Environmental factors in primary biliary cirrhosis

Seminars in Liver Disease

Volumn 34, Issue 3, 2014, Pages 265-272

  Juran, Brian D ^a   Lazaridis, Konstantinos N ^a  

^a MAYO CLINIC   (United States)

Author keywords

autoimmunity; environment; primary biliary cirrhosis

Indexed keywords

ANTIBIOTIC AGENT; ANTIGEN;

ARTICLE; ENVIRONMENTAL FACTOR; GEOGRAPHIC DISTRIBUTION; HUMAN; HYGIENE; MOLECULAR MIMICRY; PATHOGENESIS; PREVALENCE; PRIMARY BILIARY CIRRHOSIS; PRIORITY JOURNAL; RISK FACTOR; SMOKING; URINARY TRACT INFECTION; ADVERSE EFFECTS; AUTOIMMUNITY; DEMOGRAPHY; ENVIRONMENT; GENETIC PREDISPOSITION; GENETICS; GENOTYPE ENVIRONMENT INTERACTION; HYGIENE HYPOTHESIS; IMMUNOLOGY; INTRAHEPATIC BILE DUCT; LIFESTYLE; LIVER CIRRHOSIS, BILIARY; PATHOLOGY; URINARY TRACT INFECTIONS;

AUTOIMMUNITY; BILE DUCTS, INTRAHEPATIC; ENVIRONMENT; GENE-ENVIRONMENT INTERACTION; GENETIC PREDISPOSITION TO DISEASE; HUMANS; HYGIENE HYPOTHESIS; LIFE STYLE; LIVER CIRRHOSIS, BILIARY; MOLECULAR MIMICRY; PREVALENCE; RESIDENCE CHARACTERISTICS; RISK FACTORS; SMOKING; URINARY TRACT INFECTIONS;

EID: 84904974336     PISSN: 02728087     EISSN: 10988971     Source Type: Journal    
DOI: 10.1055/s-0034-1383726     Document Type: Article

References (107)

