Abundant pleiotropy across neuroimaging modalities identified through a multivariate genome-wide association study.

Genetic pleiotropy is abundant across spatially distributed brain characteristics derived from one neuroimaging modality (e.g. structural, functional or diffusion magnetic resonance imaging [MRI]). A better understanding of pleiotropy across modalities could inform us on the integration of brain function, micro- and macrostructure. Here we show extensive genetic overlap across neuroimaging modalities at a locus and gene level in the UK Biobank (N = 34,029) and ABCD Study (N = 8607). When jointly analysing phenotypes derived from structural, functional and diffusion MRI in a genome-wide association study (GWAS) with the Multivariate Omnibus Statistical Test (MOSTest), we boost the discovery of loci and genes beyond previously identified effects for each modality individually. Cross-modality genes are involved in fundamental biological processes and predominantly expressed during prenatal brain development. We additionally boost prediction of psychiatric disorders by conditioning independent GWAS on our multimodal multivariate GWAS. These findings shed light on the shared genetic mechanisms underlying variation in brain morphology, functional connectivity, and tissue composition.

Hypothalamic Pilomyxoid Astrocytoma in a Child with Lipodystrophy.

Pilomyxoid astrocytoma is a rare form of pediatric CNS malignancy first classified in 2007 by the World Health Organization. The tumors are similar to pilocytic astrocytomas, sharing both some imaging and histologic traits. However, pilomyxoid astrocytomas portend a more ominous prognosis, with more aggressive local tendencies and a greater proclivity for leptomeningeal spread. Although tissue sampling is ultimately required to differentiate pilocytic astrocytomas and pilomyxoid astrocytomas, some imaging features can be used to suggest a pilomyxoid astrocytoma, including homogeneous enhancement, leptomeningeal seeding, and lack of intratumoral cysts. In this article, a case of a hypothalamic pilomyxoid astrocytoma is described, in which the presenting disorder was profound generalized lipodystrophy. The aforementioned imaging characteristics of pilomyxoid astrocytomas are reviewed, as are the pathologic features of such tumors, including their angiocentric cellular arrangement and myxoid background.

The effect of compliance with a perioperative goal-directed therapy protocol on outcomes after high-risk surgery: a before-after study.

Perioperative goal-directed therapy is considered to improve patient outcomes after high-risk surgery. The association of compliance with perioperative goal-directed therapy protocols and postoperative outcomes is unclear. The purpose of this study is to determine the effect of protocol compliance on postoperative outcomes following high-risk surgery, after implementation of a perioperative goal-directed therapy protocol. Through a before-after study design, patients undergoing elective high-risk surgery before (before-group) and after implementation of a perioperative goal-directed therapy protocol (after-group) were included. Perioperative goal-directed therapy in the after-group consisted of optimized stroke volume variation or stroke volume index and optimized cardiac index. Additionally, the association of protocol compliance with postoperative complications when using perioperative goal-directed therapy was assessed. High protocol compliance was defined as ≥ 85% of the procedure time spent within the individual targets. The difference in complications during the first 30 postoperative days before and after implementation of the protocol was assessed. In the before-group, 214 patients were included and 193 patients in the after-group. The number of complications was higher in the before-group compared to the after-group (n = 414 vs. 282; p = 0.031). In the after-group, patients with high protocol compliance for stroke volume variation or stroke volume index had less complications compared to patients with low protocol compliance for stroke volume variation or stroke volume index (n = 187 vs. 90; p = 0.01). Protocol compliance by the attending clinicians is essential and should be monitored to facilitate an improvement in postoperative outcomes desired by the implementation of perioperative goal-directed therapy protocols.

Cerebellar volume and cerebellocerebral structural covariance in schizophrenia: a multisite mega-analysis of 983 patients and 1349 healthy controls.

