The positive effects of 12 weeks of probiotics and vitamin D in chronic schizophrenia?

The findings reported by Amir Ghaderi and colleagues [1] (open-access) provide the blogging fodder today, and the results of a study looking at a "novel combination of vitamin D and probiotic on metabolic and clinical symptoms in chronic schizophrenia." Said probiotic formulation contained "Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri, and Lactobacillus fermentum (each 2 × 109)" and was delivered over a period of 12 weeks alongside a vitamin D supplement - "50,000 IU vitamin D3 every 2 weeks" - utilising a "randomized, double-blind, placebo-controlled trial" design. We are also told that the trial protocol was "retrospectively registered."

The Ghaderi study wasn't solely focused on what their combined intervention might do for the 'clinical symptoms' of schizophrenia despite this being a prominent part of the results obtained. They also wanted to examine things like "biomarkers of oxidative stress and cardiometabolic risk in chronic schizophrenia." This was done via the measurement of marker compounds pertinent to establishing total antioxidant capacity, total glutathione levels and high-sensitivity C-reactive protein (hs-CRP) among other things.

Results: first things first, vitamin D supplementation raised vitamin D levels in those who received the vitamin D + probiotic supplement. Not exactly an unexpected result I grant you, but important from the point of view that any subsequent findings *could* be linked to those increasing vitamin D levels. Further: "Vitamin D and probiotic co-supplementation was associated with a significant improvement in the general... and total PANSS scores." PANSS stands for the Positive and Negative Syndrome Scale and has some important uses in the context of schizophrenia, and the presentation of positive and negative symptoms. That all being said, the authors also mention how their supplementation combination did not seemingly affect scores on another measure included in the study - the Brief Psychiatric Rating Scale (BPRS) - which kinda demonstrates that vitamin D + probiotics is not a panacea for every aspect of schizophrenia.

Researchers also report on how their combined supplement also *correlated* with a some changes in those oxidative stress and cardiometabolic risk measures included for study in line with other study results (see here). There's quite a bit of data so I won't provide details. Suffice to say that some of them might be 'positively' important to those health inequalities that seem to follow a diagnosis of schizophrenia (see here).

What else? Well, I can't seem to find too much in the way of side-effects details in the Ghaderi paper so I'm assuming that it wasn't a significant issue. The fact that participants in the study were "being hospitalized during the intervention" means that they were, I assume, being monitored with greater assiduity than for example if they were in the community, including looking for potential side-effects.

And with that, and the requirement for further study (see here and see here), I say no more...

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[1] Ghaderi A. et al. Clinical and metabolic response to vitamin D plus probiotic in schizophrenia patients. BMC Psychiatry. 2019; 19:77.

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Autism and the measurement of urinary amino acids

Today's post concerns the findings reported by Aiping Liu and colleagues [1] who, following the analysis of urine samples from a group of children diagnosed with an autism spectrum disorder (ASD) and a not-autism control group, concluded that there may be something to see with regards to the urinary excretion of amino acids.

First things first, amino acids are the building blocks of proteins. Long chains of amino acids form different proteins (and peptides) that serve multiple biological functions. But making up proteins is but one of the roles of amino acids, as a variety of other functions are also included in their repertoire; notably also being the raw material for the formation of some neurotransmitters and related compounds (see here for example).

Liu et al approached their analysis of amino acids in relation to autism from the point of view of their measurement being "potential novel metabolic biomarkers for ASD." This follows something of a trend in autism research circles whereby patterns of certain amino acids and their associated chemistry in certain biofluids might have such 'potential' for some types of autism (see here and see here and see here for some other examples) albeit with certain caveats. Researchers utilised some quite well known methods when it came to their analysis - "liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based analysis" - and set to work using a tried-and-tested method (see here): "a two-step discovery–validation approach."

Analysing urine samples from nearly 60 children with autism and over 80 not-autism controls ("28 ASD and 41 TD  [typically developing] children for the discovery stage and from an additional cohort of 29 ASD and 41 TD children for the validation stage"), researchers reported detecting and identifying "63 UAA [urinary amino acid] indicators." Twenty-one of these amino acids and/or amino acid metabolites were observed to be "present at significantly different levels in the urine of ASD children compared with TD children" in both participant sets. These compounds were fairly evenly either higher or lower in the kids with autism group (10 higher and 11 lower). I was particularly interested to see that creatinine was observed to be in the significantly higher category associated with the autism group given some other results that were counter to this finding (see here and see here) including some of my own published data [2] from a few years back. Authors also mention how they "identified a panel of 7 UAA indicators that [most effectively] discriminated between the samples from ASD and TD children (lysine, 2-aminoisobutyric acid, 5-hydroxytryptamine, proline, aspartate, arginine/ornithine, and 4-hydroxyproline)."

From those compounds, a few themes emerged with regards to the biochemistry that *might* show some involvement with autism. So: "Abnormalities in the Methionine Cycle in Children With ASD", "Evidence of High Oxidative Stress Levels in Children With ASD" and "Abnormalities in 5HT Metabolism in Children With ASD" are some of the systems potentially implicated by Liu et al. Needless to say that such biological systems are by no means strangers to autism research (see here and see here for examples) albeit not necessarily always in the same direction as the Liu findings.

Caveats? Well yes, a few, such as a reliance solely on single spot urine samples rather than multiple samples from the same person, no other measures of amino acid content in blood for example, and the focus on participants diagnosed with autism excluding things like "attention-deficit hyperactivity disorder, obsessive compulsive disorder" where 'real-life autism' rarely exists in some sort of diagnostic vacuum (see here). But, the findings are interesting and once again highlight how metabolomics is something particularly valuable to autism research (see here) and complementary to genetic studies for example, when trying to decipher the very heterogeneous autisms (plural). Issues with certain amino acids when identified in the context of autism *might* also point to a wider issue (see here) that could also indicate intervention too...

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[1] Liu A. et al. Altered urinary amino acids in children with autism spectrum disorders. Front. Cell. Neurosci. 2019. Jan 10.

[2] Whiteley P. et al. Spot urinary creatinine excretion in pervasive developmental disorders. Pediatr Int. 2006 Jun;48(3):292-7.

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Behind the headline: "Autism: Scientists take 'first steps' towards biological test"

Monday 19th February 2018. I opened my computer up early in the morning and lo and behold, headlines about autism appeared, as exemplified by the BBC article titling this post: "Autism: Scientists take 'first steps' towards biological test." A cold shudder ran down my body as memories of previous 'Super-parenting' improves children's autism and similar headlines sprung to mind and with it, the question of whether big claims were being made...

