Thursday, 31 October 2013

Shift MS reports

You may have seen clips of Team G and other members fron UCLP in the MS reports by Shift MS

Here is the full interview of Prof B talking to Mariam
and then Prof you can see the minute per answer (look at the egg-timer) just wasn't going to happen.

NB. International Collaborative has been rebranded as the MS Alliance

View it bit by bit

Halloween Ghost Writer

Some people think and complain that I am a "ghost writer" maybe a cyborg they are right! I am a ghost, Happy Halloween :-)

Glaterimer acetates inhibits Macrophage function

Thamilarasan M, Hecker M, Goertsches RH, Paap BK, Schröder I, Koczan D, Thiesen HJ, Zettl UK. Glatiramer acetate treatment effects on gene expression in monocytes of multiple sclerosispatients. J Neuroinflammation. 2013 Oct;10(1):126. [Epub ahead of print]

BACKGROUND: Glatiramer acetate (GA) is a mixture of synthetic peptides used in the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). The aim of this study was to investigate the effects of GA therapy on the gene expression of monocytes.
METHODS: Monocytes were isolated from the peripheral blood of eight RRMS patients. The blood was obtained longitudinally before the start of GA therapy as well as after one day, one week, one month and two months. Gene expression was measured at the mRNA level by microarrays.
RESULTS: More than 400 genes were identified as up-regulated or down-regulated in the course of therapy, and we analyzed their biological functions and regulatory interactions. Many of those genes are known to regulate lymphocyte activation and proliferation, but only a subset of genes was repeatedly differentially expressed at different time points during treatment.
CONCLUSIONS: Overall, the observed gene regulatory effects of GA on monocytes were modest and not stable over time. However, our study revealed several genes that are worthy of investigation in future studies on the molecular mechanisms of GA therapy

Well we have had lots of potential mechanisms of action for glaterimer acetate activity and this study suggests it has an effect of macrophages in the blood=monocytes, was this modest effect a chicken or an egg or related to another action of glaterimer

Wednesday, 30 October 2013

Designing Team G

How a designer is helping researchers explain MS science

What makes Team G different..well many things

But Art, Design and Science can mix. 

Alison a Designer in our group, and a student, has been instrumental in the development and implementation of many of our public engagement activities as well as working to improve our patient experience.

Read More on the Post from the MS Trust (Click here)

Clostridium a new trigger of MS?

Has a new trigger been identified for MS? #MSBlog #MSResearch

"This is an interesting study identifying a novel exposure to a bacterium that lives in the gut of people. The authors then study exposure to this bacterium in a larger group of MSers and propose it as being a potential MS trigger. It appears that MSers may have a greater exposure to this particular bacterium than controls. Clearly this work will need to be repeated to make sure it is not a one off finding and then the temporal sequence of events will need to be studied. Causation is a complex subject and needs to be carefully considered."

"I have posted before on causation theory. If you are interested I would recommend reading my previous post I did in relation to CCSVI."

16 Oct 2012
Why are we wasting our time with this two bit theory (CCVSI)? I come on this blog to learn about B cells, EBV, Vit D... CCSVI ruined another MS website I used to visit and I can it happening here - the followers treat it as a ...

Clostridium bacterium: source Wikipedia

Rumah et al. Isolation of Clostridium perfringens Type B in an Individual at First Clinical Presentation of Multiple Sclerosis Provides Clues for Environmental Triggers of the Disease. PLoS One. 2013 Oct 16;8(10):e76359.

These investigators have isolated Clostridium perfringens type B, an epsilon toxin-secreting bacillus, from a young woman at clinical presentation of  MS with actively enhancing lesions on brain MRI. This finding represents the first time that C. perfringens type B has been detected in a human. Epsilon toxin's tropism for the blood-brain barrier (BBB) and binding to oligodendrocytes/myelin makes it a provocative candidate for nascent lesion formation in MS. They  examined a well-characterized population of MSers and healthy controls for carriage of C. perfringens toxinotypes in the gastrointestinal tract. The human commensal Clostridium perfringens type A was present in approximately 50% of healthy human controls compared to only 23% in MS patients. The examined sera and CSF obtained from two tissue banks and found that immunoreactivity to ETX was 10 times more prevalent in people with MS than in healthy controls, indicating prior exposure to ETX in the MS population. C. perfringens epsilon toxin fits mechanistically with nascent MS lesion formation since these lesions are characterized by BBB permeability and oligodendrocyte cell death in the absence of an adaptive immune infiltrate.

WikipediaClostridum perfringens is ever present in nature and can be found as a normal component of decaying vegetation, marine sediment, the intestinal tract of humans and other vertebrates, insects, and soil. There are five types of C. perfringens (A, B, C, D and E), which are identified by the main types of toxins they produce (alpha, beta, iota, epsilon and theta). Type A produces alpha toxin, type B produces alpha, beta, epsilon toxins, type C produces beta toxin, Type D produces alpha and epsilon toxin and type E can produce alpha and iota toxin. C. perfringens Type A is the most common C. perfringens type. This dietary bacteria can cause food poisoning and a condition known as gas gangrene in extreme cases.

Are you sleeping?

Veauthier C. Younger age, female sex, and high number of awakenings and arousals predict fatigue in patients with sleep disorders: a retrospective polysomnographic observational study. Neuropsychiatr Dis Treat. 2013;9:1483-1494. Epub 2013 

BACKGROUND:The Fatigue Severity Scale (FSS) is widely used to assess fatigue, not only in the context of multiple sclerosis-related fatigue, but also in many other medical conditions. Some polysomnographic studies have shown high FSS values in sleep-disordered patients without multiple sclerosis. The Modified Fatigue Impact Scale (MFIS) has increasingly been used in order to assess fatigue, but polysomnographic data investigating sleep-disordered patients are thus far unavailable. Moreover, the pathophysiological link between sleep architecture and fatigue measured with the MFIS and the FSS has not been previously investigated.
METHODS:This was a retrospective observational study (n = 410) with subgroups classified according to sleep diagnosis. The statistical analysis included nonparametric correlation between questionnaire results and polysomnographic data, age and sex, and univariate and multiple logistic regression.
RESULTS:The multiple logistic regression showed a significant relationship between FSS/MFIS values and younger age and female sex. Moreover, there was a significant relationship between FSS values and number of arousals and between MFIS values and number of awakenings.
CONCLUSION:Younger age, female sex, and high number of awakenings and arousals are predictive of fatigue in sleep-disordered patients. 
                               Forgot to take off make-up

Are you sleeping, if not talk to your neuro

Tuesday, 29 October 2013

Common Urinary Problems

Urinary tract infections. How involved do you want your neurologist to be in preventing them? #MSBlog #MSResearch

"We had a meeting yesterday to discuss service development and urinary tract problems, in particular urinary tract infections (UTIs) were one of our priorities. Continence services for MS are typically managed by community-based continence advisers, who take on all-comers with bladder and bowel problems. The problem that was highlighted by one of our MS nurses is that MSers often do not take the advice seriously and don't look after their bladders. The debate was how involved should we be in preventing UTIs without undermining the local services. The consensus from the clinical side was very involved. UTIs are major heathcare utilization problem, cause misery to MSers and probably increase the rate of disability progression. I will be posting a lot more on UTI and bladder management in the next few weeks. In the interim please re-read these two clinic speak posts."

