Distinct Pathologies Research Articles

Distinct tau pathologies in the nucleus basalis of Meynert between early-onset and late-onset Alzheimer's disease patients revealed by positron emission tomography.

Tau accumulation in the nucleus basalis of Meynert (nbM) has been documented in Alzheimer's disease (AD), but its relationship to neuropathological changes in other brain regions and cognitive deficits remains unclear, particularly between early-onset AD (EOAD) and late-onset AD (LOAD). To evaluate tau accumulation patterns in the nbM and other brain regions in EOAD and LOAD using 18F-florzolotau PET and examine correlations with cognitive function. Thirty-eight amyloid-positive AD patients (15 EOAD, 23 LOAD) and 46 healthy controls underwent 18F-florzolotau PET. Tau levels were quantified in the nbM and Braak-staging regions. Postmortem brain samples were examined to assess 18F-florzolotau binding to tau deposits. EOAD showed a higher overall tau burden, including in the nbM, compared with LOAD. However, nbM tau levels correlated more strongly with cognitive decline in LOAD than EOAD. The relationship between nbM tau and neocortical tau differed between EOAD and LOAD. Histopathology revealed abundant 18F-florzolotau labeling of neurofibrillary tangles (NFTs) and ghost tangles in AD nbM samples. This study provides the first in vivo PET evidence of differential nbM tau pathology between EOAD and LOAD, with higher accumulation but weaker correlation to cognition in EOAD. The distinct relationships between nbM and cortical tau in EOAD and LOAD suggest divergent pathological trajectories. 18F-florzolotau PET successfully visualized NFTs and extracellular ghost tangles in the nbM across AD stages. These findings highlight the importance of considering age of onset when evaluating tau pathology and its clinical correlates in AD.

Case report: Polymorphous low-grade neuroepithelial tumor of the young and supratentorial ependymoma diagnosed in an adult male

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a rare central nervous system (CNS) pathology predominantly observed in the pediatric population. Ependymomas also exhibit a peak incidence in early childhood, with rare presentations after early adulthood. In this report, we describe a rare case of a 41-year-old man diagnosed sequentially with a polymorphous low-grade neuroepithelial tumor of the young, followed by a supratentorial ependymoma within a year. He underwent tumor resection for both tumors, as well as adjuvant radiation therapy for the ependymoma. Despite these interventions, he ultimately succumbed to tumor progression and postoperative complications. Currently, no genetic syndromes are known to link these two primary CNS tumors. Two commonalities at the chromosomal and cellular level include histone gene H3F3A mutations and positive glial fibrillary acidic protein staining on immunohistochemistry. To the best of our knowledge, this unique dual pathology has not been previously described in the literature, making this case an avenue for further investigation and research into connections between these two distinct CNS pathologies.

Chronic Overlapping Pain Conditions and Nociplastic Pain

Chronic Overlapping Pain Conditions (COPCs) are a subset of chronic pain conditions commonly comorbid with one another and more prevalent in women and assigned female at birth (AFAB) individuals. Pain experience in these conditions may better fit with a new mechanistic pain descriptor, nociplastic pain, and nociplastic pain may represent a shared underlying factor among COPCs. We applied GenomicSEM common-factor genome wide association study (GWAS) and multivariate transcriptome-wide association (TWAS) analyses to existing GWAS output for six COPCs in order to find genetic variation associated with nociplastic pain, followed by genetic correlation (linkage-disequilibrium score regression), gene-set and tissue enrichment analyses. We found 24 independent single nucleotide polymorphisms (SNPs), and 127 unique genes significantly associated with nociplastic pain, and showed nociplastic pain to be a polygenic trait with significant SNP-heritability. We found significant genetic overlap between multisite chronic pain and nociplastic pain, and to a smaller extent with rheumatoid arthritis and a neuropathic pain phenotype. Tissue enrichment analyses highlighted cardiac and thyroid tissue, and gene set enrichment analyses emphasized potential shared mechanisms in cognitive, personality, and metabolic traits and nociplastic pain along with distinct pathology in migraine and headache. We use a well-powered network approach to investigate nociplastic pain using existing COPC GWAS output, and show nociplastic pain to be a complex, heritable trait, in addition to contributing to understanding of potential mechanisms in development of nociplastic pain.

