NLRP3 inflammasome as a key player in pericarditis: rationale for a targeted therapeutic strategy

Objectives. To (i) determine the formation of the NLRP3 inflammasome in the pathogenesis of pericarditis and (ii) recreate pericardial inflammation in mice with a toll-like-receptor-2/inflammasome inducer and assess the effect of anti-inflammatory drugs on inflammasome-mediated disease. Background. Acute pericarditis is typically responsive to colchicine, an anti-inflammatory drug blocking the NLRP3 inflammasome. Methods. Pericardial biopsies from patients with chronic pericarditis were stained for the inflammasome components \u2013 NLRP3, caspase-1, and ASC. A murine model of pericarditis was developed through intrapericardial injection of zymosan A. Ibuprofen and different inflammasome pathway blockers (colchicine, NLRP3 inhibitor 16673-34-0 [NLRP3inh], anakinra, and IL-1 trap) were administered, and echocardiography and tissue pathology were performed. Results. Patients with pericarditis showed increased inflammasome presence compared with controls (NLRP3: 1.9\ub10.15 vs. 1.21\ub10.1; Caspase-1: 2.5\ub10.2 vs 1.4\ub10.09; ASC: 2.4\ub10.2 vs. 1.1\ub10.3). The mouse model showed pericardial effusion (+83%), pericardial thickness (+45%), and an increased staining of inflammasome, IL-1alpha, and IL-1beta compared with sham. Treatment with ibuprofen reduced effusion compared to vehicle (-42%). Colchicine and NLRP3inh significantly reduced effusion (-28% and -46%) and inflammasome activation (-93% and -78%). NLRP3inh reduced pericardial thickness (-32%). Anakinra and IL-1 trap attenuated pericardial effusion (-13% and -43%), pericardial thickness (-20% and -44%), and inflammasome staining compared to vehicle (-75% and -96%). Conclusions. The NLRP3 activity was assessed in human pericarditis samples. Our new experimental mouse model replicated the key elements of acute pericarditis phenotype and shows the therapeutic efficacy of IL-1 blockers. NLRP3 pathway inhibition of could represent a valid therapeutic approach for the treatment of pericarditis

Steroid-induced hyperglycemia: an underdiagnosed problem or clinical inertia? A narrative review

Corticosteroids are widely diffused drugs. An important side effect is the impairment of glycemic control both in patients with known diabetes and in normoglycemic ones potentially leading to steroid-induced diabetes mellitus (SIDM). In this review based on papers released on PubMed, MEDLINE, and EMBASE from January 2015 to October 2017, we summarized and discussed main updates about the definition, the diagnosis, and the pathophysiology of steroid-induced hyperglycemia (SIH), with a look to new therapies. Main alterations responsible for the diabetogenic effect of corticosteroids are a negative impact on insulin sensitivity along with a derangement on insulin secretion, explaining the typical post-prandial hyperglycemia linked to the promotion of gluconeogenesis. An early and precise diagnosis of SIH and/or SIDM is necessary, but current criteria do not seem sensible enough. As an afterthought, the treatment should be reasoned and tailored according to proposed glycemic thresholds and patient comorbidities, choosing between antidiabetic oral drugs and insulin, the latter being preferable among hospitalized patients. SIDM and SIH are frequent problems, but often underdiagnosed due to old diagnostic criteria. Dedicated guidelines universally shared are mandatory in order to harmonize the treatment of these conditions, thus overtaking single therapeutic strategies mostly arising from literature

T-cells in myocardial infarction: Culprit instigators or mere effectors?

Immune system activation and dysfunction characterize the early phase of reperfusion after a myocardial infarction (MI). Despite initially neglected, adaptive immunity has been recently showed to play an important role in this setting. In fact, the immune system can recognize sequestered antigens released by the necrotic tissue, initiating a deleterious autoimmune vicious circle leading to worse outcome. In their recent work, Angelini et al shed the light on a new feature of post-MI which involves two "old players" of post-ischemic myocardial injury: CD31 and matrix metalloproteinase (MMP)-9. Specifically, the authors showed that an enhancement of MMP-9 release could determine the cleavage of inhibitory CD31 from CD4+ T-cells surface in patients with Acute Coronary Syndromes (ACS). These findings open the room for new studies investigating the role of MMP9 in other pathological processes associated with a reduction of CD31 functionality, such as plaque instability and rupture. Of interest, in the case of a causative role for CD31 shedding in ACS would be confirmed, there might be a potential role for the administration of CD31 protein or analogue compounds to blunt post-ischemic cardiac inflammation and improve ACS outcome

