Monday, 27 April 2015

At last...How to get relapsing progressive EAE made simple

Al-Izki S, Pryce G, O'Neill JK, Butter C, Giovannoni G, Amor S, Baker D. Practical guide to the induction of relapsing progressive experimental autoimmune encephalomyelitis in the Biozzi ABH mouse. Mult Scler Relat Disord. 2012 ;1:29-38.

Biozzi ABH mice develop a reproducible, relapsing-remitting form of experimental autoimmune encephalomyelitis (EAE) that becomes secondary progressive with disease duration. The relapses observed are T-cell dependent and can be inhibited by immune tolerance induction. In contrast the progressive neurodegeneration is T cell-independent and continues despite the re-induction of immune tolerance. Here we present a practical guide to EAE induction in the ABH mouse and approaches used to control relapses such that both autoimmune-independent and autoimmune-dependent mechanisms of neurodegeneration can be explored. Disease-related weight changes are associated with blood-brain barrier dysfunction and clinical disease. A new method for detecting neurodegeneration is described along with new experimental details that will aid in the undertaking of studies in EAE in mice, with particularly emphasis on ABH mice.

To most of your reading the blog you don't care much about animal work, but you do care about finding treatments. 

Animals are one way to do this as we showed with the phenytoin in optic neuritis study that has implications for progressive MSers. 

However, it is a research blog, and it is our research blog, so we need to engage people in what we do.  

Biozzi Mice is a strain of mice that we became custodians of and showed that is a mouse strain that is highly susceptible to relapsing autoimmunity and also has secondary progressive disease. The were bred by a Brazilian (Guido Biozzi) working in Paris, France to study the genetic regulation of the antibody response and the ABH strain made high levels of antibody (AB=antibody, H = High). This is one of the best mouse strains for drug hunting because disease is reproducible. However we have to remeber it is just one individual

The ARRIVE guidelines (CLICK) is a guideline of how to report animal studies to increase transparency.

This paper is a working protocol of how to get an control relapsing progressive EAE, This explains what is done in relation to the ARRIVE guidelines. It explains how you can get rid of relapsing disease with two simple injections.

 Much animal work is in need of this transparency, because animal studies consistently fail to translate anything useful to humans. 
I am sorry to say some of it would not translate into animal benefit because the experiments lack enough internal quality control. 

Whilst I will take stick for staying this in a public forum, the results are out there for everyone to see and it is supposed to be a constructive rather than a destructive comment.

Studies may spark an interest in science but it is often a false hope when it comes to treatment. ARRIVE Guideline number 19 asks what is the relevance to human use and so many studies uses doses that would so far exceed what is relevant to humans. 

It is written in stone in Europe that people using animals need to embrace the principles of 3Rs of animal work. This is not readin, rightin and rithmatic or reuse reduce and recycle but Refinement (of protocols to minimise suffering), Reduction (In the number of animals used) and Replacement(Using non animal alternatives). 
If we do not aim to work to high standards,in the not too distant future, ethical review committees make take the view that the ends do not justify the means.

This study was published years ago as soon as the ARRIVE guidelines came out but was invisible as MSARDS failed to be seen on Pubmed and so is invisible until last week.

CoI This produced by TeamG 

MS Awareness week 27th. What's In a Name

This week it is MS awareness week in the United Kingdom

Scientists and Neuros and health care professionals write papers every day and you are increasingly getting to see them with open source information, and it is interesting how they refer to you in these papers and grants. Maybe it is time you said what you prefer. 

What's In Name?

We have asked this before and now I am asking this again. 

Because of 
As you are aware we get Trolls visiting the blog from Time to Time

Some like to cause a bit of mischief by posting 
on the blog or elsewhere, but I am sorry to say some are 
really quite nasty individuals, who are destructive. 
They try to damage professional reputations and ruin careers
and in doing this, hasten the end of this Blog.

They will not win but I would ask you to consider helping us and
consider signing up to the MS Register 
to help us respond to the Trolls

The MS Register is a ground-breaking study designed to increase our understanding of living with MS in the UK.

Are you over 18, living in the UK, with a confirmed diagnosis of Multiple Sclerosis?(Sorry if you are not UK based, as part of my awareness I have written to NARCOSMS in the USA so see if they can do the same thing) Then you need to take part in this ground breaking study (Click here) 

Once you have completed the registration form you will find a series of questionnaires please complete them notably 
What's in a Name.

For your reassurance, The MS Register has gained official approval from the National Research Ethics Service Committee South West - Central Bristol. To gain this approval, Swansea University College of Medicine was required to go through a thorough audit of information management practices.

If you opt-out from the MS Register, your details will be deleted
If, at any point, you decide you would rather not continue to take part in the MS Register, just let the MS Register know. Although the information you have given them through our online questionnaires or clinical study will remain in their database, they will delete your name and address and will have no way of linking this information to you.

