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Men's mountain Pant Karpos, Express model.
Bitter cold, snow, wind, humidity do not hamper the potential of this Pant is designed to tackle the toughest environments, without restricting freedom of movement. The zip and contrast stitching add a touch of style and femininity that love not only with skins or crampons, but even a simple winter walk.
Rugged pants K-Shell windproof, breathable and stretchy with high lining warmth and breathability. Protective inserts in areas of increased stress in Kortec. Double powder for maximum protection from the snow.
Fabric: 78% polyamide 12% 10% polyester Polyurethane.
Opening with zip and button fastening.
Two closable pockets with zip.
Zippered ankle.
Internal gaiter.
Front logo embroidery Karpos green.
Reflective elements.
Color: GreyI/black.
Additional Info
Additional Info
|2500496 502
|Product category
|Man Trekking Pants
|Dark gray
8055688145613 -Size 52
8055688145620 -Size 54
Animasportiva ships immediately! Every order is handled with the utmost urgency. As soon as we receive the order, product retrieval occurs; then, when we receive the payment, we prepare the package and shipping follows.
We deliver via express courier: the delivery times range from 48 to 72 hours for Western Europe, and from 72 to 96 hours for the rest of Europe, United States, Canada and Australia. To improve our service you should always leave a telephone number, in order to be contacted by the carrier in case of problems with the delivery.
In order to make our service increasingly efficient please check the conditions of the package upon delivery.
If the parcel is not perfectly healthy, pick it up with reserve: next to the signature in the delivery note, mark clearly "ACCEPTED UNDER RESERVE damaged parcel".
Animasportiva refunds the amount paid with the same method used by the customer for paying (bank transfer, credit card or Paypal) in the least possible amount of time and in any case within 10 days from receipt of the product.
The refund refers to the price of the product or products returned.
It is expressly understood that the expenses incurred to return the product to Animasportiva will have to be paid by the customer.
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Regular Price: €149.90
Now only: €127.42


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This User Contract ("Contract") is executed by and between the User downloading the Fitwell application ("Application") and Fitvel Bilişim ve Sağlık Hizmetleri A.Ş. ("the Company") registered at the address Ayazağa Mahallesi, Meydan Sokak, VekoGiz Plaza Giriş Kat Daire 85, P.K. 34398 Şişli, Istanbul and regulates the terms of use and the rights and responsibilities of the Parties.
By downloading the Application, the User shall be deemed as having accepted the Terms and Conditions of this contract.
Rights and Responsibilities of the Company
The Company shall provide to the Users who download the Application advisory information regarding nutrition and sports. The information and content to be provided by the Company shall have an advisory and informative nature, where the Company shall not be held responsible for the use of the application, the scope of the content or the use of the recommendations it provides pertaining to nutrition and sports issues.
The Company shall not be responsible for any interruption or breakdown in the Application occurring due to third parties, force majeure, suppliers, connection problems, internet outage, etc.
The Application is for private and personal use only. If the Company determines that the Application has been used outside of its intended purposes, the Company may cease, suspend or permanently terminate the membership of the aforementioned User(s).
The purchasing activities conducted within the Application shall immediately be sent to the mobile device of the User. The User may be asked to connect to the Internet over Wi-Fi to access the App Store or Google Play applications. Depending on the type of mobile device and use of App Store or Google Play Store, General Terms and Conditions of App Store or Google Play Store shall be applied.
The prices offered pertaining to in-application purchasing shall be valid at the moment of submission. However, these prices may change thereafter.
FitWell requires some personal information (name, age, dietary preferences, interests, height, weight, email etc) in order to provide a high-quality service. The information stored in the FitWell servers and computers can be used for FitWell initiatives such as human subject research, periodical campaigns and special customer-specific promotions – as well as for customer classification processes that help avoid unwanted emails.
FitWell integrates with the Apple Health App and coordinates with Apple Health and Google Fit platforms. FitWell does not share any personal information or User data with third parties for any advertising or commercial purposes without User's consent.
Rights and Responsibilities of the User
The User is responsible for filling in the requested personal information completely and accurately, and updating the aforementioned information if necessary. Submission of incomplete and inaccurate personal information is the User's responsibility.
The User commits that they are at least 13 years of age. In case the User is under 13 years of age, they may not under any circumstances or for any reason use the Application. Those Users aged 13 years or above but below 18 years of age shall be considered as having received the explicit consent of their parents or legal guardians regarding the Contract.
The User declares and accepts that the contents, videos, exercises and information related to all nutrition and sports programs prepared by the Application are for informative purposes only, and that the use of the aforementioned programs is solely under the User's responsibility.
This Application have been prepared assuming that the User is in normal health and medical condition, thus the content is not customized to the User. Before using the Application, the User must consult a doctor regarding any medical problems he or she may have. It is advised that the User should not practice these programs if there is any possibility of severe medical condition. If the User has any questions about their health, they should always consult a physician or other healthcare professional.
The Application's advice is created by taking into consideration the research and scientific data compiled by the World Health Organization for individuals with similar profiles and via a special algorithm (software) that has been developed.
FitWell does not provide any diagnose or treatment for medical conditions.
The User declares and accepts that none of the programs can be replaced by any diet or exercise prescribed by a doctor, practicing any and all nutrition and sports programs within the programs is at the User's sole discretion and responsibility. The Company shall not be liable in any way, as related to the program selected and practiced by the User. It is strongly recommended that the Users apply the programs with care.
The User may at any time request the deletion of personal information kept by the Company. The Company may always send the User notifications. Both during the term of the contract and after its termination, the User is deemed to have given approval for all commercial electronic messages with marketing and advertisement purposes to be sent by the Company, its affiliates or third-party business partners, and accepts that without prior authorization he or she may be sent messages with information, marketing and/or commercial purposes via other means of communication such as automatic calling systems, facsimile, electronic mail or short message. The User may transmit his or her request to exit this system to the Company via e-mail to firstname.lastname@example.com. The User's data may be anonymized and separately analyzed, and may become subject to research and be used for both the User's sake and/or for scientific and statistical studies.
The User's data shall be kept for a period of one year as of the deletion of the application for the purpose of facilitating the re-subscription of the User.
FitWell asks for User's consent, or in the case of minors, their parent or guardian's consent for health-related human subject research.
FitWell analyses and interprets visitor behaviors and preferences as customers use the Application. This purely statistical information, which does not include any personal information, may be shared with FitWell partners to provide a customized experience for the benefit of FitWell Users.
To the extent permitted by law, FitWell may disclose User information when required by law or court order, or by government or law enforcement authorities or regulatory agencies.
The information provided by the User can only be changed following a request by that User.
Right of withdrawal
A consumer is any natural person who concludes a legal transaction for purposes that are not attributable to either their commercial or their independent professional occupation. The following right of withdrawal is only applicable to consumers.
The User have the right to withdraw from the Application any time since the Application is uploaded by the User over the Internet and can be deleted from the mobile device instantly.
The General Terms and Conditions of App Store or Google Play Store shall be applied to the right to withdraw from the in-application purchases conducted accordingly. The Company reserves the right to charge or not refund the payments for any purchased services by the User.
The Application is free of charge; separate approval shall be obtained for the sales prices, including all taxes, for in-application purchasing. The User hereby declares and accepts that the Company may unilaterally alter the Application price, in-application prices, campaigns and packages at any time, and that the User shall regularly check the update and application information related to the alterations. For the cash paid memberships; the User accepts that such memberships shall not be cancelled and there shall not be refunds for the campaign memberships. The User also accepts that the cash paid campaign memberships shall be valid until the date of expiration.
Paid Services: Certain services of the Company may be subject to payments now or in the future (the "Paid Services"). Any payment terms presented to the User in the process of using or signing up for a Paid Service are deemed part of this Agreement.
Billing: The Company uses a third-party payment processor (the "Payment Processor") to bill Users through a payment account ("Billing Account") for use of the Paid Services. The processing of payments will be subject to the terms, conditions and privacy policies of the Payment Processor in addition to this Agreement. The Company is not responsible for any error by the Payment Processor. By choosing to use Paid Services, the User agrees to pay the Company, through the Payment Processor, all charges at the prices then in effect for any use of such Paid Services in accordance with the applicable payment terms, and authorizes the Company, through the Payment Processor, to charge the User's chosen payment provider ("Payment Method"). The User agrees to make payment using that selected Payment Method. The Company reserves the right to correct any errors or mistakes that it makes even if it has already requested or received payment.
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Current Information Required. The User must provide current, complete and accurate information for their billing account. They must promptly update all information to keep their billing account current, complete and accurate (such as a change in billing address, credit card number, or credit card expiration date), and they must promptly notify the Company or its payment processor if their payment method is canceled (e.g., for loss or theft) or if they become aware of a potential breach of security, such as the unauthorized disclosure or use of their user name or password. Changes to such information can be made at Apple Store or Play Store security page depending on your purchase if the User fails to provide any of the aforementioned information, they agree that the Company may continue charging them for any use of paid services under their billing account unless the User has terminated their paid services as set forth above.
Change in Amount Authorized: If the amount to be charged to the User's Billing Account varies from the amount preauthorized by them (other than due to the imposition or change in the amount of state sales taxes), the User has the right to receive, and the Company shall provide, notice of the amount to be charged and the date of the charge before the scheduled date of the transaction. Any agreement the User has with their payment provider will govern their use of their Payment Method. The User agrees that the Company may accumulate charges incurred and submit them as one or more aggregate charges during or at the end of each billing cycle.
Reaffirmation of Authorization: The User's non-termination or continued use of a Paid Service reaffirms that the Company is authorized to charge the User's Payment Method for that Paid Service. The Company may submit those charges for payment and the User will be responsible for such charges. This does not waive the Company's right to seek payment directly from the User. The User's charges may be payable in advance, in arrears, per usage, or as otherwise described when they initially selected to use the Paid Service.
Free Trials and Other Promotions: Any free trial or other promotion that provides access to a Paid Service must be used within the specified time of the trial. The User must stop using a Paid Service before the end of the trial period in order to avoid being charged for that Paid Service. If the User cancels prior to the end of the trial period and is inadvertently charged for a Paid Service, they should contact the Company at email@example.com.
The User accepts and declares that by submitting user content through the services he or she shall grant the Company a worldwide, perpetual, unlimited and fully paid license to use such information.
Through the services, the User may purchase certain goods or additional features or Applications designed to enhance the performance of the services.
Any kind of dispute occurring or arising from this Contract shall be settled in accordance with Turkish Law, by the courts of İstanbul and Consumer Courts.

