Monosynaptic Rabies Tracing Reveals Sex- and Age-Dependent Dorsal Subiculum Connectivity Alterations in an Alzheimer's Disease Mouse Model.

The subiculum (SUB), a hippocampal formation structure, is among the earliest brain regions impacted in Alzheimer's disease (AD). Toward a better understanding of AD circuit-based mechanisms, we mapped synaptic circuit inputs to dorsal SUB using monosynaptic rabies tracing in the 5xFAD mouse model by quantitatively comparing the circuit connectivity of SUB excitatory neurons in age-matched controls and 5xFAD mice at different ages for both sexes. Input-mapped brain regions include the hippocampal subregions (CA1, CA2, CA3), medial septum and diagonal band, retrosplenial cortex, SUB, postsubiculum (postSUB), visual cortex, auditory cortex, somatosensory cortex, entorhinal cortex, thalamus, perirhinal cortex (Prh), ectorhinal cortex, and temporal association cortex. We find sex- and age-dependent changes in connectivity strengths and patterns of SUB presynaptic inputs from hippocampal subregions and other brain regions in 5xFAD mice compared with control mice. Significant sex differences for SUB inputs are found in 5xFAD mice for CA1, CA2, CA3, postSUB, Prh, lateral entorhinal cortex, and medial entorhinal cortex: all of these areas are critical for learning and memory. Notably, we find significant changes at different ages for visual cortical inputs to SUB. While the visual function is not ordinarily considered defective in AD, these specific connectivity changes reflect that altered visual circuitry contributes to learning and memory deficits. Our work provides new insights into SUB-directed neural circuit mechanisms during AD progression and supports the idea that neural circuit disruptions are a prominent feature of AD.

New rabies viral resources for multi-scale neural circuit mapping.

Comparisons and linkage between multiple imaging scales are essential for neural circuit connectomics. Here, we report 20 new recombinant rabies virus (RV) vectors that we have developed for multi-scale and multi-modal neural circuit mapping tools. Our new RV tools for mesoscale imaging express a range of improved fluorescent proteins. Further refinements target specific neuronal subcellular locations of interest. We demonstrate the discovery power of these new tools including the detection of detailed microstructural changes of rabies-labeled neurons in aging and Alzheimer's disease mouse models, live imaging of neuronal activities using calcium indicators, and automated measurement of infected neurons. RVs that encode GFP and ferritin as electron microscopy (EM) and fluorescence microscopy reporters are used for dual EM and mesoscale imaging. These new viral variants significantly expand the scale and power of rabies virus-mediated neural labeling and circuit mapping across multiple imaging scales in health and disease.

Pilot validation of on-field STR typing and human identity testing by MinION nanopore sequencing.

Nanopore sequencing technology has broad application prospects in forensic medicine due to its small size, portability, fast speed, real-time result analysis capabilities, single-molecule sequencing abilities, and simple operation. Here, we demonstrate for the first time that nanopore sequencing platforms can be used to identify individuals in the field. Through scientific and reasonable design, a nanopore MinION MK1B device and other auxiliary devices are integrated into a portable detection box conducive to individual identification at the accident site. Individual identification of 12 samples could be completed within approximately 24 h by jointly detecting 23 short tandem repeat (STR) loci. Through double-blinded experiments, the genotypes of 49 samples were successfully determined, and the accuracy of the STR genotyping was verified by the gold standard. Specifically, the typing success rate for 1150 genotypes was 95.3%, and the accuracy rate was 86.87%. Although this study focused primarily on demonstrating the feasibility of full-process testing, it can be optimistically predicted that further improvements in bioinformatics workflows and nanopore sequencing technology will help enhance the feasibility of Oxford Nanopore Technologies equipment for real-time individual identification at accident sites.

Inflammation mediates the association between furan exposure and the prevalence and mortality of chronic obstructive pulmonary disease: National Health and Nutrition Examination Survey 2013-2018.

