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1.  Utility of flexible fiberoptic bronchoscopy for critically ill pediatric patients: A systematic review 
AIM: To investigate the diagnostic yield, therapeutic efficacy, and rate of adverse events related to flexible fiberoptic bronchoscopy (FFB) in critically ill children.
METHODS: We searched PubMed, SCOPUS, OVID, and EMBASE databases through July 2014 for English language publications studying FFB performed in the intensive care unit in children < 18 years old. We identified 666 studies, of which 89 full-text studies were screened for further review. Two reviewers independently determined that 27 of these studies met inclusion criteria and extracted data. We examined the diagnostic yield of FFB among upper and lower airway evaluations, as well as the utility of bronchoalveolar lavage (BAL).
RESULTS: We found that FFB led to a change in medical management in 28.9% (range 21.9%-69.2%) of critically ill children. The diagnostic yield of FFB was 82% (range 45.2%-100%). Infectious organisms were identified in 25.7% (17.6%-75%) of BALs performed, resulting in a change of antimicrobial management in 19.1% (range: 12.2%-75%). FFB successfully re-expanded atelectasis or removed mucus plugs in 60.3% (range: 23.8%-100%) of patients with atelectasis. Adverse events were reported in 12.9% (range: 0.5%-71.4%) of patients. The most common adverse effects of FFB were transient hypotension, hypoxia and/or bradycardia that resolved with minimal intervention, such as oxygen supplementation or removal of the bronchoscope. Serious adverse events were uncommon; 2.1% of adverse events required intervention such as bag-mask ventilation or intubation and atropine for hypoxia and bradycardia, normal saline boluses for hypotension, or lavage and suctioning for hemorrhage.
CONCLUSION: FFB is safe and effective for diagnostic and therapeutic use in critically ill pediatric patients.
PMCID: PMC4326767
Bronchoscopy; Critical illness; Pediatrics; Bronchoalveolar lavage; Pulmonary disease
2.  Anti-inflammatory effects of BHBA in both in vivo and in vitro Parkinson’s disease models are mediated by GPR109A-dependent mechanisms 
Accumulating evidence suggests that neuroinflammation plays an important role in the progression of Parkinson’s disease (PD). Excessively activated microglia produce several pro-inflammatory enzymes and pro-inflammatory cytokines, leading to damage to surrounding neurons and eventually inducing neurodegeneration. Therefore, the inhibition of microglial overactivation may be a potential therapeutic strategy to prevent the further progression of PD. β-Hydroxybutyric acid (BHBA) has been shown to suppress lipopolysaccharide (LPS)-induced inflammation in BV-2 cells and to protect dopaminergic neurons in previous studies, but the underlying mechanisms remain unclear. Thus, in this study, we further investigated this mechanism in LPS-induced in vivo and in vitro PD models.
For the in vitro experiments, primary mesencephalic neuron-glia cultures were pretreated with BHBA and stimulated with LPS. [3H]dopamine (DA) uptake, tyrosine hydroxylase-immunoreactive (TH-ir) neurons and morphological analysis were evaluated and analyzed in primary mesencephalic neuron-glia cultures. In vivo, microglial activation and the injury of dopaminergic neurons were induced by LPS intranigral injection, and the effects of BHBA treatment on microglial activation and the survival ratio and function of dopaminergic neurons were investigated. Four our in vitro mechanistic experiment, primary microglial cells were pretreated with BHBA and stimulated with LPS; the cells were then assessed for the responses of pro-inflammatory enzymes and pro-inflammatory cytokines, and the NF-κB signaling pathway was evaluated and analyzed.
We found that BHBA concentration-dependently attenuated the LPS-induced decrease in [3H]DA uptake and loss of TH-ir neurons in the primary mesencephalic neuron/glia mixed culture. BHBA treatment significantly improved the motor dysfunction of the PD model rats induced by intranigral injection of LPS, and this beneficial effect of BHBA was attributed to the inhibition of microglial overactivation and the protection of dopaminergic neurons in the substantia nigra (SN). Our in vitro mechanistic study revealed that the inhibitory effect of BHBA on microglia was mediated by G-protein-coupled receptor 109A (GPR109A) and involved the NF-κB signaling pathway, causing the inhibition of pro-inflammatory enzyme (iNOS and COX-2) and pro-inflammatory cytokine (TNF-α, IL-1β, and IL-6) production.
In conclusion, the present study supports the effectiveness of BHBA in protecting dopaminergic neurons against inflammatory challenge.
PMCID: PMC4310035  PMID: 25595674
BHBA; GPR109A; Parkinson’s disease; neuroinflammation; LPS; NF-κB
3.  Relations between Stimulation of Mesolimbic Dopamine and Place Conditioning in Rats Produced by Cocaine or Drugs that are Tolerant to Dopamine Transporter Conformational Change 
Psychopharmacology  2013;229(2):307-321.
Dopamine transporter (DAT) conformation plays a role in the effectiveness of cocaine-like and other DAT-inhibitors. Cocaine-like stimulants are intolerant to DAT conformation changes having decreased potency in cells transfected with DAT constructs that face the cytosol compared to wild-type DAT. In contrast, analogs of benztropine (BZT) are among compounds that are less affected by DAT conformational change.
