The relationship between the development and/or progression of interstitial lung abnormalities (ILA) and clinical outcomes has not been previously investigated.
To determine the risk factors for, and ...the clinical consequences of, having ILA progression in participants from the Framingham Heart Study.
ILA were assessed in 1,867 participants who had serial chest computed tomography (CT) scans approximately 6 years apart. Mixed effect regression (and Cox) models were used to assess the association between ILA progression and pulmonary function decline (and mortality).
During the follow-up period 660 (35%) participants did not have ILA on either CT scan, 37 (2%) had stable to improving ILA, and 118 (6%) had ILA with progression (the remaining participants without ILA were noted to be indeterminate on at least one CT scan). Increasing age and increasing copies of the MUC5B promoter polymorphism were associated with ILA progression. After adjustment for covariates, ILA progression was associated with a greater FVC decline when compared with participants without ILA (20 ml; SE, ±6 ml; P = 0.0005) and with those with ILA without progression (25 ml; SE, ±11 ml; P = 0.03). Over a median follow-up time of approximately 4 years, after adjustment, ILA progression was associated with an increase in the risk of death (hazard ratio, 3.9; 95% confidence interval, 1.3-10.9; P = 0.01) when compared with those without ILA.
These findings demonstrate that ILA progression in the Framingham Heart Study is associated with an increased rate of pulmonary function decline and increased risk of death.
Drug-induced liver injury is a major cause of safety-related drug-marketing withdrawals. Several drugs have been reported to disrupt mitochondrial function, resulting in hepatotoxicity. The ...development of a simple and effective in vitro assay to identify the potential for mitochondrial toxicity is thus desired to minimize the risk of causing hepatotoxicity and subsequent drug withdrawal. An in vitro test method called the "glucose-galactose" assay is often used in drug development but requires prior-culture of cells over several passages for mitochondrial adaptation, thereby restricting use of the assay. Here, we report a rapid version of this method with the same predictability as the original method. We found that replacing the glucose in the medium with galactose resulted in HepG2 cells immediately shifting their energy metabolism from glycolysis to oxidative phosphorylation due to drastic energy starvation; in addition, the intracellular concentration of ATP was reduced by mitotoxicants when glucose in the medium was replaced with galactose. Using our proposed rapid method, mitochondrial dysfunction in HepG2 cells can be evaluated by drug exposure for one hour without a pre-culture step. This rapid assay for mitochondrial toxicity may be more suitable for high-throughput screening than the original method at an early stage of drug development.
Abstract The invention of hyperpolarized (HP) noble gas MRI using helium-3 (3 He) or xenon-129 (129 Xe) has provided a new method to evaluate lung function. Using HP3 He or129 Xe for inhalation into ...the lung air spaces as an MRI contrast agent significantly increases MR signal and makes pulmonary ventilation imaging feasible. This review focuses on important aspects of pulmonary HP noble gas MRI, including the following: (1) functional imaging types, (2) applications for major pulmonary diseases, (3) safety considerations, and (4) future directions. Although it is still challenging to use pulmonary HP noble gas MRI clinically, the technology offers promise for the investigation of the microstructure and function of the lungs.
•Dynamic chest radiography is a new method for quantification of diaphragmatic motion.•We analyzed diaphragmatic kinetics under forced breathing in 174 volunteers.•Mean whole excursions were 49.1 ± ...17.0 mm (right, R) and 52.1 ± 15.9 mm (left, L).•Peak inspiratory motion speeds were 26.7 ± 10.0 mm/s (R) and 32.2 ± 12.4 mm/s (L).•BMI and VC were associated with whole excursions and peak speeds of the diaphragms.
Objective: To assess diaphragmatic motion during forced breathing in a health screening center cohort by time-resolved quantitative analysis using dynamic chest radiography and demonstrate the characteristics and associations with demographics and pulmonary function of participants.
Materials and methods: This prospective study includes 174 volunteers (99 males; median 57, range 36–93 years old) that underwent dynamic chest radiography with a flat panel detector system during forced breathing in a standing position. We automatically tracked and recorded the positions of the top of the diaphragms and the excursions on images of each participant and calculated peak motion speeds based on the data. We investigated the associations with demographics and pulmonary function statistically.
Results: The average excursions of the diaphragms during forced breathing were 49.1 ± 17.0 mm (right; mean ± standard deviation) and 52.1 ± 15.9 mm (left). The peak motion speeds were 26.7 ± 10.0 mm/s (right) and 32.2 ± 12.4 mm/s (left) in the inspiratory phase and 22.1 ± 12.7 mm/s (right) and 24.3 ± 10.3 mm/s (left) in the expiratory phase. Excursions and peak motion speeds of the left diaphragm were significantly greater than the right. Higher body mass index (BMI) and vital capacity (VC) were associated with greater excursions and faster peak motion speeds of the diaphragms.
Conclusions: Time-resolved quantitative analysis of the diaphragms with dynamic chest radiography demonstrated the characteristics of diaphragmatic motion during forced breathing in a health screening cohort. Higher BMI and VC were associated with excursions and peak motion speeds of the diaphragms.
Objective
Interstitial lung disease (ILD) is a relatively common extraarticular manifestation of rheumatoid arthritis (RA) that contributes significantly to disease burden and excess mortality. The ...purpose of this study was to identify peripheral blood markers of RA‐associated ILD that can facilitate earlier diagnosis and provide insight regarding the pathogenesis of this potentially devastating disease complication.
