Risk factors for bovine periodontal disease - a preliminary study.

The work presented in this pilot study aimed to identify potential risk factors associated with bovine periodontitis development. Bovine periodontitis is a multifactorial polymicrobial infectious disease for which the aetiopathogenesis and risk factors are not fully understood. From cattle slaughtered in an abattoir in Scotland, 35 dental arcades with periodontal lesions and 40 periodontally healthy arcades were selected over seven visits for study. Multivariable logistic regression analysis was used to evaluate the association between periodontitis and the independent variables, gender, age and breed. For every increase in year of age, cattle were 1.5 times more likely to have periodontitis. A graphical analysis indicated that within the limits of this study, we could not detect any major influence of breed on the age-effect. Although logistic regression analysis demonstrated that periodontitis lesions are more prevalent with increasing age of cattle the underlying mechanisms remain unclear. It is likely that periodontitis is an important cause of oral pain in older cattle and can contribute to reduced productivity/performance. Further studies with a larger sample size are necessary to elucidate the associations between potential risk factors and periodontitis in cattle and to define its effects on animal welfare and productivity.

The influence of apical periodontitis on the concentration of inflammatory mediators in peripheral blood plasma and the metagenomic profiling of endodontic infections: Study design and protocol.

Increased systemic inflammation has been identified in presence of oral disease, specifically endodontic disease. It is important to investigate whether treatment of the oral disease ameliorates systemic inflammation. Furthermore, there is no information about the extent to which different microorganisms may trigger inflammatory response. OBJECTIVES: Primarily (i) to compare the plasma concentrations of inflammatory mediators of apical periodontitis (AP) subjects to controls, (ii) to evaluate whether elimination of the endodontic infection reduces systemic inflammation (iii) to investigate the microbiome of root canal infections. Secondarily i) to correlate the inflammatory mediator data with the microbiome data to investigate whether the type of infection influences the type and severity of the inflammatory condition ii) to examine patterns in the inflammatory mediator data before and after tooth extraction in order to establish a biomarker signature of AP/oral disease.This is a multi-centre prospective case-control intervention study. The cohort will consist of 30 healthy human volunteers with one or two teeth with a root-tip inflammation and 30 matched healthy controls. Peripheral blood will be drawn at 6 time points, 3 before and 3 after the extraction of the tooth with apical periodontitis. The teeth will be pulverized, DNA extraction and sequencing will be performed.This study aims to compare the concentration of inflammatory blood plasma proteins in between AP-subjects and controls at different time points before and after the tooth extraction in a systematic and complete way. Additionally the composition of the root canal microbiome in association with the inflammatory response of the host will be assessed.

The Prevalence and Management of Metabolic Acidosis of Chronic Kidney Disease

Aim Emerging evidence supports initiating oral sodium bicarbonate (OSB) at a serum bicarbonate (HCO3) level of less than 22mmol/L. We look to identify the prevalence of metabolic acidosis of chronic kidney disease (MA-CKD) and its management with OSB at a regional university hospital. Methods Retrospective data was collected using the national electronic renal database (eMED) to identify chronic kidney disease (CKD) patients with MA-CKD over a one-year period. Results One-hundred and forty-four patients were identified with CKD, of which 131 (89%) were tested for HCO3. MA-CKD was present in 44 patients (34%), all had eGFR< 30ml/min/1.73m2, 7 (16%) were prescribed OSB, 7(16%) OSB was contraindicated, and 37 (84%) patients managed with dietary input only. Mean HCO3 level at initiation in OSB group was 18.3±1mmol/L compared to 19.4±1.4mmol/L in dietary input only group which was statistically significant (p<0.05). Conclusion A high burden of advanced CKD was found in the regional nephrology centre, with one third of patients demonstrating MA-CKD. Majority had dietary input only. Further awareness and consensus need to be established on the benefits of treating MA-CKD with OSB.

Assessing the efficacy and cost of detergents used in a primary care automated washer disinfector.