The Bio-Molecular Dynamics of Dental Pulp in Different Clinical Scenarios

Dental pulp (DP) is a very dynamic tissue both in health and in disease. When exposed to stressors and pathological conditions. It undergoes a complex series of biological reactions whereby alterations affect the pulp tissue at tissue cellular and molecular levels. The aim of this review is to update the reader on the various bio-molecular alterations in the dental pulp under different clinical conditions: orthodontic treatment (OT), caries, pulpitis and others. The morphological changes in the composition of the DP rang from the reversible remodeling to apoptosis and sometimes necrosis. Many apoptotic factors are involved like Bcl2, Bax and the significant increase in Caspases 9 and 3, as well as, Hsp60, its possible role and its mitochodrial localization. The inflammatory responses in dental pulp and the role of diffusible and cellular factors as well as DP stem cells were highlighted, in particular, where caries was involved in the pulpitis.Recent data report changes in tissue metabolism and homeostasis inside the DP caused by OT leading to increased levels of iNOS reactivity in the nerve fibers of the pulp. Moreover, remodeling of the extra cellular matrix(ECM) is an important feature in clinical scenarios like OT and caries whereby alterations in MMP-2 and MMP-9 expression patterns are reported leading to degradation of type IV and V collagens in the ECM. Furthermore, neurogenic factors are also modified after injuries and OT. Neuropeptides play a significant role not onlyin pain perception but also in vascular responses. Substance P increases in DP and enhances pain perception and so is the increase in CGRP which is correlated with concomitant gain in bone morphogenetic protein expression resulting in more dentin formation. The role of stem cells and the possible molecular mechanisms of dentin genesis are presented in this review. They focus on important signaling proteins and the possible role of various scaffolds in this regeneration process. In conclusion, most alterations inpulpal structure are reversible unless the pulp has a history of caries, restorations, trauma or prolonged heavy orthodontic forces. Pulpal symptoms arising from these clinical conditions should be treated appropriately and swiftly.Otherwise, exacerpation of pulpitis and the interplay of the various bio-molecular factors will lead to inhibition of repair and regeneration

Anemia Due to Inflammation in an Anti-Coagulated Patient with Blue Rubber Bleb Nevus Syndrome

Background: Blue rubber bleb nevus syndrome (BRBNS) is a rare disease characterized by vascular malformations mostly involving skin and gastrointestinal tract. This disease is often associated with sideropenic anemia and occult bleeding. Methods: We report the case of chronic severe anemia in an old patient under oral anticoagulation treatment for chronic atrial fibrillation. Results: At admission, the patient also presented fever and increased laboratory parameters of systemic inflammation (ferritin 308 mcg/L, C-reactive protein (CRP) 244 mg/L). A small bluish-colored lesion over the left ear lobe was observed. Fecal occult blood test was negative as well as other signs of active bleeding. Lower gastrointestinal endoscopy revealed internal hemorrhoids and multiple teleangiectasias that were treated with argon plasma coagulation. Videocapsule endoscopy demonstrated multiple bluish nodular lesions in the small intestine. Unexpectedly, chronic severe anemia due to systemic inflammation was diagnosed in an old anticoagulated patient with BRNBS. The patient was treated with blood transfusions, hydration, antibiotic treatment, and long-acting octreotide acetate, without stopping warfarin. Fever and inflammation disappeared without any acute gastrointestinal bleeding and improvement of hemoglobin levels at three-month follow up. Conclusions: This is the oldest patient presenting with chronic anemia, in which BRNBS was also diagnosed. Surprisingly, anemia was mainly caused by systemic inflammation instead of chronic gastrointestinal bleeding. However, we would recommend investigating this disease also in old subjects with mild signs and symptoms

Separação e caracterização dos componentes de hemoglobina de Pterygoplichthys pardalis, o acaribodó

