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  • February 13, 2014
  • 11:00 AM

Neury Thursday: Genotypic Insights on Dopamine, Modafinil, and Sleep

by Allison in Dormivigilia

A recent study in the Journal of Neuroscience uncovers genetic sensitivity to drugs that increase dopamine concentrations and their subsequent effects on sleep in humans. These studies raise important concerns for primary care practitioners when prescribing meds. ... Read more »

Holst SC, Bersagliere A, Bachmann V, Berger W, Achermann P, & Landolt HP. (2014) Dopaminergic role in regulating neurophysiological markers of sleep homeostasis in humans. The Journal of neuroscience : the official journal of the Society for Neuroscience, 34(2), 566-73. PMID: 24403155  

  • February 13, 2014
  • 07:47 AM

Weight Training for Type 2 Diabetes Prevention in Women

by William Yates, M.D. in Brain Posts

This is the fifth in a series of articles examining research findings on exercise and the brain.Type 2 diabetes and obesity can contribute to risk for early cognitive decline and dementia.Strategies that reduce risk of Type 2 diabetes may indirectly contribute to brain health.Aerobic exercise and weight loss are known to reduce Type 2 diabetes risk.However, the role of weight training on diabetes risk is less clear.A recent study has shed some light on the potential role for weight training as an independent prevention strategy.Grontved and colleagues examined self-reported exercise habits and risk of developing type 2 diabetes in the Nurses' Health Study cohort.  In this cohort nearly 100,000 nurses in the U.S. complete behavior and health information in a prospective design.Subjects reported their average weekly time spent in three types of exercise categories:Resistance exercise (weight training)Low intensity exercise activitives (stretching, yoga)Aerobic physical activities (brisk walking, jogging, running etc)At baseline subjects in this study were free of a diagnosis of diabetes. During four years of follow up, 3491 women developed type 2 diabetes. These new-onset type 2 diabetes cases were compared to control women who did not develop diabetes.The primary finding from this study is that weight training was independently correlated with lower risk of developing type 2 diabetes. Subjects participating in weight training at least 60 minutes or more per week had a 25% to 40% reduction in type 2 diabetes rates.Subjects who paired 150 minutes per week of aerobic exercise with 60 minutes per week of resistance training had a 67% reduction in risk for a new diabetes diagnosis over the follow up period.An additional finding was a reduced risk for type 2 diabetes for the low intensity exercise activity.These effect sizes for exercise and type 2 diabetes risk are pretty impressive. The authors point out there are several mechanisms potentially explaining a reduction of type 2 diabetes risk with weight training. Maintaining muscle mass promotes muscle glucose utilization, glycogen lysis and regulation of insulin signaling proteins. The authors conclude combining aerobic activity with resistance training is a promising combination for reducing type 2 diabetes risk in women. The effect of this combination appears more beneficial for overweight and obese women.Readers with more interest in this research can access the free full-text manuscript by clicking on the PMID link below.Photo of tricolor heron is from the author's files.Follow the author on Twitter WRY999.Grøntved A, Pan A, Mekary RA, Stampfer M, Willett WC, Manson JE, & Hu FB (2014). Muscle-Strengthening and Conditioning Activities and Risk of Type 2 Diabetes: A Prospective Study in Two Cohorts of US Women. PLoS medicine, 11 (1) PMID: 24453948... Read more »

  • February 13, 2014
  • 07:11 AM

Isn’t it time that fad diets went out of fashion?

by Stuart Farrimond in Dr Stu's Science Blog

Channel 4’s Supersize vs Superskinny is back on the telly. The long-running health show, which challenges two ‘extreme eaters’ to swap diets for a week, used to be my TV-watching guilty pleasure. Previous series’ were known for the infamous ‘feeding tube’ – a huge Perspex cylinder into which a week’s worth of food is emptied. … Continue reading →... Read more »

Roberts DC. (2001) Quick weight loss: sorting fad from fact. The Medical journal of Australia, 175(11-12), 637-40. PMID: 11837873  

  • February 13, 2014
  • 04:45 AM

Vitamin-mineral mix for ADHD?

