The lonidamine derivative H2-gamendazole reduces cyst formation in polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating renal neoplastic disorder with limited treatment options. It is characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl- secretion. We tested the effectiveness of the indazole carboxylic acid H2-gamendazole (H2-GMZ), a derivative of lonidamine, to inhibit these processes using in vitro and in vivo models of ADPKD. H2-GMZ was effective in rapidly blocking forskolin-induced, Cl--mediated short-circuit currents in human ADPKD cells, and it significantly inhibited both cAMP- and epidermal growth factor-induced proliferation of ADPKD cells. Western blot analysis of H2-GMZ-treated ADPKD cells showed decreased phosphorylated ERK and decreased hyperphosphorylated retinoblastoma levels. H2-GMZ treatment also decreased ErbB2, Akt, and cyclin-dependent kinase 4, consistent with inhibition of heat shock protein 90, and it decreased levels of the cystic fibrosis transmembrane conductance regulator Cl- channel protein. H2-GMZ-treated ADPKD cultures contained a higher proportion of smaller cells with fewer and smaller lamellipodia and decreased cytoplasmic actin staining, and they were unable to accomplish wound closure even at low H2-GMZ concentrations, consistent with an alteration in the actin cytoskeleton and decreased cell motility. Experiments using mouse metanephric organ cultures showed that H2-GMZ inhibited cAMP-stimulated cyst growth and enlargement. In vivo, H2-GMZ was effective in slowing postnatal cyst formation and kidney enlargement in the Pkd1flox/flox: Pkhd1-Cre mouse model. Thus, H2-GMZ treatment decreases Cl- secretion, cell proliferation, cell motility, and cyst growth. These properties, along with its reported low toxicity, suggest that H2-GMZ might be an attractive candidate for treatment of ADPKD.NEW & NOTEWORTHY Autosomal dominant polycystic kidney disease (ADPKD) is a renal neoplastic disorder characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl- secretion. This study shows that the lonidamine derivative H2-GMZ inhibits Cl- secretion, cell proliferation, and cyst growth, suggesting that it might have therapeutic value for the treatment of ADPKD.

Preclinical assessment of onabotulinumtoxinA for the treatment of mild traumatic brain injury-related acute and persistent post-traumatic headache.

OBJECTIVE: Investigation of onabotulinumtoxinA in a murine model of acute and persistent post-traumatic headache. METHODS: Mild traumatic brain injury was induced with a weight drop method. Periorbital and hindpaw cutaneous allodynia were measured for 14 days. Mice were then exposed to bright light stress and allodynia was reassessed. OnabotulinumtoxinA (0.5 U) was injected subcutaneously over the cranial sutures at different post-injury time points. RESULTS: After milt traumatic brain injury, mice exhibited periorbital and hindpaw allodynia that lasted for approximately 14 days. Allodynia could be reinstated on days 14-67 by exposure to stress only in previously injured mice. OnabotulinumtoxinA administration at 2 h after mild traumatic brain injury fully blocked both transient acute and stress-induced allodynia up to day 67. When administered 72 h post-mild traumatic brain injury, onabotulinumtoxinA reversed acute allodynia, but only partially prevented stress-induced allodynia. OnabotulinumtoxinA administration at day 12, when initial allodynia was largely resolved, produced incomplete and transient prevention of stress-induced allodynia. The degree of acute allodynia correlated positively with subsequent stress-induced allodynia. CONCLUSION: Mild traumatic brain injury induced transient headache-like pain followed by long lasting sensitization and persistent vulnerability to a normally innocuous stress stimulus, respectively modeling acute and persistent post-traumatic headache.. Administration of onabotulinumtoxinA following the resolution of acute post-traumatic headache diminished persistent post-traumatic headache but the effects were transient, suggesting that underlying persistent mild traumatic brain injury-induced maladaptations were not reversed. In contrast, early onabotulinumtoxinA administration fully blocked both acute post-traumatic headache as well as the transition to persistent post-traumatic headache suggesting prevention of neural adaptations that promote vulnerability to headache-like pain. Additionally, the degree of acute post-traumatic headache was predictive of risk of persistent post-traumatic headache.

