Wednesday, 27 July 2016

Blood glutamate levels in autism meta-analysed

"The meta-analysis provided evidence for higher blood glutamate levels in ASD [autism spectrum disorder]."

That was the research bottom-line reported by Zhen Zheng and colleagues [1] (open-access available here) who surveyed the current peer-reviewed science literature in this area and found something to see based on: "Twelve studies involving 880 participants and 446 incident cases."

Drawing on the idea that glutamate is a rather important amino acid that plays a role in various biological processes including that related to the manufacture of GABA (see here), Zheng et al observed higher circulating blood levels of the stuff; a sort-of proxy for what might also be going on with regards to brain levels of glutamate. That "excess glutamate has been shown to be a potent neurotoxin that leads to neuronal cell death and plays a role in the pathophysiology of some neuropsychiatric disorders" is an important point to make as to the potential implications from the Zheng meta-analysis.

Zheng et al do mention how important glutamate is for the purposes of GABA production and in particular, how issues with glutamate decarboxylase (GAD) - a key enzyme that converts glutamate into GABA - described in some cases of autism [2] might account for the elevated levels of glutamate yet the generally lower levels of GABA seen in autism (see here). I'd be inclined to agree that this is perhaps one of the more important implications for glutamate in autism; particularly when added to the whole 'glutamate linked to epilepsy' bit knowing how close a relationship autism and epilepsy seem to share (see here).

Where next with this research area I hear you ask? Well, I'd like to know a little more not just about glutamate but also another linked amino acid called glutamine. It has already been talked about in the autism research literature a while back (see here) but a lot more follow-up work is required on these two important compounds and what their differing ratio might mean. I'd also like to see more work done on the idea that "the mood stabilizer valproic acid, which exerts neuroprotective effects against glutamate-induced excitotoxicity, is effective in ASD [autism spectrum disorder] with seizures." Yes, I know that valproic acid a.k.a valproate is a bit of a double-edged sword when it comes to autism and other offspring developmental issues under certain circumstances (see here) but much like another research story in autism (see here) timing of exposure seems to be a key issue and one wonders whether other unrelated compounds might also exert a similar neuroprotective effect.

As to the idea that "blood glutamate levels may serve as a potential biomarker in the diagnosis of ASD" made by Zheng and colleagues, we'll wait and see...

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[1] Zheng Z. et al. Blood Glutamate Levels in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. PLoS One. 2016 Jul 8;11(7):e0158688.

[2] Yip J. et al. Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: an in situ hybridization study. Autism Res. 2009 Feb;2(1):50-9.

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ResearchBlogging.org Zheng Z, Zhu T, Qu Y, & Mu D (2016). Blood Glutamate Levels in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. PloS one, 11 (7) PMID: 27390857

Tuesday, 26 July 2016

Probiotics degrading gluten peptides - part 2

I going to assume that readers have some background knowledge about probiotics, gut bacteria, bacterial dysbiosis and coeliac disease before reading this post. I'd love to be able to give detailed descriptions of each here but fear that this would turn a short post into a much longer one...

So... in a previous post titled: 'Probiotics degrading gluten peptides?' I covered the potentially important suggestion that certain types of bacteria might have the ability to breakdown (degrade) immunogenic gluten peptides. This may be particularly relevant to conditions like coeliac disease where specific peptides derived from gluten are involved in a cascade of biological processes that can and do affect a sizeable proportion of the population.

In this part 2 post I'm turning my attention to the findings reported by Alberto Caminero and colleagues [1] who observed that: "Small intestinal bacteria exhibit distinct gluten metabolic patterns in vivo, increasing or reducing gluten peptide immunogenicity." Further that: "This microbe-gluten-host interaction may modulate autoimmune risk in genetically susceptible persons and may underlie the reported association of dysbiosis and CeD [coeliac disease]."

