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IMPORTANCE: Loss of smell is an early and common presentation of COVID-19 infection. Although it has been speculated that viral infection of olfactory neurons may be the culprit, it is unclear whether viral infection causes injuries in the olfactory bulb region. OBJECTIVE: To characterize the olfactory pathology associated with COVID-19 infection in a postmortem study. DESIGN, SETTING, AND PARTICIPANTS: This multicenter postmortem cohort study was conducted from April 7, 2020, to September 11, 2021. Deceased patients with COVID-19 and control individuals were included in the cohort. One infant with congenital anomalies was excluded. Olfactory bulb and tract tissue was collected from deceased patients with COVID-19 and appropriate controls. Histopathology, electron microscopy, droplet digital polymerase chain reaction, and immunofluorescence/immunohistochemistry studies were performed. Data analysis was conducted from February 7 to October 19, 2021. MAIN OUTCOMES AND MEASURES: (1) Severity of degeneration, (2) losses of olfactory axons, and (3) severity of microvasculopathy in olfactory tissue. RESULTS: Olfactory tissue from 23 deceased patients with COVID-19 (median [IQR] age, 62 [49-69] years; 14 men [60.9%]) and 14 control individuals (median [IQR] age, 53.5 [33.25-65] years; 7 men [50%]) was included in the analysis. The mean (SD) axon pathology score (range, 1-3) was 1.921 (0.569) in patients with COVID-19 and 1.198 (0.208) in controls (P

Diabetic neuropathy (DN) is a debilitating disorder characterized by mechanical allodynia and sensory loss. It has traditionally been considered a small-fiber neuropathy, defined by the loss of free nerve endings in the epidermis. Free nerve endings, however, are nociceptors which may not be the only sensor for mechanical pain. To investigate the role of mechanoreceptors, specifically Meissner corpuscles, in the development of diabetic mechanical allodynia, our study focused on the keratinocyte-secreted brain-derived neurotrophic factor (BDNF) and its transcriptional regulator sirtuin 1 (SIRT1). Wild-type DN mice demonstrated decreased SIRT1 deacetylase activity, leading to a decrease in BDNF expression and Meissner corpuscle densities in foot skin. EpidermalSIRT1knockout (KO) mice developed exacerbated DN phenotypes including severe mechanical allodynia, markedly reduced Meissner corpuscles, and subcutaneous Aß axon degeneration. Among the major skin-derived neurotrophic factors, only BDNF was down-regulated in epidermalSIRT1KO mice. With similar KO phenotypes, epidermal BDNF appeared to belong to the same pathway as SIRT1 in modulating diabetic mechanical allodynia. Furthermore, mice overexpressing epidermal SIRT1 showed BDNF up-regulation and improved DN phenotypes, supporting an important role of epidermal SIRT1 and BDNF in skin sensory apparatus regeneration and functional recovery in the setting of diabetes.

ObjectivesCentral nervous system involvement is present in 70% of patients with hemophagocytic lymphohistiocytosis (CNS-HLH). CNS-HLH is defined by neurologic deficits, neuroimaging abnormalities, or positive cerebrospinal fluid (CSF) findings. The CSF cytomorphologic spectrum of CNS-HLH, however, has not been well investigated.MethodsA retrospective review was performed on 64 CSF specimens from pediatric and adult patients with HLH. Ten patients had clinicoradiologic evidence of CNS involvement.ResultsWe identified five CSF cytomorphologic patterns: (1) hemophagocytosis, (2) vacuolated macrophages without evidence of hemophagocytosis, (3) monocytes and/or nonvacuolated macrophages, (4) acellular specimens, and (5) bloody specimens. Patterns 1 and 2 were common in CNS-HLH and rare in patients without CNS involvement. The CSF cytomorphologic patterns did not correlate well with WBC counts or protein concentration.ConclusionsOur study offers a comprehensive view of the cytomorphologic features seen in CSF specimens from patients with HLH.

Recent characterization of spatiotemporal genomic architecture of IDH-wild-type multifocal glioblastomas (M-GBMs) suggests a clinically unobserved common-ancestor (CA) with a less aggressive phenotype, generating highly genetically divergent malignant gliomas/GBMs in distant brain regions. Using serial MRI/3D-reconstruction, whole-genome sequencing and spectral karyotyping-based single-cell phylogenetic tree building, we show two distinct types of tumor evolution in p53-mutant driven mouse models. Malignant gliomas/GBMs grow as a single mass (Type 1) and multifocal masses (Type 2), respectively, despite both exhibiting loss of Pten/chromosome 19 (chr19) and PI3K/Akt activation with sub-tetraploid/4N genomes. Analysis of early biopsied and multi-segment tumor tissues reveals no evidence of less proliferative diploid/2N lesions in Type 1 tumors. Strikingly, CA-derived relatively quiescent tumor precursors with ancestral diploid/2N genomes and normal Pten/chr19 are observed in the subventricular zone (SVZ), but are distantly segregated from multi focal Type 2 tumors. Importantly, PI3K/Akt inhibition by Rictor/mTORC2 deletion blocks distant dispersal, restricting glioma growth in the SVZ., Recent studies suggest spatial segregation of tumor initiation and manifestation in IDH-WT glioblastomas. Here, the authors use serial MRI/3D-reconstruction, whole-genome sequencing and spectral karyotyping-based single-cell phylogenetic tree building to establish this unique evolutionary mode in a murine model.

Children diagnosed with brain tumors have the lowest overall survival of all pediatric cancers. Recent molecular studies have resulted in the discovery of recurrent driver mutations in many pediatric brain tumors. However, despite these molecular advances, the clinical outcomes of high grade tumors, including H3K27M diffuse midline glioma (H3K27M DMG), remain poor. To address the paucity of tissue for biological studies, we have established a comprehensive protocol for the coordination and processing of donated specimens at postmortem. Since 2010, 60 postmortem pediatric brain tumor donations from 26 institutions were coordinated and collected. Patient derived xenograft models and cell cultures were successfully created (76% and 44% of attempts respectively), irrespective of postmortem processing time. Histological analysis of mid-sagittal whole brain sections revealed evidence of treatment response, immune cell infiltration and the migratory path of infiltrating H3K27M DMG cells into other midline structures and cerebral lobes. Sequencing of primary and disseminated tumors confirmed the presence of oncogenic driver mutations and their obligate partners. Our findings highlight the importance of postmortem tissue donations as an invaluable resource to accelerate research, potentially leading to improved outcomes for children with aggressive brain tumors.

A systematic analysis of the source duration (τ) and seismic moment (M0) for seismogenic earthquakes (MW 5.5–7.1) in the Taiwan region was completed by using a teleseismic P-wave inversion method. Irrespective of the source self-similarity, the M0–τ relationship derived in this study had a power-law form, namely M0 ∝ τ3, under the assumption that ΔσVr3 is constant following a circular fault model (Δσ: static stress drop; Vr: rupture velocity). For Taiwan’s earthquakes, the derived M0–τ relationship not only provides information to predict the source duration of large earthquakes, but also probes the rupture features of seismogenic earthquakes. That is, there are different rupture patterns for earthquakes, but the product ΔσVr3 remains nearly constant.

