Targeting macrophages with phosphatidylserine-rich liposomes as a potential antigen-specific immunotherapy for type 1 diabetes.

Type 1 diabetes (T1D) results from a breakdown in immunological tolerance, with pivotal involvement of antigen-presenting cells. In this context, antigen-specific immunotherapies have been developed to arrest autoimmunity, such as phosphatidylserine (PS)-liposomes. However, the role of certain antigen-presenting cells in immunotherapy, particularly human macrophages (Mφ) in T1D remains elusive. The aim of this study was to determine the role of Mφ in antigen-specific immune tolerance and T1D. To that end, we evaluated Mφ ability to capture apoptotic-body mimicking PS-liposomes in mice and conducted a phenotypic and functional characterisation of four human monocyte-derived Mφ (MoMφ) subpopulations (M0, M1, M2a and M2c) after PS-liposomes uptake. Our findings in mice identified Mφ as the most phagocytic cell subset in the spleen and liver. In humans, while phagocytosis rates were comparable between T1D and control individuals, PS-liposome capture dynamics differed among Mφ subtypes, favouring inflammatory (M1) and deactivated (M2c) Mφ. Notably, high nanoparticle concentrations did not affect macrophage viability. PS-liposome uptake by Mφ induced alterations in membrane molecule expression related to immunoregulation, reduced secretion of IL-6 and IL-12, and diminished autologous T-cell proliferation in the context of autoantigen stimulation. These results underscore the tolerogenic effects of PS-liposomes and emphasize their potential to target human Mφ, providing valuable insights into the mechanism of action of this preclinical immunotherapy.

Association between toothbrushing and cardiovascular risk factors: a cross-sectional study using Korean National Health and Nutrition Examination Survey 2015-2017.

BACKGROUND: Previous studies have suggested that frequent toothbrushing is associated with a lower risk of future cardiovascular events. We sought to investigate further the relationship between toothbrushing, cardiovascular risk factors, and lifestyle behaviours. METHODS: We analysed a cross-sectional survey including 13,761 adults aged 30 years or older without a history of cardiovascular diseases from the Korean National Health and Nutritional Examination Survey. Conventional cardiovascular risk factors (blood pressure, lipid profiles, and fasting glucose), and inflammatory markers (high-sensitivity C-reactive protein [hsCRP], and white blood cell counts [WBC]) were investigated in relation to the frequency of toothbrushing. RESULTS: The estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk, calculated using the pooled cohort equations was 13.7%, 9.1%, and 7.3% for participants who reported toothbrushing 0-1, 2, and ≥ 3 times a day, respectively. Both conventional risk factors and inflammatory markers were significantly associated with frequent toothbrushing. However, after adjusting potential confounding factors such as age, sex, comorbidities, and lifestyle behaviours, only inflammatory markers were remained as significant factors. CONCLUSIONS: Oral hygiene behaviours are closely linked to cardiovascular risk factors. This study suggests that reduced systemic inflammatory burden may explain the benefit of improved oral hygiene in terms of cardiovascular risk.

Association between subclinical atherosclerosis and oral inflammation: A cross-sectional study.

