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BACKGROUND AND OBJECTIVE: Inflammatory cytokines such as tumor necrosis factor-alpha are involved in the pathogenesis of periodontal diseases. A high between-subject variation in the level of tumor necrosis factor-alpha mRNA has been verified, which may be a result of genetic polymorphisms and/or the presence of periodontopathogens such as Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola (called the red complex) and Aggregatibacter actinomycetemcomitans. In this study, we investigated the effect of the tumor necrosis factor-alpha (TNFA) -308G/A gene polymorphism and of periodontopathogens on the tumor necrosis factor-alpha levels in the periodontal tissues of nonsmoking patients with chronic periodontitis (n = 127) and in control subjects (n = 177). MATERIAL AND METHODS: The TNFA -308G/A single nucleotide polymorphism was investigated using polymerase chain reaction-restriction fragment length polymorphism analysis, whereas the tumor necrosis factor-alpha levels and the periodontopathogen load were determined using real-time polymerase chain reaction. RESULTS: No statistically significant differences were found in the frequency of the TNFA -308 single nucleotide polymorphism in control and chronic periodontitis groups, in spite of the higher frequency of the A allele in the chronic periodontitis group. The concomitant analyses of genotypes and periodontopathogens demonstrated that TNFA -308 GA/AA genotypes and the red-complex periodontopathogens were independently associated with increased levels of tumor necrosis factor-alpha in periodontal tissues, and no additive effect was seen when both factors were present. P. gingivalis, T. forsythia and T. denticola counts were positively correlated with the level of tumor necrosis factor-alpha. TNFA -308 genotypes were not associated with the periodontopathogen detection odds or with the bacterial load. CONCLUSION: Our results demonstrate that the TNFA -308 A allele and red-complex periodontopathogens are independently associated with increased levels of tumor necrosis factor-alpha in diseased tissues of nonsmoking chronic periodontitis patients and consequently are potentially involved in determining the disease outcome. [ABSTRACT FROM AUTHOR]

This study aims to conduct an applied and innovative investigation to enhance the energy quality of wood residues through hydrothermal carbonization pretreatment. For this purpose, the treatment was carried out at three different temperatures: 180, 220, and 240 °C under autogenous pressure. The in natura material and the hydrochars were characterized, and thermogravimetric analyses were performed in an O 2 atmosphere with heating rates of 2.5, 5, 10, and 20 °C min -1 . The global activation energy for natura biomass combustion was determined to be 112.49 kJ.mol -1 . On the other hand, the hydrothermal carbonization process promoted a reduction in this value for the 94.85 kJ.mol -1 . The conversion function for the in natura biomass was characterized as 1 - α , order 1, while the hydrochars was 2(1-α) [-ln(1-α)] (1⁄2) , Avrami-Erofe'ev I. Triple kinetic parameters were ascertained, and the conversion curves along with their respective derivatives were modeled, exhibiting minimal deviations between theoretical and experimental data. This facilitated the mathematical representation of the reaction processes and allowed for a comprehensive comparison of the results., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Although perianal Crohn's disease (PCD) is highly associated with the exacerbated inflammation, the molecular basis and immunological signature that distinguish patients who present a history of perianal lesions are still unclear. This paper aims to define immunological characteristics related to PCD. In this cross-sectional observational study, we enrolled 20 healthy controls and 39 CD patients. Blood samples were obtained for the detection of plasma cytokines and lipopolysaccharides (LPS). Peripheral blood mononuclear cells (PBMCs) were phenotyped by flow cytometry. Leukocytes were stimulated with LPS or anti-CD3/anti-CD28 antibodies. Our results show that CD patients had augmented plasma interleukin (IL)-6 and LPS. However, their PBMC was characterized by decreased IL-6 production, while patients with a history of PCD produced higher IL-6, IL-8, and interferon-γ, along with decreased tumor necrosis factor alpha (TNF). CD patients had augmented FoxP3 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulatory markers, though the PCD subjects presented a significant reduction in CTLA-4 expression. CTLA-4 as well as IL-6 and TNF responses were able to distinguish the PCD patients from those who did not present perianal complications. In conclusion, IL-6, TNF, and CTLA-4 exhibit a distinct expression pattern in CD patients with a history of PCD, regardless of disease activity. These findings clarify some mechanisms involved in the development of the perianal manifestations and may have a great impact on the disease management., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The transradial approach (TRA) to coronary angiography reduces vascular complications but is associated with greater radiation exposure than the transfemoral approach (TFA). It is unknown whether exposure remains higher when TRA is performed by experienced operators., Methods: Patients were randomly, prospectively assigned to TRA or TFA. The primary end point was patient radiation dose; secondary end points were the physician radiation dose and 30-day major adverse cardiac event rate. Coronary angiography was performed by experienced operators using a standardized protocol., Results: Clinical and procedural characteristics were similar between the TRA (n = 150) and TFA (n = 149) groups, and they had comparable mean (SD) radiation doses for patients (616.51 [252] vs 585.57 [225] mGy; P = .13) and physicians (0.49 [0.3] vs 0.46 [0.29] mSv; P = .32). The mean (SD) fluoroscopy time (3.52 [2.02] vs 3.13 [2.46] min; P = .14) and the mean (SD) dose area product (35,496.5 [15,670] vs 38,313.4 [17,764.9] mGy·cm2; P = .2) did not differ. None of the following factors predicted higher radiation doses: female sex (hazard ratio [HR], 0.69 [95% CI, 0.38-1.3]; P = .34), body mass index >25 (HR, 0.84 [95% CI, 0.43-1.6]; P = .76), age >65 years (HR, 1.67 [95% CI, 0.89-3.1]; P = .11), severe valve disease (HR, 1.37 [95% CI, 0.52-3.5]; P = .68), or previous coronary artery bypass graft (HR, 0.6; 95% CI, 0.2-1.8; P = .38)., Conclusion: TRA for elective coronary angiography is noninferior to TFA when performed by experienced operators., (© 2023 by the Texas Heart® Institute, Houston.)

In the last few months, the coronavirus disease 2019 (COVID-19) pandemic has affected millions of people worldwide and has provoked an exceptional effort from the scientific community to understand the disease. Clinical evidence suggests that severe COVID-19 is associated with both dysregulation of damage tolerance caused by pulmonary immunopathology and high viral load. In this review article, we describe and discuss clinical studies that show advances in the understanding of mild and severe illness and we highlight major points that are critical for improving the comprehension of different clinical outcomes. The understanding of pulmonary immunopathology will contribute to the identification of biomarkers in an attempt to classify mild, moderate, severe and critical COVID-19 illness. The interface of pulmonary immunopathology and the identification of biomarkers are critical for the development of new therapeutic strategies aimed to reduce the systemic and pulmonary hyperinflammation in severe COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fraga-Silva, Maruyama, Sorgi, Russo, Fernandes, de Barros Cardoso, Faccioli, Dias-Baruffi and Bonato.)

