AÓ ÛÎfiappleËÛË ÙˆÓ appleúfiûê ÙˆÓ ÂÍÂÏ ÍˆÓ. Basic Research of periodontal diseases: A review of recent developments

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1 BÈ ÏÈÔÁÚ ÊÈÎ AÓ ÛÎfiappleËÛË B ÛÈÎ ŒÚÂ Ó ÙˆÓ appleâúèô ÔÓÙÈÎÒÓ ÓÔÛËÌ ÙˆÓ: AÓ ÛÎfiappleËÛË ÙˆÓ appleúfiûê ÙˆÓ ÂÍÂÏ ÍˆÓ. KˆÙÛÔ ÏË * Basic Research of periodontal diseases: A review of recent developments S. Kotsovilis* EPI HæH EÈÛ ÁˆÁ : H ÔÏÔÎÏËÚˆÙÈÎ Î È ÂÓ Ùˆ ıâè ÌÂÏ ÙË ÙˆÓ appleúfiûê ÙˆÓ ÂÍÂÏ ÍÂˆÓ ÛÙËÓ Ô ÔÓÙÈ ÙÚÈÎ È- ÏÈÔÁÚ Ê appleôùâïâ ÙÌ Ì ÙË Û ÓÂ È fiìâóë Ô- ÔÓÙÈ ÙÚÈÎ ÂÎapple  ÛË. ÎÔapplefi : ÎÔapplefi ÙË apple ÚÔ Û ÂÚÁ Û Ù Ó Ë - Ó ÛÎfiappleËÛË ÙˆÓ ËÌÔÛÈ ÛÂˆÓ appleô Û ÂÙ ÔÓÙ Ó Ì ÙË B ÛÈÎ ŒÚÂ Ó ÙˆÓ appleâúèô ÔÓÙÈÎÒÓ ÓÔÛËÌ ÙˆÓ Î È ËÌÔÛÈ ÙËÎ Ó ÛÙÔ ÈÂıÓ appleâúèô ÈÎfi Ù appleô Û ÔappleÔÈ - appleôùâ ÁÏÒÛÛ appleúfiûê Ù, Û ÁÎÂÎÚÈÌ Ó applefi ÙËÓ 1Ë I ÓÔ Ú Ô ˆ Î È ÙËÓ 31Ë ÂÎÂÌ Ú Ô ÙÔ YÏÈÎfi Î È M ıô ÔÈ: Ú ÁÌ ÙÔappleÔÈ ıëîâ Ó ÙËÛË ÛÙÈ ËÏÂÎÙÚÔÓÈÎ ÛÂÈ Â ÔÌ ÓˆÓ PubMed, The Cochrane Library Î È 22 ÂappleÈÛÙËÌÔÓÈÎÒÓ appleâúèô ÈÎÒÓ. AappleÔÙÂÏ ÛÌ Ù : EappleÂÏ ÁËÛ Ó ÙÂÏÈÎ 25 ËÌÔÛÈ - ÛÂÈ applefi ÙÈ 3803 ÂÍÂÙ fiìâóâ ËÌÔÛÈ ÛÂÈ. ÌappleÂÚ ÛÌ Ù : H appleïâèôófiùëù ÙˆÓ appleúfiûê ÙˆÓ ËÌÔÛÈ ÛÂˆÓ ÂÈ ÂappleÈÎÂÓÙÚˆıÂ Î Ú ˆ ÛÙÔ appleâ Ô ÙË ÂÚÈÔ ÔÓÙÈÎ I ÙÚÈÎ Î È ÛÙÔ appleâ Ô ÙˆÓ apple - SUMMARY Introduction: The comprehensive and deep study of recent developments in dental bibliography is part of the continuing dental education. Aim: The aim of the present study was to perform a review of papers related to Basic Research of periodontal diseases, published in the international literature in any language recently, in specific from the 1st of January up to and including the 31st of December Material and Methods: Search was performed in electronic databases PubMed, The Cochrane Library and those of 22 scientific journals. Results: Twenty five articles were finally selected out of 3803 articles examined. Conclusions: The majority of recent articles has primarily centered on the field of Periodontal Medicine and on the field of host susceptibility factors and risk factors for chronic periodontitis. Periodonti- * ÂÚÈÔ ÔÓÙÔÏfiÁÔ, TÔÌ AÓÔÛÔÁÂÓÂÙÈÎ, ÿ Ú Ì I - ÙÚÔ ÈÔÏÔÁÈÎÒÓ EÚ ÓÒÓ ÙË AÎ ËÌ AıËÓÒÓ ÂÓ apple ÚÍ ÚËÌ ÙÔ fiùëûë Ù ÙË ÚÂ Ó applefi Î appleôè appleëá ÚËÌ ÙÔ fiùëûë. * Periodontist, Immunogenetics Division, Biomedical Research Foundation of the Academy of Athens There was no funding of this study by a source of funding ÂÏÏËÓÈÎ ÛÙÔÌ ÙÔÏÔÁÈÎ ÚÔÓÈÎ 57: , 2013 apple ÚÂÏ ÊıË 9/1/ ÂÎÚ ıë 12/3/2014 paper received 9/1/ accepted 12/3/

2 Ú ÁfiÓÙˆÓ Â apple ıâè ÙÔ ÍÂÓÈÛÙ Î È apple Ú ÁfiÓÙˆÓ ÎÈÓ ÓÔ ÙË ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ. H appleâúèô Ô- ÓÙ ÙÈ ÂÈ ÛÙ ÙÈÛÙÈÎ Î È ÈÔÏÔÁÈÎ Û Û ÂÙÈÛÙÂ, Ì appleôïôá ÛÈÌË ÙÂÎÌËÚ ˆÛË, Ì ÍËÌ ÓÔ Î Ó ÓÔ Î Ú ˆ ÁÈ ÙËÓ ıëúôûîïëúˆùèî Î Ú È ÁÁÂÈ Î ÓfiÛÔ, ÓÂappleÈı ÌËÙ ÂÎ ÛÂÈ ÙË Î ËÛË (Î Ú ˆ ÙË Á ÓÓËÛË appleúfiˆúˆó Î È ÂÏÏÈappleÔ ÚÒÓ ÓÂÔÁÓÒÓ Î È ÙËÓ appleúôâîï Ì ), Î ıò Î È ÙÔ È ÙË. Ú ÁÔ- ÓÙ appleô ı ÌappleÔÚÔ Û Ó Ó Ô Ó ÙË Ó ÙfiÙËÙ Ó ÙÂÎÌËÚȈıÔ Ó ˆ apple Ú ÁÔÓÙ ÎÈÓ ÓÔ ÁÈ ÙË Úfi- ÓÈ appleâúèô ÔÓÙ ÙÈ Î È appleô ÌÂÏÂÙ ıëî Ó appleúfiûê Ù appleâúèâï Ì Ó Ó ÙËÓ Î ÏÔ ıë appleâúappleï Û ÙÔ appleúô- ÛÙ ÙË, ÙË Û Ó ÛÌ ÓË Ó ÛÙ ÏÙÈÎ Âapple Ú ÛË ÙˆÓ ÔÚÌÔÓÒÓ ÙÔ Á Ó ÈÎÂ Ô Ê ÏÔ Î È ÙË ÈÙ Ì ÓË D ÛÙË ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ, Î ıò Î È ÙËÓ Âapple Ú ÛË ÙˆÓ appleúôù appleˆó ÔÏÔÁÈÎ appleúôûîfiïïëûë ÛÙËÓ appleâúèô ÔÓÙÈÎ Î Ù ÛÙ ÛË. ÍÂÈ ÎÏÂÈ È : AÓ ÛÎfiappleËÛË, B ÛÈÎ ŒÚ Ó, appleâúèô ÔÓÙÈÎ ÓÔÛ Ì Ù EI A ø H E Ó È Â Ú ˆ appleô ÂÎÙfi fiùè Ë Û ÓÂ È fiìâóë Ô ÔÓÙÈ ÙÚÈÎ ÂÎapple  ÛË appleôùâïâ ÛËÌ ÓÙÈÎ Ú ÛÙËÚÈfiÙËÙ Î È Â ı - ÓË ÙÔ Û Á ÚÔÓÔ ÎÏÈÓÈÎÔ Ô ÔÓÙÈ ÙÚÔ. M applefi ÙÈ ÌÂıfi Ô appleô ÚËÛÈÌÔappleÔÈÔ ÓÙ È ÁÈ ÙËÓ appleú ÁÌ ÙˆÛË ÙÔ apple Ú apple Óˆ ÛÙfi Ô, appleèı ÓfiÓ Ë appleï ÔÓ Ú ÓÔ Û, Â Ó È Ë Ô- ÏÔÎÏËÚˆÙÈÎ Î È ÂÓ Ùˆ ıâè ÌÂÏ ÙË ÙˆÓ appleúfiûê ÙˆÓ ÂÍÂ- Ï ÍÂˆÓ ÛÙÔ ÒÚÔ ÙË Ô ÔÓÙÈ ÙÚÈÎ È ÏÈÔÁÚ Ê. ø B ÛÈÎ ŒÚÂ Ó ı ÌappleÔÚÔ ÛÂ Ó ÔÚÈÛÙ ÙÔ appleâ Ô ÙË ÂappleÈÛÙËÌÔÓÈÎ ÚÂ Ó appleô appleâúèï Ì ÓÂÈ fiïô ÙÔ ÎÏ Ô ÙË EappleÈÛÙ ÌË Î È ÙË MË ÓÈÎ Î È ÛÙÔ ÔappleÔ Ô appleú ÁÌ ÙÔappleÔÈÂ Ù È Ì Û ÛÙËÌ ÙÈÎ ÚÂ Ó appleô appleôûîôappleâ ÛÙËÓ Âapple ÎÙ ÛË ÙË apple Ú Ô Û ÁÓÒÛË ÛÙË ıâˆ- ÚËÙÈÎ Î Ù ÓfiËÛË ÙˆÓ ıâìâïèˆ ÒÓ Ú ÎÙËÚÈÛÙÈÎÒÓ ÙˆÓ Ê ÈÓÔÌ ÓˆÓ, ˆÚ Î Ù Ó ÁÎËÓ ÌÂÛ Ó Î Ù Ï - ÁÂÈ ÛÂ Û ÁÎÂÎÚÈÌ Ó appleú ÎÙÈÎ ÂÊ ÚÌÔÁ apple Ú ÁˆÁ appleúô fióùˆó 1, 2, ÌÔÏÔÓfiÙÈ Ù ÙÔÈ ÂÊ ÚÌÔÁ Û Ó appleúôî - appleùô Ó Û ÂapplefiÌÂÓ ÛÙ È ÙË Ú Ó, fiappleˆ Ë EÊ ÚÌÔ- ÛÌ ÓË ŒÚÂ Ó 2 Ë MÂÙ ÊÚ ÛÙÈÎ ŒÚÂ Ó 3, 4. M ÛË Ù apple Ú apple Óˆ, ÛÎÔapplefi ÙË apple ÚÔ Û ÂÚÁ - Û Ù Ó Ë Ó ÛÎfiappleËÛË ÙˆÓ ËÌÔÛÈ ÛÂˆÓ appleô Û ÂÙ - ÔÓÙ È Ì ÙË B ÛÈÎ ŒÚÂ Ó ÙˆÓ appleâúèô ÔÓÙÈÎÒÓ ÓÔÛË- Ì ÙˆÓ Î È ËÌÔÛÈ ÙËÎ Ó ÛÙÔ ÈÂıÓ appleâúèô ÈÎfi Ù appleô Û ÔappleÔÈ appleôùâ ÁÏÒÛÛ appleúfiûê Ù, Û ÁÎÂÎÚÈÌ Ó applefi ÙËÓ 1Ë I ÓÔ Ú Ô ˆ Î È ÙËÓ 31Ë ÂÎÂÌ Ú Ô Y IKO KAI ME O OI ÙÚ ÙËÁÈÎ Ó ÙËÛË ÙˆÓ ËÌÔÛÈ ÛÂˆÓ ) AÓ ÙËÛË ÛÙÈ ËÏÂÎÙÚÔÓÈÎ ÛÂÈ Â ÔÌ ÓˆÓ PubMed Î È The Cochrane Library H Ó ÙËÛË ÙˆÓ ËÌÔÛÈ ÛÂˆÓ ÙË ÈÂıÓÔ È ÏÈÔ- ÁÚ Ê appleú ÁÌ ÙÔappleÔÈ ıëîâ Ì ÙË Ô ıâè appleúôûˆappleèîô 164 tis has been statistically and biologically associated, with considerable evidence, with an increased risk mainly for atherosclerotic cardiovascular disease, adverse pregnancy outcomes (mainly preterm and low-birth-weight neonate birth, and pre-eclampsia), as well as diabetes. Factors that might have the potential to be documented as risk factors for chronic periodontitis and that were recently studied included benign prostatic hyperplasia, the combined inhibitory effect of female sex hormones and vitamin D on chronic periodontitis, as well as the effect of patterns of psychological attachment on periodontal status. Key Words: Review, Basic Research, periodontal diseases INTRODUCTION It is widely accepted that continuing dental education is an important activity and responsibility of the modern dental clinician. A method, possibly the most significant one, used to achieve this goal is the comprehensive and deep study of recent developments in dental bibliography. Basic Research could be defined as the field of scientific research that comprises all branches of Science and Engineering and in which a systematic study is performed aimed at the expansion of existing knowledge or a theoretical understanding of the fundamental characteristics of phenomena, without necessarily directly resulting in specific practical applications or product development 1, 2, although such applications frequently occur at subsequent stages of research, such as Applied Research 2 or Translational Research 3, 4. On the basis of these considerations, the aim of the present study was to perform a review of papers related to Basic Research of periodontal diseases, published in the international literature in any language recently, in specific from the 1st of January up to and including the 31st of December MATERIAL AND METHODS Search strategy a) Search in electronic databases PubMed and The Cochrane Library Literature search was performed using a personal computer (PC) in electronic databases PubMed, US National Library of Medicine, and The Cochrane Library (in all subdivisions), Cochrane Collaboration from the 1st of January up to and including the 31st of December The electronic search strategy comprised the use of terms and key words periodont* AND (Am J Dent OR Aust Dent J OR Br Dent J OR Clin Oral Investig OR Eur J Oral Sci OR Int Dent J OR Int J Dent Hyg OR Int J Periodontics Restorative Dent OR J Am Dent Assoc OR J

3 ËÏÂÎÙÚÔÓÈÎÔ appleôïôáèûù ÛÙÈ ËÏÂÎÙÚÔÓÈÎ ÛÂÈ Â- ÔÌ ÓˆÓ PubMed ÙË US National Library of Medicine Î È The Cochrane Library (Û fiïâ ÙÈ appleô È ÈÚ ÛÂÈ ÙË ) ÙË Cochrane Collaboration applefi ÙËÓ 1Ë I ÓÔ Ú Ô ˆ Î È ÙËÓ 31Ë ÂÎÂÌ Ú Ô ÙÔ H ËÏÂÎÙÚÔÓÈÎ ÛÙÚ ÙËÁÈÎ Ó ÙËÛË ÙˆÓ ÂÚ ÓÒÓ appleâ- ÚÈÂÏ Ì Ó ÙË Ú ÛË ÙˆÓ fiúˆó Î È «Ï ÍÂˆÓ ÎÏÂÈ È» periodont* AND (Am J Dent OR Aust Dent J OR Br Dent J OR Clin Oral Investig OR Eur J Oral Sci OR Int Dent J OR Int J Dent Hyg OR Int J Periodontics Restorative Dent OR J Am Dent Assoc OR J Can Dent Assoc OR J Clin Dent OR J Clin Periodontol OR J Dent Educ OR J Dent Res OR J Dent OR J Esthet Restor Dent OR J Periodontal Res OR J Periodontol OR Mol Oral Microbiol OR Oral Surg Oral Med Oral Pathol OR Quintessence Int OR Swed Dent J) Î È Ù Ùfi ÚÔÓ ÙËÓ ÂÓÂÚÁÔappleÔ ËÛË ÙÔ appleâúèôúèûìô / «Ê Ï- ÙÚÔ» Publication date: from 2013/01/01 to 2013/12/31. ÂÓ ÂÙ ıëû Ó appleâúèôúèûìô Ì ÛË ÙË ÁÏÒÛÛ ÛÙËÓ Ô- appleô ËÌÔÛÈ ÙËÎ Ó ÔÈ Ú ÓÂ. ) AÓ ÙËÛË Û ËÏÂÎÙÚÔÓÈÎ ÛÂÈ Â ÔÌ ÓˆÓ ÈÂıÓÒÓ appleâúèô ÈÎÒÓ H È ÈÎ Û Ù ÈÛÔ Ó Ì Ì ÙË Û Ó appleôî ÏÔ ÌÂ- ÓË ÛÙËÓ ÂÏÏËÓÈÎ È ÏÈÔÁÚ Ê «ÌË ËÏÂÎÙÚÔÓÈÎ / È ÂÈÚfi Ó ÙËÛË» Î È ÛÙË ÈÂıÓ È ÏÈÔÁÚ Ê manual / hand search 5, 6. ÈÂÚÂ Ó ıëî Ó ËÏÂÎÙÚÔÓÈÎ ÔÈ ËÌÔÛÈ-  ÛÂÈ appleô ËÌÔÛÈ ÙËÎ Ó applefi ÙËÓ 1Ë I ÓÔ Ú Ô ˆ Î È ÙËÓ 31Ë ÂÎÂÌ Ú Ô ÙÔ 2013 ÛÙ ÎÔÚ Ê Ô Ô- ÓÙÈ ÙÚÈÎ appleâúèô ÈÎ ÁÈ Ù ÔappleÔ Ó ÌÂÓfiÙ Ó fiùè ı ÌappleÔÚÔ Û Ó Ó appleâúè Ô Ó ËÌÔÛÈ ÛÂÈ Û ÂÙÈ fiìâóâ Ì ٠appleâúèô ÔÓÙÈÎ ÓÔÛ Ì Ù, fiappleˆ Ó Ê ÚÔÓÙ È apple Ú Î - Ùˆ Î Ù ÏÊ ËÙÈÎ ÛÂÈÚ : American Journal of Dentistry, Australian Dental Journal, British Dental Journal, Clinical Oral Investigations, European Journal of Oral Sciences, International Dental Journal, International Journal of Dental Hygiene, The International Journal of Periodontics and Restorative Dentistry, The Journal of the American Dental Association, Journal of the Canadian Dental Association, The Journal of Clinical Dentistry, Journal of Clinical Periodontology, Journal of Dental Education, Journal of Dental Research, Journal of Dentistry, Journal of Esthetic and Restorative Dentistry, Journal of Periodontal Research, Journal of Periodontology, Molecular Oral Microbiology (appleúòëó Oral Microbiology and Immunology), [Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology] (appleúòëó Oral Surgery, Oral Medicine, Oral Pathology), Quintessence International, Swedish Dental Journal. Á) ÕÏÏ appleëá  ÔÌ ÓˆÓ ÕÏÏ appleëá  ÔÌ ÓˆÓ appleâúèâï Ì Ó Ó ÙË È ÏÈÔÁÚ - Ê ÙË Î ıâ ÂÍÂÙ fiìâóë ËÌÔÛ Â ÛË Û ÌÔÚÊ appleï - ÚÔ ÎÂÈÌ ÓÔ, Î ıò Î È ÔappleÔÈ appleôùâ Û ÂÙÈ fiìâóë appleïëúôêôú ËÌÔÛ Â ÛË ı ÌappleÔÚÔ Û ٠fió Ó ÂÓÙÔappleÈÛÙ Û ÔappleÔÈ appleôùâ applefi ÙÈ ËÏÂÎÙÚÔÓÈÎ ÛÂÈ Â- ÔÌ ÓˆÓ (PubMed, Cochrane Î È ËÏÂÎÙÚÔÓÈÎ ÛÂÈ Â ÔÌ ÓˆÓ ÈÂıÓÒÓ appleâúèô ÈÎÒÓ). Can Dent Assoc OR J Clin Dent OR J Clin Periodontol OR J Dent Educ OR J Dent Res OR J Dent OR J Esthet Restor Dent OR J Periodontal Res OR J Periodontol OR Mol Oral Microbiol OR Oral Surg Oral Med Oral Pathol OR Quintessence Int OR Swed Dent J) and concomitantly the activation of the restriction / filter Publication date: from 2013/01/01 to 2013/12/31. No language restrictions were applied. b) Search in electronic databases of international journals This procedure is equivalent with the so-called manual / hand search 5, 6. Articles were electronically searched that were published from the 1st of January up to and including the 31st of December 2013 in leading dental journals which were anticipated to have potentially included periodontal disease-related articles, as reported below in alphabetical order: American Journal of Dentistry, Australian Dental Journal, British Dental Journal, Clinical Oral Investigations, European Journal of Oral Sciences, International Dental Journal, International Journal of Dental Hygiene, The International Journal of Periodontics and Restorative Dentistry, The Journal of the American Dental Association, Journal of the Canadian Dental Association, The Journal of Clinical Dentistry, Journal of Clinical Periodontology, Journal of Dental Education, Journal of Dental Research, Journal of Dentistry, Journal of Esthetic and Restorative Dentistry, Journal of Periodontal Research, Journal of Periodontology, Molecular Oral Microbiology (formerly Oral Microbiology and Immunology), [Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology] (formerly Oral Surgery, Oral Medicine, Oral Pathology), Quintessence International, Swedish Dental Journal. c) Other data sources Other data sources comprised the bibliography of each article in full-text form examined, as well as any pertinent information or publication that could potentially be identified in any electronic database (PubMed, Cochrane and electronic databases of international journals). Inclusion criteria The full text of identified papers was examined for their potential inclusion in the review, on the basis of the following predetermined -at the initiation of the reviewinclusion criteria: 1) Publication in the international literature in any language from the 1st of January up to and including the 31st of December ) Association of the topic of the publication with periodontal diseases. 3) High significance degree of publication data in a certain field, specifically in clinical practice, scientific research of any type (Basic, Translational or Applied Research) or generally engineering and technology. The degree of significance of a publication also incorporates the degree of originality of a publication, 165

