Deoxysphingolipids (dSLs) are atypical sphingolipids that accumulate in several pathological settings, yet their impact on hematologic malignancies is poorly understood. Here, we investigate the pathways and mechanisms of deoxysphinganine (dSA) cytotoxicity in lymphoma cells and its potential as a therapeutic agent. dSA exhibited markedly greater cytotoxicity than canonical sphingoid bases in lymphoma cell lines, yet induced only cytostatic effects in normal human T cells, indicating a therapeutically exploitable window. Inhibition of ceramide synthase blocked the generation of deoxy(dihydro)ceramides, prevented mitochondrial depolarization, caspase activation, ER stress, and DNA damage, establishing CerS-dependent deoxysphingolipids as essential mediators of dSA-induced death. Mechanistically, dSA engaged a mitochondrial apoptotic pathway, with DNA damage occurring downstream of mitochondrial permeabilization and caspase activation, while PERK-driven ER stress occurred in parallel and was dispensable for cytotoxicity. Subtype-specific engagement of ER stress and DNA damage further suggests that dSL signaling is shaped by lineage context. The differential sensitivity between malignant lymphoid cells and normal T cells, together with the central role of CerS-derived deoxy(dihydro)ceramides, highlights deoxysphingolipid metabolism as a druggable vulnerability in lymphoma. These findings support further exploration of dSA-based strategies and targeted modulation of dSL synthesis as a novel therapeutic avenue for non-solid hematologic malignancies.
Whether the fecal metabolome differs according to intensive low-density lipoprotein cholesterol (LDL-C) target achievement among statin-treated patients is unclear. In this cross-sectional study, 124 statin-treated adults with chronic disease were stratified by fasting LDL-C into a target-achieved group (< 70 mg/dL, n = 52) and a target-not-achieved group (≥ 70 mg/dL, n = 72). Stool samples were profiled by untargeted ultra-high-performance liquid chromatography-tandem mass spectrometry, and multivariable models adjusted for age, sex, chronic kidney disease, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were used to identify metabolites independently associated with target achievement. Statin dose, treatment duration and glucose-lowering therapy were also compared between the groups. Paired 16S rRNA gene sequencing data available for a subset (n = 86) were used for integrative correlation and network analyses. Partial least-squares discriminant analysis showed separation between the two groups. Eight annotated metabolites-glutamine, glutamate, phenylalanine, N-acetyl-L-phenylalanine, L-methionine, N-acetyl-L-methionine, lysine, and N-methyl-D-aspartic acid, predominantly amino acids and their derivatives-were present at lower fecal levels in participants who achieved the LDL-C target. Metabolite set enrichment analysis implicated amino acid and nitrogen metabolism, and multiomics network analysis identified an Anaerotruncus-centered amino acid module with high degree centrality. In conclusion, LDL-C target achievement under statin therapy was associated with a coherent "low fecal amino acid" signature and an Anaerotruncus-linked microbe-metabolite hub. These findings suggest that intestinal nutrient handling and gut microbial amino acid metabolism may contribute to variability in LDL-C response, and they warrant prospective mechanistic evaluation.
Metabolic dysfunction-associated liver disease (MASLD) arises from the accumulation of triglycerides within the liver. MASLD can advance to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma. Monoacylglycerol acyltransferase 2 (MOGAT2) is essential for triglyceride synthesis and plays a significant role in regulating lipid metabolism. Here, we demonstrate the ability of a new human MOGAT 2 inhibitor, VB-85387, to inhibit the development of MASLD/MASH and further define its effects on the key metabolic pathways that progress MASH development. MASLD/MASH was induced using a methionine, choline-deficient diet (LMCD) or by streptozotocin treatment combined with high fat diet feeding (STAM-HFD). VB-85387 significantly mitigated the severity of MASLD and reduced signs of MASH in mice subjected to these two distinct diets. VB-85387-treated mice exhibited decreased fibrosis, evidenced by reduced hepatic triglyceride concentrations, hydroxyproline levels, and collagen deposition. NAS scores were consistently lower in VB-85387-treated mice across both models. VB-85387-treated mice showed induced PPARα signaling and reduced SREBP transcription, demonstrating a likely role for VB-85387 in regulating lipogenesis and fatty acid β-oxidation. STAM-HFD treated mice showed lower NF-κBp65 activation, which was associated with lower TNFα expression. IL-1β and IFNβ levels were also both reduced, suggesting VB-85387 can reduce pro-inflammatory pattern recognition receptor signaling. In addition, treatment suppressed IL-4/IL-6-dependent JAK activation. Overall, VB-85387 inhibited MASLD development by reducing liver triglyceride levels, fibrosis, and meta-inflammatory signaling. VB-85387 was as effective or superior to the MOGAT2 inhibitor phase I clinical trial drug BMS-963272 in reducing MASLD and fibrosis. VB-85387 has considerable potential for developing therapeutics targeting MASLD/MASH.
