Thursday, 5 May 2016

ClinicSpeak: coming-out of the MS closet, or not

Have you ever concealed your diagnosis of MS? #ClinicSpeak #MSResearch #MSBlog

"Are you in the MS closet? MS is a very stigmatizing disease and a lot of people with MS don't want their families, friends or colleagues to know they have MS. We noted that based on the level of traffic to this site very few people registered to become members. We found out from speaking to pwMS that they didn't want to register with the site as it would possibly label them publicly as having MS. As a result of this we took down the app for joining this site as a named member."

"We have not studied the phenomenon of concealment of the diagnosis of MS systemically, but it happens all the time. The study below highlights this issue. I have many anecdotes from my own practice regarding MS concealment. Some examples; I have one patient who is in her early 60s who has had MS for ~20 years and has never told her mother who is in her late 80's. She is worried that if her mother knew that she has MS it would 'kill her'. I have another patient who has a locked mini-fridge hidden in her cupboard to hide her interferon-beta syringes from her children, who are now teenagers. She can't bring herself to telling them. I an Asian patient who has been threatened by her parents to make sure she keeps her diagnosis secret. In some Asian communities having a diagnosis of MS not only stigmatises the individual but the whole family. In the UK we know there are at least two members of parliament who have MS; one is out of the MS closet and the other is not. Some pwMS are reluctant to disclose their MS as it may affect their prospects at work; e.g. will they be less likely to be hired or will it affect their chances of being promoted? MS is a disease of young people; do you tell your new partner that you have MS on the first date or do you conceal the diagnosis and only tell them when you think the time is right? The reasons for concealing your diagnosis of MS is long and varied, and is a sad indictment of our society and how we deal with chronic disease. Any suggestion of how we can help overcome this issue are welcome? If you have the time could you please complete this short survey. Thanks."

Cook et al. An Exploratory Investigation of Social Stigma and Concealment in Patients with Multiple Sclerosis. Int J MS Care. 201618(2):78-84. doi: 10.7224/1537-2073.2015-021.

OBJECTIVE: We conducted a preliminary investigation into dimensions of stigma and their relation to disease concealment in a sample of American adults living with multiple sclerosis (MS).

METHODS: Fifty-three adults with MS in the United States completed an online survey assessing anticipated, internalized, and isolation stigma, as well as concealment.

RESULTS: Responses to all the scales were relatively low, on average, but above scale minimums (P < .001). Ratings of isolation stigma and concealment were highest. Anticipated stigma strongly predicted concealment.

CONCLUSIONS: Many adults living with MS may be concerned that they will be the target of social stigma because of their illness. These concerns are associated with disease concealment. More research is needed to investigate how MS stigma and concealment may be independent contributors to health in patients with MS.

Water to the Rescue

Zhao M, Liu MD, Pu YY, Wang D, Xie Y, Xue GC, Jiang Y, Yang QQ, Sun XJ, Cao L. Hydrogen-rich water improves neurological functional recovery in experimental autoimmune encephalomyelitis mice. J Neuroimmunol. 2016;294:6-13.

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS). The high costs, inconvenient administration, and side effects of current Food and Drug Administration (FDA)-approved drugs often lead to poor adherence to the long-term treatment of MS. Molecular hydrogen (H2) has been reported to exhibit anti-oxidant, anti-apoptotic, anti-inflammatory, anti-allergy, and anti-cancer effects. In the present study, we explored the prophylactic and therapeutic effects of hydrogen-rich water (HRW) on the progress of experimental autoimmune encephalomyelitis (EAE), the animal model for MS. We found that prophylactic administration of both 0.36mM and 0.89mM HRW was able to delay EAE onset and reduce maximum clinical scores. Moreover, 0.89mM HRW also reduced disease severity, CNS infiltration, and demyelination when administered after the onset of disease. Furthermore, HRW treatment prevented infiltration of CD4+ T lymphocytes into the CNS and inhibited Th17 cell development without affecting Th1 cell populations. Because HRW is non-toxic, inexpensive, easily administered, and can readily cross the blood-brain barrier, our experiments suggest that HRW may have great potential in the treatment of MS.

