Venous-plexus-associated lymphoid hubs support meningeal humoral immunity.

There is increasing interest in how immune cells in the meninges-the membranes that surround the brain and spinal cord-contribute to homeostasis and disease in the central nervous system1,2. The outer layer of the meninges, the dura mater, has recently been described to contain both innate and adaptive immune cells, and functions as a site for B cell development3-6. Here we identify organized lymphoid structures that protect fenestrated vasculature in the dura mater. The most elaborate of these dural-associated lymphoid tissues (DALT) surrounded the rostral-rhinal confluence of the sinuses and included lymphatic vessels. We termed this structure, which interfaces with the skull bone marrow and a comparable venous plexus at the skull base, the rostral-rhinal venolymphatic hub. Immune aggregates were present in DALT during homeostasis and expanded with age or after challenge with systemic or nasal antigens. DALT contain germinal centre B cells and support the generation of somatically mutated, antibody-producing cells in response to a nasal pathogen challenge. Inhibition of lymphocyte entry into the rostral-rhinal hub at the time of nasal viral challenge abrogated the generation of germinal centre B cells and class-switched plasma cells, as did perturbation of B-T cell interactions. These data demonstrate a lymphoid structure around vasculature in the dura mater that can sample antigens and rapidly support humoral immune responses after local pathogen challenge.

Gut-educated IgA plasma cells defend the meningeal venous sinuses.

The central nervous system has historically been viewed as an immune-privileged site, but recent data have shown that the meninges-the membranes that surround the brain and spinal cord-contain a diverse population of immune cells1. So far, studies have focused on macrophages and T cells, but have not included a detailed analysis of meningeal humoral immunity. Here we show that, during homeostasis, the mouse and human meninges contain IgA-secreting plasma cells. These cells are positioned adjacent to dural venous sinuses: regions of slow blood flow with fenestrations that can potentially permit blood-borne pathogens to access the brain2. Peri-sinus IgA plasma cells increased with age and following a breach of the intestinal barrier. Conversely, they were scarce in germ-free mice, but their presence was restored by gut re-colonization. B cell receptor sequencing confirmed that meningeal IgA+ cells originated in the intestine. Specific depletion of meningeal plasma cells or IgA deficiency resulted in reduced fungal entrapment in the peri-sinus region and increased spread into the brain following intravenous challenge, showing that meningeal IgA is essential for defending the central nervous system at this vulnerable venous barrier surface.

Cellular infiltration in traumatic brain injury.

Traumatic brain injury leads to cellular damage which in turn results in the rapid release of damage-associated molecular patterns (DAMPs) that prompt resident cells to release cytokines and chemokines. These in turn rapidly recruit neutrophils, which assist in limiting the spread of injury and removing cellular debris. Microglia continuously survey the CNS (central nervous system) compartment and identify structural abnormalities in neurons contributing to the response. After some days, when neutrophil numbers start to decline, activated microglia and astrocytes assemble at the injury site-segregating injured tissue from healthy tissue and facilitating restorative processes. Monocytes infiltrate the injury site to produce chemokines that recruit astrocytes which successively extend their processes towards monocytes during the recovery phase. In this fashion, monocytes infiltration serves to help repair the injured brain. Neurons and astrocytes also moderate brain inflammation via downregulation of cytotoxic inflammation. Depending on the severity of the brain injury, T and B cells can also be recruited to the brain pathology sites at later time points.

Indocyanine green fluorescence video angiography reduces vascular injury-related morbidity during micro-neurosurgical clipping of ruptured cerebral aneurysms: a retrospective observational study.

