Pigeons, meet cat: "The Hans Eysenck affair: Time to correct the scientific record"

I'm heading off-piste with my musings today, drawing your attention to a paper by Anthony Pelosi [1] and an accompanying editorial by David Marks [2] (both open-access) that are likely to 'put the cat among the pigeons' in some quarters (with thanks to Matthew Dalby for bringing the Pelosi study to my Twitter attention). Indeed, the publishing journal - The Journal of Health Psychology - is no stranger to 'cat among the pigeons' discussions, as per their 2017 special edition [3] on the PACE trial "for patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS)." Perhaps interestingly, there is a 'psychosomatic' connection between the topic covered in the Pelosi paper and those critical musings on how to (or perhaps how not to) treat ME/CFS...

The person at the centre of the Pelosi paper is the late Prof. Hans Eysenck; a figure who anyone with the slightest interest in the discipline called psychology would probably have heard of. Personality was one of the major research interests for Eysenck, and in particular, the proposal of dimensions to personality: extroversion/introversion, neuroticism/stability, psychoticism/socialisation. Perhaps not as famously known about, but still influential, were Eysenck's views relating to "his persistent denial of the carcinogenic effects of tobacco." Indeed, his 'alternative view' that "certain personality traits that lead to smoking also increase the risk of developing cancer" is starting to look decidedly 'shaky' in modern times. More so when there is talk of 'funding' and 'sources of funding' potentially complicating the issue.

Pelosi (and Marks) make a case that the time is right for psychology and various other interconnected disciplines to start looking more critically at the collected published work of Eysenck and some of his colleagues. They argue that claims "about the alleged effectiveness of psychotherapy in preventing cancer" or that "behaviour therapy may be useful in prolonging life, as well as in preventing disease" have little place in modern, evidence-based, science and medicine. Pelosi - who has some important history of being slightly critical of some of Eysenck's findings alongside other notable names - also goes one stage further in suggesting that some of the "widely cited studies" published with Eysenck's name attached "have had direct and indirect influences on some people’s smoking and lifestyle choices." Further: "This means that for an unknown and unknowable number of individual men and women, this programme of research has been a contributory factor in premature illness and death." Strong words indeed.

Marks ends his editorial with open letters to the President and Principal of King's College London and the Chief Executive of the British Psychological Society (BPS) calling for further investigation of the points highlighted in the Pelosi paper. Pelosi has seemingly approached the BPS previously on this matter but apparently did not receive a particularly warm reception to his then request for further investigation of some of the science and conclusions made in this area (see here). Whether such a second request - made in the era of social media - will be acted upon differently this time is a 'wait and see' question. All of this taking into account the moves being made to make psychology a more credible science these days...

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[1] Pelosi AJ. Personality and fatal diseases: Revisiting a scientific scandal. Journal of Health Psychology. 2019. Feb 23.

[2] Marks DF. The Hans Eysenck affair: Time to correct the scientific record. Journal of Health Psychology. 2019. Feb 23.

[3] Marks DF. Special issue on the PACE Trial. Journal of Health Psychology. 2017. July 31..

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Risk of breast cancer in women with schizophrenia: meta-analysed

"In this meta-analysis of 12 cohort studies that included 125 760 women and in which conventional methods of meta-analysis had been used, schizophrenia in women was associated with an increased breast cancer incidence compared with the general population."

That was a primary findings reported by Chuanjun Zhuo & Patrick Triplett [1] following their survey of the peer-reviewed research literature on the topic of breast cancer risk and schizophrenia up to August 2017. The authors caution however that their review of this topic might not be the last word on it - "it is possible that a future study will show a decreased breast cancer risk in women with schizophrenia compared with the general population" - given "substantial between-study variance" among the research literature they examined. Another very good example of how the currency of science is probability and big sweeping generalisations may not necessarily stand the test of time.

"The status of physical health in patients with schizophrenia has become an important topic in health care management research" introduced the the Zhuo/Triplett paper, and with it, important recognition that diagnoses like schizophrenia can lead to an over-emphasis on the psychiatric often to the detriment of the somatic (see here). This, allied to other findings that have suggested that risk of premature mortality from various somatic complaints / diagnoses / issues is potentially heightened in relation to schizophrenia (see here).

Authors located studies fulfilling their study entry criteria, including "schizophrenia identified as exposure at baseline" and "documented incidence of breast cancer on follow-up" and applied their statistical analyses to results. Importantly: "Studies reporting breast cancer–related mortality rather than incidence were also excluded because the mortality outcome may be affected by many factors other than breast cancer incidence, such as comorbidities and treatments." Most of the included studies/data were found to be methodologically sound based on scores on the Newcastle-Ottawa Scale.

Alongside their finding that women with schizophrenia seemed to be at an elevated risk of breast cancer, authors also suggested that "intensive prevention and treatment against breast cancer are warranted for women with schizophrenia." So yes, this means discussing about potentially modifiable risk factors for breast cancer such as alcohol use and obesity (obesity, at the time of writing, being something of a focus for one large cancer charity here in Blighty). But this also means looking at how schizophrenia and its management might also place someone at elevated risk of something like breast cancer as a result of it sometimes being a "hormone-dependent cancer" and, as the authors note, "a significant positive association between plasma prolactin levels and the risk of breast cancer, has been observed." Minus any scaremongering, prolactin elevations have been noted following the use of certain antipsychotic medicines typically indicated for schizophrenia [2] and other conditions (see here). Any additional risk needs to be managed, and managed well.

I don't think anyone should be unduly alarmed by the Zhuo/Triplett results, but rather more mindful of the fact that a psychiatric diagnosis does not disqualify someone from other risks of more somatic conditions / complaints. The key, yet again, is screening and keeping an open mind...