We are critisized for suggesting that pharma can and do produce drugs to treat MS that work (for some people with MS). Here is a non-pharma approach in EAE. Yep water. In this study you have hydrogen rich water, which can be made by placing a metallic magnesium stick into drinking water. However, in this case it 
was bought.

Is this going to replace DMT? 

So before you rush off of get some.

Remember in EAE  a  good DMT can eliminate disease not amelirorate it. 

Part II What was found?

Group        Incidence   Time of onset   Maximum score
Control       14 of 15     11.1 (± 0.9)        3.28 (± 0.5)   
(0.36 mM)   12 of 15     12.1 (± 0.4)⁎⁎           1.94 (± 0.16)⁎⁎ 
(0.89 mM)  12 of 15     13.7 (± 0.6)⁎⁎,           1.75 (± 0.27)⁎⁎,

In the same paradigm it would be 0/15 if you gave the animals fingolimod.

However, it was administered at 20ml/kg twice a day a so that is 0.5ml in a 25g mouse at twice a day, so that is 1ml a day. 

The current limit in the UK is 5ml/kg, so this is 4 times the limit and this result is probably a consequence of stress, as mice learn what is coming and twice a day can be stressful and the volume is so big that it will (osmotically=water balance) stress the animal meaning that animals will not get disease.

Put mice next to a building site and the incidence of EAE down, if you live next to a building site, does MS go away? 

So more good stuff from the Far East :-(, where it seems pharma are relocating their pre-clinical animal studies to.

It says "All animal experiments were performed in adherence with the National Institutes of Health Guidelines on the Use of Laboratory Animals and approved by the Second Military Medical University Committee on Animal Care". 

Did the first committee get canned for actually supporting the ethical use of animals :-(. 

Yes, I will get criticized for highlighting such issues. 
Pop Science or Plop science?:-(

T cells for secondary progressive MS

Takashi Yamamura, Ben J.E. Raveney, Shinji Oki
Study of eomesodermin-expressing CD4+ T cells sheds new light on the pathogenesis of secondary progressive multiple sclerosis

In the pathology of multiple sclerosis (MS), T helper type 1 (Th1) cells secreting interferon-γ and Th17 cells producing interleukin-17 are linked with acute inflammation in the relapsing–remitting form of MS. Supportive of this, transferring Th17 cells and Th1 cells reactive to central nervous system myelin can induce the animal model for MS – experimental autoimmune encephalomyelitis (EAE). We have recently shown that CD4+ T helper (Th) cells distinct from Th1 or Th17 cells, whose functions depend on the transcription factor eomesodermin (Eomes), are pathogenic for chronic neuroinflammation associated with the late stage of EAE. For analysis, we actually used mice whose T cells lack expression of NR4A2, a critical transcription factor for Th17 cells,which is upregulated in the peripheral blood T cells from relapsing–remitting MS. In a series of experiments, we showed that a standard form of EAE induced in C57BL/6 mice with MOG 35–55 peptide is dissected by the early stage mediated by Th17 cells expressing NR4A2 and the late stage mediated by the Eomes+ Th cells. Interestingly, the Eomes+ Th cells were found to increase in the peripheral blood and cerebrospinal fluid of patients with the secondary progressive form of MS (SPMS), but not of relapsing–remitting MS, indicating that the results in chronic EAE have translational implications for understanding human SPMS.

Raveney BJ, Oki S, Hohjoh H, Nakamura M, Sato W, Murata M, Yamamura T.Eomesodermin-expressing T-helper cells are essential for chronic neuroinflammation.Nat Commun. 2015;6:8437.

