Thursday, 29 September 2011

C4B null allele and autism

Big names in autism research was covered in one of my recent posts on this blog. At the time I did not want to name names, despite focusing on Prof. Sir Michael Rutter and his various observations on autism research and what we think we know about autism. In this post, I am going to name a name: the late Reed Warren and his various research on the C4B null allele in connection to autism.

I met Reed Warren only once, very early on in my autism research career. He was a Professor of Immunology (I think) based at Utah State University in the United States. I faintly remember that at the time of meeting him he was not in the best of health and sadly passed away not long after our meeting at a conference we were both attending. At that stage in my career, I will admit that whilst aware of his work, I did not fully understand the implications of it and how it fitted into my little corner of autism research. After doing a bit of reading around the topic over subsequent years, I now feel as though I can describe and discuss, albeit perhaps not with the same authority as Warren and his colleagues.

Here goes: what is a C4B null allele?

Well, we start at the major histocompatability complex (MHC) and its link to the immune system and its regulation. Within the genetic region occupied by the MHC, several genes for the complement proteins are found including the C4 genes which encode for the C4 protein. The C4 glycoprotein appears in two forms: C4A and C4B as a function of the C4A and C4B genes. Both versions of the C4 protein are similar in function and structure but also have some distinguishing features from each other.  The C4A and C4B genes are very polymorphic; that is there are various versions of the gene switched on or off which function to varying degrees depending on heterozygoisty or homozygosity. There is a good overview of heterozygosity here and its importance for genetic diversity; basically we all have two copies of a gene as a function of our paired chromosomes and depending on whether or not a gene is expressed the same or differently on each chromosome in that pair will describe the zygosity. It is quite possible for a person to carry what's called a null allele for the C4A and/or C4B genes, which basically means that the respective gene makes little or no C4A or C4B protein. If a person is homozygous for the null allele (the gene on both chromosomes is switched off), it means that the gene should make absolutely no protein. I know I have probably not done justice to the concept of the C4B null allele with this brief description, but as with many things related to genes, such things are never easy to interprete or explain.

The C4B null allele has cropped up a few times in the research literature in connection to things like type-1 diabetes, coeliac disease and cases of recurrent spontaneous abortion. It is perhaps with autism in mind, that most of the research has been done as witnessed by papers here, here and here. OK I hear you say, so what if a C4B null allele is present, what does it mean?

Well, this is where a degree of speculation takes over, as once again the limits of my competence are tested. It is important to realise that the presence of a C4B null allele is not exclusively tied into autism. Like many genetic findings, the relationships are complex and overlapping with other conditions and asymptomy. Warren and colleagues in their papers hinted at this in their 1991 paper, and instead suggested that the presence of a C4B null allele might lay the foundations for a genetic predisposition, compounded by other issues with the immune system and exposure to one or more pathogens. Their later paper published in 1996, whilst taking into account the relatively small participant numbers included, noted the greatest frequency of one (or both?) C4B null allele was actually found in cases of reading disorder (67.7%), followed by ADHD (56.5%) and then autism (48.9%) (controls = 20.3%). This would suggest that the C4B null allele may play a role in autism, but also in these other conditions.

Following the 'game changer' that was the results of the California Autism Twin Study, I think our view of genes and autism is undergoing a bit of a shift at the moment. Whilst being no great lover of the 'autism is totally genetic' hypothesis still being banded around by some, the C4B null allele and other genetic stories are still worthy of some consideration in some cases of autism. Indeed only very recently has the C4 gene come up again in relation to some speculations on mycobacterium paratuberculosis and autism.

In memory of Reed Warren and his contribution to autism research.

Wednesday, 28 September 2011

NICE guidelines on autism diagnosis published

A very quick post on the news carried by several sites that the National Institute for Health & Clinical Excellence (NICE) have published the first of three streams on the topic of autism spectrum conditions. The National Autistic Society (NAS) carry the news (here) but the full guidance on pathways to diagnosis in the UK can be downloaded here.

At the moment I haven't read the full document so will probably post again on this subject. There are two remaining strands of guidance currently still under development as discussed in a previous post earlier this year.

Tuesday, 27 September 2011

Appetite for anti-depressants?

How about this for a figure: over 1 in 10 people living in Scotland are taking an anti-depressant on a daily basis, excluding prescriptions dispensed to hospital inpatients. The number one prescribed antidepressant was citalopram taken by 3.2% of the population daily.

I read this on the BBC website following the publication of an audit on the prescribing of medicines used in mental health by NHS Scotland and the Information Services Division of the Scottish Parliament (full report available here). The data comes one day after my last post on the rise and rise of mental ill-health over physical ill-health.

There are a few other interesting details from the collected data including:

  • A growth in the prescription of drugs targeting the symptoms of ADHD; up 3.8% in one financial year. Methylphenidate tops the league of prescriptions, taken by 5,838 children in Scotland daily in 2010/2011.
  • A growth in antipsychotics and antimanic prescriptions; up 3.9% in one year. The number one dispensed antipsychotic was quetiapine.
  • A modest estimated rise in the prescribing of anxiolytics and hypnotics; up 0.3% in one year.

A spokesman for the Scottish Labour party, Dr Richard Simpson MSP describes the figures for antidepressant prescriptions as 'extremely troubling'. I perhaps would tend to agree. The question is: what do we do about it?

Monday, 26 September 2011

The financials of mental ill-health

Health is a funny old thing. The old adage goes that you don't realise how important good health is until you don't have it. For many people when they think of health, they generally think of physical health and the onwards connotations of disease, infection and other things related to doctors and hospitals. Modern day health and its word partner in crime 'well-being' (hyphenated or not?) however reflects much more than the various physical and somatic conditions that might affect us, it also encompasses our mental health and its consequences to our lives and indeed, to our physical health.

A few reports and studies led me to this post on mental health and ill-health worthy of some consideration and comment. Today (26/09/11) the BBC website links to a paper published in the The Lancet Oncology by Sullivan and colleagues* (many colleagues!) on the unsustainable financial burden of cancer care in the developed world. The figures banded around are absolutely astronomical in terms of the costs of care, medication and new technologies implemented on our war against cancer as more cases are diagnosed and more comprehensive treatments are developed. To quote from the authors: "we spend more because we can do more to help patients".

Contrast this with another couple of reports, the first from Wittchen and colleagues** on the size and burden of mental 'disorders' in Europe. The article (full-text available) suggests that Europe-wide the numbers of people with mental ill-health, covering a wide range of conditions, is high and represents Europe's largest health challenge in the 21st century. The financial costs: don't even go there.

The second report is this paper published by Ramin Mojtabai*** on the rates of self-reported mental health disability in the United States. The bottom-line: rates of mental ill-health are rising; over a 10-year period estimated at an extra 2 million people who reported mental ill-health in the US. Again the financials: don't even go there.

The point I want to make with these comparisons is that the monetary costs of our physical ill-health on things like screening, treatment and loss to the economy from things like time off work are significant and growing. Having said that the impact of a growing population reporting mental health issues potentially represents an even greater economic burden, which perhaps due to various issues such as 'not-knowing' what causes mental ill-health and how to effectively tackle it, will likely further stretch the seemingly dwindling National finances available. Please note that I am not saying that we should pit physical health against mental health in some kind of Doug McClure 'Land that Time Forgot' gladiatorial funding contest. Merely that we need to recognise how mental ill-health rivals physical ill-health in terms of numbers but funding for research and treatment may not necessarily reflect the parity.

The last word goes to Prof. Til Wykes, who last year, spelled out how bleak the situation was and might become: "In these austere times, it is worth bearing in mind that in England alone mental health issues cost us £77bn a year".

