Volume 128 · Issue 01 · 2015

Numerous previous studies have shown that renal insufficiency (RI) in patients with acute coronary syndrome is associated with poor cardiovascular outcomes. These studies do not well address the impact of RI on the long-term outcome of patients with acute ST-elevation myocardial infarction (STEMI) in China. The aim of this study was to investigate the association of admission RI and inhospital and long-term mortality of patients with acute STEMI.

This was a multicenter, observational, prospective-cohort study. 718 consecutive patients were admitted to 19 hospitals in Beijing within 24 hours of onset of STEMI, between January 1,2006 and December 31,2006. Estimation of glomerular filtration rate (eGFR) was calculated using the modified abbreviated modification of diet in renal disease equation-based on the Chinese chronic kidney disease patients. The patients were categorized according to eGFR, as normal renal dysfunction (eGFR ≥ 90 ml∙min^-1∙1.73 m^-2), mild RI (60 ml∙min^-1∙1.73 m^-2 ≤ eGFR < 90 ml∙min^-1∙1.73 m^-2) and moderate or severe RI (eGFR < 60 ml∙min^-1∙1.73 m^-2). The association between RI and inhospital and 6-year mortality of was evaluated.

Seven hundred and eighteen patients with STEMI were evaluated. There were 551 men and 167 women with a mean age of 61.0 ± 13.0 years. Two hundred and eighty patients (39.0%) had RI, in which 61 patients (8.5%) reached the level of moderate or severe RI. Patients with RI were more often female, elderly, hypertensive, and more patients had heart failure and stroke with higher killip class. Patients with RI were less likely to present with chest pain. The inhospital mortality (1.4% vs. 5.9% vs. 22.9%, P < 0.001), 6-year all-cause mortality (9.5% vs. 19.8 vs. 45.2%, P < 0.001) and 6-year cardiac mortality (2.9% vs. 12.2% vs. 23.8%, P < 0.001) were markedly increased in patients with RI. After adjusting for other confounding factors, classification of admission renal function was an independent predictor of inhospital mortality (Odd ratio, 1.966; 95% confidence interval [CI], 1.002-3.070, P = 0.019), 6-year all-cause mortality (relative risk [RR] = 1.501, 95% CI: 1.018-4.373, P = 0.039) and 6-year cardiac mortality (RR = 1.663, 95% CI: 1.122-4.617, P = 0.042).

RI is very common in STEMI patients. RI evaluated by eGFR is an important independent predictor of short-term and long-term outcome in patients with acute STEMI.

Altered immunoresponse is associated with tumorigenesis and cancer progression. This study assessed the levels of tumor-infiltrating CD3⁺ or CD8⁺ T lymphocytes and interleukin-2 (IL-2) protein in radically resected non-small cell lung cancer (NSCLC) tissues to predict overall survival (OS) of the patients.

Paraffin-embedded tissue specimens from 129 NSCLC patients were retrospectively collected for immunostaining of CD8⁺, CD3⁺, and IL-2 expression. Clinicopathological and survival data were collected and analyzed using the Chi-squared test, Kaplan–Meier curves, and the log-rank test or the Cox regression model.

The data showed a significant inverse association between CD8⁺ T lymphocyte levels and IL-2 expression (r= −0.927; P = 0.000) and between the levels of CD8⁺ and CD3⁺ T lymphocytes (r = −0.722; P = 0.000), but a positive association between CD3⁺ T lymphocyte levels and IL-2 expression (r = 0.781; P = 0.000) in NSCLC tissues. Furthermore, the levels of CD3⁺ and CD8⁺ T lymphocytes and IL-2 expression were associated with tumor stage (P = 0.023, 0.006, and 0.031, respectively) and the level of CD8⁺ T lymphocytes was associated with the patient gender (P = 0.024). In addition, the levels of CD8⁺ T lymphocytes were associated with an unfavorable 5-year OS, whereas patients with high levels of CD3⁺ T lymphocytes in tumor lesions and IL-2-expressing tumors had significantly better 5-year OS rates than patients with low levels.

The levels of CD8⁺ T cells in tumor lesions and IL-2 expression were both independent predictors of OS for these NSCLC patients. Thus, the detection of tumor-infiltrating CD3⁺ or CD8⁺ T lymphocytes and IL-2 expression could be useful to predict the prognosis of radically resected NSCLC patients.