by Paul Whiteley in Questioning Answers

The BBC quite recently ran with the headline: "Vitamins ‘effective in treating ADHD symptoms’" discussing an interesting paper by Julia Rucklidge and colleagues* reporting results from a controlled trial of a vitamin-mineral mix on 80 adults diagnosed with Attention-Deficit Hyperactivity Disorder (ADHD). The trial entry can be seen here and NHS Choices have also given the trial the research once-over.Food n' medicine? @ Wikipedia The paper, by someone who is not an unfamiliar name to this blog based on some previous work looking at micronutrients for stress after earthquake (see here and see here), utilised the gold-standard of experimental design (double-blind randomised placebo-controlled trial). The authorship team looked at an all-in-one supplement containing things like "vitamin D, vitamin B12, folate, magnesium, ferritin, iron, calcium, zinc and copper" and compared use of it for 8 weeks against a placebo or dummy pill (see here). Their results, based on a protocol of intention-to-treat, "showed significant between-group differences favouring active treatment on self- and observer- but not clinician-ADHD rating scales". The authors conclude that their study "provides preliminary evidence of efficacy for micronutrients in the treatment of ADHD symptoms in adults, with a reassuring safety profile". I think we might have already seen a taster of these results in a publication** from late last year (2013) too.Given my interest in Prof. Rucklidge's previous research and the potential effectiveness and ease of use of a simple vitamin-mineral supplement on anxiety and stress after a major natural disaster such as an earthquake, I was always going to be drawn to this paper. Indeed, with the current weather that we are enduring here in Blighty, I dare say that there may be some further applications from the previous Rucklidge results. That also similar findings, based on an equally rigorous methodological design, have been reported in cases of autism (see here) and the growing realisation of an overlap between autism and ADHD (see here) just adds to the interest. Dare I even mention the suggested link of food and nutrition between the two conditions too (see here)?That's not to say that there isn't more to do in this area, particularly in light of the important issue of scientific replication. As Prof. Rucklidge talked about in another review paper*** preliminary support is all well and good****, but further well-controlled investigations are still required.  There is also the question of 'why'... why did supplementation with vitamins and minerals seem to 'work' on the presentation of ADHD? I can't offer a definitive answer on this, but as per some of the additional commentary on the BBC website about this work, the suggestion "that vitamins and minerals improved brain metabolism" is a front-runner explanation. Indeed, based on the study talking about treatment response** one finds a few potential starting points based on statements like: "higher baseline ferritin and lower baseline copper and vitamin D levels were associated with a better response to treatment for some but not all outcomes". Regular readers might already know about my interest in all things vitamin D, but one does wonder whether correcting this deficiency might have some interesting physiological effects not just directly related to the brain (see here) indeed harking back to that solar intensity - ADHD link posited not so long ago (see here). Indeed, other research has also turned up vitamin D deficiency as potentially being more frequent in [pediatric] ADHD***** too. I might add that I'm under no delusion that any effect is probably going to be synergistic across the various micronutrients and a lot more complicated that just a single effect on one physiological process.Still the Rucklidge results offer some really interesting insights into both ADHD, or at least some types of ADHD (the ADHDs!) and how one might go about potentially improving quality of life for those diagnosed with the condition. That cases of adult ADHD seem to be increasing****** and as the authors noted about the issue of comorbidity - "[for] those with moderate/severe depression at baseline, there was a greater change in mood favouring active treatment over placebo" - one wonders whether a cheap and cost-effective nutritional supplement may indeed have an important role to play for at least some diagnosed with ADHD, bearing in mind my blogging caveat: no medical or clinical advice given or intended. Oh and such results might indeed be timely if the recent Nature news piece on the over-selling of medication strategies for ADHD is to be believed.And to finish, treat your vitamin supplements as pharmaceutics...Now something short and loud for your listening pleasure (and for all you lovers, er, rock lovers, out there).----------* Rucklidge JJ. et al. Vitamin-mineral treatment of attention-deficit hyperactivity disorder in adults: double-blind randomised placebo-controlled trial. Br J Psychiatr. 2014: 30 Jan.** Rucklidge JJ. et al. Moderators of treatment response in adults with ADHD treated with a vitamin-mineral supplement. Prog Neuropsychopharmacol Biol Psychiatry. 2013 Dec 26;50C:163-171.*** Rucklidge JJ. & Kaplan BJ. Broad-spectrum micronutrient formulas for the treatment of psychiatric symptoms: a systematic review. Expert Rev Neurother. 2013 Jan;13(1):49-73.**** Rucklidge JJ. et al. Can micronutrients improve neurocognitive functioning in adults with ADHD and severe mood dysregulation? A pilot study. J Altern Complement Med. 2011 Dec;17(12):1125-31.***** Goksugur SB. et al. Vitamin D Status in Children with Attention Deficit Hyperactivity Disorder. Pediatr Int. 2014 Jan 13. doi: 10.1111/ped.12286.****** Montejano L. et al. Adult ADHD: prevalence of diagnosis in a US population with employer health insurance. Curr Med Res Opin. 2011;27 Suppl 2:5-11.----------... Read more »

Julia J. Rucklidge, Chris M. Frampton, Brigette Gorman, & Anna Boggis. (2014) Vitamin-mineral treatment of attention-deficit hyperactivity disorder in adults: double-blind randomised placebo-controlled trial. British Journal of Psychiatry. info:other/10.1192/bjp.bp.113.132126

  • February 13, 2014
  • 04:16 AM

Pain on debonding and our old friend the unerupted canine

by Kevin OBrien in Kevin OBrien's Orthodontic Blog

Pain on debonding and our old friend the unerupted canine This blog is concerned with two recently published papers. They are about pain on debonding and our old friend the unerupted canine. A randomised controlled trial to assess the pain associated with debonding orthodontic fixed appliances L Manghall et al Journal of Orthodontics 2013:40: 188-196 […]The post Pain on debonding and our old friend the unerupted canine appeared first on Kevin O'Brien's Orthodontic Blog.... Read more »