Food for thought.

Additional note 28/09/11: Tom Insel at the NIMH carries an interesting entry on his Director's blog about the global cost of mental ill-health (here).

* Sullivan R. et al. Delivering affordable cancer care in high-income countries. Lancet Oncology 12(10): 933-980. September 2011.

** Wittchen HU. et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. European Neuropsychopharmacology 21: 655-679. 2011.

*** Mojtabai R. National trends in mental health disability, 1997-2009. American Journal of Public Health. September 2011.

Sunday, 25 September 2011

Autism and Oxalate - rhubarb?

When trying to provide a simple description of what oxalate actually is, I am at a slight loss. I can provide you with quite a technical reference (here) showing a chemical structure, even complete with a ball and stick graphic but I don't think most people are really that interested in such an overview. This description is perhaps a little more user-friendly but still I am left slightly wanting.

Suffice to say that oxalate, a phytochemical, is a compound found in quite a few plants and vegetables (sometimes by another form, oxalic acid) and generally speaking does not seem to be a good thing to have too high a level of, particularly with its connection to kidney stones. There is quite a bit of history around oxalate and oxalic acid. I remember many years ago being told not to eat the leaves of the rhubarb plant because they were poisonous. So whilst rhubarb stalks are the primary component of perhaps the best ever dessert ever invented, rhubarb crumble, the leaves have been linked to some not-so-nice effects throughout history, with oxalic acid remaining a prime candidate.

Reading therefore a new paper by Konstantynowicz and colleagues (full-text)* including Susan Owens as part of the authorship team, that measured levels of urinary and plasma oxalate may be 2-3 times higher in children / teenagers with autism compared with non-autism controls is slightly worrisome news. I say worrisome but alongside their findings, the authors thankfully reported no greater evidence of the markers for problems with kidney stones to be present in their cohort. This is a relief given that the pain from passing kidney stones has been described as 'excruciating'. I cannot begin to imagine what this pain would be for a child if it has the ability to make grown men cry.

Susan Owens has long championed a role for oxalate in relation to some cases of autism as well as the possible usefulness of implementing a low oxalate diet. This document in addition to those previously mentioned gives about a good a description of any as to why oxalate may not be a good thing for autism (note that I am not providing any endorsement either way). The suggestion seems to revolve around values pointing either to a genetic predisposition to hyperoxalurias (endogenous synthesis perhaps) or potentially some issues with gut bacteria; various strains of the more 'beneficial' bacteria having been suggested to be involved in the safe disposal of oxalate. The latter explanation potentially tied to previous bacterial findings in cases of autism and the latest revelations from Brent Williams and colleagues. Interesting also that other gastrointestinal-related issues are also mentioned in the text of the article in question including inflammation, gut hyperpermeability and that old favourite sulphation.

As with the multitude of other findings related to autism spectrum conditions, the role of oxalate in autism is complicated. I do wonder about the 'calcium' connection with oxalate in view of how tightly it can bind to calcium ions and potentially 'drag' calcium away from various sites in the body - might it have some implications for bone health and beyond? The use of vitamin C is also another worry where oxalate levels may be high in light of some suggestion that supplementation might be a perpetuating factor for stone formation. Certainly in amongst all this, there is enough to suggest oxalate in relation to autism might be a 'watch this space' compound.

*Konstantynowicz J. et al. A potential pathogenic role of oxalate in autism. European Journal of Pediatric Neurology. September 2011.

Saturday, 24 September 2011

That's not a T-Rex its Chronic Fatigue Syndrome

Have you ever played that game where, on a semi-sunny day, you lay on the grass eyes skywards and try and fit cloud shapes to objects or people? Y'know 'that cloud looks like a T-Rex dinosaur' or 'that cloud looks like my great Aunt Matilda walking the dog'. Your interpretation might often be shared with your compadres, but more often that not our individual perception and sensation makes others sit-up and question 'Eh?'

Amongst the various descriptions, diagnoses and conditions discussed in this blog, one of the least well defined is that of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (CFS). Compared for example with autism, which has only two formal diagnostic definitions (ICD and DSM), CFS has at least three descriptions (here - see page 144 onwards) and very possibly more. More importantly that autism, as a defined condition, has a large degree of overlap between DSM and ICD versions (I always wondered why we needed both), whereas the criteria for CFS can be a little more nebulous.

Why is this relevant? Well, in order to provide accurate guesses at the numbers of people presenting with a particular condition at a particular time, you really need to make sure that they are all being 'graded' the same way in terms of definition of their symptoms. Clouds that look like T-Rex dinosaurs need to look like T-Rex dinosaurs to everyone.

An interesting paper* has appeared recently in BMC Medicine by Nacul and colleagues (open-access) on the prevalence of ME/CFS in various regions of England. The minimum prevalence rate was reported as 0.2% for all areas combined, with London showing the highest rate (0.31%) compared with other regions. Researchers however analysed more than just overall prevalence; they analysed trends in the estimated prevalence of ME/CFS based on various criteria used to characterise ME/CFS and found various similarities and differences as a result. The short introduction to the paper on the BMC website describes the paper as suggesting "..a new call to use definitions consistently will make it easier to classify sub-groups of patients according to treatment needs".

This paper and some of its findings struck a chord with me. One of the only times that I have ventured experimentally outside of autism research was when 'attempting' to categorise the symptoms present in ME/CFS in a paper published a few years back. I am not saying that our research was on a par with the latest BMC offering but we, like many other researchers, quickly discovered that CFS/ME is a mighty complex thing to pin down, not helped by having so many different criteria (and indeed overlapping conditions).

Whilst accepting that individuals often (always?) present symptoms differently even within the same condition/diagnosis and symptoms can 'move around' for lots of different reasons, standardisation of applied criteria is a cornerstone of accurate diagnosis. There is an argument that without it, diagnosis of that condition is always open to question and research into that condition is difficult at best as per one of my previous posts on the hunt for biomarkers for autism. I know that there are lots of very passionate public debates on-going in ME/CFS at the moment on various things from XMRV to researcher-abuse which on the whole tend to be as a result of just 'not knowing'. Agreeing on and implementing universal diagnostic criteria might just represent the first steps to tackling some of these issues and progressing research to make a real impact on many people's lives.

I end with an offer to walk the dinosaur with me... anyone, anyone?

* Nacul LC. et al. Prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in three regions of England: a repeated cross-sectional study in primary care. BMC Medicine. 2011

Friday, 23 September 2011

Disaccharidase levels in coeliac disease

It tends to happen. You have a particular study or topic on your mind and all of a sudden other related material seems to magically appear alongside it. Take for example my recent posts on carbohydrate metabolism and autism. Following on from some other related work published a few months back, the digestion (or problems with the digestion) of carbohydrates seems to be a rising point of interest in relation to some cases of autism. One would by the very least expect more research to be done in this area.

Then yesterday (22/09/11) this paper by Mones and colleagues* appears looking at the levels of disaccharidases in people with coeliac (celiac) disease (CD). I must admit that I don't have the full-text of the paper at present so am very much working on the summary abstract. What I gather from that information to hand is that disaccharidase deficiency seemed to be a fairly common issue in pediatric cases of CD examined by Mones; where the degree of damage to the villi, as scored using the Marsh criteria, is perhaps not as severe as partial or full villous atrophy. Indeed Mones and co. reported significant reductions in lactase, sucrase, maltase and palatinase in Marsh I/II categorised patients with CD.

