The pathogenesis of viral infections involves an immune response by cytokines, causing a deleterious effect on organ function, in addition to tissue destruction due to viral replication. Clinical ...symptoms and laboratory findings of the human coronavirus disease COVID-19, caused by the novel coronavirus SARS CoV-2, indicate cytokine involvement. Our laboratory showed that an experimental murine coronavirus (MHV-A59) can be transmitted into the brain by intranasal or intracerebral exposure and that neurovirulence is mediated by cytokine secretion. In this study we investigated which cells in the brain produce cytokines, thus functioning as the brain's innate immune system. Using tissue cultures of microglia, and clonal populations of astrocytes, we found that microglia and type I astrocytes (but not types II and III), produced pro-inflammatory cytokines in response to MHV-A59 infection. A molecularly closely related, non-encephalitic strain of the virus (MHV-2) caused in vitro infection, but without cytokine induction. Furthermore, immunofluorescence and immunohistochemistry revealed that type I astrocytes and microglia have perivascular foot processes necessary for the formation of the perivascular glymphatic system, the anatomical site of the brain's innate immune system. Cytokine secretion by type I astrocytes and microglia, as part of the brain's glymphatic and innate immune system, contributes to the pathogenesis of an encephalitic coronavirus infection, and indicates the rationale for anti-cytokine therapies for COVID-19.
•Cytokine induction mediates the neurologic pathogenesis of coronavirus infection.•Type I astrocytes and microglia send foot-processes around blood vessels in the brain, forming the glymphatic system.•The glymphatic system is the site of the brain’s innate immune system.•The brain’s innate immune system functions during coronavirus infection by the induction of pro-inflammatory cytokines.•This experimental coronavirus model system sheds light on the neurologic manifestations of the human disease COVID-19.
The alpha7 nicotinic acetylcholine receptor (nAChR) was recently described as an anti-inflammatory target in both macrophages and T cells. Its expression by immune cells may explain the ...epidemiological data claiming a negative link between cigarette smoking and several inflammatory diseases. In this study, we determined the immunological effects of alpha7 nAChR activation by nicotine. Our results indicate that the alpha7 nAChR is expressed on the surface of CD4(+) T cells and that this expression is up-regulated upon immune activation. Nicotine reduced T cell proliferation in response to an encephalitogenic Ag, as well as the production of Th1 (TNF-alpha and IFN-gamma) and Th17 cytokines (IL-17, IL-17F, IL-21, and IL-22). IL-4 production was increased in the same setting. Attenuation of the Th1 and Th17 lineages was accompanied by reduced T-bet (50%) and increased GATA-3 (350%) expression. Overall, nicotine induced a shift to the Th2 lineage. However, alpha7(-/-)-derived T cells were unaffected by nicotine. Furthermore, nicotine reduced NF-kappaB-mediated transcription as measured by IL-2 and IkappaB transcription. In vivo, administration of nicotine (2 mg/kg s.c.) suppressed the severity of CD4(+) T cell-mediated disease experimental autoimmune encephalomyelitis. alpha7(-/-) mice were refractory to nicotine treatment, although disease severity in those animals was reduced, due to impairment in Ag presentation. Accordingly, CD4(+) and CD11b(+) cells infiltration into the CNS, demyelination, and axonal loss were reduced. Our data implicate a role for the alpha7 nAChR in immune modulation and suggest that alpha7 nAChR agonists may be effective in the treatment of inflammatory disorders.
We report 10 cases of a non‐neurocytic, purely neuronal tumor affecting adults. Situated in the cerebral hemispheres, with 7 of 10 confined to the temporal lobes, most presented with seizures as ...their principal clinical manifestations. On magnetic resosnance imaging (MRI), the tumors generally appeared solid and non‐contrast enhancing with minimal diffuse infiltration, edema, or mass effect. Six examples demonstrated internal nodularity. Microscopically, the tumor cells were largely distributed into discrete and coalescent nodules exhibiting varying degrees of matrix vacuolization, principally within the deep cortical ribbon and superficial subcortical white matter. Populating elements ranged from morphologically ambiguous to recognizably neuronal, with only two cases manifesting overt ganglion cell cytology. In all cases, tumor cells exhibited widespread nuclear immunolabeling for the HuC/HuD neuronal antigens, although expression of other neuronal markers, including synaptophysin, neurofilament and chromogranin was variable to absent. Tumor cells also failed to express GFAP, p53, IDH1 R132H, or CD34, although CD34‐labeling ramified neural elements were present in the adjoining cortex of seven cases. Molecular analysis in a subset of cases failed to reveal DNA copy number abnormalities or BRAF V600E mutation. Follow‐up data indicate that this unusual neuronal lesion behaves in benign, World Health Organization (WHO) grade I fashion and is amenable to surgical control.
Prostate-specific membrane antigen (PSMA) is expressed in endothelium of vessels in malignant solid tumors but not in normal vessels.
To examine whether neovasculature of glioblastoma multiforme ...(GBM) expresses PSMA. Design.-After institutional review board approval at Memorial Sloan-Kettering Cancer Center, formalin-fixed paraffin-embedded tissue from 32 patients who underwent a maximally safe neurologic resection during 2004 to 2005 for GBM (World Health Organization criteria) was obtained. We performed immunohistochemical staining on the vessels of the GBM specimens for PSMA expression in tumor endothelium. The tissue samples were also stained for CD31 to verify that the PSMA was staining tumor vessels. The PSMA percent staining was scored: less than 5%, 6% to 25%, 26% to 50%, 51% to 75%, and 76% to 100%. Staining intensity was ranked as follows: 0 (none), 1+ (faint), 2+ (moderately-intense), and 3+ (maximum-intensity).
