Deleted in malignant brain tumors 1 (DMBT1) elicits increased VEGF and decreased IL-6 production in type II lung epithelial cells

Background: Deleted in malignant brain tumors 1 (DMBT1) is an innate defence protein expressed in the lungs of preterm infants and adults. Recent studies showed that DMBT1 is important in angiogenesis and can bind to different growth factors including VEGF. We aimed at examining relationships between VEGF and IL-6 levels to DMBT1 expression in the lungs of preterm and term infants and in lung epithelial cells in vitro. Methods: We examined by ELISA VEGF levels in 120 tracheal aspirates of 57 preterm and term infants and tested for correlation with different perinatal factors as well as with DMBT1 levels. To examine the effect of DMBT1 on VEGF and IL-6 expression we compared type II lung epithelial A549 cells stably transfected with a DMBT1 expression plasmid (DMBT1+ cells) to A549 cells stably transfected with an empty expression plasmid (DMBT1- cells). The concentrations of VEGF and IL-6 were determined via ELISA in the supernatant of the unstimulated cells and after stimulation with LPS, TNFα and Phorbol-12-myristate-13-acetate (PMA). Results: The VEGF levels in the tracheal aspirates of preterm and term infants were significantly correlated with DMBT1 levels (p = 0.0032), the postnatal age (p = 0.0073) and the presence of neonatal infection/sepsis (p = 0.0002). Unstimulated DMBT1+ A549 cells showed significantly higher VEGF expression (p = 0.0017) than DMBT1- cells. Significantly elevated VEGF levels were also confirmed for DMBT1+ cells after stimulation with TNFα (p = 0.0008), LPS (p = 0.0232) and PMA (p = 0.0025). The IL-6 levels were comparable in DMBT1+ versus DMBT1- cells without stimulation (p = 0.6028), but they were significantly reduced in DMBT1+ cells after stimulation with TNFα (p = 0.0003), LPS (p = 0.0088) and PMA (p = 0.0039). Conclusions: The data indicate that DMBT1 promotes VEGF and suppresses IL-6 production in alveolar tissues, which could point to DMBT1 having a possible role in the transition from inflammation to regeneration and being a potentially useful clinical marker

Antibiotic utilization in hospitalized children under 2 years of age with influenza or respiratory syncytial virus infection - a comparative, retrospective analysis

Background: Infections due to Respiratory Syncytial Virus (RSV) and Influenza virus (FLU) are leading causes of hospitalization in young children. Yet, there is little data on factors associated with antibiotic use in these patients. Methods: We conducted a retrospective, single-center study of all patients below 2 years of age hospitalized between 2014 and 2018. We compared children with RSV infection to children with FLU infection analyzing clinical characteristics and factors contributing to an increased rate of antimicrobial utilization. Results: RSV infection was diagnosed in 476/573 (83.1%), FLU in 95/573 (16.6%), and RSV-FLU-co-infection in 2/573 (0.3%) patients. Median age was lower for RSV compared to FLU (4 vs. 12 months; p < 0.0001). Children with RSV had longer hospitalization (5 vs. 4 days; p = 0.0023) and needed oxygen more frequently (314/476 vs. 23/95; p < 0.0001) than FLU patients. There was no significant difference in the overall antibiotic utilization between RSV and FLU patients (136/476 vs. 21/95; p = 0.2107). Logistic regression analyses revealed that septic appearance on admission (odds ratio [OR] 8.95, 95% confidence interval [CI] 1.5–54.1), acute otitis media (OR 4.5, 95% CI 2.1–9.4), a longer oxygen therapy (OR 1.40; 95% CI 1.13–1.74) and a higher C-reactive protein (CRP) (OR 1.7, 95% CI 1.5–2.0) were significantly associated with antibiotic use in both groups, but not age or pneumonia. Conclusions: In our cohort, the rate of antibiotic utilization was comparable between RSV and FLU patients, while for both groups distinct clinical presentation and a high CRP value were associated with higher antibiotic use

Simvastatin and atorvastatin attenuate VCAM-1 and uPAR expression on human endothelial cells and platelet surface expression of CD40 ligand