1. Kaplan M. M., Gershwin M. E. Primary biliary cirrhosis. N Engl J Med: 2005; 353 12 1261 1273
2. Hirschfield G. M., Chapman R. W., Karlsen T. H., Lammert F., Lazaridis K. N., Mason A. L. The genetics of complex cholestatic disorders. Gastroenterology: 2013; 144 7 1357 1374
3. Hirschfield G. M., Gershwin M. E. The immunobiology and pathophysiology of primary biliary cirrhosis. Annu Rev Pathol: 2013; 8 303 330
4. Selmi C., Mayo M. J., Bach N., et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology: 2004; 127 2 485 492
5. Lazaridis K. N., Juran B. D., Boe G. M., et al. Increased prevalence of antimitochondrial antibodies in first-degree relatives of patients with primary biliary cirrhosis. Hepatology: 2007; 46 3 785 792
6. Jones D. E., Watt F. E., Metcalf J. V., Bassendine M. F., James O. F. Familial primary biliary cirrhosis reassessed: a geographically-based population study. J Hepatol: 1999; 30 3 402 407
7. Selmi C., Meroni P. L., Gershwin M. E. Primary biliary cirrhosis and Sjögren's syndrome: autoimmune epithelitis. J Autoimmun: 2012; 39 1-2 34 42
8. Hirschfield G. M., Liu X., Han Y., et al. Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nat Genet: 2010; 42 8 655 657
9. Hirschfield G. M., Liu X., Xu C., et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med: 2009; 360 24 2544 2555
10. Juran B. D., Hirschfield G. M., Invernizzi P., et al. Italian PBC Genetics Study Group. Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants. Hum Mol Genet: 2012; 21 23 5209 5221
11. Liu J. Z., Almarri M. A., Gaffney D. J., et al. UK Primary Biliary Cirrhosis (PBC) Consortium; Wellcome Trust Case Control Consortium 3. Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nat Genet: 2012; 44 10 1137 1141
12. Liu X., Invernizzi P., Lu Y., et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet: 2010; 42 8 658 660
13. Mells G. F., Floyd J. A., Morley K. I., et al. UK PBC Consortium; Wellcome Trust Case Control Consortium 3. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet: 2011; 43 11 1164
14. Nakamura M., Nishida N., Kawashima M., et al. Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. Am J Hum Genet: 2012; 91 4 721 728
15. Hamlyn A. N., Macklon A. F., James O. Primary biliary cirrhosis: geographical clustering and symptomatic onset seasonality. Gut: 1983; 24 10 940 945
16. Prince M. I., Chetwynd A., Diggle P., Jarner M., Metcalf J. V., James O. F. The geographical distribution of primary biliary cirrhosis in a well-defined cohort. Hepatology: 2001; 34 6 1083 1088
17. McNally R. J., James P. W., Ducker S., James O. F. Seasonal variation in the patient diagnosis of primary biliary cirrhosis: further evidence for an environmental component to etiology. Hepatology: 2011; 54 6 2099 2103
18. Abu-Mouch S., Selmi C., Benson G. D., et al. Geographic clusters of primary biliary cirrhosis. Clin Dev Immunol: 2003; 10 2-4 127 131
19. Ala A., Stanca C. M., Bu-Ghanim M., et al. Increased prevalence of primary biliary cirrhosis near Superfund toxic waste sites. Hepatology: 2006; 43 3 525 531
20. Boonstra K., Kunst A. E., Stadhouders P. H., et al. the Epi PSC PBC study group. Rising incidence and prevalence of primary biliary cirrhosis: a large population-based study. Liver Int: 2014
21. Corpechot C., Chrétien Y., Chazouillères O., Poupon R. Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis. J Hepatol: 2010; 53 1 162 169
22. Gershwin M. E., Selmi C., Worman H. J., et al. USA PBC Epidemiology Group. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology: 2005; 42 5 1194 1202
23. Howel D., Fischbacher C. M., Bhopal R. S., Gray J., Metcalf J. V., James O. F. An exploratory population-based case-control study of primary biliary cirrhosis. Hepatology: 2000; 31 5 1055 1060
24. Lammert C., Nguyen D. L., Juran B. D., et al. Questionnaire based assessment of risk factors for primary biliary cirrhosis. Dig Liver Dis: 2013; 45 7 589 594
25. Liang Y., Yang Z., Zhong R. Smoking, family history and urinary tract infection are associated with primary biliary cirrhosis: a meta-analysis. Hepatol Res: 2011; 41 6 572 578
26. Mantaka A., Koulentaki M., Chlouverakis G., et al. Primary biliary cirrhosis in a genetically homogeneous population: disease associations and familial occurrence rates. BMC Gastroenterol: 2012; 12 110
27. Parikh-Patel A., Gold E. B., Worman H., Krivy K. E., Gershwin M. E. Risk factors for primary biliary cirrhosis in a cohort of patients from the United States. Hepatology: 2001; 33 1 16 21
28. Prince M. I., Ducker S. J., James O. F. Case-control studies of risk factors for primary biliary cirrhosis in two United Kingdom populations. Gut: 2010; 59 4 508 512