Although cerebellar involvement across a wide range of cognitive and neuropsychiatric phenotypes is increasingly being recognized, previous large-scale studies in schizophrenia (SZ) have primarily focused on supratentorial structures. Hence, the across-sample reproducibility, regional distribution, associations with cerebrocortical morphology and effect sizes of cerebellar relative to cerebral morphological differences in SZ are unknown. We addressed these questions in 983 patients with SZ spectrum disorders and 1349 healthy controls (HCs) from 14 international samples, using state-of-the-art image analysis pipelines optimized for both the cerebellum and the cerebrum. Results showed that total cerebellar grey matter volume was robustly reduced in SZ relative to HCs (Cohens's d=-0.35), with the strongest effects in cerebellar regions showing functional connectivity with frontoparietal cortices (d=-0.40). Effect sizes for cerebellar volumes were similar to the most consistently reported cerebral structural changes in SZ (e.g., hippocampus volume and frontotemporal cortical thickness), and were highly consistent across samples. Within groups, we further observed positive correlations between cerebellar volume and cerebral cortical thickness in frontotemporal regions (i.e., overlapping with areas that also showed reductions in SZ). This cerebellocerebral structural covariance was strongest in SZ, suggesting common underlying disease processes jointly affecting the cerebellum and the cerebrum. Finally, cerebellar volume reduction in SZ was highly consistent across the included age span (16-66 years) and present already in the youngest patients, a finding that is more consistent with neurodevelopmental than neurodegenerative etiology. Taken together, these novel findings establish the cerebellum as a key node in the distributed brain networks underlying SZ.

Genetically Defined Oligodendroglioma Is Characterized by Indistinct Tumor Borders at MRI.

BACKGROUND AND PURPOSE: In 2016, the World Health Organization revised the brain tumor classification, making IDH mutation and 1p/19q codeletion the defining features of oligodendroglioma. To determine whether imaging characteristics previously associated with oligodendroglial tumors are still applicable, we evaluated the MR imaging features of genetically defined oligodendrogliomas. MATERIALS AND METHODS: One hundred forty-eight adult patients with untreated World Health Organization grade II and III infiltrating gliomas with histologic oligodendroglial morphology, known 1p/19q status, and at least 1 preoperative MR imaging were retrospectively identified. The association of 1p/19q codeletion with tumor imaging characteristics and ADC values was evaluated. RESULTS: Ninety of 148 (61%) patients had 1p/19q codeleted tumors, corresponding to genetically defined oligodendroglioma, and 58/148 (39%) did not show 1p/19q codeletion, corresponding to astrocytic tumors. Eighty-three of 90 (92%) genetically defined oligodendrogliomas had noncircumscribed borders, compared with 26/58 (45%) non-1p/19q codeleted tumors with at least partial histologic oligodendroglial morphology (P < .0001). Eighty-nine of 90 (99%) oligodendrogliomas were heterogeneous on T1- and/or T2-weighted imaging. In patients with available ADC values, a lower mean ADC value predicted 1p/19q codeletion (P = .0005). CONCLUSIONS: Imaging characteristics of World Health Organization 2016 genetically defined oligodendrogliomas differ from the previously considered characteristics of morphologically defined oligodendrogliomas. We found that genetically defined oligodendrogliomas were commonly poorly circumscribed and were almost always heterogeneous in signal intensity.

Childhood trauma is associated with increased brain responses to emotionally negative as compared with positive faces in patients with psychotic disorders.

BACKGROUND: Childhood trauma increases risk of a range of mental disorders including psychosis. Whereas the mechanisms are unclear, previous evidence has implicated atypical processing of emotions among the core cognitive models, in particular suggesting altered attentional allocation towards negative stimuli and increased negativity bias. Here, we tested the association between childhood trauma and brain activation during emotional face processing in patients diagnosed with psychosis continuum disorders. In particular, we tested if childhood trauma was associated with the differentiation in brain responses between negative and positive face stimuli. We also tested if trauma was associated with emotional ratings of negative and positive faces. METHOD: We included 101 patients with a Diagnostic and Statistical Manual of Mental Disorders (DSM) schizophrenia spectrum or bipolar spectrum diagnosis. History of childhood trauma was obtained using the Childhood Trauma Questionnaire. Brain activation was measured with functional magnetic resonance imaging during presentation of faces with negative or positive emotional expressions. After the scanner session, patients performed emotional ratings of the same faces. RESULTS: Higher levels of total childhood trauma were associated with stronger differentiation in brain responses to negative compared with positive faces in clusters comprising the right angular gyrus, supramarginal gyrus, middle temporal gyrus and the lateral occipital cortex (Cohen's d = 0.72-0.77). In patients with schizophrenia, childhood trauma was associated with reporting negative faces as more negative, and positive faces as less positive (Cohen's d > 0.8). CONCLUSIONS: Along with the observed negativity bias in the assessment of emotional valence of faces, our data suggest stronger differentiation in brain responses between negative and positive faces with higher levels of trauma.

