BACKGROUND & AIMS: :The study was performed to examine whether indomethacin administered during the initial period of acetic acid-induced gastric ulcer healing affects future ulcer recurrence. Gastric ulcers were produced in rats by subserosal injection of acetic acid. Indomethacin (1 mg/kg/day, orally) administered either alone or concomitant with ornoprostil (50 micrograms/kg/day, orally) was started on the fourth day and continued for 56 days. In rats whose ulcer healed at the 90th day after production of ulcer, endoscopy was done every 30 days to examine recurrence of ulcer. Gastric specimens were obtained 10, 30, 60, 90, and 240 days after ulcer production for histology, to quantitate the height of regenerated mucosa, thickness of fibrous tissue, degree of polymorphonuclear cell infiltration, and PAS-positive cells. Cumulative ulcer recurrence rate was significantly higher in rats initially treated with indomethacin than in controls. Increased polymorphonuclear cell infiltration was the major histologic abnormality persisting after cessation of indomethacin. Ornoprostil reversed these abnormalities caused by indomethacin. In conclusion, the administration of indomethacin during the initial period of the ulcer healing promoted persistent polymorphonuclear cell infiltration and increased ulcer recurrence rates, possibly via a prostaglandin-dependent mechanism.

背景与目标： : 进行这项研究是为了检查在乙酸引起的胃溃疡愈合的初期服用消炎痛是否会影响未来的溃疡复发。通过浆膜下注射乙酸在大鼠中产生胃溃疡。从第4天开始单独或与ornoprostil (50微克/千克/天，口服) 联合给药吲哚美辛 (1 mg/kg/天，口服)，并持续56天。在溃疡产生后第90天溃疡愈合的大鼠中，每30天进行一次内窥镜检查以检查溃疡的复发。在溃疡产生后10、30、60、90和240天获得胃标本进行组织学检查，以定量再生粘膜的高度，纤维组织的厚度，多形核细胞浸润的程度和PAS阳性细胞。最初用吲哚美辛治疗的大鼠的累积溃疡复发率显着高于对照组。多形核细胞浸润增加是吲哚美辛停止后持续存在的主要组织学异常。Ornoprostil扭转了吲哚美辛引起的这些异常。总之，在溃疡愈合初期给予吲哚美辛可能通过前列腺素依赖性机制促进了持续性多形核细胞浸润并增加了溃疡复发率。

BACKGROUND & AIMS: :We have recently reported that parkinsonian patients show a significant GH response to gamma-hydroxybutyric acid (GHB), but not to gamma-aminobutyric acid (GABA)-ergic drug administration. In order to establish whether muscarinic cholinergic receptors mediate the GH secretion induced by GHB, normal men and parkinsonian patients were tested with GHB both in the absence and in the presence of the anticholinergic agent, pirenzepine. Both normal controls and parkinsonian patients showed a significant serum GH rise in response to GHB (25 mg/kg body weight p.o.) even though a slightly, but significantly lower response was observed in parkinsonian patients. Pretreatment with pirenzepine (100 mg p.o. 2 h before GHB) completely suppressed the GHB-induced GH release in both normal controls and parkinsonian patients. These data indicate that a cholinergic mechanism mediates the GH response to GHB in normal men. In addition the data indicate that this pathway is preserved in the parkinsonian brain.

背景与目标： : 我们最近报道说，帕金森氏症患者对 γ-羟基丁酸 (GHB) 表现出显着的GH反应，但对 γ-氨基丁酸 (GABA) 能药物的给药却没有。为了确定毒蕈碱胆碱能受体是否介导GHB诱导的GH分泌，在不存在和存在抗胆碱能药物哌仑西平的情况下，对正常男性和帕金森病患者进行了GHB测试。正常对照组和帕金森氏症患者对GHB (25 mg/kg体重p.o.) 的反应均显示出显着的血清GH升高，尽管在帕金森氏症患者中观察到的反应略有但明显降低。在正常对照和帕金森病患者中，用哌仑西平预处理 (GHB前100 mg p.o. 2小时) 完全抑制了GHB诱导的GH释放。这些数据表明，胆碱能机制介导了正常男性对GHB的GH反应。此外，数据表明该途径保留在帕金森氏脑中。