We compared the displacement of radioligand binding to various mammalian CNS sites, acute stimulation of accumbens shell dopamine levels, and place-conditioning in rats among cocaine and four BZT analogs with Cl-substitutions on the diphenyl-ether system including two with carboalkoxy substitutions at the 2-position of the tropane ring.
Binding assays confirmed high-affinity and selectivity for the DAT with the BZT analogs which also produced significant stimulation of mesolimbic dopamine efflux. Because BZT analogs produced temporal patterns of extracellular dopamine levels different from those by cocaine (3-10 mg/kg, IP), the place conditioning produced by BZT analogs and cocaine was compared at doses and times at which both the increase in dopamine levels and rates of increase were similar to those produced by an effective dose of cocaine. Despite this equilibration, none of the BZT analogs tested produced significant place conditioning.
The present results extend previous findings suggesting that cocaine-like actions are dependent on a binding equilibrium that favors the outward conformational state of the DAT. In contrast BZT analogs with reduced dependence on DAT conformation have reduced cocaine-like behavioral effects and may prove useful in development of medications for stimulant abuse.
PMCID: PMC3758386  PMID: 23612854
dopamine transporter conformation; accumbens shell; drug abuse; dopamine microdialysis; place preference; benztropine analogs; cocaine
4.  Comparison of characteristics of chronic kidney diseases between Tibet plateau and plain areas 
Background: The purpose of the current study was to investigate the pathological characteristics of chronic kidney diseases in the Tibet plateau and the plain. Methods: 77 cases from the Tibet plateau and 154 cases from the plain of renal biopsied patients with chronic kidney diseases were compared in a randomized, and parallel controlled manner. Pathological characteristics were defined according to the standards of WHO and associated classifications. Results: The ration of sex was shown that most of patients in the plateau region were female, whereas those in the plain were male. The characteristics of pathological types were shown that the patients in the plateau region were primarily minimal change disease, but IgA nephropathy was rare; meanwhile, the proportional lupus nephritis (LN) ratio of the secondary glomerulonephritis in the plateau region was significantly lower than those in the plain region. Conclusions: The current data demonstrated that the most common kidney disease in the Tibet Plateau region is still the primary glomerulonephritis as the same as those in the plain region. However, the primary glomerular disease in the plateau region is minimal change disease, and the most common clinical manifestations are the nephrotic syndrome. The IgA nephropathy in the plain is the most frequent disease. In terms of the secondary renal diseases, Henoch-Schnolein purpura nephritis are dominated in the plateau region, whereas LN-based diseases are frequently found in the plain. There is a statistical significance existed between those two groups.
PMCID: PMC4203237  PMID: 25337266
Epidemiology; plateau chronic renal disease; renal biopsy
5.  Multipotent stromal cells alleviate inflammation, neuropathology, and symptoms associated with globoid cell leukodystrophy in the twitcher mouse 
Stem cells (Dayton, Ohio)  2013;31(8):1523-1534.
Globoid cell leukodystrophy (GLD) is a common neurodegenerative lysosomal storage disorder caused by a deficiency in galactocerebrosidase (GALC), an enzyme that cleaves galactocerebroside during myelination. Bone marrow transplantation has shown promise when administered to late-onset GLD patients. However, the side effects (e.g., graft versus host disease), harsh conditioning regimens (e.g., myelosuppression), and variable therapeutic effects make this an unsuitable option for infantile GLD patients. We previously reported modest improvements in the twitcher mouse model of GLD after intracerebroventricular (ICV) injections of a low dose of multipotent stromal cells (MSCs). Goals of this study were to improve bone marrow-derived MSC (BMSC) therapy for GLD by increasing the cell dosage and comparing cell type (e.g., transduced v. native), treatment timing (e.g., single v. weekly), and administration route (e.g., ICV v. intraperitoneal). Neonatal twitcher mice received (1) 2×105 BMSCs by ICV injection, (2) 1×106 BMSCs by intraperitoneal (IP) injection, (3) weekly IP injections of 1×106 BMSCs, or (4) 1×106 lentiviral-transduced BMSCs overexpressing GALC (GALC-BMSC) by IP injection. All treated mice lived longer than untreated mice. However, the mice receiving peripheral MSC therapy had improved motor function (e.g., hind limb strength and rearing ability), twitching symptoms, and weight compared to both the untreated and ICV-treated mice. Inflammatory cell, globoid cell, and apoptotic cell levels in the sciatic nerves were significantly decreased as a result of the GALC-BMSC or weekly IP injections. The results of this study indicate a promising future for peripheral MSC therapy as a non-invasive, adjunct therapy for patients affected with GLD.
PMCID: PMC3770764  PMID: 23606584
Globoid cell leukodystrophy; mesenchymal stem cells/multipotent stromal cells/MSCs; twitcher mouse; bone marrow-derived stem cells/BMSCs; stem cell transplantation
6.  Antidepressant Effects of Ketamine on Depression-like Behavior in Juvenile Mice after Neonatal Dexamethasone Exposure 
Pediatric depression is associated with significant functional impairment at school and at work. Recently, we reported on depression-like behavior in juvenile mice neonatally exposed to dexamethasone (DEX) as a potential animal model for pediatric depression. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has promoted rapid and long-lasting antidepressant effects in patients with treatment-resistant major depression. This study was conducted to examine whether ketamine had antidepressant effects in juvenile mice after neonatal DEX exposure.
