Current guidelines suggest measuring high sensitivity C-reactive protein as an aid to coronary risk assessment in adults without cardiovascular disease (CVD). Whether other inflammatory biomarkers, such as fibrinogen, add further prognostic information is uncertain. In this cohort of initially healthy women, baseline levels of fibrinogen measured with a high-quality immunoassay provided additive value to hs-CRP and traditional risk factors in predicting incident CVD.

Mora S, Rifai N, et.al. Circulation. 2006;114:381-387.
http://circ.ahajournals.org/cgi/content/abstract/114/5/381? maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&andore xacttitle=and&andorexacttitleabs=and&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&s ortspec=relevance&volum e=114&firstpage=381&resourcetype=HWCIT

Cytokines which are produced by host cells play an important role in pathogenesis both rheumatoid arthritis (RA) and chronic periodontitis (CP). In this study, we aim to investigate the levels of Interleukin (IL)-4 and IL-10 in gingival crevicular fluid (GCF). Seventeen patients with CP, 17 patients with RA and 17 healthy controls (HC) were included. The RA group was divided into two groups according to gingival sulcus depths (RA-a: PD 3 mm, (n = 12), RA-b: PD > 3 mm, (n = 5)). For each patient, clinical parameters were recorded. The GCF samples were evaluated by enzyme-linked immunosorbent assay (ELISA) for IL-4 and IL-10 levels. IL-4 levels in the RA-a, RA-b and CP subjects were significantly lower compared to the HC subjects (p < 0.05). The mean level of IL-4 in RA-b group was significantly higher than that in CP group (p < 0.05). IL-10 mean level in the HC group was higher than those in the other groups (p < 0.05). In the RA-a group, higher IL-10 level was found compared to the CP patients (p < 0.05). Within the limitations of this preliminary report, it can be concluded that the initiation and progression of periodontal inflammation may be due to a lack or inappropriate response of the anti-inflammatory cytokines in both CP and RA.

Bozkurt FY, Ay ZY, et al. Cytokine, Volume 35, Issues 3-4, August 2006, Pages 180-185.
http://www.sciencedirect.com/science? _ob=ArticleURL&_udi=B6WDF- 4KXF2VS- 1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_ userid=10&md5=c2c0d4c5 2d4e9ae3f7e968023be1e09d

Background: Elevated levels of C-reactive protein (CRP) and decreased plasma adiponectin are associated with increased risk of atherosclerosis. Furthermore, recent observations suggested that adiponectin and tumor necrosis factor-a(TNF-a a) suppressed each ) other's production. Since periodontal disease has been suggested to act as a risk factor for atherosclerosis, we examined the effects of antimicrobial periodontal treatment on CRP, adiponectin, and TNF-a levels. Methods: Fifteen chronic periodontitis patients with various systemic conditions at high risk for atherosclerosis were enrolled in the study. Patients were non- nonsurgically treated with surgically topical application of antibiotics and mechanical debridement of calculus once a week for 1 month. Before and after therapy, CRP, adiponectin, and TNF-a levels were measured. Results: Both CRP and TNF-a levels wer were signifi- cantly decreased after treatment (P <0.01 and P <0.03, respectively), while adiponectin levels did not change significantly. Conclusions: Periodontal treatment is effective in reducing CRP and TNF-a a, while adiponectin does not , appear to be influ influenced by enced periodontal treatment. Elevated levels of CRP and TNF-a may be associated with increased risk for future development of atherosclerosis in periodontitis patients Iwamoto Y, Nishimura F, et al. .

J Periodontol 2003; 74:1231-1236.
http://www.joponline.org/doi/abs/10.1902/jop.2003.74.8.1231

Arterial thrombosis results from endovascular injury and, to a lesser extent, alterations in hemostatic equilibrium. Endothelial cell injury with the elaboration of proinflammatory mediators stimulates the process of arterial thrombosis. Although this is most often the result of endovascular injury attributable to atherosclerotic disease, other disease states can elicit a similar response as well. Epidemiological studies have identified several acquired or inherited states that may result in endothelial damage or altered hemostatic equilibrium, thereby predisposing patients to arterial thrombosis. These include hyperhomocysteinemia, elevated C-reactive protein, antiphospholipid antibodies, elevated fibrinogen, Factor VII, plasminogen activator inhibitor-1 (PAI-1), hereditary thrombophilias, and platelet hyper-reactivity. At present, the literature supports a role for hyperhomocysteinemia, elevated C-reactive protein, and elevated fibrinogen as risk factors for arterial thrombosis.

David Feinbloom; Kenneth A. Bauer. Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2043. http://atvb.ahajournals.org/cgi/content/abstract/25/10/2043

Background: Moderate elevation of C-reactive protein (CRP) is thought to predict type 2 diabetes and cardiovascular disease (CVD), both of which are associated with periodontitis. Recent studies indicate that periodontal disease is associated with moderate elevation of CRP; however, the relationship between alveolar bone loss (ABL) and CRP elevation is unclear. Methods: A total of 179 Japanese men aged 50 to 54 years old, with at least 10 teeth, were examined as part of a comprehensive health examination before retirement from the Japan Self-Defense Force. ABL was measured at proximal sites of posterior teeth on a panoramic x-ray film. The relationship between the mean ratio of ABL to root length and serum CRP level and other variables was analyzed. Results: ABL was significantly correlated with serum CRP level (P = 0.008), alkaline phosphatase (P = 0.008), high-density lipoprotein (HDL) cholesterol (P = 0.04, inversely), white blood cell count ( P <0.001), erythrocyte sedimentation rate (P = 0.002), age (P = 0.03), and smoking history ( P <0.001). In a multiple logistic regression model adjusted for age, smoking history, systolic blood pressure, body-mass index, triglyceride, and HDL cholesterol, subjects in the highest tertile of ABL had an increased risk for CRP elevation = 1.3 mg/l (odds ratio [OR] = 8.20; 95% confidence interval [CI], 1.6 to 40.7; P = 0.01) when compared to the lowest tertile of ABL. Conclusion: ABL around posterior teeth was associated with elevated CRP in Japanese men, suggesting an association between periodontal disease and increased risk of type 2 diabetes and CVD.

Saito T, Murakami M, et al. J Periodontol 2003;74:1741-1746.
http://www.joponline.org/doi/abs/10.1902/jop.2003.74.12.1741

Atherosclerosis is regarded as a dynamic and progressive disease arising from the combination of endothelial dysfunction and inflammation. This article is the second in a 2-part series examining emerging markers of inflammation and endothelial cell activation. The first article provided a brief overview of the link between inflammation, endothelial dysfunction, and atherosclerosis and began the examination of emerging inflammatory mediators. This second article continues with an exploration of more novel markers for cardiovascular disease. Conclusion: Atherosclerosis is no longer considered a pure lipid disorder.It has become increasingly clear that inflammation is at the root of atherosclerosis and its complications. In addition to playing a causal role in lesion formation, inflammation can yield predictive and prognostic information of considerable clinical utility. A number of mechanisms and mediators of inflammation have been identified, of which high-sensitivity CRP has emerged as one of the most important. In addition to serving as biomarkers of atherosclerotic events, inflammatory mediators directly participate in lesion formation, propagation, and eventual rupture and in this fashion may represent a powerful tool to assess endothelial cell activation. Clearly, understanding the mechanisms and mediators of endothelial dysregulation and inflammation may yield new targets to predict, prevent, and treat cardiovascular disease.

Szmitko PE, Wang CH, et al. Circulation. 2003;108:2041
http://circ.ahajournals.org/cgi/content/full/108/17/2041? maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=w ang&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

Background: We examined the blood test values of people who received general medical checkups and their Community Periodontal Index (CPI) score. Methods: A total of 7,452 persons (5,742 males and 1,710 females), who had general medical and dental checkups, were the subjects of the study. Many were people who worked for companies in and around Nagoya and their family members, ranging in age from 16 to 80 years. The blood test in our study consisted of 37 items used in general blood tests. Partial-mouth recordings were used to measure CPI scores. The highest CPI score for each subject was used for analysis. Odds ratios and confidence interval values were obtained using the Mantel-Haenszel method to analyze the results. Results: CPI scores of 3 and 4 were related to the test values of high-density-lipoprotein cholesterol, serum iron, white blood cell count, fasting blood sugar, glycosylated hemoglobin A1, glycosylated hemoglobin A1c A1c, and C- , Creactive protein. reactive Conclusion: Blood test values tended to show correlations with CPI scores, more clearly seen in males than in females.

Takami Y, Nakagaki H, et al. J Periodontol 2003;74:1778-1784.
http://www.joponline.org/doi/abs/10.1902/jop.2003.74.12.1778

The body's response to inflammation may play an important part in influencing the progression of atherosclerosis.

Mendall MA, Patel P, et. al. BMJ 1996;312:1061-1065 (27 April).
http://bmj.bmjjournals.com/cgi/content/ abstract/312/7038/1061

achieved LDL levels did not appear to independently impact the rate of CVE. In contrast, patients with elevated CRP levels were at higher risk of stroke or transient ischemic attack, reinforcing the link between inflammation and CVE. Condensed abstract : The goal of this PROVE IT-TIMI 22 sub-study was to examine the relationship between cholesterol, CRP, and CVE in patients on intensive and moderate statin therapy. The achieved lipid levels were similar in patients with and without a CVE; however, the achieved levels of CRP were higher in patients who subsequently developed a stroke or TIA. These findings further support the relationship between inflammation and CVE.

