Seven billion

Altogether now: 'Happy birthday to you, happy birthday to you...'

You've all seen the media coverage for quite a few days now as the world prepared to collectively sing 'Happy Birthday' to our planets 7th billion resident on 31 October 2011 according to the UN Population Division (disputed however by some of the boffins at the US Census Bureau). If you were to believe certain media outlets, there was a big clock somewhere in a control room either at the United Nations or the World Health Organisation, that was counting down the days, hours, minutes and seconds before flashing and beeping the 'it's official' birthday message. Think Jeff Goldblum and Independence Day - 'Times up'. The message supposedly being dispatched to a mother and child somewhere in the world; possibly to a country in Africa which apparently has one of the highest birth rates in the world (although I see the Philippines is laying some claim to the 7th billionth title as a consequence of being on the right side of the international date line). Lets hope the 7th billion tag does a little more for the child than the 6th billion tag did.

The BBC has quite a fun birth calculator (here) which provides you with a rough 'statistical' estimate of how many people were around on your birth date. For those of us looking back a few decades (yes only a few) it is quite thought-provoking to know that the population has increased so rapidly within a relatively short space of time.

The BBC (again!) carries an interesting series about the 7 billion figure and in particular the question of predicting what will happen to the numbers in future; click on 'Will people numbers stop rising?'. Watching this series and the various scenarios described I can't help thinking back to a recent entry on the Pharmaceutical Journal blog about prediction and an excellent quote from Physicist Niels Bohr: 'Prediction is very difficult, especially if it’s about the future'.

I will hopefully be still around for the 8 billionth birthday and will post again on this topic nearer the time, but can't guarantee too much after that. I leave you with a link to a question/answer that I (and every school aged child) have often wanted to know regarding how much 7 billion people weigh and what effect they would have on the planet?

Qigong and the Jedi massage

Please do not take any offence with the title of this post. I merely pass comment that Qigong, the practice of 'aligning breath, movement and awareness to restore balance', looks on paper similar to Qui-Gon (the Star Wars character played by Liam Neeson). Indeed I wouldn't be surprised to learn that George Lucas hadn't invented the character's name on purpose to be so similar given that ever-so skillful martial art-type philosophy and movements the hapless Jedi employed during the Star Wars saga. To any followers of Jediism, may the force be with you.

As you might imagine, some of the tenets of Qigong theory 'clash' with the more contemporary medical model of health and illness. I don't want to go too deeply into the reasons why (peer-reviewed evidence, etc) but it is perhaps as a result of this clash that Qigong and related schools of thought are often looked down on in comparison to the usual body-medicine-health evidence-based model. The word 'woo' tends to be used quite a bit.

Things seem to be changing however. A recent peer-reviewed paper caught my eye with regards to Qigong massage and autism which, I have to say, has slightly altered my opinion of the whole mind-body aspect. I should point out that I was never particularly adverse to the message of such things, particularly given the seemingly-evolving body of published work on 'mindfulness' in relation to psychology. A friend of mine, Chris Mitchell whose blog appears at the foot of this blog, has also written and talked quite a bit about his experience of mindfulness in relation to Asperger syndrome, which has also contributed to my interest in such concepts. Whether the effect is real or due to something else, I don't know, but if it works, it works.

The paper (full-text) by Silva and colleagues* describes results from a randomised-controlled trial (RCT) of Qigong massage delivered by parents to their young children with a diagnosis of autism (n=24) compared with a life-as-usual autism comparison group (n=18). There were a few other points of analysis regarding the use of home and dual programmes but I won't on this occasions travel too far into the wheres and whys because the paper is open-access and I don't have the time to make this a mega-post. Suffice to say, allowing for the relatively small participant groups and the possibility that more focused attention from parents on children might have played a role, the results did suggest some significant effects in the intervention group.

There are a number of potential messages to take home from this and other papers (admittedly from the same author group) suggestive of some effect. First is the role of occupational therapy to conditions like autism. I have previously sung the praises of good occupational therapy on this blog, which I assume is going to be the best discipline to help with such manual practices. Second is that like in other chronic conditions such as CFS, massage therapy and all that goes with it, is not necessarily the same as other complementary therapies. My coming from research which has looked at dietary intervention in relation to autism, I know a little bit about the 'label' of complementary medicine and the often 'negative' connotations that it brings. In this case, I offer no opinion on whether things like mind-body, energy or homeopathic schools of thought work or not for autism or anything else; rather that the patting, shaking and pressing movements of Qigong massage might produce tangible benefits for some children with autism (and probably their parents well-being also). Finally, I think there is a need for more experimental investigations of such hands-on therapies. Massage and autism to many conjures up images of Temple Grandin and her squeeze machine. I do also wonder whether some of the processes of Qigong massage could be incorporated into other early interventions and onwards what the cumulative effects on symptom presentation might be. Research and scientific method are the watch-words.

For now... deep breaths, relax those muscles and try to listen to your body.. your breathing, your heart beating, shutting out everything around you. Take it away** (but perhaps don't drive or operate heavy machinery anytime soon after this).

*Silva LM. et al. Early intervention for autism with a parent-delivered Qigong massage program: a randomized controlled trial. Am J Occup Ther. 2011; 65: 550-559.

** Renata Scotto & Mirella Freni "Canzonetta sull' aria".

Five serum metabolites and schizophrenia

This post extends my fascination with all things metabolomics, biomarkers and behaviourally-defined conditions. This is quite an apt post for me at the moment given that the all-singing, all-dancing Q-ToF mass spectrometer we have at work is currently receiving a little TLC from the appropriate engineer after a few days being under the weather (P.S. get well soon xxx).

I have previously talked about research presented on schizophrenia and the hunt for suitable biomarkers on this blog. Remembering back to the casein antibody link and the more recent offering on amino acids, a new study has just emerged by Yang and colleagues* with the rather interesting suggestion that just five serum markers (and one urinary marker) might be able to separate schizophrenia from not-schizophrenia equivalent to diagnostic interview.... read on.

The paper which is open-access is pretty comprehensive (aren't they always) but I will try and summarise the methods and main findings here:

• Serum and urine samples from Chinese participants diagnosed with schizophrenia (various onset psychosis) were compared with asymptomatic controls. The absence of diabetes, heavy alcohol consumption and being two weeks mood-stabilising drug free were prerequisites for study entry.
• Enrolled participants were allocated to a training set (N=124) or a test set (N=98). Sample combinations were analysed by gas chromatography - Time of Flight mass spectrometry (GC-ToF) and NMR. These methods and their important accompanying software, represent gold-standards in metabolomic analysis; the ToF bit gives you accurate mass of your compounds (mass-to-charge ratio of an ion) and the NMR, structural information about your compounds of interest.
• Principal component analysis (PCA) provided some information on how the various compounds related to the groups, and after applying a filter on the data, the detected compounds were whittled down to those which gave most discriminating power between schizophrenia and not-schizophrenia. 
• In the end five compounds detected in serum were deemed most important to discriminating schizophrenia in this participant group: glycerate, eicosenoic acid, beta-hydroxybutyrate, pyruvate and cystine. With this compound set, the receiver operating characteristics (AUC) were 0.945 in the training samples and 0.895 for the test samples. When a urinary compound was added to the set (beta-hydroxybutyrate), the AUC went to 1 (which represents a perfect classification) in both training and test sets.

