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Solid advice. This definitely gets you both thinking as a partnership, personally and financially. Two people working for the same goals doubles your efforts and can really enhance your results. Just remember not to jump ship at the first threat of a storm! Lol
10 Tips for Balancing Love and Money
It's a sad but common tune: debt threatens to divide or break up an otherwise strong couple that hadn't set up any financial ground rules. Love and money don't always go hand in hand, which means it's crucial to consider the long term repercussions of sharing your life and bank account with another person. There's no magical credit card or anti-debt potion, but here are some tips for keeping the communication lines open, the piggy bank full, and both of you crazy in love.
RELATED: 4 Ways to Divide and Conquer Expenses as a Couple
Discuss and Share Your Financial Goals
Before you get married or move in together you should tackle the tough questions, so both of you know what to expect and aren't shocked years down the road. If things are really serious, make sure to discuss your savings tactics and goals, debt, plans for providing for children and retirement plans. If you're not picking out dresses yet, discuss monthly and yearly expenses like housing, bills, and lifestyle and entertainment expenses.
Most SavvySugar readers say they wouldn't get a joint checking account with their boyfriend, but they might get one to pay for bills. Discuss the idea with your significant other.
Make a Joint Spending Plan
Make a spending plan together. Combining money means you need to communicate about how it is put to use. I recommend using a money management site like Mint.com, which will categorize your expenses and give you both a realistic picture of which areas could be targeted to trim costs.
Check out my guide to managing money as a couple for additional suggestions.
Find a Comfortable Balance
If one of you earns significantly more, talk about it instead of skirting around the difference. Figure out a fair way to cover expenses like meals and rent that works for both of you. Many of the couples I know opt for a sort of sliding scale payment plan, where you pay what you can afford instead of splitting evenly or placing the financial burden on one partner.
Save Room for Your Love
When you've gotten a handle on affording your everyday, expected expenses, begin to build up your savings in a high-interest savings account. Start putting some money toward an emergency fund and fit your monthly savings goals into your overall budget plan to avoid the excuse of not being able to afford to save.
Check out my guide to managing money as a couple for additional suggestions.
Be Honest About Spending
Be upfront about your shopping and spending habits. You shouldn't have to hide your purchases, but establish some ground rules and be honest. If you go shopping every payday and hate that your significant other makes fun of you for it, tell him. You shouldn't criticize little purchases your partner makes either, as long as they aren't adversely affecting your money. Savings is a marathon, not a sprint. There should be some wiggle room.
Manage Money as a Couple
If you are married or deeply committed, open another account just for your fixed, non-negotiable expenses, and immediately transfer the money when you're paid. Set it up so the transfer happens automatically, and neither of you will be tempted to spend that money on other things.
Check out my guide to managing money as a couple for additional suggestions.
Being Broke Ain't a Joke
If you run into a financial crisis and regularly share expenses with your partner, tell them immediately. If you are co-dependent, it's important your partner knows what to expect and how to support you. Together you can create a plan of action, whether it means one of you taking on additional expenses, cutting back on luxuries, or making a larger life change like downsizing to a smaller place or getting an additional job.
Discuss Credit Fears and History
Many women worry about their boyfriend's credit and how it might affect their credit if and when they tie the knot. In a nutshell, nothing happens to your credit when you get married. Your credit history is yours to keep, but it's important that you continue using the cards you already have in your name so that your credit history stays active. Your names will never appear on a credit report together — reports are generated for individuals only. However, if you and your husband open any joint accounts together, those will appear on both of your credit reports.
While there is no such thing as "our credit score," your husband's credit could affect you (but not your credit score) because both of your scores are considered when you apply for joint accounts or a mortgage loan. You might be faced with higher interest rates on these joint finances than if you applied for them on your own.
Trim Expenses Together
While being in a couple may mean you have a larger spending budget, challenge one another to trim unnecessary expenses together. Make major home or luxury purchases or travel decisions together and set an achievable goal, like a romantic weekend getaway, dream vacation or buying a home, as an incentive savings goal.
Maintain Your Independence
You may love your partner more than anyone on this earth, but you should always put yourself first. I suggest you maintain your savings as if you were single and insure you have a rainy day stash. You don't have to be secretive about your savings: Let your partner know you would like to maintain your own savings and explain why.
This is a guest contribution from our friends at SavvySugar. Check out more useful articles from this partner:
Disclaimer: The links and mentions on this site may be affiliate links. But they do not affect the actual opinions and recommendations of the authors.
Wise Bread is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to amazon.com.
I agree with all your points especially the one about honesty in spending. Lying or hiding purchases will lead to a broken trust which can break up the relationship even faster than money problems can.


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This article was printed from mlb, originally published .
Read more news at: https://www.mlb.com/pirates/news
Pirates claim catcher Ramon Cabrera off waivers from Detroit
The Pittsburgh Pirates today claimed catcher Ramon Cabrera off waivers from the Detroit Tigers. Cabrera will be optioned to Double-A Altoona. The announcement was made by Pirates Senior Vice President, General Manager Neal Huntington.
Cabrera hit .277 (109-for-394) with 17 doubles, five home runs and 47 RBI in 107 games this season with Double-A Erie.
Cabrera was originally signed by the Pirates as a non-drafted free agent on April 11, 2008, before being traded to Detroit on December 5, 2012, in exchange for pitcher Andy Oliver. He has been named a mid-season All-Star in four of the last time years in the South Atlantic League (2010), Florida State League (2011) and Eastern League (2012 and 2014).

subset: commoncrawl


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This is a pretty, delicious and healthy side for cookouts and potlucks. Make it now because it's really the best with fresh, sweet summer corn. I grilled the corn to give it smoky flavor, but sometimes corn is so tasty this time of year that you don't need to cook it at all (I guess it's technically "raw," but that's not a problem in this case!). Just cut it off the cob and add it to anything.
I created this recipe for a blogger recipe contest sponsored by Hodgson Mill. They make whole grain flours (really good ones), and also pasta. The very first homemade southern cornbread I ever baked was from a recipe on one of their bags of cornmeal, so they have a special place in my little cooking heart. They sent me a few boxes of their whole wheat pastas to try and use for developing a nutritious summer salad to share with friends and family.
I almost never accept products from companies because I'm rarely offered things I would actually buy or eat. However, I love whole wheat pasta, and using it in a healthy, summery side is nothing out of the ordinary around here. I can happily say I liked the Hodgson Mill pasta equally as much as my usual favorite brand.
All whole wheat pasta is not created equal, by the way. The cheap ones are usually awful, and I like when I can actually taste wheaty flavor. It's perfect with the veggie-packed pasta dishes I tend to make.
Just don't forget to cook it al dente. If you're not sure your pasta is al dente is probably isn't. Always test at least 1 minute before the shortest cooking time. If it's cooked just long enough so you can chew it, it's right. Grab your colander and drain.
Wow, that sounded bossy. Sorry, but I feel very strongly about pasta cookery.
So. if you're still reading and you think my grilled corn pasta salad looks fabulously tempting, you can enter to win $25 worth of whole wheat pasta from Hodgson Mill. They can only ship to residents of the continental U.S. so my apologies to anyone beyond those borders. Here's how:
1) "Like" my pasta recipe on the Hodgson Mill "Summer Pastabilities" Pinterest board. I'm not sure if you can do this without a Pinterest account. If you don't have one, don't worry, and read on...
2) Leave a comment on this post telling me what your favorite summer side is.
3) I have no way of knowing if you "liked" my recipe on Pinterest, so we're using the honor system. If you have no desire to join Pinterest, just leave your comment and we'll call it good.
4) Comment by July 6, and I'll let you know if you won!
Grilled Corn and Sun-Dried Tomato Pasta Salad
Cumin and tangy lime vinaigrette pair perfectly with smoky summer corn fresh from the grill. You can make this dish in advance through step two and refrigerate up to four hours. Bring to room temperature before serving, then toss with the lime vinaigrette, cilantro and feta as instructed in step three.
Serves 6 to 8
Prep time: 10 minutes
Cooking time: 20 minutes
3 large fresh ears of corn, shucked
Cooking spray
1 (10-ounce) package Hodgson Mills whole wheat bowtie pasta
1/2 cup drained sun-dried tomatoes packed in olive oil, sliced
1/2 medium red onion, thinly sliced into half moons
1 teaspoon ground cumin
Few dashes cayenne pepper, or to taste
1/4 cup fresh lime juice (from about 3 limes)
2 tablespoons canola oil
1/2 cup chopped fresh cilantro
1 cup crumbled feta cheese (about 4 ounces)
Coarse sea salt or kosher salt
Freshly ground black pepper
1. Prepare a charcoal or gas grill. Coat corn with cooking spray and grill over direct or high heat until lightly browned in spots, turning occasionally, 8 to 10 minutes. When cool enough to handle, hold one ear upright in a wide bowl or baking dish and carefully cut the kernels from the cob. Repeat with remaining ears of corn. Discard cobs and set kernels aside.
2. Cook bowties to al dente according to package directions. Add sun-dried tomatoes to a large bowl, then top with the onion. When pasta is done cooking, drain and add to bowl (the onions will lose their raw edge when topped with the hot pasta). Add corn, cumin and cayenne and stir to combine.