  • February 13, 2014
  • 12:20 AM

A Putative Role of Organic Anion Transporting Polypeptides (OATPs) In Cell Survival of Hormone-Dependent Breast and Prostate Cancers

by JCRTO in JScholar Publishers

Transporter proteins classified into the solute carrier (SLC) superfamily are essential for import of nutrients for cell survival in organisms. In the last two decades, compelling evidence has accumulated that SLC transporters interact with clinically important anticancer agents and contribute to their pharmacokinetics, particularly the biopharmaceutical processes of absorption, elimination and distribution. Furthermore, many SLC transporters have been shown to be differentially upregulated in cancer cells, and this may represent an adaptive response to altered nutritional requirements. Thus, it is likely to utilize them as carrier for efficient drug delivery as well as pharmacological target to shut off the nutrients essential for cell growth of malignant tumors. This short review will introduce organic anion transporting polypeptides which recognize endo- and exogenous organic anionic compounds and recent findings about their upregulation in cancer cells. Besides, OATP-mediated transport of sulfate conjugates of steroid hormone may contribute to cell survival and adapted growth under hormonedepleted conditions. Better understandings of pathophysiological role of OATPs may provide key information to overcome hormone-refractory breast and prostate tumors.... Read more »

Takeo Nakanishi*, Ikumi Tamai. (2013) A Putative Role of Organic Anion Transporting Polypeptides (OATPs) In Cell Survival of Hormone-Dependent Breast and Prostate Cancers. Journal of Cancer Research and Therapeutic Oncology, 1(1), 1-6. info:other/1:101

  • February 12, 2014
  • 07:47 PM

Scientific Approaches to Enriching the Lives of Sanctuary Wolves and Wolf-Dog “Hybrids”

by Cobb & Hecht in Do You Believe In Dog?

Hi Julie and Mia, I wanted to update you on some unique but exciting research that I conducted while working toward my Ph.D. at the University of Florida’s Canine Cognition and Behavior Lab. This particular research focuses on the welfare of wolves and wolf-dog “hybrids” in private sanctuaries.The common use of the term “hybrid” is perhaps the first indication of how poorly we understand these animals. The term “hybrid” is technically inaccurate – as wolves and domestic dogs are considered taxonomically the same species, so “wolfdog” or “wolf-dog cross” is more accurate. It is estimated that there are 300,000-500,000 wolfdogs in the United States, but a solid census – as well as reliable means of identifying them – is sorely needed. Hundreds of wolfdogs are either euthanized or surrendered to sanctuaries - permanent residences for unwanted, abused and neglected wolves and wolfdogs that cannot be adopted out by shelters. Although typically filled to capacity, private sanctuaries have little funding opportunities, often relying only modest private donations and volunteers to keep the facility running and ensure that the animals’ needs adequately met. Consequently, the cost of implementing traditional enrichment items (e.g., toys, objects, scents) to keep the animals stimulated may neither address this goal or prove to be financially feasible. In many cases, the goal of enrichment for captive animals is not only to increase species-typical behaviors and activity levels, but to reduce or eliminate undesirable behaviors as well. Interaction with regular, experienced volunteers, however, is an alternative approach. Many animals arrive at sanctuaries with long histories of human interaction, having been obtained by their former owners from breeders at a young age and raised in an environment similar to our pet dogs. The ResearchWe observed three pairs of wolfdogs and one pair of wolves, all of which resided for at least six months at Big Oak Wolf Sanctuary in Green Cove Springs, Florida. For years, owners John and Debra Knight and their volunteers have prioritized daily human interaction sessions to their animals without the use of food-based reinforcers. This provided a unique opportunity for me to examine the effects of human interaction alone on the animals’ behavior. Was there any scientific merit to my observations, or did I simply just want to believe that these animals were responding positively to their new lives? This also seemed to be an ideal opportunity to investigate whether human interaction was a a legitimate enrichment strategy for a captive animal population. The FindingsFor all subjects, the levels of positive, species-typical affiliative behaviors increased, as did their overall increased activity levels. Remarkably, subjects spent significantly more time playing with the other animal in their enclosure when human interaction was provided. In this way, it appears that human interaction also enhances the behaviors between the paired animals.Three wolfdogs also exhibited pacing (widely considered a stereotypic behavior in captive animals) in initial baselines. The pacing was reduced substantially or eliminated for during a human interaction sessions.These findings, published in the most recent issue of the Journal of Applied Animal Welfare Science, collectively support the notion that human interaction is in itself enriching for well-socialized wolves and wolfdogs. Needless to say, these results did not come as a surprise to volunteers at Big Oak (or the other sanctuaries I have worked with) – who have spent countless hours closely interacting with their animals. More data is certainly needed to determine if this effect is true for other wolves and wolfdogs at other sanctuaries, as well as the long-term effects of human interaction on behavioral welfare. Although the lack of scientific studies on wolfdog behavior leaves many opportunities to scientists interested in studying them, it poses a difficulty for the general public who seek objective, reliable information on wolfdogs. So, I think it’s worth ending with some recommendations for future reading.You will likely come to find that everyone has their own opinion on wolfdogs – and that is because no two wolfdogs are the same; nor are any of our experiences with them identical. I hope you’ve enjoyed reading, and I look forward to research that continues to examine ways of further improving the welfare of these wonderful – but often misunderstood – animals. Best,Lindsay R. MehrkamPh.D. CandidateCanine Cognition & Behavior LabUniversity of Florida  PS: Big Oak Wolf Sanctuary is in need of donations. Details here: Reading:... Read more »

