Molecular Signatures of Senescence in Periodontitis: Clinical Insights.

Most of the elderly population is afflicted by periodontal diseases, creating a health burden worldwide. Cellular senescence is one of the hallmarks of aging and associated with several chronic comorbidities. Senescent cells produce a variety of deleterious secretions, collectively termed the senescence-associated secretory phenotype (SASP). This disrupts neighboring cells, leading to further senescence propagation and inciting chronic inflammation, known as "inflammaging." Detrimental repercussions within the tissue microenvironment can trigger senescence at a younger age, accelerate biological aging, and drive the initiation or progression of diseases. Here, we investigated the biological signatures of senescence in healthy and diseased gingival tissues by assessing the levels of key senescence markers (p16, lipofuscin, and ß-galactosidase) and inflammatory mediators (interleukin [IL]-1ß, IL-6, IL-8, matrix metalloproteinase [MMP]-1, MMP-3, and tumor necrosis factor-α). Our results showed significantly increased senescence features including p16, lipofuscin, and ß-galactosidase in both epithelial and connective tissues of periodontitis patients compared with healthy sites in all age groups, indicating that an inflammatory microenvironment can trigger senescence-like alterations in younger diseased gingival tissues as well. Subsequent analyses using double staining with specific cell markers noted the enrichment of ß-galactosidase in fibroblasts and macrophages. Concurrently, inflammatory mediators consistent with SASP were increased in the gingival biopsies obtained from periodontitis lesions. Together, our findings provide the first clinical report revealing susceptibility to elevated senescence and inflammatory milieu consistent with senescence secretome in gingival tissues, thus introducing senescence as one of the drivers of pathological events in the oral mucosa and a novel strategy for targeted interventions.

TLR9 Mediates Periodontal Aging by Fostering Senescence and Inflammaging.

TLR9 is a critical nucleic acid sensing receptor in mediating periodontitis and periodontitis-associated comorbidities. Emerging evidence implicates TLR9 as a key sensor during aging, although its participation in periodontal aging is unexplored. Here, we investigated whether TLR9-mediated host responses can promote key hallmarks of aging, inflammaging, and senescence, in the course of periodontitis using a multipronged approach comprising clinical and preclinical studies. In a case-control model, we found increased TLR9 gene expression in gingival tissues of older (≥55 y) subjects with periodontitis compared to older healthy subjects as well as those who are younger (<55 y old) with and without the disease. Mechanistically, this finding was supported by an in vivo model in which wild-type (WT) and TLR9-/- mice were followed for 8 to 10 wk (young) and 18 to 22 mo (aged). In this longitudinal model, aged WT mice developed severe alveolar bone resorption when compared to their younger counterpart, whereas aged TLR9-/- animals presented insignificant bone loss when compared to the younger groups. In parallel, a boosted inflammaging milieu exhibiting higher expression of inflammatory/osteoclast mediators (Il-6, Rankl, Cxcl8) and danger signals (S100A8, S100A9) was noted in gingival tissues of aged WT mice compared to the those of aged TLR9-/- mice. Consistently, WT aged mice displayed an increase in prosenescence balance as measured by p16INK4a/p19ARF ratio compared to the younger groups and aged TLR9-/- animals. Ex vivo experiments with bone marrow-derived macrophages primed by TLR9 ligand (ODN 1668) further corroborated in vivo and clinical data and showed enhanced inflammatory-senescence circuit followed by increased osteoclast differentiation. Together, these findings reveal first systematic evidence implicating TLR9 as one of the drivers of periodontitis during aging and functioning by boosting a deleterious inflammaging/senescence environment. This finding calls for further investigations to determine whether targeting TLR9 will improve periodontal health in an aging population.

One-year follow-up of the immune profile in serum and selected sites of generalized and localized aggressive periodontitis.

