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We have a make-shift sensory tub that often makes its way into the middle of our kitchen where we conduct experiments, make "cakes and pies," and mess around with the feel of stuff. Some of the things we've filled it with are dry beans, oobleck, jello, vinegar and baking soda, and rice. I'm always on the lookout for neat-o objects that might challenge and delight my child, … [Read more...]
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text: PMQs Prime minister's questions: 11 May 2011 - video Sorry, your browser is unable to play this video. Please install Adobe Flash™ and try again. Alternatively upgrade to a modern browser. David Cameron and Ed Miliband each claim their party would act in the best interests of the NHS as they clash at the weekly prime minister's questions session in the House of Commons Source: Press Association Wednesday 11 May 2011 09.05 EDT Last modified on Wednesday 11 May 2011 14.03 EDT Share on Facebook Share on Twitter Share via Email Share on Pinterest Share on LinkedIn Share on Google+ Share on WhatsApp Topics PMQs NHS David Cameron Ed Miliband

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Catherine Maiko Suma (須磨・キャセリン・舞子)Hometown: Hyogo Prefecture
Age: 15
Birthday: October 23rd
Horoscope: Libra
Blood Type: A
Height: 138cm
Instrument: Piano
She is Takenomaru's (most likely half) little sister, but they haven't seen each other for a long time. They resemble each other a bit... both of them have the same hair color, but, her eyes are green while his are red. (Source:Wikipedia)
Voice ActorsNo voice actors have been added for this character, add an actor from our database.


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New Lexus CT200h
Facelift is just the start for the revamped hybrid city car from the Japanese luxury brand.
Lexus IS F
The Lexus IS F, a fire-breathing sports sedan from Lexus?
Lexus LS600hL Landaulet
Lexus has literally taken the lid off its latest creation, the LS600hL Landaulet to serve as Monaco's Royal wedding car.
Lexus CT200h
2011 Lexus CT200h
2011 Lexus CT200h
The tweaked 2011 Lexus CT200h
Lexus IS 350 Sports Luxury
Lexus IS 350 Sports Luxury road test.
The most underrated cars
Peter McKay indentifies the most underrated cars on the market.
Luxury cars put to the test
Audi A8 4.2 FSI v BMW 740i v Lexus LS600hL v Mercedes-Benz S350 CDI v Jaguar XJ 3.0D.
Lexus IS350 F Sport
Lexus IS350 F Sport.
Lexus CT200h F Sport
The CT200h F Sport will go on-sale in the first quarter of 2011 alongside two other CT200h hybrid models.
2010 Lexus CT200h
Lexus CT200h.
The Lexus CT200h
Lexus CT200h.
Lexus LFA briefcase brochure
Lexus LFA briefcase brochure
Lexus LFA supercar tester killed
Lexus supercar tester killed
Lexus V10 supercar
Lexus V10 supercar (3 images)
Lexus CT200h hybrid hatchback
Lexus Australia has confirmed it will take on its German rivals in the luxury small-car market with the company's new CT200h hybrid hatchback.
Lexus's Hybrid Bicycle concept
Lexus's Hybrid Bicycle concept features a 240-watt electric motor that boosts man-made torque (pedalling) for more effortless riding.
Lexus's CT200h
CT200h hybrid hatch that will bring new buyers to Lexus brand leaked ahead of Geneva debut.
Frankfurt 09: Lexus Australia chases LF-Ch hatchback
Lexus Australia chases LF-Ch hatchback


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Results 1 to 10 of 10
Thread: Another world
July 30th, 2005 #1
Another world
Hi all
This is my new work
Title is another world ^^
It is big size image(1000 x 800 pixel) so wait please ^^
I work 2500 x 2000 pixel by photoshop
Comment and Crit are welcome
-Another world-
-- My NEW Persnal HP = http://keun-chul.zzo.net/ --
- Similar Threads
- SketchBook: Hello World!
- Art: New Work (Haven World, World of Warcraft and Magic The Gathering)
- another world
- Art: Not the End of the World
- The World Is Not Enough
Hide this ad by registering as a memberJuly 30th, 2005 #2
nice piece I'd say:
The good:
* great colors
* gorgeous textures
* teh sexah outfit :p
The not so good:
* Some wonky anatomy (lower legs are really thin / short fingers /)
* The position of the eyepatch (?) is disturbing me a bit. It's so high up her face.
* the face in general could use some slightly more expression, is she waiting for someone, dreaming away or just enjoying the view..
Hope this helps.
July 30th, 2005 #3
its beautifully rendered, but what is the purpose of this piece? i wouldnt have guessed the title just by looking at it. to be honest its almost a little boring after a while (sorry, i mean no offense). theres a lot that implies "other worldliness", yet its only ever implied and not enforced.
July 30th, 2005 #4
Great stuff, as always. The colors are fantastic! My only criticism is the perspective of her hips and legs that looks a bit exaggerated compared to her torso and head. And, compositionally speaking, I don't think the rock in front of her helps. It seems to be pressing against the figure and goes against her gaze.
Wonderful piece.
July 30th, 2005 #5
I really like the work on the neck and shoulder areas. Although, the form is lost on other areas of the body / armour.
great feeling!
July 30th, 2005 #6
Yeah. The piece is good. The atmosphere in the background, is nicely executed I think. Currently, her positioning is very awkward. She looks like she wants to lean on her left arm for support, but you can't see the weight in the drawing. It just looks like all of her body weight is centering in her lower back, which looks incredibly uncomfortable. I would suggest putting her in a different position. Perhaps, put her right knee up, arms hugging the leg, chin resting on the knee, like she's been waiting for someone for a while. I don't know, that actually sounds a bit trite, but do something to give her more realism and character. Why is she sitting out here all by herself?
July 30th, 2005 #7
this is really good.
i would love to see some progress shots.
especially of the landscape.
i enjoy the texture a lot!
- Dan Dos Santos
July 31st, 2005 #8
possessd >> Thank you for your reply. Your crits are very helpfull to me
'stoph. >> ^^ I think the title is not good too ^^
abdrearocha >> Thank you for your crit ^^
hawken >> thank you hawken ^^
sevnraiz >> thank you ^^
DSillustration >> Thank you DS I have not progress shot ^^ and I love to see your work too
-- My NEW Persnal HP = http://keun-chul.zzo.net/ --
July 31st, 2005 #9
This is beautiful. Interesting character design and gorgeous colors. I like that eyepatch too.
...+1 exp
July 31st, 2005 #10
OH MY GOSH! dude, you think can post like a tutorial on your paintings some time soon? That would be so awesome, very awesome design i might add.


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Winter!: Prepare for holiday gaming!
As a relative late-comer to the AC series (beginning with Armored Core 2 for the PS2), I found For Answer to be an amazing achievement both graphically, and game-play wise. Extreme detail has been paid to this game and makes it stand out.
Game Traits applied to Armored Core: For Answer (X360) by BadguyEX
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Crysis is VERY well optimized (with proof)
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Join Date: Dec 2003
Location: Citadel Station
Posts: 1,676
Re: Crysis is VERY well optimized (with proof)
Originally Posted by
It is quite evident you have not followed the developement of Crysis very well. Yerli himself has stated quite some time ago that running Crysis at the absolute highest settings will be virtually impossible on current generation hardware.
They did this intentionally... why? Because that is what *PC Gaming* is all about.