4 KÚÈÙ ÚÈ ÂappleÈÏÔÁ ËÌÔÛÈ ÛÂˆÓ TÔ appleï ڠΠÌÂÓÔ ÙˆÓ ËÌÔÛÈ ÛÂˆÓ appleô ÂÓÙÔapple ÛÙËÎ Ó ÂÍÂÙ ÛÙËΠÁÈ ÙËÓ appleèı Ó ÂappleÈÏÔÁ ÙÔ ÛÙËÓ Ó ÛÎfiappleË- ÛË, ÛÂÈ ÙˆÓ ÂÍ appleúôî ıôúèûì ÓˆÓ -Î Ù ÙËÓ Ó ÚÍË ÙË ÂÚÁ Û - ÎÚÈÙËÚ ˆÓ ÂappleÈÏÔÁ ËÌÔÛÈ ÛˆÓ: 1) ËÌÔÛ Â ÛË ÛÙË ÈÂıÓ È ÏÈÔÁÚ Ê Û ÔappleÔÈ appleô- Ù ÁÏÒÛÛ applefi ÙËÓ 1Ë I ÓÔ Ú Ô ˆ Î È ÙËÓ 31Ë Â- ÎÂÌ Ú Ô ÙÔ ) ÛË ÙÔ ÓÙÈÎÂÈÌ ÓÔ ÙË ËÌÔÛ Â ÛË Ì ٠appleâ- ÚÈÔ ÔÓÙÈÎ ÓÔÛ Ì Ù. 3) Y ËÏfi ıìfi ÛËÌ ÓÙÈÎfiÙËÙ ÙˆÓ Â ÔÌ ÓˆÓ ÙË ËÌÔÛ Â ÛË Û Πappleôèô ÒÚÔ Î È ÂÈ ÈÎfiÙÂÚ ÛÙËÓ ÎÏÈÓÈÎ appleú ÎÙÈÎ, ÛÙËÓ ÂappleÈÛÙËÌÔÓÈÎ ÚÂ Ó ÔappleÔÈ Û- appleôùâ ÌÔÚÊ ( ÛÈÎ, ÌÂÙ ÊÚ ÛÙÈÎ ÂÊ ÚÌÔ- ÛÌ ÓË ÚÂ Ó ) Â Ú ÙÂÚ ÛÙË ÌË ÓÈÎ Î È ÙËÓ ÙÂ- ÓÔÏÔÁ. O ıìfi ÛËÌ ÓÙÈÎfiÙËÙ ÌÈ ËÌÔÛ Â - ÛË ÂÌappleÂÚÈ ÂÈ Î È ÙÔ ıìfi appleúˆùôù apple ÙË, ËÏ - Û appleôèô ıìfi  ÙÂ Ë ËÌÔÛ Â ÛË appleâúè ÂÈ Â Ô- Ì Ó appleô ÂÓ Ô Ó ËÌÔÛÈ Ù appleôù ÛÙÔ apple ÚÂÏıfiÓ,  ÙÂ, ÎfiÌ Î È Ó apple ÚfiÌÔÈ ÙÔ È Ô ı Ì ÙÔ Â- ÔÌ Ó Ô Ó ËÌÔÛÈ Ù ÛÙÔ apple ÚÂÏıfiÓ Û appleúôáâ- Ó ÛÙÂÚ ËÌÔÛÈ ÛÂÈ, Û appleôèô ıìfi Ë applefi ÍÈÔÏfi- ÁËÛË ËÌÔÛ Â ÛË ı ÌappleÔÚÔ ÛÂ Ó ıâˆúëıâ fiùè appleïâ- ÔÓÂÎÙÂ Ó ÓÙÈ ÙˆÓ appleúôáâó ÛÙÂÚˆÓ ËÌÔÛÈ ÛÂˆÓ (ÁÈ apple Ú ÂÈÁÌ, applefi appleïâ Ú ÌÂıfi ˆÓ Û Â È ÛÌÔ ÙË Ú Ó, Û ÏÏÔÁ, ÔÚÁ ÓˆÛË apple ÚÔ Û ÛË ÙˆÓ Â ÔÌ ÓˆÓ). A OTE E MATA EappleÈÏÔÁ ËÌÔÛÈ ÛÂˆÓ ( Ó. 1) H ËÏÂÎÙÚÔÓÈÎ Ó ÙËÛË Û fiïâ ÙÈ ËÏÂÎÙÚÔÓÈÎ - ÛÂÈ Â ÔÌ ÓˆÓ (PubMed, Cochrane Î È ËÏÂÎÙÚÔÓÈÎ ÛÂÈ Â ÔÌ ÓˆÓ ÈÂıÓÒÓ appleâúèô ÈÎÒÓ) Û ÓÔÏÈÎ apple Ú - Û Â 3803 ËÌÔÛÈ ÛÂÈ appleô appleïëúô Û Ó ÙÔ 1Ô ÎÚÈÙ ÚÈÔ Â- appleèïôá (apple Ó Î 1). MÂÙ ÙË ÌÂÏ ÙË ÙÔ appleï ÚÔ ÎÂÈÌ - ÓÔ ÙˆÓ ËÌÔÛÈ ÛÂˆÓ ÙÒÓ Î È ÛÂÈ ÙÔ 2Ô ÎÚÈÙËÚ - Ô ÂappleÈÏÔÁ Û ÓÔÏÈÎ ÂappleÂÏ ÁËÛ Ó 878 ËÌÔÛÈ ÛÂÈ appleô Û ÂÙ ÔÓÙ Ó Ì ٠appleâúèô ÔÓÙÈÎ ÓÔÛ Ì Ù (apple Ó Î 1). M ÛË ÙÔ 3Ô ÎÚÈÙ ÚÈÔ ÂappleÈÏÔÁ, ÙÂÏÈÎ ÂappleÂÏ ÁËÛ Ó ÛÙËÓ apple ÚÔ Û Ó ÛÎfiappleËÛË 25 ËÌÔÛÈ ÛÂÈ (apple Ó Î 1). K Ù Ù ÍË ÙˆÓ ËÌÔÛÈ ÛÂˆÓ appleô ÂappleÂÏ ÁËÛ Ó ( Ó. 1 Î È 2) OÈ ËÌÔÛÈ ÛÂÈ appleô ÂappleÂÏ ÁËÛ Ó Î ÙÂÙ ÁËÛ Ó Ì ÛË ÙÔ appleâúèô ÈÎfi appleúô Ï ÛË (apple Ó Î 1) Î È ÙÔ ÓÙÈΠÌÂÓfi ÙÔ (apple Ó Î 2). H Î Ù Ù ÍË ÙˆÓ ËÌÔÛÈ ÛÂˆÓ Ì ÛË ÙÔ ÓÙÈΠÌÂÓfi ÙÔ Û ÌÂÁ ÏÔ ıìfi ÛÙËÚ ıëîâ ÛÙË ıâì ÙÈÎ Î Ù - Ù ÍË appleô ÚËÛÈÌÔappleÔÈ ıëîâ ÛÙÔ ÎÏ ÛÈÎfi Û ÁÁÚ ÌÌ KÏÈ- ÓÈÎ ÂÚÈÔ ÔÓÙÔÏÔÁ ÙˆÓ K ıëáëùòó Jan Lindhe, Niklaus P. Lang Î È Thorkild Karring 7, 8. K ÚÈ appleôùâï ÛÌ Ù / Â Ú Ì Ù ÙˆÓ ËÌÔÛÈ ÛÂˆÓ appleô ÂappleÂÏ ÁËÛ Ó ( Ó. 2) T Î ÚÈ appleôùâï ÛÌ Ù / Â Ú Ì Ù ÙˆÓ ËÌÔÛÈ ÛÂˆÓ 166 i.e. to what extent either the article contains data that have never been published in the past, or, even if similar data or data of the same topic have been published in the past in preceding articles, to what extent it could be feasible to consider the article under examination to be advantageous over previous articles (for example, in terms of methods of study design, data collection, organization or presentation). RESULTS Article selection (Table 1) The electronic search in all electronic databases (PubMed, Cochrane and databases of international journals) provided a total of 3803 articles fulfilling the 1st inclusion criterion (Table 1). Following full-text examination of these articles and on the basis of the 2nd inclusion criterion, a total of 878 periodontal disease-related articles was selected (Table 1). On the basis of the 3rd inclusion criterion, a total of 25 articles were finally selected in the present review (Table 1). Classification of selected articles (Tables 1 and 2) Articles selected were classified according to the journal of publication (Table 1) and their topic (Table 2). Article classification according to their topic was based, to a great extent, on the thematic classification employed in the classical textbook of Clinical Periodontology edited by Professors Jan Lindhe, Niklaus P. Lang and Thorkild Karring 7, 8. Main results / findings of selected articles (Table 2) The main results / findings of articles selected can be summarized as in the following paragraphs, ordered on the basis of article topic (Table 2). a) Descriptive Epidemiology of periodontal diseases Epidemiology of periodontal diseases comprises Descriptive Epidemiology, Aetiologic Epidemiology, Analytical Epidemiology and Experimental / Interventive Epidemiology 9. In this paragraph only issues of Descriptive Epidemiology will be examined, whereas the remaining issues will be incorporated in subsequent paragraphs of the review. Recent articles in the field of Descriptive Epidemiology were few in number. In a cross-sectional study, the prevalence of periodontitis and putative risk indicators were investigated in 215 adult Kiriri Indians living in an isolated Indian area in Northeast Brazil 10. Statistical analysis revealed that putative risk factors for periodontitis were age 35 years, male gender, education <9 years and the presence of smoking or diabetes 10. In conclusion, it appeared that the prevalence of moderate or advanced periodontitis in the isolated population of Brazilian Indians is clearly high 10, as generally in the country of Brazil 11. In more developed countries, the prevalence of periodo-

5 Ó Î 1. EappleÈÏÔÁ ËÌÔÛÈ ÛÂˆÓ ÂÚÈÔ ÈÎfi ËÌÔÛÈ ÛÂÈ appleô ÂÍÂÙ ÛÙËÎ Ó (N) ËÌÔÛÈ ÛÂÈ Û ÂÙÈ fiìâóâ Ì ٠appleâúèô ÔÓÙÈÎ ÓÔÛ Ì Ù appleô ÂÍÂÙ ÛÙËÎ Ó (N) ËÌÔÛÈ ÛÂÈ appleô ÙÂÏÈÎ ÂappleÂÏ ÁËÛ Ó (N, Û ÁÁÚ Ê ) American Journal of Dentistry Australian Dental Journal British Dental Journal Clinical Oral Investigations Nibali Î È Û Ó European Journal of Oral Sciences International Dental Journal International Journal of Dental Hygiene The International Journal of Periodontics and Restorative Dentistry The Journal of the American Dental Association Journal of the Canadian Dental Association The Journal of Clinical Dentistry Journal of Clinical Periodontology Figueiredo Î È Û Ó , Boland Î È Û Ó , Nibali Î È Û Ó , Graetz Î È Û Ó , Tonetti & van Dyke *, Chapple & Genco *, Sanz & Kornman *, Linden & Herzberg * Journal of Dental Education Journal of Dental Research Shusterman Î È Û Ó , Nunn Î È Û Ó , Kebschull Î È Û Ó Journal of Dentistry Journal of Esthetic and Restorative Dentistry Journal of Periodontal Research Canabarro Î È Û Ó Journal of Periodontology Renvert Î È Û Ó , Waraaswapati Î È Û Ó , Jönsson Î È 167

6 Û Ó , Trindade Î È Û Ó , Hakki Î È Û Ó , Tonetti & van Dyke *, Chapple & Genco *, Sanz & Kornman *, Linden & Herzberg * Molecular Oral Microbiology (appleúòëó Oral Microbiology and Immunology) Huang Î È Û Ó , Nagano Î È Û Ó , Madeira Î È Û Ó Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology (appleúòëó Oral Hammad Î È Û Ó. Surgery, Oral Medicine, Oral Pathology) Quintessence International De Iudicibus Î È Û Ó Swedish Dental Journal Wahlin Î È Û Ó ÕÏÏ appleëá  ÔÌ ÓˆÓ Al Mubarak Î È Û Ó ÓÔÏÔ ËÌÔÛÈ ÛÂˆÓ ÁÈ fiï Ù appleâúèô ÈÎ 3803* 878* 25* YappleÔÛËÌÂÈÒÛÂÈ / Û ÓÙÔÌÔÁÚ Ê Â : * H ËÌÔÛ Â ÛË Ù Û ÌappleÂÚÈÂÏ ÊıË Ù Ùfi ÚÔÓ ÛÙ appleâúèô ÈÎ Journal of Clinical Periodontology Î È Journal of Periodontology. ÙÔ Û ÓÔÏÔ ÙˆÓ ËÌÔÛÈ ÛÂˆÓ ÂÈ Î Ù ÌÂÙÚËı ˆ Ì (1) ËÌÔÛ Â ÛË. N: ÚÈıÌfi Û Ó.: Û ÓÂÚÁ Ù appleô ÂappleÂÏ ÁËÛ Ó ÌappleÔÚÔ Ó Ó Û ÓÔ ÈÛÙÔ Ó fiappleˆ Ê ÓÂ- Ù È ÛÙÈ apple Ú ÁÚ ÊÔ appleô ÎÔÏÔ ıô Ó, ÔÌËÌ Ó Ì ÛË ÙÔ ÓÙÈΠÌÂÓÔ ÙˆÓ ËÌÔÛÈ ÛÂˆÓ (apple Ó Î 2). 168 ) ÂÚÈÁÚ ÊÈÎ EappleÈ ËÌÈÔÏÔÁ appleâúèô ÔÓÙÈÎÒÓ ÓÔÛËÌ ÙˆÓ H EappleÈ ËÌÈÔÏÔÁ ÙˆÓ appleâúèô ÔÓÙÈÎÒÓ ÓÔÛËÌ ÙˆÓ appleâúèï Ì- ÓÂÈ ÙËÓ ÂÚÈÁÚ ÊÈÎ EappleÈ ËÌÈÔÏÔÁ, ÙËÓ AÈÙÈÔÏÔÁÈÎ EappleÈ ËÌÈÔÏÔÁ, ÙËÓ AÓ Ï ÙÈÎ EappleÈ ËÌÈÔÏÔÁ Î È ÙËÓ ÂÈ- Ú Ì ÙÈÎ / ÚÂÌ ÙÈÎ EappleÈ ËÌÈÔÏÔÁ 9. Â Ù Ó ÙËÓ apple - Ú ÁÚ ÊÔ ı ÂÍÂÙ ÛÙÔ Ó ÌfiÓÔÓ ËÙ Ì Ù ÂÚÈÁÚ ÊÈÎ EappleÈ ËÌÈÔÏÔÁ, ÂÓÒ Ù applefiïôèapple ı Ì Ù ı ÂÓÛˆÌ ÙˆıÔ Ó Û ÂapplefiÌÂÓ apple Ú ÁÚ ÊÔ ÙË Ó ÛÎfiappleËÛË. OÈ appleúfiûê Ù ËÌÔÛÈ ÛÂÈ ÛÙÔ appleâ Ô ÙË ÂÚÈÁÚ ÊÈ- Î EappleÈ ËÌÈÔÏÔÁ Ù Ó Ï Á Û ÚÈıÌfi. Â Ì Û Ántitis is definitely lower. As a characteristic example, it is of interest to examine recent epidemiological studies in Sweden 12, 13. Thus, in an epidemiological study the prevalence and extent of periodontitis were investigated in year-old adults in SkÆane County in Sweden - developed county with a population comprising 13% of the total population of Sweden- of which 451 patients finally agreed to participate 12. Three groups were formed: The first group (PD-) exhibited no or minor loss of marginal supporting bone (<1/3 of the dental root length) and was found to constitute 69% of study population 12. The second group (PD) exhibited marginal supporting bone loss of 1/3 of root length in <30% of teeth, corresponded to localized periodontitis, and was

7 Table 1. Article selection Journal Articles examined (N) Periodontal disease-related articles examined (N) Articles finally selected (N, authors) American Journal of Dentistry Australian Dental Journal British Dental Journal Clinical Oral Investigations Nibali et al European Journal of Oral Sciences International Dental Journal International Journal of Dental Hygiene The International Journal of Periodontics and Restorative Dentistry The Journal of the American Dental Association Journal of the Canadian Dental Association The Journal of Clinical Dentistry Journal of Clinical Periodontology Figueiredo et al , Boland et al , Nibali et al , Graetz et al , Tonetti & van Dyke *, Chapple & Genco *, Sanz & Kornman *, Linden & Herzberg * Journal of Dental Education Journal of Dental Research Shusterman et al , Nunn et al , Kebschull et al Journal of Dentistry Journal of Esthetic and Restorative Dentistry Journal of Periodontal Research Canabarro et al Journal of Periodontology Renvert et al , Wara-aswapati et al , Jönsson et 169

8 al , Trindade et al , Hakki et al , Tonetti & van Dyke *, Chapple & Genco *, Sanz & Kornman *, Linden & Herzberg * Molecular Oral Microbiology (appleúòëó Oral Microbiology and Immunology) Huang et al , Nagano et al , Madeira et al Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology (appleúòëó Oral Hammad et al. Surgery, Oral Medicine, Oral Pathology) Quintessence International De Iudicibus et al Swedish Dental Journal Wahlin et al Other data sources Al Mubarak et al Total articles for all journals 3803* 878* 25* Footnotes / abbreviations: * This article was simultaneously published in Journal of Clinical Periodontology and Journal of Periodontology. In total articles, it has been counted as one (1) article. N: number et al.: and others (et alii) 170 ÚÔÓÈÎ ÚÂ Ó ÈÂÚÂ Ó ıëî Ó Ë Û ÓfiÙËÙ ÙË appleâúèô- ÔÓÙ ÙÈ Î È ÓËÙÈÎÔ apple Ú ÁÔÓÙ ÎÈÓ ÓÔ Û 215 Â- Ó ÏÈΠIÓ È ÓÔ Kiriri, appleô Î ÙÔÈÎÔ Û Ó ÛÂ Ì appleôìô- ÓˆÌ ÓË appleâúèô IÓ È ÓˆÓ ÛÙË BÔÚÂÈÔ Ó ÙÔÏÈÎ BÚ È- Ï 10. H ÛÙ ÙÈÛÙÈÎ Ó Ï ÛË appleôî Ï Â fiùè ÔÈ ÓËÙÈÎÔ apple Ú ÁÔÓÙ ÎÈÓ ÓÔ ÁÈ ÙËÓ appleâúèô ÔÓÙ ÙÈ Ù Ó Ë ËÏÈ- Î 35 ÂÙÒÓ, ÙÔ ÚÛÂÓÈÎfi Ê ÏÔ, Ë ÌfiÚʈÛË <9 ÂÙÒÓ Î È Ë apple ÚÍË Î appleó ÛÌ ÙÔ È ÙË 10. ÌappleÂÚ ÛÌ ÙÈ- Î, Ê ÓËΠfiùè Ë Û ÓfiÙËÙ ÙË Ì ÛË appleúôîâ ˆÚËÌ - ÓË appleâúèô ÔÓÙ ÙÈ ÛÙÔÓ appleôìôóˆì ÓÔ appleïëı ÛÌfi ÙˆÓ IÓ È ÓˆÓ ÙË BÚ ÈÏ Â Ó È Û ÊÒ ËÏ 10, fiappleˆ ÁÂÓÈ- Î ÈÛ ÂÈ ÛÙË ÒÚ ÙË BÚ ÈÏ 11.  appleèô Ó appleù ÁÌ Ó ÒÚÂ Ë Û ÓfiÙËÙ ÙË appleâúèô Ô- ÓÙ ÙÈ ÛÊ ÏÒ Â Ó È ÌËÏfiÙÂÚË. ø Ú ÎÙËÚÈÛÙÈfound to constitute 20% of study population 12. The third group (PD+) presented with marginal supporting bone loss of 1/3 of root length in 30% of teeth, corresponded to generalized periodontitis, and was found to constitute 11% of study population 12. Due to the increase in the average life span of human populations in western societies during the past decades, epidemiological studies specifically focused on older adult populations are of particular interest. In a recent epidemiological cross-sectional study 13, 1147 older participants aged 60 to 96 years, members of the Karlskrona community -historical baroque urban area of southeastern Sweden- were selected at random from the Swedish civil registration database, the globally first -