Methods
Patients with RA who were enrolled in a well‐characterized Chinese identification cohort or a US replication cohort were subclassified as having RA–no ILD, RA–mild ILD, or RA–advanced ILD, based on high‐resolution computed tomography scans of the chest. Multiplex enzyme‐linked immunosorbent assays (ELISAs) and Luminex xMAP technology were used to assess 36 cytokines/chemokines, matrix metalloproteinases (MMPs), and acute‐phase proteins in the identification cohort. Unadjusted and adjusted logistic regression models were used to quantify the strength of association between RA‐ILD and biomarkers of interest.
Results
MMP‐7 and interferon‐γ–inducible protein 10 (IP‐10)/CXCL10 were identified by multiplex ELISA as potential biomarkers for RA‐ILD in 133 RA patients comprising the Chinese identification cohort (50 RA–no ILD, 41 RA‐ILD, 42 RA–indeterminate ILD). The findings were confirmed by standard solid‐phase sandwich ELISA in the Chinese identification cohort as well as an independent cohort of US patients with RA and different stages of ILD (22 RA–no ILD, 49 RA‐ILD, 15 RA–indeterminate ILD), with statistically significant associations in both unadjusted and adjusted logistic regression analyses.
Conclusion
Levels of MMP‐7 and IP‐10/CXCL10 are elevated in the serum of RA patients with ILD, whether mild or advanced, supporting their value as pathogenically relevant biomarkers that can contribute to noninvasive detection of this extraarticular disease complication.
The
promoter polymorphism (rs35705950) has been associated with interstitial lung abnormalities (ILA) in white participants from the general population; whether these findings are replicated and ...influenced by the ILA subtype is not known. We evaluated the associations between the
genotype and ILA in cohorts with extensive imaging characterisation.We performed ILA phenotyping and
promoter genotyping in 5308 and 9292 participants from the AGES-Reykjavik and COPDGene cohorts, respectively.We found that ILA was present in 7% of participants from the AGES-Reykjavik, 8% of non-Hispanic white participants from COPDGene and 7% of African-American participants from COPDGene. Although the
genotype was strongly associated (after correction for multiple testing) with ILA (OR 2.1, 95% CI 1.8-2.4, p=1×10
), there was evidence of significant heterogeneity between cohorts (I
=81%). When narrowed to specific radiologic subtypes, (
subpleural ILA), the
genotype remained strongly associated (OR 2.6, 95% CI 2.2-3.1, p=1×10
) with minimal heterogeneity (I
=0%). Although there was no evidence that the
genotype influenced survival, there was evidence that
genotype improved risk prediction for possible usual interstitial pneumonia (UIP) or a UIP pattern in non-Hispanic white populations.The
promoter polymorphism is strongly associated with ILA and specific radiologic subtypes of ILA, with varying degrees of heterogeneity in the underlying populations.
The Hippo pathway plays an important role in the growth, development, and regeneration of cells and organs. Transcriptional enhanced associate domain (TEAD), a transcription activator of the Hippo ...pathway, forms the complex with a transcriptional coactivator yes-associated protein (YAP) or a transcriptional coactivator PDZ-binding motif (TAZ). Their excessive activations are involved in carcinogenesis such as malignant pleural mesothelioma (MPM), and thus inhibition of the TEAD complex is expected to have potent anticancer activity against MPM. On the other hand, YAP or TAZ conditional knockout mice have been reported to show abnormal findings in various tissues, including the kidney, liver, and lung. In the present study, we evaluated the systemic toxicity of K-975, a novel TEAD inhibitor, in rats. When K-975 was administered orally to rats for 1 week, proteinuria suggestive of nephrotoxicity was observed. Electron microscopy revealed that K-975 at 300 mg/kg induced glomerular podocyte foot process effacement. After a 2-week recovery period, proteinuria with foot process effacement was recovered completely. Urinalysis and urinary biomarker evaluation suggested that the urinary albumin index (urinary albumin/urinary creatinine) was the most sensitive marker for detecting K-975-induced nephrotoxicity. After 3 cycles of 1-week administration followed by 2-week recovery periods, nephrotoxicity was reversible; however, incomplete reversibility was observed in rats with severe proteinuria. In conclusion, this study revealed that in rats, oral K-975 treatment induced severe proteinuria by podocyte foot process effacement, which was reversible and monitorable by the urinary albumin index, suggesting important information for developing K-975 as an anticancer drug.
PurposeTo investigate if clinical non-contrast chest CT studies obtained with PCD CT using much lower radiation exposure can achieve the same image quality as with the currently established EID ...protocol.Materials/methodsA total of seventy-one patients were identified who had a non-contrast chest computed tomography (CT) done on PCD CT and EID CT scanners within a 4-month interval. Five fellowship trained chest radiologists, blinded to the scanner details were asked to review the cases side-by-side and record their preference for images from either the photon-counting-detector (PCD) CT or the energy-integrating detector (EID) CT scanner.ResultsThe median CTDIvol for PCD-CT system was 4.710 mGy and EID system was 7.80 mGy (p < 0.001). The median DLP with the PCD-CT was 182.0 mGy.cm and EID system was 262.60 mGy.cm (p < 0.001). The contrast to noise ratio (CNR) was superior on the PCD-CT system 59.2 compared to the EID-CT 53.3; (p < 0.001). Kappa-statistic showed that there was poor agreement between the readers over the image quality from the PCD and EID scanners (κ = 0.19; 95 % CI: 0.12 - 0.27; p < 0.001). Chi-square analysis revealed that 3 out of 5 readers showed a significant preference for images from the PCDCT (p ≤ 0.012). There was no significant difference in the preferences of two readers between EID-CT and PCD-CT images.ConclusionThe first clinical PCD-CT system allows a significant reduction in radiation exposure while maintaining image quality and image noise using a standardized non-contrast chest CT protocol.
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