**The University of Western Australia** Periodontal Medicine  Dr Pradeep Koppolu, Associate Professor Leticia A Miranda Dr Pradeep Koppolu, Associate Professor Leticia A Miranda The University of Western Australia logo featuring a shield with blue and yellow elements, a swan symbol, and the text 'SEEK WISDOM' along with the full university name. **Reading Resources** **Clinical Periodontology and Implant Dentistry, 2 Volume Set** by Niklaus P. Lang, , Jan Lindhe, , and Niklaus P Lang PUBLISHER John Wiley & Sons, Incorporated DATE 2015-03-25 **CHAPTER 26** **Impact of Periodontal Infection on Systemic Health** Brian L. Mealey | Perry R. Klokkevold | Yvonne L. Hernandez-Kapila For online-only content on periodontal disease and pregnancy outcome, periodontal disease and chronic obstructive pulmonary disease, and periodontal disease and acute respiratory infections, please visit the companion website at eBooks.Health.Elsevier.com. **JDR Centennial Series** **Periodontal Medicine: 100 Years of Progress** J.D. Beck¹ , P.N. Papapanou², K.H. Philips³, and S. Offenbacher¹   **Clinical Periodontology and Implant Dentistry, 2 Volume Set** by Niklaus P. Lang, Jan Lindhe, and Niklaus P Lang PUBLISHER John Wiley & Sons, Incorporated DATE 2015-03-25 **CHAPTER 26** **Impact of Periodontal Infection on Systemic Health** Brian L. Mealey | Perry R. Klokkevold | Yvonne L. Hernandez-Kapila For online-only content on periodontal disease and pregnancy outcome, periodontal disease and chronic obstructive pulmonary disease, and periodontal disease and acute respiratory infections, please visit the companion website at eBooks.Health.Elsevier.com. **JDR Centennial Series** **Periodontal Medicine: 100 Years of Progress** J.D. Beck¹ , P.N. Papapanou², K.H. Philips³, and S. Offenbacher¹ Book cover image for 'Clinical Periodontology and Implant Dentistry', showing a figure in periodontal attire. Header banner for Chapter 26 titled 'Impact of Periodontal Infection on Systemic Health' with authors Brian L. Mealey, Perry R. Klokkevold, and Yvonne L. Hernandez-Kapila listed below. # Association of oral and general health – a new paradigm? **“You cannot have good general health without good oral health”**. Seymour 2007 **“Our mouth is connected to our whole body !!!”** **“The mouth is the window to general health”** Alpert 2017 **“Care of the mouth should be an integral part of overall medical care”**. Migliorati & Madrid 2007   "You cannot have good general health without good oral health". Seymour 2007 "Our mouth is connected to our whole body !!!" "The mouth is the window to general health" Alpert 2017 "Care of the mouth should be an integral part of overall medical care". Migliorati & Madrid 2007 Photo of a red and white plastic dental model showing teeth and gums, representing oral health. Medical diagram series illustrating human anatomy. It shows five figures from front view: respiratory system, skeletal system, muscular system, digestive system, and circulatory system. This visual supports the slide's theme connecting oral health to general body systems. **Association of oral and general health – a new paradigm?** SYSTEMIC DISEASES → PERIODONTITIS More than a 100 systemic diseases and 500 medications have oral manifestations. Kane, 2017 SYSTEMIC DISEASES ← PERIODONTITIS  SYSTEMIC DISEASES → PERIODONTITIS More than a 100 systemic diseases and 500 medications have oral manifestations. Kane, 2017 SYSTEMIC DISEASES ← PERIODONTITIS Medical diagram illustrating the connection between oral health and systemic conditions. The image features a central illustration of a tooth with inflamed gums and periodontal pockets. A dotted line extends from the tooth to icons representing various organs (heart, lungs, stomach, etc.), visually demonstrating that 'Periodontal disease can cause tooth loss and affect the rest of the body'. The EFP logo is present in the top left corner. **Association of oral and general health – a new paradigm?** # This is not new... **300 aC** - **Hippocrates** reportedly cured systemic conditions by pulling out infected teeth. **1900** – **Dr Hunter** and **Dr Miller** – “focal infection” theory Clinical experience and case reports No systemic disease resolution after complete extractions **1989** - **Mattila and coworkers** Evidence from well designed epidemiological studies began to emerge of possible linkages between poor oral health and atherosclerotic CVD **1997** – **Chapel Hill symposium** - Emergence of Periodontal Medicine **2012** - **EFP/AAP** – Periodontitis and Systemic diseases – EPF Manifesto **300 aC** – **Hippocrates** reportedly cured systemic conditions by pulling out infected teeth. **1900** – **Dr Hunter** and **Dr Miller** – "focal infection" theory - Clinical experience and case reports - No systemic disease resolution after complete extractions **1989** – **Mattila and coworkers** - Evidence from well designed epidemiological studies began to emerge of possible linkages between poor oral health and atherosclerotic CVD **1997** – **Chapel Hill symposium** – Emergence of Periodontal Medicine **2012** – **EFP/AAP** – Periodontitis and Systemic diseases – EPF Manifesto University logo for The University of Western Australia. **Periodontal Medicine** Periodontal medicine is a collective term commonly used to describe how periodontal infection/inflammation may affect extraoral health. Periodontal medicine is a collective term commonly used to describe how periodontal infection/inflammation may affect extraoral health. The University of Western Australia logo featuring the university crest and name. Association of oral and general health – a new paradigm? **Since then, an exponential rise in the number of studies investigating links between periodontal diseases and many diseases:** **Cardiovascular diseases** **Diabetes** **Adverse pregnancy outcomes** **Respiratory diseases** **Kidney diseases** **Rheumatoid arthritis and other autoimmune diseases** **Obesity** **Cognitive impairments** **Alzheimer** **Cancer** Winning & Linden 2015  Since then, an exponential rise in the number of studies investigating links between periodontal diseases and many diseases: - Cardiovascular diseases - Diabetes - Adverse pregnancy outcomes - Respiratory diseases - Kidney diseases - Rheumatoid arthritis and other autoimmune diseases - Obesity - Cognitive impairments - Alzheimer - Cancer Winning & Linden 2015 Circular diagram showing 'Chronic Periodontitis' in the center surrounded by bubbles representing associated systemic diseases: Atherosclerotic Cardiovascular Disease, Diabetes, Adverse Pregnancy Outcome, Respiratory disease, Chronic kidney disease, Rheumatoid arthritis, Cognitive impairment, Obesity, Metabolic syndrome, and Cancer. Arrows indicate bidirectional relationships between periodontitis and these conditions. # Association of oral and general health – a new paradigm? ## Gum Disease & Your Whole Body Health Over 50% of adults in the U.S. have some degree of gum disease. But did you know the impact goes far beyond your mouth... | Condition | Risk Association | | :--- | :--- | | **Osteoporosis** | People with gum disease may be at a higher risk of osteoporosis. | | **Stroke** | People with severe gum disease have a 3x to 4x higher risk of brain stroke. | | **Alzheimer's & Dementia** | Gum disease may be linked to Alzheimer's disease and dementia from oral bacteria that spread through the bloodstream. | | **Cancer** | Several studies show strong evidence linking gum disease with an increased risk of oral cancer and pancreatic cancer. | | **Respiratory Disease** | Gum disease can worsen conditions such as COPD and may play a role in the contraction of pneumonia, bronchitis & emphysema. | | **Heart Disease** | People with gum disease are 2x as likely to have heart disease. | | **Diabetes** | Nearly 22% of diabetes patients have gum disease. | | **Rheumatoid Arthritis** | RA patients are 8x more likely to have gum disease. | ### Statistically, gum disease is higher in men (56.4%) than in women (38.4%). **MEN** * **Impotence:** Men in their 30s with severe gum disease are 3x more likely to suffer from erectile dysfunction. Prolonged chronic inflammation associated with gum disease can damage blood vessels leading to impotence. * **Prostate Health:** Studies show that the prostate-specific antigen (PSA), an enzyme created in the prostate that is normally secreted in very small amounts, is secreted at higher levels in men with gum disease and prostate cancer. * **Cancer in Men:** Research has found that men with a history of gum disease are 14% more likely to develop cancer than men with healthy gums. Men with gum disease may be 49% more likely than women to develop kidney cancer, 54% more likely to develop pancreatic cancer, and 30% more likely to develop blood cancers. **WOMEN** * **Puberty & Menstruation:** An increased level of sex hormones causes higher blood circulation to the gums, increasing the gum's sensitivity, susceptibility to irritation, and the growth of bacteria just beneath the gums. These same hormones can cause menstruation gingivitis – red, swollen, tender or bleeding gums, and sores on the inside of the cheek – which typically occurs right before a woman's period and clears up once it has started. * **Pregnancy & Preterm Births:** Pregnant women with untreated gum disease may be more likely to have a preterm baby. * **Menopause & Post-Menopause:** Women may experience changes in their mouths, including discomfort in the mouth, dry mouth, pain and burning sensations in the gum tissue, and altered taste. In addition, post-menopausal women with osteoporosis are 86% more likely to develop gum disease, while women with gum disease have a higher risk of having osteoporosis. --- ## WHAT PROBLEMS COULD POOR DENTAL HEALTH CAUSE? ```mermaid