Coronavirus disease 19 (COVID‐19) is a rapidly evolving pandemic caused by the coronavirus Sars‐CoV‐2. Clinically manifest central nervous system symptoms have been described in COVID‐19 patients and ...could be the consequence of commonly associated vascular pathology, but the detailed neuropathological sequelae remain largely unknown. A total of six cases, all positive for Sars‐CoV‐2, showed evidence of cerebral petechial hemorrhages and microthrombi at autopsy. Two out of six patients showed an elevated risk for disseminated intravascular coagulopathy according to current criteria and were excluded from further analysis. In the remaining four patients, the hemorrhages were most prominent at the grey and white matter junction of the neocortex, but were also found in the brainstem, deep grey matter structures and cerebellum. Two patients showed vascular intramural inflammatory infiltrates, consistent with Sars‐CoV‐2‐associated endotheliitis, which was associated by elevated levels of the Sars‐CoV‐2 receptor ACE2 in the brain vasculature. Distribution and morphology of patchy brain microbleeds was clearly distinct from hypertension‐related hemorrhage, critical illness‐associated microbleeds and cerebral amyloid angiopathy, which was ruled out by immunohistochemistry. Cerebral microhemorrhages in COVID‐19 patients could be a consequence of Sars‐ CoV‐2‐induced endotheliitis and more general vasculopathic changes and may correlate with an increased risk of vascular encephalopathy.
Clinically manifest central nervous system symptoms are common in COVID‐19 patients but their causes are still unknown. We present here four patients who tested positive for Sars‐CoV‐2 with cerebral haemorrhages which were most prominent at the grey and white matter junction of the neocortex and the brainstem. We present evidence of intracerebral endotheliitis in COVID‐19 patients which could predispose to more general vasculopathic changes and may correlate with an increased risk of vascular encephalopathy.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Microglial activation is a hallmark of most neurodegenerative disorders, and is particularly conspicuous in prion diseases. However, the role of microglia, which function as both primary immune ...effector cells and professional phagocytes in the central nervous system, remains contentious in the context of neurodegeneration. Here, we evaluated the effect of microglial depletion/deficiency on prion pathogenesis. We found that ganciclovir-mediated microglial ablation on tga20/CD11b-thymidine kinase of Herpes simplex virus (HSVTK) cerebellar organotypic cultured slices markedly aggravated prion-induced neurotoxicity. A similar deterioration of disease was recapitulated in in vivo microglial depletion in prion-infected tga20/CD11b-HSVTK mice. Additionally, deficiency of microglia in interleukin 34 knockout (IL34(-/-)) mice again resulted in significantly augmented proteinase K-resistant prion protein deposition and accelerated prion disease progression. These results provide unambiguous evidence for a general protective role of microglia in prion pathogenesis.
Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression ...for individual patients is of pivotal importance. However, only biomarkers for highly aggressive tumors are established (
and
), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma.
DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases.
Both CNV- and methylation family-based subgrouping independently resulted in increased prediction accuracy of risk of recurrence compared with the WHO classification (c-indexes WHO 2016, CNV, and methylation family 0.699, 0.706, and 0.721, respectively). Merging all risk stratification approaches into an integrated molecular-morphologic score resulted in further substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference
= .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 2.48-7.57 and 3.34 1.28-8.72 retrospective and prospective validation cohorts, respectively).
Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction.