OK you can perhaps see why this paper and its data is so exciting. Move over diagnostic interview, hello serum and urine analysis? The authors delve a little deeper into the compounds reported in their findings and their potential relationship to schizophrenia. At least three of the compounds recorded are tied into the degradation of glyceride and fatty acids which might point to energy metabolism as being implicated in schizophrenia. Some of this might (might!) also link back to related findings in certain types of autism and in particular talk of mitochondrial issues? Cystine is also discussed a little more in the paper and again, some familiar words to autism in relation to things like glutathione and homocysteine; I also wonder whether the findings of low cystine in urine and high in serum might also tie into some of the sulphation issues so unfortunately lost from the current autism research landscape.

As always there are some important things to say about this study before we get too carried away. First is the population used; all Chinese. Whether such markers are applicable to populations outside of China remains to be seen. Second is the relatively small participant group looked at and issues relating to any comorbidity which have not really been fully addressed. Finally are the comparisons of the findings with other, similar studies. The Rujescu findings mentioned in my last post on amino acids suggested that four amino acids might be discriminatory for schizophrenia. As far as I can tell, none of these amino acids, in either plasma or urine, showed up on the current paper (allowing for point one on different peoples and different profiles).

I will perhaps read and re-read the current paper just to make sure that I am seeing all that is being said. Likewise I might just flick through some of the autism research in this area (such as the Yap paper from last year) just to see if there are any other areas of 'overlap'.

* Yang J. et al. Potential metabolite markers of schizophrenia. Molecular Psychiatry. October 2011.

An ASBO for fizzy pop?

For my non-UK audience, ASBO refers to an anti-social behaviour order normally handed down by the powers that be to errant children and adults for a variety of delinquent behaviours. Whilst the above link to the Wikipedia entry for ASBOs lists what commonly comes under the heading of 'delinquent behaviour', there have been occasions reported on where ASBOs have been used for 'other reasons' like in this particular story.

A recent study by Sara Solnick & David Hemenway* suggests that non-human things might also qualify for an ASBO based on their potential association with the behaviour of our youth. The authors suggested that there may be a dose-dependent relationship between non-diet fizzy drink consumption and aggression and violence amongst 14-18 year olds schooling in Boston, USA.

The methods and findings:

• Based on the responses of nearly 1900 young people to a questionnaire on consumption of non-diet carbonated soft drinks over a week, respondents were put into a low consumption category (4 or less 12 fluid ounce cans per week) or a high consumption category (5 or more).
• Participants were then asked about their behaviour regarding aggression and violence towards family, friends, etc and whether they had carried a knife or a gun during the past year.
• Controlling for various other factors such as age, gender, sleep and alcohol consumption, high consumption of fizzy drinks was associated with more reported aggressive and violent behaviours. The increase was equivalent to what is normally seen when alcohol and tobacco are looked at in relation to anti-social behaviours.

Whilst being a study of association and carrying various potential forms of bias attached to things like retrospective self-reporting with no physiological measures to speak of, the suggestion from this paper (if true) has widespread implications. The prize for best headline on this story must go to the Yorkshire Post who report that 'teenagers more likely to pop on fizzy drink diet' (sigh). Not surprisingly various experts have pointed out that the causes of aggression and violence are likely to be multiple and triggered by lots of different factors, including social factors, and that too literal interpretation of these results is likely to simplify what is a very complicated issue.

Putting aside the multitude of variables potentially involved for one moment, I find myself drawn to the questions of why the authors got the results they did. Is it because those who drink lots and lots of fizzy pop are inherently more likely to be aggressive and violent, or is there some ingredient/s in these drinks which might, in certain amounts and in certain cases, exert some biological effect involved in the presentation of anti-social behaviours? Sugar, caffeine and other ingredients fall under suspicion although proving causation is entirely a different matter. Dr Emily Deans posted an entry on diet and violence earlier this year which alongside the 'Twinkie Defence' might provide some insight into the biological mechanisms (whether direct or secondary knock-on effects on other nutrients for example). Indeed without trying to medicalise or stigmatise any group, one has to wonder whether the results from a few years back on food additives and hyperactivity might also provide some clues to further study.

For now this research, whilst preliminary and in need of substantial replication, perhaps points to another reason, outside of oral hygiene, why 'moderation' should be a word coming back into fashion when it comes to our fizzy pop-filled culture.

* Solnick S & Hemenway D. The ‘Twinkie Defense’: the relationship between carbonated non-diet soft drinks and violence perpetration among Boston high school students. Inj Prev. October 2011.

Airways and autism

A brief post this one, based on some interesting, 'thinking outside the box' data recently presented at CHEST 2011 by physician Dr Barbara Stewart. For those (like me) not familiar with CHEST 2011, this is the annual get-together for the American College of Chest Physicians to discuss all-things related to chest medicine.

Dr Stewart presented a poster, the abstract for which is here*, which suggested that bronchoscopic evaluation of 49 children diagnosed with autism with a cough showed 'abnormalities' in the lower airways characterised by doubled branches or 'doublets'. I can't pretend to be an expert on such matters but I am reliably informed that if we picture the airways dividing like branches of a tree, one branch on one side and the other on the other side, a doublet is where twin branches come off together.

The whys and hows of these results, which were present in 100% of her participant group, are still a little hazy. Dr Stewart is cautious in her findings and the requirement for further replication of the work with a larger cohort and appropriate control groups. The speculation that this finding might be, quote: 'why the population of children with autism spectrum disorder are not truly athletic people' is perhaps a little premature. Appreciating that motor issues seem to be associated with some cases of autism, I don't yet know of any literature which evidences autism and athleticism not to be linked (if you do, please let me know). If there is a wider association between these findings and why people, generally, do not wish to be athletic...

I will be interested to see where this research leads. Not only do we have a potential correlator, physical correlator, being potentially tied to a behaviourally-presented condition like autism, where the word 'marker' might (might) be appropriate, one has to wonder how this finding ties into the day-to-day functioning of people with autism, especially those who might be prone to cough and other bronchial issues like asthma. Assuming that such a bronchial issue is a genetically-controlled (?) process, could this tie into findings in other areas like brain or gut or something related to embryological development? Who knows.

To end and following all the relevant 'elf and safety guidelines, how about some Money for Nothing?

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* Stewart B. Can bronchoscopic airway anatomy be an indicator of autism? Chest (Meeting abstracts). October 2011

Shiver me timbers and raise the mast

Whilst Johnny Depp is the latter day face of the Pirate set, I always thought that Errol Flynn was by far the best buccaneer, particularly with his role in the 1935 classic 'Captain Blood'. And while I would love to talk more about pirates, the seven seas and the infamous skull and crossbones banner, the title of this post actually refers to another sort of mast outside of the tall, nautical-related thing, mast cells, and their potential role in some cases of autism spectrum conditions.

If you want to read quite an extensive review of mast cells then look no further than here. If you want the Mr Men version that I tend to prefer, it might go something like this: originating in bone marrow, mast cells are found in various tissues and contain several amines including histamine and serotonin alongside various cytokines. When activated by allergic and possibly non-allergic immunogloblulins as well as other compounds including some viruses, mast cells release their 'inner' contents and the party begins. Mast cells and their activation have a huge research base behind them; one of the most recent investigations centres on the engineering of molecules to out-compete allergens.

