兴奋胆碱能通路对内毒素血症和肠缺血/再灌注动物肝脏功能的保护作用

目的:观察不同方式激活胆碱能受体途径对内毒素血症和肠缺血/再灌注动物肝脏功能的保护作用.方法:静脉注射内毒素(LPS,10 mg/kg和5 mg/kg)复制大鼠内毒素血症模型(每组10只),肠系膜上动脉夹闭1 h后松夹复制肠缺血/再灌注模型(每组6只),兔肠系膜上动脉部分阻断后4 h恢复血流复制兔肠部分缺血/再灌注模型(每组5只).内毒素血症大鼠分别施与迷走神经刺激或电针副交感神经相关穴位(后三里穴),并分别设模型组、假手术组和迷走神经切断组或电针假穴组;肠缺血/再灌注动物经肠袋(距离回盲部15 cm处起始,向空肠端作一个长约10 cm肠袋,保留血液供应)给予卡巴胆碱(大鼠:0.1 mg/kg;兔:3μg/kg),并设假手术组和模型组.各组大鼠于实验结束时、各组兔于上动脉阻断0、2、4、6、8 h及1、2、3 d取股动脉血测定血浆丙氨酸转氨酶(ALT)活性.结果:与模型组、迷走神经切断组或电针假穴组比较,采用迷走神经刺激或电针刺激副交感神经相关穴位(后三里穴)明显降低内毒素血症大鼠早期血浆ALT活性(P＜0.05或P＜0.01);肠缺血及再灌注后大鼠ALT明显升高,肠袋给予卡巴胆碱后ALT水平均有明显改善.肠袋输注卡巴胆碱兔血浆ALT活性在缺血/再灌注早期较缺血前增加,再灌注后逐渐恢复,伤后3 d基本接近正常水平,而模型组则逐渐升高.结论:通过刺激副交感神经或局部给予拟胆碱药的方式激活胆碱能受体途径对内毒素血症和肠缺血/再灌注动物肝脏功能具有不同程度的保护作用.     

Once Daily Calcineurin Inhibitor Monotherapy in Pediatric Liver Transplantation

This report describes a group of pediatric liver transplant recipients who have undergone once daily calcineurin inhibitor (CNI) monotherapy at Children's Memorial Hospital, Chicago, between January 1, 2001 and November 30, 2008. We defined success as normal liver enzymes at 1 year after dose change, with normal enzymes throughout all follow‐up. Patients who did not meet the set criteria or had lost an organ to chronic rejection were not considered for this therapeutic strategy. There were 147 patients in our organ transplant tracking record (OTTR) who were ≥ 5 years post liver transplant. Of these, 56 underwent reduced dose, once daily CNI monotherapy. Patients who met the set criteria were placed on once daily calcineurin inhibitor at half their previous dose. Fifty patients successfully achieved this dose change, while six patients failed at a mean of 3.7 ± 3.2 months following the dosing change. The mean interval from transplant was significantly longer in those patients who were successful compared to those who failed dose change (p < 0.05). Importantly, there have been no graft losses. Reduced dose, once daily CNI monotherapy is safe in carefully selected recipients, with a longer interval post liver transplantation increasing the likelihood of success.     

肾移植术后Ⅰ型原发性高草酸尿症复发致移植肾功能不全的多学科综合诊疗

目的  探讨肾移植术后Ⅰ型原发性高草酸尿症（PH）复发的临床特点和多学科综合诊疗（MDT）的经验。方法  对1例接受同种异体肾移植手术后不明原因移植肾功能短期内迅速下降的病例进行MDT讨论,总结MDT在诊断罕见遗传性疾病以及提高肾移植受者长期存活中的作用。结果  经MDT讨论,患者确诊为Ⅰ型PH复发,排除排斥反应后恢复常规免疫抑制方案,嘱大量饮水,予优质蛋白和低磷饮食、维生素B6、钙剂等保守治疗措施并积极防治并发症。患者移植肾功能恶化延缓,但仍在肾移植术后5个月恢复规律血液透析至投稿日。结论肾移植术后Ⅰ型PH复发较为罕见,临床主要表现为复发性肾结石,移植肾功能下降,且并发症多,患者预后不良。通过MDT讨论患者病情,明确诊断,确定最佳治疗方案,延缓了病情进展,改善了患者预后。     

