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The RTI Model: RESPONSE TO INSTRUCTION. WHAT IS IT ? HOW DOES IT WORK? ARE WE COMMITTED?. Response To Intervention. RTI is the practice of providing high-quality instruction and intervention matched to student need , monitoring progress frequently to make decisions
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Using Power Standards and DATA: 3 Rotations
Use of adopted Curriculum ( HM) to :
Use of adopted Curriculum ( HM) to :
Suggestions and Possibilities
4/5: Jan, Jose, Terry, Nancy, ?
3: Jan, Tony, Jose, ?
1/2: Jan, Lynn, Jose, Tony, ?
The hard question we need to answer in Response to Instruction is
Are we using our resources in the best way to meet the needs of as many kids as we can?
FBB BB Ba Pro Adv
Blue= 3Orange=4Green=5
Data says that we have many students to move forward who's
needs are not being met. How do we do this and not flat line?
AYP standards have gone up to 56% of our students must be
proficient to stay in Safe Harbor and get out of PI status.
Can we start one level at a time?
What grades may want to look at implementing this PROCESS in January?
What grade levels might be interested in exploring options to providing equity across the school using our resources?
What do we have to be faithful to if we do not respond to instruction using this model? Ie. Quality of UA time? How are we ensuring that the necessary reading skills are being taught daily and systematically? Interventions?
If we really put our effort this year to get out of PI status, it could free us of mandates and allow for more creative teaching. How can we continue as A WHOLE SCHOOL to work towards this?
Thanks, the decision is yours. Shared leadership means that , exactly.What will you do as a team to ensure that all students' needs are met at every level. We can do it our way in an equitable fashion.


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I paid a visit to Juan and Bill at the Cubariqueño booth at the show and did a little video with them where they tell us about their latest releases. I smoked the Themis Toro this week and was really impressed! The Themis has a Ecuador Connecticut wrapper around Nicaraguan binder and filler and is available in Toro and Robusto sizes. The band has the Protocol stylized "P" in gold with a gold foot ribbon. It's a beautiful looking cigar crafted in the La Zona factory like the rest of their cigars. The cigar is absolutely delicious, smooth and rich with a creamy texture and loads of flavor, this isn't a mild Connecticut, it's a solid medium. The signature shade wrapper nuttiness/grassiness is there a little in the background, but the Nicaraguan fillers compliment it very nicely. The Themis might be one of the best cigars I've smoked from the show so far, not that I've gotten started really, but it's setting the bar pretty high.
I last night I grabbed a Protocol Probable Cause Churchill, I could have gone with the Lancero, but I decided to save that for another time. I love Lanceros, but I have to be in the right mood. The Churchill is a bit on the short side at 6½" x 48 with a box press, giving it more of a Lonsdale feel. Not a bad thing at all. The Probable Cause has a San Andrés wrapper from Mexico, again with Nicaraguan binder and fillers. The wrapper is a rich, dark brown, and I was excited to smoke it. I had smoked this last year, my thoughts can be found here, and really liked it. I thought the Churchill format made it a little less strong, if you know what I mean, but it had the same great espresso/cocoa flavor with a unique spice that I really like. I can see digging into the Lanceros in the not too distant future. Another great cigar! One of the things I really like about the Protocol line is that they have limited their sizes to only two or three per line, with a Corona Gorda, Lancero, Robusto, Toro and this Churchill spread across the three blends.
Here's the video I shot at the show with Bill and Juan. I've done better video work than I did this time around, but I had help in the past, which makes a difference. It gets the message across though. Thanks again to Juan and Bill for spending a few minutes with me! This is truly a brand that's made it because of social media!
That's all for now, until the next time,

subset: commoncrawl


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Having recently seen the tasteless Jezebel post "Fuck You, Cats,"* I expected the article in my Google Alerts titled "Cat Lovers Deserve to Die," to be a similarly poorly written rant of a post.
Instead, I found a tasteless campaign for the Lung Cancer Alliance by advertising agency Laughlin Constable that attempts (poorly) to convey the message that"Lung cancer doesn't discriminate, and neither should you."
In addition to being offensive, it's bad advertising. The ultimate case of good (?) idea with bad execution. And being both a cat woman and an advertising executive, I feel the need to explain my point-of-view.
1) Chose your stereotypes wisely. Cats are actually tortured and killed for sport every day. Cat lovers are maligned every day. Let's not give assholes encouragement they don't need. Not to mention it muddies the communication. "Waitresses Deserve To Die," while equally offensives better conveys the idea of random and baseless discrimination.
2) Get your stereotypes right. The point of using a cliché or archetype in advertising is to telegraph something quickly. So if you must use one, get it right. The (hipster) advertising agency creatives clearly never googled "Crazy Cat Lady." Because instead of casting for this…
…they cast for Stepford-Wife-Meets-Cheer-Leader (on drugs).
3) Get to the point. People look at and listen to ads for seconds (often against their will). The campaign makes the public work too hard. Advertising doesn't have time for deep involved dialogue.
ADVERTISING: Cat Lovers Deserve to Die.
PERSON: No they don't. Why would you say that?
ADVERTISING: Well, they deserve to die if they have lung cancer.
PERSON: That's stupid.
ADVERTISING: You're right, it is stupid. But hose with lung cancer are stigmatized because people think they brought the disease upon themselves.
PERSON: Well, according for Centers for Disease Control and Prevention, smoking is the leading cause of lung cancer.
ADVERTISING: But they were lied to for decades and told smoking wasn't addictive.
and so on, and so on….
David Kiefaber said it much more succinctly in Ad Week when he wrote, "(it's) a bold and socially complex message, one that's tough to decipher from any ad, much less one that says 'a modern social archetype' deserves to die."
4) Why ya gotta be so negative? A visit to the Lung Cancer Alliance website NoOneDeservesToDie.org reveals compelling facts that effectively get the points across without the shock-value.
"It's the deadliest cancer, claiming more lives than colon, breast cancer and prostate cancer combined."
"1 in 14 Americans will be diagnosed with lung cancer. That's 12 of the average FB users 172 friends."
5) All PR is not good PR. Marketing professor Ken Wong from Queens University summed it up best when he said, "Nobody's talking about the plight of cancer patients. Everybody is just talking about how offensive the ad is." Well, I guess it could be considered good PR for a previously little-known advertising agency. Wait, what were they called again?
What do you guys think? Am I being too harsh? Is everyone being too sensitive? Did I lose you after I stopped talking about cats?
PS – While I have your attention, will you vote for Kip so that he can be a famous TV star (and marry a dog?)? Plus, if he/we wins, I'll donate $500 to a rescue or two! You only need to vote 1 time EVER (not an everyday type thing!).
As of this morning, he is in the top 15 and we just need to get him into the top 10 by Monday!
Just follow the directions below.
1) Click on Wendy And Lucky Diamond's Pet Wedding of the Century FB page.
2) "Like" the page
3) Scroll down the page
4) Vote for Kip
PPS – It would also be pretty hysterical to see two single, professional, New York City ladies having their pets marry before they do! Ha!


text: I've recently been eyeing the mono lockit. Should I buy the tivoli pm first or a lockit? I'm 22 and I usually either carry a small purse, like pochette small OR a small wallet, sunglasses, a paperback book, wristlet as a little makeup bag, and a small agenda. Will the lockit fit all that? Is the vachetta on the lockit too much to care for? Ugh I think I might end up getting both at some point, but I'm really wondering which to get first and would love some feedback from people who own one or the other. Thanks.