A single dose (10 mg/kg) of ketamine or vehicle was injected into juvenile mice at days 29-32 after neonatal DEX (or saline) exposure (days 1-3). The sucrose preference test, tail suspension test, and forced swimming test were performed 24, 40, and 46 hours, respectively, after injection of ketamine.
Ketamine (10 mg/kg) significantly improved depression-like behavior in DEX-treated juvenile mice.
This finding suggests that ketamine confers antidepressant effects in an animal model of pediatric depression.
PMCID: PMC4153858  PMID: 25191502
Depression; Dexamethasone; Ketamine; NMDA receptors; Antidepressants
7.  Liver fibrosis evaluation by ARFI and APRI in chronic hepatitis C 
AIM: To explore the value of liver fibrosis assessment by acoustic radiation force impulse (ARFI) and the AST/PLT ratio index (APRI) in chronic hepatitis C patients.
METHODS: One hundred and twenty eight patients with chronic hepatitis C were examined using ARFI elastometry and APRI, calculated according to known formulae. The gold standard of liver biopsy was referred; ROC curve analysis was used to assess all ARFI and APRI values. The corresponding cut-off values, sensitivities, and specificities were calculated and compared. In addition, the correlation of liver fibrosis stages in chronic hepatitis C patients with ARFI measurements and APRI were also tested to evaluate significant data.
RESULTS: The values of ARFI in S1-S4 were 1.23 ± 0.34 m/s, 1.48 ± 0.43 m/s, 2.06 ± 0.45 m/s, and 2.30 ± 0.87 m/s. The values of APRI in S1-S4 were 0.31 ± 0.45 m/s, 0.28 ± 0.38 m/s, 0.58 ± 0.59 m/s and 0.65 ± 0.34 m/s. ARFI (r = 0.649, P < 0.05) showed a better correlation with liver fibrosis stages in chronic hepatitis C than APRI (r = 0.478, P < 0.05). The areas under the ROC curves for ARFI and APRI were 0.775 and 0.721 for stages ≥ S2, 0.901 and 0.787 for stages ≥ S3, and 0.792 and 0.780 for S = 4, respectively.
CONCLUSION: Both ARFI and APRI could evaluate liver fibrosis stages in chronic hepatitis C. ARFI is more accurate than the APRI index.
PMCID: PMC4110585  PMID: 25071348
Liver fibrosis; Chronic hepatitis C; Acoustic radiation force impulse; AST/PLT ratio index; Sensitivity; Specificity
8.  Developmental tuning of reflexive attentional effect to biological motion cues 
Scientific Reports  2014;4:5558.
The human visual system is extremely sensitive to the direction information retrieved from biological motion. In the current study, we investigate the functional impact of this sensitivity on attentional orienting in young children. We found that children as early as 4 years old, like adults, showed a robust reflexive attentional orienting effect to the walking direction of an upright point-light walker, indicating that biological motion signals can automatically direct spatial attention at an early age. More importantly, the inversion effect associated with attentional orienting emerges by 4 years old and gradually develops into a similar pattern found in adults. These results provide strong evidence that biological motion cues can guide the distribution of spatial attention in young children, and highlight a critical development from a broadly- to finely-tuned process of utilizing biological motion cues in the human social brain.
PMCID: PMC4080220  PMID: 24990449
9.  Quantification of Photocyanine in Human Serum by High-Performance Liquid Chromatography-Tandem Mass Spectrometry and Its Application in a Pharmacokinetic Study 
Photocyanine is a novel anticancer drug. Its pharmacokinetic study in cancer patients is therefore very important for choosing doses, and dosing intervals in clinical application. A rapid, selective and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated for the determination of photocyanine in patient serum. Sample preparation involved one-step protein precipitation by adding methanol and N,N-dimethyl formamide to 0.1 mL serum. The detection was performed on a triple quadrupole tandem mass spectrometer operating in multiple reaction-monitoring (MRM) mode. Each sample was chromatographed within 7 min. Linear calibration curves were obtained for photocyanine at a concentration range of 20–2000 ng/mL (r > 0.995), with the lower limit of quantification (LLOQ) being 20 ng/mL. The intrabatch accuracy ranged from 101.98% to 107.54%, and the interbatch accuracy varied from 100.52% to 105.62%. Stability tests showed that photocyanine was stable throughout the analytical procedure. This study is the first to utilize the HPLC-MS/MS method for the pharmacokinetic study of photocyanine in six cancer patients who had received a single dose of photocyanine (0.1 mg/kg) administered intravenously.
