Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease

To study the genetic association and epistatic interaction of the interleukin (IL)-10 and IL-10/STAT3 pathways in pediatric inflammatory bowel disease (IBD). METHODSA total of 159 pediatric inflammatory IBD patients (Crohn’s disease, n = 136; ulcerative colitis, n = 23) and 129 matched controls were studied for genetic association of selected single nucleotide polymorphisms (SNPs) of the IL-10 gene and the genes IL10RA, IL10RB, STAT3, and HO1, from the IL-10/STAT3 signaling pathway. As interactions between SNPs from different loci may significantly affect the associated risk for disease, additive (a) and dominant (d) modeling of SNP interactions was also performed to examine high-order epistasis between combinations of the individual SNPs. RESULTSThe results showed that IL-10 rs304496 was associated with pediatric IBD (P = 0.022), but no association was found for two other IL-10 SNPs, rs1800872 and rs2034498, or for SNPs in genes IL10RA, IL10RB, STAT3, and HO1. However, analysis of epistatic interaction among these genes showed significant interactions: (1) between two IL-10 SNPs rs1800872 and rs3024496 (additive-additive P = 0.00015, Bonferroni P value (Bp) = 0.003); (2) between IL-10RB rs2834167 and HO1 rs2071746 (dominant-additive, P = 0.0018, Bp = 0.039); and (3) among IL-10 rs1800872, IL10RB rs2834167, and HO1 rs2071746 (additive-dominant-additive, P = 0.00015, Bp = 0.005), as well as weak interactions among IL-10 rs1800872, IL-10 rs3024496, and IL-10RA (additive-additive-additive, P = 0.003; Bp = 0.099), and among IL10RA, IL10RB, and HO1 genes (additive-dominant-additive, P = 0.008, Bp = 0.287). CONCLUSIONThese results indicate that both the IL-10 gene itself, and through epistatic interaction with genes within the IL-10/STAT3 signaling pathway, contribute to the risk of pediatric IBD.

QUANTITATIVE REDOX SCANNING OF TISSUE SAMPLES USING A CALIBRATION PROCEDURE

The fluorescence properties of reduced nicotinamide adenine dinucleotide(NADH)and oxidizedflavoproteins(Fp)including flavin adenine dinucleotide(FAD)in the respiratory chain are sensitive indicators of intracellular metabolic states and have been applied to the studies of mitochondrial function with energy-linked processes.The redox scanner,a three-dimensional(3D)low temperature imager previously developed by Chance et al.,measures the in vivo metabolicproperties of tissue samples by acquiring fluorescence images of NADH and Fp.The redox ratios,i.e.Fp/(Fp+NADH)and NADH/(Fp+NADH),provided a sensitive index of the mitochondrialredox state and were determined based on relative signal intensity ratios.Here we report thefurther development of the redox scanning technique by using a calibration method to quantifythe nominal concentration of the fluorophores in tissues.The redox scanner exhibited very goodlinear response in the range of NADH concentration between 165–1318µM and Fp between90–720µM using snap-frozen solution standards.Tissue samples such as human tumor mousexenografts and various mouse organs were redox-scanned together with adjacent NADH and Fpstandards of known concentration at liquid nitrogen temperature.The nominal NADH and Fpconcentrations as well as the redox ratios in the tissue samples were quantified by normalizing the tissue NADH and Fp fluorescence signal to that of the snap-frozen solution standards.This calibration procedure allows comparing redox images obtained at different time,independent of instrument settings.The quantitative multi-slice redox images revealed heterogeneity inmitochondrial redox state in the tissues.

Pretreatment of caffeine leads to partial neuroprotection in MPTP model of Parkinson＇s disease

Parkinson＇s disease （PD） is disorder affecting more than a common neurodegenerative 1% people above 60 years of age worldwide, manifesting as the impaired motor function such as tremors, rigidity, akinesia/bradykinesia and postural inefficiency with a reduced life expectancy （Dorsey et al., 2007）. PD is believed to be the end result of the progressive death of dopaminergic neurons in the substantia nigra pars compacta （SNc）.

