Periodontal disease and cerebral atherosclerotic disease. Translational study

Although an association has been established between periodontal disease (PD) and large vessel ischemic stroke, little is known about the relationship between PD and lacunar infarct (LI), a subtype of cerebral small vessel disease that is responsible for almost 25% of the ischemic stroke cases. Our aim was, therefore, to investigate whether PD is linked with LI and if so, to study potential mechanisms underlying this association. In the present study we found that PD was positively associated with LI and, when present, emerged as one of the main contributors to an enhanced systemic inflammatory state promoting endothelial dysfunction with elevated levels of IL-6, PTX3, sTWEAK, and Aβ1-40 in LI patients. Moreover, moderate to severe active PD was an independent predictor of poor functional outcome in LI patients. These findings were corroborated in a preclinical in vivo study in the rodent model, in which experimental PD induced with lipopolysaccharide from Porphyromonas gingivalis was associated with a mild systemic inflammatory response with disruption of the vascular endothelial function

Pentraxin 3 (PTX3): A Molecular Marker of Endothelial Dysfunction in Chronic Migraine

Even though endothelial dysfunction is known to play a role in migraine pathophysiology, studies regarding levels of endothelial biomarkers in migraine have controversial results. Our aim was to evaluate the role of pentraxin 3 (PTX3) and soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK) as potential biomarkers of endothelial dysfunction in chronic migraine (CM). We performed a case-control study including 102 CM patients and 28 control subjects and measured serum levels of markers of endothelial dysfunction (PTX3 and sTWEAK) and inflammation [high-sensitivity C-reactive protein (hs-CRP)] as well as brachial artery flow-mediated dilation (FMD) during interictal periods. Interictal serum levels of PTX3 and sTWEAK were higher in CM patients than in controls (1350.6 ± 54.8 versus 476.1 ± 49.4 pg/mL, p < 0.001 and 255.7 ± 21.1 versus 26.4 ± 2.6 pg/mL, p < 0.0001; respectively). FMD was diminished in CM patients compared to controls (9.6 ± 0.6 versus 15.2 ± 0.9%, p < 0.001). Both PTX3 and sTWEAK were negatively correlated with FMD (r = −0.508, p < 0.001 and r = −0.188, p = 0.033; respectively). After adjustment of confounders, PTX3 remained significantly correlated to FMD (r = −0.250, p = 0.013). Diagnosis of CM was 68.4 times more likely in an individual with levels of PTX3 ≥ 832.5 pg/mL, suggesting that PTX3 could be a novel biomarker of endothelial dysfunction in CMThis research was funded by Spanish Ministry of Economy and Competitiveness—Institute of Health Carlos III, Grant/Award Numbers: PI15/01578S

Severe Periodontitis and Biomarkers of Bacterial Burden. Results From a Case-Control and Intervention Clinical Trial

Background and aims: Periodontitis is an inflammatory-infectious disease. Identifying markers of systemic exposure of periodontitis might be of interest to study its interaction with other conditions. Soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) is upregulated during bacterial infections. Our aim was therefore to investigate whether periodontitis and its treatment are associated with bacterial endotoxin and sTREM-1. Methods: Fifty patients with severe periodontitis and 50 age-matched controls were included in a case-control study (all never smokers). A secondary analysis of a previously published intervention study was performed, in which included 69 patients with severe periodontitis were randomized to receive either intensive (IPT) or control periodontal therapy (CPT) and monitored over 6 months. Serum levels of bacterial endotoxin and sTREM-1 were determined at one time point (case-control study) and at baseline, 1 day, 1 and 6 months after periodontal treatment (intervention study). Results: Severe periodontitis was associated with elevated circulating endotoxin levels when cases (22.9 ± 2.2 EU/ml) were compared to controls (3.6 ± 0.5 EU/ml, p < 0.001) and with sTREM-1 levels (1302.6 ± 47.8 vs. 870.6 ± 62.0 pg/ml, p < 0.001). A positive correlation was observed between sTREM-1 and endotoxin levels (r = 0.4, p < 0.001). At 6 months after treatment, IPT significantly decreased serum levels of sTREM-1 compared to CPT (adjusted mean difference of 500.2 pg/ml, 95% CI: 18.9-981.4; p = 0.042). No substantial differences were noted in endotoxin levels at any time point after treatment between groups. Conclusions: Severe periodontitis is linked to increased circulating endotoxin and sTREM-1 levels and following IPT a reduction in sTREM-1 levels is observed

Mild systemic inflammation enhances response to OnabotulinumtoxinA in chronic migraineurs

