Low-dose intestinal Trichuris muris infection alters the lung immune microenvironment and can suppress allergic airway inflammation

Immunological cross talk between mucosal tissues such as the intestine and the lung is poorly defined during homeostasis and disease. Here, we show that a low-dose infection with the intestinally restricted helminth parasite Trichuris muris results in the production of Th1 cell-dependent gamma interferon (IFN-γ) and myeloid cell-derived interleukin-10 (IL-10) in the lung without causing overt airway pathology. This cross-mucosal immune response in the lung inhibits the development of papain-induced allergic airway inflammation, an innate cell-mediated type 2 airway inflammatory disease. Thus, we identify convergent and nonredundant roles of adaptive and innate immunity in mediating cross-mucosal suppression of type 2 airway inflammation during low-dose helminth-induced intestinal inflammation. These results provide further insight in identifying novel intersecting immune pathways elicited by gut-to-lung mucosal cross talk

Intestinal epithelial cell-intrinsic deletion of Setd7 identifies role for developmental pathways in immunity to helminth infection

The intestine is a common site for a variety of pathogenic infections. Helminth infections continue to be major causes of disease worldwide, and are a significant burden on health care systems. Lysine methyltransferases are part of a family of novel attractive targets for drug discovery. SETD7 is a member of the Suppressor of variegation 3-9-Enhancer of zeste-Trithorax (SET) domain-containing family of lysine methyltransferases, and has been shown to methylate and alter the function of a wide variety of proteins in vitro. A few of these putative methylation targets have been shown to be important in resistance against pathogens. We therefore sought to study the role of SETD7 during parasitic infections. We find that Setd7-/- mice display increased resistance to infection with the helminth Trichuris muris but not Heligmosomoides polygyrus bakeri. Resistance to T. muris relies on an appropriate type 2 immune response that in turn prompts intestinal epithelial cells (IECs) to alter differentiation and proliferation kinetics. Here we show that SETD7 does not affect immune cell responses during infection. Instead, we found that IEC-specific deletion of Setd7 renders mice resistant to T. muris by controlling IEC turnover, an important aspect of anti-helminth immune responses. We further show that SETD7 controls IEC turnover by modulating developmental signaling pathways such as Hippo/YAP and Wnt/β-Catenin. We show that the Hippo pathway specifically is relevant during T. muris infection as verteporfin (a YAP inhibitor) treated mice became susceptible to T. muris. We conclude that SETD7 plays an important role in IEC biology during infection

Aortic stenosis and aortic regurgitation express different titin isoforms: Differences and relationships with functional and geometric characteristics

Background-Titin represents an important biomechanical sensor which determines compliance and diastolic/ systolic function of the left ventricle (LV). To assess the different titin-isoform expression and the relationships with functional and geometric patterns, we analyzed titin-isoform expression and cardiomyocytes contractile functioninmyocardialbiopsysamplesofpatientsundergoingaorticvalvereplacement(AVR)foraorticstenosis (AS)and for aorticregurgitation (AR). Method-Specimens,collectedfromtheLVof35withASand35withARundergoingAVRwereanalyzedfortitinisoform expression and cardiomyocytes force measurement. Ten donor hearts were analyzed as controls for normal values. Results were implemented with preoperative geometry and function assessed by Doppler echocardiography. Results-Comparedtocontrols,N2BA/N2Btitin-isoformsratiowasreducedto0.24inAS(p b 0.001)butincreased to 0.51 in AR (p b 0.001). N2BA/N2B titin-isoforms ratio was further reduced in 8 patients with severe (restrictive) diastolic dysfunction (0.17 ± 0.03, p b 0.001) but was increased in patients with severe systolic dysfunction (0.58 ± 0.07, p b 0.001). As compared to controls, Fpasive was higher in AS (6.7 ± 0.2 vs 4.4 ± 0.4kN/m2,p b 0.001)butwaslowerinAR(3.7±0.2vs4.4±0.4kN/m2,p b 0.001).Totalforcewascomparable. FpassivewassignificantlyhigherinAS patientswithseverethanwithmoderateLVdiastolicdysfunction(7.1± 0.5 vs 6.6.±0.6,p=0.004). Conclusions-titin-isoform expression differs in AS and AR as adaptive response to different pathophysiologic scenarios. Co-expressing isoforms at varying ratios results in modulation of the passive mechanical behavior of the LV at different degree of dysfunction and allows for compensative adjustment of the diastolic/systolic properties of the myocardium

Continuative statin therapy after percutaneous coronary intervention improves outcome in coronary bypass surgery: A propensity score analysis of 2501 patients

ObjectivesA history of percutaneous coronary intervention increases the risk of death and complications of coronary artery bypass grafting. This retrospective multicenter study evaluated the impact of continuative use of statin on postoperative outcomes when subsequent elective coronary artery bypass grafting is required after percutaneous coronary intervention.MethodsAmong 14,575 patients who underwent isolated first-time coronary artery bypass grafting between January 2000 and December 2010, 2501 who had previous percutaneous coronary intervention with stenting and fulfilled inclusion criteria were enrolled. Continuative statin therapy was used in 1528 patients and not used in 973 patients. Logistic multiple regression and propensity score analyses were used to assess the risk-adjusted impact of statin therapy on in-hospital mortality and major adverse cardiac events. The Cox proportional hazards model was constructed to assess the effect of continuative statin therapy on 24-month outcome.ResultsAt multivariate analysis, age more than 70 years, 3-vessel or 2-vessel plus left main coronary disease, multivessel percutaneous coronary intervention, ejection fraction 0.40 or less, diabetes mellitus, and logistic European System for Cardiac Operative Risk Evaluation 5 or greater were independent predictors of hospital mortality and major adverse cardiac events. After propensity score matching, conditional logistic regression analysis demonstrated that continuative statin therapy before coronary artery bypass grafting reduced the risk for hospital and 2-year mortality (odds ratio [OR], 0.27; 95% confidence interval [CI], 0.12-0. 57; P = .004 and OR, 0.6; 95% CI, 0.36-0.96; P = .04, respectively) and major adverse cardiac events (OR, 0.31; 95% CI, 0.18-0.78; P = .003 and OR, 0.5; 95% CI, 0.34-0.76; P = .006, respectively).ConclusionsLong-term statin treatment after percutaneous coronary intervention improves early and midterm outcome when surgical revascularization will be required

