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When the end is nearPosted Wednesday, August 24, 2011, at 6:48 PM
This is very personal and I don't want it to be a poor me blog.
I'm sure that many of you that follow the blogs and comment on them are old enough to either have been in the situation I'm in now, or will be someday. That situation is the impending death of your last parent and it's affect on your life. Two years ago after a chest x-ray, my Mother was told that there was a growth on her lung, and because of it's location and her age, that there wasn't really much that could be done but wait and watch. My Mother was 93 at the time. My Mother has always been the strong and sensible type so her reaction didn't surprise me. She looked at the doctor and said "You're right". No more, no less. A month ago she called me saying she was having hard time breathing. She didn't call 911, just me. I made the call to 911. To make a long story short, she was taken to the hospital, checked out and had another chest x-ray. I was the one the doctor talked to first. I was the one that heard the words "Six months to twenty-four months." I was the one asked how much to tell her. Knowing my Mother, the choice was easy. I told the doctor to tell her everything. True to form my Mother didn't crumble. She knew this day was coming, but had put it to the back of her mind and never thought of. I knew and never dwelled on it. It was at the hospital that they discovered that she had lost a lot of her lung function and would have to be on O2 almost all the time. They explained all this to her and asked her what she wanted to do. Her answer again was direct and to the point. "Well since I have been barely able to take care of myself lately, I sure as hell can't go home now." She made the choice I could not and would not make for her. She chose long term care, Hospice care, a nursing home. Call it what you will, it is simply a place to go and wait for the end. About a decade ago she had filled out a document called The Five Wishes, it went into detail what she wanted, didn't want, and how she expected to be cared for when the end was near. This is a great document that should be filled out by everyone. Later she also gave me her durable health care power of attorney. Another valuable document. The only thing she didn't do was to grant me a general durable power of attorney. That would represent the end of her freedom. This last month has been filled with work, raising my grandson, and a never ending stream of paperwork and phone calls. There are those who already know I have been an active alcoholic for 30+ years and have only been sober for the last 17 months. These blogs have been a way to hold onto my sanity. An outlet of sorts. Something to help keep my mind occupied. If I seem testy at times, I apologize in advance. It seems very fitting that I am blogging here as my Mother is a proud Veteran of WW2, and as such her ashes will be interred at the Idaho Veterans Cemetery. In the 6 years she has been here, she has come to love this state. Thank you once again for the very warm welcome into your community. Comments Showing comments in chronological order [Show most recent comments first] For anyone interested in The Five Wishes, here is a link. You can print it off, you don't need to pay for it. If you do decide to pay for it, consider it a donation of sorts. http://www.agingwithdignity.org/forms/5w... -- Posted by royincaldwell on Thu, Aug 25, 2011, at 6:42 AM
Thank you, Mr. Pratt, for sharing your experience and for your kind words about our Five Wishes advance directive. It has helped literally millions of families in the 16 years it has been available nationally. People like it because it's easy to understand and use and covers personal, spiritual and family issues in addition to medical and legal ones. Wish 1 is the durable power of attorney for health care designation. To learn more, go to www.agingwithdignity.org. One of the commenters said it is free, but it isn't. Individual copies are $5 each, but only $1 each in quantities of 25 or more. The link given was to our read-only PDF. -- Posted by Paul Malley on Thu, Aug 25, 2011, at 7:19 AM
What an amazing mother you have! I am sure that she regards you as a true blessing during this difficult time. Sobriety is never easy, but you obviously have inherited some tremendous strength from your mother. I too, have been helping raise my grandchildren for the past 6 years. It is a mixed blessing, but a blessing nonetheless. We will keep your family in our thoughts and prayers. -- Posted by KH Gal on Thu, Aug 25, 2011, at 7:33 AM
It's sad when a parent is nearing the end of life. Those old memories start pouring in... Sometimes you have to make choices you don't want to make. It certainly isn't easy when your caring for your Grandson. We got our Grandson when he was only 10 months old and we raised him up until he moved out when he was 20 years old. He never knew his Mom.... Then we took my Mom in when he was about 14 years old. It was a very stressful time, and Grandson being a teenager when we took Mom in. lol! Stay positive and if you need to talk you can email me at firstname.lastname@example.com -- Posted by MsMarylin on Thu, Aug 25, 2011, at 12:45 PM
ONE DAY AT A TIME.....TALK TO HER SHE HAS THINGS TO SAY YOU NEED TO HEAR.........HANG TOUGH YOU KNOW HOW TO GET ME...........I WILL BE AT BARDENAY EAGLE ON WEDNESDAY THE 31ST....6-9 ..GOD BLESS -- Posted by lamont on Thu, Aug 25, 2011, at 4:23 PM
OFF EAGLE ROAD NEXT TO THE HILTON HOTEL.....RIGHT ON THE RIVER....I THINK THE SIGN SAYS RIVER RUN...YOU MAKE A RIGHT DRIVE DOWN TO FIRST RIGHT AND MAKE ANOTHER YOU WILL BE LOOKING AT THE HILTON AND THE BARDENAY NEXT TO IT ON YOUR LEFT........WE ARE ON THE PATIO IN THE BACK.....ARE YOU OK?????????? -- Posted by lamont on Thu, Aug 25, 2011, at 5:19 PM
Hanging in there brother. Some days better than others, but no crisis or insane thoughts. You know what I mean. I know when to holler and have a phone full of numbers. Thanks for the concern. Just wondering where it was at so if I'm not working I might swing by. -- Posted by royincaldwell on Thu, Aug 25, 2011, at 6:02 PM
A View From The Independent Side - Archives - Blog RSS feed - Comments RSS feed - Send email to Roy Pratt - Login I'm an almost 61 year old transplant from California 6 1/2 years ago. I work in road construction, those dastardly flaggers. My family roots go back to New England farms, not the big city. The last town I lived in when in California grew from 16K to 40K in 10 years, and that was enough to drive me out. I don't engage in or tolerate name calling. Name calling reduces an adult discussion to grade school play yard level.
I have never served in the military, but have family members who have, dating back to WW1. I am neither a Democrat nor a Republican. I am neither extremely Liberal or Conservative. I am raising my 16 year old grandson, not what I expected at this age, and dealing with those issues as well as my health and near retirement which are 2 things I intend to talk about. I decided to try my hand at this thanks to the warm welcome I have received on Mike's blog. When I take a position, I will defend it until I am shown that I am mistaken, and when that happens, I apologize. There are other things about me that will come out over time I'm sure.
Hot topics This is a Man and a Company that GETS IT! A celebration of what America should be about!(43 ~ 7:25 AM, Mar 2)
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We thoroughly enjoyed our tour! Our Captain, Sully, was fun and we learned all kinds of things about wonderful Boston!
Doing what: Boston Duck Tour
An amazing experience, even though it was quite cold. Several whales spotted and they were magnificent... A couple were quite close to the boat and thus able to appreciate how big they are. Would definitely do it again and recommend to anyone visiting Boston.
Doing what: Boston Whale Watching Cruise
Great cruise, we were so lucky we met several minke whales and seals but most of all 7 humpback whales in total, alone or in small groups, mostly mother and calf with another female. The staff was quite experienced in spotting the whales and pointing them to us and also recognizing them by the tail, so calling them by name and explaining a little af what is know of each individual.
We could see them swimming close to the surface for breathing and then diving looking for food showing their tails, unforgettable experience.
What I also liked is that all this was done paying attention at minimizing the impact on the animals, keeping distance and using a waterjet propelled boat.
Doing what: Boston Whale Watching Cruise
Capt Paul Reverse (think that was his name) was brilliant! Enjoyed the tour very much and he made us want to stay longer in Boston to explore further. Alas, the bloody Red Sox were in town and we could not get accommodation so we had to move on to Providence to find a bed. Would like to come back one day. Great tour!!
Doing what: Boston Duck Tour
We had a great time on this tour. The "driver / captain " was very knowledgeable and entertaining
Doing what: Boston Duck Tour
I couldn't have asked for a more energetic tour guide! I got a great recap of history along with some great humor. A great way to tour Boston when you only have a day.
Doing what: Boston Duck Tour
nice though the food was not great ..and the space appeared to be too cramped unless u had a big group and u could get a large table ..
Doing what: Boston Dinner Cruise
out tour guide was hilarious and told us a lot of interesting facts. It was a great time enjoyed by all. Our tour guides name was dr. duck I think.
Doing what: Boston Duck Tour
Great food and it was really fun. Must try this Dinner Cruise.
Doing what: Boston Sunset Dinner Cruise with Buffet
The tour guides are all awesome. Their personalities give a different perspective on the same history you will hear on all the boats. This was my 2nd time, and I'd go again.
Doing what: Boston Duck Tour
This trip was an absolute blast!!!! All six of us enjoyed every single minute and we're already talking @ planning the next trip!!! Our tour guide was simply fabulous, all the kids ( even us big kids ) just laughed the whole time. Boston is an incredible city and this tour is truly the best way to visit. If you're intown do yourself a BIG favor and take the tour!!!!!
Doing what: Boston Duck Tour
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Contact Us
John C. Coonley School
Address: 4046 N. Leavitt Street Chicago, IL 60618
Phone: 773-534-5140
Fax: 773-534-5213
Bus Company:
Falcon Bus Company: 773-638-8000
Map and Directions:
Coonley School is located between Leavitt, Bell, Belle Plaine and Irving Park. The main entrance is on Levitt Street.
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As of Friday, October 28, 2011
© Copyright 2014
Clayton News Daily
Henry County police are praising the attentiveness of some Stockbridge neighbors in helping to catch alleged burglars inside a house in their neighborhood.
The neighbors called police to a Stockbridge neighborhood where they believed there was a burglary in progress, on Oct. 25, according to Henry Police Sgt. Mike Ireland.
"Neighbors observed three males entering into [the] residence and notified the police," said Ireland. "Officers arrived at the location and found all three subjects inside the residence. The homeowner was not familiar with the suspects," added Ireland.
Dennis Justo DelaRosa, Najee Egypt Stephens, and Michael Johnathan Vanconey, were arrested and charged with burglary and marijuana possession.
The three alleged burglars appeared before Henry County Magistrate Court Judge Robert Godwin Wednesday. All were jailed under bonds of $15,000 each.
Vanconey and DelaRosa were released from the Henry County Jail on the same day. Stephens remained in jail at press time Friday.
More like this story
- Neighbor's watch effort helps nab burglary suspect ( January 20, 2012 )
- Two indicted in burglary case ( May 31, 2010 )
- Suspect arrested in May burglary ( July 30, 2009 )
- Woman charged in alleged burglary in Stockbridge ( July 12, 2010 )
- Burglary Suspects found in dumpster by police ( June 2, 2010 )


