Macrophage infiltration of white adipose tissue (WAT) is implicated in the metabolic complications of obesity. The precipitating event(s) and function(s) of macrophage infiltration into WAT are ...unknown. We demonstrate that >90% of all macrophages in WAT of obese mice and humans are localized to dead adipocytes, where they fuse to form syncytia that sequester and scavenge the residual "free" adipocyte lipid droplet and ultimately form multinucleate giant cells, a hallmark of chronic inflammation. Adipocyte death increases in obese (db/db) mice (30-fold) and humans and exhibits ultrastructural features of necrosis (but not apoptosis). These observations identify necrotic-like adipocyte death as a pathologic hallmark of obesity and suggest that scavenging of adipocyte debris is an important function of WAT macrophages in obese individuals. The frequency of adipocyte death is positively correlated with increased adipocyte size in obese mice and humans and in hormone-sensitive lipase-deficient (HSLsuperscript -/-) mice, a model of adipocyte hypertrophy without increased adipose mass. WAT of HSLsuperscript -/- mice exhibited a 15-fold increase in necrotic-like adipocyte death and formation of macrophage syncytia, coincident with increased tumor necrosis factor-alpha gene expression. These results provide a novel framework for understanding macrophage recruitment, function, and persistence in WAT of obese individuals.
Zika virus (ZIKV) infection during pregnancy is linked to microcephaly, which is attributed to infection of developing brain structures. ZIKV infects neural progenitor cells in vitro, though its ...effects on other developmentally relevant stem cell populations, including cranial neural crest cells (CNCCs), have not been assessed. CNCCs give rise to most cranial bones and exert paracrine effects on the developing brain. Here, we report that CNCCs are productively infected by ZIKV, but not by the related dengue virus. ZIKV-infected CNCCs undergo limited apoptosis but secrete cytokines that promote death and drive aberrant differentiation of neural progenitor cultures. Addition of two such cytokines, LIF or VEGF, at levels comparable to those secreted by ZIKV-infected CNCCs is sufficient to recapitulate premature neuronal differentiation and apoptotic death of neural progenitors. Thus, our results suggest that CNCC infection by ZIKV may contribute to associated embryopathies through signaling crosstalk between developing face and brain structures.
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•Zika virus, but not dengue, productively infects cranial neural crest cells (CNCCs)•Neurospheres co-cultured with ZIKV-infected CNCCs display altered morphology•ZIKV infection drives CNCCs to secrete elevated levels of neurodevelopmental cytokines•The cytokines LIF and VEGF are sufficient to trigger premature neuronal differentiation
Cranial neural crest cells are direct progenitors of the bones and cartilage of the skull and influence central brain development through paracrine secretions. Bayless, Greenberg et al. demonstrate that Zika virus (ZIKV) productively infects cranial neural crest cells, driving cytokine secretion that leads to aberrant neural development in vitro.
Daclizumab high-yield process (HYP) is a humanized monoclonal antibody that binds to CD25 (alpha subunit of the interleukin-2 receptor) and modulates interleukin-2 signaling. Abnormalities in ...interleukin-2 signaling have been implicated in the pathogenesis of multiple sclerosis and other autoimmune disorders.
We conducted a randomized, double-blind, active-controlled, phase 3 study involving 1841 patients with relapsing-remitting multiple sclerosis to compare daclizumab HYP, administered subcutaneously at a dose of 150 mg every 4 weeks, with interferon beta-1a, administered intramuscularly at a dose of 30 μg once weekly, for up to 144 weeks. The primary end point was the annualized relapse rate.
The annualized relapse rate was lower with daclizumab HYP than with interferon beta-1a (0.22 vs. 0.39; 45% lower rate with daclizumab HYP; P<0.001). The number of new or newly enlarged hyperintense lesions on T2-weighted magnetic resonance imaging (MRI) over a period of 96 weeks was lower with daclizumab HYP than with interferon beta-1a (4.3 vs. 9.4; 54% lower number of lesions with daclizumab HYP; P<0.001). At week 144, the estimated incidence of disability progression confirmed at 12 weeks was 16% with daclizumab HYP and 20% with interferon beta-1a (P=0.16). Serious adverse events, excluding relapse of multiple sclerosis, were reported in 15% of the patients in the daclizumab HYP group and in 10% of those in the interferon beta-1a group. Infections were more common in the daclizumab HYP group than in the interferon beta-1a group (in 65% vs. 57% of the patients, including serious infection in 4% vs. 2%), as were cutaneous events such as rash or eczema (in 37% vs. 19%, including serious events in 2% vs. <1%) and elevations in liver aminotransferase levels that were more than 5 times the upper limit of the normal range (in 6% vs. 3%).
