Endovascular treatment decision-making in acute ischemic stroke patients with large vessel occlusion and low National Institutes of Health Stroke Scale: insights from UNMASK EVT, an international multidisciplinary survey.

PURPOSE: Many stroke patients with large vessel occlusion present with a low National Institutes of Health Stroke Scale (NIHSS). There is currently no level 1A recommendation for endovascular treatment (EVT) for this patient subgroup. From a physician's standpoint, the deficits might only be slight, but they are often devastating from a patient perspective. Furthermore, early neurologic deterioration is common. The purpose of this study was to explore endovascular treatment attitudes of physicians in acute ischemic stroke patients presenting with low admission NIHSS. METHODS: In an international cross-sectional survey among stroke physicians, participants were presented the scenario of a 76-year-old stroke patient with an admission NIHSS of 2. Survey participants were then asked how they would treat the patient (A) given their current local resources, and (B) under assumed ideal conditions, i.e., without external (monetary or infrastructural) constraints. Overall, country-specific and specialty-specific decision rates were calculated and clustered multivariable logistic regression performed to provide adjusted measures of effect size. RESULTS: Two hundred seventy-five participants (150 neurologists, 84 interventional neuroradiologists, 30 neurosurgeons, 11 affiliated to other specialties) from 33 countries provided their treatment approach to this case scenario. Most physicians favored an endovascular treatment approach, either combined with intravenous alteplase (55.3% under assumed ideal and 52.0% under current working conditions) or as single treatment (11.3% under assumed ideal and 8.4% under current conditions). CONCLUSION: Despite the limited evidence for endovascular therapy in acute stroke patients with low NIHSS, most physicians in this survey decided to proceed with endovascular therapy. A randomized controlled trial seems warranted.

Influence of Guidelines in Endovascular Therapy Decision Making in Acute Ischemic Stroke: Insights From UNMASK EVT.

Background and Purpose- The American Heart Association and the American Stroke Association guidelines for early management of patients with ischemic stroke offer guidance to physicians involved in acute stroke care and clarify endovascular treatment indications. The purpose of this study was to assess concordance of physicians' endovascular treatment decision-making with current American Heart Association and the American Stroke Association stroke treatment guidelines using a survey-approach and to explore how decision-making in the absence of guideline recommendations is approached. Methods- In an international cross-sectional survey (UNMASK-EVT), physicians were randomly assigned 10 of 22 case scenarios (8 constructed with level 1A and 11 with level 2B evidence for endovascular treatment and 3 scenarios without guideline coverage) and asked to declare their treatment approach (1) under their current local resources and (2) assuming there were no external constraints. The proportion of physicians offering endovascular therapy (EVT) was calculated. Subgroup analysis was performed for different specialties, geographic regions, with regard to physicians' age, endovascular, and general stroke treatment experience. Results- When facing level 1A evidence, participants decided in favor of EVT in 86.8% under current local resources and in 90.6% under assumed ideal conditions, that is, 9.4% decided against EVT even under assumed ideal conditions. In case scenarios with level 2B evidence, 66.3% decided to proceed with EVT under current local resources and 69.7% under assumed ideal conditions. Conclusions- There is potential for improving thinking around the decision to offer endovascular treatment, since physicians did not offer EVT even under assumed ideal conditions in 9.4% despite facing level 1A evidence. A majority of physicians would offer EVT even for level 2B evidence cases.

Factors Associated With the Decision-Making on Endovascular Thrombectomy for the Management of Acute Ischemic Stroke.