Mega JL, Morrow DA, et al. Journal of Thrombosis and Thrombolysis, Volume 22, Number 1 / August, 2006, http://www.springerlink.com/content/741j686630768782/? p=074be5c62cac44ab980715597fe3dc41&pi=9 9.

Highsensitivity C-reactive protein (hsCRP) is associated with adverse cardiovascular outcomes in acute coronary syndromes (ACS). The ability to formulate recommendations regarding clinical use of hsCRP is limited by a paucity of data regarding several key issues. The purpose of this study was to evaluate hsCRP across the spectrum of ACS.. Increased baseline concentrations of hsCRP are strongly associated with mortality and heart failure across the ACS spectrum. hsCRP measurement should be performed early after presentation and index diagnosis-specific cutpoints should be used. Lower CRP in patients on prior aspirin or statin therapy, is a finding which supports the hypothesis that these agents may affect the inflammatory processes in acute coronary syndrome.

Scirica BM, Morrow, DA, et al. Clinical Chemistry 53:1800-1807, Oct 2007.
http://www.clinchem.org/cgi/content/abstract/53/10/1800

C-reactive protein (CRP), a marker of inflammation that has been shown in multiple prospective epidemiological studies to predict incident myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death. CRP levels have also been shown to predict risk of both recurrent ischemia and death among those with stable and unstable angina, those undergoing percutaneous angioplasty, and those presenting to emergency rooms with acute coronary syndromes. CRP is an independent predictor of future cardiovascular events that adds prognostic information to lipid screening, to the metabolic syndrome, and to the Framingham Risk Score.

Ridker PM, Circulation: Journal of the American Heart Association: Volume 107(3) 28 January 2003 pp 363-369, http://pt.wkhealth.com/pt/re/circ/fulltext.00003017-200301280- 00017.htm;jsessionid=GdsbRvFtQ8wg71bkQySLXZ1GXT5pcLhGS5mJTfPnvMWsJL5Zvm3m! 869285401!- 949856145!8091!-1

a recently published prospective study comprising 28 000 women, Ridker et al showed that C-reactive protein (CRP) is a better predictor of the risk of cardiovascular events than low-density lipoprotein (LDL) cholesterol. The implication of this and many other supporting studies is profound and will change the way we screen and manage our patients with atherosclerosis and its associated clinical syndromes. CRP is one of the acute phase proteins that increase during systemic inflammation. 2,3 Individuals without inflammation usually have CRP levels below 1 µ µg/mL; however, patients with g/bacterial infections, autoimmune diseases, and cancer frequently have CRP level as high as 100 µ µg/mL or even higher. g/It is clear that a high CRP level has no specificity in differentiating disease entities from one another. Despite its lack of specificity, CRP has now emerged as one of the most powerful predictors of cardiovascular risk. Even more remarkable, CRP's predictive power resides in the range between 1 to 5 µ µg/mL, which was previously regarded to be normal in the era g/preceding the highsensitivity CRP test. In fact, tests showing serum CRP levels greater than 10 µ µg/mL in apparently healthy g/men or women should be repeated to exclude occult infection or other systemic inflammatory process (see Figure). To understand CRP's transition from an acute phase protein to a most useful inflammatory biomarker for predicting future cardiovascular events, we must know more about the role of the immune system in the pathogenesis of atherosclerosis.

Yeh ETH, Willerson JT. Circulation 2003;107:370.
http://circ.ahajournals.org/cgi/content/extract/107/3/370? maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=r idker&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

because C-reactive protein and LDL cholesterol measurements tended to identify different highrisk groups, screening for both biologic markers provided better prognostic information than screening for either alone. Independent effects were also observed for C-reactive protein in analyses adjusted for all components of the Framingham risk score. These data suggest that the C-reactive protein level is a stronger predictor of cardiovascular events than the LDL cholesterol level and that it adds prognostic information to that conveyed by the Framingham risk score.

Ridker PM, Rifai N, et.al., NEJM, Nov 14, 2002 Vol. 347:1557-1565 No 20.
http://content.nejm.org/cgi/content/ abstract/347/20/1557

Plasma C-reactive protein (CRP) concentration is a strong predictor of atherosclerosis. However, to date, there is no in vivo evidence that CRP is proatherogenic. Conclusions- Human CRP transgene expression causes accelerated aortic atherosclerosis in apoE-/- mice. CRP was detected in the lesion, which was associated with increased C3 deposition and increased AT1-R, vascular cell adhesion molecule-1, and collagen expression. These data document a proatherogenic role for CRP in vivo. Paul A, Ko KWS, Chan L, et al Circulation. 2004;109:647-655

http://circ.ahajournals.org/cgi/content/abstract/109/5/647? maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext= lawrence+chan&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

Several large prospective studies have shown that baseline levels of C-reactive protein (CRP) are an independent predictor of cardiovascular events among apparently healthy individuals. However, prospective data on whether CRP predicts cardiovascular events in diabetic patients are limited so far. High plasma levels of CRP were associated with an increased risk of incident cardiovascular events among diabetic men, independent of currently established lifestyle risk factors, blood lipids, and glycemic control.

Schulze M, Rimm EB, et.al. Diabetes Care 27:889-894, 2004.
http://care.diabetesjournals.org/cgi/content/abstract/27/4/889? maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&auth or1=Schulze&searchid=1081215809897_10507&stored_search=&FIRSTINDEX=0&sortspec=rel evance&volume=27&first page=889&journalcode=diacare

The authors concluded that increasing levels of Creactive protein are an independent predictor of cardiovascular events and are even more strongly associated with cardiovascular risk than increased LDL cholesterol levels.

http://www.aafp.org/afp/20030315/ tips/27.html

High C-reactive protein (CRP) is associated with increased coronary heart disease risk. Few long-term data in the elderly are available. In older men and women, elevated CRP was associated with increased 10-year risk of CHD, regardless of the presence or absence of cardiac risk factors. A single CRP measurement provided information beyond conventional risk assessment, especially in intermediate-Framingham-risk men and high- Framingham-risk women.

Cushman M, Arnold A, et.al. Circulation. 2005;112:25-31.
http://circ.ahajournals.org/cgi/content/ abstract/112/1/25

Inflammation plays a pivotal role in atherosclerosis. In addition to being a risk marker for cardiovascular disease, much recent data suggest that C-reactive protein (CRP) promotes atherogenesis via effects on monocytes and endothelial cells. The metabolic syndrome is associated with significantly elevated levels of CRP. Plasminogen activator inhibitor-1 (PAI-1), a marker of atherothrombosis, is also elevated in the metabolic syndrome and in diabetes, and endothelial cells are the major source of PAI-1. This study makes the novel observation that CRP induces PAI-1 expression and activity in HAECs and thus has implications for both the metabolic syndrome and atherothrombosis.

American Heart Assoc Journal Circulation, 2003;107:398-404 404. Devaraj S et.al, Univ of California, Davis Medical Center. . http://circ.ahajournals.org/cgi/content/abstract/107/3/398

Objective: To examine whether C-reactive protein (CRP) level is a risk factor for aging macula disorder (AMD) in a general population. .Conclusion: Elevated baseline levels of HsCRP were associated with the development of early and late AMD in this large population-based cohort.

Boekhoorn SS, Vingerling JR, Witteman JCM, Hofman A, et al. Arch Ophthalmol. 2007;125:1396- 1401.
http://archopht.ama-assn.org/cgi/content/short/125/10/1396

The Framingham Coronary Heart Disease (CHD) prediction score is recommended for global risk assessment in subjects prone to CHD. Recently, Creactive protein (CRP) has emerged as an independent predictor of CHD. We sought to assess the potential of CRP measurements to enhance risk prediction based on the Framingham Risk Score (FRS) in a large cohort of middle-aged men from the general population. Our results suggest that CRP enhances global coronary risk as assessed by the FRS, especially in intermediate risk groups. This might have implications for future risk assessment.]

Koenig W, Löwel H, et.al. Circulation. 2004;109:1349-1353.
http://circ.ahajournals.org/cgi/content/abstract/109/11/1349

Inflammatory reactions in coronary plaques play an important role in the pathogenesis of acute atherothrombotic events; inflammation elsewhere is also associated with both atherogenesis generally and its thrombotic complications. Recent studies indicate that systemic markers of inflammation can identify subjects at high risk of coronary events. These results confirm the prognostic relevance of CRP, a sensitive systemic marker of inflammation, to the risk of CHD in a large, randomly selected cohort of initially healthy middle-aged men. They suggest that low-grade inflammation is involved in pathogenesis of atherosclerosis, especially its thrombo-occlusive complications.

Koenig et al, Circulation. 1999;99:237-242.
http://circ.ahajournals.org/cgi/content/abstract/ circulationaha;99/2/237

C- Creactive protein (CRP) reactive is an independent determinant of risk of stroke among both men and women. Emerging data suggest that CRP may be a mediator as well as a marker of atherosclerosis. CRP induces expression of cellular adhesion molecules, interleukin-6, and endothelin-1 by endothelial cells. CRP also mediates monocyte chemoattractant protein-1 induction, and it has been shown to mediate uptake of LDL by macrophages. Furthermore, smooth muscle cells and macrophages in arterial tissue have been shown to produce CRP, a process that is substantially upregulated in atherosclerotic plaque.

