Friday 30 August 2013

Schizophrenia and C-reactive protein

Discussions on the various studies hinting at a possible connection between inflammation (however you wish to define this) and autism, at least some of the autisms, have cropped up with increasing frequency on this blog (see here and here). I wouldn't go so far as to say that a causal link has been established yet; as in 'inflammation causes autism', or indeed 'autism cause inflammation' but inflammation. in it's various guises, is certainly one to watch.
Amusing the muses @ Wikipedia 

Outside of autism, and bearing in mind an increasingly vocal research voice suggesting common ground (see here) and connections between autism and other more psychiatrically-defined conditions such as the schizophrenia spectrum (see here), similar work also suggests a possible connection between inflammatory markers and other conditions.

Indeed today's post is dedicated to some of the cumulative work looking at schizophrenia and inflammation, and in particular one of the more reliable markers of inflammation, C-reactive protein (CRP) linked to all manner of health ills (see here for example).

I arrived at this post after reading the paper by Lin and colleagues* and their assertion that subject to much more confirmatory research being required, cases of schizophrenia which were also following a medication regime (antipsychotic meds) seemed more likely to present with elevations in CRP. The medication element to the study reflects some interest in how antipsychotics might be able to affect the CRP measure, bearing in mind the results are still fairly limited in this area (see this paper by Diaz and colleagues**).

The paper by Miller and colleagues*** provides a pretty good summary of the various research undertaken so far on CRP and schizophrenia. They concluded that there was "a 28% prevalence of an elevated CRP level in patients with schizophrenia and related disorders" and onwards quite a strong implication of increased inflammation being associated with schizophrenia. Importantly as per the autism example, this does not necessarily mean that inflammation is causative of schizophrenia or vice-versa.

It is noteworthy that a name which has appeared more than once on this blog has also thrown their research hat into the schizophrenia-CRP arena. Faith Dickerson (with a mention for Robert Yolken too), famous around these parts for her various studies on schizophrenia with the gondii in mind (see here) and a few other potential important associations (see here), also suggested that CRP levels tended to be on the higher side in cases of schizophrenia****. They reported that even after adjusting for various potentially modifying variables such as smoking status (see here) and body mass index (BMI) (see here), CRP levels were elevated in their participants with schizophrenia above and beyond asymptomatic controls and even those diagnosed with bipolar disorder. That bipolar disorder bit has also been explored a little bit more with CRP in mind too*****.

Importantly Dickerson and the other authors included in this mini-review post highlight how elevated CRP outside of any direct connection with either the onset or perpetuation of schizophrenia might place a person at enhanced risk of various health-related issues (see here). Without wishing to sound too morbid, heart health in schizophrenia for example, does not seem to have a great track record as per some previous discussions on this blog (see here). That finding perhaps as part of a greater package of issues with physical health screening and mental illness (see this paper from Barley and colleagues******) and some inequality which appears to be present.

Just before I go, I wonder if it would be worth mentioning a few other potential points of interest which perhaps require some further investigation. I touched upon the topic of homocysteine - the big 'H' - and schizophrenia in a previous post (see here) and also an intersecting area dealing with folate metabolism (see here). Homocysteine, whilst still the topic of some debate, was at one time talked about with issues related to things like cardiovascular health (see this paper by Wald and colleagues*******). Appreciating that humans are very complex creatures and sweeping generalisations about one compound = risk of one disease seem to serve little use, one might choose to enquire whether CRP levels might correlate with homocysteine and whether this clarifies any health-related relationship or not? Something along the lines of this paper but with larger participant numbers and without the interfering variables. Indeed as per another Dickerson paper******** whether CRP plus [insert variable of your choice here] might provide further insights into how CRP levels could even affect some of the facets of schizophrenia itself.

And very, very finally and quickly, I do wonder about the questions raised by Berk and colleagues********* (open-access) bearing in mind no medical advice is given or intended.

To close, are you just living for the weekend?

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* Lin CC. et al. Increased high-sensitivity C-reactive protein levels in Taiwanese schizophrenic patients. Asia Pac Psychiatry. 2013 Jun;5(2):E58-63. doi: 10.1111/appy.12078.

** Diaz FJ. et al. Possible effects of some antipsychotic drugs on C-reactive protein in a drug-naïve psychotic sample. Schizophr Res. 2010 Aug;121(1-3):207-12. doi: 10.1016/j.schres.2010.06.002.

*** Miller BJ. et al. C-Reactive Protein Levels in Schizophrenia. Clin Schizophr Relat Psychoses. 2013 Feb 21:1-22

**** Dickerson F. et al. C-reactive protein is elevated in schizophrenia. Schizophr Res. 2013 Jan;143(1):198-202. doi: 10.1016/j.schres.2012.10.041.

***** Dickerson F. et al. Elevated C-reactive protein and cognitive deficits in individuals with bipolar disorder. J Affect Disord. 2013 May 17. pii: S0165-0327(13)00340-6. doi: 10.1016/j.jad.2013.04.039.

****** Barley E. et al. Interventions to encourage uptake of cancer screening for people with severe mental illness. Cochrane Database Syst Rev. 2013 Jul 16;7:CD009641.

******* Wald DS. et al. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002 Nov 23;325(7374):1202.

******** Dickerson F. et al. Additive effects of elevated C-reactive protein and exposure to Herpes Simplex Virus type 1 on cognitive impairment in individuals with schizophrenia. Schizophr Res. 2012 Jan;134(1):83-8. doi: 10.1016/j.schres.2011.10.003.

********* Berk M. et al. Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness. BMC Med. 2013 Mar 18;11(1):74.

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ResearchBlogging.org Lin CC, Chang CM, Liu CY, & Huang TL (2013). Increased high-sensitivity C-reactive protein levels in Taiwanese schizophrenic patients. Asia-Pacific psychiatry : official journal of the Pacific Rim College of Psychiatrists, 5 (2) PMID: 23857813

Wednesday 28 August 2013

NICE guidance for managing children with autism

"The circle is now complete".

Like the end of another very famous trilogy (the original saga if you please), NICE, the National Institute for Health & Clinical Excellence or should that be the National Institute for Health & Care Excellence based here in good old Blighty have completed their evidence-based look at the autism spectrum disorders (as per the quite recent DSM-V diagnostic title) and formally published the last in their triad of guidance: Autism - management of autism in children and young people (see here). This follows my posting of the draft guidance (see here).