Balance between IL-3 and type Iinterferons and their interrelationship with FasL dictates lifespan and effector functions of human basophils.

BACKGROUND: In contrast to eosinophils and neutrophils, the regulation of the lifespan of human basophils is poorly defined, with the exception of the potent anti-apoptotic effect of IL-3 that also promotes pro-inflammatory effector functions and phenotypic changes. Type I IFNs (IFN-α, IFN-ß), which are well known for their anti-viral activities, have the capacity to inhibit allergic inflammation. OBJECTIVE: To elucidate whether type I IFNs have the potential to abrogate the lifespan and/or effector functions of human basophils. METHODS: We cultured human basophils, and for comparison, eosinophils and neutrophils, with IL-3, interferons, FasL and TRAIL, alone or in combination, and studied cell survival, effector functions and signalling pathways involved. RESULTS: Despite an identical pattern of early signalling in basophils, eosinophils and neutrophils in response to different types of interferons, only basophils displayed enhanced apoptosis after type I IFN treatment. IFN-γ prolonged survival of eosinophils but did not affect the lifespan of basophils. IFN-α-mediated apoptosis required STAT1-STAT2 heterodimers and the contribution of constitutive p38 MAPK activity. Whereas the death ligands FasL and TRAIL-induced apoptosis in basophils per se, IFN-α-mediated apoptosis did neither involve autocrine TRAIL signalling nor did it sensitize basophils to FasL-induced apoptosis. However, IFN-α and FasL displayed an additive effect in killing basophils. Interestingly, IL-3, which protected basophils from IFN-α-, TRAIL- or FasL-mediated apoptosis, did not completely block the additive effect of combined IFN-α and FasL treatment. Moreover, we demonstrate that IFN-α suppressed IL-3-induced release of IL-8 and IL-13. In contrast to IFN-α-mediated apoptosis, these inhibitory effects of IFN-α were not dependent on p38 MAPK signalling. CONCLUSIONS AND CLINICAL RELEVANCE: Our study defines the unique and granulocyte-type-specific inhibitory and pro-apoptotic function of type I IFNs and their cooperation with death ligands in human blood basophils, which may be relevant for the anti-allergic properties of type I IFNs.

Survival control of malignant lymphocytes by anti-apoptotic MCL-1.

Programmed apoptotic cell death is critical to maintain tissue homeostasis and cellular integrity in the lymphatic system. Accordingly, the evasion of apoptosis is a critical milestone for the transformation of lymphocytes on their way to becoming overt lymphomas. The anti-apoptotic BCL-2 family proteins are pivotal regulators of the mitochondrial apoptotic pathway and genetic aberrations in these genes are associated with lymphomagenesis and chemotherapeutic resistance. Pharmacological targeting of BCL-2 is highly effective in certain indolent B-cell lymphomas; however, recent evidence highlights a critical role for the BCL-2 family member MCL-1 in several lymphoma subtypes. MCL-1 is recurrently highly expressed in various kinds of cancer including non-Hodgkin's lymphoma of B- and T-cell origin. Moreover, both indolent and aggressive forms of lymphoma require MCL-1 for lymphomagenesis and for their continued survival. This review summarizes the role of MCL-1 in B- and T-cell lymphoma and discusses its potential as a therapeutic target.

Fluoroscopically guided transforaminal epidural steroid injections at a quaternary-care teaching institution: effect of trainee involvement and patient body mass index on fluoroscopy time and patient dose.