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[1] Zhou C. & Triplett PT. Association of Schizophrenia With the Risk of Breast Cancer Incidence: A Meta-analysis. JAMA Psychiatry. 2018. March 7.

[2] Wu Chou AI. et al. Female schizophrenia patients and risk of breast cancer: A population-based cohort study. Schizophr Res. 2017 Oct;188:165-171.

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Risk of cancer in mums of children with autism

I very carefully approach the findings reported by Jennifer Fairthorne and colleagues [1] today detailing "the occurrence of hospital admissions and treatment/services for cancer in mothers of children with ASD [autism spectrum disorder] with or without ID [intellectual disability] compared with other mothers." Appreciating that families touched by autism probably have enough on their plate without additional talk about the 'big C', I do however think that this kind of research is important if not only as part of the process of 'caring for the carers'.

Based on the analysis of various "Western Australian administrative health databases" (something gaining research ascendancy), researchers sought to estimate the odds, sorry hazard ratios, of hospitalisation and/or use of services in relation to cancer when it came to mums of children with autism (with and without learning disability) "compared with other mothers." They concluded that there may be something more to see when it comes to elevated use of cancer services among mothers of children with autism. Mothers of children with autism but not with accompanying learning disability in particular seemed to be a group in need of quite a bit more scientific investigation.

Minus any sweeping generalisations nor scaremongering, this is important work. I've kinda touched upon the idea that risk of cancer might be something to look at in first degree relatives of those with autism (see here) before. As per reports such as the one by Erin Ingudomnukul and colleagues [2] the risk is not wildly increased similar to the risk of cancer among people with autism themselves (see here), but certainly enough to start asking more research questions about possible mechanisms and the potential applicability of preferential screening services. Indeed, on the topic of possible mechanisms it might be useful to note the growing interest in the idea that autism genes are not necessarily just genes for autism (see here) and that just outside of structural genetics, there is another branch of science ripe for further dual inquiry [3]...

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[1] Fairthorne JC. et al. Mothers of Children with Autism have Different Rates of Cancer According to the Presence of Intellectual Disability in Their Child. Journal of Autism and Developmental Disorders. 2016. July 6.

[2] Ingudomnukul E. et al. Elevated rates of testosterone-related disorders in women with autism spectrum conditions. Horm Behav. 2007 May;51(5):597-604.

[3] Latham KE. et al. The epigenetic lorax: gene-environment interactions in human health. Epigenomics. 2012 Aug;4(4):383-402.

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Fairthorne, J., de Klerk, N., Leonard, H., & Whitehouse, A. (2016). Mothers of Children with Autism have Different Rates of Cancer According to the Presence of Intellectual Disability in Their Child Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-016-2847-9

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

On the question of suicide risk and chronic fatigue syndrome

The paper by Emmert Roberts and colleagues [1] (open-access) forms the basis of today's post and the finding that: "There was no significant difference in age-standardised and sex-standardised mortality ratios (SMRs) for all-cause mortality... or cancer-specific mortality in patients with chronic fatigue syndrome when compared with the general population in England and Wales." This is good news indeed bearing in mind how much a diagnosis of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) can affect so many aspects of a person's life (see here).

The news about the diagnosis of CFS/ME not increasing 'all-cause mortality' is however tempered by the finding that author's results did show "a substantial increase in mortality from suicide"; something that has been picked up by some quarters of the media (see here). I might also direct readers to an accompanying commentary attached to the Roberts paper (see here).

The Roberts paper is open-access but a few points are worth highlighting.

Based on a participant group of over 2000 people diagnosed with CFS identified "using data from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) register", authors set about calculating mortality rates over a 7-year observation period (2007-2013). As per previous 'issues' on how a diagnosis of CFS is arrived at (see here) we are told that "the most inclusive criteria, and thus included all patients with a clinical diagnosis of chronic fatigue syndrome" were used.

Mortality details were cross-referenced with the participant group data initially "from the “Service User Death Report” of “the Spine”, maintained by NHS Care Records Service." Some further checking on the basis of the death certificate details and cross-referencing with ICD-10 codes "for cause of death" provided further details. Various other variables were also analysed including ethnicity, socio-economic status (SES) and the: "Presence of a lifetime diagnosis of depression was defined as having had a recorded depressive episode (ICD-10 code: F32.x) or recurrent depressive disorder (F33.x)."

Results: after some examination of the data authors "identified 2147 cases of chronic fatigue syndrome in CRIS with 17 deaths." Just over 1500 women were included for study and 11 of them had died (11/1533). Of 614 men included for study, 6 had died (6/614). Most deaths (n=8) were "from malignant neoplasm" but 5 deaths were recorded as suicide. Further: "When stratified by lifetime diagnosis of depression, 216 patients had a recorded lifetime diagnosis of F32.x or F33.x. Four (26%) of 17 patients who died had a lifetime diagnosis of depression, for two of whom the cause of death was suicide." The authors conclude that theirs is "the first study to show a specific increased risk of suicide in a population of patients with chronic fatigue syndrome compared with the general population." But also: "if there had been two fewer deaths by suicide, this risk would not be significantly increased."

Without belittling the tragedy that is suicide and the devastating impact it can have on a person's family and friends (as well as themselves), I do think it is worth reiterating a few cold, objective points. First, yes the suicide rate was heightened in this group over this period in comparison to population figures, but the overall number of cases was still low. Second, without making too many sweeping generalisations about depression, two of those five cases of suicide had a history of depression. Given the quite widely accepted greater vulnerability to suicide (attempted or actual) following a diagnosis of depression (see here), one could argue that a diagnosis of CFS/ME is potentially only coincidental to any such association. Other research has asked similar questions [2]. That is also if you assume that depression as a condition should not be included under the banner of ME/CFS [3]? Indeed reiterating that statement about 'if there were two fewer deaths by suicide, this risk would not be significantly increased' one *could* argue that the suicide rate in relation to CFS/ME is actually not increased with the depression findings taken into account. Finally, I'd also suggest that given the extent of the debilitating symptoms often associated with CFS/ME and the 'cruel' way that some/many people with CFS/ME have been treated down the years, the suicide rate reported by Roberts is perhaps lower than I think many people would have expected. Although not directly comparable with the Roberts data, suicide has been discussed on other occasions in the peer-reviewed domain with CFS/ME in mind [4].

