text:
The golden boy of the velodrome may be a greenhorn to road racing, but tonight Marty Nothstein is riding for nothing less than victory.
''I go for victory every time,'' Nothstein says. ''I like to race and I like to win.''
Nothstein, who won the gold medal in track match sprint cycling in the 2000 Sydney Olympics, arrived in Athens late Friday night after a race in Shelby, N.C., to participate in his first Xcelerate Twilight Criterium.
''(The Athens criterium) is one of the biggest crits of the year. It is a prestigious race to win and the best racers in the nation will be there,'' Nothstein says.
Nothstein began cycling in 1987 at the velodrome near his hometown of Trexlertown, Pa., and has been a disciplined track racer ever since. His career highlights feature an array of wins, including seven world championship medals and three world titles, 19 national track titles, and an Olympic silver medal in addition to his Olympic gold. Two of his three world titles were won in 1994, which marked the first double-gold medal performance at a world championship by a U.S. cyclist.
Despite a career distinguished by victory, Nothstein describes himself as a man haunted by what he perceived as failure when he lost the gold medal by a literal hair's-breadth to two-time gold medallist Jens Fiedler of Germany in the 1996 Olympic Games in Atlanta.
The Nothstein file
Height: 6 feet, 2 inches
Weight: 215
Born: Feb. 10, 1971, Allentown, Pa.
Hometown: Trexlertown, Pa.
Residence: Trexlertown, Pa.
Family: Wife, Christi; son, Tyler; daughter, Devon
Discipline: Track
Team: Mercury-Viatel
Seven world championship medals, including three world titles, 19 national track titles, one Olympic gold medal and an Olympic silver medal.
''There were nights I woke up thinking, 'What did I do wrong?' '' Nothstein says. ''I committed my life to something and lost by less than a centimeter. From that day, winning the gold in 2000 dominated my life.''
For the four years following Atlanta, Nothstein was totally focused on redeeming his loss to Fiedler. On Sept. 20, he finally got his chance, when the two met again in the Olympic match sprint semifinals.
This time he beat Fiedler in two consecutive rides. Later that night, he captured the gold medal when he beat Florian Rousseau of France, again in two consecutive rides. It was the first time an American has won a gold in cycling since Steve Hegg's Olympic victory in individual pursuit at the 1984 Los Angeles Games.
Said Nothstein of his moment of victory, ''It was great! No doubt!''
Nothstein says that several professional cycling teams from the United States and Europe have tried to recruit him since his silver-medal finish in Atlanta, but until this year he hadn't signed with any teams because of his total commitment to winning the gold in Sydney.
Now, with his Olympic victory behind him, he says he finally feels that he can pursue other races and cycling disciplines, although his major career goals such as the September Goodwill Games and the World Championships are still track-oriented.
This year Nothstein is racing on the road as part of Team Mercury-Viatel, with whom he signed a two-year contract. He says he doesn't know how many Mercury-Viatel riders will be racing in Athens tonight, but he feels sure there will be a full squad.
Though the track discipline to which he is accustomed is a notoriously individual sport, Nothstein insists he is a team player.
''If someone on the team wins, that's a win for me. I'd like to see Chris Pic (a Mercury-Viatel team member from Dahlonega) win, but the team manager will make the call as to who we push across,'' he said.
Track and criterium cycling differ greatly, but Nothstein says the adjustment hasn't been that hard because road cycling has always been a major component of his track training, which he describes as more intense as well as more physically and mentally rigorous than road training.
''Training for a good track cyclist is very demanding,'' he says.
Nothstein said he averages about 500 miles per week regardless of whether he's training for track or road racing. But his track regime also includes intense weight workouts at least twice a week.
Furthermore, he emphasizes that the key to successful track racing lies in the ability to analyze his competitors and devise complex strategies based on their weaknesses and strengths.
There is no hiding the showman in Marty Nothstein, and he seems to be looking forward to putting on a strong performance for the people of Athens.
''Athens has a strong cycling community, which is refreshing to race in because people understand the sport and appreciate the race,'' he says.
Nothstein says he isn't intimidated by the crowds of 20,000 to 30,000 fans who line the Twilight Criterium course each year to cheer the racers. He said he's used to huge cheering sections and enjoys his fan base.
''If anything, it (a large crowd) will electrify my mood and performance. I like to race for a crowd, and people appreciate me giving a race my best shot.''
''I hope 50,000 will come,'' he said. ''Tell them the fastest man in the world will be there.''
This article published in the Athens Daily News on Saturday, April 28, 2001.
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text: Neil Brown wrote: > On Tuesday June 23, tyasui redhat com wrote: >>>> MD-RAID1 solves this problem by having counters in superblocks on both >>>> legs. If some leg dies, the counter on the other devices is increased. If >>>> the dead disk comes online again, it is found that it has old counter and >>>> cannot be trusted. >>>> >>>> Would it be possible to extend a logical volume when converting it to a >>>> raid1 and use the last area of the volume as a superblock? >>>> >>>> Mikulas >>> This is an old thread, I am just trying to revitalize it! :-) How about >>> dm-raid1 taking superblock storage as arguments in the command line, >>> just like the log device? The superblock storage is entirely managed by >>> the kernel, LVM just allocates it. Error handling can be instant this >>> way. LVM can auto convert the exiting mirrors to this kind of mirrors if >>> space is available. >> Interesting idea. The superblock storage managed by kernel is really >> important to handle an error quickly inside the kernel. > > I don't think that it is important to handle errors quickly - they > really shouldn't happen often enough that speed is an issue. All you > need to do is handle errors correctly. Not really. Quick error handling is not for preventing this issue but shorten system downtime. Fixing this issue is most important, but it is better to have discuss other approach, too. > I would suggest that you simply get raid1 to block any write requests > until all drive failures have been acknowledged by userspace. > So you would need to differentiate between an acknowledged drive > failure and an unacknowledged failure. Writes block when ever there > are unacknowledged failures. > Then you need a message that can be sent to the raid1 to acknowledge > the failure of a particular device. > 'suspend' would need to fail if there are any unacknowledged failures > as otherwise it would block. As we discuss in this thread, your suggestion is quite similar to what malahal proposed more than one year ago. malahal us ibm com wrote: > > Look at this patch > > http://permalink.gmane.org/gmane.linux.kernel.device-mapper.devel/4973 > > > > It essentially generates an uevet and waits for the user level code to > > act on it and send a message to unblock it. This is a simple approach, but all write I/Os are blocked before write errors are processed by userspace (dmeventd). Depending on the error, such as timeout, the recovery procedure in userspace may take a long time and application sensitive to delay will have another problem. superblock approach may solve this data corruption issue without an additional delay. When dm-raid1 detects a write error, it can disable the mirror leg quickly and ask userspace to process aftertreatment. I would like to continue discussion how to fix this issue. Thanks, Taka

subset: commoncrawl


text:
Business Law
Ask a Business Lawyer. Get Business Law Questions Answered ASAP.
Good morning. You can do two things...i) you can immediately terminate his rights and cause him to leave; and ii) you can also file a civil suit against him for any damages you suffer as a result of his breach of Section 4.9 in the event any of your employees or other independent contractors leave as a result of his solicitations.
I hope this has given you the guidance you were seeking. I wish you the best of luck!
If you have a follow-up question, please remember that there might be a delay between your follow up questions and my answers because I may be helping other clients or taking a break.
If I have adequately answered your question, even though the answer might not have been the one for which you hoped, I would appreciate it if you would please click the GREEN ACCEPT button so that I receive credit for my work; otherwise, though you have made a deposit, I do not receive credit.
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The information given here is not legal advice. As all states have different intricacies in their laws, the information given is general only. This communication does not establish an attorney-client relationship with you. I hope this answer has been helpful to you.


text:
I cant believed i am saying this but i am stoked for the preseason lol. Watching teams position battles will be extra fun this pre season
I will be glued to my PC or TV watching most of the preseason cant wait for Saturday and see how the Bears and Colts look.
Will have to DVR the Colts game((Bears play at the same time) but am excited
what will everyone be looking for in the preseason?