  • February 12, 2014
  • 06:04 PM

Antioxidants and cancer – Of men and mice (2)

by Aurelie in Coffee break Science

* This post is a companion to the previous one in which I talked about antioxidants and cancer in a more general manner. Here I will focus on one particular scientific article. A study recently published in Science Translational Medicine … Continue reading →... Read more »

Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, & Bergo MO. (2014) Antioxidants accelerate lung cancer progression in mice. Science translational medicine, 6(221). PMID: 24477002  

  • February 11, 2014
  • 11:11 PM

(DE) -Ubiquitination in The TGF-β Pathway

by JCRTO in JScholar Publishers

Aberrations in the enzymes that modify ubiquitin moieties have been observed to cause a myriad of diseases, including cancer. Therefore a better understanding of these enzymes and their substrates will lead to the identification of prospective druggable targets. Here we discuss the role of ubiquitin modifying enzymes in the canonical TGF-β pathway highlighting the ubiquitin regulating enzymes, which may potentially be targeted by small molecule inhibitors.

... Read more »

Prasanna Vasudevan Iyengar, Pieter Johan Adam Eichhorn*. (2013) (DE) -Ubiquitination in The TGF-ß Pathway. Journal of Cancer Research and Therapeutic Oncology, 1(1), 1-6. info:other/1:102

  • February 11, 2014
  • 04:03 PM

Environmental toxicants and autism reviewed

by Paul Whiteley in Questioning Answers

So: "The findings of this review suggest that the etiology of ASD [autism spectrum disorder] may involve, at least in a subset of children, complex interactions between genetic factors and certain environmental toxicants that may act synergistically or in parallel during critical periods of neurodevelopment, in a manner that increases the likelihood of developing ASD".That's the conclusion reached by a huge review paper by Dan Rossignol and colleagues* (open-access). I'm going to say no more aside from inviting readers to put half an hour aside, read and digest the significant work that has gone into this paper. Oh, and aside from including the autism research tag-team that is Rossignol and Frye (see here and see here and see here), a certain S Genuis also appears on the authorship list (see here and see here).Toodle pip.----------* Rossignol DA. et al. Environmental toxicants and autism spectrum disorders: a systematic review. Translational Psychiatry. 2014; 4: e360; doi:10.1038/tp.2014.4----------D A Rossignol, S J Genuis, & R E Frye (2014). Environmental toxicants and autism spectrum disorders: a systematic review Translational Psychiatry DOI: 10.1038/tp.2014.4... Read more »

  • February 11, 2014
  • 11:33 AM

Overhead Power Lines Don’t Increase Risk of Leukemia

by dailyfusion in The Daily Fusion

Children who live near overhead power lines in early life do not have a greater risk of developing childhood leukemia, researchers from the Childhood Cancer Research Group at the University of Oxford have found.... Read more »

  • February 11, 2014
  • 08:33 AM

Exercise and a Healthy Hippocampus in Middle Age

by William Yates, M.D. in Brain Posts

The beneficial effects of exercise on the brain has received significant research attention in children and older adults.Fewer research studies target young and middle aged adults.William Killgore and colleagues recently addressed this population in a study published in Scientific Reports.They preformed a cross-sectional correlation study of brain structure and self-reported exercise habits.Sixty one men and women between the ages of 18 and 45 years of age were recruited for the study.Subjects were recruited from the Boston metropolitan area and were excluded if they had a significant medical, neurological or psychiatric problem. Additional exclusion criteria included history of severe head injury or current use of psychotropic drugs.Subjects were questioned about the level of physical activity.  Seventy five percent of the subjects endorsed regular physical activity with an average of 2.3 sessions per week lasting an average of 45 minutes.Brain structural volumes were measured via structural magnetic resonance imaging using a 3.0 Tesla scanner. The key finding from their study was a significant positive correlation between minutes of weekly exercise and size of the regions of the right hippocampus.The hippocampus was a specific region of interest expressed before the analysis as this region has previously been associated with exercise effects. The hippocampus plays a key role in memory function.Extending their analysis outside of the original hippocampal regions, the authors noted a additional positive correlation between minutes of exercise per week and greater gray matter volume in the left posterior insula region.The authors note the insular cortex is linked to central control of cardiovascular function. Additionally, the insula is involved in modulation of emotions, appetite and motivation. This region may play a role in the beneficial effects of exercise on mood and weight regulation.This is an important research study. However, it is limited to a cross-sectional correlation design. Correlation does not equal causation. Additionally, self-report exercise levels may differ significantly from actual exercise levels producing a potential bias.Nevertheless, this study adds to what we know about exercise and the brain. The results support an important role for exercise in brain hippocampal health throughout the lifespan including middle age.Readers with more interest in the study can access the free full-text article by clicking on the PMID link in the citation below.Photo of a snowy egret near Port Aransas, TX is from the author's files.Follow the author on Twitter at WRY999.Killgore WD, Olson EA, & Weber M (2013). Physical exercise habits correlate with gray matter volume of the hippocampus in healthy adult humans. Scientific reports, 3 PMID: 24336512... Read more »

