Cell-Free DNA and CXCL10 Derived from Bronchoalveolar Lavage Predict Lung Transplant Survival.

Standard methods for detecting chronic lung allograft dysfunction (CLAD) and rejection have poor sensitivity and specificity and have conventionally required bronchoscopies and biopsies. Plasma cell-free DNA (cfDNA) has been shown to be increased in various types of allograft injury in transplant recipients and CXCL10 has been reported to be increased in the lung tissue of patients undergoing CLAD. This study used a novel cfDNA and CXCL10 assay to evaluate the noninvasive assessment of CLAD phenotype and prediction of survival from bronchoalveolar lavage (BAL) fluid. A total of 60 BAL samples (20 with bronchiolitis obliterans (BOS), 20 with restrictive allograft syndrome (RAS), and 20 with stable allografts (STA)) were collected from 60 unique lung transplant patients; cfDNA and CXCL10 were measured by the ELISA-based KIT assay. Median cfDNA was significantly higher in BOS patients (6739 genomic equivalents (GE)/mL) versus STA (2920 GE/mL) and RAS (4174 GE/mL) (p < 0.01 all comparisons). Likelihood ratio tests revealed a significant association of overall survival with cfDNA (p = 0.0083), CXCL10 (p = 0.0146), and the interaction of cfDNA and CXCL10 (p = 0.023) based on multivariate Cox proportional hazards regression. Dichotomizing patients based on the median cfDNA level controlled for the mean level of CXCL10 revealed an over two-fold longer median overall survival time in patients with low levels of cfDNA. The KIT assay could predict allograft survival with superior performance compared with traditional biomarkers. These data support the pursuit of larger prospective studies to evaluate the predictive performance of cfDNA and CXCL10 prior to lung allograft failure

Advanced glycation end products:An emerging biomarker for adverse outcome in patients with peripheral artery disease

AbstractPatients with peripheral artery disease (PAD) suffer from widespread atherosclerosis. Partly due to the growing awareness of cardiovascular disease, the incidence of PAD has increased considerably during the past decade. It is anticipated that algorithms to identify high risk patients for cardiovascular events require being updated, making use of novel biomarkers. Advanced glycation end products (AGEs) are moieties formed non-enzymatically on long-lived proteins under influence of glycemic and oxidative stress reactions. We elaborate about the formation and effects of AGEs, and the methods to measure AGEs. Several studies have been performed with AGEs in PAD. In this review, we evaluate the emerging evidence of AGEs as a clinical biomarker for patients with PAD

Evolutionary constraints on the long-period subdwarf B binary PG1018-047

We have revisited the sdB+K-star long-period binary PG 1018–047 based on 20 new high-resolution Very Large Telescope/Ultraviolet and Visual Echelle Spectrograph spectra that provided regular coverage over a period of more than 26  m. We refine the period and establish that the orbit is significantly eccentric (P = 751.6 ± 1.9 d and e = 0.049 ± 0.008). A simultaneous fit derived from the narrow metal lines visible in the spectrum of the sdB star and the metal lines in the red part of the spectrum that originate from the companion provides the mass ratio, MMS/MsdB = 1.52 ± 0.04, for the system. From an NLTE model atmosphere analysis of the combined spectra, we find Teff = 29900 ± 330 K, log g = 5.65 ± 0.06 dex and log(nHe/nH) = –3.98 ± 0.16 dex for the primary, consistent with a B-type hot subdwarf star. The spectral contribution of the companion is consistent with a K5V-type star. With the companion having a mass of only ∼ 0.7 M⊙, this system lies close to the boundary below which stable Roche lobe overflow (RLOF) cannot be supported. To model the evolution of such a system, we have extended earlier MESA models towards lower companion masses. We find that both phase-dependent mass loss during RLOF, when 30 to 40 per cent of the available mass is lost through the outer Lagrange point and phase-dependent mass loss during RLOF in combination with a circumbinary disc of maximum MCB = 0.001 M⊙ could have formed the PG 1018–047 binary system

