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  • April 24, 2017
  • 04:22 AM

Promising mouse model for Ngly1 deficiency

by adam phillips in It Ain't Magic

A recent study of Ngly1 deficient mice used a secondary knockout to create double knockouts with symptoms similar to human NGLY1 deficiency.... Read more »

  • April 24, 2017
  • 03:05 AM

Sensory issues in adult ADHD controlling for autistic symptoms...

by Paul Whiteley in Questioning Answers

I was intrigued to read the paper by Bijlenga and colleagues [1] reporting on "the prevalence of sensory hyper- and hyposensitivity among adults with ADHD [attention-deficit hyperactivity disorder], controlling for autistic symptoms."The authors concluded that among their cohort of over 100 adults diagnosed with ADHD, both sensory hyper- and hyposensitivity symptoms as described by response to the Adolescent/Adult Sensory Profile-NL (AASP-NL), were over-represented compared with population norm data. Interestingly, authors also took a snapshot of 'autistic symptoms' based on responses to the Autism-spectrum Quotient (AQ) and reported that: "Adults with ADHD had more autistic symptoms" but: "Sensory hypo- and hypersensitivity were both related to an increased ADHD score, even showing a dose-response relationship, but not to any autistic symptom or comorbid disorder."My intrigue stems from a few implications of such findings, with the requirement for much more study. First is the quite important overlap between autism and ADHD (see here) confirmed symptom-wise in the Bijlenga paper. Second is the idea that, within this cohort at least, adults with ADHD may variably present with sensory issues. Third, assuming that the AQ 'does what it says on the tin' with regards to screening for autistic symptoms (see here), the lack of a notable connection between autistic symptoms and sensory sensitivities in the context of adult ADHD might have some important implications related to my first point when autism and ADHD appear simultaneously. Indeed it poses the question: are sensory issues, now noted in specific relation to autism via at least one diagnostic schedule (see here) actually 'a core part of all autism' or perhaps a feature of something else for some?Reiterating that more research is required (not least more formal screening for autism over and above the use of AQ or related screening schedules) that last point/question might actually make more sense than many people might first realise. If, for example, we take the view that autism rarely exists in some sort of diagnostic vacuum (see here and see here) and that science and clinical practice really needs to be more proactive when it comes to an autism diagnosis being a starting point not the finishing line (see here), it's not beyond the realms of possibility that sensory issues for some might have been spuriously linked to autism when in fact other comorbid labels/symptoms better account for their presentation. This not only has implications for screening/diagnosis but also management of said sensory symptoms, as per other reports talking about the use of stimulant medication indicated for ADHD 'affecting' aspects of odour sensitivities for example [2]. By saying that I'm not making any sweeping judgements about pharmacotherapy for ADHD treating sensory issues present alongside autism, merely that new avenues might open up.A final quick glance at some of the other peer-reviewed literature on the topic of sensory issues and ADHD reveals that there is some history in this area [3]. Said sensory issues have also been *linked* to some of the other behavioural facets noted in cases of ADHD [4]. Perhaps, in light of such data, it is time for ADHD - whether in symptoms or in label - to be taken into account when sensory issues are discussed in the context of autism in the science literature and in clinical practice?----------[1] Bijlenga D. et al. Atypical sensory profiles as core features of adult ADHD, irrespective of autistic symptoms. Eur Psychiatry. 2017 Feb 21;43:51-57.[2] Romanos M. et al. Improved odor sensitivity in attention-deficit/hyperactivity disorder. Biol Psychiatry. 2008 Dec 1;64(11):938-40.[3] Clince M. et al. Comparing and Exploring the Sensory Processing Patterns of Higher Education Students With Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorder. Am J Occup Ther. 2016 Mar-Apr;70(2):7002250010p1-9.[4] Shimizu VT. et al. Sensory processing abilities of children with ADHD. Braz J Phys Ther. 2014 Jul-Aug;18(4):343-52.----------Bijlenga D, Tjon-Ka-Jie JY, Schuijers F, & Kooij JJ (2017). Atypical sensory profiles as core features of adult ADHD, irrespective of autistic symptoms. European psychiatry : the journal of the Association of European Psychiatrists, 43, 51-57 PMID: 28371743... Read more »

Bijlenga D, Tjon-Ka-Jie JY, Schuijers F, & Kooij JJ. (2017) Atypical sensory profiles as core features of adult ADHD, irrespective of autistic symptoms. European psychiatry : the journal of the Association of European Psychiatrists, 51-57. PMID: 28371743  

  • April 22, 2017
  • 06:14 AM

Autistic adults as critical autism experts (with research caveats)

by Paul Whiteley in Questioning Answers

"Findings suggest that autistic adults should be considered autism experts and involved as partners in autism research."That was the conclusion reached in the paper by Kristen Gillespie-Lynch and colleagues [1] (open-access) reporting on the results of an online survey assessing "autism knowledge and stigma among 636 adults with varied relationships to autism, including autistic people and nuclear family members." Among the various groups of people who contributed to the survey, several viewpoints emerged. The message primarily however was that: "autistic people are autism experts through their lived experiences." I don't think many people would quibble with such findings.A few other details emerged from the Gillespie-Lynch study that merit discussion. Many participants showed a "reduced tendency to view autism through a deficit-defined medical model compared with non-autistic people." This is perhaps not an unexpected finding given the history of applying the medical model to autism and the rise and rise of the neurodiversity movement that "challenges the medical model" in particular respect over the question of deficit vs. difference and implications thereof. Although the medical model provides the means to identify and diagnose autism or autism spectrum disorder (ASD) (on the basis of deficits), it's not unexpected that for some, once those tasks have been completed, the 'treatment' side of the model is not necessarily a top priority; or at least not as important as addressing the various inequalities that seem to stem from a diagnosis. That being said, I do agree with the authors sentiments that: "the neurodiversity movement and the medical model overlap in recognizing that supports are needed to ameliorate challenges associated with autism." Those challenges are variable and person-dependent but include the effects of both core and peripheral signs and symptoms and the various over-represented comorbidities that seem to follow a diagnosis of autism (see here). I would, at this point, also caution on using the words 'biopsychosocial model' in the context of autism as the authors have included in their discussions, given what it has meant for other labels (see here) and the potential 'psychologising' of some important medical symptoms.I added the words 'with research caveats' to the title of this post to ensure that such a positive message about autism and the autism spectrum is not just given a 'free pass' when it comes to scrutiny of the scientific method, the way the study was carried out and the applicability of the results to the entire autism spectrum. This was an online survey not a face-to-face piece of research (other related research has similarly used such a method and on more than one occasion) and the authors acknowledge that they: "did not verify diagnosis of participants who self-identified as autistic" for example. Given what we are beginning to see when it comes to some of the 'self-screening' instruments out there regarding possible autism or not (see here), I'm always a little cautious that self-diagnosis / self-identification does not necessarily mean [eventual] clinician-diagnosed autism and how important this is when it comes to correctly ascertaining the wants and wishes of those diagnosed as being on the spectrum.On the point about the representativeness of this research, the authors also note: "Findings may not generalize to autistic participants who lack the verbal and computer skills needed to complete the survey." Yet another example it seems of this important issue.I have to say that I'm also a little disheartened that yet again an important group that was once very firmly on the autism spectrum aren't really given the credit they deserve according to the Gillespie-Lynch findings: "Autistic participants were more likely to recognize that most children cannot outgrow autism." The 'optimal outcome' children and adults it seems, still represent one of the most maligned groups associated with the autism spectrum (assuming that optimal outcome occurring in up to 9% of the autism population is not an insignificant figure). This despite the fact that even the diagnostic stability of the most 'high-functioning' cases of autism can wobble it seems (see here) even into adulthood. One of the premier experts on autism also seems to agree according to some recent media (see here). I often wonder if the seeming lack of acceptance of this group/feature might have something to do with the 'identity' side of autism and the idea that within the vast heterogeneity of autism (or the plural autisms if you prefer) the use of 'them and us descriptions' like 'neurotypical' are perhaps not as binary or long-lasting as many would believe or want to believe?Within the context of [approximate] phrases such as 'if you've met one person with autism, you've met one autistic person' there is caution in over-generalising these latest results but they are nonetheless important. I think it would be rather fitting to end with a few choice phrases from the Gillespe-Lynch paper: "As many of our survey respondents indicated, each person, regardless of whether or not they are autistic, is unique" and: "Some autistic people seek out factual knowledge about autism while others believe that they can only be experts in their own particular form of autism." Either way, the insights provided by people on the autism spectrum (all parts of the autism spectrum and indeed, across the age ranges) should be valued, and where possible, incorporated into research and practice.And one voice from the autism spectrum carries some rather sensible messages...----------[1] Gillespie-Lynch K. et al. Whose Expertise Is It? Evidence for Autistic Adults as Critical Autism Experts. Front. Psychol. 2017. March 28.----------Gillespie-Lynch, K., Kapp, S., Brooks, P., Pickens, J., & Schwartzman, B. (2017). Whose Expertise Is It? Evidence for Autistic Adults as Critical Autism Experts Frontiers in Psychology, 8 DOI: 10.3389/fpsyg.2017.00438... Read more »

