Clinical characteristics of pediatric patients with treatment-refractory Tourette syndrome: An evidence-based survey in a Chinese population.

BACKGROUND: Tourette syndrome (TS) is a complex neurodevelopmental condition marked by tics, as well as a variety of psychiatric comorbidities, such as obsessive-compulsive disorders (OCDs), attention deficit hyperactivity disorder (ADHD), anxiety, and self-injurious behavior. TS might progress to treatment-refractory Tourette syndrome (TRTS) in some patients. However, there is no confirmed evidence in pediatric patients with TRTS. AIM: To investigate the clinical characteristics of TRTS in a Chinese pediatric sample. METHODS: A total of 126 pediatric patients aged 6-12 years with TS were identified, including 64 TRTS and 62 non-TRTS patients. The Yale Global Tic Severity Scale (YGTSS), Premonitory Urge for Tics Scale (PUTS), and Child Behavior Checklist (CBCL) were used to assess these two groups and compared the difference between the TRTS and non-TRTS patients. RESULTS: When compared with the non-TRTS group, we found that the age of onset for TRTS was younger (P < 0.001), and the duration of illness was longer (P < 0.001). TRTS was more often caused by psychosocial (P < 0.001) than physiological factors, and coprolalia and inappropriate parenting style were more often present in the TRTS group (P < 0.001). The TRTS group showed a higher level of premonitory urge (P < 0.001), a lower intelligence quotient (IQ) (P < 0.001), and a higher percentage of family history of TS. The TRTS patients demonstrated more problems (P < 0.01) in the "Uncommunicative", "Obsessive-Compulsive", "Social-Withdrawal", "Hyperactive", "Aggressive", and "Delinquent" subscales in the boys group, and "Social-Withdrawal" (P = 0.02) subscale in the girls group. CONCLUSION: Pediatric TRTS might show an earlier age of onset age, longer duration of illness, lower IQ, higher premonitory urge, and higher comorbidities with ADHD-related symptoms and OCD-related symptoms. We need to pay more attention to the social communication deficits of TRTS.

Comparison of diagnostic validity of two autism rating scales for suspected autism in a large Chinese sample.

BACKGROUND: Autism is the most common clinical developmental disorder in children. The childhood autism rating scale (CARS) and autistic autism behavior checklist (ABC) are the most commonly used assessment scales for diagnosing autism. However, the diagnostic validations and the corresponding cutoffs for CARS and ABC in individuals with suspected autism spectrum disorder (ASD) remain unclear. Furthermore, for suspected ASD in China, it remains unclear whether CARS is a better diagnostic tool than ABC. Also unclear is whether the current cutoff points for ABC and CARS are suitable for the accurate diagnosis of ASD. AIM: To investigate the diagnostic validity of CARS and ABC based on a large Chinese sample. METHODS: A total of 591 outpatient children from the ASD Unit at Beijing Children's Hospital between June and November 2019 were identified. First, the Clancy autism behavior scale (CABS) was used to screen out suspected autism from these children. Then, each suspected ASD was evaluated by CARS and ABC. Receiver operating characteristic (ROC) curve analysis was used to compare diagnostic validations. We also calculated the area under the curve (AUC) for both CARS and ABC. RESULTS: We found that the Cronbach alpha coefficients of CARS and ABC were 0.772 and 0.426, respectively. Therefore, the reliability of the CARS was higher than that of the ABC. In addition, we found that the correlation between CARS and CABS was 0.732. Next, we performed ROC curve analysis for CARS and ABC, which yielded AUC values of 0.846 and 0.768, respectively. The cutoff value, which is associated with the maximum Youden index, is usually applied as a decision threshold. We found that the cutoff values of CARS and ABC were 34 and 67, respectively. CONCLUSION: This result indicated that CARS is superior to ABC in the Chinese population with suspected ASD.

Decreased interoceptive accuracy in children with autism spectrum disorder and with comorbid attention deficit/hyperactivity disorder.

