document_title: List of Super Bowl champions

question_text: who played in the past three super bowls

text: List of Super Bowl champions

text: Super Bowl Championship (1966–present)

text: Numbers in parentheses in the table are Super Bowl appearances as of the date of that Super Bowl and are used as follows:

text:
Winning team and losing team columns indicate the number of times that team has appeared in a Super Bowl as well as each respective teams' Super Bowl record to date.
Venue column indicates number of times that stadium has hosted a Super Bowl.
City column indicates number of times that metropolitan area has hosted a Super Bowl.

text:
National Football League (NFL, 1967–1970)
American Football League (AFL, 1967–1970)

NFL champion‡
(4, 2–2)
AFL champion^
(4, 2–2)

National Football Conference (NFC, 1971–present)
American Football Conference (AFC, 1971–present)

NFC champion*
(48, 25–23)
AFC champion†
(48, 23–25)

text:
Game
Date
Winning team
Score
Losing team
Venue
City
Attendance
Ref

01 !I
000000001967-01-15-0000January 15, 1967
Green Bay Packers 01 !Green Bay Packers‡
(1, 1–0)
3510 !35–10
Kansas City Chiefs 01 !Kansas City Chiefs^
(1, 0–1)
Los Angeles Memorial Coliseum 01 !Los Angeles Memorial Coliseum
Los Angeles, California 01 !Los Angeles, California[note 1]
061946 !61,946
[11]

02 !II
000000001968-01-14-0000January 14, 1968
Green Bay Packers 02 !Green Bay Packers‡
(2, 2–0)
3314 !33–14
Oakland Raiders 01 !Oakland Raiders^
(1, 0–1)
Miami Orange Bowl 01 !Miami Orange Bowl
Miami, Florida 01 !Miami, Florida[note 2]
075546 !75,546
[12]

03 !III
000000001969-01-12-0000January 12, 1969
New York Jets 01 !New York Jets^
(1, 1–0)
1607 !16–7
Indianapolis Colts 01 !Baltimore Colts‡
(1, 0–1)
Miami Orange Bowl 02 !Miami Orange Bowl (2)
Miami, Florida 02 !Miami, Florida (2)[note 2]
075389 !75,389
[13]

04 !IV
000000001970-01-11-0000January 11, 1970
Kansas City Chiefs 02 !Kansas City Chiefs^
(2, 1–1)
2307 !23–7
Minnesota Vikings 01 !Minnesota Vikings‡
(1, 0–1)
Tulane Stadium 01 !Tulane Stadium
New Orleans, Louisiana 01 !New Orleans, Louisiana
080562 !80,562
[14]

05 !V
000000001971-01-17-0000January 17, 1971
Indianapolis Colts 02 !Baltimore Colts†
(2, 1–1)
1613 !16–13
Dallas Cowboys 01 !Dallas Cowboys*
(1, 0–1)
Miami Orange Bowl 03 !Miami Orange Bowl (3)
Miami, Florida 03 !Miami, Florida (3)[note 2]
079204 !79,204
[15]

06 !VI
000000001972-01-16-0000January 16, 1972
Dallas Cowboys 02 !Dallas Cowboys*
(2, 1–1)
2403 !24–3
Miami Dolphins 01 !Miami Dolphins†
(1, 0–1)
Tulane Stadium 02 !Tulane Stadium (2)
New Orleans, Louisiana 02 !New Orleans, Louisiana (2)
081023 !81,023
[16]

07 !VII
000000001973-01-14-0000January 14, 1973
Miami Dolphins 02 !Miami Dolphins†
(2, 1–1)
1407 !14–7
Washington Redskins 01 !Washington Redskins*
(1, 0–1)
Los Angeles Memorial Coliseum 02 !Los Angeles Memorial Coliseum (2)
Los Angeles, California 02 !Los Angeles, California (2)[note 1]
090182 !90,182
[17]

08 !VIII
000000001974-01-13-0000January 13, 1974
Miami Dolphins 03 !Miami Dolphins†
(3, 2–1)
2407 !24–7
Minnesota Vikings 02 !Minnesota Vikings*
(2, 0–2)
Rice Stadium 01 !Rice Stadium
Houston, Texas 01 !Houston, Texas
071882 !71,882
[18]

09 !IX
000000001975-01-12-0000January 12, 1975
Pittsburgh Steelers 01 !Pittsburgh Steelers†
(1, 1–0)
1606 !16–6
Minnesota Vikings 03 !Minnesota Vikings*
(3, 0–3)
Tulane Stadium 03 !Tulane Stadium (3)
New Orleans, Louisiana 03 !New Orleans, Louisiana (3)
080997 !80,997
[19]

10 !X
000000001976-01-18-0000January 18, 1976
Pittsburgh Steelers 02 !Pittsburgh Steelers†
(2, 2–0)
2117 !21–17
Dallas Cowboys 03 !Dallas Cowboys*
(3, 1–2)
Miami Orange Bowl 04 !Miami Orange Bowl (4)
Miami, Florida 04 !Miami, Florida (4)[note 2]
080187 !80,187
[20]

11 !XI
000000001977-01-09-0000January 9, 1977
Oakland Raiders 02 !Oakland Raiders†
(2, 1–1)
3214 !32–14
Minnesota Vikings 04 !Minnesota Vikings*
(4, 0–4)
Rose Bowl 01 !Rose Bowl
Los Angeles, California 03 !Pasadena, California (3)[note 1]
103438 !103,438
[21]

12 !XII
000000001978-01-15-0000January 15, 1978
Dallas Cowboys 04 !Dallas Cowboys*
(4, 2–2)
2710 !27–10
Denver Broncos 01 !Denver Broncos†
(1, 0–1)
Louisiana Superdome 01 !Louisiana Superdome
New Orleans, Louisiana 04 !New Orleans, Louisiana (4)
076400 !76,400
[22]

13 !XIII
000000001979-01-21-0000January 21, 1979
Pittsburgh Steelers 03 !Pittsburgh Steelers†
(3, 3–0)
3531 !35–31
Dallas Cowboys 05 !Dallas Cowboys*
(5, 2–3)
Miami Orange Bowl 05 !Miami Orange Bowl (5)
Miami, Florida 05 !Miami, Florida (5)[note 2]
079484 !79,484
[23]

14 !XIV
000000001980-01-20-0000January 20, 1980
Pittsburgh Steelers 04 !Pittsburgh Steelers†
(4, 4–0)
3119 !31–19
Los Angeles Rams 01 !Los Angeles Rams*
(1, 0–1)
Rose Bowl 02 !Rose Bowl (2)
Los Angeles, California 04 !Pasadena, California (4)[note 1]
103985 !103,985
[24]

15 !XV
000000001981-01-25-0000January 25, 1981
Oakland Raiders 03 !Oakland Raiders†
(3, 2–1)
2710 !27–10
Philadelphia Eagles 01 !Philadelphia Eagles*
(1, 0–1)
Louisiana Superdome 02 !Louisiana Superdome (2)
New Orleans, Louisiana 05 !New Orleans, Louisiana (5)
076135 !76,135
[25]

16 !XVI
000000001982-01-24-0000January 24, 1982
San Francisco 49ers 01 !San Francisco 49ers*
(1, 1–0)
2621 !26–21
Cincinnati Bengals 01 !Cincinnati Bengals†
(1, 0–1)
Pontiac Silverdome 01 !Pontiac Silverdome
Detroit, Michigan 01 !Pontiac, Michigan[note 1]
081270 !81,270
[26]

17 !XVII
000000001983-01-30-0000January 30, 1983
Washington Redskins 02 !Washington Redskins*
(2, 1–1)
2717 !27–17
Miami Dolphins 04 !Miami Dolphins†
(4, 2–2)
Rose Bowl 03 !Rose Bowl (3)
Los Angeles, California 05 !Pasadena, California (5)[note 1]
103667 !103,667
[27]

18 !XVIII
000000001984-01-22-0000January 22, 1984
Oakland Raiders 04 !Los Angeles Raiders†
(4, 3–1)
3809 !38–9
Washington Redskins 03 !Washington Redskins*
(3, 1–2)
Tampa Stadium 01 !Tampa Stadium
Tampa, Florida 01 !Tampa, Florida
072920 !72,920
[28]

19 !XIX
000000001985-01-20-0000January 20, 1985
San Francisco 49ers 02 !San Francisco 49ers*
(2, 2–0)
3816 !38–16
Miami Dolphins 05 !Miami Dolphins†
(5, 2–3)
Stanford Stadium 01 !Stanford Stadium
San Francisco, California 01 !Stanford, California[note 1]
084059 !84,059
[29]

20 !XX
000000001986-01-26-0000January 26, 1986
Chicago Bears 01 !Chicago Bears*
(1, 1–0)
4610 !46–10
New England Patriots 01 !New England Patriots†
(1, 0–1)
Louisiana Superdome 03 !Louisiana Superdome (3)
New Orleans, Louisiana 06 !New Orleans, Louisiana (6)
073818 !73,818
[30]

21 !XXI
000000001987-01-25-0000January 25, 1987
New York Giants 01 !New York Giants*
(1, 1–0)
3920 !39–20
Denver Broncos 02 !Denver Broncos†
(2, 0–2)
Rose Bowl 04 !Rose Bowl (4)
Los Angeles, California 06 !Pasadena, California (6)[note 1]
101063 !101,063
[31]

22 !XXII
000000001988-01-31-0000January 31, 1988
Washington Redskins 04 !Washington Redskins*
(4, 2–2)
4210 !42–10
Denver Broncos 03 !Denver Broncos†
(3, 0–3)
Qualcomm Stadium 01 !San Diego–Jack Murphy Stadium[note 3]
San Diego, California 01 !San Diego, California
073302 !73,302
[32]

23 !XXIII
000000001989-01-22-0000January 22, 1989
San Francisco 49ers 03 !San Francisco 49ers*
(3, 3–0)
2016 !20–16
Cincinnati Bengals 02 !Cincinnati Bengals†
(2, 0–2)
Hard Rock Stadium 01 !Joe Robbie Stadium[note 3]
Miami, Florida 06 !Miami Gardens, Florida (6)[note 2]
075129 !75,129
[33]

24 !XXIV
000000001990-01-28-0000January 28, 1990
San Francisco 49ers 04 !San Francisco 49ers*
(4, 4–0)
5510 !55–10
Denver Broncos 04 !Denver Broncos†
(4, 0–4)
Louisiana Superdome 04 !Louisiana Superdome (4)
New Orleans, Louisiana 07 !New Orleans, Louisiana (7)
072919 !72,919
[34]

25 !XXV
000000001991-01-27-0000January 27, 1991
New York Giants 02 !New York Giants*
(2, 2–0)
2019 !20–19
Buffalo Bills 01 !Buffalo Bills†
(1, 0–1)
Tampa Stadium 02 !Tampa Stadium (2)
Tampa, Florida 02 !Tampa, Florida (2)
073813 !73,813
[35]

