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Translational insights into myocardial deformation and fibrosis in hypertrophic cardiomyopathy using diffusion tensor MRI
Get PDFBACKGROUND: Hypertrophic cardiomyopathy (HCM) diagnosis often occurs after myocardium thickening develops, delaying intervention. Cardiac diffusion tensor imaging (cDTI) detects microstructural myocardial remodeling, offering potential for improved risk stratification, especially in patients with preserved ejection fraction. OBJECTIVES: The objective of the study was to determine whether cDTI-derived fractional anisotropy (FA), mean diffusivity, and helix angle (HA) identify myocardial disarray and structural remodeling in HCM in patients and in mouse models. METHODS: Cardiovascular magnetic resonance imaging at 3T with cDTI (FA, mean diffusivity, and HA) and cine imaging was performed in 10 HCM patients with prior late gadolinium enhanced imaging and 10 healthy volunteers. In parallel, 6 myosin binding protein C3-knock-in and 6 wild-type mice (7-8 weeks) underwent cine-cardiovascular magnetic resonance imaging (9.4 T), ex vivo cDTI, scanning electron microscopy, and histology for microstructural, collagen area fraction and fibrosis analysis. RESULTS: HCM patients exhibited reduced FA vs controls (0.29 ± 0.03 vs 0.34 ± 0.02; P = 0.002), correlating with strain impairment (R2 = 0.67; P = 0.003) and reaching the lowest value in patients with late gadolinium enhancement (P = 0.02). In knock-in mice, the reduction in FA mirrored the human findings. However, additional alterations were observed, including elevated HA transmurality, significant systolic dysfunction, and a strong correlation between FA and interstitial fibrosis. CONCLUSIONS: FA may reflect critical aspects of myocardial remodeling in HCM, including fibrosis, and mechanical dysfunction, as demonstrated in both preclinical and clinical settings. Its ability to detect abnormalities even in patients with preserved ejection fraction supports its potential as a translational marker for risk stratification and guiding therapeutic intervention
Directed vascularization in bone regeneration requires bone marrow reconstitution
Get PDFBone has the unique ability to regenerate without scarring, yet the cellular dynamics and directional organization underlying this process, and how they are linked to marrow reconstitution, remain incompletely understood. To investigate these mechanisms, we developed a novel double osteotomy model in mice, involving transplantation of a 2-mm bone graft between genetically distinct fluorescent reporter lines (yellow fluorescent protein and red fluorescent protein). This approach enabled precise tracking of cellular migration and vascularization over 3, 7, and 14 d post-transplantation. Our findings revealed directed migration of host-derived proximal bone marrow cells into the graft, starting at day 3 and leading to complete host cell infiltration by day 14. CD146-positive blood vessels, mainly originating from the proximal host marrow, invaded the graft coinciding with graft marrow remodeling. Marrow disintegration within the graft occurred prior to vascular and cellular invasion, with subsequent reconstitution progressing from the proximal side. Flushing the graft marrow cavity prior to transplantation resulted in more extensive marrow niche formation by day 14 suggesting that marrow reconstitution can proceed more rapidly without the need for prior remodeling. This study introduces a new model to dissect the spatial and temporal coordination of cellular migration and vessel invasion during bone regeneration. Our results uncover the directional nature of healing and underscore the critical role of marrow reconstitution in guiding regenerative processes—insights that may inform surgical and biomaterial strategies to enhance bone repair
Distinct transcriptomic and epigenomic responses of mature oligodendrocytes during disease progression in a mouse model of multiple sclerosis
Get PDFMultiple sclerosis (MS) is a chronic autoimmune disease that targets mature oligodendrocytes (MOLs) and their myelin. MOLs are heterogeneous and can transition to immune-like states in MS. However, the dynamics of this process remain unclear. Here, we used single-cell multiome assay for transposase-accessible chromatin and RNA sequencing targeting oligodendroglia (OLG) from the experimental autoimmune encephalomyelitis (EAE) MS mouse model at multiple disease stages. We found that immune OLG states appear at early disease stages and persist to late stages, which can be consistent with epigenetic memory of previous neuroinflammation. Transcription factor activity suggested immunosuppression in OLG at early disease stages. Different MOLs exhibit differential responsiveness to EAE, with MOL2 exhibiting a stronger transcriptional immune response than MOL5/MOL6, and showed divergent responses at the epigenetic level during disease evolution. Our single-cell multiomic resource highlights dynamic and subtype-specific responses of OLG to EAE, which might be amenable to modulation in MS
Human gut microbiome researches over the last decade: current challenges and future directions
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Evaluating large language model workflows in clinical decision support for triage and referral and diagnosis
