Identification of Novel Independent Correlations between Cellular Components of the Immune System and Strain-Related Indices of Myocardial Dysfunction in CKD Patients and Kidney Transplant Recipients without Established Cardiovascular Disease.

The role of immune system components in the development of myocardial remodeling in chronic kidney disease (CKD) and kidney transplantation remains an open question. Our aim was to investigate the associations between immune cell subpopulations in the circulation of CKD patients and kidney transplant recipients (KTRs) with subclinical indices of myocardial performance. We enrolled 44 CKD patients and 38 KTRs without established cardiovascular disease. A selected panel of immune cells was measured by flow cytometry. Classical and novel strain-related indices of ventricular function were measured by speckle-tracking echocardiography at baseline and following dipyridamole infusion. In CKD patients, the left ventricular (LV) relative wall thickness correlated with the CD14++CD16- monocytes (ß = 0.447, p = 0.004), while the CD14++CD16+ monocytes were independent correlates of the global radial strain (ß = 0.351, p = 0.04). In KTRs, dipyridamole induced changes in global longitudinal strain correlated with CD14++CD16+ monocytes (ß = 0.423, p = 0.009) and CD4+ T-cells (ß = 0.403, p = 0.01). LV twist and untwist were independently correlated with the CD8+ T-cells (ß = 0.405, p = 0.02 and ß = -0.367, p = 0.03, respectively) in CKD patients, whereas the CD14++CD16+ monocytes were independent correlates of LV twist and untwist in KTRs (ß = 0.405, p = 0.02 and ß = -0.367, p = 0.03, respectively). Immune cell subsets independently correlate with left ventricular strain and torsion-related indices in CKD patients and KTRs without established CVD.

Translation and cross-cultural adaptation of the Kidney Transplant Questionnaire 25 to Greek.

BACKGROUND: Kidney transplantation leads to continuous improvement in the survival rates of kidney transplant recipients (KTRs) and has been established as the treatment of choice for patients with end-stage kidney disease. Health-related quality of life (HRQoL) has become an important outcome measure. It is highly important to develop reliable methods to evaluate HRQoL with disease-specific questionnaires. AIM: To translate the disease-specific instrument Kidney Transplant Questionnaire 25 (KTQ-25) to the Greek language and perform a cross-cultural adaptation. METHODS: The translation and adaptation of the original English version of the KTQ-25 to the Greek language were performed based on the International Quality of Life Assessment. RESULTS: Eighty-four KTRs (59 males; mean age 53.5 ± 10.7 years; mean estimated glomerular filtration rate 47.7 ± 15.1 mL/min/1.73 m2; mean transplant vintage 100.5 ± 83.2 months) completed the Greek version of the KTQ-25 and the 36-item Short-Form Health Survey, and the results were used to evaluate the reliability of the Greek KTQ-25. The Cronbach alpha coefficients for all the KTQ-25 dimensions were satisfactory (physical symptoms = 0.639, fatigue = 0.856, uncertainty/fear = 0.661, appearance = 0.593, emotions = 0.718, total score = 0.708). The statistically significant correlation coefficients among the KTQ-25 dimensions ranged from 0.226 to 0.644. The correlation coefficients of the KTQ-25 dimensions with the SF-36 physical component summary (PCS) ranged from 0.196 to 0.550; the correlation coefficients of the KTQ-25 with the SF-36 mental component summary (MCS) ranged from 0.260 to 0.655; and the correlation coefficients of the KTQ-25 with the total scores with the SF-36 PCS and MCS were 0.455 and 0.613, respectively. CONCLUSION: According to the findings, the Greek version of the KTQ-25 is valid and reliable for administration among kidney transplant patients in Greece.

Neutrophil Extracellular Traps and Pancreatic Cancer Development: A Vicious Cycle.

Neutrophil extracellular traps (NETs) are a neutrophil-generated extracellular network of chromatin and chromatin-bound molecules with antimicrobial potency. Recent data suggest that NETs are associated with cancer progression and cancer-associated hypercoagulability. Pancreatic adenocarcinoma (PDAC) is a lethal type of cancer in which hypercoagulability and cancer-related thrombosis are among the main complications. In the current report, we summarize the available data on the interplay between NET formation and PDAC development. We conclude that NETs support a dual role during PDAC progression and metastasis. Their formation is on the one hand an important event that shapes the cancer microenvironment to support cancer cell proliferation, invasion and metastasis. On the other hand, NETs may lead to cancer-associated thrombosis. Both mechanisms seem to be dependent on distinct molecular mechanisms that link inflammation to cancer progression. Collectively, NET formation may contribute to the pathogenesis of PDAC, while during cancer development, the proinflammatory environment enables the induction of new NETs and thrombi, forming a vicious cycle. We suggest that targeting NET formation may be an effective mechanism to inhibit both PDAC development and the accompanying hypercoagulability.

