Tuesday, 31 May 2016

CrowdSpeak: blog administrator & charity

How do you feel about supporting the Barts-MS Blog via crowd-funding? #CrowdSpeak #MSBlog #MSResearch

"As part of our efforts to find, and redefine, our mojo and evolve the blog it has become clear that we need a blog administrator to lessen our work load and to support all the planned activities going forward. This is particularly important for managing the guest posts and to handle editorial issues.We have asked you in the past about monetising the blog, i.e. advertising (GoogleAds) and sponsored posts, and you said no."



"Some of you have suggested crowd-funding to achieve this aim. Do you agree with this or not? To do this we would need to start our own charity to handle the funds; this would make it easier for us to manage and use the funds. We could potentially use the charity for other MS-related activities, for example other hard to fund initiatives."



Thanks.

Chronic pain - Wile E. Cyote style

Chronic pain disrupts the reward circuitry in multiple sclerosis

Daniela Seixas, Jacqueline Palace and Irene Tracey. European Journal of Neuroscience.
DOI: 10.1111/ejn.13272.

Abstract

Pain commonly affects multiple sclerosis (MS) patients, and has the potential to become chronic and burden an already damaged central nervous system. Imaging studies are providing insights into brain restructuring associated with chronic pain and different chronic pain conditions seem to evoke distinct plasticity patterns. Our objective was to study the structural and functional brain changes of chronic neuropathic pain of MS. Employing structural and resting functional magnetic resonance imaging we compared MS patients with chronic central pain with MS patients without pain matched with respect to age, gender, subtype and duration of MS and disability. Mean duration of pain was 7.6 years. Comparing the pain and no-pain groups, brain functional default-mode network differences were found. There was decreased coactivation in the caudate nucleus and nucleus accumbens bilaterally. Also, for the relapsing-remitting subgroup of patients, grey matter thickness changes predominated in the pain group in the mesial region of the temporal lobes, caudate, putamen, thalami and the fronto-parietal cortex; in the group without pain, changes predominated in the frontopolar and orbitofrontal cortices and in the occipital areas. A dysfunction in the reward system in chronic pain of MS was found, particularly in the brain areas involved in its motivational aspects, as such probably reflecting the maladaptive physiology of chronic pain, and possibly the signature of pain in MS, in a disease where reward impairment seems to be already one of its features.

Wile E. Cyote's antics to capture the road runner also end in pain.

Is pain one of nature's cruel jokes, a fail safe against stupidity, or is it a sign of frailty of an organic system? I'll let you decide. Our untimely departure from the blogosphere has caused our readers significant pain, and I would like to sincerely apologise for this. Having read through your comments, I see now that the blog is greater than the sum of its parts.

For those who suffer from MS related pain (whether it be caused by stiffness/spasticity or nerve pain/neuropathic pain), the findings from this commentary should interest you.

Pain control is multibillion dollar franchise, and yet our understanding of it is small. Firstly, it is important to understand that the hardwiring of you brain changes with pain over time, and this varies based on the nature of the pain. Part of this change is visible in the brain resting-state networks (RSNs); the brain regions that are working during wakefulness when the brain is resting (similar to your computer CPU which is churning away in the background even though you're not using it!). Secondly, changes here may also affect the function of the brain region concerned.

Here, the authors studied MS patients with pain for 7.6y on average. Using imaging, they studied the restructuring of the brain in MS in those with pain and without pain. They found changes between the two groups in the RSN network called the default-mode network (DMN). The DMN is usually silent during demanding tasks (for example, running), but is involved in cognition (memory, intelligence, planning for the future, and social interactions). In the DMN, in those experiencing chronic pain, there was reduced activation of brain regions (the caudate nucleus and nucleus accumbens; see Figure 1) that are linked to motivational ('wanting') aspects of behaviour, including reward, suggesting that this is impaired.

Figure 1: Default-mode network (DMN) comparison between pain and no pain groups revealed decreased activation in the caudate nucleus and nucleus accumbens bilaterally.

Therefore, even if different types of chronic pain are associated with distinct anatomical 'brain signatures', in MS at least both pain and reward seem to share the same neuroanatomical pathways. The question remains whether being on the receiving end of a reward can ameliorate pain?

Monday, 30 May 2016

Is failure of an arm of MS SMART on the cards?

Zhang T, Kingwell E, De Jong HJ, Zhu F, Zhao Y, Carruthers R, Petkau J, Gustafson P, Oger J, Tremlett H. Association between the use of selective serotonin reuptake inhibitors and multiple sclerosis disability progression. Pharmacoepidemiol Drug Saf. 2016 May 23. doi: 10.1002/pds.4031. [Epub ahead of print]

BACKGROUND:Benefits of selective serotonin reuptake inhibitors (SSRIs) in modifying the multiple sclerosis (MS) disease course have been suggested, but their ability to delay disability progression remains unknown. We examined the association between SSRI exposure and MS disability progression.
METHODS: A nested case-control study was conducted using the British Columbia (Canada) Multiple Sclerosis clinical data linked to health administrative data. The primary outcome was a sustained score of 6 (requires a cane to walk) on the Expanded Disability Status Scale (EDSS), and the secondary outcome was the onset of secondary progressive MS (SPMS, an advanced stage of MS). The cases were those who reached a study outcome and were matched with up to four randomly selected controls by sex, age, EDSS and calendar year at study entry using incidence density sampling. The associations between disability worsening and SSRI exposure were assessed with conditional logistic regression models, adjusted for confounders.
RESULTS:A total of 3920 patients were included in the main analyses, of which 272 reached sustained EDSS 6 and 187 reached SPMS. SSRI exposure was significantly different between patients who reached sustained EDSS 6 and controls [adjusted odds ratio (adjOR):1.44; 95% confidence interval (CI):1.03-2.01]. However, SSRI exposure was not significantly different between those who reached SPMS and their controls (adjOR:1.35; 95%CI:0.89-2.04).
CONCLUSION: We found no evidence to suggest that SSRI exposure was associated with a delay in MS disability accumulation or progression.


MS-SMART is a trial of three drugs verses placebo in the hope of slowing secondary progression. This study aimed to study ibudilast but a US group got their hands on it first and so it was dropped in MS-SMART, and replaced with Prozac.

The logic of how this (Fluoxitine) will work in progression has never really been presented by the SMART team.

