How many people do doctors kill?

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The authors define medical error as “death due to

1) an error in judgment, skill, or coordination of care,

2) a diagnostic error,

3) a system defect resulting in death or a failure to rescue a patient from death, or

4) a preventable adverse event.” (Letter to CDC by Makary et al., 2016)

I reproduced the authors’ definition because there is a hot debate in the medicine field as to what constitutes a medical error and what is preventable vs. unpreventable. It might seem clear cut to you and me, but after I perused a few papers from both sides I must admit that things seem (a bit) more complicated than I thought. Personally, I’m all onboard with the above definition.

Also, there is an ongoing fight about the actual number of deaths attributable to medical errors. I don’t have the time to read or get into that fight. So I’ll ask only one question: does it matter if the number is in the hundreds of thousands or merely tens of thousands? No, it doesn’t; medical errors need to be tackled head on, no matter how many people they kill. There will always be victims because doctors are humans and they make mistakes, like everybody else. But that doesn’t mean that they and their hospitals shouldn’t be held accountable. We, as patients, children and parents of patients, want that number to be as small as possible, is as simple as that. If the processes and methods of counting, assessing, and judging medical errors are kept hidden or worse, buried through misleading or downright false paperwork, then how can we trust the judgment of medical professionals? The authors’ letter to CDC attempts to do just that: by getting the hospitals to acknowledge medical errors on death certificates, the issue is becoming more visible. Where there is visibility and transparency, programs can then be implemented to reduce those numbers, whatever they may be.

Actually, the fact that the number of deaths attributable to medical error is disputable is a case in point; if there was a clear definition of what medical error is and a clear way of tracking it, then we would have a starting point on how to reduce its occurrence. And that’s why I will leave my picture where it is: to support the conversation around the need to better track medical error.

P.S.1 A newer paper, Stockwell et al. (2018) found that 10 % of the pediatric admissions in US hospitals end up with preventable adverse effects, most frequently as a result of  hospital-acquired infections, followed by intravenous line complications, gastrointestinal harms, respiratory-related harms, and other causes (p. 4). The more worrisome fact is that this percentage is unchanged, at least between 2007 and 2012.

P.S.2 Just to make it clear, I will always go to doctors with an MD after their name, even if they make mistakes, because they give me and my loved ones the best chance of healing and survival. Calling out that there is more work to be done to improve our safety, particularity in the washing hands department (can’t believe this is still a thing!), doesn’t mean that I will go in the cuckoo land of homeopathy, chiropracty, and other “alternative” medicine.

REFERENCES:

  1. Makary MA, & Daniel M. (3 May 2016). Medical error – the third leading cause of death in the US. BMJ, 353:i2139. doi: 10.1136/bmj.i2139, PMID: 27143499. ARTICLE | NPR cover
  2. Joo S, Daniel M, Xu T, & Makary, MA (1 May 2016). RE: Methodology used for collecting national health statistics, Open Letter to U.S. Centers for Disease Control and Prevention FREE FULLTEXT PDF

By Neuronicus, 13 October 2019

High fructose corn syrup IS bad for you

Because I cannot leave controversial things well enough alone – at least not when I know there shouldn’t be any controversy – my ears caught up with my tongue yesterday when the latter sputtered: “There is strong evidence for eliminating sugar from commonly used food products like bread, cereal, cans, drinks, and so on, particularly against that awful high fructose corn syrup”. “Yeah? You “researched” that up, haven’t you? Google is your bosom friend, ain’t it?” was the swift reply. Well, if you get rid of the ultra-emphatic air-quotes flanking the word ‘researched’ and replace ‘Google’ with ‘Pubmed’, then, yes, I did researched it and yes, Pubmed is my bosom friend.

Initially, I wanted to just give you all a list with peer-reviewed papers that found causal and/or correlational links between high fructose corn syrup (HFCS) and weight gain, obesity, type 2 diabetes, cardiovascular disease, fatty liver disease, metabolic and endocrine anomalies and so on. But there are way too many of them; there are over 500 papers on the subject in Pubmed only. And most of them did find that HFCS does nasty stuff to you, look for yourselves here. Then I thought to feature a paper showing that HFCS is differently metabolized than the fructose from fruits, because I keep hearing that lie perpetrated by the sugar and corn industries that “sugar is sugar” (no, it’s not! Demonstrably so!), but I doubt my yesterday’s interlocutor would care about liver’s enzymatic activity and other chemical processes with lots of acronyms. So, finally, I decided to feature a straight forward, no-nonsense paper, published recently, done at a top tier university, with human subjects, so I won’t hear any squabbles.

Price et al. (2018) studied 49 healthy subjects aged age 18–40 yr, of normal and stable body weight, and free from confounding medications or drugs, whose physical activity and energy-balanced meals were closely monitored. During the study, the subjects’ food and drink intake as well as their timing were rigorously controlled. The researchers varied only the beverages between groups, in such a way that one group received a drink sweetened with HFCS-55 (55% fructose, 45% glucose, as the one used in commercially available drinks) with every controlled meal, whereas the other group received an identical drink in size (adjusted for their energy requirements in such a way that it provided the same 25% of it), but sweetened with aspartame. The study lasted two weeks. No other beverage was allowed, including fruit juice. Urine samples were collected daily and blood samples 4 times per day.

There was a body weight increase of 810 grams (1.8 lb) in subjects consuming HFCS-sweetened beverages for 2 weeks when compared with aspartame controls. The researches also found differences in the levels of a whole host of acronyms (ppTG, ApoCIII, ApoE, OEA, DHEA, DHG, if you must know) involved in a variety of nasty things, like obesity, fatty liver disease, atherosclerosis, cardiovascular disease, stroke, diabetes, even Alzheimer’s.

This study is the third part of a larger NIH-funded study which investigates the metabolic effects of consuming sugar-sweetened beverages in about 200 participants over 5 years, registered at clinicaltrials.gov as NCT01103921. The first part (Stanhope et al., 2009) reported that consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans” (title), and the second part (Stanhope et al., 2015) found that “consuming beverages containing 10%, 17.5%, or 25% of energy requirements from HFCS produced dose-dependent increases in circulating lipid/lipoprotein risk factors for cardiovascular disease and uric acid within 2 weeks” (Abstract). They also found a dose-dependant increase in body weight, but in those subjects the results were not statistically significant (p = 0.09) after correcting for multiple comparisons. But I’ll bet that if/when the authors will publish all the data in one paper at the end of clinical trials they will have more statistical power and the trend in weight gain more obvious, as in the present paper.  Besides, it looks like there may be more than three parts to this study anyway.

The adverse effects of a high sugar diet, particularly in HFCS, are known to so many researchers in the field that they have been actually compiled in a name: the “American Lifestyle-Induced Obesity Syndrome model, which included consumption of a high-fructose corn syrup in amounts relevant to that consumed by some Americans” (Basaranoglu et al., 2013). It doesn’t refer only to increases in body weight, but also type 2 diabetes, cardiovascular disease, hypertriglyceridemia, fatty liver disease, atherosclerosis, gout, etc.

The truly sad part is that avoiding added sugars in diets in USA is impossible unless you do all – and I mean all – your cooking home, including canning, jamming, bread-making, condiment-making and so on, not just “Oh, I’ll cook some chicken or ham tonight” because in that case you end up using canned tomato sauce (which has added sugar), bread crumbs (which have added sugar), or ham (which has added sugar), salad dressing (which has sugar) and so on. Go on, check your kitchen and see how many ingredients have sugar in them, including any meat products short of raw meat. If you never read the backs of the bottles, cans, or packages, oh my, are you in for a big surprise if you live in USA…

There are lot more studies out there on the subject, as I said, of various levels of reading difficulty. This paper is not easy to read for someone outside the field, that’s for sure. But the main gist of it is in the abstract, for all to see.

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P.S. 1. Please don’t get me wrong: I am not against sugar in desserts, let it be clear. Nobody makes a more mean sweetalicious chocolate cake or carbolicious blueberry muffin than me, as I have been reassured many times. But I am against sugar in everything. You know I haven’t found in any store, including high-end and really high-end stores a single box of cereal of any kind without sugar? Just for fun, I’d like to be a daredevil and try it once. But there ain’t. Not in USA, anyway. I did find them in EU though. But I cannot keep flying over the Atlantic in the already crammed at premium luggage space unsweetened corn flakes from Europe which are probably made locally, incidentally and ironically, with good old American corn.

