51886 research outputs found
Sort by
Left atrial reservoir strain as a predictor of cardiac dysfunction in a murine model of pressure overload
No full textAim: Left atrial (LA) strain is emerging as a valuable metric for evaluating cardiac function, particularly under pathological conditions such as pressure overload. This preclinical study investigates the predictive utility of LA strain on cardiac function in a murine model subjected to pressure overload, mimicking pathologies such as hypertension and aortic stenosis.
Methods: High-resolution ultrasound was performed in a cohort of mice (n = 16) to evaluate left atrial and left ventricular function at baseline and 2 and 4 weeks after transverse aortic constriction (TAC). Acute adaptations in cardiac function were assessed in a subgroup of mice (n = 10) with 3 days post-TAC imaging.
Results: We report an increase in LA max volume from 11.0 ± 4.3 μL at baseline to 26.7 ± 16.7 μL at 4 weeks (p = 0.002) and a decrease in LA reservoir strain from 20.8 ± 5.4% at baseline to 10.2 ± 6.9% at 4 weeks (p = 0.001). In the acute phase, LA strain dysfunction was present at 3 days (p < 0.001), prior to alterations in LA volume (p = 0.856) or left ventricular (LV) ejection fraction (p = 0.120). LA reservoir strain correlated with key indicators of cardiac performance including left ventricular (LV) ejection fraction (r = 0.541, p < 0.001), longitudinal strain (r = -0.637, p < 0.001), and strain rate (r = 0.378, p = 0.007). Furthermore, markers of atrial structure and function including LA max volume (AUC = 0.813, p = 0.003), ejection fraction (AUC = 0.853, p = 0.001), and strain (AUC = 0.884, p < 0.001) all predicted LV dysfunction.
Conclusion: LA strain and function assessments provide a reliable, non-invasive method for the early detection and prediction of cardiac dysfunction in a model of pressure overload
Pathway Enrichment of Longitudinal AD Endophenotypes Identifies Potential Therapeutic Targets for Modifying Disease Trajectory
No full textBackground:
Alzheimer’s disease (AD) is characterized by longitudinal changes of biomarker endophenotypes over the course of the disease prodrome, onset, and progression. The genetic pathways that influence these heterogenous changes in longitudinal endophenotype trajectories may provide insight into disease mechanisms and represent potential therapeutic targets.
Methods:
Longitudinal endophenotypes from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were selected: amyloid‐β (Amyloid PET and CSF), total tau and phosphorylated tau (CSF), glucose metabolism (FDG PET), neurodegeneration (atrophy on MRI), and cognition (composite scores for memory and executive functioning). Genome‐wide association analysis for the selected longitudinal endophenotypes was performed using Linear Mixed Modelling (LMM; LME4 R package), with (Time x Subject) as a random effect and age as the time variable. Gene‐based association analysis was performed using MAGMA on SNP P values from the LMM. The SNP to gene assignment was performed in two steps to select SNPs with a functional relation to each target gene: SNPs within gene transcription start and end positions, and SNPs that have significant eQTLs in brain tissue from the MetaBrain eQTL project. Gene‐based analysis results were then processed for gene‐set enrichment with MAGMA and the C2 curated gene set collection from the Gene Set Enrichment Analysis (GSEA) Molecular Signatures Database (MSigDB).
Results:
Pathway enrichment analysis identified 19 pathways (Figure 1) as significantly associated with longitudinal trajectories of AD endophenotypes. These pathways fall into six groups, with each pathway group having stronger association with different types of endophenotypes. Immune and cytoskeletal pathways largely associated with changes in amyloid trajectory. Metabolic pathways associated strongly with changes in amyloid and tau trajectories. Glycosylation pathways were associated with changes in brain atrophy. Pathways related to cell and neuronal signaling associated with changes in cognition, tau, and amyloid trajectories. Cell growth and survival was associated with changes in neurodegeneration trajectory (structural atrophy and hypometabolism).
