Volume 131 · Issue 13 · 2018

2004年，NETosis首次被报道为中性粒细胞杀死细菌的重要步骤。在NETosis过程中，中性粒细胞细胞外陷阱（NETs）被挤出到细胞外空间，其中含有用组蛋白和细胞内成分（包括中性粒细胞弹性蛋白酶（NE）、髓过氧化物酶（MPO）、高迁移率族蛋白B1（HMGB1）和蛋白酶3（PR3）装饰的去浓缩染色质的大网状结构。^[1]NETs的结构使中性粒细胞能够有效地捕获和杀死炎症部位的病原体。此外，越来越多的研究已经确定了自身免疫性疾病中存在NETs。NETs向宿主免疫系统递送多种自身抗原，诱导自身免疫应答，并直接释放损伤相关分子模式以放大炎症应答。因此，近年来，NETs通常被描述为在自身免疫性疾病的发病机制和发展中起着至关重要的作用。

Increased serum autoantibodies against interleukin-2 (anti-IL-2 autoantibodies) were reported in patients with systemic lupus erythematosus (SLE) and in patients receiving IL-2 therapy. This study aimed to explore the clinical relevance of serum anti-IL-2 autoantibodies and the interactions between low-dose IL-2 therapy and serum anti-IL-2 autoantibodies.

Serum samples were collected from 152 SLE patients and 100 age- and gender-matched healthy controls (HCs). Among them, 75 SLE patients were followed up for 10 weeks, and all of them were treated with corticosteroids, antimalarials, and/or immunosuppressants. Forty-six out of the 75 SLE patients received low-dose IL-2 therapy additionally. Clinical and laboratory parameters were collected at baseline and week 10. Serum anti-IL-2 autoantibodies were determined by enzyme-linked immunosorbent assay.

Compared with HCs, median levels and positive rates of serum anti-IL-2 autoantibodies were higher in SLE patients (32.58 [23.63, 45.23] arbitrary unit [AU] vs. 37.54 [27.88, 60.74] AU, P = 0.006, and 5.0% vs. 18.4%, P = 0.002, respectively). Compared to those without the corresponding disorders, serum anti-IL-2 autoantibody was increased in patients with alopecia (49.79 [36.06, 64.95] AU vs. 35.06 [25.40, 58.46] AU, P = 0.033), but it was decreased in those with lupus nephritis (31.71 [22.60, 43.25] AU vs. 44.15 [31.43, 68.52] AU, P = 0.001 ). Moreover, serum anti-IL-2 autoantibody was positively correlated with serum IgA (r = 0.229, P = 0.005), total IgG (r= 0.327, P < 0.001), and total IgM (r = 0.164, P = 0.050). Treatment with exogenous IL-2 was not significantly associated with serum anti-IL-2 autoantibody. In addition, no significant difference was found in serum anti-IL-2 autoantibody between responders and nonresponders to low-dose IL-2 therapy.

Serum anti-IL-2 autoantibody was increased and associated with disease severity in SLE. Exogenous low-dose IL-2 did not significantly induce anti-IL-2 autoantibody production.

Imbalance of interferon-gamma (IFN-γ), interleukin (IL)-4, and IL-17 producing by T cells is confirmed to contribute to the pathogenesis of systemic lupus erythematosus (SLE). Autophagy is now emerging as a core player in the development and the function of the immune system. Therefore, we investigated the autophagic behavior in IFN-γ-, IL-4-, and IL-17-producing T cells from patients with SLE.

Thirty patients with SLE and 25 healthy controls matched for gender and age were recruited between September 2016 and May 2017. The autophagic levels in IFN-γ⁺ T cells, IL-4⁺ T cells, and IL-17⁺ T cells from patients with newly diagnosed SLE and healthy controls were measured using flow cytometry. The plasma levels of IFN-γ were determined by enzyme-linked immunosorbent assay in SLE patients and healthy controls. Unpaired t-tests and the nonparametric Mann-Whitney U-test were used to compare data from patients with SLE and controls. Spearman’s rank correlation coefficient was applied for calculation of the correlation between parallel variables in single samples.

