Tumours develop a chaotic system of blood vessels to raid the body’s normal blood supply. Some of the latest anti-cancer drugs (Vascular Disrupting Agents) work by damaging these vessels: the tumour is then denied access to nutrients essential for its growth. However, to reveal the extent to which such therapies actually conquer the tumour we need to measure blood flow in the tumour vessels.... Read more »
Brunker J, & Beard P. (2012) Pulsed photoacoustic Doppler flowmetry using time-domain cross-correlation: accuracy, resolution and scalability. The Journal of the Acoustical Society of America, 132(3), 1780-91. PMID: 22978905
Religions tend to evolve and adapt to benefit a society the most. The first religion can be uncovered from ancient anthropomorphic sculptures 42,000 years ago.... Read more »
WU Fei-fei,JIN Li-ji,LI Xiao-yu,LI Hua-qiang,CAO Zhen-hui,YOU Jian-song,XU Yong-ping(Ministry of Education Center for Food Safety of Animal Origin,College of Life Science and Technology, Dalian University of Technology,Dalian 116024,China). (2012) Research progress in active ingredients and pharmacological effects of deer antler. Chinese Journal. info:/
Q: Why don’t I write much about nutrition? A: I barely believe anything I read about it. After spending the last decade with my head in the ‘health and fitness’ industry, I’ve developed a healthy skepticism – literally. It’s probably because I’ve seen so many fads come and go, myths busted, and contradictory research. Now, I take most of what I read with a grain of salt – and I’m probably healthier because of it.
Here’s why:... Read more »
Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, & Gluud C. (2012) Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane database of systematic reviews (Online). PMID: 22419320
Smith-Spangler C, Brandeau ML, Hunter GE, Bavinger JC, Pearson M, Eschbach PJ, Sundaram V, Liu H, Schirmer P, Stave C.... (2012) Are organic foods safer or healthier than conventional alternatives?: a systematic review. Annals of internal medicine, 157(5), 348-66. PMID: 22944875
Nothing is certain, but blood pressure does increase in the end of winter and beginning of spring. According to Aurametrix users and google statistics. As a matter of fact, it highly correlates with tax fever - as found by Google Correlate algorithm comparing millions of web queries. But the reason for raising blood pressure is not always taxes. Seasonal variation in blood pressure was noticed and described more than 50 years ago and was connected to periods of decreasing outdoor temperature. It happens to healthy individuals and those who suffer from high blood pressure, especially in the elderly. The figure shows fluctuations in blood pressure observed by French researchers in a large study of 9294 65+ old residents of Bordeaux, Dijon, and Montpellier. Both systolic and diastolic parts of blood pressure as well as heart rate measurements significantly differed across the seasons with a clear trend for increase in colder months. And decreases following warmer weather - the higher the temperature, the larger the blood pressure decreases. Changes in blood pressure relative to outdoor temperature were largest in the elderly (80+ years old). On average, for a 15°C decrease in outdoor temperature, Systolic blood pressure (SBP) increased 0.8 mm Hg in those aged 65 to 74 years compared with 5.1 mm Hg in the oldest group (≥80 years). For a 15°C increase in temperature, SBP decreased 9.9 mm Hg in the youngest group vs 13.8 mm Hg in those 80 years or older. Winter increases in blood pressure did not seem to be caused by increased alcohol consumption and decreased activity. Neither were they dependent on the indoor temperatures - spending over 12 hours in warm rooms did not help.The inverse correlation of blood pressure and outdoor temperature is even stronger for "apparent temperature"- aka the perceived coldness derived from the combination of temperature and wind. And it was observed all over the world - as documented in studies performed in US, Denmark, China, Japan... Possible explanations include direct thermoregulation-mediated vasoconstriction, hypothalamic-pituitary-adrenocortical axis (HPAA) and sympathetic nervous system (SNS) activation, sodium/volume retention and impaired endothelial-dependent vasodilatation. Reduced sleep duration or quality could be also contributing.Environmental hypertensionology is a very young science. Many things in our environment can cause high blood pressure. The exact mechanisms are not well understood, but systems like Aurametrix could utilize the wealth of empirical evidence and use it for prediction and prevention.The high blood pressure season is almost over. Fortunately, many critically ill people made it through and, hopefully, learned more. Let's gear up to make the next time easier.======================================================================= REFERENCES Alpérovitch, A. (2009). Relationship Between Blood Pressure and Outdoor Temperature in a Large Sample of Elderly IndividualsThe Three-City Study Archives of Internal Medicine, 169 (1) DOI: 10.1001/archinternmed.2008.512Halonen, J., Zanobetti, A., Sparrow, D., Vokonas, P., & Schwartz, J. (2010). Relationship between outdoor temperature and blood pressure Occupational and Environmental Medicine, 68 (4), 296-301 DOI: 10.1136/oem.2010.056507Brook RD, Weder AB, & Rajagopalan S (2011). "Environmental hypertensionology" the effects of environmental factors on blood pressure in clinical practice and research. Journal of clinical hypertension (Greenwich, Conn.), 13 (11), 836-42 PMID: 22051429... Read more »
Alpérovitch, A. (2009) Relationship Between Blood Pressure and Outdoor Temperature in a Large Sample of Elderly IndividualsThe Three-City Study. Archives of Internal Medicine, 169(1), 75. DOI: 10.1001/archinternmed.2008.512
Halonen, J., Zanobetti, A., Sparrow, D., Vokonas, P., & Schwartz, J. (2010) Relationship between outdoor temperature and blood pressure. Occupational and Environmental Medicine, 68(4), 296-301. DOI: 10.1136/oem.2010.056507
Brook RD, Weder AB, & Rajagopalan S. (2011) "Environmental hypertensionology" the effects of environmental factors on blood pressure in clinical practice and research. Journal of clinical hypertension (Greenwich, Conn.), 13(11), 836-42. PMID: 22051429