9 Ó Î 2. OÈ ËÌÔÛÈ ÛÂÈ appleô ÂappleÂÏ ÁËÛ Ó Î Ù Ù ÁÌ Ó Ì ÛË Ùo ÓÙÈΠÌÂÓfi ÙÔ AÓÙÈΠÌÂÓÔ ËÌÔÛÈ ÛÂˆÓ AÚÈıÌfi ËÌÔÛÈ ÛÂˆÓ (N) ÁÁÚ Ê (Û Â È ÛÌfi ) ËÌÔÛÈ ÛÂˆÓ ÂÚÈÁÚ ÊÈÎ EappleÈ ËÌÈÔÏÔÁ appleâúèô ÔÓÙÈÎÒÓ 3 ÓÔÛËÌ ÙˆÓ (Û ÓfiÙËÙ, Âapple appleùˆûë Î È Ú ÙËÙ ) MÈÎÚÔ ÈÔÏÔÁ appleâúèô ÔÓÙÈÎÒÓ ÓÔÛËÌ ÙˆÓ 5 AÓÔÛÔÏÔÁ appleâúèô ÔÓÙÈÎÒÓ ÓÔÛËÌ ÙˆÓ 2 Ú ÁÔÓÙ ÎÈÓ ÓÔ Î È apple Ú ÁÔÓÙ  apple ıâè 8 ÙÔ ÍÂÓÈÛÙ ÁÈ ÙË ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ Figueiredo Î È Û Ó (Û Á ÚÔÓÈÎ ÚÂ Ó ) 10, Wahlin Î È Û Ó (Û Á ÚÔÓÈÎ ÚÂ Ó ) 12, Renvert Î È Û Ó (Û Á ÚÔÓÈÎ ÚÂ Ó ) 13 Canabarro Î È Û Ó (ex vivo ÚÂ Ó ) 20, Al Mubarak Î È Û Ó (Û Á ÚÔÓÈÎ ÚÂ Ó ) 21, Hammad Î È Û Ó (ex vivo ÚÂ Ó ) 22, Huang Î È Û Ó (ex vivo ÚÂ Ó ) 23, Nagano Î È Û Ó (in vitro ÚÂ Ó ) 24 Madeira Î È Û Ó ( ÚÂ Ó Û appleâèú Ì Ùfi ˆ ) 30, Wara-aswapati Î È Û Ó (ex vivo ÚÂ Ó ) 31 Boland Î È Û Ó ( ÚÂ Ó ÛıÂÓÒÓ-Ì ÚÙ - ÚˆÓ) 33, Jönsson Î È Û Ó (Û Á ÚÔÓÈÎ & in vitro ÚÂ Ó ) 34, Nibali Î È Û Ó (ÂappleÈÛÙÔÏ appleúô ÙÔ È ı ÓÙ Û ÓÙ ÍË ) 36, Trindade Î È Û Ó (ex vivo ÚÂ Ó ) 37, De Iudicibus Î È Û Ó (ex vivo ÚÂ Ó ) 38, Shusterman Î È Û Ó ( ÚÂ Ó Û appleâèú Ì Ùfi ˆ ) 39, Graetz Î È Û Ó ( Ó ÚÔÌÈÎ ÚÂ Ó ) 42, Nunn Î È Û Ó ( Ó ÚÔÌÈÎ ÚÂ Ó ) 43 EappleÈıÂÙÈÎ appleâúèô ÔÓÙ ÙÈ 3 ÂÚÈÔ ÔÓÙÈÎ I ÙÚÈÎ - T appleâúèô ÔÓÙÈÎ ÓÔÛ Ì Ù 4 ˆ Î Ó ÓÔ ÁÈ Û ÛÙËÌ ÙÈÎ ÓÔÛ Ì Ù Î È apple ıôïôáèî Î Ù ÛÙ ÛÂÈ Hakki Î È Û Ó (ÂappleÈÛÙÔÏ appleúô ÙÔ È ı - ÓÙ Û ÓÙ ÍË ) 51, Kebschull Î È Û Ó (ex vivo ÚÂ Ó ) 52, Nibali Î È Û Ó (ex vivo ÚÂ Ó ) 53 Tonetti & van Dyke 2013 (ÔÌfiʈÓÔ / ÎÔÈÓ Û - Ó ÓÂÛË ÂappleÈÛÙËÌÔÓÈÎfi applefiúèûì ) 55, Chapple & Genco 2013 (ÔÌfiʈÓÔ / ÎÔÈÓ Û Ó ÓÂÛË ÂappleÈ- ÛÙËÌÔÓÈÎfi applefiúèûì ) 56, Sanz & Kornman 2013 (Ô- ÌfiʈÓÔ / ÎÔÈÓ Û Ó ÓÂÛË ÂappleÈÛÙËÌÔÓÈÎfi applefi- ÚÈÛÌ ) 57, Linden & Herzberg 2013 (ÔÌfiʈÓÔ / ÎÔÈÓ Û Ó ÓÂÛË ÂappleÈÛÙËÌÔÓÈÎfi applefiúèûì ) 58 ÓÔÏÔ ËÌÔÛÈ ÛÂˆÓ 25 ÓÙÔÌÔÁÚ Ê Â : N: ÚÈıÌfi Û Ó.: Û ÓÂÚÁ Ù Îfi apple Ú ÂÈÁÌ Â Ó È ÂÓ È Ê ÚÔÓ Ó ÂÍÂÙ ÛÙÔ Ó appleúfi- ÛÊ Ù ÂappleÈ ËÌÈÔÏÔÁÈÎ Ú Ó ÛÙË Ô Ë 12, ÁÎÂÎÚÈÌ Ó, Û ÌÈ ÂappleÈ ËÌÈÔÏÔÁÈÎ ÌÂÏ ÙË ÈÂÚÂ Ó ıë- Î Ó Ë Û ÓfiÙËÙ Î È Ë ÎÙ ÛË ÙË appleâúèô ÔÓÙ ÙÈ Û 1000 ÂÓ ÏÈΠËÏÈÎ ÂÙÒÓ ÛÙo NÔÌfi SkÆane ÙË Ô Ë - Ó appleù ÁÌ ÓÔ ÓÔÌfi Ì appleïëı ÛÌfi appleô appleôùâ- Ï ÙÔ 13% ÙÔ Û ÓÔÏÈÎÔ appleïëı ÛÌÔ ÙË Ô Ë - - established in nationwide civil registry. Men exhibited a higher prevalence of periodontitis compared to women, while the prevalence of periodontitis was constantly increasing with increasing age 13, as also reported by previous epidemiological studies 14, 15. Therefore, gender and age were statistically significantly associated with the prevalence of periodontitis, while the presence of 171

10 Table 2. Selected articles classified according to their topic Article topic Number of articles (N) Authors (design) of articles Descriptive Epidemiology of periodontal 3 diseases (prevalence, incidence and severity) Microbiology of periodontal diseases 5 Immunology of periodontal diseases 2 Figueiredo et al (cross-sectional study) 10 ; Wahlin et al (cross-sectional study) 12 ; Renvert et al (cross-sectional study) 13 Canabarro et al (ex vivo study) 20 ; Al Mubarak et al (cross-sectional study) 21 ; Hammad et al (ex vivo study) 22 ; Huang et al (ex vivo study) 23 ; Nagano et al (in vitro study) 24 Madeira et al (animal study) 30 ; Wara-aswapati et al (ex vivo study) 31 Risk factors and host susceptibility 8 factors for chronic periodontitis Aggressive periodontitis 3 Periodontal Medicine Periodontal diseases 4 as a risk for systemic diseases and conditions Boland et al (case-control study) 33 ; Jönsson et al (cross-sectional & in vitro study) 34 ; Nibali et al (letter to the editor) 36 ; Trindade et al (ex vivo study) 37 ; De Iudicibus et al (ex vivo study) 38 ; Shusterman et al (animal study) 39 ; Graetz et al (retrospective study) 42 ; Nunn et al (retrospective study) 43 Hakki et al (letter to the editor) 51 ; Kebschull et al (ex vivo study) 52 ; Nibali et al (ex vivo study) 53 Tonetti & van Dyke 2013 (consensus report) 55 ; Chapple & Genco 2013 (consensus report) 56 ; Sanz & Kornman 2013 (consensus report) 57 ; Linden & Herzberg 2013 (consensus report) 58 Total articles 25 Abbreviations: N: number et al.: and others (et alii) applefi ÙÔ ÔappleÔ Ô 451 ÛıÂÓÂ ÙÂÏÈÎ Û ÌÊÒÓËÛ Ó Ó Û ÌÌÂÙ Û Ô Ó 12. ËÌ Ù ÛÙËÎ Ó ÙÚÂÈ ÔÌ Â : H appleúòùë ÔÌ (PD-) apple ÚÔ Û Â ÌË ÂÓÈÎ ÌËÏ appleòïâè ÛÙËÚÈÎÙÈÎÔ ÔÛÙÔ (<1/3 ÙÔ Ì ÎÔ ÙË Ô ÔÓÙÈÎ Ú - ) Î È Ú ıëîâ fiùè apple ÚÙÈ Â ÙÔ 69% ÙÔ appleïëı ÛÌÔ ÙË ÚÂ Ó 12. H Â ÙÂÚË ÔÌ (PD) apple ÚÔ Û Â appleò- ÏÂÈ ÛÙËÚÈÎÙÈÎÔ ÔÛÙÔ 1/3 ÙÔ Ì ÎÔ Ú ÛÂ appleô- ÛÔÛÙfi 30% ÙˆÓ ÔÓÙÈÒÓ, ÓÙÈÛÙÔÈ Ô ÛÂ ÛÂ ÂÓÙÔappleÈÛÌ - ÓË appleâúèô ÔÓÙ ÙÈ Î È Ú ıëîâ Ó appleôùâïâ ÙÔ 20% ÙÔ appleïëı ÛÌÔ ÙË ÚÂ Ó 12. H ÙÚ ÙË ÔÌ (PD+) apple ÚÔ - Û Â appleòïâè ÛÙËÚÈÎÙÈÎÔ ÔÛÙÔ 1/3 ÙÔ Ì ÎÔ Ú 172 diabetes, increased C reactive protein ( 5.0 mg/l), body overweight, cardiovascular diseases and dental visits had no such association 13. Smoking had a marginally statistically non-significant association (p=0.054) with the prevalence of periodontitis 13. In spite of frequent dental visits of the older population, the prevalence of periodontitis still remained moderate to high 13. b) Microbiology of periodontal diseases It has been known since the 1980s that yeasts and most

11 Û appleôûôûùfi 30% ÙˆÓ ÔÓÙÈÒÓ, ÓÙÈÛÙÔÈ Ô Û Û ÁÂÓÈ- ÎÂ Ì ÓË appleâúèô ÔÓÙ ÙÈ Î È Ú ıëîâ Ó appleôùâïâ ÙÔ 11% ÙÔ appleïëı ÛÌÔ ÙË ÚÂ Ó 12. fiሠÙË ÍËÛË ÙÔ Ì ÛÔ ÚfiÓÔ ˆ ÙˆÓ ÓıÚÒappleÈÓˆÓ appleïëı ÛÌÒÓ ÛÙÈ ÙÈÎ ÎÔÈÓˆÓ Â Î Ù ÙÈ ÙÂÏ - Ù Â ÂÎ ÂÙ Â, Ô Ó È È ÙÂÚÔ ÂÓ È Ê ÚÔÓ ÂappleÈ ËÌÈÔ- ÏÔÁÈÎ Ú Ó appleô ÂÛÙÈ Ô Ó ÂÈ ÈÎ Û appleïëı ÛÌÔ ÙË ÙÚ ÙË ËÏÈÎ.  ÌÈ appleúfiûê ÙË ÂappleÈ ËÌÈÔÏÔÁÈÎ Û Á ÚÔÓÈÎ ÚÂ Ó ËÏÈÎÈˆÌ ÓÔÈ Û ÌÌÂÙ ÔÓÙ ËÏÈÎ 60 ˆ 96 ÂÙÒÓ, Ì ÏË ÙË ÎÔÈÓfiÙËÙ ÙË Karlskrona -ÈÛÙÔÚÈÎ baroque ÛÙÈÎ appleâúèô ÙË ÓÔ- ÙÈ Ó ÙÔÏÈÎ Ô Ë - ÂappleÂÏ ÁËÛ Ó Ù applefi ÙËÓ Â- ıóèî ÛË Â ÔÌ ÓˆÓ ÌËÙÚÒˆÓ ÙˆÓ appleôïèùòó ÙË Ô Ë-, ÙËÓ appleúòùë apple ÁÎÔÛÌ ˆ -È Ú ıâ Û applefi ÙÔ Â- ıóèî ÛË Â ÔÌ ÓˆÓ ÌËÙÚÒˆÓ ÙˆÓ appleôïèùòó ÂÓfi ÎÚ - ÙÔ. OÈ Ó ÚÂ Â Ó ÌÂÁ Ï ÙÂÚË Û ÓfiÙËÙ appleâúèô Ô- ÓÙ ÙÈ Û ÁÎÚÈÙÈÎ Ì ÙÈ Á Ó ÎÂ, ÂÓÒ Ë Û ÓfiÙËÙ ÙË appleâúèô ÔÓÙ ÙÈ Í ÓfiÙ Ó ÛÙ ıâú Ì ÙËÓ ÍËÛË ÙË ËÏÈÎ 13, fiappleˆ ÂÈ Ó ÊÂÚıÂ Î È applefi apple Ï ÈfiÙÂÚ ÂappleÈ ËÌÈÔÏÔÁÈÎ Ú Ó 14, 15. K Ù Û Ó appleâè, ÙÔ Ê ÏÔ Î È Ë ËÏÈÎ Û Û ÂÙ ÔÓÙ Ó ÛÙ ÙÈÛÙÈÎ ÛËÌ ÓÙÈÎ Ì ÙË Û ÓfiÙËÙ ÙË appleâúèô ÔÓÙ ÙÈ, ÂÓÒ Ë apple ÚÍË È ÙË, Ë ÍËÌ ÓË C ÓÙÈ ÚÒÛ appleúˆùâ ÓË ( 5.0 mg/l), ÙÔ - ÍËÌ ÓÔ ÛˆÌ ÙÈÎfi ÚÔ, Ù Î Ú È ÁÁÂÈ Î ÓÔÛ Ì Ù Î È ÔÈ Ô ÔÓÙÈ ÙÚÈÎ ÂappleÈÛÎ ÂÈ ÂÓ apple ÚÔ Û Ó Ù ÙÔÈ Û Û ÙÈÛË 13. TÔ Î appleóèûì   ÔÚÈ Î ÛÙ ÙÈÛÙÈÎ ÌË ÛË- Ì ÓÙÈÎ Û Û ÙÈÛË (p=0.054) Ì ÙË Û ÓfiÙËÙ ÙË appleâ- ÚÈÔ ÔÓÙ ÙÈ 13. Ú ÙÈ Û Ó Ô ÔÓÙÈ ÙÚÈÎ ÂappleÈÛÎ - ÂÈ ÙÔ appleïëı ÛÌÔ ÙË ÙÚ ÙË ËÏÈÎ, Ë Û ÓfiÙËÙ ÙË appleâúèô ÔÓÙ ÙÈ ÂÍ ÎÔÏÔ ıô ÛÂ Ó apple Ú Ì ÓÂÈ Ì ÛË ˆ ËÏ 13. ) MÈÎÚÔ ÈÔÏÔÁ appleâúèô ÔÓÙÈÎÒÓ ÓÔÛËÌ ÙˆÓ Aapplefi ÙË ÂÎ ÂÙ ÙÔ 1980 Ù Ó ÁÓˆÛÙfi fiùè ÔÈ ÌÔÌ ÎË- ÙÂ Î È Û ÓfiÙÂÚ Ë Candida albicans (appleâú appleô 83% ÙˆÓ ÌÔÌ Î ÙˆÓ 16 ) appleôèî Ô Ó appleâúèô ÔÓÙÈÎÔ ı Ï ÎÔ - ÛıÂÓÒÓ Ì ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ 17, ÂappleÈıÂÙÈÎ appleâúèô Ô- ÓÙ ÙÈ (ÙfiÙ ÔÓÔÌ fiìâóë «ÂÊË ÈÎ appleâúèô ÔÓÙ ÙÈ») 18, Û appleâúèûù ÙÈÎ ÌË ÓÙ appleôîúèófiìâó ÛÙË Û Ì ÙÈÎ appleâ- ÚÈÔ ÔÓÙÈÎ ıâú appleâ 16 Û ÔÍ  appleâúèô ÔÓÙÈÎ Î Ù - ÛÙ ÛÂÈ Û ÓÔÛÔÎ Ù ÛÙ ÏÌ ÓÔ ÛıÂÓ 19. Ú fiï Ù, ÔÈ Ú Ó appleô ËÌÔÛÈ ÙËÎ Ó Ì ÚÈ ÙÔ 2000 Ù Ó ÔÏÈÁ ÚÈıÌÂ. K Ù ÙË ÂÎ ÂÙ ÙÔ 2000 Î È ÛÙË Û Ó - ÂÈ Î Ú ˆ Î Ù Ù ÙÂÏ ٠ÙÚ ÚfiÓÈ ÂÈ apple Ú ÙË- ÚËıÂ Ì ÍÈÔÛËÌ ˆÙË ÍËÛË ÙÔ ÚÈıÌÔ ÙˆÓ ÂÚ - ÓÒÓ appleô ÂÍÂÙ Ô Ó ÙË Û Û ÙÈÛË ÙË C. albicans Î È Ï- ÏˆÓ ÌÔÌ Î ÙˆÓ Ì ÙË Ú ÙËÙ ÙˆÓ appleâúèô ÔÓÙÈÎÒÓ ÓÔÛËÌ ÙˆÓ. Â Ì appleúfiûê ÙË Ú Ó, Ó Î È appleôïï Â Ë ÌÔÌ Î - ÙˆÓ (Candida parapsilosis, Rhodotorula sp., Candida dubliniensis Î È Candida tropicalis) ÓÂ Ú ıëû Ó Û - ÛıÂÓ Ì ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ, ÌfiÓÔÓ Ë C. albicans apple Ú Â Û fiïô ÙÔ ÛıÂÓ 20. H Û ÓfiÙËÙ ÙˆÓ - ÌÔÌ Î ÙˆÓ Ù Ó ÛÙ ÙÈÛÙÈÎ ÛËÌ ÓÙÈÎ ËÏfiÙÂÚË ÛÙËÓ appleúôîâ ˆÚËÌ ÓË ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ ÛÂ Û ÁÎÚÈÛË Ì ÙËÓ Ú fiìâóë-ì ÛË ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ (47% Ó ÓÙÈ 17%, ÓÙ ÛÙÔÈ, p=0.043), Î ıò Î È ÛÂ Û ÁÎÚÈÛË Ì ÙËÓ ÔÌ ÂÏ Á Ô ÙˆÓ appleâúèô ÔÓÙÈÎ ÁÈÒÓ ÙfiÌˆÓ frequently Candida albicans (83% approximately of yeasts 16 ) colonize periodontal pockets of patients with chronic periodontitis 17, aggressive periodontitis (at that time termed juvenile periodontitis ) 18, in cases non-responsive to conventional periodontal therapy 16 or in acute periodontal conditions in immunocompromised patients 19. Nonetheless, studies published up to 2000 were too few. Throughout the 2000s and subsequently mainly during the past three years, a notable increase in the number of studies investigating the association of C. albicans and other yeasts with the severity of periodontal diseases. In a recent study, although many yeast species (Candida parapsilosis, Rhodotorula sp., Candida dubliniensis and Candida tropicalis) were detected in chronic periodontitis patients, only C. albicans was present in all patients 20. The frequency of yeasts was statistically significantly higher in severe chronic periodontitis compared with slight-moderate chronic periodontitis (47% vs. 17%, respectively, p=0.043), as well as compared with the control group of periodontally healthy individuals (47% vs. 15%, respectively, p=0.033) 20. No statistically significant differences existed between patients with slightmoderate chronic periodontitis and periodontally healthy individuals 20. Study conclusion was that colonization frequency of periodontal pockets by certain yeasts and mainly C. albicans is significantly associated with the severity of chronic periodontitis 20. In a cross-sectional study including 42 patients exhibiting chronic periodontitis and type 2 diabetes, the total frequency of Candida species was 52% and, more specifically, the maximal frequency was that of species C. albicans (38%), much higher than that of the remaining species C. dubliniensis (9.5%), C. tropicalis (4.7%) and C. glabrata (4.7%) 21. The frequency of Candida species was reported to be higher in males compared with females, in patients aged over 40 years compared with patients of a lower age, in patients with non-controlled diabetes (defined as the presence of blood levels of glycated haemoglobin HbA1c >9%) compared with patients with well-controlled diabetes (defined as the presence of blood levels of glycated haemoglobin HbA1c <6%), and finally in patients with probing pocket depth 5 mm compared with patients with probing pocket depth ranging between 3 mm and 4 mm 21. In another similar recent study, it was concluded that the frequency of Candida species in periodontal pockets of type 2 diabetic patients was increased in females and in cases of low level of metabolic control of diabetes 22. Molecular Microbiology has increased our knowledge on micro-organisms by utilizing modern research methods. For example, genotyping methods, such as polymerase chain reaction or restriction fragment length polymorphism analysis (also known as RFLP analysis), have been used to differentiate Aggregatibacter actinomycetemcomitans strains and to assess the relation of specific A. actinomycetemcomitans genotypes with distinct forms of periodontal diseases 23. A recent study, to the best of our 173