Continuing: "This study highlights the importance of adequate assessment of mood and other psychiatric symptoms in patients with chronic fatigue syndrome, because lifetime diagnosis of depression is an independent risk factor for increased risk of completed suicide in this population. Although completed suicide was a rare event, the findings strengthen the case for robust psychiatric assessment by mental health professionals when managing individuals with chronic fatigue syndrome." I don't think anyone would quibble with the idea that a comprehensive assessment be provided to patients with ME/CFS given what is known about how psychology can be affected by the presentation of the condition (see here) and also that depression is not something to be taken lightly. I am however cautious of the idea that a 'robust psychiatric assessment' is the only thing offered to patients - "when managing" -  particularly when there is a wealth of peer-reviewed evidence on the more 'biological side' of the condition too (see here) with potentially important implications for treatment for example. I am, for example, going to be talking about the case report from Galán and colleagues [5] soon on how the "initial symptoms of mitochondrial disease in adults can easily be mistaken with CFS." Indeed, going back to that paper by Zdunke and colleagues [6] on how "there may be important differences in illness characteristics across individuals with CFS in the US and the UK, and this has implications for the comparability of research findings across these two countries" one might appreciate how much further the UK experience of CFS/ME needs to go in order to put biology and genetics on a research/clinical practice par with the influence of psychology and psychiatry in relation to the label.

And just in case you might not believe that CFS/ME can be a life-limiting condition, due respect should be paid to those who've paid the ultimate price as a result of their diagnosis.

For those who might need it, details of someone who will listen...

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[1] Roberts E. et al. Mortality of people with chronic fatigue syndrome: a retrospective cohort study in England and Wales from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) Register. Lancet. 2016. Feb 9.

[2] Fuller-Thomson E. & Nimigon J. Factors associated with depression among individuals with chronic fatigue syndrome: findings from a nationally representative survey. Fam Pract. 2008 Dec;25(6):414-22.

[3] Jason LA. et al. Unintended Consequences of not Specifying Exclusionary Illnesses for Systemic Exertion Intolerance Disease. Diagnostics (Basel). 2015 Jun 23;5(2):272-86.

[4] Jason LA. et al. Causes of death among patients with chronic fatigue syndrome. Health Care Women Int. 2006 Aug;27(7):615-26.

[5] Galán F. et al. Mitochondrial Myopathy in Follow-up of a Patient With Chronic Fatigue Syndrome. J Investig Med High Impact Case Rep. 2015 Sep 24;3(3):2324709615607908.

[6] Zdunek M. et al. A Cross Cultural Comparison of Disability and Symptomatology Associated with CFS. Int J Psychol Behav Sci. 2015;5(2):98-107.

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Roberts, E., Wessely, S., Chalder, T., Chang, C., & Hotopf, M. (2016). Mortality of people with chronic fatigue syndrome: a retrospective cohort study in England and Wales from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) Register The Lancet DOI: 10.1016/S0140-6736(15)01223-4

Risk of cancer in autism: probably not excessive as more data emerge

A quote to begin: "Taken together, there are no published evidence to suggest that there is a high overall concordance between ASD [autism spectrum disorders] and cancer or between ASD and specific cancers."

Those words reported by Svend Erik Mouridsen and colleagues [1] (who knows a thing or two about autism research) should offer some relief to both people on the autism spectrum and their loved ones.

Based on the analysis of over 100 adults "diagnosed with infantile autism (IA) in childhood" compared with over 330 asymptomatic (not-autism) controls in Denmark, researchers found that 8 adults (6.8%) with autism has registered at least one cancer diagnosis and 17 people (5.1%) of the comparison group the same over a 30+ year period. The authors suggest that although there was no statistically significant increased risk in their cohort of people with autism "it is important to recognize that adults with IA [infantile autism] are at similar risk for these diseases." Once again, a diagnosis of autism is seemingly protective against nothing when it comes to other diseases/conditions/labels appearing.

Although to some degree reassuring about the excess risk of cancer in cases of autism, I am minded to bring in a previous post I wrote on this topic (see here) based on some important work coming out of the research powerhouse that is Taiwan [2]. Based on a considerably larger participant sample (~8400 people diagnosed with autism), the numbers of those with autism developing cancer were equally small to that of Mouridsen but greater than generally expected. The excess cancer risk on that occasion seemed to be specifically linked to being male and also covered a younger age group. I say this accepting that cancer risk with autism in mind might not be the same the world over.

The currently available peer-reviewed research literature in this population does not seem to indicate any wildly significantly greater risk of cancer as a function of being diagnosed on the autism spectrum. What it does suggest is that outside of specific overlap between cancer genes and so-called autism genes (see here) is that people with autism need to be screened the same way everyone else is for their risk of cancer save any health inequalities emerging, particularly as the population ages and eyes start to turn towards ageing and autism (see here). I might also add that if there is certain psychiatric comorbidity attached to a diagnosis of autism, one may need to be mindful that this could potentially impact on mortality rates (see here) and therefore adjust care accordingly.

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[1] Mouridsen SE. et al. Risk of cancer in adult people diagnosed with infantile autism in childhood: A longitudinal case control study based on hospital discharge diagnoses. Research in Autism Spectrum Disorders. 2016; 23: 203-209.

