On projectively related Einstein metrics in Riemann-Finsler geometry

综述China &Foreign Medical Treatment 中外医疗肠神经胶质细胞在炎症性肠病中的作用研究进展杜俊艳1，骆淑娥2，温萌11.甘肃卫生职业学院附属医院门诊部，甘肃兰州 730207；2.解放军96640部队医院外一科，甘肃兰州730030［摘要］ 近年来，肠神经胶质细胞（enteric glial cell, EGC ）在炎症性肠病（inflammatory bowel disease, IBD ）发病机制中引起广泛关注。

在IBD 患者中，肠道EGC 通过释放细胞因子和介质参与调节肠道炎症反应，EGC 与肠道上皮细胞、免疫细胞和神经元等相互作用，参与调节肠道的免疫平衡和功能，EGC 在炎症性肠病治疗中的潜在应用，调控和干预EGC 有望为治疗提供新思路和策略。

［关键词］ 肠神经系统；肠神经胶质细胞；胶质细胞源性神经营养因子-胶质细胞系源性神经营养因子受体α1/原癌基因自分泌环路［中图分类号］ R4 ［文献标识码］ A ［文章编号］ 1674-0742（2023）09(a)-0195-04Advances in the Study of the Role of Enteric Glial Cells in Inflammatory Bowel DiseaseDU Junyan 1, LUO Shu'e 2, WEN Meng 11.Outpatient Department, Affiliated Hospital of Gansu Health Vocational College, Lanzhou, Gansu Province, 730207 China;2.Department of Surgery, PLA 96640 Army Hospital, Lanzhou, Gansu Province, 730030 China[Abstract] In recent years, enteric glial cells (EGC) have attracted widespread attention in the pathogenesis of inflam⁃matory bowel disease (IBD). In IBD patients, intestinal EGCs are involved in the regulation of intestinal inflammatory responses through the release of cytokines and mediators, and EGCs interact with intestinal epithelial cells, immune cells, and neurons to participate in the regulation of intestinal immune homeostasis and function. The potential appli⁃cation of EGC in the treatment of inflammatory bowel disease, modulation and intervention of EGC is expected to pro⁃vide new ideas and strategies for treatment.[Key words] Enteric nervous system; Enteric glial cells; GDNF-GFRa1/RET autocrine loop溃疡性结肠炎（ulcerativecolitis, UC ）是一种与克罗恩病（crohn's disease, CD ）同属炎性肠病（in⁃flammatory bowel disease, IBD ）的慢性反复发作的肠炎[1]。

Nature子刊全基因组关联分析揭示肠道微生物群的改变有助于颅内未破裂动脉瘤的进展推荐：江舜尧编译：小鹿同学编辑：小菌菌中国医学科学院和北京协和医学院国家心血管疾病研究中心阜外医院心血管疾病国家重点实验室陈敬洲研究员等人于2020年6月25日在国际顶级期刊Nature Communications发表题目《Alterations of gut microbiota contribute to the progression of unruptured intracranial aneurysms》的文章，该研究对颅内未破裂动脉瘤（UIA）患者和健康对照者的粪便样品进行了全基因组关联研究，结合小鼠模型的粪便移植实验，研究者发现Hungatella hathewayi的丰度改变影响牛磺酸的循环水平，并与UIA的发生率增加相关。

文章摘要颅内未破裂动脉瘤（UIA）是一种威胁生命的脑血管疾病。

肠道微生物的组成变化是否参与了UIAs的发展尚不清楚。

研究者在国内UIA患者和健康对照者两个队列内以及接受人类供体粪便移植的小鼠中进行了一项病例对照的全基因组关联研究。

粪便移植后，UIA菌群足以在小鼠中诱发UIAs。

研究者确定了与UIA相关的肠道微生物物种与循环中牛磺酸的变化相关。

具体来说，人和动物体内Hungatella hathewayi的丰度明显降低，并且与牛磺酸循环中的浓度呈正相关。

与此结果一致地是，通过管饲法对小鼠施用H. hathewayi可以使其血清内牛磺酸的水平正常化，并保护小鼠免于颅内动脉瘤的形成和破裂。

牛磺酸的补充也可以逆转颅内动脉瘤的进展。

研究者的发现有助于深入了解H. hathewayi相关的牛磺酸消耗作为UIAs发病机理中关键因素的潜在作用。

文中重要图片说明图1 | UIA患者中肠道菌群的改变。

图2 | UIA患者中肠道微生物种类的改变。

图3 | 肠道微生物物种将UIA患者与健康对照者区分开。

白质纤维病变束重叠等方法White matter fiber lesion overlap bundle weighting method refers to the phenomenon in which the lesions of white matter fibers in the brain overlap and affect the function of the brain. This is a common problem in neuroimaging and can lead to various cognitive and motor impairments in individuals.白质纤维病变束重叠等方法是指脑白质纤维病变相互重叠，并影响大脑功能的现象。

这是神经影像学中的常见问题，会导致个体各种认知和运动功能障碍。

One perspective to look at this problem is from the technical aspect. Researchers and clinicians have been developing various imaging techniques and mathematical algorithms to accurately detect and quantify white matter fiber lesions. These techniques include diffusion tensor imaging, tractography, and lesion segmentation algorithms.从技术方面来看，研究人员和临床医生一直在开发各种影像技术和数学算法，以准确检测和量化白质纤维病变。

这些技术包括扩散张量成像、纤维束追踪和病变分割算法。

Another perspective to consider is the impact of white matter fiber lesions on individuals. These lesions can lead to a wide range of symptoms, including motor deficits, cognitive impairments, and emotional disturbances. Individuals with severe lesions may experience difficulties in daily activities and have a diminished quality of life.另一个要考虑的角度是白质纤维病变对个体的影响。

类黄酮防治阿尔茨海默症的研究进展黄菊青张英*（浙江大学生物系统工程与食品科学学院杭州310058）摘要随着人类寿命的延长和人口老龄化的加剧，阿尔茨海默症已成为威胁老年人健康的主要疾病之一。

目前，类黄酮对AD 的治疗和防治作用日益引起人们的关注。

大量研究表明，类黄酮能抑制AD 样病变并逆转啮齿动物认知缺陷，摄取富含类黄酮的食物有利于改善神经认知功能。

本文从AD 的发病机制出发，概述近5年来国内外关于类黄酮防治AD 的研究进展。

关键词阿尔茨海默症；发病因子；类黄酮；膳食功能因子文章编号1009-7848（2014）02-0193-08阿尔茨海默症（Alzheimer ’s disease ，AD ）是一种多发生于老年人的中枢神经系统退行性疾病，临床主要表现为认知功能障碍、记忆力减退及人格改变等[1]。

