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Allied Health & Chiropractic is a full service sports and occupational medicine clinic that incorporates medical care, physical therapy, chiropractic and massage in the Ohio City/Tremont neighborhood on West 25th street.
We are dedicated to helping you get out of pain by combining skill and expertise that spans the entire medical spectrum. Our office is located next to Lutheran Hospital, and our doctors are part of the Cleveland Orthopedic and Spine Hospital and the Cleveland Clinic Health System Physicians Organization.
- Our medical doctor, A.K. Moghal M.D., has a 30 years of experience i in general surgery and occupational medicine.
- We have a general orthopedic surgeon, William M. Bohl M.D., who sees patients at AHC on Mondays. Dr. Bohl graduated from Case Western Reserve Medical School and has been practicing since 1977. He is on the medical staff at Lutheran Hospital and St. Vincent Charity Hospital.
- Our nurse practitioner, Sarah Williams, MSN-CNP is an experienced professional who specializes in musculoskeletal and holistic health.
- Our chiropractors, Dr. Ty Dahodwala, Dr. Heidi Williams, and Dr. Eric Wolk are committed to bringing you comprehensive, personal, hands-on care with the highest quality and comfort. Dr. Wolk is full body certified in Active Release Technique.
- Our physical therapist, Maggie Mandic, DPT, has an extensive background in Graston Technique and sports injury rehabilitation.
We specialize in the treatment of:
- BWC/Work related injuries
- Auto/Personal Injuries
- Lower back pain
- Sciatica
- Neck pain
- Disc pain
- Auto/Personal Injuries
- Shoulder/Joint pain
- Sports injuries
- Stress
- Wellness care
Contact us today to schedule your initial consultation. We can accommodate same day appointments and are a participating provider for all major insurances.
Our team-oriented approach incorporates medical/pain management, chiropractic care, physical therapy and massage to properly treat your condition. We work with an excellent team of orthopedic surgeons, pain management specialists, radiologists and neurologists to make sure you get the most comprehensive care you need.


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subset: commoncrawl


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Utenriksdepartementet fraråder alle reiser til eller opphold i Irak
Utenriksdepartementet fraråder reise eller opphold som ikke er strengt nødvendig til grenseområdene nærmere enn 3 km mot Syria og Irak.
Foreign Minister Børge Brende has condemned the terrorist attack in Baghdad late on Saturday in the strongest possible terms. It appears to have been planned to kill and injure as many civilians as possible. This was the bloodiest of many acts of terrorism in Iraq this year.
Last updated: 15.06.2016 // Norway will host the sixth World Congress Against the Death Penalty in Oslo 21-23 June 2016. The Congress will attract 1300 participants from over 80 countries, including ministers, parliamentarians, academics, lawyers, and members of civil society.
Close to 12 million people have fled their homes because of the war in Syria, and the UN and its partners urgently need funding for their efforts in the coming years. 'We must make sure that the UN is able to support the millions of people who have been forced to flee because of the war in Syria. That is why Norway is taking the lead and making a significant contribution to the UN Refugee Agenc...
A delegation from the Norwegian Parliament's Standing Committee on Foreign Affairs and Defence, headed by Ms. Anniken Huitfeldt, chair of the Committee, visited Iraq and Turkey from 2.-to 4 March 2016.
Norway and the US are joining forces in a further initiative to support mine clearance, Norwegian Minister of Foreign Affairs Børge Brende and US Secretary of State John Kerry announced on Wednesday.
'Syria's neighbouring countries are shouldering a heavy burden and are facing major challenges. Norway will therefore contribute USD 10 million to a new financing initiative for Lebanon and Jordan,' said Minister of Foreign Affairs Børge Brende.
Det har blitt besluttet at NAV Internasjonal vil opphøre fra 31. desember 2016. Internasjonale saker vil da bli overført til andre enheter i NAV som behandler de aktuelle fagområdene.
'The crisis in Syria is having unspeakable consequences for millions of people in Syria and its neighbouring countries. The best way we can help is by providing direct assistance in Syria and the region. For this reason, Norway is now increasing its aid to Syria and the region to NOK 2.4 billion for 2016. We intend to maintain this high level of assistance and will provide a total of around NOK...
International partnership launches $1.7 million EduApp4Syria prize to help Syrian children learn to read
Stortingets utenriks- og forsvarskomité, under ledelse av Anniken Huitfeldt, besøkte Jordan, Palestina og Israel 23.–28. januar 2016.
The Ministry of Foreign Affairs is launching a new strategy today for efforts to promote freedom of expression. 'Freedom of expression and independent media are under growing pressure. Norway is therefore strengthening its international work in this field,' said Minister of Foreign Affairs Børge Brende.
Do you know an exceptional person who has gone beyond the call of duty and shown outstanding dedication and service to the displacement cause? We are asking for your help to identify inspiring and committed candidates. The deadline for nominations is 8 February 2016.
25 Damascus StreetAbdoun, AmmanP.O. Box 830510Amman - 11183 – Jordan
Phone: +962 6 5902450
E-mail: email@example.com and other permits: email@example.com
Embassy opening hours: Sunday-Thursday 09.00 - 16.00
Consular services
All telephone enquiries concerning visa and residence permits: 14.00-15:00 (Sunday-Thursday)
Submission of passport for visa application: 13:00–14:00 (Sunday–Wednesday)
Submission and collection of passport for visas: 13:00–14:00 (Sunday–Thursday)


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With Instructables you can share what you make with the world, and tap into an ever-growing community of creative experts.
I had seen a coffee table at a high end furniture store and loved it, but the price was way out of my range. So I drew up ...
Using the plans I had drawn up I went to my local steel supplier and had them cut the steel to the sizes I needed. I used 3/4" ...
I used a degreaser like GooGone to clean and prep the steel.
I used an arc welder to weld the frame pieces together, starting with the smaller table first. I used a metal angle, a level, and clamps to make ...
I used Rustoleum Black Spray Paint to paint the frames. Then used a clear coat to seal it.
I used stain grade Pine for the tops which I had cut down to size at my local Home Improvement store. If you have a Kreg Jig or ...
Using the metal driving bit on my drill I drilled 2 holes in each long side of the large table and 1 hole on either end. Then 1 ...
Now that the tops are attached you can sand them down to prep for stain (or paint, whichever you prefer.) I used a fine grit sandpaper to sand ...
Now you're done! Show off your awesome table to your friends and brag how it cost you a fraction of the one in the store!
Pretty Easy Reclaimed 2X4 and Steel Top Coffee Tableby timsway
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- Plastic liner for waste and recycling receptacles
- Made of LDPE for high strength and puncture resistance
- Coreless roll is compact to save storage space
- Measures 21 x 20 inches
- Case contains 1,000 liners
Have one to sell?
by Flexsol
Flexsol EPL22CLR LDPE Waste Can Liner, 0.45 Mil, 21" x 20", Roll, Clear (Case of 1,000)
|$48.21 ($0.05 / Liner) & FREE Shipping
In Stock.
Ships from and sold by Xcess Limited.
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The Flexsol EPL22CLR clear plastic waste receptacle liner is made of low-density polyethylene (LDPE) for high strength and puncture resistance, and comes in a coreless roll to reduce storage space requirements. The liner is 0.45 mil thick and measures 21 x 20 inches, and the case contains 1,000 liners.
FlexSol Packaging Corporation manufactures a variety of bags, films, wraps, and can liners. The company, founded in 1999, is headquartered in Pompano Beach, FL.
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By Baby's Slave on October 3, 2013
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The quality is better than I expected. It is thicker than those garbage can linters they use in the hotel rooms.
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Sep 7
Aug 10
Music Fundraising Event for two charities that focus on helping under privileged youth in Toronto. We are pleased to have Ray Robinson as our Headlining act. We have one mystery Headliner to announce so keep it locked (trust me it'll be worth it!) The Founders Rosanne Howell of RH Music www.rosannehowell.com Michelle Mondesir of Poetic Groove Productions www.poeticgrooveproductions.com The Charity RRS- www.redemptionservices.ca For more info see the Event Website www.play4purpose.ca
Jul 28
Sounds Like: Drake, Ne-Yo, Trey Songz, T-Pain, Mike Posner
Label: Abyss Music Group
Bio: I love making music of all kinds. Thank you for stopping by to check out my stuff. Enjoy!


