KIF1A is a kinesin family motor involved in the axonal transport of synaptic vesicle precursors (SVPs) along microtubules (MTs). In humans, more than 10 point mutations in KIF1A are associated with ...the motor neuron disease hereditary spastic paraplegia (SPG). However, not all of these mutations appear to inhibit the motility of the KIF1A motor, and thus a cogent molecular explanation for how KIF1A mutations lead to neuropathy is not available. In this study, we established in vitro motility assays with purified full-length human KIF1A and found that KIF1A mutations associated with the hereditary SPG lead to hyperactivation of KIF1A motility. Introduction of the corresponding mutations into the Caenorhabditis elegans KIF1A homolog unc-104 revealed abnormal accumulation of SVPs at the tips of axons and increased anterograde axonal transport of SVPs. Our data reveal that hyperactivation of kinesin motor activity, rather than its loss of function, is a cause of motor neuron disease in humans.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Maternal obesity is one of the major risk factors for pregnancy complications and is associated with low-grade chronic systemic inflammation due to higher levels of pro-inflammatory cytokines such as ...interleukin (IL)-1β. Pregnant women with obesity have abnormal lipid profiles, characterized by higher levels of free fatty acids, especially palmitic acid (PA). Previously, we reported that PA stimulated IL-1β secretion via activation of NLRP3 inflammasome in human placental cells. These observations led us to hypothesize that higher levels of PA induce NLRP3 inflammasome activation and placental inflammation, resulting in pregnancy complications. However, the effects of PA on NLRP3 inflammasome during pregnancy in vivo remain unclear. Therefore, PA solutions were administered intravenously into pregnant mice on day 12 of gestation. Maternal body weight was significantly decreased and absorption rates were significantly higher in PA-injected mice. The administration of PA significantly increased IL-1β protein and the mRNA expression of NLRP3 inflammasome components (NLRP3, ASC, and caspase-1) within the placenta. In murine placental cell culture, PA significantly stimulated IL-1β secretion, and this secretion was suppressed by a specific NLRP3 inhibitor (MCC950). Simultaneously, the number of macrophages/monocytes and neutrophils, together with the mRNA expression of these chemokines increased significantly in the placentas of PA-treated mice. Treatment with PA induced ASC assembling and IL-1β secretion in macrophages, and this PA-induced IL-1β secretion was significantly suppressed in NLRP3-knockdown macrophages. These results indicate that transient higher levels of PA exposure in pregnant mice activates NLRP3 inflammasome and induces placental inflammation, resulting in the incidence of absorption.
Background:Three-dimensional (3D) speckle tracking echocardiography (STE) after ST-elevation acute myocardial infarction (STEMI) is associated with left ventricular (LV) remodeling and 1-year ...prognosis. This study investigated the clinical significance of 3D-STE in predicting the long-term prognosis of patients with STEMI.Methods and Results:A total of 270 patients (mean age 64.6 years) with first-time STEMI treated with reperfusion therapy were enrolled. At 24 h after admission, standard 2D echocardiography and 3D full-volume imaging were performed, and 2D-STE and 3D-STE were calculated. Patients were followed up for a median of 119 months (interquartile range: 96–129 months). The primary endpoint was occurrence of a major adverse cardiac event (MACE: cardiac death, heart failure with hospitalization), and 64 patients experienced MACEs. Receiver operating characteristic curves and Cox hazard multivariate analysis showed that the 3D-STE indices were stronger predictors of MACE compared with those of 2D-STE. Additionally, 3D-global longitudinal strain (GLS) was the strongest predictor for MACE followed by 3D-global circumferential strain (GCS). The Kaplan-Meier curve demonstrated that 3D-GLS >−11.0 was an independent predictor for MACE (log-rank χ2=132.2, P<0.0001). When combined with 3D-GCS >−18.3, patients with higher values of 3D-GLS and 3D-GCS were found to be at extremely high risk for MACE.Conclusions:Global strain measured by 3D-STE immediately after the onset of STEMI is a clinically significant predictor of 10-year prognosis.