Interleukin-5 (IL-5) strongly initiates the asthmatic inflammatory response, which affects 300 million patients with asthma annually worldwide, through oxidative stress generation. Citrus flavonoids have beneficial properties, such as anti-inflammatory and antioxidant properties, but the precise molecular mechanism of the inhibition of the asthmatic inflammatory response is still unclear. This study aimed to investigate the underlying mechanisms of ROS and IL-5 reduction with citrus flavonoid treatment in PMA/ionomycin-induced EL-4 cells. Our results showed that hesperetin and gardenin A dramatically suppressed ROS and IL-5 production through distinct pathways. Interestingly, hesperidin induced HO-1 expression through the transcription factor Nrf2 coupled with the PI3K/AKT or ERK/JNK signaling pathway, consequently downregulating NFAT activity and IL-5 secretion. Likewise, gardenin A induced HO-1 expression and subsequently suppressed IL-5 production by reducing NFAT activity and upregulating PPARγ in EL-4 cells, suggesting that inducing HO-1 expression may inhibit asthmatic inflammation. Altogether, hesperidin and gardenin A have great potential for regulating the asthma-associated immune responses through antioxidant properties.

Neuronal/mixed glioneuronal tumors are central nervous system neoplasms composed of neoplastic neuronal cell components or a mixture of glial and neuronal elements. They occur in cerebral hemispheres, posterior fossa, and spinal cord. Compared with other tumors at these locations, diencephalic neuronal/glioneuronal tumors are very rare and therefore not well characterized. We hereby performed clinicopathologic evaluation on 10 neuronal/glioneuronal tumors arising from the diencephalic region. Morphologically, these tumors resemble their histologic counterparts in other locations, except that lymphocytic infiltrates and microcalcifications are more common than Rosenthal fibers or eosinophilic granular bodies. The BRAFV600 mutation rate is 75%. Given the high percentage of samples being small biopsy specimens, the subtle histologic features and molecular findings greatly aided in establishing the pathologic diagnosis in several cases. At a median follow-up of 42 months, 71% of the tumors demonstrated radiological recurrence or progression, with median progression-free survival of 18 months. Recurrence/progression is observed in tumors across different histologic subtypes, necessitating additional therapies in 56% of the cases. Despite their bland histology, diencephalic neuronal/glioneuronal tumors are not clinically indolent. Their frequent recurrences warrant a close follow-up, and the prevalent BRAF mutation makes MAPK pathway inhibition a plausible treatment option when conventional therapies fail.

Innocuous mechanical stimuli acting on the skin are detected by sensory neurons, known as low-threshold mechanoreceptors (LTMRs). LTMRs are classified based on their response properties, action potential conduction velocity, rate of adaptation to static indentation of the skin, and terminal anatomy. Here, we report organizational properties of the cutaneous and central axonal projections of the five principal hairy skin LTMR subtypes. We find that axons of neurons within a particular LTMR class are largely nonoverlapping with respect to their cutaneous end organs (e.g., hair follicles), with Aβ rapidly adapting-LTMRs being the sole exception. Individual neurons of each LTMR class are mostly nonoverlapping with respect to their associated hair follicles, with the notable exception of C-LTMRs, which exhibit multiple branches that redundantly innervate individual hair follicles. In the spinal cord, LTMR central projections exhibit rostrocaudal elongation and mediolateral compression, compared with their cutaneous innervation patterns, and these central projections also exhibit a fine degree of homotypic topographic adjacency. These findings thus reveal homotypic tiling of LTMR subtype axonal projections in hairy skin and a remarkable degree of spatial precision of spinal cord axonal termination patterns, suggesting a somatotopically precise tactile encoding capability of the mechanosensory dorsal horn.

Invasive aspergillosis (IA) is an important opportunistic infection among patients with liver disease and liver transplants. Diagnosis of IA may be challenging, especially among patients with central nervous system infection. Herein, we demonstrate the utility of next-generation sequencing of microbial cell-free DNA in the diagnosis of fungal brain abscess in a liver transplant recipient.

ObjectiveTo test the hypothesis that brain injury is more common and varied in patients receiving extracorporeal membrane oxygenation (ECMO) than radiographically observed, we described neuropathology findings of ECMO decedents and associated clinical factors from 3 institutions.MethodsWe conducted a retrospective multicenter observational study of brain autopsies from adult ECMO recipients. Pathology findings were examined for correlation with demographics, clinical data, ECMO characteristics, and outcomes.ResultsForty-three decedents (n = 13 female, median age 47 years) received autopsies after undergoing ECMO for acute respiratory distress syndrome (n = 14), cardiogenic shock (n = 14), and cardiac arrest (n = 15). Median duration of ECMO was 140 hours, most decedents (n = 40) received anticoagulants; 60% (n = 26) underwent venoarterial ECMO, and 40% (n = 17) underwent venovenous ECMO. Neuropathology was found in 35 decedents (81%), including microhemorrhages (37%), macrohemorrhages (35%), infarctions (47%), and hypoxic-ischemic brain injury (n = 17, 40%). Most pathology occurred in frontal neocortices (n = 43 occurrences), basal ganglia (n = 33), and cerebellum (n = 26). Decedents with hemorrhage were older (median age 57 vs 38 years, p = 0.01); those with hypoxic brain injury had higher Sequential Organ Failure Assessment scores (8.0 vs 2.0, p = 0.04); and those with infarction had lower peak Paco2 (53 vs 61 mm Hg, p = 0.04). Six of 9 patients with normal neuroimaging results were found to have pathology on autopsy. The majority underwent withdrawal of life-sustaining therapy (n = 32, 74%), and 2 of 8 patients with normal brain autopsy underwent withdrawal of life-sustaining therapy for suspected neurologic injury.ConclusionNeuropathological findings after ECMO are common, varied, and associated with various clinical factors. Further study on underlying mechanisms is warranted and may guide ECMO management.

Members of the miR-125 family are strongly expressed in several tissues, particularly brain, but may be dysregulated in cancer including adult and pediatric glioma. In this study, miR-125 members were downregulated in pilocytic astrocytoma (PA) as a group compared to non-neoplastic brain in the Agilent platform. In the Nanostring platform, miR-125 members were downregulated primarily in pleomorphic xanthoastrocytomas and gangliogliomas. Using CISH for miR-125b, highest levels of expression were present in grade II tumors (11/33, 33% grade II tumors with 3+ expression compared to 3/70, 4% grade I tumors) (p

Glioma is a unique neoplastic disease that develops exclusively in the central nervous system (CNS) and rarely metastasizes to other tissues. This feature strongly implicates the tumor-host CNS microenvironment in gliomagenesis and tumor progression. We investigated the differences and similarities in glioma biology as conveyed by transcriptomic patterns across four mammalian hosts: rats, mice, dogs, and humans. Given the inherent intra-tumoral molecular heterogeneity of human glioma, we focused this study on tumors with upregulation of the platelet-derived growth factor signaling axis, a common and early alteration in human gliomagenesis. The results reveal core neoplastic alterations in mammalian glioma, as well as unique contributions of the tumor host to neoplastic processes. Notable differences were observed in gene expression patterns as well as related biological pathways and cell populations known to mediate key elements of glioma biology, including angiogenesis, immune evasion, and brain invasion. These data provide new insights regarding mammalian models of human glioma, and how these insights and models relate to our current understanding of the human disease. NIH [T32 CA154274, F30-CA200345-01, R01CA139099, K12 NS080223, K08 NS090430]; Wallace Coulter Foundation; Passano Foundation; American Cancer Society-Research Scholar Grant [128970-RSG-16-012-01-CDD] This study was supported by NIH T32 CA154274 (NC), NIH F30-CA200345-01 (MBS), NIH R01CA139099 (JHR); the Wallace Coulter Foundation (JHR); the Passano Foundation (GW); NIH K12 NS080223 Neurosurgeon Research Career Development Program (GW), NIH K08 NS090430 (GW), American Cancer Society-Research Scholar Grant 128970-RSG-16-012-01-CDD (GW).

