Huntington's disease history and symptoms: Difference between revisions

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__NOTOC__
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{{Huntington's disease}}
{{Huntington's disease}}
{{CMG}}
{{CMG}} {{AE}} {{SAH}}
==Overview==
==Overview==
== History and Symptoms ==
== History and Symptoms ==
Line 7: Line 7:


'''Physicals'''
'''Physicals'''
* Jerky, random, uncontrollable movements called chorea athough some exhibit very slow movement and stiffness  
*Dementia
* Loss of determination  
*Chorea movements:
* Speaking is impaired with slurred words and uncontrollable movements of the mouth
**Jerky movements
* Eating and mobility are extremely difficult if not impossible, and full-time care is required.
**Uncontrollable movements
**Although some exhibit very slow movement and stiffness  
*Loss of determination  
*Speaking is impaired with slurred words and uncontrollable movements of the mouth
*Eating and mobility are extremely difficult if not impossible, and full-time care is required.


'''Cognitive''' :  Abilities affected are;  
'''Cognitive''' :  Abilities affected are;  
* [[Executive system|Executive function]]  
*[[Executive system|Executive function]]  
* Planning; cognitive flexibility  
*Planning; cognitive flexibility  
* Rule acquisition
*Rule acquisition
* Initiating appropriate actions
*Initiating appropriate actions
* Inhibiting inappropriate actions
*Inhibiting inappropriate actions
* Slurring of the words and some uncontrollable movement of the lips
*Slurring of the words and some uncontrollable movement of the lips
* [[Perceptual]] and [[spatial]] skills of self and surrounding environment
*[[Perceptual]] and [[spatial]] skills of self and surrounding environment
* Ability to learn new [[skills]], depending on the affected parts of the brain.
*Ability to learn new [[skills]], depending on the affected parts of the brain.