BACKGROUND: Although extensive research has established associations between chronic obstructive pulmonary disease (COPD) and environmental pollutants, the connection between furan and COPD remains unclear. This study aimed to explore the association between furan and COPD while investigating potential mechanisms. METHODS: The study involved 7,482 adults from the National Health and Nutrition Examination Survey 2013-2018. Exposure to furan was assessed using blood furan levels. Participants were categorized into five groups based on quartiles of log10-transformed blood furan levels. Logistic regression and restricted cubic spline regression models were used to assess the association between furan exposure and COPD risk. Mediating analysis was performed to assess the contribution of inflammation to the effects of furan exposure on COPD prevalence. Cox regression was used to assess the association between furan exposure and the prognosis of COPD. RESULTS: Participants with COPD exhibited higher blood furan levels compared to those without COPD (P < 0.001). Log10-transformed blood furan levels were independently associated with an increased COPD risk after adjusting for all covariates (Q5 vs. Q1: OR = 4.47, 95% CI = 1.58-12.66, P = 0.006, P for trend = 0.001). Inflammatory cells such as monocytes, neutrophils, and basophils were identified as mediators in the relationship between furan exposure and COPD prevalence, with mediated proportions of 8.73%, 20.90%, and 10.94%, respectively (all P < 0.05). Moreover, multivariate Cox regression analysis revealed a positive correlation between log10-transformed blood furan levels and respiratory mortality in COPD patients (HR = 41.00, 95% CI = 3.70-460.00, P = 0.003). CONCLUSIONS: Exposure to furan demonstrates a positive correlation with both the prevalence and respiratory mortality of COPD, with inflammation identified as a crucial mediator in this relationship.

Clinical and prognostic features associated with anti-Ro52 autoantibodies in connective tissue diseases patients with interstitial lung disease.

OBJECTIVES: To define the clinical and prognostic features associated with anti-Ro52 autoantibodies in patients with connective tissue diseases with interstitial lung disease (CTD-ILD). METHODS: A total of 238 patients with CTD-ILD were included in this single-centre retrospective cohort study. Patients with positive anti-Ro52 antibodies were selected as the study group, and those with negative anti-Ro52 antibodies were included in the control group. Clinical and follow-up data were analysed. RESULTS: Among 238 patients, 145 (60.92%) were positive for the anti-Ro52 antibody. These patients were more likely to have respiratory symptoms at baseline, with more organising pneumonia (OP) patterns and worse forced vital capacity (FVC). Follow-up data were obtained for ILD progression in 170 patients. Varying degrees of progression in pulmonary function (PF) or imaging were found in 48 patients (28.24%) with CTD-ILD. A dichotomous logistic analysis based on the presence or absence of progress showed no correlation with anti-Ro52 antibodies. During the follow-up of 170 patients, there were 35 deaths: 24 in the anti-Ro52 antibody positive group and 11 in the anti-Ro52 antibody negative group. Kaplan-Meier survival curves were used to describe the difference in survival between the two groups (mortality 17.14% vs. 12.5%, log-rank p=0.287). The multivariate logistic analysis showed that ILD progression was associated with older age, worse FVC and diffusion capacity for carbon monoxide at baseline, higher levels of C-reactive protein, serum ferritin, immunoglobulin G and lower absolute lymphocyte count. CONCLUSIONS: Anti-Ro52 antibodies may predict more severe lung damage in CTD-ILD; however, anti-Ro52 antibodies were not correlated with progression and death in patients with ILD.

Interstitial lung disease in adult patients with anti-NXP2 antibody positivity: a multicentre 18-month follow-up study.

OBJECTIVES: Anti-nuclear matrix protein 2 (NXP2) antibody is a rare myositis-specific antibody. Thus, the pattern and prognosis of interstitial lung disease (ILD) in NXP2-positive patients remain unclear. This study investigates the clinical features and effects of pulmonary complications on survival in NXP2-positive patients. METHODS: We retrospectively analysed the clinical and follow-up data of a cohort of 33 hospitalised adult patients with anti-NXP2 antibody positivity at three tertiary rheumatology centres from June 2017 to December 2020. RESULTS: Thirty-three patients were enrolled, and 87.9% (29/33) had dermatomyositis. The major pulmonary lesions manifested as various types of ILD (14/33, 42.4%), bilateral pleural effusion (2/33, 6.1%) and diffuse alveolar haemorrhage (1/33, 3%). Only 3 patients (3/33, 9.1%) had respiratory symptoms at onset. The most common lung imaging manifestations were non-specific interstitial pneumonia (NSIP) and/or organising pneumonia (OP) (11/14, 78.6%). Patients in the ILD group were older than those in the non-ILD group (p=0.002). Logistic regression analysis showed that age (p=0.008) was the only independent predictor for ILD. Kaplan-Meier survival curves displayed no association between ILD and all-cause death (log-rank p=0.84). None of the deaths during follow-up were directly related to ILD. CONCLUSIONS: Adult patients with anti-NXP2 antibody positivity mainly had dermatomyositis. Concurrent ILD is not uncommon, but clinical manifestations are often latent. NSIP and/or OP are the most common patterns. ILD is more common in older age groups. Although the prognosis of patients in the ILD group is not very poor, early screening may help to improve prognosis and quality of life.

