Rapid hydroxylation of methtryptoline (1-methyltetrahydro-β-carboline) in rat: Identification of metabolites by chiral gas chromatography-mass spectrometry

Summary Racemic methtryptoline (1-methyltetrahydro--carboline) and 5-hydroxymethtryptoline-9-carboxylic acid (6-hydroxy-1-methyltetrahydro--carboline-1-carboxylic acid) were administered intraperitoneally to rats and the components of their urine was subsequently investigated by chiral gas chromatography-mass spectrometry. Methtryptoline rapidly became hydroxylated in the 5- and 6-position and excreted in urine. There was about a ninefold predominance of the S(–) enantiomer over the other in the 5-hydroxylated species, while the 6-hydroxylation produced a small excess of the R(+) enantiomer. About 75% of the injected dose of methtryptoline was recovered in the urine as 5- and 6-hydroxylated compounds during the first 24 h period, demonstrating that hydroxylation represents the major metabolic pathway. Treatment with 6-hydroxymethtryptoline-9-carboxylic acid led to a fivefold increase in the urinary excretion of 5-hydroxymethtryptoline during the first 24 h period with a predominance of the S(–)-enantiomer, indicating a much smaller conversion rate than from methtryptoline. It was concluded that hydroxylation of methtryptoline is a likely pathway for the natural formation of 5-hydroxymethtryptoline.     

Species differences in the relative analgesic potencies of some classical opiates and opioid peptides

The analgesic ED₅₀ values of some classical morphine congeners (morphine, methadone, fentanyl, azidomorphine) in the rat and mouse tail-flick tests were found to be similar. However, several synthetic derivatives of the natural enkephalins were more potent in mice than in rats. (These analogs contain d-amino acid in position 2 and d- or l-sulfonic (or phosphonic) acid residue in position 5). -Endorpin, d-Met², Pro⁵-enkephalinamide and two partial agonists showed intermediate interspecies relative potencies. According to the data obtained, similar opiate receptors might mediate the analgesic action of classical opiates in rats and in mice. However, the opiate receptors responsible for the antinociceptive effects of the above mentioned enkephalin analogues must be dissimilar in the two species examined. The results are discussed in terms of the role of - and -receptors in mediation of the analgesic effect induced by different types of opioids.     

Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants onβ-adrenoceptors and 5-HT2 binding sites in the rat cerebral cortex

Summary The dependence of intact noradrenergic and serotonergic nerve terminals for the decrease in the number of-adrenoceptors and 5-HT₂ binding sites in the cerebral cortex produced by long-term treatment of rats with antidepressant drugs was examined. Noradrenergic nerve terminals were destroyed with the selective noradrenaline neurotoxin DSP4, and serotonergic nerve terminals were destroyed with p-chloroamphetamine (PCA). It was found that lesioning of the noradrenergic nerve terminals abolished the decrease in-adrenoceptors produced by desipramine, mianserin and zimeldine and partially antagonized that of the-adrenoceptor agonist clenbuterol. PCA pretreatment did not antagonize the long-term effects on the-adrenoceptor produced by these compounds.Lesioning of serotonergic nerve terminals affected the down-regulation of 5-HT₂ binding sites produced by long-term treatment with mianserin, desipramine and amiflamine. DSP4 pretreatment partially abolished the down-regulation of 5-HT₂ binding sites produced by long-term treatment with desipramine, while the effects of mianserin and amiflamine were unaffected by pretreatment with DSP4.     