Cardiovascular events and treatment of children with high risk medulloblastoma

Background: Children with high-risk medulloblastoma are treated with chemotherapeutic protocols which may affect heart function. We aimed to assesscardiovascular events (CVE) in children with medulloblastoma/primitive neuroectodermal tumors (PNET). Methods: We retrospectively collected data from a case series of 22 children with high-risk medulloblastoma/PNET admitted to the Santobono-Pausilipon Hospital, Naples, Italy from 2008 to 2016. All patients received the Milan HART protocol for high-risk brain malignancies as first line treatment (induction phase), followed by a consolidation phase with Thiotepa and hematopoietic stem cells transplantation, except for 1 patient who received the Milan HART as second line therapy. Four patients also received second line treatment, while 4 patients also received maintenance therapy. Patients underwent cardiac examination, including ECG, echocardiography and serum biomarkers, before antineoplastic treatment initiation and then when clinically needed. Six patients developed CVE (CVE group); 16 patients had no CVE (NO-CVE group). Findings: In the CVE group, 3 patients presented acute CVE during chemotherapy (2 patients with left ventricular (LV) dysfunction, 1 patient with arterial hypertension), while 3 patients presented chronic CVE after chemotherapy completion (2 patients with LV dysfunction, 1 patient with ectopic atrial tachycardia). After a 51 months median follow-up, 9 patients died: 4 from the CVE group (in 2 cases heart failure-related deaths) and 5 from the NO-CVE group (progression of disease). Interpretation: A relevant percentage of children treated for medulloblastoma/PNET develops CVE. Heart failure potentially due to chemotherapy may represent a cause of death. Hence, in these patients, strict cardiac surveillance is essential. Funding: No funding was associated with this study

B-type natriuretic peptide as a biochemical marker of left ventricular diastolic function: Assessment in asymptomatic patients 1 year after valve replacement for aortic stenosis.

Objectives: Left ventricular (LV) diastolic dysfunction after aortic valve replacement (AVR) carries a substantial risk of development of heart failure and reduced survival. In addition to echocardiography, B-type natriuretic peptide (BNP) provides a powerful incremental assessment of diastolic function. This study evaluates BNP as a marker of LV diastolic dysfunction in a cohort of patients with preserved LV ejection fraction who underwent AVR for pure aortic stenosis and the relationship between BNP values and the grade of LV diastolic dysfunction. Methods A total of 113 patients were included in the study. Echocardiographic evaluation was performed preoperatively, 5 days postoperatively and at 12-month follow-up, to assess LV dimensional and functional parameters. Diastolic function was labelled as normal, mild, moderate or severe dysfunction. Concomitantly, BNP levels were evaluated. Results Mild to severe diastolic dysfunction occurred preoperatively in all patients. At 12-month follow-up, 65 (62.5%) patients had mild and 25 (24.1%) moderate to severe diastolic dysfunction. BNP values, categorized for quartile distribution, correlated with diastolic dysfunction grade (P < 0.001 for each comparison). At receiver operating characteristic analysis, the BNP level of 120 pg/ml was 91% sensitive and 85% specific for diastolic disease, while 300 pg/ml was 80% sensitive and 91% specific for moderate or severe diastolic dysfunction. Twelve months after AVR, BNP values were strongly correlated with the significant echocardiographic parameters suggestive of diastolic dysfunction (P ≤ 0.006 in all cases). Conclusions The BNP level following AVR is related to diastolic disease severity and may complement echocardiographic evaluation when symptoms are unclear and LV function is difficult to interpret

Safety of aortic aneurysm repair 8 weeks after percutaneous coronary intervention for coronary artery disease: a cohort study

Guidelines advice against dual antiplatelet therapy (DAPT) discontinuation less than 12 months after percutaneous coronary intervention with drug-eluting stents (DES-PCI). However, any delay of necessary surgery in patients with descending thoracic (DTA) or abdominal aortic aneurysm (AAA), treated by DES-PCI, increases the risk of aneurysm rupture/dissection. We evaluated the safety of 8-week waiting time between DES-PCI and endovascular aortic repair (EVAR). 1152 consecutive patients with coronary artery disease (CAD) needing elective DTA or AAA repair were enrolled and divided into two groups. Group A included 830 patients treated by DES-PCI for significant CAD who underwent surgery 8 weeks after implantation. Group B included 322 patients treated by DES-PCI at least 6 months before with no residual significant CAD and treated by elective EVAR. Groups were compared according to a composite of death, myocardial infarction, stent thrombosis, cerebrovascular events and bleeding. No aneurysm rupture/dissection occurred while waiting for surgery. Hospital averse events occurred in 6.2% (52/830) group A patients versus 6.5% (21/322) group B patients (p = 0.8). Mortality was 0.7% (6/830) in group A and 0.9% (3/322) in group B (p = 0.7). Multivariate predictors of events were triple vessel DES-PCI (p 3 stents implanted (p 30 mm (p = 0.02). Eight weeks of waiting after DES-PCI in addition to an adequate management of DAPT were safe in terms of cardiac morbidity and bleeding complications. No aneurysm rupture occurred in the interval before surgery