Background: In addition to their cholesterol lowering ability, statins have proven pleiotropic effects in the cardiovascular system. Chronic inflammation with interactions between platelets and endothelial cells leads to an upregulation of activity markers of atherosclerosis. The purpose of this study was to investigate the effects of simvastatin and atorvastatin on platelets and endothelial cells in an in vitro endothelial cell model. Methods and Results: After a 24 h incubation period with either simvastatin or atorvastatin (1 &#956;mol/L), human umbilical vein endothelial cells were stimulated for 1 h with lipopolysaccharide (LPS), and were then incubated in direct contact with activated platelets. Platelet surface expression of CD40L and CD62P and expression of ICAM-1, VCAM-1, uPAR and MT1-MMP on endothelial cells were measured by flow cytometry. Supernatants were analyzed by ELISA for soluble MMP-1. The increased expression of VCAM-1 and uPAR on endothelial cells by stimulation with LPS and by direct contact with activated platelets was significantly reduced to a similar extent through pre-incubation with both atorvastatin and simvastatin (p < 0.05). Platelets without endothelial cell contact, but in direct contact with either statin, showed similar significant reductions in surface expression of CD40L (p < 0.005). Conclusions: These effects may explain the ability of statins to reduce the progression of atherosclerosis in addition to their cholesterol-lowering properties. (Cardiol J 2012; 19, 1: 20&#8211;28

Ischemic biomarker heart-type fatty acid binding protein (hFABP) in acute heart failure - diagnostic and prognostic insights compared to NT-proBNP and troponin I

Background: To evaluate diagnostic and long-term prognostic values of hFABP compared to NT-proBNP and troponin I (TnI) in patients presenting to the emergency department (ED) suspected of acute heart failure (AHF). Methods: 401 patients with acute dyspnea or peripheral edema, 122 suffering from AHF, were prospectively enrolled and followed up to 5 years. hFABP combined with NT-proBNP versus NT-proBNP alone was tested for AHF diagnosis. Prognostic value of hFABP versus TnI was evaluated in models predicting all-cause mortality (ACM) and AHF related rehospitalization (AHF-RH) at 1 and 5 years, including 11 conventional risk factors plus NT-proBNP. Results: Additional hFABP measurements improved diagnostic specificity and positive predictive value (PPV) of sole NT-proBNP testing at the cutoff <300 ng/l to “rule out” AHF. Highest hFABP levels (4th quartile) were associated with increased ACM (hazard ratios (HR): 2.1–2.5; p = 0.04) and AHF-RH risk at 5 years (HR 2.8–8.3, p = 0.001). ACM was better characterized in prognostic models including TnI, whereas AHF-RH was better characterized in prognostic models including hFABP. Cox analyses revealed a 2 % increase of ACM risk and 3–7 % increase of AHF-RH risk at 5 years by each unit increase of hFABP of 10 ng/ml. Conclusions: Combining hFABP plus NT-proBNP (<300 ng/l) only improves diagnostic specificity and PPV to rule out AHF. hFABP may improve prognosis for long-term AHF-RH, whereas TnI may improve prognosis for ACM. Trial registration: ClinicalTrials.gov identifier: NCT00143793

Is antibacterial treatment intensity lower in elderly patients? A retrospective cohort study in a German surgical intensive care unit

Background: Demographic change concurrent with medical progress leads to an increasing number of elderly patients in intensive care units (ICUs). Antibacterial treatment is an important, often life-saving, aspect of intensive care but burdened by the associated antimicrobial resistance risk. Elderly patients are simultaneously at greater risk of infections and may be more restrictively treated because, generally, treatment intensity declines with age. We therefore described utilization of antibacterials in ICU patients older and younger than 80 years and examined differences in the intensity of antibacterial therapy between both groups. Methods: We analysed 17,464 valid admissions from the electronic patient data management system of our surgical ICU from April 2006 – October 2013. Antibacterial treatment rates were defined as days of treatment (exposed patient days) relative to patient days of ICU stay and calculated for old and young patients. Rates were compared in zero-inflated Poisson regression models adjusted for patients’ sex, mean SAPS II- and TISS-scores, and calendar years yielding adjusted rate ratios (aRRs). Rate ratios exceeding 1 represent higher rates in old patients reflecting greater treatment intensity in old compared to younger patients. Results: Observed antibacterial treatment rates were lower in patients 80 years and older compared to younger patients (30.97 and 39.73 exposed patient days per 100 patient days in the ICU, respectively). No difference in treatment intensity, however, was found from zero-inflated Poisson regression models permitting more adequate consideration of patient days with low treatment probability: for all antibacterials the adjusted rate ratio (aRR) was 1.02 (95%CI: 0.98–1.07). Treatment intensities were higher in elderly patients for penicillins (aRR 1.37 (95%CI: 1.26–1.48)), cephalosporins (aRR 1.20 (95%CI: 1.09–1.31)), carbapenems (aRR 1.35 (95%CI: 1.20–1.50)), fluoroquinolones (aRR 1.17 (95%CI: 1.05–1.30), and imidazoles (aRR 1.34 (95%CI: 1.23–1.46)). Conclusions: Elderly patients were generally less likely to be treated with antibacterials. This observation, however, did not persist in patients with comparable treatment probability. In these, antibacterial treatment intensity did not differ between younger and older ICU patients, for some antibacterial classes treatment intensity was even higher in the latter. Patient-level covariates are instrumental for a nuanced evaluation of age-effects in antibacterial treatment in the ICU

