Translating in vitro prediction of cytotoxic T cell alloreactivity to hematopoietic stem cell transplantation outcome

IntroductionPreviously we developed a weighted amino acid (AA) mismatch score predictive for cytotoxic T cell (CTL) alloreactivity (in vitro CTLp assay) based on the structure of the HLA class I molecule. The aim of this study is to confirm the clinical relevance of the CTLp assay and to validate the AA mismatch score as an alternative and easy to use tool to predict permissible mismatches in hematopoietic stem cell transplantation (HSCT).MethodsWe selected patients transplanted with a 9/10 single HLA class I mismatched graft (n = 171) at three Dutch HSCT centers. A CTLp assay was performed in 73 donor–recipient pairs. As a control we selected 168 10/10 HLA matched pairs that were matched to the 9/10 single HLA class I mismatched pairs for HSCT year, donor type, patient age and diagnosis.ResultsWe observed that pairs with negative a CTLp assay had statistically significant decreased incidence of mortality after HSCT comparable to that of 10/10 HLA matched pairs. However, the weighted AA mismatch score did not significantly predict any HSCT end point of interest.ConclusionFurther investigation is needed to unravel the mechanisms involved in causing the beneficial effect of a negative CTLp assay, before other alternative tools to predict HSCT outcome may be developed.     

Predictors of Outcome for Cognitive Behaviour Therapy in Binge Eating Disorder

The aim of this naturalistic study was to identify pretreatment predictors of response to cognitive behaviour therapy in treatment‐seeking patients with binge eating disorder (BED; N = 304). Furthermore, we examined end‐of‐treatment factors that predict treatment outcome 6 months later (N = 190). We assessed eating disorder psychopathology, general psychopathology, personality characteristics and demographic variables using self‐report questionnaires. Treatment outcome was measured using the bulimia subscale of the Eating Disorder Inventory 1. Predictors were determined using hierarchical linear regression analyses. Several variables significantly predicted outcome, four of which were found to be both baseline predictors of treatment outcome and end‐of‐treatment predictors of follow‐up: Higher levels of drive for thinness, higher levels of interoceptive awareness, lower levels of binge eating pathology and, in women, lower levels of body dissatisfaction predicted better outcome in the short and longer term. Based on these results, several suggestions are made to improve treatment outcome for BED patients. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.     

Hybrid bodies and the materiality of everyday life: how people living with pacemakers and defibrillators reinvent everyday routines and intimate relations

Technologies inside bodies pose new challenges in a technological culture. For people with pacemakers and defibrillators, activities such as passing security controls at airports, using electromagnetic machines, electrical domestic appliances and electronic devices, and even intimate contacts with their loved ones can turn into events where the proper functioning of their device may be at risk. Anticipation of potentially harmful events and situations thus becomes an important part of the choreography of everyday life. Technologies inside bodies not only pose a challenge for patients living with these devices but also to theorising body‐technology relations. Whereas researchers usually address the merging of bodies and technologies, implants ask us to do the opposite as well. How are we to understand human‐technology relations in which technologies should not entangle with bodies because they serve other purposes? Based on a study of the daily life practices of people with pacemakers and defibrillators in the Netherlands and the US, I argue that disentanglement work, i.e. work involved to prevent entanglements with objects and people that may inflict harm upon implanted devices, is key to understanding how hybrid bodies can survive in today's densely populated technological landscape.     

Temperature-induced changes in structural and physicochemical properties of vernix caseosa

The skin of the third trimester fetus and early newborn exhibits a complex, multifunctional, highly hydrated but viscous skin-surface biofilm called vernix caseosa (VC). During birth, VC undergoes a substantial change from an aqueous and warm surrounding into a gaseous and colder environment postnatally. The aim of this study was to investigate the structural and physicochemical changes in VC, which accompany physiologically relevant variations in environment parameters, such as temperature and humidity. A remarkable difference was observed in water release and uptake properties: dehydration and rehydration processes take place two to four times faster at 37 degrees C than at room temperature (RT). The dehydration was irreversible; rehydration was only possible to a final weight of 55% (37 degrees C) and 46% (RT) of the pre-desiccation weight. Differential scanning calorimetry showed two different overlapping phase transitions within physiological temperature range. Investigation of the lipid organization by Fourier transform infrared spectroscopy and small-angle X-ray diffraction revealed a more disordered state of lipids at 37 degrees C than at RT, which might explain the faster dehydration and rehydration process at 37 degrees C as well as the changes in thermotropic rheological behavior. In conclusion, we demonstrated that VC properties adjust to the fundamental change from the intrauterine to the post-natal environment.     