You cited FarCry and your 6800 Ultra- you fail to realise one flaw about that analogy:
The top cards at the time of FarCry's release were the Radeon 9800XT and GeForceFX 5950U. NEITHER of those cards could run FarCry at high resolutions, with high AA and AF, and all in-game options maxed. Only the *next generation cards*- meaning the GF 6800s and Radeon x800s could. And even then, the 6800Ultra *could not* run FarCry with the sparse "beta" 1.4 patch that enables HDR- the game tanked. I know this cause my 6800GT @ just beyond Ultra clocks would tank. My setup at that time was an A64 3700, 1GB DDR400- more than sufficient for FarCry. Maybe dual 6800Ultras would have a chance, but not a single one.
My point: your 6800Ultra was considered "next-generation" at the time of FarCry's release- so to compare it to Crysis which is targeted at "next-generation" products while complaining about its performance on current-gen products is rather ignorant, no offense.
Do some research on the developement of Crysis and you'll see that you're grossly over-estimating the power of the 8800s. Crysis is coded nearly as efficiently as it can be when referring to it highest visual settings- no computer has the horsepower to handle that is the issue. This *is* how PC-Gaming *should* be. If you don't like it, stick to consoles.
Furthermore, I question your validity in regards to your knowledge about custom-building PCs. To this day no computer can run Oblivion at high resolutions, with high AA, and all in-game options maxed and never dip to lower FPSs. This very thing was discussed for near 50 pages in another thread here not too long ago. Yes, even the highest and most powerful of rigs are still brought to their knees by Oblivion at literaly the highest settings possible for that game. And it isn't all due to bad coding, a lot of it is that the computing power just is not there yet. Again, this is a good thing- it is what drives innovation in the PC market. If you really don't like it and can't stand it- then stick to console. And that's not intended as an insult, that is an honest suggestion as my attempt to guide you towards a hobby that will cause you the least frustration and lack of enjoyment.
Your right about that,he said more then a few times that "Crysis will bring even the 8800GTX to its knees" Why this is so shocking to people is whats suprising to me.The game is very well optimized,but like other AAA titles,it will take a gen or two of hardware releases before we catch up to it.
When plunder becomes a way of life for a group of men living together in society, they create for themselves, in the course of time, a legal system that authorizes it and a moral code that glorifies it. -Fred Bastiat-
The last official act of a corrupt government is to loot the nation.
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Very beautiful place and waterfall ...YSL
The clouds were perfect in this shot!
Very nice
Hi Aaron, fantastic landscape : LIKE ! Kind regards from Northern Germany : Blue Bayou
Dear AAron, this is my absolute dream landscape! Unfortunately I can not visit them. Many greetings from Germany, Wolfgang.
Wonderful canyon and good photo. L1. Michael
Clear architecture. L2. Michael
environmentally important area impacted by fracking
Very nicely composed...Like...Neale


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If the government had shut down at 12:01 a.m., no region of the United States would have suffered more than the District. City services would have been curtailed, trash uncollected, tourist dollars lost and thousands of residents with federal jobs would have faced potential furloughs.
And although it averted a shutdown, the budget deal agreed to Friday night by Congress and the White House appears to be — at best — a mixed blessing for the District.


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Diablo 3 PVP dropped.
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Join Date: Jun 2004
Location: Sonoran Desert
Posts: 6,884
Re: Diablo 3 PVP dropped.
Originally Posted by
Any guesses on how much this DLC will cost us? You know their not going to provide it for free... They will make some bull**** excuse like they did with Starcraft, "oh we just had some much content that we had to make it a separate product!" This is thanks to all those who bought that 1/3 game called Starcraft 2.
If you are expecting PVP, you shouldn't be playing a blizzard game.
Just look at wow, wow's PVP is terrible. I should know, when I played wow I was consistently in the top 1% of all players. Had all of the best gear in the game and knew all of the tricks. And when I look at wow pvp vs other games, it's downright terrible.
There's virtually no depth whatsoever. Regardless of what class/spec people play, they all tend to have their talents organized the same, so it is very much a cookie cutter system. I've looked at what changes they are planning in bringing to MoP, and they won't do a damn thing to address that problem, instead they'll just make the problem look different.
Wow PVP mechanics are also brutally simple. It's basically about preventing the other player from doing anything at all. Seriously I've never played any game other than wow which is built so heavily around crowd control.
And then if that's not bad enough, blizzard ALWAYS leaves flavor of the month specs or comps that totally demolish anything else. They'll admit when its a problem, but they don't do anything about it for 5 months. Look at mages right now, ridiculous amount of crowd control, they admit its a problem, and say they won't fix it until the next expansion. And then when they do fix it, they usually over fix it and gimp whatever they were trying to nerf, and then call it balanced. There's another FOTM spec to take its place after that, which stays broken for another 5 months.
Normally this wouldn't be a problem, except in order to get anywhere in wow pvp, you pretty much have to do just arena, which places class imbalances under a microscope. Sure they created rated BG's, but good luck organizing them because most people are too busy raiding. And even if you can arrange them, they are extremely boring and repetitive. World PVP was the only reason I played wow for as long as I did, and then they screwed that too by basically turning all of the guards into carebears, effectively making PVP and PVE servers not very different from one another.
Again I need to emphasize, blizzard does not know a DAMN THING about producing a good pvp game.
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To Arm, Or Not To Arm The Syrian Rebels?
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The White House says the United States will arm Syrian rebels, but a new poll shows most Americans don't like the idea. Guest host Celeste Headlee speaks with Shadi Hamid of The Brookings Institution, about America's current and future involvement in Syria.


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Originally written on New York Mets Report | Last updated 6/17/13
So much for the Jordany Valdespin experiment at second base until Ike Davis returns, but the premise of what I wrote earlier remains the same: the New York Mets don't have an idea of what to do with the mercurial role player. Terry Collins said he would give Valdespin a week at second base leading off. Valdespin responded by hitting .130 (3-for-23) in that span, and one week later is back to the bench. The outfield is out for now, with Collins saying he needed to see more from Kirk Nieuwenhuis, Juan Lagares, and Marlon Byrd, one of the few Mets who is hitting. Saying, `you're allowed to change,' '' Collins returned Valdespin to the bench for Monday's series opener in Atlanta. Along with that move, Daniel Murphy will go back to second and Lucas Duda will move in from left to play first. This juggling improves the Mets' defense, which is a positive. The Mets claim second base is Valdespin's natural position, but he had problems, especially turning the double play. Murphy is an upgrade...
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If there is one guy who the Steelers cannot afford to lose playing time, it is Ike. I feel this guy should be a captain. Ike might not get the interceptions, but he shuts down receivers. Not only that, Ike is the best tackling corner in the game. Yeah, Ike struggled in the beginning of the season, but he returned as the old Ike. The Steelers did not have a cure when Ike was gone for the season. Shut down corners do not come along often. The Steelers began losing as soon as Ike went down, but everybody wants to blame Ben. Ike is just as important.
Originally written on Steelers Depot | Last updated 2/5/13
Pittsburgh Steelers cornerback Ike Taylor said Tuesday on Trib Live Radio that he is back on the field training down at the Wide World of Sports complex with renowned trainer Tom Shaw. Taylor, who fractured his right ankle early in Week 11 game against the Baltimore Ravens this past season, said that he is a full go now as of Monday and that he is running up and down the hill, doing field work, and running in the sand pit. "It's hard for me just to sit down," said Taylor. "I understand this game. You can only play for so long, so they might ask you to take a rest, or take weeks off, or you Read more [...]
