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Population or Species Level
Heritible Change
Geology - age of earth - uniformitarianism
Economics - limited resource theories
Beagle - exposed to variation
Artificial Selection - exposed to the possibilty of selection
North vs. South
Due to descent
Vestigal Structures
Homologies across multiple genes
1. Ortholog vs Paralog
2. Exon Shuffling
3. Horizontal Gene Transfer
Ortholog Genes
Duplicated Gene that diverges in different species
ortho = straight; straightdown the evolutionary tree
Globin variations
para = beside; my species on the evolutionary tree
via double crossover
transposable elements
likely to produce a protein with an additional domain
Change in chromasome structure or number
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A federal government website managed by the U.S. Department of Health & Human Services
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All Resources
|Eyes on Bullying
|Tips & Facts
|Kim Storey, Ed.D. and Ron Slaby, Ph.D.
This is a bullying prevention website that provides adults who care for youth with engaging, user-friendly, and research-based tools to learn about and deal effectively with the problem of bullying.
Topics: Prevention, Respond to Bullying
For more info please visit http://www.eyesonbullying.org
|Eyes on Bullying Toolkit
|Toolkit & Training
|Kim Storey, Ed.D. and Ron Slaby, Ph.D.
This toolkit is a 43-page, downloadable booklet containing key information, useful resources, and six skills-building activities for adults to use interactively with children of any age.
Topics: Prevention, Respond to Bullying, Schools
For more info please visit http://www.eyesonbullying.org/pdfs/toolkit.pdf
|Oregon YouthLine
|Tips & Facts
|Lines for Life
Lines for Life's YouthLine is a free and confidential peer-to-peer crisis and referral line for youth and their families dealing with a variety of issues such as bullying, anxiety, self harm, suicide, relationship issues and substance use. It is staffed from 4:00-9:00 PM Pacific Time, Monday through Thursday by youth volunteers between the ages of 15-18, who are supervised at all times by an adult. Teens can reach out to the YouthLine by texting teen2teen to 839863, calling our 24/7 phone line at 877-968-8491 or visiting our website to access instant messaging or send in a question over email. Our committed volunteers come from a number of different high schools across the greater Portland, OR area, and go through 30 hours of crisis line training. They develop peer helping skills, learn about substance abuse and available treatment and develop a better understanding of a broad range of youth specific issues. YouthLine is a wonderful resource for adolescents who are in need of help, as well as those that just need a peer to listen to them. No problem is too big or too small to reach out to the YouthLine for support!
Topics: Prevention, Respond to Bullying, Kids, Youth Development, Healthy Relationships, Gender, Teen Dating Violence
For more info please visit http://oregonyouthline.org/
|Effects of bullying on children with special needs
|Lopez-Duran, N
This short article provides an overview of results from a study of the resiliency of students with disabilities who have been bullied.
Topics: Disabilities & Special Needs
For more info please visit http://www.child-psych.org/2009/05/effects-of-bullying-ichildren-with-special-needs.html
|A Thin Line
MTV's A Thin Line campaign was developed to empower youth to identify, respond to, and stop the spread of digital abuse. The campaign is built on the understanding that there's a "thin line" between what may begin as a harmless joke and something that could end up having a serious impact on youth.
Topics: Kids, Respond to Bullying, Cyberbullying
For more info please visit http://www.athinline.org/
|Truth Is (Official Music Video)
|Tips & Facts
|Marcella Fruehan
This is a song that my 16 year old daughter wrote to take a stand against bullying. She produced this video and is sharing it with schools and youth organizations to help connect with her peers, to encourage them that they are all special and loved and that bullying is wrong. Please feel free to share it!
Topics: Prevention, Respond to Bullying, Kids, Youth Development, Healthy Relationships
For more info please visit http://www.youtube.com/watch?v=jJSBWVT8aik
|They're Wrong you're Right
|Marla Adler
A video and song to empower kids , sung by a fifteen year old New Jersy girl who has been through this. They're Wrong I'm Right I don't need to Fight To prove who I am I'm just right , Just right When it comes to haters I tell em see you later To the Drama Queens and fakers They're Wrong I'm Right,, I don't need to Fight I'LL BE ALRIGHT
Topics: Respond to Bullying, Kids
For more info please visit http://www.youtube.com/watch?v=NsIE_uWKJjU
|The Middle Ages: An After School Comedy Series for Middle Schoolers, about Middle Schoolers, by Middle Schoolers
|Tips & Facts
|Matinee Scholars
An after school situation comedy, written, acted, and in some cases filmed by middle school students, YMCA attendees, or Boys/Girls clubs. The episodes created address bullying within the context of storytelling, and allow students to vent their feelings through fictional cast of a sit-com.
Topics: Prevention, Kids
For more info please visit http://www.matineescholars.com
|Matthew Shepard Foundation
|Matthew Shepard Foundation
The Matthew Shepard Foundation encourages respect for human dignity and difference by raising awareness, opening dialogues, and promoting positive change.
Topics: LGBT
For more info please visit http://www.matthewshepard.org/our-story
|Bullying Prevention Toolkit: Lesson Plans for Social-Emotional Learning
|Tips & Facts
|Michelle Manno, USC Rossier School of Education
USC Rossier School of Education has created a lesson plan guide to act as a mental health resource for teachers and classrooms, as well as students in our online teaching degree programs. "Creating Safe Spaces" offers activities that strengthen students' social-emotional skills, while focusing on social-emotional wellness as a tool for combating bullying in and outside of the classroom.
Topics: Prevention, Respond to Bullying, Schools, Youth Development
For more info please visit http://rossieronline.usc.edu/bullying-prevention-lesson-plans/

subset: commoncrawl


text:
February 24, 2017
Lower ARM rates can help you qualify for a bigger mortgage and a better house. ARMs can be fixed for up to ten years, so there is probably an ARM that minimizes your risk and saves you money.
February 24, 2017
New construction homes are selling fast. But inventory is up, and builders plan to build even more in 2017. Could negotiation power shift to buyers?
February 24, 2017
Are you FHA Streamline Refinance eligible? Use this easy-to-follow format. Updated for newest changes to FHA MIP. Today's FHA rate quotes available.
February 24, 2017
Current mortgage rates and mortgage market movement. Today's mortgage rates and mortgage news. Live rate quotes available. News and data provided by MBSQuoteline, a real-time mortgage market data service available to loan officers, real estate agents, and other finance professionals.
February 23, 2017
Home values are up another 6 percent since last year, spurred by low mortgage rates and high buyer demand. Is it time to enter the market?
February 23, 2017
Current mortgage rates are floating sideways to lower in 2017 thus far. How low will they go this year?
February 23, 2017
At a mortgage closing, you typically pay mortgage costs and escrow
February 23, 2017
Mortgage rates are keeping homes affordable, but competition is fierce. Will raising rates cool the market and make home buying easier in 2017?
February 22, 2017
Rates are low, home prices are up, and lenders are loosening cash out refinance rental property guidelines. How to cash out a rental, putting the equity to work.
February 22, 2017
Home supply is tight, but persistent buyers pushed existing home sales to a 10-year best in January. Is it time to start your home search?
February 22, 2017
The convertible HELOC combines the flexibility of a HELOC with the stability of a fixed interest rate.
February 22, 2017
Home values are rising, and buyers have decided homes are a good investment. Home purchases have dominated the market 2 straight years.
February 21, 2017
About the bi-weekly mortgage payment program, and whether it's an effective way to own your home faster. Analysis, plus today's live mortgage rates.
February 21, 2017
It pays to be a veteran. Using VA Benefits and the G.I. Bill, military borrowers get access to lower rates than the general U.S. population.
February 21, 2017
If you want to find a mortgage lender with the best deal and service, you'll need to shop a bit and obtain several mortgage quotes. Compare various combinations of interest rate and costs until you find the one that's right for you.
February 21, 2017
How soon can you buy a home after a short sale? That depends on the circumstances of the sale and the mortgage program you choose.
February 21, 2017
HOA dues are an expense that can sink many loan applications and derail personal finances. This is especially true for first-time buyers and those with marginal finances.
February 20, 2017
Think you can't be approved for a mortgage? Neither did these 3 home buyers. Read their true stories.
February 20, 2017
Single women have a lot of home-buying power. Here's how to exercise yours and get what you want.
