Usefulness of hyperintense acute reperfusion marker sign in patients with transient neurologic symptom.

It aimed to investigate the incidence and final diagnosis of hyperintense acute reperfusion marker (HARM) signs in patients initially suspected of having a transient ischemic attack (TIA).In retrospective manner, a series of consecutive series of patients who arrived at the emergency department and was initially assessed as TIA within 12 hours of symptom onset between July 2015 and December 2016 were enrolled. Conventional magnetic resonance imaging protocol including diffusion-weighted imaging (DWI) and pre- and post-contrast fluid attenuation inversion recovery imaging (FLAIR) was conducted to evaluate the ischemic lesion and prognosis. Through the review of medical records and imaging studies, their final diagnosis and its association with HARM signs on post-contrast FLAIR were investigated.A total of 174 subjects were enrolled (mean age, 64.0 ±â€Š12.9 years old; male, 54.6%; DWI lesion, 17.8%). HARM signs were observed in 18 (10%) patients, and their final diagnoses were classified as true TIA (n = 11, 61%), seizure (2, 11%), posterior reversible encephalopathy (2, 11%), reversible cerebral vascular constriction (1, 6%) and unclassified encephalopathy (2, 11%). The co-occurrence of HARM and DWI lesions were observed in 7 subjects which were 6 subjects of true TIA (ischemic stroke) and 1 subject with RCVS related ischemic stroke.The observation of HARM sign would be helpful to confirm the ischemic insult and distinguish the other disease.

Tenacity of Collateral Perfusion in Proximal Cerebral Arterial Occlusions 6-12 h after Onset.

BACKGROUND: Clinical trials have shown that benefits of endovascular recanalization (EVT) for acute ischemic stroke patients with sizable penumbral tissues seems plausible even beyond 6 h after their last seen normal (LSN). Persistency of ischemic penumbra remains unclear in delayed periods. METHODS: From a prospective stroke registry database, we identified 111 acute ischemic stroke patients who had internal carotid artery or middle cerebral artery occlusion with baseline National Institutes of Health Stroke Scale scores ≥6 points and arrived 6-12 h after LSN. Baseline information and functional outcomes were prospectively collected as a clinical registry. Attending physicians made treatment decisions for EVT based on the current guidelines and institutional protocols. MR image parameters, including the volume of diffusion-restricted lesions and mapping of the -hypoperfused area, were quantified using automated commercial software. Binary logistic regression analysis models, with modified Rankin Scale (mRS) scores of 0-1 at 3 months after stroke included as a dependent variable, were constructed. RESULTS: Between 6 and 12 h after onset, 58% had a mismatch ratio of ≥1.8 at baseline and 42% had favorable imaging profiles as determined by DEFUSE 2 study. After 9 h, there was a mismatch ratio of ≥1.8 in 47 and 38% favorable profiles. EVT was performed in 54% of cases. A 3-month mRS score of 0-1 was found in 19% (25% in EVT and 12% in medical treatment groups) of cases. EVT was associated with an increased OR of having a mRS score of 0-1 at 3 months after stroke (adjusted OR 7.59 [95% CI 1.28-61.60]). CONCLUSIONS: Penumbral tissues were persistent in a substantial proportion of anterior circulation occlusion cases 6-12 h after LSN. EVT at 6-12 h in a predominantly Asian cohort resulted in better outcomes.

Oral proteasome inhibitor with strong preclinical efficacy in myeloma models.

