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Politics, Moderate/
The Crash of 2016?
WASHINGTON -- You cannot understand the vulnerable state of the U.S. and global economies -- and nervous stock markets -- without coming to grips with the crash of "emerging-market" countries. Led by China, these are middle-income countries that, along with the poorest countries, account for 85 percent of the world's population and 60 percent of...Read more
The False Charms of Single-Payer
WASHINGTON -- Could Bernie Sanders' "Medicare for all" proposal -- national health insurance -- be as good as he says? It's doubtful.
No one claims that today's system is ideal. It's complex, confusing, costly and incomplete. Even after the Affordable Care Act, about 30 million people remain uninsured. For decades, rapid spending increased ...Read more
It's Still the Economy, Stupid!
WASHINGTON -- In 1992, James Carville popularized the adage "It's the economy, stupid." If the economy is ailing, people tend to vote against the party in the White House. That happened in the 1992 election. A recession that started in 1990 was officially over, but it didn't seem over to millions of Americans. They sent President George H.W. ...Read more
Deficits ... Who Cares?
WASHINGTON -- Just how far have budget deficits drifted off the radar screen of presidential politics? Here's one indicator: Last week, the nonpartisan Congressional Budget Office (CBO) issued its annual "Budget and Economic Outlook" report -- a detailed examination of White House and congressional policies -- and hardly anyone paid heed. The ...Read more
An Upbeat Economic Story
WASHINGTON -- Here's some good -- and generally overlooked -- news about the U.S. economy: Among major ethnic and racial groups, African-Americans scored the biggest job advances in 2015. This conclusion comes from the Economic Policy Institute (EPI), a left-leaning think tank and advocacy group. It reports that black Americans made "notable ...Read more
What's Behind the Stock Selloff?
WASHINGTON -- Capitalism has always been an epic struggle between risk and reward, and the easiest way to understand the present turmoil in world stock markets is to recognize that the two have reversed. Risk has gone up, and reward has come down. Investors have reacted by selling. Fear triumphs over greed. This, of course, increases risk and ...Read more
What is The Stock Market Saying?
WASHINGTON -- Just whether the sharp selloff of stocks signals an economic slowdown or recession is an open question. Most economists seem to think not. Strong job growth (2.7 million more payroll jobs in 2015) and low interest rates will sustain slow but steady growth. Still, the dramatic stock market decline raises other possibilities. In the ...Read more
Why Economic Growth Lags
WASHINGTON -- It's only January, but what may be the year's most important book on economics has already been published. Called "The Rise and Fall of American Growth: The U.S. Standard of Living Since the Civil War," it argues that we can't expect new technologies to rekindle rapid economic growth. Despite all the Internet hoopla, advances in ...Read more
The Green RoseStephanie Burkhart
Sonia and Ivánstan embark on a quest for the green rose in order to save Gaia from Balthyser's evil threat.
The China Bubble Pops
WASHINGTON -- The China bubble has burst. No longer are the country's economic managers viewed as magicians who can orchestrate rapid growth whatever the obstacles. No one ever believed that China's economy would grow 10 percent annually forever, but the retreat from double-digit growth has been faster than expected and underlies the country's ...Read more
The Next Recession?
EDITORS: We will update the status of the stocks after the markets close today at 4 p.m. The updated data is usually available around 5 p.m.
WASHINGTON -- It's hard not to wonder: Is the stock market telling us something? True, the market's record in forecasting recessions is horrendous. Stocks often move according to whim or fad. But just ...Read more
The Republicans' Civil War
WASHINGTON -- The Donald Trump phenomenon ranks as the great political story of 2015 -- and maybe 2016 -- but could it simply be a subplot of a bigger story: what commentator David Frum, once a speechwriter for President George W. Bush, calls the Republican party's "internal class war"? Yes, argues Frum. His thesis is laid out in engrossing ...Read more
The "Hollowing" of the Middle Class?
WASHINGTON -- We'll be hearing a lot about the middle class in the coming months. That's one sure bet for 2016, as both parties compete for votes. What's less sure is whether we'll get an accurate assessment of the middle class' condition. By now, the conventional wisdom is familiar: The top 1 percent has skimmed most income gains for itself, ...Read more
Can We Set the World's Temperature?
WASHINGTON -- On climate change, curb your enthusiasm. It's not that the recent international conference in Paris didn't take significant steps to check global warming. It did. Nearly 200 countries committed to reduce their greenhouse gas emissions. The goal of limiting warming to 2 degrees Celsius (3.6 degrees Fahrenheit) from preindustrial ...Read more
America's Stubborn Poverty
WASHINGTON -- Should we fight the "war on poverty" all over again?
Well, yes. That's the recommendation of a group of liberal and conservative poverty scholars, who spent months discussing and arguing to see if they could find common ground. They did. Their new report -- "Opportunity, Responsibility and Security" -- lays out a plausible ...Read more
How Trump Does It
WASHINGTON -- Welcome to what I've called "the politics of self-esteem." By this, I mean that increasing numbers of people, on both the right and left and most with good intentions, have become politically engaged because it makes them feel better. It raises their self-esteem. This phenomenon predates Donald Trump's candidacy, but it helps ...Read more
The Startup Slump
WASHINGTON -- There's more discouraging news about American business -- specifically about entrepreneurship.
We confidently assume that we have the world's most entrepreneurial nation, and the proof seems overwhelming. Google, Facebook and Twitter are but three (relatively) recent startups that have become corporate titans. Before them, there ...Read more
Generational Conflict: Another View
WASHINGTON -- Comes now economist Gary Burtless of the Brookings Institution, a Washington think tank, with another view of government spending on the elderly. People like me have complained for years that government is too generous, especially toward the affluent elderly. This largesse, we argue, shortchanges the young. Not so, says Burtless.
...Read more
WASHINGTON -- When it comes to cyberwar and cyberterrorism, we need to think the unthinkable, says veteran TV journalist Ted Koppel. And for Koppel, the unthinkable is this: Someone hacks into the nation's electric power grid and causes large parts of it to crash for a prolonged period.
Anyone who has endured a blackout from a storm or ...Read more
The Multinational Tax Muddle
WASHINGTON -- Whoever wins the White House next year will have to deal with an issue of almost-impenetrable complexity and contentiousness: How to tax multinational companies? On the one hand, large global firms -- which have never been shy about minimizing their taxes through deft accounting maneuvers -- are becoming more aggressive. On the ...Read more
Generational Warfare, Anyone?
WASHINGTON -- An enduring puzzle of our politics is why there isn't more generational conflict. By all rights, younger Americans should be resentful. Not only have they been tossed into the worst economy since the 1930s, but there's an informal consensus that the government, whatever else it does, should protect every cent of Social Security and...Read more


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What is RM Cash
Darrin in AZ
If there is one thing KTM could do better, it's provide the stock bike with a better seat. I used to barely make it 2 hours in the stock saddle. This upgrade is a major improvement. Now 2 hours is no problem at all. Get this. Your ass will be grateful you did.Read All Reviews
BRONCE in MO
This is my second Seat Concept's seat. The fit is great, and looks great on the bike. This is the perfect seat for your dirt bike that you ride all day, or dual sport. For a broke down dirt biker in his 50's, this is heaven. SmittyRead All Reviews

