2018年 · 第131卷第16期

Background: Obstructive sleep apnea syndrome (OSAS) is prevalent in obesity and is associated with many metabolic abnormalities. The relationship between OSAS and bone metabolism is still unclear. The aim of this study was to investigate the relationship between the severity of OSAS and bone metabolic markers. Methods: A total of 119 obese males were enrolled in this study in spring months from 2015 to 2017. All candidates underwent polysomnography, and their bone mineral density (BMD) and the serum levels of total procollagen type 1 N-terminal propeptide (t-P1NP), N-terminal midfragment of osteocalcin (N-MID), β-C-terminal telopeptide of type 1 collagen (β-CTX), vitamin D (VD), and parathyroid hormone (PTH) were measured. The analysis of variance and Pearson correlation analysis were performed for data analyses. Results: No significant differences in the mean values of BMD were observed among the obesity, mild-to-moderate OSAS, and severe OSAS groups; and the serum levels of t-P1NP and β-CTX in the severe OSAS group were significantly higher than those in the obesity group (48.42 ± 23.78 ng/ml vs. 31.98 ± 9.85 ng/ml, P < 0.001; 0.53 ± 0.24 ng/ml vs. 0.41 ± 0.13 ng/ml, P = 0.011, respectively). The serum level of VD in the obesity group was significantly higher than those in the mild-to-moderate and severe OSAS groups (both P < 0.001), and decreased as the severity of OSAS increased (P < 0.001). The serum level of PTH in the severe OSAS group was significantly higher than those in the obesity and mild-to-moderate OSAS groups (both P < 0.001). The results of correlation analysis indicated that the level of apnea-hypopnea index (AHI) was correlated with the levels of t-P1NP (r = 0.396, P < 0.001), VD (r = –0.404, P < 0.001), and PTH (r = 0.400, P < 0.001), whereas the level of minimum O2 saturation (SaO2min) was correlated with the levels of VD (r = 0.258, P = 0.016) and PTH (r = –0.376, P < 0.001). Conclusions: The levels of bone resorption and formation markers in patients with severe OSAS were significantly increased compared to obese men, and the severity of OSAS was correlated with the serum levels of t-P1NP, VD, and PTH.

Background: Base excision repair (BER) plays an important role in the maintenance of genome integrity and anticancer drug resistance. This study aimed to explore the role of BER gene polymorphisms in response to chemotherapy for advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. Methods: During the period from November 2009 to January 2016, a total of 152 patients diagnosed with NSCLC Stage IIIB and IV in the First Hospital of Jilin University were admitted into this study. The XRCC1 G28152A, MUTYH G972C, HOGG1 C1245G, and PARP1T2444C polymorphisms of all the patients were detected by mass spectrometry. The logistic regression was used for statictical analysis. All tests were bilateral test, and a P < 0.05 was considered statistically significant. Results: The logistic regression model showed that the response rate of chemotherapy of the PARP1 T2444C polymorphisms, CC genotype (odds ratio [OR]: 5.216, 95% confidence interval [CI]: 1.568–17.352, P = 0.007), TC genotype (OR: 2.692, 95% CI: 1.007–7.198, P = 0.048), as well as the genotype of TC together with CC (OR: 3.178, 95% CI: 1.229–8.219, P = 0.017) were significantly higher than those of TT wild type. There was no relationship between the MUTYH G972C, XRCC1 G28152A, and HOGG1 C1245G gene polymorphisms and chemosensitivity. Conclusions: The PARP1 2444 mutation allele C might be associated with the decreased sensitivity to platinum-based chemotherapy in advanced NSCLC. These findings may be helpful in designing individualized cancer treatment.