Among patients with relapsing-remitting multiple sclerosis, daclizumab HYP showed efficacy superior to that of interferon beta-1a with regard to the annualized relapse rate and lesions, as assessed by means of MRI, but was not associated with a significantly lower risk of disability progression confirmed at 12 weeks. The rates of infection, rash, and abnormalities on liver-function testing were higher with daclizumab HYP than with interferon beta-1a. (Funded by Biogen and AbbVie Biotherapeutics; DECIDE ClinicalTrials.gov number, NCT01064401.).
Questionnaires were completed by 5th-, 8th-, and 11th-grade public schools students in rural and suburban school districts and by undergraduates at two universities in the United States (n = 1,242). ...They were asked about their orientation to video games—the amount of time they played, their motives for doing so, and the game types they preferred—to better understand the context in which effects research might be organized. The conceptual schema for this research was the uses-and-gratifications perspective. The males in the sample played video games at twice the weekly average of the females, were consistently stronger in all measured motives than the females, and preferred physically oriented video games over the females’ preference for more traditional, thoughtful games. Younger players opted for the fantasy motive in their playing and older players more so for competition. Preference for physical games declined among the older males, and generally motives were stronger in the middle years of playing for both males and females than in the youngest and oldest age groups. Regression analyses explained considerably more variance in game playing for males than for females.
Little is known about outcomes for individuals with autism spectrum disorders (ASD) into adulthood. Several characteristics of individuals with ASD predict long-term outcomes, and the family ...environment may also play a role. The present study uses a prospective, longitudinal design to describe and predict trajectories of autism symptoms and maladaptive behaviors over 8.5 years in a large, community-based sample of adolescents and adults with ASD. Overall, autism symptoms and maladaptive behaviors were observed to improve over the study period. Above and beyond the adult’s gender, age, and level of intellectual disability, greater improvements were associated with higher levels of maternal praise (based on maternal speech samples) and higher quality mother–child relationships. Implications for future research and intervention are discussed.
Lecanemab: Appropriate Use Recommendations Cummings, J.; Apostolova, L.; Rabinovici, G. D. ...
The journal of prevention of Alzheimer's disease,
2023/9, Letnik:
10, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Lecanemab (Leqembi®) is approved in the United States for the treatment of Alzheimer’s disease (AD) to be initiated in early AD (mild cognitive impairment MCI due to AD or mild AD dementia) with ...confirmed brain amyloid pathology. Appropriate Use Recommendations (AURs) are intended to help guide the introduction of new therapies into real-world clinical practice. Community dwelling patients with AD differ from those participating in clinical trials. Administration of lecanemab at clinical trial sites by individuals experienced with monoclonal antibody therapy also differs from the community clinic-based administration of lecanemab. These AURs use clinical trial data as well as research and care information regarding AD to help clinicians administer lecanemab with optimal safety and opportunity for effectiveness. Safety and efficacy of lecanemab are known only for patients like those participating in the phase 2 and phase 3 lecanemab trials, and these AURs adhere closely to the inclusion and exclusion criteria of the trials. Adverse events may occur with lecanemab including amyloid related imaging abnormalities (ARIA) and infusion reactions. Monitoring guidelines for these events are detailed in this AUR. Most ARIA with lecanemab is asymptomatic, but a few cases are serious or, very rarely, fatal. Microhemorrhages and rare macrohemorrhages may occur in patients receiving lecanemab. Anticoagulation increases the risk of hemorrhage, and the AUR recommends that patients requiring anticoagulants not receive lecanemab until more data regarding this interaction are available. Patients who are apolipoprotein E ε4 (
APOE4
) gene carriers, especially
APOE4
homozygotes, are at higher risk for ARIA, and the AUR recommends
APOE
genotyping to better inform risk discussions with patients who are lecanemab candidates. Clinician and institutional preparedness are mandatory for use of lecanemab, and protocols for management of serious events should be developed and implemented. Communication between clinicians and therapy candidates or those on therapy is a key element of good clinical practice for the use of lecanemab. Patients and their care partners must understand the potential benefits, the potential harms, and the monitoring requirements for treatment with this agent. Culture-specific communication and building of trust between clinicians and patients are the foundation for successful use of lecanemab.
MRI white matter hyperintensity (WMH) volume is associated with cognitive impairment. We hypothesized that specific loci of WMH would correlate with cognition even after accounting for total WMH ...volume.
Subjects were identified from a prospective community-based study: 40 had normal cognition, 94 had mild impairment (defined here as a Clinical Dementia Rating CDR score of 0.5 without dementia), and 11 had mild Alzheimer's dementia. Factor analysis of a 22-item neuropsychological battery yielded 4 factors (episodic memory, executive function, spatial skills, and general knowledge). MRI WMH segmentation and analysis was performed using FreeSurfer software.
Higher WMH volume was independently associated with lower executive function and episodic memory factor scores. Voxel-based general linear models showed loci where WMH was strongly inversely associated with specific cognitive factor scores (p < 0.001), controlling for age, education, sex, APOE genotype, and total WMH volume. For episodic memory, clusters were observed in bilateral temporal-occipital and right parietal periventricular white matter, and the left anterior limb of the internal capsule. For executive function, clusters were observed in bilateral inferior frontal white matter, bilateral temporal-occipital and right parietal periventricular white matter, and the anterior limb of the internal capsule bilaterally.
