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post #22
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Join Date: Dec 2012
Location: Clackamas, Oregon
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Whoa guys! No need to be this rude even if you do suspect some exaggeration. It is fine to question but to out and out treat someone this way is not excusable. This is the one area of the forum that I do not tolerate ANY bullshit so back off!!!!
Now, for some actual tips.
When you are doing your attempted 3`s are you doing the frontside? The reason I ask is because one of the biggest issues (and I still have trouble with front 3`s) is the rider opens up too soon; usually on the first 90 degrees when facing down the hill. This will drastically slow your rotation. My issue has always been a fear of committing to it; this could be doe to conditions, not feeling it, whatever but any hesitation will kill your rotation.
One thing I have done that seemed to help me and has helped people I coach, is to actually carve the first 90 of your 3 (not in the park, I use natural features so I don`t fuck up the takeoff ramps in the park doing this). This allows you to really concentrate on that final 270 and the landing. Once I have gained the confidence of landing successfully, I don`t seem to have near as much of a hesitation issue.
Now, while I am disappointed in their delivery, the other poster`s did bring up valid points. It is hard for most of us who struggled for a long time to master good riding skills like carving, dynamic skidded, fore-aft movements, up and down unweighting, anticipatory rotation, etc to believe that a new rider with 6 days has done enough prep work in their foundational riding skills to focus on freestyle. I totally get the skiing background and wakeboarding, but just make sure you do not neglect these foundational riding skills.
I see you are in the PDX area; Which blacks are you riding at what resort; Meadows? Timberline? Just make sure you are not skipping important riding skills in your haste to master park. And if you say you don't like pow? I need to get you into Private Reserve at Meadows on a stupid deep powder day and we`ll fix that little issue.......
So, back to park.... Here`s a few more things for you to think about
This is the key for good park riding; it stands for approach, takeoff, maneuver and landing.
Your approach needs to be stable; no last minute speed corrections or trajectory changes. You should feel as if you are dialed in and patiently waiting for the takeoff.
The takeoff is key for the outcome of the trick (maneuver). You need a stable, balanced and controlled takeoff. Hucking your meat usually looks like shit and will eventually get you hurt. Far better to do smaller things well that look good than go huge and look like a whirling dervish in the air.
The Maneuver is what you do in the air (or on the box/rail) if the approach and takeoff is solid, you have a much better chance of successfully performing the maneuver. Again, progress and master simple maneuvers before jumping to more complex ones.
The landing is really the proof of the pudding. If you fuck up somewhere in the earlier stages, it is likely going to show up here. You want to be stabilized and ready to land before it happens. Get the balance, trajectory and angles dialed in be ready to reconnect with the snow. Avoid the temptation to immediately brake; allow your board to settle in and engage the edge before applying any corrections to speed and direction.
Keep your progress slow and steady and always remember as you progress, that when you want simple terrain for complex tasks. As you master say large straight airs on large features and want to start spinning, don`t do them on the large features. Go back to the small features and work your way back up. Too often I see a park rider who is nailing it on a large feature try a new maneuver but they don`t step it back and really jack themselves up trying to dial in a new trick on too big of a feature.
I give you this caution because from reading the exchange going on here you seem to me to be the time that may let ego get the better of you and not be too willing to step down to easier features to try new shit. Just remember to always ask yourself if that 3 to 5 seconds is worth jeopardizing your riding season. If you're not sure of the outcome, step it back a notch. Hope to see you at Meadows some time....
I really appreciate that you took the time to type this out.
I ride at Timberline, fusion pass whoo, but my first day was on the Palmer Snowfield haha. It was in October and it was icey! So I guess that forced me to learn quickly. Also, I watch tons of youtube videos on the tricks and skills before I go up. It helps! The reason why I am doing these larger park features is because of who I am riding with. :/ They are advanced riders and they pretty much brought me to larger features and black diamond runs and said this is what we are doing, so you are as well. So I basically said what the hell, Ill learn this stuff.
I set goals before each day and I am determined to be able to do everything they can do in less time it took them to learn. haha
The blacks I have ridden was the Snowfield, and those blacks off of pucci. Elmers and Wingles I believe.
Back to park.
I learned how to backflip on the trampoline with my board on my feet, so it was pretty easy to get the rotation out on the slopes, so thats why I can attempt those already. I wouldn't think of this trick being more difficult than any others, so why not try it?
I believe my 360 issue may lie in trying to rotate too early. Like just before leaving the lip. It sort of stalls me out. Im trying to stop that habit, is there any techniques for that?
And I have fallen pretty hard a few times on the bigger features haha. My friends thought I broke bones a couple times. But I haven't even gotten a bruise. Weird. I am pretty heavy for my height, not fat, but muscle. So I don't know if that helps me take impacts better. 180 pounds at 5'5" around 8% BF.
Thanks again for the tips
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Occupying Progressive Strategy
Emergence of the Occupy Movement in 2011 represents a sea-change in US politics. The landscape for strategic action is now transformed, enabling dramatic new opportunities for bold progressive policies to be implemented on the national stage.
This strategy brief maps out the core strengths and potential risks for progressive organizations and elected officials to build on the major advances made throughout the last year as we move into a critical election cycle.
This work was commissioned by Progressive Congress to serve its mission of supporting progressive members of Congress and the vast ecosystem of organizations they depend on to advance a progressive vision for America.
This Changes Everything
The world has shifted dramatically in the last year. We have seen the rise of a global movement that started in Tunisia and spread throughout the Middle East, Europe, then most dramatically out from the tiny Zuccoti Park of New York City where a small protest exploded onto the global stage.
The relevance of Occupy Wall Street to US politics takes many forms. Most important for progressive leaders are:
- The appearance of new language for the Progressive Movement;
- A new political reality that is global in scope and yet locally grounded in cities and towns throughout the United States;
- A cogent "cross ideology" platform for visioning the future.
Let's look at each of these in turn.
A New Language for Progressives
Two principle frames have been introduced into the discourse, fundamentally re-orienting the distribution of power held in the past by a conservative media and the Republican Party. These frames are the 99% Frame and the Occupy Frame.
The 99% Frame evokes a maximal inequality that resonates deeply with the lived experiences of working-class people in the US and around the world. The power of the Occupy Frame does two things: (1) It is a verb that represents action taken by one who has power to influence the world, and (2) it demarcates an abstract spatial location that is scalable — readily applied to both local places (e.g Occupy Oakland) and grand themes (e.g. Occupy Democracy).
The language of 99% is now widely adopted and has played a crucial role in the elevation of economic inequality and moneyed corruption of our political system. At the same time, the language of occupation provides a pathway to empowerment for the large swaths of citizens who have felt powerless and marginalized for quite some time.
A New Political Reality
The rapid emergence of protest groups in hundreds of cities across America, seemingly out of nowhere, has done much more than alter the language of politics. It's greatest power is the realization that a vast community already exists that wants fundamental (and deeply progressive) change in the United States.
For most Americans, the world has changed in two fundamental ways:
- They feel the power of grassroots democracy may not only be possible, but inevitable, through digital organizing with mobile devices and the internet.
- They no longer feel isolated and alone, now that a vast number of people has congealed around sentiments they share at a deeply emotional level.
The existence of this nascent movement has become readily perceived and impossible to ignore. It is now a tangible and powerful force in the body politic.
A "Cross Ideology" Platform
Just as profound is the observation that Occupy Wall Street has emerged through a breakdown of old political labels. A visit to one of their general assemblies demonstrates that anarchists and libertarians share cause with progressives. Even some who in the past were aligned with the Republican Party are deeply critical of corporate corruption, outsourcing of jobs, and the gridlock of partisan wrangling that keeps Congress from successfully addressing our chronic economic crisis.