Type IV sacrococcygeal teratoma with intraspinal involvement is rare and to our knowledge has not been reported previously in the literature. The authors present the case of a 2-month-old infant with a type IV sacrococcygeal teratoma diagnosed on prenatal ultrasound. Postnatal MRI revealed intraspinal extension through an enlarged sacral neuroforamina on the right side. On surgical exploration, the authors discovered a dorsal cystic tumor involving the sacral spine that extended through an enlarged S4 foramen to a large presacral component. The tumor was successfully removed to achieve a complete en bloc surgical resection. The authors review the epidemiology, pathophysiology, and treatment of sacrococcygeal teratomas with intraspinal extension.

Objectives There is a critical need to develop effective treatments for diabetic neuropathy. This study determined if a selective mGluR2/3 receptor agonist prevented or treated experimental diabetic peripheral neuropathy (DPN) through glutamate recycling and improved mitochondrial function. Methods Adult male streptozotocin treated Sprague-Dawley rats with features of type 1 diabetes mellitus (T1DM) or Low Capacity Running (LCR) rats with insulin resistance or glucose intolerance were treated with 3 or 10 mg/kg/day LY379268. Neuropathy end points included mechanical allodynia, nerve conduction velocities (NCV), and intraepidermal nerve fiber density (IENFD). Markers of oxidative stress, antioxidant response, glutamate recycling pathways, and mitochondrial oxidative phosphorylation (OXPHOS) associated proteins were measured in dorsal root ganglia (DRG). Results In diabetic rats, NCV and IENFD were decreased. Diabetic rats treated with an mGluR2/3 agonist did not develop neuropathy despite remaining diabetic. Diabetic DRG showed increased levels of oxidized proteins, decreased levels of glutathione, decreased levels of mitochondrial DNA (mtDNA) and OXPHOS proteins. In addition, there was a 20-fold increase in levels of glial fibrillary acidic protein (GFAP) and the levels of glutamine synthetase and glutamate transporter proteins were decreased. When treated with a specific mGluR2/3 agonist, levels of glutathione, GFAP and oxidized proteins were normalized and levels of superoxide dismutase 2 (SOD2), SIRT1, PGC-1α, TFAM, glutamate transporter proteins, and glutamine synthetase were increased in DRG neurons. Interpretation Activation of glutamate recycling pathways protects diabetic DRG and this is associated with activation of the SIRT1-PGC-1α–TFAM axis and preservation of mitochondrial OXPHOS function.

To characterize the mechanism of Zika virus (ZIKV)-associated microcephaly, we performed immunolabeling on brain tissue from a 20-week fetus with intrauterine ZIKV infection. Although ZIKV demonstrated a wide range of neuronal and non-neuronal tropism, the infection rate was highest in intermediate progenitor cells and immature neurons. Apoptosis was observed in both infected and uninfected bystander cortical neurons, suggesting a role for paracrine factors in induction of neuronal apoptosis. Our results highlight differential neuronal susceptibility and neuronal apoptosis as potential mechanisms in the development of ZIKV-associated microcephaly, and may provide insights into the design and best timing of future therapy. Ann Neurol 2017;82:121-127.

Idiopathic pulmonary fibrosis accounts for the lethal diffuse fibrosing lung disease, which is described with accumulation of fibroblasts, the loss and damage of lung epithelial cells, and causing respiratory failure. Excessive ROS level impairs the cellular redox level, inflammatory cell infiltration and abnormal collagen production to induce extracellular matrix accumulation. Nuclear factor-erythroid 2 related factor 2 (Nrf2) regulates antioxidant-associated genes as phytochemical target in chemoprevention. The preventive effect of organosulfuric compound diallyl sulfide (DAS) on TGF-β-induced fibrosis in lung MRC-5 fibroblast was investigated in this study. MRC-5 cells were pretreatment with DAS before 10 ng/mL TGF-β stimulation. DAS suppressed the collagen production in TGF-β-induced cells by attenuating Smad 2/3 phosphorylation through activating HO-1 level. DAS inhibited TGF-β-induced myofibroblast formation by decreasing ROS through enhancing Nrf2-related antioxidant enzyme and myofibroblast apoptosis. DAS is a potential dietary agent to inhibit TGF-β-induced fibrosis and to prevent oxidative stress-induced pulmonary fibrosis.

Background Individually, heart failure (HF) and Alzheimer’s disease (AD) are severe threats to population health, and their potential coexistence is an alarming prospect. In addition to sharing analogous epidemiological and genetic profiles, biochemical characteristics, and common triggers, the authors recently recognized common molecular and pathological features between the 2 conditions. Whereas cognitive impairment has been linked to HF through perfusion defects, angiopathy, and inflammation, whether patients with AD present with myocardial dysfunction, and if the 2 conditions bear a common pathogenesis as neglected siblings are unknown. Objectives Here, the authors investigated whether amyloid beta (Aβ) protein aggregates are present in the hearts of patients with a primary diagnosis of AD, affecting myocardial function. Methods The authors examined myocardial function in a retrospective cross-sectional study from a cohort of AD patients and age-matched controls. Imaging and proteomics approaches were used to identify and quantify Aβ deposits in AD heart and brain specimens compared with controls. Cell shortening and calcium transients were measured on isolated adult cardiomyocytes. Results Echocardiographic measurements of myocardial function suggest that patients with AD present with an anticipated diastolic dysfunction. As in the brain, Aβ40 and Aβ42 are present in the heart, and their expression is increased in AD. Conclusions Here, the authors provide the first report of the presence of compromised myocardial function and intramyocardial deposits of Aβ in AD patients. The findings depict a novel biological framework in which AD may be viewed either as a systemic disease or as a metastatic disorder leading to heart, and possibly multiorgan failure. AD and HF are both debilitating and life-threatening conditions, affecting enormous patient populations. Our findings underline a previously dismissed problem of a magnitude that will require new diagnostic approaches and treatments for brain and heart disease, and their combination.

Survival of human peripheral nervous system neurons and associated distal axons is highly dependent on energy. Diabetes invokes a maladaptation in glucose and lipid energy metabolism in adult sensory neurons, axons and Schwann cells. Mitochondrial (Mt) dysfunction has been implicated as an etiological factor in failure of energy homeostasis that results in a low intrinsic aerobic capacity within the neuron. Over time, this energy failure can lead to neuronal and axonal degeneration and results in increased oxidative injury in the neuron and axon. One of the key pathways that is impaired in diabetic peripheral neuropathy (DPN) is the energy sensing pathway comprising the nicotinamide-adenine dinucleotide (NAD(+))-dependent Sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α)/Mt transcription factor A (TFAM or mtTFA) signaling pathway. Knockout of PGC-1α exacerbates DPN, whereas over-expression of human TFAM is protective. LY379268, a selective metabolomic glutamate receptor 2/3 (mGluR2/3) receptor agonist, also upregulates the SIRT1/PGC-1α/TFAM signaling pathway and prevents DPN through glutamate recycling in Schwann/satellite glial (SG) cells and by improving dorsal root ganglion (DRG) neuronal Mt function. Furthermore, administration of nicotinamide riboside (NR), a precursor of NAD(+), prevents and reverses DPN, in part by increasing NAD(+) levels and SIRT1 activity. In summary, we review the role of NAD(+), mitochondria and the SIRT1–PGC-1α–TFAM pathway both from the perspective of pathogenesis and therapy in DPN.