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At Google I/O 2014 Developer's conference, Android Wear has an official announcement from Google and two devices were available on Google Play Store initially, LG G Watch and Samsung Gear Live. Android Wear gadgets will be compatible with most of the devices which is running Android 4.3 and up versions. Even though if you have an android smart phone with 4.3 or upper versions, i suggest you to cross-check whether your device is compatible with Android Wear or not.
How To Check the compatibility?
Google has made this process simple. Just open the following URL http://g.co/WearCheck from your Android device to check whether your device will be compatible or not. If your device is compatible then you will get a screen like below.
As of now LG G Watch and Samsung Gear Live are the two smart watched launched with Android Wear. Soon Motorola will launch Moto 360.
Related :
- Complete Guide To Android Wear Developer Preview
- Android 5.0 Update Features and Roundup
- List of Features Announced in Google I/O 2014


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Alex Is Lovesick (Alex Holeh Ahavah) 1986 DVD-Israeli movie
Comedy-Israel in the early 1950s, where Alex, who is 13, is growing up. Hebrew with English Subtitles
Comedy-Israel in the early 1950s, where Alex, who is 13, is growing up. His typical family is made up of a bossy mother, a father who suffers silently, a sweet and kind grandmother, and an odd Persian neighbor who is fighting a never-ending battle with his bald-spot. Alex falls in love with Mimi, a beauty from his class, until Lola, a Polish relative, comes to Israel in search of her lost love. Alex falls head over heels with this woman while she nurtures him. Starring: Yosef Shiloach, Eitan Enshel, Sharon Hacohen and others
- Language: Hebrew, English Subtitles
- Media: NTSC (USA) DVD


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Owens Community College directory
Think about what career is best suited for you, and where you want to study. Request more information now.
Think about what career is best suited for you, and where you want to study. Request more information now.
Think about what career is best suited for you, and where you want to study. Request more information now.
Find info concerning Owens Community College directory, and registering for elective discussion sections and seminars. As a student, your first stop should be the registrar's office, where you can pick up a free copy of both the academic calendar and course catalog, in order to find available credit classes that you may be interested in taking. You may be surprised that you can enroll for a full-time course load, without having to attend any 8am classes at all. Finally, check with the admissions office for assistance with prerequisites, tuition payment deadlines, and Owens Community College college degree information. Please use the form above to request admissions info for Owens Community College.
If you have a particular school in mind that is clearly your first choice, then early decision might work well for you. Please note that if you are accepted under early decision, you are making a commitment to attend that school, unless its financial aid package is inadequate. Usually, you can apply to only one school under the early decision program. If you're not accepted, you still have the option to apply to other schools later, during the regular application period.
Early action is similar to early decision, except that you aren't required to attend a school that accepts you. Some schools allow you to apply for early action while interested in other colleges, but some don't, so you need to request information from each school. Keep in mind that there is less incentive for an early action college to accept you because you aren't committing to attend the school. Beyond degree requirements such as Owens Community College class registration, you may consider Nevada State College graduating class for complementary electives to your primary course of study.
Admissions Counselor
North Carolina Central University
The person should be an energetic and enthusiastic individual who will articulate admissions policies and procedures to students, parents, and counselors.
5 days ago Graduate School Advisor
Grand Canyon University
Serves as liaison to the admissions offices at medical/graduate schools to promote the College programs and to gather/disseminate up-to-date information on..
5 days ago Admissions Representative
Stanbridge College
About Stanbridge College. Reporting to the Director of Admissions, the Admissions Representative is responsible for enrolling qualified students into the..
5 days ago Student Success Coach
College of DuPage
Coordinate outreach efforts with Admissions and Marketing to identify and recruit students into the S-Stem program.
7 days ago Admissions Representative
Centura College
Prefer prior admissions experience at a private for profit college or technical school. Centura College - Chesapeake, VA.
5 hours ago


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Case Reports International aims to encourage the publication of new information by providing a platform for reporting of unique, unusual and rare cases which enhance our understanding of disease process, its diagnosis, management and clinico-pathologic correlations.
Case Reports International also publishes announcements giving information about conferences, meetings, seminars, symposia, courses, and other items.


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Conservation Tools
The Sonoran Joint Venture helps provide the best available conservation tools and science to help our partners conserve birds and habitat. From decision support tools to help managers and biologists make informed decisions under uncertain circumstances to detailed accounts about needs of priority birds and habitats, the SJV works to make sure our partners have the tools they need to get the job done.
Learn More:


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Residential Construction Company Policy Statement
[Downloadable/printable version of the Residential Construction Company Policy Statement]
Dear Home Buyer(s):
It is our sincere intention that the construction of your new home and subsequent ownership be a rewarding and exciting experience. We recognize that this is a big investment and that you may experience normal anxieties during the construction process. We thank you for the trust and confidence you've demonstrated by choosing us as your builder.
The following list has been compiled for clarification purposes. If you have any questions, please don't hesitate to contact your sales representative or building supervisor. Again, thank you for choosing us.
Clearing Policy
We recognize the beauty and value of trees and how they enhance a homesite. Therefore, the only trees we will remove are those within 15–20 feet of the homesite and driveway, and those required to install the underground sanitary sewer (or septic system), storm sewer, water, gas, and electric lines.
Should you desire any additional clearing, we can refer you to the clearing contractor, with whom you may contract directly. We cannot prevent, warrant, or guarantee against tree damage or tree loss. Changes in water table, bark and root damage, increased sun exposure, and changes in grade all affect tree life and are an inevitable consequence of construction.
Land Work, Site Drainage, and Grading
We install the drive, excavate for the foundation, backfill the foundation, dig trenches to install sewers, water, gas, and electric services as required, and then grade those areas affected by construction with a bulldozer at the completion of construction. This grade is not a "finish" grade. It is the final "rough" grade to ensure positive drainage away from the house. Any expenses we incur in installing yard drains or retaining walls will be deducted from the buyer's landscaping allowance. Where no landscaping allowance exists, the buyer will be responsible for these expenses. Drainage swales affected during construction will be re-established. Any other drainage, yard drains, retaining walls, or land work is the buyer's landscaping responsibility. Those areas not affected by construction will remain the same unless specifically addressed in this contract.
Septic Systems
State and county government authorities determine the design of septic systems to protect the health, safety, and welfare of the general public. Individual septic system design is permitted by the county health department pending their review of the topography, soils, perc test results, etc., in consultation with soils engineers and installers. Your septic system is designed to properly handle all household sewage on site. However, the performance cannot be guaranteed because of the many variables beyond design control, such as, but not limited to: variances in family size and household water use, septic system maintenance, landscaping, etc.
The system will be installed as designed. WE WARRANT THAT YOUR SEPTIC SYSTEM WILL BE INSTALLED AND APPROVED BY THE COUNTY HEALTH DEPARTMENT. WE CANNOT ASSUME ANY FURTHER RESPONSIBILITY DUE TO THE MULTITUDE OF VARIABLES INVOLVED. ANY SERVICE, MAINTENANCE, OR ALTERATIONS REQUIRED SUBSEQUENT TO THE APPROVED INSTALLATION IS THE HOME OWNER'S RESPONSIBILITY.
Well Water
We will install a well, pump, pressure tank, and water line. We make no representation regarding supply or quality of water other than as required by the county (e.g., potable water at the time of inspection). The home owner is responsible for any water treatment equipment desired or required. The best way to find out about the quantity and quality of water is to ask neighbors adjacent to your homesite about their water supply.
Shading Variance
Mortar is available in a variety of colors. Black, brown, white and gray are frequently chosen to achieve a distinctive look. It is difficult to achieve an exact mortar-to-sample match when choosing a shade of color. This is due in part to the variety of cements available and the variety of sands that masons use. Every combination produces a different shade. We will do our best to achieve the mortar color selected.
Color grout for floor and wall tile may enhance your decorating, but there is a disadvantage. Regrouting is inevitable due to shrinkage. To achieve a perfect color match when regrouting is extremely difficult. We highly recommend white grout whenever possible. Note: Regrouting and caulking are home owner's responsibilities. The building supervisor can give you some regrouting and caulking tips.
Shading differences can also occur in bricks, ceramic tile, roofing, wood cabinets, etc. These are manufactured products, and perceptible, although very slight, shading differences exist on each manufacturing run.
Paint Policy
Paint colors vary under different lighting conditions. The actual paint color may vary from the sample chip. Stain color and shading will vary considerably upon application to different types of wood. Where stain enhances the natural beauty of wood, it also emphasizes the defects in wood. A perfectly uniform shade in color cannot be achieved by staining. If perfect color uniformity is required, then it must be painted. The home buyer is responsible for approving paint and stains.
To ensure that you receive the shades and colors you desire, you must meet the painter at the homesite so that you can approve the color on numerous test samples prior to full application. The painter has the right to substitute when the selection noted is unavailable, upon oral communication with you. You should then meet to approve the color substitution prior to application.
Paint Specifications
- Manufacturer/Brand: Painter's discretion, unless specifically noted on selection sheet.
- Walls: Two coats off-white decorative flat latex.
- Woodwork: Three coats (stain or prime, finish coat, face coat) off-white, eggshell, or semi-gloss enamel, latex, or oil base paint, or stained and varnished. Note: All walls and woodwork will be one color. The home buyer can opt to have painted woodwork on railings, balusters, banisters, fireplace mantels, kneewall caps, and stair stringers stained.
- Exterior: A combination of colors is standard. Exterior colors, when noted on selection sheet, are mandatory.
- Ceilings, closets, garage: Drywall texture, no paint required.
- Railings: Stained or painted one color.
Lighting Policy
A lighting allowance has been included in the price of your home, thereby giving you the freedom to choose the light fixtures that will complement your furnishings and decor. Prices of light fixtures vary considerably. We encourage you to analyze your budget prior to selecting fixtures. Your allowance provides you with enough money to adequately light your home. Should you choose to spend more than your allowance, the lighting store must have a check for the additional amount prior to releasing your fixtures for installation. Should you spend less, the balance will be credited to you at closing. We have arranged a discount for you at a local lighting distributor.
It is imperative that you select the fixtures and bulbs properly. Should a delivery of fixtures be incomplete due to backorders, shortages, or damage, your home will be completed with porcelain keyless fixtures on the interior. The cost of these fixtures will be deducted from your lighting allowance and is not refundable. At this point we will have fulfilled our contractual obligations with respect to lighting fixtures. A return trip to install a fixture will require compensation for the time and labor involved.
Note: The electrical plan shown on blueprints is for illustrative purposes only. Each house is wired according to the NEC and local code. Specific location for lights, outlets, and switches, if desired, must be specified. Heights of hanging fixtures must be specified. Hanging fixtures must be pre-wired and with adequate chain to achieve height specified. Location of recessed lights not located in soffits may vary due to mechanical and structural obstacles. Ceiling outlets intended for decorative fans must be noted so that adequate reinforcement can be installed. Please note whether fan is fan only or fan-light combination. Payment in full in advance is required for all additions. The electrical contractor will call you to arrange for a meeting at the job site so that any specific lighting, switch, or outlet locations you desire can be specified.
Job Site Visits
The job site is a risky and hazardous area during construction. Our insurance does not cover any injuries you, your family, or friends may sustain on the job site. As a result, we strongly urge you to stay out of the construction area. Please rely on the expertise of our field supervisor to ensure the proper completion of your home. Should you choose to ignore this advisory, you do so at your own risk. We understand your desire to view your home as it is being constructed, but your safety is our primary concern. Please view from the curb only.
Warranty Release (Customer Supplied Items)
We, our agents, or assigns do not warrant, implied or otherwise, any and all items, materials, and/or goods that the home buyer installs, or supplies for us to install, in the home.
Sweat Equity Program
Our Sweat Equity Program is designed to reduce the cost of the homes for home buyers who want to do some of the work themselves. We want to emphasize the magnitude of this undertaking to the unskilled. The professional craftsman will make any job seem quick and easy. It was through years of apprenticeship and hard work that they acquired their skills. Therefore, we ask that you pause a moment to seriously reflect on any work you might undertake. The Sweat Equity Program conditions are as follows:
- Only licensed and qualified subcontractors should be used to reduce the risk of an improper job.
- You must obtain a rider on your insurance policy to cover any work you perform.
- We are not responsible for any warranty or liability associated with the phase you perform.
- You must complete your phase according to our standard production cycle or you may incur interest costs due to the extended length of the construction loan period.
Exterior Wood Door Policy
You acknowledge the inherent risk of wood warping by selecting wood doors for an exterior application. You also acknowledge the risk of damage to these doors during construction. You further recognize we cannot reduce this risk through our normal methods and construction procedures. You accept that an extended period of time may elapse before these doors can be properly sealed and finished. You accept any and all responsibility for warranty, service, and damage that may result by your selection of exterior doors. Further, you release us from any and all liabilities associated with this selection.
Radon is a naturally occurring gas that is caused by the radioactive decay of the element radium. Since radium is contained in the Earth's crust and dissolves readily in water, radon can be found virtually everywhere. Preliminary studies suggest that prolonged exposure to high levels of radon gas may result in adverse health consequences.
This notice serves to advise you, the purchaser, that above average levels of radon gas may accumulate in any home, regardless of the type of home or who builds it. Because of the multitude of factors involved, it is difficult to predict whether a residence may be subject to high radon levels, unless tests to determine actual radon concentrations are conducted on a complete structure. It is in your best interest to install a sub-slab ventilation "prep" package. We understand this system is the most effective radon reduction method known at this time. It is easily installed during construction. It would be cost-prohibitive to install afterwards. We have made no investigation to determine whether there is radon gas or other environmental pollutants in the home or affecting the premises, although such conditions may exist. We have made no analysis or verification of the extent of the environmental or health hazard, if any, that may affect the premises or residents. We make no representation or warranty as to the presence or lack of radon or hazardous environmental condition, or as to the effect of radon or any such condition on the premises or residents. WE FURTHER DISCLAIM ANY PURCHASER WAIVES, UNLESS OTHERWISE EXPRESSLY PROVIDED FOR IN BUILDER'S LIMITED WARRANTY, ALL WARRANTIES EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO THE WARRANTIES OF GOOD WORKMANSHIP, HABITABILITY, MERCHANTABILITY, AND FITNESS OF PURPOSE AND INCLUDING ANY WARRANTIES THAT COULD BE CONSTRUED TO COVER THE PRESENCE OF RADON OR OTHER ENVIRONMENTAL POLLUTANTS. THE ONLY WARRANTIES WE PROVIDE TO THE PURCHASER ARE THOSE CONTAINED IN THE LIMITED WARRANTY.
Mold is a type of fungus. It occurs naturally in the environment, and it is necessary for the natural decomposition of plant and other organic material. It spreads by microscopic spores borne on the wind, and is found everywhere life can be supported. Residential home construction is not, and cannot be, designed to exclude mold spores. Moisture in the home can have many causes. Spills, leaks, overflows, condensation, and high humidity are common sources of home moisture. Good housekeeping and home maintenance practices are essential in the effort to prevent or eliminate mold growth. If moisture is allowed to remain on the growth medium, mold can develop within 24 to 48 hours. Mold can damage building components and personal property. Mold can also induce allergic reactions in susceptible people, but both the Centers for Disease Control and the National Academy of Sciences state that there is no causal link between the presence of mold and serious health conditions.
The home owner can take positive steps to reduce or eliminate the occurrence of mold growth in the home, and thereby minimize any possible adverse effects that may be caused by mold. Consult the Environmental Protection Agency's A Brief Guide to Mold, Moisture, and Your Home for further information.
Change Orders
We realize that small changes are necessary to build a custom home and we do not charge for changes that deal with material selections or allowance overages but changes can complicate the production process. They can also require a reappraisal by the construction and mortgage loan lending institutions. The written and verbal process required to cancel, re-order, and re-process the documents to communicate the change to the affected contractors, suppliers, and staff and the subsequent follow-up required to ensure it is accomplished, require a tremendous work effort. This diverts your supervisor and the office staff from their primary responsibilities—to ensure that the building process proceeds smoothly. Change orders can result in backorders, increased costs, and a delay in the completion of your home. We will not be obligated to accept any change order after this date. However, if accepted, an $ 150.00 fee is mandatory to offset these costs in addition to the cost of the change.


