Spirometry test values can be estimated from a single chest radiograph.

Introduction: Physical measurements of expiratory flow volume and speed can be obtained using spirometry. These measurements have been used for the diagnosis and risk assessment of chronic obstructive pulmonary disease and play a crucial role in delivering early care. However, spirometry is not performed frequently in routine clinical practice, thereby hindering the early detection of pulmonary function impairment. Chest radiographs (CXRs), though acquired frequently, are not used to measure pulmonary functional information. This study aimed to evaluate whether spirometry parameters can be estimated accurately from single frontal CXR without image findings using deep learning. Methods: Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and FEV1/FVC as spirometry measurements as well as the corresponding chest radiographs of 11,837 participants were used in this study. The data were randomly allocated to the training, validation, and evaluation datasets at an 8:1:1 ratio. A deep learning network was pretrained using ImageNet. The input and output information were CXRs and spirometry test values, respectively. The training and evaluation of the deep learning network were performed separately for each parameter. The mean absolute error rate (MAPE) and Pearson's correlation coefficient (r) were used as the evaluation indices. Results: The MAPEs between the spirometry measurements and AI estimates for FVC, FEV1 and FEV1/FVC were 7.59% (r = 0.910), 9.06% (r = 0.879) and 5.21% (r = 0.522), respectively. A strong positive correlation was observed between the measured and predicted indices of FVC and FEV1. The average accuracy of >90% was obtained in each estimation of spirometry indices. Bland-Altman analysis revealed good agreement between the estimated and measured values for FVC and FEV1. Discussion: Frontal CXRs contain information related to pulmonary function, and AI estimation performed using frontal CXRs without image findings could accurately estimate spirometry values. The network proposed for estimating pulmonary function in this study could serve as a recommendation for performing spirometry or as an alternative method, suggesting its utility.

Rapid three-dimensional quantification of high-intensity plaques from coronary atherosclerosis T1-weighted characterization to predict periprocedural myocardial injury.

BACKGROUND: High-intensity plaque (HIP) on magnetic resonance imaging (MRI) has been documented as a powerful predictor of periprocedural myocardial injury (PMI) following percutaneous coronary intervention (PCI). Despite the recent proposal of three-dimensional HIP quantification to enhance the predictive capability, the conventional pulse sequence, which necessitates the separate acquisition of anatomical reference images, hinders accurate three-dimensional segmentation along the coronary vasculature. Coronary atherosclerosis T1-weighted characterization (CATCH) enables the simultaneous acquisition of inherently coregistered dark-blood plaque and bright-blood coronary artery images. We aimed to develop a novel HIP quantification approach using CATCH and to ascertain its superior predictive performance compared to the conventional two-dimensional assessment based on plaque-to-myocardium signal intensity ratio (PMR). METHODS: In this prospective study, CATCH MRI was conducted before elective stent implantation in 137 lesions from 125 patients. On CATCH images, dedicated software automatically generated tubular three-dimensional volumes of interest on the dark-blood plaque images along the coronary vasculature, based on the precisely matched bright-blood coronary artery images, and subsequently computed PMR and HIP volume (HIPvol). Specifically, HIPvol was calculated as the volume of voxels with signal intensity exceeding that of the myocardium, weighted by their respective signal intensities. PMI was defined as post-PCI cardiac troponin-T > 5 × the upper reference limit. RESULTS: The entire analysis process was completed within 3 min per lesion. PMI occurred in 44 lesions. Based on the receiver operating characteristic curve analysis, HIPvol outperformed PMR for predicting PMI (C-statistics, 0.870 [95% CI, 0.805-0.936] vs. 0.787 [95% CI, 0.706-0.868]; p = 0.001). This result was primarily driven by the higher sensitivity HIPvol offered: 0.886 (95% CI, 0.754-0.962) vs. 0.750 for PMR (95% CI, 0.597-0.868; p = 0.034). Multivariable analysis identified HIPvol as an independent predictor of PMI (odds ratio, 1.15 per 10-µL increase; 95% CI, 1.01-1.30, p = 0.035). CONCLUSIONS: Our semi-automated method of analyzing coronary plaque using CATCH MRI provided rapid HIP quantification. Three-dimensional assessment using this approach had a better ability to predict PMI than conventional two-dimensional assessment.