Background and Purpose- Little is known about the real-life factors that clinicians use in selection of patients that would receive endovascular treatment (EVT) in the real world. We sought to determine patient, practitioner, and health system factors associated with therapeutic decisions around endovascular treatment. Methods- We conducted a multinational cross-sectional web-based study comprising of 607 clinicians and interventionalists from 38 countries who are directly involved in acute stroke care. Participants were randomly allocated to 10 from a pool of 22 acute stroke case scenarios. Each case was classified as either Class I, Class II, or unknown evidence according to the current guidelines. We used logistic regression analysis applying weight of evidence approach. Main outcome measures were multilevel factors associated with EVT, adherence to current EVT guidelines, and practice gaps between current and ideal practice settings. Results- Of the 1330 invited participants, 607 (45.6%) participants completed the study (53.7% neurologists, 28.5% neurointerventional radiologists, 17.8% other clinicians). The weighed evidence approach revealed that National Institutes of Health Stroke Scale (34.9%), level of evidence (30.2%), ASPECTS (Alberta Stroke Program Early CT Score) or ischemic core volume (22.4%), patient's age (21.6%), and clinicians' experience in EVT use (19.3%) are the most important factors for EVT decision. Of 2208 responses that met Class I evidence for EVT, 1917 (86.8%) were in favor of EVT. In case scenarios with no available guidelines, 1070 of 1380 (77.5%) responses favored EVT. Comparison between current and ideal practice settings revealed a small practice gap (941 of 6070 responses, 15.5%). Conclusions- In this large multinational survey, stroke severity, guideline-based level of evidence, baseline brain imaging, patients' age and physicians' experience were the most relevant factors for EVT decision-making. The high agreement between responses and Class I guideline recommendations and high EVT use even when guidelines were not available reflect the real-world acceptance of EVT as standard of care in patients with disabling acute ischemic stroke.

Investigation of adsorption characteristics of four toxic gases (nitric oxide, nitrogen dioxide, sulfur dioxide, and hydrogen chloride) on the inner surface of nickel-coated manganese steel cylinders and aluminum cylinders.

To develop standard toxic gas mixtures, it is essential to identify adsorption characteristics of each toxic gas on the inner surface of a gas cylinder. Thus, this study quantified adsorbed amounts of the four toxic gases (nitric oxide [NO], nitrogen dioxide [NO2], sulfur dioxide [SO2], and hydrogen chloride [HCl]) on the inner surface of aluminum cylinders and nickel-coated manganese steel cylinders. After eluting adsorbed gases on the inside of cylinders with ultrapure water, a quantitative analysis was performed on an ion chromatograph. To evaluate the reaction characteristics of the toxic gases with cylinder materials, quantitative analyses of nickel (Ni), iron (Fe), and aluminum (Al) were also performed by inductively coupled plasma optical emission spectrometry (ICP-OES). It was found that the amounts of NO, NO2, and SO2 adsorbed on the inner surface of aluminum cylinders were less than 1.0% at the level of 100 µmol/mol mixing ratio, whereas the signal for most heavy metal elements were below their respective detection limits. This study found that the amounts of HCl adsorbed on the inner surface of nickel-coated manganese steel cylinders were less than 5% at the level of 100 µmol/mol mixing ratio, whereas Ni (86 µmol) and Fe (28 µmol) were detected in the same cylinders. It was revealed that the adsorption mainly took place via the reaction of HCl with inner surface material of nickel-coated manganese steel cylinders. On the other hand, in the case of aluminum cylinders, the amounts of the adsorption were determined to be less than 1% at the level of HCl 100 µmol/mol mixing ratio, whereas most of Ni, Fe, and Al were detected at levels similar to their limits of detection. As a result, this study found that aluminum cylinders are more suitable for preparing HCl gas mixtures than nickel-coated manganese steel cylinders. Implications: To develop a standard toxic gas mixture, it is essential to understand the adsorption characteristics of each toxic gas inside a gas cylinder. It was found that the amounts of NO, NO2, and SO2 adsorbed inside aluminum cylinders were less than 1.0% at the level of 100 µmol/mol mixing ratio. The amounts of HCl adsorbed inside nickel-coated manganese steel cylinders were less than 5% at the level of 100 µmol/mol mixing ratio, whereas those inside aluminum cylinders were less than 1%, indicating that aluminum cylinders are more suitable for preparing HCl gas mixtures.

Pipeline embolization device for giant internal carotid artery aneurysms: 9-month follow-up results of two cases.

The pipeline™ embolization device (PED) is a braided, tubular, bimetallic endoluminal implant used for occlusion of intracranial aneurysms through flow disruption along the aneurysm neck. The authors report on two cases of giant internal carotid artery aneurysm treated with the PED. In the first case, an aneurysm measuring 26.4 mm was observed at the C3-C4 portion of the left internal carotid artery in a 64-year-old woman who underwent magnetic resonance imaging (MRI) for dizziness and diplopia. In the second case, MRI showed an aneurysm measuring 25 mm at the C4-C5 portion of the right internal carotid artery in a 39-year-old woman with right ptosis and diplopia. Each giant aneurysm was treated with deployment of a PED (3.75 mm diameter/20 mm length and 4.5 mm diameter/25 mm length, respectively). Nine months later, both cases showed complete radiological occlusion of the giant intracranial aneurysm and sac shrinkage. We suggest that use of the PED can be a therapeutic option for giant intracranial aneurysms.

