"People who do puzzles and crosswords may stave off dementia longer,” according to BBC News. The website said that mentally stimulating activities may protect the brain from memory loss but also speed up mental decline once dementia takes hold.

The story is based on research that followed 1,157 elderly people to examine how mentally stimulating activity in old age affects the development of dementia. The results suggest that being mentally active slows down cognitive decline before the onset of dementia but leads to faster decline after dementia has set in. The authors suggest that mental activity may somehow allow the brain to initially tolerate the brain changes associated with Alzheimer’s, but that decline is swifter once brain changes reach a more advanced stage.

While it is interesting, the authors’ theory was not conclusively proven by this study and will need further testing. Mental activity is only one factor that may contribute to the risk of dementia, along with genetics, environment and education. The study did not specifically test brain-training games or puzzles, as some newspapers suggested.

 

Where did the story come from?

The study was carried out by researchers from Rush University Medical Center, Chicago, and was funded by the US National Institutes of Health.

The study was published in the peer-reviewed journal Neurology. It was widely reported by the media, whose coverage was generally fair but uncritical. Some newspapers focussed on the delays in dementia symptoms seen in people who were most mentally active, while others concentrated on the swifter mental decline they exhibited once dementia eventually began.

The Daily Mirror’s claim that “thinking too hard may actually damage the brain of some older people” is misleading. The study did not specifically test the impact of brain-training games or mental puzzles, both of which were mentioned in press coverage.

 

What kind of research was this?

The researchers point out that more frequent cognitive activity has been associated with a reduced risk of cognitive decline and symptoms of dementia. However, it has not been associated with any reduction in the development of brain lesions associated with the condition.

Given that greater mental activity appears to protect brain function but not biology, the researchers argue that if cognitive activity before dementia were truly protective, it would also be associated with more rapid decline after the onset of dementia. In this cohort study, they tested the hypothesis that by delaying the onset of dementia, greater cognitive activity would “compress” the illness once it began, with the condition progressing more rapidly over a shorter time.

 

What did the research involve?

The researchers recruited 1,157 people aged over 65 who did not have dementia at the time of enrolment. Participants were selected at random from a larger study looking at risk factors for dementia. At their initial interview, they were asked to rate how frequently they took part in seven activities in which information processing plays a central role. These included watching TV, reading, doing crosswords and visiting museums. Frequency was estimated using a five-point scale, ranging from every day (5 points) to once a year or less (1 point).

The researchers used these ratings to make an overall estimate of how often people participated in mentally stimulating activities. Participants were also given four validated cognitive performance tests to assess their cognitive abilities.

The participants were followed up for an average of 12 years. Every three years, different samples of the group underwent a comprehensive clinical evaluation, in which they were classified as having no cognitive impairment, mild cognitive impairment or Alzheimer’s disease. Participants underwent further brief cognitive testing at three-yearly intervals to assess cognitive function. (Three waves of clinical evaluation were included in this ongoing study. The fifth wave is still underway.)

The researchers used validated statistical methods to look at the possible associations between people’s levels of cognitive activity and their cognitive function and clinical outcomes.

 

What were the basic results?

Clinical evaluation over the course of the study found that 614 people had no cognitive impairment, 395 had mild cognitive impairment and 148 had Alzheimer’s disease. When the researchers analysed the data, they found that:

• In the group without cognitive impairment, the annual rate of cognitive decline was reduced by 52% for each additional point on the cognitive activity scale.
• In the group with mild cognitive impairment, the rate of cognitive decline was not associated with cognitive activity level.
• In the group with Alzheimer’s disease, the average annual rate of cognitive decline increased by 42% for each point of the cognitive activity scale.

Together, these results associate greater cognitive activity with slower decline in people without cognitive impairment and faster decline in those with Alzheimer’s disease.

 

How did the researchers interpret the results?

The researchers said their results suggest that cognitive activity enhances the brain’s ability to maintain relatively normal function despite neurological degeneration. This means that after the onset of dementia, the resulting decline is more rapid. They said that the benefit of delaying the initial appearance of cognitive impairment comes at the cost of a more rapid progression of dementia when it eventually arrives.

The researchers concluded that any mentally enriching interventions, such as puzzles or acting classes, may need to be started before the development of cognitive impairment, because many people with mild cognitive impairment already have substantial physiological signs of Alzheimer’s disease in the brain.

 

Conclusion

This study has some strengths, including the large number of patients followed and the long follow-up period. Furthermore, its clinical evaluations and assessments of cognitive function were based on validated measures. The participants also represent a broad spectrum of cognitive function, ranging from no impairment to dementia.

However, the study also has limitations.

• It did not make adjustments for other factors (called confounders) which might contribute to the development of Alzheiner’s. For example, certain educational, social and genetic factors may have differed between the groups, which were not accounted for in the researchers’ analyses.
• Importantly, the assessment of cognitive activity was based on a composite measure. Since only seven cognitive activities were assessed, they may not reflect people’s true levels of cognitive activity. The use of composite measures to assess cognitive function also means that specific deficits in memory, for example, were not tested for by themselves.
• Only two to three observations were recorded for each individual in the study. Therefore, when graphed, the rate of decline in cognitive function tended to appear as a straight line, whereas a more complex pattern may have been revealed if more than three data points had been available.

Overall, this study supports the authors’ theories about the development of Alzheimer’s. However, further research that adjusts for other known risk factors is needed before any practical recommendations can be made from the results.

Links To The Headlines

Doing puzzles 'could speed up dementia'. Daily Mirror, September 2 2010

Brain teasers accelerate dementia - pick up a book instead. The Independent, September 2 2010

Keeping the mind active staves off dementia at first but speeds it up later. The Daily Telegraph, September 2 2010

Puzzles and crosswords may delay dementia, study suggests. BBC News, September 2 2010

Links To Science

Wilson RS, Barnes LL, Aggarwal NT et al. Cognitive activity and the cognitive morbidity of Alzheimer disease. Neurology, September 1 2010 (published online before print)

“Newborn babies should not be given sugar as pain relief,” read the headline in The Guardian. The newspaper said the routine use of tiny amounts of sugar before minor medical procedures is common practice but “it does not work and may damage their brains”.

Current medical guidelines recommend that babies swallow sucrose (sugar) solution before minor hospital procedures, such as the newborn heel prick blood test, as sugar solution is safe and effective at reducing pain they will feel.

The conclusions of this small study (44 babies analysed from 59 recruited for the study) directly challenge existing medical practice, with the finding that sugar did not reduce pain measured by looking at brain activity in response to a heel prick. Previous studies had all looked for a change in the baby's facial expression to know when the baby was in pain, rather than looking directly at brain activity. This method of measuring pain in babies may be more objective than interpretations of facial expressions, but more research is needed to prove this.

The study itself did not find that using sugar was associated with any ‘damage to newborn brains’, instead it explained that pain itself may affect a developing brain. If the lack of effect of sugar is confirmed in larger studies, then it can no longer be thought of as an effective pain relief drug for small babies.

Where did the story come from?

The study was carried out by a researcher from the Nuffield Department of Anaesthetics at the University of Oxford, along with colleagues from University College London and Great Ormond Street Hospital for Children all in the UK. The study was supported by the Medical Research Council and published in the peer-reviewed medical journal The Lancet.

Several other newspapers including the Mail and the Mirror also covered this story and reported it fairly. They focused on the fact that pain may cause short or long-term adverse effects on the development of the infant brain and suggested that if sugar is merely a distraction, then hugs or breastfeeding may work just as well.

What kind of research was this?

All babies have a heel prick blood test before they are eight days old to test for a variety of conditions. Currently, it is recommended that babies swallow sucrose (sugar) solution before the test to reduce any pain they may feel. Previous studies, including a systematic review of 44 studies, have suggested that sugar solution is safe and effective for reducing pain from minor hospital procedures.

In this double-blind, randomised controlled trial, the researchers wanted to find out if the sugar solution was actually reducing pain in the babies. The researchers explain that trials of pain relief in small babies are a challenge as the usual ways of reporting pain in clinical trials, such as asking for a description of the pain or using pain relief charts, cannot be used in babies. Usually in studies with babies, an observational pain score (premature infant pain profile - PIPP) is used. This combines video recordings made of the babies facial expressions (grimacing), as well as behavioural and physiological measures, such as oxygen use.