16 Aug 2013
Clinic speak: why the bladder is so important to MSers. Bladder dysfunction; is it a problem for you? #MSBlog #MSResearch #ClinicSpeak. Clinical problem: I am 36 years of age and I have developed urinary frequency and ...
06 May 2013
Clinic speak: poor sleep due to bladder overactivity. Do you have night-time bladder problems? This post is for you. #MSBlog #MSResearch "Recently I have focused on sleep problems in MS. One particular problem is ...

Epub: Castel-Lacanal  et al. Urinary complications and risk factors in symptomatic multiple sclerosis patients. Study of a cohort of 328 patients. Neurourol Urodyn. 2013 Sep 23.

AIMS: Lower urinary tract dysfunctions (LUTD) are very common in MSer and have a significant social impact, while the organic impact is discussed. This study looks at urinary complications and their risk factors in our cohort of MSers, in order to improve the management of LUTD in MS.

METHODS: Between 2004 and 2009, all MSers and managed for LUTD were included in a retrospective study. They studied the epidemiological data (age, gender), the clinical data (duration of MS, EDSS score, progression of MS) and the paraclinical data (urinary creatinine clearance, urine culture, urinary tract ultrasonography and in some cases urodynamic assessment and cystography). They then identified the urinary complications and their risk factors.

RESULTS: Three hundred twenty eight MSers , mean age 49.9 ± 12.3 years, with a MS for 14.3 ± 10 years on average and with a median EDSS score equal to 6 (1-9), were managed for LUTD. One hundred seventy eight (54%) MSers developed one or more urinary complications. They identified duration of MS greater than 8.5 years and an EDSS above 7 as risk factors.

CONCLUSION: Urinary complications are common in symptomatic MS, these results imply screening and specialized care to limit the impact on the quality of life but also to prevent urinary complications.

Pencil in the Date

You have been asking when is the Next Research Day in London will be. 

Well I cannot yet say for definite because Team G are not doing the organization. Next time it is being done by our friends in UCLP at University College London.  They have yet to definitively select the venue and find the funds to support the day.Time is ticking..

At present they have been looking into the possibility of another venue in central London and a date has been pencilled in for Saturday 17th May 2014.   

Remember this is in Pencil Only. 

Will there be an Advent calender this year? So less than a month to get the invites sorted.

Mesenchhymal Stem cells Less active on Autoimmuners

Ben-Ami E, Miller A, Berrih-Aknin S. T cells from autoimmune patients display reduced sensitivity to immunoregulation by Mesenchymal Stem Cells: Role of IL-2. Autoimmun Rev. 2013 Oct. doi:pii: S1568-9972(13)00171-7. 10.1016/j.autrev.2013.09.007. [Epub ahead of print]

Mesenchymal stem cells (MSCs) are multipotent progenitor cells which have been shown to possess broad immunoregulatory and anti-inflammatory capabilities, making them a promising tool to treat autoimmune diseases (AID). Nevertheless, as in recent years T cells from AID patients have been found to resist suppression by regulatory T cells, the question of whether they could be regulated by MSCs arises. To use MSCs as a therapeutic tool in human autoimmune diseases, one prerequisite is that T cells from autoimmune patients will be sensitive to these stem cells. The aim of this work was to investigate the ability of healthy donor derived MSCs to inhibit the proliferation of T cells from two pathophysiologically different AIDs:Multiple Sclerosis (MS) and Myasthenia Gravis (MG). We show that MSC-induced inhibition of interferon-γ production and surface expression of the CD3, CD4 and CD28 receptors by activated lymphocytes was similar in the AID patients and healthy controls. Contrarily, the MSCs' ability to suppress the proliferation of T cells of both diseases was significantly weaker compared to their ability to affect T cells of healthy individuals. Although we found that the inhibitory mechanism is mediated through CD14+ monocytes, the faulty cellular component is the patients' T cells. MSC-treated MS and MG lymphocytes were shown to produce significantly more IL-2 than healthy subjects while coupling of the MSC treatment with neutralizing IL-2 antibodies resulted in inhibition levels similar to those of the healthy controls. MSCs were also found to down-regulate the lymphocyte surface expression of the IL-2 receptor (CD25) through both transcription inhibition and induction of receptor shedding. Addition of IL-2 to MSC-inhibited lymphocytes restored proliferation thus suggesting a key role played by this cytokine in the inhibitory mechanism. Taken together, these results demonstrate the potential of a MSC-based cellular therapy for MS, MG and possibly other autoimmune diseases but also highlight the need for a better understanding of the underlying mechanisms for development and optimization of clinical protocols.

Mesenchymal stem cells are thought to have a major action by inhibiting the immune system. This study suggests that MSers may respond less well to them than non-MSers, because of an influence of a T cell growth factor, so they will not be that good as a immunosuppressor. We will need to wait and see what the ongoing clinical trials show

Does having JC virus affect the choice to stay on Tysabri

Lonergan R, Kinsella K, Kelly S, Duggan M, Scott J, O'Rourke K, Lynch T, Hutchinson M, Tubridy N, McGuigan C. Does JCV antibody positivity encourage cessation of Natalizumab therapy in Multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013 Nov;84(11):e2