TUBB8基因突变致早期胚胎发育停滞一例

青岛大学附属烟台毓璜顶医院生殖医学中心对1例反复体外受精/卵细胞质内单精子注射（IVF/ICSI）助孕后早期胚胎发育停滞的患者进行了全外显子基因检测,发现了一种新的TUBB8基因突变型（c.208C>T/p.Pro70Ser）,并进一步探讨了TUBB8基因突变与早期胚胎发育停滞之间的联系,为反复种植失败的诊断与治疗提供更多可能性。     

Identification and Validation of Nutrient State-Dependent Serum Protein Mediators of Human CD4+ T Cell Responsiveness

Intermittent fasting and fasting mimetic diets ameliorate inflammation. Similarly, serum extracted from fasted healthy and asthmatic subjects’ blunt inflammation in vitro, implicating serum components in this immunomodulation. To identify the proteins orchestrating these effects, SOMAScan technology was employed to evaluate serum protein levels in healthy subjects following an overnight, 24-h fast and 3 h after refeeding. Partial least square discriminant analysis identified several serum proteins as potential candidates to confer feeding status immunomodulation. The characterization of recombinant IGFBP1 (elevated following 24 h of fasting) and PYY (elevated following refeeding) in primary human CD4⁺ T cells found that they blunted and induced immune activation, respectively. Furthermore, integrated univariate serum protein analysis compared to RNA-seq analysis from peripheral blood mononuclear cells identified the induction of IL1RL1 and MFGE8 levels in refeeding compared to the 24-h fasting in the same study. Subsequent quantitation of these candidate proteins in lean versus obese individuals identified an inverse regulation of serum levels in the fasted subjects compared to the obese subjects. In parallel, IL1RL1 and MFGE8 supplementation promoted increased CD4⁺ T responsiveness to T cell receptor activation. Together, these data show that caloric load-linked conditions evoke serological protein changes, which in turn confer biological effects on circulating CD4⁺ T cell immune responsiveness.     

Highly Pathogenic Avian Influenza A(H5N8) Virus Spread by Short- and Long-Range Transmission,France, 2016–17

We detected 3 genotypes of highly pathogenic avian influenza A(H5N8) virus in France during winter 2016–17. Genotype A viruses caused dramatic economic losses in the domestic duck farm industry in southwestern France. Our phylogenetic analysis suggests that genotype A viruses formed 5 distinct geographic clusters in southwestern France. In some clusters, local secondary transmission might have been started by a single introduction. The intensity of the viral spread seems to correspond to the density of duck holdings in each production area. To avoid the introduction of disease into an unaffected area, it is crucial that authorities limit the movements of potentially infected birds.     

新生儿高间接胆红素血症IL-6、IL-8水平变化及其意义

目的 :探讨新生儿高间接胆红素血症 (高间胆 )血清中白细胞介素 6 (IL- 6 )及白细胞介素 8(IL- 8)水平变化及其意义。方法 :采用 EL ISA法对住院的高间胆病婴的感染组 (A组 )和非感染组 (B组 )以及对照组进行血清 IL- 6、 IL- 8及胆红素的检测 ,比较各组的胆红素、IL- 6、IL- 8水平 ,黄疸消退前后 IL- 6、IL- 8水平 ,并进行相关因素的分析。结果 :A组总胆红素 (344 .0 3± 74.5 ) μmol/ L,较 B组高 [(2 77.83± 45 .12 ) μm ol/ L],间接胆红素 (间胆 ) (32 2 .9± 72 .12 ) μm ol/ L,较B组高 [(2 5 4.2 9± 44 .8) μmol/ L],A、 B两组 IL- 6分别为 (10 1.6 2± 38.77) ng/ L、 (75 .13± 13.77) ng/ L,均显著高于对照组 [(30 .6 6± 3.17) ng/ L],A、B两组 IL- 8分别为 (190 .0 2± 5 9.0 3) ng/ L 及 (15 0 .5 4± 2 5 .6 2 ) ng/ L,均显著高于对照组 [(10 8.30± 7.37) ng/ L];两组黄疸消退前后的 IL- 6及 IL- 8比较有显著性差异 (P <0 .0 0 1) ,多因素相关分析 ,IL- 6与感染因素密切相关 (P <0 .0 1) ,IL- 8与间胆呈正相关 (P <0 .0 0 1)。结论 :IL- 6及 IL- 8水平高低可作为高间胆病因及免疫自损程度诊断手段之一。     

