2015年 · 第128卷第01期

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.

Gestational diabetes mellitus (GDM) was earlier defined as "hyperglycemia first recognized during pregnancy" and has more recently been described by American Diabetes Association (ADA) (2012) as diabetes diagnosed during pregnancy that is not clearly overt diabetes.^[1]The hyperglycemia and adverse pregnancy outcomes study (HAPO) demonstrated that the risk of adverse maternal, fetal, and neonatal outcomes continuously increase as a function of maternal glycemia at 24−28 weeks, even within ranges previously considered normal for pregnancy.^[2]After reviewing the results of the HAPO study, many international diabetes study groups, including the International Association of Diabetes and Pregnancy Study Groups and ADA have adopted the 75 g oral glucose tolerance test (OGTT) at 24−28 weeks as a screening and diagnostic test and defined new cut-off values for GDM diagnosis. The Ministry of Health of China published the criteria for GDM, that is the same as the ADA criteria on July 1, 2011. World Health Organization (WHO) has recommended the 75 g OGTT with different cut-off values as a diagnostic test since 1999, changed its recommendation on 2013. In Hongkong and Yunnan province in China, most hospital adopted the WHO 1999 criteria, nevertheless, there is no evidence of multicenter and large sample to show that the GDM population within the same ethnic group diagnosed by the new WHO criteria matches those diagnosed by the old one and consistency between the two criteria has not been reported. Thus, we conducted this study to analyze the two criteria in Chinese pregnant women.

Tuberous sclerosis complex (TSC) is a relatively common autosomal dominant genetic disorder affecting 1/14,000–1/6000 Western populations. The incidence of TSC in Chinese population is still unknown although case reports of Chinese TSC patients were documented.^[1]The main clinical features of TSC include seizures, mental retardation, and the development of hamartomas in multiple organs such as the skin, brain, lung, heart, and kidney. Indeed, the disease virtually manifests in every organ.^[2]Two causative genes for TSC, TSC1 gene on chromosome 9q34 and TSC2 gene on chromosome16p13, have been identified in 1997 and 1993 respectively. Approximately, 70% of cases of TSC arede novomutations.^[3]Chinese TSC patients are more likely to have TSC2 missense and frame shift mutations. Here, we record one Chinese TSC family and it is novel frame shift mutation of TSC2.

A previously healthy 47-year-old Chinese man presented in January 2009 with extreme fatigue, fever, and night sweats. Hepatomegaly (palpable, 2 cm in the right hypochondrium) and splenomegaly (palpable, 2 cm in the left hypochondrium) were identified, and axillary lymph nodes were swollen. A laboratory investigation showed a white blood cell (WBC) count of 39.8 × 10⁹/L with eosinophils 52% (absolute eosinophil count of 20.7 × 10⁹/L), hemoglobin level of 14.9 g/dl and platelet count of 50.0 × 10⁹/L. Bone marrow (BM) aspirate revealed hypercellular and occupied by approximately 22.0% blasts; eosinophils comprised 23.5% of total cellularity [Figure 1a]. Flow cytometry of these blast cells demonstrated expression of CD13, CD33, CD34, CD117, CD14, CD15, and human leukocyte antigen-DR indicating that myeloblasts were presented. Cytogenetic studies on BM showed a 46, XY, t (8;13)(p11.2;q12.1)[15]/46, idem,-7, der (14), +Mar[5] karyotype [Figure 1c]. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to detect gene rearrangements ofBCR/ABL,FIPIL1/PDGFRA,TEL/PDGFRBwere all negative as well asc-KITandJAK2V617Fmutations. Fluorescencein situhybridization using a dual-fusion probe confirmedFGFR1gene rearrangement [Figure 1b], theZNF198-FGFR1fusion test was done by RT-PCR usingZNF198-andFGFR1-specific primers (5′-TCCCTGTGCCTGTG TATATCCC-3′ and 5′-CGGGAAGCTCATACTCAGAGAC-3′, respectively) and showed a specific amplification product of 195 bp [Figure 1d]. Sequencing identified an in-frame fusion of exon 17 ofZNF198to exon 9 ofFGFR1[Figure 1e], which was indicative of 8p11 myeloproliferative syndrome (EMS, World Health Organization [WHO] 2008, myeloid and lymphoid neoplasms withFGFR1abnormalities^[1]). Treatment was started with imatinib (400 mg once daily) plus urbason (40 mg once daily) at day 5, about 2 weeks after initiating treatment, WBC count (30.43 × 10⁹/L) did not achieve a significant decrease and the level of hemoglobin and platelet count gradually reduced to 8.6 g/dl and 10.0 × 10⁹/L, respectively. Therefore, imatinib and urbason therapy was stopped. Subsequently, the patient received AA (aclacinomycin plus cytarabine) regimen and had a marked initial response to the first cycle of chemotherapy: The WBC and platelet count returned to normal. However, 25 days later, the patient again developed worse, his WBC rose to 52.7 × 10⁹/L. BM study revealed inadequate aspirate due to dry tap. At the time, a bone biopsy was performed and revealed a hypercellular with marked hypereosinophilia. High-dose cytarabine therapy was recommended and completed. Nonetheless, the patient failed to respond to aggressive chemotherapy and supportive treatment. He died in May 2009, 5 months after the initial diagnosis.

Retinoblastoma usually presents in children younger than 5 years. Adult retinoblastoma is rare, and diagnosis is usually made at a fairly advanced stage. We report a case with whitish, elevated, vascularized retinal mass and vitreous seeding diagnosed as undifferentiated retinoblastoma.

To the Editor: A 56-year-old man was admitted to our hospital with hematemesis and melena for 3 hours. He had also a history of upper abdominal pain after meal for 6 months and no any diseases. His vital signs were within normal limits. Physical findings were normal, but rectal examination revealed melena. Laboratory tests showed unremarkable findings and also hemostasis parameters were normal.