CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment ...options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin-mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis.
PSTPIP1 is a cytoskeletal adaptor and F-BAR protein that has been implicated in autoinflammatory disease, most notably in the PAPA syndrome: pyogenic sterile arthritis, pyoderma gangrenosum, and ...acne. However, the mechanism by which PSTPIP1 regulates the actin cytoskeleton and contributes to disease pathogenesis remains elusive. Here, we show that endogenous PSTPIP1 negatively regulates macrophage podosome organization and matrix degradation. We identify a novel PSTPIP1-R405C mutation in a patient presenting with aggressive pyoderma gangrenosum. Identification of this mutation reveals that PSTPIP1 regulates the balance of podosomes and filopodia in macrophages. The PSTPIP1-R405C mutation is in the SRC homology 3 (SH3) domain and impairs Wiskott-Aldrich syndrome protein (WASP) binding, but it does not affect interaction with protein-tyrosine phosphatase (PTP)-PEST. Accordingly, WASP inhibition reverses the elevated F-actin content, filopodia formation, and matrix degradation induced by PSTPIP1-R405C. Our results uncover a novel role for PSTPIP1 and WASP in orchestrating different types of actin-based protrusions. Our findings implicate the cytoskeletal regulatory functions of PSTPIP1 in the pathogenesis of pyoderma gangrenosum and suggest that the cytoskeleton is a rational target for therapeutic intervention in autoinflammatory disease.
•PSTPIP1 regulates the transition from podosomes to filopodia in macrophages by modulating WASP activity.•The novel PSTPIP1-R405C mutant induces filopodia formation, increases matrix degradation, and is associated with severe pyoderma gangrenosum.
To examine the antivascular and antitumor activity of the vascular targeting agent ZD6126 in combination with radiation in lung and head-and-neck (H and N) cancer models. The overall hypothesis was ...that simultaneous targeting of tumor cells (radiation) and tumor vasculature (ZD6126) might enhance tumor cell killing.
A series of in vitro studies using human umbilical vein endothelial cells (HUVEC) and in vivo studies in athymic mice bearing human lung (H226) and H and N (squamous cell carcinoma SCC1, SCC6) tumor xenografts treated with ZD6126 and/or radiation were performed.
ZD6126 inhibited the capillary-like network formation in HUVEC. Treatment of HUVEC with ZD6126 resulted in cell cycle arrest in G2/M, with decrease of cells in S phase and proliferation inhibition in a dose-dependent manner. ZD6126 augmented the cell-killing effect of radiation and radiation-induced apoptosis in HUVEC. The combination of ZD6126 and radiation further decreased tumor vascularization in an in vivo Matrigel angiogenesis assay. In tumor xenografts, ZD6126 enhanced the antitumor activity of radiation, resulting in tumor growth delay.
These preclinical studies suggest that ZD6126 can augment the radiation response of proliferating endothelial H and N and lung cancer cells. These results complement recent reports suggesting the potential value of combining radiation with vascular targeting/antiangiogenic agents.
To determine the incidence of congenital hypothyroidism in preterm infants and to identify associated risk factors.
A population-based cohort study was performed in preterm infants born at <32 weeks ...of gestational age between 2012 and 2016 in Wisconsin. Newborn screening (NBS) results and demographic data were obtained from the Wisconsin State Laboratory of Hygiene. Congenital hypothyroidism was subdivided to early TSH elevation (eTSH) and delayed TSH elevation (dTSH). Multivariate logistic regression analyses were performed to identify demographic factors associated with dTSH.
A total of 3137 preterm infants born at 22-31 weeks of gestational age were included in the study. Mean gestational age was 28.4 ± 2.4 weeks and mean birth weight was 1191 ± 399 g. Forty-nine infants were diagnosed with congenital hypothyroidism. The overall incidence of congenital hypothyroidism was 1.56%, including a 0.13% incidence of eTSH and a 1.43% incidence of dTSH. Birth weight <1000 g, multiple gestation, and initial TSH level were identified as independent predictors for dTSH.
Targeted serial NBS in Wisconsin led to a higher rate of diagnosis of congenital hypothyroidism in preterm infants than has been reported previously. The majority (92%) of congenital hypothyroidism cases were diagnosed with dTSH. Birth weight <1000 g, multiple gestation, and elevated initial TSH level were associated with increased risk for development of dTSH. We recommend obtaining targeted serial NBS in preterm infants (<32 weeks of gestational age) to improve the detection of congenital hypothyroidism.
Introduction
In the inherently noisy real world, we can rarely have full certainty about what we have just seen or heard. Thus, making a perceptual decision on sensory information, and simultaneously ...tracking our varying levels of certainty in these decisions (i.e., metacognitive abilities) are crucial components of everyday life.
