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from Dwyer Instruments, Inc.
The Series BDPA Adjustable Differential Pressure Alarm with built-in audible and visual set point indication is designed for overpressure, vacuum, and differential pressure applications. The scaled adjustment knob allows changes to the switching pressure to be made without a pressure gage. The BDPA... [See More]
- Specialty Applications: Overpressure, Vacuum
- Sound Level: 90
- Alarm Type: Buzzer
- Supply Voltage: AC (optional feature); DC or Battery (optional feature)
from Federal Signal Corporation/Industrial Systems
The Federal Signal Model 52 resonating horn produces 114dBa @ 10 feet (124dBa @ 1m) with a 1,000 foot range. It is capable of penetrating high ambient noise levels. Being electrically –activated, the Model 52 does not require an air compressor for operation. The Model 52 is able to withstand... [See More]
- Specialty Applications: For Off-Road Vehicles
- Sound Level: 114
- Alarm Type: Resonating horn
- Tone: Continuous
from Hasco Relays and Electronics International Corp.
Housing Material: ABS Plastic. Speaker Type: Voice coil impedance —8 ohm. Rated Input Voltage: 12Volts DC. Range Voltage: 6-15VDC. Sound Level: 100db. Current Draw: 400mA @ 12VDC 8 ohm load. Tone Frequency: Steady —1200HZ. Warble —800HZ to 1200HZ. 1 second ramp cycle. Operating... [See More]
- Specialty Applications: Security; Safety; Indoor
- Sound Level: 100
- Alarm Type: Siren
- Frequency: 800 to 1200
from OMEGA Engineering, Inc.
The M22 Series panel mount signaling alarms are made of heavy-duty industrial, UV stabilized polycarbonate and are intended for indoor or outdoor use. They are UL Type 4/4X/13 and IP65 approved for harsh environments and are watertight. The M22-30K models are specifically designed for the food... [See More]
- Specialty Applications: Outdoor/indoor Harsh Enviornments, Food Industry
- Frequency: 3300 to 3500
- Sound Level: 65 to 105
- Supply Voltage: AC; DC or Battery
from Pfannenberg Inc.
Blinking LED Light with Sounder, Rated for Explosive Area Use. Pfannenberg's visual and acoustic signaling devices satisfy numerous alarm, warning, and status indication requirements, including: machinery operating status, process monitoring, system startup, and building or area evacuation due to... [See More]
- Specialty Applications: Fire; MachineFailure; Process Monitoring; Safety; Smoke; Explosive Area Use
- Sound Level: 80 to 100
- Alarm Type: Siren; Bell; Whoop; Electrodynamic Horn Loudspeaker
- Tone: Continuous; Non-continuous
from Select Safety Sales, LLC
The Kidde AC Powered Plug-In Carbon Monoxide Alarm offers sensor technology to protect against the dangers of carbon monoxide. It comes with a 9V Battery back-up in order to provide continuous monitoring even during a power outage. Installation into any AC wall unit is quick and simple. A digital... [See More]
- Specialty Applications: Carbon Monoxide Alarm
- Tone: Non-continuous
- Alarm Type: Siren
- Supply Voltage: AC
from UTC Fire & Security
Low current draw. High dB output. Terminals for easy wiring. Gray flame resistant housing. Five lens colors. 150 candela strobe (clear lens). Complete with gasket and weatherproof surface back box. Engineered thermoplastic housing. 1,000 hour strobe tube. The Edwards 868STR AdaptaBeacon series is a... [See More]
- Specialty Applications: Process Monitoring; General Alarm & Signaling Applications
- Frequency: 50 to 60
- Alarm Type: Electronic Horn
- Tone: Non-continuous
from Cooper Crouse-Hinds
Designed for remote mounting in Division 1 areas [See More]
- Specialty Applications: Messaging, Alert
- Supply Voltage: AC (optional feature); DC or Battery (optional feature)
- Alarm Type: Speakers
- Mounting: Wall mount
from Global Water Instrumentation
Weather resistant housing, Easy to install [See More]
- Specialty Applications: High water levels
- Sound Level: ? to 95
- Alarm Type: Speakers
- Frequency: 2900
from Johnson Pump, An SPX Brand
The Bilge Alert ™ system uses a patented Mirus ™ field effect detector cell, which produces a micro-electrical field that detects disruptions caused by water and fluids. When activated the sensor will trigger a 100db piezo alarm and an LED light on the control panel. The sensor measures... [See More]
- Specialty Applications: Safety; Boat Water Level
- Sound Level: 100
- Alarm Type: Speakers
- Tone: Continuous
from Mallory Sonalert Products, Inc.
30mm Panel Mount with Screw Terminals [See More]
- Specialty Applications: LED
- Sound Level: 92 to 102
- Alarm Type: Continuous
- Frequency: 2900
from Pyott-Boone Electronics (PBE Group)
The Model 850 was designed as an audible and visual section alarm module. To be used in conjunction with the MineBoss Software. It can be activated remotely or linked through the MineBoss software to activate during a specific event. Both versions have an output for warning and alarm conditions,... [See More]
- Specialty Applications: Mine Wide Monitoring


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Everton manager David Moyes admits his side are missing the creative edge provided by forward Kevin Mirallas as he continues his recovery from injury.
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The Belgium international is sidelined with a hamstring problem picked up in October after initially returning to action too early.
Moyes believes the 25-year-old's absence is taking its toll on his side as they push for a top-four Premier League finish this season.
He told the Daily Mirror: "We've missed Mirallas giving us another edge.
"It might be that we've not really flowed as I would have liked attacking wise.
"It's shown in one or two results. We've missed him too long. It's a problem.
"He's probably missed the bulk of it, 10 or 12 weeks. He was a big part of what we achieved in that early part of the season when we were at our best and played some good stuff."
What will be the outcome in the match Southampton vs Everton?

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Should I get rid of my cat before my baby's born?
I've had my cat, Scooter, for eight years. Now that I'm expecting, I'm worried that I'll have to get rid of him. He's de-clawed so I'm not afraid he'll scratch my baby. But will the hair he sheds be bad for her? Will he hiss at her, sit on her, or scare her?
