Thursday, 31 August 2017

#ClinicSpeak & #GuestPost: how much social capital do you have?

Social capital is important in MS; but how important? #ClinicSpeak #GuestPost

Summary: The following post explains the concept of social capital; in essence how socially connected you are. Social capital predicts outcome in many chronic diseases and is closely linked to quality of life (QoL). MS reduces social capital, but by how much? Not enough research has been done on social capital in in the field of MS. 


It's good to be back for a second post. I have enjoyed reading all your comments on my first post about MS in South America (In case you missed it!). A lot has happened since then. This training programme has pushed me out of my comfort zone and has triggered my interest in and passion for addressing health inequalities. As always, the proof of the pudding is in the eating! Here is my new post on Social Capital.


THE UNEXPLORED ROLE OF SOCIAL CAPITAL IN MS


While previous studies have shown mixed results, emerging evidence suggests that there is an association between higher income inequality and worse health outcomes. Despite global progress in reducing poverty, inequality continues to persist and large disparities remain in health outcomes. Accordingly, researchers have become increasingly interested in exploring the effects of the socio-economic environment on individual and public health. Although the impact of social conditions on health equity is well documented, there is no consensus as to the relative importance of each factor. Many determinants are involved and, among them, social capital has emerged as one of the most interesting old ideas being revisited from a new perspective.

The social capital concept emerged in sociology early in the past century. Social capital refers to the resources derived from the cooperation between individuals and groups. It has been hypothesized to partially explain how social conditions influence health and mortality. More recently, the concept of social capital has become the subject of intense discussion, as it may represent a pathway by which public health interventions lead to health improvement. The exact nature and magnitude of these effects remain controversial as there is no standardized method to measure social capital. However, there are several tools that attempt to address its multidimensional nature.



Many types of social capital are theoretically possible, but an important distinction that should be made is between its cognitive and structural components. The structural dimension is derived from the “visible” forms of social capital and consists of networks, relationships, associations, institutions and organizations that link individuals and communities. On the other hand, the cognitive component refers to the quality of those social structures in terms of peoples’ perceptions of trust, sharing and reciprocity. The different dimensions of social capital are not necessarily mutually exclusive; they are all immersed within a multi-level analytical framework. As many social aspects are encompassed under the same concept, oversimplification and overstandardization are both equally dangerous for social capital research.

Neurological disorders represent a large burden on worldwide health. Patients with neurological conditions are embedded in social networks that may affect their outcomes. This effect has been postulated to modify the risk of dementia and the long-term prognosis in patients with stroke. Regardless of the growing recognition of the role of social capital in chronic diseases, not enough attention has been paid to its potential impact on other disabling neurological conditions such as MS.

A few researchers have explored the relationship between social support and quality of life in patients with MS. However, and to the best of our knowledge, only one study has specifically focused on social capital. The results of this study showed that in patients with MS, quality of life and social capital are somehow related. This study only evaluated one potential target. Many questions remain to be explored in our understanding of how social capital may lead to either positive or negative consequences for patients with MS.

Addressing health inequality matters! Addressing social capital matters too!!

This paper is for those who want to read further, and perhaps more deeply, about this fascinating area: https://goo.gl/GwVajR

References

1. Carpentier CL, Kozul-Wright R, Passos FD. Goal 10 - Why Addressing Inequality Matters. UN Chronicle. 2015;LI,4. https://unchronicle.un.org/article/goal-10-why-addressing-inequality-matters. Accessed 10 August 2017.

2. Bourdieu P. Forms of Capital. In: Richardson JG, ed. Handbook of theory for the sociology of education. Westport, CT: Greenwood Publisher, 1986:241-58. 


3. Nyqvist F, Pape B, Pellfolk T, et al. Structural and cognitive aspects of social capital and all-cause mortality: a meta-analysis of cohort studies. Soc Indic Res 2013;116:545-66.

4. Eriksson M. Social capital and health - implications for health promotion. Glob Health Action 2011;4:1-11.

5. Dhand A, Luke DA, Lang CE, et al. Social networks and neurological illness. Nat Rev Neurol 2016;12(10):605-12.

6. Rimaz S, Mohammad K, Dastoorpoor M, et al. Investigation of Relationship Between Social Capital and Quality of Life in Multiple Sclerosis Patients. Global Journal of Health Science. 2014;6(6):261-272.

7. Harpham T, Grant E, Thomas E. Measuring social capital within health surveys: key issues. Health Policy and Planning 2002,17(1):106-111.

A new type of publication will it make a difference?

Alongside growing discontent, the scientific community has answered by driving forward a raft of open science reforms. From initiatives to making research data publicly available, to ensuring that all published research can be read by the public, the aim of these reforms is simple: to make science more credible and accessible, for the benefit of other scientists and the public who fund scientific research.
Today one of these reforms takes hold for the first time in clinical medicine: a new type of journal article called a Registered Report in which the journal commits to publishing clinical trials regardless of their outcome.

Registered Reports: Peer review before results are known to align scientific values and practices

  • Peer review occurs prior to observing the outcomes of the research.
  • Manuscripts that survive pre-study peer review receive an in-principle acceptance that will not be revoked based on the outcomes, but only on failings of quality assurance, following through on the registered protocol, or unresolvable problems in reporting clarity or style.


