NHS Choices - Health News Behind the Headlines

Researchers have found an association between the inflammatory bowel condition ulcerative colitis and the “gene that encodes for interleukin 10 (IL10) – a compound which regulates inflammation”, BBC News website reports. Ulcerative colitis affects around 100,000 people in the UK, and symptoms include bloody diarrhoea, abdominal pain, losing weight and needing to go to the toilet frequently. The website reports that “the administration of interleukin 10 to individuals with colitis has been reported to have a positive effect in initial studies, although this potential therapy has not been assessed more thoroughly”.

This study points researchers towards areas of the genome that warrant further study in people with ulcerative colitis, although the variant(s) that actually causes this increase has not yet been identified. However, further studies will be needed to investigate whether IL10 treatment would be helpful for people with ulcerative colitis.

Where did the story come from? Dr Andre Franke from Christian–Albrechts University in Germany, and colleagues from other universities in Europe, carried out this research. The study was funded by the German Ministry of Education and Research (BMBF). It was an advance online publication in the peer-reviewed scientific journal, Nature Genetics.

What kind of scientific study was this? This was a genetic case-control study called a genome-wide analysis. The researchers were looking for particular genetic variations that were associated with the susceptibility to developing a form of inflammatory bowel disease called ulcerative colitis. This disease is estimated to affect between 21 and 246 people per 100,000 of the population in North America and Europe. It is known that genetics plays a role in developing ulcerative colitis, as siblings of people with the disease are six to nine times more likely to develop this disease than the general population.

The researchers identified 1,167 people with ulcerative colitis (cases) and 777 people who did not have the condition (controls). They obtained DNA samples for all of the cases and controls, and looked at 440,794 specific points across the DNA, called SNPs, where single “letters” of the genetic sequence are known to vary. They then compared the sequences to see if there were any SNPs where a particular “letter” was more common in the cases than in the controls. If a particular “letter” or variant is more common among cases than controls, this variant is said to be “associated” with the disease.

To confirm their findings, the researchers repeated their test on DNA from an additional 1,855 cases with ulcerative colitis and 3,091 healthy controls from three other European studies. Researchers carrying out these tests were blinded to whether the DNA came from a person with ulcerative colitis or not. Only those variants that showed association with the disease in both tests were included. The researchers went on to look at which genes lay close to these associated variants, as they may be involved in the development of the disease.

What were the results of the study? In their first analysis of 1,944 people with or without ulcerative colitis (cases and controls), the researchers identified a number of variants that were significantly more common in people who had ulcerative colitis (cases). They took the 20 variants showing the strongest association with the disease, and tested these in three additional sets of cases and controls (replication samples).

Five of these variants showed a strong association with the disease across all three replication samples. Three of these variants lay near to a complex (group) of HLA genes (genes involved in the immune system) on chromosome 6, while one variant was near to the IL10 gene on chromosome 1; another one was near to the ARP2C region on chromosome 2. These susceptibility variants were estimated to be associated with between 9.8% and 47.8% of the risk of developing ulcerative colitis.

The researchers went on to look at the variant near to IL10 in more detail, as this gene produces a protein which has a suppressive effect on the immune system and has previously been thought to play a role in inflammatory bowel disease, such as ulcerative colitis. When the original and replication samples were pooled, this variant was associated with an increase of 35% in the odds of developing ulcerative colitis. The researchers looked at 22 more variants in and around IL10 in cases and controls, and found that a number of these variants also showed association with ulcerative colitis. Their findings suggested that there might be more than one variation in this region contributing to the increase in risk of ulcerative colitis.

The researchers also determined the sequence of the entire IL10 gene in 94 people with ulcerative colitis, 94 people with Crohn’s disease (another form of inflammatory bowl disease) and 94 healthy controls. Although they found a number of variations in the sequence of the gene, they did not identify a single variation that was clearly responsible for causing an increased risk of developing the condition.

What interpretations did the researchers draw from these results? The researchers concluded that their findings suggested that a defect in IL10 function is key to the development of ulcerative colitis. They suggest that IL10 “should be worthy of consideration in clinical trials in [ulcerative colitis]”.

What does the NHS Knowledge Service make of this study? This study provides evidence that variations within the region of the IL10 gene are contributing to the risk of developing ulcerative colitis, although the variant(s) that actually causes this increase has not yet been identified. The findings were replicated in more than one group of people, and this increases the confidence in these results. As the authors suggest, further studies will be needed to investigate whether IL10 treatment would be helpful for people with ulcerative colitis. The previous use of this agent in human studies may make it easier for these trials to start, but it will still be a number of years until the results of such trials will be available. It is not known yet whether this treatment provides benefits to people with ulcerative colitis.

“Hospitals have been warned not to over-dilute cleaning chemicals amid fears that this could boost antibiotic resistance in bacteria” says the BBC News website today. A study in the US found that exposing the bacteria Staphylococcus aureus to low concentrations of a wide range of antiseptic and antibacterial solutions lead to the formation of strains that had “a higher number of ‘efflux pumps’, a feature found on the surface of their cells which allows them to get rid of toxic molecules”, the website says. These pumps can also remove certain antibiotics, such as ciprofloxacin, from the bacteria.

This study did show that there was a possibility of increasing “efflux pump” levels after exposure to low levels of certain cleaning chemicals (disinfectants and antiseptics known as biocides) and dyes. However, it did not investigate directly whether this has been responsible for the development of either antibiotic- or biocide-resistant bacteria in hospitals. Unlike antibiotics, biocides can be used in very high concentrations, and the findings of this study suggest it may be important to use sufficiently high concentrations of cleaning products. Further research into whether different kinds of cleaning products or ways of using them could avoid this potential source of antibiotic-resistant bacteria is warranted.

Where did the story come from? Dr Aurélie Huet and colleagues from the John D. Dingell Department of Veterans Affairs (VA) Medical Center and Wayne State University School of Medicine in Detroit, USA, and the Université de Bretagne Occidentale in France carried out this research. The study was funded by VA Research Funds. It was published in the peer-reviewed scientific journal, Microbiology.

What kind of scientific study was this? This was a laboratory study where researchers were investigating whether exposure of the Staphylococcus aureus bacteria to low levels of certain cleaning products (biocides) and dyes used in hospitals can lead to increased expression of the genes that are involved in drug resistance. These genes produce proteins called multidrug resistance (MDR) protein pumps. These proteins sit in the cell membrane of the bacteria and work by forcing unwanted toxins out of the cell, giving the bacteria a low level of resistance to the chemicals’ effects. In ‘superbugs’, such as MRSA, these MDR pumps also remove antibiotics from the cell, and this prevents the antibiotics from working properly.

The researchers took blood samples from patients and obtained eight strains of S. aureus bacteria. Five of these strains had been found to be resistant to the antibiotic meticillin (methicillin), but three were susceptible to the antibiotic. This type of resistant bacteria is a cause of hospital-acquired infections, and is commonly known as methicillin resistant S. aureus (MRSA). As a control, the researchers also obtained some S. aureus bacteria grown in the laboratory.