I seem to have been focusing a lot on folic acid (vitamin B9) and vitamin B12 these days. It's not that I'm in anyway choosing the direction taken, it just happens that the published papers are appearing that way.And as if to prove my point, enter the paper by Joshua Roffman and colleagues* (open-access) reporting results from a gold-standard, randomised, double-blind, placebo-controlled study on the addition of folic acid and vitamin B12 supplement to antipsychotic medication for a group of adults with chronic schizophrenia.MTHFR, FOLH = word score @ Wikipedia The paper is open-access but a few summary points are worth mentioning bearing in mind Dr Emily Deans has already discussed this research:One hundred and forty participants diagnosed with schizophrenia but psychiatrically stable were included for initial study. They were all taking an antipsychotic for 6 months "but displayed persistent symptoms despite antipsychotic treatment".As per the study protocol, participants were randomly split into folate-vitamin B12 supplementation or placebo. Actually whilst it was random, it was stratified random, meaning that randomisation took into account serum folate levels which were measured at baseline and formed an important part of the study outcomes. Indeed, the split was also not 50:50 in each group; instead weighted towards the supplementing group. On most other variables the groups showed no significant difference (age, gender splits, medications, SES). That is aside from serum vitamin B12 levels, where the experimental group showed a significantly higher mean level at baseline compared to the placebo group (631 pg/ml vs. 511 pg/ml respectively).The primary outcome measure was the change in negative symptoms as judged by the SANS. Not being an expert on schizophrenia, I was interested to read about the characterisation of positive and negative symptoms in schizophrenia and, as the authors put it, "considerable disability is associated with negative symptoms and cognitive deficits, for which effective treatment is not available".Results: after 16 weeks of study, there were lots and they were mixed in with some DNA genotyping data pertinent to genes involved in the folate metabolism cycle. So our old Scrabble friend MTHFR (see here) got a look in, as did MTR (methionine synthase) - as per my previous post. One gene in particular seemed to get quite well caught up in the study results: FOLH1 - which among other things is involved in folate transfer and absorption. Mention of the words 'glutamate excitotoxicity' alongside FOLH1 also stirs up some interesting thoughts. So, yadda, yadda, "folate and vitamin B12 improves negative symptoms of schizophrenia" but only modestly given the "15% difference in SANS scores" between the experimental and placebo groups. Importantly in these days of personalised medicine, the FOLH1 gene was the focus, in that FOLH1 484C>T variant seemed to tie into treatment response. This was slightly at odds with what had been noted on another occasions**.So, if a participants was homozygous - as in identical copies of the same allele - for FOLH1 484T, they were more likely to show greater benefit from the supplements. I'll come back to this shortly.That's not also to say that there weren't other gene related findings tied into intervention response. As the authors note about MTHFR 677C>T "only T allele carriers exhibited a significant benefit for active treatment over placebo for negative symptoms". Thankfully in line with what has previously been discussed***.Every paper covered on this blog is a learning journey for me and this one is no exception. Likewise, it is always interesting to see when results don't exactly pan out as they are predicted to. In the case of the Roffman paper, it was the FOLH1 gene findings which didn't go to plan, and how contrary to the expected role of the 484C variant, the so-called low-functioning variant which one would expect to have reduced folate absorption - as was demonstrated in a separate asymptomatic cohort - it was actually the presence of the high-functioning variant (484T) which governed a positive treatment response.In light of these findings, and the fact that red blood cell (RBC) levels of folate grew and grew in the experimental group over the course of the trial (although not significantly related to the change in negative symptoms), one starts to ponder other explanations to account for the results.I've gone over MTHFR so won't say much more on that. The authors touch upon one potentially pertinent issue - DNA methylation - which is where I always seem to end up back to when talking about folate and MTHFR and the like. That for example, the supplementation of folic acid and vitamin B12 might, just might, impact on important reactions such as the recycling of homocysteine back to methionine onward to the production of SAMe is one possible effect. Indeed, it is a shame that elements of the methionine cycle were not measured over the course of the current trial. I could go on. I could ask what kind of vitamin B12 was used as a supplement, whether the oral dosage form is the ideal way to get vitamin B12 into the body, whether outside of the reported symptoms, there may have been other variables affected by the results and whether despite increasing levels of folate, there were corresponding increases to levels of the active form of folic acid, 5-methyltetrahydrofolate? Indeed on that last point apparently there are plans afoot to look at the use of 5-methyltetrahydrofolate (or as the authors call it 1-methylfolate)...Please stop now... and so I shall.----------* Roffman JL. et al. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry. March 2013.** Roffman JL. et al. Genetic variation throughout the folate metabolic pathway influences negative symptom severity in schizophrenia. Schizophr Bull. 2013; 39: 330-338.*** Hill M. et al. Folate supplementation in schizophrenia: a possible role for MTHFR genotype. Schizophr Res. 2011; 127: 41-45.----------... Read more »
Roffman JL, Lamberti JS, Achtyes E, Macklin EA, Galendez GC, Raeke LH, Silverstein NJ, Smoller JW, Hill M, & Goff DC. (2013) Randomized Multicenter Investigation of Folate Plus Vitamin B12 Supplementation in Schizophrenia. JAMA psychiatry (Chicago, Ill.), 1-9. PMID: 23467813
The Journal of Strength and Conditioning Research is a good portal for the S&C coach. However, I keep reading articles in it that make me question its scientific rigour. I’ve already written about a recent paper in which a completely invalid methodology was used (although I must thank them for this as it was a great teaching tool). Now, they have published an article entitled “Changes in Height, Body Weight, and Body Composition in American Football Players From 1942 to 2011″.... Read more »
Anzell AR, Potteiger JA, Kraemer WJ, & Otieno S. (2013) Changes in height, body weight, and body composition in American football players from 1942 to 2011. Journal of strength and conditioning research / National Strength , 27(2), 277-84. PMID: 23222088
Two recent studies - the ominously named "fecal transplant" study and another on acne-causing bacteria - reinforce a compelling idea about our microbiomes that has been brewing for a few years: that some infectious diseases may be due in part to a disharmonious balance between pathogenic bad-guy bacteria and our resident commensal good-guy bacteria. ... Read more »
van Nood, E., Vrieze, A., Nieuwdorp, M., Fuentes, S., Zoetendal, E., de Vos, W., Visser, C., Kuijper, E., Bartelsman, J., Tijssen, J.... (2013) Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. New England Journal of Medicine, 368(5), 407-415. DOI: 10.1056/NEJMoa1205037
Color coding allows smokers to easily identify their former brands.