I've talked about the other strands of NICE guidance for autism before on this blog, covering pathways to diagnosis and autism in adulthood including the issue of medication and core symptoms. To recap: here in the UK, NICE are charged with providing the evidence-based clinical guidance on what does and doesn't work for diagnosing and managing all manner of health-related conditions.

With autism in mind, NICE were charged with trying to make some sense of the myriad of research results produced on the topic of autism, and offer something like a coherent set of national standards for autism; in particular focused on the core symptoms of autism. Not an easy task when faced with such a heterogeneous diagnosis complicated by all manner of possible comorbidities.

So what does the guidance suggest?

  • Well, despite covering a sizeable proportion of all manner of autism intervention and management strategies, the message is a familiar one: a dearth of authoritative data on what might and might not work but social-communication strategies offer probably the best option including focusing on joint attention.
  • I'm very pleased to say that throughout the document is recognition of the fact that autism can and does present alongside comorbidity and such comorbidity can affect symptoms including the so-called challenging behaviours.
  • Anxiety receives some welcome attention, although I'm slightly hesitant to endorse the suggestion that CBT (cognitive behavioural therapy) should be the preferred route of tackling such anxiety. Talking therapy might very well have some effect for some people, but as per the study by Mazurek and colleagues (see this post), there's still a gap in the knowledge base about the role that anxiety plays when it comes to autism.
  • I'm sure that some people will have picked up the guidance that neither antipsychotics, antidepressants or anticonvulsants should be used to manage the core symptoms of autism similar to the adult guidance.
  • Even more that exclusion diets (including gluten- and casein-free diets - GFCF diets) should also not be used in the context of managing core behaviours. Personally, I'm OK with this. As per the more detailed guidance, the evidence for use of GFCF diets is still wanting in terms of methodological quality (including my own contributions to this area). That combined with the possibility that such diets might be targeting more peripheral areas of functioning such as inattention and hyperactivity (see this post) which then have a knock-on effect suggests that we aren't quite there yet in bring dietary intervention 'mainstream' into management guidance. The suggestion that more work needs to be done in this area should hopefully move dietary intervention up the list of research priorities... hopefully, as per recent investigations. And to quote: "You may also be offered a special diet to help with problems other than autism".
  • Transition from child to adult services also gets a mention. Alongside the changes in things like SEN provision, one would hope that the cliff-edge that is post-16 provision should turn into more of step rather than a void.

What's missing from the guidance? Well in my view, whilst discussion is made of trials such as one by Jim Adams and colleagues on vitamin supplementation (see here) and the early work being reported on things like NAC (see here), none of these areas figure in the final summary guidance. There also appears to be no mention of the various amino acid, immunological or other biologically-mediated findings which is rather disappointing. That for example autism (sorry, the autisms) might also results from issues with branched-chain amino acids (see here) or PKU (see here) are important points; more so when you consider that simple interventions might actually be able to impact on symptom presentation. And then there is the whole mitochondrial story, everyone's favourite scrabble classic MTHFR and its link to folinic acid, vitamin B12, tetrahydrobiopterin (BH4)... the list goes on.

Appreciating that the evidence base around lots of areas in autism is still in its infancy, I take heart that NICE have cast an eye over autism and various facets of its presentation. That also it provides a roadmap for where research should be looking more closely is something else to take from the guidance and its potential ability to direct research funding into priority areas.

Tuesday 27 August 2013

Stem cell transplantation and autism: early days

My attention was recently caught by the publication of the study by Yong-Tao Lv and colleagues* (open-access) reporting results based on the use of stem cell transplantation in a small group of children diagnosed with an autism spectrum disorder (ASD).

I know that this research area is still a little bit of a hot potato when it comes to a heterogeneous, behaviourally-defined condition like autism (sorry, the autisms). As I intimated in a previous article about some related study in this area (see the ClinicalTrials.gov entry here) there are still quite a lot of unanswered questions about whether stem cell therapy is 'right' for autism or not; the progress of which is not helped by the historical propagation of the therapy via all those Google ads for specialist clinics offering stem cell services.

The new paper is open-access and includes a notable addition to the authorship group - one Paul Ashwood from UC Davis who has appeared more than once on this blog - and basically reports the results of a trial investigating "the safety and efficacy of combined transplantation of human cord blood mononuclear cells (CBMNCs) and umbilical cord-derived mesenchymal stem cells (UCMSCs) in treating children with autism". Without trying to rehash the authors findings, they basically suggested that (a) aside from some cases of transient fever, stem cell therapy was relatively 'safe' when it came to the monitoring of various measures, at least over the course of the investigative period and (b) compared with a control group who only received "professional sensory integration and behavioral rehabilitation therapy", two other groups of children who received CBNMC and CBMC + UCMSC transplantation in addition to behavioural intervention showed various "improvements" according to the behavioural measures used over the course of the 24 week trial. Indeed, the combination therapies CBMC + UCMSC transplantation "showed larger therapeutic effects than the CBMNC transplantation alone". That being said, this was quite a small trial and the trial was non-blinded and non-randomised.

I'm going to reiterate my oft-cited caveat about this blog not giving medical or clinical advice particularly when it comes to something as 'new' as stem cell therapy being suggested for autism. I am inclined to point you towards another archive post where stem cell transplants were mentioned with autism (or at least mouse models of autism) in mind, based on the impressive work coming out of Paul Patterson's laboratory (see here) and how immune function, development and behaviour might be players at the same table for some cases of autism. The more recent paper has gone beyond mouse models....

Every therapeutic option which is put forward for 'managing' the characteristics of autism needs to start somewhere when it comes to testing for safety and efficacy and stem cell therapy is no exception. Whilst questions still remain about the long-term safety and effects of such transplantations and indeed, whether there is any appetite for such an intervention, the research toe has well and truly been dipped into the experimental waters.

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* Yong-Tao Lv. et al. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. Journal of Translational Medicine 2013, 11:196

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ResearchBlogging.org Yong-Tao Lv (2013). Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism Journal of Translational Medicine DOI: 10.1186/1479-5876-11-196

Monday 26 August 2013

An anti-viral for chronic fatigue syndrome?