Mones presented cases where the level of immunopathology was relatively slight (compared with the nuclear wasteland of Marsh IV pathology) yet overall carbohydrate metabolism was significantly impaired.  It has long been known that CD shows more than a passing relationship to disaccharidase deficiency and that the level of deficiency seems to increase according to the level of mucosal damage.

It is also fast becoming recognised that outside of what might be called 'classical' CD, there seems to be a 'spectrum' of gluten sensitivity which does not follow normal CD diagnostic markers yet still may benefit from the implementation of a gluten-free diet. The intestinal pathology accompanying these gluten spectrum conditions remains a little bit of a mystery but on the basis of what is being seen in CD and also in recent days, autism, perhaps there are a few clues as to what and where we should be looking.

* Mones RL. et al. Disaccharidase deficiency in pediatric patients with celiac disease and intact villi. Scandinavian Journal of Gastroenterology. September 2011.

Thursday, 22 September 2011

Is loneliness bad for your health?

A few weeks back I posted an entry on hikikomori, a 'condition' characterised by withdrawal from social life and the active pursuit of isolation for a period of 6 months or more. The gist of the post was that this phenomenon whilst having a cultural connection to places like Japan and Korea, might not necessarily be an exclusively socially-mediated condition as per the various explanations put forward for it but rather be reflective of other biological and/or psychiatric processes also involved.

This post got me thinking about lots of things, most notably what happens to the physical and mental health of those people undertaking hikikomori and whether the lack of physical contact might be detrimental to them and their overall health. The answer: probably, but its complicated. The New Scientist recently carried an interesting opinion piece about loneliness and how aside from the the psychological aspect to it, loneliness might be have some physiological effects also, at least according to John Cacioppo of the University of Chicago.

As with articles such as this one, there is always a quote which is designed to grab your attention. In the case of Prof. Cacioppo it is this one "curing loneliness is as good for your health as giving up smoking". Mighty big words indeed. But does the literature back him up and if so, what are the implications for states like hikikomori? Indeed what about the social aspects of autism spectrum conditions; are there implications to be had?

Whilst not wishing to turn this into some kind of mega-post on loneliness and physical health, there are a few studies to suggest some correlation between health and loneliness. I say suggesting some correlation, but as with many things, people don't just live in a vacuum, so it is difficult (impossible?) just to say that loneliness causes this, that or the other. Indeed, as per the paper by Shankar and colleagues highlighted above, loneliness may not directly affect health, but rather health behaviours, so things like smoking and exercise and diet. They do however make an interesting differentiation between loneliness and social isolation and note some individual correlations based on social isolation.

Cacioppo is not without some research interest in this area. As per the New Scientist article, a recent study of his indicated some interest genetic features potentially attached to loneliness in areas of stress and inflammation (inflammation is a key feature of some of his other work) suggesting some evolutionary mechanisms at work. For me the most tantalising aspect to this work is the suggestion that our behaviour, our biochemistry and our genes work in unison; so behaviour can guide our biochemistry much like the suggestion that it might guide our gut bacteria also.

As to autism spectrum conditions is there any overlap with this line of research? Well I suppose it depends on where you look. Outside of language, problems with social interaction is one of the primary features for a diagnosis of autism, although like many things, this varies from person to person. Certainly loneliness and feelings of social isolation are present for quite a few people on the autism spectrum, particularly adults, but the question of whether this is related to their autism or partly mediated by a lack of opportunities to engage in social activities like employment, social networks (not the computer variety), etc is fundamental to any question of causation.  As to the physiological correlates, well autism does have more than a passing relationship with inflammation in its various forms, but would it be too much to suggest that this is 'caused' by social isolation and loneliness outside of the myriad of other possible correlates?

Given the number of times I have used a question mark in this post, readers can perhaps see that this is an area requiring a lot more thought and research and I have very few answers to offer. What I perhaps would like to see more research on is how the social interactive side of autism links into loneliness, links into other health behaviours, links into things like depression links into inflammation. If (and it is still a very big 'if') there was some possible connection between these elements, can we intervene and would a doctor ever be able to prescribe social interaction and community as a 'cure' for loneliness? Would every person with autism necessarily want such a prescription?

Wednesday, 21 September 2011

Biomarkers for autism

Perhaps one of the primary stumbling blocks for the various strands of autism research is the lack of objective 'markers' to denote cases of autism from not-autism. Sure, we have the various diagnostic descriptions of autism based on observable behaviour and analysis of developmental history, and these do a pretty good job of providing diagnostic information. The problem however is that the 'label' of autism, whilst good for assessing strengths and weaknesses, accessing the relevant services and opportunities and in some cases providing an 'explanation' for the presentation of specific behaviours, is not actually a very objective and definitive concept when it comes to studying autism. Don't believe me? How about the relative stability / instability of autism presentation?

I must add that not for one minute I am suggesting that autism is not autism or there is anything wrong with the 'observe and checklist' method currently used; there is not - its the only thing we have at the moment and the clinicians who carry out such assessments are indeed skilled. My point is that the lack of markers outside of just presented behaviour is a significant hindrance to autism research and in particular the various searches for genetic and environmental factors potentially linked to the condition.

A new paper published in Nature Reviews by Walsh and colleagues* discusses some of the issues around biomarker research in autism. The paper is open-access and can be viewed here.

It is quite a good read and provides a good overview of the various challenges facing biomarker research in autism (or should that be autisms).  Issues such as heterogeneity, co-morbidity and the changing ideas of what autism is both diagnostically and culturally, are all covered in the paper. Gone perhaps are the days when autism was going to be diagnosed on the basis of one or perhaps two genes, compounds or anatomical structures to be replaced by something altogether more complex and multi-disciplinary. I am taken back to my post a few days ago on the presentation by Prof David Amaral and the sterling work at the MIND Institute on more than on 'type' of autism.

It strikes me that one of the ways forward in trying to determine biomarkers for autism is to concentrate less on a 'universal' biomarker for autism and instead similar to the MIND Institute model, looking at subgroups. Move away from the autism diagnostic label as your starting point and focus on other things, such as response to a particular intervention or strategy and compare your 'responders' and 'non-responders' to ascertain any biological/genetic/anatomical differences. Not only would this inform about which people on the autism spectrum might benefit from which interventions, but eventually one might assume that such markers would delineate those all important subgroups which might lead into some interesting areas.

Just a thought.

* Walsh P. et al. In search of biomarkers for autism: scientific, social and ethical challenges. Nature Reviews: Neuroscience. Vol 12. October 2011.

Tuesday, 20 September 2011

The legacy of Desert Storm

This post represents a little bit of a departure from the my normal autism research-related musings. The topic however is something that has cropped up during the course of my career on several occasions. Read on and see more.

Having recently commemorated the shocking events of 10 years ago on that fateful Tuesday morning September 11th 2001, the repercussions of those atrocities continue to reverberate across the globe. Whilst Afghanistan remains an active theatre of operations, the memory is still fresh from Operation Iraqi Freedom and the whys and wherefores of that conflict that left so many families devoid of loved ones. Casting your mind back further to the early 1990s, and in particular the conflict known as Operation Desert Storm, some interesting questions still remain outstanding on the health implications to military and civilian populations alike as a result of the 'Video Game War'. A recent paper by Lea Steele and colleagues* published in the journal Environmental Health Perspectives provides further evidence (adding to a growing body of research) suggesting that deployed military personnel experienced various illnesses potentially as a result of several exposures on and off the battlefield.