Posted: 06/13/2002 by a BabyCenter Member
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I have a cat, and she is about 8 months old. She's still a little fiesty, but I'm not too worried about her hurting my girls. I'm due in a couple of weeks, and my only concern is that when I put foot rattles on them, she'll pounce. So far, she hasn't gotten in the bassinets or swings, but she loves to sleep in the recliner in the nursery. I don't mind as long as she doesn't sleep in the babies' things. She DOES like the soft, rattley toys, though. I just put them up because I'm sure she can't distinguish baby toys from her own.posted 11/24/2003 by hhpeoria
I am thrilled to see that people have the same attitude about their "furry children" as I do. I cant stand hearing people tell me "get rid of the cats because they will harm the baby". Im not raising lions and tigers!! My oldest cat has been around since my first two children were born (over twelve years ago) and they absolutly ADORE her. More importantly, when you have a pet your child can learn the importance of being kind to animals. My girls watch over our two cats like they are our children as well. I wouldnt think of giving them away any more than I would my "human children". Just be careful your kitty doesnt want to take a nap on the BABY as it may on YOUR belly!! Good luck!posted 11/18/2003 by a BabyCenter Member
Someone on here mentioned letting your cat outside, then letting it back in. When a cat is outside, it is exposed to a variety of diseases. Wether it be from other cats or the little wild critters it will be hunting. Those diseases will then be brought into your house. Plus, they have no defense if they are declawed, or survival skills if they've been indoors their entire life. Raising your child with animals will also help prevent asthma and alergies. I currently have 3 house cats, 5 barn cats, 2 dogs and 3 horses. I can't wait to be able to introduce our DD to all of them. We hope that she becomes as much of an animal lover as her father and I are.posted 08/15/2008 by Jaime81
I have 2 cats and a dog. While pregnant my husband was on litter box duty. We also bought a CD called Preparing Fido (but there are others out there - you can find them using a search engine) filled w/ baby sounds. It helped to adjust the animals to the baby noises.posted 07/30/2008 by newmommyat35a
I grew up with cats myself, and will not get rid of my cats. Personally, I think both of my cats will just run from the baby - that's what I have seen with my friends that have cats. Also - when a friend of mind had a baby about 6 months ago - the doctor at the hospital had her husband take the baby's hat home that he wore in the hospital to let the cats smell it prior to bringing the baby home. My friend's cat actually sleeps on the floor in the baby's room under the crib - almost like he's protecting him. Personally, I wouldn't worry about it - unless your cat starts marking territory, I really don't think he is going to give you any problems - like others have said - cats typically run from children and loud noises - believe me - he won't sit on her. If nothing else, the baby will scare the cat!posted 07/11/2008 by dexysmom
If you even consider "Getting rid" of your cat, you shouldn't have one in the first place. It is not an accessory.You've had it for 8 years. How do you think he will cope with the rejection and understand it? He is not an old t-shirt that you can dump at a charity shop. He is an animal with feelings and attachments.posted 07/09/2008 by charmedwn
I wouldn't worry about the baby. My two fully-clawed cats (they were seven and eight, respectively, when baby #1 came home) have never done a thing to harm the kids - even when provoked. On the other hand, one of our cats didn't end up doing well. He was always high-strung and stressed, and when my daughter came home he licked all the fur off his belly. His stress level never did drop, and he got sick; we just had to put him down this week, at the young age of 12.posted 12/07/2007 by momtomerry
I'm due next month, March 2014 & I've made the decision to definitely give my cat up for adoption. Personally, between the litter smell and cats loving to play (i.e. jumping into the crib, playing and grabbing at the playard toys) I would recommend it maybe until the baby is a little older.posted 01/29/2014 by a BabyCenter Member
I am very scared, I have been pregnant for 5 weeks and I have gotten 3 cats, my husband and I want to get rid of them..:-(posted 12/07/2011 by a BabyCenter Member
The trick to having happy cats after you have a baby is to make sure you still give them plenty of attention. I've heard more than one story of friends who had cats and the cat got jealous of the baby and started peeing on everything, the baby's things in particular. If your cat starts doing this, it's because it's mad at you for not paying it enough attention.posted 03/04/2010 by nerobben
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White Christmas is a 1954 American musical film directed by Michael Curtiz and starring Bing Crosby, Danny Kaye, Rosemary Clooney, and Vera-Ellen, loosely based on the 1942 film Holiday Inn. Filmed in Technicolor, White Christmas features the songs of Irving Berlin, including the title song, "White Christmas." Produced and distributed by Paramount Pictures, the film is notable for being the first to be released in VistaVision, a wide-screen process developed by Paramount that entailed using twice the surface area of standard 35mm film. This large-area negative was used to yield finer-grained standard-sized 35 mm film prints.
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Megan Fox in photos
Published On: Aug 07 2014 09:11:35 AM CDT
As Megan Fox stars in "Teenage Mutant Ninja Turtles," take a minute to look back at the actress' career to this point.
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Let's make sure everyone's teeth have a chance.
What's the Debate?
A quick primer on both sides of the fluoride debate.
Questions About Fluoride?
We are here to help navigate the science to find the credible answers you are looking for.
New Fluoride Tools and Posters Available in English and Spanish
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Organizations that experience dramatic workload demand spikes will benefit from software defined networking, but for other firms SDN might not be worth the trouble
Software and hardware vendors have been ramping up their software define networking offerings lately as SDN continues to create quite a buzz among enterprise organizations.
AGO network frames HP's SDN story
Time to pay attention to all that SDN hype: analyst
Networking leaders team to make SDN platform
IT management software firm SolarWinds Inc. has come up with a checklist of eight things to be considered before grabbing a ride on the SDN bandwagon:
Check your industry – Software define networking works best for cloud providers and organizations where workload demands spike rapidly such as retail companies and financial services firms.
Healthcare and publishing organizations that have pretty uniform demands and not likely to require frequent changes in application workloads, will probably find little benefit from SDN, according to Sanjay, Castelino, vice-president of marketing for SolarWinds.
Network complexity – If your organization has to manage and configure numerous local area networks (LANs) or virtual local area networks, (VLANs), software defined networking could be for you.
Network size – Capacity planning is critical when considering SDN. If your organization deals with hundreds of internet protocol (IP) addresses, you could benefit from the automation provided by SDN. If your IT shop manages 50 or less IP addresses, SDN might not be worth the trouble, said Castelino.
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- Adult Adventure
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They are Synthetic Baltic Amber Plugs, since Genuine Baltic Amber is harvested one piece at a time by hand, along the shores of the Baltic Sea. Amber dates back 40 to 70 Million years, when there where dinosaurs roaming around, so it is fair to say that it is very durable, and has been in style for a long, long time.
All pieces are priced individually. For a pair order 2.
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Baby Laugh A-lot is a doll that was marketed primarily towards young girls, with its childish laughter. The maker of this video dubs the theme music from the horror movie "Friday the 13th" to give the commercial a very creepy feel.
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Anadarko Announces Pricing Of $2.0 Billion Of Senior Notes
This news release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 as amended and Section 21E of the Securities and Exchange Act of 1934 as amended.
No assurance, however, can be given that such expectations will prove to have been correct.
A number of factors could cause actual results to differ materially form the projections, anticipated results or other expectations expressed in this news release.
See "Risk Factors" in the Company's 2009 Annual Report on Form 10-K, Quarterly Reports on Form 10-Q for the quarters ending March 31, 2010 and June 30, 2010, and other public filings and press releases.
Anadarko undertakes no obligation to publicly update or revise any forward-looking statements.
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Little Feet Keychain Favors
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These little feet are just so sweet on keychain favors for baby's big day,
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Description and details:
- Each measures 1" x 1.25" (3" long with chain and ring)
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Concerto in C Major "Triple" for Violin, Cello, and Piano
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Bärenreiter's new Urtext edition of Beethoven's Triple Concerto is a completely fresh revision of this warm and beautiful showpiece. Errors abounded in all previous editions, but with the assistance of three newly-discovered sources, editor Jonathan Del Mar has cleaned up the text, corrected wrong notes and rhythms and (for the first time since 1807) presented the work in a way that a musician of Beethoven's day might have recognized, with all necessary information for directing the piece included in the solo piano part.
- Piano reduction with separate parts for all three soloists
- Draws on three new sources
- Correction of many errors found in previous editions
Publisher: Barenreiter
Composer: Beethoven, Ludwig Van
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Age: 19-24 Skin: Combination, Fair, Neutral Hair: Blond, Straight, Medium Eyes: Blue
A great conditioner with a nice subtle scent. Doesn't leave my hair too greasy but still keeps it looking shiny and healthy.
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Frying 101: When and How to Pan-Fry and Deep-Fry
There's no easier way to please a crowd than by serving up a platter of light and crispy fried delights. But getting that perfectly crunchy, crusty outside and a thoroughly cooked, greaseless inside is not always easy. To make delicious fried foods every time, follow our tips and tricks, and test out this batch of tempting fried recipes in your own kitchen.
Need more help in the kitchen? Try one of our other useful guides, like this one that covers all you need to know about chicken, or check out our ultimate baking tips and tricks.
By Lauren Haslett
Pan-frying can sometimes be as tricky as deep-frying, but it does require less oil, often making it more manageable for the home cook. There's no special equipment needed, like baskets, and there's less waste. However, just as with deep-frying, it is crucial to check the oil is hot enough before adding foods to the pan even though less oil is used, foods will still absorb it and become soggy if added to below-temperature oil. To test the oil temperature without a thermometer, drop a few pieces of stale bread, bread crumbs, or a pinch of flour into the pan. If it immediately starts to sizzle (but does not instantly burn), your oil is at the perfect temperature.