Gavin J. Blake; Paul M. Ridker,
http://atvb.ahajournals.org/cgi/content/full/22/10/1512

Prospective data suggest that measurement of CRP adds clinically important prognostic information to the metabolic syndrome.

Ridker PM, Buring JE, et al. Circulation. 2003;107:391.
http://circ.ahajournals.org/cgi/content/ abstract/107/3/391

C-reactive protein (CRP) has emerged as an interesting novel and potentially clinically useful marker for increased cardiovascular risk. This is an attractive concept because atherosclerosis is a disease characterized by chronic arterial inflammation and suggests the possibility that subclinical states of atherosclerosis can be identified by an increase in circulating markers of inflammation before acute events occur. Based on data obtained primarily from in vitro studies it has also been proposed that CRP in itself is actively contributing to disease progression and that it should be considered as true risk factor and consequently as a target for intervention. The association between moderately elevated CRP levels and an increased risk for development of cardiovascular disease is well established.

Jan Nilsson. Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1527. http://atvb.ahajournals.org/cgi/content/full/25/8/1527

Temporomandibular joint disorders (TMD) comprise a group of chronic painful conditions of mastication in the temporomandibular joint (TMJ). Although the association between TMD and internal derangement of the TMJ is well documented, the functional relevance is still unclear. Increased concentrations of inflammatory mediators have been identified in the synovial fluid of affected patients with TMD, suggesting an underlying degenerative or inflammatory process. The aim of this study was to generate a comprehensive cytokine expression profile in TMD. Conclusions: This study confirmed previous reports of elevated cytokine levels in TMD. Additionally, we identified previously undescribed cytokines that were upregulated and correlated significantly with the presence of JE. We were able to identify novel cytokines that have hitherto not been described in TMD. Strategies targeting the identified cytokines may represent a novel therapy option in TMD.

Matsumoto K, Honda K, et.al. Dentomaxillofacial Radiology (2006) 35, 432-441. http://dmfr.birjournals.org/cgi/content/abstract/35/6/432

Although periodontal diseases are initiated by bacteria that colonize the tooth surface and gingival sulcus, the host response is believed to play an essential role in the breakdown of connective tissue and bone, key features of the disease process. An intermediate mechanism that lies between bacterial stimulation and tissue destruction is the production of cytokines, which stimulates inflammatory events that activate effector mechanisms. These cytokines can be organized as chemokines, innate immune cytokines, and acquired immune cytokines. Although they were historically identified as leukocyte products, many are also produced by a number of cell types, including keratinocytes, resident mesenchymal cells (such as fibroblasts and osteoblasts) or their precursors, dendritic cells, and endothelial cells. Chemokines are chemotactic cytokines that play an important role in leukocyte recruitment and may directly or indirectly modulate osteoclast formation. This article focuses on aspects of osteoimmunology that affect periodontal diseases by examining the role of cytokines, chemokines, and immune cell mediators. It summarizes some of the key findings that attempt to delineate the mechanisms by which immune factors can lead to the loss of connective tissue attachment and alveolar bone. In addition, a discussion is presented on the importance of clarifying the process of uncoupling, a process whereby insufficient bone formation occurs following resorption, which is likely to contribute to net bone loss in periodontal disease.

Graves D. Journal of Periodontology, 2008, Vol. 79, No. 8s, Pages 1585-1591. http://www.joponline.org/doi/full/10.1902/jop.2008.080183

Tumor necrosis factor: A member of a superfamily of proteins proteins, each with , 157 amino acids, which induce necrosis (death) of tumor cells and possess a wide range of proinflammatory actions. Tumor necrosis factor is a multifunctional cytokine with effects on lipid metabolism, coagulation, insulin resistance, and the function of endothelial cells lining blood vessels. Blocking the action of TNF has been shown to be beneficial in reducing the inflammation in inflammatory diseases.

http://www.medterms.com/script/main/art.asp? articlekey=25458

Periodontitis is associated with elevated levels of C-reactive protein and fibrinogen and it may be a coronary heart disease risk factor. Periodontitis seems to increase C-reactive protein only in some individuals, presumably the ones reacting to it with a systemic inflammatory reaction. Periodontal treatment decreases C-reactive protein levels in these individuals and it may thus decrease their risk of coronary heart disease.

Mattila K, Vesanen M, et al, BMC Infectious Diseases 2002, 2:30. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=138813&rendertype=abstract

Interleukin-1.BETA.(IL-1.BETA.) and tumor necrosis factor-.ALPHA.(TNF- .ALPHA.), two potent inflammatory cytokines in periodontitis, were believed to play a significant role in production of matrix metalloproteinases(MMPs), which might be involved in bone loss and connective tissue breakdown. On the other hand, IL-1.BETA. had been shown to induce expression of decorin which was a major small proteoglycan participating in the maintenance of periodontal tissue integrity. These cytokines appeared to have a divergent biochemical function in either tissue degradation or regeneration process. To elucidate the molecular mechanisms involved in periodontitis, we examined the effects of IL-1.BETA. and TNF-.ALPHA. on expression of MMPs, tissue inhibitors of matrix metalloproteinases(TIMPs), type I collagen and decorin in cultured human periodontal ligament fibroblasts(HPLF). Northern blot analyses showed that each cytokine alone increased the expression of MMP-1 and MMP-2 mRNA and no synergistic effect of these cytokines were detected. Furthermore, Western blot analyses showed that each cytokine increased the production of partially activated MMP-1, while only TNF-.ALPHA. participated in the formation of fully activated MMP-1. Since MMP-3 and plasmin were reported to be important activators of MMP-1, we have examined the effects of inflammatory cytokines on the expression of MMP-3 and urokinase type plasminogen activator (uPA), an activator of plasminogen to plasmin. Neither IL-1.BETA. nor TNF-.ALPHA. participated in the induction of active form of MMP-3 or uPA, suggesting that the enzyme and the activator were not involved in the cascade of MMP-1 activation. Whereas IL- 1.BETA. or TNF-.ALPHA. alone increased the expression of decorin mRNA, the addition of both cytokines resulted in suppression of the decorin gene expression. The production of type I collagen mRNA was markedly decreased by either cytokine and the synergistic suppressive effect of these cytokines was detected

Hasegawa Eli, Sasaguri Ken'ichi, et al. Journal of the Kanagawa Odontological Society, Vol. 35; No. 1; Pp 27-28(2000).
http:// sciencelinks.jp/jeast/ article/200103/000020010300A1036009.php

Periodontitis is a common, often undiagnosed, chronic infection of the supporting tissues of the teeth, epidemiologically associated with cardiovascular diseases. Since Creactive protein (CRP) and other systemic markers of inflammation have been identified as risk factors for cardiovascular diseases, we investigated whether these factors were elevated in periodontitis. Periodontitis results in higher systemic levels of CRP, IL-6, and neutrophils. These elevated inflammatory factors may increase inflammatory activity in atherosclerotic lesions, potentially increasing the risk for cardiac or cerebrovascular events. Loos BG, Craandijk J, et al.

Journal of Periodontology, October 2000, Vol. 71, No. 10, Pages 1528-1534. http://www.joponline.org/doi/abs/10.1902/jop.2000.71.10.1528

In the current Adult Treatment Panel guidelines for cardiovascular risk detection, the plasma-based markers recommended for use in global risk assessment or in the definition of the metabolic syndrome are low-density lipoprotein cholesterol (LDL-C), highdensity lipoprotein cholesterol, and triglycerides. It is widely recognized, however, that more than half of all future vascular events occur in individuals without overt hyperlipidemia. . Although risk-scoring systems that additionally evaluate traditional risk factors such as smoking, hypertension, and diabetes greatly improve risk prediction, multiple studies demonstrate that 20% to 25% of all future events occur in individuals with only 1 of these factors. Moreover, the prevalence of traditional risk factors is almost as high in those without disease as in affected individuals. As our understanding of the pathobiology of atherothrombosis has improved, researchers have attempted to evaluate the activities of these biological processes by measuring markers in plasma or urine (ie, biomarkers). Indeed, a series of candidate biomarkers reflecting inflammation, hemostasis, thrombosis, and oxidative stress have been evaluated as potential clinical tools in an effort to improve risk prediction. To be useful in a clinical setting, the biomarker of interest must be shown in multiple prospective studies to predict future cardiovascular events. Retrospective studies are of limited value because they are prone to bias and cannot exclude the possibility that the particular biomarker is elevated as a result of, rather than a cause of, disease. To be used widely, the proposed biomarker should provide independent information on risk or prognosis beyond that available from global assessment algorithms such as the Framingham Risk Score. The biomarker additionally should be easy to measure in a cost-effective manner in outpatient settings. This typically requires an inexpensive and standardized commercial assay with low variability that does not require specialized plasma collection or assay techniques. Although not a critical issue for risk prediction, the biomarker will have broader acceptance if reduction of the biomarker leads to reduced vascular risk. Several established and emerging novel biomarkers for vascular risk meet these criteria, although few are ready for clinical practice. With the exception of high-sensitivity C-reactive protein (hsCRP), none has demonstrated additive value over and above Framingham risk scoring, and few are supported by commercial assays that achieve appropriate levels of standardization and accuracy for clinical use. Additionally, no clear evidence exists that lowering plasma levels of any of these biomarkers, including hsCRP, lowers vascular risk. However, many of these novel biomarkers provide important insights into the pathophysiology of atherothrombosis and serve as important research tools. This overview focuses on established and emerging biomarkers in the prediction of atherothrombotic events in apparently healthy individuals and thus includes discussion of markers of inflammation, fibrinolysis, oxidative stress, and altered lipids. It is important to recognize that other emerging vascular biomarkers, including brain natriuretic peptide and myeloperoxidase, have shown initial promise in the setting of acute myocardial ischemia but have yet to be evaluated in outpatient screening of healthy individuals. Other novel markers emerging in primary prevention include those related to adipocyte function, including adiponectin..There is considerable pathophysiologic and clinical interest in the development of novel biomarkers for inflammation, hemostasis, thrombosis, and oxidative stress that may help in the detection of individuals at high risk for future vascular events. However, . few of these markers have demonstrated an ability to predict risk over and above information available from global assessment tools such as the Framingham Risk Score, and no evidence is available demonstrating that specific reductions in any of these novel markers will lower vascular risk. Although this overview has focused on the role of biomarkers for prognosis in primary prevention, it remains possible that several biomarkers will prove useful for demonstrating efficacy of therapy or in predicting specific patient groups more or less likely to benefit from targeted interventions. It also remains probable that no single biomarker will emerge that provides appropriate information for all clinical settings; thus, multimarker approaches also need evaluation. Ongoing efforts in plasma-based biomarker research will simultaneously need to address novel pathways of disease and carefully evaluate clinical applications and clinical efficacy.

