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“Bone marrow transplants cure mental illness – in mice”, reports The Guardian. It says “scientists in the US claim to have used a bone marrow transplant to cure mental illness in a study that could have profound implications for patients with psychiatric problems”.

The research involved genetically engineered mice that were lacking a gene called Hoxb8. These mice groom themselves so excessively that they remove patches of fur and develop sores. This condition is similar to a human condition called trichotillomania.

The researchers found that a type of immune system cell called microglia could be responsible for the mouse behaviour. These cells develop in the bone marrow and migrate to the brain. When the Hoxb8 mutant mice were given bone marrow from normal mice, the excessive grooming lessened and in some cased stopped.

These findings are of particular interest as they suggest an unexpected link between behaviour and a type of immune system cell. They do not mean that bone marrow transplants can cure mental illness in humans. Further research is needed to determine whether these cells play a role in humans with trichotillomania.

 

Where did the story come from?

The study was carried out by researchers from the University of Utah. One of the study authors was funded by the Howard Hughes Medical Institute. The study was published in the peer-reviewed scientific journal Cell.

The Guardian provides a good account of this research, and the headline reports clearly and early on that the study is in mice.

 

What kind of research was this?

This research was in genetically modified mice that lacked the Hoxb8 gene. These mice groom themselves so much that they remove their fur and cause skin wounds in some areas. The reason behind this behaviour is unclear, but the researchers say it is very similar to that seen in the human condition trichotillomania, a type of obsessive-compulsive disorder where people compulsively pull out their hair. Here, the researchers were looking for a biological explanation for the mice’s behaviour.

This type of animal research is used to further understand the biological basis of human disease. Improved understanding of which cells are involved in the development of a disease may eventually help treatment for human conditions, but this process usually takes considerable time. Because of the differences between species, developing exact animal models of human diseases can be difficult. For this reason, findings in animal disease models ideally need to be confirmed in humans.

 

What did the research involve?

In this study, the researchers used genetically engineered mice that lacked the Hoxb8 gene. These mice display excessive grooming of themselves and their cage mates, and they have an altered perception of noxious chemicals and heat. The study aimed to determine which cells are involved in the development of these symptoms.

Expecting that the brain would be involved, the researchers began by looking at the brains of normal mice to identify the cells in which the Hoxb8 gene was active. They found that in the brains of normal mice the Hoxb8 gene was active in immune system cells called microglia. At least some of the body’s microglia develop in the bone marrow and then migrate to the brain. It was within these bone marrow-derived microglia cells that the Hoxb8 gene appeared to be active. To test the effects of the lack of Hoxb8 on microglia in the brain, the researchers compared the number of these cells in the brains of normal mice and in mice lacking Hoxb8 .

To further investigate whether defective microglia cause the excessive grooming in the mice without Hoxb8, the mice were given bone marrow transplants from either normal mice or other Hoxb8-lacking mice. The theory was that a bone marrow transplant from normal mice would allow mice lacking in Hoxb8 to develop normal immune cells with active Hoxb8. If these cells were involved in this behaviour, the transplant might counteract the excessive grooming.

 

What were the basic results?

The researchers found that in the brains of normal mice, the only cells where the Hoxb8 gene was active were immune system cells called microglia. Adult mice lacking Hoxb8 had fewer microglia in their brains than normal mice.

When Hoxb8 mutant mice were given a bone marrow transplant with normal bone marrow cells, the amount of excessive grooming and hair removal lessened. Some mice fully recovered. The Hoxb8 mutant mice’s noxious chemical and temperature-sensing abnormalities were not corrected by the transplant. Mice that lacked Hoxb8 and received a transplant of bone marrow cells from other mice lacking Hoxb8 did not stop their excessive grooming and hair removal.

The researchers found that if they genetically engineered mice to be missing the Hoxb8 gene in their bone marrow only, they developed the excessive grooming behaviour but not the noxious chemical and temperature sensing abnormalities. However, if they genetically engineered mice to lack the Hoxb8 gene in their spinal cords only, the mice developed the noxious chemical and temperature-sensing abnormalities but not the excessive grooming behaviour.

 

How did the researchers interpret the results?

The researchers conclude that the compulsive behavioural disorder seen in mice lacking the Hoxb8 gene is associated with microglia – a type of immune cell located in the brain. This directly links mouse behaviour with the function of immune cells developed from bone marrow.

 

Conclusion

This type of animal research is used to further understand the biological basis of human disease. Improved understanding of which cells play a role in the development of a disease may eventually help treatment for human conditions, but this may well take a long time.