It is perhaps important to make a few points before proceeding. As well as being the first modern action to be broadcast live to the masses, remembering all those picture of Tomahawk cruise missiles being deployed from the coaliton battlegroup, the 1990 Persian Gulf War has been described as one of the most toxic wars in history. Saddam Hussein and his followers were known to use chemical weapons on their own population as exemplified by the Halabja attack; an attack which is thought to have used various chemical agents including mustard gas and the nerve agents sarin and VX. Although the picture is still fuzzy about whether such agents were deployed against coalition troops, the environment was always going to be a hostile one for lots of other reasons such as burning oil fields and various depleted uranium tipped munitions employed on top of the various other hurdles posed by a pretty inhospitable natural environment. Although the subject of some debate in a dwindling number of quarters, it does appear that many deployed personnel returned from the conflict in a pretty poor state of health; indeed even 10 years after, their health was still the cause of some concern. Termed, 'Gulf War Illness' or 'Gulf War Syndrome', the US Department of Veteran Affairs website carries quite a lot of information about what the syndrome includes. I am going to stop there on the background data because the research base to the condition is huge and could take up a whole blog in itself.

Back to the Steele paper. Their findings based on 144 veterans who met author specified criteria for Gulf War Illness suggested that several different factors and scenarios might have been instrumental to their symptoms depending on whether personnel were in active theatre or not. For forward deployed troops, reported proximity to SCUD missile explosions and the use of pyridostigmine bromide (PB) pills, also called NAPS (anti-nerve agents), were associated with illness. For support personnel not seeing front line action, the use of pesticides on clothing or skin were associated with illness.

Bearing in mind various limitations of this paper, the results are complex yet interesting. I have previously touched upon pesticide exposure in relation to autism and what the various classes of pesticides might be capable of so won't give much more space to this factor aside from what is already known about the health effects of DEET and lindane. PB pills have long been the source of speculation in terms of their potential health effects. Professor Mohamed Abu Donia has published extensively on the 'interacting' effects of pesticides and PB medication. As for the SCUD explosions, I don't know. It does perhaps make you wonder what the payload might have been in these missile particularly when you see what was potentially hosted at some Iraqi munitions dumps.

I mentioned at the start of this post about how Gulf War illness is something not unfamiliar to my time in autism research. One of the questions that has been asked over the years concerns what happened to the offspring of those veterans who were conceived after their service. Did those environmental exposures (and possibly others) so detrimental to the health of many of them have any effects on their children? How about concentrations of toxic trace elements and autism as discussed by this study** by Fido and Al-Saad based in Kuwait? Relevant or not?

* Steele L. et al. Complex factors in the etiology of Gulf War Illness: wartime exposures and risk factors in veteran subgroups. Environmental Health Perspectives. September 2011.
** Fido A. & Al-Saad S. Toxic trace elements in the hair of children with autism. Autism. August 2005.

Monday, 19 September 2011

Animal magic all in the amygdala

Children, generally speaking, are interested in animals. Not all animals and not everyone likes the same animals but show kids a dog, a horse or even an ant crawling on the ground, and it is most likely that you will get some kind of positive response. Take children to a wildlife park or an aquarium and for at least one animal, you can almost see the cogs whirring as they take in this living, moving object in front of them. I've seen it in action many times, most notably on a recent trip to an aquarium and the response to seahorses i.e. bewilderment. Indeed children are often interested in animals that don't even exist anymore. Nearly 20 years after Jurassic Park, dinosaurs and all things dino-related still have the ability to mesmerise (and terrify!).

A recent study by Florian Mormann and colleagues* published in Nature Neuroscience offers some clues as to why humans might be so interested in animals and our potential innate ability to notice and direct our attention to animals. I'm not the first to talk about this study by the way as witnessed by this entry by the BPS Research Digest. Anyhow, the study carried out on 41 patients receiving treatment for drug-resistant epilepsy involved mind-mapping of various parts of the brain. When it came to showing pictures of animals, neuronal activity seemed to peak in the right amygdala of patients; such activity later found not to be related to their participant's epilepsy. The authors concluded that such activity may be evidence for the amygdala as a dedicated part of the brain related to animals as part of our evolutionary relationship with animals as predators and food.

Whilst this was a relatively small study, Mormann and colleagues were very detailed in their examination of the participants involved and their mapping of the brain areas 'lighting up' in response to the animal stimuli over other things like people, landmarks and objects. The amygdala is part of the limbic system which, as described in a previous post on rats being attracted to cats, is thought to be quite an ancient part of the brain evolutionary wise. It perhaps makes sense that we would have a dedicated centre for animal recognition given our close relationship with them down the centuries over relatively new additions to our environment like buildings and everyday objects like telephones and TVs. Who knows in a few thousand years time we might have a dedicated brain centre for things like the computer (in whatever form it takes then).

This work could potentially offer some explanation why animals so strongly feature in relation to many conditions including cases of autism spectrum conditions. Interventions such as hippotherapy (horses not real hippopotamuses), swimming with dolphins and assistance dogs have all, at one time or another, come under the spotlight in relation to autism. I must admit that at times I have been a little 'snooty' about the claims behind individual interventions such as the dolphin therapy; assuming that any child, autistic or not, would probably enjoy some contact with dolphins and questioning how exactly such an experience might long-term affect the presentation of autism. If we are to extrapolate the Mormann findings to these experiences, could there be some kind of connection with the amygdala which has been suggested to show some relationship with autism? Who knows, but it does offer an interesting targets for further research and perhaps puts relationships like the one between Temple Grandin and her cattle-huggers into a new light.

To finish, children growing up in the UK in the 1970s-1980s perhaps will remember one man for making animals our friends, Johnny Morris. Animal Magic.

* Mormann F. et al. A category-specific response to animals in the right human amygdala. Nature Neuroscience. August 2011.

Saturday, 17 September 2011

Carbs and dysbiosis in autism reloaded

I have had a day to reflect upon the new paper by Brent Williams and colleagues published in PLoS ONE on carbohydrate digestion and dysbiosis in autism covered in my last post. I am still of the opinion that this is a 'game-changer' to borrow a phrase; not so much in the concepts it discusses which many have been talking about for quite a few years, but the fact that it is all bundled into a smart peer-reviewed package so perhaps making the research more 'accessible' to those working at the sharp end.

A few further details from the Williams paper are also noteworthy based on my very, very limited knowledge of the techniques used:

  • This was a study looking at 'bacterial community composition' in intestinal biopsies taken from the ileum and cecum. This is a new way of looking at the world of gut bacteria outside of the analysis of 'number twos' ('free fecal material' as the authors put it) more traditionally seen in autism research. It is however a more invasive way of looking at things also. I suppose it gives a more real-time picture of what is going on in various sections of the gut assuming that like human communities before the onset of globalisation, different ethnicities inhabit different parts of our tiny rock.
  • Decreased mRNA (messenger RNA) expression for dissacharidases and hexose transporters was a feature of the autism group analysis. In other words, the source material for enzymes such as sucrase isomaltase, maltase glucoamylase and lactase was not quite what it should have been in the ileal biopsies; nearly 75% of participants had combined deficiencies in all three enzymes. Quite a nice summary of the various hexose transporters can be found here. Two transporters were looked at in the study: sodium-dependent glucose cotransporter (SGLT1) and glucose transporter 2 (GLUT2). Two-thirds of the autism group were found to show deficiencies in both. Two-thirds of the autism study group had mRNA deficiencies in all 5 genes.
  • The 'ratio' measurements undertaken on bacterial communities pointed to some interesting findings. Decreasing Bacteriodetes and increasing Firmicutes or Proteobacteria were the main findings for the autism group, taking into consideration the different biopsy areas analysed. Further analysis of the Firmicutes directed the authors to Clostridiales which further directed them to specifics: Lachnospiraceae and Ruminococcaceae as being predominant. Lachnospiraceae has been linked to the introduction of high grain diets - at least if you are a beef cow. They also suggested that probiotic use might interfere with the bacterial ratios identified (included in a Table S5 just in case you want to see more).
There is an awful lot of information in this paper and unless you happen to be a molecular biologist with a combined degree in microbiology and enzymology, it is a struggle to get all that information out. I don't doubt that as this paper percolates through the various autism communities (lay and research) more details will emerge related to the findings and their significance. 