26 !XXVI
000000001992-01-26-0000January 26, 1992
Washington Redskins 05 !Washington Redskins*
(5, 3–2)
3724 !37–24
Buffalo Bills 02 !Buffalo Bills†
(2, 0–2)
Metrodome 01 !Metrodome
Minneapolis, Minnesota 01 !Minneapolis, Minnesota
063130 !63,130
[36]

27 !XXVII
000000001993-01-31-0000January 31, 1993
Dallas Cowboys 06 !Dallas Cowboys*
(6, 3–3)
5217 !52–17
Buffalo Bills 03 !Buffalo Bills†
(3, 0–3)
Rose Bowl 05 !Rose Bowl (5)
Los Angeles, California 07 !Pasadena, California (7)[note 1]
098374 !98,374
[37]

28 !XXVIII
000000001994-01-30-0000January 30, 1994
Dallas Cowboys 07 !Dallas Cowboys*
(7, 4–3)
3013 !30–13
Buffalo Bills 04 !Buffalo Bills†
(4, 0–4)
Georgia Dome 01 !Georgia Dome
Atlanta, Georgia 01 !Atlanta, Georgia
072817 !72,817
[38]

29 !XXIX
000000001995-01-29-0000January 29, 1995
San Francisco 49ers 05 !San Francisco 49ers*
(5, 5–0)
4926 !49–26
San Diego Chargers 01 !San Diego Chargers†
(1, 0–1)
Hard Rock Stadium 02 !Joe Robbie Stadium (2)[note 3]
Miami, Florida 07 !Miami Gardens, Florida (7)[note 2]
074107 !74,107
[39]

30 !XXX
000000001996-01-28-0000January 28, 1996
Dallas Cowboys 08 !Dallas Cowboys*
(8, 5–3)
2717 !27–17
Pittsburgh Steelers 05 !Pittsburgh Steelers†
(5, 4–1)
Sun Devil Stadium 01 !Sun Devil Stadium
Phoenix, Arizona 01 !Tempe, Arizona[note 1]
076347 !76,347
[40]

31 !XXXI
000000001997-01-26-0000January 26, 1997
Green Bay Packers 03 !Green Bay Packers*
(3, 3–0)
3521 !35–21
New England Patriots 02 !New England Patriots†
(2, 0–2)
Louisiana Superdome 05 !Louisiana Superdome (5)
New Orleans, Louisiana 08 !New Orleans, Louisiana (8)
072301 !72,301
[41]

32 !XXXII
000000001998-01-25-0000January 25, 1998
Denver Broncos 05 !Denver Broncos†
(5, 1–4)
3124 !31–24
Green Bay Packers 04 !Green Bay Packers*
(4, 3–1)
Qualcomm Stadium 02 !Qualcomm Stadium (2)[note 3]
San Diego, California 02 !San Diego, California (2)
068912 !68,912
[42]

33 !XXXIII
000000001999-01-31-0000January 31, 1999
Denver Broncos 06 !Denver Broncos†
(6, 2–4)
3419 !34–19
Atlanta Falcons 01 !Atlanta Falcons*
(1, 0–1)
Hard Rock Stadium 03 !Pro Player Stadium (3)[note 3]
Miami, Florida 08 !Miami Gardens, Florida (8)[note 2]
074803 !74,803
[43]

34 !XXXIV
000000002000-01-30-0000January 30, 2000
Los Angeles Rams 02 !St. Louis Rams*
(2, 1–1)
2316 !23–16
Tennessee Titans 01 !Tennessee Titans†
(1, 0–1)
Georgia Dome 02 !Georgia Dome (2)
Atlanta, Georgia 02 !Atlanta, Georgia (2)
072625 !72,625
[44]

35 !XXXV
000000002001-01-28-0000January 28, 2001
Baltimore Ravens 01 !Baltimore Ravens†
(1, 1–0)
3407 !34–7
New York Giants 03 !New York Giants*
(3, 2–1)
Raymond James Stadium 01 !Raymond James Stadium
Tampa, Florida 03 !Tampa, Florida (3)
071921 !71,921
[45]

36 !XXXVI
000000002002-02-03-0000February 3, 2002
New England Patriots 03 !New England Patriots†
(3, 1–2)
2017 !20–17
Los Angeles Rams 03 !St. Louis Rams*
(3, 1–2)
Louisiana Superdome 06 !Louisiana Superdome (6)
New Orleans, Louisiana 09 !New Orleans, Louisiana (9)
072922 !72,922
[46]

37 !XXXVII
000000002003-01-26-0000January 26, 2003
Tampa Bay Buccaneers 01 !Tampa Bay Buccaneers*
(1, 1–0)
4821 !48–21
Oakland Raiders 05 !Oakland Raiders†
(5, 3–2)
Qualcomm Stadium 03 !Qualcomm Stadium (3)[note 3]
San Diego, California 03 !San Diego, California (3)
067603 !67,603
[47]

38 !XXXVIII
000000002004-02-01-0000February 1, 2004
New England Patriots 04 !New England Patriots†
(4, 2–2)
3229 !32–29
Carolina Panthers 01 !Carolina Panthers*
(1, 0–1)
NRG Stadium 01 !Reliant Stadium[note 3]
Houston, Texas 02 !Houston, Texas (2)
071525 !71,525
[48]

39 !XXXIX
000000002005-02-06-0000February 6, 2005
New England Patriots 05 !New England Patriots†
(5, 3–2)
2421 !24–21
Philadelphia Eagles 02 !Philadelphia Eagles*
(2, 0–2)
ALLTEL Stadium 01 !Alltel Stadium
Jacksonville, Florida 01 !Jacksonville, Florida
078125 !78,125
[49]

40 !XL
000000002006-02-05-0000February 5, 2006
Pittsburgh Steelers 06 !Pittsburgh Steelers†
(6, 5–1)
2110 !21–10
Seattle Seahawks 01 !Seattle Seahawks*
(1, 0–1)
Ford Field 01 !Ford Field
Detroit, Michigan 02 !Detroit, Michigan (2)[note 1]
068206 !68,206
[50]

41 !XLI
000000002007-02-04-0000February 4, 2007
Indianapolis Colts 03 !Indianapolis Colts†
(3, 2–1)
2917 !29–17
Chicago Bears 02 !Chicago Bears*
(2, 1–1)
Hard Rock Stadium 04 !Dolphin Stadium (4)[note 3]
Miami, Florida 09 !Miami Gardens, Florida (9)[note 2]
074512 !74,512
[51]

42 !XLII
000000002008-02-03-0000February 3, 2008
New York Giants 04 !New York Giants*
(4, 3–1)
1714 !17–14
New England Patriots 06 !New England Patriots†
(6, 3–3)
University of Phoenix Stadium 01 !University of Phoenix Stadium
Phoenix, Arizona 02 !Glendale, Arizona (2)[note 1]
071101 !71,101
[52]

43 !XLIII
000000002009-02-01-0000February 1, 2009
Pittsburgh Steelers 07 !Pittsburgh Steelers†
(7, 6–1)
2723 !27–23
Arizona Cardinals 01 !Arizona Cardinals*
(1, 0–1)
Raymond James Stadium 02 !Raymond James Stadium (2)
Tampa, Florida 04 !Tampa, Florida (4)
070774 !70,774
[53]

44 !XLIV
000000002010-02-07-0000February 7, 2010
New Orleans Saints 01 !New Orleans Saints*
(1, 1–0)
3117 !31–17
Indianapolis Colts 04 !Indianapolis Colts†
(4, 2–2)
Hard Rock Stadium 05 !Sun Life Stadium (5)[note 3]
Miami, Florida 10 !Miami Gardens, Florida (10)[note 2]
074059 !74,059
[54]

45 !XLV
000000002011-02-06-0000February 6, 2011
Green Bay Packers 05 !Green Bay Packers*
(5, 4–1)
3125 !31–25
Pittsburgh Steelers 08 !Pittsburgh Steelers†
(8, 6–2)
Cowboys Stadium 01 !Cowboys Stadium
Arlington, Texas 01 !Arlington, Texas
103219 !103,219
[55]

46 !XLVI
000000002012-02-05-0000February 5, 2012
New York Giants 05 !New York Giants*
(5, 4–1)
2117 !21–17
New England Patriots 07 !New England Patriots†
(7, 3–4)
Lucas Oil Stadium 01 !Lucas Oil Stadium
Indianapolis, Indiana 01 !Indianapolis, Indiana
068658 !68,658
[56][57]

47 !XLVII
000000002013-02-03-0000February 3, 2013
Baltimore Ravens 02 !Baltimore Ravens†
(2, 2–0)
3431 !34–31
San Francisco 49ers 06 !San Francisco 49ers*
(6, 5–1)
Louisiana Superdome 07 !Mercedes-Benz Superdome (7)
New Orleans, Louisiana 10 !New Orleans, Louisiana (10)
071024 !71,024
[56][58]

48 !XLVIII
000000002014-02-02-0000February 2, 2014
Seattle Seahawks 02 !Seattle Seahawks*
(2, 1–1)
4308 !43–8
Denver Broncos 07 !Denver Broncos†
(7, 2–5)
MetLife Stadium 01 !MetLife Stadium
East Rutherford, New Jersey 01 !East Rutherford, New Jersey
082529 !82,529
[59]

49 !XLIX
000000002015-02-01-0000February 1, 2015
New England Patriots 08 !New England Patriots†
(8, 4–4)
2824 !28–24
Seattle Seahawks 03 !Seattle Seahawks*
(3, 1–2)
University of Phoenix Stadium 02 !University of Phoenix Stadium (2)
Phoenix, Arizona 03 !Glendale, Arizona (3)[note 1]
070288 !70,288
[60][61]

50 !50 [note 4]
000000002016-02-07-0000February 7, 2016
Denver Broncos 08 !Denver Broncos†
(8, 3–5)
2410 !24–10
Carolina Panthers 02 !Carolina Panthers*
(2, 0–2)
Levi's Stadium 01 !Levi's Stadium
San Francisco, California 02 !Santa Clara, California (2)[note 1]
071088 !71,088
[61][62][63]

51 !LI
000000002017-02-05-0000February 5, 2017
New England Patriots 09 !New England Patriots†
(9, 5–4)
3428 !34–28 (OT)
Atlanta Falcons 02 !Atlanta Falcons*
(2, 0–2)
NRG Stadium 02 !NRG Stadium (2)[note 3]
Houston, Texas 03 !Houston, Texas (3)
070807 !70,807
[61][62][63]

52 !LII
000000002018-02-04-0000February 4, 2018
Philadelphia Eagles 03 !Philadelphia Eagles*
(3, 1–2)
4133 !41–33
New England Patriots 10 !New England Patriots†
(10, 5–5)
U.S. Bank Stadium 01 !U.S. Bank Stadium
Minneapolis, Minnesota 02 !Minneapolis, Minnesota (2)
067612 !67,612
[64][65]