PMCID: PMC4094845  PMID: 25050190
10.  A case of blastic plasmacytoid dendritic cell neoplasm with ecchymotic lesions on the whole body 
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) derived from plasmacytoid dendritic cell precursors is a very rare, and characterized by cutaneous and bone marrow involvement and leukemic spread. The neoplasm presents with an aggressive behavior, and the clinical findings include cytopenia, particularly thrombocytopenia. The tumor cells are negative for antigens of T- and B- cell lines. However, these cells express CD4, CD56 and CD123, which are markers of plasmacytoid dendritic cells, and negative for Epstein-Barr virus (EBV). From this point of view, a 71-year-old man who was initially found to have a cutaneous mass on his face and thorax was reported here, and initially was diagnosed as “eczema”. The skin rashes then became aggravated on a trial of low dose topical corticosteroid for 2 months. According to skin biopsy, the tumor cells reveal an immature blastic appearance and positive for CD4 and CD56, negative for CD3, CD20, indicating a diagnosis of BPDCN. Here, we report the dismal course of a patient with BPDCN without accepting further therapy, and only survived 3 months.
PMCID: PMC4129059  PMID: 25120824
Blastic plasmacytoid dendritic cell neoplasm; BPDCN; neoplasm
11.  Comparison of long non-coding RNAs, microRNAs and messenger RNAs involved in initiation and progression of esophageal squamous cell carcinoma 
Molecular Medicine Reports  2014;10(2):652-662.
Traditionally, cancer research has focused on protein-coding genes, which are considered the principal effectors and regulators of tumorigenesis. Non-coding RNAs, in particular microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have been widely reported to be important in the regulation of tumorigenesis and cancer development. However, to the best of our knowledge, investigation of the expression profiles of lncRNAs and a comparison of the involvement of lncRNAs, miRNAs and messenger RNAs (mRNAs) in esophageal tumorigenesis and development have not previously been performed. In the current study, intrinsic associations among the expression profiles of lncRNAs, miRNAs and mRNAs from normal esophageal tissues and those from cancer tissues were investigated. Oligonucleotide microarrays were used to detect the expression profiles of the three types of RNA in the canceration processes of human esophageal squamous cell carcinoma (ESCC) tissues. It was demonstrated that the different RNAs exhibit associated patterns of expression among normal esophageal epithelium, low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and carcinoma tissues, particularly in the critical period of canceration (HGIN to ESCC). Furthermore, the results indicated a high level of similarity in the potential function of lncRNAs, miRNAs and mRNAs in the processes of ESCC development. In the current study, a first generation atlas of lncRNA profiling and its association with miRNAs and mRNAs in the canceration processes of ESCC were presented.
PMCID: PMC4094766  PMID: 24888564
long non-coding RNA; microRNA; messenger RNA; esophageal squamous cell carcinoma; canceration processes; bioinformatic analysis
12.  Road traffic noise frequency and prevalent hypertension in Taichung, Taiwan: A cross-sectional study 
Environmental Health  2014;13:37.
Epidemiological studies have reported the association between hypertension and exposure to road traffic noise, but the association between noise frequency characteristics is not clear. This study investigated the association between exposure to different frequency components of road traffic noise and the prevalence of hypertension in central Taiwan.
We recruited 820 residents living near main roads for more than 3 years. Frequency components of traffic noise and traffic flow rates during 0900–1700 on weekdays were measured simultaneously in 2008. Multiple logistic regressions were conducted to estimate odds ratios (ORs) for diagnosed hypertension, adjusting for potential confounders and the total traffic flow rate.
The high-exposure group (≥ the median of noise levels [decibels, dB]) at 63 Hz, 125 Hz and 1000 Hz had ORs for hypertension of 2.77 (95% confidence interval [CI]: 1.17-6.52), 4.08 (95% CI: 1.57-10.63) and 1.98 (1.00-3.92) (95% CI: 1.00-3.92), respectively, compared to the low-exposure group (< the median of noise levels [dB]). There was an increasing trend in the prevalence of hypertension by exposure to road traffic noise at 63, 125 and 1000 Hz in all subjects and in men. Total subjects exposed to ≥ 51 dB at 125 Hz had an OR of 4.65 (95% CI = 1.46-14.83) compared to those exposed to < 47 dB.
With the possible bias of exposure misclassification and a bias from using diagnosed hypertension, these results suggest that exposure to road traffic noise at low and hearing-sensitive frequencies may be associated with hypertension and exposure to noise at 125 Hz may have the greatest risk for hypertension.
PMCID: PMC4038380  PMID: 24886205
Cross-sectional study; Hypertension; Prevalence; Transportation noise
13.  Comparison of conventional medicine, TCM treatment, and combination of both conventional medicine and TCM treatment for patients with chronic obstructive pulmonary disease: study protocol of a randomized comparative effectiveness research trial 
Trials  2014;15:153.
Chronic obstructive pulmonary disease (COPD) affects millions worldwide. Although many therapies exist and are being developed to relieve symptoms and reduce mortality, few data are available to understand which of the therapeutic alternatives is the most cost-effective for COPD patients in everyday clinical practice, especially for traditional Chinese medicine (TCM). Comparative effectiveness research can help patients, clinicians, and decision-makers make best informed treatment decisions where such evidence was previously lacking. This study aims to compare the effectiveness and economic evaluation of three treatments: (1) conventional Western medicine; (2) TCM treatments, which have been evaluated and have certain effect; and (3) a combination of both conventional Western medicine and TCM treatments, and then determine which treatment is the most suitable for COPD patients.