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I hate Halloween.
There. I said it.
Isn't that bad, coming from a mother of three children? Shouldn't I be reveling in this kid-centric holiday, planning and making their costumes weeks in advance, like a good mom does?
But no, I kind of dread Halloween beginning Oct. 1. Maybe it's because it's the first sudden flurry of activity after the long summer and stressful start of the school year. Suddenly, the calendar becomes packed with school parties, fall festival and volunteering, plus trying to decide on three costumes and then gathering the supplies for them all. I'm just never quite ready for it when it hits.
But the main reason I'm so anti-Halloween is because the traditions that go along with it (eating ridiculous amounts of sugar and celebrating all things evil and gory) are the opposite of everything we try to instill in our children all year long. Trick-or-treating is the WORST. Think about it: We are forever warning our children about Stranger Danger, and yet, we take them out in the dark of night (and sometimes on a school night!) and goad them into knocking on strangers' doors and taking candy from these strangers. And even though we've all had it drilled into our heads since we were little that strangers put razor blades and drugs in the candy, we're all, "Go on, sweetie, go knock on that door and hold your bucket out, and remember to say thank you!"
Every year, while the girls and their cousins are knocking on some random door, there I am at the end of the driveway, going "Who came up with this tradition? This is terrible. We're making our kids go knock on some pervert's door and letting them take candy from them! It's so dumb! Halloween should be banned!"
And every year, there's my Halloween-loving sister, going, "Oh, get over it, ya Scrooge, it's tradition!"
That's not to say we don't get into it or celebrate it. The twins have always chosen their own costumes, and they're almost always homemade, which is saying a lot, as I am not a lover of crafting. In past years, they've been sushi, an ant-infested picnic table, cotton candy, an ice-cream cone and a bubble bath, winning prizes in the costume contests almost every time. (Score for the non-crafty mom!)
This year, because they were too indecisive (Twin A), or procrastinated too much (Twin B), we kept it simple. Twin A was a "spa girl" and Twin B was a gypsy, both of which were easy to put together with stuff we already had around the house. Little Miss decided months ago that she wanted to be Snow White, which was even easier, since we already had the costume from previous years, and only had to buy a new wig:
I do have a lot of fun helping the girls dress up, but I admit it's probably one of very few things I won't be too sad to see them outgrow. The tween twins are almost there, but not quite yet. They still had fun dressing up and trick-or-treating this year—especially when we hit the house where the nice old man always hands out money instead of candy. (They know his house—it's the one with the Bentley parked out in front.)
Every year, I get into Halloween less and less, putting up fewer decorations and barely glancing at those little booklets for fun ideas. In fact, this year, I didn't put up a single decoration, other than the tiny pumpkin Little Miss brought home from her field trip to a farm. Thankfully, Little Miss is afraid of anything remotely creepy, therefore I get a reprieve from getting the boxes of decorations down (I only have two) and stretching those pesky cobwebs all over the house. The scariest decoration we have is a pumpkin with a sensor on it that says, "Boo! Did I scare you?" when you walk by. She has nightmares about that thing so there is no way it's coming inside.
The twins weren't quite that skittish, and we got into the holiday more with them. Every year since they were toddlers, we would drive more than an hour away to a farm with a pumpkin patch, where we'd let them pick their pumpkins, and I'd take a million adorable pictures of all things fall. Then we'd come home, let them dig the gunk out, and I'd make roasted pumpkin seeds. But for some reason (usually due to poor planning and lack of time) we haven't gone, nor have we even carved pumpkins for the last two years. I know, lame.
Lucky for us, my sister is the complete opposite. She lives for Halloween, and is one of those who decks out her house both inside and out as much as most people do for Christmas: skeleton-bone streamers, bleeding pictures, ghosts, monster footprints, spider webs, rats, life-size hanging ghouls, rattling skeletons, creepy snakes, screeching cats. Come October, her house looks like one of those Halloween superstores.
And she carries the theme into her menu for the evening. This year she made "feet of meet" (foot-shaped mini meatloaves, complete with mangy toenails made from Brazil nuts), pizza that looked like candy corn, some kind of bloody punch, mashed potatoes with green-olive eyeballs, witch-finger cookies and rolls with finger hot dogs sticking out. You get the picture:
Clearly, that's why we go there every year, plus she has a better neighborhood for trick-or-treating.We don't get a lot of trick-or-treaters in our neighborhood and never stay home on Halloween night.
Especially not since the time two years ago, when just as we were getting ready to leave, our doorbell rang. "Don't answer it, I don't have anything!" I said. But it was too late. The girls opened the door and there was a hayride-load of about 15 kids holding their pillowcases and buckets open expectantly. The girls and Hubby ran to the pantry in a panic and came back with handfuls of stale Easter candy and—wait for it—conversation hearts. I'm still mortified.
That night, we came home to find our pumpkins all smashed up all over the yard. We got the message: Our "treats" sucked and we'd been "tricked."
I guess that's what happens when the kids find out who the neighborhood Scrooge is.


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Cox College roster
Think about what career is best suited for you, and where you want to study. Request more information now.
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Information about Cox College roster, and registering for discussion sections and departmental electives. Not all recruiting is done like NCAA Division I teams. College coaches are constantly looking for the best players to fill next year's open positions, and rely on many different methods to finding the right recruits. If you haven't been noticed, cold-calling coaching staff can get you an initial interview. Finally, check with your major department for assistance with prerequisites, tuition payment deadlines, and Cox College Athletics information. Please use the form above to request admissions info for Cox College.
Track stars have revealed the secret to developing running speed. Most athletes simply run out of breath long before they need to stop running, because they aren't able to get the oxygen into their muscles fast enough. By taking deep breaths, and building up the supply of oxygen in your blood, you can prevent muscle cramps. As lactic acid builds up, and muscle fatigue sets in, untrained players think they've reached their limit.
Track teams, and well-coached basketball and football teams for that matter, train by sprinting short distances, over and over. It's not fun, but it works. After a few months of training, the lungs begin to process oxygen more efficiently, and players find that they can run long distances non-stop, or sprint for a longer period of time. Students must meet specific eligibility requirements each year to participate in Baltimore City Community College baseball camp 2017. Beyond consideration for Cox College roster, you may think about University of San Francisco online class for complementary electives to your primary course of study.
Corporate Health Coach/ Personal Trainer
Wellness Council of Arizona
Current Personal Trainer Certification. As a Wellness Council of Arizona Corporate Health Coach/ Personal Trainer, you will provide activities such as..
2 days ago Texas Athletic Coaches (2017-2018)
Great Hearts Academies
Basketball and Soccer. Basketball, Track and Field, Tennis. ATHLETIC COACHES - Great Hearts Academies in Texas (2017-2018).
1 day ago Pharmacy Technician Specialist (16459)
Personal/ Associate Development. Trains, coordinates and directs pharmacy staff in all aspects of third party plan administration.
2 days ago Physical Education Teacher/Varsity Football Coach
Isidore Newman School
Act as an assistant coach for a winter or spring sport (basketball, soccer baseball, tennis or track).
3 days ago Assistant Coach Girls Soccer
Bellevue School District
Comply with WIAA coaching clock hour program. Assist the Head Coach in all matters relative to the sports season..
1 day ago


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Only the daring and the foolish might be the axiom to go by after MBTA transit cops last night arrested our collective hero, Philip Urban after images of the man receiving a blow job on the platform of an Orange Line station in downtown Boston earlier this month went the viral course.
Yes that's right kids, I'll order what he is having. Or will you?
According to a report via the bostonglobe officers from the Special Crimes Unit arrested the 50 year old man of Malden Thursday night and charged him with open and gross lewdness.
Things got sticky (pun intended) when Philip Urban and his partner (who has yet to be identified and accounted for, but will she now?) when alarmed passengers noticed the 'fun couple' standing next to a column at State Street Station on May 13 circa 2.30 pm (not even 2.30 am kids- how shocking!) and getting gritty.
Cops would be notified of the good subway platform cheer after a photo of the fun act was shared on Facebook and of course went viral.
Reports the bostonglobe: After widely distributing surveillance photos of Urban on their own Facebook page and blog this week, officers were able take Urban into custody.
Offered Transit Police Lieutenant Richard Sullivan: 'We received some tips, but we put a lot of time into reviewing images from our public safety cameras, and we were able to track him to Malden.'
Adding: 'Conduct like that is not going to be tolerated.'
For his good times, the man now faces the prospect of being listed on the state's sex offender list ('but it was only an early afternoon blowjob your honor!!') if he has been previously convicted of any prior open and gross lewdness charges.
Of course some commentators have wondered if prosecutors are going too far in bringing the man on a sex offender's list cause technically speaking no one was sexually violated.
Our collective hero now faces up to three years in state prison and a $300 fine.
Philip Urban is to be arraigned Friday in Boston Municipal Court, according to police.