The recent publication of the trial results by Jose Montoya and colleagues* looking at the possibility that the anti-viral drug valganciclovir (see here for some description) might provide clinical benefit for some patients diagnosed with chronic fatigue syndrome (CFS) is the source material for today's post. The ClinicalTrial.gov entry for the study is here.
Virology Founder @ Wikipedia 

Indeed, when reading the Wikipedia entry for how the valganciclovir - lets call it VGCV to save my poor typing hands - trial was long awaited on the back of some rather more preliminary observations (see here** and here***), one gets the idea that the recent Montoya paper might eventually turn out to be something pretty important. That being said, I'm going to turn to my old caveat on this blog about not providing medical or clinical advice.

The value-added on the recent trial was that it was methodological, a lot more comprehensive that the previous trial by the author: now being double-blind and placebo-controlled and following participants over a period of 6 months. The authors also used a suite of measures to ascertain physical and mental fatigue: the "Multidimensional Fatigue Inventory (MFI-20) and Fatigue Severity Scale (FSS)" alongside "monocyte and neutrophil counts and cytokine levels".

They found a few differences between VGCV and placebo in their group, some of them significant and some of them not so. Importantly - long quote coming up - "statistically significant differences in trajectories between groups were observed in MFI-20 mental fatigue subscore (P=0.039), FSS score (P=0.006), and cognitive function (P=0.025). VGCV patients experienced these improvements within the first 3 months and maintained that benefit over the remaining 9 months." Interesting too that among the biological results there were signs of a shift in immune function towards Th1 in the VGCV group (see here for a description) among other things.

OK, a couple of steps back first. This was a study based on quite a well-defined group of people with CFS who also presented with signs of an immune response (IgG antibodies) against human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV). I understand that these viruses or rather exposure to these viruses have been discussed with CFS in mind previously (see here**** and here***** for example) outside of the historical viral reference (PVFS) although there still remains some 'discussion' about their role and relationship to CFS if and when detected.

To add to that viral - immune link, I note also that similar anti-viral preparations have also been examined with CFS in mind as per this study by Lerner and colleagues****** who used valaciclovir and even earlier this study******* using ganciclovir. Whilst methodologically sound, one might also reasonably expect that further research be undertaken following on from the Montoya and other results with a larger patient cohort.

I appreciate that to some, viral infections and CFS is still a little bit of a thorny issue in light of the quite recent XMRV story (see here for the drama) and even earlier some chatter about the use of transfer factor********. There is, therefore, always the possibility that the latest Montoya research might unfortunately suffer a sort of death by association as a consequence of any perceived link, despite the fact that as far as I can see they steered clear of anything murine leukemia virus-related virus in their work. Indeed as an aside, I should also point out the very interesting work being done on HERVs and myalgic encephalomyelitis (ME) which may or may not be relevant to the Montoya investigation too.

That also there is still some historical debate about the nature of CFS and the use of things like graded exercise and CBT as front-line treatment options (of which I am providing no opinion) is also another potential stumbling block to moving work like that of the Montoya paper out of the research domain and into something a little more accessible to specific patient groups. My view, as I've indicated in quite a few other posts on the subject of CFS, is that we are probably talking about a heterogeneous condition (possibly even a spectrum of conditions manifesting common symptoms. Sound familiar?) which appears to be multi-factorial in nature and pathology (see here and here and here for example). It's therefore highly likely that as Montoya and colleagues indicated "VGCV may have clinical benefit in a subset of CFS patients" as might other intervention options. The trick like Montoya has done, is to search out potential markers for what will work for who.

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* Montoya JG. et al. Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome. J Med Virol. 2013 Aug 19. doi: 10.1002/jmv.23713.

** Watt T. et al. Response to valganciclovir in chronic fatigue syndrome patients with human herpesvirus 6 and Epstein-Barr virus IgG antibody titers. J Med Virol. 2012 Dec;84(12):1967-74. doi: 10.1002/jmv.23411.

*** Kogelnik AM. et al. Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue. J Clin Virol. 2006 Dec;37 Suppl 1:S33-8.

**** Burbelo PD. et al. No serological evidence for a role of HHV-6 infection in chronic fatigue syndrome. Am J Transl Res. 2012;4(4):443-51.

***** Lerner AM. et al. IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome. In Vivo. 2004 Mar-Apr;18(2):101-6.

****** Lerner AM. et al. Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up. In Vivo. 2007 Sep-Oct;21(5):707-13.

******* Lerner AM. et al. A small, randomized, placebo-controlled trial of the use of antiviral therapy for patients with chronic fatigue syndrome. Clin Infect Dis. 2001 Jun 1;32(11):1657-8.

******** Ablashi DV. et al. Use of anti HHV-6 transfer factor for the treatment of two patients with chronic fatigue syndrome (CFS). Two case reports. Biotherapy. 1996;9(1-3):81-6.

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ResearchBlogging.org Montoya JG (2013). Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome J Med Virol DOI: 10.1002/jmv.23713

Friday 23 August 2013

Recurrence of autism in siblings

It is a question that I'd imagine most paediatricians or related healthcare professionals get asked a lot when it comes to the autism spectrum conditions: "my child has autism, what is the risk that any future siblings might also develop the condition?"
Sisters @ Wikipedia 

Indeed, whole initiatives have been formed to build on the fact that the appearance of offspring autism does seem to carry an enhanced risk of other siblings also presenting on the spectrum* (open-access) as per the Autism Speaks High Risk Baby Siblings Research Consortium (BSRC). That being said, if your first language is not English when living in an English-speaking country, you might not necessarily get a prompt diagnosis (see here).

To add to the growing scientific literature on this topic, the recent paper by Therese Grønborg and colleagues** is the topic of today's post and their assertion that depending on whether brothers or sisters are full siblings and their birth year, the risk of recurrence of an autism spectrum disorder (ASD) varied between about 4% and 10% in Denmark, quite a bit higher than the Danish population prevalence of just over 1% (or even more?) but itself probably an under-estimate given the issue of stoppage. Jon Brock over at Cracking the Enigma is quoted on some analysis of these results (see here). Indeed, the headline which quite a few press elements have picked up on is that the "overall relative recurrence risk for ASDs was 6.9" equating to a nearly 7-fold increased risk of autism if an older siblings has been diagnosed with ASD.