Sulforaphene targets NLRP3 inflammasome to suppress M1 polarization of macrophages and inflammatory response in rheumatoid arthritis.

This work aimed to explore the therapeutic effect and target of sulforaphene (LF) in mice with rheumatoid arthritis (RA). Lipopolysaccharide (LPS) and IFN-γ were added to induce the M1 polarization of SMG cells, and later cells were pretreated with 5 µM and 15 µM LF. M1 cell proportion was detected by flow cytometry (FCM), inflammatory factors were measured by enzyme-linked immunosorbent assay, and protein levels were analyzed by western blotting (WB) assay. Besides, small molecule-protein docking and pull-down assays were carried out to detect the binding of LF to NLRP3. After the knockdown of NLRP3 in SMG cells, the effect of LF was further detected. The RA mouse model was induced with collagen antibody and LPS, after LF intervention, H&E staining was performed to detect the pathological changes in mouse synovial membrane, whereas safranin O-fast green staining was performed to detect cartilage injury, NLRP3 inflammasome and inflammatory factor levels in tissues. LF suppressed M1 polarization of macrophages, reduced M1 cell proportion and inflammatory factor levels, and suppressed the activation of NLRP3 inflammasome. After NLRP3 knockdown, LF did not further suppress the M1 polarization of macrophages. Pull-down assay suggested that LF bound to NLRP3. As revealed by mouse experimental results, LF inhibited bone injury in mice, decreased M1 cell infiltration and inflammatory response in tissues, and inhibited NLRP3 inflammasome expression in tissues. LF targets NLRP3 to suppress the M1 polarization of macrophages and decrease tissue inflammation in RA.

MMP19 Variants in Familial and Sporadic Idiopathic Pulmonary Fibrosis.

BACKGROUND: Gene variants have been identified in patients with familial or sporadic idiopathic pulmonary fibrosis (IPF). These variants may partially account for the genetic risk of IPF. The aim of this study was to identify potential genes involved in both familial and sporadic IPF. METHODS: A Han family in northern China with four members diagnosed with IPF was investigated in this observational study. Whole-exome sequencing (WES) was used to identify germline variants underlying disease phenotypes in five members of this family. Candidate rare variants were validated by Sanger sequencing in samples from 16 family members and 119 patients with sporadic IPF. The plasma levels of proteins encoded by the above candidate genes were also examined in 16 family members, 119 other patients with sporadic IPF and 120 age- and sex-matched healthy controls. RESULTS: In a Chinese Han family, MMP19 c.1222 C > T was identified in all familial IPF patients and six offspring from generations III and IV. This variant introduces a premature stop codon, which may damage protein function. Sanger sequencing revealed that 7.6% (9/119) of sporadic IPF patients harbored three MMP19 variants. The genetic risk analysis for pulmonary fibrosis showed that MMP19 c.1499 C > T and c.1316G > A were significantly associated with an increased risk of IPF (OR 3.66, p = 0.028 and OR 8.64, p < 0.001, respectively). The plasma levels of MMP19 were significantly higher in patients with sporadic or familial IPF than in healthy controls (all p < 0.001). CONCLUSIONS: MMP19 variants were identified in familial or sporadic IPF, thus providing a potential new clue into IPF pathogenesis.

Mendelian randomization analysis suggests no causal influence of gastroesophageal reflux disease on the susceptibility and prognosis of idiopathic pulmonary fibrosis.