BACKGROUND: Natalizumab, a monoclonal α-4-integren receptor antibody, is an effective immunomodulator in highly active relapsing remitting Multiple Sclerosis (HARRMS). Natalizumab has been associated with PML (progressive multifocal leucoencephaopathy), due to opportunistic reactivation of JC polyomavirus (JCv). PML risk may influence decisions to continue therapy. Risk relates to 3 identified risk factors: serum anti-JCv antibodies, prior immunosuppression and prolonged natalizumab therapy (>2 years). Recent commercial availability of a serum JCv-antibody screening test (STRATIFY JCV TM) has been incorporated into a risk-stratification algorithm, presented to patients to help guide treatment. Influence of antibody testing on risk perception and decision to proceed with treatment has not been widely established.
AIM: To examine treatment decisions of patients receiving natalizumab based on their JCv-antibody status.
PATIENTS AND METHODS: Serum JCv-antibodies tested annually in patients receiving natalizumab for HARRMS. Clinical data and decisions to stop natalizumab based on JCv status recorded.
RESULTS:JCv antibody status was available in 112 natalizumab patients. Mean natalizumab duration 27.4 months (2-72). Antibodies detected in 55 (49.1%): 2 (3.6%) stopped due to JCv+ve alone, 14 (25.5%) due to prolonged therapy (>2years), 1 (1.8%) due to prolonged therapy and past immuosuppression, 3 (5.5%) disability progression, 1 (1.8%) to conceive. (12.3% of JCv negative patients stopped due to prolonged therapy). No significant difference in mean natalizumab duration or disease-modifying therapy history between JCv Ab+ve and Ab-ve groups (p>0.05). Other PML risks (>2 years, past immunosuppression) did not differ significantly between JCv+ve patients who opted to continue compared to those choosing to stop (p>0.05).
DISCUSSION: JCv antibody status had little influence on this cohort's decision to discontinue or remain on natalizumab therapy. It is important that patients understand therapeutic benefits and potential risks of alternative treatments before discontinuing due to JCv status alone. Further validation of this risk stratification measure is important.

Monday, 28 October 2013

Survey results on a question of consent

Majority of you would willing for third parties to access your personal health information for research. #MSBlog #MSResearch

"Thank you for completing the following survey. The message is clear that the majority of you favor this initiative."

25 Oct 2013
"Some of you who are interested in big data and use of medical records for research will find this article of interest. It has implications for MS research as most clinicians are now collecting outcome data on people with MS.

Comments from the survey
  1. As long as my personal info stuff that could harm me. Or some sort of block for things like social security other info I am fairly willing what's the harm. How else can this puzzle be solved?
  2. As long as the research furthers the understanding of MS. No if the data is used for meaningless research to pad someones CV.
  3. Why not help try and prevent others from going through the same thing?! Everyone should do their bit in trying to help. 
  4. MS is a battle and hopefully, we're all on the same side.
  5. Together we can be strong, whereas individually we are weak.
  6. I don't see the harm in it.
  7. Easy way to support research. Anyway, privacy is an illusion.
  8. While we have "protections" here in the U.S., they are far less effective than we pretend. I've done some work with databases, and to put it simply true anonymity is darn near impossible. 
  9. At my work recently, Paul Ohm gave a presentation about "privacy." He was the outgoing head of electronic data security for the Federal Trade Commission. In it he talked about the gov. of Massachusetts signing a bill allowing all medical records to be compiled and "stripped of personally identifiable information" so they could be used for outcomes research. Long story short, the Federal Bureau of Investigations was at a graduate students house 2 weeks later because she had sent him his complete medical history with every diagnosis ever received, every prescription ever written, etc. That was in the early 90's. Have computers gotten less powerful in the past 20 years? How many times have you hit accept on a user agreement on-line? He estimates it would take 1,000 hours for every man, woman and child in the U.S. to read the ones we agree without reading. 
  10. There is no absolute privacy and hasn't been for decades. If it hasn't hurt me yet, I'd like to think some good research should come of my records being open. I wrote about his presentation at my work:
  11. or you can google Paul Ohm and look at his work.
  12. On an anonymous basis? no problem. (as long as there is no Facebook-login-option.)
  13. I need to look into this issue further, but I am wary of selling NHS information to private companies. This Governments policy of creeping privatisation has made me nervous.
  14. As long as it really is anonymised.
  15. Of course the sharing of medical records has to be executed properly.
  16. Method of data protection must be shared with patients.
  17. NHS related researchers free access but pharmas pay going rate
  18. GCHQ refused. All access.

Mitoxantrone in Young Msers

Etemadifar M, Afzali P, Abtahi SH, Ramagopalan SV, Nourian SM, Murray RT, Fereidan-Esfahani M. Safety and efficacy of mitoxantrone in paediatric patients with aggressive multiple sclerosis. Eur J Paediatr Neurol. 2013 Oct. doi:pii: S1090-3798(13)00131-1. 10.1016/j.ejpn.2013.09.001. [Epub ahead of print] 

The purpose of this study was to assess the safety and efficacy of mitoxantrone (MX) in pediatric patients with aggressive multiple sclerosis (MS).
METHODS: A retrospective analysis on paediatric MS patients treated with MX was performed with regards to demographic/clinical parameters and magnetic resonance imaging (MRI) findings.
RESULTS: 19 definite paediatric MS cases with mean ± SD age of 15.4 ± 2.8 years underwent 20 mg MX for control of their severe/frequent relapses, high EDSS score or new and active brain MRI lesions. After a median follow-up period of 30[12-60] months, 14 cases (73%) were relapse free; the EDSS score decreased by at least 0.5 in 16 cases (84.2%); and gadolinium-enhancing lesion volume fell by 84.2% in 16 cases. Adverse events included nausea and vomiting, fatigue, alopecia, palpitation, cardiomyopathy and mild leukopenia. All adverse events were mild and transient.
CONCLUSION: Our results suggest MX is a good candidate for treatment of children with worsening RRMS and SPMS. Recommendations regarding patient selection, treatment administration, and close follow-up should be considered. Continuing research is needed to establish its efficacy and safety profile in a multinational collaboration with careful follow-up of adverse events.

It will be interesting to look at the long-term follow up

Happy with Tecfidera

Kappos L, Gold R, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Sarda SP, Agarwal S, Zhang A, Sheikh SI, Seidman E, Dawson KT.
Quality of life outcomes with BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: The DEFINE study. Mult Scler. 2013 Oct 22. [Epub ahead of print]

BACKGROUND:Oral BG-12 (dimethyl fumarate), approved for the treatment of the relapsing forms of MS, has demonstrated clinical efficacy with an acceptable safety profile in the Phase III "Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting Multiple Sclerosis(RRMS)" (DEFINE) and "Comparator and an Oral Fumarate in RRMS" (CONFIRM) studies.
OBJECTIVES:To evaluate the health-related quality of life (HRQoL) impairment that is associated with RRMS and to assess the effects of BG-12 on HRQoL in the DEFINE study.
METHODS:Patients with RRMS were randomized to BG-12 240 mg twice (BID) or three times (TID) daily, or placebo, for 2 years. HRQoL was assessed by the Short Form-36 (SF-36), global assessment of well-being visual analog scale and the EuroQol-5D.
RESULTS:In the 1237 patients from DEFINE, HRQoL impairment was greatest in patients who had higher disability scores and in those who had experienced relapse. Change in SF-36 physical component summary scores during 2 years' treatment significantly favored BG-12 over placebo (both doses: p < 0.001). We saw similar benefits in other measures of functioning and general well-being as early as Week 24. These benefits were maintained during the study.
CONCLUSIONS:Our results add to evidence for a negative impact of RRMS on HRQoL and they demonstrate the benefits of BG-12 on HRQoL measures, which coupled with significant clinical efficacy, further support its use as a new treatment for RRMS.