Background: Cleaning of re-usable medical devices is a critical control point in the decontamination cycle, although defined end-points of the process are controversial. Objective: Investigate cleaning efficacy and cost of different detergent classes in an automated washer disinfector (AWD) designed for dental practice. Methods: Loads comprised test soiled dental hand instruments in cassettes and extraction forceps. Residual protein assayed using the International standard method (ISO 15883-5:2005) 1% SDS elution with ortho-phthalaldehyde (OPA) or GBox technology (on instrument OPA analysis). Short (60 minutes) and long (97 minutes) AWD cycles were used with four different classes of detergents, tap water and reverse osmosis water. Results: SDS elution analysis (N = 612 instruments) demonstrated four detergents with both wash cycles achieved equivalent cleanliness levels and below a threshold of 200 µg protein/instrument. GBox methodology (N = 575) using UK Department of Health threshold of 5 µg/instrument side demonstrated that tap water performed with the greatest efficacy for all types of instruments and cycle types. Conclusions: Using International standard methodology, different detergent classes had equivalence in cleaning efficacy. Cheaper detergents used in this study performed with similar efficacy to more expensive solutions. Findings emphasise the importance of validating the detergent (type and concentration) for each AWD.

Stem cell-like populations and immunoregulatory molecules in periodontal granulation tissue.

BACKGROUND AND OBJECTIVES: Determine the presence of mesenchymal stem cells (MSCs) in healthy periodontal tissue and periodontal granulation tissue (GT) and explore associations between immuno-regulatory molecules and selected subgingival microorganisms. MATERIAL AND METHODS: Mesenchymal stem cells were isolated, propagated and characterised by flow cytometry from a region of healthy gingival tissue and inflamed GT of 10 systemically healthy non-smokers with chronic periodontitis. Tissue levels of immunoregulatory molecules were determined by qPCR and Gingival Crevicular Fluid (GCF) levels by ELISA. Subgingival plaque levels of periodontal pathogens were determined by qPCR RESULTS: Cells with MSC-properties were isolated from both inflamed GT and healthy gingival (G) tissue. A pro-inflammatory process predominated in GT which was partly reflected in GCF and putative periodontal pathogens were higher at diseased sites. However, there was no significant difference in surface levels of mesenchymal (CD90, CD73, CD146, CD271, STRO-1), endothelial (CD105, CD106), hematopoietic (CD34, CD45) and embryonic (SSEA-4) stem cell markers between MSCs isolated from GT and G tissue. CONCLUSION: Periodontal lesions, albeit inflamed, retain healing potential as inferred by the presence of MSC-like cells with similar immunophenotypic characteristics to those found in healthy periodontal tissue. Therefore, there might be merits for healing in preserving sufficient GT in-situ during periodontal surgery.

Reducing the risk of iatrogenic Creutzfeldt-Jakob disease by improving the cleaning of neurosurgical instruments.

BACKGROUND: In all, there have been 178 variant Creutzfeldt-Jakob disease (vCJD) patients diagnosed in the UK, with an estimated maximum 1:2000 carriage rate based on archived appendix and tonsil tissue, implying that infection may be rare but carriage relatively frequent. Previous workers have identified that maintenance of surgical instruments in a humid atmosphere after use and prior to cleaning assists cleaning efficacy. Recently the Department of Health/Advisory Committee on Dangerous Pathogens UK have recommended a surgical instrument cleanliness threshold post cleaning of <5 µg protein per instrument side. AIM: To quantify cleanliness of neurosurgical instruments and to investigate cost-effective measures for improved cleaning. METHODS: Two instrument protein quantification methods were used: one based on the International Standard (15883 series) using sodium dodecyl sulphate elution and ortho-phthalaldehyde reaction, and a second in-situ protein fluorescence detection system (ProReveal) providing results per instrument side. In-vitro investigation of the efficacy of some commercial and in-house pre-clean wetting agents was undertaken using artificial test soil and stainless steel discs under standard conditions. In-vivo evaluation of best-performing in-vitro agents was undertaken on craniotomy sets. FINDINGS: ProReveal technology demonstrated that 163 out of 187 (87%) neurosurgical instruments had <5 µg residual protein per instrument side. The use of proprietary National Health Service plastic bags and sterile water-soaked wound pads were equivalent in efficacy to commercial pre-cleaning wetting products and significantly less expensive. CONCLUSION: Although we demonstrate low in-situ protein levels on neurosurgical instruments and the beneficial effects of keeping instruments moist, other cleaning critical-control points such as instrument loading patterns should also be monitored.

