Prior anticoagulation and bridging thrombolysis improve outcomes in patients with atrial fibrillation undergoing endovascular thrombectomy for anterior circulation stroke.

BACKGROUND: Where stroke occurs with pre-existing atrial fibrillation (AF)studies validating the safety and efficacy of bridging thrombolysis, and the use of endovascular thrombectomy (EVT) in the setting of prior anticoagulation, are limited to single-center reports. METHODS: In a retrospective analysis, AF patients undergoing EVT for anterior circulation large vessel occlusion stroke enrolled in a prospectively-maintained, international multicenter database (International Stroke Perfusion Imaging Registry (INSPIRE)) between 2016 and 2019 were studied. Patients were categorized by anticoagulation status: anticoagulated (warfarin/non-vitamin K oral anticoagulants) versus not anticoagulated. Patients not anticoagulated were further divided into intravenous thrombolysis versus no thrombolysis. Outcomes compared between groups included 90-day modified Rankin Scale, 90-day mortality, rates of symptomatic intracerebral hemorrhage (sICH), and good reperfusion (modified Thrombolysis In Cerebral Infarction (mTICI) 2b-3). RESULTS: Of 563 AF patients, 118 (21%) were on anticoagulation. AF patients on anticoagulation showed improved 90-day functional outcomes (adjusted odds ratio (aOR) 1.68, 95% confidence interval (95% CI) 1.00 to 2.82). Mortality (26.3% vs 23.8%), sICH (4.5% vs 3.9%), and rates of good reperfusion (91.3% vs 88.0%) were similar between those anticoagulated and those not anticoagulated. Thrombolysis before EVT in AF patients was independently associated with improved 90-day functional outcomes (aOR 1.81, 95% CI 1.18 to 2.79) and reduced mortality (aOR 0.51, 95% CI 0.31 to 0.84), with similar sICH rates (3.4% vs 4.5%). CONCLUSIONS: Anticoagulated patients with AF who underwent EVT had improved 90-day functional outcomes and similar sICH rates. Thrombolysis before EVT in AF patients was associated with improved 90-day functional outcomes and reduced mortality.

Pipeline shield with single antiplatelet therapy in aneurysmal subarachnoid haemorrhage: multicentre experience.

BACKGROUND: The Pipeline Embolisation Device with Shield technology (PED-Shield) is suggested to have reduced thrombogenicity. This reduced thrombogenicity may make it possible to use safely in the acute treatment of aneurysmal subarachnoid haemorrhage (aSAH) on single antiplatelet therapy (SAPT). OBJECTIVE: To evaluate the safety and efficacy of the off-label use of PED-Shield with SAPT for the acute treatment of aSAH. METHODS: Patients who underwent acute treatment of ruptured intracranial aneurysms with the PED-Shield with SAPT were retrospectively identified from prospectively maintained databases at three Australian neurointerventional centres. Patient demographics, aneurysm characteristics, clinical and imaging outcomes were reviewed. RESULTS: Fourteen patients were identified (12 women), median age 64 (IQR 21.5) years. Aneurysm morphology was saccular in seven, fusiform in five, and blister in two. Aneurysms arose from the anterior circulation in eight patients (57.1%). Six (42.9%) patients were poor grade (World Federation of Neurological Societies grade ≥IV) SAH. Median time to treatment was 1 (IQR 0.5) day. Complete or near complete aneurysm occlusion (Raymond-Roy <3) was achieved in 12 (85.7%) patients at the end of early-acute follow-up (median day 7 after SAH). Permanent, treatment-related morbidity occurred in one (7.1%) patient and one (7.1%) treatment-related death occurred. The use of a postoperative heparin infusion (n=5) was associated with a higher rate of all complications (80.0% vs 11.1%, p=0.023) and symptomatic complications (60% vs 0.0%, p=0.028). No symptomatic ischaemic or haemorrhagic complications were observed in the patients who did not receive a post-operative heparin infusion. Nine (64.3%) patients were functionally independent on discharge from the treatment centre. CONCLUSION: The PED-Shield may be safe to use in the acute treatment of ruptured intracranial aneurysms with SAPT. Further investigation with a formal treatment registry is needed.

