早期诊断急性肾损伤的生物学标志物研究现状

急性肾损伤(AKI)是一种常见的严重疾病.由于缺乏诊断AKI的早期生物学标志物,往往导致早期有效治疗的延误.目前对于诊断AKI新的生物学标志物的研究已发展到了临床研究阶段,最有希望成为早期诊断AKI的生物学标志物包括中性粒细胞明胶酶相关脂质运载蛋白、IL-18、肾损伤分子-1和L-脂肪酸结合蛋白.本文就近年来关于上述几种生物学标志物的研究作一综述,为应用早期诊断AKI的生物学标志物提供理论依据.     

缺氧缺血新生大鼠脑组织caspase-1和白细胞介素18 mRNA表达及其关系探讨

目的研究caspase-1及其底物之一白细胞介素(IL)-18 mRNA的表达在缺氧缺血性脑损伤(HIBD)中的作用及其意义.方法 112只7日龄新生Wistar大鼠按照完全随机化方法分为对照组、HIBD 3、8、24 h、3、6和14 d组,每组16只.其中8只采用RT-PCR 方法检测caspase-1和IL-18 mRNA在HIBD后脑皮层中的表达及其相关性,另外8只光镜下观察脑组织病理学改变.结果对照组有caspase-1 mRNA少量表达(0.2918 ± 0.0809),HIBD 24 h组其水平开始增加(0.5222 ± 0.0941,与对照组比较P<0.01),6 d达高峰(0.7886 ± 0.0480,与其余各组相比P<0.01), 此后下降,但HIBD 14 d (0.5314 ± 0.1272)仍可检测出.对照组IL-18 mRNA水平为0.3218 ± 0.0466,HIBD 24 h至6 d其表达逐渐增加(24 h 0.5823 ± 0.0740; 3 d0.6976 ± 0.1073; 6 d 0.9110±0.0647,与对照组比较均为P<0.01),并达高峰(HIBD 6 d组与其余各组相比P<0.01).HIBD后IL-18 mRNA的表达在时间上与caspase-1具有紧密相关性(r=0.871,P<0.01).组织学检查发现神经元变性、坏死在HIBD 1～6天逐渐加重.结论 HIBD后caspase-1和IL-18 mRNA的表达逐渐增加,其变化规律与光镜观察到的脑损伤进展的时间框架吻合,提示它们均参与了新生鼠HIBD的病理形成过程.     

新生儿缺氧缺血性脑病血清caspase-1和IL-18水平变化的研究

目的：研究新生儿缺氧缺血性脑病(HIE)时血清半胱氨酸1(caspase1)和白细胞介素18(IL18)的变化及其临床意义。方法：采用酶联免疫吸附法(ELISA)检测70例HIE患儿及22例正常足月新生儿第3天血清caspase1和IL18的水平。结果：①新生儿HIE组血清caspase1和IL18明显高于对照组,两组比较差异均有显著性(P<0.05);②与对照组比较,轻、中、重度HIE组血清caspase1水平明显增高(P<0.05,<0.01,<0.01)。HIE组间两两比较,中度与轻度组比较差异有显著性(P<0.01);重度组与其他两组比较血清caspase1水平均明显升高(P<0.01);③轻、中、重度HIE组血清IL18与对照组比较,中、重度HIE组血清IL18水平明显增高(P<0.01);HIE组间血清IL18两两比较,中度与轻度组比较差异有显著性(P<0.05);重度组与其他两组比较均明显升高(P<0.01);④血清caspase1与IL18呈正相关(γ=0.6677,P=0.0013)。结论：血清caspase1水平与HIE临床分度基本一致,可作为辅助诊断HIE及协助其临床分度的可靠指标;急性期HIE血清IL18水平的测定是早期辅助诊断HIE及判断病情严重程度的重要指标。     