Gillespie-Lynch, K., Kapp, S., Brooks, P., Pickens, J., & Schwartzman, B. (2017) Whose Expertise Is It? Evidence for Autistic Adults as Critical Autism Experts. Frontiers in Psychology. DOI: 10.3389/fpsyg.2017.00438  

  • April 21, 2017
  • 04:32 AM

Parental exposures and risk of offspring autism: some curious details

by Paul Whiteley in Questioning Answers

"Overall, our results were consistent with no positive association between parental asthmagen exposure and ASD [autism spectrum disorder] in the children."So said the findings reported by Alison Singer and colleagues [1] (open-access) continuing a research theme from this group [2] looking at whether "parental workplace exposures to risk factors for asthma (“asthmagens”)" might have relevance to offspring risk for autism.Based on data derived from some of those oh-so-important Scandinavian research registries (this one based in Denmark), researchers initially looked at some 12,000 cases (where autism was mentioned in medical records) compared with over 48,000 controls (not autism) to ascertain whether parental work exposures might play some role in autism risk. This numbers were eventually boiled down somewhat.Despite the opening line to the post, there were some curious details to emerge from the collected analyses. So: "We observed an inverse association between any maternal occupational asthmagen exposure and ASD in the children." Researchers reported that maternal occupational exposure actually seemed to be protective against the development of offspring autism according to their findings. They note that this finding was "largely explained by latex exposures" on the basis of linking occupational codes "to an asthma-specific job exposure matrix (JEM)." In other words, they didn't specifically look at latex exposure in every single case but rather relied on the probability that a particular occupation would entail this or other exposure.A few other curious details also emerged: "Some paternal occupational asthmagen categories were positively associated with ASD, including bioaerosols..., pharmaceutical drugs (manufacturing or extensive handling)..., and metals." The authors tend to talk down these findings as per the suggestion that: "Some of these associations could be chance findings resulting from multiple comparisons or could reflect bias, such as unmeasured confounding" but I would perhaps be a little more cautious about rejecting them outright. Indeed the authors note on one point in relation to maternal exposures: "While adjustment for unmeasured confounding could bring the association to the null, the confounding would need to be implausibly strong to mask a positive association."I've covered the topic of parental (occupational) exposures and offspring autism risk before on this blog (see here) alongside associated research (see here). The current take-away message from quite a bit of this research is that there may be target classes of compounds to 'look out for' when it comes to offspring autism risk, but as of yet there is no smoking gun. One also needs to read such research in the context of the myriad of 'associations' that have been made with offspring autism risk down the years (see here for example) and how genes and environment might mix in relation to the plural autisms. Cumulative effects are more likely over single factors.Insofar as the current Singer results, I do feel that the authors might have been a little premature in making the sweeping claims that they have on the basis of their findings: "this large population-based case-control study does not suggest a positive measurable association between parental occupational asthmagen exposure and ASD." I say this in the context that 'asthmagen' exposure could be incurred via several routes (see here). I don't doubt that the correlations/findings reported by Singer could be 'due to chance', but until such claims can be independently verified in direct study (see here for one idea) and perhaps tested in animal models for example, they should really just report what they found without fear, favour or complication...----------[1] Singer AB. et al. Parental exposures to occupational asthmagens and risk of autism spectrum disorder in a Danish population-based case-control study. Environmental Health. 2017 16: 31.[2] Singer AB. et al. Maternal Exposure to Occupational Asthmagens During Pregnancy and Autism Spectrum Disorder in the Study to Explore Early Development. J Autism Dev Disord. 2016 Nov;46(11):3458-3468.----------Singer, A., Burstyn, I., Thygesen, M., Mortensen, P., Fallin, M., & Schendel, D. (2017). Parental exposures to occupational asthmagens and risk of autism spectrum disorder in a Danish population-based case-control study Environmental Health, 16 (1) DOI: 10.1186/s12940-017-0230-8... Read more »

  • April 20, 2017
  • 05:19 AM

DHM attenuates obesity-induced slow-twitch-fiber decrease via FLCN/FNIP1/AMPK pathway

by Joana Guedes in BHD Research Blog

Obesity is often associated with decreases in the proportion of skeletal muscle slow-twitch fibers and insulin sensitivity. Slow-twitch fibers are rich in mitochondria and utilize fatty acid oxidative phosphorylation for energy production. In their new study, Zhou et al. (2017) explore the role of the FLCN/FNIP1/AMPK signalling pathway in obesity-induced reductions in slow-twitch fibers and insulin sensitivity in skeletal muscle using high-fat-diet-induced (HFD) obese mice, ob/ob mutant mice, and palmitate-treated C2C12 myotubes. The authors also assess the effects of dihydromyricetin (DHM) on the obesity-induced decrease in slow-twitch fibers, and the molecular mechanisms responsible for this effect.... Read more »

  • April 20, 2017
  • 04:37 AM

"a gradual decline in recorded diagnoses of CFS/ME since 2001"?

by Paul Whiteley in Questioning Answers

The quote forming the title of today's post comes from the paper by Simon Collin and colleagues [1] (open-access available here) who, based on analysis of the UK "Clinical Practice Research Datalink (CPRD), formerly known as the General Practice Research Database (GPRD)" set out to look at the "Incidence of CFS/ME [chronic fatigue syndrome/ myalgic encephalomyelitis], FM [fibromyalgia], post-viral fatigue syndrome (PVFS), and asthenia/debility." I say incidence but that last sentence should really read as  'recorded incidence'.Searching the research database between January 2001 and December 2013, researchers looked at the [recorded] incidence (that's incidence not prevalence) of the various fatigue-related conditions/labels recorded by participating GP (general practice) surgeries.Recorded diagnoses of CFS/ME showed a soft but noticeable decline over the period of study: "Annual incidence of CFS/ME decreased from 17.5 [per 100,000 people] in 2001 to 12.6 in 2013." A similar decline was also noted in respect of PVFS and asthenia/debility. When however it came to FM, there was an overall increase in cases between 2001 and 2013 (albeit characterised by peaks and troughs in recorded diagnoses across specific years).Some other important data were also reported on. So: "All diagnoses showed strong evidence of variation by age and sex" and estimated socio-economic status (SES). Further: "Incidence rates of CFS/ME were 2.4-fold higher among women... with peak incidence in the 40–49 years age group." Women were also more likely to be over-represented in relation to a diagnosis of FM too.This is potentially important data. It suggests that at least among participating GP practices in the CPRD, recorded diagnoses of CFS/ME seem to be going down. The caveats however mentioned by the researchers do need to be highlighted, not least that they "examined recorded data rather than actual incidence, i.e. we are describing incidence rates of GPs’ recording of diagnostic codes" and "diagnoses were not independently validated." In other words, this is data based on "GPs enter[ing] medical diagnoses and symptoms as Read codes." I might also add in another quote from the authors too: "In 2005, 48% of GPs in one English region did not feel confident about making a diagnosis of CFS/ME, and 28% did not recognise CFS/ME as a legitimate illness." A bit of an issue by all accounts if one would like to get accurate data on incidence or prevalence.I also have a to raise a point in relation to this latest data and how it compares with other data produced by the same research group (see here). Keeping in mind that incidence is not the same as prevalence, I bring back to your attention the findings reported by Collin and colleagues [2] on another occasion suggesting that nearly 2% of 16-year olds in the ALSPAC cohort were affected by CFS. More work needs to be done when it comes to official monitoring of the numbers of cases of CFS/ME (and FM) outside of just reliance on GP practice recordings in order to get a true picture of numbers of cases. Of course, there is another possible explanation for the fall in recorded diagnoses: GPs are increasingly understanding that some of the symptoms included under the banner of CFS/ME overlap with various other conditions/labels too...----------[1] Collin SM. et al. Trends in the incidence of chronic fatigue syndrome and fibromyalgia in the UK, 2001-2013: a Clinical Practice Research Datalink study. J R Soc Med. 2017 Jan 1:141076817702530.[2] Collin SM. et al. Chronic Fatigue Syndrome at Age 16 Years. Pediatrics. 2016 Feb;137(2):e20153434.----------Collin SM, Bakken IJ, Nazareth I, Crawley E, & White PD (2017). Trends in the incidence of chronic fatigue syndrome and fibromyalgia in the UK, 2001-2013: a Clinical Practice Research Datalink study. Journal of the Royal Society of Medicine PMID: 28358988... Read more »