Recipe: Crispy Pork Cutlets with Cabbage-Ham Mash


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Vitro Launches Rebranding Effort for Wild Turkey - Posted October 30, 2013
Ah sweet bourbon, brownest of the brown liquors. MDC-owned, San Diego-based Vitro, responsible for the interesting Asics campaigns... [AgencySpy]
After Decades Covering Penn State Football, WJAC Sports Anchor Stepping Down - Posted November 10, 2011
A man who has been part of the Penn State sports community for decades is stepping down this week. No, not Joe Paterno. Longtime WJAC sports anchor ... [TVSpy]


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What: The public is invited to attend a celebration of what would have been Samantha Runnion's sweet 16th birthday.
When: 10 a.m. July 26
Where: Outside the Federal Building, 11000 Wilshire Blvd., Los Angeles. A tree and permanent memorial for Samantha were dedicated there five years ago.
Erin Runnion has created a guide for parents that can be downloaded for free from the U.S. Department of Justice's National Sex Offender Registry, at www.nsopw.gov.
For more information or to donate, visit www.thejoyfulchild.org.
SOUTH MAIN DIVIDE ROAD, RIVERSIDE COUNTY – Erin Runnion splashes the arid soil with bottled water.
Watering the sunflower seeds she planted where the body of her 5-year-old daughter, Samantha, was found, Runnion takes in the sweeping view of the steep, rugged hills on the eastern edge of the Santa Ana Mountains in Riverside County – a popular launching point for paragliders.
"I do like to imagine she just...soared," Runnion says. "That she just took off from this painful place."
Ten years after the abduction, sexual assault and murder of the Stanton girl became a national story, Runnion visited the spot off Ortega Highway where authorities found Samantha's body on a cliff overlooking Lake Elsinore.
She came not to dwell on the horrors of what happened to Samantha, but to talk about the legacy of a girl whose death kick-started the Amber Alert system in California and who continues, through a foundation set up by her mother, to help fuel efforts to keep the nation's youth protected from predators.
"It's important for me to remind people who were touched (by Samantha) 10 years ago to rethink what they've done in the last decade, and hopefully help us stop this from happening again," says Runnion, emptying several bottles of water onto the dirt.
"There's no value in my experiencing this without sharing."
• • •
Runnion, 37, who first visited this spot in late June, along with two Orange County Sheriff's Department officials and a TV reporter and cameraman, says she never anticipated its beauty.
She wanted to come to the trail near Ortega Highway because she hadn't been there yet. She tried once to find it on her own, but couldn't.
"One of the ways I coped with all of this was to be almost cruel to myself in terms of forcing myself to face the facts, and this was one that I had not yet faced," Runnion says.
Visiting the spot the first time was "horrible, but wonderful," says Runnion, now a nationally known advocate for child safety.
"It was horrible in the sense that it did make it all very real again. But I'm standing there watching people paraglide, and Samantha would have loved that. She would have absolutely loved it."
• • •
Samantha was abducted on July 15, 2002, outside her Stanton home by a Lake Elsinore man who sexually assaulted and asphyxiated the brown-eyed girl. He posed her body on the trail.
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What are the best approaches for quick data restoration?
Kevin Beaver explains the best approaches for quick data restoration in this expert response.
I'm a strong believer of not complicating things if they don't have to be. But I do realize that you absolutely have to have some semblance of structure and preparedness in place if you're going to respond appropriately rather than react inappropriately. So, start by prioritizing your critical systems, documenting specifically what needs to be done, and then test your procedures to validate the process. And be sure to take all of these...
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Start learning with our library of video tutorials taught by experts. Get started
Delves into the process of using Dreamweaver CS3 to develop a fully interactive, accessible site.
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quote:The Departed Babel Letters from Iwo Jima Little Miss Sunshine The Queen
quote:Letters from Iwo Jima Little Miss Sunshine
quote:How was Children of Men not even mentioned for best picture for the 79th AA
quote:The film itself was too heavy, too risky, and didn't play to oscar-worthy tropes.
quote:But Children of Men is among the greatest films ever made, and was AT LEAST as good as The Departed.
quote: I've only seen Babel once, but I really enjoyed it (if memory serves)
quote:Babel is one of those movies that makes you think it's better than it is via presentation. you FEEL like this is supposed to be some profound statement, and people don't have the balls to be like "this fricking suuuuuuucks."


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Adventures in Muscle - Part 2Part 2 - Tapping into her potentialMilly was super nervous as she filled out her goals sheet for the weightlifting class the Sunday night before it was due. She had done some research and found all the weightlifting records for men and women and not really knowing what she was doing, she split the difference between the men's and women's records. "Hah! There's no way I'll be able to do that…" she thought terrified, yet still a part of her brain that was now suddenly awakened insisted on guiding her hand into the shapes of those impossible numbers.It was the same thing the day of class. Most of her mind was screaming "Don't turn in that ridiculous form!!" while a very quickly growing part of her put one foot in front of the other and turned it in. It was done! She was committed and had set a goal! She nearly bolted from class at what she had done and trembling went to the first exercise for the day's body parts. The instructor had
Adventures in Muscle - Part 1Adventures in Muscle (Part 1)By Katrina"Weightlifting? That's the only gym option left??" Milly exclaimed!"That's right Miss… Maybe you should've signed up for your senior year of classes earlier," the guidance counselor replied. "You need two gym credits and both semesters that's the only option left.""Fine! I'll survive the jocks and the amazons somehow…!" she said stomping off.At the start of the semester she made her way to the gym with trepidation. She was a pretty senior but not necessarily fit and had avoided anything active most of her life, which is why she now had to finish off these last two gym credits in order to graduate."Alright everyone, gather around," the weights instructor called out. "This first week we're going to focus on the various lifts you'll be working on this semester and proper form. We're also going to be assessing your strength and putting together a goals chart that will track your progress and be a record of y
Adventures in Muscle - Part 4Part 4 - Silly Rumors"Oh, you know how people talk… They see me do curls with 50 pound dumbells and they think I'm the Incredible Hulk or something. You've seen me use those when I max out.""I have…" Christian said going all dreamy eyed."Well, I'm not the Hulk or anything, I've just discovered that I really like lifting weights. Actually, what are you doing next Friday night? Would you like to go out with me?" Milly asked scratching her head and flexing her arm at the same time so that it would inflate the sleeve of the bulky sweater she was wearing. It was weird, before building up her physical strength, she never had the confidence to boldly ask a boy out… It seemed that confidence was yet another byproduct of muscles!He definitely noticed her inflated arm and after his eyes stopped bugging out at the size of her sleeve he said that he'd love to go out with her. She was so happy she gave him a quick kiss on his cheek
Grace and Shawn Chapter 2: A Light WorkoutGrace and Shawn Chapter 2: A Light Workoutby MagnusMagnetoCommissioned by Up2nogd1Part 1. Immediately after Chapter 1"I believe you'll want more protein cream for your continued workout." Dr. Newman stated."You know it!" Grace cheerfully responded, smiling widely.Newman returned the smile before reaching into his lab coat pocket and producing another tube of the fortified protein cream. "Here you go." he said, reaching his hand out to give Grace the container."Hmmm..." Grace brought her finger to her chin, causing a small, shapely bicep to pop up. "Something tells me that you'd enjoy putting that on me." she stated with a playful wink.A familiar shade of red appeared on the 28 year old's face. "Well... I... Not to impose on our professional relationship...""Go ahead doc. I kind of like the idea of a personal servant." she explained, extending her arms outward, granting Newman permission to apply the cream onto her body.The scientist continued blushing heavily as he twis
Adventures In Muscle - Part 3Part 3 - Bulking Up"Ooooh… He seems to like that I'm all strong and muscley and stuff." Milly thought to herself, "How cool! I never thought my muscles would be sexy to guys… I think I'll work hard for a few more weeks and surprise him with my uber buffness!" The part of her that was freaked out by being all muscular and gross was oddly subdued during this train of thought. Maybe now that it saw that there were benefits beyond just being strong, it was staying quiet to see how it would all play out. It also helped that now she had another goal to meet. Meanwhile the part of her wanting to grow as big as possible was furiously planning how to grow as much muscle as possible over the next few weeks. She went to the weights coach after class, risking a totally worth it tardy to her next class, to ask if she would be able to lift in the gym after school too. He looked at her progress chart and saw that she was mak
The Duel (Female Muscle Growth story)The Duel - A Female Muscle Growth Storyby magnusmagnetoWe were certain to sit in as equal positioning as possible. She wanted this competition to rely on our physical abilities alone. It was agreed that we wouldn't bend our wrists or intentionally use any non-arm part of our bodies to provide additional power. As we locked hands a surprising bulge rose from her arm. She had certainly been working out since the last time I saw her, a few months ago. I wondered if it was in preparation of this battle; as I arrived, she was insistent on arm-wrestling. It didn't really matter though, I'm in decent enough shape thanks to my genetics, so my arms were about 13 inches. Not to mention I had stronger shoulders and longer arms. I guess my playful jab that she'd have to get into better shape to beat me at anything physical really got to her. Regardless, I had to admit, she looked great, especially in he


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New Directions | Back Again | Power Dinner
- TVNewser: Lisa Murphy and Bloomberg TV have parted ways.
