Volume 135 · Issue 15 · 2022

脂肪干细胞（ADSCs）已有报道具有多向分化潜能，并能促进细胞增殖生长、神经再生功能，成为一种很有前途的创伤修复治疗方案。源自ADSCs的外来体（ADSCs-Exos）具有优异的组织修复功能，包括高水平的血管内皮生长因子A、成纤维细胞生长因子2、肝细胞生长因子、血小板衍生生长因子亚基BB和其他重要的伤口愈合因子。^[1]补充图1，http://links.lww.com/CM9/A828是外泌体形成和释放模型的简化图。

肥胖症已经成为一种全球性流行病，在过去50年中，肥胖症的患病率已经增加到大流行水平。^[1]据世界卫生组织（WHO）统计，全球超重和肥胖成年人>21亿，其中超重15亿，肥胖6.4亿。^[2]据预测，世界成年人口中有57.8%（33亿人）的体重指数将达到25公斤/米²到2030年或更高，这在发达国家和发展中国家都是一个巨大的挑战。^[3,4]在美国，成人肥胖和重度肥胖患病率持续上升；据估计，到2030年，近二分之一的成年人将患有肥胖症，近四分之一的成年人预计患有严重肥胖症。^[5]据报道，≥18岁居民超重和肥胖发生率分别为34.3%和16.4%，6~17岁儿童和青少年分别为11.1%和7.9%，6岁以下儿童分别为6.8%和3.6%。^[6]儿童和青少年超重和肥胖发病率的问题以惊人的速度增长，对整个社会构成了巨大的威胁。^[7]因此，迫切需要找到控制肥胖增长的有效手段，在科学研究和公共政策两方面探索新途径。

Nasal insertion is the preferred method for non-intubated patients in flexible bronchoscopy; however, the relatively narrow nasal cavity results in difficulties related to bronchoscope insertion. This study aimed to investigate whether pre-operative nasal probe tests could reduce the time to pass the glottis, improve the first-pass success rate and patients’ tolerance, and reduce postoperative bleeding.

This three-arm prospective randomized controlled trial was conducted in a tertiary hospital between May and October 2020. Three hundred patients requiring diagnosis and treatment using flexible bronchoscopy were randomly allocated to three groups: control group, simple cotton bud detection group (CD group), and adrenaline + lidocaine detection group (AD group). The primary outcome was the time to pass the glottis. Secondary outcomes included the first-pass success rate, the patients’ tolerance scores, and post-operative bleeding. One-way analysis of variance, Kruskal-Wallis H test, Chi-squared test, Fisher’s exact test, and Bonferroni’s multiple comparison tests were used in this study.

In total, 189 men and 111 women were enrolled in this study, with a mean age of 55.72 ± 12.86 years. The insertion time was significantly shorter in the AD group than in the control group (18.00 s [12.00–26.50 s] vs. 24.00 s [14.50–45.50 s], P = 0.005). Both the AD (99% vs. 83%, χ² = 15.62, P < 0.001) and CD groups (94% vs. 83%, χ² = 5.94, P = 0.015) had a significantly higher first-pass success rate than the control group. Compared with the control group, post-operative bleeding (1% vs. 13%, χ² = 11.06, P < 0.001) was significantly lower in the AD group. However, no significant difference was found in the patients’ tolerance scores.

Pre-operative nasal cavity probe tests especially with adrenaline and lidocaine during flexible bronchoscopy can significantly reduce the time to pass the glottis, improve the first-pass success rate, and reduce post-operative nasal bleeding. Pre-operative nasal probe tests are recommended as a time-saving procedure for patients undergoing flexible bronchoscopy.

Chinese Clinical Trial Registry (ChiCTR), ChiCTR2000032668; http://www.chictr.org.cn/showprojen.aspx?proj=53321.

Feeding intolerance (FI) among intensive care unit (ICU) patients undergoing early continuous enteral nutrition (EN) is related to poor outcomes. This study aimed to explore the prevalence and risk factors of FI in ICU patients.

We retrospectively enrolled 1057 patients who received early continuous EN via a nasogastric tube between January 2014 and August 2019. The prevalence of FI during the first 7 days of ICU stay was calculated, and the risk factors were investigated using multivariate logistic regression analysis.