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I don't normally write about Lucky Generals stuff. But I'm having one of those so-excited-about-work-moments, that I hope you'll excuse me. Especially as I could do with your help.
This morning, we helped launch a bid to challenge Sepp Blatter for FIFA's presidency and "Reboot football" for good. The bid is headed by the legendary David Ginola, backed by the marketing ninjas of Paddy Power and guided by the legal experts at the reform group Change FIFA. Lucky Generals and M&C Saatchi PR are handling the communications while Crowdfunder.co.uk is managing the fundraising side of things.


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Originally written on Mets360.com | Last updated 1/16/13
While the Wipons are leveraged to the hilt, this offseason has been a textbook case about how a team and a general manager use leverage (or have it used against them.) While TNT canceled the TV show ŌĆ£Leverage,ŌĆØ that word is still being used more today than IŌĆÖm guessing any of us would have imagined just five years ago. So, what is leverage? The dictionary definition is as follows: 1. a. The action of a lever. b. The mechanical advantage of a lever. 2. Positional advantage; power to act effectively: ŌĆ£started his . . . career with far more social leverage than his father had enjoyedŌĆØ (Doris Kearns Goodwin). 3. The use of credit or borrowed funds to improve oneŌĆÖs speculative capacity and increase the rate of return from an investment, as in buying securities on margin. WeŌĆÖre focused more on the definitions listed second and third, although at this point it shouldnŌĆÖt surprise us if the first definition makes it into our sports lexicon soon, too. The Wilpons are leveraged to the hilt ŌĆō...
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Being single is not taboo—Susan Peters
Her initial dream was to become an air hostess but all that changed when a movie crew walked into her boutique cum eatery in Kano some years back. Ever since, Kano State-born Susan Peters has grown from an ordinary business woman in Northern Nigeria to an emerging Nollywood actress. She opened up on her life, acting career and her passion for fashion in this interview with AHMED BOULOR.
COULD you let us into your time as a student of Video Wave Institute? What was the experience like?
It was tedious but fun during my course at Video Waves. All other classes were easy but the stage was difficult as you have to deliver your lines and others. But it was worth it in the end. I came out as overall best female with a distinction in my class.
Have you featured in any Yoruba, Igbo or Hausa movie before, knowing fully well that you speak the three languages fluently?
I featured in a Yoruba movie produced by Funke Akindele, entitled Ransom. I have not featured in any other one yet, but hopefully, I will get to feature in a Hausa or Ibo film very soon.
Could you recall your growing up years in the city of Kano?
The only thing I was told by my mom was that I got lost at some point as a baby in Kano and they had to look for me but I was later found.
How did you come about being a model?
I have always loved fashion from childhood; I won the best dressed girl on campus even while growing up. So it has been a part of me from the onset.
Do you regret not becoming an air hostess?
No, not at all; I love my job as an actress and I don't miss that at all. I still wear my short stuffs when I want to and when I travel out, I see them and I just smile.
How did your chance meeting with a movie crew spark your interest to become an actress?
They met with me in my salon and boutique in Kano; I also had an eatery section so they wanted to use the eatery to shoot a scene in the movie. The director asked if I could sit on the empty table and mime and that was it. After they showed the first episode of the movie, he came back and asked if I have the dream to become an actress and I said no. But I had unknowingly sparked up a passion for acting; that was how my journey into Nollywood began.
What's the first movie you featured in?
It was Wasted Effort, directed by Andy Amenechi. I played Ramsey Noah's younger sister alongside Rita Dominic. I was nervous at first but later settled in. The movie set became fun after all.
How did you get the role?
I was auditioned along side many other actors at the National Council for Arts and Culture (NCAC) Secretariat at the National Theatre, Lagos and eventually got shortlisted.
What has the journey been like thus far since you started acting in 2002?
It has been good, bad and ugly but the good always over shadow the rest, so I thank God.
What has it been like relocating from the north to the south in pursuit of your dream?
Well, it has been one hell of a journey. In the North, everything is more serene but there is too much chaos in the South. Lagos has taught me a lot of lessons especially from people that work for me; most of them are not straightforward. Everyone wants to scrape your head but I guess I have adjusted to the system. No wonder the phrase "This is Lagos".
Have you tried your hands at writing any script for a major Nollywood production?
Yes, I am writing a couple of stories but it is taking so much time to be completed because there are many tasks to be done. I have also done some major roles in movies such as Sound of Poverty, God Mother, Spiritual War and Domino, a TV series. I have also featured in other Nollywood movies such as Bursting Out, Nollywood Hustlers, Wicked Intensions, Stone Face, Sacred Lies, Heartless, Timeless Passion, Behind the Plots and lots more.
Do you still find time for your interior décor business?
Yes I do. I have people working for me; when I get the jobs and I do my part, I send them ahead to locations to finish the job.
What has it been like coping with the transformation of being an ordinary business woman in Northern Nigeria to an emerging Nollywood actress?
The only thing that has changed really is my everyday life. I am more cautious now than before, nothing, however, has changed. I still travel when I have the time; I also shop when I am on holidays.
Why are you still single despite possessing striking features?
Why am I still single? It is as if it's a taboo. I have a lot of admirers and suitors; the problem is finding real love, so one has to be careful.
What's your take on 'togetherness' in Nollywood? Do you think Nollywood actors are united?
That is a subject that still does not have a cure, until we all realise that the industry is big enough to take everyone, then maybe it will change. Someday, God will finally smile on us. Then maybe we will be united.
What has your experience with E4 PR been like?
It has been quiet; they got me to feature for Black Hair Europe magazine. I am sure more stuffs will come up soon.
You are being touted as the biggest celebrity on the red carpet these days. How do you feel about that?
Even Hollywood celebs go to the red carpet when they are invited. Though, I get a lot of invitations, I do not attend all events. I usually attend most of these movie premieres because you get to meet people, interact and network.
How did you feel being named City People Most Fashionable Celeb recently?
I felt happy, it means they actually know that I love fashion and it's a passion for me. I am glad and I thank God.
What's your grouse with blogger, Linda Ikeji?
I have no grouse against her. She is doing her job and she has every right to post whatever she wants on her blog. My grievance was that she never celebrated my achievements, even when my assistant in the UK sent her some information she never posted. She only posts news of people she is close to. I have built my brand single handedly without any help from her so why would she suddenly claim to have made me? In what sense did she make me? It's really an insult; and for her family to attack me on the social media is wrong.
What's your relationship like with other Nollywood actresses?
I love them all. I give them all the regard, even my contemporaries too. Everyone knows I am a people's person.
What's your greatest turn-off?
I hate liars and back-stabbers.
Despite your seeming spotless career as an actress, some close watchers still feel you are controversial.
Well it is better to be mysterious; that way people don't really demystify you.
Have you encountered any major challenges in assisting the Senate President in conducting free polio vaccination in your state?
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'I used my three children for blood money'
RESIDENTS of Asaba and Oko towns in Oshimilli South Local Government Area of Delta State were stunned last weekend when a popular akara (bean cake) ... Full story


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My business mentor recently extended a challenge to my coaching group. We were to choose one of these options, to focus on for one month: 1) No news, 2) No sugar, or 3) No judging.