Background Sacral schwannomas are very rare nerve sheath tumors. Patients usually present with a variety of nonspecific symptoms, which often lead to a delay in diagnosis. Although most schwannomas are benign, they present surgical challenges owing to their proximity to neurologic and other anatomic structures. Case Description This 58-year-old female presented with a 2-month old history of left-sided perineal and radicular pain secondary to a right S2 sacral nerve root schwannoma. The sacral mass demonstrated homogenous enhancement with cystic changes in a T2-weighted magnetic resonance imaging sequence. The patient underwent S1–S3 laminectomy and tumor excision through a posterior surgical approach. Intraoperative monitoring was used to distinguish nonfunctional tissue during tumor resection. The patient had an unremarkable postoperative course. Conclusions Sacral schwannomas can present with a variety of nonspecific symptoms. They pose unique challenges given their location, size, and involvement of surrounding structures. Complete surgical resection is the main goal of sacral schwannoma treatment. A combined anterior-posterior surgical approach and a multidisciplinary surgical team are associated with improved outcomes.

RATIONALE: A major factor contributing to the expanding knowledge of CNS tumors, specifically DMG biology is the selfless gift from patients and their families of postmortem tumor tissue. To facilitate this, we developed a postmortem donation program for collection of tissue and biospecimens for accelerating biology studies of end stage disease for pediatric CNS tumors. METHODS: Our postmortem program entails coordinating tissue donations, compiling clinical data, processing of whole brain, spinal cord, biofluids, and germline controls. Through our protocol, primary and disseminated tumor specimens are designated for molecular characterization and for generation of a matched preclinical model. RESULTS: During the past eight years, we coordinated and accrued over 50 autopsy cases including diffuse midline gliomas, ATRT, ETANTR, CPC from 20 institutions across North America and the United Kingdom. We report that approaching a family at the time of progression has provided the most successful outcome for consent to our program. Patient age range was from 11months to 20 years old. The median time from postmortem donation to tissue processing range was 13 hours with the earliest time point being 4 hours and the longest being 96 hours. All collected specimens were successfully processed and assessed for DNA/RNA integrity using bioanalyzer, attempted primary neurosphere cultures and cryopreserved for future molecular studies. PDX generation from fresh tissue proved more successful compared to primary neurospheres and post mortem time did not seem to have an effect. We have successfully generated models that represent molecular subgroups of DMGs such as H3.3/ H3.1- K27M and H3 WT. All generated preclinical models were validated by STR analysis and immunohistochemical assays using human mitochondrial antibodies. IMPACT: Postmortem tissue donations serve as an invaluable source for access to end-stage disease biology, generation of PDX models, studying patterns of tumor migration, testing combination therapy and preclinical drug testing.

Survival of human peripheral nervous system neurons and associated distal axons is highly dependent on energy. Diabetes invokes a maladaptation in glucose and lipid energy metabolism in adult sensory neurons, axons and Schwann cells. Mitochondrial (Mt) dysfunction has been implicated as an etiological factor in failure of energy homeostasis that results in a low intrinsic aerobic capacity within the neuron. Over time, this energy failure can lead to neuronal and axonal degeneration and results in increased oxidative injury in the neuron and axon. One of the key pathways that is impaired in diabetic peripheral neuropathy (DPN) is the energy sensing pathway comprising the nicotinamide-adenine dinucleotide (NAD+)-dependent Sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α)/Mt transcription factor A (TFAM or mtTFA) signaling pathway. Knockout of PGC-1α exacerbates DPN, whereas overexpression of human TFAM is protective. LY379268, a selective metabolomic glutamate receptor 2/3 (mGluR2/3) receptor agonist, also upregulates the SIRT1/PGC-1α/TFAM signaling pathway and prevents DPN through glutamate recycling in Schwann/satellite glial (SG) cells and by improving dorsal root ganglion (DRG) neuronal Mt function. Furthermore, administration of nicotinamide riboside (NR), a precursor of NAD+, prevents and reverses DPN, in part by increasing NAD+ levels and SIRT1 activity. In summary, we review the role of NAD+, mitochondria and the SIRT1-PGC-1α-TFAM pathway both from the perspective of pathogenesis and therapy in DPN.

Anaplastic astrocytomas are aggressive glial cancers that present poor prognosis and high recurrence. Heterozygous IDH1 R132H mutations are common in adolescent and young adult anaplastic astrocytomas. In a majority of cases, the IDH1 R132H mutation is unique to the tumor, although rare cases of anaplastic astrocytoma have been described in patients with mosaic IDH1 mutations (Ollier disease or Maffucci syndrome). Here, we present two siblings with IDH1 R132H mutant high grade astrocytomas diagnosed at 14 and 26 years of age. Analysis of IDHR132H mutations in the siblings' tumors and non-neoplastic tissues, including healthy regions of the brain, cheek cells, and primary teeth indicate mosaicism of IDHR132H. Whole exome sequencing of the tumor tissue did not reveal any other common mutations between the two siblings. This study demonstrates the first example of IDH1 R132H mosaicism, acquired during early development, that provides an alternative mechanism of cancer predisposition.

In diabetic neuropathy, there is activation of axonal and sensory neuronal degeneration pathways leading to distal axonopathy. The nicotinamide-adenine dinucleotide (NAD+)-dependent deacetylase enzyme, Sirtuin 1 (SIRT1), can prevent activation of these pathways and promote axonal regeneration. In this study, we tested whether increased expression of SIRT1 protein in sensory neurons prevents and reverses experimental diabetic neuropathy induced by a high fat diet (HFD). We generated a transgenic mouse that is inducible and overexpresses SIRT1 protein in neurons (nSIRT1OE Tg). Higher levels of SIRT1 protein were localized to cortical and hippocampal neuronal nuclei in the brain and in nuclei and cytoplasm of small to medium sized neurons in dorsal root ganglia. Wild-type and nSIRT1OE Tg mice were fed with either control diet (6.2% fat) or a HFD (36% fat) for 2 months. HFD-fed wild-type mice developed neuropathy as determined by abnormal motor and sensory nerve conduction velocity, mechanical allodynia, and loss of intraepidermal nerve fibres. In contrast, nSIRT1OE prevented a HFD-induced neuropathy despite the animals remaining hyperglycaemic. To test if nSIRT1OE would reverse HFD-induced neuropathy, nSIRT1OE was activated after mice developed peripheral neuropathy on a HFD. Two months after nSIRT1OE, we observed reversal of neuropathy and an increase in intraepidermal nerve fibre. Cultured adult dorsal root ganglion neurons from nSIRT1OE mice, maintained at high (30 mM) total glucose, showed higher basal and maximal respiratory capacity when compared to adult dorsal root ganglion neurons from wild-type mice. In dorsal root ganglion protein extracts from nSIRT1OE mice, the NAD+-consuming enzyme PARP1 was deactivated and the major deacetylated protein was identified to be an E3 protein ligase, NEDD4-1, a protein required for axonal growth, regeneration and proteostasis in neurodegenerative diseases. Our results indicate that nSIRT1OE prevents and reverses neuropathy. Increased mitochondrial respiratory capacity and NEDD4 activation was associated with increased axonal growth driven by neuronal overexpression of SIRT1. Therapies that regulate NAD+ and thereby target sirtuins may be beneficial in human diabetic sensory polyneuropathy.