BACKGROUND: The proteasome is a validated anti-cancer target and various small-molecule inhibitors are currently in clinical development or on the market. However, adverse events and resistance associated with those proteasome inhibitors indicate the need for a new generation of drugs. Therefore, we focused on developing an oral proteasome inhibitor with improved efficacy and safety profiles. METHOD: The in vitro inhibition of the 20S proteasome catalytic activities was determined in human multiple myeloma (MM) cellular lysates with fluorogenic peptide substrates specific for each catalytic subunit. Cell cytotoxicity was assessed with the ATP bioluminescence assay using human cell samples from tumor cell lines, MM patients or normal healthy donors. In mice bearing human MM xenografts, a single dose of LC53-0110 was administered orally, and concentration-time profiles of LC53-0110 and the 20S proteasome catalytic activities in plasma, blood, and tumor were determined. The efficacy of repeat-dose compound with regard to tumor growth inhibition in vivo was also evaluated in the same MM xenograft models. RESULTS: LC53-0110 is far more specific for the chymotrypsin-like proteolytic (ß5) site of the 20S proteasome as compared to bortezomib, carfilzomib, or ixazomib. LC53-0110 treatment showed accumulation of ubiquitinated proteins, inhibited cell viability with a low nM range potency in various tumor cell lines, and showed potent activity on CD138(+) cells isolated from MM patients who are resistant/refractory to current FDA-approved drug treatment. When a single dose was administered orally to tumor-bearing mice, LC53-0110 showed both greater maximum and sustained tumor proteasome inhibition as compared with ixazomib in MM xenograft models. The robust pharmacodynamic responses in tumor correlated with tumor growth regression. In addition, LC53-0151, an analog of LC53-0110, in combination with pomalidomide, a third-generation immunomodulatory drug, showed synergistic inhibition of tumor growth both in vitro and in the xenograft mouse model. CONCLUSIONS: In view of the in vitro, in vivo, and ex vivo profiles, further investigation of additional LC compounds in preclinical studies is warranted for the nomination of a clinical development candidate.

Recanalization Rate and Clinical Outcome in Acute Carotid-T Occlusion.

BACKGROUND: Acute carotid-T occlusion results in both low recanalization rates and poor outcomes. We investigated clinical outcomes and recanalization in a rare case of thrombolytic therapy. METHODS: A consecutive series of patients with acute carotid-T occlusion who were treated with either bridging intravenous (IV) plus intra-arterial (IA) thrombolysis or IA alone were analyzed. Complete recanalization was defined as a thrombolysis in cerebral infarction (TICI) grade of 3. A favorable outcome was defined as a modified Rankin Scale (mRS) score of ≤2. RESULTS: Of the 40 patients, 6 (15%) had favorable outcomes, and 34 (85%) had poor outcomes. Favorable outcomes were significantly associated with a lower National Institutes of Health Stroke Scale (NIHSS) score after revascularization treatment and higher rates of complete recanalization (p < 0.01, p < 0.024, respectively). Complete recanalization was achieved in all patients with favorable clinical outcomes and 5 (83%) patients had received combined IV/IA thrombolysis (p = 0.381). CONCLUSIONS: The results suggest that complete recanalization for acute carotid-T occlusion improves clinical outcomes. In that regard, bridging IV/IA thrombolysis may be more efficacious than IA alone.

Design and synthesis of novel 2-(indol-5-yl)thiazole derivatives as xanthine oxidase inhibitors.

Xanthine oxidase (XO) inhibitors have been widely used for the treatment of gout. Indole rings are frequently used as active scaffold in designing inhibitors for enzymes. Herein, we describe the structure-activity relationship for novel xanthine oxidase inhibitors based on indole scaffold. A series of novel tri-substituted 2-(indol-5-yl)thiazole derivatives were synthesized, and their in vitro inhibitory activities against xanthine oxidase and in vivo efficacy lowering uric acid level in blood were measured. Among them, 2-(3-cyano-2-isopropylindol-5-yl)-4-methylthiazole-5-carboxylic acid exhibits the most potent XO inhibitory activity (IC50 value: 3.5nM) and the excellent plasma uric acid lowering activity. Study of structure activity relationship indicated that hydrophobic moiety (e.g., isopropyl) at 1-position and electron withdrawing group (e.g., CN) at 3-position of indole ring and small hydrophobic group (CH3) at 4-position of the thiazole ring enhanced the XO inhibitory activity. Hydrophobic substitution such as isopropyl at 1-position of the indole moiety without any substitution at 2-position has an essential role for enhancing bioavailability and therefore for high in vivo efficacy.

Clinical practice guideline for the management of intracranial aneurysms.

PURPOSE: An intracranial aneurysm, with or without subarachnoid hemorrhage (SAH), is a relevant health problem. The rupture of an intracranial aneurysm is a critical concern for individual health; even an unruptured intracranial aneurysm is an anxious condition for the individual. The aim of this guideline is to present current and comprehensive recommendations for the management of intracranial aneurysms, with or without rupture. MATERIALS AND METHODS: We performed an extensive literature search, using Medline. We met in person to discuss recommendations. This document is reviewed by the Task Force Team of the Korean Society of Interventional Neuroradiology (KSIN). RESULTS: We divided the current guideline for ruptured intracranial aneurysms (RIAs) and unruptured intracranial aneurysms (UIAs). The guideline for RIAs focuses on diagnosis and treatment. And the guideline for UIAs focuses on the definition of a high-risk patient, screening, principle for treatment and selection of treatment method. CONCLUSION: This guideline provides practical, evidence-based advice for the management of patients with an intracranial aneurysm, with or without rupture.

