A Systematic Review and Meta-Analysis of the Pathology Underlying Aneurysm Enhancement on Vessel Wall Imaging.

Intracranial aneurysms are common, but only a minority rupture and cause subarachnoid haemorrhage, presenting a dilemma regarding which to treat. Vessel wall imaging (VWI) is a contrast-enhanced magnetic resonance imaging (MRI) technique used to identify unstable aneurysms. The pathological basis of MR enhancement of aneurysms is the subject of debate. This review synthesises the literature to determine the pathological basis of VWI enhancement. PubMed and Embase searches were performed for studies reporting VWI of intracranial aneurysms and their correlated histological analysis. The risk of bias was assessed. Calculations of interdependence, univariate and multivariate analysis were performed. Of 228 publications identified, 7 met the eligibility criteria. Individual aneurysm data were extracted for 72 out of a total of 81 aneurysms. Univariate analysis showed macrophage markers (CD68 and MPO, p = 0.001 and p = 0.002), endothelial cell markers (CD34 and CD31, p = 0.007 and p = 0.003), glycans (Alcian blue, p = 0.003) and wall thickness (p = 0.030) were positively associated with enhancement. Aneurysm enhancement therefore appears to be associated with inflammatory infiltrate and neovascularisation. However, all these markers are correlated with each other, and the literature is limited in terms of the numbers of aneurysms analysed and the parameters considered. The data are therefore insufficient to determine if these associations are independent of each other or of aneurysm size, wall thickness and rupture status. Thus, the cause of aneurysm-wall enhancement currently remains unknown.

Retinal macroglia changes in a triple transgenic mouse model of Alzheimer's disease.

The retinas of Alzheimer's disease (AD) patients and transgenic AD animal models display amyloid beta deposits and degeneration of ganglion cells. Little is known, however, about the glial changes in the AD retina. The present study used a triple transgenic mouse model (3xTG-AD), which carries mutated human amyloid precursor protein, tau, and presenilin 1 genes and closely mimics the human brain pathology, to investigate retinal glial changes in AD. AD cognitive symptoms are known to begin in the 3xTG-AD mice at four months of age but plaques and tangles are not seen until six to twelve months. Müller cells in 3xTG-AD animals were GFAP-positive, indicating activation, at the earliest time point investigated, nine months. Astrocyte activation was also suggested in the 3xTG-AD mice by an apparent increase in size and process number. Another glial marker, S100, was expressed by astrocytes in both the non-transgenic (NTG) controls and 3xTG-AD retinas. Labeling was predominantly nuclear in nine month non-transgenic (NTG) control mice but was also seen in the cytoplasm and processes at 18 months of age. Interestingly, the nuclear localization was not as prominent in the 3xTG-AD retina even at nine months with labeling observed in astrocyte processes. The diffusion of S100 suggests the possible secretion of this protein, as is seen in the brain, with age and, more profoundly, associated with AD. Several dense, abnormally shaped, opaque structures were noted in all 3xTG-AD mice investigated. These structures, which were enveloped by GFAP and S100-positive astrocytes and Müller cells, were positive for amyloid beta, suggesting that they are amyloid plaques. Staining control retinas with amyloid showed similar structures in 30% of NTG animals but these were fewer in number and not associated with glial activation. The results herein indicate retinal glia activation in the 3xTG-AD mouse retina.

RIPK1 is essential for Herpes Simplex Virus-triggered ZBP1-dependent necroptosis in human cells.

Necroptosis initiated by the host sensor Z-NA Binding Protein-1 (ZBP1) is essential for host defense against a growing number of viruses, including Herpes Simplex Virus-1 (HSV-1). Studies with HSV-1 and other necroptogenic stimuli in murine settings have suggested that ZBP1 triggers necroptosis by directly complexing with the kinase RIPK3. Whether this is also the case in human cells, or whether additional co-factors are needed for ZBP1-mediated necroptosis, is unclear. Here, we show that ZBP1-induced necroptosis in human cells requires RIPK1. We have found that RIPK1 is essential for forming a stable and functional ZBP1-RIPK3 complex in human cells, but is dispensable for the formation of the equivalent murine complex. The RIP Homology Interaction Motif (RHIM) in RIPK3 is responsible for this difference between the two species, because replacing the RHIM in human RIPK3 with the RHIM from murine RIPK3 is sufficient to overcome the requirement for RIPK1 in human cells. These observations describe a critical mechanistic difference between mice and humans in how ZBP1 engages in necroptosis, with important implications for treating human diseases.

Periocular Histiocytoid Carcinoma: Potential Diagnostic Challenges.

Cutaneous histiocytoid carcinoma can occur as a primary tumor of the periocular region. Morphologically similar histiocytoid carcinomas arising as primary tumors of the breast have a predilection for orbital metastases. They can occasionally contain regions with prominent vacuolated cytoplasm and minimal nuclear atypia, which mimic benign histiocytic lesions. Differentiating nonneoplastic, primary neoplastic, and metastatic histiocytoid lesions involving the periorbita can be challenging for both the clinician and the pathologist, and this distinction has management implications. Herein, we present 3 cases to illustrate the challenges of diagnosing periocular histiocytoid carcinoma.

Multi-faceted computational assessment of risk and progression in oligodendroglioma implicates NOTCH and PI3K pathways.

Oligodendrogliomas are diffusely infiltrative gliomas defined by IDH-mutation and co-deletion of 1p/19q. They have highly variable clinical courses, with survivals ranging from 6 months to over 20 years, but little is known regarding the pathways involved with their progression or optimal markers for stratifying risk. We utilized machine-learning approaches with genomic data from The Cancer Genome Atlas to objectively identify molecular factors associated with clinical outcomes of oligodendroglioma and extended these findings to study signaling pathways implicated in oncogenesis and clinical endpoints associated with glioma progression. Our multi-faceted computational approach uncovered key genetic alterations associated with disease progression and shorter survival in oligodendroglioma and specifically identified Notch pathway inactivation and PI3K pathway activation as the most strongly associated with MRI and pathology findings of advanced disease and poor clinical outcome. Our findings that Notch pathway inactivation and PI3K pathway activation are associated with advanced disease and survival risk will pave the way for clinically relevant markers of disease progression and therapeutic targets to improve clinical outcomes. Furthermore, our approach demonstrates the strength of machine learning and computational methods for identifying genetic events critical to disease progression in the era of big data and precision medicine.

Incomplete cauda equina syndrome secondary to haemorrhage within a Tarlov cyst.

Sacral perineural (Tarlov) cysts are benign, cerebrospinal fluid containing lesions of the spinal nerve root sheath. They are usually asymptomatic; however, a small proportion have the potential to cause compression of nerve roots and/or the cauda equina.We report a case of a 61-year-old man who presented with acute onset back pain associated with bilateral radiculopathy. Between referral and consultation, the patient developed urinary dysfunction which resolved spontaneously.MRI revealed haemorrhage within a Tarlov cyst, resulting in compression of the cauda equina. Due to the considerable clinical improvement at the time of consultation, surgical decompression of the cyst was not considered to be indicated.An interval MRI scan 8 weeks later demonstrated that the haemorrhage within the perineural cyst had spontaneously resolved and the patient remained asymptomatic at 5-year follow-up.