While some risks bubble forth from this unlikely stew (discussed below), it is clear that new alliances can be formed around a bold vision for the future. The majority of Americans want affordable health care, living wage jobs, and strong communities. And they want to believe in American democracy again.
It is here that progressive leaders have the most to contribute. We have called for election finance reform, universal health care, and a robust social safety net as central policy recommendations for years. Our opportunity rests on the ability to build lasting trust with a movement that has grown from a deep cynicism with politics-as-usual.
Risks to Consider
Engaging successfully with the Occupy Movement will require some thoughtfulness and care, otherwise it could backfire. Let's look at a handful of important risks that must be included in any attempt to build on OWS success:
Risk #1: Avoid Being A "Co-opter"
OWS is built on a foundation of distrust in prior sources of power. Attempts to "take their message and run" will be seen as opportunistic and reinforce the cynicism of politics-as-usual.
Recommendation: Elevate the movement itself by joining with it. Acknowledge that OWS emerged on its own and that you want to be a part of it. This will affirm the legitimate role of OWS leaders while showing sympathy with their cause.
Risk #2: Take Care Not to Marginalize the Grassroots
Many supporters of Obama's 2008 campaign have disengaged from politics because they felt marginalized by an "insider agenda" advanced by the Obama Administration. This neglect of the grassroots, whether real or perceived, has created the power vacuum from which OWS swept onto the stage. Many have an attitude of "once bitten, twice shy" and will balk at top-down approaches that place them on the margins.
Recommendation: Restore the language of "Yes We Can" and seek meaningful partnerships with grassroots organizations. Use social media tools to elevate ideas from everyday citizens and credit them for inspiring you to adopt them. Be interactive!
Risk #3: Avoid Being A "Tinkerer"
OWS is principally a rebuke against the massive gap between the scale of threats and responses offered by elected officials. There is no incremental policy change that restores integrity to our democracy, nor faith in the direction of our country.
Recommendation: Boldly advocate for meaningful and transformative change. Popularity of OWS demonstrates that the American people want nothing less than a full-scale redistribution of power away from corporations and the obscenely wealthy. Respond accordingly with Constitutional Amendments that curtail corporate power, legislation that restructures our economy toward a clean energy future, and posturing that demonstrates your strong opposition to status-quo politics.
Risk #4: Don't Let The Real Culprits Shift Blame
The majority of Americans are suffering right now. They know in their bones that something is wrong with our country. And the instigators of the shock doctrine that created this mess continue to get away with it.
Recommendation: Lay blame where it belongs — with the reckless bankers and their enablers who have infiltrated our government. Demonstrate how the Republican Party is in bed with these criminals. And, vital to your own legitimacy, acknowledge that some culprits reside in the Democratic Party. Go on a crusade to weed these contaminants out. Bring down the full force of righteous indignation of a people who have been betrayed by past leadership.
The only way to take advantage of the Occupy Movement is to take its demands seriously. Our country is fundamentally threatened with total economic (and moral) collapse. Take this threat seriously and you will win the support of the American people.

subset: commoncrawl


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W. Scott DeLoach gets 97 months in a federal penitentiary for stealing $36 million from construction firm PBS&J and making illegal campaign contributions. His accounting manager also faces jail time.
Stephen Taub, CFO.com | US
July 18, 2007
The former CFO and another former executive at an engineering consulting firm were sentenced Wednesday in connection with their role in a $36-million embezzlement.
W. Scott DeLoach, the former finance exec of PBS&J, an employee-owned national engineering and construction, was sentenced to 97 months in federal prison for his role in the scheme, according to the Miami Herald.
He also received a two-year sentence, to run concurrently, for pleading guilty to using ''strawmen'' to illegally contribute $11,000 to the 2004 campaign of Senator Mel Martinez (R-Florida), according to the paper.
In addition, Rosario Licata, a former manager, was sentenced to 63 months in prison, according to the report. The Herald noted that sentencing for former accounting manager Maria M. Garcia was postponed until Thursday so Judge James Lawrence King could review documents filed under seal by her attorneys.
The paper said the U.S. Attorney's Office recommended that Garcia receive a 66-month sentence, below the recommended sentencing guidelines, because she initially told authorities about the embezzlement.
Last September, Deloach, Licata and Garcia pled guilty to charges that they engaged in a scheme to embezzle more than $35 million from PBS&J Corp. from 1992 through March 2005, according to an announcement at the time from R. Alexander Acosta, United States Attorney for the Southern District of Florida. Deloach also pled guilty to making illegal campaign contributions.


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FPR would like to thank Christopher Carroll Smith for this guest post. Chris is an emerging Mormon Studies scholar out of Claremont Graduate University, in the tradition of Jan Shipps.B. H. Roberts, a member of the First Council of the Seventy, is better known for his efforts as an apologist than as a politician, but this is a man who was regarded by some of his contemporaries as the most prominent Democratic orator in the state of Utah. Roberts, in fact, was elected to the United States … [Read more...]
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text:
The Very Best Time to Practice Is…
Something that's been coming up in my conversations a lot lately is trying to find the "right time" to do something that gets your mind and body back on speaking terms. As in, "I just need to find the right time." I can so help with this, I think to myself when I hear this lament. Because I just so happen to know when the right time is! I love when that happens!
So, without further hoo-ha, the single best time to practice is:
Every day. If that makes you groan — because it seems so obvious, or too hard, or whatever — remember: it can be for only 2 minutes. In fact, William J. Broad, a New York Times journalist and author of The Science of Yoga said in his Fresh Air interview that research supports that a shorter, more regular practice is more beneficial then less frequent, longer practices. "If you do a little [yoga] everyday it's like putting a little money in the bank every month," he explained. (And I pumped my fist in my home office.) The results grow exponentially over time, because you get better and better able to give yourself what you need (clarity, relaxation, energy, insight) in the moment you need it. Saving all your angst up for a yoga binge on the weekends doesn't afford you the same power.
If the thought of doing something good for yourself for a few minutes every day sounds too daunting (I pray it doesn't — you have two minutes for yourself every day, right? Right??), then these are the other very best times to practice:
Whenever you remember. The hardest thing about any mind-body practice is having the clarity of thought to stop thinking about all you have going on and instead think, "I need to get right with myself." Perhaps that's not your language — you might think, "I need a break," "I wish I could crawl in to bed," "I need a glass of wine," or "Calgon, take me away!" But I'm willing to bet that you actually have a moment during the course of most days where you actually tell yourself you need to step out of the rushing river and hang out on the riverbank. The trick, then, is learning to transform that thought into action.
Whenever you get a reminder. Some days are so wacky that you won't remember that you have an arsenal of tool at your discretion to help you get your mind and body back on speaking terms. On those days, you'll need an outside trigger. For example — your pre-schooler starts whining, you hear a song on the radio that talking about breathing (and so many of them do, have you noticed?), a friend posts an article about stress on Facebook. Again, you have to transform the thought in to action and stop, drop, and breathe (at the very least), but once you have the awareness, you're already on your way.
At a certain time of day. From a more practical and planned-out perspective, there are several times of day that I've found are extra conducive to sneaking in a little yoga, meditation, mindful housekeeping, what have you. Tying your practice to a recurring event helps make it second nature. Options include:
- Right after you wake up. Roll out of bed, hit the bathroom, and then go directly to your mat (or your personal practice equivalent). I promise, even if your morning routine is rushed and you can only squeeze in a minute or two, you will savor that peaceful beginning and return to it in your mind throughout the day.
