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Background: Emerging evidence has indicated that small airway dysfunction (SAD) contributes to the clinical expression of asthma. Objectives: The aim of the study was to explore the relationships of SAD assessed by forced expiratory flow between 25 and 75% (FEF25–75%), with clinical and inflammatory profile and treatment responsiveness in asthma. Method: In study I, dyspnea intensity (Borg scale), chest tightness, wheezing and cough (visual analog scales, VASs), and pre- and post-methacholine challenge testing (MCT) were analyzed in asthma patients with SAD and non-SAD. In study II, asthma subjects with SAD and non-SAD underwent sputum induction, and inflammatory mediators in sputum were detected. Asthma patients with SAD and non-SAD receiving fixed treatments were prospectively followed up for 4 weeks in study III. Spirometry, Asthma Control Questionnaire (ACQ), and Asthma Control Test (ACT) were carried out to define treatment responsiveness. Results: SAD subjects had more elevated ΔVAS for dyspnea (p = 0.027) and chest tightness (p = 0.032) after MCT. Asthma patients with SAD had significantly elevated interferon (IFN)-γ in sputum (p < 0.05), and Spearman partial correlation found FEF25–75% significantly related to IFN-γ and interleukin-8 (both having p < 0.05). Furthermore, multivariable regression analysis indicated SAD was significantly associated with worse treatment responses (decrease in ACQ ≥0.5 and increase in ACT ≥3) (p = 0.022 and p = 0.032). Conclusions: This study indicates that SAD in asthma predisposes patients to greater dyspnea intensity and chest tightness during bronchoconstriction. SAD patients with asthma are characterized by non-type 2 inflammation that may account for poor responsiveness to therapy.

Background: Although studies have consistently linked obesity and asthma, the potential influence of visceral obesity on asthma has not been well investigated. Objective: To study the associations of visceral fat area (VFA) and clinical and inflammatory features of asthma and to further explore the effects of VFA on the future risk of asthma exacerbation. Methods: A 12-month prospective cohort study based on the Australasian Severe Asthma Network was designed to observe patients with stable asthma grouped by the median value of VFA. The clinical and inflammatory features of asthma were compared between the low VFA (VFAlow) and high VFA (VFAhigh) groups. Relationships between VFA and clinical and inflammatory features of asthma were analyzed by using correlation analysis. Univariate and multivariable negative binomial regression analyses were performed to investigate the association of VFA with exacerbations within a 12-month follow-up period. Results: The patients in the VFAhigh group were older and had a longer asthma duration. Interleukin (IL) 6 and IL-8 in sputum were higher, whereas fractional exhaled nitric oxide (FeNO) and blood eosinophils were lower in the VFAhigh group. Gender-differentiated correlations of VFA with clinical and inflammatory variables were observed in age, FeNO, immunoglobulin E, blood total white cells and neutrophils, and sputum IL-1β and IL-8. Furthermore, compared with the VFAlow group, the VFAhigh group was at significantly increased risk of moderate-to-severe exacerbations (adjusted incidence rate ratio [IRR] 1.55 [95% confidence interval {CI}, 1.06‐2.28; p = 0.025), severe exacerbations (adjusted IRR 2.25 [95% CI, 1.26‐4.04]; p = 0.007), and emergency visits (adjusted IRR 5.33 [95% CI, 1.78‐17.16]; p = 0.003). Conclusion: The level of VFA was associated with specific clinical and inflammatory characteristics of asthma. Furthermore, VFA, as an independent risk factor, was associated with an increased risk of exacerbations. It indicated that VFA would provide more potential clinical implications for asthma management.

BACKGROUND Depressive symptoms worsen asthma outcomes; however, the mechanism remains largely unexplored. OBJECTIVE This study aimed to determine whether depressive symptom-associated immune inflammation correlates with impaired bronchodilator response (BDR) and airway inflammatory phenotypes. METHODS Eligible adults with asthma (n = 198) underwent clinical assessment, sputum induction and blood sampling. Depressive symptoms were defined by scores on the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). Pre- and post-bronchodilator spirometry was performed for BDR. Airway inflammatory phenotypes were defined by sputum cell counts. CRP, IL-1β, IL-5, IL-6, IL-8, TNF-α, IFN-γ, CCL17 and CCL22 in serum and sputum were detected. RESULTS Compared with the non-depressive group (n = 174), the depressive group (n = 24) exhibited impaired BDR (P = 0.032) and increased sputum neutrophils (P = 0.023), which correlated with the HADS-D scores (P = 0.027 and P = 0.029). Levels of IL-1β, TNF-α and IFN-γ in the serum and those of IL-1β and IFN-γ in the sputum were elevated in the depressive group compared to those in the non-depressive group (all P