text:
Of the three million Canadians living with diabetes, 90 per cent have been diagnosed with type 2 diabetes.2 Despite the numerous treatment options available, approximately 50 per cent of patients don't reach the level of glucose control recommended by their doctor.3
"Living with diabetes can be extremely frustrating and discouraging," said Mississauga resident, Jatinder Bawa, who has lived with type 2 diabetes for 10 years. "While I have made some lifestyle changes to control my condition, there were times when I wasn't well-managed and it was hard to always stay motivated without seeing some signs of improvement."
INVOKANA: A New Way of Treating Diabetes
As glucose is filtered from the blood in the kidneys it is reabsorbed into the bloodstream. SGLT2 is an important transporter responsible for this reabsorption. INVOKANA selectively inhibits SGLT2 and as a result, promotes the loss of glucose in the urine, lowering blood sugar levels in adults with type 2 diabetes.
"In clinical trials, INVOKANA had a great impact on patients by improving glycemic control, while reducing body weight and systolic blood pressure," said Dr. Ronald Goldenberg, endocrinologist, LMC Diabetes & Endocrinology. "INVOKANA was also associated with a low incidence of hypoglycemia, which is something that is often associated with diabetes medications. This new treatment provides an exciting option for physicians and patients."*
Clinical Trial ProgramThe Health Canada approval of INVOKANA is based on a comprehensive global Phase 3 clinical program, including 713 Canadians in six studies, which was one of the largest global clinical programs in type 2 diabetes ever conducted. INVOKANA has been studied as a single agent (monotherapy), in combination with metformin and in combination with other glucose-lowering agents, including insulin, in patients who need further glucose control.4
Results from this program showed that the 100 mg and the 300 mg doses of INVOKANA significantly improved glycemic control, body weight and systolic blood pressure.5
In two studies comparing INVOKANA as an add-on therapy with metformin to current standard treatments, INVOKANA dosed at 300 mg provided superior reductions compared to sitagliptin and to glimepiride in both A1C levels (measure that reflects the average blood sugar levels over the past three months) and body weight.6,7
Results from the Phase 3 clinical program showed INVOKANA was generally well tolerated. The most common adverse events with INVOKANA are genital mycotic (fungal) infections, urinary tract infections and increased urination. These specific adverse events were generally mild to moderate in intensity and infrequently led to discontinuation in Phase 3 studies.8 Due to its mechanism of action INVOKANA may cause volume depletion (dehydration). Uncommon adverse events related to reduced intravascular volume including orthostatic hypotension, postural dizziness (both defined as fainting, feeling dizzy or lightheaded due to a drop in blood pressure when you stand up) and hypotension (low blood pressure). This happens more often in older people (aged 75 and over), people with kidney problems and people taking water tablets (diuretics). For additional information on adverse events please visit the Canadian Product Monograph at www.janssen.ca.9
About INVOKANA 10
INVOKANA is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus. INVOKANA is currently approved for use in 39 countries.
About Type 2 Diabetes
Type 2 diabetes is a disease in which the pancreas does not produce enough insulin and/or the body does not properly use the insulin it makes. As a result, glucose builds up in the blood instead of being used for energy.11 If left untreated or improperly managed, diabetes can result in a variety of complications, including heart disease, kidney disease, eye disease and nerve damage.12 The financial burden of diabetes is also significant. By 2020 it is estimated that the number of Canadians with diabetes will grow to over four million13 and diabetes will cost the Canadian healthcare system $16.9 billion per year.14
About Janssen Inc.
Janssen Inc. is one of the Janssen Pharmaceutical Companies of Johnson & Johnson, which are dedicated to addressing and solving some of the most important unmet medical needs in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we bring innovative products, services and solutions to people throughout the world. Please visit www.janssen.ca for more information.
*Dr. Ronald Goldenberg was not compensated for any media work. He has been a paid consultant to Janssen Inc.
References______________________1 INVOKANA Product Monograph. Page 3. May 2014.2 Canadian Diabetes Association. Diabetes Fact Sheet. Available at: http://www.diabetes.ca/files/Diabetes_Fact_Sheet.pdf. Accessed April 2, 2014.3 Bailey CJ. Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacol Sci. 2011;32 (2):63-71.4 INVOKANA Product Monograph. Page 35. May 2014.5 INVOKANA Product Monograph. Page 37. May 2014.6 INVOKANA Product Monograph. Page 40. May 20147 INVOKANA Product Monograph. Page 44. May 2014.8 INVOKANA Product Monograph. Page 8. May 2014.9 INVOKANA Product Monograph. Page 8. May 2014.10 INVOKANA Product Monograph. Page 3. May 2014.11 Canadian Diabetes Association. Type 2 Diabetes: The Basics. Available at: http://www.diabetes.ca/documents/for-professionals/112020_08-399_type-2-diabetes-the-basics_0413_lc_final.pdf. Accessed April 2, 2014. 12 Canadian Diabetes Association. Diabetes Fact Sheet. Available at: http://www.diabetes.ca/files/Diabetes_Fact_Sheet.pdf. Accessed April 2, 2014.13 Canadian Diabetes Association. Diabetes: Canada at the Tipping Point. Available at: http://www.diabetes.ca/CDA/media/documents/publications-and-newsletters/advocacy-reports/canada-at-the-tipping-point-english.pdf. Accessed April 29, 2014. 14 Canadian Diabetes Association. The Prevalence and Costs of Diabetes. Available at: http://www.diabetes.ca/documents/about-diabetes/PrevalanceandCost_09.pdf. Accessed April 2, 2014.
SOURCE Janssen Inc.


text:
Tramadol is a pain relief pill, which is employed in the treatment of severe to moderate pain. There are two types of pills which you can get in any online prescription drugstore. They are called as Tramadol immediate release and Tramadol extended release. Read on to understand the difference between these two formulations.
Release speed
The extended release version releases the drug into the body in a slow manner. The effect of the drug would stay in the system for 10-12 hours. In cases of immediate release, the drug stays in the system for 4-6 hours. This release speed dictates the dose limit. Usually, the XR is taken once a day and IR can be taken once every 8 hours.
Since XR stays in the system for long, the chances of overdosing or drug interactions are high. For instance, an alcoholic might drink alcohol while still having the substance in the body. The intensity of side effects will also be high when Tramadol XR interacts with certain drugs like cough syrup, a sleep medication.
In the case of extended release pill, the capsule is excreted but in the case of immediate release, the shell is not excreted. This does not mean that the medicine was not absorbed by the body. It just means that the working mechanism is slightly different.
Course length
Immediate release is used for those who want Tramadol for a short period of time. In the case of chronic pain or when a patient wants the drug around the clock, extended release is used.
Pediatric patient
Pediatric patients should not use an extended-release version of Tramadol. This is because the drug should not stay long in their system. In the case of using extended release, serious side effects would be experienced. Immediate release version can be used for children but only if they are older than four years.
Elderly patient
Senior citizens are not usually recommended to use extended release Tramadol, in most cases. In the case of using it, the dose will be very minimal, to avoid serious side effects. Immediate release tablets are given more often to senior citizens.
Renal and liver patients
Extended release Tramadol is not recommended for those with any problem in their liver or kidney. Any person with a life-threatening medical condition in brain, heart, lungs, liver, kidney or other parts of the body would not be given the extended release.
Side effects
The probability of incidence of side effects is very high in case of extended release since it remains in the system for long. Though there are side effects in immediate release, the probability of occurrence is comparatively low.
Scope of use
Due to its limitations in terms of time of action, dose limitation and others, not everyone can use extended release. Thus, it has a very small scope of use than the immediate release version of Tramadol.
Other than these, both the Tramadol versions are narcotic–like painkillers which are used for moderate to severe pain. Both of them have the same allergic symptoms, side effects, overdose symptoms, drug interaction and others. Both of them are not recommended for pregnant woman and lactating mothers. Though they have a lot of similarities, one should not interchange the drugs for any reason, without consulting a doctor. Switching from extended release to immediate release without consent from a doctor is poised with many health risks.
In short, Tramadol extended release is a stronger version of the drug that stays in the system for long. A part of the drug gets released immediately into the system and the rest would be released slowly. Thus, the effect of the drug can be seen for a longer time period. This type of drug is not suitable for many people. The immediate release is the normal tablet which gets absorbed by the body immediately. It would stay in the system for a couple of hours before being excreted.


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hi all , re-posting this over here at the suggestion of the adafruit help on the other tread...here is the post to save some time...viewtopic.php?f=19&t=37058&p=183128#p182793
used this as a starting point...http://playground.arduino.cc/uploads/Le ... relays.pdf and now i need to give it a bit of delay on releasing the relay, so it stay on just a bit longer...it only energizes for maybe 1/2 sec or less, it sometimes will trigger the right response in the zoom, but mostly it is not quite enough time(if i hold the button down, it will multiple pulse and still not enough time, but again sometimes it will trigger the zoom). need maybe a 1sec pulse time and that would prob. be enough i know a cap maybe can do this, just not sure of value and placement...i dont want to go with a 555 timer or anything else, just need to extend the time just a bit...thanks gang.


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Former University of Arizona and NFL kicker turned Tucson restaurant owner, Max Zendejas, was indicted in Pima County Superior Court on damage and theft charges related to his recently closed UA area restaurant.
The indictment alleges that from March to May 15 Zendejas, 49, "knowingly controlled property of the University of Arizona...with the intent to deprive the University of Arizona of such property" at his restaurant, Zendejas 13 located at 1628 E. Sixth St. The property includes a walk-in refrigerator, compressors, ceiling fans and kitchen sinks worth more than $25,000.
The indictment also alleges Zendejas "recklessly defaced or damaged property belonging to the University of Arizona" causing more than $10,000 in damages at the restaurant.
Zendejas opened the Mexican restaurant and bar across the street from Arizona Stadium in 2010.
The restaurant closed on April 12.
The University of Arizona Police Department would not release police reports citing an open investigation.
Zendejas played for the UA in the early 1980s followed by one season in the NFL with the Washington Redskins and two with the Green Bay Packers.
He then became involved in restaurants and different family businesses in the Phoenix area.
Zendejas is also a co-owner of the Blue Moon Nightclub, 1901 S. Fourth Ave.
Contact reporter Veronica Cruz at firstname.lastname@example.com or at 573-4224.


text:
im 44 and for the last couple of years i have noticed (as has everyone else)that i have bags way under my eyes but not under my eyelids, more sitting on top of my cheek bones, i tend now to smile alot more cause the bags dont look as bad when i do, as a result i have deep crows feet now, i am hoping my botox treatment will eliminate both my wrinkles and bags, am i hoping for to much?
Baggy and Wrinkly Under Eyes - Dublin, Ireland
Im 44 and for the last couple of years i have...
Was this review helpful? {{ voteCountOthers + ' other' + (voteCountOthers == 1 ? '' : 's') }} found this helpful


