NHS Choices

Drugs may work better at certain times of the day

NHS Choices - Behind the Headlines - Tue, 28/10/2014 - 11:00

“Take your medication at the right time of day or it might not work,” The Independent reports.

The news is based on a study which looked at the pattern of genes made in 12 different mouse organs, to see if any of the genes showed a circadian rhythm (the “body clock”: where the body reacts to a day and night cycle).

Nearly half of genes that code for proteins showed a circadian rhythm in at least one mouse organ. 

In most organs, such as the liver, the researchers noted that the expression (activity) of many genes peaked during “rush hours” before dawn and dusk.

The researchers found that the majority of best-selling drugs, and medicines listed as “essential” by the World Health Organization (WHO), directly target products of rhythmic genes. As some of these drugs remain active for short periods (have short "half-lives"), the time the drug is taken could impact on how well it works.

However, in the wild, mice are primarily nocturnal (mainly active at night), in contrast to people who are diurnal (mainly active during the day), so the genes that are expressed in a circadian rhythm might be different.

Although this study suggests that medication timing could be modified to improve effectiveness, further studies will be required to determine optimal drug timing. 

 

Where did the story come from?

The study was carried out by researchers from the University of Pennsylvania and the University of Missouri, and was funded by the US National Heart, Lung and Blood Institute, and by the Defense Advanced Research Planning Agency (DARPA).

The study was published in the peer-reviewed scientific journal PNAS. This article is open access, meaning that it can be read for free online.

This study was well covered by the UK media. BBC News also featured a useful infographic about the body clock and its impact on biological function.

 

What kind of research was this?

This was an animal study, which aimed to look at the pattern of the genes made in mice over a 24-hour period.

It should be noted that mice in the wild are primarily nocturnal, in contrast to people, who are diurnal, so the genes expressed in a circadian rhythm might be different. Although this study suggests medication timing could be modified to improve effectiveness, further studies will be required to determine optimal drug timing. 

 

What did the research involve?

The researchers looked at the genes that were being made in 12 different mouse organs every two hours over a 48-hour period. The organs that they examined were the:

  • brainstem
  • cerebellum
  • hypothalamus
  • heart
  • aorta
  • kidney
  • adrenal gland
  • liver
  • lung
  • skeletal muscle
  • brown fat
  • white fat

They looked for genes that cycled over a 24-hour (one-day) period.

 

What were the basic results?

The researchers found that 43% of the genes that code for proteins show a circadian rhythm somewhere in the body.

The liver had the most circadian genes, whereas the hypothalamus (part of the brain) had the fewest.

In most organs, the researchers noted that the expression of many oscillating genes peaked during “rush hours”, before dawn and dusk.

The researchers also found that some genes that don’t code for proteins get expressed in a circadian rhythm.

The researchers found that the majority of best-selling drugs, and medicines listed as “essential” by the WHO, directly target products of rhythmic genes. As some of these drugs have short half-lives, the time the drug is taken could impact on how effective they are.

 

How did the researchers interpret the results?

This study found that nearly half of all genes in the mice oscillated with a circadian rhythm somewhere in the body. They go on to say that "a majority of best-selling drugs in the United States target circadian gene products. Many of these drugs have relatively short half-lives, and our data predict which may benefit from timed dosing.”

 

Conclusion

This study looked at the pattern of genes made in 12 different mouse organs, to see if any of the genes showed a circadian, or 24-hour, rhythm.

43% of the genes that code for proteins showed a circadian rhythm in at least one mouse organ. The liver had the most circadian genes, whereas the hypothalamus (part of the brain) had the fewest.

In most organs, the researchers noted that the expression of many oscillating genes peaked during “rush hours” before dawn and dusk.

Although this study suggests that medication timing could be modified to improve effectiveness, further studies will be required to determine optimal drug timing. 

Until further evidence is forthcoming, you should follow the advice that comes with your medication in terms of when to take it.

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

Links To The Headlines

Take your medication at the right time of day or it might not work, scientists say. The Independent, October 27 2014

Body clock: 'Rush hour' transformation discovered. BBC News, October 28 2014

Drugs may work better depending on time of day. The Daily Telegraph, October 27 2014

Links To Science

Zhang R, Lahens NF, Balance HI, et al. A circadian gene expression atlas in mammals: Implications for biology and medicine. PNAS. Published online October 27 2014

Categories: NHS Choices

Lab-grown killer cells could treat brain tumours

NHS Choices - Behind the Headlines - Mon, 27/10/2014 - 11:00

"Scientists … have discovered a way of turning stem cells into killing machines to fight brain cancer," BBC News reports. While the results of this study were encouraging, the research involved mice, not humans.

