To Cross or Not to Cross: Using MRI-Histology to Characterize Dense Collagenous Plaque in Critical Limb Ischemia.

Peripheral artery disease (PAD) is caused by atherosclerotic buildup in the lower extremities, leading to obstruction and inadequate perfusion to the peripheral vasculature. Impenetrable plaques initially treated with percutaneous vascular intervention (PVI) have led to worse secondary bypass outcomes and amputation in patients. In this case report, we discuss the importance of using magnetic resonance imaging (MRI) histology in PVI planning in a patient with critical limb ischemia. PVI attempts to recanalize the limb failed because of an impenetrable occlusion in the popliteal artery that was not identified on routine preoperative imaging. Subsequent bypass occluded multiple times eventually requiring an above-knee amputation. An MRI-histology protocol-using ultrashort echo time (UTE) and T2-weighted (T2W) sequences-that was performed prior to the index PVI identified the occlusion as a dense collagen plaque. Histology analysis of the amputated specimen confirmed the MRI finding. This imaging modality offers a novel approach to characterize plaque composition and morphology, thereby identifying lesions at greatest risk of PVI failure and potentially playing an important role in selecting the right candidates for an endovascular-first approach.

Catheter-Directed Interventions for the Treatment of Lower Extremity Deep Vein Thrombosis.

Lower extremity deep vein thrombosis (DVT) leads to significant morbidity including pain, swelling, and difficulty walking in the affected limb. If left untreated, DVT increases the risk of pulmonary embolism (PE), recurrent venous thromboembolism (VTE), and post thrombotic syndrome (PTS). The objective of this review was to identify catheter-directed interventions and their success rates for the treatment of lower extremity DVT. A comprehensive search of current and emerging catheter-directed interventions for lower extremity DVT treatment was conducted in PubMed and Google Scholar. Clinical trials, retrospective and prospective observational studies, and case reports were identified to classify percutaneous mechanical thrombectomy (PMT), catheter-directed thrombolysis (CDT), and pharmacomechanical CDT (PCDT) devices based on their mechanism of action and indication of use. Catheter-directed interventions such as PMT, CDT, and PCDT offer an alternative therapeutic strategy for DVT management, particularly in patients with limb-threatening conditions and absolute contraindications to anticoagulants. Currently, there are limited guidelines for the use of mechanical and pharmacomechanical devices because of the lack of clinical evidence available for their use in treatment. Future studies are required to determine the short and long-term effects of using catheter-directed interventions as well as their effectiveness in treating acute versus subacute and chronic DVT.

Low cerebral blood flow is a non-invasive biomarker of neuroinflammation after repetitive mild traumatic brain injury.

Previous work has shown that non-invasive optical measurement of low cerebral blood flow (CBF) is an acute biomarker of poor long-term cognitive outcome after repetitive mild traumatic brain injury (rmTBI). Herein, we explore the relationship between acute cerebral blood flow and underlying neuroinflammation. Specifically, because neuroinflammation is a driver of secondary injury after TBI, we hypothesized that both glial activation and inflammatory signaling are associated with acute CBF and, by extension, with long-term cognitive outcome after rmTBI. To test this hypothesis, cortical CBF was non-invasively measured in anesthetized mice 4 h after 3 repetitive closed head injuries spaced once-daily, at which time brains were collected. Right hemispheres were fixed for immunohistochemical staining for glial activation markers Iba1 and GFAP while left hemispheres were used to quantify Iba1 and GFAP expression via Western blot as well as 32 cytokines and 21 phospho-proteins in the MAPK, PI3K/Akt, and NF-κB pathways using a Luminex multiplexed immunoassay. N = 8/7 injured/sham C57/black-6 adult male mice were studied. Within the injured group, CBF inversely correlated with Iba1 expression (R = -0.86, p < .01). Further, partial least squares regression analysis revealed significant correlations between CBF and expression of multiple pro-inflammatory cytokines, including RANTES and IL-17. Finally, within the injured group, phosphorylation of specific signals in the MAPK and NF-κB intracellular signaling pathways (e.g., p38 MAPK and NF-κB) were significantly positively correlated with Iba1. In total, our data indicate that acute cerebral blood flow after rmTBI is a biomarker of underlying neuroinflammatory pathology.

Heme and hemoglobin suppress amyloid ß-mediated inflammatory activation of mouse astrocytes.

Glial immune activity is a key feature of Alzheimer's disease (AD). Given that the blood factors heme and hemoglobin (Hb) are both elevated in AD tissues and have immunomodulatory roles, here we sought to interrogate their roles in modulating ß-amyloid (Aß)-mediated inflammatory activation of astrocytes. We discovered that heme and Hb suppress immune activity of primary mouse astrocytes by reducing expression of several proinflammatory cytokines (e.g. RANTES (regulated on activation normal T cell expressed and secreted)) and the scavenger receptor CD36 and reducing internalization of Aß(1-42) by astrocytes. Moreover, we found that certain soluble (>75-kDa) Aß(1-42) oligomers are primarily responsible for astrocyte activation and that heme or Hb association with these oligomers reverses inflammation. We further found that heme up-regulates phosphoprotein signaling in the phosphoinositide 3-kinase (PI3K)/Akt pathway, which regulates a number of immune functions, including cytokine expression and phagocytosis. The findings in this work suggest that dysregulation of Hb and heme levels in AD brains may contribute to impaired amyloid clearance and that targeting heme homeostasis may reduce amyloid pathogenesis. Altogether, we propose heme as a critical molecular link between amyloid pathology and AD risk factors, such as aging, brain injury, and stroke, which increase Hb and heme levels in the brain.