Glioma represents one of the most aggressive tumors in the central nervous system, with clinical management facing significant challenges including high recurrence rates and therapeutic resistance. Ferroptosis, an iron-dependent form of cell death, holds potential for glioma treatment, yet tumor cells frequently develop evasion mechanisms. This study elucidates the molecular mechanisms by which hypoxic microenvironment confers ferroptosis resistance in glioma cells, focusing on the pivotal role of the HIF-1α/SREBP1 signaling axis and its downstream effectors FASN and SCD1. Our experimental results demonstrate that hypoxic conditions significantly upregulate HIF-1α expression and confer resistance to RSL3-induced ferroptosis. Mechanistic studies reveal that HIF-1α promotes SREBP1 activation, which subsequently upregulates FASN and SCD1 expression to suppress lipid peroxidation.Furthermore, the HIF-1α-specific inhibitor PX-478 effectively reverses hypoxia-induced ferroptosis resistance and significantly enhances tumor cell sensitivity to ferroptosis inducers. In vivo experiments confirm the potent antitumor effects of PX-478 combined with RSL3. This study systematically elucidates the role of the HIF-1α-SREBP1-FASN/SCD1 signaling axis in ferroptosis regulation in glioma, providing important theoretical foundations and experimental support for developing HIF-1α-targeted ferroptosis therapies.
BACKGROUND:Lipoprotein(a) [Lp(a)] reflects inherited atherothrombotic risk, whereas the C-reactive protein-triglyceride-glucose index (CTI) integrates systemic inflammation, triglyceride-related lipid disturbance, and glucose-related metabolic stress. Their individual and joint association with angiographic coronary lesion burden in acute coronary syndrome (ACS) remain incompletely defined. We examined whether CTI complements Lp(a) in characterizing coronary lesion burden in ACS. MATERIALS AND METHODS:This retrospective, single-center study included 2,836 consecutive patients with ACS who underwent coronary angiography. Coronary lesion burden was assessed using continuous Gensini score, a high Gensini score, and multivessel disease (MVD). Multivariable regression, restricted cubic spline analyses, CTI-stratified analyses, incremental receiver operating characteristic analyses, and internally validated machine-learning analyses with SHAP interpretation were performed. RESULTS:Higher Lp(a) and CTI level were both associated with greater coronary lesion burden. Compared with Lp(a) <75 nmol/L, Lp(a) ≥175 nmol/L was associated with high Gensini score (OR, 1.51 [95% CI, 1.17-1.96]) and MVD (OR, 1.69 [95% CI, 1.27-2.26]). Each 1-SD increase in CTI was associated with high Gensini score (OR, 1.47 [95% CI, 1.35-1.60]) and MVD (OR, 1.18 [95% CI, 1.08-1.28]). Among inflammatory-lipid indices, CTI showed the most consistent associations and provided the largest numerical incremental discrimination beyond Lp(a). The associaton between ver high Lp(a) and coronary lesion burden was more pronounced at higher CTI levels, particular for MVD. Machine-learning analyses further supported the relevance of both CTI and Lp(a). CONCLUSIONS:In patients with ACS, higher Lp(a) and CTI level were associated with greater angiographic coronary lesion burden. CTI may complement Lp(a) by capturing inflammatory-metabolic status, supporting their joint assessment for more refined characterization of lesion-burden risk in ACS.