Which would you choose? Continue reading
My business mentor recently extended a challenge to my coaching group. We were to choose one of these options, to focus on for one month: 1) No news, 2) No sugar, or 3) No judging.
Which would you choose? Continue reading
My heart won't stop hurting. I'm sure you've all heard the news that Kate Kelly and John Dehlin have been summoned to church court for their activities related to the Ordain Women movement and the Mormon LGBT movement. I'm not upset because I'm an ardent supporter of either movement. I'm upset because I firmly believe that every Saint deserves to have a voice in our community. I'm upset because I am so grateful to people like Kate and John who are willing to say "dangerous" things out loud, when so many of us want to, but are too afraid to. I'm upset because of the atmosphere of fear that enters into our faith community when this sort of thing happens. What can I safely say? What causes dear to my heart will be "approved" by my respected church leaders? Do I trust my own spirit to hear and interpret the voice of the Holy Spirit, or do I leave that solely to my leaders, who I am sure listen to the same Spirit? What do I do when those spiritual interpretations collide? This sort of conundrum causes all sorts of self doubt. Some walk. Sometimes I wonder if the best of us walk, and if my choice to stay is foolish or faithful. I'll say it right here at the start, though: despite all its man-made quirks and flaws, I love the Church and am convinced it holds the power of full salvation. So I stay. But right now, it just hurts. Continue reading
Woman begging, by Tomas Castelazo
The man who sidled into the back of the rented Hungarian chapel was unprepossessing, at best. He was slightly built and dark-haired, wearing a cheap, white button-down shirt and nondescript pants. Certainly, there was nothing in his appearance to explain why the elders straightened to attention, why my companion and I exchanged knowing glances. The members had noticed his arrival, too. A slight rustle and murmuring swept through the small congregation.
The elders had brought an investigator with them that Sunday. I wondered what the young man would make of the newcomer's inevitable testimony about the truth of the Book of Mormon and Joseph Smith's calling—and the apostasy of every prophet since. Continue reading
Olea has decided 2013 is a year of discovery, both of the world around her (she is currently living in the south of France, her first time overseas) and the potential within her. She would describe herself as open-hearted and optimistic (she loves words starting with an o), and her best friend tried to convince her to use the word "wise", but clearly that didn't work.
I have always felt a special connection to the sisters in my life. I loved the Young Women's program, and often it was the only place in my life that I felt I belonged. When I moved from Adelaide to Melbourne, at the end of high school, to join my family who'd been there all year, I was looking forward to joining Relief Society. I had visited during holidays, and spent time with the young women, but when I went to Relief Society, I felt accepted and wanted in a deeper way than I ever had before. In classes, I was encouraged to share my experiences and testimony, and my needs and opinions were considered when planning activities, though I was only 18 and new to the ward. Our ward was very small when I first arrived – it had just been split, and wasn't much bigger than a branch – and over the course of 6 years, we moved to a new building (from our rented hall-plus-a-few-classrooms) and now we are worried around Stake Conference times in case of more splits.
My first activity, as part of the new Enrichment focus that encouraged small groups organised by sisters, was a book club. We met monthly in a sister's home and read, among others, The Pilgrim's Progress, Don Quixote, something by Charles Dickens that I have since removed from my memory, Love in the Time of Cholera, The Lovely Bones and My Sister's Keeper. We discussed authors' intentions, favourite characters and unexpected plot twists. We discussed our families and friends and personal experiences, we shared philosophical views and argued about ideas, sometimes even relating to the book we'd read, often until (and occasionally after) midnight. Continue reading
Allison Mitton received a BA in English language from Brigham Young University and an MA in publishing and writing from Emerson College in Boston. While in Boston, she developed a great love for poetry, printmaking, Salman Rushdie, and all things nautical. Though recently relocated to Seattle, Allison still harbors a not-so-secret desire to move to Rhode Island and set up a printmaking shop in a barn overlooking the sea. If so inclined, you can blog stalk her at amittonmonologue.blogspot.com.
Last Christmas, my mother gave each of her children a copy of Corrie ten Boom's The Hiding Place. She told us it was a book that meant a great deal to her, and that it contains a powerful message of hope and love and forgiveness. It was one of many books I received for Christmas that year, and when I returned home to Boston I added it to my ever-growing collection. Then I promptly forgot about it.
Soon after my return, I began to feel some anger toward one of my good friends. We had been close friends for a while, but a series of very minor events aggravated me. Though he never did anything intentionally hurtful, I felt like he sometimes took advantage of our friendship, and I resented him for it. Continue reading


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Apple Store
4th Street
1823 4th StreetBerkeley, CA 94710
(510) 898-3341Driving directions and map
|Store hours:
|Mon - Sat:
|10:00 a.m. - 8:00 p.m.
|11:00 a.m. - 6:00 p.m.
Apple Store
4th Street
1823 4th StreetBerkeley, CA 94710
(510) 898-3341
How to get here:View store information
The Apple Store is located at 1823 4th Street in Berkeley, CA. Traveling on I-80, exit University Avenue and head east. 4th Street is ahead on the left. The Apple Store is near the intersection of 4th Street and Hearst Avenue, a block north of University Avenue. Closest parking for the Apple Store is on the street in front of the store or a block north on 4th street.
Apple Camp
Free workshops where kids can make their own movies or interactive books.Learn more
Schedule a try-on appointment.
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on Apple Watch in an Apple
Retail Store.
Personal Setup
We can help you set up your Apple Watch the way you like. And we'll point out some great apps to help you personalize it.Learn more
The new MacBook
Available to order online. Visit an Apple Retail Store for a hands-on demo.Learn more
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The SK Testimonials Plugin allows you to list and display Testimonials on your site. You can list them in any order, by groups, through widgets or sh
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James Franklin
Penn State's James Franklin Returns To Yankee Stadium For First Pitch
Penn State head coach James Franklin returned to Yankee Stadium for a first pitch.
James Franklin Accidentally Face Times Fan From Philly: 'Coach, You've Got The Wrong Number!'
James Franklin put together a top-15 2015 recruiting class in the country, and accidentally called a fan on National Signing Day.
Flavor Flav Was On Hand For Penn State vs. Purdue
Many wondered why Flavor Flav was at the Penn State Purdue basketball game on Saturday.
Bob Shoop To Remain Defensive Coordinator At Penn State
Penn State will retain defensive coordinator Bob Shoop despite interest from LSU.
Penn State Striving For Offensive Line Development
Offensive linemen gaining additional experience is vital for the program, coach James Franklin said.
Penn State Falls To No. 10 Michigan State 34-10 On Senior Day
Michigan State proved to be too much for the Nittany Lions to handle as Penn State lost big Saturday.
Penn State's James Franklin Is 8th Highest Paid College Football Coach
Penn State's James Franklin is the eighth highest paid college football coach.
Temple Readies For Saturday Visit To Penn State
Matt Rhule and his Temple Owls head to State College to take on the Penn State Nittany Lions.
Report: Penn State Drops Recruit Linked To Hazing Incident
Penn State has reportedly moved on from Myles Hartsfield, a recruit who has been linked to the hazing scandal at Sayreville War Memorial High School.
Northwestern Gives Penn State Their First Loss, 29-6
Northwestern went to Happy Valley and spoiled Penn State's Homecoming.