ValveVision AI - a multimodal language model for qualitative reporting of the aortic valve in echocardiography

Abstract Background The precise assessment of the aortic valve via echocardiography is critical for early detection and management of aortic valve diseases. Until recently, previous studies have examined machine learning models to estimate individual measurements and severity of aortic stenosis (AS) from echocardiographic images. These image processing algorithms, while precise in their narrow focus, fall short in mirroring the holistic and interconnected clinical judgment typical of human echocardiographers in producing a qualitative report. Large language models (LLMs), particularly image-to-text multi-modal LLMs, are a fundamental advance in the field of deep learning with implications for a host of applications in medical imaging. They promise to encapsulate not just discrete data points typical in traditional machine learning, but also the complex contextual interrelations in clinical diagnosis. Methods In this study, a large-scale heterogeneous database of echocardiographic images containing over 90,681 studies with textual descriptors of the aortic valve was used to train a single, image-to-text multimodal LLM called ValveVision AI. The ground truth textual summaries were drafted by level III echocardiographers in a clinical setting between 2015-2020. BLEU and ROUGE score was calculated. The models were retrospectively assessed on a holdout dataset. Reviewing physicians compared the generated summary to the ground truth and binarily agreed or rejected it. Receiver Operating Characteristics (ROC) for distinct pathologies were also assessed (Figure I). Results ValveVision AI performed with a BLEU score of 0.45 and a ROUGE score of 0.49. The performance of the model in reporting on classification of moderate/severe vs none/mild AS in concordance with the validation protocol described above achieved a specificity of 91.98% and a sensitivity of 83.89%, along with more precise qualitative description. Qualitatively, the model exhibited the capability of zero-shot learning in certain instances, however, this result remains an area of exploration. Conclusion This study represents to our knowledge, the first attempt at an image-representation to text-tokenizer deep learning model architecture to mimic the thought and subtlety of echocardiographic qualitative analysis of the aortic valve. The results suggest that this multimodal LLM has sufficient accuracy to create a preliminary textual summary of the aortic valve that, if paired with a point of care ultrasound (POCUS) device in a primary care setting, may facilitate case triage, increase efficiency, and determine a more precise care pathway for patients.

Cluster-Based White Matter Signatures and the Risk of Dementia, Stroke, and Mortality in Community-Dwelling Adults.

Markers of white matter (WM) injury on brain MRI are important indicators of brain health. Different patterns of WM atrophy, WM hyperintensities (WMHs), and microstructural integrity could reflect distinct pathologies and disease risks, but large-scale imaging studies investigating WM signatures are lacking. This study aims to identify distinct WM signatures using brain MRI in community-dwelling adults, determine underlying risk factor profiles, and assess risks of dementia, stroke, and mortality associated with each signature. Between 2005 and 2016, we measured WMH volume, WM volume, fractional anisotropy (FA), and mean diffusivity (MD) using automated pipelines on structural and diffusion MRI in community-dwelling adults aged older than 45 years of the Rotterdam study. Continuous surveillance was conducted for dementia, stroke, and mortality. We applied hierarchical clustering to identify separate WM injury clusters and Cox proportional hazard models to determine their risk of dementia, stroke, and mortality. We included 5,279 participants (mean age 65.0 years, 56.0% women) and identified 4 distinct data-driven WM signatures: (1) above-average microstructural integrity and little WM atrophy and WMH; (2) above-average microstructural integrity and little WMH, but substantial WM atrophy; (3) poor microstructural integrity and substantial WMH, but little WM atrophy; and (4) poor microstructural integrity with substantial WMH and WM atrophy. Prevalence of cardiovascular risk factors, lacunes, and cerebral microbleeds was higher in clusters 3 and 4 than in clusters 1 and 2. During a median 10.7 years of follow-up, 291 participants developed dementia, 220 had a stroke, and 910 died. Compared with cluster 1, dementia risk was increased for all clusters, notably cluster 3 (hazard ratio [HR] 3.06, 95% CI 2.12-4.42), followed by cluster 4 (HR 2.31, 95% CI 1.58-3.37) and cluster 2 (HR 1.67, 95% CI 1.17-2.38). Compared with cluster 1, risk of stroke was higher only for clusters 3 (HR 1.55, 95% CI 1.02-2.37) and 4 (HR 1.94, 95% CI 1.30-2.89), whereas mortality risk was increased in all clusters (cluster 2: HR 1.27, 95% CI 1.06-1.53, cluster 3: HR 1.65, 95% CI 1.35-2.03, cluster 4: HR 1.76, 95% CI 1.44-2.15), compared with cluster 1. Models including clusters instead of an individual imaging marker showed a superior goodness of fit for dementia and mortality, but not for stroke. Clustering can derive WM signatures that are differentially associated with dementia, stroke, and mortality risk. Future research should incorporate spatial information of imaging markers.