AD 的主要病理特点为显著的大脑皮质萎缩，组织学变化包括细胞外出现淀粉样斑块沉积，神经元胞体内出现神经原纤维缠绕，神经元细胞大量减少，突触消失[2]。

随着人类寿命的延长和人口老龄化的加剧，AD 在发展中国家和发达国家的发病率呈快速增长趋势[3]。

目前，临床上对AD 的治疗尚缺乏较有效的药物，现有药物的毒副作用及昂贵的医疗费用给个人、家庭和社会带来了沉重的精神和经济负担。

类黄酮是一类广泛存在于自然界的天然多酚类化合物，除传统意义上的抗氧化、抗癌、抗炎、抗菌等作用外，近年来类黄酮防治AD 的作用日益引起关注。

本文从AD 的发病机制出发，综述类黄酮防治AD 的研究进展。

1AD 发病机制AD 发病机制复杂，至今尚未十分清楚。

根据AD 的病理特征，目前主要有3种假说，即：A β假说、tau 蛋白假说和中枢胆碱能损伤假说。

1.1A β假说在过去数十年的研究中，关于AD 发病机制目前较为公认的学说是A β假说。

该假说认为AD 患者脑组织中的老年斑（淀粉样斑块）主要由A β（β-amyloid ）组成，脑中A β的过度沉积是AD 发生的直接诱因[4]。

NeuronArticleEpisodic Future Thinking ReducesReward Delay Discounting through an Enhancement of Prefrontal-Mediotemporal InteractionsJan Peters1,*and Christian Bu¨chel11NeuroimageNord,Department of Systems Neuroscience,University Medical Center Hamburg-Eppendorf,Hamburg20246,Germany*Correspondence:j.peters@uke.uni-hamburg.deDOI10.1016/j.neuron.2010.03.026SUMMARYHumans discount the value of future rewards over time.Here we show using functional magnetic reso-nance imaging(fMRI)and neural coupling analyses that episodic future thinking reduces the rate of delay discounting through a modulation of neural decision-making and episodic future thinking networks.In addition to a standard control condition,real subject-specific episodic event cues were presented during a delay discounting task.Spontaneous episodic imagery during cue processing predicted how much subjects changed their preferences toward more future-minded choice behavior.Neural valuation signals in the anterior cingulate cortex and functional coupling of this region with hippo-campus and amygdala predicted the degree to which future thinking modulated individual preference functions.A second experiment replicated the behavioral effects and ruled out alternative explana-tions such as date-based processing and temporal focus.The present data reveal a mechanism through which neural decision-making and prospection networks can interact to generate future-minded choice behavior.INTRODUCTIONThe consequences of choices are often delayed in time,and in many cases it pays off to wait.While agents normally prefer larger over smaller rewards,this situation changes when rewards are associated with costs,such as delays,uncertainties,or effort requirements.Agents integrate such costs into a value function in an individual manner.In the hyperbolic model of delay dis-counting(also referred to as intertemporal choice),for example, a subject-specific discount parameter accurately describes how individuals discount delayed rewards in value(Green and Myer-son,2004;Mazur,1987).Although the degree of delay discount-ing varies considerably between individuals,humans in general have a particularly pronounced ability to delay gratification, and many of our choices only pay off after months or even years. It has been speculated that the capacity for episodic future thought(also referred to as mental time travel or prospective thinking)(Bar,2009;Schacter et al.,2007;Szpunar et al.,2007) may underlie the human ability to make choices with high long-term benefits(Boyer,2008),yielding higher evolutionaryfitness of our species.At the neural level,a number of models have been proposed for intertemporal decision-making in humans.In the so-called b-d model(McClure et al.,2004,2007),a limbic system(b)is thought to place special weight on immediate rewards,whereas a more cognitive,prefrontal-cortex-based system(d)is more involved in patient choices.In an alternative model,the values of both immediate and delayed rewards are thought to be repre-sented in a unitary system encompassing medial prefrontal cortex(mPFC),posterior cingulate cortex(PCC),and ventral striatum(VS)(Kable and Glimcher,2007;Kable and Glimcher, 2010;Peters and Bu¨chel,2009).Finally,in the self-control model, values are assumed to be represented in structures such as the ventromedial prefrontal cortex(vmPFC)but are subject to top-down modulation by prefrontal control regions such as the lateral PFC(Figner et al.,2010;Hare et al.,2009).Both the b-d model and the self-control model predict that reduced impulsivity in in-tertemporal choice,induced for example by episodic future thought,would involve prefrontal cortex regions implicated in cognitive control,such as the lateral PFC or the anterior cingulate cortex(ACC).Lesion studies,on the other hand,also implicated medial temporal lobe regions in decision-making and delay discounting. In rodents,damage to the basolateral amygdala(BLA)increases delay discounting(Winstanley et al.,2004),effort discounting (Floresco and Ghods-Sharifi,2007;Ghods-Sharifiet al.,2009), and probability discounting(Ghods-Sharifiet al.,2009).Interac-tions between the ACC and the BLA in particular have been proposed to regulate behavior in order to allow organisms to overcome a variety of different decision costs,including delays (Floresco and Ghods-Sharifi,2007).In line with thesefindings, impairments in decision-making are also observed in humans with damage to the ACC or amygdala(Bechara et al.,1994, 1999;Manes et al.,2002;Naccache et al.,2005).Along similar lines,hippocampal damage affects decision-making.Disadvantageous choice behavior has recently been documented in patients suffering from amnesia due to hippo-campal lesions(Gupta et al.,2009),and rats with hippocampal damage show increased delay discounting(Cheung and Cardinal,2005;Mariano et al.,2009;Rawlins et al.,1985).These observations are of particular interest given that hippocampal138Neuron66,138–148,April15,2010ª2010Elsevier Inc.damage impairs the ability to imagine novel experiences (Hassa-bis et al.,2007).Based on this and a range of other studies,it has recently been proposed that hippocampus and parahippocam-pal cortex play a crucial role in the formation of vivid event repre-sentations,regardless of whether they lie in the past,present,or future (Schacter and Addis,2009).The hippocampus may thus contribute to decision-making through its role in self-projection into the future (Bar,2009;Schacter et al.,2007),allowing an organism to evaluate future payoffs through mental simulation (Johnson and Redish,2007;Johnson et al.,2007).Future thinking may thus affect intertemporal choice through hippo-campal involvement.Here we used model-based fMRI,analyses of functional coupling,and extensive behavioral procedures to investigate how episodic future thinking affects delay discounting.In Exper-iment 1,subjects performed a classical delay discounting task(Kable and Glimcher,2007;Peters and Bu¨chel,2009)that involved a series of choices between smaller immediate and larger delayed rewards,while brain activity was measured using fMRI.Critically,we introduced a novel episodic condition that involved the presentation of episodic cue words (tags )obtained during an extensive prescan interview,referring to real,subject-specific future events planned for the respective day of reward delivery.This design allowed us to assess individual discount rates separately for the two experimental conditions,allowing us to investigate neural mechanisms mediating changes in delay discounting associated with episodic thinking.In a second behavioral study,we replicated the behavioral effects of Exper-iment 1and addressed a number of alternative explanations for the observed effects of episodic tags on discount rates.RESULTSExperiment 1:Prescan InterviewOn day 1,healthy young volunteers (n =30,mean age =25,15male)completed a computer-based delay discounting proce-dure to estimate their individual discount rate (Peters and Bu ¨-chel,2009).This discount rate was used solely for the purpose of constructing subject-specific trials for the fMRI session (see Experimental Procedures ).Furthermore,participants compiled a list of events that they had planned in the next 7months (e.g.,vacations,weddings,parties,courses,and so forth)andrated them on scales from 1to 6with respect to personal rele-vance,arousal,and valence.For each participant,seven subject-specific events were selected such that the spacing between events increased with increasing delay to the episode,and that events were roughly matched based on personal rele-vance,arousal,and valence.Multiple regression analysis of these ratings across the different delays showed no linear effects (relevance:p =0.867,arousal:p =0.120,valence:p =0.977,see Figure S1available online).For each subject,a separate set of seven delays was computed that was later used as delays in the control condition.Median and range for the delays used in each condition are listed in Table S1(available online).For each event,a label was selected that would serve as a verbal tag for the fMRI session.Experiment 1:fMRI Behavioral ResultsOn day 2,volunteers performed two sessions of a delay dis-counting procedure while fMRI was measured using a 3T Siemens Scanner with a 32-channel head-coil.In each session,subjects made a total of 118choices between 20V available immediately and larger but delayed amounts.Subjects were told that one of their choices would be randomly selected and paid out following scanning,with the respective delay.Critically,in half the trials,an additional subject-specific episodic tag (see above,e.g.,‘‘vacation paris’’or ‘‘birthday john’’)was displayed based on the prescan interview (see Figure 1)indicating which event they had planned on the particular day (episodic condi-tion),whereas in the remaining trials,no episodic tag was pre-sented (control condition).Amount and waiting time were thus displayed in both conditions,but only the episodic condition involved the presentation of an additional subject-specific event tag.Importantly,nonoverlapping sets of delays were used in the two conditions.Following scanning,subjects rated for each episodic tag how often it evoked episodic associations during scanning (frequency of associations:1,never;to 6,always)and how vivid these associations were (vividness of associa-tions:1,not vivid at all;to 6,highly vivid;see Figure S1).Addition-ally,written reports were obtained (see Supplemental Informa-tion ).Multiple regression revealed no significant linear effects of delay on postscan ratings (frequency:p =0.224,vividness:p =0.770).We averaged the postscan ratings acrosseventsFigure 1.Behavioral TaskDuring fMRI,subjects made repeated choices between a fixed immediate reward of 20V and larger but delayed amounts.In the control condi-tion,amounts were paired with a waiting time only,whereas in the episodic condition,amounts were paired with a waiting time and a subject-specific verbal episodic tag indicating to the subjects which event they had planned at the respective day of reward delivery.Events were real and collected in a separate testing session prior to the day of scanning.NeuronEpisodic Modulation of Delay DiscountingNeuron 66,138–148,April 15,2010ª2010Elsevier Inc.139and the frequency/vividness dimensions,yielding an‘‘imagery score’’for each subject.Individual participants’choice data from the fMRI session were then analyzed byfitting hyperbolic discount functions to subject-specific indifference points to obtain discount rates (k-parameters),separately for the episodic and control condi-tions(see Experimental Procedures).Subjective preferences were well-characterized by hyperbolic functions(median R2 episodic condition=0.81,control condition=0.85).Discount functions of four exemplary subjects are shown in Figure2A. For both conditions,considerable variability in the discount rate was observed(median[range]of discount rates:control condition=0.014[0.003–0.19],episodic condition=0.013 [0.002–0.18]).To account for the skewed distribution of discount rates,all further analyses were conducted on the log-trans-formed k-parameters.Across subjects,log-transformed discount rates were significantly lower in the episodic condition compared with the control condition(t(29)=2.27,p=0.016),indi-cating that participants’choice behavior was less impulsive in the episodic condition.The difference in log-discount rates between conditions is henceforth referred to as the episodic tag effect.Fitting hyperbolic functions to the median indifference points across subjects also showed reduced discounting in the episodic condition(discount rate control condition=0.0099, episodic condition=0.0077).The size of the tag effect was not related to the discount rate in the control condition(p=0.56). We next hypothesized that the tag effect would be positively correlated with postscan ratings of episodic thought(imagery scores,see above).Robust regression revealed an increase in the size of the tag effect with increasing imagery scores (t=2.08,p=0.023,see Figure2B),suggesting that the effect of the tags on preferences was stronger the more vividly subjects imagined the episodes.Examples of written postscan reports are provided in the Supplemental Results for participants from the entire range of imagination ratings.We also correlated the tag effect with standard neuropsychological measures,the Sensation Seeking Scale(SSS)V(Beauducel et al.,2003;Zuck-erman,1996)and the Behavioral Inhibition Scale/Behavioral Approach Scale(BIS/BAS)(Carver and White,1994).The tag effect was positively correlated with the experience-seeking subscale of the SSS(p=0.026)and inversely correlated with the reward-responsiveness subscale of the BIS/BAS scales (p<0.005).Repeated-measures ANOVA of reaction times(RTs)as a func-tion of option value(lower,similar,or higher relative to the refer-ence option;see Experimental Procedures and Figure2C)did not show a main effect of condition(p=0.712)or a condition 3value interaction(p=0.220),but revealed a main effect of value(F(1.8,53.9)=16.740,p<0.001).Post hoc comparisons revealed faster RTs for higher-valued options relative to similarly (p=0.002)or lower valued options(p<0.001)but no difference between lower and similarly valued options(p=0.081).FMRI DataFMRI data were modeled using the general linear model(GLM) as implemented in SPM5.Subjective value of each decision option was calculated by multiplying the objective amount of each delayed reward with the discount fraction estimated behaviorally based on the choices during scanning,and included as a parametric regressor in the GLM.Note that discount rates were estimated separately for the control and episodic conditions(see above and Figure2),and we thus used condition-specific k-parameters for calculation of the subjective value regressor.Additional parametric regressors for inverse delay-to-reward and absolute reward magnitude, orthogonalized with respect to subjective value,were included in theGLM.Figure2.Behavioral Data from Experiment1Shown are experimentally derived discount func-tions from the fMRI session for four exemplaryparticipants(A),correlation with imagery scores(B),and reaction times(RTs)(C).(A)Hyperbolicfunctions werefit to the indifference points sepa-rately for the control(dashed lines)and episodic(solid lines,filled circles)conditions,and thebest-fitting k-parameters(discount rates)and R2values are shown for each subject.The log-trans-formed difference between discount rates wastaken as a measure of the effect of the episodictags on choice preferences.(B)Robust regressionrevealed an association between log-differences indiscount rates and imagery scores obtained frompostscan ratings(see text).(C)RTs were signifi-cantly modulated by option value(main effectvalue p<0.001)with faster responses in trialswith a value of the delayed reward higher thanthe20V reference amount.Note that althoughseven delays were used for each condition,somedata points are missing,e.g.,onlyfive delay indif-ference points for the episodic condition areplotted for sub20.This indicates that,for the twolongest delays,this subject never chose the de-layed reward.***p<0.005.Error bars=SEM.Neuron Episodic Modulation of Delay Discounting140Neuron66,138–148,April15,2010ª2010Elsevier Inc.Episodic Tags Activate the Future Thinking NetworkWe first analyzed differences in the condition regressors without parametric pared to those of the control condi-tion,BOLD responses to the presentation of the delayed reward in the episodic condition yielded highly significant activations (corrected for whole-brain volume)in an extensive network of brain regions previously implicated in episodic future thinking (Addis et al.,2007;Schacter et al.,2007;Szpunar et al.,2007)(see Figure 3and Table S2),including retrosplenial cortex (RSC)/PCC (peak MNI coordinates:À6,À54,14,peak z value =6.26),left lateral parietal cortex (LPC,À44,À66,32,z value =5.35),and vmPFC (À8,34,À12,z value =5.50).Distributed Neural Coding of Subjective ValueWe then replicated previous findings (Kable and Glimcher,2007;Kable and Glimcher,2010;Peters and Bu¨chel,2009)using a conjunction analysis (Nichols et al.,2005)searching for regions showing a positive correlation between the height of the BOLD response and subjective value in the control and episodic condi-tions in a parametric analysis (Figure 4A and Table S3).Note that this is a conservative analysis that requires that a given voxel exceed the statistical threshold in both contrasts separately.This analysis revealed clusters in the lateral orbitofrontal cortex (OFC,À36,50,À10,z value =4.50)and central OFC (À18,12,À14,z value =4.05),bilateral VS (right:10,8,0,z value =4.22;left:À10,8,À6,z value =3.51),mPFC (6,26,16,z value =3.72),and PCC (À2,À28,24,z value =4.09),representing subjective (discounted)value in both conditions.We next analyzed the neural tag effect,i.e.,regions in which the subjective value correlation was greater for the episodic condi-tion as compared with the control condition (Figure 4B and Table S4).This analysis revealed clusters in the left LPC (À66,À42,32,z value =4.96,),ACC (À2,16,36,z value =4.76),left dorsolateral prefrontal cortex (DLPFC,À38,36,36,z value =4.81),and right amygdala (24,2,À24,z value =3.75).Finally,we performed a triple-conjunction analysis,testing for regions that were correlated with subjective value in both conditions,but in which the value correlation increased in the episodic condition.Only left LPC showed this pattern (À66,À42,30,z value =3.55,see Figure 4C and Table S5),the same region that we previously identified as delay-specific in valuation (Petersand Bu¨chel,2009).There were no regions in which the subjective value correlation was greater in the control condition when compared with the episodic condition at p <0.001uncorrected.ACC Valuation Signals and Functional Connectivity Predict Interindividual Differences in Discount Function ShiftsWe next correlated differences in the neural tag effect with inter-individual differences in the size of the behavioral tag effect.To this end,we performed a simple regression analysis in SPM5on the single-subject contrast images of the neural tag effect (i.e.,subjective value correlation episodic >control)using the behavioral tag effect [log(k control )–log(k episodic )]as an explana-tory variable.This analysis revealed clusters in the bilateral ACC (right:18,34,18,z value =3.95,p =0.021corrected,left:À20,34,20,z value =3.52,Figure 5,see Table S6for a complete list).Coronal sections (Figure 5C)clearly show that both ACC clusters are located in gray matter of the cingulate sulcus.Because ACC-limbic interactions have previously been impli-cated in the control of choice behavior (Floresco and Ghods-Sharifi,2007;Roiser et al.,2009),we next analyzed functional coupling with the right ACC from the above regression contrast (coordinates 18,34,18,see Figure 6A)using a psychophysiolog-ical interaction analysis (PPI)(Friston et al.,1997).Note that this analysis was conducted on a separate first-level GLM in which control and episodic trials were modeled as 10s miniblocks (see Experimental Procedures for details).We first identified regions in which coupling with the ACC changed in the episodic condition compared with the control condition (see Table S7)and then performed a simple regression analysis on these coupling parameters using the behavioral tag effect as an explanatory variable.The tag effect was associated with increased coupling between ACC and hippocampus (À32,À18,À16,z value =3.18,p =0.031corrected,Figure 6B)and ACC and left amygdala (À26,À4,À26,z value =2.95,p =0.051corrected,Figure 6B,see Table S8for a complete list of activa-tions).The same regression analysis in a second PPI with the seed voxel placed in the contralateral ACC region from the same regression contrast (À20,34,22,see above)yielded qual-itatively similar,though subthreshold,results in these same structures (hippocampus:À28,À32,À6,z value =1.96,amyg-dala:À28,À6,À16,z value =1.97).Experiment 2We conducted an additional behavioral experiment to address a number of alternative explanations for the observed effects of tags on choice behavior.First,it could be argued thatepisodicFigure 3.Categorical Effect of Episodic Tags on Brain ActivityGreater activity in lateral parietal cortex (left)and posterior cingulate/retrosplenial and ventro-medial prefrontal cortex (right)was observed in the episodic condition compared with the control condition.p <0.05,FWE-corrected for whole-brain volume.NeuronEpisodic Modulation of Delay DiscountingNeuron 66,138–148,April 15,2010ª2010Elsevier Inc.141tags increase subjective certainty that a reward would be forth-coming.In Experiment 2,we therefore collected postscan ratings of reward confidence.Second,it could be argued that events,always being associated with a particular date,may have shifted temporal focus from delay-based to more date-based processing.This would represent a potential confound,because date-associated rewards are discounted less than delay-associated rewards (Read et al.,2005).We therefore now collected postscan ratings of temporal focus (date-based versus delay-based).Finally,Experiment 1left open the question of whether the tag effect depends on the temporal specificity of the episodic cues.We therefore introduced an additional exper-imental condition that involved the presentation of subject-specific temporally unspecific future event cues.These tags (henceforth referred to as unspecific tags)were obtained by asking subjects to imagine events that could realistically happen to them in the next couple of months,but that were not directly tied to a particular point in time (see Experimental Procedures ).Episodic Imagery,Not Temporal Specificity,Reward Confidence,or Temporal Focus,Predicts the Size of the Tag EffectIn total,data from 16participants (9female)are included.Anal-ysis of pretest ratings confirmed that temporally unspecific and specific tags were matched in terms of personal relevance,arousal,valence,and preexisting associations (all p >0.15).Choice preferences were again well described by hyperbolic functions (median R 2control =0.84,unspecific =0.81,specific =0.80).We replicated the parametric tag effect (i.e.,increasing effect of tags on discount rates with increasing posttest imagery scores)in this independent sample for both temporally specific (p =0.047,Figure 7A)and temporally unspecific (p =0.022,Figure 7A)tags,showing that the effect depends on future thinking,rather than being specifically tied to the temporal spec-ificity of the event cues.Following testing,subjects rated how certain they were that a particular reward would actually be forth-coming.Overall,confidence in the payment procedure washighFigure 4.Neural Representation of Subjective Value (Parametric Analysis)(A)Regions in which the correlation with subjective value (parametric analysis)was significant in both the control and the episodic conditions (conjunction analysis)included central and lateral orbitofrontal cortex (OFC),bilateral ventral striatum (VS),medial prefrontal cortex (mPFC),and posterior cingulate cortex(PCC),replicating previous studies (Kable and Glimcher,2007;Peters and Bu¨chel,2009).(B)Regions in which the subjective value correlation was greater for the episodic compared with the control condition included lateral parietal cortex (LPC),ante-rior cingulate cortex (ACC),dorsolateral prefrontal cortex (DLPFC),and the right amygdala (Amy).(C)A conjunction analysis revealed that only LPC activity was positively correlated with subjective value in both conditions,but showed a greater regression slope in the episodic condition.No regions showed a better correlation with subjective value in the control condition.Error bars =SEM.All peaks are significant at p <0.001,uncorrected;(A)and (B)are thresholded at p <0.001uncorrected and (C)is thresholded at p <0.005,uncorrected for display purposes.NeuronEpisodic Modulation of Delay Discounting142Neuron 66,138–148,April 15,2010ª2010Elsevier Inc.(Figure 7B),and neither unspecific nor specific tags altered these subjective certainty estimates (one-way ANOVA:F (2,45)=0.113,p =0.894).Subjects also rated their temporal focus as either delay-based or date-based (see Experimental Procedures ),i.e.,whether they based their decisions on the delay-to-reward that was actually displayed,or whether they attempted to convert delays into the corresponding dates and then made their choices based on these dates.There was no overall significant effect of condition on temporal focus (one-way ANOVA:F (2,45)=1.485,p =0.237,Figure 7C),but a direct comparison between the control and the temporally specific condition showed a significant difference (t (15)=3.18,p =0.006).We there-fore correlated the differences in temporal focus ratings between conditions (control:unspecific and control:specific)with the respective tag effects (Figure 7D).There were no correlations (unspecific:p =0.71,specific:p =0.94),suggesting that the observed differences in discounting cannot be attributed to differences in temporal focus.High-Imagery,but Not Low-Imagery,Subjects Adjust Their Discount Function in an Episodic ContextFor a final analysis,we pooled the samples of Experiments 1and 2(n =46subjects in total),using only the temporally specific tag data from Experiment 2.We performed a median split into low-and high-imagery participants according to posttest imagery scores (low-imagery subjects:n =23[15/8Exp1/Exp2],imagery range =1.5–3.4,high-imagery subjects:n =23[15/8Exp1/Exp2],imagery range =3.5–5).The tag effect was significantly greater than 0in the high-imagery group (t (22)=2.6,p =0.0085,see Figure 7D),where subjects reduced their discount rate by onaverage 16%in the presence of episodic tags.In the low-imagery group,on the other hand,the tag effect was not different from zero (t (22)=0.573,p =0.286),yielding a significant group difference (t (44)=2.40,p =0.011).DISCUSSIONWe investigated the interactions between episodic future thought and intertemporal decision-making using behavioral testing and fMRI.Experiment 1shows that reward delay dis-counting is modulated by episodic future event cues,and the extent of this modulation is predicted by the degree of sponta-neous episodic imagery during decision-making,an effect that we replicated in Experiment 2(episodic tag effect).The neuroi-maging data (Experiment 1)highlight two mechanisms that support this effect:(1)valuation signals in the lateral ACC and (2)neural coupling between ACC and hippocampus/amygdala,both predicting the size of the tag effect.The size of the tag effect was directly related to posttest imagery scores,strongly suggesting that future thinking signifi-cantly contributed to this effect.Pooling subjects across both experiments revealed that high-imagery subjects reduced their discount rate by on average 16%in the episodic condition,whereas low-imagery subjects did not.Experiment 2addressed a number of alternative accounts for this effect.First,reward confidence was comparable for all conditions,arguing against the possibility that the tags may have somehow altered subjec-tive certainty that a reward would be forthcoming.Second,differences in temporal focus between conditions(date-basedFigure 5.Correlation between the Neural and Behavioral Tag Effect(A)Glass brain and (B and C)anatomical projection of the correlation between the neural tag effect (subjective value correlation episodic >control)and the behav-ioral tag effect (log difference between discount rates)in the bilateral ACC (p =0.021,FWE-corrected across an anatomical mask of bilateral ACC).(C)Coronal sections of the same contrast at a liberal threshold of p <0.01show that both left and right ACC clusters encompass gray matter of the cingulate gyrus.(D)Scatter-plot depicting the linear relationship between the neural and the behavioral tag effect in the right ACC.(A)and (B)are thresholded at p <0.001with 10contiguous voxels,whereas (C)is thresholded at p <0.01with 10contiguousvoxels.Figure 6.Results of the Psychophysiolog-ical Interaction Analysis(A)The seed for the psychophysiological interac-tion (PPI)analysis was placed in the right ACC (18,34,18).(B)The tag effect was associated with increased ACC-hippocampal coupling (p =0.031,corrected across bilateral hippocampus)and ACC-amyg-dala coupling (p =0.051,corrected across bilateral amygdala).Maps are thresholded at p <0.005,uncorrected for display purposes and projected onto the mean structural scan of all participants;HC,hippocampus;Amy,Amygdala;rACC,right anterior cingulate cortex.NeuronEpisodic Modulation of Delay DiscountingNeuron 66,138–148,April 15,2010ª2010Elsevier Inc.143。