How did they arrive at such conclusions? Well, it all started with some bacterial seeding, where "bacteria isolated from the small intestine of CeD patients or healthy controls" was implanted into a germ-free mouse/mice. Said mice were given gluten (gluten gavage) and various measures of gliadin content and the extent of breakdown of gluten proteins were measured. The specific peptides "produced by bacteria used in mouse colonization" were subjected to analysis via one of the gold-standards of analytical chemistry: LC-MS/MS. Said peptides were then evaluated for their immunogenic potential "using peripheral blood mononuclear cells from celiac patients after receiving a 3-day gluten challenge."

Results: well I've already mentioned that different types of intestinal bacteria seemed to have different patterns of gluten protein degradation. This is rather important because not 10-15 years ago most people in the know would have suggested that gluten protein degradation is solely under the control of the body's biological systems designed for this purpose. Now it appears, there may be bacterial helping hands also at work. So: "Lactobacillus spp. from the duodenum of non-CeD controls degraded gluten peptides produced by human and Psa [Pseudomonas aeruginosa] proteases, reducing their immunogenicity." But for every 'good guy' there must be a 'bad guy' and in this case Psa assumes that role: "Psa-modified gluten peptides activated gluten-specific T-cells from CeD patients."

One still has to be a little cautious about this and other related work as things stand but such results are promising. Not only because more and more the gut microbiome is being implicated in conditions like coeliac disease (see here for example) but also because there may be something that can be done about it [2] and science has the technology to identify other potential gluten-digesting bacteria [3] too. Indeed, alongside a suite of other potential intervention options (see here for example) the management of conditions like coeliac disease by avoidance of dietary gluten may eventually not be the only option. Whether this may also extend to the slightly more grey areas of gluten sensitivity (see here) remains to be seen as does the idea that certain bacteria might also 'work' on accompanying issues such as those linked to gut barrier integrity [4]...

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[1] Caminero A. et al. Duodenal bacteria from patients with celiac disease and healthy subjects distinctly affect gluten breakdown and immunogenicity. Gastroenterology. 2016 Jun 30. pii: S0016-5085(16)34713-8.

[2] Duar RM. et al. Identification and characterization of intestinal lactobacilli strains capable of degrading immunotoxic peptides present in gluten. J Appl Microbiol. 2015 Feb;118(2):515-27.

[3] Berger M. et al. Rapid isolation of gluten-digesting bacteria from human stool and saliva by using gliadin-containing plates. Exp Biol Med (Maywood). 2015 Jul;240(7):917-24.

[4] Orlando A. et al. Lactobacillus GG restoration of the gliadin induced epithelial barrier disruption: the role of cellular polyamines. BMC Microbiol. 2014 Jan 31;14:19.

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ResearchBlogging.org Caminero, A., Galipeau, H., McCarville, J., Johnston, C., Bernier, S., Russell, A., Jury, J., Herran, A., Casqueiro, J., Tye-Din, J., Surette, M., Magarvey, N., Schuppan, D., & Verdu, E. (2016). Duodenal bacteria from patients with celiac disease and healthy subjects distinctly affect gluten breakdown and immunogenicity Gastroenterology DOI: 10.1053/j.gastro.2016.06.041

Monday, 25 July 2016

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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ResearchBlogging.org 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

Saturday, 23 July 2016

On probiotics and irritable bowel syndrome (IBS)

Granted, I am taking a slight departure from the material typically discussed on this blog by introducing the paper by Yan Zhang and colleagues [1] who reported the findings of a meta-analysis examining "the efficacy of different probiotic types, doses and treatment durations in IBS [irritable bowel syndrome] patients diagnosed by Rome III criteria via a meta-analysis of randomized controlled trials (RCTs)." The results however - "Probiotics are an effective pharmacological therapy in IBS patients" - were important enough for me to think about discussing, particularly in the context that IBS might not be stand-alone condition (see here) and some recent research in progress [2] (see here for my take) that could illustrate some wider relevance.

The Zhang paper is open-access so doesn't need any grand rewriting from me in terms of methods or findings but a few things stick out. First is the fact that quite a few different probiotic preparations have been experimentally examined with IBS in mind. From the 21 studies looked at by Zhang et al, we have some recurring themes including different types of Lactobacillus acidophilus and Lactobacillus rhamnosus for example being included in the preparations. The inclusion of a preparation called VSL#3 also caught me eye in light of some discussions about a potential 'antibiotic brain' recently on this blog (see here) and what might reverse this in mice. Of additional note was the use of an old friend: Saccharomyces boulardii that continues to impress [3].