The researchers then exposed the different strains to low-to-moderate levels of various dyes and biocides (i.e. levels that were not high enough to kill the bacteria outright). The biocides and dyes used included pentamidine, cetrimide, chlorhexidine, norfloxacin and ethidium bromide, among others. In the first experiment, the bacteria were exposed to one of the dyes or biocides for two days, and any surviving bacteria were then isolated. In the second experiment, bacteria were exposed to increasing levels of the chemicals over a number of days; again, any surviving bacteria were isolated.

The researchers then took the ‘parent’ bacterial strain and the groups of surviving bacteria from both of these experiments and measured the levels of activity of the seven genes that produce MDR pump proteins. If the researchers identified bacteria that had increased the production of these proteins after exposure to the biocides and dyes, they looked at what genetic mutations had occurred to cause this increase. They also looked at how well the parent and the surviving mutated bacteria could pump out the dye, ethidium bromide.

What were the results of the study? The researchers found that exposure of S. aureus to certain biocides and dyes led to the appearance of mutated forms of the bacteria that had increased levels of activity of one or more genes.

Some of the bacteria showed an increased resistance to the biocides and dyes that they were exposed to, but did not have an increase in the activity of the seven MDR pump genes that they looked at. This suggested that there may be other MDR genes responsible for this resistance.

When the researchers looked at the how well the mutant bacteria could pump out the dye ethidium bromide they found that although some of the mutated bacteria could pump out more dye than their parent bacteria, some could not.

What interpretations did the researchers draw from these results? The researchers concluded that S. aureus bacteria that are repeatedly exposed to non-lethal concentrations of biocides can develop resistance to these chemicals by increasing the activity of MDR pump genes. Such bacteria might pose a threat to patients who are being treated with certain antibiotics that can also be pumped out of the bacteria by the same MDR pumps. They suggest that using cleaning agents that cannot be pumped out of bacteria by MDR pumps might reduce this effect.

What does the NHS Knowledge Service make of this study? This study illustrates the possibility that exposing bacteria to low levels of certain cleaning chemicals and dyes can increase the resistance of the bacteria to these chemicals, and potentially to other chemicals such as antibiotics. It is not clear whether this type of exposure has been responsible for the development of antibiotic- or biocide-resistance in hospitals, and if so, what contribution it has made to this phenomenon relative to the overuse of antibiotics. This study does not suggest that cleaning should be stopped, but does suggest that it is important to use sufficiently high concentrations of these chemicals to kill any bacteria. Further research into whether different kinds of cleaning products or ways of using them could avoid this potential source of antibiotic-resistant bacteria is warranted.

“Sick leave 'link to early death'” is the headline on the BBC news website, suggesting that people who have “long spells of sick leave for psychiatric reasons” are twice as likely to die from cancer as healthier employees. A study in over 6,000 civil servants also found that “those who had taken a long period of sick leave had a 66% higher risk of early death”, the website adds.

There are some limitations to this analysis of data from a large study. Although it suggests that there was a 2.5-fold increase in likelihood of cancer death with absence for ‘psychiatric’ reasons, the actual number of people dying in this category was very small. Also, the definition of ‘psychiatric’ absences is not clear.

It is important for employers to keep accurate records of absences to be aware of their employees’ health and allow early identification of cases where extra support may be needed – either from healthcare professionals or in the work environment. Accurate records could also be an important source of data for further studies such as this.

Where did the story come from? Dr Jenny Head and colleagues from University College London, Karolinska Institutet in Sweden, and the Finnish Institute of Occupational Health in Finland carried out this study. The research (the Whitehall II study) was funded by grants from the Medical Research Council, the British Heart Foundation, the Health and Safety Executive, the Department of Health, the National Institutes of Health, the Agency for Healthcare Policy Research and the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health. It was published in the peer-reviewed medical journal, the British Medical Journal.

What kind of scientific study was this? This publication is based on an analysis of data from the Whitehall II study – a prospective cohort study of civil servants in the UK that started in 1985. The Whitehall study enrolled all London-based office staff aged 35 to 55 years from 20 civil service departments. Seventy-three per cent of those approached agreed to participate, leaving a final cohort of 10,308 (6,895 men and 3,413 women). Between 1985 and 1988, participants were screened for entry into the study, and computerised sickness absence records were reviewed for the participants since 1985. Absence records were available for 9,179 civil servants.

In this publication, the researchers were interested in whether medically certified sickness over a three-year period was linked to mortality, and whether the diagnosis behind people’s sickness absences affected this risk. Diagnostic codes for absence had been recorded by the civil service and the researchers in this study converted these codes into disease categories. These categories were based on the morbidity coding system of the Royal College of General Practitioners, but four extra categories were added (gastrointestinal, headache and migraine, neurosis and neurosis ill-defined). The three-year exposure period was defined as the three years after baseline screening (for those departments that had computer records of absence at the beginning of the study) and three years from January 1 1991 for departments who didn’t collect computerised records until 1991.

Data about deaths was available through the National Health Service Central Register mortality register. All-cause mortality and deaths from cardiovascular disease and cancer were recorded from the start of the participants’ three-year exposure period until September 30 2004. The researchers took into account other factors that may have an effect on mortality, including smoking, alcohol consumption, high blood pressure, self-rated health, presence of longstanding illness (diabetes, heart disease, respiratory illness, cancer etc), disability or infirmity.

The researchers used statistical methods to assess whether there was a link between the number of sickness absences in the three-year period and death from all or any cause. They also investigated whether the prediction of mortality was greater when they looked at the specific reason for work absence. Both of these analyses took into account (were adjusted for) other factors that may be linked with mortality, such as smoking, drinking and general health.

What were the results of the study? Not all participants in the Whitehall II study were included in the analyses due to missing data or incomplete three-year exposure (i.e. the participant died or left the civil service). 3,830 participants were excluded and an investigation of their characteristics revealed that, as a group, those who were excluded had a lower mortality.

Of the 6,478 participants who were included in this study, 288 had died during follow-up. People with more than one medically certified absence (absence of greater than seven days duration) during the three-year exposure period were 1.7 times more likely to die than those with no such absences. They also found that the more absences a person had, the greater their risk of death.

When they looked at specific diagnoses, the highest risk for death was due to absences for ‘circulatory problems’ (4.7 times increased risk of death), followed by surgical operations (2.16 times increased risk), neurosis (ill-defined; 2.03 times increased risk), injury (1.66 times increased risk) and diseases of the respiratory system (1.63 times increased risk of death). There were a small number of people absent for ‘cancer’ and of those (10 people), their risk of death was 21.3 times more likely than those without absences, though the estimate was not very accurate given the small sample.

Researchers also looked at link between absence (overall and for particular reasons) and cause of death. They found that being absent overall was associated with cardiovascular and cancer deaths. Absence for infectious or parasitic disease, circulatory problems, respiratory illness and surgical operations were all significantly linked to cardiovascular death. When looking at reasons for absence and cancer-related death, only psychiatric absences and surgical operations were significantly linked. Further breakdown of ‘psychiatric’ absence into ‘neurosis’ and ‘neurosis ill-defined’ found that there was only a link with ‘neurosis ill-defined’.

What interpretations did the researchers draw from these results? The researchers conclude that “knowing the diagnosis for medically certified sickness absence from work significantly improves the prediction of mortality”. They say that “unexpectedly, employees who had one or more absence for psychiatric reasons had a considerable 2.5-fold greater cancer mortality”.

