Hostname: page-component-78c5997874-4rdpn Total loading time: 0 Render date: 2024-11-16T21:14:26.919Z Has data issue: false hasContentIssue false

The association of depression and painful physical symptoms–a review of the European literature

Published online by Cambridge University Press:  16 April 2020

A. Garcia-Cebrian*
Affiliation:
European Health Outcomes Research, Erl Wood Manor, Sunninghill Road, Windlesham, SurreyGU20 6PH, UK
P. Gandhi
Affiliation:
UK Medical, Eli Lilly and Co., Basingstoke, UK
K. Demyttenaere
Affiliation:
Department of Psychiatry, University Hospital Gasthuisberg, Belgium
R. Peveler
Affiliation:
Mental Health Group, University of Southampton, UK
*
*Corresponding author. E-mail address: [email protected] (A. Garcia-Cebrian).
Get access

Abstract

Objective:

The presence of painful physical symptoms may confound the diagnosis of major depressive disorder and may worsen patient prognosis. Epidemiological literature was reviewed to investigate the association between depression and painful physical symptoms.

Method:

MEDLINE and EMBASE database searches were conducted. Studies where a definable organic basis for pain was given were excluded. The search was unrestricted by language but limited to European studies and countries. After filters were applied, 70 eligible studies were reviewed.

Results:

The majority of studies reviewed showed an association between depression and painful physical symptoms. Over 40% of all studies examining the association between pain and depression were carried out in pain clinics in secondary care. Very few studies were conducted in psychiatric settings.

Conclusion:

The findings of this review suggest that painful physical symptoms may be an important part of the depressive syndrome. Although the relationship between depression and painful physical symptoms is not yet fully understood, findings suggest that diagnosis and treatment of depression should involve investigating and treating the full spectrum of symptoms (emotional and physical). Further research in psychiatric and generalist settings is needed to elucidate the relationship between depression and painful physical symptoms as experienced by patients and at the clinical level.