The aryl hydrocarbon receptor (AHR) is widely expressed in immune and non-immune cells of the gut and its activation has been correlated to the outcome of inflammatory bowel diseases (IBD). In ulcerative colitis and Crohn's disease, there is an excessive chronic inflammation with massive accumulation of leukocytes in the gut, in an attempt to constrain the invasion of pathogenic microorganisms on the damaged organ. Accordingly, it is known that dietary components, xenobiotics, and some chemicals or metabolites can activate AHR and induce the modulation of inflammatory responses. In fact, the AHR triggering by specific ligands during inflammatory conditions results in decreased IFNγ, IL-6, IL-12, TNF, IL-7, and IL-17, along with reduced microbial translocation and fibrosis in the gut. Moreover, upon AHR activation, there are increased regulatory mechanisms such as IL-10, IL-22, prostaglandin E 2 , and Foxp3, besides the production of anti-microbial peptides and epithelial repair. Most interestingly, commensal bacteria or their metabolites may also activate this receptor, thus contributing to the restoration of gut normobiosis and homeostasis. In line with that, Lactobacillus reuteri, Lactobacillus bulgaricus, or microbial products such as tryptophan metabolites, indole-3-pyruvic acid, urolithin A, short-chain fatty acids, dihydroxyquinoline, and others may regulate the inflammation by mechanisms dependent on AHR activation. Hence, here we discussed the potential modulatory role of AHR on intestinal inflammation, focused on the reestablishment of homeostasis through the receptor triggering by microbial metabolites. Finally, the development of AHR-based therapies derived from bacteria products could represent an important future alternative for controlling IBD.

Novel metal complexes have received much attention recently because of their potential anticancer activity. Notably, ruthenium-based complexes have emerged as good alternatives to the currently used platinum-based drugs for cancer therapy, with less toxicity and fewer side effects. The beneficial properties of Ru, which make it a highly promising therapeutic agent, include its variable oxidative states, low toxicity, and high selectivity for cancer cells. The present study evaluated the cytotoxic effects of a ruthenium complex, namely cis -[Ru(1,10-phenanthroline) 2 (imidazole) 2 ] 2+ (RuC), on human hepatocellular carcinoma (HepG2) and human cervical adenocarcinoma (HeLa) cells and analyzed metabolic parameters. RuC reduced HepG2 and HeLa cell viability at all tested concentrations (10, 50, and 100 nmol/L) at 48 h of incubation, based on the MTT, Crystal violet, and neutral red assays. The proliferation capacity of HepG2 cells did not recover, whereas HeLa cell proliferation partially recovered after RuC treatment. RuC also inhibited all states of cell respiration and increased the levels of the metabolites pyruvate and lactate in both cell lines. The cytotoxicity of RuC was higher than cisplatin (positive control) in both lineages. These results indicate that RuC affects metabolic functions that are related to the energy provision and viability of HepG2 and HeLa cells and is a promising candidate for further investigations that utilize models of human cervical adenocarcinoma and mainly hepatocellular carcinoma., (© 2020 The Authors.)

Introduction: Food allergies are inflammatory conditions mediated by Th2 and probably STAT-6 dependent immune responses., Objective and Design: Here we investigated the role of Signal Transducer and Activator of Transcription 6 (STAT-6) in development of inflammation in peanut allergy., Methods: To induce food allergy, wild-type (WT) and mice deficient for STAT-6 (Stat6 -/- ) were sensitized with peanut proteins and challenged with peanut seeds., Results: WT animals lost weight and refused the peanut diet, in contrast to Stat6 -/- mice, which had a better maintenance of body weight and more regular seeds' consumption. The augmented peanut-specific IgG, IgG1 and IgE in the allergic WT was abolished in Stat6 -/- animals that also presented increased IgG2a. There was an overall reduction in the gut mediators in the absence of STAT-6, including those related to inflammatory and Th2 responses, in contrast to a rising counter regulatory and Th1 reaction in Stat-6 -/- mice. These animals had IFN-γ and IL-10 similar to WT after the four-week challenge. Most interestingly, Stat-6 -/- mice had no intestinal damage, in contrast to WT animals, which had inflammatory infiltrate, tissue destruction, epithelial exulceration, edema, congestion and loss of villous architecture in the small gut segments., Conclusions: STAT-6 plays an important role in the establishment of the Th2 inflammatory responses and intestinal damage in peanut allergy., (Copyright © 2019. Published by Elsevier España, S.L.U.)

Background & Aims: Genetic factors may impact nonalcoholic fatty liver disease (NAFLD) severity. We aimed to assess the prevalence of patatin-like phospholipase domain-containing 3 protein (PNPLA3) gene rs738409 C > G polymorphism in Brazilian individuals with type 2 diabetes and to investigate its association with liver disease severity, diabetic chronic degenerative complications, and metabolic control., Methods and Results: PNPLA3 genotyping was performed and classified as CC, CG, and GG. Clinical and laboratory data were obtained, including chronic degenerative diabetes complications. Liver stiffness and steatosis were evaluated by transient hepatic elastography with CAP using FibroScan®. Multiple logistic regression was performed to investigate the association of PNPLA3 G allele with clinical and laboratory variables and with hepatic fibrosis/steatosis. Three hundred three patients were included (118 male, mean age 59 ± 9.5 years). The G allele frequency was 32.5% (CC 47%, CG 41%, and GG 12%). Significant liver fibrosis and severe steatosis were diagnosed in 26% and 43% of patients, respectively. The variables independently associated with the G allele were coronary artery disease (OR: 2.25; 95% CI: 1.03-4.88; p = 0.04), better glycemic control (OR for having an HbA 1c  ≥ 8% [64 mmol/mol]: 0.53; 95% CI: 0.31-0.89; p = 0.01), and significant liver fibrosis (OR: 1.82; 95% CI: 1.04-3.17; p = 0.03)., Conclusion: In individuals with diabetes and NAFLD, PNPLA3 gene rs738409 C > G polymorphism is a marker for the risk of significant liver fibrosis and cardiovascular disease and may be associated with better glycemic control., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Current therapies for inflammatory bowel diseases (IBD) are aimed at controlling the exacerbated response in the gut, but no treatment is fully effective for many refractory patients. Mesenchymal stromal cells (MSC) are multi-potent cells with regulatory immunosuppressive activity that may control inflammatory diseases. In this study, we investigated the short- and especially the long-term protective effects of MSC on experimental colitis. We show that MSC elicited protection to acute intestinal inflammation with gain of weight, improvement in the clinical disease score and expressive reduction in the mortality rate of treated mice. MSC changed the population of neutrophils, eosinophils and augmented the frequency of CD4 T lymphocytes in the gut-draining lymph nodes, together with reduced accumulation of these cells in the colon intraepithelial compartment. Interestingly, there were increased levels of programmed death 1 (PD-1) and glucocorticoid-induced tumour necrosis factor receptor family-related receptor (GITR) in the spleen regulatory T cells of mice that received MSC treatment, which also presented a reversal in the pattern of immune response in the gut, with diminished inflammatory, T helper type 1 (Th1) and Th17 profile, in contrast to augmented Th2 responses. Most strikingly, this balanced response elicited by a single administration of MSC during the acute colitis persisted long-term, with restored goblet cells, eosinophils and maintenance of elevated gut interleukin (IL)-4, besides increased CD4 + CD25 + PD-1 + cells in the spleen and reduced Th17 response in mesenteric lymph nodes (MLN) of treated mice on day 60. Taken together, our findings provided a significant contribution to translational immunology by pointing human adipose tissue-derived MSC as a novel therapeutic approach with long-term beneficial regulatory effects in experimental colitis., (© 2019 British Society for Immunology.)