- After showering, before dressing. This is my current favorite time. It gives my hair a chance to air dry and my moisturizer to soak in before I have to present myself to anyone (including my family). My closet is actually a small room, and I put a mat right in there, so I'd feel compelled to do a downdog each time I get dressed and undressed.
- Any time you switch gears. Just before the kids come home, right after you get in from work, during the day before you embark on a new task, or first thing after the kids are asleep are all marvelous times to swim in your own waters and emerge refreshed.
- With the kids. If you feel you keep waiting and waiting until the kids are engrossed in something, just invite them to practice with you. They'll likely be way into it. Or, they'll get bored and wander off. Either way, you get some time in.
- As part of your bedtime routine. We spend so much energy on making sure our kids get a regular bedtime routine, but it's as good for us as it is for them. Build 10 minutes in to your end-of-the-day ablutions and notice how it affects your sleep. Wow.
Those are my best thoughts, but I'd love to hear yours. Leave a comment and let me know when you get your mind and body working on the same thing at the same time. Let's inspire each other!
Take care and keep breathing,
9 Responses to "The Very Best Time to Practice Is…"
I take a little "me time" when I'm on the toilet. I got the idea from Kris Carr two months ago. When I heard it, I though, "When is pee time, not me time?" Then I made a point to observe my bathroom habits. After a week, I realized I NEVER EVER just sit with my thoughts in the bathroom. I constantly found myself reaching for a magazine or rattling off my to-do list in my head from the toilet. Now I use the time to breathe mindfully and chill out. I certainly don't do this all the time (it's hard to break old habits), but I always do it when I remember how peaceful I feel after a little breather.
Thanks for the encouraging article. Last year I started my yoga pratice as soon as I woke up. It started out as 10 minutes. Now I easily practice for a blissful 30 minutes daily. It'sthe best thing I do for myself!
You are so right about this!
I am a personal trainer and often tell my clients the same thing about exercise; get a bit done, don't worry about a 60 minute workout, find a time that works for you.
Funny how I'm in the exact same mindset about yoga. My schedule only allows me to get to the studio once a week, but I've been practicing for over 8 months now, I should be able to do a bit on my own every day!
Thanks for this great post!
Kate, I love this post. Indeed a short, even minute long practice is beneficial. The suggestions for busy Moms to find time are excellent. Much gratitude and keep up the great work. Marjorie
With a dog and a 15-month-old boy to take care of, and a husband living in the next state, I find myself hurting for time to eat and sleep, let alone do yoga. I've found it easiest to roll out the mat while my son is playing on the floor. I can do some sun salutations or even just plank pose while he crawls around me. He loves the mat, too, so sometimes he climbs on it, too. It's a good way to keep an eye on him, interact with him, and still get some practice in. Plus, it helps me relax around him, as kids absorb their parent's stress very easily!
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A new edition of a book first published in Bogotá, this English edition is a crucial addition to the literature on Latin American business history for a wider English-speaking audience, and it will be of interest to business and economic historians generally. Essays are included by leading economic historians of Latin America from the UK and from other... more...
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This book is a wide-ranging and innovative study of Israeli-Lebanese relations from the birth of the Jewish state in 1948 to the Israel-Lebanon War of 2006. Israel's relationship with its Arab neighbours is a subject of perennial interest in the Middle East. The relationship between Israel and Lebanon has taken numerous forms since the establishment... more...
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Skeleton Appetizer Plates
You can't have a Halloween party without proper plates! These Skeleton Appetizer Plates make a wonderful spooky setting for a Halloween Party. Not only are they made with night-black glass and silver skeleton decals, they are a pretty, but creepy decor for your table.
Watch out for the vampires when you sit down at the table. These Vampire Teeth Place Card Holders make a bold and scary statement when you have a Halloween Party.Tags: Halloween, Halloween Parties, mommy, child, placecard holders, table decor, halloween decor, Vampire Place Card Holders, halloween decorationsAdded 9 Years Ago from Pottery Barn


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Maggie's Daycare
Alameda, CA
To view the State's license info—inspections, citations, and complaints—click the License number below. Also see About Childcare & Preschool Reviews.
Parent Reviews
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Oct 2009
Maggie's Daycare in Alameda - 17 years of experience.
Current spaces available in a clean, well organized and loving home daycare. My 2 children both attended Maggie's from walking until they started at EBI. They absolutely love Maggie and I love that she took such good care of them. She really gives each child the attention they need and they can feel that she really cares for them.
She provides 3 hot meals, and 2 healthy snacks daily. The whole first floor of her home is dedicated to her daycare and all the couches, tables, beds and furniture are child size. She regularly washes furniture coverings and shampoos carpets. She also has a nice outdoor space, front for bikes and the back for play houses and toys.
She is open 7:00 am - 6:00 pm year round. Her hourly rate is $6.00 per hour and daily rate is $45. She takes children walking up to age 5 and is licensed for 8 kids. Each day she provides music, alphabet time and singing. She is located on San Antonio in Alameda, CA.
For a visit please call Maggie at 510-865-2014. License number 013411529


text: Please help if you can! Many of you seem very knowlegable on how to cure reloading problems and I'm sure you must have come across this one before. When using my MEC STEEL MASTER 3.5" I'm having great difficulty with wads sticking to the bottom of the rammer tube after I've tried to seat them in the shell case. This means that as I lift the handle back up the rammer tube pulls the wad straight back out of the case. It doesn't seem to matter how much pressure is used to seat the wad wether it be 20lbs or 120lbs the wads stick every time. I'm using multi metal and TPS 3.5" and CGR 350 wads which are available over here and very similar to TPS. Any ideas anyone? :withstupid:


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Description: This is a USB to TTL Serial Cable which allows for a simple way to connect TTL interface devices to USB. The I/O pins of this cable are configured to operate at 3.3V specifically with a Raspberry Pi with each serial pin broken apart. Thanks to its separated pins, this cable is a perfect candidate for powering, connecting, and accessing the login and debug console on the Raspberry Pi.
The FTDI cable is designed around an FT232, which is housed in a USB-A connector. The other side of the cable is terminated with a separated 4-pin connector with the following pinout: RX (Yellow), TX (Orange), VCC (Red), and GND (Black). A link to the FTDI drivers can be found in the Documents section below.
Note: Please be aware that while the I/O pins in this cable operate at 3.3V, the VCC pin is 5V. The VCC pin is NOT 3.3V like the I/O pins.
Hello! Is the 3.3v RX pin 5V tolerant? thanks,
I just received some of these and did find out that the VCC pin is connected direct to the USB connector, so it outputs 5V.
This should be mentioned in the description. I don't know why it isn't.
How long is it? For the other FTDI cables that info is in the schematic (where it doesn't belong), but no schematic here. 1.80m?
Will this work for connecting the Serial LCD kit (LCD-10097) to my computer, i.e. does that kit accept 3.3V on the data line just fine?
Nice! This is almost as cheap as buying an old CA-42 Nokia data cable from eBay and replacing the connector, but a lot less hassle!
VCC is 3.3VDC at ?? ma ~= 500ma I would guess but no document so wanted to ask.
My experience with similar FTDI cables is that while the I/O is at 3.3V levels, the VCC pin would be 5V coming directly from the USB socket. But verification from someone in the know would be good….
This cable lacks the DTR signal which is needed if you intend to connect to a microprocessor whose bootloader is triggered by DTR, as are Arduino and others.
No DTR fore resetting Arduinos?