Second, and related to the first point, are the authors conclusions that: "Single probiotics, a low dose, and a short treatment duration were more effective with respect to overall symptom response and QoL [quality of life]." The authors provide some rather interesting forest plots illustrating how the analysed data helped them reach this conclusion; albeit bearing in mind that "the effects of individual probiotic species" were not analysed in the current meta-analysis. In other words, some preparations seem to work pretty well but we don't know enough about which ones used under which circumstances.

Finally, I noted that the whilst the use of a placebo was an important eligibility criteria for inclusion in their meta-analysis - "the studies were randomized controlled trials (RCTs) that compared probiotics with placebo" - the authors did not shy away from the fact that: "An appreciable placebo effect was detected in some studies, which may have minimized the effects of probiotics." Placebo effects and IBS is something again, that has been discussed before on this blog (see here) bearing in mind I'm not saying that IBS is 'all in the mind' or anything like that.

Set within the context of other recent meta-analyses concluding that: "There were alterations of gut microbiota in IBS patients and it implied that alterations of gut microbiota might be involved in the pathogenesis of IBS" [4] one shouldn't necessarily be surprised that there may have been effects from the use of probiotics in cases of IBS. Assuming that an oral probiotic is able to survive the stomach environment and actually colonise [parts of] the gastrointestinal (GI) tract (if only for a defined amount of time) the cost-effectiveness of this intervention coupled with the low rates of side-effects makes for impressive reading in terms of the treatment of at least some cases of IBS.

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[1] Zhang Y. et al. Effects of probiotic type, dose and treatment duration on irritable bowel syndrome diagnosed by Rome III criteria: a meta-analysis. BMC Gastroenterology. 2016; 16: 62.

[2] Santocchi E. et al. Gut to brain interaction in Autism Spectrum Disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters. BMC Psychiatry. 2016 Jun 4;16:183.

[3] Szajewska H. & Kołodziej M. Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea. Aliment Pharmacol Ther. 2015 Oct;42(7):793-801.

[4] Zhuang X. et al. Alterations of gut microbiota in patients with irritable bowel syndrome: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2016 Jun 14.

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ResearchBlogging.org Zhang Y, Li L, Guo C, Mu D, Feng B, Zuo X, & Li Y (2016). Effects of probiotic type, dose and treatment duration on irritable bowel syndrome diagnosed by Rome III criteria: a meta-analysis. BMC gastroenterology, 16 (1) PMID: 27296254

Friday, 22 July 2016

Surgery for "chronic idiopathic constipation" and autism

I can't profess to be an expert on the techniques called sigmoidectomy and appendicostomy so won't even try and pretend that I am. From what I gather from Dr Google, the latter is a surgical technique generally performed to "help deliver enemas more easily" to relieve constipation, whilst the former involves the surgical removal of some or all of the sigmoid colon. Both are only generally indicated when traditional methods of treating constipation for example, fail.

The reason I'm briefly talking about sigmoidectomy and appendicostomy today revolves around the paper by Luis De La Torre and colleagues [1] who following a review of 8 cases of "chronic idiopathic constipation complicated by megarectosigmoid and fecal incontinence" reported that half of their small cohort "have autism" whilst all "had severe social problems." They reported that after their surgery "all patients were having daily bowel movements without fecal accidents."

For regular readers I probably don't have to stress the substantial weight of peer-reviewed scientific evidence suggesting that functional bowel issues are over-represented when it comes to a diagnosis of autism. For any newcomers straying onto this blog (a dangerous thing indeed!) I might direct you to one of my more recent entries on this important comorbidity (see here) and how despite some headline fails (see here) preferential screening for bowel issues should really follow an autism diagnosis. Add it to the list of screening potentially indicated...