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Chris Lim
Chinese wind owners face cash crunch as state subsidy stops
12 November 2012 04:13 GMT
China puts up more funding to help stimulate solar growth
13 November 2012 11:58 GMT
China's wind capacity could reach 300GW by 2020, study claims
19 September 2012 10:41 GMT
By Dominique Patton, Singapore
Wednesday, December 05 2012
Updated: Friday, December 21 2012
China has ordered its grid companies to pay developers outstanding subsidies owed for renewable energy generated two years ago.
Payment of the subsidies – a fixed amount allocated on top of the regular tariff for coal power-generated electricity – has ground to a halt in some provinces since October 2010, contributing significantly to mounting receivables at China's major wind farm operators.
In a statement dated 26 November and posted online this week, the National Development and Reform Commission (NDRC), China's chief economic policymaking body, requires that grid companies pay subsidies for the period from October 2010- April 2011 within 10 working days.
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Stay Informed Knowledge is power! CanWEA delivers news on the latest developments in the Canadian wind energy industry. Learn more.
Did you know? Wind farms can be built in less than a year - faster than many other types of power plants.
WindSight Fall 2013 Conference '13 Highlights
home > media centre > news releases
MONTRÉAL, Dec. 21 /CNW/ - The Canadian Wind Energy Association (CanWEA) welcomes the announcement of 12 new community and native wind farm projects in Quebec, totaling 291.4 MW. These projects will generate nearly $1 billion of investments in Quebec's regions.
The wind energy industry, together with its municipal and community partners, is continuing to grow and develop in Quebec. "This is excellent news for the communities that will host these projects. Besides major investments, this announcement also ensures the creation of nearly 3,450 full-time jobs in Quebec by 2015," points out Robert Hornung, President of CanWEA.
The wind energy industry is very well established in Quebec and keeps expanding. CanWEA recently revealed its vision for the future development of wind farms in Quebec beyond 2015. "Quebec's wind energy potential is immense. We will have 4,000 MW installed by 2015, and we would like to see a further 8,000 MW added to that goal between 2016 and 2025. This would generate over 91,000 jobs, investments of more than $25 billion, and nearly $95 million in annual spin-offs in the communities in the long term," adds Mr. Hornung.
CanWEA stresses the fact that more wind megawatts need to be allocated in order to reach the goal set by the Quebec government's energy strategy. "We are asking the Quebec government to move quickly to draw up a complete inventory of these "orphan" megawatts and launch a new procurement process to ensure that the objective of 4,000 MW will be met in 2015, which will enable Quebec to benefit from this 100% renewable form of energy as well as the investments and jobs that come with it," concludes Mr. Hornung.
About CanWEA: CanWEA is the voice of Canada's wind energy industry, actively promoting the responsible and sustainable growth of wind energy on behalf of its 450 members. A national non-profit association, CanWEA serves as Canada's leading source of credible information about wind energy and its social, economic and environmental benefits. The document WindVision 2025: A Strategy for Quebec is available at: http://www.canwea.ca/pdf/canwea-quebec-windvision-e-web-final.pdf
For further information: Jean-François Nolet, 514-244-8888


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Bought a Mask from Mike7822. I would defiantly buy from this member again!! Once he received payment he shipped very fast! User was very honest about the product. He did not hold any info back.
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Pacman Classic Pacman. Use the arrow keys to move, eat the dots, and avoid ghosts. 1/1/2005 12:00:00 AM 279,353
X Bound Play breakout with a full 360 degree rotation of your paddle. The blocks are in a circle around you. 1/1/2005 12:00:00 AM 60,248
Missile Strike Protect your base from the asteroids by blowing them up with missiles. 1/1/2005 12:00:00 AM 69,863


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The guest house had a warm and welcoming feel with a large, spotlessly clean and comfortable family room. I was impressed with the fast response to my initial enquiry and the hosts were attentive and accommodating. Breakfast is continental, with an excellent selection including hot porridge. Location is about 7 minutes walk from city centre and location is quiet Excellent... More
- Also Known As:
- Aldersyde Guesthouse Aberdeen, Scotland


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- Overview & Map
- Game Day Tips
- Directions
- How to Buy a Pass
For fans heading to the Coliseum and the USC campus on game day, Go Metro. Metro's bus and rail lines will help get you past the traffic and parking hassles and straight to the action.
To plan the trip that's best for you, check the directions tab or use the
Trip Planner.
Metro Service to the Coliseum
- View printable map (156KB)
Note: Metro will provide extra service on northbound Local Line 204 after games from the northeast corner of Vermont Av/Exposition Bl.
Riding the Expo Line
- Pay Before You Board
- $1.50 per boarding; $5 for Day Pass
- Fares are sold on TAP cards; buy them at ticket vending machines or from a Metro representative
- Tip: Load your TAP card in advance to avoid waiting in line
- Choose the Nearest Station
- East side of Coliseum: Use Expo Park/USC Station
- West side of Coliseum: Use Expo/Vermont Station
- Service runs approximately every six minutes before and after games
Riding the Silver Line
- Pay When You Board
- Cash – $2.45 per boarding
- Day Pass – $5, loaded onto a TAP card
- Use 37th St/USC Station
- Elevated station is on the Harbor Fwy at 37th St, approximately two blocks north of the Coliseum
- Service runs approximately every 20 minutes during the day and every 30-60 minutes in the evening
- Extra service will be added in both directions before and after each game
While on Board
- Small coolers and picnic baskets are okay to bring on board, but please keep aisles clear
- Eating or drinking while in stations or on board Metro buses and trains is not permitted
- Please do not bring barbeque grills, flammable products or oversized items on board
- Obey all traffic signals and instructions from Metro staff
- Look both ways before crossing the tracks and street
- Stand back from the edge of the train platforms and curbs at bus stops
Fan & Customer Code of Conduct
All Metro passes and stored value are sold on TAP, a durable plastic card you can use again and again.
TAP cards can be purchased and reloaded four ways:
- From any Metro Customer Center or from one of 400 sales locations throughout LA. For a map of sales outlets, click here.
- Online at taptogo.net. New cards take approximately one month to arrive in the mail.
- On-board buses (Day Passes only).
- From TAP vending machines (TVMs) at Metro Rail stations. Follow the steps below to purchase or load a TAP card from a TVM.
Tip: Load your TAP card with a $5 Day Pass in advance of the game to avoid waiting in line for your return trip.
And if you're attending more than one game, save time by loading Day Passes for future use onto your card, too.
Note that there is a one-time $1 fee for new TAP cards.


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Fishing regulations are in effect for two years from April 1, 2012, through March 31, 2014. A fishing year is defined as April 1 of one calendar year through March 31 of the following calendar year. NOTE: In the event of emergency changes to the 2012-14 proclamation, Game and Fish will issue a statewide press release and post new information on its website.
New for 2012-2014 - Summary of major changes
2012 - 2014 Fishing Regulations Guide
- Northern pike daily and possession limits are increased to five and 10 statewide.
- Most waters will be open to darkhouse spearfishing, except for a small number of lakes that contain muskie. Lakes where darkhouse spearfishing is not allowed are Braun Lake, Logan County; New Johns Lake, Burleigh County; East Park Lake, West Park Lake and Lake Audubon, McLean County; McClusky Canal; Heckers Lake, Sheridan County; Red Willow Lake, Griggs County; Sweet Briar Dam, Morton County; and the Red and Bois de Sioux rivers.
- Added Sundays for snag-and-release only during the paddlefish season.
- Added a 14-inch walleye length restriction to six lakes in southeast North Dakota – Alkali Lake, Buffalo Lake and Tosse Slough in Sargent County; and Lake Elsie, Lueck Lake and West Moran Lake in Richland County.
- Increased the minimum harvest length of a muskie to 48 inches.
- Added Mott Watershed in Hettinger County and Nelson Lake in Oliver County to the list of "no live baitfish" lakes.
- Eliminated the 24-inch minimum length restriction for northern pike at North and South Golden lakes in Steele County.