Ridker PM, Brown NJ, et al. Circulation 2004;109:IV-6-IV-19).
http://circ.ahajournals.org/cgi/content/full/109/25_suppl_1/IV- 6? maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=ridker&searchid=1&FIRSTIN DEX=0&resourcetype=H WCIT

Most studies have evaluated serum C-reactive protein (CRP) levels in chronic periodontitis (CP) patients, and a few investigations have examined gingival crevicular fluid (GCF) CRP levels. The aims of this study were to determine GCF and serum levels of high-sensitivity CRP (HsCRP) in CP patients with or without coronary artery disease (CAD) and to investigate the relationship between the GCF and serum HsCRP levels in CP patients with and without CAD. . Patients with CP and CP + CAD had statistically significant elevations in serum HsCRP levels compared to healthy subjects. However, HsCRP levels of GCF did not differ from those of the control and CP groups or the control and CP + CAD groups. Further studies are needed to clarify the relationship between GCF CRP levels and periodontal diseases.

Tuter G, Kurtis B, Serdar M. Journal of Periodontology 2007, Vol. 78, No. 12, Pages 2319-2324 , http://www.joponline.org/doi/abs/10.1902/jop.2007.070150 .

Background and Objective: The aim of this work was to investigate periodontal status, in relation to inflammatory markers and cortisol, in the gingival crevicular fluid and saliva of a homogenous group of women on long-term sick leave for job-stress related depression in comparison to nondepressed women. Conclusion: Women on long-term sick-leave for depression had more severe periodontitis and higher concentrations of interleukin-6 in gingival crevicular fluid than healthy controls. An alteration of the immune system in these patients might be interpreted as reflecting the consequences of long-term stress exposure and might contribute to worse periodontal conditions in these particular patients.

Johannsen A, Rydmark I, et al., Journal of Periodontal Research Volume 42 Issue 6 Page 546-552, December 2007, http://www.blackwell-synergy.com/doi/abs/10.1111/ j.1600-0765.2007.00980.x

Inflammation plays a major role in atherothrombosis, and measurement of inflammatory markers such as high-sensitivity C-reactive protein (HSCRP) may provide a novel method for detecting individuals at high risk of plaque rupture. Several large-scale prospective studies demonstrate that HSCRP is a strong independent predictor of future myocardial infarction and stroke among apparently healthy men and women and that the addition of HSCRP to standard lipid screening may improve global risk prediction among those with high as well as low cholesterol levels. Because agents such as aspirin and statins seem to attenuate inflammatory risk, HSCRP may also have utility in targeting proven therapies for primary prevention. Inexpensive commercial assays for HSCRP are now available; they have shown variability and classification accuracy similar to that of cholesterol screening. Risk prediction algorithms using a simple quintile approach to HSCRP evaluation have been developed for outpatient use. Thus, although limitations inherent to inflammatory screening remain, available data suggest that HSCRP has the potential to play an important role as an adjunct for global risk assessment in the primary prevention of cardiovascular disease.

Ridker PM Circulation. 2001;103:1813.
http://circ.ahajournals.org/cgi/content/full/103/13/1813#F4

As expected, elevated serum hsC-rp concentration and serum WBC counts are associated with acute coronary heart disease. (2) Elevated serum hsC-rp values are associated with radiographically defined periodontitis in subjects with no evidence of CVD.

Persson G., Pettersson T., et al, J Clin Perio 32: 219-224, 2005.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=15766362&dopt=Abstract

There are exciting new developments regarding the molecular mechanisms involved in the influence of circulating proinflammatory molecules within cells of the blood-brain barrier (BBB) during systemic immune challenges. These molecules, when present in the circulation, have the ability to trigger a series of events in cascade, leading to either the mitogen-activated protein (MAP) kinases/nuclear factor kappa B (NF- B) or the janus kinase (JAK)/signal transducer and activator of transcription (STAT) transduction pathways in vascular-associated cells of the central nervous system (CNS). The brain blood vessels exhibit both constitutive and induced expression of receptors for different proinflammatory ligands that have the ability to stimulate these signaling molecules. Depending on the challenges and the cytokines involved, the transduction signal(s) solicited in cells of the BBB may orient the neuronal activity in a very specific manner in activating the transcription and production of soluble factors, such as prostaglandins (PGs). It is interesting to note that cytokines as well as systemic localized inflammation stimulate the cells of the BBB in a nonselective manner (i.e., within both large blood vessels and small capillaries across the brain). This nonselectivity raises several questions with regard to the localized neuronal activation induced by different experimental models of inflammation and cytokines. It is possible that the selectivity of the neuronal response is a consequence of the fine interaction between

Type 1 diabetes (T1DM) is associated with increased cardiovascular mortality. It is a proinflammatory state as evidenced by increased circulating biomarkers and monocyte activity. The toll-like receptors (TLRs) are pattern recognition receptors, expressed abundantly on monocytes. TLR2 and TLR4 are important in atherosclerosis. However, there is a paucity of data examining TLR2 and TLR4 expression in T1DM and examining its contribution to the pro-inflammatory state. Objective: Thus, we examined TLR2 and TLR4 expression in monocytes from T1DM patients compared to controls (n=31/group)..Conclusion: Thus, we make the novel observation that TLR2 and TLR4 expression and signaling are increased in T1DM and contribute to the pro-inflammatory state.

Devaraj S, Dasu MR, Jialal I, et al. Online Journal of Clinical Endocrinology & Metabolism, Nov 20, 2007. http://jcem.endojournals.org/cgi/ content/abstract/jc.2007- 2185v1? maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&author1=Jialal&andorexacttitle=and& andorexacttitleabs =and&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype =HWCIT

Most studies have evaluated serum C-reactive protein (CRP) levels in chronic periodontitis (CP) patients, and a few investigations have examined gingival crevicular fluid (GCF) CRP levels. The aims of this study were to determine GCF and serum levels of high-sensitivity CRP (HsCRP) in CP patients with or without coronary artery disease (CAD) and to investigate the relationship between the GCF and serum HsCRP levels in CP patients with and without CAD. . Patients with CP and CP + CAD had statistically significant elevations in serum HsCRP levels compared to healthy subjects. However, HsCRP levels of GCF did not differ from those of the control and CP groups or the control and CP + CAD groups. Further studies are needed to clarify the relationship between GCF CRP levels and periodontal diseases.

Tuter G, Kurtis B, Serdar M. Journal of Periodontology 2007, Vol. 78, No. 12, Pages 2319-2324 , http://www.joponline.org/doi/abs/10.1902/jop.2007.070150 .

A recent search (Google News) for media articles published on inflammation identified more than 9,000 stories in a 4-week period in 2008. . This interest by the media and public is being fueled by an explosion of scientific knowledge on inflammation and chronic diseases of aging. For example, a recent PubMed search for scientific publications on "inflammation" published within a 12-month period prior to May 1, 2008 returned >16,500 papers. During the same period, 161 papers were published on "periodontal disease" and "inflammation." Recognition of the research advances and importance of inflammatory mechanisms in essentially all of the chronic diseases of aging, including periodontal diseases, led the American Academy of Periodontology to convene a conference on January 29 and 30, 2008 in Boston titled, "Inflammation and Periodontal Diseases: A Reappraisal." This conference brought together opinion leaders in several major diseases and in the inflammatory mechanisms that seem to underlie and unify all of these diseases. Inflammation is now known to play a critical role in diseases that are not usually classified as inflammatory diseases, such as cardiovascular disease and Alzheimer's disease. Although this conclusion is the result of many years of research, much of the knowledge has crystallized into coherent concepts only very recently. The Boston conference brought together many of the people who have lead the new thinking relative to inflammation. Much of this new knowledge and the new concepts are captured in outstanding short overview papers in this supplement to the Journal of Periodontology Periodontology.

