Longitudinal Assessment of Enhancing Foci of Abnormal Signal Intensity in Neurofibromatosis Type 1.

BACKGROUND AND PURPOSE: Patients with neurofibromatosis 1 are at increased risk of developing brain tumors, and differentiation from contrast-enhancing foci of abnormal signal intensity can be challenging. We aimed to longitudinally characterize rare, enhancing foci of abnormal signal intensity based on location and demographics. MATERIALS AND METHODS: A total of 109 MR imaging datasets from 19 consecutive patients (7 male; mean age, 8.6 years; range, 2.3-16.8 years) with neurofibromatosis 1 and a total of 23 contrast-enhancing parenchymal lesions initially classified as foci of abnormal signal intensity were included. The mean follow-up period was 6.5 years (range, 1-13.8 years). Enhancing foci of abnormal signal intensity were followed up with respect to presence, location, and volume. Linear regression analysis was performed. RESULTS: Location, mean peak volume, and decrease in enhancing volume over time of the 23 lesions were as follows: 10 splenium of the corpus callosum (295 mm3, 5 decreasing, 3 completely resolving, 2 surgical intervention for change in imaging appearance later confirmed to be gangliocytoma and astrocytoma WHO II), 1 body of the corpus callosum (44 mm3, decreasing), 2 frontal lobe white matter (32 mm3, 1 completely resolving), 3 globus pallidus (50 mm3, all completely resolving), 6 cerebellum (206 mm3, 3 decreasing, 1 completely resolving), and 1 midbrain (34 mm3). On average, splenium lesions began to decrease in size at 12.2 years, posterior fossa lesions at 17.1 years, and other locations at 9.4 years of age. CONCLUSIONS: Albeit very rare, contrast-enhancing lesions in patients with neurofibromatosis 1 may regress over time. Follow-up MR imaging aids in ascertaining regression. The development of atypical features should prompt further evaluation for underlying tumors.

Radiomics of Pediatric Low-Grade Gliomas: Toward a Pretherapeutic Differentiation of BRAF-Mutated and BRAF-Fused Tumors.

BACKGROUND AND PURPOSE: B-Raf proto-oncogene, serine/threonine kinase (BRAF) status has important implications for prognosis and therapy of pediatric low-grade gliomas. Currently, BRAF status classification relies on biopsy. Our aim was to train and validate a radiomics approach to predict BRAF fusion and BRAF V600E mutation. MATERIALS AND METHODS: In this bi-institutional retrospective study, FLAIR MR imaging datasets of 115 pediatric patients with low-grade gliomas from 2 children's hospitals acquired between January 2009 and January 2016 were included and analyzed. Radiomics features were extracted from tumor segmentations, and the predictive model was tested using independent training and testing datasets, with all available tumor types. The model was selected on the basis of a grid search on the number of trees, opting for the best split for a random forest. We used the area under the receiver operating characteristic curve to evaluate model performance. RESULTS: The training cohort consisted of 94 pediatric patients with low-grade gliomas (mean age, 9.4 years; 45 boys), and the external validation cohort comprised 21 pediatric patients with low-grade gliomas (mean age, 8.37 years; 12 boys). A 4-fold cross-validation scheme predicted BRAF status with an area under the curve of 0.75 (SD, 0.12) (95% confidence interval, 0.62-0.89) on the internal validation cohort. By means of the optimal hyperparameters determined by 4-fold cross-validation, the area under the curve for the external validation was 0.85. Age and tumor location were significant predictors of BRAF status (P values = .04 and <.001, respectively). Sex was not a significant predictor (P value = .96). CONCLUSIONS: Radiomics-based prediction of BRAF status in pediatric low-grade gliomas appears feasible in this bi-institutional exploratory study.

Deep Learning for Pediatric Posterior Fossa Tumor Detection and Classification: A Multi-Institutional Study.