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Multiple sclerosis
Multiple sclerosis | |
Classification and external resources | |
Demyelination by MS. The CD68 colored tissue shows several macrophages in the area of the lesion. Original scale 1:100
DiseasesDB | 8412 |
MedlinePlus | 000737 |
eMedicine | neuro/228 oph/179 emerg/321 pmr/82 radio/461 |
MeSH | D009103 |
GeneReviews |
Multiple sclerosis (MS), also known as disseminated sclerosis or encephalomyelitis disseminata, is an inflammatory disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to communicate, resulting in a wide range of signs and symptoms,[1][2] including physical, mental,[2] and sometimes psychiatric problems.[3] MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms).[4] Between attacks, symptoms may go away completely; however, permanent neurological problems often occur, especially as the disease advances.[4]
While the cause is not clear, the underlying mechanism is thought to be either destruction by the immune system or failure of the myelin-producing cells.[5] Proposed causes for this include genetics and environmental factors such as infections.[2][6] MS is usually diagnosed based on the presenting signs and symptoms and the results of supporting medical tests.
There is no known cure for multiple sclerosis. Treatments attempt to improve function after an attack and prevent new attacks.[2] Medications used to treat MS while modestly effective can have adverse effects and be poorly tolerated. Many people pursue alternative treatments, despite a lack of evidence. The long-term outcome is difficult to predict, with good outcomes more often seen in women, those who develop the disease early in life, those with a relapsing course, and those who initially experienced few attacks.[7] Life expectancy is 5 to 10 years lower than that of an unaffected population.[1]
As of 2008, between 2 and 2.5 million people are affected globally with rates varying widely in different regions of the world and among different populations.[8] The disease usually begins between the ages of 20 and 50 and is twice as common in women as in men.[9] The name multiple sclerosis refers to scars (sclerae—better known as plaques or lesions) in particular in the white matter of the brain and spinal cord.[10] MS was first described in 1868 by Jean-Martin Charcot.[10] A number of new treatments and diagnostic methods are under development.
Signs and symptoms
A person with MS can have almost any neurological symptom or sign; with autonomic, visual, motor, and sensory problems being the most common.[1] The specific symptoms are determined by the locations of the lesions within the nervous system, and may include loss of sensitivity or changes in sensation such as tingling, pins and needles or numbness, muscle weakness, very pronounced reflexes, muscle spasms, or difficulty in moving; difficulties with coordination and balance (ataxia); problems with speech or swallowing, visual problems (nystagmus, optic neuritis or double vision), feeling tired, acute or chronic pain, and bladder and bowel difficulties, among others.[1] Difficulties thinking and emotional problems such as depression or unstable mood are also common.[1] Uhthoff's phenomenon, a worsening of symptoms due to exposure to higher than usual temperatures, and Lhermitte's sign, an electrical sensation that runs down the back when bending the neck, are particularly characteristic of MS.[1] The main measure of disability and severity is the expanded disability status scale (EDSS), with other measures such as the multiple sclerosis functional composite being increasingly used in research.[11][12][13]
The condition begins in 85% of cases as a clinically isolated syndrome over a number of days with 45% having motor or sensory problems, 20% having optic neuritis, and 10% having symptoms related to brainstem dysfunction, while the remaining 25% have more than one of the previous difficulties.[14] The course of symptoms occurs in two main patterns initially: either as episodes of sudden worsening that last a few days to months (called relapses, exacerbations, bouts, attacks, or flare-ups) followed by improvement (85% of cases) or as a gradual worsening over time without periods of recovery (10-15% of cases).[9] A combination of these two patterns may also occur[4] or people may start in a relapsing and remitting course that then becomes progressive later on.[9] Relapses are usually not predictable, occurring without warning.[1] Exacerbations rarely occur more frequently than twice per year.[1] Some relapses, however, are preceded by common triggers and they occur more frequently during spring and summer.[15] Similarly, viral infections such as the common cold, influenza, or gastroenteritis increase their risk.[1] Stress may also trigger an attack.[16] Women with MS who become pregnant experience less relapses; however, during the first months after delivery the risk increases.[1] Overall, pregnancy does not seem to influence long-term disability.[1] Many events have not been found to affect relapse rates including vaccination, breast feeding,[1] physical trauma,[17] and Uhthoff's phenomenon.[15]
The cause of MS is unknown; however, it is believed to occur as a result of some combination of environmental factors such as infectious agents and genetics.[1] Theories try to combine the data into likely explanations, but none has proved definitive. While there are a number of environmental risk factors and although some are partly modifiable, further research is needed to determine whether their elimination can prevent MS.[18]
MS is more common in people who live farther from the equator, although exceptions exist.[1][19] These exceptions include ethnic groups that are at low risk far from the equator such as the Samis, Amerindians, Canadian Hutterites, New Zealand Māori,[20] and Canada's Inuit,[9] as well as groups that have a relatively high risk close to the equator such as Sardinians,[9] Palestinians and Parsis.[20] The cause of this geographical pattern is not clear.[9] While the north-south gradient of incidence is decreasing,[19] as of 2010 it is still present.[9]
MS is more common in regions with northern European populations[1] and the geographic variation may simply reflect the global distribution of these high-risk populations.[9] Decreased sunlight exposure resulting in decreased vitamin D production has also been put forward as an explanation.[21][22] A relationship between season of birth and MS lends support to this idea, with fewer people born in the northern hemisphere in November as compared to May being affected later in life.[23] Environmental factors may play a role during childhood, with several studies finding that people who move to a different region of the world before the age of 15 acquire the new region's risk to MS. If migration takes place after age 15, however, the person retains the risk of his home country.[1][18] There is some evidence that the effect of moving may still apply to people older than 15.[1]
MS is not considered a hereditary disease; however, a number of genetic variations have been shown to increase the risk.[24] The probability is higher in relatives of an affected person, with a greater risk among those more closely related.[2] In identical twins both are affected about 30% of the time, while around 5% for non-identical twins and 2.5% of siblings are affected with a lower percentage of half-siblings.[1][2][25] If both parents are affected the risk in their children is 10 times that of the general population.[9] MS is also more common in some ethnic groups than others.[26]
Specific genes that have been linked with MS include differences in the human leukocyte antigen (HLA) system—a group of genes on chromosome 6 that serves as the major histocompatibility complex (MHC).[1] That changes in the HLA region are related to susceptibility has been known for over thirty years,[27] and additionally this same region has been implicated in the development of other autoimmune diseases such as diabetes type I and systemic lupus erythematosus.[27] The most consistent finding is the association between multiple sclerosis and alleles of the MHC defined as DR15 and DQ6.[1] Other loci have shown a protective effect, such as HLA-C554 and HLA-DRB1*11.[1] Overall, it has been estimated that HLA changes account for between 20 and 60% of the genetic predisposition.[27] Modern genetic methods (genome-wide association studies) have discovered at least twelve other genes outside the HLA locus that modestly increase the probability of MS.[27]
Infectious agents
Many microbes have been proposed as triggers of MS, but none have been confirmed.[2] Moving at an early age from one location in the world to another alters a person's subsequent risk of MS.[6] An explanation for this could be that some kind of infection, produced by a widespread microbe rather than a rare one, is related to the disease.[6] Proposed mechanisms include the hygiene hypothesis and the prevalence hypothesis. The hygiene hypothesis proposes that exposure to certain infectious agents early in life is protective, the disease being a response to a late encounter with such agents.[1] The prevalence hypothesis proposes that the disease is due to an infectious agent more common in regions where MS is common and where in most individuals it causes an ongoing infection without symptoms. Only in a few cases and after many years does it cause demyelination.[6][28] The hygiene hypothesis has received more support than the prevalence hypothesis.[6]
Evidence for a virus as a cause include: the presence of oligoclonal bands in the brain and cerebrospinal fluid of most people with MS, the association of several viruses with human demyelination encephalomyelitis, and the occurrence of demyelination in animals caused by some viral infection.[29] Human herpes viruses are a candidate group of viruses. Individuals having never been infected by the Epstein-Barr virus are at a reduced risk of getting MS, whereas those infected as young adults are at a greater risk than those having had it at a younger age.[1][6] Although some consider that this goes against the hygiene hypothesis, since the non-infected have probably experienced a more hygienic upbringing,[6] others believe that there is no contradiction, since it is a first encounter with the causative virus relatively late in life that is the trigger for the disease.[1] Other diseases that may be related include measles, mumps and rubella.[1]
Smoking has been shown to be an independent risk factor for MS.[21] Stress may be a risk factor although the evidence to support this is weak.[18] Association with occupational exposures and toxins—mainly solvents—has been evaluated, but no clear conclusions have been reached.[18] Vaccinations were studied as causal factors; however, most studies show no association.[18] Several other possible risk factors, such as diet and hormone intake, have been looked at; however, evidence on their relation with the disease is "sparse and unpersuasive".[21] Gout occurs less than would be expected and lower levels of uric acid have been found in people with MS. This has led to the theory that uric acid is protective, although its exact importance remains unknown.[30]
The three main characteristics of MS are the formation of lesions in the central nervous system (also called plaques), inflammation, and the destruction of myelin sheaths of neurons. These features interact in a complex and not yet fully understood manner to produce the breakdown of nerve tissue and in turn the signs and symptoms of the disease.[1] Additionally MS is believed to be an immune-mediated disorder that develops from an interaction of the individual's genetics and as yet unidentified environmental causes.[2] Damage is believed to be caused, at least in part, by attack on the nervous system by a person's own immune system.[1]
The name multiple sclerosis refers to the scars (sclerae – better known as plaques or lesions) that form in the nervous system. These lesions most commonly affect the white matter in the optic nerve, brain stem, basal ganglia, and spinal cord, or white matter tracts close to the lateral ventricles.[1] The function of white matter cells is to carry signals between grey matter areas, where the processing is done, and the rest of the body. The peripheral nervous system is rarely involved.[2]
To be specific, MS involves the loss of oligodendrocytes, the cells responsible for creating and maintaining a fatty layer—known as the myelin sheath—which helps the neurons carry electrical signals (action potentials).[1] This results in a thinning or complete loss of myelin and, as the disease advances, the breakdown of the axons of neurons. When the myelin is lost, a neuron can no longer effectively conduct electrical signals.[2] A repair process, called remyelination, takes place in early phases of the disease, but the oligodendrocytes are unable to completely rebuild the cell's myelin sheath.[31] Repeated attacks lead to successively less effective remyelinations, until a scar-like plaque is built up around the damaged axons.[31] These scars are the origin of the symptoms and during an attack magnetic resonance imaging (MRI) often shows more than ten new plaques.[1] This could indicate that there is a number of lesions below which the brain is capable of repairing itself without producing noticeable consequences.[1] Another process involved in the creation of lesions is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons.[1] A number of lesion patterns have been described.[32]
Apart from demyelination, the other sign of the disease is inflammation. Fitting with an immunological explanation, the inflammatory process is caused by T cells, a kind of lymphocyte that plays an important role in the body's defenses.[2] T cells gain entry into the brain via disruptions in the blood–brain barrier. The T cells recognize myelin as foreign and attack it, explaining why these cells are also called "autoreactive lymphocytes".[1]
The attack of myelin starts inflammatory processes, which triggers other immune cells and the release of soluble factors like cytokines and antibodies. Further breakdown of the blood–brain barrier, in turn cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins.[2] Inflammation can potentially reduce transmission of information between neurons in at least three ways.[1] The soluble factors released might stop neurotransmission by intact neurons. These factors could lead to or enhance the loss of myelin, or they may cause the axon to break down completely.[1]
Blood–brain barrier
The blood–brain barrier is a part of the capillary system that prevents the entry of T cells into the central nervous system. It may become permeable to these types of cells secondary to an infection by a virus or bacteria. After it repairs itself, typically once the infection has cleared, T cells may remain trapped inside the brain.[2] Gadolinium cannot cross a normal BBB and, therefore, Gadolinium-enhanced MRI is used to show BBB breakdowns.[33]
Multiple sclerosis is typically diagnosed based on the presenting signs and symptoms, in combination with supporting medical imaging and laboratory testing.[14] It can be difficult to confirm, especially early on, since the signs and symptoms may be similar to those of other medical problems.[1][34] The McDonald criteria, which focus on clinical, laboratory, and radiologic evidence of lesions at different times and in different areas, is the most commonly used method of diagnosis[8] with the Schumacher and Poser criteria being of mostly historical significance.[35] While the above criteria allow for a non-invasive diagnosis, some state that the only definitive proof is an autopsy or biopsy where lesions typical of MS are detected.[1][36][37]
Clinical data alone may be sufficient for a diagnosis of MS if an individual has had separate episodes of neurologic symptoms characteristic of the disease.[36] In those who seek medical attention after only one attack, other testing is needed for the diagnosis. The most commonly used diagnostic tools are neuroimaging, analysis of cerebrospinal fluid and evoked potentials. Magnetic resonance imaging of the brain and spine may show areas of demyelination (lesions or plaques). Gadolinium can be administered intravenously as a contrast agent to highlight active plaques and, by elimination, demonstrate the existence of historical lesions not associated with symptoms at the moment of the evaluation.[36][38] Testing of cerebrospinal fluid obtained from a lumbar puncture can provide evidence of chronic inflammation in the central nervous system. The cerebrospinal fluid is tested for oligoclonal bands of IgG on electrophoresis, which are inflammation markers found in 75–85% of people with MS.[36][39] The nervous system in MS may respond less actively to stimulation of the optic nerve and sensory nerves due to demyelination of such pathways. These brain responses can be examined using visual- and sensory-evoked potentials.[40]
Clinical courses
Several subtypes, or patterns of progression, have been described. Subtypes use the past course of the disease in an attempt to predict the future course. They are important not only for prognosis but also for treatment decisions. In 1996, the United States National Multiple Sclerosis Society described four clinical courses:[4]
- relapsing remitting
- secondary progressive
- primary progressive
- progressive relapsing.
The relapsing-remitting subtype is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits that occur during attacks may either resolve or leave problems, the latter in about 40% of attacks and being more common the longer a person has had the disease.[1][14] This describes the initial course of 80% of individuals with MS.[1] When deficits always resolve between attacks, this is sometimes referred to as benign MS,[41] although people will still build up some degree of disability in the long term.[1] On the other hand, the term malignant multiple sclerosis is used to describe people with MS having reached significant level of disability in a short period of time.[42] The relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS). In CIS, a person has an attack suggestive of demyelination, but does not fulfill the criteria for multiple sclerosis.[1][43] 30 to 70% of persons experiencing CIS later develop MS.[43]
Secondary progressive MS occurs in around 65% of those with initial relapsing-remitting MS, who eventually have progressive neurologic decline between acute attacks without any definite periods of remission.[1][4] Occasional relapses and minor remissions may appear.[4] The most common length of time between disease onset and conversion from relapsing-remitting to secondary progressive MS is 19 years.[44] The primary progressive subtype occurs in approximately 10–20% of individuals, with no remission after the initial symptoms.[14][45] It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements.[4] The usual age of onset for the primary progressive subtype is later than of the relapsing-remitting subtype. It is similar to the age that secondary progressive usually begins in relapsing-remitting MS, around 40 years of age.[1]
Progressive relapsing MS describes those individuals who, from onset, have a steady neurologic decline but also have clear superimposed attacks. This is the least common of all subtypes.[4]
Unusual types of MS have been described; these include Devic's disease, Balo concentric sclerosis, Schilder's diffuse sclerosis, and Marburg multiple sclerosis. There is debate on whether they are MS variants or different diseases.[46] Multiple sclerosis behaves differently in children, taking more time to reach the progressive stage.[1] Nevertheless, they still reach it at a lower average age than adults usually do.[1]
Although there is no known cure for multiple sclerosis, several therapies have proven helpful. The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability. As with any medical treatment, medications used in the management of MS have several adverse effects. Alternative treatments are pursued by some people, despite the shortage of supporting evidence.