This study used an electroencephalography (EEG) cap to measure the electrical activity in the brain in response to pain as well as the usual PIPP response. The researchers monitored the brain activity of the babies during the heel prick test to look for a particular pattern of pain-specific brain activity, to see if the sugar solution caused a reduction in the pain response.

Care was taken to ensure no one involved in the study knew which babies had received which intervention.

What did the research involve?

The researchers carried out their study from February 2009 to March 2010. The participants were all healthy newborn infants born at 37-43 weeks of pregnancy and were less than eight days old when tested.

The researchers excluded babies from the study if they showed signs of tissue damage on the lower limbs, had previous surgery, serious illness or were born to diabetic mothers or opioid users. The babies were randomly assigned to receive either 0.5mL of 24% of sucrose solution or an equivalent volume of sterile water on the tongue.

A non-painful control stimulus was used first in all babies. The heel prick device was placed on the heel but the blade did not puncture the skin. The solution was then placed on the tongue two minutes before the actual heel prick took place.

Recording electrodes were positioned on the scalp to record the EEG, using the EEG cap. The researchers also used videos to record the behaviour and the facial expressions of the infants along with heart rate and oxygen levels in the blood and reflex movements of the limbs during the heel prick.

The researchers analysed the results on 20 out of 29 from the sucrose group and 24 out of 30 allocated to the sterile water group. The dropouts were mainly due to technical failure of the EEG, for example because of excessive movement. Only one parent withdrew consent in the sterile water group.

What were the basic results?

The measure of brain activity after the painful heel prick did not differ significantly between infants who received sucrose: mean 0.1 (95% Confidence Interval [CI] 0.04 to 0.16) compared with those who received sterile water: mean 0.08 (95% CI 0.04 to 0.12) p=0.46.

The PIPP score, a combined measure of heart rate, oxygen levels and facial expression (grimacing) scored from the video, was significantly lower in infants given sucrose compared with those given sterile water. Furthermore, significantly more infants had no change in facial expression after sucrose administration; 7 of 20 given sterile water (35%) compared with none of 24 given sucrose (p<0.0001).

How did the researchers interpret the results?

The researchers say that oral sucrose does not significantly affect activity in neonatal brain or spinal cord pain circuits, and therefore might not be an effective pain reliever.

They say that the ability of sucrose to reduce the PIPP scores observed in newborn infants after a painful event should not be interpreted as pain relief.

Conclusion

This study has used objective measures of pain in a small sample of infants and used careful blinding and randomisation to reduce bias. There are a few limitations due to the study size, but the conclusions are likely to challenge the currently held belief that sugar is an effective treatment for the pain of minor procedures in infants. The limitations mentioned by the researchers were:

• The small sample size of 44 infants analysed, which could mean that this study was not powered to observe subtle effects that sucrose might have on the brain processes used for pain.
• A measure of pain in infants is necessarily indirect (because they cannot describe the sensation), and so even though the electrophysiological measures reported in this study are more objective it is not clear that they are measuring the conscious pain experience of the newborn infant.
• The significant reduction of PIPP scores with sucrose confirm the results of the systematic review that looked at this as their main outcome. 
• The drop out of 15 infants (25% of those recruited) may have affected the reliability of the results.

The study itself had not identified harms associated with the use of sugar and it is an extrapolation to suggest that the use of sucrose for newborn pain relief ‘may damage their brains’. This may be particularly alarming for parents or doctors to read and is not a finding of this study. There is growing evidence that some newborns’ experience of pain may have lasting adverse effects on their neurodevelopment but to state this in a way that suggests that a study has shown that using sugar causes damage to newborn brains is unhelpful.

The researchers suggest that this single-centre trial should be repeated in a larger sample of infants, and that the new EEG measurement method should be used to test the effect of other known pharmacological analgesic drugs, such as morphine. This seems like sensible advice.

Links To The Headlines

Newborn babies should not be given sugar as pain relief, says study. The Guardian, September 2 2010

Pain relief is not so sweet for babies. Daily Mirror, September 2 2010

A hug, the sugar-free way to ease baby's pain. Daily Mail, September 2 2010

Links To Science

Slater R, Cornelissen L, Fabrizi L et al. Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial. The Lancet, [Early Online Publication] September 1 2010

Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database of Systematic Reviews 2010, Issue 1

Shah PS, Aliwalas LL, Shah VS. Breastfeeding or breast milk for procedural pain in neonates. Cochrane Database of Systematic Reviews 2006, Issue 3

Scientists have discovered genes that may be behind migraines, “opening the door to a cure”, reported the Daily Mirror. The newspaper said that these genes normally control the levels of a brain chemical called glutamate, but a variant form of the gene may lead to a build-up of glutamate within the nerve cells. According to the paper, halting this build-up could help stop migraines.

The study behind this story scanned the DNA of several thousand people with and without a history of migraine. It compared their genetics and identified a particular gene variant that was more common in migraine sufferers. The study adds to our understanding of the complex processes that lead to migraines and highlights that there may be genetic causes.

This is important research, but finding genes that are linked to a condition is very different from developing a safe treatment based on this knowledge. Overall, it is premature for newspapers to suggest that this research may soon produce a cure for migraines. Migraine is a complex condition in which the interaction between genes and the environment is likely to be important, meaning there may not be a single cause or cure.

 

Where did the story come from?

The study was carried out by researchers from the Wellcome Trust Genome Campus in Cambridge and from research groups across the world. The work was supported by several groups, including the Wellcome Trust, and was published in the peer-reviewed medical journal Nature Genetics.

Some newspapers optimistically announced that this study may lead to a cure for migraines, but a great deal of further research is needed before we know if this genetic discovery can improve the diagnosis or treatment of migraines.

 

What kind of research was this?

Migraine is an episodic headache disorder that is more common in women. The cause is thought to be related to changes in levels of particular chemicals in the brain and many potential triggers have been identified. These include dietary factors, physical triggers such as poor posture and tiredness, emotional triggers including stress, anxiety and depression, and environmental triggers. Some people also experience migraines after taking certain medications.

This was a genome-wide association (GWA) study which scanned people’s DNA to look for genetic factors that may be involved in migraines. GWA studies are commonly used to investigate whether particular genetic variants (such as mutations in DNA) are associated with certain conditions. The general approach is to assess the DNA sequences of a group of individuals with a condition and compare them to the DNA sequences in a group of unaffected individuals. In this study, researchers set out to identify genetic variants associated with the most common forms of migraine.

 

What did the research involve?

The researchers enrolled 3,279 people who suffered from migraines (cases) and 10,747 people who did not have the condition (controls). People were mainly recruited from headache clinics across Europe. Migraine was diagnosed by clinical experts through questionnaires and interviews.

As is common with this type of study, researchers then performed a “replication phase” to verify their initial findings in a separate, independent population. The replication phase examined separate samples of people from Denmark, Iceland, the Netherlands and Germany, plus a sample that combined all of these. In total, these replication tests examined a further 3,202 cases and 40,062 matched controls.

Migraine can sometimes be accompanied or preceded by visual distortions, called aura, which resemble bright rings of light. As well as being analysed as a single group, the participants who experienced migraines were further classified into subgroups based on their symptoms. These were a migraine with aura only group, migraine with and without aura group, and migraine without aura only group.

The researchers then assessed and discussed literature to identify the biological mechanisms that may be affected by the genetic variants identified.

 

What were the basic results?

The researchers identified one variant, called rs1835740, that was associated with migraine in both the initial and replication samples. People possessing the variant were about 1.5 to 1.8 times more likely to experience migraines than those without the variant. The researchers discussed what is known about the variant and its positioning within the DNA. They said that it is positioned between two genes that are involved in the body’s production of glutamate, a chemical in the brain that is involved in transmitting messages between nerve cells.

 

How did the researchers interpret the results?

The researchers concluded that their study has established a particular genetic variant (rs1835740) as a genetic risk factor for migraine. They say that, to their knowledge, this is the first time a study has done this.

