Protocol design for randomized clinical trial to compare underwater cold snare polypectomy to conventional cold snare polypectomy for non-pedunculated colon polyps of size 5-10 mm (COLDWATER study).

BACKGROUND: Colorectal cancer is internationally the third leading cause of death from a malignant disease. The aim of screening colonoscopy in adults > 45 years of age is early diagnosis and treatment of precancerous polyps. Endoscopic polyp removal (polypectomy) can be achieved with various techniques depending on the size, morphology, and location of the polyp. According to current guidelines, small non-pedunculated polyps should be removed with a cold snare after the colorectal lumen has been insufflated with air (conventional cold snare polypectomy).In recent years, several studies have described the benefits of water aided colonoscopy, as well as the safety and efficacy of underwater cold snare polypectomy for large colon polyps. However, there are insufficient data on conventional and underwater techniques for small polyps, the most commonly diagnosed colorectal polyps. METHODS: We have designed a prospective randomized double-blind clinical trial to compare the safety and efficacy of conventional and underwater cold snare polypectomy for non-pedunculated polyps 5-10 mm in size. A total of 398 polyps will be randomized. Randomization will be carried out using the random numbers method of Microsoft Excel 2016. The primary endpoint is the muscularis mucosa resection rate. Secondary endpoints are the depth and percentage of R0 excisions, complications, and the recurrence rate at follow-up endoscopy 6-12 months after polypectomy. DISCUSSION: We hypothesize underwater polypectomy will result in a higher muscularis mucosa resection rate. The results of our study will provide useful data for the development of guidelines in polypectomy techniques for non-pedunculated polyps 5-10 mm in size. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT05273697.

A micro-Raman and X-ray study of erupted submarine pyroclasts from El Hierro (Spain) and its' astrobiological implications.

The pumice volcanic samples could have possible connections to the evolution of life and give us insight about their bio-geochemical processes related. In this regard, the samples from the volcanic eruption from La Restinga (El Hierro, Spain) in 2011 have been mainly studied by means of Raman spectroscopy. The research also includes analysis of XRD, Scanning Electron Microscopy and Optical Microscopy to support the Raman analysis. The results show that the Raman methods and mineral analyses are in strong agreement with the results obtained from other authors and techniques. The internal white foamy core (WFC) of the studied pumice samples shows amorphous silica, Fe-oxides, Ti-oxides, quartz, certain sulfates, carbonates, zeolites and organics. On the other hand, the external part (dark crust - DC) of these samples mainly presents primary-sequence mineralogy combined with some secondary alteration minerals such as olivine, feldspar, pyroxene, amorphous silica, and Fe-oxide. Raman spectroscopy detected other minerals not yet reported on these samples like barite, celestine and lepidocrocite. Also, the different chemometric and calibration methods for Raman spectroscopy in elemental composition, mineral classification and structural characterization has been successfully applied. From the astrobiological perspective, the research was also complemented with comparisons to other similar samples from terrestrial analogs. The main consideration was taking into account the proposed hypothesis regarding the potential behavior of the pumice as a substrate for the evolution of life. Furthermore, the detailed analysis from La Restinga eruption is coherent with the mineral phases and processes discussed from previous literature. The white internal part fulfills the conditions to work as an organic reservoir, confirmed by the detection of organic matter and selected minerals that could be used as energy sources for bacterial communities. The external layers of the samples work as a shielding layer to protect the organics from decay in extreme conditions. Finally, here we have demonstrated that the characteristics and advantages of Raman spectroscopy could help to assess and understand the possible biogenicity and alteration processes of any geological sample to be found on Mars.

Screening for Diabetes Risk Using Integrated Dental and Medical Electronic Health Record Data.