P.S. 2 I am not so naive, blind, or zealous to overlook the studies that did not find any deleterious effects of HFCS consumption. Actually, I was on the fence about HFCS until about 10 years ago when the majority of papers (now overwhelming majority) was showing that HFCS consumption not only increases weight gain, but it can also lead to more serious problems like the ones mentioned above. Or the few papers that say all added sugar is bad, but HFCS doesn’t stand out from the other sugars when it comes to disease or weight gain. But, like with most scientific things, the majority has it its way and I bow to it democratically until the new paradigm shift. Besides, the exposés of Kearns et al. (2016a, b, 2017) showing in detail and with serious documentation how the sugar industry paid prominent researchers for the past 50 years to hide the deleterious effects of added sugar (including cancer!) further cemented my opinion about added sugar in foods, particularly HFCS.

References:

  1. Price CA, Argueta DA, Medici V, Bremer AA, Lee V, Nunez MV, Chen GX, Keim NL, Havel PJ, Stanhope KL, & DiPatrizio NV (1 Aug 2018, Epub 10 Apr 2018). Plasma fatty acid ethanolamides are associated with postprandial triglycerides, ApoCIII, and ApoE in humans consuming a high-fructose corn syrup-sweetened beverage. American Journal of Physiology. Endocrinology and Metabolism, 315(2): E141-E149. PMID: 29634315, PMCID: PMC6335011 [Available on 2019-08-01], DOI: 10.1152/ajpendo.00406.2017. ARTICLE | FREE FULTEXT PDF
  1. Stanhope KL1, Medici V2, Bremer AA2, Lee V2, Lam HD2, Nunez MV2, Chen GX2, Keim NL2, Havel PJ (Jun 2015, Epub 22 Apr 2015). A dose-response study of consuming high-fructose corn syrup-sweetened beverages on lipid/lipoprotein risk factors for cardiovascular disease in young adults. The American Journal of Clinical Nutrition, 101(6):1144-54. PMID: 25904601, PMCID: PMC4441807, DOI: 10.3945/ajcn.114.100461. ARTICLE | FREE FULTEXT PDF
  1. Stanhope KL1, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, Hatcher B, Cox CL, Dyachenko A, Zhang W, McGahan JP, Seibert A, Krauss RM, Chiu S, Schaefer EJ, Ai M, Otokozawa S, Nakajima K, Nakano T, Beysen C, Hellerstein MK, Berglund L, Havel PJ (May 2009, Epub 20 Apr 2009). Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. The Journal of Clinical Investigation,119(5):1322-34. PMID: 19381015, PMCID: PMC2673878, DOI:10.1172/JCI37385. ARTICLE | FREE FULTEXT PDF

(Very) Selected Bibliography:

Bocarsly ME, Powell ES, Avena NM, Hoebel BG. (Nov 2010, Epub 26 Feb 2010). High-fructose corn syrup causes characteristics of obesity in rats: increased body weight, body fat and triglyceride levels. Pharmacology, Biochemistry, and Behavior, 97(1):101-6. PMID: 20219526, PMCID: PMC3522469, DOI: 10.1016/j.pbb.2010.02.012. ARTICLE | FREE FULLTEXT PDF

Kearns CE, Apollonio D, Glantz SA (21 Nov 2017). Sugar industry sponsorship of germ-free rodent studies linking sucrose to hyperlipidemia and cancer: An historical analysis of internal documents. PLoS Biology, 15(11):e2003460. PMID: 29161267, PMCID: PMC5697802, DOI: 10.1371/journal.pbio.2003460. ARTICLE | FREE FULTEXT PDF

Kearns CE, Schmidt LA, Glantz SA (1 Nov 2016). Sugar Industry and Coronary Heart Disease Research: A Historical Analysis of Internal Industry Documents. JAMA Internal Medicine, 176(11):1680-1685. PMID: 27617709, PMCID: PMC5099084, DOI: 10.1001/jamainternmed.2016.5394. ARTICLE | FREE FULTEXT PDF

Mandrioli D, Kearns CE, Bero LA (8 Sep 2016). Relationship between Research Outcomes and Risk of Bias, Study Sponsorship, and Author Financial Conflicts of Interest in Reviews of the Effects of Artificially Sweetened Beverages on Weight Outcomes: A Systematic Review of Reviews. PLoS One, 11(9):e0162198.PMID: 27606602, PMCID: PMC5015869, DOI: 10.1371/journal.pone.0162198. ARTICLE | FREE FULTEXT PDF

By Neuronicus, 22 March 2019

Pooping Legos

Yeah, alright… uhm… how exactly should I approach this paper? I’d better just dive into it (oh boy! I shouldn’t have said that).

The authors of this paper were adult health-care professionals in the pediatric field. These three males and three females were also the participants in the study. They kept a poop-diary noting the frequency and volume of bowel movements (Did they poop directly on a scale or did they have to scoop it out in a bag?). The researchers/subjects developed a Stool Hardness and Transit (SHAT) metric to… um.. “standardize bowel habit between participants” (p. 1). In other words, to put the participants’ bowel movements on the same level (please, no need to visualize, I am still stuck at the poop-on-a-scale phase), the authors looked – quite literally – at the consistency of the poop and gave it a rating. I wonder if they checked for inter-rater reliability… meaning did they check each other’s poops?…

Then the researchers/subjects ingested a Lego figurine head, on purpose, somewhere between 7 and 9 a.m. Then they timed how much time it took to exit. The FART score (Found and Retrieved Time) was 1.71 days. “There was some evidence that females may be more accomplished at searching through their stools than males, but this could not be statistically validated” due to the small sample size, if not the poops’. It took 1 to 3 stools for the object to be found, although poor subject B had to search through his 13 stools over a period of 2 weeks to no avail. I suppose that’s what you get if you miss the target, even if you have a PhD.

The pre-SHAT and SHAT score of the participants did not differ, suggesting that the Lego head did not alter the poop consistency (I got nothin’ here; the authors’ acronyms are sufficient scatological allusion). From a statistical standpoint, the one who couldn’t find his head in his poop (!) should not have been included in the pre-SHAT score group. Serves him right.

I wonder how they searched through the poop… A knife? A sieve? A squashing spatula? Gloved hands? Were they floaters or did the poop sink at the base of the toilet? Then how was it retrieved? Did the researchers have to poop in a bucket so no loss of data should occur? Upon direct experimentation 1 minute ago, I vouchsafe that a Lego head is completely buoyant. Would that affect the floatability of the stool in question? That’s what I’d like to know. Although, to be fair, no, that’s not what I want to know; what I desire the most is a far larger sample size so some serious stats can be conducted. With different Lego parts. So they can poop bricks. Or, as suggested by the authors, “one study arm including swallowing a Lego figurine holding a coin” (p. 3) so one can draw parallels between Lego ingestion and coin ingestion research, the latter being, apparently, far more prevalent. So many questions that still need to be answered! More research is needed, if only grants would be so… regular as the raw data.

The paper, albeit short and to the point, fills a gap in our scatological knowledge database (Oh dear Lord, stop me!). The aim of the paper was to show that ingested objects by children tend to pass without a problem. Also of value, the paper asks pediatricians to counsel the parents to not search for the object in the faeces to prove object retrieval because “if an experienced clinician with a PhD is unable to adequately find objects in their own stool, it seems clear that we should not be expecting parents to do so” (p. 3). Seems fair.

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REFERENCE: Tagg, A., Roland, D., Leo, G. S., Knight, K., Goldstein, H., Davis, T. and Don’t Forget The Bubbles (22 November 2018). Everything is awesome: Don’t forget the Lego. Journal of Paediatrics and Child Health, doi: 10.1111/jpc.14309. ARTICLE

By Neuronicus, 27 November 2017

No licorice for you

I never liked licorice. And that turns out to be a good thing. Given that Halloween just happened yesterday and licorice candy is still sold in USA, I remembered the FDA’s warning against consumption of licorice from a year ago.

So I dug out the data supporting this recommendation. It’s a review paper published 6 years ago by Omar et al. (2012) meant to raise awareness of the risks of licorice consumption and to urge FDA to take regulatory steps.

The active ingredient in licorice is glycyrrhizic acid. This is hydrolyzed to glycyrrhetic acid by intestinal bacteria possessing a specialized ß-glucuronidase. Glycyrrhetic acid, in turn, inhibits 11-ß-hydroxysteroid dehydrogenase (11-ß-HSD) which results in cortisol activity increase, which binds to the mineralcorticoid receptors in the kidneys, leading to low potassium levels (called hypokalemia). Additionally, licorice components can also bind directly to the mineralcorticoid receptors.