•妇幼医学-中国当代医药2021年6月第28卷第17期体外受精-胚胎移植助孕与自然受孕的分娩情况及新生儿结局分析孙晓燕杨嫦玉广东省珠海市妇幼保健院，广东珠海519000［摘要］目的探讨体外受精-胚胎移植(IVF-ET)受孕与自然受孕产妇的分娩情况及新生儿情况。

方法回顾性分析2019年1~12月珠海市妇幼保健院收治的8318例产妇的临床资料及分娩新生儿信息，根据受孕方式分为试管组(孕妇523例,新生儿611例)和正常组(孕妇7795例,新生儿7911例)。

比较两组分娩方式、分娩相关并发症及新生儿结局。

结果试管组剖宫产发生率高于正常组，差异有统计学意义(P<0.05)；试管组早产、前置胎盘、产后岀血、子痫发生率均高于正常组，差异有统计学意义(P<0.05)；两组难产率和胎膜早破发生率比较，差异无统计学意义(P>0.05)；试管组的新生儿感染性肺炎及低出生体重发生率均高于正常组，差异有统计学意义(P<0.05)o结论IVF-ET助孕的产妇患者分娩并发症及新生儿并发症风险增高,增加剖宫产手术概率，应注意围生期护理，及时处理并发症。

［关键词］体外受精-胚胎移植;分娩方式；分娩并发症；新生儿结局［中图分类号］R714.8［文献标识码］A［文章编号］1674-4721(2021)6(b)-0126-04Delivery of in vitro fertilization-embryonic transplantation assisted con­ception and natural conception and neonatal outcomes analysisSUN Xiao-yan YANG Chang-yuZhuhai MaLernal and Child Health HospiLal,Guangdong Province,Zhuhai519000,China［Abstract］Objective To investigate the birth of in vitro fertilization-embryonic transplantation(IVF-ET)assisted con­ception and natural conception and neonatal conditions.Methods A retrospective analysis was conducted on8318 puerperae's clinical data and delivery of newborns from January2019to December2019in our hospital.According to different conceptions,they were divided into a test tube group(523cases of pregnant women,611cases of neonates) and a normal group(7795cases of pregnant women,7911cases of neonates).The mode of delivery,complications as­sociated with delivery,and neonatal outcomes were compared in the two groups.Results The incidence of cesarean section of the test tube group was higher than that in the normal group,and the difference was statistically significant (P<0.05).The incidence rates of premature birth,placenta previa,postpartum bleeding,and eclampsia in the test tube group were higher than those of the normal group,the differences were statistically significant(P<0.05).There were no statistically significant differences in the incidence rates of dystocia or premature rupture of fetal membranes between the two groups(P>0.05).The incidence rates of neonatal infectious pneumonia and low birth weight were higher than those of the normal group with statistical significance(P<0.05).Conclusion The risks of deli very-related complications and neonatal complications are increased in IVF-ET assisted conception,which increases the probability of cesarean section,should pay attention to perinatal care,and treat complications in time.［Key words］In vitro fertilization-embryonic transplantation;Mode of delivery;Childbirth-related complications;Neona­tal outcome体外受精-胚胎移植(IVF-ET)作为当今治疗不孕的常用方法之一，自1978年开始使用并发展至今,为无数家庭带来希望与幸福。

如何回复编辑和审稿人 Company Document number：WTUT-WT88Y-W8BBGB-BWYTT-19998专题半月谈 - 如何回复编辑和审稿人作者：QIN 提交日期：2010-12-09 06:25:55 PM | 访问量：713专题半月谈 - 如何回复编辑和审稿人应战友要求，在版主的支持下，本人在此设立一个半月谈专题-如何回复编辑和审稿人实例分析。

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3.同时亦欢迎各高级战友按以下格式增加实例（请注意版权问题）。