What does the NHS Knowledge Service make of this study? This study examines the link between absences from work (both generally and for specific reasons) and mortality overall and from cancer or cardiovascular causes. The finding that absence for psychiatric reasons is linked to an increased likelihood of death due to cancer is described as “unexpected”. The researchers did not explore why this might be the case.

There are several points to highlight in relation to this study, which should be kept in mind when interpreting the results:

• When broken down into the different categories, the absolute numbers of people who died were small. Only 12 people had psychiatric reasons for absence and died from cancer-related causes. This is a small number, and the results may have occurred by chance. The researchers acknowledge that sub-sample size is a problem, and that their results “need replication”. The small size means that the study was also underpowered to explore gender differences or differences across employment grade (a proxy indicator of socioeconomic status). 
• Also, when the researchers further explored ‘psychiatric’ reasons, i.e. breaking it down into its constituent ‘neurosis’ and ‘neurosis ill-defined’, they found that only ‘ill-defined’ neurosis was linked to cancer death. This definition included tiredness and stress, which may have nothing to do with mental illness (i.e. may be indicators of physical illness).
• The researchers also say that “the recorded diagnosis for a sickness absence may not cover all of the actual causes”. This is an important limitation, and is reflected by the finding that only 64% of recorded reasons for absence corresponded with GP diagnoses around that time. ‘Coexisting’ illness would not have been captured in the absentee records. 
• To determine whether the civil service codes for diagnosis were accurate, researchers obtained information from GPs for all absences greater than 21 days between 1985 and 1990, and assessed whether there was agreement between GP records and civil service codes. They found a 64% agreement. 
• In their analyses, the researchers took into account smoking and alcohol consumption, so they can be sure that the link between psychiatric absences and cancer mortality was not due to differences in drinking or smoking behaviour. However, there are other confounding factors that may be responsible for this, and these were not measured. The researchers suggest that one reason might be that depression interferes with help-seeking behaviour, delaying early detection and treatment of cancer. 
• Relationships between sickness and absence may be similar in other populations, but when generalising findings to other work groups it should be noted that these were all civil servants working in London. Typical personal and social lifestyle and working pressures may differ across occupations.

It is important for employers to keep accurate records of absences to be aware of their employees’ health and allow early identification of cases where extra support may be needed – either from healthcare professionals or in the work environment. Accurate records are also an important source of data for further such studies.

“‘Switch’ in brain linked to weight gain” is the headline in The Daily Telegraph. If this switch is faulty, the newspaper says, then the body will not recognise that it is full, and “the brain sends out signals to eat more and to store more sugars as fat”. The newspaper suggests “drugs could be used to suppress this switch and help people get back to a healthy weight”.

The news report is based on a complex study in mice. The findings suggest that there is a chemical in the brains of the mice that may be key in regulating the response to overnutrition, which ultimately leads to obesity and associated problems. However, mice and humans have very different metabolisms, so the results will need to be confirmed in humans, and research will need to go into developing safe drugs for humans and safe methods of delivering drugs to a very specific site in the brain. These developments are undoubtedly a long way off.

Where did the story come from? Dr Xiaoqing Zhang and colleagues from the University of Wisconsin and the University of California carried out this study. The research was funded by grants from the National Institutes of Health, American Diabetes Association and by UW-Madison start-up funds. It was published in the peer-reviewed medical journal, Cell.

What kind of scientific study was this? The study behind this news report is an animal study. The researchers were interested in looking at the link between overnutrition and the activation of inflammation pathways in a part of the brain called the hypothalamus. This region controls temperature, hunger and thirst, and it regulates hormone releases in the body. One disease characterised by chronic metabolic inflammation is type 2 diabetes, the result of which is insulin resistance. The effects of inflammation on organs such as the liver and adipose tissue have been studied extensively, but the effects of inflammation on the central nervous system, including the brain, are less well-known.

There are a variety of chemicals involved in the inflammatory response to overnutrition. In this study, the researchers explored the role of a particular chemical (IKKβ/NF-κB) which they suspected was responsible for the hypothalamus not functioning correctly, leading to obesity and related problems. Researchers removed the hypothalamus and other organs from mice to find out where the chemical IKKβ/NF-κB was concentrated. They also looked at the levels of NF-κB in the hypothalamus to study the effects of overfeeding mice a high-fat diet, and whether obese mice had higher levels of NF-κB than normal mice.

In further experiments, researchers delivered genes for IKKβ by injection to the brains of mice to see whether this could induce the activation or inactivation of NF-κB. In another part of the study, the researchers investigated what role IKKβ/NF-κB plays in insulin and leptin resistance in the hypothalamus. The activity of insulin and leptin are both critical for regulating fuel availability in the body (and therefore preventing excess energy stores).

What were the results of the study? The researchers confirmed that in normal physiology, chemical IKKβ/NF-κB exists in an inactive form, and in this form it inhibits the activity of the inflammatory protein NF-κB. In mice fed normal food, the levels of NF-κB were low. In obese mice, they found that activity of NF-κB in the hypothalamus was five to six times higher. IKKβ/NF-κB was also involved in insulin and leptin resistance in the hypothalamus.

What interpretations did the researchers draw from these results? Researchers conclude that their study suggests that the chemical IKKβ/NF-κB, which is normally not activated in the hypothalamus, may be activated – leading to inflammation – in response to chronic over-nutrition. They say that ‘hypothalmic IKKβ/NF-κB’ could underlie the entire family of modern diseases induced by over-nutrition and obesity.

What does the NHS Knowledge Service make of this study? This complex animal study has profiled the activity of a chemical called IKKβ/NF-κB, which in normal physiology is inactive, but overnutrition causes it to be activated, and this leads to an inflammatory response. This finding will be of interest to the scientific community, which will seek to replicate the findings.

While the researchers are optimistic that their “results suggest a novel therapeutic strategy for combating the ever-increasing spread of obesity and associated diseases”, it will be some time before we see the application of these findings in humans. It will be difficult, for example, to develop anti-inflammatory drugs that specifically target the brain. The study was also conducted in mice in a disease model that was similar to obesity. But there are likely to be huge metabolic differences between mice and humans, so it is not clear whether the exact same reactions happen in response to over-nutrition in the human brain. Human research, which is the only way to establish this, is still a long way off.

This is exciting research, and IKKβ/NF-κB may be the obesity ‘master switch’, but this needs to be confirmed in humans and then used to develop drugs that target the part of the brain where it acts.

“Research at Oxford University has found believers can draw on their religion to endure suffering with greater fortitude,” The Daily Telegraph reported. Many newspapers covered a study in which Catholic and non-religious volunteers were given electric shocks while they studied religious and non-religious paintings. It was reported that Catholics felt less pain when they were shown a picture of the Virgin Mary. MRI scans also showed that areas of the brain involved in inhibiting pain response were activated in Catholic participants as they studied the religious image.

