Thursday, 31 July 2014

Employment: Norway is tragically the exception

Is Norway's runaway success in relation to MSer employment linked to their top ranking in the Human Development Index? #MSBlog #MSResearch

"Yesterday Mouse Doc discussed the article below that showed the employment rate amongst MSers living in county of Norway was 45% at 19 years. These are by far the best figures I have seen to date. I am hoping they indicate a trend that may be driven by early access to DMTs and an alteration in the natural history of MS. In other words by preventing relapse and the accrual of disability MSers are more likely to be staying in employment. On the other side of the coin these figures may be unique to Norway. Norway Ranks number 1 in the world in relation to the Human development Index (HDI). HDI is considered a better measure of a country's progress than income growth. I have embedded key data slides in relation to HDI for your information; it will allow you to see how well your country is doing. It is tragedy, but not surprising, that a large part of your outcome in relation to MS is probably related to which country you live in. The UK comes, embarrassingly, 27th in the league table; which is kind of where I would expect it be, based on the EMSP's barometer data, if  these figures referred directly to MS outcomes."

"Is being employed a badge of health for MSers? Should we be including relative employment rates when we compare the effectiveness of DMTs? Which DMT is likely to maximize your chances of staying employed, or becoming employed? If only we had this data."

Bøe-Lunde et al. Employment among Patients with Multiple Sclerosis-A Population Study. PLoS One. 2014 ;9(7):e103317. 

OBJECTIVE: To investigate demographic and clinical factors associated with employment in MS.

METHODS: The study included 213 (89.9%) of all MS patients in Sogn and Fjordane County, Western Norway at December 31st 2010. The patients underwent clinical evaluation, structured interviews and completed self-reported questionnaires. Demographic and clinical factors were compared between patients being employed versus patients being unemployed and according to disease course of MS.

RESULTS: After a mean disease duration of almost 19 years, 45% of the population was currently full-time or part- time employed. Patients with relapsing -remitting MS (RRMS) had higher employment rate than patients with secondary (SPMS) and primary progressive (PPMS). Higher educated MS patients with lower age at onset, shorter disease duration, less severe disability and less fatigue were most likely to be employed.

CONCLUSIONS: Nearly half of all MS patients were still employed after almost two decades of having MS. Lower age at onset, shorter disease duration, higher education, less fatigue and less disability were independently associated with current employment. These key clinical and demographic factors are important to understand the reasons to work ability in MS. The findings highlight the need for environmental adjustments at the workplace to accommodate individual 's needs in order to improve working ability among MS patients.

No Oligoclonal bands in your CSF means that you do better

Multiple sclerosis patients lacking oligoclonal bands in the cerebrospinal fluid have less global and regional brain atrophy.
Ferreira D, Voevodskaya O, Imrell K, Stawiarz L, Spulber G, Wahlund LO, Hillert J, Westman E, Karrenbauer VD.
J Neuroimmunol. 2014. pii: S0165-5728(14)00181-7. doi: 10.1016/j.jneuroim.2014.06.010. [Epub ahead of print]

To investigate whether multiple sclerosis (MS) patients with and without cerebrospinal fluid (CSF) oligoclonal immunoglobulin G bands (OCB) differ in brain atrophy. Twenty-eight OCB-negative and thirty-five OCB-positive patients were included. Larger volumes of total CSF and white matter (WM) lesions; smaller gray matter (GM) volume in the basal ganglia, diencephalon, cerebellum, and hippocampus; and smaller WM volume in corpus callosum, periventricular-deep WM, brainstem, and cerebellum, were observed in OCB-positives. OCB-negative patients, known to differ genetically from OCB-positives, are characterized by less global and regional brain atrophy. This finding supports the notion that OCB-negative MS patients may represent a clinically relevant MS subgroup.

