Complement activation and long-term graft function in ABO-incompatible kidney transplantation

BACKGROUND: ABO-incompatible and ABO-compatible kidney transplantation are equivalent in terms of short-term graft and patient survival. This is thought to be the result of ABO-incompatible graft accommodation, which occurs when anti-blood group antibodies re-occur after transplantation but somehow do not yield their detrimental effect. The underlying mechanism is unclear, but one of the hypotheses is that this is the result of complement inhibition. Since virtually all ABO-incompatible graft biopsies are C4d positive, this complement inhibition must occur somewhere in the complement cascade after the formation of C4d has already taken place, but where exactly is unclear. It is also unclear whether complement inhibition is complete. Incomplete accommodation could explain why recent studies have shown that long-term graft function in ABO-incompatible transplantation is somewhat inferior to ABO-compatible kidney transplantation.AIM: To unravel the relationship between pre-transplant anti-ABO antibodies, complement activation, and long-term graft function.METHODS: We included all 27 ABO-incompatible transplantations that were performed between 2008 and 2013 at the Academic Medical Center Amsterdam and the University Medical Center Groningen. For each ABO-incompatible transplantation, we included four ABO-compatible controls matched by age, sex, and transplantation date.RESULTS: Graft and patient survival were not significantly different. The slope of kidney function during five-year follow-up was also not significantly different, but ABO-incompatible recipients did have a lower kidney function at three months (creatinine clearance 58 vs 69 mL/min, P = 0.02, Modification of Diet in Renal Disease 46 vs 52 mL/min/1.73 m2, P = 0.08), due to a high rate of early rejection (33% vs 15%, P = 0.03), mostly T-cell mediated. Pre-transplant anti-ABO IgG titers were positively correlated with C5b-9 staining, which itself was positively correlated with the occurrence of T-cell mediated rejection. This may be the result of concurrent C5a formation, which could function as a costimulatory signal for T-cell activation.CONCLUSION: Co-stimulation of T-cell activation by ongoing complement activation by anti-ABO antibodies may be responsible for an impaired long-term graft function in ABO-incompatible kidney transplantation.</p

Compatibility of neutrino DIS data and global analyses of parton distribution functions

Neutrino\antineutrino deep inelastic scattering (DIS) data provide useful constrains for the flavor decomposition in global fits of parton distribution functions (PDF). The smallness of the cross-sections requires the use of nuclear targets in the experimental setup. Understanding the nuclear corrections is, for this reason, of utmost importance for a precise determination of the PDFs. Here, we explore the nuclear effects in the neutrino\antineutrino-nucleon DIS by comparing the NuTeV, CDHSW, and CHORUS cross-sections to the predictions derived from the latest parton distribution functions and their nuclear modifications. We obtain a good description of these data and find no apparent disagreement between the nuclear effects in neutrino DIS and those in charged lepton DIS. These results also indicate that further improvements in the knowledge of the nuclear PDFs could be obtained by a more extensive use of these sets of neutrino data.Comment: 16 pages, 8 figure

Probing the low transverse momentum domain of Z production with novel variables

The measurement of the low transverse momentum region of vector boson production in Drell-Yan processes has long been invaluable to testing our knowledge of QCD dynamics both beyond fixed-order in perturbation theory as well as in the non-perturbative region. Recently the D\O\ collaboration have introduced novel variables which lead to improved measurements compared to the case of the standard QT variable. To complement this improvement on the experimental side, we develop here a complete phenomenological study dedicated in particular to the new \phi* variable. We compare our study, which contains the state-of-the-art next-to-next-to-leading resummation of large logarithms and a smooth matching to the full next-to-leading order result, to the experimental data and find excellent agreement over essentially the entire range of \phi*, even without direct inclusion of non-perturbative effects. We comment on our findings and on the potential for future studies to constrain non-perturbative behaviour.Comment: 20 pages, 7 figures. Version accepted for publication in JHEP. A figure with comparison to RESBOS has been adde

The sputum transcriptome better predicts COPD exacerbations after the withdrawal of inhaled corticosteroids than sputum eosinophils.

Introduction: Continuing inhaled corticosteroid (ICS) use does not benefit all patients with COPD, yet it is difficult to determine which patients may safely sustain ICS withdrawal. Although eosinophil levels can facilitate this decision, better biomarkers could improve personalised treatment decisions. Methods: We performed transcriptional profiling of sputum to explore the molecular biology and compared the predictive value of an unbiased gene signature versus sputum eosinophils for exacerbations after ICS withdrawal in COPD patients. RNA-sequencing data of induced sputum samples from 43 COPD patients were associated with the time to exacerbation after ICS withdrawal. Expression profiles of differentially expressed genes were summarised to create gene signatures. In addition, we built a Bayesian network model to determine coregulatory networks related to the onset of COPD exacerbations after ICS withdrawal. Results: In multivariate analyses, we identified a gene signature (LGALS12, ALOX15, CLC, IL1RL1, CD24, EMR4P) associated with the time to first exacerbation after ICS withdrawal. The addition of this gene signature to a multiple Cox regression model explained more variance of time to exacerbations compared to a model using sputum eosinophils. The gene signature correlated with sputum eosinophil as well as macrophage cell counts. The Bayesian network model identified three coregulatory gene networks as well as sex to be related to an early versus late/nonexacerbation phenotype. Conclusion: We identified a sputum gene expression signature that exhibited a higher predictive value for predicting COPD exacerbations after ICS withdrawal than sputum eosinophilia. Future studies should investigate the utility of this signature, which might enhance personalised ICS treatment in COPD patients

