Citations

ObjectiveWhile thrombosis and pregnancy loss are the best‐known clinical features of antiphospholipid syndrome (APS), many patients also exhibit “extra‐criteria” manifestations, such as thrombocytopenia. The mechanisms that drive APS thrombocytopenia are not completely understood, and no clinical biomarkers are available for predicting antiphospholipid antibody (aPL)–mediated thrombocytopenia. Calprotectin is a heterodimer of S100A8 and S100A9 that is abundant in the neutrophil cytoplasm and released upon proinflammatory neutrophil activation. Here, we sought to evaluate the presence, clinical associations, and potential mechanistic roles of circulating calprotectin in a cohort of primary APS and aPL‐positive patients.MethodsLevels of circulating calprotectin were determined in plasma by the QUANTA Flash chemiluminescent assay. A viability dye‐based platelet assay was used to assess the potential impact of calprotectin on aPL‐mediated thrombocytopenia.ResultsCirculating calprotectin was measured in 112 patients with primary APS and 30 aPL‐positive (without APS criteria manifestations or lupus) patients as compared to patients with lupus (without APS), patients with unprovoked venous thrombosis (without aPL), and healthy controls. Levels of calprotectin were higher in patients with primary APS and aPL‐positive patients compared to healthy controls. After adjustment for age and sex, calprotectin level correlated positively with absolute neutrophil count (r = 0.41, P < 0.001), positively with C‐reactive protein level (r = 0.34, P = 0.002), and negatively with platelet count (r = −0.24, P = 0.004). Mechanistically, we found that calprotectin provoked aPL‐mediated thrombocytopenia by engaging platelet surface toll‐like receptor 4 and activating the NLRP3‐inflammasome, thereby reducing platelet viability in a caspase‐1‐dependent manner.ConclusionThese data suggest that calprotectin has the potential to be a functional biomarker and a new therapeutic target for APS thrombocytopenia.image

AbstractThis systematic review and meta‐analysis of randomised controlled trials (RCTs) aimed to evaluate the efficacy, safety, and tolerability of fluvoxamine for the outpatient management of COVID‐19. We conducted this review in accordance with the PRISMA 2020 guidelines. Literature searches were conducted in MEDLINE, EMBASE, International Pharmaceutical Abstracts, CINAHL, Web of Science, and CENTRAL up to 14 September 2023. Outcomes included incidence of hospitalisation, healthcare utilization (emergency room visits and/or hospitalisation), mortality, supplemental oxygen and mechanical ventilation requirements, serious adverse events (SAEs) and non‐adherence. Fluvoxamine 100 mg twice a day was associated with reductions in the risk of hospitalisation (risk ratio [RR] 0.75, 95% confidence interval [CI] 0.58–0.97; I 2 = 0%) and reductions in the risk of healthcare utilization (RR 0.68, 95% CI 0.53–0.86; I 2 = 0%). While no increased SAEs were observed, fluvoxamine 100 mg twice a day was associated with higher treatment non‐adherence compared to placebo (RR 1.61, 95% CI 1.22–2.14; I 2 = 53%). In subgroup analyses, fluvoxamine reduced healthcare utilization in outpatients with BMI ≥30 kg/m2, but not in those with lower BMIs. While fluvoxamine offers potential benefits in reducing healthcare utilization, its efficacy may be most pronounced in high‐risk patient populations. The observed non‐adherence rates highlight the need for better patient education and counselling. Future investigations should reassess trial endpoints to include outcomes relating to post‐COVID sequelaes. Registration: This review was prospectively registered on PROSPERO (CRD42023463829).

Infantile neuroaxonal dystrophy (INAD) is caused by recessive variants in PLA2G6 and is a lethal pediatric neurodegenerative disorder. Loss of the Drosophila homolog of PLA2G6 , leads to ceramide accumulation, lysosome expansion, and mitochondrial defects. Here, we report that retromer function, ceramide metabolism, the endolysosomal pathway, and mitochondrial morphology are affected in INAD patient-derived neurons. We show that in INAD mouse models, the same features are affected in Purkinje cells, arguing that the neuropathological mechanisms are evolutionary conserved and that these features can be used as biomarkers. We tested 20 drugs that target these pathways and found that Ambroxol, Desipramine, Azoramide, and Genistein alleviate neurodegenerative phenotypes in INAD flies and INAD patient-derived neural progenitor cells. We also develop an AAV-based gene therapy approach that delays neurodegeneration and prolongs lifespan in an INAD mouse model.

Abstract The COVID‐19 pandemic and its accompanying infection control measures introduced sudden and significant disruptions to the lives of children and adolescents around the world. Given the potential for negative impacts on the mental health of youths as a result of these changes, we conducted a systematic review and meta‐analysis to examine the prevalence of depressive symptoms, anxiety symptoms, and sleep disturbances in children and adolescents during the pandemic. We searched major literature databases for relevant cross‐sectional or longitudinal studies that included primary and secondary school students or children and adolescents ≤18 years of age. Prevalence values were extracted, logit‐transformed, and pooled. Based on 191 included studies with 1,389,447 children and adolescents, we found the pooled prevalence of depressive symptoms, anxiety symptoms, and sleep disturbances to be 31%, 31%, and 42%, respectively. Age, grade levels, education levels, gender, geographical regions, and electronics use were correlated with the prevalence of mental health symptoms. The prevalence of mental health symptoms also increased with time, although signs of recovery and stabilization were also observed. Overall, the results from this review demonstrate the need for increased mental health research, monitoring, and intervention for children and adolescents during the current and future pandemics.