'''Psychopathological''' : Psychopathological symptoms vary more than cognitive and physical symptoms, and may include  
'''Psychopathological''' : Psychopathological symptoms vary more than cognitive and physical symptoms, and may include  
* [[Anxiety]]
*[[Anxiety]]
* [[Clinical depression|Depression]]
*[[Clinical depression|Depression]]
* [[Compulsion|Compulsivity]] which can cause [[addictions]] such as [[alcoholism]] and [[gambling]], or [[hypersexuality]].
* [[Compulsion|Compulsivity]] which can cause [[addictions]] such as [[alcoholism]] and [[gambling]], or [[hypersexuality]].
* Unable to recognize expressions of [[disgust]] in others and also don't show reactions of disgust to foul odors or tastes.<ref>Mitchell IJ, Heims H, Neville EA, Rickards H. [http://www.neuro.psychiatryonline.org/cgi/content/full/17/1/119 Huntington's disease patients show impaired perception of disgust in the gustatory and olfactory modalities.] ''Journal of Neuropsychiatry and Clinical Neuroscience'', 17:119-121, February 2005. PMID 15746492</ref> The inability to recognize disgust in others appears in carriers of the Huntington gene before symptoms are manifest.<ref>Sprengelmeyer R, Schroeder U, Young AW, Epplen JT. "Disgust in pre-clinical Huntington's disease: a longitudinal study." ''Neuropsychologia.'' 2006;44(4):518-33. Epub 2005 August 11. PMID 16098998</ref> A number of related studies have been published.<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&term=%22Huntington+Disease%22%5BMAJR%5D+disgust PubMed search for "Huntington's disease" and "disgust"]</ref>
* Unable to recognize expressions of [[disgust]] in others and also don't show reactions of disgust to foul odors or tastes.<ref>Mitchell IJ, Heims H, Neville EA, Rickards H. [http://www.neuro.psychiatryonline.org/cgi/content/full/17/1/119 Huntington's disease patients show impaired perception of disgust in the gustatory and olfactory modalities.] ''Journal of Neuropsychiatry and Clinical Neuroscience'', 17:119-121, February 2005. PMID 15746492</ref> The inability to recognize disgust in others appears in carriers of the Huntington gene before symptoms are manifest.<ref>Sprengelmeyer R, Schroeder U, Young AW, Epplen JT. "Disgust in pre-clinical Huntington's disease: a longitudinal study." ''Neuropsychologia.'' 2006;44(4):518-33. Epub 2005 August 11. PMID 16098998</ref> A number of related studies have been published.<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&term=%22Huntington+Disease%22%5BMAJR%5D+disgust PubMed search for "Huntington's disease" and "disgust"]</ref>
'''Common Symptoms'''
*The common symptoms of Huntington`s disease are given below:<ref name="pmid23966256">{{cite journal |vauthors=McCusker EA, Gunn DG, Epping EA, Loy CT, Radford K, Griffith J, Mills JA, Long JD, Paulsen JS |title=Unawareness of motor phenoconversion in Huntington disease |journal=Neurology |volume=81 |issue=13 |pages=1141–7 |date=September 2013 |pmid=23966256 |pmc=3795599 |doi=10.1212/WNL.0b013e3182a55f05 |url=}}</ref><ref name="pmid15358067">{{cite journal |vauthors=Blekher TM, Yee RD, Kirkwood SC, Hake AM, Stout JC, Weaver MR, Foroud TM |title=Oculomotor control in asymptomatic and recently diagnosed individuals with the genetic marker for Huntington's disease |journal=Vision Res. |volume=44 |issue=23 |pages=2729–36 |date=October 2004 |pmid=15358067 |doi=10.1016/j.visres.2004.06.006 |url=}}</ref><ref name="pmid9425536">{{cite journal |vauthors=Lasker AG, Zee DS |title=Ocular motor abnormalities in Huntington's disease |journal=Vision Res. |volume=37 |issue=24 |pages=3639–45 |date=December 1997 |pmid=9425536 |doi=10.1016/S0042-6989(96)00169-1 |url=}}</ref><ref name="pmid16855205">{{cite journal |vauthors=Blekher T, Johnson SA, Marshall J, White