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From Emory University, Atlanta, GA 30322.
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Lawrence S. Phillips, MD, Division of Endocrinology, Emory University, 101 Woodruff Circle, WMRB Room 1027, Atlanta, GA 30322; e-mail, firstname.lastname@example.com.
Current Author Addresses: Dr. Phillips: Division of Endocrinology, Emory University, 101 Woodruff Circle, WMRB Room 1027, Atlanta, GA 30322.
Dr. Twombly: Division of Endocrinology, Emory University, 101, Woodruff Circle, Room 1301, Atlanta, GA 30322.
Hypertension is the most important health problem that clinicians don't manage well. Blood pressure control is particularly important for patients with diabetes (1), but providers may be less likely to intensify therapy for hypertension than for hyperglycemia (2), and antihypertensive therapy in patients with diabetes is sometimes less intensive than in patients without diabetes (3)—the opposite of what it should be. In many patients, blood pressure levels remain above goal because providers do not initiate or intensify therapy when clinically indicated. We have characterized this problem as "clinical inertia" (4).
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I am puzzled by the recommendation of Phillips and Twombly (1) to change antihypertensive therapy based on single blood pressure measurements and by their dismissal of home monitoring, given the marked variability of blood pressure over time, especially in older patients with systolic hypertension. I have observed fluctuations in systolic pressure of up to 100 points in 24 hours in clinically stable patients in both inpatient and outpatient settings. If I have verified in my clinic the reliability of a patient's blood pressure machine, is the average of multiple home measurements not more important than a single clinic measurement?
Changing an antihypertensive regimen based on a single blood pressure reading appears to me analogous to changing a diabetic regimen based on a single blood sugar without looking at the overall pattern and A1C. The cautious approach of the clinicians in the overdue study by Kerr and colleagues in the same issue (2) appears even more appropriate if we restate their uncertainty about the "true" blood pressure (as blood pressure truly does fluctuate) as uncertainty about the average blood pressure. Pursuing the analogy to diabetic management, would it not be a logical approach to encourage most hypertensive patients to perform home monitoring and to base treatment decisions on the average blood pressure over several weeks or months?
1. Phillips LS, Twombly JG. It's time to overcome clinical inertia. Ann Intern Med. 2008;148:783-785.
2. Kerr EA, Zikmund-Fisher BJ, Klamerus ML, Subramanian U, Hogan MM, Hofer TP. The role of clinical uncertainty in treatment decisions for diabetic patients with uncontrolled blood pressure. Ann Intern Med. 2008;148:717-727.
None declared
In their comments on the article concerning clinical inertia in the treatment of hypertension in diabetic patients (1), Phillips and Twombley suggest that "every occurrence of blood pressure above goal should prompt intensification of treatment." This conflicts with the current recommendations of the Seventh Joint Commission (JNC7), which state:
"Self-monitoring of BP at home and work is a practical approach to assess differences between office and out-of-office BP prior to consideration of ABPM. For those whose out-of-office BPs are consistently <130/80 mmHg despite an elevated office BP, and who lack evidence of target organ disease, 24-hour monitoring or drug therapy can be avoided."(2)
Rather than suffering from clinical inertia, clinicians may be simply following the guidelines. Until the guidelines are revised to clarify how to deal with discrepancies between office and home blood pressure readings, clinicians cannot be faulted for following them.
(1) Philips, LS, Twombley, JG. It's Time to Overcome Clinical Inertia. Ann Intern Med, 2008, 148:783-785
(2) Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003 Dec;42(6):1206-52
In their recent editorial, Phillips and Twombly suggest that clinical inertia is easily overcome if providers "run the numbers first and deal with blood pressure and glucose before asking about other problems."(1) While managing vascular risk factors is extremely important in reducing the risk of diabetes complications, their approach dramatically oversimplifies the realities of clinical care.
Kerr and colleagues show that clinician and patient uncertainty around blood pressure management is an important determinant of treatment decisions.(2) Uncertainty can take many forms, from belief in the level of evidence supporting guidelines to concern about side effects and measurement error. As we noted in our ACP evidence review on managing blood pressure in diabetes,(3) there are no clinical trials showing benefit to treating to a systolic blood pressure goal of less than 140 mmHg. The supporting evidence for lower targets is purely observational, and the possibility of harming patients by overtreating diastolic blood pressure is real.(4) Nevertheless, Phillips and Twombly recommend that every time a blood pressure reading is elevated, clinicians should intensify therapy. This approach promotes potentially harmful polypharmacy, given that most patients with diabetes require at least 2-3 blood pressure medications,(3) and also increases the risk of non- adherence due to side effects and cost.
Further, treating every blood pressure above goal markedly oversimplifies the realities of blood pressure measurement and variability. Consider the related issue of cholesterol management. In a recent issue of Annals, it was shown that repeated cholesterol measurement leads to more noise than signal, and thus causes unnecessary medication adjustment.(5) Given the vagaries of blood pressure measurement and phenomena like white coat hypertension, this is likely to be an even larger issue for hypertension.
Finally, we strongly object to the concept of "running the numbers" first, which is completely at odds with fundamental principles of primary care interactions. If primary care physicians focused on the numbers first, they would end up imposing their own priorities onto patients, rather than letting patients help set the agenda. Consider a visit with a depressed patient or one with chronic pain. Until a physician addresses such issues, there is little chance of managing chronic conditions well. Kerr and colleagues clearly show that competing demands are a major predictor of provider response to elevated blood pressure.(2) The open- ended nature of initial contact helps us to prioritize care and is essential for establishing patient rapport and trust. A subspecialist in hypertension or endocrinology might arguably be justified in addressing the numbers and pushing off other patient concerns. But no plausible argument can be made that primary care physicians treat the numbers, not the patient.
1. Phillips L, Twombly JG. It's time to overcome clinical inertia. Ann Intern Med 2008; 148: 783-5.
2. Kerr EA, Zikmund-Fisher B, Klamerus M et al. The role of clinical uncertainty in treatment decisions for diabetic patients with uncontrolled blood pressure. Ann Intern Med 2008; 148: 728-736.
3. Vijan S, Hawyard RA. Treatment of hypertension in type 2 diabetes: Blood pressure goals, choice of agents, and setting priorities in diabetes care. Ann Internal Med. 2003; 138: 593-602.
4. Messerli FH, Mancia G, Conti CR et al. Dogma disputed: Can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med 2006; 144: 884-893.
5. Glasziou P, Irwig L, Hertier S, et al. Monitoring cholesterol levels: measurement error or true change? Ann Intern Med 2008; 148: 656-61.
To the Editor:
RE: It's Time to Overcome Clinical Inertia, Editorial, 20 May 2008
We read with appreciation the innovative paper by Kerr et. al.(1) However, the accompanying editorial by Phillips and Twombly is based solely in the "index condition" framework, where one condition is viewed to be of paramount interest.(2) The editorialists argue that blood pressure is the "most" important condition not well treated. Surely, this valuation depends on the defining perspective, whether it be the public health, cost, or the health of an individual patient. We suggest that this is the wrong way in which to frame the issue as it fails to adequately acknowledge a patient-centered perspective of chronic illness care, in which all the conditions a patient has are considered, in terms of the relative benefit of treating each condition in the presence of their other conditions, the cumulative effect of all the recommended treatments, and the individual's treatment priorities.(3,4)
Their treatment paradigm is similarly flawed.(2) Treating "every occurrence" of elevated blood pressure will, for some patients, threaten important outcomes such as functional capacity, quality of life, continence, and psychological well being. Adding a new medication or increasing medication dose is a major clinical decision, as doing so potentially reduces adherence to other medications, increases risk of side effects, adds to treatment burden or caregiver burdens, and increases costs. Thus, before augmenting therapy, it would be prudent to explore adherence, self-management strategies, issues related to treatment burden and patient preferences, and to engage patients to identify their treatment goals for all their conditions. Assuming that all patients want to talk about their "numbers first" violates the principles of patient- centered care. Finally, the paradigm doesn't acknowledge relative attributable benefit within one condition or consider all the conditions a person has.(4) That is, achieving a reduction in systolic blood pressure from 160 to 140 is likely to produce a greater benefit in hypertension specific outcomes compared with achieving a reduction from 133 to 128. In the latter case, it may be more important to discuss anticoagulation for atrial fibrillation, treatment of depression, or a family issue.
Defining "clinical inertia," as a "failure" is a pejorative construct. On the one hand, it may be that physicians are not treating an important problem as effectively as possible. Alternatively, physicians may be providing patient-centered care, accounting for patients' individual situations and multimorbidity.(5) Rather than enforcing nearly absolute rules, new paradigms should be developed to understand these issues in greater depth.
1. Kerr EA, Zikmund-Fisher BJ, Klamerus ML, Subramanian U, Hogan MM, Hofer TP. The role of clinical uncertainty in treatment decisions for diabetic patients with uncontrolled blood pressure. Ann Intern Med. 2008;148:717- 727.
2. Phillips LS, Twombly JG. It's time to overcome clinical inertia. Ann Intern Med. 2008 May 20;148(10):783-5.
3. Boyd CM, Darer JD, Boult C, Fried LP, Boult L, Wu AW. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: Implications for pay for performance. JAMA. 2005 Aug 10;294(6): 716-24.