In this analysis of a cohort of people with MS it indicates that more people with progressive MS take an SSRI (serotonin reuptake inhibitor, so it blocks break-down of serotinin, a neurotransmitter that limits depression). Is it that people take an SSRI to slow progression or is it that more people with progressive MS are depressed, which is more likely. The the data does not support the view that SSRI slows the accumulation for disability. 

Now this is observational rather than a trial and it must be said that the odds ratios of an influence are very large from 0.9 (No effect) to 2 (twice as good). MS-SMART will be the proof in the pudding, but maybe it does not bode well. 

Furthermore, non-use of an SSRI is going to be a condition of participation of MS-SMART, but as the target population is thus more likely to show depression and will be treated, it is going to make it more difficult to recruit to the MS-SMART trial. Therefore fluoxitine may not have been the best third choice.

I don't wish to put you off the trial and if you are eligible you should consider this.

(CLICK HERE http://www.ms-smart.org/)


Even if you end up in the fluoxetine arm your mental health may be be improved and by being in a trial you generally do better due to the strong placebo effect.


ClinicSpeak: intermittent fasting

Will intermittent fasting turnout to be an effective DMT? #ClinicSpeak #MSBlog #MSRsearch

"One of our readers pointed me to the paper below on the apparent health benefits of fasting. The animal study suggests fasting promotes resistance to stress and possibly increased life span. They showed that alternating fasting with feasting extended the lifespan of yeast independently of established genetic factors.  In mice, fasting and feeding,  elevated the number of stem cells and their regenerative capacity. Interestingly, in old mice, this strategy promoted the development of new neuronal cells, i.e. it may have neurorestorative capacity. They then discuss a pilot clinical trial, of three cycles of fasting and feasting which decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects. The authors claim their results support the use of cycles of fasting to promote health. The question is how do we test this strategy safely in MS?"


"As you know intermittent fasting and low-carb diets are currently very popular. These include the Atkins Diet (high-protein low-carb), Dukan Diet (French version of the Atkins diet), more recently the Banting Diet (high-fat, high-protein, low-carb) and the paleo diet (high-fat, high-protein, low-processed carb). How do they work? The theory is they starve the body of sugars and change your metabolism by switching off, or lowering, your circulating levels of insulin. Too much insulin is bad for you and drives the so called metabolic syndrome (truncal obesity, fatty liver, insulin resistance, high cholesterol, hypertension, increased cancer risk, etc.). Interestingly these diets, including intermittent starvation, cause you to become ketotic; your body starts making ketones to feed your brain. Ketones may have several benefits to health, including brain health. There is emerging evidence that they may actually reduce your appetite and ketones may be neuroprotective. There is some evidence that ketogenic diets can improve mitochondrial function (see previous post on  this). Neurologists have also known for decades that some forms of epilepsy are ketone responsive and we treat patients with specific epilepsy syndromes using ketogenic diets. The metabolic changes that underlie ketosis include the rapid mobilisation of fats from adipose tissue, which is why these diets are so effective at causing rapid weight loss. Interestingly, the so called 5:2 diet in which you fast for 2 days of the week may also work via intermittent ketosis."

"How is this all relevant to MS? There is some evidence that ketosis may be neuroprotective in an animal model of MS and the hypothesis paper below makes the case for ketogenic diets as a potential treatment of progressive MS. There are currently some dietary studies testing these hypotheses in MS. I have invited Ellen Mowry, the principal investigator on a trial testing the 5:2 diet, to do a guest post on this subject; let's hope she does it soon."

"What all this tells us is that systemic biology, i.e. metabolism, is important for the brain and may impact on MS. What we need is the evidence before making any recommendations. So if you are considering doing one of these diets please make sure you have discussed it with your neurologist, specialist nurse or family doctor."


Brandhorst et al. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015 Jul 7;22(1):86-99.

Prolonged fasting (PF) promotes stress resistance, but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.

Sunday, 29 May 2016

NewsSpeak: FDA approves daclizumab

Another milestone for daclizumab in the treatment of relapsing forms of MS. #MSBlog #MSResearch #NewsSpeak

"The FDA has approved daclizumab (Zinbryta) for the treatment of relapsing forms of MS. However, the FDA have recommended it be used second or third line, presumably because of its safety profile and need for monitoring. The US label is very different to the recommendation of the CHMP (Committee for Human use of Medicinal Products, see below), which has recommend daclizumab for relapsing forms of MS, a label not too dissimilar to that of alemtuzumab (Lemtrada) in Europe. It is interesting that the EMA's and FDA's approach to labelling of MS DMTs has flipped. In the past the FDA simply licensed DMTs for relapsing forms of MS and then allowed people with MS, neurologists and payers to sort out how the drug was used in clinical practice. In contrast, the CHMP used to license treatments with a narrow indication, for example natalizumab is licensed for rapidly evolving severe MS and fingolimod for highly-active MS in people with MS who have failed another therapy. The labelling of alemtuzumab, and now daclizumab, shows a change of heart; the FDA have become more conservative and the EMA less conservative, or dare we say liberal? Is this an interesting observation?"

"I am very upbeat about daclizumab because it has an interesting mode of action. Daclizumab is not immunosuppressive, but immunomodulatory. It binds to the so called high affinity IL2 receptor that is mainly expressed on proliferating T cells and T-reg cells; by doing this it diverts IL2 away from these cells to the intermediate IL2 receptor that is expressed on a population of cells called CD56-bright NK or natural killer cells. The expansion of the NK cells is most likely how this drug works. NK-cells are able to regulate T-cells, by killing them, and NK-cells are antiviral. Importantly, daclizumab appears to leave CD4+, CD8+ and B cell function relatively intact. For example, antibody responses to the flu vaccine in daclizumab treated MSers is fine. These latter observations are important as we need both our T and B cells to fight infection. The one downside of blunting the T-cell proliferative responses is that it takes longer to mount an adequate immunological response to common infections. This is probably why we see more infections, and more severe infections, in the daclizumab treated groups of study subjects. Please note these are common infections and not opportunistic infections. If you choose to go onto daclizumab you will need to take infections seriously and get them treated promptly."

