Carotid Artery Injury Research Articles

Exosomes derived from mesenchymal stem cells inhibit neointimal hyperplasia by activating the Erk1/2 signalling pathway in rats

BackgroundRestenosis is a serious problem in patients who have undergone percutaneous transluminal angioplasty. Endothelial injury resulting from surgery can lead to endothelial dysfunction and neointimal formation by inducing aberrant proliferation and migration of vascular smooth muscle cells. Exosomes secreted by mesenchymal stem cells have been a hot topic in cardioprotective research. However, to date, exosomes derived from mesenchymal stem cells (MSC-Exo) have rarely been reported in association with restenosis after artery injury. The aim of this study was to investigate whether MSC-Exo inhibit neointimal hyperplasia in a rat model of carotid artery balloon-induced injury and, if so, to explore the underlying mechanisms.MethodsCharacterization of MSC-Exo immunophenotypes was performed by electron microscopy, nanoparticle tracking analysis and western blot assays. To investigate whether MSC-Exo inhibited neointimal hyperplasia, rats were intravenously injected with normal saline or MSC-Exo after carotid artery balloon-induced injury. Haematoxylin-eosin staining was performed to examine the intimal and media areas. Evans blue dye staining was performed to examine re-endothelialization. Moreover, immunohistochemistry and immunofluorescence were performed to examine the expression of CD31, vWF and α-SMA. To further investigate the involvement of MSC-Exo-induced re-endothelialization, the underlying mechanisms were studied by cell counting kit-8, cell scratch, immunofluorescence and western blot assays.ResultsOur data showed that MSC-Exo were ingested by endothelial cells and that systemic injection of MSC-Exo suppressed neointimal hyperplasia after artery injury. The Evans blue staining results showed that MSC-Exo could accelerate re-endothelialization compared to the saline group. The immunofluorescence and immunohistochemistry results showed that MSC-Exo upregulated the expression of CD31 and vWF but downregulated the expression of α-SMA. Furthermore, MSC-Exo mechanistically facilitated proliferation and migration by activating the Erk1/2 signalling pathway. The western blot results showed that MSC-Exo upregulated the expression of PCNA, Cyclin D1, Vimentin, MMP2 and MMP9 compared to that in the control group. Interestingly, an Erk1/2 inhibitor reversed the expression of the above proteins.ConclusionOur data suggest that MSC-Exo can inhibit neointimal hyperplasia after carotid artery injury by accelerating re-endothelialization, which is accompanied by activation of the Erk1/2 signalling pathway. Importantly, our study provides a novel cell-free approach for the treatment of restenosis diseases after intervention.

Pharmacologic Therapy is Not Associated with Stroke Prevention in Patients with Isolated Blunt Vertebral Artery Injury

Vertebral artery injury (VAI) is often grouped with carotid artery injury into a broader classification of blunt cerebrovascular injury, despite fundamental differences in mechanism of injury and outcome. This study seeks to evaluate the efficacy of medical therapy in preventing strokes for isolated VAI. Patients with isolated blunt VAI (2011-2018) were identified from the trauma registry of a level I trauma center. A retrospective chart review was conducted excluding patients with concomitant carotid artery injury. Factors examined included demographics, injury characteristics, anatomic classification, and management strategy. Patients were stratified by whether they received pharmacological (antiplatelet or anticoagulation) therapy. The primary outcome was new posterior circulation stroke within 30days of injury as confirmed by imaging studies. A total of 206 patients with blunt VAI were included. Median Injury Severity Score was 17 and 33 (16.0%) patients presented with Glasgow Coma Scale <8. The most common mechanism of injury was motor vehicle collision (58.7%). The injuries were bilateral in 38 (18.5%) patients and 73 (35.4%) suffered multisegmental injuries. The anatomic severity of injuries was Grade 1=38.8%, Grade 2=25.7%, Grade 3=4.9%, Grade 4=30.6%, and Grade 5=0.5%. There was no correlation between anatomic grade and stroke (P=0.11) or initiation of pharmacologic therapy (P=0.30). In total, 172 (84%) patients received pharmacological therapy with no differences in baseline characteristics between treated and untreated patients. Overall, the 30-day stroke rate was 1.9%. There was no difference in stroke rate between patients who received medical therapy versus those who did not (5.9% vs. 1.2%, P=0.13). In subgroup analysis by injury severity, medical therapy did not improve stroke rates. Among patients treated with aspirin, there was no difference in stroke rate between doses of 81 vs. 325mg (1.1% vs. 0%, P=1). Isolated VAI is associated with a very low risk of stroke and treatment withmedical therapies including antiplatelet or anticoagulation does not improve risk of stroke.