REDOX IMAGING OF THE p53-DEPENDENT MITOCHONDRIAL REDOX STATE IN COLON CANCER EX VIVO

The mitochondrial redox state and its heterogeneity of colon cancer at tissue level have not been previously reported.Nor has how p53 regulates mitochondial respi ration been measured at(deep)tissue level,presumably due to the unavailability of the technology that has sufficient spatial resolution and tissue penetration depth.Our prior work demonstrated that the mito-chondrial redox state and its intnatumor heterogeneity is associated with cancer aggressiveness in human melanoma and breast cancer in mouse models,with the more metastatic tumons exhi-bit ing localized negions of more oxidized redox state.Using the Chance redox scanner with an in-plane spatial resolution of 200 pm,we imaged the mitochondrial redox state of the wild-type p53 colon tumors(HCT116 p53 ut)and the p5-deleted colon tumors(HCT116 p53-/-)by cllcting the fuorescence si gnals of nicotinamide adenine dimucleotide(NA DH)and oxidized flavoproteins [Fp,including favin adenine dinucleotide(FAD)]from the mouse xenogmafts snap frozen at low temperature.Our results show that:(1)both tumor lines have significant degree of intratumor heterogeneity of the redox state,typically exhibiting a distinct bi modal distribution that either correlates with the spatial core-rim pattern or the“hot/oold”oxida tion-roduction patches;.(2)the p531-group is significantly more beterogencous in the mitochondrial redox state and has a more oxidized turmor core compared to the p53 wt group when the tunor sizes of the two groups are matched;(3)the tumor size dependence of the redox indices(such as Fp and Fp redox ratio)is significant in the p531-group with the larger ones being more oxidized and more hetero-geneous in their redox state,particularly more oxidized in the tumor central regions;(4)the H&E staining images of tumor soctions grossly correlate with the redox images.The present work is the first to reveal at the submillimeter scale the intratumor heterogeneity pattem of the mitochon-drial redox state in colon cancer and the first to indicate that at tissue level the mitochondial redox state is p53 dependent.The findings should assist in our understanding on colon cancer pa thology and developing new imaging biomarkers for dlinical applications.

SPECIAL SECTION IN MEMORY OF PROFESSOR BRITTON CHANCE

Britton Chance,an Olympic gold medalist in sailing(Helsinki,1952),was also one of the best and most legendary sailors in science.Britton Chance was born in Wilkes-Barre,Pennsylvania,USA on July 24th,1913.He received a B.S.degree in 1935,an M.S.in 1936 and a Ph.D.degree in Physical Chemistry in 1940,all from the University of Pennsylvania.From Cambridge University he received his second Ph.D.degree in Physiology in 1942.

INTRODUCTION TO THE SPECIAL SECTION IN MEMORY OF DR. BRITTON CHANCE

Hanged on the wall outside the office of Dr.Chance at the University of Pennsylvania is a thick plaque(
4-1:5 feet)dedicated to Dr.Chance by his students at his 90'th birthday,saying桃李天下(Tao Li Tian Xia).This is a traditional Chinese idiom praising great teachers.桃李天下literally means"peaches and plums all over the world".

Positron emission tomography/computed tomography imaging appearance of benign and classic “do not touch” osseous lesions