"Where will daclizumab will be placed in the current treatment paradigm? As always I say it has a role in DMT-naive MSers, typically those with more active disease, as an alternative to natalizumab or alemtuzumab. It is also a good escalation option instead of DMF, fingolimod, natalizumab or alemtuzumab. The fact that it is not overtly immunosuppressive may make it appealing to some people. The latter is particularly important that we are now seeing an opportunistic infection signal emerging with drugs that are immunosuppressive, i.e. DMF (lymphopaenics) and fingolimod. Finally, it will likely be the switch drug of choice when transitioning MSers onto who are JCV+ on natalizumab and at risk if PML onto another DMT. The fact that daclizumab is not immunosuppressive and the NK-cells may have antiviral effects make it appealing with regard to the potential carry-over risk of PML. I am aware that a safety switch study is being proposed to support this strategy."

"The downside of daclizumab is the possibility of secondary immune mediated adverse events in particular skin hypersensitivity, hepatitis and inflammatory bowel disease, hence the requirement for daclizumab treated patients to have regular monthly blood monitoring. The secondary immune-mediated events on daclizumab may be related to its impact on T-reg cell function; depriving these cells of IL2 reduced their numbers. Despite the latter hypothesis there is no definitive link between T-reg numbers, and function, and the occurrence of adverse events."

"Please note that daclizumab is another repurposed drug. At one stage in its life-cycle it was used as an add-on drug to manage solid organ transplant rejection. Hats off the the groups at the NIH, Biogen and Abbvie for developing this drug. Based on its mode of action I think daclizumab should be tested in progressive MS; let's hope Biogen and Abbvie do a progressive trial. I have always used the mode of action of daclizumab to support my viral hypothesis. If we ever get to use the drug in the UK I have several add-on studies I would like to do to test the antiviral hypothesis; i.e. another Charcot Project study."

"For the immunologists reading this post; daclizumab also reduces the numbers of lymphoid tissue inducer cells (LTIs). LTIs play a role in the development of organized lymphoid structures and hence may affect antibody responses within the central nervous system (CNS). It will be interesting to see if the treatment effect of daclizumab may relate to its effects on this population of cells and its effect of lymphoid-like structures in the central nervous system of MSers. We need more data on the latter; at this point this is only an hypothesis."



Excerpts from the FDA press release:

“Zinbryta provides an additional choice to patients who may require a new option for treatment,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research.

The effectiveness of Zinbryta was shown in two clinical trials. One trial compared Zinbryta and Avonex in 1,841 participants who were studied for 144 weeks. Patients on Zinbryta had fewer clinical relapses than patients taking Avonex. The second trial compared Zinbryta with placebo and included 412 participants who were treated for 52 weeks. In that study, those receiving Zinbryta had fewer relapses compared to those receiving placebo.

Zinbryta should generally be used only in patients who have had an inadequate response to two or more MS drugs because Zinbryta has serious safety risks, including liver injury and immune conditions. Because of the risks, Zinbryta has a boxed warning and is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy.

The boxed warning tells prescribers that the drug can cause severe liver injury, including life-threatening and fatal events. Health care professionals should perform blood tests to monitor the patient’s liver function prior to starting Zinbryta, monthly before each dose, and for up to six months after the last dose.

The boxed warning also highlights other important risks of Zinbryta treatment including immune conditions, such as inflammation of the colon (non-infectious colitis), skin reactions, and enlargement of lymph nodes (lymphadenopathy).

Additional highlighted warnings include hypersensitivity reactions (anaphylaxis or angioedema), increased risk of infections, and symptoms of depression and/or suicidal ideation.

The most common adverse reactions reported by patients receiving Zinbryta in the clinical trial that compared it to Avonex include cold symptoms (nasopharyngitis), upper respiratory tract infection, rash, influenza, dermatitis, throat (oropharyngeal) pain, eczema, and enlargement of lymph nodes. The most common adverse reactions reported by patients receiving Zinbryta when compared to placebo are depression, rash, and increased alanine aminotransferase.

The CHMP (EMA) Summary of Opinion:


CoI: multiple

Drugs Studies from the AAN

ProfG on CLAD and why he thinks it will come back

Clinical efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis (RRMS): final results from the 120-week phase IIIb extension trial to the CLARITY study (Poster 3.028). Authors: Gavin Giovannoni, Giancarlo Comi, Stuart Cook, Peter Rieckmann, Kottil Rammohan, Per Soelberg-Sorensen, Patrick Vermersch, E. Martin and Fernando Dangond




Some of you could not see the poster of the Alemtuzumab 10 year data so listen to Mario Habek give an info burst. 





Finally we have Prof Mark Freedman talking Aubagio.

Final Outcomes of the Teriflunomide Phase 2 Extension Study: 13 Years of Efficacy and Safety Results (Poster 3.027). Authors: Marcelo Kremenchutzky, Mark S Freedman, Amit Bar-Or, Annie Purvis, Myriam Benamor, Philippe Truffinet, and Paul W O’Connor


Prof Freedman will be back soon and has done a Guest Post on his soon to be published research. I can't wait.

CoI: None

Saturday, 28 May 2016

CongressSpeak & BrainHealh: European Neurological Association Meeting 2016 - Copenhagen

I am trying not to neglect my own brain health, but it is difficult. #CongressSpeak #ENA2016 #BrainHealth #MSBlog

"I am not a happy bunny; I am about to spend another weekend working, including bank holiday Monday. Monday is a holiday in the UK; it is called a bank holiday because the banks are closed. I had to get-up at 6am this morning to pack and travel to Copenhagen (still in transit) to attend the 2nd congress of the European Neurological Association (ENA). I am a bit frustrated that I didn't have to time for a run. On balance my brain health is suffering (sleep deprivation and too little exercise) and my personal wellness (not enough downtime). Saying that the ENA is an important meeting that can't be missed. Although it is not one of the 'big MS meetings', it is a meeting that a large number of general neurologists attend and is therefore an excellent forum to get across our 'Brain Heath: Time Matters' message. I will get at least three opportunities to discuss the policy document."

"I have uploaded the ENA programme for you to browse; if you search the document you will find the term 'multiple sclerosis is used 166 times, in other words there is a lot of activity in relation to MS at this meeting."

"I am involved with 8 abstracts; I will personally be presenting two. I will also be talking on one of the satellite symposia  on 'The time to act: optimising patient care'.  My talk is essentially a call to action and is underpinned by all the important issues presented in our 'Brain Health: time matters' policy document. I will upload my slides after the symposium."

"When I get back to London next week I will summarise the meeting for you and give you my highlights (post and pod-cast)."