Lipoprotein metabolism is significantly different between mice and humans thus making it difficult to model disorders of human lipid metabolism in transgenic mice. Systemic lipoprotein metabolism is predominantly governed by hepatocytes, and mice with humanized livers display human-like lipid profiles. Here we report a highly efficient method to knock out genes in human hepatocytes while retaining their ability to repopulate immune deficient rodents. As proof-of-principle Fah deficient, immune compromised mice were repopulated with Apolipoprotein B (APOB) knockout human hepatocytes. Mice humanized with knockout cells recapitulated typical features of human hypobetalipoproteinemia. We conclude that at least some human lipid metabolism disorders can be modeled in liver chimeric mice using human knockout hepatocytes.
OBJECTIVES:Electrical stimulation (ES) during stereoelectroencephalography (SEEG) plays a key role in functional mapping in drug-resistant epilepsy. In pediatrics, protocols must account for neurodevelopmental stage. Moreover, pediatric data remain scarce and protocols vary substantially across centers. Such heterogeneity limits comparability between studies and hinders the evaluation of stimulation efficacy and its prognostic value for postoperative functional deficits. This work aims to provide expert consensus to harmonize SEEG stimulation protocols in the pediatric population. METHODS:A multidisciplinary task force of French experts from French pediatric epilepsy surgery centers reviewed existing guidelines and integrated current knowledge from developmental neurosciences. Through consensus, pediatric-specific parameters and practices were defined. RESULTS:The task force establishes practical guidance for stimulation frequency, intensity, and duration adapted to children, with emphasis on safety, feasibility, and neurodevelopmental context. Suggested protocols are designed to optimize both epileptogenic zone (EZ) delineation and functional mapping while enabling multicenter comparability. CONCLUSION:The proposed methods provide a framework for safe and effective pediatric SEEG stimulation. They aim to standardize clinical practice, improve presurgical evaluations, and support collaborative research in pediatric epilepsy surgery.
OBJECTIVES:To evaluate whether the deep learning model IGENet-TS, a time-domain convolutional neural network (CNN), can classify expert-selected EEG excerpts containing visible generalised epileptiform activity from genetic generalised epilepsy (GGE) versus normal healthy-control excerpts, and whether this selected-excerpt task generalises across centres. METHODS:We performed a retrospective selected-excerpt classification study of 455 routine 32-channel EEGs: 237 from Cuenca (107 GGE, 130 controls) for development and 218 from Bremen (106 GGE, 112 controls) for external testing. Each GGE recording contributed a 120-s resting-state segment containing at least one visible generalised discharge; controls contributed representative normal resting background. IGENet-TS analysed thirty non-overlapping 4-s windows per segment and averaged window probabilities to obtain a segment-derived label. RESULTS:Repeated 70:30 internal testing yielded sensitivity 98.15% (95% CI 97.52-98.78), specificity against healthy-control excerpts 97.95% (97.40-98.50), accuracy 98.04% (97.45-98.63), F1 98.05% (97.50-98.60) and AUC 0.98 (0.96-1.00). Externally, sensitivity was 97.02% (96.39-97.65), specificity against healthy-control excerpts 96.80% (96.19-97.41), accuracy 96.91% (96.24-97.58), F1 96.62% (95.97-97.27) and AUC 0.97 (0.95-0.99). DISCUSSION/CONCLUSION:The IGENet-TS model distinguished curated discharge-containing GGE excerpts from normal healthy-control excerpts with stable centre-separated performance. These results support technical feasibility for the selected-excerpt classification task, but do not validate unattended full-recording EEG interpretation or clinical workflow use.