53 !LIII
000000002019-02-03-0000February 3, 2019 [note 5]
X 2019 !2018–19 AFC champion† at 2018–19 NFC champion*
0019 !—
X 2019 !To be determined (TBD)
Mercedes-Benz Stadium 01 !Mercedes-Benz Stadium
Atlanta, Georgia 03 !Atlanta, Georgia (3)
TBD
[66][67]

54 !LIV
000000002020-02-02-0000February 2, 2020 [note 5]
X 2020 !2019–20 NFC champion* at 2019–20 AFC champion†
0020 !—
X 2020 !To be determined
Hard Rock Stadium 06 !Hard Rock Stadium (6)[note 3]
Miami, Florida 11 !Miami Gardens, Florida (11)[note 2]
TBD
[66][67]

55 !LV
000000002021-02-07-0000February 7, 2021 [note 5]
X 2020 !2020–21 AFC champion† at 2020–21 NFC champion*
0021 !—
X 2021 !To be determined
Raymond James Stadium 03 !Raymond James Stadium (3)
Tampa, Florida 05 !Tampa, Florida (5)
TBD
[66][67]

56 !LVI
000000002022-02-06-0000February 6, 2022 [note 5]
X 2021 !2021–22 NFC champion† at 2021–22 AFC champion*
0022 !—
X 2022 !To be determined
City of Champions Stadium 01 !Los Angeles Stadium at Hollywood Park
Los Angeles, California 08 !Inglewood, California (8)[note 1]
TBD
[66][67]

Game
Date
Winning team
Score
Losing team
Venue
City
Attendance
Ref

text: Consecutive winners

text: Seven franchises have won consecutive Super Bowls, one of which (Pittsburgh) has accomplished it twice:

text:
Green Bay Packers (Super Bowls I and II)
Miami Dolphins (VII and VIII)
Pittsburgh Steelers (twice: IX and X as well as XIII and XIV)
San Francisco 49ers (XXIII and XXIV)
Dallas Cowboys (XXVII and XXVIII)
Denver Broncos (XXXII and XXXIII)
New England Patriots (XXXVIII and XXXIX)

text: No franchise has yet won three Super Bowls in a row, although several have come close:

text:
The Green Bay Packers won the first two Super Bowls, and also won the NFL championship the preceding year.
The Miami Dolphins appeared in three consecutive Super Bowls (VI, VII, and VIII), winning the last two.
The Pittsburgh Steelers won two consecutive Super Bowls (IX and X); the following season they were eliminated in the AFC championship game by the eventual Super Bowl champion Oakland Raiders. They also won two more consecutive Super Bowls (XIII and XIV) for four wins in six seasons.
The San Francisco 49ers won two consecutive Super Bowls (XXIII and XXIV); the following season they were eliminated in the NFC championship by the eventual Super Bowl champion New York Giants.
The Dallas Cowboys won two consecutive Super Bowls (XXVII and XXVIII); the following season they were eliminated in the NFC championship game by the eventual champion San Francisco 49ers. The Cowboys won Super Bowl XXX the following year for three wins in four seasons.
The New England Patriots won Super Bowl XXXVI, which was two years before their consecutive wins in XXXVIII and XXXIX, for three wins in four seasons. They did not make the playoffs in the intervening season (XXXVII). The Patriots also won Super Bowls XLIX and LI and in the intervening season (50) were eliminated in the AFC championship game by the eventual champion Denver Broncos.

text: Consecutive losers

text: Three franchises have lost consecutive Super Bowls:

text:
Buffalo Bills (4) (Super Bowls XXV, XXVI, XXVII, and XXVIII) – The only team to appear in four straight Super Bowls, let alone lose in all four appearances.
Minnesota Vikings (2) (Super Bowls VIII and IX) – They also lost Super Bowl XI, and were knocked out of the playoffs for Super Bowl X by the eventual losers the Dallas Cowboys for three losses in four seasons.
Denver Broncos (2) (Super Bowls XXI and XXII) – They also lost Super Bowl XXIV, but did not even make the playoffs for Super Bowl XXIII for three losses in four seasons.

text: Super Bowl appearances by team

text:
NFL‡/NFC* teams (27 wins)
AFL^/AFC† teams (25 wins)

NFL‡/AFC† team[note 6]

text: In the sortable table below, teams are ordered first by number of appearances, then by number of wins, and finally by number of years since last appearing in a Super Bowl. In the "Seasons" column, bold years indicate winning seasons, and italic years indicate games not yet completed.

text:
Appearances
Team
Wins
Losses
Winning
percentage
Seasons

10A-05W-01YA-02YW !10
New England Patriots†
05W-02YW !5
05L-01YL !5
.500
1985 !1985,† 1996,† 2001,† 2003,† 2004,† 2007,† 2011,† 2014,† 2016,† 2017†

08A-06W-08YA-10YW !8
Pittsburgh Steelers†[note 6]
06W-10YW !6
02L-08YL !2
.750
1974 !1974,† 1975,† 1978,† 1979,† 1995,† 2005,† 2008,† 2010†

08A-05W-23YA-23YW !8
Dallas Cowboys*
05W-23YW !5
03L-40YL !3
.625
1970 !1970,* 1971,* 1975,* 1977,* 1978,* 1992,* 1993,* 1995*

08A-03W-03YA-03YW !8
Denver Broncos†
03W-03YW !3
05L-05YL !5
.375
1977 !1977,† 1986,† 1987,† 1989,† 1997,† 1998,† 2013,† 2015†

06A-05W-06YA-24YW !6
San Francisco 49ers*
05W-24YW !5
01L-06YL !1
.833
1981 !1981,* 1984,* 1988,* 1989,* 1994*, 2012*

05A-04W-08YA-08YW !5
Green Bay Packers‡*
04W-08YW !4
01L-21YL !1
.800
1966 !1966,‡ 1967,‡ 1996,* 1997,* 2010*

05A-04W-07YA-07YW !5
New York Giants*
04W-07YW !4
01L-18YL !1
.800
1986 !1986,* 1990,* 2000,* 2007,* 2011*

05A-03W-27YA-27YW !5
Washington Redskins*
03W-27YW !3
02L-35YL !2
.600
1972 !1972,* 1982,* 1983,* 1987,* 1991*

05A-03W-16YA-35YW !5
Los Angeles/Oakland Raiders^†
03W-35YW !3
02L-16YL !2
.600
1967,^ 1976,† 1980,† 1983,† 2002†

05A-02W-34YA-45YW !5
Miami Dolphins†
02W-45YW !2
03L-34YL !3
.400
1971 !1971,† 1972,† 1973,† 1982,† 1984†

04A-02W-09YA-12YW !4
Baltimore/Indianapolis Colts‡†[note 6]
02W-12YW !2
02L-09YL !2
.500
1968 !1968,‡ 1970,† 2006,† 2009†

04A-00W-42YA-53YW !4
Minnesota Vikings‡*
00W-53YW-04A-25YA !0
04L-42YL !4
.000
1969 !1969,‡ 1973,* 1974,* 1976*

04A-00W-25YA-53YW !4
Buffalo Bills†
00W-53YW-04A-25YA !0
04L-25YL !4
.000
1990 !1990,† 1991,† 1992,† 1993†

03A-01W-17YA-19YW !3
St. Louis/Los Angeles Rams*
01W-19YW !1
02L-17YL !2
.333
1979 !1979,* 1999,* 2001*

03A-01W-03YA-04YW !3
Seattle Seahawks*
01W-04YW !1
02L-03YL !2
.333
2005 !2005,* 2013,* 2014*

03A-01W-01YA-01YW !3
Philadelphia Eagles*
01W-01YW !1
02L-14YL !2
.333
1980 !1980,* 2004,* 2017*

02A-02W-06YA-06YW !2
Baltimore Ravens†[note 7]
02W-06YW !2
00L-22YL-02A-06YA !0
1.000
2000 !2000,† 2012†

02A-01W-49YA-49YW !2
Kansas City Chiefs^†
01W-49YW !1
01L-52YL !1
.500
1966 !1966,^ 1969^

02A-01W-12YA-33YW !2
Chicago Bears*
01W-33YW !1
01L-12YL !1
.500
1985 !1985,* 2006*

02A-00W-30YA-53YW !2
Cincinnati Bengals†
00W-53YW-02A-30YA !0
02L-30YL !2
.000
1981 !1981,† 1988†

02A-00W-03YA-23YW !2
Carolina Panthers*
00W-23YW-02A-03YA !0
02L-03YL !2
.000
2003 !2003,* 2015*

02A-00W-02YA-53YW !2
Atlanta Falcons*
00W-53YW-02A-02YA !0
02L-02YL !2
.000
1998 !1998,* 2016*

01A-01W-50YA-50YW !1
New York Jets^†
01W-50YW !1
00L-53YL-01A-50YA !0
1.000
1968 !1968^

01A-01W-18YA-18YW !1
Tampa Bay Buccaneers*
01W-18YW !1
00L-44YL-01A-18YA !0
1.000
2002 !2002*

01A-01W-09YA-09YW !1
New Orleans Saints*
01W-09YW !1
00L-52YL-01A-09YA !0
1.000
2009 !2009*

01A-00W-24YA-53YW !1
San Diego/Los Angeles Chargers†
00W-53YW-01A-24YA !0
01L-24YL !1
.000
1994 !1994†

01A-00W-19YA-53YW !1
Houston/Tennessee Oilers/Tennessee Titans†
00W-53YW-01A-19YA !0
01L-19YL !1
.000
1999 !1999†

01A-00W-10YA-53YW !1
St. Louis/Arizona Cardinals*
00W-53YW-01A-10YA !0
01L-10YL !1
.000
2008 !2008*

00A-00W-53YA-53YW-11CG !0
Cleveland Browns†[note 6][note 7]
00W-53YW-00A-53YA-11CG !0
00L-53YL-00A-53YA-11CG !0
–
none

00A-00W-53YA-53YW-05CG !0
Detroit Lions*
00W-53YW-00A-53YA-05CG !0
00L-53YL-00A-53YA-05CG !0
–
none

00A-00W-23YA-23YW-00CG !0
Jacksonville Jaguars†
00W-23YW-00A-23YA-00CG !0
00L-23YL-00A-23YA-00CG !0
–
none

00A-00W-16YA-16YW-00CG !0
Houston Texans†
00W-16YW-00A-16YA-00CG !0
00L-16YL-00A-16YA-00CG !0
–
none

text: Teams with no Super Bowl appearances

text: Four current teams have never reached the Super Bowl. Two of them held NFL league championships prior to Super Bowl I in the 1966 NFL season:

text:
Cleveland Browns, NFL champions four times in 1950, 1954, 1955, and 1964; appeared in seven other NFL championship games in 1951, 1952, 1953, 1957, 1965, 1968, and 1969; and appeared in three AFC Championship Games in 1986, 1987, and 1989.[68] The Browns are officially viewed as one continuous franchise that began in 1946 as a member of the All-America Football Conference, joined the NFL in 1950, suspended operations from 1996 to 1998, and resumed play in 1999.[69] The Baltimore Ravens were an expansion team created in 1996 with former Browns players.[70]
Detroit Lions, NFL champions four times in 1935, 1952, 1953, and 1957; appeared in one other NFL Championship Game in 1954; and appeared in one NFC Championship Game in 1991[71]
Jacksonville Jaguars, 1995 expansion team; appeared in three AFC Championship Games in 1996, 1999, and 2017.[72]
Houston Texans, 2002 expansion team; Divisional Round appearances in 2011, 2012, and 2016 seasons.