29. Boonstra K., Beuers U., Ponsioen C. Y. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol: 2012; 56 5 1181 1188
30. Kim W. R., Lindor K. D., Locke G. R. III., et al. Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology: 2000; 119 6 1631 1636
31. Metcalf J. V., Bhopal R. S., Gray J., Howel D., James O. F. Incidence and prevalence of primary biliary cirrhosis in the city of Newcastle upon Tyne, England. Int J Epidemiol: 1997; 26 4 830 836
32. Chong V. H., Telisinghe P. U., Jalihal A. Primary biliary cirrhosis in Brunei Darussalam. Hepatobiliary Pancreat Dis Int: 2010; 9 6 622 628
33. Watson R. G., Angus P. W., Dewar M., Goss B., Sewell R. B., Smallwood R. A. Melbourne Liver Group Low prevalence of primary biliary cirrhosis in Victoria, Australia. Gut: 1995; 36 6 927 930
34. Simpson S. Jr, Blizzard L., Otahal P., Van der Mei I., Taylor B. Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry: 2011; 82 10 1132 1141
35. Triger D. R. Primary biliary cirrhosis: an epidemiological study. BMJ: 1980; 281 6243 772 775
36. Vine M. F., Stein L., Weigle K., et al. Effects on the immune system associated with living near a pesticide dump site. Environ Health Perspect: 2000; 108 12 1113 1124
37. Carpenter D. O., Shen Y., Nguyen T., Le L., Lininger L. L. Incidence of endocrine disease among residents of New York areas of concern. Environ Health Perspect: 2001; 109 06 845 851
38. Amano K., Leung P. S., Rieger R., et al. Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid. J Immunol: 2005; 174 9 5874 5883
39. McNally R. J., Ducker S., James O. F. Are transient environmental agents involved in the cause of primary biliary cirrhosis? Evidence from space-time clustering analysis. Hepatology: 2009; 50 4 1169 1174
40. Hézode C., Lonjon I., Roudot-Thoraval F., et al. Impact of smoking on histological liver lesions in chronic hepatitis C. Gut: 2003; 52 1 126 129
41. Tsochatzis E., Papatheodoridis G. V., Manolakopoulos S., Tiniakos D. G., Manesis E. K., Archimandritis A. J. Smoking is associated with steatosis and severe fibrosis in chronic hepatitis C but not B. Scand J Gastroenterol: 2009; 44 6 752 759
42. Corpechot C., Gaouar F., Chrétien Y., Johanet C., Chazouillères O., Poupon R. Smoking as an independent risk factor of liver fibrosis in primary biliary cirrhosis. J Hepatol: 2012; 56 1 218 224
43. Zein C. O., Beatty K., Post A. B., Logan L., Debanne S., McCullough A. J. Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: A cross validated retrospective assessment. Hepatology: 2006; 44 6 1564 1571
44. Bluhm A. L., Weinstein J., Sousa J. A. Free radicals in tobacco smoke. Nature: 1971; 229 5285 500
45. Hecht S. S. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst: 1999; 91 14 1194 1210
46. Pryor W. A., Stone K. Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann N Y Acad Sci: 1993; 686 12 27, discussion 27-28
47. Thielen A., Klus H., Müller L. Tobacco smoke: unraveling a controversial subject. Exp Toxicol Pathol: 2008; 60 2-3 141 156
48. Arnson Y., Shoenfeld Y., Amital H. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J Autoimmun: 2010; 34 3 J258 J265
49. Glossop J. R., Dawes P. T., Mattey D. L. Association between cigarette smoking and release of tumour necrosis factor alpha and its soluble receptors by peripheral blood mononuclear cells in patients with rheumatoid arthritis. Rheumatology (Oxford): 2006; 45 10 1223 1229
50. Lee S. H., Goswami S., Grudo A., et al. Antielastin autoimmunity in tobacco smoking-induced emphysema. Nat Med: 2007; 13 5 567 569
51. Shan M., Cheng H. F., Song L. Z., et al. Lung myeloid dendritic cells coordinately induce TH1 and TH17 responses in human emphysema. Sci Transl Med: 2009; 1 4 4 10
52. Bernuzzi F., Fenoglio D., Battaglia F., et al. Phenotypical and functional alterations of CD8 regulatory T cells in primary biliary cirrhosis. J Autoimmun: 2010; 35 3 176 180
53. Harada K., Van de Water J., Leung P. S., et al. In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis: predominance of the Th1 subset. Hepatology: 1997; 25 4 791 796
54. Shimoda S., Ishikawa F., Kamihira T., et al. Autoreactive T-cell responses in primary biliary cirrhosis are proinflammatory whereas those of controls are regulatory. Gastroenterology: 2006; 131 2 606 618
55. Kroening P. R., Barnes T. W., Pease L., Limper A., Kita H., Vassallo R. Cigarette smoke-induced oxidative stress suppresses generation of dendritic cell IL-12 and IL-23 through ERK-dependent pathways. J Immunol: 2008; 181 2 1536 1547
56. Burroughs A. K., Rosenstein I. J., Epstein O., Hamilton-Miller J. M., Brumfitt W., Sherlock S. Bacteriuria and primary biliary cirrhosis. Gut: 1984; 25 2 133 137