Hypomagnesaemia and its determinants in a contemporary primary care cohort of persons with type 2 diabetes

AIMS: Among persons with type 2 diabetes mellitus (T2DM) hypomagnesaemia has been reported in 14-48% of patients. This may be of significance given the emerging associations of hypomagnesaemia with glucometabolic disturbances and possibly even complications. We assessed the prevalence of hypomagnesaemia and its determinants, in a well-defined cohort of persons with T2DM treated in primary care. METHODS: Observational cohort study among persons with T2DM treated in primary care in the Northeast of the Netherlands. Magnesium was measured using a colorimetric endpoint assay (Roche). Hypomagnesaemia was defined as a serum magnesium level <0.70 mmol/L. Pearson correlations were performed to correlate variables with serum magnesium. Next, a stepwise backward regression model was made. RESULTS: Data of 929 persons (55% male) with a mean age of 65 (± 10) years, diabetes duration 6.5 [3.0-10.1] years, and HbA1c concentration 6.7 (± 0.7)% (50 (± 9) mmol/mol) were analysed. Serum magnesium was 0.79 (± 0.08) mmol/L. The percentage of persons with magnesium deficiency was 9.6%. Age, diabetes duration, BMI, HbA1c, use of metformin, sulfonylurea derivatives, and DPP4 inhibitors were negatively associated with magnesium concentrations. In contrast, LDL cholesterol and serum creatinine were positively associated serum magnesium. CONCLUSIONS: Hypomagnesaemia was present in 9.6% of T2DM patients treated in primary care. This percentage is remarkably lower than reported previously, possibly due to the unselected nature of our population. Concerning T2DM-related factors, only BMI, HbA1c and the use of metformin, sulfonylurea derivatives and DPP4 inhibitors correlated negatively with magnesium concentrations

Broncho-alveolar lavage fluid recovery correlates with airway neutrophilia in lung transplant patients

SummaryBroncho-alveolar lavage (BAL) is important to assess airway inflammation. There is debate about the volume instilled, but the variation of BAL fluid recovery (BFR) has received little attention. We investigated the association between BFR and rejection/infection status after lung transplantation (LTx).We combined clinical findings, FEV1, transbronchial biopsies and BAL analysis (BFR, interleukin-8 (IL8), cell counts, microbiology) of 115 samples/LTx patients. The patients were divided into 4 groups: stable (subdivided in colonized and non-colonized), acute rejection (AR), Bronchiolitis Obliterans Syndrome (BOS) and infection.BFR was significantly lower in AR, BOS and infection, and correlated with the severity of AR and BOS. A 10ml decrease of BFR was associated with a FEV1 decrease of 4.4% and a %neutrophils and IL8 increase of 9.6% and 9.7pg/ml, respectively. Colonized stable patients had no significant differences in airway inflammation, FEV1 and BFR compared to the non-colonized stable patients.We conclude that a low BFR is an indicator of lung rejection or infection. BFR variation is related to airway obstruction and neutrophilic inflammation, which can cause an increased compliance of the airway wall, making it more collapsible. Airway colonization in stable patients had no effect on airway inflammatory parameters, BFR and FEV1

The Effect of Psyllium Husk on Intestinal Microbiota in Constipated Patients and Healthy Controls