BACKGROUND: Specific procedural complications in aneurysm surgery are broadly related to vascular territory compromise and brain/nerve retraction; vascular complications account for about half of this. Intraoperative indocyanine green video angiography (ICG-VA) provides real-time high spatial resolution imaging of the cerebrovascular architecture, allowing immediate quality assurance of aneurysm occlusion and vessel integrity. The aim of this study was to examine whether the routine use of ICG-VA reduced early procedural complications related to vascular compromise or injury during micro-neurosurgical clipping of ruptured cerebral aneurysms. METHODS: Retrospective comparative observational study of 412 adult good-grade (WFNS 1 or 2) SAH patients who had undergone microsurgical clipping without (n = 200, 2001-2004) or with (n = 212, 2009-2015) ICG-VA in a high-volume neurosurgical centre. RESULTS: The ICG-VA group had a significantly lower incidence of procedural vascular complications (7/212; 3.3%) compared with the non-ICG-VA group (19/200; 9.5%) (Fisher's exact test p = 0.0137). CONCLUSIONS: ICG-VA is a straightforward, easy-to-use, intraoperative adjunct which significantly reduces avoidable 'technical error' related morbidity.

A case series of early and late cranioplasty-comparison of surgical outcomes.

BACKGROUND: Cranioplasty is an increasingly common procedure performed in neurosurgical centres following a decompressive craniectomy (DC), however, timing of the procedure varies greatly. OBJECTIVES: The aim of this study is to compare the surgical outcomes of an early compared to a late cranioplasty procedure. METHODS: Ninety adult patients who underwent a prosthetic cranioplasty between 2014 and 2017 were studied retrospectively. Timing of operation, perioperative complications and length of stay were assessed. Early and late cranioplasties were defined as less or more than 3 months since craniectomy respectively. RESULTS: Of the 90 patients, 73% received a late cranioplasty and 27% received an early cranioplasty. The median interval between craniectomy and cranioplasty was 13 months [range 3-84] in late group versus 54 days [range 33-90] in early group. Twenty-two patients in the early group (91%) received a cranioplasty during the original admission while undergoing rehabilitation. Complications were seen in 25 patients (28%). These included wound or cranioplasty infection, hydrocephalus, symptomatic pneumocephalus, post-operative haematoma and cosmetic issues. The complication rate was 21% in the early group and 30% in the late group (P value 0.46). There was no significant difference in the rate of infection or hydrocephalus between the two groups. Length of stay was not significantly increased in patients who received an early cranioplasty during their initial admission (median length of stay 77 days versus 63 days, P value 0.28). CONCLUSION: We have demonstrated the potential for early cranioplasty to be a safe and viable option, when compared to delayed cranioplasty.

Consensus statement from the International Consensus Meeting on the Role of Decompressive Craniectomy in the Management of Traumatic Brain Injury : Consensus statement.

BACKGROUND: Two randomised trials assessing the effectiveness of decompressive craniectomy (DC) following traumatic brain injury (TBI) were published in recent years: DECRA in 2011 and RESCUEicp in 2016. As the results have generated debate amongst clinicians and researchers working in the field of TBI worldwide, it was felt necessary to provide general guidance on the use of DC following TBI and identify areas of ongoing uncertainty via a consensus-based approach. METHODS: The International Consensus Meeting on the Role of Decompressive Craniectomy in the Management of Traumatic Brain Injury took place in Cambridge, UK, on the 28th and 29th September 2017. The meeting was jointly organised by the World Federation of Neurosurgical Societies (WFNS), AO/Global Neuro and the NIHR Global Health Research Group on Neurotrauma. Discussions and voting were organised around six pre-specified themes: (1) primary DC for mass lesions, (2) secondary DC for intracranial hypertension, (3) peri-operative care, (4) surgical technique, (5) cranial reconstruction and (6) DC in low- and middle-income countries. RESULTS: The invited participants discussed existing published evidence and proposed consensus statements. Statements required an agreement threshold of more than 70% by blinded voting for approval. CONCLUSIONS: In this manuscript, we present the final consensus-based recommendations. We have also identified areas of uncertainty, where further research is required, including the role of primary DC, the role of hinge craniotomy and the optimal timing and material for skull reconstruction.

Simultaneous navigated cervico-thoracic and thoraco-lumbar fixation.

STUDY DESIGN: Case report. OBJECTIVE: To investigate the feasibility of using two independent image guidance systems to simultaneously fix multiple segment spine fractures. Image guidance is increasingly used to aid spinal fixation. We describe the first use of multiple navigation systems during a single procedure allowing for multi-segment spinal fixations to be performed simultaneously and capitalizing the advantages of navigation. METHOD: Two Medtronic Stealth Station S7™ systems with O-arm image capture were used to guide fixation of C6 and T12, unstable, AO A4, three-column fractures, in a patient with ankylosing spondylitis. RESULTS: Two surgical teams were able to perform cervico-thoracic and thoraco-lumbar fixations simultaneously. Operative time was 2.5 h. Post-operative imaging showed accurate instrumentation placement. The patient recovered without any neurological sequelae. CONCLUSIONS: Optical independence of the Medtronic Stealth Station™ system allowed for simultaneous navigation guided fixation of multiple segment fractures without compromising accuracy. This may result in shortened operative time and morbidity associated with prolonged prone positioning of polytrauma patients, as well as reducing radiation exposure for theatre staff.

Non-invasive Intracranial Pressure Assessment in Brain Injured Patients Using Ultrasound-Based Methods.

BACKGROUND: Non-invasive measurement of intracranial pressure (ICP) can be invaluable in the management of critically ill patients. Invasive measurement of ICP remains the "gold standard" and should be performed when clinical indications are met, but it is invasive and brings some risks. In this project, we aim to validate the non-invasive ICP (nICP) assessment models based on arterious and venous transcranial Doppler ultrasonography (TCD) and optic nerve sheath diameter (ONSD). METHODS: We included brain injured patients requiring invasive ICP monitoring (intraparenchymal or intraventricular). We assessed the concordance between ICP measured non-invasively with arterious [flow velocity diastolic formula (ICPFVd) and pulsatility index (PI)], venous TCD (vPI) and ICP derived from ONSD (nICPONSD) compared to invasive ICP measurement. RESULTS: Linear regression showed a positive relationship between nICP and ICP for all the methods, except PIv. ICPONSD showed the strongest correlation with invasive ICP (r = 0.61) compared to the other methods (ICPFVd, r = 0.26, p value = 0.0015; PI, r = 0.19, p value = 0.02, vPI, r = 0.056, p value = 0.510). The ability to predict intracranial hypertension was highest for ICPONSD (AUC = 0.91; 95% CI, 0.85-0.97 at ICP > 20 mmHg), with a sensitivity and specificity of 85%, followed by ICPFVd (AUC = 0.67; 95% CI, 0.54-0.79). CONCLUSIONS: Our results demonstrate that among the non-invasive methods studied, ONSD showed the best accuracy in the detection of ICP.

Ultrasound non-invasive measurement of intracranial pressure in neurointensive care: A prospective observational study.

BACKGROUND: The invasive nature of the current methods for monitoring of intracranial pressure (ICP) has prevented their use in many clinical situations. Several attempts have been made to develop methods to monitor ICP non-invasively. The aim of this study is to assess the relationship between ultrasound-based non-invasive ICP (nICP) and invasive ICP measurement in neurocritical care patients. METHODS AND FINDINGS: This was a prospective, single-cohort observational study of patients admitted to a tertiary neurocritical care unit. Patients with brain injury requiring invasive ICP monitoring were considered for inclusion. nICP was assessed using optic nerve sheath diameter (ONSD), venous transcranial Doppler (vTCD) of straight sinus systolic flow velocity (FVsv), and methods derived from arterial transcranial Doppler (aTCD) on the middle cerebral artery (MCA): MCA pulsatility index (PIa) and an estimator based on diastolic flow velocity (FVd). A total of 445 ultrasound examinations from 64 patients performed from 1 January to 1 November 2016 were included. The median age of the patients was 53 years (range 37-64). Median Glasgow Coma Scale at admission was 7 (range 3-14), and median Glasgow Outcome Scale was 3 (range 1-5). The mortality rate was 20%. ONSD and FVsv demonstrated the strongest correlation with ICP (R = 0.76 for ONSD versus ICP; R = 0.72 for FVsv versus ICP), whereas PIa and the estimator based on FVd did not correlate with ICP significantly. Combining the 2 strongest nICP predictors (ONSD and FVsv) resulted in an even stronger correlation with ICP (R = 0.80). The ability to detect intracranial hypertension (ICP ≥ 20 mm Hg) was highest for ONSD (area under the curve [AUC] 0.91, 95% CI 0.88-0.95). The combination of ONSD and FVsv methods showed a statistically significant improvement of AUC values compared with the ONSD method alone (0.93, 95% CI 0.90-0.97, p = 0.01). Major limitations are the heterogeneity and small number of patients included in this study, the need for specialised training to perform and interpret the ultrasound tests, and the variability in performance among different ultrasound operators. CONCLUSIONS: Of the studied ultrasound nICP methods, ONSD is the best estimator of ICP. The novel combination of ONSD ultrasonography and vTCD of the straight sinus is a promising and easily available technique for identifying critically ill patients with intracranial hypertension.