OK, I know that this is not new news. That more than one child in the same family might have autism is a reality that many, many families have experienced. Science has been talking a long time about the heritability of autism (and the broader phenotype) from quite a few perspectives; even though genes are probably not working in isolation (see this archive post) alongside that new Sheriff in town called epigenetics (see here). Another important issue taken up from this recent paper outside of the disparity between this population-based study and other more clinical samples - the estimates from the Grønborg paper are lower than that found in other studies - is how those just-as-important half siblings seem to indicate other potential issues also being pertinent areas for further investigation (think the nine months that made us and things like folate even the folding placenta for example).

There is always a need for this kind of basic science in autism circles not only for research purposes but also to inform families about risk (bearing in mind that risk is risk) and potentially inform services such as education and health as a function of things like heightened comorbidity too (see here). Indeed if I had to add anything to this area of investigation it would be to include autism as part of a wider suite of conditions/characteristics which may very well be noted in other siblings (see here) as per some other interesting work with its roots quite a few moons ago (see here).

And just in case you need it, here is a nice article from the BBC about the value of having siblings.

[Update September 2013: The full text of the Grønborg paper is available here].

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* Ozonoff S. et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011 Sep;128(3):e488-95. doi: 10.1542/peds.2010-2825. Epub 2011 Aug 15.

** Grønborg TK. et al. Recurrence of Autism Spectrum Disorders in Full- and Half-Siblings and Trends Over Time A Population-Based Cohort Study. JAMA Pediatr. 2013;():-. doi:10.1001/jamapediatrics.2013.2259

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ResearchBlogging.org Grønborg TK (2013). Recurrence of Autism Spectrum Disorders in Full- and Half-Siblings and Trends Over Time A Population-Based Cohort Study JAMA Pediatrics DOI: 10.1001/jamapediatrics.2013.2259

Wednesday 21 August 2013

Blood biomarkers and suicide

Science can be a pretty cold thing.

Take for example some of the discussions on the recent paper by Helen Le-Niculescu and colleagues* (open-access) on the potential for a suite of blood biomarkers to predict suicidal behaviour (see here for some more commentary). The very complicated tragedy that is suicide - whether attempted or completed - [potentially] boiled down to genes, and in particular the product expression of one gene, SAT1 described by the authors as "head and shoulders above the rest" in terms of its [potential] predictive capability.

The Good Samaritan @ Wikipedia 
With my science hat on, I was obviously interested in this research, and how despite the relatively small participant group "In each of the suicide completers, the increase in SAT1 was at least three s.d. above the average levels".

But then as I read the words again, the realisation set in that these 'completers' were not just mice or rats in a cage, they were people. People who only 24 hours prior to their inclusion in the study were alive. And then for whatever reasons decided to end their life and with it the hopes and dreams of their parents, siblings, partners, extended family and friends.

Don't get me wrong, I'm not saying that we shouldn't be actively engaging in research looking at how we might eventually predict those at greatest risk from suicide. On the contrary, if this work pans out and survives replication the potential savings both in terms of that most precious commodity (life) and beyond could be enormous. But it is still an 'if' and those were real people.

The Le-Niculescu paper is open-access so I'm not going to go through it with a fine-toothed comb on this occasions. Suffice to say that this study, following previous interest from this authorship group (see here), set out to explore whether it was possible to predict and track suicidal states, particularly in those at high-risk for suicide as per their selection of participants diagnosed with "a major mood disorder (bipolar disorder)".

This involved first looking at blood gene expression in participants focused specifically on those who "switched from having no suicidal thoughts to scoring highly on a suicide-risk scale". The myriad of data this generated was then subject to analysis via an author favourite technique called Convergent Functional Genomics (see here**) used "to identify and prioritize from the list of differentially expressed gene biomarkers of relevance to suicidality". It was then a process of checking the top ranking gene biomarkers in those suicide completers (drawn from a different population) and "Niculescu's team was left with six which they was reasonably confident were indicative of suicide risk". More boiling down of the biomarkers was accomplished by looking at a further group of those hospitalised for suicide (attempts) and "SAT1, PTEN, MARCKS and MAP3K3 might be not only state biomarkers but trait biomarkers as well".

In all the chatter about this study, one particular question was floating around my mind: if these biomarkers are verified, does this mean we could eventually affect gene or biochemistry and somehow alter the behaviour of those attempting or thinking of attempting suicide?

Actually the authors do mention some potentially important information about this. They report for example, that the drug clozapine might affect expression of some of the biomarkers "in opposite direction to our human suicidality data in previous independent animal model pharmacogenomics studies conducted by us". Clozapine as they note is indicated for suicidality under certain circumstances (see here). Fair enough, an antipsychotic might help, bearing in mind it is an antipsychotic and carries some of the usual side-effects (see here).

But they also mention another possibility that requires some further study, as per this quite long quote:

"Several of the biomarkers from our current study (SAT1, S100A8, IL1B and 16 others) were changed in expression by omega-3 treatment in the blood of the circadian clock gene DBP (D-box binding protein) knock-out mouse model in opposite direction to our human suicidality data".

So, fatty acids, particularly those of the omega-3 variety might [might!] also impact on some of those biomarkers too? This point in particular is of real interest to me and this blog. A quick trawl of the literature looking at measured fatty acids and suicidality turns up some interesting data as per studies like this one*** and this one****. I don't think anyone has convincingly said that fatty acids 'cause' suicide because suicide is a very complicated process reliant on more than just biology, but the association is an interesting one. Some recent coincidental literature on suicides in prison (see here) confirms the multi-faceted nature of suicide.

Indeed, I've talked previously on this blog about how nutrition, in many forms, has been associated with suicide risk as per the vitamin D and independently, the lithium research (see here) reported in the scientific literature. To stress again, these are associations; so one has to be cautious not to say too much at the present time about causation.

I started this post by saying how cold science is when it comes to its operation. I suppose I should end by saying that science is cold, at least in the way it is carried out and reports, because it has to be. It has to be cold and objective. Assuming that the Le-Niculescu findings are successfully replicated however, science then can start to move out of the freezer and into something rather 'warmer' approaching real-life with regards to its translation into potentially saving lives.

To close, just in case you need to talk to someone, remember that these guys are only a phone call or email away (similar organisations are also in the US and other parts of the world).

