The Anatomy and Physiology of Pain CO’s CURE
Description: The Anatomy and Physiology of Pain COs CURE Hospital Medicine Pilot Learning Objectives Gain insight into of the anatomy and physiology of pain Recognize terminology Identify the bodys physiological response to pain Recognize the effects
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slide1. The Anatomy and Physiology of Pain CO’s CURE Hospital Medicine Pilot<br>
slide2. Learning Objectives Gain insight into of the anatomy and physiology of pain
Recognize terminology
Identify the body’s physiological response to pain
Recognize the effects of pain on the different body systems
Apply knowledge to assess and treat pain<br>
slide3. Pain THE TEACHING:
Medically - pain is a symptom of an underlying condition
THE MISSION:
Find the source of pain
Holistically treat the pain
THE GOAL:
Return to a realistic, productive life “An unpleasant sensory and emotional experience associated with actual or potential tissue damage.”<br>
slide4. The Purpose of Pain Prevents serious injury
A light touch to something hot forces a quick reaction before serious injury occurs
Teaches avoidance
A painful activity teaches what not to repeat or when to seek help
Prevents permanent damage
Joint pain limits activity
Surgery requires down time for healing<br>
slide5. The Pain Roadmap Pain sensation involves a series of complex interactions between peripheral nerves and the central nervous system
Pain is a dynamic, bidirectional process
Multiple areas of the nervous system help process pain signals
Normal and pathologic processes underlie pain mechanisms<br>
slide6. The Origin of Pain<br>
slide7. The Process of Pain Physiology Pain sensation is modulated by two types of neurotransmitters or neurochemicals:
Neurochemicals that excite pain or try to initiate pain
Neurochemicals that inhibit or try to stop the pain
Pain sensation is composed of four basic processes:
Transduction
Transmission
Modulation
Perception<br>
slide8. The Process of Pain Physiology<br>
slide9. The Transmission of Pain: Afferent Axons<br>
slide10. The Transmission of Pain: Timing The thickness of a nerve fiber correlates directly to the speed with which information travels
The thicker the nerve fiber, the faster information travels
A-alpha, A-beta and A-delta nerve fibers are insulated with a protective covering called the myelin sheath, which helps with nerve conductivity
C nerve fibers are unmyelinated
A-delta and C fibers are the main fibers responsible for the transmission of pain, however new studies suggest A-beta fibers may have an important role to play in the diagnosis and treatment of pain<br>
slide11. Transmission of Pain: Pull it Together Peripheral Sensory Nerve Spinal Cord Thalamus Cortex Pain! PAG Periaqueductal Gray Matter C
A-delta
Afferent neurons Modulation Pain Signals Transduction Perception Pain Signals Serotonin
Endorphins
Enkephalins
Dynorphin Neurochemical
Pain Inhibitors Descending Inhibition Epinephrine
Cortisol
ACTH Neurochemical
Pain Initiators Glutamate – Central
Substance P – Central
Bradykinin - Peripheral
Prostaglandins - Peripheral Transmission Descending Pathway Ascending Pathway<br>
slide12. Breakout of Pain CO’s CURE Module Five<br>
slide13. Acute Pain
Occurs in response to injury or illness
Responds well to interventions
Resolves well as healing proceeds
Short-lived
Less than three months
Often accompanied by sympathetic nervous system arousal
Adaptive pain response
Helpful pain response, which produces a behavior that promotes healing Chronic Pain
Multiple underlying mechanisms
Requires multi-modal and interdisciplinary treatment approaches
Pain that persists beyond the “normal” time expected to heal
Longer than three months
Changes in both peripheral and central nervous system processing
If acute pain is not managed well will move into the chronic phase Acute Pain vs. Chronic Pain<br>
slide14. Acute Pain vs. Chronic Pain Nociceptive Pain
ACUTE Neuropathic Pain
CHRONIC Nociplastic Pain
TYPICAL
CHRONIC<br>
slide15. Pain: Types of Pain<br>
slide16. Pain: Nociceptive and Neuropathic<br>
slide17. Acute Pain: Nociceptive What is nociceptive pain?
Normal response to an injury of tissues
Most common type of pain
What are nociceptors?
Nerves that detect or find noxious stimuli
What is nociception?
