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Background: Infiltrative astrocytic tumors with and without isocitrate dehydrogenase (IDH) mutation frequently contain mutations in the TP53 tumor suppressor gene. Disruption of normal p53 protein activity confers neoplastic cells with a number of oncogenic properties and is a common feature of aggressive malignancies. However, the high prevalence of TP53 mutation and its pathogenic role in IDH-mutant (IDHmut) astrocytoma is not well understood., Methods: We performed a retrospective analysis of molecular and clinical data from patients with IDHmut astrocytoma at the University of Pittsburgh Medical Center between 2015 and 2019 as our initial cohort. We validated and expanded our findings using molecular and clinical data from The Cancer Genome Atlas., Results: We show that the TP53 mutational spectrum in IDHmut astrocytomas is dominated by a single hotspot mutation that codes for the R273C amino acid change. This mutation is not enriched in IDH-wildtype astrocytomas. The high prevalence of TP53 R273C mutation is not readily explained by known mutagenic mechanisms, and TP53 R273C mutant tumors have lower transcriptional levels of proliferation-related genes compared to IDHmut astrocytomas harboring other forms of mutant p53. Despite lower proliferation, TP53 R273C mutant tumors tend to progress more quickly and have a shorter overall survival than those with other TP53 mutations, particularly in male patients., Conclusions: Our findings suggest that compared to other TP53 mutations, IDHmut astrocytomas may select for TP53 R273C mutations during tumorigenesis. The genotype, sex, and mutation-specific findings are clinically relevant and should prompt further investigation of TP53 R273C ., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Introduction: Post-herpetic neuralgia is a crippling complication of varicella zoster virus (VZV) reactivation, also known as zoster disease. In rare cases, VZV spreads to the spinal cord and causes myelitis. There is a paucity of data on spinal cord histopathology in the subacute phase of post-herpetic neuralgia and VZV myelitis., Case Description: In this report, we present a case of post-herpetic neuralgia in a patient who died 5 weeks after initiation of symptoms. Autopsy limited to the spinal cord revealed severe tissue vacuolization associated with macrophage and lymphocytic infiltration that was most intense in the right posterior horn, corresponding to an area of magnetic resonance imaging (MRI) T2-weighted hyperintensity. There was some extension of the inflammatory response to the ipsilateral posterior column, dorsolateral column, precentral gray matter, and contralateral lateral column. No significant axonal or myelin loss was observed. Nerve roots and meninges were free of significant inflammation., Discussion: Our findings provide histopathological insight into early subacute changes in post-herpetic neuralgia and suggest the involvement of the cord and subsequent macrophage and lymphocyte inflammatory response may lead to pain fiber irritation and the clinical pain syndrome of post-herpetic neuralgia., Competing Interests: Compliance with ethical standardsThe authors declare that they have no conflict of interest.We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during the course of this research.

Acute amphetamine (AMPH) exposure elevates extracellular dopamine through a variety of mechanisms that include inhibition of dopamine reuptake, depletion of vesicular stores, and facilitation of dopamine efflux across the plasma membrane. Recent work has shown that the DAT substrate AMPH, unlike cocaine and other nontransported blockers, can also stimulate endocytosis of the plasma membrane dopamine transporter (DAT). Here, we show that when AMPH enters the cytoplasm it rapidly stimulates DAT internalization through a dynamin-dependent, clathrin-independent process. This effect, which can be observed in transfected cells, cultured dopamine neurons, and midbrain slices, is mediated by activation of the small GTPase RhoA. Inhibition of RhoA activity with C3 exotoxin or a dominant-negative RhoA blocks AMPH-induced DAT internalization. These actions depend on AMPH entry into the cell and are blocked by the DAT inhibitor cocaine. AMPH also stimulates cAMP accumulation and PKA-dependent inactivation of RhoA, thus providing a mechanism whereby PKA- and RhoA-dependent signaling pathways can interact to regulate the timing and robustness of AMPH's effects on DAT internalization. Consistent with this model, the activation of D1/D5 receptors that couple to PKA in dopamine neurons antagonizes RhoA activation, DAT internalization, and hyperlocomotion observed in mice after AMPH treatment. These observations support the existence of an unanticipated intracellular target that mediates the effects of AMPH on RhoA and cAMP signaling and suggest new pathways to target to disrupt AMPH action.

Human parechovirus 3 (HPeV3) is a picornavirus associated with neurologic disease in neonates. Human parechovirus 3 infection of preterm and term infants is associated with seizures and destructive periventricular white matter lesions. Despite unremarkable cerebrospinal fluid (CSF), HPeV3 RNA can be amplified from CSF and nasopharyngeal and rectal swabs. We report pathologic findings in 2 autopsy cases of infants with active HPeV3 infection. Both children were born approximately 1 month premature and were neurologically intact but, after a few weeks, developed seizures and radiologic evidence of white matter lesions. Neuropathologic examination demonstrated classic severe periventricular leukomalacia in the absence of an immune response. Human parechovirus 3 sequences were identified in RNA extracted from CSF, sera, and tissues. Human parechovirus 3 in situ hybridization detection of infected cells was limited to meninges and associated blood vessels in addition to smooth muscle of pulmonary vessels. Ultrastructural evaluation of meninges demonstrated dense core structures compatible with picornavirus virions. These findings suggest that encephalopathic changes are secondary to infection of meninges and potential compromise of vascular perfusion. Thus, parechovirus infection of vascular smooth muscle may be a more general pathogenic process.

Background: Immunization against beta-amyloid (Aβ) is a promising approach for the treatment of Alzheimer's disease, but the optimal timing for the vaccination remains to be determined. Preventive immunization approaches may be more efficacious and associated with fewer side-effects; however, there is only limited information available from primate models about the effects of preclinical vaccination on brain amyloid composition and the neuroinflammatory milieu., Methods: Ten non-human primates (NHP) of advanced age (18-26 years) and eight 2-year-old juvenile NHPs were immunized at 0, 2, 6, 10 and 14 weeks with aggregated Aβ42 admixed with monophosphoryl lipid A as adjuvant, and monitored for up to 6 months. Anti-Aβ antibody levels and immune activation markers were assessed in plasma and cerebrospinal fluid samples before and at several time-points after immunization. Microglial activity was determined by [(11)C]PK11195 PET scans acquired before and after immunization, and by post-mortem immunohistochemical and real-time PCR evaluation. Aβ oligomer composition was assessed by immunoblot analysis in the frontal cortex of aged immunized and non-immunized control animals., Results: All juvenile animals developed a strong and sustained serum anti-Aβ IgG antibody response, whereas only 80 % of aged animals developed detectable antibodies. The immune response in aged monkeys was more delayed and significantly weaker, and was also more variable between animals. Pre- and post-immunization [(11)C]PK11195 PET scans showed no evidence of vaccine-related microglial activation. Post-mortem brain tissue analysis indicated a low overall amyloid burden, but revealed a significant shift in oligomer size with an increase in the dimer:pentamer ratio in aged immunized animals compared with non-immunized controls (P < 0.01). No differences were seen in microglial density or expression of classical and alternative microglial activation markers between immunized and control animals., Conclusions: Our results indicate that preventive Aβ immunization is a safe therapeutic approach lacking adverse CNS immune system activation or other serious side-effects in both aged and juvenile NHP cohorts. A significant shift in the composition of soluble oligomers towards smaller species might facilitate removal of toxic Aβ species from the brain.

Aim: We sought to define the mechanism of total body irradiation (TBI)-induced seizures in NOS1(-/-) mice and amelioration by intra-esophageal manganese superoxide dismutase-plasmid liposomes (MnSOD-PL)., Materials and Methods: We evaluated the role of vagus nerve pathways in irradiation-induced seizures using biochemical, physiologic, and histopathologic techniques., Results: Heterozygous NOS1(+/-) mice demonstrated radioresistance similar to wild-type C57BL/6NHsd mice (p=0.9269). Irradiation-induced lipid peroxidation in fetal brain cultures from NOS1(-/-) or wild-type mice was reduced by MnSOD-PL. Right-sided vagotomy did not alter the TBI radiation response of wild-type or reverse the radiosensitivity of NOS1(-/-) mice. Excised esophagus from irradiated NOS1(-/-) mice demonstrated an increased histopathologic inflammatory response compared to C57BL/6NHsd mice., Conclusion: NOS1(-/-) mice represent a model system for dissecting the developmental abnormalities leading to esophageal-mediated TBI-induced seizures.