Short-term toxicity study of 1-aminobenzotraizole, a CYP inhibitor, in Wistar rats.

1-Aminobenzotriazole (ABT) is a pan-specific, mechanism-based inhibitor of CYP P450 enzymes, often used as co-treatment to investigate the metabolism-dependent toxicity of drugs or chemicals. To assess the confounding effects of ABT in such kind of mechanistic studies, a repeated dose toxicity study with ABT following 7 days oral administration at 0, 25, 50 and 100 mg/kg/day was performed in Wistar rats (5 rats/sex/group). Wistar rat is selected as a model being one of the well characterized rodent species, widely used for toxicity and toxicokinetics studies. The standard parameters of general toxicity study viz. clinical signs, body weight, feed consumption, clinical, gross and histopathology were evaluated. The ABT was tolerated up to the highest tested dose of 100 mg/kg/day. No clinical signs, mortality or effect on feed consumption at any dose. Slight increase in body weight gain was noted in ABT treated females. Increased reticulocyte, and decreased triglycerides, BUN, A/G ratio and plasma potassium; increased weight of liver, kidneys, adrenals and thyroid was noted in ABT treated animals. Microscopically, hypertrophic findings were noted in liver, thyroid, adrenal glands, pituitary and uterus. Some of these changes were observed at as low as 25 mg/kg/day, therefore, NOEL could not be established. Based on this study, it is concluded that ABT is tolerable up to 100 mg/kg/day with some variations in clinical pathology, organ weight and histopathology; these changes should be considered during the assessment of any mechanistic study with ABT. Findings of this manuscript were presented at 58th meeting of the Society of Toxicology, Baltimore, 11 March 2019.

Improving drought tolerance in rice: Ensuring food security through multi-dimensional approaches.

Drought has been highly prevalent around the world especially in Sub-Saharan Africa and South-East Asian countries. Consistent climatic instabilities and unpredictable rainfall patterns are further worsening the situation. Rice is a C3 staple cereal and an important food crop for the majority of the world's population and drought stress is one of the major growth retarding threats for rice that slashes down grain quality and yield. Drought deteriorates rice productivity and induces various acclimation responses that aids in stress mitigation. However, the complexity of traits associated with drought tolerance has made the understanding of drought stress-induced responses in rice a challenging process. An integrative understanding based on physiological adaptations, omics, transgenic and molecular breeding approaches successively backed up to developing drought stress-tolerant rice. The review represents a step forward to develop drought-resilient rice plants by exploiting the knowledge that collaborates with omics-based developments with integrative efforts to ensure the compilation of all the possible strategies undertaken to develop drought stress-tolerant rice.

N-Butyldeoxygalactonojirimycin Induces Reversible Infertility in Male CD Rats.

This study shows for the first time that an iminosugar exerts anti-spermiogenic effect, inducing reversible infertility in a species that is not related to C57BL/6 male mice. In CD rats, N-butyldeoxygalactonojirimycin (NB-DGJ) caused reversible infertility at 150 mg/kg/day when administered daily as single oral dose. NB-DGJ inhibited CD rat-derived testicular ß-glucosidase 2 (GBA2) activity at 10 µM but did not inhibit CD rat-derived testicular ceramide-specific glucosyltransferase (CGT) at doses up to 1000 µM. Pharmacokinetic studies revealed that sufficient plasma levels of NB-DGJ (50 µM) were achieved to inhibit the enzyme. Fertility was blocked after 35 days of treatment and reversed one week after termination of treatment. The rapid return of fertility indicates that the major effect of NB-DGJ may be epididymal rather than testicular. Collectively, our in vitro and in vivo studies in rats suggest that iminosugars should continue to be pursued as potential lead compounds for development of oral, non-hormonal male contraceptives. The study also adds evidence that GBA2, and not CGT, is the major target for the contraceptive effect of iminosugars.