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Mobile Share Value Plans
MOBILE SHARE VALUE PLANS: Prices shown are for plans currently offered to new and existing customers. Above may not reflect promotional or retired plans. Prices are for service only and include monthly plan charge & per device monthly access charge. Devices: Sold separately. AT&T Next installment charges and other device purchase costs are extra. Data Overage: If you exceed the amount of data in your plan or other allotments during your billing period, additional data will automatically be provided in increments of 300MB at $20 per 300MB on a 300MB plan, or 1GB at $15 per GB. Unless otherwise specified, data allowances, including overages and Rollover Data, must be used in the billing period provided or they will be forfeited. Data: Data for use in the United States, Puerto Rico and the U.S. Virgin Islands (the "Domestic Coverage Area" or "DCA") only. Select 15GB and higher plans also include data usage in Mexico. Additional or promotional data may not be available for use outside the DCA. Tethering and Mobile Hotspot use for up to five (5) simultaneous devices. Authorized users on the account may temporarily suspend data access for each device on the plan. Data access will be restored at the beginning of the next billing cycle. Monthly charges will continue to apply. Rollover Data: Unused data from the monthly plan allowance rounds up to the nearest MB and carries over for one billing period. Rollover Data automatically expires after one billing period or with any plan change (such as changing data amounts or termination). Rollover Data is used after your monthly plan allowance. Eligibility: Available to consumers and IRUs. For full service terms and conditions see visit att.com/wirelessterms. Device Limits: 10 per plan. UNLIMITED TALK: For phones only. Includes unlimited calls within the DCA and Mexico. Svc may be terminated for excessive roaming (see Wireless Customer Agreement at att.com/wca). Unlimited Talk to Canada and Mexico: Only included on the current Mobile Share Value plans 15GB and above. For phones only. Includes unlimited International Long Distance (ILD) calling from Domestic Coverage Area to Mexico and Canada only. You may be charged for calls to special or premium service numbers. Calls to Other Countries: Select plans also include ILD calling from the DCA and Mexico to countries other than Canada and Mexico. Per minute pay-per-use rates apply unless an ILD service package is added to the line placing such calls. Rates subject to change without notice. For rates, see att.com/worldconnect. UNLIMITED TEXT: Standard Messaging – For phones only. Includes unlimited number of messages up to 1 MB in size within and from the DCA and Mexico to more than 190 countries for text messages and 120 countries for picture and video messages. AT&T may add, change, and remove included countries at its discretion without notice. Messages sent through applications may incur data or other charges. Visit att.com/text2world for details. Advanced Messaging – For customers with Advanced Messaging capable devices only. Both sender and recipient(s) must be AT&T postpaid wireless customers with HD Voice accounts, and both must have their devices turned on and be within AT&T's owned and operated DCA only (third party coverage and use in Mexico are excluded). Includes unlimited number of messages up to 10MB in size. Additional restr's apply and can be found at att.com/advancedmessaging. Wireless Home Phone ("WHP"): is a wireless voice service (CMRS). Wireless Home Phone and Internet ("WHPI"): is a CMRS & mobile broadband Internet access service. Plan 15GB or higher required. WHP & WHPI General: Messaging excluded. For emergency calls, provide location to 911 operator. Devices have backup battery but landline equip. with separate power will not place/receive calls (including 911) during outage. Not compatible with landline dependent services like medical alert monitoring systems. Other compatibility limitations apply. For WHP details visit att.com/getwirelesshomephone and att.com/getwirelesshome for WHPI details. Connected Wearables: Is a wireless phone designed to be worn that is capable of making/receiving calls without being connected to another wireless device. For a list of devices visit att.com/wearableslist. Connected Devices: Includes eligible connected vehicles, cases, and other select devices. Mexico Service Restrictions: Plan usage not available on WHP, WHPI, & Connected Devices and Wearables. Pay-per-use roaming rates will apply on these devices. IRU: Service discount described in your organization's AT&T business agreement is available only for Mobile Share Value Plans 2GB or higher. Discount applies only to the monthly plan charge, and not monthly device access charges. See att.com/mobilesharevalue or a store representative for more plan details.
MOBILE SHARE DATA PLANS: do not include Rollover Data. Pricing: For service only and include monthly plan charge and monthly access charge per device. Devices: Only data-only devices may be added to this plan. Smartphones, basic and quick messaging phones are prohibited. Devices are sold separately. Tablet installment and other device purchase costs additional. Data Overage: If you exceed the amount of data in your plan during your billing period, additional data will automatically be provided in increments of 1GB at $15 per GB. Data allowances, including overages, must be used in billing period provided or will be forfeited. Data: for use in DCA only. Select 15GB and higher plans also include data usage in Mexico. Additional or promotional data may not be available for use outside the DCA. Tethering and mobile hotspot use is allowed for up to 5 simultaneous devices. Authorized users on the account may temporarily suspend data access for each device using the Mobile Share Data Plan. Data access will be restored at the beginning of the next billing cycle. Monthly charges will continue to apply. Mexico Service Restrictions: Plan usage not available on Connected Devices and Wearables. Pay-per-use roaming rates will apply on these devices when in Mexico. Device Limits: 10 per plan for consumers and IRUs. Limit on number of financed devices perwireless account applies. See a store representative for more plan details.
GENERAL WIRELESS SERVICE TERMS: Subject to Wireless Customer Agreement found at att.com/wca. Service is not for resale. If AT&T determines your use of the services violates any of the applicable terms or polices found in the Wireless Customer Agreement, we may in our sole discretion suspend, modify, terminate, or restrict your service. Excessive Usage: You get an off-net (roaming) usage allowance for each service. If you exceed the allowance, your service(s) may be restricted or terminated. Other restrictions apply and may result in service termination. If you purchased a device that requires a term commitment, an Early Termination Fee applies if you cancel service after the first 14 days, and before your term ends. See att.com/equipmentETF for details on what fee may apply for your device and how the fee is prorated over time. Activation/upgrade fee per line (up to $45) and deposit may apply. A fee may be charged if convert from a prepaid or session-based plan or when activate an additional device. Credit approval may be required. AT&T reserves the right to suspend or terminate service to your account, place any non-complying device on an appropriate plan, and/or add any other required element of a plan. Other Monthly Charges: Apply per line and may include taxes, federal/state universal service charges, Regulatory Cost Recovery Charge (up to $1.25), gross receipts surcharge, Administrative Fee, and other government assessments which are not government-required charges. Pricing, promotions, restrictions and terms subject to change and may be modified, discontinued, or terminated at any time without notice. Service is intended for use primarily within the DCA.
For internal and illustrative use only. The above is only a summary of the product and/or service. Please see and/or provide customer with rate plan or other applicable brochure for all terms and conditions of service. ©2015 AT&T Intellectual Property. All rights reserved. AT&T, the AT&T logo & all other marks contained herein are trademarks of AT&T Intellectual Property and/or AT&T affiliated companies. All other marks contained herein are the property of their respective owners.


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I'm Adam Mainprize, the Senior Facility Manager. Myself and the friendly staff here at Bridlington are here to help ensure your visit to our facility is an enjoyable one.
East Riding Leisure Bridlington The Promenade, Bridlington, YO15 2QQ
(01262) 606715
Download swimming timetable
Table Tennis
Sports Hall Hire
5-a-side Football (3 courts)
5-a-side Football (4 courts)
Soft Play
Cricket Nets
Basketball / Netball
Indoor Bowls Sessions
Junior Coaching
We will make it easy for you to know what services are available to you, when and at what cost. We will make it easy for you to let us know what you think of our services. We will make sure all our staff are trained to the correct level. We will make sure that our sites are clean and safe to use.
We will provide a value for money service on time with accurate information on venues, activities, times and prices. We respond to our customer's comments, suggestions and complaints in a sympathetic and open manner, providing feedback and remedial actions, within set time scales. We provide helpful, experienced and informative staff to ensure that your visit is enjoyable and safe. We maintain the highest possible standards of health and safety and provide a clean and comfortable environment for all our customers.
Customer Services Standards (pdf 331kb opens in new window)
Leisure Survey Satisfaction Results (pdf 2mb opens in new window)
East Riding Leisure