The tobacco industry has once again made a mockery of the Food and Drug Administration’s attempts to ban ‘light” cigarettes from the marketplace, by simply eliminated the objectionable wording and substituting an easily-decoded color scheme. In a brochure prepared for cigarette retailers marked “For trade use only: not to be shown or distributed to customers,” tobacco giant Philip Morris wrote that “some cigarettes and smokeless packaging is changing, but the product remains the same.”
Research done at Harvard demonstrates "the continued attempts of the industry to avoid reasonable regulation of tobacco products,” said Hillel Alpert, co-author of a new study on light cigarettes, in a prepared statement. The Family Smoking Prevention and Tobacco Control Act (FSPTCA) of 2009 highlights the banning of light cigarettes as a critical mission, since cigarettes marketed in this way are in fact no safer than regular cigarettes. What makes a cigarette Light or Ultra-light is a series of tiny holes drilled through the filter (See earlier post). This “filter ventilation” was calibrated to the descriptors: Ultra-lights had more holes drilled in the filter than Lights. Studies have demonstrated conclusively that such filter schemes do not make smoking safer or cut down on related diseases. A 2001 report from the National Cancer Institute documented how smokers were compensating for the ventilation holes by smoking more cigarettes, smoking them more intensely, or by blocking the filter holes with fingers or lips.
In a study for Tobacco Control, Gregory Connolly and Hillel Alpert of the Harvard School of Public Health documented the process. In 2010, Philip Morris sent manuals to retailers detailing how they were to deal with the new sales situation. Philip Morris made clear that “current pack descriptors such as light, ultra-light and mild will be removed from all packages.” All well and good. However, the Philip Morris material also specified how a series of new package names were to be doled out. Marlboro Light became Marlboro Gold. Marlboro Mild morphed into Marlboro Blue. And Marlboro Ultra-light reemerged as Marlboro Silver.
When the researchers commissioned a large public survey to document the state of affairs one year after the official “light” ban, they found that “88%-91% of smokers found it either ‘somewhat easy’ or ‘very easy’ to identify their usual brand of cigarettes by the banned descriptor names, Lights, Mediums or Ultra-Lights.” Sales figures for these brands in the first two quarters of 2010 were essentially unchanged, the authors report. They conclude that “the majority of smokers of brands in all categories correctly identified their brands’ pack color.”
The lesson here may well be that countries like Australia and the UK are on the right track: Plain packaging may be best. If lawmakers allow “misleading numbers, the use of colors, imagery, brand extensions, and other devices that contribute to deception” in place of words, nothing has really changed. “The findings of the present research strongly suggest that tobacco manufacturers have evaded one of the most important provisions of the FSPTCA for protecting the public health from the leading cause of preventable death and disease,” the authors conclude.
In a press release, co-author Gregory Connolly, director of the Center for Global Tobacco Control at Harvard, explained that the industry “was found guilty by a federal court in 2006 for deceptively promoting ‘light’ cigarettes as safer after countless smokers who switched to lights died prematurely, thinking they had reduced their health risks.”