Although this study was carefully designed, any interpretations to be made from these results are limited due to a number of factors. The experiment only involved a small number of people, subjective assessments of pain were used, and the research was limited to looking at Catholics and non-believers in their response to two images. Additionally, the electric shocks that were given cannot be considered truly representative of pain and medical illness. Religious faith (or its absence) is a highly individual matter. Healthcare professionals who are supporting people suffering from pain and illness and who are considering broaching religious issues should do so with full respect for all belief systems and personal boundaries.

The research was carried out by Katja Wiech and colleagues from the Universities of Oxford and Cambridge. The study was supported by the Oxford Centre for Science of the Mind, and was funded by the Templeton Foundation. The study was published in the peer-reviewed medical journal, Pain.

The authors state that although religious belief is often claimed to relieve physical pain, how this happens from a psychological and neurological standpoint is unclear. They say is it not implausible that religious states and practices can influence pain, and although the effect of religious belief on pain has not been investigated in a controlled experimental setting, a number of studies have demonstrated that psychological processes can modulate pain.

In this experimental study, the authors wanted to investigate the effect that religious belief has on pain, and the psychological and neural mechanisms underlying it. Their theory was that by helping believers to reinterpret the significance of pain, some degree of emotional detachment is achieved.

The researchers recruited 12 practising Roman Catholics and 12 non-religious subjects, including people with atheist and agnostic views. All subjects were healthy with no medical illnesses; their average age was 26 and 70% were female. All subjects filled out a questionnaire on their beliefs, confirming that they fulfilled the criteria of either having no religious or spiritual beliefs, or that they were devout Catholics who prayed daily, attended weekly mass and took part in confession. The subjects were told that the objective of the study was to see whether pain experience differed when viewing images of different content, but not told that the aim was to investigate the effect of religious belief.

The experiment was conducted in four parts, and involved the religious and non-religious groups being alternately exposed to religious and non-religious pictures. Each trial lasted for eight minutes and during this time, the subjects received a series of 20 electrical stimuli via the back of their left hand. Thirty seconds before each electrical shock, they were shown either an image of the Virgin Mary praying, or a painting by Leonardo da Vinci, which was similar but had no religious connotations. The picture remained in view while the shock was administered, but disappeared for a split second before the shock was given as a warning to the subject that the shock was coming. The intensity of the shocks had been individually calibrated for each subject, to correct for differences in pain sensitivity among them. The calibration procedure involved each participant being given a series of 10 shocks of increasing intensity to which they gave a verbal intensity rating of between 0 and 100. The point at which they each rated the level as 80 was the intensity used during the experiment.

A baseline image of a white dot was displayed at the end of each trial to act as a control. MRI scanning was performed during each trial.

Following each trial, the participants rated their subjective experience of the pain, and how the image had affected them. They gave an average pain intensity for the trial using a visual analogue scale from 0 = not painful at all, to 100 = very painful. They rated the effect that the image had on their mood using a scale varying from -50 (negative mood) to +50 (positive mood). They also gave a rating of how much the image had helped them to cope with the pain, as well as the familiarity of the image, using a visual analogue scale from 0 = not at all, to 10 = very much.

The researchers analysed differences (in pain experience, mood effect of the image, familiarity of the image and coping with pain) between the religious groups (comparing Catholics to non-believers), and within each subject (comparing the religious image to the non-religious image exposure).

The researchers found that the Catholics’ and non-believers’ experience of pain was not significantly different. However, the Catholic group perceived significantly less pain when presented with an image of the Virgin Mary than with the non-religious image. Non-believers rated their pain experience as equally intense with both images presented.

Ratings of mood differed significantly between the groups, and the Catholic group reported significantly more positive mood when shown an image of the Virgin Mary. Conversely, the non-believer group reported more positive mood when shown the non-religious image. A more positive mood correlated with significantly reduced pain experience in the Catholic group, but not in the non-believers group. Additionally, the image of the Virgin Mary helped the Catholic group cope with pain significantly more than the non-religious image, while the non-believers coped equally well with either image.

The MRI scans showed that all the subjects demonstrated activation of areas of the brain involved in pain processing, and there was no difference between the groups. However, comparing the effects of the religious and non-religious images between the groups, the researchers found that when presented with an image of the Virgin Mary, the Catholic group showed more activity in a part of the brain that the researchers had hypothesised has an effect on pain modulation (the right ventrolateral prefrontal cortex). Although the non-believers rated the non-religious image as being preferred by them, presentation of this image was not associated with increased activation in this brain area.

The authors concluded that presentation of a religious image enables believers to reduce how intense they found a painful stimulus to be, and that this effect might be mediated by pain-regulatory processes within certain parts of the brain.

This research was carefully designed to investigate the psychological and neural mechanisms behind religious belief and how it influences pain. However, there are important limitations to consider:

• All the subjects were aware that the objective of the study was to see whether pain experience differed when viewing images of different content. Although they had not been informed that the study was specifically investigating religious beliefs, it seems probable that they may have been able to guess this, and that this would subsequently have the potential for biasing subjective responses to pain in the Roman Catholic group when viewing an image of the Virgin Mary. However, as the authors state, this bias might be expected to have had less influence on the more objective brain imaging assessment.
• The study was small (involving only 24 people), and therefore it is possible that differences in the more objective MRI images are due to chance.
• The study involved only individuals of the Catholic faith and their response to one image during an experimental scenario. It is not possible to generalise these results to other stimuli of religious faith, to others’ faiths, or conversely to conclude that pain relief of this sort occurs only through “belief in God”, as one newspaper headline states.
• The experimental situation involving electrical shocks, where the participants knew their health was not in danger, may not be representative of the more complex physical, emotional and social situation of real-life pain and illness.

Many areas of a person’s life can be influenced by their faith, and religious or spiritual beliefs are known to support many in times of pain or illness. However, the interpretations or conclusions that can be made from this experimental situation are uncertain. Faith is a highly individual matter, and healthcare professionals who are supporting people suffering from pain and illness and who are considering broaching religious issues must do so with full respect for all belief systems and personal boundaries.

The common cold virus “could increase child’s risk of asthma ten-fold”, reports The Daily Telegraph. When a group of children (who had parents with asthma or other allergies) were followed from birth to six years, it was found that those “close to the age of three who develop wheezing with the virus have a 30-fold risk of becoming asthmatic by the time they turn six”, the newspaper says.

Although this study does demonstrate an association between wheezing during childhood colds and later asthma, it does not mean that the cold is the cause of asthma. It may simply be that people who are more likely to have asthma in later life are also more likely to have wheezing when they have a cold or other viral illness during early childhood. Asthma is a difficult condition to diagnose in children, and although wheeze is the most well-known symptom, it can present in many different ways. Many children who develop asthma do not go on to have asthma as adults. This study should not be taken to mean that common colds – which are unavoidable – cause asthma.

Where did the story come from? Daniel Jackson and colleagues from the University of Wisconsin-Madison and Wisconsin State Laboratory of Hygiene carried out this research. The study was funded by the National Institute of Health. The study was published in the peer-reviewed medical journal, American Respiratory Critical Care Medicine.

What kind of scientific study was this? This was a cohort study where the researchers aimed to investigate the relationship between specific childhood illnesses and early development of asthma.

A group of 259 children (born between 1998 and 2000) were recruited from birth and followed up at the ages of one, three and six as part of the Childhood Origins of Asthma (COAST) study. All had at least one parent who suffered from a respiratory allergy (determined using a positive allergen skin test) and/or had medically diagnosed asthma.