Acute central retinal artery occlusion associated with livedoid vasculopathy: a variant of Sneddon's syndrome.

Livedoid vasculopathy (LV) is characterized by a long history of ulceration of the feet and legs and histopathology indicating a thrombotic process. We report a case of acute central retinal artery occlusion in a 32-year-old woman who had LV. She showed no discernible laboratory abnormalities such as antiphospholipid antibodies and no history of cerebrovascular accidents. Attempted intra-arterial thrombolysis showed no effect in restoring retinal arterial perfusion or vision. The central retinal artery occlusion accompanied by LV in this case could be regarded as a variant form of Sneddon's syndrome, which is characterized by livedo reticularis and cerebrovascular accidents.

Effects of bamboo charcoal and bamboo vinegar as antibiotic alternatives on growth performance, immune responses and fecal microflora population in fattening pigs.

This study was carried out to investigate the effects of bamboo charcoal and bamboo vinegar as alternatives of antibiotics in the diet of fattening pigs and their influence on growth performance, immune responses and fecal microflora populations. Crossed pigs (n = 144, 79 kg body weight) were divided into 12 heads per pen, four diets and three replications. The basal diet (negative control: NC) was supplemented with 0.3% antibiotics (positive control: PC), 0.3% bamboo charcoal (BC) and 0.3% bamboo vinegar (BV). Average daily weight gain and feed efficiency were higher (P < 0.05) in PC, BC and BV. The concentration of lactate dehydrogenase and cortisol were lower (P < 0.05), but the concentration of immunoglobulin G (IgG) and IgA were higher (P < 0.05) in PC, BC and BV. Counts of coliform bacteria and Salmonella spp. were lower (P < 0.05), while the counts of fecal anaerobic total bacteria and lactic acid bacteria were higher (P < 0.05) in PC, BC and BV. A reasonable inclusion of bamboo charcoal or bamboo vinegar as antibiotics in the diet of fattening pigs leads to a better growth performance, immune responses and fecal microflora populations. The results of the present study suggest that bamboo charcoal or bamboo vinegar could be a potential additives in animal production as an alternative to antibiotics.

Optimal headrest height for the best laryngoscopic view: by anatomical measurements.

BACKGROUND: We hypothesized that the oro-pharyngolaryngeal axes, occipito-atlanto-axial extension (OAA) angle and intubation distance would be influenced by the height of headrests. METHODS: Twenty patients were enrolled. The Macintosh 3 blade was used for direct laryngoscopy without a headrest or with the headrest of 6 or 12 cm high in randomized order, whereas a lateral radiograph of the neck was taken when the best laryngoscopic view was obtained. The following measurements were made: (1) the axis of the mouth (MA), the pharyngeal axis (PA), the laryngeal axis (LA), and the line of vision (LV). The various angles between these axes were defined: α angle between MA and PA, ß angle between PA and LA, and δ angle between LV and LA. (2) Intubation distance, (3) mentovertebral distance, and (4) OAA angle. RESULTS: Compared with 12-cm and no headrest, the δ angle decreased significantly with 6-cm headrest (19.4°/29.2°/29.2° in 6-cm/12-cm/no headrest, respectively; P < .001), and the intubation distance increased significantly (46.2/37.3/38.7 mm in 6-cm/12-cm/no headrest, respectively; P < .001). Mentovertebral distance was smallest (107.0/106.7/98.5 mm; P < .05) at 12-cm headrest. Occipito-atlanto-axial extension angle was largest significantly (40.7°/35.2°/34.5°; P < .05) at 6-cm headrest. CONCLUSION: We conclude that compared with no or 12-cm headrest, 6-cm headrest could facilitate more alignment of these axes, increase the OAA angle, and enlarge the intubation distance.

A retrieval thrombectomy technique with the Solitaire stent in a large cerebral artery occlusion.