The headline is prompted by the creation of stem cells genetically engineered to produce a type of poison known as pseudomonas exotoxin. This poison was made to target a specific type of brain tumour cell (glioblastoma) by linking it to antibody fragments.

This technique has been used with great success to treat blood cancers such as leukaemia, but has been less successful at treating solid tumours. The researchers suggest this is because it only remains active for a short amount of time (has a short half-life) and because it may be difficult to reach the tumour.

To overcome these problems, the researchers genetically engineered neural stem cells, which could make pseudomonas exotoxin while being resistant to the poison themselves.

The poison-making stem cells were able to kill these brain cancer cells both in the laboratory and in mice engineered to develop brain tumours.

The results are promising, but, as the researchers themselves point out, "Translation into human patients would need to be adapted to tackle the challenges imposed by the new host [a human being]".

 

Where did the story come from?

The study was carried out by researchers from Massachusetts General Hospital, the Dana-Farber Cancer Institute, and Harvard University.

It was funded by the US National Institutes of Health.

The study was published in the peer-reviewed biological journal, Stem Cells.

The story was well covered by BBC News and The Independent. Both make it clear this was a mouse study.

 

What kind of research was this?

This mouse study aimed to develop and test genetically engineered neural stem cells, which can make the poison pseudomonas exotoxin while being resistant to the poison themselves.

Pseudomonas exotoxin blocks cells from making proteins, which leads to the death of the targeted cells. The pseudomonas exotoxin was linked to an antibody fragment to target it at cells that had specific receptors present on their surfaces. These particular receptors are often present in glioblastomas (a specific type of brain tumour) and not on normal cells.

The researchers say pseudomonas exotoxin linked to antibody fragments have been used with great success to treat blood cancers, but have been less successful at treating solid tumours. They suggest this is because it only remains active for a short amount of time and it may be difficult to reach the tumour.

To overcome these problems, the researchers genetically engineered neural stem cells. So far the technique has only been tested in mice and on these specific cancer cells in the laboratory, so much more work will need to be done to ensure it is safe and effective in people.

 

What did the research involve?

Briefly, the researchers genetically engineered neural stem cells to make the poison pseudomonas exotoxin.

The researchers tested the activity of the poison-making stem cells on cells grown in the laboratory and on mice.

 

What were the basic results?

The researchers initially tested their poison-making stem cells on glioblastoma cells grown in the laboratory. When the stem cells and the glioblastoma cells were grown together, the glioblastoma cells died. The glioblastoma cells expressing the highest amount of the tumour-specific receptor were most sensitive to the stem cells.

The researchers then looked at whether the poison-making stem cells would work in animals. They mixed tumour cells and the poison-making stem cells and put them under the skin of mice. The poison-making stem cells were able to kill the tumour cells.

According to the researchers, one of the major limitations of current glioblastoma therapy is the inadequate distribution of chemotherapy drugs to the tumour that remains after surgery.

Surgery aims to remove all of the tumour, but cannot always remove all of it safely. Some tumours develop deep inside the brain, so removing them completely could lead to significant brain damage.

After surgery to remove a tumour, the researchers inserted poison-making stem cells in mice that were engineered to develop glioblastomas.

No tumours could be detected in mice who had the poison-making stem cells inserted by 21 days after surgery, but tumour masses could be detected in the control mice.

The poison-making stem cells also improved average survival from 26 days in the control group to 79 days in the treated mice.

The researchers finally tested the poison-making stem cells on glioblastoma cells from human patients. The poison-making stem cells were able to kill the glioblastoma cells that expressed the tumour-specific receptor.

 

How did the researchers interpret the results?

The researchers concluded that stem cell-based delivery of pseudomonas exotoxin can increase the likelihood of anti-tumour response by increasing the amount of time the poison is delivered for, and by eliminating the need for multiple invasive administrations.

 

Conclusion

This study has described the creation of genetically engineered neural stem cells that make the poison pseudomonas exotoxin. The stem cells were also made resistant to the poison themselves. The poison was linked to an antibody fragment to target it towards a specific type of brain tumour cell (glioblastoma).

Glioblastoma are usually very aggressive cancers, and the current treatment would usually involve surgical removal followed by radiotherapy and chemotherapy to try to kill the residual cancer cells.

This treatment regime can result in significant side effects, and there is no guarantee of achieving a complete cure.

In this study, the poison-making stem cells were able to kill these brain tumour cells both in the laboratory and in a mouse model.

So far the technique has only been tested in mice and on these specific brain cancer cells in the laboratory. This means much more work is needed to ensure it is safe and effective in people with brain cancer.

