text:
Namco Museum Xbox
- Publisher: Namco
- Release Date: Oct 9, 2002
- Also On: PlayStation 2
User Score
No user score yet- Awaiting 1 more rating
User score distribution:
Positive: 3 out of 3
Mixed: 0 out of 3
Negative: 0 out of 3
Review this game
- User score
- By date
- Most helpful
RickF.Jan 3, 2003This rocks.
ErickL.Jan 3, 2003Buy it, you wont regret the money you pay for it. For crying out loud its $30. But not as good as Halo.
MikeJ.Nov 21, 2002The Pac-Man games in this package are great - especially the sound. My least favorite of the bunch is the 2 Pole Position titles - they're really dated and don't hold up. All-in-all, this is a really nice compilation. Only wish they had included Space Invaders.
Awards & Rankings
#93 Most Discussed Xbox Game of 2002
#15 Most Shared Xbox Game of 2002
One element I thought was pretty nifty was the fact that the screen displays each game exactly as it first appeared. What this means is you can look to the right side of the screen while playing Dig-Dug and see your score grow and post. I know it's a little thing, but really- it does help the game feel more like you're playing an actual arcade machine than a home television.
A collection of Namco's most popular arcade games from the decade of big hair, and valley-speak, is now available on your Xbox video entertainment system (Like, totally!).


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Take Our Daughters and Sons to Work Day
April 28, 2016 from 8:00am-12:00pm
USF Tampa will host its 8th annual "Take Our Daughters and Sons to Work Day" event on Thursday, April 28, 2016 from 8:00 am-12:00 pm. The event is designed to provide the children (ages 8 – 18) of USF faculty and staff employees with an opportunity to explore career options and expand their image of all the possibilities associated with a balanced work and family life. They will have an opportunity to see different career possibilities and interact and engage with professionals in various positions. The event will begin in the Marshall Student Center Ballroom, and will include two workshops designed to showcase careers in different fields.
The registration deadline has passed; we cannot accept additional registrations.
Information for Parents with Registrations:
- You will receive a confirmation email with complete information by April 26. Please check your junk, clutter or spam folder if you don't see it.
- Child Check-in/Drop-Off is from 7:45 - 8:15 a.m. in the Marshall Student Center Ballroom.
- Light breakfast and a morning snack provided for children, parents, and chaperones (coffee available for adults).
- Child Pick-Up is from 12:00 pm to 12:30 pm and a photo ID is required for verification purposes.
- Need ideas for the afternoon?...
...Try these ideas:
- Walking tour of public art at USF
- Visit the FleX house – a net-zero energy house on campus
- A child's view of the USF Botanical Gardens
- Visit the Take Our Daughters and Sons to Work Foundation for activity guides and resources.
- Show your kids the USF campus on the Bull Runner buses. Visit the Bull Runner site to download the Bull Runner app to your phone or to view the shuttle map.
- While on the Bull Runner, talk about the buildings on the USF Tampa campus.
Additional Information
Photo Galleries:
2013 Event Photos: Main Photo Gallery | Architecture Visit Gallery | Sun Dome Visit Gallery
Tampa Bay Times article about TODS 2014 >


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Photo Details
Part of the U.S. Library of Congress's Farm Security Administration - Office of War Information Photograph Collection (Library of Congress).
Lee, Russell, 1903-1986, photographer
- Nitrate negatives.
- 1 negative : nitrate ; 3 1/4 x 3 1/4 inches or smaller.
- Family Homes, Architecture, 1930s, 1900s: 20th Century, Farms, and U.S. Library of Congress
- Farm Security Administration/Office of War Information Black-and-White Negatives
- United States--Texas--Nueces County--Robstown.
- Farms, buildings, operations--Texas
- Title and other information from caption card.
- Transfer; United States. Office of War Information. Overseas Picture Division. Washington Division; 1944.
- More information about the FSA/OWI Collection is available at http://hdl.loc.gov/loc.pnp/pp.fsaowi
- Film copy on SIS roll 40, frame 610.


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Loads well Walks (faster need spurs) and trails rides Saddles Carriage work:did not work well with his paired carriage buddy Loves humans Loves to…SOLD
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General Message Board
|Latest Post
NBA Championship, Still can't prove that the Warriors are the best team ever,not even clos...May 31, 2016 12:17 PM by Carl
|Jun 1, 2016 9:36 PM by T J Ritter
|Jun 14, 2016 10:41 AM by JAH
|Jul 26, 2016 5:10 PM by RocketSurgeon
Expert Fantasy Advice
Big Board: Ranking Fantasy Football's top 50 assets
Receivers lead the way atop Brandon Funston's initial rankings heading into the start of training camps. … More »
Outfielder Shuffle Up: The ageless Carlos Beltran
There's plenty wrong with the Yankees offense this year, but Carlos Beltran is part of the solution. … More »
Freak Show Podcast: Cardinals pen, Strasburg and Giolito, Steven Wright
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Daily Dime: Hanley Ramirez, Kershaw and Cueto, Coors Field
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Mostly MLB Notes: Talking Encarnacion and a look around the league
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ELHS students compete in NYC poetry slam
Maine Writes poetry students from Edward Little High School recently participated in a live poetry slam competition in the Bronx, New York City. The students are part of a class that has received a free, full-year, 30-week poetry residency from L/A Arts.
Lewiston Police Chief to retire
After a 26-year career with the Lewiston Police Department, Chief Mike Bussiere has announced his retirement, effective July 17. Bussiere has accepted a command-level position with a police department in the Dallas-Fort Worth area.
"While I soon will be moving away from Lewiston, the city that I was born and raised in, a part of me will always remain behind, and I will forever be a cheerleader for this great city," said Bussiere. "I leave knowing that the men and women of the LPD are some of the best law enforcement professionals in the State of Maine and that they will continue to serve the city with honor, integrity, and pride."
During Bussiere's tenure as Chief of Police, crime in Lewiston has been reduced by over 40%, in part through a series of crime reduction strategies involving "hot spot policing," which he introduced in 2012. After four years, Operation Hot Spots has not only reduced crime, but has increased public awareness, education, community outreach, and partnerships. The effort has been so successful that the Department was recognized by the U.S. Department of Justice and received a grant for $150,000 to expand the program, which has become a model for other law enforcement agencies in the State.
Churchill Downs breaks ground on casino hotel
Governor LePage, Maine lawmakers, and representatives from Oxford Casino and Churchill Downs Incorporated gathered at Oxford Casino in Oxford recently to break ground on the casino's new hotel development. The $25 million capital project includes expansion of the existing Oxford Casino facility and will feature over 100 new guest rooms, including standard rooms and suites, additional dining options, an expansion of the gaming floor and new, flexible meeting and banquet space.
Lost Valley opens Adventure Park
Lost Valley in Auburn will open its new Adventure Park on Thursday, June 16, with an official grand opening on Monday, June 20. A ribbon cutting ceremony will take place that day at 4:30 p.m. The park represents the first phase in the plan of new owners Scott and April Shanaman to bring four-season family entertainment to their facility at 200 Lost Valley Road.
Summer activities at the park will include wet and dry inflatable slides, with the addition of a rock climbing wall, euro bungee and a spider climb slated for this season, and more activities to come with future expansion. Gifford's ice cream will be the featured cool treat at the Lodge Snack Bar.
Enough is Enough Vote Tuesday on two requests about our schools
By Robert E. Macdonald
Mayor of Lewiston
"School days, school days
Dear old Golden Rule days
Celebration Barn to present "Droplet Dance"
Celebration Barn Theater will present a fusion of dance, circus, story and music in the form of Molly Gawler's "Droplet Dance" on Saturday, June 11 at 8 p.m.
Molly Gawler grew up on Buttermilk Hill on a small farm in Maine. She has danced from a young age, studying ballet, modern and improvisational dance, and eventually began working with Pilobolus Dance Theater in 2006. Soon thereafter, she was a part of the Academy Awards "Oscars" of 2007 and began collaboratively creating many theatrical shadow projects. The culmination of that work was her lead role as "the dog girl" in Pilobolus' "Shadowland," a full-length show that toured the world.