Conclusions:
Pathway enrichment analysis of genetic variation associated with longitudinal changes of AD endophenotypes identified pathways that uniquely associate with trajectories of key AD biomarkers and cognition. These pathways may provide insight into AD pathological mechanisms and constitute new potential therapeutic targets to modify disease trajectory
A DAT1 gene and APOE ε4 interaction is associated with apathy and structural brain changes in Alzheimer’s Disease
No full textBackground:
Apathy in patients with Alzheimer’s disease (AD) is associated with significant morbidity. We examined whether interactions between genetic variants related to neurotransmitter systems and regional brain atrophy are associated with apathy in patients with mild cognitive impairment (MCI) and AD.
Method:
For 1162 participants in the Alzheimer’s Disease Neuroimaging Initiative, including those with AD, MCI and cognitively normal individuals, a partial least squares correspondence analysis (PLS‐CA) modeled interactions between single nucleotide polymorphisms (SNPs), structural whole‐brain imaging variables, and apathy.
Result:
An interaction between apathy, the possession of an APOE (apolipoprotein E) ε4 allele combined with minor homozygosity for the DAT1 (dopamine transporter 1) gene, and brain atrophy.
Conclusion:
The results point to an association of a dopaminergic genetic marker and apathy in AD and may inform future design of clinical trials of apathy, as well as new treatment targets
Characterization of the A1527G variant of ABCA7 in an animal model for late‐onset Alzheimer’s disease
No full textBackground:
Genome‐wide association studies (GWAS) identified the ATP binding cassette subfamily A member 7 (ABCA7) gene as increasing risk for Alzheimer’s disease (AD). ABC proteins transport various molecules across extra and intra‐cellular membranes. ABCA7 is part of the ABC1 subfamily and is expressed in brain cells including neurons, astrocytes, microglia, endothelial cells and pericytes. However, the mechanisms by which variations in ABCA7 increase risk for AD are not known.
Method:
The IU/JAX/PITT MODEL‐AD Center identified the A1527G variant in ABCA7 (ABCA7*A1527G) as a putative LOAD risk factor. CRISPR/CAS9 was first used to introduce Abca7*A1527G variant to B6.APOE4.Trem2*R47H (LOAD1) mice to assess the transcriptional profiling on brain hemispheres from different ages. The Abca7*A1527G was then incorporated into B6.APOE4.Trem2*R47H.hAb (LOAD2) mice to further evaluate its contribution to LOAD. Female and male LOAD2.Abca7*A1527G and LOAD2 mice were characterized at 4, 12, and 24 months using the following phenotyping pipeline: behavior, PET/CT, multi‐omics, fluid biomarkers, electrophysiology, cognition, and neuropathology.
Result:
Brain transcriptional profiling showed that Abca7*A1527G induced changes in gene expression that are similar to some of those observed in human AD (e.g., granulocyte/neutrophil migration, and insulin receptor signaling). LOAD2.Abca7*A1527G showed no aging cognitive deficit but did show significant sex‐ and region‐dependent increases in brain glycolysis paralleled by reduced tissue perfusion yielding progressive age‐related uncoupled phenotypes between 4‐12 and 4‐24 months. While multi‐resolution consensus clustering of regional covariance matrices revealed an increase in cluster number and organization in LOAD2.Abca7*A1527G over LOAD2 for both sexes at 4 months, the cluster number and complexity were reduced by 24 months. Importantly, LOAD2.Abca7*A1527G, but not LOAD2, displayed a similar age‐dependent reduction in cluster number for both sexes. Consistent with the uncoupled phenotype, IL6, IL10, and TNFα were elevated in plasma with genotype, but were not age dependent. Conversely, brain levels of IL4, IL12, TNFα, and CXCL1 were decreased, whereas IL2 and IL10 were elevated in LOAD2.Abca7*A1527G relative to LOAD2. Lastly, assessment of plasma levels of Ab40‐Ab42 revealed an age‐dependent increase in both genotypes.
Conclusion:
Data collected to date support a model whereby variations in ABCA7 exert risk for AD through interactions between cerebrovasculature, microglia, and peripheral immune cells
A Second Look: Retrospective Identification of Thrombotic Microangiopathy in Pediatric Stem Cell Transplant Patients With Veno‐Occlusive Disease
No full textBackground: Veno-occlusive disease (VOD) and transplant-associated thrombotic microangiopathy (TA-TMA) remain a diagnostic and therapeutic challenge for patients undergoing hematopoietic stem cell transplant (HSCT). Both VOD and TA-TMA share an underlying etiology of microvascular endothelial damage. Potential under-recognition of TA-TMA in the context of VOD leaves HSCT recipients vulnerable to additional endothelial damage, and risk of end-organ failure.
