Comorbid association of obstructive sleep apnea (OSA) and thrombotic primary antiphospholipid syndrome (tPAPS): A more severe phenotype?

OBJECTIVE: We aimed to evaluate the frequency of obstructive sleep apnea (OSA) in patients with thrombotic primary antiphospholipid syndrome (tPAPS), to investigate the performance of screening tools for OSA in this scenario and to compare clinical/laboratorial differences in tPAPS patients with and without OSA. METHODS: We consecutively enrolled patients with tPAPS to undergo sleep studies using a portable monitor. OSA was defined as apnea-hypopnea index ≥15 events/h. Frequency of OSA in tPAPS was evaluated and compared with age-, gender-, and BMI-matched controls (1:3 ratio) from the Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil). Next, we tested the performance of three different screening tools for assessing OSA in patients with tPAPS. Finally, patients with tPAPS were stratified according to OSA status comparing their clinical and laboratory characteristics (including damage burden measured by Damage Index for Antiphospholipid Syndrome [DIAPS] and biomarkers associated with thrombosis) using standard statistical procedures. RESULTS: Fifty-two patients were included for analysis (females: 82.7%; mean age: 48 ± 14 years; body-mass index: 31.1 ± 6.5 Kg/m2; 25% with moderate-severe OSA). When compared to matched controls from ELSA-Brasil (n = 115), there was no significant differences in the frequencies of OSA (tPAPS: 12/42 [28.6%] vs. controls: 35/115 [30.4%], p = 0.821). Among screening tools, NoSAS had the highest area under ROC curve (AUC 0.806, CI 95% 0.672-0.939, p = 0.001), followed by STOP-Bang (AUC 0.772, CI 95% 0.607-0.938, p = 0.004). Patients with comorbid tPAPS and OSA presented higher levels of von Willebrand factor (vWF) (median 38.9 vs. 32.6, p = 0.038) and DIAPS (median 5 vs. 2, p = 0.020), when compared to those without OSA. OSA remained statistically associated with higher DIAPS, even after controlling for age, disease duration and BMI. CONCLUSION: OSA is common in patients with tPAPS, with rates comparable to a non-referred population. Both NoSAS and STOP-Bang scores seems to be useful for screening OSA in these patients. Patients with tPAPS+OSA had higher damage burden and higher levels of vWF, which might suggest a more severe phenotype of tPAPS in this scenario.

Obstructive sleep apnea and hypertension-mediated organ damage in nonresistant and resistant hypertension.

The potential role of obstructive sleep apnea (OSA) in hypertension-mediated organ damage (HMOD) may be influenced by the presence of resistant hypertension (RH). Herein, we enrolled patients with hypertension from a tertiary center for clinical evaluation and performed a sleep study to identify OSA (apnea-hypopnea index ≥15 events/h) and a blinded analysis of four standard HMOD parameters (left ventricular hypertrophy [LVH], increased arterial stiffness [≥10 m/s], presence of retinopathy, and nephropathy). RH was diagnosed based on uncontrolled blood pressure (BP) (≥140/90 mmHg) despite concurrent use of at least three antihypertensive drug classes or controlled BP with concurrent use of ≥4 antihypertensive drug classes at optimal doses. To avoid the white-coat effect, ambulatory BP monitoring was performed to confirm RH diagnosis. One-hundred patients were included in the analysis (mean age: 54 ± 8 years, 65% females, body mass index: 30.4 ± 4.5 kg/m²). OSA was detected in 52% of patients. Among patients with non-RH (n = 53), the presence of OSA (52.8%) was not associated with an increased frequency of HMOD. Conversely, among patients with RH, OSA (51.1%) was associated with a higher incidence of LVH (RH-OSA,61%; RH + OSA,87%; p = 0.049). Logistic regression analysis using the total sample revealed that RH (OR:7.89; 95% CI:2.18-28.52; p = 0.002), systolic BP (OR:1.04; 95% CI:1.00-1.07; p = 0.042) and OSA (OR:4.31; 95% CI:1.14-16.34; p = 0.032) were independently associated with LVH. No significant association was observed between OSA and arterial stiffness, retinopathy, or nephropathy. In conclusion, OSA is independently associated with LVH in RH, suggesting a potential role of OSA in RH prognosis.

Evidence Linking PPARG Genetic Variants with Periodontitis and Type 2 Diabetes Mellitus in a Brazilian Population.