12 (47% Ó ÓÙÈ 15%, ÓÙ ÛÙÔÈ, p=0.033) 20. ÂÓ apple Ú Ó ÛÙ ÙÈÛÙÈÎ ÛËÌ ÓÙÈÎ È ÊÔÚ ÌÂÙ Í ÙˆÓ ÛıÂÓÒÓ ÌÂ Ú fiìâóë-ì ÛË ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ Î È ÙˆÓ appleâúèô- ÔÓÙÈÎ ÁÈÒÓ ÙfiÌˆÓ 20. TÔ Û Ìapple Ú ÛÌ ÙË ÚÂ Ó - Ù Ó fiùè Ë Û ÓfiÙËÙ appleô ÎÈÛË ÙˆÓ appleâúèô ÔÓÙÈÎÒÓ ı Ï - ÎˆÓ applefi ÔÚÈÛÌ ÓÔ ÌÔÌ ÎËÙÂ Î È Î Ú ˆ ÙËÓ C. albicans ÂÈ ÛËÌ ÓÙÈÎ Û Û ÙÈÛË Ì ÙË Ú ÙËÙ ÙË ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ 20. Â Ì Û Á ÚÔÓÈÎ ÚÂ Ó appleô appleâúèâï Ì Ó 42 ÛıÂ- Ó appleô ÂÌÊ ÓÈ Ó ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ Î È È ÙË Ù appleô 2, Ë Û ÓÔÏÈÎ Û ÓfiÙËÙ ÙˆÓ ÂÈ ÒÓ Candida Ù Ó 52% Î È, ÂÈ ÈÎfiÙÂÚ, Ë Ì ÁÈÛÙË Û ÓfiÙËÙ Ù Ó ÙÔ Â - Ô C. albicans (38%), Î Ù appleôï ÌÂÁ Ï ÙÂÚË ÙˆÓ applefi- ÏÔÈappleˆÓ ÂÈ ÒÓ C. dubliniensis (9.5%), C. tropicalis (4.7%) Î È C. glabrata (4.7%) 21. H Û ÓfiÙËÙ ÙˆÓ ÂÈ ÒÓ Candida Ó Ê ÚıËΠÌÂÁ Ï ÙÂÚË ÛÙÔ Ó Ú ÛÂ Û ÁÎÚÈÛË Ì ÙÈ Á Ó ÎÂ, Û ÛıÂÓ ӈ ÙˆÓ 40 ÂÙÒÓ ÛÂ Û ÁÎÚÈÛË Ì ÌÈÎÚfiÙÂÚÔ Û ËÏÈÎ ÛıÂÓÂ, Û ÛıÂÓ Ì ÌË Â- ÏÂÁ fiìâóô È ÙË (ÔÚÈ fiìâóô ˆ apple ÚÍË ÂappleÈapple ˆÓ ÁÏ ÎÔ ÏÈˆÌ ÓË ÈÌÔÛÊ ÈÚ ÓË ÙÔ Ì ÙÔ HbA1c >9%) Û ÁÎÚÈÙÈÎ Ì ÛıÂÓ ÌÂ Î Ï ÂÏÂÁ fiìâóô È - ÙË (ÔÚÈ fiìâóô ˆ apple ÚÍË ÂappleÈapple ˆÓ ÁÏ ÎÔ ÏÈˆÌ ÓË ÈÌÔÛÊ ÈÚ ÓË ÙÔ Ì ÙÔ HbA1c <6%) Î È Ù ÏÔ Û ÛıÂÓ Ì ÎÏÈÓÈÎfi ıô ı Ï ÎˆÓ 5 mm ÛÂ Û ÁÎÚÈÛË Ì ÛıÂÓ Ì ÎÏÈÓÈÎfi ıô ı Ï ÎˆÓ ÌÂÙ Í 3 mm Î È 4 mm 21.  ÏÏË apple ÚÂÌÊÂÚ appleúfiûê ÙË ÚÂ Ó appleúô Î -  ÙÔ Û Ìapple Ú ÛÌ fiùè Ë Û ÓfiÙËÙ ÙˆÓ ÂÈ ÒÓ Candida ÛÙÔ appleâúèô ÔÓÙÈÎÔ ı Ï ÎÔ ÛıÂÓÒÓ ÌÂ È ÙË Ù appleô 2 Ù Ó ÍËÌ ÓË ÛÙÈ Á Ó ÎÂ Î È Û appleâúèappleùòûâè ÌËÏÔ ÂappleÈapple Ô ÌÂÙ ÔÏÈÎÔ ÂÏ Á Ô ÙÔ È ÙË 22. H MÔÚÈ Î MÈÎÚÔ ÈÔÏÔÁ ÂÈ Í ÛÂÈ ÙÈ ÁÓÒÛÂÈ Ì ÁÈ ÙÔ ÌÈÎÚÔÔÚÁ ÓÈÛÌÔ ÍÈÔappleÔÈÒÓÙ Û Á ÚÔÓ Â- Ú ÓËÙÈÎ ÌÂıfi Ô. È apple Ú ÂÈÁÌ, Ì ıô ÔÈ ÁÔÓÈ- È Î Ù appleôappleô ËÛË, fiappleˆ Ë Ï ÛÈ ˆÙ ÓÙ Ú ÛË appleô- Ï ÌÂÚ ÛË Ë Ó Ï ÛË appleôï ÌÔÚÊÈÛÌÒÓ Ì ÎÔ ÙÌË- Ì ÙˆÓ DNA appleúôâú fiìâóˆó applefi È Ûapple ÛË ÙÔ DNA Ì appleâúèôúèûùèî Ó Ì (ÁÓˆÛÙ Î È ˆ Ó Ï ÛË RFLP), - Ô Ó ÚËÛÈÌÔappleÔÈËı ÁÈ Ó È ÊÔÚÔappleÔÈ ÛÔ Ó Ù ÛÙÂÏ - Ë ÙÔ Aggregatibacter actinomycetemcomitans Î È ÁÈ Ó ÂÎÙÈÌËıÂ Ë Û ÛË Û ÁÎÂÎÚÈÌ ÓˆÓ ÁÔÓÔÙ appleˆó ÙÔ A. actinomycetemcomitans ÌÂ È ÊÔÚÂÙÈÎ ÌÔÚÊ ÙˆÓ appleâ- ÚÈÔ ÔÓÙÈÎÒÓ ÓÔÛËÌ ÙˆÓ 23. MÈ appleúfiûê ÙË Ú Ó, Î ı fi- ÛÔÓ ÁÓˆÚ Ô ÌÂ, Â Ó È Ë appleúòùë appleô appleôî Ï appleùâè ÙÈ È - ÊÔÚ ˆ appleúô ÙË Û ÛÙ ÛË Î È ÙËÓ ÎÊÚ ÛË ÙÔ Û Ófi- ÏÔ ÙÔ ÁÔÓÈ ÈÒÌ ÙÔ ÌÂÙ Í ÙˆÓ ÛÙÂÏ ÒÓ ÙÔ A. actinomycetemcomitans Ì JP2 Î È ÌË JP2 ÁÔÓÔÙ appleô 23.  ÏÏË ÌÂÏ ÙË, ÔÈ fima ÏÏËÏÔ Â DNA 84 ÛÙÂÏ ÒÓ Porphyromonas gingivalis ÈÂÚÂ Ó ıëî Ó ÚËÛÈÌÔappleÔÈÒ- ÓÙ ÏÏËÏÔ ÈÛË DNA 24. EappleÈappleÚfiÛıÂÙ, Ë ÓÙÈÁÔÓÈÎfiÙË- Ù ÙˆÓ ÊÈÌappleÚÈÒÓ FimA, appleô Û Ì ÏÏÔ Ó ÛÙÔ Û ËÌ ÙÈ- ÛÌfi ÙÔ ÈÔÏÔÁÈÎÔ ÌÂÓ Ô / ÈÔ ÌÂÓ Ô Î ıôú ÛÙËΠ̠ÙË Ú ÛË ÂÈ ÈÎÒÓ ÓÙÈÔÚÒÓ,  ÔÌ ÓÔ fiùè ÔÈ Ê - ÌappleÚÈ ÂÌÊ Ó Ô Ó ÓÙÈÁÔÓÈÎ ÂÙÂÚÔÁ ÓÂÈ ÌÂÙ Í ÙˆÓ ÁÔÓÔÙ appleˆó ÙˆÓ ÛÙÂÏ ÒÓ ÙÔ P. gingivalis 24. Á) AÓÔÛÔÏÔÁ appleâúèô ÔÓÙÈÎÒÓ ÓÔÛËÌ ÙˆÓ M applefi ÙÈ ÛËÌ ÙÔ ÔÙÈÎ Ô Ô ÛÙÈ ÔappleÔ Â ÂÈ ÂappleÈ- ÎÂÓÙÚˆıÂ Ë appleúfiûê ÙË ÚÂ Ó ÛÙËÓ AÓÔÛÔÏÔÁ Â Ó È 174 knowledge, is the first to reveal the differences in the content and expression of the entire genome between A. actinomycetemcomitans strains of JP2 and non-jp2 genotypes, differences that could interpret the distinct virulence of diverse A. actinomycetemcomitans strains 23. In another study, the fima DNA sequences of 84 Porphyromonas gingivalis strains were investigated using DNA sequencing 24. Moreover, the antigenicity of FimA fimbriae, which contribute to biofilm formation, was determined using specific antisera, given that fimbriae present with antigenic heterogeneity among P. gingivalis strain genotypes 24. c) Immunology of periodontal diseases One of the signalling pathways in which recent research in Immunology has focused on is that of Toll-like receptors (TLRs). TLRs are transmembrane proteins 25, 26 with a large extracellular domain, all containing a cytoplasmic Toll-interleukin (IL)-1 receptor (TIR) domain that functions as a signal transducer 27, 28. TLRs belong to pattern recognition receptors (PRRs) and are usually expressed in antigen-presenting cells, such as macrophages and dendritic cells 27, 28. These cells recognize structurally conserved microorganism-derived molecules termed pathogen-associated molecular patterns (PAMPs), such as bacterial lipopolysaccharide (LPS), thus playing a crucial role in the initiation of an immune response 27, 28. TLRs are characterized by specificity and therefore specific TLRs recognize specific PAMPs 27, 28. All TLRs, except TLR3, signal through the adapter protein myeloid differentiation primary-response 88 (MyD88) 29. The intracellular signalling pathways of TLRs finally - within the cell nucleus- activate the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells or simply nuclear factor kappa B (NF-ÎB) 27, 28. Transcription factor NF-ÎB activates transcription and consequently inflammatory cytokine secretion and the initiation of an inflammatory response 27, 28. Another subtle and important point is that apart from the MyD88-dependent pathway (used by TLR2/1, TLR2/6, TLR4, TLR5, TLR7/8, TLR9 and TLR11), TLR3 or TLR4 can signal through a MyD88-independent pathway 27, 28. In the field of periodontal research, a study investigated the role of LPS from A. actinomycetemcomitans - TLR4 - MyD88-dependent and MyD88-independent pathways in alveolar bone loss in MyD88-/-, TRIF-/- or TRIF-/-/MyD88- /- knockout mice, as well as C57BL6/J wild-type (WT) control mice 30. This study concluded that MyD88-dependent signalling pathway can mediate A. actinomycetemcomitans LPS-induced formation of osteoclasts and subsequent loss of alveolar bone 30. In another study, the expression of TLR2, TLR4 and TLR9 and their association with periodontopathogens were investigated using reverse transcription-polymerase chain reaction (RT-PCR) and quantitative real-time polymerase chain reaction (qpcr), respectively, in gingival tissues and subgingival plaque samples collected from 19 chronic periodontitis patients and 16 periodontally healthy su-

13 Ù ÙˆÓ appleô Ô ˆÓ appleô appleúôûôìôè Ô Ó ÙËÓ appleúˆùâ ÓË 25, 26 Toll ( appleô Ô ˆÓ TLR). OÈ appleô Ô Â TLR Â Ó È È - ÌÂÌ Ú ÓÈÎ appleúˆùâ Ó ÌÂ Ì ÌÂÁ ÏË Â͈ΠÙÙ ÚÈ appleâ- ÚÈÔ, appleô appleâúè Ô Ó Ì Î ÙÙ ÚÔappleÏ ÛÌ ÙÈÎ appleâúèô Toll- appleô Ô ÙË ÈÓÙÂÚÏ ΠÓË -1, Ë ÔappleÔ ÏÂÈÙÔ ÚÁ ˆ ÌÂÙ ÙÚÔapple / ÌÂÙ È ÛÙ ÛËÌ ÙˆÓ 27, 28. OÈ appleô Ô-  TLR Ó ÎÔ Ó ÛÙÔ appleô Ô Â Ó ÁÓÒÚÈÛË ÌÔÚÈ - ÎÒÓ ÏÏËÏÔ ÈÒÓ / ÌÔÙ ˆÓ ( appleô Ô Â PRR) Î È Û Ó - ıˆ ÂÎÊÚ ÔÓÙ È Û ÓÙÈÁÔÓÔapple ÚÔ ÛÈ ÛÙÈÎ Î ÙÙ Ú, fiappleˆ Ù Ì ÎÚÔÊ Á Î È Ù ÂÓ ÚÈÙÈÎ Î ÙÙ Ú 27, 28. T Î ÙÙ Ú Ù Ó ÁÓˆÚ Ô Ó ÔÌÈÎ È ÙËÚËÌ Ó Î Ù ÙËÓ ÂÍ ÏÈÍË ÌfiÚÈ ÌÈÎÚÔ È Î appleúô Ï ÛË, appleô ÔÓÔÌ - ÔÓÙ È ÌÔÚÈ Î ÏÏËÏÔ Â / ÌÔÙ Û ÂÙÈ fiìâó Ì apple ıôáfióô apple Ú ÁÔÓÙ (PAMPs), fiappleˆ Ô ÎÙËÚÈ - Îfi ÏÈappleÔappleÔÏ Û Î Ú ÙË (LPS), apple ÔÓÙ Î ıôúèûùèîfi ÚfiÏÔ ÛÙËÓ Ó ÚÍË ÌÈ ÓÔÛÈ Î ÓÙ Ú ÛË 27, 28. OÈ - appleô Ô Â TLR Ú ÎÙËÚ ÔÓÙ È applefi ÂÈ ÈÎfiÙËÙ Î È ÂappleÔ- Ì Óˆ Û ÁÎÂÎÚÈÌ ÓÔÈ / ÂÈ ÈÎÔ appleô Ô Â TLR Ó ÁÓˆÚ - Ô Ó Û ÁÎÂÎÚÈÌ Ó / ÂÈ ÈÎ ÌÔÙ PAMPs 27, 28. ŸÏÔÈ ÔÈ appleô Ô Â TLR, Ì ÂÍ ÚÂÛË ÙÔÓ appleô Ô TLR3, ÌÂÙ Ê ÚÔ Ó Û Ì Ù Ì Ûˆ ÙË appleúˆùâ ÓË appleúôû ÚÌÔÁ 88 ÙË appleúˆùôáâóô ÓÙ Ú ÛË ÛÙË È ÊÔÚÔappleÔ ËÛË Ì ÂÏÈÎÒÓ Ï ÎÒÓ Î ÙÙ ÚÈÎÒÓ ÛÂÈÚÒÓ (MyD88) 29. OÈ ÂÓ Ô- Î ÙÙ ÚÈ ÛËÌ ÙÔ ÔÙÈÎ Ô Ô ÙˆÓ appleô Ô ˆÓ TLR ÙÂÏÈ- Î -Ì Û ÛÙÔÓ Î ÙÙ ÚÈÎfi apple Ú Ó - ÂÓÂÚÁÔappleÔÈÔ Ó ÙÔ ÌÂÙ - ÁÚ ÊÈÎfi apple Ú ÁÔÓÙ «apple ÚËÓÈÎfi apple Ú ÁÔÓÙ ÂÓÈÛ Ù ÙˆÓ ÂÏ ÊÚÈÒÓ Ï Û ˆÓ Î ÙˆÓ ÓÔÛÔÛÊ ÈÚÈÓÒÓ ÙˆÓ ÂÓÂÚÁÔappleÔÈËÌ ÓˆÓ B ÏÂÌÊÔÎ ÙÙ ÚˆÓ» appleï apple ÚËÓÈÎfi apple Ú ÁÔ- ÓÙ Î B (NF-ÎB) 27, 28. O ÌÂÙ ÁÚ ÊÈÎfi apple Ú ÁÔÓÙ NF-ÎB ÂÓÂÚÁÔappleÔÈ ÙË ÌÂÙ ÁÚ Ê Î È ÎÔÏÔ ıˆ ÙËÓ ÎÎÚÈÛË ÊÏÂÁÌÔÓˆ ÒÓ Î ÙÙ ÚÔÎÈÓÒÓ Î È ÙËÓ Ó ÚÍË ÌÈ ÊÏÂÁ- ÌÔÓÒ Ô ÓÙ Ú ÛË 27, 28. ŒÓ ÏÏÔ ÏÂappleÙfi Î È ÛËÌ ÓÙÈÎfi ÛËÌÂ Ô Â Ó È fiùè ÂÎÙfi - applefi ÙËÓ MyD88-ÂÍ ÚÙÒÌÂÓË ÛËÌ ÙÔ ÔÙÈÎ Ô fi (appleô ÚË- ÛÈÌÔappleÔÈÂ Ù È applefi ÙÔ TLR2/1, TLR2/6, TLR4, TLR5, TLR7/8, TLR9 Î È TLR11), ÔÈ appleô Ô Â TLR3 TLR4 ÌappleÔÚÔ Ó Ó appleôûù ÏÏÔ Ó Û Ì Ù Ì Ûˆ Ì ÌË ÂÍ Ú- ÙÒÌÂÓË applefi ÙËÓ MyD88 ÛËÌ ÙÔ ÔÙÈÎ Ô Ô 27, 28. ÙÔ appleâ Ô ÙË appleâúèô ÔÓÙÈÎ Ú Ó, Ì ÌÂÏ ÙË ÈÂ- Ú ÓËÛ ÙÔ ÚfiÏÔ ÙˆÓ ÛËÌ ÙÔ ÔÙÈÎÒÓ Ô ÒÓ LPS ÙÔ A. actinomycetemcomitans - TLR4 - MyD88-ÂÍ ÚÙÒÌÂÓˆÓ ÛËÌ ÙÔ ÔÙÈÎÒÓ Ô ÒÓ Î È MyD88- ÌË ÂÍ ÚÙÒÌÂÓˆÓ Ô ÒÓ ÛÙËÓ appleòïâè ÙÔ Ê ÙÓÈ ÎÔ ÔÛÙÔ Û appleôóù ÎÈ Ì ÌÂ- Ù ÏÏ ÍÂÈ apple ÏÔÈÊ Î È ÙˆÓ Ô ÏÏËÏÔÌfiÚÊˆÓ ÙˆÓ ÁÔÓÈ ˆÓ MyD88 (MyD88-/- appleôóù ÎÈ ), TRIF (TRIF-/- appleôóù - ÎÈ ) Î È ÙˆÓ Ô ÁÔÓÈ ˆÓ (TRIF-/-/MyD88-/- appleôóù ÎÈ ), Î ıò Î È C57BL6/J ÁÚÈÔ Ù appleô appleôóù ÎÈ ÂÏ Á Ô 30. H ÚÂ Ó Ù Î Ù ÏËÍ ÛÙÔ Û Ìapple Ú ÛÌ fiùè Ë MyD88-Â- Í ÚÙÒÌÂÓË ÛËÌ ÙÔ ÔÙÈÎ Ô fi ÌappleÔÚÂ Ó ÌÂÛÔÏ Â ÛÙÔ Û ËÌ ÙÈÛÌfi ÙˆÓ ÔÛÙÂÔÎÏ ÛÙÒÓ appleô Âapple ÁÂÙ È applefi ÙÔÓ LPS ÙÔ A. actinomycetemcomitans Î È ÛÙËÓ Âapple Îfi- ÏÔ ıë appleòïâè ÙÔ Ê ÙÓÈ ÎÔ ÔÛÙÔ 30.  ÏÏË ÚÂ Ó Ë ÎÊÚ ÛË ÙˆÓ appleô Ô ˆÓ TLR2, TLR4 Î È TLR9 Î È Ë Û Û ÙÈÛ ÙÔ Ì appleâúèô ÔÓÙÔapple ıôáfió ÌÈÎÚfi È ÈÂÚÂ Ó ıëîâ ÚËÛÈÌÔappleÔÈÒÓÙ Ï ÛÈ ˆÙ - ÓÙ Ú ÛË appleôï ÌÂÚ ÛË ÌÂ Ó ÛÙÚÔÊË ÌÂÙ ÁÚ Ê ÙÔ ÂÍÂÙ fiìâóô RNA (RT-PCR) Î È appleôûôùèî Ï ÛÈ ˆÙ - ÓÙ Ú ÛË appleôï ÌÂÚ ÛË Û appleú ÁÌ ÙÈÎfi ÚfiÓÔ (Î Ù ÙËÓ bjects 31. Moreover, the mechanism of the induction of TLRs by P. gingivalis was examined ex vivo in human gingival fibroblasts 31. In conclusion, this study revealed that P. gingivalis can induce TLR2 and TLR9 expression in chronic periodontitis and that in human gingival fibroblasts TLR2 expression is dependent on tumor necrosis factor (TNF), at least in part, because the impact of other factors is also possible 31. d) Risk factors 32 and host susceptibility factors 32 for chronic periodontitis In a case-control study, based on linked electronic medical and dental records, statistical analysis revealed that periodontitis was statistically significantly associated with type 1 or 2 diabetes, hypertension, hypercholesterolaemia, hyperlipidaemia and pregnancy- or childbirthrelated conditions 33. An important finding of this study was a previously unknown association of periodontitis with benign prostatic hyperplasia 33. A cross-sectional epidemiological study, based on data derived from the U.S. National Health and Nutrition Examination Survey between 2001 and 2004, to the best of our knowledge, is the first study reporting on the combined inhibitory effect of female sex hormones and vitamin D on periodontitis 34. In this study, the use of hormone replacement therapy was related to improved levels of attachment and higher number of teeth only in women presenting with sufficient serum levels of vitamin D ( 20 ng/ml) 34. Genetic host susceptibility factors for chronic periodontitis represent a separate category of host susceptibility factors 32, 35. Since the 1990s and especially during the 2000s, periodontal genetic research has focused on the identification of numerous genes and gene polymorphisms, particularly those related to the immune pathogenic mechanism of chronic periodontitis or other forms of periodontal disease, such as polymorphisms of genes encoding interleukins, TNF or its receptors, immunoglobulin receptors, metalloproteinases (MMPs) or their tissue inhibitors (TIMPs), and other molecules 32, Psychosocial risk factors for periodontitis are of particular interest. According to the attachment theory, the normal social and emotional development of an infant or a child requires a normal relationship with at least one primary caregiver, usually a parent 40. Attachment is the affectional connection of an infant or a child with the caregiver 41. A recent study assessed associations between periodontal parameters and patterns of psychological attachment 42. Apart from systemic risk factors for periodontal diseases, local risk factors have also been examined recently. In the United States, the prophylactic extraction of nonerupted and asymptomatic third molars is the most prevalent oral surgical procedure, aimed at the prevention of potential disease, such as caries or periodontitis, in adjacent teeth in the future 43. Some data are available, although limited, that retaining non-erupted and asymptomatic third molars significantly increases the risk for the initiation and/or progression of periodontitis in the adjacent second molars 44, 45. A recent cohort study confirmed this previously reported assertion