text:
The Global FlyFisher
Simply the Best Place to go for Online Fly Fishing and Fly Tyinghttp://globalflyfisher.com/gallery/super-simple-fly-photos/
Super simple fly photos
This is the über simple lightweight guide to taking pictures of your flies - finished flies or for step-by-steps - even with your phone!
What you will need
1) A camera. Duh! A simple, compact digital camera with a macro or close-up setting is ideal, but a phone will do in a tight spot even though it's far from good. The macro is very important, and is a must for shooting any fly but the biggest ones, and phones might have macro settings, but they have no macro lens! More on that later.
2) A clip, a vise or something else to hold the fly. You can use your tying vise, but an electrical clip on a base is also fine. Even a piece of wood will do.
3) Something to hold the camera. A real tripod is optional, but makes life easier. You can also do with a block of wood, a glue clamp or whatever you can find that fixes the camera in one place in the same height as the fly. A bit of gaffer tape can make sure it doesn't move.
4) A lamp or two. Simple table top lamps like what you use for your tying is fine. One is sufficient for most purposes, but two is better. And identical if possible and the larger the reflector the better.
Preparing the camera
Make sure you have a memory card with space and a full battery for the purpose.
Find the macro setting on the camera and turn it on. Some cameras can't go close enough when zoomed. Zoom out if that's the case.
Turn off the flash. Make sure it doesn't turn on automatically. Most cameras have a no-flash setting. If you can't find it, consider taping black gaffer or cardboard over the flash. The built-in flash is normally no good for macro images.
The really low lowdown
If you do nothing else, do this:
1) Prepare the phone or camera as mentioned above if you can
2) Shoot with the phone or camera level with the fly and an even or distant background
3) If you use a phone, lay it on its side and shoot horizontal pictures
4) Have enough light. A work lamp is good. The sun is not. It's too sharp and harsh.
Setting up
The easiest setup is simply made on a table top or some other flat and sufficiently large surface.
Mount the fly in a vise or clip and set that and the camera up so that you get the image crop that you want. Make sure that the whole fly is in the frame.
Also make sure your camera can focus on the fly by simply holding it in your hand a going close enough to get the picture you want. Shoot a test shot and check in on a computer.
Once you have found the distance, set the camera permanently in a small tripod, a clamp or on a wooden block, a box or whatever. Use some tape to secure it so it doesn't move if you have no tripod.
Check that the image is OK and sharp. If the camera focuses every time you press the shutter release, also make sure that it actually focuses on the fly every time you take a picture and not on the background.
Things to avoid
If the phone has a macro setting, use it! It does very little optically, but it sets the camera to acquire the best possible shots when close up.
Turn off the flash as mentioned above with a normal camera.
Secure the phone so that it doesn't move. It must be in the horizontal position. We want pictures that are wider than they are high, and a vertical phone does not shoot good fly photos - unless your fly is higher than it's long, of course...
It can be tricky to mount the phone, but either get a thingamajig that enables it to be clamped to a table's edge (a couple of cheap glue clamps or strong clothes pins might do the job) or simply tape it to whatever is convenient. I have made a setup using a wooden block and a couple of strong rubber bands, and that works like a charm. Simple and cheap.
You need to keep the lens and most of the display free, so you can operate the camera. Most phones require you to press the screen to focus and press an on-screen button to take the picture, and you simply can't repeat those motions identically for each shot if you are hand holding the phone.
And if the phone rings? Well, I already laugh inside imagining you with your ear to a taped or clamped down phone... Let it ring! Unless of course it's a fishing buddy who wants to take you fishing.
Set up your background. It needs to be vertical behind the fly, but not too close. Use a couple of wooden blocks, boxes or what you have at hand to hold it. Gaffer's tape is your friend again. You can also hang it from something tall enough.
Make sure that the distance is sufficient to make the background blur but not so far away that it doesn't cover the whole image. We do not want the living room, tying desk or office peeking into a corner or edge of the image. The surroundings should be completely blocked out by the background.
Simply buy a couple of pieces of paper large enough. A2 or about 15x20 inches or larger is a good size, which will work for most setups.
You can of course also use a wall - a uniformly colored one with no picture frames, no wall sockets or other distractions.
The light is the one most critical thing to set up properly.
If you have one lamp, simply put it right over the fly slightly to the front of the fly and as close as possible but without getting any part of the lamp in the picture. Make sure you have no shadows or reflections on the background.
A smaller lamp (spot type) might need some kind of diffusion. A simple piece of white paper is the easy solution. Simply tape it over the front of lamp in a large arc, forming a large surface between the lamp and the fly.
The first lamp in the two lamp setup is placed similar to when using one. Over the fly in the front, and close.
You use the second lamp to soften the shadows on the fly and light up the fly from the side to the rear. This lamp is placed a bit further away from the fly. Be careful that this lamp does not reflect or make the fly cast a shadow on the background.
We don't want shadows!
The light is the one most critical thing to set up properly.
Mount the fly you want to shoot in the clamp or vise, making sure that you don't move anything around.
Press the shutter button carefully. Make sure you have focus on the fly and take the picture.
Check the result on a computer unless the screen on the back of your camera or phone is really good and supports zooming in.
When you are satisfied, you can just shoot away, and make sure to shoot a few extra pictures of each fly. They might come out identical, but the risk of a blurred or shaken photo is there, so backups are always useful.
People love step-by-step image series, and if you want to do those, it takes a bit more work.
There's essentially two ways to go:
1) Tie the fly as you usually do, but make pauses and transfer the partly tied fly to the photo setup. Make a half hitch or two for every step, leave the thread on the fly and move it back and forth between tying and shooting.
2) Set the photo gear and background up so that you can shoot while tying. This takes more preparation and a bit of dexterity while tying, but gives a way more consistent result. Doing this with a phone is close to impossible, but can be done by people with patience and a strong heart.
Save your setup
When you are done and break down your mini studio, make a mental or written note of the way things were arranged - or take a picture of it with some other camera, like your smartphone. This will enable you to set up the same way the next time you want to take fly pictures.
Checking your pictures
You need to check the result on a computer. The screen on your camera or phone isn't really adequate. Transfer the images via cable or a card reader, or use Dropbox or a similar service to get them out of the phone.
Make sure the fly is sharp and nicely lit.
If not, it's back to the drawing board, changing your setup and shooting some more.
1) Get a small tripod if you use a camera. That easily ensures the same framing every time. Small table top tripods only cost a few dollars and are excellent for this purpose. Small ones can be had for nothing on Amazon, eBay or in your local photo shop. All cameras have a screw thread in the bottom for mounting it on the tripod head.
2) If the camera supports manual focus, you can consider turning off autofocus (AF) to avoid it refocusing on every shot.
3) Set the white balance to iridescent or tungsten light. Most cameras will automatically measure the color of the light, but if a picture of a white background comes out very yellow or even orange, you can override this setting and force the camera to adjust to the warm light of bulbs. Remember to set it back to auto when you are done.
4) Use the self timer to avoid shake. The camera might move while exposing because you push it when triggering the shutter. This can be avoided by using the self timer like when you shoot family portraits with yourself in them.
Thanks, Martin. This
Thanks, Martin. This is an excellent tutorial. I should be able to take photos good enough to frame as gifts. I really appreciate it.
Read more about why you should register.


text:
Benitez named interim manager of Chelsea
Chelsea have surprisingly brought Rafael Benitez out of the coaching wilderness, hiring the Spaniard in an interim role after mercilessly firing the man who guided the club to its first Champions League title just six months ago.
Benitez agreed to a contract with the European champions until the end of the season, nearly two years after being fired by Inter Milan in his last coaching position. He filled the vacancy created by Roberto Di Matteo's sudden departure earlier in the day following the team's dip in form over the past month.
Tuesday's 3-0 loss to Juventus proved to be Di Matteo's final match in charge, the result in Turin leaving Chelsea third in its Champions League group and in danger of becoming the first holders to fail to reach the knockout stage.
"I am extremely proud of the successes and trophies that we were able to bring to the club in recent months," said Di Matteo, who also won the FA Cup last season during his spell as interim coach before being taken on full-time in June.
"Lifting Chelsea's first Champions League trophy, in Munich, was the best achievement in club history and without doubt the highlight of my career to date, both as a player and manager. It is a memory I will treasure for the rest of my life."
Di Matteo's exit was another demonstration of the ruthlessness of Chelsea owner Roman Abramovich, who is up to his ninth manager since buying the club in 2003.
The 52-year-old Benitez comes with experience, having also been in charge of Valencia and Liverpool - the club where he won the Champions League in 2005 and took it to the 2007 final. Chelsea fans will be concerned about Benitez's record at Inter, where he lasted barely six months, and also his style of play, which is widely regarded as defensive.
"The owner and the board believe that in Benitez we have a manager with significant experience at the highest level of football, who can come in and immediately help deliver our objectives," Chelsea said in a statement.
Benitez was flying to London from Abu Dhabi and will meet the squad for the first time at the club's training ground tomorrow. His first match in charge will be in the Premier League on Sunday at home to Manchester City, the reigning champion and unbeaten leader.
Chelsea has dropped to third place in the standings after picking up just two points from its past four matches - a record that, dovetailed with Chelsea's disappointing defense of its European title, left Di Matteo exposed.
Given Abramovich's history of hastily firing managers, there was a certain inevitability about Di Matteo's demise, even though the Swiss-born Italian was awarded a two-year contract only about four months ago.
Di Matteo was told by chairman Bruce Buck and chief executive Ron Gourlay that he had been fired at a 4am meeting at the club's training ground, soon after landing back in England following a flight from Turin. He is believed to have already said farewell to his players in the dressing room after the loss to Juventus.
"Wow, Chelsea have sacked their manager!! ... its a madness," Manchester United defender Rio Ferdinand said on Twitter.
Andre Villas-Boas, who was fired by Chelsea to give Di Matteo a chance to manage his former club, described the goings-on at the west London club as "just another day at the office".
"That's football," said Real Madrid coach Jose Mourinho, another to have been jettisoned by Abramovich. "I'm never happy when a manager is sacked. It can happen to me and is a feeling that no one likes to have."
Chelsea was in disarray when Di Matteo, then an assistant coach, took over from Villas-Boas in March. The former Italy midfielder brought together squabbling factions within the squad and led the team to the club's seventh FA Cup title by beating Liverpool in the final and then a first Champions League trophy, defeating Barcelona in the semi-finals then Bayern at the German club's home ground.
Di Matteo, with his typical coolness, has also been praised for the way he handled a racism case involving John Terry that engulfed the club. Chelsea is in the middle of another racism incident, having accused a Premier League referee of abusing one of its players.
"It's been a difficult day," Chelsea playmaker Juan Mata said on his Facebook page. "I would like to thank him for all this time with us and wish him the best of luck for the future."
In the Premier League, Chelsea had been leading for much of the season but trails Manchester City and Manchester United in the title race.
The team is third in Group E of the Champions League behind Shakhtar Donetsk and Juventus with one match left. The Blues next face Danish club FC Nordsjaelland, but they will be eliminated even if they win if Juventus earns a point in Ukraine.
In Benitez's favour is his experience and close relationship with Fernando Torres from their time together at Anfield. Getting the best out of Torres could be crucial to pleasing Abramovich, who signed the Spain striker for 50 million pounds in January 2011.
Hiring Benitez is a risk, however, given his trademark defensive approach. Abramovich is widely known to prefer a more attractive style, as demonstrated by spending a combined reported 70 million pounds on attackers Oscar, Eden Hazard, Marko Marin and Victor Moses in the offseason.
For that reason, Benitez's appointment may just be a stop-gap measure to give Abramovich more time to lure the man widely believed to be his first choice as coach, Pep Guardiola.
Guardiola is on a one-year sabbatical after leaving Barcelona at the end of last season and may yet replace Benitez in the offseason.