text:
In a debate filled with barbs, put-downs, interruptions, and insults, Donald Trump didn't separate himself from the rest of the field by being more combative or more outrageous—although at moments, he was clearly trying. Trump, instead, set himself apart by delivering a ringing defense of the "New York values" that Senator Ted Cruz accused him of embodying. "New York is a great place," he said. "It's got great people, it's got loving people, wonderful people. When the World Trade Center came down, I saw something that no place on Earth could have handled more beautifully, more humanely than New York." His tone turned somber:
And the people in New York fought and fought and fought, and we saw more death, and even the smell of death—nobody understood it. And it was with us for months, the smell, the air. And we rebuilt downtown Manhattan, and everybody in the world watched and everybody in the world loved New York and loved New Yorkers.
It was Trump's best moment of the campaign: a stirring tribute to a cosmopolitan city, and an invocation of national unity, beating back a crude attempt to divide Americans against each other.
What preceded it was less inspiring. Trump stood by his contention that Ted Cruz may not be a "native-born citizen," and therefore may be ineligible for the presidency. Cruz hotly disputed that, and the weight of the scholarly consensus is firmly on his side. It was vintage Trump: blustering, insinuating, and flat-out fabricating. And it helped make the defense of New York that followed seem even more unusual.
That exchange also stood out because so much of the other drama on the stage Thursday night seemed so familiar. Ben Carson affably flubbed his foreign-policy questions; John Kasich emphasized his record in Ohio and tried to look more serious than his rivals; Jeb Bush delivered solid points in a style that robbed them of most of their impact; Chris Christie talked up his record as a prosecutor while brazenly denying other things he's done; and Cruz sparred repeatedly with Marco Rubio.
With just a few weeks left before Iowa voters head to the caucuses, almost all of the candidates came to North Charleston, South Carolina, looking to shake things up. For the most part, that failed to happen.
But Ted Cruz, who's clinging to a narrow lead in Iowa, didn't just take hits from Trump. The fiercest attack of the night came from Rubio, who rattled off a detailed list of specific stands on which he accused the Texas senator of reversing himself, branding him a cynical opportunist, not a consistent conservative. "I appreciate your dumping your oppo-research folder on the debate stage," Cruz smirked.
"No, it's your record," Rubio shot back.
The debate also featured a war over trade wars. Trump was pressed to defend past comments supportive of slapping retaliatory tariffs on Chinese imports. Instead of backing away from tariffs, he stressed the need for a firm response to the rising power. Economists across the country held their heads, and his rivals gleefully pounced. But as they took turns explaining the economic theory of why tariffs ultimately hurt consumers, Trump simply insisted that he'd be tough enough to make the Chinese crumble. By Friday, there will likely be dozens of columns explaining the downsides of tariffs; whether any of them will dissuade Trump supporters from believing that he alone has the resolve to right America's trade deficit with China is another matter entirely.
It's equally fair to wonder whether any of these performances will alter the trajectory of the race. Trump was closing in on Cruz in Iowa even before the debate, and riding high in the national polls. Marco Rubio turned in another superb performance on the stage, but his past skill as a debater has never brought him the surge of support that he needs to challenge the frontrunners. Ben Carson's fading campaign will continue to fade. Jeb Bush, Chris Christie, and John Kasich are still jockeying for establishment support.
One thing that was different on Thursday night was the audience, generously salted with members of the Republican National Committee, in town for their winter meeting. The presence of the literal Republican establishment didn't restrain candidates from touting their outsider credentials. But it did reflect the tensions roiling the party, as parts of the crowd cheered loudly for Trump, as others booed.
But if RNC Chair Reince Preibus was worried, he didn't let it show. "It's clear we've got the most well-qualified and diverse field of candidates from any party in history," he tweeted afterwards. The field may be yuuge, but the candidates are the best. The head of the Republican establishment adopting the argot of Trump seemed a perfect end to the night.
Carson: "If my mother were Secretary of the Treasury, we would not be in a deficit situation."
There was a trade war over trade wars on stage just now. Trump understands trade, but he also understands audiences—and he's unrelenting in his attacks on China, and the need to take a harder line. Other candidates—Kasich, Rubio, Bush, Cruz—try hard to deliver textbook explanations of the dangers of tariffs. But for Trump, this is all about showing toughness toward a rising China. And he seems to carry a large chunk of the crowd with him.
Trump: "There's something going on. And it's bad."
That invocation of inchoate fear is a perfect encapsulation of his campaign.
When Donald Trump takes a long, detailed question, and answers with a flat, "No," it draws cheers every time. In this case, he's asked whether he wants to reverse his proposal for banning Muslims from entering the United States. There have been boos from this crowd tonight, but it's hushed as he refuses to back away from bigotry, and cheers when he's finished.
The moderator just presumed that the right thing to do is removing Assad from power––but Ted Cruz, Donald Trump, and perhaps others on that stage disagree, and believe the U.S. should focus on fighting ISIS in cooperation with Russia.
Cruz is asked what he means when he accuses Trump of holding New York values. "I think most people know exactly what New York values are," says Cruz. It's a remarkable spectacle—a candidate for president implying that being a citizen of its largest city is somehow un-American.
The stress on the vital importance of mental-health care is a welcome development; Trump is absolutely right that states have shifted resources away from treatment in the past several decades. But better mental-health care is unlikely to curb gun violence, because very little of it is committed by the mentally ill. There's a basic disconnect between these answers and the data.
"Neil, I was mentioned, too," interjects Carson. "You were?"
"Yeah, he said everybody."
Well, good for Carson. As long as the moderators are going to construe the rules this absurdly, he might as well get a word in.
Is Cruz eligible to be president? Earlier today, we published a detailed legal memorandum written by Bryan Garner, editor in chief of Black's Law Review, and a distinguished research professor of law at Southern Methodist University. It's the most thorough exploration of the legal questions I've seen—and tries to put the matter to rest once and for all. You can read it for yourself.
Cruz notes that some who've weighed in have gone so far as to suggest that both parents of a candidate would need to be born on American soil; Trump's mother was born in Scotland. "On the issue of citizenship, Donald, I'm not going to use your mother's birth against you. You're an American, as is everyone else on this stage."
Cruz gets asked about his undisclosed $750,000 loan from Goldman Sachs used to finance his election to the Senate. "Thank you for passing on that hit-piece on the front page of The New York Times," he says. This has been a favorite tactic of Cruz's, pivoting from the specifics of any charge he faces to attack the establishment. "Yes, I made a paperwork error, disclosing it on one piece of paper instead of the other," he says. That's not going to cut it. Elections experts have called it a clear violation of the rules, of the sort that's generally sanctioned.
Chris Christie says that in his administration, "tin-pot mullahs" would know better than to seize American craft. In 2001, early in the administration of George W. Bush, China held 24 American airmen for 11 days, until Bush apologized. Compared to that, the prompt return of the unharmed sailors looks less like a humiliation than a triumph.
"According to our Facebook research, jobs is one of the biggest issues…" solemnly intones Fox Business's Maria Bartiromo. Some things don't require Facebook research to understand.
The last time the Republicans debated, nine candidates took the stage, Ben Carson was a leading contender, and George Pataki's run for office seemed all but over. Now seven are left, Carson is an afterthought, and Pataki's candidacy is finally over.
After a wild 12 months, the unpredictable 2016 presidential race has finally entered 2016, and it's starting to settle down. Donald Trump sits atop the polls, with Ted Cruz a clear second. In Iowa, where voters will caucus on February 1, those roles are reversed—although Trump has lately been closing the gap. A host of establishment candidates are jostling for position behind them, waiting to shoot ahead if they stumble. Marco Rubio, Jeb Bush, John Kasich, and Chris Christie are hoping to survive long enough to exploit any such opportunities.
As my colleague Russell Berman writes, one shift is that the long-simmering tensions between Trump and Cruz are finally out in the open. Trump has suggested that Cruz's birth in Canada renders him ineligible to be president, while Cruz has attacked Trump's "New York values," which he declined to define other than to say that "they're not Iowa values and they're not New Hampshire values." Whether that conflict will carry over to the debate stage, or whether they'd prefer to trade punches at a safe remove, remains to be seen.
Ben Carson's once high-flying campaign is locked in a tailspin, from which it seems unlikely to emerge. The other four candidates are left to decide whether to set themselves apart by punching up at the frontrunners, by trying to take down each other, or by aiming to rise above the squabbling on stage.
The debate is being held in the Coliseum and Performing Arts Center in North Charleston, South Carolina. The city came to national attention last April, when Officer Michael Slager shot Walter Scott in the back as he fled, killing him. Slager, charged with murder, was released on bond last week. Ten miles away sits Emanuel A.M.E. Church. In June, Dylann Roof was welcomed to a prayer service there, sat for an hour, and then shot and killed nine. And on Tuesday night, South Carolina Governor Nikki Haley used her rebuttal to the State of the Union address to remember what happened next:
We didn't turn against each other's race or religion. We turned toward God, and to the values that have long made our country the freest and greatest in the world.
The debate over the use of force by police, the question of gun violence, and the challenges of pluralism have not received much attention in the Republican debates to this point. But one reason the parties now have four early states—Iowa, New Hampshire, South Carolina, and Nevada—is to ensure that issues of regional and local salience make their presence felt on the campaign trail. That will be the case tonight, whether these questions take center stage, or become conspicuous by their absence.
You can follow every twist and turn of the race with our 2016 Distilled election dashboard, find out more about the candidates by using our 2016 Cheat Sheet, and see how viewers are responding to the candidates with our real-time emoji tracker. And follow along with us, as we liveblog the Republican debate.
—Yoni Appelbaum