When talking about mast cells in relation to autism, one name crops up quite a lot: Theoharis Theoharides based at Tufts University. Indeed there is some pretty useful information on Dr Theoharides' Faculty website about mast cells (with lots of nice diagrams) and the various research he has been involved with. In autism, two papers about mast cells predominate this post, here* and here**. Both papers are of a more 'review' type structure rather than fizz-bang experiments but both contain some interesting details:

• Allergy is something that had cropped up a few times in connection to autism; indeed I posted about the topic a while back. The overview of allergy research related to autism contained in both papers reviewed in this post suggests that it is a complicated picture made up of IgE-mediated allergy and other classes of immunoglobulin effects. As per usual in autism, no one-size-fits-all. 
• I was taken aback by the suggestion that 1 in 10 children presenting with mastocytosis or 'mast cell activation syndrome' also presented with an autism spectrum condition (as compared with 1 in 100 of the general pediatric population). If this is a reproducible finding then it might be an important one bearing in mind association and causation not necessarily being the same thing.
• Mast cell activation has been linked to lots of different things including permeability of various membranes such as the blood-brain barrier and the gut. Aside from the fact that lots of factors, different factors, are going to be involved in alterations of these complicated barriers, there are some interesting implications on how far 'upstream' mast cell activation might be in things like hyperpermeability of the gut (leaky gut). I note also that a lot of the general literature on mast cell activation and leaky gut centres on the primary role of stress. Psychology influencing biology? How about some of the behavioural or pharmacological measures to reduce stress and anxiety and any knock-on effects?

I kinda hinted that IgE might be a primary activator of mast cells but there may also be other compounds that also do a similar job in stimulating mast cells into action. So it was that when levels of the neuropeptide neurotensin (NT) potentially tied into mast cell activation, were measured in autism vs. controls. Levels of NT were elevated in the autism group. I was also interested to read that serum levels of beta-endorphin were not significantly different from controls and how that might (not) tie into some of the dietary findings in autism. Another post methinks.

The last word on any role for mast cells in autism should be 'interesting'. Interesting because a whole new world opens up on the physiological mechanism by which various stressors, biological and psychological, might be able to activate mast cells and onwards release a cascade of compounds and events tied into some pretty consistent biological ideas associated with at least some cases of autism. If mast cells are part of the complex biological picture of autism, the next question is what we do about them, indeed can we do anything about them and if so, what effect might it have on the presentation of core or peripheral behaviours associated with autism?

* Theoharides T. et al. Mast cell activation and autism. Biochemica et Biophysica Acta. 2011

** Angelidou A. et al. Brief report: "Allergic symptoms" in children with autism spectrum disorders. More than meets the eye? JADD. 2011

Autism and birth order

Being resident in the United Kingdom with its often quirky customs and practices, I know a thing about the power of birth order. Whilst offering no opinion on the rights and wrongs of our monarchy system, I do know that first born (sons) tend to get the lion's share when it comes to 'ruling over us' (with the same offer soon to be granted to first born daughters apparently).

The science of birth order has found some interest for lots of different things; potentially relating to our measured intellectual ability and our personality and disposition for example. I don't quite know if I believe such sweeping generalisations from this collected body of research, but I guess many of these more psychological differences might reflect the trials and tribulations of the family dynamic and that bullying big brother or sister.

Health has also come under the birth order spotlight. The idea that first born children are more likely to suffer with allergies, including food allergies than subsequent siblings, is an interesting concept potentially tied into things like the hygiene hypothesis. Parents of more than one child probably know already about the concept of 'bringing infections home to share' with siblings and what joys that can bring alongside the 'first baby being wrapped in cotton wool' effect.

A recent paper by Turner and colleagues* suggests that there may be more than a passing association between birth order and 'risk' of autism. The theory goes that depending on where you are in relation to your sibling/s, might determine some risk of autism or facet of autism. This is nothing new. For quite a few years now, various groups have suggested that in some cases, there may be a 'pattern' of risk based on your position in the sibling stakes. Some have linked this back to parental age; others have talked about genetics; others have talked about other factors.

Turner and colleagues approached this question in a slightly more 'mathematical' way than has been previously applied. The methods and results, bearing in mind that the paper is open-access:

• Three different cohorts were included for analysis, based on the AGRE, NIMH and Simons Simplex collections. AGRE and NIMH were primarily composed of multiplex families (families with more than one child presenting with autism) whilst the Simons Simplex was comprised of one child with autism, the other sibling not. The total number of families and children included was notable.
• Statistics were applied (rank-sum test, inverse rank-sum test, chi-squared) and suggested that for multiplex families (more than 1 child with autism) there was an inverse-V shape pointing towards the middle ranks being more likely to be diagnosed (particularly the second child) and in simplex families, risk is linear and increases with each additional birth, also potentially linked to gender. 

Before we get too carried away with these results (and the various biases included), it is important to understand that mathematical models and statistics are fine for looking at risk and trends in data in a theoretical sense, but when it comes to real life, the whole thing becomes a lot more complicated. I think back to the recent article on low birth weight covered in this post and the subsequent comments left by many parents of children with autism on many websites indicating their child's birth weight did not fall into that category. Lots of factors involved.

Still data like this, alongside other information, all adds to the body of literature. In these days of biological phenotypes of autism, this could represent an interesting variable. There is one little detail mentioned in the paper which I find very interesting: a possible role for epigenetics - changes in gene activity without changes in the genetic code - or to you and me, environmental factors. It works in flies and most probably works for humans too; although at this stage, I make no comparisons with the topic in question.

* Turner T. et al. Quantifying and modeling birth order effects in autism. PLoS ONE. October 2011.

Glad I MET you

Another choice paper has emerged from the MIND Institute on everyone's favourite topic, autoimmunity and autism. The full-text paper by Heuer and colleagues* (including Judy Van de Water and Paul Ashwood on the authorship list) looked at the the MET gene in mums of children with autism vs. controls and how variations to it may relate to the the presence of autoantibodies to foetal brain and the production of messenger cytokines.

For those of you who might not have met MET before (!) this is a gene which has attracted quite a bit of interest with regards to autism spectrum conditions down the years. The International Molecular Genetic Study of Autism Consortium (IMGSAC), which I am not entirely sure is still functioning following the move of one of the heads quite recently, published quite a bit on this gene and its possible connection to autism. This and other findings have been quite robust in their results. Even other compounds tied into the MET gene functions, such as hepatocyte growth factor seems to tie into some of the genetic findings of the gene. One of the most comprehensive overviews of MET that I have read is on this blog.

Dare I also mention a possible link between MET and gastrointestinal factors associated with some cases of autism?

Anyhow, the current paper discusses some further interesting developments on a possible MET-autism relationship. The basics and summary:

• Mums of children with an autism spectrum condition (n=202) were compared with mums of control children (n=163) as part of the CHARGE study. This means that the authors were about as positive as they were ever going to be that what they saw in their autism group was autism and the control group was not-autism.
• Mums' samples were assayed for a band pattern of maternal antibodies to foetal brain proteins (37 + 73-kDa) and genotyped for the MET gene, specifically the SNP associated with autism (rs1858830) and various cytokines and chemokines. 
• The results: 19 mums of children with autism (9%) showed antibody patterns to foetal brain compared with zero controls. Among this subgroup of 19, 11 were homozygous for the C allele SNP (remember back to my post where I mentioned zygosity... if you dare); 7 of the remaining were heterozygous for the SNP and 1 didn't show the variant. 
• Even among those mums of children with autism who were negative for the foetal brain band stuff, 28% were homozygous for the SNP, 43% heterozygous and roughly a quarter did not show the variant at all (29%).
• The authors conclude that the MET C allele frequency was higher in those mums of children with autism who presented with antibodies compared with those who did not show antibodies to foetal brain protein despite there being some overlap.
• Furthermore, those with the SNP (whether homozygous or heterozygous) showed significantly reduced MET protein levels compared with non-variant homozygous controls; albeit with variant (C allele) homozygous participants showing only slightly lower levels of the protein than heterozygous participants (whose mean amount figures don't appear to be given in the paper). 
• When comparing geneotype data and cytokine data, those with the SNP showed some significant correlation between their SNP, levels of the MET protein and the production of IL-10 (an anti-inflammatory cytokine). If mums were homozygous for the SNP variant, there was a 1.8 fold decrease in IL-10 although no specific data seems to be provided for the variant heterozygous group aside from a graph showing an almost comparable drop in IL-10 production. There were no other significant differences/associations with the other six cytokines/chemokines included for analysis.