Dural venous sinus stenting for idiopathic intracranial hypertension: An updated review.

BACKGROUND: Dural venous sinus stenting (DVSS) is an accepted treatment option in selected patients with medically refractory idiopathic intracranial hypertension and obstructive venous outflow physiology prior to cerebrospinal flow diversion (CSFD) surgery. There are no randomized controlled studies focusing on outcomes and complication rates for dural venous sinus stenting. PURPOSE: We present the largest comprehensive meta-analysis on DVSS for idiopathic intracranial hypertension (IIH) focusing on success rates, complications, and re-stenting rates to date. We also present a simplified approach to direct retrograde internal jugular vein (IJ) access for DVSS that allows for expedited procedures. MATERIALS AND METHODS: We performed a retrospective electronic PubMed query of all peer-reviewed articles in the last 15 years between 2003 to 2018. We included all patients who underwent dural venous sinus stenting for a medically refractive IIH and excluded articles without sufficient data on outcomes, complication rates and re-stenting rates. We also evaluated and compared outcomes in patients undergoing direct retrograde IJ access DVSS to traditional transfemoral vein access. RESULTS: A total of 29 papers and 410 patients who underwent DVSS met criteria for inclusion. DVSS was associated with high technical success [99.5%], low rates of repeated procedure [10%], and low major complication rates [1.5%]. CONCLUSION: Our retrospective comprehensive review of DVSS for medically refractory IIH suggests that stenting in appropriately chosen patients is associated with low complication rates, high technical success, and low repeat procedure rates.

Chronic nicotine improves cognitive and social impairment in mice overexpressing wild type α-synuclein.

In addition to dopaminergic and motor deficits, patients with Parkinson's disease (PD) suffer from non-motor symptoms, including early cognitive and social impairment, that do not respond well to dopaminergic therapy. Cholinergic deficits may contribute to these problems, but cholinesterase inhibitors have limited efficacy. Mice over-expressing α-synuclein, a protein critically associated with PD, show deficits in cognitive and social interaction tests, as well as a decrease in cortical acetylcholine. We have evaluated the effects of chronic administration of nicotine in mice over-expressing wild type human α-synuclein under the Thy1-promoter (Thy1-aSyn mice). Nicotine was administered subcutaneously by osmotic minipump for 6 months from 2 to 8 months of age at 0.4 mg/kg/h and 2.0 mg/kg/h. The higher dose was toxic in the Thy1-aSyn mice, but the low dose was well tolerated and both doses ameliorated cognitive impairment in Y-maze performance after 5 months of treatment. In a separate cohort of Thy1-aSyn mice, nicotine was administered at the lower dose for one month beginning at 5 months of age. This treatment partially eliminated the cognitive deficit in novel object recognition and social impairment. In contrast, chronic nicotine did not improve motor deficits after 2, 4 or 6 months of treatment, nor modified α-synuclein aggregation, tyrosine hydroxylase immunostaining, synaptic and dendritic markers, or microglial activation in Thy1-aSyn mice. These results suggest that cognitive and social impairment in synucleinopathies like PD may result from deficits in cholinergic neurotransmission and may benefit from chronic administration of nicotinic agonists.

Synthesis and molecular docking studies of oxochromenyl xanthenone and indolyl xanthenone derivatives as anti-HIV-1 RT inhibitors.

A series of novel oxochromenyl xanthenone and indolyl xanthenone derivatives were obtained by one-pot reaction of substituted salicylaldehyde, 4-hydroxy coumarin/indole and dimedone at ambient temperature condition using eco-friendly reusable ionic liquid [Hmim]HSO4 in ethanol solvent. Excellent yields, mild reaction condition, and simple experimental work-up procedure are some of the advantages of this method. The obtained derivatives were studied for their molecular docking as an anti-HIV-1 RT. All synthesized compounds from indolyl xanthenone and chromenyl xanthenone series were be docked into the non-nucleoside inhibitor binding pocket (NNIBP) of HIV-1 RT. Compounds 4r, 4j and 4k was found to be good around -12.487, -12.457, -12.256, respectively, with respective to native ligand TMC278, was found to be -13.413 which confirms that these compounds might have potent RT inhibition activity.