Nope. We do have FTDI cables and FTDI boards that do, you can also just manually hit the reset button. This cable is specifically for communicating over serial with things like a Raspberry Pi, PCDuino, etc.
The Raspberry Pi uses 3.3 V logic on its GPIO and com port lines. FTDI makes both 5V and 3.3V cables like this, so whzt you are supplying may be the correct 3.3V one. But your description states otherwise i.e. it mentions 5v IO.
I was thinking the same thing. I bet it is just an error in the text. In the photos, the USB connector shell is labeled "FTDI 3.3V"
Totes. Was just an error. Thanks!
Based on 13 ratings:
This product works well, but I thought it was regulating the USB 5V down to 3.3V. I realize now that I didn't read closely enough.
I bought this to connect to my Raspberry Pi console. After a little experimentation, it worked fine (connect Tx to Rx; not Tx to Tx).
I found it reliable and easy to connect.
Performs right out of the box, good driver support from the manufacturer!
And here's why …
needed an out-of-the-box solution for communicating with the UART on an Atmel XMEGA eval board.
This thing was plug in and go.
no fuss, no muss.
What else can I say?
This cable is a great price and great value. I used it to build a usb programming cradle for fire dept Motorola minitor 3 and 4 pagers. Works flawlessly after updating the drivers from the product page. The shipping was fast and packing was super.
Very happy with the purchase! The cable assembly is very reliable and we have had no issues!
I hate ftdi i feel dirty for buying a product from them. I wish they used a cp2012 or anything else but evil ftdi.
Buy three, you know you'll need them.
It's doing what was supposed to do, the connection from place A to B.
Works like advertised


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Oregon Historical County Records Guide
Deschutes County Scenic Images
Three Creek Lake
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Three Creek Lake and the Tam McArthur Rim in the Cascade Mountains south of Sisters. (Photo No. desDA0117)
About this image
Dimensions: 2509 x 3779 pixels (300 dpi version); Date created: June 2009; Camera: Nikon D80 Digital SLR; Lens: Nikon AF-S DX Zoom-Nikkor 18-135mm f/3.5-5.6G IF-ED; Photographer citation: Gary Halvorson, Oregon State Archives; Keywords/Tags: vertical, Oregon, Deschutes County, Three Creek Lake, Tam McArthur Rim, Cascade Mountains, boats, dock, recreation, snow-covered, shore, trees, blue sky.
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County guide home | Scenic images home


text:
Intellifinishing Parent Company Ranks On Inc.'s 5000 Fastest
The company had 90 percent growth since 2009, going from $17.5 million in sales to $33.2 million, which ranks it as the 24th fastest growing company in its home state of Kansas in the Inc. rankings.
Inc. magazine ranked the parent company of Intellifinishing ‑ Kasa Companies ‑as number 3446 on its seventh annual Inc. 500|5000, a ranking of the nation's fastest-growing private companies.
Kasa Companies is made up of the following entities: Kasa Controls & Automation, IntelliFinishing, and Kasa Fab. The company has had 90 percent growth since 2009, going from $17.5 million in sales to $33.2 million, which ranks it as the 24th fastest growing company in its home state of Kansas in the Inc. rankings.
"The uncertainty in the world economy as well as our nation's struggles have made success in manufacturing a challenge," said Dan Stutterheim, CEO of Kasa Companies, Inc. "Kasa's success and subsequent Inc. ranking represent the confidence our customers have in us, our expansion efforts in providing new technologies and services, the launch of IntelliFinishing, and the continual efforts of our employee-owners of our existing offerings: Kasa Controls & Automation and Kasa Fab. We are all proud to be on Inc.'s list."
In a stagnant economic environment, median growth rate of 2013 Inc. 500|5000 companies is an impressive 142 percent. The companies on this year's list report having created over 520,000 jobs in the past three years, and aggregate revenue among the honorees reached $241 billion.
Complete results of the Inc. 5000, including company profiles and an interactive database that can be sorted by industry, region, and other criteria, can be found at www.inc.com/5000 with the page identifying Kasa Companies, Inc. at inc.com/profile/kasa-companies


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Dartmouth, NS, Canada < change city >
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Reception Sites (57)
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Sizzler BBQ Catering Sin...
Atlantic Canada,
1-800-805-2227 or 902-892-6160
Caterers, Barbecues/Picnics
2 ratings, 2 reviews, 2 weddings
We used the sizzler,local vendor for our reception meal. Outstanding food. Buffet...
Westin Nova Scotian Hote...
1181 Hollis St
Halifax, NS, Canada
1 rating, 1 review, 6 weddings
See above.
Saege Bistro
5883 Spring Garden Road
Halifax, NS, Canada
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1 rating, 1 review, 4 weddings
The location and staff were fantastic! We rented the whole restaurant for our wed...
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I was able to personalize and make our invites exactly how I had envisioned. We h...
Fisherman's Cove - Build...
1531 Shore Road
Halifax, NS, Canada
Hotels/Accommodations, Cere...
1 rating, 1 review, 2 weddings
This place was great for a small wedding - very cosy and intimate. Guests loved ...
Do It All Events
Halifax, Nova Scotia
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Shannon was incredible! Her patience, professionalism and personal touches to our...
Banook Canoe Club
17 Banook Ave
Dartmouth, NS B3A
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Amazing location, the deck is beautiful and perfect for a summer wedding, we had ...
Casino Nova Scotia
1983 Upper Water Street
Halifax, NS, Canada
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1 rating, 1 review, 2 weddings
The Compass Room - Amazing. It was exactly the look and feel we wanted for our m...
Henneberry Room - Marine...
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1 rating, 1 review, 1 wedding
Again, can't say enough positive. Marlene, who looks after this place, was aweso...
The Fine Tuners
Halifax, Nova Scotia B3H 2T5, Canada
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Fantastic live music, fiddle and bass player. Celtic tunes. Essential for a marit...


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Being an well-balanced and intelligent person
In the well-balanced and intelligent person, the aura is bright and vivid, but dark spots when the mind is unbalanced appear.
Fourth aura
The fourth aura is the emanation of the higher mind of man or spiritual principle. His color is green. We are here in the domain of imagination, inspiration and intuition, creativity in art and literature Who is Kyle Leon?
Thursday aura
The fifth aura plays earlier. This aura manifests the essence of the spirit of man.
Occult science tells us that the conditions in the lower forms of consciousness are the result of forces occurring in the spiritual body. It is the receiving
station of all data of the lower aspects and writes the impressions received by them.
The fifth aura is the most important, since it is the point of union between the individual and the cosmos. There is a delicate range of individual life and
the ocean of consciousness shared by all.
Sixth and seventh aura
The sixth and seventh are superior aura belonging to more cosmic aspects to particular individuals http://health.revieweds.com/
The average man has not developed its potential to such heights and these auras can only be seen circling the body of initiates and Masters.
At this time we cannot but speak of a more comprehensively about the chakras to allow for a better understanding of how color therapy can be used because the
physical interconnect the seven centers and rays that attracts a predominant color necessary for the harmony of the individual as a whole.