In-situ molybdenum nano-attached particle synthesis from spent Mo scrap.

Radio frequency thermal plasma is a versatile process for engineering powder preparation owing to its high energy density and reactivity. Molybdenum powders were prepared from molybdenum sheet scrap by RF thermal plasma in association with powder comminution process. Molybdenum scrap which was used in high temperature environment was friable enough to be broken into micropowders by hammer milling. Spherical molybdenum micro-powder was obtained from the hammer milled powders were treated via thermal plasma. On the other hand, vaporization and condensation pathway for nanoparticle synthesis is largely dependent on both thermo-physical properties and thermal plasma properties. In this regard, molybdenum trioxide was chosen for the feedstock of nanoparticle synthesis. Additional reactivity of argon-hydrogen thermal plasma, oxide feedstock was fully reduced to bcc molybdenum. Considering different reaction pathway of each feedstock, molybdenum nanoparticle attached molybdenum spherical micro-powder could be effectively synthesized by feeding a blended feedstock of molybdenum micro-powder and molybdenum trioxide micro-powder into argon-hydrogen thermal plasma.

Ribonuclease inhibitor regulates neovascularization by human angiogenin.

Human angiogenin (ANG) is a homologue of bovine pancreatic ribonuclease (RNase A) that induces neovascularization. ANG is the only human angiogenic factor that possesses ribonucleolytic activity. To stimulate blood vessel growth, ANG must be transported to the nucleus and must retain its catalytic activity. Like other mammalian homologues of RNase A, ANG forms a femtomolar complex with the cytosolic ribonuclease inhibitor protein (RI). To determine whether RI affects ANG-induced angiogenesis, we created G85R/G86R ANG, which possesses 10(6)-fold lower affinity for RI but retains wild-type ribonucleolytic activity. The neovascularization of rabbit corneas by G85R/G86R ANG was more pronounced and more rapid than by wild-type ANG. These findings provide the first direct evidence that RI serves to regulate the biological activity of ANG in vivo.

TMEM16A confers receptor-activated calcium-dependent chloride conductance.

Calcium (Ca(2+))-activated chloride channels are fundamental mediators in numerous physiological processes including transepithelial secretion, cardiac and neuronal excitation, sensory transduction, smooth muscle contraction and fertilization. Despite their physiological importance, their molecular identity has remained largely unknown. Here we show that transmembrane protein 16A (TMEM16A, which we also call anoctamin 1 (ANO1)) is a bona fide Ca(2+)-activated chloride channel that is activated by intracellular Ca(2+) and Ca(2+)-mobilizing stimuli. With eight putative transmembrane domains and no apparent similarity to previously characterized channels, ANO1 defines a new family of ionic channels. The biophysical properties as well as the pharmacological profile of ANO1 are in full agreement with native Ca(2+)-activated chloride currents. ANO1 is expressed in various secretory epithelia, the retina and sensory neurons. Furthermore, knockdown of mouse Ano1 markedly reduced native Ca(2+)-activated chloride currents as well as saliva production in mice. We conclude that ANO1 is a candidate Ca(2+)-activated chloride channel that mediates receptor-activated chloride currents in diverse physiological processes.

Advections with significantly reduced dissipation and diffusion.

Back and Forth Error Compensation and Correction (BFECC) was recently developed for interface computation using a level set method. We show that BFECC can be applied to reduce dissipation and diffusion encountered in a variety of advection steps, such as velocity, smoke density, and image advections on uniform and adaptive grids and on a triangulated surface. BFECC can be implemented trivially as a small modification of the first-order upwind or semi-Lagrangian integration of advection equations. It provides second-order accuracy in both space and time. When applied to level set evolution, BFECC reduces volume loss significantly. We demonstrate the benefits of this approach on image advection and on the simulation of smoke, bubbles in water, and the highly dynamic interaction between water, a solid, and air. We also apply BFECC to dye advection to visualize vector fields.

TRPV1 recapitulates native capsaicin receptor in sensory neurons in association with Fas-associated factor 1.