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Princeton City Council member Thom Walker says that after sitting in on orderly annexation talks with Baldwin Township he still has no idea what his neighbor to the south is looking for in terms of an agreement.
"To this day I don't know what Baldwin wants, what they advocate," Walker said.
But he's very willing to learn. So is Princeton Mayor Jeremy Riddle.
The two Princeton lawmakers say they don't know the path to reaching an annexation agreement with Baldwin Township, but they agree that the path will take them down 128th Street to the Baldwin Town Hall.
The Princeton City Council on Thursday, March 22 voted to resume meeting with township officials and work towards a goal of negotiating an orderly annexation agreement.
The move comes in response to a Feb. 7, 2012 letter from Baldwin Township officials stating that it was the township's desire to resume meetings.
The letter came after a January 2012 letter from City Administrator Mark Karnowski that stated that he, Riddle and one council member wished to discontinue further meetings.
"We are very disappointed with your committee's desire to abandon as important a negotiation as this is for our communities," Baldwin Chairman Jay Swanson wrote.
At issue is a 30-year agreement that would shape both the boundaries of Princeton and Baldwin Township as the two communities grow into the next three decades.
On March 22 the council sat down to address the annexation issue. The city has three options in responding to Baldwin, Karnowski told the councilors: maintain the status quo and do nothing in regards to annexation, resume discussions and hold down costs by not involving attorneys at this point, or resume discussions with the aid of a facilitator.
Walker advocated for meeting with a facilitator and offered to meet at the Baldwin Town Hall on the township's home turf.
Reggie Edwards, a facilitator who worked with Princeton and Baldwin Township on the annexation issue in 2003, has offered to facilitate discussions once again. Edwards is the former director of the Region Nine Development Commission in Mankato. Edwards resigned from the post in October after requesting a leave of absence following his September performance review.
Walker said he didn't see an annexation agreement being reached without a facilitator. Riddle seemed to agree.
"I'm willing to try once and see if it speeds things up," Riddle said.
Added Walker, "I definitely don't want legal representatives there telling us what (an agreement) should look like."
Reaching an annexation agreement doesn't appear to be a hard concept, said Walker, who added that he must be missing something.
"No one's saying it's hard," Riddle said. "The players just keep changing."
Riddle said he has a goal of meeting before May.


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Hot 107.9 Website Is Now Optimized For Your Smartphone With New Mobile Version
We know that being one of the hottest listeners in Acadiana means that you're always on the go. Whether it's school, partying, kids, shopping, tanning, clubbing, traveling, twerking, working out, or whatever you do – you're life is mobile. So we figured that since the majority of what you do is mobile, then it only made sense to give you the best mobile experience of our Hot 107.9 website, with a brand new look and feel that is optimized for your smartphone.
It's literally everything you love about our normal Hot 107.9 website, but specifically tailored to view and interact with on your smartphone. The new mobile version of our site puts our biggest stories right in your face at the top of a new homepage that shows all of the latest stories in the order in which they were posted.
If you want to see the latest stories, just scroll down easily using your opposable thumbs. (sorry dolphins, we haven't made a version for you yet)
When you find a story you want to read, just click on it and it will quickly load up (faster than before). You will also notice BIG share buttons so you can quickly and easily share interesting stories with your friends on Facebook and Twitter.
At any point, you can tap the icon on the top left of your screen and open up a full menu of options to navigate to other parts of our website with ease. There is also a search bar to quickly search the website for keywords, tags and more.
Easily browse through the profiles of your favorite DJ, listen live, contact us, or check out our playlist right in the palm of your hand.
Taking Hot 107.9 on the go is better than ever now with the new mobile version of our website, fully optimized for your smartphone. Best of all, there is no update, downloading or hassle of setting anything up. It just "works." Just type in www.1079ishot.com and you're good to go.
We hope you're as excited as we are about our new website design. It's optimized for mobile use on your smartphone, so go out and do whatever it is that the hottest listeners in Acadiana do and never miss a beat!
While you're at it, make sure you have RadioPup; our free smartphone app, and stay connected with us at all times (in the least creepy way possible, lol)
Did you check out the new mobile version of our website? Tell us what you think!


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|Song Title
Trae Tha Truth - Life on da Edge Lyrics (feat. Shyna, T.C.)
Trae Tha Truth – Life on da Edge Lyrics (feat. Shyna, T.C.)
Ah-ha, we doing it one more time ya heard me
Man the streets in me, the streets done made me
I grew up thugging, believe that
Me and Trae, we gon riot this year
Y'all gon respect that to the fullest, man look
We doing it like this here, check the peoples out man look
[Hook: Shyna]
It's kinda hard to maintain, living like a true soldier
Living life on the edge, has got me so caught up
It's kinda hard to maintain, living like a true soldier
Everyday is a test, and I just won't give up
I remember back in the day, I was confused as a child
And never thought that I would grew up, to be this wild
I'm living life on the edge, to maintain is my job
They wanna see me crack under pressure, but giving in this too hard
They better get they army to swarm me, thinking they taking me out
I been a soldier out the gates, so fuck what you talking about
Guerilla Maab till I'm leaving, Trae, Dougie D and Z-Ro
Call it what you wanna, you plex and you'll be six feet below
Cause I been insane living, ever since my brother was gone
Finally facing up with the truth, that he ain't coming back home
I know it's wrong moving on, and though it seems the game'll never change
I don't knock, I gotta be strapped with a shank and a glock
Cause niggas be crucial on my block
And ain't no way they taking my stripes, I ain't going out without a fight
Unless they catch a nigga, sleeping in the night
And even still there ain't no killing me, even if I die
I bet the world fin to remember me, a real nigga from the streets
I'm out chea cousin, rioting and thugging
You could catch me in the hood, grinding and hustling
The streets mad me, all the radios play me
Ain't no turning back, ain't no nigga could fade me
I'm still on a cash route, and I'm in a tight situation
Dog, the ball blast out
Still pulling masks out, at any time
Play with me whodi, you buy it and never find
Bitches make them cop calls
While my money keep the cops off, got Trae posted
With a Mack, 'case anything pops off
I'm a made man young hustler, ain't no wankster in me
When I riot duck, that's that gangster in me
Head buster, got them people talking
I'm playing with a six shot, I'ma fuck off this some whodi
Cause the streets too hot, too hot
Even nothing but the devil running me hot, and I'm going crazy
All the shit that I be facing, is what got me turning shady
They tell me to keep my head up, and it's easy for them to say
Cause they ain't going through what I'm through, each and every day
When you living like I'm living, and the block get bled
Running from the cops, praying them niggas never leave for dead
Cause I done seen it from every way, where the thugs and killas play
A nigga from around the way, that'll be strapped down with a K
And ain't trying to murder nobody, I just wanna live my life
And I can't focus on my life, when these motherfuckers be shife
And I be searching for another way, please watch over Trae
Heavenly Father guide me out, so I can live another day
I gotta hold on, everything I got on the line
Surviving is what I'ma do, so I'ma ride behind mine
Like it was all that I had, or it be all that I got
Even if I lose everything, it just ain't in me to stop
I'm trying so hard, to maintain
Knowing my life, will never be the same [x2]
[Trae Tha Truth – Life on da Edge Lyrics (feat. Shyna, T.C.)]
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|Trae Tha Truth Lyrics
|"Losing Composure" (2003)
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Family tree▼
m. 24 Jun 1769
Facts and Events
Augustus Henry FitzRoy, 3rd Duke of Grafton, KG, PC (28 September 1735 – 14 March 1811), styled Earl of Euston between 1747 and 1757, was a British Whig of the Georgian era. He is one of a handful of dukes who have served as Prime Minister.
He became Prime Minister in 1768 at the age of 33, leading the supporters of William Pitt, and was the youngest person to have held the office until the appointment of William Pitt the Younger 15 years later. However, he struggled to demonstrate an ability to counter increasing challenges to Britain's global dominance following the nation's victory in the Seven Years' War. He was widely attacked for allowing France to annex Corsica, and stepped down in 1770, handing over power to Lord North.


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"My awesome dream vacation would be a two-week trip in the Outback." — Erik Greenfield & Little Vegas (Henderson)
"I would love to go to Italy. To Venice, since it's going under. I'd love to go there." — Chelsea Palacios (Henderson)
"I'd say a trip around Europe to all the art museums ... such as the Louvre." — Evan Appel (Las Vegas)
"I want to go to Africa to see all of the different animals and wildlife." — Giselle Gomez (Las Vegas)
"I've already had one. It was on the John C. Stennis aircraft carrier. It was overnight and I was 200 miles out at sea. It wasn't really a vacation, but a great experience." — Howie Bell (Henderson)


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Sculptural Driftwood Cocktail Table
Incredibly sculptural and figural driftwood cocktail table. This table has better lines and forms than most of the driftwood tables that we have ever seen. Excellent original condition. This base will support a larger top if desired.
View more items in categories:
Coffee Tables, Furniture, Sold, Tables


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- {{matchup.date.fullday}}{{matchup.date.month + ' ' + matchup.date.day}}
Canucks slip past Sabres
Brad Lukowich's tally in the third period lifted the Vancouver Canucks past the Buffalo Sabres 3-2 on Monday night.
Vancouver won as -135 home favorites, while the game played UNDER the 5.5-goal total listed by oddsmakers.
Henrik Sedin had a goal and an assist for the Canucks, who got a pair of helpers from Daniel Sedin in the payday.
Thomas Vanek and Adam Mair scored for Buffalo, which outshot Vancouver 32-25 on the night.


