Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors

Adeno-associated viral vectors (rAAV) are frequently used in gene therapy trials. Although rAAV vectors are of low immunogenicity, humoral as well as T cell responses may be induced. While the former limits vector reapplication, the expansion of cytotoxic T cells correlates with liver inflammation and loss of transduced hepatocytes. Because adaptive immune responses are a consequence of recognition by the innate immune system, we aimed to characterize cell autonomous immune responses elicited by rAAV in primary human hepatocytes and nonparenchymal liver cells. Surprisingly, Kupffer cells, but also liver sinusoidal endothelial cells, mounted responses to rAAV, whereas neither rAAV2 nor rAAV8 were recognized by hepatocytes. Viral capsids were sensed at the cell surface as pathogen-associated molecular patterns by Toll-like receptor 2. In contrast to the Toll-like receptor 9-mediated recognition observed in plasmacytoid dendritic cells, immune recognition of rAAV in primary human liver cells did not induce a type I interferon response, but up-regulated inflammatory cytokines through activation of nuclear factor κB. CONCLUSION: Using primary human liver cells, we identified a novel mechanism of rAAV recognition in the liver, demonstrating that alternative means of sensing rAAV particles have evolved. Minimizing this recognition will be key to improving rAAV-mediated gene transfer and reducing side effects in clinical trials due to immune responses against rAAV.     

A risk of essential thrombocythemia in carriers of constitutional CHEK2 gene mutations

Germline mutations of the CHEK2 gene have been reported in some myeloid and lymphoid malignancies, but their impact on development of essential thrombocythemia has not been studied. In 16 out of 106 (15.1%) consecutive patients, newly diagnosed with essential thrombocythemia, we found one of four analyzed CHEK2 mutations: I157T, 1100delC, IVS2+1G>A or del5395. They were associated with the increased risk of disease (OR=3.8; P=0.002). The median age at ET diagnosis among CHEK2+/JAK2V617F+ patients was seven years lower than that among CHEK2-/JAK2V617F+ (52 vs. 59 years; P=0.04), whereas there was no difference in the medians of hematologic parameters between these groups. The results obtained suggest that CHEK2 mutations could potentially contribute to the susceptibility to essential thrombocythemia. The germline inactivation of CHEK2, as it seems, has no direct impact on the development of disease, but it could cause disruption of cell cycle checkpoints and initiate or support the cancerogenic process of essential thrombocythemia at a younger age.     

Postmorbid learning of saxophone playing in a patient with frontotemporal dementia

Some patients with frontotemporal dementia (FTD) show an artistic enhancement of musical abilities. However, no patients with FTD, to date, have been reported to be able to learn how to play a musical instrument after disease onset. Herein we describe a patient (J. K.) who had never played any musical instruments premorbidly, but who learned to play the saxophone after being diagnosed with a behavioral variant of FTD. He mastered a repertoire that consisted of 10 pieces of Korean folk songs over a period of three years. Furthermore, his saxophone skills were high enough to outperform other students in his class.     

The Effect of Stimulus Parameters on TMS–EEG Muscle Artifacts

BackgroundWhen transcranial magnetic stimulation (TMS) is delivered close to the lateral aspects of the head, large-amplitude (～10–1000 μV) biphasic electroencephalographic (EEG) deflections, peaking at around 4–10 and 8–20 ms, appear.ObjectiveTo characterize the spatiotemporal features of these artifacts, to quantify the effect of stimulus parameters on them, and thus, to study the feasibility of different measurement procedures to decrease the artifacts online. Furthermore, to show that these deflections, when measured with a sample-and-hold system, mainly result from excitation of cranial muscles.MethodsThree subjects received TMS to 16 sites over the left hemisphere. TMS-compatible EEG was recorded simultaneously. Four other subjects received TMS to M1 with different coil rotation and tilt angles and stimulation intensities. We also stimulated a conductive phantom and recorded simultaneous EEG to exclude the possibility of residual electromagnetic artifacts.ResultsThe artifacts were largest when the stimulator was placed above cranial muscles, whereas stimulation of relatively central sites far from the muscles produced muscle artifact-free data. The laterally situated EEG channels were most severely contaminated. The artifacts were significantly reduced when reducing the intensity or when tilting or rotating the coil so that coil wings moved further away from the temporal muscle, while brain responses remained visible. Stimulation of the phantom did not produce such large-amplitude biphasic artifacts.ConclusionAltering the stimulation parameters can reduce the described artifact, while brain responses can still be recorded. The early, laterally appearing, large biphasic TMS-evoked EEG deflections recorded with a sample-and-hold system are caused by cranial muscle activation.     

Do maternal attributions play a role in the acceptability of behavioural interventions for problem behaviour in children with autism spectrum disorders?

The present study explored the relationship between parental attributions and treatment acceptability of behavioural interventions for problem behaviour in children with autism spectrum disorders (ASD). Mothers of children with ASD aged 3–9 years (N = 139) completed survey measures that assessed demographics, parental attributions, treatment acceptability of parent-focused and child-focused behavioural interventions, severity of their child's disruptive behaviour, and severity of their child's ASD symptoms. The results showed that parental attributions of parent-referent stability, but not the other attributional dimensions, negatively predicted treatment acceptability of a parent-focused behavioural intervention, even when severity of disruptive behaviour was statistically controlled. Conversely, no associations were found between any attributional dimension and treatment acceptability of a child-focused behavioural intervention. Preliminary analyses also revealed that mothers’ ratings of the severity of their child's disruptive behaviour were significantly negatively associated with the acceptability of both parent-focused and child-focused behavioural interventions. The findings have potential implications for professionals to identify and challenge distorted attributions of parent-referent stability to promote parental acceptance of a parent-focused behavioural intervention for problem behaviour in children with ASD.     

Unintended Consequences of Implementing a National Performance Measurement System into Local Practice

BACKGROUND  

Although benefits of performance measurement (PM) systems have been well documented, there is little research on negative unintended consequences of performance measurement systems in primary care. To optimize PM systems, a better understanding is needed of the types of negative unintended consequences that occur and of their causal antecedents.