This research may give clues as to what type of cells may be involved in trichotillomania in humans, and is likely to spur on further research into the link between the immune system and this condition. Until this research has been completed, it will not be clear whether drugs targeting microglia might be a new way of treating this condition. As such, these findings do not have any immediate implications for treating trichotillomania.

The current study does not suggest that bone marrow transplants can cure mental illness. Bone marrow transplant was simply one of the techniques used to study which cells were involved in the mice’s trichotillomania-like condition. The findings are of particular interest because a link between immune system cells and these behavioural symptoms was unexpected.

Links To The Headlines

Bone marrow transplants cure mental illness – in mice. The Guardian, May 28 2010

Links To Science

Chen S-K, Tvrdik P, Peden E, et al. Hematopoietic Origin of Pathological Grooming in Hoxb8 Mutant Mice. Cell 2010; 141: 775-785

“Brushing your teeth twice a day could save you from a heart attack”, the Daily Mail has reported.

Its story is based on a study from Scotland, which looked at the potential association between how often people brushed their teeth and their risk of cardiovascular disease. It found that people who never or rarely brushed their teeth were 70% more likely to get cardiovascular disease than those who brushed their teeth twice a day. People with poor oral hygiene also had higher blood levels of specific chemical marker of inflammation, which is thought to increase the risk of developing heart disease.

This type of research cannot prove that poor oral hygiene causes cardiovascular disease as it may simply be that people who follow a healthy lifestyle also brush their teeth more. Equally, the results of this analysis were adjusted to account for this likelihood. The study is in line with other research suggesting a link between periodontal (gum) disease, inflammation and cardiovascular disease. Overall, this study does suggest that brushing may reduce the risk of cardiovascular disease in addition to the clear benefits of preventing tooth decay and keeping gums healthy.

 

Where did the story come from?

The study was carried out by researchers from the Department of Epidemiology and Public Health, University College London. It did not receive any specific grants from any funding agencies. The study was published in the peer-reviewed British Medical Journal.

Newspaper reporting of this research was generally fair, with most stories reporting the main result accurately – that people who reported poor oral hygiene had a 70% increased risk of cardiovascular disease, compared to those who brushed their teeth twice a day. The BBC correctly reported that poor oral had not been proved as a cause of heart attacks, as this study has found only an association between the two. The Daily Mail’s headline, “Clean your teeth twice a day to keep a heart attack at bay” ignored other established risk factors for cardiovascular disease, such as obesity and smoking.

 

What kind of research was this?

This study was based on data from the Scottish Health Survey, a cross-sectional survey undertaken every three to five years, of a nationally representative sample of the general population in Scotland.  Over the past two decades there has been increasing interest in a possible link between periodontal disease (i.e. gum disease and inflammation tissue surrounding teeth) and cardiovascular disease.  Most periodontal disease is associated with inflammation. It is now thought that inflammation in the body (including mouth and gums) is also associated with damage to arteries, which can in turn lead to heart disease.

While some smaller studies have looked at the possible association between confirmed periodontal disease and cardiovascular disease, this is the first large population study to look at self-reported oral hygiene and the risk of both inflammation and heart disease. Although this type of study on its own cannot prove cause and effect, the size of the study and the fact that the participants were followed for more than eight years on average makes the findings notable.

 

What did the research involve?

Researchers combined data from three of the Scottish surveys undertaken between 1995 and 2003, involving 11,869 men and women with an average age of 50 years. Survey interviewers and nurses  had visited Scottish households and collected data on demographics and lifestyle. This includes risk factors for cardiovascular disease, such as smoking, physical exercise, blood pressure and medical family history. People taking part were also asked how often they visited the dentist and how often they brushed their teeth – twice, once or less than once a day.

To find out what happened to participants over time, each survey was linked to a database of hospital admissions and deaths, which was followed up until December 2007. The study researchers used the database to look at the underlying causes at both the fatal and non-fatal cases of cardiovascular disease, heart attacks and admissions for bypass surgery. Blood samples were collected from 4,830 people who consented, and they were laboratory tested for two proteins called C reactive protein and fibrinogen, both of which are markers for inflammation.

The researchers then used established statistical techniques to analyse this body of information. They calculated the risk of heart disease and death in relation to frequency of toothbrushing, plus the association between oral hygiene and levels of inflammatory markers. Their modelling made adjustments to account for the influence of major factors that might contribute to people’s risk, such as smoking, obesity and family history. The figures were also adjusted for age, sex and socioeconomic group.

 

What were the basic results?