subset: commoncrawl


text:
«i wish to get her pin injection style just on the glitory tourching only»
Kagney Linn Karter bounces her phat oiled booty on his oversized pole
Duration: 3min 01sec Views: 56 438 Submitted: 4 years ago Submitted by:
Description: Busty blonde slut with a delicious big booty Kagney Linn Karter enjoys taking a kinky ride on a thick cock. She slides her sweet moist cooch down on her man's big fat boner and rides it wildly before sucking on it.
Pornstars: Kagney Linn Karter


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Relocating isn't a simple task. Even for skilled Brooklyn movers, it is a daunting experience. The mystery of moving to an alternative city, the physical and mental pressure of having your house prepared to sell, transferring personal items, and the whole packing itself could really put you down. In case you have families, you must cope up with their worry over a new environment. This consists of new schools and making new friends. You also must start looking for a new job. In some services, there will be advice you can get about the city. This service is perfect for anyone moving from dormitories or small condominiums. There are lots of people who receive this service, especially in Brooklyn. Service providers generally label this one as 2000 pounds worth of products. They are generally heavy to pass up as shipment, but too small to qualify as minimal local package. This service is usually outlined to local relocation between 50 and 100 miles inside the same state. This can vary on the distance level per company. Generally, local transfers may be less than 100 miles. The rate for this service will be ranged per hour and multiplied by the personnel required to complete the task.
This service is where the movers do all in for your personal needs. The team will ready your things, put them all on the van, and drive it towards the given destination. They can even unpack your things for you. If you like packing things and just require professional services to transfer your items, you may also customize the service. If you wish to ensure the safety of your valuables, you could get this service. Carex Shipping and Movers special services takes care of all the fragile products and safely bring it to the destination.


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Contact Info / Websites
Recent Movie Reviews
The Hermit
Rated 4 / 5 stars
Nice, simple concept. You used a good mix of angles, but also used them at the right times. You were also able to tell a story without dialogue, and I know that's tricky. Your animation skills are definitely there, too.
Alpha-Nuva responds:
Backgrounds are tedious to make as is. Making backgrounds in Photoshop was a pain in the ass, and not all too worth it because the resolution came out fuzzy in the end. Debating whether I'll do that ever again.


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- Services
- We strive to provide complete care for our patients. Learn more about all the services we provide.
You are using an outdated browser. Please upgrade your browser to improve your experience.
Patient Facilities
Cat Room
Dog Room
The Recovery Room and ICU
Isolation Area
Office Hours
Appanasha's Clinic Hours:
Friday 7:30am - 6:00pm
Saturday 8:00am - 3:00pm
*Closed on Sundays, Major Holidays and During Inclement Weather*
For after hour emergencies call:
Fox Valley Animal Referral Center
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Various Affidavit Why It Is An Important Application For Families To Accept A Adolescent
There are assorted families that are absorbed in acceptance for assorted reasons, a lot of of them feel a alarm to advice kids while others are disturbing with infertility and a lot of attending at it as a abundant way to alpha a family. Whatever is the acumen that a lot of families or humans accept acquired their absorption adoption, abeyant parents needs to yield altered factors into application as to why they accept to accept a child. The aboriginal accommodation abeyant parents accept to get to accede is what age, sex and aswell chase that they accept a assertive alternative for and it is important for families to adjudge whether a ancestors can handle a ancestors group.
They accept to aswell get to apperceive if they can handle a adolescent that is behavioural issues and aswell a adolescent which has altered kinds of medical needs to accomplish abiding they accept the adolescent that they would love. Amount is aswell addition important issue, adoptions can calmly amount to about anywhere from tens of bags of dollars depending on area and aswell how families would get to plan to accept a adolescent that they would usually want.
Once all of these factors accept been calmly discussed again it can discussed by families to accomplish an important accommodation amid calm and aswell all-embracing acceptance of assorted accouchement all over the world. Assertive citizens can accept a lot of adolescents from over 100 assorted countries, a lot of all-embracing adoptions are from ceramics and aswell Russia and a lot of of the all-embracing adoptions would absorb accouchement that are beneath than 5 years old.
Female Chinese accouchement mostly predominate all-embracing adoptions because of the chinese cultural ethics on accepting to aftermath macho brood for their own association and aswell country. A lot of families that are absolutely absorbed in an all-embracing acceptance would charge to acquaintance a accountant bureau that can calmly accede with the laws of the adopted country and their own country to accurately accept a child. There are mostly two basal kinds of acceptance in a lot of countries and that is breed and aswell accouchement that are over 5 years of age, baby acceptance are mostly handled by clandestine agencies all over the apple today.
If they are traveling to accept a adolescent which is 5 years old, that has behavioural and aswell medical needs again acceptance of these kids are faster and aswell atomic big-ticket for humans to accept a adolescent of their actual own. These kinds of kids are usually victims of abandonment, carelessness and aswell corruption and aswell could not acknowledgment to their own parents home and they aswell get accompaniment allotment to advice parents pay for their care.


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Q: I found the radiation leaks from Japan's tsunami-damaged nuclear plants truly frightening. Someone at my health-food store said everyone should start eating more seaweed. How would that help? — Deirdre, San Diego
A: We love seaweed as a low-calorie, high-nutrient addition to soups, salads and sandwiches. And many types of seaweed contain alginate, which prevents about 78 percent of radioactive products from being absorbed by your bones and teeth. Seaweed also contains iodine, which takes up residence in your thyroid and keeps any radioactive iodine that's around from being able to settle there, where it can cause cancer.
But like the potassium iodide tablets that flew off the shelves after Japan's disaster, seaweed won't protect you from radiation burns, sickness or cancer elsewhere in your body. Plus, eating large amounts of iodine-laden seaweed every day when you're in no radiation danger has a downside: It actually can slow or halt healthy thyroid activity.
If you do buy seaweed, check the label carefully for its origin. Don't buy seaweed from waters near Japan; it could be contaminated with radioactive iodine.
Otherwise, your biggest radiation risk is likely from unnecessary medical tests. About half your personal radiation exposure probably is from X-rays and CT scans. The other half arrives naturally from the cosmos, smoking and radon (have you checked your home?). If you're afraid of becoming your own nightlight, always ask if each and every X-ray or scan is necessary. And for heaven's sake, don't smoke.
Q: I'm allergic to aspirin. What can I take instead to lower my heart attack risk? — Victor, via email
A: You're not alone. Roughly 10 percent of people are allergic to non-steroidal anti-inflammatory drugs such as aspirin, which is nothing to sneeze at: This allergy can trigger breathing trouble and even anaphylaxis, a severe reaction that can be fatal. Prescription blood thinners can do some of aspirin's heart-protecting job, but they aren't worry-free. Some require frequent medical checks to be sure you don't develop internal bleeding. Other substances that decrease inflammation include the DHA form of omega-3s, lycopene, lutein, vitamin D-3, coffee, small amounts of alcohol, physical activity and brightly colored fruits and veggies.
If your doctor thinks you'd get substantial benefit from aspirin, ask about aspirin desensitization, a procedure that gradually exposes you to increasing levels of aspirin over a period of days. Do not try this on your own. Medical supervision is a must.
Q: I'm worried about gaining weight when I go through menopause. Am I doomed to having an expanding waistline? — Jennifer, Wyncote, Pa.
A: Trust us docs — the only thing certain in life is death. Unlike Ben Franklin, we don't even include taxes anymore because some famous folks (not us!) have found ways to avoid them entirely. Happily, you can do the same with menopausal weight gain.


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Some progress, and some frustrations.
That's how city leaders described their efforts to fight crime in St. Louis this past year.
Tuesday afternoon, Mayor Francis Slay and Chief of Police Sam Dotson shared crime statistics from 2016 and revealed new plans to battle crime in the new year.
Overall, police report the total amount of crime in 2016 is down from 2015. The St. Louis Metropolitan Police Department reported 26,013 crimes in 2016, and 24,941 crimes in 2016 — a more than four percent drop.
Police report the number of property crimes dropped 6.6 percent. That includes a drop in burglaries, larcenies and vehicle thefts, which Dotson said hit their lowest number in decades.
Still plaguing the city, however, are the violent crimes. Those increased 4.4 percent this year, and include homicides, rapes, robberies and aggravated assault.
The number of homicides remained the same. In 2015 and in 2016, police count 188 reported killings. Most of those homicides were committed with a firearm.
"One hundred eighty-eight people lost their lives to senseless and destructive violence in the city of St. Louis last year," Slay said. "Not one of those untimely deaths was warranted."
"That's frustrating, that crime is one of the most stubborn — where we focus a significant amount of our attention and our detectives," Dotson said.
Dotson introduced one strategy he hopes will reduce gun crime.
"What we found is, if we can target shootings — non fatal shootings that happened — we can interrupt a cycle of violence that can keep retaliatory shootings from occurring and reduce the number of homicides in other cities we've seen successful," he said.
Dotson hopes to launch a program called the St. Louis Gun Crime Intelligence Center this spring. The idea is modeled after a program in Denver, Colorado and involves federal partnerships to more quickly investigate shell casings at shooting scenes.
"We are able to now put those shell casings into a database that's populated by agencies all over the region and all over the country, to develop investigative leads – where our officers can go out in 24-48 hours and help interrupt the cycle of violence," Dotson explained.
Dotson and Slay both want to see more cameras around the city. They said the city-wide system that feeds into the Real Time Crime Center has helped police solve crimes already. Police say the license plate recognition technology led to dozens of arrests last year.
Both city leaders said police can't solve the crime problem alone.
Slay talked about a decision voters will make in April, whether to approve a half-cent sales tax in the city of St. Louis. If approved, Slay said the city will spend the money raised between infrastructure and public safety.