Aliskiren Improved the Endothelial Repair Capacity of Endothelial Progenitor Cells from Patients with Hypertension via the Tie2/PI3k/Akt/eNOS Signalling Pathway.

Background Studies show that aliskiren exerts favourable effects not only on endothelial progenitor cells (EPCs) but also on endothelial function. However, the mechanism of the favourable effect of aliskiren on EPCs from patients with hypertension is unclear and remains to be further studied. Methods The object of this study was to investigate and assess the in vitro function of EPCs pretreated with aliskiren. After treated with aliskiren, the human EPCs were transplanted into a nude mouse model of carotid artery injury, and the in vivo reendothelialization of injured artery was estimated by staining denuded areas with Evans blue dye via tail vein injection. Results We found that aliskiren increased the in vitro migration, proliferation, and adhesion of EPCs from patients with hypertension in a dose-dependent manner and improved the reendothelialization capability of these EPCs. Furthermore, aliskiren increased the phosphorylation of Tie2, Akt, and eNOS. After the blockade of the Tie2 signalling pathway, the favourable effects of aliskiren on the in vitro function and in vivo reendothelialization capability of EPCs were suppressed. Conclusions This study demonstrates that aliskiren can improve the in vitro function and in vivo reendothelialization capability of EPCs from patients with hypertension via the activation of the Tie2/PI3k/Akt/eNOS signalling pathway. These findings further indicate that aliskiren is an effective pharmacological treatment for cell-based repair in hypertension-related vascular injury.

MiR-18a-5p Promotes Proliferation and Migration of Vascular Smooth Muscle Cells by Activating the AKT/Extracellular Regulated Protein Kinases (ERK) Signaling Pathway.

BackgroundmicroRNAs (miRNAs) play important roles in abnormal proliferation and migration of vascular smooth muscle cells (VSMCs), which lead to restenosis in coronary artery disease. Nevertheless, the role of miR-18a-5p and how it works in VSMCs remain unknown.Material/MethodsmiR-18a-5p expression was determined by fluorescence quantitative real-time polymerase chain reaction (qRT-PCR) analysis of tissues from 20 patients with stent restenosis, and rats with carotid artery injury, as well as VSMCs. A cell viability assay was used to measure cell proliferation. Cell migration abilities were assessed by transwell migration assay and wound healing assays. To identify miR-18a-5p targets, a dual-luciferase reporter assay was performed. Western blot analysis and immunofluorescence techniques were used to assess the protein expression levels of AKT and ERK. The rescue effects of miR-18a-5p on the proliferation or migration of VSMCs were evaluated after exposure to the AKT inhibitor MK-2206 and ERK inhibitor PD98059.ResultsThe expression level of miR-18a-5p was significantly higher in the blood serum of patients with stent restenosis and in rats with carotid artery injury, and the expression of AKT and ERK was higher after carotid artery injury. The proliferation and migration abilities of VSMCs were accelerated by the overexpression of miR-18a-5p. It was found that miR-18a-5p directly modulates AKT/ERK signaling. Upregulated miR-18a-5p increased the protein expression levels of AKT and ERK and we found a positive correlation between miR-18a-5p expression level and expression of AKT and ERK. Additionally, the promoting effect of miR-18a-5p on VSMCs proliferation, migration, and invasion was reversed by ERK inhibitor or AKT inhibitor.ConclusionsmiR-18a-5p can promote proliferation of VSMCs by activating the AKT/ERK signaling pathway.

Navigation-Assisted Balloon Eustachian Tuboplasty for Eustachian Tube Dilatory Dysfunction.

Objectives.Balloon Eustachian tuboplasty (BET) is a novel treatment method for Eustachian tube dilatory dysfunction (ETD). However, surgeons cannot identify the insertion depth of the catheter during BET, resulting in potential risks such as internal carotid artery (ICA) injury. Therefore, we developed an image-guided navigation balloon catheter to identify the insertion depth of the catheter and to establish awareness of the proximity of the ICA. This study aimed to evaluate the technical feasibility of this image-guided navigation balloon catheter system in patients with ETD.Methods.Twenty-nine patients (38 ears; nine bilateral; 21 right ears, and 17 left ears) diagnosed with ETD were assessed. All patients who showed no improvement despite medical therapy with topical steroids, anti-reflux medication, and the Valsalva maneuver for a minimum of 6 weeks received image-guided navigation-assisted BET. The 7-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7) score and Valsalva maneuver were used to evaluate patients’ symptoms preoperatively and at the postoperative follow-up.Results.Image-guided navigation-assisted BET was safely performed in all patients. The mean total ETDQ-7 score was 25.4±7.1 preoperatively, 17.5±6.2 at 1 month, and 15.2±7.0 at 6 months (P<0.001). In total, a Valsalva maneuver was possible for 28 of 38 ears (73.7%) at the time of the patient’s final visit at 6 months post-procedure.Conclusion.Image-guided navigation balloon catheters are a potentially valuable tool in patients with ETD. Their use is also technically feasible and safe when performing BET to treat ETD.