Hallucinations, such as confidently reporting a human voice or face when none was present, are a hallmark of psychotic disorders but also occur among the normal population. Particularly in patients with psychotic disorders, these misperceptions are linked to confident beliefs in their actual existence. However, whether patients’ confidence is only increased during such erroneous perceptions and whether perceptual and metacognitive decisions arise from supramodal mechanisms across sensory modalities remains unknown.
Objectives
In the laboratory, we tested perceptual and metacognitive decisions under varying levels of sensory certainty in healthy adults and patients with psychotic disorders admitted to a psychiatry ward (N
con
=32, N
pat
=12; age = 19-49; F2x.x diagnoses).
Methods
Specifically, participants had to detect human voices or faces against briefly presented noisy backdrops and subsequently rate their confidence in the accuracy of their perceptual decision (Fig 1A,B,C). We further hypothesised that probabilistic cues prior to blocks of trials can bias participants’ choices and hallucination probability (i.e., confident false alarms).
Results
Patients exhibited higher perceptual sensitivity in the auditory than the visual task, alongside a generally stronger decision bias towards fewer ‘voice/face’ choices (Fig 2A,B). This bias was more pronounced in the visual domain. Decision performance was overall higher on the auditory task but lower for patients (predicted minimum > 55%; Fig 2C). Strong correlations between auditory accuracy and PANSS hallucination scores of patients and LSHS scores of healthy participants suggest an effect of these hallucinatory experiences on accurate perception.
Metacognitive abilities were reduced in patients across both modalities: They exhibited general overconfidence, which was stronger for incorrect trials (Fig 3A). Patients’ confidence ratings were inversely related to the probability of choosing ‘voice/face’. Combining both perceptual and confidence decisions, patients showed higher hallucinations probability in the auditory task, particularly in more difficult trials (i.e., with less informative sensory evidence; Fig 3B).
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Conclusions
In sum, patients with psychotic disorders exhibit increased decision bias accompanied by increased confidence, and thus a reduced fidelity in their metacognitive abilities. The modality differences are in line with phenomenology and reported hallucination rates. These results suggest stronger priors in psychotic disorders resulting in worse perceptual acuity and assessment of this perception.
Disclosure of Interest
None Declared
Prostatic acid phosphatase (PAP) is a prostate tumor antigen. We have previously demonstrated that a DNA vaccine encoding PAP can elicit antigen-specific CD8+ T cells in rodents. We report here the ...results of a phase I/IIa trial conducted with a DNA vaccine encoding human PAP in patients with stage D0 prostate cancer.
Twenty-two patients were treated in a dose-escalation trial with 100 microg, 500 microg, or 1,500 microg plasmid DNA, coadministered intradermally with 200 microg granulocyte-macrophage colony-stimulating factor as a vaccine adjuvant, six times at 14-day intervals. All patients were observed for 1 year after treatment.
No significant adverse events were observed. Three (14%) of 22 patients developed PAP-specific IFN gamma-secreting CD8+ T-cells immediately after the treatment course, as determined by enzyme-linked immunospot. Nine (41%) of 22 patients developed PAP-specific CD4+ and/or CD8+ T-cell proliferation. Antibody responses to PAP were not detected. Overall, the prostate-specific antigen (PSA) doubling time was observed to increase from a median 6.5 months pretreatment to 8.5 months on-treatment (P = .033), and 9.3 months in the 1-year post-treatment period (P = .054).
The demonstration that a DNA vaccine encoding PAP is safe, elicits an antigen-specific T-cell response, and may be associated with an increased PSA doubling time suggests that a multi-institutional phase II trial designed to evaluate clinical efficacy is warranted.
Chimpanzees are among the closest living relatives to humans and, as such, provide a crucial comparative model for investigating primate brain evolution. In recent years, human brain mapping has ...strongly benefited from enhanced computational models and image processing pipelines that could also improve data analyses in animals by using species-specific templates. In this study, we use structural MRI data from the National Chimpanzee Brain Resource (NCBR) to develop the chimpanzee brain reference template Juna.Chimp for spatial registration and the macro-anatomical brain parcellation Davi130 for standardized whole-brain analysis. Additionally, we introduce a ready-to-use image processing pipeline built upon the CAT12 toolbox in SPM12, implementing a standard human image preprocessing framework in chimpanzees. Applying this approach to data from 194 subjects, we find strong evidence for human-like age-related gray matter atrophy in multiple regions of the chimpanzee brain, as well as, a general rightward asymmetry in brain regions.
Many newborn screening (NBS) programs now perform repeat or serial NBS to detect congenital hypothyroidism. There is wide variation in thyroid-stimulating hormone (TSH) cutoffs used by NBS programs. ...Data on TSH reference ranges in preterm infants at increasing postnatal age are limited. Our study objective was to determine TSH reference ranges for preterm infants born at <32 weeks' gestation.