BACKGROUND: The relationship between gastroesophageal reflux disease (GERD) and the susceptibility as well as the prognosis of idiopathic pulmonary fibrosis (IPF) has been previously suggested, with the potential confounding factor of smoking not adequately addressed. In light of this, we conducted a Mendelian randomization (MR) study to investigate the causal effects of GERD on the susceptibility and prognosis of IPF while excluding smoking. METHODS: We chose GERD as the exposure variable and employed genome-wide association data to examine its association with susceptibility, forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLco), and transplant-free survival (TFS) in patients with IPF as the outcome variables. MR analyses were performed using the inverse variance weighted (IVW) method, and sensitivity analyses were conducted using the MR-PRESSO outlier test, Cochran's Q test, MR-Egger intercept test, and leave-one-out sensitivity analysis. Additionally, to mitigate the potential effects of smoking on our MR estimates, we conducted a multivariable MR (MVMR) analysis by adjusting for smoking. RESULTS: The univariable MR analysis demonstrated no causal effect of GERD on FVC (ßIVW = 26.63, SE = 48.23, P = 0.581), DLco (ßIVW = 0.12, SE = 0.12, P = 0.319), and TFS (HRIVW = 0.87, 95% CI = 0.56 to 1.35, P = 0.533) in patients with IPF. Furthermore, sensitivity analysis revealed no evidence of heterogeneity, horizontal pleiotropy, or outlier single nucleotide polymorphisms. The MVMR analysis showed no causal effect of GERD on susceptibility to IPF after adjusting for smoking (ORIVW = 1.30, 95% CI = 0.93 to 1.68, P = 0.071). These findings were consistent in the replication cohort. CONCLUSIONS: The link between GERD and its potential impact on susceptibility to IPF may not be of a direct causal nature and could be influenced by factors such as smoking. Our findings did not reveal any evidence of a causal relationship between GERD and the FVC, DLco, and TFS of patients with IPF.

Cluster features in fibrosing interstitial lung disease and associations with prognosis.

BACKGROUND: Clustering is helpful in identifying subtypes in complex fibrosing interstitial lung disease (F-ILD) and associating them with prognosis at an early stage of the disease to improve treatment management. We aimed to identify associations between clinical characteristics and outcomes in patients with F-ILD. METHODS: Retrospectively, 575 out of 926 patients with F-ILD were eligible for analysis. Four clusters were identified based on baseline data using cluster analysis. The clinical characteristics and outcomes were compared among the groups. RESULTS: Cluster 1 was characterized by a high prevalence of comorbidities and hypoxemia at rest, with the worst lung function at baseline; Cluster 2 by young female patients with less or no smoking history; Cluster 3 by male patients with highest smoking history, the most noticeable signs of velcro crackles and clubbing of fingers, and the severe lung involvement on chest image; Cluster 4 by male patients with a high percentage of occupational or environmental exposure. Clusters 1 (median overall survival [OS] = 7.0 years) and 3 (OS = 5.9 years) had shorter OS than Clusters 2 (OS = not reached, Cluster 1: p < 0.001, Cluster 3: p < 0.001) and 4 (OS = not reached, Cluster 1: p = 0.004, Cluster 3: p < 0.001). Clusters 1 and 3 had a higher cumulative incidence of acute exacerbation than Clusters 2 (Cluster 1: p < 0.001, Cluster 3: p = 0.014) and 4 (Cluster 1: p < 0.001, Cluster 3: p = 0.006). Stratification by using clusters also independently predicted acute exacerbation (p < 0.001) and overall survival (p < 0.001). CONCLUSIONS: The high degree of disease heterogeneity of F-ILD can be underscored by four clusters based on clinical characteristics, which may be helpful in predicting the risk of fibrosis progression, acute exacerbation and overall survival.

