Identification of benzofuran central cores for the inhibition of leukotriene A(4) hydrolase.

Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD).

Intra-arterial bevacizumab with blood brain barrier disruption in a glioblastoma xenograft model.

PURPOSE: In this study we investigated the treatment response and survival of intra-arterial (IA) compared to intra-peritoneal (IP) delivery of bevacizumab (BV) in a glioblastoma (GBM) xenograft mouse model. METHODS: 3x10(5) U87-Luc cells were stereotactically implanted into the cortex of 35 nude mice and grouped for treatment (n = 7 in each group): IP saline (group 1), single IP BV (group 2), biweekly IP BV for 3 weeks (group 3), single intra-arterial (IA) BV alone (group 4) and single IA BV with blood brain barrier disruption (BBBD) (group 5). Tumor growth was monitored every 3 to 4 days using bioluminescence imaging (BLI) and survival was analyzed by the Kaplan Meier method. Tumor tissue was analyzed using H&E staining and immunohistochemistry. RESULTS: Based on BLI, BV treated mice showed a delayed tumor growth over time compared to control. Kaplan Meier analysis demonstrated a median survival time of 28 days for group 1,31 days for group 2, 34 days for group 3, 36 days for group 4 and 36 days for group 5 (p < 0.0001). Mice treated with repeated IP BV (p = 0.003) or single IA BV with (p = 0.015) or without (p = 0.005) BBBD showed a significant survival benefit compared to single IP BV treated mice. Post mortem analysis revealed a histological pattern with a more discontinuous border between tumor and mouse brain in the repeated IP BV and single IA BV with or without BBBD treated mice compared to the sharply defined edges of single IP BV treated and control mice. CONCLUSIONS: In this study we showed a significant survival benefit of repeated IP BV and single IA BV with or without BBBD treated mice compared to single IP BV treated and control mice in a U87 xenograft model.

Azabenzthiazole inhibitors of leukotriene A4 hydrolase.

Previously, benzthiazole containing LTA(4)H inhibitors were discovered that were potent (1-3), but were associated with the potential for a hERG liability. Utilizing medicinal chemistry first principles (e.g., introducing rigidity, lowering cLogD) a new benzthiazole series was designed, congeners of 1-3, which led to compounds 7a, 7c, 12a-d which exhibited LTA(4)H IC(50)=3-6 nM and hERG Dofetilide Binding IC(50)=8.9-> >10 µM.

Predicting postoperative hydrocephalus in 227 patients with skull base meningioma.

OBJECT: Some patients develop communicating hydrocephalus after meningioma surgery, and this can develop into a serious clinical condition. However, this has rarely been addressed in the literature. Therefore, the authors sought to determine predictive patient variables for the occurrence of postoperative hydrocephalus following skull base meningioma surgery. METHODS: For this purpose, the authors retrospectively analyzed all patients who underwent resection of intracranial meningiomas between 1998 and 2009 at the Department of Neurosurgery, University Hospital Zurich, Switzerland. Of 594 patients with meningioma, 227 (38%) had a lesion located at the skull base, and thus were included for analysis. The following patient variables were examined: demographic data (age and sex); tumor number (solitary vs multiple); tumor side and localization within the skull base region (anterior, medial, posterior); infiltration of the cavernous sinus; compression of the optic channel/optic nerve; tumor volume; preoperative embolization (yes/no); duration of surgery; Simpson grade of resection; histopathological features (WHO grade); number of surgeries (single vs multiple); preoperative embolization; duration of hospital stay; tumor recurrence; use of an artificial dural substitute; postoperative infection rate; and clinical outcome (Glasgow Outcome Scale score at discharge and at 3 months, and vital status at last follow-up). Hierarchical clustering, factor analysis, and stepwise regression models revealed a ranking list for the top predictive variables for the occurrence of postoperative hydrocephalus. RESULTS: A total of 35 patients (5.9%) of the cohort of 594 developed communicating postoperative hydrocephalus, with no patient manifesting obstructive hydrocephalus. Of these 35 patients, 18 had a meningioma located at the skull base (18 [7.9%] of 227), in contrast to 17 patients with meningiomas in other locations (17 [4.6%] of 367). The following patient variables correlated with the occurrence of hydrocephalus, as defined by factor analysis: age, duration of surgery, duration of hospital stay, tumor volume, postoperative infection, and preoperative embolization. A stepwise regression analysis of the latter variables identified 2 variables as significantly predictive: age (p = 0.0012) and duration of surgery (p = 0.0013). CONCLUSIONS: In this study, the incidence of communicating postoperative hydrocephalus was almost twice as high in patients with skull base lesions as in patients with meningiomas in other locations. Patient age, duration of surgery, duration of hospital stay, tumor volume, postoperative infection, and preoperative embolization were associated with the occurrence of hydrocephalus. In the statistical prediction model, patient age and duration of surgery were the most significant predictors of postoperative hydrocephalus after skull base meningioma surgery.