Selective autophagy associated with iron overload aggravates non-alcoholic steatohepatitis via ferroptosis.

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) that causes cirrhosis and hepatocellular carcinoma. Iron is an essential trace element in the body; however, excess iron can cause tissue damage and dysfunction. Iron overload is often observed in patients with NASH, and the amount of iron accumulated in the liver positively correlates with the histological severity of NASH. Ferroptosis, a novel form of iron-dependent cell death, is caused by the accumulation of lipid peroxidation and oxidative stress and is related to NASH. In addition, ferroptosis is closely related to autophagy, an intracellular self-degradation process. Although autophagy has many beneficial effects, it may also be harmful to the organism, for example, inducing ferroptosis. It is unclear whether iron overload aggravates NASH via autophagy. The aim of this research is to determine the mechanism by which iron overload induces ferroptosis via autophagy and aggravates NASH. Stroke-prone spontaneously hypertensive rats (SHRSP5/Dmcr) were divided into two groups and fed a high-fat and high-cholesterol (HFC) diet for eight weeks. Iron dextran was administered to the Fe group in addition to the HFC diet. Blood analysis, histological staining, calcineurin activity assay, quantitative reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence staining, and electron microscopy were performed. The results showed that iron overload promoted autophagy via nuclear translocation of transcription factor EB (TFEB) and induced ferritinophagy, which is the autophagic degradation of ferritin. In addition, the HFC diet induced lipophagy, the autophagic degradation of lipid droplets. The Fe group also exhibited promoted ferroptosis and aggravated hepatic inflammation and fibrosis. In conclusion, iron overload accelerates ferritinophagy and lipophagy, aggravating NASH pathology via ferroptosis. These findings indicate the therapeutic potential of inhibiting autophagy and ferroptosis for treating NASH.

Antioxidant action of xanthine oxidase inhibitor febuxostat protects the liver and blood vasculature in SHRSP5/Dmcr rats.

BACKGROUND: Xanthine oxidase (XO) generates reactive oxygen species during uric acid production. Therefore, XO inhibitors, which suppress oxidative stress, may effectively treat non-alcoholic steatohepatitis (NASH) and atherosclerosis via uric acid reduction. In this study, we examined the antioxidant effect of the XO inhibitor febuxostat on NASH and atherosclerosis in stroke-prone spontaneously hypertensive 5 (SHRSP5/Dmcr) rats. METHODS: SHRSP5/Dmcr rats were divided into three groups: SHRSP5/Dmcr + high-fat and high-cholesterol (HFC) diet [control group, n = 5], SHRSP5/Dmcr + HFC diet + 10% fructose (40 ml/day) [fructose group, n = 5], and SHRSP5/Dmcr + HFC diet + 10% fructose (40 ml/day) + febuxostat (1.0 mg/kg/day) [febuxostat group, n = 5]. Glucose and insulin resistance, blood biochemistry, histopathological staining, endothelial function, and oxidative stress markers were evaluated. RESULTS: Febuxostat reduced the plasma uric acid levels. Oxidative stress-related genes were downregulated, whereas antioxidant factor-related genes were upregulated in the febuxostat group compared with those in the fructose group. Febuxostat also ameliorated inflammation, fibrosis, and lipid accumulation in the liver. Mesenteric lipid deposition decreased in the arteries, and aortic endothelial function improved in the febuxostat group. CONCLUSIONS: Overall, the XO inhibitor febuxostat exerted protective effects against NASH and atherosclerosis in SHRSP5/Dmcr rats.

Therapeutic effect of ouabagenin, a novel liver X receptor agonist, on atherosclerosis in nonalcoholic steatohepatitis in SHRSP5/Dmcr rat model.