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Discussion in 'Nintendo Wii Gaming' started by PinkFloyd, Aug 24, 2007.
Any one know if Project Hammer or Disaster: Day of Crisis were really canceled or not?
Project HAMMER is lying on Ice. It's not official canceled, but they don't work at it anymore.
Disaster is still in development, but no infos are coming through. Possibly on TGS.


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This well cared for, two story town home in Rancho Viejo features a welcoming courtyard to enter the main level with an open living/dining area, upgraded tile floors and gas kiva style fireplace, a kitchen with upgraded cabinets, granite counters and large pantry. There is also a laundry room, powder room and a generous finished two car garage. Upstairs are 2 bedrooms with en-suite baths. Both bedrooms have fantastic mountain views! Off the master suite is a large deck with mountain views east and west. Other features include refrigerated air, new carpet, new paint throughout, wood blinds and ceiling fan. Plus, an absolutely amazing location directly across from the village plaza and just steps to the village market; close to shopping, major highways, the community college and elementary school, and surrounded by miles of trails and open space. This is the Village at Rancho Viejo!
Senior Vice President/ Brokerage Manager
m: (505) 690-3003
o: (505) 988-2533


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These Cinquain Tribute poems are examples of Cinquain poems about Tribute. These are the best examples of Cinquain Tribute poems written by international PoetrySoup poets
If you don't find the poem you want here, try our incredible, super duper, all-knowing, advanced poem search engine.
The poem(s) are below...
The One Who Survives
She lives
against all odds
'needle in a haystack'
stranger gave her a new kidney
new life
Sandra M. Haight
~13th Place~
Contest: The One Who Survives
Sponsor: Sara Kendrick
Judged: 02/11/2016
Via her plea on Facebook, my friend's young daughter received a kidney
from a perfect stranger in August 2015.
Copyright © Sandra Haight | Year Posted 2016
Yellow Black-seeded
Soaking Shimmering Sun
Serenity Showing Sturdy Sensitivity
Copyright © sima mittal | Year Posted 2013
lingered in hole
always she pursued hope
She was a conqueror in life
Feb 11-2016
Written for "NEVER - ALWAYS - SOMETIMES - Poetry Contest"
Copyright © Rahy Hy | Year Posted 2016
Tall, Spotty-Brown
Chewing Leafy Trees
Animal Dignity In Motion
High walls
Deep moat surrounding
In the Dark Ages
Copyright © R.A. Marschall | Year Posted 2016
Bird of the gods
Long legged wading fowl
Live in wetlands, forests and plains
Copyright © R.A. Marschall | Year Posted 2017


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Reading With Rogues August – Velvet Vol 1
Every second Tuesday, we hold our graphic novel reading club! It will be hosted at Homefield Grill across the street in one of their private rooms, so in addition to fun talk about comics, you can buy delicious food and drinks, including a pretty stunning array of beers on tap.
The next meeting is on Tuesday, August 12th, starting at 7 PM and running until we run out of stuff to talk about (usually about 9:30 or 10:00 PM). Folks can come and go as they please, and we should have room for up to 20 people, possibly more.
The managers of Rogues Gallery will be on hand to talk about comics and hopefully get everybody chatting… we're hoping to extend the vibe of our New Comics Wednesdays to everyone who maybe doesn't get a chance to talk comics with their regular group of friends, or just can't get enough comics talk.
Each meeting of the graphic novel club will have a book we choose as a headliner. We'll offer a 15% discount on that book from the time of the announcement to the night of the graphic novel club. While we're perfectly happy to have you bring one you already bought, we're hoping folks will choose to buy this book from us rather than download it digitally or buy it somewhere else, to help us keep funding these get-togethers.
This month's book is Velvet Vol 1: Before the Living End by Ed Brubaker and Steve Epting. The 15% off sale starts effective now, and will run until we close at 9 PM on Tuesday, August 12th. (Since we're new to this, if you're buying the book of the month, you might want to remind the clerk at checkout about the discount.)
We'd love for folks to RSVP on the Facebook event page just so we can have a rough headcount, but walk-ins are absolutely welcome. And while we'll focus the discussions around the graphic novel of the month, we'll almost certainly be talking about other comics and graphic novels. Also, for the time being, since there's alcohol available, it's later at night and we're probably going to be offering graphic novels that are aimed at an older audience, we're making this an 18 and up event. If parents want to bring their 15-17 year olds, that's OK, but just be aware that we may be talking about mature subject matter in the discussions.
We look forward to talking comics with you!


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Product Partnership
Another possibility for your organization is to help raise awareness of Make-A-Wish in Luxembourg and raise funds for a WISH at the same time.
This can be done by linking your product to Make-A-Wish Luxembourg. With every product sold, a portion of the proceeds go to the WISH children. A nice win-win solution where you and your customers help a great cause.
For more information or to get started, please contact Marcel Hagendoorn via firstname.lastname@example.com or call 314 595.
Make-A-Wish® Luxembourg ASBL
EMERGENCY Phone: +352-661-629.629
BANK: Banque et Caisse d'Epargne de l'Etat


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Carmaker Mercedes-Benz has started a service that allows customers needing replacement parts to know in advance what it will cost.
The "Fixed Price Repairs" service provides a transparent pricing structure, meaning customers will know the cost and fitting of a selection of standard items before they take their car to an official Mercedes workshop.
The service covers its most popular models, regardless of age, and is set to be extended to other models in 2010.
Pricing for the parts relate to each model. Examples of this include replacing an A-Class rear wiper blade for £14, or the front brake pads for a C-Class costing £100, including VAT and labour.
The car manufacturer already offers a number of schemes to clients including vehicle collection and delivery, savings for owners of older cars, and the "Mercedes-Benz To You" programme, which provides free checks on vehicles at homes or at work.
Copyright © Press Association 2009


text: There is no specific day for gay pride to be celebrated. In the United States gay pride month is the month of June with celebrations happening thoughout the month. For Boston there is a gay pride week which for 2010 will be June 4 -13. At Walt Disney World it is the first weekend in June. Around the world each country has it's own celebrations and they range from May – September.


text: We had lost contact...Combination of things Adam was doing better, I lost access to a vehicle to get to appts which were 2 hrs each way by bus, I was exhusted...trying new medications, appts, doctors, etc... I remember getting a letter sometime back saying a different doctors name on it so i figured our Dr...(Dr Tammy as Adam had so affectionately come to call her) must have relocated...I googled her name last night and this is what i found. Im so shocked and saddened...She was only 38 yrs old...young daughter must be about 4 now. I wish I knew so I could have told how truly blessed we were to hav her in our lives. She was like part of our family...Adam started seeing her in /98 when she worked at Sick Kids Hospital in Toronto. She had just graduated in /95...She moved to a different agency and assured me she'd take Adam with her even though he didnt filt the criteria or the service boundaries for that agency...she took him and did as much as she could herself to keep his file out of sight of administrators. He loved her...she truly cared for him. The last time he saw her he was 13. She was pretty much the only doctor he needed for all those years. SHe did it all...practitioner, advocate, counsellor, co-ordinator, guidance... called you on things when she though you needed it...She took Shawn too later on when she needed help...she knew her since she was a baby....I can't believe that happened...An angel for sure...I can't even tell Adam right now with all he's going thru.