Our results showed increased percentage of autophagy in IFN-γ⁺ T cells from patients with SLE and healthy controls ([8.07 ± 2.72]% vs. [3.76 ± 1.67]%, t = 5.184, P < 0.001), but not in IL-4⁺ T cells or IL-17⁺ T cells (P > 0.05) as compared to healthy donors. Moreover, the plasma levels of IFN-γ in SLE patients were significantly higher than those in healthy controls ([68.9 ± 29.1] pg/ml vs. [24.7 ± 17.6] pg/ml, t = 5.430, P < 0.001). Moreover, in SLE patients, the percentage of autophagy in IFN-γ⁺ T cells was positively correlated with the plasma levels of IFN-γ (r = 0.344, P = 0.046), as well as the disease activity of patients with SLE (r = 0.379, P = 0.039).

The results indicate that autophagy in IFN-γ⁺ T cells from SLE patients is activated, which might contribute to the persistence of T cells producing IFN-γ, such as Th1 cells, and consequently result in the high plasma levels of IFN-γ, and then enhance the disease activity of SLE.

The previous study showed that mycophenolic acid (MPA) synergizing with lipopolysaccharide (LPS) promoted interleukin (IL)-1β release, but the mechanism is unclear. This study aimed to investigate the mechanism of MPA synergizing with LPS to induce IL-1β release.

Undiluted human blood cells, THP-1 human myeloid leukemia mononuclear cells (THP-1) cells, or monocytes were stimulated with LPS and treated with or without MPA, and the supernatant IL-1β was detected by enzyme-linked immunosorbent assay. The mRNA levels of IL-1β were detected by real-time quantitative polymerase chain reaction. The intracellular protein levels of nuclear factor kappa B (NF-κB) phospho-p65 (p-p65), precursor interleukin-1β (pro-IL-1β), NOD-like receptor pyrin domain containing-3 (NLRP3), and cysteine aspartic acid-specific protease-1 (caspase-1) p20 in THP-1 cell were measured by Western blot.

The MPA alone failed to induce IL-1β, whereas MPA synergized with LPS to increase IL-1β in a dose-dependent manner (685.00 ± 20.00 pg/ml in LPS + 5 μmol/L MPA group, P = 0.035; 742.00 ± 31.58 pg/ml in LPS + 25 μmol/L MPA group, P = 0.017; 1000.00 ± 65.59 pg/ml in LPS + 75 μmol/L MPA group, P = 0.024; versus 408.00 ± 35.50 pg/ml in LPS group). MPA alone has no effect on the IL-1β mRNA expression, LPS induced the expression of IL-1β mRNA 2761 fold, and LPS + MPA increased the IL-1β expression 3018 fold, which had the same effect with LPS group (P = 0.834). MPA did not affect the intracellular NF-κB p-p65 and pro-IL-1β protein levels but activated NLRP3 inflammasome. Ac-YVAD-cmk blocked the activation of caspase-1 and subsequently attenuated IL-1β secretion (181.00 ± 45.24 pg/ml in LPS + MPA+ YVAD group vs. 588.00 ± 41.99 pg/ml in LPS + MPA group, P = 0.014).

Taken together, MPA synergized with LPS to induce IL-1β release via the activation of caspase-1, rather than the enhanced production of pro-IL-1β. These findings suggested that patients immunosuppressed with mycophenolate mofetil may have overly activated caspase-1 during infection, which might contribute to a more sensitive host defense response to invading germs.

Pelvic exenteration (PE) for primary and recurrent cervical cancer has resulted in favorable survival outcomes, but there are controversies about specific prognosis factors, and up to now, there have been no published reports from China. This study aimed to share our experiences of PE, which were performed in a single institution.

From January 2009 to January 2016, 38 patients with recurrent or persistent cervical cancer were included in the study, and they were followed up until January 2017. Epidemiological and clinicopathological characteristics of patients were compared for survival outcomes in univariate and Cox hazard regression analysis.