Penn State Ranked In Top 25 College Football Power Rankings
Penn State is ranked in the top 25 in the new college football power rankings, after their 13-10 win over Rutgers.
Penn State Coach Grateful For Bowl Chance
Penn State coach James Franklin sat behind a microphone, bantered with the media, and gamely tried to steer questions toward this weekend's game at Rutgers. "I would like to talk about Rutgers, Rutgers, Rutgers, Rutgers," Franklin said, "and then maybe a little bit more about Rutgers."
Video: Penn State Opens Season Saturday In Dublin
Penn State opens their season in Dublin, Ireland on Saturday against the University of Central Florida.
Report: Penn State Could Have Bowl Ban Lifted
Penn State's bowl ban could be reduced for the 2015 season, according to a report.
Christian Hackenberg Becomes Penn State's First Ever Sophomore Captain
Christian Hackenberg was named Penn State's first ever sophomore captain on Wednesday.


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OKLAHOMA CITY (AP) — An Illinois man with a long history of mental illness has been charged with plotting to attack dozens of churches after a hotel maintenance worker in Oklahoma spotted the makings of Molotov cocktails in a trash bin and alerted police.
Gregory Arthur Weiler II, 23, of Elk Grove Village, Ill., has been charged under a strict Oklahoma anti-terrorism law put in place after the federal building bombing in Oklahoma City in 1995. The law makes terrorism hoaxes a crime as well as any effort to plan or help plan an act of terrorism.
Weiler was arrested Thursday after a worker at a motel in Miami, Okla., spotted bottles and other suspicious items in a garbage bin, according to a police affidavit.
Officers found bomb-making materials in Weiler's room along with torn bits of paper that, when assembled, contained directions for making Molotov cocktails, a list of 48 local churches, a hand-drawn map of the churches, and an outline of a plan to plant bombs.
Weiler has been held without bond on charges of threatening to use an explosive or incendiary device and violating the Oklahoma Antiterrorism Act. Online court records indicate he has applied for a court-appointed attorney and is due in court on Oct. 22.
According to an affidavit filed by Det. Jeff Frazier, a maintenance worker alerted Miami police after noticing a pile of brown bottles with cloth wicks attached by duct tape in a trash bin at the Legacy Inn and Suites, which sits just off a major interstate. A funnel and 5-gallon red gasoline can also had been dumped in the bin.
While background checks were being done on the hotel's 18 guests, the maintenance worker accidentally walked into Weiler's room and saw Weiler with similar items and a Walmart receipt showing the purchase of other items, the affidavit said.
Police found pieces of paper in the trash with details of the plot, plans to videotape the bombings and the words: "Try to get away with it ... maybe a plan out of town?"
Weiler's family said he has a long history of mental illness, and Miami Police Chief George Haralson said his answers during questioning ranged from rambling to coherent.
Haralson said it wasn't clear whether Weiler posed a real threat to churches and the community.
"He had the means and the ability to carry this out," he said. "How does one assess the threat?"
Weiler's parents both committed suicide, and Weiler has battled drug addiction and "a lot of mental illnesses" that led to a suicide attempt in the eighth grade, said his cousin Johnny Meyers.
Continue reading this story on the...


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Big Ten releases 2012-13 men's hoops schedule
The Big Ten Conference announced the 2012-13 Big Ten men's basketball schedule Thursday. The conference season begins on New Year's Eve and culminates in March with the Big Ten Men's Basketball Tournament at the United Center in Chicago.
Find out more about: Big Ten Schedules


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Christian Amulets - Old New Testament Woodwork Bible | Unique Gifts & Silver Charm Jewelry
Cover is made from a variety of precious wo...more
1 Recommendation
Suntrader's recommendation
Artist Jack Jaget has mastered the art of wooden bookbinding in this majestic English language Old & New Testament Bible with a vivid Bible scene on the the cover in beautiful colorings. Scene is from the opening of the Song of Songs, 13th-14th century. Cover is made from a variety of precious woods, and has gold plated metal corners. Closure is a leather and gold plated metal clasp. Finally, the whole piece is meticulously hand-painted with fine lacquer and gold leaf, making this Bible a true gift to be passed along through the generations.
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International Book Week
by, 25th September 2012 at 04:59 PM (313 Views)
"sed quid facit Ministerium Magium?"
It's international book week. The rules: Grab the closest book to you, turn to page 52, post the 5th sentence as your status. Don't mention the title. Copy the rules as part of your status. Try and guess the book.
no idea if it actually is but I saw this on Facebook so here it is.
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Former New York Jets superfan Ed Anzolone, aka "Fireman Ed," is not the only notorious supporter of his favorite NFL team. The Miami Dolphins have a noteworthy nut job as well, and he goes by the name "Big Papa Pump." Big Papa Pump, who has been a Dolphins season ticket holder for 17 years, went off on Ed for quitting on the Jets during an appearance on Sports Talk: The Ticket on Tuesday morning. "If you're stepping down because of what you see, getting your butt whupped week-in and week-out and you haven't been to the Super Bowl since Super Bowl III, that is a wuss," he told Hochman and Zaslow according to ESPNNewYork.com. "You don't back out of your team like that. That's something you don't do. You don't step down from being a superfan. You don't do that. Fireman Ed, you're a disgrace, man. "This team is looking up to him and this is what he's telling them? You quit? You just give up? If you're winning and you quit, it's another thing. But you're losing and you quit, that's even worse." As you may have heard, Fireman Ed said he stepped down because of the increase in confrontations that he has had to deal with during this disappointing Jets season. Not only does BPP believe Ed is a disgrace for jumping ship, he also doesn't believe he would ever be welcomed back after the way he left. "You can't come back," he said. "You have to come back as somebody else. Maybe he can be Nurse Ed. He can't come back as Fireman Ed, there's no way. You can't welcome him back. How can you trust him?" Are these guys living in their own world or what? I don't know about you, but I'm thinking superfan charity boxing match at either SunLife Stadium or The Meadowlands. Photo credit: AP Photo/David J. Phillip
Seems like papa pump has his facts wrong. fireman ed didn't quit because of the teams record, etc. he quit because he was tired of fighting the jets "fans" who were really giving it to him to the point he felt that he could have bodily harm done to him.
I agree, BPP didnt have all the facts. Either way it's unfortunate that this issue even came up where Fireman Ed was getting hassled by fellow Jets fans. Even tho I'm not a Jets fan, nor live in the area I am still a sports fan, and hope to see Fireman Ed come back and that ALL Jets fans welcome him w/ open arms!!!!!
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New Delhi, Jaipur & Agra: Icons of India, Plus Flights
Gate 1 Travel •
Escape Kit
- A Nine-Day Trip to India ($1,499 to $2,599 per Person) Including:
- Round-Trip International Flights from New York City (JFK) to Indira Gandhi International Airport (DEL) in Delhi
- Two Nights at The Park New Delhi, Two Nights at the Ramada Jaipur, and Two Nights at the Trident Agra
- Six Breakfasts, Two Lunches, and Three Dinners
- All Transports and 24-Hour Airport Arrival-and-Departure Services
- Local English-Speaking Tour Guides, Sightseeing Tours, and Entrance Fees per Itinerary
- Airline Taxes, Fuel Surcharges, and Hotel/Resort Fees
- Priced per Person Based on Double Occupancy (See Fine Print)
You'll never forget this trip to India, where flavorful food, bustling bazaars, and the Taj Mahal await.
