Highlights
•Behavioral marker of inhibitory/excitatory neurotransmission is perturbed in autism
•Marker predicts higher-order autistic symptom severity
•Inhibitory and excitatory neurotransmitters measured in the brain predict behavior
•Action of the inhibitory neurotransmitter, GABA, is reduced the autistic brain
Summary
An imbalance between excitatory/inhibitory neurotransmission has been posited as a central characteristic of the neurobiology of autism [ 1 ], inspired in part by the striking prevalence of seizures among individuals with the disorder [ 2 ]. Evidence supporting this hypothesis has specifically implicated the signaling pathway of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), in this putative imbalance: GABA receptor genes have been associated with autism in linkage and copy number variation studies [ 3–7 ], fewer GABA receptor subunits have been observed in the post-mortem tissue of autistic individuals [ 8, 9 ], and GABAergic signaling is disrupted across heterogeneous mouse models of autism [ 10 ]. Yet, empirical evidence supporting this hypothesis in humans is lacking, leaving a gulf between animal and human studies of the condition. Here, we present a direct link between GABA signaling and autistic perceptual symptomatology. We first demonstrate a robust, replicated autistic deficit in binocular rivalry [ 11 ], a basic visual function that is thought to rely on the balance of excitation/inhibition in visual cortex [ 12–15 ]. Then, using magnetic resonance spectroscopy, we demonstrate a tight linkage between binocular rivalry dynamics in typical participants and both GABA and glutamate levels in the visual cortex. Finally, we show that the link between GABA and binocular rivalry dynamics is completely and specifically absent in autism. These results suggest a disruption in inhibitory signaling in the autistic brain and forge a translational path between animal and human models of the condition.
via Reduced GABAergic Action in the Autistic Brain: Current Biology.
This finding has revolutionary implications for the biology of autism. For example, it is possible that exposure to certain drugs (such as antidepressants) during pregnancy may predispose to autism. This study will prompt many more studies of the effect of GABA in autism. There are already a number of drugs available that mimic or transmute the effects of GABA in the brain. There is, of course, gabapentin, which is an analog of GABA but is thought to act at an entirely different neurotransmitter site. There is also baclofen, which resembles GABA as well. Finally, there is the are newer drugs that may be used either in research or therapeutically.
The study itself is an eloquent demonstration of the ability of the MR scanner to detect individual chemical compounds in the brain. It discovered that there is no change in the total amount of GABA (an inhibitory neurotransmitter) in the brain, but that autistic people seem to have difficulty controlling their binocular vision because of a deficiency in signalling due to a defect in the GABA pathway.
The study also offers the possibility of non-invasively detecting and evaluating the severity of autism, a potentially life-saving breakthrough. Only time will tell, after replication and extension of these findings, what new diagnostic and therapeutic techniques can accomplish.
CEO of Turing Pharmaceuticals Arrested
Martin Shkreli, CEO of Turing Pharmaceuticals, was involved in a Ponzi scheme, charged prosecutors today. He was released on five million dollars bail, secured by a checking account, his father, and his brother. This arrest has “nothing to do” with the enormous price increase he imposed on Daraprim, a generic drug used by about 8,000 people a year for toxoplasmosis and malaria prophylaxis. The technical charge is “securities fraud” involving a different drug company, Retrophin, and his activities as a hedge fund manager.
Mr. Shkreli, 32, has been involved in a Twitter war with some of his critics; he also distinguished himself by spending two million dollars for the only copy of a Wu-Tang Clan disc.
A lawyer who worked with him, Evan L. Greebel, was also arrested and released on one million dollars bail.
The fraud began at least by 2010, when he claimed that his hedge fund had made over 37 percent profits when it in fact had lost 18 percent and claimed assets of 35 million dollars. In 2011 he started Retrophin, whose strategy was to buy up old neglected generic drugs and jack up their prices. For example, he took Thiola, a drug used to prevent kidney stones in certain rare cases, and raised the price from $1.50 to $30. He was sued by Retrophin, who claimed that he “used the company as his personal piggy bank” (NYT), and to repay investors in his hedge fund who were unhappy at their losses.
I cannot avoid a grim smile of Schadenfreude at the downfall of this most unpleasant man. See also my blog post of September 20, 2015, about the Daraprim price increase.
In 2008, third year medical student Bradford Perez wrote a letter to his dean complaining of the statistical problems with the methods used by researcher Anil Potti (who recently was sanctioned by the ORI, has left research, and is now practicing in North Dakota.)