Process whereby signals are sent to the brain by nociceptor receptors
What is the cause of nociceptive pain?
Injury to body tissue to the skin, muscle and bones
Examples:
Postoperative pain, bruises, burns, fractures, overused joints
Patients will present with dull, heavy, aching pain that spreads over a wide area<br>
slide18. Chronic Pain: Neuropathic What is neuropathic pain?
Chronic pain lasts more than six-months
What is the cause of neuropathic pain?
Pain caused by a primary lesion or disease in the somatosensory nervous system causing varying degrees of pain sensations
What is some the cause of neuropathic pain?
Nerve damage due to some type of a viral infection or a disease involving the central or peripheral nervous system (neuralgias)
Examples:
Arthritis, migraines, shingles, multiple sclerosis, shingles
Patients will present with a variety of symptoms from numbness to burning to stinging, pins and needles and pricking sensations<br>
slide19. Chronic Pain: Nociplastic What is nociplastic pain?
Nonnociceptive and nonneuropathic pain
Inflammatory response
How does nociplastic pain work?
Activation and sensitization of nociceptive pain pathway by a variety of mediators released at a site of tissue
What causes nociplastic pain?
Abnormal processing in the central nervous system, however the reason for this abnormality is generally unknown
Examples:
Fibromyalgia, irritable bowel syndrome, chronic fatigue syndrome
Patients will present with a variety of symptoms seen in both acute and chronic pain patients<br>
slide20. Mixed Pain What is mixed pain?
Mixed pain share common clinical characteristics of all three types of pain
nociceptive, neuropathic and nociplastic
Potential Examples:
Sciatica, cancer pain, lumbar spinal stenosis<br>
slide21. Other Types of Pain<br>
slide22. Chronic Pain Syndrome: CPS “A chronic pain syndrome is the combination of chronic pain and the secondary complications that are making the original pain worse”
Institute for Chronic Pain<br>
slide23. Interaction of Complex Pain Nociceptive Pain
ACUTE Neuropathic Pain
CHRONIC Nociplastic Pain
TYPICALLY
CHRONIC MIXED PAIN<br>
slide24. Functional Effects of Pain<br>
slide25. Functional Effects of Pain<br>
slide26. Psychological Effects of Pain<br>
slide27. ACUTE
PAIN Surgery or injury causes inflammation Impact of Pain: Acute to Chronic Path CHRONIC
PAIN<br>
slide28. Infants and children
Elderly
Racial and ethnic groups
Women
People with current or past history of substance abuse/addiction
Cognitively impaired, non-verbal people Groups at High Risk for Pain Management<br>
slide29. Take Home Points The body’s reaction to pains to is complex and multifaceted
Pain is transmitted from the site of injury to the brain by electrical signals
Physiological changes triggered by pain are helpful in the beginning but become harmful if they continue
Understanding the anatomy and physiology of pain helps health professionals to find better ways to treat pain
Key interventions to prevent and treat pain begin with holistic pain assessments
Check the Society of Hospital Medicine Pain Pathways for treatment guidelines.<br>
slide30. References https://www.ncbi.nlm.nih.gov/books/NBK412/
https://www.researchgate.net/publication/323539036_Epigenetics_as_a_mechanism_linking_developmental_exposures_to_long-term_toxicity/link/5c3b335d458515a4c7226428/download
https://www.nursingtimes.net/clinical-archive/pain-management/anatomy-and-physiology-of-pain-18-09-2008/
https://www.nursingtimes.net/clinical-archive/pain-management/understanding-the-effect-of-pain-and-how-the-human-body-responds-26-02-2018/
https://www.ncbi.nlm.nih.gov/books/NBK219252/
Pain and Disability: Clinical, Behavioral, and Public Policy Perspectives
https://advances.sciencemag.org/content/5/7/eaaw1297
https://www.pnas.org/content/102/36/12950
The subjective experience of pain: Where expectations become reality
Tetsuo Koyama, John G. McHaffie, Paul J. Laurienti, Robert C. Coghill