February 20, 2017
For the right person, the HECM reverse mortgage is an outstanding product. But it's not for everyone. Learn about the program, and alternatives.
Most Popular Posts
October 8, 2015U.S. homeowners are eligible for tax credits and tax deductions from the IRS. Maximize your tax return claims. Complimentary mortgage rate quotes available. Updated for 2015.
January 28, 2017Credit score requirements are dropping for the FHA mortgage. Analysis and effect on U.S. home buyers, plus today's live FHA mortgage rates.
January 19, 2016About the Fannie Mae HomePath Mortgage program plus details for getting approved. Read more about HomePath. Get today's live mortgage rates.
March 11, 2016The waiting period before you can make a mortgage application after a "significant derogatory event" has been cut by half. Get more on Fannie Mae's update.
March 11, 2016The waiting period before you can make a mortgage application after a "significant derogatory event" has been cut by half. Get more on Fannie Mae's update.
February 1, 2016Experts said mortgage rates would over 4.5% by now. They're not. They're in the 3s. What will happen in February, though? Is now the time to lock?
October 17, 2016Step-by-step instructions for accepting a cash downpayment gift on a home, including a ready-to-use gift letter template.
January 26, 2015For the first time in more than a decade, the FHA has lowered its mortgage insurance premiums (MIP). Complete analysis and review, plus a complimentary FHA rate quote.
November 9, 2015You'll need a good FICO to access today's best mortgage rates. How to shop for a loan and get your credit pulled without lowering your overall credit score.
April 8, 2015Fannie Mae's Conventional 97 mortgage program is official. Just 3% down and ultra-low mortgage insurance rates. Easy-to-follow guidelines.
September 9, 2016Another low-downpayment option is available to today's home buyers. The 97% LTV program can be used to refinance, too. Q&A plus access to live rate quotes.
February 21, 2017About the bi-weekly mortgage payment program, and whether it's an effective way to own your home faster. Analysis, plus today's live mortgage rates.
August 23, 2016Learn how to calculate your loan-to-value (LTV) and see what mortgage programs may be available to you. Mortgage rates available, too.
January 2, 2017Defining "residual income" for VA borrowers, and listing requirements by state and by size of your family. Analysis, plus live VA rate quotes which are typically 25 basis points (0.25%) or more below comparable conventional rates.
May 26, 2016It's easier than ever to get a mortgage loan approved, but certain behaviors can ruin your loan-in-process. A detailed list, plus access to today's rates.
July 31, 2016Mortgage borrowers make the same common mistakes which increase their mortgage closing costs. How to make better choices for your purchase or refinance home loan.
January 17, 2017About the USDA Rural Housing Program (Section 502), including household income limits for 2017. Lookup table by county, plus mortgage rates.
September 7, 2016Details on mortgage discount points. How they work and what they cost. Compare today's discount points and get today's live mortgage rates.
July 20, 2016You don't need to make a 20% downpayment to purchase a home. Review popular low- and no-downpayment mortgage programs and get a complimentary mortgage rate quote.
September 26, 2016A step-by-step, non-biased walkthrough of today's home buying process. Read more, plus get access to today's live mortgage rates which are currently near their lowest of all-time.
March 5, 2014You don't need a 20% downpayment to buy a home. Mortgage guidelines are loosening and mortgage rates are low. Read more and get today's rates.


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Yay! My mad linguistic skills are still intact despite falling into disuse. I learned Amy Farah Fowler's secret language on the second watching of The Pulled Groin Extrapolation. Wasn't even trying to; almost passively understood it.
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Third Grade Activities
Help your third grader enjoy activities learning critical skills by following step-by-step instructions and using easy-to-find materials. Play math card games and explore themes third graders can get excited about. These activities are great for parents and educators to teach multiplication, collaborative writing, and third grade science topics. Try third grade arts and crafts next.
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Third Grade
Play the Bag Game: Learn Parts of Speech
Parts of speech can be a difficult and dreary concept for many kids, but you can quickly turn that feeling around with this fun game.
Candy Corn Science
Young scientists develop a hypothesis, conduct an experiment, and then revise their hypothesis to find out which common household liquids dissolve candy corn.
Number Maker: A Card Game to Practice Place Value
Here's a super fun game to get in some place value practice with your child!
Make Your Own Cloud!
Clouds are formed when warm and cold air meet. Here's a way for kids to see it all up close!
The Science of Sound
What causes sound? Here's a simple science experiment that adds a visual element to the science of sound to help kids better understand this tricky concept.
Find the Math Fact Family
Practice of math facts is usually limited to drill sheets and flashcards. But kids are more likely to tune in to math facts if practice is presented as a game!
Multiplication Tables Game
Practice multiplication facts and geography at the same time in this fun third grade math card game.
Build Vocabulary with Prefixes and Suffixes
Here's a fun game that you can play at home to get your child thinking about prefixes and suffixes.
Play Sentence Scramble
This hands-on family activity gives your child practice creating compound sentences, while teaching him skills that will help him become a better writer!
Frogs In Winter
Help your child create a tasty treat that will demonstrate exactly how frogs survive a freezing season.
Real World Math
You can try this simple activity with your third grader to get him thinking about the real world math you use everyday.
Balloon Air Pressure Magic
Get your sense of humor ready for this fun science experiment that demonstrates the fundamental physics of air pressure.
Play Triangle Flash!: A Math Game
This is a great game to help your child learn number concepts in multiplication and division.
Coin Riddles: What's in Your Wallet?
Here's a math activity that uses coin riddles to help your third-grader improve his coin-counting and logical thinking skills.
Tour the Planets
This interdisciplinary card game will have your third grader working on math facts as he travels through the solar system!
Defensive Multiplication
Defend your cards in this multiplication math game! Your kid will enjoy using strategy to build equations and win points in this activity.
Fun With Reading
This game turns prediction, a major component of third grade reading, into a fun game.
Vinegar and Baking Soda Balloon
Set your young chemist up for an afternoon of science-fueled magic with a deceptively simple activity starring baking soda and vinegar!
Tic-Tac-Toe Multiplication
Play tic-tac-toe and help your kid memorize multiplication facts!
Native American Pictographs
An ancient form of writing gets new life in an activity designed to help your child read understand what life was like for early Native Americans.
A Rapid Rounding Game
This kinesthetic game will help your child practice rounding and get the adrenaline rushing!
Make Your Own Marshmallows
Make your own marshmallows and mix up some very interesting third grade chemistry lessons while you're at it!
Sticky Note Project
Representing the story in a visual way makes it easier for your child to compare the traits of various characters.


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How to Help Someone Who Is Having a Seizure
When someone is having is seizure, they will often experience involuntary movement, changes in behavior, and awareness for lasting a couple minutes to an hour. If you've never witnessed a seizure, you might be shocked, confused, scared, worried, or all of the above. The most important thing, however, is for you to remain calm.
1Know the circumstances under which you should call for emergency medical services. If you are concerned for the person's safety and feel unable to help the person, you should call for emergency medical attention, but in many cases, a person having a seizure will not need emergency assistance. Often, a person will have medication with them. Ask when you can. This is helpful and can be useful to them right away. Get emergency assistance if:
- The person doesn't have a MedicAlert necklace or bracelet that says "epilepsy" or "seizure".
- The seizure occurred in water.
- A seizure occurs after the person complains of a sudden, severe headache or if it follows a head injury[1]
- A seizure occurs after inhaling fumes or poison[2]
- A seizure occurs with other signs of stroke, such as trouble speaking or understanding speech, loss of vision, and inability to move part or all of one side of the body.[3]
- They are pregnant, hurt, or have a necklace or bracelet that says "diabetic". [4]
- The seizure lasts more than 3 minutes[5]
- A second seizure starts shortly after the first one stops, or if the person has already had a seizure in the past 24 hours.[6]
- The person stops breathing for more than 30 seconds [7]
- An hour after the seizure stops, the person does not respond normally or suffers from reduced awareness, drowsiness, confusion, nausea or vomiting, fever, or an inability to walk/stand.[8]
2Become familiar with different kinds of seizures. The key to recognizing if a person is having a seizure, and knowing what to do, is to be prepared.[9]
- Partial seizures affect only part of the brain.
