Intradialytic cycling does not exacerbate microparticles or circulating markers of systemic inflammation in haemodialysis patients

Purpose Patients receiving haemodialysis (HD) display elevated circulating microparticle (MP) concentration, tissue factor (TF) expression and markers of systemic inflammation, though regular intradialytic cycling (IDC) may have a therapeutic effect. This study investigated the impact of regular, moderate-intensity IDC on circulating MPs and inflammatory markers in unit-based HD patients. Methods Patients were cluster-randomised to intervention (n = 20, age: 51.4 ± 18.1 years, body mass: 77.6 ± 18.3 kg, mean ± SD) or no-exercise control (n = 20, 56.8 ± 14.0 years, 80.5 ± 26.5 kg). Intervention participants completed 30 min of moderate intensity (rating of perceived exertion [RPE] of 12–14) IDC, thrice weekly for 6 months. Pre-dialysis venous blood samples were obtained at 0, 3 and 6 months. Circulating MP phenotypes, cytokines, chemokine and MP TF expression were quantified using flow cytometry and cytometric bead array assays. Results Despite high exercise compliance (82%), no IDC-dependent effects were observed for any MP, cytokine or chemokine measure (p ≥ 0.051, ηρ2 ≤ 0.399) other than TNF-α (p = 0.001, ηρ2 = 0.186), though no significance was revealed upon post hoc analysis. Conclusion Six months of regular, moderate-intensity IDC had no effect on MPs, cytokines or chemokines. This suggests that the exercise did not exacerbate thrombotic or inflammatory status, though further functional assays are required to confirm this. Trial registration ISRCTN1129707, prospectively registered on 05/03/2015.

The pathogenetic significance of endothelial dysfunction in the development of diabetic nephropathy in patients with type 2 diabetes mellitus

Objective: to determine the level of circulating markers of endothelial dysfunction (endothelin‑1, von Willebrand factor (vfV), endothelial NO-synthase (e‑NOS)) in the blood serum of patients with type 2 diabetes mellitus (DM), as well as to assess the pathogenetic significance endothelial dysfunction in the development of diabetic nephropathy.Materials and methods: the study included 93 patients with type 2 DM, including 28 men (30.1%) and 65 women (69.9%), aged 30 to 79 years, the average age of patients was 59.7±8.4 of the year. The main group included patients with both newly diagnosed type 2 DM and a long-term diabetic history. The duration of the disease averaged 9.5±7.5 years. The majority of patients with DM type 2 (92.5%) at the time of inclusion in the study had various variants of microvascular complications of diabetes, only a small number of patientsin this group (7.5%) had no signs of diabetic angiopathy. Signs of various stages of diabetic nephropathy were observed in 60 patients (69.2%). The comparison group consisted of 30 patients with essential arterial hypertension, including 12 men (40%) and 18 women (60%), aged 34 to 70 years, on average 56.1 ± 8.1 years. The control group consisted of 32 apparently healthy individuals. In all patients, along with routine methods of clinical, laboratory and instrumental examination, the level of circulating markers of endothelial dysfunction (endothelin‑1, von Willebrand factor (vWF), endothelial NO-synthase (e‑NOS)) in blood serum was measured using enzyme-linked immunosorbent assay (ELISA).Results: in patients with DM type 2 and diabetic nephropathy, a statistically significant increase in the concentration of circulating markers of endothelial dysfunction was revealed in comparison with hypertensive patients and healthy individuals. An increase in the level of endothelin‑1 relative to the borderline reference value was found in 73 (78.5±4.1%), vfV in 63 (67.7±4.8%) and e‑NOS in 65 (69.9±4.7%) of patients with DM type 2. In the groups of participants with hypertension and healthy individuals, endothelial imbalance was noted by us significantly less often than in patients with DM type 2, the levels of endothelin‑1 and vfV in people with hypertension were increased in more cases than in healthy individuals. It was noted that the levels of circulating markers of endothelial dysfunction increase with an increase in the duration of DM type 2, and also significantly increase under conditions of carbohydrate decompensation.Conclusion: the results obtained confirm the pathogenetic role of endothelial dysfunction in the development of diabetic nephropathy in patients with type 2 diabetes, increasing endothelial imbalance in persons with a long diabetic history and lack of compensation for carbohydrate metabolism.

Total parasite biomass but not peripheral parasitaemia is associated with endothelial and haematological perturbations in Plasmodium vivax patients