 

Conclusion

This was a well-conducted and well-described genetic study that followed a recognised approach for studies in this field. There are some points to consider:

• One proposed cause of neurological disorders is a problem with ion channels (pores in the nerve cell walls that aid the transmission of nerve signals). The researchers say that in their study, they did not identify any associations between known ion channel genes and migraine.
• Possessing the rs1835740 genetic variant put people at an increased risk of migraine, but not all people with the variant experienced migraine. Conversely, some people without the variant experienced migraine, illustrating that other factors are also behind migraine.
• Despite speculation by newspapers, there is still more work to be done in this field and it is too soon to claim that a cure for migraine is on the way. While a particular genetic variant has been associated with migraine, it is unclear how this could lead to a cure as there is not yet any way to remove a variant from a person’s DNA. Drugs that block its action may one day be developed.
• The researchers note that the majority of their samples are from headache clinics and that their study needs replication in population-based samples.

The findings of this research increase our understanding of the biochemistry of neurological disorders, and this important study will pave the way for future research. These next research steps should also examine how genetics interact with the environment, as environmental triggers also play a part in the development of migraine.

The developing and testing of drugs can be a long and complicated process. If future studies result in improvements in the treatment of migraine, they are likely to be some way off.

Links To The Headlines

Revolutionary new scan shows key to migraines is in the genes. The Independent, August 30 2010

Found, migraine gene that could lead to a cure. Daily Mail, August 30 2010

Genes associated with migraine risk pinpointed. The Daily Telegraph, August 30 2010

Migraine gene sparks cure hope. Daily Mirror, August 30 2010

Links To Science

Anttila V, Stefansson H, Kallela M et al. Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nature Genetics, 29 August 2010

A diet combining fruit and vegetables with foods such as fish, poultry and nuts “can protect you against heart attack”, reported The Independent.

The news is based on a well-conducted trial which tested the DASH diet, a diet high in fruit and vegetables but low in saturated fat that is recommended by the US government. The study enrolled 459 healthy people with slightly high blood pressure and randomly assigned them to follow the DASH diet, a high-fat “American” diet or an American diet supplemented with more fruit and vegetables. After eight weeks, the DASH diet lowered blood pressure and cholesterol, and decreased the participants’ risk of developing heart disease in the next 10 years more than the other diets.

This study has numerous strengths, but it only estimated future heart disease risk rather than monitoring participants over 10 years. Additionally, the risk of heart disease at the start of this study was very low at only 1%, and the DASH diet reduced this risk by only a minimal amount. Despite these small limitations, this study demonstrates the importance of blood pressure as a risk factor for coronary heart disease and the role a balanced diet might play in reducing this risk.

 

Where did the story come from?

This study was carried out by researchers from Johns Hopkins University, Baltimore. This particular trial was funded by the US National Center for Research Resources, and individual researchers received various other grants and research awards. The trial used data from a previous study, the DASH trial, which was sponsored by the US National Heart, Lung and Blood Institute. The study was published in the peer-reviewed medical journal Circulation.

In general, The Independent accurately reflected the findings of this well-conducted study, but did not mention some important limitations.

 

What kind of research was this?

This randomised controlled trial investigated the effects of dietary pattern on the 10-year risk of coronary heart disease (CHD). A randomised controlled trail is the best way of investigating a treatment’s ‘efficacy’, i.e. its effectiveness under ideal test conditions.

Dietary studies frequently have an inherent limitation in that it is difficult to accurately control how well a person adheres to the experimental diet being tested. However, this trial had the benefit of providing all the participants’ meals.

 

What did the research involve?

The researchers analysed findings of the Dietary Approaches to Stop Hypertension (DASH) trial, a previous study that assessed how various short-term dietary interventions affected high blood pressure. The trial had enrolled 459 healthy people with an average age of 45 and blood pressure that was on the high side of normal (average 131/85 mmHg) but not yet considered to be high. The researchers excluded participants with any significant illness, high cholesterol, any cardiovascular event in the previous six months or a BMI higher than 35kg/m2 (a BMI over 25kg/m2 is above ideal weight).

Participants were randomly assigned to follow one of three dietary patterns for eight weeks:

• a control diet: a “typical American diet”, high in saturated fat and cholesterol, low in minerals such as calcium and magnesium
• the F/V diet: rich in fruit and vegetables but otherwise similar to the control diet
• the DASH diet: rich in fruit, vegetables and low-fat dairy, and with a higher ratio of polyunsaturated fat to saturated fat than the other diets

Diets were reportedly prepared in research kitchens, with lunch and dinner prepared on site and breakfast provided for participants in a cooler to be eaten at home. Participants were also asked to record any additional items they consumed, including drinks and added salt. Blood pressure was measured on five occasions during the last two weeks of the study and the average measure was calculated. Cholesterol was also checked.

This subsequent study took the data from the DASH trial and applied the Framingham heart risk tool, a recognised method for predicting an individual’s risk of developing coronary heart disease (CHD). The researchers estimated the 10-year CHD risk of each participant at the beginning of the study and after eight weeks of their assigned diet. This heart risk calculation method takes into account several factors that can contribute to CHD risk, including gender, age, blood pressure, smoking status and diabetes.

 

What were the basic results?

At the start of the study, all participants had a low risk of developing CHD within the next 10 years (0.98% on average). The researchers found that, compared with the control diet, following the DASH diet for eight weeks:

• lowered blood pressure
• lowered total cholesterol
• lowered LDL (“bad” cholesterol)
• lowered HDL (“good” cholesterol)

At the end of the eight-week study period, there was no significant difference in 10-year CHD risk between the control and F/V diet groups. However, the DASH group had a significantly greater decrease in their 10-year CHD risk compared to the control group and the F/V group.

Over the course of the trial, participants in the DASH group had:

• an 18% decrease in their CHD risk compared to those in the control group (relative risk [RR] 0.82, 95% confidence interval [CI] 0.75 to 0.90)
• an 11% decreased risk compared to those in the F/V group (RR 0.89, 95% CI 0.81 to 0.97)

 

How did the researchers interpret the results?

The researchers concluded that the DASH diet, which was low in saturated fat and high in fruit and vegetables, decreased the 10-year CHD risk more than a diet high in fruit and vegetables alone or a typically American control diet that was high in saturated fat.

 

Conclusion

This well-conducted trial benefits from its relatively large size, accurate provision of the three randomised diets and high study completion rates (95%). It also featured a reliable study outcome by using the average of a series of blood pressure measures, which is preferable to relying on a single blood pressure reading.

The study found that eight weeks of the DASH diet, which was rich in fruit and vegetables and low in saturated fat, lowered blood pressure and cholesterol. This contributed to a decrease in predicted 10-year CHD risk. The DASH diet reduced this risk by 18% compared to a high-saturated fat “American” diet and by 11% compared to a diet similar to the American diet but with higher intake of fruit and vegetables.

Some points to note when interpreting this study include:

• All participants in this study had a low risk of developing coronary heart disease in the next 10 years (only about 1%). The DASH diet lowered this 1% risk by approximately one-tenth compared with the diet high in fruit and vegetables and by approximately one-fifth compared to the high-fat diet. Therefore, although the DASH diet lowered risk further, the overall risk remained low in all groups and the differences in risk between the groups were small.
• Although the tool used to calculate 10-year CHD is fairly reliable and commonly used, it is still only an estimate. The people were not followed up over 10 years to see whether they developed heart disease.
• This was only a brief eight-week intervention period. The effects of continuing these diets in the long term are unclear.
• The content of these diets is unclear. Although the newspapers reported that a more balanced diet involving nuts, chicken and fish was the most beneficial, the researchers did not describe the particular foods the participants ate, the calorific content or how much fat and cholesterol the diets contained.
• There were some differences between the three dietary groups at the start of the study. Those in the DASH group had a lower starting cholesterol level than participants in the F/V and control groups. This is an important difference as it could affect blood pressure.
• 60% of the participants in the trial were of African-American ethnicity, 35% were white and the remainder were of other ethnicity. Subgroup analysis also demonstrated that there was a greater decrease in CHD-risk in African-American participants. Therefore, it seems that these results are most applicable to this population group, which should be taken into account when generalising results to all ethnic populations.
• As the researchers acknowledge, this study was too small to reliably predict how the diets tested may affect other population subgroups, such as postmenopausal women, people with higher CHD risk or people with existing CHD.

Overall, this well-conducted study demonstrates the importance of blood pressure as a risk factor for coronary heart disease. It also supports the benefits of fruit and vegetables and low saturated fat as part of a healthy lifestyle to further modify the risk of heart disease.