4. Kent DM, Alsheikh-Ali A, Hayward RA. Competing risk and heterogeneity of treatment effect in clinical trials. Trials. 2008 May 22;9:30.
5. Weiss CO, Boyd CM, Wolff J, Yu Q, Leff B. Patterns of prevalent major chronic disease among older adults in the United States. JAMA. 2007 Sep 12;298(10):1160-2.
Since sending my Rapid Response on May 27, I have now learned of a joint scientific statement (published online May 22 ahead of print) recommending routine home monitoring for the majority of patients with hypertension and use of those results to guide therapy (1).
1. Pickering TG, Miller NH, Ogedegbe G, Krakoff LR, Artinian NT, Goff D. Call to action on use and reimbursement for home blood pressure monitoring: a joint scientific statement from the American Heart Association, American Society of Hypertension, and Preventive Cardiovascular Nurses Association. Hypertension. 2008;52:1-9.
Treating diabetic hypertension in today's busy office practice is often a losing proposition (1). Time constraints, competing patient demands (2), patient noncompliance (3), and clinical uncertainty (4) can all impede our patients' progress toward optimal blood pressure control. In their editorial, "It's Time to Overcome Clinical Inertia", Phillips and Twombly cite clinical uncertainty and subsequent inertia on the part of the physician as the root of the problem. They suggest a paradigm shift in the management of diabetic hypertension: ". . . once hypertension is diagnosed, every occurrence of blood pressure above goal should prompt intensification of therapy unless contraindicated by problems, such as hypotension. " In order to put this paradigm into practice, clinicians should "'run the numbers' first and deal with blood pressure and glucose before asking about other problems (5)."
There are inherent problems with this approach. First, there are multiple causes for isolated elevations in blood pressure. Diabetics, like everyone else, sprain their ankles, catch colds, rush to their appointments, and drink their morning coffee. Pain, over-the-counter medications such as decongestants, physical activity and caffeine can all transiently raise blood pressure (6-8). If we don't take the time to first discuss these "comorbid conditions" - which are often the primary reason for the visit - then we risk overtreating our patients. Even if our patients tolerate intensification in therapy when they may not need it, there is the extra financial burden, the possibility of medication interaction, as well as the concern over noncompliance that accompanies an escalating pill count.
White Coat Syndrome is another entity that affects physician's confidence and ability to treat hypertension. In the last few years, however, the availability of accurate and inexpensive automatic sphygmomanometers has all but erased this source of uncertainty. Numerous studies have established their accuracy in the ambulatory setting (9-11). It is relatively simple for patients to check their blood pressures two or three days per week, record their readings and fax, mail, email, or bring their blood pressure log to their doctor. Patients can bring their monitors to their next office visit, regardless of the reason for that visit, in order to insure that the home monitor correlates closely with the office sphygmomanometer. Once confirmed, medication adjustment can be made based on the patients' blood pressure log with very little uncertainty and without cutting into the office time needed to address the patients' other complaints. Everybody wins.
References 1. Berlowitz DR, Ash AS, Hickey EC, Glickman M, Friedman R, Kader B. Hypertension management in patients with diabetes: the need for more aggressive therapy. Diabetes Care. 2003;26:355-9 2. Parchman, ML, Pugh JA, Romero RL, Bowers KW. Competing demands or clinical inertia: the case of elevated glycosylated hemoglobin. Ann Fam Med. 2007;5:196-201. 3. Grant R, Adams AS, Trinacty CM, Zhang F, Kleinman K, Soumerai SB, et al. Relationship between patient medication adherence and subsequent clinical inertia in type 2 diabetes glycemic management. Diabetes Care. 2007;30:807-12. 4. Kerr EA, Zikmund-Fisher BJ, Klamerus ML, Subramanian U, Hogan MM, Hofer TP. The role of clinical uncertainty in treatment decisions for diabetic patients with uncontrolled blood pressure. Ann Intern Med. 2008;148:717-27 5. Phllips LS, Twombly JG. It's time to overcome clinical inertia. Ann Intern Med. 2008;148:783-4. 6. Reeves RA. Does this patient have hypertension? JAMA 1995;273:1211- 18. 7. Lake CR, Gallant S, Masson E, Miller P. Adverse drig effects attributed to phenylpropanolamine: a review of 142 case reports. Am J Med 1990;89:195 -208. 8. Jee SH, He J, Whelton PK, et al. The effect of chronic coffee drinking on blood pressue. Hypertension 1999;33:647-52. 9. Kleinert HD, Harshfield GA, Pickering TG, et al. What is the value of home blood pressure measurement in patients with mild hypertension? Hypertension 1984 Jul-Aug;6(4):574-8. 10. Verberk WJ, Kroon AA, Kessels AG, de Leeuw PW. Home Blood Pressure Measurement A Systematic Review. J Am Coll Cardiol 2005 Sep 6;46(5):743- 751. 11. Asayama K, Ohkubo T, Kikuya M, et al. Prediction of stroke by self- measurement of blood pressure at home versus casual screening blood pressure measurement in relation to the Joint National Committee 7 classification: the Ohasama study. Stroke 2004 Oct;35(10):2356-61.
We thank the responders to our editorial for their thoughtful concerns, but we believe that hypertension management needs to improve, and we address the issues they raise.
While clinical inertia can be a pejorative term, acknowledging our own deficiencies (1) was a key first step in improving our care (2). Requiring that every detail of recommendations for care be based on evidence from clinical trials can lead to "evidence-based paralysis" (3) "" failure to act in the absence of specific trial-based evidence; the <140 mmHg systolic blood pressure (SBP) goal is well supported (4). Although intensification of therapy promotes polypharmacy and risks nonadherence, these are part of the cost of better hypertension management. Fortunately, emphasis by the provider increases adherence (5;6); patients will be more likely to take hypertension medications if we emphasize their importance "" and if we don't mention blood pressure, patients may conclude that it's not important.
Addressing blood pressure (an "index condition") at the start of visits might seem to go against having visits be patient-centered, but patients might emphasize symptomatic over asymptomatic problems. Finding the best balance is not simple, and it is our responsibility to help patients appreciate the importance of disorders such as hypertension and diabetes. While blood pressure shouldn't dominate, it shouldn't be overlooked; our paradigm should help avoid errors of omission. We also recognize that fluctuations in SBP can be substantial, especially in the elderly and in patients with type 1 diabetes, but variability is usually damped when blood pressure is better controlled. Accordingly, it is reasonable to recommend that blood pressure above goal should always prompt intensification unless there are problems such as orthostasis.
We agree that complications from hypertension are linked more tightly to ambulatory blood pressure than to measurements in the office, but ambulatory pressures aren't always available, and we don't know how best to use them. The risk from office SBP 140 mmHg corresponds to that of a lower average ambulatory pressure (7) or a lower first morning pressure (8), but it isn't clear exactly how low ambulatory pressures must be to be reassuring. Our paradigm responds to office pressure-based guidelines (4), and was designed to be universally applicable.
Our understanding of the basis for clinical inertia has been advanced by the demonstration of contributions from "clinical uncertainty" (9) and "competing demands" (10), but it's been almost seven years since the concept was promulgated (11); we believe that rather than further studies of mechanisms, it's time to focus on overcoming clinical inertia. The management paradigm we offer (12) should help us to move forward.
Reference List
(1) El-Kebbi IM, Ziemer DC, Musey VC, Gallina DL, Bernard AM, Phillips LS. Diabetes in urban African-Americans. IX. Provider adherence to management protocols. Diab Care. 1997;20:698-703.
(2) Ziemer DC, Doyle JP, Barnes CS, Branch WT, Jr., Cook CB, El- Kebbi IM et al. An intervention to overcome clinical inertia and improve diabetes mellitus control in a primary care setting: Improving Primary Care of African Americans with Diabetes (IPCAAD) 8. Arch Intern Med. 2006;166:507-13.
(3) Ziemer DC, Phillips LS. The Dogma of "Tight Control": Beyond the Limits of Evidence""Reply. Arch Int Med. 2006;166:1672.
(4) Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JLJr et al. The Seventh Report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA. 2003;289:2560-2571.
(5) Francis V, Korsch BM, Morris MJ. Gaps in doctor-patient communication: patients' response to medical advice. N Engl J Med. 1990;280:535.
(6) Bonds DE, Camacho F, Bell RA, Duren-Winfield VT, Anderson RT, Goff DC. The association of patient trust and self-care among patients with diabetes mellitus. BMC Fam Pract. 2004;5:26.
(7) Sega R, Corrao G, Bombelli M, Beltrame L, Facchetti R, Grassi G et al. Blood pressure variability and organ damage in a general population: results from the PAMELA study (Pressioni Arteriose Monitorate E Loro Associazioni). Hypertension. 2002;39:710-714.
(8) Kamoi K, Miyakoshi M, Soda S, Kaneko S, Nakagawa O. Usefulness of home blood pressure measurement in the morning in type 2 diabetic patients. Diab Care. 2002;25:2223.
(9) Kerr EA, Zikmund-Fisher BJ, Klamerus ML, Subramanian U, Hogan MM, Hofer TP. The role of clinical uncertainty in treatment decisions for diabetic patients with uncontrolled blood pressure. Ann Intern Med. 2008;148:717-27.
(10) Turner BJ, Hollenbeck CB, Weiner M, Tenconi M-TP, Tang SSK. Do unrelated comorbidities negatively influence hypertension management? Annals Int Med. 2008;148:576-84.
(11) Phillips LS, Branch WT, Jr., Cook CB, Doyle JP, El-Kebbi IM, Gallina DL et al. Clinical inertia. Ann Int Med. 2001;135:825-34.
(12) Phillips LS, Twombly JG. It's time to overcome clinical inertia. Ann Intern Med. 2008;148:783-85.
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Local resident qualifies for James Madison dean's list
February 7, 2013
HARRISONBURG, Va. — Kelsey Lineburg, of Charles Town, has been named to the dean's list for the 2012 James Madison University fall semester. Lineburg is a freshman, majoring in engineering....
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quote: Don't matter to me, I was just curious :o
quote: What issues other than supply were there with the original? I was one of the first adopters of it and never had an issue. Know quite a few other people with them, and no issues to speak of either.Just curious is all :)