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text:
Here's the recap from day five, the final day of the conference, May 31. I'm not going to recap the last few talks, though I will tell you that this morning featured a stimulating session with Drs. Robert Priest of TEDS and David Lee of Evangel Seminary. In their papers, the speakers considered the topic [Read More…]
Henry Center Travelogue, Day Five: Final Thoughts
Contemplate Heaven with Me for a Minute: Edward's "Heaven Is a World of Love", Pt. 3
I'm glad that some of you are enjoying these quotations from "Heaven Is a World of Love." Here's the final one you'll see on this blog. It encapsulates the themes seen in the previous quotations and paints a beautiful metaphysical, emotional, and spiritual picture of the realm to come. Wherever you are, take just four [Read More…]
Interesting Books I'm Reading; Also, a Time of Transition
1. Richistan–A pop sociology book on America's "new rich" economic class. I'm just a little ways into it, but it looks very interesting. I'm not sure why, but I love pop sociology stuff. The study of culture has always drawn me, and I enjoy finding out what the broad mass of people are doing and [Read More…]
The Rise of the Pastor-Theologian
Came across this quotation by Jonathan Edwards scholar Doug Sweeney. Those familiar with Edwards's works will recognize Sweeney as an editor of volume 23 of the Works volumes (it's pretty sensational to have your name alongside that of Jonathan Edwards on the author listing). Sweeney is an impressive scholar, but he is also a man [Read More…]


text: St. Joseph Hospital held their annual "Lights Of Remembrance" dedication on Wednesday. Each year, the hospital invites members of the community to remember and honor their loved ones as they turn on their Christmas lights outside the building. Children from St. John's choir in Bangor sang Christmas carols while refreshments were served.Mr. and Mrs. Claus even made an appearance. Community members who donated a financial gift could have the name of a loved one hung on "The Remembrance Tree" inside the hospital. But organizers say, the event is more important than just that. "The most important thing to us is that we gather collectively and care about each other. If someone wants to make a gift in response to that, that is fine too," said Kassie Zeigler, Executive Director of Community Networks and Foundations at St. Joseph Healthcare. Organizers tell us that this year's event was especially meaningful to them. The longtime steward of the lighting, Mary Clift, lost her husband Edwin on November 24th. He was the chair of St. Joseph Hospital's board of trustees. Hospital employees say they would be remembering him tonight.


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Numerous factors can affect skeletal regeneration, including the extent of bone injury, mechanical loading, inflammation and exogenous molecules. Bisphosphonates are anticatabolic agents that have been widely used to treat a variety of metabolic bone diseases. Zoledronate (ZA), a nitrogen-containing bisphosphonate (N-BP), is the most potent bisphosphonate among the clinically approved bisphosphonates. Cases of bisphosphonate-induced osteonecrosis of the jaw have been reported in patients receiving long term N-BP treatment. Yet, osteonecrosis does not occur in long bones. The aim of this study was to compare the effects of zoledronate on long bone and cranial bone regeneration using a previously established model of non-stabilized tibial fractures and a new model of mandibular fracture repair. Contrary to tibial fractures, which heal mainly through endochondral ossification, mandibular fractures healed via endochondral and intramembranous ossification with a lesser degree of endochondral ossification compared to tibial fractures. In the tibia, ZA reduced callus and cartilage formation during the early stages of repair. In parallel, we found a delay in cartilage hypertrophy and a decrease in angiogenesis during the soft callus phase of repair. During later stages of repair, ZA delayed callus, cartilage and bone remodeling. In the mandible, ZA delayed callus, cartilage and bone remodeling in correlation with a decrease in osteoclast number during the soft and hard callus phases of repair. These results reveal a more profound impact of ZA on cartilage and bone remodeling in the mandible compared to the tibia. This may predispose mandible bone to adverse effects of ZA in disease conditions. These results also imply that therapeutic effects of ZA may need to be optimized using time and dose-specific treatments in cranial versus long bones.
Citation: Yu YY, Lieu S, Hu D, Miclau T, Colnot C (2012) Site Specific Effects of Zoledronic Acid during Tibial and Mandibular Fracture Repair. PLoS ONE 7(2): e31771. https://doi.org/10.1371/journal.pone.0031771
Editor: Sudha Agarwal, Ohio State University, United States of America
Received: July 7, 2011; Accepted: January 15, 2012; Published: February 16, 2012
Copyright: © 2012 Yu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was funded by NIH-NIDCR R03 DE016701 to CC, NIH-NIAMS R01 AR053645 to TM and R01 AR057344 to CC and TM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Bisphosphonates (BP) are synthetic analogs of pyrophosphate that can be incorporated in vivo into mineralized tissues [1]. Due to their potent effects on osteoclastic bone resorption, BP are widely used for the treatment and/or prevention of metabolic bone diseases characterized by increased osteoclast activity such as Paget's disease, metastatic and osteolytic bone diseases, as well as osteoporosis [2]. These anti-resorptive effects of BP are also explored for improvement of callus strength and fracture healing in combination with anabolic treatments [3]. There are two major classes of bisphosphonates. The first group contains the less potent, non-nitrogen containing BP that can be metabolized into nonhydrolyzable analogues of ATP [4] and the second group contains the more potent, nitrogen containing BP such as alendronate, risedronate, and zoledronate (ZA). These potent BPs interfere with the mevalonate biosynthetic pathway and inhibit protein prenylation, which is important for osteoclast function [2], [5]. In 2002, intravenous ZA was approved to treat patients with multiple myeloma and bone metastases. Although ZA is the most effective BP in clinical use, undesirable effects have been reported that require better understanding of its mechanisms of action in bone. Cases of osteonecrosis of the jaw (ONJ) have been reported in patients treated with high dose of nitrogen containing bisphosphonates [6]–[8], but no reports were found in long bones. As ONJ is often associated with implant procedures, the bone repair process occurring around the implant is considered a key event leading to bone necrosis. The adverse effects of ZA could result from differences in mandibular and long bone repair. Bones in the head and the appendicular skeleton are derived from distinct cell lineages during embryonic development, which may lead to differences in their regenerative capacities and susceptibility to bisphosphonate treatment [9]–[11]. The goal of this study was to contrast the impact of ZA on the repair of mandibular and tibial fractures. We used a well-established model of non-stabilized tibial fracture and created a mouse mandibular fracture model to evaluate the effects of ZA on cranial versus long bone repair at the cellular and molecular levels. Bisphosphonates may not only act on osteoclast function but also on other cell types that are required for a timely repair process including osteoblasts, chondrocytes and endothelial cells [12], [13]. Therefore, we assessed the consequences of ZA treatment on cartilage and bone formation within the fracture callus, as well as matrix remodeling, osteoclasts and angiogenesis.
Materials and Methods
Zoledronate Treatment
All procedures followed protocols approved by the UCSF Animal Care and Use Committee (approval number AN080353-02B). Adult C57B6 wild type mice (males 3–4 month old) were anesthetized with an intraperitoneal injection of 50 mg/ml Ketamine/0.5 mg/ml Metedomidine (0.03 ml/mouse) and received 3 µg (0.1 mg/kg) Zoledronate (ZA) (Zometa, Novartis Pharma AG, Basel Switzerland) in 200 µl saline intravenously once 4 weeks before fracture and once at the time of fracture. This dosage is based on that which is typically used for treatment of multiple myeloma or breast cancer in humans [7], [14]. Control mice received the same volume of saline solution intravenously.
Non-stabilized tibial fractures
Adult C57B6 wild type mice (males 3–4 month old) were anesthetized with an intraperitoneal injection of 50 mg/ml Ketamine/0.5 mg/ml Medetomidine (0.03 ml/mouse). Closed, standardized non-stabilized fractures were produced in the mid-diaphysis of the right tibia via three point bending as previously described [15] (Fig. 1). Mice were sacrificed by cervical dislocation following an intraperitoneal injection of 2% Avertin (0.5 ml/mouse) and fracture calluses were collected at 5, 7, 10, 14, 21 and 28 days post-fracture (n = 5 per group). Mandibular and tibial fractures were induced in two separate groups of animals.