Parkinson's disease (PD) can disrupt retinal, early cortical, oscillatory, and distributed visuoperceptual processing. This structured integrative review synthesized human evidence from pattern electroretinography (PERG), electroretinography (ERG), optical coherence tomography (OCT)-linked and conventional visual evoked potentials (VEPs), visual event-related potentials (ERPs), electroencephalography (EEG), steady-state visual evoked potentials (ssVEPs), and occipital transcranial magnetic stimulation-electroencephalography (TMS-EEG), with searches verified up to 18 July 2026. Findings were organized into four domains: 1) Retinal and retinocortical contributions: retinal dysfunction can delay or attenuate afferent input, yet concurrent retinal physiology is rarely measured; therefore VEP abnormalities cannot generally be assigned specifically to cortex. 2) Early visual encoding: prolonged pattern-reversal P100 latency is the most reproducible finding, including a pooled 6.04-ms delay across 20 case-control studies, whereas amplitude findings are inconsistent. 3) Oscillatory dynamics: PD-specific ssVEP evidence suggests altered contextual gain, but it derives from one small unreplicated study; gamma-band and task-EEG findings remain sparse and confound-sensitive. 4) Higher-order and network-level processing: visual ERPs, resting microstates, and occipital TMS-EEG indicate possible associations with hallucinations, cognition, and network connectivity, but current studies are cross-sectional or unreplicated. Overall, PD is characterized by multilevel visual-pathway dysfunction rather than a single cortex-specific biomarker. Ophthalmic status, retinal physiology, medication state, cognition, mood, sleep, and recording quality should be controlled before electrophysiological measures are used for localization, stratification, or prognosis.
Objective Persistent symptoms after SARS CoV-2 infection, often designated as "long COVID”, continue to be an ongoing health issue. Previously, we reported electromyography (EMG) and single fiber EMG (SFEMG) abnormalities in long COVID. This study aimed to assess the long-term neuromuscular manifestations of long COVID. Methods In this follow-up study, fifty patients (39 females and 11 males, mean age at baseline: 48.1 ± 9.3 years) with long COVID showing myopathic (EMG and/or abnormal SFEMG at diagnosis were re-evaluated. The disease duration was 1.2 ± 0.6 years at baseline. The mean follow-up interval was 1.38 years. Quantitative EMG (qEMG) was performed on the biceps brachii (BB), vastus medialis (VM), and tibialis anterior (TA), while SFEMG was performed on the extensor digitorum communis (EDC) and TA, at baseline and follow-up on the same muscles and side. EMG, SFEMG, and clinical scores were compared using paired parametric or nonparametric tests. Results Fatigue Assessment Scale (FAS) scores were unchanged (35.8 ± 7.7 vs 34.0 ± 9.4; p > 0.05). Motor unit potential (MUP) amplitudes and durations increased in BB, TA, and VM (p = 0.0001), while the frequency of polyphasic potentials remained unchanged (p > 0.05). SFEMG findings in TA and EDC were also unchanged (p > 0.05). At baseline, 78% of individuals showed myopathic qEMG and 54% abnormal SFEMG; at follow-up, 18% had myopathic qEMG, 56% abnormal SFEMG, and 40% showed normal EMG and SFEMG. Discussion Myopathic changes decreased over time; however, SFEMG abnormalities and clinical scores remained persistent. These findings suggest ongoing neuromuscular dysfunction, although other mechanisms may also contribute to persistent long COVID symptoms.
High-altitude polycythemia (HAPC) remains prevalent among Tibetans despite genetic adaptations, including EPAS1/HIF2A. Excessive erythrocytosis elevates blood viscosity and increases cardiopulmonary risk, yet erythrocyte metabolic and membrane-lipid mechanisms of HAPC and of therapeutic erythrocytapheresis (TE) remain incompletely defined. We conducted integrated metabolomic and lipidomic profiling of washed erythrocytes from HAPC patients and non-HAPC (NHAPC), and from patients with HAPC after TE. Relative to NHAPC, HAPC showed coordinated erythrocyte remodeling spanning amino acid and purine metabolism together with membrane phospholipid and lipid structure (unsaturation and chain length) changes. The disease contrast was multiomic, whereas the acute post-TE contrast was lipid-dominant, consistent with apheresis acting primarily through erythrocyte removal. K-means stratification revealed clinically meaningful TE response heterogeneity, but erythrocyte omics did not define stable responder subtypes. These findings point to erythrocyte membrane lipids as a persistent molecular feature of HAPC and of the acute TE response.
