Rabbit antithymocyte globulin induces rapid expansion of effector memory CD8 T cells without accelerating acute graft versus host disease

Rabbit antithymocyte globulin (Thymoglobulin(®)) is commonly used as graft-versus-host disease (GvHD) prophylaxis. Since we found similar total CD8 T cell numbers in patients with and without Thymoglobulin(®) therapy within the first six months after allogeneic hematopoietic stem cell transplantation, we have analyzed the reconstitution of the CD8 T cell compartment in detail. After T cell-depletion, higher and more sustained proliferative capacity of memory CD8 T cells resulted in their rapid expansion, whereas the fraction of naive CD8 T cells decreased. Importantly, this shift towards effector memory CD8 T cells did not accelerate the incidence of GvHD

Utilization of TREC and KREC quantification for the monitoring of early T- and B-cell neogenesis in adult patients after allogeneic hematopoietic stem cell transplantation

BACKGROUND: After hematopoietic stem cell transplantation (HSCT) T- and B-cell reconstitution from primary lymphoid organs are a prerequisite for an effective early lymphocyte reconstitution and a long-term survival for adult patients suffering from acute leukemia. Here, we asked whether quantification of T cell receptor excision circle, (TREC) and kappa-deleting recombination excision circle (KREC) before and within six month after allogeneic HSCT could be used to measure the thymic and bone marrow outputs in such patients. METHODS: We used a duplex real time PCR assay to quantify the absolute copy counts of TREC and KREC, and correlated the data with absolute cell counts of CD3+CD4+ T-cell and CD19+ B-cell subsets determined by flow cytometry, respectively. RESULTS: By comparing two recently proposed naive T cell subsets, CD31+ naive and CD31- naive T cells, we found a better correlation for the CD31+ subset with TREC level post alloHSCT, in line with the assumption that it contained T cells recently derived from the thymus, indicating that TREC levels reflected real thymic de novo production. Transitional as well as naive B cells highly correlated with KREC levels, which suggested an association of KREC levels with ongoing bone marrow B cell output. CD45RO+ memory T cells and CD27+ memory B cells were significantly less correlated with TREC and KREC recovery, respectively. CONCLUSION: We conclude that simultaneous TREC/ KREC quantification is as a suitable and practicable method to monitor thymic and bone marrow output post alloHSCT in adult patients diagnosed with acute leukemia

UvA-DARE (Digital Academic Repository)

In vivo delayed-type hypersensitivity skin test anergy in human immunodeficiency virus type 1 infection is associated with T cell nonresponsiveness in vitr

Sleep as a model to understand neuroplasticity and recovery after stroke : observational, perturbational and interventional approaches

Our own experiences with disturbances to sleep demonstrate its crucial role in the recovery of cognitive functions. This importance is likely enhanced in the recovery from stroke; both in terms of its physiology and cognitive abilities. Decades of experimental research have highlighted which aspects and mechanisms of sleep are likely to underlie these forms of recovery. Conversely, damage to certain areas of the brain, as well as the indirect effects of stroke, may disrupt sleep. However, only limited research has been conducted which seeks to directly explore this bidirectional link between both the macro and micro-architecture of sleep and stroke. Here we describe a series of semi-independent approaches that aim to establish this link through observational, perturbational, and interventional experiments. Our primary aim is to describe the methodology for future clinical and translational research needed to delineate competing accounts of the current data. At the observational level we suggest the use of high-density EEG recording, combined analysis of macro and micro-architecture of sleep, detailed analysis of the stroke lesion, and sensitive measures of functional recovery. The perturbational approach attempts to find the causal links between sleep and stroke. We promote the use of transcranial magnetic stimulation combined with EEG to examine the cortical dynamics of the peri-infarct stroke area. Translational research should take this a step further using optogenetic techniques targeting more specific cell populations. The interventional approach focuses on how the same clinical and translational perturbational techniques can be adapted to influence long-term recovery of function

Does functional diversity increase effectiveness of community care teams?

