Predictive, preventive, personalised and participatory periodontology: ‘the 5Ps age’ has already started

EPMA Journal

Sergio Matarasso¹  Carlo Cafiero¹ 

[1] University of Naples “FEDERICO II”, Naples 80131, Italy

关键词: Gingival crevicular fluid;    Saliva;    Host-derived diagnostic markers;    Cone beam computed tomography;    Gas chromatographs;    Lab-on-a-chip;    Participatory periodontology;    Personalised periodontology;    Preventive periodontology;    Predictive periodontology;   

Others  :  801590
DOI  :  10.1186/1878-5085-4-16

 received in 2013-03-19, accepted in 2013-05-06,  发布年份 2013

【 摘 要 】

An impressive progress in dentistry has been recorded in the last decades. In order to reconsider guidelines in dentistry, it is required to introduce new concepts of personalised patient treatments: the wave of predictive, preventive and personalised medicine is rapidly incoming in dentistry. Worldwide dentists have to make a big cultural effort in changing the actual ‘reactive’ therapeutic point of view, belonging to the last century, into a futuristic ‘predictive’ one. The first cause of tooth loss in industrialised world is periodontitis, a Gram-negative anaerobic infection whose pathogenesis is genetically determined and characterised by complex immune reactions. Chairside diagnostic tests based on saliva, gingival crevicular fluid and cell sampling are going to be routinely used by periodontists for a new approach to the diagnosis, monitoring, prognosis and management of periodontal patients. The futuristic ‘5Ps’ (predictive, preventive, personalised and participatory periodontology) focuses on early integrated diagnosis (genetic, microbiology, host-derived biomarker detection) and on the active role of the patient in which networked patients will shift from being mere passengers to responsible drivers of their health. In this paper, we intend to propose five diagnostic levels (high-tech diagnostic tools, genetic susceptibility, bacterial infection, host response factors and tissue breakdown-derived products) to be evaluated with the intention to obtain a clear picture of the vulnerability of a single individual to periodontitis in order to organise patient stratification in different categories of risk. Lab-on-a-chip (LOC) technology may soon become an important part of efforts to improve worldwide periodontal health in developed nations as well as in the underserved communities, resource-poor areas and poor countries. The use of LOC devices for periodontal inspection will allow patients to be screened for periodontal diseases in settings other than the periodontist practice, such as at general practitioners, general dentists or dental hygienists. Personalised therapy tailored with respect to the particular medical reality of the specific stratified patient will be the ultimate target to be realised by the 5Ps approach. A long distance has to be covered to reach the above targets, but the pathway has already been clearly outlined.

【 授权许可】

   
2013 Cafiero and Matarasso; licensee BioMed Central Ltd.

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【 参考文献 】

• [1]European Association for Predictive, Preventive and Personalised Medicine - EPMA [http://www.epmanet.eu webcite]
• [2]Golubnitschaja O, Costigliola V, EPMA: General report & recommendations in predictive, preventive and personalised medicine 2012: white paper of the European Association for Predictive, Preventive and Personalised Medicine. EPMA J 2012, 3:14.
• [3]Lindhe J, Lang NP, Karring T: The anatomy of periodontal tissue. In Clinical Periodontology and Implant Dentistry. Volume 1. 5th edition. Edited by Lindhe J, Karring T, Araujo M. Copenhagen: Blackwell Munksgaard; 2008:3-48.
• [4]Armitage GC: Development of a classification system for periodontal diseases and conditions. Ann Periodontol 1999, 4:1-6.
• [5]Socransky SS: Microbiology of periodontal disease – present status and future considerations. J Periodontol 1977, 48(9):497-504.
• [6]Sweeney EA, Alcoforado GA, Nyman S, Slots J: Prevalence and microbiology of localized prepubertal periodontitis. Oral Microbiol Immunol 1987, 2(2):65-70.
• [7]Bimstein E, Treasure ET, Williams SM, Dever JG: Alveolar bone loss in 5-year-old New Zealand children: its prevalence and relationship to caries prevalence, socio-economic status and ethnic origin. J Clin Periodontol 1994, 21(7):447-450.
• [8]Sjödin B, Matsson L: Marginal bone loss in the primary dentition. A survey of 7-9-year-old children in Sweden. J Clin Periodontol 1994, 21(5):313-319.
