Intestinal fibrosis induced by chronic and recurrent colitis, which is exacerbated by bowel stenosis, stricture, and obstruction, is challenging to treat. Toll-like receptor 4 (TLR4) stimulates ...innate and acquired immunity in response to specific microbial components, but the role of TLR4 in intestinal fibrosis is largely unknown. We investigated its role in intestinal fibrosis using not only a murine fibrosis model but also human myofibroblasts and intestinal epithelial cells. Colon fibrosis was induced in TLR4-deficient (TLR4
) mice and its wild-type counterparts with 3% dextran sulfate sodium. Absence of TLR4 gene attenuated chronic inflammation and colonic macrophages infiltration; intestinal fibrosis and collagen deposition were suppressed. Also, the production of tumor necrosis factor-α, interleukin-12p40, and transforming growth factor-β was reduced in TLR4-deficient peritoneal macrophages. TLR4 was silenced in CCD-18Co cells by small interfering RNA (siRNA), and matrix metalloproteinase-1, tissue inhibitor of metalloproteinase, and collagen α1 expression was evaluated. Role of TLR4 in epithelial-mesenchymal transition (EMT) was evaluated in HCT116 cells. Suppression of TLR4 transcription by siRNAs affected myofibroblasts activity, collagen synthesis, and EMT in the human cancer cell line. Thus, we suggest that TLR4 can be an essential mediator in intestinal chronic inflammation and fibrosis, indicating that TLR4 signaling is a potential therapeutic target for intestinal fibrosis.
Mechanical thrombectomy is an effective treatment method for large-vessel occlusion stroke (LVOS); however, it has limited efficacy for intracranial atherosclerotic disease (ICAD)-related LVOS. We ...investigated the use of cerebral blood volume (CBV) maps for identifying ICAD as the underlying cause of LVOS before the initiation of endovascular treatment (EVT).
We reviewed clinical and imaging data from patients who presented with LVOS and underwent endovascular treatment between January 2011 and May 2021. The CBV patterns were analyzed to identify an increase in CBV within the hypoperfused area and estimate infarct patterns within the area of decreased CBV. Comparisons were made between the patients with an increase in CBV and those without, and among the estimated infarct patterns: territorial, cortical wedge, basal ganglia-only, subcortical, and normal CBV. Overall, 243 patients were included. CBV increase in the hypoperfused area was observed in 23.5% of patients. A significantly higher proportion of ICAD was observed in those with increased CBV than in those without (56.4% versus 19.8%;
<0.001). Regarding the estimated infarct patterns on the CBV, ICAD was most frequently observed in the normal CBV group (territorial, 14.9%; cortical wedge, 10.0%; basal ganglia-only, 43.8%; subcortical, 35.7%; normal, 61.7%). CBV parameters, including "an increase in CBV," "normal CBV infarct pattern," and "an increase in CBV or normal CBV infarct pattern composite," were independently associated with ICAD.
An increased CBV or normal CBV pattern may be associated with ICAD LVOS on the pretreatment perfusion imaging.
The prevalence of colorectal neoplasm in patients with non-alcoholic fatty liver disease has increased twice as high as that in the general population. FibroScan is a new modality for evaluating ...hepatic steatosis. This study aimed to investigate the relationship between the risk of high-risk colorectal neoplasia and hepatic steatosis examined using FibroScan. This was a cross sectional study of prospectively enrolled subjects who were scheduled to undergo index colonoscopy as a health screening between March 2018 and February 2019. The severity of steatosis was graded as normal, mild, moderate, or severe using FibroScan. A total of 140 consecutive subjects were enrolled and sequentially examined using FibroScan and colonoscopy. Subjects with hepatic steatosis had more high-risk colorectal neoplasia than those without hepatic steatosis. In addition, tumor size was larger in subjects with hepatic steatosis. In multivariable analysis, severe hepatic steatosis was an independent risk factor for high-risk colorectal neoplasia (adjusted odds ratio: 3.309, confidence interval: 1.043-10.498, p = 0.042). Alcohol consumption was also identified as a risk factor for high-risk colorectal neoplasia. In conclusion, severe hepatic steatosis on FibroScan is associated with the development of high-risk colorectal neoplasia. Thus, physicians should be aware of the association between colorectal neoplasia and hepatic steatosis assessed by FibroScan and its clinical implications.
Abstract
Psoriasis, a chronic and systemic inflammatory disorder characterized by activation of the interleukin (IL)-23/IL-17 axis, may be associated with the intestinal microbiota through the ...so-called “gut–skin axis.” Clusterin is a glycoprotein ubiquitously distributed in mammalian tissues; however, its role in psoriasis is unclear. Therefore, we evaluated the role of clusterin in psoriatic skin inflammation, systemic inflammation, and colitis using a murine model of IMQ-induced psoriasis. In IMQ-treated clusterin-knockout (
clusterin
−/−
) mice, the expressions of inflammatory cytokines in clusterin-silenced human keratinocytes and intestinal microbial composition were analyzed. We also examined clusterin expression in the skin tissues of patients with psoriasis. IMQ-induced psoriatic skin inflammation is suppressed in
clusterin
−/−
mice. Long-term administration of IMQ induced systemic inflammation and colitis; however, both were alleviated by the genetic deletion of clusterin. Genetic silencing of clusterin in human keratinocytes inhibited the production of inflammatory cytokines involved in the initiation and progression of psoriasis. The composition of the intestinal microbiota in IMQ-treated
clusterin
−/−
and wild-type mice was different. Genetic deletion of clusterin suppressed the increase in the Firmicutes/Bacteroidetes (F/B) ratio. Skin tissues of patients with psoriasis showed high clusterin expression. In conclusion, inhibition of clusterin decreased psoriatic skin inflammation, systemic inflammation, colitis, and altered the F/B ratio in an IMQ-induced murine psoriasis model.
In a clinical setting, an individual subject classification model rather than a group analysis would be more informative. Specifically, the subtlety of cortical atrophy in some frontotemporal ...dementia (FTD) patients and overlapping patterns of atrophy among three FTD clinical syndromes including behavioral variant FTD (bvFTD), non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA) give rise to the need for classification models at the individual level. In this study, we aimed to classify each individual subject into one of the diagnostic categories in a hierarchical manner by employing a machine learning-based classification method.
We recruited 143 patients with FTD, 50 patients with Alzheimer's disease (AD) dementia, and 146 cognitively normal subjects. All subjects underwent a three-dimensional volumetric brain magnetic resonance imaging (MRI) scan, and cortical thickness was measured using FreeSurfer. We applied the Laplace Beltrami operator to reduce noise in the cortical thickness data and to reduce the dimension of the feature vector. Classifiers were constructed by applying both principal component analysis and linear discriminant analysis to the cortical thickness data. For the hierarchical classification, we trained four classifiers using different pairs of groups: Step 1 - CN vs. FTD + AD, Step 2 - FTD vs. AD, Step 3 - bvFTD vs. PPA, Step 4 - svPPA vs. nfvPPA. To evaluate the classification performance for each step, we used a10-fold cross-validation approach, performed 1000 times for reliability.
The classification accuracy of the entire hierarchical classification tree was 75.8%, which was higher than that of the non-hierarchical classifier (73.0%). The classification accuracies of steps 1-4 were 86.1%, 90.8%, 86.9%, and 92.1%, respectively. Changes in the right frontotemporal area were critical for discriminating behavioral variant FTD from PPA. The left frontal lobe discriminated nfvPPA from svPPA, while the bilateral anterior temporal regions were critical for identifying svPPA.
In the present study, our automated classifier successfully classified FTD clinical subtypes with good to excellent accuracy. Our classifier may help clinicians diagnose FTD subtypes with subtle cortical atrophy and facilitate appropriate specific interventions.
The fecal immunochemical test (FIT) is widely used in screening for colorectal cancer (CRC), but FIT results can be positive for diseases other than CRC.
We investigated the association between ...positive results of FIT and the incidence of dementia using a nationwide database.
FIT-positive participants were collected from a database provided by the Korean National Health Insurance Service.
The incidence of all kinds of dementia was higher in FIT-positive than FIT-negative subjects (p < 0.0001). FIT-positive participants had a higher risk of Alzheimer's disease (AD) (p < 0.0001) and vascular dementia (p = 0.0002), compared to participants with FIT negativity. The risk of all kinds of dementia or AD in FIT-positive participants was higher in younger (age < 65 years) than older participants (p < 0.0001 for all kinds of dementia; p = 0.0002 for AD).
FIT positivity was correlated with an increased risk of dementia, especially in participants under 65 years of age. The study suggests that clinicians can consider dementia when FIT-positive participants fail to show any malignancies.
Purpose
In this study, we used machine learning to develop a new method derived from a ligand-independent amyloid (Aβ) positron emission tomography (PET) classifier to harmonise different Aβ ligands.
...Methods
We obtained 107 paired
18
F-florbetaben (FBB) and
18
F-flutemetamol (FMM) PET images at the Samsung Medical Centre. To apply the method to FMM ligand, we transferred the previously developed FBB PET classifier to test similar features from the FMM PET images for application to FMM, which in turn developed a ligand-independent Aβ PET classifier. We explored the concordance rates of our classifier in detecting cortical and striatal Aβ positivity. We investigated the correlation of machine learning-based cortical tracer uptake (ML-CTU) values quantified by the classifier between FBB and FMM.
Results
This classifier achieved high classification accuracy (area under the curve = 0.958) even with different Aβ PET ligands. In addition, the concordance rate of FBB and FMM using the classifier (87.5%) was good to excellent, which seemed to be higher than that in visual assessment (82.7%) and lower than that in standardised uptake value ratio cut-off categorisation (93.3%). FBB and FMM ML-CTU values were highly correlated with each other (R = 0.903).
