Objectives
This study aimed to examine the association between statin exposure and dementia risk in individuals with hypercholesterolaemia using data from the NHIS‐HEALS database between 2002 and ...2015.
Methods
Subjects were classified into statin exposure and statin nonexposure groups according to medication possession ratio. Dementia was defined as those with primary diagnostic dementia codes such as F00‐F03, G30, G31.1, G31.9 or G31.82. Cox proportional hazards regression models were adopted after stepwise adjustment for confounders to investigate the prospective association between statin exposure and dementia risk.
Results
During the follow‐up period (median follow‐up 11.7 years), 711 cases of dementia occurred, accounting for 11.5% of the total study population (statin exposure group, 8.2%; statin nonexposure group, 12.9%). Compared to the statin nonexposure group, fully adjusted hazard ratios (HRs) (95% confidence intervals CIs) for overall dementia in the statin exposure group were 0.63 (0.43–0.91) and 0.62 (0.50–0.78) in men and women, respectively. Compared to the statin nonexposure group, the HRs (95% CIs) for Alzheimer’s disease and related dementia, vascular dementia and other types of dementia in the statin exposure group were 0.54 (0.32–0.91), 2.45 (0.69–8.68) and 0.59 (0.32–1.07), respectively, in men and 0.53 (0.38–0.73), 1.29 (0.42–3.96) and 0.70 (0.51–0.96), respectively, in women.
Conclusions
Hypercholesterolaemic individuals exposed to statin had a lower risk of overall dementia and Alzheimer’s disease and related dementia in both sexes, and a lower risk of other types of dementia in women, than subjects who were not exposed to statins.
Juggling with Light Bae, Albert J; Hanstorp, Dag; Chang, Kelken
Physical review letters,
02/2019, Letnik:
122, Številka:
4
Journal Article
Recenzirano
We discovered that when a pair of small particles is optically levitated, the particles execute a "dance" whose motion resembles the orbits of balls being juggled. This motion lies in a plane ...perpendicular to the polarization of the incident light. We ascribe the dance to a mechanism by which the dominant force on each particle cyclically alternates between radiation pressure and gravity as each particle takes turns eclipsing the other. We explain the plane of motion by considering the anisotropic scattering of polarized light at a curved interface.
The endothelial protein C receptor (EPCR)-dependent cleavage of protease activated receptor 1 (PAR-1) by either activated protein C (APC) or thrombin in lipid rafts initiates protective signaling ...responses in endothelial cells.
To investigate the mechanism by which APC and thrombin interact with and cleave PAR-1 in lipid rafts.
We constructed two types of PAR-1 cleavage reporter constructs in which a secreted alkaline phosphatase (ALP) was fused to the extracellular domain of PAR-1. The first construct has a transmembrane domain capable of uniformly anchoring the fusion protein to the membrane surface, while the second construct has the recognition sequence for targeting the fusion protein to lipid rafts/caveolae in transfected cells.
Both APC and the Gla-domainless (GD)-APC cleaved the PAR-1 exodomain with similar efficiency in HUVECs transfected with the first construct. Unlike APC, GD-APC did not cleave PAR-1 in cells transfected with the second construct; however, prior treatment of cells with S195A mutants of either protein C or thrombin led to the GD-APC cleavage of PAR-1 with a comparable or higher catalytic efficiency. The same results were obtained if the cellular signaling properties of APC and GD-APC were monitored in the TNF-alpha-induced endothelial cell apoptosis and permeability assays.
The lipid raft localization renders the scissile bond of the PAR-1 exodomain unavailable for interaction with coagulation proteases. The binding of either the Gla-domain of protein C to EPCR or exosite-1 of thrombin to the C-terminal hirudin-like sequence of PAR-1 changes the membrane localization and/or the conformation of the PAR-1 exodomain to facilitate its recognition and subsequent cleavage by these proteases.
Background
Both vertebrobasilar dolichoectasia (VBD) and cerebral microbleeds (CMBs) are related with the risk of intracerebral hemorrhage. We aimed to examine the relationship between the VBD and ...CMB in ischaemic stroke patients.
Methods
A consecutive series of 182 patients hospitalized because of ischaemic stroke or transient ischaemic attack (TIA), and who underwent gradient echo brain magnetic resonance imaging were retrospectively recruited from a prospective stroke registry. CMB locations were categorized into anterior and posterior circulation. Ectasia was defined as basilar artery (BA) diameter > 4.5 mm, and dolichosis, as either BA bifurcation above the suprasellar cistern or lateral to the margin of the clivus or dorsum sellae. Whether VBD is associated with CMB anywhere in the brain or in anterior or posterior circulation territories was analysed using binary and multinomial logistic regression models.
