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NHS Choices: Behind the headlines   + / -  
last updated: Sat, 28 Feb 2015 13:40:28 GMT

 Fri, 27 Feb 2015 13:00:00 GMT Healthy older adults carry leukaemia mutations

BBC News reports that, according to researchers, “It is ‘almost inevitable’ that your blood will take the first steps towards leukaemia as you age”.

Researchers analysed the blood of 4,219 people, looking for DNA errors (mutations) linked to blood cancers (leukaemia).

The number of mutations in healthy older people without the disease was higher than expected. The research focused on 15 genetic hotspots of leukaemia-linked mutations and found them in 0.8% of individuals aged under 60, and 19.5% of those aged 90 or older. 

The media quoted figures suggesting that more than 70% of people in their 90s would have some form of leukaemia-associated mutation. This was based on predictions of the prevalence of other mutations outside of the 15 tested. 

The good news is that this form of age-related leukaemia is highly unlikely to kill you. The bad news is you are far more likely to die of something else before the mutations trigger the onset of leukaemia.

Still, as some are predicting that average lifespans will rise dramatically in the decades ahead, the results of this study could become more of an issue for future generations, and might also apply to other cancer types.

 

Where did the story come from?

The study was carried out by researchers from Wellcome Trust Sanger Institute, Cambridge (UK), and was funded by the Wellcome Trust, Leukaemia Lymphoma Research, the Kay Kendal Leukaemia Fund and the Spanish Ministerio de Economía y Competitividad  Subprograma Ramón y Cajal.

The study was published in the peer-reviewed medical journal Cell Reports. It is open-access, so is free to read and download online.

Generally, the media reported the story accurately. The Independent quoted Dr Vassiliou, senior author of the study, reassuring readers that: “These mutations will be harmless for the majority of people, but for a few unlucky carriers, they will take the body on a journey towards leukaemia. We are now beginning to understand the major landmarks on that journey”.

One small gripe is with the choice of figures used. The main study result was that leukaemia-linked mutations were found in 0.8% of under-60s and 19.5% of over 90s. This was based on studying 15 leukaemia-linked hotspots. 

Both the Independent and the BBC quoted figures suggesting that 20% of 50 to 60 year olds, and over 70% of over 90s, had dormant leukaemia-linked mutations. These much higher figures come from the study discussion and were not directly tested in the current research. They were figures based on assumptions about combining results from the 15 hotspots with other non-hotspot mutations from previous studies. We are not able to appraise the non-hotspot mutations studies, so we don’t know how accurate these figures are.

 

What kind of research was this?

This was a genetic study investigating how common small, leukaemia-linked DNA changes were in cancer-free adults.

Cancers, including leukaemia, develop through the combined action of mutations that are acquired over time. The researchers say that leukaemia-associated DNA mutations can occur without evidence of the disease. They wanted to find out how common these were in healthy people, and how common they were as people got older.

 

What did the research involve?

The researchers analysed DNA samples at 15 pre-defined leukaemia-associated mutation hotspots, using highly sensitive tests. They analysed the DNA of 4,219 people aged 17 and over.

The majority of DNA tests were on healthy people, but for comparison, they analysed the genes of a number of blood cells from people with myeloid leukaemia.

The production of the range of different types of mature white blood cells starts with a small number of stem cells. More specialised cells develop from these, like tree branches. The stem cells replicate themselves, producing clones. Some of these clones receive signals from the body, causing them to replicate and develop (differentiate) into more specialised white blood cells. Different signals produce different types of cells. The researchers were looking at what stage in the production process the mutations were occurring. If the mutations happened early in the differentiation process, they would be found in many downstream white cell types. If they occurred later, then they would be found in fewer cell types.

 

What were the basic results?

The main results were that age-related leukaemia-linked mutations were much more common than previously predicted.

Using only the 15 hotspots studied, they identified leukaemia-linked mutations in 0.8% of individuals under 60, rising to 19.5% of those aged 90 years and over. Coupling these estimates with other mutation rates from previous studies (outside of the 15 hotspots tested) they came up with much higher estimates. They predicted that more than 70% of people aged 90 or older would have some form of leukaemia-associated mutation. The 70% figure made it into the media coverage; the 19.5% was not mentioned.