External Validation of SpineNetV2 on a Comprehensive Set of Radiological Features for Grading Lumbosacral Disc Pathologies

BackgroundIn recent years, the integration of Artificial Intelligence (AI) models has revolutionized the diagnosis of Low Back Pain (LBP) and associated disc pathologies. Among these, SpineNetV2 stands out as a state-of-the-art, open-access model for detecting and grading various intervertebral disc pathologies. However, ensuring the reliability and applicability of AI models like SpineNetV2 is paramount. Rigorous validation is essential to guarantee their robustness and generalizability across diverse patient cohorts and imaging protocols. MethodsWe conducted a retrospective analysis of MRI images of 1747 lumbosacral intervertebral discs (IVDs) from 353 patients (mean age, 54 ± 15.4 years, 44.5% female) with various spinal disorders, collected between September 2021 and February 2023 at X-Ray Service s.r.l. The SpineNetV2 system was used to grade 11 distinct lumbosacral disc pathologies, including Pfirrmann grading, disc narrowing, central canal stenosis, spondylolisthesis, (upper & lower) endplate defects, (upper & lower) marrow changes, (right & left) foraminal stenosis, and disc herniation, using T2-weighted sagittal MR images. Performance metrics included accuracy, balanced accuracy, precision, F1 score, Matthew's Correlation Coefficient, Brier Score Loss, Lin's concordance correlation coefficients, and Cohen's kappa coefficients. Two expert radiologists provide annotations for these discs. The evaluation of SpineNetV2′s grading is compared against expert radiologists' assessments. ResultsSpineNetV2 demonstrated strong performance across various metrics, with high agreement scores (Cohen's Kappa, Lin's Concordance, and Matthew's Correlation Coefficient exceeding 0.7) for most pathologies. However, lower agreement was found for foraminal stenosis and disc herniation, underscoring the limitations of sagittal MR images for evaluating these conditions. ConclusionsThis study highlights the importance of external validation, emphasizing the need for comprehensive assessments of deep learning models. SpineNetV2 exhibits promising results in predicting disc pathologies, with findings guiding further improvements. The open-source release of SpineNetV2 enables researchers to independently validate and extend the model's capabilities. This collaborative approach promotes innovation and accelerates the development of more reliable and comprehensive deep learning tools for the assessment of spine pathology.