[2] Chiang H-L. et al. Risk of Cancer in Children, Adolescents, and Young Adults with Autistic Disorder. J Pediatrics. 2014. 18 November.

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Mouridsen, S., Rich, B., & Isager, T. (2016). Risk of cancer in adult people diagnosed with infantile autism in childhood: A longitudinal case control study based on hospital discharge diagnoses Research in Autism Spectrum Disorders, 23, 203-209 DOI: 10.1016/j.rasd.2015.12.010

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

Higher cancer mortality rates associated with mental illness

The findings reported by Steve Kisely and colleagues [1] were of some interest recently and their assertion that despite cancer incidence being "the same as the general population for most psychiatric disorders" or even slightly reduced when a diagnosis of schizophrenia was for example received, mortality due to cancer was "increased in psychiatric patients."

Such findings were based on their examination of: "Mental health records [that] were linked with cancer registrations and death records from 2002 to 2007." It follows other work from these authors in this area including that looking at the gap in life expectancy 'from preventable physical illness in psychiatric patients' [2].

Head-scratching (no, not for that reason) aside as to why cancer should be more deadly for those diagnosed with a psychiatric condition, the authors suggest that lifestyle factors such as alcohol or tobacco use probably wouldn't account for the quandary presented. One suggestion however - "inequity in access to specialist procedures" - does invite further investigation on the back of what has been previously reported in the area of psychiatric diagnosis and health inequality (see here for example).

Indeed, 'disparities in cancer-related healthcare provision' was also one of the explanations put forward by one researcher who replied to my tweet about the Kisely paper (and he should know) complete with reference to research backing up this claim [3]. The Mitchell paper found that: "Rates of mammography screening are lower in women with mental illness, particularly women with SMI [severe mental illness]." Whilst this only covers one type of cancer and one type of screening method, the idea that cancer screening and treatment resources may be 'failing' those with a psychiatric diagnosis is an important one also covered by other researchers [4]. Indeed, Martens et al suggested that "good continuity of care by primary care physicians" may mitigate the issues like screening uptake and the idea of a more 'joined-up' service delivery between psychiatry and other branches of clinical care.

Of the various messages to come from the Kisely findings, I'd like to think that a primary one is that of psychiatric diagnoses not appearing in some sort of clinical vacuum with regards to other symptoms and conditions being present and what effect they can have on quality of life. As per my ramblings about autism and the wide spectrum of comorbidities that can and do impact on health and quality of life, we need to be mindful of how presentation of behavioural / psychiatric symptoms can impact on the presentation and treatment of other conditions, many of which are perfectly treatable / manageable in modern medicine.

But the question is not completely answered [5]... and one wonders whether the findings from Minna Torniainen and colleagues [6] on a potential 'protective effect' from antipsychotics on early mortality in cases of schizophrenia might also bring some potential explanation(s) to the table?

To close: The Force Awakens trailer number 2.

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[1] Kisely S. et al. Why do psychiatric patients have higher cancer mortality rates when cancer incidence is the same or lower? Aust N Z J Psychiatry. 2015 Mar 31. pii: 0004867415577979.

[2] Lawrence D. et al. The gap in life expectancy from preventable physical illness in psychiatric patients in Western Australia: retrospective analysis of population based registers. BMJ. 2013 May 21;346:f2539.

[3] Mitchell AJ. et al. Breast cancer screening in women with mental illness: comparative meta-analysis of mammography uptake. Br J Psychiatry. 2014 Dec;205(6):428-35.

[4] Martens PJ. et al. Are cervical cancer screening rates different for women with schizophrenia? A Manitoba population-based study. Schizophr Res. 2009 Aug;113(1):101-6.

[5] Chang CK. et al. A cohort study on mental disorders, stage of cancer at diagnosis and subsequent survival. BMJ Open. 2014 Jan 29;4(1):e004295.

[6] Torniainen M. et al. Antipsychotic Treatment and Mortality in Schizophrenia. Schizophr Bull. 2015; 41: 656-663.

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Kisely S, Forsyth S, & Lawrence D (2015). Why do psychiatric patients have higher cancer mortality rates when cancer incidence is the same or lower? The Australian and New Zealand journal of psychiatry PMID: 25829481

Early mortality in mums of children with autism or intellectual disability

I know the paper by Jenny Fairthorne and colleagues [1] (open-access) is probably not the happiest thing to read with their conclusion that: "During the study period, mothers of children with intellectual disability or ASD [autism spectrum disorder] had more than twice the risk of death" but their message is nonetheless an important one.

Based on data derived from "state-wide databases" covering women living in Western Australia who gave birth between 1983 and 2005, researchers detected mums with a child diagnosed with autism and/or intellectual disability (learning disability if you prefer) and cross-referenced findings with "the state mortality registry" providing information on "dates and cause of death by ICD-9 or 10 codes". Various study (case) groups were formed on the basis of offspring diagnosis - intellectual disability (ID) of unknown cause (further separated based on levels of ID), ID of known cause (specifically Down syndrome or other) and a diagnosis of autism spectrum disorder (ASD) with and without ID - and aided analyses.

After some correction for various confounders including maternal age and socio-economic status (SES), from a starting population of some 300,000 mothers, approximately 1% had died before 2011 (the longer follow-up period). To quote: "Twenty-five years after the birth of their index child, the survival rates of mothers of children with no intellectual disability and no ASD were about 98%, followed by 96% for mothers of children with ASD and 95% for mothers of children with intellectual disability." These group difference were significant and led researchers to draw the conclusion: "Mothers from all case groups had an increased risk of death during the study period."

A few other details are also recorded in the Fairthorne study. "Mothers with both a psychiatric disorder and a child with intellectual disability or ASD had about six and a half times the risk of death" was an important finding reported by the authors. When it came to the cause of death, various factors were over-reported in case group mums including cancers, cardiovascular disease and death by misadventure (death due to an unintentional accident, homicide or suicide according to the authors' criteria).