Isolated oculomotor nerve palsy in patients with mild head injury.

Isolated oculomotor nerve palsy following head injury is uncommon. It can only be diagnosed with confidence if it is known to have developed immediately following trauma and if adequate investigations exclude secondary causes. The recovery is only partial and this has repercussion on patients' quality of life.

Bone morphogenetic protein receptor type II deficiency and increased inflammatory cytokine production. A gateway to pulmonary arterial hypertension.

RATIONALE: Mutations in bone morphogenetic protein receptor type II (BMPR-II) underlie most cases of heritable pulmonary arterial hypertension (PAH). However, disease penetrance is only 20-30%, suggesting a requirement for additional triggers. Inflammation is emerging as a key disease-related factor in PAH, but to date there is no clear mechanism linking BMPR-II deficiency and inflammation. OBJECTIVES: To establish a direct link between BMPR-II deficiency, a consequentially heightened inflammatory response, and development of PAH. METHODS: We used pulmonary artery smooth muscle cells from Bmpr2(+/-) mice and patients with BMPR2 mutations and compared them with wild-type controls. For the in vivo model, we used mice heterozygous for a null allele in Bmpr2 (Bmpr2(+/-)) and wild-type littermates. MEASUREMENTS AND MAIN RESULTS: Acute exposure to LPS increased lung and circulating IL-6 and KC (IL-8 analog) levels in Bmpr2(+/-) mice to a greater extent than in wild-type controls. Similarly, pulmonary artery smooth muscle cells from Bmpr2(+/-) mice and patients with BMPR2 mutations produced higher levels of IL-6 and KC/IL-8 after lipopolysaccharide stimulation compared with controls. BMPR-II deficiency in mouse and human pulmonary artery smooth muscle cells was associated with increased phospho-STAT3 and loss of extracellular superoxide dismutase. Chronic lipopolysaccharide administration caused pulmonary hypertension in Bmpr2(+/-) mice but not in wild-type littermates. Coadministration of tempol, a superoxide dismutase mimetic, ameliorated the exaggerated inflammatory response and prevented development of PAH. CONCLUSIONS: This study demonstrates that BMPR-II deficiency promotes an exaggerated inflammatory response in vitro and in vivo, which can instigate development of pulmonary hypertension.

Transforming growth factor-ß(1) represses bone morphogenetic protein-mediated Smad signaling in pulmonary artery smooth muscle cells via Smad3.