Efficacy of Dose-Escalated Hypofractionated Radiosurgery for Arteriovenous Malformations.

There is considerable controversy about the management of arteriovenous malformations (AVMs) that are high risk for surgical resection. Stereotactic radiosurgery (SRS) has a reported success rate of less than 50% with unacceptably high rates of radiation necrosis with larger AVM volumes. Neither volume staging nor hypo-fractionated SRS have conclusively been demonstrated to improve results. We hypothesized that the failure of previous hypo-fractionation SRS trials was due to an insufficient biologically effective dose (BED) of radiation. We initiated a pilot study of treating AVM patients with a total dose divided into three or five fractions designed to deliver the equivalent BED of 20 Gy in a single fraction (α/ß =3). We performed a retrospective analysis of 37 AVM patients who had a minimum of two years of follow-up or underwent obliteration. Patients were treated with 30 Gy/3 fractions, 33 Gy/3 fractions, or 40 Gy/5 fractions using a CyberKnife device (Accuracy Incorporated, Madison, Wisconsin, United States). The primary endpoint was complete AVM obliteration, determined by MRA imaging. Most obliterations were confirmed with diagnostic cerebral angiography. Secondary endpoints were post-radiosurgery hemorrhage and radiation-related necrosis. Kaplan-Meier analysis was used to determine obliteration rates. From 2013 to 2021, 37 patients fitting inclusion criteria were identified (62% male, average age at treatment = 48.88 years). Fifteen (41%) patients had prior treatment (surgery, radiosurgery, embolization) for their AVM, 32 (86%) had AVMs in eloquent locations, 17 (46%) had high-risk features, and 14 (38%) experienced AVM rupture prior to treatment. The average modified radiosurgery-based AVM score (mRBAS) was 1.81 (standard deviation (SD)= 0.52), and the mean AVM volume was 6.77 ccs (SD = 6.09). Complete AVM obliteration was achieved in 100% of patients after an average of 26.13 (SD = 14.62) months. The Kaplan-Meier analysis showed AVM obliteration rates at one, two, and three years to be 16.2%, 46.9%, and 81.1%, respectively. Post-operative AVM rupture or hemorrhage occurred in one (2.7%) patient, after nine months. Radiation necrosis occurred in four (11%) patients after an average period of 17.3 (SD =14.7) months. The SRS dose used in this study is the highest BED of any AVM hypofractionation trial in the published literature. This study suggests that dose-escalated hypofractionated radiosurgery can be a successful strategy for AVMs with acceptable long-term complication rates. Further investigation of this treatment regimen should be performed to assess its efficacy.

First multicenter study evaluating the utility of the BENCHMARKTM BMXTM 81 large-bore access catheter in neurovascular interventions.

INTRODUCTION: This study is the first multicentric report on the safety, efficacy, and technical performance of utilizing a large bore (0.081″ inner diameter) access catheter in neurovascular interventions. METHODS: Data were retrospectively collected from seven sites in the United States for neurovascular procedures via large bore 0.081″ inner diameter access catheter (Benchmark BMX81, Penumbra, Inc.). The primary outcome was technical success, defined as the access catheter reaching its target vessel. Safety outcomes included periprocedural device-related and access site complications. RESULTS: There were 90 consecutive patients included. The median age of the patients was 63 years (IQR: 53, 68); 53% were female. The most common interventions were aneurysm embolization (33.3%), carotid stenting (12.2%), and arteriovenous malformation embolization (11.1%). The transradial approach was most used (56.7%), followed by transfemoral (41.1%). Challenging anatomic variations included severe vessel tortuosity (8/90, 8.9%), type 2 aortic arch (7/90, 7.8%), type 3 aortic arch (2/90, 2.2%), bovine arch (2/90, 2.2%), and severe angle (<30°) between the subclavian artery and target vessel (1/90, 1.1%). Technical success was achieved in 98.9% of the cases (89/90), with six cases requiring a switch from radial to femoral (6.7%) and one case from femoral to radial (1.1%). There were no access site complications or complications related to the 0.081″ catheter. Two postprocedural complications occurred (2.2%), unrelated to the access catheter. CONCLUSION: The BMX™ 81 large-bore access catheters was safe and effective in both radial and femoral access across a wide range of neurovascular procedures, achieving high technical success without any access site or device-related complications.