The peroxisome proliferator-activated receptor gamma (PPARG) gene encodes a transcription factor involved in the regulation of complex metabolic and inflammatory diseases. We investigated whether single nucleotide polymorphisms (SNPs) and haplotypes of the PPARG gene could contribute with susceptibility to develop periodontitis alone or together with type 2 diabetes mellitus (T2DM). Moreover, we evaluated the gene-phenotype association by assessing the subjects' biochemical and periodontal parameters, and the expression of PPARG and other immune response-related genes. We examined 345 subjects with a healthy periodontium and without T2DM, 349 subjects with moderate or severe periodontitis but without T2DM, and 202 subjects with moderate or severe periodontitis and T2DM. PPARG SNPs rs12495364, rs1801282, rs1373640, and rs1151999 were investigated. Multiple logistic regressions adjusted for age, sex, and smoking status showed that individuals carrying rs1151999-GG had a 64% lower chance of developing periodontitis together with T2DM. The CCGT haplotype increased the risk of developing periodontitis together with T2DM. The rs1151999-GG and rs12495364-TC were associated with reduced risk of obesity, periodontitis, elevated triglycerides, and elevated glycated hemoglobin, but there was no association with gene expression. Polymorphisms of the PPARG gene were associated with developing periodontitis together with T2DM, and with obesity, lipid, glycemic, and periodontal characteristics.

COVID-19: Understanding the impact of anti-hypertensive drugs and hydroxychloroquine on the ACE1 and ACE2 in lung and adipose tissue in SHR and WKY rats.

Hypertensive individuals taking anti-hypertensive drugs from renin-angiotensin system inhibitors may exhibit a more severe evolution of the disease when contracting the SARS-CoV-2 virus (COVID-19 disease) due to potential increases in ACE2 expression. The study investigated ACE1 and ACE2 axes and hydroxychloroquine in the lungs and adipose tissue of male and female normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHRs). SHRs were treated with losartan (10 mg/kg/day) or captopril (10 mg/kg/day) for 14 days or 7 days with hydroxychloroquine (200 mg/kg/day) in drinking water. WKY rats were also treated for 7 days with hydroxychloroquine. Blood pressure (BP), protein, and mRNA expression of ACE1 and ACE2 were analyzed in serum, adipose, and lung tissues. Losartan and captopril reduced BP in both sexes in SHR, whereas hydroxychloroquine increased BP in WKY rats. Losartan reduced ACE2 in serum and lungs in both sexes and in adipose tissue of male SHRs. Captopril decreased ACE2 protein in the lung of females and in adipose tissue in both sexes of SHRs. Hydroxychloroquine decreased ACE1 and ACE2 proteins in the lungs in both sexes and adipose tissue in male SHRs. In female WKY rats, ACE2 protein was lower only in the lungs and adipose tissue. Losartan effectively inhibited ACE2 in male and captopril in female SHRs. Hydroxychloroquine inhibited ACE2 in male SHRs and female WKY rats. These results further our understanding of the ACE2 mechanism in patients under renin-angiotensin anti-hypertensive therapy and in many trials using hydroxychloroquine for COVID-19 treatment and potential sex differences in response to drug treatment.

Antepartum periodontitis treatment and risk of offspring screening positive for autism spectrum disorder.

BACKGROUND: To evaluate if treating maternal periodontal disease, a pro-inflammatory condition, during pregnancy (intervention) compared to after pregnancy (control) reduces the likelihood of offspring screening positive for autism spectrum disorder (ASD). METHODS: In a follow-up study to the MOTOR randomized trial, we compared rates of positive screens on the Modified Checklist for Autism in Toddlers (M-CHAT) among n = 306 two-year-old toddlers and correlated findings to maternal and cord blood pro-inflammatory interleukin-6 (IL-6). RESULTS: Toddlers in the intervention group had decreased risk of a positive M-CHAT screen (adjusted RR = 0.53, 95% CI 0.29-0.99). Toddlers screening positive compared to negative had higher mean IL-6 in cord blood (1.58 ± 1.14 vs. 1.09 ± 0.72 p = 0.001) and maternal IL-6 change from baseline (1.30 ± 0.61 vs 0.96 ± 0.62 p = 0.03). CONCLUSIONS: Treating periodontal disease during pregnancy reduced risk of a positive ASD screen. M-CHAT positivity was associated with increased IL-6 in maternal and cord blood. CLINICAL TRIAL: Trial Registration numbers: Clinicaltrials.gov NCT03423836.

Polymorphisms in risk genes of type 2 diabetes mellitus could be also markers of susceptibility to periodontitis.