This single-center retrospective cohort study analyzed the 1-year real-world treatment outcomes of 63 consecutive eyes (of 60 patients) with neovascular age-related macular degeneration (nAMD) that ...were switched from intravitreal brolucizumab (IVBr) to intravitreal faricimab (IVF) and managed on a treat-and-extend regimen with discontinuation criteria. After the switch, patients opted to continue IVF, to switch back to IVBr, or receive photodynamic therapy (PDT). Thirty-eight patients continued IVF, 16 patients were switched back to IVBr, 2 patients received PDT, and 4 patients paused treatment. Best-corrected visual acuity (BCVA), central subfield thickness (CST), subfoveal choroidal thickness (sf-CT), and injection intervals were compared immediately before and 1 year after the initial IVF. Whereas there was no change in BCVA and CST; 0 - 0.0969 to 0.125, P = 0.58, - 1.5 - 27.8 to 13.5, P = 0.11 µm, respectively, sf-CT decreased significantly; - 19.5 - 45.5 to 7.75, P = 0.015 µm. The patients switched back showed no significant change in sf-CT. The injection interval extended significantly in the IVF continuation and the switch-back group (2.0 and 3.0 weeks, respectively; P = 0.0007 and 0.0078) in eyes with a pre-switching interval of less than 12 weeks. Faricimab shows promise as a safe and effective alternative to brolucizumab for treating nAMD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A new anti-vascular endothelial growth factor agent, brolucizumab, was approved by the United States Food and Drug Administration in 2019. We evaluated whether brolucizumab reduces the treatment ...burden of neovascular age-related macular degeneration (nAMD) after switching by examining 1-year treatment outcomes in a real-world setting. This retrospective single-institution study included 107 consecutive eyes with nAMD treated with brolucizumab. Among these eyes, 30 with treatment-naïve nAMD and 77 treated with other anti-VEGF agents for more than a year were included. All eyes were managed using a treat and extend (TAE) or modified TAE regimen. The last injection intervals at 52 weeks were 12.9 and 12.1 weeks in the treatment-naïve and switch therapy groups, respectively. Among switch therapy group patients whose pre-switch injection intervals were shorter than 120 days (n = 62 eyes), the injection interval was significantly longer after the switch than before, with a mean difference of 2.7 weeks (P < 0.0001). Intraocular inflammation events occurred in 2 and 7 treatment-naïve and switch therapy patients, respectively. In conclusion, brolucizumab might reduce the treatment burden in patients who required the injection of other anti-VEGF agents with a 120-day interval or shorter, despite a relatively high discontinuation rate due to intraocular inflammation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background: The role of left atrial (LA) function in the long-term prognosis of ST-elevation acute myocardial infarction (STEMI) is still unclear.Methods and Results: Percutaneous coronary ...intervention (PCI) was performed in 433 patients with the first episode of STEMI within 12 h of onset. The patients underwent echocardiography 24 h after admission. LA reservoir strain and other echocardiographic parameters were analyzed. Follow up was performed for up to 10 years (mean duration, 91 months). The primary endpoint was major adverse cardiovascular events (MACE): cardiac death or hospitalization due to heart failure (HF). MACE occurred in 90 patients (20%) during the follow-up period. Multivariate Cox hazard analyses showed LA reservoir strain, global longitudinal strain (GLS), age and maximum B-type natriuretic peptide (BNP) were the significant predictors of MACE. Kaplan-Meier curves demonstrated that LA reservoir strain <25.8% was a strong predictor (Log rank, χ2=76.7, P<0.0001). Net reclassification improvement (NRI) demonstrated that adding LA reservoir strain had significant incremental effect on the conventional parameters (NRI and 95% CI: 0.24 0.11–0.44) . When combined with GLS >−11.5%, the patients with LA reservoir strain <25.8% were found to be at extremely high risk for MACE (Log rank, χ2=126.3, P<0.0001).Conclusions: LA reservoir strain immediately after STEMI onset was a significant predictor of poor prognosis in patients, especially when combined with GLS.
Background:Two-dimensional (2D) and three-dimensional (3D) speckle tracking echocardiography (STE) after ST-elevation acute myocardial infarction (STEMI) can predict the prognosis. This study ...investigated the clinical significance of a serial 3D-STE can predict the prognosis after onset of STEMI.Methods and Results:This study enrolled 272 patients (mean age, 65 years) with first-time STEMI treated with reperfusion therapy. At 24 h after admission, standard 2D echocardiography and 3D full-volume imaging were performed, and 2D-STE and 3D-STE were calculated. Within 1 year, 19 patients who experienced major adverse cardiac events (MACE; cardiac death, heart failure requiring hospitalization) were excluded. Among the 253 patients, 248 were examined with follow-up echocardiography. The patients were followed up for a median of 108 months (interquartile range: 96–129 months). The primary endpoint was the occurrence of a MACE; 45 patients experienced MACEs. Receiver operating characteristic curves and Cox hazard multivariate analysis showed that the 2D-global longitudinal strain (GLS) and 3D-GLS at 1-year indices were significant predictors of MACE. The Kaplan-Meier curve demonstrated that a 3D-GLS of >−13.1 was an independent predictor for MACE (log-rank χ2=165.5, P<0.0001). The deterioration of 3D-GLS at 1 year was a significant prognosticator (log-rank χ2=36.7, P<0.0001).Conclusions:The deterioration of 3D-GLS measured by STE at 1 year after the onset of STEMI is the strongest predictor of long-term prognosis.
Intraperitoneal adhesion is a common complication of cesarean section, and adhesion barriers are often used to prevent postoperative adhesion. However, the association between the use of adhesion ...barriers and infections after cesarean section remains unknown. This study aimed to evaluate the association.
Using the administrative claims database of a single prefecture in Japan, we identified all patients who underwent cesarean section from June 2014 to February 2019. A multivariable logistic regression model fitted with a generalized estimating equation was used to compare the postoperative outcomes between patients who received intraperitoneal adhesion barriers during cesarean section and those who did not. The primary outcome was intraperitoneal or uterine infections within 3 months after cesarean section, including intraperitoneal abscess, pelvic inflammatory disease, peritonitis, uterine wound infection, endometritis, and adnexitis.
A total of 1,392 patients with 1,498 cesarean section cases were reviewed. Adhesion barriers were used in 1,153/1,498 (77.0%) cases. One hundred and fourteen (9.9%) intraperitoneal or uterine infections occurred in the group with and 15 (4.3%) in the group without adhesion barriers. The proportion of intraperitoneal or uterine infections was significantly higher in the group with than in the group without adhesion barriers (9.9% and 4.3%, respectively; adjusted odds ratio = 2.59; 95% confidence interval, 1.40–4.77; P = .002).
The use of adhesion barriers was associated with an increase in intraperitoneal or uterine infections after cesarean section.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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