Eating 2 ounces of black licorice a day for at least two weeks (which is roughly equivalent to 2 mg/kg/day of pure glycyrrhizinic acid) is enough to produce disturbances in the following systems:

  • cardiovascular (hypertension, arrhythmias, heart failure, edemas)
  • neurological (stroke, myoclonia, ocular deficits, Carpal tunnel, muscle weakness)
  • renal (low potassium, myoglobinuria, alkalosis)
  • and others

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Although everybody is affected by licorice consumption, the most vulnerable populations are those over 40 years old, those who don’t poop every day, or are hypertensive, anorexic or of the female persuasion.

Unfortunately, even if one doesn’t enjoy licorice candy, they still can consume it as it is used as a sweetener or flavoring agent in many foods, like sodas and snacks. It is also used in naturopathic crap, herbal remedies, and other dangerous scams of that ilk. So beware of licorice and read the label, assuming the makers label it.

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Licorice products (Images: PD, Collage: Neuronicus)

REFERENCE: Omar HR, Komarova I, El-Ghonemi M, Fathy A, Rashad R, Abdelmalak HD, Yerramadha MR, Ali Y, Helal E, & Camporesi EM. (Aug 2012). Licorice abuse: time to send a warning message. Therapeutic Advances in Endocrinology and Metabolism, 3(4):125-38. PMID: 23185686, PMCID: PMC3498851, DOI: 10.1177/2042018812454322. ARTICLE | FREE FULLTEXT PDF

By Neuronicus, 1 November 2018

Locus Coeruleus in mania

From all the mental disorders, bipolar disorder, a.k.a. manic-depressive disorder, has the highest risk for suicide attempt and completion. If the thought of suicide crosses your mind, stop reading this, it’s not that important; what’s important is for you to call the toll-free National Suicide Prevention Lifeline at 1-800-273-TALK (8255).

The bipolar disorder is defined by alternating manic episodes of elevated mood, activity, excitation, and energy with episodes of depression characterized by feelings of deep sadness, hopelessness, worthlessness, low energy, and decreased activity. It is also a more common disease than people usually expect, affecting about 1% or more of the world population. That means almost 80 million people! Therefore, it’s imperative to find out what’s causing it so we can treat it.

Unfortunately, the disease is very complex, with many brain parts, brain chemicals, and genes involved in its pathology. We don’t even fully comprehend how the best medication we have to lower the risk of suicide, lithium, works. The good news is the neuroscientists haven’t given up, they are grinding at it, and with every study we get closer to subduing this monster.

One such study freshly published last month, Cao et al. (2018), looked at a semi-obscure membrane protein, ErbB4. The protein is a tyrosine kinase receptor, which is a bit unfortunate because this means is involved in ubiquitous cellular signaling, making it harder to find its exact role in a specific disorder. Indeed, ErbB4 has been found to play a role in neural development, schizophrenia, epilepsy, even ALS (Lou Gehrig’s disease).

Given that ErbB4 is found in some neurons that are involved in bipolar and mutations in its gene are also found in some people with bipolar, Cao et al. (2018) sought to find out more about it.

First, they produced mice that lacked the gene coding for ErbB4 in neurons from locus coeruleus, the part of the brain that produces norepinephrine out of dopamine, better known for the European audience as nor-adrenaline. The mutant mice had a lot more norepinephrine and dopamine in their brains, which correlated with mania-like behaviors. You might have noticed that the term used was ‘manic-like’ and not ‘manic’ because we don’t know for sure how the mice feel; instead, we can see how they behave and from that infer how they feel. So the researchers put the mice thorough a battery of behavioral tests and observed that the mutant mice were hyperactive, showed less anxious and depressed behaviors, and they liked their sugary drink more than their normal counterparts, which, taken together, are indices of mania.

Next, through a series of electrophysiological experiments, the scientists found that the mechanism through which the absence of ErbB4 leads to mania is making another receptor, called NMDA, in that brain region more active. When this receptor is hyperactive, it causes neurons to fire, releasing their norepinephrine. But if given lithium, the mutant mice behaved like normal mice. Correspondingly, they also had a normal-behaving NMDA receptor, which led to normal firing of the noradrenergic neurons.

So the mechanism looks like this (Jargon alert!):

No ErbB4 –> ↑ NR2B NMDAR subunit –> hyperactive NMDAR –> ↑ neuron firing –> ↑ catecholamines –> mania.

In conclusion, another piece of the bipolar puzzle has been uncovered. The next obvious step will be for the researchers to figure out a medicine that targets ErbB4 and see if it could treat bipolar disorder. Good paper!

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P.S. If you’re not familiar with the journal eLife, go and check it out. The journal offers for every study a half-page summary of the findings destined for the lay audience, called eLife digest. I’ve seen this practice in other journals, but this one is generally very well written and truly for the lay audience and the non-specialist. Something of what I try to do here, minus the personal remarks and in parenthesis metacognitions that you’ll find in most of my posts. In short, the eLife digest is masterly done. As my continuous struggles on this blog show, it is tremendously difficult for a scientist to write concisely, precisely, and jargonless at the same time. But eLife is doing it. Check it out. Plus, if you care to take a look on how science is done and published, eLife publishes all the editor’s rejection notes, all the reviewers’ comments, and all the author responses for a particular paper. Reading those is truly a teaching moment.

REFERENCE: Cao SX, Zhang Y, Hu XY, Hong B, Sun P, He HY, Geng HY, Bao AM, Duan SM, Yang JM, Gao TM, Lian H, Li XM (4 Sept 2018). ErbB4 deletion in noradrenergic neurons in the locus coeruleus induces mania-like behavior via elevated catecholamines. Elife, 7. pii: e39907. doi: 10.7554/eLife.39907. PMID: 30179154 ARTICLE | FREE FULLTEXT PDF

By Neuronicus, 14 October 2018

Treatment for lupus

Science has trends, like everything else. Some are longer or shorter lived, depending on how many astonishing discoveries are linked to that given subject. The 2000’s were unquestionably the years of the DNA. Many a grant have been written (and granted) for whole-genome surveys of this and that. Alternative splicing followed. The ’10s saw the rise of various -omics: transcriptomics, metabolomics, proteomics etc. Then everybody and his mamma got on the cart of epigenetics. With a side of immune stuff. Now, move aside epigenetics, here comes the microbiome. And CRISPR.

That is not to say that the not so hip subjects of the bygone years are thoroughly squeezed of knowledge and we throw them aside like some dry dead end and never touch them again. Not at all, not a bit. The trends only mark the momentary believes of the purse holders about which direction the next panaceum universalis will jump from.

Here comes a groundbreaking paper on the gut microbiome. It’s groundbreaking because it comes with a cure for systemic lupus erythematosus (SLE). Possibly autoimmune hepatitis and others autoimmune diseases as well.

An autoimmune disease is a terrible malady that is often incurable and sometimes deadly. It happens when the immune system starts attacking the body. One hypothesis as to why that happens posits that after a particular infection, maybe a particularly nasty one, the immune system doesn’t stop attacking, but now in the absence of an enemy it turns on its own body in genetically susceptible individuals.

Vieira et al. (2018) worked with genetically susceptible mice. And the bombshell comes right there in the first page: after treatment with an oral antibiotic (vancomycin or ampicillin, but not neomycin), mice genetically designed to develop lupus had lower “mortality, lupus-related autoantibodies, and autoimmune manifestations” (p. 1156). Then the researchers took a closer look at the bodies of these mice and observed that 82% of the mice had spleens and livers infected with Enterococcus gallinarum, a gut bacterium that should stay in the gut. But this bacterium is capable of weakening the gut barriers by loosening the tightness of the junctions between gut cells and then migrate to liver, spleen, and lymph nodes. Its high abundance in these places triggers a systemic immune response. Then the authors force-fed some germ-free mice with E. galinarum and saw that the mice developed systemic autoimmune pathology.

As if that’s not enough of a news story, the researchers developed a vaccine against this bacterium. The vaccine is very specific (being made of heat-killed E. gallinarum) and results in reduced levels of serum autoantibodies and prolonged survival rate in the lupus-prone mice.

So people don’t quibble, and rightly so, that those are rodents and humans are not (well, most of them, anyway), the authors looked at the liver biopsies of three humans with SLE and five with autoimmune hepatitis (AIH). They were positive for E. gallinarum, but the controls, i. e. healthy humans, were not. Also, when healthy human liver cells were stimulated with E. gallinarum they displayed autoimmune responses, just like in the murine cells. Finally, you don’t have to undergo a liver biopsy to see if you’re infected with E. gallinarum, just a specific blood test to see if you have increased antibody titers against this bug (or its RNA) as most SLE and AIH patients did.