BACKGROUND: The local and systemic immunological profiles of important inflammatory mediators in the localized (LAgP) and generalized (GAgP) forms of aggressive periodontitis are still unknown, as well as the effect of periodontal therapy on these parameters. The aim of this prospective study was to evaluate clinical and immune responses of patients with AgP undergoing nonsurgical treatment. MATERIAL AND METHODS: Eighteen patients with GAgP, 10 with LAgP and 10 healthy participants were included in this study. AgP participants were submitted to scaling and root planing plus systemic antibiotics (amoxicillin and metronidazole). At baseline and 1-year follow-up were measured clinical parameters, such as probing depth [PD] and clinical attachment loss [CAL], and the levels of 10 immunological mediators (GM-CSF, M-CSF, MCP-1, ICAM-1, CXCL8, IL-1ß, TNF-α, IL-17, IL-4, and IL-10) in the gingival crevicular fluid (GCF) of selected sites [AgP forms: PD ≥ 6 mm or the deepest, bleeding on probing (BoP) and bone loss measured by periapical radiography; healthy individuals: PD ≤ 3 mm, no BoP, no bone loss] and serum. RESULTS: After periodontal treatment both forms of AgP presented a significant reduction of PD and CAL, an increase of GM-CSF, ICAM-1, MCP-1, TNF-α, IL-17, IL-4, and IL-10 in the GCF, as well as of GM-CSF and IL-4 in the serum, and a reduction in the serum concentration of IL-1ß. Serum levels of M-CSF, ICAM-1, and MCP-1 remained significantly below those found in healthy individuals in both forms of AgP even after therapy. An increase in the systemic or local levels of MCP-1, ICAM-1 and the anti-inflammatory profile (IL-4, IL-10) was correlated with an improvement in clinical parameters of LAgP patients. Also, a local reduction of IL-1ß levels in both forms of AgP was correlated with an increase in the clinical attachment gain. CONCLUSION: Nonsurgical periodontal therapy was successful in improving clinical parameters and modulating the immune response in both forms of AgP. However, this therapeutic approach does not seem to affect the deficient level of important serum mediators involved in mechanisms of cell transmigration.

Immunological and microbiological periodontal profiles in isolated growth hormone deficiency.

BACKGROUND: Growth hormone (GH) has been identified as an important regulator of the immune response. We have previously shown that adults with isolated GH deficiency (IGHD) due to a mutation in the GH releasing hormone receptor (GHRHR) gene, have a greater chance of having periodontitis. However, the interaction of GH with periodontal tissues is still unknown, and this population has emerged as a unique model to investigate this issue. Therefore, we evaluated the microbiological and immunological periodontal profiles of such individuals. METHODS: Nineteen IGHD and 19 controls matched by age, sex, diabetes, and smoking status, were enrolled in this case-control study. Periodontal clinical parameters (probing depth [PD] and clinical attachment loss [AL]) were measured at six sites per tooth. Immune mediators (C-reactive protein, matrix metalloproteinase [MMP]-8, MMP-9, interleukin [IL]-1α, IL-6, IL-8, tumor necrosis factor [TNF]-α, adiponectin, and leptin) were analyzed by enzyme-linked immunosorbent assay (ELISA) in the gingival crevicular fluid (GCF) in four non-adjacent sites for each participant (two with PD ≤3 mm [shallow sites] and two with PD ≥7 mm or the worst PD found in the mouth [deep sites]). Bacterial quantification (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia) of subgingival biofilm samples collected from these same sites was performed by quantitative real-time polymerase chain reaction (qPCR). RESULTS: IGHD individuals presented higher values of PD and AL, and increased levels of CRP, IL-8, MMP-8, and adiponectin in the GCF. Bacterial quantification did not identify differences between the two groups. CONCLUSION: IGHD alters the local immune response in periodontal pockets leading to greater attachment loss, and GH stands out as an important hormone to be evaluated in the pathogenesis of periodontitis.

Medium-term outcomes of 78,808 patients after heart valve surgery in a middle-income country: a nationwide population-based study.

BACKGROUND: Heart valve surgery outcomes are unknown in middle-income countries and thus cannot be used in health system decision making processes. This study estimated in-hospital mortality and medium and long-term survival. METHODS: This was a retrospective study of 78,806 patients who underwent heart valve surgery between 2001 and 2007 in Brazil. Two national databases were used, the Hospital Information System and the Mortality Information System. Kaplan-Meier survival analysis and log-rank tests were performed. Maximum and median follow-up was 7.7 and 2.8 years, respectively (0.002-7.707). RESULTS: Valve replacement accounted for 69.1% of procedures performed. Mitral stenosis, the most common valve injury, represented 38.9% of the total. In 94.7% of mitral stenosis patients, aetiology was rheumatic heart disease. In-hospital mortality was 7.6% and was higher for women, for patients who had undergone concomitant coronary artery bypass grafting (CABG) and for the elderly. Overall survival was 69.9% at the end of follow-up. Survival was worst among elderly, male and concomitant CABG patients (P<0.001). CONCLUSIONS: Rheumatic heart disease is still a major public health problem in Brazil. In-hospital mortality and global survival rates of patients who have undergone heart valve surgery were less satisfactory than those reported in high-income countries. The findings of this study can contribute to guiding decision making processes in middle-income countries similar to Brazil and others concerned with improving the quality of care.