The second problem with clinical trials is a form of cherry picking called hidden outcome switching. Back in the 1980s, the medical community decided that clinical trials should be registered in advance, pre-specifying the study design, outcome measures, and analysis plan. One of the reasons this was brought in was to stop cherry picking by researchers, either deliberately or unconsciously. In any study with a lot of variables, it is relatively easy to find a positive result by changing the main outcome measure after looking at the data or by using a different type of analysis to the one originally planned. 

Publication bias places researchers under enormous pressure to engage in cherry picking – all the incentives in academia point researchers toward cutting corners and fooling themselves (and others) in the interests of publishing in prestigious journals. So it comes as little surprise that cherry picking is rife in clinical trials: a 2014 analysis found that around 1 in 3 trials change their primary outcome measure after the trial is complete,




The first step is to treat the publication process as we would treat a clinical trial itself and ensure that journals are kept blind to the results when they decide whether to accept or reject articles. This guarantees that positive and negative results are on equal footing in the published literature. And secondly, we need to ensure that researchers adhere to their registered trial protocols, or at least explain why deviations from protocol are required. For this, peer review of the protocol provides the answer.

A new type of article called a Registered Report provides both of these features. 

Hooray some say, I say whoopy-do.

Will it mean the endless sea of rubbish underpowered clinical trials stop?...I doubt it. 

Will it make clinical trials be published? I doubt it. 

This is a vehicle for academics to get their dreary trials published. 

At present there are Journals of clinical trials where you can publish your clinical trial design.

If they reviewed and said your clinical trial is pants...would it stop you?

We want to see the clinical trials done by companies published like the "inhibition of BAFF" So you get your trial design accepted but you decide not to publish the failed trial.

Now lets look at the journals who have signed up to this, we are missing the New England Journal of Medicine and Nature and Science...They care about the result and not the trial.

You have an easy way of ensuring companies publish results but it needs some guts...guts from the regulators, and guts from the journals, which are supposed to require trials to be registered as part of publication.

Let people registered with clinical trials.gov have a 24 month window from the end of the trial and if they do not publish the trial, refuse to allow future registrations..hence publications.

Companies would loose the advertising medium.

Yeah......it ain't going to happen. People don't have the jajce!

However, we can't talk on this can we....ProfG? 

Where is the INSPIRE trial publication?....Time to Pull your finger out:-)

Wednesday, 30 August 2017

#ClinicSpeak & #ResearchSpeak: what dose of vitamin D?

What dose of vitamin D supplementation do I recommend? #ResearchSpeak #ClinicSpeak

Summary: This blog post makes the case for using an initial dose of vD supplementation (5,000U/day) and then to test blood levels of vD after approximately 6 weeks to adjust the dose accordingly. I use evolutionary medicine to define a treatment target of blood vD levels.

The study below has shown that moderate vitamin D (vD) supplementation (10,400 IU/day) was safe in pwMS and had favourable effects on the immune system. The immunological changes on moderate dose vD are congruent with the effects we would want to see if MS was an 'autoimmune disease'; e.g. they found a reduction in the proportion of interleukin-17+ve-CD4+ T cells so-called putative autoreactive T cells in MS.

Why do I say moderate dose vD supplementation rather than high-dose? This is because 10,400IU per day is physiological vD supplementation. If you go into the mid-summer sunlight with your upper body exposed for ~20-30 minutes your skin will produce this sort of dose of vD; therefore 10,400IU is not high-dose. The good news is that this study confirms other studies that moderate dose vD supplementation is safe and not associated with any toxicity or adverse events.

To remind you it is our policy to advise all our patients to ensure they are vD replete; we aim for a plasma level of 25OH-vD3 of greater than 100 nmol/L and less than 250 nmol/L. I start by recommending 5,000IU/day and testing blood levels about 12 weeks later. If levels are still low and the patient has been adherent then we increase the dose to 10,000 IU/day and if too high we reduce the dose to between 2,000-4,000IU/day. It is clear that plasma levels of vD are highly variable and are affected by dietary and multiple genetic factors. I never tell my patients that this will improve or help their MS; we say it may do but the real reason for being vD replete is to improve, or maintain, your bone health. Please note we do not recommend calcium supplementation in parallel with vD supplementation. As far as we are concerned there is no reason for pwMS to take calcium supplements unless they have thin bones (osteopenia or osteoporosis). If you are taking moderate or high-dose vD and calcium supplements together you will need to have your calcium levels monitored (please discuss this with your doctor).

Who's advice am I giving? We tend to favour the Vitamin D Council's advice regarding the initial dose of supplementation. With regard to our target level of plasma vD levels; I have adopted the evolutionary medicine approach espoused by Reinhold Veith (see old slide show below). This theory is based on what your vD levels would be if you worked outdoors with skin exposed (lifeguards & farm labourers) and what vD levels are in hunter-gatherer societies. Using a reference population gets around the likely problem that modern societies are vD deficient and hence you can use population mean vD levels to establish a normal range of plasma vD levels.

The problem I have with vD supplementation is adherence; pwMS simply forget to take their supplements and don't take our advice when it comes to getting their relatives on supplements as well.


Sotirchos  et al. Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. Neurology. 2015 Dec 30. pii: 10.1212/WNL.0000000000002316.

OBJECTIVE: To study the safety profile and characterize the immunologic effects of high- vs low-dose cholecalciferol supplementation in patients with multiple sclerosis (MS).


METHODS: In this double-blind, single-center randomized pilot study, 40 patients with relapsing-remitting MS were randomized to receive 10,400 IU or 800 IU cholecalciferol daily for 6 months. Assessments were performed at baseline and 3 and 6 months. 

RESULTS: Mean increase of 25-hydroxyvitamin D levels from baseline to final visit was larger in the high-dose group (34.9 ng/mL; 95% confidence interval [CI] 25.0-44.7 ng/mL) than in the low-dose group (6.9 ng/mL; 95% CI 1.0-13.7 ng/mL). Adverse events were minor and did not differ between the 2 groups. Two relapses occurred, one in each treatment arm. In the high-dose group, we found a reduction in the proportion of interleukin-17+CD4+ T cells (p = 0.016), CD161+CD4+ T cells (p = 0.03), and effector memory CD4+ T cells (p = 0.021) with a concomitant increase in the proportion of central memory CD4+ T cells (p = 0.018) and naive CD4+ T cells (p = 0.04). These effects were not observed in the low-dose group. 

CONCLUSIONS: Cholecalciferol supplementation with 10,400 IU daily is safe and tolerable in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects in MS, which include reduction of interleukin-17 production by CD4+ T cells and decreased proportion of effector memory CD4+ T cells with concomitant increase in central memory CD4+ T cells and naive CD4+ T cells.

CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that cholecalciferol supplementation with 10,400 IU daily is safe and well-tolerated in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects.

Antidote to synthetic Cannabinoids...What has this research got to do with MS?

THIS STORY HAS NOTHING TO DO WITH NALOXONE
IN CONTRAST TO THAT INFERRED  BY SOME TWEETS

Pryce G, Baker D. Antidote to cannabinoid intoxication: Inverse cannabinoid receptor one (CB1) agonism by N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidse (AM251) reverses the hypothermic effects of cannabinoid receptor one agonism by 1-Naphthalenyl [4-(pentyloxy)-1-naphthalenyl] methanone (CB13) in mice.
Br J Pharmacol. 2017 Aug 11. doi: 10.1111/bph.13973. [Epub ahead of print]

BACKGROUND & PURPOSE:Cannabis is a recreational drug leading to intoxication, due to cannabinoid receptor one (CB1 ) stimulation. However, more recently herbs mixed with synthetic cannabinoids sometimes known as "Spice" and "Black Mamba" have been increasing used and their high CB1 receptor affinity means not only marked intoxication, but life-threatening complications and an increasing number of deaths. Whilst many studies have indicated that prophylactic CB1 receptor antagonism can block cannabimimetic effects in animals and humans. The aim of the study was to determine whether CB1 antagonism could reverse physical cannabimimetic effects.
EXPERIMENTAL APPROACH: Cannabimimetic effects, measured by the hypothermic response following sedation and hypomotility, were induced by 1-Naphthalenyl[4-(pentyloxy)-1-naphthalenyl] methanone (synthetic CB1 agonist) in Biozzi ABH mice. N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251. CB1 antagonist/inverse agonist) was subsequently administered and the influence on cannabimimetic effects assessed.
KEY RESULTS: In this study, the pre-existing, central nervous system-related cannabimimetic effects, measured via the hypothermic effect, induced by CB1 receptor agonism where therapeutically treated and were rapidly reversed by CB1 receptor antagonism/inverse agonism. There was also a subjective reversal of visually-evident sedation.
CONCLUSIONS & IMPLICATIONS: Cannabinoid receptor antagonists have been used in thousands of people and so may provide a single-dose antidote to cannabinoid intoxication, which may save human life, if the life-threatening effects are mediated by the cannabinoid receptor and not off-target influences of the synthetic cannabinoids or non-cannabinoids within the recreational drug mixture.


So another paper is served up and this one is about stopping intoxication with cannabis. What it has got to do with MS?

Nothing, unless you are using synthetic cannabinoids like Spice and if you are, the next question is why? ...stop it now

People take cannabis to alleviate symptoms but if you are buying street cannabis you don't know how much THC is in it and so you may get more than you bargained for. However with cannabis the high isn't going to kill you.

Synthetic cannabinoids are uber dope and are much more potent. We had some that are over a thousand times more potent than THC and they would get you spaced out if you were stupid enough to take them.

However, people buy marsh mellow plant sprinkle a synthetic on the plant and give it a scent put it in a baggie and call it Spice, Black mamba,etc.

The synthetic used to change to keep ahead of the law but since last year they are now all illegal in the UK,

The synthetics can get people very intoxicated and there are an increasing number of deaths reported. Now, this could be due to an impurity or non-cannabinoid action, but it could be due to the cannabinoid system such as a seizure or a heart issue as cannabinoids can make your heart race. 

