Role of dexamethasone in the long‐term functional maturation of MSC‐laden hyaluronic acid hydrogels for cartilage tissue engineering

The purpose of study was to investigate the maturation of mesenchymal stem cells (MSC) laden in HA constructs with various combinations of chemically defined medium (CM) components and determine the impact of dexamethasone and serum on construct properties. Constructs were cultured in CM with the addition or withdrawal of media components or were transferred to serum containing media that partially represents an in vivo‐like condition where pro‐inflammatory signals are present. Constructs cultured in CM+ (CM with TGF‐β3) and DEX? (CM+ without dexamethasone) conditions produced robust matrix, while those in ITS/BSA/LA? (CM+ without ITS/BSA/LA) and Serum+ (10% FBS with TGF‐β3) produced little matrix. While construct properties in DEX? were greater than those in CM+ at 4 weeks, properties in CM+ and DEX? reversed by 8 weeks. While construct properties in DEX? were greater than those in CM+ at 4 weeks, the continued absence or removal of dexamethasone resulted in marked GAG loss by 8 weeks. Conversely, the continued presence or new addition of dexamethasone at 4 weeks further improved or maintained construct properties through 8 weeks. Finally, when constructs were converted to Serum (in the continued presence of TGF‐β3 with or without dexamethasone) after pre‐culture in CM+ for 4 weeks, GAG loss was attenuated with addition of dexamethasone. Interestingly, however, collagen content and type was not impacted. In conclusion, dexamethasone influences the functional maturation of MSC‐laden HA constructs, and may help to maintain properties during long‐term culture or with in vivo translation by repressing pro‐inflammatory signals. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1717–1727, 2018.

     

基于AdaBoost算法的药物—靶向蛋白作用预测算法

对靶向蛋白的药物作用进行预测可以促进药物新作用的发现。新近的研究更倾向于单独将特定的矩阵填补算法应用在靶向蛋白和药物的相互作用预测中。单模型的矩阵填补算法准确度较低,因此应用在药物—靶向蛋白作用预测方面也难以获得满意的结果。AdaBoost算法是一种由多分类器组合生成强分类器的算法框架,其在分类应用领域的实用性和有效性已被证明。靶向蛋白的药物作用预测是一个矩阵填补问题,即是一种评分预测过程,因此本文在使用AdaBoost算法对药物—靶向蛋白作用进行预测前,将药物—靶向蛋白作用预测的矩阵填补问题转化为分类问题,将AdaBoost算法应用在靶向蛋白的药物作用预测评分上,充分利用AdaBoost算法框架对多个弱分类器进行融合从而提升性能,得以进行准确的药物—靶向蛋白作用预测。基于公测数据集的实验结果表明,本文提出的算法在预测准确度方面超过了大多数经典算法和新近算法,较好地克服了新近基于机器学习方法单算法的局限性,更好地挖掘隐含因素,有效提升了预测准确度。     

Tigecycline-induced inhibition of mitochondrial DNA translation may cause lethal mitochondrial dysfunction in humans

BackgroundA 65-year-old patient developed an unexplained and ultimately lethal metabolic acidosis under prolonged treatment with tigecycline. Tigecycline is known to have a selective inhibitory effect on eukaryotic mitochondrial translation. The underlying molecular mechanisms of the metabolic acidosis in this patient were explored.MethodsOxidative phosphorylation system (OXPHOS) analysis, blue native polyacrylamide gel electrophoresis followed by in-gel activity staining in mitochondria, molecular analysis of mitochondrial DNA (mtDNA) for genomic rearrangements and sequencing of the rRNA genes was performed on the subject's skeletal muscle.ResultsOXPHOS analysis revealed a combined deficiency of the complexes I, III, IV and V, with a preserved function of complex II (encoded by nuclear DNA), thus demonstrating a defective mtDNA translation. There were no known underlying mitochondrial genetic defects. The patient had a (m.1391T>A) variant within the 12SrRNA gene in heteroplasmy (50–60%).ConclusionsThis patient developed an ultimately lethal mitochondrial toxicity while receiving prolonged treatment with tigecycline, which was caused by a defective translation of the mtDNA. Tigecycline is known to suppress eukaryotic mitochondrial DNA translation, but until now this effect has been considered to be clinically insignificant. The observations in this patient suggest a clinically significant mitochondrial toxicity of tigecycline in this patient, and warrant further investigation.     