Background A pandemic of SARS‐CoV‐2 infection broke out all over the world, however, epidemiological data and viral shedding in pediatric patients are limited. Methods We conducted a retrospective, multi‐center study, and followed up with all children from the families with SARS‐CoV‐2 infected members in Zhejiang Province, China. All infections were confirmed by testing the SARS‐CoV‐2 RNA with RT‐PCR method, and epidemiological data between children and adults in the same families was compared. Effect of antiviral therapy was evaluated observationally and fecal viral excretion times among groups with different antiviral regiments were compared with Kaplan Meier plot. Results By February 29, 2020, 1298 cases from 883 families were confirmed with SARS‐CoV‐2 infection and 314 of which were families with children. Incidence of infection in child close contacts was significantly lower than that in adult contacts (13.2% vs 21.2%). The mean age of 43 pediatric cases was 8.2 years and mean incubation period was 9.1 days. Forty (93.0%) were family clustering. Thirty‐three children had COVID‐19 (20 pneumonia) with mild symptoms and 10 were asymptomatic. Fecal SARS‐CoV‐2 RNA detection was positive in 91.4% (32/35) cases and some children had viral excretion time over 70 days. Viral clearance time was not different among the groups treated with different antiviral regiments. No subsequent infection was observed in family contacts of fecal‐viral‐excreting children. Conclusion Children have lower susceptibility of SARS‐CoV‐2 infection, longer incubation and fecal viral excretion time. Positive results of fecal SARS‐CoV‐2 RNA detection were not used as indication for hospitalization or quarantine. This article is protected by copyright. All rights reserved.

To test the potential efficacy of recombinant macrophage inhibitory cytokine-1 (MIC-1/GDF15) as an obesity therapeutic. Male C57BL/6 J mice, either fed on normal chow or high-fat diet for 16 weeks to induce diet-induced obesity, were infused with either recombinant MIC-1/GDF15 or vehicle for 34 days by osmotic minipump. During the experimental period metabolic parameters were measured. Blood and tissue were collected for analysis of inflammatory markers. MIC-1/GDF15 decreased food intake and body weight of high-fat-fed and chow-fed mice compared with their vehicle-treated control mice. MIC-1/GDF15 reduced body weight, accompanied by greater reduction in fat mass in high-fat-fed mice compared to its effect on chow-fed mice. Further, whilst MIC-1/GDF15-treated chow-fed mice lost lean as well as fat mass, MIC-1/GDF15-treated high-fat-fed mice lost fat mass alone. This reduction in body weight and adiposity was due largely to reduced food intake, but MIC-1/GDF15-treated high-fat-fed mice also displayed increased energy expenditure that may be due to increased thermogenesis. MIC-1/GDF15-treated high-fat-fed mice also had higher circulating level of adiponectin and lower tissue expression, and circulating levels of leptin and inflammatory mediators associated with insulin resistance. Peripheral insulin and glucose intolerance were improved in both MIC-1/GDF15-treated high-fat-fed and chow-fed mice compared to that of their vehicle-treated control mice. MIC-1/GDF15 is highly effective in reducing adiposity and correcting the metabolic dysfunction of mice with high-fat fed. These studies suggest that MIC-1/GDF15 may be a candidate anti-obesity therapeutic.

Background Asthma is a heterogeneous airway disease, so it is crucial to clearly identify clinical phenotypes to achieve better asthma management. Objective To identify and prospectively validate asthma clusters in a Chinese population. Methods Two hundred eighty-four patients were consecutively recruited and 18 sociodemographic and clinical variables were collected. Hierarchical cluster analysis was performed by the Ward method followed by k -means cluster analysis. Then, a prospective 12-month cohort study was used to validate the identified clusters. Results Five clusters were successfully identified. Clusters 1 (n = 71) and 3 (n = 81) were mild asthma phenotypes with slight airway obstruction and low exacerbation risk, but with a sex differential. Cluster 2 (n = 65) described an "allergic" phenotype, cluster 4 (n = 33) featured a "fixed airflow limitation" phenotype with smoking, and cluster 5 (n = 34) was a "low socioeconomic status" phenotype. Patients in clusters 2, 4, and 5 had distinctly lower socioeconomic status and more psychological symptoms. Cluster 2 had a significantly increased risk of exacerbations (risk ratio [RR] 1.13, 95% confidence interval [CI] 1.03–1.25), unplanned visits for asthma (RR 1.98, 95% CI 1.07–3.66), and emergency visits for asthma (RR 7.17, 95% CI 1.26–40.80). Cluster 4 had an increased risk of unplanned visits (RR 2.22, 95% CI 1.02–4.81), and cluster 5 had increased emergency visits (RR 12.72, 95% CI 1.95–69.78). Kaplan-Meier analysis confirmed that cluster grouping was predictive of time to the first asthma exacerbation, unplanned visit, emergency visit, and hospital admission ( P Conclusion We identified 3 clinical clusters as "allergic asthma," "fixed airflow limitation," and "low socioeconomic status" phenotypes that are at high risk of severe asthma exacerbations and that have management implications for clinical practice in developing countries.

