T2-FLAIR mismatch sign and machine learning-based multiparametric MRI radiomics in predicting IDH mutant 1p/19q non-co-deleted diffuse lower-grade gliomas.

AIM: To investigate the application of the T2-weighted (T2)-fluid-attenuated inversion recovery (FLAIR) mismatch sign and machine learning-based multiparametric magnetic resonance imaging (MRI) radiomics in predicting 1p/19q non-co-deletion of lower-grade gliomas (LGGs). MATERIALS AND METHODS: One hundred and forty-six patients, who had pathologically confirmed isocitrate dehydrogenase (IDH) mutant LGGs were assigned randomly to the training cohort (n=102) and the testing cohort (n=44) at a ratio of 7:3. The T2-FLAIR mismatch sign and conventional MRI features were evaluated. Radiomics features extracted from T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), FLAIR, apparent diffusion coefficient (ADC), and contrast-enhanced T1WI images (CE-T1WI). The models that displayed the best performance of each sequence were selected, and their predicted values as well as the T2-FLAIR mismatch sign data were collected to establish a final stacking model. Receiver operating characteristic curve (ROC) analyses and area under the curve (AUC) values were applied to evaluate and compare the performance of the models. RESULTS: The T2-FLAIR mismatch sign was more common in the IDH mutant 1p/19q non-co-deleted group (p<0.05) and the area under the curve (AUC) value was 0.692 with sensitivity 0.397, specificity 0.987, and accuracy 0.712, respectively. The stacking model showed a favourable performance with an AUC of 0.925 and accuracy of 0.882 in the training cohort and an AUC of 0.886 and accuracy of 0.864 in the testing cohort. CONCLUSION: The stacking model based on multiparametric MRI can serve as a supplementary tool for pathological diagnosis, offering valuable guidance for clinical practice.

[Clinical characteristics and esophageal function tests of refractory gastroesophageal reflux disease].

Objective: To analyze the clinical characteristics and pathogenesis of refractory gastroesophageal reflux disease(RGERD). Methods: The patients with acid regurgitation, heartburn and extraesophageal symptoms were enrolled in the study from November 2015 to September 2017 at Peking University Third Hospital. All the subjects filled the informed consent.Questionnaire, SCL-90, SAS and SDS scales were recorded. A 24 hour pH-impedance monitoring and esophageal high resonance manometry were carried out. According to the response to proton pump inhibitor(PPI), the patients were divided into RGERD and non-RGERD(NRGERD)groups. The clinical characteristics were compared between these two groups. Logistic regression was used to analyze the risk factors of RGERD. Results: One hundred and nineteen patients were finally enrolled in the study including 61 RGERD (51.3%) and 58 NRGERD patients (48.7%).The body mass index (BMI) and rates of, typical GER symptoms including acid regurgitation in RGERD patients were significantly lower than those in NRGERD patients (P<0.05).While the atypical GER symptoms such as poststernal discomfort or chest pain were more common in RGERD group (P<0.05).RGERD patients presented less acid reflux events and lower proximal segment reflux ratio than NRGERD patients. No obvious differences were found in the manometry metrics between these two groups. The scores of somatization, depression and hostility in RGERD patients by SCL-90 scales were significantly higher than those in NRGERD patients (P<0.05), and depression score was an independent risk factor for RGERD [OR=3.915 (95%CI 1.464-10.466), P =0.007]. Conclusions: RGERD patients present more atypical symptoms and pathological non-acid reflux.Depression is an independent risk factor for RGERD.

[Study of etiology and esophageal motility characteristics of esophagogastric junction outlet obstruction patients].

