, the main difficulty is trying to reduce the potential impact of factors other than the factor of interest (binge drinking) that could affect results. The researchers do this by measuring these factors and then using statistical methods to remove their effect in their analyses. This may not entirely remove their effect, and unknown and unmeasured factors could be having an effect, but it is the best way we have to try and isolate the impact of interest alone.

 

What did the research involve?

The researchers assessed the women’s alcohol consumption by questionnaire at 18 and 32 weeks into their pregnancy. They assessed their offspring’s mental health and school performance at age 11 using parent and teacher questionnaires, and their academic performance. They then analysed whether children of mothers who had engaged in binge drinking during pregnancy differed to children of mothers who had not.

Of the over 14,000 pregnant women in the study, 7,965 provided information on their alcohol consumption at both 18 and 32 weeks. They were asked about:

  • how many days in the past four weeks she had drunk at least four units of alcohol
  • how much and how often they had drunk alcohol in the past two weeks or around the time the baby first moved (only asked at 18 weeks)
  • how much she currently drank in a day (only asked at 32 weeks)

The researchers used this information to determine if the women:

  • had engaged in binge drinking at least once in pregnancy (defined as four or more units/drinks in a day) 
  • drank at least one drink a day at either 18 or 32 weeks

The children’s mental health was assessed using a commonly used standard questionnaire given to teachers and parents. This questionnaire (called the “Strengths and Difficulties Questionnaire”) gives an indication of the level of problems in four areas: 

  • emotional
  • conduct
  • hyperactivity/inattention
  • peer relationships

The Strengths and Difficulties Questionnaire also gives an overall score, and this is what the researchers focused on, as well as the conduct and hyperactivity/inattention scores. The researchers also obtained the children’s results on standard Key Stage 2 examinations taken in the final year at primary school. The researchers had information on 4,000 children for hyperactivity and conduct problems, and just under 7,000 children for academic results.

When the researchers carried out their analyses to look at the effect of binge drinking, they took into account a range of factors that could potentially influence results (potential confounders). These included:

  • mother’s age in pregnancy
  • parents’ highest education level
  • smoking in pregnancy
  • drug use in pregnancy
  • maternal mental health in pregnancy
  • whether the parents owned their house
  • whether the parents were married
  • whether the child was born prematurely
  • the child’s birthweight
  • the child’s gender

 

What were the basic results?

The researchers found that about a quarter of women (24%) reported having engaged in binge drinking at least once in pregnancy. Over half (59%) of the women who reported binge drinking at 18 weeks in their pregnancy also reported having engaged in binge drinking at 32 weeks.

Less than half of the women (about 44%) who had engaged in binge drinking reported doing so on more than two occasions in the past month. Women who had engaged in binge drinking were more likely to have more children, to also smoke or use illegal drugs in pregnancy, to have experienced depression in pregnancy, to have a lower level of education, to be unmarried and to be in rented accommodation.

Initial analyses showed children of mothers who had engaged in binge drinking at least once in pregnancy had higher levels of parent- and teacher-rated problems, and worse school performance than children of mothers who had not engaged in binge drinking. Their average difference in three problem scores was less than one point (possible score range 0 to 10 for conduct and hyperactivity/inattention problems, and 0 to 40 for the total problems score), and their average KS2 score was 1.82 points lower.

However, once the researchers took into account potential confounding factors, these differences were no longer large enough to rule out the possibility of having occurred by chance (that is, they were no longer statistically significant).

The researchers repeated their analyses for girls and boys separately. They found that even after adjustment, girls whose mothers had engaged in binge drinking in pregnancy did have higher levels of parent-rated conduct, hyperactivity/inattention and total problems (average score difference less than one point).

If the researchers looked at binge drinking and daily drinking separately, after adjustment they found children of women who had engaged in binge drinking in pregnancy, but did not drink daily, had higher levels of teacher-rated hyperactivity/inattention problems (average score 0.28 points higher) and lower KS2 scores (average 0.81 points lower).

 

How did the researchers interpret the results?

The researchers concluded that occasional binge drinking in pregnancy appears to increase risk of hyperactivity/inattention problems and lower academic performance in children at age 11, even if the women do not drink daily.

 

Conclusion

This prospective cohort study has suggested that even occasional binge drinking in pregnancy may increase the risk of hyperactivity/inattention problems and lower academic performance when the children reach 11 years old.

The strengths of the study are its design – selecting a wide and representative population sample collecting data prospectively – and using standardised questionnaires to assess the children’s outcomes.

Assessing the impact of alcohol in pregnancy on children’s outcomes is difficult. This is partly because assessing alcohol consumption is always difficult. People may not want to report their true consumption, and even if they do, there are difficulties in accurately remembering past consumption. In addition, as this link can only be assessed by observational studies (ethically you couldn’t do a trial that randomised pregnant women to binge drink), it is always possible that additional factors are having an effect.

The study found that women who had engaged in binge drinking in pregnancy were also more likely to have other unhealthy behaviours, such as smoking, and to be socioeconomically disadvantaged. The researchers tried to remove the effects of all of these factors, but this may not entirely remove the effect.

This latest study carried out a large number of analyses looking at different outcomes. The differences identified were generally small, and they weren’t always large enough to be statistically significant after taking into account potential confounders. They also weren’t always found across both boys and girls, or across both teachers’ and parents’ assessment of the child. These differences weren’t always large enough to be statistically significant. However, they do appear to suggest potential for some links, particularly in the area of hyperactivity/inattention.

The researchers note that even with small individual effects, the effect across the population as a whole can be considerable. The small effect may also reflect that it represents an average effect across all levels of binge drinking – ranging from one to many times.

We may never have completely concrete proof of an exact level at which harm occurs, and under which alcohol consumption in pregnancy is safe. Therefore, we have to work with the best information that is available. There is growing evidence that as well as how much we drink, the pattern of how we drink may be important.

Current UK recommendations from the National Institute for Health and Care Excellence (NICE) already advise that women who are pregnant should avoid binge drinking or getting drunk. It is also recommended that:

  • women who are pregnant should avoid alcohol in the first three months of pregnancy
  • if women choose to drink alcohol later in pregnancy, they should drink no more than two (preferably only one) UK units, no more than twice (preferably once) a week.

Analysis by Bazian. Edited by NHS ChoicesFollow Behind the Headlines on TwitterJoin the Healthy Evidence forum.

Links To The Headlines

Binge drinking ONCE during pregnancy can damage your child's mental health and school results. Daily Mail, September 11 2014

Prenatal alcohol consumption linked to mental health problems. The Guardian, September 11 2014

This is how much alcohol you can have during pregnancy before it harms newborn’s mental health. Metro, September 10 2014

Links To Science

Sayal K, et al. Prenatal exposure to binge pattern of alcohol consumption: mental health and learning outcomes at age 11. European Child & Adolescent Psychiatry. Published September 11 2014


 

 
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