A conventional experimental autoimmune encephalomyelitis (EAE) model induced in C57BL/6 mice with MOG35–55 (control) shows persistent paralysis lasting more than several months. 

(Funny that when you have lost all the nerves in the spinal cord that you find that you can't walk:-) and it is interesting that it is OK to leave mice paralysed for several months...only in the Far East? 
So much for the 3Rs and ethical review of animal experiments!)

In a recent study , it was reported that late-onset EAE was induced in mice whose T cells lack expression of NR4A2, a transcription factor for T helper type 17 cells (NR4A2 KO). The results allowed us to conclude that EAE can be separated into the acute and late stage, characterized by acute inflammation caused by NR4A2 + T cells and the late stage, which is independent of NR4A2 expression, but dependent on eomesodermin-positive cytotoxic T helper cells.

So this study makes the idea that Eome expressing T cells drive secondary progression

Eomes is known to associate with natural killer cells and CD8+ cytotoxic T cells. Reminiscent of this, the Eomes+ Th cells were found to have cytolytic potentials that are mediated by granzyme B. We have also data suggesting that granzyme B plays a critical role in the neurodegeneration associated with chronic EAE. A variety of immunological and pharmacological interventions, including granzyme B siRNA, proved to be efficacious for treating the chronic EAE induced in NR4A2 conditional knockout mice.

Currently, there is no approved drug for SPMS. The pathogenesis of SPMS remains obscure, though the presence of germinal center in the central nervous system from SPMS autopsy cases suggests the role of autoantibody and immune-mediated pathology. Our study shows that the Eomes+ Th cells and their functional molecules are a potential target for therapy in SPMS. It is also possible that the Eomes+ Th cells might be involved in the chronic neuroinflammation associated with other inflammatory or neurodegenerative disorders. To answer the questions, further characterization of the Eomes+ Th cells and study of developmental pathways for the unique CD4+ T cells are underway 

You have been claiming there are no new ideas on blog so here is one that secondary progression is caused by T cells expressing Eomes and these are more common in MS.
However, is the blood is going to contain loads and loads of the disease causing cells? Or is it likely that they are only a very tiny fraction of the blood cells. 

So if you are seeing loads of eomes is it going to be disease-related? or maybe age-related? as people with secondary progressive MS are going to be older and eight years older in this case?

Recently we had Steinman L, Zamvil SS. (Beginning of the end of two-stage theory purporting that inflammation then degeneration explains pathogenesis of progressive multiple sclerosis. claiming its all B cells and immunology and now here is another one...

Secondary progression is caused by T cells. They
express Eomesodermin also known as T-box brain protein 2 (Tbr2) and knockout of this affects nerve development and have small brains. These eome expressing cells make granzyme which is a toxin protein made by T cells.

So MS is all autoimmunity

Only one spanner in the works is why has T cell immunotherapy such as with alemtuzumab and HSCT not halted secondary progression?  

Why was this issue not addressed in the paper..Simple question to ask?

Is it  just rubbishy EAE with very late onset? 

Will it ever be repeated?

Wednesday, 4 May 2016

ClinicSpeak: rebound post-fingolimod

Rebound post-fingolimod is not just an observation; it is food for thought! #ClinicSpeak #MSResearch #MSBlog

"The danger of stopping drugs that target trafficking of lymphocytes into the CNS (natalizumab) and/or sequester lymphocytes in lymph nodes (fingolimod and other emerging S1P modulators) are well known. The study below is just more evidence to support the phenomenon of rebound that occurs on stopping fingolimod. I find it fascinating that when you remove the brakes on the immune system and allow the so called 'auto-reactive lymphocytes' the opportunity to recirculate, they enter the CNS and cause disease activity that can be way and beyond what you would have expected, based on baseline levels of disease activity documented before patients started on these therapies. In the case of fingolimod we have even seen rebound in patients with PPMS who had to stop fingolimod after the negative phase 3 INFORMS trial results. Isn't it interesting that a DMT, such as fingolimod or for that matter natalizumab, can convert a non-relapsing phenotype into a relapsing phenotype? This is just further evidence that the MS disease classification based on clinical course is flawed."