If MSers did not have oligoclonal bands they appeared to do better, is this cause and effect. If there is limited immune activation in the CNS then there appears to be less damage, but should this be a different subset of MS?. If there is no difference in response to therapy, which currently appears to be the case then surely there is limited merit in this but it could be of relevance when recruiting for trials such that this subset is equally represented in studies

Progression is this an easy mountain to CLIMB

Raghavan K, Healy BC, Carruthers RL, Chitnis T. Progression rates and sample size estimates for PPMS based on the CLIMB study population. Mult Scler. 2014 Jul. pii: 1352458514541976. [Epub ahead of print]

BACKGROUND: The clinical trial design for primary progressive multiple sclerosis (PPMS) requires understanding of disability progression in modern patient cohorts.
OBJECTIVE: The objective of this paper is to characterize demographic and clinical characteristics of PPMS and assess rate of disability progression.
METHODS: We studied PPMS (n = 73) and relapsing-onset MS (ROMS) patients (n = 1541) enrolled in CLIMB, a longitudinal study of MS patients at the Brigham and Women's Hospital (Boston, MA). Disability progression for each group was compared using interval-censored survival analysis and time to six-month sustained progression.
RESULTS: The PP group had a 1.09:1 male:female ratio compared to 1:2.89 for the RO group and greater mean age of onset (PP: 44.4±9.6; RO: 32.7±9.9; p < 0.0001). Motor symptoms at onset and first symptoms localized to spinal cord were each strongly associated with PPMS (p < 0.001). Median time from onset to EDSS 6.0 was faster in PPMS (p < 0.001). PPMS patients progressed faster to EDSS 3 (p < 0.001) and from EDSS 3 to 6 (p < 0.001). Median time to sustained progression in the PP group was 4.85 years (95% CI 2.83-8.35), significantly faster than the RO group (p < 0.001).
CONCLUSIONS: Our modern PPMS cohort is demographically similar to previously studied cohorts. PPMS is associated with faster disability accrual than ROMS. Current real-world observations of time to sustained progression will inform design of new clinical trials for PPMS.

CLIMB (Comprehensive Longitudinal Investigation of Multiple Berosis) is based at Harvard. The CLIMB study is a large-scale, long-term study of patients with MS. It is designed to investigate the course of the disease in the current era of treatment. The main goals of the study are to:

1. Identify predictors of future disease course when patients are at the beginning of their illness.

They found males and age of onset and spinal disease

2. Determine the effects of treatment on disease progression and accumulation of disability.

I suspect you are asking what treatments..need to do better
In this study people with progressive MS were behaving as predicted in terms of their progression rates, is this to be expected because they are not recieving any effective treatments. 

However the question is if PPMSers are in trials then will this rate be the same. In the CUPID trial of tetrahydrocannabinol people in the trial progressed at at much slower rate than predicted.

I am sure the key aspect on your tounge is where are the treatments?

Mice work may send you down the wrong path becuase of the mouse you use

Kraev A. Parallel universes of Black Six biology. Biol Direct. 2014 Jul 19;9(1):18

Creation of lethal and synthetic lethal mutations in an experimental organism is a cornerstone of genetic dissection of gene function, and is related to the concept of an essential gene. Common inbred mouse strains carry background mutations, which can act as genetic modifiers, interfering with the assignment of gene essentiality. The inbred strain C57BL/6J, commonly known as "Black Six", stands out, as it carries a spontaneous homozygous deletion in the nicotinamide nucleotide transhydrogenase (Nnt) gene [GenBank: AH009385.2], resulting in impairment of steroidogenic mitochondria of the adrenal gland, and a multitude of indirect modifier effects, coming from alteration of glucocorticoid-regulated processes. Over time, the popular strain has been used, by means of gene targeting technology, to assign "essential" and "redundant" qualifiers to numerous genes, thus creating an internally consistent "parallel universe" of knowledge. It is unrealistic to suggest phasing-out of this strain, given the scope of shared resources built around it, however, continuing on the road of "strain-unawareness" will result in profound waste of effort, particularly where translational research is concerned. The review analyzes the historical roots of this phenomenon and proposes that building of "parallel universes" should be urgently made visible to a critical reader by obligatory use of unambiguous and persistent tags in publications and databases, such as hypertext links, pointing to a vendor's strain description web page, or to a digital object identifier (d.o.i.) of the original publication, so that any research done exclusively in C57BL/6J, could be easily identified.