Type
Original article
Copyright
Copyright © Elsevier SAS 2006

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

American Psychiatric Association. Diagnostic and statistical manual of mental disorders DSM-IV. 4th ed Washington, DC: American Psychiatric Association; 2000. 345346. (489)Google Scholar
Badcock, L.J., Lewis, M., Hay, E.M., McCarney, R., Croft, P.R.et al.Chronic shoulder pain in the community: a syndrome of disability or distress? Ann. Rheum. Dis. 2002; 61:128131.CrossRefGoogle ScholarPubMed
Badger, L., Degruy, F., Hartman, J., Plant, M.A., Leeper, J., Anderson, R.et al.Patient presentation, interview content, and the detection of depression by primary care physicians Psychosom. Med. 1994; 56:128135.CrossRefGoogle ScholarPubMed
Bair, M.J., Eckert, G.J., Robinson, R.L., Stang, P.E., Croghan, T.W., Kroenke, K.et al.Impact of pain on depression treatment efficacy J. Gen. Intern. Med. S17 2000 183.Google Scholar
Barsky, A.J., Borus, J.F.Somatization and medicalization in the era of managed care JAMA 1995; 274:19311934.CrossRefGoogle ScholarPubMed
Becker, N., Thomsen, A.B., Olsen, A.K., Sjogren, P., Bech, P., Eriksen, J.et al.Pain epidemiology and health related quality of life in chronic non-malignant pain patients referred to a Danish multidisciplinary pain center Pain 1997; 73:393400.CrossRefGoogle Scholar
Beekman, A.T., Kriegsman, D.M., Deeg, D.J., van Tilburg, W.et al.The association of physical health and depressive symptoms in the older population: age and sex differences Soc. Psychiatry Psychiatr. Epidemiol. 1995; 30:3238.CrossRefGoogle ScholarPubMed
Benjamin, S., Barnes, D., Berger, S., Clarke, I., Jeacock, J.et al.The relationship of chronic pain, mental illness and organic disorders Pain 1988; 32:185195.CrossRefGoogle ScholarPubMed
Benjamin, S., Morris, S., McBeth, J., Macfarlane, G.J., Silman, A.J.et al.The association between chronic widespread pain and mental disorder Arthritis Rheum. 2000; 43:561567.3.0.CO;2-O>CrossRefGoogle ScholarPubMed
Berthelot, J.-M., Glemarec, J., Laborie, Y., Varin, S., Maugars, Y.et al.Reasons for rheumatology department admission in 125 patients with disk-related sciatica Rev. Rhum. 1999; 66:267290.Google ScholarPubMed
Berto, P., D’Ilario, , Ruffo, P., Di Virgilio, R., Rizzo, F.et al.Depression: cost-of-illness studies in the international literature, a review J. Ment. Health Policy Econ. 2000; 3:310.3.0.CO;2-H>CrossRefGoogle ScholarPubMed
Bildt, C., Alfredsson, L., Michelsen, H., Punnett, L., Vingard, E., Torgen, M.et al.Occupational and nonoccupational risk indicators for incident and chronic low back pain in a sample of the Swedish general population during a 4-year period: an influence of depression? Int. J. Behav. Med. 2000; 7:372392.CrossRefGoogle Scholar
Braccili, T., Montebello, D., Verdecchia, P., Crenca, R., Redondi, A., Turri, E.et al.Evaluation of anxiety and depression in childhood migraine Eur. Rev. Med. Pharmacol. Sci. 1999; 3:3739.Google ScholarPubMed
Bridges, K.W., Goldberg, D.P.Somatic presentation of DSM III psychiatric disorders in primary care J. Psychosom. Res. 1985; 29:563569.CrossRefGoogle ScholarPubMed
Brochet, B., Michel, P., Barberger-Gare, P., Dartigues, J.F., Henry, P.et al.Pain in the elderly: an epidemiological study in south-western France Pain Clin. 1992; 5:7379.Google Scholar
Bultitude, M., Young, J., Bultitude, M., Allan, J.et al.Loin pain haematuria syndrome: distress resolved by pain relief Pain 1998; 76:209213.CrossRefGoogle ScholarPubMed
Burton, A.K., Tillotson, K.M., Main, C.J., Add Hollis, S.et al.Psychosocial predictors of outcome in acute and subchronic low back trouble Spine 1995; 20:722728.CrossRefGoogle ScholarPubMed
Croft, P.R., Papageorgiou, A.C., Ferry, S., Thomas, E., Jayson, M.I., Silman, A.J.et al.Psychologic distress and low back pain. Evidence from a prospective study in the general population Spine 1995; 20:27312737.CrossRefGoogle ScholarPubMed