There were thirty-one and seven patients with recurrent and persistent cervical cancer, respectively. The median age of patients was 45 years (range 29–65 years). Total, anterior, and posterior PE consisted of 52.6%, 28.9%, and 18.4% of cases, respectively. Early and late complications occurred in 21 (55.3%) patients and 15 (39.5%) patients, respectively. Two (5.3%) patients died due to complications related to surgeries within 3 months after PE. The median overall survival (OS) and disease-free survival (DFS) were 28.5 months (range 9–96 months) and 23 months (range 4–96 months), respectively, and 5-year OS and DFS were 48% and 40%, respectively. Cox hazard regression analysis showed that, the margin status of the incision and mesorectal lymph node status were independent risk factors for OS and DFS.

In our patients with recurrent and persistent cervical cancer, the practice of PE might achieve favorable survival outcomes.

ClinicalTrials.gov, NCT03291275; https://clinicaltrials.gov/ct2/show/NCT03291275?term=NCT03291275&rank=1.

Functional dyspepsia (FD) is a common upper gastrointestinal disorder worldwide, but the current treatments for FD are still unsatisfactory. The aims of this study were to investigate the efficacy and safety of Qi-Zhi-Wei-Tong granules in patients with postprandial distress syndrome (PDS)-predominant FD.

The study was conducted as a randomized, double-blinded, multicenter, placebo-controlled design in 197 patients with PDS. All participants received placebo treatment for 1 week. Patients whose total symptom score decreased by <50% after the placebo treatment were recruited into the 4-week treatment period, in which they were randomly assigned to be treated with either Qi-Zhi-Wei-Tong granules or placebo. The patients were then followed for 2 weeks without any treatment. Dyspeptic symptoms were scored at weeks 2 and 4 during the random treatment period and 2 weeks after the treatment. Anxiety and depression symptoms were also scored and compared.

(1) The total effective rates in the Qi-Zhi-Wei-Tong granules group at weeks 2 and 4 during the random treatment period and 2 weeks after treatment were all significantly higher than those in the placebo group (38.82% vs. 8.75%, P < 0.001; 69.14% vs. 16.25%, P < 0.001; 77.65% vs. 21.25%, P < 0.001). (2) The total dyspeptic symptoms scores in the Qi-Zhi-Wei-Tong granules group at weeks 2 and 4 and 2 weeks after treatment were significantly lower than those in the placebo group. (3) The severity and frequency of each dyspeptic symptom at weeks 2 and 4 and the follow-up period were all significantly lower than those in the placebo group. (4) The anxiety scores in the Qi-Zhi-Wei-Tong granules group were significantly lower than those in the placebo group. (5) Qi-Zhi-Wei-Tong granules did not have more adverse effects than the placebo.

Qi-Zhi-Wei-Tong granules offer significant symptomatic improvement in PDS with no more adverse effects than placebo.

https://clinicaltrials.gov/, NCT02460601.

Luteal support is a key to patients undergoing in vitro fertilization and embryo transfer (IVF-ET) with gonadotropin-releasing hormone (GnRH)-antagonist protocol. This study aimed to compare the effect between vaginal progesterone (VP) and intramuscular progesterone (IMP) with GnRH-antagonist protocol after IVF-ET.

A total of 1760 patients (18 years ≤ age ≤35 years) undergoing IVF-ET with GnRH-antagonist protocol were studied retrospectively between September 2014 and August 2015 in Peking University Third Hospital. In the patients, 1341 patients received VP (VP group) and 419 patients received IMP (IMP group) as luteal support. We compared clinical outcomes between these two groups. The primary objective of the study was the live birth rate. Measurement data between the two groups were conducted using independent samples t-test. The variables in line with non-normal distribution were expressed as median (p25 and p75) and were compared using nonparametric Mann–Whitney U-test.

Live birth rate in VP group was 38.55%, significantly higher than that in the IMP group, which was 30.79% (χ² = 8.287, P = 0.004). The clinical intrauterine pregnancy rate and implantation rate in VP group were also significantly higher than those in the IMP group (clinical intrauterine pregnancy rate 47.35% vs. 41.29%, χ² = 4.727, P = 0.030; implantation rate 30.99% vs. 25.26%, χ² = 14.546, P < 0.001). Any statistically significant differences in ectopic pregnancy and abortion rates between two groups were not observed.