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Drift away on a gorgeous beach-inspired Dune sofa, with modern, square arms and generous cushioning, or relax on the stylish circular swivel chair. The gently textured fabric upholstery comes in a choice of shades, and you can choose a subtle or glamorous look with reversible scatter cushions that turn to reveal bold colours and vibrant patterns. Versatile, stylish and timeless—that's Dune.
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THE Australian share market is set for a positive start to trade, after a slight recovery in technology stocks pushed Wall Street higher.
At 0700 AEST on Wednesday, the June share price index futures contract was up 24 points at 5,428.
In economic news on Wednesday, Westpac and the Melbourne Institute release their latest survey of consumer sentiment. The Australian Bureau of Statistics publishes housing finance data for February and international merchandise imports data for March.
In company news, Energy Resources of Australia holds its annual general meeting in Darwin.
The market on Tuesday closed relatively flat.
The benchmark S&P/ASX200 index dropped 3.1 points, or 0.06 per cent, to 5,410.6.
The broader All Ordinaries index lost 6.9 points, or 0.13 per cent, to 5,409.2.


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July 7, 2010
A new report from the National Center for Health Statistics (NCHS), the nation's chief health statistics agency, suggests the longstanding perception uninsured patients are clogging the nation's emergency rooms (ERs) is a myth. There is a widespread perception uninsured patients are a leading source of unnecessary ER visits because they lack a primary care provider, a perception echoed by President Obama and other political leaders as a rationale for their recently passed health care legislation, says Devon M. Herrick, a health economist and senior fellow at the National Center for Policy Analysis.
The report finds ER use is more closely associated with Medicaid enrolled patients. They seek care in the ER more frequently than both the uninsured and those covered by private insurance.
Other findings:
- Nearly one-third (32 percent) of Medicaid enrollees used the ER at least once during a 12-month period in 2007.
- Individuals with private health coverage were only about half as likely (17 percent) to visit an ER, and a similar proportion -- one in five -- of individuals without health coverage did so.
- Medicaid enrollees were three times as likely (15 percent vs. 5 percent) as the privately insured, and twice as likely as the uninsured (15 percent vs. 7 percent), to have visited an ER twice in the previous year.
Nearly 120 million ER visits are made in the United States each year -- approximately 11 percent of all U.S. ambulatory care visits. Some of that care could be done elsewhere, says Dr. Stephen Nichols, a regional medical officer for Schumacher Group, which contracts for emergency department services at community hospitals.
"In general, 5 percent to 25 percent of patients who visit an emergency department in a community hospital have non-urgent complaints that could easily have been addressed in an outpatient setting," he says.
Dr. John Dunn, a specialist in emergency medicine in Brownwood, Texas, agrees and thinks the number of non-emergencies is even higher. "Thirty percent to forty percent are emergencies or urgent care and deserve treatment within a reasonable time," says Dunn. "But it is care that could be seen to in an urgent care clinic or a well-equipped office, though the patients probably are better off in the emergency department."
Source: Devon Herrick, "Report: Uninsured Emergency Room Use Greatly Exaggerated," Heartland Institute, July 7, 2010.
For study:
Browse more articles on Health Issues


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The Arizona Cardinals were pleased with the performance of running back Andre Ellington last year towards the end of the season, and there are many analysts that believe he will have a breakout season in 2014.
Ellington is an electric running back who has the ability to break a big play at any given moment, and that will help the Carson Palmer led Cardinals' offense this year. He will not just be used in the running game either, as he can be a lethal receiver out of the backfield at times as well.
Ellington played in 15 regular season games last year with the Cardinals, picking up 652 yards and three touchdowns on 118 carries. He was unable to get consistent playing time due to Rashard Mendenhall being on the roster, but Mendenhall walking and retiring this offseason, the running back position is Ellington's to dominate.
There are still some question marks surrounding whether or not he has the ability to be a workhorse type of back, but it is hard to argue with the type of production that he has shown in the limited playing time that he has received.
One of the main reasons that Ellington didn't play as much as he should have last season, was that the coaching staff didn't completely trust him to be their number one back. That has changed this offseason, and head coach Bruce Arians has made it clear that he will be putting the football in Ellington's hands this coming season. Arians also added that Ellington has gained 10 pounds of muscle this offseason, which will be a big addition as far as durability is concerned.
There simply won't be much competition in the backfield for Ellington for carries, and that is another reason that his value is up at this point in time. With Mendenhall deciding to walk away from the game and retire, that leaves just Stepfan Taylor and Jonathan Dwyer to compete for carries with him. While both of those players are talented, they are not going to even contest Ellington's grip on the starting position.
All that being said, the most underrated aspect of Ellington's game is his ability to make plays as a receiver out of the backfield. Carson Palmer is very excited about the chance that he has to work with his running back as a receiver, and it could end up making the Cardinals' offense twice as dangerous as it was last year. Ellington caught 39 passes for 371 yards and a touchdown last season, and his targets are sure to go up. The Cardinals understand that they simply need to get him the football in open field, and let him make plays.
Overall, the future hasn't looked brighter for the Cardinals' running attack in quite some time. Ellington has the "star" potential that everyone saw in him coming out of Clemson, and he is ready to prove himself in the NFL this coming season. Don't be surprised to see Ellington become one of the most electrifying and up-and-coming running backs in the league this coming season.


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Mark Halperin Offically Returns to NBC News, MSNBC
After regular appearances on NBC News and MSNBC's flagship show Morning Joe, Mark Halperin is set to officially return to NBC News and MSNBC as senior political analyst. Halperin is the former managing editor of Bloomberg Politics and co-host of Bloomberg Television's With All Due Respect, which was canceled the week after the November 2016 presidential election; he exited Bloomberg shortly thereafter. Before joining Bloomberg Politics, Halperin served as a senior political analyst at NBC News. He is also the co-author of Game Change, and Double Down: Game Change 2012, books chronicling the 2008 and 2012 presidential elections, respectively, and former President Obama's rise to the White House. Follow NBC News on Twitter.


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By using the Card, the member unconditionally accepts and agrees to comply with and abide by these Terms and Conditions as stated herein or as may be modified at any time by Kidsstoppress Media Pvt Ltd without any prior notice to the member. The decisions of Kidsstoppress for all matters relating to this Terms and Conditions shall be final and binding in all respects and that no correspondence will be entertained regarding the same.
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Mastering Time Warner's Future
Related Articles
- Fifth wheel. // Quill;Oct93, Vol. 81 Issue 8, p7
Reports on Time Warner's plans to launch a network to compete with ABC, CBS, NBC and Fox. Description of network; Stumbling blocks to Warner's plans; Potential effects of plan on Warner Brothers studio-supplied programming.
- Time Warner postpones the future. Steinert-Threlkeld, Tom // Inter@ctive Week;05/12/97, Vol. 4 Issue 15, p23
Opinion. Focuses on Time Warner Inc.'s deployment of a full-service cable television network in Orlando, Florida. Significance of cable TV; Plan to start putting interactive set-top boxes in its cable networks.
- Time Warner unit. Harrington, John // Crain's New York Business;1/30/95, Vol. 11 Issue 5, p38
Reports on Time Warner Inc.'s unit Warner Bros.' plan to launch its first overseas cable television network in Latin America.
- TW pacts for Spanish webs. Hopewell, John // Daily Variety;6/12/2003, Vol. 279 Issue 47, p6
Reports that Time Warner Inc. (TW) has signed a cable carriage deal with Spanish pubcaster Radiotelevision Espanola for three channels to air on TW' DTV Spanish package in part of New York.
- TW crunches TBS numbers. Dempsey, John // Variety;08/04/97, Vol. 367 Issue 13, p30
Reports on Time Warner's release of its calculations showing how cable television operators will benefit from the company's transformation of its TBS SuperStation network into a basic cable network. Per-subscriber license fees proposed by Time Warner; Projected revenues for cable operators.
- Turnerbout: No women's net. McAdams, Deborah D. // Broadcasting & Cable;08/16/99, Vol. 129 Issue 34, p16
Reports on Time Warner's decision to postpone its plan to launch the proposed The Women's Channel for-women cable television network. Reasons for the company's decision.
- Turner fights for carriage. Donohue, Steve // Electronic Media;09/13/99, Vol. 18 Issue 37, p10
Reports on Time Warner Inc.'s legal fight to secure carriage for the Turner South regional cable television channel in the United States. Companies in discussion with Time Warner for carriage commitments; Outcome of Turner's legal dispute with Fox.
- TBS Superstation switch on hold. J.M.H. // Broadcasting & Cable;06/30/97, Vol. 127 Issue 27, p10
Reports on the delay in TBS Superstation's conversion to a conventional cable television network because Time Warner Inc. needs the consent of ESPN and Fox Broadcasting. National television rights held by ESPN and Fox to Major League Baseball games; Time Warner's plans to convert TBS from...
- U.S. plugs into France's cable. Farrell, Pia // Hollywood Reporter;7/25/95, Vol. 338 Issue 11, pI-1
Reports on Time Warner Inc.'s winning of a bid to run the cable networks in France. Protests against the entry of Time in the French cable market; Time Warner's plan to scout for other lucrative contracts across France; Other American companies making inroads into France.


