Low-Dose Intravenous Alteplase in Wake-Up Stroke

Background and Purpose—We assessed whether lower-dose alteplase at 0.6 mg/kg is efficacious and safe for acute fluid-attenuated inversion recovery-negative stroke with unknown time of onset. Methods—This was an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4.5 hours (eg, wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg or standard medical treatment if magnetic resonance imaging showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on fluid-attenuated inversion recovery. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0–1). Results—Following the early stop and positive results of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke), this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age, 74.4±12.2 years). Favorable outcome was comparable between the alteplase group (32/68, 47.1%) and the control group (28/58, 48.3%; relative risk [RR], 0.97 [95% CI, 0.68–1.41]; P=0.892). Symptomatic intracranial hemorrhage within 22 to 36 hours occurred in 1/71 and 0/60 (RR, infinity [95% CI, 0.06 to infinity]; P>0.999), respectively. Death at 90 days occurred in 2/71 and 2/60 (RR, 0.85 [95% CI, 0.06–12.58]; P>0.999), respectively. Conclusions—No difference in favorable outcome was seen between alteplase and control groups among patients with ischemic stroke with unknown time of onset. The safety of alteplase at 0.6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions

Direct evidence for pitavastatin induced chromatin structure change in the KLF4 gene in endothelial cells.

Statins exert atheroprotective effects through the induction of specific transcriptional factors in multiple organs. In endothelial cells, statin-dependent atheroprotective gene up-regulation is mediated by Kruppel-like factor (KLF) family transcription factors. To dissect the mechanism of gene regulation, we sought to determine molecular targets by performing microarray analyses of human umbilical vein endothelial cells (HUVECs) treated with pitavastatin, and KLF4 was determined to be the most highly induced gene. In addition, it was revealed that the atheroprotective genes induced with pitavastatin, such as nitric oxide synthase 3 (NOS3) and thrombomodulin (THBD), were suppressed by KLF4 knockdown. Myocyte enhancer factor-2 (MEF2) family activation is reported to be involved in pitavastatin-dependent KLF4 induction. We focused on MEF2C among the MEF2 family members and identified a novel functional MEF2C binding site 148 kb upstream of the KLF4 gene by chromatin immunoprecipitation along with deep sequencing (ChIP-seq) followed by luciferase assay. By applying whole genome and quantitative chromatin conformation analysis {chromatin interaction analysis with paired end tag sequencing (ChIA-PET), and real time chromosome conformation capture (3C) assay}, we observed that the MEF2C-bound enhancer and transcription start site (TSS) of KLF4 came into closer spatial proximity by pitavastatin treatment. 3D-Fluorescence in situ hybridization (FISH) imaging supported the conformational change in individual cells. Taken together, dynamic chromatin conformation change was shown to mediate pitavastatin-responsive gene induction in endothelial cells

Initial experience of transpapillary gallbladder biopsy using newly designed device delivery system

Transpapillary gallbladder biopsy has been reported for the diagnosis of gallbladder disease, and this procedure requires special biopsy forceps or a large-diameter pusher catheter. We retrospectively examined consecutive patients who underwent transpapillary gallbladder biopsy using a newly designed device delivery system (Endosheather; Piolax Medical Device, Kanagawa, Japan). We evaluated 11 patients (median age, 71 years [28-85]) who underwent transpapillary gallbladder biopsy from June 2021 to July 2022. The selective gallbladder cannulation and delivery system insertion success rate was 90.9% (10/11). The target lesion biopsy success rate was 63.6% (7/11). The biopsy time (i.e., time to completion of biopsy after successful guidewire placement) was 8.7 (5.4-32.7) min. In 1 patient in whom all 6 gallbladder bile juice cytology results were benign, the biopsy result was suspicious of adenocarcinoma. The final diagnosis for this patient was gallbladder cancer. Adverse events occurred in 2 patients. In 1 patient, acute cholecystitis occurred and required emergency surgery. Transpapillary gallbladder biopsy using the Endosheather is a potential option for the diagnosis of gallbladder disease. A good indication for this technique is considered to be wall thickening at the gallbladder fundus, where it is difficult to differentiate between benign and malignant lesions by imaging modalities such as ultrasonography or endoscopic ultrasound. The addition of transpapillary gallbladder biopsy may be advantageous when performing bile juice cytology using a nasogallbladder drainage tube for the diagnosis of gallbladder disease