"If you haven't done so already I would recommend reading our policy document and if you agree with it please pledge your support and sign-up for updates; we have a large programme of activities planned for this year all aimed at getting the policies front of mind and acted upon. The latter however needs support from the MS community, which includes readers of this blog. Thank you."


CoI: multiple 

Friday, 27 May 2016

SurveySpeak: routine cognitive testing

Wow MSers want routine annual cognitive testing. #SurveySpeak #MSBlog #MSResearch

"The following are the results of yesterday's survey. It is clear that the majority of you want to be offered cognitive testing. Professor Dawn Langdon will be happy. Regular cognitive testing may bring one of the hidden problems of MS out into the open and reinforce the observation that MS is a preventable dementia. Ignoring the impact of MS on cognition could be referred to as the 'ostrich syndrome'."



Saving Animals is the name of the game, but is the Masterchef approach to Science going to be Counterproductive

Prof B presented at this weeks nights "Pint of Science " 
offering in London in the Beautiful Mind section

It was nothing to do with potatoes as shown in the advert above.
but a Journey of Discovery that started with an unlikely observation
in a Beetle (Cow pea weevil) and ended in MS.
ProfB presented the group's lastest findings in MS to a public audience. He asked for no tweets, as he revealed our way to potentially control spasticity (So what happened in Clerkenwell, stays in Clerkenwell (area in central London). There was no filming). Maybe you will get this at the research day or you will have to wait until it is published).

The UK government has been pressing for open-ness about animal research and QMUL have signed up to this.

Therefore, they want us to talk about our Animal work and the pint for Science was an opportunity to do this. The Blog is also another conduit, so sad to say we not going to be a completely animal-free zone.

However, if you want such papers discussed then pop them into comments as a suggestion of "What do you think of this?  We may then have a look and post

However, few people will go in public to talk about animal studies, in case there is a militant animal rights protester in the audience.

This harks back to the bad-old days of harassment and life-threatening actions by a few sad individuals (In the USA exchange "abortion" for "animal-rights" activists to get the gist). The UK Government have been clamping down on the activities of the militants, but it is still easier not to put your head above the parapet, as we are being watched;-)

However, as basic research is an important part of the drug discovery process for MS, it is important that people understand some of the issues relating to animals work as it relates to MS and how animals are part of the drug development process. It also  indicates why such research can be very expensive.


The National Centre for the 3Rs of Animals in Research sponsored the session and specifically asked to talk about the beasties.

 As you can see. The talk was given by an electrically powered (see the cable:-) ProfB robot look alike, just in case there were any nutters there. There weren't and the audience was lovely. 


Adoption of the principle of refining experiments to maximise knowledge creation and reduce animal suffering such that you reduce the numbers of animals used and where possible you should strive to replace the use of animals with non-sentient or in silico alternatives is at the heart of the 3Rs. 

This is part of European Legislation on Animal use. However this seems at odds in the way that Animal Science has been moving, notably from our chums in the US.
Masterchef (UK) is a cooking contest, where the people strive for Michelin-starred delivery of food. Time and time again, we see the contestants take the same ingredient and cook it “3-ways”.  e.g cook the breast, make the leg meat into a meatball, and a jus from the liver , etc. etc, This approach can create wonderful looking and tasting puds and dishes, but it appears this is the way that experimental work is going.

So to get “Nature/Science-starred” research papers there is an increasing tendency to do the experiment “3-ways”.  So you do the experiment in three/multiple different MS models or go after the same target and select multiple ways to hit the same thing. So much work that you can't argue against it. 

So costly that most people can't repeat it:-(.  

However, doing this is, is surely blowing the concept of 3Rs out of the water? 

I guess people will say that by getting the "right" answer then the extra animal use can be justified, but is it the right answer?
What happens in human is probably the critical point.  

However, such an experimental approach, leading to experimental design by numbers :-(, is becoming prescriptive and grant and paper referees are asking for the same experiment to be done using different models.  

Do you have to go with the flow or simply sink? 

Thursday, 26 May 2016

ResearchSpeak: reflections on the ABN

My pod-casting experiment from the ABN #ResearchSpeak #ABN2016 #MSBlog 

I spent most of last week at the annual Association of British Neurologists (ABN) meeting in Brighton. I chaired two debates, presented 4 posters and was co-presenter on another 2 posters. I also networked and met many young neurologists and saw some old friends.

The debates:

Debate 1: ‘Was the NICE mandate that pwMS should have annual cognitive assessments appropriate or not?’


Professor Dawn Langdon made the case for annual cognitive assessments arguing that knowing if someone with MS had cognitive impairment would affect how you manage them. Cognitive impairment is associated with poor drug adherence and difficulties with following self-management strategies. For example, pwMS who have cognitive impairment are more likely to get recurrent urinary tract infections. I suspect that this may not be causal, but simply an association; i.e. people with cognitive impairment may simply have a greater chance of associated bladder problems. She was implying that they were less likely to follow medical advice on how to manage their bladders and adhere to their treatments. She also stressed that annual cognitive assessments does not mean full neuropsychometric testing, but could simply be done using a rapid screening battery such as BICAMS (Brief Cognitive Assessment in MS). She slipped in that BICAMS takes 15 minutes to do and needs to be done by a healthcare professional. At our centre with 1200+ MSers on our books that is 400 hours of testing per year. Dr Brenner, a good friend of mine, argued against the motion. He focused on the NHS resources it would require, and consume, implement annual cognitive assessments across the UK; resources he felt would be better used on more pressing problems. He made the point that as we have no treatment for MS-related cognitive impairment it was unethical to do the tests. Do pwMS want to know they are cognitively impaired? He assumed that pwMS wouldn’t want to know about an MS complication they could do littke about. I am not sure we can make any assumptions, this is a question that needs to be answered by you people with MS.

There were too few voters to really assess which way this debate went, but the debate generated lively discussions. I concluded that this debate needs a larger audience and should include people with the disease. I wonder if NICE asked MSers their opinion before recommending annual cognitive assessments?



Debate 2: ‘To manage MS properly we need a new MS disease activity score or DAS’


As chairman I set the scene drawing on the experience of rheumatolgists who have been using the RA DAS (disease activity scale) for decades. In RA a DAS score is used as a metric to treat-2-target. The RA-DAS semi-objectively measures how active RA is and allows rheumatologists to assess how effective their DMARDs (disease-modifying antirheumatic drugs) are at controlling RA. The RA-DAS has been instrumental the paradigm of treating-2-target that underpins what we are trying to copy and promote in MS.