- GalleyCat: "Game of Thrones" is coming back for a third season. Nerds everywhere celebrate by discussing if dragons were real.
- FishbowlDC: Time adds more celebrity power to its White House Correspondents' Dinner table. And no, it's not Carrot Top.


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The Phone Call from Beyond
- 42 Strange, but true story:
About twelve years ago, I was working nights as an LPN at an inpatient hospice unit. It was a quiet night. I was sitting in a patient's room with the patient and her family.
I will call the patient "Gladys."
Gladys was quietly actively dying, and her son "Bill" and daughter-in-law "Sue" were with her. I heard the phone ring at the desk. The CNA "Mary", answered it, took a message and met me in the hallway. She said "That was a weird call. It was some guy named "Harry." He said to tell Gladys that he'll be here for her in a half hour."
I walked back to the patient's room and relayed the message to Bill, Sue and Gladys. Gladys was non-responsive, so I leaned over and spoke the message quietly in her ear. The message didn't make sense to me, but I figured the family would know what is was about. Bill and Sue didn't say anything, but they gave me the strangest look. I went back to the desk.
A couple of minutes later, Bill and Sue came to the desk. Sue said "Are you sure the caller's name was Harry? The only Harry we know is Gladys' husband, and he's been dead for five years." Mary was sitting there, and read from the message log, confirming the message.
Bill said "That doesn't make any sense." Then he and Sue went back to Gladys' room. A little while later, Sue came to tell me that Gladys was not breathing. I went to check. She breathed two more times, and stopped. I assessed for signs of life, and wrote down the time of death and called the Charge Nurse, who confirmed it.
When we checked, we saw that Gladys' time of death was one half hour TO THE MINUTE from the time that Harry called. Mary said that his voice had had an echoing, staticy quality to it.
Was it really Gladys' dead husband calling to let everyone know her time was at hand? Who knows!?
We all talked about that incident for a long time after that.
About Hellllllo Nurse
Hellllllo Nurse has '15' year(s) of experience. Joined Oct '02; Posts: 4,774; Likes: 815.3Nov 15, '07 by callmekiplingOh jeez. creepy story!
while we're on the topic of phones and death..
I had a guy (captain gravity from a previous thread) whose family I got close to
in the time I knew him. After his burial we all went to lunch, and it turns out his son owns the restaurant, so the doors got locked and the afternoon was spent watching home videos on the TV over the bar.
This was last november, in the fall, and for some reason I'd taken my dad's car instead of my own. So a few hours (and perhaps I'll admit a drink or two) too late, I drove home. Dad's parking spot was across the street in a big pile of leaves.
I woke up, first in the house as always, the next day feeling a bit wonky from all the brandy 'n rolling rock.. and can't find my cell phone. I'm digging around in dad's car, in the leaf pile I parked it over, can't find it. Later on in the day I resolve to drive back to the bar, and find my phone in the driver's seat of my car.
So mine's not as creepy as yours, but I can't help but feel that the dead guy's last good deed in life was to drop off my phone for me6Nov 15, '07 by leslie :-Di didn't find that story, creepy at all.
if anything, i was comforted by it.
i immediately knew "harry" must have been her beloved husband.
i love, love, LOVE these stories...
and believe every single word.
working in an inpt hospice, i see many of this phenomena.
ea and every time, i can only smile...
leslie0Nov 16, '07 by angelkea014Oh... geez...
is that for real????
-angelkea0147Nov 16, '07 by Hellllllo NurseYes, it absolutely happened. I have no idea who it was on the phone- if it was her dead husband, a wrong number, or what. But the caller did ask for "Gladys" and say he would be there in 1/2 hr- he did say his name was "Harry."
And yes, Gladys did die in exactly a half hour.
A number of other very strange and unusual things happened in the nearly five years I worked hospice, but some of them were so strange, and unbelievable, I don't even want to write about them here.
Leslie has experienced similar things, as she states in her comment above.
Anyone who has worked hospice for any amount of time is bound to witness things they don't understand and can't explain.Last edit by Hellllllo Nurse on Nov 16, '071Nov 17, '07 by Ms KyleeOooh.. this gave me goosebumps.... I swear my Dad is ringing my phone.. there is never anyone there.. but the phone rings constantly.1Nov 17, '07 by Diary/DairyThank you for the story Hellllllo.....very interesting.4Nov 19, '07 by bagladyrn GuideI want to share an equally strange story that I haven't talked to anyone about - still not sure what to make of it.
My dad passed away suddenly almost 3 years ago in January. The following Christmas Eve while my mom was home alone the phone rang. The male caller said "Hello honey, Merry Christmas!" My mother, ever polite responded "Thank you, but who is this?" He replied "You know who this is - it's Bill!" (My father's name). My mom managed to tell him she thought he had a wrong number before hanging up. It was a couple of hours before she called me to relate this.
Knowing it wasn't my father, she still takes comfort in believing it was a message of some sort. Me - I'm not sure what I think...


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San Michele Villa Belmont
Official Contact Details - San MichelePhone: 202-232-4010 Fax: 703-549-6517
San Michele sits 25 feet from the water's edge, on a spot fortified by the Spanish in the early 1500's and prized ever since as a protected anchorage.
- Price from 4900 USD / Week
- Capacity up to 12 people
- 6 bedrooms & 6 bathrooms
Last updated: 12/13/2005
This is your property ?
These exclusive and deluxe waterfront rental properties offer visitors total privacy on the Caribbean Sea. With white sand beach, private pools, luxurious Jamaican decor, all-inclusive format, full staff (w/ childcare), lush tropical foliage, this will be a vacation travel experience to cherish...
Prices & deals
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Location & area
The site is surrounded by water on three sides, possessing extraordinary vistas of mountains meeting the Caribbean, stands of bamboo and fruit trees, and an unspoiled sea sometimes punctuated by the dugout canoes of local fisherman. This part of Jamaica is renowned for its deep-sea fishing and excellent snorkeling, with beautiful coralheads right at hand.
- Address:
- Villas on Bluefields Bay, West Indie, Belmont, Jamaica
- Accommodation located in:
- coastal, near fishing area, near horse riding, near restaurants & bars, near tennis courts, near the beach, near walking trails, near water sports, resort, village, waterfront!
Amenities & services
This property contains a main house which was significantly remodeled in 1999 and then got a new second floor addition in early 2000. This addition contains two magnificent seaview master bedrooms/baths and a stunning outdoor terrace tucked behind the two enormous palm trees. The first floor now has an expansive living room, a large dining room, the two original bedrooms and baths, and an enormous kitchen and staff porch. The adjacent guest cottage contains two more bedrooms and baths, and has a third room which can be utilized by children if necessary. If your vacation ideal includes hearing the sound of waves at your doorstep, sleeping in an old canopy bed, and enjoying beautifully served meals prepared by your own staff, then you will agree that a stay at San Michele is an unforgettable experience.