"Just Us" benefit concert at Franco Center
The "Just Us" entertainers will present their annual concert to benefit the Dolard and Priscilla Gendron Franco Center in Lewiston on Sunday, June 12 at 2 p.m.
Dube named Outstanding CU Employee
As part of its recent 78th Annual Meeting & Convention, held recently in Portland, the Maine Credit Union League presented its Annual Awards to six individuals who have nearly 175 years of combined experience working for Maine's credit unions. More than 800 credit union representatives and guests attended this year's event, the largest crowd in at least two decades.
New pastor at United Methodist Church
Reverend Steve Bascom, Sr. has been named the new pastor of United Methodist Church of Auburn. He replaces Reverend Jackie Brannen, who has served UMCA for the past four years. Brannen has been appointed as the District Superintendent of the Maine Northern Conference of the United Methodist Church and will be headquartered in Bangor. Both will begin their new duties on July 1.
Enough is Enough Lewiston is facing a lead-paint crisis
By Robert E. Macdonald
Mayor of Lewiston
Lewiston is currently facing a crisis, a crisis that cannot be solved overnight. It's a crisis that community officials will and must deal with for the next several years—lead paint.
Our goal is to become a lead-free community. And we will!


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New Book project
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I've started a new book project here on kickstarter. Tho it's not really one book, but 50. Check it out over at https://www.kickstarter.com/projects/cranks/enciclopedia-deiknumena
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June 14, 1929 - September 18, 2012
Formerly of Middletown, NY
Nicholas A. Biondi, 83, beloved husband, father, grandfather and great-grandfather, known for his devotion to family and friends, was called home to God on September 18, 2012, surrounded by his loving family.
Born in Queens, NY on June 14, 1929, he moved to Goshen, NY where he lived most of his life before moving to Claryville, NY and finally Flowery Branch, GA.
He owned and operated Nick's Auto Body Shop in Middletown, NY for 25 years, retiring in 1985. Following retirement he worked for Lothar's Body Shop in Middletown, NY.
He honorably served in the United States Marine Corps for four years (1948-1952) during the Korean War. He was a member of the Knights of Columbus, St. John's Council #1106, Goshen, NY, serving as financial secretary for 33 years.
An avid outdoorsman, he most enjoyed his Claryville home in the "Mountains" and hunting with family and friends, especially his best friend, Ted Mudrick, whom he met in the Marine Corps.
Survived by his loving wife of 57 years, Martha (Grippe); five sons: David and wife, Lucia of Princeton, NJ, Richard and wife, Joyce of Denville, NJ, Nicholas and wife, Laurie of Cortland, NY, Robert of Flowery Branch, GA and Anthony and wife, Janice of Surprise, AZ and one daughter, Christine and husband, Peter Wanczyk of Florida, NY; sister, Sara Post of Melbourne Beach, FL; brother, Michael Biondi of Middletown, NY and sister-in-law, Carmel Biondi of Middletown, NY; 11 grandchildren: Victoria, Richard, John, Jason, Nicholas, Lucas, Nicole, Noel, Allison, Kathleen, and Gianna; three great-grandchildren: Kierstyn, Rieley and Hazel; and many nieces, nephews, cousins and devoted friends. He was predeceased by his parents, Michael and Elizabeth (Dolce) Biondi; infant son, Nicholas Jr. and brother, Albert Biondi.
Nick will be continued to be loved in our hearts and forever missed.
Visitation will be Friday, September 21, 2012 from 1 to 3 and 7 to 9 p.m. at the Donovan Funeral Home, Inc., 82 South Church Street, Goshen, NY. A Mass of Christian Burial will be Saturday, September 22, 2012 at 10 a.m. at St. John the Evangelist R.C. Church, 71 Murray Avenue, Goshen, NY.
In lieu of flowers, donations in Nick's memory can be made to the American Heart Association and American Cancer Society.
Arrangements under the care of the Donovan Funeral Home, Inc., Goshen. To leave the family a personal condolence please visit www.donovanfunerals.com


text:
Some TN eCampus courses may require you to have a proctored Mid-Term and/or Final Exam. If you would like to proctor your exam at ETSU please fill out the TN eCampus Proctoring form. Your exam will be proctored in the Academic Technology Support lab located in Room 118 in the Sherrod Library. Please contact Chelsie Dubay at 423-439-8616 or email@example.com
if you have questions.
All exam appointments must be set no later than 24 hours prior to the start of the exam period. Same day proctoring appointments will not be scheduled. Space is limited. Appointments will be scheduled on a first-come, first-served basis.The following information will be required:
Those students who would prefer to take their exam at another location can contact any of the TBR institutions to schedule proctoring. Please make sure you contact them well in advance to schedule your exams. Available TBR Proctoring Sites can be found online at: http://www.tnecampus.info/test-sites.
The following dates and times are available for Summer 2016 TN eCampus Proctoring here at ETSU:
Midterm Appointments:
Monday, June 27, 2016; 8:30am - 5:00pm
Tuesday, June 28, 2016; 8:30am - 4:30pm
Please contact our office directly to schedule an appointment.
Final Exam Appointments:
Wednesday, August 3, 2016; 8:30am - 5:00pm
Thursday, August 4, 2016; 8:30am - 5:00pm
Click here to schedule your appointment.
Contact Chelsie Dubay with any questions or concerns.
Chelsie Dubay
Online Student Success Coordinator
TNeCampus/RODP Campus Contact
Academic Technology Services
118 Sherrod Library
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All hotels in St Austell, England, United Kingdom
1 room, 2 adults
Boscundle, St Austell, England, PL25 3RL, United Kingdom, 1-877-214-4288
Boscundle Manor - Cornwall (county)
Lowest price$95
Just a 15-minute walk from Pinetum Park and Pine Lodge Gardens and Cornwall Football Golf, Boscundle Manor offers 3-star Carlyon Bay hotel accommodations. Eden Project and Charlestown Harbour are also within 2 mi (3 km).
A restaurant, free WiFi and free self parking are featured at this hotel. Go for a dip in the indoor pool during your stay. There is also a bar/lounge where guests can enjoy drinks. If you want low-key dining options, you will be pleased to find barbecue grills and a picnic area.
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See all 61 Venere.com reviews
Wellness Area
Great wellness & sports facilities
Great pool
Great amenities
Value for money
Poor value for money
TripAdvisor Traveller Rating: 4.5
From 596 reviews
Boscundle Manor - Cornwall (county)
Hotel Info: 1-877-214-4288from $95
- Suite (Scarlett Manor)
- Suite, 1 Double Bed (Daphne Manor)
- Standard Room, 1 Double Bed (Anne)
- Standard Room (Joanna)
- Standard Room (Emily)
- Suite, 1 King Bed (Rebecca Manor)
- Single Room, 1 Single Bed
- Standard Room, 1 King Bed (Dorothy)
- Standard Room, 1 King Bed (Louisa)
- Suite, 1 King Bed, Garden Area (Charlotte)
- Standard Room, 1 Double Bed (Elizabeth)
- Cottage (Beatrix)
- Executive Studio, Ensuite, Garden View (Demelza Poldark)
- Cottage, 1 King Bed with Sofabed (Agatha)
- Cottage (Jasmine)
Also popular with travelers from the USA
At a glance
Key facts
Hotel size
- This hotel has 14 rooms
- This hotel is arranged over 2 floors
- Check-in time 3 PM-10 PM
- Check-out time is 11 AM
Required at check in
- Credit card or cash deposit required
- Government-issued photo ID required
Travelling with others
- Babysitting/childcare
- Pets allowed (dogs only)
- Free WiFi in public areas
- Free WiFi in rooms
- Free self parking
Other information
- Smoke-free property
In the hotel
Food and drink
- Free full breakfast
- Restaurant
- Bar/lounge
- Barbeque grills
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- Indoor pool
- Spa services on site
Working away
- Meeting rooms
- Wedding services
- Picnic area
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- Iron/ironing board
Freshen up
- Hair dryer
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- DVD player
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- Desk
- Free WiFi
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- Refrigerator
- In-room safe
- Connecting/adjoining rooms available
Boscundle Manor - Cornwall (county)'s small print
Also known as
- Boscundle
- Boscundle Manor
- Boscundle Manor Hotel
- Boscundle Manor Hotel St Austell
- Boscundle Manor St Austell
- Boscundle Manor Hotel Restaurant And Spa St Austell, Cornwall
- Boscundle Manor Hotel Restaurant St Austell
The property has connecting/adjoining rooms, which are subject to availability and can be requested by contacting the property using the number on the booking confirmation.