text: In addition, Detroit, Houston, and Jacksonville have hosted Super Bowls, making Cleveland the only current NFL city that has neither hosted nor had its team play in a Super Bowl.

text: Teams with long Super Bowl droughts

text: Although Jacksonville and Houston have never appeared in a Super Bowl, there are teams whose most recent Super Bowl appearance is older than when Jacksonville and Houston joined the NFL (1995 and 2002, respectively), resulting in longer Super Bowl droughts than these teams for the following eight teams.

text: Two of these teams have not appeared in the Super Bowl since before the AFL–NFL merger in 1970:[73]

text:
New York Jets (most recently appeared in Super Bowl III, 1968 season)
Kansas City Chiefs (Super Bowl IV in 1969 season)

text: However, the Jets and the Chiefs are the only non-NFL teams to win the Super Bowl, both being members of the now-defunct AFL at the time.

text: The most recent Super Bowl appearance for the following teams was after the AFL–NFL merger, but prior to the 1995 regular season:

text:
Minnesota Vikings (Super Bowl XI, 1976 season)
Miami Dolphins (Super Bowl XIX, 1984 season)
Cincinnati Bengals (Super Bowl XXIII, 1988 season)
Washington Redskins (Super Bowl XXVI, 1991 season)
Buffalo Bills (Super Bowl XXVIII, 1993 season)
Los Angeles Chargers (played as San Diego Chargers in Super Bowl XXIX, 1994 season)

text: Teams with Super Bowl appearances but no victories

text: Eight teams have appeared in the Super Bowl without ever winning. In descending order of number of appearances, they are:

text:
Minnesota Vikings (4), appeared in Super Bowls IV, VIII, IX, and XI. They won the NFL Championship Game in 1969, the last year before the AFL–NFL merger, but failed to win the subsequent Super Bowl. An NFL expansion team in 1961, they have no pre-Super Bowl league championships.
Buffalo Bills (4), appeared in Super Bowls XXV, XXVI, XXVII, and XXVIII. Their second and last AFL championship was in 1965, the season before the first Super Bowl.
Cincinnati Bengals (2), appeared in Super Bowls XVI and XXIII. An AFL expansion team in 1968, they have no pre-Super Bowl league championships.
Atlanta Falcons (2), appeared in Super Bowls XXXIII and LI. An expansion team in 1966, they have no pre-Super Bowl league championships.
Carolina Panthers (2), appeared in Super Bowls XXXVIII and 50. A post-merger expansion team, their first season was in 1995.
Arizona Cardinals (1), appeared in Super Bowl XLIII. Their last championship was in 1947 as the Chicago Cardinals.
Los Angeles Chargers (1), appeared in Super Bowl XXIX as the San Diego Chargers. Their only AFL championship was in 1963.
Tennessee Titans (1), appeared in Super Bowl XXXIV. They won the first two AFL Championships in 1960 and 1961 as the Houston Oilers.

text: Super Bowl rematches

text: The following teams have faced each other more than once in the Super Bowl:

text:
Dallas Cowboys and Pittsburgh Steelers (3) – Super Bowls X and XIII were won by Pittsburgh, and Super Bowl XXX was won by Dallas. See also Cowboys–Steelers rivalry.
Miami Dolphins and Washington Redskins (2) – Super Bowl VII was won by Miami, and Super Bowl XVII was won by Washington.
Cincinnati Bengals and San Francisco 49ers (2) – Super Bowls XVI and XXIII were both won by San Francisco.
Buffalo Bills and Dallas Cowboys (2) – Super Bowls XXVII and XXVIII, the only rematch in consecutive seasons, were both won by Dallas.
New England Patriots and New York Giants (2) – Super Bowls XLII and XLVI were both won by New York.
New England Patriots and Philadelphia Eagles (2) – Super Bowl XXXIX was won by New England, Super Bowl LII was won by Philadelphia.


document_title: Anyone for tennis?

question_text: where did the phrase tennis anyone come from

root

text: Anyone for tennis?

text: This article possibly contains original research. Please improve it by verifying the claims made and adding inline citations. Statements consisting only of original research should be removed. (April 2017) (Learn how and when to remove this template message)

tag: table

text: This article contains embedded lists that may be poorly defined, unverified or indiscriminate. Please help to clean it up to meet Wikipedia's quality standards. Where appropriate, incorporate items into the main body of the article. (April 2017)

text: The phrase Anyone for tennis? is thought to have originated from George Bernard Shaw's 1914 play Misalliance, in which Johnny Tarleton asks "Anybody on for a game of tennis?"[1] This phrase is often used to typify a particular genre of drawing room comedy about the leisured upper class.[citation needed]

tag: p

text: This phrase has been used several times in popular culture, including by Daffy Duck in the cartoon shorts The Ducksters, Rabbit Fire, and Drip-Along Daffy, the song "Beautiful Girl" in the movie musical Singin' in the Rain, and as the title of a song by the British blues-rock band Cream. In episode 33 of Monty Python's Flying Circus, a spoof of Sam Peckinpah's violent movies begins with a genteel lawn party; the line "I say, anyone for tennis?" is the ironic cue for an explosion of overblown, horrific violence. It is also mentioned in the popular 1975 song Patricia the Stripper by Chris de Burgh.

text: Other uses of the phrase in pop culture include:

text:
As a tagline for a brand of tennis apparel seen in the movie Any Questions for Ben?, where the lead actor plays the role of a strategic brand manager.
In the game EcoQuest 2, the protagonist says the phrase whenever he uses the tennis racket.
The stage play Anyone for Denis?, referring to Denis Thatcher.
In June 2012, after the English national football team was eliminated from that year's European championships, The Sun newspaper announced that Britain could still win Wimbledon, using the headline "Anyone for Tennis?" This headline gained notoriety two weeks later when British hopeful Andy Murray lost the Wimbledon final, and The Sun asked "Anyone for Ennis?" in reference to hopes that English track-and-field athlete Jessica Ennis could take home the gold in that year's Summer Olympics.

tag: ul


document_title: Bring It On Again

question_text: why does whittier quit the squad in bring it on again

text: Bring It On Again

text: Plot[edit]

text: Whittier arrives at the fictional California State College hoping to join the national champion varsity cheerleading team. She meets up with her friend from cheerleading camp, Monica, and they're both impressive at the tryouts. Head cheerleader Tina is ready to ask them to join the team, but Greg goes a step further, telling Tina that Whittier will be the next head cheerleader. This angers Tina's pal Marni who had the position staked out, but at the urging of Dean Sebastian, Tina goes along with the plan, taking Whittier under her wing. Whittier meets Derek, a campus D.J. who immediately takes an interest in her. Tina is very demanding and controlling and warns Whittier that Derek is not the type of boy she should be dating. Monica is bothered by Tina's meddling, but Whittier momentarily lets her cheerleading ambition get the better of her, and betrays Derek. Then, Tina, upset with Monica's sassy attitude, punishes her which leads to an injury and she forces Whittier to choose between her friendship and the squad. Whittier and Monica get fed up and quit Tina's tyranny, but Whittier's school spirit cannot be suppressed. With Monica's help, she gathers up the outcasts from the drama club, the dance club, and other groups that have lost their funding because of the squad and forms a ragtag squad of her own, determined to battle the varsity squad for a spot at the national championship. The two teams end up competing for the spot at nationals, with Whittier's squad ultimately winning. Afterward, Whittier offers Tina a spot on her squad, a position that Tina initially refuses but ends up wanting. The film ends with Tina sucking up to Whittier and Monica, deciding she wants to be on their squad after all, while Marni comically throws a fit.

text: Cast[edit]

text:
Anne Judson-Yager as Whittier Smith
Bree Turner as Tina Hammersmith
Kevin Cooney as Dean Sebastian
Faune A. Chambers as Monica
Bryce Johnson as Greg
Richard Lee Jackson as Derek
Bethany Joy Lenz as Marni Potts
Holly Towne as Janice
Dennis Hemphill Jr. as Francis
Felicia Day as Penelope Hope
Katherine Bailess as Colleen Lipman
Joshua Gomez as Sammy Stinger
Kelly Stables as Tiny Blonde
Brian Wade as Fatneck
Darren Geare as Croquet Teammate
Jerry Trainor as Smug Guy


document_title: Huntington's disease

question_text: what chromosome has the genetic mutation for huntington's disease

question_tokens: what chromosome has the genetic mutation for huntington 's disease

text: Huntington's disease

text: Signs and symptoms[edit]

text:
Reported rates of behavioral symptoms in Huntington's disease[11]

Irritability
38–73%

Apathy
34–76%

Anxiety
34–61%

Depressed mood
33–69%

Obsessive and compulsive
10–52%

Psychotic
3–11%

text: Symptoms of Huntington's disease most commonly become noticeable between the ages of 35 and 44 years, but they can begin at any age from infancy to old age.[12][13] In the early stages, there are subtle changes in personality, cognition, and physical skills.[12] The physical symptoms are usually the first to be noticed, as cognitive and behavioral symptoms[14] are generally not severe enough to be recognized on their own at the earlier stages.[12] Almost everyone with Huntington's disease eventually exhibits similar physical symptoms, but the onset, progression and extent of cognitive and behavioral symptoms vary significantly between individuals.[15][16]

text: The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea.[12] Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, lack of coordination, or slowed saccadic eye movements.[12] These minor motor abnormalities usually precede more obvious signs of motor dysfunction by at least three years.[15] The clear appearance of symptoms such as rigidity, writhing motions or abnormal posturing appear as the disorder progresses.[17] These are signs that the system in the brain that is responsible for movement has been affected.[18] Psychomotor functions become increasingly impaired, such that any action that requires muscle control is affected. Common consequences are physical instability, abnormal facial expression, and difficulties chewing, swallowing, and speaking.[17] Eating difficulties commonly cause weight loss and may lead to malnutrition.[19][20] Sleep disturbances are also associated symptoms.[21] Juvenile HD differs from these symptoms in that it generally progresses faster and chorea is exhibited briefly, if at all, with rigidity being the dominant symptom. Seizures are also a common symptom of this form of HD.[17]