• [9]Lang N, Bartold PM, Cullinan M, Jeffcaot M, Mombelli A, Murakami S, Page R, Papapanou P, Tonetti M, Van Dyke T: Consensus report: aggressive periodontitis. Ann Periodontol 1999, 4:53.
• [10]Tonetti MS, Mombelli A: Early-onset periodontitis. Ann Periodontol 1999, 4(1):39-53.
• [11]Lindhe J, Lang NP, Karring T: Aggressive periodontitis. In Clinical Periodontology and Implant Dentistry. Volume 2. 5th edition. Edited by Tonetti M, Mombelli A. Copenhagen: Blackwell Munksgaard; 2008:429-449.
• [12]Loevy HT: Genetic aspects of periodontal disease. Quintessence Int 1976, 5:1-4.
• [13]Kinane DF, Hart TC: Genes and gene polymorphisms associated with periodontal disease. Crit Rev Oral Biol Med 2003, 14:430-449.
• [14]Loos BG, John RP, Laine ML: Identification of genetic risk factors for periodontitis and possible mechanisms of action. J Clin Periodontol 2005, 32(Suppl 6):159-179.
• [15]Keijser BJ, Zaura E, Huse SM, van der Vossen JM, Schuren FH, Montijn RC, Ten Cate JM, Crielaard W: Pyrosequencing analysis of the oral microflora of healthy adults. J Dent Res 2008, 87:1016-1020.
• [16]Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL Jr: Microbial complexes in subgingival plaque. J Clin Periodontol 1998, 25:134-144.
• [17]Slots J, Slots H: Bacterial and viral pathogens in saliva: disease relationship and infectious risk. Periodontol 2000 2011, 55:48-69.
• [18]Zambon JJ, Christersson LA, Slots J: Actinobacillus actinomycetemcomitans in human periodontal disease. Prevalence in patient groups and distribution of biotypes and serotypes within families. J Periodontol 1983, 54:707-711.
• [19]Asikainen S, Chen C, Slots J: Likelihood of transmitting. Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis in families with periodontitis. Oral Microbiol Immunol 1996, 11:387-394.
• [20]Altman LC, Baker C, Fleckman P, Luchtel D, Oda D: Neutrophil mediated damage to human gingival epithelial cells. J Periodontal Res 1992, 27:70-79.
• [21]Weiss SJ: Tissue destruction by neutrophils. N Engl J Med 1989, 320:365-376.
• [22]Dewhirst FE, Ago JM, Peros W, Stashenko P: Synergism between parathyriod hormone and interleukin-1 in stimulating bone resorption in organ culture. J Bone Miner Res 1987, 2:127-134.
• [23]Beutler B, Cerami A: Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature 1986, 320:584-588.
• [24]Cox SW, Eley BM: Detection of cathepsin B- and L-, elastase-, tryptase-, trypsin-, and dipeptidyl peptidase IV-like activities in crevicular fluid from gingivitis and periodontitis patients with peptidyl derivatives of 7-amino-4-trifluoromethyl coumarin. J Period Res 1989, 24:351-353.
• [25]Burgess TL, Qian Y, Kaufman S, Ring BD, Van G, Capparelli C, Kelley M, Hsu H, Boyle WJ, Dunstan CR, Hu S, Lacey DL: The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. J Cell Biol 1999, 145(3):527-538.
• [26]Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N, Sato Y, Goto M, Yamaguchi K, Kuriyama M, Kanno T, Murakami A, Tsuda E, Morinaga T, Higashio K: Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 1998, 139(3):1329-1337.
• [27]Stabholz A, Stabholz A, Soskolne AW, Shapira L: Genetic and environmental risk factors for chronic periodontitis and aggressive periodontitis. Periodontol 2000 2010, 53:138-153.
• [28]International Diabetes Federation [http://www.idf.org/diabetesatlas/5c/ webcite update 2012]
• [29]Hanes PJ, Krishna R: Characteristics of inflammation common to both diabetes and periodontitis: are predictive diagnosis and targeted preventive measures possible? EPMA J 2010, 1:101-116.
• [30]Tervonen T, Oliver RC: Long-term control of diabetes mellitus and periodontitis. J Clin Periodontol 1993, 20:431-435.
• [31]Cianciola LJ, Park BH, Bruck E, Mosovich L, Genco RJ: Prevalence of periodontal disease in insulin-dependent diabetes mellitus (juvenile diabetes). J Am Dent Assoc 1982, 104:653-660.