  • April 19, 2017
  • 04:31 AM

Allergy and ADHD meta-analysed and guess what...

by Paul Whiteley in Questioning Answers

"Reports of frequent manifestation of allergic diseases in children with attention deficit hyperactivity disorder (ADHD) have been the subject of mounting clinical interest."OK, go on."The objective of this study was to compile and assess available studies on the association between ADHD and allergic diseases in children."And your findings... "children with ADHD are more likely to have asthma, allergic rhinitis, atopic dermatitis, and allergic conjunctivitis than their counterparts. Interventions including strategies for managing allergies in children with ADHD would be beneficial."So said the systematic review and meta-analysis published by Celine Miyazaki and colleagues [1] (open-access) who provide quite a good 'where we're at' update when it comes to a potentially important intersection between a developmental condition (ADHD) and a series of somatic, immune-based conditions (allergy).Regular readers of this blog might already know that I have a blogging interest in all-things immune system and behaviour (see here for example). Indeed, acknowledging that the immune system may be doing so much more than protecting us from the multitude of viral, bacterial and other insults we face each day is gaining some real [peer-reviewed] scientific momentum.Boiling down the peer-reviewed literature to five studies meeting the meta-analysis criteria laid out by authors, cumulatively including some 60,000 research participants (including data derived from that wonderful Taiwanese research registry that I keep going on about), researchers set to work on the examining the various findings. Nearly 8,000 of the 61,811 children included for study were diagnosed with ADHD and various allergic diseases were 'examined' in the context of the ADHD label or without the label. The results were as mentioned in the first paragraph.When it came to looking at which specific allergic disease diagnoses were most strongly linked to ADHD a familiar theme emerged: "children with ADHD have an 80% increased odds of asthma compared with children without ADHD." I'm beginning to lose track of the number of times I've covered this association down the blogging years (see here and see here and see here). Indeed, these results add to other reviews on this topic [2] previously covered on this blog (see here).The nature of the association? Well, more studies are still required. The authors talk about some work looking at possible overlapping genetic issues with autoimmunity in mind, and that is probably going to be quite important. More than that however is the idea that other less-genetic factors might also play a role. Y'know how social factors such as poverty might figure (see here) for example. I'm also minded to bring in the possibility of an 'association' between food allergy and behavioural symptoms (see here) in light of other work. Such a connection might also implicate all-manner of other bodily systems including the [hyped-up] field of microbiomics for example. Suffice to say that connections are likely to be complex and potentially numerous.The other implication from the Miyazaki results is another thing I've been going on about for some years on this blog: preferential screening. Y'know, when a diagnosis of asthma for example, is received, how about screening for ADHD and related developmental issues? Or, the other way around, screen for allergic diseases when a diagnosis of ADHD is received? And then there's the intervention angle, and some potentially useful data from both other developmental/behavioural diagnoses and allergy symptoms (see here) and some rather more direct evidence (see here)?To close, my brood have just discovered Little Britain and the laughter has gone on and on and on...----------[1] Miyazaki C. et al. Allergic diseases in children with attention deficit hyperactivity disorder: a systematic review and meta-analysis. BMC Psychiatry. 2017; 17: 120.[2] Schans JV. et al. Association of atopic diseases and attention-deficit/hyperactivity disorder: A systematic review and meta-analyses. Neurosci Biobehav Rev. 2017 Mar;74(Pt A):139-148.----------Miyazaki, C., Koyama, M., Ota, E., Swa, T., Mlunde, L., Amiya, R., Tachibana, Y., Yamamoto-Hanada, K., & Mori, R. (2017). Allergic diseases in children with attention deficit hyperactivity disorder: a systematic review and meta-analysis BMC Psychiatry, 17 (1) DOI: 10.1186/s12888-017-1281-7... Read more »

  • April 18, 2017
  • 04:21 AM

"Asthma was associated with increased risk for schizophrenia"

by Paul Whiteley in Questioning Answers

'Big data' Taiwan is once again the topic of a post on this blog as the results published by Wei-Chen Wang and colleagues [1] (open-access available here) receive an airing, specifically that: "Asthma was associated with increased risk for schizophrenia."There are some common themes attached to these findings. Taiwan is already a research-favourite place on this blog as a result of their use of the National Health Insurance Research Database (NHIRD) for various research purposes. I can't name all the occasions I've talked about research from Taiwan based on the NHIRD but a few of them can be seen here and here. Another commonality of this latest research from Wang et al is the idea that physical illness with a substantial immune system component to it *might* show an important connection to a behavioural/psychiatric disorder. Asthma and related atopic diseases has been mentioned on a few other occasions (see here and see here). Hold those thoughts for now...This time around Wang and colleagues "aimed to investigate the association between asthma, corticosteroid use, and schizophrenia." Comparing 'measures of schizophrenia' in some 25,000 participants diagnosed with asthma and 50,000 without asthma over 7 years, and adjusting for various potentially confounding variables - "sex, age, residence, socioeconomic status, corticosteroid use, outpatient and emergency room visit frequency, Charlson comorbidity index, and total length of hospital stays days for any disorder" - the results were interesting. Not least that "asthma was associated with significantly greater hazard ratio for incident schizophrenia." Researchers also noted that various other confounding variables also showed a relationship with schizophrenia such as rural residence, poor general health and lower economic status. "Corticosteroid use was not associated with increased risk for schizophrenia" we are also told.Whilst interesting, the results do not say that everyone with asthma is at risk of developing schizophrenia. Not even close. The rates of schizophrenia identified in the Wang study were also quite low overall despite the large starting populations studied: "Of the total 75,069 subjects, 238 were diagnosed with schizophrenia during the study period: 100 (0.40%) of subjects were in the asthma cohort and 138 (0.28%) in the non-asthma cohort."But, set within the context of other independent datasets [2] observing "the existence of an association between atopic disorders in general and asthma in particular and the risk of developing schizophrenia" there is cause for further investigation into any association. Not least that Wang et al describe their results in the context that: "a convergent disturbance in the immune-inflammatory system may contribute to the pathoetiology of asthma and schizophrenia." Y'know, all that talk that among the [plural] schizophrenias, one or two phenotypes might, to some quite large extent, be linked to immune function or dysfunction. Well, it's not as if we haven't got some quite reliable research clues already (see here). There may also be some subsequent discussions on the requirement for enhanced screening for something like schizophrenia as and when a diagnosis of asthma (or other atopic disease) is diagnosed as per other data (see here).Finally, going back to the previous research occasions when asthma has been *correlated* with labels such as attention-deficit hyperactivity disorder (ADHD) and even autism, I'm wondering whether there could be wider links present when it comes to immune-related conditions and behavioural presentations. It's pretty well known that various behavioural/developmental/psychiatric labels tend to 'club together' (see here and see here for examples). There is also a growing realisation that alongside overlapping genetics and biology when it comes to such labels, the days of autism genes for example, just being genes for autism are beginning to drift off (see here); something probably relevant to conditions such as ADHD and schizophrenia too. So, could it be that immune system related conditions such as asthma and atopic disease, might have lots and lots of implications in relation to many developmental/behavioural/psychiatric labels? Even more intriguing, are there clues to possible intervention avenues too? (with no medical or clinical advice given or intended).We await further investigations...----------[1] Wang WC. et al. Asthma, corticosteroid use and schizophrenia: A nationwide population-based study in Taiwan. PLoS One. 2017 Mar 28;12(3):e0173063.[2] Pedersen MS. et al. Schizophrenia in patients with atopic disorders with particular emphasis on asthma: a Danish population-based study. Schizophr Res. 2012 Jun;138(1):58-62.----------Wang WC, Lu ML, Chen VC, Ng MH, Huang KY, Hsieh MH, Hsieh MJ, McIntyre RS, Lee Y, & Lee CT (2017). Asthma, corticosteroid use and schizophrenia: A nationwide population-based study in Taiwan. PloS one, 12 (3) PMID: 28350822... Read more »