I probably have not done the results justice with this brief summary but I hope you get the gist of what they found. It is a rather 'dense' set of results they produced and I have to admit, my head is hurting a little after going through them all so please do not take my word as Gospel.

The MIND Institute have been pretty much leaders on the analysis of gene-environment interactions in autism in recent times with a particular focus on the immune system. This is not another of their studies fitting into this category as opposed to the SNPs and vits study published earlier this year, given the current study focusing on genes controlling biochemistry. Having said that no-one, as yet, seems to be able to say where and how these SNPs might originate; whether it is just a chance, random phenomenon or something tied into environment, perhaps even when mums (and dads) were conceived? Should we be looking at grandparents also?

I note that the words 'genetic test' for autism risk have already surfaced on the back of these results. I am staying well away from this area for lots of reasons; not least because the results are not black-and-white and that this is more of an ethical area of discussion.

* Heuer L. et al. Association of a MET genetic variant with autism-associated  maternal autoantibodies to fetal brain proteins and cytokine expression. Translational Psychiatry. October 2011.

The people effects of the financial crisis

One of my 'other musings' posts this one but I will perhaps mention autism as a sideline.

If 2008, 2009, 2010 and 2011 will be remembered for anything, it will be the words 'global economic crisis' and 'austerity measures' reflective of the situation that we all seem to have found ourselves in. Whether these words will be forever linked to 2012 and beyond... who knows? Not being an Economist or anything related, I'm not going to get all political and try and discuss why we are in this position; merely to note that we are where we are and lots and lots of people are suffering as a result.

Perhaps one of the most long-suffering peoples caught up in this crisis are the Greeks. I'm not talking about their Government and other institutions who have overseen successive periods of growth and spending (and spending!), but rather the average Joe or Jane (Costas and Maria in Greek-speak) who have seen cuts in wages, services and jobs. Timely that another general strike begins there today. Many people seem eager to opine as to why Greece was particularly sensitive to the economic crisis but the bottom line is that it is the masses who suffer; and in many cases, the most vulnerable. A touch of irony that 'crisis' is a word derived from Greek as no doubt Gus Portokalos in My Big Fat Greek Wedding would have told us.

A recent letter published in the Lancet addresses another side-effect of the financial crisis in Greece, indeed probably the most important side-effect, the health and wellbeing of the Nation. The letter by Kentikelenis and colleagues makes a few eye-catching points about how the economic crisis is now starting to impact on people's lives not just their bank accounts and livelihoods. I was drawn to a few things:

• The rates of unmet medical and dental care increased pre-crisis 2007 to mid-crisis 2009; although the reasons were not necessarily just because of the affordability of health care.
• Health outcomes have worsened as reported by the escalating suicide rate and also numbers of cases of HIV infection coinciding with increased drug abuse and prostitution. There are reliable reports of individuals deliberately exposing themselves to HIV to benefit from the economic and social measures in place.
• Alcohol consumption seems to have dropped and drink-driving offending rates have decreased.

One should perhaps bear in mind that the data presented by Kentikelenis et al is predominantly based on comparisons between 2007 and 2009 before the 'real' austerity measures associated with the economic crisis started to bite.

Other reports add to the dark clouds over health in Greece suggesting that mental health is also deteriorating in many more Greeks, possibly (probably!) tied into the country's financial problems. This piece in Time magazine suggests that more people are seeking the help of mental health practitioners, with waiting times increasing for consultations for things like anxiety and depression. It probably does not help to see that mental health and social services which people are becoming ever more reliant on, will themselves also be cut/suspended as part of the snowball of austerity measures being put in place.

With all the cuts on-going, the question of what is being done for autism-related services in Greece is also at the back of my mind. Having conversed (quite a few years ago) with several people and organisations in Greece with a link to autism, the attitudes and service provision pre-crisis could perhaps most reliably be described as 'developing' at that stage. With the various austerity measures coming into place, it is perhaps incumbent on the Greek Government to ensure that the social and financial gains made in the area of autism and mental health in general, are not seen as an easy money-saving target, alongside the realisation that the health of the Nation, physical and mental, is the health and future of Greece.

Now back to Joanna Lumley and happier memories of the Cradle of Modern Civilisation...

* Kentikelenis A. et al. Health effects of financial crisis: omens of a Greek tragedy. Lancet. October 2011.

Birth weight and autism again (and again)

Following on from the news that low birth weight might put a person at greater risk of autism, there has been a flurry of activity on this topic. Lots of headlines about the 'increased risk' and lots of discussion about it on various social media and other platforms.

Lo and behold pretty much 24 hours after the 'hype' about the paper, details of another paper drop into my inbox, this time from Schieve and colleagues* published in the Annals of Epidemiology. After some more mathematical and statistical wizardry, Schieve and co. come to the conclusion that various birth factors might well be linked to some cases of autism but on the whole, ".. the contribution of many of these factors to the recently observed ASD increase is likely minimal".

I can't pretend to be able to offer a definitive overview of the mathematical model used in this recent study but they applied it to various pregnancy- and birth-related factors including: low birth weight (and very low birth weight), preterm births, multiple births, caeasarean section deliveries, breech presentation, and use of assisted reproductive technologies, all based on existing datasets. Their main message, that less than 1% of the observed increase in cases of autism is likely due to these factors.

Understanding that this paper does not rule out an increased risk of autism from various pregnancy and birth factors, it does suggest that the current data on such factors does not yet provide a satisfactory answer to questions of why so many more children (and adults) are being diagnosed with an autism spectrum condition. I may be looking at apples and oranges here (risk vs. reasons for an increase in numbers of cases) but ultimately increased risk is going to potentially tie into the wider argument on the numbers of cases.

Whilst not advocating that anyone place their universal trust in maths and statistics, particularly when applied to heterogeneous conditions like autism, I do wonder whether we are seeing another piece to the puzzle when it comes to investigating autism on the basis of phenotypes and clustering of symptoms and characteristics. My mind wanders back to the recent news from Prof. David Amaral on biological phenotypes and whether this is just one more factor to add to the array of others proposed. Such pregnancy and birth factors may be a major component of one person's 'route' to an autism spectrum condition; for others, an insignificant drop in an ocean of other risks.

* Schieve LA. et al. Have secular changes in perinatal risk factors contributed to the recent autism prevalence increase? Development and application of a mathematical assessment model. Annals of Epidemiology. 2011.