The Destination
In Delhi, denim-clad teenagers skip about the streets with cell phones plastered to their ears listening to the latest Bollywood track. Mere miles away on the slopes of a nearby rural village, cows move freely down dirt roads past women in saris preparing midday meals by hand. This is India: a contradiction in culture, in time, and in history, and one of the few places on earth where historical change unfolds in real time before your eyes.
Escape to this eons-old civilization that stands teetering on the edge of an illustrious past and an ever-promising future with this nine-day trip to India from Gate 1 Travel.
The Itinerary
day 1: Take an overnight flight—complete with meals, complimentary drinks, and in-flight entertainment—from New York (JFK) to Delhi.
day 2: Arrive in Delhi where guides will greet you and ensure your transfer to your 4.5-star hotel. Enjoy the day at your leisure.
Overnight at The Park New Delhi.
day 3: Enjoy a cycle rickshaw ride through the intricate and chaotic streets around Old Delhi. Visit the Jama Masjid mosque, Bangla Sahib Sikh Temple, and the home where Mahatma Gandhi spent his final days. You'll also see the India Gate, the Parliament House, and the Presidential Palace. This evening, your tour manager will walk you through the itinerary with a welcome orientation.
Overnight at The Park New Delhi. Breakfast and lunch provided.
day 4: Travel to Jaipur, the famed Pink City of India that was painted as such in honor of a 19th-century visit from the Prince of Wales. Depart Delhi via an air-conditioned coach bus and stop to see UNESCO World Heritage site Qutab Minar, the world's tallest brick minaret, before continuing to Jaipur. On arrival, stop by a jewelry shop and visit the local bazaar.
Overnight at Ramada Jaipur. Breakfast and dinner provided.
day 5: Embark on an excursion to the 16th century Amber Fort via jeep (or elephant back, if available), and admire views of Jaipur's original city walls and the Maotha Lake below. Browse the Rajasthan textile and handicrafts shops, then venture off on your own to see the city's many colorful bazaars brimming with flowers and spices or the City Palace and its delightful gardens.
Overnight at Ramada Jaipur. Breakfast provided.
day 6: Travel to the medieval city of Agra. On the way, you'll stop to visit the village of Abhaneri—about three hours outside Agra—and peer into the Chand Baori stepwell that dates back to the 8th century. Nearby, a visit to the temple of Harshat Mata, ornately dedicated to the goddess of joy and happiness, is a must-see. When you arrive in Agra, use the remainder of your day for self-guided exploration.
Overnight at Trident Agra hotel. Breakfast, lunch, and dinner provided.
day 7: Your trip's magnum opus builds in a dramatic crescendo to an iconic visit to the Taj Mahal. The monumental construction, which took 22 years to complete, is most famous for its white-marble dome—of which you'll have your fill with a visit to a local marble shop following your tour.
Overnight at Trident Agra hotel. Breakfast provided.
day 8: Depart Agra for Delhi, where you'll arrive at the DoubleTree by Hilton Gurgaon and enjoy a farewell dinner at the hotel. Included ground transfer will transport you to the airport late in the evening or shortly after midnight for your return flight home.
Breakfast and dinner provided.
day 9: Arrive back in the United States.
The Dates
New York City (JFK) departure dates in 2014:
10/27, 10/30, 11/6 ($1,799)
11/10 ($1,699)
11/20, 11/24 ($1,899)
12/1, 12/4 ($2,099)
12/11 ($1,999)
New York City (JFK) departure dates in 2015:
1/15 ($1,499)
1/19 ($1,699)
1/22, 2/2 ($1,499)
2/5, 2/9 ($1,599)
2/19, 2/23, 2/26, 3/2, 3/5, 3/9, 3/12, 3/16, 3/19, 3/23 ($1,699)
"India bristles with an eclectic mélange of ethnic groups; an intoxicating cultural cocktail for the traveller. With such astonishing diversity, you will be taken on a journey that will linger in your mind long after you've left her shores."-- Lonely Planet
"Gate 1 helped us book a great vacation deal and they had friendly customer service. I'm glad I discovered them."-- LivingSocial Member
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the fine print
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The disease course in multiple sclerosis (MS) is influenced by many factors, including age, sex, and sex hormones. Little is known about sex-specific changes in disease course around age 50, which may represent a key biological transition period for reproductive aging.
Male and female subjects with no prior chemotherapy exposure were selected from a prospective MS cohort to form groups representing the years before (38–46 years, N=351) and after (54–62 years, N=200)age 50. Primary analysis assessed for interaction between effects of sex and age on clinical (Expanded Disability Status Scale, EDSS; relapse rate) and radiologic (T2 lesion volume, T2LV; brain parenchymal fraction, BPF) outcomes. Secondarily, we explored patient-reported outcomes (PROs).
As expected, there were age- and sex- related changes with male and older cohorts showing worse disease severity (EDSS), brain atrophy (BPF), and more progressive course.
There was no interaction between age and sex on cross-sectional adjusted clinical (EDSS, relapse rate) or radiologic (BPF, T2LV) measures, or on 2-year trajectories of decline.
There was a significant interaction between age and sex for a physical functioning PRO (SF-36): the older female cohort reported lower physical functioning than men (p=0.002). There were no differences in depression (Center for Epidemiological Study – Depression, CES-D) or fatigue (Modified Fatigue Impact Scale, MFIS) scores.
There was no interaction between age and sex suggestive of an effect of reproductive aging on clinical or radiologic progression. Prospective analyses across the menopausal transition are needed.
Keywords:Demyelinating disease; Multiple sclerosis; Natural history studies; MRI; Disease progression; Menopause; Gender
Multiple sclerosis (MS) affects almost three times more women than men. The incidence and disease course of MS are modulated by a complex interplay among genetic susceptibility, sex hormones, and the environment [1-3]. Both sex and age influence disease course, with both advanced age and male sex associated with worsening disability and more rapid progression of disease [4-8]. Interestingly, we found that women whose onset of MS symptoms occurred after age 50 are more likely to have a progressive course than women with an earlier symptom onset, and the female: male ratio for individuals in this group is lower than in individuals with onset between ages 18-49 [9].This suggests that the endocrine changes associated with menopause may reduce sexual dimorphism in disease course in later years.
In this study, we use prospectively collected data to examine disease course in men and women with MS in cohorts that represent the years before and after age 50. We examine the interaction between age and sex to test the hypothesis that women experience acceleration in their trajectory of decline after age 50, relative to similarly aged men [10].
The Partners Multiple Sclerosis Center is a regional MS referral center in the Northeastern United States. To date, over 2000 of our patients are enrolled in our detailed longitudinal cohort study (Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital, CLIMB), with follow-up for an average of 2.6 (SD 2.8) years. All CLIMB patients have a diagnosis of MS as defined by the 2005 McDonald criteria, or a clinically isolated syndrome (CIS) with an MRI suggestive of MS. Demographic characteristics (race and ethnicity by NIH criteria) and complete MS history are recorded upon enrollment. Neurological examinations are obtained every 6 months, and brain MRIs annually. We excluded subjects with prior exposure to cyclophosphamide and mitoxantrone, to minimize potential confounding effects of iatrogenic menopause.