Management and outcomes of wartime cervical carotid artery injury.

Cervical carotid artery injuries entail high morbidity and mortality and are technically challenging to repair. This retrospective study describes the management and outcomes of cervical carotid injuries sustained during the recent wars in Iraq and Afghanistan. The Department of Defense Trauma Registry was queried to identify US military personnel who sustained battle-related cervical carotid injury between January 2002 and December 2015. Retrospective chart reviews of the military Electronic Health Record were performed on patients identified. Demographics, injury characteristics, surgical management, and outcomes were reviewed. Statistical analysis was performed to identify associations between injury and management factors, as well as stroke and mortality. In total, 67 patients (100% male; age, 25 ± 7 years) were identified with cervical carotid artery injuries. Fifty-six patients (84%) sustained a common carotid artery (CCA) or internal carotid artery (ICA) injury, and 11 patients (16%) had an isolated external carotid artery (ECA) injury. The anatomic distribution of injury was as follows: CCA, 26 (38.8%); ICA, 24 (35.8%); CCA and ICA 2 (3%); ICA and ECA 3 (4.5%); and CCA, ICA, and ECA 1 (1.5%). Of the 56 CCA or ICA injuries, 39 underwent vascular repair, 9 (16%) were managed with ligation, 1 was treated with a temporary vascular shunt but succumbed to injuries before vascular repair, and 7 (13%) were treated nonoperatively. Seven (23%) of 30 ICA injuries were ligated compared with 2 (7.7%) of 26 injuries isolated to the CCA (p = 0.02). Compared with repair, ligation of the CCA/ICA was associated with a higher rate of stroke (89% vs. 33%, p = 0.003) and increased mortality without statistical significance (22% vs. 10%, p = 0.3). Every patient who underwent ICA ligation had a stroke (7/7). There was no difference in Injury Severity Score between the ligation and repair groups (23.8 ± 10.6 vs. 24.7 ± 13.4, p = 0.9). At a mean follow-up of 34.5 months, 10 of 17 stroke survivors had permanent neurologic deficits. In modern combat, penetrating injuries involving the cervical carotid arteries are relatively infrequent. In this experience, isolated ICA injuries were three times more likely to be ligated than those involving the CCA. As a surgical maneuver, ICA ligation resulted in stroke in all cases. Retrospective cohort analysis, level III.

Expression of Nik-related kinase in smooth muscle cells attenuates vascular inflammation and intimal hyperplasia.

Inflammation of the vascular microenvironment modulates distinct types of vascular cells, and plays important roles in promoting atherosclerosis, stenosis/restenosis, and vascular-related diseases. Nik-related kinase (Nrk), a member of the Ste20-type kinase family, has been reported to be selectively expressed in embryonic skeletal muscle. However, whether Nrk is expressed in adult vascular smooth muscle, and if it influences intimal hyperplasia is unclear. Here, we found that Nrk is abundantly expressed in cultured vascular smooth muscle cells (VSMC) and mouse arterial intima. Treatment of mouse VSMCs with lipopolysaccharide (LPS) or platelet-derived growth factor significantly reduced Nrk expression. In addition, expression of Nrk was significantly reduced in regions of neointimal formation caused by guide-wire carotid artery injuries in mice, as well as in human atherosclerotic tissues, when compared to normal vessels. We identified that expression of matrix metalloproteinases (MMP3, MMP8 and MMP12) and inflammatory cytokines/chemokines (CCL6, CCL8, CCL11, CXCL1, CXCL3, CXCL5 and CXCL9) are synergistically induced by Nrk siRNA in LPS-treated mouse VSMCs. Moreover, we found that resveratrol significantly impaired LPS- and Nrk siRNA-induced expression of MMP3, CCL8, CCL11, CXCL3 and CXCL5. These results suggested that Nrk may play important roles in regulating pathological progression of atherosclerosis or neointimal- hyperplasia-related vascular diseases.

Multidisciplinary Management of Low-velocity Nonmissile Penetrating Head Injuries.