OBJECTIVES: This study aimed to investigate polymorphisms in genes considered molecular biomarkers of type 2 diabetes mellitus (T2DM) to assess whether they are associated with periodontitis, and relating them to the periodontal status, glycemic and lipid profile of the subjects. DESIGN: We investigated individuals who underwent complete periodontal examination and biochemical evaluation. We categorized them into three groups: (i) periodontitis with T2DM (Periodontitis+T2DM group, n = 206); (ii) periodontitis without T2DM (Periodontitis group, n = 346); and (iii) healthy individuals without Periodontitis or T2DM (Healthy group, n = 345). We investigated three single nucleotide polymorphisms (SNPs) for AGER, RBMS1 and VEGFA genes. We applied multivariate logistic and multiple linear regression models for all groups and stratified the subjects by sex and smoking habits. RESULTS: Compared with RBMS1-rs7593730-CC+CT genotype carriers, RBMS1-rs7593730-TT carriers were more susceptible to periodontitis [odds ratio (OR) = 2.29; 95% confidence interval (CI) = 1.04-5.01; P-value = 0.033]. Among AGER-rs184003-CC carriers, never smokers had reduced risks of periodontitis and Periodontitis+T2DM than ever smokers. For either RBMS1-rs7593730-CC or VEGFA-rs9472138-CC carriers, never smokers had less susceptibility to develop periodontitis than ever smokers. Compared with AGER-rs184003-CC carriers, AGER-rs184003-AA carriers presented fewer remaining teeth. VEGFA-rs9472138-TT carriers showed a lower percentage of sites with characteristics of active periodontal disease (bleeding on pocket probing and interproximal clinical attachment level) compared with VEGFA-rs9472138-CC carriers. CONCLUSIONS: In the studied population, AGER rs184003, RBMS1 rs7593730, and VEGFA rs9472138, which are considered genetic markers for T2DM, were associated with periodontitis without T2DM or periodontitis together with T2DM.

Polymorphisms in Genes of Lipid Metabolism Are Associated with Type 2 Diabetes Mellitus and Periodontitis, as Comorbidities, and with the Subjects' Periodontal, Glycemic, and Lipid Profiles.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and periodontitis (P) commonly occur as comorbidities, but the commonalities in the genetic makeup of affected individuals is largely unknown. Since dyslipidemia is a frequent condition in these individuals, we investigate the association of genomic variations in genes involved in lipid metabolism with periodontal, glycemic, lipid profiles, and the association with periodontitis and T2DM (as comorbidities). METHODS: Based on clinical periodontal examination and biochemical evaluation, 893 subjects were divided into T2DM+P (T2DM subjects also affected by periodontitis, n = 205), periodontitis (n = 345), and healthy (n = 343). Fourteen single-nucleotide polymorphisms (SNPs) were investigated: LDLR gene (rs5925 and rs688), APOB (rs676210, rs1042031, and rs693), ABCC8 (rs6544718 and 6544713), LPL (rs28524, rs3735964, and rs1370225), HNF1A (rs2650000), APOE (rs429358 and rs7412), and HNF4A (rs1800961). Multiple linear and logistic regressions (adjusted for covariates) were made for all populations and stratified by sex and smoking habits. RESULTS: Individuals carrying APOB-rs1042031-CT (mainly women and never smokers) had a lower risk of developing periodontitis and T2DM (T2DM+P); altogether, this genotype was related with healthier glycemic, lipid, and periodontal parameters. Significant disease-phenotype associations with gene-sex interaction were also found for carriers of APOB-rs1676210-AG, HNF4A-rs1800961-CT, ABCC8-rs6544718-CT, LPL-rs13702-CC, and LPL-rs285-CT. CONCLUSIONS: Polymorphisms in lipid metabolism genes are associated with susceptibility to T2DM-periodontitis comorbidities, demonstrating gene-sex interaction. The APOB-rs1042031 was the most relevant gene marker related to glucose and lipid metabolism profiles, as well as with obesity and periodontitis.

Polymorphisms and haplotypes in the Interleukin 17 Alfa gene: potential effect of smoking habits in the association with periodontitis and type 2 diabetes mellitus.