Specific WMH loci are closely associated with executive function and episodic memory, independent of total WMH volume. The anatomic locations suggest that WMH may cause cognitive impairment by affecting connections between cortex and subcortical structures, including the thalamus and striatum, or connections between the occipital lobe and frontal or parietal lobes.
A subset of patients with cerebral amyloid angiopathy (CAA) present with cognitive symptoms, seizures, headaches, T2-hyperintense MRI lesions, and neuropathologic evidence of CAA-associated vascular ...inflammation.
To analyze the risk factors, diagnostic characteristics, and long-term course of this disorder.
We assessed 14 consecutive patients with pathologically diagnosed CAA-related inflammation, 12 with available neuroimaging and follow-up data. Patients were evaluated for MRI appearance, APOE genotype, and clinical course over a 46.8 +/- 29.1-month follow-up.
Baseline MRI scans were characterized by asymmetric T2-hyperintense lesions extending to the subcortical white matter and occasionally the overlying gray matter, with signal properties suggesting vasogenic edema. Subjects could be divided into three groups based on response to immunosuppressive treatment: monophasic improvement (7/12), initial improvement followed by symptomatic relapse (3/12), and no evident response to treatment (2/12). The volume of MRI hyperintensities correlated with the severity of clinical symptoms. One patient experienced symptomatic intracerebral hemorrhage within a region of recurrent MRI hyperintensity. The APOE epsilon4/epsilon4 genotype was strongly associated with CAA-related inflammation, present in 76.9% (10/13) of subjects vs 5.1% (2/39) with symptomatic but noninflammatory CAA (p < 0.0001).
Cerebral amyloid angiopathy-related inflammation represents a clinically, pathologically, radiographically, and genetically distinct disease subtype with implications for clinical practice and ongoing immunotherapeutic approaches to Alzheimer disease.
Magnetic resonance (MR) imaging and computed tomography (CT) are increasingly being used in diagnosis and follow-up of congenital pulmonary vein anomalies in neonates and infants. Such anomalies ...include total or partial anomalous pulmonary venous return, sinus venosus defect, malposition of the septum primum, cor triatriatum, pulmonary vein atresia or stenosis, and abnormal number or course of the pulmonary veins. MR imaging provides a wealth of anatomic and functional data that are valuable in case management and planning intervention. Gadolinium-enhanced MR angiography is the mainstay of anatomic evaluation. Ventricular volumetry with two-dimensional steady-state free-precession sequences and flow analysis with cine phase-contrast imaging provide physiologic information that may be used to calculate the degree of right heart enlargement and the shunt fraction, allowing the cardiologist to determine the functional importance of the lesion. CT provides superior spatial resolution and short imaging times but at the expense of exposure to ionizing radiation.
To understand and predict large, complex, and chaotic systems, Earth scientists build simulators from physical laws. Simulators generalize better to new scenarios, require fewer tunable parameters, ...and are more interpretable than nonphysical deep learning, but procedures for obtaining their derivatives with respect to their inputs are often unavailable. These missing derivatives limit the application of many important tools for forecasting, model tuning, sensitivity analysis, or subgrid‐scale parametrization. Here, we propose to overcome this limitation with deep emulator networks that learn to calculate the missing derivatives. By training directly on simulation data without analyzing source code or equations, this approach supports simulators in any programming language on any hardware without specialized routines for each case. To demonstrate the effectiveness of our approach, we train emulators on complete or partial system states of the chaotic Lorenz‐96 simulator and evaluate the accuracy of their dynamics and derivatives as a function of integration time and training data set size. We further demonstrate that emulator‐derived derivatives enable accurate 4D‐Var data assimilation and closed‐loop training of parametrizations. These results provide a basis for further combining the parsimony and generality of physical models with the power and flexibility of machine learning.
Plain Language Summary
Many Earth science simulators are implemented as monolithic programs that calculate changes in the state of a system over time. In many cases, using or improving these simulators also requires the derivatives of their outputs with respect to inputs, which describe how future states depend on past states. These derivatives can be difficult or costly to compute. Several recent studies have applied deep learning (DL) to simulation data to construct emulators of their dynamics. Here, we use the fact that DL models can be easily and automatically differentiated to obtain approximate derivatives of the original simulator and test this idea on a simple and common chaotic model of the atmosphere. We verify in several experiments that the emulator derivatives, which require neither additional training nor extensive postprocessing to obtain, can indeed be used as a valid substitute for the derivatives of the simulator.
Key Points
Deep learning models trained on simulation data can learn the dynamics of Earth science simulators
Deep learning models also learn the input–output derivatives of the state‐update function, which are unavailable for many simulators
We show on Lorenz‐96 that these learned derivatives can be used directly for data assimilation and parametrization tuning
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