57. Rosenstein I. J., Hazlehurst G. R., Burroughs A. K., Epstein O., Sherlock S., Brumfitt W. Recurrent bacteriuria and primary biliary cirrhosis: ABO blood group, P1 blood group, and secretor status. J Clin Pathol: 1984; 37 9 1055 1058
58. Butler P., Hamilton-Miller J. M., McIntyre N., Burroughs A. K. Natural history of bacteriuria in women with primary biliary cirrhosis and the effect of antimicrobial therapy in symptomatic and asymptomatic groups. Gut: 1995; 36 6 931 934
59. Floreani A., Bassendine M. F., Mitchison H., Freeman R., James O. F. No specific association between primary biliary cirrhosis and bacteriuria? J Hepatol: 1989; 8 2 201 207
60. Varyani F. K., West J., Card T. R. An increased risk of urinary tract infection precedes development of primary biliary cirrhosis. BMC Gastroenterol: 2011; 11 95
61. Varyani F. K., West J., Card T. R. Primary biliary cirrhosis does not increase the risk of UTIs following diagnosis compared to other chronic liver diseases? Liver Int: 2013; 33 3 384 388
62. Ulett G. C., Totsika M., Schaale K., Carey A. J., Sweet M. J., Schembri M. A. Uropathogenic Escherichia coli virulence and innate immune responses during urinary tract infection. Curr Opin Microbiol: 2013; 16 1 100 107
63. Wang J., Yang G. X., Zhang W., et al. Escherichia coli infection induces autoimmune cholangitis and antimitochondrial antibodies in NOD.B6 (Idd10/Idd18) mice. Clin Exp Immunol: 2014; 175 2 192 201
64. Mattner J., Savage P. B., Leung P., et al. Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe: 2008; 3 5 304 315
65. Nilsson H. O., Taneera J., Castedal M., Glatz E., Olsson R., Wadström T. Identification of Helicobacter pylori and other Helicobacter species by PCR, hybridization, and partial DNA sequencing in human liver samples from patients with primary sclerosing cholangitis or primary biliary cirrhosis. J Clin Microbiol: 2000; 38 3 1072 1076
66. Abdulkarim A. S., Petrovic L. M., Kim W. R., Angulo P., Lloyd R. V., Lindor K. D. Primary biliary cirrhosis: an infectious disease caused by Chlamydia pneumoniae ? J Hepatol: 2004; 40 3 380 384
67. Vilagut L., Parés A., Viñas O., Vila J., Jiménez de Anta M. T., Rodés J. Antibodies to mycobacterial 65-kD heat shock protein cross-react with the main mitochondrial antigens in patients with primary biliary cirrhosis. Eur J Clin Invest: 1997; 27 8 667 672
68. Barzilai O., Sherer Y., Ram M., Izhaky D., Anaya J. M., Shoenfeld Y. Epstein-Barr virus and cytomegalovirus in autoimmune diseases: are they truly notorious? A preliminary report. Ann N Y Acad Sci: 2007; 1108 567 577
69. Morshed S. A., Nishioka M., Saito I., Komiyama K., Moro I. Increased expression of Epstein-Barr virus in primary biliary cirrhosis patients. Gastroenterol Jpn: 1992; 27 6 751 758
70. Bogdanos D. P., Pares A., Baum H., et al. Disease-specific cross-reactivity between mimicking peptides of heat shock protein of Mycobacterium gordonae and dominant epitope of E2 subunit of pyruvate dehydrogenase is common in Spanish but not British patients with primary biliary cirrhosis. J Autoimmun: 2004; 22 4 353 362
71. Durazzo M., Rosina F., Premoli A., et al. Lack of association between seroprevalence of Helicobacter pylori infection and primary biliary cirrhosis. World J Gastroenterol: 2004; 10 21 3179 3181
72. Taylor-Robinson D., Sharif A. W., Dhanjal N. S., Taylor-Robinson S. D. Chlamydia pneumoniae infection is an unlikely cause of primary biliary cirrhosis. J Hepatol: 2005; 42 5 779 780
73. Shapira Y., Agmon-Levin N., Renaudineau Y., et al. Serum markers of infections in patients with primary biliary cirrhosis: evidence of infection burden. Exp Mol Pathol: 2012; 93 3 386 390
74. Gershwin M. E., Mackay I. R. The causes of primary biliary cirrhosis: convenient and inconvenient truths. Hepatology: 2008; 47 2 737 745
75. Oldstone M. B. Molecular mimicry as a mechanism for the cause and a probe uncovering etiologic agent(s) of autoimmune disease. Curr Top Microbiol Immunol: 1989; 145 127 135
76. Oldstone M. B. Molecular mimicry, microbial infection, and autoimmune disease: evolution of the concept. Curr Top Microbiol Immunol: 2005; 296 1 17
77. Bogdanos D., Pusl T., Rust C., Vergani D., Beuers U. Primary biliary cirrhosis following Lactobacillus vaccination for recurrent vaginitis. J Hepatol: 2008; 49 3 466 473
78. Bogdanos D. P., Baum H., Grasso A., et al. Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis. J Hepatol: 2004; 40 1 31 39
79. Bogdanos D. P., Baum H., Okamoto M., et al. Primary biliary cirrhosis is characterized by IgG3 antibodies cross-reactive with the major mitochondrial autoepitope and its Lactobacillus mimic. Hepatology: 2005; 42 2 458 465