• [32]Löe H: Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care 1993, 16:329-334.
• [33]Grossi SG, Zambon JJ, Ho AW, Koch G, Dunford RG, Machtei EE, Norderyd OM, Genco RJ: Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. J Periodontol 1994, 65:260-267.
• [34]Grossi SG, Genco RJ: Periodontal disease and diabetes mellitus: a two-way relationship. Ann Periodontol 1998, 3:51-61.
• [35]D’aiuto F, Parkar M, Andreou G, Suvan J, Brett P, Ready D, Tonetti MS: Periodontitis and systemic inflammation: control of the local infections is associated with a reduction of serum inflammatory markers. J Dent Res 2004, 83:156-160.
• [36]Iwamoto Y, Nishimura F, Nakagawa M, Sugimoto H, Shikata K, Makino H, Fukuda T, Tsuji T, Iwamoto M, Murayama Y: The effect of antimicrobial periodontal treatment on circulating tumor necrosis factor-alpha and glycated hemoglobin level in patients with type 2 diabetes. J Periodontol 2001, 72(6):774-778.
• [37]Nishimura F, Murayama Y: Periodontal inflammation and insulin resistance–lessons from obesity. J Dent Res 2001, 80:1690-1694.
• [38]Promsudthi A, Pimapansri S, Deerochanawong C, Kanchanavasita W: The effect of periodontal therapy on uncontrolled type 2 diabetes mellitus in older subjects. Oral Dis 2005, 11:293-298.
• [39]Aldridge JP, Lester V, Watts TL, Collins A, Viberti G, Wilson RF: Single-blind studies of the effects of improved periodontal health on metabolic control in type 1 diabetes mellitus. J Clin Periodontol 1995, 22:271-275.
• [40]Christgau M, Palitzsch KD, Schmalz G, Kreiner U, Frenzel S: Healing response to non-surgical periodontal therapy in patients with diabetes mellitus: clinical, microbiological, and immunologic results. J Clin Periodontol 1998, 25:112-124.
• [41]Darré L, Vergnes JN, Gourdy P, Sixou M: Efficacy of periodontal treatment on glycaemic control in diabetic patients: a meta-analysis of interventional studies. Diabetes Metab 2008, 34:497-506.
• [42]Simpson TC, Needleman I, Wild SH, Moles DR, Mills EJ: Treatment of periodontal disease for glycaemic control in people with diabetes. Cochrane Database Syst Rev 2010., 12(5) CD004714
• [43]Tonetti MS: Cigarette smoking and periodontal diseases: etiology and management of disease. Ann Periodontol 1998, 3:88-101.
• [44]Calsina G, Ramon JM, Echeverria JJ: Effects of smoking on periodontal tissues. J Clin Periodontol 2002, 29:771-776.
• [45]Machuca G, Rosales I, Lacalle JR, Machuca C, Bullon P: Effect of cigarette smoking on periodontal status of healthy young adults. J Periodontol 2000, 71:73-78.
• [46]Palmer RM, Wilson RF, Hasan AS, Scott DA: Mechanisms of action of environmental factors – tobacco smoking. J Clin Periodontol 2005, 32(Suppl 6):180-195.
• [47]Rieder C, Joss A, Lang NP: Influence of compliance and smoking habits on the outcomes of supportive periodontal therapy (SPT) in a private practice. Oral Health Prev Dent 2004, 2:89-94.
• [48]Ritchie CS: Obesity and periodontal disease. Periodontol 2000 2007, 44:154-163.
• [49]Kershaw EE, Flier JS: Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004, 89:2548-2556.
• [50]Saito T, Shimazaki Y, Sakamoto M: Obesity and periodontitis. N Engl J Med 1998, 339:482-483.
• [51]Al-Zahrani MS, Bissada NF, Borawskit EA: Obesity and periodontal disease in young, middle-aged, and older adults. J Periodontol 2003, 74:610-615.
• [52]Linden G, Patterson C, Evans A, Kee F: Obesity and periodontitis in 60-70-year-old men. J Clin Periodontol 2007, 34:461-466.
• [53]Genco RJ, Grossi SG, Ho A, Nishimura F, Murayama Y: A proposed model linking inflammation to obesity, diabetes, and periodontal infections. J Periodontol 2005, 76:2075-2084.