3. Add lime juice and canola oil to a small jar with a tight-fitting lid and shake vigorously until emulsified (if you don't have a jar, whisk together in a small bowl). Add to bowtie mixture and stir to combine. Stir in cilantro and feta. Season to taste with salt and black pepper. Serve warm or at room temperature.


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8 Reviews
1964 Pac T Boot
- Hardy winter boots for the heavy snow
- Waterproof construction keeps your socks dry
- Thick felt lining offers warmth in sub-freezing temps
- Rubber shell outsole sheds snow and slush
- Herringbone pattern designed for grip on ice and snow
- Lace closure provides a secure, adjustable fit
- Item #SRL0033
Tech Specs
Gearhead Help
Tech Specs
- Reviews
What do you think about this product?
Have questions about this product?
Great Boots!
- Familiarity: I gave it as a gift but have feedback to share
- Fit: True to size
- Size Bought: 12
- Height: 6'2"
- Weight: 200lbs
I got these for my boyfriend after her had tried numerous other sorels. The caribou's were just too big and bulky for everyday wear. These boots were the perfect medium, they still had the classic sorel look but without the massive bulk.
Awesome Boots!
- Familiarity: I've put it through the wringer
These are awesome. They are warm and very comfortable. I highly recommend them.
well.. they last a long time..
I bought a pair from Scheels in Helena Montana back in the mid 70's . They saved my life in a snow storm in the Ruby mountains. I used them to hunt elk on the northern border of Yellowstone in January.
I am now on my third set of liners. cant find a reason to replace 'em
Most of my miles on these are from behind a snowblower in SLC and Chicago. I'd say they are not really acceptable as a hiking or extreme hunting type boot. They just don't have enough foot support for extended long range stuff. However they do two things very, very very well. They keep your feet warm and dry.
Good boots
Just bought the Sorel 64's and wore them for music fest in Steamboat CO. It was snow the majority of the trip and was icy and extremely slushy or watery around the music fest tents like usual. The boots performed well kept my feet completely dry and toasty. A down side to these boots is the sole in general. It's really thin uncomfortable for walking on hard surfaces and the sole patern allows for a lot of slipping in icy spots. The removable linner is great as I wore them without socks at times and are really easy to wash that way. The 64's are a little more low profile when compared to the caribou. They look and fit nicely with jeans where the caribou are far more bulky.
hot, but not with pants inside.
got em for my husband who has been wearing the same beat ol sorels for like ten years. (ugh) he likes them but insists on tuckig his pants into them? why, god, why? also, will only wear them when its colder than zero degrees, says they are hot as shit.
Just curious...is he supposed to have 6 inches of his pants legs scrunched up on top of them? Between the two I'd pick tucked in for looks. Also, scrunching them up on top kind defeats the purpose of having the snow collar if the snow ever gets above the boot height. We are men. Function over looks. :) It's sort of the same but opposite reason ladies will spend an entire evening in heels so steep they cant even walk by the end of the night. Why god, why would you do that to yourself? :)
Present for sig other, he likes them
Got em for my boyfriend this winter to walk the dog with since it gets to -20 around here and we get a good amount of snow and his hiking boots are about to fall apart.
He says they are Good in the snow, keep his feet warm, however not good for walking long distances as there is no structure to them, they bend in and rub the back of his ankle.
Good shoes
These are great shoes. Very solid and practical.
Review Title
I had to return, due to the boot running a bit small in length.
Do these boots really keep your feet warm...
Do these boots really keep your feet warm at 40 below?
No, the ratings these companies put on their boots is a bunch of BS. If you really want warm winter boots you have too look in the mountaineering department or something similar like La Sportivas or plastic boots- but I'm guessing that you wouldn't want those kinds of boots for shoveling the driveway or walking the dog.
I have heard that SOREL hasn't made their boots very well since they started making them in China. Pretty depressing if you ask me. Who Doesn't make their products in China anymore? What do people have to do to get high quality nowadays?
I just replaced a 25 year old or more pair of Canadian made Sorel's for a new Chinese pair because the tread wore down smooth. To be fair the new outer boots seem to be of good quality (time will tell), but the inserts are much thinner than the originals even though they are all rated at 9mm thickness. The Canadian made inserts are 30% thicker than the Chinese inserts. I had bought extra inserts for my old boots and had like new ones to put in my new boots. The old ones were rated at only -10f. The inferior Chinese ones are rated at -40f. The old inserts are much warmer than the new ones.
Write your question here...When rated at...
Write your question here...When rated at -40 F., what does that actually mean in real world conditions?
Whats the difference between this boot and...
Whats the difference between this boot and the caribou? Is it just the color and tread pattern, or are the liners different weight and the uppers different material?
PowPow- Both boots are rated to -40°. The Caribus weigh slightly more than the Pacs. The Caribu also has a deeper tread on its sole, making it slightly better for off-road hikes and icy areas. . The tread on the Pacs doesn't grip as well. The Caribus' upper is a nubuck leather while these are embossed leather. I believe nubuck leather is tougher. Here is the difference between the two liners:
"ThermoPlus® InnerBoots: Pioneered by Sorel in 1993 after extensive field testing. ThermoPlus® InnerBoots provide superb warmth, moisture transfer, comfort, and durability. An advanced four-layer construction wicks perspiration from the foot, maximizes thermal insulation, and reflects body heat back to the foot for a warm, dry foot "climate".
1. Soft, short loop polyester Minktex® (green inner layer) maximizes contact to quickly wick perspiration from the foot.
2. Black polypropylene core insulates and facilitates wicking process.
3. Radiantex® foil reflects body heat back to the foot.
4. Polyester/viscose blend (camel outerlayer) insulates and stores moisture away from the foot.
Washable/Recycled InnerBoots: Pre-consumer recycled polyester. Ideal for children's boots where InnerBoots are exposed to excessive dirt and perspiration. A unique two-layer construction wicks moisture from feet and provides excellent insulation."
Write your question here...I am interested...
Write your question here...I am interested in the Sorel 1964 pac t boot. Does it come in a womens size and if not, what size in mens would you recommend? I wear an 8 1/2 to a 9 in womens.
Probably a 6.5 in these in mens since they run a little big. I see all they have is size 7, they might be ok if your closer to a 9 in womens and are planning on thick socks and insoles.
I say you should get the women's tan caribou. I have tried them on and they are surprisingly good looking for having such a good sole. I wish I had gotten them! Check em out before you resort to buying men's sizes, you will like them
does Sorel 1964 Pac T run a little big and...
does Sorel 1964 Pac T run a little big and so should I order on the small size?
They do run just a bit big so you could either size down just a bit or do what I did and most people end up doing.......stick with the same size and give yourself some room for thicker socks or for an extra pair of insoles when you're running thinner socks.Hope that helps.
My husband has trouble getting into and...
My husband has trouble getting into and out of the boots as he says they do not unlace far enough for him to get his foot in and out. Do any sorels unlace farther down than others???
Well these type of duck boots are all like that.The nicest I have come are across and easier to take offare the sorel conquest they sell them here.They are the best sorel has to offer as far as these type go for deep snow.I love mine
Where can I find these boots in a size 15...
Where can I find these boots in a size 15 or 16 wide?
The best thing to do is shoot Backcountry.com customer support an email, or do a live chat, and ask if they can do a special order. They're great with hooking people up that way, if they're available.


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Best Buy Has Customer Arrested For Using $2 Bills
Posted by Andru Edwards - Categories: Corporate News,
Just when we think they are doing some good in the tech world, they go and mess it up, as always. Best Buy customer Mike Bolesta simply wanted to purchase a car stereo. After being assured that a particular model would fit, he realized the Best Buy sales rep was incorrect (this sounds familiar). After being told the installation fee would be waived due to the error, he was able to get the correct stereo. When he got home, he received a call from Best Buy saying he needed to pay the fee. Upset about the horrible service he received, Mike decided to pay the $144 charge using only $2 bills. Now, there is no law against this. $2 bills are still legal tender here in the United States. He handed over 57 bills, and should have been able to be on his way. Instead, he was asked accusingly if they were real. Then they called the cops. I feel for ya Mike, it's just unfortunate that I have heard stories like this in the past - and yours probably won't be the last. Anyone else have a story of horrible customer service at an electronics retailer?
(Thanks antman!)
Read More | WorldNetDaily
JellyBarn FoolsJelly Image Sharing
Posted by Andru Edwards - Categories: Internet,
We were able to mess around with the first product from JellyBarn, the very humorous FoolsJelly interface. For all of you that love to "caption this pic", this site is for you. Basically, you can view any submissions from other users thus far - or you can create your own. The ones you create can be sent to friends by email, and you can also choose to place it on the FoolsJelly site into their gallery. Here are the features of FoolsJelly:
- Upload your own image for use in two optional postcards to send out via email. You can add text to the postcards in the following ways either by using the cartoon bubble quote, or the "inspiring" poster with a title and subtitle text.
- Reply to the postcard with your own text or by uploading your own image.
- Forward a postcard you received to another person.