text:
You scored 100% Poly, 85% BDSM, 88% Roleplay, and 57% Gay/Lesbian!
Their Analysis (Vertical line = Average)
They scored 100% on poly, higher than 91% of your peers.
They scored 85% on bdsm, higher than 91% of your peers.
They scored 88% on roleplay, higher than 84% of your peers.
They scored 57% on gender, higher than 55% of your peers.
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The field of biogerontology has made great strides towards understanding the biological processes underlying aging, and the time is ripe to look towards applying this knowledge to the pursuit of aging interventions. Identification of safe, inexpensive, and non-invasive interventions that slow the aging process and promote healthy aging could have a significant impact on quality of life and health care expenditures for the aged. While there is a plethora of supplements and interventions on the market that purport to slow aging, the evidence to validate such claims is generally lacking. Here we describe the development of an aging interventions testing program funded by the National Institute on Aging (NIA) to test candidate interventions in a model system. The development of this program highlights the challenges of long-term intervention studies and provides approaches to cope with the stringent requirements of a multi-site testing program.
Biogerontology is the study of normal aging and age-associated diseases, both of which contribute to lifespan, the decline in quality of life at older ages, and the cost of health care in the final years. Interventions that can slow the aging process, delay the onset of age-associated diseases, and promote maintenance of strength and vitality will be of great benefit to the elderly. Unfortunately, the quest for anti-aging therapies has produced a marketplace full of unproven remedies. It is imperative that the scientific community address this need with rigorous, reproducible studies on candidate interventions to identify those with potential for a positive impact on healthy aging.
One problem encountered in analyzing the research literature on interventions for aging, aside from its paucity, is that reports from different laboratories analyzing the same interventions often report different results. There are many factors contributing to the variability, including the model organism chosen as the test subject, the design of the intervention study, and the location of the testing labs. For example, there is variation in the lifespan of a single strain of mice published in different studies, as shown by the median lifespan of untreated, ad libitum fed, male C57BL/6 mice from the nine published reports presented in Fig. 1. The longest median survival age is 22% greater than the shortest. The preliminary results of the ITP, as discussed in more detail later in this paper, and in Miller et al. (2007), showed a similar site-to-site variation in the lifespan of the HET mice used in this program. For male control mice at the three sites, the mean median lifespan was 799 days, with a range (minimum to maximum) of 137 days, or 17% of the mean. For females, the mean median lifespan was 881 days, with a range of 51 days, or 6% of the mean.
When using a rodent model to test interventions, the choice of species, strain and sex can have a large effect on the outcome. This is illustrated by studies on caloric restriction (CR) in rodents. Two independent studies reported a significant extension of lifespan by CR in male C57BL/6 mice but not in male DBA/2 mice (Forster et al. 2003; Turturro et al. 1999). Female DBA/2 mice did show a significant lifespan extension in response to CR, illustrating why it is important to test any intervention in both sexes (Turturro et al. 1999). An earlier study demonstrated that DBA/2f male mice did not exhibit an extension in lifespan in response to CR but did when given a protein-restricted, isocaloric diet (Fernandes et al. 1976). BALB/c mice also appear to be resistant to the benefits of CR (N.L. Nadon, unpublished data). Had the first CR studies been done only in DBA/2 males and BALB/c mice, this very informative line of research might not have been pursued.
This paper outlines the design of the National Institute on Aging (NIA) Interventions Testing Program (ITP) and discusses the challenges faced in setting up large-scale, multi-site testing protocols. We present the importance of standard operating procedures (SOPs), some issues unique to long-term interventions studies and approaches to address these issues. Lastly, we provide a brief summary of early results obtained in the ITP as they support the importance of SOPs in multi-site studies.
The ITP was developed to test candidate diets, supplements and compounds for their ability to extend lifespan and promote healthy aging in a mouse model. A detailed description of the mission of the ITP is available on the ITP website (http://www.nia.nih.gov/ResearchInformation/ScientificResources/InterventionsTestingProgram.htm). Testing is performed in triplicate at three independent sites: The Jackson Laboratory, the University of Michigan, and the University of Texas Health Sciences Center—San Antonio. The importance of testing in triplicate will be discussed in more detail later, as our early results demonstrate site-to-site variation even in the control mice. Candidate interventions include pharmaceuticals, food supplements, special diet compositions, plant extracts and other additives. We require that all data be repeatable, so interventions must be chemically defined well enough for replication of experiments. The compounds chosen for testing tend to be those with either preliminary data showing beneficial effects on aging in mice or strong theoretical justification backed up by evidence of increased life span in short-lived models such as nematodes or fruit flies or both. The ITP is not funded to carry out dose response studies for every compound chosen, but rather tests one dose for which there is strong evidence to support its potential to improve healthy aging and extend lifespan in a mouse model.
The ITP was developed after a planning workshop held in 1999 that included experts from diverse fields of study relating to aging (Warner et al. 2000). Many model systems were discussed, ranging from flies to large mammals, and the genetically heterogeneous (HET) mouse model was deemed to be the best fit. Mice are economical and there is a huge volume of literature on the genetics and genomics, physiology, behavior and biochemistry of the mouse. HET mice were chosen because they provide reproducible genetic variation within the population, and because HET mice are not as likely to exhibit the strain-specific characteristics and pathology observed in inbred strains. We believe that this model is more reflective of the general characteristics of the laboratory mouse and will provide more robust findings that would be seen in a single inbred strain.
The specific stock of HET mice used in the ITP is a cross of four inbred strains, generated by breeding two F1 hybrids, CB6F1 X C3D2F1. They are equivalent to the UM-HET3 mice described by Miller and Chrisp (1999). Pathology at death in UM-HET3 mice includes a wide range of lesions and conditions, and previous studies have demonstrated that a combination of data on early life body weight gain, T cell subset levels, and leptin and thyroid hormone levels are predictive of lifespan in HET mice (Miller et al. 2002; Lipman et al. 2004; Harper et al. 2004). These genetically heterogeneous mice have also proven valuable in genetic association studies, adding another level of information that can be mined from these studies (Harper et al. 2003; Volkman et al. 2003; Wisser et al. 2004; Wolf et al. 2004).
The importance of genetic heterogeneity is brought home by the strain-specific differences that have been reported for many aspects of the physiology and biochemistry of mice. For example, significant differences have been reported in the cardiovascular changes that occur during rapid eye movement (REM) sleep: in C57BL/6 and C3H mice, the arterial blood pressure decreases during REM sleep and there are no changes in heart rate; in BALB/c mice arterial blood pressure and heart rate increase; and in DBA/2 mice arterial blood pressure increases and heart rate decreases (Campen et al. 2002). Another example of strain differences is seen through tests of exercise performance. In a forced endurance treadmill test, C57BL/6 performed poorest of the strains tested, yet on a voluntary treadmill test, C57BL/6 mice performed best, staying on the longest and running the fastest and the greatest distance of the strains tested (Lerman et al. 2002).
Responses to toxic exposures also illustrate underlying physiological and biochemical differences among strains. Hepatocarcinogenesis can be promoted by high fat diet and by phenobarbitol, and while C57BL/6 mice are resistant to both promoters, C3H mice are sensitive to both promoters and DBA/2 mice are resistant to high fat diet but sensitive to phenobarbitol (Ahotupa et al. 1993). The induction of antioxidant pathways mirrored the sensitivity to hepatocarcinogenesis, with C3H mice showing the greatest induction of glutathione and catalase in response to a high-fat diet (Ahotupa et al. 1993). Strain-specificity has been reported in the induction of neurodegeneration by excitotoxins, with C57BL/6 mice much more resistant to both kainic acid and quinolinic acid than DBA/2 mice, and in the induction of beta cell dysfunction by high glucose, where again DBA/2 mice are more sensitive (McLin et al. 2006; Zraika et al. 2006). Additional strain differences in physiology are reviewed in Nadon (2006).
To add another example relevant to many animal colonies, the response to Helicobacter infection varies greatly by strain. Helicobacter hepaticus infection is innocuous in most mouse strains, but can cause hepatitis in some, including BALB/c and C3H/HeNCr (Zenner 1999). Because helicobacter is common in many animal colonies, the number of Helicobacter species known is still growing and, because the full extent of pathology caused by helicobacter species is probably not yet known, it is important for long-term studies to be performed in animal colonies of known pathogen status, if possible under specific pathogen free (SPF) conditions.
The ITP developed SOPs to ensure that environmental conditions at the three sites are as uniform as possible. Lighting, temperature, housing, and diet are controlled and monitored. It is particularly challenging to provide uniform environmental conditions at independent institutions, as each institution has its own policies and procedures, but the interim results presented later in this paper illustrate how important it is to develop SOPs to which all test sites can adhere.
In the ITP, HET mice for each year's set of interventions are bred over a period of 6–8 months. The mice are weaned at 19–21 days of age and are group-housed, typically three males or four females per cage, using corn cob bedding. The first litter is not used for ITP testing so that all litters are the product of experienced mothers. At 42 days of age, ID chips are implanted and the mice are randomly assigned to experimental or control groups. More details are provided in Miller et al. (2007).
A power analysis was performed (by A. Galecki, University of Michigan, and S. Pletcher, Baylor College of Medicine) to determine the number of mice needed per experimental group to be able to detect a 10% change in lifespan as compared to control groups, at 80% power, as described in Miller et al. (2007). Each experimental group includes 36 females and 44 males per site, for a total of 108 females and 132 males for each intervention tested. The males are over-represented because of the expectation that some cages will have to be culled due to fighting. The control lifespan group is twice the size of the experimental groups, and all experimental groups are compared to the same control group.
In addition to the experimental and control lifespan groups, two other groups of mice have been set up. One is a pair-fed group, equal in size to the experimental groups, and used to control for any change in food intake due to taste or other characteristics of the test compounds/diets. The mice are weighed at biweekly intervals for the first 2 months on the experimental diets, and the pair-fed mice are fed to maintain their weight at the same level as the lightest experimental group. Once it is clear that there is no effect on body weight for any of the agents tested in a given year's group, the pair-fed group is removed from the study. The other group is labeled the monitor mice. They are treated the same as the experimental groups but they are not included in the lifespan study so they can be used for invasive experiments needed to demonstrate the bioactivity or effectiveness of the compounds/diets.
Differences in diet are one of the confounding factors when comparing lifespan studies from different laboratories. Turturro et al. (1999) reported differences in both body weight and lifespan when C57BL/6 mice were fed different diets. It was particularly striking that female C57BL/6 mice fed NIH31 diet had a median survival age that was about 25% greater than females fed Emory-Morse911 diet, which uses casein as the primary protein source rather than the fish meal and grains used in NIH31. The ITP mice are fed NIH31 diet with 4% fat, available ad libitum, from the time the interventions are initiated. The food is prepared and sterilized, and then the test compounds are added and the food is re-pelleted without use of heat. The food is prepared in bulk every 4 months and the same batches are used by all three sites. Most treatment protocols begin feeding the experimental diets at 4 months of age, although some have been started later in life. The ITP mice are also provided acidified water, pH 2.5, ad libitum.
Lifespan in any model system is influenced by a complex set of interactions among normal aging processes, incidence and age-of-onset of age-associated diseases, and development of non-age-associated diseases. To determine the effect of an aging intervention, it is important to look at the full lifespan, not just the median lifespan. Some deaths during the first half of the life span are related to early acting genetic defects, accidents, and age-independent disease. For example, mouse urinary syndrome (MUS) is a potentially lethal condition that does not exhibit age-dependence typical of senescence-related diseases; it commonly occurs in the 4-way cross mice used in this program and could potentially account for a significant portion of the male deaths before the median survival age, but likely none of the male deaths after the median survival age (Miller et al. 1998). It should be noted that the environmental conditions that promote or inhibit MUS are poorly understood and to date MUS has been virtually absent from the ITP mice.
An example of how reliance on median survival only to define lifespan can give misleading results is presented in Fig. 2, which shows lifespan results for the effects of dietary restriction in wild-type mice and obese, leptin-deficient ob/ob mutant mice (from Harrison et al. 1991). The data for median life span (left panel) give two false conclusions: (1) that dietary restriction did not improve survival of normal B6 mice; and (2) dietary restriction improved survival of ob/ob mice only to the level of ad libitum-fed lean B6 mice. Following the entire life span (right panel) illustrates the fallacy of these two conclusions because (1) dietary restriction actually had a significant effect on the life span of normal mice, and (2) it increased the life span of ob/ob mice beyond normal, to that of calorie-restricted lean B6 mice. Thus, focusing on median life span may systematically exclude interventions that retard aging, if those interventions fail to prevent mice from dying before the median survival age. Comparison of two groups for the proportion of mice reaching very old age provides more information about aging rate than tests based on median lifespan alone (Klebanov and Harrison 2002). The age at which the last mouse in a cohort dies is also of limited value since it is a single data point. The ITP has decided to evaluate questions about maximum lifespan operationally by comparing the proportion of mice still alive in each group at each age when the pooled population has reached the 90% mortality point, in order to capture the effect of the treatments on the breadth of the lifespan.
While lifespan studies are important, lifespan is not the sole, or even necessarily the best, measurement of the effectiveness of a compound to promote healthy aging. Other physiological, biochemical and behavioral parameters are important adjuncts to the lifespan study. However, the cost of long-term interventions studies using statistically relevant numbers is significant and for this reason the ITP design is a two-phase program. Phase I studies include determination of lifespan and a few measurements of overall health status such as activity monitoring, measurement of T cell subsets, and select hormone quantifications. Animals dying in the study are preserved so that necropsy information can be obtained for those interventions that significantly increase or decrease life span. Those interventions that show promise in Phase I will go on to Phase II, which will include a larger array of ancillary studies in addition to a replicate lifespan study.
The ITP solicits proposals from the extramural research community for compounds, supplements and diets that have potential to extend lifespan and promote healthy aging. The proposals go through a two-tier review and prioritization process, using experts from the research community to evaluate the scientific merit, feasibility and priority of the proposals. The types of compounds/diets proposed to date have been quite varied and have included pharmaceuticals, modifications in micronutrient content, and compounds with antioxidant and/or anti-inflammatory activity. While it is usually considered preferable to test purified compounds, sometimes it is worthwhile to test a natural extract if there is potential for bioactivity of multiple compounds in the extract. In such cases, added measures must be taken to ensure consistency of the extract over the testing period.
One of the biggest challenges the ITP has faced has been evaluating the preliminary data supporting the prioritization of interventions and determining appropriate doses in the mouse model. Preliminary data has come from studies in a variety of model systems ranging from invertebrates to humans. The ITP often conducts short-term studies to evaluate bioavailability, efficacy (activity), and toxicity of compounds before investing in the large-scale study. Some pilot studies are needed because, while less complex organisms have proven vital for understanding basic biology, interventions often have different effects when given to complex organisms. This may result from differences in metabolism, differences in target organs or both. For a specific example, in nematodes, reduction of function mutations for genes in the dauer pathway increase life span. The dauer pathway genes are orthologous to genes of the insulin and IGF-1 signal transduction pathways in mammals. Because diminished signaling in these pathways increases life span in worms, fruit flies, and mammals, these pathways appear to govern an evolutionarily conserved, genetic clock of aging (Tatar et al. 2003). However, the insulin and the IGF-1 pathways in mammals are more complex than the dauer pathway in invertebrates. There are two problems with simply testing mutations that reduce functions of the insulin and IGF-1 pathways in mice. First, reduction-of-function mutations in the insulin pathway produce insulin resistance and promote diabetes, thus masking potential beneficial effects on aging (LaMothe et al. 1998). Second, reduction-of-function mutations in the IGF-1 pathway elevate growth hormone (GH, the trophic modulator of IGF-1) by removing its negative feedback signal. GH antagonizes insulin, so elevated circulating GH can cause insulin resistance, which might mask any beneficial effects of diminished IGF-1 signaling (Lembo et al. 1996).
In the ITP, test agents are incorporated into irradiation-sterilized diet (5LG6, Purina, St. Louis, MO), which is based on the NIH 31 formulation with 4% fat (Rader et al. 1986). Table 1 lists the compounds in testing as of May 2007. Aspirin and nitroflurbiprofen (NFP), two non-steroidal anti-inflammatory agents that inhibit both COX-1 and COX-2, were tested because chronic inflammation is associated with many chronic diseases of aging, and may contribute to those diseases. Aspirin also has anti-thrombotic and anti-oxidant properties (Shi et al. 1999; Vane 2000; Weissmann 1991). At therapeutic doses, it suppresses production of TNFα by an effect on NF-κB signals (Shackelford et al. 1997). Aspirin may also have indirect effects on oxidative damage to proteins by acetylation of ε-amino residues, thus blocking inter- and intra-protein crosslinks as well as glycation reactions (Shi et al. 1999; Caballero et al. 2000; Jones and Hothersall 1993; Weber et al. 1995).
Nitroflurbiprofen (NFP) is a nitric oxide (NO)-releasing flurbiprofen derivative (Ongini and Bolla 2006). It crosses the blood–brain barrier, and so in principle might protect against chronic inflammation in the central nervous system (CNS). The NO-releasing moiety of NFP protects against GI toxicity, protects the cardiovascular system and enhances the anti-inflammatory effect, therefore making the drug safer during chronic administration. Furthermore, 6–12 months of exposure of mice to NFP did not produce overt signs of toxicity, and it was also safe in early human studies (Brunelli et al. 2007; Van and Kadish 2005; Ongini and Bolla 2006).
Nordihydroguaiaretic acid (NDGA) has both anti-oxidant and anti-inflammatory properties (Wood et al. 2004). NDGA suppresses pro-inflammatory gene expression and prostaglandin E2 (PGE2) production (West et al. 2004). NDGA was reported to delay death in Wistar rats and slow disease progression and increase lifespan in SOD1 mutant mice (Buu-Hoi and Ratsimamanga 1959; West et al. 2004).
PBN (α-phenyl-N-tert-butyl nitrone) is a nitrone, known to stabilize free radicals, and protects against age-related diseases including stroke and cancer (Floyd 1990; Zhao et al. 1994; Floyd et al. 2002; Nakae et al. 2003). PBN extended lifespan of short-lived SAM-P8 mice, and has been reported to increase life spans in both C57BL/6J mice and Sprague-Dawley rats when started at about 2 years of age (Edamatsu et al. 1995; Saito et al. 1998; Sack et al. 1996). The principal metabolite of PBN is its 4-hydroxy derivative, 4-OH-PBN, which is being tested in the ITP.
Caffeic acid phenethyl ester (CAPE), a product of the propolis of honeybee hives, possesses strong antioxidant, anti-inflammatory, and immunomodulatory capabilities (Bhimani et al. 1993; Sud'ina et al. 1993; Borrelli et al. 2002). Even low doses of CAPE inhibit oxidant production and formation of oxidized bases in mouse skin DNA and in HeLa cells exposed to phorbol ester tumor promoters (Bhimani et al. 1993; Frenkel et al. 1993). Topical applications of CAPE suppress TPA-induced tumor promotion in mouse skin, suggesting that CAPE possesses anti-carcinogenic properties (Frenkel et al. 1993).
Enalapril maleate is an angiotensin converting enzyme (ACE) inhibitor. ACE inhibitors have been reported to modulate hypertension, obesity, diabetes, and congestive heart failure in both aged humans and rodent models (Ferder et al. 1992, 1994; Inserra et al. 1995, 1996; de Cavanagh et al. 1997, 1999; Gambassi et al. 2000; Kuno et al. 2003). ACE inhibitors may regulate metabolic function, decrease oxidative stress in many tissues, and reduce age and disease related chronic inflammation (de Cavanagh et al. 1997, 1999). Rats injected with enalapril for 6 months had reduced blood pressures, better physical performance in various tasks than controls, and reduced fat mass, but not lean mass, with age (Carter et al. 2002).
Rapamycin is an antifungal, immunosuppressive, potential anticancer drug that acts by inhibition of the protein kinase TOR (target of rapamycin) (Garber 2001; Guba et al. 2002). Its immunosuppressive actions are due to inhibition of proliferation of helper T cells (Lorberg and Hall 2004). TOR proteins may play key roles in nutrient response systems, and abrogation of TOR in Caenorhabditis elegans adults extends lifespan (Vellai et al. 2003). In current models, nutrient signaling through mTOR kinase is integrated with insulin/growth factor signaling so that, in mammals, rapamycin may affect nutritional, mitogenic and insulin metabolic signaling in a coordinated fashion, in some ways reminiscent of dietary restriction (Manning and Cantley 2003; Kim et al. 2003).
Simvastatin inhibits HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase. Inhibitors of this enzyme, referred to as "statins," are clinically effective in reducing cardiovascular disease (Bonetti et al. 2003). Statins appear to have effects independent of reducing cholesterol, including anti-oxidant and anti-inflammatory properties, and stimulation of bioavailability of nitric oxide (Bonetti et al. 2003).
Resveratrol has been shown to increase life span in yeast, fruit flies and nematodes, and killifish, and it extends median life spans in C57BL/6J mice that are fed a high fat diet (Howitz et al. 2003; Wood et al. 2004; Baur et al. 2006; Valenzano et al. 2006). Resveratrol is a potent sirtuin stimulator and it also reduces acute inflammation in vivo and free radicals and mutations in vitro, inhibits tumor generation in response to the DMBA carcinogen, and protects against early death from injected neuroblastoma cells (Jang et al. 1997; Chen et al. 2004). In a summary of current knowledge, Baur and Sinclair (2006) outline several possible mechanisms by which resveratrol might retard mammalian aging, including stimulation of sirtuin protein deacetylases as well as effects on the estrogen receptor, cycloxygenase, toll receptors, and cytochrome P450 enzymes.
In addition to the scientific merit of proposals, there are several important issues to consider when choosing which long-term interventions to test. They include: (1) the ease of administration; (2) the stability of the compound; (3) the rate at which the agent is eliminated or metabolized in mice; (4) whether the compound has efficacy at the chosen dose; and (5) the cost of administration. The ITP is reluctant to accept any treatment that requires repeated subcutaneous or intraperitoneal injections or oral gavage, because of the expense involved in treating so many animals daily over a life time, the added cost for a separate control group subjected to mock injections or similar daily handling, and the concern that repeated injections might be harmful to the mice. Delivery of compounds by osmotic minipump or repeated administration of a slow-release preparation would have similar disadvantages, including the need for a separate set of control animals. Delivery of compounds in drinking water is possible, although only for compounds that are water soluble and stable in solution at room temperature. Although this method is easier than oral dosing by gavage, it is still much more labor intensive than administration in food and there is the risk of reduced uniformity across centers since the solutions must be made up at each center. To date, all interventions tested in the ITP are compounds that can be administered in the food.
Before beginning a study, it is sometimes necessary to verify that the compound retains activity after incorporation into mouse chow and that therapeutic blood levels of the drug can be achieved. Our experience with rapamycin illustrates the kind of problems that can be encountered in studies of the effects of dietary additives. In an initial pilot study, we analyzed food and blood levels of rapamycin at several starting doses. The results revealed that rapamycin was not stable in food but that therapeutic blood levels can be achieved if the mice received a sufficient amount of rapamycin in food.
To solve the problem of instability in food, rapamycin was sent to the Southwest Research Institute (San Antonio, TX) for microencapsulation by dissolving the rapamycin in an organic solvent containing a dissolved enteric coating (Eudragit S100). This methacrylate polymer is stable at pH levels below 7 and thus protects the rapamycin from the acidic conditions of the stomach; the protective coating dissolves in the small intestine, permitting absorption of the active agent. Samples of encapsulated and unencapsulated rapamycin were incorporated into commercial mouse chow at a concentration of 7 ppm and the levels of rapamycin in the food were assayed (Fig. 3). The encapsulated rapamycin survived the process of incorporation into the chow better than the unencapsulated rapamycin, as demonstrated by the 3-fold higher concentration of rapamycin detected in the diet made with encapsulated rapamycin than in the diet made with unencapsulated rapamycin. Diets made from encapsulated and unencapsulated rapamycin were fed to mice for 3 weeks and concentrations of rapamycin in 200 µl whole blood samples were determined using HPLC with UV detection. The average blood level observed after feeding the encapsulated rapamycin was greater than 25 ng/ml, which compares favorably with therapeutic levels in human treatment protocols of at least 12 ng/ml (Fig. 4). By contrast, mice fed the diet prepared with unencapsulated rapamycin had less than 2.5 ng/ml, which is the detection limit of the assay. As a result of the pilot study data and unpublished work by the sponsors, the dose was increased to 14 ppm in the diet for the longevity studies, as shown in Table 1.
The principal goal of Phase I elements of the ITP is to identify compounds that delay or decelerate the aging process, using the commonly accepted endpoint of an increase in maximal longevity as a surrogate for an anti-aging effect attributable to a diet, drug, or genetic manipulation. It is often preferred to substitute a test based on the number of animals still alive at some arbitrary substitute percentile, for example the age at which 90% mortality is observed. Tests that depend on the mean age at death of the longest-lived 10% of each population, though they frequently appear in the published literature, have been shown to be invalid, in the sense that they have a substantially higher Type I error rate than the nominal value chosen by the investigator (Wang et al. 2004). Wang et al. (2004) have presented, validated, and documented the power of a number of alternate "quantile" tests, based upon comparing the proportion of live mice in each of two (or more) test groups at the age at which 90% of the mice in the combined group have died; the ITP has adopted this statistical approach. Since the outcome of the test will not depend at all on the age at death of mice surviving past this point, it is not necessary to wait until the death of the longest-lived mouse to evaluate the hypothesis of interest.
The cohort I group consists of aspirin, NFP, NDGA and 4-OH-PBN. Because about 30% of cohort I test mice remained alive at the time of the interim analysis, it was not possible to evaluate our principal hypothesis that one or more of the test agents extends measures of maximum longevity (Miller et al. 2007). The data at hand did, however, permit us to test another hypothesis, one of lesser but still substantial interest, i.e., whether any of the test compounds diminish mortality risks at earlier points in the survival distribution. To avoid the inflation of Type I error rates that accompany repeated, sequential testing of related hypotheses on the same test population, we decided in advance to conduct an analysis on the date at which at least 50% of the male control mice had died at each site, i.e., at the median mortality point at the site at which males were longest-lived. A report of this interim analysis has been published, so here we present a synopsis of the report and some of its implications for study design and interpretation (Miller et al. 2007).
The first unexpected finding was the extent of variation in the survival data amongst the sites. At two of the test sites, University of Texas (UT) and the Jackson Laboratory (TJL), mortality risks for male mice were significantly higher than for female mice (P<0.0001), but there was no significant difference in survival patterns between males and females at the third test site, University of Michigan (UM). The difference between males and females in calculated median survival was 77 days at TJL and 137 days at UT, but only 36 days at UM. Conversely, there was a highly significant difference in survival patterns of males across the three sites (P<0.0001), but no difference among the sites in female survival. Median survival for males at UM was 116 days longer than the median survival at the other two sites combined.
We do not have a ready explanation for this disparity among test sites in median survival, or for its restriction to male mice. The ITP protocols were designed to try to minimize inter-site differences, including the use of the same stock of test mice, the same supplier of bedding, the same source of drug-containing rodent chow, and agreed-upon protocols for many other aspects of the test procedures. Although each site used the same source of food starting at the age at which mice were placed on the experimental diets, there were differences among the sites in the sources and formulations of food used for the breeding cages and for weanling mice prior to imposition of the experimental diets, typically at age 4 months. This is a correctable source of variation that will be removed in future test cohorts. There are other differences among sites which might alter survival patterns, relating perhaps to differences in noise levels, proximity to other mice, traffic levels, details of air-flow or water quality, etc., but at present we do not know which of these or perhaps other unspecified factors must be addressed to achieve uniformity of survival curves across test sites.
The interim analysis shows that NDGA leads to a significant decline in mortality risk in the first half of the lifespan. The primary statistical method was to use the log-rank test with stratification by site, so that each of the five treatment groups (four experimental diets plus the control) was compared to the pooled survival experience at each test site. The result showed a highly significant effect of treatment (P<0.005), showing that at least some of the groups differed in survival rate from one another. A follow-up analysis, using data for each test site separately, showed significant effects at TJL (P<0.01) and at UT (P<0.04), but not at UM, the site with the fewest deaths at the time of analysis. Each of the four experimental diets was then compared, again with stratification by test site, to the control group. This calculation showed a significant difference for NDGA versus controls, at P=0.0004 for the pooled data, and with P=0.02 and P=0.005 for TJL and UM males ,respectively. The results for the mice at UM showed a similar trend, with better survival in NDGA-treated males than in controls, but the effect was not statistically significant. We believe this may be the first documented example in which a test agent has diminished mortality risks, at least through the median life span, at multiple test sites for mice on a standard diet. The use of genetically heterogeneous mice for the ITP should increase the chances that the findings will prove replicable on a range of genetic backgrounds.
While NDGA did not have a significant effect on survival of female mice, at the time of the interim analysis fewer than 50% of the females had died at each site, thus diminishing statistical power. It will be of interest to evaluate effects of all test agents on females when the final analysis is performed. None of the other test compounds led to a significant difference, for data pooled across sites, in comparison to survival of the control animals for male mice. There was a trend towards improved survival among aspirin-treated males (P=0.07 by the log-rank test). A re-analysis using the Wilcoxon-Breslow statistic, which gives greater weight to early deaths, produced P=0.03 for the pooled data set, stratified by site. Analysis of the completed data set, when it becomes available, will produce more definitive information on the effects of aspirin and the other tested agents.
Another surprising observation was the site-to-site variation in weight gain trajectories. Mice were weighed at each site at the ages of 6, 12, 18, and 24 months, and at some sites also at earlier ages, in part to test the idea that effects of the tested compounds might be attributable to alterations in caloric intake or metabolic efficiency. NDGA-treated males at UT and TJL showed no difference in average weight compared to control males. NDGA-treated males at UM were significantly, but only slightly, lower in weight than controls (1.2 grams, about 3% of mean weight) at 12 months of age; this difference could not be attributed to NDGA because these two groups of mice differed in mean weight by about 13% at 6 months of age, i.e., prior to NDGA administration. Thus it seems very unlikely that the effect of NDGA on male survival was due to an effect on appetite or caloric intake. Unexpectedly, there was a substantial, and statistically significant, difference in the weight of both male and female mice among the test sites, with mice at UM lighter in weight than mice at the other two sites at all time points. It is plausible that uncontrolled differences in the source and formulation of food provided to breeder mice and weanlings may have caused this long-term alteration in weight trajectories, and production of mice for future ITP tests will need to employ a standardized approach to weanling production.
In sum, the NIA ITP demonstrates the power of multi-site studies on interventions for aging, as well as the many concerns that must be addressed in the development of such a program. It is hoped that published results from the ITP will stimulate further studies by other investigators, on the mechanisms of actions of effective interventions and on the efficacy in other animal models and human populations. Phase II testing is being designed to broaden the characterization of the effects of Phase II interventions on age-associated conditions and to facilitate collaborative studies with laboratories outside the ITP.
This work was support by grants from the National Institutes of Health U01-AG-022307 (R.S.), U01-AG-022303 (R.A.M.) and U01-AG-022308 (D.E.H.).
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Someone has just handed you one of your internal organs and helpfully informed you that it is now your sole responsibility to keep this organ alive and breathing. Yes, you. You who have just recovered from major surgery/had twenty nine stitches in a delicate part of your anatomy. Good luck with that!
There was a loud sigh, the sound of snoring and then a sudden jolt as he jumped, waking himself and his wife up. Yes, the other evening it was another dad who fell asleep first during the relaxation session at the end of one of our Wise Hippo hypnobirthing classes. And you know what? It's so often the way!
Mainstream media were quick to focus on the proposal that women should have a £3000 budget and a choice of birth places and carers. The Times describes this as women being "handed £3000 by the NHS," a scenario which seems as unlikely as its tone seems dismissive of women's abilities to think straight if presented with such quantities of money.
Many people told me their horror stories of birth. Many people rolled their eyes or laughed at me when I said I wanted a homebirth for my first baby. Many people told me I was being naieve or foolish. And many people close to me thought I wouldn't be able to do it: that I wouldn't stay at home the whole time, not for my first baby, or that I wouldn't cope without strong pain relief.
Fear can hold us back in all aspects of our lives and childbirth is no different. If you expect a difficult birth, you're much more likely to get one. If you are positive and have the right tools to help you cope, you're much more likely to have a good experience. In a nutshell, that's what hypnobirthing is all about.
With so much happening around the world, it truly feels there's now a global movement to support women's rights in childbirth, and that movement is fast gathering momentum. Change is happening. More people are being brought into the conversation. More people are now more aware of human rights in childbirth.