• [54]Al-Zahrani MS, Borawski EA, Bissada NF: Increased physical activity reduces prevalence of periodontitis. J Dent 2005, 33:703-710.
• [55]Al-Zahrani MS, Borawski EA, Bissada NF: Periodontitis and three health-enhancing behaviors: maintaining normal weight, engaging in recommended level of exercise, and consuming a high-quality diet. J Periodontol 2005, 76:1362-1366.
• [56]Kiecolt-Glaser JK, Ricker D, George J, Messick G, Speicher CE, Garner W, Glaser R: Urinary cortisol levels, cellular immunocompetency, and loneliness in psychiatric inpatients. Psychosom Med 1984, 46:15-23.
• [57]Boyapati L, Wang HL: The role of stress in periodontal disease and wound healing. Periodontol 2000 2007, 44:195-210.
• [58]Peruzzo DC, Benatti BB, Ambrosano GM, Nogueira-Filho GR, Sallum EA, Casati MZ, Nociti FH Jr: A systematic review of stress and psychological factors as possible risk factors for periodontal disease. J Periodontol 2007, 78:1491-1504.
• [59]Wactawski-Wende J: Periodontal diseases and osteoporosis: association and mechanisms. Ann Periodontol 2001, 6:197-208.
• [60]Von Wowern N, Klausen B, Olgaard K: Steroid-induced mandibular bone loss in relation to marginal periodontal changes. J Clin Periodontol 1992, 19:182-186.
• [61]Yoshihara A, Seida Y, Hanada N, Miyazaki H: A longitudinal study of the relationship between periodontal disease and bone mineral density in community-dwelling older adults. J Clin Periodontol 2004, 31:680-684.
• [62]Ramseier CA: Periodontal chart. [http://www.periodontalchart-online.com/uk/index.asp webcite]
• [63]Lang NP, Adler R, Joss A, Nyman S: Absence of bleeding on probing. An indicator of periodontal stability. J Clin Periodontol 1990, 17:714-721.
• [64]Lang NP, Joss A, Tonetti MS: Monitoring disease during supportive periodontal treatment by bleeding on probing. Periodontol 2000 1996, 12:44-48.
• [65]Joss A, Adler R, Lang NP: Bleeding on probing. A parameter for monitoring periodontal conditions in clinical practice. J Clin Periodontol 1994, 21:402-408.
• [66]Lang NP, Tonetti MS: Periodontal risk assessment (PRA) for patients in supportive periodontal therapy (SPT). Oral Health Prev Dent 2003, 1:7-16.
• [67]Ramseier CA: Periodontal risk assessment. [http://www.perio-tools.com/pra/en/index.asp webcite]
• [68]Chapple ILC: Periodontal diagnosis and treatment – where does the future lie? Periodontol 2000 2009, 51:9-24.
• [69]Point of Care Diagnostic Testing World Markets. TriMark Publications, LLC 2012.
• [70]American Dental Association: Statement on oral fluid diagnostics. [http://www.ada.org/1890.aspx webcite]
• [71]Albandar JM, Brunelle JA, Kingman A: Destructive periodontal disease in adults 30 years of age and older in the United States, 1988–1994. J Periodontol 1999, 70:13-29.
• [72]Ashton R, Padala C, Kane RS: Microfluidic separation of DNA. Curr Opin Biotechnol 2003, 14:497-504.
• [73]Paegel BM, Blazej R, Mathies RA: Microfluidic devices for DNA sequencing: sample preparation and electrophoretic analysis. Curr Opin Biotechnol 2003, 14:42-50.
• [74]Lion N, Rohner TC, Dayon L, Arnaud IL, Damoc E, Youhnovski N, Wu ZY, Roussel C, Josserand J, Jensen H, Rossier JS, Przybylski M, Girault HH: Microfluidic systems in proteomics. Electrophoresis 2003, 24:3533-3562.
• [75]Huh D, Gu W, Kamotani Y, Grotberg JB, Takayama S: Microfluidics for flow cytometric analysis of cells and particles. Physiol Meas 2005, 26:R73-R98.
• [76]Srinivasan V, Pamula VK, Fair RB: An integrated digital microfluidic lab-on-a-chip for clinical diagnostics on human physiological fluids. Lab Chip 2004, 4:310-315.