Hippocampal neural circuit connectivity alterations in an Alzheimer's disease mouse model revealed by monosynaptic rabies virus tracing.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with growing major health impacts, particularly in countries with aging populations. The examination of neural circuit mechanisms in AD mouse models is a recent focus for identifying new AD treatment strategies. We hypothesize that age-progressive changes of both long-range and local hippocampal neural circuit connectivity occur in AD. Recent advancements in viral-genetic technologies provide new opportunities for semi-quantitative mapping of cell-type-specific neural circuit connections in AD mouse models. We applied a recently developed monosynaptic rabies tracing method to hippocampal neural circuit mapping studies in AD model mice to determine how local and global circuit connectivity to hippocampal CA1 excitatory neurons may be altered in the single APP knock-in (APP-KI) AD mouse model. To determine age-related AD progression, we measured circuit connectivity in age-matched littermate control and AD model mice at two different ages (3-4 vs. 10-11 months old). We quantitatively mapped the connectivity strengths of neural circuit inputs to hippocampal CA1 excitatory neurons from brain regions including hippocampal subregions, medial septum, subiculum and entorhinal cortex, comparing different age groups and genotypes. We focused on hippocampal CA1 because of its clear relationship with learning and memory and that the hippocampal formation shows clear neuropathological changes in human AD. Our results reveal alterations in circuit connectivity of hippocampal CA1 in AD model mice. Overall, we find weaker extrinsic CA1 input connectivity strengths in AD model mice compared with control mice, including sex differences of reduced subiculum to CA1 inputs in aged female AD mice compared with aged male AD mice. Unexpectedly, we find a connectivity pattern shift with an increased proportion of inputs from the CA3 region to CA1 excitatory neurons when comparing young and old AD model mice, as well as old wild-type mice and old AD model mice. These unexpected shifts in CA3-CA1 input proportions in this AD mouse model suggest the possibility that compensatory circuit increases may occur in response to connectivity losses in other parts of the hippocampal circuits. We expect that this work provides new insights into the neural circuit mechanisms of AD pathogenesis.

Spatial coding defects of hippocampal neural ensemble calcium activities in the triple-transgenic Alzheimer's disease mouse model.

Alzheimer's disease (AD) causes progressive age-related defects in memory and cognitive function and has emerged as a major health and socio-economic concern in the US and worldwide. To develop effective therapeutic treatments for AD, we need to better understand the neural mechanisms by which AD causes memory loss and cognitive deficits. Here we examine large-scale hippocampal neural population calcium activities imaged at single cell resolution in a triple-transgenic Alzheimer's disease mouse model (3xTg-AD) that presents both amyloid plaque and neurofibrillary pathological features along with age-related behavioral defects. To measure encoding of environmental location in hippocampal neural ensembles in the 3xTg-AD mice in vivo, we performed GCaMP6-based calcium imaging using head-mounted, miniature fluorescent microscopes ("miniscopes") on freely moving animals. We compared hippocampal CA1 excitatory neural ensemble activities during open-field exploration and track-based route-running behaviors in age-matched AD and control mice at young (3-6.5 months old) and old (18-21 months old) ages. During open-field exploration, 3xTg-AD CA1 excitatory cells display significantly higher calcium activity rates compared with Non-Tg controls for both the young and old age groups, suggesting that in vivo enhanced neuronal calcium ensemble activity is a disease feature. CA1 neuronal populations of 3xTg-AD mice show lower spatial information scores compared with control mice. The spatial firing of CA1 neurons of old 3xTg-AD mice also displays higher sparsity and spatial coherence, indicating less place specificity for spatial representation. We find locomotor speed significantly modulates the amplitude of hippocampal neural calcium ensemble activities to a greater extent in 3xTg-AD mice during open field exploration. Our data offer new and comprehensive information about age-dependent neural circuit activity changes in this important AD mouse model and provide strong evidence that spatial coding defects in the neuronal population activities are associated with AD pathology and AD-related memory behavioral deficits.

Low-ratio somatic NLRC4 mutation causes late-onset autoinflammatory disease.

OBJECTIVES: We aim to investigate the genetic basis of a case of late-onset autoinflammatory disease characterised by arthritis, recurrent fever and skin rashes. METHODS: We performed whole-exome/genome sequencing and digital droplet PCR (ddPCR) to identify the pathogenic somatic mutation. We used single-cell RNA sequencing (scRNA-seq), intracellular cytokine staining, quantitative PCR, immunohistochemistry and western blotting to define inflammatory signatures and to explore the pathogenic mechanism. RESULTS: We identified a somatic mutation in NLRC4 (p.His443Gln) with the highest mosaicism ratio in the patient's monocytes (5.69%). The somatic mutation resulted in constitutive NLRC4 activation, spontaneous apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) aggregation, caspase-1 hyperactivation and increased production of interleukin (IL)-1ß and IL-18. Moreover, we demonstrated effective suppression of inflammatory cytokine production by targeting gasdermin D, an approach that could be considered as a novel treatment strategy for patients with NLRC4-associated autoinflammatory syndrome. CONCLUSIONS: We reported a case of a late-onset autoinflammatory disease caused by a somatic NLRC4 mutation in a small subset of leucocytes. We systemically analysed this condition at a single-cell transcriptomic level and revealed specific enhancement of inflammatory response in myeloid cells.