SummaryBackground Serum macrophage inhibitory cytokine-1 (MIC-1/GDF15) concentration has been associated with colonic adenomas and carcinoma. Aims To determine whether circulating MIC-1/GDF15 serum concentrations are higher in the presence of adenomas and whether the level decreases after excision. Methods Patients were recruited prospectively from a single centre and stratified into five groups: no polyps (NP); hyperplastic polyps (HP); sessile serrated ademona (SSA); adenomas (AP); and colorectal carcinoma (CRC). Blood samples were collected immediately before and 4 weeks after colonoscopy. MIC-1/GDF15 serum levels were quantified using ELISA. Results Participants (n=301) were stratified as: NP; n=116 (52%), HP; n=37 (12%), SSA; n=19 (7%), AP; n=68 (23%); and CRC; n=3 (1%). Patients were excluded from the study due to nondiagnostic pathology (n=9, 3%) and exclusion criteria (n=20, 6%). In the 272 remaining subjects (M=149; F=123), age (P=.005), history of colonic polyps (P=.003) and family history of colonic polyps (P=.002) were associated with presence of adenomas. Baseline median MIC-1/GDF15 serum levels increased significantly from NP 609 (460-797) pg/mL, HP 582 (466-852) pg/mL, SSA 561 (446-837) pg/mL to AP 723 (602-1122) pg/mL and CRC 1107 (897-1107) pg/mL; (P

Our aim was to study the changes in bone age and serum osteocalcin levels before and after adenotonsillectomy (AT) in children with obstructive sleep apnea hypopnea syndrome (OSAHS). A total of 58 OSAHS children (37 males and 21 females) with the mean age of 6.68 ± 1.11 years were enrolled and assessed by x-ray-based bone age estimation and enzyme-linked immunosorbent assay-based measurement of serum osteocalcin levels, before surgery and 6 months after AT. SPSS 19.0 software was used for statistical analysis. Our results revealed that bone age and serum osteocalcin levels in OSAHS patients were significantly lower than normal controls before AT (P < 0.05). Within 6 months after surgery, the bone age and the serum osteocalcin levels were significantly elevated in OSAHS patients (P < 0.05), compared with those before surgery. Serum osteocalcin levels and bone age are negatively correlated with apnea-hypopnea index, oxygen desaturation index, the percentage of the total recorded time spent below 90% oxygen saturation, and Epworth sleepiness scale scores (all P < 0.05). Our findings suggested that bone age and serum osteocalcin levels may be correlated with the development of OSAHS in children. AT may improve bone age and serum osteocalcin levels in OSAHS children.

Growth Differentiation Factor-15 (GDF15) is a divergent TGF-beta superfamily cytokine that is overexpressed by most cancers and is induced by anticancer therapy. Transgenic and induced animal models suggest that it protects from cancer development but the mechanisms are uncertain. We investigated the role of immunity in GDF15 induced reduction in prostate cancer (PCa) growth. The C57BL/6 transgenic TRAMP prostate cancer prone mice were bred with mice that were immunodeficient and/or systemically overexpressed GDF15. We developed a novel orthotopic TRAMP PCa model in which primary TRAMP tumor cells were implanted into prostates of mice to reduce the study time. These mice were administered recombinant mouse GDF15, antibody to CD8, PD1 or their respective controls. We found that GDF15 induced protection from tumor growth was reversed by lack of adaptive immunity. Flow cytometric evaluation of lymphocytes within these orthotopic tumors showed that GDF15 overexpression was associated with increased CD8 T cell numbers and an increased number and proportion of recently activated CD8+CD11c+ T cells and a reduced proportion of "exhausted" CD8+PD1+ T cells. Further, depletion of CD8 T cells in tumor bearing mice abolished the GDF15 induced protection from tumor growth. Infusion of GDF15 into mice bearing orthotopic TRAMP tumor, substantially reduced tumor growth that was further reduced by concurrent PD1 antibody administration. GDF15 overexpression or recombinant protein protects from TRAMP tumor growth by modulating CD8 T cell mediated antitumor immunity and augments the positive effects of anti-PD1 blockers.

Elevated circulating levels of the divergent transforming growth factor-beta (TGFb) family cytokine, growth differentiation factor 15 (GDF15), acting through its CNS receptor, glial-derived neurotrophic factor receptor alpha-like (GFRAL), can cause anorexia and weight loss leading to anorexia/cachexia syndrome of cancer and other diseases. Preclinical studies suggest that administration of drugs based on recombinant GDF15 might be used to treat severe obesity. However, the role of the GDF15-GFRAL pathway in the physiological regulation of body weight and metabolism is unclear. The critical site of action of GFRAL in the CNS has also not been proven beyond doubt. To investigate these two aspects, we have inhibited the actions of GDF15 in mice started on high-fat diet (HFD).The actions of GDF15 were inhibited using two methods: (1) Groups of 8 mice under HFD had their endogenous GDF15 neutralised by monoclonal antibody treatment, (2) Groups of 15 mice received AAV-shRNA to knockdown GFRAL at its hypothesised major sites of action, the hindbrain area postrema (AP) and the nucleus of the solitary tract (NTS). Metabolic measurements were determined during both experiments.Treating mice with monoclonal antibody to GDF15 shortly after commencing HFD results in more rapid gain of body weight, adiposity and hepatic lipid deposition than the control groups. This is accompanied by reduced glucose and insulin tolerance and greater expression of pro-inflammatory cytokines in adipose tissue. Localised AP and NTS shRNA-GFRAL knockdown in mice commencing HFD similarly caused an increase in body weight and adiposity. This effect was in proportion to the effectiveness of GFRAL knockdown, indicated by quantitative analysis of hindbrain GFRAL staining. We conclude that the GDF15-GFRAL axis plays an important role in resistance to obesity in HFD-fed mice and that the major site of action of GDF15 in the CNS is GFRAL-expressing neurons in the AP and NTS.