  • February 11, 2014
  • 08:24 AM

Yoghurt Is Good For Type 2 Diabetes

by Geetanjali Yadav in United Academics

Researchers found that dairy product intake is associated with a lower risk of type 2 diabetes. They not only examined the risk of diabetes in relation to consumption of total dairy products, but also distinguished between different dairy products.... Read more »

  • February 10, 2014
  • 11:53 PM

Exploring New Strategies to Monitor Autophagy and Related Cell Death Pathways Using Raman Spectroscopy

by JCRTO in JScholar Publishers

Macroautophagy, (heretofore referred to as autophagy) is thought to play a pivotal role in tumorigenesis and tumor cell survival. Autophagy is a self-degradative cellular process that recycles intracellular components such as proteins and lipids, and may also be used to clear extraneous or damaged organelles. Through this process, metabolites such as amino acids or fatty acids can be liberated for use by the cell. While basal levels of autophagy are required for cellular homeostasis, autophagy is most commonly induced in response to metabolic stressors. In this way, autophagy may be utilized by cancer cells to adapt to the tumor microenvironment, which may be hypoxic and/or nutrient low, or as an adaptive response to cytotoxic insult by chemotherapeutic agents. Conversely, excessive or dysregulated autophagy may be part of the cell death pathway continuum, having been previously implicated in both apoptosis and necrosis [1, 2]. In addition, down regulation of tumor autophagy may promote immune evasion by disrupting the antigen-processing pathway [3, 4]. Therefore, further investigation of autophagy’s role in tumor cell survival and death is warranted.... Read more »

Martin Isabelle, Vincent I Poon, Zoe V Petropoulos, Samantha J Harder, Julian J Lum*. (2013) Exploring New Strategies to Monitor Autophagy and Related Cell Death Pathways Using Raman Spectroscopy. Journal of Cancer Research and Therapeutic Oncology, 1(1), 1-5. info:other/1:103

  • February 10, 2014
  • 04:41 AM

Optimal outcome (and autism) by any other name

by Paul Whiteley in Questioning Answers

In my annual review of all things autism research covered on this blog, the accolade of paper of the year for 2013 went to [drum roll maestro]... that optimal outcome paper by Deborah Fein and colleagues* (see here and here for more information). Detailing the experiences of well-defined group of children previously diagnosed with an autism spectrum disorder (ASD) who no longer met the diagnostic criteria, the notions that (a) there may be differences in the developmental trajectories of children on the autism spectrum (a shocker, I know), and (b) at least one of those trajectories might include moving out of the autism spectrum, was nothing short of ground-breaking.The daily ship jam @ Wikipedia Whilst discussions still continue about the Fein findings and indeed, whether for example, moving outside of the diagnostic domains of an autism diagnosis actually translates as a better shot at real-world issues such as gaining meaningful (and financially rewarding) employment or living an independent life relatively free of medication or ill-health, the notion of optimal outcomes really stoked the autism research fire. The paper by Deborah Anderson and colleagues** (including Cathy Lord on the authorship list) treads in similar footsteps with their suggestion that: "some cognitively able children with ASD who participate in early intervention have very positive outcomes". The paper capitalising on the question of what variables and factors might influence positive outcomes and indeed, optimal outcome. I will also direct you to some views on this paper over at the SFARI blog too.As I do so many times on this blog, I have to thank Natasa from providing the full-text version of the Anderson paper for discussion here. Reading through the Anderson paper, I dare say we might have a contender for the paper of the year 2014 as per their study which spanned 17 years, prospectively following a group of children diagnosed with autism. Just before I go on I should point out that I think we've already seen earlier data from the Anderson group on this cohort as per this 2007 publication*** and this 2009 publication**** (see here for open-access).A few details from their latest:From a starting sample number of some 213 children initially referred for "possible autism" or with "non-ASD developmental delays" all under 37 months of age, 142 now young adults were in contact with researchers at 19 years of age including 85 youths who were diagnosed with ASD in early childhood.An important quote: "A battery of diagnostic and psychometric instruments was administered in person when children were 2, 3, 5... 9 and 19 years, free of charge". This battery included the ADI-R, the ADOS (PL-ADOS), the Mullen Scales of Early Learning (MSEL), VABS and quite a bit more. That and the fact that logs were kept noting things like medication and "educational and intervention treatments" among participants.Based on the division of participants diagnosed with autism into two groups as a function of (verbal) IQ at aged 19 (a) IQ less than 70 denoting 'Cognitively less able' (n=53) and (b) IQ equal or more than 70 ('Cognitively able' n=32), the authors reported that: "Intellectual disability at 19 was accurately predicted by age 2 about 85% of the time from IQ scores alone". Further that: "lower cognitive and adaptive abilities, along with more ASD-related symptoms at 2, predict membership in the VIQ <70 group [the 'Cognitively less able' group] 17 years later". That cognitive abilities may be predictive of future outcome is something which was also touched upon in the review paper by Magiati and colleagues*****.When it came to those members of the 'Cognitively able' group', well: "Of the 32 VIQ ≥70 youths, eight no longer retained a clinical diagnosis of ASD at age 19". These 'optimal outcomers' were described as a 'Very Positive Outcome' (VPO) group. Indeed, it also seems that alongside 'losing' their diagnosis of autism, this VPO group also seemed not to be affected by issues such as depression: "Twenty-nine percent (n=7) of the VIQ ≥70-ASD youths had scores suggesting possible depression while none of the VPO youths had elevated scores" and also did not present with clinically elevated scores in areas of irritability or hyperactivity neither.Perhaps more importantly than just scores and test results, the authors note that: "There was a strong trend toward higher rates of employment among VPO youths" added to their increased rates of independent living (away from the family home). Oh and no reports of having to take psychotropic medications. That being said the authors note that even when VPO was not 'achieved' at least some of the 'Cognitively able' group were: "doing very well in several areas" with many being "quite independent within their social contexts".There is the promise of more data to come from this group insofar as the "stability of very positive outcomes", which with all the talk about diagnostic stability (see here) is an interesting prospect. What we can take from the current data from Anderson is that similar to the Fein results and other recent results, there may be multiple trajectories in autism when looked at longitudinally, and for some at least, a diagnosis of autism is not necessarily a lifelong event. I keep going on about it, but surely this must be another string to the bow for the concept of the autisms?What else would I like to see from the Anderson data in publications to come? Well, maybe a few more details about the types of interventions that were reported over the course of children growing up might be a good place to start over above just "early treatment.. defined as at least 20 hr (once per week parent-training for 6 months)" in relation to the VPO group. At least then we'd be able to gauge what their relative contribution might or might not have been to youth outcome. Oh and I'm not just talking about educational and behavioural intervention either (see the recent paper by RogerAkins and colleagues***** which was covered in a recent post). I'd also like to know whether comorbidity played it's part in terms of outcome; y'know whether the onset of epilepsy or seizure disorder for example, affected later presentation.These and lots of other questions which I'm hoping we'll see answered (or at least discussed) in future papers from this group. Watch this space...I'll leave you with some Bob Marley and Stir it up.----------* Fein D. et al. Optimal outcome in individuals with a history of autism. ... Read more »