Acute attacks
During symptomatic attacks, administration of high doses of intravenous corticosteroids, such as methylprednisolone, is the usual therapy,[1] with oral corticosteroids seeming to have a similar efficacy and safety profile.[47] Although, in general, effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery.[48] The consequences of severe attacks that do not respond to corticosteroids might be treatable by plasmapheresis.[1]
Disease-modifying treatments
Relapsing remitting multiple sclerosis
Eight disease-modifying treatments have been approved by regulatory agencies for relapsing-remitting multiple sclerosis (RRMS) including: interferon beta-1a, interferon beta-1b, glatiramer acetate, mitoxantrone, natalizumab, fingolimod,[49] teriflunomide[50] and dimethyl fumarate.[51] Their cost effectiveness as of 2012 is unclear.[52]
In RRMS they are modestly effective at decreasing the number of attacks.[49] The interferons and glatiramer acetate are first-line treatments[14] and are roughly equivalent, reducing relapses by approximately 30%.[53] Early-initiated long-term therapy is safe and improves outcomes.[54][55] Natalizumab reduces the relapse rate more than first-line agents; however, due to issues of adverse effects is a second-line agent reserved for those who do not respond to other treatments[14] or with severe disease.[53] Mitoxantrone, whose use is limited by severe adverse effects, is a third-line option for those who do not respond to other medications.[14] Treatment of clinically isolated syndrome (CIS) with interferons decreases the chance of progressing to clinical MS.[1][56] Efficacy of interferons and glatiramer acetate in children has been estimated to be roughly equivalent to that of adults.[57] The role of some of the newer agents such as fingolimod, teriflunomide, and dimethyl fumarate, as of 2011, is not yet entirely clear.[58]
Progressive multiple sclerosis
No treatment has been shown to change the course of primary progressive MS[14] and as of 2011 only one medication, mitoxantrone, has been approved for secondary progressive MS.[59] In this population tentative evidence supports mitoxantrone moderately slowing the progression of the disease and decreasing rates of relapses over two years.[60][61]
Adverse effects
The disease-modifying treatments have several adverse effects. One of the most common is irritation at the injection site for glatiramer acetate and the interferons (up to 90% with subcutaneous injections and 33% with intramuscular injections).[62] Over time, a visible dent at the injection site, due to the local destruction of fat tissue, known as lipoatrophy, may develop.[62] Interferons may produce flu-like symptoms;[63] some people taking glatiramer experience a post-injection reaction with flushing, chest tightness, heart palpitations, breathlessness, and anxiety, which usually lasts less than thirty minutes.[64] More dangerous but much less common are liver damage from interferons,[65] systolic dysfunction (12%), infertility, and acute myeloid leukemia (0.8%) from mitoxantrone,[60][66] and progressive multifocal leukoencephalopathy occurring with natalizumab (occurring in 1 in 600 people treated).[14][67]
Fingolimod may give rise to hypertension and bradycardia, macular edema, elevated liver enzymes or a reduction in lymphocyte levels.[58] Tentative evidence supports the short term safety of teriflunomide, with common side effects including: headaches, fatigue, nausea, hair loss, and limb pain.[49] There have also been reports of liver failure and PML with its use and it is dangerous for fetal development.[58] Most common side effects of dimethyl fumarate are flushing and gastrointestinal problems.[51][58] While dimethyl fumarate may lead to a reduction in the white blood cell count there were no reported cases of opportunistic infections during trials.[68][69]
Associated symptoms
Both medications and neurorehabilitation have been shown to improve some symptoms, though neither changes the course of the disease.[70] Some symptoms have a good response to medication, such as an unstable bladder and spasticity, while others are little changed.[1] For neurologic problems, a multidisciplinary approach is important for improving quality of life; however, it is difficult to specify a 'core team' as many different health services may be needed at different points in time.[1] Multidisciplinary rehabilitation programs increase activity and participation of people with MS but do not influence impairment level.[71] There is limited evidence for the overall efficacy of individual therapeutic disciplines,[72][72][73] though there is good evidence that specific approaches, such as exercise,[74][75] and psychology therapies, in particular cognitive behavioral approaches are effective.[76]
Alternative treatments
Over 50% of people with MS may use complementary and alternative medicine, although percentages vary depending on how alternative medicine is defined.[77] The evidence for the effectiveness for such treatments in most cases is weak or absent.[77][78] While there is tentative evidence that vitamin D may be useful, evidence is insufficient for a definitive conclusion.[79] Treatments of unproven benefit used by people with MS include: dietary supplementation and regimens,[77][80][81] relaxation techniques such as yoga,[77] herbal medicine (including medical cannabis),[77][82] hyperbaric oxygen therapy,[83] self-infection with hookworms, reflexology and acupuncture.[77][84] Regarding the characteristics of users, they are more frequently women, have had MS for a longer time, tend to be more disabled and have lower levels of satisfaction with conventional healthcare.[77]
The expected future course of the disease depends on the subtype of the disease; the individual's sex, age, and initial symptoms; and the degree of disability the person has.[7] Female sex, relapsing-remitting subtype, optic neuritis or sensory symptoms at onset, few attacks in the initial years and especially early age at onset, are associated with a better course.[7][85]
The average life expectancy is 30 years from onset, which is 5 to 10 years lower than that of unaffected people.[1] Almost 40% of people with MS reach the seventh decade of life.[85] Nevertheless, two-thirds of the deaths are directly related to the consequences of the disease.[1] Suicide is more common, while infections and other complications are especially dangerous for the more disabled.[1] Although most people lose the ability to walk before death, 90% are capable of independent walking at 10 years from onset, and 75% at 15 years.[85][86]
The number of people with MS, as of 2010, is 2–2.5 million (approximately 30 per 100,000) globally, with rates varying widely in different regions.[8][9] It is estimated to have resulted in 18,000 deaths that year.[87] In Africa rates are less than 0.5 per 100,000, while they are 2.8 per 100,000 in South East Asia, 8.3 per 100,000 in the Americas, and 80 per 100,000 in Europe.[8] Rates surpass 200 per 100,000 in certain populations of Northern European descent.[9] The number of new cases that develop per year is about 2.5 per 100,000.[8]
Rates of MS appear to be increasing, this however may be explained simply by better diagnosis.[9] Studies on populational and geographical patterns have been common[28] and have led to a number of theories about the cause.[6][18][21]
MS usually appears in adults in their late twenties or early thirties but it can rarely start in childhood and after 50 years of age.[8][9] The primary progressive subtype is more common in people in their fifties.[45] Similar to many autoimmune disorders, the disease is more common in women, and the trend may be increasing.[1][19] As of 2008, globally it is about two times more common in women than in men.[8] In children, it is even more common in females than males,[1] while in people over fifty, it affects males and females almost equally.[45]
Medical discovery
The French neurologist Jean-Martin Charcot (1825–1893) was the first person to recognize multiple sclerosis as a distinct disease in 1868.[88] Summarizing previous reports and adding his own clinical and pathological observations, Charcot called the disease sclerose en plaques. The three signs of MS now known as Charcot's triad 1 are nystagmus, intention tremor, and telegraphic speech (scanning speech), though these are not unique to MS. Charcot also observed cognition changes, describing his patients as having a "marked enfeeblement of the memory" and "conceptions that formed slowly".[10]
Before Charcot, Robert Carswell (1793–1857), a British professor of pathology, and Jean Cruveilhier (1791–1873), a French professor of pathologic anatomy, had described and illustrated many of the disease's clinical details, but did not identify it as a separate disease.[88] Specifically, Carswell described the injuries he found as "a remarkable lesion of the spinal cord accompanied with atrophy".[1] Under the microscope, Swiss pathologist Georg Eduard Rindfleisch (1836–1908) noted in 1863 that the inflammation-associated lesions were distributed around blood vessels.[89][90] During the 20th century theories about the cause and pathogenesis were developed and effective treatments began to appear in 1990s.[1]
Historical cases
There are several historical accounts of people who lived before or shortly after the disease was described by Charcot and probably had MS.
A young woman called Halldora who lived in Iceland around 1200 suddenly lost her vision and mobility but, after praying to the saints, recovered them seven days after. Saint Lidwina of Schiedam (1380–1433), a Dutch nun, may be one of the first clearly identifiable people with MS. From the age of 16 until her death at 53, she had intermittent pain, weakness of the legs, and vision loss—symptoms typical of MS.[91] Both cases have led to the proposal of a "Viking gene" hypothesis for the dissemination of the disease.[92]
Augustus Frederick d'Este (1794–1848), son of Prince Augustus Frederick, Duke of Sussex and Lady Augusta Murray and the grandson of George III of the United Kingdom, almost certainly had MS. D'Este left a detailed diary describing his 22 years living with the disease. His diary began in 1822 and ended in 1846, although it remained unknown until 1948. His symptoms began at age 28 with a sudden transient visual loss (amaurosis fugax) after the funeral of a friend. During the course of his disease, he developed weakness of the legs, clumsiness of the hands, numbness, dizziness, bladder disturbances, and erectile dysfunction. In 1844, he began to use a wheelchair. Despite his illness, he kept an optimistic view of life.[93][94] Another early account of MS was kept by the British diarist W. N. P. Barbellion, nom-de-plume of Bruce Frederick Cummings (1889–1919), who maintained a detailed log of his diagnosis and struggle.[94] His diary was published in 1919 as The Journal of a Disappointed Man.[95]
There is ongoing research looking for more effective, convenient, and tolerable treatments for relapsing-remitting MS; creation of therapies for the progressive subtypes; neuroprotection strategies; and effective symptomatic treatments.[96]
During the 2000s and 2010s, there has been approval of several oral drugs that are expected to gain in popularity and frequency of use.[97] Several more oral drugs are under investigation, one being laquinimod, which was announced in August 2012 and is in a third phase III trial after mixed results in the previous ones.[98] Similarly, studies aimed to improve the efficacy and ease of use of already existing therapies are occurring. This includes the use of new preparations such as the PEGylated version of interferon-β-1a, which it is hoped may be given at less frequent doses with similar effects.[99][100] Request for approval ofpeginterferon beta-1a is expected during 2013.[100]
Monoclonal antibodies have also raised high levels of interest. Alemtuzumab, daclizumab, and CD20 monoclonal antibodies such as rituximab, ocrelizumab and ofatumumab have all shown some benefit and are under study as potential treatments.[69] Their use has also been accompanied by the appearance of potentially dangerous adverse effects, the most important of which being opportunistic infections.[97] Related to these investigations is the development of a test for JC virus antibodies, which might help to determine who is at greater risk of developing progressive multifocal leukoencephalopathy when taking natalizumab.[97] While monoclonal antibodies will probably have some role in the treatment of the disease in the future, it is believed that it will be small due to the risks associated with them.[97]
Another research strategy is to evaluate the combined effectiveness of two or more drugs.[101] The main rationale for using a number of medications in MS is that the involved treatments target different mechanisms and, therefore, their use is not necessarily exclusive.[101] Synergies, in which one drug improves the effect of another are also possible, but there can also be drawbacks such as the blocking of the action of the other or worsened side-effects.[101] There have been several trials of combined therapy, yet none have shown positive enough results to be considered as a useful treatment for MS.[101]
Research on neuroprotection and regenerative treatments, such as stem cell therapy, while of high importance, are in the early stages.[102] Likewise, there are not any effective treatments for the progressive variants of the disease. Many of the newest drugs as well as those under development are probably going to be evaluated as therapies for PPMS or SPMS.[97]
Disease biomarkers
While diagnostic criteria are not expected to change in the near future, work to develop biomarkers that help with diagnosis and prediction of disease progression is ongoing.[97] New diagnostic methods that are being investigated include work with anti-myelin antibodies, and studies with serum and cerebrospinal fluid, but none of them has yielded reliably positive results.[104]
At the current time, there are no laboratory investigations that can predict prognosis. Several promising approaches have been proposed including: interleukin-6, nitric oxide and nitric oxide synthase, osteopontin, and fetuin-A.[104] Since disease progression is the result of degeneration of neurons, the roles of proteins showing loss of nerve tissue such as neurofilaments, tau, and N-acetylaspartate are under investigation.[104] Other effects include looking for biomarkers that distinguish between those who will and will not respond to medications.[104]
Improvement in neuroimaging techniques such as positron emission tomography (PET) or magnetic resonance imaging (MRI) carry a promise for better diagnosis and prognosis predictions, although the effect of such improvements in daily medical practice may take several decades.[97] Regarding MRI, there are several techniques that have already shown some usefulness in research settings and could be introduced into clinical practice, such as double-inversion recovery sequences, magnetization transfer, diffusion tensor, and functional magnetic resonance imaging.[105] These techniques are more specific for the disease than existing ones, but still lack some standardization of acquisition protocols and the creation of normative values.[105] There are other techniques under development that include contrast agents capable of measuring levels of peripheral macrophages, inflammation, or neuronal dysfunction,[105] and techniques that measure iron deposition that could serve to determine the role of this feature in MS, or that of cerebral perfusion.[105] Similarly, new PET radiotracers might serve as markers of altered processes such as brain inflammation, cortical pathology, apoptosis, or remylienation.[106] Antibiodies against the Kir4.1 potassium channel maybe related to MS.[107]
Chronic cerebrospinal venous insufficiency
In 2008, vascular surgeon Paolo Zamboni suggested that MS involves narrowing of the veins draining the brain, which he referred to as chronic cerebrospinal venous insufficiency (CCSVI). He found CCSVI in all patients with MS in his study, performed a surgical procedure, later called in the media the "liberation procedure" to correct it, and claimed that 73% of participants improved.[108] This theory received significant attention in the media and among those with MS, especially in Canada.[109] Concerns have been raised with Zamboni's research as it was neither blinded nor controlled, and its assumptions about the underlying cause of the disease is not backed by known data.[110] Also, further studies have either not found a similar relationship or found one that is much less strong one,[111] raising serious objections to the hypothesis.[112] The "liberation procedure" has been criticized for resulting in serious complications and deaths with unproven benefits.[110] It is, thus, as of 2013 not recommended for the treatment of MS.[113] Additional research investigating the CCSVI hypothesis are underway.[114]
See also
- ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be Compston A, Coles A (October 2008). "Multiple sclerosis". Lancet 372 (9648): 1502–17. doi:10.1016/S0140-6736(08)61620-7. PMID 18970977.
- ^ a b c d e f g h i j k l m Compston A, Coles A (April 2002). "Multiple sclerosis". Lancet 359 (9313): 1221–31. doi:10.1016/S0140-6736(02)08220-X. PMID 11955556.
- ^ Murray ED, Buttner EA, Price BH (2012). "Depression and Psychosis in Neurological Practice". In Daroff R, Fenichel G, Jankovic J, Mazziotta J. Bradley's neurology in clinical practice. (6th ed. ed.). Philadelphia, PA: Elsevier/Saunders. ISBN 1-4377-0434-4.
- ^ a b c d e f g h Lublin FD, Reingold SC; National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis (April 1996). "Defining the clinical course of multiple sclerosis: results of an international survey". Neurology 46 (4): 907–11. doi:10.1212/WNL.46.4.907. PMID 8780061.
- ^ Nakahara, J; Maeda, M; Aiso, S; Suzuki, N (February 2012). "Current concepts in multiple sclerosis: autoimmunity versus oligodendrogliopathy.". Clinical reviews in allergy & immunology 42 (1): 26–34. doi:10.1007/s12016-011-8287-6. PMID 22189514.
- ^ a b c d e f g h Ascherio A, Munger KL (April 2007). "Environmental risk factors for multiple sclerosis. Part I: the role of infection". Annals of Neurology 61 (4): 288–99. doi:10.1002/ana.21117. PMID 17444504.
- ^ a b c Weinshenker BG (1994). "Natural history of multiple sclerosis". Annals of Neurology 36 (Suppl): S6–11. doi:10.1002/ana.410360704. PMID 8017890.
- ^ a b c d e f g World Health Organization (2008). Atlas: Multiple Sclerosis Resources in the World 2008. Geneva: World Health Organization. pp. 15–16. ISBN 92-4-156375-3.
- ^ a b c d e f g h i j k l m Milo R, Kahana E (March 2010). "Multiple sclerosis: geoepidemiology, genetics and the environment". Autoimmun Rev 9 (5): A387–94. doi:10.1016/j.autrev.2009.11.010. PMID 19932200.
- ^ a b c Clanet M (June 2008). "Jean-Martin Charcot. 1825 to 1893" (PDF). Int MS J 15 (2): 59–61. PMID 18782501.
* Charcot, J. (1868). "Histologie de la sclerose en plaques". Gazette des hopitaux, Paris 41: 554–5. - ^ Kurtzke JF (1983). "Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS)". Neurology 33 (11): 1444–52. doi:10.1212/WNL.33.11.1444. PMID 6685237.
- ^ Amato MP, Ponziani G (August 1999). "Quantification of impairment in MS: discussion of the scales in use". Mult. Scler. 5 (4): 216–9. PMID 10467378.
- ^ Rudick RA, Cutter G, Reingold S (October 2002). "The multiple sclerosis functional composite: a new clinical outcome measure for multiple sclerosis trials". Mult. Scler. 8 (5): 359–65. PMID 12356200.
- ^ a b c d e f g h i Tsang, BK; Macdonell, R (December 2011). "Multiple sclerosis- diagnosis, management and prognosis.". Australian family physician 40 (12): 948–55. PMID 22146321.
- ^ a b Tataru N, Vidal C, Decavel P, Berger E, Rumbach L (2006). "Limited impact of the summer heat wave in France (2003) on hospital admissions and relapses for multiple sclerosis". Neuroepidemiology 27 (1): 28–32. doi:10.1159/000094233. PMID 16804331.
- ^ Heesen C, Mohr DC, Huitinga I, et al. (March 2007). "Stress regulation in multiple sclerosis: current issues and concepts". Mult. Scler. 13 (2): 143–8. doi:10.1177/1352458506070772. PMID 17439878.