OBJECTIVE To determine whether anxiety and depression are associated with greater respiratory discomfort in asthma. METHODS Adults with asthma (n = 230) underwent methacholine (Mch) challenge. Anxiety and depression, asthma control, and quality of life were evaluated at study entry by using the Hospital Anxiety and Depression Scale, Asthma Control Test, and Asthma Quality of Life Questionnaire, respectively. Qualitative descriptors of breathlessness, dyspnea intensity (modified Borg scale and visual analog scale [VAS]), and other respiratory symptoms were evaluated before and after Mch challenge. RESULTS Patients were classified as neither anxiety nor depression (NAD), anxiety only, depression only (D), or both anxiety and depression (AD) according to the Hospital Anxiety and Depression Scale score. Asthma Control Test and Asthma Control Test, and Asthma Quality of Life Questionnaire scores were lowest in the AD group (both p < 0.001). VAS scores for dyspnea and wheezing before Mch challenge were highest in the AD group (both p < 0.05). The increase in the modified Borg scale score after Mch challenge was higher in the AD group (mean [standard deviation] 2.5 ± 2.0) than in the NAD (1.5 ± 1.5) and D (0.8 ± 0.9) groups (p = 0.006 and p = 0.003, respectively). Most descriptors of breathlessness were more prevalent in the anxiety only, D, and AD groups than in the NAD group. Multivariable logistic regression models indicated that anxiety increased the risk of dyspnea (odds ratio 1.10, p < 0.001 for the Borg score; odds ratio 3.84, p = 0.032 for the VAS score) but not for other respiratory symptoms. CONCLUSIONS Anxiety but not depression was associated with greater perceived dyspnea intensity but not other measures of respiratory discomfort in individuals with asthma. Anxiety may shape the quality and intensity of dyspnea at a given respiratory load.

Background Despite advances in asthma management, exacerbations constitute a significant health economic burden. Objective To observe the efficacy and safety of Chinese herbal medicine formula entitled PingchuanYiqi (PCYQ) granule, on acute asthma and to explore its possible mechanism. Materials and methods This proof-of-concept study consisted of a randomized, double-blind, placebo-controlled trial in patients with acute asthma (n = 300). Participants with acute mild-to-moderate asthma recruited from seven centers in China were randomly assigned to receive PCYQ or placebo. The primary outcomes were PEF (L/min) and total asthma symptom scores. Furthermore, a panel of cytokines including serum IL-4, IL-5, IL-6, IL-8, IL-1β, IL-17A, IFN-α, IFN-β, IFN-γ, CRP, CCL-5, IP-10, and PGD2 levels was detected using ELISA. Results The PCYQ (n = 139) significantly improved the morning PEF on day 4 (349.73 ± 93.92 vs. 313.56 ± 92.91 L/min, P = 0.004) and day 7 (360.42 ± 94.39 vs. 329.52 ± 95.97 L/min, P = 0.023), and the evening PEF on day 4 (352.65 ± 95.47 vs. 320.58 ± 95.30 L/min, P = 0.012) and day 7 (360.42 ± 94.39 vs. 336.86 ± 95.59 L/min, P = 0.029) in comparison with the placebo (n = 143). The PCYQ also improved the clinical symptoms scores and reduced the puffs of short-acting β2-agonist (all P Conclusion The PCYQ as the Chinese herbal medicine formula significantly improves lung function and symptoms of acute asthma, and reduces SABA dosage possibly via decrease of inflammatory biomarkers such as IL-5, IL-8, IL-1β and PGD2. Trial registration ISRCTN61674768 ( http://www.isrctn.com/ ).

Recent reports suggest that staphylococcal exotoxins, acting as superantigens, activate T cells with subsequent massive proliferation, thereby contributing to the etiology of chronic rhinosinusitis with nasal polyps (CRSwNP). The objectives of this study are (1) to demonstrate directly the presence of staphylococcal exotoxins in nasal mucosa and sinonasal polyp tissue, and (2) provide indirect evidence of the effect of superantigens on the T cells expressing the target of superantigen, i.e., the β variable chain receptor (TCRBV) in polyp tissue and peripheral blood of patients with CRSwNP. Sinonasal polyp tissue and peripheral blood specimens were obtained from 37 patients with chronic rhinosinusitis (22 patients with bilateral nasal polyps, 15 without nasal polyps) and 12 normal subjects for comparative negative controls. Tissue specimens were assayed by enzyme-linked immunosorbent assay (ELISA) for the most common staphylococcal exotoxins (A–D) and toxic shock syndrome toxin type 1. Fresh tissue and blood samples were analyzed by flow cytometry to determine the expression of TCRBV. In the CRSwNP subjects 12 of 22 samples (54.54%) demonstrated reactivity for at least 1 staphylococcal exotoxin, while 2 of the 12 were positive for 2 toxins. There were no positive results in the CRS without nasal polyps or control groups. There was a clear trend of increased TCRBV expression in the ELISA-positive group both for tissue and blood specimens. Staphylococcal superantigens were present in the nasal cavity of patients with CRSwNP with a high percentage of TCRBV, which suggests the possibility of superantigens as etiological agents of CRSwNP.