What we found was that we could turn off the "high" within a few minutes using a cannabinoid receptor antagonist. It is not surprising that an antagonist can block the action of the drug from working but we could not find an example where an antagonist was used to turn off a pre-existing high. 

Some people think that cannabidiol can do this, but it can only affect the buzz and does not turn the high off. 

In this paper we describe a simple experiment that was done a few years ago, when we could legally hold cannabinoids. Now you need a licence costing about 5 grand a year. The use of CB13 as the agonist is not important, it was one that we were researching on at the time, but it could induce a "mouse high", when we gave the antagonist or should I say "inverse agonist" it turned the "high completely" off within a few minutes so it could act as a antidote.

So may be, if there was a Pot epi-pen people it could be used in peolpe at risk of dying from overdose of "Spice". If it were available perhaps the 14 year Girl from Bristol who died a few weeks ago may still be here.

There was one inverse agonist that was licenced to treat obesity and it was made by Sanofi...the maker of Alemtuzumab. It blocked cannabinoid receptors in appetite centres in the brain to block the munchies, but it also affected centres controlling depression leading a few people to commit suicide. However, thousands of people have taken the drug (rimonabant) without a problem and if it is a matter of life or death, you'ld risk it. However, sadly Sanofi were not interested, when I asked. 

Do I have the energy to develop this, or something like it? Maybe something for Prof. David Nutt (ex UK drug Tsar to the Government) to sink his teeth into. This week we are more busy with our presentations for Roehampton (a London Suburb)....yes the MD's get to go to the most exotic places to present. 

(a) Neuroprotection in an experimental model of multiple sclerosis via fatty acid amide hydrolase or monoacyl glycerol lipase inhibition

(b) Neuroprotection in an experimental model of multiple sclerosis via opening of big conductance, calcium-activated potassium channels.


Do you get the significance of this? 

Tuesday, 29 August 2017

Guest post: The effects of parental MS on children

By Julie Moberg, MA, RN, PhD, postdoc. at the Danish Multiple Sclerosis Registry and the Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Denmark.




Background
How multiple sclerosis (MS) among parents affects their children in childhood has been reported in some studies, but little is known about the consequences later in adult life.
The potential influence on the children can arise from the variety of symptoms of the chronic illness, including fatigue and disability, which can restrict daily life of the persons with MS and might result in less energy for activities and loss of job with social implications for the family.

Methods
In my PhD thesis, we identified all persons with MS from the Danish MS Registry with onset between 1950 and 1986 to be used in two register-based studies. The Danish Civil Registration System provided the anonymized identity of their 4,177 children along with 33,416 randomly chosen people from the Danish population of the same sex and year of birth. Statistics Denmark provided information about school grades, education, employment, income, and disability pension of all the persons in our study on the individual level in an encrypted anonymized dataset.

In addition, we also performed an interview study about young adults’ experiences with parental MS. I interviewed 14 persons between 18 and 25 years with parental MS. This age group was chosen because they were young enough to remember their childhood vividly and mature enough to reflect about it.

Results
Children with a parent with MS compared with other children achieved a higher grade point average in basic school. They attained similar levels of education. There was a strong tendency toward more of them attaining health-related educations.

We found that at age 30, the children of MS patients had 11% lower chance of being employed. At age 30 they had a 31% higher risk of receiving disability pension than the children of non-MS families, and at age 40 the risk was 20% higher. The mean income at the age interval of 45 to 49 years was similar, but children of MS patients had a 9% lower chance of belonging to the high-income group (earning more than EUR 33,650 annually amounting to about GBP 30,500).

The interviewed participants revealed that one of the greatest challenges of having a parent with MS is achieving a balance between caring for others and asserting one’s own desires.

Considerations
Having a parent with MS might have social consequences later in life: in spite of attaining the same educational levels, it seems that they had a greater risk of low income and higher risk of transfer income than children from families without MS.

However, one unexpected benefit of having a parent with MS was the higher school grades. This might indicate character building with a greater sense of responsibility because of the role as a caregiver. Also, the young adults interviewed had experiences of caring for others, and putting them first (above their own wishes and needs). Amongst those being cared for and coming first in the young people's lives were: the parent with MS, the other parent, and siblings, and they continued this pattern of care and self-sacrifice toward friends and partners. This was also in keeping with the tendency that more children of parents with MS were more likely to study health-related education.

The results of caring and self-sacrifice might partly explain some of the findings in the register-based studies. The children might continue taking care of their parents while striving to find a balance between helping others and fulfilling their own adult lives.

Conclusion
Parental MS influences the life of their children far into adulthood.

COI: None.