A clear correlation exists between microbiota and the dysregulation of the immune response in Inflammatory Bowel Diseases (IBD), which comprise Crohn's disease (CD) and ulcerative colitis (UC). These unbalanced reactions also involve humoral responses, with antibodies against Saccharomyces cerevisiae. Thus, here we aimed to quantify IgA and IgG specific to S. cerevisiae (ASCA) in quiescent CD and UC, to correlate the production of these antibodies with patient's inflammatory response and disease clinical presentation. Twenty-nine subjects (16 CD and 13 UC) and 45 healthy controls were enrolled in this study and had plasma samples tested for ASCA and cytokines (IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α), besides clinical evaluation. IBD patients had increase IgA and IgG ASCA, especially those with colonic (L2) and fistulizing (B3) CD. Similarly, patients who dropped out the treatment had augmented ASCA, while IgG was reduced in those receiving sulfasalazine treatment. Furthermore, the quiescent CD patients had elevated IL-6 on plasma, especially in the absence of treatment, together with increased counter regulatory response of IL-10. There was a positive correlation between IgA and IgG on CD but not UC, as well as between IgA and TNF in total IBD patients. In addition, the levels of IgG x TNF, IgA x IL-10 and IgG x IL-10 were also correlated in CD, indicating that ASCA production may be influenced by the inflammatory response. Finally, we concluded that ASCA could be pointed as relevant biomarker of CD presentation and residual inflammation, even in clinical remission patients.

To analyze the participation of the enzyme 5-lipoxygenase (5-LO) in skin repair, WT wounds were compared to those in 5-LO deficient mice (5-LO -/- ), which presented faster closure and reduced inflammatory infiltrate in the skin, together with increased CD4 regulatory T cells markers in the draining lymph nodes. The 5-LO -/- wounds also had diminished TNF-α, CCL11, CCL7, CCL2, CXCL9, CCR1 and CXCR2 mRNA expression in the lesions, besides differential extracellular matrix remodeling. Furthermore, when cysteinyl leukotriene (cysLT) and leukotriene (LTB 4 ) receptors were antagonized in WT mice, there was a remarkable reduction in TNF-α expression and faster skin healing, similarly to the findings in 5-LO -/- animals. Finally, our results suggested that 5-LO products, in special cysLT and LTB 4 , underline skin inflammation that follows skin injury and their neutralization may be an important strategy to improve cutaneous healing., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The present study evaluated the in vivo antitumor effects and toxicity of a new Ru(II) compound, cis-(Ru[phen] 2 [ImH] 2 ) 2+ (also called RuphenImH [RuC]), against Walker-256 carcinosarcoma in rats. After subcutaneous inoculation of Walker-256 cells in the right pelvic limb, male Wistar rats received 5 or 10mgkg -1 RuC orally or intraperitoneally (i.p.) every 3 days for 13 days. A positive control group (2mgkg -1 cisplatin) and negative control group (vehicle) were also used. Tumor progression was checked daily. After treatment, tumor weight, plasma biochemistry, hematology, oxidative stress, histology, and tumor cell respiration were evaluated. RuC was effective against tumors when administered i.p. but not orally. The highest i.p. dose of RuC (10mgkg -1 ) significantly reduced tumor volume and weight, induced oxidative stress in tumor tissue, reduced the respiration of tumor cells, and induced necrosis but did not induce apoptosis in the tumor. No clinical signs of toxicity or death were observed in tumor-bearing or healthy rats that were treated with RuC. These results suggest that RuC has antitumor activity through the modulation of oxidative stress and impairment of oxidative phosphorylation, thus promoting Walker-256 cell death without causing systemic toxicity. These effects make RuC a promising anticancer drug for clinical evaluation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Assisted reproductive techniques have significantly contributed to animal breeding programs. Similarly, genomics has provided important information and tools to improve the accuracy of selection. However, the greatest benefits of those tools can only be expected when they are combined, allowing animals to be selected accurately early in life. Therefore, obtaining DNA samples from embryos without compromising their viability is essential for the consolidation of preimplantation genomic selection. We aimed to evaluate the effect on the gestation rate of conducting a biopsy of in vivo (VV) and in vitro-produced (IVP) bovine embryos. The VV and IVP embryos were distributed into two groups: VV-B (biopsied embryos; n = 380) and VV-C (intact embryos-controls; n = 229) and IVP-B (biopsied embryos; n = 91) and IVP-C (intact embryos-controls; n = 227), respectively. After biopsy, embryos from both groups VV-B and IVP-B were cultured for an additional 3 hours before being transferred to synchronized recipients. To evaluate the quality of the DNA obtained in the biopsies, this was used to determine the sex of embryos by polymerase chain reaction. No effect (P > 0.05) of the biopsy was observed for any of the treatments, the pregnancy rate at D 60 post-transfer being similar for VV-B: 206/380 (54.21%) and VV-C: 128/229 (55.89%) and for IVP-B: 24/91 (26.37%) and IVP-C: 45/227 (19.82%). Also, no effect (P > 0.05) of the embryo's stage of development was detected on percentage of pregnant recipients when in vitro embryos were transferred. From the biopsies analyzed, about 90% had the sex determined, confirming that DNA was there and it was efficiently amplified. The results indicated that biopsy does not affect the viability of IVV and IVP bovine embryos and can be used in commercial programs to associate assisted reproductive technologies with genomic selection., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The clinical benefits of short-term therapy with glucocorticoids (GC) in patients with inflammatory bowel disease (IBD) are widely known. However, the effects of this treatment towards the re-establishment of the regulatory network in IBD are not fully explored. We have evaluated the immunological effects of the abbreviated GC therapy in experimental colitis induced by 3% dextran sulphate sodium in C57BL/6 mice. Treatment with GC improved disease outcome, constrained circulating leucocytes and ameliorated intestinal inflammation. The control of the local inflammatory responses involved a reduction in the expression of interferon-γ and interleukin-1β, associated with augmented mRNA levels of peroxisome proliferator-activated receptors (α and γ) in intestine. Furthermore, there was a reduction of CD4 + T cells producing interferon-γ, together with an increased frequency of the putative regulatory population of T cells producing interleukin-10, in spleen. These systemic alterations were accompanied by a decrease in the proliferative potential of splenocytes of mice treated in vivo with GC. Notably, treatment with GC also led to an increase in the frequency of the regulatory markers GITR, CTLA-4, PD-1, CD73 and FoxP3, more prominently in spleen. Taken together, our results pointed to a role of GC in the control of leucocyte responsiveness and re-establishment of a regulatory system, which probably contributed to disease control and the restoration of immune balance. Finally, this is the first time that GC treatment was associated with the modulation of a broad number of regulatory markers in an experimental model of colitis., (© 2016 John Wiley & Sons Ltd.)