Few studies evaluate interrelationships between periodontitis (P) and Type 2 Diabetes Mellitus (T2DM). The aim of this study is to investigate the genetic susceptibility to periodontitis alone, or concomitant with T2DM (as comorbidities), analyzing single nucleotide polymorphisms (SNPs) in the Interleukin 17 alpha (IL17A) gene, considering the biochemical profile and smoking habits on the subjects' periodontal status. We investigated 879 individuals divided into: T2DM subjects also affected by severe or moderate periodontitis (T2DM-P, n = 199); non-diabetics with severe or moderate periodontitis (PERIODONTITIS, n = 342); and healthy subjects (HEALTHY, n = 338). Subjects underwent complete periodontal examination, history of smoking habits, glycemic and lipid biochemical evaluation. DNA from buccal cells was utilized to genotype the SNPs rs2275913, rs3819024 and rs10484879. The impact of the subjects' biochemical profile was analyzed in their periodontal status. Each SNP was analyzed independently, and as haplotypes, by multiple logistic regressions, adjusted for covariates, and also stratifying the groups by age, sex and smoking habits. Independently of the periodontitis degree, poorly-controlled T2DM subjects showed worse glycemic and lipid profile. Multiple logistic regressions demonstrated that smokers and former-smokers carrying the GG genotype of rs3819024 seemed to have higher risk for T2DM-Periodontitis (OR = 6.33; 95% CI = 1.26-31.77, p = 0.02), and mainly for T2DM alone (OR = 5.11; 95% CI = 1.37-19.06, p = 0.01), than never smokers. We found the potential effect of smoking habits in the association of IL17A-rs3819024-GG with diseased phenotypes. Because the observed wide confidence intervals, further studies enrolling larger populations, and SNPs' functional evaluations are needed to better understand our findings.

Association of type 2 diabetes mellitus and periodontal disease susceptibility with genome-wide association-identified risk variants in a Southeastern Brazilian population.

OBJECTIVE: Genome-wide association studies (GWAS) and literature have identified polymorphisms in the KCNJ11, HNF1A, IRS1, TCF7L2, CDKAL1, CDKN2B, RPSAP52, GPR45 HHEX, IL18, and RUNX2 genes associated with type 2 diabetes mellitus (T2DM) and/or periodontitis (P) in diverse populations, and we sought to evaluate them as genetic risk variants for these diseases in the Brazilian population. MATERIAL AND METHODS: Periodontal, glycemic, and lipid data were obtained from 931 individuals divided into: control (n = 334), periodontitis (P; n = 358), and periodontitis associated with T2DM (P + T2DM; n = 239). After genotyping, associations between polymorphisms and pathologies were tested by multiple logistic and linear regressions, adjusting for age, sex, and smoking habits. RESULTS: Considering the studied subjects, the increased risk to develop periodontitis in the periodontitis P + T2DM group was found for HNF1A-rs7957197-TA, CDKAL1-rs7754840-CG, RPSAP52-rs1531343-GC, TCF7L2-rs7903146-TT, and CDKN2B-rs7018475-GG. The association of these genetic variants for TCF7L2 and CDKN2B was confirmed for female, never smokers, and poorly controlled P + T2DM. CDKN2B-rs7018475 was associated with worse glycemic condition and periodontal parameters. CONCLUSION: These five reported genetic variants were associated in the studied Southeastern Brazilian population as genetic risk variants of periodontitis and T2DM associated to periodontitis as comorbidity. Gene-phenotype associations with sex and smoking habits and the CDKN2B-rs7018475 with the poor glycemic control and more severe periodontal conditions should be further investigated. CLINICAL RELEVANCE: Polymorphisms in the CDKAL1-rs7754840, HNF1A-rs7957197, RPSAP52-rs1531343, TCF7L2-rs7903146, and CDKN2B-rs7018475 might predispose to periodontitis and T2DM associated with periodontitis. These findings may be useful in public health genomics and future advanced clinical practice, since genetic carriage can be measured before disease onset, being of potential great benefit for treatment planning and prognosis in early disease stages.

Validation in a Brazilian population of gene markers of periodontitis previously investigated by GWAS and bioinformatic studies.