graph TD A[POOR DENTAL HEALTH] --> B(STROKES) A --> C(HEART DISEASE) A --> D(MOUTH CANCER) A --> E(DIABETES) A --> F(GUM DISEASE) A --> G(TOOTH LOSS) A --> H(BAD BREATH) A --> I(DENTAL DECAY) A --> J(LUNG CONDITIONS) ```   Over 50% of adults in the U.S. have some degree of gum disease. But did you know the impact goes far beyond your mouth... | Condition | Risk Association | | :--- | :--- | | **Osteoporosis** | People with gum disease may be at a higher risk of osteoporosis. | | **Stroke** | People with severe gum disease have a 3x to 4x higher risk of brain stroke. | | **Alzheimer's & Dementia** | Gum disease may be linked to Alzheimer's disease and dementia from oral bacteria that spread through the bloodstream. | | **Cancer** | Several studies show strong evidence linking gum disease with an increased risk of oral cancer and pancreatic cancer. | | **Respiratory Disease** | Gum disease can worsen conditions such as COPD and may play a role in the contraction of pneumonia, bronchitis & emphysema. | | **Heart Disease** | People with gum disease are 2x as likely to have heart disease. | | **Diabetes** | Nearly 22% of diabetes patients have gum disease. | | **Rheumatoid Arthritis** | RA patients are 8x more likely to have gum disease. | Statistically, gum disease is higher in men (56.4%) than in women (38.4%). **MEN** - **Impotence:** Men in their 30s with severe gum disease are 3x more likely to suffer from erectile dysfunction. Prolonged chronic inflammation associated with gum disease can damage blood vessels leading to impotence. - **Prostate Health:** Studies show that the prostate-specific antigen (PSA), an enzyme created in the prostate that is normally secreted in very small amounts, is secreted at higher levels in men with gum disease and prostate cancer. - **Cancer in Men:** Research has found that men with a history of gum disease are 14% more likely to develop cancer than men with healthy gums. Men with gum disease may be 49% more likely than women to develop kidney cancer, 54% more likely to develop pancreatic cancer, and 30% more likely to develop blood cancers. **WOMEN** - **Puberty & Menstruation:** An increased level of sex hormones causes higher blood circulation to the gums, increasing the gum's sensitivity, susceptibility to irritation, and the growth of bacteria just beneath the gums. These same hormones can cause menstruation gingivitis – red, swollen, tender or bleeding gums, and sores on the inside of the cheek – which typically occurs right before a woman's period and clears up once it has started. - **Pregnancy & Preterm Births:** Pregnant women with untreated gum disease may be more likely to have a preterm baby. - **Menopause & Post-Menopause:** Women may experience changes in their mouths, including discomfort in the mouth, dry mouth, pain and burning sensations in the gum tissue, and altered taste. In addition, post-menopausal women with osteoporosis are 86% more likely to develop gum disease, while women with gum disease have a higher risk of having osteoporosis. **WHAT PROBLEMS COULD POOR DENTAL HEALTH CAUSE?** POOR DENTAL HEALTH → STROKES, HEART DISEASE, MOUTH CANCER, DIABETES, GUM DISEASE, TOOTH LOSS, BAD BREATH, DENTAL DECAY, LUNG CONDITIONS Infographic titled 'Gum Disease & Your Whole Body Health' showing connections between gum disease and various systemic conditions. The diagram includes icons for Osteoporosis (bone with cracks), Stroke (brain with red swirls), Alzheimer's & Dementia (brain with question marks), Cancer (stomach/kidney illustration), Respiratory Disease (lungs/airways), Heart Disease (heart with X), Diabetes (sugar cubes/syrup), and Rheumatoid Arthritis (hand/wrist). Below these are two text boxes labeled 'MEN' and 'WOMEN' detailing gender-specific risks such as impotence, prostate health, cancer in men, puberty/menstruation issues, preterm births, and menopause effects. Circular diagram from British Dental Health Foundation titled 'WHAT PROBLEMS COULD POOR DENTAL HEALTH CAUSE?'. A central tooth icon is surrounded by connected circles representing: HEART DISEASE, STROKES, MOUTH CANCER, DIABETES, GUM DISEASE, TOOTH LOSS, BAD BREATH, DENTAL DECAY, and LUNG CONDITIONS. Each circle contains an illustrative icon (e.g., heart, brain, ribbon, lungs). **Box 26.1 Organ Systems and Conditions Possibly Influenced by Periodontal Infection** **Cardiovascular and Cerebrovascular Systems** Atherosclerosis Coronary heart disease Angina Myocardial infarction Cerebrovascular accident (stroke) Erectile dysfunction Anemia **Endocrine System** **Metabolic syndrome** Diabetes mellitus **Reproductive System** Preterm and low-birth-weight infants Preeclampsia **Respiratory System** Chronic obstructive pulmonary disease Acute bacterial pneumonia **Kidney Diseases** Renal insufficiency Chronic kidney disease End-stage kidney disease **Autoimmune Diseases** Rheumatoid arthritis Ankylosing spondylitis **Cognitive Function** Dementia Alzheimer disease **Cancers** Colorectal Pancreatic Hepatocellular Others  **Organ Systems and Conditions Possibly Influenced by Periodontal Infection** **Cardiovascular and Cerebrovascular Systems** - Atherosclerosis - Coronary heart disease - Angina - Myocardial infarction - Cerebrovascular accident (stroke) - Erectile dysfunction - Anemia **Endocrine System** - Metabolic syndrome - Diabetes mellitus **Reproductive System** - Preterm and low-birth-weight infants - Preeclampsia **Respiratory System** - Chronic obstructive pulmonary disease - Acute bacterial pneumonia **Kidney Diseases** - Renal insufficiency - Chronic kidney disease - End-stage kidney disease **Autoimmune Diseases** - Rheumatoid arthritis - Ankylosing spondylitis **Cognitive Function** - Dementia - Alzheimer disease **Cancers** - Colorectal - Pancreatic - Hepatocellular - Others Table listing organ systems and conditions possibly influenced by periodontal infection, categorized into: Cardiovascular and Cerebrovascular Systems (Atherosclerosis, Coronary heart disease, Angina, Myocardial infarction, Cerebrovascular accident (stroke), Erectile dysfunction, Anemia); Endocrine System (Metabolic syndrome, Diabetes mellitus); Reproductive System (Preterm and low-birth-weight infants, Preeclampsia); Respiratory System (Chronic obstructive pulmonary disease, Acute bacterial pneumonia); Kidney Diseases (Renal insufficiency, Chronic kidney disease, End-stage kidney disease); Autoimmune Diseases (Rheumatoid arthritis, Ankylosing spondylitis); Cognitive Function (Dementia, Alzheimer disease); and Cancers (Colorectal, Pancreatic, Hepatocellular, Others). **THE UNIVERSITY OF** **WESTERN AUSTRALIA** Eubiotic Oral Microbiome AMP Mucosal Barrier Oral Mucosae Tissue Neutrophil Dysbiotic Oral Microbiome Inflammation Ulceration and precancerous lesions Increased Tumor Aggressiveness **Epithelial Barrier Dysfunction** *T. denticola* Tight Junction **Chronic Inflammation** *P. gingivalis* Cytokine Neutrophil Macrophage **Genetic Damage** *S. gordonii* Reactive Oxygen Species **Epigenetic Modulation** *T. denticola* Histone **TLR2-Integrin Crosstalk** *T. denticola* TLR2 MyD88 Integrin FAK Crosstalk **Fig. 26.1** Mechanisms of oral microbiome dysbiosis that promote carcinogenesis. Epithelial barrier disruption, bacterial invasion, chronic inflammation, genetic and epigenetic modulation, and altered tumor cell migration and signaling are mechanisms by which an oral microbiome dysbiosis can promote carcinogenesis.  **Mechanisms of oral microbiome dysbiosis that promote carcinogenesis.** - **Epithelial Barrier Dysfunction** – *T. denticola* – Tight Junction - **Chronic Inflammation** – *P. gingivalis* – Cytokine, Neutrophil, Macrophage - **Genetic Damage** – *S. gordonii* – Reactive Oxygen Species - **Epigenetic Modulation** – *T. denticola* – Histone - **TLR2-Integrin Crosstalk** – *T. denticola* – TLR2, MyD88, Integrin, FAK, Crosstalk Epithelial barrier disruption, bacterial invasion, chronic inflammation, genetic and epigenetic modulation, and altered tumor cell migration and signaling are mechanisms by which an oral microbiome dysbiosis can promote carcinogenesis. Labelled diagram: A schematic illustrating the progression from a healthy 'Eubiotic Oral Microbiome' to 'Increased Tumor Aggressiveness'. The left column depicts the tissue changes: starting with intact mucosa, progressing to 'Dysbiotic Oral Microbiome' and 'Inflammation', then 'Ulceration and precancerous lesions', and finally a large malignant tumor mass. Arrows connect these stages to five specific mechanisms on the right: 'Epithelial Barrier Dysfunction' (showing *T. denticola* disrupting tight junctions), 'Chronic Inflammation' (showing *P. gingivalis*, cytokines, neutrophils, and macrophages), 'Genetic Damage' (showing *S. gordonii* and Reactive Oxygen Species damaging DNA), 'Epigenetic Modulation' (showing *T. denticola* affecting histones), and 'TLR2-Integrin Crosstalk' (showing *T. denticola* activating TLR2, MyD88, Integrin, and FAK pathways). **Conclusions**: Periodontal medicine now constitutes an important part of clinical periodontal research. Research activity in periodontal medicine has grown continuously since the early 2000s, and exploration of registers gives a useful up-to-date snapshot of this constantly evolving field of research  **Conclusions**: Periodontal medicine now constitutes an important part of clinical periodontal research. Research activity in periodontal medicine has grown continuously since the early 2000s, and exploration of registers gives a useful up-to-date snapshot of this constantly evolving field of research. A phylogenetic-like circular diagram illustrating systemic conditions hypothesized to be related to periodontal diseases. The center represents the root of the MeSH classification hierarchy, with branches radiating outward to