Glioblastomas also only account for a portion of all brain cancers. It is not known whether the treatment could ever be developed to treat other types of brain cancer.

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

Links To The Headlines

Cancer-killing stem cells engineered in lab. BBC News, October 25 2014

Stem cells that can kill cancer have been engineered by scientists. The Independent, October 25 2014

Links To Science

Stuckey DW, Hingtgen SD, Karakas N, et al. Engineering toxin-resistant therapeutic stem cells to treat brain tumors. Stem Cells. Published online October 25 2014

Categories: NHS Choices

A mug of cocoa is not a cure for memory problems

NHS Choices - Behind the Headlines - Mon, 27/10/2014 - 10:00

"Cup of cocoa could give the elderly the memory of a 'typical 30 or 40-year-old'," The Independent reports.

Before you race down to the supermarket to pick up a tub of chocolatey powder, you might want to pause to consider some facts that rather undermine this headline.

The news is based on a small study that found a specially formulated cocoa-based drink high in "flavanols" made older people slightly faster, but no more accurate, in memory tests.

The research, which happened over a period of just three months, also looked at brain scans of the test subjects. It found increased activity in an area of the brain thought to be involved in cognition and memory – the dentate gyrus.

It is difficult to gauge whether the modest improvements seen in testing would have a significant impact on a person's daily life or functioning.

The prospect of halting or reversing dementia or age-related cognitive decline through simple changes in your diet is incredibly appealing. But while the results of this study suggest the particular product tested could improve cognition and memory, it certainly does not prove this.

 

Where did the story come from?

The study was carried out by researchers from universities based in New York, and was funded by US National Institutes of Health grants, as well as what was described as an "unrestricted grant" from Mars Incorporated.

One of the study authors declared a financial conflict of interest as they were also employed by Mars. As Mars is one of the globe's leading makers of chocolate products, this may represent a potential conflict of interest.

The study was published in the peer-reviewed journal, Nature Neuroscience.

The majority of the media coverage portrayed this study as showing cocoa was effective at improving memory, which you might assume means a better and more accurate recall of things. In reality, the research was more limited and the improvements were only seen in the speed of memory tasks, not in the accuracy of tasks.

The most frivolous headlines came from The Independent, with "Cup of cocoa could give the elderly the memory of a 'typical 30 or 40-year-old'," and the Daily Express, with its front page headline claiming that, "new study proves cup of cocoa can boost the brain". These statements are premature, potentially misleading and are not justified by this research alone.

The Independent's unfortunate headline may simply have parroted a press release on the research from Columbia University. In the press release, one of the researchers was quoted as saying, "If a participant had the memory of a typical 60-year-old at the beginning of the study, after three months that person on average had the memory of a typical 30- or 40-year-old."

The study did not recruit anyone aged 30 to 40 to test this directly, so it appears to be an assumption. The main study publication itself also did not make these bold claims – they were confined to the press release.

Larger long-term trials may show whether more rounded improvement in cognitive ability and memory are possible using high flavanol supplements.

 

What kind of research was this?

This was a small randomised control trial testing the effect of a low- or high-cocoa diet on age-related memory decline in older adults.

The researchers state the function of a brain region called the dentate gyrus declines as people age, and is therefore considered to be a possible source of age-related memory decline.

This study first looked to find evidence that lower dentate gyrus function was indeed related to memory decline and, secondly, to test an intervention to stop the decline or reverse it.

A randomised control trial is one the best study designs to investigate whether dietary interventions such as this can influence cognitive ability.

The downside is that they tend to be very expensive to set up and run, so are often short and involve small numbers (as was the case with this study), which limits the applicability of the results to other populations.

 

What did the research involve?

The study involved asking volunteers aged 50 to 70, who were free from cognitive impairment, to follow a three-month lifestyle intervention containing diet and exercise elements.

Before and after the intervention, the research team compiled brain scans of the dentate gyrus region of the volunteers and tested their cognitive abilities to see if the diet, exercise or both elements together were influencing signs of age-related cognitive decline.

The study participants were free from illness, but were selected to be physically inactive and not to be above-average fitness. They were also excluded if they had a medical condition that didn't allow them to undertake aerobic activity. Anyone who routinely took dietary or herbal supplements was also excluded from the study.

The volunteers were randomised into one of four groups:

  • high flavanol with aerobic exercise (eight people)
  • high flavanol without aerobic exercise (11 people)
  • low flavanol with aerobic exercise (nine people)
  • high flavanol without aerobic exercise (nine people)

The people in the groups were similar in terms of age, educational level and gender.