text: Cognitive abilities are progressively impaired.[18] Especially affected are executive functions, which include planning, cognitive flexibility, abstract thinking, rule acquisition, initiation of appropriate actions, and inhibition of inappropriate actions.[18] As the disease progresses, memory deficits tend to appear. Reported impairments range from short-term memory deficits to long-term memory difficulties, including deficits in episodic (memory of one's life), procedural (memory of the body of how to perform an activity) and working memory.[18] Cognitive problems tend to worsen over time, ultimately leading to dementia.[18] This pattern of deficits has been called a subcortical dementia syndrome to distinguish it from the typical effects of cortical dementias e.g. Alzheimer's disease.[18]

text: Reported neuropsychiatric manifestations are anxiety, depression, a reduced display of emotions (blunted affect), egocentrism, aggression, and compulsive behavior, the latter of which can cause or worsen addictions, including alcoholism, gambling, and hypersexuality.[11] Difficulties in recognizing other people's negative expressions have also been observed.[18] The prevalence of these symptoms is highly variable between studies, with estimated rates for lifetime prevalence of psychiatric disorders between 33% and 76%.[11] For many sufferers and their families, these symptoms are among the most distressing aspects of the disease, often affecting daily functioning and constituting reason for institutionalization.[11] Suicidal thoughts and suicide attempts are more common than in the general population.[12] Often individuals have reduced awareness of chorea, cognitive and emotional impairments.[22]

text: Mutant Huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by such expression outside the brain. These abnormalities include muscle atrophy, cardiac failure, impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy.[23]

text: Genetics[edit]

text: All humans have two copies of the Huntingtin gene (HTT), which codes for the protein Huntingtin (HTT). The gene is also called HD and IT15, which stands for 'interesting transcript 15'. Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between individuals and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant Huntingtin protein (mHTT). The differing functions of these proteins are the cause of pathological changes which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant and almost fully penetrant: mutation of either of a person's HTT alleles causes the disease. It is not inherited according to sex, but the length of the repeated section of the gene and hence its severity can be influenced by the sex of the affected parent.[24]

text: Genetic mutation[edit]

text: HD is one of several trinucleotide repeat disorders which are caused by the length of a repeated section of a gene exceeding a normal range.[25] The HTT gene is located on the short arm of chromosome 4[25] at 4p16.3. HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat.[25] CAG is the 3-letter genetic code (codon) for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the PolyQ region.[26]

text:
Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats[25]

Repeat count
Classification
Disease status
Risk to offspring

<26
Normal
Will not be affected
None

27–35
Intermediate
Will not be affected
Elevated but <<50%

36–39
Reduced Penetrance
May or may not be affected
50%

40+
Full Penetrance
Will be affected
50%

text: Generally, people have fewer than 36 repeated glutamines in the polyQ region which results in production of the cytoplasmic protein Huntingtin.[25] However, a sequence of 36 or more glutamines results in the production of a protein which has different characteristics.[25] This altered form, called mutant huntingtin (mHTT), increases the decay rate of certain types of neurons. Regions of the brain have differing amounts and reliance on these types of neurons, and are affected accordingly.[17] Generally, the number of CAG repeats is related to how much this process is affected, and accounts for about 60% of the variation of the age of the onset of symptoms. The remaining variation is attributed to environment and other genes that modify the mechanism of HD.[25] 36–39 repeats result in a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. In some cases the onset may be so late that symptoms are never noticed.[27] With very large repeat counts, HD has full penetrance and can occur under the age of 20, when it is then referred to as juvenile HD, akinetic-rigid, or Westphal variant HD. This accounts for about 7% of HD carriers.[28]

text: Inheritance[edit]

text: Huntington's disease has autosomal dominant inheritance, meaning that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent.[12] Since penetrance of the mutation is very high, those who have a mutated copy of the gene will have the disease. In this type of inheritance pattern, each offspring of an affected individual has a 50% risk of inheriting the mutant allele and therefore being affected with the disorder (see figure). This probability is sex-independent.[29]

text: Trinucleotide CAG repeats over 28 are unstable during replication, and this instability increases with the number of repeats present.[27] This usually leads to new expansions as generations pass (dynamic mutations) instead of reproducing an exact copy of the trinucleotide repeat.[25] This causes the number of repeats to change in successive generations, such that an unaffected parent with an "intermediate" number of repeats (28–35), or "reduced penetrance" (36–40), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD.[25] Such increases in the number of repeats (and hence earlier age of onset and severity of disease) in successive generations is known as genetic anticipation.[25] Instability is greater in spermatogenesis than oogenesis;[25] maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length.[25][30] It is rare for Huntington's disease to be caused by a new mutation, where neither parent has over 36 CAG repeats.[31]

text: In the rare situations where both parents have an expanded HD gene, the risk increases to 75%, and when either parent has two expanded copies, the risk is 100% (all children will be affected). Individuals with both genes affected are rare. For some time HD was thought to be the only disease for which possession of a second mutated gene did not affect symptoms and progression,[32] but it has since been found that it can affect the phenotype and the rate of progression.[25][33]

text: Mechanism[edit]

text: The huntingtin protein interacts with over 100 other proteins, and appears to have multiple biological functions.[34] The behavior of this mutated protein is not completely understood, but it is toxic to certain cell types, particularly in the brain. Early damage is most evident in the striatum, but as the disease progresses, other areas of the brain are also more conspicuously affected. Early symptoms are attributable to functions of the striatum and its cortical connections—namely control over movement, mood and higher cognitive function.[24] DNA methylation also appears to be changed in HD.[35]

text: Huntingtin function[edit]

text: HTT is expressed in all mammalian cells. The highest concentrations are found in the brain and testes, with moderate amounts in the liver, heart, and lungs.[24] The function of HTT in humans is unclear. It interacts with proteins which are involved in transcription, cell signaling, and intracellular transporting.[24][36] In animals genetically modified to exhibit HD, several functions of HTT have been found.[37] In these animals, HTT is important for embryonic development, as its absence is related to embryonic death. Caspase, an enzyme which plays a role in catalyzing apoptosis, is thought to be activated by the mutated gene through damaging the ubiquitin-protease system. It also acts as an anti-apoptotic agent preventing programmed cell death and controls the production of brain-derived neurotrophic factor, a protein which protects neurons and regulates their creation during neurogenesis. HTT also facilitates vesicular transport and synaptic transmission and controls neuronal gene transcription.[37] If the expression of HTT is increased and more HTT produced, brain cell survival is improved and the effects of mHTT are reduced, whereas when the expression of HTT is reduced, the resulting characteristics are more typical of the presence of mHTT.[37] In humans the disruption of the normal gene does not cause the disease.[24] It is thought that the disease is not caused by inadequate production of HTT, but by an increase in the toxic function of mHTT in the body.[24]

text: Cellular changes[edit]

text: There are multiple cellular changes through which the toxic function of mHTT may manifest and produce the HD pathology.[38][39] In its mutant (i.e. polyglutamine expanded) form, the protein is more prone to cleavage that creates shorter fragments containing the polyglutamine expansion.[38] These protein fragments have a propensity to undergo misfolding and aggregation, yielding fibrillar aggregates in which non-native polyglutamine β-strands from multiple proteins are bonded together via hydrogen bonds.[40] These aggregates share the same fundamental cross-β amyloid architecture seen in other protein deposition diseases. Over time, the aggregates accumulate to form inclusion bodies within cells, ultimately interfering with neuron function.[38][40] Neuronal inclusions run indirect interference. Inclusion bodies have been found in both the cell nucleus and cytoplasm.[38] Inclusion bodies in cells of the brain are one of the earliest pathological changes, and some experiments have found that they can be toxic for the cell, but other experiments have shown that they may form as part of the body's defense mechanism and help protect cells.[38]

text: Several pathways by which mHTT may cause cell death have been identified. These include: effects on chaperone proteins, which help fold proteins and remove misfolded ones; interactions with caspases, which play a role in the process of removing cells; the toxic effects of glutamine on nerve cells; impairment of energy production within cells; and effects on the expression of genes.[40][41]

text: An additional theory that explains another way cell function may be disrupted by HD proposes that damage to mitochondria in striatal cells is of central importance (numerous accounts of mitochondrial metabolism deficiency have been found). Mutant Huntingtin protein has been found to play a key role in mitochondrial dysfunction.[42] The impairment of mitochondrial electron transport can result in higher levels of oxidative stress and release of reactive oxygen species.[43]

text: The interactions of the altered huntingtin protein with numerous proteins in neurons leads to an increased vulnerability of glutamine, which, in large amounts, has been found to be an excitotoxin. Excitotoxins may cause damage to numerous cellular structures. Although glutamine is not found in excessively high amounts, it has been postulated that because of the increased vulnerability, even normal amounts glutamine can cause excitotoxins to be expressed.[40]

text: Macroscopic changes[edit]

text: HD affects the whole brain, but certain areas are more vulnerable than others. The most prominent early effects are in a part of the basal ganglia called the neostriatum, which is composed of the caudate nucleus and putamen.[24] Other areas affected include the substantia nigra, layers 3, 5 and 6 of the cerebral cortex, the hippocampus, purkinje cells in the cerebellum, lateral tuberal nuclei of the hypothalamus and parts of the thalamus.[25] These areas are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells.[25] Striatal spiny neurons are the most vulnerable, particularly ones with projections towards the external globus pallidus, with interneurons and spiny cells projecting to the internal pallidum being less affected.[25][44] HD also causes an abnormal increase in astrocytes and activation of the brain's immune cells, microglia.[45]

text: The basal ganglia—the part of the brain most prominently affected in early HD—play a key role in movement and behavior control. Their functions are not fully understood, but current theories propose that they are part of the cognitive executive system[18] and the motor circuit.[46] The basal ganglia ordinarily inhibit a large number of circuits that generate specific movements. To initiate a particular movement, the cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released. Damage to the basal ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled, which results in an awkward start to motion or motions to be unintentionally initiated, or a motion to be halted before, or beyond, its intended completion. The accumulating damage to this area causes the characteristic erratic movements associated with HD.[46] The spontaneous and erratic physical movements associated with HD are classified as a type of hyperkinetic dysarthria. Because of the basal ganglia's inability to inhibit movements, individuals affected by it will inevitably experience a reduced ability to produce speech and swallow foods and liquids (dysphagia).[47]

text: Transcriptional dysregulation[edit]

text: CREB-binding protein (CBP), a transcriptional coregulator, is essential for cell function because as a coactivator at a significant number of promoters, it activates the transcription of genes for survival pathways.[41] Furthermore, the amino acids that form CBP include a strip of 18 glutamines. Thus, the glutamines on CBP interact directly with the increased numbers of glutamine on the HTT chain and CBP gets pulled away from its typical location next to the nucleus.[48] Specifically, CBP contains an acetyltransferase domain to which HTT binds through its polyglutamine-containing domain.[49] Autopsied brains of those who had Huntington's disease also have been found to have incredibly reduced amounts of CBP.[48] In addition, when CBP is overexpressed, polyglutamine-induced death is diminished, further demonstrating that CBP plays an important role in Huntington's disease and neurons in general.[41]