Diamond burs versus curettes in root planing: a randomized clinical trial.

BACKGROUND: This study compares diamond burs and curettes by clinical, microbiological, biochemical and scanning electron microscopic parameters and treatment time data in the non-surgical periodontal treatment of patients with chronic periodontitis. METHODS: Two quadrants of each of the 12 patients received root planing with diamond burs, whereas the other two quadrants were treated with curettes. Clinical periodontal measurements were recorded at baseline and then 1, 3 and 6 months after completion of non-surgical periodontal treatment. Subgingival plaque and gingival crevicular fluid samples were obtained at baseline and 1-month control. Twenty-one hopeless teeth received root planing with diamond burs or curettes or no treatment and then extracted for microscopic evaluations. RESULTS: Clinical periodontal parameters improved similarly with both treatment modalities. Microbiological analyses revealed similar findings for the bacterial load (16S gene copy numbers) and ratio of each bacterium to the total bacterial count at baseline and 1-month control. Cytokine levels in the gingival crevicular fluid samples exhibited differences between the two treatments. Scanning electron microscopic analyses indicated that diamond burs were better in terms of calculus removal and loss of tooth substance indices but roughness index values were better for curettes. CONCLUSIONS: Diamond burs provide findings comparable with curettes in root planing.

Home haemodialysis in Ireland.

BACKGROUND: Home haemodialysis (HHD) has the potential to impact positively on patient outcomes and health resource management. There has been rejuvenated international interest in HHD in recent years. AIM: We aimed to review the activity and outcomes of the Irish HHD Programme since inception (2009-16). DESIGN: Retrospective review. METHODS: Patient data were collected using the national electronic Renal Patient database (eMEDRenal version 3.2.1) and individual centre records. All data were recorded in a coded fashion on a Microsoft Excel Spread-sheet and analysed with Stata SE software. RESULTS: One hundred and one patients completed training and commenced HHD; a further fourty-five patients were assessed for HHD suitability but did not ultimately dialyse at home. Twenty patients switched to nocturnal HHD when this resource became available. The switch from conventional in-centre dialysis to HHD led to an increase in the mean weekly hours on haemodialysis (HD) and a reduction in medication burden for the majority of patients. The overall rate of arteriovenous fistula (AVF) as primary vascular access was 62%. Most HHD complications were related to access function or access-related infection. Over the 7-years, 29 HHD patients were transplanted and 9 patients died. No deaths resulted directly from a HHD complication or technical issue. CONCLUSIONS: Patient and technique survival rates compared favourably to published international reports. However, we identified several aspects that require attention. A small number of patients were receiving inadequate dialysis and require targeted education. Ongoing efforts to increase AVF and self-needling rates in HD units must continue. Psychosocial support is critical during the transition between dialysis modalities.

Failure of non-vacuum steam sterilization processes for dental handpieces.

BACKGROUND: Dental handpieces are used in critical and semi-critical operative interventions. Although some dental professional bodies recommend that dental handpieces are sterilized between patient use there is a lack of clarity and understanding of the effectiveness of different steam sterilization processes. The internal mechanisms of dental handpieces contain narrow lumens (0.8-2.3 mm) which can impede the removal of air and ingress of saturated steam required to achieve sterilization conditions. AIM: To identify the extent of sterilization failure in dental handpieces using a non-vacuum process. METHODS: In-vitro and in-vivo investigations were conducted on widely used UK bench-top steam sterilizers and three different types of dental handpieces. The sterilization process was monitored inside the lumens of dental handpieces using thermometric (TM; dataloggers), chemical indicator (CI), and biological indicator (BI) methods. FINDINGS: All three methods of assessing achievement of sterility within dental handpieces that had been exposed to non-vacuum sterilization conditions demonstrated a significant number of failures [CI: 8/3024 (fails/no. of tests); BI: 15/3024; TM: 56/56] compared to vacuum sterilization conditions (CI: 2/1944; BI: 0/1944; TM: 0/36). The dental handpiece most likely to fail sterilization in the non-vacuum process was the surgical handpiece. Non-vacuum sterilizers located in general dental practice had a higher rate of sterilization failure (CI: 25/1620; BI: 32/1620; TM: 56/56) with no failures in vacuum process. CONCLUSION: Non-vacuum downward/gravity displacement, type N steam sterilizers are an unreliable method for sterilization of dental handpieces in general dental practice. The handpiece most likely to fail sterilization is the type most frequently used for surgical interventions.