K, Hui S, Weaver M, Gray J, Yee R, Stout JC, Beristain X, Wojcieszek J, Foroud T |title=Saccades in presymptomatic and early stages of Huntington disease |journal=Neurology |volume=67 |issue=3 |pages=394–9 |date=August 2006 |pmid=16855205 |doi=10.1212/01.wnl.0000227890.87398.c1 |url=}}</ref><ref name="pmid11176966">{{cite journal |vauthors=Kirkwood SC, Su JL, Conneally P, Foroud T |title=Progression of symptoms in the early and middle stages of Huntington disease |journal=Arch. Neurol. |volume=58 |issue=2 |pages=273–8 |date=February 2001 |pmid=11176966 |doi= |url=}}</ref><ref name="pmid8487272">{{cite journal |vauthors=Di Maio L, Squitieri F, Napolitano G, Campanella G, Trofatter JA, Conneally PM |title=Onset symptoms in 510 patients with Huntington's disease |journal=J. Med. Genet. |volume=30 |issue=4 |pages=289–92 |date=April 1993 |pmid=8487272 |pmc=1016334 |doi= |url=}}</ref><ref name="pmid19026253">{{cite journal |vauthors=van Duijn E, Kingma EM, Timman R, Zitman FG, Tibben A, Roos RA, van der Mast RC |title=Cross-sectional study on prevalences of psychiatric disorders in mutation carriers of Huntington's disease compared with mutation-negative first-degree relatives |journal=J Clin Psychiatry |volume=69 |issue=11 |pages=1804–10 |date=November 2008 |pmid=19026253 |doi= |url=}}</ref><ref name="pmid8487273">{{cite journal |vauthors=Di Maio L, Squitieri F, Napolitano G, Campanella G, Trofatter JA, Conneally PM |title=Suicide risk in Huntington's disease |journal=J. Med. Genet. |volume=30 |issue=4 |pages=293–5 |date=April 1993 |pmid=8487273 |pmc=1016335 |doi= |url=}}</ref><ref name="pmid21605914">{{cite journal |vauthors=Wetzel HH, Gehl CR, Dellefave-Castillo L, Schiffman JF, Shannon KM, Paulsen JS |title=Suicidal ideation in Huntington disease: the role of comorbidity |journal=Psychiatry Res |volume=188 |issue=3 |pages=372–6 |date=August 2011 |pmid=21605914 |pmc=3790459 |doi=10.1016/j.psychres.2011.05.006 |url=}}</ref><ref name="pmid22119091">{{cite journal |vauthors=Hubers AA, Reedeker N, Giltay EJ, Roos RA, van Duijn E, van der Mast RC |title=Suicidality in Huntington's disease |journal=J Affect Disord |volume=136 |issue=3 |pages=550–7 |date=February 2012 |pmid=22119091 |doi=10.1016/j.jad.2011.10.031 |url=}}</ref><ref name="pmid18070848">{{cite journal |vauthors=van Duijn E, Kingma EM, van der Mast RC |title=Psychopathology in verified Huntington's disease gene carriers |journal=J Neuropsychiatry Clin Neurosci |volume=19 |issue=4 |pages=441–8 |date=2007 |pmid=18070848 |doi=10.1176/jnp.2007.19.4.441 |url=}}</ref><ref name="pmid11511702">{{cite journal |vauthors=Paulsen JS, Ready RE, Hamilton JM, Mega MS, Cummings JL |title=Neuropsychiatric aspects of Huntington's disease |journal=J. Neurol. Neurosurg. Psychiatry |volume=71 |issue=3 |pages=310–4 |date=September 2001 |pmid=11511702 |pmc=1737562 |doi= |url=}}</ref><ref name="pmid8660149">{{cite journal |vauthors=Zappacosta B, Monza D, Meoni C, Austoni L, Soliveri P, Gellera C, Alberti R, Mantero M, Penati G, Caraceni T, Girotti F |title=Psychiatric symptoms do not correlate with cognitive decline, motor symptoms, or CAG repeat length in Huntington's disease |journal=Arch. Neurol. |volume=53 |issue=6 |pages=493–7 |date=June 1996 |pmid=8660149 |doi= |url=}}</ref><ref name="pmid11097960">{{cite journal |vauthors=Tsuang D, Almqvist EW, Lipe H, Strgar F, DiGiacomo L, Hoff D, Eugenio C, Hayden MR, Bird TD |title=Familial aggregation of psychotic symptoms in Huntington's disease |journal=Am J Psychiatry |volume=157 |issue=12 |pages=1955–9 |date=December 2000 |pmid=11097960 |doi=10.1176/appi.ajp.157.12.1955 |url=}}</ref><ref name="pmid11253840">{{cite journal |vauthors=Snowden J, Craufurd D, Griffiths H, Thompson J, Neary D |title=Longitudinal