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Mapping Lithuanians: Examining Russian Imperial Ethnic Cartography (1840s-1880s). Vytautas Petronis, PhD candidate in History, South Stockholm University-College [email protected] Ethnic cartography in the Russian Empire. Cartography:
Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.
Vytautas Petronis,
PhD candidate in History, South Stockholm University-College
- Notes in the "economical journals" (ekonomicheskie zhurnaly):
- Collecting economic, geographical and other information about the surveyed territories;
The Latvian and Lithuanian ethno-linguistic territories (a fragment from Šafařik's map in Slovanský národopis (1842))
The Lithuanian ethno-linguistic territory around the city of Vil'na (fragments from Koeppen's Etnograficheskii atlas Evropeiskoi Rossii (1848))
The Lithuanian and Latvian ethnic territory (fragment from Koeppen's Etnograficheskaia Karta Evropeiskoi Rossii (1851))
The Lithuanian inhabited territory in Rittikh's Atlas narodonaseleniia Zapadno-Russkogo kraia po veroispovedaniiam (1864)
Alterations of the ethnic composition in the North Western provinces
found in the French (on the left) and Russian (on the right)
The Latvian and Lithuanian inhabited territories
(fragment from Erckert's Atlas Ethnographique des provinces habitées
en totalité ou en partie par des Polonais (1863))
The Lithuanian ethnic territory on Rittikh's
Etnograficheskaia karta Evropeiskoi Rossii (1875 - fragment)


text:
Privacy Policy
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Can Kenyan men do what this amazing father does? Kenyan LADIES love it (VIDEO)Editor's Choice, Lifestyle, Videos 06:59
Monday, November 21, 2016 - This guy lovingly bathing his baby is a glimmer of hope in the age of absentee fathers and sp*rm donors.
While most men leave their wives or partners to take care of the baby especially in the early stages when a baby is born, this guy has proven that men can also come handy.
There is also the aspect of bonding between a father and his child that goes on as the new father cares for his baby and from this video, the baby seemed to enjoy.
Could this be one of the reasons why these men from West Africa attract women like magnets?
Watch the video below.
The Kenyan DAILY POST.


text:
Substitute multiple text strings (vba)
The user defined function demonstrated below replaces multiple old text strings with new text strings in a cell. The custom function is case insensitive.
Formula in cell B2:
VBA code
Function SubstituteMultiple(text As String, old_text As Range, new_text As Range) Dim i As Single For i = 1 To old_text.Cells.Count Result = Replace(LCase(text), LCase(old_text.Cells(i)), LCase(new_text.Cells(i))) text = Result Next i SubstituteMultiple = Result End Function
- Go to VB Editor (Alt+F11)
- Click Insert
- Click Module
- Paste code to module
- Exit VB Editor
Download excel *.xlsm file
Substitute existing text with multiple text strings in a cell range.xlsm
Category: Substitute replace
5 Responses to "Substitute multiple text strings (vba)"
Do you have a version that is case sensitive?
Great solution, thanks!
this is best solution from whole google search results , Thanks very much.
but there is little difference within Substitute and SubstituteMultiple:
Substitude Multiple Changes Texts UperCase symbols To LowCase, can someone help how to fix this?
Leave a Reply
How to add a formula to your comment:
your formula
How to add VBA code to your comment:
[vb 1="vbnet" language=","]
VBA code
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Contact Oscar
You can contact me through this webpage


text:
Results 1 to 17 of 17
September 6th, 2007, 02:58 PM #1
CJ.com is Down
- Join Date
- January 18th, 2005
- Posts
- 2,511
Tried from two different ISPs. Page Cannot Be Displayed.
Affiliate links are working fine.
September 6th, 2007, 03:16 PM #2
Can't login
- Join Date
- June 27th, 2007
- Posts
- 8
I can get to the homepage but could not login to my account
September 6th, 2007, 03:21 PM #3
Same Here It's been about an hour and a half here in NY I was surprised to put in a twelve hour day yesterday with no problems but todays another story. Must be time for a nap
September 6th, 2007, 03:28 PM #4
Heh. So what else is new?I would rather live my life as if there is a God and die
to find out there isn't, than live my life as if there
isn't and die to find out there is.
September 6th, 2007, 03:37 PM #5
Happens every month around this time, give it 2 days and you'll be back on track.
September 6th, 2007, 03:43 PM #6Originally Posted by Ehphil
September 6th, 2007, 03:47 PM #7
Sounds like that needs to be an honest conversation with yourself. I hear everyone complain constantly about CJ, yet we are all still here...I am genuinly intersted in what keeps you (forum readers/contributers) on CJ?
September 6th, 2007, 03:48 PM #8
The fact that I still make money, despite the numerous roadblocks CJ throws our way constantly. And that some of my favorite partnerships are with CJ merchants and not available on another network or in-house.
September 6th, 2007, 03:52 PM #9
Originally Posted by spacedog
- Join Date
- September 6th, 2007
- Location
- MidSouth
- Posts
- 4
You said a Mouth Full, and that is what it is about, some of the merchants keep you there.
September 6th, 2007, 03:59 PM #10
Back up.I would rather live my life as if there is a God and die
to find out there isn't, than live my life as if there
isn't and die to find out there is.
September 6th, 2007, 04:05 PM #11
Yes, some of the merchants keep me there. But it's like a restaurant with amazing food and horrible service. Eventually you hope against hope that the chef moves to another restaurant that cares about their customers. Or you just stop going.
September 6th, 2007, 04:06 PM #12
- Join Date
- January 18th, 2005
- Location
- Moved, Asia
- Posts
- 400
Working again.IRS
Don't ask why the ball doesn't come.
September 6th, 2007, 04:22 PM #13
Originally Posted by spacedog
- Join Date
- September 6th, 2007
- Location
- MidSouth
- Posts
- 4
Ageed, although sometimes the chef moves to a place that is worse not better. This has been the case for me with a couple of my better performers.
September 7th, 2007, 12:19 PM #14Originally Posted by Ehphil
It's time the merchants lay into CJ and tell them to invest more into the backend of their systems. JMO of course
Can you imagine the stock holders of Google, MSN, Yahoo and so on if their sites were down like CJ is????
September 7th, 2007, 12:35 PM #15
Interesting, we're actually starting up with SAS (and hoping to switch over completely in a few months) for many of the above reasons, the customer service, as well as the nickle and diming on everything possible. As a merchant, I would think that CJ would want to make it easy for us to generate sales, rather they charge for everything. I would think that if enough top producing publishers asked, merchants would move. Start asking.
September 7th, 2007, 01:03 PM #16Originally Posted by Ehphil
Also note that CJ has been up and down all morning.
September 7th, 2007, 02:08 PM #17Originally Posted by Packy
Say there are 10 applications to review. I click into "Manage Affiliates", click "Pending Review", click a pending app to get a pop up of the affiliate's info and review their app and websites. Now here's where the system decides it'd like to use as much of the available server muscle as possible...
The first app is in India, lists "http://-" as their website and includes "software" among their promotion methods.
The efficient way to handle this would be for me to click decline and have the pop up window reload with the new status of declined, then I would close the window and click the next app down the list, but in CJ's resource intensive bizzarro world the steps are as follows:
1. Click decline and a new window pops over the current pop with a set of radio buttons for a basic decline and an auto-decline option with another decline button.
2. Click the decline button and the new window reloads with a declined message and a close button.
3. Click the close button and the window closes and reloads the affiliate info pop with a declined status and a close button.
4. Click the close button and the info pop closes and the list of pending affiliates refreshes to only include the remaining 9.
Neat, but way too many clicks and database hits on an already slow system.
I want to click decline and click close, not click decline, select decline option, click decline, click close, click close and wait for the pending apps list to refresh. It's a fundamental part of running a program and should be designed for efficiency of completing the task, but instead is designed with as many extra steps and database hits as they could come up with. Multiplied by thousands of advertisers and those extra clicks and DB calls slow CJ down for all of us.
I'd love to have you all in the CleanItSupply program over on CJ, but I also understand the frustrations and wish they'd do a lot more to eliminate them.Eathan Mertz
Black Cat Mining - Gold Prospecting & Rockhounding Equipment


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Ipswich v Brighton - Tuesday 19:45
The evidence against them is mounting, but the jury's still out on Ipswich this season. It's not a guilty verdict just yet. The Tractor Boys have looked lifeless for the most part and a promotion charge seems unlikely but you write Mick McCarthy off at your peril. His outstanding track record at this level buys him more time than most.
McCarthy looked thoroughly fed-up in the wake of Saturday's 1-0 defeat to Leeds and concerns are growing that his days at Portman Road might be numbered, that this is a relationship going nowhere. But then you look at the respective shot data of these two teams and you can only conclude that 11/4 about the home win is a big price here. Too big.
It's purely a matter of scale. We know Brighton are the real deal in this season's promotion race - level or thereabouts with Norwich, just behind big-spending Newcastle - and we can safely their defeats will be in single figures come the end of the campaign. But this is the Championship, and few come close to McCarthy's record of negotiating quick turnarounds.
Since the start of the 2012/13 season, Ipswich boast a remarkable W20 D8 L4 record in Tuesday night fixtures (2.13 points per game), so this looks like the ideal acid test of whether McCarthy's powers are beginning to fail him. The Ipswich/Ipswich half time/full time option at 6/1 is the best supplemtary wager. Brighton's last ten defeats have all been suffered this way.