BACKGROUND & AIMS: PURPOSE:Inhibition of protein kinase C (PKC) and rho-kinase (ROCK) may represent a new way of influencing outflow facility through isolated relaxation of the trabecular meshwork (TM). This work was performed to investigate the existence of calcium-independent contraction in this smooth-muscle-like tissue and its modulation by targeting the rho-guanosine triphosphatase (GTPase)-mediated pathway. METHODS:Isometric tension measurements of bovine TM and ciliary muscle (CM) were performed. Intra- and extracellular calcium buffering was accomplished with EGTA and 1, 2-bis(2-aminophenoxy)-ethane-N,N:,N:,N:',N:'-tetra-acetic acid tetrakis/acetoxymethhyl ester (BAPTA-AM) followed by stimulation of PKC with phorbolester (PMA) or 4alpha-phorbol. Calcium-independent contraction was blocked using the highly specific ROCK inhibitor Y-27632. Western blot analysis and immunoprecipitation was performed using human TM cells. RESULTS:In TM, carbachol induced partial contraction under conditions of extracellular calcium depletion (22. 1% +/- 2.3% versus 100%, n = 9). The membrane-permeable calcium chelator BAPTA-AM completely blocked this response (1.1% +/- 1.4% versus 100%, n = 9). When calcium was completely blocked, PMA induced contraction in TM (16.7% +/- 5.9% versus 100%, n = 9) but not in CM (1.8% +/- 2.5% versus 100%, n = 6). The inactive PMA analogue 4alpha-phorbol did not induce contraction, indicating that activation of PKC is involved in this contractile response. The ROCK inhibitor Y-27632 completely blocked the calcium-independent PMA-induced contraction in TM. Western blot analysis and immunoprecipitation revealed the expression of the rho-A protein in human TM cells. CONCLUSIONS:The data indicate that contrary to CM, the TM features calcium-independent contractile mechanisms linked to rho-A and PKC isoforms that do not require calcium for activation. ROCK inhibitors may allow specific modulation of the TM to enhance outflow facility, thus lowering intraocular pressure.

背景与目标：

BACKGROUND & AIMS: :Serotonin can induce analgesia when injected directly into the brain, but analgesia after peripheral administration has been more difficult to show. The pentobarbital anesthetized mouse (PAM) model, developed to alleviate some of the problems involved in the measurement of tail flick latency, was used to assess the action of peripherally administered serotonin. Mice were anesthetized with about 65 mg/kg of sodium pentobarbital IP and their tail flick latencies measured while they were in stage III anesthesia. In these anesthetized mice, IP serotonin induced a significant analgesia that was much more robust than that found in awake mice. The analgesic effect was dose-dependent from 0.25 mg/kg to 10 mg/kg but was not blocked by the antiopiate naltrexone. Of several psychotropic agents tested, only amitriptyline, mianserin, and trazodone had significant effects on analgesia in the PAM model. The analgesic effect of serotonin was reproduced by the 5HT2 agonist DOI and totally blocked by the 5HT2 antagonist NPP. These results show the utility of the PAM model in studying nonopiate analgesia and suggest that the analgesic action of serotonin is mediated primarily through the 5HT2 receptor.

背景与目标： : 当直接注射到大脑中时，5-羟色胺可以诱导镇痛，但是外周给药后的镇痛更加难以显示。戊巴比妥麻醉小鼠 (PAM) 模型旨在缓解甩尾潜伏期测量中涉及的一些问题，用于评估外周给药的5-羟色胺的作用。用约65 mg/kg的戊巴比妥钠IP麻醉小鼠，并在处于III期麻醉时测量其甩尾潜伏期。在这些麻醉的小鼠中，IP 5-羟色胺诱导了明显的镇痛作用，其镇痛作用比清醒小鼠的镇痛作用要强大得多。镇痛作用是剂量依赖性的，从0.25 mg/kg到10 mg/kg，但不被抗阿片类纳曲酮阻断。在测试的几种精神药物中，在PAM模型中，只有阿米替林，米安色林和曲唑酮对镇痛有显着影响。5-羟色胺的镇痛作用由5HT2激动剂DOI复制，并被5HT2拮抗剂NPP完全阻断。这些结果表明PAM模型在研究非阿片类镇痛中的实用性，并表明5-羟色胺的镇痛作用主要通过5HT2受体介导。