Literature
  • Frank J, Tatum C, Tucker S. On small shoulders. Learning from the experiences of former young carers. London: The Children's Society; 1999. Free to read
  • Lackey NR, Gates MF. Adults' recollections of their experiences as young caregivers of family members with chronic physical illnesses. J Adv Nurs 2001;34:320-8. PubMed link
  • Moberg JY, Magyari M, Koch-Henriksen N, Thygesen LC, Laursen B, Soelberg Sørensen P. Educational achievements of children of parents with multiple sclerosis: A nationwide register-based cohort study. J Neurol 2016;263(11), 2229-2237. doi: 10.1007/s00415-016-8255-4. Free to read link, PubMed link
  • Moberg JY, Laursen B, Koch-Henriksen N, Thygesen LC, Brødsgaard A, Soelberg Sørensen P, Magyari M. Employment, disability pension and income for children with parental multiple sclerosis. Mult Scler. 2017 Jul;23(8):1148-1156. doi: 10.1177/1352458516672016. PubMed link
  • Moberg JY, Larsen D, Brødsgaard A. Striving for balance between caring and restraint. Young adults’ experiences with parental multiple sclerosis. J Clin Nurs 2017;26(9-10):1363-1374. doi: 10.1111/jocn.13587. PubMed link
  • Moberg JY. Life course of children with parental multiple sclerosis. Dan Med J 2017;64(8):B5399. Free to read link.

Photographs by Dorthe Stauning Rasmussen

Minocycline as a neuroprotectant

Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis

Luanne M. Metz, M.D., David K.B. Li, M.D., Anthony L. Traboulsee, M.D., Pierre Duquette, M.D., Misha Eliasziw, Ph.D., Graziela Cerchiaro, Ph.D., Jamie Greenfield, M.P.H., Andrew Riddehough, B.Sc., Michael Yeung, M.D., Marcelo Kremenchutzky, M.D., Galina Vorobeychik, M.D., Mark S. Freedman, M.D., Virender Bhan, M.D., Gregg Blevins, M.D., James J. Marriott, M.D., Francois Grand’Maison, M.D., Liesly Lee, M.D., Manon Thibault, M.D., Michael D. Hill, M.D., and V. Wee Yong, Ph.D., for the Minocycline in MS Study Team

N Engl J Med 2017; 376:2122-2133June 1, 2017DOI: 10.1056/NEJMoa1608889

Background

On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis.

Methods

During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T2-weighted MRI, cumulative number of new lesions enhanced on T1-weighted MRI [“enhancing lesions”], and cumulative combined number of unique lesions [new enhancing lesions on T1-weighted MRI plus new and newly enlarged lesions on T2-weighted MRI]).

Results

A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo.

Conclusions

The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887.)




It is important to pay attention. 

To what specifically you might ask? Why, to everything... 

Neurologists are notorious for paying attention to detail, some may consider this peculiar - even borderline autistic. So, in this fashion and not simply for diegetic entertainment, I'm able to say that the Yong group have trialed minocycline as a neuroprotectant in just about every neurological disorder they can get their hands on. In science this is tantamount to using the same run of numbers in the national lottery to improve the odds. But they've seem to have hit the jackpot with this one - the disorder being, multiple sclerosis.

Minocycline is a semi-synthetic tetracycline (antibiotic, commonly used for acne treatment), but also has additional biological actions, including anti-inflammatory properties and anti-apoptotic effects (process by which cell death occurs in the body). In short, potentially a good neuroprotectant.

Metz et al. gave 100mg twice a day of minocycline to 72 subjects and placebo (dummy treatment) to 70 subjects. There was some imbalance between the two groups at the start of the trial, in that the placebo group were more likely to have their first symptom in the spinal cord (increased likelihood of being disabling) and have more than one enhancing lesion on their baseline MRI head scan (i.e. more active). At the end of the study, 23 in the minocycline group and 41 in the placebo group reached the primary outcome of conversion to multiple sclerosis from clinically isolated syndrome (i.e. a single demyelinating event only) - see figure below. The adjusted risk difference of 18.5 % at 6 months is similar to that with other disease-modifying therapies for multiple sclerosis (24% for IFNb-1b, 26% IFNb-1a, 18% teriflunomide, 25% cladrabine). MRI scans were not available in ~37% of participants after month 3 in the placebo group which may have introduced bias in the MRI analysis which favoured minocycline in terms of change in T2 lesion load and mean GAD enhancing lesions.



Figure Participants Who Reached the Outcome of Conversion to Multiple Sclerosis (MS) over the Course of 24 Months.

There were more adverse events in the minocycline group (86% vs 61% in placebo) and included rash, teeth discolouration and dizziness.

Overall, despite the underpowered study, the minocycline trial is a success for MS. Here is a toast to the Yong group for their tenacity and gumption, and to all neurologists and scientists out there who keep going! I would say watch this space as the minocycline saga unwinds.

Monday, 28 August 2017

#NewsSpeak: Results from CHANGE-MS Phase 2b Study

Are HERVs in the final common pathway that leads to demyelination in MS? #NewsSpeak #ResearchSpeak

It is very difficult for me to comment on these results without seeing the data firsthand. However, as there is no difference at 6-months between active- and placebo-treated subjects this trial must be interpreted as being negative. Please note that GNbAC1 targets the envelope protein of probably one human endogenous retrovirus or HERV.  GNbAC1 is a monoclonal antibody and is not an antiviral agent, hence this study does not exclude a role of HERVs in the pathogenesis or molecular pathway of MS. 