Needless to say, I am extremely happy with this paper. Who wouldn’t be?! It’s a cure paper! I know, I know, they don’t say that, but what does this sound to you?:

“Administration of oral vancomycin or an intramuscular vaccine against E. gallinarum prevent translocation, Th17/Tfh cell induction, autoantibody production and autoimmune-related mortality (Supplemental, p. 62).”

Call it a very promising cure or a highly effective treatment if you like, but it stares you in the face for what it is as it did the researchers who already patented their stuff and are currently conducting clinical trials.

Most of the paper is in the Supplemental material, not in the 4 pages and a bit in Science. So even if the paper is under the paywall, the Supplementals are not. Be ready for a 71 page worth of 167 MB of data though.

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REFERENCE: Manfredo Vieira S, Hiltensperger M, Kumar V, Zegarra-Ruiz D, Dehner C, Khan N, Costa FRC, Tiniakou E, Greiling T, Ruff W, Barbieri A, Kriegel C, Mehta SS, Knight JR, Jain D, Goodman AL, Kriegel MA (9 Mar 2018). Translocation of a gut pathobiont drives autoimmunity in mice and humans.  Science, 359(6380):1156-1161. doi: 10.1126/science.aar7201. PMID: 29590047, DOI: 10.1126/science.aar7201. ARTICLE |  Supplemental Material | Yale press release

By Neuronicus, 8 April 2018

No Link Between Mass Shootings & Mental Illness

By Neuronicus, 25 February 2018

On Valentine’s Day another horrifying school mass shooting happened in USA, leaving 17 people dead. Just like after the other mass shootings, a lot of people – from media to bystanders, from gun lovers to gun critics, from parents to grandparents, from police to politicians – talk about the link between mental illness and mass shootings. As one with advanced degrees in both psychology and neuroscience, I am tired to explain over and over again that there is no significant link between the two! Mass shootings happen because an angry person has had – or made to think they had – enough sorrow, stress, rejection and/or disappointment and HAS ACCESS TO A MASS KILLING WEAPON. Yeah, I needed the caps. Sometimes scientists too need to shout to be heard.

So here is the abstract of a book chapter called straightforwardly “Mass Shootings and Mental Illness”. The entire text is available at the links in the reference below.

From Knoll & Annas (2015):

“Common Misperceptions

  • Mass shootings by people with serious mental illness represent the most significant relationship between gun violence and mental illness.
  • People with serious mental illness should be considered dangerous.
  • Gun laws focusing on people with mental illness or with a psychiatric diagnosis can effectively prevent mass shootings.
  • Gun laws focusing on people with mental illness or a psychiatric diagnosis are reasonable, even if they add to the stigma already associated with mental illness.

Evidence-Based Facts

  • Mass shootings by people with serious mental illness represent less than 1% of all yearly gun-related homicides. In contrast, deaths by suicide using firearms account for the majority of yearly gun-related deaths.
  • The overall contribution of people with serious mental illness to violent crimes is only about 3%. When these crimes are examined in detail, an even smaller percentage of them are found to involve firearms.
  • Laws intended to reduce gun violence that focus on a population representing less than 3% of all gun violence will be extremely low yield, ineffective, and wasteful of scarce resources. Perpetrators of mass shootings are unlikely to have a history of involuntary psychiatric hospitalization. Thus, databases intended to restrict access to guns and established by guns laws that broadly target people with mental illness will not capture this group of individuals.
  • Gun restriction laws focusing on people with mental illness perpetuate the myth that mental illness leads to violence, as well as the misperception that gun violence and mental illness are strongly linked. Stigma represents a major barrier to access and treatment of mental illness, which in turn increases the public health burden”.

REFERENCE: Knoll, James L. & Annas, George D. (2015). Mass Shootings and Mental Illness. In book: Gun Violence and Mental Illness, Edition: 1st, Chapter: 4, Publisher: American Psychiatric Publishing, Editors: Liza H. Gold, Robert I. Simon. ISBN-10: 1585624985, ISBN-13: 978-1585624980. FULLTEXT PDF via ResearchGate | FULLTEXT PDF via Psychiatry Online

The book chapter is not a peer-reviewed document, even if both authors are Professors of Psychiatry. To quiet putative voices raising concerns about that, here is a peer-reviewed paper with open access that says basically the same thing:

Swanson et al. (2015) looked at large scale (thousands to tens of thousands of individuals) data to see if there is any relationship between violence, gun violence, and mental illness. They concluded that “epidemiologic studies show that the large majority of people with serious mental illnesses are never violent. However, mental illness is strongly associated with increased risk of suicide, which accounts for over half of US firearms–related fatalities”. The last sentence is reminiscent of the finding that stricter gun control laws lower suicide rate.

REFERENCE: Swanson JW, McGinty EE, Fazel S, Mays VM (May 2015). Mental illness and reduction of gun violence and suicide: bringing epidemiologic research to policy. Annals of Epidemiology, 25(5): 366–376. doi: 10.1016/j.annepidem.2014.03.004, PMCID: PMC4211925. FULLTEXT | FULLTEXT PDF.

Further peer-reviewed bibliography (links to fulltext pdfs):

  1. Guns, anger, and mental disorders: Results from the National Comorbidity Survey Replication (NCS-R): “a large number of individuals in the United States have anger traits and also possess firearms at home (10.4%) or carry guns outside the home (1.6%).”
  2. News Media Framing of Serious Mental Illness and Gun Violence in the United States, 1997-2012: “most news coverage occurred in the wake of mass shootings, and “dangerous people” with serious mental illness were more likely than “dangerous weapons” to be mentioned as a cause of gun violence.”
  3. The Link Between Mental Illness and Firearm Violence: Implications for Social Policy and Clinical Practice: “Firearm violence is a significant and preventable public health crisis. Mental illness is a weak risk factor for violence despite popular misconceptions reflected in the media and policy”.
  4. Using Research Evidence to Reframe the Policy Debate Around Mental Illness and Guns: Process and Recommendations: “restricting firearm access on the basis of certain dangerous behaviors is supported by the evidence; restricting access on the basis of mental illness diagnoses is not”.
  5. Mental Illness, Mass Shootings, and the Politics of American Firearms: “notions of mental illness that emerge in relation to mass shootings frequently reflect larger cultural stereotypes and anxieties about matters such as race/ethnicity, social class, and politics. These issues become obscured when mass shootings come to stand in for all gun crime, and when “mentally ill” ceases to be a medical designation and becomes a sign of violent threat”.

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By Neuronicus, 25 February 2018

Old chimpanzees get Alzheimer’s pathology

Alzheimer’s Disease (AD) is the most common type of dementia with a progression that can span decades. Its prevalence is increasing steadily, particularly in the western countries and Australia. So some researchers speculated that this particular disease might be specific to humans. For various reasons, either genetic, social, or environmental.

A fresh e-pub brings new evidence that Alzheimer’s might plague other primates as well. Edler et al. (2017) studied the brains of 20 old chimpanzees (Pan troglodytes) for a whole slew of Alzheimer’s pathology markers. More specifically, they looked for these markers in brain regions commonly affected by AD, like the prefrontal cortex, the midtemporal gyrus, and the hippocampus.

Alzheimer’s markers, like Tau and Aβ lesions, were present in the chimpanzees in an age-dependent manner. In other words, the older the chimp, the more severe the pathology.

Interestingly, all 20 animals displayed some form of Alzheimer’s pathology. This finding points to another speculation in the field which is: dementia is just part of normal aging. Meaning we would all get it, eventually, if we would live long enough; some people age younger and some age older, as it were. This hypothesis, however, is not favored by most researchers not the least because is currently unfalsifiable. The longest living humans do not show signs of dementia so how long is long enough, exactly? But, as the authors suggest, “Aβ deposition may be part of the normal aging process in chimpanzees” (p. 24).