subset: commoncrawl


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Ponds Deep Cleanser Cold Cream
1278 reviews
76% would repurchase
Package Quality: 3.4
Price: $$
Package Quality: 3.4
Price: $$
INGREDIENTSMineral Oil, Aqua, Ceresin, Beeswax, Triethanolamine, Behenic Acid, Fragrance, Ceteth-20, Cetyl Alcohol, Carbomer, DMDM Hydantoin, Iodopropynyl Butylcarbamate, Methylparaben.
Age: 19-24
Skin: Acne-prone, Medium, Not Sure
Hair: Brown, Curly, Medium
Eyes: Brown
I love this stuff. I have very sensitive skin and can not use many products on my face but this doesn't irritate it. I rinse my face with water, apply cold cream, wipe it off with a towel and put on moisturizer and I'm good to go. This does a great job at removing revlon colorstay. My only problem is with the packaging. I wish it came in a tub.
Age: 25-29
Skin: Sensitive, Fair-Medium, Warm
Hair: Brown, Straight, Fine
Eyes: Brown
I love this cleanser!!!
First of all, it remove makeup and deep clean your pores. I mean it takes waterproof mascaras off!!
And after that it leaves your skin very moisturizing and not dry. I am loving this, one big jar last me for about 6 months now and it's only half way down the jars. Basically, i just need two jars and it will last me for a year!!
I just wish the packaging was a pump because it's not very sanitizing to keep dipping in and out. I use a cotton swap or wooden stick to do it. I must re-purchases this again of course, money saving and great quality!! It's a must have, girls!!
Age: 25-29
Skin: Sensitive, Dark, Cool
Hair: Black, Kinky, Fine
Eyes: Brown
*sighs* Another product that caused an allergic reaction. I only used it as a foundation/makeup remover. Every time I use it, my face would get this burning sensation and my lips would start to swell slightly. I used it about three times before I gave up. Eventually the rash and "acne" would disappear. Pity since it is cheap. I guess I am stuck with using apricot oil.
Age: 25-29
Skin: Combination, Fair-Medium, Not Sure
Hair: Black, Other, Other
Eyes: Black
I really really want to love this product, the smell is nice, it is a classic product that has been around for years, it takes off my mascara well but it breaks me out!
I might continue to use it as a make up remover, not as a cleanser itself.
Age: 25-29
Skin: Combination, Medium, Not Sure
Hair: Black, Other, Other
Eyes: Brown
I hope this product will be around forever! I have combination skin, which is oily around the T-zone but dry around the cheeks area. My skin is at worst in the winter time when I cannot get it balanced enough to wear foundation or mineral makeup without revealing the flakiness of my skin. My cheeks were blotchy and dry all the time.
I began researching for a product to help balance my skin during the winter time. Then I found Pond's Cold Cream. A regular sized jar costs around $5-6 so I thought it was worth a try. Initially, I wasn't too sure about it because it was a little messy and cumbersome to use. The main ingredient is mineral oil, hence it is rather oily and would not wash off with water. You'd have to wipe if off with a soft paper towel or a warm wash cloth. I chose using a wash cloth because it is less messy.
Aside from the cumbersomeness, I was very happy with the result only after a few days. I was half expecting my T-zone to get even oilier, but surprisingly it helped balanced out my skin. My cheeks were no longer dry and my entire face felt so smooth. My foundation and mineral makeup also went on flawlessly.
I continued to use it at cleanser to remove my makeup at night, and in the morning to give my skin some extra moisture. At night time, I would apply about a quarter size and rub it all over my face and neck on before going into the shower. This helps protect my skin from the hot water, and also to deep moisturize my skin. I would then wipe it off with a warm wash cloth when I'm about to step out of the shower. It removes ALL of my makeup, including my waterproof mascara. I do not use any additional cleanser afterward. At times my skin feels so soft and smooth that I skip out on my moisturizer. I also have extremely sensitive skin and it does not irritate my skin or make it feel tight. During the summer time, because of the humidity, I instead of using it twice a day, I would only use it at night.
It has been two years since I have been using Ponds Cold Cream and I can't be happier. My skin is in the best condition it has ever been and I am saving so much money from not buying expensive cleanser.
Be warned that it has a very distinct smell that may not be for everyone. For me, I only wish the smell was more pleasant but this does not deter me from using it. My husband, on the other hand, wishes that I stop using it all together! However, he has been a good sport about it seeing how good it has been for my skin.
I am hoping and praying that POND'S will continue to make this product forever!
Age: 19-24
Skin: Sensitive, Fair, Cool
Hair: Brunette, Wavy, Coarse
Eyes: Brown
PRODUCT INFORMATION: This classic rich cream deep cleans down to the pores to remove even the most stubborn makeup and impurities, while leaving skin soft and smooth.
The white, opaque cream is packaged in a 190 mL matted, white plastic jar with a Tiffany-coloured plastic screw top. This product is not fragrance-free.
Directions: Massage gently over face and throat. Remove with a warm washcloth.
MY THOUGHTS: I purchased a 190 mL container of POND'S Cold Cream for normal or dry skin at Save-On-Foods for $8.99 CAD. The product is very thick, like yogurt or softened cream cheese, while the fragrance reminds me of roses. Cold cream is an emulsion of water and certain fats, including beeswax and fragrance, to remove makeup. Oils like mineral oil and jojoba oil (which are slower to spoil) now replace the traditional olive oil along with alcohol, glycerin and lanolin. Meanwhile, borax is responsible for the whiteness in cold cream. The name itself derives from the cooling sensation left behind by the cream.
The product did a satisfactory job of removing my makeup and Shiseido sunscreen. Note: I did need to use warm water to adequately remove the cold cream from my face. In addition, I follow this product with Aveeno's Ultra-Calm Foaming Cleanser. In regards to maintaining sanitary practices, I use a small spoon instead of my fingers to scoop out the product.
Paula Begoun rates this product as average due to its outdated, greasy texture. However, both she and Dr. Leslie Baumann agree that this cleanser is best suited for dry, sensitive skin types.
INGREDIENTS: Mineral Oil, Aqua, Ceresin, Beeswax, Triethanolamine, Ceteth-20, Parfum, Behenic Acid, Montan Wax, Cetyl Alcohol, Carbomer, DMDM Hydantoin, Iodopropynyl Butylcarbamate.
MYSELF: I'm an Euro-Canadian with combination and sensitive skin that is prone to clogged pores (Baumann skin type: OSPW). continued >>
Age: 18 & Under
Skin: Normal, Medium, Not Sure
Hair: Black, Other, Other
Eyes: Brown
takes off all makeup
can use it anywhere
leaves a very oily, gunky feeling afterwards
dislike the packaging; I would prefer it in a tube or something
I would not buy this product again because even though it is great at taking off makeup, it takes a lot of effort and i hate hate HATE the feeling it leaves afterward
Age: 36-43
Skin: Dry, Medium, Warm
Hair: Brunette, Straight, Fine
Eyes: Brown
Great for waterproof mascara! Also for taking off my MAC full coverage foundation which basically cements itself into my skin. I use facial tissue to remove the product as opposed to a cotton pads (sometimes the cotton fibers stick to my lashes). Removes every trace of makeup but does leave a greasy film. I definitely need to follow-up with Mary Kay's Velocity Foaming Cleanser and then a toner and I feel like my face is super clean and soft. At the end of the day, put the cold cream all over your face and jump in the shower and use your washcloth--- the water and steam makes the grime melt away. This is sooo cheap and sooo good. I once read a biography on Jackie Kennedy and it said she constantly slathered Pond's Cold Cream on her face as a moisturizer. I thought it was odd that she could afford any product in the world, yet chose Ponds...
Age: 19-24
Skin: Normal, Fair-Medium, Neutral
Hair: Blond, Straight, Other
Eyes: Green
I Love his cleanser :) at first, I really did not like this because of the gross oily feeling it left on my skin (this was when I was around 16, and wasn't using this to remove my makeup) Anywho, after hearing tons of raves that this is great for removing eyemakeup, foundation etc...I decided to try it again. One of my local liquidating store has boxes of this stuff for only $2.00- so I grabbed one and have since fallen in love =) I first apply this on my eyes and it does not sting or irritate them at all, which is nice. After about a one minute or two, I remove it with a makeup remover towelette or a cloth and it effortlessely removes eyemakeup without drying out your skin around your eyes. I also like this to remove face makeup, it removes my Revlon colorstay foundation and Maybelline powder nicley. A cheap, cult favorite product that truly works!
Age: 19-24
Skin: Oily, Medium, Not Sure
Hair: Brown, Other, Other
Eyes: Brown
I use this as an eye makeup remover, and although its a bit messy, it does the job. I'm terrified of the idea of applying this to my entire face though. After turning 20 my skin went crazy and now im trying to battle acne, so this on my face was was just not gonna happen. As an eyemakeup remover though this is quite nice, I do use a makeup removing cloth instead of tissue since I like to be thorough.
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Dry Skin? by Michelle Phan


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Reagan's stirring salute to Skutnik inspired me to research and memorize his story for a seventh-grade English class assignment. Skutnik was a young worker at the Congressional Budget Office. He had been driving home from work when Air Florida Flight 90 fell from the sky just 20 seconds after takeoff from Washington National Airport.
Skutnik jumped out of his car near the Fourteenth Street Bridge, where a crowd watched helplessly as a female passenger screamed for help in the icy waters. A helicopter rescue team had tossed her a line, but she was unable to hold on. Skutnik instinctively ripped off his overcoat, kicked off his shoes, dove into the river, and pulled 22-year-old flight attendant Priscilla Tirado to safety. She and four others survived. (Skutnik, a remarkably humble man who refused to be called a hero, still lives and works in the nation's capital.)
After Reagan's speech, a cynical press referred sneeringly to the "Lenny Skutnik moment." This elitist disdain for recognizing everyday heroes persists. Just last year, linguist Geoffrey Nunberg complained in The New York Times about "bathetic 'Skutnik moments.'"
"Bathetic"? I didn't know that condescending word when I was 11. But I do know that on a chilly night in January 1982, the president ignited a young heart. It was my "Ronald Reagan moment" -- an indelible moment when the exceptional goodness of America, and the boundless capacity of ordinary Americans to do extraordinary things, came alive. The flame endures.
Bush mocks Rubio and his fans: Stop whining that it's "unfair" that you're being attacked by another candidate's Super PAC | Allahpundit


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The world's tallest raft ride in Venice, Italy; The Master Blaster in Texas; the only slide in the world that runs through a rain forest.
The world's tallest water slide in Brazil; monster tube that throws you down three stories in 12 seconds; a slide built for speed.
The world's largest indoor water park; the world's longest water ride; a ride that sends you back to the pre-historic ages.
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Kansas Same Day Dentures
Proud to present resources for Kansas same day dentures, plastic partials, metal partials, dental implants, adjustments, tooth extractions, relines.
Kansas Same Day Dentures
It could be very important to schedule a denture consultation appointment to help the Kansas dental professional make sure there are no unseen needs their customer may need. For example, sometimes tooth extractions may be needed before a denture can be made.
While some may believe this is a setback on getting Kansas dentures, it also could be beneficial as wearing a denture with a potential mouth problem could make life miserable. It also is important to remember, dental professionals are in the business to make sure the mouth is healthy when a denture is worn. During a consultation, a dental examination may occur along with discussion about the different kinds of dentures available along with the different characteristics different styles of dentures can offer.
In addition, should there be a need for extractions, dental impressions will be needed during the consultation from which will enable the making of a temporary denture to be worn after the tooth extraction, and worn while the mouth heals.
New Kansas same day dentures
Out of habit most folks feel obligated to get new dentures during their appointment, and could pay more for this mistake. Some folks might not understand the consequences when choosing same day dentures. While it is quite conventient to get the same day of visit, these dentures might not be made with long lasting materials. Meaning, on average, quality dentures are made to last at least five years, while cheap dentures made the same day usually lasts in a much shorter time.
Other Services
Kansas Services
- Adjustments
- Extractions
- Partial Dentures
- Dentures
- Denture Implants
- Dental Consultation
- Immediate Dentures
- Routine Cleanings
- Implant Restorations
720 Murray St
Wichita, KS 67212
Franklin Hunt DDS
801 S 55th St
Kansas City, KS 66106
Michael Michel DDS
2951 SW Wanamaker Dr
Topeka, KS 66614


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The province has issued a high-wind warning for the south basin of Lake Winnipeg for both today and Sunday, urging property owners to take precautions.
North winds are forecast to increase through the day Saturday, reaching up to 65 kilometres per hour Sunday morning. The winds are forecast to diminish late Sunday.
Manitoba Infrastructure and Transportation also issued a moderate wind warning for the south basin of Lake Manitoba.
Wind speed and direction could raise levels by more than a metre along the south shore of Lake Winnipeg and between 0.3 and 0.6 metres on the south shore of Lake Manitoba, according to the department's hydrologic forecasting and water management centre. The winds could also produce big waves, it said.


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Have you been looking for they key to Gods design for your marriage and family?
Click on the picture for product detail
Come alongside Pastor Brian and Cheryl Brodersen as they encourage husbands and wives to grow together as a couplespiritually.
Join Brian and Cheryl Brodersen in this hilarious, yet deeply serious, dialog that is so much fun to watch.
Includes both Volumes 1 and 2 in MP3 format.
Volume number 1 of a series of Bible Studies on CD for husbands & Wives by Chuck Smith
Volume number 2 of a series of Bible Studies on CD for husbands & Wives by Chuck SmithClick on the picture for product detail
Pastor Chuck discusses the blessings of both personal and marital relationships and the biblical truths that testify to a love that lasts.
Powerful forces are at work to strike at the foundations of the family unit.
Terms and Conditions


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17 1/2 in. Passier english saddle
Older, well loved, 17 1/2 in. Passier all-purpose saddle with a 6 in. medium tree. It is in fair, used condition. It is past it's show days, but it is a comfortable saddle for everyday pleasure and trail riding. $100.00. PM for link to pics and details.
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Recipe by: MARLEE
Original recipe yields 12 servings
Based on a 2,000 calorie diet
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Ready In
See how to make a creamy Alaskan-style halibut chowder.
See how to make creamy chowder with scallops, potatoes, and bacon.
See the simple secrets to making quick, creamy crawfish chowder.
Well, now, I'm surprised. This just didn't sound like it would work-and all that thyme!! Well, it did! I reduced the clam juice to a little over three cups and it improved the overall texture, m...


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Searched for: "exploring raid configurations"
About 30 results for "exploring raid configurations"
Experts shine light on overcoming virtualization adoption challenges
Read about the interesting results of an SMB virtualization study, and then discover what guidelines and advice two IT two experts offer about adopting and then managing virtualization.
Five free disaster recovery tools
The law of averages dictates that disaster will strike you. When it does, you can only hope you have prepared for it.
Protect your data with Windows 8 Storage Spaces
Protect your data in Windows 8 with this step-by-step process of setting up a Storage Spaces configuration.
Case Study: Help4IT UK
help4IT is a managed IT solution provider based in London, UK that has partnered with Vembu StoreGrid to offer a comprehensive managed online backup service to its diverse set of c...
Calculate IOPS in a storage array
What drives storage performance? Is it the iSCSI/Fiber Channel choice? The answer might surprise you. Scott Lowe provides insight into IOPS.
A server virtualization project success story
Westminster College's VMware ESX-based server consolidation project is in place and running very smoothly. The college's CIO details their solution and discusses why it's a success.
Review: KACE Networks KBOX 1100 Systems Management Appliance
KACE Networks markets its KBOX Systems Management appliance as delivering a fully integrated systems management solution.
Use Reverse Integration to slipstream Windows Vista SP1 and SP2
Having a Windows Vista install DVD with the latest service packs can be very helpful - especially if you reinstall Windows more than a couple of times a year or if you have to deploy Windows Vista to ...
Using the Share and Storage Management Console in Windows Server 2008
At the core, though, file serving--one of the original "killer-apps" that introduced networking to many an organization--still reigns supreme on the needs list of organizations and the reason why most...
Secure your computer after a Windows install or reinstall
Alan Norton details five ways to better secure your Microsoft Windows computer immediately following a clean install until all the important security updates can be installed.