Increased aortic stiffness has been recognized as a predictor of adverse cardiovascular outcomes in some clinical conditions, such as in patients with arterial hypertension and end-stage renal disease, in population-based samples and, more recently, in type 2 diabetic patients. Patients with type 2 diabetes have higher aortic stiffness than non-diabetic individuals, and increased aortic stiffness has been correlated to the presence of micro- and macrovascular chronic diabetic complications. We aimed to review the current knowledge on the relationships between aortic stiffness and diabetic complications, their possible underlying physiopathological mechanisms, and their potential applications to clinical type 2 diabetes management., Competing Interests: The authors declare no conflict of interest.

Purpose of Review: This article reviews the current knowledge on the prognostic importance of ambulatory blood pressure (BP) monitoring parameters in patients with apparent treatment-resistant hypertension., Recent Findings: Although mean 24-h ambulatory BPs have been consistently established as better cardiovascular risk predictors than clinic (office) BPs in several clinical settings, and ambulatory BP monitoring is generally indicated in patients with resistant hypertension; there were only five previous longitudinal prospective studies that specifically evaluated the prognostic importance of ambulatory BP monitoring parameters in resistant hypertensive patients. These studies are carefully reviewed here. In conjunction, they demonstrated that office BP levels have little, if any, prognostic value in resistant hypertensive patients. Otherwise, several ambulatory BP monitoring parameters are strong cardiovascular risk predictors, particularly nighttime sleep BPs and the non-dipping pattern. Most relevant, the ambulatory BP monitoring diagnosis of true resistant hypertension (i.e., patients with uncontrolled ambulatory BPs, either daytime or nighttime) doubled the risk of future occurrence of major cardiovascular events in contrast to patients with white-coat resistant hypertension (i.e., with controlled ambulatory BPs despite uncontrolled office BPs). This review reinforces the pivotal role of serial ambulatory BP monitoring examinations in the clinical management of patients with resistant hypertension.

Short bowel syndrome (SBS) is characterized by a massive intestinal loss after surgery resection. Likewise, disturbances involving the intestine, which represents a complex immune environment, may result in breakdown of homeostasis and altered responses, thus leading to unpredictable clinical outcomes. However, the consequences of bowel resection were poorly investigated until now. Therefore, this study aimed to evaluate the immunological status of SBS-patients. For this purpose, ten subjects and nine healthy controls were evaluated. Along with some metabolic disturbances, the main results showed higher levels of the inflammatory cytokine IL-6 in plasma among SBS-patients. However, there were no differences in the frequency of CD3 + , CD3 + CD4 + or CD3 + CD8 + T lymphocytes. An augmented frequency in CD4 + and CD8 + cells producing IFN-γ was also observed in peripheral blood mononuclear cells (PBMC), together with elevated percentage of CD4 + cells producing IL-10. No differences were observed in the frequency of total CD4 + CD25 - , CD4 + CD25 + lymphocytes nor in the expression of FoxP3 or GITR. Nevertheless, SBS-patients showed higher frequency of the regulatory T cell population CD4 + CD25 + CD39 + cells in PBMC. In conclusion, these data pointed to SBS as an important disturbance that compromises not only the intestinal environment but also negatively influences systemic immune components., (Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Background: The prognostic value of C-reactive protein (CRP) is controversial in type 2 diabetes mellitus. We aimed to assess it in a cohort of high cardiovascular risk diabetic patients., Methods and Results: CRP was measured at baseline and during the second year of follow-up in 616 patients. The primary end points were a composite of total fatal and nonfatal cardiovascular events (CVEs), major CVEs, and all-cause and cardiovascular mortalities. Association between baseline and second-year CRP with end points were evaluated by multivariable Cox survival analyses. Baseline median CRP was 2.8 mg/L (interquartile range: 1.2-6.0 mg/L), and 47.8% of the patients either increased or persisted with high CRP levels during the first 2 years of follow-up. After a median follow-up of 8.4 years, 131 total CVEs occurred (89 major CVEs), and 129 patients died (53 of cardiovascular causes). Baseline and second-year CRP, analyzed as a continuous variable and dichotomized at >3.0 mg/L, were significantly associated with total and major CVEs occurrence (with adjusted hazard ratios between 1.22 and 1.34 for increments of 1-SD log of continuous CRP, and between 1.47 and 1.89 for dichotomized CRP), but not with mortality. Additionally, increasing CRP levels or persisting with high levels were associated with a 1.84 (95% CI: 1.10-3.06) excess risk of major CVEs, independent of baseline CRP values., Conclusions: Baseline and serial changes in CRP levels provide cardiovascular risk prediction independent of standard risk factors and glycemic control, and may be useful to refine cardiovascular risk stratification in high-risk patients with type 2 diabetes mellitus., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Purpose: To investigate the profile of disability in patients with type 2 diabetes and to evaluate its associated variables., Method: The Canadian Occupational Performance Measure (COPM) assessed disabilities in 475 type 2 diabetic individuals. The activities were categorised by the International Classification of Functioning, Disability and Health. The Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) was used to evaluate pain, emotional and physical functioning domains of life-quality. Multivariable logistic regression assessed the independent correlates of better/worse performance., Results: Median COPM score was 4.5 (interquartile range 3-6). Problems in mobility (53.6%), self-care (21.1%) and daily-life (13.0%) were most frequently self-reported. Presence of restriction/pain in the upper limbs (odds ratio [OR]: 1.66; 95% CI: 1.11-2.47; p=0.013) and of peripheral neuropathy (OR: 1.64; 95% CI: 1.06-2.53; p=0.026) were associated with greater chance of worse performance. Higher values of SF-36 in pain and emotional domains (each 10 point increase; OR: 0.92 95% CI: 0.85-0.98; p=0.011; OR: 0.96; 95% CI: 0.92-1.00; p=0.063, respectively) and physical activity (OR: 0.63; 95% CI: 0.41-0.98; p=0.042) were associated with better performance., Conclusions: Type 2 diabetic patients frequently reported disabilities in mobility, self-care and daily-life domains; and its associated factors were the presence of depression, upper limb pain and diabetic peripheral neuropathy. Implications for Rehabilitation The Canadian Occupational Performance Measure (COPM) instrument can be applied to patients with diabetes, as it identifies several disabilities, mostly in mobility, self-care and domestic life areas. Rehabilitation directed to upper limb pain/limitation and to lower limb peripheral neuropathy shall be implemented and may improve diabetic patients' performance and quality of life. A patient-centered rehabilitation strategy, guided by the COPM, may enable greater independence and autonomy, but this should be confirmed in future intervention studies.