Plasmodium vivax is the major cause of human malaria in the Americas. How P. vivax infection can lead to poor clinical outcomes, despite low peripheral parasitaemia remains a matter of intense debate. Estimation of total P. vivax biomass based on circulating markers indicates existence of a predominant parasite population outside of circulation. In this study we investigate associations between both peripheral and total parasite biomass and host response in vivax malaria. We analysed parasite and host signatures in a cohort of uncomplicated vivax malaria patients from Manaus, Brazil, combining clinical and parasite parameters, multiplexed analysis of host responses and ex vivo assays. Patterns of clinical features, parasite burden and host signatures measured in plasma across the patient cohort were highly heterogenous. Further data deconvolution revealed two patient clusters, here termed Vivaxlow and Vivaxhigh. These patient subgroups were defined based on differences in total parasite biomass but not peripheral parasitaemia. Overall Vivaxlow patients clustered with healthy donors and Vivaxhigh patients showed more profound alterations in haematological parameters, endothelial cell (EC) activation and glycocalyx breakdown and levels of cytokines regulating different haematopoiesis pathways compared to Vivaxlow. Vivaxhigh patients presented more severe thrombocytopenia and lymphopenia, along with enrichment of neutrophils in the peripheral blood and increased neutrophil-to-lymphocyte ratio (NLCR). When patients' signatures were combined, high association of total parasite biomass with a subset of markers of EC activation, thrombocytopenia and lymphopenia severity was observed. Finally, machine learning models defined a combination of host parameters measured in the circulation that could predict the extent of parasite infection outside of circulation. Altogether, our data show that total parasite biomass is a better predictor of perturbations in host homeostasis in P. vivax patients than peripheral parasitaemia. This supports the emerging paradigm of a P. vivax tissue reservoir, in particular in the hematopoietic niche of bone marrow and spleen.

Exosomes: A Forthcoming Era of Breast Cancer Therapeutics

Despite the recent advancements in therapeutics and personalized medicine, breast cancer remains one of the most lethal cancers among women. The prognostic and diagnostic aids mainly include assessment of tumor tissues with conventional methods towards better therapeutic strategies. However, current era of gene-based research may influence the treatment outcome particularly as an adjunct to diagnostics by exploring the role of non-invasive liquid biopsies or circulating markers. The characterization of tumor milieu for physiological fluids has been central to identifying the role of exosomes or small extracellular vesicles (sEVs). These exosomes provide necessary communication between tumor cells in the tumor microenvironment (TME). The manipulation of exosomes in TME may provide promising diagnostic/therapeutic strategies, particularly in triple-negative breast cancer patients. This review has described and highlighted the role of exosomes in breast carcinogenesis and how they could be used or targeted by recent immunotherapeutics to achieve promising intervention strategies.

Epigenome and phenome study reveals circulating markers pertinent to brain health

Characterising associations between the epigenome, proteome and phenome may provide insight into molecular regulation of biological pathways governing health. However, epigenetic signatures for many neurologically-associated plasma protein markers remain uncharacterised. Here, we report an epigenome and phenome-wide association study of the circulating proteome in relation to brain health. We perform epigenome-wide studies of 4,235 plasma proteins (n=778), identifying 2,895 CpG-protein associations (protein quantitative trait methylation loci; pQTMs) after stringent correction for multiple testing. These were independent of known genetic protein quantitative trait loci (pQTL) and common lifestyle effects, extending current knowledge by analysing a further 3,286 protein measurements with 2,854 novel pQTMs. We then perform a phenome-wide study of each protein in relation to neurological traits in 1,065 individuals, identifying 644 proteins related to cognitive, brain imaging phenotypes or APOE status. By integrating our pQTM dataset with our phenome association study, we uncovered 88 epigenetic associations for protein markers of neurological traits, 83 of which were previously unreported. These data are pertinent to understanding heterogeneity in brain health.

The effect of pre-operative methylprednisolone on postoperative delirium in elderly patients undergoing gastrointestinal surgery: a randomized, double-blind, placebo-controlled trial

Background Pre-operative administration of methylprednisolone reduced circulating markers of endothelial activation. This randomized, double-blind was to evaluate whether a single pre-operative dose of methylprednisolone reduced the rate of postoperative delirium (POD) in older patients undergoing gastrointestinal surgery, and its association with the shedding of endothelial glycocalyx markers. Methods 168 patients, aged 65–80 years and scheduled for laparoscopic gastrointestinal surgery, were randomized to 2 mg·kg -1 methylprednisolone (Group M, n = 84); or equivalent dose of placebo (Group C, n = 84). The primary outcome was the incidence of delirium during the first 5 days after surgery, assessed by the confusion assessment method (CAM). POD severity was rated daily using CAM-Severity (CAM-S). Level of syndecan-1, heparan sulfate, tumor necrosis factor-α(TNF-α), and brain-derived neurotrophic factor (BDNF) were measured at baseline, 1-day, and 3-day after surgery. Results Compared with placebo, methylprednisolone greatly reduced the incidence of delirium at 72 h following surgery [9(10.7%) versus 20(23.8%), P =0.03, OR=2.22(95%CI 1.05-4.59)]. No between-group difference was found in the cumulative CAM-S score (P=0.14). The levels of heparan sulfate, syndecan-1, and TNF-α in Group M were lower than that in Group C (P <0.05 and P <0.01), while the level of BDNF in Group M was higher than that in Group C (P <0.01). Conclusions Pre-operative administration of methylprednisolone does not reduce the severity of POD, but may reduce the incidence of delirium after gastrointestinal surgery in elderly patients, which may be related to a reduction in circulating markers of endothelial degradation, followed by the increase of BNDF level.