Pulmonary hypertension in patients with pneumoconiosis with progressive massive fibrosis.

OBJECTIVES: This study aims to explore the prevalence and clinical features of pulmonary hypertension (PH) in patients with progressive massive fibrosis (PMF) and its correlation with large opacities on CT scans. METHODS: This retrospective study collected 235 patients with PMF, and 199 were eligible for analysis. The probability of PH development was estimated based on tricuspid regurgitation velocity measured by echocardiogram. The size and the location of large opacities on chest CT were recorded. Potential risk factors for PH secondary to PMF were analysed using regression analysis. RESULTS: The prevalence of a high or intermediate probability of PH was 39.7% in patients with PMF. Type C of large opacities (OR 6.99, 95% CI 2.34 to 23.00, p<0.001) and central type of the large opacities (OR 8.12, 95% CI 2.89 to 24.71, p<0.001) were identified as the risk factors for PH secondary to PMF. Over a median follow-up of 32.8 months, the survival rate was 73.3% in the PH group, significantly lower than that in the non-PH group (96.6%, p<0.001). CONCLUSIONS: Over one-third of patients with PMF developed PH. The increased size and the central distribution of large opacities were identified as the risk factors.

Serum Oncomarkers in Patients with MPO-ANCA-Positive Vasculitis: Diagnostic and Prognostic Predictive Values for Interstitial Lung Disease.

PURPOSE: To explore in myeloperoxidase-antineutrophil cytoplasmic autoantibody-associated vasculitis (MPO-AAV) the value of circulating oncomarkers in identifying interstitial lung disease (ILD) and predicting prognosis. METHODS: Newly diagnosed MPO-AAV patients were evaluated retrospectively at a single center. The serum levels of carbohydrate antigen (CA) 19-9, CA125, cytokeratin fraction 21-1 (CYFRA21-1), carcinoembryonic antigen, squamous cell carcinoma antigen, and neuron-specific enolase were compared between patients with and without ILD. The strength of the oncomarkers in identifying ILD was assessed through logistic regression and receiver operating characteristic (ROC) curves. Correlation analysis was applied to detect the associations between oncomarkers and ILD severity. The significance of serum oncomarkers as prognosis predictors for MPO-AAV associated ILD was evaluated by survival analysis. RESULTS: 169 MPO-AAV patients were included and ILD was found in 101 patients. Serum CA125, CA19-9, and CYFRA21-1 were significantly higher in patients with ILD than those without ILD. The area under the ROC curve of CA19-9, CA125, and CYFRA21-1 for identifying ILD was 0.701, 0.660, and 0.711, respectively. A specificity of 98.5% for diagnosing ILD was found for CA19-9 at the recommended normal level. CA19-9 was positively correlated with HRCT fibrosis score (r = 0.498, p < 0.001) and CYFRA21-1 was correlated with ground-glass score (r = 0.316, p = 0.002). Both CA19-9 and CYFRA21-1 were independent risk factors for all-cause mortality in patients with ILD. CONCLUSION: Serum CA19-9 and CYFRA21-1 might be useful markers in the diagnosis, disease severity evaluation, and prognosis prediction of MPO-AAV-associated ILD.

High-resolution computed tomography features of asbestosis versus fibrotic hypersensitivity pneumonitis: an observational study.