Dehydroepiandrosterone (DHEA) is a hormone that plays an important role in the modulation of inflammatory responses. However, the precise mechanisms that link the actions of this androgen with protection or susceptibility to inflammatory bowel diseases (IBD) remain uknown. Here we showed that low dose DHEA inhibited proliferation of spleen cells and IFN-у production. The hormone was not toxic to myeloid lineage cells, although it caused necrosis of spleen cells at the intermediate and highest doses in vitro (50 and 100μM). The treatment of C57BL/6 mice with DHEA during colitis induction by dextran sodium sulfate (DSS) led to a reduction in weight loss and clinical signs of disease. There were decreased peripheral blood monocytes on day 6 of DSS exposure and treatment, besides increase in circulating neutrophils in the tissue repair phase. DHEA also led to reduced lamina propria cellularity and restoration of normal colon length. These results were accompanied by decreased expression of IL-6 and TGF-β mRNA, while IL-13 was augmented in the colon on day 6, which was probably related to attenuation of inflammation. There was retention of CD4(+) cells in the spleen after use of DHEA, along with augmented frequency of CD4(+)IL-4(+) cells, decreased CD4(+)IFN-ɣ(+) in spleen and constrained CD4(+)IL-17(+) population in the mesenteric lymph nodes. Moreover, splenocytes of mice treated with DHEA became hyporesponsive, as observed by reduced proliferation after re-stimulation ex-vivo. In conclusion, DHEA modifyies leukocyte activity and balances the exacerbated immune responses which drive local and systemic damages in IBD., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Background: C-reactive protein (CRP) is a biomarker of systemic low-grade inflammation and a cardiovascular risk predictor in several clinical conditions. However, its prognostic value has never been examined in patients with resistant hypertension., Methods: In a prospective study, 476 patients with resistant hypertension had CRP levels measured at baseline, together with other clinical laboratory variables, including ambulatory blood pressures (BPs). Primary end points were a composite of major fatal or nonfatal cardiovascular events, all-cause mortality, and cardiovascular mortality. Multiple Cox regression assessed the associations between CRP levels and end points., Results: Median CRP was 3.8mg/l (interquartile range: 2.0-7.2mg/l). After a median follow-up of 9 years, 103 major cardiovascular events occurred, and 120 patients died, 62 from cardiovascular causes. Patients with CRP levels above the median value had a doubled excess risk of major cardiovascular events (95% confidence interval: 1.29-3.06; P = 0.002) and an 86% higher risk of cardiovascular death (95% confidence interval: 1.07-3.25; P = 0.029), after adjustments for potential confounders including traditional cardiovascular risk factors and ambulatory BP and dipping pattern. A high CRP equally predicted coronary (hazard ratio: 2.04; 95% confidence interval: 1.10-3.76; P = 0.023) and cerebrovascular events (hazard ratio: 2.72; 95% confidence interval: 1.30-5.67; P = 0.007). In interaction and sensitivity analyses, CRP levels were stronger predictors of worse cardiovascular outcomes in younger and obese patients, and in those with uncontrolled ambulatory BPs and with the nondipping pattern., Conclusions: In patients with resistant hypertension, elevated serum CRP levels is predictive of worse cardiovascular prognosis above and beyond other cardiovascular risk factors, including ambulatory BP levels and dipping patterns., (© American Journal of Hypertension, Ltd 2016. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aims: Subclinical hypercortisolism was reported to be more prevalent among diabetic, obese and hypertensive patients. Our primary aim was to investigate the prevalence of subclinical hypercortisolism in patients from the Rio de Janeiro Type 2 Diabetes (RIO-T2D) Cohort; and secondarily to assess its associated factors., Methods: From May 2013 to August 2014, 393 diabetic outpatients underwent overnight 1mg dexamethasone suppression test (DST). Patients with non-suppressive morning cortisol (≥1.8μg/dl) were further evaluated with nocturnal salivary cortisol, two readings >0.35μg/dl were considered confirmatory for subclinical hypercortisolism., Results: One-hundred twenty-eight patients (32.6%) failed to suppress morning cortisol, and in 33 patients (8.6%) subclinical hypercortisolism was confirmed. Independent correlates of a positive DST were older age (OR: 1.04; 95% CI: 1.01-1.07; p=0.007), number of anti-hypertensive drugs in use (OR: 1.26; 95% CI: 1.05-1.50; p=0.012), longer diabetes duration (OR: 1.03; 95% CI: 1.004-1.06; p=0.023), and presence of diabetic nephropathy (OR: 1.70; 95% CI: 1.01-2.87; p=0.047). Independent correlates of confirmed subclinical hypercortisolism were a greater number of anti-hypertensive medications (OR: 1.54; 95% CI: 1.14-2.06; p=0.004), shorter diabetes duration (OR: 0.92; 95% CI: 0.87-0.98; p=0.006), and increased aortic stiffness (OR: 2.81; 95% CI: 1.20-6.57; p=0.017); metformin use was protective (OR: 0.27; 95% CI: 0.10-0.73; p=0.010)., Conclusion: Patients with type 2 diabetes had a high prevalence of subclinical hypercortisolism, and its presence was associated with more severe hypertension and increased aortic stiffness., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background & Aims: Type 2 diabetes mellitus (T2DM) is a risk factor for cardiovascular disease (CVD) and advanced stages of non-alcoholic fatty liver disease (NAFLD). The aim was to evaluate the association between aortic stiffness, a preclinical CVD marker, with advanced liver fibrosis identified by transient elastography (TE) in T2DM outpatients with NAFLD., Methods: This longitudinal study included 291 T2DM patients with NAFLD detected by ultrasonography, who had two carotid-femoral pulse wave velocity (cf-PWV) measurements and a TE examination (Fibroscan(®) ) performed over a median follow-up of 7 years. Advanced liver fibrosis (corresponding to ≥ F3 stage) was considered as median values >7.9 kPa (M probe) or >7.2 kPa (XL probe). Increased aortic stiffness was defined as cf-PWV >10 m/s., Results: Eighty patients (27.5%) had advanced liver fibrosis. Overall, there was an increase in cf-PWV of 0.1 m/s/year (1% per year). Both a high aortic stiffness at the 2nd cf-PWV examination [odds ratios (OR): 3.0; 95% CI: 1.3-7.2; P = 0.011] and a serial increase in aortic stiffness (OR: 2.1; 95% CI: 1.0-4.3; P = 0.046) were associated with increased odds of having advanced liver fibrosis. Patients who presented either an increase in aortic stiffness or persisted with high values had significantly higher mean liver stiffness than those who either decreased aortic stiffness or persisted with normal cf-PWV values (mean difference: 2.1 kPa, 95% CI: 0.5-3.7 kPa, P = 0.012), after adjustments for anthropometric-demographic and clinical laboratory covariates., Conclusions: In T2DM patients with NAFLD, a high or increasing aortic stiffness predicted development of advanced liver fibrosis on TE., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide. Liver inflammation and fibrosis related to NAFLD contribute to disease progression and increasing liver-related mortality and morbidity. Increasing data suggest that NAFLD may be linked to atherosclerotic vascular disease independent of other established cardiovascular risk factors. Central arterial stiffness has been recognized as a measure of cumulative cardiovascular risk marker load, and the measure of carotid-femoral pulse wave velocity (cf-PWV) is regarded as the gold standard assessment of aortic stiffness. It has been shown that increased aortic stiffness predicts cardiovascular morbidity and mortality in several clinical settings, including type 2 diabetes mellitus, a well-known condition associated with advanced stages of NAFLD. Furthermore, recently-published studies reported a strong association between NAFLD and increased arterial stiffness, suggesting a possible link in the pathogenesis of atherosclerosis and NAFLD. We sought to review the published data on the associations between NAFLD and aortic stiffness, in order to better understand the interplay between these two conditions and identify possible common physiopathological mechanisms.