specific conditions such as Cardiovascular Diseases, Nutritional & Metabolic Diseases, Musculoskeletal Diseases, Respiratory Tract Diseases, Female Urogenital Diseases & Pregnancy Complications, Male Urogenital Diseases, Pathological Conditions/Signs & Symptoms, Neoplasms, Bacterial Infections & Mycoses, Virus Diseases, Digestive System Diseases, Nervous System Diseases, Reproductive & Urinary Physiological Phenomena, Hemic & Lymphatic Diseases, Skin & Connective Tissue Diseases, Immune System Diseases, Physiological Phenomena, and Immune System Phenomena. Each branch terminates in a two-colored rectangular bar (red for category A, grey for B1+B2), where the length is proportional to the number of registered studies. **THE UNIVERSITY OF WESTERN AUSTRALIA** The EFP MANIFESTO: Perio and General Health The EFP MANIFESTO – Perio and General Health – is a call to action in terms of prevention, early detection and treatment of periodontitis. It is the first formal declaration in international dentistry to condense years of research into the links between periodontal disease and systemic illnesses into an acknowledgement of periodontitis as a major public health issue. This MANIFESTO calls upon all dental and health professionals to act in the prevention, early diagnosis, and effective treatment of periodontal disease in order to combat the devastating oral and general health effects for the individual and society. The views and intentions herein expressed are informed by the rigorous scientific analysis of the evidence base for reported links between periodontal and systemic diseases, as carried out at the 9th European Workshop in Periodontology, an event jointly organised by the European Federation of Periodontology and the American Academy of Periodontology, and held at La Granja de San Ildefonso, Segovia, Spain. Consensus was reached by the experts at this meeting (in November 2012) that periodontal disease should be acknowledged as a major public health issue, that all dental and medical professionals should be provided with relevant treatment guidelines, and that recommendations be given for future research to help clarify these associations and their consequences in terms of primary prevention. The EFP MANIFESTO: Perio and General Health The EFP MANIFESTO – Perio and General Health – is a call to action in terms of prevention, early detection and treatment of periodontitis. It is the first formal declaration in international dentistry to condense years of research into the links between periodontal disease and systemic illnesses into an acknowledgement of periodontitis as a major public health issue. This MANIFESTO calls upon all dental and health professionals to act in the prevention, early diagnosis, and effective treatment of periodontal disease in order to combat the devastating oral and general health effects for the individual and society. The views and intentions herein expressed are informed by the rigorous scientific analysis of the evidence base for reported links between periodontal and systemic diseases, as carried out at the 9th European Workshop in Periodontology, an event jointly organised by the European Federation of Periodontology and the American Academy of Periodontology, and held at La Granja de San Ildefonso, Segovia, Spain. Consensus was reached by the experts at this meeting (in November 2012) that periodontal disease should be acknowledged as a major public health issue, that all dental and medical professionals should be provided with relevant treatment guidelines, and that recommendations be given for future research to help clarify these associations and their consequences in terms of primary prevention. The University of Western Australia institutional logo featuring a shield with a swan and the motto 'Seek Wisdom'. A composite graphic containing the EFP (European Federation of Periodontology) logo and the International Diabetes Federation logo. Event branding for the Perio & Cardio Workshop held in Madrid, 2019, displaying logos for EFP and the World Heart Federation. # How periodontitis and peri-implantitis can systemically affect individuals?!? **The University of Western Australia** ## Possible pathways **Direct mechanism** * Direct infection by periodontal bacteria through ulcerated pocket epithelium and bloodstream **Indirect mechanism** * Systemic inflammation model Inflammatory response to periodontal infection has systemic effects Inflammation itself is involved in the pathogenesis of many chronic illnesses Seymour 2007; Linden 2015, Falcao & Bullon 2019 **Possible pathways** **Direct mechanism** - Direct infection by periodontal bacteria through ulcerated pocket epithelium and bloodstream **Indirect mechanism** - Systemic inflammation model - Inflammatory response to periodontal infection has systemic effects - Inflammation itself is involved in the pathogenesis of many chronic illnesses Seymour 2007; Linden 2015, Falcao & Bullon 2019 University of Western Australia logo located in the top right corner. How periodontitis and peri-implantitis can systemically affect individuals?!? **Possible pathways** - periodontitis: infected or ulcerated gingiva and bone resorption - worsening of periodontal disease - limited systemic response: - TNF, IL-1β, IL-6 - CRP - Fibrinogen - Serum amyloid A - systemic inflammation: - bacteria from the gums enter the bloodstream - bacteria seed to multiple organs: - heart: either via the blood or directly from the gums. - liver: via the bloodstream or directly from the gums. - gut: via swallowing bacteria or directly from the gums. - brain: directly from the gums. - kidney: via the bloodstream. - placenta: via the bloodstream. - bone: via the bloodstream. - adipose tissue: via the bloodstream. - pancreas: via the bloodstream. - lungs: via the bloodstream. - testis: via the bloodstream. - dysbiosis - bacteria from the gums disrupt the balance of the gut microbiome - endotoxemia - bacteria enter the bloodstream, causing a systemic inflammatory response - acute-phase response - systemic inflammation leads to the production of acute-phase proteins - inflammation-induced pregnancy complications - systemic inflammation during pregnancy can lead to complications such as preterm birth, low birth weight, and preeclampsia. **Sources:** - Hajishengallis, Z. (2015). Theoretical impetus for the association between periodontitis and cardiovascular disease. *Nature Reviews Immunology*, 15(6), 377-382. - Hajishengallis, Z., & Chavakis, T. (2011). Ancestral insights into the pathogenicity of periodontal bacteria. *Nature Reviews Immunology*, 11(5), 327-336.  **Possible pathways** - periodontitis: infected or ulcerated gingiva and bone resorption - worsening of periodontal disease - limited systemic response: - TNF, IL-1β, IL-6 - CRP - Fibrinogen - Serum amyloid A - systemic inflammation: - bacteria from the gums enter the bloodstream - bacteria seed to multiple organs: - heart: either via the blood or directly from the gums. - liver: via the bloodstream or directly from the gums. - gut: via swallowing bacteria or directly from the gums. - brain: directly from the gums. - kidney: via the bloodstream. - placenta: via the bloodstream. - bone: via the bloodstream. - adipose tissue: via the bloodstream. - pancreas: via the bloodstream. - lungs: via the bloodstream. - testis: via the bloodstream. - dysbiosis - bacteria from the gums disrupt the balance of the gut microbiome - endotoxemia - bacteria enter the bloodstream, causing a systemic inflammatory response - acute-phase response - systemic inflammation leads to the production of acute-phase proteins - inflammation-induced pregnancy complications - systemic inflammation during pregnancy can lead to complications such as preterm birth, low birth weight, and preeclampsia. **Sources:** - Hajishengallis, Z. (2015). Theoretical impetus for the association between periodontitis and cardiovascular disease. *Nature Reviews Immunology*, 15(6), 377-382. - Hajishengallis, Z., & Chavakis, T. (2011). Ancestral insights into the pathogenicity of periodontal bacteria. *Nature Reviews Immunology*, 11(5), 327-336. A labelled diagram illustrating the systemic pathways of periodontitis. On the left is a cross-section of a tooth showing 'Biofilm' on the gum line and 'Periodontitis (Inflamed or ulcerated gingiva and bone resorption)' at the root. Arrows indicate pathways for 'Systemic bacterial dissemination', 'Systemic inflammation', 'Swallowing', and 'Dysbiosis'. These connect to central nodes: 'TNF, IL-1β and IL-6', 'Endotoxaemia', and 'Acute-phase response'. The diagram shows these factors affecting the 'Liver' (producing CRP, Fibrinogen, Serum amyloid A), 'Heart' (Promotion of atherosclerosis), and 'Gut'. An arrow from the liver points to an illustration of a fetus in utero with placental inflammation, labeled 'Inflammation-induced pregnancy complications'. Source credit 'Nature Reviews | Immunology' is visible. **THE UNIVERSITY OF WESTERN AUSTRALIA** **CHRONIC** **ACUTE** | **Chronic: Atherosclerosis** | **Acute: Thromboembolism** | | :--- | :--- | | ↓ | ↓ | | **Narrowing of coronary arteries** | **Occlusion of coronary arteries** | | ↓ | ↘ | | | **Myocardial ischemia** | | ↙ | ↓ | | **Angina<br>Myocardial infarction** | | **Fig. 26.2** Acute and chronic pathways to ischemic heart disease. Coronary heart disease–related events, such as angina and myocardial infarction, may be precipitated by either pathway or both pathways. **FACTOR: AFFECTS BLOOD VISCOSITY** * Plasma fibrinogen * Plasma lipoproteins (LDL/VLDL) * White blood cell count **Fig. 26.3** Factors that affect blood viscosity in health. *LDL*, Low-density lipoprotein; *VLDL*, very-low-density lipoprotein. **↓** **BLOOD VISCOSITY** **↑** **BLOOD VISCOSITY** **↑ Ischemic heart disease** **Fig. 26.4** The effect of infection on blood viscosity. Increased plasma fibrinogen and von Willebrand factor cause hypercoagulability. When they are combined with an increased white blood cell count, the blood viscosity increases, thereby increasing the risk of coronary ischemia.    **CHRONIC** | **ACUTE** :--- | :--- **Chronic: Atherosclerosis** | **Acute: Thromboembolism** ↓ | ↓ **Narrowing of coronary arteries** | **Occlusion of coronary arteries** ↓ | ↘ | **Myocardial ischemia** ↙ | ↓ **Angina<br>Myocardial infarction** | **Fig. 26.2** Acute and chronic pathways to ischemic heart disease. Coronary heart disease–related events, such as angina and myocardial infarction, may be precipitated by either pathway or both pathways. **FACTOR: AFFECTS BLOOD VISCOSITY** - Plasma fibrinogen - Plasma lipoproteins (LDL/VLDL) - White blood cell count **Fig. 26.3** Factors that affect blood viscosity in health. *LDL*, Low-density lipoprotein; *VLDL*, very-low-density lipoprotein. ↓ **BLOOD VISCOSITY** ↑ ↑ **Ischemic heart disease** **Fig. 26.4** The effect of infection on blood viscosity. Increased plasma fibrinogen and von Willebrand factor cause hypercoagulability. When they are combined with an increased white blood cell count, the blood viscosity increases, thereby increasing the risk of coronary ischemia. Flowchart diagram illustrating the acute and chronic pathways to ischemic heart disease (CHD). The diagram starts with 'Coronary heart disease (CHD) risk factors' at the top, branching into two main pathways: 'Chronic' leading to 'Atherosclerosis', then 'Narrowing of coronary arteries', then 'Myocardial ischemia', and finally 'Angina / Myocardial infarction'; and 'Acute' leading to 'Thromboembolism', then 'Occlusion of coronary arteries', which also leads to 'Myocardial ischemia'. Both pathways converge before reaching the final outcomes. Simple flowchart diagram showing factors affecting blood viscosity in health. A box lists three bullet points: 'Plasma fibrinogen', 'Plasma lipoproteins (LDL/VLDL)', and 'White blood cell count'. An arrow points downward from this list to a box labeled 'Blood viscosity'. Flowchart diagram illustrating the effect of infection on blood viscosity and subsequent ischemic heart disease. It begins with 'Systemic or periodontal infection', leading to a box listing increased levels of 'Fibrinogen', 'White blood cell count', and 'von Willebrand factor' (each marked with an upward arrow). This leads to a box labeled '↑ Blood viscosity', which in turn leads to 'Ischemic heart disease'. **Direct mechanism** • Direct infection by periodontal bacteria through ulcerated pocket epithelium and bloodstream • Ulcerated pocket epithelium allows bacteria entrance • Bacteremia is common after periodontal examination (Daly et al 2001) • Bacterial byproducts, such as LPS, also disseminate in the bloodstream (Gentx 2002) The University of Western Australia - Direct infection by periodontal bacteria through ulcerated pocket epithelium and bloodstream - Ulcerated pocket epithelium allows bacteria entrance - Bacteremia is common after periodontal examination (Daly et al 2001) - Bacterial byproducts, such as LPS, also disseminate in the bloodstream (Gentx 2002) The University of Western Australia institutional logo featuring a shield with an open book and a swan. **Indirect mechanism** • Systemic inflammation model • Blood and tissue cells where these antigens relocate produce inflammatory mediators • Excessive production of inflammatory mediators in periodontal lesions/sites enter bloodstream and affect distant organs • Liver = acute phase response - Systemic inflammation model - Blood and tissue cells where these antigens relocate produce inflammatory mediators - Excessive production of inflammatory mediators in periodontal lesions/sites enter bloodstream and affect distant organs - Liver = acute phase response The University of Western Australia institutional logo featuring a shield with a swan and open books. # Systemic Inflammation Model - Periodontitis ## 1. Increase circulating levels of pro-inflammatory cytokines **IL-1/IL-6/TNF-a** ## 2. Diminish circulating levels of anti-inflammatory cytokines **IL-4/IL-10** ## 3. Alter blood counts: * + **Leukocytes** * + PMN * + **Platelets** * - **Lymphocyte** * - **Erythrocytes** ## 4. Increase circulating levels of acute phase response: non-specific systemic markers of inflammation **C-reactive protein** and **fibrinogen (ESR)** Daiuto et al 2004, Loos 2005, Gomes-Filho et al 2011, Mattuella et al 2014, Anad et al 2016, Romandini et al 2018  **Systemic Inflammation Model – Periodontitis** 1. Increase circulating levels of pro-inflammatory cytokines - IL-1/IL-6/TNF-a 2. Diminish circulating levels of anti-inflammatory cytokines - IL-4/IL-10 3. Alter blood counts: - + **Leukocytes** - + PMN - + **Platelets** - - **Lymphocyte** - - **Erythrocytes** 4. Increase circulating levels of acute phase response: non-specific systemic markers of inflammation - C-reactive protein and fibrinogen (ESR) Daiuto et al 2004, Loos 2005, Gomes-Filho et al 2011, Mattuella et al 2014, Anad et al 2016, Romandini et al 2018 Clinical photograph showing the upper anterior teeth with visible gingival inflammation, bleeding upon probing, and signs of periodontitis. ### **Left Flowchart: The Influence of Periodontal Infection on Atherosclerosis** | Step | Description | |------|-------------| | 1 | **Periodontal infection** | | 2 | → **Gram-negative bacteremia/LPS** | | 3 | → **Endothelial damage**<br>Platelet adhesion/aggregation<br>Monocyte infiltration/proliferation | | 4 | → **Cytokine/growth factor production**<br>Thrombus formation | | 5 | → **Atheroma formation**<br>Vessel wall thickening<br>Thromboembolic events | **Fig. 26.6** The influence of periodontal infection on atherosclerosis. Periodontal pathogens and their products result in damage to the vascular endothelium. Monocytes and macrophages enter the vessel wall and produce cytokines that further increase the inflammatory response and propagate the atheromatous lesion. Growth factor production leads to smooth muscle proliferation in the vessel wall. Damaged endothelium also activates platelets, thereby resulting in platelet aggregation and potentiating thromboembolic events. *LPS*, Lipopolysaccharide. --- ### **Right Flowchart: Cardiovascular and Periodontal Consequences of the Hyper-responsive Monocyte/Macrophage Phenotype (MØ⁺)** | Step | Description | |------|-------------| | 1 | **MØ⁺ phenotype** ——→ **Risk factors for atherosclerosis** ——→ **Hypercoagulability**<br>Atheroma formation<br>Thromboembolism | | 2 | **Periodontal pathogens** ——→ **Periodontitis** ——→ **Chronic bacterial challenge**<br>Proinflammatory cytokines<br>Acute phase reactants ——→ **Vascular effects** ——→ **Hypercoagulability**<br>Atheroma formation<br>Thromboembolism | **Fig. 26.7** The cardiovascular and periodontal consequences of the hyper-responsive monocyte/macrophage phenotype (MØ⁺). In combination with other risk factors, the MØ⁺ phenotype predisposes individuals to both atherosclerosis and periodontitis. Bacterial products and inflammatory mediators associated with periodontitis affect vascular endothelium, monocytes and macrophages, platelets, and smooth muscle and may increase blood coagulability. This may further increase atherosclerosis and may result in thromboembolism and ischemic events.   **The Influence of Periodontal Infection on Atherosclerosis** | Step | Description | |------|-------------| | 1 | **Periodontal infection** | | 2 | → **Gram-negative bacteremia/LPS** | | 3 | → **Endothelial damage**<br>Platelet adhesion/aggregation<br>Monocyte infiltration/proliferation | | 4 | → **Cytokine/growth factor production**<br>Thrombus formation | | 5 | → **Atheroma formation**<br>Vessel wall thickening<br>Thromboembolic events | **Fig. 26.6** The influence of periodontal infection on atherosclerosis. Periodontal pathogens and their products result in damage to the vascular endothelium. Monocytes and macrophages enter the vessel wall and produce cytokines that further increase the inflammatory response and propagate the atheromatous lesion. Growth factor production leads to smooth muscle proliferation in the vessel wall. Damaged endothelium also activates platelets, thereby resulting in platelet aggregation and potentiating thromboembolic events. *LPS*, Lipopolysaccharide. **Cardiovascular and Periodontal Consequences of the Hyper-responsive Monocyte/Macrophage Phenotype (MØ⁺)** | Step | Description | |------|-------------| | 1 | **MØ⁺ phenotype** ——→ **Risk factors for atherosclerosis** ——→ **Hypercoagulability**<br>Atheroma formation<br>Thromboembolism | | 2 | **Periodontal pathogens** ——→ **Periodontitis** ——→ **Chronic bacterial challenge**<br>Proinflammatory cytokines<br>Acute phase reactants ——→ **Vascular effects** ——→ **Hypercoagulability**<br>Atheroma formation<br>Thromboembolism | **Fig. 26.7** The cardiovascular and periodontal consequences of the hyper-responsive monocyte/macrophage phenotype (MØ⁺). In combination with other risk factors, the MØ⁺ phenotype predisposes individuals to both atherosclerosis and periodontitis. Bacterial products and inflammatory mediators associated with periodontitis affect vascular endothelium, monocytes and macrophages, platelets, and smooth muscle and may increase blood coagulability. This may further increase atherosclerosis and may result in thromboembolism and ischemic events. A vertical flowchart illustrating the progression from periodontal infection to atheroma formation. It consists of five sequential rectangular nodes connected by downward arrows. The steps are: 1) Periodontal infection, 2) Gram-negative bacteremia/LPS, 3) Endothelial damage (Platelet adhesion/aggregation, Monocyte infiltration/proliferation), 4) Cytokine/growth