Immunohistochemical staining on the vessels of 32 paraffin-embedded GBM specimens revealed that all 32 (100%) specimens exhibited staining for PSMA to a variable extent. Of these, 22 of 32 specimens (69%) had more than 51% vascular staining for PSMA. The intensity of staining was 2+ to 3+ in most of the specimens (29 of 32; 91%).
Prostate-specific membrane antigen is expressed in the vasculature of GBM vessels, thus rendering a potential novel therapeutic vascular target. A clinical trial with a cytotoxin-conjugated antibody to PSMA is planned.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
BACKGROUND:To describe a case of optic neuropathy associated with intravascular lymphoma (IVL).
METHODS:Case report and review of the literature.
RESULTS:A case of asymmetric binocular vision loss is ...described, preceded by transient vision loss. Associated optic perineural enhancement and enhancing and diffusion-positive cortical lesions were observed on magnetic resonance imaging. Biopsy of the cerebellum revealed exclusively intraluminal neoplastic B-cells consistent with IVL.
CONCLUSIONS:Patients with IVL may rarely present with optic nerve involvement, presumably due to small vessel occlusion. The presentation may mimic features of anterior ischemic optic neuropathy including an acute onset and disc edema. Although optic nerve enhancement and associated white matter lesions may suggest optic neuritis, enhancement of the optic nerve sheath, as in this case, has a wide differential diagnosis, which includes giant cell arteritis. IVL should be considered in atypical cases of optic neuropathy accompanied by enhancing, diffusion-positive brain lesions that are not within a specific vascular territory.
Abstract
BACKGROUND
Traditional treatment for symptomatic subdural hematoma (SDH) has been surgical evacuation, but recurrence rates are high and patients often harbor complex medical comorbidities. ...Growth and recurrence is thought to be due to the highly friable nature of the vascularized membrane that forms after initial injury. There have been reported cases of middle meningeal artery (MMA) embolization for treatment of recurrent SDH after surgical evacuation with the goal of eliminating the arterial supply to this vascularized membrane.
OBJECTIVE
To present the first known case series of MMA embolization as upfront treatment for symptomatic chronic SDHs that have failed conservative management in lieu of surgical evacuation.
METHODS
Five patients with symptomatic chronic SDHs underwent MMA embolization using PVA microparticles at our institution. Size of SDH was recorded in maximum diameter and total volume.
RESULTS
Four patients underwent unilateral and 1 underwent bilateral MMA embolization successfully. All cases had significant reduction in total volume of SDH at longest follow-up scan: 81.4 to 13.8 cc (7 wk), 48.5 to 8.7 cc (3 wk), 31.7 and 88 to 0 and 17 cc (14 wk, bilateral), 79.3 to 24.2 cc (8 wk), and 53.5 to 0 cc (6 wk). All patients had symptomatic relief with no complications. Histologic analysis of the chronic SDH membrane in a separate patient that required surgery revealed rich neovascularization with many capillaries and few small arterioles.
CONCLUSION
MMA embolization could present a minimally invasive and low-risk initial treatment alternative to surgery for symptomatic chronic SDH when clinically appropriate.
Abstract Exercise training may decrease insulin resistance (IR) and increase glucose tolerance. However, the adaptive responses in skeletal muscle at the molecular and genetic level have not been ...clearly understood. Here we used oligonucleotide microarray analysis to dissect the effects of high-fat diet (HFD) and regular aerobic exercise on global gene expression in the skeletal muscle of C57BL/6 mice. C57BL/6 male mice (n = 40) were fed with normal chow (n = 20) and HFD (n = 20) for 8 weeks. The animals were then divided into 1 of 4 intervention groups: groups of mice fed with normal chow and HFD accompanied with 6-week treadmill running (60 min/d) at 75% maximum oxygen consumption (NE and HE) and their sedentary control groups (NC and HC). Oligonucleotide microarray was applied to analyze the effect of aerobic exercise and HFD at the transcriptional level, and selected genes were confirmed by real-time polymerase chain reaction. Our data showed that 6 weeks of aerobic exercise improved the plasma lipid profile and reversed the glucose intolerance induced by HFD. A set of 503 genes was differentially expressed in samples of HC mice as compared with those of the NC group. Forty of those genes were identified as involved in the process of aerobic exercise ameliorating IR by comparing the changes in expression profiles between the HE and HC groups. These changes include genes involved in metabolism, defense, and inflammation and genes of unknown function. Aerobic exercise training is able to ameliorate IR of mice maintained with HFD. The biochemical pathways involved in ameliorating IR identified in this study may represent potential targets for the treatment of IR.
Microglia (MG) are enigmatic cells of the central nervous system (CNS). MG are morphologically, antigenically and functionally flexible, and have the potential for mobility and proliferation. MG are ...professional antigen-presenting cells and constitute part of the local CNS innate immune system, communicating with other immune cells via chemokines, cytokines and growth factors. MG contain several antigenic and functional markers similar to macrophages and dendritic cells (DCs), but also present several differences from DCs. The exact role(s) played by MG in the normal human CNS is the topic of lively debate. MG participate in many reactive processes in the CNS and are therefore an integral part of lesions in a variety of pathologic conditions. It is thought that MG may exacerbate diverse neurological conditions, including viral encephalitis, AIDS, Multiple Sclerosis (MS) and Alzheimer's disease. A recurrent theme is the perpetuation by MG of pathological cycles of monocyte recruitment, activation and cytopathic secretions, and/or auto antigen presentation.
Abstract Collision tumors of the sella turcica involving metastases to pituitary adenomas are rare. We report a case of a collision tumor involving metastatic lung cancer with an emphasis on the ...neuroimaging and histopathological studies. A review of the literature including the diagnostic and management implications as well as pathogenetic mechanisms is also discussed.
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