Neuroprotective effects of umbelliferone and esculetin in a mouse model of Parkinson's disease.

The production of reactive oxygen species and mitochondrial dysfunction in the brain are both associated with the progression of several neurodegenerative diseases, including Parkinson's disease. These characteristics are also observed when rodents are exposed to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a compound that causes nigrostriatal dopaminergic neurotoxicity and that has been used previously for assessing the effectiveness of neuroprotective agents. In this study, the neuroprotective effects of two coumarins, umbelliferone and esculetin, against MPTP-induced neurotoxicity were examined in C57BL/6J mice. The results show that dietary administration of umbelliferone and esculetin significantly attenuated MPTP-induced neurotoxicity in the substantia nigra pars compacta but not striatum, as measured by tyrosine hydroxylase staining. Both coumarins also prevented an MPTP-induced increase in nitrosative stress as measured by 3-nitrotyrosine immunoreactivity and also maintained glutathione levels in MPTP-exposed mice as well as in cell lines exposed to the metabolite 1-methyl-4-phenylpyridinium. Umbelliferone and esculetin also prevented MPTP-dependent caspase 3 activation, an indicator of apoptosis, but did not inhibit monoamine oxidase activity. This is the first time that the neuroprotective capabilities of these coumarins have been demonstrated, and the results indicate that umbelliferone and esculetin can protect against MPTP-induced neurotoxicity in the mouse. These compounds can cross the blood-brain barrier, so their effectiveness indicates that they have the potential to protect in neurodegenerative disease such as Parkinson's disease.

A mild and efficient one-pot synthesis of ß-amino carbonyl compounds via Mannich reaction under ambient temperature condition.

We have developed an efficient protocol for the synthesis of ß-amino carbonyl compounds using phenylboronic acid as effective and eco-friendly catalyst via one-pot three-component Mannich reaction. Excellent yields, mild reaction condition, and simple experimental work-up procedure are some of the advantages of this method, which makes it a useful protocol for the synthesis of ß-amino carbonyl compounds.

Comparative cost analysis of liquid embolization systems for brain arteriovenous malformation using a real-world US hospital database: TRUFILL® versus OnyxTM.

BACKGROUND: Liquid embolic systems (LES) such as n-butyl cyanoacrylate-based TRUFILL® and ethylene vinyl-alcohol copolymer-based OnyxTM are widely used for the embolization of brain arteriovenous malformations (bAVMs). The purpose of this study was to compare hospital cost and length of stay (LOS) among unruptured bAVM patients undergoing embolization procedures with TRUFILL versus Onyx LES. METHODS: Adult patients with unruptured bAVMs undergoing endovascular embolization with TRUFILL or Onyx LES between January 1, 2010 and June 30, 2020 were identified from the Premier Healthcare Database. Baseline covariates among the two groups were balanced using propensity score matching. Outcomes including total procedure cost, supply cost, and LOS were examined. A Generalized Estimating Equation model was used to assess outcomes in the matched cohorts. RESULTS: A total of 1072 patients were included in the study; 140 embolized with TRUFILL (mean age 47.06 [15.72] years, 45.70% male) and 932 embolized with Onyx (mean age 46.80 [16.65] years, 52.30% male). In the post-match cohort, the total procedure costs were lower for the TRUFILL (n = 130) versus Onyx (n = 333) group, though not significantly ($36,798 vs. $40,988; odds ratio [OR] = 0.90, 95% confidence interval [CI]: 0.73-1.10; p = 0.30). However, supply cost was significantly lower for hospitalizations with TRUFILL compared to Onyx use ($13,281 vs. $16,371, OR = 0.81, 95% CI: 0.68, 0.98; p = 0.026). Hospital LOS was similar in these two groups (TRUFILL: 4.05 vs. Onyx: 4.06 days; OR = 1.00, 95% CI: 0.70, 1.42; p = 0.99). CONCLUSIONS: In a large, multi-center, real-world sample of patients undergoing bAVM embolization, TRUFILL use was associated with significantly lower supply cost compared to Onyx use.