Press release: BusinessWire. GeNeuro and Servier Announce Six-Month Results from CHANGE-MS Phase 2b Study in Multiple Sclerosis. August 28, 2017 01:30 AM Eastern Daylight Time

GeNeuro and Servier announced their 6-month results from the 12-month CHANGE-MS Phase 2b study of three doses of GNbAC1 for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). The data showed that GNbAC1 is well tolerated and that there is no statistical difference at 6-months between GNbAC1 and placebo in the study’s primary endpoint of reducing the number of cerebral Gad-enhancing lesions as measured by MRI, nor on the other MRI measures of neuroinflammation. Relapses in the overall population decreased by over 50% relative to the year prior to study but there was no significant difference at 6 months between treated and placebo groups. Based on the unique mechanism of action and pharmacokinetics of GNbAC1, the study will continue, as planned, exploring potential benefits of the drug on MRI and clinical measures, including remyelination properties, with final results from the full 12-month expected in the first quarter of 2018.

GNbAC1 is the result of more than 25 years of research into human endogenous retroviruses (HERVs), including 15 years at Institut Mérieux and INSERM, a French national medical research institute. Found in the human genome, certain HERVs have been linked to various autoimmune and neurodegenerative diseases. Researchers have demonstrated that the retroviral envelope protein encoded by a HERV-W family human endogenous retrovirus (pHERV-W), which has been identified in brain lesions of patients with MS, particularly in active lesions, stimulated inflammatory processes through an interaction with the TLR4 receptor of innate immunity and inhibited neuron remyelination. pHERV-W env has also been identified in the pancreas of Type 1 diabetes (T1D) patients. By neutralizing pHERV-W env, GNbAC1 could at the same time block these pathological inflammatory processes and restore remyelination in MS patients and maintain insulin production in T1D patients. As pHERV-W env has no known physiological function, GNbAC1 is expected to have a good safety profile, without directly affecting the patient’s immune system, as observed in all clinical trials to date.

CoI: multiple

#ClinicSpeak & #DietSpeak: could diet be the next DMT?

Are you what you eat? How healthy is your diet? #ClinicSpeak #DietSpeak

Whilst on holiday I spent several days with a very good friend of mine, from South Africa, who now lives in the US. His wife is a card-carrying dietician, who runs her own consulting business that helps athletes, companies and individuals improve their health and wellness through diet and exercise. After listening to her and seeing her methods in action, it became clear to me that my approach of leaving dietary and exercise interventions up to you and your general practitioners to implement is wrong; it doesn't work. As part of 'the holistic management' of multiple sclerosis, we need to engage with lifestyle and wellness interventions more proactively. I am convinced they should be promoted as part of our disease-modifying therapy offering. 

The saying 'you are what you eat' may be overused, but it captures the essence of what you need to do to optimise your health and wellness. We are aware from a recent dietary audit of patients attending Bart-MS that the average diet of pwMS living in London is very poor. Our interpretation of the audit results was that it is not MS specific, but simply reflects the poor diet of the general population of London, and presumably the whole country. Despite ongoing public health campaigns and wide media coverage on healthy eating, it is clear that most people either don't listen, ignore the advice or don't feel it is necessary to change their behaviour. I am aware that the issues around healthy eating are complex and that the food landscape is mired in politics and is heavily influenced by big business with vested interests. 


From 'Viva: You are what you eat'

We have tended to shy away from promoting any specific diet for the management of MS. Saying this I have done several posts on diet and its effect on MS; two particular posts, one on ketogenic diets (5th-Jan-2016) and the other on intermittent fasting (30th-May-2016) generated interest and quite a lot of discussion. There is emerging evidence of that intermittent ketosis and fasting may have general health benefits, which include potential benefits for pwMS. I, therefore, plan to do a series of posts on diet and nutrition in relation to MS over the next few months. These will be general posts about diet and nutrition and will give advice on what you can do to optimise your own diet to improve your general health and wellness. The aim of this exercise is to generate content to produce a #ClinicSpeak tool to help you manage your diet as part of the holistic self-management of MS. 


Please note a themed series of posts in relation to one topic, that is not specifically related to research or a political campaign, is something we have not done before. Is this something you would find useful going forward? We could, for example, do a series on bladder management, DMT monitoring, etc. This content could then be migrated onto a curated site such as ClinicSpeak to make navigation easier. Thoughts? 

CoI: nil in relation to this post

Sunday, 27 August 2017

Whartons Jelly Stem cells do the trick

Hosseini A, Estiri H, Akhavan Niaki H, Alizadeh A, Abdolhossein Zadeh B, Ghaderian SMH, Farjadfar A, Fallah A.Multiple Sclerosis Gene Therapy with Recombinant Viral Vectors: Overexpression of IL-4, Leukemia Inhibitory Factor, and IL-10 in Wharton's Jelly Stem Cells Used in EAE Mice Model. Cell J. 2017; 19(3):361-374.