AAN 2015: low testosterone level in the womb increase risk of MS

Low androgens in utero linked to increase risk of MS in males #AAN2015 #MSBlog #MSResearch

"I note there has been some recent discussions about testosterone and MS. Two presentations at the AAN link low testosterone levels in utero or early childhood with an increased risk of MS. The first study shows that the ratio of the length of the ring finger to the index finger, the so called 2D:4D ratio, is higher in male MSers than controls. A lower 2D:4D ratio is associated with lower prenatal (before birth) or in utero (in the womb) androgen levels (testosterone is one of the androgens). The second study, done by the brilliant Julia Pakpoor (still in medical school) using NHS hospital records report a strong positive association (a five-fold elevation of rates) between testicular hypofunction and the subsequent development of MS in males. If these studies are correct this is another emerging risk factor that can be targeted when thinking of preventing, or at least lowering, the risk of developing MS. The latter must not be confused with the hypothesis that testosterone may be used as a disease-modifying therapy to treat MS. I am aware that there is emerging evidence for this, but until properly designed and powered studies are done we can't be sure. We also need to be aware that testosterone supplementation comes with risk, the most concerning include cancer and cardiovascular events (myocardial infarction and stroke)."


Study 1

Bove et al. The male 2D:4D digit ratio: a proxy for prenatal androgen exposure and a risk biomarker for multiple sclerosis. AAN 2015: S38.005.

OBJECTIVE: To compare the 2D:4D digit ratio, a proxy for prenatal androgen levels, in men with and without multiple sclerosis (MS).

BACKGROUND: In adult men with MS, low testosterone levels are associated with worse disease severity. We hypothesized that low prenatal androgen levels, during this key period of hormonal modulation, might represent a risk factor for MS. A higher ratio of an individual’s second and fourth digit lengths (2D:4D ratio) may reflect lower prenatal androgen levels. (PNAS 2011 108:16289)

DESIGN/METHODS: We obtained two digital scans of the right hand for 100 men with MS presenting to a scheduled clinic visit, and 130 men without autoimmune disease (HCs). All individuals were aged 18-65, right-handed, and reported no prior hand trauma. Digit length was calculated using digital calipers by two investigators blinded to disease status. The 2D:4D ratio was averaged over the two scans. Our primary statistical analysis was a cross-sectional comparison of the 2D:4D ratio between MS subjects and HCs using two-sample t-test.

RESULTS: The mean age of MS subjects was 42.4 and of HCs was 41.3 (p=0.49, two-sample t-test). The mean (SD) 2D:4D ratio was higher in MS patients (0.954 (0.0399)) than in HCs (0.9443 (0.0335)) (adjusted difference= 0.00985; 95% CI: 0.00031-0.0194; p=0.0431). There was no effect of age on these findings in an age-adjusted linear regression. Finally, in the 44 MS patients who had both morning testosterone levels and a 2D:4D ratio available for analysis, there was no correlation between the two measures (Pearson’s r = 0.07, p = 0.6507).

CONCLUSIONS: In this study, male MS patients had a higher 2D4D ratio than HCs, suggestive of lower prenatal androgen levels. These findings support an emerging role of low androgens during key developmental periods as a risk factor for MS.

STUDY SUPPORTED BY: NMSS, American Brain Foundation.

Study 2

Pakpoor et al. Testicular Hypofunction and Multiple Sclerosis Risk: A Record-Linkage Study. AAN 2015: P1.101.

OBJECTIVE: To investigate a potential association between testicular hypofunction (TH), as a proxy for low testosterone levels, and multiple sclerosis (MS) risk.

BACKGROUND: Gender is an important factor influencing MS risk. MS in males typically onsets at a later age, which coincides with an age-related decline in testosterone.

DESIGN/METHODS: We analysed linked English national Hospital Episode Statistics from 1999 to 2011. A TH cohort of 5049 males was constructed by identifying the first episode of day-case care or hospital admission in which TH was coded. A reference cohort (3.4 million males) and obesity cohort (given the possibility of obesity being a confounding factor) were constructed in similar ways. We searched for any subsequent day-case or inpatient admission for, or death from, MS in these cohorts. We calculated rates for MS, stratified and then standardized by age, sex, calendar year of first recorded admission, region of residence, and socio-economic status. Further, using the same methodology we analysed the dataset for the risk of TH following MS.

RESULTS: The standardised rates of MS were 37.79 per 100,000 person-years in the TH cohort and 8.17 per 100,000 person-years in the reference cohort. The adjusted rate ratio (RR) was 4.62 (95% confidence interval 2.30-8.24, p<0.0001). In the TH cohort, all MS cases occurred more than one year after the first TH episode. The RR of MS following obesity in males was 1.47 (95% CI 1.20-1.80, p=0.0001). The difference is significant and obesity is unlikely to be an important confounder. The RR of TH following an admission for MS was 1.07 (95% CI 0.43-2.2, p=0.98).

CONCLUSIONS: We report a strong positive association (a five-fold elevation of rates) between TH and subsequent MS in males. This is the first human study to link low testosterone to increased MS risk and future work should characterize the relationship.

CoI: this study was performed by members of team G

It's MS Awareness Week in the UK

We do not make any money from his website and do not advertise but one of the biggest things that came from Pharma interest in MS, which makes a positive impact to people with MS, is the MS Specialist Nurse.

The MS Trust is running a campaign to ensure you all get access to an MS Nurse..Join the campaign.....I have....and sign up! 

It costs you nothing except about a minute of your time.

Click Here