BACKGROUND Classic “do not touch” and benign osseous lesions are sometimes detected on 18-Ffluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) studies. These lesions are often referred for biopsy because the physician interpreting the PET/CT may not be familiar with the spectrum of 18F-FDG uptake patterns that these lesions display. AIM To show that “do not touch” and benign osseous lesions can have increased 18FFDG uptake above blood-pool on PET/CT;therefore, the CT appearance of these lesions should dictate management rather than the standardized uptake values (SUV). METHODS This retrospective study evaluated 287 independent patients with 287 classic “do not touch”(benign cystic lesions, insufficiency fractures, bone islands, bone infarcts) or benign osseous lesions (hemangiomas, enchondromas, osteochondromas, fibrous dysplasia, Paget’s disease, osteomyelitis) who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) at a tertiary academic healthcare institution between 01/01/2006 and 12/1/2018. The maximum and mean SUV, and the ratio of the maximum SUV to mean blood pool were calculated. Pearson’s correlations between lesion size and maximum SUV were calculated. RESULTS The ranges of the maximum SUV were as follows: For hemangiomas (0.95-2.99), bone infarcts (0.37-3.44), bone islands (0.26-3.29), enchondromas (0.46-2.69), fibrous dysplasia (0.78-18.63), osteochondromas (1.11-2.56), Paget’s disease of bone (0.93-5.65), insufficiency fractures (1.06-12.97) and for osteomyelitis (2.57- 12.64). The range of the maximum SUV was lowest for osteochondromas (maximum SUV 2.56) and was highest for fibrous dysplasia (maximum SUV of 18.63). There was at least one lesion that demonstrated greater 18F-FDG avidity than the blood pool amongst each lesion type, with the highest maximum SUV ranging from 9.34 times blood pool mean (osteomyelitis) to 1.42 times blood pool mean (hemangiomas). There was no correlation between the maximum SUV and the lesion size except for enchondromas. Larger enchondromas had higher maximum SUV (r = 0.36, P = 0.02). CONCLUSION The classic “do not touch” lesions and classic benign lesions can be 18F-FDG avid. The CT appearance of these lesions should dictate clinical management rather than the maximum SUV.

Observer Variability in BI-RADS Ultrasound Features and Its Influence on Computer-Aided Diagnosis of Breast Masses

Objective: Computer classification of sonographic BI-RADS features can aid differentiation of the malignant and benign masses. However, the variability in the diagnosis due to the differences in the observed features between the observations is not known. The goal of this study is to measure the variation in sonographic features between multiple observations and determine the effect of features variation on computer-aided diagnosis of the breast masses. Materials and Methods: Ultrasound images of biopsy proven solid breast masses were analyzed in three independent observations for BI-RADS sonographic features. The BI-RADS features from each observation were used with Bayes classifier to determine probability of malignancy. The observer agreement in the sonographic features was measured by kappa coefficient and the difference in the diagnostic performances between observations was determined by the area under the ROC curve, Az, and interclass correlation coefficient. Results: While some features were repeatedly observed, κ = 0.95, other showed a significant variation, κ = 0.16. For all features, combined intra-observer agreement was substantial, κ = 0.77. The agreement, however, decreased steadily to 0.66 and 0.56 as time between the observations increased from 1 to 2 and 3 months, respectively. Despite the variation in features between observations the probabilities of malignancy estimates from Bayes classifier were robust and consistently yielded same level of diagnostic performance, Az was 0.772-0.817 for sonographic features alone and 0.828-0.849 for sonographic features and age combined. The difference in the performance, ΔAz, between the observations for the two groups was small (0.003-0.044) and was not statistically significant (p < 0.05). Interclass correlation coefficient for the observations was 0.822 (CI: 0.787-0.853) for BI-RADS sonographic features alone and for those combined with age was 0.833 (CI: 0.800-0.862). Conclusion: Despite the differences in the BI-RADS sonographic features between different observations, the diagnostic performance of computer-aided analysis for differentiating breast masses did not change. Through continual retraining, the computer-aided analysis provides consistent diagnostic performance independent of the variations in the observed sonographic features.

Editorial--The centennial celebration of Dr.Britton Chance

To celebrate the scientific legacy and spirit of the late Dr.Brtton Chance(1913-2010)and his 100thbir thday,t he Brit ton Chance International Symposium on Metabolic Imaging and Spectroscopy was heldat the Perelman School of Medicine,University of Pennsylvania on June 18-19th,2013.The symposium brought toget her over 200 physicists,engineers,biologists and clinicians from all over the world includingEurope,Asia and North America.The latest research innovations and clinical progresses by optical,nuclear magnetic resonance(NMR)and nuclear medicine methods were presented and discussed extensively.

Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging([^(18)F]AV-133)

The 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine （MPTP）-induced parkinsonism model, particularly in non-human primates, remains the gold-standard for studying the pathogenesis and assessing novel therapies for Parkinson＇s disease. However, whether the loss of dopaminergic neurons in this model is progressive remains controversial, mostly due to the lack of objective in vivo assessment of changes in the integrity of these neurons. In the present study, parkinsonism was induced in cynomolgus monkeys by intravenous administration of MPTP （0.2 mg/kg） for 15 days; stable parkinsonism developed over 90 days, when the symptoms were stable. Noninvasive positron emission tomographic neuroimaging of vesicular monoamine transporter 2 with 9-[18F] fluoropropyl-（＋）-dihydrotetrabenazine （[18F]AV-133） was used before, and 15 and 90 days after the beginning of acute MPTP treatment. The imaging showed evident progressive loss of striatal uptake of [18SF]AV-133. The dopaminergic denervation severity had a significant linear correlation with the clinical rating scores and the bradykinesia subscores. These findings demonstrated that [18F]AV-133 PET imaging is a useful tool to noninvasively evaluate the evolution of monoaminergic terminal loss in a monkey model of MPTP-induced parkinsonism.

数字乳腺X线摄影和中心组合断层投照对乳腺密度百分比的估算

目的评价临床数字乳腺X线摄影与中心组合数字乳腺断层（DBT）投照成像估算乳腺密度百分比（PD）读片者间和同一读片者内的一致性。材料与方法本研究经学术委员会通过并符合健康医疗保险要求，所有病人均签署知情同意书。对39例女性（31～80岁．平均年龄51岁）的匿名数字乳腺x线摄影和中心DBT投照行乳腺PD估算。

用超短回波时间MRI技术量化活体内皮质骨的水含量

目的开发和评价超短回波时间放射状MRI技术作为人活体内一种新的骨定量方法在量化骨水(bone water,BW)含量中的作用。

乳腺X线成像实质复杂性的影像组学表型:乳腺癌风险评估中提高乳腺密度的探讨

目的使用影像组学特征确定乳腺X线成像实质复杂性的表型,并评估它们与乳腺密度和其他乳腺癌风险因素的关联。材料与方法选取从2012年9月1日—2013年2月28日采用数字乳腺X线成像进行筛查的女性病人的横断面样本(n=2 029;年龄35~75岁,平均55.9岁),使用计算机图像分析方法量化样本的乳腺密度,提取实质的纹理特征。

This research was supported by E.U.FP6 Integrated Project“Molecular Imaging”LSHG-CT-2003-503259 and E.U.FP7 Collaborative Project“FMT-XCT”.R.F.acknowledges support from the Marie Curie Program EST-MolecImag Early Stage Training MEST-CT-2004-007643.

We have imaged mitochondrial oxidation-reduction states by taking a ratio of mitochondrial fluorophores:NADH(reduced nicotinamide adenine dinucleotide)to Fp(oxidized flavoprotein).Although NADH has been investigated for tissue metabolic state in cancer and in oxygen deprived tissues,it alone is not an adequate measure of mitochondrial metabolic state since the NADH signal is altered by dependence on the number of mitochondria and by blood absorption.The redox ratio,NADH/(Fp+NADH),gives a more accurate measure of steady-state tissue metabolism since it is less dependent on mitochondrial number and it compensates effectively for hemodynamic changes.This ratio provides important diagnostic information in living tissues.In this study,the emitted fluorescence of mouse colon in situ is passed through an emission filter wheel and imaged on a CCD camera.Redox ratio images of the healthy and hypoxic mouse intestines clearly showed significant differences.Furthermore,the corrected redox ratio indicated an increase from an average value of 0.51±0.10 in the healthy state to 0.92±0.03 in dead tissue due to severe ischemia(N=5).We show that the CCD imaging system is capable of displaying the metabolic differences in normal and ischemic tissues as well as quantifying the redox ratio in vivo as a marker of these changes.

