复方丹参滴丸对老年冠心病患者血流变学、血脂及炎性反应递质的影响

目的：探究复方丹参滴丸对老年冠心病患者血流变学、血脂及炎性反应递质的影响。方法：选取2015年1月至2017年12月海南省人民医院收治的老年冠心病患者154例作为研究对象，按照随机数字表法随机分为对照组和观察组，每组77例。对照组采用常规西药治疗，观察组在此基础上加服复方丹参滴丸。比较治疗前后2组患者的血流变学、血脂、炎性反应递质和疗效。结果：观察组治疗有效率为92.21%，明显高于对照组治疗有效率79.22%，差异有统计学意义（P<0.05）。治疗后，2组总胆固醇（TC）、三酰甘油（TG）和低密度脂蛋白（LDL）水平均升高，差异有统计学意义（P<0.05），且观察组高于对照组，2组差异有统计学意义（P<0.05）。2组血流变学指标、高密度脂蛋白（HDL）、IL-6和TNF-α水平治疗后均降低（P<0.05），且观察组降低更明显，差异有统计学意义（P<0.05）。结论：复方丹参滴丸联合常规西药治疗冠心病患者，能够调节脂代谢，降低炎性反应，改善血流变学。     

Fractal dimension in CT low attenuation areas is predictive of long-term oxygen therapy initiation in COPD patients: Results from two observational cohort studies

BackgroundSome chronic obstructive pulmonary disease (COPD) patients develop hypoxemia with disease progression, with some even requiring long-term oxygen therapy (LTOT). Lung function, especially diffusing capacity, and the annual decline in PaO₂, are reported to be predictive factors of chronic respiratory failure. However, the association between lung morphometry evaluated using computed tomography (CT) images and LTOT initiation is unknown.MethodsWe retrospectively evaluated the relationship between clinical indices, including pulmonary function, body mass index (BMI), and CT parameters, at baseline and LTOT initiation in two prospective COPD cohorts. In the Nara Medical University cohort (n = 76), the low attenuation area (LAA) and its fractal dimension (fractal D) were adapted as the indices for parenchymal destruction in CT images. The association between these CT measurements and LTOT initiation was replicated in the Kyoto University cohort (n = 130).ResultsIn the Nara Medical University cohort, lower BMI (hazard ratio [HR]:0.70, p = 0.006), lower % diffusing capacity (%DLCO) (HR: 0.92, p = 0.006), lower %DLCO/VA (HR, 0.90, p = 0.008), higher RV/TLC (HR, 1.26, p = 0.012), higher LAA% (HR: 1.18, p = 0.001), and lower fractal D (HR: 3.27 × 10^?8, p < 0.001) were associated with LTOT initiation. Multivariate analysis in the Kyoto University cohort confirmed that lower %DLCO and lower fractal D were independently associated with LTOT initiation, whereas LAA% was not.ConclusionFractal D, which is the index for morphometric complexity of LAA in CT analysis, is predictive of LTOT initiation in COPD patients.     

Can a pragmatic responsive feeding scale be developed and applied globally?

Responsive feeding (RF) has been recognized as necessary to prevent all forms of malnutrition including stunting and childhood obesity. Specific RF guidelines have been developed, but it is unclear how RF behaviours can be monitored systematically. Therefore, developing valid and reliable abbreviated and pragmatic RF scales is an important global priority. This is challenging, as RF is a construct with multiple dimensions including recognizing and responding to hunger and satiety cues, providing a nurturing environment during feeding episodes, and understanding how feeding needs evolve as a function of the developmental stage of the young child. Further, RF is embedded within the responsive parenting framework that in addition to RF includes sleep, soothing and play routines and the interconnections between them. A recent pioneer study conducted in a rural area of Cambodia validated an 8‐item RF scale through direct feeding observations of 6‐ to 23‐month‐old infants at home, as part of two cross‐sectional surveys conducted before and after a complementary feeding intervention. It is important for similar research to be conducted elsewhere to find out if it is possible or not to develop a core RF scale that is valid and reliable and that has adequate specificity and sensitivity for application in community studies and population surveys globally. As highlighted in this article, different definitions of RF have been used in the field; thus, it is important to reach consensus on a single definition to help move this research area forward.     