BACKGROUND: To describe preliminary experiences and the procedural details of retrieval thrombectomy using a self-expanding and fully retrievable Solitaire stent (ev 3 Inc., CA, USA) in acute ischemic stroke (AIS) patients with large artery occlusions. METHODS: Eight patients with AIS were treated by mechanical thrombectomy using a self-expanding, fully retrievable stent (Solitaire, ev 3 Inc., CA, USA). The stent was deployed to cover the whole intra-arterial clot and then it was slowly retrieved while occluding the internal cerebral artery (ICA) with a balloon guiding catheter. Additionally, continuous negative pressure was applied through the balloon guiding catheter with a specially designed gun device. Occlusion sites were M1 in six cases including one combined supraclinoid ICA occlusion and the other combined M2 occlusion, M2 in 1 case and one basilar artery top. RESULTS: Complete recanalization was achieved in all patients. Procedure time was 45 min or less in seven cases and 70 min in one case. Distal emboli occurred in one case in which the balloon guide catheter was not used. Only in this case was intraarterial fibrinolytics infusion necessary. There was no post-operative intracranial hemorrhage. CONCLUSIONS: In our experience, retrieval thrombectomy with the Solitaire stent was a simple and effective method for reopening large cerebral arteries in AIS patients.

Superficial temporal artery to middle cerebral artery bypass in acute ischemic stroke and stroke in progress.

BACKGROUND: Surgical reperfusion may be beneficial in patients with acute ischemic stroke who are ineligible for thrombolysis. OBJECTIVE: To evaluate the outcome of superficial temporal artery to middle cerebral artery (STA-MCA) bypass in acute stroke and stroke in progress. METHODS: The clinical and radiological data of 9 patients treated by STA-MCA bypass requiring urgent reperfusion but ineligible for intra-arterial thrombolysis (IAT) were reviewed. Pooled analysis was performed of published literature concerning STA-MCA bypass in acute stroke (21 cases in 2 articles). RESULTS: Of the 9 patients enrolled, symptom aggravation occurred during medical treatment in 4 patients and after IAT in 2. Three patients were ineligible for IAT despite being within 8 hours of symptom onset. Bypass significantly improved National Institutes of Health Stroke Scale scores (preoperatively, 12.4±4.88; 3 days postoperatively, 8.6±6.39, P=.046; discharge, 5.4±5.15, P=.008; 3 mo postoperatively 3.7±4.82, P=.008) without significant infarction growth by diffusion weighted imaging (preoperatively, 15.0±8.87 mL; 7 days postoperatively, 15.2±8.28 mL; P=.110). Abnormal perfusion regions (mean transit time>145% of contralateral side value) were reduced in all cases (2.63±0.93 mL). Good outcomes (modified Rankin scale≤2) were achieved by 6 patients. Pooled analysis with our patients showed a significant neurological improvement (P<.001) and a good outcome in 25 (83.3%) patients without hemorrhage or complication. CONCLUSION: STA-MCA bypass may be beneficial to patients with acute stroke or stroke in progress who are ineligible for IAT. Furthermore, it appears safe when the infarction is small. These findings indicate that STA-MCA bypass could be considered as a treatment option in selected patients with acute stroke or stroke in progress.

Intraarterial abciximab for treatment of thromboembolism during coil embolization of intracranial aneurysms: outcome and fatal hemorrhagic complications.

OBJECT: Experience with intraarterial abciximab for the treatment of thromboembolism during endovascular coil embolization is limited. The authors report the outcome of intraarterial abciximab use, with an emphasis on fatal hemorrhagic complications. METHODS: Between March 2003 and May 2006, the authors treated 606 aneurysms by using endovascular coil embolization, and in 32 (5.3%) of these aneurysms (31 patients) an intraarterial thrombus developed. Sixteen of these aneurysms were ruptured and the other 16 were unruptured. Arterial thrombi were totally occlusive in 3 and partially occlusive in the remaining 29 cases. Intraarterial abciximab was administered at a concentration of 0.2 mg/ml as a bolus of 4-15 mg over a period of 15-30 minutes. RESULTS: Complete thrombolysis was achieved in 17 (53%) and partial thrombolysis in 15 (47%) of 32 lesions. Twenty-eight patients (90.3%) were asymptomatic after abciximab thrombolysis, but 3 had postprocedural rebleeding that occurred after abciximab treatment; all of these patients had recently experienced an aneurysm rupture. Of these patients, 1 displayed severe thrombocytopenia and the other 2 showed a > 25% reduction in platelet count after abciximab treatment. CONCLUSIONS: Intraarterial abciximab is effective for the treatment of thromboembolic complications that occur during intracranial aneurysm coil insertion. Nevertheless, attention should be paid to prevent potentially fatal complications such as thrombocytopenia and hemorrhage, especially in patients with a ruptured aneurysm.