Dr Leonora Fisniku, from Haywards Heath, argued for a new MS-DAS. She opened the debate by reviewing the treatment landscape and made the argument that because most of the inflammatory disease activity in MS occurs below the surface, i.e. the iceberg analogy, we need to use biomarkers (MRI) to quantify MS disease activity. She made a strong theoretical argument for a MS-DAS without actually defining what components should would include in her score. Dr Waqar Rashid, from Brighton, countered her argument with a pragmatic approach telling us to shy away from perfectionism and to use what we have already and what we have been trained to do in the clinic. He argued that there is no reason to reinvent the wheel and that we should simply use what we collect routinely in clinic to make an assessment of whether the patient is active or not. In other words the clinician's acumen. He stressed the difficulties we would face with having to validate a new MS-DAS and that it is unlikely to capture all aspects of the disease. Both debaters covered the EDSS and mentioned its failings, but neither were brave enough to confine it to history. I was surprised that the vote went against the MS-DAS. I suspect what won the day was that Dr Rashid managed to exploit neurologists fears of a new unvalidated MS-DAS consuming valuable clinic time and forcing neurologists to change the way they practice clinical neurology. Neurologists don’t like change; they have been examining the nervous system the same way for over 100 years, why change the way we do things with better tools? This debate generated a lot of discussion from the floor, a lot of which focused on a prognostic scoring systems rather than the issue at hand.

I am of the opinion that a new MS-DAS is essential; we need it to get wide adoption of the treat-2-target approach of NEDA. Its development would clearly need careful consideration and multi-stakeholder input if it had any chance of being adopted. I personally would argue for it to include a PROM (patient-related outcome measure). A PROM will at least get the individual with MS engaged with the process of monitoring their own disease activity. The latter aspect may be why the RA-DAS has been so successful as a change agent in the management of RA. As I have said before patient-engagement is a no-brainer and one of the most underused therapeutic interventions we have. A MS-DAS could also be used as a driver of quality. If your neurologist refused to use the MS-DAS you may be tempted to find another neurologist who did. Now wouldn’t that be something worth talking about? I am aware from comments on this blog that some of you have done this already and moved neurologists simply to get annual MRI scans.

The posters:

Although the posters were up for most of the meeting we had just over an hour to stand by the posters to field questions from the attendees. This caused me problems although I had three posters in a row the fourth poster was in another location so I had to split my time between the two locations. It was a pity because the data in all my posters was worth talking about. The isolated poster showed that disability improvement on alemtuzumab occurs across most functional systems of the EDSS and is not simply limited to one functional system. On reflections isn’t amazing that with the more effective DMTs we can now expect disability improvement? Interestingly, we are seeing disability improvement occurring in years 3 and 4 and not just in year 1 and 2 post-alemtuzumab. This challenges the dogma about recovery mechanisms in the central nervous system and finally buries the dogma that the EDSS progression is a one-way street. Disability improvement, or the promise of disability improvement, is in itself proof of how far we have come with the treatment of MS. For the cynics and nihilists out there ‘eat your hat’.





Another ground-shifting poster was the ORATORIO study results (ocrelizumab in PPMS). This study is the first study to show a DMT slowing the rate of disability progression in PPMS. This is has to be one of the most significant things to happen in the field of MS in the last 10 years. Despite this I am concerned that NICE may not view ocrelizumab as a treatment for PPMS very favourably. NICE always assesses cost-effectiveness using an incremental cost model. For PPMS the cost-effectiveness of ocrelizumab will be compared to what is out there already, i.e. best supportive care. The latter will cause problems because ocrelizumab will presumably be licensed for RRMS where the comparison will be with existing DMTs that are high-cost. So the cost per QALY for treating RRMS will command a higher price than that for PPMS. Will this be the opportunity for NICE to demand differential pricing? Will the NHS pay less for ocrelizumab in PPMS compared to RRMS? Differential pricing of this nature is called value-based pricing whereby healthcare payers pay for what they get. In reality this is the system that airlines use for booking flights and what Uber use in the APP with surge pricing. Why shouldn't we bring value-based, or surge, pricing to the field of MS? Comments; I am particularly interested to hear Pharma’s perspective on this.




I also presented two posters on daclizumab. One was on NEDA rates in the phase 3 study and the other the effectiveness of daclizumab in study subjects in the extension study of the phase 2b, SELECT-SELECTION, study, appropriately called the SELECTED study. Please note that although I sat on the steering committee of the SELECT and SELECTION studies I had nothing to do with their names. There is a whole field dedicated to the naming of clinical trials; if you get the acronym right the study develops a life of its own. Not unexpectedly in the phase 3 ??? study the chances of NEDA were higher on daclizumab than interferon-beta. In the extension, or SELECTED, study the relapse rate appeared to continue to go down, hinting that the efficacy of daclizumab may increase with time. We actually saw the evidence for the ramping up of efficacy in the original SELECT study on MRI. Despite the daclizumab efficacy data, I spent most of my time at the daclizumab posters enthusing over daclizumab’s mode of action or MOA. Dac’s MOA challenges the core immunological dogma around the pathogenesis of MS. As I have said many times before daclizumab is not an immunosuppressive drug and it works by subtly changing the IL2 (interleukin 2) signaling pathways diverting IL2 away from activated T cells and T-reg cells towards the CD56-bright NK cell population. The expansion of this latter cell population seems to be closely linked to Dac’s efficacy. What is more the number of T-reg cells go down; this contrary to what we have been told by immunologists that MS is a immune mediated disease that is linked to abnormally regulated T-cells. An interesting discussion will be where Dac fits into the current treatment paradigm; I have thoughts on this but this will be a discussion for another time. 







My ABN highlight:

The real highlight of the meeting was Prof. Compston’s ABN gold medal acceptance speech. It was about his medical life from the time he entered medical school up until the present and his current retirement plans writing historical books. He summarised his career as a neurologist covering his research into the genetics and treatment of MS, his time as an editor of Brain (one of the premier neurology journals, or argubly the premier neurology journal) and his legacy - a large number of his trainees now head-up neurology departments across the UK. He voice broke a few times during his talk as it was clearly very emotional speech. Getting to an end of such a glittering career and reflecting on it must be very nostalgic. I personally find nostalgia one of the most powerful of emotions; it is not necessarily a sad, or happy, emotion, but it somehow brings tears to my eyes. At the end of the talk he was given a standing ovation; the first time I have experienced this at an ABN gold medal ceremony.