BACKGROUND AND PURPOSE: Posterior fossa tumors are the most common pediatric brain tumors. MR imaging is key to tumor detection, diagnosis, and therapy guidance. We sought to develop an MR imaging-based deep learning model for posterior fossa tumor detection and tumor pathology classification. MATERIALS AND METHODS: The study cohort comprised 617 children (median age, 92 months; 56% males) from 5 pediatric institutions with posterior fossa tumors: diffuse midline glioma of the pons (n = 122), medulloblastoma (n = 272), pilocytic astrocytoma (n = 135), and ependymoma (n = 88). There were 199 controls. Tumor histology served as ground truth except for diffuse midline glioma of the pons, which was primarily diagnosed by MR imaging. A modified ResNeXt-50-32x4d architecture served as the backbone for a multitask classifier model, using T2-weighted MRIs as input to detect the presence of tumor and predict tumor class. Deep learning model performance was compared against that of 4 radiologists. RESULTS: Model tumor detection accuracy exceeded an AUROC of 0.99 and was similar to that of 4 radiologists. Model tumor classification accuracy was 92% with an F1 score of 0.80. The model was most accurate at predicting diffuse midline glioma of the pons, followed by pilocytic astrocytoma and medulloblastoma. Ependymoma prediction was the least accurate. Tumor type classification accuracy and F1 score were higher than those of 2 of the 4 radiologists. CONCLUSIONS: We present a multi-institutional deep learning model for pediatric posterior fossa tumor detection and classification with the potential to augment and improve the accuracy of radiologic diagnosis.

MR Imaging-Based Radiomic Signatures of Distinct Molecular Subgroups of Medulloblastoma.

BACKGROUND AND PURPOSE: Distinct molecular subgroups of pediatric medulloblastoma confer important differences in prognosis and therapy. Currently, tissue sampling is the only method to obtain information for classification. Our goal was to develop and validate radiomic and machine learning approaches for predicting molecular subgroups of pediatric medulloblastoma. MATERIALS AND METHODS: In this multi-institutional retrospective study, we evaluated MR imaging datasets of 109 pediatric patients with medulloblastoma from 3 children's hospitals from January 2001 to January 2014. A computational framework was developed to extract MR imaging-based radiomic features from tumor segmentations, and we tested 2 predictive models: a double 10-fold cross-validation using a combined dataset consisting of all 3 patient cohorts and a 3-dataset cross-validation, in which training was performed on 2 cohorts and testing was performed on the third independent cohort. We used the Wilcoxon rank sum test for feature selection with assessment of area under the receiver operating characteristic curve to evaluate model performance. RESULTS: Of 590 MR imaging-derived radiomic features, including intensity-based histograms, tumor edge-sharpness, Gabor features, and local area integral invariant features, extracted from imaging-derived tumor segmentations, tumor edge-sharpness was most useful for predicting sonic hedgehog and group 4 tumors. Receiver operating characteristic analysis revealed superior performance of the double 10-fold cross-validation model for predicting sonic hedgehog, group 3, and group 4 tumors when using combined T1- and T2-weighted images (area under the curve = 0.79, 0.70, and 0.83, respectively). With the independent 3-dataset cross-validation strategy, select radiomic features were predictive of sonic hedgehog (area under the curve = 0.70-0.73) and group 4 (area under the curve = 0.76-0.80) medulloblastoma. CONCLUSIONS: This study provides proof-of-concept results for the application of radiomic and machine learning approaches to a multi-institutional dataset for the prediction of medulloblastoma subgroups.

Novel potassium channels encoded by the Shaker locus in Drosophila photoreceptors.

The Shaker gene, responsible for A-type potassium channels in Drosophila muscle, encodes a large family of transcripts capable of generating a variety of kinetically distinct A channels when expressed in oocytes. We describe a distinct class of A channel encoded by the Shaker gene in a novel preparation of dissociated Drosophila photoreceptors. Whole-cell recordings reveal a rapidly inactivating A current that is absent in Shaker mutants and that can be readily isolated in cell-attached patches. Although very similar to their muscle counterparts, the photoreceptor A channels show a striking 40-50 mV negative shift in their voltage-operating range. Two mutations (ShE62 and T(1;Y)W32), which exclude only certain classes of Shaker transcripts, were used to show that photoreceptor A channels are encoded by multiple transcripts distinct from those encoding muscle A channels, while PCR techniques identified four transcripts (ShA1, ShA2, ShG1, and ShG2) in mRNA from dissected retina.