Compound trans-4-(p-bromophenyl)-4-(dimethylamino)-1-(2-thiophen-2-yl-ethyl)-cyclohexanol (C8813), structurally unrelated to morphine, is a novel analgesic. The present study examined the antinociception, opioid receptor selectivity and in vitro activity of C8813. The antinociceptive activity was evaluated using mouse hot plate and acetic acid writhing tests. In mouse hot plate test, the antinociceptive ED(50) of C8813 was 11.5 microg/kg, being 591 times and 3.4 times more potent than morphine and fentanyl respectively. In mouse writhing test, the antinociceptive ED(50) of C8813 was 16.9 microg/kg, being 55 times and 2.3 times more active than morphine and fentanyl respectively. In the opioid receptor binding assay, C8813 showed high affinity for mu-opioid receptor (K(i) = 1.37 nM) and delta-opioid receptor (K(i) = 3.24 nM) but almost no affinity for kappa-opioid receptor (at 1 microM). In the bioassay, the inhibitory effect of C8813 in the guinea-pig ileum (GPI) was 16.5 times more potent than in the mouse vas deferens (MVD). The inhibitory effects of C8813 in the GPI and MVD could be antagonized by mu-opioid receptor antagonist naloxone and delta-opioid receptor antagonist ICI174,864 respectively. However, the inhibitory effect of C8813 in the rabbit vas deferens was very weak. These results indicated that C8813 was a potent analgesic and a high affinity agonist for the mu- and delta-opioid receptors.

The effect of l-12-chloroscoulerine (l-CSL), a novel ligand with dual dopamine D1 receptor agonistic and D2 receptor antagonistic actions, on the development of morphine-induced conditioned place preference (CPP) was investigated in mice. Morphine (10 mg/kg)-induced place preference was dose dependently suppressed by coadministration of l-CSL (5, 10 and 20 mg/kg), which induced neither place preference nor place aversion when administered alone at a dose of 20 mg/kg. The D1 receptor antagonist SCH23390 (0.1 mg/kg) suppressed, whereas the D2 receptor agonist (+/-)-2-(N-phenylethyl-N-propyl)-amino-5-hydroxytetralin (PPHT) (0.5 mg/kg) had no influence on the development of morphine-induced place preference. However, SCH23390 (0.1 mg/kg) did not affect, whereas PPHT (0.5 mg/kg) reversed the suppressive effect of l-CSL on the development of morphine-induced place preference. These results indicate that l-CSL suppresses the development of place preference of morphine by blocking D2 receptors.

T lymphocytes, which are characterized by longevity and immune memory, play an important role in airway inflammation in asthma. Here, we assessed the association between immune memory and histone deacetylation and/or acetylation status.CD4 + CD45RB(low) cells (memory T (Tm)) obtained from the spleens of asthma mice models were co-cultured with glucocorticoids (GCs), trichostatin A (TSA) or anacardic acid (AA) and adoptively transferred to naïve mice. Interleukin (IL)-4, 5 and 13 and IFN-γ concentrations were measured in culture supernatants and bronchoalveolar lavage fluid (BALF). Histone deacetylase (HDAC) and histone acetyltransferase (HAT) activities and the expression of T-bet, GATA-3, HDACs 1-11 and alveolar eosinophilic inflammation index (AEII) were determined in lung tissues.Culture supernatants and the BALF showed similar cytokine profiles. AA and GCs significantly inhibited HAT activity (P = 0.002 and P = 0.018), whereas TSA inhibited and GCs promoted HDAC activity (P = 0.004 and P = 0.025). HDACs 7, 9 and 10 were upregulated by AA and GCs (all P 0.032), while HDAC11 was upregulated by GCs (P = 0.028). GC-induced inhibition of Tm histone acetylation alleviated AEII by downregulating IL-4, 5 and 13, similar to the effect of AA.Histone hyperacetylation status induced by low expression of HDACs 7, 9 and 10 in allergen-specific Tm cells contributes to eosinophilic airway inflammation. The mechanism by which GCs improve airway inflammation involves the upregulation of HDACs 7, 9, 10 and 11 and especially HDAC-10. The role of individual HDACs and AA as novel therapeutic agents for allergic asthma needs to be explored in the future.

Objective. The aim of this study was to compare the differences in thyroid hormone, intelligence, attention, and quality of life (QoL) of children with obstructive sleep apnea hypopnea syndrome (OSAHS) before and after endoscopic adenoidectomy.Method. A total of 35 OSAHS children (21 males and 14 females with a mean age of6.81±1.08years) were included in this study for analyzing the levels of thyroid hormone, intelligence, attention, and QoL. There were 22 children underwent endoscopic adenoidectomy with bilateral tonsillectomy (BT), while the other 13 children who underwent endoscopic adenoidectomy without bilateral tonsillectomy without BT.Results. Our results revealed no significant difference in serum free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) levels in OSAHS children before and after endoscopic adenoidectomy (allP>0.05). However, there were significant differences in full-scale intelligence quotient (FIQ) (92.45±5.88versus106.23±7.39,P<0.001), verbal intelligence quotient (VIQ) (94.17±15.01versus103.91±9.74,P=0.006), and performance intelligence quotient (PIQ) (94.12±11.04versus104.31±10.05,P=0.001), attention (98.48±8.74versus106.87±8.58,P<0.001), and total OSA-18 scores (87.62±17.15versus46.61±10.15,P<0.001) between before and after endoscopic adenoidectomy in OSAHS children.Conclusion. Our findings provided evidence that the intelligence, attention, and QoL of OSAHS children may be significantly improved after endoscopic adenoidectomy.