14 ÂÎÙ ÏÂÛË ÙË ÌÂıfi Ô ) (qpcr), ÓÙ ÛÙÔÈ, ÛÂ Ô ÏÈÎÔ ÈÛÙÔ Î È Â ÁÌ Ù appleôô ÏÈÎ appleï Î appleô Û ÓÂÏ ÁË- Û Ó applefi 19 ÛıÂÓ Ì ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ Î È 16 appleâúèô ÔÓÙÈÎ ÁÈ ÙÔÌ 31. EappleÈappleÚfiÛıÂÙ, Ô ÌË ÓÈÛÌfi ÙË Âapple ÁˆÁ ÙˆÓ appleô Ô ˆÓ TLR applefi ÙÔÓ P. gingivalis ÂÍÂÙ ÛÙËΠex vivo Û ÓıÚÒappleÈÓÂ Ô ÏÈÎ ÈÓÔ Ï ÛÙ 31. ÌappleÂÚ ÛÌ ÙÈÎ, Ù Ë ÚÂ Ó appleôî Ï Â fiùè Ô P. gingivalis ÌappleÔÚÂ Ó Âapple ÁÂÈ ÙËÓ ÎÊÚ ÛË ÙˆÓ appleô Ô - ˆÓ TLR2 Î È TLR9 ÛÙË ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ Î È fiùè ÛÙÈ ÓıÚÒappleÈÓÂ Ô ÏÈÎ ÈÓÔ Ï ÛÙÂ Ë ÎÊÚ ÛË ÙÔ appleô Ô- TLR2 ÂÍ ÚÙ Ù È applefi ÙÔÓ apple Ú ÁÔÓÙ Ó ÎÚˆÛË ÙˆÓ fiáîˆó (TNF), ÙÔ Ï ÈÛÙÔÓ ÂÓ Ì ÚÂÈ, ÂappleÂÈ Ë Âapple Ú ÛË ÏÏˆÓ apple Ú ÁfiÓÙˆÓ Â Ó È Âapple ÛË appleèı Ó 31. ) Ú ÁÔÓÙ ÎÈÓ ÓÔ 32 Î È apple Ú ÁÔÓÙ  apple ıâè ÙÔ ÍÂÓÈÛÙ 32 ÁÈ ÙË ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ Â Ì ÌÂÏ ÙË ÛıÂÓÒÓ-Ì ÚÙ ÚˆÓ ÛÈÛÌ ÓË ÛÂ È Û Ó-  ÂÌ Ó ËÏÂÎÙÚÔÓÈÎ È ÙÚÈÎ Î È Ô ÔÓÙÈ ÙÚÈÎ Ú Â, Ë ÛÙ ÙÈÛÙÈÎ Ó Ï ÛË appleôî Ï Â fiùè Ë appleâúèô ÔÓÙ ÙÈ Û Û ÂÙÈ fiù Ó ÛÙ ÙÈÛÙÈÎ ÛËÌ ÓÙÈÎ Ì ÙÔ È ÙË Ù - appleô 1 2, ÙËÓ apple ÚÙ ÛË, ÙËÓ appleâú ÔÏËÛÙÂÚÔÏ ÈÌ, ÙËÓ appleâúïèappleè ÈÌ Î È Ì apple ıôïôáèî Î Ù ÛÙ ÛÂÈ Û ÂÙÈ- fiìâóâ Ì ÙËÓ ÂÁÎ ÌÔÛ ÓË ÙÔÓ ÙÔÎÂÙfi 33. ŒÓ ÛËÌ - ÓÙÈÎfi  ÚËÌ ÙË ÌÂÏ ÙË Ù Ù Ó Ì ÁÓˆÛÙË ˆ Û ÌÂÚ Û Û ÙÈÛË ÙË appleâúèô ÔÓÙ ÙÈ Ì ÙËÓ Î ÏÔ ıë appleâúappleï Û ÙÔ appleúôûù ÙË 33. M Û Á ÚÔÓÈÎ ÂappleÈ ËÌÈÔÏÔÁÈÎ Ú Ó, ÛÈÛÌ ÓË Û  ÔÌ Ó appleúôâú fiìâó applefi ÙËÓ EıÓÈÎ ŒÚÂ Ó EÍ Ù - ÛË ÙË YÁÂ Î È È ÙÚÔÊ ÙˆÓ HÓˆÌ ÓˆÓ ÔÏÈÙÂÈÒÓ ÙË AÌÂÚÈÎ ÌÂÙ Í 2001 Î È 2004, Î ı fiûôó ÁÓˆÚ - Ô ÌÂ, Â Ó È Ë appleúòùë ÚÂ Ó appleô ÂÈ ÂÍÂÙ ÛÂÈ ÙË Û Ó- ÛÌ ÓË Ó ÛÙ ÏÙÈÎ Âapple Ú ÛË ÙˆÓ ÔÚÌÔÓÒÓ ÙÔ Á - Ó ÈÎÂ Ô Ê ÏÔ Î È ÙË ÈÙ Ì ÓË D Âapple ÙË appleâúèô ÔÓÙ ÙÈ- 34. ÙËÓ ÚÂ Ó Ù Ë ÚËÛÈÌÔappleÔ ËÛË ÙË ıâú appleâ - ÓÙÈÎ Ù ÛÙ ÛË ÔÚÌÔÓÒÓ Û ÂÙÈ fiù Ó Ì ÂÏÙÈˆÌ Ó Âapple appleâ appleúfiûê ÛË Î È ÌÂÁ Ï ÙÂÚÔ ÚÈıÌfi ÔÓÙÈÒÓ ÌfiÓÔ Û Á Ó Î Ì Âapple ÚÎ Âapple appleâ ÈÙ Ì ÓË D ÛÙÔÓ ÔÚfi (>20 ng/ml) 34. OÈ ÁÂÓÂÙÈÎÔ apple Ú ÁÔÓÙ  apple ıâè ÙÔ ÍÂÓÈÛÙ ÛÙË Úfi- ÓÈ appleâúèô ÔÓÙ ÙÈ ÓÙÈappleÚÔÛˆappleÂ Ô Ó Ì Í ˆÚÈÛÙ Î - ÙËÁÔÚ apple Ú ÁfiÓÙˆÓ Â apple ıâè ÙÔ ÍÂÓÈÛÙ 32, 35. Aapplefi ÙË ÂÎ ÂÙ ÙÔ 1990 Î È È È ÙÂÚ Î Ù ÙË ÂÎ ÂÙ ÙÔ 2000, Ë appleâúèô ÔÓÙÈÎ ÁÂÓÂÙÈÎ ÚÂ Ó ÂÈ ÂÛÙÈ ÛÙ ÛÙÔÓ ÂÓÙÔappleÈÛÌfi appleôï ÚÈıÌˆÓ ÁÔÓÈ ˆÓ Î È ÁÔÓÈ È ÎÒÓ appleôï - ÌÔÚÊÈÛÌÒÓ, È È ÙÂÚ ÙÒÓ appleô Û ÂÙ ÔÓÙ È Ì ÙÔÓ ÓÔ- ÛÈ Îfi apple ıôáâóâùèîfi ÌË ÓÈÛÌfi ÙË ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ- ÏÏˆÓ ÌÔÚÊÒÓ ÙË appleâúèô ÔÓÙÈÎ ÓfiÛÔ, fiappleˆ appleô- Ï ÌÔÚÊÈÛÌÒÓ ÁÔÓÈ ˆÓ appleô Έ ÈÎÔappleÔÈÔ Ó ÈÓÙÂÚÏ ΠÓÂ, ÙÔÓ apple Ú ÁÔÓÙ TNF ÙÔ appleô Ô Â ÙÔ, ÙÔ appleô Ô-  ÓÔÛÔÛÊ ÈÚÈÓÒÓ, ÌÂÙ ÏÏÔappleÚˆÙÂ Ó Û (MMPs) È- ÛÙÈÎÔ Ó ÛÙÔÏ ÙÔ (TIMPs) Î È ÏÏ ÌfiÚÈ 32, OÈ ÔÎÔÈÓˆÓÈÎÔ apple Ú ÁÔÓÙ ÎÈÓ ÓÔ ÁÈ ÙËÓ appleâúèô- ÔÓÙ ÙÈ Ô Ó È È ÙÂÚÔ ÂÓ È Ê ÚÔÓ. ÌÊˆÓ Ì ÙË «ıâˆú ÙË appleúôûîfiïïëûë», Ë Ê ÛÈÔÏÔÁÈÎ ÎÔÈÓˆÓÈÎ Î È Û Ó ÈÛıËÌ ÙÈÎ Ó appleù ÍË ÂÓfi ÓËapple Ô apple È ÈÔ - apple ÈÙ ÙË Ê ÛÈÔÏÔÁÈÎ Û ÛË Ì ÙÔ Ï ÈÛÙÔÓ Ó ÙÔÌÔ appleô ÙÔ ÊÚÔÓÙ ÂÈ / ÊÚÔÓÙÈÛÙ, Û Ó ıˆ Ó Ó ÁÔÓ 40. «ÚÔÛÎfiÏÏËÛË» Â Ó È Ë Û Ó ÈÛıËÌ ÙÈÎ È Û Ó ÂÛË Â- 176 e) Aggressive periodontitis On the basis of the definition of aggressive periodontitis (localized or generalized) in the 1999 International Workshop for a Classification of Periodontal Diseases and Conditions 46, 47, in the present review all recent studies that have used criteria for selecting aggressive periodontitis patients other than the three primary criteria officially determined (for example, studies defining ag- 48, 49 gressive periodontitis solely on the basis of patient age) or studies not mentioning criteria for aggressive periodontitis 50 have been excluded. In a recent letter to the Editor of Journal of Periodontology 51, the importance of strict adherence to the 1999 official nomenclature 46, 47 has also been emphasized. In a study, genes associated with the immune response, apoptosis and various signalling pathways were found to be overexpressed in aggressive periodontitis, in contrast to chronic periodontitis, which was characterized by an overexpression of genes associated with epithelial integrity and metabolism 52. The importance of this study 52 lies in the accumulation of data that could be used in the future, along with other similar data, in order to discriminate aggressive from chronic periodontitis on the basis of gene expression at the molecular level, which in turn might have the potential of challenging the current 46 classification of periodontal diseases and conditions. In another study, host response to non-surgical and surgical periodontal treatment was examined in 12 nonsmoking United Kingdom Caucasian aggressive periodontitis patients in relation to interleukin-6 haplotypes 53. In the context of this study, the term haplotype refers to statistically associated single-nucleotide polymorphisms located on the same single chromosome of a pair of chromosomes 54. Interleukin-6-haplotype-positive patients exhibited a higher tendency for enhanced periodontal catastrophe, as revealed by clinical periodontal parameters, as well as a more intense inflammatory / immune response 53. Although periodontal therapy provided beneficial effects in all patients, interleukin-6-haplotype-positive patients presented with a less efficacious therapeutic outcome 53. f) Periodontal Medicine - Periodontal diseases as a risk for systemic diseases and conditions In April 2013, the European Federation of Periodontology (EFP) and the American Academy of Periodontology (AAP) simultaneously co-published consensus reports in the Journal of Clinical Periodontology and the Journal of Periodontology. These reports had been formed in November 2012 in a joint workshop held in Segovia, Spain, with the participation of more than 70 international experts (6 Chairs, 24 Reviewers, 45 Participants and 7 Officers). In these consensus reports, scientific evidence was accumulated that periodontitis can affect certain systemic diseases, primarily atherosclerotic cardiovascular disease (a collective term comprising coronary heart disease, cerebrovascular disease and peripheral

15 Ófi ÓËapple Ô apple È ÈÔ Ì ÙÔ ÙÔÌÔ appleô ÙÔ ÊÚÔÓÙ ÂÈ / ÊÚÔÓÙÈÛÙ 41. M appleúfiûê ÙË Ú Ó, Î ı fiûôó ÁÓˆÚ - Ô ÌÂ, Ù Ó Ë appleúòùë appleô ÍÈÔÏfiÁËÛ ÙÈ Û Û ÂÙ ÛÂÈ ÌÂÙ Í ÙË appleâúèô ÔÓÙ ÙÈ Î È ÙˆÓ appleúôù appleˆó ÔÏÔ- ÁÈÎ appleúôûîfiïïëûë 42. EÎÙfi applefi Û ÛÙËÌ ÙÈÎÔ apple Ú ÁÔÓÙ ÎÈÓ ÓÔ ÁÈ Ù appleâúèô ÔÓÙÈÎ ÓÔÛ Ì Ù, ÙÔappleÈÎÔ apple Ú ÁÔÓÙ ÎÈÓ ÓÔ Ô Ó Âapple ÛË appleúfiûê Ù ÂÍÂÙ ÛÙÂ. ÙÈ HÓˆÌ Ó ÔÏÈ- Ù  ÙË AÌÂÚÈÎ, Ë appleúôê Ï ÎÙÈÎ ÂÍ ÁˆÁ ÙˆÓ ÌË - Ó ÙÂÈÏ ÓÙˆÓ Î È Û ÌappleÙˆÌ ÙÈÎÒÓ ÙÚ ÙˆÓ ÁÔÌÊ ˆÓ Â Ó È Ë appleèô Û Ó ÛÙÔÌ ÙÈÎ ÂÈÚÔ ÚÁÈÎ Âapple Ì ÛË, appleôûîôappleòóù ÛÙËÓ appleúfiïë Ë appleèı Ó ÓfiÛÔ, fiappleˆ ÙÂÚË fió appleâúèô ÔÓÙ ÙÈ, Û apple Ú Î ÌÂÓ fióùè ÛÙÔ Ì ÏÏÔÓ 43. MÂÚÈÎ Â ÔÌ Ó Â Ó È È ı ÛÈÌ, Ó Î È appleâúèôúèûì Ó, ÁÈ ÙÔ fiùè Ë È Ù ÚËÛË ÙˆÓ ÌË Ó ÙÂÈÏ ÓÙˆÓ Î È Û - ÌappleÙˆÌ ÙÈÎÒÓ ÙÚ ÙˆÓ ÁÔÌÊ ˆÓ Í ÓÂÈ ÛËÌ ÓÙÈÎ ÙÔÓ Î Ó ÓÔ ÁÈ ÙËÓ Ó ÚÍË Î È ÂÍ ÏÈÍË ÙË appleâúèô ÔÓÙ ÙÈ- ÛÙÔ apple Ú Î ÌÂÓÔ Â ÙÂÚÔ ÁÔÌÊ Ô 44, 45. M appleúfiûê ÙË ÌÂÏ ÙË ÎÔÔÚÙÒÓ ÂappleÈ Â ˆÛ ÙfiÓ ÙÔÓ appleúô- ÁÂÓ ÛÙÂÚÔ ÈÛ ÚÈÛÌfi 43. Â) EappleÈıÂÙÈÎ appleâúèô ÔÓÙ ÙÈ M ÛË ÙÔÓ ÔÚÈÛÌfi ÙË ÂappleÈıÂÙÈÎ appleâúèô ÔÓÙ ÙÈ (ÂÓÙÔappleÈÛÌ ÓË ÁÂÓÈÎÂ Ì ÓË ) ÛÙÔ ÈÂıÓ ÌapplefiÛÈÔ ÁÈ ÙËÓ T ÍÈÓfiÌËÛË ÙˆÓ ÂÚÈÔ ÔÓÙÈÎÒÓ NÔÛËÌ ÙˆÓ Î È ıôïôáè- ÎÒÓ K Ù ÛÙ ÛÂˆÓ ÙÔ , 47, ÛÙËÓ apple ÚÔ Û Ó ÛÎfiappleË- ÛË fiïâ ÔÈ appleúfiûê Ù Ú Ó appleô Ô Ó ÚËÛÈÌÔappleÔÈ ÛÂÈ ÎÚÈÙ ÚÈ ÂappleÈÏÔÁ ÛıÂÓÒÓ Ì ÂappleÈıÂÙÈÎ appleâúèô ÔÓÙ ÙÈ È ÊÔÚÂÙÈÎ applefi Ù ÙÚ appleúˆùôáâó ÎÚÈÙ ÚÈ appleô Ô Ó Â- apple ÛËÌ Î ıôúèûùâ 48, 49 (ÁÈ apple Ú ÂÈÁÌ, Ú Ó appleô ÔÚ - Ô Ó ÙËÓ ÂappleÈıÂÙÈÎ appleâúèô ÔÓÙ ÙÈ appleôîïâèûùèî Ì ÛË ÙËÓ ËÏÈÎ ÙÔ ÛıÂÓÔ ) Ú Ó appleô ÂÓ Ó Ê ÚÔ Ó ÎÚÈÙ ÚÈ ÁÈ ÙËÓ ÂappleÈıÂÙÈÎ appleâúèô ÔÓÙ ÙÈ 50 Ô Ó appleôîïâè- ÛÙÂ. Â Ì appleúfiûê ÙË ÂappleÈÛÙÔÏ appleúô ÙÔ È ı ÓÙ Û ÓÙ - ÍË ÙÔ appleâúèô ÈÎÔ Journal of Periodontology 51, Ë ÛËÌ Û ÙË ÛÙËÚ appleúôûîfiïïëûë ÛÙËÓ Âapple ÛËÌË ÔÚÔÏÔÁ ÙÔ , 47 ÂÈ Âapple ÛË ÙÔÓÈÛÙÂ. Â Ì Ú Ó, Ù ÁÔÓ È appleô Û ÂÙ ÔÓÙ Ó Ì ÙËÓ ÓÔ- ÛÈ Î ÓÙ Ú ÛË, ÙËÓ applefiappleùˆûë Î È È ÊÔÚ ÛËÌ ÙÔ- ÔÙÈÎ Ô Ô Ú ıëî Ó Ó appleâúâîêú ÔÓÙ È ÛÙËÓ ÂappleÈıÂÙÈÎ appleâúèô ÔÓÙ ÙÈ, Û ÓÙÈ È ÛÙÔÏ Ì ÙË ÚfiÓÈ appleâ- ÚÈÔ ÔÓÙ ÙÈ, Ë ÔappleÔ Ú ÎÙËÚÈ fiù Ó applefi appleâú ÎÊÚ - ÛË ÙˆÓ ÁÔÓÈ ˆÓ appleô Û ÂÙ ÔÓÙ È Ì ÙËÓ ÂappleÈıËÏÈ Î ÎÂ- Ú ÈfiÙËÙ Î È ÌÂÙ ÔÏÈÛÌfi 52. H ÛËÌ Û ÙË ÚÂ Ó - Ù 52 ÁÎÂÈÙ È ÛÙË Û ÁÎ ÓÙÚˆÛË Â ÔÌ ÓˆÓ appleô ı ÌappleÔ- ÚÔ Û Ó Ó ÚËÛÈÌÔappleÔÈËıÔ Ó ÛÙÔ Ì ÏÏÔÓ, applefi ÎÔÈÓÔ Ì ÏÏ apple ÚÂÌÊÂÚ Â ÔÌ Ó, Ì ÛÙfi Ô Ó È ÎÚÈıÂ Ë Â- appleèıâùèî appleâúèô ÔÓÙ ÙÈ applefi ÙË ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ Ì ÛË ÙË ÁÔÓÈ È Î ÎÊÚ ÛË ÛÙÔ ÌÔÚÈ Îfi Âapple appleâ Ô, appleô Ì ÙË ÛÂÈÚ ÙË ı ÌappleÔÚÔ Û ÓËÙÈÎ Ó ı ÛÂÈ - applefi ÌÊÈÛ ÙËÛË ÙËÓ ÙÚ Ô Û 46 Ù ÍÈÓfiÌËÛË ÙˆÓ appleâúèô- ÔÓÙÈÎÒÓ ÓÔÛËÌ ÙˆÓ Î È apple ıôïôáèîòó Î Ù ÛÙ ÛˆÓ.  ÏÏË Ú Ó, Ë ÓÙ Ú ÛË ÙÔ ÍÂÓÈÛÙ ÛÙË ÌË ÂÈ- ÚÔ ÚÁÈÎ Î È ÂÈÚÔ ÚÁÈÎ appleâúèô ÔÓÙÈÎ ıâú appleâ ÂÍÂÙ - ÛÙËΠ۠12 ÌË Î appleó ÔÓÙ K Î ÛÈÔ ÛıÂÓ ÙÔ HÓˆÌ ÓÔ B ÛÈÏÂ Ô Ì ÂappleÈıÂÙÈÎ appleâúèô ÔÓÙ ÙÈ ÛÂ Û - Ó ÚÙËÛË Ì ÙÔ appleïôù appleô ÙË ÈÓÙÂÚÏ ΠÓË ÙÔ appleï ÛÈÔ Ù ÙË Ú Ó, Ô fiúô «appleïfiù appleô» Ó Ê arterial disease) 55, diabetes 56 and adverse pregnancy outcomes 57 -mainly preterm neonate birth (of less than 37 weeks gestational age); low-birth-weight neonate birth (of weight <2500 g); and pre-eclampsia- and secondarily chronic obstructive pulmonary disease, pneumonia, obesity, metabolic syndrome, rheumatoid arthritis, chronic kidney disease, cognitive impairment (collective term including any characteristic acting as a barrier to a cognitive process) and cancer 58. More specifically, overall it appears that a) epidemiological evidence supports the association of periodontitis with an increased risk for atherosclerotic cardiovascular disease 55, preterm and low-birth-weight neonate birth and pre-eclampsia 57, whereas epidemiological evidence of the association of periodontitis with glycaemic control, complications and progression of diabetes is limited 56 ; b) in vitro, animal or clinical studies support that biological mechanisms exist that possibly can interpret the association of periodontitis with an increased risk for atherosclerotic cardiovascular disease 55, diabetes 56 and adverse pregnancy outcomes 57 ; and c) trials support that periodontal therapy can significantly contribute to the improvement of type 2 diabetic control 56, whereas more trials are required with respect to the effect of periodontal therapy on atherosclerotic cardiovascular disease 55, type 1 diabetes 56, adverse pregnancy outcomes 57 and the adjunctive use of antimicrobials in periodontal therapy of diabetic patients 56. DISCUSSION In this study, a review of papers related to Basic Research of periodontal diseases was performed, that were published in the international literature in any language recently, in specific from the 1st of January up to and including the 31st of December From this review it transpires that the majority of recent articles has primarily centered on the field of Periodontal Medicine and on the field of host susceptibility factors and risk factors for chronic periodontitis, while a lower number of studies has examined Microbiology of periodontal diseases, aggressive periodontitis, as well as Descriptive Epidemiology and Immunology of periodontal diseases. It is of interest to make a comparison between the novel data revealed by the recent studies of the present review and data published in previous studies. For instance, in a Swedish epidemiological study in an elderly population published in 2013, the statistical association of diabetes or cardiovascular disease with periodontitis did not reach statistical significance (>0.05 in all statistical tests) 13, whereas in preceding studies in elderly populations the aforementioned associations were significant in the case of diabetes 59, 60 and cardiovascular disease The main positive aspects of the above-mentioned epidemiological study could be considered to be the record of recent epidemiological data in Sweden, the specific study of the 177