INTRODUCTION Previously thought to be rare, recent case series have shown that IDH mutations in young patients are more common than previously described. In this study, we analyzed IDH-mutant tumors to determine clinical significance of these mutations in children, adolescents and young adults. METHODS Through this multi-institution study (10 institutions), we collected 64 IDH1/2-mutant infiltrating astrocytoma specimens from 58 patients aged 4–26 (M:F, 0.4:0.6). Specimens included 46 low-grade (LGG) and 18 high-grade (HGG) astrocytomas. Tumor sequencing data (n=45), germline sequencing data (n=37) and outcome data (n=40) was analyzed. RESULTS Similar to adults, most sequenced tumors had a co-mutation in the TP53 gene, while ATRX mutations were less common and primarily seen in HGGs. Approximately 60% (n=21) of patients with germline data available had a mutation in a cancer predisposition gene. Mismatch repair (MMR) mutations were most common (n=12; MSH6 n=9), followed by TP53mutations (n=7). All patients with MMR gene mutations had HGGs and poor progression free (PFS=10% at 2 years, mean TTP=9 months) and overall (OS CONCLUSION IDH-mutant tumors in pediatric patients are strongly associated with cancer predisposition and increased risk for progression/recurrence or malignant transformation. Routine screening for IDH1/2 mutations in children with grade 2–4 astrocytomas could greatly impact patient management.

SummaryObjective To demonstrate an association between magnetic resonance imaging (MRI) findings and pathologic characteristics in children who had surgery for medically refractory epilepsy due to focal cortical dysplasia (FCD). Methods We retrospectively studied 110 children who had epilepsy surgery. Twenty-seven patients with FCD were included. Thirteen had temporal lobe epilepsy (TLE) and 14 had extra-temporal lobe epilepsy (ETLE). Three patients had associated mesial temporal sclerosis. Preoperative 3T MRIs interleaved with nine controls were blindly re-reviewed and categorized according to signal alteration. Pathologic specimens were classified according to the 2011 International League Against Epilepsy (ILAE) classification and compared to MRI studies. Results Rates of pathology subtypes differed between TLE and ETLE (χ2(3) = 8.57, p = 0.04). FCD type I was more frequent in TLE, whereas FCD type II was more frequent in ETLE. In the TLE group, nine patients had temporal tip abnormalities. They all exhibited gray–white matter blurring with decreased myelination and white matter hyperintense signal. Blurring involved the whole temporal tip, not just the area of dysplasia. These patients were less likely to demonstrate cortical thickening compared to those without temporal tip findings (χ2(1) = 9.55, p = 0.002). Three of them had FCD Ib, three had FCD IIa, two had FCD IIIa, and one had FCD IIb; MRI features could not entirely distinguish between FCD subtypes. TLE patients showed more pronounced findings than ETLE on MRI (χ2(1) = 11.95, p = 0.003, odds ratio [OR] 18.00). In all cases of FCD, isolated blurring was more likely to be associated with FCD II, whereas blurring with decreased myelination was seen with FCD I (χ2(6) = 13.07, p = 0.042). Significance Our study described associations between MRI characteristics and pathology in children with FCD and offered a detailed analysis of temporal lobe tip abnormalities and FCD subtypes in children with TLE. These findings may contribute to the presurgical evaluation of patients with refractory epilepsy.

Conflicting challenges abound in the management of the newborn with intractable epilepsy related to hemimegalencephaly. Early hemispherectomy to stop seizures and prevent deleterious consequences to future neurocognitive development must be weighed against the technical and anesthetic challenges of performing major hemispheric surgery in the neonate. We hereby present our experience with two neonates with hemimegalencephaly and intractable seizures who were managed using a strategy of initial minimally invasive embolization of the cerebral blood supply to the involved hemisphere. Immediate significant seizure control was achieved after embolization of the cerebral blood supply to the involved hemisphere followed by delayed ipsilateral hemispheric resection at a later optimal age. The considerations and challenges encountered in the course of the management of these patients are discussed, and a literature review is presented.

Cerebral radiation necrosis (CRN) is a toxicity of radiation therapy that can result in significant, potentially life-threatening neurologic deficits. Treatment for CRN has included surgical resection, corticosteroids, hyperbaric oxygen therapy (HBOT), and bevacizumab, but no consensus approach has been identified. We reviewed the available literature to evaluate efficacy of treatment approaches. Using methods specified in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines when possible, we conducted searches of Ovid MEDLINE, Embase and Pubmed to identify studies reporting on outcomes for children (≤21 years old) with CRN. Eligible studies from 1990 to 2014 describing central nervous system (CNS) radiation necrosis with details of both treatment and outcomes were included. Eleven studies meeting criteria were identified. Of the nine studies with total patient denominators, 37 of 806 patients developed CRN (incidence = 4.6 %). Patients received treatment courses of steroids alone (n = 13), steroids with bevacizumab (n = 11) or HBOT (n = 12). Patients who failed to respond to steroids were more likely to be older than steroid-responsive patients (p = 0.009). With the exception of steroid-related adverse events, there was only one report of an adverse event (brainstem stroke) potentially attributable to intervention (bevacizumab). Those who received proton beam RT were both younger (p = 0.001) and had a shorter time to development of CRN (p = 0.079). The most common treatment following steroid initiation was addition of bevacizumab or HBOT, with good success and minimal toxicity. However, randomized controlled trials are needed to establish a definitive treatment algorithm that can be applied to children affected by CRN.

There is no curative treatment for patients with diffuse intrinsic pontine glioma (DIPG). However, with the recent availability of biopsy and autopsy tissue, new data regarding the biologic behavior of this tumor have emerged, allowing greater molecular characterization and leading to investigations which may result in improved therapeutic options. Treatment strategies must address both primary disease sites as well as any metastatic deposits, which may be variably sensitive to a particular approach. In this case report, we present a patient with DIPG treated with irradiation and serial investigational agents. The clinical, pathological and molecular phenotypes of both the progressive primary tumor as well as concomitant metastatic deposits obtained at autopsy are discussed. While some mRNA differences were demonstrated, all analyzed sites of disease shared similar mutational arrangements, suggesting that targeting the mutations of the primary tumor may be effective for all sites of disease.

Seizure freedom following resection of focal cortical dysplasia (FCD) correlates with complete resection of the dysplastic cortical tissue. However, difficulty with intraoperative identification of the lesion may limit the ability to achieve the surgical objective of complete extirpation of these lesions. Intraoperative magnetic resonance imaging (iMRI) may aid in FCD resections. The objective of this study is to compare rates of postoperative seizure freedom, completeness of resection, and need for reoperation in patients undergoing iMRI-assisted FCD resection versus conventional surgical techniques. We retrospectively reviewed the medical records of pediatric subjects who underwent surgical resection of FCD at Children’s National Medical Center between March 2005 and April 2015. At the time of the last postoperative follow-up, 11 of the 12 patients (92 %) in the iMRI resection group were seizure free (Engel Class I), compared to 14 of the 42 patients (33 %) in the control resection group (p = 0.0005). All 12 of the iMRI patients (100 %) achieved complete resection, compared to 24 of 42 patients (57 %) in the control group (p = 0.01). One (8 %) patient from the iMRI-assisted resection group has required reoperation, compared to 17 (40 %) patients in the control resection group. Our results suggest that the utilization of iMRI during surgery for resection of FCD results in improved postoperative seizure freedom, completeness of lesion resection, and reduction in the need for reoperation.