Get PDFAccurate medical decision-making is critical for both patients and clinicians. Patients often struggle to interpret their symptoms, determine their severity, and select the right specialist. Simultaneously, clinicians face challenges in integrating complex patient data to make timely, accurate diagnoses. Recent advances in large language models (LLMs) offer the potential to bridge this gap by supporting decision-making for both patients and healthcare providers. In this study, we benchmark multiple LLM versions and an LLM-based workflow incorporating retrieval-augmented generation (RAG) on a curated dataset of 2000 medical cases derived from the Medical Information Mart for Intensive Care database. Our findings show that these LLMs are capable of providing personalized insights into likely diagnoses, suggesting appropriate specialists, and assessing urgent care needs. These models may also support clinicians in refining diagnoses and decision-making, offering a promising approach to improving patient outcomes and streamlining healthcare delivery
Relevance of choroid plexus volumes in multiple sclerosis
Get PDFBACKGROUND: The choroid plexus (ChP) plays a pivotal role in inflammatory processes that occur in multiple sclerosis (MS). The enlargement of the ChP in relapsing-remitting multiple sclerosis (RRMS) is considered to be an indication of disease activity and has been associated with periventricular remyelination failure. This cross-sectional study aimed to identify the relationship between ChP and periventricular tissue damage which occurs in MS, and to elucidate the role of neuroinflammation in primary progressive multiple sclerosis (PPMS). METHODS: ChP volume was assessed by a novel deep learning segmentation method based on structural MRI data acquired from two centers. In total, 141 RRMS and 64 PPMS patients were included, along with 75 healthy control subjects. In addition, T1w/FLAIR ratios were calculated within periventricular bands to quantify microstructural tissue damage and to assess its relationship to ChP volume. RESULTS: When compared to healthy controls, ChP volumes were significantly increased in RRMS, but not in patients with PPMS. T1w/FLAIR ratios in the normal appearing white matter (NAWM) showing periventricular gradients were decreased in patients with multiple sclerosis when compared to healthy control subjects and lower T1w/FLAIR ratios radiating out from the lateral ventricles were found in patients with PPMS. A relationship between ChP volume and T1w/FLAIR ratio in NAWM was found within the inner periventricular bands in RRMS patients. A longer duration of disease was associated with larger ChP volumes only in RRMS patients. Enlarged ChP volumes were also significantly associated with reduced cortex volumes and increased lesion volumes in RRMS. CONCLUSIONS: Our analysis confirmed that the ChP was significantly enlarged in patients with RRMS, which was related to brain lesion volumes and which suggested a dynamic development as it was associated with disease duration. Plexus enlargement was further associated with periventricular demyelination or tissue damage assessed by T1w/FLAIR ratios in RRMS. Furthermore, we did not find an enlargement of the ChP in patients with PPMS, possibly indicating the reduced involvement of inflammatory processes in the progressive phase of MS. The association between enlarged ChP volumes and cortical atrophy in RRMS highlighted the vulnerability of structures close to the CSF
Intermuscular adipose tissue and lean muscle mass assessed with MRI in people with chronic back pain in Germany: a retrospective observational study
Get PDFBACKGROUND: Chronic back pain (CBP) affects over 80 million people in Europe, contributing to substantial healthcare costs and disability. Understanding modifiable risk factors, such as muscle composition, may aid in prevention and treatment. This study investigates the association between lean muscle mass (LMM) and intermuscular adipose tissue (InterMAT) with CBP using noninvasive whole-body magnetic resonance imaging (MRI). METHODS: This cross-sectional analysis used whole-body MRI data from 30,868 participants in the German National Cohort (NAKO), collected between 1 May 2014 and 1 September 2019. CBP was defined as back pain persisting >3 months. LMM and InterMAT were quantified via MRI-based muscle segmentations using a validated deep learning model. Associations were analyzed using mixed logistic regression, adjusting for age, sex, diabetes, dyslipidemia, osteoporosis, osteoarthritis, physical activity, and study site. FINDINGS: Among 27,518 participants (n = 12,193/44.3% female, n = 14,605/55.7% male; median age 49 years IQR 41; 57), 21.8% (n = 6003; n = 2999/50.0% female, n = 3004/50% male; median age 53 years IQR 46; 60) reported CBP, compared to 78.2% (n = 21,515; n = 9194/42.7% female, n = 12,321/57.3% male; median age 48 years IQR 39; 56) who did not. CBP prevalence was highest in those with low (5000 MET min/week) self-reported physical activity levels (24.6% (n = 10,892) and 22.0% (n = 3800), respectively) compared to moderate (500–5000 MET min/week) levels (19.4% (n = 12,826); p < 0.0001). Adjusted analyses revealed that a higher InterMAT (OR 1.22 per 2-unit Z-score; 95% CI 1.13–1.30; p < 0.0001) was associated with an increased likelihood of chronic back pain (CBP), whereas higher lean muscle mass (LMM) (OR 0.87 per 2-unit Z-score; 95% CI 0.79–0.95; p = 0.003) was associated with a reduced likelihood of CBP. Stratified analyses confirmed these associations persisted in individuals with osteoarthritis (OA-CBP LMM: 22.9 cm3/kg/m; InterMAT: 7.53% vs OA-No