Gut commensal Alistipes as a potential pathogenic factor in colorectal cancer

Although previous research has shown that inflammation is associated with development of colorectal cancer (CRC), questions remain about whether inflammatory factor-secreting bacteria play a crucial role in CRC development. The potential role of gut microbiota in secreting inflammatory factors involved in the carcinogenesis of CRC among Chinese patients was explored in this study. 16S rRNA sequencing was utilized to evaluate the distinct microbial characteristics between patients with CRC and colorectal adenoma. The serum levels of TNF-α, IL-6 and IL-10 were measured using Enzyme-linked immunosorbent assay (ELISA), while the expression of LRG1 and TGF-β1 in tissues was evaluated by immunohistochemistry. The correlation between gut microbiota and inflammatory factor signaling was analyzed. Compared with the adenoma group, CRC patients exhibit distinct pathologies. Moreover, elevated levels of CEA, erythrocytes and haemoglobin in the blood of CRC patients were found. In addition, CRC patients have significantly higher levels of TNF-α, IL-6, IL-10, LRG1 and TGF-β1. Spearman correlation analysis revealed that LRG1 was positively related to IL-6 and TNF-α, respectively. The correlation analysis results of TGF-β1 were consistent with the above. The abundance of Blautia and Streptococcus was lower in CRC patients, while the relative abundance of Alistipes, Peptostreptococcus and Porphyromonas was significantly elevated. Moreover, positive correlations between Alistipes and inflammatory factor signaling were also found. Our results suggest that gut commensal Alistipes is a key bacterium with pro-inflammatory properties in the CRC carcinogenesis. TNF-α and IL-6 associated with Alistipes might activate LRG1/TGF-β1 signaling which contributed to the carcinogenesis of CRC.

Health Hazards Associated with Dietary Exposure of Female Rat to Cadmium-Contaminated Cooked Rice: Biochemical, Hormonal, and Histopathological Analysis.

The actual exposure, bioavailability, and body burden of dietary cadmium (Cd) vary with the food matrix. Here, we evaluated the health hazards of 45-day long-term exposure of growing Sprague-Dawley (SD) female rats to a natural and endogenous Cd-contaminated brown and white cooked rice dietary model. Cd was found mainly in the duodenum, kidney, and liver; the cecum and colon also contained substantial amounts of Cd in rats fed Cd-contaminated cooked white rice (cWR-test) but not Cd-contaminated cooked brown rice (cBR-test). Damage due to Cd exposure was reflected in liver dysfunction, altered estradiol levels, and distinctive pathologies in organ systems, although urinary Cd (U-Cd) excretion and blood Cd (B-Cd) were not detectable, suggesting that these are not the most accurate or appropriate biomarkers for evaluating dietary Cd exposure. Brown rice, despite being higher in Cd, can reduce Cd absorption and distribution in organs and increase the volume of Cd-containing feces, even achieving slightly higher excretion and lower apparent absorption rates of Cd than white rice, thereby reducing Cd damage to the body. The beneficial components of brown rice such as more dietary fiber, rice bran oil and polyphenol were speculated therefore to confer a degree of protection or repair. Nevertheless, the high apparent absorption levels observed here (> 5%) and signs of significant physical damage indicate that more stringent Cd intake guidelines and measures are needed to minimize Cd levels in rice.

Relapsing tumefactive demyelination lesions: A unique, distinct inflammatory brain pathology.

We report the case of a patient suffering from biopsy-proven relapsing tumefactive demyelinating lesions (TDLs) of the central nervous system who had five relapses in 16 years. No signs/symptoms suggestive of alternative pathologies emerged during the follow-up. A limited benefit was observed with intravenous (IV) high-dose steroids, while both plasma exchange and IV immunoglobulin G (IgG) administration were ineffective. A long-lasting (9 years) but transient clinical stabilization was obtained with cyclophosphamide. Our case supports the view that recurrent TDL is a relapsing brain inflammation not belonging to multiple sclerosis (MS) or myelin oligodendrocyte glycoprotein (MOG)-/AQP4-associated disorders. TDL concept and clinical features should be revised.

Patterns of cerebral damage in multiple sclerosis and aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders-major differences revealed by non-conventional imaging.