OBJECTIVES:Immunotherapy and gene therapy play important roles in modern medicine. The aim of this study is to evaluate the overexpression of interleukin-4 (IL-4), IL-10 and leukemia inhibitory factor (LIF) in Wharton's jelly stem cells (WJSCs) in the experimental autoimmune encephalomyelitis (EAE) mice model.
MATERIALS AND METHODS:In this experimental study, a DNA construction containing IL- 4, IL-10 and LIF was assembled to make a polycistronic vector (as the transfer vector). Transfer and control vectors were co-transfected into Human Embryonic Kidney 293 (HEK-293T) cells with helper plasmids which produced recombinant lentiviral viruses (rLV). WJSCs were transduced with rLV to make recombinant WJSC (rWJSC). In vitro protein and mRNA overexpression of IL-4, LIF, and IL-10 were evaluated using quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA) and western blot (WB) analysis. EAE was induced in mice by MOG-CFA and pertussis toxin. EAE mice were injected twice with 2×105 rWJSCs. The in vivo level of IL-4, LIF, IL-10 cytokines and IL-17 were measured by ELISA. Brain tissues were analyzed histologically for evaluation of EAE lesions.
RESULTS:Isolated WJSCs were performed to characterize by in vitro differentiation and surface markers were analyzed by flow cytometry method. Cloning of a single lentiviral vector with five genes was done successfully. Transfection of transfer and control vectors were processed based on CaPO4 method with >90% efficiency. Recombinant viruses were produced and results of titration showed 2-3×107 infection-unit/ml. WJSCs were transduced using recombinant viruses. IL-4, IL-10 and LIF overexpression were confirmed by ELISA, WB and qPCR. The EAE mice treated with rWJSC showed reduction of Il-17, and brain lesions as well as brain cellular infiltration, in vivo. Weights and physical activity were improved in gene-treated group.
CONCLUSIONS:These results showed that gene therapy using anti-inflammatory cytokines can be a promising approach against multiple sclerosis (MS). In addition, considering the immunomodulatory potential of WJSCs, an approach using a combination of WJSCs and gene therapy will enhance the treatment

This is another cure of the week in animals study but I thought the title was interesting apparent Wharton's jelly (substantia gelatinea funiculi umbilicalis) is a gelatinous substance within the umbilical cord also present in vitreous humor of the eyeball, largely made up of mucopolysaccharides (hyaluronic acid and chondroitin sulfate). efficacy. They added some genes and it cured EAE.

#NewsSpeak & #ThinkSpeak: blog rejuvenation

We need your help to rejuvenate the blog #NewsSpeak #ThinkSpeak #MSBlog

Just back from my family holiday and for the first time in a long time I feel well, have a manageable workload and have a list of things to do in the new academic year that will refocus our research and educational agenda on the things we do best. Whilst away I had a complete break from academic activities including the blog, which is why I probably feel so well. 
I read some very stimulating books, unrelated to MS and neurology, that have provided me with food for thought. 



High on the ToDo list to do is to review our blogging activity and to improve our offering. From discussions with numerous pwMS, comments on the blog and emails (thank you) we are aware that we have lost our core readership and that most of you now have problems understanding our posts. We are aware, from our web analytics, that the number of people who read the blog regularly has fallen and the number of times you come back for information is decreasing. 

Alison Thomson (designer) and Beki Aldam (writer), our public engagement gurus, have reviewed our content and blogging activity and have compared it to well-described attributes of successful blogs and have identified several issues. Alison and Beki are confident that we can reverse our decline and are planning to take us back to basics. As part of our rejuvenation, they will be re-training us in the art of writing for a lay audience. Their aim is to improve the quality and reduce the quantity, of our offering so that the majority of our readers will understand what we are writing about - 'less is more'. 

If you have any suggestions to help us please feel free to comment on the blog or send Alison and Beki an email (bartsmsblog@gmail.com). For example, one potential option is to change very little, but provide you with tools to curate our content. What do you think? 

Saturday, 26 August 2017

TeamG helps develop a licenced drug

The new eagle has landed, 

http://multiple-sclerosis-research.blogspot.com/2017/08/another-eagle-no-maven-has-landed.html

As you may know us academics are beaten with a stick to produce papers and to produce papers that have "Impact". This is some science babble invented to assess research groups by the UK Government

As a basic scientist it is very difficult to do something and see it all the way through to have "Impact" on Society, which is what they assess us on.

We provided the first science evidence why cannabis would work for MS and we also did work that helped pharma deal with the regulators but no "impact" for that one, because the idea was at a different university. It was eleven years between the discover and the impact

However, for neurologists it is much easier. 

Do a trial and that's the start of impact. In fact for us basic scientist it seems that our clinical colleges are dead good at ensuring we have no impact. 

The positive..em failed THC trial in progression
The positive.....can't be bothered to repeat and implement change...optic neuritis trial.

If you produce the data that can change clinical practice...this is clearly impact.

Thus licensing of Mavenclad is surely impact we have been involved with

Someone asked ProfG if we work for Merck, because we talk about cladribine. Is that surprising as ProfG was lead author on phase III work and was instrumental in developing the approach? Furthermore DrK has been using generic cladribine.

So first answer is no we do not work for Merck, however ProfG works with all companies with MS drugs and DrK also discloses such activities too. 

Did people care about this when movectro was gone and buried and we were the lone voice. 