factor production (Thrombus formation), and 5) Atheroma formation (Vessel wall thickening, Thromboembolic events). Below the chart is the caption describing how pathogens damage vascular endothelium, monocytes produce cytokines, and growth factors lead to smooth muscle proliferation. A complex flowchart diagram explaining the link between MØ⁺ phenotype and periodontitis leading to cardiovascular disease. It features two input boxes at the top ('MØ⁺ phenotype' and 'Periodontal pathogens') that converge through intermediate stages ('Risk factors for atherosclerosis' and 'Chronic bacterial challenge') into a final outcome box ('Hypercoagulability', 'Atheroma formation', 'Thromboembolism'). The diagram includes text labels such as 'Vascular effects' connecting pathways. The caption explains how the MØ⁺ phenotype predisposes individuals to both conditions and how inflammatory mediators increase blood coagulability. # **Acute phase response = CRP and ESR** ## Non specific systemic inflammation markers ### C-Reactive Protein - **Chronic infections**: > **3.0 mg/L** (*H. pilori, Chlamydia*) > *MedicineNet © 2019* > **Inflammation Markers | C-Reactive Protein (CRP), Cardiac** > **CRP Clinical Levels: 0.00 - 3.00 mg/L** > The clinical levels here are the standard lab ranges. your goal is to move into the low and moderate ranges. <Low risk></Low risk> 0 — 1.0 <Moderate Risk></Moderate Risk> 1.0 — 3.00 <High Risk></High Risk> 3.00+   **Acute phase response = CRP and ESR** Non specific systemic inflammation markers **C-Reactive Protein** - **Chronic infections**: > **3.0 mg/L** (*H. pilori, Chlamydia*) **CRP Clinical Levels: 0.00 - 3.00 mg/L** - Low risk: 0 – 1.0 - Moderate Risk: 1.0 – 3.00 - High Risk: 3.00+ Labelled biological diagram illustrating the synthesis and function of C-Reactive Protein (CRP). The diagram shows a sequence starting with 'Infection or inflammation' triggering IL-6 and IL-1β. These cytokines act on the Liver to stimulate CRP synthesis within Hepatocytes (involving NF-κB/C/EBPβ in the nucleus), leading to Plasma CRP release. Arrows indicate CRP's role in activating Complement (C1q) against Bacteria, binding to Phagocytes via Fcγ receptors, interacting with Apoptotic cells, and causing Inflammation at tissue sites. It also depicts Monomeric CRP potentially activating Monocytes and Neutrophils. Bar chart titled 'Inflammation Markers | C-Reactive Protein (CRP), Cardiac'. The x-axis represents CRP levels from 0 to 3.00+. The bar is segmented by risk level: 'Low risk' (0-1.0, light orange), 'Moderate Risk' (1.0-3.00, darker orange), and 'High Risk' (3.00+, red arrowhead). Text notes that MedicineNet © 2019 source and the goal is to stay in low/moderate ranges. Table 1. Overview of Case-Control Studies Reporting on C-Reactive Protein (CRP) Plasma Levels (mg/l) in Periodontitis Patients and Healthy Controls | Reference | Patients <br> N | Mean ± SD | Median | Controls <br> N | Mean ± SD | Median | P* | |---|---|---|---|---|---|---|---| | Ebersole et al. 1997⁴⁴ | 40 | 9.12 ± 1.61 | † | 35 | 2.17 ± 0.41 | † | <0.001 | | Fredriksson et al. 1998¹⁵ | 17 | 2.62 ± 2.90 | † | 17 | 0.87 ± 1.73 | † | 0.04 | | Fredriksson et al. 1999¹⁶ | 37 | † | 2.0 | 38 | † | 0 | 0.012 | | Loos et al. 2000¹² | 107 | 2.64 ± 3.48 | 1.4 | 43 | 1.21 ± 1.34 | 0.9 | 0.017‡§ | | Noack et al. 2001⁴⁵ | 50 | 4.06 ± 5.55 | † | 65 | 1.70 ± 1.91 | † | 0.011† | | Glurich et al. 2002⁴⁶ | 26 | 2.40 ± 1.89 | † | 20 | 1.68 ± 1.42 | † | >0.05 | | Craig et al. 2003⁴⁷ | 44 | 5.78 ± 1.07 | † | 25 | 2.46 ± 1.44 | † | >0.05 | | Buhlin et al. 2003⁴² | 50 | 3.28 ± 4.64 | † | 46 | 1.74 ± 1.68 | † | <0.05 | | Bizzarro et al. 2005¹⁸ | 91 | 3.12 ± 3.81 | 1.9 | 39 | 1.88 ± 2.04 | 0.9 | 0.074¶∥ | * Indicates strength of the observed differences between patients and controls. † Values not reported. ‡ P value calculated for the purpose of this review; in original article, the adjusted P value is 0.030 for a difference between three groups: healthy controls, patients with localized periodontitis, and patients with generalized periodontitis, with the generalized periodontitis group having the highest value and the control group having the lowest value (also see Figure 3). § P value calculated for the purpose of this review; in original article, the adjusted P value is 0.197 for a difference between three groups: healthy controls, patients with moderate periodontitis, and patients with severe periodontitis, with the severe periodontitis group having the highest value and the control group having the lowest value. ¶ P value adjusted for background variables and potential confounding factors reported in original paper.  **Overview of Case-Control Studies Reporting on C-Reactive Protein (CRP) Plasma Levels (mg/l) in Periodontitis Patients and Healthy Controls** | Reference | Patients N | Mean ± SD | Median | Controls N | Mean ± SD | Median | P* | |---|---|---|---|---|---|---|---| | Ebersole et al. 1997⁴⁴ | 40 | 9.12 ± 1.61 | † | 35 | 2.17 ± 0.41 | † | <0.001 | | Fredriksson et al. 1998¹⁵ | 17 | 2.62 ± 2.90 | † | 17 | 0.87 ± 1.73 | † | 0.04 | | Fredriksson et al. 1999¹⁶ | 37 | † | 2.0 | 38 | † | 0 | 0.012 | | Loos et al. 2000¹² | 107 | 2.64 ± 3.48 | 1.4 | 43 | 1.21 ± 1.34 | 0.9 | 0.017‡§ | | Noack et al. 2001⁴⁵ | 50 | 4.06 ± 5.55 | † | 65 | 1.70 ± 1.91 | † | 0.011† | | Glurich et al. 2002⁴⁶ | 26 | 2.40 ± 1.89 | † | 20 | 1.68 ± 1.42 | † | >0.05 | | Craig et al. 2003⁴⁷ | 44 | 5.78 ± 1.07 | † | 25 | 2.46 ± 1.44 | † | >0.05 | | Buhlin et al. 2003⁴² | 50 | 3.28 ± 4.64 | † | 46 | 1.74 ± 1.68 | † | <0.05 | | Bizzarro et al. 2005¹⁸ | 91 | 3.12 ± 3.81 | 1.9 | 39 | 1.88 ± 2.04 | 0.9 | 0.074¶∥ | * Indicates strength of the observed differences between patients and controls. † Values not reported. ‡ P value calculated for the purpose of this review; in original article, the adjusted P value is 0.030 for a difference between three groups: healthy controls, patients with localized periodontitis, and patients with generalized periodontitis, with the generalized periodontitis group having the highest value and the control group having the lowest value (also see Figure 3). § P value calculated for the purpose of this review; in original article, the adjusted P value is 0.197 for a difference between three groups: healthy controls, patients with moderate periodontitis, and patients with severe periodontitis, with the severe periodontitis group having the highest value and the control group having the lowest value. ¶ P value adjusted for background variables and potential confounding factors reported in original paper. A structured table summarizing data from nine case-control studies regarding C-Reactive Protein (CRP) plasma levels. The table is divided into two main sections: 'Patients' (with columns for Reference, N, Mean ± SD, Median) and 'Controls' (with columns for N, Mean ± SD, Median), followed by a P-value column indicating statistical significance. The rows list specific studies including Ebersole et al. 1997, Fredriksson et al. 1998/1999, Loos et al. 2000, Noack et al. 2001, Glurich et al. 2002, Craig et al. 2003, Buhlin et al. 2003, and Bizzarro et al. 2005. Data includes sample sizes (N), mean values with standard deviations, and median values where available (indicated by dagger symbols † for missing data). The bottom section contains footnotes explaining the asterisk (*) for difference strength, dagger (†) for unreported values, and symbols (§, ¶, ||) for adjusted or calculated P-values referencing comparisons between healthy controls, localized periodontitis, generalized periodontitis, moderate, and severe periodontitis groups. <table> <tr> <th>Age</th> <th>Male</th> <th>Female</th> </tr> <tr> <td>0-50</td> <td><15 mm/h</td> <td><20 mm/h</td> </tr> <tr> <td>51-85</td> <td><20 mm/h</td> <td><30 mm/h</td> </tr> <tr> <td>>85</td> <td><30 mm/h</td> <td><42 mm/h</td> </tr> </table>   | Age | Male | Female | |---|---|---| | 0-50 | <15 mm/h | <20 mm/h | | 51-85 | <20 mm/h | <30 mm/h | | >85 | <30 mm/h | <42 mm/h | A table listing reference values for Erythrocyte Sedimentation Rate (ESR) categorized by age and gender. Columns include 'Age', 'Male', and 'Female'. Rows show: Age 0-50 (<15 mm/h Male, <20 mm/h Female), Age 51-85 (<20 mm/h Male, <30 mm/h Female), and Age >85 (<30 mm/h Male, <42 mm/h Female). Source cited at bottom. An infographic explaining the ESR test. It shows two test tubes before and after 1 hour with RBCs settling. Labels indicate 'The distance, in mm, the RBC fall in 1 hour' and 'Clumps of Red Blood Cells'. A bulleted list on the right explains that high ESR can be seen in inflammatory diseases, infections, autoimmune diseases, chronic kidney diseases, viral infections, pregnancy, and cancer. The University of Western Australia International Journal of Health Sciences A Scientific Publications by Qassim University ▶ Int J Health Sci (Qassim). 2016 Apr;10(2):293–307. **Periodontal Systemic Connections-Novel Associations-A Review of the Evidence with Implications for Medical Practitioners** Butchibabu Kalakonda$^{a,\ad}$, **Pradeep Koppolu**$^{a}$, **Kusai Baroudi**$^{a}$, **Ashank Mishra**$^{b}$ ▶ Author information ▶ Copyright and License information PMCID: PMC4825901 PMID: **27103910** Electronic databases such as PubMed, Google Scholar and Cochrane databases were used as source of the data for relevant studies published from 2005 up to 2015 with the following keywords, ""Periodontal disease”, "systemic conditions”, "periodontal disease and Alzheimer’s”, "Periodontal disease and Schizophrenia”, "Periodontal disease and Psoriasis” and "Periodontal disease and erectile dysfunction". The evidence presented ascertains that a reasonable and modest association does exist between Periodontal disease and Alzheimer’s, Schizophrenia, Erectile dysfunction, as well as Psoriasis and thus establishes periodontal disease as a potential risk factor. Int J Health Sci (Qassim). 