Undiagnosed diabetes and prediabetes present a serious public health challenge. We previously reported that data available in the dental setting can serve as a tool for early dysglycemia identification in a primarily Hispanic, urban population. In the present study, we sought to determine how the identification approach can be recalibrated to detect diabetes or prediabetes in a White, rural cohort and whether an integrated dental-medical electronic health record (iEHR) offers further value to the process. We analyzed iEHR data from the Marshfield Clinic, a health system providing care in rural Wisconsin, for dental patients who were ≥21 y of age, reported that they had never been told they had diabetes, had an initial periodontal examination of at least 2 quadrants, and had a glycemic assessment within 3 mo of that examination. We then assessed the performance of multiple predictive models for prediabetes/diabetes. The study outcome, glycemic status, was gleaned from the medical module of the iEHR based on American Diabetes Association blood test cutoffs. The sample size was 4,560 individuals. Multivariate logistic regression revealed that the best performance was achieved by a model that took advantage of the iEHR. Predictors included age, sex, race, ethnicity, number of missing teeth, percentage of teeth with at least 1 pocket ≥5 mm from the dental EHR, and overweight/obesity, hypertension, hyperlipidemia, and smoking status from the medical EHR. The model achieved an area under the receiver operating characteristic curve of 0.71 (95% confidence interval, 0.69-0.72), yielding a sensitivity of 0.70 and a specificity of 0.62. Across a range of populations, informed by certain patient characteristics, dental care team members can play a role in helping to identify dental patients with undiagnosed diabetes or prediabetes. The accuracy of the prediction increases when dental findings are combined with information from the medical EHR. Knowledge Transfer Statement: Prediabetes and diabetes often go undiagnosed for many years. Early identification and care can lead to improved glycemic outcomes and prevent wide-ranging morbidity, including adverse oral health consequences, in affected individuals. Information available in the dental office can be used by clinicians to identify those who remain undiagnosed or are at risk; the accuracy of this prediction increases when combined with information from the medical electronic health record.

Dental findings and identification of undiagnosed hyperglycemia.

A change in the American Diabetes Association guidelines added hemoglobin A1c (HbA1c) to the assays for diabetes diagnosis, but evidence suggests that glucose vs. HbA1c criteria may identify different segments of the affected population. We previously demonstrated that oral findings offer an opportunity for the detection of undiagnosed abnormal fasting plasma glucose (FPG) among dental patients who present with diabetes risk factors. In this new cross-sectional study, we sought to extend these observations. The first goal, using data from 591 new participants, was to assess our previously identified hyperglycemia detection models when HbA1c is used for case definition. The second goal, using data from our total cohort of 1,097 participants, was to evaluate the models' performance regardless of whether an FPG or an HbA1c is used for diagnosis. The presence of ≥ 26% teeth with deep pockets or ≥ 4 missing teeth correctly identified 72% of pre-diabetes or diabetes cases in the HbA1c sample and 75% in the total population. The addition of a point-of-care HbA1c ≥ 5.7% increased correct identification to 87% and 90%, respectively. These results demonstrate the validity of our prediction models regardless of the test used for diabetes or pre-diabetes diagnosis in the clinical setting and underscore the contribution dentists can make.

Identification of unrecognized diabetes and pre-diabetes in a dental setting.

Many diabetic patients remain undiagnosed, and oral findings may offer an unrealized opportunity for the identification of affected individuals unaware of their condition. We recruited 601 individuals who presented for care at a dental clinic, were ≥40 years old, if non-Hispanic white, and ≥30 years old, if Hispanic or non-white, and had never been told they have pre-diabetes or diabetes. Those with at least one self-reported diabetes risk factor (N=535) received a periodontal examination and a point-of-care hemoglobin A1c (HbA1c) test. A fasting plasma glucose (FPG) test was used as the study outcome, signifying potential diabetes or pre-diabetes. Performance characteristics of simple models of dysglycemia (FPG≥100 mg/dL) identification were evaluated and optimal cut-offs identified. A model including only two dental variables had an estimated area under the receiver operating characteristic curve (AUC) of 0.65. The addition of a point-of-care HbA1c test improved the AUC to 0.79 (p<0.001). The presence of ≥26% deep pockets or ≥4 missing teeth correctly identified 73% of true cases; the addition of an HbA1c≥5.7% increased correct identification to 92%. Analysis of our data suggests that oral healthcare professionals have the opportunity to identify unrecognized diabetes and pre-diabetes in dental patients and refer them to a physician for further evaluation and care.