An Open Drug Discovery Competition: Experimental Validation of Predictive Models in a Series of Novel Antimalarials.

The Open Source Malaria (OSM) consortium is developing compounds that kill the human malaria parasite, Plasmodium falciparum, by targeting PfATP4, an essential ion pump on the parasite surface. The structure of PfATP4 has not been determined. Here, we describe a public competition created to develop a predictive model for the identification of PfATP4 inhibitors, thereby reducing project costs associated with the synthesis of inactive compounds. Competition participants could see all entries as they were submitted. In the final round, featuring private sector entrants specializing in machine learning methods, the best-performing models were used to predict novel inhibitors, of which several were synthesized and evaluated against the parasite. Half possessed biological activity, with one featuring a motif that the human chemists familiar with this series would have dismissed as "ill-advised". Since all data and participant interactions remain in the public domain, this research project "lives" and may be improved by others.

Hypothermic Machine Perfusion of Kidney Transplant: A Mini-Review.

Most kidney grafts are marginal and from deceased donors, which yield worse clinical outcomes. Hypothermic machine perfusion has created a paradigm shift in kidney preservation. This mini-review summarizes the main points of hypothermic machine perfusion of kidney transplants that should be known by any physician and surgeon involved with kidney transplantation. Specifically, this review explains a proposed mechanism of action of hypothermic machine perfusion of kidney transplants. This review also describes the clinical effectiveness of hypothermic machine perfusion and explains how to evaluate and predict graft functionality according to machine parameters and perfusate biomarkers. Finally, treatment options and the most recent studies on oxygenated hypothermic machine perfusion are mentioned.

Longitudinal Assessment of Electrolyte Disorders in a Cohort of Chronic Stable Kidney Transplant Recipients.

BACKGROUND: Kidney transplantation is complicated by various electrolyte disturbances with variable reported prevalence and incidence and of multifactorial pathogenesis. The aim of our study was the retrospective longitudinal assessment of the serum electrolytes in a cohort of stable kidney transplant recipients (KTRs) and the possible associated parameters, including graft function and medications. METHODS: We included 93 stable KTRs under follow-up in our hospital's kidney transplant unit. Serum magnesium, calcium, phosphorus, potassium, sodium, and urine sodium levels were recorded retrospectively during 3 consecutive years. In addition, comorbidities, biochemical parameters, medications, and graft function (estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation and 24-hour urinary protein [uTpr]) were recorded. RESULTS: Mean age at baseline was 51 ± 11 years; 64 KTRs were men (68.8%), 17 (18.3%) had diabetes, 79 (85%) had hypertension, and 11 (11.8%) had cardiovascular disease. Mean eGFR and uTpr (mg/24 h) at study initiation were 47.1 ± 13.5 mL/min/1.73 m2 and 369.4 ± 404.2 mg/24 h, respectively. Hypomagnesemia was the most common disturbance observed in 21.7% of KTRs. Patients with hypomagnesemia displayed higher parathyroid hormone levels and more frequently had diabetes. Hypophosphatemia was recorded in 9.7% of KTRs during the first year. Hyperkalemia, hypokalemia, and hypercalcemia were rare (<5%). Mean serum and urine sodium concentration remained stable during the study, whereas urinary sodium levels showed a positive correlation with uTpr (P < .05). CONCLUSIONS: In our cohort of KTRs, there were no significant electrolyte disorders, either in terms of frequency or severity, with hypomagnesemia being the most prevalent disturbance. The identification of potential associated risk factors and clinical data correlations are pivotal for the development of individualized and evidence-based therapeutic approach and decisions.

Survival of Peritoneal Membrane Function on Biocompatible Dialysis Solutions in a Peritoneal Dialysis Cohort Assessed by a Novel Test.