AIM: To investigate whether there are differences in fluoroscopy time and patient dose for fluoroscopically guided lumbar transforaminal epidural steroid injections (TFESIs) performed by staff radiologists versus with trainees and to evaluate the effect of patient body mass index (BMI) on fluoroscopy time and patient dose, including their interactions with other variables. MATERIALS AND METHODS: Single-level lumbar TFESIs (n=1844) between 1 January 2011 and 31 December 2013 were reviewed. Fluoroscopy time, reference point air kerma (Ka,r), and kerma area product (KAP) were recorded. BMI and trainee involvement were examined as predictors of fluoroscopy time, Ka,r, and KAP in models adjusted for age and gender in multivariable linear models. Stratified models of BMI groups by trainee presence were performed. RESULTS: Increased age was the only significant predictor of increased fluoroscopy time (p<0.0001). Ka,r and KAP were significantly higher in patients with a higher BMI (p<0.0001 and p=0.0009). When stratified by BMI, longer fluoroscopy time predicted increased Ka,r and KAP in all groups (p<0.0001). Trainee involvement was not a statistically significant predictor of fluoroscopy time or Ka,r in any BMI category. KAP was lower with trainees in the overweight group (p=0.0009) and higher in male patients for all BMI categories (p<0.02). CONCLUSION: Trainee involvement did not result in increased fluoroscopy time or patient dose. BMI did not affect fluoroscopy time; however, overweight and obese patients received significantly higher Ka,r and KAP. Male patients received a higher KAP in all BMI categories. Limiting fluoroscopy time and good collimation practices should be reinforced in these patients.

Reduced heart rate variability in schizophrenia and bipolar disorder compared to healthy controls.

OBJECTIVE: Despite current diagnostic systems distinguishing schizophrenia (SZ) and bipolar disorder (BD) as separate diseases, emerging evidence suggests they share a number of clinical and epidemiological features, such as increased cardiovascular disease (CVD) risk. It is not well understood if poor cardiac autonomic nervous system regulation, which can be indexed non-invasively by the calculation of heart rate variability (HRV), contributes to these common CVD risk factors in both diseases. METHOD: We calculated HRV in 47 patients with SZ, 33 patients with BD and 212 healthy controls. Measures of symptom severity were also collected from the patient groups. RESULTS: Heart rate variability was significantly reduced in both these disorders in comparison with the healthy participants; however, there were no HRV differences between disorders. Importantly, these reductions were independent of the medication, age or body mass index effects. There was also preliminary evidence that patients with reduced HRV had increased overall and negative psychosis symptom severity regardless of SZ or BD diagnosis. CONCLUSION: We suggest that HRV may provide a possible biomarker of CVD risk and symptom severity in severe mental illness. Thus, our results highlight the importance of cardiometabolic screening across SZ and bipolar spectrum disorders.

Impact of Software Modeling on the Accuracy of Perfusion MRI in Glioma.

BACKGROUND AND PURPOSE: Relative cerebral blood volume, as measured by T2*-weighted dynamic susceptibility-weighted contrast-enhanced MRI, represents the most robust and widely used perfusion MR imaging metric in neuro-oncology. Our aim was to determine whether differences in modeling implementation will impact the correction of leakage effects (from blood-brain barrier disruption) and the accuracy of relative CBV calculations as measured on T2*-weighted dynamic susceptibility-weighted contrast-enhanced MR imaging at 3T field strength. MATERIALS AND METHODS: This study included 52 patients with glioma undergoing DSC MR imaging. Thirty-six patients underwent both non-preload dose- and preload dose-corrected DSC acquisitions, with 16 patients undergoing preload dose-corrected acquisitions only. For each acquisition, we generated 2 sets of relative CBV metrics by using 2 separate, widely published, FDA-approved commercial software packages: IB Neuro and nordicICE. We calculated 4 relative CBV metrics within tumor volumes: mean relative CBV, mode relative CBV, percentage of voxels with relative CBV > 1.75, and percentage of voxels with relative CBV > 1.0 (fractional tumor burden). We determined Pearson (r) and Spearman (ρ) correlations between non-preload dose- and preload dose-corrected metrics. In a subset of patients with recurrent glioblastoma (n = 25), we determined receiver operating characteristic area under the curve for fractional tumor burden accuracy to predict the tissue diagnosis of tumor recurrence versus posttreatment effect. We also determined correlations between rCBV and microvessel area from stereotactic biopsies (n = 29) in 12 patients. RESULTS: With IB Neuro, relative CBV metrics correlated highly between non-preload dose- and preload dose-corrected conditions for fractional tumor burden (r = 0.96, ρ = 0.94), percentage > 1.75 (r = 0.93, ρ = 0.91), mean (r = 0.87, ρ = 0.86), and mode (r = 0.78, ρ = 0.76). These correlations dropped substantially with nordicICE. With fractional tumor burden, IB Neuro was more accurate than nordicICE in diagnosing tumor versus posttreatment effect (area under the curve = 0.85 versus 0.67) (P < .01). The highest relative CBV-microvessel area correlations required preload dose and IB Neuro (r = 0.64, ρ = 0.58, P = .001). CONCLUSIONS: Different implementations of perfusion MR imaging software modeling can impact the accuracy of leakage correction, relative CBV calculation, and correlations with histologic benchmarks.