Contrast gain reduction in fly motion adaptation.

In many species, including humans, exposure to high image velocities induces motion adaptation, but the neural mechanisms are unclear. We have isolated two mechanisms that act on directionally selective motion-sensitive neurons in the fly's visual system. Both are driven strongly by movement and weakly, if at all, by flicker. The first mechanism, a subtractive process, is directional and is only activated by stimuli that excite the neuron. The second, a reduction in contrast gain, is strongly recruited by motion in any direction, even if the adapting stimulus does not excite the cell. These mechanisms are well designed to operate effectively within the context of motion coding. They can prevent saturation at susceptible nonlinear stages in processing, cope with rapid changes in direction, and preserve fine structure within receptive fields.

The metabolic cost of neural information.

We derive experimentally based estimates of the energy used by neural mechanisms to code known quantities of information. Biophysical measurements from cells in the blowfly retina yield estimates of the ATP required to generate graded (analog) electrical signals that transmit known amounts of information. Energy consumption is several orders of magnitude greater than the thermodynamic minimum. It costs 10(4) ATP molecules to transmit a bit at a chemical synapse, and 10(6)-10(7) ATP for graded signals in an interneuron or a photoreceptor, or for spike coding. Therefore, in noise-limited signaling systems, a weak pathway of low capacity transmits information more economically, which promotes the distribution of information among multiple pathways.

MRI Characteristics of Primary Tumors and Metastatic Lesions in Molecular Subgroups of Pediatric Medulloblastoma: A Single-Center Study.

BACKGROUND AND PURPOSE: Molecular grouping of medulloblastoma correlates with prognosis and supports the therapeutic strategy. We provide our experience with the imaging features of primary and metastatic disease in relation to the molecular groups. MATERIALS AND METHODS: One hundred nineteen consecutive patients (mean age, 7.3 ± 3.8 years at diagnosis; male, 79 [66.4%]) with a confirmed diagnosis of medulloblastoma and interpretable pretreatment MRIs were retrieved from our data base from January 2000 to December 2016. Each patient was assigned to wingless, sonic hedgehog, group 3, or group 4 molecular groups. Then, we determined the imaging features of both primary and metastatic/recurrent disease predictive of molecular groups. RESULTS: In addition to recently reported predictors based on primary tumor, including cerebellar peripheral location for sonic hedgehog (adjusted odds ratio = 9, P < .0001), minimal enhancement of primary group 4 tumor (adjusted odds ratio = 5.2, P < .0001), and cerebellopontine angle location for wingless (adjusted odds ratio = 1.4, P = .03), ependymal metastasis with diffusion restriction and minimal postcontrast enhancement ("mismatching pattern") (adjusted odds ratio = 2.8, P = .001) for group 4 and spinal metastasis for group 3 (adjusted odds ratio = 1.9, P = .01) also emerged as independent predictors of medulloblastoma molecular groups. Specifically, the presence of a metastasis in the third ventricular infundibular recess showing a mismatching pattern was significantly associated with group 4 (P = .02). CONCLUSIONS: In addition to imaging features of primary tumors, some imaging patterns of metastatic dissemination in medulloblastoma seem characteristic, perhaps even specific to certain groups. This finding could further help in differentiating molecular groups, specifically groups 3 and 4, when the characteristics of the primary tumor overlap.

Visual motion: dendritic integration makes sense of the world.

Flies use a system of specialised neurons to read the patterns of visual motion - optic flow - induced by the their movements. Recent experiments illustrate how the dendrites of these neurons reach out to assemble patterns of optic flow and encode them reliably.

Visual ecology and voltage-gated ion channels in insect photoreceptors.