BACKGROUND & AIMS: BACKGROUND:To study the role of lysosomal decomposition and elimination of old bone matrix, as well as the mechanism of promoting chondrocyte growth and bone recovery through the perspective of TFEB-mediated lysosomal autophagy. METHODS:Rat models of acute knee injury were designed, and autophagy flow was detected by injection of autophagy inhibitors 3-methyladenine. Autophagy flow was detected by RFP-GFP-LC3 double fluorescence molecule. The expression of TFEB, DRAM, MAPLC3, and MITF were analyzed by Western blot, and the expression of genes NITF, Bcl2, and TYR in rat cartilage tissues were detected by RT-PCR. RESULTS:The number of autophagosomes was increasing in the auto group compared with the inhibitor-auto group and normal group. There was a significant difference of LC3 levels in the auto group and inhibitor-auto group compared with the normal control. The expression of TFEB, DRAM, MAPLC3, and MITF proteins by Western blot analysis were significantly increased in the auto group and decreased in the inhibitor-auto group. The expression of NITF, Bcl2, and TYR by RT-PCR determination were higher in the auto group and inhibitor-auto group than the normal group. CONCLUSIONS:Autophagy can inhibit apoptosis, promote chondrocyte growth and bone regeneration, and restore knee joint injury of rats. The main mechanism is to promote the effect of TFEB-mediated lysosomal autophagy.

背景与目标：

BACKGROUND & AIMS: :There are no automatic links between the functional advantages and pressures associated with delegation to independent agencies for Health Technology Assessment (HTA) and their emergence in national regulatory spaces. We argue that the rise of these organizations is mediated by contextual factors, which must be explained. Accordingly, we analyze the German 'regulatory space' for health policy decision-making, identifying contextual factors relevant to the adoption of the Efficiency Frontier approach. Based on qualitative interviews with key stakeholders, we argue that the development of the Efficiency Frontier can be associated with cultural reluctance to frame healthcare prioritization decisions around cost based valuations of human health and related doubts about the validity of metrics for human health gain. Based on this finding, we conclude that the delegation of authority to independent HTA agencies follows a broadly evolutionary pattern, in which contextual factors allow for significant variation in institutional and methodological responses to the functional pressures and advantages leading to their establishment.

背景与目标： : 与授权给独立的卫生技术评估机构 (HTA) 相关的功能优势和压力与它们在国家监管空间中的出现之间没有自动联系。我们认为，这些组织的兴起是由上下文因素介导的，必须对此进行解释。因此，我们分析了德国卫生政策决策的 “监管空间”，确定了与采用效率前沿方法有关的背景因素。基于对主要利益相关者的定性访谈，我们认为效率边界的发展可能与文化上不愿围绕基于成本的人类健康评估制定医疗保健优先决策以及对人类健康收益指标有效性的相关怀疑有关。基于这一发现，我们得出结论，将权力下放给独立的HTA机构遵循一种广泛的进化模式，在这种模式下，背景因素允许机构和方法对导致其建立的功能压力和优势的反应发生重大变化。

BACKGROUND & AIMS: AIMS:The aims of this study were as follows: (a) to determine if social support mediates the relationship between economic stress and quality of life; and (b) to explore whether participants' ages would moderate the indirect relationship between economic stress and quality of life through social support. DESIGN:A questionnaire-based, cross-sectional study. METHODS:From January 2015-June 2016, a total of 300 patients with chronic wounds were recruited from three hospitals. Data regarding economic stress, social support and quality of life were collected through survey questionnaires. The moderated mediation analysis was examined using the Hayes' PROCESS macro modelling tool, based on the bias-corrected bootstrapping method. RESULTS:Economic stress was negatively correlated with quality of life and social support. The indirect effect of economic stress on quality of life through social support was negative. Furthermore, age moderated the relationship between economic stress and quality of life, as well as the relationship between economic stress and social support. CONCLUSION:Reducing economic stress and improving social support are important strategies for improving quality of life in patients with chronic wounds, especially for younger patients. IMPACT:Patients with chronic wounds experience considerable economic stress and severely impaired quality of life; however, little is known about the inner mechanisms of this relationship. This study emphasized the importance of providing social support in coping with the damage that economic stress causes to health. Clinical nurses should strengthen the comprehensive assessment of the socioeconomic status of patients and adjust nursing plans timely, to reduce the economic burden of patients based on the rational use of wound care materials. Moreover, when nursing for patients with chronic wounds, especially the elders, caregivers should strengthen the evaluation of social support and develop interventions to improve social support.