Methods: A cohort of 44 pediatric HSCT recipients diagnosed with VOD between 2010and 2019 were retrospectively evaluated for the development of TA-TMA within 1 week before and 2 months after VOD diagnosis. Patients were classified into three categories: sole diagnosis of VOD (VOD), concurrent clinical diagnosis of TA-TMA during the VOD course (VOD+TA-TMA), and patients with VOD who on retrospective review satisfied criteria for diagnosis of TA-TMA (VOD+rTA-TMA).
Results: A total of 42 patients were evaluated and 50% of the patients were diagnosed clinically with TA-TMA (5) or where retrospectively identified to have TA-TMA (16). There was no difference in the severity of the course of VOD between the three groups based on need for intubation, dialysis, and pediatric intensive care unit (PICU) care. Patients in the VOD only group had the highest survival at 1 year (66.7%, n = 14) compared with patients in the VOD+TA-TMA group (60%, n = 3) and VOD+rTA-TMA group (62.5%, n = 10), p = 0.9582.
Conclusion: Better understanding of the association between these two endotheliopathies is essential to improve diagnosis, treatment, and prevention of potentially fatal adverse outcomes in transplant recipients
Utilization of Cannabidiol in Post-Organ-Transplant Care
No full textCannabidiol (CBD) is one of the major phytochemical constituents of cannabis, Cannabis sativa, widely recognized for its therapeutic potential. While cannabis has been utilized for medicinal purposes since ancient times, its psychoactive and addictive properties led to its prohibition in 1937, with only the medical use being reauthorized in 1998. Unlike tetrahydrocannabinol (THC), CBD lacks psychoactive and addictive properties, yet the name that suggests its association with cannabis has significantly contributed to its public visibility. CBD exhibits diverse pharmacological properties, most notably anti-inflammatory effects. Additionally, it interacts with key drug-metabolizing enzyme families, including cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT), which mediate phase I and phase II metabolism, respectively. By binding to these enzymes, CBD can inhibit the metabolism of co-administered drugs, which can potentially enhance their toxicity or therapeutic effects. Mild to moderate adverse events associated with CBD use have been reported. Advances in chemical formulation techniques have recently enabled strategies to minimize these effects. This review provides an overview of CBD, covering its historical background, recent clinical trials, adverse event profiles, and interactions with molecular targets such as receptors, channels, and enzymes. We particularly emphasize the mechanisms underlying its anti-inflammatory effects and interaction with drugs relevant to organ transplantation. Finally, we explore recent progress in the chemical formulation of CBD in order to enhance its bioavailability, which will enable decreasing the dose to use and increase its safety and efficacy
Reproducibility of Centiloid Values in Real‐World Amyloid PET Data: Comparison of the Imaging Dementia‐Evidence for Amyloid Scanning (IDEAS) to Four Large Research Datasets
No full textBackground:
The Centiloid framework was developed to harmonize amyloid‐PET quantification across radiotracers and processing pipelines to facilitate data sharing and merging; it is now widely used across research and clinical trials. As we just completed the quantification of 10,361 amyloid‐PET scans from the largest “real‐world” study of amyloid‐PET (IDEAS) and are about to release the data, we aimed to compare the distribution of IDEAS Centiloid values with other available datasets.
Method:
In IDEAS, amyloid scans were acquired across 343 facilities and centrally processed at UCSF using a PET‐only pipeline. We also had access to PET data from our own UCSF Alzheimer’s Disease Research Center and the LEADS study. Using the GAAIN platform, we identified two other cohorts with available Centiloids: ADNI and MCSA. For each cohort, we collected Centiloids, demographic, and basic clinical data. Gaussian mixture models (GMM) were fitted to Centiloid values for each cohort, and data‐driven Centiloid cutoffs were calculated as mean + 2SD of the first Gaussian. Finally, we compared Centiloids to PET visual reads (when available) and determined the Centiloid cutoff value maximizing correspondence between visual read and binarized Centiloids based on Cohen’s kappa.