The paper behind the headlines this time around was from Attia Anwar and colleagues [1] (open-access) and I have to say at first sight I was really rather interested in the specific topic under investigation. Namely: "to explore the diagnostic utility of proteotoxic biomarkers in plasma and urine, plasma protein glycation, oxidation, and nitration adducts, and related glycated, oxidized, and nitrated amino acids (free adducts), for the clinical diagnosis of ASD [autism spectrum disorder]." Interested because the words 'amino acids' (an area of interest to this blog) were mentioned and also that their description of using "stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry" plays to the analytical chemistry nerd that I've seemingly become down the years.

So, bearing in mind the Anwar paper is open-access, what were the hows-and-whys of this 'first steps' research? Well, the initial premise was a sensible one as words like '3-nitrotyrosine (3-NT)' are mentioned following other research noting this compound with some autism in mind (see here). It all ties into the process of oxidative stress and neuroinflammation that are becoming more readily accepted to be part-and-parcel of at least some autism (see here and see here). Researchers set out to see if they could detect some important compounds involved in the process of protein homeostasis (amino acids are the building blocks of protein) and whether, by using the process of machine learning on the derived data (see here for another example of this being applied to autism), the possibility of a diagnostic test for autism might be forthcoming from such work. Yes, this was another example of metabolomics being applied to autism research (see here and see here) and seems to continue a research journey from members of this authorship group [2].

Urine and plasma samples were the chosen analytical media, as authors report on the recruitment of 38 children diagnosed with an ASD and 31 not-autism controls. Yet again, the words 'healthy controls' are used to denote not-autism; something that we really shouldn't be seeing in this day and age. I'd also, by the way, say the same things about the term 'neurotypical' too (see here). The autism group did seem to have quite an extensive diagnostic work-up as both ADOS and CARS scores are presented. Spot blood and urine samples were provided by all and metabolomic analysis was begun...

Results: bearing in mind the significant complexity of both urine and plasma samples when it comes to the presence of small molecules and metabolites, the use of that mass spec method made short work of detecting the glycation markers indicated for study. I note also authors also provide some results on various amino acids in both urine and plasma that is, I think, rather important.

The first thing that struck me was the authors use of a compound called creatinine to correct for sample strength and dilution. I'd like to think I know a thing or two about creatinine (urinary) in relation to some autism on the back of a bit of published research a decade or so back [3]. Our conclusion then and also in some other independent work since (see here) is that caution is required when using creatinine as a corrector with autism in mind...

Having said that, a few findings are noteworthy: "we identified changes in plasma protein AGE [advanced glycation endproducts] and oxidation adducts, increased CML [Nε-carboxymethyl-lysine], CMA [Nω-carboxymethylarginine], and DT [dityrosine] and decreased 3DG-H [3-deoxyglucosone] in ASD." I'm not all too familiar with all of those compounds listed but going back to my observation on oxidative stress being something pertinent to some autism [4], I think there are some important connections to be seen. I note also that at least one of the findings - increased DT residue content of plasma proteins - might also provide a role for those trillions of wee beasties that call us home, the gut microbiota. Mention of the gastrointestinal (GI) tract in the context of autism is likely not to sit well with some people, despite multiple evidence of involvement for some in both a functional sense (see here) and also at a more biological level (see here).

Then to the headline maker: "Algorithms to discriminate between ASD and healthy controls gave strong diagnostic performance with features: plasma protein AGEs—CML, CMA—and 3-deoxyglucosone-derived hydroimidazolone, and oxidative damage marker, DT. The sensitivity, specificity, and receiver operating characteristic area-under-the-curve were 92%, 84%, and 0.94, respectively." Those sensitivity and specificity stats aren't bad at all. They are certainly on a par with other 'classification' attempts with autism in mind, such as when cortisol and a suite of cytokines got the same analytical treatment for example (see here). The trouble is that such stats are based on a relatively small sample size and indeed, children aged between 5-12 years old. Given that many children (but not all) are diagnosed quite a bit earlier than 5 years of age, one has to wonder how relevant any biological test might be at such a later age. One is left feeling that perhaps the discrimination analysis part of the Anwar paper should have perhaps been left until replication on an independent cohort with a larger sample size was carried out, and perhaps relying on more than one testing occasion.

I was also a little bit 'put out' that I couldn't find any 'limitation' discussions in the paper by Anwar et al. There was lots of chatter about how this, that and t'other might relate to biological processes pertinent to some autism but in the discussion section there was very little about what could be wrong with the results as they stand (e.g, small sample sizes). In the current age also when autism is more and more being talked about as NOT being a stand-alone diagnosis (see here) and indeed, probably is a more plural diagnosis ("the autisms"), it is always worthwhile mentioning how any obtained results might have to be framed in those contexts. Yes, authors did have exclusion criteria for study entrance: "Subjects with ascertained medical and neurological comorbidity were excluded, through a medical work up including electroencephalography (recorded during awake and sleep), cerebral magnetic resonance imaging, standard clinical and neurological examination, neurometabolic, and genetic investigations (including comparative genomic hybridization array, molecular assay for Fragile X and MECP2)" but autism pure might not be so typical in the real world [5].

Although some people have reacted quite strongly to the Anwar results, I do think this is quite a good study. No, as it stands, I don't think it can say that autism might be diagnosed on the basis of a urine and/or blood sample. Indeed, we've been here before (see here for example). But it does provide some welcome insight into some of the potential biology associated with at least some autism, and once again, champions the use of some really, really advanced metabolomic technology to provide potential systems biology insights into at least some autism...

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[1] Anwar A. et al. Advanced glycation endproducts, dityrosine and arginine transporter dysfunction in autism - a source of biomarkers for clinical diagnosis. Molecular Autism. 2018; 9: 3.

[2] Anwar A. et al. Quantitation of plasma thiamine, related metabolites and plasma protein oxidative damage markers in children with autism spectrum disorder and healthy controls. Free Radic Res. 2016 Nov;50(sup1):S85-S90.

[3] Whiteley P. et al. Spot urinary creatinine excretion in pervasive developmental disorders. Pediatr Int. 2006 Jun;48(3):292-7.

[4] Rossignol DA. & Frye RE. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front Physiol. 2014 Apr 22;5:150.

[5] Gillberg C. & Fernell E. Autism plus versus autism pure. J Autism Dev Disord. 2014 Dec;44(12):3274-6.