Connolly G.N. & Alpert H.R. (2013). Has the tobacco industry evaded the FDA's ban on 'Light' cigarette descriptors?, Tobacco Control, PMID: 23485704
... Read more »
Connolly Gregory N, & Alpert Hillel R. (2013) Has the tobacco industry evaded the FDA's ban on 'Light' cigarette descriptors?. Tobacco control. PMID: 23485704
Avid followers of the autism research circuit must have noticed the increasing tide of studies looking at a possible role for maternal immune activation (MIA) in relation to risk of offspring autism spectrum disorder (ASD). It's a topic I've covered more than once on this blog; predominantly in relation to the work of people like Paul Patterson and his colleagues (see here), observations on things like C-reactive protein (see here) and the various ways to experimentally mimic such MIA in the mouse model of autism / schizophrenia / other for example (see here).Squeakers @ Wikipedia So it is in this post that I'm serving a double helping of the MIA model of autism as per the publication of studies from Jared Schwartzer and colleagues from the MIND Institute* (open-access) and Robert Naviaux and colleagues** (open-access).Both studies looked at the effects of artificial induction of MIA in the mouse model following poly I:C use as an immunostimulant. Thereafter the two studies went their separate ways as Schwartzer looked at the variable of mouse strain on the after-effects of MIA on offspring and Naviaux looked at the role of purinergic signaling.I'll say right now that I am neither qualified nor experienced enough to go into these papers with any great detail. So I won't; instead a brief overview of each - bearing in mind their open-access status - and some interesting factoids which have already been mentioned in the autism research peer-reviewed domain which might tie into results.The work of Schwartzer and colleagues basically "indicate[s] the need to consider how genetic predisposition may exacerbate or protect against the effects of environmental insults in the etiology of ASD". In other words, based on a mouse model looking at different strains of mouse, the specific genetic make-up of that mouse model might impact on offspring presentation after an artificial MIA event.In their case they looked at the C57BL/6J and BTBR T+tf/J inbred mouse strains and concluded that the dangermouse that is the BTBR strain combined with the poly I:C stressor seemed to "be synergistic resulting in greater behavioral impairment than from either factor alone" when compared with the C57BL/6J mouse strain. Some interesting variables are noted including elevations in cytokines like IL-6 (see here) and IL-17 (see here) in the BTBR offspring mice compared to C57BL/6J mice alongside some sex specific behavioural differences. All in all, some very interesting observations; and on that sex-specific notion, not completely at odds with other work in this area (see here).The work of Naviaux and colleagues - summarised quite well here - has definitely taken the interest of the media as per headlines such as 'New drug that may help reverse autism' or should that be 'Century old drug could beat autism'. I'm confused. The long-and-short of it is that based on the analysis of the MIA mouse model - C57BL/6J mice - there was a suggestion that "hyperpurinergia is a fundamental and treatable feature of the multisystem abnormalities in the poly(IC) mouse model of autism spectrum disorders". Treatable via "antipurinergic therapy (APT)" which in this study was via the drug suramin. The observant reader should immediately be comparing Schwartzer and Naviaux and the MIA mouse models chosen and results obtained.Anyhow, Naviaux et al continue in their observations on how MIA affected offspring mice and how the administration of suramin seemed to have some pretty wide-ranging effects on offspring mice. Alongside various behavioural effects on social and coordination issues, suramin administration was reported to show important effects such as "the preservation of cerebellar Purkinje cells", which as I discussed in a recent post, have more than a token link to cases of autism. "Suramin treatment strongly increased the expression of the nicotinic acetylcholine receptor subunit α7 (nAchRα7) in cerebral synaptosomes of MIA animals" was another potentially important finding in view of other work in this area. In all, "16 multisystem features of this model were either corrected or improved by suramin treatment".Impressive stuff I hear you say. Indeed all the more impressive given that the authors on purpose did not start suramin treatment until 6 weeks because they "wished to test the hypothesis that many of the autism-like features of the MIA model were treatable after they appear". And apparently there is more to come according to the authors, with the promise of human trials of suramin...But just before you pop down to your local doctor or pharmacist to ask for suramin (off-label), it might be worth pointing out a few things. Mice. Yep, this was a study of mice and as per the Schwartzer study, not necessarily the best and only mouse model of autism from an MIA point of view. Indeed if I needed to go back to the BTBR mouse and its overlap with autism, I might also recall some work looking at that most forgotten of autism research parameters, sulphate (sulfate) and findings related to the BTBR model (see here). Mice are not humans and suramin is to be added to a growing list of mouse findings with an autism slant (see here and here).That the US National Cancer Institute holds an entry for suramin should also give you some idea as to what uses the drug has and why bearing in mind it was injected into the study mice. Alongside its anti-parasitic effects related to things like sleeping sickness, the activity of suramin has been linked to its blocking of various growth factor binding which might yet hold some clue to other effects of the drug outside of competitive inhibiting of purinergic signalling (see here and here). As with most medicines, there are other effects to keep in mind which might also tie into results. And then there are the reported side-effects...I'm not by any means trying to belittle the Naviaux results of suramin in the MIA mouse model of autism so please do not take this post as such. I am very keen to see some replication studies done in other mouse and other anim... 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Schwartzer JJ, Careaga M, Onore CE, Rushakoff JA, Berman RF, & Ashwood P. (2013) Maternal immune activation and strain specific interactions in the development of autism-like behaviors in mice. Translational psychiatry. PMID: 23481627
Naviaux, R., Zolkipli, Z., Wang, L., Nakayama, T., Naviaux, J., Le, T., Schuchbauer, M., Rogac, M., Tang, Q., Dugan, L.... (2013) Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model. PLoS ONE, 8(3). DOI: 10.1371/journal.pone.0057380
Are you required to backboard a patient who was shot in the neck no matter how the patient is presenting? 
That is the entire question that was asked at The Paramedic’s Edge.