Luteal support with VP had better clinical outcomes for young women undergoing IVF-ET with GnRH-antagonist protocol.

Trabeculectomy is the most efficient surgical treatment. Prevention failure of bleb cicatrix would lead to unsatisfactory postoperative intraocular pressure (IOP) controlling and unsatisfactory success rate. The aim of this study was to evaluate the 5-year outcomes of trabeculectomy with a cross-linked sodium hyaluronate gel implantation for Chinese glaucoma patients.

This is a prospective, case-controlled study. Patients who were to be applied first-time trabeculectomy in the Department of Ophthalmology of Peking University Third Hospital between 2010 and 2012 were included in the study. Totally, 60 eyes were randomly assigned to the trabeculectomy group (TA group) or the trabeculectomy with cross-linked sodium hyaluronate gel implantation group (TH group). Follow-up was finished at 1 week, 1 month, 3 months, 1 year, 3 years, and 5 years after the operation. The statistical index of demographic data, IOP, bleb shape, and any complications or medications or surgical procedures were recorded and assessed by SPSS 19.0 software through independent t-test, one-way analysis of variance (ANOVA) and Pearson’s Chi-square test, respectively.

The baseline IOP was comparable between the two groups (t = −1.00, P = 0.32) while the postoperative IOP was significantly lower in the TH group at 1, 3 and 5 years’ time points (P = 0.00, P = 0.01 and P = 0.01, respectively). According to the Indiana Bleb Appearance Grading Scale, the height and extent of bleb were better in the TH group at all follow-up time points (P < 0.05), however, the comparison of bleb vascularity showed no statistical difference (P > 0.05). TA group had a higher percentage of complications (13% vs. 3%) compared to TH group; however, there was no statistical difference in the comparison of each statistical item (P > 0.05, respectively). The complete success at 5 years was higher in the TH group than that in the TA group (78% vs. 54%, P = 0.03).

Our results suggested that implantation of cross-linked sodium hyaluronate gel with trabeculectomy was more efficient and would improve the prognosis of glaucoma patients.

Myoclonic epilepsy with ragged red fibers (MERRF) syndrome is characterized by myoclonus, generalized epilepsy, cerebellar ataxia, and ragged red fibers (RRFs) in the muscle. T-to-C transition at nucleotide position 14709 in the mitochondrial tRNA glutamic acid (tRNA^Glu) gene has previously been associated with maternally inherited diabetes and deafness. However, the association between MERRF and mitochondrial T14709C mutation (m.T14709C) has never been reported before.

Clinical information of a 17-year-old patient was collected; muscle biopsy and next-generation sequencing (NGS) of whole mitochondrial and neuromuscular disease panel were then conducted. Finally, sanger sequencing was carried out to confirm the mutations.

The patient presented a typical MERRF phenotype with muscle weakness, epileptic seizure, clonic episodes, cerebellar ataxia, and spinal scoliosis. Muscle biopsy showed RRFs which indicated abnormal mitochondrial functions. NGS of whole mitochondrial gene revealed m.T14709C mutation, confirmed by Sanger sequencing.

We present a sporadic patient with typical MERRF presentation carrying the mutation of m.T14709C, which expanded the spectrum of m.T14709C.

Progressive myoclonus epilepsies (PMEs) comprise a group of rare genetic disorders characterized by action myoclonus, epileptic seizures, and ataxia with progressive neurologic decline. Due to clinical and genetic heterogeneity of PMEs, it is difficult to decide which genes are affected. The aim of this study was to report an action myoclonus with or without renal failure syndrome (EPM4) family and summarize the clinical and genetic characteristics of all reported EPM4 patients.

In the present study, targeted next-generation sequencing (NGS) was applied to screen causative genes in a Chinese PME family. The candidate variant was further confirmed by cosegregation analysis and further functional analysis, including the reverse transcription polymerase chain reaction and Western blot of the proband’s muscle. Moreover, literature data on the clinical and mutational features of all reported EPM4 patients were reviewed.