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Miscellaneous Drugs: Table of Contents
Miscellaneous drugs
- XIAP Gene Therapy
- Pridopidine (Huntexil, ACR-16)
- Caspase-6 Inhibition
- Tetrabenazine
- Other Neuroprotective Compounds
- Miraxion (LAX-101)
- The Heat-Shock Response
Drug Summary: Pridopidine, also known as Huntexil or ACR-16, is a dopamine stabilizer intended to improve voluntary movements and reduce chorea. Initial clinical trials – the MermaiHD and HART studies – show promising results, but drug regulation agencies have requested another trial before pridopidine can be sold to the general public.
control relevant
The brain plays a delicate balancing act: it needs to maintain the right levels of many brain chemicals in order to orchestrate movements and execute thoughts. In people with Huntington's disease (HD), that balance is threatened; the brain has trouble regulating neurotransmitters, chemicals in the brain that transfer messages between neurons. This causes miscommunication between different parts of the brain. As a result, people with HD have less control over behaviors and movements that are usually directed by the affected neurotransmitters, as described in greater detail here. Pridopidine, which is being investigated as a treatment for the motor symptoms of HD, is thought to restore the balance of neurotransmitters that the brain needs to function.
Specifically, pridopidine is believed to work by stabilizing levels of the neurotransmitter dopamine in the brain. Dopamine has a number of different roles depending on what part of the brain it acts on, but in the HD brain, the most relevant function is its effects on motion. Dopamine in the striatum, a part of the brain responsible for planning and controlling movements, helps coordinate voluntary motions (like walking or waving) and prevent involuntary motions (like the unwanted dance-like movements of chorea), as discussed in more detail here.
However, sometimes there's too much of a good thing. When there's too much dopamine in certain parts of the striatum, the brain has trouble stopping involuntary movements, which causes chorea. On the other hand, when there's too little, the brain can't start voluntary movements, and the symptoms – such as stiffness, staggering, and difficulties speaking – get in the way of everyday life. The brain walks a tightrope as it tries to maintain the right balance of neurotransmitters, and the slightest disturbance can cause movements to falter (Andre et al., 2011).
As a dopamine stabilizer, pridopidine is thought to reduce the effects of dopamine when there's too much, and increase its effects when there's too little. When dopamine levels are too high, pridopidine interacts with dopamine receptors, which act as the "ears" the neuron uses to "hear" dopamine. These receptors have a very specific shape that allows them to bind and recognize dopamine, and when levels of dopamine are high, the receptors change shape as they become more active. Pridopidine is particularly attracted to the "active" form of the receptor and lodges itself in the spot where dopamine usually binds, preventing dopamine from interacting with the receptor. In this way, pridopidine blocks the dopamine receptor from sensing and responding to dopamine when dopamine levels are too high (Pontel et al., 2010).
Conversely, when levels of dopamine are low, pridopidine has a round-about way of increasing dopamine production. HD affects more than just dopamine: low levels of the neurotransmitter glutamate in a region of the brain called the cortex are also associated with the disease (Pontel et al., 2010). The cortex is the part of our brain that helps us think and plan, and tells the striatum what voluntary movements to perform. Pridopidine raises glutamate levels in the cortex, allowing it to communicate better with the striatum. This increases dopamine levels in the parts of the striatum that had too little. By increasing glutamate signaling in the cortex, pridopidine increases dopamine levels in certain parts of the striatum, allowing voluntary movements to occur (Andre et al., 2011).
Pridopidine therefore plays two opposing roles in the brain, which stabilize dopamine levels. In this way, pridopidine is thought to help the brain reestablish a normal balance of neurotransmitters, and thus regain control over motion.
Neurosearch, a pharmaceutical company based in Sweden, has conducted two different clinical trials on pridopidine.
The MermaiHD study was a phase III clinical trial, conducted in 32 centers spread across eight countries in Europe. 437 HD patients were randomly assigned to one of three groups: one treatment group received 45 mg of pridopidine once per day; the second treatment group received 45 mg of pridopidine twice per day; the control group received a placebo. To prevent potential bias, MermaiHD was a double-blind study; neither doctors nor patients knew whether the patient was receiving pridopidine.
After 6 months, patients were given the opportunity to continue participating in the study for another 6 months. In this "open-label" phase, the 357 patients who opted to proceed took 45 mg of pridopidine twice daily – no patients were given placebo. The purpose of the open-label segment of the study was to test whether pridopidine is safe and effective for longer periods of time.
Preliminary results suggest that pridopidine might help HD patients control motor symptoms. Doctors measured patients' progress using the modified Motor Score (mMS), which tests a patient's ability to perform voluntary movements. Results suggest that patients taking pridopidine performed better on the mMS; patients taking 45 mg of pridopidine twice daily averaged a 1.0 point improvement on the test. However, the results of the mMS did not reach the goals that the scientists had set out to prove: these results reached a statistical significance level of p=0.042. This means that there is a 4.2% probability that pridopidine is no better than a placebo, and that these results occurred by chance; they had originally aimed for a p=0.025.
However, further data analysis indicates that pridopidine may still hold promise. The mMS is just a subsection of a more widely-used test called the Unified Huntington's Disease Rating Scale (UHDRS), which is described in more detail here. When measured on the motor category of the UHDRS, a test called the UHDRS-TMS, the results were very significant: Patients taking 45 mg of pridopidine twice per day had a 3.0 point improvement, at a statistical significance level of p=0.004. To put that in perspective, HD patients generally experience a 3-point annual decline in their UHDRS-TMS score. This strongly indicates that pridopidine improves motor symptoms of HD.
Furthermore, pridopidine did not appear to have notable side effects, and didn't make other symptoms of the disease worse. This was a concern because other treatments, such as tetrabenazine, sometimes cause depression and other side effects if they change neurotransmitters too much in the wrong parts of the brain, as described here.
In the HART study, Neurosearch and the Huntington Study Group teamed up to study pridopidine further. The HART study was a phase IIb clinical trial, which measures how well a drug works at the prescribed dose. The study was also conducted to see whether pridopidine is effective and safe, and to establish an optimal dose. HART enrolled 227 patients, and was run in 28 centers across America and Canada. Like the MermaiHD study, the HART study was randomized, double-blind, and placebo-controlled.
To determine the dose, there was one placebo group and three treatment groups; patients received 10 mg, 22.5 mg, or 45 mg of pridopidine twice per day.
After just 12 weeks, a significant effect was seen in the group taking the largest dose, 45 mg. Total motor function, as measured by the UHDRS-TMS, improved by 2.8 points, which was statistically significant with a p=0.039. Again, the original test – the mMS – did not show statistical significance, though it did show a strong trend with p=0.078.
The HART study backed up the findings of the MermaiHD study and also helped scientists determine which dose of pridopidine is most effective. This study will continue in an open-label phase, where patients who participated in HART are given the opportunity to continue taking pridopidine until the U.S. Food and Drug Administration (FDA) decides whether or not to approve pridopidine.
Pridopidine significantly improves motor function, and has a positive effect on both voluntary and involuntary motor actions. Furthermore, it is very well tolerated, even when patients are taking other drugs, such as antipsychotics. However, pridopidine isn't a "miracle drug" – while the findings are very hopeful, the drug has only been shown to improve motor symptoms; there is no evidence that it can "cure" the disease. Also, pridopidine's effects seem to be limited to motor symptoms; patients experienced no significant changes in cognition, mood, or general ability to function in day-to-day life.
Individually, neither MermaiHD nor HART lived up to the original standards the researchers had set out to meet. However, statistical significance was reached when the results of the two studies were combined, and when the UHDRS-TMS was used to evaluate patients. Based on these results, Neurosearch lobbied the FDA, which regulates American drugs, and the European Medicines Agency (EMA), which regulates European drugs, to accept pridopidine as a treatment for HD. However, both organizations have asked for another phase III clinical trial to validate that pridopidine lives up to these promises. Neurosearch has declared that it will carry out a further trial, but has not yet announced further details. If it successfully passes this trial, the FDA and EMA would be likely to allow pridopidine to start being marketed as a treatment for HD.
M. Hedlin, 7.16.11More
The X-Linked Inhibitor of Apoptosis Protein (XIAP) gene is a gene present in normal body cells that inhibits the activity of caspases 9, 3, and 7. A caspase is an enzyme that degrades proteins and is involved in certain types of cell death, also known as apoptosis. In Huntington's disease (HD), the presence of mutant huntingtin clumps, or aggregates, activates caspases. Once a caspase is activated, it can cut mutant huntingtin protein into smaller pieces, making the mutant huntingtin protein more toxic and causing brain cells to die. Remember that some evidence exists that apoptosis of brain cells is the root of the neurodegenerative problems in HD. To learn more about cell death in HD, click here.
Because the XIAP gene inhibits caspase activity, it can prevent cell death, which means it has great potential in the treatment of neurodegenerative diseases such as HD. The goal of XIAP gene therapy is to inject this gene into cells that are affected by HD so that apoptosis does not occur.
In 2005, researchers working for the pharmaceutical company Neurologix Incorporated tested the potential of the XIAP gene both in vitro (outside of a living organism) and in vivo (inside of a living organism). In vitro, the scientists added the XIAP gene (also known as dXIAP) to brain cells that were designed to have the HD mutation. The study found that the addition of dXIAP significantly decreased the number of cells that died due to apoptosis. The scientists also confirmed the potential of XIAP gene therapy in rat models. The rats were engineered to have symptoms of Parkinson's disease, a disease that, like HD, results in brain cell death. Researchers found that the neurons of rats that were injected with dXIAP were protected against apoptosis.
In the same study, the scientists also aimed to determine more specifically how XIAP gene therapy works. To do this, they engineered four mutant versions of the dXIAP gene. In each mutant version, a different small section of the gene was mutated so that its function was disrupted. Each of these mutant versions was injected into HD-mutant cells to test their effectiveness. The scientists found that only a mutation in a section called BIR3 prevented dXIAP from effectively stopping cell death. This means that the BIR3 section, specifically, is most crucial to the success of XIAP gene therapy. This was useful because the scientists already knew that the BIR3 domain commonly interacts with caspase 9. Thus they concluded that the neuroprotective effect of the XIAP gene may primarily work by stopping the activity of caspase 9 rather than caspase 3 or 7.
Neurologix Incorporated has taken the initiative to determine how the XIAP protein could be used to treat neurodegenerative symptoms in HD patients. In 2008, the company was given exclusive rights to use XIAP to develop a treatment for HD. As mentioned above, Neurologix has already shown that XIAP gene therapy has some effect in preventing cell death in rodents, but it is not yet ready to be tested in humans. Many more experiments with rodent models of HD have to be done before XIAP gene therapy can even be considered a possible treatment for HD in humans. Neurologix does plan to conduct clinical trials in humans, but it is unknown when they will be ready and able to begin these trials.
-C. Garnett, 2-28-10More
There is ample evidence that Huntington's disease is associated with a specific genetic mutation that produces an expanded polyglutamine chain in the huntingtin protein. This mutation causes huntingtin to become a misfolded protein with an altered shape. One of the hallmarks of HD is the build-up of short, broken fragments of the altered huntingtin protein in the nucleus of the nerve cell. There are many theories regarding the actual role of these fragments of altered huntingtin protein in the nerve cell's nucleus. However, many scientists believe that the accumulation of these fragments in the nucleus directly underlies the death of nerve cells in HD. Nerve cell death is responsible for the many cognitive, behavioral, and motor symptoms of HD (for more information about HD symptoms, click here.
The nucleus of a mammalian cell is enclosed by a nuclear envelope, a membrane that features many small openings or "pores." (The nuclear membrane and its pores can be seen in Segment 4 of the "Basics of HD" video: click here to view that segment.) These pores allow different molecules to move back and forth between the nucleus and the cytoplasm. But these pores are very small and allow only smaller molecules to cross the nuclear envelope. Larger molecules require other, more complex mechanisms to be transported into the nucleus, and these mechanisms often take longer as well.
The altered huntingtin protein associated with HD normally resides in the cytoplasm of a nerve cell because it is too big to be able to easily cross the envelope into the nucleus. But when that intact protein is cut up into small fragments, those fragments can easily move into the nucleus and cause dangerous problems for the cell. Proteases are a family of proteins that break up other proteins into smaller pieces. Studies have shown that a specific group of proteases called caspases play a big role in cutting up altered huntingtin into small fragments that can move from the cytoplasm into the nucleus.
A recent study from the lab of Michael Hayden at the University of British Columbia has shown that a particular caspase protein, named caspase-6, may be responsible for the type of huntingtin fragments that lead to nerve cell death and symptoms in HD. In the study, scientists used a mouse model of HD and changed the altered huntingtin protein so that caspase-6 could no longer cut it into fragments. They found that these mice showed no evidence of nerve cell death and they never developed any symptoms of HD. This finding suggests that a drug that inhibits the activity of caspase-6 may be a treatment for HD.
Caspase-6 is not the only protein to cut up altered huntingtin into fragments. Previous studies have shown that caspases can be divided into three rough categories (for more on caspases, click here). There are "ICE-like" caspases (named for their similarity to another kind of protease called the interleukin-1b converting enzyme), "initiator" caspases, and "effector" caspases. ICE-like caspases include caspase-1, 4, and 5. These three seem to play a role in fragmenting proteins involved in processes like inflammation, rather than fragmenting the huntingtin protein. Initiator caspases include caspase-3, 7, and 2, and convert the inactive form of an effector caspase to an active form by cutting off one or two small fragments from the inactive effector caspase. The three effector caspases include caspase-6, 8, and 9, which are the caspases that (when activated by the initiator caspases) actually break down most other proteins.
But there is much overlap between all the caspases, and some fit in more than one category. Furthermore, each of these nine caspases have different target sites where they interact with other proteins. Target sites are specific short sequences of amino acids within a protein where the caspase cuts the protein. Studies have shown that caspase-1, 3, and 6 all target altered huntingtin protein, but they do so at different target sites. The altered huntingtin protein has three locations that have the right target sequences for cleavage by caspase-1. However, for unknown reasons, caspase-1 does not fragment the altered huntingtin protein very much. There are four sites in the altered huntingtin protein that serve as targets for caspase-3. Two of them are active, and caspase-3 does indeed fragment the huntingtin protein at these points. The other two sites are considered "silent" because caspase-3 does not use those targets to fragment huntingtin. Finally, there is only one site that caspase-6 can target, and it's an active site, so caspase-6 does fragment the huntingtin protein.
While it was known for some time that both caspase-3 and caspase-6 break down huntingtin protein into fragments, it was not known if all of the resulting fragments enter the nucleus and cause nerve cell death. It seemed possible that the fragments that were particularly toxic to the nerve cell were specifically generated by one of the two caspases. So in their study, Hayden and co-workers used a mouse model of HD, and mutated the altered huntingtin protein so that either the caspase-3 or caspase-6 protein would not find its usual target. This involved changing the specific amino acid sequence that caspase-3 (or -6) usually targets, and only changing that part so that the rest of the huntingtin protein acts the same. Most of the target sites for caspases are only 4 amino acids long, so it is not difficult to selectively change that part.
Hayden's group generated one mouse that had all four of the caspase-3 target sites changed and inactivated, one mouse that had the single caspase-6 target sites changed and inactivated, and one mouse that had all of the caspase-3 sites and the caspase-6 site changed and inactivated. They tested all of the types of mice to make sure that they were expressing similar amounts of the huntingtin protein, and that the expanded polyglutamine chains were roughly the same length. In so doing, the researchers ensured that the main difference between these mice was the ability for caspases-3 and 6 to fragment the huntingtin protein.
One way to test for nerve cell death is simply to measure the weight of the brain at a certain age in HD mice and compare it with the weight of the brain in other strains of mice. The less the brain weighs, the more you can assume there is nerve cell death. Previous studies have shown that mice with altered huntingtin protein (that can be targeted by both caspase-3 and 6) lose about 10% of their brain mass as compared to healthy, wild-type mice without the altered huntingtin protein. This loss of brain mass can be attributed to nerve cell death due to the HD associated protein. The first thing that the Hayden group observed was that the mice with altered huntingtin protein resistant to both caspase-3 and caspase-6 did not have that 10% loss of brain mass. Instead, the mice were much more similar to the healthy, wild-type mice.
Then, to determine which of the caspases—3, 6, or both—were necessary for brain mass loss, Hayden and coworkers tested each of the other two mouse lines they had generated. They found that the mice with huntingtin protein resistant to caspase-3 cleavage had similar brain mass loss as mice with the HD associated huntingtin protein. In other words, fragments generated by caspase-3 are not the fragments that cause nerve cell death. But these mice still generated fragments due to caspase-6.
Next, they tested the mice with huntingtin protein resistant to caspase-6 cleavage, and they found that these mice had no significant brain mass loss. They were similar to healthy, wild-type mice and to the mice that had huntingtin protein resistant to both caspase-3 and 6 cleavage. Notably, these mice were still generating fragments due to caspase-3. But since these mice had no evidence of brain mass loss, it is evident that fragments selectively generated by the action of caspase-6, but not caspase-3, are toxic and cause nerve cell death.
Additionally, Hayden and his group tested the motor coordination of each type of mouse. What they found was that both the mice resistant to caspase-6 action and the mice resistant to caspase-3 and -6 action, were able to perform normally, just like healthy, wild-type mice. The mice resistant to only caspase-3 action performed poorly, just like mice with the regular HD-associated huntingtin protein. This result shows that selective inhibition of caspase-6 not only prevents brain mass loss, it also prevents motor symptoms of HD.
Finally, they looked specifically at the location of fragments of huntingtin protein within the nerve cell. Mice with the HD-associated huntingtin protein and mice that have caspase-3 resistance (but generate fragments cut by caspase-6) both have fragments that enter the nucleus early in the mouse's lifetime. Both healthy, wild-type mice and mice that are resistant to caspace-6 (but generate caspase-3 fragments), show little to no signs of huntingtin fragments entering the nucleus. In the caspase-6 resistant mice, researchers saw some fragments enter the cell very late in life, but they still did not cause nerve cell death or symptoms. This points to the idea that it is the action of fragments (created selectively by caspase-6) inside the nucleus that causes toxicity and nerve cell death. If fragments created selectively by caspase-6 are the ones to enter the nucleus, then caspase-6 inhibition might prevent that toxicity and might prevent HD symptoms.
A few uncertainties remain to be considered in the Hayden Lab study. Most significantly, it is unknown whether altering the specific amino acid sites that caspase-3 and -6 target has any effect on the rest of the huntingtin protein itself. Perhaps in addition to being targets for caspases, those sites determine huntingtin structure, stability, or clearance. If so, we cannot know whether the lab's findings on the role of caspase-6 would hold true in human patients. Furthermore, caspase-6 might have other important functions in the cell that an inhibitory drug would impede. Finally, we do not know if there are other caspases or caspase sites that play a significant role in creating the specific huntingtin fragments that lead to nerve cell death in humans. More work will have to be done to answer all of these questions and ensure that any caspase-6 inhibitors developed as drugs are safe and effective.
Nevertheless, this research has excited the HD community. Finding a drug to inhibit the action of caspase-6 seems a promising direction for treatments, and the work that must be done is very practical and logical. Researchers will look for chemical compounds that might inhibit caspase-6, test them in mice with the human version of HD, and if successful, then move on to clinical trials. Hayden says he hopes to start human clinical trials within five years. In fact, at the Cure HD Initiative (CHDI), a nonprofit drug development research organization for Huntington's disease, efforts are already underway to develop a safe, effective caspase-6 inhibitor. This area of research will be important to watch for the next few years.
-J. SeidenfeldMore
Chorea is one of the most common and debilitating motor symptoms experienced by people with Huntington's Disease. Tetrabenazine (TBZ) has been the drug of choice for treating chorea in 10 countries for more than a decade. However, TBZ has not been widely used in the U.S. because, until recently, the drug had not been approved by the FDA for the treatment of chorea. In August of 2008, the FDA approved a form of TBZ, called Xenazine, for the treatment of chorea, making the drug available to HD patients in the U.S. TBZ is also available under the name Xenazine in Europe and Australia, and under the name Nitoman in Canada. According to reports from countries where TBZ has been used for a longer period of time, 80% of patients show an improvement in chorea. It is important to note that TBZ treats some of the symptoms of HD but is not a cure because it does not affect the underlying mechanisms or progression of the disease.
TBZ cannot fix the proteins that are damaged in HD, but it can help reduce one of their harmful effects: chorea. Recall that chorea is believed to be caused by increased activity of the neurotransmitter dopamine. TBZ exerts its anti-choreic effects by reducing the amount of dopamine in the brain in two ways. The first way and more widely recognized way is by preventing dopamine from being released into pockets at the end of each neuron called vesicles. These pockets store neurotransmitters, like dopamine, and release them into the synapse at certain times. When a signal to release the neurotransmitters is received, the vesicles are transported to the ends of nerve cells for release through the membraneof the neuron into the synapse. Special proteins called vesicular monoamine transporters (VMATs) are responsible for putting neurotransmitters into the vesicles. TBZ binds to the VMATs, preventing them from performing this function. As such, neurotransmitters like dopamine are not stored in vesicles and cannot be released into the synapse where they would otherwise affect other nerve cells.
The second way that TBZ reduces dopamine is by blocking dopamine receptors. TBZ binds to receptors on the surface of the receiving nerve cell, blocking dopamine from binding and passing on its message. The mechanism of inhibiting dopamine receptors, however, is thought to be less significant at the TBZ dosages used in HD patients. For more information on the neurobiology of HD, click here. Because it has the potential to block dopamine on both sides of the synapse, TBZ is thought to be that much more effective at treating choreic movement disorders.
TBZ depletes neurotransmitters other than dopamine in the brain, such as serotonin and norepinephrine. As a result, it can produce several side effects. By decreasing the amount of serotonin in the brain, TBZ may increase the risk of clinical depression. Also, as a dopamine-depleting drug, TBZ can sometimes lead to Parkinsonian motor symptoms. Parkinson's disease is the result of too little dopamine in the brain, and is characterized by rigidity and difficulty initiating movement. It is very unlikely, though, that people with HD would get Parkinsonian side effects from using TBZ, as their dopamine levels are so high. For more information on the relationship between HD and Parkinson's disease, click here. Among people with HD who experience side effects with TBZ, most report mild symptoms such as drowsiness, constipation, insomnia (already a common occurrence in HD), akathisia, drooling, and weakness.
TBZ has been in use in countries outside the U.S. since 1960, so many studies have been conducted on the drug.
Mikkelsen (1983) studied the tolerance of TBZ during long-term use. The results of this study showed infrequent and usually mild side effects. Only 5 of 124 participants discontinued the use of TBZ because of adverse effects. The researcher concluded that long-term treatment with TBZ appears to be quite safe.
Pearson & Reynolds (1988) linked TBZ with dopamine depletion by examining brain tissue from people with HD. They looked at people who had been treated with TBZ during their lifetimes, and compared their levels of neurotransmitters to the levels of people who had never been treated with TBZ. They found that those who had received TBZ treatment had lower concentrations of neurotransmitters in all areas of the brain that they studied, compared to those who never received TBZ treatment. These researchers found the greatest decrease of neurotransmitter was dopamine in a part of the striatum called the caudate, an area of the brain important in movement. For more information on HD and the brain, click here. However, the decrease in neurotransmitter was not limited to dopamine, but also included serotonin and similar molecules, which suggested the possibility of side effects. This study confirmed the findings of animal studies that TBZ treats chorea by depleting neurotransmitters in the brain.
Ondo, et al. (2002) tested the efficacy and tolerability of TBZ for treating chorea in 19 people with HD. Participants started with dosages of 25 milligrams per day, with a weekly increase to 150 milligrams per day. These participants had the option of not increasing the dose if they were satisfied with the results at any given stage, or if they began experiencing negative side effects at higher doses. They were evaluated at the beginning and end of the study. These evaluations included a videotaped portion, where they were rated using the motor section of the Abnormal Involuntary Movements Scale (AIMS). The videotapes showed an average improvement of 3.4 points on the AIMS (out of 42 total), with improvements attributable to TBZ in 15 of the 19 participants (two had improved before taking TBZ, one did not change, and one did not return for re-evaluation). When participants were asked to subjectively report their condition, none reported a worsening of their symptoms. Only one participant reported more than mild side effects. For this person, akathisia (feelings of restlessness and urges to move about) improved when the dose was lowered. Before taking part in this study, 13 of the 19 participants had tried at least one medication for chorea that they reported to be ineffective. All of the participants who completed this study, however, decided to continue taking TBZ to treat their chorea. The researchers concluded that TBZ is effective and well-tolerated.
Huntington Study Group (HSG) and Prestwick Pharmaceuticals (2006) collaborated on a clinical trial involving TBZ called TETRA-HD. Led by Dr. Frederick J. Marshall from the University of Rochester Medical Center, TETRA-HD is a phase III clinical trial with the goal of determining the optimal dosage of TBZ in treating chorea and other involuntary movements in people with HD. The trial was carried out at 16 different HSG sites in the United States, involving a total of 84 participants with HD. 54 of the participants were randomly assigned to receive TBZ for 12 weeks with increasing dosages over the first 7 weeks. The other 30 served as the comparison group and received a placebo. The results of the study found that TBZ is effective in treating chorea and that its side effects are less severe than those associated with other anti-choreic drugs. On the CGI Global Improvement Scale, 6.9% of the patients receiving placebo had more than minimal improvement compared to 45.1% of the patients receiving TBZ. Clinical assessments showed that TBZ was associated with drowsiness and insomnia in four patients, depressed mood in two, parkinsonism in two and akathisia in two. Most cases of adverse effects improved after adjusting dosage levels, but the risk of side effects such as increased risk of suicide, must still be acknowledged. These results confirm the benefits of TBZ usage in ameliorating the symptoms of chorea.
On August 15, 2008 the Food and Drug Administration (FDA) approved the first treatment for HD in the United States when federal regulators cleared Xenazine, a form of tetrabenazine made by Prestwick Pharmaceuticals Inc., for treating chorea. Although Xenazine cannot cure HD and may have harmful side effects, the FDA approval will increase the number of treatment options available to HD patients.
A series of events led up to the approval of Xenazine. The results of the TETRA-HD study were reported in October 2004 and subsequently published in the reputable, peer-reviewed journal Neurology in 2006. In April 2005, Prestwick Pharmaceuticals, the manufacturers of TBZ, announced that they had filed a New Drug Application with the FDA. The approval of this application was not expected to take long because Prestwick was granted "fast track" and orphan drug status for TBZ by the FDA. Orphan drug status is given to drugs that treat diseases that affect fewer than 200,000 people in the U.S., and the companies that produce them receive additional incentives to get them to market. In December 2007 the FDA Advisory Committee unanimously recommended Xenazine to be approved, and in August 2008 it was officially approved.
T. Wang, 2/6/09; recorded by B. Tatum, 8/21/12More
Scientists are currently investigating various compounds that are known to have neuroprotective effects. These compounds exert their effects through various mechanisms, often through a combination of the mechanisms discussed above. While most of these compounds are not currently being investigated as treatments for HD specifically, they are believed to have beneficial effects on people with various neurological diseases such as stroke, Alzheimer's Disease, Parkinson's Disease, etc. Many neurological diseases seem to have similar disease mechanisms, thus giving rise to the possibility that these compounds might eventually be potential HD treatments as well.
Ethyl-EPA is made from eicosapentaenoic acid (EPA), an omega-3 fatty acid. (For information on omega-3 fatty acids, click here.)
Ethyl-EPA, also known as Miraxion or LAX-101, is a novel compound that may function as a neuroprotectant by preventing the degradation of brain tissue through a variety of proposed mechanisms. The compound might inhibit harmful enzymes known as phospholipases and might also stabilize the phospholipid components of cell membranes and mitochondria, both of which play important roles in cell regulation and brain function. Ethyl-EPA might also have anti-inflammatory effects. Clinical trials, however, show mixed results; the TREND-HD study indicated that ethyl-EPA has no benefit over short time periods (6 months), but might help motor symptoms of HD over long periods of time. Further study is necessary to determine whether or not ethyl-EPA can be used to treat HD.
A phospholipase is a type of enzyme that converts the phospholipids on cell membranes into free fatty acids and other fat-soluble substances. Phospholipases are grouped into four major classes: A, B, C, and D. It turns out that in the case of several neurodegenerative diseases, including Alzheimer's and possibly HD, increased activity of phospholipase A2 (PLA2) may be responsible for an abnormally large release of free fatty acids from membrane phospholipids, as well as the accumulation of lipid peroxides. Lipid peroxidation is defined as the process whereby free radicals "steal" electron from the lipids of cell membranes, resulting in cell damage and increased production of even more free radicals. (For more information on lipid peroxidation, click here). Thus, an initial increase in PLA2 activity, along with the accumulation of lipid peroxide products, may set in motion a type of "snowball" effect whereby harmful products such as lipid peroxides and free radicals are produced, molecules that then go on to generate even more harmful substances.
Ethyl-EPA is thought to act as a PLA2 inhibitor. As discussed earlier, increased PLA2 activity may degrade nerve cell membranes by initiating the release of free fatty acids from the membranes. Fatty acids are an essential component of nerve cell membranes; membrane fluidity, which is necessary for normal cell functioning and health, depends almost entirely on the precise balanced composition of fatty acids and phospholipids in the membrane. (For more information on the importance of membrane fluidity, click here). The effect of taking fatty acids away from the membrane and altering its composition may affect the membrane fluidity in such a way that important nutrients may become less able to enter the cell and harmful substances may become more able to enter. Oxygen, glucose, and other nutrients that the cell needs to survive all must pass through the membrane before entering the cell. Conversely, the membrane must block harmful substances so they don't enter the cell. Thus, by initiating the release of free fatty acids from membranes, increased PLA2 activity indirectly puts nerve cells in danger by decreasing the overall effectiveness of the nerve cell membrane. It follows that if ethyl-EPA is able to inhibit (prevent the activity of) PLA2, the release of free fatty acids would be prevented and the normal functioning of the membrane would be maintained.
Increased PLA2 activity also contributes to inflammation, which is a process that plays a large role in the course of HD. Here's how the inflammation process works: in response to any form of trauma or infection, certain cells in the body produce messenger substances called cytokines. (For more information on inflammation, click here). These cytokines, in turn, act upon another group of cells, causing them to synthesize and release PLA2. The effect is like opening the flood-gates. When PLA2 is released, it breaks down the cell membrane (as mentioned previously) and causes the release of a sea of inflammatory agents such as prostaglandins and leukotrienes. This increase in inflammatory agents sets the stage for the production of free radicals and reactive oxygen species, and hence for lipid peroxidation and further damage to membrane proteins. By inhibiting PLA2, ethyl-EPA controls the inflammation process and prevents it from spiraling out of control.
Puri, et al. (2002) conducted a six-month controlled study of seven patients with advanced Huntington's disease (four received placebo, three received ethyl-EPA). The study was conducted at Hammersmith Hospital in London. Six months following the initiation of treatment, all of the patients who received ethyl-EPA showed significant improvement in comparison to the placebo group as measured by the orofacial component of the Unified Huntington's Disease Rating Scale (UHDRS). All patients receiving placebo experienced worsening of the disease, as measured by the orofacial component of the UHDRS. Overall, there was an average 34% improvement for the patients receiving ethyl-EPA and an average 23% decline for the patients receiving placebo. Furthermore, there were no adverse effects associated with the treatment.
In addition to the orofacial component, patients treated with ethyl-EPA showed significant improvement on the total movement score of the UHDRS in comparison to the patients receiving placebo (an average 16% improvement for the ethyl-EPA group versus an average 38% decline for the placebo group). Furthermore, brain MRI scans of two patients on ethyl-EPA demonstrated an increase in overall brain size. Conversely, MRI scans of two patients on placebo each showed a decrease in brain size, consistent with neurodegenerative progression in patients with Huntington's disease.
Vaddadi, et al. (2002) performed a controlled clinical study at Monash University in Melbourne, Australia at the same time as the study done by Dr. Puri's group above. In the Vaddadi group's study, seventeen people with Huntington's disease were treated for nineteen to twenty months with a ethyl-EPA prototype drug. When the results from the Puri study became available, Vaddadi's study was halted on ethical grounds in order to offer treatment with ethyl-EPA to those who were on placebo. Before it was halted, however, valuable data in support of the efficacy of ethyl-EPA was obtained. On the UHDRS motor sub-scale, seven of eight patients on placebo deteriorated during the trial, whereas five of nine patients receiving active drug improved. The other primary measurement used was the Rockland-Simpson Dyskinesia Rating Scale. In the placebo group, six of eight patients deteriorated, and in the active drug group, seven of nine improved. As in the Puri study, no adverse effects associated with treatment were observed. Even though these two clinical trials each included only a small group of patients, the positive results were striking. The drug seemed like it had the potential to have a significant clinical benefit in the treatment of HD.
Laxdale Limited (2001) decided to further test the efficacy of the drug by conducting a 135-patient phase III controlled study. Laxdale Limited began a large-scale study in 2001. The study tested 135 subjects at six different centers in the United States, Canada, the United Kingdom, and Australia. This study was a phase III double-blind, placebo-controlled study in which the drug was tested over the course of 12 months. Subjects were rated after 12 months of using ethyl-EPA using the Total Motor Score 4 (TMS 4) subscale of the United Huntington's Disease Rating Scale (UHDRS), the standard rating scale for trials in this disease. The results of this study were announced In February 2003, when it was revealed that statistical significance was not achieved in the entire study patient population. However, this lack of significance was explained primarily by the fact that many patients did not fully follow the study procedure. In those patients who did comply with the protocol, a trend to statistical significance was observed. Only 1 out of the 135 participants experienced a treatment related side effect (gastrointestinal upset).
When the clinical data was analyzed further, it was found that the group of patients with a CAG repeat length of less than 45 showed a statistically significant improvement over those patients receiving placebo, whereas patients with a CAG repeat length of greater than 45 did not. It is believed that there is a direct link between CAG repeat length and age of onset, disease progression and clinical symptoms. It is estimated that 65% of people with HD have a CAG repeat length of less than 45. This means that ethyl-EPA has the potential to improve motor function in over 65% of people with HD.
This finding, however, does not rule out the possibility that ethyl-EPA can help people with higher CAG counts. There is a realistic possibility that there is a confound at play here: on average, people with more than 45 repeats have an earlier onset of HD. Because the drug may have greater benefits for people with later disease onset, these patients with more than 45 repeats may not have responded as well to the treatment. Of course, without further study, there is no way to conclude whether the number of CAG repeats does or does not affect the effectiveness of the drug.
Although the previous study did not conclusively prove the effectiveness of ethyl-EPA in treating HD, the results were promising and valuable information was obtained. This information, along with discussions with the FDA and feedback from the European Medicines Evaluation Agency ("EMEA"), will be used to design another ethyl-EPA study. CAG repeat lengths in the patients will be an important component in the design of the next study. It will allow experimenters to more accurately target patients with this specific gene variant, particularly relating to age and onset of the disease. The Huntington's Study Group will be conducting the study in people who have mild to moderate Huntington's disease. Researchers at 43 sites in the United States and Canada will each enroll approximately 7-8 research subjects. Results are expected sometime in late 2006.
TREND-HD (2008): Ethyl-EPA showed mixed results in a phase III clinical trial, called TREND-HD. This study, conducted by the Huntington Study Group, had two phases. In the first phase, 316 HD adults were randomly assigned to either the treatment group, which received 1 gram of ethyl-EPA twice per day, or the control group, which received a placebo. This was a double-blind study; neither doctor nor patient knew what the patient was receiving, so as to remove any potential bias from the experiment. After six months, the two groups were compared, and the results were grim; there was no significant difference between the two groups on the TMS 4; patients in the treatment group did not have improved motor or cognitive symptoms relative to the placebo group.
However, the study continued, as the investigators wanted to know whether a longer-term treatment with ethyl-EPA might be useful. The second phase of the study lasted another six months. For this phase, the 192 patients who remained involved in the study were all treated with ethyl-EPA. Patients were not told whether they were given placebo or ethyl-EPA during the first 6 month time period. At the end of the study, the patients that had been taking ethyl-EPA for a full year had better scores on the TMS 4 than patients who had received placebo for 6 months then ethyl-EPA for 6 months. They had better scores on tests of chorea and motor symptoms, but there was no difference in the two groups on measures of cognition, mood, or function. These results suggest that ethyl-EPA might be a useful treatment, particularly with those with fewer than 45 CAG repeats, but that its effects are only seen after a longer period of time. The scientists concluded that ethyl-EPA is not effective for short treatment times, but should be studied over longer time periods
D. McGee, 1-23-06, updated by M. Hedlin, 6-30-11More
Cells of all kinds are often exposed to sudden changes in their environment that cause stress. They often respond to stress by making different sets of proteins that protect the cell and return it to a healthy balanced state called homeostasis. These stress responses work together to make sure that cells and tissues are protected from the many challenges they encounter. In this chapter, we will look at the heat-shock response, which is a specific response to stress involved in HD and other diseases associated with misfolded proteins.
The heat-shock response is a set of well-ordered and regulated responses to stress in the cell. The most important feature of the heat-shock response is the production of a group of proteins known as the heat-shock proteins (hsps). These proteins can protect the cell by helping it survive under conditions that would normally be lethal.
Conditions that trigger the heat-shock response in a cell can come from a wide variety of sources, such as exposure to toxic chemicals, or temperatures below or above a certain range. It is also triggered when a person has a fever, an infection, cancer, or a neurodegenerative disease like HD. The heat-shock response can come in handy during the natural stages of a cell's growth as well, even without stress to trigger it.
It is not yet clear how these different factors trigger the heat-shock response. We do know that all of these factors cause various proteins to misfold. To learn more about misfolded proteins in HD, click here. When enough misfolded proteins are present in a cell, it recognizes that there is a problem and triggers the heat-shock response to protect itself from the lethal conditions.
Heat-shock proteins are part of a larger group of proteins called molecular chaperones. Essentially, they are the kinds of molecular chaperones whose numbers dramatically increase during the heat-shock response. In order better understand how hsp's work, we must have a more general understanding of how molecular chaperones work.
Even under normal, unstressed conditions, cells have to keep a very close watch on how well their proteins are folding. As proteins are being translated, their component amino acids are being assembled as a straight chain; they are not yet in the final three-dimensional shape that is so important for their correct function. Certain proteins called molecular chaperones bind to these newly created protein chains and help to fold them into their correct shape. Molecular chaperones help to make sure that protein folding is correct, efficient, and that the number of unfolded proteins is kept to a minimum. One problem with having too many unfolded or misfolded proteins in the cell is that they can interact with each other in ways that may lead to the formation of aggregates, not unlike those formed by mutant huntingtin proteins. For more on proteins and protein folding, click here.
The large, diverse family of molecular chaperones includes (but is not limited to) many heat-shock protein families. It is important to note that some heat-shock proteins are present in the cell at a certain level all the time, even under non-stressed conditions. The heat-shock protein families include hsp40, hsp60, hsp70, hsp90, hsp100, and the "small hsps." The numbers in the names of these families that distinguish them refer to the size of the proteins. For example, hsp70s are approximately 70,000 daltons in size. Daltons are a standard unit of measuring mass in proteins.
When the cell recognizes that there are a lot of misfolded proteins, it triggers the heat-shock response. The first step is the activation of a transcription factor named heat-shock factor. The heat-shock factor can be activated very quickly once stress is recognized, which allows it to be a very effective protective mechanism.
In humans, there are actually three different heat-shock factors that trigger the heat-shock response. Having different forms of heat-shock factors allows the cell to have specialized heat-shock responses, depending on which kind of stress it is exposed to. All three of these heat-shock factors are very important, but for the purpose of this discussion, we will be referring to heat-shock factor 1. This factor is the main one involved in the stress response in HD.
Heat-shock factor 1 is activated in response to environmental and disease-related stress. During non-stressed conditions, heat-shock factor 1 is normally present in the cell as a monomer, or a single copy. This is its inactive, non-functional form. When the cell triggers the heat-shock response, three heat-shock factor 1 proteins bind together to form a trimer – the active form.
This activated heat-shock factor 1 binds to DNA at regions where genes for heat-shock proteins are located. At this point, the number of heat-shock proteins produced in the cell dramatically increases. We will now look at how a few of these heat-shock protein families function when the cell is stressed, using HD as a model.
In HD, a large amount of mutant huntingtin protein is produced in the cell and forms aggregates. This aggregation triggers the heat-shock response and many heat-shock proteins are produced to deal with the problem. In HD, hsp70, with the help of hsp40, binds all over the outer surfaces of misfolded huntingtin proteins. The hsp70 coat changes the way the misfolded huntingtin proteins interact with each other and prevents the formation of aggregates. Furthermore, the hsp70 coat may prevent harmful interactions with other proteins in the cell. For more about ways mutant huntingtin can inhibit other proteins in the cell, click here. Thus, it is possible that the hsp70 heat-shock protein may suppress the toxic effects of huntingtin aggregation.
There is very little research about how other heat-shock protein families interact with huntingtin aggregates. A protein in the hsp100 family, called hsp104, reduces both the toxic effect and the size of huntingtin aggregates. In an experiment using an HD C. elegans model that demonstrates weak motor function, adding hsp104 relieves this impairment. Hsp104 may break apart the huntingtin proteins that begin the aggregation process. Hsp104 may also function in cooperation with hsp70 and hsp40 to actively break apart aggregates and lessen some of their toxic effects. However, hsp104 is only found in yeast. There are no similar proteins in mammals, so it seems unlikely to be used for some type of treatment.
There is not much research about the "small" heat-shock proteins. There is some evidence that they reduce the toxic effects of HD, but the mechanism is not yet clear.
Heat-shock proteins and heat-shock factor 1 may serve as good targets for HD therapeutics. A drug named geldanamycin is known to regulate another heat-shock protein, called hsp90. Hsp90 binds to heat-shock factor 1 and keeps it in an inactive state. Geldanamycin can bind to hsp 90, causing it to release heat-shock factor 1. Then, heat-shock factor 1 activates itself, and stimulates the production of hsp70s present in the cell. These hsp70s then relieve toxicity in the cell (for more on geldanamycin, click here. Radicicol and ansamycin are two other drugs in the same family as geldanamycin. They are used less often, but basically function in exactly the same way.)
Another compound called celastrol has recently been identified. Celastrol comes from a plant often used in Chinese herbal medicine for the treatment of fever, chills, rheumatoid arthritis, and bacterial infection. Exposure to celastrol activates heat-shock factor 1, which then triggers the heat-shock response. A celastrol-induced heat-shock response greatly increases the amount of hsp70, hsp40, and small heat-shock proteins in the cell. Collectively, these help reduce mutant huntingtin toxicity in the cell. Scientists are looking further into the structure of celastrol and how it interacts with heat-shock factor 1, and it seems to be a promising treatment.
J. Seidenfeld, 8/12/06More