BACKGROUND: Bioinformatic tools and genome-wide association studies (GWAS) have led to comprehensive identification of single nucleotide polymorphisms (SNPs) associated with periodontitis in diverse populations. Here we aimed to detect and validate the association of seven SNPs as genetic markers of susceptibility to periodontitis in a Brazilian population. METHODS: This case-control study assessed complete periodontal parameters of 714 subjects with periodontal status classified as healthy/mild periodontitis (n = 356) and moderate/severe periodontitis (n = 358). Genotyping for rs187238, rs352140, rs1360573, rs2521634, rs3811046, rs3826782, and rs7762544 SNPs were evaluated. Genetic-phenotype associations, and sex or smoking effects of SNPs on periodontitis were tested using multiple logistic regressions adjusted for covariates. RESULTS: The rs2521634-AA (close to NPY gene) presented increased risk for severe periodontitis (OR = 2.34; 95% CI = 1.19-4.59). The rs3811046-GG (IL37 gene) demonstrated increased risk for moderate periodontitis (OR = 2.58; 95% CI = 1.28-5.18). Higher risk for moderate periodontitis was found in male with rs7762544-AG close to NCR2 gene. The rs352140-TT in the TLR9 gene proved to be associated with lower risk to severe periodontitis in men. The rs2521634-AA was associated with higher percentage of interproximal probing pocket depth (P = .004). CONCLUSIONS: This is the first evidence of validation in a Brazilian population of genetic markers of periodontitis previously investigated by GWAS and bioinformatics studies. SNPs in the NPY, IL37, and NCR2 genes were associated with susceptibility to moderate or severe periodontitis; whereas the TLR9 marker was associated with lower chance to develop severe periodontitis. Those SNPs had sex- and smoking-habit-specific effects on periodontitis; reinforcing the genetic profile predisposing to periodontitis.

Renal alterations caused by ligature-induced periodontitis persist after ligature removal in rats.

BACKGROUND AND OBJECTIVE: Periodontitis may crosstalk with renal diseases, yet that remains unclear. We investigated whether the renal alterations caused by induced periodontitis are reversible after removal of the ligatures in experimental ligature-induced periodontitis. MATERIAL AND METHODS: Twenty-four female rats were divided into three groups: control (without periodontitis), periodontitis (20 days of ligature-induced periodontitis), and P20-20 (20 days of ligature-induced periodontitis and 20 days after ligature removal). The following periodontal parameters were assessed: gingival bleeding index, probing pocket depth, myeloperoxidase activity, and alveolar bone height. For renal tissues, histopathology, malonaldehyde (MDA) levels, glutathione (GSH) content, and renal weight were evaluated. In the blood, creatinine, uric acid, albumin, total cholesterol, total protein, and glucose levels were assessed. Total protein and creatinine levels in urine were also investigated. RESULTS: Rat renal tissues did not demonstrate reversal of periodontitis-related changes in the P20-20 group in terms of MDA, GSH, and histopathological evaluations when compared to the periodontitis group. Accordingly, only total cholesterol levels were reversible in the P20-20. CONCLUSION: Renal alterations caused by ligature-induced periodontitis persisted even after removal of ligatures in rats.

Functional haplotype in the Interleukin8 (CXCL8) gene is associated with type 2 Diabetes Mellitus and Periodontitis in Brazilian population.

BACKGROUND AND AIM: Type 2 Diabetes Mellitus (T2DM) and Periodontitis (P) are prevalent multifactorial disorders worldwide, sharing a bidirectional relationship influenced by the genetic susceptibility of the host immune system. We investigated whether SNPs in the Interleukin 8 (IL8, alias CXCL8) gene could be associated with T2DM and Periodontitis. METHODS: Genomic DNA was obtained from 874 Brazilian individuals divided into: Healthy group (n = 307), Periodontitis group (n = 334), and individuals affected by both T2DM and Periodontitis (T2DM_P) group (n = 233). The SNPs -251(T>A) rs4073, +396(T>G) rs2227307 and +781(C>T) rs2227306 were genotyped by TaqMan®. Multiple logistic regressions were used to determine the degree of association between polymorphisms (and haplotypes) with periodontitis and T2DM adjusted for known confounders. RESULTS: The additive model revealed that the heterozygous AT(-251), GT(+396) and CT(+781) genotypes showed a lower risk for the diseased phenotypes, and carriers of the TTC/TTC haplotype were significantly susceptible to T2DM and Periodontitis concomitantly, as well to isolated Periodontitis (mainly the severe form). CONCLUSIONS: We concluded, for the first time, that these functional CXCL8 SNPs, and the homozygous TTC haplotype are relevant genetic factors for T2DM and Periodontitis as comorbidities, as well as for severe Periodontitis susceptibility in Brazilian population.

Blood Pressure Increase in Hypertensive Individuals During Resistance Training Protocols With Equated Work to Rest Ratio.