The prescribed anaerobic exercise was one hour a day, four days a week. The high-flavanol intake group took 900mg cocoa flavanols with 138mg of epicatechin (another flavanol) every day, compared with the low-flavanol group, who consumed 10mg cocoa flavanols and less than 2mg epicatechin per day.

It isn't completely clear how the diet supplement element was delivered, but the researchers describe how participants were given the flavanols as a packet, possibly to dissolve in water like an instant chocolate drink.

Brain scans used a high-resolution variant of functional magnetic resonance imaging (fMRI) to map the precise site of age-related dentate gyrus dysfunction. fMRI allows scientists to see blood flow and volume in the brain as a sign of activity.

Cognitive abilities were assessed using a test called ModBent. ModBent has a matching element that involves showing complex images and asking people to "Click on the figure that looks exactly like the one you just saw as quickly as possible".

It also has a recognition element, which also shows complex images and asks people, "Is this one of the figures you saw earlier?"

The test scores are built up using both the speed of the answer (reaction time) and how many were recalled correctly (delayed retention). ModBent score was used in this study because it has previously been shown to deteriorate with age.

 

What were the basic results?

The study was completed by 37 people.

The main finding was that people given high-flavanol supplements had a significantly faster ModBent reaction times, but showed no improvement in retention tests. People who were given high flavanols were, on average, 630ms faster than the low-flavanol group after the intervention.

This was mirrored by a higher dentate gyrus function in the high-flavanol group compared with the low-flavanol group, as assessed in the brain scans.

Interestingly, this effect was unrelated to the exercise component. This was a surprise to the researchers, as previous research suggested regular exercise could reduce cognitive decline.

They investigated this further and found the exercise had not led to any physiological changes in VO2 max, one of many measures of cardiovascular fitness, which measures the amount of oxygen you use while exercising at maximum capacity.

From this, the researchers concluded people had not stuck to the exercise component of the intervention, so the results related to this were not valid. 

 

How did the researchers interpret the results?

The researchers stated that, "Our results indicate that dietary cocoa flavanol consumption enhanced DG [dentate gyrus] function," and the cognitive test and brain scan results "provide evidence that age-related changes in the DG observed in aging humans underlie and drive a hippocampal-dependent component of cognitive aging."

 

Conclusion

This small randomised control trial found giving people a supplement high in cocoa flavanols for three months appeared to improve the function of a brain area – the dentate gyrus.

Decreased activity in the dentate gyrus is thought to be involved in age-related memory decline. People who had high-flavanol supplements performed tests assessing cognitive ability more quickly than those who had low-flavanol supplements.

The prospect of halting or reversing age-related cognitive decline through simple changes in your diet is very appealing, and this study suggests one way it might be possible. However, this study alone does not prove this as it has a number of limitations, including:

  • The group sizes were small. Only 37 people took part and they were further subdivided into groups of less than 10 for most comparisons.
  • There were tiny differences in caffeine and theobromine levels in the high- and low-flavanol cocoa packets, making it possible that substances other than flavanols mediated the effects seen.
  • Only reaction times, and not accuracy of performance, improved. Memory improvements weren't shown directly – participants may have improved their reaction times by simply paying more attention to the task. It is not known whether the observed changes in reaction times would have had any meaningful difference in terms of the person's daily life and functioning.
  • Participants who exercised regularly or took regular herbal or vitamin supplements were excluded from the study, meaning results in this group might be different.
  • None of the participants in this trial were reported to have any cognitive impairment, and longer-term diagnoses of cognitive impairment or dementia were not assessed, so it is not known whether high flavanol intake is of any benefit in preventing these outcomes.

It is also important to point out that the cocoa supplement used was specially formulated for the trial. You shouldn't be led to believe that drinking lots of hot chocolate bought in a supermarket, which can be very high in sugar, will necessarily boost your brain power: it may just boost your waistline. In fact, lots of hot chocolate could raise your blood pressure and increase your risk of tooth decay.

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

Links To The Headlines

Cup of cocoa could give the elderly the memory of a 'typical 30 or 40-year-old'. The Independent, October 27 2014

Cocoa could be the secret to good memory in old age. The Daily Telegraph, October 26 2014

How a cup of cocoa before bed 'can help improve your memory': Chemical found in the beans could help fight against dementia. Mail Online, October 27 2014

Beat memory loss with a cup of cocoa! Change of diet BOOSTS brain. Daily Express, October 27 2014

Links To Science

Brickman AM, Khan UA, Provenzano FA, et al. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nature Neuroscience. Published online October 26 2014

Categories: NHS Choices

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