Background: MicroRNAs (miRNAs) have been extensively studied over the decades and have been identified as potential molecular targets for cancer therapy. To date, many miRNAs have been found participating in the tumorigenesis of non-small cell lung cancer (NSCLC). The present study was designed to evaluate the functions of miR-125b-1-3p in NSCLC cells. Methods: MiR-125b-1-3p expression was detected in tissue samples from 21 NSCLC patients and in NSCLC cell lines using the real-time polymerase chain reaction. A549 cell lines were transfected with a miR-125b-1-3p mimic or miR-125b-1-3p antisense. Cell counting kit-8, wound healing, Matrigel invasion assays, and flow cytometry were used to assess the effects of these transfections on cell growth, migration, invasion, and apoptosis, respectively. Western blotting was used to detect apoptosis-related proteins, expression of S1PR1, and the phosphorylation status of STAT3. Significant differences between groups were estimated using Student’s t-test or a one-way analysis of variance. Results: MiR-125b-1-3p was downregulated in NSCLC samples and cell lines. Overexpression of miR-125b-1-3p inhibited NSCLC cell proliferation (37.8 ± 9.1%, t = 3.191, P = 0.013), migration (42.3 ± 6.7%, t = 6.321, P = 0.003), and invasion (57.6 ± 11.3%, t = 4.112, P = 0.001) and simultaneously induced more NSCLC cell apoptosis (2.76 ± 0.78 folds, t = 3.772, P = 0.001). MiR-125b-1-3p antisense resulted in completely opposite results. S1PR1 was found as the target gene of miR-125b-1-3p. Overexpression of miR-125b-1-3p inhibited S1PR1 protein expression (27.4 ± 6.1% of control, t = 4.083, P = 0.007). In addition, S1PR1 siRNA decreased STAT3 phosphorylation (16.4 ± 0.14% of control, t = 3.023, P = 0.015), as in cells overexpressing miR-125b-1-3p (16.7 ± 0.17% of control, t = 4.162, P = 0.026). Conclusion: Our results suggest that miR-125b-1-3p exerts antitumor functions in NSCLC cells by targeting S1PR1.

Background: Follistatin-like 1 (FSTL1) is a novel profibrogenic factor that induces pulmonary fibrosis (PF) through the transforming growth factor-beta 1 (TGF-β1)/Smad signaling. Little is known about its effects on PF through the non-Smad signaling, like the mitogen-activated protein kinase (MAPK) pathway. Therefore, this study aimed to investigate the role of FSTL1 in PF through the MAPK signaling pathway and its mechanisms in lung fibrogenesis. Methods: PF was induced in Fstl1+/− and wild-type (WT) C57BL/6 mice with bleomycin. After 14 days, the mice were sacrificed, and lung tissues were stained with hematoxylin and eosin; the hydroxyproline content was measured to confirm PF. The mRNA and protein level of FSTL1 and the change of MAPK phosphorylation were measured by quantitative polymerase chain reaction and Western blotting. The effect of Fstl1 deficiency on fibroblasts differentiation was measured by Western blotting and cell immunofluorescence. MAPK signaling activation was measured by Western blotting in Fstl1+/− and WT fibroblasts treated with recombinant human FSTL1 protein. We pretreated mouse lung fibroblast cells with inhibitors of the extracellular signal-regulated kinase (ERK), p38, and Jun N-terminal kinase (JNK) signaling and analyzed their differentiation, proliferation, migration, and invasion by Western blotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, and transwell assays. The Student’s t-test was used to compare the differences between two groups. Results: Fstl1 deficiency attenuated phosphorylation of the ERK, p38, and JNK signaling in bleomycin-induced fibrotic lung tissue 14 days after injury (0.67 ± 0.05 vs. 1.22 ± 0.03, t = 14.92, P = 0.0001; 0.41 ± 0.01 vs. 1.15 ± 0.07; t = 11.19; P = 0.0004; and 0.41 ± 0.01 vs. 1.07 ± 0.07, t = 8.92, P = 0.0009; respectively), compared with WT lungs at the same time and in primary lung fibroblasts (0.82 ± 0.01 vs. 1.01 ± 0.04, t = 4.06, P = 0.0150; 1.04 ± 0.03 vs. 1.24 ± 0.03, t = 4.44, P = 0.0100; and 0.76 ± 0.05 vs. 0.99 ± 0.05, t = 4.48, P= 0.0100; respectively), compared with TGF-β1-stimulated WT group. Recombinant human FSTL1 protein in lung fibroblasts enhanced TGF-β1-mediated phosphorylation of the ERK (1.19 ± 0.08 vs. 0.55 ± 0.04, t= 6.99, P = 0.0020), p38 (1.18 ± 0.04 vs. 0.66 ± 0.03, t= 11.20, P = 0.0020), and JNK (1.11 ± 0.01 vs. 0.84 ± 0.04, t= 6.53, P = 0.0030), compared with the TGF-β1-stimulated WT group. Fstl1-deficient fibroblasts showed reduced alpha-smooth muscle actin (α-SMA) expression (0.70 ± 0.06 vs. 1.28 ± 0.11, t = 4.65, P = 0.0035, compared with the untreated WT group; 1.40 ± 0.05 vs. 1.76 ± 0.02, t = 6.31, P = 0.0007; compared with the TGF-β1-treated WT group). Compared with the corresponding condition in the control group, the TGF-β1/FSTL1-mediated α-SMA expression was significantly suppressed by pretreatment with an inhibitor of p38 (0.73 ± 0.01 vs. 1.13 ± 0.10, t = 3.92, P = 0.0078) and JNK (0.78 ± 0.03 vs. 1.08 ± 0.06, t = 4.40,P = 0.0046) signaling. The proliferation of mouse lung fibroblast cells (MLgs) significantly decreased after treatment of an inhibitor of p38 (0.30 ± 0.01 vs. 0.46 ± 0.03, t= 4.64, P = 0.0009), JNK (0.30 ± 0.01 vs. 0.49 ± 0.01, t= 12.84, P = 0.0001), and Smad2/3 (0.18 ± 0.02 vs. 0.46 ± 0.02, t= 12.69, P = 0.0001) signaling compared with the dimethylsulfoxide group. The migration and invasion cells of MLgs significantly decreased in medium pretreated with an inhibitor of p38 (70.17 ± 3.28 vs. 116.30 ± 7.11, t = 5.89, P = 0.0042 for the migratory cells; 19.87 ± 0.84 vs. 32.70 ± 0.95, t = 10.14, P = 0.0005 for the invasive cells), JNK (72.30 ± 3.85 vs. 116.30 ± 7.11, t= 5.44, P = 0.0056 for the migratory cells; 18.03 ± 0.94 vs. 32.70 ± 0.95, t= 11.00, P = 0.0004 for the invasive cells), and Smad2/3 (64.76 ± 1.41 vs. 116.30 ± 7.11, t= 7.11, P = 0.0021 for the migratory cells; 18.03 ± 0.94 vs. 32.70 ± 0.95, t = 13.29, P = 0.0002 for the invasive cells) signaling compared with the corresponding condition in the dimethylsulfoxide group. Conclusion: FSTL1 affects lung fibroblast differentiation, proliferation, migration, and invasion through p38 and JNK signaling, and in this way, it might influence the development of PF.