Whilst trying to remain as dispassionate and objective as possible on all things autism research, I still can't help raise a smile at seeing this work and the thought that something really did change following its publication. 

Carbs and dysbiosis in autism

Yes, its another quick post on gastrointestinal factors potentially being related to some cases of autism spectrum conditions. Indeed the paper at the centre of this post is, dare I say, perhaps one of the most important papers that I have covered thus far in terms of the research group involved and most importantly their findings. Strong words I think you would agree, so read on and judge for yourself.

Brent Williams and colleagues* have published a paper today in PLoS ONE on the subject of carbohydrate digestion and intestinal dysbiosis in children with autism. The paper is full-text and can be accessed here.

There is little point in me going through the paper in great detail 'cos it is open-access. I will therefore summarise what I see as the important bits.

  • Tim Buie is on the authorship list. You might remember him from various gastrointestinal (GI) related snippets in cases of autism spectrum conditions. The 'Autism Now' series on PBS NewsHour not so long ago. Lactose intolerance potentially being pretty widespread in some cases of autism. The AAP guidance on managing GI factors in autism. Not a bad list of achievements if I do say so myself.
  • A pretty well defined group of children with autism also presenting with GI problems (n=15) pitted against a control GI group (n=7). Participant numbers were fairly small so get ready with that pinch of salt.
  • The children with autism and GI problems studied may have altered genes involved in digestion according to the press release.
  • Microbial dysbiosis is present and potentially tied into the genes controlling the enzymes used to break down carbohydrates (dissacharidases).
  • Lots of different associations between various species of GI bacteria in the autism group. Bacteroidetes, Firmicutes and even some 'unclassified' bacteria present. Our old friends Clostridia were also noted with some important messages in relation to the timing of onset of GI symptoms. Importantly, they looked at 'ratios' between phyla/species and also looked in different parts of the gut. 
  • Author hypothesis: dissacharidase and hexose transporter problems alter the gut environment with regards to carb metabolism and provide a rich hungry hippo supply of material for bacteria to feast on and do their worst. A possible reason for the effectiveness of the gluten- and casein-free diet in some cases of autism? How about the specific carbohydrate diet (SCD)?

I am a bit tired right now (local time is past midnight) so perhaps will provide a more extensive overview of this paper outside of the Nosferatu period. Happy reading and good night.

* Williams B. et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS ONE. September 2011.

Friday, 16 September 2011

Assessing multiple associations in autoimmunity

Single nucleotide polymorphisms (SNPs) and/or point mutations have been a recurrent theme throughout various research on autism spectrum and lots of other conditions in recent times. The accumulated data on the subject seems to indicate several things: (i) we are all a product of mutation (whether we have autism or not), (ii) there are multiple mutations suggested to be linked to autism, although so far no one 'pattern' of mutation showing universal consistency, and (iii) the underlying reason why such mutations occur has not yet been elucidated although one would strongly suspect some role for 'environment', whatever that is taken to mean.

I say all this because a recent paper by Cotsapas and colleagues* published in the journal PLoS Genetics exemplifies SNPs in action and offers some new data on how shared SNPs across various conditions might indicate some shared effects particularly in some cases of autoimmune disease. The paper which is open-access looked at various conditions with an autoimmune component attached. This included: coeliac (celiac) disease, inflammatory bowel disease and type-1 diabetes; conditions which have been covered to varying degrees as being comorbid to some cases of autism.

Their findings based on some statistical wizardry, the cross phenotype meta-analysis, suggested that over 40% of the SNPs identified were associated with 'multiple but not all' immune mediated diseases. Interestingly they also summarised various interacting proteins encoded by the genes roundabout the identified SNPs which might implicate some shared disease risk. IL-12b and IL-23R were mentioned specifically.

I find this article to be an interesting one. It is fairly well known that your risk of developing an autoimmune condition is enhanced if you happen to suffer with one already. For example, those with type-1 diabetes are at greater risk of coeliac disease; something which a sister blogpost covered recently. Those with psoriasis are at greater risk of rheumatoid arthritis. The bonus value of the current paper is the way they approached the analysis of SNPs isolated in these autoimmune conditions in their analysis - 'assessing multiple associations to a marker'.

* Cotsapas C. et al. Pervasive sharing of genetic effects in autoimmune disease. PLoS Genetics. August 2011.

Thursday, 15 September 2011

Pycnogenol: the bark with a bite?

I start this post on pycnogenol (pic-noj-en-all) repeating my well-trodden caveats on me not being a medical physician, not giving medical advice and pleading that any interest in pycnogenol be first discussed with the appropriate health care practitioner. This last point is particularly relevant given the not-so-long-ago post on fatty acids and chemotherapeutics. I must also credit my interest in pycnogenol to Frances and her very informative emails (thank you).

A good description of what pycnogenol is and its various uses is here. A brief summary in less than 25 words: derived from the bark of the maritime pine tree, pycnogenol is a patented extract which has suggested uses for various different conditions. Indeed to give full credit to the patent holding organisation (Horphag Research), a comprehensive list of research covering its medicinal use can be found here.

Why am I talking about pycnogenol? Well because its an interesting compound and because amongst its very interesting effects, there are a few modes of action and conditions implicated which might tie into some of the other things discussed on this blog. The kind of effects I am talking about are things like it being quite a potent antioxidant, improving blood flow and possibly some effects on the immune system. All of these effects might tie into some cases of autism spectrum conditions and beyond as evidenced here, here and here (he says cautiously).

It is with Attention-Deficit (Hyperactivity) Disorder (ADHD) in mind that I found some interesting scientific duelling over pycnogenol. It all seemed to have started in the late 1990s with a few reports suggestive of some beneficial effects on symptoms, particularly concentration. This review covers some of them (alongside a few other snippets of research on its 'favourable pharmacological properties'). This was followed by several trials, double-blind, placebo-controlled, etc. which seemed to suggest a rather mixed profile in terms of effectiveness. So in this trial, neither pycnogenol nor methylphenidate outperformed the placebo. This trial said no, pycnogenol did significantly better than placebo. And so on and so on (accepting gender and age group differences between the studies). The mode of action in ADHD I hear you ask? Well, still under investigation but according to this paper (thanks Frances) by Dvorakova and colleagues, dopamine might be a primary target alongside other catecholamines.

When it comes to pycnogenol and autism, PubMed returns a big, fat zero for published articles; same goes with schizophrenia also. There are some anecdotes and discussion threads on it use but nothing experimentally concrete. This either implies that nobody is interested in looking at pycnogenol experimentally in such cases or no one is interested in looking at pycnogenol experimentally in such cases! Given the fairly often reported autism and ADHD comorbidity, and the fact that concentration problems can sometimes be an issue in some cases of autism, could we move things along and see if pycnogenol is truly the bark with a bite? After all remember the lessons from the willow bark...

Happy days for dyslexia

Arthur Fonzarelli aka The Fonz is perhaps the best known character from the show Happy Days, which just in case you did not know, was 'filmed before a live studio audience'. My memories of the Fonz... him walking in to Al's Diner real cool and banging the jukebox with that famous 'aayyy'.