希望战友回帖时紧紧围绕主题，不要讨（争）论与主题无关的话题。

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15 January 2009 （第一讲）给编辑的回复信论文题目：Pharmacokinetic and pharmacodynamic studies on the antivirus effect s of A (一种中草药) against virus B （一种病毒）所投杂志：Life Sciences投稿结果：这次大修后又经过一次小修，被接受发表编辑信内容（注：有删节）：Dear Mr. XXX,Your manuscript has been examined by the editors and qualified refere e. We think the manuscript has merit but requires revision before wecan accept it for publication in the Journal. Careful consideration m ust be given to the points raised in the reviewer comments, which are enclosed below.If you choose to submit a revision of your manuscript, please incorpo rate responses to the reviewer comments into the revised paper. A com plete rebuttal with no manuscript alterations is usually considered i nadequate and may result in lengthy re-review procedures.A letter detailing your revisions point-by-point must accompany the r esubmission.You will be requested to upload this Response to Reviewers as a separ ate file in the Attach Files area.We ask that you resubmit your manuscript within 45 days. After this t ime, your file will be placed on inactive status and a further submis sion will be considered a new manuscript.You will see a menu item called Submission Needing Revision. You will find your submission record there.Yours sincerely,Joseph J. Bahl, PhDEditorLife SciencesFormat Suggestion: Please access the Guide to Authors at our website to check the format of your article. Pay particular attention to our References style.Reviewers' comments:Reviewer #1:XXXXX （略）Reviewer #2:XXXXX （略）Editors note and suggestions:（注：编辑的建议）Title: Re-write the title to read more smoothly in contemporary Engli sh>>>Pharmacokinetic and pharmacodynamic studies of the antiviral effects of A against virus B.Abstract: Re-write the abstract to read more smoothly.A, an alkaloid isolated from C (注：一种中草药), was tested for antiv iral activity against virus B. Both in vitro and in vivo assays along with serum pharmacological experiments showed A to have potent antiv iral activity. The pharmacokinetic profile of A in Sprague/Dawley rat plasma after oral administration was measured by HPLC. Blood samples taken at selected time points were analyzed to study potential chang es in antiviral pharmacodynamics as measured by infectivity of viruse s. From the similarity of the serum concentration profiles and antivi ral activity profiles it is concluded that A it self, rather than a m etabolite, exerted the effect against the virus prior to bioinactivat ion. The need for effective clinical agents against virus B and theseresults suggest the possibility of benefit from further experiments with A.The authors should check to be sure that the terms blood samples, pla sma and serum are always used appropriately throughout the abstract a nd text.Introduction: some sentences can be made less passive. example 1st pa ragraph>>>> A appears to be the most important alkaloid isolated from the pl ant, its structural formula is shown in Fig 1. ... While it produced a general inhibition of antibody production lymphocyte proliferation was stimulated (Xia and Wang, 1997). These pharmacological properties suggest a potential use in the treatment of viral myocarditis agains t virus B that could be studied in experiments in cell culture and an imals.>>>The authors should check the entire manuscript for spelling errors (example given: in your text alkaloid is incorrectly spelled alkaloi d)>>>The authors should read the guidelines to the authors and not incl ude the first name of the authors being cited in the text. In the ref erence section the first name should be abbreviated as shown in the g uideline to authors (thus the earlier text reference should be (Liu e t al., 2003)and the remaining one should be (Chen et al., 2002)>>>>>The authors instead of directly answering the first complex ques tion of reviewer #1 may include the three questions as future researc h aim in the discussion section.>>>>>>Rather than redrawing figure the authors may choose to amend th e wording of the statistical analysis section to state that the resul t of tables are means +-SEM and for figures are +- SD.>>>>> reviewer #1 comment number 8 and reviewer # 2 comment 3 might b e satisfied by inclusion of a representative photo of cells and heart showing CPE. Remember most readers of the journal have never seen wh at you are trying to describe.Joseph Bahl, PhD Editor 2 Life Sciences作者回复信原稿：Dear Dr. Bahl,I’m （注：正式信函不要简写）very appreciate （注：不适合作为给编辑回信的开始，同时有语法错误）for your comments and suggestions.I （注：实际上是学生做的）have conducted in vivo antivirus experiment s again （注：要表明是应审稿人或编辑建议而作）. Mice were sacrificed on 15 days and 30 days after infection. Death rate, heart weight to b ody weight ratio (HW/BW), virus titers and pathologic slices （注：用词错误）were calculated（注：用词不当）. Production of mRNA of IL-10, IFN-γand TNF-αwere （注：语法错误）measured by RT-PCR.I have revised this manuscript and especially paid much attention to your comments and suggestions. I would like to re-submit it to LIFE S CIENCE. Title of manuscript has been changed to “The antivirus effects of A against virus B and its pharmacokinetic behaviour in SD rats serum” to make it more clear and smooth.Answers to Reviewers’ questions were as follows: （注：可附在给编辑的回复信后）Reviewer #1:XXXXXReviewer #2:XXXXXEditors note and suggestions:Title: Re-write the title to read more smoothly in contemporary Engli shAnswer:I have rewrite the title to “The antivirus effects of A against viru s B and its pharmacokinetic behaviour in SD rats serum” to make it m ore clear and smooth（注：多处语法错误）.Abstract: Re-write the abstract to read more smoothly.Answer:I have revise the abstract carefully to make it more smooth and infor mative（注：语法错误）.The authors should check to be sure that the terms blood samples, pla sma and serum are always used appropriately throughout the abstract a nd text.Answer:I have paid attention to this question and it is clearer （注：不具体）.Introduction:some sentences can be made less passive.Answer:I have revise the whole paper to make sentences less passive and obta ined help of my colleague proficient in English （注：语法错误，句子不通顺）.The authors should check the entire manuscript for spelling errors Answer:I’m very sorry to give you so much trouble for those spelling errors （注：不必道歉，按建议修改即可）. I have carefully corrected them.The authors should read the guidelines to the authors and not include the first name of the authors being cited in the text. In the refere nce section the first name should be abbreviated as shown in the guid eline to authors (thus the earlier text reference should be (Liu et a l., 2003) and the remaining one should be (Chen et al., 2002)Answer:I changed the style of references.Rather than redrawing figure the authors may choose to amend the word ing of the statistical analysis section to state that the result of t ables are means +-SEM and for figures are +- SD.Answer:（注：作者请编辑公司帮回答）reviewer #1 comment number 8 and reviewer # 2 comment 3 might be sati sfied by inclusion of a representative photo of cells and heart showi ng CPE. Remember: most readers of the journal have never seen what yo u are trying to describe.Answer:Thank you for your suggestions. I have supplemented pictures of cardi ac pathologic slices in the paper (Fig2).I have to apologize for giving you so much trouble because of those m isspelling and confusing statements （注：一般不是延误或人为失误，不必轻易道歉，按建议修改即可）. Your comments and suggestions really he lped me a lot. I have put great efforts to this review. I wish it can be satisfactory.If there’s （注：正式信函不要简写）any information I can provide, pl ease don’t hesitate to contact me.Thank you again for your time and patience. Look forward to hear （注：语法错误）from you.Yours SincerelyXxxx Xxxx (通讯作者名)建议修改稿：Dear Dr. Bahl,Thanks you very much for your comments and suggestions.As suggested, we have conducted in vivo antivirus experiments. Mice w ere sacrificed on 15 days and 30 days after infection with virus B. M ortality, heart weight to body weight ratio (HW/BW), virus titers and pathologic scores were determined. In addition, mRNA expression of I L-10, IFN-γ and TNF-α were measured by RT-PCR.We have revised the manuscript, according to the comments and suggest ions of reviewers and editor, and responded, point by point to, the c omments as listed below. Since the paper has been revised significant ly throughout the text, we feel it is better not to highlight the ame ndments in the revised manuscript （正常情况最好表明修改处）.The revised manuscript has been edited and proofread by a medical edi ting company in Hong Kong.I would like to re-submit this revised manuscript to Life Sciences, a nd hope it is acceptable for publication in the journal.Looking forward to hearing from you soon.With kindest regards,Yours SincerelyXxxx Xxxx (通讯作者名)Replies to Reviewers and EditorFirst of all, we thank both reviewers and editor for their positive a nd constructive comments and suggestions.Replies to Reviewer #1:Xxxxx （略）Replies to Reviewer #2:Xxxxx （略）Replies to the Editors note and suggestions:Title: Re-write the title to read more smoothly in contmeporary Engli shAnswer:I have rewrite the title to “The antivirus effects of Sophoridine ag ainst Coxsackievirus B3 and its pharmacokine tics in rats” to make it more clear and read more smoothly.Abstract: Re-write the abstract to read more smoothly.Answer:I have rewritten the abstract to make it more informative and read mo re smoothly.The authors should check to be sure that the terms blood samples, pla sma and serum are always used appropriately throughout the abstract a nd text.Answer:I have paid attention to this issue, and they are now used appropriat ely throughout the abstract and text in the revised manuscript.Introduction:some sentences can be made less passive.Answer:I have revised the whole paper to make sentences less passive with th e help of the editing company.The authors should check the entire manuscript for spelling errorsAnswer:This has been done by us as well as the editing company.The authors should read the guidelines to the authors and not include the first name of the authors being cited in the text. In the refere nce section the first name should be abbreviated as shown in the guid eline to authors (thus the earlier text reference should be (Liu et a l., 2003) and the remaining one should be (Chen et al., 2002)Answer:I have changed the style of references according to the journal.Rather than redrawing figure the authors may choose to ament the word ing of the statistical analysis section to state that the result of t ables aremeans +-SEM and for figures are +- SD.Answer:SD has been used throughout the text, and shown in the Figs. 3 and 4 in the revised manuscript.reviewer #1 comment number 8 and reviewer # 2 comment 3 might be sati fied by inclusion of a representative photo of cells and heart showin g CPE. Remember: most readers of the journal have never seen what you are trying to describe.Answer:Thank you very much for the suggestion. I have added pictures of card iac pathologic changes in the revised manuscript (Fig. 2).很好的经验，谢谢分享！31 January 2009 （第二讲）给审稿人的回复信论文题目：Clinical implications of XXXX (一种病理指标) in X cancer所投杂志：BMC Cancer.结果：这次大修后被接受发表（同时编辑在接受信中提出课题是否得到伦理委员会同意的问题。