- Simple partial seizures (SPS). The person is awake and aware of what's happening; there could be twitching of one limb, unusual smell or taste, a strange feeling (like "pins and needles") or a sudden intense feeling of fear or joy. The person will usually need gentle reassurance.[10]
- Complex partial seizures (CPS). Consciousness is affected, and the person might wander around, behave strangely, and seem confused. It can last from a few seconds to a few minutes. Don't restrain them, gently guide them away from any dangerous situations (like a busy road), and speak quietly and calmly until they are reoriented. [11]
- Primary generalized seizures are seizures that occur due to a broad electrical discharge in the brain that involves both sides simultaneously [12]
- Absence or petit mal seizures. The person may look blank and cease to respond to what's going on around them. Stay with them and guide them away from dangerous situations. [13]
- Tonic and Atonic seizures. In a tonic seizure, the person's muscles suddenly get stiff and if they're standing, they might fall backwards. [14] In an atonic seizure, the person's muscles will suddenly relax and they get "floppy" -- they'll often fall forward instead of backwards. Both seizures are brief and sudden, and the person tends to recover quickly. [15]
- Myoclonic seizures are when a person's limb (or part of their limb) starts jerking. These seizures are brief, and they often happen shortly after waking up. They can happen in clusters. [16]
- Tonic clonic (convulsive) or grand mal seizures. The person falls to the ground and makes shaking or jerking movements. Their breathing is affected, they may go blue, and they may bite their tongue. Emergency services should be called as a long grand mal seizure may be life threatening, and may be the first symptom of a severe neurological disorder if the patient does not have epilepsy.[17]
- Partial seizures affect only part of the brain.
3Ease the person to the floor so they don't fall. If possible, roll the person onto their side, so that if they vomit, they don't choke on or inhale it.[18] (It is best to roll them onto their left side, however, do not become flustered if you forget this; either side is better than leaving them on their back.)
- Whatever you do, don't ever restrain a person having a seizure, even if they are moving violently. Instead, move any objects that could injure them away from them.[19]
4Make sure the person is breathing. If their breathing is difficult, check that nothing is blocking their airway, like food.[9] Otherwise, do not insert anything into the person's mouth.
- Although some sources recommend putting a handkerchief or any rolled up fabric between the teeth so that the person doesn't bite his or her tongue, the prevailing advice is that you may do more harm than good by trying to put something (even water, pills, or food) in their mouth.
- You should never place any items into a person's mouth while they are having a seizure since an object may block their airway if dislodged, becoming life-threatening.
5Help prevent them from hurting themselves.
- In grand mal seizures, the person can hit their head against the floor repeatedly. If their head is striking the floor, or some object that you cannot move, you may cushion their head gently with a pillow, cushion, jacket, or any soft object, but do not restrain their head or any other part of their body.[20]
- Loosen any constrictive clothing unless they're jerking too much (ties, belts, shirt collars). If the person is wearing a necklace, unhook it if you can.
- A cold wet cloth on the forehead may help. If the person is wearing a hair clip, remove it.
- Move furniture and other obstacles out of the way -- anything that they might bump into, or that might fall onto them. Keep an eye out for sharp cornered items, or things that will shatter into sharp edges when broken.
6Check for any kind of ID card or medical jewelry. There might be some information on it that will help you help them.
7Monitor the person's condition until they regain consciousness.
- It will be nice for the victim to get privacy -- urge people to move on and stop staring; close the door. This is for the safety of the onlookers, as well as to keep the person having the seizure from feeling embarrassed, vulnerable, or confused.
- The person might have wet themselves; if so, try to hide this to spare any embarrassment.
8Put the person in the recovery position. Presuming they're on their back and you're at their side:[9]
- Put the arm that's closest to you at a right angle to their body, with the palm facing upwards.
- Lift the other arm across their body and put the back of their hand against their cheek; hold it there.
- Lift the knee that's furthest from you so that their leg is bent and their foot is flat on the floor.
- Pull the bent knee towards you, and the person's body should roll onto their side, keeping your hand against their cheek. The knee should remain bent so that the leg is at a right angle to their body.
9Write down any details as soon as you get the chance. This can be extremely valuable to the person who had the seizure, as well as to their doctor.[9]
- Part of the body the seizure started in
- Parts of the body affected
- Warning signs before the seizure
- Length of the seizure
- What was the person was doing before and after the seizure?
- Did their mood change?
- Were there any triggers, like tiredness, hunger, or feeling queasy?
- Were there any unusual sensations they spoke of?
- What made you notice that they were having a seizure -- a noise? Did they fall? Did their eyes roll? If they fell, did they fall forward, backward, or in some other way?
- Did the person appear "blank" before or during the seizure?
- Did they do anything unusual, like mumble or fiddle with their clothing?
- Did their appearance change, like the color of their face, lips, hands?
- Did their breathing change in any way?
- If at school call parents immediately after it happens.
10When they come to, stay with them for at least 20 minutes. Reassure them that they are safe. Take the person to a doctor or emergency room if they sustained any injuries during the seizure.
Community Q&A
Should I put something cold on the person's face?wikiHow ContributorI don't think putting something on their face will make them feel any better. The best thing would be to call for medical help right away.
What should I do if someone is standing up and they have a seizure?wikiHow ContributorGently guide them to the floor and be sure to move any furniture that might be in the way. Once you have done that, call 911 immediately and stay with the person until emergency personnel arrive.
If the person having a seizure is sitting in an armchair, should I move him to the floor?wikiHow ContributorIt depends on the type of seizure he is having. If it is small, and the person is shaking, but still conscious, then there may be no need to move him/her. Just make sure that the area around him/her is soft in case he falls. Also, it helps to talk to the person - even if they cannot respond.
How do I help someone who had a seizure after hitting her head?wikiHow ContributorSeizure after head trauma often indicates brain damage. The condition may be severe. The safest option is to place her on her side and call for emergence medical service.
Should you hold their head if they are hitting it against the ground?wikiHow ContributorNo, holding the head could cause damage to the head and neck. Instead, use a soft pillow or some other type of padding behind the head.
If someone is sleeping and you know they're about to have one, should you try to wake them up?Gently shake them. If they don't wake up or respond, let them be, don't force them to wake up. Stay with them, if they start having trouble breathing, clear their airway, remove tight clothing, and call an ambulance.
I have a friend who had 6 grand mal seizures on the way to the hospital and spent 6 days hospitalized. After not remembering 3 days, she came back home and seemed fine for a few days, but now all she does is sleep and has problems moving and talking. How long will it take her to make a full recovery?wikiHow ContributorIt's hard to say, as recovery times are different for each individual. However, I can share with you my own experience, as I have had epilepsy almost all of my life. A grand mal takes everything out of me. I am extremely weak for days, a bit confused and disoriented, and very tired. It usually takes me 4 days to fully recover from one grand mal. Give her as much time as she needs. Six grand mal seizures are nothing to play around with. The most I've had in one day was three. Unfortunately, some people may never recover.
If someone is having a seizure in a pool, what should I do?wikiHow ContributorA seizure in water is a life-threatening situation. If someone is having a seizure in any sort of water, get in the water and support the person with the head tilted so the face and head stay above the surface. Remove the person from the water as soon as the active movements of the seizure have ceased.
Should an ambulance be called for average seizures that last 10 to 13 minutes?wikiHow ContributorYes. You should call a doctor for seizures that last longer than three minutes.
What should I do if my friend is having seizures, but the doctor says that there is nothing wrong with her?wikiHow ContributorThere is clearly something wrong, and the doctor is incompetent or just uncaring. She should see another doctor, and ideally, get a referral to a neurologist, who knows much more about such disorders and can give her a more detailed examination.
What does it mean if a seizure is followed by a lot of burps?
A player has a seizure and is not injured or in shock and he needs to be moved, should he be moved and how
What does it mean when I have a seizure, vomit, and your eyes are rolled back?
What if they are having a heart attack and a seizure?
Does a stroke cause petite mal-seizures and what is a petite mal-seizure? Can anyone have this type of seizure without having a stroke? What can I do if someone is having a petite mal-seizure?
- A partial seizure can develop into a generalized seizure, and sometimes the person is aware of it coming. If so, help them get safe before it happens.
- After seizure, have the person rest. Seizures can be violent and very painful so don't assume they're ready to carry on as usual once the seizure stops.
- Do not restrain them. This can cause injury to the victim and/or yourself.