Clinically, acute kidney injury (AKI) is one of the most frequent complications of Naja atra (N. atra) envenomation, primarily attributed to snake venom phospholipase A2 (SVPLA2). Although the SVPLA2 inhibitor varespladib shows great therapeutic promise, the underlying mechanisms remain incompletely understood. Herein, we integrated multi-omics and molecular biology approaches to investigate the critical role of SVPLA2 in N. atra venom-induced AKI as evidenced by pharmacological inhibition with varespladib. Proteomic profiling identified HRAS and CCND1 as key mediators of SVPLA2-induced nephrotoxicity. Mechanistically, SVPLA2 disrupts lipid raft integrity, impairing HRAS palmitoylation-dependent plasma membrane localization and GTPase activity. This defect suppresses phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, causing apoptosis and cell cycle arrest in renal tubular epithelial cells, enforced activation of PI3K-AKT signaling effectively rescued cells from injury. Beyond direct cytotoxicity, SVPLA2 profoundly remodels the renal immune microenvironment. SVPLA2 enhances glycolysis by upregulating hexokinase 2 (HK2) while suppressing fatty acid oxidation through downregulation of carnitine palmitoyltransferase IA, thereby metabolically driving M1 polarization. This metabolic shift impairs macrophage efferocytosis and sustains inflammatory injury. HK2 knockdown reverses these effects in macrophages. Taken together, this study reveals a dual epithelial-immune mechanism by which SVPLA2 activity critically contributes to N. atra venom-induced AKI, as evidenced by pharmacological inhibition with varespladib. These findings highlight PI3K-AKT signaling and HK2 as potential therapeutic targets for N. atra-triggered AKI.
Pancreatic lipase is the major enzyme responsible for breaking down dietary triglycerides in the intestines. A previous report suggested that intestinal angiopoietin-like 4 (ANGPTL4) might serve as an endogenous inhibitor of pancreatic lipase and thus regulate fat absorption. As ANGPTL4 expression is reportedly induced by high-fat-diet feeding, we hypothesized that induction of ANGPTL4 by a high-fat diet would lead to an increased inhibition of pancreatic lipase, less breakdown of dietary triglycerides, and ultimately a reduced rate of postprandial triglyceride absorption. To test this hypothesis, we generated intestinal epithelial cell-specific ANGPTL4 knockout mice, fed them diets with varying levels of fat, and measured postprandial triglyceride absorption and intestinal triglyceride lipase activity. As we hypothesized, we found that chronic high-fat feeding reduced the rate of postprandial triglyceride absorption in mice. However, this regulation of postprandial triglyceride absorption appeared to be largely independent of ANGPTL4, as similar decreases were observed in both wild-type and intestinal epithelial cell-specific ANGPTL4 knockout mice. We conclude that there is mechanism by which chronic high-fat feeding reduces the rate of secretion of dietary triglycerides into the circulation, but that this mechanism does not require intestinal ANGPTL4.
Weight rebound remains the core challenge in the long-term management of obesity. Although current mechanistic understanding mainly focuses on physiological adaptations, the role of biomechanical factors remains largely unexplored. This study aims to investigate the contribution of lysyl oxidase (LOX)-mediated adipose tissue (AT) stiffening to the process of weight rebound. Our clinical analysis first established a correlation among obesity, elevated AT stiffness, and higher LOX levels. We then demonstrated that the weight rebound model mice displayed accelerated lipid accumulation and worsened metabolic functions. Importantly, AT stiffness dynamically increased during obesity, failed to normalize after weight loss due to persistent fibrosis, and reached its highest level during the regain stage. LOX expression followed an identical temporal pattern, showing a strong positive correlation with tissue stiffness. Mechanistically, mimicking a high-stiffness microenvironment in vitro promoted adipocyte differentiation and lipid accumulation in a LOX-dependent manner. Crucially, pharmacological inhibition of LOX in vivo significantly attenuated the rate of weight rebound. Our findings provide supportive evidence that LOX-mediated AT stiffening creates a pro-adipogenic mechanical microenvironment that contributes to accelerated weight rebound and metabolic deterioration, highlighting the LOX-stiffness axis as a potential therapeutic target for preventing weight rebound.