The letter was essentially ignored, and no substantial investigation occurred until a number of professional statisticians complained about the essentially fraudulent statistical methods used by Dr. Potti. These methods were used to select what were advertised as “personalized” cancer treatments based on genomic analysis of the individual tumors. These treatments were no more useful, and in some cases less useful, than randomly selected treatments, but many patients went through this clinical “research” and received treatment at his hands.
The letter Bradford Perez wrote is here.
The Perez letter was on top of concerns expressed by biostatisticians Baggerly and Coombes at MD Anderson in November 2006 in correspondence with Potti’s lab that continued for some time without result. Their concerns were dismissed by a superficial investigation that didn’t look at the data or any of the methods; this external review wasn’t completed until December 2009. In November 2007, Coombes et al published their concerns along with a rebuttal from Potti in Nature Medicine.
Anil Potti started a research fellowship under Joseph Nevins in 2004, in a lab established by Nevins in 2000. Potti started his own independent laboratory in 2006. The cancer trials he was involved in suspended new patient enrollment in November 2009. They were restarted in January 2010. In June 2010, NCI concluded that it was not satisfied with the data analysis and asked Potti’s lab to retrieve all data and computer programs from their lab for review.
Anil Potti was placed on administrative leave in July 2010 when it was uncovered that he had falsely claimed he had had a scholarship in England.
In October 2010, Duke officials informed NCI that they had found numerous flaws in Potti’s datasets and that his 2007 paper would have to be retracted.
In November 2010, Potti resigned from Duke and went to work as an oncologist in North Carolina. He left that position in 2011 after receiving a reprimand from the Medical Board of North Carolina for his research behavior at Duke and is now reported working in North Dakota, where he did his original residency in internal medicine after graduating from a medical school in India.
A timeline of the Potti scandal is here.
It didn’t take long, only several years, for Duke to respond to Perez’ letter. As for Perez himself, he resigned from the Potti lab, had his name taken off several research papers, and took another year of research study at a different lab so that he could get into a residency in radiological oncology.
A word to the wise from Will Rogers
Never miss a good chance to shut up — Will Rogers
The Kernel of Truth in the New Testament
At this time of year it is appropriate to discuss Jesus and to try to figure out who he really was. The recent publication of a reconstructed portrait of Jesus as a first century Jerusalem resident shows ever more vigor in historical study of this once obscure subject.
The Shroud of Turn is a good example of the confusion that can arise if provenance is disputed. The Shroud is, as we know through radiocarbon dating, an object created during the middle ages, and through pollen analysis, we can surmise it was made in Turkey or nearby. Thus, as an historical object, the Shroud is interesting but cannot be expected to show a true likeness of Jesus Christ, “King of the Jews.”
To get a better likeness, it is first important to gather as much eyewitness evidence as possible. The four “Gospels” of the New Testament (there are many more “gospels” in the Apocrypha) could none of them have been eyewitnesses; only “Q” (short for “Quellungen” or sources in German) was arguably an eyewitness and that original text has been lost or mislaid.
There is one eyewitness who is unimpeachable and that is Josephus. However, we do not have his original text and the earliest known text has Jesus, but in an obvious interpolation, probably inserted by second or third century Armenian divines. The figure who most looks like Jesus in Josephus from an historical point of view is John the Baptist.
The stories of Paul are obvious inventions and cannot be verified. His claim that the Messiah had already arrived in Jerusalem may only be trusted if we assume that the real Jesus was not named Jesus and is thus hidden in Josephus’ text.
My conclusion is that the person the Christians should be worshiping as their Messiah is John the Baptist.
My greetings for a Merry Christmas, Happy Hanukah, and a glorious Kwanzaa! And a happy New Year.
Don’t look back. You’re not headed that way.
The inhomogeneity, or lack of it, of the Universe– Invitation to Cosmologists to Explain This
http://news.yahoo.com/universe-isnt-fractal-study-finds-215053937.html The universe isn’t fractal, this article claims.
http://arxiv.org/abs/1311.1104 Gamma ray bursts appear to cluster into a structure a billion light years long, too big to be produced in the time since the Big Bang.
http://mnras.oxfordjournals.org/content/405/3/2009.abstract?ijkey=dee165dd1cdd9c394d4f6c3ad6bbd7d468d7997a&keytype2=tf_ipsecsha Fractal dimension as a measure of the scale of homogeneity. “The scale of homogeneity depends very weakly on the choice of tracer of the density field. Thus the suggested definition of the scale of homogeneity is fairly robust.”
http://www.world-science.net/othernews/130111_LQG.htm refers to this paper: http://arxiv.org/pdf/1211.6256v1.pdf which reports the discovery of a structure defined by large quasar groups (LQG’s) that is “larger than the homogeneity scale of the R-W concordance cosmology” –saying that anything larger than 1.2 billion light years across violates the Cosmological Principle… by being inhomogenous.