Are you happy with BG-12, well if it works yep.

CD8 can be nothing cells

Leuenberger T, Paterka M, Reuter E, Herz J, Niesner RA, Radbruch H, Bopp T, Zipp F, Siffrin V. The Role of CD8+ T Cells and Their Local Interaction with CD4+ T Cells in Myelin Oligodendrocyte Glycoprotein35-55-Induced Experimental Autoimmune Encephalomyelitis. J Immunol. 2013 Oct. [Epub ahead of print]T cells have an essential role in the induction of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Although for CD4+ T cells it is well established that they contribute to the disease, less is known about the role of CD8+ T cells. Our aim was to determine the individual contribution of CD4+ and CD8+ T cells in myelin oligodendrocyte glycoprotein (MOG)35-55-induced EAE. We investigated MOG35-55-activated CD8+ T cells to clarify their potential to induce or attenuate EAE. We monitored the behaviour of CD8+ T cells and their interaction with CD4+T cells directly at the site of inflammation in the CNS using intravital imaging of the brainstem of EAE-affected living anesthetized mice. We found that mice without CD4+ T cells did not develop relevant clinical signs of disease, although CD8+ T cells were present in the CNS of these mice. These CD8+ T cells displayed reduced motility compared with those in the presence of CD4+ T cells. In mice that harboured CD4+ and CD8+ T cells, we saw a similar extent of clinical signs of EAE as in mice with only CD4+ T cells. Furthermore, the dynamic motility and viability of CD4+ T cells were not disturbed by CD8+ T cells in the lesions of these mice. Therefore, we conclude that in MOG35-55-induced EAE, CD8+ T cell accumulation in the CNS represents instead an epiphenomenon with no impact on clinical disease or on the effects of CD4+ T cells, the latter being the true inducers of the disease.

We have been talking about CD8 cells first they were suppressor cells , then they were cytotoxic killing machines and now there are a few studies reporting they are suppressor cells, but in this paper they are just nothing cells. This is some fancy imaging, but at the end of the day it tells us what we already knew 10-15 years ago using monoclonal antibodies, that if you deplete CD8 positive T cells not much happens, deplete CD4 T cells and EAE stops.

Study of CD8 cells is important as some MS pathologists suggest that CD8 cells are more common than CD4 T cells...Does this tell us that MS has a viral cause?

Sunday, 27 October 2013

B cell Depletion inhibits relapses

Evdoshenko E, Maslyanskiy A, Lapin S, Zaslavsky L, Dobson R, Totolian A, Skoromets A, Bar-Or A Dynamics of B-Cell Populations in CSF and Blood in Patients Treated with a Combination of Rituximab and Mitoxantrone.. ISRN Neurol. 2013;2013:748127.

Background. Mitoxantrone (MTX) and Rituximab (RTX) are successfully used for treatment of multiple sclerosis (MS) and can be combined to increase efficacy. 

Objective. We used MTX, RTX, and methylprednisolone in a single combined regiment and observed patients prospectively.
Methods. We present results of observational pilot study of combined therapy of RTX and MTX in 28 patients with active MS. Therapeutic protocol consisted of two infusions within 14 days. First infusion was 1000 mg methylprednisolone (MP) IV, 1000 mg RTX IV, and 20 mg MTX IV. On day 14, 1000 mg MP IV and 1000 mg RTX IV were given. Patients were followed prospectively from 12 to 48 months. 
Results and Conclusion. There were no relapses among all 28 patients during the observation period. B-cell depletion of CD19+ and CD19+/CD27+ memory B-cell subpopulation in both compartments was confirmed in all patients at 6 months. We found a more rapid reconstitution of B cells in the CSF than in the peripheral blood and longstanding depression of CD19+CD27+ memory B-cell. 
Conclusion. Effectiveness of combined regimen of RTX and MTX could be related to longstanding depletion of CD19+CD27+ memory B-cell subset.

So B cell depletion is yet again shown to be effective in treating relapses, the immunology brigade think it is because you are depleting antigen presenting cells that block T cell function. Have they got it all wrong and it really is the B cell that is important or do B cell harbor a trigger for MS, such as something like a virus? Get rid of the virus and you remove the trigger.

However before you think about rushing out for some mitoxantrone read on.

Risks from Mitoxatrone

Ellis RJ, Brown S, Boggild M. Therapy related acute leukaemia with mitoxantrone: 4 years on, what is the risk and can it be limited? J Neurol Neurosurg Psychiatry. 2013 Nov;84(11):e2 
BACKGROUND: Therapy related acute leukaemia (TRAL) is a concern for neurologists and patients when considering treatment with Mitoxantrone for Multiple Sclerosis (MS). In 2008 we performed a literature review to determine the risk of TRAL, the associated mortality and potential relationship to total dose exposure.1 Four years on, there have inevitably been numerous further reports of TRAL associated with mitoxantrone therapy for MS, and we have therefore re-reviewed the literature to attempt to establish a definitive risk and stratify this according to dose.

METHODS:A literature search was undertaken for relevant articles to identify all reported cases of TRAL in MS and data extracted from cases reporting individual exposure (dose or mg/m2) and timing of TRAL. We also identified all case series of >50 patients, reporting follow-up and complications of treatment with Mitoxantrone in MS and combined this with the 250 cases from the Walton Centre, Liverpool treated since 1997.

RESULTS: Case series including 12,511 patients were identified; mean dose of Mitoxantrone was 90.1 mg/m2 (range 12-242 mg/m2). TRAL was diagnosed in 0.72%; with a number needed to harm of 139.2 patients. In 142 TRAL cases sufficient data was available to inform analysis of exposure. Onset was a median of 22 months following treatment (range 1-64). APL was the most common leukaemia subtype (58.0%) and AML second most frequent (35.1%). Thirty-seven of 124 TRAL patients had died (29.8%). Eighty-two percent of cases (n=117) occurred in patients exposed to >60 mg/m,2 relative risk 1.86 (p=0.018), when comparing cumulative dose <60 mg/m2 against >60 mg/m2 strongly suggesting a relationship to dose, as is the case with cardiac and reproductive adverse events.
DISCUSSION: Whilst there remains the potential for publication bias to over-estimate the risk, the current review suggests an incidence of TRAL following Mitoxantrone of 1 in 139, significantly higher than our previous analysis of all available data in 2008. The data further highlights that treatment regimes which limit the cumulative dose to <60 mg/m2 (around 100-120 mg for most patients) will minimise the risk of late leukaemia. It is essential that clinicians and patients are aware of this significant risk before embarking on a highly effective, but potentially life-limiting treatment.
Read the conclusions

Saturday, 26 October 2013

Grey Matter Disease Predicts Disability

Do you have gray matter damage? It matters. #MSBlog #MSResearch

"This small study confirms what has already been published about the importance of gray matter pathology and MS prognosis. Gray matter, matters."