At regular clinic visits during the first year of life, samples of mucus from the nose and throat were taken, and these were analysed for a number of common childhood viruses. Samples were also taken during periods of respiratory illness (these were identified by parents who contacted a study coordinator). When the children were one and three years of age, the researchers measured the levels of a particular antibody (IgE) that is known to be associated with allergic reactions. At five years, skin-prick testing was performed for a number of common environmental and household allergens.

Episodes of ‘viral infection’ were defined as when a virus was detected in a mucus sample. If the child was suffering from symptoms, this was referred to as ‘viral illness’. In order to be considered a ‘wheezing respiratory illness’ during the first three years of life, one or more criteria had to be fulfilled:

• Wheeze diagnosed by a doctor.
• Prescription of bronchodilator medication.
• Specific diagnosis given of asthma (or exacerbation of), wheezing illness, bronchiolitis or reactive airways disease.

At the end of the sixth year ‘current asthma’ was diagnosed based on the documentation of one or more of the following over the previous year:

• Asthma diagnosed by a doctor. 
• Use of a (physician-prescribed) bronchodilator for cough or wheeze. 
• Use of daily inhaled steroids or other asthma control medication. 
• Step-up plan of bronchodilator and inhaled corticosteroids during illness. 
• Use of oral steroids during illness.

The researchers examined the relationship between asthma at six years and the cause of wheezing illness during the first three years of life, taking into account other confounding factors including parental asthma, exposure to passive smoking, animals in the house, etc.

What were the results of the study? Wheezing respiratory illnesses were very common during the first three years of life, with 454 episodes documented in the whole study group. For 97% of these episodes, nasal samples were obtained. In 90% of the samples, viruses were detected, with rhinovirus (the cause of common cold) being by far the most common, identified in 48% of cases.

Respiratory syncytial virus (the common cause of bronchiolitis – an inflammatory airways infection which occurs in babies under one years old) was the second most common virus, occurring in 21% of samples.

In the 48 illnesses which involved multiple viral infection, rhinovirus was present in 60%. Children diagnosed with asthma had a significantly increasing number of rhinovirus infections with each year of life (one through to three) compared with children without asthma at six who had had far fewer infections and a significant decrease in number over the years.

Twenty-eight per cent of children had asthma (based on the defined criteria) by age six. Among these, 48% had intermittent asthma, 34% had mild persistent asthma and 18% had moderate persistent asthma.

Analyses were carried out on the risk of diagnosis of asthma and any link with rhinovirus infection or respiratory syncytial virus only, as these were the viruses most commonly identified. When compared with children who were not infected with either of these viruses, children who had wheezing illness in the first three years of life were 9.8 times more likely to have asthma diagnosed by age six if they had rhinovirus infection. They were 2.6 times more likely if it was respiratory syncytial virus infection; and 10 times more likely if it was infection with either rhinovirus or respiratory syncytial virus.

In the first year of life, wheezing illness with rhinovirus infection and allergen sensitivity both independently increased the risk of asthma at age six years (2.8 times and 3.6 times respectively). But for the third year of life, the risk of asthma was far greater if there was a wheezing illness with rhinovirus infection (25.6 times) compared with the risk from allergen sensitivity (3.4 times). Almost 90% of children who had a wheezing illness associated with rhinovirus in their third year of life had asthma diagnosed by age six.

Other non-viral factors significantly associated with asthma at age six were having older siblings in the house, and having food sensitivity during the first year of life.

What interpretations did the researchers draw from these results? The authors conclude that of the community–acquired viral infections which cause wheezing in infancy and childhood, rhinovirus was the most significant predictor of the subsequent development of asthma at six years.

Asthma has a wide variety of risk factors, both genetic and environmental, and these environmental risk factors include exposure to bacterial and viral infections. Therefore it is not surprising to find that those who already have some inherited disposition towards asthma and then develop a wheeze during a viral illness may be more likely to go on to develop asthma. Although this study demonstrates associations of the common cold with asthma, it does not mean that the cold is the cause of asthma. There are some points to consider:

• The group of children included in the study were already at higher risk. They were selected on the basis of having a parent or parents with either asthma or respiratory allergies. Therefore risk among this group (who may be more predisposed to developing asthma) cannot be considered to be representative of other groups. 
• The size of the group was relatively small, and larger observational studies would be needed to provide confirmation of the results. 
• The study has only considered asymptomatic infection and symptomatic wheezing illnesses in the community that did not require hospitalisation. Had more serious respiratory infections been considered, different viruses might have been detected and found to correlate with risk.
• Asthma at age six (diagnosed by fulfilling certain criteria over the past year of life) does not necessarily mean that the condition will persist into later childhood or adulthood.

The common cold is an unavoidable infection and most of us will suffer from repeated episodes during our lifetimes. It should also be noted that wheeze during an infective illness is extremely common in childhood, and it does not necessarily mean that a child has asthma or will develop asthma in the future. Asthma is always a difficult condition to diagnose in children. Although wheeze is the most well-known symptom, it can present in many different ways, and parents should be aware of other possibilities. For instance, sometimes a persistent nocturnal cough may be the only symptom.

“Vitamin C supplements could cut the effectiveness of cancer drugs”, reports the Daily Mail. US scientists have found that, in the laboratory, cancer cells treated with vitamin C resist drug treatment by up to 70% and “tumours grew more rapidly”, the newspaper says.

This study used laboratory and animal models of leukaemia and lymphoma, and found that vitamin C decreased the cancer-killing properties of a number of common anti-cancer drugs. However, the study used cells in the laboratory, which limits the application of the results to humans.

If people who are taking anti-cancer drugs are concerned, they could avoid taking additional vitamin C supplementation. However, readers should not be concerned about normal daily intake of vitamin C through a balanced diet, as it remains an important nutrient for human health.

Where did the story come from? Mark Heaney and colleagues at Memorial Sloan-Kettering Cancer Center and Herbert Irving Comprehensive Cancer Center, New York Presbyterian Hospital, Columbia University, New York, carried out this research. The study was funded by the New York State Department of Health, and with grants from the National Institute of Health, Leukaemia and Lymphoma Society, a Doris Duke Distinguished Clinical Science Award and the Lewis Family Foundation. It was published in the peer-reviewed medical journal, Cancer Research.

What kind of scientific study was this? This was a laboratory study. The researchers were interested in finding out if vitamin C – an antioxidant – would block the effects of anti-cancer drugs that are known to generate reactive oxygen species as part of their mode of action. This study aimed to investigate this in the laboratory using leukaemia and lymphoma cells and commonly used cancer drugs, including doxorubicin, cisplatin, vincristine, methotrexate and imatinab. The researchers investigated the effect of the drugs on the cells when they had been treated with the chemical form of vitamin C used in the body (dehydroascorbic acid), and when there had been no treatment.

The researchers looked at the effects of pre-treatment with dehydroascorbic acid on cancer cell viability, cell death, the clone-generating properties of the cells, reactive oxygen species and effects upon the mitochondria within the cells (the structures that provide the chemical energy source of the cell). The cytotoxic (cell-killing) properties of the cancer drugs were investigated by looking at the formation of new colonies of cancer cells.