- Never leave that person behind. Leaving it without assistance would cause issues.
- After a seizure stops, people usually don't remember what happened so, try to keep them calm and provide further help. Any undo stress may cause them to have another seizure and that may lead to severe consequences.
- Put something under them, like a pillow.
- A person can have multiple seizures, one after the other, without recovering in between. If this lasts for more than 30 minutes, it's called a status epilepticus, or just status. If this happens, the person may need to see a doctor about it, but if they have status in a tonic clonic seizure, this is a medical emergency and you should immediately call for help (don't wait 30 minutes).[9]
Sources and Citations
- ↑ http://www.webmd.com/epilepsy/tc/helping-a-person-during-an-epileptic-seizure-topic-overview
- ↑ http://www.webmd.com/epilepsy/tc/helping-a-person-during-an-epileptic-seizure-topic-overview
- ↑ http://www.webmd.com/epilepsy/tc/helping-a-person-during-an-epileptic-seizure-topic-overview
- ↑ http://www.webmd.com/epilepsy/tc/helping-a-person-during-an-epileptic-seizure-topic-overview
- ↑ http://www.webmd.com/epilepsy/tc/helping-a-person-during-an-epileptic-seizure-topic-overview
- ↑ http://www.webmd.com/epilepsy/tc/helping-a-person-during-an-epileptic-seizure-topic-overview
- ↑ http://www.webmd.com/epilepsy/tc/helping-a-person-during-an-epileptic-seizure-topic-overview
- ↑ http://www.webmd.com/epilepsy/tc/helping-a-person-during-an-epileptic-seizure-topic-overview
- ↑ 9.09.19.29.39.4http://www.epilepsysociety.org.uk/AboutEpilepsy/Firstaid
- ↑ http://www.epilepsy.com/epilepsy/seizure_simplepartial
- ↑ http://www.epilepsy.com/epilepsy/seizure_complexpartial
- ↑ http://www.epilepsy.com/epilepsy/types_seizures
- ↑ http://www.epilepsy.com/epilepsy/seizure_absence
- ↑ http://www.epilepsy.com/epilepsy/seizure_tonic
- ↑ http://www.epilepsy.com/epilepsy/seizure_atonic
- ↑ http://www.epilepsy.com/epilepsy/seizure_myoclonic
- ↑ http://www.epilepsy.com/epilepsy/seizure_tonicclonic
- ↑ http://www.webmd.com/epilepsy/tc/helping-a-person-during-an-epileptic-seizure-topic-overview
- ↑ http://www.webmd.com/epilepsy/tc/helping-a-person-during-an-epileptic-seizure-topic-overview
- ↑ http://www.webmd.com/epilepsy/tc/helping-a-person-during-an-epileptic-seizure-topic-overview
Article Info
Featured Article
Categories: Featured Articles | First Aid and Emergencies | Neurological Disorders
In other languages:
Italiano: Aiutare Qualcuno Che Ha una Crisi Epilettica, Español: ayudar a alguien con una convulsión, Português: Ajudar Alguém que está Tendo uma Convulsão, Русский: помочь человеку с судорожным припадком, Français: aider une personne qui souffre de convulsions
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Mirror Match Website Forum
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Project Budget$100 - $200 USD
Project Description
I would like to mirror match a website forum. I currently have vbulletin installed. The only difference would be of course the banner and colour scheme of the website. I will supply the adsense code to the winner
Forum software attached. Please host on your own server(s).
1. Colour scheme: Use [url removed, login to view] colour scheme
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The median home value in Cameron, TX is $81,600.
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lower than
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The national median home value is $177,414.
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Great Place to build a home. Nice neighborhood. Close to shopping center and downtown.
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Tiludronate treatment improves structural changes and symptoms of osteoarthritis in the canine anterior cruciate ligament model
- Maxim Moreau1, 2,
- Pascale Rialland1,
- Jean-Pierre Pelletier2,
- Johanne Martel-Pelletier2,
- Daniel Lajeunesse2,
- Christielle Boileau2,
- Judith Caron2,
- Diane Frank1,
- Bertrand Lussier1,
- Jerome RE del Castillo1,
- Guy Beauchamp1,
- Dominique Gauvin1, 2,
- Thierry Bertaim3,
- Dominique Thibaud4 and
- Eric Troncy1, 2Email author
DOI: 10.1186/ar3373
© Moreau et al.; licensee BioMed Central Ltd. 2011
Received: 15 October 2010
Accepted: 21 June 2011
Published: 21 June 2011
The aim of this prospective, randomized, controlled, double-blind study was to evaluate the effects of tiludronate (TLN), a bisphosphonate, on structural, biochemical and molecular changes and function in an experimental dog model of osteoarthritis (OA).
Baseline values were established the week preceding surgical transection of the right cranial/anterior cruciate ligament, with eight dogs serving as OA placebo controls and eight others receiving four TLN injections (2 mg/kg subcutaneously) at two-week intervals starting the day of surgery for eight weeks. At baseline, Week 4 and Week 8, the functional outcome was evaluated using kinetic gait analysis, telemetered locomotor actimetry and video-automated behaviour capture. Pain impairment was assessed using a composite numerical rating scale (NRS), a visual analog scale, and electrodermal activity (EDA). At necropsy (Week 8), macroscopic and histomorphological analyses of synovium, cartilage and subchondral bone of the femoral condyles and tibial plateaus were assessed. Immunohistochemistry of cartilage (matrix metalloproteinase (MMP)-1, MMP-13, and a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS5)) and subchondral bone (cathepsin K) was performed. Synovial fluid was analyzed for inflammatory (PGE2 and nitrite/nitrate levels) biomarkers. Statistical analyses (mixed and generalized linear models) were performed with an α-threshold of 0.05.
A better functional outcome was observed in TLN dogs than OA placebo controls. Hence, TLN dogs had lower gait disability (P = 0.04 at Week 8) and NRS score (P = 0.03, group effect), and demonstrated behaviours of painless condition with the video-capture (P < 0.04). Dogs treated with TLN demonstrated a trend toward improved actimetry and less pain according to EDA. Macroscopically, both groups had similar level of morphometric lesions, TLN-treated dogs having less joint effusion (P = 0.01), reduced synovial fluid levels of PGE2 (P = 0.02), nitrites/nitrates (P = 0.01), lower synovitis score (P < 0.01) and a greater subchondral bone surface (P < 0.01). Immunohistochemical staining revealed lower levels in TLN-treated dogs of MMP-13 (P = 0.02), ADAMTS5 (P = 0.02) in cartilage and cathepsin K (P = 0.02) in subchondral bone.
Tiludronate treatment demonstrated a positive effect on gait disability and joint symptoms. This is likely related to the positive influence of the treatment at improving some OA structural changes and reducing the synthesis of catabolic and inflammatory mediators.
Osteoarthritis (OA) is among the most common musculoskeletal conditions [1]. This disease leads to functional disability and a reduced quality of life [2]. The abnormal biomechanics are believed to be among the major risk factors of disease progression and joint tissue damage [3].
Subchondral bone turnover is a well-defined component of OA [4]. The interactive process between articular cartilage and subchondral bone is complex and not yet fully understood. Yet, as these tissues are intimately related components of the joint, treatment to limit excessive bone remodelling is believed to have a possible positive effect on the global evolution of OA structural changes. Indeed, bone anti-resorptive agents have been shown to limit the development of OA structural changes in a number of experimental models [5]. For instance, inhibition of bone remodelling by licofelone [6] and calcitonin [7] in the experimentally transected canine anterior cruciate ligament (ACL) model of OA was shown to reduce cartilage lesions. Similar evidence also emerged from the work done on oestrogen replacement therapy in ovariectomized monkeys [8].
Bisphosphonates (BPs) are a well-known class of molecules that contain two phosphonate groups attached to a single carbon atom, forming a "P-C-P" structure. The antiresorptive effects of these biochemical analogs of inorganic pyrophosphate have been demonstrated in skeletal diseases where excessive bone resorption is present [9]. The anion of tiludronic acid (tiludronate, TLN) is a non-nitrogen-containing BP that acts on bone through mechanisms that involve induction of osteoclast apoptosis and prevention of extracellular degradation and of pro-inflammatory cytotrafficking [10], leading to decreased mineralized matrix resorption. This drug is recommended for skeletal disorders characterized by an increased and abnormal bone remodelling, such as Paget's disease, and is currently the only BP approved in veterinary medicine to alleviate clinical signs of an OA condition in horses [11]. There is yet insufficient data to claim a potentially beneficial effect of TLN on the pathological changes encountered in OA.