OBJECTIVE: To analyze the causes of the esophagogastric junction outlet obstruction (EGJOO) patients, to discuss the differences of the clinical manifestation and esophageal motility characteristics between the anatomic EGJOO (A-EGJOO) and functional EGJOO (F-EGJOO) subgroups, and to search the diagnostic values of the specific metrics for differentiating the subgroups of EGJOO patients. METHODS: For the current retrospective study, all the patients who underwent the esophageal high resonance manometry test were retrospectively analyzed from Jan 2012 to Oct 2018 in Peking University Third Hospital. The EGJOO patients were enrolled in the following research. The clinical characteristics, such as symptoms and causes of the patients were studied. Then the patients were divided into two subgroups as A-EGJOO subgroup and F-EGJOO subgroup. The clinical symptoms and the main manometry metrics were compared between these two subgroups. The significant different metrics between the two groups were selected to draw receiver operating characteristic (ROC) curves and the diagnostic values were analyzed in differentiating the A-EGJOO and F-EGJOO subgroups. RESULTS: The most common symptom of EGJOO was chest pain or chest discomfort (30.63%), then the dysphagia (29.73%), and acid regurgitation/heartburn (27.03%). Non-erosive reflux disease (36.04%) was the most popular cause for EGJOO, then the reflux esophagitis (17.12%). Besides the intra-EGJOO and extra-EGJOO lesions, the connective tissue disease (6.31%) and central nervous diseases (2.70%) were found to be the etiology of EGJOO. The causes of the rest 19 EGJOO were unknown. A-EGJOO patients presented significantly higher intra bolus pressure (IBP) than that of F-EGJOO [6.80 (5.20, 9.20) mmHg vs. 5.10 (3.10, 7.60) mmHg, P=0.016]. The area under curve of IBP was 0.637. When IBP≥5.15 mmHg, the sensitivity was 78.60% and specificity 50.70% to differentiate A- or F-EGJOO. CONCLUSION: Chest pain or chest discomfort was the most common symptom in EGJOO patients. Besides the intraluminal structural disorders, the extra-luminal causes were found in EGJOO patients. A-EGJOO presented higher IBP than that of F-EGJOO patients. The cutoff value of IBP to differentiate A-EGJOO from EGJOO was 5.15 mmHg with sensitivity 78.06% and specificity 50.70%. However for the low area under curve, the diagnostic value of IBP was limited.

Heme oxygenase-1 directly binds STAT3 to control the generation of pathogenic Th17 cells during neutrophilic airway inflammation.

BACKGROUND: Specific JAK/STAT pathways play a critical role in the functional differentiation of distinct Th subsets. Previously, we showed that HO-1, a stress-inducible protein, inhibits Th17 cell differentiation and alleviates neutrophilic airway inflammation, but the responsible molecular basis remains unclear. METHODS: We employed Th17-skewing differentiation and NEA mouse models to study the role of HO-1 in regulating IL-6-STAT3-RORγt/SOCS3 signaling pathway to control Th17 cell-mediated neutrophilic airway inflammation. The levels of cytokines and expressions of relative signaling molecules were measured by ELISA, western blot, and qPCR, respectively. Frequency of CD4+ IL-17A+ , CD4+ IL-6R+ , and CD4+ IL-23R+ cells was analyzed by FCM. The interaction between HO-1 and signaling pathway-related proteins was determined by co-immunoprecipitation and western blot. RESULTS: Here, we show that hemin-induced HO-1 overexpression is required to mediate this process. Specifically, HO-1 decreased STAT3 phosphorylation but not IL-6R/IL-23R expression or JAK1/JAK2 activation in CD4+ T cells. The effect was accompanied by co-inhibition of SOCS3, a negative feedback factor of STAT3 activation. HO-1 bound to three domains on STAT3 (DNA-binding, linker, and transactivation domains) to directly regulate STAT3 activation. Conversely, either forced expression of a constitutively active STAT3 mutant or application of small-interfering RNA (siRNA) for HO-1 reversed these effects. CONCLUSIONS: Our data suggest that HO-1 exerts its inhibitory effect on Th17 cell differentiation by directly associating and blocking STAT3 phosphorylation. We speculate that hemin may be a potential therapeutic candidate for the treatment of other types of immune and pulmonary inflammatory-related diseases.

The motility of esophageal sphincters during liquid and solid bolus swallows: a multicenter normative value study of high-resolution manometry in China.

BACKGROUND: It is gradually accepted that solid bolus swallow needs to be added to the procedure of manometry. The motility differences in the upper esophageal sphincter (UES) and lower esophageal sphincter (LES) were not well described. Sierra Scientific Instruments solid-state high-resolution manometry (HRM) system, the most popular HRM system in China, lacks the Chinese normative values for both liquid and solid bolus swallow parameters. METHODS: The esophageal HRM data of 88 healthy volunteers were analyzed. The parameters of both sphincters in resting stage were summarized and those during solid and liquid swallows were compared. KEY RESULTS: Normative HRM values of sphincter parameters in solid and liquid bolus swallows in China were established. The UES residual pressure of solid bolus swallows was lower than that of liquid bolus (0.3±5.5 mm Hg vs 4.8±5.9 mm Hg, P=.000). The time parameters of UES relaxation between two types of bolus swallows were similar. In solid bolus swallows, the intrabolus pressure (IBP) (13.8±5.1 mm Hg vs 10.9±5.7 mm Hg, P=.000) and LES relaxation time (11.0±2.1 seconds vs 8.7±1.3 seconds, P=.000) were higher. The 4-second integrated relaxation pressure between both bolus swallows was similar. CONCLUSIONS & INFERENCES: The function of the UES and LES between solid and liquid bolus swallows is different. Chinese HRM parameters are different from the Chicago Classification (http://www.chictr.org.cn, Number ChiCTR-EOC-15007147).