Cannabidiol (CBD), a non-psychoactive phytocannabinoid from Cannabis sativa, exhibits anti-inflammatory and antioxidant properties. We therefore hypothesized that CBD may modulate atherosclerosis development; however, preclinical evidence remains limited and sex-specific effects are poorly understood. Male and female apolipoprotein E-deficient (ApoE-/-) mice were fed a Western-type diet for 12 weeks and received either a CBD nanoemulsion (≈80 mg/kg/day) or vehicle via drinking water. Atherosclerosis was quantified by aortic plaque area, and lipidomic profiling together with aortic root proteomics were used to characterize CBD-induced metabolic changes. CBD treatment significantly reduced aortic plaque area in male but not female mice, without affecting body weight or standard serum lipid parameters. Untargeted lipidomics revealed sex-specific remodeling of the serum lipidome in males, including enrichment of ether-linked triacylglycerols, a class connected to ether-lipid metabolism; however, no lipid class emerged as a robust correlate of plaque burden. Proteomic analysis identified male-specific downregulation of mitochondrial oxidative and stress-related pathways, consistent with reduced vascular oxidative burden. In vitro, CBD attenuated oxLDL-induced oxidative stress and inflammatory activation in endothelial cells, supporting a direct vascular effect. CBD elicited no comparable molecular or plaque changes in females. Collectively, chronic CBD administration exerts a sex-dependent, anti-atherogenic effect in male ApoE-/- mice, associated with downregulation of mitochondrial oxidative metabolism and attenuation of endothelial oxidative and inflammatory activation, alongside remodeling of ether-linked lipid metabolism whose contribution to plaque protection remains to be established. These findings highlight the importance of incorporating sex-specific responses in future mechanistic and translational studies of CBD in atherosclerosis.
CREST superfamily members are a series of multi-transmembrane proteins conserved across a wide range of species. There are approximately 20 members in mammals. CREST superfamily members have been assigned various functions, including those of receptors, transporters, enzymes, and membrane fusion factors. Recent functional and structural analyses of CREST superfamily members have revealed that all members possess a structure resembling an enzymatic active site that catalyzes hydrolysis reactions. Furthermore, it is becoming increasingly clear that they interact with various membrane lipids and are involved in lipid metabolism. This review summarizes current knowledge of the structure and function of each CREST superfamily member and explores their potential as lipid-metabolizing enzymes.
Cardiolipin (CL) is a unique dimeric phospholipid essential for mitochondrial integrity and stress signaling. While most CL is present in the inner mitochondrial membranes (IMM), CL can be exposed to the outer mitochondrial membrane (OMM) under specific physiological and pathological conditions; however, the mechanisms regulating its metabolism at the OMM are poorly defined. Based on its striking structural similarity to cardiolipin deacylase 1 protein (Cld1p), a yeast CL hydrolase, we hypothesized that α/β-hydrolase domain-containing protein 4 (ABHD4) functions as a mammalian CL hydrolase. We identified two isoforms of mouse ABHD4 arising from alternative splicing: ABHD4-1 localizes to lipid droplets, whereas ABHD4-2 selectively targets mitochondria and is enriched in oxidative tissues. We demonstrate that ABHD4 selectively hydrolyzes CL in vitro, producing monolysocardiolipin and dilysocardiolipin. Site-directed mutagenesis identified catalytic serine residues as essential for enzymatic activity in ABHD4 and its Drosophila homolog, Pummelig. In contrast to Cld1p, which resides in the IMM, topological analyses indicate that ABHD4-2 and Pummelig-2 localize to the cytosolic face of the OMM, a conserved orientation that suggests a function distinct from classic acyl chain remodeling of CL. In brown adipocytes, ABHD4-2 overexpression reduces mitochondrial membrane potential in an activity-dependent manner. In silico analyses further reveal conservation of the catalytic triad across yeast, insect, and mammalian orthologs, supporting an evolutionarily conserved role for this enzyme family in CL metabolism. Together, these findings identify ABHD4-2 as an OMM-localized phospholipase with preferential CL hydrolase activity and define an isoform-specific pathway linking CL metabolism to mitochondrial stress responses.