Introduction: Despite growing evidence regarding the benefits of resistance training in hypertension, the large and abrupt rise of systolic blood pressure (SBP) observed during resistance exercise execution has resulted in concern about its safety. However, the manipulation of the resistance training protocol (RTP) organization, maintaining the work to rest ratio equated between protocols (W:R-equated), may reduce the SBP increase. Purpose: To compare cardiovascular responses during two W:R-equated RTPs (3 × 15:88 s vs. 9 × 5:22 s - sets × reps: rest between sets) performed in exercises for the lower and upper limbs. Methods: Twelve medicated hypertensives (48 ± 8 years) randomly performed two RTPs in the bilateral leg extension (BLE) and unilateral elbow flexion (UEF) exercises at 50% 1RM. Increases (Δ) of SBP, heart rate (HR) and rate pressure product (RPP) during the exercises were measured by photoplethysmography. Results: In both BLE and UEF exercises, Δ SBP was significantly greater during 3 × 15:88 s than 9 × 5:22 s (peak values: BLE = + 84 ± 39 vs. + 67 ± 20 mm Hg, and UEF = + 46 ± 25 vs. + 37 ± 18 mm Hg, respectively, both p < 0.05). ΔHR and ΔRPP were significantly higher in the 3 × 15:88 s than 9 × 5:22 s in BLE (peak values + 45 ± 17 vs. + 30 ± 8 bpm, and + 15,559 ± 5570 vs. + 10,483 ± 2614 mm Hg. bpm). Conclusion: In medicated hypertensives, a RTP combining more sets with less repetitions per set and shorter rest intervals between sets (i.e., 9 × 5:22 s) produced a smaller increase in cardiovascular load (ΔSBP, ΔHR and ΔRPP) during its execution than a protocol with fewer longer sets (i.e., 3 × 15:88 s).

Maintaining barrier function of infected gingival epithelial cells by inhibition of DNA methylation.

BACKGROUND: Infection and inflammation induce epigenetic changes that alter gene expression. In periodontal disease, inflammation, and microbial dysbiosis occur, which can lead to compromised barrier function of the gingival epithelia. Here, we tested the hypotheses that infection of cultured human gingival epithelial (HGEp) cells with Porphyromonas gingivalis disrupts barrier function by inducing epigenetic alterations and that these effects can be blocked by inhibitors of DNA methylation. METHODS: Primary HGEp cells were infected with P. gingivalis either in the presence or absence of the non-nucleoside DNA methyltransferase (DNMT) inhibitors RG108, (-) epigallocatechin-3-gallate (EGCG), or curcumin. Barrier function was assessed as transepithelial electrical resistance (TEER). DNA methylation and mRNA abundance were quantified for genes encoding components of three cell-cell junction complexes, CDH1, PKP2, and TJP1. Cell morphology and the abundance of cell-cell junction proteins were evaluated by confocal microscopy. RESULTS: Compared to non-infected cells, P. gingivalis infection decreased TEER (P < 0.0001) of HGEp cells; increased methylation of the CDH1, PKP2, and TJP1 (P < 0.0001); and reduced their expression (mRNA abundance) (P < 0.005). Pretreatment with DNMT inhibitors prevented these infection-induced changes in HGEp cells, as well as the altered morphology associated with infection. CONCLUSION: Pathogenic infection induced changes in DNA methylation and impaired the barrier function of cultured primary gingival epithelial cells, which suggests a mechanism for systemic consequences of periodontal disease. Inhibition of these events by non-nucleoside DNMT inhibitors represents a potential strategy to treat periodontal disease.

Genetic polymorphisms in the Interleukins IL1B, IL4, and IL6 are associated with concomitant periodontitis and type 2 diabetes mellitus in Brazilian patients.

OBJECTIVE: To assess whether single nucleotide polymorphisms (SNPs) in the IL10, IL1A, IL1B, IL4, TNFA, IL6, OPG, RANK, and RANKL genes, "classically" related with periodontitis, could be associated with susceptibility to T2DM, and also with both diseases concomitantly. BACKGROUND: There are common pathogenic mechanisms in type 2 diabetes mellitus (T2DM) and periodontitis, but the knowledge of the genetic aspect of this is limited. In patients affected by concomitant T2DM and periodontitis, whose incidence is increasing, there is scarce information regarding the gene-phenotype association, including whether there are genes able to influence both diseases as comorbidities. METHODS: Periodontal clinical parameters and biochemical profile (Insulin, Fasting Glycemia, HbA1c, Triglycerides, Total Cholesterol, HDL-cholesterol, and LDL-cholesterol) data were obtained from 894 individuals divided into following three groups: Healthy (H; n = 347), Periodontitis (P; n = 348), and Periodontitis + T2DM (P + T2DM; n = 199). DNA from oral epithelial cells was collected for genotyping. Associations between SNPs and pathologies were tested by multiple logistic regression models, adjusting for age, sex, and smoking habits. We also investigated whether there are sex or smoking effects of each SNP in these phenotypes. RESULTS: The rs1143634-GA (IL1B) SNP showed significantly less likely to develop P + T2DM for all population and mainly for women (adjusted OR = 0.37, 95% CI = 0.16-0.88), while women carrying the rs224320 CT (IL4) were more susceptible to develop P + T2DM (adjusted OR = 1.81, 95% CI = 1.04-3.15). Men carrying the rs1800795-CC (IL6) genotype were less likely to develop T2DM (adjusted OR = 0.12, 95% CI = 0.02-0.70, P = .01). CONCLUSIONS: Some SNPs in the IL1B, IL4, and IL6 genes demonstrated sex-influenced association with concomitant periodontitis and T2DM, increasing the evidence of a common genetic component between these diseases and contributing with the understanding of their common pathogenic mechanisms.