背景与目标：

BACKGROUND & AIMS: :Maslinic acid is found in various natural sources, most notably in pomace olive oil, and exerts pro-apoptotic activities in various cancer cells in vitro. In the present study, DU145 human prostate cancer cells were cultured with 0-25 μm-maslinic acid to examine the effects of maslinic acid on the metastatic capacity of prostate cancer cells. Maslinic acid significantly (P <0.05) inhibited the basal and epidermal growth factor (EGF)-induced migration (27-64 %), invasion (23-60 %) and adhesion (8-40 %) of DU145 cells. Maslinic acid significantly (P <0·05) down-regulated both basal and EGF-stimulated secretion of matrix metalloproteinase (MMP)-9 (25-67 %), MMP-2 (50-86 %), urokinase-type plasminogen activator (uPA, about 100 %), vascular endothelial growth factor (VEGF, 98-100 %) and tissue inhibitors of metalloproteinases (TIMP)-1, as well as expression of uPA receptor (uPAR), intercellular adhesion molecules (22-33 %), vascular cell adhesion molecules (23-46 %) and E-cadherin, whereas it increased TIMP-2 secretion. Maslinic acid dramatically reduced the levels of hypoxia-inducible factor-1α (HIF-1α) protein and mRNA; the reduction was accompanied by reduced stability, nuclear levels and transcriptional activity of HIF-1α. The levels of phospho-Akt and phospho-extracellular signal-related kinase (ERK) were reduced in cells treated with maslinic acid, and the phosphoinositide 3-kinase inhibitor LY294002 and the mitogen-activated protein kinase kinase inhibitor PD98059 reduced HIF-1α levels and VEGF secretion. The results show that maslinic acid markedly inhibited the migration, invasion and adhesion of DU145 prostate cancer cells. Suppressing HIF-1α activation by inhibiting Akt and ERK activation may be part of the mechanism by which maslinic acid inhibited uPAR, E-cadherin, VEGF and MMP expression in DU145 cells.

背景与目标： : Maslinic酸存在于各种天然来源中，最显着的是果渣橄榄油中，并在体外在各种癌细胞中发挥促凋亡活性。在本研究中，用0-25μm-maslinic酸培养DU145人前列腺癌细胞，以检查maslinic酸对前列腺癌细胞转移能力的影响。大西林酸显著 (P <0.05) 抑制基底和表皮生长因子 (EGF) 诱导的DU145细胞迁移 (27-64%) 、侵袭 (23-60%) 和粘附 (8-40%)。山麦酸显著 (P & lt; 0.05) 下调基质金属蛋白酶-9 (25-67%) 、MMP-2 (50-86%) 、尿激酶型纤溶酶原激活物 (uPA，约100%) 、血管内皮生长因子 (VEGF，98-100%) 和金属蛋白酶 (TIMP)-1的组织抑制剂，以及uPA受体 (uPAR)，细胞间粘附分子 (22-33%)，血管细胞粘附分子 (23-46%) 和E-钙粘蛋白的表达，而它增加了TIMP-2分泌。Maslinic酸显着降低了缺氧诱导因子-1α (HIF-1α) 蛋白和mRNA的水平; 降低伴随着HIF-1α 的稳定性，核水平和转录活性降低。在用山糖酸处理的细胞中，磷酸-Akt和磷酸-细胞外信号相关激酶 (ERK) 的水平降低，磷酸肌醇3-激酶抑制剂LY294002和丝裂原活化蛋白激酶抑制剂PD98059降低了HIF-1α 水平和VEGF分泌。结果表明，大西林酸可明显抑制DU145前列腺癌细胞的迁移、侵袭和粘附。通过抑制Akt和ERK激活来抑制HIF-1α 激活可能是maslinic酸抑制DU145细胞中uPAR，E-cadherin，VEGF和MMP表达的部分机制。