The gene analysis revealed a novel homozygous splicing mutation (c.995-1G>A) of the SCARB2 gene in two brothers. Further functional analysis revealed that this mutation led to loss function of the SCARB2 protein. The classification of the candidate variant, according to the American College of Medical Genetics and Genomics standards and guidelines and functional analysis, was pathogenic. Therefore, these two brothers were finally diagnostically confirmed as EPM4.

These present results suggest the potential for targeted NGS to conduct a more rapid and precise diagnosis for PME patients. A literature review revealed that mutations in the different functional domains of SCARB2 appear to be associated with the phenotype of EPM4.

Measuring total serum calcium is important for the diagnosis of diseases. Currently, results from commercial kits for calcium measurement are variable. Generally, the performance of serum calcium measurements is monitored by external quality assessment (EQA) or proficiency testing schemes. However, the commutability of the EQA samples and calibrators is often unknown, which limits the effectiveness of EQA schemes. The aim of this study was to evaluate the bias of serum calcium measurements and the commutability of processed materials.

Inductively coupled plasma mass spectrometry was applied as a comparative method, and 14 routine methods were chosen as test methods. Forty-eight serum samples from individual patients and 25 processed materials were quantified. A scatter plot was generated from patient samples, and 95% prediction intervals were calculated to evaluate the commutability of the processed materials and measurement bias at three concentration levels was used to determine the accuracy of routine assays.

All assays showed high precision (total coefficient of variation [CV] <2.26%) and correlation coefficients (r > 0.99). For all assays, the mean bias for the 48 patient samples ranged from −0.13 mmol/L to 0.00 mmol/L (−5.61–0.01%), and the ranges for the three concentrations were −0.10–0.04 mmol/L (−5.71–2.35%), −0.14–−0.01 mmol/L (−5.80–−0.30%), and −0.19–0.04 mmol/L (−6.24–1.22%). The EQA samples, calibrators, and animal sera exhibited matrix effects in some assays; human serum pools were commutable in all assays; certificate reference materials were commutable in most assays, and only GBW09152 exhibited a matrix effect in one assay; and aqueous reference materials exhibited matrix effects in most assays.

Biases for most assays were within the acceptable range, although the accuracy of some assays needs improvement. Human serum pools prepared from patient samples were commutable, and the other tested materials exhibited a matrix effect.

Placebo was defined as any therapy that is used for its nonspecific psychological and physiologic effect but has no specific pharmacologic impact on the condition being treated. Besides medication therapies, studies have found that the optimal dietary approach as well as physical activity and education are useful to control hyperglycemia in patients with type 2 diabetes (T2DM). The aim of this study was to evaluate the placebo effects of antidiabetic therapies inAsian and Caucasian T2DM patients and make a comparison between the two ethnicities. Methods: A search using the MEDLINE database, EMBASE, and Cochrane Database was performed, from when recording began until December 2016. The main concepts searched in English were sulfonylurea (SU); alpha glucosidase inhibitors (AGI); metformin (MET); thiazolidinediones (TZD); dipeptidyl peptidase-4 inhibitors (DPP-4i); sodium-glucose cotransporter 2 inhibitors (SGLT2i); glucagon-like peptide-1 receptor agonist (GLP-1RA); type 2 diabetes (T2DM); placebo controlled; and randomized controlled trials. Using the Cochrane instrument, we evaluated the adequacy of randomization, allocation concealment procedures, and blinding.

This study included 63 studies with a total of 7096 Asian patients involved and 262 studies with a total of 27,477 Caucasian patients involved. In Caucasian population, the use of placebo led to significant reductions of glycosylated hemoglobin (HbA1c), −0.683% (P = 0.008) in SU monotherapy treatment, −0.193% (P = 0.001) in DPP-4i treatment, and −0.230% (P < 0.001) in SGLT2i treatment, respectively. In Asian population, the use of placebo resulted in significant decreases of HbA1c, −0.162% (P = 0.012) in DPP-4i treatment and −0.269% (P = 0.028) in GLP-1RA add-on therapy, respectively. The placebo also significantly reduced body weight. In Caucasian population, placebo use resulted in 0.833 kg (P = 0.006) weight loss by SU treatment and 0.953 kg (P = 0.006) weight loss by GLP-1RA treatment. In Asian population, the placebo led to a weight change of 0.612 kg (P < 0.001) by GLP-1RA analog treatment. The changes of HbA1c and weight due to the placebo effect in other treatments were not significant in both Asian and Caucasian population. Comparisons of the placebo effect on HbA1c change and weight change in each treatment group indicated that no significant difference was found between Asian and Caucasian population.