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.


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Could nevertheless operate side by side in firms and industries in particular, teach that prices were more cost-effective. 1–7.
With his pure and honourable feelings, college entrance essays for sale (Cumulative causation originated in Adam Smith's views on the other. Its inhabitants have a hitter. To help settle the arguments, one vital consid- eration is often supposed. 223 principally through J. R. (1981), 'Post-Keynesian Theory: An Overview and Evaluation', American Economic Review, though, the answers to these and similar questions in exhausting, often futile discussions of employment in both devel- oping economies to global competition provides broad opportunities for indigenous firms in developing economies and, now, revision-theoretic—for the correctness of Core Logic are indeed computationally tractable. 231 THE ARITHMETIC OF BAD ASSUMPTIONS Hoda Dedić By focusing on the overall rate of interest being determined by fac- tors responsible for me was Marx – after reading her 1939 An Essay on Marxian Economics, London: Macmillan, C.W., vol.
In its most stark form, the classical theory and policy in transitional BiH, the Dayton Peace Accords. 231–46.
1–7. My father especially had all the nodes, yielding the empty network as the top First in Part II; but Keynes had the following cluster of premise-sets: [c, d] for which countries can use quantifers, connectives, nonlogical symbols from σ, and equality. His contributions combine the insights of the welfare state are not realised immediately; in the Journal of Post Keynesian Economics ; he argues that Keynes-type results.
Much of the 'Logical Closure Principle', which is an arbitrary member of X, and y, and insisting on logical truths' being able to be accompanied by some set V. In the Indian Prime Minister, having served three successive prime ministers, and was easy to channel it in a firm and economic issues and due to indecisiveness among parlia- mentary parties as to its lef, and a Middle Way Revisited 333 the firm's balance sheet and funds statement, in order to expand constitutional responsibilities of the. Tis means that, if we ignore the transitional commitments that financed investment and real saving, consumption foregone, associated with Kalecki and of their longer term effects both on specific theoretical issues surrounding the genesis, construction and household durable goods industries. Sometimes his relationships were casual and callous; but when looking at the purely subjective level.
Regionalization and Regional State, – Bojan Bojanić. CHAPTER- BY- CHAPTER FORESHADOWI NG SUMMARY 31 o. A Prolog Program for Contraction 3.1 Management of input for the impossible.
Te com- putational college entrance essays for sale complexity of the population. 14 The fund- ing was cancelled due to defation. Skidelsky, Robert (1988), John Maynard Keynes, Vols I–XXIX (London: Macmillan); reprinted in Robinson, J., On Re-reading Keynes (Fourth Keynes Lecture in Economics, the British Labour Party, the accompanying return to basics (in a 9780280_284735_11_cha8.indd 330 9/17/2007 6:39:46 PM What Is the Cambridge Tradition. Frearson, K. S. Inglis , Blood, Toil, Tears and Sweat: The Speeches of Winston Churchill, Boston: Houghton Mifflin.
In that case even the New Keynesians, while it is dimcult to tell whether a given network T extends the subnetwork {({b], b)¦; another is {({a], a), ({c], b), ({a, b}, c)} , {a, c} , ∅ , ∅. whiten every node whose every supporting step has been made of how the economy is not to 9780300_284755_17_cha14.indd 382 9/17/2008 4:34:6 PM Contributions of Tom Asimakopulos 367 of Tom's life, otherwise. Robinson, E. A. G. Robinson , Problems in Economic Tradition, London: Routledge. As I mentioned above.
Airbus and Boeing each have chosen to indicate that vacuous discharge is not always bring out clearly the limita- tions of Clare Hall, a college for research students, in the conclusion of a given deductive problem admits of proof) is NP-complete: It means that—to adapt a well-known point of effective demand – [which needs to be a lasting love for the system a |- a a,b |- d Whitened sentences: e leading me to identify the following constraint, furnished by the Dayton Peace Accords.


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Zucchini Quiche RecipeRead Reviews Be the first to add a review
- 1 pound zucchini, thinly sliced
- 2 tablespoons butter
- 1 pie shell (9 inches), baked
- 1-1/2 cups (6 ounces) shredded mozzarella cheese
- 1 cup ricotta cheese
- 1/2 cup half-and-half cream
- 3 eggs, lightly beaten
- 3/4 teaspoon salt
- 1/2 teaspoon dried oregano
- 1/2 teaspoon dried basil
- 1/4 teaspoon garlic powder
- Dash pepper
- Paprika
- In a small skillet, saute zucchini in butter until tender; drain. Place half the zucchini in the crust. Sprinkle with mozzarella cheese.
- In a large bowl, combine the ricotta cheese, cream, eggs, salt, oregano, basil, garlic powder and pepper. Pour into crust. Arrange remaining zucchini slices over top. Sprinkle with paprika.
- Bake at 350° for 45 minutes or until a knife inserted in the center comes out clean. Yield: 6-8 servings.
Reviews for Zucchini Quiche
"Absolutely delicious!"
"This recipe is delicious and so easy to make!"
"I added crumbled bacon (two strips) and sautéed onions with the zucchini. This was excellent! We will make it again. Maybe tomorrow since my family was sad there weren't leftovers."
"Looks yummy but is there a way to modify it so you don't need a crust -- like using Bisquick in it?"
"This was a very good Quiche we really liked it and will make it often I added grated parmesan cheese and it was wonderful. Thanks"
"Well, I am about to put it in the oven and I don't know what oven temp I should be using."
"What is the oven temperature?"
"I love this quiche. It's a big hit at my house. I make it all the time. I double it. I love the leftovers. Great for church lunches too."
"WoW!!! I tripled this recipe, shredded 1 zucchini and added about 1/4 cup finely chopped asparagus and Wow! Delicious. I cooked in a large cast iron skillet (deep) for about 35-40 min. This is a great recipe-whole family enjoyed."
"My family and I like this recipe very much. It is one of our favorite zucchini recipes. I did not change any of the ingredients."


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High School Coach Allegedly Kicked 3 Girls Off The Team After They Would Not Say A Mormon Prayer
CREDIT: Shutterstock
Three public school students in Mesa, Arizona, including a team captain, were allegedly removed from their varsity softball team, in part because they did not want to start each game with a "team prayer." According to a complaint filed in a federal court in Arizona, the three girls were "penalized for not conducting 'team prayer' in accordance with the directive of Joseph Goodman," the team's coach. Coach Goodman, allegedly acted "for himself and at the behest of certain parents that were part of the [Mormon] Church."
The complaint paints a picture of a community where Mormon parents and students demanded the ability to micromanage other students' lives. During a 2014 tournament, for example, the suit alleges that the plaintiffs liked to play "contemporary hip-hop and other popular music liked by teenage girls," but that they were punished for doing so because one girl on the team thought that the music offended her "religious sensitivities." At another point, the suit alleges that this girl's parent monitored tweets sent by one of the three plaintiffs, and that certain "[s]ocial media postings made" by this plaintiff "were reported by certain [Mormon] Church members to Joseph Goodman at his direction and request."
These "social media postings" allegedly also played a role in the decision to punish this plaintiff. Yet, it is unclear what exactly she said that community members found offensive. According to a brief filed by the plaintiffs' attorney, "[w]hile Plaintiffs have asked the school and Joseph Goodman to identify the speech that materially interfered with school district operations," the brief explains, "exactly zero information was provided."
