Tuesday, 26 May 2015

What do USA and Gabon have in Common?

Apparently, it is that they research on Great Apes

In light of ProfGs comments (below), some may wonder where Gabon is

for those who don't know where the USA is

There are no groups in the UK, who use non-human primates for MS research.

A couple of days ago someone asked in the comments about the fate of Tab008, this is also known as TGN1412 and was a disaster. 

Although, it inhibited EAE in mice, anybody with Immunology 101 should have been aware that if you give a T cell mitogenic (makes them proliferate) antibody.....you get a cytokine storm in humans causing the blood system to shut down in the extremities (This led to gangrene) or even death. 

Mice live in bacterial city and can cope with CD28 super agonists like TGN1412 and apparently so could cynomolgus monkeys, which lack CD28, the target of TGN1412..oops. 

If they had tested the effect of TGN1412 in Chimpanzees, this terrible side effect would have been known. 

Which is more disturbing the picture at the top or the bottom?

With a bit of thought maybe both can be avoided.

ClinicSpeak: Is your neurologist burnt out?

How real is burnout? #ClinicSpeak #MSResearch #MSBlog

"Last week was one of the hardest I have had working as a clinical academic, administrator, teacher and MSologist. My diary was simply sea of blue space with virtually no free time. I did manage to work from home last Wednesday on an urgent grant application; the deadline is the 3rd June and it will be touch and go if we make it. The grant is a large programme of research tackling progressive MS. Despite booking the day off work, I still had teleconferences and the endless avalanche of emails to deal with. After clocking in 18 hours at my desk I think we may have a chance of getting it in on time and in good enough shape to convince the reviewers to recommend funding it. May be I am fooling myself; the success rate with MRC grants is less than 10%."

"Thursday started with a strategy meeting on our MS sevice at Barts and finished with a very long and emotionally draining MS clinic. I had to rush home quickly to look after my daughter's needs as my wife was away at an important company meeting. I had to get up at 5am on Friday to get to the Sofitel at Heathrow airport to chair an International meeting on a policy paper to promote brain health in MSers and to treat MS holistically. We are hoping to launch the policy document at a satellite symposium at ECTRIMS this year. Overall, I think the meeting went well, but by the time I go back home I was exhausted. I am beginning to understand the meaning of burnout (see abstract below)."

"Saturday started with a quiet walk on the common with my dog, listening to a BBC Radio 4 debate on animal welfare. I was recommended by a colleague of mine and friend who recently retired from the hustle and bustle of academic life. It is well worth listening to if you have access to BBC podcasts."

At the end of May 2015, there will be a debate in a New York court about whether two chimpanzees kept in a university laboratory are being illegally detained, and should be released into a sanctuary. Laboratory research on chimpanzees is banned in most of the world, though the US, along with Gabon, still allows it. Hear a discussion on whether animals, including primates, should be used for research, and whether they are entitled to “rights” - or just “humane treatment”. The debate is chaired by Owen Bennett Jones and includes the leading philosopher opponent to the concept of animal rights Professor Carl Cohen, as well as a distinguished philosopher Colin McGinn, a lawyer and a leading animal rights advocate Steven Wise, a neurobiologist Sir Colin Blakemore and someone who grew up with Nim Chimpsky - a New York resident Jenny Lee. 

"Just when I thought I was free of thinking-MS I saw a man with a walking frame trying to walk his dog. He had a spastic paraparesis (weak in both legs) and a foot drop. He nearly fell several times getting from his car to the bench next to the bandstand on Clapham Common. He had a small dog, it looked like a Scottish Terrier, on one of those long extendable leads. The dog simply wound the lead around the bench and got it knotted around the walker. It was then I noticed the man was also very incoordinate and was having difficulty dealing with the lead and the his dog. The sad thing he was younger than me, I would have guessed in his early 40s, and based on simple deductive reasoning most likely had MS. It was clear to me that as hard as I tried the week was destined to be MS and nothing else. It was at this exact moment that I decided not to do any work over the weekend and almost got there if it wasn't for my usual insomnia that got me up at 2.30am on Monday morning. Thankfully, the remainder of yesterday was a holiday in England, the so called second May Bank holiday so I had the day off to spend with the family and friends visiting from Malaysia. I am about to leave for the airport to travel to the CMSC meeting in Indianapolis; I have two platform and several poster presentations, so it is back to my day job. I will keep you posted on what happens at the CMSC meeting."