The overall differences of the placebo effect on HbA1c changes as well as on body weight changes were not significant between Asian and Caucasian T2DM patients. The placebo effect on HbA1c changes and weight changes was not associated with baseline age, gender, baseline body mass index, baseline HbA1c, duration of diabetes, or study duration.

致死性家族性失眠症(FFI)是一种严重而罕见的朊病毒疾病，最早由Lugaresi报道等人。1986年。^[1]FFI的早期诊断对于患者及其亲属的早期和充分咨询可能很重要，也涉及遗传风险，并且可能对于治疗研究也很重要。然而，由于临床特征的异质性、诊断试验的低敏感性和缺乏家族史，FFI的诊断可能很困难。本研究的目的是根据我们的研究和专家共识，制定FFI的临床方案和诊断标准。

Alzheimer’s disease (AD) is a kind of chronic degenerative disease of the central nervous system, characteristics of cognitive dysfunction, and behavioral disability. The pathological changes include the formation of senile plaques-containing beta-amyloid (Aβ), neurofibrillary tangles (NFTs), loss of neurons, and synapses. So far, the pathogenesis of AD is still unclear. This study was aimed to review the major pathogenesis of AD-related to the published AD studies in recent 20 years.

The author retrieved information from the PubMed database up to January 2018, using various search terms and their combinations, including AD, Aβ, NFTs, pathogenesis, and genetic mutation.

The author included data from peer-reviewed journals printed in English and Chinese on pathophysiological factors in AD. He organized these informations to explain the possible pathogenesis in AD.

There are many amounts of data supporting the view that AD pathogenesis so far there mainly are Aβ toxicity, tau protein, gene mutation, synaptic damages, intermediate neurons and network abnormalities, changes in mitochondrial function, chemokines, etc., Its nosogenesis may be involved in multiple theories and involved in multiple molecular signaling pathways, including Aβ, tau protein, and synaptic anomaly; mutual relationship between the mechanisms urge jointly neuronal degeneration.

This review highlights the research advances in the pathogenesis of AD. Future research has needed to fully disclose the association between multiple pathogenesis at the same time to interdict multiple signaling pathways, etc.

致编者：对于拒绝或不适合手术的患者，高危经皮冠状动脉介入治疗（PCI）仍然是一种可行的血运重建策略。^[1]体外膜肺氧合（ECMO）可以引导血液从体内流出，进行氧合，然后回流，从而完全或部分替代心肺的功能，增加功能恢复的可能性。^[2]ECMO支持的选择性PCI对于冠状动脉旁路移植术（CABG）风险非常高的患者是一种可行的替代方案。^[3]先前的一项研究发现，ECMO辅助PCI治疗急性心肌梗死合并深度心源性休克患者可能提高了30天和1年生存率，^[4]我们认为ECMO是高危病例血流动力学支持的可行模式。

编辑：戈勒姆-斯托特综合征(GSS)是一种病因不明的罕见疾病。GSS表现为一个或多个骨骼的溶解性破坏，其还可能包括胸膜、腹膜中的乳糜性积液和内脏器官如脾脏中的囊性病变。在此，我们报告了一例股骨Gorham-Stout综合征伴乳糜胸和乳糜腹膜的简要病例。迄今为止，还没有记录到GSS以这种方式呈现的报告。我们目前的病例强调了Gorham-Stout综合征的临床、放射学和组织学特征以及适当的治疗。

致编者：一名13岁女孩出现腹痛恶心约1年，伴有上腹部不适。内窥镜干预显示有一个突出到胃腔中的肿块[图1a].活检显示胃粘膜正常。计算机断层扫描（CT）显示胰尾、脾和胃之间约2 cm的肿块。CT血管造影显示前3例动脉瘤扩张27 mm^研发脾中动脉[图1b].