New insights into the biological role of mammalian ADARs; the RNA editing proteins

The ADAR proteins deaminate adenosine to inosine in double-stranded RNA which is one of the most abundant modifications present in mammalian RNA. Inosine can have a profound effect on the RNAs that are edited, not only changing the base-pairing properties, but can also result in recoding, as inosine behaves as if it were guanosine. In mammals there are three ADAR proteins and two ADAR-related proteins (ADAD) expressed. All have a very similar modular structure; however, both their expression and biological function differ significantly. Only two of the ADAR proteins have enzymatic activity. However, both ADAR and ADAD proteins possess the ability to bind double-strand RNA. Mutations in ADARs have been associated with many diseases ranging from cancer, innate immunity to neurological disorders. Here, we will discuss in detail the domain structure of mammalian ADARs, the effects of RNA editing, and the role of ADARs in human diseases

Management of acute aortic syndrome with evolving individualized precision medicine solutions: Lessons learned over two decades and literature review

BackgroundThoracoabdominal acute aortic syndrome is associated with high morbidity and mortality. We aim to scrutinize our evolving strategies for acute aortic syndrome (AAS) management using minimally invasive and adaptive surgical techniques over two decades.MethodsThis is a longitudinal observational study at our tertiary vascular centre from 2002 to 2021. Out of 22,349 aortic referrals, we performed 1,555 aortic interventions over twenty years. Amongst 96 presented with symptomatic aortic thoracic pathology, 71 patients had AAS. Our primary endpoint is combined aneurysm-related and cardiovascular-related mortality.ResultsThere were 43 males and 28 females (5 Traumatic Aortic Transection (TAT), 8 Acute Aortic Intramural Hematoma (IMH), 27 Symptomatic Aortic Dissection (SAD) and 31 Thoracic Aortic Aneurysm (TAA) post-SAD) with a mean age of 69. All the patients with AAS received optimal medical therapy (OMT), but TAT patients underwent emergency thoracic endovascular aortic repair (TEVAR). Fifty-eight patients had an aortic dissection, of which 31 developed TAA. These 31 patients with SAD and TAA received OMT initially and interval surgical intervention with TEVAR or sTaged hybrId sinGle lumEn Reconstruction (TIGER). To increase our landing area, we performed a left subclavian chimney graft with TEVAR in twelve patients. The average follow-up duration was 78.2 months, and eleven patients (15.5%) had combined aneurysm and cardiovascular-related mortality. Twenty-six percentage of the patients developed endoleaks (EL), of which 15% required re-intervention for type II and III. Four patients who had paraplegia (5.7%) and developed renal failure died. None of our patients had a stroke or bowel ischaemia. Twenty patients had OMT, eight of these were patients with acute aortic hematoma, and all eight died within 30 days of presentation.ConclusionAcute aortic hematoma is a sinister finding, which must be closely monitored, and consideration is given to early intervention. Paraplegia and renal failure result in an increased mortality rate. TIGER technique with interval TEVAR has salvaged complex situations in young patients. Left subclavian chimney increases our landing area and abolishes SINE. Our experience shows that minimally invasive techniques could be a viable option for AAS

Two decades of experience in explantation and graft preserving strategies following primary endovascular aneurysm repair and lessons learned