Antiphospholipid syndrome (APS) is an autoimmune thrombophilia diagnosed by established clinical and serological criteria, distinguishing it from other causes of venous thromboembolism (VTE). This study investigated whether VTE is associated with plasma lipidome changes and whether an APS-specific lipid signature can be identified. We performed quantitative mass spectrometry-based lipidomics on plasma from healthy controls (n = 16), patients having VTE without APS (n = 16) and triple-positive APS patients (n = 17), profiling 224 lipid species across all major classes. Ceramide species (Cer 18:1;O2/16:0,/18:0,/20:0 and/26:0) and the Cer 18:0/Cer 24:0 ratio were elevated in both VTE groups relative to healthy controls, consistent with a shared thrombotic state. To identify APS-specific changes, LASSO logistic regression defined a minimal discriminating lipid panel. PE 40:5 (elevated 1.69-fold in APS), SM 43:2;O2 and PC O-34:2 (both reduced by 21%-24%) were combined into a parameter-free composite score that discriminated APS from VTE without APS with an AUC of 0.857. PE 40:5 has previously been associated with cardiovascular inflammatory activation, whilst reduction of PC O-34:2 may reflect increased conversion to platelet-activating factor and/or plasmalogen consumption under the pro-inflammatory conditions of APS. The co-occurrence of elevated ceramides and decreased SM 43:2;O2 in APS raises the hypothesis of enhanced acid sphingomyelinase activity driving sphingomyelin-to-ceramide conversion. Prospective validation in larger cohorts is warranted to assess its utility as a complement to serological APS diagnostics. In conclusion, despite the limited sample size, plasma lipidomics identifies a three-lipid composite score that discriminates APS from VTE without APS.
OBJECTIVES:F-waves are late motor responses traditionally elicited via supramaximal stimulation. However, submaximal stimulation may offer a more sensitive probe for assessing spinal motoneuron excitability. This study characterizes F-wave recruitment curves using graded submaximal stimulation across various intrinsic hand muscles. METHODS:F-waves were recorded from the abductor pollicis brevis (APB), abductor digiti minimi (ADM), and first dorsal interosseous (FDI) in 15 healthy subjects (ages 35-78). Four stimulus intensities were employed-10%, 20%, 30%, and 100% of the maximal compound muscle action potential (CMAP) amplitude-with 20 stimuli delivered per intensity. Analysis focused on F-wave frequency, amplitude, and matched F-wave/CMAP ratios (F-wave/CMAPm), where the F-wave and CMAP were recorded at identical stimulus intensities. RESULTS:Most parameters correlated positively with stimulus intensity; however, F-wave/CMAPm consistently decreased as intensity increased. The ADM exhibited a distinct recruitment profile, with F-wave persistence rising steeply at low intensities and reaching near-saturation at 30%, while showing no significant amplitude differences between submaximal levels. In contrast, the APB and FDI displayed more linear recruitment patterns for both persistence and amplitude. DISCUSSION:Submaximal stimulation reliably elicits F-waves and reveals muscle-specific excitability profiles. The ADM's high excitability suggests a more readily recruitable motoneuron pool. Furthermore, the inverse relationship between F-wave/CMAPm and stimulus intensity suggests the early recruitment of larger, highly excitable Type II motoneurons. This refined recruitment curve approach may provide valuable insights into the "split-hand" phenomenon observed in amyotrophic lateral sclerosis.