Allergic airway disorder is characterized by an increase in the level of reactive oxygen species (ROS). The induction of inflammation and hyperresponsiveness by an allergen was ameliorated by antioxidants in vivo. This study investigated the protective effects and underlying mechanism of diallyl sulfide (DAS) on ovalbumin (OVA)-induced allergic asthma of BALB/c mice. The animals were intraperitoneally sensitized by inhaling OVA to induce chronic airway inflammation. By administering DAS, a decrease of the infiltrated inflammatory cell counts and the levels of IL-4 and IL-10 in bronchoalveolar lavage fluid as well as the OVA-specific immunoglobulin E levels in sera were observed. DAS also effectively inhibited OVA-induced inflammatory cell infiltration and mucus hypersecretion in lung tissue. Several OVA-induced inflammatory factors (ROS, 8-hydroxy-2'-deoxyguanosine, 8-iso-prostaglandin F2α, and NF-κB) were inhibited by DAS. In addition, DAS increased OVA inhalation-reduced levels of Nrf2 activation by regulating microRNA-144, -34a and -34b/c. Together, the pathogenesis of OVA-induced asthma is highly associated with oxidative stress, and DAS may be an effective supplement to alleviate this disease.

Sirtuin1 (SIRT1) protein uses NAD+ as a substrate to deacetylate transcription factors, cofactors, and histones to enhance mitochondrial function. We tested the hypothesis whether increased expression of SIRT1 protein in dorsal root ganglion (DRG) neurons would rescue mice from peripheral neuropathy induced by a high fat diet (HFD). Neuron-specific, doxycycline (DOX)-inducible, SIRT1 protein over expressing C57BL6 transgenic mouse (nSIRT1OE Tg) were generated. Expression of SIRT1 protein was observed in small to medium sized DRG neurons. nSIRT1OE was shut off by feeding, weaned Tg mice, with DOX in the diet for 12 weeks. The Tg mice were divided into 3 groups. Group # 1: nSIRT1OE Tg mice fed with standard diet (STD) plus DOX for 4 months; Group # 2: nSIRT1OE Tg mice fed with HFD plus DOX for 4 months; Group # 3: nSIRT1OE Tg mice fed with HFD plus DOX for 2 months until they develop neuropathy and then switched to HFD minus DOX for additional 2 months. Neuropathy was determined by mechanical allodynia thresholds (MAT) and nerve conduction velocity (NCV) at 0, 2 and 4 months. Intraepidermal nerve fiber density (IENFD) was measured at 4 months. MAT, NCV and IENFD were decreased in HFD-fed (Group # 2) mice compared to STD-fed mice (Group # 1) at 2 and 4 months. In Group # 3 mice, 2 months after turning on nSIRT1OE, we observed a reversal of mechanical allodynia, NCV and attenuation of IENFD (Group # 3 compared to Group # 2). Western blot of protein extracts from DRG neurons showed that HFD increased acetylation of proteins and SIRT1OE abolished the HFD-induced acetylation of proteins. The mitochondrial bioenergetics profile of cultured adult DRG neurons showed that hyperglycemia induced a decrease in the spare respiratory capacity in wild type (WT) DRG neurons. This was corrected in nSIRT1OE Tg DRG neurons. In type 2 diabetic neuropathy, altered acetylation of proteins and reduced mitochondrial function via a defective SIRT1 pathway may contribute to developing distal axonopathy. Disclosure K. Chandrasekaran: None. C. Ho: None. M. Salimian: None. P.H. Kumar: None. S. Konduru: None. J.W. Russell: None.

Background Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare, low-grade adnexal neoplasm that most commonly involves the eyelid. Analogous to solid papillary carcinoma of the breast, it probably represents a precursor lesion to mucinous carcinoma. Here, we describe 11 cases of EMPSGC with molecular analysis. Methods We performed a retrospective search of the Johns Hopkins Medical Institute pathology database and identified 11 cases of EMPSGC. Immunohistochemistry was performed for chromogranin, synaptophysin, neuron specific enolase, estrogen receptor (ER), epithelial membrane antigen (EMA), cytokeratin 7 (CK7), and cytokeratin 20 (CK20). Array comparative genomic hybridization (aCGH) and BRAFV600E pyrosequencing were performed on two and three cases, respectively. Results We observed a strong female predilection (73% females, 8/11 cases) with an average age of 66 years (range, 56-83 years). EMPSGCs were associated with adjacent benign sweat gland cysts (3/11), atypical intraductal proliferation (1/11), and mucinous carcinoma (1/11). Immunohistochemically, all tumors expressed at least one neuroendocrine marker, ER, EMA, and CK7, and were negative for CK20. aCGH demonstrated a 6p11.2 to 6q16.1 deletion (1/2 cases). All cases were negative for BRAFV600E mutation (3/3 cases). Conclusion This series provides further histopathologic support that EMPSGC represents a multistage progression to mucinous carcinoma. Additional studies are needed to understand its molecular mechanisms.

Among brain tumors, the BRAF V600E mutation is frequently associated with pleomorphic xanthoastrocytomas (PXAs) and gangliogliomas (GGs). This oncogenic mutation is also detected in ~5 % of other pediatric low-grade gliomas (LGGs) including pilocytic astrocytomas (PAs) and diffuse astrocytomas. In the current multi-institutional study of 56 non-PXA/non-GG diencephalic pediatric LGGs, the BRAF V600 mutation rate is 36 %. V600-mutant tumors demonstrate a predilection for infants and young children (

The criteria of mechanical reliability in solder joints can be identified and described by comparative evaluation via drop test and high speed pendulum impact test. Systematic samples of assembly and attachment joints with various Pd additions were employed and investigated in this study. The statistical values of mechanical performances were calculated and compared. Better high speed impact performance of SAC305/ENEPIG attachment joints with 0.06 μm Pd layers was confirmed owing to the single Cu 6 Sn 5 phase growth. However, the comparative measurement of the better performance on drop testing exhibited in ENEPIG/SAC305/immersion Sn assembly joints with 0.1 μm Pd layers deposit resulted from the thinner and layer-type IMC growth. The correlation between the cracks propagation and Pd addition was established on the basis of the elemental X-ray color mapping via Field-Emission Electron Probe Microanalyzer (FE-EPMA). It is expected that through comparison between impact and drop test in mechanical reliability, a criterion of joints reliability can be established. Besides, the optimal Pd layer deposit for the ENEPIG surface finish in the attachment and assembly solder joints was demonstrated and confirmed.