Macrophage inhibitory cytokine-1 (MIC-1/GDF15) modulates food intake and body weight under physiological and pathological conditions by acting on the hypothalamus and brainstem. When overexpressed in disease, such as in advanced cancer, elevated serum MIC-1/GDF15 levels lead to an anorexia/cachexia syndrome. To gain a better understanding of its actions in the brainstem we studied MIC-1/GDF15 induced neuronal activation identified by induction of Fos protein. Intraperitoneal injection of human MIC-1/GDF15 in mice activated brainstem neurons in the area postrema (AP) and the medial (m) portion of the nucleus of the solitary tract (NTS), which did not stain with tyrosine hydroxylase (TH). To determine the importance of these brainstem nuclei in the anorexigenic effect of MIC-1/GDF15, we ablated the AP alone or the AP and the NTS. The latter combined lesion completely reversed the anorexigenic effects of MIC-1/GDF15. Altogether, this study identified neurons in the AP and/or NTS, as being critical for the regulation of food intake and body weight by MIC-1/GDF15.

Differences of analgesia and withdrawal response among ohmefentanyl stereoisomers have been studied. In the present study, Quantitative comparison of reinforcing effects of ohmefentanyl stereoisomers and morphine was performed by using a conditioned place preference design in mice. Results showed that morphine and ohmefentanyl stereoisomers were able to increase significantly the time spent in the drug-paired side with respect to vehicle treated animals. A good linear correlation between doses of drugs and number of mice with place preference was found within a given dose range. On the basis of the dose-response curve analysis, ohmefentanyl stereoisomers displayed a significant difference in place preference ED50. The addictive index (analgesic ED50/place preference ED50) was used to assess the addictive potential of drugs. It was demonstrated that the addictive potential of ohmefentanyl stereoisomers did not exhibit a large difference as addictive index. Among these stereoisomers, the addictive potential of compound F9208 was markedly lower than that of morphine.

The important roles of myogenic regulatory factors (MRFs) have been well addressed in the process of mammalian skeletal myogenesis, while limited research has been performed in small ruminants. Furthermore, the effects of gender on the development of skeletal muscle and MRFs expression remain unknown. In this study, we identified the caprine Myf5, Myf6, MyoD and myogenin genes and quantified their expressions at six different postnatal time points by real-time RT-PCR. The sex has a marked effect on the expression differences of Myf5, MyoD and myogenin in the five investigated skeletal muscles, while minor influence on the expression difference of Myf6 except for Semitendinosus and Quadriceps femoris tissues (P 0.001). The histological sections of muscles revealed a constant increase of muscle fiber diameter with aging but non-significant differences between genders. We provide novel evidence for MRFs expression in age- and gender-dependent manners, which will contribute to prioritizing these genes as potential candidate genes for trait-associated study and provide a foundation for understanding the molecular control of skeletal muscle growth in goat species.

The performance of asthma control test (ACT) at baseline for predicting future risk of asthma exacerbation has not been previously demonstrated. This study was designed to explore the ability of the baseline ACT score to predict future risk of asthma exacerbation during a 12-month follow-up.This post hoc analysis included data from a 12-month prospective cohort study in patients with asthma (n = 290). The time to the first asthma exacerbation was analyzed and the association between baseline ACT scores and future risk of asthma exacerbation was calculated as adjusted odds ratio (OR) using Logistic regression models. Further, sensitivity and specificity were estimated at each cut-point of ACT scores for predicting asthma exacerbations.The subjects were divided into three groups, which were uncontrolled (U, n = 128), partly-controlled (PC, n = 111), and well controlled (C, n = 51) asthma. After adjustment, the decreased ACT scores at baseline in the U and PC groups were associated with an increased probability of asthma exacerbations (OR 3.65 and OR 5.75, respectively), unplanned visits (OR 8.03 and OR 8.21, respectively) and emergency visits (OR 20.00 and OR 22.60, respectively) over a 12-month follow-up period. The time to the first asthma exacerbation was shorter in the groups with U and PC asthma (all P0.05). The baseline ACT of 20 identified as the cut-point for screening the patients at high risk of asthma exacerbations had an increased sensitivity of over 90.0% but a lower specificity of about 30.0%.Our findings indicate that the baseline ACT score with a high sensitivity could rule out patients at low risk of asthma exacerbations and predict future risk of asthma exacerbations in clinical practice.