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ADHD symptoms and chronic fatigue syndrome?

With the pinnacle of the season of 'jolly' almost upon us, I'd like to make some brief discussion on the findings reported by Denise Rogers and colleagues [1] and specifically the observation that: "ADHD [attention-deficit hyperactivity disorder] symptoms were significantly greater in the CFS [chronic fatigue syndrome] group than in HC [healthy controls]."

With the aim of examining both the prevalence of fatigue in cases of ADHD and the prevalence of ADHD symptoms in adults with CFS (a term 'linked to' the condition called myalgic encephalomyelitis), researchers set about investigating several measures including self-reported (that's 'self-reported') fatigue "across groups of adults with ADHD (N = 243), CFS (N = 86), and healthy controls (HC) (N = 211)." The results were interesting insofar as that previous sentence on ADHD symptoms perhaps not being uncommon in cases of CFS vs. asymptomatic controls but also that: "Fatigue is a common clinical feature of attention deficit hyperactivity disorder (ADHD) in adulthood."

Accepting that there may be important implications from the notion that fatigue may be part and parcel of at least some ADHD (see here for example), the idea that ADHD signs and symptoms might be over-represented in cases of CFS is interesting, if not necessarily novel [2]. Minus any sweeping generalisations or psychobabble explanations of hows-and-whys (we've had quite enough of those in relation to CFS), I'd like to think that such an association could shed some light on the possible shared genetics, epigenetics and biochemistry of both conditions. Given also some initial data emerging on the potential usefulness of something like methylphenidate (indicated for cases of ADHD) for cases of CFS (see here) there are also avenues to explore in relation to shared drug targets across both conditions (see here for some discussion on oxidative stress for example). I'd like to see more study on this topic, bearing in mind how broad labels like CFS and ADHD can be. I'm also wondering whether researchers might also one day replace examination of ADHD traits with autistic traits so as to perhaps provide data on whether there may be other important associations to be had...

And with that I wish you all a very Merry Christmas and a happy and healthy New Year. I'm not done just yet with this years blogging adventures as my annual 'what was hot in autism research in 2016' post is scheduled sometime next week (if you're interested/bored of turkey/bored of watching Christmas films - delete as appropriate).

Music to close and as always at this time of year, it wouldn't be the same without Kirsty and Shane. And please, do try to stay out of the drunk tank this Christmas...

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[1] Rogers DC. et al. Fatigue in an adult attention deficit hyperactivity disorder population: A trans-diagnostic approach. Br J Clin Psychol. 2016 Dec 5.

[2] Sáez-Francàs N. et al. Attention-deficit hyperactivity disorder in chronic fatigue syndrome patients. Psychiatry Res. 2012 Dec 30;200(2-3):748-53.

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Rogers, D., Dittner, A., Rimes, K., & Chalder, T. (2016). Fatigue in an adult attention deficit hyperactivity disorder population: A trans-diagnostic approach British Journal of Clinical Psychology DOI: 10.1111/bjc.12119

On genes, environment, broccoli and autism (again)

Picture: Carl Warner: http://www.carlwarner.com/

I'm serving up two peer-reviewed papers for your reading delight today which draw attention to the ideas that (a) the 'causes' of autism are likely complex and as heterogeneous as the label itself, (b) gene x environment interactions affecting risk of autism are starting to get some good scientific research airtime and (c) don't 'dis the broccoli [chemical] autism connection just yet...

The first paper by Brandon Pearson and colleagues [1] (open-access) has already found some media interest as per the Guardian headline: 'Agricultural fungicides are 'bad news for neurons', study suggests'. Exposing mouse neurons - "cortical neuron-enriched cultures" - to several hundred chemicals (careful of that word) found in the modern environment, researchers concluded that several compounds "produce transcriptional changes in vitro that are similar to those seen in brain samples from humans with autism, advanced age and neurodegeneration (Alzheimer’s disease and Huntington’s disease)." That is, several types of chemicals quite commonly found in the modern environment seemed to alter gene expression in those mouse neuron enriched cultures that weren't a million miles away from that noted previously in conditions such as autism for example.

Mouse neurons, you might be thinking? Well, obviously one has to be a little cautious about extrapolating from mouse to humans (see here) but researchers did include some comparison analysis looking at "the gene expression profile of our cultures with brain cell-type-specific expression data sets and human brain gene expression data sets." The result: "cortical cultures show strong transcriptional similarities to the human brain."

Clustering chemicals based on "concordant gene expression changes", six groups emerged. Cluster 2 chemicals, containing such pesticides as rotenone, pyridaben and fenpyroximate  and also various compounds under the heading of the strobilurins seemed show some particularly interesting results insofar as they "mimicked the transcriptional changes of two post-mortem ASD [autism spectrum disorder] brain expression data sets in a bidirectional manner." The effects of this cluster of compounds also seemed to unite various conditions with autism including Alzheimer’s disease and Huntington’s disease and the "aging brain". My interest was particularly piqued by that last association in light of other research results (see here).

When it came to the 'effects' of those chemicals in terms of genetic and biological processes, researchers put forward some not unfamiliar potential roles: "These chemicals, most of which inhibit mitochondrial complex I or III, stimulated free radical production and disrupted microtubules." Words like 'oxidative stress' start to emerge as they have done in previous autism research (see here) and yet again, inflammation or inflammatory processes seem also to be indicated. Indeed, the authors also make mention of how effects such as free radical production "can be reduced by pretreating with a microtubule stabilizer, an antioxidant, or with sulforaphane." Yes indeed, sulforaphane - the chemical found in broccoli - might indeed be moving back up the autism research agenda (see here for some previous background).

There is obviously lots more work to do in this area before anyone gets too carried away. The authors note: "While usage and residue levels of cluster 2 chemicals on conventionally grown foods are increasing, in the absence of causality, it is premature to draw correlations with the increased prevalence of ASD and other brain disorders." Lessons could be learned from other blanket suggestions about 'chemicals' and autism (see here) as well as an appreciation for the concept of the the plural autisms (see here). Then there are the practicalities of whether ingesting such compounds on food or in water is the same as direct exposure to cortical neuron-enriched cultures? Or indeed, whether there may be other routes of contact? I might also suggest that further studies should focus on looking for the metabolites of such agents too [2] bearing in mind the concept of statistically significant thresholds...