The observations made by De La Torre et al represent the extreme of tackling functional constipation as and when it appears and how such a bowel issue can not only wreck quality of life but also potentially put someone in a life-threatening situation (yes, it has sadly happened and with autism mentioned). Nobody likes the idea of surgically removing parts of the gastrointestinal (GI) tract nor 'creating a pathway from belly button to the large intestine' in any patient, less so when that patient may have autism and potentially other comorbidity leaving open significant debate on issues such as informed consent. But, given the current lack of knowledge about the hows and whys of constipation when it occurs alongside autism, I think we are going to see more and more extreme cases such as this in both the clinical and research domains.

The onus therefore is on putting any prejudice aside when the words 'bowel' and 'autism' are strung together in the same sentence (see here) and making some real scientific strides into the mechanisms potentially involved in such over-representation. People diagnosed with autism and suffering some often quite terrible bowel issues deserve so much more than just further health inequality...

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[1] De La Torre L. et al. Primary sigmoidectomy and appendicostomy for chronic idiopathic constipation. Pediatr Surg Int. 2016 Jul 2.

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ResearchBlogging.org De La Torre L, Cogley K, Calisto J, Nace G, & Correa C (2016). Primary sigmoidectomy and appendicostomy for chronic idiopathic constipation. Pediatric surgery international PMID: 27372298

Thursday, 21 July 2016

Sensory processing issues are present throughout the autism spectrum

I want to make an initial point about the paper by Corentin Gonthier and colleagues [1] and their research findings titled: 'Sensory Processing in Low-Functioning Adults with Autism Spectrum Disorder: Distinct Sensory Profiles and Their Relationships with Behavioral Dysfunction', I'm not a great fan of the use of the term 'functioning' when it comes to autism.

Yes, I know what message it's trying to convey in terms of 'severity' of autism and/or accompanying learning (intellectual) disability and/or the level of day-to-day adaptive skills a person possesses with the aim of providing some indication of how 'able' or 'disabled' they are. My issue, and indeed I'm not the only one with a bee in their bonnet about this, are that the terms 'low functioning' and 'high functioning' rarely provide an accurate portrayal of the cumulative aspects of a person. One example of this can be seen in the quite depressing statistics when it comes to employment and autism, and how even those 'high-functioning' people on the spectrum, sometimes with above average intellect, are much less likely to be employed than their peers. High-functioning does not always mean 'can-function' in real life (even those with seemingly impressive skills) and importantly, tends to take little account of how comorbid issues such as anxiety can be so utterly disabling for a person.

I digress. The Gonthier study set about asking an important question about an important group: do the various sensory processing issues quite commonly reported in those on the more able side of the autism spectrum also extend to those peoples with more profound difficulties? Based on data "collected for a representative sample of inpatients in autism care centers (N = 148) and a non-clinical control group" researchers concluded that yes, sensory dysfunction is "highly prevalent in low-functioning adults with ASD [autism spectrum disorder]" but no, there is no 'one-size-fits-all' profile for this population. Indeed, that lack of a universal profile in the cohort studied pretty much mirrors what has been noted in  the 'more able' autism phenotype.

One other detail mentioned in the Gonthier findings also caught my eye in that sensory dysfunction "predicts specific patterns of behavioral disorders" at least in this cohort. This is an intriguing suggestion that potentially amongst the myriad of issues falling under the heading of 'challenging behaviours' for example, there may be a role for sensory processing issues too. It does kinda make sense that sensory issues could invoke some of those so-called challenging behaviours allied to other research looking, for example, at how pain might manifest among some of those on the autism spectrum (see here). It also makes for an even stronger case that screening for the presence of ophthalmic issues as one potential source/complication of those sensory issues should be more widely indicated irrespective of where someone lies on the autism spectrum (see here) (and whatever description you use of their place on the spectrum).

But a lot more research is required on the topic of sensory processing issues, and indeed, covering the entire autism spectrum in line with other writings [2] ...

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[1] Gonthier C. et al. Sensory Processing in Low-Functioning Adults with Autism Spectrum Disorder: Distinct Sensory Profiles and Their Relationships with Behavioral Dysfunction. J Autism Dev Disord. 2016 Jun 30.