Unfortunately, “the chimpanzees in this study did not participate in formal behavioral or cognitive testing” (p. 6). So we cannot say if the animals had AD. They had the pathological markers, yes, but we don’t know if they exhibited the disease as is not uncommon to find these markers in humans who did not display any behavioral or cognitive symptoms (Driscoll et al., 2006). In other words, one might have tau deposits but no dementia symptoms. Hence the title of my post: “Old chimpanzees get Alzheimer’s pathology” and not “Old chimpanzees get Alzheimer’s Disease”

Good paper, good methods and stats. And very useful because “chimpanzees share 100% sequence homology and all six tau isoforms with humans” (p. 4), meaning we have now a closer to us model of the disease so we can study it more, even if primate research has taken significant blows these days due to some highly vocal but thoroughly misguided groups. Anyway, the more we know about AD the closer we are of getting rid of it, hopefully. And, soon enough, the aforementioned misguided groups shall have to face old age too with all its indignities and my guess is that in a couple of decades or so there will be fresh money poured into aging diseases research, primates be damned.

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REFERENCE: Edler MK, Sherwood CC, Meindl RS, Hopkins WD, Ely JJ, Erwin JM, Mufson EJ, Hof PR, & Raghanti MA. (EPUB July 31, 2017). Aged chimpanzees exhibit pathologic hallmarks of Alzheimer’s disease. Neurobiology of Aging, PII: S0197-4580(17)30239-7, DOI: http://dx.doi.org/10.1016/j.neurobiolaging.2017.07.006. ABSTRACT  | Kent State University press release

By Neuronicus, 23 August 2017

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Midichlorians, midichloria, and mitochondria

Nathan Lo is an evolutionary biologist interested in creepy crawlies, i.e. arthropods. Well, he’s Australian, so I guess that comes with the territory (see what I did there?). While postdoc’ing, he and his colleagues published a paper (Sassera et al., 2006) that would seem boring for anybody without an interest in taxonomy, a truly under-appreciated field.

The paper describes a bacterium that is a parasite for the mitochondria of a tick species called Ixodes ricinus, the nasty bugger responsible for Lyme disease. The authors obtained a female tick from Berlin, Germany and let it feed on a hamster until it laid eggs. By using genetic sequencing (you can use kits these days to extract the DNA, do PCR, gels and cloning, pretty much everything), electron microscopy (real powerful microscopes) and phylogenetic analysis (using computer softwares to see how closely related some species are) the authors came to the conclusion that this parasite they were working on is a new species. So they named it. And below is the full account of the naming, from the horse’s mouth, as it were:

“In accordance with the guidelines of the International Committee of Systematic Bacteriology, unculturable bacteria should be classified as Candidatus (Murray & Stackebrandt, 1995). Thus we propose the name ‘Candidatus Midichloria mitochondrii’ for the novel bacterium. The genus name Midichloria (mi.di.chlo′ria. N.L. fem. n.) is derived from the midichlorians, organisms within the fictional Star Wars universe. Midichlorians are microscopic symbionts that reside within the cells of living things and ‘‘communicate with the Force’’. Star Wars creator George Lucas stated that the idea of the midichlorians is based on endosymbiotic theory. The word ‘midichlorian’ appears to be a blend of the words mitochondrion and chloroplast. The specific epithet, mitochondrii (mi.to′chon.drii. N.L. n. mitochondrium -i a mitochondrion; N.L. gen. n. mitochondrii of a mitochondrion), refers to the unique intramitochondrial lifestyle of this bacterium. ‘Candidatus M. mitochondrii’ belongs to the phylum Proteobacteria, to the class Alphaproteobacteria and to the order Rickettsiales. ‘Candidatus M. mitochondrii’ is assigned on the basis of the 16S rRNA (AJ566640) and gyrB gene sequences (AM159536)” (p. 2539).

George Lucas gave his blessing to the Christening (of course he did).

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Acknowledgements: Thanks go to Ms. BBD who prevented me from making a fool of myself (this time!) on the social media by pointing out to me that midichloria are real and that they are a mitochondrial parasite.

REFERENCE: Sassera D, Beninati T, Bandi C, Bouman EA, Sacchi L, Fabbi M, Lo N. (Nov. 2006). ‘Candidatus Midichloria mitochondrii’, an endosymbiont of the tick Ixodes ricinus with a unique intramitochondrial lifestyle. International Journal of Systematic and Evolutionary Microbiology, 56(Pt 11): 2535-2540. PMID: 17082386, DOI: 10.1099/ijs.0.64386-0. ABSTRACT | FREE FULLTEXT PDF 

By Neuronicus, 29 July 2017

Aging and its 11 hippocampal genes

Aging is being quite extensively studied these days and here is another advance in the field. Pardo et al. (2017) looked at what happens in the hippocampus of 2-months old (young) and 28-months old (old) female rats. Hippocampus is a seahorse shaped structure no more than 7 cm in length and 4 g in weight situated at the level of your temples, deep in the brain, and absolutely necessary for memory.

First the researchers tested the rats in a classical maze test (Barnes maze) designed to assess their spatial memory performance. Not surprisingly, the old performed worse than the young.

Then, they dissected the hippocampi and looked at neurogenesis and they saw that the young rats had more newborn neurons than the old. Also, the old rats had more reactive microglia, a sign of inflammation. Microglia are small cells in the brain that are not neurons but serve very important functions.

After that, the researchers looked at the hippocampal transcriptome, meaning they looked at what proteins are being expressed there (I know, transcription is not translation, but the general assumption of transcriptome studies is that the amount of protein X corresponds to the amount of the RNA X). They found 210 genes that were differentially expressed in the old, 81 were upregulated and 129 were downregulated. Most of these genes are to be found in human too, 170 to be exact.

But after looking at male versus female data, at human and mouse aging data, the authors came up with 11 genes that are de-regulated (7 up- and 4 down-) in the aging hippocampus, regardless of species or gender. These genes are involved in the immune response to inflammation. More detailed, immune system activates microglia, which stays activated and this “prolonged microglial activation leads to the release of pro-inflammatory cytokines that exacerbate neuroinflammation, contributing to neuronal loss and impairment of cognitive function” (p. 17). Moreover, these 11 genes have been associated with neurodegenerative diseases and brain cancers.

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These are the 11 genes: C3 (up), Cd74  (up), Cd4 (up), Gpr183 (up), Clec7a (up), Gpr34 (down), Gapt (down), Itgam (down), Itgb2 (up), Tyrobp (up), Pld4 (down).”Up” and “down” indicate the direction of deregulation: upregulation or downregulation.

I wish the above sentence was as explicitly stated in the paper as I wrote it so I don’t have to comb through their supplemental Excel files to figure it out. Other than that, good paper, good work. Gets us closer to unraveling and maybe undoing some of the burdens of aging, because, as the actress Bette Davis said, “growing old isn’t for the sissies”.

Reference: Pardo J, Abba MC, Lacunza E, Francelle L, Morel GR, Outeiro TF, Goya RG. (13 Jan 2017, Epub ahead of print). Identification of a conserved gene signature associated with an exacerbated inflammatory environment in the hippocampus of aging rats. Hippocampus, doi: 10.1002/hipo.22703. ARTICLE

By Neuronicus, 25 January 2017

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Don’t eat snow

Whoever didn’t roll out a tongue to catch a few snowflakes? Probably only those who never encountered snow.

The bad news is that snow, particularly urban snow is bad, really bad for you. The good news is that this was not always the case. So there is hope that in the far future it will be pristine again.

Nazarenko et al. (2016) constructed a very clever contraption that reminds me of NASA space exploration instruments. The authors refer to this by the humble name of ‘environmental chamber’, but is in fact a complex construction with different modules designed to measure out how car exhaust and snow interact (see Fig. 1).

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Fig. 1 from Nazarenko et al. (2016, DOI: 10.1039/c5em00616c). Released under CC BY-NC 3.0.

After many experiments, researchers concluded that snow absorbs pollutants very effectively. Among the many kinds of organic compounds soaked by snow in just one hour after exposure to fume exhaust, there were the infamous BTEX (benzene, toluene, ethylbenzene, and xylenes). The amounts of these chemicals in the snow were not at all negligible; to give you an example, the BTEX concentration increased from virtually 0 to 50 and up to 380 ug kg-1. The authors provide detailed measurements for all the 40+ compounds they have identified.

Needless to say, many these compounds are known carcinogenics. Snow absorbs them, alters their size distributions, and then it melts… Some of them may be released back in the air as they are volatile, some will go in the ground and rivers as polluted water. After this gloomy reality check, I’ll leave you with the words of the researchers:

“The accumulation and transfer of pollutants from exhaust – to snow – to meltwater need to be considered by regulators and policy makers as an important area of focus for mitigation with the aim to protect public health and the environment” (p. 197).