There are really several questions being asked.... Read more »
Stuke, L., Pons, P., Guy, J., Chapleau, W., Butler, F., & McSwain, N. (2011) Prehospital Spine Immobilization for Penetrating Trauma—Review and Recommendations From the Prehospital Trauma Life Support Executive Committee. The Journal of Trauma: Injury, Infection, and Critical Care, 71(3), 763-770. DOI: 10.1097/TA.0b013e3182255cb9
. (2001) The cause of neurologic deterioration after acute cervical spinal cord injury. Journal of Neurosurgical Anesthesiology, 13(3), 280-281. DOI: 10.1097/00008506-200107000-00022
A recent study on mice, baboons and few volunteering patients revealed that a non-steroidal anti-inflammatory drug (NSAID) called meloxicam increases significantly the number of hematopoietic stem cells entering the blood stream. The study can potentially help patients requiring a hematopoietic stem cell (HSC), most notably leukemia victims. The study was carried out by researchers, led by Louis Pelus, at Indiana University's School of MedicineFull Story... Read more »
Hoggatt, J., Mohammad, K., Singh, P., Hoggatt, A., Chitteti, B., Speth, J., Hu, P., Poteat, B., Stilger, K., Ferraro, F.... (2013) Differential stem- and progenitor-cell trafficking by prostaglandin E2. Nature. DOI: 10.1038/nature11929
This image, spreading over the Internet, suggests that frequent ejaculation lowers the risk of prostate cancer with one third. But is it also true? We checked the original research paper to find out.
... Read more »
Electroconvulsive treatment (ECT) remains one of the most effective treatments for major depressive disorder (MDD).The mechanism of action for ECT in MDD is unclear. Research targeting brain changes in ECT is an important pathway to understanding the mechanism of action for ECT.Patients with MDD show disruptions in brain functional connectivity as measures by functional magnetic resonance imaging (fMRI). The connectivity abnormalities in MDD have included changes in limbic, cortical and default networks.Abbott and colleagues recently published an analysis of resting state connectivity changes with ECT in a series of subjects with MDD. Key elements of the design of their study included:Subjects: 12 subjects with MDD with an average age of 66 years including three subjects with psychotic depressionECT parameters: Subjects received an average of 11 standard right unilateral or bitemporal treatmentsfMRI: Functional connectivity measures were assessed before and after ECT using independent component analysis techniquesStatistical analysis: Connectivity measures were compared within subjects pre and post ECT using paired t-tests. Additionally, subjects were compared to a group of non-depressed individual using two-sample t-tests The key findings from the study included:At baseline depressed subjects showed deficits in connectivity involving the posterior default mode network, the dorsomedial prefrontal cortex and the dorsolateral prefrontal cortexRemission of depression in ECT-treated subjects reversed the baseline deficits in posterior default mode network, the dorsomedial prefrontal cortex and the dorsolateral prefrontal cortexRemission with ECT was specifically linked to changes functional connectivity in the dorsomedial prefrontal cortex and the dorsolateral prefrontal cortex The authors note their findings may be useful in the eventual development of identifying MDD subjects most likely to benefit from ECT. Additionally, they note research into the mechanism of action of ECT may provide insight into less intense and more accessible treatment approaches such as transcranial magnetic stimulation therapies.This is an important study and holds promise that better targeted treatment for MDD may include non-pharmacologic brain stimulation approaches.Interested readers can learn more about the specifics of this manuscript by clicking on the link below.Photo of black-bellied whistling ducks from Venice, FL rookery from the authors files.Abbott, C., Lemke, N., Gopal, S., Thoma, R., Bustillo, J., Calhoun, V., & Turner, J. (2013). Electroconvulsive Therapy Response in Major Depressive Disorder: A Pilot Functional Network Connectivity Resting State fMRI Investigation Frontiers in Psychiatry, 4 DOI: 10.3389/fpsyt.2013.00010... Read more »
Abbott, C., Lemke, N., Gopal, S., Thoma, R., Bustillo, J., Calhoun, V., & Turner, J. (2013) Electroconvulsive Therapy Response in Major Depressive Disorder: A Pilot Functional Network Connectivity Resting State fMRI Investigation. Frontiers in Psychiatry. DOI: 10.3389/fpsyt.2013.00010
Actually the title of this post is a bit of a misnomer.I'm not really asking readers to say 'no' to sapropterin, otherwise known as tetrahydrobiopterin or BH4, for autism as if it were some kind of Zammo-esque drugs in the toilet scenario (note: for anyone born post-Grange Hill golden era or for my non-UK readers, you might want to follow this link to see what I'm going on about). But neither am I saying yes, as per my prime directive on this blog: no medical or clinical advice given or intended (resistance is futile... and all that).Mr Bronson / Admiral Ozzel @ BBC NewsThe 'no' actually refers to NO - nitric oxide - and in particular the findings reported by Richard Frye and colleagues* (including Jill James yet again) on the potential involvement of NO metabolism in the behavioural changes noted when BH4 was introduced to a small cohort of children diagnosed with autism. I think we might have seen shadows of this study presented at IMFAR 2012.OK, a quick description might be in order first. I've covered BH4 previously on this blog (see here) and some of the various roles that it plays; not least in its co-factor duties for the metabolism of some important aromatic amino acids eventually into things like neurotransmitters. Also not forgetting the potential role for BH4 in relation to managing conditions like PKU also (see here). Similarly, NO has also appeared on this blog before (see here). The Frye paper stresses the important role that BH4 has in the production of NO.A few details from the Frye paper bearing in mind it is open-access:Starting with 10 participants (aged 2-6 years) diagnosed with an autism spectrum disorder (ASD) whose parents agreed "to not change any traditional or alternative medical or behavioral therapy during the study", various measures of behaviour and language function were charted over the course of a 16-week