The liver X receptor (LXR) can enhance cholesterol transporters, which could remove excess cholesterol from foam cells in atheromas. LXR has two subtypes: LXRα, which aggravates hepatic lipid accumulation, and LXRß, which does not. In 2018, ouabagenin (OBG) was reported as a potential LXRß-specific agonist. We aimed to examine whether OBG specifically affects LXRß in nonalcoholic steatohepatitis (NASH); it did not aggravate hepatic steatosis and can suppress the development of atherosclerosis. SHRSP5/Dmcr rats fed a high-fat and high-cholesterol diet were divided into four groups as follows: (I) L-NAME group, (II) L-NAME/OBG group, (III) OBG (-) group, and (IV) OBG (+) group. All groups' rats were intraperitoneally administered L-NAME. The L-NAME/OBG group's rats were intraperitoneally administered OBG and L-NAME simultaneously. After L-NAME administration, the OBG (+) group's rats were administered OBG, while the OBG (-) group's rats were not. Although all rats developed NASH, OBG did not exacerbate steatosis (L-NAME/OBG and OBG (+) groups). In addition, endothelial cells were protected in the L-NAME/OBG group and foam cells in the atheroma were reduced in the OBG (+) group. OBG is an LXRß-specific agonist and has a potential therapeutic effect on atherosclerosis without developing lipid accumulation in the liver.

SHRSP5/Dmcr rats fed a high-fat and high-cholesterol diet develop disease-induced sarcopenia as nonalcoholic steatohepatitis progresses.

BACKGROUND: Secondary sarcopenia develops as a result of a bedridden state and illnesses, such as cachexia, liver disease, and diabetes. However, there is a lack of animal models to investigate the underlying mechanisms and potential treatments for secondary sarcopenia. Recently, secondary sarcopenia has been associated with the prognosis of nonalcoholic steatohepatitis. This study aimed to investigate whether stroke-prone spontaneously hypertensive rat 5 (SHRSP5/Dmcr) which developed severe nonalcoholic steatohepatitis by a high-fat and high-cholesterol (HFC; containing 2% cholic acid) diet is a useful model of secondary sarcopenia. METHODS: SHRSP5/Dmcr rats were divided into 6 groups fed with a Stroke-Prone (SP: normal chow) or HFC diets for different periods (4, 12, and 20 weeks), and WKY/Izm rats were divided into 2 groups fed an SP or HFC diet. Body weight, food intake, and muscle force were measured weekly for all rats. After the end of the diet period, skeletal muscle strength evoked by electrical stimulation was recorded, blood was collected, and organ weight was measured. The sera were used for biochemical analysis and the organs were used for histopathological analysis. RESULTS: SHRSP5/Dmcr rats fed an HFC diet developed nonalcoholic steatohepatitis, and their skeletal muscles, especially fast muscles, showed atrophy, indicating that muscle atrophy is aggravated by the progression of nonalcoholic steatohepatitis. In contrast, WKY/Izm rats fed an HFC diet did not exhibit sarcopenia. CONCLUSIONS: This study suggests that SHRSP5/Dmcr rats could be a useful novel model for investigate the mechanism of secondary sarcopenia disorder associated with nonalcoholic steatohepatitis.

Increased Glycine-conjugated and Unconjugated Bile Acid Levels Associated with Aggravation of Nonalcoholic Steatohepatitis and Cardiovascular Disease in SHRSP5/Dmcr Rat.

The SHRSP5/Dmcr is a useful animal model for the development of nonalcoholic steatohepatitis (NASH) pathology when fed a high-fat, high-cholesterol diet, and further drug interventions can lead to concomitant cardiovascular disease. While SHRSP5/Dmcr rats have been used for basic research related to NASH, details of their bile acid metabolism in this condition are unknown. In this study, we aimed to clarify the changes in the serum bile acid (BA) fractions associated with NASH and found that glycine-conjugated and unconjugated bile acid increased with worsening NASH and cardiovascular disease while taurine-conjugated BA relatively decreased.