Investigating steam penetration using thermometric methods in dental handpieces with narrow internal lumens during sterilizing processes with non-vacuum or vacuum processes.

BACKGROUND: Dental handpieces are required to be sterilized between patient use. Vacuum steam sterilization processes with fractionated pre/post-vacuum phases or unique cycles for specified medical devices are required for hollow instruments with internal lumens to assure successful air removal. Entrapped air will compromise achievement of required sterilization conditions. Many countries and professional organizations still advocate non-vacuum sterilization processes for these devices. AIM: To investigate non-vacuum downward/gravity displacement, type-N steam sterilization of dental handpieces, using thermometric methods to measure time to achieve sterilization temperature at different handpiece locations. METHODS: Measurements at different positions within air turbines were undertaken with thermocouples and data loggers. Two examples of widely used UK benchtop steam sterilizers were tested: a non-vacuum benchtop sterilizer (Little Sister 3; Eschmann, Lancing, UK) and a vacuum benchtop sterilizer (Lisa; W&H, Bürmoos, Austria). Each sterilizer cycle was completed with three handpieces and each cycle in triplicate. FINDINGS: A total of 140 measurements inside dental handpiece lumens were recorded. The non-vacuum process failed (time range: 0-150 s) to reliably achieve sterilization temperatures within the time limit specified by the international standard (15 s equilibration time). The measurement point at the base of the handpiece failed in all test runs (N = 9) to meet the standard. No failures were detected with the vacuum steam sterilization type B process with fractionated pre-vacuum and post-vacuum phases. CONCLUSION: Non-vacuum downward/gravity displacement, type-N steam sterilization processes are unreliable in achieving sterilization conditions inside dental handpieces, and the base of the handpiece is the site most likely to fail.

The epithelial cell response to health and disease associated oral biofilm models.

BACKGROUND AND OBJECTIVE: Different bacteria differentially stimulate epithelial cells. Biofilm composition and viability are likely to influence the epithelial response. In vitro model systems are commonly used to investigate periodontitis-associated bacteria and their interactions with the host; therefore, understanding factors that influence biofilm-cell interactions is essential. The present study aimed to develop in vitro monospecies and multispecies biofilms and investigate the epithelial response to these biofilms. MATERIAL AND METHODS: Bacterial biofilms were cultured in vitro and then either live or methanol-fixed biofilms were co-cultured with epithelial cells. Changes in epithelial cell viability, gene expression and cytokine content of culture supernatants were evaluated. RESULTS: Bacterial viability was better preserved within mixed-species biofilm culture than within single-species biofilm culture. Both mixed- and single-species biofilms stimulated increased expression of mRNA for interleukin 8 (IL8), C-X-C motif chemokine ligand 3 (CXCL3), C-X-C motif chemokine ligand 1 (CXCL1), interleukin 1 (IL1), interleukin 6 (IL6), colony-stimulating factor 2 (CSF2) and tumour necrosis factor (TNF), and the response was greatest in response to mixed-species biofilms. Following co-culture, cytokines detected in the supernatants included IL-8, IL-6, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, with the greatest release of cytokines found following co-culture with methanol-fixed, mixed-species biofilms. CONCLUSIONS: These data show that epithelial cells generate a distinct cytokine gene- and protein-expression signature in response to live or fixed, single- or multispecies biofilms.

Gingival Toll-like receptor and cytokine messenger RNA levels in equine periodontitis and oral health.