Links To The Headlines

Revealed: the diet that can protect you against heart attacks. The Independent, August 31 2010

Links To Science

Chen ST, Maruthur NM, Appel LJ. The Effect of Dietary Patterns on Estimated Coronary Heart Disease Risk: Results from the Dietary Approaches to Stop Hypertension (DASH) Trial. Circulation: Cardiovascular Quality and Outcomes. August 31 2010 (published online before print)

“Men who find themselves unable to sleep during the small hours of the night may end up dying younger,” reported the Daily Mail.

This study looked at people’s insomnia and their risk of dying over a 14-year period. At the start of the study, people filled out a questionnaire on their history of insomnia and were observed for one night in a sleep laboratory. Men who reported a history of insomnia and slept for less than six hours in the lab were four times more likely to die in the follow-up period than those without insomnia who slept for six hours or more in the lab.

These findings require careful interpretation and do not prove that insomnia increases the risk of early death. Sleep duration was only objectively measured once, so it may not represent a typical sleep pattern or confirm that a person had insomnia. In addition, the study’s middle-aged participants were originally enrolled to investigate sleep disordered breathing, so they were not randomly selected and are unlikely to represent the general population.

In short, this research does not provide strong evidence that insomnia is linked to an early death, and it sheds no light on possible reasons behind a link. Further research is needed.

 

Where did the story come from?

The study was carried out by researchers from Pennsylvania State University College of Medicine in the US, and was funded by the National Institutes of Health. It was published in the peer-reviewed scientific journal Sleep.

The study was widely reported in the media. Few reports looked at the study’s limitations.

 

What kind of research was this?

This prospective cohort study examined whether insomnia and getting less than six hours a night affected the risk of death from any cause. The participants reported their insomnia themselves, and sleep duration was measured in a single night’s observation in a sleep laboratory.

This type of study, in which large groups of people are followed over time, are useful in assessing whether conditions or circumstances (in this case, insomnia and objectively measured sleep duration) are associated with later events (here, mortality). However, this cohort is limited in that it is a secondary analysis of a group of participants who were originally enrolled to investigate the age distribution of people with sleep disordered breathing.

The researchers point out that insomnia has never been linked to any serious medical disorders, such as cardiovascular problems. However, recent research has associated it as a risk factor for high blood pressure and diabetes. They speculate that severe insomnia is likely to be associated with higher mortality, saying this theory is supported by studies showing that insomniacs suffer from increased heart and metabolic rates and impaired heart rate variability.

The researchers say that previous findings relating to insomnia and mortality have been inconsistent. They point out that these studies relied only on self-reported sleep disturbance, did not measure sleep duration objectively, and did not always control for confounders. Here, they aimed to examine the association between insomnia and mortality while taking these factors into account.

 

What did the research involve?

The research was the secondary analysis of a larger study on sleep-disordered breathing. That larger study interviewed 16,583 people by telephone, asking them questions about their sleep habits. From this cohort, 741 men of average age 50, and 1,000 women of average age 47, agreed to take part in the sleep analysis study (representing 67.8% of men and 65.8% of women who had been asked to take part).. This selection was not random, and the researchers say that they had chosen a larger-than-usual proportion of people with a high BMI and who were at greater risk of sleep-disordered breathing.

All participants completed a comprehensive sleep history questionnaire and physical examination. Their sleep was evaluated for one night in the sleep laboratory, using polysomnography, a comprehensive recording of all biophysical changes that occur during sleep. They were then divided into two categories according to how long they had slept. Those who slept six hours or more were put in the normal sleep duration group, while those who slept less than six hours were in the short duration group.

On the same evening as the laboratory visit, the group also filled in a standardised questionnaire covering demographics, sleep-related questions (including questions on sleep disorders) and general health questions. The presence of insomnia was defined as insomnia that had lasted for at least one year.

The men in the study were followed up for 14 years, and the women for 10 years. People who died were identified using social security numbers matched to federal and state death record services. The possible association between insomnia, objectively measured sleep duration and the risk of mortality was assessed using standard statistical methods. The findings were adjusted to take account of possible confounders, such as age, race, education, body mass index, smoking, alcohol, depression and sleep-disordered breathing. The participants were also asked if they were being treated for diabetes or high blood pressure.

 

What were the basic results?

Overall, during the study period, 21% of men and 5% of women died. The main findings are as follows:

• In men, the risk of dying in the 14-year follow-up was increased in those who slept less than six hours in the lab and had also reported a history of insomnia, compared to men who had normal sleep duration and no insomnia. This analysis was adjusted for diabetes, high blood pressure and other potential confounders (OR 4.00, CI 1.14-13.99).
• Further analysis of these high-risk males (those reporting insomnia and with short sleep duration in the lab) revealed that men who also had diabetes or high blood pressure had the highest risk of death during follow-up (OR 7.17, CI 1.41-36.62) compared to men with no reported insomnia and normal sleep duration in the lab.
• Men with insomnia and short sleep duration who were not affected by diabetes or high blood pressure no longer had a significantly increased risk of death compared to males with ‘normal sleep’ (OR 1.45 CI 0.13-16.14) – i.e. diabetes and blood pressure modified the effect of insomnia upon mortality.
• There was no increased risk in men who reported insomnia but whose objectively measured sleep duration was six hours or more. Nor was there any increased risk in men who had not complained of insomnia, but whose sleep duration was less than six hours.
• Women had no association between insomnia, short sleep duration and a higher mortality.

 

How did the researchers interpret the results?

Men with chronic insomnia and objectively measured short sleep duration had a higher risk of dying early, say the researchers, independent of other factors associated with mortality. People who had diabetes or high blood pressure showed a far stronger association between insomnia and short sleep duration. They say that the diagnosis and treatment of insomnia should be targeted by public health policy.

 

Conclusion

This study has found that in middle-aged men, self-reported insomnia and objectively measured short sleep duration was associated with a greater risk of death during the 14-year follow-up period, compared with men who did not have insomnia or short sleep duration. However, these findings require careful interpretation and do not prove that insomnia increases the risk of early death:

• The study has an important limitation in that it is a secondary analysis of a study set up to assess the age distribution of people with sleep-disordered breathing. As such, the participants were not selected at random. All of them had a higher risk of sleep-disordered breathing, and the women had markedly higher BMIs. These factors may affect both mortality risk and insomnia. Therefore, the results should be interpreted with caution and cannot easily be generalised to the wider population.
• Sleep duration was only objectively measured in the laboratory once, at the start of the study, so the results may not have been typical or accurate. In men who reported a history of insomnia (self-reported sleep problems lasting at least a year) only those who slept for a shorter duration in the lab had an increased risk. However, a single night’s observation in this artificial environment does not necessarily ‘confirm’ that the person had insomnia. Those men who just reported a history of insomnia had no greater mortality risk than those who did not report sleep problems. Of note, the increased risk calculated for the men with insomnia and who slept for less than six hours in the lab had a wide confidence interval, which questions the reliability of this finding.
• The study found that men with diabetes or high blood pressure who suffered insomnia and slept for less than six hours in the lab were at an even greater risk of dying during follow-up than those without these conditions. Again, however, the very wide confidence intervals suggest the need for caution with these results.
• Although the researchers tried to adjust their findings for other factors that could have influenced mortality and sleep, it is possible that other confounding factors influenced the results. Insomnia may be related to numerous medical or psychological conditions that can also affect mortality risk.

To sum up, this research is not strong evidence that insomnia is linked to an early death, and it sheds no light on possible reasons behind a link. Further research is needed.

Links To The Headlines

Bad sleep 'a male killer'. Daily Mirror, September 1 2010

How insomnia 'can send men to an early grave' - But are women immune to the dangers?. Daily Mail, September 1 2010

Insomniac men 'four times more likely to die early'. The Daily Telegraph, September 1 2010

Why a bad night’s sleep can prove fatal. Metro, September 1 2010

Insomnia: men who can’t sleep are ‘at risk of an early grave’. Daily Express, September 1 2010

Links To Science

Vgontzas AN, Liao D, Pejovic S, et al. Insomnia with Short Sleep Duration and Mortality: The Penn State Cohort. Sleep, 2010

A “genetic excuse for obesity ‘is a myth’”, reported The Daily Telegraph. It said, “people could work off around 40 per cent of the extra weight that “fat genes” laid on them by exercising.”