• [77]Tangerman A: Halitosis in medicine: a review. Int Dent J 2002, 52:201-206.
• [78]Golberg S, Kozlovsky A, Gordon D: Cadaverine as a putative component of oral malodor. J Dent Res 1994, 73:1168-1172.
• [79]Ratcliff PA, Johnson PW: The relationship between oral malodor, gingivitis, and periodontitis. J Periodontol 1999, 70:485-489.
• [80]Rosenberg M: Clinical assessment of bad breath: current concepts. J Am Dent Assoc 1996, 127:475-482.
• [81]Persson S, Edlund MB, Claesson R, Carlsson J, Persson S, Edlund MB, Claesson R, Carlsson J: The formation of hydrogen sulfide and methyl mercaptan by oral bacteria. Oral Microbiol Immunol 1990, 5:195-201.
• [82]Morita M, Wang HL: Relationship of sulcular sulfide level to severity of periodontal disease and BANA test. J Periodontol 2001, 72:74-78.
• [83]Rosenberg M, Leib E: Experiences of an Israeli malodor clinic. In Bad Breath: Research Perspectives. Edited by Rosenberg M. Tel Aviv: Ramot Publishing, Tel Aviv University; 1995:137-148.
• [84]Hanada M, Koda H, Onaga K, Tanaka K, Okabayashi T, Itoh T, Miyazaki H: Portable oral malodor analyzer using highly sensitive In2O3 gas sensor combined with a simple gas chromatography. Anal Chim Acta 2003, 475:27-35.
• [85]Salako NO, Philip L: Comparison of the use of the Halimeter and the Oral Chroma™ in the assessment of the ability of common cultivable oral anaerobic bacteria to produce malodorous volatile sulfur compounds from cysteine and methionine. Med Princ Pract 2011, 20:75-79.
• [86]Hatcher DC, Hatcher DC: Operational principles for cone-beam computed tomography. J Am Dent Assoc 2010, 141:3S-6S.
• [87]Nikolopoulos GK, Dimou NL, Hamodrakas SJ, Bagos PG: Cytokine gene polymorphisms in periodontal disease: a meta-analysis of 53 studies including 4178 cases and 4590 controls. J Clin Periodontol 2008, 35:754-767.
• [88]Kobayashi T, Yamamoto K, Sugita N, van der Pol WL, Yasuda K, Kaneko S, van de Winkel JG, Yoshie H: The Fc gamma receptor genotype as a severity factor for chronic periodontitis in Japanese patients. J Periodontol 2001, 72:1324-1331.
• [89]Loos BG, De Straat FG L-V, Van de Winkel JG, Van der Velden U: Fcgamma receptor polymorphisms in relation to periodontitis. J Clin Periodontol 2003, 30:595-602.
• [90]March CJ, Mosley B, Larsen A, Cerretti DP, Braedt G, Price V, Gillis S, Henney CS, Kronheim SR, Grabstein K: Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs. Nature 1985, 315:641-647.
• [91]Kornman KS, Crane A, Wang HY, Di Giovine FS, Newman MG, Pirk FW, Wilson TG Jr, Higginbottom FL, Duff GW: The interleukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol 1997, 24:72-77.
• [92]Gore EA, Sanders JJ, Pandey JP, Palesch Y, Galbraith GM: Interleukin-1beta + 3953 allele 2: association with disease status in adult periodontitis. J Clin Periodontol 1998, 25:781-785.
• [93]Taylor JJ, Preshaw PM, Donaldson PT: Cytokine gene polymorphism and immunoregulation in periodontal disease. Periodontol 2000 2004, 35:158-182.
• [94]Yoshie H, Kobayashi T, Tai H, Galicia JC: The role of genetic polymorphisms in periodontitis. Periodontol 2000 2007, 43:102-132.
• [95]Papapanou PN, Neiderud AM, Sandros J, Dahlén G: Interleukin-1 gene polymorphism and periodontal status. A case–control study. J Clin Periodontol 2001, 28:389-396.
• [96]Cattabriga M, Rotundo R, Muzzi L, Nieri M, Verrocchi G, Cairo F, Pini PG: Retrospective evaluation of the influence of the interleukin-1 genotype on radiographic bone levels in treated periodontal patients over 10 years. J Periodontol 2001, 72:767-773.