Well the Fonz may well have closed his appearances on Happy Days but that does not mean that the actor who played him cannot still make headlines as today's revelation about Henry Winkler demonstrate. Mr Winkler received an honorary OBE (Officer of the Order of the British Empire) from HRH the Queen's representative recently for his various services to people with dyslexia as reported by the BBC.

In other reports from earlier this year, Mr Winkler discusses his own childhood and the problems he faced at school until his diagnosis received in adulthood. I have yet to cover dyslexia and related diagnoses on this blog but perhaps will at some point. For now, these are certainly happy days for the Fonz and happy days for the work he continues to do to raise the profile of reading and writing problems which a significant proportion of children and adults continue to face.

Wednesday, 14 September 2011

Road crossing behaviour and ADHD

Do you remember your Green Cross Code? If you lived in the UK during the 1970s or 1980s you'll probably remember the towering figure of Dave Prowse, he of Darth Vader, as the Green Cross Code Man and his message about pedestrian safety when crossing the road.

Over the years quite a bit of Government information and education combined with a fair bit of nudge theory has helped to improve child safety whilst crossing our ever busier roads. The fact remains however that quite a few children do still get hit by cars when crossing the road. The reasons why are complicated. Drivers not adhering to the speed limit, children being children and running across the road without looking. Lots of reasons. With all the recent chatter on wandering and autism (including that new ICD code), one could perhaps also see how specific groups of children might be at an increased risk of injury as a result of things like crossing the road.

A new-ish study* published in the journal Pediatrics looked at road crossing behaviour in children diagnosed with ADHD. The study by Stavrinos and colleagues used an artificial 'virtual' environment to analyse the road-crossing behaviours of 78 children (aged 7-10 years), half of whom were diagnosed with ADHD (ADHD-combined type), half of whom served as asymptomatic controls. Their results:

  • Children from both groups looked left and right before crossing. They also waited before crossing.
  • Children from the ADHD group tended to pick riskier places to cross, for example between parked cars.
  • The ADHD group had more 'close calls', so picking more risky moments to cross than the non-ADHD group.

The authors note that the children with ADHD were "...looking.. but they are failing to see". A few explanations have been put forward to account for the results; ranging from medication wearing off to problems with executive functioning (things like planning behaviour and impulse control). One perhaps can't rule out the artificial nature of the experimental conditions as potentially also having some bearing on the results; a danger-free road crossing virtual experiment is a little different from the 'real' world. Whatever the reason for the results, there are perhaps some important lessons that can be gleaned from such research. How we structure our roads and their surrounding environment, our developing educational material and strategies specifically for those with ADHD and other developmental conditions about risk in this and other similar situations, and also how we build our cars and educate our drivers to ensure that, should the worst happen, the car gives as much protection to the pedestrian as possible.

In the end remember: stop, look, listen think.

* Stavrinos D. et al. Mediating factors associated with pedestrian injury in children with Attention-Deficit/Hyperactivity Disorder. Pediatrics. July 2011

Tuesday, 13 September 2011

Chronic illness and healthcare for autism

Three articles caught my eye today in relation to some recurrent themes on this blog about autism not being protective of other chronic conditions and how some of the most 'disabling' aspects of autism are not necessarily due to the presentation of overt symptoms or comorbidities.

The first paper by Tyler and colleagues* examined risk for several chronic diseases including obesity, high blood pressure and high blood cholesterol levels in autism vs. matched controls. They suggested that hyperlipidemia in particular, set adults with autism aside from controls but importantly noted that anywhere from a fifth to a third of the autistic population surveyed presented with one of the chronic illnesses specified previously. I don't need to say much more about this paper aside from the words 'it's about time'. It has taken long enough for society to realise that conditions such as schizophrenia might place someone at greater risk of some of these issues. Now perhaps autism can benefit from similar health screening.

The next paper by Lai and colleagues ** perhaps ties into several things already discussed on this blog in relation to the effects of unmet health needs. Lai looked at dental health, finding that 12% of parents questioned said their child with autism had unmet dental needs. Even 1 in 10 children who had been to the dentist were reported still to have unmet dental needs. Whilst they suggested that behaviour was one 'barrier' to getting those needs met, they also suggested that unmet dental needs were present across the autism spectrum, implying ability and severity were not deciding factors in this health care 'hole' but possibly also other things like cost. Dental hygiene and health is fast becoming an important variable in several health-related matters. How about oral hygiene and your risk of cardiovascular disease? With autism in mind, I have previously touched upon the need for some sleuthing when trying to determine factors associated with self-injury and aggression.

The final paper by Parellada and colleagues *** is the more 'feel-good' paper reporting not on unmet health needs or risk factors but rather what can be done to make healthcare more accessible to people with autism. I need to find out more about this paper so as to make a more detailed post on it but first impressions are that they were doing a pretty good job in looking not just at autism as a triad (dyad?) of symptoms but rather a more rounded approach encompassing things like nutrition and gastroenterology. Indeed realising that you have a person first and a person 'with autism' second, is a key advancement to removing some of the barriers that a label of autism might bring about and therefore making healthcare accessible to all.

* Tyler CV. et al. Chronic disease risks in young adults with autism spectrum disorder: forewarned is forearmed. Am J Intellect Dev Disabil. September 2011

** Lai B. et al. Unmet dental needs and barriers to dental care among children with autism spectrum disorders. JADD. September 2011

*** Parellada M. et al. Specialty care programme for autism spectrum disorders in an urban population: a case-management model for healthcare delivery in an ASD population. Eur Psychiatry. September 2011

Monday, 12 September 2011

Not all good news for fish oils

I'm sure that you've all seen the headlines and hype about the humble fish oil and those yummy omega-3 fatty acids down the years. Good for the heart, good for developing foetuses, good for mental health. There is even some suggestion that it might be a useful complementary therapy for some cases of autism. Blimey! Why don't they just add it to tap water.

Well, there might be a good reason for keeping an open mind about oily fish and fish oil supplements based on a new piece of research suggesting some potential drug interaction. The study in question is this one by Roodhart and colleagues* published in the journal Cancer Cell. The main message has been summarised by various news sources but the BBC carry as good as any description. Cancerous tumours generally don't like to be destroyed by the various chemotherapy drugs currently on offer. One of the ways in which they develop resistance to one drug, cisplatin, according to Prof. Emile Voest's team, is via the production of two fatty acids, an n-6 (omega-6), 12-oxo-5,8,10-heptadecatrienoic acid (KHT) and an n-3 (omega-3), hexadeca-4,7,10,13-tetraenoic acid (16:4), so-called platinum-induced polyunsaturated fatty acids, which start a chemical chain reaction leading to resistance. I should perhaps also point out that these fatty acids are made endogenously via mesenchymal stem cells. Such fatty acids are also apparently "abundantly present in commercially available fish oil products".

The point Voest and colleagues are making is that additional fish oil supplementation may not be the best course of action when such chemotherapeutics are being taken; at least until more investigations are carried out.

There are lots of interesting points to be made from research such as this. Of course there are lots of reasons for drug resistance, some genetic and some more environmental. Hippocrates (I think) was quoted as suggesting that we let food be thy medicine. I don't fundamentally disagree with this notion, but highlight the possibility that food might also be our poison as is the case of gluten in coeliac disease, or for certain food constituents as in this case, at least contra-treatment. Diet or dietary supplements and drug interactions is an important point. Grapefruit for example, has quite a few noted adverse drug interactions, which either limit the effectiveness of medications or sometimes potentially much worse. There are others being discovered regularly.