text: Diagnosis[edit]

text: Medical diagnosis of the onset of HD can be made following the appearance of physical symptoms specific to the disease.[12] Genetic testing can be used to confirm a physical diagnosis if there is no family history of HD. Even before the onset of symptoms, genetic testing can confirm if an individual or embryo carries an expanded copy of the trinucleotide repeat in the HTT gene that causes the disease. Genetic counseling is available to provide advice and guidance throughout the testing procedure, and on the implications of a confirmed diagnosis. These implications include the impact on an individual's psychology, career, family planning decisions, relatives and relationships. Despite the availability of pre-symptomatic testing, only 5% of those at risk of inheriting HD choose to do so.[24]

text: Clinical[edit]

text: A physical examination, sometimes combined with a psychological examination, can determine whether the onset of the disease has begun.[12] Excessive unintentional movements of any part of the body are often the reason for seeking medical consultation. If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD. Cognitive or behavioral symptoms are rarely the first symptoms diagnosed; they are usually only recognized in hindsight or when they develop further. How far the disease has progressed can be measured using the unified Huntington's disease rating scale, which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments.[51][52] Medical imaging, such as computerized tomography (CT) and magnetic resonance imaging (MRI), can show atrophy of the caudate nuclei early in the disease, as seen in the illustration to the right, but these changes are not, by themselves, diagnostic of HD. Cerebral atrophy can be seen in the advanced stages of the disease. Functional neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), can show changes in brain activity before the onset of physical symptoms, but they are experimental tools, and are not used clinically.[25]

text: Predictive genetic testing[edit]

text: Because HD follows an autosomal dominant pattern of inheritance, there is a strong motivation for individuals who are at risk of inheriting it to seek a diagnosis. The genetic test for HD consists of a blood test which counts the numbers of CAG repeats in each of the HTT alleles.[53] Cutoffs are given as follows:

text:
40 or more CAG repeats: full penetrance allele (FPA).[54] A "positive test" or "positive result" generally refers to this case. A positive result is not considered a diagnosis, since it may be obtained decades before the symptoms begin. However, a negative test means that the individual does not carry the expanded copy of the gene and will not develop HD.[25] The test will tell a person who originally had a 50 percent chance of inheriting the disease if their risk goes up to 100 percent or is eliminated. A person who tests positive for the disease will develop HD sometime within their lifetime, provided he or she lives long enough for the disease to appear.[25]
36 to 39 repeats: incomplete or reduced penetrance allele (RPA). It may cause symptoms, usually later in the adult life.[54] There is a maximum risk of 60% that a person with an RPA will be symptomatic at the age of 65 years, and a 70% risk of being symptomatic at the age of 75 years.[54]
27 to 35 repeats: intermediate allele (IA), or large normal allele. It is not associated with symptomatic disease in the tested individual, but may expand upon further inheritance to give symptoms in offspring.[54]
26 or fewer repeats: Not associated with HD.[54]

text: Testing before the onset of symptoms is a life-changing event and a very personal decision.[25] The main reason given for choosing testing for HD is to aid in career and family decisions.[25] Before 1993 there was not an available test for individuals to learn if they carried the Huntington's gene. At that time surveys indicated that 50–70% of at-risk individuals would have been interested in receiving testing, but since predictive testing has been offered far fewer choose to be tested.[55] Over 95% of individuals at risk of inheriting HD do not proceed with testing, mostly because there is no treatment.[25] A key issue is the anxiety an individual experiences about not knowing whether they will eventually develop HD, compared to the impact of a positive result.[24] Irrespective of the result, stress levels have been found to be lower two years after being tested, but the risk of suicide is increased after a positive test result.[24] Individuals found to have not inherited the disorder may experience survivor guilt with regard to family members who are affected.[24] Other factors taken into account when considering testing include the possibility of discrimination and the implications of a positive result, which usually means a parent has an affected gene and that the individual's siblings will be at risk of inheriting it.[24] In one study genetic discrimination was found in 46% of individuals at risk for Huntington's disease. It occurred at higher rates within personal relationships than health insurance or employment relations.[56] Genetic counseling in HD can provide information, advice and support for initial decision-making, and then, if chosen, throughout all stages of the testing process.[57] Because of the implications of this test, patients who wish to undergo testing must complete three counseling sessions which provide information about Huntington's.[58]

text: Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders, such as autosomal dominant cerebellar ataxias.[24][59][60] Presymptomatic testing for HD has also influenced testing for other illnesses with genetic variants such as polycystic kidney disease, familial Alzheimer's disease and breast cancer.[59] The European Molecular Genetics Quality Network have published yearly external quality assessment scheme for molecular genetic testing for this disease and have developed best practice guidelines for genetic testing for HD to assist in testing and reporting of results.[61]

text: Preimplantation genetic diagnosis[edit]

text: Embryos produced using in vitro fertilization may be genetically tested for HD using preimplantation genetic diagnosis (PGD). This technique, where one or two cells are extracted from a typically 4- to 8-cell embryo and then tested for the genetic abnormality, can then be used to ensure embryos affected with HD genes are not implanted, and therefore any offspring will not inherit the disease. Some forms of preimplantation genetic diagnosis—non-disclosure or exclusion testing—allow at-risk people to have HD-free offspring without revealing their own parental genotype, giving no information about whether they themselves are destined to develop HD. In exclusion testing, the embryos' DNA is compared with that of the parents and grandparents to avoid inheritance of the chromosomal region containing the HD gene from the affected grandparent. In non-disclosure testing, only disease-free embryos are replaced in the uterus while the parental genotype and hence parental risk for HD are never disclosed.[62][63]

text: Prenatal testing[edit]

text: It is also possible to obtain a prenatal diagnosis for an embryo or fetus in the womb, using fetal genetic material acquired through chorionic villus sampling. An amniocentesis can be performed if the pregnancy is further along, within 14–18 weeks. This procedure looks at the amniotic fluid surrounding the baby for indicators of the HD mutation.[64] This, too, can be paired with exclusion testing to avoid disclosure of parental genotype. Prenatal testing can be done when a parent has been diagnosed with HD, when they have had genetic testing showing the expansion of the HTT gene, or when they have a 50% chance of inheriting the disease. The parents can be counseled on their options, which include termination of pregnancy, and on the difficulties of a child with the identified gene.[65][66]

text: In addition, in at-risk pregnancies due to an affected male partner, non-invasive prenatal diagnosis can be performed by analyzing cell-free fetal DNA in a blood sample taken from the mother (via venipuncture) between six and twelve weeks of pregnancy.[54] It has no procedure-related risk of miscarriage (excepting via needle contamination).[54]

text: Differential diagnosis[edit]

text: About 99% of HD diagnoses based on the typical symptoms and a family history of the disease are confirmed by genetic testing to have the expanded trinucleotide repeat that causes HD. Most of the remaining are called HD-like (HDL) syndromes.[17][67] The cause of most HDL diseases is unknown, but those with known causes are due to mutations in the prion protein gene (HDL1), the junctophilin 3 gene (HDL2), a recessively inherited unknown gene (HDL3—only found in two families and poorly understood), and the gene encoding the TATA box-binding protein (SCA17, sometimes called HDL4). Other autosomal dominant diseases that can be misdiagnosed as HD are dentatorubral-pallidoluysian atrophy and neuroferritinopathy. There are also autosomal recessive disorders that resemble sporadic cases of HD. These include chorea acanthocytosis and pantothenate kinase-associated neurodegeneration. One X-linked disorder of this type is McLeod syndrome.[67]

text: Management[edit]

text: There is no cure for HD, but there are treatments available to reduce the severity of some of its symptoms.[68] For many of these treatments, evidence to confirm their effectiveness in treating symptoms of HD specifically are incomplete.[69][70] As the disease progresses the ability to care for oneself declines, and carefully managed multidisciplinary caregiving becomes increasingly necessary.[69] Although there have been relatively few studies of exercises and therapies that help rehabilitate cognitive symptoms of HD, there is some evidence for the usefulness of physical therapy, occupational therapy, and speech therapy.[12] An association between caffeine intake and earlier age of onset in Huntington's disease has been found[71][72] but, since this finding was based on retrospective questionnaire data rather than a blinded, randomized trial or case-control study, this work is a poor basis for guiding lifestyle decisions.[73]

text: Therapy[edit]

text: Weight loss and eating difficulties due to dysphagia and other muscle discoordination are common, making nutrition management increasingly important as the disease advances.[69] Thickening agents can be added to liquids as thicker fluids are easier and safer to swallow.[69] Reminding the affected person to eat slowly and to take smaller pieces of food into the mouth may also be of use to prevent choking.[69] If eating becomes too hazardous or uncomfortable, the option of using a percutaneous endoscopic gastrostomy is available. This is a feeding tube, permanently attached through the abdomen into the stomach, which reduces the risk of aspirating food and provides better nutritional management.[74] Assessment and management by speech-language pathologists with experience in Huntington's disease is recommended.[12]

text: People with Huntington's disease may see a physical therapist for non-invasive and non-medication-based ways of managing the physical symptoms. Physical therapists may implement fall risk assessment and prevention, as well as strengthening, stretching, and cardiovascular exercises. Walking aids may be prescribed as appropriate. Physical therapists also prescribe breathing exercises and airway clearance techniques with the development of respiratory problems.[75] Consensus guidelines on physiotherapy in Huntington's disease have been produced by the European HD Network.[75] Goals of early rehabilitation interventions are prevention of loss of function. Participation in rehabilitation programs during early to middle stage of the disease may be beneficial as it translates into long term maintenance of motor and functional performance. Rehabilitation during the late stage aims to compensate for motor and functional losses.[76] For long-term independent management, the therapist may develop home exercise programs for appropriate people.[77]

text: Additionally, an increasing number of people with Huntington’s disease are turning to palliative care, which aims to improve quality of life through the treatment of the symptoms and stress of serious illness, in addition to their other treatments.[78]

text: Medications[edit]

text: Tetrabenazine was approved in 2008 for treatment of chorea in Huntington's disease in the US.[79] Other drugs that help to reduce chorea include neuroleptics and benzodiazepines.[13] Compounds such as amantadine or remacemide are still under investigation but have shown preliminary positive results.[80] Hypokinesia and rigidity, especially in juvenile cases, can be treated with antiparkinsonian drugs, and myoclonic hyperkinesia can be treated with valproic acid.[13]

text: Psychiatric symptoms can be treated with medications similar to those used in the general population.[69][70] Selective serotonin reuptake inhibitors and mirtazapine have been recommended for depression, while atypical antipsychotic drugs are recommended for psychosis and behavioral problems.[70] Specialist neuropsychiatric input is recommended as people may require long-term treatment with multiple medications in combination.[12]

text: Education[edit]