IntroductionPenetrating head injuries (PHIs) can have diverse presentations and mechanisms; therefore, treatment methods have not been clearly outlined. Vascular injury is common and foreign body removal is often required. We present three cases to illustrate low-velocity nonmissile penetrating head injuries (NPHIs) and discuss a multidisciplinary approach.MethodsWe present a case series from our institution that illustrates the importance of multidisciplinary treatment of these injuries. All injuries are low- velocity NPHIs with separate mechanisms and anatomical locations.ResultsMultidisciplinary management involving neurosurgery, otolaryngology, and neuroendovascular surgery is represented in our case series with all patients having good clinical outcomes. Our first case is a 34-year-old male who presented neurologically intact after a stabbing in the left temporal region with concerns for external carotid artery injury and maxillary sinus injury. Our second case is a 37-year-old male who presented with a self-inflicted nail gun injury that penetrated the right temporal bone, right temporal lobe, bilateral sphenoid sinus, and left petrous carotid canal with concerns of petrous internal carotid injury. Our third case is a 31-year-old male who presented after an accidental nail gun injury that penetrated through the oral cavity, hard palate, and left sphenoid sinus and ending in the left cavernous sinus with concerns of cavernous internal carotid injury.Conclusion Careful consideration must be taken when evaluating low-velocity NPHIs. Particular attention must be given when an associated vascular injury is suspected. Our case series highlights the importance of a multidisciplinary approach in achieving good clinical outcomes in PHIs.

Ursodeoxycholic acid inhibits intimal hyperplasia, vascular smooth muscle cell excessive proliferation, migration via blocking miR-21/PTEN/AKT/mTOR signaling pathway

ABSTRACT Excessive migration and proliferation of vascular smooth muscle cells (VSMCs) are critical cellular events that lead to intimal hyperplasia in atherosclerosis and restenosis. In this study, we investigated the protective effects of ursodeoxycholic acid (UDCA) on intimal hyperplasia and VSMC proliferation and migration, and the underlying mechanisms by which these events occur. A rat unilateral carotid artery was ligated to induce vascular injury and the microRNA (miRNA) expression profiles were determined using miRNA microarray analysis. We observed that UDCA significantly reduced the degree of intimal hyperplasia and induced miR-21 dysregulation. Restoration of miR-21 by agomir-miR-21 reversed the protective effects of UDCA on intimal hyperplasia and proliferation in vivo. In vitro, UDCA suppressed PDGF-BB-induced VSMC proliferation, invasion and migration in a dose-dependent manner, whereas the suppressive effect of UDCA was abrogated by overexpression of miR-21 in PDGF-BB-incubated VSMCs. Furthermore, we identified that miR-21 in VSMCs targeted the phosphatase and tensin homolog (PTEN), a tumor suppressor gene, negatively modulated the AKT/mTOR pathway. More importantly, we observed that that UDCA suppressed AKT/mTOR signaling pathway in the carotid artery injury model, whereas this pathway was reactivated by overexpression of miR-21. Taken together, our findings indicated that UDCA inhibited intimal hyperplasia and VSMCs excessive migration and proliferation via blocking miR-21/PTEN/AKT/mTOR signaling pathway, which suggests that UDCA may be a promising candidate for the therapy of atherosclerosis.

New ischemic lesions on brain magnetic resonance imaging in patients with blunt traumatic cerebrovascular injury.

Patients with blunt cerebrovascular injuries are at risk of thromboembolic stroke. Although primary prevention with antithrombotic therapy is widely used in this setting, its effectiveness is not well defined and requires further investigation. The aim of this study was to evaluate the utility of magnetic resonance imaging (MRI)-detected ischemic brain lesions as a possible future outcome for randomized clinical trials in this patient population. This prospective observational study included 20 adult blunt trauma patients admitted to a level I trauma center with a screening neck CTA showing extracranial carotid or vertebral artery injury. All subjects lacked initial evidence of an ischemic stroke and were managed with antithrombotic therapy and observation and then underwent brain MRI within 30 days of the injury to assess for ischemic lesions. The MRI scans included diffusion, susceptibility, and Fluid-attenuated Inversion Recovery (FLAIR) sequences, and were reviewed by two neuroradiologists blinded to the computed tomography angiography (CTA) findings. Eleven CTAs were done in the emergency department upon admission. There were 12 carotid artery dissections and 11 unilateral or bilateral vertebral artery injuries. Median interval between injury and MRI scan was 4 days (range, 0.1-14; interquartile range, 3-7 days). Diffusion-weighted imaging evidence of new ischemic lesions was present in 10 (43%) of 23 of the injured artery territories. In those injuries with ischemic lesions, the median number was 8 (range, 2-25; interquartile range, 5-8). None of the lesions were symptomatic. Blunt cerebrovascular injury was associated with a higher mean ischemic lesion count (mean count of 3.17 vs. 0.14, p < 0.0001), with the association remaining after adjusting for injury severity score (p < 0.0001). In asymptomatic blunt trauma patients with CTA evidence of extracranial cerebrovascular injury and treated with antithrombotic therapy, nearly half of arterial injuries are associated with ischemic lesions on MRI. Therapeutic/care management, level IV.