Dickens, C., Jayson, M., Creed, F., Linder, J.Psychological correlates of pain behavior in patients with chronic low back pain Psychosomatics 2002; 43:4248.CrossRefGoogle ScholarPubMed
Ekselius, L., Eriksson, M., Von Knorring, L., Linder, J.et al.Personality disorders and major depression in patients with somatoform pain disorders and medical illnesses in relation to age at onset of work disability days Eur J Psychiat 1996; 10:3543.Google Scholar
Ericsson, M., Poston, W.S.C., Linder, J., Taylor, J.E., Haddock, K., Foreyt, J.P.et al.Depression predicts disability in long-term chronic pain patients Disabil. Rehabil. 2002; 24:334340.CrossRefGoogle ScholarPubMed
Farooq, S., Gahir, M.S., Okyere, E., Sheikh, A.J., Oyebode, F.et al.Somatization: a transcultural study J. Psychosom. Res. 1995; 39:883888.CrossRefGoogle ScholarPubMed
Fava, M.Somatic symptoms, depression and antidepressant treatment J. Clin. Psychiatry 2002; 63:305307.CrossRefGoogle ScholarPubMed
Feinmann, C.Psychogenic facial pain: presentation and treatment J. Psychosom. Res. 1983; 27:403410.CrossRefGoogle ScholarPubMed
Finne-Soveri, U.H., Ljunggren, G., Schroll, M., Jónsson, P.V., Hjaltadottir, I., El Kholy, K.et al.Pain and its association with disability in institutional long-term care in four Nordic countries Can. J. Aging 2000; 19:3849.CrossRefGoogle Scholar
Fishbain, D.A., Cutler, R., Rosomoff, H.L., Rosomoff, R.S.et al.Chronic pain-associated depression: antecedent or consequence of chronic pain? A review Clin. J. Pain 1997; 13:116137.CrossRefGoogle ScholarPubMed
Forrest, A.J., Wolkind, S.N.Masked depression in men with low back pain Rheumatol. Rehabil. 1974; 13:148153.CrossRefGoogle ScholarPubMed
Fritzsche, K., Sandholzer, H., Brucks, U., Cierpka, M., Deter, H.C., Harter, M.et al.Psychosocial care by general practitioners – where are the problems? Results of a demonstration project on quality management in psychosocial primary care Int. J. Psychiatry Med. 1999; 29:395409.CrossRefGoogle ScholarPubMed
Garcia-Campayo, J., Lobo, A., Perez-Echeverria, J., Campos, R.et al.Three forms of somatization presenting in primary care settings in Spain J. Nerv. Ment. Dis. 1998; 186:554560.CrossRefGoogle ScholarPubMed
Geerlings, S.W., Twisk, J.W., Beekman, A.T., Deeg, D.J., van Tilburg, W.et al.Longitudinal relationship between pain and depression in older adults: sex, age and physical disability Soc. Psychiatry Psychiatr. Epidemiol. 2002; 37:2330.CrossRefGoogle ScholarPubMed
Goldberg, D., Bridges, K.Somatic presentations of psychiatric illness in primary care settings J. Psychosom. Res. 1988; 32:137144.CrossRefGoogle Scholar
Goodacre, S., Mason, S., Arnold, J., Angelini, K.et al.Psychologic morbidity and health-related quality of life of patients assessed in a chest pain observation unit Ann. Emerg. Med. 2001; 38:369376.CrossRefGoogle Scholar
Greden, J.Physical symptoms of depression: unmet needs J. Clin. Psychiatry 64(Suppl. 7)2003 511.Google ScholarPubMed
Guitart, J., Gimenez-Grouselles, J.Prevalencia de puntos dolorosos tipo fibromialgia en una poblacion reumatologica. Evaluacion de diversas variables Rev Soc Esp Dolor 1999; 6:412419.Google Scholar
Gureje, O., Simon, G.E., Von Korff, M.A cross-national study of the course of persistent pain in primary care Pain 2001; 92:195200.CrossRefGoogle ScholarPubMed
Gureje, O., Von Korff, M., Simon, G.E., Gater, R.et al.Persistent pain and well-being. A World Health Organization study in primary care JAMA 1998; 280:147151.CrossRefGoogle ScholarPubMed
Hamilton, M.Development of a rating scale for primary depressive illness Br. J. Soc. Clin. Psychol. 6(4)1967 278279.CrossRefGoogle ScholarPubMed
Harma, A.M., Kaltiala-Heino, R., Rimpela, M., Rantanen, P.et al.Are adolescents with frequent pain symptoms more depressed? Scand. J. Prim. Health Care 2002; 20:9296.CrossRefGoogle ScholarPubMed