Reiterating that the Fairthorne paper makes for quite uncomfortable reading, there are some potentially important lessons to be learned from the collected data. First and foremost I should stress that the excess percentages of deaths reported during the study period were overall, quite small for the case groups. Whilst there was an excess of deaths over and above that seen in the asymptomatic control group, the data do not suggest that mothers of children with autism or Down syndrome for example, are facing a gigantic excess risk. Risk is risk and influenced by lots of different variables. I say all that with my cold, dispassionate science goggles on, recognising that each death is a mother lost.

That being said, one might make a case for further inspection of maternal (and paternal) health and wellbeing as and when a diagnosis of autism and/or ID is received in one or more offspring. I've covered the topic of parental stress and autism before on this blog (see here) and the [evidence-based] ways and means it might be reduced. Stress is mentioned in the Fairthorne paper as potentially being one factor linking parenting and early mortality although I'd also suggest the concepts of resilience and coping might also require investigation.

Maternal health issues such as a history of psychiatric issues and/or more somatic diagnoses like diabetes and obesity are also covered in the discussion on possible reasons for the added risk in case groups. As per the research suggesting that some of these factors alone or in combination might increase the risk of offspring autism for example (see here), management of said issues should also rank high on the list of monitoring parental wellbeing. Lifestyle issues such as tobacco smoking and poor exercise regimes can also be mitigated if and when required.

Finally, I want to make one further point specifically related to the idea that cancer may feature as one reason for the excess mortality noted in the current study. Late last year (2014) I covered the complicated issue of cancer risk and autism (see here) on the basis of some further 'big data' derived from the Taiwan National Health Insurance database [2]. In amongst the discussions on that post was some mention of a familial history of certain cancers potentially being heightened in cases of autism on the basis of data from Ingudomnukul and colleagues [3]. The Fairthorne data corroborates this view, and further implies screening should perhaps be preferentially extended to mums of children with ID and/or autism. Early detection can save lives.

Mortality and autism is never going to be a great topic to discuss whether based on personal experience or the peer-reviewed evidence base. Linked to the suggestion that a diagnosis of autism - or at least some of the comorbidities which it can carry - for example, might also elevate the risk of early mortality (see here), I believe that it is time to start bigger conversations on how science and society can go about reducing such risk and reducing health inequality. Mothers, like their children, are precious things...

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[1] Fairthorne J. et al. Early Mortality and Primary Causes of Death in Mothers of Children with Intellectual Disability or Autism Spectrum Disorder: A Retrospective Cohort Study. PLoS ONE. 2014; 9(12): e113430.

[2] Chiang H-L. et al. Risk of Cancer in Children, Adolescents, and Young Adults with Autistic Disorder. J Pediatrics. 2014. 18 November.

[3] Ingudomnukul E. et al. Elevated rates of testosterone-related disorders in women with autism spectrum conditions. Horm Behav. 2007 May;51(5):597-604.

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Fairthorne J, Hammond G, Bourke J, Jacoby P, & Leonard H (2014). Early Mortality and Primary Causes of Death in Mothers of Children with Intellectual Disability or Autism Spectrum Disorder: A Retrospective Cohort Study. PloS one, 9 (12) PMID: 25535971

Risk of cancer associated with autism: small but present

Whilst understanding the power that headlines can have, alongside the way that statistics can sometimes mislead and/or be misrepresented, I don't want to shy away from the findings presented by Huey-Ling Chiang and colleagues [1] reporting that: "patients with autistic disorder have an increased risk of cancer."

Curiosity often leads to trouble.

Based yet again on data derived from the fantastic resource that is the Taiwan National Health Insurance database (see here for some other research examples taken from this dataset), authors looked at the medical insurance records of over 8000 young people diagnosed with an autism spectrum disorder (ASD) living in Taiwan. They found something of an excess risk for various groups and various cancers although only actually recording that: "cancer occurred in 20 individuals with autism". I used the word 'only' in that last sentence to demonstrate how rare a cancer diagnosis was to the autism group as a whole; realising however that for those 20 people, receipt of such a diagnosis probably carried all the emotions for them and their families that one might expect following such news.

The Chiang findings reported in particular an increased cancer risk in relation to males over females and that: "The number of cancers of genitourinary system was significantly in excess of the expected number... and increased risk was found in ovarian cancer." What these findings suggest to me is that awareness and screening for cancer should perhaps be more commonplace in various discussions with autism in mind, particularly in light of how receipt of a diagnosis of ASD seems to offer very little protection against various other comorbidity being potentially diagnosed (see here) and where delays in diagnosis of comorbid conditions can potentially lead. Indeed, other research crossing into some cases of autism concluded something similar [2] when it came to cancer screening access.

Insofar as the other literature on this topic, I do want to go through some additional studies. I am shying away from talking too much about the various research which has for example, implicated some genetic issues with an individual autism diagnosis in mind that have also crossed over into cancer research too [3]. Yes, such studies might be important, but genes and cancer is still a very, very complicated area [4] as indeed, is the current collected literature on genes and autism (see here).

Autism and cancer has previously received a rather mixed review when it comes to any sort of correlation/relationship. The paper from Blatt and colleagues [5] reviewing the records of cases of paediatric cancer for signs of autism concluded that there was not a "high concordance" between the two diagnoses. That being said, their slightly lower participant numbers (N=702) than that included in the Chiang study together with the focus on autism being present in those already diagnosed with various cancers could be seen as study/methodological differences.

A few case reports can also be found in the research literature in this area. The case report from Lisa Radcliff [6] provides an interesting account of breast cancer diagnosis and treatment for a woman diagnosed with autism. Detailing a slightly older age group than the Chiang paper included, the Radcliff paper covered various issues - including legal and ethical - associated with the diagnosis and treatment of cancer also taking into account how autism can manifest and to some extent, complicate things. There are other similar report examples about cancer and autism in the peer-reviewed literature [7] I might add.