- ^ Martinelli V (2000). "Trauma, stress and multiple sclerosis". Neurol. Sci. 21 (4 Suppl 2): S849–52. doi:10.1007/s100720070024. PMID 11205361.
- ^ a b c d e f Marrie RA (December 2004). "Environmental risk factors in multiple sclerosis aetiology". Lancet Neurol 3 (12): 709–18. doi:10.1016/S1474-4422(04)00933-0. PMID 15556803.
- ^ a b c Alonso A, Hernán MA (July 2008). "Temporal trends in the incidence of multiple sclerosis: a systematic review". Neurology 71 (2): 129–35. doi:10.1212/01.wnl.0000316802.35974.34. PMID 18606967.
- ^ a b Pugliatti M, Sotgiu S, Rosati G (July 2002). "The worldwide prevalence of multiple sclerosis". Clin Neurol Neurosurg 104 (3): 182–91. doi:10.1016/S0303-8467(02)00036-7. PMID 12127652.
- ^ a b c d Ascherio A, Munger KL (June 2007). "Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors". Annals of Neurology 61 (6): 504–13. doi:10.1002/ana.21141. PMID 17492755.
- ^ Ascherio A, Munger KL, Simon KC (June 2010). "Vitamin D and multiple sclerosis". Lancet Neurol 9 (6): 599–612. doi:10.1016/S1474-4422(10)70086-7. PMID 20494325.
- ^ Kulie T, Groff A, Redmer J, Hounshell J, Schrager S (2009). "Vitamin D: an evidence-based review". J Am Board Fam Med 22 (6): 698–706. doi:10.3122/jabfm.2009.06.090037. PMID 19897699.
- ^ Dyment DA, Ebers GC, Sadovnick AD (February 2004). "Genetics of multiple sclerosis". Lancet Neurol 3 (92): 104–10. doi:10.1016/S1474-4422(03)00663-X. PMID 14747002.
- ^ Hassan-Smith, G; Douglas, MR (October 2011). "Epidemiology and diagnosis of multiple sclerosis.". British journal of hospital medicine (London, England : 2005) 72 (10): M146–51. PMID 22041658.
- ^ Rosati G (April 2001). "The prevalence of multiple sclerosis in the world: an update". Neurol. Sci. 22 (2): 117–39. doi:10.1007/s100720170011. PMID 11603614.
- ^ a b c d Baranzini SE (June 2011). "Revealing the genetic basis of multiple sclerosis: are we there yet?". Current Opinion in Genetics & Development 21 (3): 317–24. doi:10.1016/j.gde.2010.12.006. PMC 3105160. PMID 21247752.
- ^ a b Kurtzke JF (October 1993). "Epidemiologic evidence for multiple sclerosis as an infection". Clin. Microbiol. Rev. 6 (4): 382–427. doi:10.1128/CMR.6.4.382. PMC 358295. PMID 8269393.
- ^ Gilden DH (March 2005). "Infectious causes of multiple sclerosis". The Lancet Neurology 4 (3): 195–202. doi:10.1016/S1474-4422(05)01017-3. PMID 15721830.
- ^ Spitsin S, Koprowski H (2008). "Role of uric acid in multiple sclerosis". Curr. Top. Microbiol. Immunol. 318: 325–42. PMID 18219824.
- ^ a b Chari DM (2007). "Remyelination in multiple sclerosis". Int. Rev. Neurobiol. 79: 589–620. doi:10.1016/S0074-7742(07)79026-8. PMID 17531860.
- ^ Pittock SJ, Lucchinetti CF (March 2007). "The pathology of MS: new insights and potential clinical applications". Neurologist 13 (2): 45–56. doi:10.1097/01.nrl.0000253065.31662.37. PMID 17351524.
- ^ Ferré JC, Shiroishi MS, Law M (November 2012). "Advanced techniques using contrast media in neuroimaging". Magn Reson Imaging Clin N Am 20 (4): 699–713. doi:10.1016/j.mric.2012.07.007. PMID 23088946.
- ^ Trojano M, Paolicelli D (November 2001). "The differential diagnosis of multiple sclerosis: classification and clinical features of relapsing and progressive neurological syndromes". Neurol. Sci. 22 (Suppl 2): S98–102. doi:10.1007/s100720100044. PMID 11794488.
- ^ Poser CM, Brinar VV (June 2004). "Diagnostic criteria for multiple sclerosis: an historical review". Clin Neurol Neurosurg 106 (3): 147–58. doi:10.1016/j.clineuro.2004.02.004. PMID 15177763.
- ^ a b c d McDonald WI, Compston A, Edan G, et al. (July 2001). "Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis". Annals of Neurology 50 (1): 121–7. doi:10.1002/ana.1032. PMID 11456302.
- ^ Polman CH, Reingold SC, Edan G, et al. (December 2005). "Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria"". Annals of Neurology 58 (6): 840–6. doi:10.1002/ana.20703. PMID 16283615.
- ^ Rashid W, Miller DH (February 2008). "Recent advances in neuroimaging of multiple sclerosis". Semin Neurol 28 (1): 46–55. doi:10.1055/s-2007-1019127. PMID 18256986.
- ^ Link H, Huang YM (November 2006). "Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness". J. Neuroimmunol. 180 (1–2): 17–28. doi:10.1016/j.jneuroim.2006.07.006. PMID 16945427.
- ^ Gronseth GS, Ashman EJ (May 2000). "Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology 54 (9): 1720–5. doi:10.1212/WNL.54.9.1720. PMID 10802774.
- ^ Pittock SJ, Rodriguez M (2008). "Benign multiple sclerosis: a distinct clinical entity with therapeutic implications". Curr. Top. Microbiol. Immunol. 318: 1–17. doi:10.1007/978-3-540-73677-6_1. PMID 18219812.
- ^ Feinstein, A (2007). The clinical neuropsychiatry of multiple sclerosis (2nd ed. ed.). Cambridge: Cambridge University Press. p. 20. ISBN 052185234X.
- ^ a b Miller D, Barkhof F, Montalban X, Thompson A, Filippi M (May 2005). "Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis". Lancet Neurol 4 (5): 281–8. doi:10.1016/S1474-4422(05)70071-5. PMID 15847841.
- ^ Rovaris M, Confavreux C, Furlan R, Kappos L, Comi G, Filippi M (April 2006). "Secondary progressive multiple sclerosis: current knowledge and future challenges". Lancet Neurol 5 (4): 343–54. doi:10.1016/S1474-4422(06)70410-0. PMID 16545751.
- ^ a b c Miller DH, Leary SM (October 2007). "Primary-progressive multiple sclerosis". Lancet Neurol 6 (10): 903–12. doi:10.1016/S1474-4422(07)70243-0. PMID 17884680.
- ^ Stadelmann C, Brück W (November 2004). "Lessons from the neuropathology of atypical forms of multiple sclerosis". Neurol. Sci. 25 (Suppl 4): S319–22. doi:10.1007/s10072-004-0333-1. PMID 15727225.
- ^ Burton, JM (Dec 12, 2012). "Oral versus intravenous steroids for treatment of relapses in multiple sclerosis.". Cochrane Database of Systematic Reviews (12): CD006921 (Orig. rev.). doi:10.1002/14651858.CD006921. PMID 23235634.
- ^ Multiple sclerosis : national clinical guideline for diagnosis and management in primary and secondary care (pdf). London: Royal College of Physicians. 2004. pp. 54–57. ISBN 1-86016-182-0. PMID 21290636. Retrieved 6 February 2013.
- ^ a b c He, D; Xu, Z; Dong, S; Zhang, H; Zhou, H; Wang, L; Zhang, S (Dec 12, 2012). "Teriflunomide for multiple sclerosis". In Zhou, Hongyu. Cochrane database of systematic reviews (Online) 12: CD009882. doi:10.1002/14651858.CD009882.pub2. PMID 23235682.
- ^ "FDA approves new multiple sclerosis treatment Aubagio" (Press release). US FDA. 2012-09-12. Retrieved 2013-01-21.
- ^ a b "Biogen Idec's TECFIDERA™ (Dimethyl Fumarate) Approved in US as a First-Line Oral Treatment for Multiple Sclerosis" (Press release). Biogen Idec. 2013-03-27. Retrieved 2013-06-04.
- ^ Manouchehrinia, A; Constantinescu, CS (October 2012). "Cost-effectiveness of disease-modifying therapies in multiple sclerosis.". Current neurology and neuroscience reports 12 (5): 592–600. doi:10.1007/s11910-012-0291-6. PMID 22782520.
- ^ a b Hassan-Smith, G; Douglas, MR (November 2011). "Management and prognosis of multiple sclerosis.". British journal of hospital medicine (London, England : 2005) 72 (11): M174–6. PMID 22082979.
- ^ Freedman MS (January 2011). "Long-term follow-up of clinical trials of multiple sclerosis therapies". Neurology 76 (1 Suppl 1): S26–34. doi:10.1212/WNL.0b013e318205051d. PMID 21205679.
- ^ Qizilbash N, Mendez I, Sanchez-de la Rosa R (January 2012). "Benefit-risk analysis of glatiramer acetate for relapsing-remitting and clinically isolated syndrome multiple sclerosis". Clin Ther 34 (1): 159–176.e5. doi:10.1016/j.clinthera.2011.12.006. PMID 22284996.
- ^ Bates D (January 2011). "Treatment effects of immunomodulatory therapies at different stages of multiple sclerosis in short-term trials". Neurology 76 (1 Suppl 1): S14–25. doi:10.1212/WNL.0b013e3182050388. PMID 21205678.
- ^ Johnston J, So TY (June 2012). "First-line disease-modifying therapies in paediatric multiple sclerosis: a comprehensive overview". Drugs 72 (9): 1195–211. doi:10.2165/11634010-000000000-00000. PMID 22642799.
- ^ a b c d Killestein J, Rudick RA, Polman CH (November 2011). "Oral treatment for multiple sclerosis". Lancet Neurol 10 (11): 1026–34. doi:10.1016/S1474-4422(11)70228-9. PMID 22014437.
- ^ Kellerman, Rick D.; Edward N. Hanley Jr MD (2011). Conn's Current Therapy 2012: Expert Consult - Online and Print. Philadelphia: Saunders. p. 627. ISBN 1-4557-0738-4.
- ^ a b Martinelli Boneschi, F; Vacchi, L; Rovaris, M; Capra, R; Comi, G (May 31, 2013). "Mitoxantrone for multiple sclerosis.". Cochrane database of systematic reviews (Online) 5: CD002127. doi:10.1002/14651858.CD002127.pub3. PMID 23728638.
- ^ Marriott, JJ; Miyasaki, JM; Gronseth, G; O'Connor, PW; Therapeutics and Technology Assessment Subcommittee of the American Academy of, Neurology (May 4, 2010). "Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.". Neurology 74 (18): 1463–70. doi:10.1212/WNL.0b013e3181dc1ae0. PMC 2871006. PMID 20439849.
- ^ a b Balak, DM; Hengstman, GJ; Çakmak, A; Thio, HB (December 2012). "Cutaneous adverse events associated with disease-modifying treatment in multiple sclerosis: a systematic review.". Multiple sclerosis (Houndmills, Basingstoke, England) 18 (12): 1705–17. doi:10.1177/1352458512438239. PMID 22371220.
- ^ Sládková T, Kostolanský F (2006). "The role of cytokines in the immune response to influenza A virus infection". Acta Virol. 50 (3): 151–62. PMID 17131933.
- ^ Munari L, Lovati R, Boiko A (2004). "Therapy with glatiramer acetate for multiple sclerosis". In Munari, Luca M. Cochrane database of systematic reviews (Online) (1): CD004678. doi:10.1002/14651858.CD004678. PMID 14974077.
- ^ Tremlett H, Oger J (November 2004). "Hepatic injury, liver monitoring and the beta-interferons for multiple sclerosis". J. Neurol. 251 (11): 1297–303. doi:10.1007/s00415-004-0619-5. PMID 15592724.
- ^ Comi G (October 2009). "Treatment of multiple sclerosis: role of natalizumab". Neurol. Sci. 30. Suppl 2 (S2): S155–8. doi:10.1007/s10072-009-0147-2. PMID 19882365.
- ^ Hunt, D; Giovannoni, G (February 2012). "Natalizumab-associated progressive multifocal leucoencephalopathy: a practical approach to risk profiling and monitoring.". Practical neurology 12 (1): 25–35. doi:10.1136/practneurol-2011-000092. PMID 22258169.
- ^ "NDA 204063 - FDA Approved Labeling Text". US Food and Drug Agency. 27 March 2013. Retrieved 5 April 2013.
"NDA Approval". US Food and Drug Agency. 27 March 2013. Retrieved 5 April 2013. - ^ a b Saidha S, Eckstein C, Calabresi PA (January 2012). "New and emerging disease modifying therapies for multiple sclerosis". Annals of the New York Academy of Sciences 1247: 117–37. doi:10.1111/j.1749-6632.2011.06272.x. PMID 22224673.
- ^ Kesselring J, Beer S (October 2005). "Symptomatic therapy and neurorehabilitation in multiple sclerosis". Lancet Neurol 4 (10): 643–52. doi:10.1016/S1474-4422(05)70193-9. PMID 16168933.
- ^ Khan F, Turner-Stokes L, Ng L, Kilpatrick T (2007). "Multidisciplinary rehabilitation for adults with multiple sclerosis". In Khan, Fary. Cochrane Database Syst Rev (2): CD006036. doi:10.1002/14651858.CD006036.pub2. PMID 17443610.
- ^ a b Steultjens EM, Dekker J, Bouter LM, Leemrijse CJ, van den Ende CH (2005). "Evidence of the efficacy of occupational therapy in different conditions: an overview of systematic reviews". Clinical rehabilitation 19 (3): 247–54. doi:10.1191/0269215505cr870oa. PMID 15859525.
- ^ Steultjens EM, Dekker J, Bouter LM, Cardol M, Van de Nes JC, Van den Ende CH (2003). "Occupational therapy for multiple sclerosis". In Steultjens, Esther EMJ. Cochrane database of systematic reviews (Online) (3): CD003608. doi:10.1002/14651858.CD003608. PMID 12917976.
- ^ Gallien P, Nicolas B, Robineau S, Pétrilli S, Houedakor J, Durufle A (2007). "Physical training and multiple sclerosis". Ann Readapt Med Phys 50 (6): 373–6, 369–72. doi:10.1016/j.annrmp.2007.04.004. PMID 17482708.
- ^ Rietberg MB, Brooks D, Uitdehaag BMJ, Kwakkel G (2005). "Exercise therapy for multiple sclerosis". In Kwakkel, Gert. Cochrane Database of Systematic Reviews (1): CD003980. doi:10.1002/14651858.CD003980.pub2. PMID 15674920.
- ^ Thomas PW, Thomas S, Hillier C, Galvin K, Baker R (2006). "Psychological interventions for multiple sclerosis". In Thomas, Peter W. Cochrane Database of Systematic Reviews (1): CD004431. doi:10.1002/14651858.CD004431.pub2. PMID 16437487.
- ^ a b c d e f g Huntley A (January 2006). "A review of the evidence for efficacy of complementary and alternative medicines in MS". Int MS J 13 (1): 5–12, 4. PMID 16420779.
- ^ Olsen SA (2009). "A review of complementary and alternative medicine (CAM) by people with multiple sclerosis". Occup Ther Int 16 (1): 57–70. doi:10.1002/oti.266. PMID 19222053.
- ^ Jagannath, VA; Fedorowicz, Z; Asokan, GV; Robak, EW; Whamond, L (Dec 8, 2010). "Vitamin D for the management of multiple sclerosis.". Cochrane database of systematic reviews (Online) (12): CD008422. doi:10.1002/14651858.CD008422.pub2. PMID 21154396.
- ^ Farinotti M, Simi S, Di Pietrantonj C, et al. (2007). "Dietary interventions for multiple sclerosis". In Farinotti, Mariangela. Cochrane database of systematic reviews (Online) (1): CD004192. doi:10.1002/14651858.CD004192.pub2. PMID 17253500.
- ^ Grigorian A, Araujo L, Naidu NN, Place DJ, Choudhury B, Demetriou M. (September 2011). "N-acetylglucosamine inhibits T-helper 1 (Th1)/T-helper 17 (Th17) cell responses and treats experimental autoimmune encephalomyelitis.". J Biol Chem 286 (46): 40133–41. doi:10.1074/jbc.M111.277814. PMID 21965673.
- ^ Chong MS, Wolff K, Wise K, Tanton C, Winstock A, Silber E (2006). "Cannabis use in patients with multiple sclerosis". Mult. Scler. 12 (5): 646–51. doi:10.1177/1352458506070947. PMID 17086912.
- ^ Bennett M, Heard R (2004). "Hyperbaric oxygen therapy for multiple sclerosis". In Bennett, Michael H. Cochrane database of systematic reviews (Online) (1): CD003057. doi:10.1002/14651858.CD003057.pub2. PMID 14974004.
- ^ Adams, Tim (23 May 2010). "Gut instinct: the miracle of the parasitic hookworm". The Observer.
- ^ a b c Phadke JG (May 1987). "Survival pattern and cause of death in patients with multiple sclerosis: results from an epidemiological survey in north east Scotland". J. Neurol. Neurosurg. Psychiatr. 50 (5): 523–31. doi:10.1136/jnnp.50.5.523. PMC 1031962. PMID 3495637.
- ^ Myhr KM, Riise T, Vedeler C, et al (February 2001). "Disability and prognosis in multiple sclerosis: demographic and clinical variables important for the ability to walk and awarding of disability pension". Mult. Scler. 7 (1): 59–65. PMID 11321195.
- ^ Lozano, R (Dec 15, 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.". Lancet 380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. PMID 23245604.
- ^ a b Compston A (October 1988). "The 150th anniversary of the first depiction of the lesions of multiple sclerosis". J. Neurol. Neurosurg. Psychiatr. 51 (10): 1249–52. doi:10.1136/jnnp.51.10.1249. PMC 1032909. PMID 3066846.
- ^ Lassmann H (October 1999). "The pathology of multiple sclerosis and its evolution". Philosophical Transactions of the Royal Society B 354 (1390): 1635–40. doi:10.1098/rstb.1999.0508. PMC 1692680. PMID 10603616.
- ^ Lassmann H (July 2005). "Multiple sclerosis pathology: evolution of pathogenetic concepts". Brain Pathology 15 (3): 217–22. doi:10.1111/j.1750-3639.2005.tb00523.x. PMID 16196388.
- ^ Medaer R (September 1979). "Does the history of multiple sclerosis go back as far as the 14th century?". Acta Neurol. Scand. 60 (3): 189–92. doi:10.1111/j.1600-0447.1979.tb08970.x. PMID 390966.
- ^ Holmøy T (2006). "A Norse contribution to the history of neurological diseases". Eur. Neurol. 55 (1): 57–8. doi:10.1159/000091431. PMID 16479124.
- ^ Firth, D (1948). The Case of August D`Esté. Cambridge: Cambridge University Press.
- ^ a b Pearce JM (2005). "Historical descriptions of multiple sclerosis". Eur. Neurol. 54 (1): 49–53. doi:10.1159/000087387. PMID 16103678.
- ^ Barbellion, Wilhelm Nero Pilate (1919). The Journal of a Disappointed Man. New York: George H. Doran. ISBN 0-7012-1906-8.
- ^ Cohen JA (July 2009). "Emerging therapies for relapsing multiple sclerosis". Arch. Neurol. 66 (7): 821–8. doi:10.1001/archneurol.2009.104. PMID 19597083.
- ^ a b c d e f g Miller AE (2011). "Multiple sclerosis: where will we be in 2020?". Mt. Sinai J. Med. 78 (2): 268–79. doi:10.1002/msj.20242. PMID 21425270.
- ^ Jeffrey, susan (9 Aug 2012). "CONCERTO: A Third Phase 3 Trial for Laquinimod in MS". Medscape Medical News. Retrieved 21 May 2013.
- ^ Kieseier BC, Calabresi PA (March 2012). "PEGylation of interferon-β-1a: a promising strategy in multiple sclerosis". CNS Drugs 26 (3): 205–14. doi:10.2165/11596970-000000000-00000. PMID 22201341.
- ^ a b "Biogen Idec Announces Positive Top-Line Results from Phase 3 Study of Peginterferon Beta-1a in Multiple Sclerosis" (Press release). Biogen Idec. 2013-01-24. Retrieved 2013-05-21.
- ^ a b c d Milo R, Panitch H (February 2011). "Combination therapy in multiple sclerosis". J. Neuroimmunol. 231 (1-2): 23–31. doi:10.1016/j.jneuroim.2010.10.021. PMID 21111490.
- ^ Luessi F, Siffrin V, Zipp F (September 2012). "Neurodegeneration in multiple sclerosis: novel treatment strategies". Expert Rev Neurother 12 (9): 1061–76; quiz 1077. doi:10.1586/ern.12.59. PMID 23039386.
- ^ Mehta V, Pei W, Yang G, et al. (2013). "Iron is a sensitive biomarker for inflammation in multiple sclerosis lesions". PLoS ONE 8 (3): e57573. doi:10.1371/journal.pone.0057573. PMC 3597727. PMID 23516409.
- ^ a b c d Harris VK, Sadiq SA (2009). "Disease biomarkers in multiple sclerosis: potential for use in therapeutic decision making". Mol Diagn Ther 13 (4): 225–44. doi:10.2165/11313470-000000000-00000. PMID 19712003.
- ^ a b c d Filippi M, Rocca MA, De Stefano N, et al. (December 2011). "Magnetic resonance techniques in multiple sclerosis: the present and the future". Arch. Neurol. 68 (12): 1514–20. doi:10.1001/archneurol.2011.914. PMID 22159052.
- ^ Kiferle L, Politis M, Muraro PA, Piccini P (February 2011). "Positron emission tomography imaging in multiple sclerosis-current status and future applications". Eur. J. Neurol. 18 (2): 226–31. doi:10.1111/j.1468-1331.2010.03154.x. PMID 20636368.
- ^ Methner, A; Zipp, F (2013 Feb). "Multiple sclerosis in 2012: Novel therapeutic options and drug targets in MS.". Nature reviews. Neurology 9 (2): 72–3. doi:10.1038/nrneurol.2012.277. PMID 23338282.
- ^ Zamboni P, Galeotti R, Menegatti E, et al. (April 2009). "Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis". J. Neurol. Neurosurg. Psychiatr. 80 (4): 392–9. doi:10.1136/jnnp.2008.157164. PMC 2647682. PMID 19060024.
- ^ Pullman D, Zarzeczny A, Picard A (2013). "Media, politics and science policy: MS and evidence from the CCSVI Trenches". BMC Med Ethics 14: 6. doi:10.1186/1472-6939-14-6. PMC 3575396. PMID 23402260.
- ^ a b Qiu J (May 2010). "Venous abnormalities and multiple sclerosis: another breakthrough claim?". Lancet Neurol 9 (5): 464–5. doi:10.1016/S1474-4422(10)70098-3. PMID 20398855.
- ^ Ghezzi A, Comi G, Federico A (February 2011). "Chronic cerebro-spinal venous insufficiency (CCSVI) and multiple sclerosis". Neurol. Sci. 32 (1): 17–21. doi:10.1007/s10072-010-0458-3. PMID 21161309.
- ^ Dorne H, Zaidat OO, Fiorella D, Hirsch J, Prestigiacomo C, Albuquerque F, Tarr RW. (October 2010). "Chronic cerebrospinal venous insufficiency and the doubtful promise of an endovascular treatment for multiple sclerosis". J NeuroIntervent Surg 2 (4): 309–311. doi:10.1136/jnis.2010.003947. PMID 21990639.
- ^ Baracchini C, Atzori M, Gallo P (March 2013). "CCSVI and MS: no meaning, no fact". Neurol. Sci. 34 (3): 269–79. doi:10.1007/s10072-012-1101-2. PMID 22569567.
- ^ van Zuuren, EJ; Fedorowicz, Z; Pucci, E; Jagannath, VA; Robak, EW (Dec 12, 2012). "Percutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis patients.". Cochrane database of systematic reviews (Online) 12: CD009903. doi:10.1002/14651858.CD009903.pub2. PMID 23235683.
Further reading
- Langgartner M, Langgartner I, Drlicek M (April 2005). "The patient's journey: multiple sclerosis". BMJ 330 (7496): 885–8. doi:10.1136/bmj.330.7496.885. PMC 556161. PMID 15831874.
External links
- Multiple sclerosis on the Open Directory Project
- Database for analysis and comparison of global data on the epidemiology of MS