"Brain atrophy which includes loss of gray matter is an important metric that is beginning to be included in clinical decision algorithms regarding treatment. The presence of gray  matter atrophy at baseline, and progressive atrophy on treatment predicts a poor outcome. The problem is getting the metric to be reported by our radiologists. The main problem is that the current measures of brain atrophy are too variable in the short-term to be used on individual MSers."

Epub: Filippi et al. Gray matter damage predicts the accumulation of disability 13 years later in MS.Neurology. 2013 Oct 11.

OBJECTIVES: To assess the value of conventional and magnetization transfer (MT) MRI measures of white matter (WM) and gray matter (GM) damage, and their 12-month change, in predicting long-term disability and cognitive impairment in multiple sclerosis (MS).

METHODS: Conventional and MT MRI brain scans were obtained at baseline and at 12 months in 73 MSers, who were followed prospectively with clinical visits and rating of the Expanded Disability Status Scale score and the MS severity score (MSSS) for a median period of 13.3 years. At 13-year follow-up, a neuropsychological assessment was also performed when possible. T2-hyperintense and T1-hypointense lesion volumes, GM fraction (GMF), WM fraction, thalamic fraction, average lesion MT ratio (MTR), average GM MTR, average normal-appearing WM MTR, and thalamic MTR were measured. Random forest and multivariable analyses were performed to identify the predictors of neurologic deterioration and cognitive impairment at 13 years.

RESULTS: At 13-year follow-up, 66% of MSers showed significant worsening of disability and 37% had worsened cognitively. The multivariable model, in which Expanded Disability Status Scale deterioration at final follow-up was the dependent variable, identified baseline GMF (odds ratio [OR] = 0.79, p = 0.01) as the only predictor of worsening of disability (C-index = 0.69). Baseline disease duration (OR = 1.50, p = 0.08) and average GM MTR (OR = 0.87, p = 0.03) were independent variables associated with cognitive deterioration (C-index = 0.97). Baseline MSSS (β = 0.50, p < 0.0001) and baseline GMF (β = -0.32, p = 0.0005) predicted MSSS at follow-up (r2 = 0.45).

CONCLUSIONS: GM damage is one of the key factors associated with long-term accumulation of disability and cognitive impairment in MS.

09 Jul 2013
Methods: These investigators used a selective reminding paradigm to determine whether deficient initial learning or delayed retrieval represents the primary memory deficit in 44 persons with MS. Brain atrophy was measured ...
28 May 2013
The only way we are going to get brain atrophy up the agenda is for you to ask your neurologist about whether or not you have evidence of brain atrophy on your MRI. Unless the atrophy is gross atrophy, i.e. visible to the ...

Blood vessels similar in MS and Non-MS brains

Grabner G, Dal-Bianco A, Hametner S, Lassmann H, Trattnig S.Group specific vein-atlasing: An application for analyzing the venous system under normal andmultiple sclerosis conditions. J Magn Reson Imaging. 2013 Oct 22. doi: 10.1002/jmri.24393. [Epub ahead of print]
PURPOSE:To create a group-specific vein-atlas based on healthy control subjects to visualize the average venous system under normal conditions and to compare the venous volume portion in multiple sclerosis (MS) lesions with that atlas.
Susceptibility-weighted imaging (SWI), as well as T1-weighted imaging, was performed at 7 Tesla on nine healthy controls and nine age-matched MS patients. Automatic vein segmentation was performed on SWI data. The vessel segmentation results of the healthy controls were non-linearly transformed into a model space, and subsequently averaged to create the vein-atlas. Thirteen normal-appearing white matter (NAWM) regions and 18 MS lesions were manually segmented in the patient data, and were used to calculate the venous volume portion in individual patient data and in corresponding regions within the vein-atlas.
RESULTS:The vein-atlas illustrates the average venous network of the control group. The venous volume portion in MS lesions was significantly higher (P < 0.05) compared with the corresponding regions in the vein-atlas. NAWM regions did not differ significantly (P > 0.05) from corresponding atlas regions.
CONCLUSION:The developed vein-atlas shows the average venous system of a specific population and allows, therefore, the evaluation of the venous system of individual subjects.

There are the production of larger vessels in MS lesions but not much difference elsewhere

CCSVI October

Macgowan CK, Chan KY, Laughlin S, Marrie RA, Banwell B. Cerebral arterial and venous blood flow in adolescent multiple sclerosis patients and age-matched controls using phase contrast MRI. J Magn Reson Imaging. 2013 Sep 30. doi: 10.1002/jmri.24388. [Epub ahead of print]

PURPOSE:Altered cerebrovascular blood flow has been proposed as a mechanism for multiple sclerosis (MS). The primary objective of this study was to measure arterial and venous blood flow in adolescent MS patients and healthy controls (HC), in whom confounding factors such as age and lifestyle are less influential.
MATERIALS AND METHODS:Phase-contrast magnetic resonance imaging (MRI) was used to measure flow in 26 MS patients and 26 controls aged 17.7 ± 1.8 and 17.8 ± 2.1 years, respectively. Flow was measured in the left and right internal carotid arteries (ICA), vertebral arteries (VA), internal jugular veins (IJV), and epidural veins (EV). Eighteen MS patients returned for a second MRI examination after 6 months. In all participants, ultrasound criteria for chronic cerebrospinal venous insufficiency (CCSVI) were also evaluated.
RESULTS:Flows (mL/min) in the MS group versus HC group were as follows: right ICA = 262 ± 57 vs. 263 ± 32, left ICA = 260 ± 67 vs. 270 ± 36, right VA = 96 ± 50 vs. 103 ± 30, left VA = 104 ± 37 vs. 118 ± 41, right IJV = 342 ± 180 vs. 345 ± 195, left IJV = 190 ± 131 vs. 250 ± 148, right EV = 33 ± 29 vs. 48 ± 43, and left EV = 36 ± 35 vs. 44 ± 28 (P > 0.17 for all comparisons). In MS participants, a non-significant trend to lower flow in the left IJV was observed, and the flow pulsatility index in the epidural veins was higher. Two MS participants met ultrasound criteria for CCSVI, but no significant difference in flow was detected.
CONCLUSION: No population difference in flow rate was detected in adolescent MS participants relative to age-matched controls.