作者单位:200092上海市上海交通大学医学院附属新华医院消化内科第一作者:孙超,女,47岁,医学博士,副主任医师㊂主要从事慢性肝病防治研究㊂E-mail:csun7682@通讯作者:范建高,E-mail:fanjiangao@ ㊃病例报道㊃未分化结缔组织病相关肝纤维化1例报告孙超,段晓燕,葛文松,范建高㊀㊀ʌ关键词ɔ㊀结缔组织病;肝纤维化㊀㊀DOI:10.3969/j.issn.1672-5069.2024.03.038㊀㊀Undifferentiated connective tissue disease associated liver fibrosis:A case report㊀Sun Chao,Duan Xiaoyan,Ge Wensong, et al.Department of Gastroenterology,Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine,Shanghai 200092,China㊀㊀ʌKey wordsɔ㊀Undifferentiated connective tissue disease;Liver fibrosis㊀㊀结缔组织病(connective tissue disease,CTD)是风湿性疾病中的一大类,以血管和结缔组织慢性炎症性改变为主要发病基础,累及多个器官㊂未分化CTD(undifferentiated CTD,UCTD)是CTD的一种特殊类型,相对少见,可累及肝脏,引起肝损害,临床表现缺乏特异性,易漏诊误诊[1]㊂本文报道一例因反复肝功能异常为首发表现就诊消化科,伴有肝纤维化㊁间质性肺炎和亚临床甲状腺功能减退症,最终被诊断为UCTD及相关肝纤维化和间质性肺炎,给予皮质激素和羟氯喹治疗后患者肝功能指标恢复正常㊂现回顾性分析该例的诊疗过程并进行文献复习,供临床医师参考㊂1㊀病例摘要患者女性,54岁㊂因 发现反复肝功能异常4年 于2023年5月3日入院㊂4年前无明显诱因患者自觉双手指遇冷发白,偶有中上腹隐痛,每次持续约10分钟,进食后可好转,就诊当地医院,化验外周血发现丙氨酸氨基转移酶(alanine transaminase, ALT)为43U/L,天冬氨酸氨基转移酶(aspartate transaminase,AST)为46U/L,碱性磷酸酶(alkaline phosphatase,ALP)为184U/L,γ-谷氨酰转肽酶(γ-glutamyl transpeptadase,GGT)为260U/L,总胆红素(total bilirubin,TBIL)为19.5μmol/L㊂腹部超声提示肝脏形态大小正常,脾稍大㊂未予治疗㊂后多次复查肝功能,均提示ALT和AST轻度升高㊂2年前患者因左肩疼痛2月于当地医院住院,查血清ALT42U/L,AST85U/L,ALP163U/L,GGT196U/L㊂抗核抗体(antinuclear antibody,ANA)1:1000弱阳性㊂抗着丝粒蛋白B抗体阳性,抗双链DNA抗体阴性㊂诊断为 免疫性肝损害,左肩周炎 ,给予泼尼松㊁硫唑嘌呤㊁熊去氧胆酸等治疗1月,复查肝功能指标未见明显好转,自行停药㊂后未规律随访㊂今年2月患者再次在当地卫生院复查ALT38U/L,AST151 U/L,ALP205U/L,GGT294U/L,TBIL11.8μmol/L,直接胆红素(direct bilirubin,DBIL)3.6μmol/L,遂就诊我院㊂既往无饮酒史,无药物过敏史,10年前行子宫肌瘤切除术,5年前因胆囊结石行胆囊切除术㊂查体:体温36.3ħ,脉搏76次/分,呼吸18次/分,血压105/60mmHg㊂身高158cm,体质量65kg,体质指数26.03kg/m2,腰围81cm,臀围97cm㊂全身皮肤和巩膜无明显黄染,无肝掌㊁蜘蛛痣,心肺听诊无异常发现,腹部查体无特殊㊂查血常规㊁C反应蛋白正常,凝血酶原时间10.4s,血沉23mm/h㊂胆汁酸11.7μmol/L,ALT17U/L,AST108U/L,ALP176U/L, GGT186U/L,TBIL9.1μmol/L和白蛋白(albumin, ALB)40.5g/L㊂肾功能和尿蛋白正常㊂空腹血糖5.0mmol/L,糖基化血红蛋白5.3%,空腹胰岛素54.7pmol/L㊂稳态型评估法胰岛素抵抗指数1.8㊂血清总胆固醇正常,甘油三脂2.6mmol/L,高密度脂蛋白胆固醇0.1mmol/L,低密度脂蛋白胆固醇3.7mmol/L㊂肿瘤标志物正常㊂血清嗜肝病毒和EB病毒㊁巨细胞病毒标志物均为阴性,ANA(1:640)阳性,ANA(1:1280)弱阳性,抗着丝粒蛋白B抗体阳性,抗Ro-52阳性,类风湿因子㊁抗双链DNA抗体㊁抗Smith抗体㊁抗线粒体抗体-M2㊁抗平滑肌抗体㊁抗肝肾微粒体抗体㊁抗肝细胞溶质抗原1型抗体㊁抗可溶性肝抗原抗体㊁抗心磷脂抗体均为阴性㊂IgM4.8 g/L,IgG㊁IgA㊁IgE正常㊂IgG4正常㊂铜蓝蛋白正常㊂血清游离三碘甲状腺原氨酸4.6pmol/L,游离四碘甲状腺原氨酸14.3pmol/L,促甲状腺素5.9uIU/mL,抗促甲状腺激素受体抗体㊁抗甲状腺过氧化物酶抗体均正常㊂结核感染T细胞检测阴性㊂腹部超声示肝㊁胰㊁双肾未见明显异常,脾稍大㊂双侧甲状腺胶样结节,双侧甲状腺弥漫性病变㊂超声检查全身淋巴结无肿大㊂胸部CT平扫见肺多发磨玻璃结节,右肺上叶和中叶结节,两肺间质性炎症㊂腹部增强磁共振见肝门区数枚结节,考虑肿大的淋巴结,腹部脏器未见明显异常㊂在超声引导下肝穿刺活检术,病理学检查提示肝细胞部分气球样变,少数细胞脂肪变(<5%),可见点灶状坏死,局灶出血坏死,网状纤维塌陷,见少量淋巴细胞和中性粒细胞浸润,未见细胞内淤胆及胆栓㊂汇管区见中等量淋巴细胞和中性粒细胞浸润㊂局灶轻度界面炎,可见汇管区和窦周纤维化,个别汇管区小叶间静脉腔闭塞(图1)㊂免疫组化检查见胆管细胞角蛋白7阳性,细胞角蛋白19阳性㊂马松和网状纤维染色见汇管区和窦周纤维化,糖原染色阳性,提示慢性活动性肝炎(G2S2),不除外自身免疫性疾病可能㊂经风湿免疫科和呼吸科多学科会诊,临床诊断UCTD,间质性肺炎,亚临床甲状腺功能减退症,高脂血症,甲状腺结节㊂给予强的松30mg.d-1口服,羟氯喹200mg.d-1口服治疗㊂2个月后随访,患者肝功能恢复正常㊂图1㊀肝组织病理学表现(HE,400ˑ)2　讨论本文报道了一例UCTD引起的长期反复慢性肝损害,逐渐发展为肝纤维化,且伴间质性肺炎㊁亚临床甲状腺功能减退症等多系统表现㊂目前,UCTD的诊断标准尚不统一,但通常采用1999年Mosca提出的初步分类标准:包括至少一种CTD的临床表现,ANA阳性,至少三年的病程,但不符合任一确定CTD的分类标准[2]㊂研究发现仅30%UCTD患者在3~5年后进展为某种确定的CTD[3,4]㊂其中14%~20%患者最终发展为系统性红斑狼疮[5]㊂一项来自西班牙758例UTCD患者研究报道,随访11年,14%患者进展为确定的CTD,24%患者临床症状缓解,62%患者仍为UCTD[6]㊂因多数UCTD患者数十年后仍保持未分化状态,故目前多认为UCTD可能是CTD分类中一种独立的疾病㊂早期UCTD往往症状不明显,或仅有非特异性的临床表现,如乏力㊁低热㊁淋巴结肿大等㊂患者常先出现血清自身抗体阳性,再逐步出现临床症状㊂稳定期UCTD常见的症状有关节痛/关节炎㊁雷诺现象㊁皮疹㊁口腔溃疡㊁干眼症㊁白细胞减少㊁贫血和血小板减少㊁间质性肺炎,相对而言,浆膜炎(心包炎)㊁心脏病变(如心肌炎,心律失常)㊁消化系统(食管运动异常㊁吸收不良综合征)等症状不常见㊂肾脏疾病(膜性肾小球肾炎,肾病综合征)㊁神经系统损害(三叉神经痛㊁无菌性脑炎)及危及生命仅偶见报道[6,7]㊂该患者病程4年,反复肝功能异常,有雷诺现象,间质性肝炎,ANA高滴度,患者否认反复发热㊁口腔溃疡㊁明显口眼干,未见颜面皮疹㊁猖獗性龋齿,双手关节未见明显畸形,无确定CTD的典型症状和体征,符合UCTD的诊断㊂UCTD患者发生肝功能异常的原因包括UCTD 本身,也包含自身免疫性肝炎㊁原发性硬化性胆管炎㊁原发性胆汁性胆管炎㊁代谢相关脂肪性肝病㊁药物性肝损伤等其他肝脏本身的疾病[3]㊂临床上,区分UCTD肝脏受累和UCTD合并原发肝病具有一定的难度㊂该患者肝损害原因复杂,首先考虑UCTD 本身通过免疫介导引起的肝损害㊂此外,该患者ALT正常,IgG正常,肝组织只有局灶轻度界面炎,无大量浆细胞浸润,无玫瑰花环样结构和淋巴细胞穿入现象,使用国际自身免疫性肝炎诊断积分系统打分为13分,暂不考虑合并自身免疫性肝炎㊂虽有超重㊁血脂异常,但患者腰围正常,血糖正常,无胰岛素抵抗,腹部超声和MRI未提示脂肪肝,肝组织细胞脂肪变<5%,合并代谢相关脂肪性肝病也不考虑㊂综上所述,该患者肝损害主要还是由UCTD引起的㊂治疗UCTD的主要药物是皮质激素㊁羟氯喹和非甾体类抗炎药物,不到三分之一患者需要免疫抑制药物(硫唑嘌呤㊁甲氨蝶呤㊁吗替麦考酚酯等)治疗[1]㊂羟氯喹可以抑制多形核细胞的趋化性,抑制前列腺素合成,具有抗炎㊁调节免疫和抗凝作用㊂与糖皮质激素联合使用可以控制关节㊁皮肤粘膜和全身炎性症状[1]㊂若常规治疗效果差或严重器官受累时,加用免疫抑制剂是关键的治疗方法,可减轻与UCTD相关的炎症症状㊂该患者在确诊为UCTD时,予以皮质激素联合羟氯喹治疗后肝功能好转㊂多数UCTD患者预后良好,10a生存率达到90%以上[6]㊂患者的预后主要与其受累及的器官相关㊂虽然多数患者可能进展为确定的CTD,但多症状较轻,并发症发生少,预后相对较好[7]㊂即使UCTD患者疾病难以痊愈,多数病情保持稳定或自行缓解,很少恶化[8]㊂当然,该例患者将来是否仍为UCTD还是演变为确定的CTD需长期随访㊂总之,对于反复肝功能异常的患者,不仅需仔细排查肝脏本身的疾病,还需警惕结缔组织病的可能,特别是患者出现雷诺现象㊁多脏器功能异常等表现,且伴有自身抗体阳性时,更应及时进行相关检查,以尽早确立诊断和治疗㊂伦理学声明:本例患者已签署知情同意书㊂利益冲突声明:所有作者声明均不存在利益冲突㊂作者贡献声明:孙超负责收集临床资料和撰写论文;段晓燕和葛文松参与论文起草和修改;范建高修改文章关键内容㊂ʌ参考文献ɔ[1]Rubio J,Kyttaris VC.Undifferentiated connective tissue disease:comprehensive review.Connectivetissue sisease:Comprehensive re-view.Curr Rheumatol Rep,2023,25(5):98-106. [2]Mosca M,Neri R,Bombardieri S.Undifferentiated connectivetissue diseases(UCTD):a review of the literature and a proposal for preliminary classification criteria.Clin Exp Rheumatol,1999,17(5):615-620.[3]莫颖倩,严青,叶霜,等.未分化结缔组织病和混合性结缔组织病的诊疗规范.中华内科杂志,2022,61(10):1119-1127.[4]Radin M,Rubini E,Cecchi I,et al.Disease evolution in a long-term follow-up of104undifferentiated connective tissue disease pa-tients.Clin Exp Rheumatol,2022,40(3):575-580. [5]Drehmel KR,Erickson AR,England BR,et al.Applying SLICCand ACR/EULAR systemic lupus erythematosus classification criteria in a cohort of patients with undifferentiated connective tissue disease.Lupus,2021,30(2):280-284.[6]Sciascia S,Roccatello D,Radin M,et al.Differentiating betweenUCTD and early-stage SLE:from definitions to clinical approach.Nat Rev Rheumatol,2022,18(1):9-21.[7]Garcia-Gonzalez M,Rodriguez-Lozano B,Bustabad S,et al.Un-differentiated connective tissue disease:predictors of evolution into definite disease.Clin Exp Rheumatol,2017,35(5):739-745.[8]Radin M,Cecchi I,Barinotti A,et al.Identifying subsets of pa-tients with undifferentiated connective tissue disease:Results from a prospective,real-world experience using particle-based multi-ana-lyte technology.Autoimmun Rev,2023,22(5):103298.(收稿:2024-01-08)(本文编辑:陈从新)。

2023年11月 第9卷 第11期芪苈强心胶囊联合尼可地尔治疗慢性肺心病伴冠心病心衰患者的效果熊云志1，罗宗梅2，徐菱31.深圳市盐田区人民医院心血管内科，广东深圳 518081；2.贵州省贵阳市第二人民医院心血管内科，贵州贵阳 550081；3.深圳市罗湖区人民医院妇科，广东深圳 518005摘要 目的 综合分析芪苈强心胶囊联合尼可地尔治疗慢性肺源性心脏病（简称慢性肺心病）伴冠心病心力衰竭的临床治疗效果。

方法 回顾性选取2021年10月—2022年12月深圳市盐田区人民医院收治的60例慢性肺心病伴冠心病心力衰竭患者的临床资料。

按照患者入院顺序分为对照组（30例，应用尼可地尔治疗）和研究组（30例，在对照组基础上应用芪苈强心胶囊治疗），比较两组患者的临床治疗有效率、心功能指标及生存质量。

结果 与对照组比较，研究组临床治疗总有效率（90.00%）更高，差异有统计学意义（χ2=4.706，P <0.05）；治疗后，研究组左室射血分数、每搏输出量高于对照组，左室舒张末期内径低于对照组，差异有统计学意义（P <0.05）；治疗后，研究组生存质量评分均高于对照组，差异有统计学意义（P <0.05）。