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The Associated Press
NEW YORK � Rescuers working amid cold, gusty winds and billowing smoke pulled four additional bodies overnight from the rubble of two Manhattan apartment buildings, as the death toll rose Thursday to at least seven from a gas leak-triggered explosion that reduced the area to a pile of smashed bricks, splinters and mangled metal.
The explosion Wednesday morning in East Harlem injured more than 60 people, with searchers still trying to locate at least five others a day later. Mayor Bill de Blasio told firefighters at the scene Thursday morning, "I can only imagine knowing that at any moment you might find a body, how difficult that is."
Crews used generator-powered floodlights and thermal imaging cameras to identify heat spots � bodies or pockets of fire � at the site on Park Avenue and 116th Street. Police guarding the scene wore surgical masks and neighborhood residents covered faces with scarfs amid the thick, acrid air.
Edward Kilduff, the Fire Department's chief of department, said the amount of debris had been reduced to about 1� floors by Thursday morning. He said rescuers were concerned about the stability of a free-standing wall at the back of the scene.
Firefighters were perched on surrounding rooftops, dousing the still-smoldering debris from above, drawing huge clouds of thick smoke that swirled over Park Avenue and wafted through the neighborhood.
Construction equipment with iron jaws picked up the smoldering debris, first depositing it on the pavement, then hoisting it onto trucks that hauled it away. The debris included structural beams, pieces of windows and residents' belongings.
Workers initially were hampered from fully accessing the building space because of a sinkhole caused by a subsurface water main break. The weather also posed a challenge, with temperatures dropping into the 20s overnight and rain falling.
The fiery blast erupted around 15 minutes after a neighboring resident reported smelling gas, authorities said. The Con Edison utility said it immediately sent workers to check out the report, but they didn't arrive until it was too late.
The explosion shattered windows a block away, rained debris onto elevated commuter railroad tracks close by, cast a plume of smoke over the skyline and sent people running into the streets.
"It felt like an earthquake had rattled my whole building," said Waldemar Infante, a porter who was working in a basement nearby. "There were glass shards everywhere on the ground, and all the stores had their windows blown out."
Hunter College identified one victim as Griselde Camacho, a security officer who worked at the Silberman School of Social Work building. Hunter said Comacho, 45, had worked for the college since 2008.
Page 2 of 2 - Also killed was Carmen Tanco, 67, a dental hygienist.
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Tea Pot Show- Grass Lake
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There will be a collection of vintage and modern teapots will be on display throughout the Coe House Museum (at 371 W. Michigan Ave., at the corner of Michigan Ave and Wolf Lake Rd in Grass Lake, Michigan). You can see the exhibit on two dates:
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on January 8, 2013 - 9:03 PM
, updated January 9, 2013 at 1:48 AM
LOCKPORT – A former attorney who practiced law in North Tonawanda for more than 40 years was sentenced Tuesday to two years in Niagara County Jail for looting a Wheatfield man's estate of more than $150,000.
Roger J. Niemel, 70, who was disbarred in 2011 in an unrelated case, pleaded guilty Oct. 8 to third-degree grand larceny and second-degree criminal possession of a forged instrument. He also was ordered to make restitution of $153,264. County Judge Sara Sheldon Farkas sentenced him to a year in jail on each charge, to be served consecutively.
The thefts from the estate of Chester Kawalec occurred from 2005 to 2008, according to Assistant District Attorney Brian D. Seaman. Kawalec, 84, died in 2005 and left an estate worth more than $800,000, which included assets in personal accounts and those in joint accounts with his adult daughter, Marcia Poirer-DeNapoli of Niagara Falls, Ont., and her two children.
Surrogate Court files reported that Poirer-DeNapoli went to another North Tonawanda attorney, Robert E. Nicely, in August 2011 to help move the estate toward closure and was told of the thefts in Sept. 20, 2011.
DePoirer-DeNapoli appeared in court Tuesday and listened as Seaman read a letter from her that described how the family had been affected. She said Niemel had been a family attorney for as long as she could remember and even attended both her parents' funerals.
"I thought he was trusted and honest. Mr. Niemel abused that trust and gave me incorrect legal advice … I did not expect to be abused by a trusted family adviser," Poirer-DeNapoli wrote.Seaman said even though Niemel is 70 years old and had no criminal record, he should still be incarcerated for violating that trust.
Niemel told Farkas he had nothing to say, other than to offer an apology to Kawalec's family. He was then handcuffed by court officers while his wife patted away a few tears.
Niemel lost his law license in March 2011 in an unrelated case for misappropriating $20,500 from a Grand Island woman and violating 11 rules of professional conduct, according to a ruling from the Appellate Division of State Supreme Court. He was disbarred in a default judgment by that court after he twice failed to appear to respond to the charges. He was ordered to make full restitution to the Grand Island woman, but no prosecution resulted.
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PITTSBURGH - For the first time since he was taken in the third round in the 2009 draft, Mike Wallace will miss a regular-season game for the Steelers.
It might well be the first of many games Pittsburgh plays without the speedster receiver going forward.
An injury in his left hip and hamstring area will prevent Wallace from playing in the Steelers' season finale Sunday against the Cleveland Browns. He will be an unrestricted free agent, leaving his status with the team for beyond this season in question.
Wallace isn't the only veteran who might have attended his final practice as a Steelers player Friday. On the heels of a non-winning season and with salary-cap issues upcoming, Pittsburgh (7-8) has some decisions to make on several longtime stalwarts who have been tenured contributors to championship teams.
Wallace, Casey Hampton, Rashard Mendenhall, Max Starks, James Harrison, Larry Foote and Charlie Batch have a combined 59 years of service for the Steelers, 12 starts in Super Bowls for the team and 11 championship rings.
There is reason to believe the game against Cleveland (5-10) will be the final one for many in that group as part of the organization.
"I don't know who's going to be out the door or who's going to be re-signed, but it's always a business first," Foote said. "From a selfish standpoint on defense, we were No. 1 in the league - so bring us all back, keep us all. But I never know what's their plans and (general manager) Kevin Colbert can run a team better than I can."
Starks, who will start his 96th game at tackle for the Steelers on Sunday, and Hampton, the team's nose tackle for the past 12 seasons, both hinted this week they could envision playing elsewhere.
The Steelers' most recent two second-round draft picks - and rookies of the year - are tackles. That doesn't bode well for Starks, who rebounded from injury each of the past two years to become a reliable starter for the Steelers by the time the season ended.
"I think the writing's on the wall, so to speak," Starks said. "I had a great run - nine years here. I've gotten to be a part of three Super Bowl teams and got a chance to grasp two of those Lombardis, so it's an excellent career. If I have to move on, this will always be home for me."