Staphylococcal exotoxins (SEs), acting as superantigens, activate the beta variable chains of T-cell receptors (TCRVbeta) with subsequent massive proliferation and corresponding excursion of gene spectra, thereby contributing to the etiology of chronic rhinosinusitis with nasal polyps (CRSwNP).To demonstrate the presence of SEs in sinonasal mucosa, and determine the effect of superantigens on the T cells expressing the target of superantigen, i.e. TCRVbeta in patients with CRSwNP.Nasal mucosa and sinonasal polyp tissue specimens were obtained from 37 patients with CRS (22 with bilateral nasal polyps, 15 without nasal polyps). Specimens were assayed by enzyme-linked immunosorbent assay (ELISA) for SEs (SEA, SEB, SEC, SED) and toxic shock syndrome toxin type-1 (TSST-1), and analyzed by flow cytometry and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively, to determine the expression of TCRVbeta repertoire.In the CRSwNP subjects 12 of 22 samples (54.54%) demonstrated reactivity for staphylococcal exotoxins. There was no positive result in the CRS without nasal polyps or normal control group. There was a high percentage of Vbeta+ T cells in the superantigen-positive group. The expressional intensity of Vbeta3, 14, 15, 17, and 20 was specifically enhanced in SEB-positive subjects, as well as that of Vbeta2 and 6.1-3 in specimens that were TSST-1-positive compared with those that were negative for superantigens (all p0.05). There were no dominantly expressed Vbeta fragments in ELISA-negative specimens.

To detect the expression of glucocorticoid receptor (GR) alpha and beta in nasal polyps, and analyze the possible relationship between over-expression of GR beta and steroid insensitivity.The expression of GR alpha and GR beta was examined by immunohistochemical SP method in the specimens from 17 patients with recurring nasal polyp, 18 patients with chronic rhinosinusitis and nasal polyp (CRSwNP), and 12 patients with chronic rhinosinusitis without nasal polyp (CRSsNP) that did not recur during follow-up for 1.5 - 2 years.The difference of numbers of GR alpha-positive cells (x +/- s) between groups with recurrent nasal polyp (20.2 +/- 6.9), CRSwNP (20.7 +/-7.2) , CRSsNP (16.9 +/- 7.2) and normal subjects (16.1 +/- 5.3) was not significant (P0.05). The numbers of GR beta-positive cells in recurring group (34.2 +/- 7.4) or CRSwNP (31.5 +/- 5.9) were higher than that in CRSsNP (19.8 +/- 7.8) and normal group (10.1 +/- 6.7) respectively (all P0.05). There was a trend toward higher level in recurring polyp compared with that of CRSwNP patients without recurrence in follow-up period, although this was not statistically different (P = 0.558). The difference of GR beta/GR alpha ratios (x +/- s) in recurring specimens (1.80 +/- 0.47) and CRSwNP group (1.65 +/- 0.49) was significant compared with normal group (0.77 +/- 0.66) respectively (P0.05), while there was no significance compared with CRSsNP (1.23 +/- 0.27, P0.05).The high expression of GR beta in nasal polyp is related to the development of nasal polyp.

To analyse the relationship between superantigens produced by Staphylococcus aureus and the mRNA expression of T-cell receptor V beta region (TCR Vbeta), and to investigate the possible role of Staphylococcal superantigens in the pathogenesis of nasal polyps.Sinonasal mucus and polyp/mucosa tissue were obtained from patients with chronic rhinosinusitis (22 patients with bilateral nasal polyps, 15 without nasal polyps) and 12 normal subjects as comparative negative controls. Mucus specimens were assayed by enzyme-linked immunosorbent assay (ELISA) for Staphylococcal exotoxins,and analyzed for the expression of TCR Vbeta genes using the technique of reverse transcriptase-polymerase chain reaction (RT-PCR).The percentages of Staphylococcus exotoxins in nasal polyps were 54.54% (21/22) for chronic rhinosinusitis with nasal polyp (CRSwNP) subjects. There were no positive results in the CRSsNP or control groups. The expressional intensity of Vbeta3 (10.02), Vbeta14 (3.54), Vbeta15 (2.39), Vbeta17 (3.48), and Vbeta20 (2.94) was increased significantly for Staphylococcal exotoxin B (SEB) positive subjects (P0.05). Vbeta2 (13.8) and Vbeta6. 1-3 (6.53) were significantly highly expressed for toxic shock syndrome toxin-1 (TSTf-1) positive subjects in CRSwNP group (P0.05). There were no dominantly used Vbeta fragments in ELISA- negative specimens. In the group of chronic rhinosinusitis without nasal polyp (CRSsNP), most of TCR Vbeta gene subfamilies demonstrated a trend toward higher expressional levels compared with those of normal controls, although there was no statistical difference (P0.05).There was relationship between Staphylococcal superantigens and the excursion of TCR Vbeta gene spectra in nasal polyp, and superantigens possibly play an important role in the pathogenesis of CRSwNP.