If you're still here after all that, the second paper I want to talk about is that from Sarah Wong and colleagues [3] that has also received a bit of media attention. The focus this time was on a gene called p53 (see here for some background) and how issues with this gene might be 'over-represented' when it comes to autism following on from other work by some of the same authors [3]. First of all, please don't get too fixated by mention of the words 'cancer gene' when it comes to p53 given it's [protein] tumour suppressing capabilities. As I've discussed before, the risk of cancer does not seem to be elevated any more than the general population risk when it comes to autism (see here). Perhaps of greater relevance to the Wong findings is the idea that p53 has other 'activities' such as that related to oxidative stress (yes, that again) and "DNA repair, bioenergetics and mitochondrial DNA (mtDNA) copy number maintenance."

Based on data from CHARGE (beincharge!), researchers garnered blood samples from 66 children diagnosed with an autism spectrum disorder (ASD) and "race-, gender-, and age-matched typically neurodeveloping children (n = 46)" (authors words not mine). They analysed for mtDNA copy number and deletions and p53 gene copy ratios and found them to be "more common in children with AU [autism] and their fathers." The authors translate their findings as pointing to "a role for deficient DNA repair capacity not driven by paternal age." They also suggest that environment might intersect with genetics in relation to 'severity' scores of autism obtained for their cohort: "gene x environment interaction seems to play a greater role in children with autism with less severe symptoms."

Taken together the Pearson and Wong findings point to some interesting 'associations' potentially relevant to [some] autism. The idea that certain components of the modern-day environment might increase the risk of autism is nothing new but the way that Pearson et al went about studying the possible relationship is. The results from Wong et al suggesting that there might be issues with the gene 'whose role is to suppress cellular damage from environmental stressors' suggests that exposure patterns might not necessarily be where it's all at when looking at compound/chemical X or Y in relation to autism risk. I'm also inclined to direct you to some previous discussion about the caspases and autism (see here) in light of the involvement of p53 with the process of apoptosis (programmed cell death) in mind. As I've mentioned before, the biological mechanisms for how people deal with various xenobiotics needs a lot more investigation in autism research circles (see here); something that might similarly extend to genetic mechanisms too.

Oh, and just in case you think that I'm pushing the either/or of genetic and environment when it comes to autism, I'm not, as words like epigenetics spring to mind and the idea that genomic instability might, for example, have quite a few different dimensions (see here)...

To close, I'm thinking of branching out... football (soccer) pundit perhaps?

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[1] Pearson BL. et al. Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration. Nat Commun. 2016 Mar 31;7:11173.

[2] Domingues VF. et al. Pyrethroid Pesticide Metabolite in Urine and Microelements in Hair of Children Affected by Autism Spectrum Disorders: A Preliminary Investigation. Int. J. Environ. Res. Public Health 2016; 13: 388.

[3] Wong S. et al. Role of p53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study. Pediatrics. 2016. March 31.

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Pearson, B., Simon, J., McCoy, E., Salazar, G., Fragola, G., & Zylka, M. (2016). Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration Nature Communications, 7 DOI: 10.1038/ncomms11173




Wong, S., Napoli, E., Krakowiak, P., Tassone, F., Hertz-Picciotto, I., & Giulivi, C. (2016). Role of p53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study PEDIATRICS, 137 (4) DOI: 10.1542/peds.2015-1888

Folate receptor autoantibodies (FRAAs) and a 'type' of autism?

"This study suggests that FRAAs [folate receptor α (FRα) autoantibodies] are associated with specific physiological and behavioral characteristics in children with ASD [autism spectrum disorder] and provides support for the notion that these biomarkers may be useful for subgrouping children with ASD, especially with respect to targeted treatments."

So said the study findings published by Richard Frye and colleagues [1] (open-access) who continued a research theme looking at FRAAs and their manifestation in 'some' autism. If you've already clicked that link in the last paragraph, you should have something of a flavour for what FRAAs are and what has already been discussed with autism in mind. If you didn't, the long and short of it is FRAAs describing the possibility of issues with folate transport as noted in the condition cerebral folate deficiency (CFD) are also being reported alongside some autism. The subsequent use of folinic acid (a vitamer of folic acid) to compensate might be something to consider for at least some on the autism spectrum bearing in mind my not giving any medical or clinical advice. I might also direct readers to a previous post with a helpful graphic on how the folate cycle also links in to some other important metabolic processes (see here) which is particularly timely in light of more publications on the topic of 'MTHFR'. I'll come back to this shortly.

This time around, Dr Frye and colleagues set about looking at whether those with autism also with issues around FRAAs present with a 'specific type' of autism, also taking into account different types of FRAAs - blocking and blinding. Serum samples for 94 children diagnosed with an ASD were analysed for blocking and binding FRAAs. At the same time, various markers covering redox, methylation, immune function and vitamin status were also determined and various measures of behaviour examined.

Results: "Fifty seven percent of the participants were positive for either the blocking or binding FRAAs, with 17% positive for blocking FRAA and 51% positive for the binding FRAA; 11% were positive for both FRAAs." From a behavioural/psychometric perspective: "ASD children positive for the blocking FRAA demonstrated better communication on the Vineland Adaptive Behavior Scale, stereotyped behavior on the Aberrant Behavioral Checklist and mannerisms on the Social Responsiveness Scale." In other words, those children with evidence of FRAAs, particularly blocking FRAAs, seemed to "have less severe ASD symptoms." The authors make mention of the term 'optimal outcome' with regards to this group, which is interesting when you consider the status of this often contentious line of research (see here).

The results of the various biological assays employed showed some interesting results. So: "ASD children with the blocking FRAA appear to have a more favorable redox and inflammation profile with relatively better glutathione and CT [3-Chlorotyrosine] indices than FRAA blocking negative children." Further, although folate levels were not significantly different between the groups on the basis of the presence of blocking or binding FRAAs (or neither), levels of vitamin B12 did show some differences: "Children positive for the binding FRAA were found to have higher serum B12 levels as compared to those negative for binding FRAAs."

Appreciating that it is still early days when it comes to FRAAs and autism, this and other research is crying out for independent replication with some appropriate cautions that FRAAs are not seemingly just confined to a diagnosis of autism (see here). The idea that those with autism with a specific type of FRAA (blocking) might present with a more favourable ASD profile in terms of symptoms and also biochemistry invites the question of whether the presence of such biology might actually be 'beneficial' bearing in mind the limited participant numbers included in the Frye study. I know that this might sound at odds with the whole folate-autism link that has been built up over the years, but as I've said before on this blog, folate metabolism and autism is a mighty complicated topic (see here). Likewise, is the idea that the presence of binding FRAAs might be something to 'target' given their seemingly less favourable biological and behavioural profile.