Venous sinus stenting for the treatment of isolated pulsatile tinnitus: Results of a prospective trial.

OBJECTIVES: This prospective study evaluates the effectiveness and safety of venous sinus stenting for patients with isolated pulsatile tinnitus and lateral sinus stenosis. METHODS: Patients with isolated pulsatile tinnitus and lateral sinus stenosis with a minimum trans stenotic gradient of 4 mm Hg were treated with stenting. Pulsatile tinnitus before and after treatment was assessed with the Tinnitus Handicap Inventory (THI). Periprocedural adverse events, neurological complications, clinical and radiographic follow-up were also recorded. RESULTS: A total of 42 patients (41 females and 1 male) were included in the study (median age of 37.5 years). Thirty patients had post-stenotic fusiform and 12 had post-stenotic saccular venous sinus aneurysm. In addition to stenting, coils were used to treat the patients with saccular venous aneurysms. The median follow-up was 5 months (range 1 to 34 months). Most patients had complete (39/42) or near-complete (2/42) resolution of their pulsatile tinnitus post-procedure. There were no serious adverse events. CONCLUSION: Stenting of the lateral venous sinus is a safe and effective treatment for patients with isolated pulsatile tinnitus due to venous sinus stenosis.

Missed cerebrovascular events during prolonged sedation for COVID-19 pneumonia.

Cerebrovascular complications among critically ill patients with COVID-19 have yet to be fully characterized. In this retrospective case series from a single academic tertiary care referral center in New York City, we present 12 patients with ischemic or hemorrhagic strokes that were found on imaging after a period of prolonged sedation in the setting of COVID-19 pneumonia. This series demonstrates a pattern of cerebrovascular events clinically masked by deep sedation required for management of COVID-19 related acute respiratory distress syndrome (ARDS). Of the 12 patients included, 10 had ischemic stroke, 4 of which had hemorrhagic conversion, and 2 had primary intracerebral hemorrhage. Ten patients were on therapeutic anticoagulation prior to discovery of their stroke, and the remainder received intermediate dose anticoagulation (in a range between prophylactic and therapeutic levels). Additional studies are needed to further characterize the counterbalancing risks of ischemic and hemorrhagic stroke, as well as the optimal management of this patient population.

Indole- and benzothiophene-based histamine H3 antagonists.

Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.

Surgical management of pediatric cerebral arteriovenous malformations.

BACKGROUND: Arteriovenous malformations (AVMs) are the most common cause of intracerebral hemorrhage in children. Different options exist for their successful management consisting of surgery, endovascular embolization, stereotactic radiosurgery, or a combination of these treatments. DISCUSSION: In this paper, we discuss the different treatment modalities in the treatment of pediatric cerebral AVMs emphasizing the role of surgery and endovascular embolization as a preoperative strategy.

Primary intradiploic pterional epidermoid cyst.

A 72-year-old woman who developed a left temporal protrusion was referred to our center. An MRI showed a heterogeneous mass in the left temple with T2 signal hyperintensity within the intradiploic space of the greater wing of the sphenoid bone, measuring 2.4 x 2.1 cm. The patient underwent a surgical removal of the mass through the pterional approach. Pathology showed an epidermoid cyst. Intradiploic epidermoid cysts of the skull are rare benign tumors of the skull. These lesions grow slowly and are composed of epidermoid cells debris rich in cholesterol. The prophylactic removal of these tumors with the goal of preventing recurrences is recommended.