To study the role of superantigens produced by Staphylococcus aureus in the pathogenesis of nasal polyps.sinonasal mucus and polyp/mucosa tissue were obtained from sixty-nine patients with chronic rhinosinusitis (42 patients with bilateral nasal polyps, 27 without nasal polyps). Samples from twelve normal subjects were also obtained for comparative negative controls. Mucus specimens were cultured for bacteria. Tissue specimens were assayed by ELISA for staphylococcal exotoxins. In addition, the histopathology of nasal polyps was studied. The paraffin sections were stained with hematoxylin and eosin, and these were examined for eosinophil counts.The percentages of Staphylococcus aureus in sinonasal mucus were 7.1 for chronic rhinosinusitis with nasal polyp (CRSwNP) subjects, 3.7% for chronic rhinosinusitis without nasal polyps (CRSsNP). and 0 for controls respectively. There were no significant differences between these groups. In CRSwNP subjects 23 of 42 samples (54.76%) demonstrated reactivity for at least one staphylococcal exotoxin. There were no positive results in the CRSsNP or control groups. The mean eosinophil counts were 23. 94+/-13. 88 in CRSwNP group, 0.29+/-0.51 in CRSsNP group, and 0. 08+/-0.28 in controls. The differences in these three groups were all significant ( P0.05). There was a trend toward higher eosinophil levels in polyps of ELISA-positive patients compared with that of ELISA-negative patients, although this was not statistically different ( P0.05).There were correlation between Staphylococcal superantigens and nasal CRSwNP, and superantigens were possible etiological agents in the pathogenesis of CRSwNP.

To investigate the receptor binding affinity and naloxone-precipitated cAMP overshoot of dihydroetorphine, fentanyl, heroin, and pethidine in Sf9 insect cells expressing human mu-opioid receptor (Sf9-mu cells).Competitive binding assay of [3H]ohmefentanyl was used to reveal the affinity for mu-opioid receptor in Sf9-mu cells. [3H]cAMP RIA was used to determine cAMP level. Antinociceptive activity was evaluated using degree 55 mouse hot plate test. Naloxone-precipitated withdrawal jumping was used to reflect physical dependence in mice.All drugs displayed antinociceptive activity and produced physical dependence in mice. The K(i) values of dihydroetorphine, fentanyl, heroin, and pethidine in competitive binding assay were (0.85+/-0.20) nmol, (59.1+/-11.7) nmol, (0.36+/-0.13) micromol, and (12.2+/-3.8) micromol respectively. The binding affinities of these drugs for mu-opioid receptor in Sf9-mu cells were paralleled to their antinociceptive activities in mice. After chronic pretreatment with these drugs, naloxone induced cAMP withdrawal overshoot in Sf9-mu cells. The dependence index in Sf9-mu cells was calculated as K(i) value in competitive binding assay over EC(50) value in naloxone-precipitated cAMP assay. The physical dependence index in mice was calculated as antinociceptive ED(50)/withdrawal jumping cumulative ED(50). There was a good linear correlation between dependence index in Sf9-mu cells and physical dependence index in mice.The Sf9-mu cells could be used as a cell model to evaluate the receptor binding affinity and physical dependent liability of analgesic agents.

The TGF-b superfamily cytokine MIC-1/GDF15 circulates in all humans and when overproduced in cancer leads to anorexia/cachexia, by direct action on brain feeding centres. In these studies we have examined the role of physiologically relevant levels of MIC-1/GDF15 in the regulation of appetite, body weight and basal metabolic rate. MIC-1/GDF15 gene knockout mice (MIC-1(-/-)) weighed more and had increased adiposity, which was associated with increased spontaneous food intake. Female MIC-1(-/-) mice exhibited some additional alterations in reduced basal energy expenditure and physical activity, possibly owing to the associated decrease in total lean mass. Further, infusion of human recombinant MIC-1/GDF15 sufficient to raise serum levels in MIC-1(-/-) mice to within the normal human range reduced body weight and food intake. Taken together, our findings suggest that MIC-1/GDF15 is involved in the physiological regulation of appetite and energy storage.

The TGF-b superfamily cytokine MIC-1/GDF15 circulates in the blood of healthy humans. Its levels rise substantially in cancer and other diseases and this may sometimes lead to development of an anorexia/cachexia syndrome. This is mediated by a direct action of MIC1/GDF15 on feeding centres in the hypothalamus and brainstem. More recent studies in germline gene deleted mice also suggest that this cytokine may play a role in physiological regulation of energy homeostasis. To further characterize the role of MIC-1/GDF15 in physiological regulation of energy homeostasis in man, we have examined diurnal and food associated variation in serum levels and whether variation in circulating levels relate to BMI in human monozygotic twin pairs. We found that the within twin pair differences in serum MIC-1/GDF15 levels were significantly correlated with within twin pair differences in BMI, suggesting a role for MIC-1/GDF15 in the regulation of energy balance in man. MIC-1/GDF15 serum levels altered slightly in response to a meal, but comparison with variation its serum levels over a 24hour period suggested that these changes are likely to be due to bimodal diurnal variation which can alter serum MIC-1/GDF15 levels by about plus or minus 10% from the mesor. The lack of a rapid and substantial postprandial increase in MIC-1/GDF15 serum levels suggests that MIC1/GDF15 is unlikely to act as a satiety factor. Taken together, our findings suggest that MIC-1/GDF15 may be a physiological regulator of energy homeostasis in man, most probably due to actions on long-term regulation of energy homeostasis., published_or_final_version