The findings reported by Kao and colleagues [8] (open-access) suggesting that "there may be an association between autism and specific forms of cancer" is also worthwhile mentioning in this post. Granted, the authors were looking more generally at 'correlating' autism prevalence and "the Incidence of Specific Female and Male Cancers" for possible shared risk factors, so perhaps again slightly different from the Chiang paper. Their findings however that "the cumulative exposure to estrogen from endogenous and external sources is an established risk factor for both breast... and uterine... cancer, the two cancers that appear to be most consistently correlated with autism" is noteworthy and perhaps ties into some other autism research (see here).

Just before I let this topic go, I do want to pass some comment on the [limited] research asserting that a familial history of certain cancers might show more than a passing relationship to at least some cases of autism. I read something about this quite recently and some, it has to be said, rather disparaging comments about the possibility of any overlap. Without trying to make mountains out of molehills, the paper by Erin Ingudomnukul and colleagues [9] represents one of the primary sources of peer-reviewed evidence suggestive of a possible link between certain types of cancer being present in both women with autism and their first degree relatives. To quote: "Compared to controls, significantly more mothers of ASC [autism spectrum condition] children reported (a) severe acne, (b) breast and uterine cancers, tumors, or growths, and (c) family history of ovarian and uterine cancers, tumors, or growths." This perhaps complements some of the more anecdotal data that I've come across down the years but very much implies that a lot more work needs to be done to confirm or refute such findings.

I want to end this post with a reiteration of the relative rarity of cancer occurring when a diagnosis of autism is received despite the headline of an increased risk present in the Chiang paper. I say this not to downplay the fact that autism is seemingly protective of nothing when it comes to other comorbidity, but merely not to sensationalise this area or add any further worry to those with autism or their families.

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[1] Chiang H-L. et al. Risk of Cancer in Children, Adolescents, and Young Adults with Autistic Disorder. J Pediatrics. 2014. 18 November.

[2] Osborn DP. et al. Access to cancer screening in people with learning disabilities in the UK: cohort study in the health improvement network, a primary care research database. PLoS One. 2012;7(8):e43841.

[3] Crespi B. Autism and cancer risk. Autism Res. 2011 Aug;4(4):302-10.

[4] Dawson MA. & Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012 Jul 6;150(1):12-27.

[5] Blatt J. et al. Autism in children and adolescents with cancer. Pediatr Blood Cancer. 2010 Jan;54(1):144-7.

[6] Radcliff L. Breast cancer and autism. J Adv Pract Oncol. 2013 Mar;4(2):113-7.

[7] Kim HS. et al. Squamous cell carcinoma of the lung in an autistic child who has never smoked. J Pediatr Hematol Oncol. 2011 Jul;33(5):e216-9.

[8] Kao HT. et al. The correlation between rates of cancer and autism: an exploratory ecological investigation. PLoS One. 2010 Feb 23;5(2):e9372.

[9] Ingudomnukul E. et al. Elevated rates of testosterone-related disorders in women with autism spectrum conditions. Horm Behav. 2007 May;51(5):597-604.

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Chiang, H., Liu, C., Hu, Y., Chen, S., Hu, L., Shen, C., Yeh, C., Chen, T., & Gau, S. (2014). Risk of Cancer in Children, Adolescents, and Young Adults with Autistic Disorder The Journal of Pediatrics DOI: 10.1016/j.jpeds.2014.10.029

Mortality and autism

I know the topic of this post is not exactly great dinner table conversation, particularly at this time of year during the season of goodwill to all.  Nevertheless I'm posting today on the paper by Deborah Bilder and colleagues* looking at mortality and causes of death in relation to autism spectrum disorder (ASD) simply because there are important lessons which can be learned and applied with relative ease as a result of some of their collected data.

Regular readers might know that one of my interests on this blog is the issue of health inequality when it comes to conditions like autism and indeed beyond. It's a sad fact that whilst autism generates quite a lot of discussion, research, politics and emotion, the message that people with autism are people first, and hence are at least facing the same risk (if not more) of developing health-related complications, can get a little lost in the noise. I'm as guilty as anyone in losing this message with my constant ramblings on the wonders of autism research.

Papers like the one from Bilder et al however reinforce the view that autism, in some cases, might very well place a person at increased risk of early mortality and outside of just seeing a person with autism, we could do a lot by putting the person and their physical health and wellbeing first and foremost.

A few bullet-points from the Bilder paper:

• The study was based in quite an important geographical area for autism research, Utah. Important because as I've blogged about before, Utah has been the focus of some milestone studies on autism, in particular the UCLA-University of Utah Epidemiologic Study of Autism. Indeed some of the original data from that initiative has quite recently become the source of some discussion as part of the autism numbers game and the transition from DSM-III to DSM-IV.
• In particular, the authors sought to follow-up the cases of autism identified during the UCLA-University of Utah study and estimate the mortality hazard rate ratio (HRR) whilst look at the patterns of mortality and what factors were linked to death. The authors define HRR as: "an estimate of the excess risk associated with the identified exposure (i.e. ASD case status) as a constant effect over a specific time period (i.e. interval since case ascertainment) while adjusting for selected covariates (i.e.birth risk factors)".
• Based on a cohort of 305 adults with autism (DSM-III and DSM-IV-TR diagnosed/reclassified participants), 29 people (9.5%) had died by the end of 2011. 
• Most of the deceased were male, and the age at time of death varied between 7 - 46 years old.
• The HRR overall was 9.91 compared to population controls (N=2466). When taking into account the different genders, the HRR for males was 7.92 and for women with an ASD a staggering 20.71 (without covariates).
• As one would expect, there were various causes of death indicated on death certificates, ranging from seizures to cardiac-related disorders. Epilepsy was a prominent feature for quite a few of the cohort as per the range of physical disease comorbidity observed in cases. That being said, and without making any judgements, death listed as a result of an "open wound of hip" in one case invites further investigation. 
• Death by unnatural causes were relatively few although "two individuals died from an adverse event related to medication".