Proceedings of the National Academy of Sciences Sep 2005, 102 (36) 12950-12955; DOI: 10.1073/pnas.0408576102;<br>
slide31. References National Pharmaceutical Council, INC, Joint Commission on Accreditation of Healthcare Organizations. (2001, December). . Barriers to the Appropriate Assessment and Management of Pain. Pain: Current Understanding of Assessment, Management, and Treatments. (15-16). Retrieved from: https://www.npcnow.org/system/files/research/download/Pain-Current-Understanding-of-Assessment-Management-and-Treatments.pdf
Niculescu, A. B., Le-Niculescu, H., Levey, D. F., Roseberry, K., Soe K. C., Rogers, J., Khan, F., … White, F. A., (2019, February 12). Towards precision medicine for pain: diagnositic biomarkers and repurposed drugs. Molecular Psychiatry 24:(501–522). Retrieved from: https://www.nature.com/articles/s41380-018-0345-5
Otis, J.A., Macone, A., (2019, April). When to Use Opioids: What I Didn’t Learn in Medical School. Practical Pain Management. Retrieved from: https://www.practicalpainmanagement.com/resource-centers/opioid-prescribing-monitoring/when-use-opioids-what-didnt-learn-medical-school
Riberio-Pinho, F. A., Verri Jr., W. A., Chiu, I. M., (2017, January). Nociceptor Sensory Neuron-Immune Interactions in Pain and Inflammation. Trends Immunol. 38(1) 5-19. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5205568/pdf/nihms821842.pdf
University of Wisconsin School of Medicine and Public Health: Pain Management (2010). Retrieved from: http://projects.hsl.wisc.edu/GME/PainManagement/index.html
Waller C. (2018). Colorado Hospital Association Opioid Safety Summit: The Addiction Treatment Ecosystem.
Wilensky, B.
Adapted from Woolf CJ. Ann Intern Med. 2004;140:441-451.
https://annals.org/aim/article-abstract/717288/pain-moving-from-symptom-control-toward-mechanism-specific-pharmacologic-management?volume=140&issue=6&page=441
Chong MS, Bajwa ZH. J Pain Symptom Manage. 2003;25:S4-S11.
Younger J, Aron A, Parke S, Chatterjee N, Mackey S (2010) PLOS ǀ ONE “Viewing Pictures of a Romantic Partner Reduces Experimental Pain: Involvement of Neural Reward Systems. Retrieved from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013309<br>
slide32. References BBC Horizon (2011). I Cut off My Arm to Save My Life. The Secret World of Pain – BBC Two. Retrieved from: https://www.youtube.com/watch?v=r9YFk7-Dsgw
Cox S (2010) Nursing Standard. Basic Principles of Pain Management: assessment and intervention. (Vol 25, Issue 1). Retrieved from: https://pdfs.semanticscholar.org/e7e6/423e73ce5696e2a2f1e2596258736fb2f486.pdf
Dmitry, A.M., Fleming, A., (2019, April). Pain Assessment: Review of Current Tools. Practical Pain Management. Retrieved from: https://www.practicalpainmanagement.com/resource-centers/opioid-prescribing-monitoring/list-clinically-tested-validated-pain-scales
Fink. R. (2000, July). Pain assessment: the cornerstone to optimal pain management. Baylor University Medical Center Proceedings, 38 (3), 236-239. Retrieved from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1317046/
Gereau IV, R. W., Sluka, K. A., Maixner, W., Savage, S. R., Price, T. J., Murinson, B. B., Sullivan, M. D…. Fillingim, R. B. (2014, December). The Journal of Pain 12: 1203-1215. http://americanpainsociety.org/uploads/about/position-statements/APS_Pain_Research_Agenda_White_Paper.pdf
Hartman, S. Vietnam veterans honor a fallen soldier 50 years later. (2019, July 19). CBS News. Retrieved from:. https://www.cbsnews.com/news/vietnam-veterans-honor-fallen-soldier-leonard-nitzsche-50-years-later-2019-07-19/
International Association for the Study of Pain: https://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698
Macintyre PE, Schug SA (2007) Acute Pain Management." A Practical/Guide. Third edition. Saunders Elsevier, Edinburgh.
McCaffery M (1972) Nursing Management of the Patient with Pain. Lippincott, Williams & Wilkins, Philadelphia, PA.