Van .] Dyke TE. Journal of Periodontology 2008, Vol. 79, No. 8s, Pages 1501-1502, http://www.joponline.org/doi/full/10.1902/jop.2008.080279

Recent data have . revealed that the plasma concentration of inflammatory mediators, such as tumour necrosis factor-a (TNF-a a) and ) interleukin interleukin-6 (IL-6), is -increased in the insulin resistant states of obesity and type 2 diabetes, raising questions about the mechanisms underlying inflammation in these two conditions. It is also intriguing that an increase in inflammatory mediators or indices predicts the future development of obesity and diabetes. Two mechanisms might be involved in the pathogenesis of inflammation. Firstly, glucose and macronutrient intake causes oxidative stress and inflammatory changes. Chronic overnutrition (obesity) might thus be a proinflammatory state with oxidative stress. Secondly, the increased concentrations of TNF-a and IL IL-6, associated -with obesity and type 2 diabetes, might interfere with insulin action by suppressing insulin signal transduction. This might interfere with the anti-inflammatory effect of insulin, which in turn might promote inflammation.

Dandona P, Aljada A, Bandyopadhyay A. Trends in Immunology Immunology, Vol. 25, Issue 1, Jan 2004, P 4-7. , http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6W7H-49YH899- 1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version= 1&_urlVersion=0&_userid =10&md5=f92755b6c587b8b7a67701c6d0579e0c

The understanding of the pathophysiology governing atherosclerosis supports a prominent role for inflammation pathways in plaque initiation and progression that result in stroke and myocardial infarction. Elevated levels of inflammatory markers in the blood, such as C-reactive protein and CD40 ligand/CD40, in concert with increased expression of adhesion molecules, chemokines, cytokines, matrix metalloproteinases (MMP), and inflammatory cells in the plaque, characterize the symptomatic atherothrombotic state.

Thomas J. DeGraba, MD Stroke. 2004;35:2712.
http://stroke.ahajournals.org/cgi/content/full/35/11_suppl_1/2712

C-reactive protein, a marker of inflammation circulating in the blood already associated with increased risk of heart disease, can also be used to identify a person's risk of developing colon cancer, according to a Johns Hopkins study.

http://www.hopkinsmedicine.org/Press_releases/2004/02_10_04.html

Background: Lipopolysaccharide (LPS)- stimulated macrophages (M[Phi]) produce excess tumor necrosis factor (TNF), and the direct inhibition of I[kappa]B phosphorylation and its subsequent separation from the nuclear factor [kappa]B (NF[kappa]B)-I[kappa]B complex has been experimentally supported as a mechanism for [omega]-3 fatty acid (FA) inhibition of this TNF response. However, TNF production is a "late" event in the LPS-mduced M[Phi] inflammatory cascade, and in addition to NF[kappa]B-associated pathways, a separate transcription factor, activator protein-1 (AP-1) is an important pathway for M[Phi] proinflammatory cytokine production. The mitogenactivated protein kinase (MAPK) cascade regulates both NF[kappa]B-I[kappa]B-and AP-1-associated gene transcription through several cross-amplifying phosphorylation kinases, specifically p44/42 [ie, extracellular signal-regulated kinase (ERK) 1/2], p38, and c/jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK). The activation of these kinases occurs in the proximal MAPK cascade and activation modulates AP-1 activation. In this set of experiments, it was hypothesized that inhibition of MAPK signaling phosphorylation kinases by [omega]-3 fatty acids in a model of LPSstimulated M[Phi]s would alter the activation of the proinflammatory cytokine transcription factor AP-1. . Conclusions: [omega]-3 FA inhibited p44/42 and JNK/SAPK phosphorylation; however, p38 remained unchanged. Phosphorylation of p44/42 and JNK/SAPK are the immediate prior steps in AP-1 activation. Attenuated AP-1 activation and subsequent attenuated gene-level proinflammatory cytokine elaboration is anticipated after inhibition of these MAPK intermediates and is confirmed by the reduction in AP-1 activity. These results provide further evidence for the transcriptional level regulation in the elaboration of proinflammatory cytokines by [omega]-3 FA in this M[Phi] model.

Babcock TA, Kurland A, et.al. Journal of Parenteral and Enteral Nutrition 27:176-181, 2003. http://findarticles.com/p/articles/mi_qa3762/is_200305/ai_n9216984

There is an increased risk of death associated with elevated levels of IL-6 and CRP in nondisabled older persons. These findings may broaden our understanding of the health correlates and consequences of low-level inflammation, as well as providing a new way to identify high-risk subgroups for anti-inflammatory interventions.

Harris TB, Ferrucci Luigi, et al., Am J Med. 1999;106:506-512.
http://dceg.cancer.gov/pdfs/harris1065061999.pdf

C-reactive protein (CRP) and glycohemoglobin (HbA1c) are established risk factors for the development of cardiovascular disease. Inflammation, indicated by hs-CRP, and hyperglycemia, indicated by HbA1c, jointly contribute to the cardiovascular risk of patients with advanced atherosclerosis. Patients with both hs-CRP and HbA1c in the upper quartiles (>0.44 mg/dL and >6.2%, respectively) are at particularly high risk for poor cardiovascular outcome.

Schillinger et al, Circulation. 2003;108:2323.
http://circ.ahajournals.org/cgi/content/ abstract/108/19/2323

OBJECTIVE: To elucidate the correlations between joint effusion (JE) on T2-weighted magnetic resonance images (MRI) of the temporomandibular joint (TMJ) and the levels of various cytokine receptors, cytokine antagonists, and protein in the synovial fluid of patients with temporomandibular joint disorders (TMD). STUDY DESIGN: Fifty-five TMJs of 55 patients with TMD were scanned by MRI, and synovial fluid samples were obtained on the same day. The grade of JE was evaluated on a scale of 0 to 3: Grades 0 and 1 indicated absence, and grades 2 and 3 indicated the presence of JE. Correlations were evaluated between JE and the concentrations of soluble tumor necrosis factor receptors I and II (sTNFR-I and sTNFR-II, respectively), IL-6 soluble receptor (IL-6sR), IL-1 soluble receptor type II, and IL-1 receptor antagonist and protein in the synovial fluid of patients with TMD. RESULTS: The concentrations of sTNFR-I and protein in the group with JE (18 joints) were significantly higher than in the group without JE (37 joints). In addition, there were significant positive correlations between the grade of JE and the levels of sTNFR-I, sTNFR-II, and protein. CONCLUSIONS: sTNFRs and protein may play important roles in the pathogenesis of TMD. These mediators seem to influence the expression of JE, which may reflect synovial inflammation of the TMJ.

Kaneyama K, Segami N, et.al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005 Apr;99(4):411-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=15772591&dopt=Citation

The combined effects of hypoxia and interleukin 1, lipopolysaccharide, or tumor necrosis factor alpha on the expression of genes encoding endothelial constitutive and inducible nitric oxide synthases, endothelin 1, interleukin 6, and interleukin 8 were investigated in human primary pulmonary endothelial cells and whole pulmonary artery organoid cultures. Hypoxia decreased the expression of constitutive endothelial nitric oxide synthase (NOS-3) mRNA and NOS-3 protein as compared with normoxic conditions. The inhibition of expression of NOS-3 corresponded with a reduced production of NO. A combination of hypoxia with bacterial lipopolysaccharide, interleukin 1 beta, or tumor necrosis factor alpha augmented both effects. In contrast, the combination of hypoxia and the inflammatory mediators superinduced the expression of endothelin 1, interleukin 6, and interleukin 8. Here, we have shown that inflammatory mediators aggravate the effect of hypoxia on the down-regulation of NOS-3 and increase the expression of proinflammatory cytokines in human pulmonary endothelial cells and whole pulmonary artery organoid cultures.

Ziesche R, Petkov V, et al. Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12478-83.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=8901607&dopt=Abstract

Low-grade inflammation is associated with insulin resistance and precedes the onset of type 2 diabetes mellitus in adults, but there are no comparable data in youth. The objective of the study was to characterize the pattern of subclinical immune activation that is associated with indices of obesity and insulin resistance in youth and analyze whether this association is explained by obesity. Conclusions: We found that a differential low-grade immune activation is associated with parameters of obesity in adolescents. Moreover, there is evidence that IL-6, IL-18, IP-10, and adiponectin (inversely) are associated with insulin resistance and that these associations can mainly be attributed to obesity.

Herder C, Schneitler S, et al. Journal of Clinical Endocrinology & Metabolism, Vol. 92, No. 12 4569-4574. http://jcem.endojournals.org/cgi/ content/abstract/92/12/4569

To examine the association of low-grade systemic inflammation with diabetes, as well as its heterogeneity across subgroups, we designed a case-cohort study representing the 9-year experience of 10,275 Atherosclerosis Risk in Communities Study participants. . In conclusion, a low-grade inflammation predicts incident type 2 diabetes.

Duncan BB, Schmidt MI, et al. Diabetes 52:1799- 1805, 2003.
http://diabetes.diabetesjournals.org/cgi/content/full/52/7/1799

The timely breakdown of extracellular matrix (ECM)1 is essential for embryonic development, morphogenesis, reproduction, and tissue resorption and remodeling. The matrix metalloproteinases (MMPs), also called matrixins, are thought to play a central role in these processes. The expression of most matrixins is transcriptionally regulated by growth factors, hormones, cytokines, and cellular transformation. The proteolytic activities of MMPs are precisely controlled during activation from their precursors and inhibition by endogenous inhibitors, - macroglobulins, and tissue inhibitors of metalloproteinases (TIMPs).. Matrixins participate in many normal biological processes (e.g. embryonic development, blastocyst implantation, organ morphogenesis, nerve growth, ovulation, cervical dilatation, postpartum uterine involution, endometrial cycling, hair follicle cycling, bone remodeling, wound healing, angiogenesis, apoptosis, etc.) and pathological processes (e.g. arthritis, cancer, cardiovascular disease, nephritis, neurological disease, breakdown of blood brain barrier, periodontal disease, skin ulceration, gastric ulcer, corneal ulceration, liver fibrosis, emphysema, fibrotic lung disease, etc.)