Interoception refers to the awareness of internal physiological state. Several previous studies reported that people with autism spectrum disorders (ASD) and adults with attention-deficit/hyperactivity disorder (ADHD) have diverse patterns of interoception, but the extent of literature is limited and inconsistent. This study aimed to investigate the interoceptive accuracy (IA) in children with ASD, children with comorbid ASD and ADHD, and typically developing (TD) children with high and low levels of autistic traits. We administered the eye-tracking interoceptive accuracy task (EIAT) to 30 children with ASD, 20 children with comorbid ASD and ADHD, and 63 TD controls with high and low levels of autistic traits. Parent-report scales concerning ASD and ADHD symptoms were collected. ASD children with and without comorbid ADHD both exhibited lower IA than TD children. Reduced IA was also found in TD children with high-autistic traits relative to those with low-autistic traits. IA was negatively correlated with autistic and ADHD symptoms. Atypical cardiac interoception could be found in children with ASD. Difficulties in sensing and comprehending internal bodily signals in childhood may be related to both ASD and ADHD symptoms. LAY SUMMARY: The present study examined interoceptive accuracy (IA) in children with autism spectrum disorders (ASD), children with comorbid ASD and attention-deficit/hyperactivity disorder (ADHD), and typically developing (TD) children with high and low levels of autistic traits. ASD children with and without comorbid ADHD both exhibited lower IA than TD children. TD children with high-autistic traits exhibited decreased IA compared to those with low-autistic traits. These results have implications for understanding sensory atypicality found in ASD and ADHD.

Current Status, Diagnosis, and Treatment Recommendation for Tic Disorders in China.

Tic disorders (TD) are a group neuropsychiatric disorders with childhood onset characterized by tics, i.e. repetitive, sudden, and involuntary movements or vocalizations; and Tourette syndrome (TS) is the most severe form of TD. Their clinical manifestations are diverse; and are often associated with various psychopathological and/or behavioral comorbidities, including attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), anxiety, depression, and sleep disorders. Individual severity and response to treatment are highly variable, and there are some refractory cases, which are less responsive to conventional TD treatment. TD/TS are also common in the Chinese pediatric population. To help improve the understanding of TD for pediatricians and other health professionals, and to improve its diagnosis and treatment in China, the Chinese Child Neurology Society (CCNS) has developed an Expert Consensus on Diagnosis and Treatment of TD in China, which is based on our clinical experience and the availability therapeutic avenues. It is focused on clinical diagnosis and evaluation of TD and its comorbidities, psychological and educational intervention, nonpharmacological therapy, pharmacological treatment, including traditional Chinese medicine and acupuncture, as well as prognosis in children with TD in China. A summary of the current status of TD and up-to-date diagnosis and treatment recommendations for TD in China is presented here.

Premonitory urges located in the tongue for tic disorder: Two case reports and review of literature.

BACKGROUND: Premonitory urges (PUs) was defined as the uncomfortable physical sensations of inner tension that can be relieved by producing movement responses. Nearly 70%-90% patients with Tourette syndrome reported experiences of PUs. CASE SUMMARY: In this paper, we present two cases of young patients with PUs located in their tongue, which is very rare and easily misdiagnosed in clinical work. Both two young patients complained of an itchy tongue and cannot help biting their tongue. These two cases were worth reporting because it was rare that PUs was the initial symptom and located in the tongue. The results indicated that PUs seem to play an important role in the generation of tics. CONCLUSION: Thus, PUs may be the first process, and an essential part, of the formation of tics.

Reliability and Validity of Simplified Chinese STOP-BANG Questionnaire in Diagnosing and Screening Obstructive Sleep Apnea Hypopnea Syndrome.

The main purpose of this study was to assess the reliability and validity of the simplified Chinese STOP-BANG Questionnaire (SBQ) as a diagnosing and screening tool for obstructive sleep apnea hypopnea syndrome (OSAHS). Two hundred and ten patients with suspected OSAHS were recruited in this study. The simplified Chinese SBQ was completed twice before and after polysomnography (PSG) monitoring. SPSS 20.0 was used to analyze the test-retest reliability, discriminant validity, comparative validity and predictive validity of the SBQ. Fourteen patients were excluded on account of fragmentary data, and valid 196 were divided into four groups: non-OSAHS group (n=28, 14.29%), mild OSAHS group (n=28, 14.29%), moderate OSAHS group (n=31, 15.81%) and severe OSAHS group (n=109, 55.61%). The test-retest coefficient for the first four items was 0.810, 0.679, 0.775, 0.963 respectively and the total score of the STOP questionnaire was 0.854. The analysis of discriminant validity revealed that there were significant differences among four groups in the total score of the SBQ and scores of item 1, 3, 7 and 8, which were also validated between patients with normal blood oxygen saturation and different degrees of hypoxemia. The SBQ evaluation showed low consistency with diagnostic gold standard PSG (κ=0.303, P<0.05). When taking apnea hypopnea index (AHI) ≥5/h, ≥15/h and ≥30/h as cut-offs to evaluate the SBQ predictive value, the areas under ROC curve were 0.77, 0.81 and 0.78, the sensitivity was 90.48%, 93.57% and 93.33%, and corresponding negative predictive values were 40.74%, 66.67% and 85.19%, respectively. It was suggested that the simplified Chinese version of SBQ had good reliability, and could distinguish the severity of OSAHS. Despite its limited diagnostic accuracy, the SBQ can be considered as an ideal tool for screening OSAHS with superior predictive validity.