Evolução de indicadores socioeconômicos e da mortalidade cardiovascular em três estados do Brasil / Evolution of socioeconomic indicators and cardiovascular mortality in three brazilian states

FUNDAMENTO: Doenças do aparelho circulatório são a primeira causa de morte no Brasil. OBJETIVO: Correlacionar taxas de mortalidade por doenças do aparelho circulatório nos Estados de Rio de Janeiro, São Paulo, Rio Grande do Sul, e em suas capitais, entre 1980 e 2008, com indicadores socioeconômicos coletados a partir de 1949. MÉTODOS: Populações e óbitos obtidos no Datasus/MS. Calcularam-se taxas de mortalidade por doenças isquêmicas do coração, doenças cerebrovasculares, causas mal definidas, doenças do aparelho circulatório (DApCirc) e todas as causas, ajustadas pelo método direto e compensadas por causas mal definidas. Dados de mortalidade infantil foram obtidos nas secretarias estaduais e municipais de saúde e no IBGE. Dados de PIB e escolaridade foram obtidos no Ipea. As taxas de mortalidade e os indicadores socioeconômicos foram correlacionados pela estimação de coeficientes lineares de Pearson, para determinar a defasagem anual otimizada. Foram estimados os coeficientes de inclinação da regressão entre a dependente doença e a independente indicador socioeconômico. RESULTADOS: Houve redução da mortalidade nos três Estados, essa ocorreu especialmente por queda de mortalidade por doenças cardiovasculares, em especial das doenças cerebrovasculares. A queda da mortalidade por doenças do aparelho circulatório foi precedida por redução da mortalidade infantil, elevação do produto interno bruto per capita e aumento na escolaridade, com forte correlação entre indicadores e taxas de mortalidade. CONCLUSÃO: A variação evolutiva dos três indicadores demonstrou correlação quase máxima com a redução da mortalidade por DApCirc. Essas relações sinalizam a importância na melhoria das condições de vida da população para reduzir a mortalidade cardiovascular.

BACKGROUND: Cardiovascular diseases are the major cause of death in Brazil. OBJECTIVE: To correlate cardiovascular mortality rates in the states of Rio de Janeiro, São Paulo and Rio Grande do Sul, and in their capitals, between 1980 and 2008, with socioeconomic indicators collected from 1949 onwards. METHODS: Population and death data were obtained from the Brazilian Unified Health System databank (Datasus). Mortality rates due to the following were calculated and adjusted by use of the direct method and compensated for poorly defined causes: ischemic heart diseases; cerebrovascular diseases; cardiovascular diseases; poorly defined causes; and all causes. Child mortality data were obtained from state and municipal health secretariats and from the Brazilian Institute of Geography and Statistics (IBGE). Information on gross domestic product (GDP) and educational level was obtained from the Brazilian Institute of Applied Economic Research (Ipea). The mortality rates and socioeconomic indicators were correlated by using the estimation of Pearson linear coefficients to determine optimized year lag. The inclination coefficients of the regression between the dependent variable "disease" and the independent variable "socioeconomic indicator" were estimated. RESULTS: The three states showed a reduction in mortality, which was especially due to a decrease in cardiovascular mortality, mainly of cerebrovascular diseases. The decrease in cardiovascular mortality was preceded by a reduction in child mortality, an elevation in the per capita GDP, and an increase in the educational level, and a strong correlation between indicators and mortality rates was observed. CONCLUSIONS: The three indicators showed an almost maximum correlation with the reduction in cardiovascular mortality. Such relationship indicates the importance of improving quality of life to reduce cardiovascular mortality.

Qualidade da informação sobre cirurgia de revascularização do miocárdio em prontuários: o caso da abrangência - Rio de Janeiro, 1999 - 2003 / Quality of information in medical records of myocardial revascularization surgery: case study of their scope Rio de Janeiro, 1999 - 2003

A abrangência das informações nos prontuários de cirurgia de revascularização do miocárdio (RVM) está relacionada com a qualidade do atendimento. Avaliar a abrangência dos registros de RVM no município do Rio de Janeiro (MRJ), de 1999 a 2003. Selecionaram-se amostras aleatórias de pacientes de RVM em hospitais públicos do MRJ, de 1999 a 2003. Estimaram-se os percentuais de ausência de registro de dados sociodemográficos, fatores de risco, comorbidades, exames complementares e complicações...

[Balanced cardiovascular disease mortality from 1980 to 1999--Brazil]. / Mortalidade compensada por doenças cardiovasculares no período de 1980 a 1999--Brasil.