BACKGROUND: The aim of this cross-sectional study was to investigate the association between carotid intima-media thickness (c-IMT) values and periodontal and peri-implant diseases in a sample of patients with hypertension. METHODS: A total of 151 participants with presence of at least one dental implant in function for >5 years were recruited. Anthropometric measurements, 24-h ambulatory blood pressure monitoring, ultrasound assessment of carotid arteries (c-IMT and presence of plaque) were recorded and venous blood samples obtained. An oral examination was performed by calibrated examiners to ascertain prevalence and severity of periodontal and peri-implant diseases. Binomial logistic regression was performed to investigate the potential association between various measures of exposure of dental diseases and predictors of cardiovascular risk (c-IMT > 0.9 mm and presence of plaque or their combination). RESULTS: Diagnosis of periodontitis (OR 6.71, 95% CI: 2.68-16.76, P < 0.001), cumulative mucosal/gingival inflammation (Periodontal Screening and Recording score) (OR 1.25, 95% CI:1.12-1.41, P < 0.001), and mucositis (OR 3.34, 95% CI:1.13-9.85, P < 0.05) were associated with c-IMT > 0.9 mm and/or plaque presence independent of age, sex, smoking, 24 h systolic blood pressure and body mass index differences. No statistically significant results were noted for peri-implantitis. Linear regression models confirmed a positive association of cumulative mucosal/gingival inflammation (ß = 0.011, SE 0.002, P < 0.001), diagnosis of periodontitis (ß = 0.114, SE 0.020, P < 0.001), and peri-implant diseases (ß = 0.011, SE 0.002, P < 0.001) with increased c-IMT values. CONCLUSIONS: This study confirms a positive association between mucosal/gingival inflammation and subclinical atherosclerosis assessed by c-IMT values and the presence of carotid plaque in patients with hypertension, independent of traditional cardiovascular risk factors. Future studies are needed to further characterize this relationship.

Expert Recommendations for Using Time-in-Range and Other Continuous Glucose Monitoring Metrics to Achieve Patient-Centered Glycemic Control in People With Diabetes.

New metrics for assessing glycemic control beyond HbA1c have recently emerged due to the increasing use of continuous glucose monitoring (CGM) in diabetes clinical practice. Among them, time in range (TIR) has appeared as a simple and intuitive metric that correlates inversely with HbA1c and has also been newly linked to the risk of long-term diabetes complications. The International Consensus on Time in Range established a series of target glucose ranges (TIR, time below range and time above range) and recommendations for time spent within these ranges for different diabetes populations. These parameters should be evaluated together with the ambulatory glucose profile (AGP). Using standardized visual reporting may help people with diabetes and healthcare professionals in the evaluation of glucose control in frequent clinical situations. The objective of the present review is to provide practical insights to quick interpretation of patient-centered metrics based on flash glucose monitoring data, as well as showing some visual examples of common clinical situations and giving practical recommendations for their management.

Sobre la naturaleza del conocimiento médico y su enseñanza (Parte I) / About the nature of medical knowledge and teaching in the field (Part one)

Introducción: En la actualidad persiste una discusión de larga data en cuanto al grado de especificidad de la educación médica en relación con la educación general. Se han postulado una serie de supuestos educativos propios que confieren características distintivas a la enseñanza de esta profesión. Tales peculiaridades, en el ámbito de la docencia, tienen sus raíces en la propia naturaleza del conocimiento médico y su práctica. Objetivo: Exponer la naturaleza del conocimiento médico y las especificidades de su enseñanza. Posicionamiento del autor: La formación del docente de medicina, con una perspectiva filosófica basada en la crítica de la experiencia y con enfoques epistemológicos de fondo, es una de las áreas críticas que debe recibir atención. Los saberes de carácter metacognitivo, en relación con la naturaleza del conocimiento médico y su enseñanza, deben formar parte tanto del conocimiento de los profesores de medicina como de los propios estudiantes. Conclusiones: La atención clínica de pacientes individuales representa la actividad más característica de la profesión médica. El proceso de diagnóstico constituye la piedra angular del razonamiento clínico. La autoexplicación, la reflexión estructurada, y las oportunidades de actividad clínica constituyen los fundamentos de una eficiente educación médica(AU)

Introduction: A long-standing discussion is still held nowadays concerning the degree of specificity of medical education with respect to general education. A series of educational assumptions have been postulated that confer distinctive characteristics to the teaching of the medical profession. In the field of teaching, such peculiarities are rooted in the very nature of medical knowledge and its practice. Objective: To expose the nature of medical knowledge and the specificities of teaching in the field. Author's position: The training of medical professors, with a philosophical perspective based on the critique of experience and epistemological approaches, is one of the critical areas that should receive attention. Knowledge of a metacognitive nature, in relation to the nature of medical knowledge and teaching in the field, should be part of both the knowledge of medical professors and students themselves. Conclusions: Clinical care of individual patients is an activity inherent to the medical profession. The diagnostic process is the cornerstone of clinical reasoning. Self-explanation, structured reflection and opportunities for clinical activity, are the foundations of efficient medical education(AU)

Access to dental care and blood pressure profiles in adults with high socioeconomic status.

BACKGROUND: Reduced access to dental care may increase cardiovascular risk; however, socioeconomic factors are believed to confound the associations. We hypothesized that the relation persists despite economic wellness and high education, with reduced access to dental care affecting cardiovascular risk at least in part through its effect on blood pressure (BP), possibly mediated by systemic inflammation. METHODS: We first assessed the sociodemographic and clinical characteristics related to last dental visit timing (≤ or >6 months; self-reported) using national representative cross-sectional data. Then, the association of last dental visit timing with clinic BP was selectively investigated in highly educated, high income participants, further matched for residual demographic and clinical confounders using propensity score matching (PSM). The mediating effect of systemic inflammation was formally tested. Machine learning was implemented to investigate the added value of dental visits in predicting high BP over the variables included in the Framingham Hypertension Risk Score among individuals without an established diagnosis of hypertension. RESULTS: Of 27,725 participants included in the population analysis, 46% attended a dental visit ≤6 months. In the PSM cohort (n = 2350), last dental visit attendance >6 months was consistently associated with 2 mmHg higher systolic BP (P = 0.001) and with 23 to 35% higher odds of high/uncontrolled BP compared with attendance ≤6 months. Inflammation mildly mediated the association. Access to dental care improved the prediction of high BP by 2%. CONCLUSIONS: Dental care use impacts on BP profiles independent of socioeconomic confounders, possibly through systemic inflammation. Regular dental visits may contribute to preventive medicine.

Impact of the treatment of periodontitis on systemic health and quality of life: A systematic review.

AIM: To investigate the effect of treatment of periodontitis on systemic health outcomes, pregnancy complications, and associated quality of life. MATERIALS AND METHODS: Systematic electronic searches were conducted to identify randomized controlled trials with minimum 6-month follow-up and reporting on the outcomes of interest. Qualitative and quantitative analyses were performed as deemed suitable. RESULTS: Meta-analyses confirmed reductions of high-sensitivity C-reactive protein (hs-CRP) [0.56 mg/L, 95% confidence interval (CI) (-0.88, -0.25), p < .001]; interleukin (IL)-6 [0.48 pg/ml, 95% CI (-0.88, -0.08), p = .020], and plasma glucose [1.33 mmol/l, 95% CI (-2.41, -0.24), p = .016], and increase of flow-mediated dilation (FMD) [0.31%, 95% CI (0.07, 0.55), p = .012] and diastolic blood pressure [0.29 mmHg, 95% CI (0.10, 0.49), p = .003] 6 months after the treatment of periodontitis. A significant effect on preterm deliveries (<37 weeks) was observed [0.77 risk ratio, 95% CI (0.60, 0.98), p = .036]. Limited evidence was reported on quality-of-life (QoL) outcomes in the included studies. CONCLUSIONS: Treatment of periodontitis results in systemic health improvements including improvement in cardiometabolic risk, reduction in systemic inflammation and the occurrence of preterm deliveries. Further research is however warranted to confirm whether these changes are sustained over time. Further, appropriate QoL outcomes should be included in the study designs of future clinical trials.

Association Between Periodontitis and Blood Pressure Highlighted in Systemically Healthy Individuals: Results From a Nested Case-Control Study.

[Figure: see text].

Periodontal therapy and treatment of hypertension-alternative to the pharmacological approach. A systematic review and meta-analysis.