text: Home > Entertainment Piolo Pascual gears up for busy year ABS-CBN News Posted at Jan 15 2013 11:58 AM | Updated as of Jan 15 2013 07:58 PM Share Save Facebook Twitter GPlus LinkedIn Actor Piolo Pascual. File photo MANILA, Philippines -- Actor Piolo Pascual is expecting a busy year with several projects already lined up for him in 2013, including a new series and a movie. Pascual is set to return to primetime TV via "Apoy Sa Dagat" with actress Angelica Panganiban as his leading lady. Aside from the series, Pascual is also set to release a new album and a movie "On The Job" with Gerald Anderson and Rayver Cruz. "Ang 'Apoy Sa Dagat' is going to come out a few weeks from now. We'd been working on it since mid-year last year," the actor said in an interview on "Umagang Kay Ganda" on Tuesday. "I'm happy. Marami tayong sinimulan last year, ngayon lahat 'yon ipapalabas. I'm excited because we are starting the year right," Pascual added. Not sick In the interview, Pascual also assured his fans who are getting worried about his obvious weight loss. The actor explained he is now into swimming and cycling on top of his regular workouts. "Sa pinaggagagawa ko sa buhay ko sa pagtakbo-takbo ko, sa training ko nagsi-swimming ako nagba-bike ako. Eh naa-adik ako sa bike lately, tapos nagwo-workout pa ako," he said. He added: "Tapos eating right at sleeping right, pati ang pagtulog nakakapayat yan, tamang oras sa pagtulog, so wala akong sakit." Share Save Facebook Share on Twitter GPlus LinkedIn Read More: Piolo Pascual /news/01/23/18/3-mag-iina-timbog-sa-shabu/life/01/23/18/new-eats-chef-luigi-muhlach-tweaks-pulutan-classics-in-greenbelt-beerhouse/news/01/23/18/3-binatilyong-snatcher-arestado/video/news/01/23/18/bato-iginiit-na-hindi-sila-naniniktik-sa-media/video/news/01/23/18/pimentel-kamara-dapat-maghintay-sa-desisyon-ng-senado-sa-con-ass


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Three-star wide receiver/defensive back Kevin Cummings (6-2, 165, 4.5) from Encino (Calif.) Crespi is having an outstanding senior season on both sides of the ball. He recently received his first offer.
"My senior year is going great right now," Cummings said. "My team is 6-1, and I've been doing well on defense and offense."
"This year my goal is still to break 1,000 yards receiving," Cummings said." Right now I'm sitting at 450 yards, but we have a few games left plus playoffs to try and get that."
"I want to win a championship because last year we almost won but came up one game short. So that's what I'm trying to do."
"Colleges are recruiting me for both defensive back and wide receiver," Cummings said. "I'll play both in college. I'm been playing receiver mostly, but lately I've been playing some defensive back."
"This past week I got an offer from San Diego State to play safety," Cummings said. "I've also been talking to Stanford, San Jose State, Oregon State and Arizona State."
"San Diego State is my first offer so they're at the top of my list, but as more offers come in I'll continue to keep my options open," Cummings said. "When the season is over I'll have a chance to look over everything."
"I haven't set up any official visits yet, but I am talking to San Diego State about setting a visit up," Cummings said. "I would love to visit Oregon State and San Jose State. I'm around UCLA a lot so a visit wouldn't be that big but I'd love to get an offer from them.
What is Cummings looking for in a school?
"The important thing is whether I'll be able to play," Cummings said. "I'm all about competing, I want to compete. If they have wide receivers I'll come in and compete and hopefully take one of the spots. I just want to go to a school where I can see myself playing and hopefully doing big things."
What does Cummings like about the recruiting process?
"I just like how the schools show interest in you," Cummings said. "I like talking to all the coaches about their program, and how they run the program. It's confusing at times, but also fun."


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For The Dancing And The Dreaming-
John Powell
Lời bài hát For The Dancing And The Dreaming
I'll swim and sail on savage seas
with never a fear of drowning
and gladly ride the waves of life
if you would marry me
No scorching sun nor freezing cold
will stop me on my journey
if you will promise me your heart
And love me for eternity
My dearest one, my darling dear
Your mighty words astound me
But I've no need for mighty deeds
when I feel your arms around me
But I would bring you rings of gold
I'd even sing you poetry
and I would keep you from all harm
if you would stay beside me
I have no use for rings of gold
I care not for your poetry
I only want your hand to hold
I only want you near me
To love and kiss to sweetly (hold?)
for the dancing and the dreaming
through all life's sorrows and delights
I'll keep your laugh beside(inside?) me
I'll swim and sail a savage sea
With never a fear of drowning
I'd gladly ride the waves so white
And you will marry me!


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This is for the 5 Ingredients Challenge:
- Purple - throughout
- Tag - I'm calling my journal spot a tag
- Ribbon - Above and below the pics
- Circle(s) - Used a circle mask (most of which is covered up - bad planning), and buttons for the circles
- The Date - written on the journal spot.
DD with one of those bubble shooters. She declared it was "Bubblestorming!" Thanks to Lisa (dancinirish90) for the journal card. It's the last one of the set I got in a RAK last year.
CS: Bazzill Flintstone (not in store)
Alphas: Remarks ("Storming")
Ribbon: Hobby Lobby
Mask: Mister Huey's
Buttons: Stash
Ink: ColorBox (White)
Journal spot: Technique Tuesday
Sketch is from the March MSC - week 2! I never got around to using it during the actual challenge.
Entered in the following challenge:
*JULY* 5 Ingredients + Yours Challenge!
$5.00 $4.49
$3.70 $2.99
$5.00 $4.00
Item Discontinued
$0.89 $0.62
$2.99 $2.09