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From Our 2009 Archives
Oral Contraceptives May Help Treat Asthma
Latest MedicineNet News
Study Shows Oral Contraceptives May Benefit Some Premenstrual Women
Salynn Boyles
Reviewed By Brunilda Nazario, MD
Nov. 6, 2009 -- Treatment with oral contraceptives may benefit premenopausal women with asthma, even if their asthma symptoms are not strongly linked to their monthly menstrual cycles, early research suggests.
In a small but rigorously designed study, researchers from the University of Alberta confirmed that fluctuating levels of the sex hormones estrogen and progesterone have a direct impact on markers of airway inflammation.
Oral contraceptives are already used as a complementary asthma treatment in women whose symptoms are closely tied to their menstrual cycles.
The new research suggests a much broader group of women may also benefit, study researcher Piush J. Mandhane, MD, PhD, tells WebMD.
"Until now, we did not have the data to show that estrogen and progesterone influence asthma," he says. "Now we have it and it opens up new areas of inquiry for the management of asthma in women."
Hormones, Asthma Symptoms Measured Daily
The study included 17 premenopausal women with moderate to severe asthma who met with the research team daily over the course of a complete menstrual cycle (around 36 days).
Estrogen and progesterone levels were measured at each visit. Asthma symptoms and markers of airway inflammation were also monitored daily, and allergy skin-prick tests were conducted every other day.
"This study took a lot of dedication on the part of everyone involved," Mandhane says. "We endured snow storms, power outages, and university closures. When people were going away for weekend trips I would be at their house at 5 a.m. or an assistant would be there."
This dedication meant that almost 99% of the planned daily assessments were actually carried out.
Nine of the women in the study were using oral contraceptives and eight were not. Four of the 17 had menstrual-cycle associated asthma symptoms.
"Since women taking oral contraceptives don't have significant changes in estrogen and progestin through their menstrual cycles, we did not expect to see changes in markers of asthma through the cycle," Mandhane says. "Women who are not on oral contraceptives should have changes in estrogen and progesterone and as a result they should have changes in these markers. That is what we found."
He says women who experience big fluctuations in progesterone but few changes in estrogen during their cycle are probably most vulnerable to cycle-related asthma.
The study was published this week in the November issue of the journal Chest.
Mandhane believes the findings justify larger studies examining oral contraceptives as a treatment for asthma in premenopausal women.
SOURCES: Mandhane, P.J. Chest, November 2009; vol 136: pp 1301-1307.
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Directions to Lete Youth Hostel
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Map & Directions
Chinese Address/ 地址: 青海省西宁市城中区建材巷国际村公寓5号15层
From Xining Train Station:
- Take the bus No.31 or 103 or 16
- Then get off at 'Shi Yi Zhong/十一中' bus stop
- Walk across the road, walk down at 'Jian Cai Xiang/建材巷' road for 200 meters. When you see the 15-floor building on your left side with a yellow-board sign with our name in front of the gate, please enter and take the elevator to get to the 15th floor, then walk up one more floor, you will be arriving at the reception.
From the airport:
- Take the airport bus for 21 Yuan get to 'Xi Men' bus stop at downtown. It takes half a hour. - Then take taxi from there to 'Guo Ji Cun Gong Yu No. 5 Building/国际村公寓#5楼', where Lete Youth Hostel is located, for 8 Yuan, about 10 minutes.
There are 4 long-distance bus stations. They are still changing the bus schedule cause the main bus station at Xining train station is just open, you could take bus #31 or 103 or 16 (Check direction above). Please call us and consult about direction if you land at other bus stations.
From any other place in the city of Xining:
- One bus stop near by the hostel is No.16, 17, 18, 31, 82 and the bus stop is called as 'Shi Yi Zhong/十一中'
- The another bus stop near by the hostel is No. 30, 104 and the bus stop is called 'San Zhong/三中'
Please feel free to call us at +86(0)9718202080, if you need us to instruct the driver to find us!