On closer inspection, they found that mutations DNMT3A-R882 were most common and, although their prevalence increased with age, were found in individuals as young as 25. By contrast, mutations affecting spliceosome genes SF3B1 and SRSF2, closely associated with the myelodysplastic syndromes, were identified only in those aged over 70 years, with several individuals harbouring more than one mutation.

Myelodysplastic syndrome is an uncommon condition of unknown cause, that can lead to a drop in the number of healthy blood cells being produced. In some cases, it can progress into acute myeloid leukaemia.

Mutations in gene NPM1 were not seen in the group. This gene is thought to act as a “gatekeeper” to leukaemia. If it goes wrong, your risk of leukaemia rises considerably. As the group were symptom-free, it is not surprising that this gene was not affected in most people.

 

How did the researchers interpret the results?

The study group said: “individuals without overt features of a haematological [blood] disorder may harbor hemopoietic cell clones [blood stem cells] carrying leukemia-associated mutations” and that accumulating these mutations “is an almost inevitable consequence of aging in humans”

 

Conclusion

This study estimated that 0.8% of individuals under 60, and 19.5% of those aged 90 years and over, had leukaemia-linked mutations. These mutations caused no immediate harm and the people didn’t have leukaemia. The mutations were lurking in the background, but could have the potential to contribute to leukaemia in the future.

The research primarily focused on 15 genetic hotspots of leukaemia-linked mutations.

However, in their discussion, they predicted that more than 70% of people aged 90 or older would have some form of leukaemia-associated mutation. This formed the basis of their comment that these mutations seem an inevitable part of ageing. It is important to realise that this much higher estimate was not directly tested in the study. That is not to say it is not true, but we can’t confirm or refute it either way. Further research could confirm this prediction.

Scientists know that cancer is caused by the accumulation of genetic mutations over many years. This is why most cancers occur in older people, and the risk of cancer increases with age. What is surprising about this study is the relatively high prevalence of leukaemia-linked background mutations in healthy adults. The implication is that if people were to live a lot longer, say 150 years, they might expect to get leukaemia. In theory, this could also apply to some other types of cancer.

This is all largely theoretical. The impact on the average person is minimal, though if lifespans continue to increase, it could be a potential problem for your grandchildren.

It’s important to remember that we can all reduce our risk of cancer by making some simple changes to our lifestyle.

For example, healthy eating, taking regular exercise and stopping smoking will help to lower your risk.

Read more about how a healthy lifestyle can help to reduce your chances of developing cancer

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

Links To The Headlines

DNA develops to acquire genetic mutations linked with cancer as you get older, says study. The Independent, February 26 2015

Leukaemia mutations 'almost inevitable', researchers say. BBC News, February 27 2015

Links To Science

McKerrell T, Park N, Moreno T, et al. Leukemia-Associated Somatic Mutations Drive Distinct Patterns of Age-Related Clonal Hemopoiesis. Cell Reports. February 26 2014

 Fri, 27 Feb 2015 11:30:00 GMT Does deadly diet drug DNP defeat diabetes?

"A chemical [DNP] which caused munitions factory workers to lose weight inexplicably in the First World War could cure diabetes," The Daily Telegraph reports. The banned weight loss drug looked effective and safe when given in a modified form to rats bred to have diabetes.

The potential benefits of DNP surfaced in WW1 munitions workers who lost a lot of weight after being exposed to it. DNP sped up their metabolism, leading to rapid weight loss. After being made into a weight loss drug in the 1930s, it was quickly withdrawn, as it was proven highly toxic.

The problem was that it sped up the metabolism to a dangerously high rate, causing a range of serious side effects, and some deaths. Illegal sales of the drug have caused a number of deaths in the UK in recent years.

Researchers at Yale University wanted to see if it was possible to harness DNP’s metabolic properties, while removing the toxic effects.

They created a slow-release version of DNP, called CRMP, which improved the way the liver processed fat and improved other measures linked to type 2 diabetes risk in rats. As it delivered DNP at a much lower dose over time, there were no toxic effects.

This is encouraging research that should lead to further studies.

The version of DNP that is available through illegal sales, typically via the internet, is toxic, even in tiny amounts. Do not take it under any circumstances.

 

Where did the story come from?