Expanded transnasal approaches to the skull base in the Middle East: Where do we stand?

ABSTRACTBACKGROUND: Endoscopic transnasal surgery has gained rapid global acceptance over the last two decades. The growing literature and understanding of anterior skull base endoscopic anatomy, in addition to new dedicated endoscopic instruments and tools, have helped to expand the use of the transnasal route in skull base surgery.OBJECTIVE: Report our early experience in expanded endoscopic transnasal surgery (EETS) and approach to skull base neoplasms.DESIGN: Descriptive, retrospective case series.SETTING: Major tertiary care center.PATIENTS AND METHODS: A retrospective case review was conducted at King Saud University Medical City between December 2014 and August 2019. Cases with skull base neoplasms that underwent EETS were included. EETS was defined as endoscopic surgical exposure that extended beyond the sellar margins (prechiasmatic sulcus superiorly, clival recess inferiorly, cavernous carotid lines laterally). Routine transsphenoidal pituitary neoplasms, neoplasms of sinonasal origin and meningoencephaloceles were excluded.MAIN OUTCOME MEASURES: Preoperative clinical assessment, imaging results, surgical approach, and hospital course were all retrieved from the patient electronic charts. Clinical follow-up, perioperative complications, and gross residual tumor rates were documented and reviewed.SAMPLE SIZE AND CHARACTERISTICS: 45 cases of EETS, 13 males and 32 females with mean age of 39.0 (17.7) years (range 2–70 years).RESULTS: The series comprised a wide range of pathologies, including giant pituitary adenoma (8 cases), meningioma (23 cases), craniopharyngioma (4 cases), chordoma (4 cases), optic pathway glioma (2 cases), epidermoid neoplasms (2 cases), astrocytoma (1 case), and teratoma (1 case). For the entire series, gross total resection was achieved in 25/45 operations (55.5%). Postoperative cerebrospinal fluid leak was the most common complication observed in 9 patients (20%) which were all managed endoscopically. Major vascular complications occurred in 2 patients (4.4%) and are described. Other complications are outlined as well. No mortality was observed.CONCLUSIONS: EETS to the skull base can be done with results comparable to traditional approaches. More work is needed to expand our experience, improve outcomes, and educate the public and medical community in our region about the usefulness of this approach.LIMITATIONS: Sample size and study design.CONFLICT OF INTEREST: None.

SUN-038 HOMOCYSTEINE EXACERBATES IRI-INDUCED ACUTE KIDNEY INJURY VIA PROMOTING MEGAKARYOCYTE MATURATION AND PROPLATELET FORMATION

Platelets are crucial regulatory factors of acute kidney injury (AKI), as they are present in high numbers in the circulation and could release massive bioactive factors, which participate in intra-renal inflammation and haemostasis. After ischaemia-reperfusion injury (IRI), unbalanced macrocirculation and microcirculation lead to hypoxaemic injury and inflammatory response and haemostatic processes (platelet sequestration and thrombin). Homocysteine (Hcy), the important intermediate product of methionine cycle, is elevated as related genetic enzymatic deficiencies or nutritional defects which interfere metabolism of methionine. Moderate hyperhomocysteinemia (HHcy) is defined as total plasma Hcy in the range of 16-30uM, which is emerged as prothrombotic factor, influencing coagulative status and endothelial function and modulating platelet aggregation. We therefore aimed to evaluate the effects of hcy levels on platelet in IRI-induced AKI. Experiments were performed using 6 to 8 weeks old male C57BL/6 mice. To generate HHcy mice, mice were fed with high methionine diet containing 19.56g/kg methionine for 3 weeks. IRI induced AKI were performed by bilateral renal pedicles clamped for 30min in 37℃ with or without oral clopidogrel. After 48h, mice were euthanized and blood and kidney tissues were collected. For FeCl3 carotid artery injury, filter paper soaked in FeCl3 solution (3.5%) was placed on the right carotid artery for 90 seconds. Flow was recorded by Doppler Image scanner. As to deep venous thrombosis, the inferior vena cava was ligated for 48h and the length and weight of thrombus were recorded. A preparation of MKs was obtained from femora and tibiae BM of C57BL/6. Fetal liver-derived MKs was from the liver of mouse fetuses aged 13-15 days. The MKs was incubated with Hcy or not. In the present research, we found hyperhomocysteinemia mice developed more severe renal injury after IRI shown as more severe renal tubular damage and higher serum creatinine. Furthermore, the excess injury would be counteracted by oral clopidogrel compared with normal plasma Hcy level mice. Intriguingly, we observed that platelet counts rise by 30% in methionine-induced HHcy. The time required to form an occlusive thrombus in mice subjected to FeCl3 carotid artery injury was sharply shorter and the length and weight of deep venous thrombosis was significantly increased in HHcy model. We hypothesized that Hcy could regulate platelet production by affecting megakaryocytes. MKs cultured with Hcy or obtained from HHcy model increased proplatelet production and had higher ploidy. However, the amount of MKs and precursor cells were not change differently. In conclusion, the present study demonstrates that HHcy increases platelet counts by promoting megakaryocyte maturation and proplatelet formation. The results further suggest that mechanism of HHcy exacerbates IRI-induced acute Kidney Injury.