3例成人斯蒂尔病并发噬血细胞综合征患者的临床特点分析并文献复习

目的：探讨成人斯蒂尔病（AOSD）并发噬血细胞综合征（HPS）患者的临床表现、实验室指标特点和治疗预后情况,为其临床诊治提供依据。方法：收集3例AOSD并发HPS患者的性别、年龄、发热峰值温度、皮疹、关节肿痛、肝脾淋巴结肿大及治疗和预后情况等临床数据以及外周血白细胞（WBC）数量、中性粒细胞绝对值（NE#）、淋巴细胞绝对值（LY#）、单核细胞绝对值（MO#）、红细胞（RBC）、血红蛋白（HGB）、血小板（PLT）、天门冬氨酸氨基转移酶（AST）、谷丙氨酸氨基转移酶（ALT）、谷氨酰转肽酶（GGT）、碱性磷酸酶（ALP）、胆碱酯酶（CHE）、血清铁蛋白（SF）、纤维蛋白原（FBG）及骨髓象等实验室数据,并对其进行回顾性分析。结果：一般情况,3例患者均为50岁以上女性,出现HPS的时间分别为AOSD发病后的1个月、1个月和5个月。临床表现,3例AOSD患者均以发热、皮疹和关节疼痛为首发症状,均无肝脾肿大,仅患者3在AOSD初期出现淋巴结肿大,经糖皮质激素治疗后发热、皮疹、关节肿痛及淋巴结肿大症状均好转。并发HPS后3例患者均再次首先出现发热症状,体温均在39℃以上,其中2例患者出现黄疸,出现HPS后均未发现肝脾及淋巴结肿大。实验室指标特点,血细胞减少和持续升高的SF为AOSD并发HPS的早期敏感指标,肝功能酶学及FBG水平的变化均滞后于血细胞和SF变化。AOSD并发HPS患者肝功能异常以ALT水平升高最为明显。血细胞减少早期行骨穿活检即可发现吞噬现象。结论：AOSD并发HPS患者的临床特点为不明原因的再发持续高热,实验室指标的特点为血细胞减少（尤其是血小板减少）、SF持续升高、重度肝损伤（以ALT水平升高为主）、纤维蛋白原减少和骨穿活检出现吞噬现象;AOSD并发HPS患者应早发现、早治疗,以降低其复发率及死亡率。     

ALT持续正常的HBeAg阴性慢性HBV感染者临床特征

目的 分析ALT持续正常的HBeAg阴性慢性HBV感染者临床特征。 方法 回顾性收集60例2013年9月—2020年1月于延安大学附属医院感染病科门诊就诊的ALT持续正常HBeAg阴性慢性HBV感染者。比较患者基线和随访终点各指标的差异,统计随访结束时患者HBV DNA、HBsAg自然转阴以及肝炎活动、肝硬化和肝癌的累计发生率。计量资料两组间比较采用配对t检验或Wilcoxon符号秩和检验。 结果 所有患者随访24.00~72.00月,其中31例患者在随访过程中行肝组织活检,18例（58.1%）患者肝脏伴有轻度损伤,13例（41.9%）患者肝脏存在中度损伤。患者的HBsAg、HBeAb、HBcAb、ALT和ALB水平随访前和随访后差异均有统计学意义（P均<0.05）,而HBV DNA、AST和LSM水平差异均无统计学意义（P均>0.05）。随访结束时6例患者检测不到HBV DNA;4例患者出现HBsAg自然阴转;2例患者出现肝炎活动;2例患者发展为肝硬化;1例患者进展为肝细胞癌。 结论 约30.0%的ALT持续正常HBeAg阴性慢性HBV感染者有抗病毒治疗指征。此类患者如果条件允许应积极行肝组织活检评估肝脏损伤程度;临床医生也可以根据患者的病毒学、影像学和人口学特征直接给予抗病毒治疗。     

A population pharmacokinetic study of tacrolimus in healthy Chinese volunteers and liver transplant patients

Aim:

To develop a population pharmacokinetic (PopPK) model of tacrolimus in healthy Chinese volunteers and liver transplant recipients for investigating the difference between the populations, and for potential individualized medication.