Intra-arterial neuroprotective therapy as an adjunct to endovascular intervention in acute ischemic stroke: A review of the literature and future directions.

Mechanical thrombectomy for acute ischemic stroke due to large vessel occlusion has been shown to significantly improve outcomes. However, despite efficient rates of recanalization (60-90%), the rates of functional independence remain suboptimal (14-58%), most likely due to pathways of cell death in the brain that have already committed despite successful reperfusion. Pharmacologic neuroprotection provides a potential means of preventing this inevitable damage through targeting excitotoxicity, reactive oxygen species, cellular apoptosis, and inflammation. Numerous clinical trials using various neuroprotective agents have failed, but the majority of these trials did not include endovascular reperfusion, and thus the drugs were not reaching the therapeutic target. Intra-arterial delivery of neuroprotective agents via the guide catheter already in place for mechanical thrombectomy could provide a way to deliver high doses directly to the affected territory while limiting systemic exposure. Agents that have shown promise via the intra-arterial route in preclinical as well as some clinical models include magnesium sulfate, verapamil, cold saline, stem cells, and various combined approaches. Targeted hypothermia, achieved with intra-carotid infusion of cold saline, may provide an effective means of achieving hypothermia of the ischemic tissue while avoiding the systemic effects that have limited its use previously. Combination therapy of targeted hypothermia and a cocktail of drugs that provide anti-excitotoxic, anti-oxidant, anti-apopototic, and anti-inflammatory effects may provide an ideal approach that deserves further study in clinical trials.

Safely traversing venous sinus stenosis: The "Cobra" technique.

Venous sinus stenting is an accepted and minimally invasive treatment for idiopathic intracranial hypertension associated with significant venous sinus stenosis. There is inherent difficulty in navigating past the region of venous stenosis in order to safely deliver and deploy a stent. We have developed the "Cobra" technique, which allows for the safe and efficient navigation past regions of high-grade venous sinus stenosis.

Single arm access venous sinus stenting (SAVeS) technique: Technical note.

Intracranial venous sinus stenting is gaining acceptance as an effective treatment for idiopathic intracranial hypertension (IIH). The typical approach is via femoral venous and arterial access for transvenous stenting with simultaneous angiography. These patients are at an above average risk for groin complications considering obesity is typically associated with IIH and the need for heparinization and dual antiplatelet therapy. Here, we describe cerebral venography, angiography, and venous sinus stenting via a single upper extremity. We utilize a transradial approach for angiography and a venous access via the brachial or basilic vein. Over a series of 28 consecutive procedures, we were able to successfully access the intracranial venous sinuses via the arm without access site complications. This method offers the advantages of immediate patient mobilization after the procedure and more easily monitored and compressible access sites for easier post-procedural care.

Anterior spinal artery syndrome caused by thoracic disc herniation.

We present a case of a midline thoracic disc herniation causing acute anterior spinal artery (ASA) syndrome successfully managed surgically. A 54-year-old female with no significant past medical history presented with sudden onset severe back pain followed by rapidly evolving paraparesis with urinary and bowel incontinence. Her neurological exam was consistent with ASA syndrome. An MRI revealed T2 signal change in the thoracic spinal cord and midline disc herniation at the level of T8/T9. Spinal angiography revealed an ASA arising the right T11 segmental artery with no flow towards the T8/T9 region. The patient underwent a T8/T9 discectomy with a lateral interbody fusion that resulted in dramatic clinical improvement. A postoperative angiogram confirmed improvement of flow in the ASA. This is the first report of an angiographically confirmed symptomatic ASA syndrome caused by a thoracic disc herniation successfully managed with up-front surgery.

Endovascular preoperative embolization for temporomandibular joint replacement surgery.