The case of a 75-year-old man with a history of lymphoma, recent upper respiratory tract infection, and a protracted course of encephalopathy is presented. Radiologically, findings were consistent with posterior reversible encephalopathy syndrome. A brain biopsy revealed evidence of endothelial activation, T-cell trafficking, and vascular endothelial growth factor expression, suggesting that systemic immune system activation may be involved with triggering posterior reversible encephalopathy syndrome. In addition, underlying cerebral amyloid angiopathy may have contributed to the initial nonclassical edema distribution by compromising autoregulatory blood flow mechanisms.

Aberrant activation of Akt is a common finding in adult malignant gliomas, resulting in most cases from mutations or deletions involving PTEN, which allows constitutive Akt phosphorylation. In contrast, we have previously reported that pediatric malignant gliomas, which are morphologically similar to lesions arising in adults, have a substantially lower incidence of genomic alterations of PTEN. The objective of this study was to determine whether Akt activation was also an uncommon finding in childhood malignant gliomas and whether this feature was associated with survival. To address this issue, we examined the frequency of Akt activation, determined by overexpression of the activated phosphorylated form of Akt (Se(473)) on immunohistochemical analysis, in a series of 53 childhood malignant gliomas obtained from newly diagnosed patients treated on the Children's Oncology Group ACNS0126 and 0423 studies. The relationship between Akt activation and p53 overexpression, MIB1 labeling, and tumor histology was evaluated. The association between Akt activation and survival was also assessed. Overexpression of activated Akt was observed in 42 of 53 tumors, far in excess of the frequency of PTEN mutations we have previously observed. There was no association between Akt activation and either histology, p53 overexpression, or MIB1 proliferation indices. Although tumors that lacked Akt overexpression had a trend toward more favorable event-free survival and overall survival (p = 0.06), this association reflected that non-overexpressing tumors were significantly more likely to have undergone extensive tumor removal, which was independently associated with outcome. Activation of Akt is a common finding in pediatric malignant gliomas, although it remains uncertain whether this is an independent adverse prognostic factor. In view of the frequency of Akt activation, the evaluation of molecularly targeted therapies that inhibit this pathway warrants consideration for these tumors.

Angiomatoid fibrous histiocytoma (AFH) is a rare soft-tissue neoplasm that most commonly appears in the limbs, typically affecting children and young adults. The tumor has a propensity for local recurrence and recurrent hemorrhage but rarely for remote metastasis. To date, only 2 reports have documented an intracranial occurrence of the tumor (1 of which was believed to be metastatic disease). This is the second report of primary intracranial AFH. Additionally, hemorrhage from an intracranial AFH lesion has yet to be reported, and little is known about the radiographic characteristics and biological behavior of these lesions. In this report, the authors describe the case of a patient with recurrent hemorrhage due to primary multifocal intracranial AFH. Initially misdiagnosed as a cavernous malformation and then an unusual meningioma, the tumor was finally correctly identified when there was a large enough intact resection specimen to reveal the characteristic histological pattern. The diagnosis was confirmed using immunohistochemical and molecular studies.

Mutations in isocitrate dehydrogenase enzyme isoforms 1 (IDH1) and 2 (IDH2) have been identified in many adult astrocytomas and oligodendrogliomas. These mutations are targeted to specific codons (e.g. R132 in IDH1 and R172 in IDH2), making assays to detect them in clinical specimens feasible. We describe a simple and accurate molecular assay for detection of IDH1/2 mutations on routine formalin-fixed paraffin-embedded tissues. Using this polymerase chain reaction-based assay, we tested 75 glial neoplasms and 57 nonneoplastic conditions that can mimic gliomas including radiation changes, viral infections, and infarcts. Of the gliomas, 37 (49%) were positive for IDH1 or IDH2 mutations; the most common mutation was IDH1 (97%). Two of 12 gangliogliomas were positive for IDH1 mutation, and both had unfavorable clinical outcomes (p < 0.03). None of the nonneoplastic cases were positive for IDH mutations. The assay detected IDH mutations in biopsy material containing mostly glioma and in concomitant near-miss stereotactic core biopsies that were otherwise equivocal for the presence of glioma by light microscopy. These results indicate that testing for IDH1/2 mutations can be effectively performed in a clinical setting and can enhance the accuracy of diagnosis of gliomas when traditional diagnostic methods are not definitive.

Conjoined twinning is a rare form of twinning, in which 2 bodies are attached, and is classified according to the anatomic place of attachment. An extremely rare form of conjoined twinning is janiceps conjoined twinning, in which 2 faces are attached but oriented in opposite directions. In this report, we present an unusual and difficult-to-classify case of conjoined male twins with partial duplication of craniofacial, upper oropharyngeal, and cardiac organs. We believe this to be one of the few reported cases of janiceps asymmetrus. We describe in detail the gross and microscopic pathology and offer some insights into the possible embryogenesis and distinction from the other rare form of conjoined twinning with facial duplication, diprosopus.

Arachidonic acid modulates both electrical and biochemical properties of membrane proteins involved in cellular signaling. In Xenopus laevis oocytes expressing the excitatory amino acid transporter EAAT4, physiologically relevant concentrations of arachidonic acid increase the amplitude of the substrate-activated current by roughly twofold at -60 mV. This stimulation is not attributable to the modulation of either substrate/ion cotransport or the ligand-gated chloride current, the major conductance associated with this carrier. Ion-substitution experiments reveal that arachidonic acid stimulates a proton-selective conductance. The effect does not require metabolism of arachidonic acid and is not blocked by inhibitors of endogenous oocyte ion-exchangers. This proton conductance expands the complex repertoire of the ligand-gated channel properties associated with EAAT4.

The specific diagnosis of AD as a particular dementia from which a patient suffered assumes, debatably, a reasonably pure clinicopathological entity in which the same concatenation of lesions will not be encountered in others dying with a similar clinical disorder. Statistically complex computations such as multivariate analyses of morphometric data from our laboratory and similar attempts in Swedish and British series may not prove pragmatic for pathological confirmation. The Braaks' schema posits six stages in the evolution of AD. Unfortunately, application of this model to 50 British autopsies cannot reliably identify those cases clinically diagnosed as demented. Furthermore, lack of universal definition for each of the probable lesional subtypes augments the difficulty devising a quantitative consensus. Disease stage refers to a progressive increase in anatomical (geographic) extent of involvement, whereas, grade refers to a progressive increase in severity of affliction within any one site. There is only a tendency for stage and grade to progress in parallel. Nor is it obligatory that either always does progress. More energies should be concentrated upon determining which histopathological abnormality is most injurious to neuronal integrity. Dutch workers opine that in both normal aging and AD, claims of massive, neocortical nerve cell loss may have been based on inadequate morphometry and/or a loss of markers. Requiring urgent resolution is whether cellular changes seen in brains of aging normals represent merely the earliest phase of typical AD (and therefore a good model for Alzheimer pathogenesis), or rather reflect a totally different aging syndrome distinct from AD. We have proposed that abnormalities in the hippocampal formation (with or without neocortical neuronal lesions) may underlie a decline of all higher cognitive functions in senile dementia Alzheimer type. West and colleagues optical disector approach likewise shows that neurodegeneration associated within aging individuals' hippocampi is quantitatively and qualitatively distinct from the neuronal loss in AD. Clinical confreres' imprecision whether or when to term subtle cognitive loss "incipient AD" is understandably mirrored by residual neuropathological struggles to dichotomize such brains as "normative aging" distinct from "putative AD."

Ultracentrifugation and graded molecular sieving, as well as a sensitive sandwich enzyme-linked immunosorbent assay were used to isolate and quantitate the amounts of water-soluble oligomers of beta amyloid (Abeta) peptides N-40 and N-42 in cerebral cortex of normal and Alzheimer disease (AD) brains. AD brains contained 6-fold more water-soluble Abeta (wsAbeta) than control brains. The majority of water-soluble peptides in most AD cases was A beta N-42, representing 12 times the amount found in control brains. The wsAbeta was present in the form of monomers and oligomers ranging from less than 10 kDa to greater than 100 kDa. The amount of wsAbeta N-42 in AD brains is about 50 times greater than the level of soluble Abeta N-42 found in the CSF of AD patients. This disparity may be due to the rapid association of wsAbeta N-42 into fibrillar deposits and/or to the integrity of the anatomical barriers which separate the two extracellular spaces. In this paper, we consider soluble any form of Abeta which has not yet polymerized into its insoluble, filamentous form. This includes both the newly synthesized forms of Abeta and those peptides which may be loosely attached to insoluble filaments but which can, nevertheless, still be considered soluble. It has been previously shown that, once it has aggregated into its filamentous form, the Abeta peptides are resistant to disaggregation and degradation by a number of denaturing agents and aqueous buffers containing proteolytic enzymes. Therefore, it is likely that the water-soluble Abeta peptides we quantified are precursors to its insoluble, filamentous form. Consequently, reducing the levels of soluble Abeta in AD brains could have profound effects on AD pathophysiology.

A cDNA was isolated from human brain that encodes an amino acid sequence 34-39% identical to previously published glutamate transporter sequences. Injection of RNA transcribed from this cDNA into Xenopus oocytes resulted in expression of a transport activity with the properties of the neutral amino acid uptake system ASC. Superfusion of alanine, serine, and cysteine evoked sodium-dependent inward currents in voltage-clamped oocytes expressing the transporter. These currents were dose-dependent, stereospecific, and saturable, with Km values ranging from 29 to 88 microM. Northern blot analyses revealed ubiquitous expression of this gene, termed ASCT1, consistent with the general metabolic role ascribed to system ASC.

Recurrent meningitis in the absence of an identifiable causative organism or anatomical source is a difficult diagnostic challenge for any infectious disease consultant. We evaluated a 49-year-old woman with episodes of meningitis which occurred on at least nine separate occasions for over 24 years. No causative organism, physical agent, or underlying disease process was identified as the source of this patient's recurrent lymphocytic meningitis. When computerized tomographic head scanning was first performed in 1977, a prominence of the left lateral ventricle was evident. It was not until the area was subsequently evaluated with magnetic resonance imaging techniques 13 years later that a lesion could be clearly identified, removed, and evaluated at pathology. Time alone will tell whether the lesion, a cavernous hemangioma, was truly the cause of this patient's recurrent aseptic meningitis for 24 years.

The molecular nature of the related infectious agents that cause Creutzfeldt-Jakob disease (CJD) and scrapie is poorly understood, and an agent-specific nucleic acid genome has not yet been identified. Several biological manifestations of these agents resemble those seen in retrovirus-induced diseases. We therefore attempted to identify an agent-specific retrovirus-like RNA transcript in CJD infectious fractions. A series of synthetic oligonucleotides complementary to known mammalian retroviral primer binding sites were used in a primer extension assay. Substrate nucleic acids isolated from partially purified hamster brain CJD infectious fractions and from parallel normal brain fractions were compared with total starting brain RNA. This sensitive exogenous strong-stop reaction revealed that CJD infectious fractions contained a series of potential retroviral RNAs including apparent transcripts of endogenous hamster IAP genes. Most transcripts selectively recovered in the fractions were substantially protected from micrococcal nuclease digestion, and at least one substrate RNA, consistent with an intracisternal A particle, was packaged in a form that had the same buoyant density as CJD infectivity. Although a completely CJD-specific transcript was not identified, the copurification of potential retroviral transcripts with CJD infectivity suggests that models of disease involving retrovirus-like nucleic acid elements deserve further consideration.