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★★★★★ All levels 30 levels: "Angry Birds FREE" 15 levels & "Angry Birds Seasons FREE" 15 levels!!! Using our tips you will be able to finish each level ...
Discontinued App
Puzzle | iPhone, iPad
Tools | iPhone, iPad
★★★★★ All levels 30 levels: "Angry Birds FREE" 15 levels & "Angry Birds Seasons FREE" 15 levels!!! Using our tips you will be able to finish each level successfully with all three stars. *Free updates keep coming! *Cheats and walkthrough. *Original content and graphics. *No internet connection needed! *Compatible with iPod/iPod4,iPhone/iPhone4/iPad/iOS4 Now you will be able to achieve 3 stars on all levels! Legal Notice / Disclaimer: This is an unofficial guide to Angry Birds. This unofficial guide was created by ApperLeft Ltd. ApperLeft Ltd is not endorsed by or affiliated with Rovio Mobile Ltd or Clickgamer Technologies. Neither Rovio Mobile Ltd or Clickgamer Technologies nor has anyone else authorised, sponsored or sanctioned this unofficial guide. It is the sole creation and responsibility of ApperLeft. All characters and their names and all places and events and all other aspects concerning Angry Birds are the property of their respective owners. All trademark and copyright concerning Angry Birds Seasons.are the property of their respective owners. We make no claim to and do not have any rights to any of the foregoing. All images were cropped and used only to convey what the application is about, In creating this unofficial guide to Angry Birds, We assert its rights under the "fair use" doctrine pursuant to United States copyright law and the equivalent in other jurisdictions. If you believe that there has been a contravention of your proprietary rights then email details to email@example.com.
Version: 1.35
Size: 17.4 MB
Price: 0,89 €
Developed by Apperleft Ltd
Day of release: 0000-00-0


text:
Starting February 1st through the 5th you can get any of the files below at 40% OFF...
You can easily access the store by clicking on the file you would like to purchase...
HaPpY VaLeNtInEs!!!
Tuesday, January 31, 2012
Sunday, January 24, 2010
Valentine Die-cuts
Once you click an image it will take you to my little corner in the Paperthreads store, after you make your purchase you can download a zip file in the format that you need. With in each zip file you will find your purchased file, an image of the product, illustrated instructions to easily cut and piece your die-cuts and a terms of use.
HaPpY ScRaPpInG!
Posted by Carrie Schwartz at 7:49 PM No comments:
Subscribe to: Posts (Atom)


text:
Converter utilities capable of zix file to rar format conversion.
ZIX archives are notoriously distributed on torrents sites, but are nothing more than a variant of ZIP that can be opened with a malware known as WinZIX.
It is better to download the files in other format and delete .zix files. If you really wish to recover .zix files, use tools such as such UnZixWin or UnZixHTA that removes all the rubbish data from these archives and creates regular ZIP files. After that, you can repack the to RAR with any of the zip to rar tools available - should you really need it.
Unfortunately, there is no detailed software record in the database for this conversion.
Additional links: zix file extension details, rar file extension details
Back to conversion search


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Nollywood has also caught the 'Reggae Blues' bug and a movie of the same title is set to drop soon which is inspired by singer, HarrySong.
One of Nigeria's most recent popular phrase "Even your boo get a boo", went viral few weeks ago shortly after 5 Star Music singer, HarrySong, dropped his biggest hit, "Reggae Blues."
Just like we all expected, Nollywood has caught the bug and a movie of the same title is set to drop soon. Odira Nwobu and Adanma, who starred in the movie, shared the poster on their Instagram pages and it has left Nigerians in raptures.
Singer, HarrySong saw the hilarious movie poster online and reposted it and wrote; "EVEN UR BOO GET A BOO???? NOLLYWOOD ON THE MATTER…YA'LL WATCH OUT FOR THIS ONE..#D'BOO #REGGAEBLUES."


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The shipment was very fast, the items were great, and the prices are unbeatable. Thank you MJM, I'm a definite repeat customer.
Read More ->
I continue to be impressed with the personable attention I receive from the staff of MJM, especially the hospitality of Jeff Mash. My experience has...
Read More ->


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Designer Babies
Historical Background
Scientific Research
Controversial Arguments
The Patient
The Medical Professional
Government Regulations
Healthcare Insurance Providers
What are designer babies?
The term "designer babies" was originally derived from media and
journalists . It refers to a baby who is created artificially with the help of
in-vitro fertilization. The artificial effect applies to the babies' characteristics and traits.
Create a free website
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Welcome, Guest
If you have a question regarding coaxial, telephone, and building wire, power cable, insulation, extrusion, bunching, stranding, braiding, etc. post it here.
TOPIC: Contaminant
Contaminant 5 years 10 months ago #423
Dear all,
I am a low voltage XLPE compounder. I am running black and natural color for the compound. Every time when my production machine swings from black to natural compound, I have to use out about 300 - 400kg of virgin material to purge the black/ contaminated. Even though the natural compound looks white, there are still some contaminants in the products.
Can I ask if anyone has a remedy for this? Your help will be very much appreciated.
The administrator has disabled public write access.
Re: Contaminant 5 years 10 months ago #424
There are certain facts of life that are hard to get around and I expect this is one of them. Since you are manufacturing low voltage XLPE, I imagine you are purging the compounding extruder with natural polyethylene containing no organo-peroxides at all. This suggests that there is no or very little peroxide bearing polyethylene in the purged compound once the majority of the compounded black XLPE polyethylene is captured and discarded. It may then be possible to capture and regrind the remaining "gray" polyethylene in say a hot melt granulator and that this material could then be proportionally fed into the next run of the black XLPE formulation. The danger of course is that some larger concentrations of peroxide bearing polyethylene could go through the compounding extruder a second time and result in precured or already crosslinked contaminants in the finished compound. Other contaminants such as plant dirt and foreign materials could also be a problem. This will depend on operator/ process engineering expertise, the sophistication of your compounding extruder, plant cleanliness and local specifications. You may wish to discuss this further with the compounding extruder manufacturer.
Kindest Regards,
Peter J. Stewart-Hay
Stewart-Hay Associates
The administrator has disabled public write access.
Re: Contaminant 5 years 10 months ago #425
Further from Contaminant
I have faced the same problem as well. I have been using virgin material to clean up the compounding extruder for years. I have been told that I can either add in purging compound or processing aids (PPA) to do the cleaning. I would like to ask what are the difference and advantages between purging compound and processing aids in terms of the quality of the product."
:: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: ::
I am neither a chemist nor chemical engineer so the following are strictly my personal opinions:
"Purging Compounds and Polymer Processing Aids (PPA) are just one more material to purchase and use in the hope that one will get a faster clean out and thus use less material. My experience with extruders that pump thermosetting and thermoplastic polyolefin compounds is that these extras are not justifiable in terms of saving money. Moreover, the common PPA compounds on the market are fluorinated, expensive and environmentally harmful. Instead I suggest that one use a natural polyethylene thermoplastic compound to clean out the extruder but continuously vary the extruder speed to "scrub" the screw and barrel so to speak.
Others may have different opinions and I would very much appreciate if they are posted on this Forums thread.
:: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: :: ::
Extracts from a Presentation Titles - Processing Aids in Extrusion of Polyethylene
By: M.H. Wagner (1), M. Müller (1), O. Kulikow (2), K. Hornung (2)
(1) - Technische Universität Berlin, Polymertechnik/-physik
(2) - Universität der Bundeswehr der München, Luft- und Raumfahrttechnik
Polymer Processing Aids (PPAs) are often used improve extrusion flow instabilities in LLDPE and metallocene PE such as melt fracture and this is often referred to as "snakeskin".
Metallocene Polyethylene (mPE)
• mPE is a new development which is of special interest because of narrow molar mass distribution:
• Polyethylene made from metallocene catalysts en.wikipedia.org/wiki/Post-metallocene_catalyst is tougher, stronger and cleaner than resin made from conventional catalysts
• The film manufactured with metallocene PE offers down-gauging opportunities to reduce costs and environmental pollution
Typical Polymer Processing Aids (PPAs) are:
a) Fluorinated PPAs:
• "Viton FreeFlow™" - DuPont
• "Dynamar" - Dyneon (3M)
• "Kynar " - Atofina Chemicals
• "Metablen A" - Mitsubishi Rayon Co., Ltd.
b) The use of less than 500 ppm of thermoplastic elastomers:
• "Elastollan" – Elastogran
• "Baymod" – Bayer
C) The usee of less than 500 ppm Silicone Elastomers
• TPSE" – Wacker Chemie
Kindest Regards,
Peter J. Stewart-Hay
Stewart-Hay Associates
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Time to create page: 0.182 seconds


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-CNC数控系统与编码器组成闭环控制系统。CNC controller has the automatic function of inspection of inspection and compensation.the parallelism of the sheet to be cut off and the precision of the shear size can be ensured.The cutting stroke and cutting times could be controlled also.
- The cutting times can be displayed on a digital displayer,and the stroke of top blades could be adjusted steplessly.Also,the adjustment of the gap between tools can be showed on a indicating dial.
- The front feeding system adopts rolling ball screw,rolling guiding way and pneumatic clamping unit.The feeding precision can reach±0.10mm.
- Protective fence and the safety interlocker to ensure the operation safety.