I have not had a personal penny directly from Merck, not yet at least :-), nor one that I remember. I did give them a mouse colony (as I did to anyone asking for them) so they could do EAE work, but me or my University did not ask for or receive anything....although we did get offered free mice, if  they were surplus to requirements.    

So in 2010 ProfG was the lead author on the oral cladribine paper (CLARITY) study. I think we can claim a bit of involvement about something that surely has impact.  

A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P, Vermersch P, Chang P, Hamlett A, Musch B, Greenberg SJ; CLARITY Study Group.
N Engl J Med. 2010: 362:416-426.


Movectro was licensed in Russia and Australia but then CLARITY however, turned out to be the CALAMITY study as Merck had only done one trial and the regulators wanted two. 

They (Merck) dug their heels in and said "no more"  and removed cladribine from the market. They had lost the race with Novartis to be the first oral treatment 

It shows some money, over no money, is not good enough.......if you want lots of money. Have they not heard of Chuck Barris?

No...Neither had I until I went to Wiki

Impact down the toilet and a few smug people have a laugh.

But all was not lost, so in 2011, I hatched a cunning plan to bring back cladribine and get real impact by getting treatment for all. 


After a year long search to find a Neurologist, other than ProfG (too conflicted), outside the group, I eventually found one in Sir Jeremy who then spoke to DrK who rose to the challenge and I wasted a year. 

The Fox took shape.

Enter CLEAR-MS and the white knights drip feeding the World that cladribine was not dead and could be useful,  

For 5 years we kept the drug in the world's eye, until Merck woke up and decided they had made a mistake to bin their drug.

First we tackled the central bit of mud, stuck to the Movectro wall.



This was the cancer risk that had appeared in the trial and was the central feature that sunk the molecule.

We did a meta analysis and argued against the fluke phase III CLARITY trial result. This is less worse than the result with ocrelizumab in PPMS which the FDA approved

No support from Merck, just an honest belief that cladribine had merit as a treatment

As Manchester University/Brian Cox made the argument that he was responsible for an increase in physics students going to University to get an Impact Statement in REF2014  

Surely we can make the argument that Merck bringing back cladribine was all our doing...Impact Ref 2021. 

OK ProfG will be horrified by the trumpet-blowing, but he is in the air returning from holiday..hence being incognito on the blog in recent weeks, so can't take it down for a few hours:-)

Of course you, and actually I, will say that is b******s, to claim everything, but Manchester University did make that Impact statement for Prof Cox.... and was successful......Amaaaaaaaazing

So forgive my bit of horn blowing.

You can argue these actions have nothing to do with that. 

But what is the evidence?

Some may say it was the introduction of alemtuzumab that made the difference, because it was realised that an effective drug, with high side effects, could be approved.

So, still maybe we can claim some impact. 

Although it is clear the alemtuzumab was invented in Cambridge (Waldmann & Winter et al.), by people from Oxford, by Medics (Compston & Coles et al.) from Cambridge who ran the trials who no doubt claimed impact in their REF 2014. 

However, when it came to getting the drug licensed the Cambridge group went on holiday and could not be seen. Rev. Prof Coles was off on Sabbatical. ProfG was the guy who stepped up to the plate to help pharma do the important regulatory stuff that helped get alemtuzumab licensed, and licensed as first line treatment in Europe. 

So we can even claim we were the people that helped create the environment for the return of oral cladribine. Furthermore

DrK has been banging the Cladribine drum and Merck has heard it and this has also helped them revive their oral cladribine programme, maybe as the best way of stopping us developing cladribine for RRMS.
So back to Cladribine and when the EMA came knocking, ProfG was back there trying to do his bit to get oral cladribine, approved in Europe. It worked and oral cladribine now called Mavenclad is arriving in Europe.  Impact!

Will it crack the USA?
DrK did an independent study to indicate that the issues with cancer that was cause for concern by the FDA was no worse than for any other treatment and certainly not as bad as that found in the PPMS study of ocrelizumab. Ocrelizumab was approved for PPMS by the FDA. This study surely will give confidence for Merck to approach the FDA for a licence.

Furthermore, whilst Movectro was on holiday getting a make-over and realising that it is not possible for academics to licence MS drugs, DrK has been practicing what the General Medical Council preach...

Laura Waters“The General Medical Council is very clear that a clinician has a duty to make sure patients are informed of all treatment choices, whether they’re available on the NHS or not.” 

We  have given people with no choice an option and we used off-label cladribine. This has helped us determine how cladribine actually may work.

Will we tell Merck? Sure we will! 

If we find an issue will we tell the world, sure we will. 
That is transparency.

Furthermore,  could this now be the agent (generic) of choice in Low and Middle Income Countries as we have long been arguing. 

Off-label does not have to mean second best. It also gives people an option for people who can't swallow.

Maybe Merck will do a compassionate programme and give low and middle Income the drug for the cost of generic cladribine.
Now that would be impact as the average drug cost is higher than the annual income from many countries.

We can dream.

OK I will come clean, it is all Merck's Hard work that brought Mavenclad to be a reality.

So now I will have to shut up about cladribine.....Phew I here you say, in case you say I'm a Merck mouth piece...I'm not!

CoI: None DrK& ProfG most definitely