The researchers used cultures of human chronic myeloid leukaemia and lymphoma cells, as well as creating a ‘mouse model’ by injecting mice with lymphoma cells. The human cells were incubated in the laboratory with an ascorbic acid solution. Ascorbic acid had been incubated with ascorbate oxidase to generate dehydroascorbic acid (vitamin C). Following incubation with the vitamin C substances, the cells were incubated for two days with the anti-cancer drugs and then assessed. The mice that had developed palpable tumours after the lymphoma injections were injected with vitamin C and doxorubicin or doxorubicin alone before being killed humanely. The dimensions of the tumours and drug levels were then assessed.

What were the results of the study? Treatment with dehydroascorbic acid caused a decrease in the cell-killing (cytotoxic) properties of the anti-cancer drugs, with a dose-dependent effect (higher dehydroascorbic acid doses had greater effect). In the mouse model, when vitamin C was administered before treatment with doxorubicin significantly larger tumours were seen than among the mice that had been treated with doxorubicin only.

The decrease in the cell-killing properties of the drugs did not appear to be due to the effects of vitamin C upon the reactive oxygen species in the cells, suggesting that this was not the method of the cell protection. However, vitamin C did appear to prevent the effects that the anti-cancer drugs would normally have upon the electrical potential of the surface membrane of the mitochondria within the cells.

What interpretations did the researchers draw from these results? The researchers conclude that in this model (which is representative of leukaemia and lymphomas in humans), vitamin C administered before a number of commonly used anti-cancer drugs antagonises the efficacy of the drugs by preserving the electrical potential of the mitochondrial surface membrane. They say that this supports the hypothesis that vitamin C supplementation during cancer treatment may have a detrimental effect upon the efficacy of treatment given.

What does the NHS Knowledge Service make of this study? This study used models of leukaemia and lymphoma, and examined the effects of a number of common chemotherapy and anti-cancer drugs (which had various mechanisms of actions) when they were administered after treatment with vitamin C. The study found that vitamin C decreased the cancer-killing properties of the drugs by inhibiting the effects that the drugs would normally have upon the mitochondria in the cells.

This study involved applying vitamin C to cancer cells, both human and mouse, in the laboratory. This means its application to live humans is limited. It is unclear how the concentrations of vitamin C (in its various chemical forms) used in the laboratory can be related to those that are achieved by taking vitamin supplements. Vitamin C was applied directly to tumour cells, and this may not be representative of absorption through the body. Also, vitamin C was given two hours before treatment, so it is not possible to tell what the effects would be if the time before treatment was increased or if the vitamin C was given after the drugs.

Nevertheless, these findings will need further research. For now, if people who are taking these anti-cancer drugs are concerned, they could avoid taking additional vitamin C supplementation. Readers should not be concerned about normal daily intake of vitamin C through a balanced diet, as it remains an important nutrient for human health.

“Children who spend large amounts of time with their fathers have higher IQs,” The Daily Telegraph reported. It said that, according to a new study, fatherly involvement in a child’s early life can also affect their career prospects. The Daily Mail also covered the story and said the study suggests that fathers who take a more active role have children that grow up to be more intelligent and climb higher up the social ladder.

This was a long-term study that followed 11,000 British men and women since their birth in 1958. While the study has some strengths in that it involved a large number of people over many years, it has several limitations. These mostly relate to how the information on fatherly involvement was initially collected, and certain measures that were not taken, such as independent measures of motherly involvement. The information on the father’s involvement was captured in 1969, and how applicable these findings are to today’s style of parenting is questionable. Intelligence is reliant on a variety of genetic and environmental factors.

Daniel Nettle from the Centre for Behaviour and Evolution, Institute of Neuroscience at Newcastle University, carried out this research. No sources of funding were reported in the journal article. The study was published in the peer-reviewed medical journal, Evolution and Human Behaviour.

The author of this cohort study said that previous research has indicated that fathers become more involved with sons than with daughters, and that fathers in higher socioeconomic groups spend more time with their children than those of lower socioeconomic groups. The author wanted to investigate whether the amount of contact between father and child influences child outcomes. Specific attention was given to whether socioeconomic status and child gender influences fatherly involvement, and whether the level of involvement affects child IQ and social mobility. Possible reasons for this were explored.

The author used data from the National Child Development Study, an ongoing investigation of all 17,146 children born in the UK in a single week in March 1958 and their parents. The participants have received regular assessments over the past 50 years, most recently in 2004-5 at the age of 46. This particular study used data collected in 1965, 1969, 1974, 2000 and the most recent assessment in 2004-05. The number of participants varied at each assessment time, ranging from 10,979 to 15,051. Paternal involvement was principally assessed in 1969 when the children were about 11 years old. Mothers were asked about levels of fatherly involvement with possible responses of ‘inapplicable’, ‘leaves it to mother’, ‘significant but less than mother’, or ‘equal to mother’. When this data was cross-checked with other data from the cohort period, it was found that in 86% of cases the response ‘inapplicable’ referred to the father not living in the household with the child.

Socioeconomic status was assessed using a system of five occupational classes common in British National Statistics (I = professional through to V = unskilled). Social mobility was assessed by comparing the child’s social class in 2000 with that of the father in 1958. The IQ measure was a general ability (GA) score taken at age 11 (details of assessment not given in this report), which is said to have high validity with educational and occupational attainment. The researcher looked at relationships between GA score and paternal involvement, including other variables such as number of brothers and sisters.

Level of paternal involvement varied by socioeconomic class, with 65% of class I fathers spending an ‘equal to mother’ amount of time with the child compared to 59% of class V fathers. Fathers who ‘left it to mother’ increased from 4% in class I to 14% in class V. If a child was a girl, they had significantly increased odds that their father would be in a category other than ‘equal to mother’. Odds also increased with each additional brother in the family, i.e. ‘greater numbers of siblings were associated with lower paternal involvement’. Overall, fathers invested more time with the child when they were of higher socioeconomic status, when the child was a boy, and when there were fewer children in the household.

As expected, IQ at 11 varied with child sex (girls scoring higher than boys), number of brothers and sisters (more siblings associated with lower score), and the father’s social class (higher class associated with higher IQ). The father’s role at age 11 also had an effect on IQ, with greater involvement associated with higher IQ. There was also an interaction between the father’s role and their social class, with greater paternal involvement having a larger effect on IQ when the father was of a higher social class.

There was also a significant effect of paternal involvement on their offspring’s social mobility (at age 42 years), with those who received more fatherly involvement more likely to increase social class (in addition to other expected patterns, e.g. males being more socially mobile than females, more siblings associated with less mobility). The author then goes on to discuss the psychology and social patterns that influence fatherly involvement.

The author concludes that the study has demonstrated that increased paternal involvement positively influences the child’s IQ at age 11 and their level of social mobility at the age of 42. There was also an effect of socioeconomic status, with fathers of higher socioeconomic status spending more time with their children. It was also found that fathers of higher socioeconomic status who had more contact with their children had greater influence on the child’s IQ than fathers of lower socioeconomic status who spent equivalent amounts of time with their children. There were no differences seen between sons and daughters in terms of the effect that their father’s time had on them.