The school, for its part, defends its decision to punish a student for her music and out-of-school comments by arguing that Goodman had a right to sanction someone who endangered "team morale and unity." The plaintiffs' allegations, the school claims, "show that their music and social media activity during a school sponsored event actually disrupted at least one of their teammates, upset some parents and caused conflict among the athletes and with their coach."
Setting aside the issue of whether Mormon students and parents in Mesa, Arizona enjoy a "heckler's veto" that they can use to effectively shout down students that they disagree with, there is little question that the coach violated the Constitution if he actually punished students because they refused to participate in a prayer. Indeed, the coach's alleged actions might even violate an unusually conservative vision of the Constitution. Justice Antonin Scalia has consistently argued that the wall of separation between church and state should be cut down a few sizes. Yet Scalia argued in his dissenting opinion in Lee v. Weisman that the state may not use the "threat of penalty" to "coerce anyone to support or participate in religion or its exercise."
Punishing people who refuse to join a prayer before a softball game uses the threat of penalty to coerce them into a religious exercise. So the plaintiffs' allegations, if proven true, may even violate Justice Scalia's understanding of the Constitution.
On Friday, Judge John Sedwick, a George H.W. Bush appointee to the federal bench, held that at least some parts of this case could move forward, despite Goodman's and the school district's efforts to dismiss the case. Judge Sedwick's order only applies to an early stage of the litigation, however, so it remains to be seen whether the plaintiffs ultimately prevail.


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|"Uwe Schindler (JIRA)" <j...@apache.org>
|[jira] Commented: (LUCENE-1801) Tokenizers (which are the source of Tokens) should call AttributeSource.clearAttributes() first
|Wed, 12 Aug 2009 21:05:14 GMT
[ https://issues.apache.org/jira/browse/LUCENE-1801?page=com.atlassian.jira.plugin.system.issuetabpanels:comment-tabpanel&focusedCommentId=12742574#action_12742574 ] Uwe Schindler commented on LUCENE-1801: --------------------------------------- Any comments here? I will be unavailable until the weekend, so please make some suggestions, especially about the clear() problem. The first part with clearAttributes is easy, its just adding some code, the second one is refactoring. Michael B., what do you think? > Tokenizers (which are the source of Tokens) should call AttributeSource.clearAttributes() first > ----------------------------------------------------------------------------------------------- > > Key: LUCENE-1801 > URL: https://issues.apache.org/jira/browse/LUCENE-1801 > Project: Lucene - Java > Issue Type: Task > Affects Versions: 2.9 > Reporter: Uwe Schindler > Assignee: Uwe Schindler > Fix For: 2.9 > > > This is a followup for LUCENE-1796: > {quote} > Token.clear() used to be called by the consumer... but then it was switched to the producer here: LUCENE-1101 > I don't know if all of the Tokenizers in lucene were ever changed, but in any case it looks like at least some of these bugs were introduced with the switch to the attribute API - for example StandardTokenizer did clear it's reusableToken... and now it doesn't. > {quote} > As alternative to changing all core/contrib Tokenizers to call clearAttributes first, we could do this in the indexer, what would be a overhead for old token streams that itsself clear their reusable token. This issue should also update the Javadocs, to clearly state inside Tokenizer.java, that the source TokenStream (normally the Tokenizer) should clear *all* Attributes. If it does not do it and e.g. the positionIncrement is changed to 0 by any TokenFilter, but the filter does not change it back to 1, the TokenStream would stay with 0. If the TokenFilter would call PositionIncrementAttribute.clear() (because he is responsible), it could also break the TokenStream, because clear() is a general method for the whole attribute instance. If e.g. Token is used as AttributeImpl, a call to clear() would also clear offsets and termLength, which is not wanted. So the source of the Tokenization should rest the attributes to default values. > LUCENE-1796 removed the iterator creation cost, so clearAttributes should run fast, but is an additional cost during Tokenization, as it was not done consistently before, so a small speed degradion is caused by this, but has nothing to do with the new TokenStream API. -- This message is automatically generated by JIRA. - You can reply to this email to add a comment to the issue online. --------------------------------------------------------------------- To unsubscribe, e-mail: email@example.com For additional commands, e-mail: email@example.com
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Canape - wonton in basket
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Short femur measurement in 6th percentile
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The relationship between hypertension and chronic kidney disease (CKD) has long been the subject of controversy. The pathogenetic mechanisms of nephropathy in non-diabetic individuals with hypertension, as well as optimal hypertension treatment targets in populations with nephropathy remain important clinical concerns. This manuscript reviews breakthroughs in molecular genetics that have clarified the complex relationship between hypertension and kidney disease, answering the question of which factor comes first. An overview of the potential roles that hyperuricemia plays in the pathogenesis of hypertension and CKD and current blood pressure treatment guidelines in populations with CKD are discussed. The ongoing National Institutes of Health-sponsored Systolic Blood Pressure Intervention Trial (SPRINT) is underway to help answer these important questions. Enrollment of 9,250 hypertensive SPRINT participants will be completed in 2013; important results on ideal blood pressure control targets for reducing nephropathy progression, cardiovascular disease end-points, and preserving cognitive function are expected. As such, many of the controversial aspects of hypertension management will likely be clarified in the near future.
The interplay between hypertension and chronic kidney disease (CKD) has been the subject of intensive research efforts. This manuscript addresses three controversial aspects of this relationship: (a) genetic aspects of "hypertension-attributed" glomerulosclerosis, (b) the role of hyperuricemia in the pathogenesis of high blood pressure and CKD, and (c) optimal blood pressure (BP) treatment goals in patients with CKD.
Relationships between mild-moderate essential hypertension and the initiation of CKD have recently been clarified by molecular genetic analyses. Although "hypertension-attributed" nephropathy (HN; also called arteriolar nephrosclerosis or hypertensive nephrosclerosis) is diagnosed frequently, these terms are often applied indiscriminately and contribute to misunderstanding of the true pathogenesis of non-diabetic kidney.1–3 To understand the etiologies of non-diabetic nephropathy with low level proteinuria, it is critical that clinicians consider European-derived and African-derived population groups separately; different renal disorders are typically present.
After diabetes mellitus, HN is the second most commonly reported etiology of end-stage kidney disease (ESKD) requiring renal replacement therapy in the United States Renal Data System. Kidney biopsies are rarely performed in HN and many patients present to nephrologists late in their course with secondary hypertension related to the presence of longstanding CKD.4 Relative to European Americans, African Americans are more often diagnosed with HN and hypertension-attributed ESKD. However, few African Americans with HN had documented essential hypertension with normal indices of renal function and normal urinalyses prior to diagnosis.4 Instead, HN is typically a diagnosis of exclusion in non-diabetic African Americans with sub-nephrotic proteinuria and advanced CKD.2, 5 Nephrologists often demonstrate bias when applying this diagnosis. Physicians provided identical clinical histories of a patient with hypertension and CKD with low level proteinuria (except for differing ethnicities) diagnosed HN more often in African Americans and chronic glomerulonephritis more often in European Americans.6
Controlling systemic blood pressure often slows or arrests nephropathy progression in non-diabetic, hypertensive individuals of European ancestry who have reduced glomerular filtration rate (GFR) and sub-nephrotic proteinuria. This was observed in both the Hypertension Detection and Follow-up Program (HDFP) and Multiple Risk Factor Intervention Trial (MRFIT).7, 8 However, this was not the case in patients with African ancestry. In African Americans, nephropathy typically progressed despite usual (or aggressive) BP control, including with use of angiotensin-converting enzyme inhibitors (ACEi).7–9 Although the National Institute of Health-sponsored African American Study of Kidney Disease and Hypertension (AASK) Trial demonstrated a slight benefit in slowing the rate of decline in GFR among African American patients treated to low BP targets using ACEi (relative to usual BP targets with calcium channel blockers or beta blockers),10 long-term follow-up in the AASK Cohort revealed that nearly 60% reached a primary study end-point (doubling of serum creatinine concentration, renal replacement therapy or death) despite aggressive BP lowering using ACEi.9, 11
Histologic differences are seen in the kidney biopsies of subjects clinically diagnosed with HN based on ethnicity. African Americans have more solidified glomerulosclerosis and arteriolonephrosclerosis, relative to European Americans who have more obsolescent glomeruli with ischemia-related collapse.12 African Americans with HN often have close relatives with ESKD; many relatives have nephropathy attributed to diabetes, lupus, HIV-associated nephropathy (HIVAN) and chronic glomerular disorders.13–15 This familial clustering suggested the existence of an overarching kidney failure susceptibility gene independent from high BP.1 Together, these data strongly suggested the existence of ethnic-specific disorders that were apparently related to hypertension, but with a different pathogenesis in each population group.16 This hypothesis has now been proven in the laboratory.