This news report is based on a study that looked at how much physical activity over 20,000 people in Norfolk did and whether they were genetically more likely to be overweight. The researchers found that, although some genes increased the likelihood of having a higher BMI (body mass index), being active meant that these “genetically predisposed” individuals were less likely to be overweight. At the same time, being inactive increased the amount of weight they were likely to gain.

Current recommendations are that everyone should do at least five 30-minute sessions of moderate exercise a week as part of a healthy lifestyle. The results of this research suggest that this is beneficial for maintaining a healthy BMI, even in people who may be genetically prone to being overweight.

Where did the story come from?

The study was carried out by researchers from the University of Cambridge and was funded by Cancer Research UK, the Medical Research Council, British Heart Foundation, Food Standards Agency, Department of Health and Academy of Medical Sciences. It was published in the peer-reviewed medical journal PLoS Medicine.

The Telegraph, Sun and Daily Express all accurately reported the results of this study. The newspapers quoted the study’s author, Dr Ruth Loos, who stated: “It goes to show we’re not complete slaves to our genetic make-up.”

What kind of research was this?

This was a cohort study that investigated the extent to which people with a genetic susceptibility to becoming obese can change their weight with exercise. The research was based on previous genetic studies, which had identified 12 possible positions on 11 genes where differences between people in their DNA sequence could influence BMI. However, although the studies showed an association between variations in the genetic sequence at these positions and BMI, they only seemed to have a very small effect on a person’s risk of obesity. This suggested that lifestyle played a greater role, and the new study aimed to investigate this in more detail.

What did the research involve?

The participants were part of a larger cohort study, called the EPIC-Norfolk study, which involved 25,631 people living in Norwich. The participants were aged 39–79 years old during a health check that took place between 1993 and 1997. They had a second health check between 1998 and 2000. During the health checks, the participants’ weight and height were measured and their BMI calculated. In a questionnaire, the participants were asked about the amount of physical activity they usually did each week, at work and during their free time. Based on this questionnaire, they were classified as:

• inactive (sedentary job with no recreational activity)
• moderately inactive (sedentary job with less than half an hour a day recreational activity, or a standing job with no recreational activity)
• moderately active (sedentary job with half an hour to one hour of recreational activity a day, or a standing job with less than half an hour of exercise a day, or a physical job with no recreational activity)
• active (sedentary or standing job with more than one hours’ recreational activity a day, or a physical job with some recreational activity, or a heavy manual job)

The researchers had DNA from 21,631 participants of the larger cohort. These participants were all of white European descent. The researchers looked at the genetic sequence at the 12 positions on the 11 genes to see if the genetic variations associated with susceptibility to obesity were present. At each of the 12 positions, the participants were given a score, which indicated whether their DNA sequence gave them an increased genetic predisposition to becoming obese. The scores were then added together to give an overall score.

The researchers used a standard statistical technique, called logistic regression, to assess the strength of the association between an increased genetic predisposition for obesity and high BMI at the first health check. They then determined if they could still predict whether an individual would be obese, based on their genetic predisposition, if the analysis was repeated with people grouped according to their activity levels.

The researchers then looked at the interaction between genetic predisposition and physical activity, and the likelihood that a participant would put on weight in each year between the first and second health checks (a period of one to seven years).

What were the basic results?

The researchers found that for each of the 12 genetic variations that increased the predisposition for obesity, there was a 0.154kg/m² increase in BMI. This corresponded to a 1,445g increase in body weight for each variation in an individual who was 1.70m tall.

Each increase in physical activity level was associated with a 0.313kg/m² reduction in BMI. This corresponded to a decrease of 904g in body weight for a person who was 1.70m tall.

When the participants were grouped according to the four physical activity levels and the association between genetic predisposition and BMI was assessed, the researchers found that physical activity modified the effect on BMI of the genetic predisposition score. An increase in genetic predisposition score was associated with a 0.205kg/m² increase in BMI in the inactive individuals (an extra 592g for a person 1.70m tall), but only a 0.126kg/m² increase in active individuals (an extra 364g for a person 1.70m tall).

The researchers found that physical activity modified the association between genetic predisposition to obesity and BMI at the first health check and over follow-up.

How did the researchers interpret the results?

According to the researchers, their study shows that “a physically active lifestyle can modify the genetic predisposition to obesity”. They say that “living a physically active lifestyle is associated with a 40% reduction in the genetic predisposition to common obesity” and “promoting physical activity, particularly in those who are genetically predisposed, may be an important approach to controlling the current obesity epidemic.”

Conclusion

This large cohort study found that physical activity decreased the likelihood of having a higher BMI in people with a genetic predisposition to being overweight. One strength of this study is that it looked at a large population, which is important for assessing gene-environment interactions. However, the study has some limitations which the researchers highlight:

• The amount of physical activity was assessed with a self-administered questionnaire. Reporting physical activity in this subjective way may have led participants to over- or under-estimate the amount of physical activity they did.
• The participants included in the study were all white and of European descent. This population may not reflect the UK population as a whole.

This study shows that, although some people may have a genetic predisposition to being overweight, physical activity can prevent weight gain in these individuals. Current recommendations are that people should do at least five 30-minute sessions of moderate activity a week as part of a healthy lifestyle.

Links To The Headlines

Your genes made you fat? Rubbish… Just get some exercise. The Sun, September 1 2010

Weight: why having fat parents is no bar to being trim. Daily Express, September 1 2010

Genetic excuse for obesity 'is a myth'. The Daily Telegraph, September 2010

Links To Science

Li S, Zhao JH, Luan J et al. Physical Activity Attenuates the Genetic Predisposition to Obesity in 20,000 Men and Women from EPIC-Norfolk Prospective Population Study. PLoS Med 2010; 7(8)

Shaw KA, Gennat HC, O'Rourke P, Del Mar C. Exercise for overweight or obesity. Cochrane Database Syst Rev 2006, Issue 4

“Smoking cannabis from a pipe can significantly reduce chronic pain in patients with damaged nerves,” reported the BBC. It added that improvements in sleep and anxiety were seen.

This news story is based on a small randomised controlled trial in 23 people, which found that a low dose of inhaled cannabis (lower than that needed to cause euphoria or a “high”) modestly improved reported pain in patients who had neuropathic pain.

This is a well-conducted study, but its small size means that it is not possible to tell whether the results demonstrate a real association between cannabis and pain relief, or if they are due to chance.

More research in larger groups of people over a longer period of time is needed to see if the effects of cannabis for this type of pain can be replicated. In addition, there are health concerns related to the use of smoked cannabis, including mental health problems and lung damage.

It is important to point out that cannabis is a class B drug, which is illegal to possess or supply, and is not licensed in any form for medical use.

 

Where did the story come from?

The study was carried out by researchers from McGill University, Canada, and was funded by The Canadian Institutes of Health. The study was published in the (peer-reviewed) Canadian Medical Association Journal.
 
This research was covered well by The Daily Telegraph and the BBC, though the study did not find any evidence for effects on anxiety or depression, as the Telegraph headline suggests.

 

What kind of research was this?

This randomised controlled trial investigated whether cannabis can relieve neuropathic pain (neuralgia) – severe pain caused by the abnormal activity of nerve cells. Various events can set off neuropathic pain, including surgery, trauma or shingles.

The researchers say that although there are drug treatments for neuropathic pain, such as anticonvulsants, antidepressants, opioids and local anaesthetics, their effectiveness varies between patients. Some patients are put off taking them because of unpleasant side effects. They say there is anecdotal evidence that cannabis relieves chronic neuropathic pain and improves sleep. The researchers wanted to investigate whether these reported effects could be replicated under controlled experimental conditions.

This type of study design is the most appropriate way of determining whether a drug is effective. However, this was a very small trial in only 23 people, so it is not possible to conclude that the results are due to chance alone.

 

What did the research involve?

The study recruited people who had experienced neuropathic pain for at least three months as a result of trauma or surgery. The participants ranked their current level of pain on a 10-point scale, and patients reporting pain intensity greater than four were included. Excluded from the study was anyone whose pain was due to cancer, anyone who had heart or lung disease, and those who had any type of substance abuse, a history of psychiatric disorders, or who were pregnant. In total, 23 people were eligible to participate in the study.