IL1RN and KRT13 Expression in Bladder Cancer: Association with Pathologic Characteristics and Smoking Status

Purpose. To validate microarray data on cytokeratin 13 (KRT13) and interleukin-1 receptor antagonist (IL1RN) expression in urothelial carcinoma of the urinary bladder (UCB) and to correlate our findings with pathologic characteristics and tobacco smoking. Methods. UCB tissue samples (n=109) and control samples (n=14) were obtained from transurethral resection and radical cystectomy specimens. Immunohistochemical staining of KRT13 and IL1RN was performed and semiquantitative expression scores were assessed. Smoking status was evaluated using a standardized questionnaire. Expression scores were correlated with pathologic characteristics (tumor stage and grade) and with smoking status. Results. Loss of KRT13 and IL1RN expression was observed in UCB tissue samples when compared to controls (P=0.007, P=0.008) in which KRT13 and IL1RN expression were high. IL1RN expression was significantly reduced in muscle-invasive tumors (P=0.003). In tissue samples of current smokers, a significant downregulation of IL1RN was found when compared to never smokers (P=0.013). Conclusion. Decreased expressions of KRT13 and IL1RN are common features of UCB and are associated with aggressive disease. Tobacco smoking may enhance the loss of IL1RN, indicating an overweight of proinflammatory mediators involved in UCB progression. Further validation of the influence of smoking on IL1RN expression is warranted

Risk factor paradox: No prognostic impact of arterial hypertension and smoking in patients with ventricular tachyarrhythmias

Background: Data regarding the outcome of patients with ventricular tachyarrhythmias related to arterial hypertension (AHT) and smoking is limited. The study sought to assess the prognostic impact of AHT and smoking on survival in patients presenting with ventricular tachyarrhythmias. Methods: All consecutive patients surviving ventricular tachycardia (VT) and ventricular fibrillation (VF) upon admission to the University Medical Center Mannheim (UMM), Germany from 2002 to 2016 were included and stratified according to AHT and smoking by propensity score matching. The primary prognostic endpoint was all-cause mortality at 30 months.Results: A total of 988 AHT-matched patients (494 each, with and without AHT) and a total of 872 smoking-matched patients (436 each, with and without smoking) were included. The rates of VT and VF were similar in both groups (VT: AHT 60% vs. no AHT 60%; smokers 61% vs. non-smokers 62%; VF: AHT 35% vs. no AHT 38%; smokers 39% vs. non-smokers 38%). Neither AHT nor smoking were associated with the primary endpoint of long-term all-cause mortality at 30 months (long-term mortality rates: AHT/no AHT, 26% vs. 28%; log-rank p = 0.525; smoking/non-smoking, 22% vs. 25%; log-rank p = 0.683).Conclusions: Paradoxically, neither AHT nor smoking were associated with differences of long-term all-cause mortality in patients presenting with ventricular tachyarrhythmias

Pulmonary cancers across different histotypes share hybrid tuft cell/ionocyte-like molecular features and potentially druggable vulnerabilities