Harter, M., Reuter, K., Weisser, B., Schretzmann, B., Aschenbrenner, A., Bengel, J.et al.A descriptive study of psychiatric disorders and psychosocial burden in rehabilitation patients with musculoskeletal disease Arch. Phys. Med. Rehabil. 2002; 83:461468.CrossRefGoogle Scholar
Hotopf, M., Mayou, R., Wadsworth, M., Wessely, S.et al.Temporal relationships between physical symptoms and psychiatric disorder. Results from a national birth cohort Br. J. Psychiatry 1998; 173:255261.CrossRefGoogle ScholarPubMed
Ierodiakonou, C.S., Iacovides, A.Somatic manifestations of depressive patients in different psychiatric settings Psychopathology 1987; 20:136143.CrossRefGoogle ScholarPubMed
Ihlabaek, C., Eriksen, H.R., Ursin, H.Prevalence of subjective health complaints (SHC) in Norway Scand. J. Public Health 2002; 30:2029.CrossRefGoogle Scholar
Jackel, W.H., Gerdes, N., Cziske, R., Jacobi, E.et al.Epidemiologie rheumatischer Beschwerden in der Bundesrepublik Deutschland. Daten zur Pravalenz und zur korperlichen und psychosozialen Beeintrachtigung Z. Rheumatol. 1993; 52:281288.Google Scholar
Jensen, I.B., Nygren, A., Lundin, A.Cognitive-behaviour treatment for workers with chronic spinal pain: a matched and controlled cohort study in Sweden Occup. Environ. Med. 1994; 51:145151.CrossRefGoogle Scholar
Kirmayer, L., Robbins, J., Dworkind, M., Yaffe, M.J.et al.Somatization and the recognition of depression and anxiety in primary care Am. J. Psychiatry 1993; 150:734741.Google ScholarPubMed
Kurtze, N., Gundersen, K.T., Svebak, S.The role of anxiety and depression in fatigue and patterns of pain among subgroups of fibromyalgia patients Br. J. Med. Psychol. 1998; 71:185194.CrossRefGoogle ScholarPubMed
Kurtze, N., Svebak, S.Fatigue and patterns of pain in fibromyalgia: correlations with anxiety, depression and co-morbidity in a female county sample Br. J. Med. Psychol. 2001; 74:523527.CrossRefGoogle Scholar
Lamb, S.E., Guralnik, J.M., Buchner, D.M., Ferrucci, L.M., Hochberg, M.C., Simonsick, E.M.et al.Factors that modify the association between knee pain and mobility limitation in older women: the Women’s Health and Aging Study Ann. Rheum. Dis. 2000; 59:331337.CrossRefGoogle ScholarPubMed
Lascelles, R.G.Atypical facial pain and depression Br. J. Psychiatry 1966; 112:651659.CrossRefGoogle ScholarPubMed
Lecrubier, Y., Boyer, P., Lepine, J., Weiller, E.The identification of psychiatric disorders in primary care Eur. Psychiatry 11(Suppl 4)1996 178179.CrossRefGoogle Scholar
Leino, P., Magni, G.Depressive and distress symptoms as predictors of low back pain, neck-shoulder pain, and other musculoskeletal morbidity: a 10-year follow-up of metal industry employees Pain 1993; 53:8994.CrossRefGoogle ScholarPubMed
Lepine, J.P., Gastpar, M., Mendlewicz, J., Tylee, A.Depression in the community: the first pan-European study DEPRES (Depression Research in European Society) Int. Clin. Psychopharmacol. 1997; 12:1929.CrossRefGoogle Scholar
Lindsay, P., Wyckoff, M.The depression-pain syndrome and its response to antidepressants Psychosomatics 22(7)1981 571573. (576–7)CrossRefGoogle Scholar
Linton, S.J., Hellsing, A.-L., Bryngelsson, I.-L.Psychosocial and functional risk factors in the early stages of back pain: effects on moderate pain Int. J. Behav. Med. 2000; 7:291304.CrossRefGoogle Scholar
Livingstone, G., Watkins, V., Milne, B., Manela, M.V., Katona, C.et al.Who becomes depressed? The Islington community study of older people J. Affect. Disord. 2000; 58:125133.CrossRefGoogle Scholar
Lobo, A., Garcia-Campayo, J., Campos, R., Marcos, G., Perez-Echeverria, M.J.et al.Somatisation in primary care in Spain: I. Estimates of prevalence and clinical characteristics Br. J. Psychiatry 1996; 168:344348.CrossRefGoogle ScholarPubMed
Madland, G., Feinmann, C., Newman, S.Factors associated with anxiety and depression in facial arthromyalgia Pain 2000; 84:225232.CrossRefGoogle ScholarPubMed
Magni, G., Salmi, A., De Leo, D., Ceola, A.et al.Chronic pelvic pain and depression Psychopathology 1984; 17:132136.CrossRefGoogle ScholarPubMed