结论 芪苈强心胶囊联合尼可地尔治疗慢性肺心病伴冠心病心力衰竭患者的临床治疗效果显著。

关键词 芪苈强心胶囊；尼可地尔；慢性肺心病伴冠心病心力衰竭；临床治疗效果；心功能；生存质量中图分类号 R 541541..5 文献标志码 Adoi10.11966/j.issn.2095-994X.2023.09.11.39Qili Qiangxin Capsule Combined with Nicorandil in the Treatment of Patients with Chronic Pulmonary Heart Disease Accompanied by Coronary Heart Disease and Heart FailureXIONG Yunzhi 1, LUO Zongmei 2, XU Ling 31.Department of Cardiovascular Medicine, Yantian District People's Hospital, Shenzhen, Guangdong Province, 518081 China;2.Depart⁃ment of Cardiovascular Medicine, Guiyang Second People's Hospital, Guiyang, Guizhou Province, 550081 China;3.Department of Gynecol⁃ogy, Luohu District People's Hospital, Shenzhen, Guangdong Province, 518005 ChinaAbstract Objective To comprehensively analyze the clinical therapeutic effect of Qili Qiangxin capsule combined with nicorandil in the treat⁃ment of chronic pulmonary heart disease (referred to as chronic pulmonary heart disease) with coronary heart failure. Methods The clinical data of 60 patients with chronic pulmonary heart disease with CHD and heart failure treated in Yantian District People's Hospital of Shenzhen from October 2021 to December 2022 were retrospectively selected. Patients were divided into control group (30 cases, treatment with nicodil) and study group (30 cases, treatment with Qiliqiangxin capsule on the basis of control group) according to the order of admission. Clinical treatment effectiveness, cardiac function indexes, quality of life of the two groups were compared. Results Compared with the control group, the total effective rate of the study group (90.00%) was higher, the difference was statistically significant (χ2=4.706, P <0.05).After treatment, the left ventricular ejection fraction and output per beam in the study group were higher than those in the control group, and the left ventricu⁃lar end-diastolic diameter was lower than that in the control group, the differences were statistically significant (P <0.05). After treatment, the quality of life score of the study group was higher than that of the control group, and the difference was statistically significant (P <0.05). Con⁃clusion The clinical therapeutic effect of Qili Qiangxin capsule combined with nicorandil in the treatment of patients with chronic pulmonary* 中西医结合研究 *收稿日期：2023-09-02；修回日期：2023-09-23作者简介：熊云志（1982-），男，本科，主治医师，研究方向为心血管病。