Nagase H, Woessner Jr, JF. J Biol Chem Chem, vol. 274, Issue , 31, 21491-21494, July 20, 1999. http://www.jbc.org/cgi/content/short/274/31/21491

This working group sought to translate the rapidly growing body of evidence for inflammation as a key process in atherosclerosis into clinical and public health practice. Basic science and epidemiological studies have developed an impressive case that atherogenesis is essentially an inflammatory response to a variety of risk factors and the consequences of this response lead to the development of acute coronary and cerebrovascular syndromes. Although several cytokines, acute-phase reactants, and cellular responses to inflammatory stimuli potentially might be predictive of clinical disease, the laboratory tests to assess inflammation are limited to those that are employable in clinical settings, have commercially available assays that can be standardized, and have adequate precision. On the basis of these considerations, it is most reasonable to limit current assays of inflammatory markers to hs-CRP, measured twice, either fasting or nonfasting, with the average expressed in mg/L, in metabolically stable patients..In patients with stable coronary disease or acute coronary syndromes, hs-CRP measurement may be useful as an independent marker for assessing likelihood of recurrent events, including death, myocardial infarction, or restenosis after percutaneous coronary intervention.

Pearson TA, Mensah GA, et al. Circulation 2003;107:409)
http://circ.ahajournals.org/cgi/content/full/107/3/499

Current views regard atherosclerosis as a dynamic and progressive disease arising from the combination of endothelial dysfunction and inflammation.1-6 The vascular endothelium, located at the interface of blood and tissue, is able to sense changes in hemodynamic forces and bloodborne signals and react by synthesizing and releasing vasoactive substances. Vascular homeostasis is maintained by a balance between endothelium-derived relaxing and contracting factors. With disruption of this balance, mediated by inflammatory and traditional cardiovascular risk factors, the vasculature becomes susceptible to atheroma formation. Inflammatory mediators appear to play a fundamental role in the initiation, progression, and eventual rupture of atherosclerotic plaques. As evidence accumulates linking inflammatory processes to atherogenesis, markers of inflammation and endothelial activation may become useful by providing additional information about a patient's risk of developing cardiovascular disease, as well as providing new targets for treatment.7,8 This review article is the first part of a two-article series examining emerging markers of inflammation and cardiovascular disease. Part 1 will provide a brief overview of the link between inflammation, endothelial dysfunction, and atherosclerosis and will begin highlighting emerging inflammatory mediators of endothelial cell (EC) activation, a discussion that will be continued in Part 2.

Szmitko PE, Wang CH, et al. Circulation. 2003;108:1917
http://circ.ahajournals.org/cgi/content/full/108/16/1917? maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=w ang&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

[Heart attack survivors who suffer advanced gum disease show significantly higher levels of a protein in their blood called C-reactive protein (CRP) than such patients without gum disease, new University of North Carolina at Chapel Hill research indicates.

UNC News Service.
http://www.unc.edu/news/archives/nov00/deliar111300.htm

Current guidelines for cardiovascular risk detection are controversial with regard to the clinical utility of different lipid measures, non-high-density lipoprotein cholesterol (non-HDL-C), lipid ratios, apolipoproteins, and C-reactive protein (CRP). Non-HDL-C and the ratio of total cholesterol to HDL-C were as good as or better than apolipoprotein fractions in the prediction of future cardiovascular events. After adjustment for age, blood pressure, smoking, diabetes, and obesity, high-sensitivity CRP added prognostic information beyond that conveyed by all lipid measures.

Ridker P, Rafai N, et.al. JAMA. 2005;294:326-333.
http://jama.ama-assn.org/cgi/ content/abstract/294/3/326

Current knowledge states that periodontal diseases are chronic inflammatory reactions raised in response to periodontopathogens. Many cell types and mediators, including Th1 and Th2 lymphocytes, cytokines and chemokines, appear to be involved in the immunopathogenesis of periodontal diseases. Chemokines, a family of chemotactic cytokines, bind to specific receptors and selectively attract different cell subsets to the inflammatory site. They can also interact with classical cytokines and modulate the local immune response. Chronic periodontitis patients exhibited a more frequent and higher expression of monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR4, and higher expression of IL-10. It is possible that chemokines, in addition to the classical cytokines, are involved in the immunopathogenesis of periodontal disease, driving the migration and the maintenance of several inflammatory cell types such as polymorphonuclear leukocytes, dendritic cells (DCs) , natural killer cells, macrophages, and subsets of lymphocytes in the gingival tissues. These cells are thought to participate in the inflammatory and immune reaction that takes place in periodontal disease, killing pathogens, presenting antigens, and producing cytokines. The selective recruitment of polarized lymphocyte subsets could result in differential cytokine production at the site of response, which is supposed to determine the stable or progressive nature of the lesion. Besides, the role of chemokines as activators and chemoattracts of osteclasts may be involved in the determination of disease severity.

Garlet G.P, Martins W. et al., Journal of Periodontal Research, Volume 38, Number 2, April 2003, pp. 210- 217(8). http://www.ingentaconnect.com/content/mksg/per/2003/00000038/00000002/art00015

CRP levels are predictive of heart disease, and as a predictor for heart disease, is superior to and independent of cholesterol.

http://www.perio.org/ consumer/happy-heart.htm

Treating periodontal disease with scaling and root planing combined with a topical antibiotic gel can significantly lower the levels of two inflammatory proteins associated with a heightened risk of heart disease.

Grossi S. ADA News Release.
http://www.ada.org/prof/resources/pubs/adanews/adanewsarticle.asp?articleid=841

Periodontal treatment is effective in . reducing CRP and TNF- a value, mechanisms independent of adiponectin. Thus, the results indicate that periodontal inflammation up-regulate CRP and TNF-a a, although still for the most part in the healty reference range. Elevated level of CRP and , TNF-a might be associated with increased risk for future development of atherosclerosis in periodontal patients.

Iwamoto Y, Nishimura, F, et al., Okayama University Graduate School of Medicine and Dentistry, Japan. http://iadr.confex.com/iadr/2003Goteborg/techprogram/abstract_30513.htm

Measurement of the acute-phase reactant C-reactive . protein (CRP) has been used historically in the diagnosis and monitoring of active infection or inflammation. Recent prospective epidemiologic studies have demonstrated that CRP, at concentrations within the reference interval, is a strong predictor of myocardial infarction stroke, sudden cardiac death, and peripheral arterial disease in apparently healthy adults.

Nader Rifai1,2,a and Paul M. Ridker2,3. Clinical Chemistry. 2003;49:666-669.)
http://www.clinchem.org/cgi/content/ full/49/4/666

Whole Gram-negative bacteria associated with juvenile and adult periodontitis, and their respective extracted lipopolysaccharides (LPS), were tested for the ability to activate quiescent human peripheral blood monocytes. Results indicate that monocytes are activated by free LPS or LPS bound to Gramnegative pathogenic periodontal bacteria to produce monokines which may contribute to the destruction of periodontal bone.

R. A. Lindemann, J. S. Economou., Journal of Dental Research, Vol 67, 1131-1135. http://jdr.iadrjournals.org/cgi/content/abstract/67/8/1131

In this study, we detected several cytokines in GCF using a cytokine antibody array system, including both inflammatory cytokines and various growth factors. Therefore, periodontal disease may participate in the wound healing process and in tissue destruction via the inflammatory process.

Sakai A, Ohshima M, et. al., Journal of Periodontology 2006.050340.
http://www.joponline.org/doi/abs/10.1902/jop.2006.050340

OBJECTIVE: To measure the levels of the proinflammatory cytokines, interleukin (IL)-1 beta, IL-6, tumor necrosis factor- (TNF) alpha, IL-8, and interferon- (IFN) gamma in synovial fluid samples taken from patients with temporomandibular disorders (TMD). STUDY DESIGN: We studied 6 asymptomatic volunteers and 51 patients with TMD. The IL-1 beta, IL-6, TNF-alpha, IL-8, and IFN-gamma levels in temporomandibular joint synovial fluid were measured using enzyme-linked immunosorbent assay. RESULTS: Measurable level of at least one cytokine in the synovial fluid was found in 40 (64.5%) of 62 joints in the patients: IL-1 beta and IFN-gamma were each detected in 18 (29.0%) of 62 joints; IL-6 in 13 (21.0%) of 62 joints; IL-8 in 11 (19.3%) of 57 joints; and TNF-alpha in only 5 (8.1%) of 62 joints. None of these cytokines was detectable in the synovial fluid in the control group. Furthermore, there was a strong correlation between the detection of IL-1 beta and pain in the joint area. CONCLUSIONS: These data clearly demonstrate increased levels of several proinflammatory cytokines in certain patients with TMD and suggest that these cytokines may play a role in the pathogenesis of synovitis and degenerative changes of the cartilaginous tissue and bone of the temporomandibular joint.