We analyzed serial TSH levels on NBS performed on infants born between 22 and 31 weeks' gestation from 2012 to 2016 in Wisconsin. The study cohort was divided into 2 groups (22-27 and 28-31 weeks), and TSH percentiles were defined from birth to the term equivalent gestational age.
The study cohort consisted of 1022 and 2115 infants born at 22 to 27 and 28 to 31 weeks' gestation, respectively. The 95th percentile TSH level for the group born at 22 to 27 weeks' gestation gradually decreased and reached a nadir at ∼10 to 11 weeks. In contrast, for the group born at 28 to 31 weeks' gestation, the 95th percentile TSH level reached a nadir at ∼5 to 6 weeks. At 3 to 4 weeks after birth, the 95th percentile TSH level ranged from 11 to 11.8 μIU/mL for the group born at 22 to 27 weeks' gestation and ranged from 8.2 to 9 μIU/mL for the group born at 28 to 31 weeks' gestation.
Using a statewide cohort of preterm infants, we constructed TSH reference charts from birth to the term equivalent gestation for preterm infants born at <32 weeks' gestation. Use of a single cutoff for all preterm infants might lead to misdiagnosis. The differences in TSH levels according to gestational-age categories might explain the increased frequency in congenital hypothyroidism diagnoses among preterm infants. These data are useful for defining age-adjusted NBS TSH cutoffs for preterm infants.
Historically, the human frontal pole (FP) has been considered as a single architectonic area. Brodmann's area 10 is located in the frontal lobe with known contributions in the execution of various ...higher order cognitive processes. However, recent cytoarchitectural studies of the FP in humans have shown that this portion of cortex contains two distinct cytoarchitectonic regions. Since architectonic differences are accompanied by differential connectivity and functions, the frontal pole qualifies as a candidate region for exploratory parcellation into functionally discrete sub-regions. We investigated whether this functional heterogeneity is reflected in distinct segregations within cytoarchitectonically defined FP-areas using meta-analytic co-activation based parcellation (CBP). The CBP method examined the co-activation patterns of all voxels within the FP as reported in functional neuroimaging studies archived in the BrainMap database. Voxels within the FP were subsequently clustered into sub-regions based on the similarity of their respective meta-analytically derived co-activation maps. Performing this CBP analysis on the FP via k-means clustering produced a distinct 3-cluster parcellation for each hemisphere corresponding to previously identified cytoarchitectural differences. Post-hoc functional characterization of clusters via BrainMap metadata revealed that lateral regions of the FP mapped to memory and emotion domains, while the dorso- and ventromedial clusters were associated broadly with emotion and social cognition processes. Furthermore, the dorsomedial regions contain an emphasis on theory of mind and affective related paradigms whereas ventromedial regions couple with reward tasks. Results from this study support previous segregations of the FP and provide meta-analytic contributions to the ongoing discussion of elucidating functional architecture within human FP.
•Co-activation based parcellation resulted with a 3-cluster solution.•Frontopolar cortices yielded a lateral, ventromedial, and dorsomedial cluster.•Unique functional decoding of each cluster was identified via BrainMap metadata.
Background. We estimated the vaccine effectiveness (VE) of tetanus-diphtheria-acellular pertussis vaccine (Tdap) for preventing pertussis among adolescents during a statewide outbreak of pertussis in ...Wisconsin during 2012. Methods. We used the population-based Wisconsin Immunization Registry (WIR) to construct a cohort of Wisconsin residents born during 1998-2000 and collect Tdap vaccination histories. Reports of laboratory-confirmed pertussis with onset during 2012 were matched to WIR clients. Incidence rate ratios (IRRs) of pertussis and Tdap VE estimates (1 - IRR)*100%, by year of Tdap vaccine receipt and brand (Boostrix/Adacel), were estimated using Poisson regression. Results. Tdap VE decreased with increasing time since receipt, with VEs of 75.3% (95% confidence interval CI, 55.2%-86.5%) for receipt during 2012,68.2% (95% CI, 60.9%-74.1%) for receipt during 2011, 34.5% (95% CI, 19.9%-46.4%) for receipt during 2010, and 11.9% (95% CI, -11.1% to 30.1%) for receipt during 2009/2008; point estimates were higher among Boostrix recipients than among Adacel recipients. Among Tdap recipients, increasing time since receipt was associated with increased risk, and receipt of Boostrix (vs Adacel) was associated with decreased risk of pertussis (adjusted IRR, 0.62 95% CI, .52-74). Conclusions. Our results demonstrate waning immunity following vaccination with either Tdap brand. Boostrix was more effective than Adacel in preventing pertussis in our cohort, but these findings may not be generalizable to adolescent cohorts that received different diphtheria-tetanus-acellular pertussis vaccines (DTaP) during childhood and should be further examined in studies that include childhood DTaP history.
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