Long term follow-up of bifurcation aneurysms treated with braided stent assisted coiling and complex T- and Y- stent constructs.

BACKGROUND: Stent assisted coil embolization (SACE) of bifurcation aneurysms is challenging. Heterogeneous results have been achieved to date, but largely for laser cut stents. While braided stents offer multiple technical advantages, their long term efficacy has yet to be validated. OBJECTIVE: To report the first long term 18 month results for the durability of bifurcation aneurysms treated with braided stents. MATERIALS AND METHODS: Over a 4 year period, 59 consecutive patients with 60 bifurcation aneurysms underwent elective braided SACE across three Australian neurovascular centers. 17 of these aneurysms underwent T- or Y-shaped stent constructs. All patients had immediate, 6 month and 18 month clinical and radiological follow-up. Radiological assessment was made on modified Raymond-Roy occlusion scores while clinical assessment was based on the modified Rankin Scale. Subgroup analysis of 17 aneurysms treated with multi-stent constructs was conducted. RESULTS: 6 month follow-up data were available for 59 aneurysms and 18 month follow-up data for 58 aneurysms. Satisfactory aneurysm occlusion was achieved in 97% at inception and at 6 months, and 98% at 18 months. Good neurological outcomes were achieved in 95% at 18 months. Similar satisfactory results were achieved with the multi-stent construct cohort. Intraprocedural thromboembolic events were recorded in 5% and delayed events in 2%. Technical complications were found in 5%. All complication rate was 13%. CONCLUSION: Braided SACE was safe, efficacious, and durable at the long term 18 month follow-up, including for multi-stent constructs. Preliminary results indicate favorable clinical and radiological outcomes compared with laser cut stents.

Long-term follow-up of aneurysms treated electively with woven stent-assisted coiling.

BACKGROUND: Preliminary short-term results for stent-assisted coil embolization (SACE) using woven/braided stents have been promising. However, evidence supporting mid- to long-term efficacy and durability is lacking. OBJECTIVE: To report the long-term results for the durability of elective intracranial aneurysms treated with woven stents. MATERIALS AND METHODS: Between May 2012 and May 2015, 98 consecutive patients with 103 aneurysms underwent elective woven SACE across three Australian neurovascular centres. All patients had immediate, 6- and 18-month clinical and radiological follow-up. Radiological assessment was performed with modified Raymond-Roy occlusion scores based on angiography results, while clinical assessment was based on the modified Rankin Scale. RESULTS: Six-month follow-up was available in 100 aneurysms, and an 18-month follow-up in 97 aneurysms. Total occlusion rates of 82% were achieved at inception, 82% at 6 months, and 90% at 18 months. Satisfactory occlusion with small neck remnants was present in 17% at inception, 16% at 6 months, and 9% at 18 months. Good neurological outcomes were achieved in 95% at 18 months. Intraprocedural thromboembolic events were recorded in 3% and delayed events in 1% (all in patients taking clopidogrel). Aneurysm recurrence occurred in one patient (1%). Technical complications occurred in 5%. The total complication rate was 10%. CONCLUSIONS: Woven SACE is safe, efficacious, and durable at long-term 18-month follow-up, with very low recurrence and re-treatment rates. Preliminary results appear better than those for traditional laser-cut stents.

Use of aspirin as sole oral antiplatelet therapy in acute flow diversion for ruptured dissecting aneurysms.