As interprofessional collaboration becomes more commonplace in health and social care, both scholars and practitioners are searching for ways to make the most out of functionally diverse teams. Earlier research has shown that the presence of different functional backgrounds may lead teams to perform better, because they have a larger pool of knowledge and experience to draw from. Other studies show, however, that functional diversity increases categorization, reduces team cohesion, and complicates interpersonal communication, thereby reducing performance. It remains unclear under which conditions positive or negative outcomes may occur. The present research tested the influence of functional diversity on team identity, team performance, and client satisfaction, and examined factors which may moderate these relationships. Based on earlier studies in this specific context, we focused on three team processes as possible moderators: shared vision, interaction frequency, and team reflexivity. In a survey among health and social care professionals working in community care teams in the Netherlands (n = 167), all three are shown to moderate the relationship between functional diversity and team effectiveness. In the absence of these processes, functional diversity appears to reduce team outcomes, whereas when these processes are present, the relationships are positive. In sum, in order for community care teams to reap the benefits of functional diversity, it is essential that members develop a shared vision, interact frequently, and practice team reflexivity

Reduction of Pavlovian bias in schizophrenia: Enhanced effects in clozapine-administered patients

The negative symptoms of schizophrenia (SZ) are associated with a pattern of reinforcement learning (RL) deficits likely related to degraded representations of reward values. However, the RL tasks used to date have required active responses to both reward and punishing stimuli. Pavlovian biases have been shown to affect performance on these tasks through invigoration of action to reward and inhibition of action to punishment, and may be partially responsible for the effects found in patients. Forty-five patients with schizophrenia and 30 demographically-matched controls completed a four-stimulus reinforcement learning task that crossed action ("Go" or "NoGo") and the valence of the optimal outcome (reward or punishment-avoidance), such that all combinations of action and outcome valence were tested. Behaviour was modelled using a six-parameter RL model and EEG was simultaneously recorded. Patients demonstrated a reduction in Pavlovian performance bias that was evident in a reduced Go bias across the full group. In a subset of patients administered clozapine, the reduction in Pavlovian bias was enhanced. The reduction in Pavlovian bias in SZ patients was accompanied by feedback processing differences at the time of the P3a component. The reduced Pavlovian bias in patients is suggested to be due to reduced fidelity in the communication between striatal regions and frontal cortex. It may also partially account for previous findings of poorer "Go-learning" in schizophrenia where "Go" responses or Pavlovian consistent responses are required for optimal performance. An attenuated P3a component dynamic in patients is consistent with a view that deficits in operant learning are due to impairments in adaptively using feedback to update representations of stimulus value

Synaptic and transcriptionally downregulated genes are associated with cortical thickness differences in autism.

Differences in cortical morphology-in particular, cortical volume, thickness and surface area-have been reported in individuals with autism. However, it is unclear what aspects of genetic and transcriptomic variation are associated with these differences. Here we investigate the genetic correlates of global cortical thickness differences (ΔCT) in children with autism. We used Partial Least Squares Regression (PLSR) on structural MRI data from 548 children (166 with autism, 295 neurotypical children and 87 children with ADHD) and cortical gene expression data from the Allen Institute for Brain Science to identify genetic correlates of ΔCT in autism. We identify that these genes are enriched for synaptic transmission pathways and explain significant variation in ΔCT. These genes are also significantly enriched for genes dysregulated in the autism post-mortem cortex (Odd Ratio (OR) = 1.11, Pcorrected  10-14), driven entirely by downregulated genes (OR = 1.87, Pcorrected  10-15). We validated the enrichment for downregulated genes in two independent data sets: Validation 1 (OR = 1.44, Pcorrected = 0.004) and Validation 2 (OR = 1.30; Pcorrected = 0.001). We conclude that transcriptionally downregulated genes implicated in autism are robustly associated with global changes in cortical thickness variability in children with autism