Multiple sclerosis and aquaporin-4 antibody neuromyelitis optica spectrum disorders are distinct autoimmune CNS disorders with overlapping clinical features but differing pathology. Multiple sclerosis is primarily a demyelinating disease with the presence of widespread axonal damage, while neuromyelitis optica spectrum disorders is characterized by astrocyte injury with secondary demyelination. Diagnosis is typically based on lesion characteristics observed on standard MRI imaging and antibody testing but can be challenging in patients with in-between clinical presentations. Non-conventional MRI techniques can provide valuable diagnostic information by measuring disease processes at the microstructural level. We used non-conventional MRI to measure markers of axonal loss in specific white matter tracts in multiple sclerosis and neuromyelitis optica spectrum disorders, depending on their relationship with focal lesions. Patients with relapsing-remitting multiple sclerosis (n = 20), aquaporin-4 antibody-associated neuromyelitis optica spectrum disorders (n = 20) and healthy controls (n = 20) underwent a 3T brain MRI, including T1-, T2- and diffusion-weighted sequences, quantitative susceptibility mapping and phase-sensitive inversion recovery sequence. Tractometry was used to differentiate tract fibres traversing through white matter lesions from those that did not. Neurite density index was assessed using neurite orientation dispersion and density imaging model. Cortical damage was evaluated using T1 relaxation rates. Cortical lesions and paramagnetic rim lesions were identified using phase-sensitive inversion recovery and quantitative susceptibility mapping. In tracts traversing lesions, only one out of 50 tracts showed a decreased neurite density index in multiple sclerosis compared with neuromyelitis optica spectrum disorders. Among 50 tracts not traversing lesions, six showed reduced neurite density in multiple sclerosis (including three in the cerebellum and brainstem) compared to neuromyelitis optica spectrum disorders. In multiple sclerosis, reduced neurite density was found in the majority of fibres traversing (40/50) and not traversing (37/50) white matter lesions when compared to healthy controls. A negative correlation between neurite density in lesion-free fibres and cortical lesions, but not paramagnetic rim lesions, was observed in multiple sclerosis (39/50 tracts). In neuromyelitis optica spectrum disorders compared to healthy controls, decreased neurite density was observed in a subset of fibres traversing white matter lesions, but not in lesion-free fibres. In conclusion, we identified significant differences between multiple sclerosis and neuromyelitis optica spectrum disorders corresponding to their distinct pathologies. Specifically, in multiple sclerosis, neurite density reduction was widespread across fibres, regardless of their relationship to white matter lesions, while in neuromyelitis optica spectrum disorders, this reduction was limited to fibres passing through white matter lesions. Further studies are needed to evaluate the discriminatory potential of neurite density measures in white matter tracts for differentiating multiple sclerosis from neuromyelitis optica spectrum disorders.

Patient-reported outcome of lumbar decompression with instrumented fusion for low-grade spondylolisthesis: influence of pathology and baseline symptoms.

Low-grade isthmic and degenerative spondylolisthesis (DS) of the lumbar spine are distinct pathologies but both can be treated with lumbar decompression with fusion. In a very large cohort, we compared patient-reported outcome in relation to the pathology and chief complaint at baseline. This was a retrospective analysis using the EUROSPINE Spine Tango Registry. We included 582 patients (age 60 ± 15years; 65% female), divided into four groups based on two variables: type of spondylolisthesis and chief pain complaint (leg pain (LP) versus back pain). Patients completed the COMI preoperatively and up to 5years follow-up (FU), and rated global treatment outcome (GTO). Regression models were used to predict COMI-scores at FU. Pain scores and satisfaction ratings were analysed. All patients experienced pronounced reductions in COMI scores. Relative to the other groups, the DS-LP group showed between 5%and 11% greater COMI score reduction (p < 0.01 up to 2years'FU). This group also performed best with respect to pain outcomes and satisfaction. Long-term GTO was 93% at the 5year FU, compared with between 82% and 86% in the other groups. Regardless of the type of spondylolisthesis, all groups experienced an improvement in COMI score after surgery. Patients with DS and LP as their chief complaint appear to benefit more than other patients. These results are the first to show that the type of the spondylolisthesis and its chief complaint have an impact on surgical outcome. They will be informative for the consent process prior to surgery and can be used to build predictive models for individual outcome.