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By Russ Pirozek at DigitalNoob
One of the last events of the Con season will be underway in a few short days, and Aspen Comics has been gracious enough to list the times and events that will be held during this years Long Beach Comic-Con. While the convention is only a few short days, there will still be plenty to see during the event. They will also have a LBCC variant ofExecutive Assistant: Assassins #5 on display and for sale in limited quantities, with only three hundred issues and seventy-five prints available.
To see the rest of this press release, check out EGMNOW.com/DigitalNoob


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"White men love natural hair!"
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Join Date: Feb 2009
Posts: 164
Wednesday, August 12, 2009 at 03:03AM
slips out of thread without making any comments
LMAO, you know I was gonna say something to this affect, but I was like let me say something positive.
Really I would also like to add to my comment that I would hope that it wouldn't matter to anyone what other people think about what naturally grows out of your head.
I know the OP is biracial and your father is white. I'm not sure if that bares any relevance to anything. But I mean your dad married and fathered children with a black woman, so there's bound to be some white guys out there who will appreciate all that comes with being with a woman of African descent.
But all I'm saying is if they didn't like your hair, that shouldn't make you feel any kind of way. I know for a solid fact that if other people didn't like my hair this way they could go kick rocks. I mean it's always nice to get compliments but you have to have a love affair with yourself, you know what I mean?
Also I'd be leery of those "exotic" comments. I mean what are you some type of rare plant or bird?
I know that I don't know you, but I'm just trying to give some honest caring advice. Just be careful and don't fall for the okidoke.
Btw NappyCurlyCrown you have been cracking me up every time I read your comments since I've been frequenting this curly forum more and more.


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The Board of Water and Light's Citizens Advisory Panel on New Generation recommended "wait-and-see" on a proposed billion-dollar coal and biomassfueled power plant in late January, but the utility's general manager says the facility may still turn out to be in BWL's future.
Saying the panel's report "came up with some pretty good conclusions," General Manager J. Peter Lark added that "the conclusions didn't say, 'The hybrid plant is not the way to go.' They said, 'Step back, watch your load.' The 11-member panel, whose report became public on Jan. 26, began work in 2008 after BWL proposed the 350megawatt hybrid plant to replace the Eckert Power Station, portions of which are more than 55 years old and whose staged shutdown is set to begin in 2017. The hybrid plant would be fueled by two-thirds low sulfur coal. Waste wood, paper and crop residue would supply the rest.
When BWL announced its plans to build the hybrid plant in May 2008, Lark called it "the smartest, most economical and most environmentally sensitive option we have.' He also warned of 52 percent to 55 percent rate increases without the plant and if the board purchased electricity on the open market. Building the plant, he estimated, would hike rates 18 percent to 21 percent.
Environmental critics sharply disagreed, saying the hybrid plant would lock the utility into a 50-year continued reliance on coal and ignored options like weatherization and efficiency programs to reduce demand and small-scale distributed energy resources. The citizens group Lansing Can Do Better rose up to stop the proposal.
The panel said there are too may uncertainties about federal climate change legislation affecting coal generation, the state and local economy and the availability of a steady biomass supply. Lark acknowledged all of these issues, saying "the economy went into the tank" after the hybrid plant was proposed. As the panel's work went on, he said, "It became really clear that there were some problems with the plan as we had put it forward."
BWL, Lark added, has learned that a consistent stream of biofuels is going to be difficult to secure. "People were telling us they had such a stream, and now we're having trouble finding the stream. Every day we hear new things about 'Oh, I've got some bio you can burn,' but if you're going to do a major plant, you've got to have a substantial stream of biomass, and really, as yet, I don't think we've found that."
Although biomass is considered a renewable energy source, it is not necessarily cleaner than coal. Coal and biomass plants emit similar amounts of soot and, in some cases, greater amounts of nitrogen oxide and volatile organic compounds, which contribute to summertime smog.
Coal's problems are even bigger. Coal burning also releases naturally occurring mercury and is a major source of greenhouse gas emissions, especially carbon dioxide. A recent U.S. Environmental Protection Agency finding that carbon dioxide is a pollutant under terms of the Clean Air Act positions the agency to write rules limiting emissions of the gas in the event Congress hits a stalemate on energy and climate change legislation.
Despite all this, Michigan utilities continue to press ahead with coal plant plans, including an 830-megawatt Consumers Energy facility in Bay City that the state Department of Natural Resources and Environment approved in December over environmental group objections.
While saying she is encouraged by the citizen panel report, Anne Woiwode, executive director of the Sierra Club Michigan chapter, added, "We can't ignore that the BWL has not yet abandoned the proposed coal plant. We hope the board listens to the panel but also goes beyond that to make sure that investments in meeting our energy needs move the area forward toward a clean, efficient and renewable energy future."
Added Woiwode: "For a year and a half the residents and ratepayers that are part of Lansing Can Do Better have been raising questions, bringing information and urging the BWL administration, the panel and board to address our electric needs through energy efficiency and renewable energy. This report shows significant progress in that direction."
Former Michigan Attorney General Frank Kelley, who co-chaired the citizens panel, called the Eckert plant "obsolete" and said the board will have to use a "patchwork" of options to respond to generation issues.
Joan Nelson, a panel member and director of the Allen Neighborhood Center, cited " a strong consensus" for delaying the decision to invest in a new facility. "I'm pleased about the board's commitment to aggressively pursuing other options, including energy efficiency strategies and technologies," she said, adding that these are the quickest, easiest and cheapest approach to reducing energy use and costs.
Lark said the panel's recommendation for a closer look at a natural gas-fired plan was a good one. "I think a natural gas plant would make a lot of sense at this point. We haven't decided which way we're going to go. But we're going to study those recommendations very seriously.
"What I would see coming out of their recommendations is that we keep the biotype plant in the back of our heads, let's take a look at gas, and there's a suggestion that we buy from another utility," Lark said, but he added that transmission of that power would be "costly."


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Three teens were taken to the hospital Monday evening after a rollover accident while racing on SW 40th Street in Lancaster County.
According to Lancaster County Sheriff's deputies, the driver of a 1999 Dodge Avenger, 19-year-old Dalton Walker was racing another vehicle.
Both cars were headed westbound on Claire Street when Walker tried to pass the car in front of him. As he passed the slower car, an eastbound vehicle appeared, forcing Walker to avoid the vehicle. He then lost control, causing the vehicle to hit a culvert, go airborne, then roll several times.
Walker and 18-year-old passenger Savannah Carter were ejected when the car rolled. Emergency crews had to cut 14-year-old Austin Baldwin out of the vehicle.
All three were last reported in critical condition, but had non-life threatening injuries at Bryan West Campus.
Austin Baldwin says Walker told him they were going for a drive, but didn't mention racing.
Baldwin's mother, Austin Baldwin says while she's happy the teens survived, she hopes other teens their age learn an important lesson.
"We've all made mistakes in our life and done things that we shouldn't have and I guess the kids just have a higher price to pay," she said. "Racing should be done on the racetrack."
Both Walker and the other driver were cited for engaging in a speed contest. Walker was cited for no insurance.


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GORDON Strachan left Southampton in 2004, months before the arrival of a gawky teen- ager from Whit-church, Cardiff, whom he would soon regard as one of the finest players on the planet.
The worlds of Gareth Bale and the new Scotland manager will collide at Hampden in six weeks and such is the imminent threat posed by the Tottenham playmaker, who scored twice in their 2-1 win over Newcastle yesterday, that discussions have already been held in the Scotland camp about devising a system to stop him. However, the conclusion reached was a troubling one: the only surefire way to prevent him wreaking havoc is to stop him getting the ball in the first place.
Loading article content
"We have already spent a couple of days thinking about the March games, talking about systems that we are going to play against," said Strachan, as he raked over the 1-0 victory against Estonia at Pittodrie on Wednesday. "But Gareth Bale is Gareth Bale. You are talking about one of the top players in the world just now. I have been fortunate to watch him in the last two years and sometimes he is unstoppable. He is that good. Whether it is a terrific run, or a shot, a goal or something special, I have never been at a game where he has not done anything and I have seen him live 12 or 13 times in the last year. He is just a great, great player. But like anybody, you need the ball before you become unstoppable."
Bale was certainly known to the south coast club during Strachan's time there as the then 14-year-old athlete, capable of running 100m in 11.4 seconds, was training at their satellite academy in Bath. But the Scot had plenty of other talents to run the rule over. Southampton, where Alan Shearer took his first steps as a footballer, has also seen the rites of passage of Theo Walcott, Wayne Bridge, Dexter Blackstock, Andrew Surman and Alex Oxlade-Chamberlain, with current wonderkid Luke Shaw showing the magic dust is still there.
"I just missed Gareth but I had Theo Walcott," Strachan said. "They have made a fortune from that Academy and I mean a real fortune, if you tot up the ones who have left there."
Whether the enterprising 4-2-3-1 employed during the first 45 minutes on Wednesday – with Chris Burke and Steven Naismith out wide – leaves them vulnerable to the thrusts of Bale from the right, or whether they be better served with the more defensively-minded Charlie Mulgrew in a 4-4-2, Strachan doesn't envisage huge changes to the squad which served him well at Pittodrie.
But Gary Caldwell, whose wife had a baby last week, James Forrest and Ross McCormack could all come back into contention, and Strachan will make use of an SFA gadget called Wyscout to help reach a decision.
"I can't be there personally to watch them all but we have a wonderful thing here called Wyscout, so if I want to see Matt Phillips' last six games I can watch his every touch," said Strachan. "I can spend an hour and a half in the morning just watching Matt Phillips, every touch he has in all his games. It is a phenomenal tool."
Although his intensive media duties made his brain hurt more than usual, this was a positive start for the new manager. He made use of Aberdeen youth players to give his attacking and defensive players their own dedicated session and with five clear days to work ahead of the Wales match, he feels further close contact with his coaching methods can improve even veteran international players.
There is also more to come in terms of style, Strachan having asked his central defenders to play a more "basic" game than planned due to a gluepot of a Pittodrie pitch, but he was delighted with the response from the players, even if there was the odd double take. "They were great," Strachan said. "But they have to get my sense of humour because sometimes I will say something and they think 'is he serious'?"