Methods:

A set of 1100 sparse trough concentration data points from 112 orthotopic liver transplant recipients, as well as 851 dense data points from 40 healthy volunteers receiving a single dose of tacrolimus (2 mg, po) were collected. PopPK model of tacrolimus was constructed using the program NONMEM. Related covariates such as age, hepatic and renal functions that were potentially associated with tacrolimus disposition were evaluated. The final model was validated using bootstrapping and a visual predictive check.

Results:

A two-compartment model of tacrolimus could best describe the data from the two populations. The final model including two covariates, population (liver transplant recipients or volunteers) and serum ALT (alanine aminotransferase) level, was verified and adequately described the pharmacokinetic characteristics of tacrolimus. The estimates of V2/F, Q/F and V3/F were 22.7 L, 76.3 L/h and 916 L, respectively. The estimated CL/F in the volunteers and liver transplant recipients was 32.8 and 18.4 L/h, respectively. Serum ALT level was inversely related to CL/F, whereas age did not influence CL/F. Thus, the elderly (≥65 years) and adult (<65 years) groups in the liver transplant recipients showed no significant difference in the clearance of tacrolimus.

Conclusion:

Compared with using the sparse data only, the integrating modeling technique combining sparse data from the patients and dense data from the healthy volunteers improved the PopPK analysis of tacrolimus.     

Branched-chain amino acids and alanine as indices of the metabolic control in Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients

Summary Alterations in plasma branched-chain amino acids (valine, isoleucine and leucine) and alanine have been described in patients with insulin-dependent diabetes mellitus who have poor metabolic control. To assess the relevance of these abnormalities as indices of metabolic control, we sequentially evaluated plasma amino acids in 14 poorly controlled diabetics (seven Type 1 (insulin-dependent) and seven Type 2 (non-insulin-dependent) patients) until good control was achieved. The sum of branched-chain amino acids in both groups of uncontrolled diabetic patients was significantly increased compared with the values for the same subjects in good metabolic control. No statistically significant differences were present between ketotic and non-ketotic uncontrolled patients. The amelioration of the diabetic state with either insulin treatment or oral hypoglycaemic agents, reduced progressively branched-chain amino acids. The sum of valine, isoleucine and leucine strictly correlated with daily urinary glucose (r=0.73), but less well with fasting blood glucose (r=0.43), nonesterified fatty acids (r=0.46) and glycosylated haemoglobin (r=0.38). Alanine did not show any statistically significant differences at various stages of diabetic control. Branched-chain amino acids, but not alanine, may be used as indices of short-term diabetic control.     

Liver steatosis assessment: Correlations among pathology,radiology, clinical data and automated image analysis software

Quantitating hepatic steatosis is important in many liver diseases and liver transplantation. Since steatosis estimation by pathologists has inherent intra- and inter-observer variability, we compared and contrasted computerized techniques with magnetic resonance imaging measurements, pathologist visual scoring, and clinical parameters. Computerized methods applied to whole slide images included a commercial positive pixel count algorithm and a custom algorithm programmed at our institution. For all liver samples (n = 59), including pediatric, adult, frozen section, and permanent specimens, statistically significant correlations were observed between pathology, radiology, and each image analysis modality (r = 0.75–0.97, p < 0.0001), with the strongest correlations in the pediatric cohort. Statistically significant relationships were observed between each method and with body mass index (r = 0.37–0.56, p from <0.0001 to <0.05) and with albumin (r = 0.55–0.64, p < 0.05) but not with alanine aminotransferase or aspartate aminotransferase. Although pathologist assessments correlated (r = 0.64–0.86, 0.92–0.97, and 0.78–0.91 for microvesicular, macrovesicular, and overall steatosis, respectively), the absolute values of hepatic steatosis visual assessment were susceptible to intra- and inter-observer variability, particularly for microvesicular steatosis. Image analysis, pathologist assessments, radiology measurements, and several clinical parameters all showed correlations in this study, providing evidence for the utility of each method in different clinical and research settings.