Changes in endolymphatic hydrops visualized by magnetic resonance imaging after sac surgery.

The purpose of the study was to observe changes in endolymphatic hydrops by using intratympanic injection of gadolinium and magnetic resonance imaging (MRI) before and after endolymphatic sac surgery in patients with unilateral Meniere's disease. Thirteen patients with unilateral Meniere's disease undergoing endolymphatic sac surgery were retrospectively and prospectively analyzed. Three-dimensional fluid-attenuated inversion recovery or three-dimensional real inversion recovery MRI was performed 24 h after an intratympanic injection of gadolinium to grade the presence of endolymphatic hydrops. Among the 13 patients with hydrops confirmed by preoperative MRI, vestibular hydrops had no significant change in all patients; cochlear hydrops became negative in 2 patients, and remained unchanged in the other 11 patients after surgery. Definite vertigo attacks were substantially controlled in one patient and completely controlled in 12 patients during a follow-up period of 8-34 months after surgery. The hearing levels were improved in 3 patients, remained unchanged in 7 patients, and decreased in 3 patients. In conclusion, endolymphatic sac surgery does not always alleviate endolymphatic hydrops in patients with Meniere's disease. Relief from vertigo cannot always be attributed to the remission of hydrops. A change in hearing levels cannot be explained by hydrops status alone.

A meta-analysis on the efficacy and safety of St John's wort extract in depression therapy in comparison with selective serotonin reuptake inhibitors in adults.

OBJECTIVE: The aim of the study was to investigate the efficacy and safety of St John's wort extract and selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression. METHODS: Databases were searched for studies comparing efficacy and/or safety of St John's wort extract with SSRIs in depression from 1966 to April 2015. Stata software was used for statistical analysis. RESULTS: Twenty-seven studies met the study entry criteria. A total of 3,126 patients with depression were included. St John's wort extract did not differ from SSRIs in clinical response, remission, and mean reduction in Hamilton Rating Scale for Depression score. St John's wort extract had a significantly lower rate of adverse events compared to SSRIs (summary relative risk: 0.77; 95% confidence interval: 0.70, 0.84, P=0.00) and had fewer withdrawals due to adverse events. St John's wort extract had superior safety in the management of patients with depression. CONCLUSION: Both St John's wort extract and SSRIs are effective in treating mild-to-moderate depression. St John's wort extract is safer than SSRIs.

Distinct mucosal immunopathologic profiles in atopic and nonatopic chronic rhinosinusitis without nasal polyps in Central China.

BACKGROUND: The role of atopy to aeroallergens in chronic rhinosinusitis without nasal polyps (CRSsNP) remains unclear. This study aimed to investigate the mucosal immunopathologic characteristics of CRSsNP with and without atopy to inhalant allergens. METHODS: Thirteen nonatopic CRSsNP patients, 9 atopic CRSsNP patients, and 11 nonatopic control subjects were enrolled in this study. The expression of type 1, 2, and 17 cytokines, growth factors, and chemokines for T cell subsets and granulocytes in sinonasal mucosa was detected using Bio-Plex suspension chip technology or enzyme-linked immunosorbent assay (ELISA). Subjective symptoms were scored on a visual analogue scale (VAS), while disease severity on computed tomography (CT) was graded by the Lund-Mackay CT scoring system. RESULTS: There was no significant difference in VAS and CT scores between atopic and nonatopic CRSsNP. Compared with control, both atopic and nonatopic CRSsNP demonstrated increased interferon γ (IFN-γ) levels in sinonasal mucosa. In contrast, although no difference in interleukin 5 (IL-5), IL-13 and eotaxin-1 expression, or mucosal eosinophil infiltration, was found between the control and whole CRSsNP group, atopic CRSsNP manifested an increased expression of IL-5, IL-13 and eotaxin-1, as well as an enhanced infiltration of mucosal eosinophils in comparison with control and nonatopic CRSsNP. Mucosal eosinophil infiltration correlated with IL-5 and eotaxin-1 expression. No difference in IL-12, IL-4, IL-6, IL-17A, IL-8, myeloperoxidase, "regulated upon activation normal T cell expressed and presumably secreted" (RANTES), or chemokine (C-X-C motif) ligand 10 (CXCL10) protein expression was found among control, atopic CRSsNP, and nonatopic CRSsNP. CONCLUSION: Atopic and nonatopic CRSsNP have distinct mucosal immunopathologic profiles. CRSsNP is a heterogeneous disorder consisting of multiple groups of biological subtypes, or "endotypes," which may argue for different therapeutic strategies.