Miller, F. H., Choi, M. J., Angeli, L. L., Harland, A. A., Stamos, J. A., Thomas, S. T., . . . Rubin, L. H. (2009). Web site usability for the blind and low-vision user. Technical Communication, 57, 323-335.<br>
slide2. Learning Objectives Gain insight into of the anatomy and physiology of pain
Recognize terminology
Identify the body’s physiological response to pain
Recognize the effects of pain on the different body systems
Apply knowledge to assess and treat pain<br>
slide3. Pain THE TEACHING:
Medically - pain is a symptom of an underlying condition
THE MISSION:
Find the source of pain
Holistically treat the pain
THE GOAL:
Return to a realistic, productive life “An unpleasant sensory and emotional experience associated with actual or potential tissue damage.”<br>
slide4. The Purpose of Pain Prevents serious injury
A light touch to something hot forces a quick reaction before serious injury occurs
Teaches avoidance
A painful activity teaches what not to repeat or when to seek help
Prevents permanent damage
Joint pain limits activity
Surgery requires down time for healing<br>
slide5. The Pain Roadmap Pain sensation involves a series of complex interactions between peripheral nerves and the central nervous system
Pain is a dynamic, bidirectional process
Multiple areas of the nervous system help process pain signals
Normal and pathologic processes underlie pain mechanisms<br>
slide6. The Origin of Pain<br>
slide7. The Process of Pain Physiology Pain sensation is modulated by two types of neurotransmitters or neurochemicals:
Neurochemicals that excite pain or try to initiate pain
Neurochemicals that inhibit or try to stop the pain
Pain sensation is composed of four basic processes:
Transduction
Transmission
Modulation
Perception<br>
slide8. The Process of Pain Physiology<br>
slide9. The Transmission of Pain: Afferent Axons<br>
slide10. The Transmission of Pain: Timing The thickness of a nerve fiber correlates directly to the speed with which information travels
The thicker the nerve fiber, the faster information travels
A-alpha, A-beta and A-delta nerve fibers are insulated with a protective covering called the myelin sheath, which helps with nerve conductivity
C nerve fibers are unmyelinated
A-delta and C fibers are the main fibers responsible for the transmission of pain, however new studies suggest A-beta fibers may have an important role to play in the diagnosis and treatment of pain<br>
slide11. Transmission of Pain: Pull it Together Peripheral Sensory Nerve Spinal Cord Thalamus Cortex Pain! PAG Periaqueductal Gray Matter C
A-delta
Afferent neurons Modulation Pain Signals Transduction Perception Pain Signals Serotonin
Endorphins
Enkephalins
Dynorphin Neurochemical
Pain Inhibitors Descending Inhibition Epinephrine
Cortisol
ACTH Neurochemical
Pain Initiators Glutamate – Central
Substance P – Central
Bradykinin - Peripheral
Prostaglandins - Peripheral Transmission Descending Pathway Ascending Pathway<br>
slide12. Breakout of Pain CO’s CURE Module Five<br>
slide13. Acute Pain
Occurs in response to injury or illness
Responds well to interventions
Resolves well as healing proceeds
Short-lived
Less than three months
Often accompanied by sympathetic nervous system arousal
Adaptive pain response
Helpful pain response, which produces a behavior that promotes healing Chronic Pain
Multiple underlying mechanisms
Requires multi-modal and interdisciplinary treatment approaches
Pain that persists beyond the “normal” time expected to heal
Longer than three months
Changes in both peripheral and central nervous system processing
If acute pain is not managed well will move into the chronic phase Acute Pain vs. Chronic Pain<br>
slide14. Acute Pain vs. Chronic Pain Nociceptive Pain
ACUTE Neuropathic Pain
CHRONIC Nociplastic Pain
TYPICAL
CHRONIC<br>
slide15. Pain: Types of Pain<br>
slide16. Pain: Nociceptive and Neuropathic<br>
slide17. Acute Pain: Nociceptive What is nociceptive pain?
Normal response to an injury of tissues
Most common type of pain
What are nociceptors?
Nerves that detect or find noxious stimuli
What is nociception?
Process whereby signals are sent to the brain by nociceptor receptors
What is the cause of nociceptive pain?