Birth weight and autism again

This is not the first time that the issue of birth weight in connection to autism has been discussed on this blog. Earlier this year a meta-analysis of various birth issues potentially linked to autism was published and blogged about which included birth weight, low birth weight, as a potential connector. The strength of that paper lay in the fact that it was a meta-analysis; so kinda the top of the tree level of inquiry.

The journal Pediatrics again publishes a study discussing the birth weight - autism connection. Jennifer Pinto-Martin and colleagues* report on a prospective population-based study that suggests that children born weighing less that 2kg (4.4lbs) may be five times more likely to present with an autism spectrum condition than those born heavier.

The details:

• A regional cohort of children (n=1,105) followed as part of the Neonatal Brain Hemorrhage Study during 1984 and 1989 were included for analysis. Infants weighing between 501 and 2000g were prospectively enrolled and followed through childhood into adulthood. 
• At 16 years old, just over half of the original group (n=623) were screened for autism based on either a previous diagnosis of autism or 'liberal' cutoff scores on the SCQ or other measure. Positive screens were detected in 117 of the 623 (18.8%). 
• Author diagnostic testing of a proportion of positive-screeners and negative-screeners was carried out when participants were 21 years old using those gold-standards, ADOS and ADI revealing that of 70 positive screeners at 16 years old, 11 (14.3%) were confirmed as presenting with an autism spectrum condition and 3 out of 119 negative-screeners (2.5%) met criteria for an autism spectrum condition.
• Balancing out positive and negative-screener results suggested an estimated prevalence rate of 5% for the entire cohort. This is compared with a 1% figure produced by the CDC back in 2006.

There are a few other details from this study which, whilst not significant at 5%, were nevertheless interesting. So the lower the birth weight, the higher the risk of autism and low birth weight was more often linked to autism in boys than girls. There are also some limitations set by the authors on the current dataset in view of the lack of normal birth weight control groups and the quite high loss at follow-up statistics.

I note that this study has again 'hit' the media headlines hard with places like the BBC reporting on it. With all due credit they also cite people like Prof. Dorothy Bishop who provides a good balance in that many children with autism are not born low birth weight and many low birth weight children do not have autism. Others have also discussed the important issue of low birth weight and learning disability as being perhaps a more primary relationship.

You can tell that this research, as with any longitudinal investigation, is a real labour of love for Pinto-Martin and colleagues. The results are interesting and due credit should be given to the possible 'risk' that comes with low birth weight without however getting too excited about the 'directness' of any relationship between autism and birth weight.

* Pinto-Martin JA. et al. Prevalence of autism spectrum disorder in adolescents born weighing <2000 grams. Pediatrics. October 2011.

Facial phenotypes of autism?

Since a small boy, many moons ago, I have always had a fascination with cars. I'm not talking about the inner workings of cars - I barely know a spark plug from a fan belt - but rather how the front of cars (lights, grill, etc) share more than a passing resemblance to faces and expressions of faces. Odd I know, but trawling the Internet it is a relief to know that others share this... this... 'interesting' hobby like this article in the LA Times on the 10 most sinister car faces. Seems Disney might have been on to something with the Cars franchise?

Putting aside whether you drive a 'sinister' car or perhaps a car with a more happy go-lucky face, the type of face cars have is very often a good indicator of the brand and other cars made by the same manufacturer. Without name-dropping most people would recognise a BMW face as a BMW face and a Ford face as a Ford face. But what about if you moved from the faces of inanimate objects to human faces. How about faces serving as phenotypes or 'markers' of conditions like autism?  

A recent study by Alridge and colleagues* (full-text) cropped up on my research radar. I was initially a little weary about posting on this study for fear of being misconstrued. Differentiating faces based on groups has a rather dark recent history and studies which attempt to classify in this way are always going to have this cloud lurking nearby. In the end I have decided to post and the Aldridge study details some interesting findings.

Because the paper is open-access I won't summarise in too much detail what was done and what was found. Suffice to say that 105 boys (n=64 with autism) aged between 8 and 12 years old were investigated using the 3dMDcranial System to map their faces. After some statistical wizardry, face coordinates and differences between them were used to see if the autism group could be differentiated from controls and whether there were any correlations between autistic faces and clinical and behavioural markers. The results: yes, 39 of 136 total linear distances were statistically significantly different between autism and control groups around the nose, philtrum and the eyes but the results overlapped between the groups. Authors also discussed a couple of sub-groups based on autism severity scores and diagnosis given that might be present.

I was interested to see that the authors suggested that the results seemed to match their clinical opinion of autism as per a quote: "This facial phenotype is similar to one we recognised clinically..". Interesting also on their link to the facial phenotype described and Kanner's original description of a 'beautiful face' being associated with some cases of autism.

This is not the first time this kind of research has been done. Then as now, the suggestion was that brain and other tissues develop in tandem with each other and there is much genetic and signalling overlap including Sonic hedgehog (which was mentioned a few days back in this post). I have often wondered about brain and other tissue such as gut tissue sharing some embryological connections also. Just a thought.

As the authors point out there are some limitations to this study. White males might well make up a large proportion of the autistic population but autism is not exclusive to them. I note that some exclusionary criteria were applied on the experimental group but I can find no mention of any other comorbidities such as epilepsy, other developmental diagnoses or other health complaints as being present or not. Maternal health during pregnancy and little things like any gestational complications/exposures/ factors are also absent from the paper. As has also been described in recent days, accurately gauging IQ in cases of autism might currently be more art than science, which might have quite broad implications for lots of autism research particularly those which use IQ as a factor in cluster analysis.

The final word on loving the face you have goes to Peter Gabriel and the fantastic Sledgehammer video.

* Aldridge K. et al. Facial phenotypes in subgroups of pre-pubertal boys with autism spectrum disorders are correlated with clinical phenotypes. Molecular Autism. October 2011.

At least two sides to every story

This is a blog predominantly about autism research but now and again I have been known to wander. One topic which I wander off into quite a bit is Chronic Fatigue Syndrome (CFS) / Myalgic Encephalomyelitis (ME)  as exemplified by posts like this and this. I wander into CFS/ME because, like autism, here is a spectrum of conditions asking more questions than answering them. One of the more 'heated' areas of questioning in CFS/ME has been around the various twists and turns of the XMRV story.

I'm not going to rehash the same stuff in this post but the main points focus on the almost operatic battle on the question of detecting XMRV: yes I can, no you can't. Yes we can find it in some samples from people with CFS/ME according to this article published in 2009*. No we can't, in this recent paper** which has gone hand in hand with a partial retraction and some discussions on various Internet sites which I am not going to cite in this post.

Up until a few days ago I didn't know all that much about the work coming out of the Whittemore Peterson Institute (WPI) led by Dr Judy Mikovits aside from what I read in cyberspace. I knew a little bit about the backstory: Dr Mikovits asked to leave and the continuing debate about why and what will happen to various research and grants. I know a little bit more now after seeing Dr Mikovits present some of her data and answer some of the questions about this whole story and where it might go next. As in the title of this post, there are always at least two sides to every story. Let me elaborate.

It was a fresh clear Autumnal Friday evening when Dr Mikovits made a presentation at the Education Centre of Sunderland Royal Hospital at the behest of the Sunderland & South Tyneside ME/CFS Support Group. The first impression I got about Dr Mikovits is that she knows her stuff. She is no stranger to research after all with a quite impressive publication record spanning her varied career, covering areas of HIV, product formulation and drug discovery and cancer research. Her work in HIV and retroviruses potentially tied into DNA methylation is perhaps most interesting alongside the now pretty well established link between some viruses and some cancers.