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We started out with the best intentions: create a blog, where we would foster a discussion about hiring at startup companies from all different perspectives, and compare notes about what life is really like at startups —everything from "the nuances of compensation and stock options, how to pick a winner, is this lifestyle for you, tips on work/life balance, insights from the trenches, etc."
We had ideas, and interviews, and all sorts of stuff planned—and then it dropped off.
It's now time to fix that. Starting today, we're going to make a serious push to become a source for all things startup. As you already got a preview of earlier today (check that out here), we've got a bunch of stuff planned for the summer and beyond, like:
- "Summer of Startups," a series profiling startup companies and what it's like to work there.
- Different perspectives from CEOs and executives, to venture investors, right down to recently hired employees, on what it's like to live and work the startup life, including the hiring process.
- The best resources around the internet on finding a job, interview guidance, etc. as it applies to startups
- Some of that discussion and informed opinion stuff we were talking about when we first launched our blog.
We think this is one of the most interesting times to be working at, or considering working for a startup, (go watch the live stream of TechCrunch Disrupt—you'll get an idea of why) but we still don't see a really great resource for information on what it's really like to work at one of these exciting companies, and how to identify the most promising startup employment opportunities.
That's what we'll try to provide over the coming weeks and months. We hope you stay tuned.


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Residential Damage and Billing
The Middlebury College Residential Life Damage/Billing System brochure is updated and publicized annually by the Office of Facilities Services. The brochure is intended as a guideline to provide the approximate cost of repair to frequently damaged items on campus. Actual costs may vary due to the complexity of the repair and actual cost of materials.
Policies on vandalism, theft of furnishings and theft of services may be viewed in the Middlebury College Handbook.
The residential damage billing system is administered by the appropriate Commons office which oversees a property or the Office of the Dean of Students. All questions about student damage bills should be directed to your Commons Coordinator.


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Coach Ron Rivera said the Panthers have to find a way to close out games if they're ever going to take the next step as a football team.
So far that hasn't happened.
The Panthers (0-2) surrendered a fourth quarter lead for the second consecutive week, losing in heartbreaking fashion when Stevie Johnson caught a 2-yard touchdown pass from EJ Manuel with 2 seconds left to lift the Buffalo Bills to a 24-23 win Sunday.
"It's time to get over the hump," Rivera said Monday. "We've been through this – and that is the thing that is disheartening. You'd like to believe that we've gotten to the point where we've learned from these things and now it's about getting things done."
Since Rivera took over as head coach in 2011, the Panthers have lost 10 games after they've held a lead in the fourth quarter – tied with the Philadelphia Eagles for the most in the league, according to STATS INC.
• The Panthers announced Monday that free safety Charles Godfrey has torn his right Achilles tendon and is out for the season.
BUCCANEERS: Safety Dashon Goldson was suspended for one game for flagrant and repeat violations of NFL safety rules prohibiting hits to the head and neck area of defenseless players.
Goldson was penalized for unnecessary roughness in the second quarter of Sunday's game against New Orleans.
LIONS: Coach Jim Schwartz says tests on Reggie Bush's left knee were "encouraging," and his ailment isn't a long-term injury.
Bush took a helmet to his left knee in the first half Sunday at Arizona and played only briefly in the third quarter.
JAGUARS: Running back Maurice Jones-Drew has a tendon strain in his left foot, and the team hopes he won't miss any games.
SEAHAWKS: The fan group attempting to set a Guinness World Records mark for the loudest stadium says it set a record during Sunday's game against San Francisco.
In the first quarter of Seattle's win, the decibel reading taken during a sack of Colin Kaepernick was 131.9 decibels.
The previous record for "loudest crowd roar at a sports stadium," was 131.76 decibels, set in 2011 in Turkey at the Ali Sami Yen Sport Complex Turk Telekom Arena during a soccer match between Galatasaray SC and Fenerbahce.


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Both players came through the ranks of the club's academy but failed to secure regular positions in the first team and manager Paul Lambert opts not to renew their contracts
|Aston Villa are 7/2 with William Hill to be relegated in 2014-15
The 24-year-old made his first steps into the first team in 2009-10 and scored the Premier League's landmark 20,000th goal in a game against Arsenal in December 2011.
Lambert told the club's official website: "We wish Marc the best in his future career and acknowledge the contribution he has made to the club over the past several years, having graduated from our academy.
"We also wish Nathan the best for his career and thank him for his efforts since he, too, graduated from our academy."
Both men are former England Under-21s internationals.


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The knowledge and talents of thousands of adults with autism are wasted because they lack the social and communication skills to get by in the workplace. In Milton Keynes, there is a huge gap in support for adults with autism who do not have a learning disability. Without support, unemployment, isolation and mental health problems are commonplace in this group of people.
We would like to provide a service that would encourage those with particular talent or skill to develop it, by providing a supportive, comfortable, environment. There would be a manager who would enable them to sell their produce online or elsewhere.
To get Talent Unlimited MK off the ground, we need £5000 to apply for charitable status, of which we've raised £1000 already. Please donate as much as you can to help us reach our £4000 target.
If you would like to become part of the project please contact Jane Lynds on firstname.lastname@example.com or Simon Rice on firstname.lastname@example.com


text: 11/25/16 4/09/13 POPSUGAR Celebrity Celebrity Couples Chris Hemsworth and Elsa Pataky at Oceana Ball | Photos Chris and Elsa Make a Stunning Couple For a Big Night Out in NYC April 9, 2013 by Meghan Rooney 32 Shares Chat with us on Facebook Messenger. Learn what's trending across POPSUGAR. View On One Page Photo 5 of 21 ADVERTISEMENT () Start Slideshow Share This Link Copy What's Your Reaction? Thanks for your reaction Don't forget to share this with your friends! ← Use Arrows Keys → 5 0 previous images -10 more images Previous Next Start Slideshow Oceana BallLuke HemsworthChris HemsworthCelebrity CouplesElsa PatakyKate Walsh


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Cartridge, Cold, 2-7/8", for Use With Zurn 2 Handle Widespread Manual Faucets
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|Zoro #: G1555757 Mfr #: 59517007
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Product Description
Cartridge, Cold, Material Ceramic, Brass, For Use With Zurn 2 Handle Widespread Manual Faucets, For Use With Item Number 29VL93, 29VL95, 29VM11, 29VM07, G5389246, For Use With Mfr. Model Number Z831R4-XL, Z831C4-XL, Z831R1-XL, Z831B4-XL, Size 2-7/8 In., Includes replacement stem and o ring
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- This product has been certified by a third party to be compliant with the "Safe Drinking Water Act" requirements for low lead in potable (human consumption - drinking and cooking) and non-potable water applications (non-human consumption).


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The Firearm Blog has a link to an innovative AR accessory to 'get around' California's asinine laws
The FRS-15 is a nifty looking AR-15 stock designed for the California market. In California you can use pre-ban full capacity magazines, with a standard magazine release, in semi-automatic rifles which do not have a pistol grip, adjustable stock or flash suppressor. The FRS-15 does not have a pistol grip (as defined by the State of California) and is not adjustable.
Ugly as sin, but I'm a KRISS fan, so I don't have a lot of room to talk.
However, the point I want to make is that items like pistol grips and adjustable stocks have nothing to do with how a gun is used. Ray Ray isn't going to give a rats ass about adjustable stocks, nor will he decide to not kill George Washington Mercury Lincoln Continental Jr. the Third simply because there is a lack of a pistol grip.
Even then, there's a way around it all. The bullet still comes out of the barrel at the same speed, carrying the same amount of energy, at the same rate of fire regardless of the furniture available. But as we all know, it has nothing to do with lowering crime, it has everything to do with making gun ownership so fraught with peril that people simply give up. Lord knows, this is why I do not own a suppressor.
You know, if you don't care about hitting anything and just want a bullet-hose that will endanger anything in the direction you're "aiming" it...
And yes, it is a better ergonomic layout for Ice-Dog to spray from the hip than an EEEEEEEVULLLLL pistol grip. . .
Bet it bump-fires nicely, too. {chuckle}
Regardless of the laws and how we comply with them, it's always healthy to show some disrespect to our legislative representatives, if only to remind them that they aren't divine.