If venous abnormalities were causal in MS, then they would be seen in young MSers, this adds further weight to the fact that they are age related events and therefore unlikely to be causal

Traboulsee AL, Knox KB, Machan L, Zhao Y, Yee I, Rauscher A, Klass D, Szkup P, Otani R, Kopriva D, Lala S, Li DK, Sadovnick D.Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study. Lancet. 2013 Oct . doi:pii: S0140-6736(13)61747-X. 

Chronic cerebrospinal venous insufficiency has been proposed as a unique combination of extracranial venous blockages and haemodynamic flow abnormalities that occurs only in patients with multiple sclerosis and not in healthy people. Initial reports indicated that all patients with multiple sclerosis had chronic cerebrospinal venous insufficiency. We aimed to establish the prevalence of venous narrowing in people with multiple sclerosis, unaffected full siblings, and unrelated healthy volunteers.
METHODS: We did an assessor-blinded, case-control, multicentre study of people with multiple sclerosis, unaffected siblings, and unrelated healthy volunteers. We enrolled the study participants between January, 2011 and March, 2012, and they comprised 177 adults: 79 with multiple sclerosis, 55 siblings, and 43 unrelated controls, from three centres in Canada. We assessed narrowing of the internal jugular and azygous veins with catheter venography and ultrasound criteria for chronic cerebrospinal venous insufficiency proposed by Zamboni and colleagues. Catheter venography data were available for 149 participants and ultrasound data for 171 participants.
FINDINGS: Catheter venography criteria for chronic cerebrospinal venous insufficiency were positive for one of 65 (2%) people with multiple sclerosis, one of 46 (2%) siblings, and one of 32 (3%) unrelated controls (p=1·0 for all comparisons). Greater than 50% narrowing of any major vein was present in 48 of 65 (74%) people with multiple sclerosis, 31 of 47 (66%) siblings (p=0·41 for comparison with patients with multiple sclerosis), and 26 of 37 (70%) unrelated controls (p=0·82). The ultrasound criteria for chronic cerebrospinal venous insufficiency were fulfilled in 35 of 79 (44%) participants with multiple sclerosis, 17 of 54 (31%) siblings (p=0·15 for comparison with patients with multiple sclerosis) and 17 of 38 (45%) unrelated controls (p=0·98). The sensitivity of the ultrasound criteria for detection of greater than 50% narrowing on catheter venography was 0·406 (95% CI 0·311-0·508), and specificity was 0·643 (0·480-0·780).
INTERPRETATION: This study shows that chronic cerebrospinal venous insufficiency occurs rarely in both patients with multiple sclerosis and in healthy people. Extracranial venous narrowing of greater than 50% is a frequent finding in patients with multiple sclerosis, unaffected siblings, and unrelated controls. The ultrasound criteria are neither sensitive nor specific for narrowing on catheter venography. The significance of venous narrowing to multiple sclerosis symptomatology remains unknown.

Some say this should be the final curtain for CCSVI. How much more evidence is needed? This backs up the Italian MS Society study

Zivadinov R, Karmon Y, Dolic K, Hagemeier J, Marr K, Valnarov V, Kennedy CL, Hojnacki D, Carl EM, Hopkins LN, Levy EI, Weinstock-Guttman B, Siddiqui AH.Multimodal noninvasive and invasive imaging of extracranial venous abnormalities indicative of CCSVI: results of the PREMiSe pilot study. 
BMC Neurol. 2013 Oct 20;13(1):151. [Epub ahead of print]

BACKGROUND: There is no established noninvasive or invasive diagnostic imaging modality at present that can serve as a 'gold standard' or "benchmark" for the detection of the venous anomalies, indicative of chronic cerebrospinal venous insufficiency (CCSVI). We investigated the sensitivity and specificity of 2 invasive vs. 2 non-invasive imaging techniques for the detection of extracranial venous anomalies in the internal jugular veins (IJVs) and azygos vein/vertebral veins (VVs) in patients with multiple sclerosis (MS).

METHODS: The data for this multimodal imaging comparison pilot study was collected in phase 2 of the "Prospective Randomized Endovascular therapy in Multiple Sclerosis" (PREMiSe) study using standardized imaging techniques. Thirty MS subjects were screened initially with Doppler sonography (DS), out of which 10 did not fulfill non-invasive screening procedure requirements on DS that consisted of >=2 venous haemodynamic extracranial criteria. Accordingly, 20 MS patients with relapsing MS were enrolled into the multimodal diagnostic imaging study. For magnetic resonance venography (MRV), IJVs abnormal findings were considered absent or pinpoint flow, whereas abnormal VVs flow was classified as absent. Abnormalities of the VVs were determined only using non-invasive testing. Catheter venography (CV) was considered abnormal when >=50% lumen restriction was detected, while intravascular ultrasound (IVUS) was considered abnormal when >=50% restriction of the lumen or intra-luminal defects or reduced pulsatility was found. Non-invasive and invasive imaging modality comparisons between left, right and total IJVs and between the VVs and azygos vein were performed. Because there is no reliable way of non-invasively assessing the azygos vein, the VVs abnormalities detected by the non-invasive testing were compared to the azygos abnormalities detected by the invasive testing. All image modalities were analyzed in a blinded manner by more than one viewer, upon which consensus was reached. The sensitivity and specificity were calculated using contingency tables denoting the presence or absence of vein-specific abnormality findings between all imaging modalities used individually as the benchmark.
RESULTS: The sensitivity of CV + IVUS was 68.4% for the right and 90% for the left IJV and 85.7% for the azygos vein/VVs, compared to venous anomalies detected on DS. Compared to the venous anomalies detected on MRV, the sensitivity of CV + IVUS was 71.4% in right and 100% in left IJVs and 100% in the azygos vein/VVs; however, the specificity was 38.5%, 38.9% and 11.8%, respectively. The sensitivity between the two invasive imaging techniques, used as benchmarks, ranged from 72.7% for the right IJV to 90% for the azygos vein but the IVUS showed a higher rate of venous anomalies than the CV. There was excellent correspondence between identifying collateral veins on MRV and CV.
CONCLUSIONS: Non-invasive DS screening for the detection of venous anomalies indicative of CCSVI may be a reliable approach for identifying patients eligible for further multimodal invasive imaging testing of the IJVs. However, the non-invasive screening methods were inadequate to depict the total amount of azygos vein/VVs anomalies identified with invasive testing. This pilot study, with limited sample size, shows that both a non-invasive and invasive multimodal imaging diagnostic approach should be recommended to depict a range of extracranial venous anomalies indicative of CCSVI. However, lack of invasive testing on the study subjects whose results were negative on the DS screening and of healthy controls, limits further generalizibility of our findings. In addition, the findings from the 2 invasive techniques confirmed the existence of severe extracranial venous anomalies that significantly impaired normal blood outflow from the brain in this group of MS patients.