The Bilder paper does make somber reading when you realise that behind every statistic there was a person and a family. Indeed looking at the list of deceased, their intellectual and autism classification, their cause of death and importantly, their accompanying physical disease, one is struck by the heterogeneity present.

With my cold, dispassionate research spectacles on a few points caught my eye.

It was interesting to note how many cases cite cerebral palsy (CP) for example, as a comorbidity to their autism diagnosis (I counted 6 cases of the 29 deceased). I'm not inferring that CP was the cause of death, even though it was listed as a factor in at least one case, but rather that those cases with comorbid CP might indicate some elevated risk of early mortality as per the literature on excess mortality in CP** alone.

Reports of comorbid Sanfilippo syndrome were also present in more than one case of autism, two actually. Given the rarity with which this syndrome appears - anywhere between 1 in 100,000 to 1 in 1,000,000 in the general population - to see even one case in the current cohort should automatically be a cause of some interest bearing in mind presentation can include autistic features and the syndrome previously being mentioned in the autism research literature*** (2 / 222 cases of autism). Given the poor prognosis of Sanfilippo syndrome, one might reasonably assume some impact on mortality where autism also appears alongside.

I also observed that cancers and neoplasms did not seem to prominently figure among the deceased as a cause of death. One could argue that given the relatively young mean age of the deceased, this might play a role in mortality and indeed the lack of accompanying information on things like cancer treatment and survival among this cohort. But I'm interested in this phenomenon, especially when one considers what the population at large - as in everyone whether with autism or not - generally tend to die of (see this post for more information).

The low prevalence of death by unnatural causes also caught my attention. I've talked fairly recently about the wandering and autism research which was published and how wandering can, in a few cases, lead to the very worst outcome when autism is involved. As far as I can surmise and allowing for the difference in age groups looked at, wandering was not implicated in any of the cases looked at by Bilder. I'm not able to provide an in-depth view of wandering leading to the circumstances of early mortality in autism, but one speculates whether an overall increase in cases of autism might be a factor in the very public recording of death implicating wandering. Same goes for issues like suicide, recently discussed with autism in mind****.

Finally, I can't leave this post without commenting on those two people where death was linked to medication use. In both cases, individuals were in their late 30s-early 40s, and one case also carried a diagnosis of schizophrenia. Accepting that medicines - particularly those with a psychotropic effect - are still a voyage of discovery in terms of their precise effects and mode of action, pharmacotherapy is as much about good medicines management as it is about the effects of the drugs themselves. I note for example one case where poisoning due to exposure to "unspecified" drugs is cited alongside the word 'obesity'. The relationship between these concepts has been discussed before including the important issue of side-effects.

The take-home message from this post is best left to another comment from the paper:

"The elevated mortality risk associated with ASD in the study cohort appeared related to the presence of comorbid medical conditions and intellectual disability rather than ASD itself suggesting the importance of coordinated medical care for this high risk sub-population of individuals with ASD."

I would struggle to disagree.

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* Bilder D. et al. Excess mortality and causes of death in autism spectrum disorders: a follow up of the 1980s Utah/UCLA Autism Epidemiologic Study. J Autism Dev Disord. September 2012.

** Strauss D. et al. Causes of excess mortality in cerebral palsy. Dev Med Child Neuol. 1999; 41: 580-585.

*** Ververi A. et al. Clinical and laboratory data in a sample of Greek children with autism spectrum disorders. J Autism Dev Disord. 2012; 42: 1470-1476.

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Bilder D, Botts EL, Smith KR, Pimentel R, Farley M, Viskochil J, McMahon WM, Block H, Ritvo E, Ritvo RA, & Coon H (2012). Excess Mortality and Causes of Death in Autism Spectrum Disorders: A Follow up of the 1980s Utah/UCLA Autism Epidemiologic Study. Journal of autism and developmental disorders PMID: 23008058

GcMAF, nagalase and autism

I think it might be worth starting this blog post with (a) reference to my very well-trodden caveat of not making any medical recommendations on this blog and (b) a little bit of a description of some of the key terms connected with the paper by Jeff Bradstreet and colleagues* (open-access) on nagalase, GcMAF and autism bearing in mind my amateur status in this area. I might also add, don't shoot the messenger.

I'm the big eater @ Wikipedia  

Macrophages. It all begins with monocytes, white blood cells produced in bone marrow from hematopoietic stem cells. Monocytes grow into different types of macrophages.

Macrophages, known as the big eaters of the immune system, are present in every cell of the body and include microglia (in the brain).

As part of their big eating duties, macrophages enjoy dining out on the odd invading pathogen or cell programmed for destruction as well as telling other immune cells what to do. A sort of Mr Creosote if you will (without the bucket). If you want the Star Wars version of macrophages (I'm not kidding) ... here you go (open-access).

Macrophages are activated by Gc-MAF (Gc Macrophage Activating Factor). The production of Gc-MAF is affected by nagalase (alpha-N-acetylgalactosaminidase) encoded by the gene NAGA. Nagalase affects the Gc protein (vitamin D3 binding protein) which has a knock-on effect blocking the production of Gc-MAF. The more nagalase activity, the less Gc-MAF is a rough-and-ready way to look at it. Less Gc-MAF equates as less macrophage activation according to this logic and some potential onward effects for immune function.