open-trial of BH4 (Kuvan).Alongside the behavioural and psychometric measures used (which included the VABS and PLS), CSF samples were collected via lumbar puncture (not normally recommended because of its invasiveness) and blood samples used to measure for various marker compounds including BH4, the amino acids L-arginine and L-citrulline and everyone's favourite redox coverboy/covergirl, glutathione.Results: bearing in mind that this was an open-trial and that no control group or placebo arm was used, the authors report some interesting changes to various parameters. So language (receptive at least) showed a significant improvement across the group across the testing periods (baseline, 8 weeks, 16 weeks). Some of the VABS subscales also indicated some positive changes (albeit one of them, VABS personal daily living, presented with a p-value of 0.061, I assume to denote Nick Berry style 'we nearly made it').The biological stuff: well there was an increase in the reduced-to-oxidised glutathione ratio (good thing) and a decrease in levels of 3-Chlorotyrosine (3CT) (also a good thing) over the course of intervention, positive in terms of oxidative stress (redox status) and the presence of "reactive nitrogen species" respectively (see below).Findings also pointed to "a fundamental change in pterin metabolism" coinciding with BH4 supplementation. I won't pretend to know all the ins-and-outs but it all has to do with supplementation modifying the reduced-to-oxidised pterin ratio and degradation of BH4 onwards to the appearance of something called peroxynitrite which is not particularly a good thing. I think this article** (open-access) might explain it a little better than I could.The authors also reported that despite no significant change in NO metabolism markers (arginine and citrulline, and their ratio), it did appear that baseline levels of these compounds were allied to behavioural outcomes. Specifically improvements on the behavioural parameters "were related to higher baseline arginine and arginine-to-citrulline ratio".Importantly, BH4 supplementation was generally well tolerated with "only one patient discontinuing the medication because of mild adverse effects".Yes, this was a very small trial, and yes again, there was no control group, no placebo and no blinding. It is preliminary work, of that there is no doubt. I find it a little unusual that the authors also chose HPLC with electrochemical detection when it came to the measurement of important metabolites like CSF levels of BH4. A little bit '80s' if you'll forgive me, given the startlingly increased precision offered by mass spec and NMR techniques as exemplified by papers like this one. Indeed even more odd that LC-MS was used for the analysis of amino acids: why not all metabolites? It should also be noted that Dr Frye is listed as having a potential conflict of interest in this paper via receipt of funding from the producers of Kuvan for this trial; not that this should or did influence the findings in any way, shape or form.Nevertheless there are a number of interesting observations which might require some follow-up from this paper. That for example, a higher baseline level of arginine seemed to quite strongly correlate (r=0.91) with the PLS total raw score (language) as a result of BH4 supplementation is a point worth following up, particularly in these days emphasising the identification of best- and non-responders to various interventions for the autisms. The implication being that "only some of the participants were able to significantly change their NO metabolism with the dose o... Read more »
Frye RE, Delatorre R, Taylor HB, Slattery J, Melnyk S, Chowdhury N, & James SJ. (2013) Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study. Translational psychiatry. PMID: 23462988
In a recent preclinical study on rabbits, researchers from the National University of Ireland Galway showed that administering allogeneic mesenchymal stem cells (MSCs) has the potential to speed up wound recovery in diabetic patients. The study may help one day help treat wounds of diabetic patients, especially the ones presenting with diabetic foot ulcers, which often lead to debilitating leg amputations.Full Story... Read more »
O'Loughlin, A., Kulkarni, M., Creane, M., Vaughan, E., Mooney, E., Shaw, G., Murphy, M., Dockery, P., Pandit, A., & O'Brien, T. (2013) Topical Administration of Allogeneic Mesenchymal Stem Cells Seeded in a Collagen Scaffold Augments Wound Healing and Increases Angiogenesis in the Diabetic Rabbit Ulcer. Diabetes. DOI: 10.2337/db12-1822
Nanoparticles carrying a toxin found in bee venom can destroy human immunodeficiency virus (HIV) while leaving surrounding cells unharmed, researchers at Washington University School of Medicine in St. Louis have shown. The finding is an important step toward developing a vaginal gel that may prevent the spread of HIV, the virus that causes AIDS.... Read more »
Julia Evangelou Strait. (2013) Nanoparticles loaded with bee venom kill HIV. Washington University in St. Louis Newsroom. info:/
Where to start with this very long post... where to start?That autism, some cases of autism, also coincide with various comorbidities sometimes including severe gastrointestinal (GI) issues is a relatively undisputed finding these days. I'm actually getting a little bored of saying this myself on this blog and I'm sure some readers are getting bored of hearing it too.Health inequalityLymphocytic infiltration @ Wikipedia The reason why I continue to keep hammering away at this line however is because there is a substantial gap between what the peer-reviewed literature is saying about GI factors coexisting with cases of autism and the real-world experiences of many people (children and adults) with autism in terms of getting such symptoms/conditions investigated and properly treated.A health inequality if ever there was one; indeed why else would the folks over at Treating Autism feel compelled to have to produce a document on the medical comorbidities in autism spectrum disorders highlighting such an issue?An autism-specific IBD variant?With this in mind, today's post concerns the paper published by Stephen Walker and colleagues* (open-access) which suggests that when it comes to the more GI disease-related aspect of bowel disturbance linked to autism - as in inflammatory bowel disease (IBD) - it appears that such GI disease