So 50% of MSers tested did not have doppler ultrasound evidence of CCSVI but more invasive techniques found venous abnormalities which low specificity.

Using patient data for research

How do you feel about your anonymous medical records being used for clinical research? #MSBlog #MSResearch

"Some of you who are interested in big data and use of medical records for research will find this article of interest. It has implications for MS research as most clinicians are now collecting outcome data on people with MS. Should we be allowed to use this data without consent? You may be aware that the NHS has opened up its data for all to use; you can purchase anonymised data for research. I have recently seen health utilization data pre and post starting a DMT that a pharmaceutical company had purchased from the NHS. The data showed that MSers on a specific DMT used less healthcare resources, supporting the cost-effectiveness of the treatment."

"How do you feel about your data being used for research and sold to third parties for research purposes? Some people state that this is unethical? I am not sure it is. The underlying principles of contemporary medical ethics are threefold; (1) to prevent study participants from harm, or potential harm, (2) to protect personal data and (3) to obtain informed consent. As long as we uphold these principles and get approval for the study via a formal ethics and a peer-review process this should be fine. This is what we call self-regulation. We have to remember what we are doing the research for; to hopefully improve the lives of MSers. What do you think? Please have your say by completing the survey below."

Ewen Callaway. UK push to open up patients’ data. Nature 502, 283 (17 October 2013) doi:10.1038/502283a.


...... In August, posters began appearing in doctor’s practices across England, urging patients to say yes to their medical records being used for scientific research — or, more precisely, not to say no.....

...... The move, now gathering momentum, is part of a campaign by the UK government, alongside major research funders such as the Wellcome Trust in London, to convince a sceptical public to share their health details with researchers, through a system in which patients must expressly opt out. Privacy advocates are encouraging them to do just that.........

..... The government’s plans are part of a shake-up of health data in the National Health Service (NHS) in England, the world’s largest public-health system, that cares for about 53 million people. Following reforms made in April, it will in the coming weeks begin radically changing the way it handles patients’ records. This will involve establishing a central repository to connect hitherto disparate electronic data from general practitioners’ (GP) practices, hospitals and disease registries.......

....... According to some proponents of the plan, patients have little reason to opt out. “People think their records are being shared much more than they already are,” says Nicola Perrin, head of policy at the Wellcome Trust, the UK’s biggest funder of biomedical research. She worries that the public in England have not been adequately informed about the benefits of records sharing, such as improved health care, nor about measures intended to protect privacy. “I think there is underlying support for it, provided one can explain that there are safeguards, and that it isn’t your most personal secrets that researchers want to get,” she adds......

Friday, 25 October 2013

Moderated comments

"All comments on the blog will now be moderated. Several, recent and past, comments posted on this blog have made accusations against individuals that could be considered libelous. Although these comments were made anonymously Google may have the ability to identify these people. I have been told from a legal perspective that posting anonymously does not protect you from libel. To try and prevent any libel cases we have taken the decision to moderate all future comments. Anonymous postings will still be allowed."

Libel = a published false statement that is damaging to a person's reputation; a written defamation.

Aspirin reduces facial flushing with BG12

Aspirin reduces facial flushing with BG12. #MSBlog #MSResearch

"Dimethyl-fumarate, DMF or BG12 is an effective DMT. It is given orally as a twice a day dose. One of the main side effects of the drug is facial flushing that comes on shortly after taking the tablet and subsides within 4-6 weeks. Occasionally the flushing is severe and results in MSers stopping BG12. It is therefore welcome to see the paper below that shows aspirin can reduce this side effect. This should make BG12 more tolerable."

"Us Europeans are still waiting for a decision from Biogen-Idec about if and when the drug will be launched. Let's hope soon. I have several patients under my care who are waiting patiently to start this medication. It will be a great tragedy if we can't access the drug."

BACKGROUND: Delayed-release dimethyl fumarate (DR-DMF) has cytoprotective and antiinflammatory properties and has recently been approved in the United States as an oral treatment for relapsing forms of multiple sclerosis. The most common adverse events associated with DR-DMF are flushing and gastrointestinal (GI) events, the incidences of which diminish over time.

OBJECTIVE: The purpose of this study was to evaluate the tolerability and pharmacokinetic (PK) profile of DR-DMF with or without concomitant acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor.

METHODS: Healthy volunteers (N = 56) were randomized to receive different dosing regimens of DR-DMF or matching placebo with or without pretreatment with 325 mg aspirin for 4 days. Plasma levels of the active metabolite monomethyl fumarate were assessed on days 1 and 4. Flushing and GI events were assessed using patient-reported scales. Potential flushing mediators were explored.

RESULTS: DR-DMF showed a safety, tolerability, and PK profile consistent with previous clinical experience, with no evidence of accumulation. Pretreatment with aspirin had no effect on the primary PK parameters, AUC0-10h, or Cmax. Flushing severity, assessed by 2 subject-reported rating scales, was generally mild and was rated highest at the start of treatment. Pretreatment with aspirin reduced flushing incidence and intensity without affecting GI events or the PK profile of DR-DMF. In some DR-DMF-treated individuals, plasma concentrations of a prostaglandin D2 (PGD2) metabolite were increased.

CONCLUSIONS: In healthy volunteers, DR-DMF was well tolerated over 4 days of dosing, with a PK profile consistent with that previously reported and no evidence of accumulation. Aspirin pretreatment reduced the incidence and intensity of flushing without affecting GI events or the DR-DMF PK profile. Elevated levels of PGD2 in some DR-DMF-treated individuals suggest that flushing may be, at least in part, prostaglandin mediated.

CoI: multiple

Targeting blood proteins for a treatment option. The power to reproduce.

Gur-Wahnon D, Mizrachi T, Maaravi-Pinto FY, Lourbopoulos A, Grigoriadis N, Higazi AA, Brenner T.The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention. J Neuroinflammation. 2013 Oct 11;10(1):124. [Epub ahead of print].
BACKGROUND:Extracellular proteases such as plasminogen activators (PAs) and matrix metalloproteinases modulate cell-cell and cell-matrix interactions. Components of the PA/plasmin system have been shown to be increased in areas of inflammation, and have been suggested to play a role in inflammatory neurologic disorders such as epilepsy, stroke, brain trauma, Alzheimer's' disease and multiple sclerosis (MS). In the present study, we evaluated the involvement of the PA system in the animal model of MS, experimental autoimmune encephalomyelitis (EAE).