BACKGROUND & AIMS: BACKGROUND:Stunted growth in early infancy is a public health problem in low-and-middle income countries. Evidence suggests heavy agricultural work during pregnancy is inversely associated with maternal body mass index (BMI) and infant birth weight in low- and middle-income countries; but pathways linking agricultural work to length-for-age Z-scores (LAZ) in early infancy have not been examined. This study aimed to investigate the relationship between agricultural work during pregnancy, post-natal maternal BMI and LAZ among young infants in rural Pakistan; and explored whether maternal BMI mediated the relationship between agricultural work and infant LAZ. METHODS:A cross-sectional survey was conducted from December 2015 to January 2016 in rural Sindh, Pakistan. Mother-infant dyads were recruited via systematic random cluster sampling at 2-12 weeks' post-partum (n = 1161). Anthropometric measurements (maternal and infant height/length and weight) and questionnaire data were collected. Multivariable linear regression and structural-equation based mediation analyses were used to examine associations of agricultural work during pregnancy with maternal BMI and infant LAZ. RESULTS:During pregnancy, women reported engaging in livestock-related work (57.0%), crop-related work (42.7%), and cotton harvesting (28.4%). All three forms of agricultural work were negatively associated with maternal BMI (β = - 0.67 [- 1.06; - 0.28], β = - 0.97 [- 1.51; - 0.48]; and β = - 0.87 [- 1.33; - 0.45], respectively). Maternal engagement in cotton harvesting alone was negatively associated with infant LAZ after controlling for confounding factors. The total negative effect of cotton harvesting on infant LAZ was - 0.35 [- 0.53; - 0.16]. The indirect effect of maternal BMI on infant LAZ was - 0.06 [- 0.08; - 0.03], revealing that 16% (- 0.06/- 0.35) of the relationship between cotton harvesting and infant LAZ, after adjustment, was mediated via maternal BMI. CONCLUSION:These results underscore a need to reduce labour-intensive agricultural workload demands during pregnancy, especially in cotton harvesting, to reduce risks of negative maternal energy balance and poor growth outcomes in early infancy.

背景与目标：

BACKGROUND & AIMS: :The insulin-like effects of tungstate (W) and molybdate (Mo) were studied in rat adipocytes and compared to those of vanadate. Other than being less potent, W and Mo resembled vanadate in stimulating lipogenesis, in activating glucose oxidation, in enhancing rate of hexose uptake, and in inhibiting lipolysis. Tungstate and molybdate did not activate the insulinreceptor tyrosine kinase (InsRTK). Quercetin which blocks InsRTK activity and insulin stimulation of glucose metabolism, failed to inhibit when these bioeffects were stimulated by W or Mo. The metalooxide, however, activated a staurosporine sensitive non receptor, cytosolic protein tyrosine kinase (CytPTK), and staurosporine blocked W or Mo dependent lipogenesis in rat adipocytes. Staurosporine did not prevent Mo and W either from activating hexose transport, or from inhibiting lipolysis. Tungstate and molybdate were less effective than vanadate in inhibiting adipose PTPases in cell free systems. Membranal PTPases were more sensitive to W and Mo inhibition than cytosolic PTPases. While the presence of a nucleophile such as hydroxylamine reversed inhibition of PTPase by vanadate it did not affect inhibition by W or Mo. In summary, the insulinomimetic effects of W and Mo appear to resemble qualitatively that of vanadate in all respects. Both act in an insulin receptor-independent-fashion, activate CytPTK and trigger additional effects that are not mediated by the InsRTK or by CytPTK. The quantitative differences may be attributed to reduced capacity of W and Mo relative to vanadate to inhibit the relevant PTPases in intact cells.

背景与目标： : 在大鼠脂肪细胞中研究了钨酸盐 (W) 和钼酸盐 (Mo) 的胰岛素样作用，并与钒酸盐进行了比较。除了效力较弱之外，W和Mo在刺激脂肪生成，激活葡萄糖氧化，提高己糖摄取率和抑制脂解作用方面类似于钒酸盐。钨酸盐和钼酸盐不会激活胰岛素受体酪氨酸激酶 (InsRTK)。槲皮素可阻断InsRTK活性和胰岛素刺激葡萄糖代谢，但当W或Mo刺激这些生物效应时，槲皮素无法抑制。然而，金属氧化物激活了星形孢菌素敏感的非受体，胞质蛋白酪氨酸激酶 (cyptk)，星形孢菌素阻断了大鼠脂肪细胞中W或Mo依赖性脂肪生成。星形孢菌素不能阻止Mo和W激活己糖转运或抑制脂解。钨酸盐和钼酸盐在抑制无细胞系统中的脂肪PTPases的效果不如钒酸盐。膜al PTPases对W和Mo抑制比胞质PTPases更敏感。虽然亲核试剂 (例如羟胺) 的存在使钒酸盐对PTPase的抑制作用逆转，但不会影响W或Mo的抑制作用。总而言之，W和Mo的胰岛素模拟作用在所有方面都与钒酸盐的定性相似。两者均以不依赖胰岛素受体的方式起作用，激活cyptk并触发InsRTK或cyptk未介导的其他作用。定量差异可能归因于W和Mo相对于钒酸盐抑制完整细胞中相关PTPases的能力降低。