Suppression of nitric oxide synthase aggravates non-alcoholic steatohepatitis and atherosclerosis in SHRSP5/Dmcr rat via acceleration of abnormal lipid metabolism.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a progressive subtype of non-alcoholic fatty liver disease (NAFLD) that is closely related to cardiovascular disease (CVD). Nitric oxide (NO) plays a critical role in the control of various biological processes. Dysfunction of the NO signaling pathway is associated with various diseases such as atherosclerosis, vascular inflammatory disease, and diabetes. Recently, it has been reported that NO is related to lipid and cholesterol metabolism. Chronic NO synthase (NOS) inhibition accelerates NAFLD by increasing hepatic lipid deposition. However, the detailed relationship between NO and abnormal lipid and cholesterol metabolism in NAFLD/NASH has not been completely explained. We aimed to determine the effects of NOS inhibition by N omega-nitro-L-arginine methyl ester hydrochloride (L-NAME), a NOS inhibitor, on NASH and CVD via lipid and cholesterol metabolism. METHODS: Stroke-prone spontaneously hypertensive rats were fed a high-fat and high-cholesterol diet for 8 weeks and administered L-NAME for the last 2 weeks. Following blood and tissue sampling, biochemical analysis, histopathological staining, quantitative RT-PCR analysis, and western blotting were performed. RESULTS: L-NAME markedly increased hepatic triglyceride (TG) and cholesterol levels by promoting TG synthesis and cholesterol absorption from the diet. L-NAME increased the mRNA levels of inflammatory markers and fibrotic areas in the liver. Cholesterol secretion from the liver was promoted in rats administered L-NAME, which increased serum cholesterol. L-NAME significantly increased the level of oxidative stress marker and lipid deposition in the arteries. CONCLUSIONS: NOS inhibition simultaneously aggravates NASH and atherosclerosis via hepatic lipid and cholesterol metabolism.

Basic characteristics between mechanomyogram and muscle force during twitch and tetanic contractions in rat skeletal muscles.

The mechanomyogram (MMG) is a signal measured by various vibration sensors for slight vibrations induced by muscle contraction, and it reflects the muscle force during electrically induced-contraction or until 60%-70% maximum voluntary contraction, so the MMG is considered an alternative and novel measurement tool for muscle strength. We simultaneously measured the MMG and muscle force in the gastrocnemius (GC), vastus intermedius (VI), and soleus (SOL) muscles of rats. The muscle force was measured by attaching a hook to the tendon using a load cell, and the MMG was measured using a charged-coupled device-type displacement sensor at the middle of the target muscle. The MMG-twitch waveform was very similar to that of the muscle force; however, the half relaxation time and relaxation time (10%), which are relaxation parameters, were prolonged compared to those of the muscle force. The MMG amplitude correlated with the muscle force. Since stimulation frequencies that are necessary to evoke tetanic progression have a significant correlation with the twitch parameter, there is a close relationship between twitch and tetanus in the MMG signal. Therefore, we suggest that the MMG, which is electrically induced and detected by a laser displacement sensor, may be an alternative tool for measuring muscle strength.

Coronary High-Intensity Plaques at T1-weighted MRI in Stable Coronary Artery Disease: Comparison with Near-Infrared Spectroscopy Intravascular US.

Background The histologic nature of coronary high-intensity plaques (HIPs) at T1-weighted MRI in patients with stable coronary artery disease remains to be fully understood. Coronary atherosclerosis T1-weighted characterization (CATCH) enables HIP detection by simultaneously acquiring dark-blood plaque and bright-blood anatomic reference images. Purpose To determine if intraplaque hemorrhage (IPH) or lipid is the predominant substrate of HIPs on T1-weighted images by comparing CATCH MRI scans with findings on near-infrared spectroscopy (NIRS) intravascular US (IVUS) images. Materials and Methods This study retrospectively included consecutive patients who underwent CATCH MRI before NIRS IVUS between December 2019 and February 2021 at two facilities. At MRI, HIP was defined as plaque-to-myocardium signal intensity ratio of at least 1.4. The presence of an echolucent zone at IVUS (reported to represent IPH) was recorded. NIRS was used to determine the lipid component of atherosclerotic plaque. Lipid core burden index (LCBI) was calculated as the fraction of pixels with a probability of lipid-core plaque greater than 0.6 within a region of interest. Plaque with maximum LCBI within any 4-mm-long segment (maxLCBI4 mm) greater than 400 was regarded as lipid rich. Multivariable analysis was performed to evaluate NIRS IVUS-derived parameters associated with HIPs. Results There were 205 plaques analyzed in 95 patients (median age, 74 years; interquartile range [IQR], 67-78 years; 75 men). HIPs (n = 42) at MRI were predominantly associated with an echolucent zone at IVUS (79% [33 of 42] vs 8.0% [13 of 163], respectively; P < .001) and a higher maxLCBI4 mm at NIRS (477 [IQR, 258-738] vs 232 [IQR, 59-422], respectively; P < .001) than non-HIPs. In the multivariable model, HIPs were independently associated with an echolucent zone (odds ratio, 24.5; 95% CI: 9.3, 64.7; P < .001), but not with lipid-rich plaque (odds ratio, 2.0; 95% CI: 0.7, 5.4; P = .20). Conclusion The predominant substrate of T1-weighed MRI-defined high-intensity plaques in stable coronary artery disease was intraplaque hemorrhage, not lipid. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Stuber in this issue.

