Molecular Analysis of Caprine Enterovirus Circulating in China during 2016–2021: Evolutionary Significance

Here, we report the characterization of 13 novel caprine/ovine enterovirus strains isolated from different regions in China during 2016–2021. Immunoperoxidase monolayer assay showed that these viral strains shared strong cross-reaction with the previously reported caprine enterovirus CEV-JL14. Alignment analysis of the complete nucleotide sequences revealed 79.2%–87.8% and 75.0%–76.7% sequence identity of these novel caprine enterovirus strains to CEV-JL14 and TB4-OEV, respectively. Phylogenetic analyses clustered these novel strains to EV-G based on the amino acid sequences of P1 and 2C+3CD. Moreover, phylogenetic analysis of these caprine enterovirus strains identified three new EV-G types using VP1 sequences. These results demonstrate the genetic variations and the evolution of caprine enterovirus.     

PXR activation impairs hepatic glucose metabolism partly via inhibiting the HNF4α–GLUT2 pathway

Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4α)‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4α expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4α expression, while silencing PXR upregulated HNF4α and GLUT2 expression. Silencing HNF4α decreased GLUT2 expression, while overexpressing HNF4α increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4α reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4α mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4α downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4α plasmid increased Slc2a2 promoter activity. Hnf4α silencing or pregnenolone-16α-carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4α recruitment to the Slc2a2 promoter. Liver-specific Hnf4α deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4α and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4α‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.Key words: Pregnane X receptor, Hepatocyte nuclear factor 4-alpha, Glucose transporter 2, Hepatic glucose uptake, Diabetes, Drug-induced hyperglycemia     

不同模式新辅助治疗食管癌的疗效分析

目的 探讨食管癌不同模式新辅助治疗的疗效分析。方法 回顾性分析2015年1月至2022年5月于安阳市肿瘤医院行新辅助治疗的食管鳞癌(ESCC)患者的资料,共纳入542例患者,其中放化疗(NCRT)组137例,化疗(NCT)组241例,免疫加化疗(NICT)组164例;女性198例,男性344例;≤65岁289例,＞65岁253例。首要研究终点包括主要病理缓解(MPR)率、病理完全缓解(pCR) 率,次要研究终点包括总生存(OS)、无进展生存(PFS)和安全性。生存分析采用Kaplan-Meier方法,并采用Log-rank检验进行组间比较。采用Cox比例风险回归模型进行预后因素分析。结果 NCRT组的MPR率和pCR率分别为66.4%(91/137)和35.8%(49/137),NCT组分别为35.3%(85/241)和6.6%(16/241),NICT组分别为63.4%(104/164)和31.1%(51/164)(χ²=1.67, P＜0.001)。NCRT组的1、2、3年的OS分别为89.8%、82.3%、72.3%,NCT组分别为85.9%、71.4%、61.4%,NICT组分别为91.9%、81.5%、77.8%,差异有统计学意义(χ²=9.20,P＜0.01);NCRT组的1、2、3年的PFS分别为81.5%、67.9%、66.6%,NCT组分别75.9%、61.0%、53.5%,NICT组分别为80.1%、65.5%、65.3%,差异有统计学意义(χ²=4.62,P＜0.05)。多因素分析显示,治疗方式、T分期、N分期是OS的独立影响因素(P＜0.05)。3组不良反应及术后并发症差异无统计学意义(P＞0.05)。结论 与NCT对比,NICT与NCRT有更高的pCR、MPR和生存获益,因此新辅助免疫可作为食管癌术前治疗手段之一,但仍需大型的随机对照研究进一步证实。     

Global,regional and national burden of gastroesophageal reflux disease, 1990–2019: update from the GBD 2019 study

BackgroundBecause trends in the epidemiology and burden of gastroesophageal reflux disease (GERD) are changing, reinvestigating the geographical differences and trend changes is essential. Here we evaluated the latest epidemiologic patterns and trends for GERD, using data from Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019.MethodsAnnual case numbers, age-standardized rates of prevalence, incidence, and years of life lived with disability (YLDs), and their estimated annual percentage changes (EAPCs) for GERD between 1990 and 2019 were derived from the GBD 2019 study. Association between GERD burden and socio-demographic index (SDI) was also investigated.ResultsIn 2019, there were 783.95 million cases of GERD globally. Between 1990 and 2019, the total number of prevalent cases, incident cases, and YLDs increased by 77.53%, 74.79%, and 77.19%, respectively. The global age-standardized incidence rate (ASIR) and age-standardized YLD rate (ASYR) increased during this period (EAPC = 0.06 and 0.05, respectively). Tropical Latin America and East Asia had the highest and lowest age-standardiZed prevalence rate (ASPR), ASIR, and ASYR in 2019, respectively. From 1990 to 2019, prevalent cases, incident cases, YLDs, and their corresponding age-standardized rates of GERD were higher in females than males in all years. Higher SDI was associated with lower ASPR, ASIR, and ASYR of GERD in 2019.ConclusionsGERD will continue to be a major public health burden due to increasing numbers of prevalent cases, incident cases, and YLDs. In order to tackle this troublesome disease, it is crucial to understand the changes in both global and regional trends in epidemiology and the burden for policymakers and other stakeholders.

