NUDT15 is a key genetic factor for prediction of hematotoxicity in pediatric patients who received a standard low dosage regimen of 6-mercaptopurine

6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT15¹3 and NUDT15¹2 genotypes were at a 10–15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT15¹3 and NUDT15¹2, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients.     

Applications of geospatial analyses in health research among homeless people: A systematic scoping review of available evidence

BackgroundUnequal housing access resulted in more than 150 million homeless people worldwide, with millions more expected to be added every year due to the ongoing climate-related crises. Homeless population has a counterproductive effect on the social, psychological integration efforts by the community and exposure to other severe health-related issues. Geographic Information Systems (GIS) have long been applied in urban planning and policy, housing and homelessness, and health-related research.MethodsWe used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method to systematically review 24 articles collected from multiple databases (n = 10) that focused on health-related issues among homeless people and used geospatial analysis techniques in their research.ResultsOur findings indicated a geographic clustering of case study locations– 26 out of the 31 case study sites are from the USA and Canada. Studies used spatial analysis techniques to identify hotspots, clusters and patterns of patient location and population distribution. Studies also reported relationships among the location of homeless shelters and substance use, discarded needles, different infectious and non-infectious disease clusters.ConclusionMost studies were restricted in analyzing and visualizing the patterns and disease clusters; however, geospatial analyses techniques are useful and offer diverse techniques for a more sophisticated understanding of the spatial characteristics of the health issues among homeless people. Better integration of GIS in health research among the homeless would help formulate sensible policies to counter health inequities among this vulnerable population group.     

Lateral Lymph Nodes in Rectal Cancer: Do we all Think the Same? A Review of Multidisciplinary Obstacles and Treatment Recommendations

Lateral lymph nodes in low, locally advanced, rectal cancer have proven implications for local recurrence rates, which increase drastically in the presence of persistently enlarged lateral lymph nodes. These clinical implications warrant a thorough understanding of lateral nodal disease with awareness and knowledge from all three specialties involved – radiology, radiation oncology, and surgery – to ensure proper treatment. Relevant literature for each specialty, including all current guidelines and perspectives, were examined. Variations in definitions and treatment paradigms were evaluated. There is still no consensus for the standardized treatment of lateral nodal disease. Each discipline works according to their own available evidence, but relevant data are scarce. Current international guidelines and standard recommendations for the diagnostics and treatment of lateral lymph nodes are lacking. This results in differing perspectives and interpretations between the disciplines which can lead to challenging communication in an area where multidisciplinary collaboration is essential. This review addresses this by presenting the current evidence, perspectives and practices of each specialty and makes suggestions for each phase of the diagnostic and treatment process for patients with lateral nodal disease. By doing this, steps are taken toward achieving international consensus, and multidisciplinary collaboration.     

3D打印可拆卸垂体瘤切除模型的真实性评估

目的探究可拆卸经鼻垂体腺瘤切除操作模型的真实性,并初步探讨了模型的教学性。方法利用患者CT建模、精细优化及3D打印技术构建可拆卸垂体腺瘤切除模型。评估者为19名来自北京协和医院的本院及进修医师,其中年资<10分入"低年资组";年资≥10分入"高年资组"。每位医师分别对3D打印垂体腺瘤切除模型进行操作,并于操作前后分别填写调查问卷、评估量表。结果高年资组的探查经验均高于低年资组。真实度项目的得分均在4附近,各评分项间无明显差异;"切除垂体腺瘤"步骤的真实性评分相对较低;高年资组评分普遍低于低年资组。操作前低年资组信心评分显著低于高年资组,操作后两组评分趋于一致;低年资组的垂体腺瘤切除信心评分变化显著高于高年资组(P<0.05)。结论该模型具有较高的真实性,可用于教学试验进一步评估教学效果。     

Diagnostic approach to well-differentiated hepatocellular carcinoma

Well-differentiated hepatocellular mass-lesions in non-cirrhotic livers have a differential diagnosis of focal nodular hyperplasia, regenerative hepatic pseudotumors, hepatic adenoma, hepatocellular carcinoma, and fibrolamellar carcinoma. Despite significant advances in characterizing these pseudotumors and tumors, they remain a diagnostic challenge, especially on needle biopsy. This review focuses on a systematic diagnostic approach, one that allows confident diagnosis of these lesions.     

Redox active or thiol reactive? Optimization of rapid screens to identify less evident nuisance compounds

Compounds that exhibit assay interference or undesirable mechanisms of bioactivity are routinely encountered in assays at various stages of drug discovery. We observed that assays for the investigation of thiol-reactive and redox-active compounds have not been collected in a comprehensive review. Here, we review these assays and subject them to experimental optimization to improve their reliability. We demonstrate the usefulness of our assay cascade by assaying a library of bioactive compounds, chemical probes, and a set of approved drugs. These high-throughput assays should complement the array of wet-lab and in silico assays during the initial stages of hit discovery campaigns to pursue only hit compounds with tractable mechanisms of action.     

Effect of Preclinical Simulation on Family Nurse Practitioner Student’s Readiness for Practice

This project aimed to enhance clinical education preparation in a family nurse practitioner graduate program in rural central Appalachian by providing a psychomotor skills-based simulation with the use of the defusing, discovering, and deepening (3D) debriefing method. The students were surveyed after graduation to determine effectiveness. Program outcomes to measure readiness to practice were graduation, employment, and certification rates. The postgraduation surveys indicated the simulation contributed to an increase in psychomotor skill performance, practicing safe patient care, and making independent decisions in practice. Common themes emerged of feeling “prepared for practice” and being “more marketable” with the procedural skills learned in the simulation.     