Why is it important? Well in cancer research, there is some preliminary chatter that tumors might be able to affect Gc-MAF function by way of altering nagalase activity (open-access)**. Such is the effect of increased nagalase and depressed Gc-MAF function that this has been put forward as a potential explanation of why cancers are able to 'avoid' the immune system and so develop unchecked. There is also some very preliminary evidence that giving supplemental Gc-MAF as an injection might affect cancer growth in animal models*** and human participants**** although this is still an area of some controversy given that one lab seems to be producing all the research.

So what's the logic of this area with autism in mind? I can't claim to be able to provide a definitive answer but one suggestion from press releases such as this one, are the reports of high levels of nagalase activity to be present in quite a few of the cohorts with autism looked at. Remember, nagalase negatively affects levels of Gc-MAF so potentially disrupting the activation of macrophages. Outside of malignant cells, there is a suggestion that elevated nagalase activity might be part and parcel of issues with immune function in cases of autism onwards to things like the presence of some kind of viral activity. Indeed this last point on viruses and nagalase I assume comes from other results on the use of Gc-MAF in the clearance of HIV infection***** bearing in mind replication is still required for this area of work.

So eventually we get back to the paper from Bradstreet and colleagues and in more detail:

• Described as a chart review, 40 participants with autism who sought testing for nagalase activity, pre- and post assessment of nagalase following Gc-MAF injections were followed.
• Diagnosis of participants was determined by having already received a DSM-IV diagnosis of autism independent of the study together with some in-house assessments on the severity of presentation.
• Blood draws signalled the start of the nagalase activity assessment which was shipped to a lab already versed in looking for the enzymatic activity. 
• Gc-MAF was injected on a weekly basis covering an average of 14 injections to get those macrophages stimulated, and nagalase activity assessed again.
• Results: nagalase activity was generally higher in the autism group than the various reference ranges cited by the assaying laboratory.
• Nagalase activity levels dropped in quite a few participants following Gc-MAF administration (24 of 40 decreased to within laboratory reference ranges) and "uncontrolled observations of GcMAF therapy indicated substantial improvements in language, socialization and cognition". Before we get too carried away though, lets remember those words "uncontrolled observations". 
• Importantly (very importantly) no significant side-effects were reported, bearing in mind reports of elevated body temperature occurred post infusion and words like "By the second month, no patients experienced significant febrile events" were used.
• The authors conclude that more research is required in this area.

OK. With the science hat on, one reiterates that this was a very, very preliminary case review and although Gc-MAF was "checked for sterility in-house and externally by the UK Health Protection Agency" apparently, this is still a compound under investigation and is still very experimental. I've not specifically made mention of Gc-MAF on this blog before this post. That being said, I have talked about nagalase in relation to some speculations on the now de-discovered work on XMRV and chronic fatigue syndrome (CFS).

There are some obvious questions raised from the findings reported by Bradstreet. So, assuming all that Gc-MAF does and how it apparently does it, the whole 'underactive immunity' side of autism comes into play. Indeed I'm immediately drawn back to the work by Harumi Jyonouchi and colleagues on SPAD and immunodeficiency detected in their cohort and the possible link with gastrointestinal (GI) dysfunction. That and the low IgA findings also observed on more than one occasion in cases of autism. Of course balancing all that with other findings indicative of other issues with immune function in cases of autism such as an overactive immune system and the whole autoimmunity side of things. I should perhaps also stress that I am not equating autism with HIV or cancer or anything else based on the description of these findings.

Perhaps just as important is the whole viral infection link being implied in some cases of autism by this work. I know this starts to take us into some quite uncomfortable territory with autism in mind as per the study by Mady Hornig and colleagues****** (including virus hunter Ian Lipkin) on a (mostly) lack of measles virus in reply to studies like the one from Kawashima and colleagues*******. I'm not really in a position to offer an expert opinion as to whether this is proof positive that specific viruses are or aren't involved in autism, over an above the multitude of viruses everyone comes across in a lifetime, albeit with an immune response in full working order and the focus being on autisms not autism. Think also back to that most classical autism-viral connection which looked at rubella******** quite a few years back. And then all those ancient remnants of viruses which we all carry in our genome and have been recently looked at with autism in mind and whether there are any connections to be made or not.

Irrespective of any controversy this might unearth - which I assume it probably will - the Bradstreet results are peer-reviewed results and hence worthy of further independent analysis. Perhaps Prof. Lipkin might once again step up to this task?

[Update: you may also want to have a look at the second time Gc-MAF has cropped up on the autism  research circuit too.]

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* Bradstreet JJ. et al. Initial observations of elevated alpha-N-acetylgalactosaminidase activity associated with autism and observed reductions from GC protein—macrophage activating factor injections. Autism Insights. 2012. 4: 31-38.

** Korbelik M. et al. The value of serum alpha-N-acetylgalactosaminidase measurement for the assessment of tumour response to radio- and photodynamic therapy. Br J Cancer. 1998; 77: 1009-1014.

*** Yamamoto N. & Nataparaju VR. Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor. Cancer Res. 1997 Jun 1;57(11):2187-92.

**** Yamamoto N. et al. Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF). Int J Cancer. 2008; 122: 461-467.

***** Yamamoto N. et al. Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF). J Med Virol. 2009; 81: 16-26.

****** Hornig M. et al. Lack of association between measles virus vaccine and autism with enteropathy: a case-control study. PLoS ONE. 2008; 3: e3140.

******* Kawshima H. et al. Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism. Dig Dis Sci. 2000; 45: 723-729.

******** Chess S. Follow-up report on autism in congenital rubella. J Autism Child Schizophr. 1977; 7: 69-81.

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James Jeffrey Bradstreet, Emar Vogelaar, & Lynda Thyer (2012). Initial observations of elevated alpha-N-acetylgalactosaminidase activity associated with autism and observed reductions from GC protein—macrophage activating factor injections Autism Insights