Wang WC, Lu ML, Chen VC, Ng MH, Huang KY, Hsieh MH, Hsieh MJ, McIntyre RS, Lee Y, & Lee CT. (2017) Asthma, corticosteroid use and schizophrenia: A nationwide population-based study in Taiwan. PloS one, 12(3). PMID: 28350822  

  • April 17, 2017
  • 03:00 PM

The continuing trials and tribulations of PACE

by Paul Whiteley in Questioning Answers

I honestly hadn't intended talking about the PACE trial - "pacing, graded activity, and cognitive behaviour therapy: a randomised evaluation" in relation to chronic fatigue syndrome (CFS) - quite so much on this blog. Others have done it so much better than I ever could.My interest however keeps being piqued in relation to the results originally produced suggesting that: "CBT [cognitive behaviour therapy] and GET [graded exercise therapy] can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome" and the subsequent myriad of voices quite unanimously suggesting that one perhaps needs to be a little careful with such sweeping generalisations (see here).OK, for anyone new to this topic, below are a few of the previous occasions that it has been discussed on this blog in chronological order:Chronic Fatigue Syndrome and various factors (2014) (see here)Chronic fatigue syndrome and the detrimental application of the 'biopsychosocial model' (2016) (see here)PACE-gate! (2016) (see here)PACE trial recovery data and chronic fatigue syndrome (2017) (see here)PACE trial recovery data and chronic fatigue syndrome - a reply (2017) (see here)I want to add a few more 'science references' to this issue because some important things are being discussed in the peer-reviewed domain, in the context that CBT and GET at the moment, are considered 'best practice' here in the UK and beyond when it comes to CFS. That may change in future times (see here) as it has in other parts of the world (see here) but that's where we are at the time of writing. I might add that the addition of new references to this post is a rather more descriptive thing minus too much additional commentary from me, and that the views represented are those of the authors. I wrote this post on 9 April 2017 so it is accurate up to that point.OK, starting with the editorial from Keith Geraghty [1] mentioned in that PACE-gate! post, we have an authors reply to some of the points raised [2]. The main crux of the reply is to correct "misunderstandings and misrepresentations of the PACE trial." Next up was a paper by Leonard Jason [3] (someone with quite an impressive research track record when it comes to CFS) and some comments on the pacing intervention (adaptive pacing therapy, APT) used and "patient selection ambiguity." This is a particularly interesting paper because APT - "based on the envelope theory of chronic fatigue syndrome" where the symptoms of CFS are "not reversible by changes in behaviour" - did not hit the 'research spot' according to the original PACE trial results.I want to next include the paper by Luis Nacul and colleagues [4] into proceedings, and a role for "selection bias and disease misclassification" when it comes to studies on CFS (and myalgic encephalomyelitis, ME). To quote from them: "When studies using the broad Oxford criteria... were excluded, a virtual disappearance of effect for graded exercise therapy (GET), cognitive behaviour therapy (CBT) and other psychological therapies recommended by the NICE guidelines (National Institute for Health and Care Excellence.. was revealed." Guess which criteria (among the many available) were used in the original trial?Onward. The paper by Steven Lubet [5] titled: 'Investigator bias and the PACE trial' sets out quite an 'accusation' in that: "the PACE investigators “impartiality might reasonably be questioned”." This is a theme that crops up again shortly. The paper by Tom Kindlon [6] asked whether graded exercise in particular, could be thought of as 'safe and risk-free'? I set this question within the context that the original PACE trial did find that: "Non-serious adverse events were common" and GET did seem to produce the largest number of 'serious adverse effects' in number if not in participants.Nearly there. Next up is the paper from Carolyn Wishire [7] who, when talking about "lively discussion", reports on various potential forms of bias in behavioural intervention studies using the PACE study as a kind of template. This author was the lead on the recent peer-reviewed commentary (open-access) re-analysing the 'recovery' data subsequently published in relation to the PACE trial. Then, we have the paper by Jonathan Edwards [8] who notes that the PACE trial represents a lesson in how research design needs to develop further when it comes to science in general. To quote: "The failure of the academic community to recognise the weakness of trials of this type suggests that a major overhaul of quality control is needed." And finally Charles Shepherd [9] provides further commentary on the PACE trial and a call for independent review.And rest.There is quite a lot to take in from those various publications and I don't doubt that this is not the last we are going to hear about the PACE trial. Allied to articles such as this one describing how: "Physicians used to dismiss the disease as psychosomatic" (past tense) it certainly would not out of place to suggest that there are still questions that need to be answered about the design and results obtained from the PACE trial and their applicability to the (very) wide CFS/ME population. To quote again from the paper by Edwards [8]: "If they are still ill [those diagnosed with CFS/ME], presumably these approaches have failed and the priority is to find something more effective." Wise words indeed.To close, it's here... the first glimpse of The Last Jedi.----------[1] Geraghty KJ. ‘PACE-Gate’: When clinical trial evidence meets open data access. J Health Psychology. 2016. Nov 1.[2] White PD. et al. Response to the editorial by Dr Geraghty. J Health Psychology. 2017. Jan 24.[3] Jason LA. The PACE trial missteps on pacing and patient selection. J Health Psychology. 2017. Feb 1.[4] Nacul L. et al. How have selection bias and disease ... Read more »

White, P., Chalder, T., Sharpe, M., Angus, B., Baber, H., Bavinton, J., Burgess, M., Clark, L., Cox, D., DeCesare, J.... (2017) Response to the editorial by Dr Geraghty. Journal of Health Psychology, 2147483647. DOI: 10.1177/1359105316688953  

  • April 13, 2017
  • 04:40 AM

Video Interaction for Promoting Positive Parenting in autism: yes but not quite...