BACKGROUND: Asbestosis and fibrotic hypersensitivity pneumonitis (FHP) share the pathogenetic mechanisms induced bronchiolocentric fibrotic process secondary to inhalation exposure. Under the occupational and environmental mixed exposures, asbestosis and FHP are needed to make the differential diagnoses on high-resolution computed tomography (HRCT), especially in the countries still using asbestos. The study aimed to analyze the HRCT features of asbestosis versus FHP. METHODS: The patients with asbestosis or with HP were sequentially recruited in this comparative study at Beijing Chaoyang Hospital between January 2006 and December 2016. Patients' clinical data were obtained from a predesigned charts. The international classification of HRCT for occupational and environmental respiratory diseases was used to categorize chest imaging findings in patients. The calculation of test statistics was used to compare the imaging features of asbestosis and FHP. RESULTS: 341 patients with asbestosis and 158 patients with HP were sequentially recruited, among which 204 patients with asbestosis and 74 patients with FHP were eligible for data analysis. Patients with asbestosis were older and had a longer latent period until disease manifestation than those with FHP. Asbestosis was characterized by irregular and/or linear opacities, with lower lung preponderance, accompanied by ground-glass opacities and mosaic attenuation. Notably, 98.5% of patients with asbestosis showed benign pleural abnormalities, and 39.7% of these patients had diffuse pleural thickening with parenchymal bands and/or rounded atelectasis. Abnormalities of the mediastinal and diaphragmatic pleura were observed only in cases of asbestosis, and this finding showed high specificity for the diagnosis for asbestosis compared with that for FHP. Subpleural dots or diaphragmatic pleural abnormalities showed moderate sensitivity and high specificity for diagnosis of asbestosis compared with that for FHP. Interobserver reliability was good for evaluation of imaging findings including honeycombing, pleural calcification, lymphadenectasis, and lymph node calcification. CONCLUSIONS: HRCT-based imaging findings can distinguish between asbestosis and FHP to a certain extent, particularly with regard to subpleural dots and diaphragmatic pleural abnormalities that characterize the former.

Small airway dysfunction in pneumoconiosis: a cross-sectional study.

BACKGROUND: Although several histological studies have documented airway inflammation and remodelling in the small airways of dust-exposed workers, little is known regarding the prevalence and risk factors of small airway dysfunction (SAD) in pneumoconiosis. The present study investigated the prevalence and characteristics of spirometry-defined SAD in pneumoconiosis and assessed the risk factors for associated with SAD. METHODS: A total of 1255 patients with pneumoconiosis were invited to participate, of whom 1115 patients were eligible for final analysis. Spirometry was performed to assess SAD using the following three indicators: maximal mid-expiratory flow and forced expiratory flow 50% and 75%. SAD was defined as at least two of these three indicators being less than 65% of predicted value. Logistic regression analyses were used to analyse the relationships between clinical variables and SAD. RESULTS: Overall, 66.3% of patients with pneumoconiosis had SAD, among never-smokers the prevalence of SAD was 66.7%. The proportion of SAD did not differ among the subtypes of pneumoconiosis. In addition, SAD was present across the patients with all stages of pneumoconiosis. Even among those with forced expiratory volume in 1 s (FEV1) ≥ 80% and FEV1/forced vital capacity ratio ≥ 70%, 40.8% of patients had SAD. Patients with SAD were older than patients without SAD, more likely to be women and heavy smokers. Importantly, patients with SAD had more severe airflow obstruction, air trapping, and diffusion dysfunction. All patients with both pneumoconiosis and chronic obstructive pulmonary disease had SAD. Based on multivariate analysis, overall, aged 40 years and older, female sex, heavy smoking, body mass index ≥ 25.0 kg/m2 and pneumoconiosis stage III were significantly associated with increased risk of SAD. Among the never smokers, risk factors for SAD included female sex, BMI ≥ 25.0 kg/m2, pneumoconiosis stage II and stage III CONCLUSION: Spirometry-defined SAD is one of the common functional abnormalities caused by occupational dust exposure and should be taken into account when monitoring respiratory health of workers to guide the early precautions and management in pneumoconiosis.

Small airway dysfunction in Chinese patients with idiopathic pulmonary fibrosis.

BACKGROUND: Recent years, idiopathic pulmonary fibrosis (IPF) is thought to be a disease of alveoli as well as small airways. This study aimed to demonstrate the clinical feature, predictor, and prognosis of small airway dysfunction (SAD) in Chinese patients with IPF. METHODS: We enrolled 416 patients with IPF who hospitalized in Beijing Chao-Yang Hospital from 2000 to 2014 in this study, and the follow-up ended at December 2016. We collected demographic information, clinical examination results, spirometry results, HRCT results, and blood gas results during the study. Logistic regression analysis was used to identify the predictor for SAD. The COX proportional hazard model was used to analysis the prognosis effect of SAD. RESULTS: Among all the participants, 165 (39.66%) patients had SAD. FEV1 (% predicted) and FEV3/FVC were significantly associated with SAD in patients with IPF. IPF patients with lower FEV1 (% predicted, OR 30.04, 95% CI 9.61-93.90) and FEV3/FVC (OR 77.76, 95% CI 15.44-391.63) had increased risk for SAD. Patients with SAD were associated with significantly increased risk of mortality in patients with IPF (HR 1.73, 95% CI 1.02-2.92), as well as in IPF patients without other pulmonary comorbidities (COPD, emphysema, and asthma). CONCLUSIONS: Spirometry-defined SAD was like 40% in patients with IPF. Lower FEV1 (% predicted) and FEV3/FVC were main predictors for SAD. IPF patients with SAD showed poorer prognosis.