Basophils exhibit antibacterial activity through extracellular trap formation.

Basophils are primarily associated with immunomodulatory functions in allergic diseases and parasitic infections. Recently, it has been demonstrated that both activated human and mouse basophils can form extracellular DNA traps (BETs) containing mitochondrial DNA and granule proteins. In this report, we provide evidence that, in spite of an apparent lack of phagocytic activity, basophils can kill bacteria through BET formation.

ASFNR recommendations for clinical performance of MR dynamic susceptibility contrast perfusion imaging of the brain.

MR perfusion imaging is becoming an increasingly common means of evaluating a variety of cerebral pathologies, including tumors and ischemia. In particular, there has been great interest in the use of MR perfusion imaging for both assessing brain tumor grade and for monitoring for tumor recurrence in previously treated patients. Of the various techniques devised for evaluating cerebral perfusion imaging, the dynamic susceptibility contrast method has been employed most widely among clinical MR imaging practitioners. However, when implementing DSC MR perfusion imaging in a contemporary radiology practice, a neuroradiologist is confronted with a large number of decisions. These include choices surrounding appropriate patient selection, scan-acquisition parameters, data-postprocessing methods, image interpretation, and reporting. Throughout the imaging literature, there is conflicting advice on these issues. In an effort to provide guidance to neuroradiologists struggling to implement DSC perfusion imaging in their MR imaging practice, the Clinical Practice Committee of the American Society of Functional Neuroradiology has provided the following recommendations. This guidance is based on review of the literature coupled with the practice experience of the authors. While the ASFNR acknowledges that alternate means of carrying out DSC perfusion imaging may yield clinically acceptable results, the following recommendations should provide a framework for achieving routine success in this complicated-but-rewarding aspect of neuroradiology MR imaging practice.

Correlation of the Patient Reported Outcomes Measurement Information System with legacy outcomes measures in assessment of response to lumbar transforaminal epidural steroid injections.

BACKGROUND AND PURPOSE: The Patient Reported Outcomes Measurement Information System is a newly developed outcomes measure promulgated by the National Institutes of Health. This study compares changes in pain and physical function-related measures of this system with changes on the Numeric Rating Pain Scale, Roland Morris Disability Index, and the European Quality of Life scale 5D questionnaire in patients undergoing transformational epidural steroid injections for radicular pain. MATERIALS AND METHODS: One hundred ninety-nine patients undergoing transforaminal epidural steroid injections for radicular pain were enrolled in the study. Before the procedure, they rated the intensity of their pain by using the 0-10 Numeric Rating Pain Scale, Roland Morris Disability Index, and European Quality of Life scale 5D questionnaire. Patients completed the Patient Reported Outcomes Measurement Information System Physical Function, Pain Behavior, and Pain Interference short forms before transforaminal epidural steroid injections and at 3 and 6 months. Seventy and 43 subjects replied at 3- and 6-month follow-up. Spearman rank correlations were used to assess the correlation between the instruments. The minimally important differences were calculated for each measurement tool as an indicator of meaningful change. RESULTS: All instruments were responsive in detecting changes at 3- and 6-month follow-up (P < .0001). There was significant correlation between changes in Patient Reported Outcomes Measurement Information System scores and legacy questionnaires from baseline to 3 months (P < .05). There were, however, no significant correlations in changes from 3 to 6 months with any of the instruments. CONCLUSIONS: The studied Patient Reported Outcomes Measurement Information System domains offered responsive and correlative psychometric properties compared with legacy instruments in a population of patients undergoing transforaminal epidural steroid injections for radicular pain.

A multiarm randomized field trial evaluating strategies for udder health improvement in Swiss dairy herds.