16 ÚÂÙ È Û ÛÙ ÙÈÛÙÈÎ Û Û ÂÙÈ fiìâóô ÌÔÓÔÓÔ ÎÏÂÔÙÈ È- ÎÔ appleôï ÌÔÚÊÈÛÌÔ appleô ÂÓÙÔapple ÔÓÙ È ÛÙÔ ÈÔ ÚˆÌfi- ÛˆÌ applefi Ó Â ÁÔ ÚˆÌÔÛˆÌ ÙˆÓ 54. OÈ ıâùèîô ÛıÂ- Ó Û appleïôù appleô ÙË ÈÓÙÂÚÏ ΠÓË -6 apple ÚÔ Û Ó - ËÏfiÙÂÚË Ù ÛË ÁÈ ÍËÌ ÓË appleâúèô ÔÓÙÈÎ Î Ù ÛÙÚÔÊ, fiappleˆ Ê ÈÓfiÙ Ó applefi ÙÈ ÎÏÈÓÈÎ appleâúèô ÔÓÙÈÎ apple Ú Ì - ÙÚÔ, Î ıò Î È appleâúèûûfiùâúô ÓÙÔÓË ÊÏÂÁÌÔÓÒ Ë / - ÓÔÛÈ Î ÓÙ Ú ÛË 53. Ú fiïô appleô Ë appleâúèô ÔÓÙÈÎ ıâú - appleâ apple Ú Û Â Â ÂÚÁÂÙÈÎ appleôùâï ÛÌ Ù Û fiïô ÙÔ ÛıÂÓÂ, ÔÈ ıâùèîô Û appleïôù appleô ÙË ÈÓÙÂÚÏ ΠÓË -6 ÛıÂÓ apple ÚÔ Û Û Ó ÏÈÁfiÙÂÚÔ ÈÎ ÓÔappleÔÈËÙÈÎfi ıâú appleâ - ÙÈÎfi appleôù ÏÂÛÌ 53. ÛÙ) ÂÚÈÔ ÔÓÙÈÎ I ÙÚÈÎ - T appleâúèô ÔÓÙÈÎ ÓÔÛ Ì Ù ˆ Î Ó ÓÔ ÁÈ Û ÛÙËÌ ÙÈÎ ÓÔÛ Ì Ù Î È apple ıôïôáèî Î Ù ÛÙ ÛÂÈ TÔÓ AappleÚ ÏÈÔ ÙÔ 2013, Ë E Úˆapple Î OÌÔÛappleÔÓ ÂÚÈÔ- ÔÓÙÔÏÔÁ Î È Ë AÌÂÚÈÎ ÓÈÎ AÎ ËÌ ÂÚÈÔ ÔÓÙÔ- ÏÔÁ Ù Ùfi ÚÔÓ applefi ÎÔÈÓÔ ËÌÔÛ Â Û Ó ÔÌfiÊˆÓ / ÎÔÈÓ Û Ó ÓÂÛË ÂappleÈÛÙËÌÔÓÈÎ appleôú ÛÌ Ù ÛÙ appleâúèô- ÈÎ Journal of Clinical Periodontology Î È Journal of Periodontology. T appleôú ÛÌ Ù Ù Â Ó È ÌÔÚʈı ÙÔ ÂÎ Ì ÚÈÔ ÙÔ 2012 ÛÂ Ó ÎÔÈÓfi ÂappleÈÛÙËÌÔÓÈÎfi Û - ÌapplefiÛÈÔ appleô Ï Â ÒÚ ÛÙË Segovia ÙË IÛapple Ó, Ì ÙË Û ÌÌÂÙÔ Óˆ ÙˆÓ 70 ÂÈ ÈÎÒÓ ÛÙÔ ÈÂıÓ ÒÚÔ (6 appleúô-  Ú fióùˆó, 24 ÂÈ ÈÎÒÓ appleô appleú ÁÌ ÙÔappleÔ ËÛ Ó ÙÈ Ó - ÛÎÔapple ÛÂÈ, 45 Û ÌÌÂÙ fióùˆó Î È 7 ÂappleÈÛ ÌˆÓ).  ٠٠ÔÌfiÊˆÓ ÂappleÈÛÙËÌÔÓÈÎ appleôú ÛÌ Ù, Û ÁÎÂÓÙÚÒıËÎÂ Ë ÂappleÈÛÙËÌÔÓÈÎ ÙÂÎÌËÚ ˆÛË ÁÈ ÙÔ fiùè Ë appleâúèô ÔÓÙ ÙÈ ÌappleÔÚÂ Ó ÂappleËÚ ÛÂÈ ÔÚÈÛÌ Ó Û ÛÙËÌ ÙÈÎ ÓÔÛ Ì Ù, Î Ú ˆ ÙËÓ ıëúôûîïëúˆùèî Î Ú È ÁÁÂÈ Î ÓfiÛÔ (Û ÏÏÔÁÈÎfi fiúô appleô appleâúèï Ì ÓÂÈ ÙË ÛÙÂÊ ÓÈ Î Ú È Î ÓfiÛÔ, ÙË ÓfiÛÔ ÙˆÓ ÂÁÎÂÊ ÏÈÎÒÓ ÁÁ ˆÓ / Â- ÁÎÂÊ ÏÈÎ ÁÁÂÈ Î ÓfiÛÔ Î È ÙËÓ appleâúèêâúèî ÚÙËÚÈ Î ÓfiÛÔ) 55, ÙÔ È ÙË 56 Î È ÙÈ ÓÂappleÈı ÌËÙ ÂÎ ÛÂÈ ÙË Î ËÛË -Î Ú ˆ ÙË Á ÓÓËÛË appleúfiˆúˆó ÓÂÔÁÓÒÓ 57 (Û <37  ÔÌ Â ÙË Î ËÛË ), ÙË Á ÓÓËÛË ÂÏÏÈappleÔ ÚÒÓ ÓÂÔ- ÁÓÒÓ ( ÚÔ <2500 g) Î È ÙËÓ appleúôâîï Ì - Î È Â ÙÂ- Ú fióùˆ ÙË ÚfiÓÈ appleôêú ÎÙÈÎ appleóâ ÌÔÓÔapple ıâè / appleóâ ÌÔÓÈÎ ÓfiÛÔ, ÙËÓ appleóâ ÌÔÓ, ÙËÓ apple Û ÚÎ, ÙÔ ÌÂ- Ù ÔÏÈÎfi Û Ó ÚÔÌÔ, ÙË ÚÂ Ì ÙÔÂÈ ÚıÚ ÙÈ, ÙË Úfi- ÓÈ ÓÂÊÚÈÎ ÓfiÛÔ, ÙË ÓÔËÙÈÎ ÂÍ Ûı ÓËÛË (Û ÏÏÔÁÈÎfi fi- ÚÔ appleô appleâúèï Ì ÓÂÈ Î ıâ Ú ÎÙËÚÈÛÙÈÎfi appleô Ú ˆ ÊÚ ÁÌfi Û Πıâ ÓÔËÙÈÎ ÈÂÚÁ Û ) Î È ÙÔÓ Î ÚÎ ÓÔ 58. EÈ ÈÎfiÙÂÚ, Û ÓÔÏÈÎ Ê ÓÂÙ È fiùè ) ÂappleÈ ËÌÈÔÏÔÁÈÎ ÙÂÎÌËÚ ˆÛË appleôûùëú ÂÈ ÙË Û Û ÙÈ- ÛË ÙË appleâúèô ÔÓÙ ÙÈ Ì ÍËÌ ÓÔ Î Ó ÓÔ ÁÈ ÙËÓ - ıëúôûîïëúˆùèî Î Ú È ÁÁÂÈ Î ÓfiÛÔ 55, ÙË Á ÓÓËÛË appleúfiˆúˆó Î È ÂÏÏÈappleÔ ÚÒÓ ÓÂÔÁÓÒÓ Î È ÙËÓ appleúôâîï Ì- 57, ÂÓÒ Ë ÂappleÈ ËÌÈÔÏÔÁÈÎ ÙÂÎÌËÚ ˆÛË ÙË Û Û ÙÈÛË ÙË appleâúèô ÔÓÙ ÙÈ Ì ÙÔÓ ÁÏ Î ÈÌÈÎfi ÏÂÁ Ô, ÙÈ ÂappleÈappleÏÔÎ Î È ÙËÓ ÂÍ ÏÈÍË ÙÔ È ÙË Â Ó È appleâúèôúèûì ÓË 56, ) in vitro Ú ÓÂ, Ú Ó Û appleâèú Ì Ùfi ˆ ÎÏÈÓÈÎ Ú Ó appleôûùëú Ô Ó fiùè apple Ú Ô Ó ÈÔÏÔÁÈÎÔ ÌË ÓÈ- ÛÌÔ appleô appleèı ÓfiÓ ÂÚÌËÓÂ Ô Ó ÙË Û Û ÙÈÛË ÙË appleâúèô- ÔÓÙ ÙÈ Ì ÍËÌ ÓÔ Î Ó ÓÔ ÁÈ ıëúôûîïëúˆùèî Î Ú È ÁÁÂÈ Î ÓfiÛÔ 55, ÙÔ È ÙË 56 Î È ÙÈ ÓÂappleÈı ÌËÙ ÂÎ ÛÂÈ ÙË ÂÁÎ ÌÔÛ ÓË 57 Î È 178 elderly population, as well as the use of diverse definitions of periodontitis on the basis of probing pocket depth and alveolar bone loss 13. In the research field of Microbiology of periodontal diseases, recent studies included in the present review concluded that the frequency of colonization of periodontal pockets by certain yeasts and primarily C. albicans exhibits significant association with the severity of chronic periodontitis 20, 21. This conclusion has been supported by a preceding study 64, but not by another study 65. At this point, it should be pointed out that the documentation of a causal association between a given infectious agent and a multifactorial infectious disease, such as periodontitis, requires the fulfillment of specific criteria, such as Socranskys criteria 66 -which can be used as an alternative to Koch s postulates 67 - and therefore it cannot be performed solely on the basis of the increased frequency of colonization of periodontal pockets by microbial agents or solely on the basis of statistical associations. Although the colonization of periodontal pockets by yeasts was already known since the 1980s 16-19, it is clear that due to the limited number of existing studies, as well as due to the partial disagreement of their results, additional studies are required to draw definite conclusions. In the field of Immunology of periodontal diseases, recent studies have focused on the role of the signalling pathways of TLRs in periodontal inflammation 30, 31. Generally, in the field of biomedical research the signalling pathways of TLRs have been shown to participate in a plethora of inflammatory and immune responses and for this reason their discovery has been regarded as one of the most important discoveries in Immunology within 68, 69 the past two decades The first TLR member in humans -now known as TLR1- was described in and was mapped in , though already since 1991 it had been reported that interleukin-1 receptor exhibited similar cytoplasm domain with that of Toll receptor in Drosophila 72. In 1997, the potential of a TLR member - now known as TLR4- to induce the expression of genes that participate in adaptive immune response 73, while in the subsequent year it was reported that Tlr4 in mammals has been adapted primarily to serve the recognition of LPS of Gram-negative bacteria 74. For the latter discovery 74, as well as for the discovery that signalling pathways of Toll receptors in Drosophila significantly contribute to survival after fungal infections 75, Drs. Beutler and Hoffmann, respectively, were awarded with a Nobel Prize in These studies underscore the importance of microbial recognition by TLRs in the activation of innate immunity 76. In particular, it is now clear that TLRs are the most potent inducers of inflammatory response and that most microorganisms or microbial molecules capable of stimulating the immune system can be recognized by TLRs 68. Finally, this was the first clear case in which PRRs of innate immunity were capable of controlling the activation of adaptive immunity 68. In the field of periodontal research, the expression of TLR4 -the main receptor of the LPS of Gram-negative

