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Journal of Clinical Medicine May 2024Amyotrophic lateral sclerosis (ALS) is a neuromuscular progressive disorder characterized by limb and bulbar muscle wasting and weakness. A total of 30% of patients...
Amyotrophic lateral sclerosis (ALS) is a neuromuscular progressive disorder characterized by limb and bulbar muscle wasting and weakness. A total of 30% of patients present a bulbar onset, while 70% have a spinal outbreak. Respiratory involvement represents one of the worst prognostic factors, and its early identification is fundamental for the early starting of non-invasive ventilation and for the stratification of patients. Due to the lack of biomarkers of early respiratory impairment, we aimed to evaluate the role of chest dynamic MRI in ALS patients. We enrolled 15 ALS patients and 11 healthy controls. We assessed the revised ALS functional rating scale, spirometry, and chest dynamic MRI. Data were analyzed by using the Mann-Whitney U test and Cox regression analysis. We observed a statistically significant difference in both respiratory parameters and pulmonary measurements at MRI between ALS patients and healthy controls. Moreover, we found a close relationship between pulmonary measurements at MRI and respiratory parameters, which was statistically significant after multivariate analysis. A sub-group analysis including ALS patients without respiratory symptoms and with normal spirometry values revealed the superiority of chest dynamic MRI measurements in detecting signs of early respiratory impairment. Our data suggest the usefulness of chest dynamic MRI, a fast and economically affordable examination, in the evaluation of early respiratory impairment in ALS patients.
PubMed: 38892814
DOI: 10.3390/jcm13113103 -
International Journal of Molecular... May 2024The mechanism underlying podocyte dysfunction in minimal change disease (MCD) remains unknown. This study aimed to shed light on the potential pathophysiology of MCD...
The mechanism underlying podocyte dysfunction in minimal change disease (MCD) remains unknown. This study aimed to shed light on the potential pathophysiology of MCD using glomerular proteomic analysis. Shotgun proteomics using label-free quantitative mass spectrometry was performed on formalin-fixed, paraffin-embedded (FFPE) renal biopsies from two groups of samples: control (CTR) and MCD. Glomeruli were excised from FFPE renal biopsies using laser capture microdissection (LCM), and a single-pot solid-phase-enhanced sample preparation (SP3) digestion method was used to improve yield and protein identifications. Principal component analysis (PCA) revealed a distinct separation between the CTR and MCD groups. Forty-eight proteins with different abundance between the two groups (-value ≤ 0.05 and |FC| ≥ 1.5) were identified. These may represent differences in podocyte structure, as well as changes in endothelial or mesangial cells and extracellular matrix, and some were indeed found in several of these structures. However, most differentially expressed proteins were linked to the podocyte cytoskeleton and its dynamics. Some of these proteins are known to be involved in focal adhesion (NID1 and ITGA3) or slit diaphragm signaling (ANXA2, TJP1 and MYO1C), while others are structural components of the actin and microtubule cytoskeleton of podocytes (ACTR3 and NES). This study suggests the potential of mass spectrometry-based shotgun proteomic analysis with LCM glomeruli to yield valuable insights into the pathogenesis of podocytopathies like MCD. The most significantly dysregulated proteins in MCD could be attributable to cytoskeleton dysfunction or may be a compensatory response to cytoskeleton malfunction caused by various triggers.
Topics: Humans; Nephrosis, Lipoid; Proteomics; Podocytes; Kidney Glomerulus; Male; Female; Adult; Proteome; Laser Capture Microdissection; Middle Aged
PubMed: 38891801
DOI: 10.3390/ijms25115613 -
Cells May 2024Podocyte health is vital for maintaining proper glomerular filtration in the kidney. Interdigitating foot processes from podocytes form slit diaphragms which regulate... (Review)
Review
Podocyte health is vital for maintaining proper glomerular filtration in the kidney. Interdigitating foot processes from podocytes form slit diaphragms which regulate the filtration of molecules through size and charge selectivity. The abundance of lipid rafts, which are ordered membrane domains rich in cholesterol and sphingolipids, near the slit diaphragm highlights the importance of lipid metabolism in podocyte health. Emerging research shows the importance of sphingolipid metabolism to podocyte health through structural and signaling roles. Dysregulation in sphingolipid metabolism has been shown to cause podocyte injury and drive glomerular disease progression. In this review, we discuss the structure and metabolism of sphingolipids, as well as their role in proper podocyte function and how alterations in sphingolipid metabolism contributes to podocyte injury and drives glomerular disease progression.