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* Le-Niculescu H. et al. Discovery and validation of blood biomarkers for suicidality. Molecular Psychiatry. 20 August 2013. doi: 10.1038/mp.2013.95

** Le-Niculescu AB. & Le-Niculescu H. Convergent Functional Genomics: what we have learned and can learn about genes, pathways, and mechanisms. Neuropsychopharmacology. 2010 January; 35(1): 355–356.

*** Lewis MD. et al. Suicide deaths of active-duty US military and omega-3 fatty-acid status: a case-control comparison. J Clin Psychiatry. 2011 Dec;72(12):1585-90. doi: 10.4088/JCP.11m06879.

**** Vaz JS. et al. Omega-6 fatty acids and greater likelihood of suicide risk and major depression in early pregnancy. J Affect Disord. 2013 May 30. pii: S0165-0327(13)00346-7. doi: 10.1016/j.jad.2013.04.045.

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ResearchBlogging.org Le-Niculescu H (2013). Discovery and validation of blood biomarkers for suicidality Molecular Psychiatry DOI: 10.1038/mp.2013.95

Tuesday 20 August 2013

Mind-body exercise and self-control in autism?

Despite knowing a little something about the discipline of psychology and in particular, it's varied success/failure (delete as appropriate) when applied to a complicated condition like autism, I'll admit that I do have some difficulty in grasping certain ideas and concepts which make up the psychological research landscape.
Yin yang? @ Wikipedia 

Take for example the concept of mindfulness, which is definitely starting to be another 'big thing' when it comes to psychology stressing how the mind might be able to influence all manner of things including several physical 'frailties'. It's fascinating to me how something as simple as glorified meditation might be able to do so much.

A good example of mindfulness at work was seen in Dr Michael Mosley's recent BBC Horizon venture on 'The Truth About Personality'. Wherein the 5:2 diet (see here) was replaced by some interesting discussion on how we could all become much happier and less anxious through mindfulness and an interesting technique called cognitive bias modification (CBM). Aside from making an important mention of the concept of epigenetics and how we should be looking at the function of the genome as well as its structure, it was interesting to see Dr Mosley report some benefit from the interventions at the end of the program, measured also via more objective means over and above his subjective 'I feel better' sentiments.

This very long-winded introduction brings me to the topic of today's post on a mind-body exercise regime and autism following the publication of a study by Agnes Chan and colleagues* (open-access) who reported some success from their Chan-based mind-body exercise program on self-control (see here for the trial registration). The SFARI blog has also recently posted about this study (see here).

Before heading into the paper I should point out that this is not the first time that this type of program has been talked about with autism in mind. For example, I stumbled across this paper** by the same authorship group which talked about some potential effects from "a Shaolin-medicine-based dietary modification" which talked about removing foods which "will generate excessive internal heat and adversely affect the temper and cognitive functions" to include "ginger, garlic, green onion, spicy foods, eggs, meat, and fish". I don't really want to comment on the hows and whys of 'excessive internal heat' on autism in this post so will leave it there for now and allow readers to draw their own conclusions. I might also add that I've talked Chinese medicine and autism before on this blog as per the 'Jedi' massage (see here, lightsaber not required).

OK back to the Chan-based mind-body exercise program on self-control. The program is based on the practice of Nei Yang Gong and essentially includes "sets of slow movements that emphasize smooth, gentle, and calm movements". The authors suggest that these movement help with self-awareness and mental self-control but can also help in the reduction of stress (something all too familiar where autism is mentioned). They add that it is a slightly different program from just mindfulness and mediation. There are plenty of videos on the web illustrating the types of movements it includes.

The authors randomly allocated 46 children diagnosed with an autism spectrum condition to either the Chan-based mind-body exercise program under analysis or something called progressive muscle relaxation although only 20 kids in each trial arm completed the four-week study. Alongside measuring neuropsychological functioning, authors also ATECd the kids to pick up parent-reported behaviour changes and looked at event-related EEG results during "an inhibitory control test, namely, the Go/No-Go task".

The results: "the autistic children in the experimental group showed better self-control than those in the control group after the one-month intervention" based on the results of the neuropsychological tests. Analysis of the ATEC scores however were not so clean-cut as both groups were reported to show [variable] positive changes on the subscales (the experimental group generally however showing a more pronounced positive effect). The authors do note that when it came to looking at specific issues such as temper outbursts "the experimental group reported a significantly greater reduction" over the control group. Oh and did I mention that there were some changes on the EEG too? (bearing in mind my considerable non-expertise when it comes to this dark art).

OK, I know its tempting to look at this paper and its results and start to criticise based on things like the lack of blinding to group allocation / intervention regime and the use of the ATEC (but wait a minute...). There was also, for example, no treatment as usual group included in the study you might say. But just hold on a minute, when it comes to ascertaining medication in relation to autism and other conditions for example, on more than one occasion there has been criticism that researchers have been too over-reliant on drug vs. nothing (or placebo) over drug A vs. drug B. At least the authors in this study were able to say that their program was better than just muscle relaxation techniques. Perhaps the next study to be done would be comparing their program with something more pharmacological?

Likewise in our modern Western medical system which we all love, it is perhaps easy to rather disparagingly talk about things like 'internal heat' whilst carrying that little smirk on our faces as if 'we know better'. I don't know enough about Chinese medicine to say whether this is something real and tangible or just some ancient hand-me-down. All I can see is that the authors have made an attempt to (experimentally) bring their expertise to bear on a group of people who are probably more prone than most to issues with things like self-control and anxiety. And if it worked, well, it worked. That and I assume the fact that once one has been trained in the ways of Nei Yang Gong, it's probably going to be something that can done quite easily and certainly quite affordably in the longer term (probably also with minimum side effects I would imagine).

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* Chan AS. et al. A Chinese Mind-Body Exercise Improves Self-Control of Children with Autism: A Randomized Controlled Trial. PLoS ONE. 2013; 8(7): e68184. doi:10.1371/journal.pone.0068184

** Chan AS. et al. A chan dietary intervention enhances executive functions and anterior cingulate activity in autism spectrum disorders: a randomized controlled trial. Evid Based Complement Alternat Med. 2012;2012:262136. doi: 10.1155/2012/262136.