AIM: Quantitative comparison of the effects of intensive (IPT) or conventional (CPT) periodontal treatment on arterial blood pressure, endothelial function and inflammatory/metabolic biomarkers. MATERIALS AND METHODS: A systematic search was conducted to identify randomized controlled trials (RCT) of IPT (supra and subgingival instrumentation). Eight RCTs were included in the meta-analysis. Difference in change of systolic blood pressure (SBP) and diastolic blood pressure (DBP) before and after IPT or CPT were the primary outcomes. The secondary outcomes included: endothelial function and selected inflammatory/anti-inflammatory (CRP, IL-6, IL-10, IFN-γ) and metabolic biomarkers (HDL, LDL, TGs). RESULTS: The overall effect estimates (pooled Weighted Mean Difference (WMD)) of the primary outcome for SBP and DBP was -4.3 mmHg [95%CI: -9.10-0.48], p = 0.08 and -3.16 mmHg [95%CI: -6.51-0.19], p = 0.06 respectively. These studies were characterized by high heterogeneity. Therefore, random effects model for meta-analysis was performed. Sub-group analyses confirmed statistically significant reduction in SBP [WMD = -11.41 mmHg (95%CI: -13.66, -9.15) P < 0.00001] and DBP [WMD = -8.43 mmHg (95%CI: -10.96,-5.91)P < 0.00001] after IPT vs CPT among prehypertensive/hypertensive patients, while this was not observed in normotensive individuals. The meta-analyses showed significant reductions in CRP and improvement of endothelial function following IPT at all analysed timepoints. CONCLUSIONS: IPT leads to improvement of the cardiovascular health in hypertensive and prehypertensive individuals.

Modelo Teórico Sistema de Créditos Académicos para la carrera de medicina en Cuba / Theoretical Model for the Academic Credit System for medical studies in Cuba

Introducción: La formación de médicos en Cuba posee reconocido prestigio nacional e internacional, lo que ha favorecido el aumento de la cooperación internacional, tanto en el posgrado como en el pregrado; sin embargo, el plan de estudios de la carrera de medicina no contempla los créditos académicos que faciliten los procesos de homologación y convalidación para la incorporación al mercado laboral. Objetivo: Diseñar un Modelo Teórico del Sistema de Créditos Académicos para la carrera de medicina en Cuba que favorezca la homologación y convalidación en el contexto de la internacionalización. Métodos: Se efectuó una investigación de desarrollo en el campo pedagógico con enfoque mixto, mediante la aplicación de métodos y procedimientos cualitativos y cuantitativos para la obtención de la información por diferentes vías o fuentes. Se aplicó la triangulación metodológica para la integración de los resultados. Resultados: El diseño del modelo teórico tuvo una concepción integral y participativa en respuesta a las necesidades de la homologación y convalidación. Este modelo teórico se estructuró en los niveles teórico normativo -comprende los referentes teóricos, las dimensiones y los indicadores- y teórico conceptual -abarca sus propios componentes y su interrelación para lograr el propósito deseado. Conclusiones: La modelación como método científico permitió la elaboración del Modelo Teórico del Sistema de Créditos Académicos en Cuba, para favorecer los procesos de homologación y convalidación en el contexto de la internacionalización(AU)

Introduction: The Cuban doctor training program has national and international prestige, which has favored the increase of international cooperation, both in postgraduate and undergraduate degrees. However, the syllabus for the medical studies does not include academic credits that facilitate homologation and validation processes allowing insertion into the labor market. Objective: To design a theoretical model of the academic credit system for medical studies in Cuba that favors homologation and validation in the international context. Methods: A development research was carried out in the pedagogical field with a mixed approach, using qualitative and quantitative methods and procedures to obtain information through different routes or sources. Methodological triangulation was used to integrate the results. Results: The design of the theoretical model had comprehensive and participatory conception in response to the needs of homologation and validation. This theoretical model was structured at theoretical-normative levels -including theoretical referents, dimensions and indicators and theoretical conceptual. It encompasses its own components and their interrelation to achieve the desired purpose. Conclusions: The modeling as a scientific method allowed preparing the theoretical model of the academic credit system in Cuba, to favor the homologation and validation processes in the international context(AU)

Antigen-specific immunotherapy combined with a regenerative drug in the treatment of experimental type 1 diabetes.

Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing ß-cells. To revert type 1 diabetes, the suppression of the autoimmune attack should be combined with a ß-cell replacement strategy. It has been previously demonstrated that liraglutide, a glucagon-like peptide-1 receptor agonist, restores ß-cell mass in type 1 diabetes, via α-cell transdifferentiation and neogenesis. We report here that treatment with liraglutide does not prevent type 1 diabetes in the spontaneous non-obese diabetic (NOD) mouse model, but it tends to reduce leukocytic islet infiltration. However, in combination with an immunotherapy based on tolerogenic liposomes, it is effective in ameliorating hyperglycaemia in diabetic NOD mice. Importantly, liraglutide is not detrimental for the tolerogenic effect that liposomes exert on dendritic cells from patients with type 1 diabetes in terms of membrane expression of molecules involved in antigen presentation, immunoregulation and activation. Moreover, the in vivo effect of the combined therapy was tested in mice humanised with peripheral blood mononuclear cells from patients with type 1 diabetes, showing no adverse effects in leukocyte subsets. In conclusion, the combination therapy with liraglutide and a liposome-based immunotherapy is a promising candidate strategy for type 1 diabetes.

Active gingival inflammation is linked to hypertension.

BACKGROUND: Cardiovascular diseases (CVD) including hypertension, are characterized by underlying systemic inflammation. Periodontitis, which can impact the systemic inflammatory burden has recently been linked to high blood pressure (BP). However, the relationship of gingival bleeding, as an easily accessible marker of periodontal disorder, with hypertension, remains unclear. METHODS: Survey-based propensity score matching (PSM) incorporating major confounders shared between hypertension and periodontal diseases was applied to cross-sectional NHANES III data from 5396 adults at least 30 years old who underwent BP measurement and periodontal examination, identifying two matched groups with and without gingival bleeding. The association of bleeding gums with SBP (mmHg) and high/uncontrolled BP was then assessed with generalized additive models incorporating inflammatory markers. Stratification by periodontal status (healthy; gingivitis; stable periodontitis; unstable periodontitis) was performed. Variables importance was estimated using machine learning. RESULTS: Gingival bleeding (gingivitis; unstable periodontitis) was independently associated with +2.6 mmHg (P < 0.001) SBP compared with no bleeding (healthy periodontium; stable periodontitis), and with greater odds (OR = 1.42; 95% CI = 1.19-1.68; P < 0.001) of high/uncontrolled BP. Participants with unstable periodontitis had higher SBP than those with stable periodontitis (+2.1 mmHg; P < 0.001) or gingivitis (+5.3 mmHg; P < 0.001). Unstable periodontitis and gingivitis were consistently associated with increased risk of high/uncontrolled BP (OR = 1.65, 95% CI = 2.14-1.82; OR = 1.49, 95% CI = 1.22-1.82, respectively). Inflammatory markers allowed a maximum of 12% gain in the models' predictive power. CONCLUSION: Gingival bleeding contributes to shaping the relationship between periodontal diseases and BP, but the burden represented by periodontitis is also crucial. Periodontal evaluation might be of importance in difficult to control hypertension.

Repurposed Analog of GLP-1 Ameliorates Hyperglycemia in Type 1 Diabetic Mice Through Pancreatic Cell Reprogramming.

Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing ß-cells. An ideal immunotherapy should combine the blockade of the autoimmune response with the recovery of functional target cell mass. With the aim to develop new therapies for type 1 diabetes that could contribute to ß-cell mass restoration, a drug repositioning analysis based on systems biology was performed to identify the ß-cell regenerative potential of commercially available compounds. Drug repositioning is a strategy used for identifying new uses for approved drugs that are outside the scope of the medical indication. A list of 28 non-synonymous repurposed drug candidates was obtained, and 16 were selected as diabetes mellitus type 1 treatment candidates regarding pancreatic ß-cell regeneration. Drugs with poor safety profile were further filtered out. Lastly, we selected liraglutide for its predictive efficacy values for neogenesis, transdifferentiation of α-cells, and/or replication of pre-existing ß-cells. Liraglutide is an analog of glucagon-like peptide-1, a drug used in patients with type 2 diabetes. Liraglutide was tested in immunodeficient NOD-Scid IL2rg-/- (NSG) mice with type 1 diabetes. Liraglutide significantly improved the blood glucose levels in diabetic NSG mice. During the treatment, a significant increase in ß-cell mass was observed due to a boost in ß-cell number. Both parameters were reduced after withdrawal. Interestingly, islet bihormonal glucagon+insulin+ cells and insulin+ ductal cells arose during treatment. In vitro experiments showed an increase of insulin and glucagon gene expression in islets cultured with liraglutide in normoglycemia conditions. These results point to ß-cell replacement, including transdifferentiation and neogenesis, as aiding factors and support the role of liraglutide in ß-cell mass restoration in type 1 diabetes. Understanding the mechanism of action of this drug could have potential clinical relevance in this autoimmune disease.

Periodontitis and Hypertension: Is the Association Causal?

High blood pressure (BP) and periodontitis are two highly prevalent conditions worldwide with a significant impact on cardiovascular disease (CVD) complications. Poor periodontal health is associated with increased prevalence of hypertension and may have an influence on BP control. Risk factors such as older age, male gender, non-Caucasian ethnicity, smoking, overweight/obesity, diabetes, low socioeconomic status, and poor education have been considered the common denominators underpinning this relationship. However, recent evidence indicates that the association between periodontitis and hypertension is independent of common risk factors and may in fact be causal in nature. Low-grade systemic inflammation and redox imbalance, in particular, represent the major underlying mechanisms in this relationship. Neutrophil dysfunction, imbalance in T cell subtypes, oral-gut dysbiosis, hyperexpression of proinflammatory genes, and increased sympathetic outflow are some of the pathogenetic events involved. In addition, novel findings indicate that common genetic bases might shape the immune profile towards this clinical phenotype, offering a rationale for potential therapeutic and prevention strategies of public health interest. This review summarizes recent advances, knowledge gaps and possible future directions in the field.

Association between Periodontitis and High Blood Pressure: Results from the Study of Periodontal Health in Almada-Seixal (SoPHiAS).

Periodontitis is a common chronic inflammatory disease which could have an important impact on blood pressure (BP). This study aimed to explore (a) the association between periodontal health and BP in a large representative cohort, (b) the predictive value of diagnosis of periodontitis in undiagnosed raised BP and (c) whether age is a mediator of this relationship. In total, 1057 randomly recruited individuals (mean age, 60.9 ± 16.3 years, 57.7% women) underwent periodontal clinical assessment and one-single BP measurement using an automated sphygmomanometer device. Logistic and linear regression models were used to estimate the odds of hypertension based on periodontitis case definitions. Mediation analysis was performed to understand the effect of age on the association of periodontitis with hypertension. Adjusted logistic model for gender, smoking habits and body mass index confirmed the association between high BP and periodontitis (OR = 2.31, 95%CI: 1.75-3.04, p < 0.001). Among 168 participants with undiagnosed high BP (15.9% of the study sample), 62.5% had periodontitis (n = 105). In this study, the association between periodontitis with both systolic blood pressure (SBP) (77.6%, p < 0.001) and diastolic blood pressure (DBP) (66.0%, p < 0.001) was mediated by age. Periodontitis is closely linked to BP in a representative Portuguese population.