BACKGROUND. Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM).METHODS. To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency.RESULTS. We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM.CONCLUSION. Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies.FUNDING. This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L’Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).
In Table 2, the mutation for patient no. 11 in the column labeled "cDNA, aa change" is incorrect. The correct mutation is NM_002524.4:c.182A>G; NRAS p.(Q61R). The JCI regrets the error.
Objective:Severe Coronavirus disease 2019 (COVID-19) is associated with an extensive pneumonitis, and frequent coagulopathy. We sought the true incidence of thrombotic complications in critically ill patients with severe COVID-19 on the intensive care unit (ICU), with or without extracorporeal membrane oxygenation (ECMO). Design:We undertook a single-centre, retrospective analysis of 72 critically ill patients with COVID-19 associated acute respiratory distress syndrome admitted to ICU. CT angiography of the thorax, abdomen and pelvis were performed on admission as per routine institution protocols, with further imaging as clinically indicated. The prevalence of thrombotic complications and the relationship with coagulation parameters, other biomarkers and survival were evaluated..
S evere acute respiratory failure is the dominant cause of death in patients with coronavirus disease 2019 (CO-VID-19) (1). The pathophysiology and imaging features of severe COVID-19 pneumonia have been the focus of considerable interest from the outset of the pandemic. In early disease, widespread ground-glass opacification predominates at thoracic CT (2-6) and is supposedly associated with highly compliant lungs and disrupted vasoregulation (7). Vascular dysregulation is believed to be consequence of exaggerated activation of inflammatory and coagulation cascades (termed immunothrombosis) (1,(8)(9)(10)(11)(12). Later in the course of disease, CT more commonly shows consolidation and fibrosis associated with lower lung compliance (13).There is growing evidence from radiologic and pathologic studies of a significant vasculopathy in COVID-19 pneumonia (14-17); in a recent study of postmortem lungs in COVID-19, there were widespread microthromboses and striking new vessel formation (16). Furthermore, based on qualitative analyses, a number of studies have highlighted the potential role of dual-energy CT pulmonary angiography (DECTPA) (15,(18)(19)(20)(21). Accordingly, in the present study, we aimed to evaluate the relationships between a quantitative measure of perfusion at DECTPA (relative perfused blood volume [PBV], ie, PBV relative to pulmonary artery enhancement [PBV/PAenh]) ( 22) and (a) disease duration, (b) right ventricular dysfunction (RVD) at echocardiography, (c) d-dimer levels, and (d) obstruction score (23) in patients with severe COVID-19 pneumonia. A secondary aim was to compare PBV/PAenh in COVID-19 pneumonia to that of healthy volunteers.
Childhood empyema incidence has increased markedly in South Auckland. Paediatric S. aureus empyema is becoming increasingly common in South Auckland. Pre-hospital antibiotic prescribing may mitigate the need for surgical intervention in our population.
Amyloidosis cutis dyschromica (ACD) is a rare form of primary cutaneous amyloidosis (PCA). There is a paucity of information in the dermatology literature to guide its diagnosis, investigation and treatment. We present two siblings with ACD and summarise the epidemiology, clinical features, natural history and treatments in 48 cases of ACD from the literature. Familial cases were more common (37) than sporadic cases. ACD is predominantly reported in those of East and South-East Asian ethnicity (63%). The mean age of onset was 6 years in familial cases, and 23 years in sporadic cases. The clinical features of familial and sporadic ACD do not differ substantially. Pruritus was the only symptom, and was reported in 19% of all cases. There were no reported ACD cases with systemic amyloidosis. Acitretin was reported to result in improvement in seven of 10 patients treated. Routine investigation for systemic involvement is not necessary. Acitretin may be helpful.
Deoxycholic acid (DCA) is a secondary bile acid that modulates signalling pathways in epithelial cells. DCA has been implicated in pathogenesis of colon carcinoma, particularly by activation of the protein kinase C (PKC) pathway. Ursodeoxycholic acid (UDCA), a tertiary bile acid, has been observed to have chemopreventive effects. The aim of this study was to investigate the effect of DCA and UDCA on the subcellular localization and activity of PKCeta and its downstream effects on Golgi structure in a colon cancer cell model. PKCeta expression was localized to the Golgi in HCT116 colon cancer cells. DCA induced fragmentation of the Golgi in these cells following activation of PKCeta and its downstream effector protein kinase D (PKD). Pretreatment of cells with UDCA or a glucocorticoid, dexamethasone, inhibited DCA-induced PKCeta/PKD activation and Golgi fragmentation. Knockdown of glucocorticoid receptor (GR) expression using small interfering RNA or inhibition using the GR antagonist mifepristone attenuated the inhibitory effect of UDCA on Golgi fragmentation. Elevated serum and faecal levels of DCA have been previously reported in patients with ulcerative colitis (UC) and colon cancer. Analysis of Golgi architecture in vivo using tissue microarrays revealed Golgi fragmentation in UC and colorectal cancer tissue. We have demonstrated that DCA can disrupt the structure of the Golgi, an organelle critical for normal cell function. Inhibition of this DCA-induced Golgi fragmentation by UDCA was mediated via the GR. This represents a potential mechanism of observed chemopreventive effects of UDCA in benign and malignant disease of the colon.
Key Points Question What is the prevalence of fibromuscular dysplasia, aneurysms, dissection, and tortuosity in extracoronary arteries of patients who developed a spontaneous coronary artery dissection (SCAD)? Findings In this case series including 173 patients with SCAD, using magnetic resonance angiography with blinded interpretation of the findings, 32% of the patients had fibromuscular dysplasia, 8% had aneurysms, and 2% had dissections; the prevalence of arterial tortuosity was similar in cases and controls. Extracoronary vascular events over a median 5-year follow-up were rare. Meaning The findings of this blinded analysis suggest that, in patients with SCAD, severe multivessel fibromuscular dysplasia, aneurysms, and dissections are infrequent and seldom associated with clinically evident vascular events.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.