Some reflections after the meeting:

Many times we the community are criticised for not making progress in MS research. The problem is we tend to look at what happens from year to year. When you look at it from Professor Compston’s perspective and take a 40-year view of the field you realise that so much has changed. It is simply quite incredible what has happened to MS in the last 40 years. We now have treatments that render MSers with NEDA, i.e. putting some of them into long-term remission with the promise of a cure in a proportion of them. With ocrelizumab we now have a DMT that has been shown to be effective in PPMS. We have refined our diagnostic criteria and are better at excluding MS mimics from being inappropriately diagnosed as having MS. We know so much more about the causal pathway of MS and are beginning to use this knowledge to discuss and design MS prevention studies. Are there really some humbugs out there who still think we have made so little progress in MS research? If there are I suggest they take a 40 year helicopter view of the field rather than a very short-sighted one, or two, year view of the field. Another option who be to spend an afternoon discussing MS research with Professor Compston.

CoI: multiple

Wednesday, 25 May 2016

Clinical trials from three different perspectives


This post coincides with International Clinical Trials Day which is celebrated each year around the world, on or around the 20 May to commemorate the day that James Lind started his famous trial. This week, across the Barts Health NHS Trust site a number of activities are taking place to educate, raising awareness and celebrate some of the brilliant research going on in our area. Our contribution to this shares the experience of taking part in a clinical trial either as a person with MS, an MS researcher and a MSologist.

----------------------------------------

The patient perspective:

"Like many people when first diagnosed with MS there is the inevitable "why me" but also a realisation of helplessness due to a lack of drugs to fight, slow down or even just simply delay PPMS. The only thing I could do was to lose some weight and keep myself fit and with that in mind I started immediately and continue now weekly physiotherapy sessions, but I was keen to do more. This lead me to look at drug trials to fight back - take the war to the enemy!

Since then I have been involved in 3 drugs trials over a number of years and given that I have few if any allergies, no needle fears (important believe me, given the number of times that you need to give blood!) and time on my hands I guess I am a reasonably good trials patient. In addition to this there is also an altruistic motive, I am keen to help develop drugs for all pwMS and also ensure that that those clever people developing drugs get the opportunity to trial them. In return I get regular health check ups and access to the medical staff at the Royal London, which I consider to be a plus factor and I also am now on very good terms with most of Prof G's team! Additionally you also have the opportunity to maybe get a drug ahead of the general population and test its efficacy.

There are of course occasions when you really do not want to spend time in a hospital and some trials have been a little more demanding than I would necessarily wish, but overall I would suggest to all pwMS to sign up for a trial if it convenient for them to do so - you never know what might come of it.”

----------------------------------------

The researchers perspective:

"I am Lucia and I work in the Lab to test the trial samples - this helps to determine if the trial drug is effective. I also take care of all associated paperwork, as everything in a trial needs to be documented: this is important for the participants’ safety as well as for the reliability of the results.

The vast majority of trials nowadays are testing a new drug against the best current one and not against a placebo: this eliminates the risk of going without treatment for the duration of the trial. To enrol in a trial the clinician must give you full knowledge of the possible risks and benefits; your agreement is given by signing an ‘Informed Consent’ form. Moreover, you can withdraw from a trial at any time without the need to give a reason.

To run a trial we have to adhere to national and international regulation and must have the approval of an independent ethical committee; Lab and documentation are also regularly inspected by regulatory bodies. As much as it is sometimes exhausting and frustrating for me to keep on top of all these piles of paperwork I feel all of this is essential to ensure the trial participants’ wellbeing is the first priority. It is also important to safeguard the scientific value of the trial - in other words, there must be strong scientific data to prove the drug is indeed effective.

What from outside might look like a lot of unnecessary red tape it is in my opinion a guarantee only really improved and beneficial treatments will reach the clinic. I enjoying working in clinical trials as the results of the analysis I perform on samples could lead to better therapies being available to people with MS."

----------------------------------------

The clinicians perspective:

"As a clinician, doing a neurological diagnosis is usually challenging but always rewarding. Unfortunately the lack of effective treatments for neurological patients could be a huge problem. Therefore, it is important to seek for innovative and more effective therapies to allow patients affected with neurological disorders to improve their lives on a day-to-day basis.

Clinical research, especially clinical trials, has taught me the importance of searching for new and more effective therapies for people suffering from devastating neurological disorders such as MS. Being part of clinical research projects is one of the most rewarding activities I have experienced in my medical career. As a clinical research fellow, I am involved in developing research objectives, projects and proposals, helping in the conduction of internal and collaborative research projects, and disseminating research findings through scientific publications and conferences. The objective of our clinical research is to find more effective therapies for people with multiple sclerosis.

Apart from the technical work we have to do, I always try to have some time to chat with people with MS and hear their necessities, this is priceless as patients have little time during the normal NHS appointments to talk about more general problems that are important during the time of designing research projects. Besides, some patients are opened to share some personal gifts they have, like Sam who shared with me poetry he writes in his blog:

“I try daily to always be happy, I know life is hard but it's best to go throw it with sum1 so lively…” Sam*

This is very gratifying!

----------------------------------------

You can find out more information about the different events taking part across Barts Health here. We are also working to update our trials tab on this blog.

PoliticalSpeak: Saving Good Sams

Save the Good Samaritan; help Barts-MS mobilise support. #MSBlog #PoliticalSpeak #GoodSams

"This is a post and a call for all the MSers who are under our care at the 'Royal London Hospital'. This post is blatantly political but it is relevant to the care of people with MS who attend the MS service at the Royal London Hospital. The Pub, or Public House, is quintessential English. The pub is not just a place to drink beer, wine, cider or even something a little bit stronger, it is a unique social centre, it is usually the focus of community life in villages, towns and cities throughout the length and breadth of the country."

"In our little patch, between our research Institute and the hospital, there is pub called the 'Good Samaritan' or 'Good Sams'. We love 'Good Sams' it is the one institution that makes our patch social. Closing it down would destroy 'social capital', which is worth so much more than 'capital'. We meet in 'Good Sams' to celebrate promotions, successful PhD vivas, the passing of exams, birthdays, births, etc. We chew the cud in Good Sams and many an MS research hypothesis has been born in Good Sams. 'Good Sams' is where our medical and dental student celebrate the completion of their end of year exams. In short 'Good Sams' is the heart and soul of Barts and The London Medical and Dental School and The Royal London Hospital."