by Paul Whiteley in Questioning Answers

"Video feedback may help babies ‘at risk of autism’" went one write-up of the study results published by Jonathan Green and colleagues [1] (open-access available here). Continuing a theme of kids at risk of autism potentially 'avoiding' an autism diagnosis (see here) following the use of "a 12-session parent-mediated social communication intervention delivered between 9 and 14 months of age (Intervention in the British Autism Study of Infant Siblings-Video Interaction for Promoting Positive Parenting)" there is some degree of optimism from these latest results together with a pinch of 'not-so-fast'...Including data from some 54 families - "28 intervention, 26 nonintervention" - researchers reported on the effects of interventions vs. no intervention on various aspects of functioning primarily the "severity of autism prodromal symptoms." Prodromal means early symptoms and is more readily associated with other labels/conditions. The authors reported that results were not completely cut-and-dried in terms of effect(s) of intervention on diagnostic outcome for example (i.e. there were "no intervention effects on diagnostic outcome") but potentially something to see when it comes to the 'severity' of autism prodromal symptoms and "parent-dyad social communication." The authors also noted that measures of communication and language did show something of a trend towards some benefit observed in the intervention group, but did not yield any significant difference when comparing intervention with no intervention over the quite long study period (39 months). This contrasts with their previous results [2] possibly indicating something rather more adverse when it came to intervention and aspects of language/communication. I might also draw your attention to the fact that from a bank of some 84 families invited to join the study, just over half actually agreed or fulfilled the criteria for joining.I know this is an area of research that people really want to see work. Alongside other early intervention research in relation to autism (see here for example), the idea that some small adjustments to early interactions might affect the presentation of autism still enjoys quite a lot of support in various quarters. The thing is that these and other results whilst suggesting that things like 'parental responsiveness' can improve as a result of intervention(s), have so far shown that important outcomes for young children are far less impressive. This is something evident across quite a lot of the research literature in this area even when meta-analysed (see here including some chatter about effect sizes).I'm not suggesting that we everyone just 'gives up' when it comes to early interventions like the one described by Green and colleagues. I do however think science and clinical practice needs to be a little more focused on things like potential best-responders to such interventions (as it does for many other aspects of autism science) and not so focused on creating grand media headlines. I might also throw in the idea that study design is something that needs to be improved particularly in light of other recent findings [3] talking about how "placebo-like effects represent substantial challenges for randomized controlled trials (RCTs) that use treatment as usual" (guess what many studies in this area use as their comparator?) Accepting that variables such as the plural autisms (see here) are inevitably going to affect results from such studies, I'm minded to suggest that quite a few more resources need to be committed to looking at the possible 'hows and whys' of autism coming about before any talk about early parent-mediated intervention becoming widespread. So, questions like whether screening for inborn errors of metabolism in relation to autism (see here) could be a good first step as part of the mantra 'diagnosis is a starting point not the finishing line' and then taking things from there...----------[1] Green J. et al. Randomised trial of a parent-mediated intervention for infants at high risk for autism: longitudinal outcomes to age 3 years. J Child Psychol Psychiatry. 2017 Apr 10.[2] Green J. et al. Parent-mediated intervention versus no intervention for infants at high risk of autism: a parallel, single-blind, randomised trial. Lancet Psychiatry. 2015. Jan 22.[3] Jones RM. et al. Placebo-like response in absence of treatment in children with Autism. Autism Res. 2017. 12 April.----------Green J, Pickles A, Pasco G, Bedford R, Wan MW, Elsabbagh M, Slonims V, Gliga T, Jones EJ, Cheung CH, Charman T, Johnson MH, & British Autism Study of Infant Siblings (BASIS) Team. (2017). Randomised trial of a parent-mediated intervention for infants at high risk for autism: longitudinal outcomes to age 3 years. Journal of child psychology and psychiatry, and allied disciplines PMID: 28393350... Read more »

Green J, Pickles A, Pasco G, Bedford R, Wan MW, Elsabbagh M, Slonims V, Gliga T, Jones EJ, Cheung CH.... (2017) Randomised trial of a parent-mediated intervention for infants at high risk for autism: longitudinal outcomes to age 3 years. Journal of child psychology and psychiatry, and allied disciplines. PMID: 28393350  

  • April 12, 2017
  • 04:39 AM

On a 'bidirectional relationship' between depression and autoimmune disorders

by Paul Whiteley in Questioning Answers

"We replicated the finding that autoimmune disorders are frequently comorbid with depression, using a longitudinal national birth cohort and self-report data, which is increasingly used in the study of depression."So said the findings reported by Jack Euesden and colleagues [1] (open-access) adding further to a growing peer-reviewed literature base [2] citing a 'connection' between immune function/dysfunction and the presentation of psychiatric/behavioural features (see here). And yes, their results did seem to add to other work more generally on the overlapping presence of autoimmune disorders and something like mood disorder (see here) and specifically with certain autoimmune parameters in mind (see here).Drawing on data from the National Child Development Study (NCDS), an initiative based here in Blighty that "comprised of all children born in England, Scotland and Wales, in one week of 1958", researchers posed various questions to participants. These included querying them about their medical histories in respect of "23 autoimmune disorders" and questioning around "three self-report measures of depression onset" at various stages of the 1958 participant cohort. These were self-report measures but alongside, researchers also accessed data from blood samples with respect to genetic analyses.Results: based on data from over 8100 participants, approximately 4% of the sample "reported ever being diagnosed with an autoimmune disorder." Alongside, some 1500 participants (18%) reported "ever experiencing depression" (i.e. were described as 'positive' for the measures of depression used during the study). When looking at the data combined, researchers concluded that there was significant 'comorbidity' between the self-reports of depression and the self-reports of autoimmune disease. As per the title of this post, the nature of the relationship was bi-directional in that: "Autoimmune disorder onset associated with increased subsequent hazard of depression onset" and "depression increased subsequent hazard of autoimmune disorder onset."Keeping in mind that self-report whilst a good rough-and-ready measure is not exactly the same as analysis of medical records when it comes to confirming any diagnosis nor that depression screens are the same as face-to-face diagnosis for something like clinical depression, there are some important implications raised from this and other related work. Analysis of 'shared pathways' between something like depression and autoimmune disease (bearing in mind, both terms cover quite a lot of clinical area) is perhaps something to consider. We're already beginning to realise that something like 'autism genes are not just genes for autism' and no doubt such a sentiment extends to other behavioural/psychiatric labels too. I note the authors also head down the [previously trodden] path suggesting that immune-based treatments might serve more than one purpose when it comes to the correlation between depression and autoimmune disease (see here). Keeping also in mind that autoimmune disease basically reflects a loss of immune tolerance to self, one wonders how deep the rabbit hole might go. If we take one specific autoimmune condition, coeliac disease, where the primary treatment is the use of a gluten-free diet, does this mean that such a diet might be useful for some types of depression too (see here)?There are still lots of questions still to be asked/answered with regards to the 'connection' between depression and autoimmune disease. But research such as this from Euesden et al represents further realisation that the immune system seems to be doing quite a bit more than just protecting us from the odd pathogen...----------[1] Euesden J. et al. A bidirectional relationship between depression and the autoimmune disorders – New perspectives from the National Child Development Study. PLoS ONE. 2017; 12(3): e0173015.[2] Andersson NW. et al. Depression and the risk of autoimmune disease: a nationally representative, prospective longitudinal study. Psychol Med. 2015 Dec;45(16):3559-69.----------Euesden J, Danese A, Lewis CM, & Maughan B (2017). A bidirectional relationship between depression and the autoimmune disorders - New perspectives from the National Child Development Study. PloS one, 12 (3) PMID: 28264010... Read more »

  • April 11, 2017
  • 10:22 AM

Risking Limb for Life? (A Guest Post)