REASONS FOR PERFORMING STUDY: Equine periodontitis is a common and painful condition. However, the disease often goes unnoticed by owners and is thus a major welfare concern. The aetiopathogenesis of the condition remains poorly understood and has been investigated in few studies. The innate immune system is known to play an important role in human periodontitis, but its role in equine periodontitis has not been examined. OBJECTIVES: To quantify the messenger (m)RNA levels of Toll-like receptors (TLRs) and cytokines in gingival tissue from orally healthy horses and those affected by periodontitis. STUDY DESIGN: Observational study. METHODS: Gingival tissue samples were taken post-mortem from 13 horses with no clinical signs of oral disease and 20 horses with periodontitis. mRNA levels of TLR2, TLR4 and TLR9 and cytokines interleukin-1ß (IL-1ß), tumour necrosis factor-α (TNF-α), IL-4, IL-6, IL-10, IL-12, IL-17 and interferon-γ (IFN-γ) were determined using quantitative real-time PCR. The statistical significance of results was assessed using appropriate t tests. RESULTS: mRNA levels of all TLRs and cytokines were upregulated in equine periodontitis. Significant increases in mRNA levels of TLR2, TLR9, IL-4, IL-10, IL-12 (P≤0.05) and IFN-γ (P≤0.01) were observed for both unweighted and age-weighted analyses of diseased gingival tissue samples compared with healthy gingival samples. In comparisons of samples of periodontitis lesions with healthy gingival control samples from the same horse, significant increases in mRNA levels of TLR4, TLR9, IL-10, IFN-γ (P≤0.05), TLR2, IL-1ß and IL-12p35 (P≤0.01) were observed. CONCLUSIONS: This study has provided an initial insight into the involvement of the immune system in equine periodontitis. Increased mRNA levels of TLR2, TLR4 and TLR9 indicate substantial microbial challenge in diseased gingival tissue. A mixed Th1/Th2/Th17 cytokine response is produced in equine periodontitis. Further studies are required to more fully characterise the role of the innate immune system in this disease.

ANCA-associated vasculitis: a comparison of cases presenting to nephrology and rheumatology services.

BACKGROUND: Anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis (AAV) is a disease characterized by inflammation of small vessels and detectable ANCA in the circulation. Patients may develop a broad spectrum of clinical features ranging from indolent sino-nasal disease and rashes to fulminant renal failure or acute life-threatening pulmonary haemorrhage. Consequently, patients with AAV present to a variety of specialties including nephrology and rheumatology, whose training and approaches to management of such patients may differ. There is little literature comparing patients presenting to different specialties and their outcomes. METHODS: We compared two cohorts of patients with ANCA-positive AAV presenting to either the rheumatology or nephrology department at Galway University Hospitals from June 2002 to July 2011. A standardized data collection form was used to collect information regarding baseline demographics, manifestations of AAV, initial management, relapses and complications. RESULTS: Forty-five patients were included in this study (15 rheumatology/30 nephrology). The nephrology cohort was older, had a higher C-reactive protein, Birmingham Vascular Activity Score and ANCA titer at presentation compared to the rheumatology group. Induction treatment varied between the cohorts with rheumatology patients most commonly receiving a combination of oral corticosteroids (73%) and methotrexate (60%) and nephrology patients receiving a combination of intravenous corticosteroids (93%) and cyclophosphamide (90%). Fifty-three percent of the rheumatology patients who completed induction therapy relapsed compared to 30% of the nephrology patients. CONCLUSION: This study presents two different cohorts of patients with the same disease that were managed by two different disciplines. It highlights the heterogeneity of AAV and the importance of interdisciplinary communication and cooperation when managing these patients.

The effect of periodontal scaling and root polishing on serum IL-17E concentrations and the IL-17A:IL-17E ratio.