A multicenter, pragmatic, randomized, controlled trial is adopted. A total of 360 patients will be recruited and randomly assigned to one of the three treatments group, with 120 in each group. Patients in the conventional Western medicine group will be given Salbutamol, Formoterol, Salmeterol/fluticasone, respectively, according to the guidelines. For the TCM group, patients will be given Bufei granule, Bu-Fei Jian-Pi granule, Bu-Fei Yi-Shen granule, and Yi-Qi Zi-Shen granule based on their corresponding TCM syndrome patterns, respectively. For the combination of conventional medicine and TCM treatments group, patients will be given a combination of conventional Western medicine and TCM granules. Treatments in each group are recognized as a whole comprehensive intervention. After the 26-week treatment, another 26 weeks will be followed up. The outcome measures including the frequency and duration of acute exacerbations, lung function, dyspnea, exercise capacity, quality of life, and economic evaluation will be assessed.
It is hypothesized that each of the three treatments will have beneficial effects in reducing the frequency and duration of acute exacerbations, improving exercise capacity and psychosocial function of COPD patients. In addition, the combination of conventional medicine and TCM treatments may be most suitable for COPD patients with better effectiveness and economic evaluation.
Trial registration NCT01836016.
PMCID: PMC4017822  PMID: 24885672
Chronic obstructive pulmonary disease; Comparative effectiveness research; Traditional Chinese medicine
14.  Taxonomy of the Colocasiomyia gigantea species group (Diptera, Drosophilidae), with descriptions of four new species from Yunnan, China 
ZooKeys  2014;41-64.
Species of the genus Colocasiomyia de Meijere feed/breed on inflorescences/infructescences of the plants from the families Araceae, Arecaceae and Magnoliaceae. Although most of them utilize plants from the subfamily Aroideae of Araceae, three species of the recently established C. gigantea species group make use of plants of the subfamily Monsteroideae. We describe four new species of the gigantea group found from Yunnan, China: Colocasiomyia longifilamentata Li & Gao, sp. n., C. longivalva Li & Gao, sp. n., C. hailini Li & Gao, sp. n., and C. yini Li & Gao, sp. n. The species delimitation is proved in virtue of not only morphology but also DNA barcodes, i.e., sequences of the partial mitochondrial COI (cytochrome c oxidase subunit I) gene. Some nucleotide sites with fixed status in the alignment of the COI sequences (658 sites in length) are used as “pure” molecular diagnostic characters to delineate species in the gigantea group.
PMCID: PMC4023246  PMID: 24843281
Adaptation; aroid; character-based barcoding; cohabitation; genetic distance; integrated taxonomy; Rhaphidophora clade
15.  Long-term effects of three Tiao-Bu Fei-Shen therapies on NF-κB/TGF-β1/smad2 signaling in rats with chronic obstructive pulmonary disease 
The three Tiao-Bu Fei-Shen (Bufei Jianpi, Bufei Yishen, Yiqi Zishen) granules have been confirmed for their beneficial clinical efficacy in chronic obstructive pulmonary disease (COPD) patients on reducing frequency and duration of acute exacerbation, improving syndromes, pulmonary function and exercise capacity. But the short- or long-term mechanism of them is not fully clear. Nuclear factor (NF)-κB/transforming growth factor (TGF)-β1/smad2 signaling pathway is involved in the progress of inflammation and remodeling in chronic obstructive pulmonary disease COPD. This study aimed to explore the long-term effects mechanism of Tiao-Bu Fei-Shen granules by regulating NF-κB/TGF-β/Smads signaling in rats with COPD.
Sprague Dawley rats were randomized into control, model, Bufei Jianpi, Bufei Yishen, Yiqi Zishen and aminophylline groups. COPD rats, induced by cigarette smoke and bacterial infections exposures, were administrated intragastricly by normal saline, Bufei Jianpi, Bufei Yishen, Yiqi Zishen granules or aminophylline from week 9 through 20, respectively. At week 20 and 32, lung tissues were harvested. Immunohistochemistry was used to detect interleukin (IL)-1β and tumor necrosis factor (TNF)-α, quantitative real-time polymerase chain reaction (qRT-PCR) was used for TGF-β1 and Smad2 mRNA analysis, western blotting was used to determine the phosphorylation of NF-κB (p-NF-κB) and IκBα (p-IκBα).
COPD rats had marked airway injury, such as chronic airway inflammation and remodeling, emphysema, which were improved in the three traditional Chinese medicines (TCM)-treated animals. The levels of IL-1β, TNF-α, p-NF-κB, p-IκBα, TGF-β1 and Smad2 were significantly higher in COPD rats than in controls, while they were dramatically reduced in the three TCM- and aminophylline-treated groups. At the meantime, all these endpoints were significantly lower in three TCM-treated groups than in aminophylline group, especially in Bufei Jianpi and Bufei Yishen groups. Compared to week 20, all endpoints decreased significantly in three TCM groups at week 32.
The three Tiao-Bu Fei-Shen therapies can reduce pulmonary inflammation and remodeling in COPD and have significant long-term effects. NF-κB/TGF-β1/smad2 signaling might be involved in the mechanism.
