One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: homocysteine and beyond.

Hyperhomocysteinemia is a risk factor for cognitive decline and dementia, including Alzheimer disease (AD). Homocysteine (Hcy) is a sulfur-containing amino acid and metabolite of the methionine pathway. The interrelated methionine, purine, and thymidylate cycles constitute the one-carbon metabolism that plays a critical role in the synthesis of DNA, neurotransmitters, phospholipids, and myelin. In this study, we tested the hypothesis that one-carbon metabolites beyond Hcy are relevant to cognitive function and cerebrospinal fluid (CSF) measures of AD pathology in older adults. Cross-sectional analysis was performed on matched CSF and plasma collected from 120 older community-dwelling adults with (n = 72) or without (n = 48) cognitive impairment. Liquid chromatography-mass spectrometry was performed to quantify one-carbon metabolites and their cofactors. Least absolute shrinkage and selection operator (LASSO) regression was initially applied to clinical and biomarker measures that generate the highest diagnostic accuracy of a priori-defined cognitive impairment (Clinical Dementia Rating-based) and AD pathology (i.e., CSF tau phosphorylated at threonine 181 [p-tau181]/β-Amyloid 1-42 peptide chain [Aβ1-42] >0.0779) to establish a reference benchmark. Two other LASSO-determined models were generated that included the one-carbon metabolites in CSF and then plasma. Correlations of CSF and plasma one-carbon metabolites with CSF amyloid and tau were explored. LASSO-determined models were stratified by apolipoprotein E (APOE) ε4 carrier status. The diagnostic accuracy of cognitive impairment for the reference model was 80.8% and included age, years of education, Aβ1-42, tau, and p-tau181. A model including CSF cystathionine, methionine, S-adenosyl-L-homocysteine (SAH), S-adenosylmethionine (SAM), serine, cysteine, and 5-methyltetrahydrofolate (5-MTHF) improved the diagnostic accuracy to 87.4%. A second model derived from plasma included cystathionine, glycine, methionine, SAH, SAM, serine, cysteine, and Hcy and reached a diagnostic accuracy of 87.5%. CSF SAH and 5-MTHF were associated with CSF tau and p-tau181. Plasma one-carbon metabolites were able to diagnose subjects with a positive CSF profile of AD pathology in APOE ε4 carriers. We observed significant improvements in the prediction of cognitive impairment by adding one-carbon metabolites. This is partially explained by associations with CSF tau and p-tau181, suggesting a role for one-carbon metabolism in the aggregation of tau and neuronal injury. These metabolites may be particularly critical in APOE ε4 carriers

Hyaluronic acid levels are increased in complicated parapneumonic pleural effusions

Background and Aim. Hyaluronic acid (HA) is a component of extracellular matrix and may play a role in the pleural inflammation which is implicated in parapneumonic effusions.The aim of the current study was to investigate HA levels in serum and pleura in patients with parapneumonic effusions. Methods. We prospectively studied pleural and serum levels of HA in 58 patients with pleural effusions due to infection (complicated and uncomplicated parapneumonic effusions), malignant effusions and transudative effusions due to congestive heart failure. In addition to HA, TNF-α and IL-1β levels were determined in pleural fluid and serum by ELISA. Results. The median±SD HA levels (pg/ml) in pleural fluid of patients with complicated effusions (39.058±11.208) were significantly increased (p<0.005), compared to those with uncomplicated parapneumonic effusions (11.230±1.969), malignant effusions (10.837±4.803) or congestive heart failure (5.392±3.133). There was no correlation between pleural fluid and serum HA values. Pleural fluid TNF-α levels (146±127 pg/mL) and IL-1β levels (133.4±156 pg/mL) were significantly higher in patients with complicated parapneumonic effusions compared to patients with other types of effusion (p<0.05). No significant association between HA and TNF-α or IL-1β was found. Conclusions. HA may play a significant role in the inflammatory process which characterises exudative infectious pleuritis. Further investigation might reveal whether HA is a useful marker in the management of parapneumonic effusions