I do have one or two other points to make before I leave you. First, although mention is made of serum levels of the various biological analytes under investigation, one should be mindful of how representative these values are across the body. High serum vitamin B12 does not necessarily mean high brain levels of vitamin B12 for example (and alongside vitamin B12 I would have liked to have seen some data on the compound that is methylmalonic acid). Second, although mention is made of "methylenetetrahydrofolate reductase" (MTHFR), it would be interesting to see how many of the group presented with genetic issues with the production of this enzyme in light of previous findings (see here) and onwards the nature of any connection with FRAAs and autism.

This is interesting work but lots more investigation is implied.

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[1] Frye RE. et al. Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups. Front. Neurosci. 2016. March 9.

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Frye, R., Delhey, L., Slattery, J., Tippett, M., Wynne, R., Rose, S., Kahler, S., Bennuri, S., Melnyk, S., Sequeira, J., & Quadros, E. (2016). Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups Frontiers in Neuroscience, 10 DOI: 10.3389/fnins.2016.00080

Methyl B12 for autism? Placebo-controlled results say maybe...

"Methyl B12 treatment improved clinician-rated symptoms of ASD [autism spectrum disorder] that were correlated with improvements in measures of methionine metabolism and cellular methylation capacity."

Those were the very encouraging results published by Robert Hendren and colleagues [1] who can now update their ClinicalTrials.gov study entry (see here). Building on the ideas that: "Children with autism spectrum disorder (ASD) have been reported to have reduced ability to methylate DNA and elevated markers of oxidative stress" (topics that have been covered on this blog before), researchers undertook a gold-standard trial - randomised, placebo-controlled - to ascertain the effect (if any) of "8 weeks of treatment with methyl B12 (75 μg/kg) or saline placebo every 3 days in a subcutaneous injection." The success of the treatment was measured by "the Clinical Global Impressions-Improvement (CGI-I) score" accompanied by "changes in the Aberrant Behavior Checklist (ABC) and the Social Responsiveness Scale (SRS)" scores. At the same time, researchers also looked at various biochemical parameters pertinent to "methionine methylation and antioxidant glutathione metabolism."

Based on the 50 children ("mean age 5.3 years") who completed the study, researchers reported a trend of improvement in autistic and related behaviours following the methyl B12 injections. Importantly, the primary outcome measure - the CGI-I scores - rated by clinicians, showed a trend of being "statistically significantly better (lower) in the methyl B12 group (2.4) than in the placebo group (3.1) (0.7 greater improvement in the methyl B12 group, 95% CI 1.2-0.2, p = 0.005)." Biological parameters also showed changes: "increases in plasma methionine (p = 0.05), decreases in S-adenosyl-l-homocysteine (SAH) (p = 0.007) and improvements in the ratio of S-adenosylmethionine (SAM) to SAH (p = 0.007), indicating an improvement in cellular methylation capacity" following the use of methyl B12 compared with placebo.

Accepting that 'subcutaneous injection' of methyl B12 is hardly a 'user-friendly' option and may very well scupper plans to use this particular intervention option for quite a few, these are potentially important results. I'm really quite interested in how vitamin B12 'vitamers' might show some links to at least some 'types' of autism (see here) including the measurement of 'brain levels' of the stuff (see here). The Hendren results suggest that quite a few more research resources might be needed in this area. I wonder also if this future research agenda would include the 'baby and bathwater' compound that is methylmalonic acid in relation to autism too (see here)?

I do also have to point out that previous research from members of this research team has not been so complimentary about the use of methyl B12 in cases of autism [2] despite the idea that there may be 'responders' to this type of intervention. To quote: "methyl B12 may alleviate symptoms of autism in a subgroup of children, possibly by reducing oxidative stress. An increase in glutathione redox status (GSH/GSSG) may provide a biomarker for treatment response to methyl B12." Such differences in reported results are not unfamiliar to autism research (the rule rather than the exception) but perhaps provides a further focus for clarification of effect.

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[1] Hendren RL. et al. Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism. J Child Adolesc Psychopharmacol. 2016 Feb 18.

[2] Bertoglio K. et al. Pilot study of the effect of methyl B12 treatment on behavioral and biomarker measures in children with autism. J Altern Complement Med. 2010 May;16(5):555-60.

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Hendren RL, James SJ, Widjaja F, Lawton B, Rosenblatt A, & Bent S (2016). Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism. Journal of child and adolescent psychopharmacology PMID: 26889605

MOCOS: a new candidate for autism research

I'll freely admit that until reading the paper by François Féron and colleagues [1] (open-access available here) I had never heard of MOCOS (MOlybdenum COfactor Sulfurase) before.

Described as "an enzyme of the purine metabolism that sulfurates the molybdenum cofactor, thus allowing the two downstream enzymes—xanthine dehydrogenase (XDH) and aldehyde oxidase (AOX1)—to be active", researchers reported that in nasal stem cells provided by a small group of adults diagnosed with an autism spectrum disorder (ASD), MOCOS was down-regulated compared with analyses of similar cells from asymptomatic controls. They concluded that differences related to MOCOS might be important: "likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders."

I'm intrigued.

The Féron paper is open-access but a few details might be useful:

• Eleven participants diagnosed with autism (autism spectrum disorder, ASD) were included for study. Interestingly, DSM-5 diagnostic criteria were used to confirm the presence of ASD. Age and gender matched asymptomatic (for autism) controls were also used. As per the supplementary information included with the main article (see here), the authors characterised their participant group pretty well from various different angles.
• A nasal biopsy was performed on participants in order to extract "nasal olfactory stem cells" based on a previously published technique [2]. Again, it's new news to me that you can get stem cells from the nose but apparently the "olfactory epithelium is also a nervous tissue that produces new neurons every day to replace those that are damaged by pollution, bacterial of viral infections. This permanent neurogenesis is sustained by progenitors but also stem cells residing within both compartments of the mucosa, namely the neuroepithelium and the underlying lamina propria."
• Based on a "non-hypothesis-driven approach" Féron et al set about looking for "transcriptome anomalies" between the groups. Alongside other potentially important differences they stumbled across MOCOS in relation to their autism cohort and decided to look-see whether this might have some impact on cerebral functions using a classical worm model - Caenorhabditis elegans (C. elegans). A "genetic ablation of mocs-1 (the MOCOS ortholog)" engineered into the worm induced "an alteration of the response to oxidative stress and is responsible for abnormal neurotransmission phenotypes." Human cell studies confirmed this data.