OBJECTIVES: The serum IL-17A:IL-17E ratio has previously been demonstrated to be a clinical marker of periodontitis. The aim of this study was to determine the effects of non-surgical periodontal treatment on the serum IL-17A:IL-17E ratio. MATERIALS AND METHODS: Forty chronic periodontitis patients completed this study and received periodontal treatment comprising scaling and root planing plus ultrasonic debridement. Clinical data were recorded at baseline, 6 weeks (R1) after treatment completion (full-mouth or quadrant-scaling and root planing) and 25 weeks after baseline (R2). Serum samples were taken at each time point and cytokines concentrations determined by ELISA. RESULTS: Following treatment, statistically significant reductions were noted in clinical parameters. However, IL-17A and IL-17E concentrations were significantly greater than baseline values before- and after-adjusting for smoking. The IL-17A:IL-17E ratio was lower at R1 and R2. Serum IL-6 and TNF levels were significantly lower at R1 only. Also exclusively at R1, serum IL-17A and IL-17E correlated positively with clinical parameters, while the IL-17A:IL-17E ratio correlated negatively with probing pocket depth and clinical attachment. CONCLUSION: Increased serum IL-17E and a reduced IL-17A:IL-17E ratio may be indicative and/or a consequence of periodontal therapy. Therefore, the role of IL-17E in periodontal disease progression and the healing process is worthy of further investigation. CLINICAL RELEVANCE: IL-17E may be a valuable biomarker to monitor the healing process following periodontal treatment as increased IL-17E levels and a reduced IL-17A:IL-17E ratio could reflect clinical improvements post-therapy. Therefore, monitoring serum IL-17E might be useful to identify individuals who require additional periodontal treatment.

Is there an association between obstructive sleep apnea syndrome and periodontal inflammation?

OBJECTIVES: The aim of this study is to assess salivary, serum biomarkers, and subgingival bacteria as putative candidates in the potential association between obstructive sleep apnea syndrome (OSAS) and periodontal disease. MATERIALS AND METHODS: Fifty-two patients were grouped according to the severity of OSAS: 13 participants served as controls, 17 patients had mild-to-moderate OSAS, and 22 severe OSAS. Serum, saliva, and subgingival plaque samples were collected, and clinical periodontal parameters were recorded. Salivary, serum concentrations of interleukin-6 (IL-6), tumour necrosis factor (TNF-α), osteoprotegerin, soluble Receptor activator of nuclear factor kappa B ligand (sRANKL), and apelin were analysed by enzyme-linked immunosorbent assay. Bacterial counts were determined by real-time QPCR on plaque microbial DNA preparations. RESULTS: There was a significant change in the composition of microbes in plaque particularly in severe OSAS samples (p < 0.01). Statistical analyses indicated significantly higher salivary IL-6 levels in both OSAS groups compared to controls (p < 0.05). Salivary apelin levels were significantly higher in the severe OSAS group compared to the control group. Serum levels of these biomarkers and salivary osteoprotegerin, sRANKL levels were similar in the study groups. The incidence and duration of apnea positively correlated with clinical periodontal parameters (p < 0.05). CONCLUSION: OSAS appeared to alter the tested bacteria in plaque, correlate with increasing periodontal disease severity, have additive effect on salivary IL-6. CLINICAL RELEVANCE: OSAS is likely to associate with periodontal disease.

The effect of renal sympathetic denervation on nocturnal dipping in patients with resistant hypertension; observational data from a tertiary referral centre in the Republic of Ireland.

OBJECTIVE: Renal sympathetic denervation (RSD) is an emerging device based treatment for patients with resistant hypertension. Nocturnal dipping (ND) is defined as a decrease in BP of 10-20 % during sleep, and has been shown to be protective against cardiovascular disease. This study examined the effect of RSD on the 24 h BP profile of patients with resistant hypertension. METHODS AND RESULTS: The first 23 consecutive patients with resistant hypertension scheduled for renal denervation in a single centre were included. 24 h ambulatory blood pressure monitors (ABPM) were given to patients pre-procedure and 9 months post-procedure. RSD led to a statistically non-significant reduction in overall 24 h ABPM BP (150/85 ± 12/9 vs. 143/84 ± 15/11 mmHg; P > 0.05) despite a reduction in the number of antihypertensive medications (4.9 ± 1.2 vs. 4.3 ± 1.2; P = 0.001). There were improvements in systolic ND 1.7 ± 8 vs. 5.2 ± 8 %; P < 0.05), diastolic ND (5.2 ± 8 vs. 10.2 ± 9 %; P < 0.05) and mean arterial pressure (MAP) ND (4.2 ± 8 vs. 8.0 ± 8 %; P < 0.05). Non-significant changes in ND status were observed in systolic (17 vs. 43 % of participants; P > 0.05), diastolic (30 vs. 43 % of participants; P > 0.05) and MAP (22 vs. 39 % of participants; P > 0.05) measurements. CONCLUSIONS: These data suggest that RSD may lead to an improvement in nocturnal dipping in selected patients with resistant hypertension. This may have cardiovascular benefits even if reduction in BP is not achieved with RSD.