Epidermal growth factor (EGF) was originally characterized as a growth factor for various cell types1,2 and was subsequently shown to affect a number of cellular and molecular processes3,4, of which many might be considered as a part of the pleiotropic growth response (enhanced uptake of glucose, uridine and amino acids and stimulated synthesis of protein, RNA and DNA). Very early responses to EGF, such as increased sodium fluxes5 and stimulation of tyrosine phosphorylation6, have been proposed to mediate some or all of EGF's effects. In a number of tissues, EGF has been shown to increase the synthesis of specific proteins7-10. We have investigated the effects of EGF on prolactin synthesis in the GH4 rat pituitary cell line to gain further insight into the mechanism of EGF's actions on cellular functions. Addition of EGF to GH4 cells results in a three- to sixfold stimulation of prolactin synthesis, as well as a partial inhibition of cell growth7,8. In this report, we demonstrate that the increased prolactin synthesis appears to be the result of a rapid stimulation of prolactin gene transcription by EGF. It is tempting to speculate that very early transcription by EGF. It is tempting to speculate that very early transcriptional effects on specific genes, such as reported here in te case of the prolactin gene in GH4 cells, may mediate some or all of the later effects of EGF on cell cycle regulation in those cells for which it serves as a growth factor.

In experiments designed to study the mechanism by which peptide hormones binding to their plasma membrane receptors stimulate the expression of specific genes, the transcription of two neuroendocrine genes, prolactin and growth hormone, was analyzed in a rat pituitary cell line. The results showed that cyclic adenosine monophosphate (cyclic AMP) stimulates the transcription of discrete subsets of eukaryotic genes by at least two independent molecular mechanisms. Cyclic AMP stimulated growth hormone gene transcription and phosphorylation of a 19,000-dalton nuclear protein; this appears to reflect direct nuclear actions of the cyclic AMP-dependent protein kinase. In contrast, the stimulation by cyclic AMP of prolactin gene transcription appears to reflect activation of a discrete calcium-dependent event.

The tripeptide hypothalamic releasing factor, thyrotropin-releasing hormone (TRH), rapidly increases prolactin gene transcription 7- to 12-fold in the GH4 rat pituitary cell line. The maximal rates of transcription are achieved within minutes and begin to attenuate within 1 h following addition of TRH. This transcriptional response appears to account for the observed effects of TRH on the accumulation of prolactin mRNA and the stimulation of prolactin biosynthesis. The rapid transcriptional effects of TRH include a large number of polymerase II-catalyzed transcription units. Addition of TRH to GH4 cell cultures also rapidly induces the phosphorylation of a 23,000-dalton chromatin-associated basic protein, distinct from known high mobility group or histone proteins and referred to as basic regulated phosphoprotein. The time course of TRH-stimulated prolactin transcription and basic regulated phosphoprotein phosphorylation demonstrates that the signal generated by TRH binding to its plasma membrane receptor rapidly reaches the cell nucleus.

Cyclic adenosine monophosphate (AMP) analogs or agents that increase intracellular cyclic AMP rapidly stimulate transcription of the prolactin gene in a line of cultured rat pituitary cells. This effect is correlated with the phosphorylation of a chromatin-associated basic protein designated BPR. These data are consistent with the postulate that increased intracellular cyclic AMP concentrations induce rapid transcriptional effects on specific genes in eukaryotes, mediated by direct or indirect phosphorylation of a specific chromatin-associated protein or proteins.

The polypeptide thyrotropin-releasing hormone (TRH) and epidermal growth factor (EGF) stimulate, within seconds to minutes, the transcription of the prolactin gene in a rat pituitary cell line (GH4). Because a series of agents that act to stimulate prolactin secretion fail to alter prolactin gene transcription, it is suggested that secretory events are neither obligatory for nor causal of hormone-induced transcriptional stimulation. Elevation of cytosolic-free calcium does not stimulate prolactin gene transcription; however, several agents that act to antagonize calcium-dependent processes inhibit or abolish both TRH and EGF stimulation of prolactin gene transcription and a specific hormone-dependent nuclear phosphorylation. In contrast, inhibitors of the slow calcium channel exert minimal effects on TRH-stimulated prolactin gene expression, suggesting that calcium influx through membrane channels is not crucial for the observed nuclear actions of TRH. Activation of protein kinase C by phorbol esters mimics the nuclear actions of TRH. In the presence of increased intracellular calcium levels, the effects of 12-O-tetradecanoyl phorbol 13-acetate on prolactin gene transcription are quantitatively identical to those observed in response to TRH or EGF.