Tuft cells are chemosensory epithelial cells in the respiratory tract and several other organs. Recent studies revealed tuft cell-like gene expression signatures in some pulmonary adenocarcinomas, squamous cell carcinomas (SQCC), small cell carcinomas (SCLC), and large cell neuroendocrine carcinomas (LCNEC). Identification of their similarities could inform shared druggable vulnerabilities. Clinicopathological features of tuft cell-like (tcl) subsets in various lung cancer histotypes were studied in two independent tumor cohorts using immunohistochemistry (n = 674 and 70). Findings were confirmed, and additional characteristics were explored using public datasets (RNA seq and immunohistochemical data) (n = 555). Drug susceptibilities of tuft cell-like SCLC cell lines were also investigated. By immunohistochemistry, 10–20% of SCLC and LCNEC, and approximately 2% of SQCC expressed POU2F3, the master regulator of tuft cells. These tuft cell-like tumors exhibited “lineage ambiguity” as they co-expressed NCAM1, a marker for neuroendocrine differentiation, and KRT5, a marker for squamous differentiation. In addition, tuft cell-like tumors co-expressed BCL2 and KIT, and tuft cell-like SCLC and LCNEC, but not SQCC, also highly expressed MYC. Data from public datasets confirmed these features and revealed that tuft cell-like SCLC and LCNEC co-clustered on hierarchical clustering. Furthermore, only tuft cell-like subsets among pulmonary cancers significantly expressed FOXI1, the master regulator of ionocytes, suggesting their bidirectional but immature differentiation status. Clinically, tuft cell-like SCLC and LCNEC had a similar prognosis. Experimentally, tuft cell-like SCLC cell lines were susceptible to PARP and BCL2 co-inhibition, indicating synergistic effects. Taken together, pulmonary tuft cell-like cancers maintain histotype-related clinicopathologic characteristics despite overlapping unique molecular features. From a therapeutic perspective, identification of tuft cell-like LCNECs might be crucial given their close kinship with tuft cell-like SCLC

Type 2 diabetes is independently associated with all-cause mortality secondary to ventricular tachyarrhythmias

Objectives: The study sought to assess the prognostic impact of type 2 diabetes in patients presenting with ventricular tachyarrhythmias on admission. Background: Data regarding the prognostic outcome of diabetics presenting with ventricular tachyarrhythmias is limited. Methods: A large retrospective registry was used including all consecutive patients presenting with ventricular tachycardia (VT) and fibrillation (VF) on admission from 2002 to 2016. Patients with type 2 diabetes (diabetics) were compared to non-diabetics applying multivariable Cox regression models and propensity-score matching for evaluation of the primary prognostic endpoint of long-term all-cause mortality at 2 years. Secondary prognostic endpoints were cardiac death at 24 h, in-hospital death at index, all-cause mortality at 30 days, all-cause mortality in patients surviving index hospitalization at 2 years (i.e. “after discharge”) and rehospitalization due to recurrent ventricular tachyarrhythmias at 2 years. Results: In 2411 unmatched high-risk patients with ventricular tachyarrhythmias, diabetes was present in 25% compared to non-diabetics (75%). Rates of VT (57% vs. 56%) and VF (43% vs. 44%) were comparable in both groups. Multivariable Cox regression models revealed diabetics associated with the primary endpoint of long-term all-cause mortality at 2 years (HR = 1.513; p = 0.001), which was still proven after propensity score matching (46% vs. 33%, log rank p = 0.001; HR = 1.525; p = 0.001). The rates of secondary endpoints were higher for in-hospital death at index, all-cause mortality at 30 days, as well as after discharge, but not for cardiac death at 24 h or rehospitalization due to recurrent ventricular tachyarrhythmias. Conclusion: Presence of type 2 diabetes is independently associated with an increase of all-cause mortality in patients presenting with ventricular tachyarrhythmias on admission

Statin therapy is associated with improved survival in patients with ventricular tachyarrhythmias

Objectives: The study sought to assess the impact of statin therapy on survival in patients presenting with ventricular tachyarrhythmias. Background: Data regarding the outcome of patients with statin therapy presenting with ventricular tachyarrhythmias is limited. Methods: A large retrospective registry was used including all consecutive patients presenting with ventricular tachycardia (VT) or fibrillation (VF) from 2002 to 2016. Patients with statin were compared to patients without statin therapy (non-statin). The primary prognostic endpoint was long-term all-cause death at 3 years. Uni- and multivariable Cox regression analyses were applied in propensity-score matched cohorts. Results: A total of 424 matched patients was included. The rates of VT and VF were similar in both groups (VT: statin 71% vs. non-statin 68%; VF: statin 29% vs. 32%; p = 0.460). Statin therapy was associated with lower all-cause mortality at long-term follow-up (mortality rates 16% versus 33%; log rank, p = 0.001; HR = 0.438; 95% CI 0.290–0.663; p = 0.001), irrespective of the underlying type of ventricular tachyarrhythmia (VT/VF), left ventricular ejection fraction (LVEF) &gt; 35%, presence of an activated implantable cardioverter defibrillator (ICD), cardiogenic shock or cardiopulmonary resuscitation (CPR). Conclusion: Statin therapy is independently associated with lower long-term mortality in patients presenting with ventricular tachyarrhythmias on admission. Trial registration: Clinicaltrials.gov, NCT02982473 , 11/29/2016, Retrospectively registered