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OBJECTIVE: Hypoxia is an important risk factor for pulmonary arterial remodeling in pulmonary arterial hypertension (PAH). Pulmonary artery smooth muscle cell (PASMC) proliferation is a major contributor to pulmonary vascular remodeling. The intermediate-conductance Ca2+-activated K+ channel (Kca3.1) has been implicated in disease states characterized by excessive cell proliferation, but its role in hypoxia-induced PASMC proliferation is unknown. In the present study, we sought to investigate the effect of TRAM-34 (triarylmethane-34), a selective blocker of Kca3.1, on hypoxia-induced PASMC proliferation and underlying mechanisms. METHODS: PASMC was exposed to hypoxia (2% O2) for 24 hours, cell proliferation and cell cycle analysis were measured by cell counting kit (CCK-8) and flow cytometry. Cell signaling were examined using Quantitative real-time PCR and Western blotting. RESULTS: CCK8 results showed that TRAM-34 reduced PASMC proliferation under hypoxia. Flow cytometry revealed that TRAM-34 inhibited PASMC proliferation by G0/G1 arrest. Quantitative real-time PCR and western blotting results showed that Kca3.1 mRNA and protein levels were greater in PASMC after hypoxia exposure for 24 hours. Elevated BMP2 (bone morphogenetic protein 2) levels and decreased BMPR2/Smad1 signaling activation were also observed under hypoxia, which were significantly attenuated by TRAM-34 intervention. CONCLUSIONS: These results suggest that Kca3.1 inhibition with TRAM-34 inhibited hypoxia-induced PASMC proliferation in the G0/G1 phase. The capability of TRAM-34 to increase BMPR2/p-Smad1 signaling may be part of the mechanisms for hypoxia-induced cell proliferation. Thus, our study implies that blockade of kca3.1 might provide benefits to attenuating PAH vascular remodeling. [ABSTRACT FROM AUTHOR]

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BACKGROUND AND OBJECTIVES: Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality among patients with congenital heart disease (CHD). Earlier diagnosis of PAH would be of great benefit for the estimation of the CHD, the grasp of the indications for surgery and prognosis. PATIENTS AND METHODS: We assessed the diagnostic accuracy of Doppler echocardiography (D-ECHO) in detecting PAH in patients with CHD and the value of estimation about ventricular morphology and function of PAH-CHD patients. 123 CHD patients evaluated for suspected PAH were prospectively recruited. D-ECHO was performed and estimated right ventricular systolic pressure (RVSP) was measured to screen for PAH. Subsequently, pulmonary hemodynamic parameters were measured by right heart catheterization (RHC) for definitive diagnosis of PAH. RESULTS: RHC identified 66/123 (54%) patients with PAH. The noninvasive cut-point was: estimated right ventricular systolic pressure (RVSP) > 36.5 mm Hg by D-ECHO. D-ECHO classified 107 subjects correctly (sensitivity 89.4%, specificity 84.2%). The area under receiver-operating characteristic curve (AUC) was 0.96 for D-ECHO. A positive significant correlation (r = 0.853, p < 0.01) was found between RVSP measured by D-ECHO and systolic pulmonary arterial pressure (sPAP) measured by RHC. In addition, D-ECHO showed higher RVSP, left ventricular internal diameter (LV), right atrial diameter (RA), right ventricular internal diameter (RV), left ventricular end-diastolic diameter (EDD), left ventricular diastolic end-diastolic volume (EDV) and mitral velocity A wave (AMV) values in the PAH-CHD group than in the CHD group (p < 0.05). CONCLUSIONS: D-ECHO is not only an important noninvasive diagnostic technique for PAH- CHD patients, but also a tool which can indicate the ventricular remodeling and diastolic dysfunction induced by PAH to some extent. [ABSTRACT FROM AUTHOR]

Objective: To study the characteristics and clinical significance of pulmonary function test and kerbs von den lungen 6 (KL-6) in anti-synthetase syndrome related interstitial lung disease (ASSD-ILD) and idiopathic pulmonary fibrosis (IPF). Methods: The clinical data of 43 patients with ASSD-ILD (ASSD-ILD group) from May 2015 to May 2017 were collected retrospectively, including 12 males and 31 females, and 34 patients with IPF (IPF group) treated in the First Affiliated Hospital of Zhengzhou University during the same period, including 28 males and 6 females, were also included. The basic information, and the value of pulmonary function test [pulmonary function parameters included the forced vital capacity expressed as percent predicted (FVC%pred), the forced expiratory volume in 1 second expressed as percent predicted (FEV(1)%pred), the ratio of FVC to FEV(1) (FVC/FEV(1)), the peak expiratory flow expressed as percent predicted (PEF%pred), the forced expiratory flow at 25%, 50%, 75% of FVC as percent predicted (FEF(25)%pred, FEF(50)%pred, and FEF(75)%pred), the maximum mid-expiratory flow as percent predicted (MMEF% pred), and the diffusing capacity for carbon monoxide as percent predicted (DLCO% pred)], and serum KL-6 level in ASSD-ILD and IPF were compared. Results: The FEV(1)%pred, FEF(50)%pred, FEF(75)%pred, and MMEF%pred values in ASSD-ILD group were significantly lower than those in IPF group (all P< 0.05), while the FVC% pred, FVC/FEV(1), PEF% pred, FEF(25)%pred, and DLCO% pred values in ASSD-ILD group had no significant difference compared with IPF group (all P> 0.05). There was no significant difference in serum KL-6 level between ASSD-ILD group and IPF group [(1 169±911) vs (1 210±908) U/ml, t =0.62, P =0.463]. Follow-up analysis showed that the serum KL-6 level of ASSD-ILD patients who died within two years was significantly higher than that of survivors [(2 060±1 168) vs (1 042±858) U/ml, t =2.93, P =0.041]. The serum KL-6 level of patients who died within two years of IPF patients was also significantly higher than that of patients who survived [(1 767±865) vs (1 089±894) U/ml, t =2.53, P =0.026]. The serum KL-6 level in ASSD-ILD group was negatively correlated with FVC%pred ( r =-0.43, P =0.004), FEV(1)%pred ( r =-0.39, P =0.010) and DLCO% pred ( r =-0.41, P =0.006). There was no correlation between serum KL-6 level and pulmonary function test indexes in IPF group (all P> 0.05). Conclusions: There is difference in pulmonary function test between ASSD-ILD patients and IPF patients. High serum KL-6 level will be predictive of poor prognosis.

Objective: To evaluate the diagnostic value of the heparin-binding protein (HBP), procalcitonin (PCT) and acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score in ventilator-associated pneμmonia (VAP). Methods: A total of 160 patients who required tracheotomy or intubation and assisted breathing with invasive mechanical ventilator from the First Affiliated Hospital of Zhengzhou University from January 2015 to January 2017 was included in this prospective study,and divided into VAP group and no-VAP group based on if VAP happened or not; the VAP group was further divided into deterioration group and improvement group based on the curative effect after anti-infective treatment for 1 week. A total of 40 community acquired pneumonia (CAP) patients and 30 healthy volunteers were also included as control groups. The levels of HBP and PCT in blood of the subjects were tested with enzyme-linked immuno sorbent assay (ELISA) and chemiluminescence immunoassay (ECLIA) respectively, APACHE Ⅱ score was utilized to assess the severity of illness. The difference of HBP, PCT levels and APACHE Ⅱ score among the groups were analyzed. Receiver operating characteristic(ROC) curve was utilized to analyze the diagnostic value of HBP, PCT, APACHE Ⅱ score in VAP. Results: A total of 230 subjects participated in this study, including 68 VAP patients, 92 non-VAP patients, 40 CAP patients and 30 healthy volunteers. Before administration of mechanical ventilation, there were no statistically significant differences in HBP, PCT and APACHE Ⅱ score between VAP group and non-VAP group (all P> 0.05). The levels of HBP,PCT and APACHE Ⅱ score were (41.4±21.3) μg/L,(0.355±0.254) μg/L,(13.4±2.5) respectively when the VAP was diagnosed,which were higher than those within the first 12 h of mechanical ventilation (7.3±2.7) μg/L, (0.080±0.038) μg/L, (8.4±2.0), all P< 0.001). The HBP, PCT and APACHE Ⅱ score had no significant difference between within the first 12 h of mechanical ventilation and after mechanical ventilation in non-VAP group (all P> 0.05). The levels of HBP was positively correlated with PCT and APACHE Ⅱ score ( r= 0.82, 0.68, all P< 0.001). In deterioration group,the HBP,PCT and APACHE Ⅱ score after 1 week of anti-infective treatment were higher than those when the VAP was diagnosed (all P< 0.001). No matter it is when the VAP was diagnosed or after anti-infective treatment for 1 week,the levels of HBP, PCT and APACHE Ⅱ score in deterioration group were higher than those in the improvement group (all P< 0.001). The area under curve (AUC) of HBP+APACHE Ⅱ score, PCT+APACHE Ⅱ score for VAP diagnosis was 0.98, 0.95 respectively. The sensitivity of HBP+APACHE Ⅱ score in the diagnosis of VAP was lower than PCT+APACHE Ⅱ score (94.1% vs 95.6%),and the specificity was higher (92.4% vs 82.6%). Conclusion: The diagnostic value of HBP+APACHE Ⅱ score for early VAP is superior to PCT+APACHE Ⅱ score.

Objective: To evaluate the predictive value of Wells score, revised Geneva score combined with D-dimer for the risk of pulmonary embolism in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods: In this study, 234 AECOPD patients underwent CT pulmonary angiography from March 1, 2013 to December 31, 2015 in the First Affiliated Hospital of Zhengzhou University. The basic data of the patients were collected and the patients were classified into AECOPD combined with pulmonary embolism group(pulmonary embolism group) and AECOPD group according to CT pulmonary angiography results. All patients were scored by Wells score and revised Geneva score. The receiver operating characteristic (ROC) curves were generated and the Z test was applied to evaluate the predictive value by comparing the area under the ROC curves (AUC). Results: Totally 32(13.7%) patients had pulmonary embolism out of the 234 AECOPD patients. The AUC by Wells score, revised Geneva score, D-dimer, Wells score + D-dimer, revised Geneva score + D-dimer were 0.869 (95% CI: 0.789-0.949), 0.710 (95% CI: 0.588-0.832), 0.866 (95% CI: 0.790-0.941), 0.926 (95% CI: 0.874-0.977), 0.855 (95% CI: 0.751-0.959). The AUC of Wells score and D-dimer were significantly greater than that of revised Geneva score ( Z =2.14, 2.12, both P <0.05); the AUC of Wells score + D-dimer was significantly greater than revised Geneva score + D-dimer ( Z =2.73, P <0.05). Conclusion: The predictive value of Wells score + D-dimer for pulmonary embolism in AECOPD patients is higher than revised Geneva score + D-dimer.

Objective: To explore the prognosis and risk factors of pyelectasis in high-risk infants. Methods: This was a retrospective study. Totally 960 high-risk infants, who accepted type B ultrasonic examination for fetus at 28th week of gestation and for newborns in 48 hours after birth, were included in the study in departments of obstetrics and eonatology, Shunyi Maternal and Children's Hospital of Beijing Children's Hospital during May 2012 to April 2013. The degree of pyelectasis was classified using Grignon grade and the paients were followed up for 3 years. The factors of epidemiology, high risk pregnant women, fetus and high-risk newborns that relate to pyelectasis were summarized. High-risk factors were analyzed by using logistic multivariate regression analysis. Results: Of 960 high-risk infants, 103 had abnormal urinary ultrasound results, 87 (9.1% of high-risk infants) were diagnosed with pyelectasis, 16 (1.7% of high-risk infants) were diagnosed with congenital anomalies of the kidney and urinary tract. According to the degree of pyelectasis, 68 infants were Grignon grade Ⅰ, male:female ratio=5.8∶1, left side:right side ratio=1.91∶1; 19 infants were Grignon grade Ⅱ, male:female ratio=5.33∶1, left side:right side ratio=2.12∶1. Postnatal follow-up results showed that pyelectasis disappeared in 48 cases (55% of pyelectasis cae), 40 infants were Grignon grade Ⅰ (59% of all Grignon grade Ⅰ patients), 8 infants were Grignon grade Ⅱ (42% of all Grignon grade Ⅱ patients); The result of risk factors analysis showed that the risk of pyelectasis in males was 4.368 times that of females (95% CI: 2.33-8.189, P< 0.05); the risk of pyelectasis in low birth weight infants was 22.434 times that of non low birth weight infants (95% CI : 5.883-85.547, P< 0.05). Conclusion: The incidence of pyelectasis in high-risk infants was 9.1%. The mitigation rate of pyelectasis in Grignon grade Ⅰ to Ⅱ in fetal or newborn period is high. Patients in Grignon grade Ⅲ and above in fetal or new born period had high risk of congenital anomalies of the kidney and urinary tract. The risk of pyelectasis of male was higher than that of female; the risk of pyelectasis of low birth weight infant was higher than appropriate for gestational age infants.

Objective: To investigate the feasibility of the remote control endovascular robotic system in interventional angiography. Method: The endovascular robotic system Heifetz™ and the matched steerable catheter Mirage™ were used to cannulate all the target vessels in the vascular model and cerebral arteries originated from the aorta of Bama mini-pigs under fluoroscopic guidance. The technical success rate, cannulation time and exposure dose were all collected and compared with the result of using conventional techniques. Result: All the target vessels were successfully cannulated.The average cannulation time for the steerable catheter into left subclavian artery, left common carotid artery, brachiocephalic artery, right common carotid artery and right subclavian artery in the vascular model was (21.3±2.8)s, (28.8±5.2)s, (17.7±2.6)s, (31.5±5.1)s and (24.2±3.7) s, respectively, while the average exposure dose was (9.3±1.2)mGy, (12.4±2.2)mGy, (7.4±1.2)mGy, (14.2±2.5)mGy and( 10.4±1.9)mGy, respectively. The endovascular robotic system completed the cerebral angiography in Bama mini-pigs successfully. The average cannulation time for left innominate artery, right innominate artery, right subclavian artery, common internal carotid trunk, left internal carotid artery and right internal carotid artery was (41.5±6.8)s, (29.1±3.7)s, (40.7±5.5)s, (40.1±5.8)s, (59.6±9.0)s and( 60.3±10.1)s, respectively, while the average exposure dose was (40.6±6.5)mGy, (36.0±5.2)mGy, (39.8±6.1)mGy, (43.9±6.7)mGy, (51.0±7.4)mGy and( 50.1±7.8)mGy, respectively. There was no significant difference between robotic and conventional group in success rate, cannulation time and exposure dose. Conclusion: The remote digital control endovascular robotic system could cannulate the target vessel in both vascular model and complete the cerebral angiography in Bama mini-pigs, which shows the feasibility of using this robotic system in endovascular intervention procedures under remote control.

Objective: To investigate the levels of neuropeptide S in the brain of asthmatic mice with anxiety and the effects of inflammatory mediatores on changes of neuropeptide S in in vitro experiments. Methods: According to the random number table method, 40 BALB/C mice were randomly divided into 4 groups: the control group, the asthma group, the anxiety group and the asthma and anxiety group. The relative expressions of neuropeptide S mRNA in the brain tissue of each group were detected by quantitative real-time polymerase chain reaction(QRT-PCR). Rat cortex neurons obtained by primary culture were divided into 4 groups: the PBS control group, the interleukin-1 beta group, the interleukin-6 group and the tumor necrosis factor-alpha group. After stimulation with inflammatory cytokines the mRNA expressions of neuropeptide S were measured by QRT-PCR and neuropeptide S levels in the cell culture supernatants were measured by emzyme linked immunosorbent assay(ELISA). Results: The relative expressions of neuropeptide S mRNA were decreased in the anxiety group(0.87±0.05) and the asthma and anxiety group(0.79±0.03)compared with the control group(1.00±0.05)and the asthma group(0.96±0.06), most notably in the asthma and anxiety group (all P <0.05). Compared to the PBS control group[(1.00±0.06), (50.6±1. 8)ng/L] and the interleukin-1 beta group[(0.94±0.08), (49.5±1.0)ng/L], the levels of neuropeptide S mRNA and neuropeptide S were decreased in the interleukin-6 group[(0.88±0.07), (45.4±1.2)ng/L] and the tumor necrosis factor-alpha group[(0.86±0.07), (46.0±1.0)ng/L](all P <0.05). There were no significant differences between the interleukin-1 beta group and the PBS control group(all P >0.05). Conclusions: Up-regulated interleukin-6 and tumor necrosis factor-alpha in asthma can inhibit the secretion of neuropeptide S in neuronal cells. The decline of brain neuropeptide S, which has anti-anxiety effect, may lead to the occurrence of anxiety, which may be a potential mechanism of comorbidity of asthma and anxiety.

The aim of this study was to investigate the association between four single nucleotide polymorphisms in NR3C1 (Tth111I, BclI, ER22/23EK, and N363S), which encode the glucocorticoid receptor, and asthma susceptibility in patients from the Henan Province of China. Three hundred and twenty-eight patients with asthma and 60 healthy volunteers were recruited to this study. The target SNPs were genotyped by polymerase chain reaction (PCR)-high resolution melting and PCR-restriction fragment length polymorphism. The frequencies of the AA (8.84%) and GG (30.79%) genotypes of Tth111I were higher, and that of the AG genotype was lower (60.37%), in the asthma patients compared to that seen in healthy controls (5.00, 26.67, and 68.33%, respectively). On the other hand, asthma patients showed higher frequencies of the AA genotype (78.05%) of N363S, and lower frequencies of the AG and GG genotypes (15.55 and 6.40%), compared to healthy volunteers (71.67, 18.33, and 10.00%, respectively). Neither of these differences were found to be statistically significant. Moreover, we observed no significant differences in the genotype or allele frequencies of the BclI and ER22/23EK SNPs between the patient and control groups. In conclusion, SNPs in NR3C1 were not significantly associated with asthma in patients from the Henan Province. Patients showed higher frequencies of the AA and GG genotypes of Tth111I and the AA genotype of the N363S SNP compared to healthy volunteers, although these differences were not significant.

Numerous studies have evaluated the association between polymorphisms of a disintegrin and metalloproteinase 33 (ADAM33) gene and chronic obstructive pulmonary disease (COPD) risk; however, the results remain conflicting. The aim of this study was to investigate whether ADAM33S2 and -T1 polymorphisms are associated with susceptibility to COPD risk in the Chinese population. Publications addressing the association between ADAM33S2 or T1 polymorphisms and COPD risk were selected from the PubMed, Cochrane Library, Embase, CNKI, and Wanfang databases. Two independent reviewers extracted data from the studies. Statistical analysis was performed using the RevMan 5.0.25 and STATA 11.0 software. Six case-control studies were retrieved, including a total of 1201 COPD patients and 1203 controls. Meta-analysis results showed a significant association between the T1 polymorphism and COPD risk in both dominant model [odds ratio (OR) = 2.54, 95% confidence interval (CI) = 1.40-4.61, P = 0.002] and recessive model (OR = 3.50, 95%CI = 2.11-5.81, P < 0.00001) comparisons. For S2, no significant association was found in any genetic model. This suggests that the T1 polymorphism of ADAM33 would increase the risk of COPD in a Chinese individual, whereas the S2 polymorphism might not be a risk factor for COPD. To further evaluate the gene-to-gene and gene-to-environment interactions on ADAM33 genetic variations and COPD risk, more studies using large sample sizes of patients are needed.

Objective: To evaluate the overall diagnostic performance of the p16 methylation for diagnosing malignant pleural effusion (MPE)., Methods: All published literature in English and Chinese were reviewed. Sensitivity, specificity, likelihood ratio and diagnostic odds ratio (DOR) were pooled by using random-effects model or fixed-effects model. Summary receiver operating characteristic (SROC) curve was used to evaluate the overall diagnostic value., Results: Six studies were included with a total of 378 cases. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and DOR of p16 methylation in the diagnosis of MPE were 0.41 [95% confidence interval (CI) 0.35, 0.48], 0.97 [95% CI 0.93, 0.99], 9.57 [95% CI 4.53, 20.20], 0.61 [95% CI 0.45, 0.82] and 19.82 [95% CI 8.35, 47.04], respectively. The area under the curve (AUC) was 0.864., Conclusion: Pleural p16 methylation test plays a useful role in the diagnosis of MPE.

We have screened the p53 status of 156 human cell lines, including 142 tumor cell lines from 27 different tumor types and 14 cell lines from normal tissues by using functional analysis of separated alleles in yeast. This assay enables us to score wild-type p53 expression on the basis of the ability of expressed p53 to transactivate the reporter gene HIS3 via the p53-responsive GAL1 promotor in Saccharomyces cerevisiae. Of 142 tumor cell lines, at least 104 lines (73.2%) were found to express the mutated p53 gene: 94 lines (66.2%) were mutated in both alleles, three lines (2.1%) were heterozygous, and no p53 cDNA was amplified from seven lines (4.9%). Of the 14 cell lines originating from normal tissues, all the transformed or immortalized cell lines expressed mutant p53 only. Yeast cells expressing mutant p53 derived from 94 cell lines were analyzed for temperature-sensitive growth. p53 cDNA from eight cell lines showed p53-dependent temperature-sensitive growth, growing at 30 degrees C but not at 37 degrees C. Four temperature-sensitive p53 mutations were isolated: CAT-->CGT at codon 214 (H214R), TAC-->TGC at codon 234 (Y234C), GTG-->ATG at codon 272 (V272M), and GAG-->AAG (E285K). Functionally wild-type p53 was detected in 38 tumor cell lines (26.8%) and all of the diploid fibroblasts at early and late population doubling levels. These results strongly support the previous findings that p53 inactivation is one of the most frequent genetic events that occurs during carcinogenesis and immortalization.

The carboxy-terminal portion of the p53 protein contains the tetramerization domain, and the introduction of multiple missense mutations in this domain disrupts the formation of p53 tetramers, resulting in the production of dimeric or monomeric forms of p53. It has recently been shown that a single missense or nonsense mutation in this domain affects the functional properties of p53 both in yeast and in mammalian cells. In this study, we tested the oligomerization of p53 with mutations in the oligomerization domain, when expressed in a human osteosarcoma cell line, Saos-2, in vivo. We found that single point mutations, including two missense and two nonsense mutations, in the alpha-helix of the oligomerization domain disrupted the oligomerization of p53, but that p53 still retained its ability to inhibit colony formation of cells to some degree. These results suggest that oligomerization and the carboxy-terminal basic domain are not prerequisite for p53-dependent tumor suppression, and this may explain why few of the tumor-derived p53 mutations that have been examined so far are carboxy-terminal mutations.

We have detected both germ-line and somatic p53 mutations in lymphocytes, cell lines and tumor tissues using a functional analysis of p53 tumor suppressor gene based on yeast transcription assay. Through our screening projects of the p53 gene, a number of missense p53 mutations were identified as loss-of-function mutations. This method, previously termed FASAY, is rapid, sensitive, less-expensive and can be automated for screening both somatic and germ-line p53 mutations.