Background: In the classical psychological refractory period (PRP) paradigm, two stimuli are presented in brief succession, and participants are asked to make separate speeded responses to both stimuli. Due to a central cognitive bottleneck, responses to the second stimulus are delayed, especially at short stimulus-onset asynchrony (SOA) between the two stimuli. Although the mechanisms of dual-task interference in the classical PRP paradigm have been extensively investigated, specific mechanisms underlying the cross-modal PRP paradigm are not well understood. In particular, it remains unknown whether the dominance of vision over audition manifests in the cross-modal PRP tasks. The present study aimed to investigate whether the visual dominance effect manifests in the cross-modal PRP paradigm. Methods: We adapted the classical PRP paradigm by manipulating the order of a visual and an auditory task: the visual task could either precede the auditory task or vice versa, at either short or long SOAs. Twenty-five healthy participants took part in Experiment 1, and thirty-three new participants took part in Experiment 2. Reaction time and accuracy data were calculated and further analyzed by repeated-measures analysis of variance. Results: The results showed that visual precedence in the Visual-Auditory condition caused larger impairments to the subsequent auditory processing than vice versa in the Auditory-Visual condition: a larger delay of second response was revealed in the Visual-Auditory condition (135 ± 10 ms) than the Auditory-Visual condition (88 ± 9 ms). This effect was found only at the short SOAs under the existence of the central bottleneck, but not at the long SOAs. Moreover, this effect occurred both when the single visual and the single auditory task were of equal difficulty in Experiment 1 and when the single auditory task was more difficult than the single visual task in Experiment 2. Conclusion: Results of the two experiments suggested that the visual dominance effect occurred under the central bottleneck of cognitive processing.