Lacosamide monotherapy for the treatment of childhood epilepsy with centrotemporal spikes

ObjectiveChildhood epilepsy with centrotemporal spikes (CECTS) is known as age-limited focal epilepsy syndrome in childhood. Lacosamide is a third-generation antiepileptic drug. This study aimed to evaluate the efficacy of lacosamide monotherapy for the treatment of CECTS.MethodsWe enrolled 18 patients (6 girls and 12 boys) who met the following criteria: 1) the age of onset of the seizures was between 3 and 13 years of age; 2) showing at least hemifacial and/or oropharyngeal seizures; 3) interictal discharges in central and/or middle temporal electrodes; 4) no intellectual disability; 5) treatment duration of lacosamide monotherapy over 6 months. We retrospectively collected and analyzed clinical data and treatment information. We evaluated the seizure occurrences during 0–3, 4–6, and 7–12 months from the treatment initiation and the last 6 months of the follow-up. We also evaluated the outcomes as seizure-free if the patients developed no seizures both over 6 months and 3 times of pretreatment mean seizure interval at the last follow-up.ResultsOf the patients, 39%, 67% and 72% were seizure-free during 0–3, 4–6, and 7–12 months from treatment initiation, respectively. Finally, 83% of the patients achieved seizure freedom. Seizure freedom was achieved in 72% during the first 4 months of treatment. All patients continued lacosamide monotherapy during the study, although four patients showed transient fatigue or somnolence.ConclusionsLacosamide showed good efficacy for controlling seizures with fewer adverse effects, and therefore may be a good candidate as a first-line medication for the treatment of new-onset CECTS.     

Keyhole与Sugarbaker术治疗造口旁疝单中心十年疗效对比

目的探讨造口旁疝不同手术方式的治疗效果。 方法回顾性分析2012-2022年山东省立医院收治的102例采用Keyhole或Sugarbaker术式进行造口旁疝修补患者的临床资料,其中Keyhole术40例,Sugarbaker术62例,根据是否为腹腔镜辅助又分为开放组21例,腔镜组81例。观察不同手术组在手术时间、住院时间、术中出血量、术后胃肠功能恢复时间以及腹胀、疼痛、切口感染、肠漏、肠梗阻、肠坏死等并发症,并随访术后复发情况。 结果手术时间：Keyhole组较Sugarbaker组长（P<0.05）,开放组较腔镜组长（P<0.05）;腹胀发生率：开放组显著高于腔镜组（P<0.05）;其余指标虽有差异,但无统计学意义。 结论无论采用Keyhole还是Sugarbaker术式、开放或腹腔镜手术进行造口旁疝修补,在严重并发症和复发率方面都是相似的,采用Sugarbaker术较Keyhole术手术时间更短,Keyhole组复发率高,但差异无统计学意义。开放手术用时更长,术后腹胀情况更重。     

经脐单孔腹腔镜治疗胃十二指肠溃疡穿孔的临床研究

目的:探讨经脐单孔腹腔镜修补术治疗胃十二指肠溃疡的疗效及其对机体炎症反应的影响。方法:选取2016年10月—2020年5月我院收治的胃十二指肠溃疡穿孔患者90例,采用随机数字表法分为单孔组(n=47)和多孔组(n=43),单孔组行经脐单孔腹腔镜胃十二指肠溃疡穿孔修补术,多孔组行传统多孔腹腔镜胃十二指肠溃疡穿孔修补术。比较两组患者手术情况、胃肠功能恢复情况及术后并发症发生情况;对比两组患者术前、术后1 d、术后7 d及术后14 d 降钙素原(PCT)、白细胞介素-6(IL-6)及总免疫球蛋白E(T-IgE)水平。结果:与多孔组比较,单孔组患者术后镇痛剂使用率(18.60% vs 4.26%)、住院时间[(8.54±1.68)vs(7.22±1.43)]明显降低(P<0.05),术后肠鸣音出现时间[(31.15±4.13)h vs(27.70±3.36)h]、胃肠功能恢复时间[(40.74±6.08)min vs(33.58±5.63)min]、首次排气时间[(51.73±6.68)vs(41.13±5.67)]及首次排便时间[(59.52±8.38)vs(46.48±7.12)]均显著缩短(P<0.05)。单孔组术后7 d、14 d,血清PCT、IL-6及T-IgE水平显著低于多孔组[术后7 d,PCT:(0.32±0.15)ng/mL vs (0.43±0.17)ng/mL,IL-6:(1.05±0.26)pg/mL vs (1.15±0.39 )pg/mL,T-IgE:(119.59±28.51)IU/mLvs(125.46±25.63)IU/mL;术后14 d,PCT:(0.27±0.11)ng/mL vs (0.37±0.19)ng/mL,IL-6:(0.94±0.41)pg/mL vs(1.06±0.32)pg/mL,T-IgE:(96.51±32.15)IU/mLvs(102.83±21.36)IU/mL],差异有统计学意义(P<0.05)。单孔组患者术后并发症发生率为2.12%,显著低于多孔组(13.95%),差异有统计学意义(P<0.05)。结论:经脐单孔腹腔镜修补术治疗胃十二指肠溃疡穿孔疗效显著,能有效缩短患者住院时间,降低患者术后并发症发生率,促进患者胃肠功能恢复,减轻机体炎症反应,具有较好的临床应用价值。