[Comparison of clinical features and high-resolution esophageal motility characteristics between esophagogastric junction outflow obstruction and type â ¡ achalasia patients].

OBJECTIVES: To compare the clinical features and high-resolution esophageal motility-impedance characteristics among esophagogastric junction outflow obstruction (Eoo) patients, type Ⅱ achalasia (Ach) patients and healthy controls (Con), in order to explore the values of esophageal high-resolution manometry (HRM) in diagnosis and treatment of Eoo patients. METHODS: Patients with dysphagia were enrolled from December 2011 to December 2014 at the outpatient department of Peking University Third Hospital, so were age-matched healthy volunteers. All the patients with organic obstruction were excluded. All the participants were tested with high-resolution esophageal motility-impedance measurement, the patients were diagnosed as Eoo or Ach according to the Chicago classification criteria. Clinical features and esophageal motility characteristics of Eoo, Ach and Con were analyzed. RESULTS: A total of 23 Eoo, 24 Ach and 20 Con were enrolled, whose gender ratios, average ages and body mass indexes were of no significant differences(all P>0.05). (1) The Eoo group had higher percentage of food reflux[21.7% (5/23) vs 0(0/24), P=0.005]and belching[17.4% (4/23) vs 0 (0/24), P=0.013], but lower percentage of dysphagia[47.8% (11/23) vs 79.2% (19/24), P=0.025]and vomiting[0(0/23) vs 12.5%(3/24), P=0.040]compared with the Ach group, with no significant differences in other symptoms(all P>0.05). Besides, the Eoo group had lower Eckardt scores than the Ach group[1(1, 2) vs 3 (2, 5), P<0.001]. (2) The lower esophageal sphincter (LES) basal pressure-minimum in the Eoo was higher than the Con[(26.73±2.77) vs (17.16±1.76) mmHg, P<0.05]. The mean LES basal pressure; and the LES integrated relaxation pressure (IRP), IRP-maximum, and LES relaxation percentage were significantly different among Eoo, Ach and Con[(19.80±1.25) vs (35.95±2.36), (8.43±0.72) mmHg, both P<0.05; (23.22±2.02) vs (48.37±3.71), (12.32±1.29) mmHg, bothP<0.05; 38.61%±3.10% vs 12.42%±5.66%, 64.00%±3.85%, both P<0.05]. (3) There were significant differences in velocity, amplitude, and duration of esophageal peristaltic wave and intrabolus pressure (all P<0.05) among Eoo, Ach and Con; and failed contraction percentage, panesophageal pressurization percentage, premature contraction percentage, and rapid contraction percentage of Eoo were lower than Ach (all P<0.05) while complete contraction percentage of Eoo was high compared with Ach (P<0.001), but no significant differences between Eoo and Con. (4) The Eoo had significantly less incomplete bolus clearance[0.00% (0.00%, 20.00%) vs 100.00% (90.00%, 100.00%), P<0.001]and shorter bolus transit time[(5.44±0.29) s vs (24.13±1.69) s, P<0.001]than Ach, but there were no significant differences between Eoo and Con in these two indexes[0.00% (0.00%, 20.00%) vs 0.00% (0.00%, 9.75%); (5.44±0.29) s vs (5.30±0.19) s; both P>0.05]. CONCLUSIONS: The clinical manifestations and esophageal HRM characteristics of Eoo appear to be between Ach and Con, which suggests that Eoo may be an early-stage of Ach. Further study of the pathophysiological characteristics of Eoo patients may provide more evidence to elucidate the pathogenesis of achalasia.

[The characteristics of esophagogastric junction contractile index in patients with gastroesophageal reflux disease or functional heartburn].