Background: On diagnosis of human immunodeficiency virus (HIV) infection, a person may have been infected already for many years. This study aimed to estimate the duration of HIV infection at the time of diagnosis. Methods: Newly diagnosed HIV cases in Dehong, China, from 2008 to 2015 were studied. Duration of infection at the time of diagnosis was calculated using the first CD4 cell count result after diagnosis and a CD4 depletion model of disease progression. Multiple linear regression analysis was used to investigate the associated risk factors. Results: A total of 5867 new HIV cases were enrolled. Overall, mean duration of infection was 6.3 years (95% confidence interval [CI]: 6.2, 6.5). After adjusting for confounding, significantly shorter durations of infection were observed among participants who were female (beta: −0.37, 95% CI: −0.64, −0.09), Dai ethnicity (beta: −0.28, 95% CI: −0.57, 0.01), and infected through injecting drug use (beta: −1.82, 95% CI: −2.25, −1.39). Compared to the hospital setting, durations were shorter for those diagnosed in any other settings, and compared to 2008, durations were shorter for those diagnosed all years after 2010. Conclusion: Although the reduction in duration of infection at the time of diagnosis observed in Dehong was significant, it may not have had a meaningful impact.

Background: MicroRNAs (miRNAs) are key regulators during tumor initiation and progression. MicroRNA-375 (MiR-375) has been proven to play a tumor-suppressive role in various types of human malignancies; however, its biological role in clear cell renal cell carcinoma (ccRCC) remains unclear. The purpose of this study was to explore the biologic role as well as the underlying mechanism of miR-375 in ccRCC progression. Methods: Quantitative polymerase chain reaction (qPCR) was applied to test the expression of miR-375 in tissues and cell lines by t-test. Functional experiments were used to investigate the biological role of miR-375 utilizing a gain-of-function strategy. The target of miR-375 was investigated by bioinformatic analysis and further verified by luciferase reporter assay, qPCR, Western blotting, and functional experiments in vitro. Results: Our study demonstrated that miR-375 was significantly downregulated in ccRCC tissues (cancer vs. normal, 0.804 ± 0.079 vs. 1.784 ± 0.200, t = 5.531 P < 0.0001) and cell lines, and loss of miR-375 expression significantly associated with advanced Fuhrman nuclear grades (Grade III and IV vs. Grade I and II, 1.000 ± 0.099 vs. 1.731 ± 0.189, t = 3.262 P = 0.003). Functional studies demonstrated that miR-375 suppressed ccRCC cell proliferation, migration, and invasion (all P < 0.05 in both 786-O and A498 cell lines). Multiple miRNA target prediction algorithms indicated the well-studied oncogene YWHAZ as a direct target of miR-375, which was further confirmed by the luciferase reporter assay, qPCR, and Western blotting. Moreover, restoration of YWHAZ could rescue the antiproliferation effect of miR-375. Conclusions: The data provide the solid evidence that miR-375 plays a tumor-suppressive role in ccRCC progression, partially through regulating YWHAZ. This study expands the antitumor profile of miR-375, and supports its role as a potential therapeutic target in ccRCC treatment.

Background: Perioperative emotional disorders of patients underwent abdominal aortic aneurysm (AAA) repair is an emerging area of study, and preoperative mental distress of those patients remains poorly understood. The aim of this study was to investigate the prevalence and identify the risk factors of preoperative anxiety and depression in patients scheduled for AAA repair. Methods: A total of 189 patients who underwent elective AAA repair between 2015 and 2016 were included in this study. These patients were preoperatively evaluated by Hospital Anxiety and Depression Scale (HADS). Demographics and anxiety and depression scores of the patients were documented. Logistic regression was used to identify the independent risk factors of preoperative anxiety and depression. Results: A total of 150 AAA patients were included in final analysis. Of these 150 patients, 44 patients (29.3%) had borderline anxiety or clinical anxiety, and 42 patients (28.0%) were found to have borderline or clinical depression. Female (odds ratio [OR]: 2.81, 95% confidence interval [CI]: 1.08–7.26), the American Society of Anesthesiologists (ASA) Grade 3/4 (OR: 4.34, 95% CI: 1.13–16.68), higher education (OR: 1.44, 95% CI: 1.02–2.04), and abdominal or back pain (OR: 3.08, 95% CI: 1.20–7.87) were identified as significant independent risk factors of abnormal HADS-anxiety in overall patients; and higher level of education (OR: 1.87, 95% CI: 1.16–3.01) was predictive of anxiety in patients planned for endovascular aortic repair. Besides, higher body mass index (BMI) (OR: 1.18, 95% CI: 1.04–1.33) and abdominal or back pain (OR: 3.93, 95% CI: 1.70–9.11) were predictive of abnormal preoperative HADS-depression in overall patients. Conclusion: As for patients scheduled for AAA repair, female, higher ASA, higher level of education, and symptom may be independent risk factors for preoperative anxiety, and symptom and higher BMI may predict preoperative depression.