Sigsbee & Bernat. Physician burnout: A neurologic crisis. Neurology. 2014 Dec 9;83(24):2302-6. d

The prevalence of burnout is higher in physicians than in other professions and is especially high in neurologists. Physician burnout encompasses 3 domains: (1) emotional exhaustion: the loss of interest and enthusiasm for practice; (2) depersonalization: a poor attitude with cynicism and treating patients as objects; and (3) career dissatisfaction: a diminished sense of personal accomplishment and low self-value. Burnout results in reduced work hours, relocation, depression, and suicide. Burned-out physicians harm patients because they lack empathy and make errors. Studies of motivational factors in the workplace suggest several preventive interventions: (1) Provide counseling for physicians either individually or in groups with a goal of improving adaptive skills to the stress and rapid changes in the health care environment. (2) Identify and eliminate meaningless required hassle factors such as electronic health record "clicks" or insurance mandates. (3) Redesign practice to remove pressure to see patients in limited time slots and shift to team-based care. (4) Create a culture that promotes career advancement, mentoring, and recognition of accomplishments.

Are all Cops created equal....seems not

Kolitz S, Hasson T, Towfic F, Funt JM, Bakshi S, Fowler KD, Laifenfeld D, Grinspan A, Artyomov MN, Birnberg T, Schwartz R, Komlosh A, Hayardeny L, Ladkani D, Hayden MR, Zeskind B, Grossman I. Gene expression studies of a human monocyte cell line identify dissimilarities between differently manufactured glatiramoids. Sci Rep. ;5:10191. doi: 10.1038/srep10191.

Glatiramer Acetate (GA) has provided safe and effective treatment for multiple sclerosis (MS) patients for two decades. It acts as an antigen, yet the precise mechanism of action remains to be fully elucidated, and no validated pharmacokinetic or pharmacodynamic biomarkers exist. In order to better characterize GA's biological impact, genome-wide expression studies were conducted with a human monocyte (THP-1) cell line. Consistent with previous literature, branded GA upregulated anti-inflammatory markers (e.g. IL10), and modulated multiple immune-related pathways. Despite some similarities, significant differences were observed between expression profiles induced by branded GA and Probioglat, a differently-manufactured glatiramoid purported to be a generic GA. Key results were verified using qRT-PCR. Genes (e.g. CCL5, adj. p < 4.1 × 10-5) critically involved in pro-inflammatory pathways (e.g. response to lipopolysaccharide, adj. p = 8.7 × 10-4) were significantly induced by Probioglat compared with branded GA. Key genes were also tested and confirmed at the protein level, and in primary human monocytes. These observations suggest differential biological impact by the two glatiramoids and warrant further investigation.

The Cop-wars are set to begin as the patents of glaterimer expire and the biosimilars arrive. However the cop-wars have been going for some time in the courts. Glaterimer is a random mix of cop-polymer and so is not the same from one batch to another however, the generics companies argue that their stuff is just as good the original. However this may not be the case. 

They took 4 batches of GA and compared it with a single batch of probioglat and looked at the effect on a macrophage line and they show it activates a different set of cytokines over 120 were upregulated and over 20 down regulated(remember there is 30,000 genes. So they may not e the same.

It is argued that the efficacy rate in Mexico has dropped since the generics entered the Market. However as this to highlight the conflicts this is a paper by Teva employees and they do not compare GA verses Probioglat, which surely they have done as they want to convince us that "it is rubbish throw it in the bin". 