Enhanced monocyte migration and pro-inflammatory cytokine production by Porphyromonas gingivalis infection.

BACKGROUND AND OBJECTIVE: Porphyromonas gingivalis, a major periodontal pathogen, has been reported to be involved in atherogenesis. In order to further understand this pathogen's link with systemic inflammation and vascular disease, we investigated its influence on murine monocytes and macrophages from three different sources. MATERIAL AND METHODS: Concanavalin A-elicited peritoneal macrophages, peripheral blood monocyte-derived macrophages and WEHI 274.1 monocytes were infected with either P. gingivalis 381 or its non-invasive fimbriae-deficient mutant, DPG3. RESULTS: Infection with P. gingivalis 381 markedly induced monocyte migration and significantly enhanced production of the pro-inflammatory cytokines, tumor necrosis factor-alpha and interleukin-6. Consistent with a role for this pathogen's major fimbriae and/or its invasive capacity, infection with DPG3 had a minimal effect on both monocyte attraction and pro-inflammatory cytokine production. CONCLUSION: Since monocyte recruitment and activation are important steps in the development of vascular inflammation and atherosclerosis, these results suggest that P. gingivalis infection may be involved in these processes.

Intravenous immunoglobulins induce CD32-mediated platelet aggregation in vitro.

BACKGROUND: Intravenous immunoglobulins (IVIg) and cytomegalovirus immunoglobulins (CMVIg) are currently finding increased acceptance in clinical states of high immune activity and in transplant recipients. A rare side-effect of their application is intravascular thrombosis, which is thought to be related to pre-existing hyperviscosity. In a previous study we have shown that rabbit antithymocyte globulin causes platelet aggregation in vitro via the Fc IgG receptor (CD32). OBJECTIVES: To investigate if IVIg and CMVIg have the potential to cause CD32-dependent platelet aggregation. METHODS: The influence of CMVIg or IVIg on platelets pre-incubated with or without monoclonal antibody AT10 was studied in an aggregometer. Expression of platelet surface activation marker CD62P was determined by fluorescence-activated cell sorting analysis and presence of soluble CD40L (sCD40L) was evaluated by enzyme-linked immunosorbent assay. All in vitro experiments were performed using platelet concentrates from the blood bank, at therapeutic concentrations of immunoglobulins. Results Incubation of platelets with CMVIg and IVIg markedly induced platelet aggregation, and increased expression of CD62P and secretion of sCD40L. The capacity of CMVIg and IVIg to induce platelet aggregation was completely abrogated by adding the blocking antibody AT10 directed against the low-affinity Fc IgG receptor (CD32). CONCLUSIONS: Our results suggest that CMVIg and IVIg solutions with activating Fc domains are able to bind CD32 on platelets and cause platelet aggregation in vitro. These results indicate a mechanism by which in vivo intravascular thrombosis may be explained and suggest caution with concomitant use of packed platelets and IVIg in autoimmune diseases in the clinical setting.

Diabetes in the dental office: using NHANES III to estimate the probability of undiagnosed disease.

BACKGROUND AND OBJECTIVE: Recent data have suggested that in the past 15 years there has been a dramatic increase in the incidence of diabetes mellitus in the USA. However, evidence suggests that approximately one-third of diabetes cases remain undiagnosed. Because 60% of Americans see a dentist at least once per year for routine, nonemergent, care, it is reasonable to propose that the dental office can be a healthcare location actively involved in screening for unidentified diabetes. MATERIAL AND METHODS: This study used NHANES III to develop a predictive equation that can form the basis of a tool to help dentists determine the probability of undiagnosed diabetes by using self-reported data and periodontal clinical parameters routinely assessed in the dental office. RESULTS: Our analyses reveal that individuals with a self-reported family history of diabetes, hypertension, high cholesterol levels and clinical evidence of periodontal disease bear a probability of 27-53% of having undiagnosed diabetes, with Mexican-American men exhibiting the highest probability and white women the lowest. CONCLUSION: These findings suggest that the dental office could provide an important opportunity to identify individuals unaware of their diabetic status.