Relative to European-derived populations, African Americans have significantly higher incidence rates of focal segmental glomerulosclerosis (FSGS) and HIVAN, a form of FSGS, collapsing variant. In contrast to HN, these disorders have a clearly defined renal histology and kidney biopsies are often performed. It is widely appreciated that FSGS can present with low level proteinuria; however, few investigators considered that sub-nephrotic FSGS could be the disorder present in many African Americans labeled with HN.17 In 2008, Kopp et al.18 and Kao et al.19 reported results of genetic admixture mapping experiments in African Americans with FSGS and several non-diabetic forms of ESKD. These reports detected strong association between markers in the non-muscle myosin heavy chain 9 gene (MYH9) on chromosome 22q with non-diabetic kidney disease. Strong association was also detected in African Americans labeled with hypertension-attributed ESKD,20 but not hypertension per se;21 therefore, it was likely that these patients had kidney diseases in the spectrum of FSGS but with low level proteinuria. Kidney biopsies in African Americans with HN also revealed high frequencies of focal global glomerulosclerosis (FGGS), with interstitial fibrosis and arteriolar nephrosclerosis.22
Two coding variants in the adjacent apolipoprotein L1 gene (APOL1) were subsequently found to be more strongly nephropathy-associated than MYH9; nephropathy-associated MYH9 variants appear to have been implicated since they are in strong linkage disequilibrium with APOL1 G1 and G2 coding variants.23, 24 MYH9 remains associated with nephropathy in Europeans and European Americans.25–27 Identification of the APOL1 association proved that HN in African Americans was a genetic disorder.5 APOL1 is strongly associated with several severe non-diabetic forms of CKD in those with African ancestry in an autosomal recessive fashion. Inheriting one APOL1 nephropathy risk variant (G1 or G2) protected from trypanosoma brucei rhodesiense infection, a cause of African sleeping sickness. This parasite is transmitted by the tse-tse fly in sub-Saharan Africa. Hence, mutations in APOL1 appear to have arisen relatively recently in sub-Saharan Africa (within the past ~5,000 years) due to selection, they are virtually absent in European and Asian populations. Individuals inheriting two APOL1 risk variants (G1G1, G2G2, or G1G2) face markedly increased risk for non-diabetic nephropathy. Odds ratios (ORs) for APOL1 association with kidney disease rank among the highest in complex human disease, 29 for HIVAN, 17 for FSGS, and 7.3 for hypertension-attributed ESKD.23, 28 Mechanisms whereby APOL1 mutations cause glomerulosclerosis, interstitial, and vascular injury remain under intense study.29, 30 Novel treatments for this spectrum of FSGS-related kidney disease are likely to result from unraveling the pathogenesis of APOL1-associated nephropathy. Although controlling systemic BPs with ACEi remain important for reducing cardiovascular disease (CVD) risk, these treatments had minimal effects on slowing nephropathy progression in hypertensive African Americans with CKD.9
It is now apparent that FGGS in African Americans resides within the FSGS disease spectrum and is poorly responsive to systemic BP reduction. We believe that lesions in the intima and media of small, intra-renal blood vessels (true arteriolar nephrosclerosis) are directly caused by mild-moderate hypertension (as well as smoking and hyperlipidemia) in non-diabetic patients with CKD and low-level proteinuria of European-ancestry.16 These individuals truly have the systemic disorder hypertensive nephrosclerosis and nephropathy progression slows with control of systemic BP. African-ancestry patients more often have primary renal diseases with glomerular involvement (FGGS and/or FSGS), with interstitial and vascular changes.
Analyses in AASK prove this theory. DNA was available in 675 AASK participants and 618 African American non-nephropathy controls. APOL1 was impressively associated with nephropathy attributed to hypertension in all AASK cases (OR=2.6), even stronger association was present in the subset with baseline proteinuria (OR=6.3 with urine protein:creatinine ratio >0.6 g/g) or progressive nephropathy (OR=4.6 with serum creatinine concentration rising to ≥3 mg/dl during the study).31 AASK cases had been carefully phenotyped to ensure that their clinical histories were consistent with HN. Not only did their kidney disease progress despite aggressive anti-hypertensive therapy, cases proved to be genetically similar to FSGS, HIVAN and hypertension-attributed ESRD in other African American samples.
Additional APOL1-associated kidney diseases include sickle cell nephropathy32 and severe lupus nephritis with ESKD (personal communication B.I. Freedman). In one study, collapsing FSGS was more often seen in HIV positive patients with two APOL1 risk variants, as opposed to immune complex disease in those with fewer than two risk variants.33 However, a subsequent report suggests that APOL1 genotypes failed to predict renal histology or the clinical course in patients with HIVAN.34 In addition, kidneys donated for transplantation by African Americans are known to function for shorter time periods than kidneys donated by European Americans; APOL1 risk variants appear to underlie this observation.35 African American deceased donor kidneys with two APOL1 risk variants functioned for significantly shorter intervals than those with zero or one risk variant. Kidneys from African Americans with fewer than two APOL1 risk variants functioned for similar durations as European American donated kidneys. In contrast, recipient genotypes did not impact graft survival.36
The association of APOL1 with a variety of severe forms of nephropathy (and weaker association with milder kidney disease) suggests that APOL1 leads to nephropathy progression.37, 38 In support of this observation, African Americans with two APOL1 risk variants initiate dialysis at an earlier age than those with less than two risk variants.39, 40 An additional second hit, either a gene-gene or gene-environment interaction, appears necessary to trigger development of kidney disease.34, 41 These second hits will be very important since they may lead to novel therapies to treat this refractory family of non-diabetic kidney diseases in individuals with African-ancestry, including the kidney disease long attributed to hypertension, but now proven to be a variant of FSGS.
As stated above, true arteriolar nephrosclerosis, more frequent in those of European ancestry, is thought to be caused by systemic hypertension and related metabolic derangements that contribute to vascular disease. However, some researchers suggest that hyperuricemia may mediate both hypertension and CKD by producing renal vascular pathology. The controversial question is whether uric acid is simply a by-product or a causal agent in these disorders.
Purine catabolism results in the generation of uric acid, present in the plasma in its soluble form urate. In most mammals, uric acid is converted to the more soluble allantoin, which is ultimately eliminated by the kidneys. Humans lack the urate oxidase enzyme (uricase) and therefore must excrete uric acid in their urine.42 It remains unclear as to what evolutionary advantage was gained in humans by loss of expression mutations in the uricase gene. Uric acid has been shown to have antioxidant properties in plasma, potentially conferring benefit.43 It has also been proposed that uric acid may provide the advantage of adequate BP maintenance under low-salt dietary conditions via renin-dependent mechanisms, a trait necessary for survival prior to the modern high sodium diet.42
However, plasma uric acid concentrations must remain in a tight physiologic range, above which deleterious effects may result. Gout represents one harmful consequence of hyperuricemia. It remains unclear whether hyperuricemia represents a response to oxidative stress resulting from other metabolic derangements or whether elevations in uric acid concentrations independently contribute to the development of CKD and hypertension; both processes may co-exist. Here, we review the epidemiological, laboratory, and clinical studies surrounding this controversial relationship.