PMCID: PMC4006455  PMID: 24766819
Chronic obstructive pulmonary disease; Bufei jianpi; Bufei yishen; Yiqi zishen; Traditional Chinese medicine
16.  Significance of elevated ERK expression and its positive correlation with EGFR in Kazakh patients with esophageal squamous cell carcinoma 
Extracellular signal-regulated kinases (ERKs) are activated by the MAPK pathway. ERKs are downstream effectors of the epidermal growth factor receptor (EGFR), which belongs to the receptor tyrosine kinases family. Studies on the activation of the EGFR-ERK pathway in Kazakh patients with esophageal squamous cell carcinoma (ESCC) have not been reported. Using immunohistochemical staining on tissue microarrays, we investigated the protein expression of EGFR and ERK in 90 ethnic Kazakh patients with ESCC and 48 adjacent normal esophageal tissues (NETs). EGFR and ERK1 expression was localized in the cytoplasm, whereas ERK2 expression was localized in the nucleus. Both were more highly expression in the ESCC tissues than in the NETs, and the difference was considered significant (P = 0.003, 0.002, and 0.005, respectively). ERK1 and EGFR expression was positively correlated with lymph nodes metastasis (P = 0.011 and 0.013, respectively). ERK1 staining was also significantly associated with tumor-node-metastases stage of ESCC (P = 0.044). ERK2 staining was significantly associated with Histological grade (P = 0.012). Furthermore, ERK1 and EGFR expression in the ESCC tissues were positively correlated (r = 0.413, P < 0.001); EGFR was more highly expressed in the ESCC tissues with high ERK1 expression than in the ESCC tissues with low ERK1 expression (4.95 ± 0.57 vs. 3.21 ± 0.35, P = 0.01). This study is thus far the first to demonstrate the correlation between EGFR overexpression and ERK overexpression in Kazakh patients with ESCC. This correlation suggests that the EGFR-ERK signaling pathway participates in ESCC progression and can thus be used as a prognostic marker.
PMCID: PMC4069965  PMID: 24966948
Esophageal squamous cell carcinoma; Kazakh; epidermal growth factor receptor; extracellular signal-regulated kinase
17.  BHBA Suppresses LPS-Induced Inflammation in BV-2 Cells by Inhibiting NF-κB Activation 
Mediators of Inflammation  2014;2014:983401.
β-Hydroxybutyric acid (BHBA) has neuroprotective effects, but the underlying molecular mechanisms are unclear. Microglial activation plays an important role in neurodegenerative diseases by producing several proinflammatory enzymes and proinflammatory cytokines. The current study investigates the potential mechanisms whereby BHBA affects the expression of potentially proinflammatory proteins by cultured murine microglial BV-2 cells stimulated with lipopolysaccharide (LPS). The results showed that BHBA significantly reduced LPS-induced protein and mRNA expression levels of iNOS, COX-2, TNF-α, IL-1β, and IL-6. Blocking of GPR109A by PTX resulted in a loss of this anti-inflammatory effect in BV-2 cells. Western blot analysis showed that BHBA reduced LPS-induced degradation of IκB-α and translocation of NF-κB, while no effect was observed on MAPKs phosphorylation. All results imply that BHBA significantly reduces levels of proinflammatory enzymes and proinflammatory cytokines by inhibition of the NF-κB signaling pathway but not MAPKs pathways, and GPR109A is essential to this function. Overall, these data suggest that BHBA has a potential as neuroprotective drug candidate in neurodegenerative diseases.
PMCID: PMC3997897  PMID: 24803746
18.  Neural competition as a developmental process: Early hemispheric specialization for word processing delays specialization for face processing 
Neuropsychologia  2013;51(5):950-959.
Little is known about the impact of learning to read on early neural development for word processing and its collateral effects on neural development in non-word domains. Here, we examined the effect of early exposure to reading on neural responses to both word and face processing in preschool children with the use of the Event Related Potential (ERP) methodology. We specifically linked children’s reading experience (indexed by their sight vocabulary) to two major neural markers: the amplitude differences between the left and right N170 on the bilateral posterior scalp sites and the hemispheric spectrum power differences in the γ band on the same scalp sites. The results showed that the left-lateralization of both the word N170 and the spectrum power in the γ band were significantly positively related to vocabulary. In contrast, vocabulary and the word left-lateralization both had a strong negative direct effect on the face right-lateralization. Also, vocabulary negatively correlated with the right-lateralized face spectrum power in the γ band even after the effects of age and the word spectrum power were partialled out. The present study provides direct evidence regarding the role of reading experience in the neural specialization of word and face processing above and beyond the effect of maturation. The present findings taken together suggest that the neural development of visual word processing competes with that of face processing before the process of neural specialization has been consolidated.
PMCID: PMC3756286  PMID: 23462239
Neural development; Face processing; Visual word processing; ERP
19.  Inactivation of miR-34a by aberrant CpG methylation in Kazakh patients with esophageal carcinoma 
Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with dismal prognosis and high incidence and mortality in Kazakh population. MiR-34a, a direct p53 target gene, possesses tumor-suppressive properties as they mediate apoptosis, cell cycle arrest, and senescence. The reduced expression of miR-34a by methylation in various cancers has been reported.