The aims of this study were to quantify the effectiveness of specialist advice about udder health in Swiss dairy herds and to compare 3 different udder health improvement strategies against a negative control group. In 2010, 100 Swiss dairy herds with a high (between 200,000 and 300,000 cells/mL) yield-corrected bulk milk somatic cell count (YCBMSCC) were recruited for a 1-yr multiarm randomized field trial. The herds were visited between September and December 2011 to evaluate udder health-management practices and then randomly allocated into 1 of 4 study arms containing 25 herds each. The negative control study arm received neither recommendations for improving udder health nor any active support. The remaining 75 farmers received a herd-specific report with recommendations to improve udder health management. The positive control study arm received no further active support during 2012. The veterinarian study arm received additional support in the form of monthly visits by their herd veterinarian. Finally, the study group study arm received support in the form of bimonthly study group meetings where different topics concerning udder health were discussed. One year later, implementation of recommendations and changes in udder health were assessed. Of the recommendations given, 44.3% were completely implemented, 23.1% partially, and 32.6% were not implemented. No differences in implementation of recommendations were noted between the 3 study arms. At study enrollment, farmers were asked for the study arm of their preference but were subsequently randomly assigned to 1 of the 4 study arms. Farmers that were assigned to the study arm of their preference implemented more recommendations than farmers assigned to a study arm not of their preference. No decrease in the within-herd prevalence of cows that had a high (≥200,000 cells/mL) composite somatic cell count was observed in herds that had a YCBMSCC ≥200,000 cells/mL at the start of intervention. However, the 3 study arms with intervention (positive control, the veterinarian, and the study groups) prevented an increase in the within-herd prevalence of cows that had a high somatic cell count in herds with a low YCBMSCC at the start of the intervention compared with the negative control study arm. In the year after sending the report, herds assigned to the study group study arm had a reduced incidence rate of treated mastitis cases in comparison with the year before sending the report.

Intramedullary spinal cord metastases: prognostic value of MRI and clinical features from a 13-year institutional case series.

BACKGROUND AND PURPOSE: In patients with intramedullary spinal cord metastases, the impact of MR imaging and clinical characteristics on survival has not been elucidated. Our aim was to identify MR imaging and clinical features with prognostic value among patients with intramedullary spinal cord metastases from a large retrospective series. MATERIALS AND METHODS: The relevant MR imaging examination and baseline clinical data for each patient from a consecutive group of patients with intramedullary spinal cord metastases had previously been reviewed by 2 neuroradiologists. Additional relevant clinical data were extracted. The influence of clinical and imaging characteristics on survival was assessed by Kaplan-Meier survival curves and log-rank tests for categoric characteristics. RESULTS: Forty-nine patients had 70 intramedullary spinal cord metastases; 10 (20%) of these patients had multiple metastases. From the date of diagnosis, median survival for all patients was 104 days (95% CI, 48-156 days). One clinical feature was associated with decreased median survival: lung or breast primary malignancy (57 days) compared with all other malignancy types (308 days; P < .001). Three MR imaging features were associated with decreased median survival: multiple intramedullary spinal cord metastases (53 versus 121 days, P = .022), greater longitudinal extent of cord T2 hyperintensity (if ≥3 segments, 111 days; if ≤2, 184 days; P = .018), and ancillary visualization of the primary tumor and/or non-CNS metastases (96 versus 316 days, P = .012). CONCLUSIONS: Spinal cord edema spanning multiple segments, the presence of multifocal intramedullary spinal cord metastases, and ancillary evidence for non-CNS metastases and/or the primary tumor are MR imaging features associated with decreased survival and should be specifically sought. Patients with either a lung or breast primary malignancy are expected to have decreased survival compared with other primary tumor types.

The generation of neutrophils in the bone marrow is controlled by autophagy.