This study has detected interesting patterns between fatherly involvement and child’s IQ. However the study has some important limitations:

• This study relied on the mothers’ perspectives of the fathers’ involvement and only measured this once in 1969. There are three problems: firstly, the mothers’ responses may have been inaccurate. Secondly, a single assessment made on one day is unlikely to be representative of the entire duration of the child’s upbringing. Thirdly, the results cannot be easily generalised to present day parenting. The level of contact and type of relationship that today’s children have with their fathers may be quite different from the norm in the 1950s and 60s. Forty to 50 years ago it was more common for a mother to stay at home with the children and for her to take a dominant role in bringing up children while the father went to work. Today, roles are more equal.
• Mother’s were only given a limited number of responses for the question on how involved the fathers were in their child’s upbringing. The responses will have been highly individual and will not mean the same thing from one family to the next. For example, ‘equal to mother’ could mean that the child was receiving high levels of attention from both of their parents. However, the same response could also be used if both parents were working full time and were both giving the child less attention.
• It cannot be assumed that it is only contact with the father that has an effect, or whether the same would be seen with any supportive male role model. It is also not possible to say whether it has to be a male at all, as the amount of time that the child spent with the mother or other adult females was not assessed. The questionnaire only compared the father’s involvement with that of the mother’s. If it had also directly measured the mother’s involvement then greater confidence could be had in this study.
• The effects of other factors such as the parents’ education, schooling, peer groups, disruptive life events or medical comorbidity and school absence were not investigated. The level of intelligence and professional career that a child develops depends on a wide range of factors, including genetics, education, peer group, and the home and external environment in which they grow up.

”Women who were bigger than average at birth are at greater risk of breast cancer”, reports the Daily Mirror. The newspaper, along with several others, says that research summarising 32 studies, and 22,058 cases of breast cancer among a total of more than 600,000 women from developed countries has confirmed the link. The authors suggest that exposure to oestrogen in the womb both affects growth and, in some way, increases future cancer risk.

This study found that the increase in breast cancer risk due to birth size was moderate or small. For baby girls who weighed 2.5kg (5.5lbs) to 3kg (6.6lbs) at birth, there was a 9.4% risk of cancer by the age of 80 years, compared with 11.6% for those who weighed 3.5kg (7.7lbs) to 4kg (8.8lbs). Discovering links such as these in observational studies and researching the underlying mechanisms is often the first step to an understanding of the causes of disease. The limitation is that these study designs cannot prove causation, but confirming another risk factor for such an important and common cancer will point to other avenues for research.

Where did the story come from? Professor Isabel dos Santos Silva from the Department of Epidemiology and Population Health, and colleagues from the London School of Hygiene & Tropical Medicine in London conducted this research, which was funded by a Cancer Research UK programme grant and Training Fellowship. It was published in the Public Library of Science peer-reviewed and open-access journal, PLoS Medicine.

What kind of scientific study was this? This was a systematic review with meta-analysis of individual-level data from 32 studies. This type of study involves the researchers re-analysing the raw data from published and unpublished studies to obtain more precise estimates of the ‘birth size–breast cancer’ association. In some cases, this meant contacting the authors of the primary research to find out details on specific women, rather than relying on the published literature alone. Any data sent to the researchers remained anonymous.

The researchers included studies that collected information on at least one measure of birth size and also recorded new-onset breast cancers. They identified cohort studies and case-control studies (that were themselves part of larger cohort studies), by a search of the usual databases, including PubMed and Embase, up to the end of June 2007. They identified further studies by searching through reference lists and by personal communication with cancer researchers. In this way a total of 27 published and seven unpublished cohort and case-control studies were identified. Some studies were excluded from the analysis if, for example, they had contributed data to other included studies, or if the individual-level data could not be retrieved. At the end of this selection process the researchers had individual participant data from 32 studies, comprising 22,058 breast cancer cases.

As the babies tended to be smaller in studies of twins and of premature/low birthweight babies, the researchers analysed these separately from the studies reporting data on single babies. Individual participants were excluded from all analyses if they had a known history of cancer other than non-melanoma skin cancer at the start of the study. They were also excluded if all birth size data were missing.

The researchers used a statistical technique known as a random effect model to combine the estimates of effect for the studies. This model assumes that the studies are not so similar that a similar effect would be expected. Birth size was measured by weight (kg), length (cm) and head circumference (cm) at birth. The researchers looked at the effect on the rates of breast cancer of increases in these measurements in steps of about one standard deviation, that is 0.5kg (1.1lbs) for weight, 2cm (0.8inches) for length and 1.5cm (0.6inches) for head circumference.

What were the results of the study? Birth weight was positively associated with breast cancer risk in studies based on birth records. For each step increase in birth weight (0.5kg) there was an increase risk of 6% (RR 1.06, 95% confidence interval 1.02 to 1.09). There was a steady increase in the risk of breast cancer with increasing weight at birth. Compared with women who weighed 3 to 3.499kg, the risk was lower in those who weighed less than 2.5kg, and greater in those who weighed 4kg or more. Birth length and head circumference from birth records were also positively associated with breast cancer risk.

When the researchers adjusted for all three birth size variables, they showed that length at birth was the strongest independent predictor of risk. The established breast cancer risk factors, number of children and socioeconomic factors, did not appear to interfere statistically with the estimates. These were not modified by including age or menopausal status into the equation either.

What interpretations did the researchers draw from these results? The researchers say that the “pooled analysis provided evidence of moderate positive trends in the risk of breast cancer among studies based on birth records, with risk increasing with increasing birth weight, length and head circumference”.

They comment that the source of birth size data was the main source of differences between the studies (heterogeneity). They say that the positive association of birth size with breast cancer risk was found only in data from birth records but not in data from self-reports or maternal recalls when the women were adults, suggesting that their approach to analysing the recorded data only was less prone to bias.

Adjustment for weight, length and head circumference in their analysis showed that length at birth was the strongest predictor of risk, despite the fact that it tends to be measured less accurately than weight or head circumference.

The birth size effect did not appear to be confounded or modified by known breast cancer risk factors. The association between birth size and breast cancer risk was observed consistently in women born over a period of several decades, and in different geographical areas.

What does the NHS Knowledge Service make of this study? This was a large study including a large amount of birth data on women who go on to develop cancer. As the authors say, this means that the statistical power – the ability to detect an effect if one exists – is higher, therefore the study can be expected to give a more precise estimate of the strength of any link.

Heterogeneity, that is, the underlying difference between studies which can sometimes prevent valid pooling of the results, was partly addressed by the researchers by obtaining data on individual women, and defining and coding the measurements of interest (weight, length and head circumference) in a standard way, and by choosing some factors to control for across all individuals. These measurements and adjustments may have been treated differently in the original primary publications, and the ability to use raw data to maintain a standard approach is a strength of an individual-level meta-analysis such as this.