To many of the readers of the blog will say who cares...mice don't get MS but to the few interested read on
With the the development of transgenic technology, where by we can add or delete genes to worms, fruitflies, mice and almost any other species has given us a revolution in the understanding of biology. 

The transgenic technology in mice including transgenic (addition of gene) and gene knockout (removal of gene) involves taking embryonic stem cells and blastocyst (a very young embryo) usually from two strains of mice.

The C57BL/6  (little black mice that like to bite you) and the 129 strains. After this the gene knockout or transgene is put onto the C57BL/6 strain background.

This is amongst the most resistant strain in relation to developing CNS autoimmunity, yet is becoming the most used for MS research because of the transgenic technology.

The C57BL/6 mouse develops CNS autoimmunity following sensitization to myelin oligodendrocyte glycoprotein. 

In the UK to work with transgenic or mutant mice, like Shiverer (MBP myelin mutant that shivers), rumpshaker (PLP myelin mutant that sakes its booty), Jimpy (PLP myelin mutant that shakes with time) you need a licence from the UK government and have to record these details. Howevert you don't with standard lab strains. Therefore many animals used in science go missing from statistics! 

However, the silly thing is many of these so called standard lab mice also have mutations and are mutants, but because they are not obvious mutants that effect obvious health issues they slip through the net. 

The SJL mouse used in MS research has a slow retinal degeneration and go blind slowly, the C3H strain goes blind quickly, the C57BL/6 mouse prefers to drink alcohol to water Others are deaf and maybe explains why they wont; do as they are told.  

Likewise many transgenics and knockouts have no effect on animal health, but they are recorded and this is why the number of animals used in research is growing...A major government relation to the fudge factor of animal statistics. 

If transgenics that had no deleterious effect were excluded from statistics the number of animals used in animal experiments would be falling. 

I say record them all and stop the fudge!..this will put pressure on people doing cell culture with meaningless experiments to justify what they do, because at the moment becuase they are not doing experiments on a living animal it is not recorded as an experiment if you kill the animal and use its tissues.

Anyway what this paper says is that C57BL/6 have natural mutations and that these may influence the effect of the introduction of another transgene or gene knockout.

This may make some genes seem important when they may not be that essential and may make you develop a strange "world view of biology". Therefore, ideally you would want to see the effect of the gene knockout in other strains to be convinced that the transgenic is having a consistent effect.

Even within the strain obtained from different commercial breeders there can be different mutations present. So it is important when reporting work to say where the animals come from. 

As we have said many times and reported (click) that EAE in C57BL/6 can be a bit dodgy and so it is well to remember this when you are reading the scientific literature as some things may not be that reproducible. You are looking at the effect of an experiment done many times in the genetically the same individual...just remember another mouse strain is just another individual and which one behaves like most humans is key

PLEG RIDY arrives in Europe

It has been announced that the European Regulators have approved Plegridy for MS.
Plegridy is an interferon drug, the same type of treatment as Biogen Idec’s first multiple sclerosis therapy, Avonex. While Avonex typically is injected into the muscle once a week, Plegridy can be taken by injection once every two weeks and administered under the skin with a prefilled auto-injector. 

This is a pegylated interferon.PEG poly ethylene glycol is an anti-freeze, but in this application it causes the interferon to hang around for longer. So less injections......more patent life

So another interferon on the market, which makes it hang around longer,but doesn't make it work better. So just as the Patent life of avonex for MS comes to an end, it has metamorphosis into a new product..surprise, surprise.

What a name...who comes up with them?