BACKGROUND & AIMS: :Authors aimed to examine an explanatory model of risk that started with dysfunctional personality trait domains, passed through low levels of mindfulness, and culminated with problem gambling. For individuals with problem gambling, mindfulness may provide a significant avenue to prevent them from engaging in addictive behaviors and lead them to an improved sense of self-control and emotion regulation. We employed a mediation analysis design assessing 326 Caucasian adolescent regular gamblers ranging in age from 15 to 17 years who were recruited in betting or bingo halls. Using the Personality Inventory for DSM-5-Brief Form (PID-5-BF)-Children, the South Oaks Gambling Screen, and the Child and Adolescent Mindfulness Measure, we examined the hypothesis that low levels of mindfulness partially mediate the relationship between dysfunctional personality trait domains and problem gambling. The findings underline the role that may play by the core skills of mindfulness. Indeed, results suggest how adolescents with personalities characterized by antagonism, disinhibition, and negative affectivity may tend toward a lack of awareness of self-related mental states and difficulty purposefully regulating attention and dealing with negative emotions that predispose them to gambling as a means of escape from uncomfortable feelings.

背景与目标： : 作者旨在研究一种风险解释模型，该模型始于功能失调的人格特质领域，通过低正念水平，最终以问题赌博告终。对于有问题赌博的人来说，正念可能提供一个重要的途径来防止他们从事上瘾的行为，并导致他们提高自我控制和情绪调节的意识。我们采用了中介分析设计，评估了326名在博彩或宾果游戏大厅招募的年龄在15至17岁之间的白人青少年常规赌徒。使用DSM-5-Brief形式 (PID-5-BF) 的人格清单-儿童，南橡树赌博屏幕以及儿童和青少年正念措施，我们检验了以下假设: 低正念水平部分介导了功能失调的人格特质域与问题赌博之间的关系。研究结果强调了正念的核心技能可能扮演的角色。实际上，结果表明，具有以对抗，抑制和消极情感为特征的个性的青少年可能会倾向于缺乏对自我相关的心理状态的认识，并且难以有目的地调节注意力并处理使他们容易赌博的负面情绪。摆脱不舒服的感觉。

BACKGROUND & AIMS: Background:Mediation analysis can be used to evaluate the effect of an exposure on an outcome acting through an intermediate variable or mediator. For studies with small sample sizes, permutation testing may be useful in evaluating the indirect effect (i.e., the effect of exposure on the outcome through the mediator) while maintaining the appropriate type I error rate. For mediation analysis in studies with small sample sizes, existing permutation testing methods permute the residuals under the full or alternative model, but have not been evaluated under situations where covariates are included. In this article, we consider and evaluate two additional permutation approaches for testing the indirect effect in mediation analysis based on permutating the residuals under the reduced or null model which allows for the inclusion of covariates. Methods:Simulation studies were used to empirically evaluate the behavior of these two additional approaches: (1) the permutation test of the Indirect Effect under Reduced Models (IERM) and (2) the Permutation Supremum test under Reduced Models (PSRM). The performance of these methods was compared to the standard permutation approach for mediation analysis, the permutation test of the Indirect Effect under Full Models (IEFM). We evaluated the type 1 error rates and power of these methods in the presence of covariates since mediation analysis assumes no unmeasured confounders of the exposure-mediator-outcome relationships. Results:The proposed PSRM approach maintained type I error rates below nominal levels under all conditions, while the proposed IERM approach exhibited grossly inflated type I rates in many conditions and the standard IEFM exhibited inflated type I error rates under a small number of conditions. Power did not differ substantially between the proposed PSRM approach and the standard IEFM approach. Conclusions:The proposed PSRM approach is recommended over the existing IEFM approach for mediation analysis in studies with small sample sizes.