The researchers also acknowledge some limitations and biases that need consideration:

• Publication bias can be a problem with pooled analysis because studies reporting negative findings may be published less often than those that report positive results. The authors argue that as inclusion in this pooled analysis was not dependent on publication, their re-analysis is less likely to have been affected by publication bias than meta-analyses of the published literature.
• The researchers relied on direct measurements of birth size, rather than those reported by the women. This means that any measurement error or reporting bias could be lower than if they had relied on recall in questionnaires, for example. Despite this, there is still a small possibility that birth size, or other measured factors, may have been incorrectly recorded, or that breast cancers may have been misclassified.
• The researchers adjusted for the potential confounding factors on which they had information, such as maternal age, number of children and socioeconomic status. By comparing the effect estimates in the unadjusted and adjusted analysis, they show that the results showed little variation. It is important that this was done, but it cannot completely exclude residual or unmeasured confounding by these or other factors.

Overall, this is a reliable summary of observational studies, which adds precision to the estimate of the strength of a risk factor link to breast cancer. The link shown is modest at best, and is comparable to other known risk factors, such as increasing age, not having children and having a late menopause. The biological mechanisms behind the association will need further evaluation. In particular, to determine whether oestrogen alone is the common factor determining birth size and breast cancer risk or, as the authors also mention, if there is a complex interplay of several hormonal and non-hormonal factors.

“People who regularly take the blood-thinning drug warfarin may be increasing the risk of a fatal brain haemorrhage”, The Daily Telegraph reported. It said the drug is taken by many patients at risk from ischemic stroke to prevent blood clots from developing. However, a study has found that people who had a stroke and were taking the drug experienced twice as much bleeding. This in turn could cause a brain haemorrhage and death unless treated quickly.

This particular risk of warfarin has already been identified, and the aim of this study was to examine some of the details behind this risk. The benefits of warfarin are well known, but as with all drugs, there are some risks. This study itself did not measure up these benefits and risks (for example, how many ischaemic strokes the drug prevented), but instead looks at how warfarin might affect one aspect of brain haemorrhage. As the lead researcher is reported as saying, this study “shows the importance of good monitoring and adjustment of warfarin dose. People should talk to their doctors about the proper management of warfarin and learn the signs of stroke so they can get to an emergency room immediately if a stroke occurs”.

Dr Matthew L. Flaherty and colleagues from the University of Cincinnati carried out this research. The study was funded in part by the National Institute of Neurological Disorder and Stroke and a University of Cincinnati College of Medicine Medical Student Summer Research Fellowship. The study was published in the peer-reviewed medical journal, Neurology.

Warfarin use has long been associated with a greater risk of death in people who have an intracerebral haemorrhage (ICH), but it is not known exactly how it has this effect. The authors of this retrospective cohort study had a theory that warfarin use might affect intracerebral haemorrhage size, and their study was designed to test this possibility.

The researchers used medical records to identify all adults who had been admitted to hospital with an ICH in the Greater Cincinnati region in 2005. Patients living outside the region were excluded, as were patients who had previously experienced an ICH, or where the cause of bleeding was trauma or was associated with brain tumours or encephalitis, surgical procedures (endarterectomy), or with the early hospital (thrombolytic) treatment of an ischaemic stroke. Data for 258 eligible patients was extracted from the records, including their age, sex, whether they were taking anti-clotting medications (including warfarin or aspirin), what other conditions they had (e.g. diabetes, heart disease, high blood pressure), and location of the ICH.

The researchers also looked at an indicator of how well a person’s blood clots, called the INR, which was measured when the patients first presented at hospital. The INR is a ratio and a high INR indicates a higher risk of bleeding (i.e. clots are slow to form), while a low INR, close to one, indicates a normal clotting profile in the blood. People taking warfarin to prevent ischaemic stroke from atrial fibrillation, for example, aim for a mid-range INR (two to three). Data on INR was missing for 22 patients, none of whom took warfarin. The researchers assigned these people an INR value of one. The researchers also measured the volume of each participant’s ICH on their first brain scan (MRI or CT scan) using a standard technique, and recorded the time taken between onset of the stroke and the scan.

Statistical methods were then used to look at whether taking warfarin and other factors affected the size of a person’s ICH. To begin with, each factor was analysed separately (univariate analysis). Then, a second analysis of the effect of individual factors found to be associated with ICH size in the univariate analysis was carried out, taking into account all of the other associated factors (multivariate analysis). Because warfarin use was strongly associated with INR value (higher warfarin use associated with higher INR values), only INR values were used in this second analysis. The researchers also looked at the relationship between these factors and death within 90 days of the stroke.

The researchers identified 258 people (average age 68.5 years) who had been admitted with ICH in the study period. Of these, 51 had been taking warfarin. Warfarin users had higher average INR values than non-users (3.1 compared with 1.1, p<0.001). When looking at individual factors, researchers found that warfarin use, location of the haemorrhage in the brain lobes, age, and shorter time between the stroke and the brain scan were associated with larger ICHs. There was a trend for patients with higher INRs to have larger ICHs, although this trend did not reach significance.

The researchers included INR values rather than warfarin use in their second (multivariate) analysis, as there was a strong link between these two factors. This second analysis found that those with a high INR (three or above) were more likely to have larger ICHs than those with a low INR (less than 1.2). ICH size was not significantly different between patients with mid-range INRs (1.2-3) and those with low INRs. Haemorrhages were larger in people who had a shorter time between onset of their stroke and the brain scan, and haemorrhages in the lobes of the brain were larger than those deep in the brain.

A higher INR (three or above) was also found to be associated with about twice the risk of death within 90 days compared to those with low INR (less than 1.2).

The researchers concluded, “Warfarin use was associated with larger initial intracerebral hemorrhage (ICH) volume” for INRs above three, and that this difference “likely accounts for part of the excess mortality in this group”.

As the study authors report, it is already known that warfarin use can increase risk of death in people who have a haemorrhagic stroke. This aim of this study was to take a closer look at the reasons behind this. There are a number of points to note when interpreting this study:

• The number of people taking warfarin was relatively small. Results will need to be replicated in a larger, preferably prospective, study to confirm these findings.
• There is the possibility that, other than the drug itself, there were underlying differences between people on warfarin and those not on warfarin which affected the results. This is a limitation of all studies of this type. Although the researchers took into account some factors in their analyses, there may have been other factors that had an effect but were not assessed.
• Some people (85) in this study were taking drugs other than warfarin, such as aspirin, that can affect clotting. The main analyses in this study looked at the effect of INR on ICH size, and did not adjust for use of other medications. It is possible that the sizes of the ICHs in this study partially reflect not only the effects of warfarin alone, but the effects of these other drugs, or other internal or external factors, such as diet, which are known to affect INR.
• On admission for ICH, people may have received treatment to reverse the effects of any anti-clotting medication they were taking. The authors reported that it was unclear from their medical records whether the INR measurements were taken before or after this treatment, and that this could have affected their results.
• As this study only looked at people who had experienced an ICH, it cannot show what proportion of people who take warfarin experience an ICH compared to those who do not take warfarin. Therefore, it is not possible to determine from this study whether the risk of ICH or risk of death after ICH is increased with warfarin, or whether warfarin prevented death from other causes.

The benefits of anti-clotting drugs are well known, but as with all drugs, there are some risks to taking warfarin. These risks can be minimised by taking prescribed doses of warfarin according to doctors’ directions, and attending any scheduled check-ups so that effects of warfarin can be monitored.