  • February 9, 2014
  • 11:26 PM

Multiple Functional Motifs Are Required for the Tumor Suppressor Activity of a Constitutively-Active ErbB4 Mutant

by JCRTO in JScholar Publishers

ErbB4 (HER4) is a member of the ErbB family of receptor tyrosine kinases, which includes the Epidermal Growth Factor Receptor (EGFR/ErbB1), ErbB2 (HER2/Neu), and ErbB3 (HER3). Mounting evidence indicates that ErbB4, unlike EGFR or ErbB2, functions as a tumor suppressor in many human malignancies. Previous analyses of the constitutively-dimerized and –active ErbB4 Q646C mutant indicate that ErbB4 kinase activity and phosphorylation of ErbB4 Tyr1056 are both required for the tumor suppressor activity of this mutant in human breast, prostate, and pancreatic cancer cell lines. However, the cytoplasmic region of ErbB4 possesses additional putative functional motifs, and the contributions of these functional motifs to ErbB4 tumor suppressor activity have been largely underexplored. Here we demonstrate that ErbB4 BH3 and LXXLL motifs, which are thought to mediate interactions with Bcl family proteins and steroid hormone receptors, respectively, are required for the tumor suppressor activity of the ErbB4 Q646C mutant. Furthermore, abrogation of the site of ErbB4 cleavage by gamma-secretase also disrupts the tumor suppressor activity of the ErbB4 Q646C mutant. This last result suggests that ErbB4 cleavage and subcellular trafficking of the ErbB4 cytoplasmic domain may be required for the tumor suppressor activity of the ErbB4 Q646C mutant. Indeed, here we demonstrate that mutants that disrupt ErbB4 kinase activity, ErbB4 phosphorylation at Tyr1056, or ErbB4 cleavage by gamma-secretase also disrupt ErbB4 trafficking away from the plasma membrane and to the cytoplasm. This supports a model for ErbB4 function in which ErbB4 tumor suppressor activity is dependent on ErbB4 trafficking away from the plasma membrane and to the cytoplasm, mitochondria, and/or the nucleus.... Read more »

Richard M. Gallo#, Ianthe N. Bryant#, Christopher P. Mill, Steven Kaverman, David J. Riese II*. (2013) Multiple Functional Motifs Are Required for the Tumor Suppressor Activity of a Constitutively-Active ErbB4 Mutant. Journal of Cancer Research and Therapeutic Oncology, 1(1), 1-10. info:other/1:104