The prognostic importance of the nocturnal systolic blood pressure (SBP) fall, adjusted for average 24-hour SBP levels, is unclear. The Ambulatory Blood Pressure Collaboration in Patients With Hypertension (ABC-H) examined this issue in a meta-analysis of 17 312 hypertensives from 3 continents. Risks were computed for the systolic night-to-day ratio and for different dipping patterns (extreme, reduced, and reverse dippers) relative to normal dippers. ABC-H investigators provided multivariate adjusted hazard ratios (HRs), with and without adjustment for 24-hour SBP, for total cardiovascular events (CVEs), coronary events, strokes, cardiovascular mortality, and total mortality. Average 24-hour SBP varied from 131 to 140 mm Hg and systolic night-to-day ratio from 0.88 to 0.93. There were 1769 total CVEs, 916 coronary events, 698 strokes, 450 cardiovascular deaths, and 903 total deaths. After adjustment for 24-hour SBP, the systolic night-to-day ratio predicted all outcomes: from a 1-SD increase, summary HRs were 1.12 to 1.23. Reverse dipping also predicted all end points: HRs were 1.57 to 1.89. Reduced dippers, relative to normal dippers, had a significant 27% higher risk for total CVEs. Risks for extreme dippers were significantly influenced by antihypertensive treatment (P<0.001): untreated patients had increased risk of total CVEs (HR, 1.92), whereas treated patients had borderline lower risk (HR, 0.72) than normal dippers. For CVEs, heterogeneity was low for systolic night-to-day ratio and reverse/reduced dipping and moderate for extreme dippers. Quality of included studies was moderate to high, and publication bias was undetectable. In conclusion, in this largest meta-analysis of hypertensive patients, the nocturnal BP fall provided substantial prognostic information, independent of 24-hour SBP levels., (© 2016 American Heart Association, Inc.)

The adrenal glands are able to modulate immune responses through neuroimmunoendocrine interactions and cortisol secretion that could suppress exacerbated inflammation such as in inflammatory bowel disease (IBD). Therefore, here we evaluated the role of these glands in experimental colitis induced by 3% dextran sulfate sodium (DSS) in C57BL/6 mice subjected to adrenalectomy, with or without glucocorticoid (GC) replacement. Mice succumbed to colitis without adrenals with a higher clinical score and augmented systemic levels of IL-6 and lower LPS. Furthermore, adrenalectomy negatively modulated systemic regulatory markers. The absence of adrenals resulted in augmented tolerogenic lamina propria dendritic cells but no compensatory local production of corticosterone and decreased mucosal inflammation associated with increased IFN-γ and FasL in the intestine. To clarify the importance of GC in this scenario, GC replacement in adrenalectomized mice restored different markers to the same degree of that observed in DSS group. Finally, this is the first time that adrenal-derived hormones, especially GC, were associated with the differential local modulation of the gut infiltrate, also pointing to a relationship between adrenalectomy and the modulation of systemic regulatory markers. These findings may elucidate some neuroimmunoendocrine mechanisms that dictate colitis outcome.

Objectives: Toll-like receptors (TLRs) are expressed in several immune cells including blood monocytes and resident macrophages, such as microglia in the central nervous system. TLRs recognize pathogen- or damage-associated molecular patterns, leading to the release of inflammatory and toxic molecules, which can contribute to neuroinflammation associated with Parkinson's disease (PD). The aim of this study was to compare the potential of peripheral blood cells from PD patients or healthy subjects to produce cytokines after exposure to TLR agonists, and to investigate TLR2 and TLR4 expression on monocyte subsets., Methods: Twenty-one patients and 21 healthy controls were recruited. Patients were evaluated according to the Unified Parkinson's Disease Rating Scale, and Hoehn and Yahr stage. Cytokines were measured in supernatants of whole blood cultures after incubation with TLR2, TLR4, or TLR7/8 agonists, by cytometric bead array. Expression of CD14, CD16, TLR2, and TLR4 was analyzed by cytometry., Results: Patient blood cells produced lower levels of cytokines in response to TLR2 and also after TLR7/8/R848 activation than controls. Percentages of CD14+CD16+ or CD14+CD16- monocytes and TLR2 and TLR4 expression were similar between patients and controls., Conclusions: Blood leukocyte TLR2 and TLR7/8 responses are impaired in PD. This was neither associated with imbalance in monocyte subsets nor with TLR2/TLR4 expression on these cells. The association between a decreased TLR response in periphery and damage of brain in PD must be further investigated., (© 2016 S. Karger AG, Basel.)

Aims/hypothesis: Diabetic peripheral neuropathy (DPN) is a chronic microvascular complication that is strongly associated with poor glycaemic control and also with a worse prognosis. We aimed to evaluate the predictors of the development and progression of DPN in a cohort of high-risk patients with type 2 diabetes., Methods: In a prospective study, 477 patients with type 2 diabetes were clinically assessed for the presence of DPN at baseline and after a median follow-up of 6.2 years (range 2-10 years). Clinical laboratory data were obtained at study entry and throughout the follow-up. Aortic stiffness was assessed by the carotid-femoral pulse wave velocity (cf-PWV) at baseline. Multivariate Poisson regression analysis was used to examine independent predictors of the development/progression of DPN., Results: At baseline, 135 patients (28%) had DPN, and during follow-up 97 patients (20%) had either a new development or a worsening of DPN. Patients who showed a development or progression of DPN were taller and had a longer duration of diabetes, a greater prevalence of other microvascular complications and hypertension, greater aortic stiffness and poorer glycaemic control than patients who did not have new or progressive neuropathy. After adjustments for the baseline prevalence of DPN, the patient's age and sex, and the time interval between DPN assessments; an increased aortic stiffness (cf-PWV >10 m/s) were predictive of new/progressive DPN (incidence rate ratio 2.04, 95% CI 1.28, 3.23; p = 0.002). Other independent predictors were the mean first-year HbA1c level (p = 0.05), nephropathy (p = 0.006), arterial hypertension (p = 0.06) and height (p = 0.03)., Conclusions/interpretation: Increased aortic stiffness at baseline predicts the future development or progression of peripheral neuropathy, independent of diabetic metabolic control, suggesting a physiopathological link between macrovascular and microvascular abnormalities in type 2 diabetes.

Background: Endothelial function by flow-mediated (FMD) and nitroglycerin-mediated vasodilations (NMD) was scarcely investigated in resistant hypertension. We aimed to assess the independent correlates of FMD and NMD in resistant hypertensive patients, particularly their associations with ambulatory blood pressures (BP) and nocturnal BP fall patterns., Methods: In a cross-sectional study, 280 resistant hypertensive patients performed 24-h ambulatory BP monitoring, carotid-femoral pulse wave velocity, polysomnography, and brachial artery FMD and NMD by high-resolution ultrasonography. Independent correlates of FMD, NMD, and brachial artery diameter (BAD) were assessed by multiple linear and logistic regressions., Results: Median (interquartile range) FMD was 0.75% (-0.6 to +4.4%) and NMD was 11.8% (7.1-18.4%). Baseline BAD and diabetes were independently associated with both FMD and NMD. Older age and prior cardiovascular diseases were associated with altered FMD, whereas higher night-time SBP and lower nocturnal SBP fall were associated with impaired NMD. Moreover, there was a significant gradient of impaired NMD according to blunted nocturnal BP decline patterns. BAD was independently associated with age, sex, BMI, albuminuria, and nocturnal SBP fall. Further adjustments to blood flow velocity, aortic stiffness, plasma aldosterone concentration, and sleep apnea did not change these relationships., Conclusion: NMD, but not FMD, is independently associated with unfavorable night-time BP levels and nondipping patterns, and may be a better cardiovascular risk marker in patients with resistant hypertension. BAD also may provide additional prognostic information.