A recent study demonstrated that pre-emptive chronic zoledronate (a nitrogenous BP) treatment increases bone mineral density, and is chondroprotective and analgesic in both chemical (mono-iodo-acetate, MIA) and surgical experimental models of painful joint degeneration in the rat [12]. The authors showed that osteoclast-mediated resorption of cartilage at the subchondral bone/cartilage interface is an early initiating event in the pathobiology of the MIA model as opposed to chondrocyte death and subsequent mechanical erosion of the articular surface. Pre-emptive zoledronate fully inhibited the subchondral bone/cartilage molecular cross-talk [4, 13] and/or the BP could have had a direct analgesic effect. This provided further rationale to test the potency of TLN at improving functional disability and structural changes in the canine ACL model of OA.
While BPs [14, 15] and other antiresorptive agents [5–7, 16] have shown promise, mostly structural effects (inhibition of cartilage degeneration [12, 14], prevention of osteophytes [14] and reduction in bone marker turnover [15]) in animal models of OA with pre-emptive treatment, clinical results in knee OA patients have been disappointing, for example, with risedronate [17]. In OA, sclerosis of the subchondral bone is preceded by its resorption in the early phase [4, 13, 18]. This bone remodelling has also been characterized as bone marrow lesions (BML) on magnetic resonance imaging (MRI), and could also be perceived as an adaptation to changes in the biomechanics (maintaining intramedullary homeostasis [19]) or in an attempt to repair microdamages [18]. Therefore, bone remodelling has been associated with redistribution of mechanical stress [19], and the hypothesis has been advanced that to counteract it could prevent the repair of naturally occurring bone microdamage, thus increasing the susceptibility to crack initiation [20]. Moreover, in the ACL transection canine OA model, an experimental BP was demonstrated to be effective at reducing the turnover of cancellous subchondral bone, but ineffective at preventing osteophyte formation or pathologic changes of OA in the overlying cartilage [21]. Rather, a decrease in proteoglycan synthesis was observed, suggestive of impairment in the hypertrophic repair process. In contrast, chondroprotection was denoted in cruciate-deficient rats under BP treatment [12, 14] in parallel to a decrease in the expression of degradative enzymes [14] as well as of biochemical markers of cartilage degradation in human beings [17]. Also, in these studies stating a limited efficacy for BP treatment [17, 21], it has to be noted that one main limitation to inference was the relatively mild degree of OA in the control animals [21] as well as the absence of OA radiographic signs progression in placebo subjects [17].
ACL transection in dogs generates abnormal biomechanical forces and metabolic pathways that initiate structural changes on morphometry and histology [5], as well as on imaging [22, 23], mimicking those seen in naturally occurring OA. This model is additionally acknowledged to induce significant chronic gait disability and functional impairment [24, 25]. The canine ACL model of OA is valuable for assessing the evolution of functional outcomes in response to treatment [5]. In the present study, we hypothesized that the bone anti-resorptive action of TLN might curb the development of structural and functional joint lesions associated with ACL transection. We used a set of complementary tools to relate pain and functional outcomes in parallel to joint structural, biochemical and molecular changes. This allowed the evaluation of the effect of TLN on limb loading, pain/stress sensation, activity level and behaviours related to canine experimental OA conditions.
Materials and methods
Sixteen adult crossbred dogs (aged two to three years), with an average (SD) body weight of 26 (3.3) kg were used in this study. They were individually housed in galvanized steel cages (1 m (width) × 1.75 m (length) × 2.4 m (height)) fitted with automatic waterers. Dogs were included in the study after complete physical and musculoskeletal evaluation by a veterinarian, and haematological and biochemical analyses. Food (approximately 450 g Hill's Pet Nutrition Science Diet Canine Adult Original mixed with Harlan Teklab Global 27% Protein Dog Diet) was given once daily and removed overnight. Tap water (purified by filtration) was provided to the animals ad libitum.
Surgical transection of the anterior cruciate ligament (ACL)
After evaluation of baseline pain and functional outcome levels, all anaesthetized dogs were subjected to ACL transection of the right knee as previously described [26]. Under pre-emptive (transdermal fentanyl 50 or 75 μg/h, Duragesic®; Janssen Ortho, Markham, ON, Canada) and multimodal (intra-articular block combined with opioid administration) analgesia, the tibial edge was located with the thumb and index finger, followed by a medial sagittal skin incision (30 mm). The subcutaneous tissues were dissected, and a medial arthrotomy was performed, distal to the patella and parallel to the patellar ligament. A retractor was inserted to view the ACL to be sectioned, the completeness of which was verified by obtaining a large drawer motion in both flexion and extension. The capsule and the retinaculum were sutured in a simple continuous pattern. Bupivacaine (Marcaïne® 0.5%; Hospira, St-Laurent, QC, Canada) was injected (5 to 8 mL) in the capsule as an intra-articular block. Finally, the subcutaneous tissues were sutured, followed by intra-dermal and skin sutures.
One group was treated with 2 mg/kg of disodium TLN dissolved in a mannitol solution (CEVA Santé Animale, Libourne, France). The OA control group received only the vehicle solution (CEVA Santé Animale). Both treatments (0.2 mL/kg) were injected subcutaneously (SC), starting on the day of ACL transection, and repeated every two weeks up to the end of the follow-up (total of four administrations). The dose level of TLN was selected by the Sponsor based on preliminary studies in rats [27] and using an allometric scale-up to the weight of dogs.
Pain and functional evaluations
Gait analysis
In dogs, the use of a pressure-sensing walkway device acquires limb loading and is defined as a quantitative measurement of gait function [25]. Gait analysis was performed at baseline, Week 4 and Week 8 using the podobarometric recording device (Walkway® System; Tekscan Inc, Boston, MA, USA) [25, 28]. For the right (ACL-deficient) hind limb, the peak vertical force (PVF) was acquired at a trotting gait velocity ranging from 1.9 to 2.2 meters/second. Velocity and acceleration (± 0.5 meter per second2) was ensured using a set of three photoelectric cells specially designed for this podobarometric device (LACIME; École de Technologie Supérieure, Montréal, QC, Canada). The gait acquisition window was three seconds with a sampling rate set at 44 hertz, producing a total of 132 frames. Raw PVF (Kg) data from the first five valid trials were obtained for each dog and later used for statistical purposes using body weight as a covariate [25]. Data were expressed as percentage of body weight (%BW).
Pain scoring systems
The lameness and pain of treated and control OA dogs were evaluated using previously developed scoring systems, and included a visual analog scale (VAS) [29] and a composite numerical rating scale (NRS) [30]. The pain scores were obtained at baseline, Week 4 and Week 8 by the same technician [29] with a 100 mm VAS scale, coding from 0 ("no pain") to 100 ("pain intensity could not be worse"). The composite NRS, which was scored by the same veterinarian throughout the study, includes the following seven criteria: Global assessment (score 0 to 4); Evaluation of lameness while the dog is standing up (score 0 to 4), walking (score 0 to 4) and trotting (score 0 to 4); Willingness to hold up contralateral limb (score 0 to 4); Evaluation of response to palpation (score 0 to 4); Evaluation of response to flexion and extension (score 0 to 4). Inter- and intra-observer reliability of both VAS and NRS were tested and found to be highly satisfying (Spearman correlation, rho >0.72, P < 0.001).
Electrodermal activity (EDA)
Changes in skin conductance response (EDA) resulting from sympathetic neuronal activity [31] has recently been validated in the canine ACL model of OA as a measurement of stress or pain that is strongly associated with functional outcomes [30]. The EDA was recorded at baseline, Week 4 and Week 8 using a Pain Gauge® (PHIS, Inc., Dublin, OH, USA) system, which grades the signal intensity on a scale of 0 to 10, with 10 being the most painful. The device was placed for two seconds on the right palmar paw (dry and non-clipped).
Video-automated behaviour analysis
The computer-assisted behavioural analysis (The Observer v5.0.31; Noldus Information Technology, Inc., Leesburg, VA, USA) allowed the assessment of behavioural changes suggestive of a pain-related condition [32]. The capture of behavioural changes in terms of body positions and motor activities allows a non-invasive monitoring of pain-related functional disability and discomfort. Recording was performed in the outdoor runs where the dogs exercised for two consecutive hours, at baseline and at Week 8. The resulting ethogram included the following eight classes of behaviour: location in the run, body position, facial expression, vocalization, tail position, self-care, motor activity and dog interaction. The analysis of behaviour occurrence was done following the manufacturer's recommendations.
Telemetered locomotor actimetry
Acceleration-based monitoring of frequency, intensity, and duration of physical activities is a valid objective tool to monitor pain-related functional disability [30, 33]. At baseline, Week 4 and Week 8, locomotor actimetry was monitored continuously for 24 hours with an electronic chip (Actical®; Bio-Lynx Scientific Equipment, Inc., Montreal, QC, Canada) that was placed inside a protective neck collar. During this time, all dogs followed the same daily routine to ensure consistency. The cumulative locomotor activity was recorded over two minutes, thus providing 720 measurements over 24 hours. The height of peaks for each recording was scaled in arbitrary units from 0 to ∞ to quantify the intensity of locomotor actimetry [30]. Comparison of actimetry with simultaneous video-automated recordings allowed the threshold to be set between active and inactive motions at 30 units. Data were then expressed as daily averaged total intensity (considering all counts, DATI), and daily averaged active intensity (considering only counts higher than 30 in intensity as active counts, DAAI).
Macroscopic grading
At the end of the study, the dogs were euthanized under sedation with barbiturate overdose. The right knee of each dog was placed on crushed ice and dissected for quantification of gross morphological changes. Two independent observers who were blinded to treatment group allocation graded the findings with a consensual value [25, 26, 34].
Macroscopic lesion areas at the cartilage surface on the femoral condyles and tibial plateaus were measured (in mm2) with an electronic digital calliper (Digimatic Caliper model No. 2071M; Mitutoyo Corporation, Kawasaki, Japan). The depth of erosion was graded with scores ranging between 0 (a normal surface) and 4 (erosion extending to the subchondral bone).
When present, the degree of osteophyte formation was quantified by measuring the maximal width (mm) of the spurs on the medial and lateral femoral condyles as previously described [26]. For statistical purposes, data were evaluated separately for lateral and medial osteophytes and also summated for the entire condyles.
Histological grading of cartilage and synovial membrane
Full thickness cartilage sections were removed from the weight-bearing lesional areas of the femoral condyles and tibial plateaus allowing standardization of sampling [25]. Histological evaluation was performed on sagittal sections of cartilage from each femoral condyle and tibial plateau specimen [25, 26, 34]. After dissection, specimens were fixed in 4% buffered formalin and embedded in paraffin. Serial sections (5 μm) were stained with haematoxylin/Fast green and Safranin-O. The severity of cartilage pathology was graded by two independent observers using the OsteoArthritis Research Society International histopathology scoring system [35]. For statistical purposes, data from both observers were considered for the lateral and medial part of the condyles and plateaus as well as for the entire joint.
Synovial membrane
Synovial membrane was removed and processed as described above, but stained with haematoxylin/eosin. Two independent observers evaluated two specimens. The severity of synovitis was graded on a scale of 0 to 10, including four histological criteria as previously described [34]: synovial cell hyperplasia (scale 0 to 2), villous hyperplasia (0 to 3) and mononuclear (0 to 4) and polymorphonuclear (0 to 1) cell infiltration; 0 indicates normal structure. For statistical purposes, data from both observers and both specimens were considered.
Analysis of synovial fluid
At euthanasia, samples of synovial fluid were collected, measured, and then centrifuged and frozen (-80°C).
Prostaglandin (PG) E2assay
The amount of PGE2 (ng/knee) was determined using a commercially available Enzyme ImmunoAssay (Cayman Chemicals, Ann Arbor, MI, USA) according to the manufacturer's instructions, the limit of detection being 15 pg/mL. The concentration measurements were done in duplicate and the values averaged.
Nitrites and nitrates (NOx) assay
Nitrite and nitrate levels (nmol/knee) were determined by chemiluminescence [36] using a NO Analyzer (280i®, Sievers Instruments, Boulder, CO, USA), according to the manufacturer's instructions. Briefly, 0.025 mL of the supernatant was injected into the microreaction purge vessel of the analyzer. The purge vessel contained 5 mL of vanadium solution heated at 95°C. The instrument measures NOx on a gas-phase chemiluminescent reaction between NO and ozone. Each sample was analyzed in duplicate and values averaged.
Full thickness specimens from the tibial plateaus and femoral condyles were processed for immunohistochemical analysis, as previously described [6, 26, 34]. After the slides were incubated with a blocking serum (Vectastain ABC kit; Vector Laboratories, Inc., Burlingame, CA, USA) for 60 minutes, they were blotted and then overlaid with the primary antibody against the following: matrix metalloproteinase (MMP)-1 (1/40 dilution, mouse monoclonal; Calbiochem ref. #444209; EMD Biosciences, Darmstadt, Germany), MMP-13 (1/6, goat polyclonal antibody; R&D Systems, Minneapolis, MN, USA), a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS)5 (1/50, rabbit polyclonal; Cedarlane ref. #CL1-ADAMTS5; Hornby, ON, Canada), and cathepsin K (1/200, goat polyclonal; Santa Cruz Biotechnology ref. #sc-6506; Santa Cruz, CA, USA) for 18 hours at 4°C in a humidified chamber.
Each slide was stained using the avidin-biotin complex method (Vectastain ABC kit), and incubated in the presence of the biotin-conjugated secondary antibody for 45 minutes at room temperature followed by the addition of the avidin-biotin-peroxidase complex for 45 minutes. The slides were counterstained with eosin. Determination of the staining specificity as well as the immunohistochemistry analysis (three fields from each specimen examined) was done as previously described [6, 26, 34]. Each section was examined under a light microscope (Leitz Orthoplan; Leica, Inc., St. Laurent, QC, Canada) and photographed using a CoolSNAP of Photometrics camera (Roper Scientific, Rochester, NY, USA). The results are expressed as the percentage of cells staining positive for the antigen (MMP-1, -13 and ADAMTS5) in the upper zone of cartilage with the maximum value being 100%. Similarly, on decalcified specimens (see the Histomorphometry section), the number of cathepsin K positive cells was quantified in the subchondral bone, as previously described [6]. For statistical purposes, data from all specimens (tibial plateaus and femoral condyles) and all fields were considered. The data presented are the average of the three fields.
Specimens of full-thickness sections of the articular cartilage including the subchondral bone from the lesional area of the medial tibial plateau of all dogs were placed in 10% (vol/vol) formalin before being decalcified with 10% (vol/vol) formic acid in formalin for 12 hours and embedded in paraffin, as previously described [6].
Subchondral bone
Sections (5 μm) of each specimen were subjected to Fast green/Safranin-O staining. A Leitz Diaplan DMLS® microscope (Leica Microsystems, Wetzlar, Germany) connected to a personal computer (Pentium IV, using Image J software, v1.27; NIH, Bethesda, MD, USA and OSTEO II Image Analysis software; Bioquant, Nashville, TN, USA) was used to conduct the subchondral bone histomorphometry, which was performed as previously described [6, 26]. Measurement of the bone surface (mm2), trabecular thickness (μm) and trabecular separation (mm) was done according to standard conventions [6].
Calcified cartilage
The calcified cartilage histomorphometry was done for each specimen, as previously described [6]. The surface (mm2) of the calcified cartilage was calculated using the computerized program.
Statistical analysis
Linear mixed models for repeated measures were used to evaluate the effect of Time, Group and Time per Group interaction for PVF, EDA and actimetry recording using compound symmetry covariance structures. Trials (PVF) and dogs were random effects nested in treatment groups. At each time point, a group's least squares means were compared with appropriate Tukey or Bonferroni adjustments. To evaluate the effect of Time, Group and Time per Group interaction on VAS and summated NRS, repeated-measures generalized linear models with generalized estimating equations were used, where data were assumed to distribute under the Log-Gamma, and the overdispersed Poisson probability functions, respectively. For the latter variable, the variance scale factor was estimated by Pearson's chi-square/Degree of freedom. Best working matrix was determined to be first-order autoregressive following the strategy proposed by Littell et al. [37].
For the video-automated behaviour analysis, the occurrence of each specific event was cumulated. Frequencies were then compared between TLN and placebo control groups using a negative binomial regression model with baseline occurrence as covariate. Values were expressed as changes in the frequency of a given behaviour according to the tested group.
Synovial fluid volume, levels of inflammatory factors, cellular ratios and structure measurements were tested between groups using linear mixed models. Where appropriate, specimen or fields were used as random effects nested in treatment groups. Data presented as scores or counts were tested using a generalized linear model under the logistic polytomous distribution function using the proportional odds assumption, or the over-dispersed Poisson probability functions when scores were summated. Where appropriate, specimen or observers were used as random effects nested in treatment groups. Alpha threshold for significance was set at 5%. Data are presented as mean (SD). Statistical analyses were done using SPSS Statistics software v17.0 (SPSS Inc, Chicago, IL, USA) and SAS software, v9.1, (SAS Institute Inc, Cary, NC, USA).
Pain and functional outcomes
Pain and functional outcomes before and after anterior cruciate ligament transection in dogs
Evaluation methods/Groups
Week 4
Week 8
Function - kinetic gait analysis (%BW)
71.4 (3.7)
27 (11.0)
32.2 (12.4)
73.6 (6.1)
35.1 (15.5)
43.6 (9.0)
§ = 0.05
¶ <0.01
Pain - Visual analog scale (VAS, measurement)
0.0 (0.0)
37.6 (14.3)
26.8 (11.1)
0.0 (0.0)
26.9 (18.9)
15.6 (9.2)
Pain - Numerical rating scale (NRS, score)
0.0 (0.0)
19.4 (4.3)
18.3 (3.7)
0.0 (0.0)
15.5 (5.4)
15.0 (3.4)
§ = 0.03
Pain - Electrodermal activity (EDA, reading)
4.5 (2.5)
6.4 (2.5)
5.3 (2.4)
4.2 (2.7)
3.6 (2.5)
3.9 (2.4)
Function - Telemetered actimetry recording (count)
Daily averaged total intensity (DATI, no unit)
97.9 (41.4)
79.1 (22.7)
85.7 (35.8)
82.3 (25.4)
104.5 (44.6)
91.2 (33.1)
¶ = 0.04
Daily averaged active intensity (DAAI, no unit)
390.9 (101.3)
360.6 (73.9)
379.1 (127.1)
390.2 (82.9)
502.6 (145.7)
443.1 (117.1)
¶ = 0.04
Assessment provided by VAS and NRS (Table 1) echoed the temporal evolution observed with gait analysis (PVF): After surgery, both methods detected a worsening of the dogs' condition. Assessment provided by VAS revealed an improvement from Week 4 to Week 8 (P < 0.01) in both groups, without the presence of an interaction of treatment on VAS recording. Of note, TLN dogs tended to have lower VAS grades than controls (P = 0.06). With respect to NRS, groups were not significantly improved from Week 4 to Week 8 and no interaction was denoted. However, there was a significant group effect (P = 0.03) on the overall NRS recorded post surgery.
According to EDA values (Table 1), the level of pain/stress sensation recorded after surgery did not change over time in the TLN-treated dog group, whereas in the placebo control group, the maximal increase in EDA was noted at Week 4. As a result, the interaction of treatment on the temporal evolution of EDA recording demonstrated a trend (P = 0.07) without denoting group effect.
According to the video-automated analysis, there was a significant increase in the relative frequencies of two major body position behaviours suggestive of comfort for TLN dogs: Full weight bearing while standing with head down increased by a factor of 2.92 (P = 0.03); Full weight bearing while standing and looking around increased by a factor of 7.7 (P = 0.03). Similarly, two motor activities (gait) were also more frequently observed in this group: Normal walking, factor of 5.22 (P = 0.01); and normal trotting, factor of 6.34 (P = 0.01).
The telemetered recording of DATI and DAAI denoted higher movement in TLN dogs following surgery (Table 1). Conversely, placebo control dogs were less active than at baseline. This divergence led to the discernment of an interaction (P = 0.04, DATI and DAAI) of treatment on the temporal evolution of telemetered actimetry, which resulted in higher DATI recording in TLN dogs when compared to placebo control at Week 4 (P = 0.05).
Synovial fluid
The amount of joint effusion in the TLN-treated dogs (6.7 (2.8) mL) was significantly less (P = 0.01) than that found in the placebo control dogs (15.0 (7.6) mL). The TLN-treated dogs also had lower levels of PGE2 (P = 0.02) (4.4 (3.6) ng/knee) and NOx (P = 0.01) (306.2 (267.1) nmol/knee) than those treated with placebo (11.7 (7.2) ng/knee, and 766.28 (379.0) nmol/knee, respectively).
The severity of macroscopic lesions (depth and lesion surface) on the femoral condyles and tibial plateaus of TLN-treated dogs was not different from that observed in placebo control dogs (data not shown). The size of the osteophytes was similar between groups, both on medial (TLN; 6.7 (2.6) mm, placebo control; 7.0 (1.9) mm) and lateral (TLN; 6.5 (1.4) mm, placebo control; 7.1 (2.1) mm) condyles.
Histological grading of cartilage lesions did not reveal significant difference between groups. The synovial membrane score of TLN dogs (total score of 6.8 (1.1)) was similar to the placebo control dogs (total score of 6.1 (1.1)). The subset analyses revealed that the synovial lining cell score was significantly (P < 0.01) less in TLN dogs (1.0 (0.0)) compared to placebo control (1.7 (0.6)).
Histomorphometry data eight weeks after anterior cruciate ligament transection in dogs
Calcified cartilage surface (10 -2 mm 2 )
Subchondral bone surface (10 -2 mm 2 )
Trabecular thickness (10 -2 mm)
Trabecular separation (10 -3 mm)
16.9 (3.9)
75.1 (9.3)
8.9 (2.3)
86.0 (52.6)
19.8 (2.3)
86.2 (5.1)*
10.3 (2.0)
45.5 (15.1)*
Studies in the dog ACL model have provided insight into OA mechanisms and pathophysiological pathways that surround the evolution of the degenerative process. The model was proven to be most useful at the preclinical stage of drug development for testing the abilities of new therapeutic modalities to limit or halt the disease development/progression [5]. In the present study, TLN was demonstrated to have a positive effect both on some of the structural changes and on pain/function. More particularly, TLN was found to decrease the production of catabolic enzymes, bone resorption, and synovial inflammation. These were associated with improved locomotion, reduced lameness and gait disability, and improved joint pain perception. These findings are in line with the report on a rat model of OA [12] showing that the analgesic effect of the nitrogenous BP zoledronate is mediated by its anti-resorptive action. In the current study, TLN promoted better function despite the presence of cartilage lesions, which were of similar extent in OA and control dogs. This finding suggests that cartilage integrity in a weight-bearing joint is not compulsory for functional improvement. Furthermore, even when the knee joint was exposed to additional mechanical constrains related to an increase in limb support (that is, pain-relief), cartilage did not undergo excessive alteration and remained similar to control dogs.
This study demonstrated that TLN improves the functional disability following ACL transection, more specifically the limb impairment, allowing dogs to load their afflicted limb to a greater extent as demonstrated by the results of the PVF analysis. Dogs were also more active without showing evidence of severe lameness. The stress/pain sensation was also reduced by TLN treatment, as highlighted by the results of the EDA measurements, pain scoring and behaviours denoting changes in pain-related condition. Lameness improvement was found to be maximal at Week 8 (PVF, NRS and video-automated analysis of body position and motor activities), after dogs had received full TLN treatment. However, at the intermediate time-point (Week 4), the difference between TLN and placebo groups was greater than at Week 8 for both EDA and telemetered actimetry. The beneficial effect of TLN therapy on pain/function was likely related to a combination of effects including its anti-inflammatory effect shown by a reduction in synovial effusion size, synovitis score, and level of inflammatory mediators, as well as its effect on the initiation of bone remodelling [12].