- Add your postcard to the gallery and vote for it or other users' postcards.
- View other users' postcards via the gallery.
I definitely recommend everyone to check it out - its a nice interface, and can be used for humor or inspiration.
Read More | FoolsJelly
AOL Launches VoIP Service
Posted by Oscar M. Cantu Categories: Corporate News, Internet,
The Voice over IP market just got a little bit bigger. AOL has launched its VoIP service at a promotional rate of $29.99 a month for non-AOL users and $13.99 a month for AOL users. The service includes standard features found in most calling plans such as voicemail, 3-way calling, caller ID, call waiting and call forwarding. AOL's new VoIP service also includes "advanced AOL features" such as AOL voicemail, AOL call alert and AOLbyPhone. The company is trying to offer competitive prices by bundling some its services with their VoIP package. What stands out in AOL's package is that they provide enhanced 911 service, which delivers the caller's address to dispatchers when in case of emergency. This is something other companies have not been able to implement or offer as an included service. AOL is promising to make VoIP easy to install and use just like the rest of its services so that mass-market consumers may take advantage of this technology.
Read More | AOL Product Page
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Xbox 2/360 To Be Unveiled May 16
Posted by Andru Edwards - Categories: Video Games,
We knew it would happen at E3, but according to the game guru at CNN's Game Over, Chris Morris, Microsoft will unveil the next Xbox on Monday, May 16. That's two days before the E3 Expo officially begins. According to Morris, the name Xbox 360 is pretty much a shoe-in. Rumor has it that they are still debating the hard drive issue and are working hard on backwards compatibility. A foreshadowing fact is that Microsoft recently acquired silicon graphics patents. The CPU is rumored to be capable of decoding and executing in Microsoft Intermediate Language (MSIL) while at the same time being able to run x86 code for backwards compatibility with the current Xbox library. We will soon have all the info - it is now only a matter of time.
Read More | CNN - Game Over
Parodia Electronic Self-Steering Cars
Posted by Andru Edwards - Categories: Misc. Tech, Software,
We may be close to the day where cars won't require steering wheels, at least according to Milan-based Parodia Electronica. They have developed a satellite navigation system on test vehicles which responds to data generated from dGPS (differential GPS). Simply put, the software can determine the position of the test vehicles to within +/- 50 centimeters. It uses servo commands from the navigation system to actuate an electro-hydraulic steering mechanism. They have successfully navigated on public roads in Southern Italy between a set of fixed points without any steering input from the driver, as they only control the brake and accelerator. Parodia's technical director said, "The steering wheels are for show only." Sounds like in years to come, we may be able to snooze all the way to work.
Read More | Transport Trends
Car Rental Company Loses GPS Policing Case
Posted by Andru Edwards - Categories: Misc. Tech,
Chalk one up for the people. The Connecticut Supreme Court has proclaimed that a $150 "excessive wear and tear" penalty charged by Acme 'American Rental' is illegal. Acme outfitted their vehicles with GPS systems and set them up to rat you out if you drive at least 80mph for over two minutes at a time. Of course, details were buried deep within the fine print, and the GPS devices was never mentioned. The contract simply stated "Vehicles driven in excess of the posted speed limit will be charged $150 per occurrence." Some customers were fined more than once on the same rental.
Justice David M. Borden wrote, "Using the [consumer department] hearing officer's calculation, a customer would have to travel more than 1,070 miles at high speeds, without decelerating below 80 miles per hour, to cause $150 of excess wear on the vehicle." Unfortunately the ruling is in regards to the excessive fine, stating that there really was no extreme wear on the vehicle. The companies' use of GPS to track a customer's actions was not touched. So, we won this battle but we have no precedent for our coming war.
Read More | ArsTechnica
Reversible Thermoelectric Nanomaterials
Posted by Andru Edwards - Categories: Misc. Tech,
Physicists Dr. Tammy Humphrey and Dr. Heiner Linke have discovered that a particular structure and configuration of nanowires can have remarkable thermoelectric properties. Meaning that electricity can be generated from heat differentials across materials. Even better, the thermoelectric effect is reversible. This means that the nanomaterial could operate as a heat pump, in essence transferring heat. What does this all mean? There are a few things this can bring to the table - processors that don't require fans, precise control over temperature for labs and sensors, and refrigeration without pumps or chemicals. They also say it could have significant uses in energy production and transportation such as transferring engine heat to electricity for hybrid vehicles.
Read More | World Changing
Xbox 2/360 Launch Lineup May Shock The Industry
Posted by Andru Edwards - Categories: Video Games,
In an interview with the official Xbox magazine of Japan, Mr. Yoshiki Okamoto says there are many other 'big name' game developers getting behind the next gen Xbox. He said, "When announced, the lineup of launch games for the console may shock the industry." Hironobu Sakaguchi (Final Fantasy), Tetsuya Mizuguchi (Space Channel 5), and Yoshiki Okamoto are all legendary game creators in Japan. This is just one of the ways Microsoft is committed to winning the hearts and minds of Japanese gamers while wowing their American audience too. Okamoto said that if the current lineup of launch games in development for the next gen Xbox was revealed, there probably wouldn't be anyone in Japan who would be uninterested in buying one. Those are big words, but aren't they always before a launch?
Then there's Shane Kim who took over as head of Microsoft Game Studios (MGS). He has led some of the largest and most successful game launches in the publisher's history, including Fable and Halo 2. In an interview on xbox.com, he says "We've also built some great franchises that customers love and look forward to playing for many generations of Xbox, like Halo, Fable, Project Gotham Racing, and the upcoming Jade Empire and Forza Motorsport." Obviously, these games will continue to live their life on the next Xbox.
Click to continue reading Xbox 2/360 Launch Lineup May Shock The Industry
Interesting Gmail Storage Algorithm
Posted by Andru Edwards - Categories: Internet,
On Friday, April 1, Google announced their "Infinity+1" plan for Gmail accounts. The first day, we lucky Gmail account holders gained about 1MB. The second day, the gains appeared to slow down somewhat. We weren't holding our breath, considering the announcement was made on April Fool's Day - and sounded pretty foolish to boot. Here are the details of the Google storage algorithm:
- Gmail is currently rising at 1/1000 MB every 25 seconds
- A 1MB increase takes a little over 6 hours and 56 minutes
- Every day storage increases by 3.456 MB
- By April 1, 2006, Gmail accounts will be up to about 3300MB
- It takes 289 days to increase 1 gigabyte
So is Google really going to just continue to increase storage infinitely? A look at the source code indicates that the madness will end when mailboxes reach 2075 gigs:
That only applies until it reaches 2075 MB. Check the source:
var CP = [
[ 1112331600000, 1025 ],
[ 1112439600000, 2050 ],
[ 1113062400000, 2075 ]
Oh well.
Read More | Wesbran.com
PSP Multiplayer With Just One UMD Game
Posted by Andru Edwards - Categories: Video Games,
Okay, so you want to play a PSP game against a friend or two and you only have one copy of the game. On Sahas Katta's blog, he tells how he and a friend played Twisted Metal multiplayer with only one copy. Basically, it involves starting a multiplayer Ad-Hoc game with an unlimited amount of time. After the game has booted up on a system, you remove the game disc and place it into the next PSP. That next PSP joins the Ad-Hoc game set up by the first, and they are set. You can continue this with as many PSP's as are allowed to play the multiplayer game. There are a few other intricacies to making it work nicely, so check it out. This one is just too cool.
Read More | Sahas Katta
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Hey guys I am now in business with a jdm importer from winnipeg. this is what we have in stock but my partner is going to japan in march and filling a container and coming back. So if there is anything that is not on this list let me know and i will get you a price.
Work Equip 01 - $500
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text:
Guide to Geologic Hazards in Alaska
- Saltwater encroachment
- Displacement of fresh water or groundwater by the advance of salt water due to its greater density, usually in coastal and estuarine areas but also by movement of brine from beneath a playa lake toward wells discharging fresh water. Encroachment occurs when the total head of the salt water exceeds that of adjacent fresh water. Syn: sea-water intrusion, salt-water intrusion, sea-water encroachment. (Neuendorf, K.K.E. and others, 2005)
- DGGS online catalog of government agency publications relating to: Saltwater encroachment


text: MainSports & GamesJudo Listen JudoThis page draws together judo-related information for all of Special Olympics. The coaching materials and other links will help you get a good sense of how this sport contributes to Special Olympics. StoriesEventsGames JudoEvery athlete aims to prevail over the opponent by using special techniques, in the standing position by grappling his uniform, otherwise the judo gi, trying to throw him down, and in the ground position by trying to pin him down for a certain time, or by applying chocks or arm locks, which however is not allowed in Special Olympics. Judo is a sport demanding physical capabilities along with spiritual discipline.About This PageSpecial Olympics focuses on the individuality of each athlete so that coaches can train and encourage growth in skills and accomplishment. The coaching materials, rules and other resources on this page have been specially prepared for coaches working with people with intellectual disabilities. Coaching Special Olympics athletes calls for the same skills and experience that many coaches are familiar with. The extra information in our coaching guides about working with people with ID is what makes our materials helpful and valuable.