OBJECTIVE: To study the role of esophagogastric junction contractile index (EGJ-CI) in evaluating the function of anti-reflux barrier, and in differentiating patients with gastroesophageal reflux disease (GERD) from those with functional heartburn (FH). METHODS: A total of 115 patients presenting heartburn were enrolled in the study from January 2012 to June 2015.All subjects had completed Gerd-Q questionnaire and undergone gastroscopy, 24-hour pH-impedance monitoring and esophageal high-resolution manometry. GERD patients were divided into as reflux esophagitis, acid-nonerosive reflux disease (NERD) and weakly acid-NERD groups. Patients with normal esophageal mucosa, normal acid exposure and negative proton pump inhibitor test were enrolled in FH group. EGJ-CI (mmHg·cm) as well as EGJ rest pressure and 4s integrated relaxation pressure (IRP 4s) were measured. RESULTS: Among the 115 patients, 18 were reflux esophagitis [(49.0±18.9) years, M∶F=10∶8], 25 were acid-NERD [(48.7±14.4) years, M∶F=13∶12], 37 were weakly acid-NERD [(52.0±14.8) years, M∶F=15∶22] and 35 were FH [(53.6±14.8), M∶F=8∶27]. No differences of Gerd-Q scores were noticed between the four groups. (1)Negative correlations were demonstrated between EGJ-CI and esophageal acid exposure time (r=-0.283, P=0.002), EGJ-CI and acid reflux events (r=-0.233, P=0.012), EGJ-CI and weakly acid reflux events (r=-0.213, P=0.022), EGJ-CI and non-acid reflux events (r=-0.200, P=0.032). (2)The value of EGJ-CI was significantly higher in FH patients than in the three subgroups of GERD(all P<0.01). EGJ rest pressure of FH group was higher than that of acid-NERD (P<0.01). IRP 4s in acid-NERD group was lower than that of FH and weakly acid-NERD (P<0.05). (3)The area under curve (AUC) of EGJ-CI was higher than that of EGJ-CIT, EGJ rest pressure or IRP 4s(0.686 vs 0.678, 0.641 and 0.578). The cut-off value of EGJ-CI to differentiate GERD from FH was 9.74 mmHg·cm with sensitivity 82.86% and specificity 51.52%. CONCLUSIONS: The EGJ-CI values are negatively correlated with esophageal acid exposure time, weakly acid reflux events and non-acid reflux events. Thus it might be used as a metric to reflect the anti-reflux function of EGJ. According to the cut-off value of EGJ-CI 9.74 mmHg·cm, patients with GERD can be sensitively differentiated from patients with FH.

Design of a magnetic shielding system for the time of flight enhanced diagnostics neutron spectrometer at Experimental Advanced Superconducting Tokamak.

The novel neutron spectrometer TOFED (Time of Flight Enhanced Diagnostics), comprising 90 individual photomultiplier tubes coupled with 85 plastic scintillation detectors through light guides, has been constructed and installed at Experimental Advanced Superconducting Tokamak. A dedicated magnetic shielding system has been constructed for TOFED, and is designed to guarantee the normal operation of photomultiplier tubes in the stray magnetic field leaking from the tokamak device. Experimental measurements and numerical simulations carried out employing the finite element method are combined to optimize the design of the magnetic shielding system. The system allows detectors to work properly in an external magnetic field of 200 G.

Inversion of infrared imaging bolometer based on one-dimensional and three-dimensional modeling in HL-2A.

Linear regularization has been applied to the HL-2A infrared imaging bolometer to reconstruct local plasma emission with one-dimensional (1D) and three-dimensional (3D) modeling under the assumption of toroidal symmetry. In the 3D modeling, a new method to calculate the detector point response function is introduced. This method can be adapted to an arbitrarily shaped pinhole. With the full 3D treatment of the detector geometry, up to 50% of the mean-squared error is reduced compared with the 1D modeling. This is attributed to the effects of finite detector size being taken into account in the 3D modeling. Meanwhile, the number of the bolometer pixels has been optimized to 20 × 20 by making a trade-off between the number of bolometer pixels and the sensitivity of the system. The plasma radiated power density distributions have been calculated as a demonstration using 1D modeling and 3D modeling, respectively.

Minimum Fisher regularization of image reconstruction for infrared imaging bolometer on HL-2A.

An infrared imaging bolometer diagnostic has been developed recently for the HL-2A tokamak to measure the temporal and spatial distribution of plasma radiation. The three-dimensional tomography, reduced to a two-dimensional problem by the assumption of plasma radiation toroidal symmetry, has been performed. A three-dimensional geometry matrix is calculated with the one-dimensional pencil beam approximation. The solid angles viewed by the detector elements are taken into account in defining the chord brightness. And the local plasma emission is obtained by inverting the measured brightness with the minimum Fisher regularization method. A typical HL-2A plasma radiation model was chosen to optimize a regularization parameter on the criterion of generalized cross validation. Finally, this method was applied to HL-2A experiments, demonstrating the plasma radiated power density distribution in limiter and divertor discharges.