High-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is the gold standard therapy in the treatment of osteosarcoma. The plasma concentration of MTX is closely related to efficacy and toxicity. There are large individual differences. Many authors have described the pharmacokinetic (PK) profile of MTX regarding osteosarcoma under a variety of circumstances. However, no data concerning Chinese osteosarcoma patient PKs using the nonlinear mixed effects models (NONMEM) have been previously reported. The goals of this study were to establish the population pharmacokinetics (PPK) of HD-MTX treatment in Chinese osteosarcoma patients, and to explore the influence of patient covariates and between-occasion variability on drug disposition.

An intravenous HD-MTX solution (10 g/m²) was given 274 times to 148 osteosarcoma patients. MTX plasma concentrations were measured at 0, 6, 12, 24, 48 and 72 h after commencement of the infusion, and the fluorescence polarization immunoassay was used to determine MTX plasma concentrations. The PPK model and parameters were estimated using NONMEM software. The effects of fixed-effect factors were evaluated, and the final regression model was obtained.

The following population parameters were obtained using a two-compartment model: CL1 (clearance of central compartment):

(CL₁)_i = CL_1TV × [1−θ_CL1−MTXNUM × MTXNUM]×[1−θ_CL1−CrCl1 × (CrCl1−1.89)]× e^ηCL₁i (L/h). V1 (central volume):

(V₁)_i= V_1TV × e^ηV₁i (L). CL2 (clearance of peripheral compartment):

(CL₂)_i = CL_2TV × [1−θ_{CL2−BODYAREA} × (bodyarea −1.62)]×e^ηCL₂i (L h). V2 (peripheral compartment):

(V₂)_i = V_2TV × [1−θ_{V2−bodyarea} × (bodyarea-1.62)] × e^ηV₂i (L). The PPK parameters (RSD%) were CL1, V1, CL2 and V2 with values of 6.20 L/h (8.48%), 19.6 L (extremely small), 0.0172 L/h (50.9%) and 0.515 L (39.1%), respectively. Creatinine clearance and the number of methotrexate chemotherapy cycles before MTX infusion had a significant effect on the CL1, and body surface area had a significant effect on the CL2 and the V2 (P < 0. 01).

A good fit was derived for the PPK. The model could be used to provide guidance for MTX treatment and reduce adverse effects.

Abnormal neuronal differentiation plays an important role in central nervous system (CNS) development abnormalities such as Down syndrome (DS), a disorder that results directly from overexpression of genes in trisomic cells. Receptor-interacting protein 140 (RIP140) is significantly upregulated in DS brains, suggesting its involvement in DS CNS development abnormalities. However, the role of RIP140 in neuronal differentiation is still not clear. The current study aimed to investigate the effect of RIP140 overexpression on the differentiation of neuro-2a (N2a) neuroblastoma cells, in vitro.

Stably RIP140-overexpressing N2a (N2a-RIP140) cells were used as a neurodevelopmental model, and were constructed by lipofection and overexpression validated by real-time polymerase chain reaction and Western blot. Retinoic acid (RA) was used to stimulate N2a differentiation. Combining the expression of Tuj1 at the mRNA and protein levels, the percentage of cells baring neurites, and the number of neurites per cell body was semi-quantified to determine the effect of RIP140 on differentiation of N2a cells. Furthermore, western blot and the ERK1/2 inhibitor U0126 were used to identify the specific signaling pathway by which RIP140 induces differentiation of N2a cells. Statistical significance of the differences between groups was determined by one-way analysis of variance followed by the Dunnett test.

Compared to untransfected N2a cells RIPl40 expression in N2a-RIP140 cells was remarkably upregulated at both the mRNA and protein levels. N2a-RIP140 cells had a significantly increased percentage of cells baring neurites, and numbers of neurites per cell, as compared to N2a cells, in the absence and presence of RA (P < 0.05). In addition, Tuj1, a neuronal biomarker, was strongly upregulated in N2a-RIP140 cells (P < 0.05) and phosphorylated ERK1/2 (p-ERK1/2) levels in N2a-RIP140 cells were dramatically increased, while differentiation was inhibited by the ERK1/2-specific inhibitor U0126.