The researchers followed-up participants for an average of about eight years. Among the 11,869 people followed there were 555 (4.7%) cases of cardiovascular disease, of which 170 were fatal.  Most of these people were diagnosed as having coronary heart disease.

Importantly, the researchers found that:

• When all other possible influences had been taken into account, people who reported poor oral hygiene (who never or rarely brushed their teeth) had a 70% greater risk of cardiovascular disease, compared with those who brushed their teeth twice a day. (Hazard ratio (HR) 1.7 (95% confidence interval[CI] 1.3 to 2.3)
• By modelling the link between toothbrushing and inflammatory markers, the researchers say that the fully adjusted model shows a reduced rate of brushing is linked to higher levels of the two markers for inflammation – C reactive protein (ß 0.04, 95% CI 0.01 to 0.08) and fibrinogen (ß 0.08,95% CI  –0.01 to 0.18). This suggests a significant association.

The study also found that other known risk factors for cardiovascular disease, such as smoking and diabetes, had a stronger association than poor oral hygiene. For example, people who smoke had more than double the risk of cardiovascular disease than non-smokers.

Encouragingly, the researchers found oral hygiene to be generally good, with about 62% of participants reporting regular (at least every six months) visits to a dentist and 71%  reporting good oral hygiene (brushing teeth twice a day). Participants who brushed their teeth less often than twice a day were slightly older, more likely to be men, and of lower social status. They also had a high prevalence of risk factors including smoking, physical inactivity, obesity, hypertension and diabetes.

How did the researchers interpret the results?

The researchers conclude that poor oral hygiene is associated with a higher risk level of cardiovascular disease, and also with low grade inflammation. However, they point out that cause and effect is not yet proven. The results confirm previous findings that have found a link between gum disease (known to be mainly caused by poor oral hygiene) and cardiovascular disease. Experimental studies, they say, are now needed to confirm whether poor oral hygiene is a cause of cardiovascular disease or a marker for other risk factors, such as smoking.

Doctors, say the researchers, should be alert to the possibility that oral hygiene causes inflammation, and patients should be told that improving oral hygiene is beneficial, regardless of any relation to heart disease.

 

Conclusion

This is the first large study to look at a possible association between self-reported toothbrushing habits and the risk of cardiovascular disease. Its findings are in line with other studies showing a link between gum disease, inflammation and heart disease, although, as the researchers point out, it cannot prove cause and effect. Its analysis used data gathered from a large, rigorously-designed population survey that was linked to patient databases and followed people for a reasonably long period of time. It has also used recognised statistical methods.

However it should be noted that:

• although the study took account of other things that might influence whether people developed cardiovascular disease (such as smoking), it is possible that the results may have still been influenced by factors that were not measured or incompletely measured.
• Toothbrushing habits were self-reported, which could increase the chance of obtaining inaccurate data. The study did not look at clinical data on gum disease, although, as the researchers point out, previous research has shown a correlation between self-reported gum disease and clinical evaluations of the condition.

Another key point is that a 70% increased risk may sound quite large, but that it may be more useful to consider risk in terms of absolute rates, i.e. the actual numbers of people who might have been affected. Using the unadjusted figures:

• 59 people out of 538 (10.9%) who brushed their teeth less than once a day developed cardiovascular disease over about eight years
• 188 people out of 2,850 (6.6%) who brushed their teeth once a day developed cardiovascular disease over about eight years, and
• 308 people out of 8,481 (3.6%) who brushed their teeth twice a day developed cardiovascular disease over about eight years

This study did not establish a cause-and-effect relationship between oral health and cardiovascular disease. However, in theory these figures would equate to about 73 cardiovascular events in every 1,000 (10.9% minus 3.6%) being prevented by brushing teeth twice a day for eight years instead of brushing less than once a day (unadjusted). Expressed another way, only 14 people would need to do this for eight years to prevent one event (Number needed to treat =14). The analysis suggests that these people would probably have other healthy habits.

It is important to remember that good oral hygiene is important to help prevent gum disease and tooth decay, regardless of its effect on cardiovascular risk. Equally, following a healthy diet and doing regular physical activity are all important, proven ways to prevent the risk of cardiovascular disease.

Links To The Headlines

Brushing teeth ‘halts’ heart disease. BBC News, May 28 2010

Clean your teeth twice a day to keep a heart attack at bay. Daily Mirror, May 28 2010

Cleaning teeth boosts heart. Daily Mirror, May 28 2010

Links To Science

de Oliveira C, Watt R, Hamer M. Toothbrushing, inflammation, and risk of cardiovascular disease: results from Scottish Health Survey. BMJ 2010;340:c2451