(A) Sections through the calluses (green dashed-lines) of PBS- (left) and zoledronate- (right) treated mice were stained with Safranin-O/Fast Green (days 7, 10 and 14 post-fracture) to detect cartilage (arrowsheads) and Trichrome (days 21 and 28 post-fracture) to detect bone (arrows). White arrows indicate the fracture site. Scale bar = 500 µm. (B) Histomorphometric analyses of total callus volume (Top), total cartilage volume (CV, middle) and total bone volume (BV, bottom) on PBS treated and ZA treated-mice at days 7, 10, 14, 21 and 28 post-fracture (n = 6 per group). *p<0.05, **<0.01. Bars represent mean±s.d.
Non-stabilized mandibular fractures
Adult C57B6 wild type mice (males 3–4 month old) were anesthetized with an intraperitoneal injection of 50 mg/ml Ketamine/0.5 mg/ml Medetomidine (0.03 ml/mouse) and received a preoperative dose of antibiotic (cefazolin, 10 mg/kg). For non-stabilized mandibular fractures, an incision was made along the inferior portion of the right hemimandible, and the masseter muscle was divided along its length and elevated to expose the body of the mandible bone. Five holes were created using a high-speed dental drill filled with an insect-pin along the mandible bone from the coronoid process to the gonial angle of the mandible bone (Fig. 2). Fracture was created using surgical tweezers. After creating the fracture, the soft tissues and skin were closed and animals were given analgesics. All animals were fed with soft diet for at least 7 days. All animals received a subcutaneous injection of buprenorphine (1.0 mg/kg) for analgesia immediately after surgery, and 4 and 24 hours after surgery. Food intake and animal activity were monitored frequently. Mice were sacrificed by cervical dislocation following an intraperitoneal injection of 2% Avertin (0.5 ml/mouse) and fracture calluses were collected at 5, 7, 10, 14, 21 and 28 days post-fracture (n = 5 per group).
(A) To create a mandibular fracture, the skin was opened and the mandible was exposed (left). Five holes were drilled (black arrow) and the fracture was created (white arrow) by surgical tweezers. (B) Sections through the PBS- (left) and zoledronate- (right) treated calluses (green dashed-lines) were stained with Safranin-O/Fast Green (day 7 and day 10 post-fracture) to detect cartilage (arrowheads) and Trichrome (day 14, 21, and 28 post-fracture) to detect bone (arrows). White arrows indicate the fracture site. Scale bar = 500 µm. (C) Histomorphometric analyses of total callus volume (TV, Top), total cartilage volume (CV, middle) and total bone volume (BV, bottom) on PBS treated and zoledronate treated-mice at days 7, 10, 14, 21 and 28 post-fracture (n = 6 per group). *p<0.05, **<0.01. Bars represent mean±s.d.
Histological and histomorphometric analyses of cartilage and bone
Callus tissues were fixed overnight at 4°C in 4% paraformaldehyde, decalcified at 4°C in 19% EDTA (pH 7.4) for 10–14 days, then dehydrated in a graded ethanol series and embedded in paraffin. Serial sections (10 µm thick) were collected throughout the entire callus and analyzed by histomorphometry as previously described [15]–[17]. To determine the amount of cartilage within each callus, every thirtieth section was stained with Safranin-O/Fast Green. To determine the amount of bone, adjacent sections were stained with Milligan's Trichrome. Images were captured from a Leica DM 5000 B light microscope (Leica Microsystems GmbH) that was equipped with a camera (Diagnostic). The area of callus, cartilage and bone was determined using Adobe PhotoShop.
Representative sections were processed for immmunohistochemistry. Briefly, after deparaffinization and hydration, antigen retrieval was performed by incubating with 0.05% trypsin and followed by 3% H2O2 in methanol for 15 min to inhibit endogenous peroxidase activity. Slides were treated with 1.5% donkey serum or 1.5% goat serum as indicated by manufacturer's instruction (goat or rabbit ABC staining kit; Santa Cruz Biotechnology, Santa Cruz, CA). Sections were incubated with the primary antibody (affinity purified goat polyclonal antibody against Collagen type II, Santa Cruz Biotechnology, CA; affinity purified rabbit polyclonal antibody against Collagen type X, Chemicon, Millipore, Billerica, MA) diluted (1∶50) in the blocking serum in a humidified chamber at 4°C overnight. Control sections were incubated with normal goat IgG or normal rabbit IgG serums. Detection of primary antibody binding was done using goat or rabbit ABC staining kit (Santa Cruz Biotechnology, Santa Cruz, CA). Sections were developed with DAB and counterstained with 1% Fast Green.
Detection and quantification of osteoclasts in the fracture callus
Tartrate-resistant acid phosphatase (TRAP) staining was performed using a leukocyte acid phosphatase kit (Sigma) on serial sections (10 µm) that were 300 µm apart through the callus. The number of osteoclasts within the fracture callus was estimated using an Olympus CAST system (Olympus) and software by Visiopharm (Visiopharm) as previously described [18]. Briefly, fracture callus was outlined using low magnification in each section. Ten to twenty fields that covered approximately 10% of the fracture callus were systematically acquired using unbiased uniform random sampling under higher magnification. A counting frame probe was also selected to quantify the number of osteoclasts and the area of the callus within each field. Values are expressed as number of osteoclasts per mm2 callus tissue.
Detection and quantification of apoptotic cells and osteoclasts in the fracture callus
To detect osteoclasts and apoptotic cells, TUNEL assay to detect DNA fragmentation was performed using a TUNEL kit (ApopTag, Millipore) according to the manufacturer's instructions followed by TRAP staining. The number of apoptotic cells and osteoclasts within the fracture callus was estimated on three center sections using an Olympus CAST system (Olympus) and software by Visiopharm (Visiopharm) as described above.
Detection and quantification of tissue vascularity in the fracture callus
To visualize and quantify blood vessels at day 5 post-fracture, calluses were cryo-embedded in OCT. Serial sections (10 µm) that were 600 µm apart were selected throughout the callus and immunohistochemistry using an anti-platelet endothelial cell adhesion molecules (PECAM) antibody was performed [15]. For each sample, six sections were analyzed. The length density (length of blood vessels per unit volume of the reference space) of the blood vessels within the fracture callus and the surface density (area of the outer surface of blood vessels per unit volume of the reference space) of the blood vessels within the fracture callus were estimated using an Olympus CAST system (Olympus) and Visiopharm software (Visioplarm) as previously described [18], [19]. The whole callus was used as the reference space and its volume was estimated using Calvalieri's Principle [20], [21].
Zoledronic Acid affects the formation and remodeling of cartilage and bone during tibial fracture repair
To examine the long-term effects of ZA on healing of non-stabilized tibial fractures, we injected ZA intravenously 4 weeks before fracture and on the day of fracture. We chose a high dose of ZA as used in cancer patients and delivered two doses in order to maximize the incorporation of ZA within bone prior to injury [7], [14]. Histological analyses showed a delay in fracture repair in ZA-treated mice (Fig. 1A). There was less cartilage during the soft callus phase of repair (day 7 to 10 post-fracture) in ZA-treated compared to PBS-treated mice as shown by Safranin-O staining (Fig. 1A). Trichrome staining did not reveal an apparent delay in bone deposition within the callus until day 14 (data not shown). However, there was more woven bone in the callus of ZA treated mice by day 28, indicating a delay in the restoration of the bone marrow cavity (Fig. 1A). Histomorphometric analyses showed that total callus volume was smaller in ZA-treated samples compared to controls at day 7. Total callus volume gradually increased from day 7 to 14 and was reduced by day 28 post-fracture in control samples, while it remained high by day 28 in ZA-treated samples indicating a delay in callus formation and remodeling (Fig. 1B, top). Histomorphometric analyses confirmed that there was significantly less cartilage in the callus of ZA-treated samples at days 7 and 10 post-fracture (Fig. 1B, middle). Cartilage volume peaked by day 10 and decreased by day 14 in PBS-treated samples, while cartilage volume remained high by day 14 compared to day 10 in ZA-treated samples (Fig. 1B, middle). These results indicate that ZA delays both cartilage deposition and remodeling during tibial fracture repair. Bone volume was significantly higher by day 10 post-fracture and remained high by day 28 in ZA-treated samples compared to controls implying an increase in bone deposition during the soft callus phase of repair followed by a delay in bone remodeling (Fig. 1B, bottom).