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ResearchBlogging.org Agnes S. Chan (2013). A Chinese Mind-Body Exercise Improves Self-Control of Children with Autism: A Randomized Controlled Trial PLoS ONE DOI: 10.1371/journal.pone.0068184

Saturday 17 August 2013

NAC for autism: a case study

NAC or N-acetlycysteine has appeared a couple of times on this blog in relation to both autism (see here) and schizophrenia (see here). Not bad for a compound which more readily finds a home in modern medicine following paracetamol (acetaminophen) overdose or as a consequence of its mucolytic properties.

As one might imagine, the autism link is of particular interest to this blog, focused specifically on the findings of Hardan and colleagues* when it came to putting NAC to the [albeit preliminary] experimental test. The results by the way were encouraging for at least some parts of the presentation of childhood autism with the promise of more to come.

As a sort of follow-up to the Hardan paper, I'm talking today about a case report offered by Ghanizadeh & Derakhshan** (open-access) highlighting a little more individual detail following the use of NAC with an 8-year old boy diagnosed with autism. I know the word 'case report' sends a shudder down many a scientific shoulder, but as I've said quite a few times before, we ignore the N=1 in autism at our peril given the wide, wide heterogeneity present and all that associated comorbidity to contend with. Real personalised medicine you might say.

If I have managed to persuade you to listen to the rest of my ramblings on this paper and topic, there are a few important points to make about/from the Ghanizadeh paper:

  • From the description provided, the child in question seemed quite floridly autistic with the important add-ons of hyperactivity and inattention present from an early age. Although we aren't told what exactly it means, the authors note: "His laboratory examination was unremarkable".
  • Oral NAC (800mg per day) was begun as part of another trial by the authors to counteract nail-biting***. As unusual as it might sound, mail-biting has been a focus of some NAC research coincident to the presence of anxiety.
  • Indeed, the boy's nail-biting behaviours did seem to subside alongside the installation of NAC but perhaps of greater interest were the reports that "there was a marked reduction in his autism symptoms 30 days after the onset of NAC administration". OK so this report did come from the boy's parents, and without causing any offence, the issue of objectivity might come into play.
  • The types of 'changes' reported however were in core areas such as his verbal skills, social interaction and a quite unusual preoccupation with having his hair cut (I say unusual because a visit to the barber or hairdresser described by many parents about their child with autism, is often characterised by entirely the opposite reaction).
  • Aside from "a mild abdominal pain" the authors importantly say that "nothing worsened after the administration of NAC" which I take to indicate that side effects were minimal over the course of the intervention.

I should have perhaps mentioned at the beginning that there is some sound logic why NAC might have some effect on cases of autism. The amino acid cysteine as well as containing sulfur, so potentially tied into to that most forgotten areas of autism research sulfur chemistry (see here), is also the precursor to another important compound, glutathione. I know my regular readers are probably getting a little bored of me going on about this 'elephant in the room' and in particular that glutathione overview paper by Main and colleagues (see here) but a possible link is a possible link.

I was also interested to read the authors' discussions on how NAC might also have the ability to decrease "high glutamate levels". As any good biochemist will tell you, glutathione, which is dependent on cysteine, is a tripeptide which also incorporates the amino acids glycine and glutamate into its triadic manufacture. From that point of view, circumstances where any of the three amino acids were low or not optimally biologically available might affect the production of glutathione. If that happens to mean you have low cysteine levels, glutathione would be low but also this might mean levels of glutamate or glycine could be higher as a result of not being used up to make glutathione. Glutamate is another compound finding some significant interest with regards to autism and conditions presenting with autistic symptoms.

Reiterating that the Ghanizadeh paper is a case report, I do find there to be some interesting observations reported. With my speculating hat on, I do wonder whether that link with nail-biting and onwards anxiety suggested for NAC might also be part and parcel of the effect observed in this case given the quite considerable link suggested between autism and anxiety (see here)?

And by the looks of things NAC is in the research ascendancy perhaps even with a prophylactic effect****...

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* Hardan AY. et al. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry. 2012 Jun 1;71(11):956-61. doi: 10.1016/j.biopsych.2012.01.014.

** Ghanizadeh A & Derakhshan N. N-acetylcysteine for treatment of autism, a case report. J Res Med Sci. 2012 Oct;17(10):985-7.

*** Ghanizadeh A. et al. N-acetylcysteine Versus Placebo for Treating Nail Biting, A Double Blind Randomized Placebo Controlled Clinical Trial. Antiinflamm Antiallergy Agents Med Chem. 2013 May 6. [Epub ahead of print]

**** Beloosesky R. et al. Prophylactic maternal N-acetylcysteine in rats prevents maternal inflammation-induced offspring cerebral injury shown on magnetic resonance imaging. Am J Obstet Gynecol. 2013 Mar;208(3):213.e1-6. doi: 10.1016/j.ajog.2013.01.023.

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ResearchBlogging.org Ghanizadeh A, & Derakhshan N (2012). N-acetylcysteine for treatment of autism, a case report. Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences, 17 (10), 985-7 PMID: 23826003

Wednesday 14 August 2013

Leaky gut, food antibodies and autism

I'm back. After a couple weeks of hot Greek sunshine and good times it's back to work.

So... food and autism.

It's a research topic that's interested me for quite a few years now*. In particular, how certain dietary interventions might be able to 'affect' the presentation of autism**, at least some autism or at least some comorbidity?

In recent weeks there have been some pretty exciting developments in this area, not least because of the Lau paper (see here) suggestive of some potential issues with immune reactivity to gluten - one of the food components singled out as being related to autism - to be present in some cases and potentially explanatory of why dietary intervention might be useful for some on the spectrum.
Gluten and casein KOed? @ Wikipedia  

In a similar vein, I want to talk today about the paper by Laura de Magistris and colleagues*** (open-access) and their important findings reporting an increased frequency of immune reactivity to gluten and casein (the protein found in mammalian milk sources) in pediatric cases of autism following on from the Lau data.

I had mentioned this paper in a previous [mega] post on leaky gut and autism (see here). The authorship group on the de Magistris paper reads like a who's who in gluten research at the moment.

Laura de Magistris, as some readers might remember, published that groundbreaking study on gut hyperpermeability (leaky gut) in relation to autism****. Then we have the likes of Anna Sapone (the spectrum of gluten sensitivity) and finally, but by no means least, Alessio Fasano, a real research favourite for this blog and its sister (see here). Prof. Fasano is one to watch in autism research, mark my words.