Outcome of optic nerve decompression through neuroendoscopic transethmoidal-sphenoidal approach in the treatment of traumatic optic neuropathy

Objective To investigate the outcome of optic nerve decompression through neuro-endoscopic transethmoidal-sphenoidal approach in the treatment of traumatic optic neuropathy (TON). Methods The consecutive clinical data of 29 patients (32 sides) with TON who were treated at Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University from December 2013 to February 2018 were retrospectively analyzed. Preoperative visual acuity results were as follows: no light perception (NLP) in 15 sides, light perception in 14 sides, and hand moving in 3 sides. All patients underwent optic nerve decompression through neuroendoscopic transethmoidal-sphenoidal approach assisted with intraoperative neuronavigation. High-resolution skull CT scan was performed before the operation. These aspects were documented including the anatomic landmark observed during operation, visual changes of the patients and operative complications. Results The follow-up periods were 5.2±1.1 months (range: 3 to 6 months). Postoperative visual acuity results were as follows: NLP in 10 sides, light perception in 4 sides, hand moving in 4 sides, counting finger in 5 sides, and logMAR≥0.02 in 9 sides. The effective rate of operation was 59.4% (19/32). No surgical complications such as internal carotid artery injury, cerebrospinal fluid rhinorrhea or anosmia occurred. Conclusion Optic nerve decompression through transethmoidal-sphenoidal approach seems to be an effective method for the treatment of TON. The anatomic landmarks of the surgical approach are clearly defined, and intraoperative neuronavigation contributes to the safety of operation and reduces the occurrence of complications. Key words: Optic nerve injuries; Natural orifice endoscopic surgery; Treatment outcome; Optic nerve decompression; Transethmoidal-sphenoidal approach

Antagonistic relationship between the unfolded protein response and myocardin-driven transcription in smooth muscle.

Smooth muscle cells (SMCs) are characterized by a high degree of phenotypic plasticity. Contractile differentiation is governed by myocardin-related transcription factors (MRTFs), in particular myocardin (MYOCD), and when their drive is lost, the cells become proliferative and synthetic with an expanded endoplasmic reticulum (ER). ER is responsible for assembly and folding of secreted proteins. When the load on the ER surpasses its capacity, three stress sensors (activating transcription factor 6 [ATF6], inositol-requiring enzyme 1α [IRE1α]/X-box binding protein 1 [XBP1], and PERK/ATF4) are activated to expand the ER and increase its folding capacity. This is referred to as the unfolded protein response (UPR). Here, we hypothesized that there is a reciprocal relationship between SMC differentiation and the UPR. Tight negative correlations between SMC markers (MYH11, MYOCD, KCNMB1, SYNPO2) and UPR markers (SDF2L1, CALR, MANF, PDIA4) were seen in microarray data sets from carotid arterial injury, partial bladder outlet obstruction, and bladder denervation, respectively. The UPR activators dithiothreitol (DTT) and tunicamycin (TN) activated the UPR and reduced MYOCD along with SMC markers in vitro. The IRE1α inhibitor 4μ8C counteracted the effect of DTT and TN on SMC markers and MYOCD expression. Transfection of active XBP1s was sufficient to reduce both MYOCD and the SMC markers. MRTFs also antagonized the UPR as indicated by reduced TN and DTT-mediated induction of CRELD2, MANF, PDIA4, and SDF2L1 following overexpression of MRTFs. The latter effect did not involve the newly identified MYOCD/SRF target MSRB3, or reduced production of either XBP1s or cleaved ATF6. The UPR thus counteracts SMC differentiation via the IRE1α/XBP1 arm of the UPR and MYOCD repression.

Pituitary Apoplexy Case Series: Outcomes After Endoscopic Endonasal Transsphenoidal Surgery at a Single Tertiary Center

The management of pituitary apoplexy, caused by acute hemorrhage and/or infarction of a pituitary adenoma, is debated. To analyze clinical characteristics of patients undergoing endoscopic endonasal approaches (EEAs) for pituitary apoplexy. A retrospective review of patients at our institution from 2012 to 2018 undergoing EEA for pituitary apoplexy diagnosed clinically and with imaging/pathologic findings. Analysis included demographics, symptoms, neuroendocrine deficits, neuroimaging, complications, symptom resolution, and follow-up details. Fifty patients (mean age, 53 years) were included. Preoperative symptoms included headache (86%), vision loss (62%), and cranial nerve paresis (40%). Mean tumor diameter was 2.7 cm and extrasellar extension was observed in 96% of tumors. Twenty-eight tumors were hemorrhagic (76%), 24 were necrotic (65%), and 13 (35%) had both features. Magnetic resonance imaging showed gross total resection in 58% of patients. Headache and vision loss improved in 87% and 86% of presenting patients. Cranial nerve paresis resolved in 72% of patients, partially improved in 11%, and remained unchanged in 17%. There were no deaths or carotid artery injuries. Surgical complications included postoperative cerebrospinal fluid leak (n= 4, 8%), epistaxis (n= 2, 4%), postoperative abscess (n= 1, 2%), and transient postoperative vision loss requiring reoperation (n= 1, 4%). Endocrinopathies improved in 21% of patients and panhypopituitarism persisted in 48% and developed in 6% of patients. Mean follow-up time was 26 months; 2 patients experienced recurrence. EEA for pituitary apoplexy is effective in rapidly improving headache and visual symptoms. Although neuro-ophthalmic deficits often improve over time, panhypopituitarism persists in most patients after surgical resection.

Predictors of Cervical Vertebral and Carotid Artery Dissection During Blunt Trauma: Experience From a Level 1 Trauma Center

The current data available to identify the factors associated with vertebral and carotid artery dissection in the trauma setting are conflicting, and further research is needed to accurately assess these predictors. The data from 950 patients who had undergone neck computed tomography angiography (CTA) at a level 1 trauma center were analyzed. Of the 950 patients, 435 were included who had undergone neck CTA for blunt traumatic injuries. The mechanism of injury was classified as high or low impact according to the hospital criteria for trauma. Positive neurological signs included altered mental status (Glasgow coma scale score ≤15 than baseline) or focal neurological deficits. Fractures and dissections were radiologically confirmed. Multivariable logistic regression software was used to analyze the data. Of the 435 patients, 236 (54.25%) had experienced high-impact injuries, 124 (28.51%) had vertebral fractures (including 63 displaced fractures [50.81%]), and 180 (41.38%) had had positive neurological signs on presentation. Of the 435 patients, cervical carotid artery injury had been diagnosed in 9 (2.07%), and 18 patients (4.14%) had had a cervical vertebral artery injury (VAI). Carotid artery injuries did not have significant associations with positive neurological signs, age, sex, mechanism of injury, or vertebral fracture (P > 0.05 for all). Positive neurological signs and vertebral fractures were significant predictors for VAI (odds ratio, 3.19; P < 0.05; odds ratio, 9.81; P < 0.001, respectively). Age, sex, mechanism of injury, and displacement of the vertebral fracture were not significant predictors for VAI (P > 0.05 for all). Positive neurological signs and the presence of cervical vertebral fractures are significant predictors for VAI. All trauma patients with cervical spine fractures and/or positive neurological findings should be considered for surveillance imaging with neck CTA and/or magnetic resonance angiography for vascular injury screening.

Pharmacologic Therapy Is Not Associated with Stroke Prevention In Patients With Isolated Blunt Vertebral Artery Injury

Vertebral artery injury (VAI) is often grouped with carotid artery injury into a broader classification of blunt cerebrovascular injury, despite fundamental differences in mechanism of injury and outcome. This study seeks to evaluate the efficacy of medical therapy in preventing strokes for isolated VAI.

Abstract TP444: New Ischemic Lesions on Brain MRI in Patients With Blunt Traumatic Cerebrovascular Injury

Introduction: Patients admitted after high energy blunt trauma with extracranial cerebrovascular injuries on screening neck computed tomography angiography (CTA) represent a unique group of patients at risk of thromboembolic stroke. These arterial dissections account for &gt;1,000 ischemic strokes in the United States per year. Although stroke prophylaxis with antithrombotics is widely used in this setting, the risk of ischemic brain injury is unknown. Methods: This prospective observational study included 20 adult blunt trauma patients admitted with a screening CTA showing extracranial carotid or vertebral artery injury. All subjects had no initial clinical evidence of ischemic stroke, were managed with antiplatelets and observation and had brain magnetic resonance imaging (MRI) within 14 days of admission. The MRIs included diffusion, susceptibility, and FLAIR sequences to distinguish acute ischemic lesions from contusions and chronic infarctions and were read by two neuroradiologists blind to the findings of the neck CTA. A negative binomial regression adjusted for age and Injury Severity Score (ISS) was used to assess association between artery injury and lesion counts. Results: There were 12 carotid injuries and 11 unilateral or bilateral vertebral artery injuries. Mean interval between injury and MRI scan was 6.9 days. New ischemic lesions in the territory of the affected artery were present in 10 (43%) of the injured artery territories. The mean number of ischemic lesions was 7.8 (range 2-25), which was higher for territories with artery injury (mean=3.17) than those without injury (mean=0.14). None of the lesions were symptomatic. Adjusted for age and ISS, those with artery injury had a 23-fold higher average count of lesions (p=0.0004). In a sensitivity analysis excluding lesion counts &gt;1.5 standard deviation units, the association remained 11-fold higher count for artery injury (p=0.0107). Conclusions: In blunt trauma patients with CTA evidence of extracranial cerebrovascular injury and treated with antiplatelets, &gt;40% of arterial injuries are associated with ischemic lesions on MRI. Ischemic lesions on MRI may be a useful endpoint for future clinical trials of antithrombotic strategies in patients with blunt cerebrovascular injury.

Pediatric blunt cerebrovascular injuries: A national trauma database study

BackgroundThe incidence of blunt cerebrovascular injuries (BCVIs) in children is unknown. We aimed to determine the rate and consequences of BCVIs in pediatric blunt trauma patients. MethodsWe queried the National Trauma Data Bank (NTDB) for all blunt trauma patients between 2007 and 2014. BCVI patients were identified by ICD-9 codes. Demographic, emergency room, and concomitant injury data were analyzed. ResultsThere were 732,702 blunt trauma patients, and 1682 BCVIs were identified (0.23%). 791 (47%) sustained carotid artery injuries (CAIs), 957 (57%) had vertebral artery injuries (VAIs), and 4% of patients sustained both. A majority of the injuries occurred in white patients (61%) and in motor vehicle accidents (53%). The average age was 12.1 ± 5.4 years. CAIs had more skull base fractures (55% vs 35%, p < 0.0001), and cervical spine fractures were more common in VAIs (26 vs 11%, p < 0.0001). Intensive care length of stay was longer in the CAI patients (9.2 vs 7.9 days, p = 0.03), as was length of stay (12.5 vs 9.7 days, p = 0.0002). 5% of CAI patients were coded for stroke, versus 2% of VAIs (p = 0.002). ConclusionsBCVIs are rare in children. Vertebral injuries are more common. Carotid injuries are associated with a longer length of stay and higher stroke rates. Type of StudyRetrospective cohort study. Level of EvidenceIII

Murine sca1/flk1-positive cells are not endothelial progenitor cells, but B2 lymphocytes

Circulating sca1+/flk1+ cells are hypothesized to be endothelial progenitor cells (EPCs) in mice that contribute to atheroprotection by replacing dysfunctional endothelial cells. Decreased numbers of circulating sca1+/flk1+ cells correlate with increased atherosclerotic lesions and impaired reendothelialization upon electric injury of the common carotid artery. However, legitimate doubts remain about the identity of the putative EPCs and their contribution to endothelial restoration. Hence, our study aimed to establish a phenotype for sca1+/flk1+ cells to gain a better understanding of their role in atherosclerotic disease. In wild-type mice, sca1+/flk1+ cells were mobilized into the peripheral circulation by granulocyte-colony stimulating factor (G-CSF) treatment and this movement correlated with improved endothelial regeneration upon carotid artery injury. Multicolor flow cytometry analysis revealed that sca1+/flk1+ cells predominantly co-expressed surface markers of conventional B cells (B2 cells). In RAG2-deficient mice and upon B2 cell depletion, sca1+/flk1+ cells were fully depleted. In the absence of monocytes, sca1+/flk1+ cell levels were unchanged. A PCR array focused on cell surface markers and next-generation sequencing (NGS) of purified sca1+/flk1+ cells confirmed their phenotype to be predominantly that of B cells. Finally, the depletion of B2 cells, including sca1+/flk1+ cells, in G-CSF-treated wild-type mice partly abolished the endothelial regenerating effect of G-CSF, indicating an atheroprotective role for sca1+/flk1+ B2 cells. In summary, we characterized sca1+/flk1+ cells as a subset of predominantly B2 cells, which are apparently involved in endothelial regeneration.