text: The families of individuals who have inherited or are at risk of inheriting HD have generations of experience of HD, but may be unaware of recent breakthroughs in understanding the disease, and of the availability of genetic testing. Genetic counseling benefits these individuals by updating their knowledge, seeking to dispel any unfounded beliefs that they may have, and helping them consider their future options and plans. Also covered is information concerning family planning choices, care management, and other considerations.[24][81]

text: Prognosis[edit]

text: The length of the trinucleotide repeat accounts for 60% of the variation in the age symptoms appear and the rate they progress. A longer repeat results in an earlier age of onset and a faster progression of symptoms.[25][82] Individuals with more than sixty repeats often develop the disease before age 20, while those with fewer than 40 repeats may not ever develop noticeable symptoms.[83] The remaining variation is due to environmental factors and other genes that influence the mechanism of the disease.[25]

text: Life expectancy in HD is generally around 20 years following the onset of visible symptoms.[17] Most life-threatening complications result from muscle coordination and, to a lesser extent, behavioral changes induced by declining cognitive function. The largest risk is pneumonia, which causes death in one third of those with HD. As the ability to synchronize movements deteriorates, difficulty clearing the lungs and an increased risk of aspirating food or drink both increase the risk of contracting pneumonia. The second greatest risk is heart disease, which causes almost a quarter of fatalities of those with HD.[17] Suicide is the third greatest cause of fatalities, with 7.3% of those with HD taking their own lives and up to 27% attempting to do so. It is unclear to what extent suicidal thoughts are influenced by behavioral symptoms, as they signify sufferers' desires to avoid the later stages of the disease.[84][85][86] Other associated risks include choking, physical injury from falls, and malnutrition.[17]

text: Epidemiology[edit]

text: The late onset of Huntington's disease means it does not usually affect reproduction.[24] The worldwide prevalence of HD is 5–10 cases per 100,000 persons,[87][88] but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns.[24] Prevalence is similar for men and women. The rate of occurrence is highest in peoples of Western European descent, averaging around 7 per 100,000 people, and is lower in the rest of the world; e.g., one per million people of Asian and African descent. A 2013 epidemiological study of the prevalence of Huntington's disease in the UK between 1990 and 2010 found that the average prevalence for the UK was 12.3 per 100,000.[24][89] Additionally, some localized areas have a much higher prevalence than their regional average.[24] One of the highest incidences is in the isolated populations of the Lake Maracaibo region of Venezuela, where HD affects up to 700 per 100,000 persons.[24][90] Other areas of high localization have been found in Tasmania and specific regions of Scotland, Wales and Sweden.[86] Increased prevalence in some cases occurs due to a local founder effect, a historical migration of carriers into an area of geographic isolation.[86][91] Some of these carriers have been traced back hundreds of years using genealogical studies.[86] Genetic haplotypes can also give clues for the geographic variations of prevalence.[86][92] Iceland, on the contrary, has a rather low prevalence of 1 per 100,000, despite the fact that Icelanders as a people are descended of the early Germanic tribes of Scandinavia which also gave rise to the Swedes; all cases with the exception of one going back nearly two centuries having derived from the offspring of a couple living early in the 19th century.[93] Finland, as well, has a low incidence of only 2.2 per 100,000 people.[94]

text: Until the discovery of a genetic test, statistics could only include clinical diagnosis based on physical symptoms and a family history of HD, excluding those who died of other causes before diagnosis. These cases can now be included in statistics; and, as the test becomes more widely available, estimates of the prevalence and incidence of the disorder are likely to increase.[86][95]

text: History[edit]

text: Although Huntington's has been recognized as a disorder since at least the Middle Ages, the cause has been unknown until fairly recently. Huntington's was given different names throughout this history as understanding of the disease changed. Originally called simply 'chorea' for the jerky dancelike movements associated with the disease, HD has also been called "hereditary chorea" and "chronic progressive chorea".[97] The first definite mention of HD was in a letter by Charles Oscar Waters, published in the first edition of Robley Dunglison's Practice of Medicine in 1842. Waters described "a form of chorea, vulgarly called magrums", including accurate descriptions of the chorea, its progression, and the strong heredity of the disease.[98] In 1846 Charles Gorman observed how higher prevalence seemed to occur in localized regions.[98] Independently of Gorman and Waters, both students of Dunglison at Jefferson Medical College in Philadelphia,[99] Johan Christian Lund also produced an early description in 1860.[98] He specifically noted that in Setesdalen, a secluded mountain valley in Norway, there was a high prevalence of dementia associated with a pattern of jerking movement disorders that ran in families.[100]

text: The first thorough description of the disease was by George Huntington in 1872. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked; he presented his detailed and accurate definition of the disease as his first paper. Huntington described the exact pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

text: "Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease.".[96][101]

text: Sir William Osler was interested in the disorder and chorea in general, and was impressed with Huntington's paper, stating that "In the history of medicine, there are few instances in which a disease has been more accurately, more graphically or more briefly described."[98][102] Osler's continued interest in HD, combined with his influence in the field of medicine, helped to rapidly spread awareness and knowledge of the disorder throughout the medical community.[98] Great interest was shown by scientists in Europe, including Louis Théophile Joseph Landouzy, Désiré-Magloire Bourneville, Camillo Golgi, and Joseph Jules Dejerine, and until the end of the century, much of the research into HD was European in origin.[98] By the end of the 19th century, research and reports on HD had been published in many countries and the disease was recognized as a worldwide condition.[98]

text: During the rediscovery of Mendelian inheritance at the turn of the 20th century, HD was used tentatively as an example of autosomal dominant inheritance.[98] The English biologist William Bateson used the pedigrees of affected families to establish that HD had an autosomal dominant inheritance pattern.[99] The strong inheritance pattern prompted several researchers, including Smith Ely Jelliffe, to attempt to trace and connect family members of previous studies.[98] Jelliffe collected information from across New York and published several articles regarding the genealogy of HD in New England.[103] Jelliffe's research roused the interest of his college friend, Charles Davenport, who commissioned Elizabeth Muncey to produce the first field study on the East Coast of the United States of families with HD and to construct their pedigrees.[104] Davenport used this information to document the variable age of onset and range of symptoms of HD; he claimed that most cases of HD in the USA could be traced back to a handful of individuals.[104] This research was further embellished in 1932 by P. R. Vessie, who popularized the idea that three brothers who left England in 1630 bound for Boston were the progenitors of HD in the USA.[105] The claim that the earliest progenitors had been established and eugenic bias of Muncey's, Davenport's, and Vessie's work contributed to misunderstandings and prejudice about HD.[99] Muncey and Davenport also popularized the idea that in the past some HD sufferers may have been thought to be possessed by spirits or victims of witchcraft, and were sometimes shunned or exiled by society.[106][107] This idea has not been proven. Researchers have found contrary evidence; for instance, the community of the family studied by George Huntington openly accommodated those who exhibited symptoms of HD.[99][106]

text: The search for the cause of this condition was enhanced considerably in 1968, when the Hereditary Disease Foundation (HDF) was created by Milton Wexler, a psychoanalyst based in Los Angeles, California, whose wife Leonore Sabin had been diagnosed earlier that year with Huntington's disease.[108] The three brothers of Wexler's wife also suffered from this disease. The foundation was involved in the recruitment of over 100 scientists in the Huntington's Disease Collaborative Research Project who over a 10-year period worked to locate the responsible gene.

text: Thanks to the HDF, the ongoing US-Venezuela Huntington's Disease Collaborative Research Project was started in 1979, and reported a major breakthrough in 1983 with the discovery of the approximate location of a causal gene.[91] This was the result of an extensive study focusing on the populations of two isolated Venezuelan villages, Barranquitas and Lagunetas, where there was an unusually high prevalence of the disease. It involved over 18,000 people—mostly from a single extended family.

text: Among other innovations, the project developed DNA-marking methods which were an important step in making the Human Genome Project possible.[109] In 1993, the research group isolated the precise causal gene at 4p16.3,[110] making this the first autosomal disease locus found using genetic linkage analysis.[110][111]

text: In the same time frame, key discoveries concerning the mechanisms of the disorder were being made, including the findings by Anita Harding's research group on the effects of the gene's length.[112]

text: Modelling the disease in various types of animals, such as the transgenic mouse developed in 1996, enabled larger scale experiments. As these animals have faster metabolisms and much shorter lifespans than humans, results from experiments are received sooner, speeding research. The 1997 discovery that mHTT fragments misfold led to the discovery of the nuclear inclusions they cause. These advances have led to increasingly extensive research into the proteins involved with the disease, potential drug treatments, care methods, and the gene itself.[98][113]

text: The condition was formerly called 'Huntington's chorea' but this term has been replaced by 'Huntington's disease' because not all patients develop chorea and due to the importance of cognitive and behavioral problems.[114]

text: Society and culture[edit]

text: Ethics[edit]

text: Huntington's disease, particularly the application of the genetic test for the disease, has raised several ethical issues. The issues for genetic testing include defining how mature an individual should be before being considered eligible for testing, ensuring the confidentiality of results, and whether companies should be allowed to use test results for decisions on employment, life insurance or other financial matters. There was controversy when Charles Davenport proposed in 1910 that compulsory sterilization and immigration control be used for people with certain diseases, including HD, as part of the eugenics movement.[115] In vitro fertilization has some issues regarding its use of embryos. Some HD research has ethical issues due to its use of animal testing and embryonic stem cells.[116][117]

text: The development of an accurate diagnostic test for Huntington's disease has caused social, legal, and ethical concerns over access to and use of a person's results.[118][119] Many guidelines and testing procedures have strict procedures for disclosure and confidentiality to allow individuals to decide when and how to receive their results and also to whom the results are made available.[24] Financial institutions and businesses are faced with the question of whether to use genetic test results when assessing an individual, such as for life insurance or employment. The United Kingdom's insurance companies have agreed that until 2017 they will not use genetic information when writing insurance policies under GB£500,000, but Huntington's is explicitly excluded from this agreement.[120][121] As with other untreatable genetic conditions with a later onset, it is ethically questionable to perform pre-symptomatic testing on a child or adolescent, as there would be no medical benefit for that individual. There is consensus for testing only individuals who are considered cognitively mature, although there is a counter-argument that parents have a right to make the decision on their child's behalf. With the lack of an effective treatment, testing a person under legal age who is not judged to be competent is considered unethical in most cases.[39][122][123]

text: There are ethical concerns related to prenatal genetic testing or preimplantation genetic diagnosis to ensure a child is not born with a given disease.[124] For example, prenatal testing raises the issue of selective abortion, a choice considered unacceptable by some.[124] As it is a dominant disease, there are difficulties in situations in which a parent does not want to know his or her own diagnosis. This would require parts of the process to be kept secret from the parent.[124]

text: Support organizations[edit]

text: In 1968, after experiencing HD in his wife's family, Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation (HDF), with the aim of curing genetic illnesses by coordinating and supporting research.[9] The foundation and Wexler's daughter, Nancy Wexler, were key parts of the research team in Venezuela which discovered the HD gene.[9]

text: At roughly the same time as the HDF formed, Marjorie Guthrie helped to found the Committee to Combat Huntington's Disease (now the Huntington's Disease Society of America), after her husband Woody Guthrie died from complications of HD.[10]

text: Since then, support and research organizations have formed in many countries around the world and have helped to increase public awareness of HD. A number of these collaborate in umbrella organizations, like the International Huntington Association and the European HD network.[125] Many support organizations hold an annual HD awareness event, some of which have been endorsed by their respective governments. For example, 6 June is designated "National Huntington's Disease Awareness Day" by the US Senate.[126]

text: The largest funder of Huntington's disease research globally, in terms of financial expenditure,[127] is the CHDI Foundation, a US non-profit biomedical foundation that aims to "rapidly discover and develop drugs that delay or slow Huntington's disease".[128] CHDI was formerly known as the High Q Foundation. In 2006, it spent $50 million on Huntington's disease research.[127] CHDI collaborates with many academic and commercial laboratories globally and engages in oversight and management of research projects as well as funding.[129] Many organizations exist to support and inform those affected by HD.