Circulating lymphocytes and monocytes transcriptomic analysis of patients with type 2 diabetes mellitus, dyslipidemia and periodontitis.

Type 2 diabetes mellitus (T2DM), dyslipidemia and periodontitis are frequently associated pathologies; however, there are no studies showing the peripheral blood transcript profile of these combined diseases. Here we identified the differentially expressed genes (DEGs) of circulating lymphocytes and monocytes to reveal potential biomarkers that may be used as molecular targets for future diagnosis of each combination of these pathologies (compared to healthy patients) and give insights into the underlying molecular mechanisms of these diseases. Study participants (n = 150) were divided into groups: (H) systemically and periodontal healthy (control group); (P) with periodontitis, but systemically healthy; (DL-P) with dyslipidemia and periodontitis; (T2DMwell-DL-P) well-controlled type 2 diabetes mellitus with dyslipidemia and periodontitis; and (T2DMpoorly-DL-P) poorly-controlled type 2 diabetes mellitus with dyslipidemia and periodontitis. We preprocessed the microarray data using the Robust Multichip Average (RMA) strategy, followed by the RankProd method to identify candidates for DEGs. Furthermore, we performed functional enrichment analysis using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis. DEGs were submitted to pairwise comparisons, and selected DEGs were validated by quantitative polymerase chain reaction. Validated DEGs verified from T2DMpoorly-DL-P versus H were: TGFB1I1, VNN1, HLADRB4 and CXCL8; T2DMwell-DL-P versus H: FN1, BPTF and PDE3B; DL-P versus H: DAB2, CD47 and HLADRB4; P versus H: IGHDL-P, ITGB2 and HLADRB4. In conclusion, we identified that circulating lymphocytes and monocytes of individuals simultaneously affected by T2DM, dyslipidemia and periodontitis, showed an altered molecular profile mainly associated to inflammatory response, immune cell trafficking, and infectious disease pathways. Altogether, these results shed light on novel potential targets for future diagnosis, monitoring or development of targeted therapies for patients sharing these conditions.

Anti-Inflammatory Effects of Vitamin E in Response to Candida albicans.

Oral mucositis, inflammation, and ulceration that occur in the oral cavity can manifest in significant pain. A formulation was designed to investigate the potential of vitamin E to ameliorate inflammation resulting from Candida albicans in cell-based systems. Human gingival fibroblasts and THP1 cells were stimulated with heat killed C. albicans and Porphyromonas gingivalis LPS (agonists). Unstimulated cells were included as controls. Cells were also simultaneously treated with a novel denture adhesive formulation that contains vitamin E (antagonist). The experimental conditions included cells exposed to the experimental formulation or the vehicle for 2 h for mRNA extraction and analysis, and cells left for 24 h under those experimental conditions for analysis of protein expression by ELISA. ssAffymetrix expression microarray pathway analyses demonstrated that the tested formulation exhibited a statistically significant (p < 0.05) inhibition of the following key inflammatory pathways: TLR 6, IL-1 signaling (IRAK, A20), NF-kappaB, IL-6 signaling (gp130, JK2 and GRB2), TNF signaling (TNF receptor) and Arachidonic acid metabolism (PLA2). Quantitative PCR array analysis confirmed the downregulation of key inflammatory genes when cells under adhesive treatment were challenged with heat killed C. albicans. PGE2 secretion was inhibited by the tested formulation only on THP1 cells after 24 h stimulation with C. albicans. These results suggest that the active formulation containing vitamin E acetate can modulate inflammatory responses, through anti-inflammatory actions as indicated by in vitro experimental conditions.

Epigenetic reprogramming in periodontal disease: Dynamic crosstalk with potential impact in oncogenesis.