text:
Monday, October 28, 2013
Muffin Tin Monday - it's Halloween!
It's Monday. It's Halloween week. Let's see some muffin tins.
A creepy muffin tin of yesteryear:
* details for this muffin tin can be found here.
I have been dreadfully absent from blogging for many months. It's maybe a little long of a story to share (and really, not interesting either). In a nutshell, I was very sick and took a long time to recover (boo!). I'm better now (yay!). But struggling to get back into old routines, like blogging. And laundry. And showering. (kidding...kinda).
To all who have emailed and sent messages, I am sorry I didn't get back to you! Email was overwhelming for awhile. I'm lame. I'm sorry.
Now, onto the Halloween muffin tins!
7 comments:
I'm sorry that you were sick. I'm glad to see that you are back to hosting this and hope to start taking pictures and joining in again.
Hoping for next week!
- October 28, 2013 at 6:08 PM
- kewkew said... [Reply to comment]
I am so glad I decided to come over and see if you were back. I am so sorry you have been sick, but glad to know you are better. We don't celebrate Halloween, but I would like to link up our P muffin tin.
Welcome back!
- October 28, 2013 at 8:59 PM
- Mali said... [Reply to comment]
I'm SO incredibly happy you're back! :)
I missed your posts and as I saw this post a minute ago I got sooo happy! :D
Hope you're doing well!
Please don't stress yourself with doing everything like before..
Greets :3
- October 29, 2013 at 3:27 AM
- Anna Adden said... [Reply to comment]
Yay! Hopefull I can get one done :-)
- October 29, 2013 at 11:13 AM
- Smita Srivastava said... [Reply to comment]
Awww these look so so cute.
I have a worldwide Giveaway of 2 copies of my book-"Fun Food for Fussy Little Eaters' would love you t join in !!
- October 29, 2013 at 12:13 PM
- Julie@teachinggoodeaters said... [Reply to comment]
My son looked at this post and said, "That's a great lunch!" It took me a few minutes to realize that the Frankenstein was a kiwi- Brilliant!!
- October 30, 2013 at 1:49 PM
- Marissa @ Life is Fantasmic said... [Reply to comment]
It's so good to see you back!
I missed a few months of blogging because of our move, & then when I came back you were gone. It seems like forever since I've been able to see all your cute lunches!
- November 1, 2013 at 10:20 AM


text:
Miranda Lambert, Chris Young + Jerrod Niemann Perform Live in Denver – Exclusive Pictures
Miranda Lambert's On Fire Tour landed just outside of Denver, Colo. on St. Patrick's Day and left fans feeling lucky to be up close and personal with the country music superstar. Chris Young and Jerrod Niemann opened the show -- their second of three last weekend. First-timers at a Lambert concert quickly learn once the curtain drops that the singer is much more than just a pretty face. Her high-energy shows rival any artist's in any genre of music.
Flip through this gallery of exclusive photos from the March 17 show, and check out the remaining tour dates on the On Fire tour by visiting Lambert's website.
Photos by Josh Lowe for Taste of Country


text:
Driverless cars could turn out to be a scourge on humanity.
They may lead to a worldwide surge in binge drinking since drunk driving would no longer be a worry. They also could be vulnerable to hacking by terrorists who send every self-driving vehicles in the western U.S. plunging into the Grand Canyon.
And by making car travel easier, driverless vehicles could lead to more congestion and pollution.
Those are a few of the points made by economist Steven D. Levitt and journalist Stephen J. Dubner, known for their book \"Freakonomics\", in their latest tome, \"Think Like A Freak,\" which was released Monday.
Those points on driverless cars come from a chapter titled \"How to Persuade People Who Don\'t Want to Be Persuaded.\" The authors say people should avoid pretending their own argument is perfect and acknowledge the strengths of their opponent\'s argument.
Gettting back to driverless cars, advocates of this new technology ought to admit that a huge number of jobs could vanish, according to Levitt and Dubner.
\"Nearly 3 percent of the U.S. workforce — about 3.6 million people — feed their families by driving taxis, ambulances, buses, delivery trucks, tractor-trailers, and other vehicles,\" the authors write. \"What are they supposed to do when this new technology obliterates their livelihood?\"
After having their fun with the many potential negatives of self-driving cars, the authors note a big potential benefit: reducing traffic deaths.
Driverless cars might be one of the biggest lifesavers in human history, given that roughly 90% of the world\'s 1.2 million traffic deaths each year are caused by human error, they write. It\'s impossible to say whether nearly all traffic deaths actually would be eliminated, and a misprogrammed car could one day plow through a playground and kill a dozen school children, but even lowering the global death toll by 20% would be huge, according to \"Think Like A Freak.\"
\"That would save 240,000 lives around the world every year, including 36,000 children,\" Levitt and Dubner write. \"How nice it would be to lower those numbers by \'only\' 20 percent.\"
\"Freakonomics\" was initially a popular 2005 book about \"the hidden side of everything.\" Then it grew into a multimedia brand, with a documentary film titled \"Freakonomics: The Movie\" and a regular segment on American Public Media\'s Marketplace radio show.
To help promote the new book, Dubner took part Monday in an \"Ask Me Anything\" on Reddit, where he lamented that he\'s often quoted without sufficient context, but didn\'t say whether that\'s happened yet on the subject of driverless cars.
Read the AMA here, and learn more about the new book here.
–Victor Reklaitis
Follow Vic on Twitter @vicrek
Follow The Tell @thetellblog
More from MarketWatch:
Warren Buffett: Driverless cars are a big threat to auto insurers
Tesla\'s Elon Musk talks driverless cars


text: Hi, I just installed 126.96.36.199 (using The Perfect Server – Debian Wheezy (Apache2, BIND, Dovecot, ISPConfig 3). If I type the server ip in the address bar I get the /var/www content listed (as shown in the attacched image). I can solve this by putting in the folder an index.html but the question is. Is this behavior correct or is there something wrong? And if it is wrong, what can the problem be? Thank You!


text:
Whatever the Senate does or does not do today, it appears that the House will not vote on any cliff-related legislation tonight. There just isn't enough time.
Technically, therefore, we will go over the full fiscal cliff.
Congressional action may come tomorrow or on Wednesday. After that, any action will be in the hands of a new, very slightly more Democratic Congress.
December 31 was always a phony deadline. So is any other specific date. The stock market will react one way or another to the "cliff" on Wednesday. But any losses (say) can be recouped as the result of subsequent congressional action that Wall Street likes.
In any event, I'm signing off for what little remains of the year.
Happy New Year.


text:
Comments on the Mammoth Trails website
I have two comments on last week's article titled "Mammoth Trails website springs to life."
The Mammoth Lakes Trails System Coordinating Committee June 28, 2012, minutes note the total cost of the trails website as "approximately $225,000."
Measure R funds and Town General Funds were the major contributor, along with some private funds.
That amount, plus the approximately $30,000 budgeted for first year maintenance totals more than one quarter of a million dollars.
I would also like to note that the Town's paved bike paths were constructed as a result of a historically solid and amicable relationship between the Town and the Forest Service.
The bike paths were built segment by segment, starting in the early 1990s, continuing through the present.
During my 18 years here in Mammoth Lakes, including 10 years as a Forest Service Manager, I have never seen a "quirky and sometimes tempestuous relationship" between the two governmental bodies, and I doubt that this statement came from either agency.
On the contrary, whenever projects were stalled, each body exhibited patience and persistence.
The development of formal MOU's have been developed to document that historical partnership, and will soon be signed by both parties.
Sandy Hogan
Mammoth Lakes


text:
Raffle Aids Injured UW Student
The University of Wyoming Freshman Senate is holding a raffle to raise money to cover medical expenses for Cale McCormick, a UW student who was seriously injured when he was hit by a car in early February.
Tickets cost $5 each and are being sold at a table in the Wyoming Union breezeway and at the ASUW office in the lower level of the union.
"Due to the generosity of many businesses n Laramie, all prizes have been donated so that all funds go directly to help defray Cale's medical costs," says Freshman Senator Dennis Zezas. "This will help his family cover medical expenses."
UW's Dean of Students Dave Cozzens reports that McCormick continues to show progress as he recovers from his injuries.
Among the prizes available to win are:
-- Two iPads donated by the President's Office and mechanical engineering department.
-- A football jersey signed by the coaching staff, donated by the UW Athletics Department.
-- A gift bag donated by Atmosphere Mountain Works.
-- A gift bag of assorted products donated by Bath and Body Works.
-- A $20 Gift certificate to Boomers BBQ.
-- Cartouche gift certificate.
-- Free meal at EI Tamal.
-- Framed picture donated by First Interstate Bank.
-- Free sandwich from Jimmy John's.
-- Bracelet and shirt from the Knothole.
-- Free oil change and free detailing from Laramie GM.
-- Four VIP cards from McAlister's Deli.
-- UW jacket donated by UW Department of Mechanical Engineering.
-- Free visit to Laramie Spinal Care.
-- Model truck donated by NAPA.
-- Two large single topping pizzas from Papa John's.
-- Two shampoo and conditioner sets donated by Quick Cuts.
-- Gift certificates to Sheri's.