鼻咽癌患者血清新蝶呤、sCD4与sCD8检测的意义

目的探讨血清新蝶呤、sCD4及sCD8分子水平和鼻咽癌的关系及临床意义。方法采用ELISA方法检测54例初治鼻咽低分化鳞癌治疗前、后及32例健康成人的血清新蝶呤、sCD4与sCD8分子浓度。结果鼻咽癌血清新蝶呤、sCD4及sCD8浓度高于健康对照组(P＜0.001)。不同TNM分期血清新蝶呤、sCD4及sCD8水平无差异(P＞0.05);无淋巴结转移者血清新蝶呤低于有淋巴结转移者(P＜0.05)。治疗后新蝶呤、sCD4与sCD8水平比治疗前明显降低(P＜0.01),仍比对照组高(P＜0.01);治疗后6月肿瘤全消者继续保持在较低水平,肿瘤残留者则回升到治疗前水平(P＜0.01和0.05)。结论血清新蝶呤、sCD4与sCD8分子水平检测可作为鼻咽癌病情评估、疗效监测及随访的客观指标。     

基于膝关节 CT 及下肢全长 X 线片设计股骨远端截骨导板的临床应用研究

目的探讨基于膝关节 CT 及下肢全长 X 线片设计的股骨远端截骨导板在人工全膝关节置换术（total knee arthroplasty，TKA）中应用的可行性及准确性。方法以 2016 年 7 月—2017 年 2 月拟行初次 TKA 的 20 例膝关节重度骨关节炎患者作为研究对象。男 9 例，女 11 例；年龄 53～84 岁，平均 69.4 岁。体质量指数 22.1～31.0 kg/m²，平均 24.8 kg/m²。术前膝关节活动度（range of motion，ROM）为（103.0±19.4）°、疼痛视觉模拟评分（VAS）为（5.4±1.3）分、美国特种外科医院（HSS）评分为（58.1±11.3）分。术前基于下肢全长正侧位 X 线片及膝关节 CT 构建膝关节三维模型，设计并制作股骨远端截骨导板，模拟手术确定股骨远端截骨厚度。比较术前设计以及术中实际股骨远端内、外侧髁截骨厚度。记录术中失血量、术后引流量及计算隐性失血量；术后 3 个月行膝关节 ROM、VAS 评分、HSS 评分评估临床疗效；通过比较术前及术后 1 周的股骨外翻角（femoral mechanical-anatomical angle，FMAA）、股骨远端解剖外侧角（anatomical lateral distal femoral angle，aLDFA）、股骨机械轴与胫骨机械轴夹角（mechanical femoral tibial angle，mFTA）、股骨远端屈曲角（distal femoral flexion angle，DFFA）、股骨假体屈曲角（femoral prosthesis flexion angle，FPFA）、股骨假体外侧角（anatomical lateral femoral component angle，aLFC）、前翼与股骨前方皮质线夹角（α 角），评估股骨远端假体冠状面及矢状面位置。 结果于股骨远端截骨导板辅助下 TKA 均顺利完成；术前设计股骨远端内、外侧髁截骨厚度与术中实际截骨厚度差异均无统计学意义（P>0.05）。患者均获随访 3 个月。术后切口均Ⅰ期愈合，未出现关节周围感染、下肢深静脉血栓形成等并发症。除 1 例患者未行氨甲环酸治疗外，其余 19 例患者术中失血量为 30 ～150 mL，平均 73.2 mL；术后引流量为 20～500 mL，平均 154.5 mL；隐性失血量为 169.2～1 400.0 mL，平均 643.8 mL。术后 3 个月 ROM 为（111.5±11.5）°，与术前比较差异无统计学意义（t=–1.962，P=0.065）；VAS 评分为（2.4±0.9）分、HSS 评分为（88.2±7.5）分，与术前比较差异均有统计学意义（t=7.248，P=0.000；t=–11.442，P=0.000）。X 线片复查示术后 mFTA 与术前测量比较差异有统计学意义（P<0.05）；aLDFA、FMAA、DFFA 与术前测量比较差异无统计学意义（P>0.05）；FPFA、aLFC、α 角与术前规划比较差异均无统计学意义（P>0.05）。 结论基于膝关节 CT 及下肢全长 X 线片制备的股骨远端截骨导板辅助 TKA 能实现精确截骨，改善下肢冠状面和矢状面力线，减少手术失血量，早期疗效满意。     