This post is especially for budding cosmologists to either delve into or comment on. An y cosmologists out there?
Last week, the U.S. government paid Bradley Birkenfeld $104 million in the largest ever whistleblower payout for revealing the information of 19,000 alleged tax cheaters with accounts at the Swiss bank UBS. The information he provided helped the U.S. government collect more than $5 billion. Still, despite aiding the U.S. Internal Revenue Service, he was convicted of one charge of conspiracy to defraud the U.S. government and sentenced to 40-months in jail. In this international tax scandal, Birkenfeld was the only person imprisoned.
In the spring 2010 issue of World Policy Journal, Birkenfeld lays out how UBS promoted and profited from illegal tax evasion. Writing from the federal penitentiary, he argues that if whistleblowers are afraid to bring information to the authorities for fear of prosecution, they will stay silent, and illegal offshore tax havens will operate free of scrutiny.]
via Bradley Birkenfeld: the Whistleblower In His Own Words | World Policy Institute.
I would like to draw everyone’s attention to this article. I had read about it when it happened but the article fills in all the details, including the tradeoff he took: $104 mill for 40 mo in jail. Who wouldn’t take t hat, along with lifetime witness pr ot e c tio n t h at works out to almost 87 thousand dollars a day for sitting in a Club Medtype prison, exercising, eating right, and keeping up with the latest news about your 19,000 sworn enemies.
- 1Tergooi Hospital, Department of Psychiatry, Blaricum, The Netherlands.
- 2Brain Center Rudolf Magnus, University Medical Centre Utrecht, Department of Psychiatry, The Netherlands.
- 3Department of Psychosis Studies, Institute of Psychiatry, King’s College London, UK.
- 4Brain Center Rudolf Magnus, University Medical Centre Utrecht, Department of Psychiatry, The Netherlands. Electronic address: m.p.m.boks@umcutrecht.nl.
Although cannabis use is associated with an increased risk of developing psychosis, the cannabis constituent cannabidiol (CBD) may have antipsychotic properties. This review concisely describes the role of the endocannabinoid system in the development of psychosis and provides an overview of currently available animal, human experimental, imaging, epidemiological and clinical studies that investigated the antipsychotic properties of CBD. In this targeted literature review we performed a search for English articles using Medline and EMBASE. Studies were selected if they described experiments with psychosis models, psychotic symptoms or psychotic disorders as outcome measure and involved the use of CBD as intervention. Evidence from several research domains suggests that CBD shows potential for antipsychotic treatment.
Publication History
- Issue published online: 29 JAN 2009
- Article first published online: 29 JAN 2009
- (Received August 31, 2006, Revised October 30, 2006, Accepted November 20, 2006)
Article first published online: 29 JAN 2009
DOI: 10.1038/sj.bjp.0707133
2007 British Pharmacological Society
Background and purpose:
A nonpsychoactive constituent of the cannabis plant, cannabidiol has been demonstrated to have low affinity for both cannabinoid CB1 and CB2receptors. We have shown previously that cannabidiol can enhance electrically evoked contractions of the mouse vas deferens, suggestive of inverse agonism. We have also shown that cannabidiol can antagonize cannabinoid receptor agonists in this tissue with a greater potency than we would expect from its poor affinity for cannabinoid receptors. This study aimed to investigate whether these properties of cannabidiol extend to CB1 receptors expressed in mouse brain and to human CB2 receptors that have been transfected into CHO cells.
Experimental approach:
The [35S]GTPγS binding assay was used to determine both the efficacy of cannabidiol and the ability of cannabidiol to antagonize cannabinoid receptor agonists (CP55940 and R-(+)-WIN55212) at the mouse CB1 and the human CB2 receptor.
Key results:
This paper reports firstly that cannabidiol displays inverse agonism at the human CB2 receptor. Secondly, we demonstrate that cannabidiol is a high potency antagonist of cannabinoid receptor agonists in mouse brain and in membranes from CHO cells transfected with human CB2receptors.
Conclusions and implications:
This study has provided the first evidence that cannabidiol can display CB2 receptor inverse agonism, an action that appears to be responsible for its antagonism of CP55940 at the human CB2 receptor. The ability of cannabidiol to behave as a CB2 receptor inverse agonist may contribute to its documented anti-inflammatory properties.
British Journal of Pharmacology (2007) 150, 613–623. doi:10.1038/sj.bjp.0707133
Conrad Theodore Seitz 