Asymmetric induction in hydrogen-mediated reductive aldol additions to alpha-amino aldehydes catalyzed by rhodium: selective formation of syn-stereotriads directed by intramolecular hydrogen-bonding.

Rhodium-catalyzed hydrogenation of methyl vinyl ketone and ethyl vinyl ketone in the presence of N-Boc-alpha-aminoaldehydes 3a-8a at ambient temperature and pressure results in reductive C-C coupling to furnish aldol adducts 3b-8b and 3c-8c, respectively, which incorporate stereotriads that embody high levels of syn-aldol selectivity accompanied by high levels of anti-Felkin-Anh control. The collective data are consistent with a catalytic mechanism involving addition of the Z(O)-rhodium enolate to the sterically less-encumbered aldehyde pi-face of an intramolecularly hydrogen-bonded chelate through a Zimmerman-Traxler type transition structure. Stereochemical assignments are supported by single-crystal X-ray diffraction analysis of 5b-O-3,5-dinitrobenzoate, iso-5b, N-Me-iso-5b-O-3,5-dinitrobenzoate, and 7b. As revealed by HPLC analysis, optical purity of the stereochemically labile alpha-aminoaldehydes is completely preserved under the conditions of hydrogen-mediated aldol coupling. Deletion of the intramolecular hydrogen bond, as in the case of N-methyl-N-Boc-l-leucinal N-Me-5a, inverts stereoselectivity to furnish the Felkin-Anh product N-Me-iso-5b in 17% yield. Additionally, reactions performed in the presence of tert-amyl alcohol (10 equiv) exhibit markedly lower levels of anti-Felkin-Anh control (7:1 versus > or = 20:1). The collective studies suggest that intramolecular hydrogen bonding plays a key role in both activating the alpha-aminoaldehyde toward addition and directing facial selectivity.

Hydrogen-mediated aldol reductive coupling of vinyl ketones catalyzed by rhodium: high syn-selectivity through the effect of tri-2-furylphosphine.

[reaction: see text]. Catalytic hydrogenation of methyl vinyl ketone (MVK) and ethyl vinyl ketone (EVK) in the presence of diverse aldehydes at ambient temperature and pressure using tri-2-furylphosphine-ligated rhodium catalysts enables formation of aldol products with high levels of syn-diastereoselectivity. A progressive increase in diastereoselectivity is observed upon sequential replacement of phenyl residues for 2-furyl residues (Ph3P, FurPh2P, Fur2PhP, Fur3P). Hydrogen-labile functional groups, including alkynes, alkenes, benzylic ethers, and nitroarenes, remain intact under the coupling conditions.

Phosphine-mediated reductive condensation of gamma-acyloxy butynoates: a diversity oriented strategy for the construction of substituted furans.

Exposure of gamma-acyloxy butynoates to stoichiometric quantities of triphenylphosphine results in reductive condensation to afford substituted furans, by way of allenic ester intermediates. As gamma-acyloxy butynoates are readily obtained through condensation of ethyl propiolate with aldehydes followed by acylation, this method represents a powerful and mechanistically novel protocol for the convergent three-component construction of substituted furans.

Lasonolide A: structural revision and total synthesis.

The proposed structure of lasonolide A was synthesized employing radical cyclization reactions of beta-alkoxyacrylates for preparation of the tetrahydropyranyl units A and B, but the spectroscopic data did not match those of the natural product. Both enantiomers of a revised structure featuring 17E,25Z double bonds were synthesized, and the (-)-isomer was found to be the biologically active enantiomer.

Synthesis of (+)-Lasonolide A: (-)-lasonolide A is the biologically active enantiomer.

(+)-Lasonolide A was synthesized following the established procedure. (-)-Lasonolide A was found to be the biologically active enantiomer.

Lasonolide A: structural revision and synthesis of the unnatural (-)-enantiomer.

Total synthesis of the unnatural (-)-enantiomer of lasonolide A was achieved starting from ethyl l-malate. The two tetrahydropyranyl fragments were prepared stereoselectively via radical cyclization reactions of beta-alkoxyacrylates. The full structure of natural lasonolide A was determined unequivocally.