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Need a video to help promote a product still in development? Not a problem. We created this 3D animation video for tesa Tape with nothing more than a few photographs and some cellphone footage.Read more
3D Animation: Air Piping System
Applied System Technology needed help demonstrating their unique air piping system. Many of the benefits of the system are hidden from view and it was difficult for the sales team to effectively communicate some of those features. We created this 3D animation video to help illustrate the internal workings of the system and thereby making it…Read more
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Perforin mutations have been demonstrated in a proportion of patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH). In the present study, we evaluated whether some patients with lymphoma sharing clinical characteristics with HLH might harbor mutations of the perforin gene. We analyzed 29 patients and found that 4 patients, who developed either Hodgkin or non-Hodgkin lymphoma, had biallelic mutations of the perforin gene. One of these 4 patients, a 19-year-old female with T-cell lymphoma, had a brother carrying the same mutations who developed HLH. In 2 of the 4 patients with biallelic mutations of the perforin gene, we evaluated perforin expression by flow cytometry and natural killer (NK) activity and both were found to be absent. Moreover, we documented the presence of monoallelic mutations of the perforin gene in 4 more patients. One of these 4 latter patients also carried a mutation of the Fas gene. These data indicate that perforin deficiency, either alone or in combination with other mutations of genes involved in lymphocyte survival or functional activity, may be present in patients with lymphoma. These findings suggest that perforin also plays a key role in the mechanisms of immune surveillance that prevent tumor growth and/or development.
Perforin is a cytolytic protein of 555 amino acids, expressed mainly in activated cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, which plays a critical role in cell-mediated lytic function and immune surveillance, and is essential for killing via non–Fas-mediated mechanisms.1,2 In CTLs and NK cells, perforin is stored in intracytoplasmic granules. Following cell activation, perforin, in the presence of calcium, polymerizes into transmembrane tubules to form pores and allows cytolytic enzymes, such as granzyme, to enter the target cells, this resulting in cell death by osmotic lysis and apoptosis.3
In humans, biallelic mutations of the perforin gene, leading to either complete lack or severe deficiency of the encoded protein, have been found in a proportion of patients with familial hemophagocytic lymphohistiocytosis (HLH).4-7 HLH is a life-threatening disease, usually occurring in early childhood, associated with profound immune derangement and characterized by impaired T-cell and NK cell granule-mediated cytotoxic activity.8 The main features of HLH are fever, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, and, frequently, central nervous system involvement.9 Knockout mice for the perforin gene are immunodeficient and, similarly to patients with HLH, lack NK cell granule-mediated cytotoxicity. Perforin-deficient mice do not usually develop HLH although they do develop a disease mimicking HLH when infected, the lymphocytic choriomeningitis virus (LCMV),10,11 with CD8+ cells and interferon-γ being essential for development of LCMV. Moreover, these knockout mice have a high incidence of lymphoproliferative disorders, which occur late in their life, especially when also Fas deficient (lymphoproliferation [lpr]).10,12 In view of these experimental findings, we reasoned that some patients with lymphomas might also harbor mutations of the perforin gene and thus we investigated the presence of either biallelic or monoallelic mutations of the gene in a group of lymphoma patients with predefined clinical characteristics.
Patients, materials, and methods
Twenty-nine unrelated Italian patients with lymphomas (16 males, 13 females; age range 3 to 51 years) were included in this study. We decided to study patients, mainly of young age, diagnosed with lymphoma who presented with either pathologic or clinical signs of hemophagocytosis or had concomitant liver disease, reasoning that similar clinical manifestations occurred in patients with HLH. In view of the same consideration, we also chose to investigate cases of lymphoma characterized by an unexplained aggressive course. Clinical characteristics of the patients enrolled in this study are detailed in Table 1. The study was approved by the Institutional Review Board of Pediatric Hematology/Oncology, Unit of the Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy. The informed consent was provided according to the Declaration of Helsinki.
Analysis of the perforin gene mutations and of protein expression
The coding region of the perforin gene (exon 2 and exon 3) was amplified using standard polymerase chain reaction (PCR) conditions from peripheral blood mononuclear cells (PBMCs) and sequenced according to a previously published method.4 PCR products were purified using Millipore Microcon (Bedford, MA) and then sequenced in an automatic DNA analyzer (ABI 3730XL; Applied Biosystems, Foster City, CA).
Perforin expression was evaluated by fluorescence-activated cell sorter (FACS) analysis. PBMCs were first stained with fluorescein isothiocyanate (FITC)–conjugated anti-CD8 or anti-CD56 (Becton Dickinson PharMingen, San Diego, CA) for detection of surface membrane antigens. Following fixation and permeabilization using Cytofix-Cytosperm (Becton Dickinson PharMingen), for cytoplasmic staining the cells were then stained intracellularly with phycoerythrin (PE)–conjugated antiperforin antibody (Becton Dickinson PharMingen).
Analysis of the Fas gene
In 3 patients with monoallelic mutations of the perforin gene, mutation analysis of the Fas gene (Mendelian Inheritance in Man [MIM] 134637; TNFRSF6) was performed by DNA genomic sequencing. DNA was extracted from PBMCs with standard methods. Eight fragments spanning the 5′ untranslated region (UTR) and the 9 exons of the gene were amplified in 20 μL final volume containing 12 pmol of each primer, 50 ng of genomic DNA, and 0.5 units of AmpliTaq (Applied Biosystems). The used primers are listed in Table 2. Amplification was performed in a Gene Amp PCR System 9700 (PE Applied Biosystems). PCR conditions were as follows: 1 cycle at 96°C for 3 minutes; 35 cycles at 94°C for 35 seconds, melting temperature (Tm) for 35 seconds, 72°C for 35 seconds; 1 cycle at 72°C for 5 minute. The PCR products were sequenced using a Big Dye Terminator v1.1 Cycle Sequencing Kit (Applied Biosystems) and an ABI PRISM 310 Genetic Analyzer (Applied Biosystems, Warrington, United Kingdom).
NK activity assay
NK activity of PBMCs in both patients and controls was assessed by standard 51Cr-release assays using the NK-sensitive K562 cell line as target.13 Results were expressed as percent specific lysis.
Biallelic mutations of the perforin gene were found in 4 of the 29 patients examined (Table 1). Details of the clinical characteristics of these 4 patients are briefly summarized.
A 19-year-old female (Pt 1) had been successfully cured of her T-cell lymphoblastic lymphoma and 2 years later her 22-year-old brother developed HLH. These 2 siblings have been previously reported in detail14 as affected by adult-onset HLH with atypical findings at time of presentation, the relationship between HLH, lymphoma, and defect of the perforin protein being at that time unrecognized. The 2 siblings shared the same 2 mutations. The first one, in exon 2 (272C>T), changes alanine at position 91 into valine; the second one, in exon 3 (1122G>A), changes tryptophan at position 374 (within the endothelial growth factor [EGF]–like domain) into a stop codon. Both siblings had null NK activity and absent perforin expression on cell surface. Notably, the association of these 2 mutations has been observed in 3 additional patients with early onset HLH in whom NK activity was null and the perforin molecule was not expressed on lymphocyte cell surface (R.C., unpublished personal data, March 2002).
The second patient (Pt 2), a 7-year-old male, was diagnosed with stage III Epstein-Barr virus (EBV)–positive Hodgkin lymphoma. After having been successfully cured of Hodgkin disease, 3 years later he developed a large B-cell non-Hodgkin lymphoma with multiple sites of involvement, diagnosed through biopsy of a cervical node. Six months after the onset of this second lymphoproliferative disorder, during treatment with intensive chemotherapy associated with the anti-CD20 monoclonal antibody (rituximab), the patient developed liver disease and severe hemophagocytosis, which responded to treatment with etoposide and cyclosporine A. An allograft of hematopoietic stem cells from an HLA-identical unrelated volunteer was then performed. Sustained remission of both non-Hodgkin lymphoma and hemophagocytosis was obtained and now the patient is alive and disease-free 22 months after transplantation. Two mutations were identified in the perforin-coding region of this patient. The first one, in exon 3 (1304C>T), changes threonine at position 435 into methionine. The second one, in the same exon (1349C>T), results in a change from threonine at position 450 to methionine. Both mutations occur in the C2 domain, the former having been recently described.15
The third patient (Pt 3), a female, presented at age 7 years with multiple reddish nonulcerated subcutaneous nodules and B symptoms (fever and weight loss) of 2-month duration. Two surgical lesion biopsies were performed on trunk and leg, respectively, and a rare form of subcutaneous, panniculitis-like T-cell lymphoma was diagnosed. The patient's condition rapidly deteriorated and she developed pancytopenia and hepatosplenomegaly. Marrow trephine did not show lymphoma localization but revealed hemophagocytosis by histiocytes with normal morphology. The patient received chemotherapy as well as systemic steroids and cyclosporine A for control of hemophagocytosis. Despite these therapies, the patient died due to progression of disease 5 months after diagnosis. Sequencing of the coding exons of the perforin gene disclosed the following 2 mutations: the first one, in exon 2 (272C>T), changes alanine at position 91 into valine; the second one, in exon 3 (1262T>G), changes phenylalanine at position 421 into cysteine.
An 18-year-old female (Pt 4) presented with fever, malaise, and massive hepatosplenomegaly. Peripheral T-cell lymphoma associated with bone marrow infiltration was diagnosed. Marrow trephine also showed the presence of evident hemophagocytosis. The patient was treated with intensive, multiagent chemotherapy specific for T-cell lymphoma of high-grade malignancy. Unfortunately, she did not obtain clinical and hematologic sustained remission. Thus, 6 months after diagnosis she received a transplant from an HLA-identical sibling. Complete remission with engraftment of donor cells was obtained and now the patient is alive and disease-free 7 months after the allograft. This patient had 2 mutations in exon 3: the first one (914G>A) changes glycine at position 305 into aspartic acid, the second one (1066C>T) changes arginine at position 356 in tryptophan (Figure 1A).
For each patient found to have biallelic mutations of the perforin gene, both mutations found were confirmed, each in the heterozygous status, in the parents.