Background: Intravenous (IV) oxycodone has been used at induction to prevent an intubation reaction. The aims of the current study were to calculate the median effective dose (ED50) and the 95% effective dose (ED95) of an IV bolus of oxycodone that blunts the hemodynamic response to tracheal intubation with propofol according to gender and to observe the adverse events of induction-dose oxycodone. Methods: Adult patients who required general anesthesia and tracheal intubation were enrolled. Tracheal intubation was performed using unified TD-C-IV video laryngoscopy and an ordinary common endotracheal tube. Dixon’s up-and-down method was used to obtain ED50 data for women and men separately. The initial dose of oxycodone was 0.2 mg/kg for women and 0.3 mg/kg for men (step size was 0.01 mg/kg). Next, a dose-response curve from the probit analysis was generated to determine the ED50 and ED95 to blunt the intubation reaction in female and male patients. Adverse events following oxycodone injection were observed for 5 min before propofol injection. Results: Sixty-three patients were analyzed, including 29 females and 34 males. According to the probit analysis, the ED50 and ED95 of oxycodone required to blunt the intubation reaction in women were 0.254 mg/kg (95% confidence interval [CI], 0.220–0.328 mg/kg) and 0.357 mg/kg (95% CI, 0.297–2.563 mg/kg), respectively. In men, the ED50 and ED95 were 0.324 mg/kg (95% CI, 0.274–0.381 mg/kg) and 0.454 mg/kg (95% CI, 0.384–2.862 mg/kg), respectively. Men required 28% more oxycodone than women for induction (P < 0.01). The most common adverse events were dizziness (87.3%), vertigo (66.7%), sedation (74.6%), and respiratory depression (66.7%). Conclusions: Oxycodone can be used for induction to prevent intubation reactions. Gender affected the ED50 and ED95 of oxycodone for blunting the tracheal intubation reaction.

Background: Previous studies demonstrate that eccrine sweat glands are innervated by both cholinergic and adrenergic nerves. However, it is still unknown whether the secretory coils and ducts of eccrine sweat glands are equally innervated by the sympathetic nerve fibers. To well understand the mechanisms on sweat secretion and reabsorption, the differential innervation of secretory coils and ducts in human eccrine sweat glands was investigated in the study. Methods: From June 2016 to June 2017, six human skins were fixed, paraffin-embedded, and cut into 5 µm-thick sections, followed by costaining for nerve fiber markers protein gene product 9.5 (PGP 9.5), tyrosine hydroxylase (TH) and vasoactive intestinal peptide (VIP), and eccrine sweat gland markers K7, S100P, and K14 by combining standard immunofluorescence with tyramide signal amplification (IF-TSA). Stained sections were observed under the microscope, photographed, and analyzed. Results: The fluorescent signals of PGP 9.5, TH, and VIP were easily visualized, by IF-TSA, as circular patterns surrounding eccrine sweat glands, but only PGP 9.5 could be observed by standard IF. The IF-TSA method is more sensitivity than standard IF in detecting antigens expressed at low levels. PGP 9.5, TH, and VIP appeared primarily surrounding the secretory coils and sparsely surrounding the sweat ducts. Conclusion: Sweat secretion is mainly controlled by autonomic nerves whereas sweat reabsorption is less affected by nerve activity.