Human biochemistry is a complicated thing. Most of us try to keep the body machine in good working order through diet, exercise and the odd supplement here and there. What research like this tells us is that when taking our medicine for whatever ailment, treat your dietary supplements like the drugs they are and check with your physician about any possible interactions.

* Roodhart JML. et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids Cancer Cell. September 2011.

A new first for British obesity

A few papers here in the UK ran with a story about obesity and an interesting, if slightly disturbing finding related to levels in the UK. A summary of the story in the Daily Mail is shown here, with the news that a recent survey from the Department of Health found that 4 English boroughs now have levels of obesity exceeding 30% of the population of that area. Why is 30% an important figure? Well, because that was the nationwide average predicted for 2025-2030 not so long ago (although it might get even worse).

Unfortunately Gateshead here in the good 'ole North East of England comes joint top with Tamworth, followed by Swale and Medway. A link to the NHS Choices website provides some background on what is obesity and how it is measured but the simple definition is a body mass index (BMI) greater than 30. The data by the way, is derived from the Department of Health, Health Profiles data.

There are a couple of interesting points to take from this news. First is the break with the commonly-used North-South divide. For my non-UK readers, there has for many years been an assumption that various health, social and economic differences exists in the UK (mainland UK) based on your geographical position - the 'North-South divide'. So, the more traditionally industrial North classically associated with heavy industry, manufacturing, the Industrial Revolution and working men's clubs is viewed differently to the more affluent, service and finance industries directed South. The difference between regional areas is never more stark than in research like this recent article from Hacking and colleagues published in the BMJ which ran with the headlines about the widest mortality gap for 40 years. The current top 4 obesity figures suggest at least that being a 'Northerner' or a 'Southerner' does not seem to protect/enhance your chances of becoming obese given the demographic data, although does not rule out socio-economic factors as being somehow involved.

Second are the various explanations reported on to account for the figures. I was struck by the use of the term 'obesogenic environments' attributed to Prof. Danny Dorling of Sheffield University (hopefully not misquoted). By that he means, a large density of fast-food outlets and few open spaces for exercise and recreation. If one is to believe this explanation accounting for the survey results, one accepts that obesity is purely a disease of lifestyle, or indeed culture (where other evidence suggests that it might not be that simple). Having visited Gateshead several times during my residency in this part of England, I would perhaps question whether it has a greater obesogenic environment than other parts of England. Fast-food for example is everywhere and as for open spaces, well I wouldn't single out Gateshead as being any more 'built-up' than any other part of the country, having green spaces such as the People's park and for all those hours of shopping on foot because of the ahem, parking issues, Newcastle Upon Tyne only a bridge away. The current Mayor of Gateshead offers another explanation for the Gateshead results and obesity in general: deprivation. He is also quoted (hopefully again not misquoted) as saying "We're bringing healthy food into schools. The children are happy to do without chips but it's the parents who make the decisions about what they eat for tea". His words not mine ('chips' by the way is the English term for a fried potato or french fries); although there's nothing like a sweeping generalisation. Pity the poor fried chip introduced into English culture in the 1860s-1870s as part of our national dish (fish and chips), perhaps a little time before our current obesity problems.

The survey figures are indeed a cause for concern in terms of the potential health implications to those people who are overweight or obese. I however would perhaps question whether the simplistic explanations and soundbites afforded to the data do it justice. In the end, obesity like many things, is very much more complicated than we think.

Saturday, 10 September 2011

EEGs and autism and a few other conditions

Science fascinates many people including me. I love the complexity of it, the technology behind it, the sheer enormity of it. The hospital and laboratory scenes of everyone's favourite unpronounceable physician, Dr Hfuhruhurr, kinda sum up science: flashing lights, bubbling test tubes, 'the cranial screwtop method' and brains [and the words 'get that cat out of here']. During my very earliest days in research, one area of brain science was always a marvel to me: conducting and interpreting electroencephalograms (EEGs).

I have never been physically present during an EEG but have had the opportunity to look as some of the raw data produced and it fascinated me. What is perhaps so interesting is that a person, suitably trained, can look at the various squiggles of an EEG and determine the presence of an epileptic seizure and also, depending on the activity of the EEG, diagnose different types of seizure even pointing to differing epilepsy-related conditions. I know of at least one physician who is skilled in this dark art. Yes, the Force is indeed strong with them.

I talked about epilepsy and autism in a previous post, although not specifically discussing the use of EEGs. When looking at the literature about autism and EEGs, there are quite a few interesting points to note about things like the comorbidity of abnormal EEG results and the presence of epilepsy in some cases of autism. Also are the various suggestions that EEGs might serve as a potential objective early marker of autism and possibly a few other things. Mmm, we will see.

The study at the centre of this post was published in BMC Medicine by Bosl and colleagues* a few months back (full-text available here). The suggestion was that a statistical algorithm applied to EEG results might be able to classify very young children as either typical developers or as being at-risk for developing an autism spectrum condition. The results whilst small-scale made a few media waves along the lines of 'it will change the field, if this works' (comment made by one of the study authors).

Of course autism, and the various issues around it, is never so straight forward. Guaranteed that with every giant claim about diagnosis, treatment, aetiology, etc. an opposing view will always emerge, and like a classical opera, scientific battle breaks out ('no you can't, yes I can'). In the case of Bosl and colleagues it was this paper** which appeared in the same journal a few weeks later, questioning some of the claims suggested. The main crux of the criticism seems to be about the use of high-risk at population levels vs. high-risk at an individual level.

Fair's fair there is an author response to the criticism of their paper, available full-text here. They do offer some explanation for why they chose to record and report their results as they did. Credit also to them in highlighting why the media took so much interest in the story: novel medical research + lots of public interest + practical implications = a good story.

Its not just autism that is getting the EEG-biomarker treatment; so is Chronic Fatigue Syndrome (CFS) with the publication of this paper (again full-text) by Duffy and colleagues*** published in BMC Neurology. There hasn't been time for a formal scientific criticism of Duffy's paper but I'm sure it will come eventually. I have to say that the sample size included in this recent CFS paper is pretty big: 70 patients with well-defined CFS, 24 with depression, 148 with general fatigue and 390 asymptomatic controls. With a large sample size comes greater study power and hence greater predictive value. Indeed Duffy and colleagues are talking about nearly 90% of unmedicated women with CFS and over 90% of controls being correctly classified using their method.

As an outsider looking in on the world of EEG use and research, I have to say that I am intrigued by the possibilities of EEG-derived biomarkers even if only as part of a suite of investigations. Aside from the fact that EEGs are fairly inexpensive to do and importantly not invasive like the recent data on motor skills, I would like to think that the electrical activity of our brains, or rather their patterns of activity, are just waiting to be decoded in much the same way as the analysis of any other genetic or biological system might hide various secrets about our human condition. At the very least, EEGs might provide a window on the effectiveness of interventions targeting the brain as exampled here with the antidepressant treatment response.

To end, Dr Hfuhruhurr imparts his pearls of medical wisdom.

* Bosl W. et al. EEG complexity as a biomarker for autism spectrum disorder risk. BMC Medicine. February 2011.

** Griffin R. & Westbury C. Infant EEG activity as a biomarker for autism: a promising approach or a false promise? BMC Medicine. May 2011.

*** Duffy FH. et al. EEG spectral coherence data distinguish chronic fatigue syndrome patients from healthy controls and depressed patients-A case control study. BMC Neurology. July 2011.

