Nunezpotts3657

To assess whether interleukin-6 (IL-6) level is a marker of futile reperfusion in patients with acute ischemic stroke (AIS) with large vessel occlusion treated with mechanical thrombectomy (MT).

The Cohort of Patients to Identify Biological and Imaging Markers of Cardiovascular Outcomes in Stroke (HIBISCUS-STROKE) includes patients with AIS treated with MT after MRI. We performed a sequential assessment of IL-6 (admission, 6 hours, 24 hours, 48 hours and 3 months from admission). Among patients with successful reperfusion (Thrombolysis in Cerebral Infarction scale 2b/3), reperfusion was considered effective if 3-month modified Rankin Scale (mRS) score was 0 to 2 and futile if 3-month mRS score was 3 to 6. Our model was adjusted for the main confounding variables.

One hundred sixty-four patients represent the study population. One hundred thirty-three patients had successful reperfusion (81.1%), while in 46 (34.6%), reperfusion was classified as futile. In single-variable analyses, high IL-6 levels at 6, 24, and 48 hours in combination with a higher age, a prestroke mRS score >2, a history of hypertension or diabetes, lack of current smoking, a higher baseline NIH Stroke Scale score, the absence of associated intravenous thrombolysis, an intracranial internal carotid artery or a tandem occlusion, and an increased infarct growth were associated with futile reperfusion. After multivariable analyses, a high IL-6 level at 24 hours (odds ratio 6.15, 95% confidence interval 1.71-22.10) remained associated with futile reperfusion.

IL-6 is a marker of futile reperfusion in the setting of MT.

IL-6 is a marker of futile reperfusion in the setting of MT.

To determine whether 24 weeks of high-intensity progressive aerobic exercise (PAE) affects brain MRI measures in people with multiple sclerosis (MS).

We conducted a randomized, controlled, phase 2 trial (with a crossover follow-up) including an exercise group (supervised PAE followed by self-guided physical activity) and a waitlist group (habitual lifestyle followed by supervised PAE). Mildly to severely impaired patients with MS aged 18-65 years were randomized (11). The primary outcome was percentage brain volume change (PBVC) after 24 weeks, analyzed using the intention-to-treat principle.

Eighty-six participants were recruited. PBVC did not change over the intervention period (mean between-group change +0.12%, 95% confidence interval [CI] -0.27 to 0.51,

= 0.55). In contrast, cardiorespiratory fitness (+3.5 mL O

/min/kg, 2.0 to 5.1,

< 0.01) and annualized relapse rate (0.00, 0.00-0.07 vs +0.45, 0.28 to 0.61,

< 0.01) improved in the exercise group.

These findings do not support a neuroprotective effect of PAE in terms of total brain atrophy in people with MS and it did not lead to a statistically significant difference in gray matter parenchymal fraction. PAE led to improvements in cardiorespiratory fitness and a lower relapse rate. While these exploratory findings cautiously support PAE as a potential adjunct disease-modifying treatment in MS, further investigations are warranted.

NCT02661555.

This study provides Level I evidence that 24 weeks of high-intensity PAE did not elicit disease-modifying effects in PBVC in people with MS. Exploratory analyses showed that PAE may reduce relapse rate.

This study provides Level I evidence that 24 weeks of high-intensity PAE did not elicit disease-modifying effects in PBVC in people with MS. Exploratory analyses showed that PAE may reduce relapse rate.

To assess whether Alzheimer disease (AD) clinical presentation and

relate to the burden and topography of β-amyloid (Aβ) and tau pathologies using in vivo PET imaging.

We studied 119 Aβ-positive symptomatic patients aged 48-95 years, including 29 patients with logopenic variant primary progressive aphasia (lvPPA) and 21 with posterior cortical atrophy (PCA). Pittsburgh compound B (PiB)-Aβ and flortaucipir (tau)-PET standardized uptake value ratio (SUVR) images were created. General linear models assessed relationships between demographic/clinical variables (phenotype, age),

, and PET (including global cortical and voxelwise SUVR values) while controlling for disease severity using the Clinical Dementia Rating Sum of Boxes.

PiB-PET binding showed a widespread cortical distribution with subtle differences across phenotypes and was unrelated to demographic/clinical variables or

. Flortaucipir-PET was commonly elevated in temporoparietal regions, but showed marked phenotype-associated differences, wiobe-predominant pattern of tau pathology.Multidrug and toxin extrusion (MATE) transporters are expressed on the luminal membrane of renal proximal tubule cells and extrude their substrates into the luminal side of the tubules. Inhibition of MATE1 can reduce renal secretory clearance of its substrate drugs and lead to drug-drug interactions (DDIs). To address whether IC50 values of MATE1 inhibitors with regard to their extracellular concentrations are affected by the direction of MATE1-mediated transport, we established an efflux assay of 1-methyl-4-phenylpyridinium (MPP+) and metformin using the human embryonic kidney 293 model transiently expressing human MATE1. Nintedanib price The efflux rate was defined by reduction of the cellular amount of MPP+ and metformin for 0.25 minutes shortly after the removal of extracellular MPP+ and metformin. Inhibition potencies of 12 inhibitors toward MATE1-mediated transport were determined in both uptake and efflux assays. When MPP+ was used as a substrate, 8 out of 12 inhibitors showed comparable IC50 values between assays (4.7-fold). IC50 values obtained from the uptake assay using metformin showed smaller IC50 values than those from the efflux assay. Therefore, the uptake assay is recommended to determine IC50 values for the DDI predictions. SIGNIFICANCE STATEMENT In this study, a new method to evaluate IC50 values of extracellular added inhibitors utilizing an efflux assay was established. IC50 values were not largely different between uptake and efflux directions but were smaller for uptake. This study supports the rationale for a commonly accepted uptake assay with metformin as an in vitro probe substrate for multidrug and toxin extrusion 1-mediated drug-drug interaction risk assessment in drug development.