• [97]Greenstein G, Hart TC: Clinical utility of a genetic susceptibility test for severe chronic periodontitis: a critical evaluation. J Am Dent Assoc 2002, 133:452-459.
• [98]Haffajee AD, Socransky SS: Microbial etiological agents of destructive periodontal diseases. Periodontol 1994, 5:78-111.
• [99]Genco R, Kornman K, Williams R, Offenbacher S, Zambon JJ, Listgarten M, Michalowicz B, Page R, Schenkein H, Slots J, Socransky S, Van Dyke T: Consensus report periodontal diseases: pathogenesis and microbial factors. Ann Periodontol 1996, 1:926-932.
• [100]Nørskov-Lauritsen N, Kilian M: Reclassification of Actinobacillus actinomycetemcomitans, Haemophilus aphrophilus, Haemophilus paraphrophilus and Haemophilus segnis as Aggregatibacter actinomycetemcomitans gen. nov., comb. nov., Aggregatibacter aphrophilus comb. nov. and Aggregatibacter segnis comb. nov., and emended description of Aggregatibacter aphrophilus to include V factor-dependent and V factor-independent isolates. Int J Syst Evol Microbiol 2006, 56:2135-2146.
• [101]Sakamoto M, Suzuki M, Umeda M, Ishikawa I, Benno Y: Reclassification of Bacteroides forsythus as Tanerella forsythensis corrig., gen. nov., comb. nov. Int J Syst Evol Microbiol 2002, 52:841-849.
• [102]Taba M Jr, Kinney J, Kim AS, Giannobile WV: Diagnostic biomarkers for oral and periodontal diseases. Dent Clin North Am 2005, 49:551-571.
• [103]Lamster IB: Evaluation of components of gingival crevicular fluid as diagnostic tests. Ann Periodontol 1997, 2:123-137.
• [104]Sorsa T, Tjäderhane L, Konttinen YT, Lauhio A, Salo T, Lee HM, Golub LM, Brown DL, Mäntylä P: Matrix metalloproteinases: contribution to pathogenesis, diagnosis and treatment of periodontal inflammation. Ann Med 2006, 38:306-321.
• [105]Chapple ILC: Periodontal disease diagnosis: current status and future developments. J Dent 1997, 25:3-15.
• [106]Chapple ILC, Matthews JB, Thorpe GH, Glenwright HD, Smith JM, Saxby MS: A new ultrasensitive chemiluminescent assay for the site-specific quantification of alkaline phosphatase in gingival crevicular fluid. J Periodontal Res 1993, 28:266-273.
• [107]Denny P, Hagen FK, Hardt M, Liao L, Yan W, Arellanno M, Bassilian S, Bedi GS, Boontheung P, Cociorva D, Delahunty CM, Denny T, Dunsmore J, Faull KF, Gilligan J, Gonzalez-Begne M, Halgand F, Hall SC, Han X, Henson B, Hewel J, Hu S, Jeffrey S, Jiang J, Loo JA, Ogorzalek Loo RR, Malamud D, Melvin JE, Miroshnychenko O, Navazesh M, et al.: The proteomes of human parotid and submandibular/sublingual gland salivas collected as the ductal secretions. J Proteome Res 2008, 7:1994-2006.
• [108]The Human Salivary Proteome Project [http://www.skb.ucla.edu webcite]
• [109]Armitage GC: Analysis of gingival crevice fluid and risk of progression of periodontitis. Periodontol 2000 2004, 34:109-119.
• [110]Loos BG, Tjoa S: Host-derived diagnostic markers for periodontitis: do they exist in gingival crevice fluid? Periodontol 2000 2005, 39:53-72.
• [111]Nakashima K, Giannopoulou C, Andersen E, Roehrich N, Brochut P, Dubrez B, Cimasoni G: A longitudinal study of various crevicular fluid components as markers of periodontal disease activity. J Clin Periodontol 1996, 23:832-838.
• [112]Lamster IB, Holmes LG, Gross KB, Oshrain RL, Cohen DW, Rose LF, Peters LM, Pope MR: The relationship of beta-glucuronidase activity in crevicular fluid to probing attachment loss in patients with adult periodontitis. Findings from a multicenter study. J Clin Periodontol 1995, 22:36-44.
• [113]Kennett CN, Cox SW, Eley BM: Investigations into the cellular contribution to host tissue proteases and inhibitors in gingival crevicular fluid. J Clin Periodontol 1997, 24:424-431.