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Reference: Nazarenko Y, Kurien U, Nepotchatykh O, Rangel-Alvarado RB, & Ariya PA. (Feb 2016). Role of snow and cold environment in the fate and effects of nanoparticles and select organic pollutants from gasoline engine exhaust. Environmental Science: Processes & Impacts, 18(2):190-199. doi: 10.1039/c5em00616c. ARTICLE | FREE FULTEXT PDF 

By Neuronicus, 26 December 2016

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Soccer and brain jiggling

There is no news or surprise that strong hits to the head produce transient or permanent brain damage. But how about mild hits produced by light objects like, say, a volley ball or soccer ball?

During a game of soccer, a player is allowed to touch the ball with any part of his/her body minus the hands. Therefore, hitting the ball with the head, a.k.a. soccer heading, is a legal move and goals marked through such a move are thought to be most spectacular by the refined connoisseur.

A year back, in 2015, the United States Soccer Federation forbade the heading of the ball by children 10 years old and younger after a class-action lawsuit against them. There has been some data that soccer players display loss of brain matter that is associated with cognitive impairment, but such studies were correlational in nature.

Now, Di Virgilio et al. (2016) conducted a study designed to explore the consequences of soccer heading in more detail. They recruited 19 young amateur soccer players, mostly male, who were instructed to perform 20 rotational headings as if responding to corner kicks in a game. The ball was delivered by a machine at a speed of approximately 38 kph. The mean force of impact for the group was 13.1 ± 1.9 g. Immediately after the heading session and at 24 h, 48 h and 2 weeks post-heading, the authors performed a series of tests, among which are a transcranial magnetic stimulation (TMS) recording, a cognitive function assessment (by using the Cambridge Neuropsychological Test Automated Battery), and a postural control test.

Not being a TMS expert myself, I was wondering how do you record with a stimulator? TMS stimulates, it doesn’t measure anything. Or so I thought. The authors delivered brief  (1 ms) stimulating impulses to the brain area that controls the leg (primary motor cortex). Then they placed an electrode over the said muscle (rectus femoris or quadriceps femoris) and recorded how the muscle responded. Pretty neat. Moreover, the authors believe that they can make inferences about levels of inhibitory chemicals in the brain from the way the muscle responds. Namely, if the muscle is sluggish in responding to stimulation, then the brain released an inhibitory chemical, like GABA (gamma-amino butyric acid), hence calling this process corticomotor inhibition. Personally, I find this GABA inference a bit of a leap of faith, but, like I said, I am not fully versed in TMS studies so it may be well documented. Whether or not GABA is responsible for the muscle sluggishness, one thing is well documented though: this sluggishness is the most consistent finding in concussions.

The subjects had impaired short term and long term memory functions immediately after the ball heading, but not 24 h or more later. Also transient was the corticomotor inhibition. In other words, soccer ball heading results in measurable changes in brain function. Changes for the worst.

Even if these changes are transient, there is no knowing (as of yet) what prolonged ball heading might do. There is ample evidence that successive concussions have devastating effects on the brain. Granted, soccer heading does not produce concussions, at least in this paper’s setting, but I cannot think that even sub-concussion intensity brain disruption can be good for you.

On a lighter note, although the title of the paper features the word “soccer”, the rest o the paper refers to the game as “football”. I’ll let you guess the authors’ nationality or at least the continent of provenance ;).

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Reference: Di Virgilio TG, Hunter A, Wilson L, Stewart W, Goodall S, Howatson G, Donaldson DI, & Ietswaart M. (Nov 2016, Epub 23 Oct 2016). Evidence for Acute Electrophysiological and Cognitive Changes Following Routine Soccer Heading. EBioMedicine, 13:66-71. PMID: 27789273, DOI: 10.1016/j.ebiom.2016.10.029. ARTICLE | FREE FULLTEXT PDF

By Neuronicus, 20 December 2016

Amusia and stroke

Although a complete musical anti-talent myself, that doesn’t prohibit me from fully enjoying the works of the masters in the art. When my family is out of earshot, I even bellow – because it cannot be called music – from the top of my lungs alongside the most famous tenors ever recorded. A couple of days ago I loaded one of my most eclectic playlists. While remembering my younger days as an Iron Maiden concert goer (I never said I listen only to classical music :D) and screaming the “Fear of the Dark” chorus, I wondered what’s new on the front of music processing in the brain.

And I found an interesting recent paper about amusia. Amusia is, as those of you with ancient Greek proclivities might have surmised, a deficit in the perception of music, mainly the pitch but sometimes rhythm and other aspects of music. A small percentage of the population is born with it, but a whooping 35 to 69% of stroke survivors exhibit the disorder.

So Sihvonen et al. (2016) decided to take a closer look at this phenomenon with the help of 77 stroke patients. These patients had an MRI scan within the first 3 weeks following stroke and another one 6 months poststroke. They also completed a behavioral test for amusia within the first 3 weeks following stroke and again 3 months later. For reasons undisclosed, and thus raising my eyebrows, the behavioral assessment was not performed at 6 months poststroke, nor an MRI at the 3 months follow-up. It would be nice to have had behavioral assessment with brain images at the same time because a lot can happen in weeks, let alone months after a stroke.

Nevertheless, the authors used a novel way to look at the brain pictures, called voxel-based lesion-symptom mapping (VLSM). Well, is not really novel, it’s been around for 15 years or so. Basically, to ascertain the function of a brain region, researchers either get people with a specific brain lesion and then look for a behavioral deficit or get a symptom and then they look for a brain lesion. Both approaches have distinct advantages but also disadvantages (see Bates et al., 2003). To overcome the disadvantages of these methods, enter the scene VLSM, which is a mathematical/statistical gimmick that allows you to explore the relationship between brain and function without forming preconceived ideas, i.e. without forcing dichotomous categories. They also looked at voxel-based morphometry (VBM), which a fancy way of saying they looked to see if the grey and white matter differ over time in the brains of their subjects.

After much analyses, Sihvonen et al. (2016) conclude that the damage to the right hemisphere is more likely conducive to amusia, as opposed to aphasia which is due mainly to damage to the left hemisphere. More specifically,

“damage to the right temporal areas, insula, and putamen forms the crucial neural substrate for acquired amusia after stroke. Persistent amusia is associated with further [grey matter] atrophy in the right superior temporal gyrus (STG) and middle temporal gyrus (MTG), locating more anteriorly for rhythm amusia and more posteriorly for pitch amusia.”

The more we know, the better chances we have to improve treatments for people.

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unless you’re left-handed, then things are reversed.

References:

1. Sihvonen AJ, Ripollés P, Leo V, Rodríguez-Fornells A, Soinila S, & Särkämö T. (24 Aug 2016). Neural Basis of Acquired Amusia and Its Recovery after Stroke. Journal of Neuroscience, 36(34):8872-8881. PMID: 27559169, DOI: 10.1523/JNEUROSCI.0709-16.2016. ARTICLE  | FULLTEXT PDF

2.Bates E, Wilson SM, Saygin AP, Dick F, Sereno MI, Knight RT, & Dronkers NF (May 2003). Voxel-based lesion-symptom mapping. Nature Neuroscience, 6(5):448-50. PMID: 12704393, DOI: 10.1038/nn1050. ARTICLE

By Neuronicus, 9 November 2016

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Another puzzle piece in the autism mystery

Just like in the case of schizophrenia, hundreds of genes have been associated with autistic spectrum disorders (ASDs). Here is another candidate.

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Féron et al. (2016) reasoned that most of the info we have about the genes that are behaving badly in ASDs comes from studies that used adult cells. Because ASDs are present before or very shortly after birth, they figured that looking for genetic abnormalities in cells that are at the very early stage of ontogenesis might prove to be enlightening. Those cells are stem cells. Of the pluripotent kind. FYI, based on what they can become (a.k.a how potent they are), the stem cells are divided into omipotent, pluripotent, multipotent, oligopotent, and unipotent. So the pluripotents are very ‘potent’ indeed, having the potential of producing a perfect person.

Tongue-twisters aside, the authors’ approach is sensible, albeit non-hypothesis driven. Which means they hadn’t had anything specific in mind when they had started looking for differences in gene expression between the olfactory nasal cells obtained from 11 adult ASDs sufferers and 11 age-matched normal controls. Luckily for them, as transcriptome studies have a tendency to be difficult to replicate, they found the anomalies in the expression of genes that have been already associated with ASD. But, they also found a new one, the MOCOS (MOlybdenum COfactor Sulfurase) gene, which was poorly expressed in ASDs (downregulated, in genetic speak). The enzyme is MOCOS (am I the only one who thinks that MOCOS isolated from nasal cells is too similar to mucus? is the acronym actually a backronym?).