The prevalence of FI during the first 7 days of ICU stay was 10.95%. FI occurred in 159 of 1057 (15.04%) patients on ICU day 2, 114 of 977 (11.67%) patients on ICU day 3, and 86 of 715 (12.03%) patients on ICU day 7. Mechanical ventilation (MV) (odds ratio [OR]: 1.928, 95% confidence interval [CI]: 1.064–3.493, P = 0.03) was an independent risk factor for FI defined by a gastric residual volume (GRV) of 200 mL and/or vomiting, and acute renal failure (OR: 3.445, 95% CI: 1.115–10.707, P = 0.032) was an independent risk factor of FI defined by a GRV of 500 mL and/or vomiting. Continuous renal replacement therapy (CRRT) was an independent predictor regardless of the FI defined by a GRV of 200 mL (OR: 2.064, 95% CI: 1.233–3.456, P = 0.006) or 500 mL (OR: 6.199, 95% CI: 2.108–18.228, P = 0.001) in the ICU patients.

FI occurs frequently in early ICU days, especially in patients receiving MV and CRRT. However, further investigation of a consensus definition of FI and risk factors is still warranted in future studies.

Previous evidence suggests inflammation may be a double-edged sword with cancer-promoting and cancer suppressing function. In this study, we explore the impact of local and systemic inflammation on cancer growth.

Female BALB/C mice were subcutaneously implanted with foreign body (plastic plates) to build up a local inflammation and intraperitoneally injected with PolyIC or lipopolysaccharides (LPS) to build up a systemic inflammation, followed by subcutaneous injection of 5 × 10⁵ colon cancer cells. Immunohistochemistry and enzyme linked immunosorbent assay were utilized to detect the Ki67 and interleukin (IL) 6, IL-1β, and monocyte chemoattractant protein-1 expression in the tumor tissues and serum, respectively. The distributions of immune cells and expression of toll-like receptors (TLRs) were evaluated by flow cytometry (FCM) and quantitative real time-polymerase chain reaction.

The results showed that local inflammation induced by foreign body implantation suppressed tumor growth with decreased tumor weight (P = 0.001), volume (P = 0.004) and Ki67 index (P < 0.001). Compared with the control group, myeloid-derived suppressive cells sharply decreased (P = 0.040), while CD4⁺ T cells slightly increased in the tumor tissues of the group of foreign body-induced local inflammation (P = 0.035). Moreover, the number of M1 macrophages (P = 0.040) and expression of TLRs, especially TLR3 (P < 0.001) and TLR4 (P < 0.001), were significantly up-regulated in the foreign body group. Contrarily, tumor growth was significantly promoted in LPS or PolyIC-induced systemic inflammation (P = 0.009 and 0.006). FCM results showed M1 type macrophages (P = 0.017 and 0.006) and CD8⁺ T cells (P = 0.031 and 0.023) were decreased, while M2 type macrophages (P = 0.002 and 0.007) were significantly increased in tumor microenvironment of LPS or PolyIC-induced systemic inflammation group. In addition, the decreased expression of TLRs was detected in LPS or PolyIC group.

The foreign body-induced local inflammation inhibited tumor growth, while LPS or PolyIC-induced systemic inflammation promoted tumor growth. The results suggested that the different outcomes of tumor growth might be attributed to the infiltration of anti-tumor or pro-tumor immune cells, especially M1 or M2 type macrophages into tumor microenvironment.

Head and neck cancers (HNCs) are a heterogeneous group of tumors that progress owing to varied enviromental and genetic risk factors. Viral infections are threatening and adept at altering the expression of cellular transcription factors such as nuclear factor kappa B (NF-κB) and deregulation of other cellular proteins like NF kappa B inhibitor alpha (IκBα). The present study was conducted to detect high-risk genotypes of human papillomavirus (HPV) and protein expression of NF-κB signaling pathway in HNC patients with HPV infection.

For HPV detection, genomic DNA from 152 HNC tumors was extracted formalin-fixed paraffin-embedded tissue DNA kit. For genotyping, polymerase chain reaction (PCR) using a general primer, HPV type-specific primers and agarose gel electrophoresis were performed. Immunohistochemistry (IHC) was also performed on 4-μm thick tissue sections using HPV E6 monoclonal antibody. Protein expression analysis of NF-κB signaling pathway including p50, p65, and IκBα was performed using IHC.