Result:
The 5 cohorts were heterogeneous in terms of sample characteristics and radiotracers (Table 1). In all cohorts, a two‐Gaussian model was considered the best fit for the data based on the integrated completed likelihood criteria (Figure 1). The first Gaussian peaks were close to zero, with mild variability across studies (from ‐5 in IDEAS to 10 CL in MSCA). The second peak was more heterogeneous across cohorts (from 67 to 102 CL) with a rightward shift in cohorts enriched with clinically impaired patients. Mean Centiloid values in visually negative and positive scans generally matched well with results derived from GMM (Figure 2). Across all cohorts, GMM‐based Centiloid cutoffs tended to be slightly lower (18‐26) compared to those based on visual inspection (25‐31).
Conclusion:
The availability of Centiloids across cohorts enables a direct comparison of amyloid‐PET results in otherwise different studies. Despite some variability across cohorts and analysis methods, Centiloid cutoffs align well with thresholds from the existing literature
Claudin-4 Stabilizes the Genome via Nuclear and Cell-Cycle Remodeling to Support Ovarian Cancer Cell Survival
No full textHigh-grade serous ovarian carcinoma is marked by chromosomal instability, which can serve to promote disease progression and allow cancer to evade therapeutic insults. The report highlights the role of claudin-4 in regulating genomic instability and proposes a novel therapeutic approach to exploit claudin-4-mediated regulation
Experiences of sexual and reproductive health screening and counseling in the clinical setting among adolescents and young adults with rheumatic disease
No full textBackground: Our objective was to describe differences among adolescents and young adults (AYAs) with rheumatic disease using teratogens compared to non-users in receipt of sexual and reproductive health (SRH) counseling, teratogenicity knowledge, perceived importance of SRH topics, and preferences around counseling.
Methods: AYAs ages 14-23 years and assigned female at birth were recruited from pediatric rheumatology clinics at a Midwest tertiary care program. Participants completed a one-time online survey assessing SRH.
Results: One-hundred eight participants completed the survey, representing a range of rheumatic diseases. 24% reported ever having sex. 36% used a teratogen. Rates of screening and counseling regarding SRH topics were low. Notably, pregnancy prevention and emergency contraception (EC) counseling by rheumatologists were uncommon and not associated with teratogen use or sexual activity. Among AYAs on teratogens, only half reported screening for sexual activity or counseling on teratogenicity or pregnancy prevention. Gaps in pregnancy prevention and EC counseling remained even when accounting for counseling by other providers. Knowledge of medication teratogenicity was also low. AYAs reported SRH topics of high importance, and many reported recent concerns. They preferred to receive information from their rheumatologist, and most agreed it is important to talk to their rheumatologist regarding these topics.
Conclusions: AYAs with rheumatic disease report low levels of SRH screening and counseling by their rheumatologist yet report these topics are important and want to discuss them. Gaps in teratogenicity knowledge were identified. This study identifies a need for improved communication with AYAs regarding their SRH
Widespread release of translational repression across Plasmodium’s host-to-vector transmission event
No full textMalaria parasites must respond quickly to environmental changes, including during their transmission between mammalian and mosquito hosts. Therefore, female gametocytes proactively produce and translationally repress mRNAs that encode essential proteins that the zygote requires to establish a new infection. While the release of translational repression of individual mRNAs has been documented, the details of the global release of translational repression have not. Moreover, changes in the spatial arrangement and composition of the DOZI/CITH/ALBA complex that contribute to translational control are also not known. Therefore, we have conducted the first quantitative, comparative transcriptomics and DIA-MS proteomics of Plasmodium parasites across the host-to-vector transmission event to document the global release of translational repression. Using female gametocytes and zygotes of P. yoelii, we found that ~200 transcripts are released for translation soon after fertilization, including those encoding essential functions. Moreover, we identified that many transcripts remain repressed beyond this point. TurboID-based proximity proteomics of the DOZI/CITH/ALBA regulatory complex revealed substantial spatial and/or compositional changes across this transmission event, which are consistent with recent, paradigm-shifting models of translational control. Together, these data provide a model for the essential translational control mechanisms that promote Plasmodium's efficient transmission from mammalian host to mosquito vector