Relationships Among Factors Related to Childbirth and Breastfeeding Outcomes in Primiparous Women

ObjectivesTo explore the relationships among potentially modifiable factors related to childbirth and effective breastfeeding initiation at approximately 36 hours after birth and duration and exclusivity at hospital discharge, 2 weeks, 2 months, and 6 months after birth in primiparous women and to explore whether modifiable and nonmodifiable secondary factors and covariates influenced the relationships among factors related to childbirth and these breastfeeding outcomes.DesignA prospective, longitudinal, cohort study.SettingThe postpartum units of two general hospitals in eastern Canada.ParticipantsNinety-seven mother–infant dyads.MethodsWe recorded demographic, childbirth, obstetric history, and breastfeeding data through chart review. A breastfeeding observation was completed at approximately 36 hours after birth by unit nurses. Participants maintained breastfeeding logs in hospital and for 6 months after birth and completed three self-report questionnaires before discharge. We analyzed outcomes using backward stepwise linear and logistic regression.ResultsOne childbirth factor, labor induced with oxytocin, was negatively associated with effective initiation of breastfeeding, and none was related to breastfeeding duration and exclusivity at any time point. Maternal weight; professional support; and newborn’s gestational age at birth, 5-minute Apgar score, weight loss, LATCH score, and active feeds (newborn actively suckled at the breast) were significantly associated with breastfeeding outcomes.ConclusionInduction of labor with oxytocin should be used judiciously; when used, nurses must be hypervigilant to assess the mother–infant dyad for breastfeeding issues and to intervene to prevent or remediate them.     

Novel Compounds Identified by Structure-Based Prion Disease Drug Discovery Using In Silico Screening Delay the Progression of an Illness in Prion-Infected Mice

The accumulation of abnormal prion protein (PrP^Sc) produced by the structure conversion of PrP (PrP^C) in the brain induces prion disease. Although the conversion process of the protein is still not fully elucidated, it has been known that the intramolecular chemical bridging in the most fragile pocket of PrP, known as the “hot spot,” stabilizes the structure of PrP^C and inhibits the conversion process. Using our original structure-based drug discovery algorithm, we identified the low molecular weight compounds that predicted binding to the hot spot. NPR-130 and NPR-162 strongly bound to recombinant PrP in vitro, and fragment molecular orbital (FMO) analysis indicated that the high affinity of those candidates to the PrP is largely dependent on nonpolar interactions, such as van der Waals interactions. Those NPRs showed not only significant reduction of the PrP^Sc levels but also remarkable decrease of the number of aggresomes in persistently prion-infected cells. Intriguingly, treatment with those candidate compounds significantly prolonged the survival period of prion-infected mice and suppressed prion disease-specific pathological damage, such as vacuole degeneration, PrP^Sc accumulation, microgliosis, and astrogliosis in the brain, suggesting their possible clinical use. Our results indicate that in silico drug discovery using NUDE/DEGIMA may be widely useful to identify candidate compounds that effectively stabilize the protein.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00903-9) contains supplementary material, which is available to authorized users.     

Colorectal serrated pathway cancers and precursors

The serrated pathway (SP) can be viewed as two parallel, but partially overlapping, arrays of colorectal precursor lesions, and their respective endpoint carcinomas, that are distinct from those of the conventional adenoma–carcinoma sequence (APC‐pathway). In this review we focus at the outset on the clinical impact, pathological features, molecular genetics and biological behaviours of the various SP cancers. Then we summarize the clinicopathological features, classification and molecular profiles of the two main precursor lesions that anchor the respective pathways: (i) sessile serrated adenoma/polyp (SSA/P), also called sessile serrated lesion (SSL), and (ii) traditional serrated adenoma (TSA). Activating mutations of the RAS–RAF–MAPK pathway initiate and sustain the lesions of the SP, and CpG island methylation of the promoter regions of tumour suppressor and DNA repair genes play the major role in their neoplastic progression. The SP includes microsatellite stable (MSS) carcinomas that are among the most biologically aggressive colorectal carcinomas (CRC), and also accounts for the great preponderance of sporadic hypermutated, mismatch repair (MMR)‐deficient or microsatellite instable (MSI) CRC. The identification, removal and appropriate classification of at‐risk SP precursors and surveillance of individuals who harbour these lesions present a challenge and opportunity for CRC prevention and mortality reduction.     

Reactivation of heat-inactivated Ku proteins by heat shock cognate protein HSC73

Purpose: Mouse double-stranded DNA-dependent protein kinase (DNA-PK) activity is heat sensitive. Recovery of heat-inactivated DNA repair activity is a problem after combination therapy with radiation and heat. We investigated the mechanism of recovery of heat-inactivated DNA-PK activity.