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Gay Wisconsin GOPer savagely beaten: "Should have kept your f****t mouth shut," attacker says
Kyle Wood suffered a concussion, bruises, and facial abrasions.
Submitted image via Daily Caller
6:30 p.m. -- Kyle Wood has admitted he made the following story up. Click here for an update.
Last week, a strange alleged hate crime went down in Madison: A full-time volunteer for a GOP congressional candidate says he was attacked at home by a man who was apparently upset an openly gay man would work on behalf of a Republican.
-- Investigators don't believe Duluth man told truth about alleged anti-gay mob beating
-- Delmon Young allegedly yelled "F**king Jews!" at yarmulke-wearing panhandler before assault
The victim, 29-year-old Kyle Wood -- staffer for 2nd Congressional District candidate Chad Lee -- says his attacker told him, "You should have kept your faggot mouth shut."
Wood says he was getting ready for work early last Wednesday when a man knocked on the door. When he opened it, the assailant suddenly wrapped a ligature around his neck, slammed his head into a nearby mirror, and then dropped the "should have kept your mouth shut" line.
More from the Daily Caller:
"He then kidney-punched me, while at the same time saying I was 'warned,' and continued to beat me," he added.
Wood said his attacker's reference to a warning likely pointed to graffiti he found painted on his car [the week before]. The vandalism included the phrases "house trained republican faggot," "traitor," and "ur like a jew 4 hitler."
Those slurs, he explained, were references to him being a gay Republican working to help Lee, a straight GOP candidate, defeat the openly gay Democrat Mark Pocan.
Here's the police report:
The Daily Caller, a conservative news site co-founded by former Fox News commenter Tucker Carlson, quotes the leader of a gay conservative group as saying the assault reflects the "hate and vitriol directed towards a gay conservative from gay liberals," despite the fact there's no strong evidence a gay liberal was actually in any way responsible for the attack, which is still being investigated by police.
Lee's injuries were characterized by police as "minor." Assault aside, he told the Daily Caller he "will not be bullied into voting for a gay man simply because I am gay."
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Our style is dependent on that investigation. We have no single favorite signature "look." We refuse to impose a limited palette upon a widely varied world.
From conception to completion, our oversight ensures a personal attention to each garden, providing continuity of communication and vision throughout.