The effect of smoking cannabis with the active ingredient tetrahydrocannabinol (THC) was compared to smoking cannabis in which the THC had been removed (the control). Different potencies of THC were also compared to each other. Participants were not told which treatment they were given.

The control cannabis that had the THC removed was provided to the researchers by the US National Institute of Drug Abuse. The cannabis doses were prepared by blending the flowers and leaves of the plant to make three different potencies of the active drug (2.5%, 6.0% and 9.4% of THC).

Cannabis doses were delivered as single smoked inhalations taken through a pipe. The participants were instructed to inhale for five seconds as the cannabis was lit, hold the smoke in their lungs for 10 seconds, then exhale. The patients were observed taking the first dose. They then took subsequent doses at home, three times daily for five days. After 14 days, the participants swapped treatments so that those who had received the cannabis without THC then received cannabis containing the active drug. And those who had received active cannabis then received the placebo or a different dose of cannabis treatment.

In total, participants had four cycles of treatment where they received doses of 0%, 2.5%, 6% and 9.4% THC. Throughout the trial, the participants continued any routine medications that they were taking.

On the first day of each treatment period, the participants were asked about their feelings of pain, and how relaxed, stressed or happy they were. Their heart rate was also measured and a blood sample taken. During the five days of treatment or placebo, the participants were contacted by telephone and asked about their pain, how they were sleeping, their medication, and whether they were having any side effects. A urine sample was taken every day. On the fifth day of each treatment, a blood sample was taken and the participants were asked more questions about their pain, mood and quality of life.

 

What were the basic results?

The study had screened 113 participants but only 23 were eligible. Out of these, 21 completed all four cycles.

The researchers found that the average pain intensity was significantly lower on 9.4% THC cannabis (score 5.4 out of 10) than on 0% THC cannabis (6.1 out of 10) (p=0.023). However, no other comparisons between the different doses were found to be statistically significant.

Participants using 9.4% THC cannabis reported finding it easier to fall asleep and had better quality of sleep than those taking 0% THC. No differences in mood or quality of life were seen with the different THC potencies.

Of the reported side effects, none were serious or unexpected. The most frequent side effects reported by participants when taking 9.4% THC cannabis were headache, dry eyes, burning sensation, dizziness, numbness and cough. Feeling “high” and euphoric was reported once in the 2.5%, 6% and 9.4% THC cannabis treatment periods.

 

How did the researchers interpret the results?

The researchers said that the 25mg herbal cannabis with 9.4% THC, administered as a single smoked inhalation three times a day for five days, significantly reduced average pain intensity compared to placebo in adults with chronic post-traumatic or post-surgical neuropathic pain. They also said that there were improvements in measures of sleep quality, but that long-term safety and efficacy studies are needed.

 

Conclusion

This placebo-controlled trial found that cannabis containing 9.4% THC could reduce neuropathic pain compared to the placebo. However, this was a small trial with only 23 participants, so it is difficult to tell whether these results demonstrate a real association, or if they are due to chance. A much larger trial would be needed for a longer period to assess the long-term outcomes of such a treatment. Additionally, there are health concerns related to the use of smoked cannabis, including mental health problems and lung damage. Further research is needed to assess such potential side effects over the long term.

The researchers say that their study provides a way of looking at the short-term effects of smoked cannabis in a placebo-controlled trial. It is important to point out that cannabis is a class B drug, which is illegal to possess or supply, and is not licensed in any form for medical use.

Links To The Headlines

Cannabis may relieve chronic nerve pain. BBC News, August 30 2010

Smoking cannabis 'alleviates pain and depression'. The Daily Telegraph, August 30 2010

 

Links To Science

Ware MA, Wang T, Shapiro S et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. Canadian Medical Association Journal 2010, Published online ahead of print August 30

The lives of 10,000 patients could be saved each year by a “breakthrough pill”, according to the Daily Express.

The news story comes from a study that looked at whether a drug called ivabradine could help prevent deaths or hospital admissions due to chronic heart failure. This relatively common condition occurs when the heart is no longer able to pump enough blood to meet the demands of the body. The study found that over an average of 23 months, patients taking the drug experienced fewer cardiovascular deaths or hospital admissions with worsening heart failure than people taking an inactive placebo pill.

Ivabradine is a drug that lowers the heart rate and is already prescribed for some people with angina. The results of this large, multinational study demonstrate that heart rate reduction could improve the outcome for people with chronic heart failure. However, as the authors note, its results only apply to patients with a certain type of chronic heart failure that meets specific criteria. It cannot be assumed that these results apply to all patients with chronic heart failure.

 

Where did the story come from?

The study was carried out by researchers from a number of centres in Europe and the US, including the University of Gothenburg, Sweden. It was funded by Servier, a French pharmaceutical company, which was also responsible for the study’s data management and final data analysis (although these were verified by an independent statistical centre). It was published in the peer-reviewed medical journal The Lancet.

The study was widely covered by the media, and reports featured quotes from experts that suggested the drug could save 10,000 lives a year. It is unclear how this figure was reached. The study itself calculated that 26 patients would need treatment for one year to prevent one cardiovascular death or one hospital admission for worsening heart failure (the main outcomes of the study). The BBC’s headline that the drug may ‘prevent’ heart failure is misleading.

 

What kind of research was this?

This randomised controlled trial, in which both the researchers and participants were blinded, investigated whether the drug ivabradine had any effect on cardiovascular outcomes, symptoms and quality of life in patients with heart failure when used in addition to standard treatment. This kind of trial, in which patients are randomly assigned to either an active treatment or a placebo, is the best way to find out about the effects of medical treatments.

The researchers say that chronic heart failure, which affects 2-3% of the population in many industrialised countries, has a fairly poor prognosis and that the development of new medicines to treat it is crucial. In chronic heart failure, the heart is unable to pump enough blood around the body. The researchers say that reducing the heart rate could be particularly important in improving some types of chronic heart failure. This is because a lower heart rate would allow more blood to enter the chambers of the heart between each beat and reduce the effect of low blood supply to the heart muscle.

The benefits of one standard treatment for heart failure, called beta-blockers, seem to be linked in part to its heart rate-lowering properties. However, beta-blockers can have undesirable effects for heart failure patients. Ivabradine, say the researchers, seems to reduce heart rate without these side effects on the heart. It is currently licensed for use in people with angina who have a normal, regular heartbeat (sinus rhythm), either in combination with a beta-blocker or without if a beta-blocker is unsuitable or not tolerated.

 

What did the research involve?

The study was undertaken in 677 medical centres in 37 countries. Researchers enrolled 6,558 patients with moderate to severe heart failure associated with left ventricular systolic dysfunction (where contraction of the lower left heart chamber pumps an inadequate amount of blood to the rest of the body). The patients had to meet various other selection criteria, including being on stable background treatment and having a resting heart rate of at least 70 beats a minute.

Between October 2006 and June 2009, the patients were randomly assigned to receive either ivabradine or an inactive placebo drug. Both groups continued to take their standard heart failure medications, including beta-blockers. Neither patients nor researchers knew which patients were in which group. The dose of ivabradine was started at 5mg twice a day and was increased (up to a maximum dose of 7.5 mg twice a day) or decreased according to the change in each patient’s heart rate.

The patients were followed up for an average of 22.9 months. Researchers looked primarily at the “combined outcome” of cardiovascular death or admission to hospital with worsening heart failure (i.e. the occurrence of either or both outcomes). They also separately looked at a number of secondary outcomes, including deaths from any cause and all hospital admissions. All the results were analysed using standard statistical methods.

 

What were the basic results?

A small number of patients were removed from the study due to various problems. After these exclusions, final results were available for 3,241 patients in the ivabradine group and 3,264 patients in the placebo group. The main results were as follows:

• 24% of patients taking ivabradine experienced cardiovascular death and/or admission to hospital because of worsening heart failure, compared to 29% of those taking placebo (an 18% reduction in risk, hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.75 to 0.90).
• When the results were analysed separately, 16% of patients taking ivabradine were admitted to hospital with worsening heart failure, compared to 21% taking a placebo (a 26% risk reduction, HR 0.74, 95% CI 0.66 to 0.83).
• 3% of patients on ivabradine died of heart failure, compared with 5% taking a placebo (a 26% risk reduction, HR 0.74, 95% CI 0.58 to 0.94).