text:
Spinal Stimulator Plaintiff Failed To Plead Parallel Claims, Judge Says
(Nevolas opinion available. Document #28-160204-015Z.)
In 2012, Susan Nevolas was implanted with the Precision Spinal Cord Stimulator Model SC-1010C made by Boston Scientific Corp. Nevolas claims that a defect...
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text:
The guinea pig rectum, but not the colon, is innervated by a specialized class of distension-sensitive mechanoreceptors that have transduction sites corresponding to rectal intraganglionic laminar endings (rIGLEs). Rectal mechanoreceptors recorded in vitro had low threshold to circumferential stretch, adapted slowly, and could respond within 2 ms to mechanical stimulation by a piezo-electric probe. Antagonists to ionotropic N-methyl-d-aspartate (NMDA; CGS 19755, memantine) and non-NMDA (6,7-dinitroquinoxaline-2,3-dione) glutamate receptors did not affect mechanotransduction. In normal Krebs solution, the P2X purinoreceptor agonist α,β-methylene ATP reduced mechanoreceptor firing evoked by distension but simultaneously relaxed circular smooth muscle and inhibited stretch-induced contractions. Neither ATP nor α,β-methylene ATP affected mechanotransduction when transduction sites were directly compressed with von Frey hairs. The P2 purinoreceptor antagonist pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid did not affect stretch-induced firing but reduced the inhibitory effect of α,β-methylene ATP on stretch-induced firing. Under isometric conditions, blocking synaptic transmission in Ca2+-free solution reduced stretch-evoked firing but not when basal tension was restored to control levels. Under isotonic condition, Ca2+-free solution did not significantly affect load-evoked firing. The blockers of mechanogated and/or transient receptor potential channels, benzamil, Gd3+, SKF 96365, and ruthenium red inhibited stretch-induced firing but, in parallel, significantly reduced stretch-induced contractions. Benzamil and SKF 96365 were able to inhibit mechanotransduction when transduction sites were compressed with von Frey hairs. The results show that mechanotransduction is rapid but does not depend on fast exocytotic release of mediators. It is likely that stretch-activated ion channels on rIGLEs are involved in direct, physical mechanotransduction by rectal low-threshold mechanoreceptors.
- afferents
- mechanosensory transduction
distension of the gut wall activates both intrinsic and extrinsic neuronal reflex pathways and may cause conscious sensation. The mechanisms underlying activation of mechanosensitive extrinsic afferent neurons are not well understood. Two types of mechanisms, chemical and physical, have been proposed for mechanotransduction by afferent neurons in different systems. Chemical transduction relies on mediators being released from nonneuronal cells by mechanical stimulation, which then activate afferent endings via corresponding receptors. Direct mechanotransduction is characterized by having all molecular elements (mechanogated ion channels and associated proteins) located in the afferent endings, without extracellular mediators being essential (6, 17, 23). Several recent reports have provided evidence for a role for chemical transduction in primary afferent neurons in several systems. Cutaneous slowly adapting mechanoreceptor corpuscles, Merkel cells, release glutamate in response to mechanical stimuli to activate afferent nerve fibers (18). Likewise, in the cochlea, glutamate probably mediates transmission between mechanosensitive inner hair cells and spiral ganglion neurons (40). In visceral primary afferents neurons, ionotropic glutamate receptor antagonists attenuate distension-evoked firing of spinal and vagal afferents innervating the gastrointestinal tract (30, 44). ATP has been postulated to be a key signaling molecule mediating mechanosensitivity in several regions (6), and mechanosensitive release of ATP may be a ubiquitous mechanism in eukaryotic cells (3, 24, 32). Both ionotropic P2X and metabotropic P2Y purinoreceptors are expressed on sensory neurons and their endings (9, 19, 46, 57) and purinoreceptor antagonists, such as suramin, pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), and 2′,3′-O-trinitrophenyl-ATP (TNP-ATP), reduce mechanosensitivity of spinal afferents innervating the lower gut and urinary bladder (39, 52).
On the other hand, mechanogated channels also appear to be ubiquitous among eukaryiotic cells and are the prime candidates for transduction of mechanical stimuli into cellular electrochemical signals in some primary afferent neurons (23, 24). The most likely mechanosensitive ion channels belonging to TRP and/or ENaC/ASIC/degenerin of cationic and sodium ion channel families are involved in mechanotransduction in ciliated and nonciliated mechanoreceptors including mammalian extrinsic primary afferent neurons (21–23). A recent study has identified a role for a TRP channel family member (TRPA1) as the mechanotransducing channel in vertebrate hair cells (13).
In the gastrointestinal tract, both low- and high-threshold spinal mechanoreceptors have been documented (43); five main types of mechanoreceptors were identified in splanchnic and pelvic mechanosensory pathways to the mouse colon including two stretch-sensitive types of mechanoreceptor (4). Previously, we have identified rectal intraganglionic laminar endings (rIGLEs) as the mechanotransduction sites of low-threshold rectal mechanoreceptors (28). These endings are largely restricted to the rectum, being present in only small numbers in the distal colon, indicating that they comprise a specialized class of rectal mechanoreceptors (33). It has been suggested that they behave grossly as tension receptors (28) and may correspond to the muscular mechanoreceptors classified in the mouse colorectum (4). In the esophagus and stomach, morphologically similar endings, called intraganglionic laminar endings (IGLEs), are the transduction sites of vagal mechanoreceptors (54, 55). We have recently provided evidence indicating that IGLEs use direct, physical mechanisms of mechanotransduction via stretch-activated ion channels (57). The aim of this study was to investigate whether rectal mechanoreceptors in the guinea pig rectum transduce mechanical stimuli physically (via mechanosensitive ion channels) or indirectly (via release of chemicals from other cells).
Extracellular recording.
Adult guinea pigs [total no. of animals (N) = 66], weighing between 180 and 250 g, were killed by a blow to the occipital region and exsanguination, in a manner approved by the Animal Welfare Committee of Flinders University in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes (National Health and Medical Research Council of Australia, 7th ed., 2004). The method of extracellular recordings from rectal mechanoreceptor afferents in guinea pig has been described previously (28). Briefly, the distal rectum was opened up into a flat sheet, and the mucosa was removed from a 10-mm-long preparation and washed with Krebs solution (in mM: 118 NaCl, 4.75 KCl, 1.0 NaH2PO4, 25 NaHCO3, 1.2 MgSO4, 2.5 CaCl2, and 11 glucose; bubbled with 95% O2-5% CO2
In most experiments, a small array of hooks was used to attach one edge of the preparation to an isometric force transducer (DSC no.46-1001-01, Kistler-Morse, Redmond, WA) that was mounted on a tissue stretcher device (5). The slack was taken up to give a resting tension of ∼1 mN, and 60–120 min of equilibration were allowed before the experiment was started. Preparations were stretched by the microprocessor-controlled tissue stretcher (stretching by "imposed length" while recording the tension developed by the tissue), at 5 mm/s for distances of 1–3 mm and held for 10 s, at 3-min intervals. Mean firing rate of afferent units was calculated during a 10-s stretch. In all cases, stretch-evoked contraction was calculated as integrated tension (area under the curve) in (Newtons × seconds). When the effects of Ca2+-free Krebs solution were studied, stretches were applied by imposed length or by "imposed load" to the tissue. In later cases, the array of hooks was attached to the arm of an isotonic transducer via a pulley, and counterweight was increased by hanging 1- to 5-g weights. A resting load of 0.5 g was applied, and contractions of the tissues were recorded as change in length by the isotonic transducer (Harvard Bioscience, model 52-9511, S. Natick, MA).
Transduction sites ("hot spots") that correspond to rIGLEs (28) were identified by focal compression with von Frey hairs (0.1–1 mN) with tip diameters of <50 μm and marked on the tissue, using fine carbon particles attached to the tip of the hair. To determine the minimal latency of mechanotransduction, a blunt glass micropipette (∼100 μm tip diameter) was mounted on a piezoelectric element (Radio Spares, Sydney, Australia). Voltage steps (100 V, 200-ms duration) were applied to the piezoelectric activator from a stimulator (Grass DS9A, Quincy, MA) producing a rapid displacement of ∼10-μm amplitude with a latency of <0.1 ms. The tip of the pipette was placed precisely above a marked hot spot. Conduction latency was determined using a bipolar platinum stimulating electrode placed at exactly the same site above the marked hot spot. Pulses were delivered at 0.3 Hz, 0.6-ms duration, and suprathreshold voltage (10–30 V). Usually, 10–20 stimuli (mechanical and electrical) were delivered to a single hot spot, and the minimum latency for both stimuli was calculated. Studies of latency were carried out in Ca2+-free Krebs solution to prevent smooth muscle contractions during mechanical probing.
To study the effect of putative blockers of mechanogated channels on mechanotransduction, three consecutive probes with a von Frey hair (∼1 mN for 1 s, 10 s apart) on marked hot spots were delivered at 4-min intervals. In preliminary experiments, it was found that this protocol gave reproducible, submaximal responses for period of at least 3 h. Mean firing rate from the three trials was calculated for the most sensitive hot spot.
cis-4-[Phosphomethyl]-2-piperidinecarboxylic acid (CGS 19755), 6,7-dinitroquinoxaline-2,3-dione (DNQX), and memantine were obtained from Tocris (Avonmouth, UK). Gadolinium chloride, benzamil, ATP, α,β-methylene ATP (α,β-me ATP), SKF 96365, PPADS, and ruthenium red were obtained from Sigma (St. Louis, MO). Gd3+ was used in modified Krebs solution (in mM: 139 NaCl, 4.75 KCl, 5 HEPES, 1.2 MgCl2, 2.5 CaCl2, and 11 glucose; bubbled with 100% O2).
Data analysis.
Results are expressed as means ± SE. Statistical analysis was performed by Student's two-tailed t-test for paired or unpaired data or by repeated-measures one- or two-way analysis of variance using Prism 4 software (GraphPad Software, San Diego, CA). Differences were considered significant if P < 0.05.
Most of rectal afferents [no. of units (n) = 84, N = 66] were electrically silent in unstretched rectal preparations and had low thresholds (∼1 mm) to circumferential distension. After the onset of stretch using the tissue stretcher, mechanoreceptor firing showed an initial burst of firing followed by marked adaption that closely followed muscle tension in time course. These units were similar to previously described rIGLEs as transduction sites (29).
Latency of mechanotransduction.