IMAGING REDOX STATE HETEROGENEITY WITHIN INDIVIDUAL EMBRYONIC STEM CELL COLONIES

Redox state mediates embryonic stem cell(ESC)differentiation and thus offers an important complementary approach to understanding the pluripotency of stem cells.NADH redox ratio(NADH/(Fp t NADH)),where NADH is the reduced form of nicotinamide adenine dinucleotide and Fp is the oxidizedflavoproteins,has been established as a sensitive indicator of mitochondrial redox state.In this paper,we report our redox imaging data on the mitochondrial redox state of mouse ESC(mESC)colonies and the implications thereof.The low-temperature NADH/Fp redox scanner was employed to image mESC colonies grown on a feeder layer of gamma-irradiated mouse embryonicfibroblasts(MEFs)on glass cover slips.The result showed significant heterogeneity in the mitochondrial redox state within individual mESC colonies(size:~200-440μm),exhibiting a core with a more reduced state than the periphery.This more reduced state positively correlates with the expression pattern of Oct4,a well-established marker of pluripotency.Our observation is thefirst to show the heterogeneity in the mitochondrial redox state within a mESC colony,suggesting that mitochondrial redox state should be further investigated as a potential new biomarker for the stemness of embryonic stem cells.

CHOP THER APY INDUCED MITOCHONDRIAL REDOX STATE ALTERATION IN NON-HODGKIN'S LYMPHOMA XENOGRAFTS

We are interested in investigating whether cancer therapy may alter the mitochondrial redox state in cancer cells to inhibit their growth and survival.The redox state can be imaged by the redox scanner that collects the fuorescence signals from both the oxidized-fAavoproteins(Fp)and the reduced form of nicotinamide adenine dinucleotide(NADH)in snap frozen tissues and has been previously employed to study tumor aggressiveness and treatment responses.Here,with the redox scanner we investigated the effects of chemotherapy on mouse xenografts of a human diffuse large B.cell lymphoma cell line(DLCL2).The mice were treated with CHOP therapy,i.e,cyclophosphamide(C)+hydroxydoxorubicin(H)+Oncovin(O)+prednisone(P)with CHO administration on day 1 and prednisone administration on days 1-5.The Fp content of the treated group was significantly decreased(p=0.033)on day 5,and the mitochondrial redox state of the treated group was slightly more reduced than that of the control group(p=0.048).The decrease of the Fp heterogeneity(measured by the mean st andard deviation)had a border-line statistical significance(p=0.071).The result suggests that the mitochondrial metabolism of lymphoma cells was slightly suppressed and the lymphomas became less aggressive after the CHOP therapy.

Cranio-maxillofacial surgery simulation based on pre-specified target face configurations

This paper presents a novel method for assisting surgeons in automatically computing an optimal surgical plan by directly specifying the desired correction to a facial outline. First, the desired facial appearance is designed using a 3D sculpturing tool, while the cut regions of the skull are defined based on facial anatomy. Then, the deformation of the face meshes is performed using an improved biomechanical model in which virtual external forces are driven by the displacements corresponding to the differences of node coordinates between the original and specified face meshes, and free nodes and fixed nodes are defined in terms of the contact surfaces between the soft tissues and the bones within the cut regions. Finally, the shape of the contact surfaces is updated following the deformation of the soft tissues. After registering the deformable contact surfaces and the cut surfaces, the final positions of the cut bones are estimated. Evaluation of preliminary experimental results quantitatively shows the effectiveness of the proposed approach.