Her presenting style was slick, quick and pretty technical, going through the various stages of the XMRV story and some elaboration of the saga behind the headlines. A few points that I managed to jot down from her presentation:

• Whilst ME/CFS is a focus for the current virology work, she is interested in various other conditions under the umbrella of 'neuro-immune' which potentially share some overlapping features such as cytokine and chemokine abnormalities, inflammation, allergy and intolerances and oxidative stress. Epigenetics (changes in gene expression not involving alterations to the genetic code) was also mentioned. You guessed it; that also includes autism.
• We were given a crash course in human gammaretroviruses (HGRVs). Part of that focused on how these viruses might be involved in all manner of things including potentially interacting with other viruses. One or two interesting primate studies were also discussed including this one by Onlamoon and colleagues*** on disappearing viral and proviral signals in blood after a month of XMRV infection (latency and activation). Work by Makarova and colleagues**** on the low immunogenicity of the virus was also detailed.
• There was some suggestion of a signature 'footprint' cytokine and chemokine profile present in cases of CFS/ME positive for XMRV. This included: IL-8, IL-13, MIP-1alpha and MIP-1beta, TNF-alpha, IL-7, INF-alpha, IL-6, and GM-CSF. I can't readily verify this compound set, the numbers of participants it was based on and whether all were increased or decreased. I would imagine 'increased' given the functions of many being in response to viruses (and bacteria and parasites).
• Mention was also made of nagalase activity being elevated. I remember reading recently about some similar findings of nagalase being reported in cases of autism (here) albeit not formally published on. I'm not going too much further into this area because it is frighteningly outside of my competence and indeed takes CFS/ME and autism into some very unusual territory.
• The 'contamination' debate which is being widely discussed was also presented on. I can't claim to understand everything but I have the words 'plasmid contamination' and 'junction primer' scribbled in my notes if that makes sense to anyone.

The general impression I got, as a non-virologist, about the detection of XMRV and related viruses (as with any virus) is that it is complicated. It's not like saying we can detect this virus or other viruses like we can measure blood glucose levels for example. You need to avoid contamination (as we have seen recently in other areas of forensic science). You need to make sure your are using the right targets to detect the virus. You also need to think about where the virus is and how 'active' it might be (or not) and onwards whether you need to 'provoke' the activation of a virus ('provocation' can be construed in many different ways). In short it is a complicated procedure; much more complicated than I originally thought.

Dr Mikovits accepted that XMRV is probably not going to be the 'be all and end all' of CFS/ME as per the partial retraction of the Science paper. She did however stick to her guns about the potential involvement of other gammaretroviruses as perhaps a source of further investigation.

I don't claim to be an expert in this area of investigation (and speculation). Neither do I offer any view on who is right or wrong in this complicated area. What I do perhaps want to see more of is continued research done in this area as suggested by Lo and colleagues***** and their suggestions of a related polytropic family of viruses, related but not necessarily XMRV, which might be applicable to many more conditions outside of just ME/CFS. Just because the technology and methods might not be suitably honed to detect these complicated viruses, does not mean that they may not be there. The chicken and egg question is what came first: CFS/ME or virus?

As we have seen recently in Alzheimer's disease, there is a lot not known about the viruses we share our little rock with and how we interact with them and them with us.

P.S. I am only reporting what I heard. Don't shoot the messenger.

* Lombardi VC. et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science. 2009. 326: 585-589.

** Simmons G. et al. Failure to confirm XMRV/MLVs in the blood of patients with chronic fatigue syndrome: a multi-laboratory study. Science. 2011. September 2011.

*** Onlamoon N. et al. Infection, viral dissemination, and antibody responses of rhesus macaques exposed to the human gammaretrovirus XMRV. J. Virol. 2011. 85: 4547-57.

**** Makarova N. et al. Antibody responses against xenotropic murine leukemia virus-related virus envelope in a murine model. PLoS ONE. 2011. 6: e18272.

***** Lo SC. et al. Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. PNAS. 2010. 107: 15874-9.

Caspase the executioner

The very dramatic title to this post pays homage to the caspases and their role in the process of programmed cell death (apoptosis). Their 'executioner' label denotes their role in the cascade effect that ends the life of a cell. If, like me, you watch too many films and documentaries about Medieval England (don't we all?), you might picture the executioner as a hangman, face covered, being paid to go about his duties. Grim stuff indeed.

Enough of all that. Like many things connected to our very complicated human biology, the protease family known as the caspases are also involved in other processes outside of just cell death. One of these processes is inflammation and partially mediating inflammatory functions such as those linked to autoimmunity.

A recent paper by Siniscalco and colleagues* sheds some light on a possible role for the caspases in connection to autism spectrum conditions. There was always going to be some interest for me in this paper given the authorship group. When names like Laura de Magistris (she of the leaky gut) and Alessio Fasano appear, I tend to sit up and take note. Please don't take this as any kind of idol-worshipping or anything like that; merely some admiration for their collected works; sort of winners of an X-Factor for scientists (now there's a novel idea).

Anyway, I mentioned that the caspases are a group of enzymes with quite a few members. Within the family, various caspases have various different duties and show various different effects when things aren't quite as they should be. The crux of the current paper was to demonstrate whether caspase expression (mRNA and protein levels) were different in a small group of children diagnosed with autism compared with controls.

The answer bearing in mind the ever-so-small numbers included for study was yes, levels were different; and different across a few of the caspases. The messenger RNA (mRNA) levels were increased for caspases-1, -2, -4. -5. Caspases-1, -4, and -5 are important because of their connection with inflammation. Important also because the caspases need to work synergistically together in order to have their 'full activity'. When protein levels of the caspases were measured, caspases-3, -7, -12 were found to be elevated in the autistic group. Caspase-3, when activated, for example seems to play a role in neurodegenerative conditions such as Alzheimer's disease (AD) and its connection with the amyloid beta precursor protein (APP). The effect is described as an enhancing one, in that caspase-3 is in the thick of all those tangles and plaques noted in AD. Caspase-12 takes us back to inflammation and caspase-7 back to apoptosis.

Cumulatively, the various caspases examined and reported on, seem to imply inflammation and a role for the immune system in the cases studied. I am a bit baffled by the caspase-3 finding in light of the connection to AD in other work, which perhaps contrasts with what is known about APP and those wretched peptides in relation to autism. Having said that, I do realise that AD is a very complicated condition and the presence of caspase-3 may reflect other processes. So how about a possible link between caspase-3 and type-1 diabetes instead?

This is not the first time that the caspase family have appeared on the autism research landscape. Mady Hornig and colleagues (she of the recent carbohydrate metabolism paper) discussed caspase-1 in relation to apoptosis and neurodevelopmental damage in this paper from a few years back. This paper by Sheikh and colleagues reported caspase-3 as being a more direct marker of apoptosis being elevated in the cerebellum portion of the brains of people with autism. Cerebellum, autism, Eric Courchesne?

The caspases are an interesting family of enzymes, of that there is no doubt. Further large-scale trials are needed to confirm findings and subsequently to start thinking about when, how and why the caspase findings become relevant to autism and what can be done to modify any detrimental effects.

To forget all this talk about executioners, how about Huey and some News?

Siniscalco D. et al. The expression of caspases is enhanced in peripheral blood mononuclear cells of autism spectrum disorder patients. JADD. October 2011.