PCR analysis showed that 24.3% (37/152) of HNC cases were HPV positive. Among HPV positive, 86.5% (32/37) were tobacco users, while among HPV negative, 66.9% (77/115) were tobacco users. A significant association of HPV positivity and tobacco user was observed by univariate analysis [P < 0.01; odds ratio (OR): 0.310, 95% confidence interval (CI): 0.110 to 0.870]. More HPV positive patients were with poor oral hygiene (78.3%) when compared with patients with good oral hygiene (21.6%) [P < 0.03, OR: 2.440, 95% CI: 1.650 to 3.600]. The results of the logistic regression analysis showed that age, tobacco use and oral hygiene are significant predictors (P < 0.02). PCR and IHC staining results confirmed that HPV16 was predominant among HNC cases (64.8%) when compared with HPV18 (35.2%). Expression of NF-κB proteins (p50, p65, and IκBα inhibitor) were also observed in HPV and non-HPV infected HNC tissues. IHC expression of p50, and p65 showed nuclear staining, while IκBα inhibitor showed cytoplasmic staining. Protein expression in HPV cases was higher as compared to HPV naive cases (P < 0.05).

From the study, it can be established that the use of tobacco, oral hygiene, and HPV infection may be synergistically involved in modulating the expression of NF-κB signaling pathway for the development and progression of HNC in the Pakistani population.

Coronary artery disease (CAD) is the commonest cause of heart failure (HF), whereas pulmonary hypertension (PH) has not been established or reported in this patient population. Therefore, we assessed the prevalence, risk factors, and survival in CAD-associated HF (CAD-HF) complicated with PH.

Symptomatic CAD-HF patients were continuously enrolled in this prospective, multicenter registry study. Echocardiography, coronary arteriography, left and right heart catheterization (RHC), and other baseline clinical data were recorded. Patients were followed up and their survival was recorded.

One hundred and eighty-two CAD-HF patients were enrolled, including 142 with HF with a preserved ejection fraction (heart failure with preserved ejection fraction [HFpEF]; left ventricular ejection fraction [LVEF] ≥50%) and 40 with a reduced ejection fraction (heart failure with reduced ejection fraction [HFrEF]; LVEF < 50%). PH was diagnosed with RHC in 77.5% of patients. Patients with PH showed worse hemodynamic parameters and higher mortality. HFrEF-PH patients had worse survival than HFpEF-PH patients. CAD-HF patients with an enlarged left ventricular end-diastolic diameter and reduced hemoglobin were at higher risk of PH. Nitrate treatment reduced the risk of PH. Elevated creatinine and mean pulmonary arterial pressure (mPAP), diastolic pressure gradient (DPG) ≥7 mmHg, and previous myocardial infarction (MI) entailed a higher risk of mortality in CAD-HF patients with PH.

PH is common in CAD-HF and worsens the hemodynamics and survival in these patients. Left ventricle enlargement and anemia increase the risk of PH in CAD-HF. Patients may benefit from nitrate medications. Renal impairment, elevated mPAP, DPG ≥7 mmHg, and previous MI are strong predictors of mortality in CAD-HF-PH patients.

ClinicalTrials.gov, NCT02164526.

Excessive exposure to fluoride can reduce intelligence. Methylenetetrahydrofolate dehydrogenase, cyclohydrolase, and formyltetrahydrofolate synthetase 1 (MTHFD1) polymorphisms have important roles in neurodevelopment. However, the association of MTHFD1 polymorphisms with children’s intelligence changes in endemic fluorosis areas has been rarely explored.

A cross-sectional study was conducted in four randomly selected primary schools in Tongxu County, Henan Province, from April to May in 2017. A total of 694 children aged 8 to 12 years were included in the study with the recruitment by the cluster sampling method. Urinary fluoride (UF) and urinary creatinine were separately determined using the fluoride ion-selective electrode and creatinine assay kit. Children were classified as the high fluoride group and control group according to the median of urinary creatinine-adjusted urinary fluoride (UF_Cr) level. Four loci of MTHFD1 were genotyped, and the Combined Raven’s Test was used to evaluate children’s intelligence quotient (IQ). Generalized linear model and multinomial logistic regression model were performed to analyze the associations between children’s UF_Cr level, MTHFD1 polymorphisms, and intelligence. The general linear model was used to explore the effects of gene-environment and gene-gene interaction on intelligence.

In the high fluoride group, children’s IQ scores decreased by 2.502 when the UF_Cr level increased by 1.0 mg/L (β= –2.502, 95% confidence interval [CI]: –4.411, –0.593), and the possibility for having "excellent" intelligence decreased by 46.3% (odds ratio = 0.537, 95% CI: 0.290, 0.994). Children with the GG genotype showed increased IQ scores than those with the AA genotype of rs11627387 locus in the high fluoride group (P < 0.05). Interactions between fluoride exposure and MTHFD1 polymorphisms on intelligence were observed (Pinteraction < 0.05).

Our findings suggest that excessive fluoride exposure may have adverse effects on children’s intelligence, and changes in children’s intelligence may be associated with the interaction between fluoride and MTHFD1 polymorphisms.