text: Why is it that nearly every liberal initiative since the end of the New Deal—whether busing, urban development, affirmative action, welfare, gun control, or Roe v. Wade—has fallen victim to its grand aspirations, often exacerbating the very problem it seeks to solve? In this groundbreaking work, the first full treatment of modern liberalism in the United States, bestselling journalist and historian Eric Alterman together with Kevin Mattson present a comprehensive history of this proud, yet frequently maligned tradition. In The Cause, we meet the politicians, preachers, intellectuals, artists, and activists—from Eleanor Roosevelt to Barack Obama, Adlai Stevenson to Hubert Humphrey, and Billie Holiday to Bruce Springsteen—who have battled for the heart and soul of the nation.


text: It's a f....cking shame the guy is making than 90 % of the players, responsible for failed franchises, 3 lockouts in a row and the reason teams like this can't ice the best possible roster. How can owners justify around 270k/franchise for this guy? Absolutely hilarious, give a hockeyguy the job!


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Checkmate: Check Cashing Exposé
|Email Print
I'm a usually a free market kind of guy, mostly because the free market, or at least our version of it, has been good to me and my family. That being said, I understand why people think check cashing stores are ripoffs and why they should be regulated more. I think they serve a purpose, giving those without bank accounts access to their funds, but their fees are extraordinary and deserve inspection.
So, who better to inspect them than the Internets Celebrities? This nine minute clip is worth every minute both in informational and entertainment value.
This video courtesy of Consumerist, Editor Ben Popken makes a cameo too. { 4 comments, please add your thoughts now! }


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GA/AL District Curriculum & Standards
In keeping with our mission to educate, engage, and empower each student to succeed in a dynamic world the DoDEA Curriculum Content Standards and the Community Strategic Plan (CSP) provide the framework for academic excellence.
The GA/AL district does not provide all grade level programs. Dependent students living on the military installations attend schools operated by the Local Education Agency in the civilian community for grade levels not offered by DDESS.
GA/AL Schools offer a half-day Pre-K program to children who reside on post and who will be four years old on or before September 1, of the current year.
Pre-K teachers utilize a student-centered approach and encourage children to develop their abilities as they work in areas focused on computer skills, art activities, creative play, and academic readiness.
Special Education
Special Education services are available to all students including preschoolers. If you have concerns regarding your child's academic, physical, social, or language development, you may contact your child's teacher or the principal. Preschool children ages three and four years with developmental delays, physical disabilities, or speech-language problems may be eligible for services.
Contact the Special Education Office
- Fort Benning: 706-545-5520
- Fort Rucker: 334-255-2822
- Maxwell AFB: 334-953-7804
- Fort Benning: Educational and Developmental Intervention Services at 706-545-3835
- Fort Rucker: Educational and Developmental Intervention Services at 334-255-7237
- Maxwell AFB: Educational and Developmental Intervention Services at 334-953-4953
Gifted/Enrichment Program
Our program for gifted students who meet eligibility criteria for gifted or enrichment is based on curriculum that emphasizes
- Higher level thinking skills
- Creative problem solving skills
- Development of a strong self concept
- Aesthetic awareness
- Development of positive interpersonal relations
Instructional Support
All GA/AL Schools offer Instructional Support services to help accelerate student progress. Students whose standardized test scores indicate a weakness in reading and/or math may qualify to receive additional academic support in an Instructional Support program.
English-As-A-Second Language
The English-As-A-Second Language program is designed to assist students whose native language is not English.
Fort Benning
- ESL students from grades K - 8 are served at Faith Middle School and White Elementary School.
- Students in Pre-K are served in the regular classroom.
Fort Rucker
English Language Learners are immersed in a language-rich environment in the general curriculum and receive a continuum of support using a variety of service delivery models. Please contact the school principal for more information.
Maxwell AFB
English Language Learners are immersed in a language-rich environment in the general curriculum and receive a continuum of support using a variety of service delivery models. Please contact the school principal for more information.


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COLUMBIA - National legal trends and local, grassroots anti-abortion efforts appear to have converged in the S.C. Senate.
Anti-abortion measures that have rarely, if ever, gotten a hearing in what's known as the Legislature's "deliberative" chamber are scheduled to be taken up on Thursday. In the state Senate, individual senators have power to delay or kill individual pieces of legislation, which helps explain why even though both chambers are dominated by Republicans, anti-abortion measures have often been passed by the S.C. House and then don't see the light of day in the Senate.
That may change Thursday as four bills make their way to Senate subcommittees. Senators are expected to debate S. 83 and S. 457, two so-called "personhood" bills sponsored by state Sen. Lee Bright, R-Spartanburg. They define life as beginning at fertilization. That premise has been struck down by federal courts, but anti-abortion advocates say a new challenge is necessary.
S. 204, also sponsored by Bright, would require that those who perform abortions to develop a legal relationship with a local hospital known as "admitting privileges." It also makes abortion providers - many of whom are family doctors - seek an additional medical certification.
Pro-choice advocates say those are unnecessary hurdles for abortion providers. A version of the admitting privileges bill drew attention in Texas when state Rep. Wendy Davis staged an 11-hour filibuster in an effort to delay the bill. It eventually passed, and has effectively closed two out of three abortion clinics in the state, health experts say.
A fourth bill, S. 527 is the "pregnant woman's protection act," sponsored by Sen. Katrina Shealy, R-Lexington. It would essentially establish a "stand your ground" law for pregnant women that says "a pregnant woman is justified in using physical force or deadly physical force" if she feels threatened. Women's health advocates worry that the bill's language includes the definition of an unborn child as a person, which they say could be legally problematic and outlaw abortion, even though that's not the main thrust of the bill.
Shealy, South Carolina's only female senator, said that her bill is meant as a "statement" because of South Carolina's severe problem with crimes against women. She said that she wasn't aware the bill would be construed as an anti-abortion bill, but it's a position she agrees with.
"It's more to bring out the fact that women are more subject to crimes than men are," she said of the bill. She acknowledges pregnant women are already allowed under existing law to stand up to their attackers.
Pro-choice and women's health advocates say that all three measures are problematic and could have wide-ranging consequences beyond preventing abortion. Access to birth control, fertility treatments and treating pregnant women in an emergency could all be affected for the worse, they say. "It would have far reaching consequences and create . a whole range of issues that really have nothing to do with abortion but have to do with medical treatments," said Victoria Middleton, the executive director of the American Civil Liberties Union of South Carolina.
Bright, who is running for U.S. Senate, said that he has been trying to get hearings on the anti-abortion measures for years. While all of them landing on the same day is likely a coincidence, he said pressure from anti-abortion groups and pastors has pushed Senate leaders to schedule hearings.
Efforts that would declare an unborn child a person have failed 16 years in a row and never had a hearing in the Senate, Bright said.
"It's murder," Bright said of abortion. "You would think that this country would preserve the innocent."
Bright and others say that legislators have seen what has worked to prevent abortion in other states, including Texas, and hope to replicate those efforts here.
Pastor Kevin Baird of Legacy Church in Charleston said he's also seen more energy around the anti-abortion movement in recent years. Technology and science have yielded a better understanding of the unborn child, and many younger Americans are beginning to get more involved in the anti-abortion movement as a result, he said.
Baird, who plans to testify Thursday, said that 7,000 "South Carolinians died last year" due to abortion. "Who speaks for them?" Baird asked. "They are not a voting bloc. None of them are going to go up to the subcommittee and give testimony. They have no recourse or appeal considering their sentences. They are at our mercy."
The anti-abortion bill that has the best chance of passing this year, lawmakers said, is a ban of 20-week abortions currently being considered by the House. Those late-term abortions are rare and account for less than 1 percent of all abortions. Women's health advocates fear that, if the bill is passed, doctors may decide not to abort pregnancies even if it is the appropriate medical decision.
But because no South Carolina abortion clinics perform 20-week abortions, anti-abortion advocates say the bill would have little effect. "For many of us in the pro-life movement, we're scratching our heads," Baird said. "This addresses what - maybe zero to some anomaly? Then we feel like we have a victory?"
Sen. Brad Hutto, D-Orangeburg, said the bills don't have much of a chance and are a waste of time. "Republicans do not like women," he said. "I trust the women of South Carolina to be able to make decisions about their bodies, about themselves, about their lives. I don't see a group of old men in the Senate trying to toy with the healthcare of women. That is best left to them and their doctors."
Reach Jeremy Borden at 708-5837 or on Twitter @Jeremy_Borden.


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One year ago, seaside port city Charleston shocked not only Holy City residents, but the entire world when it landed on top of a list that deemed it the No. 1 tourist destination on the planet.
That came a year after the Holy City topped the list issued annually and voted on by readers of Conde Nast Traveler magazine as the top tourist destination in America.
Where will the city steeped in history with baskets of local charm and great dining rank this year in the magazine's report?
We will find out this week.
The rankings usually come out in mid-October. A little bird tells me this year will be no different. The little bird didn't know where Charleston would land this year or wouldn't say, but it's likely the city will be near the top, if not at the top.
After all, where do you go after being named the No. 1 place for tourists to visit in the entire universe, or at least that part reachable by car or airplane? It's hard to beat No. 1 in the world. From there, you either stay where you are or drop down the list.
Will there be a repeat? Will the city still be able to proclaim, "We're No. 1!"? Or will Charleston slip a notch or two? And if it does, what does it really mean?
The city hasn't changed much since last year.
It still offers horse-drawn carriage rides past historic old homes. It still offers shrimp and grits in different, delicious recipes at innumerable fine dining establishments across town. It still offers heaping helpings of friendliness and Southern charm difficult to duplicate elsewhere on the globe. It still offers access to nearby plantations where moss-draped oaks and dirt lanes hark back to the past. It's still the place where the Late Unpleasantness began, a tourist draw no matter what.
If there is a change in the city, it's the long-stalled development finally accelerating on the upper peninsula. Construction cranes sit where dilapidated, vacant buildings once blighted the landscape. Scaffolding lines many storefronts in the commercial district, an indication of progress, an infusion of capital, and a stamp of confidence in the local economy's long-term health.
Those are all good things.
So no matter where Charleston lands on this year's ranking, the Holy City will always be No. 1 in the eyes of many of those in the Lowcountry who are fortunate enough to experience it every day.
Reach Warren L. Wise at 937-5524 or twitter.com/warrenlancewise.