OBJECTIVE: To compare trends in mortality rates from cardiovascular diseases (CVD), ischemic heart diseases (IHD) and cerebrovascular diseases (CBVD) in the States of Rio de Janeiro (RJ), São Paulo (SP) and Rio Grande do Sul (RS) and respective capitals from 1980 to 1999. METHODS: Data regarding CVD deaths were obtained from Datasus, and those regarding populations were obtained from IBGE. Crude and sex and age-adjusted mortality rates were calculated using the direct method (standard population: State of Rio de Janeiro's population twenty years of age or older in 2000). Because of the relevant increase in mortality from ill-defined causes in the city and State of RJ as of 1990, the deaths were balanced prior to adjustments. The trends were analyzed using linear regressions. RESULTS: Annual declines of balanced and adjusted mortality ranged from -11.3 CVD deaths/100,000 inhabitants in the city and State of RJ to -7.4 in the city of SP. IHD mortality rates were similar in the State and city of RJ and in Porto Alegre, and lower in the city of SP (-2.5 deaths/100,000 inhabitants). CBVD mortality rates ranged from -6.0 to -2.8 deaths/100,000 inhabitants in the State of RJ and in Porto Alegre, respectively. CONCLUSION: A decline in balanced and adjusted CVD, IHD and CBVD mortality rates was observed from 1980 to 1999 in the three States and capitals. In the State and city of RJ declines in IHD were clear as of 1990, whereas declines in CBVD occurred throughout the period studied.

Mortalidade compensada por doencas cardiovasculares no período de 1980 a 1999 - Brasil / Balanced cardiovascular disease mortality from 1980 to 1999 - Brazil

OBJETIVO: Avaliar comparativamente a evolucão das mortalidades por doencas do aparelho circulatório (DAC), doencas isquêmicas do coracão (DIC) e cerebrovasculares (DCBV), no estados do Rio de Janeiro (RJ), São Paulo (SP) e Rio Grande do Sul (RS), e suas capitais, no período 1980-1999. MÉTODOS: Os dados relativos a óbitos por DAC provieram do Datasus, e os das populacões, do IBGE. Calcularam-se taxas de mortalidade brutas e ajustadas, por sexo e idade, pelo método direto (populacão padrão: maiores de vinte anos do Estado do RJ, em 2000). Em razão do crescimento relevante da mortalidade por causas mal definidas no município e no Estado do RJ, a partir de 1990, procedeu-se à compensacão dos óbitos preliminares aos ajustamentos. As tendências foram analisadas com regressões lineares. RESULTADOS: Os declínios anuais da mortalidade, compensados e ajustados, variaram de -11,3 óbitos por DAC, por cem mil habitantes, no município e no Estado do RJ, até -7,4 no município de SP. As DIC foram semelhantes no Estado e município do RJ e em Porto Alegre, sendo menores no município de SP (-2,5 óbitos por cem mil habitantes). Nas DCBV, a variacão observada foi de -6,0 a -2,8 óbitos por cem mil habitantes, no Estado do RJ e em Porto Alegre, respectivamente. CONCLUSAO: Observaram-se declínios das taxas de mortalidade compensadas e ajustadas por DAC, DIC e DCBV, no período 1980-1999, nos três estados e capitais. No RJ, Estado e município, os declínios das DIC foram nítidos a partir de 1990, enquanto as DCBV mostraram quedas em todo o período.

Prevalência dos fatores de risco para doença cardiovascular em funcionários do Centro de Pesquisas da Petrobras / Prevalence of risk factors for cardiovascular disease in employees of the Research Center at Petrobras

OBJETIVO: Determinar a prevalência de fatores de risco para doença cardiovascular em funcionários do Centro de Pesquisas da Petrobras. MÉTODOS: Em estudo descritivo transversal, foram avaliados clínica e laboratorialmente, de março de 2000 e fevereiro de 2001, empregados do Centro de Pesquisas da Petrobras, tendo sido excluídos os que não compareceram à realização do exame médico periódico anual de 2000. Calculados o percentual da ocorrência dos fatores de risco e a média e o desvio padrão das variáveis bioquímicas, da pressão arterial e do índice de massa corpórea. RESULTADOS: De um total de 1.191 empregados, foram estudados 970, sendo 75,4 por cento homens e 24,6 por cento mulheres, com idade média de 42,2 anos. A prevalência de fatores de risco foi o sedentarismo (67,3 por cento), o colesterol > 200 mg/dl (56,6 por cento), o sobrepeso (42 por cento), a obesidade (17 por cento), a hipertensão arterial (18,2 por cento), o tabagismo (12,4 por cento) e o diabetes mellitus (2,5 por cento). CONCLUSÃO: A elevada prevalência de fatores de risco para doença cardiovascular, em indivíduos jovens, alerta para a necessidade de adoção de programas de promoção de saúde e prevenção de doenças no ambiente de trabalho.