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Cubs Set Playoff RotationSubmitted by Rob G. on Fri, 09/26/2008 - 6:52pm
As announced earlier, Ryan Dempster will go Game 1 and he'll be followed by Carlos Zambrano, Rich Harden and finally Ted Lilly if a Game 4 is necessary.
As announced earlier, Ryan Dempster will go Game 1 and he'll be followed by Carlos Zambrano, Rich Harden and finally Ted Lilly if a Game 4 is necessary.
it was more no-doubt than bryant's HR. it wont make any end-of-season highlight reels, but that one was booked to leave on contact.
Javy! Javy! Javy!
How sweet was that - Cranked it!
393 happy feet
cubs take a 2 run lead in the 7th. sweet.
...and the Cards tie and take the lead in the 9th. off Familia.
Familia blows his first save of the season -- gives up 2 in 9th to the Cards.
Not much going our way these days.
bryant's back!
no-doubt HR towering to CF...tie game.
This site is as dead as the team.
AL pitcher hits a home run for a 1-0 lead. There goes perspective
Here are the ERAs for the last five starting pitchers:
At what point does the manager note it's not the "other pitcher"?
And why does he start Montero in the middle of a downturn?
Some perspective (mostly for my own benefit): Dan Straily beat MadBum 2-1 today as the Reds took 2 of 3 in SF. Giants are 2-9 since the break and their lead over LA is down to 2.5 games. So, yeah...baseball. It'll drive ya nuts.
McNutt / Archer didn't work out well for us.
The floor is more valuable than the ceiling. It's the same reason we drafted Kris Bryant instead of Jon Gray.
Apparently the Yankees had the choice of either Gleyber Torres or Eloy Jimenez in the Chapman deal, and they chose Torres.
Chapman shouldn't be reserved anymore on 40 man.
Interesting split on Heyward according to ESPN. As a CF, his slash line .292/.363/.375/.738. At RF: .212/.204/.300/.604. 21/72 as a CF, 58/273 as a RF.
He's also been better when batting 2nd, but he had a nice start in the 6 hole, but has slumped ever since. He was heating up before the All Star break, but is only hitting .108 in the 2nd half.
When we played the Reds with Chapman, I always thought of it as an eight-inning game. So now other teams have eight innings to try to get a lead against the Cubs. Should be a challenge, assuming three or four Cubs ever start hitting again.
I don't really try to get to know and like these players personally. I'm rooting for laundry, for the most part. Exceptions might be when a player makes trouble in the clubhouse or in the dugout. (Zambrano and Bradley come to mind. Also Papelbon.) But I don't think Chapman is one of those jerks.
This work is licensed under a Creative Commons Attribution-No Derivative Works 3.0 United States License.
©The Cub Reporter 2016. The Cub Reporter is in no way affiliated with the Chicago National League Ballclub.