Expression profiles of prostaglandin E2 receptor subtypes in aspirin tolerant adult Chinese with chronic rhinosinusitis.

BACKGROUND: Several studies have indicated that prostaglandin E2 and E-prostanoid (EP) receptors play a role in the pathogenesis of chronic rhinosinusitis (CRS) in white populations. However, until now there was no report about EP receptor expression and its role in the pathophysiology of CRS in Chinese patients. OBJECTIVE: To investigate the expression profiles of EP receptors, including EP1, EP2, EP3, and EP4 receptors in different Chinese patients with CRS with aspirin tolerance. METHODS: Nasal biopsy specimens were obtained from 12 controls, 12 patients with CRS without nasal polyps (CRSsNP), 12 with eosinophilic CRS with nasal polyps (CRSwNP), and 16 with noneosinophilic CRSwNP. Histopathologic characteristics were observed under a light microscope. Immunostaining was used to examine tissue localization of EP receptors. Messenger RNA and protein expression of EP receptors were examined by means of quantitative RT-polymerase chain reaction and Western blot, respectively. RESULTS: Different types of CRS presented different histopathologic hallmarks. EP receptors were expressed mainly on epithelium, glands, and infiltrating inflammatory cells in nasal tissue. In controls, patients with CRSsNP, and those with noneosinophilic CRSwNP, EP4 mRNA levels were higher than EP1, EP2, and EP3 receptors. EP2 was downexpressed, and EP1 was upexpressed in patients with eosinophilic CRSwNP. When comparing EP receptor expression among different groups, Messenger RNA and protein of EP1 receptor were significantly enhanced in eosinophilic CRSwNP, but EP2, EP3, and EP4 receptors did not show significant differences. CONCLUSION: EP receptor expressions present different features in healthy subjects and patients with CRS. The upregulated EP1 receptor in eosinophilic CRSwNP might be associated with excessive infiltrations of eosinophils and other inflammatory cells. The accurate role of the four EP receptors in the pathogenesis of different CRS remains to be further explored.

Clarithromycin and dexamethasone show similar anti-inflammatory effects on distinct phenotypic chronic rhinosinusitis: an explant model study.

BACKGROUND: Phenotype of chronic rhinosinusitis (CRS) may be an important determining factor of the efficacy of anti-inflammatory treatments. Although both glucocorticoids and macrolide antibiotics have been recommended for the treatment of CRS, whether they have different anti-inflammatory functions for distinct phenotypic CRS has not been completely understood. The aim of this study is to compare the anti-inflammatory effects of clarithromycin and dexamethasone on sinonasal mucosal explants from different phenotypic CRS ex vivo. METHODS: Ethmoid mucosal tissues from CRSsNP patients (n = 15), and polyp tissues from eosinophilic (n = 13) and non-eosinophilic (n = 12) CRSwNP patients were cultured in an ex vivo explant model with or without dexamethasone or clarithromycin treatment for 24 h. After culture, the production and/or expression of anti-inflammatory molecules, epithelial-derived cytokines, pro-inflammatory cytokines, T helper (Th)1, Th2 and Th17 cytokines, chemokines, dendritic cell relevant markers, pattern recognition receptors (PRRs), and tissue remodeling factors were detected in tissue explants or culture supernatants by RT-PCR or ELISA, respectively. RESULTS: We found that both clarithromycin and dexamethasone up-regulated the production of anti-inflammatory mediators (Clara cell 10-kDa protein and interleukin (IL)-10), whereas down-regulated the production of Th2 response and eosinophilia promoting molecules (thymic stromal lymphopoietin, IL-25, IL-33, CD80, CD86, OX40 ligand, programmed cell death ligand 1, CCL17, CCL22, CCL11, CCL5, IL-5, IL-13, and eosinophilic cationic protein) and Th1 response and neutrophilia promoting molecules (CXCL8, CXCL5, CXCL10, CXCL9, interferon-γ, and IL-12), from sinonasal mucosa from distinct phenotypic CRS. In contrast, they had no effect on IL-17A production. The expression of PRRs (Toll-like receptors and melanoma differentiation-associated gene 5) was induced, and the production of tissue remodeling factors (transforming growth factor-ß1, epidermal growth factor, basic fibroblast growth factor, platelet derived growth factor, vascular endothelial growth factor, and matrix metalloproteinase 9) was suppressed, in different phenotypic CRS by dexamethasone and clarithromycin in comparable extent. CONCLUSIONS: Out of our expectation, our explant model study discovered herein that glucocorticoids and macrolides likely exerted similar regulatory actions on CRS and most of their effects did not vary by the phenotypes of CRS.