Cytopathological characteristics of angioimmunoblastic T-cell lymphoma diagnosed by fine needle aspiration.

OBJECTIVE: To analyse the cytopathological features of fine needle aspiration (FNA) in angioimmunoblastic T-cell lymphoma (AITL) diagnostics. METHODS: Fine needle aspiration lymph node biopsy samples from 12 patients with AITL were collected at a single centre between January 2014 and December 2020. The clinical, cytological and histopathological characteristics were retrospectively analysed. RESULTS: Three male and six female patients with AITL who had a median onset age of 65 years (range 51-74 years) and a mean follow-up period of 29 months (range 12-47 months) were included. The FNA cytological and morphological analysis of the reactive lymph node background revealed diffusely distributed non-homogeneous mixed lymphocytes, including mature small lymphocytes, medium-sized lymphoid cells, immune cells, and plasma cells; some mixed eosinophils, macrophages, and an occasional mixture of visible and medium-sized lymphocytes and epithelioid cells were observed. Mitotically active lymphocytes and sporadic pigmented bodies were observed occasionally. An abnormal proliferation of follicular dendritic cells observed under the microscope is important for AITL diagnosis, and these cells are often distributed in a scattered pattern of small clusters with many nuclear morphologies. Branched capillaries are another important diagnostic clue. Two patients with AITL who achieved clinical remission after treatment experienced recurrence and were diagnosed using FNA and cell block immunohistochemistry. CONCLUSIONS: Fine needle aspiration provides clues for the diagnosis of AITL in special clinical situations, and cell block immunohistochemistry is worthy of further exploration.

Angelica sinensis Polysaccharide and Astragalus membranaceus Polysaccharide Accelerate Liver Regeneration by Enhanced Glycolysis via Activation of JAK2/STAT3/HK2 Pathway.

The promotion of liver regeneration is crucial to avoid liver failure after hepatectomy. Angelica sinensis polysaccharide (ASP) and Astragalus membranaceus polysaccharide (AMP) have been identified as being associated with hepatoprotective effects. However, their roles and specific mechanisms in liver regeneration remain to be elucidated. In the present study, it suggested that the respective use of ASP or AMP strikingly promoted hepatocyte proliferation in vitro with a wide range of concentrations (from 12.5 µg/mL to 3200 µg/mL), and a stronger promoting effect was observed in combined interventions. A significantly enhanced liver/body weight ratio (4.20%) on day 7 and reduced serum transaminase (ALT 243.53 IU/L and AST 423.74 IU/L) and total bilirubin (52.61 IU/L) levels on day 3 were achieved by means of ASP-AMP administration after partial hepatectomy in mice. Metabonomics showed that differential metabolites were enriched in glycolysis with high expression of beta-d-fructose 6-phosphate and lactate, followed by significantly strengthened lactate secretion in the supernatant (0.54) and serum (0.43) normalized to control. Upon ASP-AMP treatment, the knockdown of hexokinase 2 (HK2) or inhibited glycolysis caused by 2-deoxy-d-glucose decreased hepatocyte proliferation in vitro and in vivo. Furthermore, pathway analysis predicted the role of JAK2/STAT3 pathway in ASP-AMP-regulated liver regeneration, and phosphorylation of JAK2 and STAT3 was proven to be elevated in this promoting process. Finally, downregulated expression of HK2, an attenuated level of lactate secretion, and reduced hepatocyte proliferation were displayed when STAT3 was knocked out in vitro. Therefore, it can be concluded that ASP-AMP accelerated liver regeneration and exerted a hepatoprotective effect after hepatectomy, in which the JAK2/STAT3/HK2 pathway was actively involved in activating glycolysis.