Periodontitis is a chronic multifactorial inflammatory disease associated with microbial dysbiosis and characterized by progressive destruction of the periodontal tissues. Such chronic infectious inflammatory disease is recognized as a major public health problem worldwide with measurable impact in systemic health. It has become evident that the periodontal disease phenotypes are not only determined by the microbiome effect, but the extent of the tissue response is also driven by the host genome and epigenome patterns responding to various environmental exposures. More recently there is mounting evidence indicating that epigenetic reprogramming in response to combined intrinsic and environmental exposures, might be particularly relevant due its plasticity and potential application towards precision health. The complex epigenetic crosstalk is reflected in the prognosis and progress of periodontal diseases and may also lead to a favorable landscape for cancer development. This review discusses epigenomics modifications focusing on the role of DNA methylation and pathways linking microbial infection and inflammatory pathways, which are also associated with carcinogenesis. There is a more clear vision whereas 'omics' technologies applied to unveil relevant epigenetic factors could play a significant role in the treatment of periodontal disease in a personalized mode, evidencing that public health approach should coexist with precision individualized treatment.

Effects of bariatric surgery versus medical therapy on the 24-hour ambulatory blood pressure and the prevalence of resistant hypertension

Bariatric surgery is an effective strategy for blood pressure (BP) reduction, but most of the evidence relies on office BP measurements. In this study, we evaluated the impact of bariatric surgery on 24-hour BP profile, BP variability, and resistant hypertension prevalence. This is a randomized trial including obese patients with grade 1 and 2 using at least 2 antihypertensive drugs at maximal doses or >2 at moderate doses. Patients were allocated to either Roux-en-Y Gastric Bypass (RYGB) combined with medical therapy or medical therapy alone for 12 months. The primary outcome was the 24-hour BP profile and variability (average real variability of daytime and night time BP). We evaluated the nondipping status and prevalence of resistant hypertension as secondary end points. We included 100 patients (76% female, body mass index, 36.9±2.7 kg/m2). The 24-hour BP profile (including nondipping status) was similar after 12 months, but the RYGB group required less antihypertensive classes as compared to the medical therapy alone (0 [0­1] versus 3 [2.5­4] classes; P<0.01). The average real variability of systolic nighttime BP was lower after RYGB as compared to medical therapy (between-group difference, −1.63; 95% CI, −2.91 to −0.36; P=0.01). Prevalence of resistant hypertension was similar at baseline (RYGB, 10% versus MT, 16%; P=0.38), but it was significantly lower in the RYGB at 12 months (0% versus 14.9%; P<0.001). In conclusion, RYGB significantly reduced antihypertensive medications while promoting similar 24-hour BP profile and nondipping status. Interestingly, bariatric surgery improved BP variability and may decrease the burden of resistant hypertension associated with obesity. (AU)

Effects of Bariatric Surgery Versus Medical Therapy on the 24-Hour Ambulatory Blood Pressure and the Prevalence of Resistant Hypertension.

Bariatric surgery is an effective strategy for blood pressure (BP) reduction, but most of the evidence relies on office BP measurements. In this study, we evaluated the impact of bariatric surgery on 24-hour BP profile, BP variability, and resistant hypertension prevalence. This is a randomized trial including obese patients with grade 1 and 2 using at least 2 antihypertensive drugs at maximal doses or >2 at moderate doses. Patients were allocated to either Roux-en-Y Gastric Bypass (RYGB) combined with medical therapy or medical therapy alone for 12 months. The primary outcome was the 24-hour BP profile and variability (average real variability of daytime and night time BP). We evaluated the nondipping status and prevalence of resistant hypertension as secondary end points. We included 100 patients (76% female, body mass index, 36.9±2.7 kg/m2). The 24-hour BP profile (including nondipping status) was similar after 12 months, but the RYGB group required less antihypertensive classes as compared to the medical therapy alone (0 [0-1] versus 3 [2.5-4] classes; P<0.01). The average real variability of systolic nighttime BP was lower after RYGB as compared to medical therapy (between-group difference, -1.63; 95% CI, -2.91 to -0.36; P=0.01). Prevalence of resistant hypertension was similar at baseline (RYGB, 10% versus MT, 16%; P=0.38), but it was significantly lower in the RYGB at 12 months (0% versus 14.9%; P<0.001). In conclusion, RYGB significantly reduced antihypertensive medications while promoting similar 24-hour BP profile and nondipping status. Interestingly, bariatric surgery improved BP variability and may decrease the burden of resistant hypertension associated with obesity. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT01784848.