RIP140 overexpression promotes N2a cell neuronal differentiation by activating the ERK1/2 pathway.

The incidence of congenital coronary artery anomalies (CCAAs) is different between ethnic groups, but there is no report about Uyghur CCAAs because of the limitation of inspection methods. This study determined the prevalence of Uyghur CCAAs and analysis the difference of CCAAs between Uyghur and Han ethnic groups by the method of multi-slice computed tomography coronary angiography (MSCTCA).

Seven thousand four hundred and sixty-nine MSCTCA were analyzed for the CCAAs retroactively, 1934 were Uyghur patients while 4746 were Han patients. All the coronary artery images dates obtained by MSCTCA were evaluated for the CCAAs by two doctors.

Nineteen kinds of CCAAs were found: (1) The overall incidence of CCAAs was 2.72% (203/7469) among all patients, 2.34% (111/4746) among Han patients whereas a significant higher 3.93% (76/1934) among Uyghur patients (χ² = 12.780, P < 0.05); (2) the incidence of CCAAs among male patients was 2.48% (76/3069) in Han while 4.33% (56/1293) in Uyghur (χ² = 10.663, P < 0.05); (3) the incidence of CCAAs on the left side was 1.07% (51/4746) among Han patients while 2.17% (42/934) among Uyghur patients (χ² = 12.047, P < 0.05); (4) among these 19 kinds of CCAAs, there were significant differences of the incidence of the following kinds of CCAAs between Uyghur and Han: Left coronary artery (LCA) high location (χ² = 8.320, P = 0.004), right coronary artery (RCA) originate from left coronary sinus (χ² = 5.450, P = 0.020), and RCA originate from left Coronary sinus + LCA high location (P = 0.024).

There exists some difference in CCAAs between Uyghur and Han ethnic groups. The CCAAs incidence of Uyghur is higher than that of Han, especially in male patients and on the left side; among all kinds of CCAAs, the incidence of LCA high location, RCA originate from left coronary sinus, RCA originate from left coronary sinus + LCA high locations of Uyghur is higher than Han.

Steady-state bone marrow (SS-BM) and granulocyte colony-stimulating growth factor-primed BM/peripheral blood stem-cell (G-BM/G-PBSC) are the main stem-cell sources used in allogeneic hematopoietic stem-cell transplantation. Here, we evaluated the treatment effects of SS-BM and G-BM/G-PBSC in human leucocyte antigen (HLA)-identical sibling transplantation.

A total of 226 patients (acute myelogenous leukemia-complete remission 1, chronic myelogenous leukemia-chronic phase 1) received SS-BM, G-BM, or G-PBSC from an HLA-identical sibling. Clinical outcomes (graft-versus-host disease [GVHD], overall survival, transplant-related mortality [TRM], and leukemia-free survival [LFS]) were analyzed.

When compared to SS-BM, G-BM gave faster recovery time to neutrophil or platelet (P < 0.05). Incidence of grade III–IV acute GVHD and extensive chronic GVHD (cGVHD) was lower than seen with SS-BM (P < 0.05) and similar to G-PBSC. Although the incidence of cGVHD in the G-BM group was similar to SS-BM, both were lower than G-PBSC (P < 0.05). G-BM and G-PBSC exhibited similar survival, LFS, and TRM, but were significantly different from SS-BM (P < 0.05). There were no significant differences in leukemia relapse rates among the groups (P > 0.05).

G-CSF-primed bone marrow shared the advantages of G-PBSC and SS-BM. We conclude that G-BM is an excellent stem-cell source that may be preferable to G-PBSC or SS-BM in patients receiving HLA-identical sibling hematopoietic stem-cell transplantation.

Dual sensor (DS) for rate adaption was supposed to be more physiological. To evaluate its superiority, the DS (accelerometer [ACC] and minute ventilation [MV]) and normal sinus rate response were compared in a self-controlled way during exercise treadmill testing.