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Closed Captioned
Laura Nelkin is back with a wonderful addition to your knitting: Beads! You'll take a look at the three projects you'll make in this class and learn about the Craftsy platform.
Get help choosing the best beads and yarn for your projects. Then learn three techniques for placing beads. You'll be introduced to nupps and how to fix mistakes.
Learn to knit a fashionable cuff bracelet! Practice your new bead knitting skills as you begin this small project.
In this lesson, you'll finish the Pioneer Cuff, changing it from a flat piece of knitting into a bracelet. Bind off, block and add clasps to your cuff.
Learn the basics of choosing yarn and beads, and work up a swatch, which is an important element of any lace project. Laura designed the Accola shawl just for this class.
Now that you have the basics down, begin knitting the Accola. Follow along with Laura row by row as the lace pattern develops. Complete lace charts are included.
Create the border and learn to shape the shawl's center panel. Laura shares tips on how to keep track of your place in the pattern and how to pick up stitches.
Time to unzip your provisional cast-on and add the top edging and other finishing touches. Laura also reviews blocking, an important step in any lace project.
The lovely Clarus shawl is a familiar favorite to Laura's students in Mastering Lace Shawls. You'll learn how to add beads to this included pattern.
Once you know how to knit with beads, you'll want to add beaded touches to your other projects. Laura demonstrates on the feather-and-fan and leaf stitch patterns.
I took this class to add an extra element into my knitting and found out that it was so much more! The class is great, the patterns are beautiful, and the teacher is wonderful!
Not only is Laura Nelkin full of knitterly wisdom, but she freely shares it with those in the class. Hints and tips that are very helpful are sprinkled throughout the lessons.
- capitalK


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word describing something hitting the floor and spreading itself everywhere
the gobstoppers hit the floor and just went BOOSH all over the place
автор: the gonj bombers 1 сентября 2008
Diss; insult.
You god boosh'd!
автор: Tony R 15 февраля 2004
A portmanteau of "bitch" and "douche". It is used alternately to describe either men or women as bitches and/or douches. Derived from a certain individual's surname from a particular boarding school.
A: "I really don't like that new girl. Doesn't she make you think of you-know-who?"
B: "Yeah, I know; she's such a freaken boosh."
B: "Yeah, I know; she's such a freaken boosh."
автор: IsurvivedTHAThighschool 12 июня 2008
A person who talks in a self pitying way
My dad was a boosh when he complained about having to do all the work around the house after a long day at work.
автор: Word Doctor III 20 мая 2015


text: Brand: Organic Tagua Jewelry Style: LI-LC203 Sizes: One Size Fabric Content: NA Organic Tagua Jewelry Riverstone Handcrafted Carved And Polished Statement Necklace And Earring Set Style LC203 In Color Limon. The River Stones tagua necklace set illustrates the power of subtle earthy beauty. Featuring smooth, flat tagua slices handwoven together to make this elegant set. Secured by a toggle clasp, River Stones are designed to rest comfortably on the collarbone (approx. 18 inches -20 inches in). Available in all grain and polished colors and combo colors shown. Tagua (ta gwah). All of our Organic Tagua Jewelry are handcrafted from a palm tree nut native to the lush tropical rainforests of Ecuador. Also referred to as the Ecuadorean Ivory Palm, the Tagua tree produces several bushels of seed pods a year with up to 100 Tagua nuts per pod. These nuts are then harvested, dried, and crafted into a wide range of products from vibrant modern jewelry, ornate figurines, to everyday items like shirt buttons. Also known as Vegetable Ivory, Tagua has the same appearance, density, and feel of animal ivory without doing any harm to any animals or the rainforests where it is gathered. All of our Organic Tagua Jewelry is handmade and dyed using high-grade certified organic vegetable dyes imported from Italy. Our collections offer a wide range of bracelets, rings, earrings, necklaces, figurines, and key chains. Due to the scarcity and uniqueness of each piece, no two pieces are exactly the same. Organic Tagua Jewelry mission is to promote the beautiful, eco-friendly, and 100 Percent sustainable Tagua Ivory around the world. By doing so, we empower the artisans creating the jewelry by providing reliable employment and a decent living wage.


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Systemwide Events Calendar
La StradaMarch 9, 8:00pm - 10:00pm
Manoa Campus, Prime Time in the Earle Ernst Lab Theatre
March 6, 7, 8, 9 at 8pm; March 10 at 2pm
Based on the film by Federico Fellini Stage adaptation by Tullio Pinelli and Bernardino Zapponi, translated by Josephine Calvo and Benjamin Sota
Directed by Benjamin Sota, MFA Directing Candidate
La Strada (The Road), set in 1940 Italy and translated from Federico Fellini's film masterpiece, will be an English language debut. The performance encapsulates feelings of a vagabond life on the road. Using mask, physical theatre, pantomime, street theatre, circus skills, and inspired by this amazing film, the production explores the range of human emotion.
Post-Show Rap: Fri March 8
Ticket Prices: $13 to $16; UH Mānoa
Students with valid ID: $5
Ticket Information
$13 to $16; UH Mānoa Students with valid ID: $5
Event Sponsor
Kennedy Theatre, Manoa Campus
More Information
956-7655, firstname.lastname@example.com, http://www.hawaii.edu/kennedy/
|Saturday, March 9
|The Wellness Center - Fitness Class Schedule
Maui Campus, Pilina Bldg., Wellness Center
|Volunteer to protect Oahu from plant invaders!
Manoa Campus, Lyon Arboretum
|Orchid Culture
Harold L. Lyon Arboretum 3860 Manoa Road Honolulu, HI 96822
|Free Commuter Cycling 101 Workshop
Eki Cyclery, 1603 Dillingham Blvd.
|La Strada
Manoa Campus, Prime Time in the Earle Ernst Lab Theatre
- Highlighted dates have scheduled events.
- Select the date to view all events for that day.
Ongoing Events
- Lineage : A Family Tree of Printmakers
- The White Rose : nonviolent resistance against the Nazi regime
- Arts Exhibition: Ainu Treasures: A Living Tradition in Northern Japan
- Biggest Loser Challenge
- Phoebe Cummings: Cella
- L. Stephen Lau Water Research Endowed Scholarship 2013
- 11th Annual Temple Emanu-El Kirk Cashmere Jewish Film Festival
- Uehiro Graduate Philosophy Conference


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Deputies in Brevard County want to find the man who robbed a Chevron gas station's convenience store in Melbourne.
Deputies said a man wearing a grey shirt, blue jeans, and a black baseball cap with the word "Chicago" strong-armed a clerk out of cash and lottery tickets. The robbery happened Saturday night.
The robber never implied he had a weapon, but he physically confronted the clerk and stole his wallet as well.
The culprit is anywhere from 5'9" to 6' tall and weighs about 170 pounds, according to deputies.
Anyone with information in this case should call Crimeline at 1-800-423-TIPS.
Breaking news photos on u local


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adj. 1. One who frags you without you knowing. 2. Provider of lumber and undead minions. 3. see fraggin bastich
LoBo fraged me. I never saw him coming.
dodane przez Webster kwiecień 11, 2003
Trending Now
Can you define these popular missing words?
Top Definition
The Main Man
Lobo is often depicted ruining people's shit
dodane przez Esch8 marzec 14, 2003
a wolf, timber wolf in spanish
The lobo resembled a wolf.
dodane przez Alicia P. maj 07, 2003
Adjective describing guys who use shady and sometimes creepy techniques to pick-up girls at bars. For example, inviting one girl to a giant "afterparty" at the guy's apartment upon the bar's closure, but not telling anyone else. Or stealing the girl's keys so she has to stop by the apartment to pick them up.
He invited me to an afterparty at his place, but then there was no one there but me and him. That's so lobo.
dodane przez Lobo24 październik 21, 2009
The most badass comic book character ever. Lobo is an alien who's always stomping peoples faces in on planet Eart.
Be sure to check out the Lobo Christmas edition comic book! He shows Santa who's boss!
dodane przez werwertwgg432 styczeń 17, 2005
A word used to describe someone stupid or retarded or just overall negative. Usually not used when trying to hurt people, more like a joke.
That guy is such a lobo.
dodane przez MS & JR czerwiec 23, 2009
The stank that you smell when you go down on bar skanks.
Low+ B.O.(Body Odor)
Low+ B.O.(Body Odor)
That chick had wicked lo-bo
dodane przez DjDjD lipiec 25, 2006


text:
- Flat Rate Shipping. Any Size Order! -
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Cheer on your Baltimore Ravens in this Chambray T-shirt from Antigua! Take your Baltimore Ravens style up a notch when you wear this classy button-up. It features an embroidered Baltimore Ravens logo and two chest pockets. It's time for other Baltimore Ravens fans to rethink their team gear because you've just raised the Baltimore Ravens style bar.
- Material: 100% Cotton
- Rounded hems
- Embroidered graphic
- Button cuffs
- Two chest pockets
- Long sleeve
- Full-button front
- Machine wash, dry flat
- Officially licensed
- Imported
- Brand: Antigua
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Manufacturer direct items are shipped directly from the manufacturer. These items are not available for international or expedited shipping.
Customized items can be personalized with options such as your name, your favorite number, and/or designs. Some options may be limited by league rules.


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DELAND, Fla. – The Stetson University lacrosse team will be making its second straight appearance in the A-Sun Championship, as it takes on regular season champion Jacksonville in the A-Sun semifinals, Friday, May 2 at 1 p.m.
The Hatters (2-15, 2-3) were given a No. 4 seed and will be pitted against the top seeded Dolphins, who finished 2014 at 5-0 in the A-Sun and 12-5 overall. Stetson finished the regular season with an 18-8 victory over Howard, the second year in-a-row they defeated the Bison. SU and JU have met once before this season, a 24-8 victory for the Dolphins in DeLand and will be playing Stetson on its home field as Southern Oak Stadium in Jacksonville is site of the 2014 championship tournament.
Following the conclusion of its regular season, a half dozen Stetson players were given post-season honors from the A-Sun. Maylis Broderick and Mary Kate O'Sullivan both were named to the conference's All-Second Team and the Academic All-Conference Squad, while Amanda Parker and Danielle Horgan earned a spot on the conference's All-First Team. Lindsay Summers garnered A-Sun All-Freshman Team honors, while Caili Guilday was one of two unanimous choices for A-Sun Academic All-Conference.
In the other semifinals match-up, No. 2 seeded Elon takes on No. 3 Detroit, with the winner to advance to the A-Sun Championship Final, scheduled for Sunday, May 4 at 12 p.m.
Last season, the Hatters were ranked third in the conference and took on No. 2 Detroit in the semifinals, where they were defeated 21-7 by a Titans team that eventually lost to JU in the title game.
In terms of statistics, Horgan finished the regular season tops on the team in points (31) and assists (12), while Christina Loya scored the most goals, with her 22. Guilday led the team and the nation in saves (197), saves per game average (11.65) as well as ground balls (65), and Summers won the most draw controls with her 39.
For those fans making the trip to Jacksonville, tickets are just $5 per contest and students can get in free with a valid school ID. Live stats will be available for those not in attendance via gohatters.com and video of the contest will be streamed on ASunTV. The @StetsonLacrosse Twitter feed and Hat-Alerts will also be available for in-game updates as well.