evaluation of cognitive disorder in Huntington's disease |journal=J Int Neuropsychol Soc |volume=7 |issue=1 |pages=33–44 |date=January 2001 |pmid=11253840 |doi= |url=}}</ref><ref name="pmid8460958">{{cite journal |vauthors=Pillon B, Deweer B, Agid Y, Dubois B |title=Explicit memory in Alzheimer's, Huntington's, and Parkinson's diseases |journal=Arch. Neurol. |volume=50 |issue=4 |pages=374–9 |date=April 1993 |pmid=8460958 |doi= |url=}}</ref><ref name="pmid20610833">{{cite journal |vauthors=Duff K, Paulsen J, Mills J, Beglinger LJ, Moser DJ, Smith MM, Langbehn D, Stout J, Queller S, Harrington DL |title=Mild cognitive impairment in prediagnosed Huntington disease |journal=Neurology |volume=75 |issue=6 |pages=500–7 |date=August 2010 |pmid=20610833 |pmc=2918475 |doi=10.1212/WNL.0b013e3181eccfa2 |url=}}</ref><ref name="pmid8487272">{{cite journal |vauthors=Di Maio L, Squitieri F, Napolitano G, Campanella G, Trofatter JA, Conneally PM |title=Onset symptoms in 510 patients with Huntington's disease |journal=J. Med. Genet. |volume=30 |issue=4 |pages=289–92 |date=April 1993 |pmid=8487272 |pmc=1016334 |doi= |url=}}</ref><ref name="pmid14742590">{{cite journal |vauthors=Hamilton JM, Wolfson T, Peavy GM, Jacobson MW, Corey-Bloom J |title=Rate and correlates of weight change in Huntington's disease |journal=J. Neurol. Neurosurg. Psychiatry |volume=75 |issue=2 |pages=209–12 |date=February 2004 |pmid=14742590 |pmc=1738924 |doi= |url=}}</ref><ref name="pmid6454826">{{cite journal |vauthors=Sanberg PR, Fibiger HC, Mark RF |title=Body weight and dietary factors in Huntington's disease patients compared with matched controls |journal=Med. J. Aust. |volume=1 |issue=8 |pages=407–9 |date=April 1981 |pmid=6454826 |doi= |url=}}</ref><ref name="pmid10894218">{{cite journal |vauthors=Lodi R, Schapira AH, Manners D, Styles P, Wood NW, Taylor DJ, Warner TT |title=Abnormal in vivo skeletal muscle energy metabolism in Huntington's disease and dentatorubropallidoluysian atrophy |journal=Ann. Neurol. |volume=48 |issue=1 |pages=72–6 |date=July 2000 |pmid=10894218 |doi= |url=}}</ref><ref name="pmid18981372">{{cite journal |vauthors=Aziz NA, van der Burg JM, Landwehrmeyer GB, Brundin P, Stijnen T, Roos RA |title=Weight loss in Huntington disease increases with higher CAG repeat number |journal=Neurology |volume=71 |issue=19 |pages=1506–13 |date=November 2008 |pmid=18981372 |doi=10.1212/01.wnl.0000334276.09729.0e |url=}}</ref>
**Involuntary movements [[(Chorea)]] of face, trunk and limbs.
**Parakinesia.
**Hypotonia.
**Hyperreflexia.
**Dystonia of hands.
**Mild bradykinesia is also observed.
**Abnormal eye movements.
**Conjugate eye movements.
**Nystagmus.
**Depression.
**Paranoia, delusions, and hallucinations.
**Loss of Cognitive functions.
**Dementia.
**Aphasia.
**Apraxia.
**Weight loss and cachexia.
'''Less Common Symptoms'''
*Less common symptoms of Huntington`s disease are given below:<ref name="pmid10945661">{{cite journal |vauthors=Squitieri F, Berardelli A, Nargi E, Castellotti B, Mariotti C, Cannella M, Lavitrano ML, de Grazia U, Gellera C, Ruggieri S |title=Atypical movement disorders in the early stages of Huntington's disease: clinical and genetic analysis |journal=Clin. Genet. |volume=58 |issue=1 |pages=50–6 |date=July 2000 |pmid=10945661 |doi= |url=}}</ref><ref name="pmid6446423">{{cite journal |vauthors=Kereshi S, Schlagenhauff RE, Richardson KS |title=Myoclonic and major seizures in early adult Huntington's chorea: case-report and electro-clinical findings |journal=Clin Electroencephalogr |volume=11 |issue=2 |pages=44–7 |date=April 1980 |pmid=6446423 |doi= |url=}}</ref>
**Ataxia.
**Myoclonus.
**Seizures.
**Generalized dystonia.
==References==
==References==
{{reflist|2}}
{{reflist|2}}
{{WH}}
{{WH}}
{{WS}}
{{WS}}