Subarachnoid hemorrhage secondary to rupture of a circumferential dissecting aneurysm continues to be a treatment dilemma. Vessel sacrifice, when possible, continues to be the safest option but in certain cases this is not possible due to lack of collateral supply. In such cases, coil assisted endovascular flow diversion has become a potential option but the requirement for dual antiplatelet therapy in an unsecured intracranial aneurysm continues to raise concern.We present a 48-year-old man with a World Federation of Neurological Surgeons grade 5 subarachnoid hemorrhage, secondary to a ruptured intradural left vertebral artery dissecting aneurysm, who was treated successfully with a pipeline embolization device with Shield technology using aspirin and a single intravenous loading dose of abciximab. To our knowledge, this is the first case of an acute flow diversion performed using only aspirin as the sole oral antiplatelet agent.

The RNA profile of porcine parvovirus 4, a boca-like virus, is unique among the parvoviruses.

PPV4 transcribes its genome from a single promoter, and the RNAs are generated via alternate splicing coupled with alternate polyadenylation, a strategy similar to that of the bocaviruses; however, several differences were detected. The PPV4 ORF1 codes for four NS proteins, while the bocavirus ORF1 codes for 1-3 NS proteins. Whereas the VP1/VP2 capsid proteins of bocavirus are encoded by a single RNA, VP1 and VP2 of PPV4 are encoded by two separate RNAs. While ORF3 of PPV4 encodes two NP proteins, ORF3 of bocavirus codes for only one NP polypeptide. Taken together, PPV4 is unique among the parvoviruses.

Characterization and localization of metal-responsive-element-binding transcription factors from tilapia.

Two isoforms of MTF-1, MTF-1L (long form) and MTF-1S (short form), were cloned in tilapia (Ti) and characterized in a tilapia liver cell line, Hepa-T1. The cloned tiMTF-1L has the characteristics of all of the tiMTF-1S identified so far with the zinc finger domain having six fingers, the acidic-rich, proline-rich, and serine/threonine-rich domains; however, the short form encodes for the zinc finger domain with five zinc fingers only and no other domains. The transient transfection of tiMTF-1L into human HepG2 cells showed both constitutive and zinc-induced metal-responsive-element (MRE)-driven reporter gene expression. However, the transfection of tiMTF-1S (which lacks all three transactivation domains) into a human cell line showed reduced transcriptional activities compared with an endogenous control in both basal- and Zn(2+)-induced conditions. The tiMTF-1 isoforms were tagged with GFP and transfected into Hepa-T1 cells (tilapia hepatocytes). The nuclear translocation of tiMTF-1L was observed when the cells were exposed to a sufficient concentration of metals for 6h. However, tiMTF-1S, was localized in the nucleus with or without metal treatment. Electrophoretic mobility shift assay (EMSA) confirmed that both of the isoforms were able to bind to the MRE specifically in vitro. Tissue distribution studies showed that tiMTF-1L was more abundant than tiMTF-1S in all of the tissues tested.

Anticancer activities of sesquiterpene lactones from Cyathocline purpurea in vitro.