BACKGROUND AND PURPOSE: This retrospective study evaluates the safety and effectiveness of preoperative endovascular embolization in patients who underwent temporomandibular joint (TMJ) replacement surgery. MATERIAL AND METHODS: We included all patients treated with preoperative embolization of the internal maxillary artery (IMAX) between June 2016 and January 2019. All patients were treated by the same surgeon using standard surgical approaches and procedures. Periprocedural adverse events, blood loss during surgery and clinical follow-up are reported. RESULTS: Fourteen patients (12 females, median age 32.5) were treated with 21 embolizations of the IMAX (bilateral embolizations in seven patients) prior to TMJ replacement surgery with prosthetic joints (TMJ Concepts prostheses). Seven patients presented with TMJ ankylosis/degenerative joint disease/post-trauma deformity, four patients with Idiopathic Condylar Resorption and resultant mandibular displacement/hypoplasia, two patients with rheumatoid arthritis-associated condylar degeneration and resultant loss of mandibular position, and 1 patient being re-reconstructed following management of a prosthetic joint infection. Seven patients underwent bilateral prosthetic joint replacement. Four patients underwent additional facial skeletal surgery as part of their treatment. The mean blood volume loss during TMJ surgery was approximately 370 cc (range 100-800 cc). Joint space-specific blood loss was not recorded, but, as per the surgical team, was significantly decreased when compared to non-embolized patients. There were no intra-procedural complications. The median clinical follow-up was 3.5 months (range 1-24 months). The modified Rankin scale (mRS) was 0 before the procedure and at last clinical follow-up in all patients. After TMJ surgery, three patients reported paresthesia of the trigeminal nerve likely related to the residual condyle resection and two patients had mild facial nerve weakness (Temporal and/or Marginal Mandibular branch) related to the surgical exposures. CONCLUSION: Endovascular preoperative embolization of the IMAX is feasible, safe and likely effective in reducing blood volume loss in complex TMJ replacement surgery.

Delayed intracranial aneurysm formation after cardiac myxoma resection: Report of two cases and review of the literature.

Myxomas are slowly growing benign neoplasms and represent the most common tumor of the heart. Embolism from cardiac myxoma occurs in 30-45% of patients and in at least half of the cases cerebral arteries are affected leading mainly to embolic ischemic strokes and rarely to delayed intracranial aneurysm formation. We present two cases with delayed intracranial aneurysmal formation 14 years and 18 years after cardiac myxoma resection. To the best of our knowledge these two cases represent the longest time interval between aneurysm detection after complete cardiac myxoma resection with no recurrence confirmed by transesophageal echocardiogram. Our study also provides the longest clinical and radiological follow-up on this type of lesion.

Stent-assisted coil embolization of anterior communicating artery aneurysms using the LVIS Jr stent.

BACKGROUND AND PURPOSE: This retrospective study evaluates the safety and mid-term and long-term effectiveness of stent-assisted coil embolization of anterior communicating artery (Acomm) aneurysms treated with the LVIS Jr stent. MATERIALS AND METHODS: All patients treated with the LVIS Jr stent for Acomm aneurysms between June 2015 and March 2018 were included in the analysis. Details of the procedure's periprocedural adverse events, immediate aneurysm occlusion rates, and clinical and angiographic follow-up assessment were collected. RESULTS: A total of 25 patients with 25 aneurysms were included. Eighteen aneurysms were found incidentally. Seven patients presented with seven ruptured aneurysms: Six were remotely ruptured and one acutely ruptured. Twenty-four patients were treated successfully and one technical failure is reported. The parent arteries measured 1.4 mm to 2.9 mm in diameter (mean, 2.3 mm). Intraprocedural thromboembolic complications occurred in two patients (8%) and an intraoperative aneurysm rupture in one patient (4%). Immediate complete aneurysm occlusion was noted in 18 out of 25 patients (72%). Clinical follow-up ranged from three months to 36 months (mean, 15.8 months) and the imaging follow-up ranged from two to 35 months (mean, 14.2 months). Complete aneurysm occlusion was achieved in 14 out of 20 patients (70%) at last angiographic follow-up. Of the two patients with in-stent thrombosis, one patient had an acutely ruptured aneurysm and the other patient was treated with an LVIS Jr stent in a Y configuration. Neurological morbidity and mortality rate were 0%. CONCLUSIONS: Complex, wide-necked Acomm aneurysms can be effectively treated with stent-assisted embolization using LVIS Jr stents.