Methods: Hybrid cells containing a fragment of human chromosome 8 in scid cells (RD13B2) were used. DNA-PK activity was measured by an in vitro assay. Immunoprecipitation of the nuclear extract was performed with an anti-Ku80 antibody. Proteins co-precipitated with Ku80 were separated by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis and detected by Western blotting using anti-heat shock protein (HSP)72 and anti-heat shock cognate protein (HSC)73 antibodies. HSC73 was overexpressed with the pcDNA3.1 vector. Short hairpin (sh)RNA was used to downregulate HSC73 and HSP72.

Results: The activity of heat-inactivated DNA-PK recovered to about 50% of control during an additional incubation at 37?°C after heat treatment at 44?°C for 15?min in the presence of cycloheximide (which inhibits de novo protein synthesis). Maximal recovery was observed within 3?h of incubation at 37?°C after heat treatment. Constitutively expressed HSC73, which folds newly synthesized proteins, reached maximal levels 3?h after heat treatment using a co-immunoprecipitation assay with the Ku80 protein. Inhibiting HSC73, but not HSP72, expression with shRNA decreased the recovery of DNA-PK activity after heat treatment.

Conclusions: These results suggest that de novo protein synthesis is unnecessary for recovery of some heat-inactivated DNA-PK. Rather, it might be reactivated by the molecular chaperone activity of HSC73, but not HSP72.     

基于网络药理学方法探究补肾活血汤治疗激素性股骨头坏死的作用机制

目的:探讨补肾活血汤治疗激素性股骨头坏死(steroid-induced osteonecrosis of the femoral head,SONFH)的作用机制。方法:通过中医药整合药理学网络计算研究平台(integrative pharmacology-based network computational research platform of Traditional Chinese Medicine,TCMIP)v2.0预测、筛选补肾活血汤组方中14味中药的作用靶标,通过GeneCards、CTD和OMIM数据库查询SONFH的疾病靶点。根据获取的药物靶标和疾病靶点,进一步利用TCMIP v2.0中医药关联网络分析模块构建"药物靶标-疾病靶点"相互作用网络,根据网络拓扑特征值筛选补肾活血汤治疗SONFH的核心作用靶点。利用GO和KEGG数据库,采用富集算法挖掘上述方剂核心作用靶点的生物学功能和通路信息。结果:共获得891个补肾活血汤药物靶标和365个SONFH疾病靶点。经"药物靶标-疾病靶点"相互作用网络分析,最终筛选出31个补肾活血汤治疗SONFH核心靶点,GO功能分析富集出生物过程532条、分子功能29条,KEGG信号通路富集分析出相关通路共12条,主要涉及炎症免疫调节(chemokine signaling pathway,Toll-like receptor signaling pathway,NOD-like receptor signaling pathway,leukocyte transendothelial migration,Complement and coagulation cascades,cytokine-cytokine receptor interaction)、血管新生及血液循环调节(VEGF signaling pathway)、神经系统调节(neuroactive ligand-receptor interaction)和细胞功能调节(apoptosis,regulation of actin cytoskeleton)等方面。结论:结合SONFH的病理机制,排除缺乏特异性的信号通路,我们推测补肾活血汤可能通过调节TLR4/NF-κB和VEGF信号通路发挥补肾壮骨、活血化瘀的功效,这可能是其治疗SONFH的作用机制之一。     

藿香正气汤抑制新型冠状病毒复制过程的有效成分及机制初探＊

目的 收集藿香正气汤的主要活性成分，通过分子对接及网络药理学探讨其防控新型冠状病毒肺炎（COVID-19）的有效成分及治疗机制。方法 通过基于配体-蛋白质相互作用的计算方法，以瑞德西韦为对照，探索藿香正气汤潜在治疗COVID-19的成分，并选出对接较好成分进行药理学机制预测，初探其药理学机制。结果 本研究筛选出5种与新冠病毒3CLpro结合能力强于瑞德西韦的小分子成分。网络药理学初步预测抗病毒途径可能是通过PI3K-Akt 信号通路影响病毒复制。结论 成分C1-C5与3CLpro结合良好，推测其可能是潜在的3CLpro的抑制剂，为抗病毒天然药物的开发提供了理论依据。