BACKGROUND: Longitudinal surveillance of peritoneal membrane function is crucial in defining patients with a risk of ultrafiltration failure. Long PD is associated with increased low molecular weight solute transport and decreased ultrafiltration and free water transport. Classic PET test only provides information about low molecular solute transport, and the vast majority of longitudinal studies are based on this test and include patients using conventional dialysates. Our aim was to prospectively analyze longitudinal data on peritoneal function in patients on biocompatible solutions using a novel test. METHODS: Membrane function data were collected based on uni-PET (a combination of modified and mini PET). A total of 85 patients (age 61.1 ± 15.1 years) with at least one test/year were included. RESULTS: The median follow up was 36 months (21.3, 67.2). A total of 219 PETs were performed. One-way repeated measures ANOVA showed that there were no statistically significant differences over time in ultrafiltration, free water transport, ultrafiltration through small pores, sodium removal, D/D0 and D/PCre in repeated PET-tests. Twenty-three tests revealed ultrafiltration failure in 16 (18.8%) patients. Those patients were longer on PD, had higher D/P creatinine ratios, lower ultrafiltration at one hour with lower free water transport and higher urine volume at baseline. Multivariate analysis revealed that the variation of ultrafiltration over repeated PET-tests independently correlated only with D/Pcreatinine, free water transport and ultrafiltration through small pores. CONCLUSIONS: Uni-PET is a combination of two tests that provides more information on the function of the membrane compared with PET. Our study on a PD cohort using only biocompatible solutions revealed that function membrane parameters remained stable over a long time. Ultrafiltration failure was correlated with increased D/P creatinine and decreased free water transport and ultrafiltration through small pores.

In Surgical Colon Cancer Patients Extended-Duration Thromboprophylaxis (30 days) with the Highest Dose of Tinzaparin (4,500 IU s.c./q.d.) Normalizes the Postoperative VEGF Levels.

Background/Purpose: In colon cancer (CC) patients preoperative (pre-op) levels of VEGF-A165 (VEGF) is a strong predictor for disease recurrence. Elevated postoperative (post-op) VEGF levels could have undesirable effects by enhancing tumor growth and metastasis formation. It has been suggested that thromboprophylaxis with a Low Molecular Weight Heparin (LMWH) in surgical cancer patients, further to thromboembolic protection, may exert some anti-neoplastic properties, as well. The aim of our study was to assess the potential impact of the LMWH Tinzaparin (Innohep® - Leo Pharma, Copenhagen, Denmark), given at different doses and for different perioperative (peri-op) periods, upon the post-op variability of serum VEGF levels in surgical CC patients. Methods: A total of 54 consecutive CC patients who underwent a curative resection were randomized in four groups according to their peri-op thromboprophylaxis scheme, which was based on administrating Tinzaparin in different doses and at different periods, as follows: group I: 3,500 IU for 10 days, group II: 3,500 IU for 30 days, group III: 4,500 IU for 10 days and group IV: 4,500 IU for 30 days. Serum VEGF concentrations were evaluated on the pre-op day (Day 0) and on the 10th and 30th post-op days (Day 10 and Day 30, respectively). For statistical analyses the mixed design ANOVA was used. P < 0.05 was considered significant. Results: On Day 0, VEGF didn't differ between groups I, II, III and IV (p>0.05, for every comparison). On Day 10, VEGF was increased in all groups. Between Day 10 and Day 30, VEGF remained stable in groups I (p=0.031) and II (p=1.000) and increased significantly in group III (p=0.005). On the contrary, VEGF decreased significantly in group IV (p<0.001). The most remarkable finding was observed when we compared VEGF between Day 0 and Day 30: while in groups I, II and III, VEGF remained significantly higher compared to Day 0 (p<0.001, p=0.041 and p<0.001, respectively), on the contrary, in group IV (extended-duration with the highest dose of 4,500 IU of tinzaparin) it was comparable to Day 0 (p=1.000). Conclusions: In surgical CC patients only the recommended thromboprophylaxis scheme with the highest prophylactic dose of Tinzaparin (4,500 IU) for extended-duration (30 days) normalizes VEGF levels at the end of the first post-op month by reducing them to the pre-op levels.

Subtotal gastrectomy for diffused hemorrhagic gastritis induced by radiation, following liver resection for hilar cholangiocarcinoma. A case report.

INTRODUCTION: A rare case of hemorrhagic gastritis induced by radiation is presented, which was resistant to conservative treatment and required subtotal gastrectomy. PRESENTATION OF CASE: A 56-year-old male was initially undergone right hepatectomy, resection of the extrahepatic biliary tree, hilar lymph node dissection and hepatico-jejunostomy due to advanced hilar cholangiocarcinoma. Because of the extent of the disease, chemo-radiotherapy was administered. The patient received a total radiotherapy dose of 57.6Gy in 32 sessions. Unfortunately, diffused hemorrhagic gastritis induced by radiation was developed, which was resistant to conservative treatment (endoscopic hemostasis, transfusion). A subtotal gastrectomy was performed. The patient is in good condition 45 months after the liver resection, but with local recurrence. CONCLUSION: In resistant situations to conservative treatment and recurred bleeding of diffused hemorrhagic gastritis induced by radiation, surgical management may have a role.

Peptides in the presence of aqueous ionic liquids: tunable co-solutes as denaturants or protectants?

We studied the stability of a small ß-hairpin peptide under the influence of an aqueous 1-ethyl-3-methylimidazolium acetate ([EMIM](+)[ACE](-)) solution via all-atom molecular dynamics simulations in combination with metadynamics. Our free energy results indicate a denaturation of the peptide structure in the presence of the ionic liquid which is validated by a significant broadening of the end-to-end distance. The radial distribution functions between the ions and the peptide were used for the calculation of the preferential binding coefficients in terms of the Kirkwood-Buff theory. A significant structure dependent binding behavior of acetate to the peptide was found which can be interpreted as the main reason for the denaturation of the native conformation. The outcomes of our simulations allow us to propose a simple mechanism to explain the unfolding of the peptide with regard to the specific properties of ionic liquids. Our results are in good agreement with experimental findings and demonstrate the benefits of ionic liquids as tunable co-solutes with regard to their influence on protein structural properties.

Evaluating data mining algorithms using molecular dynamics trajectories.

Molecular dynamics simulations provide a sample of a molecule's conformational space. Experiments on the mus time scale, resulting in large amounts of data, are nowadays routine. Data mining techniques such as classification provide a way to analyse such data. In this work, we evaluate and compare several classification algorithms using three data sets which resulted from computer simulations, of a potential enzyme mimetic biomolecule. We evaluated 65 classifiers available in the well-known data mining toolkit Weka, using 'classification' errors to assess algorithmic performance. Results suggest that: (i) 'meta' classifiers perform better than the other groups, when applied to molecular dynamics data sets; (ii) Random Forest and Rotation Forest are the best classifiers for all three data sets; and (iii) classification via clustering yields the highest classification error. Our findings are consistent with bibliographic evidence, suggesting a 'roadmap' for dealing with such data.

Insights into the structure of the PmrD protein with molecular dynamics simulations.

Resistance to cationic antimicrobial peptide polymyxin B from Gram-negative bacteria is accomplished by two-component systems (TCSs), protein complexes PmrA/PmrB and PhoP/PhoQ. PmrD is the first protein identified to mediate the connectivity between two TCSs. The 3D structure of PmrD has been recently solved by NMR and its unique fold was revealed. Here, a molecular dynamics study is presented started from the NMR structure. Numerous hydrophobic and electrostatic interactions were identified to contribute to PmrD's 3D stability. Moreover, the mobility of the five loops that connect the protein's six beta-strands has been explored. Solvent-accessible surface area calculation revealed that a Leucine-rich hydrophobic cluster of the protein stabilized the protein's structure.

Molecular Dynamics as a pattern recognition tool: an automated process detects peptides that preserve the 3D arrangement of Trypsin's Active Site.

Recently, the synthesis of a molecule has been reported that belongs to a Lysine based, branched cyclic peptide class. This work explores the ability of such molecules to preserve the 3D geometry of the Trypsin's Active Site (TAS) by applying an integrated framework of automated computer procedures. The following four factors a) D/L chirality, b) different amino acids at different positions of the molecular scaffold's cyclic part, c) the application of AMBER and CHARMM force fields and d) different implicit solvation models were evaluated against TAS similarity. It was found that a number of molecules exhibit satisfactory geometric affinity to the TAS during extended Molecular Dynamics runs. We estimated that more than 2000 molecules (belonging to this class) could retain good similarity to the TAS arrangement.