A new neutral particle analyzer diagnostic and its first commissioning on HL-2A.

A new neutral particle analyzer diagnostic has been developed for HuanLiuqi-2A (commonly referred to as HL-2A), which can provide the neutral particle flux measurement along 11 separate sightlines, simultaneously, within a wider energy range (1-70 keV). It is an electrostatic type analyzer with a removable pinhole and special-shape condenser. The energy analysis can be flexibly achieved by controlling a preset stepwise high voltage on the condenser. It is compact and its field of view covers HL-2A cross section from -33 cm to 33 cm without "cross-talk." The energy spectra and ion temperature profile have been obtained during its commissioning.

Observation of turbulence suppression after electron-cyclotron-resonance-heating switch-off on the HL-2A tokamak.

The formation of a transient internal transport barrier (ITB) is observed after the electron-cyclotron-resonance-heating (ECRH) switch-off in the HL-2A plasmas, characterized by transient increase of central electron temperature. The newly developed correlation reflectometer provided direct measurements showing reduction of turbulence in the region of steepened gradients for the period of ITB formation triggered by the ECRH switch-off. Furthermore, the reduction of core turbulence is correlated in time with the appearance of a low-frequency mode with a spectrally broad poloidal structure that peaks near zero frequency in the core region. These structures have low poloidal mode number, high poloidal correlation, and short radial correlation and are strongly coupled with high-frequency ambient turbulence. Observation indicates that these structures play important roles in the reduction of the core turbulence and in improvements of the core transport after the off-axis ECRH is turned off.

The role of heme oxygenase-1 in T cell-mediated immunity: the all encompassing enzyme.

Heme oxygenase-1 (HO-1) is the rate-limiting enzyme of ferroheme metabolic pathway, which has the functions of anti-oxidation, anti-inflammatory, anti-apoptosis and anti-smooth muscle hyperplasia. Furthermore, HO-1 exerts a protective action in the diseases mediated by effector T lymphocytes such as T helper (Th) 1, Th2 and Th17. In addition, regulatory T cells (Treg) control the activity of CD4+CD25- effector cells in a suppressive manner. Numerous studies indicate that the protective action of HO-1 in diseases is through CD4+CD25+ Treg. This paper will review the current research and understanding of HO-1's role in T cells-mediated immunoregulation.

Analysis of two constitutive forms of microsomal heme oxygenase in different rat tissues.

AIM: To isolate and purify the heme oxygenase (HO) isoform in microsomal fractions of Sprague-Dawley rat liver and brain in order to understand the characteristics of the two constitutive forms and the mechanism of the occurrence of hyperbilirubinemia. METHODS: After induction by hematin and phenylhydrazine, the rat liver and brain microsomal fractions were isolated and purified by DEAE-Sephacel and hydroxyapatite. Activity and the apparent molecular weight of the two isoforms [heme oxygenase 1 (HO-1) and heme oxygenase-2 (HO-2)] were measured. Kunming mice were used to prepare antiserum against purified liver HO-2. Rat liver HO-1 and brain HO-2 preparations were analyzed by the western immunoblotting technique. RESULTS: Two isoforms were purified and identified in the treated rat liver, and HO-1 was the predominant form with a ratio of 2:1. In the native state, HO-2 activity was detectable but HO-1 activity was increased in response to hematin and phenylhydrazine, while HO-2 activity was fully refractory to these agents. The apparent molecular weights of HO-1 and HO-2 were about Mr 30000 and Mr 36000 under reducing conditions, respectively. In the untreated liver and treated brain, only one peak of HO activity exhibiting an elution profile similar to that of HO-2 of the treated liver was detected. The presence of an activity peak was not found in the elution profile at the region where the inducible isoform of HO (HO-1) was expected. The apparent molecular weight in treated brain preparation was identical to that of the purified liver HO-2. Cross-reactivity of HO-2 in the brain microsomal preparation was established, but a reactivity of HO-1 in the liver was not observed by western immunoblotting analysis when antiserum to liver HO-2 was applied. CONCLUSION: Two constitutive forms of HO, designated as HO-1 and HO-2, exist in the treated rat liver. HO-1 is an inducible enzyme. In the treated rat brain only HO-2 exists and is a molecular entity similar to that found in liver. The two constitutive forms were different in molecular weight and in inducibility and immunochemical properties.