Caspase-1及其激活的细胞因子在发育期惊厥性脑损伤中的作用

目的：半胱氨酸天冬氨酸酶(caspase)-1及其激活的细胞因子与许多疾病的炎症反应和凋亡有关,但与惊厥性脑损伤的关系目前尚不清楚。该研究旨在探讨caspase-1及其激活的细胞因子在发育期惊厥性脑损伤中的作用。方法：96只20日龄健康Sprague-Daw ley(SD)大鼠随机分为2组:对照组和惊厥组。通过三氟乙醚反复吸入制作发育期大鼠惊厥动物模型。RT-PCR方法检测各组动物反复惊厥后6 h,1,3,7 d大脑皮层caspase-1,IL-18,IL-1βmRNA的表达,同时观察脑含水量变化和光镜下大脑皮层神经元病理改变,并对脑损伤进行神经病理半定量积分。结果：①惊厥组各时间点大脑皮层caspase-1,IL-18 mRNA的表达均较对照组显著增高(P<0.05或<0.01);而IL-1βmRNA的表达呈双峰样改变,反复惊厥后6 h,1 d,7 d表达量较对照组显著增高(P<0.01),第3天表达量与对照组相比差异无显著性(P>0.05)。②惊厥后皮层神经元出现水肿和变性坏死,并可见炎性细胞浸润和凋亡细胞。③反复惊厥后6 h,1 d,3 d脑含水量均较对照组显著升高(P<0.01),第7天与对照组相比较差异无显著性(P>0.05);惊厥组各时间点脑损伤积分较对照组显著升高(P<0.01)。结论：caspase-1及其激活的细胞因子在发育期惊厥性脑损伤中发挥重要作用。     

克拉屈滨治疗儿童难治性朗格罕细胞组织细胞增生症并发肝损伤1例并文献复习

目的讨论并鉴别克拉屈滨引起的少见的不良反应—药物性肝损伤(DILI),提高克拉屈滨治疗儿童难治性朗格罕细胞组织细胞增生症(LCH)的临床用药安全性。方法回顾性分析1例1岁5月男性难治性LCH,经LCH-Ⅲ诱导方案、Japan LCH-SG 96 B诱导方案两次诱导后治疗反应差,评估病情再活动,转入更为强烈的LCH-S-2005方案:克拉屈滨9mg/(m~2·d)联合阿糖胞苷1g/(m~2·d)治疗,一个疗程共5d,并复习相关文献。结果该病例在用药后出现严重肝脏毒性,表现为肝大、显著高胆红素血症、肝酶不高,CT影像改变肝大,密度减低,门静脉周围见条状低密度影,临床表现类似肝窦闭塞综合征(SOS)。该病例同时发生了4级血液学毒性最后死于肺部感染。结论临床医师需注意克拉屈滨引起药物性肝损伤的问题,而且可能在原来存在肝脏基础疾病的患者中更易出现。克拉屈滨治疗前肝功能的充分评估、治疗过程中肝功能的密切监测、血药浓度监测、及时的病理学诊断、剂量的个体化调整等,是今后克拉屈滨应用过程中需要重视和关注的要点。     

Age-related changes in intracellular cytokine profiles and Th2 dominance in allergic children

The unbalanced T helper response has been pointed out in allergic diseases. Especially in childhood, it is important to consider the development of acquired immunity. We investigated the relationship between age and Th1, Th2, Tc1 or Tc2 cells. In addition, Th1, Th2, Tc1 or Tc2 cells in allergic diseases were compared with control subjects. Thirty-four healthy controls (0-40 years old), 200 samples of cord blood, nine patients with atopic dermatitis (AD) (1-3 years old) and five patients with bronchial asthma (BA) (2-6 years old) were studied. Surface staining with CD4, CD8 and intracellular staining with anti-interferon-gamma (IFN-gamma) and anti-interleukin (IL)-4 were carried out, and analyzed by using flow cytometry. In the healthy controls, the percentages of Th1, Tc1 or Th2 showed positive correlation with age. The absolute numbers of Th1 or Tc1 also correlated with age. Cord blood with a family history of allergic disease showed no significant difference compared to that without a family history. The percentage of Th2 in AD and BA patients was significantly higher than in the age-matched healthy controls. The increase in Th1, Th2 and Tc1 with age might reflect on the development of acquired immunity. Age matching is important when evaluating the cytokine profiles of T cells. In allergic diseases, although cord blood showed a Th1-dominant pattern, it changed to Th2 dominance in childhood, and this may reflect on some genetic background.     

Death caused by hyperglycemic hyperosmolar state at the onset of type 2 diabetes

Seven obese African American youth were considered to have died from diabetic ketoacidosis (DKA) due to type 1 diabetes, despite meeting the criteria for hyperglycemic hyperosmolar state and not for DKA. All had previously unrecognized type 2 diabetes, and death may have been prevented with earlier diagnosis or treatment.     