Thursday, 8 September 2011

Don't touch those salty balls

I, like a few people went through the 'South Park' phase quite a few years ago, watching the often crude exploits of Stan, Cartman and Kenny (and Mr Hankey) week on week. It was toilet humour, of this there is no doubt and I do wonder how many hours of my life I wasted on that show. Chef was also a prominent character in the early days of the show; remembered also for his number 1 hit song 'Chocolate salty balls'. It is hard to believe that sandwiched between the Spice Girls and Steps in late 1998, Chef was number one in the UK singles chart. This tenuous link (I should perhaps rename this site that) brings me to this post on salt and our evolutionary addiction.

The September 2011 edition of Chemistry World carries an interesting article on some research linking our ancient appetite for salt to our modern day societal addiction to drugs of abuse such as cocaine and opiates. The paper in question is this one by Wolfgang Liedtke and colleagues* recently published in PNAS. In it they claim to have identified the mechanism controlling our evolutionary appetite for salt and suggest that such a mechanism might be utilised by other addictive compounds, thus potentially explaining our societal fascination with some drugs of abuse.

I can't pretend to understand all the intricacies of the study by Liedtke and co, but the interpretation provided in the Chemistry World journal does make things a little easier. It is with this in mind that I draw a few details from said publication, properly referenced**, save any charges of plagiarism being levelled at me.

Evolutionary-wise salt is pretty vital to human existence. Indeed so vital was it to us that we built our cities near to deposits and wars have been fought over it. As with many things nowadays, you hear about salt being the bad guy in modern health and the onwards implication that we should halt our consumption. Maybe I am being a little melodramatic there because I don't think anyone actually thinks that salt should not be included in our diet; rather that we follow the tenet: everything in moderation. Certainly in these times, moderation is not necessarily a word at the forefront of consumption.

Anyhow, in the current study the genes activated by salt appetite in the hypothalamus were identified; some of those genes being the same as those regulated by drugs of abuse. After withholding salt from mice (sorry!), giving them a diuretic and increasing their salt appetite by administering the stress hormone ACTH, the researchers found that the hunger for salt made another area of the hypothalamus more susceptible to the effects of dopamine, hence making the mouse brain really, really happy when salt was eventually given. Dopamine has some pretty consistent relationships with drugs of abuse as per its reward hormone status.

Obviously this was another mouse study and one has to be careful about the interpretation. Indeed in light of some new research*** on laboratory vs. 'dirty' mice, perhaps very careful. There are a few avenues of interest from this research. The primary being that salt at higher concentrations might in certain people allow them to become addicted to overeating with the biological end-point as cocaine or morphine. With the right genes and the right environmental factors (low salt diet followed by high salt foods and stress) should salt also be called a drug of abuse?

To end, dare I post it.. take it away Isaac Hayes..

* Liedtke WB. et al. Relation of addiction genes to hypothalamic gene changes subserving genesis and gratification of a classic instinct, sodium appetite. PNAS. July 2011

** Senthilingam M. Appetite for salt linked to drug addiction. Chemistry World. 8(9) September 2011

*** Boysen P. et al. Natural killer cells in free-living Mus musculus have a primed phenotype. Molecular Ecology. September 2011.

Wednesday, 7 September 2011

Biological phenotypes of autism

Heterogeneity is a cornerstone of autism spectrum conditions. I don't like to use the snowflake metaphor because, lets face it, everyone is a snowflake (unique) whether autistic or not as a result of our genes, experiences and environment.

This heterogeneity is however a pretty major stumbling block when it comes to research into autism spectrum conditions and trying to determine anything approaching universal constants outside of the 'what-you-see' diagnostic label. Indeed forget universal constants, how about commonalities between sub-groups of people on the autism spectrum? Blogging now for just over six months, nothing has yet convinced me of anything universal uniting all cases of autism despite some indication of 'similarities' within possible sub-groups.

With all this mind, what would represent a step forward? How about being able to identify 'biological strains' of autism based on a few objective criteria outside of just behaviour? By strains, I don't mean to suggest that autism is a disease or akin to bacteria or anything like that, but rather potentially made up of various biological differences that may be common to more than one person on the spectrum.

Step forward an interesting news piece on the Autism Phenome Project and a presentation delivered very, very recently by Prof. David Amaral, the study lead at the 2011 Asia Pacific Autism Conference (APAC). I should at this point also thank Veronica Rousseau over at the Autism Researchers Link group on LinkedIn for bringing this to my attention.

At the moment there is no paper citation for me or you to look through. Just news and a speaker profile with some information about the talk in question. But the news, if accurate, is potentially quite exciting: two groups of children with autism, one characterised by regression and macrocephaly, one characterised by immune system problems. As Amaral says "The ultimate goal is when a child comes into the clinic, rather than saying you just have autism, to be able to say you have autism type A, or type B, or type C". Whilst this is exciting news for sure, a few parts of the newspaper piece did make me cringe a little. Suggesting for example that there might be different types of autism like there are different types of cancer whilst probably not intended in any negative light, slightly dilutes the message to be transmitted.

The primary implication from this work in progress if accurate and replicated, being that outcome can eventually be plotted against phenotype, so support and services tailored in the areas likely to be required for each phenotype. My obsession with the health comorbidity risks such as diabetes and coeliac disease might also eventually figure in this area. Interesting that at the same conference there is some chatter about the longer-term outcome of autism in what is a growing area of research interest. Intervention-wise, a brave new world is born, as person-specific intervention might come about through phenotype-specific markers.

We wait to see the formal publication of this work and where it takes us next.

BPS conference highlights

I am quite a faithful follower of the British Psychological Society (BPS) and their various efforts related to all things psychology in the UK. There is always some interesting tidbits in their monthly magazine 'The Psychologist' to catch the eye and Dr Christian Jarrett does a sterling job promoting psychological research on his blog BPS Research Digest seen at the foot of this blog. Don't get me wrong, I don't necessarily agree with everything psychological, including its various impact on autism down the years. But when it comes to thinks like Nudge theory, psychology plays its hand.

Today (7th September 2011) sees the start of the annual Developmental Psychology section conference coincidentally held here in the North-East of England. With it comes the inevitable press releases on what will be presented; amongst which are a few studies which caught my eye.

First is this work presented by Faye Powell from Loughborough University on the suggestion that family mealtimes might help children to become less fussy in their eating patterns. It has the obvious 'psychological' explanation attached to family social eating times with friendly 'mother-child' relationships trumping coercive pressure strategies. So carrot rather than stick works best apparently when getting children to eat new foods. I don't know why but whenever I see the words 'mother-child relationship' all I think about is Bowlby and attachment theory or baby ducks imprinting on mother ducks; the pinnacle of psychology speak.

The second presentation is by Dr Hayley Leonard and colleagues from Goldsmiths, University of London on poor motor development in early infancy for children at risk of developing an autism spectrum condition. Based on data from the British Autism Study of Infant Siblings (BASIS), her results suggest that both fine and gross motor skills were poorer in an at risk group as early as 7 months of age.

Both these studies are of interest to me and autism research. Powell's presentation whilst on more generic feeding patterns cuts to the heart of a big day-to-day issue for many children with autism (and their parents) in terms of feeding times and what a child will and will not eat. I'm not for one minute suggesting that all the various feeding problems associated with autism will be solved by eating together because they won't; eating problems occur for lots of different reasons in autism. The 'social' aspect to family mealtimes is though of some interest.

The Leonard presentation goes back to the first formal descriptions by Leo Kanner nearly 70 years ago now, and his astute observations of motor and movement problems observed in some of his patient group. Indeed even in the past few days, motor movements in autism have received research coverage. Assuming that the results are reliable and reproducible, they offer another potential non-invasive string to the bow of any would-be early detection system for the presence of an autism spectrum condition. It might also offer a few neural insights also.