Adverse effects were also examined:

• 5% of ivabradine patients had bradycardia (an abnormally low heart rate) compared to 1% of the placebo group.
• 3% of patients on ivabradine had blurred vision compared to 1% of the placebo group.
• 21% of patients on ivabradine withdrew from the study compared to 19% of patients on the placebo.

The researchers note that the overall effects of ivabradine were less marked in patients taking at least 50% of a standard dose of beta-blockers.

 

How did the researchers interpret the results?

The researchers concluded that ivabradine significantly reduced the major risks associated with heart failure when added to standard treatments. They also said the findings suggest that those with higher heart rates will benefit most.

Treatment with ivabradine was also associated with a reduction in heart rate of 15 beats a minute. Heart rate is an important physical factor that contributes to heart failure and reducing it can interrupt progression of the disease, the study authors suggest.

 

Conclusion

This large, well-conducted study has demonstrated the role that heart rate reduction may have in improving outcomes of people with heart failure. It found that the drug ivabradine, which slows heart rate, significantly reduced cardiovascular deaths and hospital admissions due to heart failure when combined with standard treatments.

The findings of this research could have implications for the treatment of some, but not all, patients with heart failure. As the researchers note, its results apply to a specific group of patients with both a stable, regular baseline heart rate of at least 70 beats a minute and left ventricular systolic function (an enlargement of the lower left chamber of the heart that means it is unable to pump enough oxygenated blood to the rest of the body). People with irregular heartbeat patterns, such as atrial fibrillation or flutter, were also excluded from the study. Overall, the effect of ivabradine in this trial cannot be said to be applicable to everyone with chronic heart failure.

It is also important to note that the results were achieved alongside the patients’ existing treatment programmes, which included beta-blockers, so no conclusions can be drawn about the effects of ivabradine in the absence of these drugs or as a replacement for them. As the researchers also point out, in many cases the recommended target doses of these other standard heart failure medications had not been reached, so it is not known whether this particular population would have been able to tolerate high doses of a beta-blocker.

Overall, the research supports the potential beneficial role of ivabradine in particular subgroups of people with heart failure.

Links To The Headlines

Ivabradine pill may prevent heart failure for thousands. BBC News, 29 August 2010

Cheap heart-failure drug could save thousands of lives. The Daily Telegraph, 29 August 2010

Pill for chest pains 'could save 10,000 lives a year'. The Guardian, 29 August 2010

£10 heart pill could save 10,000 UK lives. The Sun, 29 August 2010

Thousands in heart drug boost. Daily Express, 29 August 2010

Links To Science

Swedberg K, Komajda M, Böhm M et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. The Lancet, August 29 2010 (early online publication)

"Eating broccoli and plantain could reduce bouts of Crohn’s disease,” reported The Daily Telegraph. It said researchers have found that certain types of soluble fibre from these plants can help to prevent bacteria from sticking to the gut's walls, thereby limiting the progress of the disease.

This study looked at whether fibres from various edible plants affected the transport of E. coli bacteria across specialised cells found in the lining of the bowel. The researchers also looked at whether substances called emulsifiers (commonly found in processed foods) altered the transfer of bacteria across these cells.

They found that fibres from broccoli and plantain reduced the transmission of bacteria across cells by between 45% and 82%, while leek and apple fibres had no effect. One emulsifier, called polysorbate 80, seemed to increase the transmission of bacteria across these cells.

This preliminary laboratory study has not shown that eating broccoli or plantain reduces attacks of Crohn’s and the findings have no immediate implications for the prevention or treatment of the disease. Nevertheless, these early findings are of scientific interest and may lead the way to clinical trials investigating whether certain plant foods and dietary modifications could have an effect on disease activity in people with Crohn’s.

 

Where did the story come from?

The study was carried out by researchers from the University of Liverpool, Linkoping university, Sweden, the University of Aberdeen and Provexis Plc (a company that makes medical dietary supplements and products and that provided the plant preparations used in the study). It was funded by the Wellcome Trust, the National Institute for Health Research, the National Association for Colitis and Crohn’s Disease, the Medical Research Council and the Swedish Research Council. It was published in the peer-reviewed medical journal Gut.

Both the BBC and The Daily Telegraph correctly reported that this was a laboratory study. However their headlines (“Broccoli boosts healthy gut” – BBC) did not clarify the fact that this research used extracts of the vegetable in a laboratory-based setting rather than testing broccoli consumption in people.

 

What kind of research was this?

Crohn’s disease is a chronic (long-term) condition where there is inflammation of the lining of the digestive system. Inflammation can occur anywhere in the digestive system, from the mouth to the anus (back passage). Common signs and symptoms include pain and diarrhoea (often with blood and mucus) while other effects on the body include weight loss, skin problems and arthritis.

Genetic factors are known to play a role in the development of the disease, but environmental factors may also contribute, such as diet and bacteria present in the gut. This laboratory research aimed to look at whether the uptake of bacteria by gut cells from people with Crohn’s was affected by certain plant soluble fibres from foods as well as substances found in processed foods.

There is a high prevalence of Crohn’s disease in developed countries where the typical diet is low in fibre and high in processed food. The researchers also point out that parts of the world, such as Africa, India and Central America, where plantains are a dietary staple, have low rates of inflammatory bowel disease as well as colon cancer. Therefore diet could be having an impact on Crohn’s disease.

There is a theory that the immune system in an individual with Crohn’s could "overreact" to certain food substances and microorganisms that may be present in the gut. In the lining of the gut there are specialised cells called "membranous" or "microfold" cells (M-cells). These are involved in the transport of proteins and micro-organisms through the bowel wall to the underlying lymph tissue and lymphoid follicles (Peyer’s patches), which are part of the immune system.

Previous studies in people with Crohn’s have noted that they have greater amounts of E. coli bacteria in their gut tissue, and that these E. coli often have special characteristics which make them more able to stick to, invade and live in gut wall cells. These are called adherent invasive E. coli (AIEC) strains. It is possible that bacteria such as E. coli could cause a heightened immune response in people with Crohn’s and be involved in the development of the disease. It is also thought possible that dietary factors could be involved – either by substances in the diet directly causing an immune response, or by affecting the transport of gut bacteria through these M-cells. That M-cells and the underlying Peyer’s patches may have some role in the development of Crohn’s disease is further supported by the fact that the early inflammatory lesions of Crohn’s have been found to lie over these cells.

This laboratory study set out to investigate whether certain soluble plant fibres from foods, as well as substances found in processed foods, have any effect on the transmission of the bacteria across these cells.

 

What did the research involve?

The laboratory research used strains of E. coli that had been isolated from six people with Crohn’s, as well as five control samples from people without Crohn’s. The plant-based sources of dietary fibre they tested were prepared from broccoli, leek, apple and plantain (a member of the banana family usually cooked as a vegetable). They also included two common food emulsifiers used in processed foods.

The researchers took human colon cells and grew them in the laboratory in conditions which encouraged them to develop into M-cells. They tested these cells to make sure that they could successfully transport bacteria, to show that they had developed into M-cells.

They then carried out a number of tests on the M-cells and the "parent" colon cells that they had been grown from. The cells were grown as a layer a single cell thick in special containers in such a way that the cell layers had solutions above and below them that did not mix. The researchers then applied bacteria to the upper surface of this layer and incubated it for up to four hours. After this time they tested to see how much bacteria had been transported across the cells to reach the solution underneath the cell layer. They then tested the effects of the different preparations on the transmission of E. coli across the cell layers. They applied the soluble fibre or other food substance onto the cells before applying the bacteria and measured whether this affected the transport of E. coli across the cell layer. They also tested the effect of the same substances on E. coli transport across normal tissue samples taken from the intestines of people without Crohn’s. They then analysed all the data, using validated statistical methods.

 

What were the basic results?

As the researchers expected, more E. coli was transported across the layers of specialised M-cells than across the layers of the "parent" human colon cells. The difference in transport across M-cells and the parent colon cells was greater when they used AIEC stains of E. coli from people with Crohn’s disease than when they used E. coli from people without Crohn’s disease.