CBP LMM: 24.3 cm3/kg/m; InterMAT: 6.96% both p < 0.0001) and osteoporosis (OP-CBP LMM: 20.9 cm3/kg/m; InterMAT: 8.43% vs OP-No CBP LMM: 21.3 cm3/kg/m; InterMAT: 7.9% p = 0.16 and p = 0.0019). Higher pain intensity (Pain Intensity Numerical Rating Scale ≥4) correlated with lower LMM (2-unit Z-score deviation = OR, 0.63; 95% CI, 0.57–0.70; p < 0.0001) and higher InterMAT (2-unit Z-score deviation = OR, 1.22; 95% CI, 1.13–1.30; p < 0.0001), independent of physical activity, osteoporosis and osteoarthritis. INTERPRETATION: This large, population-based study highlights the associations of InterMAT and LMM with CBP. Given the limitations of the cross-sectional design, our findings can be seen as an impetus for further causal investigations within a broader, multidisciplinary framework to guide future research toward improved prevention and treatment
Metabolic and immune crosstalk in cardiovascular disease
No full textCardiovascular diseases including atherosclerosis and heart failure, arise from the intricate interplay of metabolic, immune, and neural dysregulation within vascular and cardiac tissues: This review focuses on integrating recent advances in metabolic and immune crosstalk of the cardiac vasculature that affects cardiometabolic health and disease progression. Coronary and lymphatic endothelial cells regulate cardiac metabolism, and their dysfunction is linked to cardiovascular diseases. Lymphatics maintain tissue homeostasis, including clearing metabolic waste, lipids, and immune cells, and their maladaptation in metabolic diseases worsens outcomes. Altered vascular endothelial metabolism in heart failure drives immune-mediated inflammation, fibrosis, and adverse cardiac remodeling. Concurrently, artery tertiary lymphoid organs formed in the adventitia of advanced atherosclerotic arteries, serve as pivotal neuroimmune hubs, coordinating local immunity through T and B cell activation and neurovascular signaling via artery-brain circuits. T cells within plaques and artery tertiary lymphoid organs undergo clonal expansion as a result of peripheral tolerance breakdown, with proinflammatory CD4(+) and CD8(+) subsets amplifying atherosclerosis, effects further shaped by systemic immune activation. Therapeutic strategies targeting endothelial cell metabolism, lymphatic dysfunction, neuroimmune crosstalk, and T cell plasticity hold promise for integrated cardiovascular disease management
Application of IVDr NMR spectroscopy to stratify Parkinson's disease with absolute quantitation of blood serum metabolites and lipoproteins
Get PDFThe challenge of early detection and stratification in Parkinson’s disease (PD) is urgent due to the current emergence of mechanism-based disease-modifying treatments. In here, metabolomic and lipidomic parameters obtained by a standardized and targeted in vitro diagnostic research (IVDr) platform have a significant potential to address therapy-related questions and generate improved biomarker panels. Our study aimed to use IVDr nuclear magnetic resonance (NMR) spectroscopy to quantify metabolites and lipoproteins in PD blood serum from different cohorts to stratify metabolically driven subtypes of idiopathic and genetic PD. Serum aliquots from three neurodegeneration biobank cohorts (287 samples in total, including 62 PD patient samples with GBA mutation, 98/43 PD patient samples of early/late stages of disease duration, 20 PD samples from patients with mutations in recessive PD genes and some smaller subgroups of mitochondrial and double mutation cases) were prepared and analyzed with IVDr NMR spectroscopy, covering 39 blood serum metabolites and 112 lipoprotein parameters. Uni- and multivariate statistics were used to identify metabolism-driven changes under consideration of typical confounders such as age, sex and disease duration and set into context with clinical biomarkers such as CSF concentrations of alpha-synuclein, neurofilament light chain, and tau protein. Based on the different PD subgroups we performed a total of eight different comparisons. Highlights from these comparisons include increased citrate and dimethylglycine with a decrease of creatinine and methionine in healthy controls and early PD group compared to GBA, PD late and recessive PD. We furthermore identified decreased HDL-3 free cholesterol in genetic PD cases compared to sporadic subject samples (sum of the PD early and PD late groups). Considering medication, we found that the levodopa equivalent daily dose (LEDD) is mostly positively correlated with tyrosine and citrate in sporadic PD compared to pyruvate and phenylalanine in genetic PD. Cerebrospinal fluid levels of alpha-synuclein were negatively correlated with alanine. Further metabolites and lipoproteins with discriminatory power for double mutation PD cases involved ornithine, 2-aminobutyrate and 2-hydroxybutyrate as well as for mitochondrial phenotypes via LDL phospholipid, apolipoprotein and cholesterol subfractions. Quantitative IVDr NMR serum spectroscopy is able to stratify PD patient samples of different etiology and can contribute to a wider understanding of the underlying metabolism-driven alterations e.g. in energy, amino acid, and lipoprotein metabolism. Though our overall cohort was large, major confounders such as age, sex and medication have a strong impact. That is why absolute quantification and detailed patient knowledge about metabolic confounders, is a premise for future translation of NMR serum spectroscopy to routine PD diagnostics