The anti-inflammatory effect of OnabotulinumtoxinA (OnabotA) has been a matter of discussion for many years. In chronic migraine, however, increased pro-inflammatory state is associated with good response to OnabotA. We aimed to investigate whether a mild systemic inflammatory state elicited by a common oral infection (periodontitis) could enhance treatment response to OnabotA. In this study, we included 61 chronic migraineurs otherwise healthy treated with OnabotA of which 7 were poor responders and 54 good responders. Before receiving OnabotA therapy, all participants underwent a full-mouth periodontal examination and blood samples were collected to determine serum levels of calcitonin gene-related peptide (CGRP), interleukin 6 (IL-6), IL-10 and high sensitivity C-reactive protein (hs-CRP). Periodontitis was present in 70.4% of responders and 28.6% of non-responders (P = 0.042). Responders showed greater levels of inflammation than non-responders (IL-6: 15.3 ± 8.7 vs. 9.2 ± 4.7 ng/mL, P = 0.016; CGRP: 18.8 ± 7.6 vs. 13.0 ± 3.1 pg/mL, P = 0.002; and hs-CRP: 3.9 ± 6.6 vs. 0.9 ± 0.8 mg/L, P = 0.003). A linear positive correlation was found between the amount of periodontal tissue inflamed in the oral cavity and markers of inflammation (IL-6: r = 0.270, P = 0.035; CGRP: r = 0.325, P = 0.011; and hs-CRP: r = 0.370, P = 0.003). This report shows that in presence of elevated systemic inflammatory markers related to periodontitis, OnabotA seems to reduce migraine attacks. The changes of scheduled inflammatory parameters after treatment and subsequent assessment during an adequate period still need to be doneThis study was partially supported by a grant from the Spanish Ministry of Economy and Competitiveness—Institute of Health Carlos III (PI15/01578). YL holds a Senior Clinical Research Fellowship supported by the UCL Biomedical Research Centre who receives funding from the NIHR (NIHR-INF-0387) and a research contract with Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (fIDIS). TS (CPII17/00027) and FC (CP14/00154) are recipients of research contracts from Miguel Servet Program of Institute of Health Carlos IIIS

Iron Deposits in Periaqueductal Gray Matter Are Associated with Poor Response to OnabotulinumtoxinA in Chronic Migraine

Previous studies have reported increased brain deposits of iron in patients with chronic migraine (CM). This study aims to determine the relation between iron deposits and outcome after treatment with OnabotulinumtoxinA (OnabotA). Demographic and clinical data were collected for this study through a prospective cohort study including 62 CM patients treated with OnabotA in the Hospital Clínico Universitario de Santiago de Compostela (Spain). Demographic and clinical variables were registered. Selected biomarkers in plasma during interictal periods (calcitonin gene-related peptide (CGRP) and pentraxin-3 (PTX3)) and neuroimaging changes (iron deposits in the red nucleus (RN), substantia nigra (SN), globus pallidus (GP), and periaqueductal gray matter (PAG), and white matter lesions (WML)) were determined. Subjects were classified in responders (≥50% reduction in headache days) or non-responders (<50%). Responders to treatment were younger (mean age difference = 12.2; 95% confidence interval (CI): 5.4–18.9, p = 0.001), showed higher serum levels of CGRP (≥50 ng/mL) and PTX3 (≥1000 pg/mL) and smaller iron deposits in the GP and PAG (mean difference = 805.0; 95% CI: 37.9–1572.1 μL, p = 0.040 and mean difference = 69.8; 95% CI: 31.0–108.6 μL, p = 0.008; respectively). Differences in PAG iron deposits remained significant after adjusting for age (mean difference = 65.7; 95% CI: 22.8–108.6 μL, p = 0.003) and were associated with poor response to OnabotA after adjustment for clinical and biochemical variables (odds ratio (OR) = 0.963; 95% CI: 0.927–0.997, p = 0.041). We conclude that larger PAG iron deposits are associated with poor response to OnabotA in CMSpanish Ministry of Economy and Competitiveness—Institute of Health Carlos III, grant/award number PI15/01578S

Influence of low insertion torque values on survival rate of immediately loaded dental implants: A systematic review and meta-analysis