The study was carried out by researchers from Yale University and was funded by United States National Institutes of Health and Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark.

Yale University has applied for a patent-related to the use of CRMP and things working in a similar way for the treatment of metabolic diseases, including non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes.

The study was published in the peer-reviewed journal Science Express.

The Daily Telegraph’s coverage was factually accurate. They made it clear the research was in rats, but also explained how: "the [research] team is confident that the research would translate to humans and are keen to start trials".

 

What kind of research was this?

This was an animal study investigating potential new uses for the banned chemical DNP for non-alcoholic fatty liver disease, which in turn, is a major risk factor for type 2 diabetes. Alternatively, both conditions can develop in tandem.

DNP has a murky past. Starting life as an ingredient of explosives in WW1, its potential use as a weight loss drug was recognised in workers handling the agent. They sweated profusely, had sky-high temperatures and lost a lot of weight. In the 1930s, it was sold as a wonder weight loss drug. However, it was quickly withdrawn, because it was highly toxic, causing side effects and, in some cases, death. 

DNP was also linked to deaths in 2013, after a resurgence among bodybuilders. This lead to the Food Standards Agency issuing a public warning about the risks of DNP, saying that: “DNP is an industrial chemical that is extremely dangerous to human health.” 
 
NAFLD is the term used when there is a build-up of fat within the liver cells that is not caused by alcohol intake. It is usually seen in people who are overweight or obese, and is associated with metabolic syndrome. A healthy liver should contain little or no fat. Most people with NAFLD do not develop serious liver problems and just have stage 1 of the disease (simple fatty liver). The most important thing that people with NAFLD can do is to go on a gradual weight loss programme and exercise regularly.

It is known that DNP has benefits on NAFLD, obesity and regulating blood glucose, but is usually too toxic to be used as a treatment. The chemical targets the mitochondria in cells. These are the little "batteries" responsible for making energy in cells, which is essential for life.

DNP speeds up the metabolism; however, our metabolic system operates at the rate it does for a reason – it is safe. Speeding up the metabolism may help burn off fat, but it can also trigger a number of dangerous side effects and potentially cause death.

This research team tried to devise a way to harness the benefits of DNP, while minimising its toxic side effects. All their experiments were in rats. This is the usual approach when testing chemicals to treat diseases, particularly dangerous ones. People and rats, both mammals, share lots of common biology, but there are differences.

 

What did the research involve?

The researchers gave groups of rats low levels of DNP and monitored its effect on fat content in the liver and other measures linked to a higher risk of type 2 diabetes. They were looking to confirm the benefits reported in previous studies.

After encouraging results, they modified DNP to create CRMP (controlled-release mitochondrial protonophore). They fed this to rats in small amounts of peanut butter to see whether it had the same benefits, with fewer side effects.

The benefits and side effects of DNP were compared with CRMP in a range of experiments lasting up to six weeks. During the experiments, rats were fed a high-fat diet and the researchers paid particular attention to changes in the function of the liver in dealing with this fat.

 

What were the basic results?

The main result was that CRMP caused fewer side effects than raw DNP, while maintaining similar benefits, including burning lots of fat, improved glucose tolerance and lower insulin levels.

When testing for specific effects, CRMP prevented the development of the rat version of NAFLD in rats fed a high-fat diet for two weeks. Similarly, it seemed to improve blood glucose regulation when given to rats with diabetes for two weeks, also improving their blood fat levels.

CRMP released the DNP-active chemical at a more gradual rate, and over a longer period, than giving straight DNP. This meant the levels in the blood did not spike as much and were lower overall. This seems to be the key to avoiding some of the worst side effects.

One of the biggest side effects of DNP was that it caused a potentially fatal very high temperature. The researchers were able to find a dose of CRMP that was beneficial to the liver, without causing a huge rise in temperature.

 

How did the researchers interpret the results?

The researchers said: "we have shown that altering the pharmacokinetics of DNP to promote a low sustained systemic release can increase the therapeutic window of this agent by more than 500-fold. Daily CRMP administration reversed NAFLD, insulin resistance, T2D [type 2 diabetes], and liver fibrosis in rats without detectable toxicity".

They added: "These data support the potential utility of mitochondrial protonophores and other mitochondrial uncoupling agents for the treatment of the related epidemics of NASH, metabolic syndrome and T2D."