That particular membrane conductances are selected for expression to enable the efficient coding of biologically relevant signals is illustrated by recent work on insect photoreceptors. These studies exploit the richness of insect vision and the accessibility of insect photoreceptors to cellular analysis in both intact animal and isolated cell preparations. The distribution of voltage-gated conductances among photoreceptors of different species correlates with visual ecology. Delayed-rectifier K+ channels are found in the rapidly responding photoreceptors of fast-flying flies. The conductance's activation range and dynamics match light-induced signals, and enable a rapid response by reducing the membrane time constant. Slow-moving flies have slowly responding photoreceptors that lack the delayed rectifier, but express an inactivating K+ conductance that is metabolically less demanding. Complementing these findings, locust photoreceptor membranes are modulated diurnally. The delayed rectifier is exhibited during the day and the inactivating K+ current is exhibited at night. Insect photoreceptors also demonstrate the amplification of signals by voltage-gated Na+ channels. In drone-bee photoreceptors, voltage-gated Na+ channels combine with K+ channels to enhance the small transient signals produced by the image of a queen bee passing over the retina. This subthreshold amplifier operates most effectively over the range of light intensities at which drones pursue queens.

Energy as a constraint on the coding and processing of sensory information.

Neurons use significant amounts of energy to generate signals. Recent studies of retina and brain connect this energy usage to the ability to transmit information. The identification of energy-efficient neural circuits and codes suggests new ways of understanding the function, design and evolution of nervous systems.

2D time-of-flight MR venography in neonates: anatomy and pitfalls.

BACKGROUND AND PURPOSE: The dural venous sinuses in neonates differ from those in adults or older children in that the caliber of venous sinuses is smaller and there is skull molding. The aim of this retrospective study is to evaluate the presence of flow gaps in venous sinuses in neonates on 2D time-of-flight (TOF) MR venography (MRV). METHODS: Fifty-one neonates underwent coronal 2D TOF MRV. Nine also had CT venography (CTV) for comparison. In 1 neonate, a further 2D TOF MRV was performed in the sagittal plane; in another neonate, images were captured in the axial plane; and in another, a further coronal TOF MRV with shorter echo time was performed. RESULTS: Flow gap was seen in the posterior aspect of the superior sagittal sinus in 35 of 51 (69%). Focal narrowing of the superior sagittal sinus, in the region of convergence of lambdoid sutures, was detected in 7 of 51 (14%). The right and left transverse sinuses demonstrated flow gap in 13 of 51 (25%) and 32 of 51 (63%) respectively. There was normal filling of contrast on CTV in the superior sagittal sinus, transverse sinus and sigmoid sinus in those cases with flow gap detected on coronal 2D TOF MRV. Right, left, and codominance of the transverse sinuses are as follows: 32 of 51 (63%), 5 of 51 (10%), and 14 of 51 (27%), respectively. The right and left sigmoid sinuses demonstrated flow gap in 7 of 51 (14%) and 8 of 51 (16%), respectively, and the left sigmoid sinus was absent in 1 of 51 (2%). CONCLUSION: The high proportion of flow gap in the venous sinuses of neonates, particularly of the superior sagittal sinus, could be attributed to the smaller caliber venous sinuses, slower venous flow, and skull molding.

Endoplasmic reticulum stress induces ligand-independent TNFR1-mediated necroptosis in L929 cells.

Endoplasmic reticulum (ER) stress-induced cellular dysfunction and death is associated with several human diseases. It has been widely reported that ER stress kills through activation of the intrinsic mitochondrial apoptotic pathway. Here we demonstrate that ER stress can also induce necroptosis, an receptor-interacting protein kinase 1 (RIPK1)/RIPK3/mixed lineage kinase domain-like protein (MLKL)-dependent form of necrosis. Remarkably, we observed that necroptosis induced by various ER stressors in L929 cells is dependent on tumor necrosis factor receptor 1 (TNFR1), but occurs independently of autocrine TNF or lymphotoxin α production. Moreover, we found that repression of either TNFR1, RIPK1 or MLKL did not protect the cells from death but instead allowed a switch to ER stress-induced apoptosis. Interestingly, while caspase inhibition was sufficient to protect TNFR1- or MLKL-deficient cells from death, rescue of the RIPK1-deficient cells additionally required RIPK3 depletion, indicating a switch back to RIPK3-dependent necroptosis in caspase-inhibited conditions. The finding that ER stress also induces necroptosis may open new therapeutic opportunities for the treatment of pathologies resulting from unresolved ER stress.

Chickenpox and stroke in childhood: a study of frequency and causation.

BACKGROUND AND PURPOSE: The purpose of this study was to determine whether infection with varicella is causal for arterial ischemic stroke (AIS) in children. METHODS: First, a prospective cohort study was conducted in young children (aged 6 months to 10 years) with AIS at 2 institutions (cohort study). The presence of varicella infection <12 months before AIS was determined and compared with the published frequency of varicella infection in the healthy pediatric population. The clinical and radiographic features of AIS were compared between the varicella and nonvaricella study cohorts. Second, a literature search of varicella-associated AIS was conducted, and the clinical and radiographic features were compared with the study nonvaricella cohort. RESULTS: In the cohort study, 22 (31%) of 70 consecutive children with AIS had a varicella infection in the preceding year compared with 9% in the healthy population. Children in the varicella cohort were more likely to have basal ganglia infarcts (P<0.001), abnormal cerebral vascular imaging (P<0.05), and recurrent AIS or transient ischemic attacks (P<0.05) than those in the nonvaricella cohort. The pooled literature analysis of 51 cases of varicella-associated AIS showed similar findings to the varicella cohort. CONCLUSION: In young children with AIS, there is a 3-fold increase in preceding varicella infection compared with published population rates, and varicella-associated AIS accounts for nearly one third of childhood AIS. Varicella-associated AIS has characteristic features, including a 2-fold increase in recurrent AIS and transient ischemic attacks. Varicella is an important risk factor for childhood AIS.

An energy budget for signaling in the grey matter of the brain.

Anatomic and physiologic data are used to analyze the energy expenditure on different components of excitatory signaling in the grey matter of rodent brain. Action potentials and postsynaptic effects of glutamate are predicted to consume much of the energy (47% and 34%, respectively), with the resting potential consuming a smaller amount (13%), and glutamate recycling using only 3%. Energy usage depends strongly on action potential rate--an increase in activity of 1 action potential/cortical neuron/s will raise oxygen consumption by 145 mL/100 g grey matter/h. The energy expended on signaling is a large fraction of the total energy used by the brain; this favors the use of energy efficient neural codes and wiring patterns. Our estimates of energy usage predict the use of distributed codes, with

Aphasia with predominantly subcortical lesion sites: description of three capsular/putaminal aphasia syndromes.

Nine cases of subcortical aphasia with capsular/putaminal (C/P) lesion sites demonstrated on computed tomographic (CT) scans were studied. Eight cases were occlusive-vascular in etiology and one was hemorrhagic. Three subcortical aphasia syndromes and three C/P lesion site patterns were observed. Patients with C/P lesion sites with anterior-superior white-matter lesion extension had good comprehension, grammatical, but slow, dysarthric speech, and lasting right hemiplegia. Patients with C/P lesion sites with posterior white-matter lesion extension across the auditory radiations in the temporal isthmus had poor comprehension, fluent Wernicke-type speech, and lasting right hemiplegia. Patients with C/P lesion sites with both anterior-superior and posterior extension were globally aphasic and had lasting right hemiplegia. Although these cases of C/P subcortical aphasia shared certain well-known features of Broca's and Wernicke's cortical aphasia syndromes, they did not completely resemble cases of either Broca's, Wernicke's, global, or thalamic aphasia in neurologic findings, CT scan lesion sites, or language behavior. Further study of the subcortical aphasias associated with these C/P lesion sites seems to be warranted.

Sexual dimorphism matches photoreceptor performance to behavioural requirements.

Differences in behaviour exist between the sexes of most animal species and are associated with many sex-specific specializations. The visual system of the male housefly is known to be specialized for pursuit behaviour that culminates in mating. Males chase females using a high-acuity region of the fronto-dorsal retina (the 'love spot') that drives sex-specific neural circuitry. We show that love spot photoreceptors of the housefly combine better spatial resolution with a faster electrical response, thereby allowing them to code higher velocities and smaller targets than female photoreceptors. Love spot photoreceptors of males are more than 60% faster than their female counterparts and are among the fastest recorded for any animal. The superior response dynamics of male photoreceptors is achieved by a speeding up of the biochemical processes involved in phototransduction and by a tuned voltage-activated conductance that boosts the membrane frequency response. These results demonstrate that the inherent plasticity of phototransduction facilitates the tuning of the dynamics of visual processing to the requirements of visual ecology.

Efficiency and complexity in neural coding.

Neural coding in the retina and lamina of fly compound eyes is amenable to detailed anatomical, physiological and theoretical analysis. This approach shows how identified cell signalling systems are optimized to maximize the transmission of information. Optimization reveals three familiar constraints, noise, saturation and bandwidth, and shows how coding can minimize their effects. Experiments reveal a fourth constraint, metabolic cost, whose properties favour the distribution of information among multiple pathways. The advantages of distributed codes will be offset by increasing complexity and the build up of noise. The optimization of coding in fly retina suggests that both noise and complexity will be reduced by matching each step in the system's operations to the input signal, and to the logical requirements of the network's ultimate function, pattern processing. This line of argument suggests tightly organized networks, laid out that information flows freely and independently, yet patterned so that the necessary contacts and transactions are made quickly and efficiently.

Macrophages (histiocytes) in various reactive and inflammatory conditions express different antigenic phenotypes.

The purpose of this study was to determine whether human tissue macrophages (M phi s) in various inflammatory/reactive conditions express different immunophenotypes. Using a large panel of monoclonal antibodies to monocyte/M phi-related antigens and a frozen-section immunoperoxidase technique, the following conditions were studied: granulomatous inflammation of unknown etiology, sarcoidosis, cat-scratch fever, toxoplasmosis, Gaucher's disease, and juvenile xanthogranulomas. The results show that there is immunophenotypic variation of the M phi s among the various inflammatory/reactive conditions. For example, the M phi s in cat-scratch fever are nearly unique in the expression of the "early inflammation" antigen identified by antibody 27E10, and the M phi s in juvenile xanthogranulomas, unlike those in most of the other conditions, lacked the antigen detected by antibody 25F9. The M phi s in Gaucher's disease differed from those in the other disorders by the combined absence of CD11b, CD14, G16/1, CD1a, CD25, and CD30. The inflammatory/reactive M phi s also exhibited differences from those in "normal" tissues, namely, a tendency toward acquisition of the antigens identified by antibodies Mac 387 and G16/1 and the more uniform expression of the "activation" antigens CD25, CD30, and CD71. The antigenic variations described here probably reflect differences in antigenic stimuli and M phi function. In addition to the possible biologic implications, this M phi immunophenotypic diversity may have practical diagnostic applications.

Chondromyxoid fibroma of bone: a clinicopathologic review of 278 cases.

In a study of the clinical, radiographic, and pathological features of chondromyxoid fibroma, the tumor was slightly more common in men, usually in the second decade of life. Almost half of the tumors involved the long bones, although the ilium and the small bones were also common sites. Roentgenograms showed a sharply marginated, lobulated, lucent defect in the metaphysis. The tumor involved the medullary bone in an eccentric fashion, and the cortex was thinned and expanded. Periosteal reaction and soft tissue extension were uncommon. Mineralization was identified in 13% of the lesions. Histologically, the tumors were almost always arranged in lobules, which were prominent (macrolobular) or somewhat indistinct (microlobular). The tumor cells were spindle-shaped or stellate and arranged in a myxoid matrix. Calcification was seen in more than one third of the cases but was rarely prominent. Hyaline cartilage and chondroblastoma-like areas were not uncommon. Approximately 18% of tumors showed bizarre nuclei. Permeation of bony trabeculae was uncommon. Treatment was conservative surgical removal; approximately one fourth of the patients had recurrence.