by Miss Behavior in The Scorpion and the Frog

By Matthew Whitley Imagine you are walking alone in parking lot, when suddenly somebody grabs you by the arm and flashes a knife, demanding your money. Do you A) scream for help, B) try to wrestle the knife away, or C) remove your arm from your shoulder and make a break for it? Disarming your assailant may seem preferable to dis-arming yourself, but for a lizard option C is a likely response. A lizard tail left behind. Image by Metatron at Wikimedia Commons.You likely have heard before that many lizards can break off their tail when trying to make an escape. This ability is called caudal autotomy; autotomy meaning the ability to shed a limb, and caudal simply being a fancy word for tail. Of course, losing a limb is no simple procedure, and lizards possess many specialized features to make caudal autotomy possible. There are two main kinds of caudal autotomy in lizards: intervertebral and intravertebral. Intervertebral refers to when the tail breaks between vertebrae, and is considered the simpler and more primitive form. Intravertebral, on the other hand, involves some more complex features. The word intravertebral refers to fracture planes found in the middle of each vertebra in the middle of the lizard’s tail. At these fracture planes, the bone can easily snap in half. This snapping of bone is performed by the lizard itself—when its tail is caught, muscles surrounding the bone just above where its tail is held squeeze tight until the bone breaks. After the bone breaks, the rest of the tail follows: the skin stretches and breaks, muscles detach, any remaining tissue divides, and—POP—the tail falls off! After snapping your arm off to run from an attacker, you would probably just bleed out in your retreat, but lizards have that covered. In their tails, lizards have sphincters (rings of muscle) along their arteries—vessels that normally carry blood to the tail. When the tail is detached, these sphincters tighten to prevent blood from gushing out. Additionally, their veins, which normally bring blood back from the tail, have valves that prevent blood from flowing backwards, similar to the valves in your heart. And while the lizard makes its escape, the dislocated tail jerks and twitches, which distracts the lizard’s assailant. The tail owes its spastic actions to fast, glycolytic muscles, a variety of muscle that can act quickly and with a lot of force, but wears out quickly. After our reptilian friend has made its daring escape, it has a new problem—it has no tail. A lizard without its tail is at a disadvantage, just as you would be without your arm. Lizards rely on their tails for several functions, including movement, nutrient storage, and social and sexual behaviors. Fortunately, lizards that exercise caudal autotomy can actually re-grow their tails, a process which itself is highly complex. In lieu of a lengthy explanation of another amazing phenomenon, I’ll share this tidbit: to regain lost nutrients and help recover, some lizards have been known to go back and eat their lost tail! So when you tear off your arm to escape a mugger, don’t forget to return to the scene of the crime to self-cannibalize…or maybe just buy some pepper spray beforehand. Here you can see that the lizard is caught by the tail, pops it off and runs away, and the tail is left twitching.Works CitedBateman, P., & Fleming, P. (2009). To cut a long tail short: a review of lizard caudal autotomy studies carried out over the last 20 years Journal of Zoology, 277 (1), 1-14 DOI: 10.1111/j.1469-7998.2008.00484.xClause, A., & Capaldi, E. (2006). Caudal autotomy and regeneration in lizards Journal of Experimental Zoology Part A: Comparative Experimental Biology, 305A (12), 965-973 DOI: 10.1002/jez.a.346Gilbert, E., Payne, S., & Vickaryous, M. (2013). The Anatomy and Histology of Caudal Autotomy and Regeneration in Lizards Physiological and Biochemical Zoology, 86 (6), 631-644 DOI: 10.1086/673889 ... Read more »

Clause, A., & Capaldi, E. (2006) Caudal autotomy and regeneration in lizards. Journal of Experimental Zoology Part A: Comparative Experimental Biology, 305A(12), 965-973. DOI: 10.1002/jez.a.346  

Gilbert, E., Payne, S., & Vickaryous, M. (2013) The Anatomy and Histology of Caudal Autotomy and Regeneration in Lizards. Physiological and Biochemical Zoology, 86(6), 631-644. DOI: 10.1086/673889  

  • April 11, 2017
  • 04:02 AM

Risk of death by injury and autism

by Paul Whiteley in Questioning Answers

"Individuals with autism appear to be at substantially heightened risk for death from injury."That was the research bottom line published by Joseph Guan & Guohua Li [1] from Columbia University Medical Center, who trawled the accumulated data included in the US National Vital Statistics System screening death certificates issued between 1999 and 2014. Of the approximate 32 million death certificates issued, researchers found that some 1300 people diagnosed as on the autism spectrum had their death recorded and recorded with mention alongside the word 'autism'.A few details about those 1367 deaths among those with autism compared with the not-autism population have captured media headlines (see here) not least the finding that: "The mean age at death for individuals with autism was 36.2 years (SD = 20.9 years), compared with 72.0 years (SD = 19.2 years) for the general population." This data tallies with other reports on premature mortality in relation to autism (see here) and also in respect of some of the over-represented comorbidity that accompanies the label such as learning (intellectual) disability (see here). I might also forward the idea that another over-represented comorbidity - attention-deficit hyperactivity disorder (ADHD) - appearing alongside autism (see here) might also have some relevance when it specifically comes to injury risk too (see here). Researchers noted that around a quarter of deaths recorded for those with autism were attributed to injury - quite a bit more than compared to those general population death stats - and that suffocation, asphyxiation and drowning made up a considerable portion of those deaths following injury.OK a step back is required here. This data does not mean that those diagnosed on the autism spectrum have a life expectancy of 36.2 years (plus or minus 20 years or so). I know it might seem a little obvious to make such a statement but I do want to make that point clear. The data did find that premature mortality due to injury and non-injury does seem to 'hit younger' when it comes to autism (bear in mind also that the majority of recorded deaths where autism was mentioned were not caused as a result of injury).Appreciating that some people have voiced their concern about these and other aspects of the Guan/Li paper (see here) I have to say that I'm slightly more focused on the pattern of death by injury reported over above whether the data is truly representative of the autistic population at large or not. Death by drowning is sadly something all too familiar when it comes to autism, particularly when taken in the context of the wandering/elopement data (see here). Yes, for some, autism, the presentation of autism and autism+, can be a life-limiting diagnosis. I know that last sentence does not make for great PR but readers should look at it in the context of other important peer-reviewed information too (see here and see here).So, what can be done to improve life prospects for those on the autism spectrum?  Well, outside of moves to reduce the multitude of health inequalities that seem to coincide with receipt of a diagnosis of autism (see here and see here for examples), there are some practical solutions. Lessons about water safety and learning to swim represent a first course of action [2] and something that may have various other beneficial effects in terms of physical fitness (another issue that pervades the autism research literature). I appreciate that some children (and adults) might be a little nervous around water but with a bit of creative thinking (i.e. making swimming fun and not just about learning to do lengths of the pool) I don't doubt that learning such a life-saving skill can be made much more palatable. In the age where cinemas and theatres have 'autism-friendly' screenings, surely autism-friendly swimming sessions can't be too far behind?In relation to reducing other potential causes of death such as suffocation and asphyxia, there may be other things to consider. I'm assuming that food and eating patterns may be something to be looked at when it comes to problems such as choking. This means education about eating small morsels of food and the importance of properly chewing food before swallowing so reducing the frequency of food packing for example. This might also have implications as and when medication is taken orally (via the mouth) and little details such as ensuring that a person drinks some water with any tablets that need to be taken. You may again think this is a rather obvious thing to say but sadly, there have been occasions when choking on food [3] has led to rather extreme consequences in the context of the autism spectrum.In short, death by injury in relation to autism is not something that should ever be accepted. Yes, injury and accidents happen, but that's not to say nothing that can be done to prevent some/many of them...----------[1] Guan J. & Li G. Injury Mortality in Individuals With Autism. American Journal of Public Health. 2017. Mar 21.[2] Pan CY. Effects of water exercise swimming program on aquatic skills and social behaviors in children with autism spectrum disorders. Autism. 2010 Jan;14(1):9-28.[3] Hudson A. et al. Packing and Problematic Feeding Behaviors in CHARGE Syndrome: A Qualitative Analysis. Int J Pediatr Otorhinolaryngol. 2016 Mar;82:107-15.----------Guan, J., & Li, G. (2017). Injury Mortality in Individuals With Autism American Journal of Public Health DOI: 10.2105/AJPH.2017.303696... Read more »

Guan, J., & Li, G. (2017) Injury Mortality in Individuals With Autism. American Journal of Public Health. DOI: 10.2105/AJPH.2017.303696  

  • April 10, 2017
  • 04:27 AM

"Predisposition" to autoimmunity and inflammatory activation linked to autistic regression?