Diabetes-related parameters and periodontal conditions in children.

BACKGROUND AND OBJECTIVE: The relationship between diabetes and periodontal diseases is well established. Our aim in this study was to explore the diabetes-related parameters that are associated with accelerated periodontal destruction in diabetic youth. MATERIAL AND METHODS: Three-hundred and fifty 6-18-year-old children with diabetes received a periodontal examination. Data on important diabetes-related variables were collected. Analyses were performed using logistic regression, with gingival/periodontal disease as the dependent variable, for the whole cohort and separately for two subgroups (6-11 and 12-18 years of age). RESULTS: Regression analyses, adjusting for age, gender, ethnicity, frequency of prior dental visits, dental plaque, and dental examiner, revealed a strong positive association between mean hemoglobin A1c over the 2 years prior to inclusion in the study and periodontitis (odds ratio = 1.31, p = 0.030). This association approached significance in the younger subgroup (odds ratio = 1.56, p = 0.052, n = 183). There was no significant relationship between diabetes duration or body mass index-for-age and measures of gingival/periodontal disease in this cohort. CONCLUSION: These findings suggest that accelerated periodontal destruction in young people with diabetes is related to the level of metabolic control. Good metabolic control may be important in addressing periodontal complications in young patients with diabetes, similarly to what is well established for other systemic complications of this disease.

Effects of periodontal therapy on serum C-reactive protein, sE-selectin, and tumor necrosis factor-alpha secretion by peripheral blood-derived macrophages in diabetes. A pilot study.

BACKGROUND AND OBJECTIVE: Diabetes is associated with an increased risk for vascular disease and periodontitis. The aim of this study was to assess the effects of periodontal treatment in diabetes with respect to alterations in the pro-inflammatory potential of peripheral blood mononuclear cells. MATERIAL AND METHODS: Ten patients with diabetes and moderate to severe periodontitis received full-mouth subgingival debridement. Blood samples for serum/plasma and mononuclear cell isolation were collected prior to and 4 wk after therapy. Mononuclear cells were analyzed by flow cytometry and stimulated with lipopolysaccharide or ionomycin/phorbol ester to determine the pro-inflammatory capacity of macrophages and lymphocytes, respectively. RESULTS: Following periodontal treatment, all patients demonstrated a significant improvement in clinical periodontal status (p < 0.05), despite only modest reduction in subgingival bacterial load or homologous serum immunoglobulin G titers. CD14(+) blood monocytes decreased by 47% (p < 0.05), and the percentage of macrophages spontaneously releasing tumor necrosis factor-alpha decreased by 78% (p < 0.05). There were no significant changes in the capacity of lymphocytes to secrete interferon-gamma. Among a number of serum inflammatory markers tested, high-sensitivity-C-reactive protein significantly decreased by 37% (p < 0.01) and soluble E-selectin decreased by 16.6% (p < 0.05). CONCLUSION: These data suggest a reduced tendency for monocyte/macrophage-driven inflammation with periodontal therapy and a potential impact on atherosclerosis-related complications in diabetic individuals.

Infection with a periodontal pathogen induces procoagulant effects in human aortic endothelial cells.

BACKGROUND: Multiple studies have demonstrated a link between periodontal infections and vascular disease. Porphyromonas gingivalis, a major periodontal pathogen, has been shown to adhere to and invade endothelial cells. OBJECTIVE: In order to dissect mechanisms underlying these observations, we assessed the role of P. gingivalis infection in modulating properties of endothelial cells linked to atherothrombosis. METHODS: Primary human aortic endothelial cells (HAEC) were infected with either P. gingivalis 381 or its non-invasive fimbriae-deficient mutant, DPG3. Markers of coagulation and thrombosis were assessed 8 h and 18 h postinfection in cell lysates and supernatants. RESULTS: Infection with P. gingivalis 381 significantly enhanced tissue factor expression and activity, and suppressed levels of tissue factor pathway inhibitor. Furthermore, P. gingivalis infection decreased levels and activity of tissue plasminogen activator, and enhanced plasminogen activator inhibitor-1 antigen and activity. Consistent with an important role for bacterial adhesion/invasion in this setting, infection with DPG3 failed to induce procoagulant properties in HAEC. Most of the above effects of P. gingivalis 381 were more apparent at the later time point (18 h postinfection). This suggests that P. gingivalis infection, rather than having an immediate and direct effect, might activate pathways that, in turn, trigger endothelial procoagulant mechanisms. CONCLUSIONS: Taken together these data demonstrate for the first time that infection with a periodontal pathogen induces procoagulant responses in HAEC.