  • February 9, 2014
  • 09:52 AM

Gene therapy for the heart

by EE Giorgi in CHIMERAS

My post today is about state-of-the-art gene therapy that delivers genes straight to heart, where the genes activate proteins critical in restoring cardiac tissue in people affected by heart failure. The technique, developed at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai, is undergoing clinical trial.Cardiovascular disease is the leading cause of death worldwide. Heart failure--a condition by which the heart weakens and no longer pumps blood efficiently throughout the body--is one of the manifestations of cardiovascular disease. According to the CDC, heart failure affects about 5.1 million people in the US, and about half of the people who develop heart failure die within 5 years of diagnosis. A lot is going on at the cellular level when muscles contract and release. Calcium ions work like a "switch" that allows the contraction to start. Therefore, it is of vital importance, for the correct functioning of the muscle, that the calcium ions are released at the right time and then reabsorbed at the end of the contraction. When this flow of calcium ions is impaired heart failure can occur. Calcium is normally stored in an organelle of the cell called sarcoplasmic reticulum. Muscle contraction is carried on thanks to the interaction of two proteins, actin and myosin. At rest, these two proteins are separated by a molecule called troponin. When the neurons send a stimulus to the muscle to contract, calcium is released from the sarcoplasmic reticulum into the cytoplasm where it binds to the troponin molecule, shifting the conformation of the complex, and making actin and myosin interact and initiate the contraction. Upon termination, calcium pumps regulate the uptake of calcium back into the sarcoplasmic reticulum. Troponin gets back between actin and myosin and the contraction stops.Therefore, muscle cells need to (1) store large amounts of calcium ions, and (2) make sure the calcium ions are free to flow during release and uptake. The release, uptake and intake of calcium ions in the cells of cardiac muscle is regulated by two proteins, SUMO-1 and SERCA2a. Reduced levels of SUMO-1 cause SERCA2a levels to drop, too, and low levels of both proteins have been associated to heart failure. The genes that encode these two proteins are down-regulated in patients suffering from heart failure, causing calcium ions to "linger" in the cells instead of flowing in and out as required for proper muscular contractions. Researchers from the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai have been studying this process in animal models and demonstrated that heart function can be substantially restored through a single dose of SUMO-1 and/or SERCA2a gene transfer [1]. Following these promising results in animals, a clinical trial started and, according to a press release from last November, the single dose gene therapy is already showing very promising results:"The new long-term follow-up results from their initial Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID 1) clinical trial found a one-time, high-dose injection of the AAV1/SERCA2a gene therapy results in the presence of the delivered SERCA2a gene up to 31 months in the cardiac tissue of heart failure patients. In addition, study results show clinical event rates in gene therapy patients are significantly lower three years later compared to those patients receiving placebo. Also, patients experienced no negative side effects following gene therapy delivery at three-year follow-up."The one dose gene therapy is delivered directly to the heart through a catheter, and the SERCA2a genes are inserted inside a modified adeno-associated virus (AAV). I've discussed viral vectors for gene therapy in the past (see this post and this one). What I didn't know at the time is that there's a new family of viral vectors fine tuned for cardiac gene therapy: they are called cardiotropic vectors [2]. AAV has been historically used in gene therapy because it is found in 80% of the human population and it is often asymptomatic, meaning that it is well tolerated in the population (basically, it is harmless). This makes it a safe means to deliver genes. However, it preferentially transfers genetic material to the liver, not the heart. Among the various things that can make gene therapy go wrong is of course, delivering the genes to the wrong target. In [2] authors Yang and Xiao discuss how by introducing specific mutations to the AAV genome they were able to construct an AAV mutant specific to the cardiac muscle tissue. These techniques make use of bioinformatic methods to reshuffle the AAV genes and introduce mutations according to prediction models to generate new variants that are then tested in mice models for organ specificity. This is quite exciting as we can foresee a future where we will have a vector for every possible tissue we need to target with gene therapy. [1] Tilemann L, Lee A, Ishikawa K, Aguero J, Rapti K, Santos-Gallego C, Kohlbrenner E, Fish KM, Kho C, & Hajjar RJ (2013). SUMO-1 gene transfer improves cardiac function in a large-animal model of heart failure. Science translational medicine, 5 (211) PMID: 24225946[2] Yang L, & Xiao X (2013). Creation of a cardiotropic adeno-associated virus: the story of viral directed evolution. Virology journal, 10 PMID: 23394344... Read more »