METHODS:EAE was induced by myelin oligodendrocyte glycoprotein (MOG) in mice deficient for the urokinase PA (uPA-/-), or the urokinase PA receptor (uPAR-/-). Mice were evaluated for EAE clinical signs and histopathologic parameters, and compared with wild-type (WT) EAE mice. Lymphocytes from the knockout (KO) and WT mice were analyzed for ex vivo restimulation, cytokine secretion, and antigen presentation. Finally, WT EAE mice were treated with PAI-1dp, an 18 amino acid peptide derived from the PA inhibitor protein (PAI-1).
RESULTS:EAE was aggravated in uPA-/- and uPAR-/- mice, and this was accompanied by more severe histopathologic features and microglial activation. By contrast, specific T- cell reactivity towards the encephalitogenic antigen MOG was markedly reduced in the KO animals, as shown by a marked reduction in proliferation and pro-inflammatory cytokine secretion in these mice. Antigen presentation was also reduced in all the KO animals, raising an immunologic paradox. When the mice were treated with PAI-1, a peptide derived from the PA system, a marked and significant improvement in EAE was seen. The clinical improvement was linked to reduced T-cell reactivity, further emphasizing the importance of the PA system in immunomodulation during neuroinflammation.
CONCLUSIONS:Cumulatively, our results suggest a role for uPA and uPAR in EAE pathogenesis, as exacerbation of disease was seen in their absence. Furthermore, the successful amelioration of EAE by PAI-1 treatment suggests that the PA system can be considered a potential site for therapeutic intervention in the treatment of neuroimmune diseases.

Whilst I will not dwell on the content save to say it shows another avenue to treat EAE by targeting the blood clotting system, 

However it is good to see that our earlier work published in two papers has been replicated. 

Whilst we may not be the first to publish stuff, we aim to produce a quality of work that others can is a shame that so many other EAE studies turn out to be non-reproducible guff. 

Part of the problem is the lack of quality control to the experiments.

Therefore it is appropriate that this week we have a publication in the Economist....It is very wasteful to have unreproducible stuff but be warned the Academic Literature is full of it.

Trouble in the Lab (Read the article)

The idea that the same experiments always get the same results, no matter who performs them, is one of the cornerstones of science’s claim to objective truth. If a systematic campaign of replication does not lead to the same results, then either the original research is flawed (as the replicators claim) or the replications are (as many of the original researchers on priming contend). Either way, something is awry.

A few years ago scientists at Amgen, an American drug company, tried to replicate 53 studies that they considered landmarks in the basic science, often co-operating closely with the original researchers to ensure that their experimental technique matched the one used first time round, they were able to reproduce the original results in just six. 

Academic scientists readily acknowledge that they often get things wrong. But they also hold fast to the idea that these errors get corrected over time as other scientists try to take the work further. Evidence that many more dodgy results are published than are subsequently corrected or withdrawn calls that much-vaunted capacity for self-correction into question. 

Scientists like to think of science as self-correcting. To an alarming degree, it is not.

This article19th October in the Economist is well worth reading

Is it all data-fracking?

Data-fracking is the fracturing of a dataset by the application of a pressurized search through as many datapoints as is necessary to find one that has the appearance of being positive. Typically, data is combined with cortisol (stress) and caffeine (coffee), and the mixture is injected at high pressure into statistical analyses to illuminate illusory correlations along which the appearance of success may migrate to a press release. The products of data-fracking tend to be more gaseous than substantive :-).

Thursday, 24 October 2013

Smoking its never too late to quit

Hedström AK, Hillert J, Olsson T, Alfredsson L. Smoking and multiple sclerosis susceptibility. Eur J Epidemiol. 2013 Oct 22. [Epub ahead of print]
Smoking is one of the most established risk factors for multiple sclerosis (MS). The aim of this study was to investigate how age at smoking debut, duration, intensity and cumulative dose of smoking, and smoking cessation influence the association between smoking and MS risk. In two Swedish population-based case-control studies (7,883 cases, 9,264 controls), subjects with different smoking habits were compared regarding MS risk, by calculating odds ratios with 95 % confidence intervals. We observed a clear dose response association between cumulative dose of smoking and MS risk (p value for trend <10 x -35). Both duration and intensity of smoking contributed independently to the increased risk of MS. However, the detrimental effect of smoking abates a decade after smoking cessation regardless of the cumulative dose of smoking. Age at smoking debut did not affect the association between smoking and MS. Smoking increases the risk of MS in a dose response manner. However, in contrary to several other risk factors for MS that seem to affect the risk only if the exposure takes place during a specific period in life, smoking affects MS risk regardless of age at exposure, and the detrimental effect slowly abates after smoking cessation.

So don't smoke to reduce your risk of MS and if your kids smoke and have not got MS, if they stop now it will reduce their risk in the future

Do Insoles Help Balance

Dixon J, Hatton AL, Robinson J, Gamesby-Iyayi H, Hodgson D, Rome K, Warnett R, Martin DJ. Effect of textured insoles on balance and gait in people with multiple sclerosis: an exploratory trial. Physiotherapy. 2013 Sep 23. doi:pii: S0031-9406(13)00074-6. 10.1016/ [Epub ahead of print]

OBJECTIVES: To investigate the immediate effects of textured insoles on balance and gait in people with multiple sclerosis (MS), and to explore any effects after 2 weeks of wear.
METHODS: Forty-six individuals with MS (34 females, 12 males), with a mean (SD) age of 49 (7) years, who could walk 100m unassisted or using one stick/crutch. Participants were tested wearing three types of insoles in a random order: control (smooth), Texture 1 (Algeos) or Texture 2 (Crocs™). Participants were allocated at random to wear one type of textured insoles for 2 weeks, after which they were retested.
MAIN OUTCOME MEASURES: Standing balance (centre of pressure excursions and velocity) was measured with eyes open and eyes closed on a Kistler force platform. Spatio-temporal parameters of gait were measured using a GAITRite system.
RESULTS: The textured insoles had no significant immediate effects on balance or gait, apart from an increase in anteroposterior sway range with eyes open for Texture 2 insoles [mean difference 4.5 (95% confidence interval 0.6 to 8.4)mm]. After 2 weeks, balance was not significantly different, but both types of textured insoles showed significant effects on spatio-temporal parameters of gait, with mean stride length increases of 3.5cm (Texture 1) and 5.3cm (Texture 2) when wearing the insoles.
CONCLUSIONS: After 2 weeks of wear, there were improvements in spatio-temporal parameters of gait. However, it is unclear whether this was a placebo effect or a learning effect.