The four main hemoglobin components of the hemolysate of Pterygoplichthys pardalis have been isolated and characterized. The functional properties investigated for the isolated components comprise the effect of pH and ATP on (i) the O2 equilibrium, (ii) the O2 dissociation kinetics, (iii) the CO combination kinetics. Component I, corresponding to approximately 50% of the total hemoglobin, is characterized by functional properties which are distinctly different from those of Components II, III and IV, which are alike. Thus it is shown, once more, that multiple components in an hemolysate fall into categories of hemoglobins characterized by distinct and complementary functional properties.Os quatro componentes de hemoglobina principais do hemolisado de Pterygoplichthys pardalis foram isolados e caracterizados. As propriedades funcionais investigadas para os componentes isolados compreendem o efeito de pH e ATP sobre(i) o equilíbrio de O2, (ii) a cinética da dissociação de O2 (iii) a cinética da combinação de CO. O componente I, corresponde a aproximadamente 50% da hemoglobina total, é caracterizado por propriedades funcionais que são diferentes das dos componentes II, III e IV, os quais são semelhantes. Assim, é provado, uma vez mais, que componentes múltiplos num hemolisado caem na categoria de hemoglobinas caracterizadas por propriedades funcionais distintas e complementares

C-Reactive Protein Levels at the Midpregnancy Can Predict Gestational Complications

Although essential for a successful pregnancy, a growing body of evidence suggests that maternal inflammation, when dysregulated, may represent a risk factor for both maternal and neonatal outcomes. Here, we assessed the accuracy of maternal C-reactive protein (CRP) concentrations at the middle phase of pregnancy in the identification of maternal adverse outcomes (MAO) until delivery. A correlation between CRP and a complicated pregnancy including both maternal and neonatal adverse outcomes has been investigated, too. In this retrospective study, conducted at the Diabetology Unit of IRCCS Ospedale Policlinico San Martino, Genoa (Italy), 380 outpatient pregnant women have been enrolled at the prenatal visit before performing a 75 g oral glucose tolerance test at 24th-26th gestational week for gestational diabetes mellitus (GDM) screening. Demographic, medical, and reproductive history has been obtained by verbal interview. Data about pregnancy and delivery have been retrieved from medical records. The median value of maternal baseline serum CRP was 3.25 \u3bcg/mL. Women experiencing MAO were older, more frequently suffering from hypertension, and showed higher CRP concentrations, with a cutoff value >1.86 \u3bcg/mL found by a ROC curve analysis to be accurately predictive for MAO. By a logistic regression analysis, serum CRP levels >1.86 \u3bcg/mL have been found to predict MAO also considering maternal age, hypertension, and GDM. Maternal CRP levels have been positively associated with overall pregnancy adverse outcomes (maternal and neonatal), too. In conclusion, in pregnant women serum levels of CRP can early recognize subjects at higher risk for maternal and neonatal complications needing a more stringent follow-up

Serum levels of VCAM-1 are associated with survival in patients treated with nivolumab for NSCLC

Background High circulating levels of cellular adhesion molecules (CAMs) in non-small cell lung cancer (NSCLC) have been supposed to act as a negative prognostic factor. Here, we explored the predictive role of pre-treatment levels of CAMs in previously treated patients receiving nivolumab for NSCLC. Materials and methods Seventy one patients with advanced NSCLC, treated with nivolumab at the dose of 3 mg/kg every 14 days, were enrolled. Maximum follow-up time was 3 years. Serum levels of Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intracellular Adhesion Molecule-1 (ICAM-1) were measured at baseline and before each nivolumab administration. Endpoints of the study were a composite outcome of survival >= 2 years or absence of disease progression at the end of the follow-up, and the overall survival. Results Composite outcome and overall survival were positively associated with VCAM-1 baseline levels and with the reduction of VCAM-1 during the treatment. After adjustment for potential confounders, the change in VCAM-1 serum levels during the treatment was an independent predictor of overall survival. Conclusions High baseline serum levels of VCAM-1 are associated with a longer survival in patients treated with nivolumab as second line treatment for NSCLC. Surviving patients experience also a significant reduction in CAMs expression during the treatment. Hence, CAMs might be promising prognostic factors in patients with NSCLC underoing immunotherapy