# of Units: 1... and each unit includes:
- Bedrooms: 6
- Bathrooms: 6
- Single beds: 1
- Double beds: 5
- Baby cots: 0
- Single sofa beds: 0
- Double sofa beds: 0
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- All Inclusive
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- ach home is staffed with excellent cooks and trained waiters providing attentive table service and using our large collection of fine china, crystal, and silver for your enjoyment. You will receive a list of menu possibilities previous to your visit which can be contoured as needed to suit your party. Our cooks are well experienced in producing meals for those who follow vegetarian diets (including vegans) and for those who follow certain kosher diets as well.
Review - San Michele
San Michele - Contact the owner
Important Notice : Avoiding Fraud
It's rare, but some helpful hints to watch out for with regards to fraud:
- It is important to NEVER wire funds or use/employ other fund transfer mechanisms such as western union: Always use a credit card to protect yourself against fraud. If owners pressure you into providing a deposit or refuse to accept credit cards, there is a high probability that this is a scam.
- If at all suspicious of fraud, ask to see their website, or any other literature they can provide or send to you. Ask them for contact details for guests who have previously stayed on their property insisting on telephone numbers. Be suspicious of emails that originate from free email services (yahoo, hotmail, gmail, etc)
- Research the property thoroughly on the internet to see if there is any history or mention of scams associated with the property.


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TK: To say the prognosis is not encouraging is an understatement. Italy has been hurt by PSA, and Chile also has found the disease but the extent of the potential damage there is much less clear. How did the disease come to New Zealand? Pollen imports are suspected. The USDA report is essential reading for all kiwifruit traders, who are being told that New Zealand kiwi exports will decline for the next two to three years. About the impact on the post harvest sector, USDA FAS reported:
New Zealand gold kiwi rocked by bacterial disease
Tom Karst


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|Name: _________________________
|Period: ___________________
This test consists of 5 multiple choice questions and 5 short answer questions.
Multiple Choice Questions
1. Stanislavsky wrote that the difficult will become easy and the easy habitual, so that the habitual may become what?
(a) Exact.
(b) Honest.
(c) Beautiful.
(d) True.
2. What was the reason for the beginning of Oedipus Rex?
(a) The onset of war.
(b) Oedipus' mother dying.
(c) Oedipus' father dying.
(d) The plague.
3. What does Mamet say that dramatic analysis is like in Chapter 6?
(a) Plotting a compass course.
(b) Solving a math equation.
(c) Literary analysis.
(d) Critical thinking.
4. What do actors erroneously try to use their intellectuality to do?
(a) Portray a sense of character.
(b) Show the ending in the scene.
(c) Portray the idea of a movie.
(d) Create subdramas.
5. According to Mamet, "In film or in the street, people who describe themselves to you are" what?
(a) Trying to get something.
(b) Lying.
(c) Being honest.
(d) Playing a role.
Short Answer Questions
1. What was the man doing on the side of the road whom the farmer met in Chapter 5?
2. What is the book of pictures of shots of a film called?
3. Where was Stanislavsky having dinner with a steamboat captain, according to Mamet in Chapter 6?
4. What was the impetus for the beginning of Citizen Kane?
5. Which chapter did Mamet recommend the students read in, A Practical Handbook for the Actor?
This section contains 246 words
(approx. 1 page at 300 words per page)


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Disclosures: Alice T Shaw, MD, PhD Consultant/Advisory Boards: Pfizer [ALK inhibitors (Crizotinib)]; Novartis [ALK inhibitors (Ceritinib)]; Ariad [ALK inhibitors (AP26113)]; Genentech [ALK inhibitors (Alectinib)]; Ignyta [ALK inhibitors (RXDX101)]. Benjamin Solomon, MBBS, PhD Constultant/Adivsory Boards: Pfizer [cancer-NSCLS (Crizotinib)]; Novartis [cancer-NSCLC (LDK378 (ceretinib))]. James R Jett, MD Grant/Research/Clinical Trial Support: Oncimmune [lung cancer biomarkers (early CDT lung blood test)]; Metabolomx [biomarker lung cancer (breath and urine test in development)]. Consultant/Advisory Boards: Quest Diagnostics [lung cancer biomarkers (blood test in development)]. Rogerio C Lilenbaum, MD, FACP Consultant/Advisory Boards: Genentech [Lung Cancer (Bevacizumab)]; Boehringer-Ingelheim [Lung Cancer (Afatinib)]. Michael E Ross, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — A group of patients with non-small cell lung cancer (NSCLC) have tumors that contain an inversion in chromosome 2 that juxtaposes the 5' end of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the 3' end of the anaplastic lymphoma kinase (ALK) gene, resulting in the novel fusion oncogene EML4-ALK [1]. This fusion oncogene rearrangement is transforming both in vitro and in vivo and defines a distinct clinicopathologic subset of NSCLC.
Tumors that contain the EML4-ALK fusion oncogene or its variants are associated with specific clinical features, including never or light smoking history, younger age, and adenocarcinoma with signet ring or acinar histology. ALK gene arrangements are largely mutually exclusive with epidermal growth factor receptor (EGFR) or KRAS mutations [2]. Screening for this fusion gene in NSCLC is important, as "ALK-positive" tumors (tumors harboring a rearranged ALK gene/fusion protein) are highly sensitive to therapy with ALK-targeted inhibitors.
The molecular pathogenesis, clinical features, and treatment of NSCLC associated with the ALK fusion oncogene are discussed here.
An overview of the treatment of metastatic NSCLC is presented separately, as are the indications for molecular testing. (See "Overview of the treatment of advanced non-small cell lung cancer" and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Molecular testing'.)
MOLECULAR PATHOGENESIS — The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion oncogene arises from an inversion on the short arm of chromosome 2 (Inv(2)(p21p23)) that joins exons 1-13 of EML4 to exons 20-29 of ALK [3]. The resulting chimeric protein, EML4-ALK, contains an N-terminus derived from EML4 and a C-terminus containing the entire intracellular tyrosine kinase domain of ALK.
Since the discovery of this fusion oncogene in 2007, multiple variants of EML4-ALK have been reported, all of which encode the same cytoplasmic portion of ALK but contain different truncations of EML4 (figure 1) [3-5]. In addition, fusions of ALK with other partners including TRK-fused gene TFG and KIF5B have also been described in lung cancer patients, but appear to be much less common than EML4-ALK [5,6].
For EML4-ALK, the EML4 fusion partner mediates ligand-independent dimerization and/or oligomerization of ALK, resulting in constitutive kinase activity. In cell culture systems, EML4-ALK possesses potent oncogenic activity [3]. In transgenic mouse models, lung-specific expression of EML4-ALK leads to the development of numerous lung adenocarcinomas [7].
The oncogenic role of the ALK fusion oncogene provides a potential avenue for therapeutic intervention. Cancer cell lines harboring the EML4-ALK translocation are effectively inhibited by small molecule inhibitors that target the ALK tyrosine kinase (TK) [8]. In vivo, treatment of EML4-ALK transgenic mice with ALK inhibitors results in tumor regression [7], supporting the notion that ALK-driven lung cancers are "addicted" to the fusion oncogene.
DIAGNOSIS — Anaplastic lymphoma kinase (ALK) gene rearrangements or the resulting fusion proteins may be detected in tumor specimens using fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and reverse transcription polymerase chain reaction of cDNA (RT-PCR) [9].
●FISH – The gold standard assay for diagnosing ALK-positive NSCLC is FISH [10-13]. The commercial break-apart probes include two differently colored (red and green) probes that flank the highly conserved translocation breakpoint within ALK. In non-rearranged cells, the overlying red and green probes result in a yellow (fused) signal; in the setting of an ALK rearrangement, these probes are separated, and splitting of the red and green signals is observed (picture 1A-B). Atypical patterns of rearrangement have also been identified, and these are also responsive to ALK inhibition. ALK gene amplification alone is not predictive of responsiveness to these agents and does not carry the same significance as rearrangement.