Despite the small participant group, the MOCOS findings might carry some weight in view of some of the other 'dysregulated' genes that turned up with the ASD group in mind. So: "9 out of these 156 genes—ADAM23, CADM1, FOS, FOSB, JAG1, MEST, OXTR, SFRP1 and XIST—have been previously associated with ASD." You might note the mention of OXTR in that list, denoting the oxytocin receptor gene bearing in mind the cautious history in that area. That also pathway analysis of the genes differentially regulated in the autism group "identified developmental disorders and gastrointestinal diseases as two of the most represented categories associated with these genes" adds to the interest, bearing in mind the term 'over-represented' when it comes to bowel issues and autism (see here).

The suggestion that "MOCOS misexpression increases sensitivity to oxidative stress" is also an important part of the Féron findings. Oxidative stress and autism has quite a bit of peer-reviewed research history (see here for example) particularly in areas such as glutathione metabolism (see here) albeit not universally [3]. It's not beyond the realms of possibility that MOCOS may indeed be a contributory factor to such issues being present in some cases.

Further work is required in this area to corroborate the Féron data using larger participant numbers for example. With that in mind, I'll be keeping my eye open for more work on MOCOS and autism and whether it lives up to its 'new player' status...

Music: Weezer and Undone.

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[1] Féron F. et al. Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders. Mol Psychiatry. 2015 Aug 4.

[2] Girard SD. et al. Isolating nasal olfactory stem cells from rodents or humans. J Vis Exp. 2011 Aug 22;(54). pii: 2762.

[3] Durieux AM. et al. Cortical and subcortical glutathione levels in adults with autism spectrum disorder. Autism Res. 2015 Aug 20.

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Féron F, Gepner B, Lacassagne E, Stephan D, Mesnage B, Blanchard MP, Boulanger N, Tardif C, Devèze A, Rousseau S, Suzuki K, Izpisua Belmonte JC, Khrestchatisky M, Nivet E, & Erard-Garcia M (2015). Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders. Molecular psychiatry PMID: 26239292

Methylphenidate: a repairer of the 'oxidative balance' in ADHD?

A fairly quick post for you today based on the findings reported by Esra Guney and colleagues [1] who examined whether markers of oxidative stress - an imbalance "between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage" - might be something to look at when it comes to cases of attention-deficit hyperactivity disorder (ADHD).

They concluded that, based on a small-ish sample size, there may be more to see when it comes to oxidative metabolism with ADHD in mind. Their findings are not a million miles away from other work in this area [2] bearing in mind the need for further investigations. I might add that given the quite strong links being put forward between autism and issues with oxidative stress (see here) and the quite consistent overlap between autism and ADHD (see here), future work might need to take quite a broad view of any relationship.

Of particular note to me in the Guney paper was mention of how differences in the oxidative stress index before and after intervention (i.e. medication) in their cohort might offer some new ideas about how certain types of medicines 'work' on cases of ADHD. So: "It was also determined that methylphenidate repairs the oxidative balance by increasing antioxidant defence mechanisms."

Methylphenidate (MPH) (known as Concerta or Ritalin) is a medication of choice for many people diagnosed with ADHD. Although by no means an expert on the whys and wherefores of how MPH works, discussions have always been a little unclear as to how something that looks chemically like an amphetamine (a stimulant) seems to have such a calming effect on some of the characteristics of ADHD. As a nootropic (so-called smart drug) the idea that MPH might work as a performance enhancer offers some clues as to how it might impact on ADHD type symptoms but still curiosity remains on it's important effects.

The idea that MPH might, in amongst its various proposed actions, also impact on processes pertinent to oxidative stress is an interesting one. Animal studies have previously suggested that administration of MPH might affect key compounds related to oxidative stress [3] in particular, related to oxidative defences. That being said, evidence has also been produced to suggest that MPH might do more to induce oxidative stress [4] than to solve any issues, so one has to be a little guarded about making too many sweeping generalisations. That drug dose might also be an important factor is something to take on board too.

Assuming further work is forthcoming to further elucidate any role for MPH in relation to the processes of oxidative stress, some intriguing prospects may lie on the research horizon.

Music: Dream Academy - Life In A Northern Town.

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[1] Guney E. et al. Attention Deficit Hyperactivity Disorder and oxidative stress: A short term follow up study. Psychiatry Res. 2015 Jul 8. pii: S0165-1781(15)00448-5.

[2] Joseph N. et al. Oxidative Stress and ADHD: A Meta-Analysis. J Atten Disord. 2013 Nov 14.

[3] Schmitz F. et al. Chronic methylphenidate administration alters antioxidant defenses and butyrylcholinesterase activity in blood of juvenile rats. Mol Cell Biochem. 2012 Feb;361(1-2):281-8.

[4] Martins MR. et al. Methylphenidate treatment induces oxidative stress in young rat brain. Brain Res. 2006 Mar 17;1078(1):189-97.

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Guney, E., Cetin, F., Alisik, M., Tunca, H., Tas Torun, Y., Iseri, E., Isik Taner, Y., Cayci, B., & Erel, O. (2015). Attention Deficit Hyperactivity Disorder and oxidative stress: A short term follow up study Psychiatry Research DOI: 10.1016/j.psychres.2015.07.003

High risk for autism = shortened telomeres?

I don't want to spend too long discussing the paper by Charles Nelson and colleagues [1] suggesting that: "Families of children with ASD [autism spectrum disorder] who have an infant show shortened telomeres relative to families with no history of ASD" but it is worth blogging about.

As per a previous entry on telomeres and autism (see here), telomeres - the biological equivalent of plastic aglets on shoelace tips to prevent fraying - are starting to enter the autism [peer-reviewed] research psyche on top of their more traditional role suggested in ageing and cancer for example (see here). Indeed, telomeres and cellular ageing are getting quite a bit of press these days with psychiatry in mind [2] as per the goings-on with schizophrenia in mind [3] and psychotic symptoms [4].

The Nelson study started from the angle that: "Exposure to psychological stress is associated with accelerated telomere shortening, and a well-established body of evidence indicates that families with a child with autism spectrum disorder (ASD) experience heightened levels of psychological stress." They also make mention of the words 'oxidative stress' and 'DNA methylation' as also potentially impacting on telomere length and at the same time having some research 'form' when it comes to autism (see here and see here respectively).