Latest revision as of 01:10, 7 September 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Syed Ahsan Hussain, M.D.[2]

Overview

History and Symptoms

Although there is no sudden loss of abilities or exhibition of symptoms, there is a progressive decline.

Physicals

  • Dementia
  • Chorea movements:
    • Jerky movements
    • Uncontrollable movements
    • Although some exhibit very slow movement and stiffness
  • Loss of determination
  • Speaking is impaired with slurred words and uncontrollable movements of the mouth
  • Eating and mobility are extremely difficult if not impossible, and full-time care is required.

Cognitive : Abilities affected are;

  • Executive function
  • Planning; cognitive flexibility
  • Rule acquisition
  • Initiating appropriate actions
  • Inhibiting inappropriate actions
  • Slurring of the words and some uncontrollable movement of the lips
  • Perceptual and spatial skills of self and surrounding environment
  • Ability to learn new skills, depending on the affected parts of the brain.

Psychopathological : Psychopathological symptoms vary more than cognitive and physical symptoms, and may include


Common Symptoms

  • The common symptoms of Huntington`s disease are given below:[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][9][21][22][23][24]
    • Involuntary movements (Chorea) of face, trunk and limbs.
    • Parakinesia.
    • Hypotonia.
    • Hyperreflexia.
    • Dystonia of hands.
    • Mild bradykinesia is also observed.
    • Abnormal eye movements.
    • Conjugate eye movements.
    • Nystagmus.
    • Depression.
    • Paranoia, delusions, and hallucinations.
    • Loss of Cognitive functions.
    • Dementia.
    • Aphasia.
    • Apraxia.
    • Weight loss and cachexia.