80. Padgett K. A., Selmi C., Kenny T. P., et al. Phylogenetic and immunological definition of four lipoylated proteins from Novosphingobium aromaticivorans, implications for primary biliary cirrhosis. J Autoimmun: 2005; 24 3 209 219
81. Selmi C., Balkwill D. L., Invernizzi P., et al. Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology: 2003; 38 5 1250 1257
82. Shimoda S., Nakamura M., Shigematsu H., et al. Mimicry peptides of human PDC-E2 163-176 peptide, the immunodominant T-cell epitope of primary biliary cirrhosis. Hepatology: 2000; 31 6 1212 1216
83. Selmi C., De Santis M., Cavaciocchi F., Gershwin M. E. Infectious agents and xenobiotics in the etiology of primary biliary cirrhosis. Dis Markers: 2010; 29 6 287 299
84. Long S. A., Quan C., Van de Water J., et al. Immunoreactivity of organic mimeotopes of the E2 component of pyruvate dehydrogenase: connecting xenobiotics with primary biliary cirrhosis. J Immunol: 2001; 167 5 2956 2963
85. Leung P. S., Quan C., Park O., et al. Immunization with a xenobiotic 6-bromohexanoate bovine serum albumin conjugate induces antimitochondrial antibodies. J Immunol: 2003; 170 10 5326 5332
86. Wakabayashi K., Lian Z. X., Leung P. S., et al. Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease. Hepatology: 2008; 48 2 531 540
87. Wakabayashi K., Yoshida K., Leung P. S., et al. Induction of autoimmune cholangitis in non-obese diabetic (NOD).1101 mice following a chemical xenobiotic immunization. Clin Exp Immunol: 2009; 155 3 577 586
88. Chen R. C., Naiyanetr P., Shu S. A., et al. Antimitochondrial antibody heterogeneity and the xenobiotic etiology of primary biliary cirrhosis. Hepatology: 2013; 57 4 1498 1508
89. Naiyanetr P., Butler J. D., Meng L., et al. Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity. J Autoimmun: 2011; 37 3 209 216
90. Bernal W., Meda F., Ma Y., Bogdanos D. P., Vergani D. Disease-specific autoantibodies in patients with acute liver failure: the King's College London Experience. Hepatology: 2008; 47 3 1096 1097, author reply 1097
91. Leung P. S., Rossaro L., Davis P. A., et al. Acute Liver Failure Study Group. Antimitochondrial antibodies in acute liver failure: implications for primary biliary cirrhosis. Hepatology: 2007; 46 5 1436 1442
92. Chang T. W., Pan A. Y. Cumulative environmental changes, skewed antigen exposure, and the increase of allergy. Adv Immunol: 2008; 98 39 83
93. Strachan D. P. Hay fever, hygiene, and household size. BMJ: 1989; 299 6710 1259 1260
94. Rook G. A. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: darwinian medicine and the 'hygiene' or 'old friends' hypothesis. Clin Exp Immunol: 2010; 160 1 70 79
95. Brown E. M., Arrieta M. C., Finlay B. B. A fresh look at the hygiene hypothesis: how intestinal microbial exposure drives immune effector responses in atopic disease. Semin Immunol: 2013; 25 5 378 387
96. Rook G. A. Hygiene hypothesis and autoimmune diseases. Clin Rev Allergy Immunol: 2012; 42 1 5 15
97. Yin L., Scott-Browne J., Kappler J. W., Gapin L., Marrack P. T cells and their eons-old obsession with MHC. Immunol Rev: 2012; 250 1 49 60
98. Yin Y., Li Y., Mariuzza R. A. Structural basis for self-recognition by autoimmune T-cell receptors. Immunol Rev: 2012; 250 1 32 48
99. Guéry L., Hugues S. Tolerogenic and activatory plasmacytoid dendritic cells in autoimmunity. Front Immunol: 2013; 4 59
100. Tian L., Humblet-Baron S., Liston A. Immune tolerance: are regulatory T cell subsets needed to explain suppression of autoimmunity? BioEssays: 2012; 34 7 569 575
101. Bogdanos D. P., Smyk D. S., Invernizzi P., et al. Tracing environmental markers of autoimmunity: introducing the infectome. Immunol Res: 2013; 56 2-3 220 240
102. Wild C. P. Complementing the genome with an exposome: the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol Biomarkers Prev: 2005; 14 8 1847 1850
103. Gause W. C., Wynn T. A., Allen J. E. Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nat Rev Immunol: 2013; 13 8 607 614
104. Taylor M. D., van der Werf N., Maizels R. M. T cells in helminth infection: the regulators and the regulated. Trends Immunol: 2012; 33 4 181 189
105. Hussaarts L., van der Vlugt L. E., Yazdanbakhsh M., Smits H. H. Regulatory B-cell induction by helminths: implications for allergic disease. J Allergy Clin Immunol: 2011; 128 4 733 739
106. Allen J. E., Maizels R. M. Diversity and dialogue in immunity to helminths. Nat Rev Immunol: 2011; 11 6 375 388
107. Aoyama H., Hirata T., Sakugawa H., et al. An inverse relationship between autoimmune liver diseases and Strongyloides stercoralis infection. Am J Trop Med Hyg: 2007; 76 5 972 976