Fasting c-peptide and insulin-like growth factor-binding protein-1 levels help to distinguish childhood type 1 and type 2 diabetes at diagnosis

BACKGROUND: Children with new onset diabetes (n = 175) were evaluated over 12-months. Patients were presumptively diagnosed with type 2 diabetes mellitus (T2DM) (n = 26) based on obesity, a relative with T2DM, the ability to wean from insulin, and absence of glutamic acid decarboxylase-65 (GAD-65) antibodies. We hypothesized that markers of insulinization at diagnosis, including fasting C-peptide and insulin-like growth factor-binding protein (IGFBP)-1, in addition to initial CO(2) levels and urine ketones, would help in distinguishing type 1 diabetes mellitus (T1DM) from T2DM. RESULTS: Children with T1DM (84 male, 65 female) had a mean age of 8.7 +/- 4.3 yr and a racial background of 78% white, 19% black, and 3% other. In contrast, children with T2DM (13 female, 13 male) had a mean age of 14.2 +/- 3.1 yr with a racial background of 58% black, 27% white, and 15% other. Fasting C-peptide level was 0.38 +/- 0.37 ng/mL in T1DM vs. 2.66 +/- 2.14 ng/mL in T2DM; a C-peptide of 0.85 ng/mL had 83% sensitivity in distinguishing T1DM from T2DM. Fasting IGFBP-1 level was 38.1 +/- 39.1 ng/mL (T1DM) vs. 3.6 +/- 4.5 ng/mL (T2DM); a value of 3.6 ng/dL could distinguish the two types of diabetes with 93% sensitivity. Urinary ketones were found in 79% of children with T1DM compared with 56% of those with T2DM, and the magnitude was associated with type of diabetes. Initial CO(2) level for T1DM was 17.9 +/- 6.9 mmol/L vs. 22.7 +/- 5.7 mmol/L for T2DM; a value of 21.5 mmol/L could distinguish the two types of diabetes with 83% sensitivity. CONCLUSIONS: In addition to obesity, family history of T2DM, and absence of GAD-65 antibodies, children with new-onset T2DM may be distinguished from those with T1DM by a combination of biochemical parameters (C-peptide, IGFBP-1, CO(2), and urine ketones).     

Pioglitazone as adjunctive therapy in adolescents with type 1 diabetes

OBJECTIVE: To determine whether the addition of the thiazoladinedione, pioglitazone, to standard therapy improves metabolic control in adolescents with type 1 diabetes (T1D) and clinical evidence of insulin resistance. STUDY DESIGN: Randomized, placebo-controlled 6-month 2-site trial of pioglitazone therapy in 35 adolescents with T1D, high insulin requirements (>0.9 U/kg/d), and suboptimal metabolic control (A1c 7.5%-11%), with the primary outcome of change in A1c. Secondary outcomes include change in insulin dose, body mass index (BMI), lipids, and waist and hip circumference. RESULTS: Metabolic control (A1c) was improved at 6 months in all subjects (P = .02). There was no significant difference between the pioglitazone and placebo treatment groups at 6 months in either change in A1c (-0.4% +/- 0.9% and -0.5% +/- 1.2%, respectively) or insulin dose. BMI SDS increased by 0.3 +/- 0.3 (kg/m(2)) in the pioglitazone group and remained unchanged in the placebo group (P = .01). There was no significant difference in change in any lipid parameters between the pioglitazone and placebo groups at 6 months. CONCLUSIONS: Adjunctive pioglitazone therapy was not effective in improving glycemic control in adolescents with T1D. Pioglitazone was associated with increased BMI.     

胆道闭锁患儿血清sICAM-1与IL-18的变化及临床意义

目的　研究可溶性细胞间粘附分子 1(sICAM 1)、白细胞介素 18(IL 18)在胆道闭锁(BA)发病机制中的作用及临床意义。方法　胆道闭锁患儿 2 1例 ,男 8例 ,女 13例 ;年龄 2个月～ 12岁 ,所有患儿诊断均经手术后病理切片证实。正常对照 12例为健康体检儿童 ,年龄 1个月～ 10岁。采用ELISA法动态测定胆道闭锁患儿手术前、后血清sICAM 1、IL 18水平。结果　胆道闭锁患儿血清sICAM 1、IL 18水平明显高于健康对照组 ,且两者呈正相关。Kasai手术后两者水平比术前无明显下降 ,且黄疸越重 ,水平越高。结论　sICAM 1、IL 18参与胆道闭锁的进行性损伤的病理过程 ,手术后两者增高表明外科手术不能完全阻止BA的炎症 ,持续增高提示预后不良     