"Good Sams was established in around 1785 and rebuilt in its present form in 1937. It is one of the last remaining pubs for those who live nearby; work for and visit The Royal London Hospital. Unfortunately, it is under threat of closure. I assume this relates to money. To the current owners: if this simply about making money this is a mistake. Please think about all the fond memories and nostalgic tears that are yet to me made and shed in 'Good Sams'. Life is so much more than pounds, pence, shekels and dimes. Whenever I enter Good Sams I feel happy and content; it enriches the quality of life of all of us her work on the Whitechapel campus and for those who come to be looked after and cared for at the Royal London Hospital. Some concerned locals have set-up a petition in an attempt to save 'Good Sams'. Barts-MS supports this petition and if you agree with us we would encourage you to support the campaign. This is not only about us, but about many an MSer who has stopped for a pint after clinic."


CoI: we work around the corner from Good Sams, chances are if you come to visit us we will treat you to a pint at 'Good Sams'."


Tuesday, 24 May 2016

Tracing your lesions through the MR Myelinoscope - news from the imaging department

Longitudinal Observation of Individual Multiple Sclerosis White Matter Lesions Using Quantitative Myelin Imaging
Kitzler HH, Köhler C, Wahl H, Eisele JC, Deoni SC; Rutt BK, Ziemssen T, Linn J. 
Poster # 1282, 24th annual meeting of ISMRM

One of you recently asked the question whether lesions on MRI can disappear, and I said yes they can, and that this has to do with several factors including lesion severity (lots of axonal loss or not), subsequent lesion repair, and the tools & techniques used to detect them (or not).  Now I just returned from Singapore after attending the International Society for Magnetic Resonance in Medicine (ISMRM), where I saw this work using an MRI technique optimised for detecting the myelin content in lesions (let's call it an "MR Myelinoscope").  It nicely shows that whilst lesions may look the same on our standard workhorse MRI, they may be quite in different "states" when looking through the MR Myelinoscope.

The panel above shows that over 12 months lesions on FLAIR (standard workhorse technique, top row) don't change very much, however the Myelinoscope (bottom row) shows dynamic change over time (see arrows): A lesion hardly visible at month 0 is largest at month 3 (demyelination), and then smaller (suggesting remyelination).



Panel showing 4 different lesion "states" (differences in myelination status over 12 months) using the MR Myelinoscope whilst standard FLAIR doesn't change.

Nice work indicating how crude our current standard MRI techniques are in monitoring the severity and dynamics of tissue changes within MS lesions.

Whilst the MR Myelinoscope technique is quite complex to implement, and therefore not available at many centres, it could be useful in trials of potentially remyelinating drugs where only a limited number of centres would be involved.

CoI: none

We're redefining our Mojo

Anyone for a Mojito cocktail? That was one recommendation. #MSBlog #MSResearch #Mojo



We’re back! Following one week of painful – albeit self-inflicted – soul searching we’ve now discussed the positioning of the blog. Thank you for all the feedback (positive and not-so positive) whilst the blog was suspended. We reviewed ALL of your comments, and felt very much encouraged to resume blogging. There are things we can improve, and below are some of our action points moving forward:

  • Posting Schedule: We drafted a posting schedule that will hopefully free up some time for the contributors. This is obviously not set in stone and won't stop us responding to current events, TV programmes, News articles in relation to MS as they come out.
  • New faces and guest posts: We will continue to invite researchers and clinicians to write guest posts, however will also offer the opportunity to people with MS, their family members, friends, and people involved in charity work. Please get in touch if you would like to contribute, however note this is a platform for MS research not for advertising.
  • Barts MS Charity: We will set up the ‘BartsMS Charity’ to support our research, maintaining the blog, and off-label prescribing initiatives, particularly in resource-poor health care environments. More information about this coming soon.
  • Better social media coverage: 
  • New ideas
    • Legibility: The blog home page will now show 5 posts at a time. What do you think? 
    • We plan to update the “Trials and Studies” section of the blog. 
    • We’re planning to extract all the clinical advice and information from previous and future posts to create an information resource that is easily searchable. 
    • Prof G promised to be more diligent with producing the case studies and hopes to get some back-room help. 
    • What about podcasting and vlogging? Do you think we need to go multimedia? 
As always, we are interested to hear your thoughts on the above and beyond. It seems as if a lot of you don't like the use of anonymous comments. It would be nice to know if many of you are repeat commentators; who knows you may take on Dr Dre at his/her own game! Can we suggest you take on a pseudonym if you don't want to let the world know who you are?

Photo credit: Dolly Clew

Tuesday, 17 May 2016

ThinkSpeak: Lost our Mojo-2?

Getting our mojo back: Barts-MS Blog #ThinkSpeak #MSResearch #MSBlog #LostMojo



Dear Readers

Thank you for your patience. Some of you are alarmed at the suspension and subsequent closure of the blog. Some of you may have read my post on 'Have we lost our Mojo' and the comments and discussion it generated. As a result of this we have decided to close the blog and reassess how it needs to evolve. Is it still needed? If yes, in what format. How to we control its content? We acknowledge that it is widely read and that some of our readers value our commentaries (thank you). However, with this comes extra responsibilities, which we need to reflect on. 

The following was our original mission statement:

"The aim of the Blog is for the Barts-MS to update you on the latest research in MS with an emphasis on the research we are involved in. A major reason for maintain the Blog is to thank the funders of our research. Funders encourage us to engage with the general public, people with MS and their families and other people with an interest in MS. We believe you have the right to know what we are spending your research money on! The purpose of our work is to improve our knowledge and understanding of MS with the goal of improving the lives of people living with this disease.

For us as a group of MS researchers the blog allows us to reflect on our work, assess its potential impact and plan for the future. For some of our research projects we need your help; this may be as a volunteer for a particular study or simply helping us to spread the word. A major benefit of the blog is that it encourages reflection and team work and provides us with an opportunity to celebrate our successes."

We will decide over the next few weeks if this mission statement is still relevant, have we stuck to our mission, have we strayed too far from it and whether or not it needs to be changed. While we considering all these issues you are welcome to comment.