Autophagy has been demonstrated to have an essential function in several cellular hematopoietic differentiation processes, for example, the differentiation of reticulocytes. To investigate the role of autophagy in neutrophil granulopoiesis, we studied neutrophils lacking autophagy-related (Atg) 5, a gene encoding a protein essential for autophagosome formation. Using Cre-recombinase mediated gene deletion, Atg5-deficient neutrophils showed no evidence of abnormalities in morphology, granule protein content, apoptosis regulation, migration, or effector functions. In such mice, however, we observed an increased proliferation rate in the neutrophil precursor cells of the bone marrow as well as an accelerated process of neutrophil differentiation, resulting in an accumulation of mature neutrophils in the bone marrow, blood, spleen, and lymph nodes. To directly study the role of autophagy in neutrophils, we employed an in vitro model of differentiating neutrophils that allowed modulating the levels of ATG5 expression, or, alternatively, intervening pharmacologically with autophagy-regulating drugs. We could show that autophagic activity correlated inversely with the rate of neutrophil differentiation. Moreover, pharmacological inhibition of p38 MAPK or mTORC1 induced autophagy in neutrophilic precursor cells and blocked their differentiation, suggesting that autophagy is negatively controlled by the p38 MAPK-mTORC1 signaling pathway. On the other hand, we obtained no evidence for an involvement of the PI3K-AKT or ERK1/2 signaling pathways in the regulation of neutrophil differentiation. Taken together, these findings show that, in contrast to erythropoiesis, autophagy is not essential for neutrophil granulopoiesis, having instead a negative impact on the generation of neutrophils. Thus, autophagy and differentiation exhibit a reciprocal regulation by the p38-mTORC1 axis.

Distribution of internal carotid artery plaque locations among patients with central retinal artery occlusion in the Eagle study population.

PURPOSE: Arterial emboli in the internal carotid artery (ICA) mainly cause cerebral ischemia; only 10 % of emboli reach the retinal arteries. Computational blood flow studies suggest that plaques situated in the ICA siphon may be a source of embolism to the ophthalmic artery (OA). To validate these calculated probabilities in patients with central retinal artery occlusion (CRAO), we reanalyzed digital subtraction angiography (DSA) images from the Multicenter Study of the European Assessment Group for Lysis in the Eye (EAGLE) study, a multicenter randomized study in patients with nonarteritic CRAO. METHODS: A reevaluation of 34 DSA studies was done from the interventional arm of the EAGLE study with regards to distribution of arterial plaques at specific ICA siphon locations and ICA stenosis. A comparison was made of plaque distribution to calculated probabilities for emboli reaching the OA from a computational fluid dynamics (CFD) model of a patient-specific ICA siphon. RESULTS: Most of the ICA plaques near the OA's origin were located in the cavernous ICA portion (31.3%). Of these, 12.5 % had plaques in the curvature opposite the OA origin, a location carrying the highest risk for embolization into the OA (according to the CFD model 12.6-13.2 % probability of embolisation into the OA). Also, 15.6 % had plaques in the paraclinoid ICA portion distal to the OA origin. CONCLUSIONS: There were 40.6% of the patients that had plaques in the cavernous and clinoid ICA portions presenting possible sources for embolic material generating RAO.

Computer-aided diagnosis improves detection of small intracranial aneurysms on MRA in a clinical setting.

BACKGROUND AND PURPOSE: MRA is widely accepted as a noninvasive diagnostic tool for the detection of intracranial aneurysms, but detection is still a challenging task with rather low detection rates. Our aim was to examine the performance of a computer-aided diagnosis algorithm for detecting intracranial aneurysms on MRA in a clinical setting. MATERIALS AND METHODS: Aneurysm detectability was evaluated retrospectively in 48 subjects with and without computer-aided diagnosis by 6 readers using a clinical 3D viewing system. Aneurysms ranged from 1.1 to 6.0 mm (mean = 3.12 mm, median = 2.50 mm). We conducted a multireader, multicase, double-crossover design, free-response, observer-performance study on sets of images from different MRA scanners by using DSA as the reference standard. Jackknife alternative free-response operating characteristic curve analysis with the figure of merit was used. RESULTS: For all readers combined, the mean figure of merit improved from 0.655 to 0.759, indicating a change in the figure of merit attributable to computer-aided diagnosis of 0.10 (95% CI, 0.03-0.18), which was statistically significant (F(1,47) = 7.00, P = .011). Five of the 6 radiologists had improved performance with computer-aided diagnosis, primarily due to increased sensitivity. CONCLUSIONS: In conditions similar to clinical practice, using computer-aided diagnosis significantly improved radiologists' detection of intracranial DSA-confirmed aneurysms of ≤6 mm.