Topics: Podocytes; Sphingolipids; Humans; Animals; Lipid Metabolism; Kidney Diseases; Membrane Microdomains
PubMed: 38891023
DOI: 10.3390/cells13110890 -
Experimental Gerontology Jun 2024Autophagy is a ubiquitous process through which damaged cytoplasmic structures are recycled and degraded within cells. Aging can affect autophagy regulation in different...
Autophagy is a ubiquitous process through which damaged cytoplasmic structures are recycled and degraded within cells. Aging can affect autophagy regulation in different steps leading to the accumulation of damaged organelles and proteins, which can contribute to cell dysfunction and death. Motor neuron (MN) loss and sarcopenia are prominent features of neuromuscular aging. Previous studies on phrenic MNs showed increased levels of the autophagy proteins LC3 and p62 in 24 month compared to 6 month old mice, consistent with the onset of diaphragm muscle sarcopenia. In the present study, we hypothesized that aging leads to increased expression of the autophagy markers LC3 and p62 in single lumbar MNs. Expression of LC3 and p62 in lumbar MNs (spinal levels L1-L6) was assessed using immunofluorescence and confocal imaging of male and female mice at 6, 18 and 24 months of age, reflecting 100 %, 90 % and 75 % survival, respectively. A mixed linear model with animal as a random effect was used to compare relative LC3 and p62 expression in choline acetyl transferase-positive MNs across age groups. Expression of LC3 and p62 decreased in the white matter of the lumbar spinal cord with aging, with ~29 % decrease in LC3 and ~ 7 % decrease in p62 expression at 24 months of age compared to 6 months of age. There was no change in LC3 or p62 expression in the gray matter with age. LC3 expression in MNs relative to white matter increased significantly with age, with 150 % increase at 24 months of age compared to 6 months of age. Similarly, p62 expression in MNs relative to white matter increased significantly with age, with ~14 % increase at 24 months of age compared to 6 months of age. No effect of sex or MN pool was observed in LC3 and p62 expression in MNs. Overall, these data suggest autophagy impairment during elongation (increased LC3) and degradation (increased p62) phases with aging in lumbar MNs.
PubMed: 38885913
DOI: 10.1016/j.exger.2024.112483 -
IScience Jun 2024The murine embryonic diaphragm is a primary model for studying myogenesis and neuro-muscular synaptogenesis, both representing processes regulated by spatially organized...
The murine embryonic diaphragm is a primary model for studying myogenesis and neuro-muscular synaptogenesis, both representing processes regulated by spatially organized genetic programs of myonuclei located in distinct myodomains. However, a spatial gene expression pattern of embryonic mouse diaphragm has not been reported. Here, we provide spatially resolved gene expression data for horizontally sectioned embryonic mouse diaphragms at embryonic days E14.5 and E18.5. These data reveal gene signatures for specific muscle regions with distinct maturity and fiber type composition, as well as for a central neuromuscular junction (NMJ) and a peripheral myotendinous junction (MTJ) compartment. Comparing spatial expression patterns of wild-type mice with those of transgenic mice lacking either the skeletal muscle calcium channel Ca1.1 or β-catenin, reveals curtailed muscle development and dysregulated expression of genes potentially involved in NMJ formation. Altogether, these datasets provide a powerful resource for further studies of muscle development and NMJ formation in the mouse.
PubMed: 38883818
DOI: 10.1016/j.isci.2024.110018 -
Factors associated with incomplete resection for large, locally invasive non-small cell lung cancer.Journal of Thoracic Disease May 2024Large, node-negative but locally invasive non-small cell lung cancer (NSCLC) is associated with increased perioperative risk but improved survival if a complete...
BACKGROUND
Large, node-negative but locally invasive non-small cell lung cancer (NSCLC) is associated with increased perioperative risk but improved survival if a complete resection is obtained. Factors associated with positive margins in this population are not well-studied.