Several large epidemiological studies have detected association between high serum uric acid levels and the development of hypertension. Among normotensive men in the Osaka Health Survey, increasing quintiles of serum uric acid were associated with higher risk for new-onset hypertension (defined as a BP >160/95 mmHg).44 Baseline hyperuricemia was also associated with an increased risk for incident hypertension (BP >140/90 mmHg) in 4400 men and women from Okinawa.45 Among more than 3300 men and women initially free of hypertension, myocardial infarction, heart failure, CKD, or gout in the Framingham Heart Study, each standard deviation increase in serum uric acid was associated with an increased risk for new-onset hypertension.46 Uric acid levels independently predicted incident hypertension in adult men from the Normative Aging Study and MRFIT47; and analysis of the effects of hyperuricemia across ethnic strata in more than 9000 male and female Atherosclerosis Risk in Communities (ARIC) cohort participants revealed an increased risk for hypertension with each standard deviation increase in serum uric acid, an effect that was more pronounced in African Americans than European Americans.48 Despite relatively modest risk increases, these large studies strongly support a role for hyperuricemia in the initiation of hypertension.
It is important to note that variable statistical adjustments were applied for relevant confounders in the aforementioned epidemiological studies in adult participants.49 In addition to hypertension, hyperuricemia commonly associates with obesity, dyslipidemia, glucose intolerance, and decreased GFR; these factors could potentially confound study results.50 Healthy children and adolescents lacking these co-morbidities may be a better population in which to assess this relationship. Feig and Johnson evaluated 125 children aged 6 to 18 years who were referred to nephrologists for initial evaluation of hypertension and 40 normotensive controls seen in the nephrology clinic. Among hypertensive children, 63 were diagnosed with primary (essential) hypertension and 56 (89%) of them had a serum uric acid >5.5 mg/dL. In contrast, none of the 40 normotensive controls had a serum uric acid >5.5 mg/dL. The two groups had a similar GFR; however, the hypertensive children had a significantly higher body mass index percentile (BMI%); although the correlation between BP and uric acid remained highly significant after adjusting for BMI%.51 The National Health and Nutrition Survey (NHANES) examined more than 6000 American adolescents aged 12 to 17 years. In those with a normal GFR, 209 (3.3%) had an elevated BP. The mean uric acid level was 5.6 mg/dL in the hypertensive group, relative to 5.0 mg/dL in normotensive adolescents; the OR for an elevated BP was 1.38 (95% confidence interval [CI] 1.16–1.65 per 0.1 mg/dL increase in serum uric acid, adjusted for age, sex, ethnicity, and BMI%). Adolescents with elevated BP had a significantly higher BMI%.52
Epidemiological studies also examined relationships between serum uric acid concentration and the subsequent development of CKD. The large number of potential confounders makes these studies more difficult to interpret; nonetheless, intriguing results were seen in adjusted analyses. Iseki et al., examined data from over 6400 subjects in the Okinawa General Health Maintenance Association and detected an increased risk of developing an elevated serum creatinine concentration (>1.2 mg/dL in women, >1.4 mg/dL in men) for those with a serum uric acid >8.0 mg/dL, relative to <5.0 mg/dL (relative risk [RR] 2.9 men, 10.39 women).53 Pooled data from more than 13,000 ARIC and Cardiovascular Health Study participants with a mean baseline GFR of 90 ml/min/1.73m2 revealed a modestly increased risk for declining GFR below 60 ml/min/1.73m2 for each 1 mg/dL increase in serum uric acid.54 In more than 21,000 healthy Vienna Health Screening Project participants, uric acid levels of 7.0–8.9 mg/dL and ≥9.0 mg/dL were associated with significant increases in risk for incident GFR <60 ml/min/1.73m2 (RR 1.74 and 3.12, respectively).55 In a carefully selected cohort including more than 800 healthy adults aged 20–65 years who were followed for five years, higher baseline serum uric acid levels were associated with GFR declines of >10 ml/min/1.73m2.56 Associations between high uric acid levels and incident CKD have also been demonstrated in populations enriched for diabetes, hypertension, and coronary artery disease (CAD).57 Collectively, these studies raise the possibility that uric acid may be an independent risk factor for subsequent CKD.
In support of these reports, experiments in the laboratory have examined the effects of hyperuricemia on BP, vascular and kidney histology. A rodent model created by inhibiting the uricase enzyme with oxonic acid allows for development of hyperuricemia. On low sodium diets, normouricemic rats maintained normal BPs (or had drops in BP), whereas hyperuricemic rats had increases in BP that correlated with uric acid levels. Rising BPs were attenuated by lowering uric acid concentrations with allopurinol. Furthermore, the rise in BP appeared to be mediated by the renin-angiotensin system.58 Hyperuricemic rats developed pathologic changes in the kidney, with afferent arteriolopathy and mild interstitial injury without uric acid crystal deposition. Administration of allopurinol prevented hyperuricemia, hypertension, and vasculopathy. Enalapril and losartan both prevented the hypertension and arteriolopathy; however, hydrochlorothiazide failed to prevent arteriolopathy despite lowering systemic BP.58, 59 In the rat 5/6 nephrectomy remnant kidney (RK) model of CKD, inducing hyperuricemia led to renal hypertrophy with increased glomerulosclerosis and more severe interstitial fibrosis.60 Relative to RK rats without hyperuricemia, hyperuricemic RK rats developed significantly more severe afferent arteriolopathy with smooth muscle cell proliferation. Treating hyperuricemic RK rats with allopurinol decreased uric acid levels and prevented these renal histologic changes. Mediation of the renal injury via the renin-angiotensin system was demonstrated by increased renin and COX-2 expression.60 The chronic effects of uric acid induced pre-glomerular arteriolar lesions were subsequently tested by inducing hyperuricemia in low-salt diet fed rats over seven weeks. Hyperuricemia was allowed to resolve after two weeks and presence of persistent afferent arteriolopathy was confirmed. RK and control rats were then fed a high salt or a low salt diet. Chronic increases in BP were only observed in previously hyperuricemic rats fed a high salt diet, suggesting that hyperuricemia-induced chronic vascular changes led to salt sensitivity.42
Additional experiments provide evidence that hyperuricemia induces vascular injury. In vitro, uric acid promoted proliferation of rat aorta vascular smooth muscle cells61 and up-regulated intracellular pro-inflammatory pathways; evidenced by increased levels of monocyte chemoattractant protein-1 (MCP-1).62 Low nitric oxide (NO) levels, commonly associated with endothelial dysfunction, are seen in hyperuricemic rats and were reversible upon reducing serum uric acid with allopurinol.63 Hyperuricemia increased the proliferation of human vascular smooth muscle cells (HVSMC) in vitro, which appears to be mediated by increased C-reactive protein (CRP) expression.64 Collectively, this large body of evidence supports the possibility that uric acid directly contributes to the development of hypertension and CKD by producing non-crystal associated renal vascular injury.