Background: Betel quid chewing has been a major risk factor for oral cancer (OC) in southern China. This study aimed to analyze the scientific publications on the relationship between betel quid chewing and OC and construct a model to quantitatively and qualitatively evaluate pertinent publications from 1998 to 2017. Methods: The publications from 1998 to 2017 were retrieved from the Web of Science Core Collection database. Microsoft Excel, Thomson Data Analyzer, VOSviewer, and CiteSpace software were used to analyze the publication outcomes, journals, countries/regions, institutions, authors, research areas, and research frontiers. Results: A total of 788 publications on the relationship between betel quid chewing and OC published until October 25, 2017, were identified. The top 4 related journals were Journal of Oral Pathology Medicine, Oral Oncology, Plos One, and International Journal of Cancer. The top five countries engaged in related research included China, India, the United States, the United Kingdom, and Malaysia. The corresponding disciplines, such as oncology, oral surgery, pathology, environmental and occupational health, and toxicology, were mainly concentrated in three disciplines. The subject terms squamous cell carcinoma, OC, betel quid, expression, oral submucous fibrosis, India, and p53 ranked first among research hotspots. The burst terms squamous cell carcinoma, OC, betel quid, and expression ranked first in research frontiers. Conclusions: Research in this area emphasized hotspots such as squamous cell carcinoma, OC, oral submucosal fibrosis, betel quid, and tobacco. The annual number of publications steadily decreased from 1998 to 2017, with a lack of a systematic study from interdisciplinary perspectives, inadequate pertinent journals, limited regions with the practice of betel quid chewing, and insufficient participation of researchers, which indicate that as the prevalence of OC increases, particularly in China, research in this area warrants further expansion.

Objective: Allergic airway diseases (AADs) are a group of heterogeneous disease mediated by T-helper type 2 (Th2) immune response and characterized with airway inflammation and remodeling, including allergic asthma, allergic rhinitis, and chronic rhinosinusitis with allergic background. This review aimed to discuss the abnormal epithelial-mesenchymal crosstalk in the pathogenesis of AADs. Data Sources: Articles referred in this review were collected from the database of PubMed published in English up to January 2018. Study Selection: We had done a literature search using the following terms "allergic airway disease OR asthma OR allergic rhinitis OR chronic sinusitis AND IL-25 OR IL-33 OR thymic stromal lymphopoietin OR fibrocyte" . Related original or review articles were included and carefully analyzed. Results: It is now believed that abnormal epithelial-mesenchymal crosstalk underlies the pathogenesis of AADs. However, the key regulatory factors and molecular events involved in this process still remain unclear. Epithelium-derived triple cytokines, including interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP), are shown to act on various target cells and promote the Th2 immune response. Circulating fibrocyte is an important mesenchymal cell that can mediate tissue remodeling. We previously found that IL-25-circulating fibrocyte axis was significantly upregulated in patients with asthma, which may greatly contribute to asthmatic airway inflammation and remodeling. Conclusions: In view of the redundancy of cytokines and "united airway" theory, we propose a new concept that IL-25/IL-33/TSLP-fibrocyte axis may play a vital role in the abnormal epithelial-mesenchymal crosstalk in some endotypes of AADs. This novel idea will guide potential new intervention schema for the common treatment of AADs sharing common pathogenesis in the future.

Objective: Due to the special anatomical structure and pathophysiological mechanism of the central nervous system (CNS), there is a big difference between the repair of brain injury and other systems of the body. More and more evidence shows that targetedly reducing the autoimmune response of brain tissue without affecting the immune function in other parts of the body will be the best optimized treatment for brain injury. Data Sources: This review was based on data in articles published in PubMed up to June 5, 2017, with the following keywords: "immune tolerance" , "traumatic brain injury" , and "central nervous system" . Study Selection: Original articles and critical reviews on immune tolerance and brain damage were selected for this review. References of the retrieved articles were also screened to search for potentially relevant papers. Results: The CNS is isolated from the immune system through the blood-brain barrier. After brain injury, brain antigens are released into the systemic circulation to induce damaging immune responses. Immune tolerance can effectively reduce the brain edema and neurological inflammatory response after brain injury, which is beneficial to the recovery of neurological function. The clinical application prospect and theoretical research value of the treatment of immune tolerance on traumatic brain injury (TBI) is worth attention. Conclusions: The establishment of immune tolerance mechanism has a high clinical value in the treatment of TBI. It opens up new opportunities for the treatment of brain damage.