Bile acids aggravate nonalcoholic steatohepatitis and cardiovascular disease in SHRSP5/Dmcr rat model.

BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is linked to an increased risk of cardiovascular disease, regardless of the risk factors in metabolic syndrome. However, the intermediary factors between NASH and cardiovascular disease are still unknown. A previous study revealed that serum and hepatic bile acid (BA) levels are increased in some NASH patients. We aimed to examine whether NASH and cardiovascular disease were aggravated by BA using an animal model. METHOD AND RESULTS: From 10 to 18 weeks of age, SHRSP5/Dmcr rats divided into 3 groups were fed 3 types of high-fat and high-cholesterol (HFC) diets which were changed in the cholic acid (CA) concentration (0%, 2%, or 4%). The nitro oxide synthase inhibition (L-NAME) was administered intraperitoneally from 16 to 18 weeks of age. The 4% CA groups showed the worst LV dysfunction and myocardial fibrosis, and demonstrated severe hepatic fibrosis and lipid depositions. In addition, a large amount of lipid accumulation was observed in the aortas of the 4% CA group, and NFκB and VCAM-1 gene expression levels were increased. These findings were not seen in the 0% CA group. CONCLUSION: In the SHRSP5/Dmcr rat model, NASH and cardiovascular disease were aggravated with increasing BAs concentrations in an HFC diet.

Seeds of Centranthus ruber and Valeriana officinalis Contain Conjugated Linolenic Acids with Reported Antitumor Effects.

Conjugated linolenic acids (CLNs) are naturally occurring fatty acids that are believed to have anticancer properties. In this study, we examined various plant seeds from herbs to discover seed oils containing CLNs. The ultraviolet spectra of total lipids from these seeds were measured. An absorption maximum around 270 nm was observed in seed oils belonging to the Valerianaceae family (Centranthus ruber and Valeriana officinalis). When the fatty acid compositions of these seed oils were measured, CLNs were detected. By silica column chromatography, neutral lipids (NLs), glycolipids, and phospholipids were eluted from seed oils of C. ruber and V. officinalis. Then, fatty acid compositions of these fractions were measured. This revealed that most of the CLNs in these seed oils existed in the NL fraction. When the NL fractions of these seed oils were reacted with lipase, CLNs showed good sensitivity to lipase hydrolysis. This suggested that the CLNs in the seed oils of C. ruber and V. officinalis existed predominantly at the sn-1,3 position of triacylglycerol and less at the sn-2 position. These results suggested that the CLNs from the seed oils of C. ruber and V. officinalis could easily be taken up by cancer cells as free fatty acids and had good potential as antitumor substances.

Non-alcoholic steatohepatitis aggravates nitric oxide synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rat model.

Non-alcoholic steatohepatitis (NASH) is linked to increased cardiovascular risk, independent of the broad spectrum of metabolic syndrome risk factors. Stroke-prone (SP) spontaneously hypertensive rats (SHRSP5/Dmcr) fed a high-fat and high-cholesterol (HFC) diet developed hepatic lesions similar to those in human NASH pathology. These rats simultaneously developed lipid deposits in the mesenteric arteries, cardiac fibrosis, endothelial dysfunction and left ventricle (LV) diastolic dysfunction. However, the intermediary factors between NASH and cardiovascular disease are still unknown. We investigated whether NASH aggravates nitric oxide (NO) synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rats. Wistar Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 and fed the stroke-prone (SP) or HFC diets for 8 weeks. To induce NO synthase inhibition, Nω -nitro-L-arginine methyl ester hydrochloride (L-NAME) mixed with drinking water was administered in the final 2 weeks. The NASH+L-NAME group demonstrated the following characteristics related to arteriosclerosis and myocardial ischaemia: (a) LV systolic dysfunction with asynergy, (b) replacement fibrosis caused by the shedding of cardiomyocytes and (c) arterial lipid deposition and coronary occlusion secondary to endothelial dysfunction. These characteristics were not observed in the NASH or non-NASH+L-NAME groups. The SHRSP5/Dmcr rat model demonstrates that NASH significantly aggravates cardiovascular risk.