Equisetum hyemale species is considered a medicinal plant used in the form of infusions to combat infectious or inflammation diseases and also diuretic effects, presenting several compounds related to these actions. In previous studies different species of Equisetum showed several phenolic compounds. The objective of this study was, for the first time, based on phytochemistry analysis to evaluate the antioxidant and antimicrobial activity. The 70% ethanolic and methanolic extracts of E. hyemale were characterized by spectrophotometric and high-performance liquid chromatography with pulsed amperometric detector analyses, as well as its antioxidant potential based on the scavenger activity of 2,2-diphenyl-1-picrylhydrazyl (DPPH). In addition was verified the antimicrobial activity by broth microdilution technique against bacteria and fungi. The extracts showed phytochemical similarity, which demonstrated the presence of phenolic compounds, the scavenging activity for free radicals was about 30% and was observed better antifungal activity against dermatophyte fungi, with minimum inhibitory concentration and minimum fungicidal concentration of 0.62 mg/mL to Trichophyton rubrum and Microsporum canis. The extracts exhibits great potential to therapeutic applications or product development, since both possess antifungal activity and antioxidant action associated with little difference in their phytochemical composition.

Chagas disease (CD) is an endemic anthropozoonosis from Latin America of which the main means of transmission is the contact of skin lesions or mucosa with the feces of triatomine bugs infected by Trypanosoma cruzi. In this article, we describe the first acute CD case acquired by vector transmission in the Rio de Janeiro State and confirmed by parasitological, serological and PCR tests. The patient presented acute cardiomyopathy and pericardial effusion without cardiac tamponade. Together with fever and malaise, a 3 cm wide erythematous, non-pruritic, papule compatible with a "chagoma" was found on his left wrist. This case report draws attention to the possible transmission of CD by non-domiciled native vectors in non-endemic areas. Therefore, acute CD should be included in the diagnostic workout of febrile diseases and acute myopericarditis in Rio de Janeiro.

Current therapies for inflammatory bowel disease (IBD) are not totally effective, resulting in persistent and recurrent disease for many patients. Mosquito saliva contains immunomodulatory molecules and therein could represent a novel therapy for IBD. Here, we demonstrated the therapeutic activity of salivary gland extract (SGE) of Aedes aegypti on dextran sulfate sodium (DSS)-induced colitis. For this purpose, C57BL/6 male mice were exposed to 3% DSS in drinking water and treated with SGE at early (days 3-5) or late (days 5-8) time points, followed by euthanasia on days 6 and 9, respectively, for sample collection. The results showed an improvement in clinical disease outcome and postmortem scores after SGE treatment, accompanied by the systemic reduction in peripheral blood lymphocytes, with no impact on bone marrow and mesenteric lymph nodes cellularity or macrophages toxicity. Moreover, a local diminishment of IFN-γ, TNF-α, IL-1β and IL-5 cytokines together with a reduction in the inflammatory area were observed in the colon of SGE-treated mice. Strikingly, early treatment with SGE led to mice protection from a late DSS re-challenging, as observed by decreased clinical and postmortem scores, besides reduced circulating lymphocytes, indicating that the mosquito saliva may present components able to prevent disease relapse. Indeed, high performance liquid chromatography (HPLC) experiments pointed to a major SGE pool fraction (F3) able to ameliorate disease signs. In conclusion, SGE and its components might represent a source of important immunomodulatory molecules with promising therapeutic activity for IBD., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: The correlates of serial changes in aortic stiffness in patients with diabetes have never been investigated. We aimed to examine the importance of glycemic control on progression/regression of carotid-femoral pulse wave velocity (cf-PWV) in type 2 diabetes., Research Design and Methods: In a prospective study, two cf-PWV measurements were performed with the Complior equipment in 417 patients with type 2 diabetes over a mean follow-up of 4.2 years. Clinical laboratory data were obtained at baseline and throughout follow-up. Multivariable linear/logistic regressions assessed the independent correlates of changes in cf-PWV., Results: Median cf-PWV increase was 0.11 m/s per year (1.1% per year). Overall, 212 patients (51%) increased/persisted with high cf-PWV, while 205 (49%) reduced/persisted with low cf-PWV. Multivariate linear regression demonstrated direct associations between cf-PWV changes and mean HbA1c during follow-up (partial correlation 0.14, P = 0.005). On logistic regression, a mean HbA1c ≥7.5% (58 mmol/mol) was associated with twofold higher odds of having increased/persistently high cf-PWV during follow-up. Furthermore, the rate of HbA1c reduction relative to baseline levels was inversely associated with cf-PWV changes (partial correlation -0.11, P = 0.011) and associated with reduced risk of having increased/persistently high aortic stiffness (odds ratio 0.82 [95% CI 0.69-0.96]; P = 0.017). Other independent correlates of progression in aortic stiffness were increases in systolic blood pressure and heart rate between the two cf-PWV measurements, older age, female sex, and presence of dyslipidemia and retinopathy., Conclusions: Better glycemic control, together with reductions in blood pressure and heart rate, was the most important correlate to attenuate/prevent progression of aortic stiffness in patients with type 2 diabetes., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

The effect of continuous positive airway pressure (CPAP) on blood pressures (BPs) in patients with resistant hypertension and obstructive sleep apnea is not established. We aimed to evaluate it in a randomized controlled clinical trial, with blinded assessment of outcomes. Four hundred thirty-four resistant hypertensive patients were screened and 117 patients with moderate/severe obstructive sleep apnea, defined by an apnea-hypopnea index ≥15 per hour, were randomized to 6-month CPAP treatment (57 patients) or no therapy (60 patients), while maintaining antihypertensive treatment. Clinic and 24-hour ambulatory BPs were obtained before and after 6-month treatment. Primary outcomes were changes in clinic and ambulatory BPs and in nocturnal BP fall patterns. Intention-to-treat and per-protocol (limited to those with uncontrolled ambulatory BPs) analyses were performed. Patients had mean (SD) 24-hour BP of 129(16)/75(12) mm Hg, and 59% had uncontrolled ambulatory BPs. Mean apnea-hypopnea index was 41 per hour and 58.5% had severe obstructive sleep apnea. On intention-to-treat analysis, there was no significant difference in any BP change, neither in nocturnal BP fall, between CPAP and control groups. The best effect of CPAP was on night-time systolic blood pressure in per-protocol analysis, with greater reduction of 4.7 mm Hg (95% confidence interval, -11.3 to +3.1 mm Hg; P=0.24) and an increase in nocturnal BP fall of 2.2% (95% confidence interval, -1.6% to +5.8%; P=0.25), in comparison with control group. In conclusion, CPAP treatment had no significant effect on clinic and ambulatory BPs in patients with resistant hypertension and moderate/severe obstructive sleep apnea, although a beneficial effect on night-time systolic blood pressure and on nocturnal BP fall might exist in patients with uncontrolled ambulatory BP levels., (© 2015 American Heart Association, Inc.)