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Wall Street Decline Takes Its Toll...
As Immunotherapy Revolutionizes the Cancer Treatment...
NSCLC is "Major Battlefield" as Merck,...
LC-MS Gains Favor Due To the...
Membrane drug transporters have been identified as a determinant of drug disposition in the body, potentially affecting absorption, pharmacokinetics, drug-drug interactions, and safety profiles. The major efflux transporters of the ABC family, including P-glycoprotein (P-gp, ABCB1, MDR1 gene), BCRP (ABCG2), and MRP2 (ABCC2), are localized to barrier tissues of the body such as intestine, liver, kidney, blood-brain barrier, and placenta, where they efflux a wide range of xenobiotics and chemicals such as statins, macrolide antibiotics, angiotensin blockers, and chemotherapeutic agents, affecting exposure and clearance in vivo.
Recently, the FDA and EMA have issued recommendations and guidelines for drug transporter studies in the pharmaceutical and biotech industries. New chemical entities are now routinely screened for potential transporter recognition and impact; interaction at clinical concentrations may indicate additional clinical trials during drug development.
Current cell-based transporter studies may involve cell lines such as Caco-2 intestinal enterocytes that express multiple transporters, requiring the use of transporter-specific substrates or inhibitors. However, substrates are often recognized by multiple transporters at different affinities, and the specificity of inhibitors is often uncertain or unknown, leading to mistaken interpretations of transporter interaction.
Utilizing CompoZr® zinc finger nucleases (ZFNs) from Sigma® Life Science, MDR1, BCRP, and MRP2 efflux transporter genes were targeted for ZFN-mediated knockout in a Caco-2 cell line. The resultant panel of single and double knockout cells show disruption of gene sequence as well as complete loss of transporter function in bidirectional transport assays to at least 40 passages post ZFN genomic-modification.
In this article, we describe the functional characterization of these cells using a set of industry-standard compounds targeting single transporters, as well as compounds displaying overlapping transporter specificity. These novel cells are powerful tools to elucidate transporter interactions without dependence on chemical inhibitors and clarify the potential impact of specific efflux transporters in drug disposition.
Cell Culture: Caco-2 subclone C2BBe1cells were obtained from ATCC and cultured in DMEM High Glucose with 10% Fetal Bovine Serum, sodium pyruvate, non-essential amino acids, L-Glutamine, and Pen/Strep. Medium was changed every 2−3 days. Cells were passaged at least once/week.
Cell Line Modification: The CompoZr protocol for cell-line modification was used to deliver ZFN pairs into the C2BBe1 cells by nucleofection. Viable cells were single -cell sorted by flow cytometry and resultant colonies were tested for mutations. Genomic DNA was amplified using ZFN Cel 1 primers followed by PCR on target regions using nested primers. DNA sequence of the target regions was analyzed to confirm gene disruption through deletion or insertion.
Bidirectional Transport Assay: C2BBe1 cells (wildtype (WT), or knockout (KO)) were cultured on 24-well Costar Transwell® plates for 20−22 days. Apical and basolateral chambers were rinsed twice and then pre-incubated at 37ºC for 30−60 min with Transport Buffer (HBSS, 25 mM glucose, 10 mM HEPES, pH 7.4). Test articles at 5 μM in Transport Buffer were added to donor chambers with fresh transport buffer added to opposite chambers. Plates were incubated at 37ºC for 2 h. Samples from both donor and receiver chambers were quantified for test articles by LC-MS/MS or fluorescence. Lucifer yellow (LY) permeability was examined post-assay to confirm monolayer integrity.
Analysis by LC-MS/MS: Concentration of test articles in donor and receiver chamber samples were analyzed by LC-MS/MS using an API-4000 Q Trap mass spectrometer with a Turbo V atmospheric pressure electrospray ionization source (AB SCIEX). Samples (40 μL) were injected onto a Fortis C8 column (2.1 × 50 mm, 5 μm) and eluted by a mobile-phase gradient specific for each test article (mobile phase A: 4 mM ammonium formate; mobile phase B: 4 mM ammonium formate in 90% (v/v) acetonitrile). Flow rate was 0.5 mL/min. MS conditions: positive or negative ionization mode (4.5 kV spray voltage); source temperature of 450ºC with multiple reaction monitoring specific for each analyte and internal standard (tolbutamide) parent-product ion pairs. Peak areas of analyte, and internal standard and resulting ratios were quantified using Analyst 1.5 (AB SCIEX).
Analysis of CDCF by Fluorescence: The nonfluorescent 5(6)-carboxy-2',7'-dichlorofluorescein-diacetate (CDCFDA) is taken up by passive diffusion into Caco-2 cells, where it undergoes hydrolysis to fluorescent CDCF. The fluorescent compound CDCF is then effluxed by MRP2. The receiver samples or fully hydrolyzed donor samples were quantified by fluorescence at 485 nm emission, 538 nm excitation, and compared to linear standard curves of CDCF to determine concentration.
Efflux Ratio (ER) Calculations: The apparent permeability (Papp, cm/sec) of test articles were determined for both Apical → Basolateral (A-B) and Basolateral → Apical (B-A) directions in the bidirectional transport assays. The efflux ratio (ER) was determined from:
ER = Papp B-A/Papp A-B
whereby an ER greater than 2 indicates an active transport process and a reduced ER to <2 in KO cell lines identifies test article as substrate to lost transporter.
Polarized transport in C2BBe1 (WT) and MDR1, BCRP, or MRP2 single and double knockout (KO) cell lines was measured in Transwell® bidirectional transport assays using probe substrates at 5 μM for 2 hr at 37 ºC. Contents of both chambers were quantitated using LC-MS/MS, and permeability and efflux ratios (ER) were calculated.
The ERs for MDR1 substrates, digoxin and erythromycin, were reduced to 1.4 and 1.04 in the MDR1 KO cells from 17.7 and 16.8 in the WT cells, respectively (Figure 1). The ER for the MRP2 substrate, 5(6)-carboxy-2',7'-dichlorofluorescein was reduced to 1.92 in the MRP2 KO from 30.0 in the WT cells (Figure 2).
ERs for BCRP substrates, estrone 3-sulfate and nitrofurantoin, were reduced to 1.76 and 1.68 in the BCRP KO cells from 22.7 and 13.2 in the WT, respectively (Figure 3). Double knockout cell lines (MDR1/BCRP KO, MDR1/MRP2 KO, and MRP2/BCRP KO) were used to identify substrates of multiple transporters. Cimetidine was confirmed as a substrate of both MDR1 and BCRP demonstrating an ER of 0.97 using the MDR1/BCRP KO cell line and ERs of >2 for all other cell lines (data not shown).
We have generated stable MDR1, BCRP, and MRP2 single and double knockout Caco-2 cell lines using CompoZr ZFN technology. The transporter KO cell lines show disrupted DNA sequence due to ZFN activity and loss of transporter function using specific substrates in the bidirectional transport assay format.
These novel knockout cell lines can identify specific transporters by comparison of transport between the WT and the KO cell lines. Digoxin and erythromycin, estrone 3-sulfate and nitrofurantoin, and CDCF were confirmed as substrates of MDR1, BCRP, and MRP2, respectively, using the single and double KO cell lines. Cimetidine was identified as a substrate of both MDR1 and BCRP in the MDR1/BCRP KO cell line.
With regulatory agencies placing greater scrutiny on identifying drug-transporter interactions, these innovative, predictive transporter KO cell lines can clarify complex drug-transporter interactions, revealing previously unidentified transporter involvement. Sigma's transporter KO cell lines are becoming a valuable tool for application in drug discovery transporter interaction assessment without dependence on the uncertainties of chemical inhibition specificities.
Kathleen E. Sampson is a senior scientist and Michael D. Mitchell ([email protected]) is a product manager of ADMETox at Sigma Life Science.
Kathleen E. Sampson is a senior scientist and Michael D. Mitchell ([email protected]) is a product manager of ADMETox at Sigma Life Science.
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Director: Ian Judge; Designer: Mark Thompson; Opening Date: 25 April 1990, Royal Shakespeare Theatre.
"Against a background of blue sky and fluffy white clouds, Mark Thompson's set features a series of doors, so beloved by farceurs, receding in crazy perspective. A huge porcupine, a centaur and a bottle of patent medicine are zanily suspended above the actors who are clad in Day-Glo costumes." Charles Spencer, Daily Telegraph, 27 April 1990
This production affected the casual, improvisational style and stereotypes of the Italian commedia dell'arte street theatre. HMR
Photographer: Donald Cooper. Courtesy of AHDS.