●IHC – Multiple monoclonal antibodies have been developed to use for the IHC detection of the ALK fusion oncogene, and IHC using these antibodies is highly sensitive and specific [14]. Thus, IHC can potentially be used to screen for and identify the presence of ALK positivity. In the United States, FISH is the only approved test to diagnose ALK-positive NSCLC, and thus FISH should be used to confirm the IHC results. In Europe, immunohistochemistry is widely used to detect ALK rearrangement.
●RT-PCR – RT-PCR of cDNA has been a commonly used screening strategy for detecting ALK gene rearrangements in NSCLC, but is no longer recommended [15]. A number of multiplex assays were developed to simultaneously capture all possible in-frame fusions between EML4 and ALK in which the kinase domain of ALK would be preserved [3,8,16]. While different breakpoints in EML4 or ALK may be detected, novel ALK fusion partners will not. Furthermore, this method is frequently limited by the quality of the RNA that can be isolated from archival tissue.
CLINICOPATHOLOGIC FEATURES — With increasing identification of this molecular abnormality, the key epidemiologic, demographic, and pathologic features associated with anaplastic lymphoma kinase (ALK) fusion oncogenes have been identified.
Epidemiology — In unselected NSCLC populations, the ALK rearrangement is a relatively rare event. In the initial report, 5 of 75 lung tumors (7 percent) demonstrated expression of the fusion transcript. The overall incidence of ALK gene rearrangements in subsequent series has been about 4 percent [3,8,11-13,16-18]. Except in rare cases, the presence of ALK gene rearrangements in NSCLC tumors tends to occur independent of epidermal growth factor receptor (EGFR) or KRAS mutations. Similar frequencies of ALK gene rearrangements have been reported in Asian and Western populations [19].
While the overall frequency of ALK fusion oncogene in the general NSCLC population is low, knowledge of the clinicopathologic features enables enrichment for this genetically defined subset. In one study in which patients were selected for genetic screening based on clinical features commonly associated with EGFR mutation, including never/light smoking status and adenocarcinoma histology, 13 percent harbored the ALK fusion oncogene. Within the group of never or light smokers in this study, the frequency of ALK positivity was 22 percent, and among never or light smokers who did not have an EGFR mutation, the frequency was 33 percent [12]. These findings suggest that in NSCLC patients with clinical characteristics associated with EGFR mutation but with negative EGFR testing, as many as one in three may harbor the ALK fusion oncogene. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'Rationale'.)
Age of onset — Patients with ALK fusion oncogene-positive lung cancer are relatively younger at onset than those without this abnormality [12,20]. The two studies that were used to support the approval of crizotinib included 255 patients whose tumors contained an ALK fusion oncogene; in this database, the median age was 52 years (range 21 to 82 years) [20]. The estimated median age for unselected patients with lung cancer is approximately 70 years [21].
Interestingly, other cancers known to harbor ALK rearrangements such as NPM-ALK positive anaplastic large cell lymphoma are also associated with younger age and are, in fact, most common in children and young adults.
Smoking history — The ALK fusion oncogene in patients with NSCLC is strongly associated with a history of never or light smoking (<10 packet years) [1,12,20]. In the crizotinib study database of 255 patients, never smokers and former smokers comprised 70 and 28 percent of cases, respectively [1,12,20].
Histology — The vast majority of lung tumors that harbor the ALK fusion oncogene are adenocarcinomas. In the 255 patients with the ALK fusion oncogene included in the crizotinib database, 97 percent were adenocarcinoma [20]. ALK rearrangement has been reported in squamous cell carcinoma, but this is rare [11,18].
Adenocarcinomas in ALK fusion oncogene positive cases from Caucasian patients are significantly more likely to have abundant signet ring cells than those with an EGFR mutation or wild type tumors [22]. Signet ring cells are frequently found in gastric cancers and rarely in cancers of other organs such as the lung. Several small case series suggest that signet ring cells may be associated with an aggressive clinical course and a poor prognosis. Whether the presence of signet ring cells in ALK fusion oncogene lung cancer has biological or clinical significance remains to be determined.
Other studies of ALK in NSCLC have not reported an association with signet ring cells, but have noted a possible association with the acinar subtype of adenocarcinoma, at least in Asian patients. This discrepancy may reflect differences in pathologic interpretation rather than ethnic differences in patients with ALK fusion oncogene-positive lung cancer.
CHEMOTHERAPY VERSUS TARGETED THERAPY — Advanced non-small cell lung cancer (NSCLC) associated with the anaplastic lymphoma kinase (ALK) fusion oncogene is highly sensitive to ALK tyrosine kinase (TK) inhibitors. Treatment with ALK TK inhibitors should be limited to patients whose tumors contain this abnormality as demonstrated by fluorescence in situ hybridization (FISH). (See 'Diagnosis' above and "Overview of the treatment of advanced non-small cell lung cancer", section on 'Initial systemic therapy'.)
An ALK inhibitor is preferred as the initial therapy for patients whose tumor contains this genetic abnormality in countries where it is approved for this indication. Preliminary results of a phase III trial comparing ALK inhibition using crizotinib with chemotherapy in treatment naïve patients have demonstrated a prolongation in progression-free survival, but not overall survival [23]. (See 'Crizotinib' below.)
In other countries, its use may be restricted to those who have progressed following chemotherapy. Thus patients should have tumor tissue assessed for the presence of ALK rearrangement, as well as for other driver mutations (especially in the epidermal growth factor receptor [EGFR]). (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Molecular testing'.)
If systemic treatment is required before the results of genotype testing are available, systemic chemotherapy rather than targeted therapy is indicated [24]. When the results of genotype testing become available, the treatment plan should be reassessed. There are no clinical trials that directly address the optimal timing of ALK inhibitors in patients who have already started on chemotherapy (algorithm 1).
If an ALK fusion oncogene is identified after the initiation of treatment, we suggest continuing chemotherapy for four cycles if therapy is tolerated and there is no evidence of disease progression. There are no data directly comparing continuation using maintenance chemotherapy versus a switch to crizotinib after completion of this initial chemotherapy. The authors' preference is to switch to crizotinib, rather than to use maintenance chemotherapy, because there are some patients who will deteriorate due to disease progression and thus miss the opportunity to be treated with an ALK inhibitor.
For patients who continue treatment with chemotherapy, crizotinib is indicated when there is evidence of disease progression. Factors that should be discussed with the patient in defining a treatment plan include the quality of the initial response to chemotherapy and the potential side effects of maintenance therapy.
ALK INHIBITORS: EFFICACY — Two tyrosine kinase (TK) inhibitors, crizotinib and ceritinib, have established roles in the treatment of anaplastic lymphoma kinase (ALK) fusion oncogene positive NSCLC, and additional agents are under development.
Crizotinib — Crizotinib is a multitargeted small molecule tyrosine kinase inhibitor, which was originally developed as an inhibitor of mesenchymal epithelial transition growth factor (c-MET); it is also a potent inhibitor of ALK phosphorylation and signal transduction [25]. This inhibition is associated with G1-S phase cell cycle arrest and induction of apoptosis in ALK-positive cells in vitro and in vivo [25]. Crizotinib also inhibits the related ROS1 receptor tyrosine kinase. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'ROS1 translocation'.)
Crizotinib induces rapid tumor regression and objective responses in the majority of patients whose tumors contain the ALK gene rearrangement [26].
The efficacy of crizotinib has been demonstrated in two randomized trials limited to patients whose tumors had the ALK rearrangement:
●Previously treated patients − A phase III trial randomly assigned 347 patients who had previously been treated with one prior platinum-based chemotherapy regimen to either crizotinib or single agent pemetrexed or docetaxel [26]. Patients who were assigned to chemotherapy were allowed to be treated with crizotinib when they developed progressive disease.