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Lilly Pulitzer Lilly Pulistzer Squeeze Eau de Parfum
- 1 reviews See the Breakdown
- Product Info | Add Your Review
Lilly Pulitzer Lilly Pulistzer Squeeze Eau de Parfum Reviews
Fruity and fun!This perfume is one of my FAVORITES during the summer! I've used a lot and own a lot of different fragrances. This is definitely in my top 10 or even 5! It's fruity and fresh. I've had this fragrance since high school and I don't ever get sick of it! It's potent but not overwhelming so you can use a little and save it up, that's why I've had it for so long. I don't think I've ever not had a compli...read morement when wearing this. It's just like sunshine and fun in a bottle. I own all 3 Lilly Pulitzer Shades and this is definitely my favorite between them. So if you don't know which to start with, get this one, you won't regret it. — 4 years, 2 months agofairyprincess | 26 reviews
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My Reasons for Reporting This


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MMA judging can be maddening, laughable, and bewildering all at the same time. There is no real method to the madness that is standardized across the board. Do attempted submissions count, or are they the same as missed punches. Is controlling someone's back without really coming close to finishing them worth more than a well-timed and spectacular reversal or escape. All of it is very subjective and controversial. How does MMA fix this problem as a whole?
Educating the new batch of judges is key. One thing they did in PrideFC so well is take the entire fight in to account. I am not saying do the same should be used in the UFC, but what I am saying is that this should be stressed to the judges on a round by round basis. Watch the round like a movie and judge it based on who did more damage or if it's too close in that category – by who controlled the round, and directed traffic so to speak. If you have ever watched a fight you probably get a clear sense of who won the round by simply applying these two filters to your viewing.
Adding two more judges might help. A 10 point must system is best used when the fight is not left up to just
three judges. Most of the time it's a best 2 out of 3 situation, but a 3 out of 5 might be better because there would probably be less chance for split decisions if the read the above paragraph. One of the main reasons that MMA has only three judges is that in MMA's infancy no one had a clue what they were doing. They needed an odd number so they chose three. It didn't help that at that time getting people to show up was near impossible, too. When I started announcing events around 2001 the judges were the local "Billy bad-asses" who claimed ridiculous 46-0 underground street fighting records, and still had all of their teeth. Judging has always been 'entertaining' to say the least.
The bottom line is that educating new judges matters. Teaching them what is considered significant and what should be taken in to account when scoring a bout is so crucial. Go watch Michael Bisping vs Matt Hammill, Jon Fitch vs. Jeff Joslin, Matt Hughes vs Matt Serra, and Mauricio Rua vs. Lyoto Machida 1. Do you agree with those outcomes?
What do you think would improve judging?Tags: "bj Penn", featured, Forrest Griffin, Judges, judging, Judgubg, mma, MMA NEWS, strikeforce news, tito ortiz, ufc news


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Power Tour is best enjoyed with others, whether that's in a convoy with like-minded enthusiasts or all crammed into one vehicle. The problem with having a car full of people on a week-long road trip is that space becomes a premium. Yes, you can pack light, but you don't want to skimp on socks (Staff Editor Thom Taylor tried that and now nobody will ride with him). Then there's the snacks and the ever-important cooler. Enter the wagon. Wagons get the cool front sheetmetal of their coupe brethren, but they have interesting proportions and they usually get really cool, unique taillights. It doesn't matter if it's an early Chevelle, tri-five Nomad or Safari two-door, a land yacht, extended-wheelbase Vista Cruiser, or something completely custom, we're digging all of the wagons we've found on Power Tour 2014. That includes the Suburbans, International Harvester Travelalls, and other SUVs as well.
All of these long roofs have us thinking. Staff Editor Elana Scherr has a Plymouth Satellite sitting in her backyard that needs to be freshened up before it hits the road. With a bit of encouragement or nagging from the wagon fans out there she might be persuaded to start on it after wrapping up work on her Challenger.
Here are all of the wagons we could find thus far on Power Tour 2014. Enjoy the gallery below and stay tuned to HOTROD.com for more Power Tour 2014 photo galleries! Click HERE for All 2014 Power Tour Route Updates , Event Coverage, and More Info. And CLICK HERE for galleries from each venue.