METHODS
We performed a retrospective cohort study using National Cancer Database (NCDB) for adult patients with >5 cm, clinically node-negative NSCLC with evidence of invasion of nearby structures [2006-2015]. Patients were classified as having major structure involvement (azygous vein, pulmonary artery/vein, vena cava, carina/trachea, esophagus, recurrent laryngeal/vagus nerve, heart, aorta, vertebrae) or chest wall invasion (rib pleura, chest wall, diaphragm). Our primary outcome was to evaluate factors associated with incomplete resection (microscopic: R1, macroscopic: R2). Kaplan-Meier analysis and cox multivariable regression models were used to evaluate overall survival (OS), 90-day mortality, and factors associated with positive margins.
RESULTS
Among 2,368 patients identified, the median follow-up was 33.8 months [interquartile range (IQR), 12.6-66.5 months]. Most patients were white (86.9%) with squamous cell histology (47.3%). Major structures were involved in 26.4% of patients and chest wall invasion was seen in 73.6%. Four hundred and seventy-eight patients (20.2%) had an incomplete resection. Multivariable analysis revealed that black race [hazard ratio (HR) 1.568, 95% confidence interval (CI): 1.109-2.218] and major structure involvement (HR 1.412, 95% CI: 1.091-1.827) was associated with increased risk of incomplete resection and surgery at an academic hospitals (HR 0.773, 95% CI: 0.607-0.984), adenocarcinoma histology (HR 0.672, 95% CI: 0.514-0.878), and neoadjuvant chemotherapy (HR 0.431, 95% CI: 0.316-0.587) were associated with decreased risk of incomplete resection. The 5-year OS was 43.7% in the entire cohort and 28.8% in patients with positive margins and 47.5% in patients with an R0 resection. Positive margin was also associated with a significantly higher 90-day mortality rate (9.9% versus 6.7%).
CONCLUSIONS
For patients with large, node-negative NSCLC invading nearby structures, R0 resection portends better survival. Treatment at academic centers, adenocarcinoma histology, and receipt of neoadjuvant chemotherapy are associated with R0 resection in this high-risk cohort.
PubMed: 38883676
DOI: 10.21037/jtd-23-989 -
Journal of Thoracic Disease May 2024Axial spondyloarthritis (axSpA) includes thoracic manifestations and changes in respiratory function that require a comprehensive understanding for effective treatment.... (Review)
Review
Thoracic manifestations and respiratory function alterations in axial spondyloarthritis and newest possibilities of ultrasound to detect changes in diaphragm-a narrative review.
BACKGROUND AND OBJECTIVE
Axial spondyloarthritis (axSpA) includes thoracic manifestations and changes in respiratory function that require a comprehensive understanding for effective treatment. This review aims to investigate these manifestations and evaluate the role of ultrasound in detecting diaphragmatic changes to provide insights for improved diagnosis and treatment strategies in axSpA patients.
METHODS
A systematic search was conducted in Index Medicus and Scopus from 2003 to 2023. Inclusion criteria included primary and secondary publications, with a focus on high-quality evidence such as randomised controlled trials and systematic reviews with or without meta-analysis. Keywords spondyloarthritis, respiratory, chest, thoracic, diaphragm and ultrasound were used in the search. A total of 22 articles were identified after duplicates, and inadequate papers were removed.
KEY CONTENT AND FINDINGS
The review included the prevalence, classification and extra-articular manifestations of axSpA, highlighting the impact on respiratory function. Thoracic manifestations and the potential impact of pharmacological interventions were detailed, and various conditions affecting respiratory dynamics were discussed. In addition, the utility of ultrasonography in assessing diaphragmatic function was explained and the techniques, parameters and measurements used to assess diaphragmatic movement, muscle thickness and respiratory mobility were described. The results illustrate the changes in diaphragmatic function in axSpA patients and their correlation with disease activity.
CONCLUSIONS
This narrative review highlights the intricate relationship between axSpA and respiratory manifestations and emphasises the significant impact on thoracic function and diaphragmatic dynamics. The utility of ultrasound in assessing diaphragmatic function offers a promising avenue for objective evaluation that provides insight into disease activity and potential therapeutic responses. This review emphasises the critical role of early diagnosis and vigilant monitoring, and advocates a multidisciplinary approach that integrates non-pharmacological interventions, particularly tailored physical activity, to maintain and improve respiratory function in axSpA patients. Increased research initiatives and awareness of pulmonary complications in axSpA are essential to optimise medical care and improve treatment outcomes in this patient group.
