Combined Transhepatic and Transjugular Approach for Mechanical Thrombectomy of Massive TIPS Thrombosis

Transjugular intrahepatic portosystemic shunt (TIPS) is a well-validated decompressive therapy option to manage ascites and variceal bleeding secondary to portal hypertension. Complications following TIPS procedures include hepatic encephalopathy, liver failure, and TIPS dysfunction. TIPS dysfunction is due to occlusion or stenosis of the TIPS shunt and can be caused by acute or chronic thrombosis. TIPS thrombosis is often treated with mechanical thrombectomy or catheter-directed thrombolytic therapy. Most cases of in-stent occlusion can be treated via a transjugular approach with recanalization or placement of additional stents. We present a case of a 72-year-old female who presented with worsening ascites 17 months after initial TIPS procedure; she was found to have a large thrombus completely occluding the TIPS stent. In our case, a combined transhepatic and transjugular approach was required for TIPS revision given the extent of well-organized clot located near the hepatic venous end of the stent, resulting from prolonged stent occlusion. This was an extremely challenging scenario with two overlapping covered stents and a bare metal stent at the hepatic venous end in the setting of chronic thrombosis and a well-organized fibrous cap. The case highlights the need for optimal initial placement of the primary TIPS shunt to avoid the need for subsequent complex interventions to maintain TIPS shunt patency

Single Center Retrospective Review of Post-Laparotomy CT Abdomen and Pelvis Findings and Trends

Purpose: To identify common findings visualized on CT following damage control laparotomy, including post-surgical changes and additional injuries, and to determine change in frequency of post-laparotomy CT at our institution over time. Methods: Single institution, IRB-Exempt, retrospective review of the University of Kentucky trauma registry from 1/2006 to 2/2019 for all trauma patients undergoing exploratory laparotomy initially and subsequently undergoing CT of the abdomen and pelvis within 24 hours. Operative findings from surgical operation notes and findings reported on post-laparotomy CT were recorded, including vascular and solid organ injuries, operative changes, free intraperitoneal fluid/air, and retroperitoneal findings. Next steps in management were also recorded. Results: In total 1,047 patients underwent exploratory laparotomy initially at our institution between 1/2006-2/2019. Of those, only 96 had a diagnostic CT of the abdomen and pelvis within 24 h after initial surgery, first occurring in 2010. Among these 96, there were 71 blunt and 25 penetrating injuries. Most common injuries recognized during exploratory laparotomy were bowel/mesentery (55), spleen (34), and liver (26). Regarding CT findings, all patients (96/96, 100%) had residual pneumoperitoneum, 84/96 (87.5%) had residual hemoperitoneum, 36/96 (37.5%) noted post-surgical changes or additional injuries to the spleen, 36/96 (37.5%) to the bowel/mesentery, and 32/96 (33.3%) to the liver, and 34/96 (35.4%) were noted to have pelvic fractures. After CT, 31/96 (32.3%) went back to the OR for relook laparotomy and additional surgical intervention and 7/96 (7.3%) went to IR for embolization. Most common procedures during relaparotomy involved the bowel (8) and solid organs (6). Conclusions: CT examination within 24 h post damage control laparotomy was exceedingly rare at our institution prior to 2012 but has steadily increased. Frequency now averages 20.5% yearly. Damage control laparotomy is an uncommon clinical scenario; however, knowledge of frequent injuries and common post-operative changes will aid in radiologist detection of additional injuries helping shape next step management and provide adequate therapy

Q134R: Small Chemical Compound with NFAT Inhibitory Properties Improves Behavioral Performance and Synapse Function in Mouse Models of Amyloid Pathology

Inhibition of the protein phosphatase calcineurin (CN) ameliorates pathophysiologic and cognitive changes in aging rodents and mice with aging-related Alzheimer\u27s disease (AD)-like pathology. However, concerns over adverse effects have slowed the transition of common CN-inhibiting drugs to the clinic for the treatment of AD and AD-related disorders. Targeting substrates of CN, like the nuclear factor of activated T cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. However, small chemical inhibitors of NFATs have only rarely been described. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that suppresses NFAT signaling, without inhibiting CN activity. Q134R partially inhibited NFAT activity in primary rat astrocytes, but did not prevent CN-mediated dephosphorylation of a non-NFAT target, either in vivo, or in vitro. Acute (≤1 week) oral delivery of Q134R to APP/PS1 (12 months old) or wild-type mice (3–4 months old) infused with oligomeric Aβ peptides led to improved Y maze performance. Chronic (≥3 months) oral delivery of Q134R appeared to be safe, and, in fact, promoted survival in wild-type (WT) mice when given for many months beyond middle age. Finally, chronic delivery of Q134R to APP/PS1 mice during the early stages of amyloid pathology (i.e., between 6 and 9 months) tended to reduce signs of glial reactivity, prevented the upregulation of astrocytic NFAT4, and ameliorated deficits in synaptic strength and plasticity, without noticeably altering parenchymal Aβ plaque pathology. The results suggest that Q134R is a promising drug for treating AD and aging-related disorders

Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer’s disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562

Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer’s disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562