-- Sports bag and gear from Sport's Locker.
-- Two $50 gift cards to Taco Johns.
-- Glasses and chairs donated by UniWyo Credit Union.
-- UW sweatshirt donated by the Admissions Office.
-- Quilt donated by Quilt Essentials.
-- Two $10 gift cards to Applebee's.
For more information, call (307) 766-8544.


text:
Despite all the publicity about "viral eradication" at this
summer's International Conference on AIDS and at the ICAAC
conference covered in this Treatment Issues, many people
continue to fail on their current HIV medications, even if
they are receiving one of the new triple combinations. (Such
therapy is sometimes called HAART, for "highly active
antiretroviral therapy.") Here are a few of the disappointing
experiences that we at Treatment Issues have heard lately:
"I'm seeing treatment failures most commonly in patients with
very high baseline viral loads -- over 100,000 -- and low CD4
counts. Those with low viral load and high CD4 counts in
general are not crashing or failing" said Gabriel Torres,
M.D., Treatment Issues' medical consultant, reporting on what
he has encountered so far with the new antiviral
Aside from their tendency to have more advanced HIV
infections, the people not responding to the new, improved
anti-HIV regimens do not all fall into any particular
pattern. Many doctors blame patient compliance for a
treatment's lack of success -- after all, the HAART regimens
require complicated schedules for taking the different drugs,
and some medications need to be taken with food while others
require an empty stomach. The number of side effects
encountered might also discourage people from taking full and
regular doses of particular drugs. But the experiences
described above all involve very conscientious and
knowledgeable people who swear they faithfully followed their
prescriptions' instructions.
One does not need to blame the patient to find reasons for
treatment failure: Some people may have gastrointestinal
problems that prevent absorption of enough drug (this
absorption problem arises for the great majority of people on
the present version of saquinavir regardless of their
digestive status). Others may have developed HIV resistant to
most nucleoside analogs due to prior sequential therapy with
these agents. Now protease inhibitor-resistant HIV is
emerging in their bodies during ostensible combination
therapy that is basically protease inhibitor monotherapy.
Still others cannot tolerate the currently available agents
-- they suffer from vomiting on ritonavir and saquinavir and
kidney stones on indinavir. Finally, there are the odder
cases, such as people with impaired livers that cannot
process the current protease inhibitors without added hepatic
At this point, there are no reliable figures about the
frequency with which the widely heralded HAART regimens are
meeting defeat. But it seems to be a common, if not the
predominant, experience. One estimate of its incidence comes
from Agouron Pharmaceuticals, which interviewed several dozen
doctors with large AIDS practices in an effort to determine
the demand for an expanded access program offering the
company's experimental protease inhibitor nelfinavir. (That
program is now in operation -- see below.) Based on the
doctors' responses, the company estimates that about 2,500
Americans with HIV and CD4 counts less than 50 already have
failed or could not take all three protease inhibitors on the
market. Agouron further estimated that 10,000 U.S. patients
with CD4 counts under 200 have failed on or are otherwise
unable to take at least two of the three protease inhibitors.
By comparison, over 50,000 Americans are now taking Merck's
protease inhibitor indinavir.
Ramon Seva, the marketing research official at Agouron who
supervised the survey cautions, "These numbers are very
rough. This was not the most controlled study because we
needed answers within a week and a half. If I had had the
time, I would have made the doctors look at their records for
specific reasons people went off the protease inhibitors and
for people who would go off drug if they had a replacement.
I'd have asked 50 to 100 docs, and it would have taken a
In particular, although CD4 cell counts rise sharply after
the introduction of potent anti-HIV therapy (combination
therapies that durably reduce viral load by 100-fold -- 2
logs -- or more), there usually is a general ceiling at 100
to 150 above the pretreatment CD4 count. This phenomenon was
observed, among other places, in the striking pilot trial of
triple combination therapy (AZT/3TC/nelfinavir) presented at
the International Conference by Martin Markowitz, M.D.,1 of
the Aaron Diamond AIDS Research Center in New York. In eleven
volunteers who continued on the regimen (there was one drop-
out), HIV levels were reduced to below the limits of
detection with the most sensitive available assay (which
detects down to 25 HIV RNA copies/ml of plasma). CD4 counts,
which initially ranged from 37 to 557, exhibited a mean
increase of 109 at week 16. (In this small study, there was
no measurable correlation between the amount of CD4 increase
and pretreatment CD4 count.)
It appears that as the pressure of the HIV infection is
relieved, existing CD4 T-cells expand to their maximum
capability, but the desperately needed new "naive" CD4 cells
that would trickle out of the bone marrow via the thymus have
yet to be observed in any quantity. This lack may occur
because people's thymus glands are too damaged by HIV
infection to allow the CD4 T-cells to mature, or it may be
that our experience with potent antiviral therapy is as yet
too limited, both in time and numbers of patients, to observe
immune healing. It could take a while for the surviving
thymus tissue as well as small surviving naive CD4 cell
population in the blood and lymph to produce noticeable
numbers of new cells.
David Ho, M.D., director of the Aaron Diamond Center,
reported to the International Conference2 that his colleagues
have in fact noted a gradual secondary increase in CD4 counts
after the initial burst, although it remains too early to
determine this secondary rise's frequency or significance in
terms of immune recovery. Emilio Emini, who directs antiviral
research at Merck Research Laboratories, has some of the most
extended data on patients' response to protease inhibitors
from the trials of his company's indinavir. Once again he can
only give his impression, which is that the second phase
immune system improvement mentioned by Dr. Ho is mostly seen
in people with less advanced disease: "Some patients with
late stage disease show no CD4 increase," Dr. Emini notes.
"Some go up 100 and are stable, and some go further down."
Aside from limits to the CD4 response, there is the question
of the durability of the viral load response to a therapy
that consists solely of antiviral compounds to which HIV can
develop resistance. Dr. Emini notes that there have been
"some" breakthrough HIV infections -- a return to measurable
HIV levels (in this case above 500 copies/ml) -- among people
whose viral loads dropped to undetectable levels during the
early indinavir monotherapy trials. These people, most of
whom have added other antiretrovirals to their regimen some
time ago, are precisely some of the people who have been on
indinavir the longest, up to two years. Sequentially adding
antiviral agents, starting with nucleoside analogs and then
adding on one of the new protease inhibitors, is a more
common experience than giving three new drugs to people
without prior exposure to any anti-HIV therapy as in the
Aaron Diamond trial. It is possible that many people have
used up their benefit from the available nucleoside analogs
one by one and now will be going through the protease
inhibitors in similar fashion.
The Merck-sponsored study of AZT/3TC/indinavir in a group
with a median 31 months prior AZT did show that adding two
new drugs (3TC and indinavir) can produce a major response:
Plasma HIV levels were still down by a median of 99 percent
and CD4 counts were up by 130 at 36 weeks.3The trial's
principal investigator, Roy Gulick, M.D., notes that it will
be of great interest to see what happens to the trial
participants in the AZT/3TC control arm when they start
receiving indinavir at the end of the trial. Dr. Gulick
noted, "This is more like a common real world situation,
where people first took AZT, then got 3TC, and are now
receiving indinavir too."
Another limitation in current therapy is that usually when
drugs are used to treat a disease, therapy is reinforced by
the immune system which is able to destroy at least whatever
residual microbes survive the administered medications.
People with progressive HIV infection clearly do not have any
intrinsic effective way to cope with treatment-resistant
mutant HIV as it arises. The further along in the course of
the disease they are, the more likely it is that their
population of CD4 cells that respond specifically to HIV
infection have been killed off by the virus, which preys
preferentially on the CD4 cells activated to defend against
infection. Their immune response, which was not entirely
effective in the first place, can only get weaker and weaker.
There is considerable hope that the new antiviral therapies
will do better than just reestablish the old equilibrium. By
controlling viral load better than the body ever could do on
its own, aggressive anti-HIV treatment might make everyone
have the viral loads of long-term nonprogressors with the
life expectancy to match. Although the analysis of several
clinical trials indicate that treatment-induced reductions of
viral load do improve patients' prognosis (see the newly
published report on ACTG trial 175, for example4), it is not
clear that they create conditions mimicking strong
immunological control.
Robert Coombs, M.D., of the University of Washington, asks,
"Does a person with a viral load of 100,000 that is
subsequently suppressed by drugs down to 10,000 have the same
outlook as a person who naturally has only 10,000? Probably
not, because immunologically, these latter people are totally
different. This is a fundamental flaw in the current
Such considerations led Anthony Fauci, director of the
National Institute of Allergy and Infectious Diseases to
declare during his address in the opening session of ICAAC
that, "We need to use our knowledge to create effective
treatment by attacking host factors as well as the virus."
Why is all this plethora of initials important? Just before
the International Conference on AIDS, researchers reported on
two individuals who had apparently been exposed to HIV many
times through unprotected sex yet remained uninfected.7
Immediately after the conference, the same research group
reported that these two individuals were missing a segment in
their genes for CCR-5 so that the receptors did not appear on
their white blood cells at all.8In spite of this defect,
these two persons were absolutely healthy. Other cell
receptors seem to be able to take over the work of the
missing CCR-5. Almost simultaneous to this report, a Belgian
team seconded these findings in other exposed but uninfected
persons. A genetic survey of this group conducted of the
prevalence of this CCR-5 genetic defect found it in 1% of 704
HIV-negative persons and in none of 723 HIV-positive persons.