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YZHTH H ÙËÓ ÂÚÁ Û Ù appleú ÁÌ ÙÔappleÔÈ ıëîâ Ó ÛÎfiappleËÛË ÙˆÓ ËÌÔÛÈ ÛÂˆÓ appleô Û ÂÙ ÔÓÙ Ó Ì ÙË B ÛÈÎ ŒÚ - Ó ÙˆÓ appleâúèô ÔÓÙÈÎÒÓ ÓÔÛËÌ ÙˆÓ Î È ËÌÔÛÈ ÙËÎ Ó ÛÙÔ ÈÂıÓ appleâúèô ÈÎfi Ù appleô Û ÔappleÔÈ appleôùâ ÁÏÒÛÛ appleúfiûê Ù, Û ÁÎÂÎÚÈÌ Ó applefi ÙËÓ 1Ë I ÓÔ Ú Ô ˆ Î È ÙËÓ 31Ë ÂÎÂÌ Ú Ô Aapplefi ÙËÓ Ó ÛÎfiappleËÛË Ù appleúôî appleùâè fiùè Ë appleïâèôófiùëù ÙˆÓ appleúfiûê ÙˆÓ ËÌÔÛÈ ÛÂˆÓ ÂÈ ÂappleÈÎÂÓÙÚˆı Π- Ú ˆ ÛÙÔ appleâ Ô ÙË ÂÚÈÔ ÔÓÙÈÎ I ÙÚÈÎ Î È ÛÙÔ appleâ Ô ÙˆÓ apple Ú ÁfiÓÙˆÓ Â apple ıâè ÙÔ ÍÂÓÈÛÙ Î È apple Ú ÁfiÓÙˆÓ ÎÈÓ ÓÔ ÙË ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ, ÂÓÒ ÌÈÎÚfiÙÂÚÔ ÚÈıÌfi ËÌÔÛÈ ÛÂˆÓ ÂÈ ÂÍÂÙ ÛÂÈ ÙË MÈÎÚÔ ÈÔÏÔÁ ÙˆÓ appleâúèô ÔÓÙÈÎÒÓ ÓÔÛËÌ ÙˆÓ, ÙËÓ ÂappleÈıÂÙÈÎ appleâúèô Ô- ÓÙ ÙÈ, Î ıò Î È ÙËÓ ÂÚÈÁÚ ÊÈÎ EappleÈ ËÌÈÔÏÔÁ Î È ÙËÓ AÓÔÛÔÏÔÁ ÙˆÓ appleâúèô ÔÓÙÈÎÒÓ ÓÔÛËÌ ÙˆÓ. E Ó È ÂÓ È Ê ÚÔÓ Ó appleú ÁÌ ÙÔappleÔÈËıÂ Ì Û ÁÎÚÈÛË ÌÂ- Ù Í ÙˆÓ Ó ˆÓ  ÔÌ ÓˆÓ appleô appleúô Î Ó applefi ÙÈ appleúfi- ÛÊ Ù Ú Ó ÙË apple ÚÔ Û Ó ÛÎfiappleËÛË Î È ÙˆÓ Â ÔÌ ÓˆÓ appleô Â Ó ËÌÔÛÈ Ù Û appleúôáâó ÛÙÂÚ - Ú ÓÂ. È apple Ú ÂÈÁÌ, Û ÛÔ Ë ÈÎ ÂappleÈ ËÌÈÔÏÔÁÈÎ - ÚÂ Ó Û appleïëı ÛÌfi ÙË ÙÚ ÙË ËÏÈÎ appleô ËÌÔÛÈ ÙË- ΠÙÔ 2013, Ë ÛÙ ÙÈÛÙÈÎ Û Û ÙÈÛË ÙÔ È ÙË ÙË Î Ú È ÁÁÂÈ Î ÓfiÛÔ Ì ÙËÓ appleâúèô ÔÓÙ ÙÈ ÂÓ ÊÙ - Û Û ÛÙ ÙÈÛÙÈÎ ÛËÌ ÓÙÈÎ Âapple appleâ (p>0.05 Û fiïâ ÙÈ ÛÙ ÙÈÛÙÈÎ ÔÎÈÌ Û Â ) 13, ÂÓÒ Û appleúôáâó ÛÙÂÚ Ú - Ó Û appleïëı ÛÌÔ ÙË ÙÚ ÙË ËÏÈÎ ÔÈ apple Ú apple Óˆ Û - Û ÂÙ ÛÂÈ ÛÙËÓ appleâú appleùˆûë ÙÔ È ÙË 59, 60 Î È ÙË Î Ú- È ÁÁÂÈ Î ÓfiÛÔ Ù Ó ÛËÌ ÓÙÈÎ. ø Î ÚÈ ıâùèî ÛËÌ ÙË appleúô Ó ÊÂÚıÂ Û ÂappleÈ ËÌÈÔÏÔÁÈÎ ÚÂ Ó ı ÌappleÔÚÔ Û Ó Ó ıâˆúëıô Ó Ë Î Ù ÁÚ Ê appleúfiûê ÙˆÓ ÂappleÈ ËÌÈÔÏÔÁÈÎÒÓ Â ÔÌ ÓˆÓ ÛÙË Ô Ë, Ë ÂÈ ÈÎ ÌÂÏ - ÙË ÙÔ appleïëı ÛÌÔ ÙË ÙÚ ÙË ËÏÈÎ, Î ıò Î È Ë Ú - ÛË È ÊÔÚÂÙÈÎÒÓ ÔÚÈÛÌÒÓ ÙË appleâúèô ÔÓÙ ÙÈ Ì ÛË ÙÔ ıô ÙˆÓ appleâúèô ÔÓÙÈÎÒÓ ı Ï ÎˆÓ Î È ÙËÓ appleòïâè ÙÔ Ê ÙÓÈ ÎÔ ÔÛÙÔ 13. ÙÔ ÂÚ ÓËÙÈÎfi appleâ Ô ÙË MÈÎÚÔ ÈÔÏÔÁ ÙˆÓ appleâúèô Ô- ÓÙÈÎÒÓ ÓÔÛËÌ ÙˆÓ, appleúfiûê Ù Ú Ó ÙË apple ÚÔ Û Ó ÛÎfiappleËÛË Î Ù ÏËÍ Ó ÛÙÔ Û Ìapple Ú ÛÌ fiùè Ë Û Ófi- ÙËÙ appleô ÎÈÛË ÙˆÓ appleâúèô ÔÓÙÈÎÒÓ ı Ï ÎˆÓ applefi ÔÚÈ- ÛÌ ÓÔ ÌÔÌ ÎËÙÂ Î È Î Ú ˆ ÙËÓ C. albicans apple - ÚÔ ÛÈ ÂÈ ÛËÌ ÓÙÈÎ Û Û ÙÈÛË Ì ÙË Ú ÙËÙ ÙË ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ 20, 21. TÔ Û Ìapple Ú ÛÌ Ùfi ÂÈ appleôûùëúè ıâ applefi Ì appleúôáâó ÛÙÂÚË ÚÂ Ó 64, ÏÏ fi È applefi Ì ÏÏË ÚÂ Ó 65. ÙÔ ÛËÌÂ Ô Ùfi appleú appleâè Ó ÂappleÈ- ÛËÌ Óı fiùè Ë ÙÂÎÌËÚ ˆÛË ÈÙÈÔÏÔÁÈÎ Û Û ÙÈÛË ÌÂ- Ù Í ÂÓfi  ÔÌ ÓÔ ÌÈÎÚÔ È ÎÔ apple Ú ÁÔÓÙ Î È Ì bacteria- has been reported since the early 2000s in cells of the periodontium, such as epithelial cells 77, fibroblasts 78 and osteoclasts 79, as well as the ability of TLR4 to recognize the LPS of the bacterium P. gingivalis 80, 81. The stimulation of TLR and TLR9 86 by virulence factors of periodontopathogenic Gram-negative bacteria has also been reported. Furthermore, it was recently reported that TLR2 and TLR4 were required for the recognition of the bacterium P. gingivalis -in a MyD88-dependent mannerand equally contributed to the induction of TNF in macrophages that was further associated with P. gingivalisinduced alveolar bone loss in vivo 87. In a recent study included in the present review, it was attempted to further investigate the role of MyD88-dependent signalling pathway in alveolar bone loss induced by the LPS of periodontopathogenic Gram-negative bacteria and, more specifically, to determine the role of specific molecules of this signalling pathway, thus its precise mechanism of action 30. In this study, it was concluded that the MyD88- dependent signalling pathway can mediate the formation (differentiation) of osteoclasts that is induced by the LPS of A. actinomycetemcomitans 30. The mechanism of this activity involves either the activation -through MyD88- dependent TNF- of the ligand of receptor activator of nuclear factor kappa beta (RANKL) and the subsequent osteoclast formation, or the restriction of the activity of factors that promote osteoblast differentiation or function, such as the transcription factor RUNX2 or the osteoblast glycoprotein osteopontin 30. Finally, the aforementioned study, to the best of our knowledge, is the first study that examines the role of MyD88-dependent signalling pathway in alveolar bone loss induced by the LPS of A. actinomycetemcomitans 30. Another recent study included in the present review, to the best of our knowledge, is the first study that examines the association between the levels of specific periodontopathogenic bacteria in the subgingival plaque and the expression -at messenger RNA level- of TLR2, TLR4 and TLR9 in tissues of patients presenting with chronic periodontitis, compared with those in periodontally healthy individuals 31. Furthermore, the mechanism of stimulation of TLRs by periodontopathogenic microorganisms in human gingival fibroblasts was investigated 31. The main conclusions of this study were that P. gingivalis can induce the expression of TLR2 and TLRT9 in chronic periodontitis and that in human gingival fibroblasts the expression of TLR2 depends on TNF, at least in part, because the influence of other factors is also plausible 31. In conclusion, it appears that although the main molecules of the signalling pathways of TLRs (MyD88-dependent or MyD88-independent signalling pathway) have been already identified, it is now considered that these signalling pathways are more complicated than what was anticipated in the early 2000s and that additional research is required both for unknown signalling molecules and for the mechanisms that regulate the aforementioned signalling pathways 68. Recent studies included in the present review, to the best 179

18 appleôï apple Ú ÁÔÓÙÈÎ ÏÔÈÌÒ Ô ÓfiÛÔ, fiappleˆ Ë appleâúèô Ô- ÓÙ ÙÈ, apple ÈÙ ÙËÓ appleï ÚˆÛË ÂÈ ÈÎÒÓ ÎÚÈÙËÚ ˆÓ, fiappleˆ Ù ÎÚÈÙ ÚÈ ÙÔ Socransky 66 -appleô ÌappleÔÚÔ Ó Ó ÚËÛÈÌÔappleÔÈËıÔ Ó ÂÓ ÏÏ ÎÙÈÎ Ó ÓÙÈ ÙˆÓ ÍÈˆÌ ÙˆÓ ÙÔ Koch 67 - Î È ÂappleÔÌ Óˆ ÂÓ ÌappleÔÚÂ Ó appleú ÁÌ ÙÔappleÔÈËı ÌfiÓÔÓ Ì ÛË ÙËÓ ÍËÌ ÓË Û ÓfiÙËÙ appleô ÎÈÛË ÙˆÓ appleâúèô Ô- ÓÙÈÎÒÓ ı Ï ÎˆÓ applefi ÌÈÎÚÔ È ÎÔ apple Ú ÁÔÓÙ ÌfiÓÔÓ Ì ÛË ÛÙ ÙÈÛÙÈÎ Û Û ÂÙ ÛÂÈ. Ú fiïôó fiùè Ë appleô ÎÈ- ÛË ÙˆÓ appleâúèô ÔÓÙÈÎÒÓ ı Ï ÎˆÓ applefi ÌÔÌ ÎËÙÂ Ù Ó ÁÓˆÛÙ Ë applefi ÙË ÂÎ ÂÙ ÙÔ , Â Ó È Û Ê fi- ÙÈ ÏfiÁˆ ÙÔ appleâúèôúèûì ÓÔ ÚÈıÌÔ ÙˆÓ apple Ú Ô ÛÒÓ Â- Ú ÓÒÓ, ÏÏ Î È ÏfiÁˆ ÙË ÌÂÚÈÎ Û ÌÊˆÓ ÙˆÓ - appleôùâïâûì ÙˆÓ ÙÔ, apple ÈÙÔ ÓÙ È ÂappleÈappleÚfiÛıÂÙ Ú - Ó ÁÈ ÙËÓ ÂÍ ÁˆÁ ÔÚÈÛÙÈÎÒÓ Û ÌappleÂÚ ÛÌ ÙˆÓ. ÙÔ appleâ Ô ÙË AÓÔÛÔÏÔÁ ÙˆÓ appleâúèô ÔÓÙÈÎÒÓ ÓÔÛËÌ - ÙˆÓ, appleúfiûê Ù Ú ÓÂ Ô Ó ÂÛÙÈ ÛÂÈ ÛÙÔ ÚfiÏÔ ÙˆÓ ÛËÌ ÙÔ ÔÙÈÎÒÓ Ô ÒÓ ÙˆÓ appleô Ô ˆÓ TLR ÛÙËÓ appleâúèô- ÔÓÙÈÎ ÊÏÂÁÌÔÓ 30, 31. ÂÓÈÎfiÙÂÚ, ÛÙÔ ÒÚÔ ÙË È ÙÚÔ- ÈÔÏÔÁÈÎ ÚÂ Ó ÂÈ ÂÈ ıâ fiùè ÔÈ ÛËÌ ÙÔ ÔÙÈÎ Ô- Ô ÙˆÓ appleô Ô ˆÓ TLR Û ÌÌÂÙ Ô Ó Û appleïëıòú ÊÏÂÁÌÔÓˆ ÒÓ Î È ÓÔÛÈ ÎÒÓ ÓÙÈ Ú ÛÂˆÓ Î È ÁÈ ÙÔ ÏfiÁÔ Ùfi Ë Ó Î Ï ÙÔ ÂÈ ıâˆúëıâ ˆ Ì applefi ÙÈ ÛËÌ ÓÙÈÎfiÙÂÚÂ Ó Î Ï ÂÈ ÛÙËÓ AÓÔÛÔÏÔÁ Î Ù ÙÈ ÙÂÏÂ Ù Â Ô ÂÎ ÂÙ Â 68, 69. O appleúòùô appleô Ô TLR ÛÙÔÓ ÓıÚˆappleÔ -Û ÌÂÚ ÁÓˆÛÙfi ˆ TLR1- appleâúè- ÁÚ ÊËΠÙÔ Î È ÚÙÔÁÚ Ê ıëîâ ÙÔ , Ó Î È Ë applefi ÙÔ 1991 Â Â Ó ÊÂÚı fiùè Ô appleô Ô ÙË ÈÓÙÂÚÏ ΠÓË -1 apple ÚÔ Û Â apple ÚfiÌÔÈÔ Î ÙÙ ÚÔappleÏ - ÛÌ ÙÈÎfi ÙÌ Ì Ì Ùfi ÙÔ appleô Ô Toll ÛÙË Drosophila 72. TÔ 1997 Ó Ê ÚıËÎÂ Ë Ó ÙfiÙËÙ Âapple ÁˆÁ applefi Ó Ó appleô Ô TLR -Û ÌÂÚ ÁÓˆÛÙfi ˆ appleô Ô TLR4- ÙË ÎÊÚ ÛË ÁÔÓÈ ˆÓ appleô Û ÌÌÂÙ Ô Ó ÛÙËÓ appleúôû ÚÌÔÛÙÈÎ / Âapple ÎÙËÙË / ÂÈ ÈÎ ÓÔÛÈ Î ÓÙ Ú - ÛË 73, ÂÓÒ ÙËÓ ÂapplefiÌÂÓË ÚÔÓÈ Ó Ê ÚıËΠfiùè Ô appleô Ô- Tlr4 ÙˆÓ ıëï ÛÙÈÎÒÓ ÂÈ appleúôû ÚÌÔÛÙÂ Î Ú ˆ ÁÈ Ó ÂÍ appleëúâùâ ÙËÓ Ó ÁÓÒÚÈÛË ÙÔ LPS ÙˆÓ ÚÓËÙÈÎÒÓ Î Ù Gram ÎÙËÚ ˆÓ 74. È ÙËÓ ÙÂÏÂ Ù Ù Ó Î - Ï Ë 74, Î ıò Î È ÁÈ ÙËÓ Ó Î Ï Ë fiùè ÔÈ ÛËÌ ÙÔ ÔÙÈ- Î Ô Ô ÙˆÓ appleô Ô ˆÓ Toll ÛÙË Drosophila ÛËÌ ÓÙÈÎ Û Ì ÏÏÔ Ó ÛÙËÓ ÂappleÈ ˆÛË ÌÂÙ applefi Ì ÎËÙÈ ÛÈÎ ÏÔÈ- ÌÒÍÂÈ 75, ÔÈ Ú. Beutler Î È Hoffmann, ÓÙ ÛÙÔÈ, ÙÈÌ - ıëî Ó ÙÔ 2011 Ì BÚ Â Ô Nobel. OÈ ÌÂÏ Ù ٠appleô- ÁÚ ÌÌ Ô Ó ÙË ÛappleÔ ÈfiÙËÙ ÙË ÌÈÎÚÔ È Î Ó ÁÓÒ- ÚÈÛË applefi ÙÔ appleô Ô Â TLR «ÛÙËÓ ÂÓÂÚÁÔappleÔ ËÛË ÙË Ê ÛÈÎ ÓÔÛ» 76. ÁÎÂÎÚÈÌ Ó, Û ÌÂÚ Â Ó È Û Ê fiùè ÔÈ appleô Ô Â TLR Â Ó È ÔÈ appleèô appleôùâïâûì ÙÈÎÔ Âapple - ÁˆÁ ÙË ÊÏÂÁÌÔÓÒ Ô ÓÙ Ú ÛË Î È fiùè Ù appleâúèû- ÛfiÙÂÚ ÌÈÎÚfi È ÌÈÎÚÔ È Î ÌfiÚÈ Ì ÙËÓ ÈÎ ÓfiÙËÙ Ó ÈÂÁ ÚÔ Ó ÙÔ ÓÔÛÈ Îfi Û ÛÙËÌ ÌappleÔÚÔ Ó Ó Ó - ÁÓˆÚÈÛÙÔ Ó applefi ÙÔ appleô Ô Â TLR 68. T ÏÔ, Ù Ó Ë appleúòùë Û Ê appleâú appleùˆûë fiappleô appleô Ô Â PRR ÙË Ê - ÛÈÎ ÓÔÛ Ù Ó ÈÎ ÓÔ Ó ÂÏ Á Ô Ó ÙËÓ ÂÓÂÚÁÔappleÔ Ë- ÛË ÙË appleúôû ÚÌÔÛÙÈÎ / Âapple ÎÙËÙË / ÂÈ ÈÎ ÓÔÛ 68. ÙÔ appleâ Ô ÙË appleâúèô ÔÓÙÈÎ Ú Ó, applefi ÙÈ Ú ÙË ÂÎ ÂÙ ÙÔ 2000 ÂÈ Ó ÊÂÚıÂ Ë ÎÊÚ ÛË ÙÔ appleô Ô TLR4 -ÙÔ Î ÚÈÔ appleô Ô ÙÔ LPS ÙˆÓ Ú- ÓËÙÈÎÒÓ Î Ù Gram ÎÙËÚ ˆÓ- Û ΠÙÙ Ú ÙÔ appleâúèô- ÔÓÙ Ô, fiappleˆ ÂappleÈıËÏÈ Î Î ÙÙ Ú 77, ÈÓÔ Ï ÛÙ 78 Î È Ô- 180 of our knowledge, reported for the first time in the literature the association of periodontitis with benign prostatic hyperplasia 33, as well as the effect of patterns of psychological attachment on periodontal status 42. Definitely, the presence of a statistical association between a factor and chronic periodontitis does not necessarily imply the presence of a causal association, because the association might also be non-causal, as reported by the great statisticians Sir Francis Galton and Karl Pearson The acceptance of a causal association between a factor and a multifactorial disease, such as chronic periodontitis, requires the fulfillment of specific criteria, such as the criteria mentioned by Sir Bradford Hill 91 or other equivalent criteria of causal association. In addition, benign prostatic hyperplasia 33 and psychological attachment patterns 42 currently are not documented risk factors for chronic periodontitis, but some early statistical indications are available for these factors. As reported in the literature, the documentation of a risk factor is a complex statistical procedure 92. Another important consideration is that cross-sectional studies provide indications for the acceptance of a factor as a potential / putative risk factor / risk indicator, while the ultimate acceptance of a factor as a risk factor additionally requires the presence of data originating from longitudinal studies 92. Since many decades ago it has been known that the fluctuations of female hormones -oestrogens / estrogens and progesterone- occurring under physiological circumstances -such as puberty 93, pregnancy 94-98, menstrual cycle 98 or menopause 99, use of hormonal contraceptives 100, or under conditions -such as hormonal disturbances 102, 103 or their therapy can affect periodontal tissues, especially in the substrate of pre-existing gingival inflammation induced by dental microbial plaque 98, 105. For example, they can influence the proportion of periodontopathogenic bacteria, such as Prevotella intermedia, in the dental microbial plaque 106, 107, angiogenesis 108, vascular / inflammatory / immune responses , connective tissue metabolism and remodelling 108, 113, salivary enzymes and redox 114 and other biological phenomena. Furthermore, from 2000s onwards, clinical studies 115, 116 have reported the effect of vitamin D on the reduction in the severity of periodontitis. These clinical findings are in agreement with those of epidemiological studies , as well as studies on the genetic polymorphisms of vitamin D receptor gene , which have been associated with the status and progression of periodontitis. In one of the aforementioned studies, a case-control study, it was concluded that vitamin D deficiency (25-hydroxyvitamin D serum levels <75 nmol/l) during pregnancy is associated with maternal periodontitis 116. Because this study 116 comprised pregnant women both in the cases group and in the control group, it did not evaluate the combined effect of female hormones and vitamin D on periodontitis. To the best of our knowledge, this combined inhibitory effect was investigated for the first time by another study of the present review 34. The biologic background of this combined effect could possibly be related to the fact that vitamin D can promote the synthesis of oestradiol /