[2] Tager-Flusberg H. et al. Conducting research with minimally verbal participants with autism spectrum disorder. Autism. 2016 Jun 26. pii: 1362361316654605.

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ResearchBlogging.org Gonthier C, Longuépée L, & Bouvard M (2016). Sensory Processing in Low-Functioning Adults with Autism Spectrum Disorder: Distinct Sensory Profiles and Their Relationships with Behavioral Dysfunction. Journal of autism and developmental disorders PMID: 27364513

Wednesday, 20 July 2016

Autism 'disclosure cards' and negative judgements?

I have to say that I initially felt slightly uncomfortable reading the study results published by Jillian Austin and colleagues [1] providing "preliminary validation for the use of autism disclosure cards in buffering negative judgment." Uncomfortable because, despite the fact that it is human nature for people to stop, stare and perhaps question something when it seems 'out of the ordinary', the idea that when children with autism specifically 'misbehave' in a public place their parents need to somehow justify their child's behaviour to a staring crowd of strangers seems a trifle unfair.

As is the experience of most parents, whether their child is diagnosed or not with autism or anything else, children are not always 'little angels' every time they are out and about ("no, it is not appropriate to start a public conversation about farting when one 'catches a whiff' of something in the shopping centre"). Most parents can usually get away with a nervous smile to any interested on-lookers (or nosey parkers) and that really should be the end of it. Of course, for some children under some circumstances, behaviour can sometimes go beyond just tantrums and onward can raise a few eyebrows but...

Austin et al started with the premise that parents of children with autism are "increasingly using disclosure cards to reduce negative perceptions" when out and about with their children to make "an invisible diagnosis apparent". They devised an experiment using "vignettes of a parent-child interaction in which the child was misbehaving and investigated the efficacy on 160 parents' perceptions." Disclosure cards were provided to some of the parent participants all of whom had at least one child aged between 6-12 years. Various factors covering "Maternal Skill Deficit and Negative Reaction" and "Sympathy for Mother" were analysed as a function of receipt of disclosure cards or not.

"Those who received the disclosure card reported significantly lower Maternal Skill Deficit and Negative Reaction to the Dyad and no difference in Sympathy for the Mother." In other words, making an 'invisible' diagnosis more visible seemed to have an effect in terms of views around 'it must the parent's fault that their child is behaving that way' (negative judgement) but did little when it came to empathising with the mother's position in that situation.

Austin and colleagues discuss how the 'invisibility' of autism and frames of reference - "people will evaluate and compare individuals to some perceived norm or standard" - in this case, so-called typically developing children, may be driving forces underlying those negative judgements from others about children on the spectrum and their parents. I can't quibble with this line of thought or what impact it might have on children and their parents (and other significant others). But it strikes me that in these days of increased numbers of children being diagnosed with autism (see here) - indeed the numbers just keep on growing - and accompanying high-profile campaigns to raise awareness about autism, movement towards the idea that every parent has to 'identify' their child as being on the autism spectrum as and when they, pardon my French, 'fart the wrong way' seems to place too much emphasis on the child and parent and not enough on their fellow citizens and their own understanding and reactions.

OK, I get that people have busy lives and that outside of media depictions (see here), most people wouldn't typically ask 'could it be autism?' when a child has a 'meltdown' in a public spot. I also get that under some circumstances, making particular groups of people aware of a person's autism might be a good thing as per contact with law enforcement agencies for example. The question however of whether strangers really need to be given quite sensitive information about a person and 'their diagnosis' just because they (the stranger) 'can't deal with a particular situation' strikes me as being more than a little one-sided...

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[1] Austin JE. et al. Influencing Perception About Children with Autism and their Parents Using Disclosure Cards. J Autism Dev Disord. 2016 May 30.

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ResearchBlogging.org Austin JE, Zinke VL, & Davies WH (2016). Influencing Perception About Children with Autism and their Parents Using Disclosure Cards. Journal of autism and developmental disorders PMID: 27241346