早些时候，腹疝的主要手术治疗是开放的亚层修补术和腹腔镜腹膜内高嵌补片（Lap-IPOM）修补术。Sublay是一种有效且安全的平面。^[1]最近，一些外科医生成功地将开放式亚基修复转移到内窥镜亚基修复（ESR），这可能会避免开放手术后的伤口事件以及Lap-IPOM修复的腹内损伤和网片并发症的潜在风险。^[1,2,3]

致编辑：严重急性呼吸综合征冠状病毒2（新型冠状病毒）是导致冠状病毒疾病2019（新冠肺炎）的病毒。^[1]作为冠状病毒中一个新的进化分支，新型冠状病毒包含约29.8千碱基，与新型冠状病毒具有79.2%的同一性。^[2]作为SARS-CoV-1的继承者，新型冠状病毒与SARS-CoV-1有着高度相似的序列和行为模式。^[3]最近的研究发现，新型冠状病毒编码18至22 nt的小病毒RNA（svRNAs），这些RNA不依赖于RNA酶III、细胞类型和宿主物种，但依赖于病毒复制的程度。^[3]有证据支持svRNAs可以从细胞质RNA病毒产生，与病毒致病性相关。^[3]如新型冠状病毒所示，抑制一种名为svRNA-N的svRNAs减少体内肺部病理学和炎症。^[4]我们验证了两种新型冠状病毒编码的小RNA的存在，并研究了它们在人支气管上皮细胞系（16HBE）中成熟过程中的促炎作用，这可能为新冠肺炎的发病机制和可能的治疗方案提供新的见解。

致编辑：食管鳞状细胞癌（ESCC）是全球第七大常见恶性肿瘤。^[1]迫切需要寻找敏感和特异的生物标志物来改善ESCC的诊断和预后。^[2]肿瘤特异性长非编码RNA（lncRNA）似乎是诊断和治疗癌症的潜在生物标志物。^[3]我们之前的研究对ESCC进行了数据挖掘分析，并从基因表达综合数据库（GEO，https：//www.ncbi.nlm.nih.gov/sites/GDSbrowser）中鉴定了失调的lncRNAs。^[4]结果表明，lncRNA浆细胞瘤变异易位1（PVT1）基因表达在ESCC肿瘤组织中显著上调。在本研究中，我们分析了使用PVT1作为肿瘤分子标志物的可行性，并讨论了其潜在的临床应用。

致编辑：系统性红斑狼疮（SLE）是一种原因不明的慢性自身免疫性疾病，可影响身体的任何器官。人乳头瘤病毒（HPV）感染与SLE患者宫颈发育不良和癌症的发展相关。HPV疫苗可有效预防HPV感染及后续HPV相关疾病。HPV疫苗接种对SLE患者是有效的、免疫原性的和安全的。^[1]然而，HPV疫苗接种后SLE发病的病例报告引起了人们对HPV疫苗安全性的担忧。^[1,2,3]

致编辑：过敏性哮喘和过敏性鼻炎（AR）是常同时发生的常见病。大约80%的过敏性哮喘患有AR症状，因为这两种疾病具有共同的免疫病理机制。致敏和接触过敏原是诱发和加重过敏性气道疾病如过敏性哮喘和AR的危险因素。随着气候变化，过敏原在不同季节的分布变得非常不均匀。因此，鉴定在不同季节和不同人群亚群中流行的特定过敏原将有助于制定有助于预防和治疗呼吸道过敏性疾病（包括过敏性哮喘和AR）的策略。本研究的主要目的是调查在不同季节首次到医院就诊的有或没有AR的过敏性哮喘患者中吸入性过敏原的分布是否具有季节特异性。

致编辑：左心室舒张功能障碍（LVDD）是自身免疫性疾病（AD）的一种未被识别的亚临床表现，预后较差。升高的血清尿酸（SUA）作为促炎因子，与普通人群以及患有心脏病的人群中的心脏功能变化相关；然而，从未在AD患者中进行过研究。因此，我们在大量广谱AD患者人群中进行了这项回顾性研究，以探讨LVDD的负担及其与SUA水平四分位数的关系。

致编辑：糖尿病（DM）是一种危害人类健康的慢性疾病，可导致不同的并发症。^[1]冠状动脉疾病是糖尿病患者最严重的并发症之一。最近，越来越多的证据表明，糖尿病冠状动脉疾病的病理生理学与冠状动脉平滑肌细胞（SMCs）中的离子通道功能障碍有关。^[2]因此，更好地了解糖尿病冠状动脉功能障碍的离子机制具有临床重要性。

致编辑：一例71岁男性患者因计算机断层血管造影（CTA）偶发延迟性Ib型内漏而被转诊。17个月前，患者使用Zenith（Cook Inc，Bloomington，IN，USA）覆膜支架对直径为4.4 cm的右髂总动脉（CIA）动脉瘤进行了血管内腹主动脉瘤修复术（EVAR）。生命体征平稳，无相关症状。腹主动脉瘤腔内修复术后8个月CTA显示无内漏[图1A].本次访视时，CTA显示左侧髂肢出现新出现的Ib型内漏[图1B].因此，我们尝试通过左股动脉穿刺进行再介入，但由于髂外动脉（EIA）严重钙化性狭窄和迂曲而失败。因此，我们进行了左腋动脉穿刺。将导丝穿过主体和左侧肢体，并通过左股动脉圈套捕获。我们尝试将覆膜支架插入已有覆膜支架的远端，但未能成功。血管造影显示导丝穿过支架和移植物之间的微小间隙，然后向髂动脉管腔伸出[图1C].因此，将另一个直径为12mm的Zenith（Cook Inc，Bloomington，IN，USA）支架移植物插入EIA中，以使EIA不那么曲折。幸运的是，导丝穿过预先存在的覆膜支架进入近端主动脉。最后，额外插入直径为12 mm的覆膜支架以处理Ib型内漏。术后第7天CTA显示无内漏[图1D].患者顺利出院。

致编辑：系统性硬化症(SSc)是一种以进行性皮肤和内脏纤维化、微血管病变和自身免疫为特征的自身免疫性疾病。在90%至95%的SSc患者中可检测到循环自身抗体（AAb）。^[1]据报道，60%~80%的SSc患者抗拓扑异构酶I抗体（ATA）、抗着丝粒抗体（ACA）、抗RNA聚合酶III抗体（ARA）呈阳性。^[2]这三种AAb是最普遍的SSc相关AAb，对SSc的诊断具有高特异性；因此，它们已被纳入2013年美国风湿病学会（ACR）/欧洲抗风湿病联盟（EULAR）定义的SSc分类标准。目前，SSc相关AAb已广泛应用于临床，有关AAb临床意义的研究仍在进行中。在我们目前的研究中，我们分析了一个特征明确的中国SSc队列中SSc相关自身抗体谱与临床表现之间的相关性。

致编辑：流行病学研究表明，细颗粒物2.5（PM2.5）暴露会增加皮肤色素沉着过度的风险。^[1]最近的一项研究证明，PM2.5可以通过芳香烃受体（AhR）/丝裂原活化蛋白激酶信号激活调节酪氨酸酶（TYR）和酪氨酸酶相关蛋白1（TYRP1）和2（TYRP2）的表达来诱导黑素生成。^[2]AhR广泛存在于皮肤细胞中，其连接控制氧化/抗氧化、表皮屏障功能、光诱导反应、先天免疫和黑素生成。它可以被二恶英和多环芳烃（PM2.5的成分）激活，其激活诱导编码I期和II期异生素代谢酶（细胞色素P450【CYP】1A1、CYP1A2和CYP1B1）的基因转录。^[3,4]BaP和有害的二恶英通过强烈的活性氧（ROS）生成激活AhR，这至少部分由CYP1A1介导。此外，CYP1A1介导的氧化应激负责在环境污染物处理的人角质形成细胞中产生促炎细胞因子，如白细胞介素（IL）-1、IL-6和IL-8。^[3,5]然而，关于PM2.5对黑素生成细胞毒性作用的研究很少。在此，我们用不同浓度的PM2.5处理人黑色素瘤细胞A375，以研究PM2.5是否可以促进黑色素生成，及其与AhR信号、氧化应激和炎症反应的关系。

到编辑：蒽环类抗生素是乳腺癌、恶性血液病和肉瘤的核心治疗策略。临床主要用药为柔红霉素和阿霉素。不幸的是，累积剂量的蒽环类药物可诱发肿瘤患者心功能障碍，如心脏毒性、心肌缺血或梗死，进而影响肿瘤治疗。^[1,2]研究人员发现，蒽环类药物诱导的心脏毒性（AIC）在治疗期间或治疗后会出现；然而，确切的机制尚不清楚。因此，最佳使用非侵入性心脏检查对于控制药物副作用是必要的。医学成像技术被认为是无创检测AIC最有效的方法。因此，为了最大限度地降低心脏风险，本文简要概述了医学成像技术的最新进展。