Maiden, N.L., Hurst, N.P., Lochhead, A., Carson, A.J., Sharpe, M.et al.Medically unexplained symptoms in patients referred to a specialist rheumatology service: prevalence and associations Rheumatol. 2003; 42:108112.CrossRefGoogle ScholarPubMed
Mallinckrodt, C., Goldstein, D., Detke, M., Lu, Y., Watkin, J.G., Tran, P.V.et al.Duloxetine: a new treatment for the emotional and physical symptoms of depression J. Clin. Psychiatry 5(1)2003 1928.Google ScholarPubMed
Masi, G., Favilla, L., Millepiedi, S., Mucci, M.et al.Somatic symptoms in children and adolescents referred for emotional and behavioral disorders Psychiatry 2000; 63:140149.CrossRefGoogle ScholarPubMed
McBeth, J., Macfarlane, G.J., Silman, A.J.Does chronic pain predict future psychological distress? Pain 2002; 96:239245.CrossRefGoogle ScholarPubMed
Merikangas, K.R., Merikangas, J.R., Angst, J.Headache syndromes and psychiatric disorders: association and familial transmission J. Psychiatr. Res. 1993; 27:197210.CrossRefGoogle ScholarPubMed
Meyer, T., Klemne, H., Herrmann-Lingen, C.Persistenz und Effekte von Depressiviat und Angstsymptomatik bei internistischen Patienten im ersten Jahr nach stationarer Behandlung Z Psychosom Mewd Psychother 2002; 48:174191.Google Scholar
Mikkelsson, M., Sourander, A., Piha, J., Salminen, J.J.et al.Psychiatric symptoms in preadolescents with musculoskeletal pain and fibromyalgia Pediatrics 1997; 100:220227.CrossRefGoogle ScholarPubMed
Mokleby, K., Blomhoff, S., Malt, U.F., Dahlstrom, A., Tauboll, E., Gjerstad, L.et al.Psychiatric comorbidity and hostility in patients with psychogenic nonepileptic seizures compared with somatoform disorders and health controls Epilepsia 2002; 43:193198.CrossRefGoogle Scholar
Montgomery, S.A., Asberg, M.A new depression scale designed to be sensitive to change Br. J. Psychiatry 1979; 134:382389.CrossRefGoogle ScholarPubMed
Morriss, R.K., Ahmed, M., Wearden, A.J., Mullis, R., Strickland, P., Appleby, L.et al.The role of depression in pain, psychophysiological syndromes and medically unexplained symptoms associated with chronic fatigue syndrome J. Affect. Disord. 1999; 55:143148.CrossRefGoogle ScholarPubMed
Moya, F., Grau, M., Riesco, N., Nunez, M., Brancos, M.A., Valdes, M.et al.Dolor lumbar cronico. Valoracion multidisciplinaria de 100 pacientes Aten. Primaria 2000; 26:239244.Google Scholar
Murray, C.J., Lopez, A.D.The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020 Cambridge, MA: Harvard School of Public Health on behalf of the World Health Organization and the World Bank; 1996.Google Scholar
Ohayon, M.M., Schatzberg, A.F.Using chronic pain to predict depressive morbidity in the general population Arch. Gen. Psychiatry 2003; 60:3947.CrossRefGoogle ScholarPubMed
Panarino, P.J.The costs of depression: direct and indirect; treatment versus nontreatment J. Clin. Psychiatry 59(Suppl. 20)1998 1114.Google Scholar
Pearson, S., Katzelnick, D., Simon, G., Manning, W.G., Helstad, C.P., Henk, H.J.et al.Depression among high utilizers of Medical Care J. Gen. Intern. Med. 1999; 14:461468.CrossRefGoogle ScholarPubMed
Perez-Stable, E., Miranda, J., Munoz, R., Ying, Y.Depression in medical outpatients. Underrecognition and misdiagnosis Arch Gen Med 1990; 150:10831088.Google ScholarPubMed
Pincus, H., Pettit, A.The societal costs of chronic major depression J. Clin. Psychiatry 62(Suppl. 6)2001 59.Google ScholarPubMed
Posse, M., Hallstrom, T.Depressive disorders among somatizing patients in primary health care Acta Psychiatr. Scand. 1998; 98:169174.CrossRefGoogle ScholarPubMed
Potter, R.G., Jones, J.M.The evolution of chronic pain among patients with musculoskeletal problems: a pilot study in primary care Br. J. Gen. Pract. 1992; 42:462464.Google ScholarPubMed
Power, C., Frank, J., Hertzman, C., Schierhout, G., Li, L.et al.Predictors of low back pain onset in a prospective British study Am. J. Public Health 2001; 91:16711678.CrossRefGoogle Scholar