Objectives: Correlates of serial aortic stiffness changes were scarcely evaluated. We aimed to evaluate them in patients with resistant hypertension, with particular attention to the importance of changes in clinic and ambulatory blood pressures (BP)., Methods: In a prospective study, two carotid-femoral pulse wave velocity (cf-PWV) measurements (three measures in each occasion) were performed with the Complior equipment in 442 resistant hypertensive patients over a mean follow-up of 4.6 years. Multivariable regressions assessed the independent correlates of changes in cf-PWV. All analyses were further adjusted for baseline cf-PWV and BP values, and for the time interval between measurements., Results: Carotid-femoral PWV had a median increase of 0.11 m/s per year (1.1% per year). Overall, 224 patients (51%) had an increase or persisted with high cf-PWV, whereas 218 (49%) reduced or persisted with low values. On multivariable regressions, both changes in clinic SBP (partial correlation 0.34, P < 0.001) and in 24-h SBP (partial correlation 0.40, P < 0.001) were correlates of changes in cf-PWV. This means that the white-coat effect, defined as the difference between clinic and daytime BPs, affected cf-PWV changes (partial correlation 0.19, P < 0.001). The other independent correlates of aortic stiffness progression were older age, presence of diabetes, higher waist circumference and worse renal function., Conclusion: The exaggerated white-coat effect, by acutely increasing clinic BPs during cf-PWV examination, may partially obscure the beneficial effects of reducing ambulatory BP levels on aortic stiffness attenuation. Arterial stiffness measurements under ambulatory conditions may be needed to correctly assess aortic stiffness changes in resistant hypertensive patients.

Crohn's disease (CD) and ulcerative colitis (UC) are intestinal disorders that comprise the inflammatory bowel diseases (IBD). These disorders have a significant effect on the quality of life of affected patients and the increasing number of IBD cases worldwide is a growing concern. Because of the overall burden of IBD and its multifactorial etiology, efforts have been made to improve the medical management of these inflammatory conditions. The classical therapeutic strategies aim to control the exacerbated host immune response with aminosalicylates, antibiotics, corticosteroids, thiopurines, methotrexate and anti-tumor necrosis factor (TNF) biological agents. Although successful in the treatment of several CD or UC conditions, these drugs have limited effectiveness, and variable responses may culminate in unpredictable outcomes. The ideal therapy should reduce inflammation without inducing immunosuppression, and remains a challenge to health care personnel. Recently, a number of additional approaches to IBD therapy, such as new target molecules for biological agents and cellular therapy, have shown promising results. A deeper understanding of IBD pathogenesis and the availability of novel therapies are needed to improve therapeutic success. This review describes the overall key features of therapies currently employed in clinical practice as well as novel and future alternative IBD treatment methods.

The prognostic importance of baseline and serial glycated hemoglobin (HbA1c) changes for cardiovascular outcomes is still debated. We aimed to evaluate it in 620 high-risk individuals with type 2 diabetes (mean age 60.4 years, 37 % males, 55 % Caucasians). Patients had HbA1c levels measured at study entry and serially during follow-up. Primary end points were total cardiovascular events (CVEs), major CVEs (non-fatal myocardial infarctions and strokes plus cardiovascular deaths) and all-cause mortality. Cardiovascular and non-cardiovascular mortalities were secondary end points. HbA1c was evaluated either as a continuous variable and categorized at clinically relevant cutoffs. Multivariate Cox regressions assessed the associations with end points. After a median follow-up of 6.6 years, 125 total CVEs occurred (90 major CVEs), and 111 patients died (64 from cardiovascular diseases). After statistical adjustments for other cardiovascular risk factors, baseline and mean first-year HbA1c predicted all end points, except non-cardiovascular deaths; and hazard ratios tended to be higher for mean first year than for baseline HbA1c. Each 1 % (10.9 mmol/mol) increase in mean first-year HbA1c increased 27 % the risk of major CVEs occurrence (95 % CI 11-45 %). Updating HbA1c for values obtained beyond the second year of follow-up did not improve its predictive performance. The cardiovascular protection was observed until HbA1c values lower than 6.5 % (48 mmol/mol). Moreover, the magnitude of HbA1c reduction during the first year of follow-up was predictive of better cardiovascular outcomes, independent of baseline HbA1c levels. In conclusion, better glycemic control, especially during the first year of follow-up, is determinant of better cardiovascular outcomes in high-risk patients with type 2 diabetes, without any detectable lower threshold level of HbA1c.

Chronic periodontitis is a multifactorial inflammatory disease that affects supporting structures of the teeth. Although the gingival response is largely described, little is known about the immune changes in the alveolar bone and neighboring tissues that could indicate periodontal disease (PD) activity. Then, in this study we identified the ongoing inflammatory changes and novel biomarkers for periodontitis in the tissues directly affected by the destructive disease in PD patients. Samples were collected by osteotomy in 17 control subjects during extraction of third molars and 18 patients with advanced PD, in which alveoloplasty was necessary after extraction of teeth with previous extensive periodontal damage. Patients presented mononuclear cells infiltration in the connective tissue next to the bone and higher fibrosis area, along with increased accumulation of IL-17(+) and TRAP(+) cells. The levels of TNF-α and MMP-2 mRNA were also elevated compared to controls and a positive and significant correlation was observed between TNF-α and MMP-2 mRNA expression, considering all samples evaluated. In conclusion, nongingival tissues neighboring large periodontal pockets present inflammatory markers that could predict ongoing bone resorption and disease spreading. Therefore, we suggested that the detailed evaluation of these regions could be of great importance to the assessment of disease progression.

Aims: Reduced heart rate variability (HRV), an early sign of diabetic cardiovascular autonomic neuropathy (CAN), is associated with worse cardiovascular outcomes. The objective was to evaluate relationships between HRV parameters and three pre-clinical cardiovascular disease markers (left ventricular hypertrophy [LVH], aortic stiffness and carotid atherosclerosis) in type 2 diabetes., Methods: In a cross-sectional study, 313 patients with type 2 diabetes performed 24-h Holter monitoring, carotid ultrasonography (intima-media thickness and plaques measurements), aortic pulse wave velocity measurement and echocardiography (left ventricular mass index [LVMI] measurement). Time-domain HRV parameters were the standard deviation of all normal RR intervals (SDNN), the standard deviation of the averaged normal RR intervals for all 5min segments (SDANN), the root mean square of differences between adjacent R-R intervals (rMSSD), and the percentage of adjacent R-R intervals that varied by >50ms (pNN50). Multivariate linear and logistic regressions assessed associations between HRV parameters and the three markers of pre-clinical cardiovascular disease., Results: Patients with reduced HRV had longer diabetes duration, greater prevalences of microvascular complications, lower physical fitness, and higher heart rate, glycated hemoglobin, albuminuria and LVMI than patients with normal HRV. On multivariate regressions, after adjustments for several confounders, reduced SDNN and SDANN were independently associated with LVH and aortic stiffness. No HRV parameter was associated with carotid atherosclerosis., Conclusions: Two reduced HRV parameters, SDNN and SDANN, which reflect cardiovascular autonomic imbalance, were associated with LVH and aortic stiffness, markers of pre-clinical cardiovascular disease. These findings may offer insights into physiopathological mechanisms linking CAN to worse cardiovascular prognosis., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)