To determine whether aberrant miR-34a methylation occurs in esophageal cancer, the DNA methylation of 23 CpGs sites in the miR-34a promoter was quantitatively analyzed in relation to the translation initiation site by MALDI -TOF mass spectrometry in 59 ESCC tissues and 34 normal tissues from the Kazakh population. Real-time PCR was used to detect the inhibition of miR-34a expression levels and to evaluate their association with methylation.
We found that miR-34a is more frequently methylated in ESCC (0.133 ± 0.040) than in controls (0.066 ± 0.045, P < 0.01). A nearly two-fold increase in miR-34a expression for the hypomethylated promoter was found in normal esophageal tissues than ESCC with hypermethylation (P <0.0001), pointing to a negative relationship between miR-34a CpG sites methylation and expression(r = −0.594, P = 0.042). The hypermethylation of miR-34a CpG_8.9 was associated with the advanced UICC stage III/IV of the esophageal cancers, and the hypermethylation of CpG_8.9 and CpG_5 of miR-34a was significantly correlated with lymph node metastasis.
Our findings suggest that miR-34a is involved in the etiology of ESCC and that hypermethylated miR-34a is a potential biomarker for ESCC diagnosis and prognosis. Moreover, targeting miR-34a methylation by demethylating agents may offer a novel strategy for anticancer therapy of ESCC.
PMCID: PMC3931274  PMID: 24528540
MiR-34a; Esophageal squamous cell carcinoma; Kazakh; Methylation
20.  Simplified Serum Neutralization Test Based on Enhanced Green Fluorescent Protein-Tagged Classical Swine Fever Virus 
Journal of Clinical Microbiology  2013;51(8):2710-2712.
The neutralization immunofluorescence test (NIFT), currently used for detecting neutralizing antibodies (NAbs) against classical swine fever virus (CSFV), is time-consuming. Here, a simplified neutralization test based on enhanced green fluorescent protein (EGFP)-tagged CSFV (EGFP-NT) was developed for direct detection of anti-CSFV NAbs without immunostaining. The relative sensitivity and specificity between EGFP-NT and NIFT or blocking enzyme-linked immunosorbent assay (ELISA) were both 100%. The NAb titers by EGFP-NT and the blocking rates by blocking ELISA showed a good correlation.
PMCID: PMC3719638  PMID: 23698523
21.  Do Preschool Children Learn to Read Words from Environmental Prints? 
PLoS ONE  2014;9(1):e85745.
Parents and teachers worldwide believe that a visual environment rich with print can contribute to young children's literacy. Children seem to recognize words in familiar logos at an early age. However, most of previous studies were carried out with alphabetic scripts. Alphabetic letters regularly correspond to phonological segments in a word and provide strong cues about the identity of the whole word. Thus it was not clear whether children can learn to read words by extracting visual word form information from environmental prints. To exclude the phonological-cue confound, this study tested children's knowledge of Chinese words embedded in familiar logos. The four environmental logos were employed and transformed into four versions with the contextual cues (i.e., something apart from the presentation of the words themselves in logo format like the color, logo and font type cues) gradually minimized. Children aged from 3 to 5 were tested. We observed that children of different ages all performed better when words were presented in highly familiar logos compared to when they were presented in a plain fashion, devoid of context. This advantage for familiar logos was also present when the contextual information was only partial. However, the role of various cues in learning words changed with age. The color and logo cues had a larger effect in 3- and 4- year-olds than in 5-year-olds, while the font type cue played a greater role in 5-year-olds than in the other two groups. Our findings demonstrated that young children did not easily learn words by extracting their visual form information even from familiar environmental prints. However, children aged 5 begin to pay more attention to the visual form information of words in highly familiar logos than those aged 3 and 4.
PMCID: PMC3899066  PMID: 24465677
22.  The hot rim sign on hepatobiliary scintigraphy (HIDA) with CT correlation 
BMJ Case Reports  2012;2012:bcr0920114778.
An older male with multiple medical comorbidities presented to the emergency room after 3 days of worsening right upper quadrant pain. The patient had an elevated white blood cell count and mildly elevated liver functions. Initial ultrasound was equivocal and further imaging with CT scan was obtained. The CT scan was read as suggestive of cholecystitis, however a hepatobiliary scintigraphy (HIDA) scan was ordered for confirmation, as the patient was a poor operative candidate. The HIDA demonstrated no bile duct or small bowel activity on initial images or delays, however a classic ‘hot rim’ sign was present, confirming acute cholecystitis. The patient ultimately underwent percutaneous cholecystostomy with drainage for treatment where acute cholecystitis was confirmed. Upon retrospective review, the CT demonstrated hyperaemia surrounding the gallbladder fossa, which is the CT scan equivalent of a scintigraphic ‘hot rim’ sign. This is an uncommon example of a radiologic sign correlation between multiple imaging modalities.
PMCID: PMC3263014  PMID: 22665866
23.  Glucose buffer is suitable for blood group conversion with α-N acetylgalactosaminidase and α-galactosidase 
Blood Transfusion  2014;12(1):61-66.