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Guidelines for Public Service Fellowships recommenders:
Thank you for writing a letter of recommendation for the Public Service Fellowship program at the Priscilla King Gray Public Service Center (PKG Center). Each year about 50 MIT students receive funding for Public Service Fellowships to help communities and service organizations build their capacity to be effective.
Our selection process relies heavily on informed, candid evaluations such as yours. Please help us to determine if the student is likely to complete the project successfully and safely. All responses will be treated confidentially and used solely for the Fellowship selection process.
If at all possible, please read a draft of the student's Fellowship application before writing your recommendation. Otherwise, please meet with the student to discuss the project details. We ask that you provide the selection committee with a letter of recommendation of no more than two pages. Either write your recommendation in the body of an email or attach a Word document. No PDFs, please. Be sure to include the following basic information:
Feel free to comment on the student's project as you wish. However, some important criteria to bear in mind are the student's:
Specific examples from your own interactions with the applicant are helpful. If there are skills that the student may need to develop in order to make a success of the project, please let us know – we may be able to help.
Email your recommendation to email@example.com by October 23. Please do not send a PDF attachment (Word documents or simple emails are fine). If you know that you will not be able to meet that deadline, email email@example.com and let us know when to expect your letter. However, it is in the student's best interest for you to submit your recommendation on time.
If you have any questions, call or email Alison Hynd 617.258.0691, email@example.com
Thank you for your help in this selection process.


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At least one seat on the Seneca County Board of Commissioners will include a new face.
According to unofficial results of Tuesday's Republican primary elections, Holly Stacy received 5,202 votes, about 65 percent, for the county commissioner seat with the term beginning Jan. 2, 2013. The seat is held by Dave Sauber, who received 2,698 votes.
Stacy has been president and CEO of the Sandusky County Chamber of Commerce since 2003, served on the Old Fort School Board and worked for the Ohio Department of Transportation and the Toledo-Lucas County Port Authority.
"I want to give a big thank you to all the supporters and voters for their confidence," Stacy said. "I really look forward to continuing the campaign and getting to meet more people in the county. We'll still be working until November."
Stacy also ran for a seat on the board in 2008 after being appointed by county Republicans. She lost to Ben Nutter.
In her campaign, Stacy said she plans to build on her experience in the business community and work with job creators to bring new employment opportunities to the county, as well as take a conservative approach to budget issues.
She plans to end her employment with all paid positions if elected in November.
Sauber, who received 35 percent of the vote according to unofficial results, has served on the board for two terms.
"I'm just very proud of what I accomplished over the past eight years," Sauber said, adding the work done by the board during his tenure was overshadowed by issues surrounding the demolition of the 1884 courthouse.
Sauber thanked those who supported him throughout his tenure and said he looks forward to continuing work on county projects such as the new juvenile detention center, a SCAT construction project and a new county court facility as he continues to serve through December.
He said he may consider a run for political office in the future.
Stacy may face independent Paul Shoemaker in the November election.
The Seneca County Board of Elections has not certified petitions submitted by Shoemaker, owner of Shooey's Cool Creations and a county employee.


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Average Ratings
3 out of 5 people recommended this car.
Consumer Reviews
Best 12K car I've ever owned!
by Farmerandre from Florissant, Missouri | January 9, 2011
We bought a 96 LX for 12,000 dollars and kept it for 12 years and put 162,000 miles on it and never spent a dime over basic maintenance. That engine was as smooth at 162K as it was at 162 miles. With the 5-speed manual, we averaged in the low 40's on long trips and averaged mid 30's in city driving. It had a large trunk and a big backseat. It was the 3rd of 5 Mazda's that we have owned. I currently drive a 07 Mazda3 that is also a great car!
Purchased a new car
Uses car for Commuting
Does recommend this car
'96 Protege LX
by MazdaSpeed from Santa Rosa, CA | January 1, 2010
This little car has everything you need for a student, commuter, or small family car. I use it for all of the above and there is plenty of room for my kids two car seats in the back and the trunk holds alot for a car it's size. Mine has power everything and has had very few problems since it was new. Got a good deal out of a neighbor who bought it new and would tell anyone looking at similar small four door sedans to look no further.
Purchased a new car
Uses car for Commuting
Does recommend this car
96'Protege ES
by PatDaddyT from Wisconsin | July 10, 2009
This car has most options for the year Alloy wheels,Sunroof and 4 Wheel ABS. For how small the engine is this car should get better MPG All it gets is about 21-23 MPG Combined.
Purchased a new car
Uses car for Work
Does not recommend this car
Great Car
by Commuter in the south from Cullman, AL | February 3, 2009
I bought my Protege new. I currently have 260K miles and have done almost no work on it. I replaced the factory brakes at 150K and the belts at 210K. Aside from tires and oil changes, I have done no other work. While it is not the greatest ride, it gets great gas milage. Only problem I have had is that the cruise control has not worked in 7 years. Overall a great car for the price.
Purchased a new car
Uses car for Commuting
Does recommend this car
96 Protege DX
by zoom zoom zoom from North Andover, MA | May 25, 2006
Very basic car that gets good gas mileage. Almost no special features. A little speed, very slow acceleration. Not very well engineered. The kind of car that you are lucky to get 100k miles out of. Not recommeded that you spend over $3,000 on one of these.
Purchased a new car
Uses car for N/A
Does not recommend this car
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text: GMAX is extremely excited to introduce the all new GM 11D ADULT dual sport helmet series. This all new GMAX dual sport helmet is truly an all season sport helmet. The 11D Helmet is loaded with features and designs normally found on others highly priced helmets, but delivered to you at a true GMAX competitive value.


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This section on health in the EU has been created as a trustworthy gateway to a wide range of information and data on health-related issues and activities at both European, national and international level. The content is produced by the European Commission, the Member States of the EU and the European Economic Area (EEA), plus EU candidate countries; by international organisations; and by pan-European non-governmental organisations in the area of public health.
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Further questions can be answered through the Contact page. The Health-EU portal supports principles and measures to increase the credibility of information on the net. It complies with the HONcode standard for trustworthy health information: verify here.


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Danger of overregulating fracking
Editor's note: The op-ed was written by William F. Shughart, J. Fish Smith Professor in Public Choice at Utah State University. In addition to running in the Deseret News it was also picked up by several other newspapers across the country, including the Arizona Daily Star, the Yakima Herald-Republic, the Gainesville Times in Georgia, and the Duluth News Tribune in Minnesota.
Danger of overregulating fracking
The Hill
By William F. Shughart II
The emergence of hydraulic fracturing to recover oil and natural gas generally is seen as an economic success story. It has vaulted the United States into the ranks of the world's top oil and gas producers and led to a manufacturing renaissance whose effects few could have foreseen at the start of the 1990s.
A dozen years ago, shale gas amounted to only 2 percent of total domestic gas production. Today, it is 40 percent and rising. Natural gas is in such ample supply that its price is one-third to one-half less here than what it fetches in Europe or Asia.


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The Jackson family, including Michael Jackson's parents Joe and Katherine and the late pop star's three young children, have gathered at the parents' home in Encino, Calif.
Earlier in the day, Janet Jackson, who is in pre-production on a film project in Atlanta, had flown into the Van Nuys airport to be with her family. "Janet Jackson is grief-stricken and devastated at the sudden loss of her brother," her manager, Kenneth Crear, said in a statment released to the press. Eyewitnesses also reported that the Rev. Jesse Jackson paid a visit to the Jackson house in Encino.
As for Michael Jackson's children, Prince Michael, 12, Paris, 11, and "Blanket," 7, "The kids are outside playing. Both Joe and Katherine are taking care of them right now," according a source close to the family. "The kids haven't spent a lot of time with Michael's family, so they are just now getting to know all the cousins and other family members."
Get more Jackson coverage on CNN.com
Jackson Family Gathers at Parents' House
Arnold Turner/ATA/Getty


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In the wake of a tragedy, it's common for pundits to talk about sports as an escape.
After Sept. 11, the people of New York had their spirits lifted by the New York Yankees' World Series run in 2001. After Hurricane Katrina, the Saints' emergence as a playoff football team was seen as a galvanizing force for a battered community.
But what happens when tragedy occurs in the middle of a sporting event?
We found out earlier this week, when bombs went off at the Boston Marathon. Several people lost their lives, while more suffered serious injuries. Certainly, our thoughts remain with the victims and their families, as well as the victims of the accident in West, Texas.
Moving forward, there's plenty to think about.
Suddenly, a sporting event wasn't a fun distraction from daily life. It was the setting for an attack.
On Friday night, Baltimore Ravens defensive coordinator Dean Pees was in Bloomdale for a dinner at Elmwood High School. Pees, who coached Elmwood's football program for four years in the 1970s, has been to the top of his profession, working in three Super Bowls. For six seasons, he worked as an assistant under Bill Belichick with the New England Patriots.
He said he maintains deep connections to the Boston area; one of his daughters still lives there.
"I've always thought, at any of those events, that might be where the next (terrorist attack) might happen, whether it be a Super Bowl, whether it be a championship game of any kind," Pees said. "You never know."
In truth, big time sporting events are a concern. There just aren't many things in our culture that can attract thousands of people in such a small space. Big stadiums could be a target for this reason. Equally, while security at sporting events has increased over the years, it's not like the airport. It can't be, with the masses of people filing through in a short period of time.
This column isn't meant to scare, but it is to make a pair of important points. First off, while sporting events allow us to act differently than we might any day of the week, they don't - they can't - provide a complete break from the world.
At the same time, fear of an attack shouldn't stop us from attending big events. Pees said it best Friday.
"You can't live your life running scared," Pees said. "You've just got to do what you do, and you don't really think about it, unfortunately, until usually after it happens."
It's a balance.
It's also a reminder.
For all the normalcy sporting events can provide in the wake of a tragedy, they are not immune to tragedy.