Mechanoreceptor afferents were slowly conducting with an average conduction velocity of 1.28 ± 0.13 m/s (n = 7, N = 6), within the C-fiber range. Focal compression of the tissue with light von Frey hairs (0.1–1 mN) activated rectal mechanoreceptors only at several highly localized sites (hot spots), which correspond to rIGLEs (28). The response latency at marked hot spots, determined for each unit using the piezoelectric probe, was 11.3 ± 2.2 ms (n = 7, N = 6). The latency for electrical stimulation from the same sites was 9.7 ± 2.3 ms (n = 7, N = 6; Fig. 1). The latter latency represents the delay due to conduction of action potential from the hot spot to the recording site. By subtracting the conduction latency from total latency for each unit, the mean delay due to mechanotransduction was calculated at 1.7 ± 0.4 ms (n = 7, N = 6). Latencies evoked by mechanical stimulation were more variable than those for electrical stimulation. Typically, shorter latencies were associated with a larger number of spikes evoked by mechanical stimulation. This suggests that small movements of the preparation may have moved hot spots relative to the probe, causing longer latencies and weaker responses when the probe was off center. Despite this variability, mechanotransduction by low-threshold rectal mechanoreceptors occurred on a millisecond time scale and must be due either to rapid chemical transmission from other cells or, alternatively, to activation via mechanogated ion channels located on rIGLEs.
Effects of glutamate ionotropic receptors antagonists on transduction of rectal mechanosensitive afferents.
Glutamate can mediate fast synaptic transmission on a submillisecond time scale via ionotropic receptors (41) and has been suggested to be involved in distension-induced activation of spinal and vagal mechanoreceptors (30, 44). The competitive antagonist to ionotropic N-methyl-d-aspartate (NMDA) receptors, CGS 19755 (30 μM), did not affect either stretch-induced firing [107 ± 19% of control for 3-mm stretch, n = 4, N = 3; not significant (NS)] or stretch-induced contraction (108 ± 5%, N = 3, NS). Similarly, the selective antagonist to non-NMDA ionotropic receptors, DNQX (100 μM), did not inhibit stretch-induced firing (91 ± 8% of control at 3-mm stretch, n = 5, N = 4, NS) or contractions (118 ± 3%, N = 4, NS). The open channel blocker of NMDA receptors, memantine (30 μM), affected neither stretch-evoked firing nor contraction (106 ± 23%, n = 5, N = 4, and 96 ± 4%, N = 4, of control 3-mm stretch, respectively). However, at 100 μM, memantine decreased stretch-induced firing slightly (to 74 ± 16% of 3-mm control stretch, NS, n = 6, N = 5) but also significantly decreased stretch-induced tension (to 62 ± 6% of control 3-mm stretch, N = 5, P < 0.005 by two-way ANOVA; Fig. 2). These results indicate that activation of ionotropic receptors by endogenous glutamate is not involved in mechanotransduction by spinal low-threshold mechanoreceptors in the guinea pig rectum.
ATP and mechanotransduction.
ATP, acting via P2X2/3 receptors, may be involved in mechanotransduction by some spinal afferents to the rat colorectum and mouse urinary bladder (39, 52). In the guinea pig rectum, the P2X-preferring agonist α,β-me ATP (30 μM for 1 min, n = 9, N = 6) evoked relaxation of circular muscle and inhibited muscle contractile responses to distension (to 15 ± 3% of control, 3-mm stretch, N = 6, P < 0.005 by paired t-test). In parallel, α,β-me ATP inhibited stretch-evoked firing (to 26 ± 6% of control, n = 9, N = 6, P < 0.005 by paired t-test) of rectal afferents (Fig. 3A). To determine whether the effect on the muscle could explain the reduced firing, studies were carried out in Ca2+-free Krebs solution. Under these conditions, basal muscle tension and stretch-evoked tension were reduced, presumably due to blockade of active muscle responses. The inhibitory effect of α,β-me ATP on muscle tension was abolished. However, even under these conditions, α,β-me ATP (30 μM) did not excite mechanosensitive endings. The nonselective P2 purinoreceptor antagonist PPADS (30 μM) did not affect stretch-induced firing of rectal mechanoreceptors in normal Krebs solution (91 ± 12% of control 3-mm stretch, n = 6, N = 4, NS by 2-way ANOVA; Fig. 3C). This concentration of PPADS (30 μM for 20 min) was effective, because in its presence, α,β-me ATP (30 μM) no longer inhibited stretch (3 mm)-evoked firing (77 ± 24% of control, n = 6, N = 4, NS by 2-way ANOVA).
To exclude the indirect effect of purines on firing due to their influence on muscle tension, the actions of ATP and α,β-me ATP were examined on firing evoked by focal compression with a von Frey hair (∼1 mN) on a previously marked hot spot. Neither α,β-me ATP (30 μM for 1 min) nor ATP (1 mM for 1 min) affected firing evoked by von Frey hair probing (91 ± 19% of control, n = 5, N = 4, NS; and 127 ± 15% of control, n = 6, N = 5, NS, respectively). Neither agonist activated low-threshold, stretch-sensitive units (Fig. 3B). However, two spontaneously active units (for which hot spots were not found) of 14 recorded units in 5 guinea pigs were slightly excited by application of 1 mM ATP. Overall, these data suggest that P2X receptors are unlikely to be involved in mechanotransduction by the majority of low-threshold mechanoreceptors.
Effects of Ca2+-free Krebs solution on mechanotransduction.
We investigated the effect of blocking all rapid synaptic neurotransmitter release mechanisms on transduction using Ca2+-free and high-Mg2+ Krebs solution. Under isometric conditions, transduction of mechanical stimuli by rectal mechanoreceptors in the guinea pig rectum persisted at a reduced level in Ca2+-free (1 mM EDTA, 6 mM Mg2+) Krebs solution (Fig. 4). The number of action potentials evoked by 3-mm stretch was significantly reduced (to 40 ± 14% of control Krebs solution, n = 9, N = 7, P < 0.05 by 2-way ANOVA). This may have been due to the significant reduction of both resting tension and stretch-evoked tension (to 12 ± 3% of control, N = 7, P < 0.001 by 2-way ANOVA; Fig. 4, E and F). After resting tension was adjusted back to the control level, 3-mm stretch evoked an increase in passive tension that was still less than that in normal Krebs solution (30 ± 32% of control, N = 7, P < 0.001 by 2-way ANOVA). However, under these conditions, stretch-induced firing was not significantly different from control (100 ± 21%, n = 9, N = 7, NS; Fig. 4, E and F). To exclude the confounding effect of changes in muscle tension, we also investigated the effects of Ca2+-free Krebs solution under isotonic conditions. Application of Ca2+-free (with 3.6 mM Mg2+) Krebs solution for 1 h did not affect significantly either firing (n = 8, N = 6, NS by 2-way ANOVA) evoked by isotonic stretching of the tissue with imposed load (10–50 mN) or the length of the preparations (N = 6, NS by 2-way ANOVA; Fig. 4, G and H). These findings indicate that Ca2+-dependent fast synaptic release is not required for mechanosensory transduction by rIGLEs in the guinea pig rectum.
Effects of stretch-activated and cationic channel blockers on transduction by rectal afferents.
We have previously showed that benzamil (a potent analog of amiloride) inhibited stretch-induced firing in the guinea pig esophagus at high concentrations (100 μM) (57). In the guinea pig rectum, benzamil (10–30 μM for 20–25 min) significantly decreased stretch-induced mechanoreceptor firing (Fig. 5A). However, it also reduced stretch-evoked increases in wall tension (Fig. 5B). Thus benzamil (30 μM) reduced firing to 22 ± 6% of control (n = 4, N = 4, P < 0.001 by 2-way ANOVA), whereas it reduced integrated tension to 33 ± 8% of control (N = 4, P < 0.001 by 2-way ANOVA). From these results, it was not possible to determine whether the inhibition of stretch-induced firing by benzamil was due to an effect on mechanogated ion channels on rIGLEs or alteration of the mechanical properties of muscle. Therefore, we studied the effects of benzamil on firing evoked by focal compression of hot spots (rIGLEs) with a von Frey hair. Benzamil (30 μM for 30–35 min) significantly reduced firing evoked by a von Frey hair (∼1 mN) probing of hot spots (63 ± 9% of control, n = 5, N = 5, P ≤ 0.01 by 1-way ANOVA). The effect was reversible by washing for 60 min with normal Krebs solution (Fig. 5C).
Gadolinium ion (Gd3+; 100 μM for 20 min) inhibited stretch-induced firing to 13 ± 8% of control (3 mm stretch, n = 4, N = 3, P < 0.01 by 1-way ANOVA) but simultaneously reduced stretch-induced muscle tone (to 24 ± 6% of control, N = 3, P < 0.01 by 1-way ANOVA; Fig. 6A). The effect of Gd3+ on stretch-induced firing developed with a time course that paralleled the inhibition of stretch-induced intramural tension (Fig. 6B). Gd3+ (100 μM for 20 min) did not affect firing evoked by von Frey hair (∼1 mN) compression of hot spots (112 ± 12% of control, n = 4, N = 4, NS by 1-way ANOVA; Fig. 6C). This suggests that the effect of Gd3+ on stretch-induced firing was probably largely due to reduction of muscle tension.
The nonselective cation channel blocker SKF 96365 (30–50 μM for 10–15 min) also inhibited stretch-induced firing. Applied at 50 μM, stretch (3 mm)-induced firing was reduced to 16 ± 15% of control (n = 3, N = 3, P < 0.001 by 2-way ANOVA). Again, this followed a parallel reduction of stretch-induced contraction of smooth muscle (to 38 ± 3% of control, N = 3, P < 0.001 by 2-way ANOVA; Fig. 7, A and B). SKF 96365 (50 μM for 15–20 min) significantly inhibited firing evoked by von Frey hair (∼1 mN) compression of hot spots (48 ± 11% of control, n = 6, N = 6, P ≤ 0.05 by 1-way ANOVA). The effect was washable within 45 min (Fig. 7C).
The nonselective TRP channel blocker ruthenium red concentration-dependently inhibited stretch-induced firing. At 30 μM for 20 min, stretch (3 mm)-induced firing was 30 ± 14% of control (n = 5, N = 4, P < 0.01 by 2-way ANOVA), but, at the same time, stretch-induced tone was reduced to 22 ± 12% of control (N = 4, P < 0.001 by 2-way ANOVA) (Fig. 8, A and B). However, ruthenium red (30 μM for 35–40 min) significantly increased the firing evoked by von Frey hair (∼1 mN) probing of hot spots (193 ± 22% of control, n = 6, N = 5, P ≤ 0.05 by 1-way ANOVA). The effect was washable for ≥60 min (Fig. 8C).
The present study has shown that mechanotransduction by low-threshold mechanoreceptors in the guinea pig rectum does not require synaptic transmission or endogenous transmitters ATP and glutamate, suggesting that stretch-activated ion channels on rIGLEs are involved in direct physical mechanotransduction by rectal low-threshold mechanoreceptors. By using a piezoelectrical probe to measure accurately responses to mechanical stimulation and subtracting conduction delays, the mechanotransduction delay was shown to be <2 ms. A similar short mechanotransduction delay of 6 ms was reported for vagal mechanoreceptors (57) and of 8 ms for low-threshold cutaneous D-hair receptors (45). In contrast, the mechanical latency for cutaneous high-threshold mechanoreceptors, in particular slowly adapting AM mechanoreceptors and polymodal nociceptors, is many times longer: up to 80 ms (45). Slowly adapting cutaneous mechanoreceptors supplying Merkel cell complexes in touch domes may rely on glutamate, released from Merkel cells, to activate afferent nerve fibers (18). Nevertheless, on its own, rapid mechanotransduction by rectal afferents is not sufficient proof that direct (nonchemical) mechanisms are responsible. At some glutamatergic central nervous system synapses, the total synaptic delay is only 150 μs (41). However, the observation that transduction persists in 0 mM Ca2+, when rapid exocytotic transmitter release is blocked, is strong evidence that chemical transduction is unlikely to be involved.