 

Conclusion

This study created a slow release version of DNP, called CRMP, that improved the way the liver processed fat and improved other measures linked to type 2 diabetes risk in rats. It did this when given for up to six weeks without the toxic side effects known to be associated with unmodified DNP.

This is encouraging research, which appears to have partially tamed some of the toxic effects of DNP, while protecting its benefits. Researchers will build on this in further studies in rats and possibly people, if these results are confirmed in more studies.

However, the current version of DNP that is available for sale illegally online is toxic to humans, even in tiny amounts, and has been linked to a number of deaths. Do not take it under any circumstances.

The study used a chemically-modified version of DNP, called CRMP, in rats. DNP on its own remains as dangerous as ever to people. CRMP’s safety in humans has not yet been tested.

This study showed proof of the concept that DNP can be modified to make it safer in rats, while maintaining its benefits. This has not yet been proven in humans.

The authors are planning further safety studies, reporting in the Telegraph that: "Given these promising results in animal models of fatty liver disease and type 2 diabetes, we are pursuing additional preclinical safety studies to take this approach to the clinic."

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

Links To The Headlines

First World War explosive could reverse diabetes, says Yale University. The Daily Telegraph, February 26 2015

Links To Science

Perry RJ, Zhang D, Zhang X, et al. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science. Published online February 26 2015

 Thu, 26 Feb 2015 11:50:00 GMT Over two hours screen time a day may raise a child’s blood pressure

"Watching TV for more than two hours a day increases the risk of raised blood pressure in children," The Daily Telegraph reports.

A large study, involving more than 5,000 children who were followed up over two years, found a link between time sitting in front of a screen and an increase in blood pressure rates.

It found that a worryingly high number of children – more than one in 10 – developed high blood pressure, a major risk factor for cardiovascular diseases (CVDs) in later life. CVDs are conditions that can damage the heart and blood vessels, such as a stroke.

Children who spent more than two hours a day on “screen time” over the two years were at increased risk, as were those with low levels of physical activity.

This study supports previous evidence that a sedentary lifestyle and low levels of physical activity are associated with high blood pressure, although it does not prove that the former causes the latter.

There are many factors that can affect blood pressure, including genetics, development in the womb, socioeconomic status and weight.

That said, the more time your child spends watching TV or playing on their PlayStation 4, the less time they are physically active.

In the UK, children aged five to 18 are advised to do at least 60 minutes of physical activity a day.

 

Where did the story come from?

The study was carried out by researchers from several academic centres worldwide, including the University of Glasgow in the UK. It was funded by the European Community Sixth Research, Technological Development and Demonstration Framework Programme.

The study was published in the peer-reviewed medical journal International Journal of Cardiology.

Both The Daily Telegraph’s and the Daily Mail’s reporting was fair, although neither paper included comment from independent experts, and they failed to explain the fact that this kind of study cannot prove cause and effect.

 

What kind of research was this?

This was an observational cohort study looking at the incidence of pre-high blood pressure and high blood pressure in children in Europe and any association between blood pressure, levels of physical activity and sedentary behaviour.

The study’s authors say high blood pressure is one of the most important factors for cardiovascular disease, and studies have shown that blood pressure levels in children and adolescents are linked to high blood pressure in adulthood. However, little is known about the risk factors for high blood pressure in childhood. Their hypothesis is that low levels of physical activity (and high levels of sedentary behaviour may contribute to the development of high blood pressure.

Sedentary behaviour was classified as the amount of time parents reported their children spending in front of a screen – whether watching TV, videos or playing computer games. It did not include other kinds of sedentary activity – such as reading.

Blood pressure is measured in millimetres of mercury (mmHg) and is recorded as two figures:

  • systolic pressure – the pressure of the blood when your heart beats to pump blood out
  • diastolic pressure – the pressure of the blood when your heart rests in between beats, which reflects how strongly your arteries are resisting blood flow

In children, high blood pressure is defined as blood pressure greater than the 95th percentile for their age, height and gender.

 

What did the research involve?

The researchers used data from a study of 16,224 children from eight European countries (Spain, Germany, Hungary, Italy, Cyprus, Estonia, Sweden and Belgium) looking at the effects of diet and lifestyle on health. The current analysis was based on 5,221 children who were between two and 10 years old at the start of the study, for whom all data was available. Of these, 5,061 children were re-examined two years later.