Vitamins and minerals: lost in translation

Vitamin D, vitamin C and the odd probiotic. That's the sum total of my daily vitamin/bacterial supplementation routine as a nearly-middle aged, borderline healthy man. Why just the three supplements? Well my diet is pretty varied, but I do live pretty far North in a place where sunshine is often in short supply particularly in the Winter months hence the vitamin D supplement just in case. I also want to keep supple and probably don't eat as much fruit as I should hence the vitamin C. My gut is my Temple and just to make sure that it stays like a Temple (quiet and serene) I take the probiotic. I take a relatively small dose of each at particular times every day (chronotherapeutics y'know) and whilst a very subjective observation, can often tell when I've 'gone without' for a while. I can hear the whispers already... hasn't he ever heard of the placebo effect? Er, yes.

Like many millions of other people around the world, vitamin (and mineral) supplementation is part of my daily dietary routine. Why did I start taking them? Well... erm, 'the research told me to Sir'. There is for example some evidence that vitamin D deficiency and supplementation could be associated with lots of different conditions and perhaps even more so for certain groups of people. Same for vitamin C. As for the probiotics, well with my borderline obsession with all things gut bacteria on this and my other blogs should be explanation enough. [Note: I'm not in any way, shape or form advocating any vitamin or mineral or probiotic use. If you need more information, speak to your healthcare provider].

Having said all this I am a firm believer in horses for courses and realise that my supplementation routine might not be for everyone, particularly for those sun-kissed, 5+ fruit and vegetable a day, healthy people out there. So it is with some recent publications which have not been easy on some vitamins and other nutraceutical supplements.  This paper by Mursu and colleagues* has received a lot (a lot!) of media coverage with some pretty sensational headlines like 'Are your vitamins killing you?' and 'We've been wasting a ton of money on vitamins and dietary supplements'. Of course when you look at what the study results actually report, you get a little more of a grounded idea of the findings which basically say that based on self-reported supplement use, there was a variably increased risk of mortality in older women (mean age: 60 years+) when supplementing with either a multi-vitamin or a few individual vitamins and minerals including iron, folic acid and copper. Without wishing to belittle what mortality actually means, some the risk was varied; based on the odds ratios detailed and what they actually translate into in terms of hazard. Some of the risk is described as dose-dependent. In other words, take more and your risk might be increased. Another detail of the study on the potentially 'positive' effects of calcium supplementation on reducing mortality for this age proband seems to have been lost in translation.

Now don't get me wrong, I am all for proper testing for safety and efficacy for everything from pharmaceutics to vitamins and minerals to probiotics even to dietary changes; everything, period. If you put it into your body, you should have the comfort of knowing that it does what it says on the box and does it in a safe a manner as possible including any details on other 'drug' interactions or contra-indications. I do however look at the press that this study seems to have received in some quarters and get the feeling that the findings are being somewhat 'beefed-up' from the original results to suit various purposes. Just me perhaps being a little neurotic.

A second study has emerged which again paints a slightly less rosy picture of the value of supplementation. Findings reported by Clarke and colleagues** suggest that some of the proposed health benefits of broccoli, the isothiocyanates, tend to be less pronounced if taken via supplement rather than the real thing as a function of their lacking an enzyme needed to metabolise them properly normally included in the vegetable.

I am actually much happier with the Clarke study; the way it was carried out and reported on (so far). Basically what it says is that Mother Nature knows what she is doing with our vegetables, fruits, etc. and whilst we all think we are skilled in the science of health and the production of 'synthetic health', we perhaps don't yet know as much as she does about the whole being greater than the sum of its parts. I can imagine a few in the medical and dietetics trades as well as the odd pharmacognosist who will see this as evidence for the message about vitamins and minerals being derived from food not supplements as being all important. That being said I, myself, am unaware of anyone who is regularly taking a broccoli supplement for anything.

I have touched upon the themes of 'association' and 'risk' in other posts on this blog. Association or correlation not being the same as causation works both ways in terms of positive and negative suggested connections. Certainly the study by Mursu and colleagues whilst interesting is no different to any other case. I'm not even going to get started on the self-report angle to the study and the potential pitfalls associated with recollection.

I suppose it all boils down to a few messages:

• treat your vitamins the same way you would your 'regular' medications (dose, side-effects, etc.),
• if you can get your vitamins and minerals from food, do so,
• always question any health claim and whether there are indeed published replicated effects (see this recent Nature blogpost),
• be proactive: research, research, research - don't take anything at face value (particularly sound-bites).
• the hazards of hazard ratios.

[Just in case you need to know, I have no conflicts of interests when writing this post. I don't have my own line of vitamins or anything, don't have any shares in vitamin companies and I am not knowingly on any council or other body with a vitamin promoting agenda].

* Mursu J. et al. Dietary supplements and mortality rate in older women. Archives of Internal Medicine. October 2011.

** Clarke JD. et al. Comparison of isothiocyanate metabolite levels and histone deacetylase activity in human subjects consuming broccoli sprouts or Broccoli Supplement. Journal of Agricultural & Food Chemistry. September 2011.

Progranulin and autism

I have forgotten the number of times that autoimmunity has been discussed in connection to autism spectrum conditions on this blog. I wouldn't say that I am obsessed with the topic; just quietly interested in how the lack of recognition of self, immunologically-speaking, seems to crop up time and time again in at least some cases of autism alongside the subsequent link to inflammation. I offer no opinion on the implications of such findings, and how 'universal' they might be to the autistic spectrum, but they certainly make for some interesting reading. Just in case you need some more discussion on this topic I present this paper (full-text) by Al-Ayadhi and Mostafa* on the the findings of low plasma progranulin levels in children with autism.

As previously mentioned, the amount of research coming out of the Saudi Arabia on autism has been thick and fast this year with some pretty novel associations being suggested. I note that they have even started to look at that most unusually named of compounds, Sonic Hedgehog Protein in relation to oxidative stress (here); fodder for a separate post methinks. The current paper on progranulin levels continues their research theme on the immune system and inflammation where previous observations have linked things like anti-ganglioside M1 auto-antibodies to some cases of autism.

A little bit of description might be useful to start with on what exactly progranulin is and why it might be important. The technical stuff about progranulin is here, but in as few words as possible: the granulins are a family of leukocyte polypeptides, some of which have cell growth modulatory activity, hence their suggested role in lots of things from wound healing to the creation of cancers. This paper suggested that levels of the source protein progranulin, might also serve as a marker for some of the components of metabolic syndrome but that's all I will say on that particular issue for now.

For the purpose of the current study, progranulin was examined in the context of being an anti-inflammatory neurotrophic factor with neuroprotective qualities. A few other details about the study and findings:

• Forty children with autism participated in the trial, all medication-free. Forty control children were also used as comparators matched for age and gender and free of any immunological condition.
• CARS was used to assess the 'level' of autistic behaviours in the experimental group; where levels of plasma progranulin were assessed in all participants.
• Children with autism had significantly lower levels of plasma progranulin (p=0.001) although there did not appear to be any link with symptom severity as judged by CARS scores, age or gender. Sixty-five percent of children with autism had reduced progranulin levels. It is interesting to note the surprising degree of 'homogeneity' of results from the autistic group compared with controls in terms of the dispersion of individual measured levels. 