PubMed: 38883670
DOI: 10.21037/jtd-23-1936 -
Experimental Biology and Medicine... 2024Podocyte injury or dysfunction can lead to proteinuria and glomerulosclerosis. Zonula occludens 1 (ZO-1) is a tight junction protein which connects slit diaphragm (SD)...
Podocyte injury or dysfunction can lead to proteinuria and glomerulosclerosis. Zonula occludens 1 (ZO-1) is a tight junction protein which connects slit diaphragm (SD) proteins to the actin cytoskeleton. Previous studies have shown that the expression of ZO-1 is decreased in chronic kidney disease (CKD). Thus, elucidation of the regulation mechanism of ZO-1 has considerable clinical importance. Triptolide (TP) has been reported to exert a strong antiproteinuric effect by inhibiting podocyte epithelial mesenchymal transition (EMT) and inflammatory response. However, the underlying mechanisms are still unclear. We found that TP upregulates ZO-1 expression and increases the fluorescence intensity of ZO-1 in a puromycin aminonucleoside (PAN)-induced podocyte injury model. Permeablity assay showed TP decreases podocyte permeability in PAN-treated podocyte. TP also upregulates the DNA demethylase TET2. Our results showed that treatment with the DNA methyltransferase inhibitors 5-azacytidine (5-AzaC) and RG108 significantly increased ZO-1 expression in PAN-treated podocytes. Methylated DNA immunoprecipitation (MeDIP) and hydroxymethylated DNA immunoprecipitation (hMeDIP) results showed that TP regulates the methylation status of the ZO-1 promoter. Knockdown of TET2 decreased ZO-1 expression and increased methylation of its promoter, resulting in the increase of podocyte permeability. Altogether, these results indicate that TP upregulates the expression of ZO-1 and decreases podocyte permeability through TET2-mediated 5 mC demethylation. These findings suggest that TP may alleviate podocyte permeability through TET2-mediated hydroxymethylation of ZO-1.
Topics: Podocytes; Zonula Occludens-1 Protein; Phenanthrenes; Diterpenes; Epoxy Compounds; Dioxygenases; Animals; DNA-Binding Proteins; Mice; Proto-Oncogene Proteins; Permeability; Humans; DNA Methylation
PubMed: 38881848
DOI: 10.3389/ebm.2024.10051 -
Respiratory Physiology & Neurobiology Jun 2024Assessing cough effectiveness, using Cough Peak Flow, is crucial for patients with Neuromuscular Diseases, such as Amyotrophic Lateral Sclerosis. Impaired cough function...
Assessing cough effectiveness, using Cough Peak Flow, is crucial for patients with Neuromuscular Diseases, such as Amyotrophic Lateral Sclerosis. Impaired cough function can contribute to respiratory decline and failure. The goal of the study is to determine the correlation between diaphragmatic excursion and cough expiratory phase, potentially utilizing ultrasonographic indices to estimate Cough Peak Flow in these patients. Twenty-two patients were enrolled in this study. The upward displacement of the diaphragm was measured with ultrasonography during voluntary cough expiration and Cough Peak Flow was simultaneously measured. A multivariable linear regression model was built to quantify the association between Cough Peak Flow and diaphragm expiratory excursion. There is significative relationship between Cough Peak Flow and diaphragm excursion with a Pearson's r coefficient of 0.86 observed in the patients group. Multiple linear regression analysis for Cough Peak Flow (Adjusted R = 0.86) revealed significant associations between Cough Peak Flow and expiratory excursion (adjusted β-coefficient: 64.78, 95 %, CI: 51.50-78.07, p<0.001) and sex (adjusted β-coefficient: -69.06; 95 % CI: -109.98 to -28.15, p=0.001). Our results predict the cough effectiveness by using M-mode diaphragmatic sonography with a potentially significant impact on therapeutic choices.
PubMed: 38879100
DOI: 10.1016/j.resp.2024.104299 -
Musculoskeletal Science & Practice Jun 2024
PubMed: 38878589
DOI: 10.1016/j.msksp.2024.102982