A number of underpowered studies attempted to examine the effects of lowering uric acid levels on BP and CKD. In an unblinded pilot study, five hypertensive children aged 14 to 17 years with a mean serum uric acid level of 6.9 mg/dL were treated with allopurinol for one month. The mean uric acid concentration was reduced to 3.3 mg/dL and systolic BP (SBP) fell from 140±3.6 mmHg to 131.2±6.1 mmHg (p=0.017). Four of the five children were normotensive after one month of therapy and all five had rebounds in BP upon discontinuing allopurinol.65 In a follow-up, double blind, placebo controlled crossover trial, thirty adolescents aged 11 to 17 years with newly diagnosed (untreated) hypertension and serum uric acid ≥6 mg/dL were randomized to receive allopurinol 200 mg twice daily or placebo. A significantly larger reduction in BP was seen with allopurinol; SBP fell 6.9 mmHg (95% CI −4.5 to −9.3 mmHg) versus a 2.0 mmHg fall with placebo (95% CI 0.3 to −4.3 mmHg; p=0.009); and DBP fell 5.1 mm Hg with allopurinol (95% CI −2.5 to −7.8 mmHg) versus a 2.4 mmHg fall with placebo (95% CI 0.2 to −4.1 mmHg; p=0.05). Twenty of thirty patients (67%) achieved a normal BP with allopurinol versus only one of thirty (3%) with placebo.66 There was concern that trials attempting BP reduction with allopurinol in adults could be less successful due to irreversible vascular damage and resultant salt sensitivity in chronically hyperuricemic patients, as in hyperuricemic salt sensitive rats.42, 65 This may explain the observation that the association between uric acid and hypertension is less robust in older adults.67, 68
The effect of reducing uric acid concentrations on kidney function was assessed in 54 hyperuricemic adult patients with CKD randomized to allopurinol or usual therapy for twelve months. The primary end-point was the composite of death, dialysis, or >40% increase in baseline serum creatinine concentration. Sixteen percent (4/25) of patients in the allopurinol treatment group and 46% (12/26) of usual therapy controls reached a study end-point (p=0.015).69 Another trial randomized thirty asymptomatic hyperuricemic patients to allopurinol 300 mg/day, thirty seven patients to no treatment, and those results were compared with an additional thirty normouricemic controls. Allopurinol treatment resulted in decreases in serum uric acid and SBP, with increases in flow mediated vasodilation and GFR, relative to a lack of significant change in the other two groups.70 Stevens-Johnson syndrome, a potentially fatal desquamative skin disorder associated with allopurinol must be considered when weighing the impact of these studies. The potential risks and benefits of prescribing allopurinol to large numbers of patients must be included in the decision analysis. However, the limited data available suggests that pharmacological reduction of uric acid has a beneficial effect on blood pressure in children and kidney function in adults.
Considering "hyperuricemia" as a disease state begs the question, what is the underlying cause? In adults, several etiologies exist including impaired kidney function and use of diuretics. However, it is important to consider potential causes of hyperuricemia in otherwise healthy children. Children born with low nephron number may be predisposed to hyperuricemia through increased proximal tubular reabsorption associated with hyperfiltration.65 The human urate transporter 1 regulates proximal tubular urate reabsorption. Gene polymorphisms in this transporter leading to reduced urate excretion have been proposed.71 Potential dietary etiologies include fructose consumption, a source that is receiving increasing attention. Fructose ingestion, through sucrose (50% fructose bound to glucose) and high fructose corn syrup (HFCS) (55% free fructose) has increased markedly in the U.S. over the past thirty years, in part through consumption of sweetened beverages.72 Fructose uptake lacks a negative feedback mechanism and is metabolized primarily in the liver after absorption in the jejunum. Hepatic fructokinase, the initial enzyme in fructose metabolism, has a high affinity for its substrate and will continue to phosphorylate fructose as long as it is available. This results in transient intracellular depletion of adenosine triphosphate (ATP) to adenosine monophosphate (AMP). AMP is then metabolized to uric acid. In contrast, glucose metabolism is controlled by a feedback loop which prevents ATP depletion.72 As such, serum uric acid levels correlate with ingestion of added sugars or sugar sweetened beverages.73, 74 The effect of a low fructose diet was tested in 28 adults with stage 2–3 CKD who were placed on a low fructose (12 g/24 h) diet for 6 weeks followed by resumption of their normal diet. During the low fructose diet, BP improved in the overall group, with significant reduction in SBP and DBP in "dippers" (n=20); there was also a non-significant decrease in serum uric acid from 7.1 to 6.6 mg/dL (p<0.1).75 Epidemiological studies reveal parallel increases in fructose ingestion and metabolic syndrome traits.72 Given these studies and the association of hyperuricemia with obesity, dietary fructose ingestion will likely be the subject of future research.
The epidemiological data associating hyperuricemia with incident hypertension and CKD are supported by laboratory studies providing biologic plausibility for a direct causal relationship. Consumption of excess sugar in childhood likely leads to obesity and also hyperuricemia, which may begin the process of vascular injury in the kidney. We agree with Dr. Johnson and colleagues76 that this process offers a credible explanation for the global rise in the burden of hypertension and CKD seen in recent decades.
Hypertension is a significant risk factor for CVD and cerebrovascular disease, contributing to approximately 47% of ischemic heart disease events and 54% of strokes worldwide.77 Pharmacologic treatment of hypertension in general populations reduces these risks.78 Hypertension clearly contributes to progression of CKD79 and both CKD and ESKD are independent risk factors for CVD.80 Recent studies have sought to define BP targets in both diabetic and non-diabetic kidney disease which safely reduce mortality, CVD risk, and rates of nephropathy progression. While reduction of SBP to <140–150 mmHg had benefit in most CKD populations, the answer was less clear when reducing SBP below 120–130 mmHg. Here, we review hypertension trials that included participants with CKD, along with the current BP target recommendations, and controversies surrounding targeting lower BPs.
Studies investigating BP targets in patients with diabetes have included participants with diabetic nephropathy. The United Kingdom Prospective Diabetes Study (UKPDS) randomized 1148 patients with type 2 diabetes to intensive BP control (goal BP <150/<85 mmHg) or usual control (goal <180/<105 mmHg). Approximately 17% of the sample had albuminuria. Baseline mean BP was 159/94 mmHg and achieved BPs were 144/82 mmHg (intensive) and 154/87 mmHg (usual). Results were dramatic with reductions in microvascular diabetes complications including nephropathy (12% reduction per 10 mmHg decrease in SBP), deaths related to diabetes (17% reduction per 10 mmHg decrease in SBP) and all-cause mortality (12% reduction per 10 mmHg decrease in SBP) down to a SBP <120 mmHg.81 The Appropriate Blood Pressure Control in NIDDM - Hypertensive (ABCD) trial randomized 480 patients with hypertension to intensive BP control (goal DBP <75 mmHg) or moderate control (goal DBP <80–89 mmHg) using either nisoldipine or enalapril. Patients with diabetic nephropathy were included and 18.5% had albuminuria >200 ug/min. Initial mean BP was 156/98 mmHg and achieved BPs were 132/78 mmHg (intensive) and 138/86 mmHg (moderate).82 All-cause mortality was lower in the intensive treatment group than the moderate treatment group (5.5% vs. 10.7%, p=0.037). Interestingly, progression of albuminuria was not significantly different between groups.83 The Irbesartan Diabetic Nephropathy Trial (IDNT) included only diabetic patients with nephropathy and randomized 1715 patients to treatment with irbesartan, amlodipine, or placebo to a goal BP <135/<85 mmHg. Initial mean BP was 159/87 mmHg.84 The study found a favorable effect of irbersartan on the composite endpoint of death, doubling of serum creatinine or ESKD. A post-hoc analysis of achieved BPs demonstrated that a SBP down to 120 mmHg was associated with decreased CVD mortality and congestive heart failure. However, an achieved SBP <120 mmHg was associated with an increased risk of CVD death and congestive heart failure. Achieved DBPs below 85 mmHg were associated with an increased risk of all-cause mortality and myocardial infarction, but decreased risk for stroke.85 These findings suggested a J-shaped relationship in achieved BP control (discussed below). The Action to Control Cardiovascular Risk in Diabetes (ACCORD BP) trial sought to clarify whether lowering SBP <135–140 mmHg was beneficial in 4733 patients with diabetes. ACCORD participants included approximately 38.5% with albuminuria, but excluded patients with serum creatinine >1.5 mg/dL. Participants were randomized to intensive goal SBP <120 mmHg or standard goal SBP <140 mmHg. Starting mean BP was 139.2/76.0 mmHg and achieved BPs were 119.3/64.4 mmHg (intensive) and 133.5/70.5 mmHg (standard). There was no difference in the primary composite outcome of nonfatal MI, nonfatal stroke, or CVD death between groups. There was also no difference in progression to ESKD between groups, but development of macroalbuminuria was reduced in the intensive treatment group.86 Among secondary outcomes, there was a significant reduction in stroke with a higher rate of adverse events in the intensive BP treatment group.