Takahashi T, Kondoh T, et.al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998 Feb;85(2):135-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=9503445&dopt=Citation

These results confirm the prognostic relevance of CRP, a sensitive systemic marker of inflammation, to the risk of CHD in a large, randomly selected cohort of initially healthy middle-aged men. They suggest that low-grade inflammation is involved in pathogenesis of atherosclerosis, especially its thrombo-occlusive complications.

http://circ.ahajournals.org/cgi/content/abstract/99/2/237

BACKGROUND: C-reactive protein (CRP), an exquisitely sensitive systemic marker of inflammation, has emerged as an independent predictor of cardiovascular diseases (CVD). Because other chronic diseases are also associated with an inflammatory response, we sought to assess the association of high-sensitivity CRP (hsCRP) with total and cause-specific mortality in a large cohort of middle- middleaged men. METHODS: We aged measured hsCRP at baseline in 3620 middle-aged men, randomly drawn from 3 samples of the general population in the Augsburg area (Southern 0Germany) in 1984-85, 1989-90, and 1994-95. Outcome was defined as all deaths, fatal CVD, fatal coronary heart disease (CHD) including sudden cardiac deaths, and cancer deaths. . CONCLUSIONS: Our results suggest that increased circulating hsCRP concentrations are associated with an increased risk of death from several widespread chronic diseases. Persistently increased hsCRP is a sensitive and valuable nonspecific indicator of an ongoing disease process that deserves serious and careful medical attention.

Koenig W, Khuseyinova N, et al. Clin Chem. 2008 Feb;54(2):335-42. http://www.ncbi.nlm.nih.gov/pubmed/18156284?ordinalpos=1&itool=EntrezSystem2.PEntrez. Pubmed.Pubmed_ResultsPane l.Pubmed_RVAbstract

Psychosocial factors are associated with the development and progress of cardiovascular disease, but the pathological mechanisms remain unclear. Psychosocial risk factors for cardiovascular disease with concentrations of inflammatory markers, were examined. The extent to which these associations are mediated by behaviors, body mass index (BMI), and diabetes mellitus, was examined. Higher levels of cynical distrust were associated with higher levels of inflammatory markers. Higher levels of chronic stress were associated with higher concentrations of IL-6 and C-reactive protein. Depression was positively associated with the level of IL-6. Psychosocial factors are associated with higher levels of inflammatory markers, most consistently for cynical distrust. Results are compatible with a mediating role of BMI, behaviors, and diabetes.

Ranjit N, Diez- Roux A, et.al. Arch Intern Med. 2007;167:174-181.
http://archinte.ama-assn.org/cgi/content/abstract/167/2/174.

BACKGROUND: Statins lower high- highsensitivity C-reactive sensitivity protein (hsCRP) and cholesterol concentrations, and hypothesis generating analyses suggest that clinical outcomes improve in patients given statins who achieve hsCRP concentrations less than 2 mg/L in addition to LDL cholesterol less than 1.8 mmol/L (<70 mg/dL). However, the benefit of lowering both LDL cholesterol and hsCRP after the start of statin therapy is controversial. We prospectively tested this hypothesis.

METHODS: In an analysis of 15 548 initially healthy men and women participating in the JUPITER trial (87% of full cohort), we prospectively assessed the effects of rosuvastatin 20 mg versus placebo on rates of non-fatal myocardial infarction, non-fatal stroke, admission for unstable angina, arterial revascularisation, or cardiovascular death (prespecified endpoints) during a maximum follow-up of 5 years (median 1.9 years), according to on-treatment concentrations of LDL cholesterol (>/=1.8 mmol/L or <1.8 mmol/L) and hsCRP (>/=2 mg/L or <2 mg/L). We included all events occurring after randomisation. This trial is registered with ClinicalTrials.gov, number NCT00239681.

FINDINGS: Compared with placebo, participants allocated to rosuvastatin who achieved LDL cholesterol less than 1.8 mmol/L had a 55% reduction in vascular events (event rate 1.11 vs 0.51 per 100 person-years; hazard ratio [HR] 0.45, 95% CI 0.34-0.60, p < 0.0001), and those achieving hsCRP less than 2 mg/ L a 62% reduction (event rate 0.42 per 100 person-years; HR 0.38, 95% CI 0.26-0.56, p<0.0001). Although LDL cholesterol and hsCRP reductions were only weakly correlated in individual patients (r values < 0.15), we recorded a 65% reduction in vascular events in participants allocated to rosuvastatin who achieved both LDL cholesterol less than 1.8 mmol/L and hsCRP less than 2 mg/L (event rate 0.38 per 100 person-years; adjusted HR 0.35, 95% CI 0.23-0.54), versus a 33% reduction in those who achieved one or neither target (event rate 0.74 per 100 person-years; HR 0.67, 95% CI 0.52-0.87) (p across treatment groups <0.0001). In participants who achieved LDL cholesterol less than 1.8 mmol/L and hsCRP less than 1 mg/L, we noted a 79% reduction (event rate 0.24 per 100 person-years; HR 0.21, 95% CI 0.09-0.52). Achieved hsCRP concentrations were predictive of event rates irrespective of the lipid endpoint used, including the apolipoprotein B to apolipoprotein AI ratio.

INTERPRETATION: For people choosing to start pharmacological prophylaxis, reduction in both LDL cholesterol and hsCRP are indicators of successful treatment with rosuvastatin. Ridker PM, Danielson E, et al. Lancet 2009 April 4;373 (9670):1175-82. http://www.ncbi.nlm.nih.gov/pubmed/19329177?dopt=Abstract

Destructive periodontal diseases have been associated with an increased risk of atherosclerotic complications; however, the potential mechanisms are yet to be defined. Inflammation plays a central role in atherosclerosis since CRP, an acute-phase protein monitored as a marker of in inflammatory status, has been identified as a major risk factor for atherosclerotic complications. flammatory Recent reports that destructive periodontal diseases can increase CRP values present the possibility that the acute- acutephase response may link these phase 2 disease processes. These results suggest that destructive periodontal disease and disease progression are associated with changes in serum components consistent with an acute-phase response.

Craig RG, Yip JK., et. al., J Periodontol 2003;74:1007-1016.
http://www.joponline.org/doi/abs/10.1902/jop.2003.74.7.1007? prevSearch=keywordsfield%3ACreactive_ protein

BACKGROUND: Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment.

METHODS: We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C- Creactive protein levels of 2.0 reactive mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.

RESULTS: The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes.

CONCLUSIONS: In this trial of apparently healthy persons without hyperlipidemia but with elevated high- highsensitivity C-reactive protein levels, sensitivity rosuvastatin significantly reduced the incidence of major cardiovascular events] Ridker PM, Danielson E, et al. N Engl J Med 2008 Nov 20;359(21)"2195-207.

http://www.ncbi.nlm.nih.gov/pubmed/18997196?dopt=Abstract

6 receptor. [Interleukin-6 (IL-6) is a multifunctional cytokine that regulates pleiotropic roles in immune regulation, inflammation, hematopoiesis, and oncogenesis. Its biological activities are shared by IL-6-family of cytokines such as leukemia inhibitory factor and oncostatin M. IL-6 exerts its biological activities through interaction with specific receptors expressed on the surface of target cells.

SBH Sciences.
http://www.sbhsciences. com/SIL6R_info.asp

Recent trials have demonstrated better outcomes with intensive than with moderate statin treatment. Intensive treatment produced greater reductions in both low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP), suggesting a relationship between these two biomarkers and disease progression.

Nissen SE, et al NEJM 352:29-38 January 6, 2005 Number 1
http://content.nejm.org/cgi/content/abstract/352/1/29? hits=20&andorexactfulltext=and&where=fulltext&searchterm=statin+ C+Reactive+nissen&search_tab=articles&sortspec=Score%2Bdesc%2BPUBDATE_SORTDATE %2Bdesc&sendit=GO&ex cludeflag=TWEEK_element&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

Complement- Complementmediated inflammation mediated exacerbates the tissue injury of ischemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger nonfunctional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C- Creactive protein (CRP), the reactive classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement1 complement1, increases , myocardial and cerebral infarct size. .Therapeutic inhibition of CRP is a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury.