doi:10.3969/j.issn.1000⁃484X.2019.16.020㊃专题综述㊃肠道微生态影响绝经后骨质疏松症发生发展的研究进展①李丽娟　林　静　王　凌　(复旦大学上海医学院附属妇产科医院暨妇产科研究所,复旦大学中西医结合研究院,上海市女性生殖内分泌相关疾病重点实验室,上海200011) 中图分类号　R711 文献标志码　A 文章编号　1000⁃484X(2019)16⁃2032⁃06[摘　要]　肠道微生物的数量是人类细胞数的数十倍,可以被看成人体的一种器官,以多种方式与宿主相互作用并影响宿主;它包含的基因数远远超过人类的基因数,被称为人体的 第二基因组”;它可以影响宿主组织(如骨组织)的发育和稳态㊂绝经后骨质疏松症是一种在绝经后妇女中高发的疾病,是指绝经后妇女由于卵巢衰退,雌激素水平下降导致骨吸收大于骨形成,出现以骨量降低和骨组织的显微结构退行性变为特征㊁骨脆性和骨折易感性增加的一种全身代谢疾病㊂女性雌激素衰退是绝经后骨质疏松症发生的重要诱因,而肠道微生物在性激素缺乏引起骨质流失的发生中处于中心地位㊂肠道微生物通过宿主的免疫系统调控骨代谢;雌激素缺乏导致的肠壁通透性增加会引起细菌移位和增强机体的炎症反应,而肠道益生菌可以通过抑制炎症反应和增强肠道上皮的屏障功能来防止骨质流失㊂肠道微生物亦可通过机体的代谢来调节骨代谢,短链脂肪酸是益生元发酵的主要产物,它能诱导IGF⁃1的产生,增加骨量㊂肠道微生物还可以通过增强营养物质摄取㊁合成人体必需营养物质从而改善机体的营养状况的方式来影响骨代谢㊂[关键词]　肠道微生物;绝经后骨质疏松症;雌激素衰竭;免疫反应;益生菌Advances in research on intestinal microbiota affecting development of post⁃menopausal osteoporosisLI Li⁃Juan,Lin Jing,WANG Ling.Obstetrics and Gynecology Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical College,Fudan University,Shanghai Institute of Integrative Medicine,Fudan University,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases,Shanghai200011,China [Abstract]　Human intestinal microbiota can be seen as a multicellular organ that interacts with the host and affects the host in a variety of ways.It is estimated to outnumber human cells10to1;it contains far more genes than human genes,known as the"second genome"of the human body;it can affect the development and homeostasis of host tissues such as bone tissue.Postmenopausal osteoporosis,a systemic metabolic disease of high prevalence in postmenopausal women,refers to low bone mass,micro⁃architectural de⁃terioration of bone tissue,bone fragility and susceptibility to fracture due to natural decline of estrogen levels during menopause.Intestinal microbiota is central in the occurrence of sex hormone deficiency⁃associated bone loss.It regulates bone metabolism through host immune system.The increased intestinal permeability caused by estrogen deficiency can lead to bacterial trans⁃location and inflammation,while intestinal probiotics may prevent bone loss by inhibiting inflammatory response and enhancing the barrier function of intestinal epithelium.It can also regulate bone metabolism through metabolism of organism.Short chain fatty acids are the main product of probiotic fermentation,which can induce IGF⁃1production and increase bone mass.Intestinal microbiota can affect bone metabolism by enhancing nutrient uptake and synthesizing essential nutrients to improve the body′s nutritional status. [Key words]　Intestinal microbiota;Postmenopausal osteoporosis;Estrogen failure;Immune response;Probiotics①本文受国家自然科学基金(31571196㊁30801502㊁81401171)㊁上海市医学引导类项目(15401932200)㊁上海市浦江人才计划(11PJ1401900)㊁日本学术振兴会海外博士后研究员项目(P08471)和上海市高峰学科(中西医结合,20150407)建设项目资助㊂作者简介:李丽娟,女,在读硕士,主要从事妇产科学方面研究, E⁃mail:1430105012@㊂通讯作者及指导教师:王　凌,女,医学博士,研究员,博士生导师,主要从事神经⁃生殖内分泌⁃免疫调节方面研究,E⁃mail:dr.wangling@㊂ 肠道微生物自人出生后即被获得,成年人肠道中存在大约1014个细菌,其数量是人体细胞的10倍之多[1]㊂肠道微生物的基因超过5×106个,比人类基因数多150倍[2],常与人类基因组共同起作用,被称为人体的 第二基因组”[3]㊂它还被认为是一种多细胞器官,以多种方式参与宿主相互作用并影响宿主[3]㊂研究表明,肠道微生物对宿主生物实现某些方面的生理功能来说是必不可少的,它可以促进难以消化的多糖代谢并产生必需的维生素,促进宿主的肠上皮和免疫系统发育分化,保护机体免受机会性病原体的侵袭,并且在维持组织稳态中起关键作用[4]㊂最近研究还表明[5],人体内微生物群影响宿主其他组织的发育和稳态,包括骨组织㊂这为我们研究和治疗绝经后骨质疏松症提供了新思路㊂在生理条件下,机体通过破骨细胞骨吸收和成骨细胞骨形成间的平衡来维持骨骼稳态[6]㊂绝经后骨质疏松症(Postmenopausal osteoporosis,PMO)是指绝经后妇女由于卵巢功能衰退,雌激素水平下降,出现以骨量降低和骨组织的显微结构退行性变为特征,骨脆性和骨折易感性增加的一种全身代谢疾病[7]㊂在绝经后妇女中,骨质疏松引起的骨折比脑卒中㊁心肌梗塞等更为常见[8]㊂由骨质疏松引起的骨折具有破坏性后果,特别是在老年人中㊂椎骨骨折是严重疼痛和跛足的根源,而髋部骨折仅在第一年就导致24%~30%的死亡率[9]㊂此外,几乎50%的幸存者遭受永久性残疾[10]㊂据报道,超过50%的绝经后妇女患有骨质疏松性骨折,预计随着预期寿命的增长而增加㊂绝经后骨质疏松症因为它的高发病率和骨质疏松性骨折的严重后果,对家庭或社会造成了严重的负担,因此,我们需要采取积极的预防和治疗措施来应对该疾病[11]㊂研究表明PMO中的骨质流失与宿主免疫反应密切相关,而宿主免疫反应又受到肠道微生物群的调控[12,13]㊂益生菌能够防止骨流失,从而在绝经后骨质疏松症中发挥积极地治疗作用[14,15]㊂肠道微生物对骨代谢的影响为PMO的管理提供了一个新的方式[16]㊂1　女性雌激素衰退是绝经后骨质疏松症发生的重要诱因 Fuller Albright早在1940年发表了他对绝经期雌激素缺乏和骨质疏松症之间因果关系的观察结果,他介绍了更年期激素治疗(Menopausal hormone therapy,MHT)预防骨质疏松症的概念[17⁃21]㊂雌激素缺乏导致骨转化(吸收和形成)的速率增加,而骨吸收和骨形成的速率并不平衡,其中骨吸收更加占优势[22]㊂更年期的初始阶段,雌激素水平下降刺激较大程度的骨吸收和较小程度的骨形成,小程度的骨形成又造成一段时间内快速的骨损失㊂初始阶段之后是一个更缓慢但更漫长的骨质流失期,这个时期主要影响到骨骼的皮质部分[12]㊂目前研究表明[23],在一定的窗口期内,激素补充治疗的益处要大于它给机体健康带来的风险㊂雌激素可以通过激活雌激素受体α㊁Wnt/β⁃Catenin信号通路[24]或Notch信号通路[25]来改善人骨髓间充质干细胞成骨分化的能力,进而起到调节骨代谢㊁保护骨组织的功能㊂Li等[6]发现与没有骨质疏松症的患者相比,患有PMO的妇女TNF⁃α水平升高㊂TNF⁃α和PMO患者体内的RANK(Recep⁃tor activator for nuclear factor⁃κB)水平呈高度正相关关系㊂在体外,TNF⁃α通过激活NF⁃κB(Nuclear factor⁃κB)信号通路和PI3K/Akt信号通路来促进破骨细胞分化因子(Receptor activator for nuclear factor⁃κB ligand,RANKL)诱导的破骨细胞分化生成㊂此外,PI3K/Akt的抑制完全阻断了TNF⁃α对NF⁃κB信号通路的活化和促破骨细胞生成的协同作用,表明TNF⁃α通过激活PI3K/Akt信号通路协同促进RANKL诱导的破骨细胞分化生成,最终在PMO发生发展中起重要作用㊂在小鼠中,卵巢切除(Ovariectomy,OVX)通过促进初始CD4+细胞分化为成熟Th17细胞来增加Th17细胞的数量,这是细胞因子如TGF⁃β㊁IL⁃6㊁IL⁃1β和TNF驱动的结果,这些因子都是由于雌激素缺乏而诱导产生的[26]㊂Th17细胞是CD4+细胞中的一类能促进破骨细胞分化的亚群[12,27],通过分泌IL⁃17A㊁IL⁃1㊁IL⁃6㊁RANKL㊁TNF以及低水平的IFN⁃γ有效地诱导破骨细胞的生成㊂IL⁃17A刺激成骨细胞释放RANKL,并通过上调RANK从而促进破骨细胞的分化㊂在PMO患者中可以观察到IL⁃17的血清水平升高㊂此外,雌激素可以直接抑制CD4+T细胞向Th17细胞的分化㊂沉默IL⁃17R或抗IL⁃17抗体能够预防OVX诱发的骨质流失,这一结果突出了IL⁃17在骨质流失中的重要性㊂总之,性激素缺乏能够促进Th17细胞的分化成熟,联合升高的TNF⁃α㊁RANKL㊁IL⁃17等细胞因子,导致PMO的发生[28]㊂雌激素缺乏是绝经后女性发生骨质疏松症的主要风险因素,50岁以上的女性中有一半在其一生中会经历与骨质疏松相关的骨折㊂以往雌激素补充疗法一直是本病的主要治疗方法,它可以缩短破骨细胞(Osteoclast,OC)寿命,减少绝经后妇女体内OC 生成,增加OC凋亡,抑制骨重吸收[29],由于雌激素补充疗法有一些令人无法接受的副作用(如增加子宫内膜癌的患病风险),所以新型疗法仍被需要来对抗绝经后骨质流失㊂2　肠道微生物在性激素缺乏引起骨质流失的发生中处于中心地位 数以万亿计的微生物栖息在肠道内,与宿主形成互利关系[30]㊂这些共生微生物被称为微生物群,整体上可以看作是一种多细胞器官,以多种不同方式与宿主进行物质交换和信息交流[16,31]㊂甚至有人提出肠道微生物群是我们的 第二基因组”,动态整合宿主及其环境的信号,影响机体健康和患病风险[3]㊂肠道微生物群在调节骨骼健康方面发挥重要作用[32],肠道微生物群在性激素缺乏引起的骨质流失的过程中处于中心地位[25]㊂在无菌(Germ⁃free, GF)小鼠中,即使在性激素缺乏的情况下,破骨细胞生成因子[如巨噬细胞集落刺激因子(M⁃CSF)㊁TNF㊁IL⁃1]的产生也不会增加,即不能刺激骨吸收或引起骨质流失㊂此外,用益生菌鼠李糖乳杆菌GG(LGG)或市售益生菌增补剂VSL#3(益生菌制剂的商品名,含有8种益生菌)每周两次治疗性激素缺陷小鼠能降低其肠道通透性,减轻肠道和骨髓炎症,完全防止骨质流失的发生;相反,补充大肠杆菌的非益生菌菌株或突变体LGG并不具有保护性㊂上述实验表明[28],肠道微生物群和肠道通透性增加在触发炎症途径中发挥重要作用,这对于在性激素缺陷小鼠中诱导骨质流失的作用至关重要㊂降低肠道通透性的益生菌有潜力成为PMO的治疗策略㊂在GF小鼠中,性激素缺乏不会促使产生TNF 的T细胞增生,也不会增加骨髓和肠中TNF的产生㊂此外,在微生物群缺乏的情况下,性激素缺乏时骨髓和肠组织中的IL⁃17水平亦没有增加㊂综上所述,肠道微生物群的调节是性激素缺乏诱导骨质流失所必需的中间环节㊂另一些研究表明[33],通过抗生素治疗改变肠道微生物组成的多样性和数目可以调节性激素缺乏雌性小鼠的骨质流失量㊂总之,肠道菌群与性激素缺乏引起的骨质流失密切相关㊂3　肠道微生物调控骨代谢的机制肠道微生物可以通过影响宿主的代谢和免疫反应,来调节机体的骨代谢,从而在PMO的发生发展中发挥重要作用㊂3.1　肠道微生物通过宿主的免疫系统调控骨代谢　与肠道相关的炎症和自身免疫病症与骨量降低有关,提示肠道与骨代谢之间存在关联[34]㊂肠道微生物被证明可以调节肠道和全身免疫反应[12],并且已经确定免疫系统与骨代谢之间存在关联,表明肠道微生物可能通过改变机体的免疫反应影响骨代谢[13]㊂小鼠免疫系统发育的最重要触发因素是出生后立即暴露于微生物组分㊂Hansen等[35]的研究表明,出生后短期Germ⁃free的存在永久改变了Treg㊁NK和NKT细胞的水平以及细胞因子的产生,即肠道微生物的延迟定殖导致免疫系统的永久性变化㊂总之存在时间窗口,能够通过肠道微生物的人工定植修改宿主未来的免疫表型㊂此外,肠道微生物的延迟定殖导致免疫系统的永久性变化㊂鉴于骨代谢与宿主免疫间的密切联系,以上研究提示,肠道微生物可能通过对宿主固有免疫的调控,间接影响骨代谢㊂肠道微生物对CD4+T细胞亚群的出现和维持有强烈的影响㊂比如分段丝状杆菌(SFB)能诱导Th17细胞的分化[36]㊁脆弱拟杆菌诱导Th1细胞和Treg的分化[37],表明肠道的微生物和宿主细胞之间存在着密切的关联㊂Sjögren等[5]研究发现,与常规培养的(Conven⁃tionally raised,CONV⁃R)小鼠相比,无菌(Cerm⁃free, GF)小鼠表现出更多的骨量,这与骨中破骨细胞数量的减少,从而使骨吸收减少相关㊂将CONV⁃R小鼠肠道微生物群移植于GF小鼠肠道内可其使骨量正常化㊂此外,GF小鼠的骨髓中CD4+T细胞和破骨细胞前体细胞的数量降低,同样,这种差异可以通过移植正常肠道菌群来消除㊂与CONV⁃R小鼠相比,GF小鼠的骨中表现出炎性细胞因子表达的降低㊂总之,肠道微生物群能调节小鼠的骨量,并且可能是通过调节免疫系统来减少破骨细胞介导的骨吸收㊂Atarashi等[38]研究发现,肠内微生物亚群如SFB㊁柠檬酸杆菌㊁大肠杆菌O157和某些细胞外病原体的定殖并黏附到肠上皮细胞(Epithelial cells, ECs)时,肠Th17细胞被诱导并聚集㊂也就是说,微生物黏附到ECs是Th17细胞被诱导的关键线索㊂而前面我们已经知道IL⁃17是引起骨量丢失的重要炎症因子,所以可以进一步推断肠道微生物确实是通过影响宿主的免疫系统来调控骨代谢的㊂3.2　肠道益生菌可以通过抑制炎症反应来防止骨质流失　益生菌被定义为在给予足量时能带来健康益处的活微生物㊂益生菌除了能调节宿主的免疫应答[39],还可以改变肠道微生物群的组成和代谢活性[40],并且能增强上皮屏障功能,后者可能是最重要的机制[41]㊂在细胞水平上,性激素缺乏引起骨丢失的重要机制是破骨细胞形成和破骨细胞寿命的增加[42,43]㊂增加破骨细胞生成的主要驱动因素是免疫因子RANKL和TNF的产生增多[44]㊂因此,依赖于性激素缺失的骨丢失被认为是一种炎性骨丢失㊂Ohlsson等[45]的研究中选择了单纯L⁃副干酪乳杆菌DSM13434(L⁃para)和L⁃副干酪乳杆菌DSM13434㊁植物乳杆菌DSM15312㊁DSM15313乳杆菌构成的乳杆菌混合物(L⁃mix),并且在OVX手术前的2周就开始分别用这两种组合的益生菌来喂养小鼠㊂L.para和L.mix处理都能保护小鼠免受OVX 诱导的骨质流失㊂益生菌治疗减少了两种炎性细胞因子TNF⁃α和IL⁃1β的表达,并增加了OVX小鼠骨中骨保护素(Osteoprotegerin,OPG)㊂OPG是RANKL的诱导受体[46],通过与RANKL的结合减少破骨细胞的产生,是破骨细胞生成的有效抑制剂㊂Britton等[32]也已经报道了益生菌的骨保护作用,他们测试了罗伊氏乳杆菌对OVX诱导的骨丢失的作用㊂结果显示罗伊氏乳杆菌治疗改变了肠道微生物的组成,在体外抑制破骨细胞的生成,防止了卵巢衰竭诱导的骨吸收㊂此外,益生菌的治疗抑制了OVX诱导的骨髓CD4+T细胞的增加,支持了肠道微生物通过调节骨中的免疫状态从而影响破骨细胞介导的骨吸收的观点㊂Parvaneh等[17]的一项研究中,也证明了益生菌长双歧杆菌(Bifidobacterium longum)能从OVX诱导的骨丢失中保护大鼠㊂生物多样性下降被认为是疾病状态的一个指标,反映出生存环境恶化和资源枯竭[47]㊂雌激素的缺失导致微生物群落多样性降低,而随着益生菌的使用,肠道中的微生物多样性将增加[48]㊂肠道微生物群与肠壁之间相互作用的失调在性激素缺陷小鼠中诱导炎症和骨质流失中起关键作用㊂3.3　肠壁通透性和骨质流失　肠上皮是宿主和肠腔微生物群之间的界面㊂肠通过细胞间隙的大小控制肠腔和黏膜下层之间的分子运输,这个选择性生理屏障能够阻挡较大直径分子通过㊂肠壁与肠腔微生物密切接触,不断识别肠腔内的外来抗原并对之做出反应[49]㊂增加的通透性允许更大的分子和潜在的抗原进入上皮黏膜下层,这可能引发异常的肠道和机体炎症反应[50]㊂因此,维持肠腔和黏膜下层之间紧密的机械屏障对健康至关重要㊂另外破骨细胞生成细胞因子是由驻留在肠上皮下组织中的免疫细胞产生,任何肠通透性改变都可能提高破骨细胞生成细胞因子水平从而影响骨密度㊂性激素对维持肠腔内常驻菌群和肠壁黏膜下层之间生理屏障的紧密性起重要作用[51],所以性激素水平的降低将增加肠道通透性㊂因此,任何可以改善肠道通透性的治疗方法都将有利于预防性激素缺失导致的骨质流失㊂益生菌即是通过降低肠道通透性的途径来降低炎症反应从而起到保护骨的作用㊂3.4　肠道微生物通过影响机体的代谢来调节骨代谢3.4.1　肠道微生物群诱导IGF⁃1并促进骨形成和生长　Yan等[52]研究发现,尽管将常规的无特定病原体(Specific⁃pathogen⁃free,SPF)的肠道微生物群移植于GF小鼠肠道内会导致宿主骨量急剧降低,但在微生物长期稳定定植的小鼠肠道内移植SPF,宿主中骨形成和骨量增加将占主导地位,导致骨骼纵向和横向的双发展㊂经检测,后者小鼠血清中胰岛素样生长因子1(Insulin⁃like growth factors,IGF⁃1)显著上升㊂IGF⁃1是一种对骨骼生长有明确正向调节作用的激素,同时可正向反映肠道微生物的定植状况㊂后者小鼠的肝脏和脂肪组织中IGF⁃1产量亦显著增加㊂相反,给常规小鼠以抗生素治疗会降低血清IGF⁃1并抑制骨形成㊂尽管目前尚未见 肠道微生物⁃IGF⁃1⁃骨代谢”调控轴的报道,鉴于IGF⁃1在骨代谢过程中的重要作用,有理由推断肠道微生物可能通过调控与骨代谢密切相关的IGF⁃1水平,参与调控机体骨代谢平衡[53]㊂另有研究表明,与GF小鼠相比,SPF小鼠的新生儿生长更快,其IGF⁃1水平更高㊂此外,他们发现,在营养不足的情况下,用特定的细菌菌株如乳酸杆菌使肠道菌群单一化足以改变 生长激素⁃IGF⁃1轴”并对小鼠的骨生长产生积极影响[54]㊂3.4.2　短链脂肪酸通过影响IGF⁃1的水平来间接影响骨代谢　同样在Yan等[52]的研究中,用短链脂肪酸(Short⁃chain fatty acids,SCFAs)补充给抗生素处理过的小鼠,会促使IGF⁃1水平和骨量恢复至与未经抗生素处理的小鼠相同的水平㊂SCFAs包括乙酸㊁丙酸㊁丁盐酸等,可通过肠上皮细胞进入机体血液循环,影响宿主的免疫反应,抑制组蛋白脱乙酰酶的作用从而促进抗炎型细胞的作用,以维持免疫稳态㊂因此,SCFAs的产生可能是微生物群增加血清IGF⁃1的一种机制㊂肠道微生物群对骨骼提供合成代谢的刺激可能由IGF⁃1介导㊂大多数数据表明微生物群体诱导宿主IGF⁃1合成以影响其生长㊂SCFAs能够诱导IGF⁃1的产生,它是益生元发酵的主要产物,赋予人体健康诸多益处,如免疫调节,SCFAs能够将脂多糖刺激单核细胞产生的细胞因子调节为抗炎细胞因子㊂3.5　肠道微生物可以通过影响机体的营养状况来影响骨代谢　影响肠道黏膜的营养摄取可能是微生物对骨重建发挥作用的重要机制㊂肠道微生物群在食物消化吸收㊁能量供应和调节维生素的生成和吸收方面起关键作用㊂对GF和CONV⁃R进行比较的研究表明,微生物群可促进肠道单糖的吸收,并诱导宿主对能量的摄取和储存[55]㊂此外,肠道微生物群合成维生素B和K族维生素[56],因此有助于确保人体有足够的维生素摄入量,特别是在食物摄入不足或不良饮食习惯所造成的营养不良的情况下㊂肠道微生物群也调节钙的吸收,这可能是通过改变腔内pH值和增加钙溶解度来实现的[57]㊂因此,肠道微生物通过对营养摄取和能量捕获的作用可以促进宿主骨骼健康㊂在营养不良的情况下,移植乳酸杆菌菌株将会促进果蝇幼虫生长,这是在最近的一项研究中发现的营养不良时微生物群对生长轴的影响[58]㊂将肠道中只有植物乳杆菌(Lp)WJL菌株或NIZO2877菌株存在的幼年小鼠和GF幼年小鼠以断奶或缺乏营养的饮食饲养,Lp WJL或Lp NIZO2877幼体的体重和身长比GF幼体有更显著的增长;并且Lp WJL 组比Lp NIZO2877组具有更显著的增长,相应的体重㊁身长和股骨长度增加有2倍之差㊂有趣的是,两种菌株之间的定量差异并不是由于食物和卡路里摄入量的差异造成的㊂因此,植物乳杆菌的生长促进作用似乎是菌株特异性的,这会进一步使我们理解益生菌对微生物群和骨的影响㊂4摇总结与展望肠道微生物在骨代谢的调节中发挥着重要的作用,它在绝经后骨质疏松症的发生发展中处于中心地位,这为绝经后骨质疏松症的预防和治疗提供了新的思路㊂肠道微生物可以通过影响宿主的免疫反应和炎症反应㊁影响营养物质的吸收以及通过益生菌的保护作用来实现对骨代谢的调节㊂目前对肠道微生物影响骨代谢的研究还不是很透彻,很多都是基于表型的研究,分子机制尚待进一步的揭示㊂我们有理由相信在未来肠道微生物将会在包括绝经后骨质疏松症等多种疾病的治疗中成为新的重要靶点㊂参考文献:[1]　Xu J,Gordon JI.Honor the symbionts[J].Proc Natl Acad Sci U SA,2003,100(18):10452⁃10459.[2]　Qin J,Li R,Raes J,et al.A human gut microbial gene catalogueestablished by metagenomic sequencing[J].Nature,2010,464 (7285):59⁃65.[3]　Zmora N,Zeevi D,Korem T,et al.Taking it personally:personalized utilization of the human microbiome in health and disease[J].Cell Host Microbe,2016,19(1):12⁃20. 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.论著.超重及肥胖青年大学生血清内脂素水平与中心动脉收缩压的关系廖明媛\田建伟\王新宴2,许波2,于心亚\张娜3 ,张亚华4【摘要】目的检测中国超重及肥胖青年大学生血清内脂素的水平，探讨血清内脂素水平与中心 动脉收缩压的关系。