Longitudinal stability of serum immunoglobulin G responses to periodontal bacteria.

BACKGROUND: The value of seroepidemiology in the study of periodontal infections has not been adequately explored. This study examined serum immunoglobulin (IgG) responses to periodontal bacteria in patients with periodontitis and periodontitis-free individuals over a 30-month period. METHODS: Eighty-nine patients with chronic periodontitis and 42 control subjects with no deep periodontal pockets and no or minimal attachment loss (30-72 years old, 43% men) were included. Patients were examined at baseline, after completed periodontal therapy 4 months post-baseline, and at 30 months, and controls, at baseline and 30 months. IgG antibodies to 19 periodontal species were determined by checkerboard immunoblotting. RESULTS: On average, patients displayed at baseline up to 800-fold higher titers than controls to all but three species. Over the 30-month period, titers remained stable at low levels in controls. In patients, periodontal conditions improved from a baseline mean probing depth of 3.6 mm, bleeding on probing of 62% and an average of 21.5 pockets of=6 mm/person, to 2.5 mm mean pocket depth, 30% bleeding on probing, and 1.2 deep pockets, at 30 months. Over time, antibody titers showed a modest decline in patients, but remained significantly elevated at 30 months in comparison with controls. Antibody-level changes over time were not significantly different between subjects that did and did not receive adjunctive systemic antibiotics. CONCLUSIONS: Conspicuous differences in IgG titers to periodontal bacteria exist between periodontitis patients and periodontally healthy controls. Despite successful periodontal therapy, titers remained elevated over a 30-month period, suggesting that serology may mark the history of past periodontal infection.

RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease.

Receptor for AGE (RAGE) is a member of the immunoglobulin superfamily that engages distinct classes of ligands. The biology of RAGE is driven by the settings in which these ligands accumulate, such as diabetes, inflammation, neurodegenerative disorders and tumors. In this review, we discuss the context of each of these classes of ligands, including advance glycation end-products, amyloid beta peptide and the family of beta sheet fibrils, S100/calgranulins and amphoterin. Implications for the role of these ligands interacting with RAGE in homeostasis and disease will be considered.

RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response.

The receptor for advanced glycation end products (RAGE) and its proinflammatory S100/calgranulin ligands are enriched in joints of subjects with rheumatoid arthritis (RA) and amplify the immune/inflammatory response. In a model of inflammatory arthritis, blockade of RAGE in mice immunized and challenged with bovine type II collagen suppressed clinical and histologic evidence of arthritis, in parallel with diminished levels of TNF-alpha, IL-6, and matrix metalloproteinases (MMP) 3, 9 and 13 in affected tissues. Allelic variation within key domains of RAGE may influence these proinflammatory mechanisms, thereby predisposing individuals to heightened inflammatory responses. A polymorphism of the RAGE gene within the ligand-binding domain of the receptor has been identified, consisting of a glycine to serine change at position 82. Cells bearing the RAGE 82S allele displayed enhanced binding and cytokine/MMP generation following ligation by a prototypic S100/calgranulin compared with cells expressing the RAGE 82G allele. In human subjects, a case-control study demonstrated an increased prevalence of the 82S allele in patients with RA compared with control subjects. These data suggest that RAGE 82S upregulates the inflammatory response upon engagement of S100/calgranulins, and, thereby, may contribute to enhanced proinflammatory mechanisms in immune/inflammatory diseases.

Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model.

Although hyperhomocysteinemia (HHcy) is a well-known risk factor for the development of cardiovascular disease, the underlying molecular mechanisms are not fully elucidated. Here we show that induction of HHcy in apoE-null mice by a diet enriched in methionine but depleted in folate and vitamins B6 and B12 increased atherosclerotic lesion area and complexity, and enhanced expression of receptor for advanced glycation end products (RAGE), VCAM-1, tissue factor, and MMP-9 in the vasculature. These homocysteine-mediated (HC-mediated) effects were significantly suppressed, in parallel with decreased levels of plasma HC, upon dietary supplementation with folate and vitamins B6/B12. These findings implicate HHcy in atherosclerotic plaque progression and stability, and they suggest that dietary enrichment in vitamins essential for the metabolism of HC may impart protective effects in the vasculature.

Receptor for advanced glycation end products, inflammation, and accelerated periodontal disease in diabetes: mechanisms and insights into therapeutic modalities.

In hyperglycemic states found in diabetics, a nonenzymatic glycation and oxidation of proteins and lipids occurs. As a result, advanced glycation end products (AGEs), particularly N epsilon-(carboxymethyl)lysine, accumulate in the plasma and tissues of diabetic subjects. This accumulation has been linked to the development of pathogenic complications of diabetes. Many of the effects of AGEs are receptor-dependent and involve a multi-ligand member of the immunoglobulin superfamily of cell surface molecules. The best characterized of these is the receptor for advanced glycation end products (RAGE), which is expressed by multiple cell types including endothelium and mononuclear phagocytes. Based on data from a variety of sources, including studies of RAGE-deficient mice, it appears that RAGE plays a central role in oral infection, exaggerated inflammatory host responses, and destruction of alveolar bone in diabetes. It is possible that antagonists of RAGE might have a valuable adjunctive therapeutic role for the management of periodontal disease found in diabetics.

Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases.

The receptor for advanced glycation end products (RAGE), a multi-ligand member of the immunoglobulin superfamily of cell surface molecules, interacts with distinct molecules implicated in homeostasis, development and inflammation, and certain diseases such as diabetes and Alzheimer's disease. Engagement of RAGE by a ligand triggers activation of key cell signalling pathways, such as p21ras, MAP kinases, NF-kappaB and cdc42/rac, thereby reprogramming cellular properties. RAGE is a central cell surface receptor for amphoterin, a polypeptide linked to outgrowth of cultured cortical neurons derived from developing brain. Indeed, the co-localization of RAGE and amphoterin at the leading edge of advancing neurites indicated their potential contribution to cellular migration, and in pathologies such as tumour invasion. Here we demonstrate that blockade of RAGE-amphoterin decreased growth and metastases of both implanted tumours and tumours developing spontaneously in susceptible mice. Inhibition of the RAGE-amphoterin interaction suppressed activation of p44/p42, p38 and SAP/JNK MAP kinases; molecular effector mechanisms importantly linked to tumour proliferation, invasion and expression of matrix metalloproteinases.

Blockade of RAGE suppresses periodontitis-associated bone loss in diabetic mice.

Diabetes is associated with increased prevalence, severity, and progression of periodontal disease. To test the hypothesis that activation of RAGE (Receptor for Advanced Glycation End products) contributes to the pathogenesis of diabetes-associated periodontitis, we treated diabetic mice, infected with the human periodontal pathogen Porphyromonas gingivalis, with soluble RAGE (sRAGE). sRAGE is the extracellular domain of the receptor, which binds ligand and blocks interaction with, and activation of, cell-surface RAGE. Blockade of RAGE diminished alveolar bone loss in a dose-dependent manner. Moreover, we noted decreased generation of the proinflammatory cytokines TNF-alpha and IL-6 in gingival tissue, as well as decreased levels of matrix metalloproteinases. Gingival AGEs were also reduced in mice treated with sRAGE, paralleling the observed suppression in alveolar bone loss. These findings link RAGE and exaggerated inflammatory responses to the pathogenesis of destructive periodontal disease in diabetes.