Key messages

• This is the most updated estimate on GERD epidemiology globally, including 204 countries, some of which were not assessed before.
• The overall burden of GERD continued to worsen with the prevalent cases increasing by 77.53% from 441.57 million in 1990 to 783.95 million in 2019.
• GERD is likely to remain a common reason for consultation in primary care, and our data may allow for health service provision planning.

     

超声诊断颌下腺炎的临床应用

目的探讨超声诊断颌下腺炎的临床应用价值。方法选取101例经手术证实的颌下腺炎的超声图像,分析颌下腺的大小、形态、内部回声及彩色血流情况。结果101例颌下腺炎中,急性炎症2例,慢性炎症99例,超声与手术病理结果符合率为98%。结论超声对颌下腺炎的诊断准确率较高,并能与颌下区占位性病变相鉴别。     

心力衰竭对门静脉频谱形态的影响

目的探讨心力衰竭对门静脉频谱形态的影响,摸索超声检查评价心功能的新途径。方法选取临床Ⅰ～Ⅲ度心力衰竭患者60例,按心衰竭程度分组,每组各20例;健康对照组20例。排除肝脏及门静脉、下腔静脉病变。经右侧肋间及剑突下探查门静脉,在取得门静脉清晰二维切面图像后,记录1～3个呼吸周期中的门静脉频谱,观察频谱形态,记录各组不同门静脉频谱形态的例数,所获资料采用统计软件SPSS11.0处理。结果健康对照组门静脉频谱均表现为单向连续频谱,各心力衰竭组出现不同程度的门静脉收缩末期反向血流,Ⅲ度心力衰竭组门静脉频谱多出现恒定的收缩末期反向血流。结论心力衰竭可导致门静脉频谱形态异常,观察门静脉频谱形态,可作为判断心力衰竭程度的辅助依据。     

Ruthenium-catalyzed asymmetric hydrogenation of aromatic and heteroaromatic ketones using cinchona alkaloid-derived NNP ligands

A series of cinchona alkaloid-based NNP ligands, including a new one, have been employed for the asymmetric hydrogenation of ketones. By combining ruthenium complexes, various aromatic and heteroaromatic ketones were smoothly reacted, yielding valuable chiral alcohols with extremely high 99.9% ee. Moreover, a proposed reaction mechanism was discussed and verified by NMR.

A series of cinchona alkaloid-based NNP ligands including a new one has been employed for the asymmetric hydrogenation of ketones. By combining ruthenium complexes, various ketones were smoothly reacted with up to 99.9% ee.