These are the figures for people who received the defective
CCR-5 gene from both parents (homozygotes). Those who possess
one normal gene and one defective one (heterozygotes) were
less frequently represented in the HIV-positive group
compared to the HIV-negative one (16% vs. 11%), indicating
that those with a discordant gene pair have some difference
in numbers or structure of this cell surface receptor than
those whose pair of CCR-5 genes is completely normal.
A final paper published in Septembe9did not find that the
heterozygotes were less likely to be HIV-positive, only that
HIV infection progresses more slowly in such individuals.
Based on data from samples collected from some long-standing
cohorts of U.S. males (either homosexual or hemophiliac),
about half the people with HIV and two normal CCR-5 genes
have an AIDS diagnosis ten years after contracting HIV. For
those with a discordant gene pair, only about 30% have AIDS.
(This gap narrows in the second decade after infection, but
does not close completely.) As for the homozygotes with
absent CCR-5 receptors, once again none could be found among
the HIV-positive men (1,343 individuals), although 17 of 512
HIV-negative men were homozygous.
At the International Conference itself, presenters confirmed
that the CC-chemokines act as suspected, by blocking their
CCR-5 receptor so that HIV cannot enter the cell.10 Hints for
possible nontoxic therapies are emerging here. Ian Clark-
Lewis of the University of British Columbia, who is an expert
on chemokines, not HIV, told Treatment Issues, "This is a
very encouraging field. Chemokines seem to be hangovers from
the past and seem to be predominately involved in unwanted
effects, when the body attacks its own tissues. Though there
are some positive effects, there are so many chemokines that
they can compensate for each other if you disrupt the
functioning of some of them."
In looking at the chemokine/second receptor/HIV interaction,
scientists have happened upon a situation where nature has
done many of the needed experiments for them. People with no
CCR-5 receptors are healthy but apparently protected against
HIV. Those with fewer or altered CCR-5s also seem somewhat
protected. It should be possible therefore to safely block
CCR-5 in people with normal receptors and protect them
against HIV. The problem is to find molecules that bind to
CCR-5 without stimulating the cell. Whether people with
normal, intact receptors will be able to compensate for the
virtual disconnecting of CCR-5 from the intercellular
signaling pathway remains to be seen. One caution has already
appeared in the form of a brief report that natural
chemokines appear to stimulate HIV replication in test tube
cultures of pure macrophages.11 It may yet turn out to be
safest to try to use molecules that bind to the part of the
gp120 molecular unit of HIV's envelope that connects to CCR-
5. But exactly what region on gp120 is involved in this
process has not been determined, so the feasibility of
targeting HIV rather than the cells is unknown.
Then there is the question of how HIV would evolve in the
face of such treatment. The virus might merely mutate into a
more pathogenic T-cell tropic variant that uses fusin as its
second receptor if CCR-5 suddenly became unavailable. While
this does not seem to be what happens in people with
heterozygous genes for CCR-5, who are slow progressors, the
effect of anti-CCR-5 treatment in someone with a firmly
established, high viral load HIV infection might be
different. At the least, any anti-binding therapy along these
lines would have to include compounds that block binding to
fusin and other possible HIV co-receptors as well as CCR-5.
Treatments that take advantage of the newly gained knowledge
of the HIV interaction with cell walls may appear fairly
soon. According to David Ho, M.D., who directs the Aaron
Diamond AIDS Research Center at which many of the experiments
on CCR-5 were conducted, "Many companies have looked at
compounds that bind to seven transmembrane receptors [the
family of receptors that includes CCR-5 and fusin] to treat
neurological and cardiac problems. Many companies already
have compounds but no one is talking about it."
One team that is talking about it just published a letter in
Nature.12This French/Swiss/Canadian group had already been
experimenting with truncated chemokines that would block CCR-
5 and similar receptors without activating the cells.
Researchers were initially looking for allergy and arthritis
therapies, but after the Gallo and other papers appeared,
they found that one of their products, a version of RANTES
missing one end, inhibits HIV very well in the test tube. The
effective concentrations are ten-fold greater than natural
RANTES, though. As to be expected, the truncated RANTES was
ineffective against a T-cell tropic HIV strain utilizing the
fusin receptor. According Ian Clark-Lewis, who was one of
these researchers, "I'd like to make this molecule ten times
more powerful. The next step is to try it out in animal
models to see if it does anything. Also, we should try to
develop a small non-protein molecule that does the same thing
as the truncated RANTES since that would be cheaper and more
Another potential therapy is already entering human trials.
British Biotech will try out BB 10010, a MIP-1a analog, on 15
HIV-positive volunteers for one week at a London hospital.
Allowable CD4 counts range from 50 to 500. This analog, which
only differs from MIP-1a by having one less amino acid, was
originally developed for use in cancer therapy and bone
marrow transplantation.
Phase II trials with multiple IL-10 infusions are now under
consideration. Dr. Fauci seems almost diffident about IL-10's
therapeutic potential, though. "Am I excited? I've been in
this business too long to be excited!" he said in an
interview. "IL-10 proves that tweaking the cytokine balance
can influence the virus, but we have to proceed very
cautiously in studying its therapeutic value. IL-10 is very
immunosuppressive. It could possibly increase viral load over
the long run -- but let's do the trials and not speculate."
There are some solid grounds for caution because like the
many other cytokines that immune system cells exchange, IL-10
has complicated, even contradictory effects. The broad-
ranging activity of interleukin-10 causes cells to go from an
active to quiescent state, which does not support HIV
replication. Dr. Fauci's lab has found that in particular,
IL-10 suppresses cellular production of IL-1, IL-6 and tumor
necrosis factor-alpha.13 These three are immune stimulating
cytokines are present at unusually high levels during HIV
infection. and they also specifically activate HIV
replication. But IL-10 itself is present at increasingly
elevated concentrations as HIV infection progresses. The
Fauci lab further found in test tube experiments that if IL-6
or TNF-a are present in conjunction with IL-10, then IL-10
acts with either of the two stimulators to further increase
HIV's activity.14 In the body, a parallel situation could
arise if IL-10's suppression of production of stimulatory
cytokines turns out to be incomplete at tolerable doses. Such
situations probably are avoidable by using IL-10 in
conjunction with aggressive HAART drug combinations and
perhaps not administering it to people whose HIV infections
are far advanced.
Then there is the worry that it could turn out that "the
operation was a success, but the patient died." Long-term IL-
10 therapy might result in merely trading one type of immune
deficiency for another. But then, a French study with the
anti-inflammatory corticosteroid prednisolone has been
following its 43 HIV-positive participants for up to three
years at last report15 without finding anything particularly
Rather, an overall long-term stability in CD4 count was noted
in people with baseline viral loads below 100,000 after
initial CD4 jumps of 250. People with higher viral loads
deteriorated after the initial CD4 increase. Due to its
small, informal design the exact study results should not be
taken with complete confidence. Also, prednisolone's
mechanism of action differs from that of IL-10. Nonetheless,
there is an indication that lengthy, generalized immune
suppression is endurable by people with HIV and could be
beneficial, at least in people with lower viral loads.
Instead, Mr. Getty's CD4 count increased to 70 before
stabilizing around 50, the highest in four years. At the same
time, his viral load slipped from 22,000 to undetectable
levels before stabilizing at under 1,000 by the second month.
He also gained 12 pounds and his chronic sinusitis and asthma
disappeared. "I haven't felt this good in a long, long
time - I'm now off antibiotics, which I used to eat like
candy," commented Mr. Getty, who continued his
AZT/3TC/indinavir regimen during and after the transplant
experiment. (He also has been receiving growth hormone
therapy except in the period around the transplant
But there is no evidence that the baboon cells took root in
Mr. Getty's body. An alternative explanation for his
improvement lies in the mild cyclosporine and radiation
therapy he received to eliminate more of his own immune
system, and hence a great deal of HIV and its target CD4
cells, so as give the transplanted cells a chance to engraft.
At least one similar response to such immune system
"ablation" plus continued antiviral therapy during bone
marrow transplantation has been reported.16 In that case, the
patient died after 47 days, due to a relapse of his lymphoma,
and long-term results were not available.
The cyclosporine and radiation may have "set the clock back"
on Mr. Getty's HIV infection as well as reduced
counterproductive immune over-stimulation. But it would be
miraculous to expect permanent HIV inhibition from one immune
suppressive treatment, especially in people with very
advanced HIV infections. Indeed, Mr. Getty's viral load is
now creeping upwards (it was 20,000 in September), although
he still free of physical illness or weakness.
He also landed in the hospital at the end of August due to
severe kidney stones from the indinavir he has been taking.
He switched to a ritonavir/saquinavir combination, but severe
nausea and diarrhea, probably from the ritonavir, made that
regimen intolerable. He also was not seeing any improvement
in his viral load. The latest word is that he is switching to
nelfinavir through the expanded access program and looking
for some new nucleoside analogs.