Zoledronic Acid delays cartilage and bone remodeling during non-stabilized mandibular fracture repair
To compare the effects of ZA on tibial and mandibular fracture repair, we developed a non-stabilized mandibular fracture model. Fractures were created from the top of the coronoid process to the gonial angle of mandible bone (Fig. 2A). Histological analyses showed that mandibular fractures healed via endochondral ossification with a lesser degree of cartilage deposition compared to non-stabilized tibial fractures (Fig. 2B). Callus size was smaller in mandibular compared to tibial fractures. As observed in tibial fractures, mandible fracture calluses were filled with woven bone by day 14 post-fracture, and gradually resorbed and bridged by day 21. Bone remodeling was well underway by day 28 (Fig. 2B, left). Histomorphometric analyses confirmed these histological analyses. Total callus volume peaked at day 10 and gradually reduced by day 28 post-fracture in PBS- and ZA-treated samples, but the total callus volume was significantly greater in ZA-treated samples compared to the controls at days 14 and 21 post-fracture indicating that there was a delay in callus remodeling (Fig. 2C, top). Cartilage formed by day 7, peaked at day 10 and decreased by day 14, but cartilage volume remained significantly high in ZA-treated calluses compared to PBS-treated calluses. Cartilage was completely resorbed by day 21 in both ZA- and PBS-treated calluses (Fig. 2C, middle). Bone volume gradually increased from day 7 to day 14 and decreased by day 28 in PBS-treated calluses, but remained high from day 14 to day 28 in ZA-treated calluses (Fig. 2C, bottom). These data indicate a delay in cartilage and bone remodeling in the repair of non-stabilized mandible fractures treated with ZA.
Zoledronic acid delays cartilage hypertrophy during tibial fracture healing
Since cartilage formation was delayed in tibial but not in mandibular fracture healing, we performed immunohistochemistry to examine chondrocyte differentiation following ZA and PBS treatment. In tibial fracture calluses, immunostaining for collagen type II was detected in chondrocytes of both PBS and ZA-treated mice by day 5 post-injury (Fig. 3A, B). However, collagen type X immunostaining was observed in PBS but not in ZA-treated calluses (Fig. 3D, E). By day 10, collagen type X was expressed in both groups (Fig. 3F and data not shown), therefore cartilage hypertrophy was delayed during tibial fracture repair as a result of ZA treatment. In mandibular fracture calluses, immunostaining for collagen type II was markedly decreased compared to tibial fractures (Fig. 3G, H), which was in concordance with decreased cartilage formation reported via histology and histomorphometry. Immunostaining for collagen type X was seen in the calluses of PBS and ZA-treated mice at days 5 and 10 post-fracture (Fig. 3J, K, L and data not shown).
Immunostaining of collagen type II (A–B, G–H, black arrows) and collagen type X (D–F, J–L, white arrows) near the periosteum within tibial (top) and mandibular (bottom) fracture calluses of PBS (left) and zoledronate (middle and right) treated mice. No staining is observed in negative controls (C and I).
Zoledronic acid reduces osteoclastogenesis during mandibular fracture healing
Callus formation and remodeling involves the deposition and breakdown of extracellular matrix by the coordinated action of osteoblasts, chondrocytes and osteoclasts. Osteoclasts are a well-known target of bisphosphonates action. Therefore, we investigated the effects of ZA on osteoclast numbers in tibial and mandibular fractures. There were no significant differences in the number of TRAP-positive cells per callus area between ZA-treated and control samples in tibial fractures, but there were less TRAP-positive cells per callus area in ZA-treated samples compared to the controls in mandibular fractures at both days 7 and 14 post-fracture (Fig. 4). To assess whether the decrease in the number of TRAP-positive cells was due to apoptosis, we performed double staining for TUNEL and TRAP at day 5 post-fracture. Overall there was minimal cell death in the callus of both tibial and mandibular fractures, and we did not observe significant differences between ZA-treated and control groups (data not shown). Dead cells were found at the fracture site, within the bone marrow and in the cortex, while TRAP-positive cells were found primarily around new bone adjacent to the periosteum and within the fracture callus (Fig. 5 and data not shown). Double staining and quantitative analyses showed that TRAP-positive cells were not TUNEL-positive, suggesting that ZA treatment did not induce osteoclast cell death (Fig. 5 and data not shown). Therefore, the decrease in the number of TRAP-positive cells were not due to increase cell death in mandibular fractures.
Stereological analyses of TRAP positive cells per area of fracture callus (n = 6 per group) in PBS- and zoledronate-treated mice at day 7 (A) and day 14 (B) post-fracture. **p<0.01. Bars represent mean±s.d.
TUNEL and TRAP double staining on ZA-treated tibial (A and B) and mandibular (C–E) fractures at day 5 post-injury. High magnifications (B, D, E) indicate apoptotic cells (black arrows) and TRAP-positive cells (white arrows) within the fracture callus. No TRAP-positive apoptotic cells can be detected at the fracture site. (A, C) Scale bar = 50 µm; (B, D, E) Scale bar = 10 µm.
Zoledronic acid reduces angiogenesis in the tibial fracture callus
Skeletal tissue deposition and remodeling is tightly linked with revascularization of the fracture site. To examine whether ZA affects vascularization, we quantified blood vessel length and surface densities in ZA- and PBS-treated calluses. Immunohistochemistry of PECAM (Fig. 6A) and stereological analyses revealed that blood vessel length density (Fig. 6B) and surface density (Fig. 6C) were significantly reduced in ZA-treated calluses compared to controls in tibial fractures but not in mandibular fractures at day 5 post-fracture. Our results also revealed that in the absence of ZA treatment, blood vessel length density and surface density were significantly higher in tibial fractures compared to mandibular fractures (Fig. 6).
(A) PECAM immunostaining (black arrows) on PBS- (top) and ZA-treated (bottom) tibial (left) and mandibular (right) fracture calluses. Scale bar = 200 µm. (B) Analysis of the length density of blood vessels within the callus (mm/mm3) and (C) analysis of the surface density of blood vessels within the callus (mm2/mm3) in PBS- and zoledronate-treated mice at day 5 post-fracture (n = 6 per group). *p<0.05. Bars represent mean±s.d.