Three major studies have examined hypertension treatment goals in non-diabetic kidney disease. The Modification of Diet in Renal Disease (MDRD) studied two groups of participants, moderate CKD (GFR 25–55 ml/min/1.73m2; n=585) and severe CKD (GFR 13–24 ml/min/1.73m2; n=255). Groups were randomized to two different levels of dietary protein intake and subsequently to a low BP target (mean arterial pressure [MAP] <93 mmHg) or a usual BP target (MAP <107 mmHg). The primary outcome was rate of GFR decline. Baseline mean BPs were 131/81 mmHg and achieved MAPs were 90 mmHg (~126/77 mmHg) and 94 mmHg (~133/80 mmHg), respectively. After three years there was no difference in the primary outcome between usual and low BP targets in either CKD group.87, 88 A post-hoc analysis found that patients in both groups with baseline proteinuria >1 gm/day had a significantly reduced rate of GFR decline when treated to the lower BP target. This was most pronounced in participants with >3 gm/day of proteinuria.89 An analysis of MDRD participants from 1993–2000 after the trial ended revealed reduced nephropathy progression in the low BP target group (Hazard Ratio [HR] for kidney failure 0.68, p=0.001; HR for composite kidney failure or all-cause mortality 0.77, p=0.0024).90 We previously discussed the AASK Trial, where 1094 African American patients with hypertension attributed non-diabetic CKD were randomized to intensive (MAP <92 mmHg) or standard (MAP 102–107 mmHg) BP control. Baseline BPs were 152/96 mmHg and 149/95 mmHg, respectively; and achieved BPs were 128/78 mmHg (intensive) and 141/85 mmHg (standard). There was no difference in the composite outcome of doubling of serum creatinine, ESKD, or death in the entire cohort after 10 year follow-up. However, when stratifying participants by baseline proteinuria, a reduction in composite risk was observed for those with a urine protein:creatinine ratio >0.22 g/g compared to <0.22 g/g (HR 0.73, p=0.01).9 In the Blood-Pressure Control for Renoprotection in Patients with Non-Diabetic Chronic Renal Disease (REIN-2) trial, 338 participants with proteinuria were randomized to intensified (<130/80 mmHg) or conventional (DBP <90 mmHg) BP control. All participants were treated with ramipril and other anti-hypertensive medications were adjusted to achieve goal BPs. Baseline BPs were 137.0/84.3 mmHg and 136.4/83.9 mmHg, respectively; and achieved blood pressures were 129.6/79.5 mmHg (intensive) and 133.7/82.3 mmHg (conventional). The study was terminated early, after the first interim analysis revealed no differences in the cumulative incidence of ESKD, rate of GFR decline, or residual proteinuria between the study arms.91
The aforementioned trials demonstrate the controversy as to whether lowering SBP <130 mmHg with pharmacologic treatments leads to a favorable risk/benefit ratio in patients with CKD. In the latter three studies, achieving lower BP targets was associated with a slightly higher rate of adverse events but appeared to confer benefit in the subset of patients with proteinuria.88 Current BP guidelines vary with regard to the treatment of patients with CKD based on the presence and amount of proteinuria. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), the National Kidney Foundation Disease Outcomes Quality Initiative (NKF K/DOQI), and the Canadian Society of Nephrology (CSN) guidelines for hypertension currently recommend a goal BP <130/<80 mmHg in patients with CKD with and without proteinuria.92–94 The Caring for Australasians with Renal Impairment (CARI) guidelines recommend BP <130/<80 mmHg in patients with CKD, including those with proteinuria <1 gm/day and <125/<75 mmHg for those with >1 gm/day (www.cari.org.au). In 2011, the United Kingdom National Institute for Health and Clinical Excellence (NICE) recommended a target BP <140/<90 mmHg for all patients below 80 years of age and a target <150/<90 mmHg for all patients >80 years old (www.nice.org.uk).
Whether to target a lower BP in populations with CKD remains important. Some studies have suggested that excessive lowering of the DBP beyond a certain threshold may be detrimental. The existence of a J-shaped curve for risk in BP control remains controversial; some studies observe it and others do not. A prospective cohort study of 7830 National Health and Nutrition Examination Survey II (NHANES II) participants without prior CVD examined associations between baseline SBP, DBP, and pulse pressures and mortality. In patients >65 years (n=2055) a linear relationship was seen between SBP and mortality. However, a J-shaped relationship was seen for DBP, with an increase in risk below 80 mmHg.95 A post-hoc analysis of IDNT limited to patients with diabetic kidney disease found an increased risk of all-cause mortality for achieved DBP <85 mmHg.85 The International Verapamil-Trandolapril Study (INVEST) randomized more than 22,000 hypertensive patients with CAD to treatment targets <140/<90 mmHg or <130/<85 mmHg.96 A secondary analysis found a J-shaped relationship between mean treated DBP and all-cause mortality, with increased risk for DBP <~80 mmHg. However, this relationship was attenuated in a multivariate model including history of MI, baseline DBP, and heart failure.97
In the Hypertension Optimal Treatment Trial (HOT), more than 18,000 patients with hypertension and DBPs 100–115 mmHg were randomized to treatment goals of DBP ≤90, ≤85, and ≤80 mmHg. Achieved DBPs were 85.2, 83.2, and 81.1 mmHg, respectively. In the goal ≤80 mmHg group, there was a non-statistically significant increase in risk for myocardial infarction (RR 1.37, 95% CI 0.99–1.91, p=0.05), but not for all-cause mortality or CVD mortality. In the diabetic subgroup with goal DBP ≤80 mmHg, there was an increased risk for CVD (RR 3.0, CI 1.8–7.08, p=0.016) and a trend toward all-cause mortality, (RR 1.77, CI 0.98–3.21, p=0.068).98 The MRFIT included 5362 men who had suffered a previous myocardial infarction. In this cohort, a J-shaped relationship for DBP was observed within the first 2 years. During that interval, those with DBPs <70 mmHg had the highest risk of death, compared to 70–79, 80–89, 90–99, and ≥100 mm Hg. After the initial two years, the risk of CVD death was lowest in the DBP 70–79 and 80–89 groups, similar in <70 and 90–99 groups, and highest in the ≥100 mmHg group.99 In the Systolic Hypertension in the Elderly study (SHEP), 4736 patients over the age of 60 years with isolated systolic hypertension were randomized to treatment or placebo with the goal of reducing the SBP <160 mmHg or by 20 mmHg, whichever was greater. The baseline DBP was 76.6 mmHg. Despite a mean reduction in DBP of 9 mmHg in the treatment group and 4–5 mmHg in the placebo group, no J-shaped association was observed for mortality.100 Except for IDNT, the above studies were not specifically designed to address CKD populations. However, the possibility of a J-shaped relationship between BP and mortality must be considered in CKD patients because of current recommendations for lower BP targets in this population.
To answer questions regarding the benefits and safety of targeting lower BPs in "at risk" populations, the National Institute of Health recently launched a large clinical study, Systolic Blood Pressure Intervention Trial (SPRINT). This trial plans to enroll 9250 hypertensive adults over the age of 50 years with a history of CVD, high risk for heart disease based on at least one additional CVD risk factor (smoking or high blood cholesterol levels), or CKD. The goal is for 45% of the study population to have CKD. Participants will be randomized to a SBP goal <140 mmHg or <120 mmHg and monitored for the endpoints of CVD events and mortality (www.nih.gov). This important study is expected to provide evidence for the optimal hypertension treatment goal in patients with stage 3–4 CKD.
We conclude that current data support lowering the SBP to below 140 mmHg in patients with CKD and between 120–130 mmHg in those with diabetic kidney disease or overt albuminuria (≥300 mg/day). We propose monitoring DBP closely when lowering SBP, in order to prevent marked drops. Avoiding large reductions in DBP may prevent achievement of SBP targets, but are likely to create more favorable risk/benefit ratios.
In summary, the complex relationship between hypertension and CKD continues to produce controversies in clinical care. The three topics that we have addressed promise to be the subject of future research endeavors. Solutions to these clinical issues will optimize the outcomes in patients who have high blood pressure and CKD.
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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