These are interesting results allowing for the small participant group examined. The authors discuss the possible relevance of their findings and that too makes for some interesting reading particular when you would expect progranulin levels to be elevated if inflammation was present as some of the literature seems to indicate inflammation is in cases of autism. Does this mean that inflammation might not be present? I don't know but then an awful lot of other results must be wrong. Does this mean that genetically there might be 'glitches' in the pathways required to make progranulin in autism in response to inflammation? I don't know either but no data on this measure seems to exist at the moment. Looking at one parameter alone and in isolation does not tend to provide a very complete picture hence the need for further investigations.

As per the authors comments on the current paper, much more research is required in what is a novel area of investigation. Knockout mice model studies, where the gene for progranulin located on chromosome 17q21 (ring any bells?) is absent, have suggested some male-dependent behaviours potentially linked to the serotonergic system, bearing in mind mice are not necessarily the same as people. A small (very small) suggestion that some cases of schizophrenia might also be linked to mutations in the progranulin gene should also be noted. The Saudi authors discuss the possibility of progranulin therapy in cases of autism but I would be hesitant at best to support such a claim at the moment without lots and lots and lots more research being done on safety and the appropriate dosing.

* Al-Ayadhi LY & Mostafa GA. Low plasma progranulin levels in children with autism. Journal of Neuroinflammation. September 2011.

Toxoplasma gondii in the crosshairs

Source: PsychCentral

Today, Monday 10th October 2011, is World Mental Health Day. It's all about raising awareness about mental health issues. It is quite timely that this years theme is 'Investing in mental health' on the back of the quite startling figures recently published about the numbers and cost (personal and financial) of mental ill-health and the relative lack of funding and research on what causes it and what to do about it.

Anyway, I commerate the day with this post on schizophrena and an old friend.

This is not the first time that the topic of Toxoplasma gondii has graced this blog and probably won't be the last time either. What is perhaps so fascinating about this parasitic protozoa is its single-minded drive to survive (and replicate) and, as a result, its ability to affect animal behaviour by whatever mechanism.

Fine if you are a rodent I hear you cry. But when it comes to human beings, much of the recent chatter about T.gondii has been on its speculated links to conditions like psychosis, mood disorders and, in extreme cases, suicide. Presentation of schizophrenia spectrum conditions and the risks associated with T.gondii infection have also figured fairly prominently in the various discussions as a result of studies like this one and this one from Faith Dickerson and colleagues. A recent study by Pedersen and colleagues* published in the American Journal of Psychiatry has confirmed an association between T.gondii infection and risk of schizophrenia. Association is one thing; causation is another. I note that Dr Emily Deans over at Evolutionary Psychiatry has just posted about this study also.

The facts and figures:

• IgG-antibodies specific to T.gondii were measured in over 45,000 women in Denmark giving birth between 1992 and 1995.
• Women were followed up until 2008 for the presence of a schizophrenia spectrum condition.
• A positive association between T.gondii antibody level and risk of schizophrenia was found; with risk varying according to the strength of the antibody response. The overall risk was 1.68, although where antibody levels were highest, that rose to 1.73.

The conclusions from the study was that where antibody levels to T.gondii were highest so the risk of schizophrenia was highest.

There are some interesting points to take from the cumulative research on T.gondii. Not everyone who is infected with this little scoundrel will go on to develop schizophrenia or other conditions. Obviously there are other factors also at work. The immune system is the first place to look; how our bodies handle such infections, viruses, bacteria and how genes and environment might interact either in a protective or facilitative fashion. I touched upon this briefly with my post on the C4B null allele in relation to autism and a few other conditions. I note also this recent publication from Whitmarsh and colleagues** published in the journal Cell Host & Microbe which suggested that knockout mice (is this the right term?) might more frequently succumb to T.gondii infection when specific cytokine signalling molecules are absent; one factor probably among many. It is not as straight-forward as to say this molecule does this and this one does this; more likely a combination of multiple factors coupled with a cascade effect confer protection or not.

So there you have it, more evidence for the influencing factor of environment on our behaviour. Makes you wonder whether we should be looking more closely at some of the treatments for T.gondii and any potential onward effects for psychological symptoms? Or do we already have our treatment measures?

* Pedersen MG. et al. Toxoplasma infection and later development of schizophrenia in mothers. Am J Psychiatry. August 2011.
** Whitmarsh RJ. et al. A critical role for SOCS3 in innate resistance to Toxoplasma gondii. Cell Host & Microbe. September 2011.

Roger Moore's eyebrows, ADHD and coeliac disease

The 'overlap' between somatic conditions and those with a more behavioural or psychological set of characteristics is of great interest to many. When such associations become apparent, and bearing in mind the old mantra 'correlation does not imply causation', it offers a potentially unique window on how body and brain are linked and how affecting one system may affect the other. A previous post discussing the beta-blocker--autism study kinda hinted at the common thread on this blog: a potential anti-hypertensive effect might impact on cognitive organisation/ability (with the caveats that I am not in anyway condoning the use of any pharmaceutic for anything or offering medical advice).

I was therefore suitably interested when this study by Niederhofer (full-text)* cropped up on the PubMed radar on the possible overlap between ADHD-like symptomatology and an over-representation of coeliac (celiac) disease (CD); indeed also what happened to behavioural symptoms when a gluten-free diet was installed. The crux of the study was that in the population studied presenting with ADHD-type symptoms according to Hypescheme (n=67), fifteen percent showed markers for coeliac disease. When I say markers, I am talking about serological testing for anti-gliadin and anti-endomysial antibodies, of which there is still some debate about the best way to diagnose coeliac disease (see NICE guidelines here). Compared with the estimated general population rates of CD, anywhere from 0.1% - 2%+, the 14.9% presented in this study is Roger Moore as James Bond eyebrow lifting (I can't actually believe that there is a Facebook group for this) bearing in mind the small participant group included in the current study. Sir Roger might also lift an eyebrow at the results of the gluten-free trial undertaken following CD diagnosis, where behavioural manifestations seemed to show an improvement when on diet.

Despite the easy-to-pick flaws in the experimental design used, these results comes as little surprise. In previous posts I talked about the possible relationship between coeliac disease and autism and case studies like this one from Stephen Genuis which suggested that adopting a gluten-free diet might have behavioural connotations as well as physical ones, at least for some. The related research from Lidy Pelsser and colleagues on diet and ADHD might also tie in; although one has to caution about the lack of data on the presence of CD in the Pelsser cohort.

What is perhaps more important is what a gluten-free diet might actually be affecting in terms of behaviour. I tried (tried!) to make a case for gluten affecting the attention and hyperactivity comorbid aspects of autism in this post which is perhaps not a million miles away from what the current study is (I think) saying. The logical step in this argument is that any effect from diet in cases of autism might be mediated through such behavioural parameters; so affecting peripheral aspects to the condition potentially might impact on core aspects and the triad, sorry, dyad, of presentation. This is perhaps a theme that needs to be explored with greater assiduity throughout autism intervention research: what is intervention actually targeting?

Outside of such speculations, this study confirms one thing: ADHD like many other developmental conditions is complex and not necessarily rooted entirely in the old noggin. There may be a requirement to screen for coeliac disease when a diagnosis of ADHD is given... too much, yes/no?

To finish, and in tribute to the best James Bond ever (Connery was good, but Moore edged it), nobody does it better... or if you prefer, the Me First and the Gimme Gimme version.. [raise eyebrow and look to camera making some witty remark like 'I think he got the point'].

* Niederhofer H. Association of attention-deficit/hyperactivity disorder and celiac disease: a brief report. Prim Care Companion CNS Disord. 2011: 13(3)