19 ÛÙÂÔÎÏ ÛÙ 79, Î ıò Î È Ë ÈÎ ÓfiÙËÙ ÙÔ appleô Ô TLR4 Ó Ó ÁÓˆÚ ÂÈ ÙÔÓ LPS ÙÔ ÎÙËÚ Ô P. gingivalis 80, 81. H È ÁÂÚÛË ÙˆÓ appleô Ô ˆÓ TLR Î È TLR9 86 applefi ÏÔÈÌÔÁfiÓÔ apple Ú ÁÔÓÙ appleâúèô ÔÓÙÔapple ıôáfióˆó ÚÓËÙÈÎÒÓ Î Ù Gram ÎÙËÚ ˆÓ Âapple ÛË ÂÈ Ó ÊÂÚıÂ. EappleÈappleÚfiÛıÂÙ, appleúfiûê Ù Ó Ê ÚıËΠfiùè ÔÈ appleô Ô-  TLR2 Î È TLR4 Ù Ó apple Ú ÙËÙÔÈ ÁÈ ÙËÓ Ó ÁÓÒÚÈ- ÛË ÙÔ ÎÙËÚ Ô P. gingivalis -Î Ù ÙÚfiappleÔ ÂÍ ÚÙÒÌÂÓÔ applefi ÙËÓ appleúˆùâ ÓË MyD88- Î È Û ÓÂÈÛ ÊÂÚ Ó ÂÍ ÛÔ ÛÙËÓ Âapple ÁˆÁ ÙÔ apple Ú ÁÔÓÙ TNF ÛÂ Ì ÎÚÔÊ Á, appleô appleâú ÈÙ Úˆ Û Û ÂÙ ÛÙËΠ̠ÙËÓ appleòïâè Ê ÙÓÈ ÎÔ Ô- ÛÙÔ appleô Âapple ÁÂÙ È applefi ÙÔ ÎÙ ÚÈÔ P. gingivalis in vivo 87. Â Ì appleúfiûê ÙË ÚÂ Ó ÙË apple ÚÔ Û Ó ÛÎfiappleËÛË, ÂappleÈappleÚfiÛıÂÙ Î ÙÂ Ï ıë Ë appleúôûapple ıâè Ó ÈÂ- Ú ÓËı appleâú ÈÙ Úˆ Ô ÚfiÏÔ ÙË MyD88-ÂÍ ÚÙÒÌÂÓË ÛËÌ ÙÔ ÔÙÈÎ Ô Ô ÛÙËÓ appleòïâè Ê ÙÓÈ ÎÔ ÔÛÙÔ appleô Âapple ÁÂÙ È applefi ÙÔÓ LPS ÙˆÓ appleâúèô ÔÓÙÔapple ıôáfióˆó ÚÓËÙÈÎÒÓ Î Ù Gram ÎÙËÚ ˆÓ Î È ÂÈ ÈÎfiÙÂÚ Ó appleúôû ÈÔÚÈÛÙÂ Ô ÚfiÏÔ Û ÁÎÂÎÚÈÌ ÓˆÓ ÌÔÚ ˆÓ Ù ÙË ÛËÌ ÙÔ ÔÙÈÎ Ô Ô, ËÏ Ô ÎÚÈ ÌË ÓÈ- ÛÌfi Ú ÛË ÙË 30. ÙËÓ ÚÂ Ó Ù appleúô Î Â ÙÔ Û - Ìapple Ú ÛÌ fiùè Ë MyD88-ÂÍ ÚÙÒÌÂÓË ÛËÌ ÙÔ ÔÙÈÎ Ô- fi ÌappleÔÚÂ Ó ÌÂÛÔÏ Â ÛÙÔ Û ËÌ ÙÈÛÌfi ( È ÊÔÚÔappleÔ - ËÛË) ÙˆÓ ÔÛÙÂÔÎÏ ÛÙÒÓ appleô Âapple ÁÂÙ È applefi ÙÔÓ LPS ÙÔ A. actinomycetemcomitans 30. O ÌË ÓÈÛÌfi Ù ÙË Ú ÛË appleâúèï Ì ÓÂÈ Â Ù ÙËÓ ÂÓÂÚÁÔappleÔ ËÛË -Ì Ûˆ ÙÔ MyD88-ÂÍ ÚÙÒÌÂÓÔ apple Ú ÁÔÓÙ TNF- ÙÔ ÌÔÚ Ô appleô Û Ó ÂÙ È Ì ÙÔÓ appleô Ô appleô ÂÓÂÚÁÔappleÔÈ ÙÔÓ apple ÚË- ÓÈÎfi ÌÂÙ ÁÚ ÊÈÎfi apple Ú ÁÔÓÙ ÎB (ÌÔÚ Ô RANKL) Î È ÙÔÓ Âapple ÎfiÏÔ ıô Û ËÌ ÙÈÛÌfi ÙˆÓ ÔÛÙÂÔÎÏ ÛÙÒÓ,  Ù ÙÔÓ appleâúèôúèûìfi ÙË Ú ÛË apple Ú ÁfiÓÙˆÓ appleô appleúô ÁÔ Ó ÙË È ÊÔÚÔappleÔ ËÛË ÙË ÏÂÈÙÔ ÚÁ ÙˆÓ ÔÛÙÂÔ Ï ÛÙÒÓ, fiappleˆ ÙÔ ÌÂÙ ÁÚ ÊÈÎÔ apple Ú ÁÔÓÙ RUNX2 ÙË ÔÛÙÂ- Ô Ï ÛÙÈÎ ÁÏ ÎÔappleÚˆÙ ÓË ÔÛÙÂÔappleÔÓÙ ÓË 30. T ÏÔ, Ë apple Ú apple Óˆ Ú Ó, Î ı fiûôó ÁÓˆÚ Ô ÌÂ, Â Ó È Ë appleúòùë ÚÂ Ó appleô ÍÈÔÏÔÁ ÙÔ ÚfiÏÔ ÙË MyD88-ÂÍ ÚÙÒÌÂÓË ÛËÌ ÙÔ ÔÙÈÎ Ô Ô ÛÙËÓ appleòïâè ÙÔ Ê ÙÓÈ ÎÔ Ô- ÛÙÔ appleô Âapple ÁÂÙ È applefi ÙÔÓ LPS ÙÔ A. actinomycetemcomitans 30. M ÏÏË appleúfiûê ÙË ÚÂ Ó ÙË apple ÚÔ - Û Ó ÛÎfiappleËÛË, Î ı fiûôó ÁÓˆÚ Ô ÌÂ, Â Ó È Ë appleúòùë appleô ÂÍÂÙ ÂÈ ÙË Û Û ÙÈÛË ÌÂÙ Í ÙˆÓ ÂappleÈapple ˆÓ Û ÁÎÂ- ÎÚÈÌ ÓˆÓ appleâúèô ÔÓÙÔapple ıôáfióˆó ÎÙËÚ ˆÓ ÛÙËÓ appleô- Ô ÏÈÎ appleï Î Î È ÙË ÎÊÚ ÛË -ÛÙÔ Âapple appleâ Ô ÙÔ ÁÁÂ- ÏÈÔÊfiÚÔ RNA- ÙˆÓ appleô Ô ˆÓ TLR2, TLR4 Î È TLR9 Û ÈÛÙÔ ÛıÂÓÒÓ Ì ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ Ó ÓÙÈ ÈÛÙÒÓ appleâúèô ÔÓÙÈÎÒ ÁÈÒÓ ÙfiÌˆÓ 31. EappleÈappleÚfiÛıÂÙ, ÈÂÚÂ Ó - ıëîâ Î È Ô ÌË ÓÈÛÌfi È ÁÂÚÛË ÙˆÓ appleô Ô ˆÓ TLR Û ÓıÚÒappleÈÓÂ Ô ÏÈÎ ÈÓÔ Ï ÛÙ applefi appleâúèô ÔÓÙÔapple - ıôáfióô ÌÈÎÚÔÔÚÁ ÓÈÛÌÔ 31. T Î ÚÈ Û ÌappleÂÚ ÛÌ - Ù ÙË ÚÂ Ó Ù Ù Ó fiùè Ô P. gingivalis ÌappleÔÚÂ Ó Âapple ÁÂÈ ÙËÓ ÎÊÚ ÛË ÙˆÓ appleô Ô ˆÓ TLR2 Î È TLR9 ÛÙË ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ Î È fiùè ÛÙÈ ÓıÚÒappleÈÓÂ Ô ÏÈÎ È- ÓÔ Ï ÛÙÂ Ë ÎÊÚ ÛË ÙÔ appleô Ô TLR2 ÂÍ ÚÙ Ù È - applefi ÙÔÓ apple Ú ÁÔÓÙ TNF, ÙÔ Ï ÈÛÙÔÓ ÂÓ Ì ÚÂÈ, ÂappleÂÈ Ë Âapple Ú ÛË ÏÏˆÓ apple Ú ÁfiÓÙˆÓ Â Ó È Âapple ÛË appleèı Ó 31. ÌappleÂÚ ÛÌ ÙÈÎ, Ê ÓÂÙ È fiùè apple Ú fiïô appleô Ù Î ÚÈ Ìfi- ÚÈ ÙˆÓ ÛËÌ ÙÔ ÔÙÈÎÒÓ Ô ÒÓ ÙˆÓ appleô Ô ˆÓ TLR (MyD88-ÂÍ ÚÙÒÌÂÓË MyD88-ÌË ÂÍ ÚÙÒÌÂÓË ÛËÌ ÙÔ- estradiol and progesterone 123, while oestrogens / estrogens can promote the synthesis of 1,25-dihydroxyvitamin D (free in the blood circulation or total) 149, but also regulate the expression of vitamin D receptor 125. In the field of aggressive periodontitis-related research, to a certain degree skepticism / scepticism has been expressed 126 on whether this particular disease has been defined with sufficient precision in the current 46 classification of periodontal diseases and conditions. The development of Genetics from 1990s onwards has contributed novel data that could possibly be used in the future to define aggressive periodontitis more accurately. During the past two decades, increased individual susceptibility to aggressive periodontitis has been associated with many genetic polymorphisms, such as those of the interleukin- 1 gene (in combination with smoking) 127, interleukin-1 receptor antagonist gene 128, interleukin-4 gene 129, interleukin-6 receptor gene 130 and interleukin-6 promoter haplotypes 131, interleukin-12r 2 gene 132, MMP-8 gene 133, TIMP-2 gene 134, FcÁ-receptor gene 135, tissue plasminogen activator gene 136, cyclooxygenase-2 gene 137 and TLR4 gene 138. Recent studies selected in the present review 52, 53 should be classified as part of this wider effort to study aggressive periodontitis on the basis of Genetics. In the field of Periodontal Medicine, in 2013 articles were published that had been previously prepared in a workshop on periodontitis and systemic diseases jointly held by EFP and AAP in Segovia of Spain in December Previous studies from the 4th European Workshop on Periodontology (Ittingen, Switzerland, 2002) 139 and from the 6th European Workshop on Periodontology (Ittingen, Switzerland, 2008) had also accumulated the scientific evidence for the fact that periodontitis can affect cardiovascular diseases 139, 141, diabetes 142 and adverse pregnancy outcomes 143. In the joint workshop held in Segovia these issues were studied in greater detail at three diverse levels (epidemiological evidence, biological mechanisms and effect of periodontal therapy on each systematic disease or condition) and, furthermore, the existing evidence was assessed on the effect of periodontitis or periodontal therapy also on other diseases, such as chronic obstructive pulmonary disease, pneumonia, obesity, metabolic syndrome, rheumatoid arthritis, chronic kidney disease, cognitive impairment and cancer 58. Furthermore, in the same workshop the importance of using Bradford Hills criteria for causation or other equivalent criteria was discussed for the documentation of a causal association between a potential causal factor and a multifactorial disease 58, 144, 145. At present, it still remains unclear whether the aforementioned statistical associations between periodontitis and systemic conditions are causal or non-causal associations 58, 144, 145, with the exception that oral microorganisms can be causative agents of lung infections 58. Overall, it is noteworthy that there are no or too few recent studies related to the Histology of the periodontium, the Molecular and Cell Biology of the periodontium, the role of dental calculus in the aetiopathogenesis of periodontal 181

20 ÔÙÈÎ Ô fi ) Ô Ó Ë ÂÓÙÔappleÈÛÙÂ, Û ÌÂÚ ıâˆúâ Ù È fi- ÙÈ ÔÈ ÛËÌ ÙÔ ÔÙÈÎ Ù Ô Ô Â Ó È appleèô appleôï appleïôîâ - applefi fi,ùè Ó ÌÂÓfiÙ Ó ÛÙÈ Ú ÙË ÂÎ ÂÙ ÙÔ 2000 Î È fiùè apple ÈÙÂ Ù È appleâú ÈÙ Úˆ ÚÂ Ó ÙfiÛÔ ÁÈ ÁÓˆÛÙ ÛËÌ ÙÔ ÔÙÈÎ ÌfiÚÈ, fiûô Î È ÁÈ ÙÔ ÌË ÓÈÛÌÔ Ú ıìèûë ÙˆÓ apple Ú apple Óˆ ÛËÌ ÙÔ ÔÙÈÎÒÓ Ô ÒÓ 68. ÚfiÛÊ Ù Ú Ó ÙË apple ÚÔ Û Ó ÛÎfiappleËÛË, Î ı fiûôó ÁÓˆÚ Ô ÌÂ, Ó ÊÂÚ Ó ÁÈ appleúòùë ÊÔÚ ÛÙË È- ÏÈÔÁÚ Ê ÙË Û Û ÙÈÛË ÙË appleâúèô ÔÓÙ ÙÈ Ì ÙËÓ Î ÏÔ ıë appleâúappleï Û ÙÔ appleúôûù ÙË 33, Î ıò Î È ÙËÓ Â- apple Ú ÛË ÙˆÓ appleúôù appleˆó ÔÏÔÁÈÎ appleúôûîfiïïëûë ÛÙËÓ appleâúèô ÔÓÙÈÎ Î Ù ÛÙ ÛË 42. B ˆ, Ë apple ÚÍË ÛÙ ÙÈÛÙÈÎ Û Û ÙÈÛË ÌÂÙ Í ÂÓfi apple Ú ÁÔÓÙ Î È ÙË ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ ÂÓ appleô ËÏÒÓÂÈ Î Ù Ó ÁÎËÓ Î È ÙËÓ apple ÚÍË ÈÙÈÔÏÔÁÈÎ Û Û ÙÈÛË, ÈfiÙÈ Ë Û Û - ÙÈÛË ı ÌappleÔÚÔ ÛÂ Ó Â Ó È Î È ÌË ÈÙÈÔÏÔÁÈÎ, fiappleˆ Ó - ÊÂÚ Ó ÔÈ ÌÂÁ ÏÔÈ ÛÙ ÙÈÛÙÈÎÔÏfiÁÔÈ Sir Francis Galton Î È Karl Pearson H appleô Ô ÈÙÈÔÏÔÁÈÎ Û Û ÙÈÛË ÌÂÙ Í ÂÓfi apple Ú ÁÔÓÙ Î È ÂÓfi appleôï apple Ú ÁÔÓÙÈÎÔ ÓÔ- Û Ì ÙÔ, fiappleˆ Ë ÚfiÓÈ appleâúèô ÔÓÙ ÙÈ, apple ÈÙ ÙËÓ appleï ÚˆÛË ÂÈ ÈÎÒÓ ÎÚÈÙËÚ ˆÓ, fiappleˆ ÙˆÓ ÎÚÈÙËÚ ˆÓ appleô - Ó Ê ÚıËÎ Ó applefi ÙÔÓ Sir Bradford Hill 91 ÏÏˆÓ ÈÛÔ - Ó ÌˆÓ ÎÚÈÙËÚ ˆÓ ÈÙÈÔÏÔÁÈÎ Û Û ÙÈÛË. ÕÏψÛÙÂ, Ë Î ÏÔ ıë appleâúappleï Û ÙÔ appleúôûù ÙË 33 Î È Ù appleúfiù apple ÔÏÔÁÈÎ appleúôûîfiïïëûë 42 ÂÓ Â Ó È Âapple ÙÔ apple ÚfiÓÙÔ ÙÂÎÌËÚÈˆÌ ÓÔÈ apple Ú ÁÔÓÙ ÎÈÓ ÓÔ ÁÈ ÙË ÚfiÓÈ appleâúèô- ÔÓÙ ÙÈ, ÏÏ appleï apple Ú Ô Ó ÁÈ ÙÔ apple Ú ÁÔÓÙ - ÙÔ Î appleôèâ appleúòèìâ ÛÙ ÙÈÛÙÈÎ ÂÓ Â ÍÂÈ. Ÿappleˆ ÂÈ Ó ÊÂÚı ÛÙË È ÏÈÔÁÚ Ê, Ë ÙÂÎÌËÚ ˆÛË ÂÓfi apple Ú - ÁÔÓÙ ÎÈÓ ÓÔ Â Ó È appleôï appleïôîë ÛÙ ÙÈÛÙÈÎ È ÈÎ Û 92. M ÏÏË ÛËÌ ÓÙÈÎ apple Ú Ù ÚËÛË Â Ó È fiùè ÔÈ Û Á ÚÔÓÈÎ Ú Ó apple Ú Ô Ó ÂÓ Â ÍÂÈ ÁÈ ÙËÓ appleô Ô ÂÓfi apple Ú - ÁÔÓÙ ˆ «ÓËÙÈÎÔ / appleèı ÓÔ apple Ú ÁÔÓÙ ÎÈÓ ÓÔ», Â- ÓÒ Ë ÙÂÏÈÎ appleô Ô ÂÓfi apple Ú ÁÔÓÙ ˆ «apple Ú ÁÔÓÙ ÎÈÓ ÓÔ» apple ÈÙ ÂappleÈappleÚfiÛıÂÙ ÙËÓ apple ÚÍË Â ÔÌ ÓˆÓ appleô appleúô Ú ÔÓÙ È applefi È ÚÔÓÈÎ Ú Ó 92. Aapplefi appleôïï ÂÎ ÂÙ Â Ù Ó ÁÓˆÛÙfi fiùè ÔÈ È Î Ì ÓÛÂÈ ÙˆÓ ÔÚÌÔÓÒÓ ÙÔ Á Ó ÈÎÂ Ô Ê ÏÔ -ÔÈÛÙÚÔÁfiÓˆÓ Î È appleúôáâûùâúfióë - appleô apple Ú ÙËÚÔ ÓÙ È ÛÂ Ê ÛÈÔÏÔÁÈÎ Î Ù ÛÙ ÛÂÈ -fiappleˆ ÂÊË Â 93, ÂÁÎ ÌÔÛ ÓË 94-98, ÌÌËÓÔ Î ÎÏÔ 98 ÂÌÌËÓfiapple ÛË 99, Ï Ë ÓÙÈÛ ÏÏËappleÙÈÎÒÓ Ê ÚÌ - ÎˆÓ 100, Û apple ıôïôáèî Î Ù ÛÙ ÛÂÈ (fiappleˆ Û ÔÚÌÔ- ÓÈÎ È Ù Ú 102, 103 Û ıâú appleâ ÙÔ Â Ó È Ó - ÙfiÓ Ó Ô Ó Âapple Ú ÛË ÛÙÔ appleâúèô ÔÓÙÈÎÔ ÈÛÙÔ, È- È ÙÂÚ Û ÊÔ appleúô apple Ú Ô Û ÊÏÂÁÌÔÓ ÙˆÓ Ô - ÏˆÓ Âapple ÁfiÌÂÓË applefi ÙËÓ Ô ÔÓÙÈÎ ÌÈÎÚÔ È Î appleï Î 98, 105. È apple Ú ÂÈÁÌ, Â Ó È Ó ÙfiÓ Ó ÂappleËÚ ÛÔ Ó ÙËÓ - Ó ÏÔÁ ÙˆÓ appleâúèô ÔÓÙÔapple ıôáfióˆó ÎÙËÚ ˆÓ, fiappleˆ ÙË Prevotella intermedia, ÛÙËÓ Ô ÔÓÙÈÎ ÌÈÎÚÔ È Î appleï - Î 106, 107, ÙËÓ ÁÁÂÈÔÁ ÓÂÛË 108, ÙÈ ÁÁÂÈ Î / ÊÏÂÁÌÔÓÒ- ÂÈ / ÓÔÛÈ Î ÓÙÈ Ú ÛÂÈ , ÙÔ ÌÂÙ ÔÏÈÛÌfi Î È - Ó Û ËÌ ÙÈÛÌfi ÙÔ Û Ó ÂÙÈÎÔ ÈÛÙÔ 108, 113, Ù ÛÈ ÏÈÎ Ó- Ì Î È ÙÔ ÔÍÂÈ Ô Ó ÁˆÁÈÎfi Ó ÌÈÎfi 114 Î È ÏÏ ÈÔÏÔ- ÁÈÎ Ê ÈÓfiÌÂÓ. EappleÈappleÚfiÛıÂÙ, applefi ÙË ÂÎ ÂÙ ÙÔ 2000 Î È ÌÂÙ ÎÏÈÓÈÎ Ú Ó 115, 116 Ô Ó Ó Ê ÚÂÈ ÙËÓ Âapple - Ú ÛË ÙË ÈÙ Ì ÓË D ÛÙËÓ ÂÏ ÙÙˆÛË ÙË Ú ÙËÙ ÙË appleâúèô ÔÓÙ ÙÈ. T ÎÏÈÓÈÎ Ù Â Ú Ì Ù Û Ìʈ- ÓÔ Ó ÌÂ Â Ú Ì Ù ÂappleÈ ËÌÈÔÏÔÁÈÎÒÓ ÂÚ ÓÒÓ , Î ıò 182 diseases, the various forms of plaque-induced gingival diseases (especially necrotizing ulcerative gingivitis), necrotizing periodontal disease, the periodontal abscess, trauma from occlusion, as well as Basic Research issues concerning the relation of Periodontology to other specialties (Endodontology / Endodontics, Orthodontics and others). These Basic Research topics were researched in the past and certainly might once more come to the fore. Finally, it should be noted that studies performed using very advanced methods of Molecular Biology, Genetics, Biotechnology and Bioinformatics, such as methods of genomics 146, 147, proteomics 148 and other pertinent advanced methods, have not been included in the present review. These methods are widely used in the entire spectrum of research (Basic, Translational and Applied Research). Because the presentation of the above-mentioned methods would necessitate an extensive and detailed analysis, it was deemed preferable to present them in a special independent review in the future. CONCLUSIONS On the basis of the preceding literature review the following main conclusions can be drawn: ñ The majority of recent articles has primarily centered on the field of Periodontal Medicine and on the field of host susceptibility factors and risk factors for chronic periodontitis. ñ In Microbiology of periodontal diseases, recent studies have supported the statistical, not necessarily causal, association of yeasts and mainly Candida albicans with periodontal diseases. ñ In Immunology of periodontal diseases, recent studies have centered on the investigation of the role of Tolllike receptor (TLR) signalling pathways in the pathogenic mechanism of periodontal diseases. ñ Factors that might have the potential to be documented as risk factors for chronic periodontitis and were recently studied included benign prostatic hyperplasia, the combined inhibitory effect of female sex hormones and vitamin D on chronic periodontitis, as well as the effect of patterns of psychological attachment on periodontal status. ñ Genetic research of periodontal diseases has focused on the identification of numerous genes and gene polymorphisms, particularly those related to the immune pathogenic mechanism of chronic periodontitis or other forms of periodontal disease, such as polymorphisms of genes encoding interleukins, tumour necrosis factor or its receptors, immunoglobulin receptors, metalloproteinases or their tissue inhibitors, and other molecules. ñ Recent studies have focused on the genetic background of aggressive periodontitis. ñ In the field of Periodontal Medicine, periodontitis has been statistically and biologically associated, with