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We previously reported that cardiotonic steroids stimulate collagen synthesis by cardiac fibroblasts in a process that involves signaling through the Na-K-ATPase pathway (Elkareh et al. Hypertension 49: 215–224, 2007). In this study, we examined the effect of cardiotonic steroids on dermal fibroblasts collagen synthesis and on wound healing. Increased collagen expression by human dermal fibroblasts was noted in response to the cardiotonic steroid marinobufagenin in a dose- and time-dependent fashion. An eightfold increase in collagen synthesis was noted when cells were exposed to 10 nM marinobufagenin for 24 h (P < 0.01). Similar increases in proline incorporation were seen following treatment with digoxin, ouabain, and marinobufagenin (10 nM × 24 h, all results P < 0.01 vs. control). The coadministration of the Src inhibitor PP2 or N-acetylcysteine completely prevented collagen stimulation by marinobufagenin. Next, we examined the effect of digoxin, ouabain, and marinobufagenin on the rate of wound closure in an in vitro model where human dermal fibroblasts cultures were wounded with a pipette tip and monitored by digital microscopy. Finally, we administered digoxin in an in vivo wound healing model. Olive oil was chosen as the digoxin carrier because of a favorable partition coefficient observed for labeled digoxin with saline. This application significantly accelerated in vivo wound healing in rats wounded with an 8-mm biopsy cut. Increased collagen accumulation was noted 9 days after wounding (both P < 0.01). The data suggest that cardiotonic steroids induce increases in collagen synthesis by dermal fibroblasts, as could potentially be exploited to accelerate wound healing.
- digitalis-like substances
- sodium-potassium-adenosinetriphosphatase
- signaling
- fibrosis
we have previously noted that the cardiotonic steroid marinobufagenin (MBG) mediates cardiac fibrosis in an experimental renal failure model (8, 10). Specifically, we observed that infusion of MBG to normal animals to achieve a plasma level similar to the level observed in experimental renal failure induced cardiac fibrosis to a similar degree, but immunization against MBG before induction of experimental renal failure markedly attenuated the development of cardiac fibrosis (10). We also observed that relatively low concentrations of MBG and other cardiotonic steroids such as ouabain and digoxin induced cardiac fibroblasts to produce greater amounts of collagen as assessed by radiolabeled proline incorporation and Western blot analysis. Furthermore, we noted that the induction of collagen production by cardiotonic steroids depended on the integrity of signaling through the Na-K-ATPase-Src-reactive oxygen species cascade (8).
As the rate of collagen formation plays a major role in wound healing (18), and because low concentrations of cardiotonic steroids, some of which are commonly employed in clinical medicine, have dramatic effects on collagen production, we examined the effect of these compounds on dermal collagen synthesis and wound healing.
Cell culture.
Human skin fibroblasts, obtained from Cambrex, were maintained in culture as described (2). Collagen production was assessed by Western blot and by radiolabeled proline incorporation as previously described (8).
DNA microarray.
Human dermal fibroblasts were treated with MBG for variable times (0, 0.25, 0.5, 0.75, 1, 2, 3, 6, 9, 12, 15, and 24 h). Cells were harvested, and RNA was isolated. RNA was isolated using the RNeasy kit (Qiagen, Valencia, CA) according to the manufacturer's instructions. Integrity of isolated RNA was examined using Agilent's RNA LabChip kits on the 2100 Bioanalyzer (Agilent, Santa Clara, CA). Gene expression profiling was conducted using the Human OneArray (Phalanx Biotechnology) containing over 30,000 sixty-mer polynucleotide probes with each probe mapped to the latest draft of the human genome (GoldenPath) printed on standard 1-in. × 3-in. glass slides.
Target synthesis, array hybridization, image processing, and data analysis.
cDNA were synthesized from the isolated RNA by reverse transcription followed by second-strand synthesis using the Amino Allyl MessageAmp II mRNA Amplification kit (Ambion, Austin, TX) with oligo(dT) primer that contains a T7 RNA polymerase promoter sequence, according to the manufacturer's specification. In vitro transcription was then performed with the purified cDNA, and amino allyl UTP was incorporated during transcription to produce amino allyl modified mRNA that was subsequently coupled to Cy dye label for hybridization to the microarray. Scanned images of microarray were analyzed using ImaGene (Biodiscovery, Danville, CA), and the output intensity data were further filtered and analyzed using custom statistical software. In brief, normalized expression data for each gene were analyzed by regression models to fit polynomial functions of the logarithm of time up to the third degree. A subset of genes with >2-fold changes for at least two consecutive time points and with significant coefficients of the highest degree (i.e., linear, quadratic, or cubic) at the significance level of 2% (to control possible type I error rate from multiple comparisons) was included in the polynomial regression analysis. Local regression models were also used to fit quadratic polynomials of the logarithm of time. For the selected genes, the patterns of gene expression were log transformed, centered by median, and subjected to cluster analyses by centered correlation and average linkage as the similarity/distance metric using the hierarchical cluster algorithm in Cluster and TreeView software suite (3, 4, 22, 24). The entire microarray data set is available for searches at http://www.ncbi.nlm.nih.gov/projects/geo (accession no. GSE9806).
In vitro wound healing.
Fibroblasts were grown to confluence and then wounded with a 10-μl pipette tip as was described (11, 16, 20). Digital photographs were taken to monitor the in vitro wound closure. Quantification of the wound closure was performed by taking the average of at least three measurements of the distance separating the intact cells at different times following the wound and expressing it as a fraction of the average distance immediately following wounding. These measurements were performed using ImageJ (version 1.32j) software (National Institutes of Health; http://rsb.info.nih.gov/ij/).
In vivo wound healing.
All of the animal experimentation described in this study was conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals using protocols approved by the University of Toledo Health Science Campus Institutional Animal Use and Care Committee.
Male Sprague-Dawley rats weighing 300–350 g were subjected to full-thickness skin biopsy performed with a 8.0-mm punch biopsy (item no. 501912, Harris Uni-core, World Precision Instruments, Sarasota, FL). Two symmetric lesions were made on the dorsum of the thorax and treated with either vehicle alone (olive oil) or MBG in olive oil (Sigma, St. Louis, MO) at 30 nM concentration and covered with hill-top bandages (no. 25 mm Chamber System, Hill Top Research, Miamiville, OH). Digital photographs were taken immediately after and 1, 2, 3, 4, 7, and 9 days following wounding. Photographs were analyzed with ImageJ as described in the vitro wound healing model. At 9 days, animals were euthanized, and the healing wound was excised for histological study and measurement of protein and collagen content. Paraffin sections were prepared and stained with trichrome stain as was reported (8, 10). Quantification of collagen on these sections was also performed using Sirius red as described by Lopez-De Leon and Rojkind (14). Briefly, deparrafinized sections were preincubated in the dark (covered with aluminum foil) with a solution of 0.1% fast green in picric acid for 15 min on a rotary shaker. The fast green solution was then replaced by a 0.1% Sirius red and 0.1% fast green mixture in picric acid and again incubated in the dark for 30 min on a rotary shaker. The staining fluids were withdrawn, and the sections were rinsed several times with distilled water to remove unbound stain. Samples were either fixed for photography or eluted for collagen studies. The elution solution consisted of a 1:1 mixture of 0.1 N NaOH and absolute methanol. One milliliter of elution solution was added to each section. The eluted stain was then read at 605 nm and 540 nm using a spectrophotometer with quantification as described previously (14). Collagen and total protein are expressed as a fraction of control samples.
Statistical analysis.
Data presented are means ± SE. Data obtained were first tested for normality. If the data did not pass the normality test, the Tukey test (for multiple groups) or the Mann-Whitney rank-sum test were used to compare data. If the data did pass the normality test, parametric comparisons were performed. If more than two groups were compared, one-way ANOVA was performed before comparison of individual groups with the unpaired Student's t-test with Bonferroni's correction for multiple comparisons. If only two groups of normal data were compared, the Student's t-test was used without correction (23). Statistical analysis was performed using SPSS software.
First, we examined whether MBG and other cardiotonic steroids stimulated dermal fibroblasts in a manner similar to that seen with cardiac fibroblasts (8). Exposure of human dermal fibroblasts to MBG resulted in dose-dependent increases in procollagen expression determined by Western blot (Fig. 1A) and radiolabeled proline incorporation (Fig. 1, B and C). In fact, the magnitude of this response was considerably more than what was seen previously with primary cardiac fibroblasts (8). Administration of other cardiotonic steroids (ouabain and digoxin) resulted in similar increases in proline incorporation (Fig. 1B). Procollagen expression (or acceleration of in vitro wound closure; see below) was not further increased by simultaneous addition of MBG and ouabain or digoxin and ouabain. Coadministration of N-acetylcysteine or inhibition of Src with PP2 blocked the stimulation of collagen synthesis by MBG (Fig. 1C). Exposure of dermal fibroblasts to greater than 10 nM concentrations of MBG, ouabain, or digoxin did not result in greater degrees of proline incorporation. Similarly, simultaneous exposure of dermal fibroblasts to 10 nM MBG and either ouabain or digoxin at 10 nM concentration did not result in more proline incorporation than seen with 10 nM MBG alone (data not shown).
To further understand the biological pathways activated by cardiotonic steroids, we investigated the genomewide effects of MBG on human skin fibroblasts by gene expression profiling. A time-course study (0, 0.25, 0.5, 0.75, 1, 2, 3, 6, 9, 12, 15, and 24 h) was conducted to examine the temporal changes in gene expression in response to MBG (Fig. 2). RNA was isolated from fibroblasts at the indicated time and compared with untreated cells. Samples were reverse-transcribed and hybridized to the human whole genome array. All the samples were hybridized in duplicate arrays. Normalized data were analyzed by regression models, and the expression levels for each gene were fitted to polynomial functions relative to the logarithm of time up to the third degree as described previously (24). Statistically, significant alterations in gene expression were recorded. A subset of these gene changes was selected for cluster analysis, and the results are displayed by TreeView software (7) (Fig. 2B).
A distinct pattern of gene expression was observed that was recapitulated in duplicate microarrays (Fig. 2A). Unfortunately, many genes involved in fibrosis (e.g., col1a) were maximally expressed at baseline, and MBG-induced increases in the expression of these genes was not possible with the loading conditions employed. However, we were able to identify a cluster of genes with common functions in inflammation, proliferation, and fibrosis as a target of the MBG effect (Fig. 2B). For example, we found changes in the expression of various chemokines, including chemokine (C-X-C motif) ligand 6, chemokine (C motif) ligand 1, macrophage migration inhibitory factor 1, and defensin β 104 within 1 h following exposure to MBG. Altered expression of other genes involved in inflammatory response, specifically a gene similar to CG11994-PA (adenine deaminase), a gene similar to galectin 9, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1, 15-hydroxyprostaglandin dehydrogenase, small proline rich protein 3, and lymphocyte cytosolic protein 1 (L-plastin) were also observed. Other immune regulatory genes such as the peptidoglycan recognition protein 1 and β-defensin 104 were also targeted by MBG. Genes involved in cell growth regulation, including two of the genes in the Drosophila FAT signaling pathway (5), the FAT tumor suppressor homolog 4 and LATS, large tumor suppressor, homolog 1, as well as the DENN/MADD domain containing 4B (DENND4B or KIAA0476) gene, were also either up- or downregulated by MBG, respectively. We also found the induction of a small cluster of zinc and ring finger transcription factors, including the ring finger and CCCH-type zinc finger domains 1 (RC3H1 or KIAA2025), zinc finger proteins 214, 225, and 322A, and transcription factor 21, by MBG.
ADAMTS (a disintegrin and metalloproteinase domain, with thrombospondin type-1 modules) is a recently described family of zinc-dependent proteases that play important roles in a variety of normal and pathological conditions, including arthritis and cancer (1). Some members of this family of proteins have recently been shown to be involved in tissue fibrosis (15). Therefore, altered expression of a cluster of genes, including the thrombospondin, type I, domain containing 2, the TAK1-binding protein 3, and sal-like 4 (SALL4), by MBG may be important for the onset of fibrosis. Coordinated changes in the expression of cadherins (protocadherin 21 and cadherin 7, type 2), the actin-bundling protein L-plastin, kelch-like protein 2 (a synaptotagmin-like protein), and KIAA1204 (a GTPase-activating protein for Cdc42) were also observed.
Next, we examined the effects of cardiac steroids on in vitro wound healing. Human dermal fibroblasts were grown to confluence and then injured with a 10-μl pipette tip as described above. These cells were either exposed to vehicle, or to MBG, ouabain, or digoxin at concentrations ranging from 0.1 nM to 100 nM. We found that MBG, ouabain, and digoxin significantly accelerated wound closure in this in vitro wound healing model at concentrations as low as 1 nM. Each of these cardiotonic steroids had similar effects on wound healing (Table 1).
Next we examined the effects of cardiotonic compounds on the in vivo model of wound closure in the rat. Rats were wounded with an 8-mm biopsy punch, creating a full-thickness lesion on both flanks. We first treated the wounds with digoxin at 10 nM concentration administered in petroleum jelly, but no effects were noted on wound closure (data not shown). Next, we examined the partition coefficient of radioactive digoxin between petroleum jelly and saline and found it to be nearly infinite. Thus we sought a carrier with a more practical partition coefficient, and a mixture of olive oil:saline was found to have a partition coefficient of 3:1. On this basis, we chose to treat wounds with 30 nM digoxin in olive oil or with olive oil alone. We observed that digoxin administered in this fashion led to a substantial acceleration of wound closure on the basis of digital photographs that were analyzed similarly to that described for the in vitro model (Fig. 3A). Histological analysis also revealed that a greater amount of dermal collagen appeared to be present in the wound area (Fig. 3B). Quantification of the Sirius red and fast green data confirmed this subjective assessment demonstrating larger amounts of collagen in the wound area (Fig. 3C).
In this study, we describe a potent effect for cardiotonic steroids on collagen production by human dermal fibroblasts that was more prominent than that which we previously reported in rat cardiac fibroblasts. More importantly, we observed that cardiotonic steroids promote and accelerate wound healing both in an in vitro and in vivo model of wound healing, raising the real possibility that cardiotonic steroids can help in facilitating wound healing in the clinical setting. The ability of the cardiotonic steroids to initiate wound healing was corroborated by gene expression profiling analysis of MBG added to human dermal fibroblasts. We observed distinct temporal changes in the expression of genes involved in inflammation and fibrosis that are consistent with the onset of wound healing (6, 9) that is characterized by changes in the expression of various inflammatory chemokines [chemokine (C-X-C motif) ligand 6, chemokine (C motif) ligand 1, macrophage migration inhibitory factor 1, and defensin β 104], and genes involved in the inflammatory response [protein similar to CG11994-PA (adenine deaminase), a gene similar to galectin 9, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1, 15-hydroxyprostaglandin dehydrogenase, small proline rich protein 3, and L-plastin], and genes that drive fibrogenesis (thrombospondin, type I, domain containing 2, the TAK1-binding protein 3, and sal-like 4).
Our data, specifically the relatively low threshold for the cardiotonic steroid-induced dermal fibroblast stimulation that corresponds closely to the circulating concentrations of MBG and other cardiotonic steroids seen in clinical scenarios, beg the question whether rapid wound healing and/or excessive fibrosis is observed in the skin of such afflicted patients. Unfortunately, the answer at this point is only a very qualified "yes." Patients with end-stage renal disease, the clinical condition that is associated with some of the very highest circulating concentrations of cardiotonic steroids, have been reported to occasionally manifest a progressive dermal fibrotic condition called nephrogenic sclerosing dermopathy. This condition is quite similar to the disease scleroderma but appears to be unique to the setting of renal disease (21). Recently, this syndrome has been associated with exposure to gadolinium when magnetic resonance imaging studies are performed in patients with advanced renal failure, but the pathophysiology is still very poorly understood (12). Also, people of African extraction are known to have substantially higher prevalence of volume-sensitive, low-renin hypertension compared with age- and sex-matched Caucasians or Asians, as well as a higher incidence of excessive scar formation following surgical or incidental wounds (13, 19). Unfortunately, there has not been any substantial attempt to systematically explore a connection between circulating concentrations of cardiotonic steroids and these clinical skin conditions, at least to the best of our knowledge, and our comments on the possible association is highly speculative.
Our data in the in vivo wound healing experiments (using one cardiotonic steroid at a single concentration) suggest that cardiotonic steroids may be helpful in situations where stimulation of fibroblast collagen production is desirable, as in accelerating wound healing. We would also stress that many of these cardiotonic steroids are either found naturally or have been used clinically for many years at concentrations far beyond what would be achieved with topical administration (17). Further development of this class of agents as therapeutics administered in a topical manner may be of interest in either accelerating wound repair or increasing dermal collagen production in settings involving nonwounded skin where increased dermal collagen would also be desirable.
Portions of this study were supported by National Heart, Lung, and Blood Institute Grant HL-67963.
We thank Carol Woods for excellent secretarial assistance.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2008 the American Physiological Society