Pepys MB, Hirschfield GM et.al,. Nature 440, 1217-1221 (27 April 2006). http://www.nature.com/nature/journal/v440/n7088/abs/nature04672.html

This review outlines the mechanisms underlying the interaction between the nervous and immune systems of the host in response to an immune challenge. The main focus is the cholinergic anti-inflammatory pathway, which we recently described as a novel function of the efferent vagus nerve. This pathway plays a critical role in controlling the inflammatory response through interaction with peripheral a7 subunit -containing nicotinic acetylcholine receptors expressed on macrophages. We describe the modulation of systemic and local inflammation by the cholinergic anti-inflammatory pathway and its function as an interface between the brain and the immune system. The clinical implications of this novel mechanism also are discussed. Introduction: Inflammation is a normal response to disturbed homeostasis caused by infection, injury, and trauma. The host responds with a complex series of immune reactions to neutralize invading pathogens, repair injured tissues, and promote wound healing. The onset of inflammation is characterized by release of pro-inflammatory mediators including tumor necrosis factor (TNF), interleukin (IL)-1, adhesion molecules, vasoactive mediators, and reactive oxygen species. The early release of pro-inflammatory cytokines by activated macrophages has a pivotal role in triggering the local inflammatory response. Excessive production of cytokines, such as TNF, IL-1ß, and high mobility group B1 (HMGB1), however, can be more injurious than the inciting event, initiating diffuse coagulation, tissue injury, hypotension, and death. The inflammatory response is balanced by anti-inflammatory factors including the cytokines IL-10 and IL-4, soluble TNF receptors, IL-1 receptor antagonists, and transforming growth factor (TGF)ß. Although simplistic the pro pro-/anti- -/terminology is widely used in the discussion of the complex cytokine network. Apart from their involvement in local inflammation, TNF and IL-1ß are signal molecules for activation of brain-derived neuroendocrine immunomodulatory responses. Neuroendocrine pathways, such as the hypothalamo-pituitary-adrenal (HPA) axis and the sympathetic division of the autonomic nervous system (SNS), control inflammation as an anti-inflammatory balancing mechanism. The host thereby mobilizes the immunomodulatory resources of the nervous and endocrine systems to regulate inflammation. Restoration of homeostasis as a logical resolution of inflammation does not always occur. Insufficient inflammatory responses may result in increased susceptibility to infections and cancer. On the other hand, excessive responses are associated with autoimmune diseases, diabetes, sepsis, and other debilitating conditions. When control of local inflammatory responses is lost, pro- proinflammatory mediators can spill into inflammatory the circulation, resulting in systemic inflammation that may progress to shock, multiple organ failure, and death. Effective therapies for diseases of excessive inflammation are needed.

Pavlov VA, Wang H, et.al. Mol Med. 2003 May-Aug; 9(5-8): 125-134. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1430829

A global risk prediction model that includes hsCRP improves cardiovascular risk classification in women, particularly among those with a 10-year risk of 5% to 20%. In models that include age, blood pressure, and smoking status, hsCRP improves prediction at least as much as do lipid measures.

Cook NR, Buring JE, et.al. Annals of Internal Medicine, Vol.145 Issue 1, P 21-29, 4 July 2006, http://www.annals.org/cgi/content/abstract/145/1/21

A complex interplay between proinflammatory stimuli and endogenous heritable-genetic vascular reparative processes has been proposed as a determinant of vascular disease activity. The validity of this premise is supported by the presence and prospective predictive value of cytokine and cellular "markers" of inflammation, including interleukins 6 and 18 and C-reactive protein (CRP). Furthermore, the fact that physiologically occurring concentrations of CRP exert proinflammatory, proatherogenic, and prothrombotic effects provides impetus to define antiinflammatory treatments capable of suppressing this incestuous marker-mediator cycle.

Kereiakes DJ. Circulation 2003;107;373-374.
http://circ.ahajournals.org/cgi/reprint/107/3/373? maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=ridker&s earchid=1&FIRSTINDEX=0&resourcetype=HWCIT

Inflammation is typically the way the body responds to injury. However, if the immune system malfunctions, this inflammatory process can damage healthy tissue. Recent research shows inflammation may play a role in diseases that are not typically considered inflammatory diseases, such as heart disease. In much the same way doctors have found a link between inflammation and heart disease, they have now found a link between inflammation and diabetes. Researchers say there are several markers of inflammation that are increased in people who have diabetes. . Researchers say the finding that inflammation is linked to the onset of type 2 diabetes may open new avenues for the prevention and treatment of the disease.

Duncan, Bruce MD. American Diabetes Assoc Meeting, San Francisco, June 2002. http://www.defeatdiabetes.org/Articles/inflam020617.htm

The purpose of this review is to indicate the role insulin plays in normal brain neurophysiology, together with the role insulin may play in the regulation of regional cerebral blood flow (rCBF). The relationship between sustained elevation of the inflammatory cytokines and brain insulin dysregulation, with respect to the serious mental disorders, is also discussed. It has been observed that, as the inflammatory cytokines increase, they exert a synergistic influence on insulin and somatostatin, by initially increasing and then decreasing insulin secretion. In the brain, increased levels of insulin result in increased glucose utilization and over-stimulation of the autonomic nervous system (ANS), while the inhibition of insulin secretion results in decreased glucose utilization and dysregulation of the hypothalamo-pituitary- pituitaryadrenal (HPA) axis. It will further be argued that these adrenal alterations in brain insulin influence rCBF in the serious mental disorders such as schizophrenia and the affective disorders. It is hypothesized that insulin regulates rCBF either directly, or indirectly via GLUT4 in the hypothalamus now considered the glucose-sensing, insulin-sensing mechanism of the brain and the body. Thus, we shall propose that insulin plays an important role in normal neurophysiology and that sustained elevation of the inflammatory cytokines dysregulates insulin secretion, rCBF, ANS and the HPA-axis in serious mental disorders.

Holden RJ. Med Hypotheses. 1999 Mar;52(3):193-200.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=10362277&dopt=Citation

The prevalence of diabetes worldwide is increasing rapidly in association with the increase in obesity. Complications are a major fear of patients with diabetes. Complications of diabetes affect many tissues and organs, causing retinopathy, nephropathy, neuropathy, cardiovascular diseases, peripheral vascular diseases, stroke, and periodontal pathologies. Immunologic abnormalities are associated with type 1 and type 2 diabetes and diabetic complications. T cell abnormalities are believed to be the major cause of autoimmune disease in type 1 diabetes, leading to the destruction of pancreatic islets. In type 2 diabetes, inflammation and activation of monocytes are postulated to be important for enhancing insulin resistance and may contribute to the loss of insulin secretory function by islet cells. Many factors can enhance insulin resistance, including genetics, a sedentary lifestyle, obesity, and other conditions, such as chronic inflammation or infection. Increases in inflammation, such as activation of monocytes and increased levels of inflammatory markers, e.g., C-reactive protein, plasminogen activator inhibitor-1, and other cytokines, were reported in insulin-resistant states without diabetes. One possible mechanism is that abnormal levels of metabolites, such as lipids, fatty acids, and various cytokines from the adipose tissue, activate monocytes and increase the secretion of inflammatory cytokines, enhancing insulin resistance. According to this model, obesity activates monocytes and enhances insulin resistance, increasing the risk for type 2 diabetes. Abnormalities in innate immunity might also participate in the development of diabetic complications. In general, hyperglycemia is the main initiator of diabetic retinopathy, nephropathy, and neuropathy, and it participates in the development of diabetic cardiovascular diseases. Although the precise role of inflammation in the development of diabetic microvascular diseases is still unclear, it is likely that inflammation induced by diabetes and insulin resistance can accelerate atherosclerosis in patients with diabetes. Also, it was shown that conditions with an inflammatory basis, such as obesity and type 2 diabetes, can contribute to periodontal disease, suggesting that periodontal abnormalities may be partly influenced by inflammatory changes. Further research is required to confirm the role of inflammation and the onset of diabetes, microvascular diseases, and periodontal pathologies.

King GL. Journal of Periodontology, 2008, Vol. 79, No. 8s, Pages 1527-1534.
http://www.joponline.org/doi/ full/10.1902/jop.2008.080246

Tumor necrosis factor alpha is a cytokine produced primarily by monocytes and macrophages. It is found in synovial cells and macrophages in the tissues. It shares many properties with another cytokine - interleukin 1. It is not unique to RA, but occurs in many inflammatory diseases, and also as a response to endotoxins from bacteria for example.

Drdoc on-line.
http:// www.arthritis.co.za/tnf.htm

TNFa is released by white blood cells, endothelium and several other tissues in the course of damage, e.g. by infection. Its release is stimulated by several other mediators, such as interleukin 1 and bacterial endotoxin. It has a number of actions on various organ systems, generally together with interleukins 1 and 6. On the liver: stimulating the acute phase response, leading to an increase in C-reactive protein and a number of other mediators. It attracts neutrophils very potently, and helps them to stick to the endothelial cells for migration. On macrophages: stimulates phagocytosis, and production of IL-1 oxidants and the inflammatory lipid prostaglandin E2 (PGE2). On other tissues: increasing insulin resistance.

http://en.wikipedia.org/wiki/Tumor_necrosis_factor

Tumor necrosis factor is a multifunctional proinflammatory cytokine, with effects on lipid metabolism, coagulation, insulin resistance, and endothelial function.

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=191160

Vitamin C supplements can reduce levels of C-reactive protein, a marker of inflammation and chronic disease risk in humans, according to a new study led by researchers at the University of California, Berkeley. Participants who took about 500 milligrams of vitamin C supplements per day saw a 24 percent drop in plasma C-reactive protein (CRP) levels after two months. The study, published in the April issue of the Journal of the American College of Nutrition, is the first time vitamin C has been shown to decrease levels of CRP, a biomarker that has garnered increasing attention among health researchers in recent years. C-reactive protein is a marker of inflammation, and there is a growing body of evidence that chronic inflammation is linked to an increased risk of heart disease, diabetes and even Alzheimer's disease, said Gladys Block, UC Berkeley professor of epidemiology and public health nutrition and lead author of the study. If our finding of vitamin C's ability to lower CRP is confirmed through other trials, vitamin C could become an important public health intervention. Inflammation occurs as part of the body's defense against infection or injury. The body triggers the production of inflammatory cytokines, such as interleukin-6, that then set off the production of CRP by the liver.

Apr-2004,
http://www.eurekalert.org/ pub_releases/2004-04/uoc--vcr041204.php