Differences between tibial and mandibular fracture repair
In this study, we investigated the differences in healing between cranial and long bones and the responses to ZA treatment in these two repair sites. We created a non-stabilized mandibular fracture model to compare healing with our previously described model of non-stabilized tibial fractures [15], [22]. While non-stabilized tibial fractures heal mostly through endochondral ossification, we show that non-stabilized mandibular fractures heal through intramembranous and endochondral ossification with a reduced amount of endochondral ossification compared to tibial fractures. Differences between tibial and mandibular fracture repair may be due to differences in their mechanical environment [22], [23]. Previous studies in our laboratory showed that tibial fractures heal via intramembranous ossification when a rigid fixation is applied to the fracture site, thus indicating that the mechanical environment influences the mode of repair [15], [22]. In the absence of mechanical stimuli, mesenchymal cells differentiate directly into osteoblasts but under the influence of mechanical stimuli cells can differentiate into osteoblasts and chondrocytes [22]. Mechanical stimuli also play a significant role in bone repair by regulating vascular growth [24], [25]. VEGF and TGF-beta are released from human fracture hematoma with mechanical loading [24]. In our study both tibias and mandibles were loaded. However, the mechanical stimuli and stress are presumably greater in the tibia due to weight bearing, which may explain the increase in callus size, number of blood vessels and degree of endochondral ossification compared to mandibular fractures.
Differences in the extent of endochondral ossification between tibial and mandibular fracture calluses may also be due to the distinct cell populations that participate in repair. Bones in the head and the trunk do not share the same embryonic origins. Long bones in the limb are derived from the trunk lateral plate mesoderm and form via endochondral ossification, while the mandible is derived from the paraxial mesoderm in the head, and forms via intramembranous ossification [10]. We previously showed that skeletal progenitor cells are recruited from the local periosteum during long bone repair [26]. Other reports indicate that cells in the mandible are recruited locally during repair [27]. Given the distinct embryonic origins of cells that constitute the mandible and the tibia, progenitor cells in the mandible may be more prone to undergo bone formation via intramembranous ossification while cells in the tibia may be more prone to undergo endochondral ossification. Yet it is interesting to note that both tibia and mandible can form bone via endochondral ossification in a non-stable mechanical environment and via intramembranous ossification in a stable mechanical environment. Regardless of the source of cells, the mechanical environment largely influences cell fate after bone injury. These fundamental differences between tibial and mandibular fractures may in part explain the differential effects of ZA in these two healing environments. On the one hand skeletal progenitors within cranial and long bones may not have the same sensitivity to ZA, thus leading to direct effects on osteoblasts and/or chondrocytes. On the other hand, indirect effects of ZA may be due to the distinct mechanical environments and effects on other cell types such as osteoclasts and endothelial cells.
Site-specific effects of Zoledronic Acid in late stages of fracture repair
Although ZA does not prevent fracture healing, we observed significant changes during healing of mandible and tibial fractures as a consequence of ZA treatment. This was not due to an insufficient dosage of ZA since we maximized the dosage based on that used in cancer therapies [7], [14]. We show that intravenous ZA injection increases the callus size and bone volume during the remodeling phase of both mandibular and tibial fracture repair. This is consistent with previous studies, which reported that ZA treatment delays bone remodeling and simultaneously increases the strength of the callus during late stages of fracture repair [28]. In addition, we report a delay in cartilage remodeling, suggesting that ZA affects matrix-remodeling in both cartilage and bone. Interestingly, we observed a more severe remodeling defect in mandibular compared to tibial fractures, which was linked to a decrease in the number of osteoclasts in the ZA treated mandibles. This decrease in osteoclast number was not due to increased cell death, and may therefore result from a decrease in the infiltration of osteoclasts in the callus [29]–[31]. This more pronounced remodeling defect in the mandible may also result from impaired osteoclast function [30]. Compared to long bones, osteoclasts in cranial bones exhibit higher levels of proteolytic enzymes and resorptive activities, which may augment their sensitivity to ZA treatment [32], [33].
Site-specific effects of Zoledronic Acid in early stages of fracture repair
Previous studies on the effect of bisphosphonates on fracture healing mostly focused on later stages of repair, where they induce a delay in callus remodeling both in stabilized and non-stabilized mechanical environments [34]–[36]. Our study reveals the effects of ZA in the early stages of bone repair and the process of endochondral ossification. We treated mice starting one month prior to the injury in order to specifically assess long-term effects of ZA and the impact on the initial stages of repair. There was a decrease in callus size and cartilage volume in the early soft callus phase of tibial fracture repair, but this effect was not seen in mandibular fractures. In parallel, ZA delayed chondrocyte hypertrophy in tibial but not mandibular fractures. A direct effect of ZA on chondrogenesis may be more apparent in tibial factures due to increased cartilage volume and higher degree of endochondral ossification. Concurrently, we detected a decrease in angiogenesis in tibial fractures treated with ZA compared to control groups. Impaired angiogenesis could result from delayed hypertrophy and delayed VEGF expression in cartilage. Several studies reported that bisphosphonates interfere with the angiogenic process through various molecular pathways [37]–[41]. This delay in re-vascularisation of the fracture site might also affect cartilage formation. Indeed, we have previously observed a correlation between low blood vessel density and inhibition of chondrogenesis during the initial phase of stabilized fracture repair [19]. In parallel, we observed early anabolic effects on bone, which can be attributed to stimulatory effects on osteoblast proliferation in vitro [42]–[45].
In conclusion, we report differential effects of ZA on cranial versus long bone repair in mice. The soft callus phase of repair was more affected in the tibia compared to the mandible with a delay in cartilage and bone deposition, in cartilage hypertrophy and angiogenesis. ZA had a more profound impact on tissue remodeling in mandibular compared to tibial fractures, which was correlated with a decrease in osteoclasts. These site-specific effects of ZA do not necessarily explain the occurrence of ONJ, since other factors are involved such as infection, combined treatment with corticosteroids, immunosuppressive agents or chemotherapy [46]–[48]. These results suggest that BP can be used as anticatabolic agents to augment bone repair with or without combination with anabolic agents [3], [28], however, the dosage and the timing of anti-resorptive therapy to augment the size and strength of the callus may change depending on the type of bone and the mechanical environment.
Author Contributions
Conceived and designed the experiments: CC. Performed the experiments: YYY SL DH. Analyzed the data: YYY CC DH TM. Contributed reagents/materials/analysis tools: DH TM. Wrote the paper: YYY CC.
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Khatri named Editor-in-Chief of Surgical Oncology journal
October 31, 2013
Vijay P. Khatri, professor in the Department of Surgery, has been named Editor-in-Chief of Surgical Oncology, an international academic medical journal.
Khatri, a surgical oncologist with the UC Davis Comprehensive Cancer Center, will lead the peer-reviewed journal, which has headquarters in England.
"It's a great honor to be selected as editor-in-chief," said Khatri. "Our goal is to really be a resource for community cancer centers, as well as academic centers. This is a great opportunity to lead a journal to the next level, to expand, and be innovative."
Khatri is the author of a leading surgery textbook, "Atlas of Advanced Operative Surgery" and more than 85 journal articles. He has been on the editorial boards of the Journal of Clinical Oncology and Annals of Surgical Oncology and is a member of the American College of Surgeons and the European Society of Surgical Oncology.
Khatri manages a broad spectrum of cancers, but his clinical interests are in rectal carcinoma and primary and metastatic liver cancer. He is also director of Faculty Development and Mentoring for the UC Davis Department of Surgery.


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Learning opportunities abound during Global Sojourns adventure
Global Sojourns focuses on weaving knowledge into the trips in a meaningful way. We do not arrange "educational trips", but rather fun, memorable travels that are filled with experiences and information. With our help, you'll be able to acquire a deep level of knowledge about the location and the people you are visiting.
If you are visiting Livingstone, Zambia or Cape Town, South Africa during your trip, you may wish to weave in a visit or two to one of the Global Sojourns Giving Circle partner projects and learn about some of the issues facing the local communities in those areas.