Previous studies of pulmonary arterial hypertension (PAH) have implicated excessive transforming growth factor (TGF)-ß1 signaling and reduced bone morphogenetic protein (BMP) signaling in the disease pathogenesis. Reduced BMP signaling in pulmonary artery smooth muscle cells (PASMCs) from patients with heritable PAH is a consequence of germline mutations in the BMP type II receptor (BMPR-II). We sought to establish whether the TGF-ß1 and BMP4 pathways interact in PASMCs, and if this is altered in cells with BMPR-II mutations. Control PASMCs or from patients with PAH harboring BMPR-II mutations were treated with BMP4, TGF-ß1, or cotreated with both ligands. Signaling was assessed by examination of Smad phosphorylation, luciferase reporters, and the transcription of BMP4 or TGF-ß1-responsive genes. TGF-ß1 attenuated BMP4-mediated inhibitors of differentiation 1/2 induction and abolished the response in BMPR-II mutant PASMCs, whereas BMP4 did not alter TGF-ß1-mediated transcription. Activin-like kinase 5 inhibition blocked this effect, whereas cycloheximide or pharmacological inhibitors of TGF-ß-activated kinase 1, extracellular signal-regulated kinase 1/2, or p38 mitogen-activated protein kinase were ineffective. BMP4 and TGF-ß1 cotreatment did not alter the activation or nuclear translocation of their respective Smad signaling proteins. Small interfering RNA for Smad3, but not Smad2, Smad6, or Smad7, reversed the inhibition by TGF-ß1. In addition, TGF-ß-activated kinase 1 inhibition blocked Smad3 phosphorylation, implying that C-terminal Smad3 phosphorylation is not required for the inhibition of BMP4 signaling by TGF-ß1. TGF-ß1 reduces BMP4 signaling in PASMCs, a response that is exacerbated on the background of reduced BMP responsiveness due to BMPR-II mutations. These data provide a rationale for therapeutic inhibition of TGF-ß1 signaling in PAH.

Results of Surgical Treatment of Aneurysmal Subarachnoid Hemorrhage in a Single Institution Over 12 Years.

OBJECTIVE: For patients with aneurysmal subarachnoid hemorrhage (aSAH) in whom endovascular treatment is not the optimal treatment strategy, microsurgical clipping remains a viable option. We examined changes in morbidity and outcome over time in patients treated surgically and in relation to surgeon volume and experience. METHODS: All patients who underwent microsurgery for aSAH from 2007 to 2019 at our institution were included. We compared technical complication rates and surgical outcomes between experienced (≥50 independent cases) and inexperienced (<50 independent cases) surgeons and between high-volume (≥20 cases/year) and low-volume (<20 cases/year) surgeons. RESULTS: Most of the 1,003 aneurysms (970 patients, median age 56 years) were in the middle cerebral (41.4%), anterior communicating (27.6%), and posterior communicating (17.5%) arteries; 46.5% were <7 mm. The technical complication rate was 7%, resulting in postoperative infarct in 4.9% of patients. Nineteen patients (2%) died within 30 days of admission. There were no significant changes in rates of technical complication, postoperative infarct, or mortality over the study period. There were no differences in postoperative infarction and technical complication rates between experienced and inexperienced surgeons (P = 0.28 and P = 0.05, respectively), but there were differences when comparing high-volume and low-volume surgeons (P = 0.03 and P < 0.001, respectively). The independent predictors of postoperative infarctions were aneurysm size (P = 0.001), intraoperative large-vessel injury (P < 0.001), and low surgeon volume (P = 0.03). CONCLUSIONS: We present real-world data on surgical morbidity and outcomes after aSAH. We demonstrated a relationship between surgeon volume and outcome for surgical treatment of aSAH, which supports the benefit of subspecialization in cerebrovascular surgery.

Surgical Resection of an Arteriovenous Malformation of the Orbital Surface of the Frontal Lobe with Olfactory Tract Preservation: 2-Dimensional Operative Video.