背景与目标：

BACKGROUND & AIMS: :Synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by the accumulation of abnormal α-synuclein in intraneuronal inclusions, named Lewy bodies. Mutations in GBA1, the gene encoding the lysosomal hydrolase glucocerebrosidase, have been identified as the most common genetic risk factor for PD and DLB. However, despite extensive research, the mechanism by which glucocerebrosidase dysfunction increases the risk for PD or DLB still remains elusive. In our study we expand the toolbox for PD-DLB post-mortem studies by introducing new quantitative biochemical assays for glucocerebrosidase and α-synuclein. Applying causal modelling, we determine how these parameters are interrelated and ultimately impact disease manifestation. We developed quantitative immuno-based assays for glucocerebrosidase and α-synuclein (total and phosphorylated at Serine 129) protein levels, as well as a liquid chromatography-mass spectrometry method for the detection of the glucocerebrosidase lipid substrate glucosylsphingosine. These assays were applied on tissue samples from frontal cortex, putamen and substantia nigra of PD (n = 15) and DLB (n = 15) patients and age-matched non-demented controls (n = 15). Our results confirm elevated p-129 over total α-synuclein levels in the insoluble fraction of PD and DLB post-mortem brain tissue and we found significantly increased α-synuclein levels in the soluble fractions in PD and DLB. Furthermore, we identified an inverse correlation between reduced glucocerebrosidase enzyme activity and protein levels with increased glucosylsphingosine levels. In the substantia nigra, a brain region particularly vulnerable in Parkinson's disease, we found a significant correlation between glucocerebrosidase protein reduction and increased p129/total α-synuclein ratios. We assessed the direction and strength of the interrelation between all measured parameters by confirmatory path analysis. Interestingly, we found that glucocerebrosidase dysfunction impacts the PD-DLB status by increasing α-synuclein ratios in the substantia nigra, which was partly mediated by increasing glucosylsphingosine levels. In conclusion, we show that the introduced immuno-based assays enable the quantitative assessment of glucocerebrosidase and α-synuclein parameters in post-mortem brain. In the substantia nigra, reduced glucocerebrosidase levels contribute to the increase in α-synuclein levels and to PD-DLB disease manifestation partly by increasing its glycolipid substrate glucosylsphingosine. This interrelation between glucocerebrosidase, glucosylsphingosine and α-synuclein parameters supports the hypothesis that glucocerebrosidase acts as a modulator of PD-DLB.

背景与目标： : 包括帕金森氏病 (PD) 和路易体痴呆 (DLB) 在内的突触核蛋白病的特征是神经内包裹体 (称为路易体) 中异常 α-突触核蛋白的积累。编码溶酶体水解酶葡萄糖脑苷脂酶的基因GBA1的突变已被确定为PD和DLB最常见的遗传危险因素。然而，尽管进行了广泛的研究，但葡萄糖脑苷脂酶功能障碍增加PD或DLB风险的机制仍然难以捉摸。在我们的研究中，我们通过引入葡萄糖脑苷脂酶和 α-突触核蛋白的新的定量生化测定法，扩展了pd-dlb死后研究的工具箱。应用因果模型，我们确定这些参数是如何相互关联并最终影响疾病表现的。我们开发了基于定量免疫的葡萄糖脑苷脂酶和 α-突触核蛋白 (在丝氨酸129下全部和磷酸化) 蛋白水平的检测方法，以及用于检测葡萄糖脑苷脂酶脂质底物葡萄糖鞘氨醇的液相色谱-质谱方法。这些检测方法应用于PD (n   =   15) 和DLB (n   =   15) 患者的额叶皮层，壳核和黑质的组织样本以及年龄匹配的非痴呆对照组 (n   =   15)。我们的结果证实，在PD和DLB死后脑组织的不溶性部分中，相对于总 α-突触核蛋白水平的p-129升高，并且我们发现PD和DLB中可溶性部分中的 α-突触核蛋白水平显着增加。此外，我们确定了葡萄糖脑苷脂酶活性降低与蛋白质水平与葡萄糖鞘氨醇水平升高之间的负相关。在黑质 (在帕金森氏病中特别脆弱的大脑区域) 中，我们发现葡萄糖脑苷脂酶蛋白减少与p129/总 α-突触核蛋白比率增加之间存在显着相关性。我们通过验证性路径分析评估了所有测量参数之间相互关系的方向和强度。有趣的是，我们发现葡萄糖脑苷脂酶功能障碍通过增加黑质中的 α-突触核蛋白比率来影响PD-DLB状态，这部分是通过增加葡萄糖鞘氨醇水平来介导的。总之，我们表明引入的基于免疫的测定法能够定量评估死后大脑中的葡萄糖脑苷脂酶和 α-突触核蛋白参数。在黑质中，葡萄糖脑苷脂酶水平的降低部分通过增加其糖脂底物葡萄糖基鞘氨醇而导致 α-突触核蛋白水平的增加和PD-DLB疾病的表现。葡萄糖脑苷脂酶，葡萄糖鞘氨醇和 α-突触核蛋白参数之间的这种相互关系支持了葡萄糖脑苷脂酶充当pd-dlb调节剂的假说。