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MPU 300x250
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RHA Releases The MA-350 Critically-Acclaimed Earphones
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RHA, the Glasgow based audio company, have launched their critically-acclaimed earphone, the MA-350, in the US. Designed and engineered in the UK, the MA-350s are machined from solid, aircraft grade aluminium, sandblasted and partially anodised in matte black.
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Monster Inspiration Noise Canceling Over the Ear Headphones: Monster, a world leader in fashionable personal audio gear, is releasing the Inspiration™, Monster's first over-ear, advanced noise-canceling headphone. Noel Lee, the CEO of Monster has designed the Inspiration headphones. He is sound and engineering innovator behind Beats™ by Dr. Dre,™. Monster Inspiration headphones feature unique and
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BERKELEY, CALIFORNIA, June 21, 2012 – Canalis today announced the launch of its new website, wwwcanalisaudio.com. The new website features detailed information, images and other news about loudspeakers and other products from Canalis, a new division of high-end audio manufacturer Spiral Groove.
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Read More »Serene Audio Talisman Desktop Speaker Review
By adam June 06, 2012
With so many desktop speakers on the market, consumers have ample combinations of sonic performances, visual designs, and price points, to choose from. Usually there are trade offs. Sonic performance normally takes the biggest hit. Rarely does a small desktop speaker capture the trifecta of great looks, reasonable price, and great sonic performance. But the
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Marlboro, N.J. – May 17, 2012 – KEF, the renowned manufacturer of innovative, reference-quality loudspeakers for over 50 years, will present a full range of award-winning products, including KEF Blade, the world's first single apparent source loudspeaker, to attendees of T.H.E. Show., held June 1-3 in Newport Beach, Calif.
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RAHWAY, N.J., May 17, 2012 – Adding a spectrum of colors to home audio systems, iHome today announced theiP76 LED Color Changing Speaker Tower with Bluetooth technology.
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MCINTOSH EXPANDS ITS LEGENDARY PROCESSOR LINE WITH THE RELEASE OF MX121 AND MX151 A/V CONTROL CENTERS – Even More Advanced Home Theater Capabilities, Including 3D Pass-Through, Maximum Performance from All Advanced Sources; MX121 Offers Wireless Access to Music from Network Devices – BINGHAMTON, NY, May 11, 2012 – McIntosh Laboratory, a global leader in home entertainment systems that has
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Northeast Region
For more information on sustainable agriculture programs and educational materials, contact the following states' coordinators.
In-depth information about activities, and contact information, can also be found at each state's SARE webpage.
State Coordinators |
Joe Bonelli Delaware
John Clendaniel
Mark VanGessel District of Columbia
Yao Afantchao
4200 Connecticut Ave.NW Maine
Ellen Mallory Maryland
Berran Rogers
Nevin Dawson Massachusetts
Sonia Schloemann |
New Hampshire
Seth Wilner New Jersey
Jack Rabin New York
Anusuya Rangarajan Pennsylvania
Charlie White Rhode Island
Heather Faubert Vermont
Debra Heleba West Virginia
Doolarie Singh-Knights
Barbara Liedl |
State Staff |
Connecticut, Massachusetts and Rhode Island
Michael Keilty Delaware and Maryland Eastern Shore
Jason Challandes Maine
Tom Molloy |
New Hampshire
Amy Ouellette New York
Violet Stone West Virginia and Western Maryland
Nola Wilson |