•At a median follow-up of 12 months, progression-free survival, the primary endpoint of the trial was significantly increased with crizotinib compared with chemotherapy (median 7.7 versus 3 months, hazard ratio [HR] for progression 0.49, 95% CI 0.37-0.64).
•The objective response rate based upon independent radiologic review was also significantly increased (65 versus 20 percent). Responses were achieved more rapidly than with chemotherapy (median time to response 6.3 versus 12.6 weeks) and were of longer duration (32 versus 24 weeks).
•There was no significant difference in overall survival (median 20.3 versus 22.8 months, HR for death 1.02). The absence of an overall survival benefit presumably reflects subsequent treatment since 64 percent of chemotherapy-treated patients had crossed over to crizotinib after progressing on chemotherapy.
●Chemotherapy naïve patients − In a second trial, 343 chemotherapy naïve patients were randomly assigned to crizotinib or chemotherapy with pemetrexed plus either cisplatin or carboplatin [23]. In a preliminary report presented at the 2014 American Society of Clinical Oncology (ASCO) meeting, progression-free survival, the primary endpoint of the trial, was significantly prolonged with crizotinib compared with chemotherapy (median 11 versus 7 months, HR 0.45, 95% CI 0.35-0.60). The objective response rate was also significantly increased (74 versus 45 percent). The difference in overall survival was not significantly different (HR 0.82, 95% CI 0.54-1.26). However, the majority of patients assigned to initial chemotherapy subsequently were treated with crizotinib.
Treatment with crizotinib is generally continued until there is evidence of disease progression. The standard approach for patients with progressive disease is the use of the second generation ALK inhibitor ceritinib. In carefully selected patients (eg, an isolated site of recurrence that can be treated with local therapy, those with extremely mild and asymptomatic progression), crizotinib may be continued after initial evidence of progressive disease [27]. (See 'Ceritinib' below.)
Surgery and/or radiation therapy are the primary treatment modalities for patients with brain metastases from NSCLC, including those with the EML4-ALK fusion oncogene [28,29]. There are only limited data on the activity of crizotinib on brain metastases in this setting. (See "Overview of the clinical manifestations, diagnosis, and management of patients with brain metastases", section on 'Overview of management' and "Systemic therapy for brain metastases", section on 'Targeted agents'.)
Isolated brain metastases (a central nervous system [CNS] relapse without evidence of extracranial progression) may be a particular problem for patients treated with crizotinib. In this setting, continuation of treatment with crizotinib after treatment of the CNS relapse with surgery and/or radiation therapy may be associated with a significant period of control of extracranial disease [30].
Resistance to crizotinib — While crizotinib is highly active in patients with ALK-positive NSCLC, almost all patients develop resistance to the drug, typically within the first few years of treatment. Several distinct mechanisms of resistance have been reported in the literature.
●In approximately one-third of resistant cases, tumors have acquired a secondary mutation within the ALK tyrosine kinase domain. The most common resistance mutation is the gatekeeper L1196M mutation, followed closely by the G1269A mutation. Other mutations occur at residues 1151, 1152, 1156, 1174, 1202, 1203, and 1206. The G1202R mutation is notable, as it confers high level resistance to crizotinib as well as to next generation ALK inhibitors (see below).
●A second mechanism of crizotinib resistance is amplification of the ALK fusion gene. This can occur alone or in combination with a secondary resistance mutation.
●Finally, a number of alternative or bypass signaling pathways have been shown to mediate crizotinib resistance. These include abnormalities in the epidermal growth factor receptor (EGFR), KIT, and insulin-like growth factor-1 receptor (IGF1R) pathways, and suggest the potential need for combination therapies to overcome resistance.
Ceritinib — Ceritinib is a second generation TK inhibitor of ALK that is approximately 20 times more potent than crizotinib. Ceritinib is indicated for patients who are resistant to or unable to tolerate crizotinib. Preclinical studies suggested that ceritinib had significant activity against cells that were either sensitive or resistant to crizotinib, including resistant tumors with the most common L1196M and G1269A resistance mutations.
After the maximum tolerated dose was established in the phase I study [31], ceritinib was studied in a dose expansion cohort of NSCLC patients with the ALK rearrangement [31,32]. Results from that expansion cohort were updated at the 2014 ASCO meeting [32]:
●A total of 246 patients with ALK positive NSCLC were treated with ceritinib. Of these patients, 163 had previously been treated with an ALK inhibitor and 83 were ALK inhibitor naïve.
●The objective response rate was 58 percent overall, 55 percent in those with prior crizotinib treatment, and 66 percent in ALK inhibitor naïve patients. The median duration of response was 10 months in the entire cohort, and 7.4 months in those with prior crizotinib treatment. The median progression-free survival for the entire cohort was 8.2 months, including 6.9 months for those previously treated with an ALK inhibitor and not estimable (lower bound of 95% CI 8.3 months) for those who had not previously received an ALK inhibitor.
Ceritinib was approved by the US Food and Drug Administration for patients who have progressed on or are intolerant of crizotinib [33].
Two phase III trials are currently recruiting patients with ALK-positive NSCLC, one in which ceritinib is being compared with single-agent chemotherapy after progression on a platinum-based doublet and on crizotinib (NCT01828112), and the other as first line treatment compared with a platinum-based doublet (NCT01828099).
Other second generation ALK inhibitors — Alectinib is another second generation ALK inhibitor that is under development.
●In a multicenter, phase I/II study, 46 patients with ALK-positive NSCLC were treated with alectinib (CH5424802) at the phase II dose level (300 mg twice daily); none had received prior treatment with an ALK inhibitor [34]. An objective response was observed in 43 cases (93 percent), including two complete and 41 partial responses; 40 of the 43 responses were ongoing at data cutoff. Treatment was well tolerated.
●In a second study, 47 patients were treated in a phase I/II study. All patients had progressed on or were intolerant of crizotinib [35]. Objective responses (including both confirmed and unconfirmed responses) were observed in 24 of 44 evaluable patients (55 percent) and 16 of 44 (36 percent) had stable disease. Eleven of 21 patients with brain metastases had an objective response (52 percent).
ALK INHIBITORS: TOXICITY — Treatment with the anaplastic lymphoma kinase (ALK) inhibitors crizotinib and ceritinib is generally well tolerated. However, there are a number of significant toxicities that may require dose modification or treatment discontinuation.
Gastrointestinal side effects — Nausea, vomiting, and diarrhea are common with both crizotinib and ceritinib, but are more severe with ceritinib. With crizotinib, less than 1 percent of these side effects were severe. However, more than one-half of patients treated with ceritinib required dose modification, and 9 percent required treatment discontinuation. (See "Enterotoxicity of chemotherapeutic agents", section on 'ALK inhibitors'.)
Hepatotoxicity — Liver function test abnormalities are occasionally seen with crizotinib and are commonly seen with ceritinib. Hepatoxicity can progress and may require dose modification or discontinuation. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease", section on 'Crizotinib and ceritinib'.)
Pneumonitis — Severe, life-threatening, or fatal treatment-related pneumonitis has been reported in 1 to 4 percent of patients treated with either crizotinib or ceritinib. The development of pneumonitis should result in discontinuation of treatment with these agents. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Crizotinib and ceritinib'.)
Other toxicities that have been observed with crizotinib include the following:
Cardiac toxicity — Cardiac toxicity is relatively frequent with both crizotinib and ceritinib:
●Sinus bradycardia is relatively frequent in patients treated with crizotinib and may be severe in some cases [36,37]. However, patients with sinus bradycardia were asymptomatic, and the bradycardia was not explained by other comorbidity or medications. Caution should be used in the concomitant administration of beta blockers in patients treated with crizotinib. (See "Cardiotoxicity of nonanthracycline cancer chemotherapy agents", section on 'Crizotinib and ceritinib'.)