BACKGROUND Positive cerebrospinal fluid (CSF) cytology typically indicates leptomeningeal dissemination of metastatic, secondary, or rarely, primary central nervous system (CNS) tumors. To the authors' knowledge, large-scale studies on clinicocytologic features of various primary CNS tumors in CSF are lacking. METHODS The authors performed a retrospective cytomorphologic study on 127 positive CSF specimens from 87 patients with a history of primary nonhematologic CNS tumors. Pertinent clinical, radiological, and histologic findings were reviewed. RESULTS Pediatric tumors accounted for the majority (82.6%) of the primary CNS tumors with positive CSF cytology. The most common radiological finding of neuraxial dissemination was diffuse leptomeningeal enhancement. Greater than 95% of the cases with positive CSF cytology were high-grade or malignant tumors. The most common tumor type was central primitive neuroectodermal tumors (47.2%). Overall, the frequency of initial metastasis was found to be lowest in central primitive neuroectodermal tumors and retinoblastomas (approximately one-third). They also had the longest latency (1.5-2 years) in cases without initial metastasis. The majority of metastatic tumors in CSF demonstrated distinct cytomorphology reminiscent of the histologic features of the primary tumor, such as prominent nucleoli, cell wrapping, and apoptosis in large cell/anaplastic medulloblastomas; rhabdoid morphology and cytoplasmic inclusions in atypical teratoid/rhabdoid tumors; large clusters of cells with scant cytoplasm and nuclear molding in retinoblastomas; nuclear pleomorphism and hyperchromasia in high-grade infiltrating astrocytomas; and small clusters/rosettes of epithelioid cells in ependymomas. CONCLUSIONS The results of the current study provide useful clinicoradiological information and cytomorphologic findings for both common and rare primary CNS tumors that cytopathologists might encounter on CSF examination. Cancer (Cancer Cytopathol) 2015;123:123–135. © 2014 American Cancer Society.

IDH mutations are considered rare in pediatric gliomas, especially in children under 14 years of age. Therefore, IDH-mutant pediatric gliomas have not been well characterized. Through this multi-institution study (5 institutions), we analyzed a total of 20 IDH1/2-mutant pediatric/AYA infiltrating astrocytoma specimens from 18 patients aged 4-26. The specimens include 15 low-grade (WHO grade II) and 5 high-grade (WHO grade III or IV) astrocytomas. A majority of the tumors appear to be early lesions based on the low cellularity, making them suitable for studying the order of driver mutations. Similar to their adult counterparts, nearly all pediatric IDH-mutant infiltrating astrocytomas (17 tumors, 85%) harbor TP53 mutation. In comparison, ATRX mutations are less frequent, detected in only 9 tumors (45%) including 4 low-grade (26% of all low-grade) and 5 high-grade tumors (100% of all high-grade). Six patients (30%) carry germline mutations in tumor suppressor or mismatch repair genes including TP53, MSH6, and RB1. All patients (N=3) with a germline mutation in MSH6 (a mismatch repair gene) had high-grade IDH-mutant astrocytomas with high genomic instability. In contrast, patients with germline TP53 mutation (Li-Fraumeni syndrome, LFS-N=2) had low-grade tumors with low mutation burden, morphologically and genetically similar to the sporadic cases. Notably, 7 out of 12 sporadic tumors harboring TP53 mutations had a TP53 mutant allele frequency that is greater than twice the IDH1/2 allelic frequency, after adjustment for TP53 loss of heterozygosity in 2 cases. This finding, together with the LFS-associated tumors, suggests that TP53 mutation may precede, or predispose to, IDH mutations in a significant fraction of astrocytomas in young patients. Our results not only define the molecular architecture of pediatric IDH-mutant infiltrating astrocytomas, but also provide insight into the genetic evolution of these tumors.

Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain cancer which presents an immense therapeutic challenge. Our previous work has shown that histone mutations (H3K27M) arise in the pontine tumor but in most cases necessitates an obligate partner mutation for tumorigenesis and spread. Our established standard operating procedure for performing autopsy has allowed us to collect 20 whole brains from DIPG patients. Sagittal sections from whole brains (n=8) were processed for histological analyses to identify the tumor migratory path (pontine to extra-pontine). Histological examination of all neuroanatomical locations indicated: i) Tumor cell infiltration to extra-pontine regions in 7/8 brains as indicated by histology, ii) In 4/7 brains, tumor cells migrated to extra-pontine regions but failed to form tumors. These regions were histologically “normal” according to the World Health Organization grading criteria, but harbored tumor cells as indicated by H3K27M stains and digital PCR. Given the age of disease onset, and neuroanatomical location, it is plausible that tumor microenvironment plays a critical role in tumor spread. To test the role of pontine microenvironment in tumorigenesis, we performed a pilot study by injecting human pontine tumor cells (n= 4 patients) into 3-4 week old murine cerebral cortex, which represents the age of DIPG disease onset. Necropsy specimens were examined for tumor presence by histological analyses for H&E and H3K27M stains. We identified tumor in both cortex (injection site) and brainstem. Tumor cells migrated to populate brainstem in all four, and cerebellum in 2/4 xenograft models. Furthermore these tumors were positive for human mitochondrial protein (MAB1273) and were authenticated by STR to demonstrate their human cell of origin. These observations strongly show the presence of: i) anatomically suitable migration paths (e.g. axonal guidance, leptomeningeal), and ii) tissue-specific microenvironment and molecular events, governing susceptibility and sensitivity of particular neuroanatomical locations to tumor formation.

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

For the past decade, it has been recognized that pediatric low-grade gliomas (LGGs) and glial-neuronal tumors carry distinct molecular alterations with resultant aberrant intracellular signaling in the Ras-mitogen-activated protein kinase pathway. The conclusions and recommendations of a consensus conference of how best to integrate the growing body of molecular genetic information into tumor classifications and, more importantly, for future treatment of pediatric LGGs are summarized here. There is uniform agreement that molecular characterization must be incorporated into classification and is increasingly critical for appropriate management. Molecular-targeted therapies should be integrated expeditiously, but also carefully into the management of these tumors and success measured not only by radiographic responses or stability, but also by functional outcomes. These trials need to be carried out with the caveat that the long-term impact of molecularly targeted therapy on the developing nervous system, especially with long duration treatment, is essentially unknown.

Alexander disease is a leukodystrophy caused by dominant missense mutations in the gene encoding the glial fibrillary acidic protein. Individuals with this disorder often present with a typical neuroradiologic pattern including white matter abnormalities with brainstem involvement, selective contrast enhancement, and structural changes to the basal ganglia/thalamus. In rare cases, focal lesions have been seen and cause concern for primary malignancies. Here the authors present an infant initially diagnosed with a chiasmatic astrocytoma that was later identified as having glial fibrillary acidic protein mutation-confirmed Alexander disease. Pathologic and radiologic considerations that were helpful in arriving at the correct diagnosis are discussed.

Alexander disease is a leukodystrophy caused by dominant missense mutations in the gene encoding the glial fibrillary acidic protein. Individuals with this disorder often present with a typical neuroradiologic pattern including white matter abnormalities with brainstem involvement, selective contrast enhancement, and structural changes to the basal ganglia/thalamus. In rare cases, focal lesions have been seen and cause concern for primary malignancies. Here the authors present an infant initially diagnosed with a chiasmatic astrocytoma that was later identified as having glial fibrillary acidic protein mutation-confirmed Alexander disease. Pathologic and radiologic considerations that were helpful in arriving at the correct diagnosis are discussed.