With that all in mind, saliva samples were analysed for family members designated as 'high risk for ASD (HRA)' or 'low risk for ASD (LRA)' as a function of "older siblings' diagnostic status." Relative average telomere length was the chosen variable analysed by a "real-time polymerase chain reaction (PCR) telomere assay."

Results: "HRA families demonstrated significantly shorter telomere length relative to LRA families." This was noted across the board when it came to family members analysed (infants, older siblings parents) although the group data comparing fathers between the groups were not significantly different. The authors conclude that: "such "high-risk" families should be monitored for the physical and mental health consequences that are often associated with accelerated telomere shortening."

This is interesting work (isn't is always?) but I'm going to advise a little caution before anyone goes assuming that telomere length is the be-all-and-end-all of autism research. The inevitable hype that has followed telomere research down the years has done some real damage to the credibility of some of the findings on telomeres in other areas so one treads a little carefully. That telomere length seems also to correlate with quite a few other interesting concepts such as inflammation for example [5] is also of potential interest, particularly when inflammation seems to crop up time and time again with [some] autism in mind (see here). I dare say that future studies of telomere length and autism might want to take quite a wide view of any association including the analysis of telomerase too.

Music: The Charlatans - The Only One I Know.

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[1] Nelson CA. et al. Shortened Telomeres in Families With a Propensity to Autism. J Am Acad Child Adolesc Psychiatry. 2015 Jul;54(7):588-94.

[2] Lindqvist D. et al. Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging. Neurosci Biobehav Rev. 2015 May 18;55:333-364.

[3] Polho GB. et al. Leukocyte telomere length in patients with schizophrenia: A meta-analysis. Schizophr Res. 2015 Jul;165(2-3):195-200.

[4] Pawelczyk T. et al. Telomere length in blood cells is related to the chronicity, severity, and recurrence rate of schizophrenia. Neuropsychiatr Dis Treat. 2015 Jun 22;11:1493-503.

[5] Jurk D. et al. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat Commun. 2014 Jun 24;2:4172.

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Nelson CA, Varcin KJ, Coman NK, DeVivo I, & Tager-Flusberg H (2015). Shortened Telomeres in Families With a Propensity to Autism. Journal of the American Academy of Child and Adolescent Psychiatry, 54 (7), 588-94 PMID: 26088664

Maternal diabetes and offspring autism risk... again

"In this large, multiethnic clinical cohort of singleton children born at 28 to 44 weeks’ gestation, exposure to maternal GDM [gestational diabetes mellitus] diagnosed by 26 weeks’ gestation was associated with risk of ASD [autism spectrum disorder] in offspring."

That was the conclusion reached by Anny Xiang and colleagues [1] (open-access) following their analysis of some 3300 children diagnosed with ASD as part of a wider cohort of over 300,000 children "born in 1995-2009 at Kaiser Permanente Southern California (KPSC) hospitals." Records of children with and without autism were examined according to the presence or not of maternal type 2 diabetes or maternal GDM during pregnancy. "Diagnosis of GDM was based on laboratory values confirming a plasma glucose level of 200 mg/dL or higher on the glucose challenge test or at least 2 plasma glucose values meeting or exceeding the following values on the 100-g or 75-g oral glucose tolerance test: fasting, 95 mg/dL; 1 hour, 180 mg/dL; 2 hours, 155 mg/dL; and 3 hours, 140 mg/dL." Autism diagnosis was based on "ICD-9 codes 299.x or equivalent KPSC codes" covering "autistic disorders, Asperger syndrome, or pervasive developmental disorder not otherwise specified (PDD-NOS) and excluded childhood disintegrative disorder and Rett syndrome."

Results: of the 3388 children diagnosed with an ASD, a large majority were deemed 'unexposed' to either maternal type 2 diabetes or GDM (87%). What this tells us is that ideas about exposure to maternal diabetes being 'universally' associated with a diagnosis of ASD in offspring are incorrect. That being said, some 115 children were exposed to maternal type 2 diabetes and 310 GDM exposed.

Taking into account the timing of exposure as per the analysis of gestational weeks at diagnosis of GDM - "26 weeks or earlier (mean of 16 weeks), after 26 weeks but prior to 30 weeks (mean of 28 weeks), and 30 weeks or later (mean of 32 weeks)" - and controlling for various potentially confounding variables such as maternal age, parity, education, household income, race/ethnicity, history of comorbidity, and sex of the child, some interesting results are reported. GDM exposure diagnosed by 26 weeks gestation was associated with something of an increased risk (hazard ratio) of offspring autism to the tune of about a 40% increased risk. At the same time, exposure to maternal pre-existing type 2 diabetes did not seem to significantly elevate the risk of offspring ASD. The Autism Speaks write-up of the Xiang trial offers this helpful statement: "the increased autism risk seen with early gestational diabetes translated into roughly seven additional cases per 1,000 pregnancies."

The reason why I titled this post 'maternal diabetes and offspring autism risk... again' is because it is not new news that maternal diabetes might have some kind of effect on offspring autism risk. I covered this research area previously on this blog (see here) based on findings such as those from Xu and colleagues [2] (open-access). Other peer-reviewed research has similarly hinted at the possibility of an association between maternal diabetes and offspring autism as part of a wider spectrum of 'effects' on the developing child [3].

"The mechanisms underlying the effects of maternal hyperglycemia on the developing fetus may involve increased oxidative stress, hypoxia, apoptosis, and epigenetic changes" according to that paper by Ornoy and colleagues [3]. With autism in mind, most of those concepts have been banded around as being linked to cases at one time or another, perhaps only missing out on the 'inflammatory' element mentioned by Xiang et al. I wouldn't like to speculate any further on what specific process might be going on (more likely a combination of effects) but given the seemingly important variable of timing, as in exposure to GDM by 26 weeks gestation, I'd suggest that epigenetics might be a front-runner [4]. Foetal programming hypothesis and all that palaver...

"Our results also suggest that screening for GDM and control of glucose levels early in pregnancy may be important in reducing ASD risk for offspring. Whether early diagnosis and treatment of GDM can reduce the risk of ASD remains to be determined." I struggle to disagree with the closing sentiments from Xiang and colleagues.

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[1] Xiang AH. et al. Association of Maternal Diabetes With Autism in Offspring. JAMA. 2015; 313: 1425-1434.

[2] Xu G. et al. Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis. J Autism Dev Disord. 2014 Apr;44(4):766-75.