方法从西安工业大学中央校区148例17~23岁的超重及肥胖青年大学生中筛选出高 血压患者45例为高血压组，血压正常者103例为对照组。

使用SphygmoCor■无创主动脉脉搏分析仪测量中 心动脉收缩压；测量外周血压；检测血清内脂素水平，并分析其与中心动脉收缩压、外周肱动脉收缩 压、舒张压及平均动脉压的关系。

结果高血压组的中心动脉收缩压、外周肱动脉收缩压、外周肱动脉 舒张压、外周肱动脉平均动脉压均高于对照组，差异具有统计学意义（P均<0.001)。

高血压组血清 内脂素水平较对照组高[(227.33±30.93 )^g/L vs. (201.58±34.03 )^g/L]，差异具有统计学意义（P<0.001)。

血清内脂素水平与中心动脉收缩压、外周肱动脉收缩压、外周肱动脉舒张压、外周肱动脉平均压呈正相关，相关系数分别为0.498、0.489、0.414、0.460 (P均<0.001)。

结论超重及肥胖青年大学 生中高血压患者血清内脂素水平高于血压正常者，并且内脂素与中心动脉收缩压及外周血压呈正相关，预示内脂素可能参与青年大学生肥胖相关性高血压的发生及发展。

【关键词】内脂素；中心动脉收缩压；青年；超重及肥胖【中图分类号】R544 【文献标志码】A【文章编号】1674-4055(2016)11-1323-03 Relationship between level of serum visfatin and central aortic systolic blood pressure in overweight or obese young college students LIAO M ing-yuan , TIAN Jian-wei, WANG Xin-yan, XU Bo, YU Xin-ya, ZHANG Na, ZHANG Ya-hua. Department of C ardiovasology, Chinese PLA Air Force General Hospital, Beijing 100142, China.C orresponding authors: TIA N Jia n-w e i, tia n jian w ei029@aliyu n.co m; WANG X in-y a n, E-m a il:tezhenke928041@[Abstract] Objective To detect the level of serum visfatin in overweight or obese young college students in China, and investigate the relationship between it and central aortic systolic blood pressure (CSBP). Methods The overweight or obese young college students (n=148 and aged from 17 to 23) were chosen from the central campus of X i’ an Technological University, and among them 45 students with hypertension were included in hypertension group and 103 with normal blood pressure (BP) were included in control group. CSBP was detected by using non-invasive SphygmoCor aortic pulse analyzer, and peripheral blood pressure was measured by using mercury sphygmomanometer. The level of serum visfatin was detected by using enzym e-linked immunosorbent assay (ELISA), and the relationship among visfatin, CSBP, peripheral brachial artery systolic pressure (BASP), peripheral brachial artery diastolic pressure (BADP) and brachial artery mean arterial pressure (BAMAP) was analyzed. Results CSBP, BASP, BADP and BAMAP were all higher in hypertension group than those in control group (all P<0.001). The level of serum visfatin was higher in hypertension group than that in control group [(227.33 ±30.93) p g/L vs. (201.58±34.03) pg/L, P<0.001]. The level of serum visfatin was positively correlated to CSBP, BASP, BADP and BAMAP (r=0.498, 0.489, 0.414, 0.460, all P<0.001). Conclusion The hypertensive patients in overweight or obese young college students have higher level of serum visfatin compared with those with normal BP. The level of serum visfatin is positively correlated to CSBP and peripheral BP, which indicates that visfatin may participate the occurrence and development of obesity-related hypertension in young students.[Key words] Visfatin; Central aortic systolic pressure; Young; Overweight and obesity原发性高血压（primary hypertension，PH)是人们日常生活当中最常见的慢性病，也是心脑 血管疾病发病的最主要的独立危险因素。

胰腺切除术后胰腺外分泌功能不全的诊治现状浦宁，安燕飞，楼文晖复旦大学附属中山医院胰腺外科，上海 200032通信作者：楼文晖， lou.wenhui@ （ORCID：0000-0001-5820-6843）摘要：胰腺外分泌功能不全引起的消化不良是胰腺切除术后常见并发症，但目前仍缺乏简单、高效、统一的诊断方法和规范化的治疗手段，且外科医师缺乏对其认识程度，导致其难以得到充分诊治。

因此，本文对胰腺切除术后胰腺外分泌功能不全的定义、发病原因、不同胰腺手术方式后发生率、现有诊断方法与治疗预防策略等几个方面的相关研究进展进行了归纳总结，以期为进一步改善胰腺切除术后胰腺外分泌功能不全的诊治提供参考。

关键词：胰腺外分泌功能不全；胰腺切除术；消化不良；诊断；治疗学基金项目：国家自然科学基金（82103409）；上海市青年科技英才扬帆计划（21YF1407100）Current status of the diagnosis and treatment of pancreatic exocrine insufficiency after pancreatectomyPU Ning， AN Yanfei， LOU Wenhui.（Department of Pancreatic Surgery， Zhongshan Hospital， Fudan University， Shanghai 200032， China）Corresponding author： LOU Wenhui， lou.wenhui@ （ORCID： 0000-0001-5820-6843）Abstract：Dyspepsia due to pancreatic exocrine insufficiency is a common complication after pancreatectomy； however， due to the lack of simple，efficient，and unified diagnostic methods，standardized treatment standards，and awareness of this disease among surgeons， it is difficult to get adequate diagnosis and treatment. Therefore， this article summarizes the research advances in the definition and pathogenesis of pancreatic exocrine insufficiency，the incidence rate of pancreatic exocrine insufficiency after different surgical procedures， and current diagnostic methods and treatment strategies， in order to provide a reference for further improving the diagnosis and treatment of pancreatic exocrine insufficiency after pancreatectomy.Key words：Exocrine Pancreatic Insufficiency； Pancreatectomy； Dyspepsia； Diagnosis； TherapeuticsResearch funding： National Natural Science Foundation of China （82103409）； Shanghai Sailing Program （21YF1407100）胰腺外分泌功能不全（pancreatic exocrine insufficiency，PEI）导致的消化不良是胰腺切除术后的一种常见并发症，发病率较高，典型症状表现为上腹部不适、脂肪泻和体质量减轻等，若不及时治疗会严重影响生活质量，并引起相关并发症［1］。

2009年上海复旦大学博士生入学复试试题(妇产科生殖内分泌与人类辅助生殖技术专业)⒈专业基础⑴简要叙述下丘脑-垂体-卵巢轴如何调节正常女性月经周期⑵生殖内分泌双激素双细胞学说⑶请用图表示成熟卵泡有哪几部分组成⑷正常受精卵形成过程⒉生殖内分泌专业试题⑴多囊卵巢综合征患者的诊断标准⑵哪些不孕症患者可以采用人类辅助生殖技术助孕⑶常用的几种体外受精-胚胎移植促排卵方案⑷人类辅助生殖技术助孕患者常见的并发症有哪几种?如何预防⑸病例分析患者＋＋，女，38岁，婚后6年，于2003年左侧输卵管妊娠切除，于2006年行子宫输卵管造影检查发现左侧输卵管缺如,右测输卵管伞端粘连输卵管积水，于2007年4月行腹腔镜切除右侧输卵管,于2008年3月采用GnRHa＋Gn促排IVF，取卵3枚，M II 3枚，D1 :2PN 3枚; D2: 2C，4C，4C;D3 : 4C，6C，8C。

当时因为子宫内膜薄，放弃移植，胚胎冷冻保存。

一直因为子宫内膜薄，没有移植，于2009年1月8日，采用激素替代周期FET，于月经第2天开始，补佳乐2mg x 5天，于月经第7天改为3mg X 5天，于月经第12天改为2/2 mg X 5天，于月经第13天突然出现胃出血，在当地医院外科急诊，经治疗后血止。

停用补佳乐，当时阴道B超检查子宫内膜厚6.5A，第15天测子宫内膜厚度为6.0A，请你对该病人下一步的冻胚移植方案提出诊疗意见⒊科研计划在今后三年的博士生研究过程中,你准备计划进行人类生殖内分泌与辅助生殖技术哪方面研究?2009年上海复旦大学博士生入学复试英语试题(妇产科生殖内分泌与人类辅助生殖技术专业)1.口语PCOS ART IUI IVFPGD TESA PESA ICSI2.英译汉⑴Investigation and treatment of repeated implantation failure followingIVF-ETPregnancy rate following one cycle of IVF and ET can be as high as 60%. But even in the very successful units, som e couples fail repeatedly. The causes for repeated im plantation failure (RIF) m ay be because of reduced endom etrial receptivity, em bryonic defects or m ultifactorial causes. Various uterine pathologies, such as thin endom etrium, altered expression of adhesive m olecules and immunological factors, m ay decrease endom etrial receptivi ty, whereas geneti c abnorm alities of the m ale or fem ale, sperm defects, em bryonic aneuploidy or zona hardening are am ong the em bryonic reasons for failure of im plantation. Endom etriosis and hydrosalpinges m ay adversely influence both. In this m ini review, we discuss the suggested m ethods for evaluation and treatm ent of RIF: repeated hysteroscopy, m yom ectom y, endom etrial stim ulation, imm unotherapy, preim plantation genetic screening (PGS), assisted hatching, zygote intra-Fallopian transfer (ZIFT), co-culture, blastocyst transfer, cytoplasm ic transfer, tailoring stim ulation protocols and salpingectom y for hydrosalpinges.⑵. Review the advances and controversies in the field of reproductive organ transplantation.Although many cancer treatments can damage female reproductive organs, leading to temporary or permanent infertility, recent advances in cancer management have translated into improved patient survival, making preservation of reproductive function a more important priority than ever before . Reproductive organ transplantation represents a new potential treatment for patients facing infertility as a result of cancer treatment .Pregnancies have now been reported from several centers after transplanting fresh and frozen ovarian tissue pieces .the longevity of the graft and its potential long-term complications are unknown . However, it seems clear that the ovarian tissue graft has a shortened life span. Allogeneic reproductive organ transplants are under investigation.Patients must take immunosuppressive medications following heterologus transplantation,and these medications can cause adverse side effects. The effects on the fetus are largely unknown.Conclusions:Despite the recent biologic and clinical advances,reproductive organ transplantation remains experimental and controversial.⑶. Premature ovarian failurePrimary premature ovarian failure (POF) results in spontaneous and irreversible cessation of menses before the age of 40 years. Abnormal Karyotype,translocations,point mutations, overian autoimmunity,pelvic infection ,cytotoxic drugs, radiotherapy, and ovarian surgery can lead to the failure of follicles to reach maturity ,The disappearance of ovarian follicular is accelerated by exposure to alkylating agents and ionizing radiation .The alkylating agents in combination with ionizing radiotherapy is particulary gonadotoxic .When given to premenopausal breast cancer patients,cyclophosphamide, methotrexate,and 5-fluorouracil resulted in ovarian failure with no effect on pituitary and adrenal functions.Another catastrophic event in the reproductive life of a woman is the loss of her uterus,secondary to congenital disorders,malignancies,surgery,or accidents.Uterine loss is a problem that that cannot be overcome in some countries where surrogacy is facing legal and social prohibitions.⑷.Reproductive outcome with immunosuppressive medications: miscarriages,embryotoxicity, and teratogenicityLessons obtained from pregnancy outcomes and reproductive outcome in patients receiving immunosuppressive medications during their pregnancies should be kept in mind before making a decision to transplant a genetically different reproductive organ graft into women. Medications used to suppress immunologic activity include nonsteroidal anti-inflammatory drugs(NSAIDs),and intravenous immunoglobulin.Observations on pregnancies established after organtransplantation showed a higher incidence of preterm deliveries,low birth weights,and maternal hypertention.。