Economic analysis of n-butyl cyanoacrylate compared with ethylene vinyl alcohol copolymer liquid embolic embolization of brain arteriovenous malformations (bAVMs) from a US hospital perspective.

BACKGROUND: In US hospitals, the liquid embolic systems (LESs) n-butyl cyanoacrylate (n-BCA) and ethylene vinyl alcohol copolymer (EVOH) are used for brain arteriovenous malformation (bAVM) embolization to achieve presurgical devascularization. The aim of this study was to perform an economic analysis comparing four techniques for bAVM embolization based on LES, ancillary device, and angiography suite time costs. METHODS: An economic model was developed comparing the embolization costs for n-BCA, EVOH with the plug and push technique, EVOH with detachable-tip microcatheters, and EVOH with balloon microcatheters. Per procedure costs were calculated for bAVMs with one to four pedicles. Annual cohort analyses were performed to evaluate the potential impact for low and high-volume centers. Sensitivity analyses were performed to determine cost drivers. RESULTS: The analyses showed that the n-BCA technique was the least costly of the four techniques. Total per procedure costs for one to four embolized pedicles ranged from $5941 to $10,074 for the n-BCA technique, $8428 to $30,345 for the EVOH balloon microcatheter technique, $12,711 to $47,477 for the EVOH plug and push technique, and $13,900 to $52,233 for the EVOH detachable-tip microcatheter technique. Cohort analyses costs for 52 annual cases ranged from $308,953 to $523,838 with the n-BCA technique and from $722,816 to $2,716,096 with the EVOH detachable-tip microcatheter technique. CONCLUSIONS: Procedure costs associated with n-BCA are lower than those with each of the three EVOH techniques examined. Future cost analyses should compare the costs of new LES products once available.

Target Ultra and Nano coils in the endovascular treatment of small intracranial aneurysms (ULTRA Registry).

OBJECTIVE: The ULTRA Registry is a national multicenter prospective study designed to assess aneurysm occlusion rates and safety profiles of the Target Ultra and Nano coils in the treatment of small intracranial aneurysms (IAs). METHODS: Patients with small (≤ 5 mm) ruptured and unruptured IAs were treated exclusively with Target Ultra and Nano coils. The primary endpoints were the initial rate of complete or near-complete aneurysm occlusion, aneurysm recurrence, and need for retreatment. Secondary endpoints were device- and procedure-related adverse events, hemorrhage from the coiled aneurysm at any time during follow-up, and clinical outcomes. RESULTS: The ULTRA Registry included 100 patients with a mean ± SD age of 56 ± 11.6 years, of whom 75 were women and 48 presented after aneurysm rupture. The mean aneurysm size was (3.5 ± 0.9) × (2.8 ± 0.9) × (3.0 ± 1.0) mm, and the mean packing density was 34.4% ± 16.7%. Posttreatment complete or near-complete occlusion reported by an independent imaging core laboratory was seen in 92% of patients at baseline and in 87%, 87%, and 83% of patients at first, second, and final follow-up, respectively. At first, second, and final follow-up, 10%, 11%, and 15%, respectively, of patients were deemed to require retreatment. There were three procedural-related ischemic strokes and one intracranial hemorrhage from wire perforation of a parent artery not involved by the aneurysm. There were no coil-related adverse events, including no intraoperative aneurysm ruptures and no known aneurysm ruptures after coiling. CONCLUSIONS: This assessment of aneurysm occlusion rates and safety profiles in ULTRA Registry study participants demonstrates excellent safety and efficacy profiles for Target Ultra and Nano coils in the treatment of small IAs.