This self-controlled study was performed in atrioventricular block patients with normal sinus function who met the indications of pacemaker implant. Twenty-one patients came to the 1-month follow-up visit. Patients performed a treadmill test 1-month post implant while programmed in DDDR and sensor passive mode. For these patients, sensor response factors were left at default settings (ACC = 8, MV = 3) and sensor indicated rates (SIRs) for DS, ACC and MV sensor were retrieved from the pacemaker memories, along with measured sinus node (SN) rates from the beginning to 1-minute after the end of the treadmill test, and compared among study groups. Repeated measures analysis of variance and profile analysis, as well as variance analysis of randomized block designs, were used for statistical analysis.

Fifteen patients (15/21) were determined to be chronotropically competent. The mean differences between DS SIRs and intrinsic sinus rates during treadmill testing were smaller than those for ACC and MV sensor (mean difference between SIR and SN rate: ACC vs. SN, MV vs. SN, DS vs. SN, respectively, 34.84, 17.60, 16.15 beats/min), though no sensors could mimic sinus rates under the default settings for sensor response factor (ACC vs. SN P-adjusted < 0.001; MV vs. SN P-adjusted = 0.002; DS vs. SN P-adjusted = 0.005). However, both in the range of 1^st minute and first 3 minutes of exercise, only the DS SIR profile did not differ from sinus rates (P-adjusted = 0.09, 0.90, respectively).

The DS under default settings provides more physiological rate response during physical activity than the corresponding single sensors (ACC or MV sensor). Further study is needed to determine if individual optimization would further improve adaptive performance of the DS.

Von Hippel-Lindau (VHL) disease is a hereditary tumor disorder caused by mutations or deletions of the VHL gene. Few studies have documented the clinical phenotype and genetic basis of the occurrence of VHL disease in China. This study armed to present clinical and genetic analyses of VHL within a five-generation VHL family from Northwestern China, and summarize the VHL mutations and clinical characteristics of Chinese families with VHL according to previous studies.

An epidemiological investigation of family members was done to collect the general information. A retrospective study of clinical VHL cases was launched to collect the relative clinical data. Genetic linkage and haplotype analysis were used to make sure the linkage of VHL to disease in this family. The VHL gene screening was performed by directly analyzing DNA sequence output. At last, we summarized the VHL gene mutation in China by the literature review.

A five-generation North-western Chinese family afflicted with VHL disease was traced in this research. The family consisted of 38 living family members, of whom nine were affected. The individuals afflicted with VHL exhibited multi-organ tumors that included pheochromocytomas (8), central nervous system hemangioblastomas (3), pancreatic endocrine tumors (2), pancreatic cysts (3), renal cysts (4), and paragangliomas (2). A linkage analysis resulted in a high maximal LOD score of 8.26 (theta = 0.0) for the marker D3S1263, which is in the same chromosome region as VHL. Sequence analysis resulted in the identification of a functional C>T transition mutation (c. 499 C>T, p.R167W) located in exon 3 of the 167^th codon of VHL. All affected individuals shared this mutation, whereas the unaffected family members and an additional 100 unrelated healthy individuals did not. To date, 49 mutations have been associated with this disease in Chinese populations. The most frequent VHL mutations in China are p.S65 W, p.N78 S, p.R161Q and p.R167 W.

The results supported the notion that the genomic sequence that corresponds to the 167^th residue of VHL is a mutational hotspot. Further research is needed to clarify the molecular role of VHL in the development of organ-specific tumors.

The efficacy of montelukast (MONT), a cysteinyl leukotriene receptor antagonist, in nonasthmatic eosinophilic bronchitis (NAEB), especially its influence on cough associated life quality is still indefinite. We evaluated the efficacy of MONT combined with budesonide (BUD) as compared to BUD monotherapy in improving life quality, suppressing airway eosinophilia and cough remission in NAEB.

A prospective, open-labeled, multicenter, randomized controlled trial was conducted. Patients with NAEB (aged 18-75 years) were randomized to inhaled BUD (200 µg, bid) or BUD plus oral MONT (10 µg, qn) for 4 weeks. Leicester cough questionnaire (LCQ) life quality scores, cough visual analog scale (CVAS) scores, eosinophil differential ratio (Eos), and eosinophil cationic protein (ECP) in induced sputum were monitored and compared.