Blood Biomarkers in Idiopathic Pulmonary Fibrosis.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease of unknown origin whose incidence has been increasing over the latest decade partly as a consequence of population ageing. New anti-fibrotic therapy including pirfenidone and nintedanib have now proven efficacy in slowing down the disease. Nevertheless, diagnosis and follow-up of IPF remain challenging. METHODS: This review examines the recent literature on potentially useful blood molecular and cellular biomarkers in IPF. Most of the proposed biomarkers belong to chemokines (IL-8, CCL18), proteases (MMP-1 and MMP-7), and growth factors (IGBPs) families. Circulating T cells and fibrocytes have also gained recent interest in that respect. Up to now, though several interesting candidates are profiling there has not been a single biomarker, which proved to be specific of the disease and predictive of the evolution (decline of pulmonary function test values, risk of acute exacerbation or mortality). CONCLUSION: Large scale multicentric studies are eagerly needed to confirm the utility of these biomarkers

Matrix Metalloproteinases in Respiratory Diseases: From Pathogenesis to Potential Clinical Implications

Matrix metalloproteinases (MMPs) are zinc-endopeptidases responsible for degradation of the extracellular matrix (ECM) components including basement membrane collagen, interstitial collagen, fibronectin, and various proteoglycans, during normal remodeling and repair processes. The turnover and remodeling of ECM must be tightly regulated since excessive or inappropriate expression of MMPs may contribute to the pathogenesis of tissue destructive processes associated with lung inflammation and disease. Despite the fact that our knowledge in the field of MMP biology is rapidly expanding, the role of MMPs in the pathogenesis of lung diseases is still not clear. The aim of the present review is to present the basic principles of MMP biology and, subsequently, to focus on the clinical and experimental evidence related to MMP activity in various lung disorders, including lung cancer, pleural effusions, chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome and interstitial lung diseases

Matrix Metalloproteinase Levels in the Differentiation of Parapneumonic Pleural Effusions

Background: Matrix metalloproteinases (MMPs) have been implicated in the escalation of fibrosis and remodeling which are central to the subsequent progression of a parapneumonic pleural effusion to empyema. Objectives: The aim of this study was the assessment of MMP-2, MMP-8 and MMP-9 in parapneumonic pleural effusions in order to examine their value in the differentiation between uncomplicated and complicated parapneumonic effusions. Methods: The study included 208 consecutive patients with pleural effusions [60 parapneumonic (27 uncomplicated parapneumonic, 17 complicated parapneumonic, 16 empyemas), 24 tuberculous, 89 malignant and 35 transudates]. Concentrations of pleural fluid and serum MMP-2, MMP-8 and MMP-9 were determined by immunoassay. Results: Pleural fluid MMP-8 and MMP-9 levels were higher in complicated parapneumonic effusions or empyema than in uncomplicated effusions, while their serum levels were higher in complicated par apneumonic effusions. MMP-2 levels were higher in uncomplicated than in complicated parapneumonic effusions or empyema. Pleural fluid MMP-2/MMP-9 ratio was the best marker to differentiate complicated from uncomplicated parapneumonic effusions, with a sensitivity of 94.1% and a specificity of 77.8% at a cut-off point of 1.32 (AUC = 0.887). Conclusions: Pleural fluid MMP-2, MMP-8 and MMP-9 may provide useful information for differentiating between uncomplicated and complicated parapneumonic effusions. Copyright (C) 2010 S. Karger AG, Base

Hyaluronic acid levels are increased in complicated parapneumonic pleural effusions