Transduction of noxious signals occurs through high-threshold receptors responding to a variety of thermal, chemical and mechanical stimuli, and defined as polymodal nociceptors. At the level of damage-sensing neurons, release of protons and high concentrations of adenosine triphosphate (ATP) act, respectively, on transient receptor potential (TRP) and acid-sensing (ASIC) ion channels, and on ionotropic ligand-gated purinergic (P2X) receptors to activate nociceptors [38]. During the early stages of inflammation, mediators such as PGs and bradykinin change the sensitivity of receptors and reduce the activation threshold for these conducting ion channels, which is the basis for peripheral sensitization. This study provides interesting new findings on the ability of TLN to reduce the inflammatory changes in the OA synovium. Hence, TLN demonstrated a clear anti-inflammatory local effect while decreasing the joint effusion and synovitis (synovial lining cells). The analyses of synovial fluid confirmed the anti-inflammatory effects reflected by a decrease in the levels of PGE2 and NOx, two well-known inflammatory mediators [39]. Inflammatory markers such as PGE2 are known to be correlated with pain and functional disability in human OA [40] as well as in the canine ACL model of OA [41]. The high level of synovial fluid NOx found in this study is in line with our previous findings in this OA model, in which the inducible NOS was found to be increased [16, 34]. It is likely that NO contributed to the disability and perception of pain [42]. Moreover, the decrease in NOx levels by TLN treatment may have contributed to the structural protective effect of the drug as previously demonstrated in this OA model [16]. Tiludronate, by inhibiting the ATP-dependent proton pumps located in the plasma membranes of the osteoclasts [43], can reduce the acidification of the bone matrix, which is the first step in the bone resorption process. In addition, TLN can disrupt adhesion of the osteoclast to the bone surface before bone resorption is initiated by modifying the phosphorylation of proteins of the cytoskeleton [44]. As well as decreasing pro-inflammatory cytotrafficking (cytokines and NO synthesis) [10], acidification and phosphorylation and, in consequence, activation of proteolytic enzymes, TLN can also inhibit activity of MMPs [45]. In the present study, TLN was found to decrease the expression of MMP-13 and ADAMTS5 in the cartilage and cathepsin K in the subchondral bone, which is in line with the findings of our previous study [6] and supports this hypothesis. The anti-inflammatory effects of TLN are interesting, as they add to the most important recognized biological effect of BPs, that is, the reduction in bone remodelling through the inhibition of osteoclastic activity. The pain and functional improvements observed under TLN therapy were present at Week 4 and maintained at Week 8. Therefore, it could be hypothesized that the actions of TLN on bone matrix and synovial inflammation would lead to a decrease in TRPV1, ASIC3, and P2X receptors activation, translating into diminished peripheral sensitization and subsequent benefits on pain sensation and mobility. Although BPs were developed for the treatment of pathologies associated with excessive bone resorption, several reports revealed that they were able to reduce the pain associated with different painful diseases. Direct analgesic effects of BPs have been largely acknowledged using reflex algesimetric tests in mice after acute administration [46]. Clodronate and pamidronate presented anti-nociceptive dose-responses, comparing favourably to aspirin and morphine, and the central and peripheral analgesia did not appear to be mediated through opioid receptors [46]. Prolonged anti-nociceptive effects have also been demonstrated for clodronate, a non-nitrogenous BP, without inducing any behavioural side effects [47]. Such action has been proposed to explain the efficacy of zoledronate in experimental rat OA models [12]. Increased osteoclastic activity, as found in OA [4, 13, 17, 18], could contribute to neuronal excitation and pain, and, therefore, inhibition of bone resorption and of nociceptor activation through anti-acid, anti-inflammatory actions would be analgesic. This hypothesis maintains an interaction of TLN with the molecular subchondral bone/cartilage cross-talk.
Subchondral bone mineral density decreases as early as one month following ACL transection [48]. In this OA model, extensive remodelling leading to a reduction in subchondral bone plate thickness, bone surface, and trabecular thickness, increased trabecular separation and loss of bone density and anisotropic properties were also reported [6, 49–51]. In this study, we found that following TLN treatment a number of those changes were reduced and closer to the values found in normal dogs [6]. More specifically, the architecture of subchondral bone and calcified cartilage was better preserved. The anti-resorptive action of TLN may explain these findings.
The advance movement and duplication of the tidemark contributes to overall thinning of the articular cartilage, thickening of the calcified cartilage while altering the biomechanic of the joint [18, 52]. In ACL-deficient dogs, the calcified cartilage undergoes thinning and an advancement of the tidemark later in the OA process [6, 48]. However, duplication of the tidemark was previously reported following 12 weeks of BP treatment [21]. Whether or not TLN affects the endochondral ossification remains to be determined as change in the calcification front was not assessed in the present study.
The decrease in cathepsin K activity observed under TLN treatment is well in line with the known mode of action of the drug at reducing osteoclastic activity [9, 10]. Given that mechanical loading governs bone architecture and mass, the greater alteration in bone structure found in placebo-treated dogs may also be explained by the lower forces transmitted to the joint as a consequence of pain-related limb disuse. Whereas previous studies using BPs [14, 15] or other antiresorptive agents [5–7] focused on the beneficial structural effects in experimental OA models, the present study highlights that the anti-resorptive effect of TLN was associated with an apparent absence of effect on cartilage lesions, but translated to beneficial analgesic and functional consequences. One must, however, take into account that the present study lasted only eight weeks, which is an obvious limiting factor regarding the exploration of the chondroprotective effect of TLN.
A recent analysis using MRI confirmed the common belief that it is likely that changes in the subchondral bone (BML) predominate in relation to OA knee pain [2, 53]. Bone marrow lesions are also associated with cartilage lesions [54]. These results support the dynamics of bone/cartilage cross-talk, and the fact that TLN affected the molecular, nociceptive, and biomechanical bone/cartilage interface in the canine ACL model. In the dog ACL model, we have observed similar relationships between MRI structural and functional changes [22, 23, 55]. Such findings further support the translational nature of results obtained in the ACL dog model to human OA.
The use of the dog ACL model in association with the complete set of functional methods used in the present study represents a most useful tool for the monitoring of pain and joint function in OA. The present study brings into perspective a possible link between joint structural changes and functional outcomes. The level of joint inflammation is an important co-factor in generating pain-related functional disability. The preservation of bone integrity also likely plays a key role in functional outcome, being required to reduce the disability occurring in ACL-deficient dogs. This is supported by the fact that TLN treatment demonstrated a positive effect on gait disability and joint symptoms, while being associated with a better preservation of calcified cartilage and subchondral bone histomorphometry, as well as reducing the synthesis of catabolic and inflammatory mediators.
anterior/cranial cruciate ligament
a disintegrin and metalloproteinase domain with thrombospondin motifs
acid-sensing ion channel
adenosine triphosphate
bone marrow lesions
daily averaged active intensity
daily averaged active intensity
electrodermal activity
matrix metalloproteinase
magnetic resonance imaging
- NOx:
nitrites and nitrates
numerical rating scale
purinergic receptors
prostaglandin E2
peak vertical force
percentage of body weight
standard deviation
transient receptor potential vanilloid 1
visual analog scale.
The authors thank Virginia Wallis for her assistance with the manuscript preparation. This study was supported in part by a grant from CEVA Santé Animale, Libourne, France, an ongoing New Opportunities Fund grant from the Canada Foundation for Innovation (#9483) for the pain/function equipment; a Discovery grant from the Natural Sciences and Engineering Research Council of Canada (#327158-2008) as operating fund for pain biomarkers, and by CRCHUM and the Osteoarthritis Chair, Université de Montréal.
Authors' Affiliations
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Struggling Sun Microsystems Inc. (JAVA) seems ready to admit it doesn't have all the answers. The company has agreed to let activist investor Southeastern Asset Management add two new independent directors to its board "as soon as reasonably practicable."
Southeastern, which is Sun's largest shareholder with 22% of the company's outstanding stock, has in recent months increased its stake and helped call attention to the plight of Sun, whose stock has fallen more than 80% from 52-week highs.
Aside from highlighting the company's business troubles, however, Southeastern has been quiet about outlining specific moves Sun could take to turn things around. While the consensus is that Sun must do something, there's been little advice forthcoming from Southeastern or any other party. Given the vagueness of Monday's announcement about the new Sun board members, it could be a while longer before anyone comes up with some sound advice. Southeastern has not disclosed the names of the new board members it plans to name, or a time frame for doing so. -Andrea Orr
See Dec. 8 press release on Southeastern naming new board members from Sun Microsystems
See Nov. 12 post on Southeastern and Sun from Tech Confidential