Spontaneous spinal hematomas: A case series

PurposeSpontaneous spinal hematoma (SSH), a rare neurological disorder, demands immediate diagnostic evaluation and intervention to prevent lasting deficits. This case series analyzes instances, particularly highlighting cases where vascular causes were identified despite inconclusive initial imaging.MethodsIn a retrospective study of 20 patients treated for SSH at a Level I spine center from 01/01/2017 to 11/15/2023, we examined demographics, clinical presentation, imaging, and treatment details. Excluding traumatic cases, we present 4 instances of SSH associated with diverse vascular pathologies.ResultsPatient ages ranged from 39 to 85 years, with a median age of 66 years. 45% were male, and 55% were female. Among 20 cases, 14 were epidural hematomas, 4 subdural, 1 combined epidural and subdural, and 1 subarachnoid hemorrhage. 85% presented with neurological deficits, while 3 solely had pain-related symptoms. 55% were under anticoagulant medication, and vascular anomalies were found in 25% of cases. The cause of SSH remained unclear in 20% of cases. MRI was performed for all patients, and DSA was conducted in 25% of cases. The 4 highlighted cases involved individuals with distinct vascular pathologies managed surgically.ConclusionUrgent attention is crucial for SSH due to possible lasting neurological consequences. The study emphasizes comprehensive diagnostics and surgical exploration, especially in cases with unclear etiology, to identify and address vascular causes, preventing hematoma progression or recurrence. Despite their rarity, vascular malformations contributing to spinal hematomas warrant particular attention.

Cryo-EM-based discovery of a pathogenic parvovirus causing epidemic mortality by black wasting disease in farmed beetles

We use cryoelectron microscopy (cryo-EM) as a sequence- and culture-independent diagnostic tool to identify the etiological agent of an agricultural pandemic. For the past 4 years, American insect-rearing facilities have experienced a distinctive larval pathology and colony collapse of farmed Zophobas morio (superworm). By means of cryo-EM, we discovered the causative agent: a densovirus that we named Zophobas morio black wasting virus (ZmBWV). We confirmed the etiology of disease by fulfilling Koch's postulates and characterizing strains from across the United States. ZmBWV is a member of the family Parvoviridae with a 5,542 nt genome, and we describe intersubunit interactions explaining its expanded internal volume relative to human parvoviruses. Cryo-EM structures at resolutions up to 2.1Å revealed single-strand DNA (ssDNA) ordering at the capsid inner surface pinned by base-binding pockets in the capsid inner surface. Also, we demonstrated the prophylactic potential of non-pathogenic strains to provide cross-protection invivo.

Glucosylceramide synthase modulation ameliorates murine renal pathologies and promotes macrophage effector function in vitro

While significant advances have been made in understanding renal pathophysiology, less is known about the role of glycosphingolipid (GSL) metabolism in driving organ dysfunction. Here, we used a small molecule inhibitor of glucosylceramide synthase to modulate GSL levels in three mouse models of distinct renal pathologies: Alport syndrome (Col4a3 KO), polycystic kidney disease (Nek8jck), and steroid-resistant nephrotic syndrome (Nphs2 cKO). At the tissue level, we identified a core immune-enriched transcriptional signature that was shared across models and enriched in human polycystic kidney disease. Single nuclei analysis identified robust transcriptional changes across multiple kidney cell types, including epithelial and immune lineages. To further explore the role of GSL modulation in macrophage biology, we performed in vitro studies with homeostatic and inflammatory bone marrow-derived macrophages. Cumulatively, this study provides a comprehensive overview of renal dysfunction and the effect of GSL modulation on kidney-derived cells in the setting of renal dysfunction.

Distinct Transcript-Level Expression Profiles and Unique Alternative Splicing in Inflammatory Myopathies.

The pathogenesis of inflammatory myopathies is poorly understood and there is a need to dissect the transcriptome in more granular ways beyond gene expression. We used a set of muscle RNA-sequencing data from different myositis subtypes grouped by their specific autoantibodies (n = 152). We quantified annotated RNA transcripts for each myositis subtype and identified uniquely expressed RNA as well as transcriptional similarities among myositis types. In addition, we quantified event-based alternative splicing with predicted protein changes. And finally, we searched for cryptic exons. We saw considerable overlap in RNA expression among subtypes. In addition, MADCAM1 was previously shown to be uniquely expressed in Mi-2 myositis; we discovered it was two noncanonical transcripts that predominantly contributed to the observed increased expression. At the transcriptional level, dermatomyositis subtypes were least similar to inclusion body myositis (IBM) or Jo1, followed by HMGCR, then SRP and other dermatomyositis subtype. Additionally, we discovered many alternative splicing events that were unique by myositis subgroup, including events in muscle dystrophy genes and one event in SRP72, which was seen uniquely in SRP myositis. Finally, we looked for previously reported cryptic exons in IBM and did not find them. The large degree of transcriptional overlap among myositis subtypes reinforces the need to use disease (in addition to healthy) controls to find unique features of autoimmune disease. Unique alterations in the transcriptome that are seen in one myositis subtype and not others advance our understanding of distinct disease pathology.