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smithaa02 - 3:04 pm on Nov 2, 2012 (gmt 0)
Sorry for the confusion Jez...My personal vote then is if you do want to keep the old domain for branding but not SEO, then I would not redirect but rather keep it as is and put a 'we have moved graphic' that people can click on. People have definitely been hit by 301'ing polluted domains to new ones. If you turn the old page into a portal to your new...maybe obfuscate it with javascript link, js redirect or flash or even nofollow the link to keep google off your back. Just seem like 301'ing is too dangerous.
A option might be a 302. Google says these are ok for advertisers because they don't pass page juice...might be worth it to research to see what happened for penguin hit sites 302'ing to new domains.


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text: Six years ago, Josh Tyrangiel was set to transform the publishing business in the digital age. In September 2006, he became editor of Time.com and assistant managing editor at Time. He advanced the media giant's Internet footprint, and then left to become editor of Bloomberg Businessweek after its December 2009 acquisition by Bloomberg L.P. Mr. Tyrangiel has earned respect for what he accomplished at Time.com, and deserves credit for getting out while the going was good. He hit the ground running—scoring a sit-down with President Obama just a month into the job—and reinvented Bloomberg Businessweek as one of the country's best general-interest magazines. Mr. Tyrangiel has made the magazine's design more interesting; he's also taken some starch out of the Bloomberg News reporting style. Mr. Tyrangiel's mentors and admirers include publishing legends Walter Isaacson and Norman Pearlstine. After Sandy, a Bloomberg Businessweek cover screamed, "IT'S GLOBAL WARMING, STUPID." Mr. Tyrangiel tweeted, "Our cover story this week may generate controversy. But only among the stupid." There's no reason not to think Josh Tyrangiel isn't headed for even bigger things.