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Nissan Altima Hybrid Repair and Maintenance
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Nissan Altima Hybrid Problems
The front struts can wear prematurely and develop a knocking noise when driving over bumps.
The AC system may blow warm air due to refrigerant loss caused by a leaking low pressure AC hose. These hoses commonly develop a leak at the hose crimp connection.
The engine mount on the right side can wear prematurely and cause excessive engine movement.
Nissan Altima Hybrid Questions
When accelerating, the noise gets louder and higher in pitch, when slowing down, the opposite. It makes the noise in Neutral, Drive, or Brake (engine breaking). When going down a hill in Neutral and accelerating under its own weight, it acts the same. Everything about the sound is related to ca...
My car smells like burning coolant and it's Leaking somewhere towards the front of the car
Is this a major issue that needs to be repaired right away? Can it do harm? What are the effects on the vehicle?
Nissan Altima Hybrid Recalls
This recall affects certain vehicles equipped Occupant Classification System (OCS) control units manufactured by Continental Automotive Systems. A varistor in the OCS control unit may have been manufactured out of specification. Under certain conditions, this could interupt the signal between the OCS and the air bag control unit (ACU), causing the passenger air bag to be suppressed in an accident. If the air bag does not deploy when needed in a crash, the risk of injury is increased. Dealers will test the signal between the OCS and ACU with a special tool to verify proper function. The seat cushion containing the OCS hardware will be replaced as necessary. The recall began November 4, 2008.
Nissan Altima Hybrid Reviews
Just received an estimate for engine repair on my 2007 hybrid with 76,000 miles on it. Apparently I need a rebuild due to carbon build up in the engine. $3500.00 plus tax, of course. I wish I knew about this potential complication before I bought the car. So much for gas savings. How about Nissan stepping up and helping out it's hybrid owners, since I am told this is a problem specific to ...
Initially the car was wonderful! After 30K we had to have the carbon build-up cleaned from the engine-thankfully it was covered under warranty. It is approaching 60K and it looks like it needs to be done again except now it will cost us $3500!! Otherwise the car handles well, great gas mileage!
160,000 miles on it now no repairs other than headlight bulbs tires and a regular 12 v battery. i just replaced the ignition coil and finally the brakes now need replacement what a car !