A proposed framework for cerebral venous congestion.

BACKGROUND: While venous congestion in the peripheral vasculature has been described and accepted, intracranial venous congestion remains poorly understood. The characteristics, pathophysiology, and management of cerebral venous stasis, venous hypertension and venous congestion remain controversial, and a unifying conceptual schema is absent. The cerebral venous and lymphatic systems are part of a complex and dynamic interaction between the intracranial compartments, with interplay between the parenchyma, veins, arteries, cerebrospinal fluid, and recently characterized lymphatic-like systems in the brain. Each component contributes towards intracranial pressure, occupying space within the fixed calvarial volume. This article proposes a framework to consider conditions resulting in brain and neck venous congestion, and seeks to expedite further study of cerebral venous diagnoses, mechanisms, symptomatology, and treatments. METHODS: A multi-institution retrospective review was performed to identify unique patient cases, complemented with a published case series to assess a spectrum of disease states with components of venous congestion affecting the brain. These diseases were organized according to anatomical location and purported mechanisms. Outcomes of treatments were also analyzed. Illustrative cases were identified in the venous treatment databases of the authors. CONCLUSION: This framework is the first clinically structured description of venous pathologies resulting in intracranial venous and cerebrospinal fluid hypertension. Our proposed system highlights unique clinical symptoms and features critical for appropriate diagnostic work-up and potential treatment. This novel schema allows clinicians effectively to approach cases of intracranial hypertension secondary to venous etiologies, and furthermore provides a framework by which researchers can better understand this developing area of cerebrovascular disease.

Major complications of dural venous sinus stenting for idiopathic intracranial hypertension: case series and management considerations.

BACKGROUND: Venous sinus stenting (VSS) is a safe, effective, and increasingly popular treatment option for selected patients with idiopathic intracranial hypertension (IIH). Serious complications associated with VSS are rarely reported. METHODS: Serious complications after VSS were identified retrospectively from multicenter databases. The cases are presented and management strategies are discussed. RESULTS: Six major acute and chronic complications after VSS were selected from a total of 811 VSS procedures and 1466 venograms for IIH. These included an acute subdural hematoma from venous extravasation, cases of both intraprocedural and delayed stent thrombosis, an ultimately fatal cerebellar hemorrhage resulting in acute obstructive hydrocephalus, venous microcatheter perforation during venography and manometry, and a patient who developed subarachnoid hemorrhage and subdural hematoma after cerebellar cortical vein perforation. The six cases are reviewed and learning points regarding complication avoidance and management are presented. CONCLUSION: We report on six rare, major complications after VSS for IIH. Familiarity with these potential complications and appropriate timely management may allow for good clinical outcomes.

Artery of Davidoff and Schechter: A Large Angiographic Case Series of Dural AV Fistulas.

The artery of Davidoff and Schechter (ADS) is the only meningeal branch of the posterior cerebral artery (PCA), supplying the medial tentorial margin and posterior portions of the falx. Given its small size, it is rarely identified on angiographic studies, unless enlarged in pathologies such as dural arteriovenous fistulas (DAVFs) or vascularized masses. This artery was first described by Wollschlaeger and Wollschlaeger in 1965, and to date, only a few reports have described its significance. The objective of this study is to report our experience with the ADS in dural fistulas from 2 tertiary medical centers and to emphasize the importance of recognizing this artery during angiographic examination of vascular tentorial and posterior fossa lesions. To our knowledge, this report demonstrates the largest angiographic case series published to date, recognizing a total of 7 patients with ADS arising secondary to a posterior fossa or tentorial DAVF and one of the largest reported series of DAVFs supplied by the ADS treated by endovascular and surgical techniques. Our cases validate the importance of prompt identification of the ADS for the diagnosis as well as endovascular treatment of vascular malformations in the posterior fossa and tentorial region.