The control and MONT groups contained 33 and 32 patients, respectively, with similar baseline characteristics. Significant with-in group improvement in CVAS, LCQ scores, Eos, and ECP was observed in both groups during treatment. After 2-week treatment, add-on treatment of MONT was significantly more effective than BUD monotherapy for CVAS decrease and LCQ scores improvement (both P < 0.05). Similar results were seen at 4-week assessment (both P < 0.05). 4-week add-on therapy of MONT also resulted in a higher percentage of patients with normal sputum Eos (<2.5%) and greater decrease of ECP (both P < 0.05).

MONT combined with BUD was demonstrated cooperative effects in improvement of life quality, suppression of eosinophilic inflammation, and cough remission in patients with NAEB.

Herpes simplex keratitis (HSK) caused by herpes simplex virus 1 (HSV-1), which has high recurrent rate and incidence of severe vision loss, is the leading cause of infectious blindness in the world. The aim was to explore the clinical efficacy of oral ganciclovir (GCV) in the prevention of recurrent HSK.

A multicenter, prospective, randomized, single-blind, and controlled clinical trial was conducted from April 2010 to June 2013. One hundred seventy-three patients (173 eyes involved) who were diagnosed as recurrent HSK definitely, including stromal keratitis and corneal endotheliitis, were divided into three groups randomly: negative control (placebo) group was topically administered with 0.15% GCV ophthalmic gel, 4 times per day and 0.1% fluorometholone eye drops, 3 times per day until resolution of HSK; positive control acyclovir (ACV) group was topically adopted the same ophthalmic gel and eye drops and additionally received oral ACV 400 mg 5 times a day for 10 weeks and followed by 400 mg 2 times per day for 6 months; test GCV group was topically adopted the same treatment as negative control group and additionally received oral GCV 1000 mg 3 times per day for 8 weeks. The symptoms and signs were evaluated before and after the therapy 1^st week, 2^nd week and then followed up every 2 weeks until recovery. Furthermore, we followed up recurrence of HSK for every 3 months after recovery and then assessed the cure time, recurrent rate and adverse reactions.

One hundred and seventy-three patients were followed up 7–48 months (mean 32.1 ± 12.3 months), but 34 patients were failed to follow-up. The cure time was 12.1 ± 4.3, 11.9 ± 4.0 weeks in negative control (placebo) group and positive control ACV group respectively (P = 0.991), which was longer than that in test GCV group (8.6 ± 2.8 weeks) and there was a significant difference between test GCV group and negative control (placebo) group or positive control ACV group (P = 0.000). Furthermore, the recurrent rate was higher in negative control (placebo) group (47.3%) than that in positive control group ACV (26.7%) and test GCV group (17.2%), and there was a great significant difference among the three groups (P = 0.007), but there was no significant difference between positive control ACV group and test GCV group (P = 0.358). In addition, there was no obvious adverse reaction expect neutropenia (only one patient in test GCV group).

Short-term oral GCV could cure recurrent HSK and endotheliitis, shorten the course, reduce recurrent rate of HSK and have confirmed safety.

妊娠期糖尿病（GDM）早期被定义为“在妊娠期间首次识别的高血糖症”，最近被美国糖尿病协会（ADA）（2012）描述为在妊娠期间诊断的糖尿病，但不是明显的糖尿病。^[1]高血糖和不良妊娠结局研究（HAPO）表明，母体、胎儿和新生儿不良结局的风险随着母体血糖在24-28周持续增加，即使在以前认为正常的妊娠范围内。^[2]在审查了HAPO研究的结果后，许多国际糖尿病研究小组，包括国际糖尿病和妊娠研究小组协会和ADA已经采用了24-28周的75g口服葡萄糖耐量试验（OGTT）作为筛查和诊断测试，并定义了GDM诊断的新临界值。中国卫生部于2011年7月1日公布了与ADA标准相同的GDM标准。世界卫生组织（世卫组织）自1999年以来一直推荐具有不同临界值的75 g OGTT作为诊断测试，并于2013年改变了其建议。在中国香港和云南省，大多数医院采用了WHO 1999标准，然而，没有多中心和大样本的证据表明根据WHO新标准诊断的同一种族的GDM人群与根据旧标准诊断的人群相匹配，并且两个标准之间的一致性尚未报道。因此，我们进行了这项研究来分析中国孕妇的这两个标准。

结节性硬化症(TSC)是一种相对常见的常染色体显性遗传疾病，影响1/14,000-1/6000的西方人群。尽管记录了中国TSC患者的病例报告，但TSC在中国人群中的发病率仍然未知。^[1]TSC的主要临床特征包括癫痫发作、精神发育迟滞以及皮肤、脑、肺、心脏和肾脏等多个器官的错构瘤的发展。事实上，这种疾病几乎表现在每个器官中。^[2]TSC的两个致病基因，染色体9q34上的TSC1基因和染色体16p13上的TSC2基因，分别于1997年和1993年被鉴定。大约70%的TSC病例是再一次突变。^[3]中国TSC患者更容易出现TSC2错义和移码突变。在这里，我们记录了一个中国TSC家族，它是TSC2的新移码突变。

一名先前健康的47岁中国男性于2009年1月出现极度疲劳、发热和盗汗。发现肝肿大（可触及，右胁肋2 cm）和脾肿大（可触及，左胁肋2 cm），腋窝淋巴结肿大。实验室检查显示白细胞计数为39.8 × 10⁹/L，嗜酸性粒细胞52%（嗜酸性粒细胞绝对计数20.7 × 10⁹/L），血红蛋白水平14.9 g/dl，血小板计数50.0 × 10⁹/L。骨髓（BM）抽吸物显示细胞过多，被约22.0%的原始细胞占据；嗜酸性粒细胞占总细胞数的23.5%[图1a].这些原始细胞的流式细胞术证明CD13、CD33、CD34、CD117、CD14、CD15和人白细胞抗原-DR的表达，表明存在成髓细胞。对BM的细胞遗传学研究显示46，XY，t（8；13）（p11.2；q12.1）[15]/46，同上，-7，der（14），+Mar[5]核型[图1c].进行逆转录酶-聚合酶链反应（RT-PCR）以检测BCR/ABL,FIPIL1/PDGFRA,电话/PDGFRB都是负面的c-试剂盒和JAK2V617F突变。荧光原地确认使用双融合探针的杂交FGFR1基因重排[图1b]，该ZNF198-FGFR1融合试验通过RT-PCR进行ZNF198-和FGFR1-特异性引物（分别为5’-TCCCTGTGCCTGTG TATATCCC-3’和5’-CGGGAAGCTCATACTCAGAGAC-3’）并显示195 bp的特异性扩增产物[图1d].测序鉴定了外显子17的框内融合ZNF198外显子9FGFR1[图1e]，其指示8p11骨髓增生综合征（EMS，世界卫生组织[世卫组织]2008，骨髓和淋巴肿瘤伴FGFR1异常^[1]).在第5天开始伊马替尼（400 mg，每日一次）加urbason（40 mg，每日一次）治疗，开始治疗后约2周，WBC计数（30.43 × 10⁹/L）未见明显下降，血红蛋白和血小板计数水平逐渐降至8.6 g/dl和10.0 × 10⁹/L。因此，停止伊马替尼和urbason治疗。随后，患者接受AA（阿克拉霉素加阿糖胞苷）方案，对第一周期化疗有明显的初始反应：WBC和血小板计数恢复正常。然而，25天后，患者再次恶化，其WBC升至52.7 × 10⁹/L。BM研究显示，由于干水龙头导致抽吸不足。当时，进行了骨活检，发现细胞增多伴明显嗜酸性粒细胞增多。推荐并完成了大剂量阿糖胞苷治疗。尽管如此，患者对积极的化疗和支持治疗没有反应。他于2009年5月去世，即初步诊断后5个月。

视网膜母细胞瘤通常发生在5岁以下的儿童中。成人视网膜母细胞瘤是罕见的，诊断通常在相当晚期。我们报告了一例白色、升高、血管化的视网膜肿块和玻璃体植入被诊断为未分化视网膜母细胞瘤的病例。

致编者：56岁男性，呕血、黑便3小时入院。有餐后上腹痛病史6个月，无任何疾病。他的生命体征在正常范围内。体格检查正常，但直肠检查显示黑便。实验室检查显示无显著发现，止血参数也正常。