不同烧结温度对双相钙磷陶瓷颗粒材料介孔结构及其成骨性能的影响

目的通过体内外实验检测不同烧结温度下制备的不同介孔直径双相钙磷陶瓷（biphasic calcium phosphate，BCP）颗粒材料成骨能力差异，为筛选具备更好临床应用参数的 BCP 材料提供依据。方法将羟基磷灰石（hydroxyapatite，HA）及 β-磷酸三钙（β-tricalcium phosphate，β-TCP）以 8∶2 比例混合后，分别在 1 050、1 150 及 1 250℃ 下烧制 3 h 制备 3 种 BCP 材料（分别设为材料1、2、3），比表面积测试法（Brunauer-Emmett-Teller test，BET）测量材料的颗粒内部孔隙率及介孔直径、体积、面积，X 线衍射（X-ray diffraction，XRD）评估材料组成成份，扫描电镜观察材料微观表面形态。体外将第 3 代 SD 大鼠 BMSCs 与各材料共培养 7 d（分别设为 A、B、C 组），扫描电镜观察细胞黏附情况，鬼笔环肽染色观察 BMSCs 贴附于材料表面后的形态，细胞计数试剂盒 8 法检测细胞增殖活性。体内建立比格犬异位成骨模型：取 9 只比格犬，于每只犬双侧竖脊肌内制作 9 个肌袋，将肌袋随机分为 3 组（每组 3 个/只），A、B、C 组分别置入材料 1、2、3。术后 1、2、3 个月分别麻醉 3 只比格犬取材行 HE、Masson 及番红固绿染色，计算 BCP 间隙中的成骨面积比；行实时荧光定量 PCR（real-time fluorescence quantitative PCR，qRT-PCR）检测成骨相关基因 ALP、骨桥蛋白（osteopontin，OPN）、骨钙素（osteocalcin，OC）的表达。结果BET 检测示随烧结温度增加，颗粒内部孔隙率无明显变化，但介孔直径、体积及面积逐渐减小；XRD 检测示 3 种材料均可见 HA 及 β-TCP 两种 X 线衍射波；扫描电镜观察示 3 种材料表面有广泛分布的微孔，孔间有空隙相连。体外实验示 BMSCs 在 3 种材料表面黏附、增殖，B、C 组材料的细胞生物相容性优于 A 组。体内实验结果示，术后 2 个月开始 3 种材料颗粒孔隙内即可见明显的骨样组织沉积。各组成骨面积比随时间延长均增加，术后 2、3 个月 A 组成骨面积比显著高于 B、C 组，1 个月时显著高于 B 组（P<0.05）。qRT-PCR 检测示，A 组成骨相关基因表达在 2 个月时出现峰值，B、C 组各成骨相关基因表达随时间延长逐渐增加。术后 1 个月 A 组 ALP 和 OPN mRNA 相对表达量显著高于 B、C 组，术后 2 个月 A 组 OC mRNA 相对表达量显著高于 B、C 组，术后 3 个月 B、C 组 ALP mRNA 相对表达量及 B 组 OPN mRNA 相对表达量显著高于 A 组（P<0.05）；其余各时间点各组间比较各基因 mRNA 相对表达量差异均无统计学意义（P>0.05）。 结论不同烧结温度下制备的 BCP 材料，其介孔直径随温度增加而减小。不同介孔直径的 BCP 材料异位成骨能力存在差异，其中直径为 12.57 nm 的 BCP 材料能更早激活成骨基因，具备更强的成骨能力。介孔直径可作为一个优化 BCP 材料成骨能力的指标。