• [114]Eley BM, Cox SW: The relationship between gingival crevicular fluid cathepsin B activity and periodontal attachment loss in chronic periodontitis patients: a 2-year longitudinal study. J Periodontal Res 1996, 31:381-392.
• [115]Chen HY, Cox SW, Eley BM: Cathepsin B, alpha2-macroglobulin and cystatin levels in gingival crevicular fluid from chronic periodontitis patients. J Clin Periodontol 1998, 25:34-41.
• [116]Cox SW, Eley BM: Cathepsin B/L-, elastase-, tryptase-, trypsin- and dipeptidyl peptidase IV-like activities in gingival crevicular fluid. A comparison of levels before and after basic periodontal treatment of chronic periodontitis patients. J Clin Periodontol 1992, 19:333-339.
• [117]Ramseier CA, Kinney JS, Herr AE, Braun T, Sugai JV, Shelburne CA, Rayburn LA, Tran HM, Singh AK, Giannobile WV: Identification of pathogen and host-response markers correlated with periodontal disease. J Periodontol 2009, 80:436-446.
• [118]Mancini S, Romanelli R, Laschinger CA, Overall CM, Sodek J, McCulloch CA: Assessment of a novel screening test for neutrophil collagenase activity in the diagnosis of periodontal diseases. J Periodontol 1999, 70:1292-1302.
• [119]Giannobile WV: Salivary diagnostics for periodontal diseases. J Am Dent Assoc 2012, 143:6S-11S.
• [120]Teng YT, Sodek J, McCulloch CA: Gingival crevicular fluid gelatinase and its relationship to periodontal disease in human subjects. J Periodontal Res 1992, 27:544-552.
• [121]Eley BM, Cox SW: Correlation between gingival crevicular fluid dipeptidyl peptidase II and IV activity and periodontal attachment loss. A 2-year longitudinal study in chronic periodontitis patients. Oral Dis 1995, 1:201-213.
• [122]Jin L, Soder B, Corbet EF: Interleukin-8 and granulocyte elastase in gingival crevicular fluid in relation to periodontopathogens in untreated adult periodontitis. J Periodontol 2000, 71:929-939.
• [123]Smith QT, Harriman L, Au GS, Stoltenberg JL, Osborn JB, Aeppli DM, Fischer G: Neutrophil elastase in crevicular fluid: comparison of a middle-aged general population with healthy and periodontitis groups. J Clin Periodontol 1995, 22:935-941.
• [124]Palcanis KG, Larjava IK, Wells BR, Suggs KA, Landis JR, Chadwick DE, Jeffcoat MK: Elastase as an indicator of periodontal disease progression. J Periodontol 1992, 63:237-242.
• [125]Belibasakis GN, Bostanci N: The RANKL-OPG system in clinical periodontology. J Clin Periodontol 2012, 39:239-248.
• [126]Giannobile WV, Al- Shammari KF, Sarment DP: Matrix molecules and growth factors as indicators of periodontal disease activity. Periodontol 2000 2003, 31:125-134.
• [127]Smith AJ, Addy M, Embery G: Gingival crevicular fluid glycosaminoglycan levels in patients with chronic adult periodontitis. J Clin Periodontol 1995, 22:355-361.
• [128]Yager P, Edwards T, Elain F, Helton K, Nelson K, Tam MR, Weigl BH: Microfluidic diagnostic technologies for global public health. Nature 2006, 442:412-418.
• [129]Giannobile WV, Beikler T, Kinney JS, Ramseier CA, Morelli T, Wong DT: Saliva as a diagnostic tool for periodontal disease: current state and future directions. Periodontol 2000 2009, 50:52-64.
• [130]Christodoulides N, Floriano PN, Miller CS, Ebersole JL, Mohanty S, Dharshan P, Griffin M, Lennart A, Ballard KL, King CP Jr, Langub MC, Kryscio RJ, Thomas MV, McDevitt JT: Lab-on-a-chip methods for point-of-care measurements of salivary biomarkers of periodontitis. Ann N Y Acad Sci 2007, 1098:411-428.
• [131]Golubnitschaja O: Time for new guidelines in advanced healthcare: the mission of The EPMA Journal to promote an integrative view in predictive, preventive and personalized medicine. EPMA J 2012, 3:5.