To characterize the mechanism of Zika virus (ZIKV)-associated microcephaly, we performed immunolabeling on brain tissue from a 20-week fetus with intrauterine ZIKV infection. Although ZIKV demonstrated a wide range of neuronal and non-neuronal tropism, the infection rate was highest in intermediate progenitor cells and immature neurons. Apoptosis was observed in both infected and uninfected bystander cortical neurons, suggesting a role for paracrine factors in induction of neuronal apoptosis. Our results highlight differential neuronal susceptibility and neuronal apoptosis as potential mechanisms in the development of ZIKV-associated microcephaly, and may provide insights into the design and best timing of future therapy. Ann Neurol 2017;82:121-127.

A new multilayer metallization, ENEPIG (Electroless Ni(P)/Electroless Pd/Immersion Au) with ultrathin Ni(P) deposit (ultrathin-ENEPIG), was designed to be used in high frequency electronic packaging in this study because of its ultra-low electrical impedance. Sequential interfacial microstructures of commercial Sn–3.0Ag–0.5Cu solders reflowed on ultarthin-ENEPIG with Ni(P) deposit thickness ranged from 4.79 μm to 0.05 μm were first investigated. Accelerated thermal aging test was then conducted to evaluate the long-term thermal stabilization of solder joints. The results showed that P-rich intermetallic compound (IMC) layer formed when the Ni(P) thickness was greater than a critical vale (about 0.18 μm). Besides, it is interesting to mention that the growth of (Cu,Ni)6Sn5 and (Cu,Ni)3Sn IMCs was suppressed with the formation of P-rich layer, i.e., Ni3P and Ni2Sn1+xP1−x phase, even though the electroless-plated Ni(P) layer was exhausted at initial stage of reflow process. The atomic Cu flux in solder joints without P-rich layer was calculated to be several times larger than that with P-rich layer formation after calculation, which implies that the P-rich layer and ultrathin Ni(P) deposit in ENEPIG served as diffusion barrier against rapid Cu diffusion.

Ketoprofen is widely used to alleviate pain and inflammation in clinical medicine; however, this drug may cause oxidative stress and lead to gastrointestinal (GI) ulcers. We previously reported that nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in protecting cells against reactive oxygen species, and it facilitates the prevention of ketoprofen-induced GI mucosal ulcers. Recent reports suggested that Nrf2 becomes unstable in the absence of DJ-1/PARK7, attenuating the activity of Nrf2-regulated downstream antioxidant enzymes. Thus, increasing Nrf2 translocation by DJ-1 may represent a novel means for GI protection. In vitro, caffeic acid increases the nuclear/cytosolic Nrf2 ratio and the mRNA expression of the downstream antioxidant enzymes, ϒ-glutamyl cysteine synthetase, glutathione peroxidase, glutathione reductase, and heme oxygenase-1, by activating the JNK/p38 pathway in Int-407 cells. Moreover, knockdown of DJ-1 also reversed caffeic acid-induced nuclear Nrf2 protein expression in a JNK/p38-dependent manner. Our results also indicated that treatment of Sprague-Dawley rats with caffeic acid prior to the administration of ketoprofen inhibited oxidative damage and reversed the inhibitory effects of ketoprofen on the antioxidant system and DJ-1 protein expression in the GI mucosa. Our observations suggest that DJ-1 plays an important role in caffeic acid-mediated protection against ketoprofen-induced oxidative damage in the GI mucosa.

This study aims to investigate the microstructure, β-Sn crystallography, micro-hardness and impact reliability of both Sn–3.0Ag–0.5Cu/Cu (SAC/Cu) and Sn–3.0Ag–0.5Cu/Ni (SAC/Ni) solder joints under various reflow processes. During the solidification step of the reflow process, solder joints were annealed at 210 °C for 50 s and 100 s, respectively. Network-type precipitations formed within the SAC/Cu joint, while dot-type precipitations distributed within the SAC/Ni joint. With the increase of annealing time, these precipitations grew larger; the interfacial intermetallic compounds (IMCs) became slightly thicker, and the hardness of solder alloys gradually decreased. Electron backscatter diffraction (EBSD) analysis indicates that the β-Sn grain structure depended on the distribution of precipitations. A high speed shear tester was used to evaluate the impact toughness of solder joints. Noteworthily, the short-time annealing can improve the impact reliability of solder joints. After annealing for 50 s, the average impact toughness of both SAC/Cu and SAC/Ni solder joints was enhanced, and the percentage of ductile fracture increased significantly. However, the growth of (Cu,Ni)6Sn5 at the SAC/Ni interface degraded the impact toughness as the SAC/Ni joint was annealed for 100 s. The variation of impact toughness in SAC/Cu and SAC/Ni is correlated to the variation of microstructure and hardness in solder joints.

Gouty arthritis is an inflammatory disease that is caused by an accumulation of monosodium urate (MSU) crystals in the joints. MSU is capable of activating the nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome, leading to interleukin-1β (IL-1β) secretion. Reactive oxygen species (ROS) are major mediators of the NLRP3/IL-1β interaction. Although nuclear factor E2-related factor 2 (Nrf2) is recognized as a transcription factor that is involved in the response to oxidative stress, the effect of MSU on Nrf2 and on Nrf2-mediated antioxidant enzymes remains unclear. The treatment of THP-1 monocytes using phorbol 12-myristate 13-acetate (PMA) was shown to initiate inflammatory responses. Here, we showed that THP-1 cells, following treatment with MSU crystals, significantly increased IL-1β release, NLRP3 inflammasome activation and ROS production. MSU also promoted the nuclear translocation of Nrf2 and activated lysosomal destabilization. Moreover, the levels of heme oxygenase-1 (HO-1) in gene and protein expressions were upregulated by MSU. MSU-induced IL-1β secretion and NLRP3 inflammasome activation were inhibited by the knockdown of Nrf2 and via the HO-1 inhibitor zinc (II) protoporphyrin IX (ZnPP). In addition, HO-1 inhibition increased the level of superoxide anion production and the consumption of glutathione. These findings suggest that Nrf2 and HO-1 mediate redox homeostasis and interact with pro-inflammatory factors in MSU-challenged THP-1 cells, thereby providing new insight into how MSU-induced gouty inflammation is mediated by specific mechanisms that are involved in the Nrf2/Ho-1 antioxidant signaling pathway.CellularMolecular Immunology advance online publication, 11 August 2014; doi:10.1038/cmi.2014.65.

ENEPIG with various thicknesses of submicron Ni(P) deposit (Ultrathin-ENEPIG) was adopted to evaluate the electrical impedance behavior, microstructural comparison, and high-speed impact resistance prior to and after isothermal aging process. The results show that when extending the aging time to 1000 h, the high-speed impact energy of ultrathin-ENEPIG with 0.31 μm Ni(P) layer deteriorated significantly. In contrast, mechanical performance maintained well for ultrathin-ENEPIG with 0.18 μm Ni(P) deposit. The loss of adhesion might be attributed to the Kirkendall voids resulting from the unbalanced diffusion for Sn and Cu in Ni 3 P crystalline. In ultrathin-ENEPIG with 0.18 μm Ni(P) deposit, on the other hand, the migration of Sn in Ni 2 Sn 1+ x P 1− x was faster than in Ni 3 P. Besides, secondary-(Cu,Ni) 6 Sn 5 layer slowed down the out-diffusion of Cu. Thereby, the unbalanced diffusion can be eliminated. The optimization of the Ni(P) deposit thickness selection in ultrathin-ENEPIG would be discussed and proposed based on the observations of the electrical behavior, joint strength evolution, and interfacial thermal stability.