Since the well-known failure of using racemic thalidomide, attention has been paid to the manufacture of optically pure compounds as effective components in pharmaceuticals and agrochemicals. Asymmetric hydrogenation of ketones, especially heteroaromatic ketones, has emerged as a popular facile route to approach enantiopure secondary alcohols as essential intermediates for the construction of biologically active molecules.^1–4 Knowles et al.⁵ pioneered the production of enantioenriched chiral compounds in 1968, and Noyori and co-workers^6–8 laid the cornerstone of asymmetric hydrogenation in 1990s. Subsequently, numerous catalytic systems have been developed. Ru-BICP-chiral diamine-KOH was developed and proved to be effective for asymmetric hydrogenation of aromatic ketones by Xumu Zhang.⁹ Cheng-yi Chen reported asymmetric hydrogenation of ketone using trans-RuCl₂[(R)-xylbinap][(R)-daipen] and afforded secondary alcohol in 92–99% ee.¹⁰ Mark J. Burk and Antonio Zanotti-Gerosa disclosed Phanephos-ruthenium-diamine complexes catalyzing the asymmetric hydrogenation of aromatic and heteroaromatic ketones with high activity and excellent enantioselectivity.¹¹ Qi-Lin Zhou et al. designed and synthesized chiral spiro diphosphines as a new chiral scaffold applied in the asymmetric hydrogenation of simple ketones with extremely high activity and up to 99.5% ee.^12–15 Similarly, Kitamura and co-workers have developed a set of tridentate binan-Py-PPh₂ ligands for the asymmetric hydrogenation of ketones affording excellent results.¹⁶ Recently, chiral diphosphines and tridentate ligands based on ferrocene have been developed for the asymmetric hydrogenation of carbonyl compound with a remarkable degree of success.^17–21 Despite many ligands for asymmetric hydrogenation of ketones have been reported, expensive reagent and multistep complicated reactions were employed to synthesize most of them.^22–24 In light of increasing industrial demand, easily obtained, cheap and practical chiral ligands are still highly desirable. In addition to chiral ligands, the selection of metals was essential for asymmetric hydrogenation.^25–27 Although Mn,^28–30 Fe,^31–34 Co,^35–37 Ni^38,39 and Cu^40,41 metals were proved to be effective for asymmetric hydrogenation in recent years, Rh,^42–44 Ir^45,46 and especially Ru remained the most preferred metals. Ruthenium^47–51 was chosen owing to its superior performances in terms of low price, selectivity and activity. Takeshi Ohkuma,⁵² Hanmin Huang^53,54 and Johannes G. de Vries⁵⁵ all successfully used ruthenium catalysts for asymmetric hydrogenation of ketones. Admittedly, there is a continuing interest in the development of cheaper, simpler and more efficient catalysts for the asymmetric hydrogenation of ketones under mild conditions to access corresponding secondary alcohols. Recently, we developed new NNP chiral ligands derived from cinchona alkaloid for the asymmetric hydrogenation of various ketones in extremely excellent results using a iridium catalytic system.⁵⁶ Prompted by these encouraging results, we were interested in exploring a ruthenium-catalyzed asymmetric hydrogenation of ketones with NNP chiral ligands derived from cinchona alkaloid. Here, we showed that changing from iridium to ruthenium, with the same simple synthetic ligands, delivered a catalyst catalyzed asymmetric hydrogenation of ketones to give the industrially important chiral alcohols with up to 99.9% ee. Although the catalytic activity of ruthenium catalyst was not as high as that of the iridium catalyst, the enantioselectivity could be maintained, and even showed higher enantioselectivity in the hydrogenation of some substrates.Chiral tridentate ligand NNP (L1–L10) were synthesized and characterized as reported in our previous publication. With tridentate ligands in hand, we began to evaluate the catalytic performance in benzylidene-bis(tricyclohexylphosphine) dichlororuthenium-catalyzed asymmetric hydrogenation of acetophenone employed as a standard substrate (Fig. 2). MeOH was found to be a better one as the conversion and enantioselectivity were 99.9% and 98.2%, respectively. Bases screening showed that Ba(OH)₂ was superior to the others, giving >99.9% conversion and 98.8% ee in the present catalytic system (Fig. 1). Ligand screening revealed that the configuration of chiral centers of cinchona alkaloids of the ligand markedly affected the catalytic performance. NNP ligands derived from cinchonine and quinidine appeared to benefit both the reaction rate and enantioselectivity, while those derived from cinchonidine and quinine had the opposite effect. Further, different NNP ligands that bearing different substituents on the phenyl rings were evaluated. Similar to our previous research, ligands with electron-withdonating substituents showed better catalytic performance than those with electron-withdrawing substituents. However, it was noted that the more electron-withdonating substituents furnished lower activity but same enantioselectivity. The optimal ligand L5 derived from quinidine with one methoxy group on benzene ring provided the corresponding chiral alcohol with 99.9% conversion and 98.8% ee. Considering that L3 derived from cinchonine had similar catalytic performance to L4 derived from quinidine, new ligand L10 similar to L5 with one methoxy group on benzene ring was synthesized and applied to the asymmetric hydrogenation of template substrate. 99.6% conversion and 97.6% ee was obtained. Hence, L5 was employed as better ligand in subsequent experiments.Open in a separate windowFig. 1The effect of different bases for the asymmetric hydrogenation of acetophenone (substrate/Ru/L5 = 500/1/2, ketones: 0.429 mol L⁻¹, base: 0.15 mol L⁻¹, MeOH: 2 mL, 30 °C, 6 MPa, 2 h.).Open in a separate windowFig. 2The effect of different solvents for the asymmetric hydrogenation of acetophenone. (substrate/Ru/L5 = 1000/1/2, ketones: 0.858 mol L⁻¹, Ba(OH)₂: 0.15 mol L⁻¹, solvent: 2 mL, 30 °C, 6 MPa, 2 h.).The effect of different ligand for the asymmetric hydrogenation of acetophenone^a

利妥昔单抗治疗难治性激素耐药型肾病综合征的疗效和安全性

目的:探讨利妥昔单抗(RTX)治疗儿童难治性激素耐药型肾病综合征(SRNS)的疗效和安全性。方法:回顾性分析2013年9月至2018年3月东部战区总医院儿科收治并接受RTX治疗的10例难治性SRNS患儿的临床资料。结果:10例患儿发病年龄(4.47±2.75)岁,男女各5例;5例(50%)肾活检为局灶节段性肾小球肾炎,...