Lack of collagen XVIII/endostatin exacerbates immune-mediated glomerulonephritis.

Collagen XVIII is a component of the highly specialized extracellular matrix associated with basement membranes of epithelia and endothelia. In the normal kidney, collagen XVIII is distributed throughout glomerular and tubular basement membranes, mesangial matrix, and Bowman's capsule. Proteolytic cleavage within its C-terminal domain releases the fragment endostatin, which has antiangiogenic properties. Because damage to the glomerular basement membrane (GBM) accompanies immune-mediated renal injury, we investigated the role of collagen XVIII/endostatin in this disorder. We induced anti-GBM glomerulonephritis in collagen XVIII alpha1-null and wild-type mice and compared the resulting matrix accumulation, inflammation, and capillary rarefaction. Anti-GBM disease upregulated collagen XVIII/endostatin expression within the GBM and Bowman's capsule of wild-type mice. Collagen XVIII/endostatin-deficient mice developed more severe glomerular and tubulointerstitial injury than wild-type mice. Collagen XVIII/endostatin deficiency altered matrix remodeling, enhanced the inflammatory response, and promoted capillary rarefaction and vascular endothelial cell damage, but did not affect endothelial proliferation. Supplementing collagen XVIII-deficient mice with exogenous endostatin did not affect the progression of anti-GBM disease. Taken together, these results suggest that collagen XVIII/endostatin preserves the integrity of the extracellular matrix and capillaries in the kidney, protecting against progressive glomerulonephritis.

Tumor necrosis factor-alpha inhibits generation of glycophorin A+ cells by CD34+ cells.

OBJECTIVE: The inhibitory effects of tumor necrosis factor-alpha (TNF-alpha) on cytokine-induced proliferation and differentiation of normal human erythroid progenitors have been characterized extensively, yet little is known about the maturation level of erythroid progenitors that are sensitive to TNF-alpha or of the expression of TNF receptors (TNFRs) in erythroid lineage. The aim of this study was to determine the extent to which human erythroid progenitor cells are sensitive to TNF-alpha, and to relate this to the expression of TNFRs in the erythroid lineage. MATERIALS AND METHODS: Highly purified human CD34+ cells underwent erythroid differentiation, with or without TNF-alpha. We used colony assay as well as a method by which colony-forming unit-erythroid (CFU-E) and glycophorin A (GPA; a specific marker for erythroid lineage) positive cells can be generated in liquid phase from purified human CD34+ cells in the presence of multiple cytokines, including stem cell factor (SCF), interleukin-3 (IL-3), and erythropoietin (EPO). During erythroid differentiation of CD34+ cells, TNFRs expression were monitored. RESULTS: TNF-alpha inhibited the generation of GPA+ cells by CD34+ cells as well as the proliferative capacity of GPA+ cells supported by EPO, IL-3, and SCF. Erythroid progenitors became resistant to the inhibitory effect of TNF-alpha as they matured. The detectable expression of TNFR-I was transient in the early phase of erythroid differentiation, whereas TNFR-II was expressed through the entire course of erythroid differentiation of CD34+ cells. CONCLUSIONS: TNF-alpha suppresses erythropoiesis by inhibiting the generation of GPA+ cells derived from CD34+ cells as well as by inhibiting the proliferative capacity of GPA+ cells. Although the presence of TNFRs does not directly indicate that the receptor(s) mediates death signaling, altered expression of TNFRs depending on the level of maturation may imply altered sensitivities to TNF-alpha in various stage of erythroid progenitors.