Results
Twenty‐four subjects (13.2%) had VBD and 48 (26.4%) had CMBs. CMBs were more frequently observed in patients with VBD than without (66.7% vs. 20.3%, P < 0.001). VBD was significantly associated with CMBs in any location (crude odds ratio, 7.88; 95% confidence interval, 3.10–20.02), in the posterior circulation territory only (9.63; 2.60–34.94), and in both territories (9.25; 3.40–26.29), but not in the anterior circulation only (1.14; 0.009–11.20). These associations remained unchanged after adjusting for age, gender, hypertension, leukoaraiosis and stroke subtype.
Conclusions
VBD in patients with ischaemic stroke or TIA is independently associated with CMBs, especially in the posterior circulation territory.
Asymptomatic hemorrhagic transformation (HT) is not associated with immediate deterioration of patients with acute ischemic stroke. However, it is unclear whether it is clinically innocuous with ...respect to long-term outcome. The aim of this study was to determine the impact of asymptomatic HT on 3-month outcome.
A consecutive series of 1,618 patients, hospitalized between January 2004 and August 2007 for ischemic stroke within 7 days from symptom onset were identified in a prospective stroke registry database. Those who had no evidence of acute cerebral ischemia on diffusion-weighted MRI, who did not undergo T2-weighted gradient echo MRI, whose modified Rankin Scale (mRS) score at 3 months after stroke onset was not available, or who had symptomatic HT were excluded. The odds ratio (OR) of asymptomatic HT was calculated for the full distribution of mRS score and adjusted for variables with p < 0.25 with respect to their associations with asymptomatic HT or functional outcome.
Of 1,412 patients eligible for the study, 100 (7.1%) had asymptomatic HT. Patients who experienced asymptomatic HT were more likely to have cardioembolic stroke, to receive thrombolytic therapy, to receive anticoagulation with heparin, and to have a higher initial NIH Stroke Scale score. The crude and adjusted ORs of asymptomatic HT for an increment of mRS score at 3 months were 2.94 (95% confidence interval 2.05-4.24) and 1.90 (1.27-2.82), respectively.
Our study shows that the odds of a worse outcome are increased by a factor of 2 in patients with asymptomatic HT compared with those without HT after acute ischemic stroke.
Transient receptor potential melastatin 7 (TRPM7) is a calcium-permeable divalent cation channel and mediates neuronal cell death under ischemic stresses. In this study, we investigated the ...contribution of TRPM7 to neuronal development in mouse primary hippocampal neurons. We demonstrated that TRPM7 channels are highly expressed in the tips of the growth cone. Either knockdown of TRPM7 with target-specific shRNA or blocking channel conductance by a specific blocker waixenicin A enhanced axonal outgrowth in culture. Blocking TRPM7 activity by waixenicin A reduced calcium influx and accelerated the polarization of the hippocampal neurons as characterized by the development of distinct axons and dendrites. Furthermore, TRPM7 coprecipitated and colocalized with F-actin and α-actinin-1 at the growth cone. We conclude that calcium influx through TRPM7 inhibits axonal outgrowth and maturation by regulating the F-actin and α-actinin-1 protein complex. Inhibition of TRPM7 channel promotes axonal outgrowth, suggesting its therapeutic potential in neurodegenerative disorders.
Activated protein C (APC) in complex with endothelial protein C receptor (EPCR) can reverse the barrier-disruptive and cytotoxic effects of proinflammatory cytokines by cleaving protease-activated ...receptor 1 (PAR-1). Recently, it was reported that the PAR-1-dependent vascular barrier-protective effect of APC is mediated through transactivation of the angiopoietin (Ang)-Tie2 signaling pathway. The antagonist of this pathway, Ang2, is stored in Weibel-Palade bodies within endothelial cells.
To determine whether the occupancy of EPCR by its ligand can switch the PAR-1-dependent signaling specificity of thrombin through the Ang-Tie2 axis.
We activated endothelial cells with thrombin before and after treating them with the catalytically inactive Ser195-->Ala substitution mutant of protein C. The expression levels of Ang1, Ang2 and Tie2 in response to thrombin were measured by both an enzyme-linked immunosorbent assay and a cell permeability assay in the absence and presence of small interfering RNA and a blocking antibody to Tie2.