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First Data™ FD-35 Pin Pad
The First Data™ FD35 device goes beyond the simple PIN pad. This comprehensive, consumer-facing device not only accepts PIN-based debit transactions and swipes traditional payment cards, it is enabled to accept chip-and-PIN cards (aka EMV), which allow customers to initiate and process their own transactions without relinquishing control of their cards. It also enables contactless transactions, as well as mobile phone payments that include the ability for merchants to drive loyalty and repeat business by generating and redeeming special offers via consumers' mobile phones.
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I just joined the board, so I thought I would give a wave general wave of "Hello".
I had my first child, a son, in March 2013. My husband signed up for the emails when I was pregnant and I never realized this forum was here. But, I'm here now!
I used to be on the Etsy forums and teams before my son was born, so I know some of the lingo and etiquette for Etsy, but not here. Just browsing some posts on the first page here I already don't know a few terms, but I'll get the hang of it. I was on TheKnot eons ago so I think some of the abbreviations are the same.
Anyway- that's me. I like to cook, I am kind of a geek, and I look forward to learning from you all!


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Gracie's jumping technique is stunning when it works. Sadly I'm pretty sure Korpi just won this.
Gracie's jumping technique is stunning when it works. Sadly I'm pretty sure Korpi just won this.
Gracie GOLD (USA)
Music: Life is Beautiful (soundtrack) by Nicola Piovani
Blue strapless dress. Silver sparkle at neckline.
3Lz+3T - nice!
3F - turnout
2Lo - twofoot
Some mistakes... I don't think it's enough for gold. 4 triples, only 3 clean
Korpi has a lot of qualities. Her spins and steps are really good. She has very clean lines. She's artistically mature. I don't get shocked with her scores at all.
I think Korpi's got the gold, but Gracie didn't crumble and should be on the podium.
112.87 (SB), total 175.03 (PB) and Silver for GOLD
Just as a side note... while Kiira is pretty, I don't get why everyones so much into her looks.
If anyone, I think Gracie should be getting the beauty PCS... she's so, so stunning!!
now another screw over in my prediction list Kiira winning , I wanted Gracie
Congratulations to all the medalists!
Very close. If Gracie had skated clean she would have had the top spot. But a good confidence-builder for her as well as a silver medal. She belongs in seniors and can swing with the big girls.
I'm OK with that. Gracie left out two key jumps, and I'm sure she still got an edge call on her 3Fs, which cost her some +GOE. This is a good competition to build on for nationals.
I do agree with Korpi winning the long but surely she should have been further behind enough for it to still have Gracie in first overall?
OMG - Korpi won! Overmarked, but did enough to win. Too many mistakes from Gracie, but a huge improvement on Skate Canada for her
Murakami deserved third
Last edited by Mao88; 11-10-2012 at 06:38 AM.
I don't get the Kiira hate. She won both on TES and PCS. Landed 5 clean triples, including 3Lz and 3Flip. Gracie had mistakes as well, doubled 2 jumpsm it's not like she skated clean
Sotnikova now has lost to Wagner. Gao, gold and zawadzki. Wow. I am very interested in finding out what is wrong with her.


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At Cedars-Sinai, we are passionate about meeting our community's most significant health needs in ways that ensure the greatest possible benefit for decades, and generations, to come. That's why we are so firmly committed to providing community health services that work to prevent and manage serious conditions like diabetes and heart disease, while promoting health and wellness.
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Top Definition
Dudes that happen to be gay, but aren't flamboyant at all. Prefer to go drink beer at a buddy's place, rather than go to the gay bar and pay for overpriced cocktails and listen to bouncy, campy club songs.
A bromo is not conceited in his looks, but is still put together decently, groomed but not over plucked.
Not to be confused by bromance.
A bromo is not conceited in his looks, but is still put together decently, groomed but not over plucked.
Not to be confused by bromance.
i.e., I really like my guy to be a bromo, not overly gay, but gay just where it counts.
by brosephstalin8 October 02, 2011
Trending Now
Can you define these popular missing words?
A homosexual friend who is also your bro.
Ryan: Mike is sooooo gay, man.
Alex: I don't give a fuck man, that kid is my bromo!
Alex: I don't give a fuck man, that kid is my bromo!
by $moak$takk November 11, 2011
Derives from combing the two words "Homo" and "Brother". Shares similar characteristics from it's origin; as in a close guy friend who sometimes comes off as being homo.
Mike has known Todd nearly all his life and the two have endured a lot of experiences together. They really must be Bromos.
by Ted241 February 27, 2007
A gay male who can commonly be found with bro types.
bro, whenever i go out, i always bring my bro mo—he's a designated wingman
by j-beat January 22, 2010
Front man for the classic alternative psychedelic rock band Bromo and the Scrub Babies. Sometimes he spells his name "Bromö." There was some concern that other Urban Dictionary definitions for "bromo" were causing confusion among his fans.
You rock, Bromo!
by pseudopoz April 22, 2013
The gay Brother(s) within a Fraternal group.
yeah Steve's my bromo, we're both ΣΩΤs.
by FraternalBromo April 22, 2013
When a straight man enjoys having gay sex with another man but is still straight in every other sense.
Tim is very much a bromo - he loves women but he likes being f--d by guys too.
by TheDefinity September 18, 2015


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Origin: United States


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Top Giving Foundations: NJ
The following list of top giving foundations in NJ is derived from The Grantsmanship Center's funding databases. All of the foundations listed have been prescreened to ensure that they have a staff, issue RFPs, or otherwise indicate an interest in receiving proposals. This also means that some foundations who give large amounts of money have been omitted because they do not meet these qualifications. A maximum of forty foundations is listed for each state.
More detailed information about these foundations, including their program areas, types of funding, application procedures, and more can be found on GrantDomain, The Grantsmanship Center's exclusive online database of funding information.
The top giving foundations in the state of NJ


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The Hib vaccine prevents Hib disease. This illness can be severe and life-threatening. The illness:
Immunization - Hib; Vaccine - Haemophilus influenzae type b conjugate
Hib vaccine is made from smaller pieces of the whole Hib bacterium. After getting the vaccine, the body learns to attack Hib bacteria if the person is exposed to it. As a result, the person will probably not get sick with infections caused by the bacteria.
Hib vaccine is one of the recommended childhood vaccines. Many states require proof that a child has received the vaccine before starting day care or preschool.
Two vaccine brands are available. Depending on which brand is given, infants and toddlers should get three or four doses (shots) total. One dose should be received at each of the following ages:
Hib can be given as a shot by itself. Or it can be combined with other vaccines and given as a single injection. Your health care provider can tell you if the combined vaccine is right for your child.
Children older than 5 and adults do not need to get Hib vaccine unless they have certain medical conditions. These conditions include HIV, sickle cell disease, among others. Your health care provider can tell you if this applies to you or your child.
Most infants who get Hib vaccine have no problems from it. Others may have mild problems such as soreness and redness where the shot was given or a low fever. Serious problems from the vaccine are rare and are mainly due to allergic reactions to parts of the vaccine.
There is no proof that links Hib vaccine to the development of autism.
No vaccine works all of the time. It is possible, though unlikely, to get infections caused by Hib even after receiving all doses (shots) of the Hib vaccine.
Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices (ACIP) Recommended Immunization Schedules for Persons Aged 0 Through 18 Years and Adults Aged 19 Years and Older - United States, 2013. MMWR. 2013;62(Suppl1):1-19.
Centers for Disease Control and Prevention. Vaccine safety and adverse events. Available at http://www.cdc.gov/vaccines/vac-gen/safety/default.htm. Accessed April 19, 2013.
DeStefano F, Price CS, Weintraub ES. Increasing exposure to antibody-stimulating proteins and polysaccharides in vaccines is not associated with risk of autism. J Pediatr. 2013; DOI10.1016/j.peds.2013.02.001.
Institute of Medicine. Immunization Safety Review Committee. Immunization Safety Review: Vaccines and Autism. Washington, DC: The National Academies Press; 2004.
Orenstein WA, Atkinson WL. Immunization. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine. 24th ed. Philadelphia, PA: Elsevier Saunders; 2011:chap 17.
On a mission to heal body, mind and spirit


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Was it? Think about it from a business perspective. In less than 48 hours due to the hiring, the league has gone from the bad guy to the good guys who offered up a great compromise that the players must now agree to or else the players become the bad guys. Even though, you know, the proposal was not much different at all from the previous ones, they just reworded it, flipped a round some numbers, continued to try to "tweek" the definition of HRR, and got a great PR firm to spin the whole thing to make them look like heroes! Perception means a lot in business.
I agree with the others that said this whole thing is actually pretty genius.
they had been working on this proposal for quite a while. before that focus group stuff came out.


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