"Why we get rebound needs to be studied further. I have proposed the concept of the field hypothesis in the past. Whatever is causing MS is allowed to proliferate and spread in the brain and spinal cord when the immune system is stopped from doing what it is supposed to do; survey the CNS. When the brakes of the immune system are then removed and immune surveillance recommences the cells find the cause of MS and set-up multi-focal inflammatory lesions, i.e. rebound. If I was a betting man I suspect the best brains to study to find the virus that causes MS are brains collected from people dying of MS on natalizumab or fingolimod who have not had immune reconstitution. The question that is often asked is why then do people on long-term fingolimod and natalizumab don't develop any problems from the proliferation of whatever is causing MS? I don't know, but may be they do we just haven't looked for it. Or we an live happily with the viral cause of MS in our brains provided we don't mount an immune response to it."

"The bottom line is if you have MS that is well controlled on fingolimod you may want consider any decision to simply stop taking it more carefully. I suspect it will be safer to transition onto another DMTs long before the action of fingolimod wears off (~3-4 weeks). The latter is really important for women on fingolimod who are planning to fall pregnant. This may be the place to use a PIRT (pulsatile immune reconstitution therapy), formerly known as induction therapies. They get the disease under control and are out of the system when the woman wants to fall pregnant. In the long-term the PIRTs will be the big disruptor in the MS DMT space. Let's hope oral cladribine gets its licence; I suspect it will be the drug of choice post-fingolimod for women wanting to fall pregnant."

Hatcher et al. Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment. JAMA Neurol. 2016 May 2. doi: 10.1001/jamaneurol.2016.0826.

IMPORTANCE: The appropriate sequencing of agents with strong immune system effects has become increasingly important. Transitions require careful balance between safety and protection against relapse. The cases presented herein highlight that rebound events after ceasing fingolimod treatment may happen even with short washout periods (4 weeks) and may perpetuate despite steroid treatment or the immediate use of fast-acting immune therapies, such as rituximab.

OBJECTIVE: To describe rebound syndrome in patients with multiple sclerosis (MS) after cessation of fingolimod treatment.

DESIGN, SETTING, AND PARTICIPANTS: Clinical and demographic data were extracted from electronic medical records from the University of California, San Francisco, Multiple Sclerosis Center from January 2014 to December 2015. Magnetic resonance images were reviewed by MS neurologists (J.S.G., E.W., B.N., and E.C.H.). Rebound syndrome was defined as new severe neurological symptoms after ceasing fingolimod treatment, with the development of multiple new or enhancing lesions exceeding baseline activity. We reviewed the PubMed database from January 2010 to December 2015 for similar cases of severe disease reactivation after ceasing fingolimod treatment using search terms fingolimod and either rebound or reactivation. Participants were included if they stopped receiving fingolimod between January 2014 and December 2015. Five patients were identified who experienced rebound after ceasing fingolimod treatment.

EXPOSURES: Each patient received treatment with oral fingolimod for various durations.

MAIN OUTCOMES AND MEASURES: Occurrence of rebound after ceasing fingolimod treatment.

RESULTS: The mean (SD) age of the 5 female patients presented in this case series was 35.2 (6.4) years. Of the 46 patients that stopped fingolimod treatment within the 2-year period, 5 (10.9%) experienced severe relapse 4 to 16 weeks after ceasing fingolimod treatment. Despite varying prior severity of relapsing-remitting course, all participants experienced unexpectedly severe clinical relapses accompanied by drastic increases in new or enhancing lesions seen on magnetic resonance imaging evidenced by a median (range) increase of 9 (0->30) new gadolinium-enhancing lesions and a median (range) of 9 (0->30) new T2 lesions. New lesion development persisted for 3 to 6 months despite treatment with corticosteroids (n = 3) and initiation of B-cell depleting therapy (n = 2). In addition, 11 patients were identified through literature review reported as having severe relapses consistent with a rebound syndrome and similar features to our 5 cases.

CONCLUSIONS AND RELEVANCE: These cases provide evidence for a fingolimod rebound syndrome at a clinically relevant frequency, highlighting the need to determine the best methods for sequencing or discontinuing MS therapies. A large prospective registry or population-based study would be helpful to confirm this rebound phenomenon and to determine contributing factors, including immune biomarkers, that increase risk for this syndrome.

CoI: multiple

Pharma wants its money back if Academic Science proves to be tosh

Will the ProfG's  be quaking in their boots as the Charcot 1 Project flopped and Merck (American version) sunk money into their black hole of clinical trials. Now Merck are saying they want their money back when academic science is not reporducible, based on this recent article which I have swiped (CLICK

If academic discoveries turn out to be wrong, one drug company wants its money back......

That’s the tough-minded proposal floated by the chief medical officer of Merck & Co as a way to fix the “reproducibility crisis,” of published scientific reports turn out to be incorrect......

Michael Rosenblatt, Merck’s executive vice president and chief medical officer, said bad results from academic labs caused pharmaceutical companies to waste millions and “threatens the entire biomedical research enterprise.”.................

It seems that Pharma have now realised that there is a load of rubbish that is published in the Science suspects much of the Pop Science that appears in the top Science rags falls into this catagegory, as we see it day in day out. 

However, the MDs take pride in the fact that our data is reproducible and have been surprised when people have come up to us to say that they can reproduce our work..Isn't this the case for all work? 

Well clearly not and there is a load of guff published, which has more holes in it than a piece of Swiss Cheese.

Pharma, like academia, have the lemming behaviour and follow the pack...often over the edge of a cliff. A few minutes thinking may save them from the drop.

Wrong results are also a problem for translational research—the kind drug companies do when they try to turn biological discoveries into actual medicines........

Yep many results won't translate to a different lab, let alone to a human and it is often easy to see why...there is no Quality control in the published work. If you spot this thenyou may save a few bob

Since companies don’t want their cash draining down ratholes.....

So why send millions courting clinicians?

 Merck are among the few organizations that have taken the trouble to double check results.

As part of the due diligance process when they acquire academic science, companies will double check results, yes it wastes money.

The key is also to have a lab doing the work that is dependable using a system that works, where there is no vested interest in the result 

I have seen pharma data from the 9-5ers where the academic lab has not checked whats happening at the weekend. These results are largely pants as they miss key information

As long as the experiment has quality control so it is believeable, I can live with the result even if it doesn't go the way I wanted it to go. A negative result can be as informative as a positive result but it takes longer to work out, why a negative result was negative.

In the case of the Canbex, as they could not go to any other lab in the world to get our stuff reproduced, they came and stood over us and watched us repeat our earlier work.

"The results aren’t pretty. Back in 2012, the biotechnology company Amgen dropped a bomb on academic science when it said it found only six of 53 “landmark” cancer papers stood up to efforts to reproduce the results of promising new research. Other studies that drug companies say can’t be replicated include one that found a cancer drug might treat Alzheimer’s and another that showed a particular gene was linked to diabetes in mice."

Maybe it is time that there was PloS Negative results:-) and those failed experiments can all be published and it would quickly show that the original research was wrong

We did some stuff on a Nature paper that did not work. It turns out that at least six labs did the same. 

However, it is not good for your career to be spending all you time saying that the stuff published by the Science semi-god is built on quick sand especially if you are an American junior researcher trying to reproduce an Amercian Demi-God who sits on all the grant panels. 

When I was a young researcher..I was once warned by one such Amercian demi-god "Don't get into doing these experiments because we are bigger than you" My response was "we had done them already and the the research idea didn't work". This was indeed what turned out to be the case, but it took a clinical trial to flop for this to be realised by the masses...but it is clear that for some people "S**t don't stick" and there are alot of teflon men and women in Science:-)

Rosenblatt says the costs of repeating wrong research are adding up. He says on average it takes “approximately two to six scientific personnel one to two years of work in an industry laboratory” to try to reproduce original experiments at an average cost of $500,000 to $2 million.

They must be paying their staff too much or the contract research organisation they are using are too expensive:-(

In his editorial, published in Science Translational Medicine, Merck’s medical chief paints a dire picture:

As the public, government, and private funders of research comprehend the extent of the problem, trust in the scientific enterprise erodes, and confidence in the ability of the scientific community to address this problem wanes. In addition, there is considerable potential for reputational damage to scientists, universities, and entire fields (for example, cancer biology, genomics, and psychology). 

Why is science wrong so often? Merck lists the usual suspects: pressure to publish and win grants, careerism, poor training of students, and journals that don’t review reports rigorously enough.

It is true that the system is geared to rewarding those publishing in the top journals in terms of grants and jobs and the pressure comes from Governments. The Research Assessment Exercises in UK put pressure on Universities (who get their money based on performance) who can then put pressure on their staff to publish, publish, publish 

Instead of trying to fix cultural problems in labs or passing new regulations, Merck thinks some punitive economic incentives are in order, specifically, a “full or partial money-back guarantee.” That is, if research that drug companies pay for turns out to be wrong, universities would have to give back the funding they got. Merck thinks this will put the pressure right where it belongs, on the scientists.

This is not an incentive surely it is a punishment, but an uninforcable punishment. I publish something and Merck goes away and does it badly and I then have to pay them...yer right.

I have a good example when pharma was doing some EAE work and they could not get it to work.  We had not been asked by them to supply protocols and had been paying another lab for advice.

They made up their own protocol based on what they thought we were doing. We swopped our material used to induce EAE, ours worked in our mice ours worked in their mice, their's didn;t work in their mice and didn't work in our mice.....If it ain't broke don't fix it,,but people will tinker...The company lab was closed down

However if companies give millions to universities to develop their patents, then do they have a point? 

However, I have been saying that clinicans destroy good ideas by bad it is not all bad science. 

But I do know that pharma do repeat stuff....maybe they should publish it and then the demi-gods would not be see to be such demi gods and then the lemmings may stop following them.

It’s unlikely that universities will jump at Merck’s offer for more accountability. That’s because they are set up to collect R&D money, not return it. If this became a requirement it would stop [university-industry] research in its tracks,” says David Winwood, a business development executive at the Pennington Biomedical Research Center in Baton Rouge, Louisiana. “Few if any public schools would have either the (financial) capacity or, I suspect, the legal authority, to enter into such an agreement.”

Buyer beware

Drug companies aren’t saints, either. Suppressing and massaging negative results from drug trials isn’t uncommon and it’s a lot more likely to harm patients than bungled academic research..... 

The other problem with Merck’s proposal to universities is it would open a kind of Pandora’s box of accountability.....companies paid for $4.6 billion in “sponsored” research at U.S. universities, hospitals, and research centers in 2014. The federal (US) government, on the other hand, spent $37.9 billion. 

So is most taxpayer-funded research wrong, too? 

Read papers... I have shown you how to read EAE papers and if they have no quality control in  hem, you can be have a fair guess that they will turn out to be mushroom food and non-reproducible. You will be abe to spot some stuff on the blog

It is funny that some people forget and can't even repeat their own published work so if that isn't based on quick sand I don't know what is.

Likewise it is a shame that companies don't think enough but the lemming mentality prevails and it is clear that some companies that have bought a load of turkies

Maybe it’s taxpayers, not Merck, who should get a check(Cheque) in the mail.

Light touch paper and stand back..remember don't kill the messenger