Aim The aim was to systematically evaluate the effect of low insertion torque values on the survival rate of immediately loaded dental implants. Materials and Methods The protocol was registered with PROSPERO (ID CRD42020189499). An electronic search was performed in PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials until June 2022 in English and Spanish. Studies analysing the failure or survival rate of immediately loaded dental implants according to different insertion torque values were included. Results Five-hundred seventy-three articles were assessed for eligibility, of which seven articles, four randomized clinical trials (RCTs), one controlled clinical trial, and two prospective case series studies were included in the qualitative analysis. The RCTs were classified as having low risk of bias and the non-RCTs as having moderate and serious risk of bias. The mean survival rate for implants with low insertion toque (≤35 Ncm) was 96% (p > .001, 95% confidence interval [CI]: 0.91–0.98) and that for implants with medium or high insertion torque (>35 Ncm) was 92% (p > .001, 95% CI: 0.86–0.96) (incidence rate ratio [IRR] = 1.05, 95% CI: 0.79–1.39, p = .175, I2 = 0.0%). Splinted implants with insertion torque >20 Ncm and single implants with insertion torque >35 Ncm had a higher survival rate than implants with lower insertion torque values (IRR = 1.05, 95% CI: 0.78–1.43, p = .956, I2 = 0.0%, and RR = 0.92, 95% CI: 0.48–1.75, p = .799, I2 = 0.0%, respectively). Different insertion torque values achieved equivalent outcomes. The mean follow-up was 24 months. Conclusions Low insertion torque values have no significant effect on survival rates of immediate loading implants at a mean follow-up of 24 monthsThere was no funding for this studyS

Periodontitis is associated with subclinical cerebral and carotid atherosclerosis in hypertensive patients: A cross‑sectional study

Objective: To examine the relationship between periodontitis and subclinical intracranial atherosclerosis. The association of periodontitis with preclinical markers of atherosclerosis in other vascular territories was also explored. Material and methods: This was a cross-sectional study where 97 elderly subjects with a previous history of hypertension received an ultrasonographic evaluation to assess subclinical atherosclerosis in different vascular territories: (1) cerebral [pulsatility (PI) and resistance index (RI) of the middle cerebral artery], (2) carotid [intima-media thickness (IMT)], and (3) peripheral [ankle-brachial index (ABI)]. Additionally, participants underwent a full-mouth periodontal assessment together with blood sample collection to determine levels of inflammatory biomarkers (leukocytes, fibrinogen, and erythrocyte sedimentation rate), lipid fractions (total cholesterol and high- and low-density lipoprotein), and glucose. Results: Sixty-one individuals had periodontitis. Compared to subjects without periodontitis, those with periodontitis showed higher values of PI (1.24 ± 0.29 vs 1.01 ± 0.16), RI (0.70 ± 0.14 vs 0.60 ± 0.06), and IMT (0.94 ± 0.15 vs 0.79 ± 0.15) (all p < 0.001). No statistically significant differences were found neither for ABI or for other clinical and biochemical parameters. An independent association was found between periodontitis and increased intracranial atherosclerosis (ORadjusted = 10.16; 95% CI: 3.14-32.90, p < 0.001) and to a lesser extent with thicker carotid IMT (ORadjusted = 4.10; 95% CI: 1.61-10.48, p = 0.003). Conclusions: Periodontitis is associated with subclinical atherosclerosis in both intracranial and carotid arteries in elderly subjects with hypertension. Clinical relevance: The association of periodontitis with intracranial atherosclerosis implies that periodontitis patients might have greater chances to develop ischemic stroke in the futureOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This study was partially supported by grants from the Xunta de Galicia (TS: IN607A2018/3 and TS: IN607D 2020/09), Spanish Ministry of Science (TS: RTI2018-102165-B-I00 and RTC2019-007373-1), Institute of Health Carlos III (PI22/00938), and RICOR-ICTUS Network (RD21/0006/003). Furthermore, this study was also supported by grants from the Interreg Atlantic Area (TS: EAPA_791/2018_ NeuroATLANTIC project), Interreg V-A España Portugal (POCTEP) (TS: 0624_2IQBIONEURO_6_E), and the European Regional Development Fund. YL is supported by a Sara Borrell fellowship (CD22/00051), and TS (CPII17/00027) and FC (CPII19/00020) are recipients of Miguel Servet contracts, all of them funded by the Institute of Health Carlos IIIS

Association of periodontitis with cognitive decline and its progression: Contribution of blood‐based biomarkers of Alzheimer's disease to this relationship