The enzyme is not known to play any role in the nervous system. Therefore, the researchers looked to see where the gene is expressed. Its enzyme could be found all over the brain of both mouse and human. Also, in the intestine, kidneys, and liver. So not much help there.

Next, the authors deleted this gene in a worm, Caenorhabditis elegans, and they found out that the worm’s cells have issues in dealing with oxidative stress (e.g. the toxic effects of free radicals). In addition, their neurons had abnormal synaptic transmission due to problems with vesicular packaging.

Then they managed – with great difficulty – to produce human induced pluripotent cells (iPSCs) in a Petri dish in which the gene MOCOS was partially knocked down. ‘Partially’, because the ‘totally’ did not survive. Which tells us that MOCOS is necessary for survival of iPSCs. The mutant cells had less synaptic buttons than the normal cells, meaning they formed less synapses.

The study, besides identifying a new candidate for diagnosis and treatment, offers some potential explanations for some beguiling data that other studies have brought forth, like the fact that all sorts of neurotransmitter systems seem to be impaired in ADSs, all sorts of brain regions, making very hard to grab the tiger by the tail if the tiger is sprouting a new tail when you look at it, just like the Hydra’s heads. But, discovering a molecule that is involved in an ubiquitous process like synapse formation may provide a way to leave the tiger’s tail(s) alone and focus on the teeth. In the authors’ words:

“As a molecule involved in the formation of dense core vesicles and, further down, neurotransmitter secretion, MOCOS seems to act on the container rather than the content, on the vehicle rather than one of the transported components” (p. 1123).

The knowledge uncovered by this paper makes a very good piece of the ASDs puzzle. Maybe not a corner, but a good edge. Alright, even if it’s not an edge, at least it’s a crucial piece full of details, not one of those sky pieces.

Reference: Féron F, Gepner B, Lacassagne E, Stephan D, Mesnage B, Blanchard MP, Boulanger N, Tardif C, Devèze A, Rousseau S, Suzuki K, Izpisua Belmonte JC, Khrestchatisky M, Nivet E, & Erard-Garcia M (Sep 2016, Epub 4 Aug 2016). Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders. Molecular Psychiatry, 21(9):1215-1224. PMID: 26239292, DOI: 10.1038/mp.2015.106. ARTICLE | FREE FULLTEXT PDF

By Neuronicus, 31 August 2016

One parent’s gene better than the other’s

Not all people with the same bad genetic makeup that predisposes them to a particular disease go and develop that disease or, at any rate, not with the same severity and prognosis. The question is why? After all, they have the same genes…

Here comes a study that answers that very important question. Eloy et al. (2016) looked at the most common pediatric eye cancer (1 in 15,000) called retinoblastoma (Rb). In the hereditary form of this cancer, the disease occurs if the child carries mutant (i.e. bad) copies of the RB1 tumour suppressor gene located on chromosome 13 (13q14). These copies, called alleles, are inherited by the child from the mother or from the father. But some children with this genetic disadvantage do not develop Rb. They should, so why not?

The authors studied 57 families with Rb history. They took blood and tumour samples from the participants and then did a bunch of genetic tests: DNA, RNA, and methylation analyses.

They found out that when the RB1 gene is inherited from the mother, the child has only 9.7% chances of developing Rb, but when the gene is inherited from the father the child has only 67.5% chances of developing Rb.

The mechanism for this different outcomes may reside in the differential methylation of the gene. Methylation is a chemical process that suppresses the expression of a gene, meaning that less protein is produced from that gene. The maternal gene had less methylation, meaning that more protein was produced, which was able to offer some protection against the cancer. Seems counter-intuitive, you’d think less bad protein is a good thing, but there is a long and complicated explanation for that, which, in a very simplified form, posits that other events influence the function of the resultant protein.

Again, epigenetics seem to offer explanations for pesky genetic inheritance questions. Epigenetic processes, like DNA methylation, are modalities through which traits can be inherited that are not coded in the DNA itself.

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Reference: Eloy P, Dehainault C, Sefta M, Aerts I, Doz F, Cassoux N, Lumbroso le Rouic L, Stoppa-Lyonnet D, Radvanyi F, Millot GA, Gauthier-Villars M, & Houdayer C (29 Feb 2016). A Parent-of-Origin Effect Impacts the Phenotype in Low Penetrance Retinoblastoma Families Segregating the c.1981C>T/p.Arg661Trp Mutation of RB1. PLoS Genetics, 12(2):e1005888. eCollection 2016. PMID: 26925970, PMCID: PMC4771840, DOI: 10.1371/journal.pgen.1005888. ARTICLE | FREE FULLTEXT PDF

By Neuronicus, 24 July 2016

Stress can kill you and that’s no metaphor

The term ‘heartbreak’ is used as a metaphor to describe the intense feeling of loss, sometimes also called emotional pain. But what if the metaphor has roots into something more tangible than a feeling, that of the actual muscular organ giving signs of failure?

Although there have been previous reports that found stress causes cardiovascular problems, including myocardial infarction, Graff et al. (2016) conducted the largest study to date that investigated this link: they had almost 1 million subjects. That’s right, 1 million people (well, actually 974 732). Out of these, almost 20% of them had a partner who died between 1995 and 2014. The chosen stressor was the loss of a loved one because “the loss of a partner is considered one of the most severely stressful life events and is likely to affect most people, independently of coping mechanisms” (p. 1-2). The authors looked at Danish hospital records for people who were diagnosed with atrial fibrillation (AF) for the first time and correlated that data with bereavement information. AF increases the risk of death due to stroke or heart failure.

The people who underwent loss had an increased risk to develop AF for 1 year after the loss. The risk was more pronounced in the first 8-14 days after the loss, the bereaved people having a 90% higher risk of developing AF than non-bereaved people. By the end of the first month the risk had declined, but still was a whooping 41% higher than the average. Only 1 year after the loss the risk of developing AF was similar to that of non-bereaved people.

The risk was even higher in young people or if the death of the partner was unexpected. The authors also looked to see if other variables play a role in the risk, like gender, civil status, education, diabetes, or cardiovascular medication and none influenced the results.

I suspect the number of people that have heart problems after major stress is actually a lot higher because of the under-reporting bias. In other words, not everybody who feels their heart aching would go to the hospital, particularly in the first couple of weeks after losing a loved one.

As for the mechanism, there is some data pointing to some stress hormones (like adrenaline or cortisol) which can damage the heart. Other substances released in abundance during stress and likely to act in concert with the stress hormones are proinflamatory cytokines which also can lead to arrhythmias.

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Reference: Graff S, Fenger-Grøn M, Christensen B, Søndergaard Pedersen H, Christensen J, Li J, & Vestergaard M (2016). Long-term risk of atrial fibrillation after the death of a partner. Open Heart, 3: e000367. doi:10.1136/openhrt-2015-000367. Article  | FREE FULTEXT PDF

By Neuronicus, 16 April 2016

Eating high-fat dairy may lower your risk of being overweight

Many people buy low-fat dairy, like 2% milk, in the hopes that ingesting less fat means that they will be less fattier.

Contrary to this popular belief, a new study found that consumption of high-fat dairy lowers the risk of weight gain by 8% in middle-aged and elderly women.

Rautiainen et al. (2016) studied 18 438 women over 45 years old who did not have cancer, diabetes or cardiovascular diseases. They collected data on the women’s weight, eating habits, smoking, alcohol use, physical activity, medical history, hormone use, and vitamin intake for  8 to 17 years. “Total dairy product intake was calculated by summing intake of low-fat dairy products (skim and low-fat milk, sherbet, yogurt, and cottage and ricotta cheeses) and high-fat dairy products (whole milk, cream, sour cream, ice cream, cream cheese, other cheese, and butter)” (p. 980).

At the beginning of the study, all women included in the analyses were normal weight.

Over the course of the study, all women gained some weight, probably as a result of normal aging.

Women who ate more dairy gained less weight than women who didn’t. This finding is due to the high-fat dairy intake; in other words, women who ate high-fat dairy gained less weight compared to the women who consumed low-fat dairy. Skimmed milk seemed to be the worst for weight gain compared to low-fat yogurt.

I did not notice any speculation as to why this may be the case, so I’ll offer one: maybe the people who eat high-fat dairy get more calories from the same amount of food so maybe they eat less overall.