Enough of the research hero-worship, the aim of the research was to look at various facets of how children with autism handle foods containing gluten and casein from an immunological and gut permeability point of view.

Some of the details:

  • One cannot say that this was an under-powered study as de Magistris and colleagues set about investigating gut permeability and a variety of gluten-coeliac markers (tTG, HLA-DQ2/DQ8 haplotypes, IgA-IgG-IgE antibodies, IgA-IgG anti-gliadin antibodies, IgA-IgG antibodies to deamidated gluten peptide, IgG-IgE casein, etc.) in 162 children diagnosed with an autism spectrum disorder (ASD) compared with 44 'healthy' controls. If all those measures sound like gibberish to you (a) don't worry, just follow the hyperlinks and (b) tune into my 'what is coeliac disease' post where quite a few of the measures were discussed.
  • The kids with autism were all fully ADOS-ed and ADI-ed to make sure that they met criteria for autism. Various other details were also collected about things like gastrointestinal (GI) history and whether or not participants were following interventions like a gluten- and casein-free (GFCF) diet. Indeed 31 participants were following - sorry "embraced" - the GFCF diet (~20%). Importantly too, among the exclusion criteria for study non-participation was a previous diagnosis of coeliac disease or inflammatory bowel disease (IBD). In other words, these were kids with autism not previously diagnosed with a serious GI complaint
  • Results: two of the children with autism were "serologically positive" for coeliac disease (1.2%) compared with none of the controls. This finding accords with other research suggesting that coeliac disease is probably not over-represented in cases of autism (bearing in mind this does not mean autism is somehow protective against coeliac disease). . 
  • Gut permeability testing revealed that about a quarter of the children with autism had "impaired intestinal barrier function" compared with about 2% of control participants (41 ASD kids vs. 1 control). As per the previous de Magistris paper, being on a GFCF diet also tended to "normalize the barrier impairment" although diet did not curb permeability altogether in comparison to the asymptomatic control group.
  • Anti-gliadin antibodies (IgG) were "higher in ASDs compared to controls and are not influenced by changes in intestinal permeability". Following a GFCF diet did, as one might expect, influence the presence of this immune response.
  • Interestingly, when it came to measuring levels of anti-deamidated gliadin peptide antibodies (IgG) the grouped values were increased in children with autism compared with controls. I'll come back to this finding shortly.
  • Total IgE titer levels (IgE being a marker for classical allergy) were not significantly different between the groups in line with other findings; although specific IgE antibodies to milk were reduced for those children with ASD on the GFCF diet. IgG antibodies to casein were increased in the autism group compared to controls (and again were influenced by the use of a GFCF diet).

Take my word for it, there are lots of potentially important findings here. That leaky gut (gut hyperpermeability if you wish) is a very real finding for quite a few children on the autism spectrum is important. I know for some people this might be difficult news to take in but, added to the fact that GFCF dietary intervention might abate this issue to some degree, one perhaps needs to put aside any prejudice about GI involvement in autism and whatever image(s) that conjures up and start to focus on how science can move this finding on further.

The deamidated gliadin peptide antibody finding is also particularly interesting. Basically the process of deamidation comes about when tTG (tissue transglutaminase also known as TG2) gets hold of gluten peptides and starts doing funny things to parts of their structure (see here*****). This then has knock-on effects for their relationship with antigen presenting cells of the immune system and the cascade of effects that brings to a condition like coeliac disease. The implication here is that whilst not being coeliac disease - indeed the lack of any significant HLA-DQ2/DQ8 haplotype findings in the autism group is testament to that - gluten peptides might still be acting on some cases of autism. I should mention that some involvement for tTG in relation to cases of autism has been previously discussed on this blog (see here). I hasten to add that we are not necessarily talking about the opioid-excess hypothesis and opioid peptides - not yet at least. If you want some more information about the whole coeliac disease process, you could do worse than have a look at my recent post on what we think we know about it (see here).

What these findings and that from Lau and colleagues****** (open-access) point to is a complicated picture of how dietary variables might affect biology in some cases of autism. It's a picture which contains several important elements not least potential issues with the breakdown (metabolism) of foods which contain gluten and casein (think CM-AT??), problems with the intestinal barrier and its proper function and even hints of autoimmunity as per tTG and the deamidated gluten peptide findings.

I personally think that autism research is starting to catch-up with other conditions that are being looked at with a dietary element to them such as schizophrenia and the work of Emily Severance and colleagues (see here and here) and David Niebuhr (see here). Whether there are any relationships between the findings in autism and schizophrenia is a question which perhaps needs answering, particularly in these days of common ground (see here) and spectrums overlapping (see here).

What's missing from the de Magistris paper? Well, given the authorship group in this study, I was expecting to hear something about [General] zonulin and whether or not that protein was measured and showed anything as per its other links (see here) with tight junctions in mind. That and mention of those other words bacterial translocation which seem to go hand-in-hand with leaky gut, (think Sutterella and autism for example).

Still I can't argue with the fact that autism research has, at last, started to delve into the very complicated world of diet and potentially offer some new avenues for further investigation. Allied to the albeit 'soft evidence' of potential effects from dietary intervention in some cases, I forsee some interesting times ahead.

Some music to close: A Small Victory perhaps?

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* Whiteley P. et al. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2012;6:344. doi: 10.3389/fnhum.2012.00344.

** Whiteley P. et al. The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Nutr Neurosci. 2010 Apr;13(2):87-100. doi: 10.1179/147683010X12611460763922.

*** de Magistris L. et al. Antibodies against food antigens in patients with autistic spectrum disorders (ASDs). BioMed Research International. 2013 (2013), Article ID 729349.

**** de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24. doi: 10.1097/MPG.0b013e3181dcc4a5.

***** van de Wal Y. et al. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol. 1998 Aug 15;161(4):1585-8.

****** Lau NM. et al. Markers of Celiac Disease and Gluten Sensitivity in Children with Autism. PLoS ONE 8(6): e66155. doi:10.1371/journal.pone.0066155

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ResearchBlogging.org de Magistris L (2013). Antibodies against Food Antigens in Patients with Autistic Spectrum Disorders BioMed Research International DOI: 10.1155/2013/729349

Saturday 10 August 2013

Fatty acids and reading ability

Although now only available to subscribers, a short while back I was very peripherally involved in helping to write an article on the science of lipidomics (see here). The crux of that overview article was that the science of biological lipids - lipidomics (yes, another one of those -omics) - is really starting to make some waves when it comes to health and wellbeing. Also that one should not be too hasty in making snap judgements about fats; not all fats are equal and without them, well, none of us would be here.
Underneath the arches @ Wikipedia 

As if to prove the point, I'm talking today about a paper from Paul Montgomery and colleagues* (open-access) who suggested that science might do well to take a closer look at specific types of fats in relation to childhood behaviour and cognitive performance.