TRPV1, a cloned capsaicin receptor, is a molecular sensor for detecting adverse stimuli and a key element for inflammatory nociception and represents biophysical properties of native channel. However, there seems to be a marked difference between TRPV1 and native capsaicin receptors in the pharmacological response profiles to vanilloids or acid. One plausible explanation for this overt discrepancy is the presence of regulatory proteins associated with TRPV1. Here, we identify Fas-associated factor 1 (FAF1) as a regulatory factor, which is coexpressed with and binds to TRPV1 in sensory neurons. When expressed heterologously, FAF1 reduces the responses of TRPV1 to capsaicin, acid, and heat, to the pharmacological level of native capsaicin receptor in sensory neurons. Furthermore, silencing FAF1 by RNA interference augments capsaicin-sensitive current in native sensory neurons. We therefore conclude that FAF1 forms an integral component of the vanilloid receptor complex and that it constitutively modulates the sensitivity of TRPV1 to various noxious stimuli in sensory neurons.

Glycosylation of onconase increases its conformational stability and toxicity for cancer cells.

Onconase (ONC) is currently in Phase III clinical trials as a cancer chemotherapeutic agent. Despite the finding that ONC contains an N-linked glycosylation site (-N69-V70-T71-), only the non-glycosylated form of the protein has been identified to date. We employed the Pichia pastoris expression system to produce recombinant glycosylated ONC (gONC) protein. Approximately 10 mg of ONC protein was secreted per liter of culture media, of which about 80% was glycosylated at N69. CD spectroscopic analyses revealed that the secondary structure of gONC is identical to that of ONC. We found that gONC contains a high-mannose core structure. Importantly, glycosylation of ONC at N69 greatly increased its toxicity for K-562 cancer cells. Specifically, the IC50 value of gONC was 50-fold lower than that of ONC. Glycosylation increased both the Tm of ONC and its resistance to proteinase K, suggesting that the elevated cytotoxicity of gONC is related to higher conformational stability.

Essential role of mitochondrial permeability transition in vanilloid receptor 1-dependent cell death of sensory neurons.

Capsaicin causes pain by activating VR1, a cloned capsaicin receptor, in sensory neurons. After the initial excitatory responses, capsaicin produces prolonged analgesia, presumably because of the neurotoxic effect that leads to the death of sensory neurons. However, the mechanism underlying capsaicin-induced cell death of sensory neurons is not known. Here we report that capsaicin induces cell death in VR1-expressing sensory neurons and VR1-transfected human embryonic kidney cells. Cell death of sensory neurons induced by capsaicin is accompanied by DNA fragmentation, TUNEL staining, and shrinkage of the nucleus in a caspase-dependent manner, indicating the apoptotic nature of the cell death. Mitochondrial permeability transition is likely to be a major component of capsaicin-induced cell death because bonkrekic acid and cyclosporin A, inhibitors of mitochondrial permeability transition, block this cell death. These results imply that capsaicin induces mitochondrial dysfunction in VR1-expressing cells, leading to apoptotic cell death, which is a well-known neurotoxic effect of capsaicin.

A general method for selection and screening of coiled coils on the basis of relative helix orientation.

We have developed a method for selecting coiled coils that associate with a given relative helix orientation from a randomized pool of proteins. To select for antiparallel dimers, we have designed a model basic region-leucine zipper (bZip) heterodimer capable of binding DNA only when the coiled coil associates with an antiparallel relative helix alignment. The dimerization domain for this bZip heterodimer is the model antiparallel coiled coil Acid-a1-Base-a1 (Oakley, M. G.; Kim, P. S. Biochemistry 1998, 37, 12603), and both monomers contain the GCN4 basic region. Although the basic regions in naturally occurring bZip proteins are located N-terminal to the leucine zipper, we have attached the GCN4 basic region to the C-terminus of Acid-a1 to allow both basic regions to contact DNA in an antiparallel heterodimer. The resulting heterodimer, BR-Base-a1-Acid-a1-BR, can bind to a direct repeat of the GCN4 half-site in vivo, leading to spectinomycin resistance in the transcription interference assay of Elledge et al. (Elledge, S. J.; Sugiono, P.; Guarente, L.; Davis, R. W. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 3689). A buried interhelical polar interaction between two Asn residues in the Acid-a1-Base-a1 heterodimer is known to specify an antiparallel helix orientation. The position of one of these buried Asn residues was randomized, and bZip heterodimers containing antiparallel coiled coils were selected using the transcription interference assay. All of the selected colonies contained Asn at the randomized position, suggesting that the selection is specific for antiparallel coiled coils.