Double Stent-Assisted (Y and X) Coil Embolization of Unruptured Intracranial Saccular Aneurysms using the Low-Profile Visualized Intraluminal Support Device-Single Center Experience.

PURPOSE: To study the feasibility, safety, and durability of the dual stent-assisted coil embolization (DSCE) technique using low-profile visualized intraluminal support (LVIS) device. METHODS: Retrospective review of our aneurysm database to identify all the patients treated with LVIS stent-assisted embolization between July 2015 and June 2017 was performed. 15% of the patients with Y- or X-configuration DSCE constituted the study population. Patient demographics, clinical presentation, aneurysm characteristics (location, dome, and dome/neck ratio), periprocedural complications, immediate and follow-up angiographic and clinical outcomes were reported. RESULTS: Twelve patients (15%) with unruptured, wide-necked branching aneurysms underwent DSCE using LVIS Junior stents. M:F-1:11. Mean age of 60 ± 11 years. 75% (n = 9) aneurysms are located in anterior circulation. Recurrent aneurysms were treated in 17% (n = 2). Mean aneurysm diameter was 8 ± 3.4 mm and the dome/neck ratio was 1.6 ± 0.4. Periprocedural complications were noted in 25% (n = 3; transient in-stent thrombus = 2 and iatrogenic rupture = 1) with no clinical sequelae. Immediate aneurysm obliteration following DSCE was noted in all (100%) patients. Mean time-of-flight (TOF) magnetic resonance angiography (MRA) follow-up was 10 ± 6 months (Range: 5-19 months). Mean clinical follow-up was 12 ± 6 months (Range: 5-21 months). Stable neck recurrence was demonstrated in 25% (n = 3). The average modified Rankin Score (mRS) at prestent, 24-hour poststent, and last clinical follow-up were: 0.5 (Range: 0-1), 0.75 (Range: 0-1), and 0.5 (Range: 0-1), respectively. CONCLUSION: We report the first dedicated DSCE experience with LVIS Junior stents in the literature. DSCE with LVIS Junior stents for intracranial complex wide-neck branching aneurysms is feasible, safe, and effective with good clinical outcomes.

[Clinical- epidemiological characteristics and predictors of coronary complications in children of Argentina with Kawasaki disease]. / Características clínico-epidemiológicas y predictores de complicaciones coronarias en niños de Argentina con enfermedad de Kawasaki.

BACKGROUND: Kawasaki disease (EK) is an acute systemic vasculitis with a risk of developing coronary aneurysms. AIM: To describe the clinical and epidemiological characteristics of children with EK in Argentina and to analyse the risk factors for the development of coronary's complications (CC). METHODS: Multicenter, retrospective, cross-sectional, observational and analytical study. It included patients younger than 18 years of age diagnosed with EK in hospitals in Argentina, between January the 1st, 2010 and December the 31th, 2013. RESULTS: N = 193 subjects. Age: medium: 29 months. Total incidence 5 cases / 10,000 hospital discharges. CC was observed in 15.5% of patients. Increased risk factors for CC: Elevated number of days with fever at the time of treatment placement (p = 0.0033); Increased of: heart frequency (p = 0.0021), erythrosedimentation (ESR) (p = 0.005), C-reactive protein (CRP) (p < 0.0001), leukocytes (p = 0.0006), neutrophils (p = 0.0021); Decreased of hematocrit (p = 0.0007) and hemoglobin (p < 0.0001).Association with CC: non-coronary cardiological alterations (OR = 10,818); PCR greater than 68 mg /L (OR = 11,596); leukocytes greater than 20,000 / mm3 (OR = 4.316); and ESR greater than 64 mm / 1 hour (OR = 4.267). CONCLUSION: The most frequent form of presentation was complete EK, the risk of CC was higher in males, younger than 5 years old, the risk factors (clinical and laboratory) were similar to those described in the literature.

Transvenous Embolization of Dural Arteriovenous Fistulas of the Hypoglossal Canal: Report of Three Cases and Review of the Literature.

In this article, we report three cases of dural arteriovenous fistulas of the hypoglossal canal treated via transvenous approach. We also perform a review of the literature on the endovascular management of this type of lesions with particular attention to the dangerous extracranial-intracranial anastomoses that can occur at this level.