Zika Virus Associated with Microcephaly Mlakar, Jernej; Korva, Misa; Tul, Nataša ...
New England journal of medicine/The New England journal of medicine,
2016-Mar-10, Letnik:
374, Številka:
10
Journal Article
Recenzirano
Odprti dostop
A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 in South and Central America and the Caribbean. A major concern associated with this infection is the apparent increased ...incidence of microcephaly in fetuses born to mothers infected with ZIKV. In this report, we describe the case of an expectant mother who had a febrile illness with rash at the end of the first trimester of pregnancy while she was living in Brazil. Ultrasonography performed at 29 weeks of gestation revealed microcephaly with calcifications in the fetal brain and placenta. After the mother requested termination of the pregnancy, a fetal autopsy was performed. Micrencephaly (an abnormally small brain) was observed, with almost complete agyria, hydrocephalus, and multifocal dystrophic calcifications in the cortex and subcortical white matter, with associated cortical displacement and mild focal inflammation. ZIKV was found in the fetal brain tissue on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay, with consistent findings on electron microscopy. The complete genome of ZIKV was recovered from the fetal brain.
The study aimed to characterize curcumin (CCM) (fluorescent yellow curry pigment) labeling of neuronal fibrillar tau inclusions (FTIs) in representative cases of 3 main tauopathiesAlzheimer ...disease(AD), progressive supranuclear palsy, and Pick disease. After identification of FTIs in hematoxylin and eosin-stained brain sections, sequential labeling and signal colocalization image analysis were used to compare CCM with thioflavine S (ThS), monoclonal antibody AT8 immunofluorescence, and Gallyas silver staining by visualizing the same FTIs. Curcumin preference for specific tau isoforms was tested with 3-repeat tau and 4-repeat tau isoform-specific immunofluorescence. Curcumin proved highly comparable to ThS and Gallyas staining in its detection of FTIs. When comparing CCM with AT8, ThS, andGallyas staining in AD and progressive supranuclear palsy, 3 types of neuronal tau deposits were observednonfibrillar intracellular material labeled only with AT8, fibrillar intracellular inclusions labeled byall the methods, and fibrillar extracellular FTIs labeled with CCM, ThS, and Gallyas staining but not with AT8. Although CCM labeling overlapped with both 3-repeat tau and 4-repeat tau in AD, it did not label 3-repeat tau FTIs in Pick disease probably because of their different ultrastructural characteristics. In summary, CCM fluorescence reliably detected neuronal FTIs in AD and progressive supranuclear palsy and surpassed AT8 immunolabeling in visualizing later stages ofFTIs, including ghost tangles. These results provide the basis for potential future applications of CCM binding of tau aggregates in diagnostic pathology and in vivo.
Light-chain deposition disease (LCDD), a rare type of monoclonal immunoglobulin deposition disease, can be presented as systemic or localized, very rarely affecting central nervous system (CNS). Only ...10 cases of CNS-LCDD have been described so far. We present an eleventh case of cerebral tumour-like LCDD, called aggregoma, and compare it with previously reported cases. A 49-year-old patient was admitted to the hospital due to a first generalized epileptic seizure. Magnetic resonance imaging (MRI) showed focal lesion in the right occipital lobe. Abundant parenchymal aggregates of pale eosinophilic material were observed, Congo red negative, Thioflavin T moderately positive, and l-light chain positive, but k negative in immunofluorescence with mild perivascular lymphoplasmacytic infiltrates in the intervening brain tissue. Clonality testing by next-generation sequencing showed the monoclonal nature of B-lymphocytes. Electron microscopy showed a finely granular ultrastructure of the aggregates without deposition in the vessel walls. A whole-body workup did not show any extra-cerebral immune dyscrasias.
Gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) arise primarily in the midline of the central nervous system of young children, suggesting a cooperation between genetics and ...cellular context in tumorigenesis. Although the genetics of H3K27M-glioma are well characterized, their cellular architecture remains uncharted. We performed single-cell RNA sequencing in 3321 cells from six primary H3K27M-glioma and matched models. We found that H3K27M-glioma primarily contain cells that resemble oligodendrocyte precursor cells (OPC-like), whereas more differentiated malignant cells are a minority. OPC-like cells exhibit greater proliferation and tumor-propagating potential than their more differentiated counterparts and are at least in part sustained by
signaling. Our study characterizes oncogenic and developmental programs in H3K27M-glioma at single-cell resolution and across genetic subclones, suggesting potential therapeutic targets in this disease.
I was born 70 years ago in the small town of Sinj, Dalmatia, Croatia, Yugoslavia. When I was 5 months old, my father was sent to prison for two years on Goli otok (Bare Island), an ill-famed prison ...for politically inappropriate people at that time. At 24 years old, he could not understand that Stalin, who was an idol for young Communists, had become an enemy overnight after the Informbiro Resolution, by which the Yugoslav Communist party was expelled from the international Communist party led by Stalin. It was a price for living free on the outer side of the Iron Curtain, between East and West, where Yugoslavia remained until the end of 1990, when the Balkan wars started. My father has stuck with Communist ideas until today, almost 95 years old. Under his influence, I entered the Communist party in high school, but very quickly realized that politics is not something I would like to practice.
Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play a significant role in cancer development as regulators of protein-coding genes. Their dysregulation was in some extent already associated ...with glioma, the most aggressive primary brain tumours in adults. The correct diagnosis and treatment selection due to high tumour heterogeneity might be difficult and inadequate, resulting in poor prognosis. Studies of expression patterns of noncoding RNAs (ncRNAs) could provide useful insight in glioma molecular development. We used the qPCR approach to screen and investigate the expression of lncRNAs that were previously deregulated in other cancer types. The study showed altered expression levels for numerous lncRNAs across histologically different glioma samples. Validation of few lncRNAs showed association of expression levels with histological subtype and/or malignancy grade. We also observed deregulated and subtype-distinctive expression for four lncRNA-associated miRNAs. Expression of few lncRNAs and miRNA was also associated with patients’ survival, showing potential prognostic value. Several ncRNAs, some already related to glioma and some, to the best of our knowledge, investigated for the first time, might be of greater importance in glioma molecular development and progression. Finding the subtype-specific lncRNA and/or miRNA expression patterns may contribute additional information for a more objective classification.
An R30 fraction from the growth medium of Aeropyrum pernix was analyzed for the protease that can digest the pathological prion protein isoform (PrP(Sc)) from different species (human, bovine, deer ...and mouse).
Degradation of the PrP(Sc) isoform by the R30 fraction and the purified protease was evaluated using the 6H4 anti-PrP monoclonal antibody. Fragments from the N-terminal and C-terminal of PrP(Sc) were also monitored by Western blotting using the EB8 anti-PrP monoclonal antibody, and by dot blotting using the C7/5 anti-PrP monoclonal antibody, respectively. For detection of smaller peptides from incomplete digestion of PrP(Sc), the EB8 monoclonal antibody was used after precipitation with sodium phosphotungstate. Characterization of the purified active protease from the R30 fraction was achieved, through purification by fast protein liquid chromatography, and identification by tandem mass spectrometry the serine metalloprotease pernisine. SDS-PAGE and zymography show the purified pernisine plus its proregion with a molecular weight of ca. 45 kDa, and the mature purified pernisine as ca. 23 kDa. The purified pernisine was active between 58 °C and 99 °C, and between pH 3.5 and 8.0. The temperature and pH optima of the enzymatic activity of the purified pernisine in the presence of 1 mM CaCl(2) were 105 °C ± 0.5 °C and pH 6.5 ± 0.2, respectively.
Our study has identified and characterized pernisine as a thermostable serine metalloprotease that is secreted from A. pernix and that can digest the pathological prion protein PrP(Sc).
Purpose: To review cases of secondary intracranial meningiomas following high-dose cranial irradiation (≥ 10 Gy) identified in Slovenia between 1968 and 1998, to determine their histological profile ...and to review the literature on this topic.
Methods and Materials: Personal files of patients treated for secondary intracranial meningioma during a 31-year period were reviewed. In cases which met the criteria for radiation-induced tumors, steroid hormone receptor and Ki-67 status were analyzed. For the literature review, computerized database systems and reference lists from respective publications were used.
Results: Five patients (2 females, 3 males), 3–11 years old at the time of cranial irradiation, developed secondary meningioma after a latency period of 9.5–31.5 years. Three patients had multiple tumors and 2 developed recurrent disease. Of 9 histologically examined tumors, 5 were graded as benign and 4 as atypical meningiomas, with Ki-67 proliferative index 3.2 ± 3.6 and 10 ± 6, respectively. The ratio between positive and negative meningiomas regarding immunostaining for progesterone and estrogen receptors was eight-to-one and six-to-three, respectively. Cumulative actuarial risk of secondary meningioma in a cohort of 445 children 16 years or younger treated with high-dose cranial irradiation between 1968 and 1990 in Slovenia at 10, 20, and 25 years was 0.53%, 1.2%, and 8.18%, respectively. Out of 126 cases of radiation-induced meningiomas reported, 57% were females and 43% were males, with mean age at presentation 33 ± 17.3 years. The majority (68%) of patients was irradiated during childhood. The latency period was significantly shorter in those who aged 5 years or less at the time of cranial irradiation (
p = 0.04), and in those with atypical/anaplastic tumor (
p = 0.01). Correlation between radiation dose and latency period could not be found.
Conclusion: Secondary meningiomas following high-dose cranial irradiation are characterized by younger age at presentation, by higher male-to-female ratio and by biologically more aggressive variants compared to primary spontaneous meningiomas. Latency period correlated with the age at the time of cranial irradiation and with tumor grade but not with irradiation dose. Ki-67 immunoreactivity correlated with histological grade. The progesterone and estrogen receptor immunoreactivity was high. The risk for development of secondary meningioma after high-dose cranial irradiation was increasing with the time of follow-up.
Murine monoclonal antibody V5B2 which specifically recognizes the pathogenic form of the prion protein represents a potentially valuable tool in diagnostics or therapy of prion diseases. As murine ...antibodies elicit immune response in human, only modified forms can be used for therapeutic applications. We humanized a single-chain V5B2 antibody using variable domain resurfacing approach guided by computer modelling. Design based on sequence alignments and computer modelling resulted in a humanized version bearing 13 mutations compared to initial murine scFv. The humanized scFv was expressed in a dedicated bacterial system and purified by metal-affinity chromatography. Unaltered binding affinity to the original antigen was demonstrated by ELISA and maintained binding specificity was proved by Western blotting and immunohistochemistry. Since monoclonal antibodies against prion protein can antagonize prion propagation, humanized scFv specific for the pathogenic form of the prion protein might become a potential therapeutic reagent.
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