They also found that:

• Both the preparations of plantain and broccoli markedly reduced the transport of E. coli across these specialised M-cells (range 45.3-82.6%).
• Apple and leek preparations had no significant effect on E. coli transport across the M-cells.
• One of the emulsifiers called polysorbate-80, increased E. coli transport across the cells, particularly the non-specialised colon cells.
• The plantain extract also reduced E. coli transport across the normal human intestine tissue samples, and polysorbate-80 increased transport across this tissue.

 

How did the researchers interpret the results?

The researchers say that transport of E coli across M-cells is reduced by soluble plant fibres such as plantain and broccoli, but increased by the emulsifier polysorbate 80. They suggest that fibre supplementation might protect against Crohn’s disease relapse by preventing bacterial invasion of intestinal mucosa, and that the effect of the food emulsifier could explain why Crohn’s rates are higher in developed countries where processed foods are common.

 

Conclusion

This carefully conducted laboratory study indicates that soluble fibres from certain plant foods can reduce the transport of E coli strains associated with Crohn’s, and their transfer across specialised cells of the bowel lining. It also shows that one emulsifier used in food processing has the opposite effect, by increasing transport.

This is early research aimed at furthering our understanding of how dietary and environmental factors might have a role in the development of Crohn’s. However, the findings have no current implications for the prevention or treatment of the disease, and it cannot be concluded from this study alone that any of these substances affect the development of Crohn’s. The study has not shown that eating broccoli or plantain reduces disease activity in Crohn’s. Even if there was an effect, it is unclear how much broccoli or plantain might be effective, or whether effective supplements of these substances could be developed.

These early findings are nevertheless of interest and may lead the way into later clinical trials investigating whether certain plant foods and dietary modifications could have an effect on disease activity in people with Crohn’s.

Links To The Headlines

Broccoli and plantain could fight Crohn's disease. The Daily Telegraph, August 26 2010

Broccoli 'boosts' healthy gut. BBC News, August 26 2010

 

Links To Science

Roberts Cl, Keita AV, Duncan SH et al. Translocation of Crohn’s disease Escherichia coli across M-cells: contrasting effects of soluble plant fibres and emulsifiers. Gut 2010; online first

You will be able to “grow your own transplant liver in a lab within just five years,” says the Daily Mail. 

This news story is based on research that demonstrated a method to develop skin cells into stem cells, which were then matured into liver cells. The researchers used this technique to develop lab-grown liver cells from patients with inherited liver diseases, which they hope might aid future research into diseases. They found that the new liver cells shared a number of characteristics with the patients' liver cells.

The method developed in this research looks likely to be an invaluable technique for creating cell cultures that could be experimented on in the lab. However, this research did not aim to investigate how a fully-functional liver or transplantable cells could be grown in a lab, both of which are years away.

 

Where did the story come from?

The study was carried out by researchers from the University of Cambridge and funded by the Wellcome Trust, the Medical Research Council and the Biomedical Research Centre of the Cambridge Hospitals National Institute for Health Research. It was published in the peer-reviewed Journal of Clinical Investigation.

News reports generally covered this research accurately. However, the headline featured in the Daily Mail (“Grow your own transplant liver in a lab within just five years”) is misleading as this research does not suggest that the techniques involved could be used for this purpose.

 

What kind of research was this?

This was a laboratory study that aimed to develop a method for converting human skin cells into liver cells. The researchers induced the skin cells to become a type of stem cell called “inducible pluripotent stem cells”. These can develop into different types of cells when provided with appropriate chemicals, such as growth-inducing (growth factor) substances.

The researchers focused on whether it would be possible to generate these stem cells from people with inherited (i.e. genetic) metabolic disorders of the liver. This group of diseases affect key proteins in the liver. These patients may be treated with a liver transplant but this surgery carries risks.

In this study, the researchers wanted to see whether skin cells taken from these liver disease patients could be converted into liver cells displaying the characteristic problems seen in the patients’ natural liver cells. If successful, the technique could be used to produce cell culture models, which could then be used to understand the mechanisms of the disease and to help develop new therapies.

 

What did the research involve?

The researchers took skin samples from seven volunteers with inherited liver diseases and three healthy control patients, and isolated skin cells called fibroblasts from this tissue.

The fibroblast skin cells were genetically modified to introduce active copies of the human genes OCT4, SOX2, c-Myc and KLF4 into the cells to make them into inducible pluripotent stem cells (iPS). These iPS cells were then grown in the laboratory. Where possible, three iPS cell lines per individual were grown to look at how much variation there would be in the process of stem cells developing into liver cells.

To make the cells develop into liver cells (differentiate) the researchers treated them with a sequence of chemicals, including growth factors and other proteins. The cells were treated with five different rounds of chemical cocktails over a period of approximately 25 days. These chemicals caused the iPS cells to first develop into endoderm cells (a type of cell normally found in embryo development), and then into more “liver-like” hepatic endoderm cells. These immature cells were finally matured into liver cells.

To check whether the stem cells had successfully developed into liver cells, the researchers looked at whether the cells produced a protein called albumin, which is typically produced by liver cells. They also examined whether they had the same appearance as liver cells, and whether they could store the chemical glycogen and break down drugs as the liver does.

 

What were the basic results?

The researchers found that 80% of the cells produced by their technique were making albumin, suggesting that these were liver-like cells. The cells were also able to perform the other liver cell functions that the researchers assessed. However, further assessment of the gene activity in the cells found that the cells were not quite fully mature and were assessed to be developmentally somewhere between the liver cells of a four-month-old foetus and adult liver cells.

They found that out of 20 iPS cell lines made from 10 individuals, 18 of these were able to differentiate into liver cells. The researchers then looked at whether the liver cells that they had made from the skin cells of the liver patients showed the same properties and defects found in the patients’ own livers.

They first examined the cells developed from an individual who had a mutation in a gene called A1ATD, which causes the accumulation of a protein called α1-antitrypsin in their liver cells. They found that this protein also accumulated in the liver cells developed from patients with the condition but not the liver cells from healthy control individuals.

Patients with familial hypercholesterolemia have high levels of LDL cholesterol. This is because they have a mutation affecting a protein called the LDL receptor, which would normally remove LDL circulating in the blood. The liver cells produced from the skin of an individual with this disease also lacked the LDL receptor protein.

Finally, they examined the liver cells produced from a person with glycogen storage disease type 1a, a condition that causes problems regulating sugar levels and abnormal accumulation of glycogen, the glucose storage molecule, within their liver cells. The liver cells derived from these individuals showed the same accumulations of glycogen and also replicated some other features of the disease, such as accumulation of fat and excessive production of lactic acid.

 

How did the researchers interpret the results?

The researchers say that inducible pluripotent stem cells (iPS) have been used to make cell culture models for a limited number of rare neurological diseases, but their research has shown that it is possible to also use this technique for non-neurological diseases, such as inherited metabolic diseases of the liver.

They then say that they have demonstrated that “human iPS cell-derived [liver cells] can be generated from multiple patients of varied genetic and disease backgrounds”. They also say that their system is “an efficient methodology for the early-stage safety and therapeutic screening of liver-targeted compounds of potential relevance to the pharmaceutical industry”.

 

Conclusion

This laboratory study has developed a method to produce liver cells from skin cells by producing inducible stem cells. The study showed the potential of this technique to produce cell culture models of inherited liver diseases. As the researchers point out, this is likely to be a useful tool to learn more about these diseases and screen for useful drugs.

However, this research was not done with the intention of growing transplantable livers, as suggested by the Daily Mail. A liver is comprised of a complex tissue of different types of cell and it has not been investigated whether the cells developed here could have the potential to be transplanted.

This is promising preliminary research that may lead to advances in the understanding of inherited liver diseases and in treatments for these conditions. The next step would be to test the processes developed in this small study on a larger number of patients to further investigate the cells generated and their potential for developing cell lines for research.

Links To The Headlines

Grow your own transplant liver in a lab within just 5 years. Daily Mail, August 26 2010

Scientists create liver cells from skin. Financial Times, August 25 2010

Liver Disease cure closer than ever as scientists find new way to copy cells. Metro, August 25 2010

Links To Science

Rashid ST, Corbineau S, Hannan N et al. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. Journal of Clinical Investigation, August 25 2010