Injury to body tissue to the skin, muscle and bones
Examples:
Postoperative pain, bruises, burns, fractures, overused joints
Patients will present with dull, heavy, aching pain that spreads over a wide area<br>
slide18. Chronic Pain: Neuropathic What is neuropathic pain?
Chronic pain lasts more than six-months
What is the cause of neuropathic pain?
Pain caused by a primary lesion or disease in the somatosensory nervous system causing varying degrees of pain sensations
What is some the cause of neuropathic pain?
Nerve damage due to some type of a viral infection or a disease involving the central or peripheral nervous system (neuralgias)
Examples:
Arthritis, migraines, shingles, multiple sclerosis, shingles
Patients will present with a variety of symptoms from numbness to burning to stinging, pins and needles and pricking sensations<br>
slide19. Chronic Pain: Nociplastic What is nociplastic pain?
Nonnociceptive and nonneuropathic pain
Inflammatory response
How does nociplastic pain work?
Activation and sensitization of nociceptive pain pathway by a variety of mediators released at a site of tissue
What causes nociplastic pain?
Abnormal processing in the central nervous system, however the reason for this abnormality is generally unknown
Examples:
Fibromyalgia, irritable bowel syndrome, chronic fatigue syndrome
Patients will present with a variety of symptoms seen in both acute and chronic pain patients<br>
slide20. Mixed Pain What is mixed pain?
Mixed pain share common clinical characteristics of all three types of pain
nociceptive, neuropathic and nociplastic
Potential Examples:
Sciatica, cancer pain, lumbar spinal stenosis<br>
slide21. Other Types of Pain<br>
slide22. Chronic Pain Syndrome: CPS “A chronic pain syndrome is the combination of chronic pain and the secondary complications that are making the original pain worse”
Institute for Chronic Pain<br>
slide23. Interaction of Complex Pain Nociceptive Pain
ACUTE Neuropathic Pain
CHRONIC Nociplastic Pain
TYPICALLY
CHRONIC MIXED PAIN<br>
slide24. Functional Effects of Pain<br>
slide25. Functional Effects of Pain<br>
slide26. Psychological Effects of Pain<br>
slide27. ACUTE
PAIN Surgery or injury causes inflammation Impact of Pain: Acute to Chronic Path CHRONIC
PAIN<br>
slide28. Infants and children
Elderly
Racial and ethnic groups
Women
People with current or past history of substance abuse/addiction
Cognitively impaired, non-verbal people Groups at High Risk for Pain Management<br>
slide29. Take Home Points The body’s reaction to pains to is complex and multifaceted
Pain is transmitted from the site of injury to the brain by electrical signals
Physiological changes triggered by pain are helpful in the beginning but become harmful if they continue
Understanding the anatomy and physiology of pain helps health professionals to find better ways to treat pain
Key interventions to prevent and treat pain begin with holistic pain assessments
Check the Society of Hospital Medicine Pain Pathways for treatment guidelines.<br>
slide30. References https://www.ncbi.nlm.nih.gov/books/NBK412/
https://www.researchgate.net/publication/323539036_Epigenetics_as_a_mechanism_linking_developmental_exposures_to_long-term_toxicity/link/5c3b335d458515a4c7226428/download
https://www.nursingtimes.net/clinical-archive/pain-management/anatomy-and-physiology-of-pain-18-09-2008/
https://www.nursingtimes.net/clinical-archive/pain-management/understanding-the-effect-of-pain-and-how-the-human-body-responds-26-02-2018/
https://www.ncbi.nlm.nih.gov/books/NBK219252/
Pain and Disability: Clinical, Behavioral, and Public Policy Perspectives
https://advances.sciencemag.org/content/5/7/eaaw1297
https://www.pnas.org/content/102/36/12950
The subjective experience of pain: Where expectations become reality
Tetsuo Koyama, John G. McHaffie, Paul J. Laurienti, Robert C. Coghill
Proceedings of the National Academy of Sciences Sep 2005, 102 (36) 12950-12955; DOI: 10.1073/pnas.0408576102;<br>