Four more patients had monoallelic mutations of the perforin gene (Table 1). In detail, 3 patients had the 272C>T mutation in exon 2, and 1 patient had a point mutation in exon 3 (755G>A) resulting in a change at position 252 from a medium-sized and polar amino acid (asparagine) to a small-sized and polar amino acid (serine).
This last patient (Pt 11 of Table 1 with liver disease) was a 27-year-old man who presented with cervical lymphadenopathy, fever, weight loss, and itching; lymph node biopsy was diagnostic for a T-cell/histiocyte-rich large B-cell lymphoma. Disease staging demonstrated multiple sites of involvement so that a diagnosis of stage IV disease, age-adjusted International Prognostic Index 4, was performed. During treatment with chemotherapy the patient developed liver failure that precluded the administration of further cycles of intensive chemotherapy. He died due to disease progression, despite treatment also with rituximab. This patient had a history of previous splenomegaly, intestinal obstruction due to mesenteric lymphadenopathy, and severe thrombocytopenia requiring splenectomy. At age 25 years he had developed cervical adenopathy. In view of the clinical symptoms associated with an increase in peripheral CD4 and CD8 double-negative T-cell receptor α/β+ lymphocytes and defective in vitro Fas-mediated apoptosis, a diagnosis of autoimmune lymphoproliferative syndrome (ALPS) had been made, and the patient had undergone exeresis of the cervical lymph nodes. Lymph node examination disclosed reactive follicular hyperplasia; bone marrow biopsy was negative for lymphoma localization. In this patient, Fas gene sequencing demonstrated a novel point mutation in intron 7 affecting a canonical splicing site (IVS7nt1G>A). The Fas mutation was inherited from his healthy father and was also present in a healthy brother, whereas the perforin gene mutation was detected in his healthy mother. Further details on this patient have been reported elsewhere.17 After having identified this double mutation of the perforin and Fas genes in this patient, we also tested 3 of the remaining 4 patients with monoallelic mutations of the perforin gene and causal mutations were not found in either the Fas gene-coding sequence or the intron-exon boundaries.
We investigated the presence of the mutations that we found in patients also in healthy controls. We found the A91V mutation in 10 of 492 control alleles (2%), the difference between patients and controls being statistically significant (P < .004). The mutation N252S was present in 1 of 660 alleles (0.2%) tested in our laboratory (492 alleles) and in another laboratory (164 alleles). This is not statistically significant due to the rarity of the event in the cohort of controls. The other mutations were not found in the controls.
In addition to the molecular analysis of the perforin gene (Figure 1A), perforin expression and NK activity were evaluated in 2 of the 4 patients with biallelic mutations of the perforin gene (Pt 1 and Pt 2). Figure 1B shows that in contrast to healthy controls, in whom perforin expression was present in both CD8+ and CD56+ lymphocytes, patients did not show perforin expression in the CD8+ or the CD56+ cells. As previously observed in early onset HLH-patients,4 lack of perforin expression was associated with undetectable NK activity (Figure 1C).
We also studied NK activity in 2 of the 4 patients with monoallelic mutations and it was present and comparable to that of healthy subjects.
The rejection of many experimental cancers by CTLs and NK cells is dependent on the pore-forming protein perforin,12,18,19 and previous work with perforin-deficient mice demonstrated that perforin plays an important role in maintaining immune surveillance,20 which protects against development of lymphoproliferative disorders in vivo.10,12 In these experimental animal models, the increased incidence of lymphoma associated with perforin deficiency is conceivably due to a defective cytotoxic mechanism physiologically involved in maintaining immune homeostasis, favoring the uncontrolled proliferation and expansion of premalignant lymphoid cells, which, in turn, may acquire a malignant phenotype.
In 1999, Stepp et al4 first suggested that, in humans, perforin deficiency is responsible for an acute immune dysregulation leading to HLH. Other mutational analyses and linkage analyses of subsets of consanguineous families have provided evidence that perforin mutations account for 20% to 40% of HLH.5-7 The results of our study, as well as previously published data on atypical HLH phenotypes,14 point to a more complex dysregulation of the immune system when perforin is absent, which may be associated with quite different clinical presentations, some patients developing HLH and others lymphoproliferative disorders. The observation of biallelic mutations of the perforin gene in patients with lymphoma and the presence in the same family of lymphoma and HLH provide further support to the hypothesis that the resulting effect of perforin mutations is likely to be more complex than previously anticipated and may vary among individuals, possibly depending on additional genetic and/or environmental factors.21 In this regard, it is also important to note that in the 4 patients reported here, the lymphomas associated with biallelic mutations of the perforin gene are of different types, including B-cell and T-cell non-Hodgkin lymphomas as well as Hodgkin disease.
The patients who had either biallelic or monoallelic mutations of the perforin gene were aged between 7 and 29 years (Table 1), suggesting that functional deficiency of the lytic activity of perforin or dysregulation of immune response associated with mutations of this pore-forming protein may be involved in the pathogenesis of lymphoproliferative disorders occurring in young people. The limited cohort of our patients does not allow for conclusions to be drawn on either the possible role of mutations of the perforin gene in the pathogenesis of the different types of lymphoma in elderly people or the real incidence of this genetic event in patients with lymphoproliferative disorders.
While frame-shift mutations or mutations of the perforin gene leading to stop codons have an unquestionable causative role in the loss of functional activity, mutations causing a single amino acid substitution have to be interpreted with more caution, being often unproved whether they are associated or not with a loss of functional activity. In particular, the role of the A91V substitution is still debated, as some researchers believe that it represents a simple polymorphism, and because it has never been found in a homozygous state in patients.7,22 The finding that NK activity was null and perforin expression was absent in Pt 1 and her brother,14 as well as in 3 other patients with a confirmed diagnosis of HLH having recurrent re-exacerbations of the disease (R.C., unpublished personal data, March 2002), is in favor of a causative role of this mutation rather than supporting it as a simple polymorphism. In these 4 HLH patients, the A91V mutation, found in compound heterozygosity with a second mutation (W374Stop in 2 cases; R232H and del283L in 1 case each), was associated with either absent or very low perforin expression, as well as with profound impairment of NK activity. In order to be cured of their disease, 3 of these 4 patients required hematopoietic stem cell transplantation. Finally, it has been recently reported that in a rat basophilic leukemia cell line this mutation results in a marked decrease of lytic activity in comparison to the wild-type line.23
The finding that 4 of the 29 patients studied had a monoallelic mutation of the perforin gene raises the question of whether and how this genetic event increases susceptibility to the development of lymphoma. One interpretative hypothesis is that monoallelic mutations of the perforin gene may act as inherited risk factors, which, in addition to other genetic variations (either somatic or constitutional) and/or in presence of environmental factors, predispose to the development of lymphomas. One piece of evidence supporting this hypothesis is represented by case 11 in Table 1, who had an additional mutation of the Fas gene.17 A pathogenetic role for defects in the Fas system in the development of lymphomas has been suggested by the identification of clonal somatic Fas mutations in B-cell lymphoproliferative disorders.24 It is thus possible to speculate on a synergistic effect of the mutations in the perforin and Fas gene in our patient. Indeed, defective Fas-mediated apoptosis might have favored prolonged survival of lymphocytes, which may then be targets for transforming events, and the combined defects in 2 major pathways of cell-mediated cytotoxicity (ie, Fas-mediated killing and the granule-exocytosis pathway) could have blunted the capacity of the immune system to eliminate transformed cells. As we did not find any mutation of the Fas gene in the 3 more patients with monoallelic mutation of the perforin analyzed, we hypothesize that additional still undiscovered genetic defects, or possibly even environmental factors, could contribute, together with the impairment of perforin function, to the development of lymphoma. In this regard, candidate molecules to be investigated could be Fas ligand and caspases 8 and 10; it cannot be excluded that patients with somatic mutations of Fas are at risk for cancers originating in Fas-defective hematopoietic cells.25,26
As immune surveillance is believed to play a major role in preventing tumor growth and/or development of autoimmune disorders, the range of clinical manifestations associated with perforin mutations may be wider than currently thought.21 In particular, our study suggests that perforin-dependent granulemediated cytolysis plays a protective role against the development of lymphoproliferative disorders not only in mice10,12 but also in humans. Future studies should extend the analysis of the frequency of mutations of this gene in larger cohorts of patients with lymphoma in order to obtain more precise information on the incidence of this genetic event and should evaluate the potential role of perforin in controlling the development and growth of other tumors arising in nonlymphoid tissues, such as melanoma, where the role played by failure of immune surveillance in the pathogenesis of the disease is believed to be crucial.
We wish to thank the patients and their families and Dr L. Magrassi for helpful discussions.
- Reprints:
Rita Clementi, Istituto di Genetica Medica, Via Forlanini 14, 27100 Pavia, Italy; e-mail: rita.clementi{at}hsr.it.
Prepublished online as Blood First Edition Paper, February 22, 2005; DOI 10.1182/blood-2004-04-1477.
Supported by grants from The Histiocyte Society and by IRCCS Policlinico S. Matteo, Pavia (C.D.); the Ministero dell'Università e Ricerca Scientifica e Tecnologica (MURST; M.G.R.); Telethon (E1170; U.R.); and AIRC (Associazione Italiana Ricerca sul Cancro), CNR (Consiglio Nazionale delle Ricerche), 6th Framework Programme European Community "ALLOSTEM," and IRCCS Policlinico S. Matteo, Pavia (F.L.).
An Inside Blood analysis of this article appears at the front of the issue.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
- Submitted April 23, 2004.
- Accepted January 31, 2005.
- Copyright © 2005 by The American Society of Hematology


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