Learning interpretable dynamics of stochastic complex systems from experimental data

Complex systems with many interacting nodes are inherently stochastic and best described by stochastic differential equations. Despite increasing observation data, inferring these equations from empirical data remains challenging. Here, we propose the Langevin graph network approach to learn the hidden stochastic differential equations of complex networked systems, outperforming five state-of-the-art methods. We apply our approach to two real systems: bird flock movement and tau pathology diffusion in brains. The inferred equation for bird flocks closely resembles the second-order Vicsek model, providing unprecedented evidence that the Vicsek model captures genuine flocking dynamics. Moreover, our approach uncovers the governing equation for the spread of abnormal tau proteins in mouse brains, enabling early prediction of tau occupation in each brain region and revealing distinct pathology dynamics in mutant mice. By learning interpretable stochastic dynamics of complex systems, our findings open new avenues for downstream applications such as control.

Immune responses to oligomeric α-synuclein in Parkinson’s disease peripheral blood mononuclear cells

Parkinson’s disease displays clinical heterogeneity, presenting with motor and non-motor symptoms. Heterogeneous phenotypes, named brain-first and body-first, may reflect distinct α-synuclein pathology starting either in the central nervous system or in the periphery. The immune system plays a prominent role in the central and peripheral pathology, with misfolded α-synuclein being placed at the intersection between neurodegeneration and inflammation. Here, we characterized the inflammatory profile and immune-phenotype of peripheral blood mononuclear cells (PBMCs) from Parkinson’s disease patients upon stimulation with α-synuclein monomer or oligomer, and investigated relationships of immune parameters with clinical scores of motor and non-motor symptoms. Freshly isolated PBMCs from 21 Parkinson’s disease patients and 18 healthy subjects were exposed in vitro to α-synuclein species. Cytokine/chemokine release was measured in the culture supernatant by Multiplex Elisa. The immune-phenotype was studied by FACS-flow cytometry. Correlation analysis was computed between immune parameters and parkinsonian motor and non-motor scales. We found that Parkinson’s disease patients exhibited a dysregulated PBMC-cytokine profile, which remained unaltered after exposure to α-synuclein species and correlated with both motor and non-motor severity, with a strong correlation observed with olfactory impairment. Exposure of PBMCs from healthy controls to α-synuclein monomer/oligomer increased the cytokine/chemokine release up to patient’s values. Moreover, the PBMCs immune phenotype differed between patients and controls and revealed a prominent association of the Mos profile with olfactory impairment, and of NK profile with constipation. Results suggest that a deranged PBMC-immune profile may reflect distinct clinical subtypes and would fit with the recent classification of Parkinson’s disease into peripheral-first versus brain-first phenotype.

Distinct Pathological Changes in Preweaning Mice Infected with Live-Attenuated Rift Valley Fever Virus Strains.