For this study, we divided subjects into twoage cohorts, aged before and after 50: Cohort 1 (C1): ages 38–46 (n=351), and Cohort 2 (C2): ages 54–62 (n=200). The menopausal transition involves a series of physiological changes associated with reproductive senescence in women, divided into a series of stages [11]. Operationally, menopause is defined as the final menstrual period, after which no further menses occur during a 12-month interval.The mean age at menopause in Western societies is 49-52 [12,13], and preliminary analysis of a reproductive history questionnaire in our clinic cohort suggests a median age of 50.7 years (unpublished data). Thus, while recognizing variability in individual age at menopause, cohorts C1 and C2 were designed to capture women before and after age 50 (ages 38–46 and 54-62), to minimize the effect of marked hormonal fluctuations at the time of menopause itself on disease characteristics.A subset of these subjects had at least two years of follow-up and therefore contributed to our analysis of change in the prior two years (N=169 and 97). We included men in these age groups in addition to women in order to provide a control group for sexcomparisons. Institutional Review Board approval was granted by the Partners Human Research Committee. Informed consent for use of clinical data and MRI information was obtained from all study subjects.
Clinical outcomes
The expanded disability status scale (EDSS [14]) score and the disease category (CIS, relapsing remitting, secondary progressive, primary progressive [15]) were recorded every 6 months by the treating physician. In addition, the occurrence of clinical relapses in the interval between visits was recorded.
MRI protocol/segmentation
Subjects were scanned with a T2-weighted axial dual echo protocol covering the whole brain (TR=3000 ms, TE=30/80 ms, 192 phase encoding steps, 256×256×54 voxels with 0.93 × 0.93×3 mm3 nominal voxel size and no interslice gaps). All baseline and follow-up scans were performed on the same 1.5 Tesla machine (GE Signa, General Electrics, Milwaukee, WI).T2LV was determined by semi-automated outlining using local thresholding and manual editing (3D Slicer 3.4, http://www.slicer.org/ webcite). Automated template driven segmentation identified normal appearing white matter, grey matter and CSF. Head size normalized BPF was calculated as follows: (grey matter + white matter + T2LV)/intracranial volume [16].
Patient reported outcomes (PROs)
In a subgroup, the following scales were completed annually: Center for Epidemiological Studies Depression Scale (CES-D [17]), Modified Fatigue Impact Scale (MFIS [18]) for fatigue, and general quality of life (SF-36 [19]). The MFIS and SF-36 were scored using the algorithm from the Multiple Sclerosis Quality of Life Inventory [20].
Statistical methods
Our primary goal was to assess the interaction between age and sex on each of our clinical and MRI measures. Secondarily, we assessed PROs.
The patient characteristics at the last visit were used for this first set of analyses. To determine if the impact of age was different in the two sexes, the interaction between age group and sex was assessed using linear regression for the MRI and PRO outcomes, negative binomial regression for the number of attacks in the previous 2 years, and proportional odds logistic regression for EDSS. The T2 lesion volume was log-transformed for this analysis. An analysis using the cube root of the lesion volume produced the same results as the analysis using the log-transformed lesion volume, and thus only the results from the latter are presented. The interaction analysis was also completed adjusting for disease duration and disease category. There were two models for disease category; the first included an indicator for current relapsing course (CIS, RRMS) versus current progressive course (PPMS, SPMS), while the second included an indicator for relapsing onset (CIS, RRMS, SPMS) versus progressive onset (PPMS). Since the results were largely unchanged between these two analyses, only the first are reported. This analysis compared the C1 and C2 cohorts. In addition to the interaction analysis, we investigated the separate effect of age and sex by stratifying on both sex and age. For our investigation of the effect of age, the two cohorts were compared in the males and females separately using a t-test for PROs, age, age at onset, and disease duration; a Wilcoxon test for the EDSS and relapse rate; and Fisher's exact test for distribution of white, Hispanic and disease type. To investigate the impact of sex with each age cohort, the same approaches were used.
In addition to the characteristics at last visit, the rate of change in the EDSS, MRI and PRO outcomes were investigated using a random intercepts model. As in the cross-sectional analysis, the primary analysis investigated the interaction between age and sex on the rate of change. The secondary analyses compared the rates of change in the age cohorts for each sex separately, and the rate in each sex was compared in each cohort separately. All analyses were completed in the statistical package R (http://www.r-project.org webcite) and SAS Software (Version 9.2).
Patient characteristics
We found that increasing age affected the distribution of several clinical parameters among CLIMB patients from the Partners MS Center (Boston, MA) who were from cohorts aged under 50 (C1: 38–46 years) and over 50 (C2: 54–62 years) (Table 1). Most notably, in both men and women, individuals in C2 had an older age at onset (p<0.0001). Nonetheless, the mean disease duration from symptom onset remained longer in the older C2 subjects (women p<0.0001 and men p=0.02). While the proportion of RRMS/CIS subjects declined in the older cohort of subject, this parameter was only significantly different in women (p<0.0001).
Table 1. Sociodemographic characteristics presented by sex and age cohort (p-values for comparison analyses are provided)
When we compared men and women within each age cohort, significantly more women than men had a relapsing course (p=0.001) in C1. In C2, women had a modest younger age at symptom onset (p=0.05) and increased disease duration (p=0.01).
Objective clinical and radiologic outcomes
Cross-sectional analysis
To address the question of whether disease course changes after age 50, we assessed whether there was evidence for statistical interaction between age and sex in their influence on clinical (EDSS, relapse rate) and radiologic (T2 lesion volume, BPF) outcomes when comparing the C1 and C2 age cohorts. No evidence for interaction was observed in the unadjusted analysis and in analyses adjusted for disease duration and disease category (Table 2). Thus, the difference between women and men was similar in both age cohorts on cross-sectional analysis.
Table 2. Cross-sectional disease characteristics compared by age cohort (ages 38–46 vs. 54–62 years) and by sex
Comparing C1 and C2, we saw the expected increase in EDSS and decline in relapse rate and BPF with increasing age, for both women (p<0.0001) and men (p=0.02 for EDSS, p=0.03 for relapse rate and p<0.0001 for BPF) (Table 2). When we compared women and men in each age cohort, C1 women had a lower EDSS than men (p=0.03).Additionally, BPF was consistently lower in men relative to women in both age cohorts (p<0.001)
Two-year longitudinal analysis
Given the availability of longitudinal data, we also examined the accumulation of MS-related disability in subjects aged before and after 50 years. Specifically, we compared the slope of change over a 2-year period in clinical and radiologic parameters between cohorts C1 and C2. The interaction analysis demonstrated no significant interaction between age and sex in any outcome (Table 3).
Table 3. Longitudinal change in clinical, radiologic and patient-reported outcomes compared by age cohort (ages 38–46 vs. 54–62 years) and by sex (slopes of change over preceding 2 years are compared)
Additionally, the slope of decline in these clinical and MRI parameters was not significantly different between the C1 and C2 age cohorts, suggesting that, within the sampled time frame, there does not appear to be a significant acceleration of decline as MS subjects go from earlier to later middle age. Men and women also did not differ in either cohort for 2-year changes in clinical and radiologic parameters.