Before going further into the paper and its findings, it's probably a good idea if I frame this research with a little bit of history in this area. I'm sure that some of you might already have heard about the suggestion that fatty acid supplementation, fish oils if you will, might show some link to cognitive performance in certain groups of children and in particular, the results of the Durham trial**. I know there was some 'discussion' about other angles of fish oil use here in the bracing North-East of England but I'm not going to go into that here. Suffice to say that fish oil research has not had the easiest of rides so far.

The Montgomery paper is open-access, but a few points to note:

  • This was a study looking at whole blood fatty acid concentrations ("broadly equating to the omega-3 index") from a fingerstick sample in just short of 500 UK children (aged 7-9 years) as part of the DOLAB study*** (open-access). DOLAB in case you didn't click on the previous link was all about seeing what happened when kids were given a DHA (docosahexaenoic acid) supplement, particularly those who were under-performing in terms of reading ability and other aspects of behaviour.
  • Indeed the participants included in this study were those children who were finding some difficulty with reading performance and whether their fatty acid profiles were somehow correlated with their presentation. Various psychometric measures were employed to assess things like reading ability (BAS-II) and behaviour (Conner's Rating Scales) of participants.
  • Results:  there were quite a few bearing in mind no control group data was included in this paper so we cannot necessarily rule out a more general 'deficiency' as being present in children. Primary among them was that blood levels of the omega-3 long-chain polyunsaturated fatty acids (LC-PUFAs) which includes both DHA and EPA (eicosapentaenoic acid), cumulatively made up only an average of 2.4% of total blood fatty acids in the group studied. The authors frame this within the context of guidance for good cardiovascular health which they report should be in the optimal region of 8-12%. Quite a disparity by all accounts.
  • They also noted that: "blood Omega-3 LC-PUFA status in these UK children significantly predicted both their behavior and their cognitive performance". In other words, higher levels were associated with things like better reading ability and "fewer ADHD-type symptoms".
  • Also notable too was the link between lower blood fatty acid levels and lower reported fish intake as per reference to parental reports on their children's eating habits.
  • The authors conclude that because of their results "the benefits from dietary supplementation with Omega-3 LC-PUFA found for ADHD, Dyspraxia, Dyslexia, and related conditions might extend to the general school population".
  • Just one last thing: for any Government official who happens to tune into this blogpost, a few interesting points to mark for your attention from the study. Reading scores were correlated with socio-economic status (SES) and behaviour problems were "higher for children entitled to free school meals" (another marker of SES). Poverty it seems, might exert an effect.

I find these to be very interesting results. I know to mention that what we and our children eat might actually have some affect on cognitive and behavioural presentation is still considered controversial in some quarters, but I personally find the research base to be worthy of attention. I'm for example, taken back to the work of Bernard Gesch and colleagues**** (open-access) on nutrition and behaviour covered by Dr Emily Deans (see here) as a template for the 'diet can affect behaviour' mantra outside of more traditional medical examples. Realising at the same time, that people are complicated creatures and dietary modifications are not a cure-all for every ill.

Also that this study was 'industry-funded' is something which some might point out as being 'significant'. For me personally, the important thing was that the COI was declared as it should have been for any research on any medicine in your medicine cabinet. Indeed one might see this as even more motivation for independent follow-up of these results...?

I've covered fatty acids previously on this blog, both with an autism research perspective (see here) and also from a 'not all good news for fish oils' perspective (see here). The lessons from both these posts were that fish oil supplementation as a sort of population-wide initiative is probably not going to be the best course of action recently emphasized by that prostate cancer link (see here).

But.... that there may be specific, perhaps many specific, groups of children or young adults who either present with certain patterns of behaviour or issues with important skills like reading alongside lower circulating levels of these fatty acids, I am finding it difficult to say we shouldn't be embarking on rigourous scientific trials looking for any potential effect from such a simple intervention. Given also that the brain for example is approximately 60% fat pointing towards our fatty evolutionary heritage, there is sound logic to ensuring adequate supplies of certain types of fatty acids are present and in particular for certain groups of people***** (open-access).

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* Montgomery P. et al. Low Blood Long Chain Omega-3 Fatty Acids in UK Children Are Associated with Poor Cognitive Performance and Behavior: A Cross-Sectional Analysis from the DOLAB Study. PLoS One. 2013 Jun 24;8(6):e66697. doi: 10.1371/journal.pone.0066697.

** Richardson AJ. & Montgomery P. The Oxford-Durham Study: A Randomized, Controlled Trial of Dietary Supplementation With Fatty Acids in Children With Developmental Coordination Disorder. Pediatrics. 2005; 115: 1360-1366.

*** Richardson AJ. et al. Docosahexaenoic Acid for Reading, Cognition and Behavior in Children Aged 7–9 Years: A Randomized, Controlled Trial (The DOLAB Study). PLoS ONE. 2013; 7(9): e43909. doi:10.1371/journal.pone.0043909

**** Gesch CB. et al. Influence of supplementary vitamins, minerals and essential fatty acids on the antisocial behaviour of young adult prisoners. Br J Psychiatr 2002; 181: 22-28.

***** dos Santos Vaz. J. et al. Dietary Patterns, n-3 Fatty Acids Intake from Seafood and High Levels of Anxiety Symptoms during Pregnancy: Findings from the Avon Longitudinal Study of Parents and Children. PLoS ONE 8(7) 2013: e67671. doi:10.1371/journal.pone.0067671

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ResearchBlogging.org Montgomery P, Burton JR, Sewell RP, Spreckelsen TF, & Richardson AJ (2013). Low Blood Long Chain Omega-3 Fatty Acids in UK Children Are Associated with Poor Cognitive Performance and Behavior: A Cross-Sectional Analysis from the DOLAB Study. PloS one, 8 (6) PMID: 23826114