BACKGROUND & AIMS: :Mediation analysis is a methodology used to understand how and why behavioral phenomena occur. New mediation methods based on the potential outcomes framework are a seminal advancement for mediation analysis because they focus on the causal basis of mediation. Despite the importance of the potential outcomes framework in other fields, the methods are not well known in prevention and other disciplines. The interaction of a treatment (X) and a mediator (M) on an outcome variable (Y) is central to the potential outcomes framework for causal mediation analysis and provides a way to link traditional and modern causal mediation methods. As described in the paper, for a continuous mediator and outcome, if the XM interaction is zero, then potential outcomes estimators of the mediated effect are equal to the traditional model estimators. If the XM interaction is nonzero, the potential outcomes estimators correspond to simple direct and simple mediated contrasts for the treatment and the control groups in traditional mediation analysis. Links between traditional and causal mediation estimators clarify the meaning of potential outcomes framework mediation quantities. A simulation study demonstrates that testing for a XM interaction that is zero in the population can reduce power to detect mediated effects, and ignoring a nonzero XM interaction in the population can also reduce power to detect mediated effects in some situations. We recommend that prevention scientists incorporate evaluation of the XM interaction in their research.

背景与目标： : 中介分析是一种用于理解行为现象发生的方式和原因的方法。基于潜在结果框架的新调解方法是调解分析的开创性进展，因为它们侧重于调解的因果基础。尽管潜在结果框架在其他领域很重要，但在预防和其他学科中，这些方法并不为人所知。治疗 (X) 和中介 (M) 对结果变量 (Y) 的相互作用是因果中介分析的潜在结果框架的核心，并提供了一种将传统和现代因果中介方法联系起来的方法。如本文所述，对于连续的中介和结果，如果XM相互作用为零，则中介效应的潜在结果估计量等于传统的模型估计量。如果XM相互作用非零，则在传统中介分析中，潜在的结果估计量对应于治疗组和对照组的简单直接和简单介导的对比。传统中介估计量和因果中介估计量之间的联系阐明了潜在结果框架中介量的含义。模拟研究表明，对人群中为零的XM相互作用进行测试可以降低检测中介效应的能力，而忽略人群中非零的XM相互作用也可以降低在某些情况下检测中介效应的能力。我们建议预防科学家在研究中纳入对XM相互作用的评估。

BACKGROUND & AIMS: :This study examined the relationship between child maltreatment, impulsivity, and deliberate self-harm in a sample of college students. Four subtypes of impulsivity (urgency, premeditation, perseverance, and sensation seeking) were examined. Results show that participants who report child maltreatment histories also report higher levels of negative affect and higher levels of impulsivity, specifically negative urgency. In addition, those who report histories of child maltreatment are more likely to endorse deliberate self-harm behaviors as an adult. Of the 4 subtypes of impulsivity, urgency was most strongly related to deliberate self-harm. Urgency, but not the other subtypes of impulsivity, mediated the relationship between child maltreatment and self-harm. The current study contributes to the understanding of the mechanisms behind deliberate self-harm behavior by suggesting that individuals with histories of child maltreatment are more likely to engage in deliberate self-harm in an attempt to quickly reduce intense negative affect.

背景与目标： : 这项研究调查了大学生样本中虐待儿童，冲动和自伤之间的关系。检查了冲动的四种亚型 (紧迫感，预谋，毅力和寻求感觉)。结果表明，报告儿童虐待史的参与者还报告了较高水平的负面影响和较高水平的冲动性，特别是负面紧迫性。此外，那些报告虐待儿童史的人更有可能认可成年后的自伤行为。在冲动的4种亚型中，紧迫感与自伤关系最密切。紧迫性，而不是冲动性的其他亚型，介导了虐待儿童和自我伤害之间的关系。当前的研究表明，有虐待儿童史的人更有可能参与自伤，以试图迅速减少强烈的负面影响，从而有助于理解自伤行为背后的机制。