Mr. Getty also hopes to get another course of ablative
therapy through a new pilot study in San Francisco that will
look at chemotherapy plus radiation in people with advanced
HIV. This study will provide some confirmation of the
putative benefits of this immune suppressive approach.
Meanwhile, the chief lesson in Mr. Getty's story is that
something can be done for people failing the new combination
therapies -- there is life after HAART failure.
Coming next month: IL-2, therapeutic vaccines and cells that
inhibit virus infection -- rather than turning off various
aspects of the immune system to subvert HIV, can we train the
immune response to be more effective?
After satiation at the International Conference in Vancouver,
the usually informative yearly Interscience Conference on
Antimicrobial Agents and Chemotherapies (ICAAC) held in New
Orleans, September 15-18 seemed to offer only Cajun-spiced
bread crumbs to many seeking information on new anti-HIV
treatments. The optimism evidenced at Vancouver, though, had
been a once-in-a-lifetime distillation, brewed from an
improved understanding of the dynamics of viral replication
and resistance, as well as the potency of the new anti-HIV
drugs. During the opening plenary ICAAC, leading virologist
Douglas Richman, M.D., of the University of California, San
Diego, noted that what happened at Vancouver was a " shift in
treatment strategy, from palliation with sequential
monotherapy to complete suppression" with potent combination
Dr. Richman reviewed how the development of viral mutations
that confer resistance to antiretroviral drugs has given the
virus an upper hand in the battle against it. He believes
that while single mutations that confer resistance to one
drug generally exist before treatment with that drug is
initiated, multiple mutations are required to defeat protease
inhibitors and combination therapy. This resistance must
evolve over time, which requires that a low level of viral
replication continue in the presence of therapy. To keep the
virus in check indefinitely, there needs to be truly complete
suppression of the virus in all the body compartments in
which the virus finds a home.
The growing number of reports of people who experience a
rebound in viral load while on combinations that include a
protease inhibitor indicate that this complete viral
suppression is not being accomplished in all patients. The
failure of the combinations to contain the virus may be due
to heavy pretreatment with nucleoside analogs. It also should
be remembered that nucleoside analogs often fail to suppress
the virus even in the absence of mutations conferring
resistance. This may be because natural processes in cells
need to alter these nucleoside analogs before they become
active against HIV, and this intracellular activation may
decrease over time. Or perhaps treatment fails because the
adverse effects of drugs such as ddI, AZT, d4T and ddC
understandably lead patients simply to stop taking the pills
over time. Resistance to the combinations also may evolve
because they just do not penetrate every part of the body in
which the virus resides, or because they are not quite
bioavailable or potent enough (see the HAART articlein this issue by Dave
ICAAC did offer a few new leads that may push us a little
closer toward finding a truly optimal combination of drugs,
or at least providing options to switch to after failing
indinavir/AZT/3TC, or whatever cocktail one is currently
ingesting. The new data include a further follow-up report on
the combination of ritonavir and saquinavir, a report on the
antiviral activity of the Glaxo Welcome/Vertex protease
inhibitor 141W94, test-tube data on novel protease inhibitors
from Ciba-Geigy and Gilead, plus the first antiviral data on
the combination of a non-nucleoside reverse transcriptase
inhibitor with a protease inhibitor (in this case DuPont
Merck's DMP 266 plus indinavir).
The long-awaited data were meager, but did confirm that the
drug has an antiviral effect which increases with the dose
(abstract LB7a). Four-week data were available for the first
four doses studied: 300 mg two or three times a day and 900
or 1,200 mg twice a day. Around ten people were enrolled in
each arm, with a median baseline CD4 count of 282 cells and
viral load of 4.83 logs. The lowest dose only reduced viral
load by 0.58 log at peak, the next two highest doses were
significantly more potent at peak, but the effect for all
three lower doses lessened by week four at around a half a
log below baseline. The highest dose reduced viral load by
almost 99 percent (1.95 log reduction). This drop was
sustained through the fourth week.
It is not clear that the lower doses are failing due to the
development of resistance. The reduced antiviral effect may
be because there are decreased levels of drug in the blood
after the first couple of weeks on therapy, due to the way
141W94 is metabolized by the liver. The same phenomenon has
been observed with ritonavir.
CD4 counts increased by a range of 35 to 110 cells over the
four week study. Side effects were mostly mild, although two
patients discontinued the study due to serious rash and one
person quit because of worsening of colitis. Nine of the
study's total of 42 enrolled patients had loose stools
(similar to what has been reported for nelfinavir).
Three people bravely elected to undergo lumbar punctures so
that the researchers could gauge the level of drug that
reached the CSF, which was found to range between 0.45 to
1.3% of what was seen in the blood. The study's presenter,
Chip Schooley, M.D., said that these were " very preliminary
data that we decided to present in light of the early reports
of very high levels of the drug in [the brains of] animals."
Dr. Schooley says that two of these patients were on lower
doses in the study. Also, in contrast to the animal studies
that measured the drug levels in brain tissue at various
timepoints (with the peak occurring five hours post-dosing),
these were measurements of drug concentrations in the CSF at
one timepoint two hours after dosing. Since protease
inhibitors bind to protein, and cerebrospinal fluid has low
levels of protein in relation to brain tissue, it could be
expected that drug levels would be lower in the CSF.
Nevertheless, Dr. Schooley notes that the level of drug that
reaches the brain is " clearly not 170% of what is seen in the
plasma." Even so, he believes that the levels in the brain
may still be adequate to treat the virus. Such antiviral
concentrations were found in the patient with the highest CSF
drug level. This patient also had very high blood levels of
the drug, though.
In a meeting with activists, Glaxo Wellcome detailed its
ongoing and planned studies for 141W94. The present dose-
ranging study is evaluating four other dosing regimens. The
company also is planning dose-ranging studies of 141W94 in
combination with the other protease inhibitors. Pivotal
clinical endpoint studies are slated to begin in the first
quarter of 1997. Activists have been working to convince
Glaxo Wellcome to commit itself to an expanded access program
at roughly the same time.
The study has enrolled at least 136 patients split into four
groups receiving either 1) 400 mg ritonavir plus 400 mg
saquinavir each twice a day, 2) 600 mg ritonavir plus 400 mg
saquinavir, again, both twice daily, 3) 400 mg ritonavir plus
400 mg saquinavir each three times a day, or 4) 600 mg
ritonavir plus 600 mg saquinavir both twice daily. The mean
baseline viral loads between the arms ranged from 4.29 to
4.72 logs, and CD4 counts were between 278 to 313 at
Each arm had a profound effect on viral activity. By week
twelve, doses one and two reduced viral load by 2.74 and 3.06
logs, respectively. Doses three and four dropped viral load
by 2.09 and 2.19 log respectively by week six, which is very
similar to (actually less than) the 2.43 log reduction after
six weeks for group one reported at Vancouver. CD4 cell count
increases for groups one and two at week 12 were 80 to 100
cells, and at six weeks 60 to 70 cells for groups three and
four. None of these differences are statistically
Circumoral paresthesia (numbness around the mouth and
tongue), nausea, diarrhea and fatigue continue to be the most
common toxicities. Elevated triglyceride levels have been
observed as well, although this has not been associated with
any physical effects. All doses seem to be equally well
tolerated except for the three times daily dosing regimen.
Although the drug-related adverse events do not seem to be
more common on this arm, they may be more severe since they
have led eight people to discontinue treatment (with only
four discontinuing on the other three arms combined).
In several ways, the protease inhibitor development programs
at Gilead and Ciba-Geigy share much in common. Each company
has a very potent protease inhibitor poised to enter human
studies that would be much simpler to manufacture and
therefore, one hopes, less expensive than the currently
marketed drugs. It is too bad that these two protease
inhibitors show dramatically reduced activity against virus
that is resistant to ritonavir and indinavir.
Meanwhile, both companies have other compounds, also very
potent and relatively simple to make, that are active against
ritonavir/indinavir resistant virus (abstracts I3 and I5 for
Gilead's compounds, and I6, I7 and I156 for Ciba-Geigy's).
Ciba-Geigy's drug may be the more interesting, as the company
has demonstrated that its protease inhibitor is also active
against virus resistant to saquinavir and 141W94 as well.
Each company realizes the advantage these compounds would
have since there will soon be a large group of people who
have failed or become resistant on the Merck and Abbott
drugs. Both companies would prefer to quickly move these
agents into human studies. The hitch is that in certain
animal studies their drugs seem to be poorly absorbed by the
digestive tract. So for the time being, each company is
slowly proceeding with their first class of protease
inhibitors while trying to quickly solve the bioavailability
problem that limits the potential of the second generation
These results may appear more dramatic than than for other
antiretroviral combinations, but other trials count 400
copies/ml as the minimum viral load. The DMP 266 study
included the less reliable viral load figures that fell below
400. Such a maneuver can have a dramatic effect when you
consider that a reduction to 4 copies/ml is 2 logs greater
than a reduction to 400 copies/ml.