2016 Apr;10(2):293–307. **Periodontal Systemic Connections-Novel Associations-A Review of the Evidence with Implications for Medical Practitioners** Butchibabu Kalakonda, Pradeep Koppolu, Kusai Baroudi, Ashank Mishra PMCID: PMC4825901 PMID: 27103910 Electronic databases such as PubMed, Google Scholar and Cochrane databases were used as source of the data for relevant studies published from 2005 up to 2015 with the following keywords, "Periodontal disease", "systemic conditions", "periodontal disease and Alzheimer's", "Periodontal disease and Schizophrenia", "Periodontal disease and Psoriasis" and "Periodontal disease and erectile dysfunction". The evidence presented ascertains that a reasonable and modest association does exist between Periodontal disease and Alzheimer's, Schizophrenia, Erectile dysfunction, as well as Psoriasis and thus establishes periodontal disease as a potential risk factor. Journal header logo containing the stylized acronym 'IJHS' and the text 'International Journal of Health Sciences'. Below this, smaller text reads 'A Scientific Publications by Qassim University'. The logo is set against a light green background. University logo located in the top right corner. It features a blue shield with a yellow book and a black swan inside, accompanied by the text 'THE UNIVERSITY OF WESTERN AUSTRALIA'. <div align="right"><b>THE UNIVERSITY<br>OF WESTERN<br>AUSTRALIA</b> </div> **Main association findings** **Cardiovascular disease** **Adverse pregnancy outcomes** <div align="left"> **Beck et al 2019** </div> <div align="left"> **Cardiovascular Disease** - 1900 - 1911: Focal Infection Theory (Miller 1911) - 1989-1990: Association between dental health and acute MI (Mattila et al. 1989) - 1993: Periodontitis is identified as an independent risk factor for CVD (DeStefano et al. 1993) - 1996: First proposed mechanism underlying periodontitis and cardiovascular disease (Beck et al. 1996) - 1998: CRP levels independently predict CVD events in healthy women (Ridker et al. 1998) - 1999 - 2000 - 2001: First study showing periodontal disease is related to a measure of atherosclerosis (Beck et al. 2001) - 2002 - 2003 - 2004: Treatment of chronic periodontitis affects circulating levels of endotoxin, CRP, TNF-a and IL-6 (Ide et al. 2004) - 2006 - 2007: Periodontal treatment demonstrates acute increase in inflammation and long-term improvement in endothelial function (Tonetti et al. 2007) - 2007 - 2010 - 2012: RCT (n=246) shows non-surgical periodontal therapy reduces CHD risk markers (Bokhari et al. 2012) - 2017: RCT (n=107) shows intensive periodontal therapy without antihypertensive medication may lower blood pressure in patients with prehypertension (Zhou et al. 2017) - 2020 </div> <div align="left"> **Adverse Pregnancy Outcomes** - Medical Condition - Cardiovascular Disease - Adverse Pregnancy Outcomes - Type of Study - Cross-sectional - Purple - Longitudinal - Yellow - Interventional - Red - 1996: First study showing association between preterm low birth weight and maternal periodontal disease (Offenbacher et al. 1996) - 1996 - 2001 - 2001: First RCT (n=400) indicating maternal periodontal therapy reduces preterm low birth weight (Lopez et al. 2002) - 2002 - 2003: Maternal periodontal disease is associated with an increased risk for preeclampsia (Boggess et al. 2003) - 2006: Periodontal disease progression during pregnancy predicts risk of very preterm delivery (Offenbacher et al. 2006) - 2009: Major RCT (n=823) found null results for periodontal treatment and risk of preterm birth (Michalowicz et al. 2006) - 2009: Largest RCT (n=1806) on periodontal therapy and preterm birth found null results (Offenbacher et al. 2009) - 2016: Periodontitis and glycemic levels appear to have opposing influences on birth weight (Gomes-Filho et al. 2016) </div>  **Main association findings** **Cardiovascular Disease** - 1900 - 1911: Focal Infection Theory (Miller 1911) - 1989-1990: Association between dental health and acute MI (Mattila et al. 1989) - 1993: Periodontitis is identified as an independent risk factor for CVD (DeStefano et al. 1993) - 1996: First proposed mechanism underlying periodontitis and cardiovascular disease (Beck et al. 1996) - 1998: CRP levels independently predict CVD events in healthy women (Ridker et al. 1998) - 1999 - 2000 - 2001: First study showing periodontal disease is related to a measure of atherosclerosis (Beck et al. 2001) - 2002 - 2003 - 2004: Treatment of chronic periodontitis affects circulating levels of endotoxin, CRP, TNF-a and IL-6 (Ide et al. 2004) - 2006 - 2007: Periodontal treatment demonstrates acute increase in inflammation and long-term improvement in endothelial function (Tonetti et al. 2007) - 2007 - 2010 - 2012: RCT (n=246) shows non-surgical periodontal therapy reduces CHD risk markers (Bokhari et al. 2012) - 2017: RCT (n=107) shows intensive periodontal therapy without antihypertensive medication may lower blood pressure in patients with prehypertension (Zhou et al. 2017) - 2020 **Adverse Pregnancy Outcomes** - 1996: First study showing association between preterm low birth weight and maternal periodontal disease (Offenbacher et al. 1996) - 1996 - 2001 - 2001: First RCT (n=400) indicating maternal periodontal therapy reduces preterm low birth weight (Lopez et al. 2002) - 2002 - 2003: Maternal periodontal disease is associated with an increased risk for preeclampsia (Boggess et al. 2003) - 2006: Periodontal disease progression during pregnancy predicts risk of very preterm delivery (Offenbacher et al. 2006) - 2009: Major RCT (n=823) found null results for periodontal treatment and risk of preterm birth (Michalowicz et al. 2006) - 2009: Largest RCT (n=1806) on periodontal therapy and preterm birth found null results (Offenbacher et al. 2009) - 2016: Periodontitis and glycemic levels appear to have opposing influences on birth weight (Gomes-Filho et al. 2016) Beck et al 2019 Timeline figure displaying two parallel columns of medical milestones from 1900 to 2020. The left column tracks 'Cardiovascular Disease' findings (e.g., Focal Infection Theory, CRP levels) and the right column tracks 'Adverse Pregnancy Outcomes' (e.g., preterm low birth weight, preeclampsia). Key visual elements include a vertical timeline axis on the far right, colored dots representing study types (Purple for Cross-sectional, Yellow for Longitudinal, Red for Interventional), and specific text annotations describing key discoveries or trials by year. # Main association findings ## Diabetes ### Beck et al 2019 ```mermaid timeline title Periodontal medicine timeline for diabetes mellitus studies 1960 : First study showing periodontal therapy reduces insulin requirement (Williams and Mahan 1960) 1989 : Periodontitis severity is associated with diabetes duration in subjects with insulin dependent diabetes (Hugoson et al. 1989) 1990 : Non-insulin dependent diabetes is positively associated with prevalence and incidence of periodontitis (Nelson et al. 1990) 1995 : First report on two RCTs showing periodontal treatment not effective overall on HbA1c in subjects with Type 1 diabetes but effective on those with poor metabolic control (Aldridge et al. 1995) 1996 : Severe periodontitis is associated with poor metabolic control in Type 2 diabetes (Taylor et al. 1996) : Periodontitis influences renal and cardiovascular complications for Type 1 diabetes patients (Thorstensson et al. 1996) 1997 : RCT of patients with non-insulin dependent diabetes demonstrates periodontal therapy with systemic antibiotics reduces HbA1c at three months (Grossi et al. 1997) 2004 : Periodontal severity is associated with development of glucose intolerance, increase in HbA1c and incident diabetes over 10 years (Saito et al. 2004) 2005 : Patients with both Type 2 diabetes and periodontitis have higher cardio-renal mortality rate than Type 2 diabetes alone (Saremi et al. 2005) 2010 : Periodontal disease associated with one or several components of metabolic syndrome in dose-response manner (Morita et al. 2010) 2013 : First RCT of non-surgical periodontal therapy in subjects with Type 2 diabetes and periodontitis showed no improvement on HbA1c levels at 12 months (Engebretson et al. 2013) 2018 : RCT (n=264) of patients with Type 2 diabetes and periodontitis showed intensive periodontal therapy that improved periodontal status significantly improved HbA1c levels at 12 months (D'Aiuto et al. 2018) ``` **Type of Study Key:** * **Interventional (Red):** 1960, 1995, 1997, 2013, 2018 * **Longitudinal (Yellow):** 1996, 2004, 2005, 2010 * **Cross-sectional (Purple):** 1989, 1990, 1996 **Figure 3.** Periodontal medicine timeline for diabetes mellitus studies. Timeline overview from 1900 to 2020 showing 12 milestone studies for periodontal medicine and diabetes mellitus, organized by type of study with descriptors. HbA1c, hemoglobin A1c or glycosylated hemoglobin; RCT, randomized controlled trial.  **Main association findings – Diabetes** Beck et al 2019 **Periodontal medicine timeline for diabetes mellitus studies** - 1960: First study showing periodontal therapy reduces insulin requirement (Williams and Mahan 1960) - 1989: Periodontitis severity is associated with diabetes duration in subjects with insulin dependent diabetes (Hugoson et al. 1989) - 1990: Non-insulin dependent diabetes is positively associated with prevalence and incidence of periodontitis (Nelson et al. 1990) - 1995: First report on two RCTs showing periodontal treatment not effective overall on HbA1c in subjects with Type 1 diabetes but effective on those with poor metabolic control (Aldridge et al. 1995) - 1996: Severe periodontitis is associated with poor metabolic control in Type 2 diabetes (Taylor et al. 1996) - 1996: Periodontitis influences renal and cardiovascular complications for Type 1 diabetes patients (Thorstensson et al. 1996) - 1997: RCT of patients with non-insulin dependent diabetes demonstrates periodontal therapy with systemic antibiotics reduces HbA1c at three months (Grossi et al. 1997) - 2004: Periodontal severity is associated with development of glucose intolerance, increase in HbA1c and incident diabetes over 10 years (Saito et al. 2004) - 2005: Patients with both Type 2 diabetes and periodontitis have higher cardio-renal mortality rate than Type 2 diabetes alone (Saremi et al. 2005) - 2010: Periodontal disease associated with one or several components of metabolic syndrome in dose-response manner (Morita et al. 2010) - 2013: First RCT of non-surgical periodontal therapy in subjects with Type 2 diabetes and periodontitis showed no improvement on HbA1c levels at 12 months (Engebretson et al. 2013) - 2018: RCT (n=264) of patients with Type 2 diabetes and periodontitis showed intensive periodontal therapy that improved periodontal status significantly improved HbA1c levels at 12 months (D'Aiuto et al. 2018) **Type of Study Key:** - **Interventional:** 1960, 1995, 1997, 2013, 2018 - **Longitudinal:** 1996, 2004, 2005, 2010 - **Cross-sectional:** 1989, 1990, 1996 **Figure 3.** Periodontal medicine timeline for diabetes mellitus studies. Timeline overview from 1900 to 2020 showing 12 milestone studies for periodontal medicine and diabetes mellitus, organized by type of study with descriptors. HbA1c, hemoglobin A1c or glycosylated hemoglobin; RCT, randomized controlled trial. Timeline diagram titled 'Periodontal medicine timeline for diabetes mellitus studies' spanning the years 1900 to 2020. It features a vertical time axis on the left and lists specific research findings as colored icons (red, yellow, purple) corresponding to interventional, longitudinal, and cross-sectional study types. The timeline includes entries such as 'First study showing periodontal therapy reduces insulin requirement (Williams and Mahan 1960)' and 'RCT (n=264) of patients with Type 2 diabetes and periodontitis showed intensive periodontal therapy that improved periodontal status significantly improved HbA1c levels at 12 months (D'Aiuto et al. 2018).' A legend in the top right corner defines the color coding for study types. **THE UNIVERSITY OF WESTERN AUSTRALIA** <div style="border: 1px solid #007bff; padding: 20px; display: inline-block; text-align: center;"> <strong>Periodontal treatment</strong> <div style="border-bottom: 1px solid #000000; width: 50%; margin: 5px auto; text-align: center;">Decreased<br>inflammation</div> <strong>Improved insulin sensitivity</strong> <div style="width: 50%; margin: 5px auto; text-align: center;">↓</div> <strong>Improved glycemic control</strong> </div> <table> <tr> <th>Gram-negative periodontal infection</th> <th rowspan="5"></th> </tr> <tr> <div style="border-bottom: 1px solid #000000; width: 50%; margin: 5px auto; text-align: center;">↑</div> </tr> <tr> <strong>Increased insulin resistance</strong> </tr> <tr> <div style="border-bottom: 1px solid #000000; width: 50%; margin: 5px auto; text-align: center;">↓</div> </tr> <tr> <strong>Worsened glycemic control</strong> </tr> </table> **Fig. 26.8** Potential effects of periodontal infection and periodontal therapy on glycemia in patients with diabetes.  **Potential effects of periodontal infection and periodontal therapy on glycemia in patients with diabetes.** Periodontal treatment → Decreased inflammation → Improved insulin sensitivity → Improved glycemic control Gram-negative periodontal infection → Increased insulin resistance → Worsened glycemic control **Fig. 26.8** Potential effects of periodontal infection and periodontal therapy on glycemia in patients with diabetes. A flowchart diagram divided into two vertical columns by a red line. The left column illustrates the negative progression: 'Gram-negative periodontal infection' leads to 'Increased insulin resistance', which leads to 'Worsened glycemic control'. The right column illustrates the positive progression: 'Periodontal treatment' leads to 'Decreased inflammation', resulting in 'Improved insulin sensitivity', which leads to 'Improved glycemic control'. All text is contained within beige rectangular boxes connected by downward arrows. <table> <tr> <td></td> <th>Bacterial infection</th> <td></td> </tr> <tr> <th colspan="3">Bacteria and products in amnion</th> <td></td> </tr> <tr> <th colspan="3">Inflammatory response with<br>cytokine production in amnion</th> <td></td> </tr> <tr> <th colspan="3">Increased amniotic<br>prostaglandin production</th> <td></td> </tr> <tr> <th colspan="3">Preterm labor</th> <td></td> </tr> <tr> <th colspan="4"><b>eFig. 26.1</b> Mechanisms by which infection may induce preterm labor.</th> </tr> </table>  | | Bacterial infection | | |---|---|---| | **Bacteria and products in amnion** | | | | **Inflammatory response with cytokine production in amnion** | | | | **Increased amniotic prostaglandin production** | | | | **Preterm labor** | | | **eFig. 26.1** Mechanisms by which infection may induce preterm labor. A vertical flowchart illustrating the progression from bacterial infection to preterm labor. The steps are: Bacterial infection -> Bacteria and products in amnion -> Inflammatory response with cytokine production in amnion -> Increased amniotic prostaglandin production -> Preterm labor. THE UNIVERSITY OF WESTERN AUSTRALIA Pan African Medical Journal Open Access Pan Afr Med J. 2013 Jul 10;15:92. doi: 10.11604/pamj.2013.15.92.2326 Estimate of CRP and TNF-alpha level before and after periodontal therapy in cardiovascular disease patients Pradeep Koppolu ¹,&, Satyanarayana Durvasula ², Rajababu Palaparthty ², Mukhesh Rao ³, Vidya Sagar ², Sunil Kumar Reddy ², Swapna Lingam ⁴ Author information | Article notes | Copyright and License information PMCID: PMC3810246 PMID: 24198887 Conclusion It can be concluded from the study that there can be a possible causal relationship between pathogenesis of periodontal disease and CVD as inferred from the statistical significant outcome in the form of decreased inflammatory biomarkers after the periodontal treatment. Pan Afr Med J. 2013 Jul 10;15:92. doi: 10.11604/pamj.2013.15.92.2326 **Estimate of CRP and TNF-alpha level before and after periodontal therapy in cardiovascular disease patients** Pradeep Koppolu, Satyanarayana Durvasula, Rajababu Palaparthty, Mukhesh Rao, Vidya Sagar, Sunil Kumar Reddy, Swapna Lingam PMCID: PMC3810246 PMID: 24198887 **Conclusion** It can be concluded from the study that there can be a possible causal relationship between pathogenesis of periodontal disease and CVD as inferred from the statistical significant outcome in the form of decreased inflammatory biomarkers after the periodontal treatment. Blue banner containing the text 'Pan African Medical Journal' and an orange 'Open Access' logo with a padlock icon. The banner also features a silhouette of a person holding a staff next to a hut. University crest featuring a shield with a swan and open books, accompanied by the text 'THE UNIVERSITY OF WESTERN AUSTRALIA'. **Evaluation of Serum C-reactive Protein Levels in Subjects with Aggressive and Chronic Periodontitis in Comparison with Healthy Controls: A Clinico-biochemical Study** Vijayalakshmi Bolla 1, ☺, P Santha Kumari 1, Surendra Reddy Munnangi 2, D Sunil Kumar 1, Y Durgabai 1, Pradeep Koppolu 3 Author information Article notes Copyright and License information PMCID: PMC5441260 PMID: 28584744 **Conclusion:** The mean CRP levels were found to be greater in CP compared to GAP subjects, but there was no statistically significant difference. **Evaluation of Serum C-reactive Protein Levels in Subjects with Aggressive and Chronic Periodontitis in Comparison with Healthy Controls: A Clinico-biochemical Study** Vijayalakshmi Bolla, P Santha Kumari, Surendra Reddy Munnangi, D Sunil Kumar, Y Durgabai, Pradeep Koppolu PMCID: PMC5441260 PMID: 28584744 **Conclusion:** The mean CRP levels were found to be greater in CP compared to GAP subjects, but there was no statistically significant difference. University of Western Australia logo with the motto 'Seek Wisdom'. Journal header for 'International Journal of Applied & Basic Medical Research', official publication of Basic Medical Scientists Association, with navigation links: Home, Current issue, Instructions, Submit article. **CASE SCENARIO 26.1** Patient: A 38-year-old female **Chief Complaint:** “I have swelling and pain in my gums.” Background Information Patient is a nonsmoker with poorly controlled diabetes mellitus (HbA1c = 8.4). Patient is overweight. She indicates brushing one to two times per day but does not floss. She reports infrequent dental visits. Her last professional dental cleaning was at least 3 years ago. Current Findings: Probing depths were generally in the range of 2 to 4 mm with localized 5 to 7 mm, BOP was 43%. **CASE-BASED QUESTIONS** 1. Does the patient’s diabetes pose an increased risk for periodontitis? A. Yes B. No 2. This patient requires nonsurgical periodontal therapy. Could periodontal therapy improve glycemic control? A. Yes B. No 3. Which of the following are complications of diabetes mellitus? A. Retinopathy B. Nephropathy C. Periodontal disease D. All of the above E. A and B **SOLUTION AND EXPLANATION** Answer: A Explanation: There is increased prevalence of periodontitis in patients with diabetes mellitus, especially if poorly controlled. Answer: A Explanation: Although there are conflicting results from different studies, numerous systematic reviews and meta-analyses have consistently shown that periodontal therapy is associated with statistically significant and clinically relevant improvement in glycemic control in patients with diabetes and periodontitis. Answer: D Explanation: Complications of diabetes mellitus include **retinopathy**, **nephropathy**, neuropathy, macrovascular disease, altered wound healing, and periodontal disease.  **CASE SCENARIO 26.1** **Patient:** A 38-year-old female **Chief Complaint:** "I have swelling and pain in my gums." **Background Information** Patient is a nonsmoker with poorly controlled diabetes mellitus (HbA1c = 8.4). Patient is overweight. She indicates brushing one to two times per day but does not floss. She reports infrequent dental visits. Her last professional dental cleaning was at least 3 years ago. **Current Findings:** Probing depths were generally in the range of 2 to 4 mm with localized 5 to 7 mm, BOP was 43%. **CASE-BASED QUESTIONS** 1. Does the patient's diabetes pose an increased risk for periodontitis? A. Yes B. No 2. This patient requires nonsurgical periodontal therapy. Could periodontal therapy improve glycemic control? A. Yes B. No 3. Which of the following are complications of diabetes mellitus? A. Retinopathy B. Nephropathy C. Periodontal disease D. All of the above E. A and B **SOLUTION AND EXPLANATION** **Answer 1:** A **Explanation:** There is increased prevalence of periodontitis in patients with diabetes mellitus, especially if poorly controlled. **Answer 2:** A **Explanation:** Although there are conflicting results from different studies, numerous systematic reviews and meta-analyses have consistently shown that periodontal therapy is associated with statistically significant and clinically relevant improvement in glycemic control in patients with diabetes and periodontitis. **Answer 3:** D **Explanation:** Complications of diabetes mellitus include **retinopathy**, **nephropathy**, neuropathy, macrovascular disease, altered wound healing, and periodontal disease. Clinical photo showing the maxillary anterior gingiva of a patient with periodontitis. The image displays erythematous (red), swollen, and inflamed gums located between the central incisors and extending to the canines. There is visible bleeding on probing indicated by small red spots in the interdental papilla area, consistent with the background information stating BOP was 43%. THE UNIVERSITY OF WESTERN AUSTRALIA **CASE SCENARIO 26.2** **Patient:** A 49-year-old African-American female. **Chief Complaint:** "I am feeling discomfort in my gums. They bleed a lot when I brush, and they are always sore." **Background Information** Patient is a smoker with controlled hypertension and uncontrolled type 2 diabetes mellitus with an HbA1c of 9.8. She is currently taking metoprolol and metformin to treat these inflammatory diseases. She reports brushing twice daily but often skips flossing or other dental aids because it hurts her gums. **Clinical Findings:** Generalized probing depths ranging from 2 to 7 mm. **Bleeding on probing** was 52% and patient exhibits poor oral hygiene (biofilm control). Gingival tissues are erythematous, edematous, and tender. | CASE-BASED QUESTIONS | **SOLUTION AND EXPLANATION** | | :--- | :--- | | 1. Which of the following diseases have been linked to (adversely affected by) periodontal disease?<br>A. Coronary heart disease<br>B. Diabetes<br>C. Myocardial infarction<br>D. All of the above | **Answer:** D<br>**Explanation:** Periodontal disease has been associated with each of these disease processes. However, causal studies still need to be performed. It is difficult because these disease processes share many of the same risk factors. Thus, the association may be among the risk factors rather than the diseases themselves. | | 2. Periodontal disease is one of the six complications of diabetes mellitus.<br>A. True<br>B. False | **Answer:** A<br>**Explanation:** Yes, along with retinopathy, nephropathy, neuropathy, macrovascular disease, and altered wound healing, periodontal disease is officially recognized by the American Diabetes Association as a common complication among patients with poorly controlled diabetes mellitus. | | 3. Periodontal therapy has a beneficial effect on glycemic control.<br>A. True<br>B. False | **Answer:** A<br>**Explanation:** This may be true for patients with poor glycemic control and more advanced periodontal destruction. Patients who improved periodontal health with treatment also experienced improvements in glycemic control. |  **CASE SCENARIO 26.2** **Patient:** A 49-year-old African-American female. **Chief Complaint:** "I am feeling discomfort in my gums. They bleed a lot when I brush, and they are always sore." **Background Information** Patient is a smoker with controlled hypertension and uncontrolled type 2 diabetes mellitus with an HbA1c of 9.8. She is currently taking metoprolol and metformin to treat these inflammatory diseases. She reports brushing twice daily but often skips flossing or other dental aids because it hurts her gums. **Clinical Findings:** Generalized probing depths ranging from 2 to 7 mm. **Bleeding on probing** was 52% and patient exhibits poor oral hygiene (biofilm control). Gingival tissues are erythematous, edematous, and tender. | CASE-BASED QUESTIONS | **SOLUTION AND EXPLANATION** | | :--- | :--- | | 1. Which of the following diseases have been linked to (adversely affected by) periodontal disease?<br>A. Coronary heart disease<br>B. Diabetes<br>C. Myocardial infarction<br>D. All of the above | **Answer:** D<br>**Explanation:** Periodontal disease has been associated with each of these disease processes. However, causal studies still need to be performed. It is difficult because these disease processes share many of the same risk factors. Thus, the association may be among the risk factors rather than the diseases themselves. | | 2. Periodontal disease is one of the six complications of diabetes mellitus.<br>A. True<br>B. False | **Answer:** A<br>**Explanation:** Yes, along with retinopathy, nephropathy, neuropathy, macrovascular disease, and altered wound healing, periodontal disease is officially recognized by the American Diabetes Association as a common complication among patients with poorly controlled diabetes mellitus. | | 3. Periodontal therapy has a beneficial effect on glycemic control.<br>A. True<br>B. False | **Answer:** A<br>**Explanation:** This may be true for patients with poor glycemic control and more advanced periodontal destruction. Patients who improved periodontal health with treatment also experienced improvements in glycemic control. | A structured table titled 'CASE-BASED QUESTIONS' and 'SOLUTION AND EXPLANATION'. It presents three medical questions regarding periodontal disease linked to other diseases, complications of diabetes mellitus, and the effect of therapy on glycemic control. The right column provides the correct answer (D, A, A respectively) and detailed explanations for each question based on the clinical case scenario provided in the header. # Thank you!!! THE UNIVERSITY OF WESTERN AUSTRALIA SEEK WISDOM  Thank you!!! THE UNIVERSITY OF WESTERN AUSTRALIA SEEK WISDOM A background image of the Milky Way galaxy showing stars and nebulae. [^1]: Original PDF page 1: [[L13 PerioMedicine.pdf#page=1|L13 PerioMedicine, p.1]] [^2]: Original PDF page 2: [[L13 PerioMedicine.pdf#page=2|L13 PerioMedicine, p.2]] [^3]: Original PDF page 3: [[L13 PerioMedicine.pdf#page=3|L13 PerioMedicine, p.3]] [^4]: Original PDF page 4: [[L13 PerioMedicine.pdf#page=4|L13 PerioMedicine, p.4]] [^5]: Original PDF page 5: [[L13 PerioMedicine.pdf#page=5|L13 PerioMedicine, p.5]] [^6]: Original PDF page 6: [[L13 PerioMedicine.pdf#page=6|L13 PerioMedicine, p.6]] [^7]: Original PDF page 7: [[L13 PerioMedicine.pdf#page=7|L13 PerioMedicine, p.7]] [^8]: Original PDF page 8: [[L13 PerioMedicine.pdf#page=8|L13 PerioMedicine, p.8]] [^9]: Original PDF page 9: [[L13 PerioMedicine.pdf#page=9|L13 PerioMedicine, p.9]] [^10]: Original PDF page 10: [[L13 PerioMedicine.pdf#page=10|L13 PerioMedicine, p.10]] [^11]: Original PDF page 11: [[L13 PerioMedicine.pdf#page=11|L13 PerioMedicine, p.11]] [^12]: Original PDF page 12: [[L13 PerioMedicine.pdf#page=12|L13 PerioMedicine, p.12]] [^13]: Original PDF page 13: [[L13 PerioMedicine.pdf#page=13|L13 PerioMedicine, p.13]] [^14]: Original PDF page 14: [[L13 PerioMedicine.pdf#page=14|L13 PerioMedicine, p.14]] [^15]: Original PDF page 15: [[L13 PerioMedicine.pdf#page=15|L13 PerioMedicine, p.15]] [^16]: Original PDF page 16: [[L13 PerioMedicine.pdf#page=16|L13 PerioMedicine, p.16]] [^17]: Original PDF page 17: [[L13 PerioMedicine.pdf#page=17|L13 PerioMedicine, p.17]] [^18]: Original PDF page 18: [[L13 PerioMedicine.pdf#page=18|L13 PerioMedicine, p.18]] [^19]: Original PDF page 19: [[L13 PerioMedicine.pdf#page=19|L13 PerioMedicine, p.19]] [^20]: Original PDF page 20: [[L13 PerioMedicine.pdf#page=20|L13 PerioMedicine, p.20]] [^21]: Original PDF page 21: [[L13 PerioMedicine.pdf#page=21|L13 PerioMedicine, p.21]] [^22]: Original PDF page 22: [[L13 PerioMedicine.pdf#page=22|L13 PerioMedicine, p.22]] [^23]: Original PDF page 23: [[L13 PerioMedicine.pdf#page=23|L13 PerioMedicine, p.23]] [^24]: Original PDF page 24: [[L13 PerioMedicine.pdf#page=24|L13 PerioMedicine, p.24]] [^25]: Original PDF page 25: [[L13 PerioMedicine.pdf#page=25|L13 PerioMedicine, p.25]] [^26]: Original PDF page 26: [[L13 PerioMedicine.pdf#page=26|L13 PerioMedicine, p.26]] [^27]: Original PDF page 27: [[L13 PerioMedicine.pdf#page=27|L13 PerioMedicine, p.27]] [^28]: Original PDF page 28: [[L13 PerioMedicine.pdf#page=28|L13 PerioMedicine, p.28]] [^29]: Original PDF page 29: [[L13 PerioMedicine.pdf#page=29|L13 PerioMedicine, p.29]] [^30]: Original PDF page 30: [[L13 PerioMedicine.pdf#page=30|L13 PerioMedicine, p.30]] [^31]: Original PDF page 31: [[L13 PerioMedicine.pdf#page=31|L13 PerioMedicine, p.31]] [^32]: Original PDF page 32: [[L13 PerioMedicine.pdf#page=32|L13 PerioMedicine, p.32]]