Thrombin upregulated the expression of both Ang1 and Tie2 but downregulated the expression of Ang2 when EPCR was occupied by its ligand. The Ang1-Tie2-dependent protective effect of thrombin was initiated through protein C inhibiting the rapid mobilization of Ang2 from Weibel-Palade bodies. Interestingly, the protein C mutant also inhibited the thrombin mobilization of P-selectin.
These results suggest a physiologic role for the low concentration of thrombin in maintaining the integrity of the EPCR-containing vasculature through the PAR-1-dependent inhibition of Ang2 and P-selectin release from Weibel-Palade bodies.
The bacterial flagellar motor (BFM) is a protein complex that confers motility to cells and contributes to survival and virulence. The BFM consists of stators that are ion-selective membrane protein ...complexes and a rotor that directly connects to a large filament, acting as a propeller. The stator complexes couple ion transit across the membrane to torque that drives rotation of the motor. The most common ion gradients that drive BFM rotation are protons (H
) and sodium ions (Na
). The sodium-powered stators, like those in the PomA/PomB stator complex of
spp., can be inhibited by sodium channel inhibitors, in particular, by phenamil, a potent and widely used inhibitor. However, relatively few new sodium motility inhibitors have been described since the discovery of phenamil. In this study, we characterized two possible motility inhibitors, HM2-16F and BB2-50F, from a small library of previously reported amiloride derivatives. We used three approaches: effect on rotation of tethered cells, effect on free-swimming bacteria, and effect on rotation of marker beads. We showed that both HM2-16F and BB2-50F stopped rotation of tethered cells driven by Na
motors comparable to phenamil at matching concentrations and could also stop rotation of tethered cells driven by H
motors. Bead measurements in the presence and absence of stators confirmed that the compounds did not inhibit rotation via direct association with the stator, in contrast to the established mode of action of phenamil. Overall, HM2-16F and BB2-50F stopped swimming in both Na
and H
stator types and in pathogenic and nonpathogenic strains.
Here, we characterized two novel amiloride derivatives in the search for antimicrobial compounds that target bacterial motility. These compounds were shown to inhibit flagellar motility at 10 μM across multiple strains: from nonpathogenic Escherichia coli with flagellar rotation driven by proton or chimeric sodium-powered stators, to proton-powered pathogenic E. coli (enterohemorrhagic E. coli or uropathogenic E. coli EHEC or UPEC, respectively), and finally, sodium-powered Vibrio alginolyticus. Broad antimotility compounds such as these are important tools in our efforts to control virulence of pathogens in health and agricultural settings.
BACKGROUND AND PURPOSEData on adjunctive intra-arterial thrombolysis during mechanical thrombectomy for refractory thrombus are sparse. The aim of this study was to evaluate the efficacy and safety ...of local intra-arterial urokinase as an adjunct to mechanical thrombectomy for refractory large-vessel occlusion. MATERIALS AND METHODSWe retrospectively evaluated patients with acute ischemic stroke who underwent mechanical thrombectomy for anterior circulation large-vessel occlusion between January 2016 and December 2019. Patients were divided into 2 groups based on the use of intra-arterial urokinase as an adjunctive therapy during mechanical thrombectomy for refractory thrombus: the urokinase and nonurokinase groups. Herein, refractory thrombus was defined as the target occlusion with minimal reperfusion (TICI 0 or 1) despite >3 attempts with conventional mechanical thrombectomy. The baseline characteristics, procedural outcomes, and clinical outcome were compared between the 2 groups. RESULTSOne hundred fourteen cases of refractory thrombus were identified. A total of 45 and 69 patients were in the urokinase and the nonurokinase groups, respectively. The urokinase group compared with the nonurokinase group showed a higher rate of successful reperfusion (82.2% versus 63.8%, P = .034), with lower procedural times (54 versus 69 minutes, P = .137). The rates of good clinical outcome, distal embolism, and symptomatic intracranial hemorrhage were similar between the 2 groups. The use of intra-arterial urokinase (OR = 3.682; 95% CI, 1.156-11.730; P = .027) was an independent predictor of successful reperfusion. CONCLUSIONSThe use of local intra-arterial urokinase as an adjunct to mechanical thrombectomy may be an effective and safe method that provides better recanalization than the conventional mechanical thrombectomy for refractory thrombus in patients with embolic large-vessel occlusion.
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