Dual source computed tomography coronary angiography in new onset cardiomyopathy

AIM: To evaluate safety and utility of coronary computed tomography angiography (CCTA) compared to invasive coronary angiography (ICA) in new cardiomyopathy. METHODS: Eighteen patients (mean age 56.5 years, 10 males) who presented for evaluation of new onset heart failure with evidence of systolic dysfunction (ejection fraction < 40%) on echocardiography and recent ICA were prospectively enrolled. Patients with known coronary artery disease, atrial fibrillation, creatinine > 1.5 g/dL, and contraindication to intravenous contrast administration were excluded. CCTA was performed using a dual source 64-slice scanner. Mean heart rate was 75 beats per minute. Stenosis was graded for each coronary segment as: none, mild (< 50%), moderate (50%-70%), severe (> 70%), or non-evaluable. Ischemic cardiomyopathy (ICM) was diagnosed if severe stenosis was present in the left main, proximal left anterior descending artery, or two or more major arteries. RESULTS: Two patients were diagnosed with ICM by ICA. CCTA correctly identified 2 patients with ICM and 16 patients as non-ICM. CCTA successfully evaluated 240/246 coronary segments with an accuracy of 97.5%, sensitivity 70%, specificity 98.7%, positive predictive value of 70%, and negative predictive value of 98.7% for identifying severe stenosis on a per-segment level. CONCLUSION: Dual source 64-slice multi-detector CCTA is a safe, accurate, and non-invasive technique for diagnosing ICM in patients presenting during the acute phase of newly diagnosed cardiomyopathy.

循证指南：弥散和灌注MRI在急性缺血性卒中诊断中的作用美国神经病学学会治疗和技术评价委员会的报告

目的 评价弥散加权成像（diffusion-weighted imaging,DWI）和灌注加权成像（perfusionweighted imaging PWI）在急性缺血性卒中患者诊断中应用的证据.方法 对1966年至2008年1月期间有关DWI和PWI诊断和预后价值的文献进行系统分析.结果和推荐 对于发病12 h内的急性缺血性卒中的诊断,DWI已被确认为有效的评价手段,且其诊断价值应高于非增强CT.为了最准确地诊断急性缺血性卒中,应进行DWI（A级推荐）;然而,在疑似急性卒中患者的总体样本中,DWI诊断缺血性卒中的敏感性并不完美.DWI诊断脑出血的准确性不在本指南的范围之内.根据Ⅱ级和Ⅲ级证据,基线DWI体积可预测前循环卒中的基线卒中严重程度（B级推荐）,但不能预测椎基底动脉系统卒中的基线卒中严重程度（C级推荐）.基线DWI病变体积可预测（最终）梗死体积（B级推荐）,并且有可能预测早期和远期临床转归（C级推荐）.与DWI相比,基线PWI体积预测基线卒中严重程度的价值较小（C级推荐）.尚无足够的证据支持或反对PWI在急性缺血性卒中诊断中的价值（U级推荐）.

头颈部肿瘤中周围神经肿瘤扩散的影像学指证:^(18)F-FDG PET图像的指引及与CT和MR的相关性

神经周围扩散(PNS)是指肿瘤沿着大神经生长,是微观上周围神经侵袭的宏观表现。这种现象最常见于头颈部,但其发生率因组织学肿瘤亚型而异。PNS是由肿瘤细胞、神经和结缔间质间复杂分子相互作用的结果。尽管PNS对患者的预后和治疗有影响,但在临床上仍存在诊断不足。相较于确认为"金标准"的MRI来说,^(18)F-脱氧葡萄糖(FDG)PET在头颈部肿瘤PNS评估中的作用尚待探讨。在PNS患者中,^(18)F-FDG PET显示受累神经的异常,也显示失神经后出现的肌肉变化。在^(18)F-FDG PET上评估PNS需要相关神经通路的知识,并且可以通过与解剖成像的融合、图像的附加处理和临床背景的回顾来改进。