might have "distinctive features" onwards to either an autism-specific IBD variant or "a prodromal phase of typical inflammatory bowel disease". We had seen a hint that this study was coming to publication based on an abstract presented as IMFAR 2012 (see here).OK, I know that this paper takes some people into uncomfortable territory. Bowel disease - lymphoid nodular hyperplasia (LNH) and enterocolitis and autism - means 1998, Lancet and retracted paper and Lord Voldemort style 'he who must not be named'. Indeed search through the Walker paper and you will see that 'he' is definitely not named among the references, or not at least as first author on any paper. This despite the fact that other, well-renowned teams have no issue in citing the retracted paper in question (see here). I'll also point out that the authorship list on the Walker paper includes Dr Arthur Krigsman who has published work in this area** (open-access) previously. Just sayin'.Anyhow, a few details from the Walker paper bearing in mind it is open to all:The name of the game was "transcriptome profiling of gastrointestinal mucosal biopsy tissue from ASDGI children and three non-ASD control groups (Crohn's disease, ulcerative colitis, and histologically normal)" to ascertain just how similar/different gene expression was. In other words, whether the molecular signature noted in cases of autism and bowel pathology (autism-GI) matches what it seen in other well-known, and relatively well characterised bowel diseases.The focus of analysis was differentially expressed transcripts (DETs) noted in ileal and colonic tissue samples from the various groups under study. The tool of analysis was microarray followed up by quantitative real-time PCR (qPCR) to "validate representative transcripts that showed differential expression by microarray". A sort of scatter gun, see what hits we make approach, followed by a more precise confirmation of said hits. Results were organised according to PCA "to determine similarity among biological replicates". Participants were 25 children diagnosed with an autism spectrum disorder (mean age around 5 years old) who all presented with a regression in previously acquired skills and some kind of inflammatory-related condition of the bowel (ileitis, colitis, ileocolitis). Indeed all presented with LNH. Most of children with ASD were following a gluten- and casein-free (GFCF) diet. Control groups were rather smaller in number and there was a bit of an age difference between them and the autism-GI group.Results: Lots. Bearing in mind the authors were looking at tissue from two different parts of the GI tract, across quite a few groups, so this is probably not unexpected. For the autism-GI group, not everyone was included in all the analyses based on the two different regions of the gut because of quality/quantity of the RNA derived from them. For both colonic and ileal mucosa gene expression profiles, the asymptomatic control group (histologically normal) tended to cluster tightly together. Not so when it came to the symptomatic groups, where the autism-GI group in particular showed quite a bit of variability "suggestive of some potential subgroup(s)". Mmm, interesting.Various comparisons were made between the groups based on the DETs identified in the two regions. I would be here all day and night listing the results of all this, so I'm cherry-picking a few bearing in mind it was a mix of up-regulated and down-regulated gene expression. (a) Autism-GI vs. asymptomatic controls (ileal mucosa): "1409 DETs unique to ASD-GI samples". DETs tended to link back to things like inflammatory bowel disease and colitis genes and the inflammatory response. Then we get down to genes related to humoral immune response, antibody production and digestive system development and function. (b) Autism-GI vs. asymptomatic controls (colonic mucosa): "1189 DETs unique to ASD-GI samples". DETs were linked to things like again gastrointestinal disease and also "neurological disease" including schizophrenia (50 genes) (see this post) and "hyperactive disorder" (16 genes) (which I take as meaning something like ADHD).Again focusing on the autism-GI group and the DETs which overlapped both ileal and colonic tissues (178 transcripts), the top associated biological functions were in relation to inflammatory disease, endocrine system development and function, and digestive system development and function. Interesting also that 3 genes also cropped up in the pathway analysis linked to "Valine, Leucine and Isoleucine Degradation". Did someone say branched-chain amino acids and autism? A very large quote: "Taken as a whole, the picture that emerges is one in which GI symptomatic children with ASD in whom cellular infiltrate is present in the ileum and colon have a distinct molecular signature that is consistent with the larger disease categories of gastrointestinal disease, and more specifically, overlaps with Crohn's disease, ulcerative colitis, and autoimmunity".ConsistencyWhat can we surmise from these results? Well potentially quite a bit but with the very strong requirement for replication, replication, repli... Read more »
Walker, S., Fortunato, J., Gonzalez, L., & Krigsman, A. (2013) Identification of Unique Gene Expression Profile in Children with Regressive Autism Spectrum Disorder (ASD) and Ileocolitis. PLoS ONE, 8(3). DOI: 10.1371/journal.pone.0058058
This is my second guest post for Science of Eating Disorders blog. Tetyana has a lovely piece up looking at Deep Brain Stimulation as a potential therapy for intractable AN. If you haven’t seen it yet, please go check it out and join the discussion! Your body responds to food long before it reaches your [...]... Read more »
Monteleone P, Serritella C, Martiadis V, & Maj M. (2008) Deranged secretion of ghrelin and obestatin in the cephalic phase of vagal stimulation in women with anorexia nervosa. Biological psychiatry, 64(11), 1005-8. PMID: 18474361
Méquinion, M., Langlet, F., Zgheib, S., Dickson, S., Dehouck, B., Chauveau, C., & Viltart, O. (2013) Ghrelin: Central and Peripheral Implications in Anorexia Nervosa. Frontiers in Endocrinology. DOI: 10.3389/fendo.2013.00015
In January, in Japan, 25 hospitals refused to permit an ambulance to transport a man who was pronounced dead when he finally arrived at a hospital.
Were the patients already in the ED (Emergency Department) less stable than this patient?