Re-Engineering Alzheimer Clinical Trials: Global Alzheimer's Platform Network.

Alzheimer's disease (AD) drug development is costly, time-consuming, and inefficient. Trial site functions, trial design, and patient recruitment for trials all require improvement. The Global Alzheimer Platform (GAP) was initiated in response to these challenges. Four GAP work streams evolved in the US to address different trial challenges: 1) registry-to-cohort web-based recruitment; 2) clinical trial site activation and site network construction (GAP-NET); 3) adaptive proof-of-concept clinical trial design; and 4) finance and fund raising. GAP-NET proposes to establish a standardized network of continuously funded trial sites that are highly qualified to perform trials (with established clinical, biomarker, imaging capability; certified raters; sophisticated management system. GAP-NET will conduct trials for academic and biopharma industry partners using standardized instrument versions and administration. Collaboration with the Innovative Medicines Initiative (IMI) European Prevention of Alzheimer's Disease (EPAD) program, the Canadian Consortium on Neurodegeneration in Aging (CCNA) and other similar international initiatives will allow conduct of global trials. GAP-NET aims to increase trial efficiency and quality, decrease trial redundancy, accelerate cohort development and trial recruitment, and decrease trial costs. The value proposition for sites includes stable funding and uniform training and trial execution; the value to trial sponsors is decreased trial costs, reduced time to execute trials, and enhanced data quality. The value for patients and society is the more rapid availability of new treatments for AD.

Does apical periodontitis have systemic consequences? The need for well-planned and carefully conducted clinical studies.

Apical periodontitis, infection of the root canal system, may have systemic consequences. This proposal has been brought forward many times in dentistry literature but the general consensus is that there is no scientific basis for an association between endodontic infections and general health. This opinion paper argues that, in order to obtain such a scientific basis, or to rule out the issue all together, we need carefully designed longitudinal challenge model (that is, intervention) studies in which we follow specific biomarkers of inflammation. These biomarkers can be those that are currently being substantiated in chronic inflammation and low-grade inflammation studies in medicine and nutritional science, where the presence of these inflammatory disorders is linked to systemic outcomes. A list of suggested biomarkers has been included.

IL-33 Exacerbates Periodontal Disease through Induction of RANKL.

Cytokines mediate the balance between protective and destructive immunity in periodontitis. We sought to investigate the role of IL-33 in periodontitis. The expression of IL-33 in gingival tissue from healthy controls (n = 10) and patients with chronic periodontitis (n = 17) was investigated. Based on a murine model of periodontal disease, the function of IL-33 was determined first by administration of exogenous IL-33 and second by inhibition of IL-33 signaling using mice deficient in the IL-33 receptor ST2. Alveolar bone level, serum antibody, and lymphocyte responses were assessed in the murine model. Expression of IL-33 and ST2 was elevated in gingival tissues from patients with chronic periodontitis as compared with healthy tissues (P < 0.05). Similarly, Il33 expression was higher in periodontal tissues of Porphyromonas gingivalis-infected mice as compared with sham-infected controls (P < 0.05). IL-33 treatment of P. gingivalis-infected mice significantly exacerbated alveolar bone loss when compared with infection or IL-33 treatment alone (P < 0.001). Conversely, P. gingivalis infection-induced alveolar bone loss was attenuated in mice lacking ST2. The percentages of T and B lymphocytes expressing nuclear factor κB ligand (RANKL) in the gingival tissues and T lymphocytes expressing RANKL in the cervical draining lymph nodes were higher in IL-33-treated P. gingivalis-infected mice versus phosphate buffered saline-treated P. gingivalis-infected controls (all P < 0.001). Targeting the RANKL pathway by osteoprotegerin administration abrogated periodontal bone destruction in P. gingivalis-infected, IL-33-treated mice. These data demonstrate a previously unrecognized role for IL-33 in exacerbating bone loss in a RANKL-dependent manner in the context of bacterial infection and suggest that this pathway may be amenable to manipulation as a novel therapeutic target in periodontitis.