It has been reported from in vivo studies that glutamate acting at NMDA receptors may be involved in responses to noxious colonic distension in the rat. Recordings from three afferent units in pelvic nerves were reported to show that memantine, an open channel blocker of NMDA ionotropic receptors, reduced the increase in firing evoked by constant pressure distension (30). In the present study, memantine at 30 μM did not affect mechanotransduction by rectal afferents. This concentration is well above the IC50 for NMDA receptors (10). In our hands, at 100 μM, memantine slightly reduced firing but strongly and significantly inhibited stretch-induced contractility. In the study of McRoberts et al. (30), balloon volume was not monitored during the study so that effects of memantine on smooth muscle contractility were not measured. It has been reported for vagal afferents in the intact rat stomach in vivo that distension-evoked firing was reduced by CNQX, memantine, and MK-801 (44). In our hands, other ionotropic glutamate antagonists for both NMDA and non-NMDA receptors (CGS 19755 and DNQX) did not affect mechanotransduction of spinal low-threshold mechanoreceptors in the guinea pig rectum. Similarly, ionotropic glutamate receptor antagonists did not inhibit stretch-induced firing in an in vitro study of vagal mechanoreceptors in the guinea pig esophagus (57). The apparent discrepancies between these findings may be due to experimental differences. First, there may be differences between species. Second, our study was restricted to a highly defined, relatively homogenous class of low-threshold mechanoreceptors, with well-characterized, specialized endings in myenteric ganglia (28). In the other studies, it is not possible to be sure of the homogeneity of recorded receptors or the sites of their sensitive endings within the gut wall. Third, in the present study, high-resolution recordings were made of muscle length and tension within a small area surrounding the receptive field; in other studies, large balloons have been used for distension with or without recordings of contractile responses. A fourth potential explanation is the difference between in vivo and in vitro preparations. It is possible that higher levels of endogenous glutamate may access visceral afferent endings in an intact, perfused organ. Despite these differences in experimental approach, our results suggest that for rIGLE-bearing low-threshold rectal mechanoreceptors, glutamatergic transmission is not required for mechanotransduction. Whether it may contribute to modulating excitability of endings, which could affect the amplitude of responses to distension, remains to be determined. It is worth pointing out that in neither of the published studies cited above did antagonists entirely block responses. In our opinion, this is consistent with a modulatory, rather than transductive role for glutamate. Alternatively, multiple transduction mechanisms, using one or more chemical messenger such as ATP, 5-HT, and glutamate, may be involved.
The purinergic hypothesis for chemical mechanotransduction by spinal afferents suggests that ATP, released from epithelium or urothelium, activates afferent nerve endings via P2X2/3 receptors during gut or bladder distension (6). ATP is well established now as a neurotransmitter in the central and peripheral nervous systems but is also released from other tissues by touch, stretch, or tissue injury (2, 3, 6, 32, 38, 52). Both ionotropic P2X and metabotropic P2Y purinoreceptors are widely expressed on sensory neurons (9, 19, 46). In the current study, neither α,β-me ATP nor ATP activated low-threshold rectal mechanoreceptors. In addition, P2X2 receptor immunoreactivity was not detected on rectal IGLEs (V. P. Zagorodnyuk and S. J. H. Brookes, unpublished observations). In contrast, in the guinea pig esophagus and stomach, IGLES of vagal low-threshold mechanoreceptors were distinctively labeled by P2X2 receptor antibodies, and nearly all of afferent units were excited by α,β-me ATP with EC50 of ∼20 μM (8, 57). The effects of purine receptor agonists on rectal mechanoreceptors were complicated by their direct inhibitory effects on smooth muscle; however, these were blocked in Ca2+-free Krebs solution (53, 59). Under identical conditions, a recent report (57) demonstrated that excitatory effects of α,β-me ATP were actually increased for vagal mechanoreceptors. In the rectum, however, we were still unable to detect the excitatory effect of α,β-me ATP on mechanoreceptors, even in Ca2+-free Krebs. The inability of purines to affect firing directly was supported by their lack of the effect on firing evoked by compression of hot spots (rIGLES) with a von Frey hair. In the rat colorectum, it was reported that α,β-me ATP at high concentrations (100 μM–1 mM) activated ∼80% of mechanosensitive fibers (50). In contrast, fewer than 50% of esophageal mechanoreceptors are activated by the P2X agonist in the mouse and none in normal ferret esophagus (35, 36). These data support significant species differences in receptor expression in visceral afferents as reported previously (58). It has been suggested that ATP, acting on autocrine P2Y1 receptors, may be involved in some vertebrate touch sensitivity (32). However, in the guinea pig esophagus, the P2Y1 receptor agonist adenosine 5′-O-(2-thiodiphosphate) (38) activated vagal tension receptors with much less efficiency than α,β-me ATP (57). In the present study, the P2 antagonist PPADS did not affect mechanotransduction but antagonized the inhibitory effect of α,β-me ATP on stretch-induced firing. In previously published studies (39, 52), PPADS, suramin, and TNP-ATP modestly inhibited the peak of stretch-induced firing of a subset of low-threshold mechanoreceptors in the rat colorectum and mouse urinary bladder. In our opinion, all these data are compatible with a modulatory, rather than transductive role for purines in low-threshold mechanoreceptors. Alternatively, multiple transductive mechanism, species, and experimental condition differences may be involved explaining apparently discrepant observations between previously published reports and the present study. Purines are released from nonneuronal cells in damaged tissue or during inflammation (2, 6). After acid-induced inflammation, vagal mechanoreceptors in the ferret esophagus become sensitive to α,β-me ATP (36). Thus purinoceptors and purine release may play an important role in setting the excitability of mechanoreceptor endings, particularly in the mucosa and especially in the context of tissue damage. Consistent with this is the observation that high-threshold mechanoreceptors are more sensitive to ATP and purinergic antagonists than low-threshold mechanoreceptors (39, 52).
The latency of mechanotransduction in rectal mechanoreceptors in the guinea pig was <2 ms. In contrast, mechanically activated ATP release typically occurs over a time scale of seconds (2, 42), even when this is mediated by "burst release" (1). ATP and other transmitters can be released very rapidly, on a submillisecond timescale, by calcium-sensitive exocytotic release mechanisms at synapses (41, 60). The use of Ca2+-free and raised Mg2+ Krebs solution is a well-established procedure to block fast exocytotic synaptic release. In our hands, Ca2+-free solution significantly reduced stretch-induced firing. However, when basal tension was readjusted to control levels, the stretch-induced firing was also restored together with a partial recovery of peak tension during the stretch. In addition, in isotonic conditions, where confounding changes in muscle tension were prevented, Ca2+-free solution did not affect load-induced firing. Thus, mechanotransduction appears to be independent of exocytotic release, as reported previously for vagal esophageal low-threshold mechanoreceptors (57). This makes it very unlikely that chemical transduction is significant for rectal mechanoreceptors.
The most likely candidates for mechanogated channels of extrinsic primary afferent neurons in mammals belong probably to TRP and/or ENaC/ASIC/degenerin families of cation and sodium ion channels (14, 15, 20, 34, 37, 51). Recent studies have provided strong evidence for a role in TRPA1 channels in mechanosensitivity of cochlear hair cells (13) and TRPC1 channels in stretch responsiveness of many cell types (29). Nonselective blockers of mechanogated channels, Gd3+, amiloride, and benzamil, can block both families of ionic channels (15, 24, 26, 48). In the present study, benzamil (10–30 μM) inhibited stretch-induced firing of rectal mechanoreceptors, but this may have been due to its effects on wall tension. The inhibitory action of benzamil on firing evoked by von Frey hair compression of transduction sites suggests that mechanogated channels are present on rIGLE-bearing, low-threshold rectal mechanoreceptors. Similar to benzamil, Gd3+ inhibited both stretch-induced firing and contraction in the rectum. The latter effect may be due to blockade of stretch-activated cation channels in smooth muscle (47, 49, 50) because Gd3+ (100 μM) did not affect the firing evoked by von Frey hair compression of hot spots. This is in agreement with previous observations for vagal mechanoreceptors, in which Gd3+ did not inhibit mechanotransduction in concentrations up to 300 μM (55, 57).
Nonselective blockers of cation TRP channels, SKF 96365 and ruthenium red (12, 26), reduced in parallel both stretch-induced firing and muscle contractility. It is likely that the latter effects were due to inhibition of cation and/or voltage-operated L-type Ca2+ channels on smooth muscle cells (11, 25, 31). When the effects of these drugs were studied on firing evoked by von Frey hair compression of transduction sites, SKF 96365 still significantly inhibited mechanotransduction, suggesting an involvement of mechanogated channels (possibly belonging to the TRP family). In contrast to SKF 96365, ruthenium red actually increased compression-evoked firing. Although it is widely used to block TRP channels, ruthenium red also inhibits with similar potency a range of K+ channels (11, 25) that could be responsible for the increased excitability of rectal afferents. It has been previously reported (56) that several types of K+ channels are involved in control of spontaneous and stretch-induced firing of vagal esophageal IGLE-bearing mechanoreceptors. It should be noted that, although the drugs used to block mechanogated channels (benzamil, Gd3+, SKF 96365, and ruthenium red) are currently the best available pharmacological tools, all of them are known to affect other classes of ion channels (7, 16, 24, 27, 31). We cannot exclude the possibility that such nonspecific action may have contributed to their effects on firing. Our results show that care must be taken when interpreting the responses to drugs that affect mechanoreceptor firing; it is important to monitor their effects on smooth muscle tone, particularly when afferents behave grossly as tension receptors.
This study was funded by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-56986.
S. J. H. Brookes is a senior research fellow of the National Health and Medical Research Council of Australia.
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 © 2005 the American Physiological Society


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