[3] Ornoy A. et al. Effect of maternal diabetes on the embryo, fetus, and children: Congenital anomalies, genetic and epigenetic changes and developmental outcomes. Birth Defects Res C Embryo Today. 2015 Mar;105(1):53-72.

[4] Lehnen H. et al. Epigenetics of gestational diabetes mellitus and offspring health: the time for action is in early stages of life. Mol Hum Reprod. 2013 Jul;19(7):415-22.

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Xiang, A., Wang, X., Martinez, M., Walthall, J., Curry, E., Page, K., Buchanan, T., Coleman, K., & Getahun, D. (2015). Association of Maternal Diabetes With Autism in Offspring JAMA, 313 (14) DOI: 10.1001/jama.2015.2707

Mercury, autism and mitochondrial dysfunction?

Appreciating that to mention the words 'mercury and autism' in the same sentence can lead to furrowed brows and invoke eye-rolling in some quarters, I don't want to shy away from the results reported by Shannon Rose and colleagues [1] (open-access here) and their suggestion that: "the epidemiological link between environmental mercury exposure and an increased risk of developing autism may be mediated through mitochondrial dysfunction". Further that their result: "support the notion that a subset of individuals with autism may be vulnerable to environmental influences with detrimental effects on development through mitochondrial dysfunction."

Having previously talked about research from this group (see here) based on their examinations of lymphoblastoid cell lines (LCLs) from people with autism, their latest paper seems to be something of an extension of this project. Based on investigations on LCLs from 16 autism/control pairings, mitochondrial respiration was examined as and when said cells were exposed to ethylmercury. A subgroup of LCLs from the autism group "exhibited a greater reduction in ATP-linked respiration, maximal respiratory capacity, and reserve capacity when exposed to ethylmercury, compared to control LCLs." Interestingly, the pre-administration of NAC (N-acetlycysteine) "reduced (normalized) baseline respiratory parameters and blunted the exaggerated ethylmercury-induced reserve capacity depletion." That being said: "LCLs derived from children with autism exhibit significant abnormalities in mitochondrial respiration at baseline with these abnormalities worsening following exposure to ethylmercury" so one has to be a little guarded about making too many universal judgements.

OK. Wearing the cold, dispassionate and [hopefully] objective blinkers of science, there may be a few important implications from this work. First is the idea that for some on the autism spectrum, the puzzle that is mitochondria and mitochondrial dysfunction may require quite a bit more investigation (see here). In these days of plural autisms (see here) the focus perhaps needs to be on subgroups too. Second, as per their previous efforts in this area [2] is the idea that various factors might have the ability to impact on mitochondrial function for some people on the autism spectrum. Third, although still very much a source of deep division within the autism and wider community, the suggestion that ethylmercury (a metabolite of the preservative thiomersal / thimerosal) might have the ability to impact on mitochondrial function for at least some on the autism spectrum perhaps requires further scrutiny. I say this based on the small participant numbers included in the Rose study and their specific focus on LCLs. The doses of ethylmercury used might also require further investigation in terms of translating results from lab to real world.

Finally, the idea that pre-treatment of LCLs with NAC might carry a protective role is rather interesting. Aside from the 'oxidative stress' implications of their findings, I wonder if such an observation might also carry some link to the suggestion that post-vaccination administration of paracetamol (acetaminophen) might be 'implicated' in cases of autism [3]. I say this from a rather non-expert stance in this area but with the knowledge that paracetamol has an effect on glutathione stores under certain circumstances. Glutathione by the way, is one part cysteine and has cropped up in other autism research (see here) as well as subsequently [4]. Separately, given also that glucuronidation is a primary pathway for metabolising paracetamol and with the work from Stein and colleagues [5] in mind (see here), I wonder if there may indeed be more to see here (although accepting that there may be other effects from such antipyretic use).

This is not the first time that mitochondrial dysfunction and "impaired oxidative–reduction" have been studied from the point of view of downstream metabolites of thiomersal as per the paper by Geier and colleagues [6]. Again, the focus on that occasion was cell lines and so one has again to be a little cautious about extrapolating results beyond that. That also other research, in studies of mouse models for example [7], have not tended to support a connection between thiomersal exposure and 'neurodevelopmental disorders' is an important point to make, bearing in mind that mice are mice and not people. Similar sentiments apply to the important recent results from Curtis and colleagues [8] too.

But... the Rose findings cannot be readily dismissed particularly with their focus being potentially relevant to a subgroup of those on the autism spectrum. Adding the paper from Mady Hornig (a very well-respected researcher) into the mix (again based on mice) [9]: "Host differences in maturation, metabolism, nutrition, sex, and autoimmunity influence outcomes" when it comes to the potential of "thimerosal-related neurotoxicity" and quite a bit more research is perhaps indicated.

Music then. Bobby Womack - Across 110th Street.

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[1] Rose S. et al. Increased susceptibility to ethylmercury-induced mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines. J Toxicol. 2015;2015:573701.

[2] Rose S. et al. Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines. Transl Psychiatry. 2014 Apr 1;4:e377.

[3] Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

[4] Abdel-Salam OME. et al. Nuclear Factor-Kappa B and Other Oxidative Stress Biomarkers in Serum of Autistic Children. OJMIP. 2015; 5: 1.

[5] Stein TP. et al. Bisphenol A Exposure in Children With Autism Spectrum Disorders. Autism Research. 2015. Jan 13.

[6] Geier DA. et al. Mitochondrial dysfunction, impaired oxidative-reduction activity, degeneration, and death in human neuronal and fetal cells induced by low-level exposure to thimerosal and other metal compounds. Toxicol Environ Chem. 2009 Jun;91(3-4):735-749.

[7] Berman RF. et al. Low-level neonatal thimerosal exposure: further evaluation of altered neurotoxic potential in SJL mice. Toxicol Sci. 2008 Feb;101(2):294-309.

[8] Curtis B. et al. Examination of the Safety of Pediatric Vaccine Schedules in a Non-Human Primate Model: Assessments of Neurodevelopment, Learning, and Social Behavior. Environ Health Perspect. 2015. Feb 18.

[9] Hornig M. et al. Neurotoxic effects of postnatal thimerosal are mouse strain dependent. Mol Psychiatry. 2004 Sep;9(9):833-45.

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Rose, S., Wynne, R., Frye, R., Melnyk, S., & James, S. (2015). Increased Susceptibility to Ethylmercury-Induced Mitochondrial Dysfunction in a Subset of Autism Lymphoblastoid Cell Lines Journal of Toxicology, 2015, 1-13 DOI: 10.1155/2015/573701