by Paul Whiteley in Questioning Answers

The paper by Ori Scott and colleagues [1] provides some very welcome interest in the concept of regression in relation to autism. As I've indicated quite a few times on this blog, regression accompanying cases of autism has [finally] been accepted by the research community at large (see here for example) but there is still some way to go with regards to the hows-and-whys of regression. There are some clues (see here) but more data is required. What the evidence available so far suggests is that sweeping generalisations about autism exclusively occurring/appearing during very early infancy or even before, are probably not as accurate as many people might realise (see here)...So, starting from the idea that autistic regression might have an important 'immune-related' component to it, the authors set about reviewing the medical charts/records of some 240 children diagnosed with an autism spectrum disorder (ASD). A small but significant proportion of the cohort presented with an "autistic regression variant". Researchers looked at various potentially important facets of those medical charts in relation to things like "febrile illness preceding initial parental concern" (in relation to autistic features) and "possible non-immune precipitants such as pregnancy and postnatal complications." Another important feature of the study was to look-see whether various autoimmune disease/conditions were a feature of the immediate family in regressing and non-regressing cases.Results: well, febrile illness did seem to be quite a lot more apparent in those children who experienced autistic regression. Indeed the figures went something like 30% in those with autistic regression and 0% in those without. Wow. Researchers also reported that rates of autoimmune disease in the immediate family were quite a bit higher in the regression group compared with non-regressing participants (33% vs. 12%). Further: "Type 1 diabetes and autoimmune thyroiditis were both more common in families with children with autistic regression." The authors conclude: "Our findings suggest that predisposition to autoimmunity, and immune/inflammatory activation, may be associated with autistic regression."Accepting that this was research based on chart reviews (and indeed chart reviews in 2014) and the relatively small group numbers presenting with autistic regression, these are potentially important findings. Familial autoimmune conditions/disease *correlating* with autism is by no means a new thing (see here). Type 1 diabetes - the one where the pancreas don't produce any insulin as a result of the body failing to recognise self as self - has some history in relation to offspring autism risk (see here). Autoimmune thyroiditis, or at least some of the biological markers of this disease, also has some research history (see here). Interestingly, autoimmune thyroid disease also might have some connection to cases of depression too (see here) which could pose some intriguing questions in relation to the body of research talking about antidepressant use being potentially important to offspring autism too (see here). It would be a brave person to say there is no possibility of a connection between these and other familial autoimmune conditions and offspring autism...The febrile illness stats produced by Scott and colleagues in relation to the regression group are really very interesting. Febrile illness denoting fever and corresponding symptoms in relation to autism onset is an area crying out for further research. Yes, febrile illness can affect onset of things like seizures and/or epilepsy and it would be rather intriguing to see whether this might play a role in the onset of some autism bearing in mind the epilepsy connection posed so far (see here). But more than that are the numerous voices talking about fever being a facet of symptoms onset under quite a few circumstances [2]. The words 'post-encephalitic' spring to mind and with it, quite a bit more scientific inquiry being indicated. And there is also another area that might benefit from some additional scrutiny in relation to developmental regression 'plus' other factors accompanying cases of autism [3]...----------[1] Scott O. et al. Clinical clues for autoimmunity and neuroinflammation in patients with autistic regression. Dev Med Child Neurol. 2017 Apr 6.[2] Mankoski RE. et al. Etiologies of autism in a case-series from Tanzania. J Autism Dev Disord. 2006 Nov;36(8):1039-51.[3] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.----------Scott O, Shi D, Andriashek D, Clark B, & Goez HR (2017). Clinical clues for autoimmunity and neuroinflammation in patients with autistic regression. Developmental medicine and child neurology PMID: 28383115... Read more »

  • April 8, 2017
  • 09:53 AM

Publication Alert: High Nucleotide Resolution Study of the Skin Virome

by Geoffrey Hannigan in Prophage

A few weeks ago some colleagues and myself published a new manuscript looking at the diversity of the human skin virome. In our previous previous work, we evaluated the diversity of viruses on the skin. Other groups have looked at virus diversity at other body sites including the gut, lungs...... Read more »

  • April 8, 2017
  • 04:13 AM

One more time folks... pregnancy folate and autism risk

by Paul Whiteley in Questioning Answers

Folate yet again on this blog? Sorry but that's just how the peer-reviewed papers have fallen..."Maternal folate supplementation during pregnancy may reduce the risk of ASD [autism spectrum disorder] in the offspring, especially in the Western population."So said the meta-analysis by Yu and colleagues [1] reporting on a topic that has seen quite a lot of research interest down the years (see here). Authors this time around cumulatively examined data for some 4,500 cases of autism compared with well over a million control (not-autism) cases and determined that on the whole "maternal folate supplementation during pregnancy significantly reduced the risk of ASD in the offspring in the total population (OR=0.798, 95%CI: 0.669-0.952, P=0.012)."What more is there to say on this topic? Well, potentially quite a bit, not least that not every study has suggested that folate is necessarily a risk reducer when it comes to offspring autism (see here) bearing in mind the potential number of confounders affecting any relationship. Of the multiple occasions that I've talked about folate and autism on this blog, I'm also minded to bring back into the frame how (a) the folate cycle, dealing with the biological metabolism of folate, and its related components is pretty complicated when it comes to a label like autism (see here) and (b) one area that is becoming particularly interesting is in relation to antibodies and folate receptors (see here for example) with autism in mind. Science still needs to do quite a bit more in relation to mechanics of any link between pregnancy folate use/levels and offspring autism risk.----------[1] Yu XF. et al. Association between maternal folate supplementation during pregnancy and the risk of autism spectrum disorder in the offspring: a Meta analysis. Zhongguo Dang Dai Er Ke Za Zhi. 2017 Mar;19(3):286-291.----------Yu XF, Li M, & Zheng Y (2017). [Association between maternal folate supplementation during pregnancy and the risk of autism spectrum disorder in the offspring: a Meta analysis]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics, 19 (3), 286-291 PMID: 28302198... Read more »

  • April 7, 2017
  • 06:22 AM

Novel FLCN mutations in Chinese patients

by Joana Guedes in BHD Research Blog

The gene FLCN is inactivated in individuals with BHD syndrome. The FLCN gene encodes the protein Folliculin, which is a putative tumour suppressor. Over 150 different FLCN mutations have been identified, most of which are likely to be pathogenic (LOVD-hosted FLCN mutation database). The majority of these mutations are frameshift, nonsense, insertion/deletion, or splice site mutations, resulting in truncation and inactivation of the encoded protein folliculin. FLCN consists of 14 exons spanning approximately 20 kb of genomic DNA (Nickerson et al., 2002).

Novel FLCN mutations are still being identified and here we discuss two case studies with novel mutations found in patients in China.... Read more »

  • April 7, 2017
  • 04:48 AM

Folate-dependent one carbon metabolism and transsulfuration pathways: biomarkers for autism?