Was this patient going to be the straw that breaks the camel’s back and result in the deaths of other patients already in the ED?
What kind of evidence do we have to justify diversion?
... Read more »
Khaleghi, M., Loh, A., Vroman, D., Chan, T., & Vilke, G. (2007) The Effects of Minimizing Ambulance Diversion Hours on Emergency Departments. The Journal of Emergency Medicine, 33(2), 155-159. DOI: 10.1016/j.jemermed.2007.02.014
Vilke, G., Castillo, E., Metz, M., Upledger Ray, L., Murrin, P., Lev, R., & Chan, T. (2004) Community trial to decrease ambulance diversion hours: The San Diego county patient destination trial. Annals of Emergency Medicine, 44(4), 295-303. DOI: 10.1016/j.annemergmed.2004.05.002
Burke, L., Joyce, N., Baker, W., Biddinger, P., Dyer, K., Friedman, F., Imperato, J., King, A., Maciejko, T., Pearlmutter, M.... (2013) The Effect of an Ambulance Diversion Ban on Emergency Department Length of Stay and Ambulance Turnaround Time. Annals of Emergency Medicine, 61(3), 303-3110. DOI: 10.1016/j.annemergmed.2012.09.009
The paper by Christina Muratore and colleagues* (open-access) including Dick Deth and Antonio Persico in the authorship line-up, is the source of today's post. Concerned with quite an important enzyme, methionine synthase (MS), and in particular MS mRNA status in post-mortem frontal cortex samples, the authors report lower levels of MS mRNA in cases of autism. I should add that quite a good overview of this paper can also be found here.Recycle @ Wikipedia OK, let's start from the beginning here. Methionine synthase (MS) is an important enzyme concerned with the regeneration of methionine from homocysteine.Homocysteine or the 'big H' has been mentioned on more than one occasion on this blog with autism in mind (see here and quite recently here). Indeed, the relationship between methionine and homocysteine intersects a number of other important cycles including those related to folate metabolism and the important methyl-giving properties of SAMe (see this post to see what I'm talking about) and further down the line, that all-important glutathione link (see this post). Oh and it's vitamin B12 dependent.Anyhow...In this study, levels of messenger RNA (mRNA) - an important part of the translation of DNA to proteins - for MS were studied in post-mortem brain samples from deceased person who were diagnosed with autism (n=10) and control, not-autism persons (n=41). Ages at death ranged from 4-30 years for the autism group and 28 weeks - 83 years for the control group.Based on the application of qRT-PCR, MS mRNA status across the lifespan of samples included suggested a "striking age-dependent decrease in mRNA levels". In other words, the older the person at time of their death, the less MS mRNA levels were detected in the frontal cortex samples. That being said, they didn't observe corresponding alterations to the level of MS protein despite this age-related change. With the autism group specifically in mind and depending on the primers used to detect specific domains of MS, mRNA levels were reduced compared to controls. The caveat being that again, levels of MS protein were not different when comparing autism vs. controls. That and the suggestion of a lack of an age-dependent decrease in MS mRNA in autism compared to that observed across control samples. Oh and the fact that addition of the pro-inflammatory cytokine TNF-α also seemed to affect levels of MS mRNA.There were also some additional findings reported which warrant further attention. So when looking at some of the main players related to that methionine cycle (including methionine, homocysteine, glutathione, etc) in frontal cortex samples (via HPLC) in autism (n=10) and control (n=8) samples, only two parameters came up different: lower, yes lower, homocysteine levels in the autism group alongside lower cystathione levels. Immediately I'm taken back to the recent paper by Jill James discussed quite recently (see here) and their cautions on the use of peripheral markers to denote what might be happening in the brain, albeit with the caveat that the Muratone group was quite a small group.There are some other details included in this paper regarding "alternative splicing of MS mRNA" but I wouldn't pretend to know all the ins-and-outs of these findings. Suffice to say that there is a suggestion that oxidative stress might have some role to play in what happens to MS both over the course of normal ageing and potentially also in cases of autism.There's not a great deal more to add about this paper. Yes, again research with a reliance on post-mortem brain samples and all the caveats that go alongside their use (cause of death, comorbidity, etc.). Again however we are presented with some tantalising data about the processes around an important enzyme which has quite a bit of research around it with autism in mind. That alongside some interesting differences found between measures in brain compared with other peripheral tissues which starts to ask some interesting questions about the application of such secondary measures.----------* Muratore CR. et al. Age-dependent decrease and alternative splicing of methionine synthase mRNA in human cerebral cortex and an accelerated decrease in autism. PLoS ONE. 2013; 8: e56927.----------Muratore, C., Hodgson, N., Trivedi, M., Abdolmaleky, H., Persico, A., Lintas, C., De La Monte, S., & Deth, R. (2013). Age-Dependent Decrease and Alternative Splicing of Methionine Synthase mRNA in Human Cerebral Cortex and an Accelerated Decrease in Autism PLoS ONE, 8 (2) DOI: 10.1371/journal.pone.0056927... Read more »
Muratore, C., Hodgson, N., Trivedi, M., Abdolmaleky, H., Persico, A., Lintas, C., De La Monte, S., & Deth, R. (2013) Age-Dependent Decrease and Alternative Splicing of Methionine Synthase mRNA in Human Cerebral Cortex and an Accelerated Decrease in Autism. PLoS ONE, 8(2). DOI: 10.1371/journal.pone.0056927
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