The children had their systolic and diastolic blood pressure measured at the start of the study and at two years follow-up. Pre-high blood pressure was defined as systolic or diastolic blood pressure from the 90th to 95th percentile for their age and height; and high blood pressure was defined as systolic or diastolic blood pressure above the 95th percentile for age and height.

Physical activity in the children was measured using an accelerometer – an electronic device which measures the intensity of exercise. The unit had to be worn for at least six hours a day, for at least three days during one week (two weekdays and one weekend day).

From this, the researchers calculated the time children spent in moderate physical activity and in vigorous physical activity. Moderate activity includes activities such as cycling, while vigorous activity includes running, football and energetic dancing.

The children were classified into two groups – those who met current physical activity guidelines – doing at least 60 minutes of physical activity daily – and those who did not meet the guidelines. They were further classified as to whether changes in physical activity levels had taken place over the two years.

The children’s parents were asked to fill in a questionnaire on their children’s sedentary behaviour, as measured by hours of TV/DVD/video viewing and computer/games-console use for both typical weekdays and weekend days. Researchers used this information to calculate the children’s “total screen time” per day. Participants were classified into two groups – those who met (US) guidelines on total screen time (two hours or less a day) and those who did not. Researchers also calculated changes in sedentary behaviour at two years.

They also included a range of potential confounders, including season, sex, age, parental education and waist circumference.

Researchers estimated the relationship between physical activity levels, reported screen time and the risk of developing high blood pressure or pre-high blood pressure. 

 

What were the basic results?

  • Researchers found that the yearly incidence of pre-high blood pressure was 121 per 1,000 children, and high blood pressure was 110 per 1,000 children.
  • Children who maintained sedentary behaviour of more than two hours a day during the two year follow-up had a 28% higher risk of having  high blood pressure (relative risk (RR) 1.28, 95% confidence interval (CI) 1.03 to 1.60).
  • Children not performing the recommended amount of physical activity (60 minutes a day) at the start of the study had a 53% higher risk of high blood pressure (RR 1.53, 95% CI 1.12 to 2.09).
  • There was no association between pre- high blood pressure and children’s behaviours.

 

How did the researchers interpret the results?

The researchers say that the incidence of pre-high blood pressure and  high blood pressure is high in European children, with those doing less than 60 minutes of physical activity daily or spending two hours or more per day in front of a screen at higher risk. They say that the results suggest regular physical activity should be promoted and sedentary behaviour discouraged in children to prevent high blood pressure and its consequences in adulthood.

 

Conclusion

The study found a worryingly high incidence of high blood pressure in children of just over 10%, instead of the expected 5%. It also found that low levels of physical activity and high levels of “screen time” raised the risk.

Although researchers adjusted their analysis for a range of other factors which might affect blood pressure (called confounders), it is always possible that other unmeasured factors could have affected the results. In addition, the study was reliant on parental estimates of the amount of sedentary behaviour their children had per day, which may be an over- or underestimate. Wearing the accelerometer may also have influenced the amount of physical activity that was performed on those days, which could also affect the results.

It’s generally agreed that many of today’s children spend too much time in front of a screen – and too little on physical activity. The real question is – what can we do about it?  

Children are more likely to accept changes to their lifestyle if they involve the whole family.  Read more about getting healthy as a family.

Also, evidence has shown that placing limits on the use of any type of screen equipment in the hours before bedtime can improve the quality of their sleep. This could then help them improve their energy and activity levels during the day.

Read more about how TVs, phones and screens impair kids' sleep.

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

Links To The Headlines

Too much TV could raise a child’s blood pressure: Watching more than two hours a day ‘makes them 30% more likely to have condition’. Mail Online, February 26 2015

Children who watch TV for more than two hours a day 'at greater risk of high blood pressure'. The Daily Telegraph, February 26 2015

Links To Science

de Moraes ACF, Carvalho HB, Siani A, et al. Incidence of high blood pressure in children — Effects of physical activity and sedentary behaviors: The IDEFICS study: High blood pressure, lifestyle and children. International Journal of Cardiology. Published online November 26 2014


 

 
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