ObjectivesWe aim to scrutinize our evolving re-intervention strategies following primary endovascular aortic aneurysm repair (EVAR) - EVAR GORE SalvAge Fabric Technique (ARAFAT), aortic sac double breasting with endograft preservation, and stent-graft explantation.MethodsWe performed 1,555 aortic interventions over the study period, including 910 EVARs. Factors associated with the need for reintervention and the likelihood of chronic fabric fatigue failure (CFFF) were investigated. Using conventional and innovative diagnostic modalities with Prone contrASt enHanced computed tomography Angiography (PASHA), 136 endoleaks (ELs) were identified (15 type I, 98 type II; 18 type III; 5 type IV).ResultsForty-four (4.84%) patients underwent re-intervention post-primary EVAR; 18 ARAFATs, 12 double breastings, and 14 explantations. Choice of re-intervention was based on patient fitness and mode of failure. Mean EL detection duration following primary EVAR was 53.3 ± 6.82 months, while mean time to re-intervention was 70.20 ± 6.98 months. The mean sac size before the primary EVAR and re-intervention was 6.00 ± 1.75 cm and 7.51 ± 1.94 cm, respectively. Polyester (61.40%) was the most commonly employed stent-graft material. Use of more than three modular stent-graft components (3.42 ± 1.31, p = 0.846); with the proximal stent-graft diameter of 31.6 ± 3.80 cm (p = 0.651) and the use of iliac limbs more than 17 mm (p = 0.364), all added together are contributing factors. We had one peri-operative mortality following explantation due to sepsis-induced multiorgan failure.ConclusionsOur re-intervention strategies matured from stent graft explantation to graft preservation with endovascular relining of the stent-graft. Graft preservation with aortic sacotomy and double breasting were used to manage concealed ELs due to aortic hygroma

Management of retroperitoneal fibrosis with endovascular aneurysm repair in patients refractory to medical management

BackgroundEarly diagnosis and treatment of under-recognized retroperitoneal fibrosis (RPF) are essential before reaching the poorly responsive fibrotic stage. Although most patients respond to medical therapy, relapses and unresponsiveness are common. However, open surgery in medically resistant patients is associated with major adverse clinical events.MethodsThis is a single-centre longitudinal study of optimal medical therapy (OMT) vs. endovascular aneurysm repair (EVAR) in patients presenting with RPF to our tertiary referral vascular centre. Out of 22,349 aortic referrals, we performed 1,555 aortic interventions over twenty years. Amongst them, 1,006 were EVAR, TEVAR and BEVAR. Seventeen patients (1.09%) had documented peri-aortic RPF.ResultsOut of the 17 RPF patients, 11 received OMT only, while 6 underwent EVAR after the failure of OMT. 82% (n = 14) were male, and the median follow-up was 62.7 months (IQR: 28.2–106). Nine (52%) had immunoglobulin G4-related disease (4 OMT vs. 5 EVAR). EVAR patients had 100% technical success without perioperative mortality. Furthermore, all the EVAR patients were symptom-free following the intervention. Pre-operative aortic RPF index (maximum peri-aortic soft tissue diameter/maximum aortic diameter) was higher in the EVAR than in OMT. However, there was a significant decrement in the aortic RPF index following EVAR (P = 0.04).ConclusionWe believe that when optimal medical therapy fails in RPF, EVAR provides a promising outcome. Further studies are recommended to establish the role of endovascular repair

The RNA-Editing Enzyme ADAR1 Controls Innate Immune Responses to RNA

The ADAR RNA-editing enzymes deaminate adenosine bases to inosines in cellular RNAs. Aberrant interferon expression occurs in patients in whom ADAR1 mutations cause Aicardi-Goutières syndrome (AGS) or dystonia arising from striatal neurodegeneration. Adar1 mutant mouse embryos show aberrant interferon induction and die by embryonic day E12.5. We demonstrate that Adar1 embryonic lethality is rescued to live birth in Adar1; Mavs double mutants in which the antiviral interferon induction response to cytoplasmic double-stranded RNA (dsRNA) is prevented. Aberrant immune responses in Adar1 mutant mouse embryo fibroblasts are dramatically reduced by restoring the expression of editing-active cytoplasmic ADARs. We propose that inosine in cellular RNA inhibits antiviral inflammatory and interferon responses by altering RLR interactions. Transfecting dsRNA oligonucleotides containing inosine-uracil base pairs into Adar1 mutant mouse embryo fibroblasts reduces the aberrant innate immune response. ADAR1 mutations causing AGS affect the activity of the interferon-inducible cytoplasmic isoform more severely than the nuclear isoform

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates

Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs. MATERIALS/METHODOLOGY: Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels.Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation.We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation