Predictive Value of Clinical, CSF and Vessel Wall MRI Variables in Diagnosing Primary Angiitis of the CNS.

Background and Objectives: Without brain biopsy, there are limited diagnostic predictors to differentiate primary angiitis of the CNS (PACNS) from intracranial atherosclerotic disease (ICAD). We examined the utility of clinical, CSF, and quantitative vessel wall magnetic resonance imaging (VWMRI) variables in predicting PACNS from ICAD. Methods: In this cross-sectional design, observational study, we reviewed electronic medical records to identify patients (18 years and older) who presented to our medical center between January 2015 and December 2021 for ischemic stroke due to intracranial vasculopathy. Patients with biopsy-proven PACNS, probable PACNS, or ICAD were included. Patients with secondary CNS vasculitis or no VWMRI data were excluded. On VWMRI, for each patient, a total of 20 vessel wall segments were analyzed for percent concentricity, percent irregularity, and concentricity to eccentricity (C/E) ratios. We also collected several clinical and CSF variables. Using logistic regression models, we assessed the diagnostic value of VWMRI, CSF, and clinical variables in predicting PACNS in patients with biopsy-proven disease. We then performed a sensitivity analysis to assess predictors of biopsy-proven and probable PACNS. Results: Thirty-two patients with ICAD (54.2%) and 27 patients with PACNS (45.8%) were included. Of the patients with PACNS, 21 (77.8%) were not biopsied and considered probable PACNS. Twenty-four patients with ICAD (75%) and 6 biopsy-proven patients with PACNS (22.2%) showed large vessel involvement and were included in the primary analysis. Encephalopathy (odds ratio [OR], 7.60; 95% CI 1.07-54.09) and seizure (OR 23.00; 95% CI 1.77-298.45) were significantly associated with PACNS. All patients were included in the sensitivity analysis, in which headache significantly predicted PACNS (OR 7.60; 95% CI 1.07-54.09). In the primary analysis, for every 1 white blood cell/µL increase in CSF, there was a 47% higher odds of PACNS (OR 1.47; 95% CI 1.04-2.07). On VWMRI, a C/E ratio >1 (OR 115.00; 95% CI 6.11-2165.95), percent concentricity ≥50% (OR 55.00; 95% CI 4.13-732.71), and percent irregularity <50% (OR 55.00; 95% CI 4.13-732.71) indicated significantly higher odds of PACNS compared with ICAD. Discussion: Our results suggest that quantitative VWMRI metrics, CSF pleocytosis, and clinical features of encephalopathy, seizure, and headache significantly predict a diagnosis of probable PACNS when compared with ICAD.

Covalent Fragment Inhibits RhoA Activation by Guanine Exchange Factors.

Ras homolog gene family member (RhoA) is a GTPase and a member of the RAS superfamily of GTPases. RhoA is a master regulator of the actin cytoskeleton. It inhibits axon growth preventing repair and recovery following spinal cord and traumatic brain injuries. Despite decades of research into the biological function of Rho GTPases, there exist no small-molecule Rho inhibitors. Here, we screen a library of cysteine electrophiles to explore whether covalent bond formation at Cys-107 leads to inhibition of RhoA activation by guanine exchange factor Trio. Two fragments, propiolamide 1 (ACR-895) and acrylamide 2 (ACR-917), inhibited RhoA nucleotide exchange by Trio in a time-dependent manner. The fragments formed a covalent bond with wild-type RhoA but not Cys107Ser RhoA mutant. Time- and concentration-dependent studies led to equilibrium constants KIs and reaction rates that correspond to t1/2 values in the single-digit hour range. One fragment was selective for RhoA over Rac1 GTPase and had no effect on KRAS nucleotide exchange by SOS1. The fragments did not inhibit RhoA binding to ROCK effector protein. This work establishes Cys-107 as a suitable site for Rho GTPase inhibition and provides fragment starting points for the future development of Rho GTPase covalent inhibitors that could have profound implications in the treatment of patients with injuries of the central nervous system.

Correction: Click functionalized biocompatible gadolinium oxide core-shell nanocarriers for imaging of breast cancer cells.

[This corrects the article DOI: 10.1039/D2RA00347C.].

Click functionalized biocompatible gadolinium oxide core-shell nanocarriers for imaging of breast cancer cells.

Site-specific delivery using functionalized nanocarriers is in high demand in imaging applications of modern clinical research. To improve the imaging capabilities of conventionally used contrast agents and expand the targeting accuracy, functional gadolinium oxide based nanocarriers originated from homogeneous core shells structures (Gd2O3@SiO2@Fe3O4) were developed using a multilayer formation approach. The synthesis and chemical configuration for the covalent binding of macrocyclic chelating agents and estrogen targeting molecules on these nanocarriers were designed by a two-step chemical synthesis method. Initially, SiO2@Fe3O4 structures were prepared and encapsulated with a homogenous thin Gd2O3 overlayer. The exterior surface of the as-prepared carriers offered chemical binding with a breast cancer specific estrogen molecule, covalently grafted through a Click-Chemistry protocol. In the next step, to enhance the diagnostic imaging capabilities of these carriers, thiocyanate-linked chelator molecule, DOTA, was attached to the surface of estrogen bound Gd2O3@SiO2@Fe3O4 using basic reaction conditions. The active amino groups before and after conjugation of estrogen molecules on the surface were quantified using a fluorescamine based approach. Due to the covalent binding of the macrocyclic chelator to the Gd2O3@SiO2@Fe3O4 surface, core shell carriers showed potential radiolabeling efficiency using positron emitter radionuclide, gallium-68 (68Ga). Intracellular uptake of estrogen-conjugated carriers was evaluated with MCF7 breast cancer cell lines using confocal laser scanning microscopy and fluorescent flow cytometry. In addition, in vitro cytotoxicity studies of functional nanocarriers as compared to bare nanoparticles showed reduced toxicity to HEK-293 cells demonstrating the role of surface attached molecules in preventing direct exposure of the Gd2O3 surface to the cells. The as-developed gadolinium based nanocarriers presented excellent capabilities as biocompatible target-specific imaging probes which indicates great potential in the field of dual-mode contrast agents.

Mediating the Fate of Cancer Cell Uptake: Dual-Targeted Magnetic Nanovectors with Biotin and Folate Surface Ligands.

Recognition of folate and biotin surface receptors by dual-functionalized nanoparticles (NPs) is key for site-selective receptor-mediated transport of anticancer drugs to cancer cells. We present here dopamine-capped iron oxide nanoprobes (Fe3O4, 10 ± 2 nm) containing two surface-grafted biologically relevant ligands, namely, folic acid (FA) and biotin (BT). The covalent attachment of both FA and BT on Fe3O4 nanoparticles was achieved by following carbodiimide coupling and click-chemistry protocols. The dual-function Fe3O4 probes were delivered into E-G7 and human HeLa cancer cell lines and tested toward their cellular uptake by immunofluorescence and flow cytometry analysis. Owing to receptor-mediated endocytosis, enhanced accumulation of nanoprobes in cancer cells was successfully monitored by confocal laser microscopy. When compared to dual-function probes, single-functionalized nanoparticles possessing either FA or BT ligands showed significantly reduced uptake in the tested cell lines, underlining the superior interaction potential of dual-purpose probes. A time-dependent receptor-mediated endocytosis of FA-Fe3O4-BT nanovectors was demonstrated by flow cytometry analysis, whereas the unfunctionalized NPs did not show any specificity in terms of uptake. Besides their specific uptake, the surface-functionalized nanoparticles exhibited promising cytotoxicity profiles by demonstrating good viability of more than 95% with analogous cancer cell lines. Our results demonstrate that dual and/or multivariate conjugation of receptor-specific ligands on NPs is highly effective in molecular recognition of surface biomarkers that enhances their potential in anticancer treatment for pretargeting-radio strategies based on biotin/avidin interactions.

Timeline of blood pressure changes after intra-arterial therapy for acute ischemic stroke based on recanalization status.

BACKGROUND: There is sparse literature on the natural history of blood pressure (BP) after intra-arterial therapy (IAT) for acute ischemic stroke (AIS). METHODS: A retrospective analysis was performed of patients with AIS who underwent IAT without endotracheal intubation for internal carotid artery terminus (ICA-T) or M1 middle cerebral artery occlusion from January 2008 to February 2012. Systolic BP (SBP) values at the beginning (First) and end (End) of IAT and for 36 h after the procedure were collected. Successful recanalization was defined as Thrombolysis In Cerebral Infarction (TICI) 2b-3. RESULTS: Sixty-two patients (14 (22.5%) ICA-T, 46 (74.2%) M1, 2 (3.2%) ICA-T+M1) met the study criteria and 37 (59.7%) achieved successful recanalization. The First and End SBP values were similar in the successful (Group R) and unsuccessful (Group NR) recanalization groups. Taking the whole cohort, End SBP was significantly lower than First SBP, but this decline was significant only in Group R. Subsequently, absolute SBP values in Group R were not significantly different from Group NR. However, when comparing the hourly decline of SBP with First SBP, Group R demonstrated a greater fall than Group NR and the decline was significantly different from hours 8 to 12 post-procedure. The SBP in Group NR then decreased further, and its difference from baseline was similar to Group R from hour 14 onwards. Mean SBP and SBP variability over 36 h were similar between the two groups. CONCLUSIONS: SBP falls significantly in patients with AIS with large vessel occlusion who recanalize with IAT. While SBP in non-recanalized patients also drops from baseline, it occurs to a lesser degree and stays higher only for a short period of time before falling to similar levels as in recanalized patients.

Safety and outcomes of simultaneous vasospasm and endovascular aneurysm treatment (SVAT) in subarachnoid hemorrhage.

BACKGROUND: Simultaneous vasospasm and endovascular aneurysm treatment (SVAT) has been shown to be effective with good clinical outcomes in small series, but these studies have not examined predictive factors for clinical outcome after treatment. OBJECTIVE: To identify the safety and efficacy of SVAT in a large multicenter patient cohort and evaluate prognostic markers of clinical outcome following SVAT. METHODS: This study retrospectively enrolled 50 consecutive patients undergoing SVAT at 11 different centers. We analyzed Hunt and Hess and Fisher grades, aneurysm location, angiographic vasospasm grade, Glasgow Outcome Scale (GOS) at discharge, and 90-day modified Rankin Scale (mRS) scores. RESULTS: A total of 50 patients undergoing SVAT between the years 2003 and 2009 were identified. Patients presented, on average, 6.48±4.45 days after subarachnoid hemorrhage. Hunt and Hess and Fisher grades were 1 (n=7), 2 (n=12), 3 (n=14), 4 (n=15), 5 (n=2), and 3 and 4 (n=33), respectively. Aneurysm location was distributed as follows: anterior (n=32), posterior (n=16), anterior and posterior (n=2). Patients with good clinical condition (Hunt and Hess score 1-3) had significantly higher odds of surviving (OR=17.5, 95% CI 1.9 to 161.5), favorable GOS (OR=4.2, 95% CI 1.2 to 14.8), and favorable 90-day mRS (OR=4.2, 95% CI 1.2 to 14.8). CONCLUSIONS: SVAT is safe, with the majority of patients achieving good clinical outcome. Patients with lower Hunt and Hess grades have higher odds of surviving and favorable clinical prognosis.

Brain Imaging Using Mobile CT: Current Status and Future Prospects.

Computed tomography (CT) is an invaluable tool in the diagnosis of many clinical conditions. Several advancements in biomedical engineering have achieved increase in speed, improvements in low-contrast detectability and image quality, and lower radiation. Portable or mobile CT constituted one such important advancement. It is especially useful in evaluating critically ill, intensive care unit patients by scanning them at bedside. A paradigm shift in utilization of mobile CT was its installation in ambulances for the management of acute stroke. Given the time sensitive nature of acute ischemic stroke, Mobile stroke units (MSU) were developed in Germany consisting of an ambulance equipped with a CT scanner, point of care laboratory system, along with teleradiological support. In a radical reconfiguration of stroke care, the MSU would bring the CT scanner to the stroke patient, without waiting for the patient at the emergency room. Two separate MSU projects in Saarland and Berlin demonstrated the safety and feasibility of this concept for prehospital stroke care, showing increased rate of intravenous thrombolysis and significant reduction in time to treatment compared to conventional care. MSU also improved the triage of patients to appropriate and specialized hospitals. Although multiple issues remain yet unanswered with the MSU concept including clinical outcome and cost-effectiveness, the MSU venture is visionary and enables delivery of life-saving and enhancing treatment for ischemic and hemorrhagic stroke. In this review, we discuss the development of mobile CT and its applications, with specific focus on its use in MSUs along with our institution's MSU experience.

Emergent mechanical thrombectomy for acute stroke using the Mindframe Capture LP system: initial single-center experience.

BACKGROUND: Mechanical thrombectomy using stentrievers is the standard of care for emergent large vessel occlusion stroke. Data on the use of stentrievers in smaller caliber vessels are sparse. OBJECTIVE: To present our initial experience with the Mindframe Capture LP device, which was designed for mechanical thrombectomy in small cerebral arteries. METHODS: A retrospective chart review was conducted of patients who underwent Mindframe device assisted emergent thrombectomy. Clinical, imaging, procedural and early follow-up data were obtained. RESULTS: Nine patients met inclusion criteria (5 men, median age 62 years). Median National Institute of Health Stroke Scale (NIHSS) score was 18 (IQR 9-22), and 6 patients received intravenous tissue plasminogen activator. Six patients had M2 segment occlusions, and 2 patients had distal M1 segment occlusions of the middle cerebral artery. One had distal basilar artery occlusion. Median vessel diameter at the thrombus was 1.7 mm (IQR 1.5-2.5). In all 9 patients the Mindframe device was used together with manual aspiration, with median groin puncture to recanalization time of 35 min (IQR 27-54), and median procedural time of 67 min (IQR 51-91). Final Thrombolysis in Cerebral Infarction score was 3 and 2b in 4 patients each (89% total), and 2a in 1 patient. No patient had any postprocedural complications or symptomatic intracerebral hemorrhage. Median postprocedure and discharge NIHSS were 4 and 1, respectively. CONCLUSIONS: Our data suggest that the Mindframe device is safe and effective for rapid treatment of acute strokes involving small caliber intracranial vessels. Further study in a larger cohort is warranted.

Solitary C1 spinal osteochondroma causing vertebral artery compression and acute cerebellar infarct.

Osteochondroma is a common benign bone lesion, usually involving the long bones. Spinal involvement is rare. The clinical presentation of spinal osteochondroma varies according to the site of the lesion. The most common reported clinical presentation is secondary to encroachment of the lesion on the spinal canal or nerve roots. Less common presentations such as a palpable neck mass, dysphagia, sleep apnea, paralysis of left vocal cord or acute respiratory distress have been reported when the lesions compress the anatomic structures anteriorly. We describe a rare case of a young patient who presented with an emergent critical condition of acute cerebellar infarct as a result of vertebral artery compression caused by a solitary C1 spinal osteochondroma.

Reversal of coagulopathy using prothrombin complex concentrates is associated with improved outcome compared to fresh frozen plasma in warfarin-associated intracranial hemorrhage.

BACKGROUND: There are no studies demonstrating that prothrombin complex concentrates (PCC) improves outcome compared FFP in patients with warfarin-associated intracranial hemorrhage. METHODS: A prospective, observational study was conducted of patients who received PCC (Bebulin VH), FFP, or PCC + FFP. All groups received vitamin K 10 mg IV. INR reversal (<1.4), adverse events (venous thromboembolism, myocardial infraction, pulmonary edema), major hemorrhage (new or worsened intracranial hemorrhage, anemia requiring transfusion or GI bleed), and 3-month functional outcome were compared between the groups using Chi squared and logistic regression analysis. RESULTS: Of 64 patients, PCC alone was used in 16 (mean dose 48 IU/kg), FFP alone in 25 (mean dose 12.5 ml/kg), and PCC + FFP in 23 (median doses 47.4 IU/kg and 11.4 ml/kg, respectively). INR correction occurred in 88, 84, and 70 %, respectively. There were no differences in time to INR correction or adverse events between the groups, but FFP alone was associated with more major hemorrhage after administration (52 %, OR 5.0, 95 % CI 1.6-15.4, P = 0.006) and PCC with less (6 %, OR 0.1, 95 % CI 0.01-0.8, P = 0.033). After adjusting for age, admission GCS, initial INR, and bleed type, the use of PCC was associated with a lower risk of death or severe disability at 3-months (adjusted OR 0.02, 95 % CI 0.001-0.8, P = 0.039), while FFP alone was associated with a higher risk (adjusted OR 51.6, 95 % CI 1.2-2163.1, P = 0.039). CONCLUSIONS: PCC adequately corrected INR without any increase in adverse events compared to FFP and was associated with less major hemorrhage and improved 3-month outcomes in patients with warfarin-associated intracranial hemorrhage.

Particle embolization of the bilateral superior and inferior alveolar arteries for life threatening dental socket hemorrhage.

Particle embolization for epistaxis and intra-oral hemorrhage are performed on an as needed basis by neurointerventionalists. A case is presented of massive oral hemorrhage associated with end stage liver disease coagulopathy after tooth extraction of bilateral maxillary and mandibular molars. A man in his fifties with end stage liver disease who presented for evaluation of a syncopal episode was determined to be in hemorrhagic shock from 2 days of persistent oral bleeding after elective tooth extractions. Conservative management with multiple blood transfusion products, packing and vasoconstrictive spray was ineffective. Microcatheter angiograms of the alveolar arteries demonstrated blood and contrast pooling within the sockets of the extracted teeth. Selection of the bilateral supplying alveolar and inferior alveolar artery branches was achieved followed by polyvinyl alcohol particle embolization (250-355 µm). Polyvinyl alcohol particle embolization of dental socket hemorrhages is technically feasible and effective.

Embolic protection devices and the Penumbra 054 catheter: utility in tandem occlusions in acute ischemic stroke.

BACKGROUND: Tandem proximal and distal occlusions in the setting of an acute stroke are therapeutic challenges. Treating either lesion first has its respective shortcomings. An approach is described which may lessen the probability of distal embolic events during emergency carotid angioplasty and stenting during an acute stroke, and simplify access to both a distal and proximal lesion. CLINICAL PRESENTATION: A 58-year-old man presented with waxing and waning neurological examination with an NIH Stroke Scale varying from 4 to 21. CT angiography demonstrated a left internal carotid artery occlusion at its origin and a left middle cerebral artery occlusion. The CT scan failed to demonstrate significant ischemic changes so the patient was brought to angiography for treatment under conscious sedation. INTERVENTION: Triaxial access into the distal middle cerebral artery was achieved followed by brief aspiration and clot maceration by opening the vessel completely. An embolic protection device was deployed through the intermediate catheter which was subsequently removed. Stenting and angioplasty were then performed, followed by removal of the embolic protection device which had visibly trapped debris. CONCLUSION: Embolic protection devices may have a role in the emergency treatment of proximal occlusions in the setting of an acute ischemic stroke. Safe deployment through an occluded vessel may be assisted by use of an intermediate catheter. The Penumbra 054 catheter may be used both to aspirate the distal thrombus and to house the embolic protection device as it is advanced past a proximal occlusion.

Circulating endothelial progenitor cells and age-related white matter changes.

BACKGROUND AND PURPOSE: The objective was to evaluate the relationship between circulating endothelial progenitor cells (EPC) and age-related white matter changes (ARWMC). Endothelial dysfunction plays a role in the development of ARWMC. EPC incorporate into sites endothelial damage and are thought to be involved in the repair of vascular risk factor induced endothelial injury. ARWMC can be evaluated using CT or MRI. METHODS: In 172 individuals, circulating EPC were defined by the surface markers CD31 and von Willebrand factor. ARWMC were rated on CT scan using the ARWMC scale and divided into 3 groups based on ARWMC scale score (ARWMC score 0 [none], score 1-10 [mild-to-moderate], score >10 [severe]). Severity of ARWMC was correlated with levels of EPC and vascular risk factors. RESULTS: On univariate analysis, EPC were found to be significantly lower in patients with severe ARWMC (P=0.01). ARWMC were also associated with hypertension (P<0.001), age (P<0.001), creatinine clearance (P=0.031), C-reactive protein (P<0.001), and use of angiotensin-converting enzyme or angiotensin receptor blocker (P=0.004). Multiple logistic regression analysis identified EPC level, age, hypertension, and hypertriglyceridemia as significant independent predictors of severe ARWMC. CONCLUSIONS: Levels of circulating EPC were significantly lower in patients with severe ARWMC. Other variables significantly associated with severe ARWMC were age, hypertension, and hypertriglyceridemia. Further study is required to delineate the pathophysiological relationship between EPC, vascular risk factors, and ARWMC.

The use of stem cells' hematopoietic stimulating factors therapy following spinal cord injury.

Spinal cord injury (SCI) remains one of the most devastating conditions in medicine, particularly due to the loss of productive life years and the high economic burden it places on our society. There are limited therapeutic options available to reduce the morbidity and mortality related to SCI. However, recent work with stem cells in repairing SCI appears to be promising, making this one of the most exciting frontiers in medicine. A brief review of the mechanisms of SCI is presented. Stem cells from a variety of sources have shown effectiveness in improving motor function after SCI in animals. The pre-clinical use of stem cells in SCI and methods of delivery are discussed. The potential use of granulocyte-colony stimulating factor (G-CSF) to increase the number of stem cells engrafting at the site of injury in order to improve neurological and motor function recovery following SCI is introduced. G-CSF, through stimulation of lymphohemopoietic stem cells in peripheral blood, can potentially cause repopulation of the SCI region with neural progenitor cells. This allows for improved functional outcomes. More pre-clinical and translational research exploring this possibility is required.