Medial orbitofrontal area arteriovenous malformations (AVMs) are located in the noneloquent cortex and typically drain superficially into Sylvian veins or the superior sagittal sinus, making them favorable for surgical treatment. However, while typically supplied by pial/cortical branches of the anterior cerebral artery (ACA), they can incorporate the recurrent artery of Heubner and other ACA perforators on their way to the anterior perforated substance located just posterior. We present a case of a 30-year-old female admitted with sudden collapse and intraventricular hemorrhage from a ruptured medial orbitofrontal area AVM. She was admitted to the intensive care unit and an external ventricular drain was placed to treat acute hydrocephalus. Catheter angiography demonstrated an AVM located just anteromedial to the termination of the internal carotid artery with a compact nidus and an associated intranidal flow aneurysm. Arterial supply originated from the orbitofrontal artery off the ACA, with medial lenticulostriates seen coursing past the nidus. Additional supply from the recurrent artery of Heubner could not be excluded. However, a hypodensity in the inferior frontal lobe seen on the presentation computed tomography scan was suggestive of a prior orbitofrontal infarct and thus cortical, rather than perforator, supply. In our practice, treatment of ruptured AVMs is dictated by the patients' clinical recovery and associated high-risk features (e.g., flow aneurysms). In this case, despite the presence of a flow aneurysm, treatment was delayed 18 days due to slow neurologic recovery and family preference. The patient remained in the intensive care unit under close neurologic observation. She was extubated on day 10, and the external ventricular drain was removed on day 12 after confirming resolution of intraventricular hemorrhage. Preoperatively the patient recovered to a Glasgow Coma Scale score of 15. Risks of treatment were discussed, and informed consent was obtained. The patient was treated using a standard pterional craniotomy. We describe the anatomic location of the lesion in the medial orbitofrontal area, the relationship to the olfactory tract and olfactory stria. We demonstrate olfactory tract dissection from its arachnoid cistern between the orbitofrontal lobe and gyrus rectus in order to access the lesion. Indocyanine green angiography is used to help surgical dissection and for quality control at the end of the procedure. We do not perform intraoperative angiography routinely; however, it can be a useful adjunct in deep and/or eloquent locations, which are difficult to image using videoangiography. Nevertheless, in the absence of intraoperative angiography close dissection directly over the nidus on the eloquent side ensures preservation of functional brain. We describe the microsurgical techniques of surgical treatment of AVMs, in particular the "cone" dissection technique of the AVM in order to allow identification of all feeding vessels and tracing "en passant" vessels from proximal to distal, as well as the use of intraoperative videoangiography to elucidate the nidus morphology and immediate postoperative quality control (Video 1, available at https://drive.google.com/file/d/1IXuLg84MwyMek1_Z1f1n7qssLThimvdx/view?usp=sharing).

Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction.

Following traumatic brain injury (TBI), raised cerebral lactate/pyruvate ratio (LPR) reflects impaired energy metabolism. Raised LPR correlates with poor outcome and mortality following TBI. We prospectively recruited patients with TBI requiring neurocritical care and multimodal monitoring, and utilised a tiered management protocol targeting LPR. We identified patients with persistent raised LPR despite adequate cerebral glucose and oxygen provision, which we clinically classified as cerebral 'mitochondrial dysfunction' (MD). In patients with TBI and MD, we administered disodium 2,3-13C2 succinate (12 mmol/L) by retrodialysis into the monitored region of the brain. We recovered 13C-labelled metabolites by microdialysis and utilised nuclear magnetic resonance spectroscopy (NMR) for identification and quantification.Of 33 patients with complete monitoring, 73% had MD at some point during monitoring. In 5 patients with multimodality-defined MD, succinate administration resulted in reduced LPR(-12%) and raised brain glucose(+17%). NMR of microdialysates demonstrated that the exogenous 13C-labelled succinate was metabolised intracellularly via the tricarboxylic acid cycle. By targeting LPR using a tiered clinical algorithm incorporating intracranial pressure, brain tissue oxygenation and microdialysis parameters, we identified MD in TBI patients requiring neurointensive care. In these, focal succinate administration improved energy metabolism, evidenced by reduction in LPR. Succinate merits further investigation for TBI therapy.

Novel nuclear nesprin-2 variants tether active extracellular signal-regulated MAPK1 and MAPK2 at promyelocytic leukemia protein nuclear bodies and act to regulate smooth muscle cell proliferation.