It is well known that the buffer plays a key role in the enzymatic reaction involved in blood group conversion. In previous study, we showed that a glycine buffer is suitable for A to O or B to O blood group conversion. In this study, we investigated the use of 5% glucose and other buffers for A to O or B to O blood group conversion by α-N-acetylgalactosaminidase or α-galactosidase.
Materials and methods
We compared the binding ability of α-N-acetylgalactosaminidase/α-galactosidase with red blood cells (RBC) in different reaction buffers, such as normal saline, phosphate-buffered saline (PBS), a disodium hydrogen phosphate-based buffer (PCS), and 5% commercial glucose solution. The doses of enzymes necessary for the A/B to O conversion in different reaction buffers were determined and compared. The enzymes’ ability to bind to RBC was evaluated by western blotting, and routine blood typing and fluorescence activated cell sorting was used to evaluate B/A to O conversion efficiency.
The A to O conversion efficiency in glucose buffer was similar to that in glycine buffer with the same dose (>0.06 mg/mL pRBC). B to O conversion efficiency in glucose buffer was also similar to that in glycine buffer with the same dose (>0.005 mg/mL pRBC). Most enzymes could bind with RBC in glycine or glucose buffer, but few enzymes could bind with RBC in PBS, PCS, or normal saline.
These results indicate that 5% glucose solution provides a suitable condition for enzymolysis, especially for enzymes combining with RBC. Meanwhile, the conversion efficiency of A/B to O was similar in glucose buffer and glycine buffer. Moreover, 5% glucose solution has been used for years in venous transfusion, it is safe for humans and its cost is lower. Our results do, therefore, suggest that 5% glucose solution could become a novel suitable buffer for A/B to O blood group conversion.
PMCID: PMC3926730  PMID: 24333060
red blood cells; α-galactosidase; α-N-acetylgalactosaminidase; glucose; blood group conversion
24.  The effect of treatment with α-glycosidases from Bacteroides fragilis on the survival of rat erythrocytes in the circulation 
Blood Transfusion  2014;12(Suppl 1):s204-s208.
It has been demonstrated recently that α1,3-galactosidase from Bacteroides fragilis can efficiently convert human group B red blood cells (RBC) to group O cells. In addition, in vitro data indicated that the enzymatic conversion process did not affect the physiological or metabolic parameters of the RBC. The aim of this study was to investigate the lifespan of enzyme- treated RBC in vivo in the circulation.
Materials and methods
This was an experimental, randomised study. The rat was selected as the experimental subject because it expresses α-1,3galactosyl on its RBC. The efficiency of Galα1,3Gal epitope removal from RBC treated with α1,3-galactosidase was tested before the transfusion experiment to track the survival of RBC in the circulation. The animals were divided into three groups and injected via the tail vein with native, mock-treated or enzyme-treated RBC labelled with fluorescein isothiocyanate. The survival rates of the fluorescently labelled RBC were monitored by flow cytometry.
Flow cytometry showed that α-galactosidase (0.02 mg/mL for RBC with a haematocrit of 30%) efficiently removed Galα1,3Gal epitopes from rat erythrocytes, although small amounts of remaining Galα1,3Gal epitopes were still detected. The in vivo data demonstrated that the half-life of enzyme-treated RBC was a little shorter than that of native RBC. However, the 24-hour survival fractions of native, mock-treated and enzyme-treated RBC were virtually identical. Most importantly, the enzyme-treated RBC, like the native RBC, were still detectable 35 days after transfusion.
Our results indicate that α-glycosidase treatment had little effect on the in vivo survival kinetics of RBC. These data add further support to the feasibility of translating enzymatic conversion technology into clinical practice.
PMCID: PMC3934257  PMID: 23149140
α1,3-galactosidase; Bacteroides fragilis; rat red blood cells; lifespan
25.  IL-21 Modulates Release of Proinflammatory Cytokines in LPS-Stimulated Macrophages through Distinct Signaling Pathways 
Mediators of Inflammation  2013;2013:548073.
The aim of this study was to investigate the anti-inflammatory effect of IL-21 on LPS-induced mouse peritoneal macrophages. The results showed that IL-21 significantly inhibited LPS-induced mRNA expression of IL-1β, TNF-α, and IL-6 in macrophages, but not of IFN-γ, IL-10, CCL5, or CXCL2. ELISA analysis showed that IL-21 also suppressed LPS-induced production of TNF-α and IL-6 in culture supernatants. Western blot analysis showed that IL-21 clearly inhibited ERK and IκBα phosphorylation and NF-κB translocation in LPS-stimulated macrophages, but it increased STAT3 phosphorylation. Flow cytometric and Western blot analysis showed that IL-21 decreased M1 macrophages surface markers expression of CD86, iNOS, and TLR4 in LPS-stimulated cells. All results suggested that IL-21 decreases IL-6 and TNF-α production via inhibiting the phosphorylation of ERK and translocation of NF-κB and promotes a shift from the M1 to M2 macrophage phenotype by decreasing the expression of CD86, iNOS, and TLR4 and by increasing STAT3 phosphorylation in LPS-stimulated cells.
PMCID: PMC3888770  PMID: 24574581

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