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Skirmish Laser Games Exeter provides the ultimate in Kids Birthday Parties at our leading Laser Games site in Stoke Woods, Exeter, Devon delivering over 15 years experience in Paintball & laser Games, with a wide range of game zones and scenarios.
Play from 8 years old.
We have a varied range of Kids Games and equipment, such as antlers! Suits with targets on the back etc! to make you day special. We have a superb covered seating area to entertain your guests; if you wish have other entertainment during, or at the end of your day.
The venue is a 120 acre woodland site and delivers Laser Games at the highest level, with games ranging in size from 10 to 140 players, although you can book individually.


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No Hurricane Sales Tax Holiday
The state legislature voted down a hurricane tax break holiday, citing a budget 4 billion dollars lighter than a year ago. This is the first time in three years the state didn't implement a sales tax holiday for hurricane season. Governor Charlie Crist urges families to prepare and says there's still an incentive to stock up.
"The good news this year is that the private sector is really stepping up to the plate," said Crist. "There's a lot of different outlets in Florida that are having specials for people to be able to purchase the kind of things that they need, coolers, water, batteries, flashlights, the essentials that you need during hurricane season to be ready to have your plan and be in place so I'm very pleased about that."
Besides the hurricane preparedness tax break, the legislature said no to a back to school tax break and a gas tax holiday.
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- Alachua County Half Cent Sales Tax Expires
- Online Sales Tax?
- Alachua County Considers 1 Cent Sales Tax For Roads


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We have a large variety of Verizon Cell Phones. Android, Apple and Blackberry devices. Find Used Cell Phones, Refurbished Cell Phones and Brand New cell phones at the lowest prices. All phones are backed with our 30 x day guarantee.
VERIZON Motorola DROID 2 Android Smart Cell Phone BAD ESN USED Fair Condition
Condition: Used
$49.95 $49.95 -
Motorola Droid Bionic XT875 Verizon 4G LTE 4.3" Phone New Open Box
Condition: New / Brand New
$149.95 $149.95
Motorola Droid X2 for Verizon Phone - No Contract Refurbished
Condition: Refurbished by Seller
$79.95 $79.95
Motorola MOTO DROID 3 XT862 Phone Verizon Refurbished
Condition: Refurbished by Seller
$134.95 $134.95


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Oracle® Fusion Middleware Oracle Reports User's Guide to Building Reports 11g Release 1 (11.1.1) Part Number B32122-01 |
View PDF |
To redefault the layout to use the additional query data:
In the Object Navigator, click the report name.
Choose Tools > Report Wizard to re-enter the wizard.
In the Report Wizard, on the Groups page, click G_custid1 in the Available Groups list and click Down to specify the Print Direction and move this group to the Displayed Groups list.
On the Fields page, click prodname and amount in the Available Fields list and click the right arrow (>) to move these fields to the Displayed Fields list.
On the Labels page, change the labels and field widths as follows:
Fields | Labels | Width |
prodname | Product Name |
30 |
amount | Amount |
9 |
On the Template page, click Finish to display your report output in the Paper Design view. It should look something like this:
Figure 19-5 Revised report layout in Paper Design view
Note that the data is still grouped by the Sales Representative with customer data listed below each Sales Representative. But now, the individual products sold to the customers are listed below each customer. The report now has multiple pages.


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I've been thinking about Sleepwalker. In a perfect world, it would be an ongoing by Warren Ellis and Kev Walker.
Well done sirOriginally Posted by Masculine Todd
It's a bit like having sex with a jellyfish: once might an interesting experiment, twice would be perversion!
-Grant Morrison
You never know what worse luck your bad luck has saved you from.
-Cormac McCarthy
I've been thinking about Sleepwalker. In a perfect world, it would be an ongoing by Warren Ellis and Kev Walker.
This storyline was always fun for me and I loved the fold out cover for the final part...
You could kind of tell Larsen was getting ready to leave Marvel and wanted to draw as many Marvel characters as he could before he left to get them out of his system.
Last edited by The Zevad; 02-23-2012 at 08:32 PM.
Also the fact Doc was still recovering from his injuries and he was back to his original non admantium arms didn't help put that scene in a postive light for me either. It just seemed so..vindictive and petty.
Which did entertain me but for other reasons.
Here's a link to a CBR article about the Hulk/Doc Ock fight....
Lots of good pics.
In my previous post you can see the fold out cover. I loved fold out covers. Round Robin: The Sidekick's Revenge had one too that I liked...
Last edited by The Zevad; 02-23-2012 at 08:22 PM.
man I freakin' loved Revenge of the Sinister Six
yeah, the two arcs posted above are pure nostalgia and some of what hooked me into comics. I still have the RotSS trade, always wanted to find another of Sidekick's Revenge


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Brandon Sturman Assistant Coach
2006-07 Football |
Brandon Sturman moved from the field to the sidelines for Valparaiso University as an assistant coach in charge of linebackers to begin the 2006 season.
An Honorable Mention All-Pioneer Football League North selection in 2005, Sturman finished his career with the Brown and Gold with 224 tackles, including 16 tackles for loss. He recovered a pair of fumbles, forced three, and picked off two passes, while blocking a pair of kicks in his four years with the Crusaders as a linebacker.
Sturman graduated from Valparaiso in 2006 with a bachelor's degree in sports management and is currently working towards a master's degree in sports administration from the University which he is slated to complete in May, 2008.
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