Patient reported outcomes (PRO's)
To explore the possibility that other features of MS may be influenced by reproductive aging, we assessed cross-sectional and longitudinal data collected using three different instruments: CES-D (depression), MFIS (fatigue) and SF-36 (quality of life, QOL). In the cross-sectional summary measures for these instruments, our analysis revealed a significantly lower physical symptom summary score (PCS) in the C2 female cohort (p=0.01) relative to C1 women, but not in the male cohorts (p=0.88) (Table 2). In a secondary analysis of the SF-36 sub-scores, we noted the presence of a substantially lower SF-36 "physical functioning" score for women in C2 relative to C1 (p<0.0001), but not for men (p=0.46) (Additional file 1: Table S1). However, there was no interaction between age and sex and any PRO outcome, in either the unadjusted or the adjusted analyses.
Additional file 1: Table S1. Cross-sectional and longitudinal patient-reported outcomes by sex for each age cohort (comparisons are provided between age cohorts and between sexes).
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In longitudinal analysis, the secondary analysis of the SF-36 sub scores revealed a significant interaction between age and sex in terms of the change in the overtime in the physical functioning sub score (p=0.002). There were no other significant differences between female age cohorts after a Bonferroni correction for multiple comparisons (Additional file 1: Table S1). There were no other significant interaction terms in longitudinal analyses of our PRO data. Thus, while there was no acceleration noted in the trajectories of decline of subjects after the age of 50 using clinical and MRI measures, female subjects may report an altered perception of their physical function at this stage of their life course.
Discussion and conclusion
In this study, we investigated whether female subjects may experience a more rapid decline after age 50, out of proportion with the age-related decline that male subjects also experience at this stage of their life. Estrogen may mediate neuroinflammatory signals and protect against neurodegeneration [21-23]. Consistent with prior studies, we found that both older age and male sex influence the disease course of MS, with men displaying a more progressive disease and more rapid accumulation of disability as measured by clinical and radiological outcomes [24,25]. However, we did not find any interaction between age and sex that would suggest a differential effect of menopause on these outcomes.
In other inflammatory disorders, such as systemic lupus erythematosis and rheumatoid arthritis, the onset of menopause has been associated with altered disease trajectory [26], presumably through estrogenic modulation of immune cells. In epilepsy, another neurologic disorder, the perimenopause is associated with exacerbation of catamenial seizures, and the menopause, with a decrease in seizure frequency. This may occur because of changes in estrogenic modulation of synaptic regulation. Peri-menopausal hormone replacement therapy (HRT) has been associated with modulatory effects in these other neurologic [27] and inflammatory diseases [26]. To our knowledge there are no clinical data specifically assessing an association between menopause and disease trajectory in multiple sclerosis, and prior patient reports have been variable, with a subset of women reporting worsening of symptoms with menopause [28-30]. These small studies also differed vastly in the reported effectiveness of HRT, from limited utility to improvement in 75% patients.
Given our prior analyses revealing that MS with onset after age 50 (late-onset MS) is more similar in women and men than MS with onset before age 50, suggesting an effect of menopause [9], the findings in this study were somewhat surprising. While an expected age-related decline was observed, it was seen both in men and women, suggesting that the change is not driven primarily by changes in female sex hormones.
Patient-reported outcomes may capture different aspects of subjects' experience with MS than episodic clinical and radiological assessments [31,32]. The findings of worsening physical functioning in older cohort of women suggest some sex-specific acceleration of functional decline or at least in the perception of this decline.
The major limitation of this study is that we were presently unable to assess the specific age at menopause in our female cohorts. Instead, we compared the trajectories of men and women in defined age cohorts using an approximation of the mean age of menopause in Western society, and excluding individuals with exposure to chemotherapy, rather than following a cohort of women through individual, well-characterized menopausal transition. During the menopausal transition, endocrine shifts may lead to a greater variability in inflammatory activity, whereas thereafter, much lower estrogen levels may make male and female profiles more similar and may be associated with more rapid clinical deterioration. Thus, long-term longitudinal analyses of women throughout their menopausal transition may be more informative about specific endocrine-associated disease patterns; however we were not able to address this question with our current dataset. Second, given the exploratory nature of this study, we included all available patients in each age cohort, leading to limited older males in particular. Given our sample sizes (258 females in C1, 153 females in C2, 93 males in C1 and 47 males in C2), we had 80% power to detect interaction effects of at least 0.575 standard deviations for any of the measures. Since this is a moderate effect size, our results demonstrate that the difference between men and women in the two age groups is not large, but to detect a mild to moderate effect size larger sample sizes would be required. Third, the two-year duration of follow up time may be too short to identify clinically meaningful effects and to identify divergent trajectories for men and women. In addition, several other confounders such as the proportion of post-menopausal women taking HRT in this study, as well as the incidence of osteoporosis or other comorbidities common in MS and potentially exacerbated at menopause [33] could not currently be ascertained, which may have an effect on measured outcomes. Further studies are underway to assess this possibility.
In an era where unprecedented numbers of women with MS are entering the menopausal transition with relatively preserved clinical function, and for whom hormone modulation therapies, if effective, may present a different benefit: risk profile than in a healthy population [34,35], further inquiries into this topic are crucial, in order to confirm or contest these preliminary findings. Our analyses suggest that large sample sizes maybe required to complete the critical first step in this research avenue, which is to better understand the potential effect of menopause on disease activity.
BPF: Brain parenchymal fraction; CES-D: Center for epidemiological studies depression scale; CIS: Clinically isolated syndrome; CLIMB: Comprehensive longitudinal investigation of multiple sclerosis at the Brigham and women's Hospital; CSF: Cerebrospinal fluid; EDSS: Expanded disability status scale; HRT: Hormone replacement therapy; MFIS: Modified fatigue impact scale; MRI: Magnetic resonance imaging; MS: Multiple sclerosis; NIH: National Institutes of Health; PPMS: Primary progressive multiple sclerosis; PRO: Patient-reported outcome; QOL: Quality of life; RRMS: Relapsing remitting multiple sclerosis; SF-36: Short-Form 36; SPMS: Secondary progressive multiple sclerosis; T2LV: T2 lesion volume.
Competing interests
RB reports no disclosures. AM reports no disclosures. BCH has received research support from Merck Serono. MH has served as an advisor or consultant for Biogen Idec, EMD Serono, Teva Neuroscience, and has served as a speaker for Biogen Idec and EMD Serono. BIG has received research support from Merck Serono. SK has served as a consultant for Epivax and Novartis. CRGholds stock in Alnylam, Nestle, Novartis, Roche, and GSK. PLD has served as a consultant for Teva Neurosciences and Biogen-Idec. TC has served as a consultant for Biogen-Idec, Sanofi Aventis, Novartis, EMD-Serono, and Teva Neurosciences, and has received grant support from Merck-Serono for unrelated activities. The authors report no potential conflict of interest for this manuscript.
Authors' contributions
RB (firstname.lastname@example.com) contributed to the design and drafting for intellectual contents of this manuscript. BH (email@example.com) and AM (firstname.lastname@example.com) contributed to the design, statistical analysis and drafting for intellectual contents of this manuscript. M. Houtchens (firstname.lastname@example.com), BG (email@example.com), SK(email@example.com) and CRG (email@example.com) contributed to intellectual contents. PLDJ (firstname.lastname@example.com) and TC (email@example.com) contributed to design and drafting for intellectual contents. All Authors' read and approved.
Supported by the National Multiple Sclerosis Society (TC-RG-4256A4/2/) and the NIH T32 (RB-5T32AI074549).
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Pre-publication history
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