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Food & Home
Brazilian Fabric Hammock
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Available here online at Hammocks.com. $39.98 and up.
Crate & Barrel's Mini Grill in Cooler Bag
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Available here at Crate & Barrel online. $29.95
True Cleaning Confessions
Method Home is currently touring the US complete with a Cleaning Confessional Booth. But, we've got a giveaway for one lucky reader.
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Gardening Week: the Root Vue
I like to think of the Root Vue as the see-through vegetable garden. Peekaboo. 'Nuff said.
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Gardening with Kids: Potted Flowers
An excellent way of honoring our earth is to let it help us grow things. It is remarkably easy to start flowers and plants and even vegetables from seed. This is an excellent project for parent and child.
Design Your Own Crib Bedding
The mom-run bedding company Javis Davis provides parents with a new easy-to-use design tool allowing them to become designers of their own made-to-order crib bedding.


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Tech Reviews
HP Officejet Pro 8600 Plus Inkjet All-In-One Printer Review
16 Jan 2013 Simon Gallagher
Western Digital TV HD Live Media Player Review
Western Digital's TV HD Live Media Player allows the user to access multimedia files on their TV simply from an external storage device. Read on to see how it shapes up...
6 Nov 2011 Simon Gallagher
Tech Review: D-Link Wireless N Home Camera DCS-930L
D-Link's latest WiFi gadget allows users to keep an eye on their home from wherever you have access to your network, without the need to leave a computer connected.
7 Oct 2011 Simon Gallagher


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The Parliamentary Under-Secretary of State for Environment, Food and Rural Affairs
Richard Benyon is a Conservative MP, and on the vast majority of issues votes the same way as other Conservative MPs.
This is a selection of Richard Benyon's votes.
We have lots more plain English analysis of Richard Benyon's voting record on issues like health, welfare, taxation and more. Visit Richard Benyon's full vote analysis page for more.
Richard Benyon never rebelled against their party in this parliament
The well-run West Berkshire Council faces a cut in the RSG of 44%, so I am grateful that my right hon. Friend and his ministerial team have listened to the many entreaties from my right hon. Friend the Member for Wokingham (John Redwood) and me. Will the Secretary of State do two things? First, will he say whether it is possible to envisage a speeding-up of work on the retention of business...
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Conservative MP for Newbury
Entered the House of Commons on 5 May 2005 — General election
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Last updated: 14 Dec 2015.
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This data was produced by TheyWorkForYou from a variety of sources. Voting information from Public Whip.


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Veks and Silence is an upcoming XNA developed title that looks absolutely ridiculous. It's a side scrolling shooter where you take on a zombie horde. The game will span over 13 levels and is set to have plenty of features and weapons. The graphics also look pretty good to for an XNA title. Also, one of the enemies in the game are sharks with butterfly wings. So awesome.
The game from the three man development team, Edible Entertainment, is currently going through peer review so we should hopefully see Veks and Silence on the Indie Games channel pretty soon.
Until then, take a look at the trailer after the break and visit the official Web site for more info and media on Veks and Silence.
[Thanks, Tristero!]