Conclusion
Our findings suggested that our novel classifier may harmonise FBB and FMM ligands in the clinical setting which in turn facilitate the biomarker-guided diagnosis and trials of anti-Aβ treatment in the research field.
RAO is caused by various etiologies and subsequent vascular events may be associated with underlying etiologies. Our aim is to investigate the etiologies of RAO, the occurrence of subsequent vascular ...events and their association in patients with RAO.
We analyzed data from 151 consecutive patients presenting with acute non-arteritic RAO between 2003 and 2013 in a single tertiary-care hospital. The primary outcome was the occurrence of a vascular event defined as stroke, myocardial infarction, and vascular death within 365 days of the RAO onset. The Kaplan-Meier survival analysis and Cox proportional hazard model were used to estimate the hazard ratio of the vascular events.
Large artery atherosclerosis (LAA) was the etiology more frequently associated with of RAO (41.1%, 62/151). During the one year follow-up, ischemic stroke and vascular events occurred in 8.6% and 9.9% of patients, respectively. Ten vascular events occurred in RAO patients attributed to LAA and 4 occurred in undetermined etiology. RAO patients with LAA had a nearly four times higher risk of vascular events compared to those without LAA (hazard ratio 3.94, 95% confidence interval 1.21-12.81). More than a half of all events occurred within one month and over three fourths of ischemic strokes occurred ipsilateral to the RAO.
After occurrence of RAO, there is a high risk of a subsequent vascular event, particularly ipsilateral stroke, within one month. LAA is an independent factor for the occurrence of a subsequent vascular event. Management for the prevention of secondary vascular events is necessary in patients with RAO especially with LAA. Large clinical trials are needed to confirm these findings.
The diagnostic performances of cerebrospinal fluid (CSF) biomarkers and amyloid positron emission tomography (PET) were compared by examining the association and concordance or discordance between ...CSF Aβ1-42 and amyloid PET, after determining our own cut-off values for CSF Alzheimer's disease (AD) biomarkers. Furthermore, we evaluated the ability of CSF biomarkers and amyloid PET to predict clinical progression. CSF Aβ1-42, t-tau, and p-tau levels were analyzed in 203 individuals 27 normal controls, 38 mild cognitive impairment (MCI), 62 AD dementia, and 76 patients with other neurodegenerative diseases consecutively recruited from two dementia clinics. We used both visual and standardized uptake value ratio (SUVR)-based amyloid PET assessments for analyses. The association of CSF biomarkers with amyloid PET SUVR, hippocampal atrophy, and cognitive function were investigated by linear regression analysis, and the risk of conversion from MCI to AD dementia was assessed using a Cox proportional hazards model. CSF p-tau/Aβ1-42 and t-tau/Aβ1-42 exhibited the best diagnostic accuracies among the CSF AD biomarkers examined. Correlations were observed between CSF biomarkers and global SUVR, hippocampal volume, and cognitive function. Overall concordance and discordance between CSF Aβ1-42 and amyloid PET was 77% and 23%, respectively. Baseline positive CSF Aβ1-42 for MCI demonstrated a 5.6-fold greater conversion risk than negative CSF Aβ1-42 . However, amyloid PET findings failed to exhibit significant prognostic value. Therefore, despite presence of a significant correlation between the CSF Aβ1-42 level and SUVR of amyloid PET, and a relevant concordance between CSF Aβ1-42 and amyloid PET, baseline CSF Aβ1-42 better predicted AD conversion.
Purpose
We developed a machine learning–based classifier for in vivo amyloid positron emission tomography (PET) staging, quantified cortical uptake of the PET tracer by using a machine learning ...method, and investigated the impact of these amyloid PET parameters on clinical and structural outcomes.
Methods
A total of 337
18
F-florbetaben PET scans obtained at Samsung Medical Center were assessed. We defined a feature vector representing the change in PET tracer uptake from grey to white matter. Using support vector machine (SVM) regression and SVM classification, we quantified the cortical uptake as predicted regional cortical tracer uptake (pRCTU) and categorised the scans as positive and negative. Positive scans were further classified into two stages according to the striatal uptake. We compared outcome parameters among stages and further assessed the association between the pRCTU and outcome variables. Finally, we performed path analysis to determine mediation effects between PET variables.
Results
The classification accuracy was 97.3% for cortical amyloid positivity and 91.1% for striatal positivity. The left frontal and precuneus/posterior cingulate regions, as well as the anterior portion of the striatum, were important in determination of stages. The clinical scores and magnetic resonance imaging parameters showed negative associations with PET stage. However, except for the hippocampal volume, most outcomes were associated with the stage through the complete mediation effect of pRCTU.
Conclusion
Using a machine learning algorithm, we achieved high accuracy for in vivo amyloid PET staging. The in vivo amyloid stage was associated with cognitive function and cerebral atrophy mostly through the mediation effect of cortical amyloid.
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