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Reference: Rautiainen S, Wang L, Lee IM, Manson JE, Buring JE, & Sesso HD (Apr 2016, Epub 24 Feb 2016). Dairy consumption in association with weight change and risk of becoming overweight or obese in middle-aged and older women: a prospective cohort study. The American Journal of Clinical Nutrition, 103(4): 979-988. doi: 10.3945/ajcn.115.118406. Article | FREE FULLTEXT PDF | SuppData

By Neuronicus, 7 April 2016

Cats and uncontrollable bursts of rage in humans

 

That many domestic cats carry the parasite Toxoplasma gondii is no news. Nor is the fact that 30-50% of the global population is infected with it, mainly as a result of contact with cat feces.

The news is that individuals with toxoplasmosis are a lot more likely to have episodes of uncontrollable rage. It was previously known that toxoplasmosis is associated with some psychological disturbances, like personality changes or cognitive impairments. In this new longitudinal study (that means a study that spanned more than a decade) published three days ago, Coccaro et al. (2016) tested 358 adults with or without psychiatric disorders for toxoplasmosis. They also submitted the subjects to a battery of psychological tests for anxiety, impulsivity, aggression, depression, and suicidal behavior.

The results showed that the all the subjects who were infected with T. gondii had higher scores on aggression, regardless of their mental status. Among the people with toxoplasmosis, the aggression scores were highest in the patients previously diagnosed with intermittent explosive disorder,

 

a little lower in patients with non-aggressive psychiatric disorders, and finally lower (but still significantly higher than non-infected people) in healthy people.

The authors are adamant in pointing out that this is a correlational study, therefore no causality direction can be inferred. So don’t kick out you felines just yet. However, as CDC points out, a little more care when changing the cat litter or a little more vigorous washing of the kitchen counters would not hurt anybody and may protect against T. gondii infection.

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Reference: Coccaro EF, Lee R, Groer MW, Can A, Coussons-Read M, & Postolache TT (23 march 2016). Toxoplasma gondii Infection: Relationship With Aggression in Psychiatric Subjects. The Journal of Clinical Psychiatry, 77(3): 334-341. doi: 10.4088/JCP.14m09621. Article Abstract | FREE Full Text | The Guardian cover

By Neuronicus, 26 March 2016

Younger children in a grade are more likely to be diagnosed with ADHD

AHDH immaturity - Copy.jpgA few weeks ago I was drawing attention to the fact that some children diagnosed with ADHD do not have attention deficits. Instead, a natural propensity for seeking more stimulation may have led to overdiagnosing and overmedicating these kids.

Another reason for the dramatic increase in ADHD diagnosis over the past couple of decades may stem in the increasingly age-inappropriate demands that we place on children. Namely, children in the same grade can be as much as 1 year apart in chronological age, but at these young ages 1 year means quite a lot in terms of cognitive and behavioral development. So if we put a standard of expectations based on how the older children behave, then the younger children in the same grade would fall short of these standards simply because they are too immature to live up to them.

So what does the data say? Two studies, Morrow et al. (2012) and Chen et al. (2016) checked to see if the younger children in a given grade are more likely to be diagnosed with ADHD and/or medicated. The first study was conducted in almost 1 million Canadian children, aged 6-12 years and the second investigated almost 400,000 Taiwanese children, aged 4-17 years.

In Canada, the cut-off for starting school in Dec. 31. Which means that in the first grade, a child born in January is almost a year older that a child born in December. Morrow et al. (2012) concluded that the children born in December were significantly more likely to receive a diagnosis of ADHD than those born in January (30% more likely for boys and 70% for girls). Moreover, the children born in December were more likely to be given an ADHD medication prescription (41% more likely for boys and 77% for girls).

In Taiwan, the cut-off date for starting school in August 31. Similar to the Canadian study, Chen et al. (2016) found that the children born in August were more likely to be diagnosed with ADHD and receive ADHD medication than the children born in September.

Now let’s be clear on one thing: ADHD is no trivial matter. It is a real disorder. It’s an incredibly debilitating disease for both children and their parents. Impulsivity, inattention and hyperactivity are the hallmarks of almost every activity the child engages in, leading to very poor school performance (the majority cannot get a college degree) and hard family life, plus a lifetime of stigma that brings its own “gifts” such as marginalization, loneliness, depression, anxiety, poor eating habits, etc.

The data presented above favors the “immaturity hypothesis” which posits that the behaviors expected out of some children cannot be performed not because something is wrong with them, but because they are simply too immature to be able to perform those behaviors. That does not mean that every child diagnosed with ADHD will just grow out of it; the researchers just point to the fact that ignoring the chronological age of the child coupled with prematurely entering a highly stressful and demanding system as school might lead to ADHD overdiagnosis.

Bottom line: ignoring the chronological age of the child might explain some of increase in prevalence of ADHD by overdiagnostication (in US alone, the rise is from 6% of children diagnosed with ADHD in 2000 to 11-15% in 2015).

References:

  1. Morrow RL, Garland EJ, Wright JM, Maclure M, Taylor S, & Dormuth CR. (17 Apr 2012, Epub 5 Mar 2012). Influence of relative age on diagnosis and treatment of attention-deficit/hyperactivity disorder in children. Canadian Medical Association Journal, 184 (7), 755-762, doi: 10.1503/cmaj.111619. Article | FREE PDF 
  1. Chen M-H, Lan W-H, Bai Y-M, Huang K-L, Su T-P, Tsai S-J, Li C-T, Lin W-C, Chang W-H, & Pan T-L, Chen T-J, & Hsu J-W. (10 Mar 2016). Influence of Relative Age on Diagnosis and Treatment of Attention-Deficit Hyperactivity Disorder in Taiwanese Children. The Journal of Pediatrics [Epub ahead print]. DOI: http://dx.doi.org/10.1016/j.jpeds.2016.02.012 Article | FREE PDF

By Neuronicus, 14 March 2016

Inhaling a bitter tasting solution may help with asthma (don’t try this at home, yet)

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Asthma is an inflammatory disease of the lungs’ airways. The airway smooth muscle (ASM) expresses a large number of G protein-coupled receptors (GPCRs). The GPCRs are proteins bound to the cell membrane that sense what happens outside the cell and thus signal the cell to engage in appropriate responses. There are many, many types of GPCRs (in the upper hundreds) all over the body. Furthermore, alternative splicing (that is reshuffling parts of the gene that codes for a protein in such a way that you can get several different proteins from the same gene) may produce new types.

In an a effort to characterize the GPCRs in the ASM in the hope of finding an asthma pharmacological target, Einstein et al. (2008) found many more types of these receptors than previously thought, produced mainly by alternative splicing. In a subsequent study, the same group found out that some of these GPCRs are the same GPCRs that are expressed by your tongue in order to taste bitterness (Desphande et al., 2010)! The researchers were not expecting this.

Moreover, the bitter receptors (called TAS2Rs) in the lungs are fully functional, that is they respond to bitter substances like quinine. The response is, surprisingly, that of relaxation of the airways. It’s surprising because the role of bitter receptors in the tongue is to signal avoidance of bitter foods, because they usually contain toxins. So Desphande et al. (2010) (and anyone else in their shoes) would have expected a similar role for the bitter receptors in the lungs: that is, upon smelling something bitter the airways would close to prevent further poisoning. The data proved this expectation to be wrong.

The work so far has been done in isolated human cells. If quinine relaxes the ASM in an Petri dish, would it do so also when the ASM is still attached to its owner? So the researchers gave some bitter inhalants to some mice who had asthma and this treatment DECREASED the airway obstruction in a dose-dependent manner.

Asthma hits 300 million people worldwide and more than a quarter million die of it per year. So this research sparks great hopes for a new treatment direction.

References:

  1. Einstein R, Jordan H, Zhou W, Brenner M, Moses EG, & Liggett SB (1 Apr 2008, Epub 24 Mar 2008). Alternative splicing of the G protein-coupled receptor superfamily in human airway smooth muscle diversifies the complement of receptors. Proceedings of the National Academy of Sciences of the United States of America, 105(13):5230-5. doi: 10.1073/pnas.0801319105. Article | FREE FULLTEXT PDF
  1. Deshpande DA, Wang WC, McIlmoyle EL, Robinett KS, Schillinger RM, An SS, Sham JS, & Liggett SB. (Nov 2010, Epub 24 Oct 2010). Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nature Medicine, 16(11):1299-304. doi: 10.1038/nm.2237. Article | FREE FULLTEXT PDF 

By Neuronicus, 10 March 2016