Background and Aim. Hyaluronic acid (HA) is a component of extracellular matrix and may play a role in the pleural inflammation which is implicated in parapneumonic effusions.The aim of the current study was to investigate HA levels in serum and pleura in patients with parapneumonic effusions. Methods. We prospectively studied pleural and serum levels of HA in 58 patients with pleural effusions due to infection (complicated and uncomplicated parapneumonic effusions), malignant effusions and transudative effusions due to congestive heart failure. In addition to HA, TNF-α and IL-1β levels were determined in pleural fluid and serum by ELISA. Results. The median±SD HA levels (pg/ml) in pleural fluid of patients with complicated effusions (39.058±11.208) were significantly increased (p<0.005), compared to those with uncomplicated parapneumonic effusions (11.230±1.969), malignant effusions (10.837±4.803) or congestive heart failure (5.392±3.133). There was no correlation between pleural fluid and serum HA values. Pleural fluid TNF-α levels (146±127 pg/mL) and IL-1β levels (133.4±156 pg/mL) were significantly higher in patients with complicated parapneumonic effusions compared to patients with other types of effusion (p<0.05). No significant association between HA and TNF-α or IL-1β was found. Conclusions. HA may play a significant role in the inflammatory process which characterises exudative infectious pleuritis. Further investigation might reveal whether HA is a useful marker in the management of parapneumonic effusions

Diagnostic accuracy of biomarkers of oxidative stress in parapneumonic pleural effusions

P&gt;Background The imbalance between oxidants and antioxidants is referred to as oxidative stress and has been associated with various respiratory disorders. The aim of this study was the assessment of 8-isoprostane (8-iso-PGF(2 alpha)) and Cu/Zn superoxide dismutase (Cu/Zn SOD) in exudative pleural effusions in order to examine the diagnostic accuracy of these markers in the differentiation between complicated and uncomplicated parapneumonic effusions. Methods The study included 214 consecutive patients with pleural effusions [68 parapneumonic (31 uncomplicated parapneumonic, 20 complicated parapneumonic, 17 empyemas), 24 tuberculous, 88 malignant and 34 transudates]. 8-Isoprostane and Cu/Zn SOD were determined by ELISA in pleural fluid and serum. Results Parapneumonic effusions were characterized by higher pleural fluid 8-isoprostane levels compared to transudative, malignant and tuberculous effusions. Pleural fluid Cu/Zn SOD levels were lower in transudates, while serum levels were higher in transudative compared to all exudative pleural effusions. Both pleural fluid 8-isoprostane and Cu/Zn SOD were higher in complicated parapneumonic effusions and empyemas compared to uncomplicated parapneumonic effusions. Pleural fluid 8-isoprostane was the most accurate test to differentiate between complicated and uncomplicated parapneumonic pleural effusions with a sensitivity of 100% and a specificity of 58 center dot 1% at a cut-off point of 35 center dot 1 (AUC = 0 center dot 848). Conclusions Pleural fluid 8-isoprostane and Cu/Zn SOD may provide useful information for the differentiation between uncomplicated and complicated parapneumonic effusions and empyemas

Matrix Metalloproteinase Levels in the Differentiation of Parapneumonic Pleural Effusions

Background: Matrix metalloproteinases (MMPs) have been implicated in the escalation of fibrosis and remodeling which are central to the subsequent progression of a parapneumonic pleural effusion to empyema. Objectives: The aim of this study was the assessment of MMP-2, MMP-8 and MMP-9 in parapneumonic pleural effusions in order to examine their value in the differentiation between uncomplicated and complicated parapneumonic effusions. Methods: The study included 208 consecutive patients with pleural effusions [60 parapneumonic (27 uncomplicated parapneumonic, 17 complicated parapneumonic, 16 empyemas), 24 tuberculous, 89 malignant and 35 transudates]. Concentrations of pleural fluid and serum MMP-2, MMP-8 and MMP-9 were determined by immunoassay. Results: Pleural fluid MMP-8 and MMP-9 levels were higher in complicated parapneumonic effusions or empyema than in uncomplicated effusions, while their serum levels were higher in complicated par apneumonic effusions. MMP-2 levels were higher in uncomplicated than in complicated parapneumonic effusions or empyema. Pleural fluid MMP-2/MMP-9 ratio was the best marker to differentiate complicated from uncomplicated parapneumonic effusions, with a sensitivity of 94.1% and a specificity of 77.8% at a cut-off point of 1.32 (AUC = 0.887). Conclusions: Pleural fluid MMP-2, MMP-8 and MMP-9 may provide useful information for differentiating between uncomplicated and complicated parapneumonic effusions. Copyright (C) 2010 S. Karger AG, Base