Still, there was a strong trend for the reduction in viral
load to be superior to the reduction seen with indinavir
alone. Eighty percent of those on combination had
" undetectable" viral loads (below 400 copies/ml) at the
combination's peak effect, but by week twelve only 55% were
below the limit of the assay's detection, which still
compared favorably to the 20% below the limit of detection on
indinavir monotherapy. CD4 cell counts jumped by more than
100 from baseline in all patients treated with indinavir.
The most commonly reported adverse events were rash,
headache, dizziness and diarrhea, but none of these events
was severe enough to lead any participant to quit the study.
One potential "adverse event" of DMP 266 was that it lowered
blood plasma levels of indinavir by 37%. This could mean that
the blood levels of indinavir are too low to suppress HIV
over the long term. The added antiviral effect of DMP 266
could counter the reduction in indinavir levels since
resistance can only occur when there is enough residual
replication to allow for it to evolve. The lower levels of
indinavir may also reduce the potential for kidney stones.
Nevertheless, preferring to err on the side of caution, the
study investigators are expanding this study and
investigating higher doses of both drugs.
A few other clinical trials of DMP 266 are currently
enrolling participants. Two are evaluating different doses of
the NNRTI in combination with AZT/3TC. One study will enroll
people with at least two months of experience on AZT/3TC, and
one is for treatment-naive patients. Another opening this
month will compare DMP 266/indinavir/AZT/3TC to
indinavir/AZT/3TC in 330 patients who are naive to DMP 266,
3TC or protease inhibitor and have CD4 cell counts between 50
and 500, with viral loads of at least 20,000. For information
on sites near you, call 800/877-8899.
It is not clear how effective nelfinavir may be in people
that harbor virus resistant to ritonavir and/or indinavir.
Most virus that has become resistant to either of these two
is resistant to nelfinavir as well.
Also, taking nelfinavir in combination with another new drug
(or two) offers the best chance of enjoying a sustained
antiviral effect. It is unfortunate that no company has had
the foresight to conduct a drug interaction study with
nelfinavir in combination with delavirdine or nevirapine.
These two newly available drugs usually can be added with
advantage along with nelfinavir to antiviral regimens since
few people have as yet been exposed to them.-TS
In addition to these warnings, the labeling dictates that
people who have been on other kidney-toxic drugs must
terminate those drugs at least a week before starting
cidofovir. (Among such drugs is foscarnet, a drug many people
with CMV retinitis may have used before switching to the only
recently approved cidofovir.) Also, the guidelines mandate
strict adherence to the schedule for administering probenecid
and intravenous hydration on the day of the cidofovir
infusion. To protect the kidneys, two grams of probenecid
must be taken three hours before the cidofovir infusion, one
gram two hours after the infusion and again eight hours that.
Intravenous hydration with one liter saline solution should
take place over a one-to-two hour period immediately before
the cidofovir infusion. If the patient can tolerate a second
liter, it should be infused over a one-to-three hour period,
either in a period overlapping the 60 minute cidofovir
infusion or immediately afterwards.
Although Gilead has gone to great effort to inform clinicians
of the proper usage of cidofovir, sending out letters to over
35,000 HIV-treating physicians, the clarity of the new
guidelines is perhaps overdue. Studies have shown that the
drug can be safely and effectively used, but the close
monitoring that participants in drug trials receive is rare
in general medical practice. When cidofovir was being
considered for approval by the Food and Drug Administration
last summer, many activists were concerned that " in the real
world, patients would not be followed rigorously enough,
resulting in adverse event rates not seen in the cidofovir
trials" -TS
Although there have been many changes in the treatment of
certain opportunistic infections such as CMV over the last
year, little has changed in the treatment of fungal
infections since the introduction of fluconazole and
itraconazole. At the same time, the rate of azole resistance
has increased dramatically. The central role that these two
azoles play in the treatment of fungal infections and fear
that resistance will develop to the drugs has led a number of
clinicians to be cautious about over using them as
prophylaxis or for mild cases of candidiasis. When azole-
resistant fungal infections crop up, there are few
alternatives available.
The toxicity and inconvenience of amphotericin B make it the
treatment of last resort. Meanwhile, controlled clinical data
on the easier-to-tolerate liposomal formulations of
amphotericin and nystatin have been long awaited. Liposomal
formulations involve surrounding medically active compounds
with tiny fat globules that allow the drugs to reach their
targets with fewer adverse effects on other tissues.
Information on the use of these drugs is beginning to trickle
in (see below), but even if safer, these liposomal compounds
still must be intravenously administered and this limits
their usage to acute infections. But a note of optimism is
emerging: The large number of presentations at ICAAC on new
agents that attack fungi in new ways suggest that the
treatment of fungal infections will undergo major changes
over the next few years.
Amphotericin B was significantly more toxic to the kidneys,
although those on AmBisome did experience some increase in
levels of serum creatinine (greater than 50%). Two patients
on amphotericin B stopped treatment due to toxicity compared
to no discontinuations on AmBisome. The study's presenter,
Dr. Leeanders of the University Hospital in Rotterdam,
concluded that "in a larger study, AmBisome may lead to a
sooner response. [It] is probably the most effective
available treatment for those with cryptococcal meningitis"
AmBisome has yet to be approved in the U.S. even though it
has been marketed in Europe and Mexico for several years.
Fujisawa is now running studies evaluating the drug in
neutropenic patients and in people with HIV and cryptococcal
Both voriconazole and SCH 56592 now have been evaluated in
dose-ranging studies. Phase II clinical studies of
voriconazole are complete, although the data are yet to be
released. Three phase III clinical endpoint studies of
voriconazole for invasive aspergillus, serious candida, and
as empiric therapy for invasive fungal infections in
neutropenic patients are anticipated to begin in Europe by
the end of the year, and to expand into the U.S. in the
beginning of 1997.
Meanwhile, Schering-Plough refuses to discuss with Treatment
Issues where or in what population the clinical trials for
SCH 56592 are being conducted, saying only that the oral form
of the drug was in international early phase studies for
" serious systemic infections." The company president and CEO
Richard Kogan, though, has publicly said that the trials
began in April, and that the drug was " orally active" (see
SCRIP June 11, pg. 8).
Laboratory and animal studies presented at the conference
documented that pradimicin is active against aspergillosis,
candida and cryptococcus (abstracts F179-F183). Although no
pradimicin-associated toxicity was observed in rabbits or
mice, some possibly drug-related liver enzyme elevations have
been noted in dose-ranging human studies of intravenous
pradimicin. Bristol-Myers currently is reviewing the data
from these early studies before deciding whether to move
ahead with this compound or one of its more than 200 analogs.
In laboratory and animal studies, the echinocandins show
activity against histoplasma, difficult-to-treat
aspergillosis and azole-resistant candida. By themselves, the
echinocandins do not seem to be active against the fungi that
cause cryptococcal meningitis, but one study noted that L-
743,872 was synergistic with amphotericin B and fluconazole
against this disease (abstracts F36, S25).
In one poster at the conference, evaluating the use of L-
743,872 in mice, an echinocandin was shown to have activity
against Pneumocystis carinii during one stage of its life
cycle (abstract F42). It is unclear whether these drugs will
prove useful as a treatment of acute PCP, since they kill
only the cyst form of the parasite (which can be thought of
as the egg) but not the active parasitic form found during
acute infection.
Merck's L-724,872 has been well tolerated in phase I dose-
ranging studies. Unfortunately, the drug is not absorbed
orally and must be given as a once-a-day intravenous
infusion. This requirement will reduce the drug's use in
clinical practice. Currently L-724,872 is in phase II non-
U.S. studies in patients with people with HIV and esophageal
Lilly's LY303366 is bioavailable when taken orally. A dose-
ranging study reported at the meeting showed that the drug is
very well tolerated, causing mild-to-moderate diarrhea and
abdominal pain only at very high doses (abstract F50). Much
lower doses achieved blood levels of the drug more than
adequate to suppress candida. The drug has a very long half-
life that will allow for once-a-day dosing. Lilly is
currently conducting a dose-ranging study of LY303366 in 160
people with HIV and oral candidiasis.
The development of another class of well-tolerated oral
antifungals could ultimately reduce the incidence of azole-
resistance or provide a feasible option for instances when
such resistance arises. There is also the possibility that
antifungal medications could be combined for hard-to-treat
infections. Appropriate drug combinations also could create
less invasive and less toxic induction therapy for conditions
such as cryptococcal meningitis. If a drug also proves active
as a prophylaxis for PCP, it could provide an alternative for
those intolerant to sulfa drugs, or reinforce prophylaxis in
the substantial number of patients with breakthrough
infections on Bactrim/Septra during late-stage disease.
But it is too soon to say whether any of these drugs will be
effective in humans. Further information, no doubt, will be
available at upcoming conferences -- certainly by next year's
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text:
Reviewed by Daniel L. (age 9)
This is the best book I have ever read. It's a hard book to put down. It has a lot of historical facts in it, which is interesting to me because I am obsessed with history! It's a nail biter because you are concerned about what will happen to Anna and her family. It helped me to learn more about how refugees from Germany had to leave their homes because of the Nazis. It made me appreciate the fact that I am from a country that allows people to believe what they want to.
I recommend this book to third graders and up. It has small print and some tough words but you'll really like it if you are interested in history.