Rift Valley fever (RVF) is a mosquito-borne zoonotic viral disease endemic to Africa and the Middle East. Live-attenuated RVF vaccines have been studied for both veterinary and human use due to their strong immunogenicity and cost-effective manufacturing. The live-attenuated MP-12 vaccine has been conditionally approved for veterinary use in the U.S.A., and next-generation live-attenuated RVF vaccine candidates are being actively researched. Assessing the virulence phenotype of vaccine seeds or lots is crucial for managing vaccine safety. Previously, preweaning 19-day-old outbred CD1 mice have been used to evaluate the MP-12 strain. This study aimed to characterize the relative virulence of three live-attenuated RVF vaccine strains in 19-day-old inbred C57BL/6 mice: the recombinant MP-12 (rMP-12), the RVax-1, and the ∆NSs-∆NSm-rZH501 strains. Although this mouse model did not show dose-dependent pathogenesis, mice that succumbed to the infection exhibited distinct brain pathology. Mice infected with ∆NSs-∆NSm-rZH501 showed an infiltration of inflammatory cells associated with infected neurons, and focal lesions formed around virus-infected cells. In contrast, mice infected with rMP-12 or RVax-1 showed a minimal association of inflammatory cells in the brain, yet the virus spread diffusely. The preweaning model is likely useful for evaluating host responses to attenuated RVFV strains, although further refinement may be necessary to quantitate the virulence among different RVFV strains or vaccine lots.

Burn pit exposure in military personnel and the potential resulting lung and neurological pathologies

IntroductionMilitary personnel and local civilians at various deployment locations are plagued with serious health conditions. Evidence points to burn pit emissions as the cause of these pathologies; however, similar diseases are also caused by environmental exposures, smoking, genetic predispositions, or other comorbidities. Burn pits, which are large smoldering piles of refuse ignited with jet or diesel fuel, contain human and medical waste as well as paint, plastics, ammunition, and other materials—each of which can be attributed to health concerns in other industrial settings. Here we compare various pathologies attributable to toxic aerosol exposures and discuss distinct pathologies that may be linked to burn pit exposures.ObjectivesWe performed a literature review where we provide information on toxic exposures that may pose relevance to burn pit exposure and furthermore, highlight what is already known about burn pit exposures and what steps need to be taken to diagnose and correlate certain respiratory pathologies to chronic exposure from overseas burn pits.Data sourcesWe conducted searches through PubMed and Google Scholar to determine where gaps in our knowledge of burn pit exposure lie. Thorough review on jet-fuel properties and particulate matter were performed as supporting evidence of potential toxins from burn pit emissions.ResultsTo date, studies on burn pit emissions consist mainly of systematic reviews and discussions to address the problem, with very few acute-exposure studies and little to no chronic-exposure studies. We found that symptoms range from respiratory pathologies to neurological deficits, but treatment has been limited as medical facilities, such as the Veterans Administration (VA), require proof that a condition is service-connected.ConclusionsTo determine the effects of burn pit exposure on humans, chronic exposure to mimicked burn pit emissions is necessary to draw definitive conclusions between phenotypic differences in pathologies linked to exposure. By determining phenotypic differences, conclusions can be made about the pathologic origins, potentially leading to future diagnoses and treatments for veterans and affected civilians.

Odontogenic Maxillary Sinusitis Microbiology Compared With Chronic Rhinosinusitis: A Meta-Analysis.

Subtypes of sinusitis have different symptoms and prognoses due to different pathogens. Odontogenic maxillary sinusitis (OMS) mainly occurs unilaterally and is different from chronic rhinosinusitis (CRS) usually occurring bilaterally in terms of clinical characteristics. However, comprehensive microbiological comparisons between OMS and CRS have never been systematically conducted and most comparisons are methodologically biased. This study aims to provide a comprehensive analysis of the microbiology associated with OMS and CRS through a meta-analysis approach in order to provide evidence for differential diagnosis of OMS and CRS from a microbiological perspective. The databases PubMed and CNKI were searched from their inception to July 2023. A random-effects model was employed to derive the pooled prevalence estimates of the identified bacterial species or genera. The 17 represented studies included 6 concerning OMS, 12 concerning CRS, and 4 concerning normal sinus, yielding 191, 610, and 92 samples, respectively. Though not statistically significant, the prevalence of Peptostreptococcus and Prevotella was generally higher in OMS compared to CRS. Notably, Fusobacterium was identified as the only genus with a significantly higher prevalence in OMS compared to CRS. Fusobacterium was significantly more prevalent in OMS compared with CRS, while Staphylococcus aureus was more prevalent in CRS than in OMS. Such differences in bacterial profile may partly explain the distinct pathology observed and contribute to the development of novel strategies for diagnosis and therapeutic interventions in OMS.