text: Research directions[edit]

text: Research into the mechanism of HD has focused on identifying the functioning of HTT, how mHTT differs or interferes with it, and the brain pathology that the disease produces. Research is conducted using in vitro methods, animal models and human volunteers. Animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of drug development.[113] Animals with chemically induced brain injury exhibit HD-like symptoms and were initially used, but they did not mimic the progressive features of the disease.[130] The identification of the causative gene has enabled the development of many transgenic animal models including nematode worms, Drosophila fruit flies, mice, rats, sheep, pigs and monkeys that express mutant huntingtin and develop progressive neurodegeneration and HD-like symptoms.[113]

text: Research is being conducted on many different approaches to prevent Huntington's disease or slow its progression. Disease-modifying strategies can be broadly grouped into three categories: reducing the level of the mutant huntingtin protein (including gene splicing and gene silencing); approaches aimed at improving neuronal survival by reducing the harm caused by the protein to specific cellular pathways and mechanisms (including protein homeostasis and histone deacetylase inhibition); and strategies to replace lost neurons. In addition, novel therapies to improve brain functioning are under development; these seek to produce symptomatic rather than disease-modifying therapies, and include phosphodiesterase inhibitors.[131][132]

text: Reducing huntingtin production[edit]

text: Gene silencing aims to reduce the production of the mutant protein, since HD is caused by a single dominant gene encoding a toxic protein. Gene silencing experiments in mouse models have shown that when the expression of mHTT is reduced, symptoms improve.[133] Safety of non-allele specific RNAi and ASO gene silencing has now been demonstrated in mice and the large, human-like brains of primates.[134][135] Allele-specific silencing attempts to silence mutant HTT while leaving wild-type HTT untouched. One way of accomplishing this is to identify polymorphisms present on only one allele and produce gene silencing drugs that target polymorphisms in only the mutant allele.[136] The first 'gene silencing' trial involving human HD patients began in 2015, testing the safety of IONIS-HTTRx, produced by Ionis Pharmaceuticals and led by UCL Institute of Neurology.[137][138] Mutant huntingtin was detected and quantified for the first time in cerebrospinal fluid from Huntington's disease mutation-carriers in 2015 using a novel 'single-molecule counting' immunoassay,[139] providing a direct way to assess whether huntingtin-lowering treatments are achieving the desired effect.[140][141] Similarly, gene splicing techniques are being looked at to try to repair a genome with the erroneous gene that causes HD, using tools such as CRISPR/Cas9.[132]

text: Improving cell survival[edit]

text: Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are correction of transcriptional regulation using histone deacetylase inhibitors, modulating aggregation of huntingtin, improving metabolism and mitochondrial function and restoring function of synapses.[133]

text: Neuronal replacement[edit]

text: Stem cell therapy is the replacement of damaged neurons by transplantation of stem cells into affected regions of the brain. Experiments have yielded mixed results using this technique in animal models and preliminary human clinical trials.[142] Whatever their future therapeutic potential, stem cells are already a valuable tool for studying Huntington's disease in the laboratory.[143]

text: Clinical trials[edit]

text: Several clinical trials of new experimental treatments are underway and planned in Huntington's disease.[144]

text: Compounds that have failed to prevent or slow progression of Huntington's disease in human trials include remacemide, coenzyme Q10, riluzole, creatine, minocycline, ethyl-EPA, phenylbutyrate and dimebon.[145]


document_title: Ask Me How I Know

question_text: when did garth brooks ask me how i know come out

text: Ask Me How I Know

text:
"Ask Me How I Know"

Single by Garth Brooks

from the album Gunslinger

Released
March 17, 2017

Format
CD single, music download

Genre
Country

Length
3:34

Label
Pearl

Songwriter(s)
Mitch Rossell

Producer(s)
Mark Miller

Garth Brooks singles chronology

"Baby, Let's Lay Down and Dance"
(2016)
"Ask Me How I Know"
(2017)

"Baby, Let's Lay Down and Dance"
(2016)
"Ask Me How I Know"
(2017)

text: "Ask Me How I Know" is a song recorded by American country music singer Garth Brooks, and written by Mitch Rossell. It was released on March 17, 2017 as the second single off Brooks's 2016 album, Gunslinger.[1][2] The single's release coincided with the announcement of Brooks performing at South by Southwest, as well as the Houston Livestock Show and Rodeo. It became his first number one song since "More Than a Memory" in 2007.[3][4]

text: Charts[edit]

text:
Chart (2017)
Peak
position

Canada Country (Billboard)[5]
30

US Billboard Hot 100[6]
71

US Country Airplay (Billboard)[7]
1

US Hot Country Songs (Billboard)[8]
13

text: Year-end charts[edit]

text:
Chart (2017)
Position

US Billboard Country Airplay[9]
40

text:
Preceded by
"Greatest Love Story"
by Lanco
Billboard Country Airplay
number-one single
December 16, 2017
Succeeded by
"Light It Up"
by Luke Bryan


document_title: Land degradation

question_text: explain the reasons for land degradation in india

text: Land degradation

text: Measures[edit]

text: Land degradation is a broad term that can be applied differently across a wide range of scenarios. There are four main ways of looking at land degradation and its impact on the environment around it:

text:
A temporary or permanent decline in the productive capacity of the land. This can be seen through a loss of biomass, a loss of actual productivity or in potential productivity, or a loss or change in vegetative cover and soil nutrients.
Action in the land's capacity to provide resources for human livelihoods. This can be measured from a base line of past land use.
Loss of biodiversity: A loss of range of species or ecosystem complexity as a decline in the environmental quality.
Shifting ecological risk: increased vulnerability of the environment or people to destruction or crisis. This is measured through a base line in the form of pre-existing risk of crisis or destruction.

tag: ol

text: A problem with defining land degradation is that what one group of people might view as degradation, others might view as a benefit or opportunity. For example, planting crops at a location with heavy rainfall and steep slopes would create scientific and environmental concern regarding the risk of soil erosion by water, yet farmers could view the location as a favourable one for high crop yields.[5]

text: Different types[edit]

text: In addition to the usual types of land degradation that have been known for centuries (water, wind and mechanical erosion, physical, chemical and biological degradation), four other types have emerged in the last 50 years:[6]

text:
pollution, often chemical, due to agricultural, industrial, mining or commercial activities;
loss of arable land due to urban construction, road building, land conversion, agricultural expansion, etc.;
artificial radioactivity, sometimes accidental;
land-use constraints associated with armed conflicts.

text: Overall, more than 36 types of land degradation can be assessed. All are induced or aggravated by human activities, e.g. sheet erosion, silting, aridification, salinization, urbanization, etc.

text: Causes[edit]

text: Land degradation is a global problem largely related to agricultural use. Causes include:

text:
Land clearance, such as clearcutting and deforestation
Agricultural depletion of soil nutrients through poor farming practices
Livestock including overgrazing and overdrafting
Inappropriate irrigation[7] and overdrafting
Urban sprawl and commercial development
Vehicle off-roading
Quarrying of stone, sand, ore and minerals
Increase in field size due to economies of scale, reducing shelter for wildlife, as hedgerows and copses disappear
Exposure of naked soil after harvesting by heavy equipment
Monoculture, destabilizing the local ecosystem
Dumping of non-biodegradable trash, such as plastics
Invasive Species
Soil degradation, e.g.

Soil contamination
Soil erosion
Soil acidification
Loss of soil carbon

text: Effects[edit]

text: Overcutting of vegetation occurs when people cut forests, woodlands and shrublands—to obtain timber, fuelwood and other products—at a pace exceeding the rate of natural regrowth. This is frequent in semi-arid environments, where fuelwood shortages are often severe.

text: Overgrazing is the grazing of natural pastures at stocking intensities above the livestock carrying capacity; the resulting decrease in the vegetation cover is a leading cause of wind and water erosion. It is a significant factor in Afghanistan. The growing population pressure, during 1980-1990, has led to decreases in the already small areas of agricultural land per person in six out of eight countries (14% for India and 21% for Pakistan).

text: Population pressure also operates through other mechanisms. Improper agricultural practices, for instance, occur only under constraints such as the saturation of good lands under population pressure which leads settlers to cultivate too shallow or too steep soils, plough fallow land before it has recovered its fertility, or attempt to obtain multiple crops by irrigating unsuitable soils.

text: High population density is not always related to land degradation. Rather, it is the practices of the human population that can cause a landscape to become degraded. Populations can be a benefit to the land and make it more productive than it is in its natural state. Land degradation is an important factor of internal displacement in many African and Asian countries.[8]

text: Severe land degradation affects a significant portion of the Earth's arable lands, decreasing the wealth and economic development of nations. As the land resource base becomes less productive, food security is compromised and competition for dwindling resources increases, the seeds of famine and potential conflict are sown.

text: Sensitivity and resilience[edit]

text: Sensitivity and resilience are measures of the vulnerability of a landscape to degradation. These two factors combine to explain the degree of vulnerability.[5] Sensitivity is the degree to which a land system undergoes change due to natural forces, human intervention or a combination of both. Resilience is the ability of a landscape to absorb change, without significantly altering the relationship between the relative importance and numbers of individuals and species that compose the community.[9] It also refers to the ability of the region to return to its original state after being changed in some way. The resilience of a landscape can be increased or decreased through human interaction based upon different methods of land-use management. Land that is degraded becomes less resilient than undegraded land, which can lead to even further degradation through shocks to the landscape.

text: Climate change[edit]

text: Significant land degradation from seawater inundation, particularly in river deltas and on low-lying islands, is a potential hazard that was identified in a 2007 IPCC report.

text:
IPCC

Assessment reports:

First (1990)

1992 sup.

Second (1995)

Third (2001)

Fourth (2007)

Fifth (2014)

Sixth (2022)

UNFCCC | WMO | UNEP

text: As a result of sea-level rise from climate change, salinity levels can reach levels where agriculture becomes impossible in very low-lying areas.