Aim To assess whether periodontitis is associated with cognitive decline and its progression as well as with certain blood-based markers of Alzheimer's disease. Materials and Methods Data from a 2-year follow-up prospective cohort study (n = 101) was analysed. Participants with a previous history of hypertension and aged ≥60 years were included in the analysis. All of them received a full-mouth periodontal examination and cognitive function assessments (Addenbrooke's Cognitive Examination (ACE) and Mini-Mental State Examination [MMSE]). Plasma levels of amyloid beta (Aβ)1-40, Aβ1-42, phosphorylated and total Tau (p-Tau and t-Tau) were determined at baseline, 12 and 24 months. Results Periodontitis was associated with poor cognitive performance (MMSE: β = −1.5 [0.6]) and progression of cognitive impairment (hazard ratio [HR] = 1.8; 95% confidence interval: 1.0–3.1). Subjects with periodontitis showed greater baseline levels of p-Tau (1.6 [0.7] vs. 1.2 [0.2] pg/mL, p < .001) and Aβ1-40 (242.1 [77.3] vs. 208.2 [73.8] pg/mL, p = .036) compared with those without periodontitis. Concentrations of the latter protein also increased over time only in the periodontitis group (p = .005). Conclusions Periodontitis is associated with cognitive decline and its progression in elderly patients with a previous history of hypertension. Overexpression of p-Tau and Aβ1-40 may play a role in this associationThis study was partially supported by grants from the Xunta de Galicia (TS & JC: IN607A2018/3, TS: IN607D 2020/09 and IN607A2022/07), Institute of Health Carlos III (TS: PI22/00938 and CB22/05/00067) and Spanish Ministry of Science (TS: RTI2018-102165-B-I00 and RTC2019-007373-1). Furthermore, this study was also supported by grants from the INTERREG Atlantic Area (TS: EAPA_791/2018_NEUROATLANTIC project), INTER-REG V A España Portugal (POCTEP) (TS: 0624_2IQBIONEURO_6_E) and the European Regional Development Fund. Moreover, several members of the research team are supported by the Institute of Health Carlos III: MAN holds an iPFIS contract (IFI18/00008), DR-S and YL are recipients of a Sara Borrell fellowship (CD21/00166 and CD22/00051, respectively) and TS held a Miguel Servet contract (CPII17/00027). Finally, AC is supported by a predoc contract of Xunta de Galicia (IN606A-2021/015). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscriptS

Cell‐Based Therapies for Alveolar Bone and Periodontal Regeneration: Concise Review

Current regenerative strategies for alveolar bone and periodontal tissues are effective and well adopted. These are mainly based on the use of a combination of synthetic/natural scaffolds and bioactive agents, obviating the incorporation of cells. However, there are some inherent limitations associated with traditional techniques, and we hypothesized that the use of cell‐based therapies as part of comprehensive regenerative protocols may help overcome these hurdles to enhance clinical outcomes. We conducted a systematic review of human controlled clinical trials investigating the clinical and/or histological effect of the use of cell‐based therapies for alveolar bone and periodontal regeneration and explored the translational potential of the different cell‐based strategies identified in the included trials. A total of 16 studies (11 randomized controlled trials, 5 controlled clinical trials) were included for data synthesis and qualitative analysis with meta‐analyses performed when appropriate. The results suggest a clinical benefit from the use of cell therapy. Improved outcomes were shown for alveolar ridge preservation, lateral ridge augmentation, and periodontal regeneration. However, there was insufficient evidence to identify best‐performing treatment modalities amongst the different cell‐based techniques. In light of the clinical and histological outcomes, we identify extraction socket and challenging lateral and vertical bone defects requiring bone block grafts as strong candidates for the adjuvant application of mesenchymal stem cells. Given the complexity, invasiveness, and costs associated with techniques that include “substantial manipulation” of tissues and cells, their additional clinical benefit when compared with “minimal manipulation” must be elucidated in future trials. Stem Cells Translational Medicine 2019;8:1286&1295Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152687/1/sct312612_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152687/2/SCT3_12612_Supplementary_files.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152687/3/sct312612.pd

Invasive Dental Treatment and Acute Vascular Events: A Systematic Review and Meta-Analysis

BACKGROUND: Acute infection/inflammation increases the risk of acute vascular events. Invasive dental treatments (IDT) trigger short-term acute inflammation. PURPOSE: To critically appraise the evidence linking IDT and acute vascular events. DATA SOURCES: Six bibliographical databases were searched up to 31st August 2021. A systematic review following PRISMA guidelines was performed. STUDY SELECTION: Intervention and observational studies reporting any acute vascular events following IDT. DATA EXTRACTION: Two reviewers independently extracted data and rated the quality of studies. Data was pooled using fixed effect, inverse variance weights analysis. RISK OF BIAS: Newcastle-Ottawa Quality Assessment Scale for observational studies and the Cochrane Handbook -Rob 2.0 for randomised controlled trials. DATA SYNTHESIS: Three out of 16 clinical studies, a total of 533,175 participants, 124,344 myocardial infarctions and of 327,804 ischemic strokes were reported. Meta-analysis confirmed that IDT did not increase incidence ratios (IR) for combined vascular events either at 1-4 weeks (IR of 1.02, 95% CIs: 0.92, 1.13) and at 5-8 weeks (IR of 1.04, 95% CIs-0.97;1.10) after treatment. LIMITATIONS: High level of heterogeneity (study designs and timepoint assessments). CONCLUSIONS: Patients who received IDT exhibited no substantial increase in vascular risk over 8 weeks post treatment