ObjectiveThis study assessed patient‐reported outcomes (PROs) in individuals with persistently positive antiphospholipid antibodies (aPL) to better understand how living with aPL may affect their quality of life.MethodsPatients completed Patient‐Reported Outcomes Measurement Information System Physical Function (PF) and Cognitive Function (CF) Short Forms as well as the pain intensity (PI) rating (scale of 1‐10). Patients were characterized for demographics, clinical manifestations of antiphospholipid syndrome (APS), cardiovascular risk factors, laboratory test results, and medication usage. Multivariate modeling was done via linear regression.ResultsOf 139 patients, 89 had primary APS, 21 had secondary APS, and 29 had persistent aPL without meeting clinical criteria for APS. The average T scores (±SD) for PF and CF were 45.4 ± 9.2 and 48.6 ± 11.6, respectively; the average for PI was 3.0 ± 2.6. Approximately half of the patients (47%) endorsed at least mild impairment in PF (T score < 45). Mean PF, CF, and PI did not differ between diagnostic groups. Individuals who endorsed more impairment on one measure also tended to endorse more impairment on another (Pearson r = 0.43‐0.59). In the multivariate models, age, smoking, pain medications, and serotonergic medications were associated with impairment in at least one PRO domain. The Damage Index for APS was significantly correlated with both PF and CF.ConclusionIndividuals living with APS endorsed more impairment in PF (and potentially CF) than expected for the general population. The relationship between certain medications and PROs warrants further study, as does the longitudinal trajectory of these and other PROs.

Abstract Activation of innate immunity in the brain is a prominent feature of Alzheimer's disease (AD). The present study investigated the regulation of innate immunity by young serum in a transgenic AD mouse model. We found that young serum significantly reduced the number of neutrophils and microglial reactivity in the brains of APP/PS1 mice. Neutrophil depletion via Ly6G neutralizing antibodies mimicked the benefits of young serum on AD brain functions. Serum proteomic analysis of young serum revealed significant enrichment of the factors VEGF-A and CXCL1, which are crucial for neutrophil migration and chemotaxis, leukocyte migration, and cell chemotaxis. Intravenously injected VEGF-A reversed Aβ-induced decreases in Cdk5 and increases in CXCL1 in vitro and blocked neutrophil infiltration into the AD brain. Endothelial Cdk5 overexpression conferred an inhibitory effect on CXCL1 and neutrophil infiltration and thereby restored memory in APP/PS1 mice. Our data uncover a previously unknown link between blood-derived VEGF signaling and neutrophil infiltration and provide a rationale for targeting endothelial Cdk5 signaling as a potential therapeutic strategy for AD.

Recessive variants in GBA1 cause Gaucher disease, a prevalent form of lysosome storage disease. GBA1 encodes a lysosomal enzyme that hydrolyzes glucosylceramide (GlcCer) into glucose and ceramide. Its loss causes lysosomal dysfunction and increased levels of GlcCer. We generated a null allele of the Drosophila ortholog Gba1b by inserting the Gal4 using CRISPR-Cas9. Here, we show that Gba1b is expressed in glia but not in neurons. Glial-specific knockdown recapitulates the defects found in Gba1b mutants, and these can be rescued by glial expression of human GBA1 . We show that GlcCer is synthesized upon neuronal activity, and it is transported from neurons to glia through exosomes. Furthermore, we found that glial TGF-β/BMP induces the transfer of GlcCer from neurons to glia and that the White protein, an ABCG transporter, promotes GlcCer trafficking to glial lysosomes for degradation.

Abstract Background: Stem cell senescence and depletion are major causes of organismal aging and aging-related diseases. The NAD–SIRT1–PARP1 axis has garnered remarkable interest owing to its significant role in regulating stem cell senescence and organismal aging. Event though our recent study showes that PBX1 overexpression attenuates hair follicle-derived mesenchymal stem cell (HF-MSC) senescence and apoptosis by regulating ROS-mediated DNA damage via downregulation of PARP1 expression, suggesting PARP1 downregulation is a common manifestation of the roles of both PBX1 and SIRT1 in the attenuation of HF-MSC senescence, and implying a potential link between PBX1 and SIRT1 via PARP1. Methods: HF-MSCs overexpressing PBX1, overexpressing both PBX1 and PARP1, downregulating SIRT1, and overexpressing PBX1 and downregulating SIRT1 were generated, and biomarkers related to cell senescence, apoptosis, DNA damage, and repair were detected at the cellular and protein levels. Results: (1) PBX1 overexpression alleviated HF-MSC senescence and apoptosis accompanied by upregulation of SIRT1 expression, downregulation of PARP1 expression, and increased intracellular NAD and ATP levels. (2) SIRT1 knockdown or PARP1 overexpression enhanced cellular senescence and apoptosis, accompanied by increased ROS accumulation and DNA damage aggravation and decreased intracellular NAD and ATP levels. (3) PBX1 overexpression rescued HF-MSC senescence and apoptosis induced by SIRT1 knockdown or PARP1 overexpression. (4) Dual luciferase reporter showed PBX1 enhanced SIRT1 expression by activating SIRT1 promoter. Conclusions: Our results reveal that a positive interaction feedback loop exists between PBX1 and SIRT1, that PBX1 is the upstream of SIRT1. To the best of our knowledge we are the first to report that there is a PBX1-SIRT1-PARP1 axis and this axis plays a critical role in alleviation of HF-MSC senescence and apoptosis. The results provide a new perspective on the mechanism of stem cell senescence and age-related disease prevention and treatment.