slide31. References National Pharmaceutical Council, INC, Joint Commission on Accreditation of Healthcare Organizations. (2001, December). . Barriers to the Appropriate Assessment and Management of Pain. Pain: Current Understanding of Assessment, Management, and Treatments. (15-16). Retrieved from: https://www.npcnow.org/system/files/research/download/Pain-Current-Understanding-of-Assessment-Management-and-Treatments.pdf
Niculescu, A. B., Le-Niculescu, H., Levey, D. F., Roseberry, K., Soe K. C., Rogers, J., Khan, F., … White, F. A., (2019, February 12). Towards precision medicine for pain: diagnositic biomarkers and repurposed drugs. Molecular Psychiatry 24:(501–522). Retrieved from: https://www.nature.com/articles/s41380-018-0345-5
Otis, J.A., Macone, A., (2019, April). When to Use Opioids: What I Didn’t Learn in Medical School. Practical Pain Management. Retrieved from: https://www.practicalpainmanagement.com/resource-centers/opioid-prescribing-monitoring/when-use-opioids-what-didnt-learn-medical-school
Riberio-Pinho, F. A., Verri Jr., W. A., Chiu, I. M., (2017, January). Nociceptor Sensory Neuron-Immune Interactions in Pain and Inflammation. Trends Immunol. 38(1) 5-19. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5205568/pdf/nihms821842.pdf
University of Wisconsin School of Medicine and Public Health: Pain Management (2010). Retrieved from: http://projects.hsl.wisc.edu/GME/PainManagement/index.html
Waller C. (2018). Colorado Hospital Association Opioid Safety Summit: The Addiction Treatment Ecosystem.
Wilensky, B.
Adapted from Woolf CJ. Ann Intern Med. 2004;140:441-451.
https://annals.org/aim/article-abstract/717288/pain-moving-from-symptom-control-toward-mechanism-specific-pharmacologic-management?volume=140&issue=6&page=441
Chong MS, Bajwa ZH. J Pain Symptom Manage. 2003;25:S4-S11.
Younger J, Aron A, Parke S, Chatterjee N, Mackey S (2010) PLOS ǀ ONE “Viewing Pictures of a Romantic Partner Reduces Experimental Pain: Involvement of Neural Reward Systems. Retrieved from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013309<br>
slide32. References BBC Horizon (2011). I Cut off My Arm to Save My Life. The Secret World of Pain – BBC Two. Retrieved from: https://www.youtube.com/watch?v=r9YFk7-Dsgw
Cox S (2010) Nursing Standard. Basic Principles of Pain Management: assessment and intervention. (Vol 25, Issue 1). Retrieved from: https://pdfs.semanticscholar.org/e7e6/423e73ce5696e2a2f1e2596258736fb2f486.pdf
Dmitry, A.M., Fleming, A., (2019, April). Pain Assessment: Review of Current Tools. Practical Pain Management. Retrieved from: https://www.practicalpainmanagement.com/resource-centers/opioid-prescribing-monitoring/list-clinically-tested-validated-pain-scales
Fink. R. (2000, July). Pain assessment: the cornerstone to optimal pain management. Baylor University Medical Center Proceedings, 38 (3), 236-239. Retrieved from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1317046/
Gereau IV, R. W., Sluka, K. A., Maixner, W., Savage, S. R., Price, T. J., Murinson, B. B., Sullivan, M. D…. Fillingim, R. B. (2014, December). The Journal of Pain 12: 1203-1215. http://americanpainsociety.org/uploads/about/position-statements/APS_Pain_Research_Agenda_White_Paper.pdf
Hartman, S. Vietnam veterans honor a fallen soldier 50 years later. (2019, July 19). CBS News. Retrieved from:. https://www.cbsnews.com/news/vietnam-veterans-honor-fallen-soldier-leonard-nitzsche-50-years-later-2019-07-19/
International Association for the Study of Pain: https://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698
Macintyre PE, Schug SA (2007) Acute Pain Management." A Practical/Guide. Third edition. Saunders Elsevier, Edinburgh.
McCaffery M (1972) Nursing Management of the Patient with Pain. Lippincott, Williams & Wilkins, Philadelphia, PA.
Miller, F. H., Choi, M. J., Angeli, L. L., Harland, A. A., Stamos, J. A., Thomas, S. T., . . . Rubin, L. H. (2009). Web site usability for the blind and low-vision user. Technical Communication, 57, 323-335.<br>