  • February 8, 2014
  • 04:14 PM

More bumetanide and autism discussion

by Paul Whiteley in Questioning Answers

For those with their ear to the autism research ground, the paper by Roman Tyzio and colleagues [1] must have sounded like a freight train coming given the volume of headlines that have been generated from this research (see here for example). Circling around the neurotransmitter, GABA (as in GABA dabba doo!), their findings based on two mouse models of autism, or rather autism and Fragile X syndrome - including the very interesting prenatal valproate (VPA) exposure model - suggested "hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations".If that all that sounds like a different language to you, it basically boiled down to GABA doing the opposite of what it is normally supposed to do i.e. primarily act as an inhibitory neurotransmitter, potentially as a result of issues with chloride levels. The fact that the 'cuddle me' hormone, oxytocin is also a suggested trigger to facilitate that excitatory-to-inhibitory transition for GABA [2] in the early days adds to the intrigue. On it's own, this finding would probably have not generated as many media headlines as it did. But when combined with the suggestion that supplementation to mother rats with the diuretic drug bumetanide just before giving birth might help make that transition for GABA to fulfil it's inhibitory destiny ("it is your destiny") in offspring the research starts to take on a slightly different perspective. The Nature news write-up of the paper provides some additional reading on this issue (see here).I've talked about bumetanide before on this blog (see here) as a consequence of the previous Lemonnier trial [3] which itself generated a fair few headlines at the time of publication. Since then, I've noted the odd mention on the drug in connection to the autism spectrum as per the case report from Grandgeorge and colleagues [4] and another paper from Lemonnier and colleagues [5] with a case of Fragile X syndrome in mind. The Grandgeorge results in particular, are worthy of inspection not least because of the focus on sensory issues and the link I make back to the very intense, intense world theory of autism [6] which has its roots in the VPA rodent model similar to the one used to test bumetanide in the Tyzio paper. I know we should be cautious of sweeping generalised models when it comes to autism (as per some chatter about the model) but lets not throw baby and bathwater out just yet. The scientific puritans out there might also be shaking their heads at the thought of case reports being mentioned here, but just remember the old adage about meeting one person with autism and all that.There is obviously a degree of step-back caution to take from the Tyzio results insofar as rats being rats not humans. I believe the accompanying editorial from Zimmerman & Connors [6] also raises a few potential issues which need to be resolved; not least how one ascertains who [humans] might be at risk for this process occurring and therefore when bumetanide might be indicated. Bear in mind too, that there are growing moves to look at reducing things like prenatal valproate exposure on the back of some regulatory statements recently being made (see here).But I have to conclude that I do find the recent Tyzio report and the previous Lemonnier trial very interesting and look forward to seeing more research on this topic including safety studies, long-term follow-up and perhaps more data on who might be more likely to benefit from this research.----------[1] Tyzio R. et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science. 2014 Feb 7;343(6171):675-9.[2] Tyzio R. et al. Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science. 2006 Dec 15;314(5806):1788-92.[3] Lemonnier E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry. 2012 Dec 11;2:e202. doi: 10.1038/tp.2012.124.[4] Grandgeorge M. et al. The effect of bumetanide treatment on the sensory behaviours of a young girl with Asperger syndrome. BMJ Case Rep. 2014 Jan 31;2014.[5] Lemonnier E. et al. Treating Fragile X syndrome with the diuretic bumetanide: a case report. Acta Paediatr. 2013 Jun;102(6):e288-90. doi: 10.1111/apa.12235.[6] Markram H. et al. The intense world syndrome--an alternative hypothesis for autism. Front Neurosci. 2007 Oct 15;1(1):77-96.-----------Tyzio R, Nardou R, Ferrari DC, Tsintsadze T, Shahrokhi A, Eftekhari S, Khalilov I, Tsintsadze V, Brouchoud C, Chazal G, Lemonnier E, Lozovaya N, Burnashev N, & Ben-Ari Y (2014). Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science (New York, N.Y.), 343 (6171), 675-9 PMID: 24503856... Read more »

Tyzio R, Nardou R, Ferrari DC, Tsintsadze T, Shahrokhi A, Eftekhari S, Khalilov I, Tsintsadze V, Brouchoud C, Chazal G.... (2014) Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science (New York, N.Y.), 343(6171), 675-9. PMID: 24503856  

  • February 7, 2014
  • 11:26 PM

Cigarette Smoking Knowledge, Attitudes, and Practices of Iranian Health Professions Students of Shiraz University of Medical Sciences, Shiraz, Iran- 2011

by JDOH in JScholar Publishers

As tobacco use is a worldwide public health problem, it is vital that all healthcare professionals be able to provide tobacco interventions for their patients. The purpose of this study was to survey Iranian health professions students to assess their tobacco knowledge, attitudes, behavior and practices
Results suggest that tobacco dependence education and cessation training should be enhanced in the health professions programs and tobacco use prevention communications should be aimed at college students, particularly males.... Read more »

Laura M. Romito*, Farideh Kouchak, Amir Soofi, Shanila Fakheri, Mehrdad Askarian. (2013) Cigarette Smoking Knowledge, Attitudes, and Practices of Iranian Health Professions Students of Shiraz University of Medical Sciences, Shiraz, Iran- 2011. Journal of Dentistry , 1(1), 1-8. info:other/

  • February 7, 2014
  • 03:02 PM


by Amy Swanston in Antisense Science

Microscopy is a technique used in the lab to look at things that you can’t see with the naked eye. There are a number of different microscopes that have been developed to do this, but today I’m going to focus on fluorescence microscopy as that’s what I have experience using! It’s also (I think) pretty interesting.

This technique is actually really simple, and is based upon the principle that when you shine high energy light onto certain substances they will absorb and emit this light at different wavelengths. If you can attach one of these fluorescent substances to whatever you’re trying to visualise, then you can look at it via a microscope.... Read more »

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