Pivotal trial of the Neuroform Atlas stent for treatment of posterior circulation aneurysms: one-year outcomes.

BACKGROUND: Stent-assisted coiling of wide-necked intracranial aneurysms (IAs) using the Neuroform Atlas Stent System (Atlas) has shown promising results. OBJECTIVE: To present the primary efficacy and safety results of the ATLAS Investigational Device Exemption (IDE) trial in a cohort of patients with posterior circulation IAs. METHODS: The ATLAS trial is a prospective, multicenter, single-arm, open-label study of unruptured, wide-necked, IAs treated with the Atlas stent and adjunctive coiling. This study reports the results of patients with posterior circulation IAs. The primary efficacy endpoint was complete aneurysm occlusion (Raymond-Roy (RR) class I) on 12-month angiography, in the absence of re-treatment or parent artery stenosis >50%. The primary safety endpoint was any major ipsilateral stroke or neurological death within 12 months. Adjudication of the primary endpoints was performed by an imaging core laboratory and a Clinical Events Committee. RESULTS: The ATLAS trial enrolled and treated 116 patients at 25 medical centers with unruptured, wide-necked, posterior circulation IAs (mean age 60.2±10.5 years, 81.0% (94/116) female). Stents were placed in all patients with 100% technical success rate. A total of 95/116 (81.9%) patients had complete angiographic follow-up at 12 months, of whom 81 (85.3%) had complete aneurysm occlusion (RR class I). The primary effectiveness outcome was achieved in 76.7% (95% CI 67.0% to 86.5%) of patients. Overall, major ipsilateral stroke and secondary persistent neurological deficit occurred in 4.3% (5/116) and 1.7% (2/116) of patients, respectively. CONCLUSIONS: In the ATLAS IDE posterior circulation cohort, the Neuroform Atlas Stent System with adjunctive coiling demonstrated high rates of technical and safety performance. Trial registration number https://clinicaltrials.gov/ct2/show/NCT02340585.

Esculetin-induced protection of human hepatoma HepG2 cells against hydrogen peroxide is associated with the Nrf2-dependent induction of the NAD(P)H: Quinone oxidoreductase 1 gene.

Esculetin (6,7-dihydroxy coumarin), is a potent antioxidant that is present in several plant species. The aim of this study was to investigate the mechanism of protection of esculetin in human hepatoma HepG2 cells against reactive oxygen species (ROS) induced by hydrogen peroxide. Cell viability, cell integrity, intracellular glutathione levels, generation of reactive oxygen species and expression of antioxidant enzymes were used as markers to measure cellular oxidative stress and response to ROS. The protective effect of esculetin was compared to a well-characterized chemoprotective compound quercetin. Pre-treatment of HepG2 cells with sub-lethal (10-25 µM) esculetin for 8h prevented cell death and maintained cell integrity following exposure to 0.9 mM hydrogen peroxide. An increase in the generation of ROS following hydrogen peroxide treatment was significantly attenuated by 8h pre-treatment with esculetin. In addition, esculetin ameliorated the decrease in intracellular glutathione caused by hydrogen peroxide exposure. Moreover, treatment with 25 µM esculetin for 8h increased the expression of NAD(P)H: quinone oxidoreductase (NQO1) at both protein and mRNA levels significantly, by 12-fold and 15-fold, respectively. Esculetin treatment also increased nuclear accumulation of Nrf2 by 8-fold indicating that increased NQO1 expression is Nrf2-mediated. These results indicate that esculetin protects human hepatoma HepG2 cells from hydrogen peroxide induced oxidative injury and that this protection is provided through the induction of protective enzymes as part of an adaptive response mediated by Nrf2 nuclear accumulation.