Misfolding of the cellular prion protein (PrPC) into the scrapie prion protein (PrPSc) results in progressive, fatal, transmissible neurodegenerative conditions termed prion diseases. Experimental ...and epidemiological evidence point toward a protracted, clinically silent phase in prion diseases, yet there is no diagnostic test capable of identifying asymptomatic individuals incubating prions. In an effort to identify early biomarkers of prion diseases, we have compared global transcriptional profiles in brains from pre-symptomatic prion-infected mice and controls. We identified Cst7, which encodes cystatin F, as the most strongly upregulated transcript in this model. Early and robust upregulation of Cst7 mRNA levels and of its cognate protein was validated in additional mouse models of prion disease. Surprisingly, we found no significant increase in cystatin F levels in both cerebrospinal fluid or brain parenchyma of patients with Creutzfeldt-Jakob disease compared to Alzheimer's disease or non-demented controls. Our results validate cystatin F as a useful biomarker of early pathogenesis in experimental models of prion disease, and point to unexpected species-specific differences in the transcriptional responses to prion infections.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
MicroRNAs (miRNAs) are important regulators of skeletal muscle regeneration, but the underlying mechanisms are still incompletely understood. Here, comparative miRNA sequencing analysis of myogenic ...progenitor cells (MPs) and non-myogenic fibroblast-adipocyte progenitors (FAPs) during cardiotoxin (CTX)-induced muscle injury uncovered miR-501 as a novel muscle-specific miRNA. miR-501 is an intronic miRNA and its expression levels in MPs correlated with its host gene, chloride channel, voltage-sensitive 5 (Clcn5). Pharmacological inhibition of miR-501 dramatically blunted the induction of embryonic myosin heavy chain (MYH3) and, to a lesser extent, adult myosin isoforms during muscle regeneration, and promoted small-diameter neofibers. An unbiased target identification approach in primary myoblasts validated gigaxonin as a target of miR-501 that mimicked the effect of miR-501 inhibition on MYH3 expression. In the mdx mouse model, which models a pathological disease state, not only was miR-501 induced in regenerating skeletal muscle, but also its serum levels were increased, which correlated with the disease state of the animals. Our results suggest that miR-501 plays a key role in adult muscle regeneration and might serve as a novel serum biomarker for the activation of adult muscle stem cells.
High-throughput analyses have revealed the presence of activating mutations in the AKT1 gene in a subpopulation of meningiomas. We report a female patient with multiple intracranial tumor ...manifestations and histologically verified meningotheliomatous meningioma in the lung. The tumor was continuously growing at multiple sites despite six surgical resections, radiotherapy, and two lines of systemic therapy. Following detection of an AKT1E17K mutation in three independent tumor samples by sequencing, treatment with AZD5363, a selective AKT inhibitor, was initiated. Ex vivo cultured meningioma cells exhibited sensitivity to the drug as shown by pAKT accumulation on immunoblots. Treatment with AZD5363 resulted, for the first time, in stable disease and minor radiographic response. The patient has been on that treatment for more than one year with ongoing clinical and radiographic response. This is the first report of an AKT1-mutant meningioma responding to AKT inhibition, suggesting that molecular screening may result in clinical benefit.
Summary Hemangiopericytomas and solitary fibrous tumors are uncommon neoplasms found in many locations, including the orbit. Both mesenchymal neoplasms share several clinicopathologic features, thus ...prompting intense debate as to whether they are variants of the same entity or merit separate designations in the orbit. These 2 entities, with the addition of giant cell angiofibroma of orbit, are of benign- to uncertain-behavior, CD34-positive, collagen-rich, specialized fibroblastic tumors, which may have overlapping or histologically identical features. In addition, so-called fibrous histiocytoma of orbit, a previous designation, has overlapping morphologic features with these tumors. To date, a large series of these collagen-rich fibroblastic tumors of the orbit has not been fully explored. Forty-one fibroblastic orbital tumors, originally diagnosed as hemangiopericytomas (n = 16), fibrous histiocytomas (n = 9), mixed tumors (hemangiopericytomas/fibrous histiocytoma) (n = 14), and giant cell angiofibromas of orbit (n = 2) between 1970 and 2009, were retrieved from our consultation files, the Ophthalmic Registry, at the Armed Forces Institute of Pathology. Slides and clinical records were reviewed, analyzed, and compared. Immunochemistry was performed for CD34, CD99, Bcl-2, Ki-67, and p53. Upon histologic review, all cases were reclassified as solitary fibrous tumor (41/41). The patients included 23 (56%) males, 17 (41%) females, and 1 unknown, with a mean age at presentation of 40.7 years (range, 16-70 years). The sites of involvement were the right orbit in 18 (44%) cases and the left in 16 (39%) cases. Tumors ranged in size from 0.4 to 5.0 cm (mean, 2.2 cm). Seventeen (41%) patients presented with an orbital mass, 8 (20%) with proptosis, 2 (5%) with painful mass, and 2 (5%) with painless mass. Duration of symptoms ranged from 3 to 96 months, with a mean of 23 months (median, 9 months). Microscopically, all lesions showed considerable similarity, varying in degree of cellularity, stromal collagen, and the presence of giant cells. Overlapping features with soft tissue giant cell fibroblastoma were observed. Immunochemistry revealed positivity for CD34 in all cases (100%), p53 in 85%, CD99 in 67.5%, and Bcl-2 in 47.5%. Although Ki-67 labeling was seen in all cases, it ranged from less than 1% in 54.3% of cases to 5% to 10% in 20% of cases. Taken together, the findings of this study suggest that orbital hemangiopericytoma and some cases previously designated as fibrous histiocytoma, giant cell angiofibroma of orbit, and solitary fibrous tumor have overlapping morphologic and immunohistochemical features and should be designated as solitary fibrous tumor. Adipocytes and unusual multivacuolated adipocytic cells may be present in these tumors, as well stromal myxoid change; and even stromal intramembranous ossification can be observed. There are overlapping features of orbital solitary fibrous tumor with another CD34-positive specialized fibroblastic tumor of soft tissue, giant cell fibroblastoma. Morphologic criteria for uncertain behavior to low-grade malignant ocular solitary fibrous tumors can be made by cytologic atypia and increased mitotic activity, but overall outcome for malignant solitary fibrous tumors of the eye should be further explored.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Prions cause transmissible infectious diseases in humans and animals and have been found to be transmissible by blood transfusion even in the presymptomatic stage. However, the concentration of ...prions in body fluids such as blood and urine is extremely low; therefore, direct diagnostic tests on such specimens often yield false-negative results. Quantitative preanalytical prion enrichment may significantly improve the sensitivity of prion assays by concentrating trace amounts of prions from large volumes of body fluids. Here, we show that beads conjugated to positively charged peptoids not only captured PrP aggregates from plasma of prion-infected hamsters, but also adsorbed prion infectivity in both the symptomatic and preclinical stages of the disease. Bead absorbed prion infectivity efficiently transmitted disease to transgenic indicator mice. We found that the readout of the peptoid-based misfolded protein assay (MPA) correlates closely with prion infectivity in vivo, thereby validating the MPA as a simple, quantitative, and sensitive surrogate indicator of the presence of prions. The reliable and sensitive detection of prions in plasma will enable a wide variety of applications in basic prion research and diagnostics.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective:
To compare measured and perceived taste function before and after surgery of patients with chronic otitis media with cholesteatoma (OMCC) to patients without cholesteatoma (patients with ...chronic suppurative otitis media CSOM and patients with lateral skull base lesions LSB).
Methods:
This prospective cohort study included 29 patients undergoing surgery for unilateral OMCC. The chorda tympani nerve (CTN) was resected in 8 of these patients. Fourteen patients undergoing surgery for unilateral CSOM and 5 patients undergoing surgery for unilateral LSB (with CTN resection) served as the comparison group. Taste function was measured using taste strips on both sides of the tongue before surgery, 2 weeks postoperatively and 3 months postoperatively. The affected side of the tongue was compared to the unaffected side. A questionnaire on taste perception was completed at each visit.
Results:
Preoperatively, cholesteatoma patients showed higher taste strip scores than non-cholesteatoma patients, indicating a larger difference between the healthy and affected sides of the tongue. Despite this difference in measured taste function few cholesteatoma patients reported taste alteration before surgery (3/29 10.3%). Postoperatively, patients with CTN resection (OMCC patients with CTN resection and LSB patients) showed a decreased measured taste function. Subjectively, only approximately 20% of these patients reported taste alteration 3 months postoperatively.
Conclusions:
Before surgery, cholesteatoma patients displayed an impaired measured taste function compared to patients without cholesteatoma (CSOM, LSB). Subjectively this was often unnoticed. After surgery, despite removal of the CTN and consequent reduction of measured taste function, few patients reported taste alteration and subjective taste perception was seen to be improving. In regards to middle ear surgery, perceived taste function does not seem to reflect measured gustatory function.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
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