Less Common Symptoms

  • Less common symptoms of Huntington`s disease are given below:[25][26]
    • Ataxia.
    • Myoclonus.
    • Seizures.
    • Generalized dystonia.

References

  1. ↑ Mitchell IJ, Heims H, Neville EA, Rickards H. Huntington's disease patients show impaired perception of disgust in the gustatory and olfactory modalities. Journal of Neuropsychiatry and Clinical Neuroscience, 17:119-121, February 2005. PMID 15746492
  2. ↑ Sprengelmeyer R, Schroeder U, Young AW, Epplen JT. "Disgust in pre-clinical Huntington's disease: a longitudinal study." Neuropsychologia. 2006;44(4):518-33. Epub 2005 August 11. PMID 16098998
  3. ↑ PubMed search for "Huntington's disease" and "disgust"
  4. ↑ McCusker EA, Gunn DG, Epping EA, Loy CT, Radford K, Griffith J, Mills JA, Long JD, Paulsen JS (September 2013). "Unawareness of motor phenoconversion in Huntington disease". Neurology. 81 (13): 1141–7. doi:10.1212/WNL.0b013e3182a55f05. PMC 3795599. PMID 23966256.
  5. ↑ Blekher TM, Yee RD, Kirkwood SC, Hake AM, Stout JC, Weaver MR, Foroud TM (October 2004). "Oculomotor control in asymptomatic and recently diagnosed individuals with the genetic marker for Huntington's disease". Vision Res. 44 (23): 2729–36. doi:10.1016/j.visres.2004.06.006. PMID 15358067.
  6. ↑ Lasker AG, Zee DS (December 1997). "Ocular motor abnormalities in Huntington's disease". Vision Res. 37 (24): 3639–45. doi:10.1016/S0042-6989(96)00169-1. PMID 9425536.
  7. ↑ Blekher T, Johnson SA, Marshall J, White K, Hui S, Weaver M, Gray J, Yee R, Stout JC, Beristain X, Wojcieszek J, Foroud T (August 2006). "Saccades in presymptomatic and early stages of Huntington disease". Neurology. 67 (3): 394–9. doi:10.1212/01.wnl.0000227890.87398.c1. PMID 16855205.
  8. ↑ Kirkwood SC, Su JL, Conneally P, Foroud T (February 2001). "Progression of symptoms in the early and middle stages of Huntington disease". Arch. Neurol. 58 (2): 273–8. PMID 11176966.
  9. ↑ 9.0 9.1 Di Maio L, Squitieri F, Napolitano G, Campanella G, Trofatter JA, Conneally PM (April 1993). "Onset symptoms in 510 patients with Huntington's disease". J. Med. Genet. 30 (4): 289–92. PMC 1016334. PMID 8487272.
  10. ↑ van Duijn E, Kingma EM, Timman R, Zitman FG, Tibben A, Roos RA, van der Mast RC (November 2008). "Cross-sectional study on prevalences of psychiatric disorders in mutation carriers of Huntington's disease compared with mutation-negative first-degree relatives". J Clin Psychiatry. 69 (11): 1804–10. PMID 19026253.
  11. ↑ Di Maio L, Squitieri F, Napolitano G, Campanella G, Trofatter JA, Conneally PM (April 1993). "Suicide risk in Huntington's disease". J. Med. Genet. 30 (4): 293–5. PMC 1016335. PMID 8487273.
  12. ↑ Wetzel HH, Gehl CR, Dellefave-Castillo L, Schiffman JF, Shannon KM, Paulsen JS (August 2011). "Suicidal ideation in Huntington disease: the role of comorbidity". Psychiatry Res. 188 (3): 372–6. doi:10.1016/j.psychres.2011.05.006. PMC 3790459. PMID 21605914.
  13. ↑ Hubers AA, Reedeker N, Giltay EJ, Roos RA, van Duijn E, van der Mast RC (February 2012). "Suicidality in Huntington's disease". J Affect Disord. 136 (3): 550–7. doi:10.1016/j.jad.2011.10.031. PMID 22119091.
  14. ↑ van Duijn E, Kingma EM, van der Mast RC (2007). "Psychopathology in verified Huntington's disease gene carriers". J Neuropsychiatry Clin Neurosci. 19 (4): 441–8. doi:10.1176/jnp.2007.19.4.441. PMID 18070848.
  15. ↑ Paulsen JS, Ready RE, Hamilton JM, Mega MS, Cummings JL (September 2001). "Neuropsychiatric aspects of Huntington's disease". J. Neurol. Neurosurg. Psychiatry. 71 (3): 310–4. PMC 1737562. PMID 11511702.
  16. ↑ Zappacosta B, Monza D, Meoni C, Austoni L, Soliveri P, Gellera C, Alberti R, Mantero M, Penati G, Caraceni T, Girotti F (June 1996). "Psychiatric symptoms do not correlate with cognitive decline, motor symptoms, or CAG repeat length in Huntington's disease". Arch. Neurol. 53 (6): 493–7. PMID 8660149.
  17. ↑ Tsuang D, Almqvist EW, Lipe H, Strgar F, DiGiacomo L, Hoff D, Eugenio C, Hayden MR, Bird TD (December 2000). "Familial aggregation of psychotic symptoms in Huntington's disease". Am J Psychiatry. 157 (12): 1955–9. doi:10.1176/appi.ajp.157.12.1955. PMID 11097960.
  18. ↑ Snowden J, Craufurd D, Griffiths H, Thompson J, Neary D (January 2001). "Longitudinal evaluation of cognitive disorder in Huntington's disease". J Int Neuropsychol Soc. 7 (1): 33–44. PMID 11253840.
  19. ↑ Pillon B, Deweer B, Agid Y, Dubois B (April 1993). "Explicit memory in Alzheimer's, Huntington's, and Parkinson's diseases". Arch. Neurol. 50 (4): 374–9. PMID 8460958.
  20. ↑ Duff K, Paulsen J, Mills J, Beglinger LJ, Moser DJ, Smith MM, Langbehn D, Stout J, Queller S, Harrington DL (August 2010). "Mild cognitive impairment in prediagnosed Huntington disease". Neurology. 75 (6): 500–7. doi:10.1212/WNL.0b013e3181eccfa2. PMC 2918475. PMID 20610833.
  21. ↑ Hamilton JM, Wolfson T, Peavy GM, Jacobson MW, Corey-Bloom J (February 2004). "Rate and correlates of weight change in Huntington's disease". J. Neurol. Neurosurg. Psychiatry. 75 (2): 209–12. PMC 1738924. PMID 14742590.
  22. ↑ Sanberg PR, Fibiger HC, Mark RF (April 1981). "Body weight and dietary factors in Huntington's disease patients compared with matched controls". Med. J. Aust. 1 (8): 407–9. PMID 6454826.
  23. ↑ Lodi R, Schapira AH, Manners D, Styles P, Wood NW, Taylor DJ, Warner TT (July 2000). "Abnormal in vivo skeletal muscle energy metabolism in Huntington's disease and dentatorubropallidoluysian atrophy". Ann. Neurol. 48 (1): 72–6. PMID 10894218.
  24. ↑ Aziz NA, van der Burg JM, Landwehrmeyer GB, Brundin P, Stijnen T, Roos RA (November 2008). "Weight loss in Huntington disease increases with higher CAG repeat number". Neurology. 71 (19): 1506–13. doi:10.1212/01.wnl.0000334276.09729.0e. PMID 18981372.
  25. ↑ Squitieri F, Berardelli A, Nargi E, Castellotti B, Mariotti C, Cannella M, Lavitrano ML, de Grazia U, Gellera C, Ruggieri S (July 2000). "Atypical movement disorders in the early stages of Huntington's disease: clinical and genetic analysis". Clin. Genet. 58 (1): 50–6. PMID 10945661.
  26. ↑ Kereshi S, Schlagenhauff RE, Richardson KS (April 1980). "Myoclonic and major seizures in early adult Huntington's chorea: case-report and electro-clinical findings". Clin Electroencephalogr. 11 (2): 44–7. PMID 6446423.

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