PURPOSE: Cyathocline purpurea has been traditionally used to treat various diseases including cancers for many years. However, these applications of C. purpurea have not been supported by pharmacological investigation. The objective of this study is to investigate the anticancer activities of three main constituents such as santamarine, 9beta-acetoxycostunolide and 9beta-acetoxyparthenolide isolated from C. purpurea in vitro. METHODS: Cell viability was determined by trypan blue exclusion and methylene blue assays. Colony formation was assessed by microtitration cloning assay. DNA synthesis was determined by tritiated thymidine incorporation assay. Cell cycle analysis was carried out by flow cytometry. Apoptosis was observed by DAPI staining assay and Caspase 3/7 activities was measured using Caspase-Glo 3/7 assay kit. RESULTS: Santamarine, 9beta-acetoxycostunolide and 9beta-acetoxyparthenolide inhibited the growth of L1210 murine leukaemia, CCRF-CEM human leukaemia, KB human nasopharyngeal carcinoma, LS174T human colon adenocarcinoma and MCF 7 human breast adenocarcinoma cells in vitro, with IC(50) in the range of 0.16-1.3 microg/mL. In L1210 model, santamarine and 9beta-acetoxycostunolide inhibited L1210 cell growth, colony formation and [(3)H]-thymidine incorporation in time- and concentration-dependent manners. Flow cytometry studies showed that santamarine and 9beta-acetoxycostunolide blocked L1210 cells in the G(2)/M phase of the cell cycle. DAPI staining and caspase activity assays showed santamarine and 9beta-acetoxycostunolide induced apoptosis and activated caspase 3 in L1210 cells. CONCLUSIONS: These results indicated that santamarine, 9beta-acetoxycostunolide and 9beta-acetoxyparthenolide exhibit significant anticancer activities in vitro. The inhibitory effects of santamarine and 9beta-acetoxycostunolide on L1210 cells are cytotoxic rather than just cytostatic. They block mitosis and reduce uptake of thymidine. The mechanism of the cytotoxicity of santamarine and 9beta-acetoxycostunolide to L1210 cells could be related to alkylation of the sulfhydryl enzymes involved in nucleic acids and protein synthesis, as previously found for other sesquiterpenes with the alpha-methylene-gamma-lactone moiety present in santamarine, 9beta-acetoxycostunolide and 9beta-acetoxyparthenolide. It may also be related to suppression of microtubular proteins. Santamarine and 9beta-acetoxycostunolide induced apoptosis of L1210 cells via activation of caspase 3.

Amelioration of experimental colitis by Astragalus membranaceus through anti-oxidation and inhibition of adhesion molecule synthesis.

AIM: To investigate the protective effects of Astragalus membranaceus (Am) against hapten-induced colitis in male Sprague-Dawley rats as well as its underlying mechanism. METHODS: Experimental colitis was induced in rats by enema administration of 2,4-dinitrobenzene sulfonic acid (DNBS). Rats were either pretreated with Am extract (2 or 4 g/kg, p.o. once daily) starting from 10 d before DNBS enema, or received Am post-treatment (2 or 4 g/kg, p.o. twice daily) on the three consecutive days following DNBS administration. Colonic lesion area and histological damage were determined, while the activities of myeloperoxidase (MPO) and xanthine oxidase, as well as reduced glutathione (GSH) content were measured in the excised colonic tissues. Besides, protein expression of inducible nitrite oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1) and P-selectin was also detected by Western blot analysis. RESULTS: Our findings had shown that both macroscopic lesion area and histological colonic damage induced by DNBS were significantly reduced by both Am pre- and post-treatments. These were accompanied by attenuation of the elevated colonic MPO activity and downregulation of the iNOS, P-selectin, and ICAM-1 protein expression. Besides, deprivation of colonic GSH level under colitis condition was also preserved. CONCLUSION: These results demonstrate that Am possesses both preventive and therapeutic potential in experimental colitis. The anti-inflammatory actions involve anti-oxidation along with inhibition of adhesion molecule synthesis in the colonic tissues.

Direct liquid chromatography determination of the reactive imine SJG-136 (NSC 694501).

SJG-136 (NSC 694501), 8,8'-[[(propane-1,3-diyl)dioxy]bis[(11aS)-7-methoxy-2-methylidene-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one], which is being developed as a DNA-interactive antitumor agent, contains highly reactive imines in the diazepinone portions of the molecule. Water or alcohol adds readily to the imino moiety to form the corresponding carbinolamine or its alkyl ether, respectively. This sensitivity to protic substances poses a formidable challenge to the formulation and HPLC assay development for the compound. After studying the solution chemistry of SJG-136 and its potential interaction with various stationary phases, two reversed-phase liquid chromatographic assays for the compound have been developed. A direct assay that separates SJG-136 from its water or methanol adducts and an indirect assay that quantifies SJG-136 as its dihydrate adduct are reported. The latter method, which is more practical for drug development, has been validated. It is reproducible (R.S.D.<2%), linear (r2=0.9999) and accurate (within 98-102% recovery), with a lower detection limit of 2.5 ng.