Design and Evaluation of a Human Immunodeficiency Virus Type 1 RNA Assay Using Nucleic Acid Sequence-Based Amplification Technology Able To Quantify Both Group M and O Viruses by Using the Long Terminal Repeat as Target

Currently available human immunodeficiency virus type 1 (HIV-1) RNA quantification assays can detect most viruses of the group M subtypes, but a substantial number are missed or not quantified reliably. Viruses of HIV-1 group O cannot be detected by any commercially available assay. We developed and evaluated a quantitative assay based on nucleic acid sequence-based amplification (NASBA) technology, with primers and probes located in the conserved long terminal repeat (LTR) region of the HIV-1 genome. In 68 of 72 serum samples from individuals infected with HIV-1 subtypes A to H of group M, viruses could be detected and quantified. In serum samples from two patients infected with HIV-1 group O viruses, these viruses as well could be detected and quantified. In contrast, the currently used gag-based assay underestimated the presence of subtype A viruses and could not detect subtype G and group O viruses. The discrepancy between the results of the two assays may be explained by the number of mismatches found within and among the probe and primer regions of the subtype isolates. These data indicate that LTR-based assays, including the NASBA format chosen here, are better suited to monitoring HIV-1 therapy than are gag-based assays in an era in which multiple HIV-1 subtypes and groups are spreading worldwide.     

Aneurysm Treatment <24 Versus 24–72 h After Subarachnoid Hemorrhage

Introduction

In patients with aneurysmal subarachnoid hemorrhage (aSAH), it is unclear whether aneurysm treatment <24 h after ictus results in better outcomes than treatment 24–72 h after aSAH. We studied whether aneurysm occlusion <24 h is associated with better outcomes than occlusion 24–72 h after aSAH.

Methods

We used two cohorts of patients with aSAH: (1) the UMC Utrecht cohort with patients admitted between 2008 and 2012 and (2) the International Subarachnoid Aneurysm Trial cohort. Aneurysm treatment was categorized into <24 h and 24–72 h after ictus. We calculated adjusted risk ratios (aRRs) with 95 % confidence intervals (CIs) using Poisson regression analyses for poor functional outcome (death or dependency) for both cohorts separately, and performed a pooled analysis based on individual patient data. We also performed a worst-case scenario analysis wherein all patients with rebleeding >3 h after admission were re-categorized into the group with aneurysm treatment 24–72 h after aSAH.

Results

We included 1,238 patients (UMC Utrecht cohort: n = 330; ISAT: n = 908). The aRR for poor outcome after treatment <24 h was in the UMC Utrecht cohort 1.84 (95 % CI: 1.25-2.70), in ISAT 1.14 (95 % CI 0.84–1.55), in the pooled analysis 1.37 (95 % CI 1.11–1.68), and in the worst-case scenario pooled analysis 1.24 (95 % CI 1.01–1.52).

Conclusion

Our results suggest that aneurysm occlusion can be performed in day time within 72 h after ictus, instead of on an emergency basis. However, due to the retrospective, non-randomized design of our study, our results cannot be considered as definitive evidence.     

The macrophage CD163 surface glycoprotein is an erythroblast adhesion receptor

Erythropoiesis occurs in erythroblastic islands, where developing erythroblasts closely interact with macrophages. The adhesion molecules that govern macrophage-erythroblast contact have only been partially defined. Our previous work has implicated the rat ED2 antigen, which is highly expressed on the surface of macrophages in erythroblastic islands, in erythroblast binding. In particular, the monoclonal antibody ED2 was found to inhibit erythroblast binding to bone marrow macrophages. Here, we identify the ED2 antigen as the rat CD163 surface glycoprotein, a member of the group B scavenger receptor cysteine-rich (SRCR) family that has previously been shown to function as a receptor for hemoglobin-haptoglobin (Hb-Hp) complexes and is believed to contribute to the clearance of free hemoglobin. CD163 transfectants and recombinant protein containing the extracellular domain of CD163 supported the adhesion of erythroblastic cells. Furthermore, we identified a 13-amino acid motif (CD163p2) corresponding to a putative interaction site within the second scavenger receptor domain of CD163 that could mediate erythroblast binding. Finally, CD163p2 promoted erythroid expansion in vitro, suggesting that it enhanced erythroid proliferation and/or survival, but did not affect differentiation. These findings identify CD163 on macrophages as an adhesion receptor for erythroblasts in erythroblastic islands, and suggest a regulatory role for CD163 during erythropoiesis.