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Colt McCoy and Rachel Glandorf have been married since 17th Jul 2010. [view couple]
Daniel "Colt" McCoy (born September 5, 1986) is an American football quarterback for the Washington Redskins of the National Football League (NFL). He was drafted by the Cleveland Browns in the third round of the 2010 NFL Draft, after playi...ng college football for the University of Texas. He has also been a member of the San Francisco 49ers.
Connect any celebrity with Colt McCoy to see how closely they are linked... romantically!


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Shakes or Wobbles problem
2002 Acura RL Front Wheel Drive Automatic 78000 miles
Have a 2002 Acura RL 3.5 w/78K miles. Noticed a mild shimmy in the steering wheel when it approaches 60 MPH plus. Not constanrt. Stops sometimes. Bad tire? Treadwear is not very good. Rotors? Wheel / tire out-of-balance?
Tuesday, August 25th, 2009 AT 11:31 AM


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Anidees AI-Crystal Tempered Glass review
MSI GeForce GTX 1060 GAMING X Review
Palit GeForce GTX 1060 Super Jetstream Review
GeForce GTX 1060 Review
GeForce GTX 1060 FCAT Frametime Analysis Review
MSI GeForce GTX 1080 GAMING Z 8G review
Corsair Neutron XTi 480 GB SSD review
3DMark TimeSpy DirectX 12 Benchmark Review
Corsair ML Series Magnetic Levitation Fan Review
Gigabyte GeForce GTX 1070 G1 GAMING review
Detonator 52.14 Win2000|XP
Posted by: Import on: 02/01/2004 03:53 AM [ 0 comment(s) ]
Windows 2000/XP Innovision placed Detonator drivers 52.14 on their servers, which is good enough for us to host them on Guru3D.com also.
The .inf file of this archive was slightly modified to ensure that all NVIDIA graphics cards will work with them

This is one of the latest builds available and also the one used by many reviewers the past week. There is no fancy installer, you need to uninstall your drivers and then manually install this driver the old fasion way.

These drivers are BETA, thus use them at your own risk and don't go complaining if something does not work right.

The file has been compressed deeply to ensure a small download size (5mb).
Tagged as: Detonator
« ATI Catalyst 3.8 Win2000|XP · Detonator 52.14 Win2000|XP · Detonator 52.16 Win98|ME »


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Work-Life Services Home Page
Work–Life Services (WLS) are five negotiated benefits programs for Executive Branch employees resulting from a collaboration between NYS and the public employee unions. These programs are designed to increase employee productivity and morale by improving the quality of work and life for employees and include: Employee Assistance Program, Worksite Child Care Centers, Flex Spending Account, NYS–Ride, and Pre–Retirement Planning.
To view or print the Work-Life Services Brochure click here.
Employer Contribution for PEF Represented Employees
As a result of the ratification of the 1 year contract, PEF represented employees who are currently enrolled in the Dependent Care Advantage Account will have the Employer Contribution automatically applied to their account for the 2016 plan year.
PEF represented employees who enroll in the Dependent Care Advantage Account with an eligible Change In Status (CIS) event will now be eligible for the Employer Contribution for the remainder of the 2016 plan year.
Please visit the Flex Spending Account Website for updates and details as they emerge.
EAP: Summer Safety Tips for Children
Summer is a great time for kids to enjoy outdoor activities. Whether they are young children or teens, it is important to keep them safe and healthy while they enjoy the summer fun.
Master Water Safety
Water-related activities are popular for getting physical activity and they have many health benefits. Learn how to prevent recreational water illnesses and help protect yourself and your kids. Always supervise children when in or around water. A responsible adult should constantly watch young children. Teach kids to swim. Formal swimming lessons can protect young children from drowning. Learn cardiopulmonary resuscitation (CPR). Your CPR skills could save someone's life. Recreational boating can be a wonderful way to spend time with family and friends. Make boating safety a priority. Wear a properly fitted life jacket every time you and your children are on the water.
Beat the Heat and Sun
Heat-related illness happens when the body's temperature control system is overloaded. Infants and children up to 4 years of age are at greatest risk. Even young and healthy people can get sick from the heat if they participate in strenuous physical activities during hot weather. For heat-related illness, the best defense is prevention. Never leave infants, children, or pets in a parked car, even if the windows are cracked open. Dress infants and children in loose, lightweight, light-colored clothing. Schedule outdoor activities during the morning and evening hours. Seek medical care immediately if your child has symptoms of heat-related illness. Just a few serious sunburns can increase the risk of skin cancer later in life. Your skin needs protection from the sun's harmful ultraviolet (UV) rays whenever you're outdoors. Always cover up. Clothing that covers your child's skin helps protect against UV rays. Use sunscreen with at least SPF (sun protection factor) 15 and UVA (ultraviolet A) and UVB (ultraviolet B) protection every time you and your child go outside.
Mosquitos and Ticks
Use an effective insect repellent while playing outdoors. Make your backyard a tick-safe zone and check yourself and your children for ticks. Ticks are easy to remove.
For additional information or assessment and referral services, contact your NYS agency EAP coordinator Coordinator List.
Center for Disease Control and Prevention
Fun at NYS Worksite Center Summer Camps
Are you looking for a summer camp for your school-aged child? Did you know that many of the NYS Worksite Child Care Centers offer summer camp for children ages five – 12? All of the worksite summer camps are conveniently located within, or in close proximity to the child care centers at various state sites. All the summer camps offer weekly themes to ensure your child will be entertained while gaining knowledge on a variety of topics in a caring environment. What questions should I ask when I call about enrolling my child for summer camp? Click here for more information
Enroll in the DCAAccount
Great news for state employees! If in order for you and your spouse (if you are married) to be able to work, you plan to send your child under the age of 13, to summer day camp, a Change in Care Provider (including summer day camp) is an eligible Change in Status event that allows you to enroll in the Dependent Care Advantage Account (DCAAcount) for the remainder of 2016. Also, the Employer Contribution is available to eligible employees who enroll in the DCAAccount to help pay for summer day camp expenses. Please visit www.flexspend.ny.gov or call (800) 358-7202 for more information, Employer Contribution rates, or to enroll.
Retirement Planning Videos
A series of short videos — the Planning Your Successful Retirement Video Guide — highlighting key information from the popular DIRECTIONS: Pre-Retirement Planning Seminars is now available. Designed for executive branch employees, the 23 videos were created in partnership with the Office of the State Comptroller, the Department of Civil Service, the NYS Deferred Compensation Plan, and the Social Security Administration. Employees can view the videos along with other pre-retirement planning information on this Work-Life Services website and also on YouTube at www.youtube.com/user/GOERWebServices.
WellNYS Everyday
The NYS Work-Life Services Employee Assistance Program recently launched a wellness initiative called WellNYS Everyday. The initiative is dedicated to educating, engaging, and empowering New York State employees and their families by encouraging participation in healthy behaviors, particularly the Monthly Challenges.
Retirement Planning Resources Workshops
The Retirement Planning Resources Workshop is a free, one-hour training, available to state agencies for their employees, regardless of years of state service. The training will not cover specific retirement information, and is not a substitute for the full-day DIRECTIONS seminars. Instead, the goal of this training program is to educate executive branch employees about the resources available so they can begin planning their retirement.
If you would like to schedule this one-hour training, you may contact Beth Brumaghim, Seminar Program Manager, at email@example.com or 518.473.4018.
NYS-Ride allows eligible state employees to pay up to $255 per month for certain work-related transportation expenses on a pre-tax basis. More than 8,000 participants who use public transportation to get to work currently enjoy the saving this program provides, while contributing to a greener environment by reducing carbon emissions, greenhouse gasses, and dependence on foreign oil.
The NYS-Ride website provides employees with quick and easy access to all the information they would need to learn about the program, calculate their savings and impact on the environment, enroll in NYS-Ride, make changes to their elections, or view their accounts. Please visit the website at www.nysride.com
2016 Flex Spending Account Changes in Status and New Employees
The FSA 2016 open enrollment period ended on November 24, 2015. Employees who experience a valid change in status on or after November 25, 2015 or during the 2016 plan year, may be eligible to enroll by submitting a Change in Status application. Visit www.flexspend.ny.gov to review the 2016 Change in Status information to determine if your situation qualifies you to enroll during the plan year.
Welcome to the Family Packet
Work-Life Services introduces the "Welcome to the Family Packet". Parenting is an exciting and challenging experience. Today's parents often face unique circumstances balancing their work and family responsibilities. As a New York State Executive Branch employee parent, you are entitled to several negotiated benefits designed to assist you with balancing work and life. The "Welcome to the Family Packet" will outline these benefits programs as well as provide educational child care and parenting brochures. We invite you to request a "Welcome to the Family Packet" if you are expecting or recently added to your family through the birth or adoption of a child. Email your request along with your name and home address to: email@example.com.
"Parenthood, it's not a job. It's an adventure" – author unknown