Nuclear and cytoplasmic scaffold proteins have been shown to be essential for temporal and spatial organization, as well as the fidelity, of MAPK signaling pathways. In this study we show that nesprin-2 is a novel extracellular signal-regulated MAPK1 and 2 (ERK1/2) scaffold protein that serves to regulate nuclear signaling by tethering these kinases at promyelocytic leukemia protein nuclear bodies (PML NBs). Using immunofluorescence microscopy, GST pull-down and immunoprecipitation, we show that nesprin-2, ERK1/2, and PML colocalize and bind to form a nuclear complex. Interference of nesprin-2 function, by either siRNA-mediated knockdown or overexpression of a dominant negative nesprin-2 fragment, augmented ERK1/2 nuclear signaling shown by increased SP1 activity and ELK1 phosphorylation. The functional outcome of nesprin-2 disruption and the resultant sustained ERK1/2 signal was increased proliferation. Importantly, these activities were not induced by previously identified nuclear envelope (NE)-targeted nesprin-2 isoforms but rather were mediated by novel nuclear isoforms that lacked the KASH domain. Taken together, this study suggests that nesprin-2 is a novel intranuclear scaffold, essential for nuclear ERK1/2 signaling fidelity and cell cycle progression.

Prelamin A acts to accelerate smooth muscle cell senescence and is a novel biomarker of human vascular aging.

BACKGROUND: Hutchinson-Gilford progeria syndrome is a rare inherited disorder of premature aging caused by mutations in LMNA or Zmpste24 that disrupt nuclear lamin A processing, leading to the accumulation of prelamin A. Patients develop severe premature arteriosclerosis characterized by vascular smooth muscle cell (VSMC) calcification and attrition. METHODS AND RESULTS: To determine whether defective lamin A processing is associated with vascular aging in the normal population, we examined the profile of lamin A expression in normal and aged VSMCs. In vitro, aged VSMCs rapidly accumulated prelamin A coincidently with nuclear morphology defects, and these defects were reversible by treatment with farnesylation inhibitors and statins. In human arteries, prelamin A accumulation was not observed in young healthy vessels but was prevalent in medial VSMCs from aged individuals and in atherosclerotic lesions, where it often colocalized with senescent and degenerate VSMCs. Prelamin A accumulation correlated with downregulation of the lamin A processing enzyme Zmpste24/FACE1, and FACE1 mRNA and protein levels were reduced in response to oxidative stress. Small interfering RNA knockdown of FACE1 reiterated the prelamin A-induced nuclear morphology defects characteristic of aged VSMCs, and overexpression of prelamin A accelerated VSMC senescence. We show that prelamin A acts to disrupt mitosis and induce DNA damage in VSMCs, leading to mitotic failure, genomic instability, and premature senescence. CONCLUSIONS: This study shows that prelamin A is a novel biomarker of VSMC aging and disease that acts to accelerate senescence. It therefore represents a novel target to ameliorate the effects of age-induced vascular dysfunction.

Longitudinal Changes in Size of Conservatively Managed Flow-Related Aneurysms Associated with Brain Arteriovenous Malformations.

BACKGROUND: Flow aneurysms (FAs) associated with brain arteriovenous malformations (AVMs) are thought to arise from increased hemodynamic stress due to high-flow shunting. This study aims to describe the changes in conservatively managed FAs after successful AVM treatment. METHODS: Patients with symptomatic AVMs and associated FAs who underwent successful treatment of the AVM between 2008 and 2017 were included. FA dimensions were measured on surveillance angiography to assess longitudinal changes. RESULTS: Thirty-two patients were identified with 48 FAs. Sixteen (33%) FAs were treated endovascularly; 18 (38%) FAs were treated surgically; and 14 (29%) FAs (11 patients) were monitored. FAs demonstrated a decrease in size from 5.0 mm to 3.8 mm (24%; P = 0.016) and 4.9 mm to 3.6 mm (27%; P = 0.013) in height and width, respectively, over a median 35 months. However, on subgroup analysis, only class IIb aneurysms demonstrated a significant decrease in size (51% reduction in largest diameter, P = 0.046) and only 3 FAs (21%) resolved. There were no hemorrhages observed during follow-up. CONCLUSIONS: While conservatively managed FAs demonstrated a reduction in size after the culprit AVM was treated, this was only significant in FAs located close to an AVM nidus (class IIb). There were no hemorrhages during the median 35 months' follow-up; however, long-term data are lacking. Our data support close observation of all conservatively managed aneurysms and a tailored approach based on the proximity to the nidus and observed changes in size.