Friday, 13 May 2016

Brain Health Slides for Pros

Here is a slide desk for Health Care Professionals

CLICK HERE


Under starting orders, Rebound of Fingolimod Withdrawal

ProfG recently posted on rebound disease activity after fingolimod 
based on the this paper

Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment. Hatcher SE, Waubant E, Nourbakhsh B, Crabtree-Hartman E, Graves JS. JAMA Neurol. 2016 May 2. doi: 10.1001/jamaneurol.2016.0826. [Epub ahead of print]

So hot on its heels comes this one

Davion JB, Cambron M, Duhin E, Chouraki A, Lacour A, Labauge P, Carra C, Ayrignac X, Vermersch P. Two cases of relapses in primary progressive multiple sclerosis after fingolimod withdrawal.J Neurol. 2016 May 9. [Epub ahead of print]

We report two cases of primary progressive multiple sclerosis (PPMS) included in the INFORMS cohort, experiencing a relapse related to a single MRI gadolinium-enhancing lesion 3 months after fingolimod withdrawal. These two patients share similarities with relapsing-remitting multiple sclerosis cases described in the same situation, suggesting that the initiating process of the active demyelinating plaques is also present in PPMS, even without relapses, but may be triggered as fingolimod is withdrawn. Although the results of the INFORMS study suggest that fingolimod may not slow down the progression, some PPMS patients might still benefit from a disease-modifying treatment.

Rebound disease activity happens with natalizumab. Here immune cells are trapped in the blood and once natalizumab treatment is stopped they are all lined up ready to go back in the brain. In contrast a depleting treatment may be associated with reactivation of disease but as cells come back slowly then reactivation does not come back with a bang. Fingolimod works effectively like natalizumab and trapps cells in the lymph glands. Stop treatment and they are ready to flow back into the blood and then the brain. So it would be surprising if rebound didn't occur.

In this study rebound relapse occurred in people with progressive MS. This occurred following the end of the trial. Will this figure be higher. About 15% of people with PPMS have active lesions, which should be suppressed by fingolimod so they rebound when fingolimod is stopped.

 I think Novartis want to tell us what the real story is.

Thursday, 12 May 2016

You are what you eat. Diet and Disease

Libbey JE, Doty DJ, Sim JT, Cusick MF, Round JL, Fujinami RS. The effects of diet on the severity of central nervous system disease: One part of lab-to-lab variability. Nutrition. 2016 Jan 21. pii: S0899-9007(16)00039-3. 

OBJECTIVE:Many things can impact the reproducibility of results from laboratory to laboratory. For example, food from various sources can vary markedly in composition. We examined the effects of two different food sources, the Teklad Global Soy Protein-Free Extruded Rodent Diet (irradiated diet) and the Teklad Sterilizable Rodent Diet (autoclaved diet), on central nervous system disease.
METHODS: Three preclinical models for human disease: Two different experimental autoimmune encephalomyelitis models (multiple sclerosis) and the Theiler's murine encephalomyelitis virus-induced seizure model (epilepsy), were examined for the effects of two different food sources on disease.
RESULTS: We found that mice fed the irradiated diet had more severe clinical disease and enhanced seizures compared with animals provided the autoclaved diet in both experimental autoimmune encephalomyelitis models examined and in the Theiler's murine encephalomyelitis virus-induced seizure model, respectively.
CONCLUSIONS:Therefore, just altering the source of food (lab chow) can have marked effects on disease severity and outcome.


In the methods of a paper you write your methods such as "animals were fed on RM-1E diet ad libitum" etc. So animals were free access to given Rat Mouse One Expanded Diet. This study shows that diet can influence disease severity. I am sure many of you will say that diet can influence MS activity. Is it the content or is it that one batch  just tastes bad

A guy in the States once reported that if you feed pregant cats with irradiated diet you can get demyelination. Bizarre

Gut bacteria getting astrocytes to save nerves

Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L, Chao CC, Patel B, Yan R, Blain M, Alvarez JI, Kébir H, Anandasabapathy N, Izquierdo G, Jung S, Obholzer N, Pochet N, Clish CB, Prinz M, Prat A, Antel J, Quintana FJ. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med. 2016. doi: 10.1038/nm.4106. [Epub ahead of print]

Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-b are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl- 3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation. 
We tend to comment on posts done in Nature and Science Journals but where to start on this one. 

The simple answer is I'm not sure I want to spent the time, getting my head round the science. Living on a few hours sleep for the madcap pleasure of Her Majesties Government, whilst doing a night shift, is not conducive to thinking. So my advice is scout round the internet to see what others are writing about this one. I am not going to do it Justice

This study contains a substantial amount of work and says that astrocytes in the spinal cords of animals with EAE are different from astrocytes in health. Yep I can buy that, you just have to look. Wonder what would be found in astrocytes with chronic disease compared to disease of a few days

They look at the genes that are different between the two and see a response that looks like the cell has been stimulated by a cytokine called and interferon. These are made to limit viral infections but in doing so also stop the proliferative capacity of the host cell infected. They then link this effect to the aryl hydrocarbon receptor (click here to read about it). 

They then do a load of EAE experiments in knockout mice and report that AHR knockout mice do worse and being immunologists they they link every thing to influences of the immune response, cytokines and their transcription factors (factors affecting the production of proteins from the genes). They then argue that the AHR on astocytes controls to modulatory effect of beta interferon. So another new mechanism for beta interferon. 

But they are on a roll and next they argue that dietary tryptophan, an amino acid involved in the  production of nerve transmitters, is metabolised by the gut bacterial into compounds that stimulate AHR and that this can influence inflammation. They can modify the microbes with antibiotics etc,  etc. and I start loosing the will to live as I push away the Zee's and you rush off for that faecal transplant:-)

However, looking at the data I can't but help thinking that we are missing a trick here. The authors show that there is no influence T cell function. But if you look at the EAE data (eg. shown above) it is shown there already and rather than being anything to do with the immune response and driving disease it how astrocytes influence how we cope with the inflammatory response and how it ultimately affects nerve loss. Because, what I see from the EAE graphs is the effect is all about saving and losing nerves

The knockouts get comparable disease but they just don't recover. The actions via the AHR are influencing nerve loss and this is fundementally more interesting that any old imunology- smology stuff. I am sure it points to the astrocyte as being an overlooked character in influencing progressive MS, but if we scientists cannot get over that there is more to progressive MS than immunology, then we may miss a few tricks and may not do the most informative experiments.

Hey Ho Back to work