●QTc interval prolongation has been observed with crizotinib, and crizotinib should be avoided in patients with congenital long QT syndrome. Treatment should be temporarily discontinued if severe QTc prolongation develops and permanently discontinued if it recurs or is accompanied by an arrhythmia, heart failure, hypotension, shock, syncope, or torsade de pointes.
Our approach is to perform an EKG at baseline in all patients treated with either crizotinib or ceritinib. Subsequently, we check an EKG if the patient develops bradycardia (whether symptomatic or not) or if the patient is started on a drug that is known to cause QTc prolongation. (See "Cardiotoxicity of nonanthracycline cancer chemotherapy agents", section on 'Crizotinib and ceritinib'.)
Cytochrome p450 interactions — Both crizotinib and ceritinib are metabolized by cytochrome P450 CYP3A4. Thus, caution should be used when it is given concomitantly with CYP3A4 inhibitors, and care is required when these agents are coadministered with other agents that are predominantly metabolized by this system (table 1).
Visual disturbances — Visual disturbances were seen in 60 to 65 percent of patients treated with crizotinib in the phase II studies [20]. These were primarily associated with the transition from dark to light. Uncommon visual manifestations included photophobia, decreased visual acuity, and blurred vision. Similar symptoms have been reported with ceritinib, but their overall incidence is less that 10 percent.
Detailed ophthalmological assessment in over 200 patients from phase II experience with crizotinib did not demonstrate any objective abnormalities associated with visual symptoms [38]. However, optic neuropathy and blindness has been reported in one case, although that may have been related to prior whole brain radiation therapy [39].
Endocrine — Endocrine complications have been reported with both crizotinib and ceritinib.
●With crizotinib, rapid depression of serum testosterone levels has been observed [40,41]. In a series of 32 patients treated with crizotinib, the mean serum testosterone level was below the lower limit of normal in 27 of 32 men (84 percent) compared with 6 of 19 (32 percent) among those not receiving crizotinib [41]. Levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were also low, suggesting a centrally mediated mechanism. A large component of the lowered total testosterone may be due to significant depression of sex hormone binding globulin. Male patients who report symptoms of hypogonadism can be referred to endocrinology to discuss potential testosterone replacement. These findings require validation in larger cohorts. (See "Clinical features and diagnosis of male hypogonadism".)
Renal cysts — Renal cysts have been reported in 4 percent of patients treated with crizotinib [20]. These cysts may be complex, and the natural history of crizotinib-associated renal cysts is not known. The cysts may be positive on PET and can create confusion with renal metastases [42]. (See "Simple and complex renal cysts in adults".)
Chemotherapy — Cytotoxic chemotherapy appears to have a similar level of activity in anaplastic lymphoma kinase (ALK)-positive patients with NSCLC compared with those with ALK-negative disease. The choice of a specific chemotherapy agent or regimen is based upon the same criteria applied in other cases of advanced NSCLC. When patients with ALK-positive advanced NSCLC require chemotherapy, pemetrexed or a pemetrexed-based regimen is generally preferred, since almost all of these patients have adenocarcinoma histology. (See "Advanced non-small cell lung cancer: Subsequent therapies for previously treated patients", section on 'Single agent chemotherapy' and "Systemic therapy for the initial management of advanced non-small cell lung cancer without a driver mutation", section on 'Effect of histology'.)
EGFR tyrosine kinase inhibitors — Patients with the ALK fusion oncogene do not appear to respond to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In a retrospective cohort of 19 patients with the ALK fusion oncogene, there were no clinical responses to EGFR TKIs, and the median time to progression was only five months [12].
●The presence of an anaplastic lymphoma kinase (ALK) fusion oncogene defines a molecular subset of non-small cell lung cancer (NSCLC) with distinct clinical and pathologic features. The patients most likely to harbor ALK rearrangement are relatively young, never or light smokers with adenocarcinoma. (See 'Molecular pathogenesis' above and 'Clinicopathologic features' above.)
●Whenever possible, therapy of patients with advanced NSCLC should be individualized based upon the molecular and histologic features of the tumor. If feasible prior to treatment, patients should have tumor tissue assessed for the presence of the ALK fusion oncogene, which is associated with sensitivity to ALK tyrosine kinase inhibitors, as well as other driver mutations such as those seen in the epidermal growth factor receptor (EGFR). (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer" and 'Chemotherapy versus targeted therapy' above.)
●For patients with advanced or metastatic NSCLC whose tumors contain a characteristic ALK fusion oncogene, we recommend initial treatment with the ALK inhibitor crizotinib rather than chemotherapy (Grade 1B). There currently are insufficient data supporting the use of ceritinib as the initial ALK inhibitor. (See 'Crizotinib' above.)
•Therapy with crizotinib should be continued until there is evidence of progressive disease. In carefully selected patients with an isolated site of recurrence that can be treated with local therapy or those with extremely mild and asymptomatic progression, crizotinib may be continued after initial evidence of progressive disease. (See 'Crizotinib' above.)
•Crizotinib should not be used in patients without ALK rearrangement. In the United States, ALK-positivity must be demonstrated by fluorescence in situ hybridization (FISH) using the US Food and Drug Administration (FDA)-approved test (Vysis Probes) in accordance with the FDA label. In Europe, immunohistochemistry is widely used to detect ALK rearrangement. (See 'Crizotinib' above.)
•Crizotinib is indicated as second-line therapy when progressive disease occurs for patients whose tumor contains the ALK fusion oncogene and initially were treated with chemotherapy. (See 'Crizotinib' above.)
●For ALK-positive patients who develop resistance to crizotinib or who are unable to tolerate crizotinib, we recommend treatment with the second generation ALK inhibitor ceritinib (Grade 1B). (See 'Ceritinib' above.)
●Chemotherapy is an appropriate option for patients who no longer respond to ALK inhibition. (See "Systemic therapy for the initial management of advanced non-small cell lung cancer without a driver mutation" and "Advanced non-small cell lung cancer: Subsequent therapies for previously treated patients".)
●In some cases, chemotherapy is required before the results of molecular testing are available. If the tumor is found to contain the ALK fusion oncogene and patients have an ongoing objective response or stable disease after completing their initial doublet chemotherapy, the authors prefer to switch to crizotinib, although both crizotinib and single-agent maintenance chemotherapy are options. Factors that should be discussed with the patient in defining a treatment plan include the quality of the initial response to chemotherapy and the potential side effects of maintenance therapy. (See "Systemic therapy for the initial management of advanced non-small cell lung cancer without a driver mutation", section on 'Molecular characterization of tumor'.)
All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.


text:
Game Questions & Answers (Q&A) service lets you ask questions about video games for game consoles or PC games. So ask your Disney's Extreme Skate Adventure question for Gamecube and get answers from real gamers or answer questions and share your insights and experience with the rest of the gaming community.
- Developer: Toys for Bob
- Publisher: Activision
- Genre: Sports Alternative Skateboarding
- Release Date: Sep 4, 2003
- ESRB: Everyone
Question & Answers
Light house olliwood
Ok im stuck and frustrated at the goal for the lighthouse how do i beat it? i can only do 1 time and then i end up accidently going on the radio disney telephone pole
Answer from: Tiiiiaaa
When you grind around the lighthouse in olliwood you have to move the controller stick right or left, or press the right and left side buttons, depending on which way the bar is slanting to, to stop the bar from going off one end. this way you are controlling it so you don't fall off.
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text:
Heat the oil in a Dutch oven or 4-quart saucepan over medium-high heat.
Add the beef and cook, stirring occasionally, until lightly browned, about 5 minutes.
Add the onions and garlic; cook until the onions are softened, about 5 minutes.
Stir in the tomatoes, tomato paste, beer, jalapeno and 1 teaspoon of cumin; bring to a simmer.
Reduce the heat and simmer, covered, about 45 minutes.
Stir in the squash, carrots, salt, and remaining 1/2 teaspoon cumin.
Cover and cook until the meat and vegetables are very tender, about 30-45 minutes long.