内毒素致新生大鼠急性肺损伤IL-18的变化

目的探讨内毒素致新生大鼠急性肺损伤与IL-18水平的关系。方法内毒素5mg/kg腹腔注射7日龄SD新生大鼠致急性肺损伤模型,同时设腹腔内注射生理盐水对照组,每组12只。注射后1、4、8h采集血,1、4h采集肺组织,检测血浆,肺组织匀浆IL-18水平。结果内毒素注射后新生大鼠1h,血浆IL18水平就显著上升(6.38±1.62)pg/ml,4h达到高峰(34.28±17.89)pg/ml,8h后明显回落(14.61±2.16)pg/ml,仍高于生理盐水对照组(1.63±1.18)pg/ml;4h组肺组织匀浆IL-18水平(508.96±105.38)pg/ml显著高于1h组(346.08±21.23)pg/ml(P<0.01),且肺组织匀浆IL-18水平高于同时点血浆IL18水平(P<0.01)。结论IL18是一种早期的致炎因子,在急性肺损伤的发生中起重要的作用,可作为急性肺损伤的诊治指标之一。     

Reduced docosahexaenoic acid synthesis may contribute to growth restriction in infants born to mothers who smoke

In newborn infants, progressive decrease in anthropometric values and impairment of the docosahexaenoic acid (DHA) status was associated with maternal smoking during pregnancy, with a parallel increase of the metabolic precursor of DHA, alpha-linolenic acid. Maternal smoking may impair DHA synthesis which may contribute to reduced fetal growth.     

Patchy white matter hyperintensity in ring chromosome 18 syndrome

Ring chromosome 18 syndrome is a chromosomal abnormality in which partial deletions occur at both ends of chromosome 18, that is, distally on the short and long arms. Previously reported brain magnetic resonance imaging (MRI) abnormalities include diffuse hyperintensity in the white matter, which has been regarded as hypomyelination because the gene for myelin basic protein production is located on the long arm of chromosome 18. We report the case of a 14‐year‐old boy with ring chromosome 18 syndrome, whose MRI showed patchy asymmetrical T2 and fluid‐attenuated inversion‐recovery hyperintensities in the deep white matter as well as diffuse hypomyelination. These patchy lesions may indicate demyelination or gliosis rather than hypomyelination. This result differs from previous reports.     

充血性心力衰竭患儿血清白细胞介素-18和淋巴细胞CD54变化

目的探讨IL-18和CDs4在小儿充血性心力衰竭（CFIF）发病中的作用，及其对z],JLCFIF的诊断价值。方法CFIF患儿52例，心功能按修订的Ross和Reithman评分系统。心功能Ⅱ级（3～6分）18例、Ⅲ级（7～9分）17例，Ⅳ级（10～12分）17例。原发疾病为扩张性心肌病、心内膜弹力纤维增生症及先天性心脏病等。对照组15例为上呼吸道感染患儿。血清IL-18水平用ELISA法进行测定，采用流式细胞术检测外周血淋巴细胞CDs4表达。结果CFIF患儿血清IL-18及CDs4均显著增高（P均〈0．001），且随CFIF加重渐增加，治疗后两者均较治疗前明显降低（P均〈0．05）；且两者在心肌病组、先天性心脏病组及其他病组3组间比较差异无显著性（P均〉0．05），但均显著高于对照组（P均〈0．01）。结论IL-18和CDs4可能参与小儿CFIF发生发展。可以作为评价CHF严重程度的生物化学标记；CFIF作为一种临床综合征，无论最初病因是否相同，免疫反应可能都具有某些共同特征。     

Interstitial Deletion of Long Arm of Chromosome 2(q3 lq33)

We describe the case of a 4-month-old girl with interstitial deletion of the long arm of chromosome 2(46,XX,del(2) (q31 q33)). Clinical features included intrauterine growth retardation, psychomotor delay, antimongoloid slanting of the palpebral fissures, hypertelorism, low set ears, cleft palate, micrognathia, luxatio coxae and pes varus. It is suggested that the gene for soluble isocitrate dehydrogenase (IDH₁) is located on 2q33.3. The activity of serum IDH₁ was in the normal range in this patient.