So it can be argued it is different would more batches give the same answer and now there are others these need to be checked

One company may argue that you are not paying more just for the packaging

Genetics or ambiguous scientific evidence? The genetic roulette.

Int J Biochem Cell Biol. 2015 May 19. pii: S1357-2725(15)00131-4. doi: 10.1016/j.biocel.2015.05.010. [Epub ahead of print]
Genomic Imprinting: A Missing Piece of the Multiple Sclerosis Puzzle? Stridh P, Kular L, Jagodic M.

Evidence for parent-of-origin effects in complex diseases such as Multiple Sclerosis (MS) strongly suggests a role for epigenetic mechanisms in their pathogenesis. In this review we describe the importance of accounting for parent-of-origin when identifying new risk variants for complex diseases and discuss how genomic imprinting, one of the best-characterized epigenetic mechanisms causing parent-of-origin effects, may impact etiology of complex diseases. While the role of imprinted genes in growth and development is well established, the contribution and molecular mechanisms underlying the impact of genomic imprinting in immune functions and inflammatory diseases are still largely unknown. Here we discuss emerging roles of imprinted genes in regulation of inflammatory responses with a particular focus on the Dlk1 cluster that has been implicated in etiology of experimental MS-like disease and Type 1 Diabetes. Moreover, we speculate on the potential wider impact of imprinting via the action of imprinted microRNAs, which are abundantly present in the Dlk1 locus and predicted to fine-tune important immune functions. Finally, we reflect on how unrelated imprinted genes or imprinted genes together with non-imprinted genes can interact in so-called imprinted gene networks (IGN) and suggest that IGNs could partly explain observed parent-of-origin effects in complex diseases. Unveiling the mechanisms of parent-of-origin effects is therefore likely to teach us not only about the etiology of complex diseases but also about the unknown roles of this fascinating phenomenon underlying uneven genetic contribution from our parents.

A hypothetical model explaining the role of parent-of-origin effects in Multiple Sclerosis and other complex diseases with similar etiologies. A well-recognized contribution of environmental factors and multiple (non-imprinted) genes to the etiology of Multiple Sclerosis might further be modulated by a contribution from genes that depend on parental origin and involve classically imprinted genes as well as non-imprinted genes that form networks with other imprinted genes. Abbreviations: IGN, imprinted gene network

Over a decade of genetic studies in MS have not provided clear answers, in fact the contributing factors maybe even more complex than imagined. The first ever genetic link identified in the 1970 was the HLA (Human Leukocyte Antigen) complex. And to date over 110 non-HLA and HLA effects are known to explain only 20% of the sibling recurrence risk!!! 

It begs the question whether their are hidden heritability residues? In a recent meta-analyses, the estimated heritability has been found to be 54% using a model of inheritance consistent of one locus with moderate effect and many loci of modest effects...The search for the modest effects has begun.

In this review the researchers focus on one such modest effect - the concept of parent-of-origin effects expressed through genomic imprinting. Parent-of-origin effects is the uneven genetic contribution from parents where phenotype depends on the parental origin of the associated allele, whilst, imprinting is the way a gene is expressed only from a maternally or paternally inherited chromosome. DNA methylation (the addition of a methyl group to DNA) is a form of imprinting which modifies the DNA resulting in an alteration in gene expression without actually changing the DNA sequence. The authors use another example, DLK1, a gene which affects the development and function of B cells and moreover can affect the expression of many immune-related genes. 

A piece of mind boggling research which lends its support to this way of thinking is that maternal half-siblings of MS-affected persons have a significantly higher risk of developing MS compared to paternal half siblings. 

It is uncertain how much of this hidden heritability may have already influenced findings from published conventional genetic studies. But what is certain is that this area of research is not for the faint hearted.

Dark Matter Garden (Chelsea Flower Show 2015), also not for the amateur horticulturist!