by Paul Whiteley in Questioning Answers

I found it a little unusual that the findings reported by Daniel Howsmon and colleagues [1] (open-access) talking about "multivariate statistical analysis presented herein [provided] unprecedented quantitative classification results for separating participants into ASD [autism spectrum disorder] and NEU [neurotypical] cohorts based solely on biochemical data" merited a rapid reply in a prominent science magazine pouring cold water on the results (see here). Not least because one of the commentators interviewed in said science magazine article is also not seemingly immune when it comes to sweeping claims being made on the basis of preliminary research findings about autism (see here as per the previous headline: 'Super-parenting' improves children's autism).No mind, the Howsmon paper - including a notable research name on the authorship list - mentions a few important compounds and biological processes in their discussions on: "Stepping towards this goal of incorporating biochemical data into ASD diagnosis." The sorts of things covered included various biological 'markers' pertinent to folate-dependent one-carbon metabolism (FOCM) and transsulfuration (TS) some of which have been fodder for this blog previously (see here and see here for examples). Researchers looked at these various compounds in blood samples from some 80 children diagnosed with an ASD and compared levels with 47 siblings and 76 age-matched controls. They applied some nifty statistics to try and determine whether any combination of the 24 analytes examined might be potential biomarker-material for an autism diagnosis. You'll note that once again the quite problematic binary description of 'neurotypical' was used to define 'not-autism' leading onwards to the inevitable questions: 'what is neurotypical?' and 'what are the boundaries of being neurotypical?' Sensible [evidence-based] answers on a postcard please.Results: "FDA [Fisher Discriminant Analysis] on seven metabolites allows sufficient separation such that a linear classifier can correctly resolve 96.9% of participants." But actually this was not the whole story as the authors also report that five compounds/variables - GSSG, tGSH/GSSG, Nitrotyrosine, Tyrosine, and fCysteine - provided the best 'fit' when it came to potentially picking out children with autism. You might note that some of those 'famous five' have some autism research history (see here). The authors similarly note that: "these variables are affected by high quality vitamin supplementation that also decreases ASD severity in at least a subset of cases." Mmm.There is definitely more science to do in this area. Biomarkers in relation to autism have come and gone down the years (see here for example) and I'm not altogether sure that using the label 'autism' as a starting point for this kind of research is necessarily the best idea (see here). Outside of just the heterogeneity and plurality - the autisms - associated with the label autism, there are other considerations to take on board such as the impact of all that over-represented comorbidity too (something that continues to 'mess around' with various 'autism is linked to..' studies).But that shouldn't stop further efforts in this area including those also looking to expand into the 'genetics' of folate metabolism alongside the biochemistry, as per everyone's favourite scrabble word 'MTHFR' (see here) and its [meta-analysed] potential contribution to some autism. I agree that we are not quite there when it comes to folate metabolism as providing a generic biomarker or set of biomarkers for autism, but there again, the authors never said that it definitively did: "it should be noted that these studies should be replicated and empirically tested on a wider scale before more definite conclusions can be drawn." Too true but the Howsmon results represent an interesting first attempt...----------[1] Howsmon DP. et al. Classification and adaptive behavior prediction of children with autism spectrum disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation. PLoS Comput Biol. 2017 Mar 16;13(3):e1005385.----------Howsmon DP, Kruger U, Melnyk S, James SJ, & Hahn J (2017). Classification and adaptive behavior prediction of children with autism spectrum disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation. PLoS computational biology, 13 (3) PMID: 28301476... Read more »

  • April 6, 2017
  • 02:44 AM

"a single intravenous infusion of autologous umbilical cord blood" and autism

by Paul Whiteley in Questioning Answers

'Could stem cells offer hope for autism?' went one media headline referencing the very preliminary "phase I, open-label trial" published by Geraldine Dawson and colleagues [1] (open-access) detailing the experiences of a single intravenous infusion of autologous umbilical cord blood in 25 children with "a confirmed diagnosis of ASD [autism spectrum disorder]."Well, the results were promising in respect of important issues such as safety in light of the tenet 'first do no harm': "Assessment of adverse events across the 12-month period indicated that the treatment was safe and well tolerated" and some potentially interesting effects were noted when it came to behaviour "across a wide range of outcome measures in this study." But much like another quite innovative study with a similar research design published quite recently (see here) one needs to be a little cautious about the limitations of this current study. Not least that: "As an uncontrolled open-label study, it is not possible to determine whether the observed behavioral changes were due to the treatment or reflect the natural course of development during the preschool period." I might add that any study mentioning the words 'stem cells and autism' in the same sentence is going to be subject to significant scrutiny (see here for example).Although the Dawson paper is open-access, here are a few choice details:"All participants had to have an available autologous umbilical cord blood unit banked at a family or public cord blood bank."  This was a study using the participants own stored cord blood - blood 'left over' from the umbilical cord and/or placenta at birth - which was initially screened to make sure it was both viable and safe: "negative maternal infectious disease markers tested on the maternal donor or cord blood product (minimally including hepatitis B, hepatitis C, human immunodeficiency virus [HIV], human T-lymphotrophic virus [HTLV], and syphilis)." Cord blood contains stem cells; cells that have significant [mighty] morphing capabilities in terms of turning into different cell types. In amongst the various peer-reviewed research (and research hype) surrounding stem cells, their use with autism in mind has been slowly creeping into the public consciousness (see here for example) with appropriate caveats.Participants were given one infusion of their cord blood samples. They were fairly closely monitored over the study duration to ensure that any adverse effects (AEs) were catalogued. Researchers reported: "A total of 92 AEs were reported in 23 participants... with a median of three events per participant. All events were graded as Mild (71 events) or Moderate (21 events)." Further: "Twelve events (13%) were considered related to the infusion, with the most common being allergic reaction, manifested by urticartia and or/cough occurring on the day of infusion (5 events in 4 participants; all Mild; 2 requiring an additional dose of IV Benadryl). The most common unrelated AEs were agitation, skin changes, and typical childhood infections, reported between 2 days and 1 year post-infusion."Alongside looking for AEs, authors also reported some changes to the various behavioural schedules included for study. Looking at scores at baseline (pre-infusion) and then at 6 and 12 months, a pattern started to emerge based on group results. So: "Most of the observed behavioral changes occurred during the first 6 months and were sustained between 6 and 12 months post-infusion." The direction of the behavioural change were all positive (i.e. behavioural measures indicated improvement) and were spread out across both parent-reported and clinician-reported schedules. Interestingly too, eye gaze measurements for some 21 participants who were scanned also showed changes: "a 20% increase in odds of gazing at the actress’ eyes over time." Researchers also noted that: "children's nonverbal IQ was correlated with change for the majority of outcomes measures, with higher nonverbal IQ being associated with greater improvements in behavior." Such a finding might also tie into some other research looking at a group termed 'optimal outcome' (see here).There is a scheme of research required to follow this preliminary study, of that there is no doubt. We don't for example, know exactly how any behavioural changes were tied into the infusion (or not) because among other things, no other physiological measurements were made over the course of the Dawson study pointing to possible mechanisms. This is not entirely unexpected given the preliminary nature of the study. I will also stress again that these results were based on participants' own stored cord blood samples not other donor samples just in case any incorrect generalisation of results is made. As an aside, I was quite interested to see the use of IV (intravenous) Benadryl in relation to some of those AEs. Benadryl is an antihistamine used to manage allergy symptoms. I've talked before on this blog about how treating allergy issues in relation to some individual cases of autism might have some interesting effects on the presentation of autistic symptoms too (see here). I wonder...I am assuming that there will be more to talk about in this area of autism research as a consequence of a concluding sentence made by the authors: "we have also included the clinician-rated CGI and additional measures as secondary endpoints in our next study, a phase II, double-blind randomized clinical trial designed to formally evaluate the efficacy of umbilical cord blood infusion in improving core symptoms of ASD." Accepting that there is still some PR to be done with regards to the issue of cord blood and stem cell use in relation to autism [2] (that also includes work related to modelling conditions like autism too [3]), I'll be interested to see whether the current Dawson results survive more rigorous scientific study...To close, skin problems in Hollywood villains. No really, someone has actually studied this... ----------[1] Dawson G. et al. Autologous Cord Blood Infusions Are Safe and Feasible in Young Children with Autism Spectrum Disorder: Results of a Single-Center Phase I Open-Label Trial. Stem Cells Translational Medicine. 2017. April 5.[2] Sharpe K. et al. In the Know and in the News: How Science and the Media Communicate About Stem Cells, Autism and Cerebral Palsy. Stem Cell Rev. 2016 Feb;12(1):1-7.[3] Wen Z. Modeling neurodevelopmental and psychiatric diseases with human iPSCs. J Neurosci Res. 2017 May;95(5):1097-1109.----------... Read more »

Geraldine Dawson, Jessica M. Sun, Katherine S. Davlantis, Michael Murias,, Lauren Franz, Jesse Troy, Ryan Simmons, Maura Sabatos-DeVito, Rebecca Durham, & Joanne Kurtzberg. (2017) Autologous Cord Blood Infusions Are Safe and Feasible in Young Children with Autism Spectrum Disorder: Results of a Single-Center Phase I Open-Label Trial. Stem Cells Translational Medicine. info:/10.1002/sctm.16-0474

  • April 5, 2017
  • 04:30 AM

Elbow Stress May Compromise Elbow Health

by Catherine E. Lewis in Sports Medicine Research (SMR): In the Lab & In the Field

Workers and athletes exposed to greater elbow stress (from vibration, high forces, or high repetition) may be more likely to develop elbow osteoarthritis. ... Read more »

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