Tetradecylthioacetic Acid Increases Hepatic Mitochondrial β-Oxidation and Alters Fatty Acid Composition in a Mouse Model of Chronic Inflammation

The administration of tetradecylthioacetic acid (TTA), a hypolipidemic and anti-inflammatory modified bioactive fatty acid, has in several experiments based on high fat diets been shown to improve lipid transport and utilization. It was suggested that increased mitochondrial and peroxisomal fatty acid oxidation in the liver of Wistar rats results in reduced plasma triacylglycerol (TAG) levels. Here we assessed the potential of TTA to prevent tumor necrosis factor (TNF) α-induced lipid modifications in human TNFα (hTNFα) transgenic mice. These mice are characterized by reduced β-oxidation and changed fatty acid composition in the liver. The effect of dietary treatment with TTA on persistent, low-grade hTNFα overexpression in mice showed a beneficial effect through decreasing TAG plasma concentrations and positively affecting saturated and monounsaturated fatty acid proportions in the liver, leading to an increased anti-inflammatory fatty acid index in this group. We also observed an increase of mitochondrial β-oxidation in the livers of TTA treated mice. Concomitantly, there were enhanced plasma levels of carnitine, acetyl carnitine, propionyl carnitine, and octanoyl carnitine, no changed levels in trimethyllysine and palmitoyl carnitine, and a decreased level of the precursor for carnitine, called γ-butyrobetaine. Nevertheless, TTA administration led to increased hepatic TAG levels that warrant further investigations to ascertain that TTA may be a promising candidate for use in the amelioration of inflammatory disorders characterized by changed lipid metabolism due to raised TNFα levels

The Surface Waters Acidification Project Palaeolimnology Programme: modern diatom/lake-water chemistry data-set

In 1983, when the Surface Waters Acidification Programme (SWAP) was announced, we were asked to design and implement a palaeolimnology sub-project involving scientists from Sweden, Norway, and the UK. Our aim was to reconstruct the acidification history of a range of sites in the three countries and to identify and evaluate the various alternative causes of lake acidification. The results of the project have been published recently (Battarbee et al. 1990, Renberg and Battarbee 1990). Although a comprehensive range of palaeolimnological methods and approaches was used in the study we recognised diatom analysis as central to the entire project. We consequently committed considerable effort to improving our diatom methodology and we were especially concerned with the pursuit of a common approach to diatom taxonomy and pH reconstruction. This effort centred on the creation and analysis of a large data-set of surface-sediment diatom assemblages and associated environmental variables from 170 sites representing the full range of lake types in the acid-sensitive and acidified regions of the three countries

An unusual case of metastasis to the left side of the heart: a case report

<p>Abstract</p> <p>Introduction</p> <p>Cardiac metastases are found in six to 20% of autopsies of patients with malignant neoplasm. The most common neoplasms that metastasize to the heart are malignant melanoma, lymphoma, and leukemia, but the relative numbers are greater with breast and lung cancers, reflecting the most common incidence of these cancers.</p> <p>Case presentation</p> <p>A 60-year-old Hispanic man presented to our hospital after being transferred from an outside hospital for workup and evaluation of an adrenal mass of the abdomen and pelvis, found on computed tomography. His chief complaint upon admission was altered mental status. Physical examination was unremarkable. He was alert and oriented and had a dry and non-erythematous oropharynx, and bilateral diffuse wheezing on lung examination. Computed tomography of the chest showed multiple hypodense lesions in the left ventricular myocardium, suggestive of metastases. There were also tiny sub-centimeter nodular densities in the right upper and lower lobes. Adrenal glands contained hypodense lesions, which showed characteristic adenocarcinomatous malignant cells.</p> <p>Conclusion</p> <p>Cancers which have metastasized to the heart are found in six to 20% of patients with malignant neoplasms. The right side of the heart is more commonly involved in metastasis. This study is unusual in that a tumor of an unknown primary origin had metastasized to the left side of the heart.</p

Big hearts, small hands:A focus group study exploring parental food portion behaviours

© The Author(s). 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: The development of healthy food portion sizes among families is deemed critical to childhood weight management; yet little is known about the interacting factors influencing parents' portion control behaviours. This study aimed to use two synergistic theoretical models of behaviour: the COM-B model (Capability, Opportunity, Motivation - Behaviour) and Theoretical Domains Framework (TDF) to identify a broad spectrum of theoretically derived influences on parents' portion control behaviours including examination of affective and habitual influences often excluded from prevailing theories of behaviour change. Methods: Six focus groups exploring family weight management comprised of one with caseworkers (n = 4), four with parents of overweight children (n = 14) and one with parents of healthy weight children (n = 8). A thematic analysis was performed across the dataset where the TDF/COM-B were used as coding frameworks. Results: To achieve the target behaviour, the behavioural analysis revealed the need for eliciting change in all three COM-B domains and nine associated TDF domains. Findings suggest parents' internal processes such as their emotional responses, habits and beliefs, along with social influences from partners and grandparents, and environmental influences relating to items such as household objects, interact to influence portion size behaviours within the home environment. Conclusion: This is the first study underpinned by COM-B/TDF frameworks applied to childhood weight management and provides new targets for intervention development and the opportunity for future research to explore the mediating and moderating effects of these variables on one another.Peer reviewedFinal Published versio