Rajala, U., Keinanen-Kiukaanniemi, S., Uusimaki, A., Kivela, S..L.et al.Musculoskeletal pains and depression in a middle-aged Finnish population Pain 1995; 61:451457.CrossRefGoogle Scholar
Reichborn-Kjennerud, T., Stoltenberg, C., Tambs, K., Roysamb, E., Kringlen, E., Torgersen, S.et al.Back-neck pain and symptoms of anxiety and depression: a population-based twin study Psychol. Med. 2002; 32:10091020.CrossRefGoogle ScholarPubMed
Rethelyi, J.M., Berghammer, R., Kopp, M.S.Comorbidity of pain-associated disability and depressive symptoms in connection with sociodemographic variables: results from a cross-sectional epidemiological survey in Hungary Pain 2001; 93:115121.CrossRefGoogle ScholarPubMed
Rost, K., Zhang, M., Fortney, J., Smith, J., Coyne, J., Smith, G.R. Jr.et al.Persistently poor outcomes of undetected major depression in primary care Gen. Hosp. Psychiatry 1998; 20:1220.CrossRefGoogle ScholarPubMed
Roy, R., Thomas, M., Berger, S.A comparative study of Canadian nonclinical and British pain clinic subjects Clin. J. Pain 1990; 6:276283.CrossRefGoogle ScholarPubMed
Salaffi, F., Ferraccioli, G.F., Carotti, M., Blasetti, P., Cervini, C.et al.La disabilita nell’artrite reumatoide: valare predittivo dell’eta e della depressione Recenti Prog. Med. 1992; 83:675679.Google Scholar
Sartorius, N.Physical symptoms of depression as a public health concern J. Clin. Psychiatry 64(Suppl. 7)2003 34.Google ScholarPubMed
Simon, G.E., Von Korff, M., Barlow, W.Health care costs of primary care patients with recognized depression Arch. Gen. Psychiatry 1995; 52:850856.CrossRefGoogle ScholarPubMed
Simon, G.E., Von Korff, M., Picinelli, M., Fullerton, C., Ormel, J.et al.An international study of the relation between somatic symptoms and depression N. Engl. J. Med. 1999; 341:13291335.CrossRefGoogle Scholar
Simon, G.E., Von Korff, M.Suicide mortality among patients treated for depression in an insured population Am. J. Epidemiol. 1998; 147:155160.CrossRefGoogle Scholar
Stahl, S.Does depression hurt? J. Clin. Psychiatry 2002; 63:273.CrossRefGoogle ScholarPubMed
Stahl, S.The psychopharmacology of painful physical symptoms in depression J. Clin. Psychiatry 2002; 63:382383.CrossRefGoogle ScholarPubMed
Tyrer, S.P., Capon, M., Peterson, D.M., Charlton, J.E., Thompson, J.W.et al.The detection of psychiatric illness and psychological handicaps in a British pain clinic population Pain 1989; 36:6374.CrossRefGoogle Scholar
Vaeroy, H., Merskey, H.The prevalence of current major depression and dysthymia in a Norwegian general practice Acta Psychiatr. Scand. 1997; 95:324328.CrossRefGoogle Scholar
Valkamo, M., Hintikka, J., Niskanen, L., Viinamaki, H.et al.Psychiatric morbidity and the presence and absence of angiographic coronary disease in patients with chest pain Acta Psychiatr. Scand. 2001; 104:391396.CrossRefGoogle ScholarPubMed
Van der Windt, D., Croft, P., Pennix, B.Neck and upper limb pain: more pain is associated with psychological distress and consultation rate in primary care J. Rheumatol. 2001; 29:564569.Google Scholar
Von Knorring, L., Perris, C., Eisemann, M., Eriksson, U., Perris, H.et al.Pain as a symptom in depressive disorders. Relationship to social background factors Eur. J. Psychiat. 3(2)1989 99104.Google Scholar
Von Knorring, , Perris, C., Eisemann, M., Eriksson, U., Perris, H.et al.Pain as a symptom in depressive disorders: I. Relationship to diagnostic subgroup and depressive symptomatology Pain 1983; 15:1926.CrossRefGoogle Scholar
Williams, A.C., Richardson, P.H.What does the BDI measure in chronic patients Pain 1993; 55:259266.CrossRefGoogle Scholar
Zwart, J.A., Dyb, G., Hagen, K., Odegard, K.J., Dahl, A.A., Bovim, G.et al.Depression and anxiety disorders associated with headache frequency. The Nord-Trondelag Health Study Eur. J. Neurol. 2003; 10:147152.CrossRefGoogle ScholarPubMed
Submit a response

Comments

No Comments have been published for this article.