眼表铁过载小鼠干眼模型的构建和机制研究

目的：通过给小鼠腹腔注射右旋糖酐铁，建立小鼠铁过载干眼模型并初步探索其可能的机制。

方法：将40只雄性C57BL/6小鼠(取右眼为实验眼)用随机数字表法将小鼠分为4组：对照组10只，每次腹腔注射生理盐水0.2mL； 低剂量组、中剂量组、高剂量组各10只为模型组，每次分别腹腔注射浓度为12.5、25、50mg/mL的右旋糖酐铁溶液0.2mL。每3d注射1次，共注射28d。注药后第7、14、28d观察各组小鼠眼表炎症指数、角膜荧光素染色、泪膜破裂时间(BUT)及泪液分泌量(SⅠt)，评估干眼及眼表炎症程度。28d后处死小鼠，取角膜、结膜及泪腺组织，进行HE染色、普鲁士蓝染色以及组织铁检测，评估小鼠炎症反应及铁过载情况； 采用酶联免疫吸附试验(ELISA)检测炎症因子白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)、基质金属蛋白酶-9(MMP-9)的表达情况。

结果：与对照组相比，模型组小鼠出现一系列干眼症状，小鼠眼表炎症指数增高，角膜荧光素染色评分增加，BUT缩短，泪液分泌量减少(均P<0.05)； 模型组小鼠角膜、结膜及泪腺组织均受到不同程度的损伤，各组织眼表铁沉积情况较对照组加重，组织铁含量明显增加(均P<0.01)； 模型组小鼠角膜、结膜及泪腺组织中炎症因子(IL-1β、TNF-α、MMP-9)的含量均高于对照组(均P<0.01)，随着右旋糖酐铁注药时间及浓度增加，小鼠干眼及眼表炎症程度逐渐加重。

结论：腹腔注射右旋糖酐铁可成功建立小鼠铁过载干眼模型，其机制可能与铁过载加重眼表炎症反应有关。     

生慧汤对APP/PS1雄性AD小鼠海马内APP代谢产物的昼夜变化影响＊

目的研究生慧汤对APP/PS1（β-amyloid precursor protein/presenilin 1246E）小鼠海马内β淀粉样前体蛋白（Amyloid precursor protein，APP）代谢产物昼夜表达的影响。方法 将56只雄性APP/PS1双转基因痴呆模型小鼠随机分为4组，分别为：痴呆模型组、褪黑素治疗组（0.78 mg·kg^-1·d^-1）、生慧汤高剂量组（27.0 g·kg^-1·d^-1）、生慧汤低剂量组（13.5 g·kg^-1·d^-1），每组14只；对照组为14只雄性C57BL/6J小鼠，连续给药30天。采用Morris水迷宫检测小鼠学习记忆能力，采用酶联免疫吸附检测（ELISA）检测不同时间段取出的海马组织sAPPα含量。对海马β淀粉样蛋白_1-40、β淀粉样蛋白_1-42表达进行免疫印迹分析。免疫组化（IHC）检测海马CA1区Aβ_1-40蛋白的表达。结果 Morris水迷宫结果表明，与对照组相比，模型组上平台潜伏期明显延长、穿越平台次数明显减少（P<0.01）；与模型组相比，生慧汤不同剂量组上平台潜伏期明显缩短（P<0.01、P<0.05），穿越平台次数明显增加（P<0.05）。ELISA结果表明，与对照组相比，模型组的sAPPα总量、各时间段（12：00、24：00）sAPPα含量明显减少（P<0.01）；与模型组相比，生慧汤不同剂量组sAPPα总量明显增多（P<0.01、P<0.05），生慧汤高剂量组仅能增加12：00 sAPPα含量（P<0.01），生慧汤低剂量组仅能增加24：00 sAPPα含量（P<0.05）。对照组sAPPα含量具有明显昼夜差异（P<0.01）。模型组sAPPα含量的昼夜差异性消失（P>0.05）。生慧汤高剂量组sAPPα含量具有昼夜差异（P<0.01），生慧汤低剂量组sAPPα含量不具有昼夜差异（P>0.05）。Western blot结果显示，与对照组相比，模型组Aβ_1-40、Aβ_1-42蛋白表达明显增加（P<0.01）；与模型组相比，生慧汤高剂量组Aβ_1-40、Aβ_1-42蛋白表达减少（P<0.05、P<0.01）；生慧汤低剂量组仅能减少Aβ_1-40蛋白的表达（P<0.05），对Aβ_1-42蛋白表达无影响（P>0.05）。免疫组化结果表明，与对照组相比，模型组Aβ_1-40表达明显增加（P<0.01）；与模型组相比，生慧汤不同剂量组Aβ_1-40表达不同程度减少（P<0.01、P<0.05）。结论 生慧汤能够改善5月龄APP/PS1阿尔茨海默病模型小鼠的学习记忆障碍，其机制可能与恢复海马内APP代谢产物sAPPα的昼夜节律性表达、从而减少Aβ的沉积有关。