Psyllium is a widely used treatment for constipation. It traps water in the intestine increasing stool water, easing defaecation and altering the colonic environment. We aimed to assess the impact of psyllium on faecal microbiota, whose key role in gut physiology is being increasingly recognised. We performed two randomised, placebo-controlled, double-blinded trials comparing 7 days of psyllium with a placebo (maltodextrin) in 8 healthy volunteers and 16 constipated patients respectively. We measured the patients’ gastrointestnal (GI) transit, faecal water content, short-chain fatty acid (SCFA) and the stool microbiota composition. While psyllium supplement had a small but significant effect on the microbial composition of healthy adults (increasing Veillonella and decreasing Subdoligranulum), in constipated subjects there were greater effects on the microbial composition (increased Lachnospira, Faecalibacterium, Phascolarctobacterium, Veillonella and Sutterella and decreased uncultured Coriobacteria and Christensenella) and alterations in the levels of acetate and propionate. We found several taxa to be associated with altered GI transit, SCFAs and faecal water content in these patients. Significant increases in three genera known to produce butyrate, Lachnospira, Roseburia and Faecalibacterium, correlated with increased faecal water. In summary, psyllium supplementation increased stool water and this was associated with significant changes in microbiota, most marked in constipated patients

Automated extraction of potential migraine biomarkers using a semantic graph

Problem Biomedical literature and databases contain important clues for the identification of potential disease biomarkers. However, searching these enormous knowledge reservoirs and integrating findings across heterogeneous sources is costly and difficult. Here we demonstrate how semantically integrated knowledge, extracted from biomedical literature and structured databases, can be used to automatically identify potential migraine biomarkers. Method We used a knowledge graph containing more than 3.5 million biomedical concepts and 68.4 million relationships. Biochemical compound concepts were filtered and ranked by their potential as biomarkers based on their connections to a subgraph of migraine-related concepts. The ranked results were evaluated against the results of a systematic literature review that was performed manually by migraine researchers. Weight points were assigned to these reference compounds to indicate their relative importance. Results Ranked results automatically generated by the knowledge graph were highly consistent with results from the manual literature review. Out of 222 reference compounds, 163 (73%) ranked in the top 2000, with 547 out of the 644 (85%) weight points assigned to the reference compounds. For reference compounds that were not in the top of the list, an extensive error analysis has been performed. When evaluating the overall performance, we obtained a ROC-AUC of 0.974. Discussion Semantic knowledge graphs composed of information integrated from multiple and varying sources can assist researchers in identifying potential disease biomarkers

The pleural mesothelium and TGF-β1 pathways in restrictive allograft syndrome : a pre-clinical investigation

BACKGROUND: Chronic lung allograft dysfunction (CLAD) hampers long-term survival after lung transplantation. Common fibrosis-related mechanisms in idiopathic pulmonary fibrosis and CLAD instigated the consideration of investigating the differential regulation of pleural mesothelium and transforming growth factor-beta(1) (TGF-beta(1)) in restrictive allograft syndrome (RAS). METHODS: TGF-beta(1) was assessed in bronchoalveolar lavage (BAL) fluid using enzyme-linked immunoassay and via immune staining of explant biopsies. To assess the role of the pleura, explanted bronchiolitis obliterans syndrome (BOS) and RAS lungs were compared using computed tomography scans, calretinin stainings, Western blot, and quantititative real-time PCR. Last, a pleural mesothelial cell line was used to assess mesothelial-to-mesenchymal transition and its inhibition. RESULTS: TGF-beta(1) was increased in BAL of RAS patients (p = 0.035), and was present in the (sub) pleural area of biopsies. Explanted RAS lungs demonstrated an increased volume fraction of pleura (p = 0.0004), a higher proportion of calretinin-positive stainings (p = 0.0032), and decreased E-cadherin (p = 0.019) and increased alpha-smooth muscle actin (p = 0.0089) mRNA expression and protein levels in isolated pleural tissue. Moreover, TGF-beta(1) stimulation of pleural mesothelial cells led to a phenotypical switch to mesenchymal cells, accompanied with an increased migratory capacity. Interleukin-1 alpha was able to accentuate TGF-beta(1). induced mesothelial-to-mesenchymal transition. None of the tested drugs could inhibit mesothelial-to-mesenchymal transition at the used concentrations. CONCLUSIONS: Our results support an interplay between TGF-beta(1) and the pleural mesothelium in the pathophysiology of RAS. (C) 2019 International Society for Heart and Lung Transplantation. All rights reserved