Disease-specific T-helper cell polarizing function of lesional dendritic cells in different types of chronic rhinosinusitis with nasal polyps.

RATIONALE: Although eosinophilic and noneosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP) exhibit distinct T-helper (Th) responses, the underlying mechanisms remain unclear. OBJECTIVES: To clarify the phenotypes and Th-cell polarizing functions of dendritic cells (DCs) in different types of CRSwNP. METHODS: DC subsets, their surface phenotypes, and Th-cell subsets were studied by means of immunohistochemistry and flow cytometry. The sorted lesional DCs were activated or cultured with autologous naive CD4(+) T cells, and cytokine production was determined by ELISA. Thymic stromal lymphopoietin and osteopontin expression were detected by means of reverse-transcriptase polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: Although elevated local Th1 and Th17 cells were noted in both eosinophilic and noneosinophilic CRSwNP, increased Th2 cells were found only in eosinophilic CRSwNP. Increased numbers of myeloid DCs, plasmacytoid DCs, and their activated subsets were found in both types of CRSwNP, but only myeloid DCs and plasmacytoid DCs from eosinophilic CRSwNP demonstrated an up-regulation of OX40 ligand (OX40L) and programmed death ligand 1(PD-L1) expression. Lesional DCs from both types of CRSwNP produced enhanced levels of IL-12, IL-6, and transforming growth factor-ß, and induced increased Th1 and Th17 responses; in contrast, only DCs from eosinophilic CRSwNP induced obviously enhanced Th2 responses, when cocultured with naive CD4(+) T cells. Blockade of OX40L and PD-L1 on lesional DCs from eosinophilic CRSwNP suppressed Th2 responses, but promoted Th1 responses in DC-T cell coculture. CONCLUSIONS: Distinct subsets of lesional DCs were found in eosinophilic and noneosinophilic CRSwNP, where OX40L/PD-L1(+) lesional DCs in eosinophilic CRSwNP could prime Th2 cells, whereas the low OX40L/PD-L1-expressing lesional DCs in noneosinophilic CRSwNP primarily induced Th1/Th17 cells.

[Relationship between tic symptom severity and amplitude of low frequency fluctuation of resting-state functional magnetic resonance imaging of Tourette syndrome].

OBJECTIVE: To examine the relationship between tic symptom severity and amplitude of low frequency fluctuation (ALFF) brain functioning of the first-episode Tourette syndrome through resting-state functional magnetic resonance imaging (fMRI). METHOD: Sixteen subjects were all recruited from the outpatient department of pediatrics, Beijing Anding Hospital, Capital Medical University and were all first-episode Tourette syndrome patients [male: 13, female: 3; age: 6-16 years; mean age: (11.00 ± 2.92) years]; mean education time: (5.06 ± 2.86) years; course: 14-104 months; mean (48.44 ± 25.00) months; scores of YGTSS at baseline: tic severity score: 37.88 ± 5.39; global damage score: 25.63 ± 12.63. All the subjects experienced resting-state fMRI scans and ALFF were calculated in three frequency ranges: 0.01-0.1 Hz, 0.01-0.027 Hz and 0.027-0.073 Hz. First-episode Tourette syndrome patients and 16 gender, age, and education-matched normal controls experienced resting-state fMRI scans. Correlation analysis was performed in between the amplitude of low frequency fluctuation (ALFF) and the severity of tic symptom. P < 0.05 and k value ≥ 10 were considered to be of significance. RESULT: In tic symptom patients, tic severity (total tic scores of YGTSS) was positively correlated with the ALFF values in the orbital part of left superior frontal gyrus (0.01-0.1 Hz:r = 0.83,0.027-0.073 Hz:r = 0.91, P < 0.05, respectively), right middle frontal gyrus (0.01-0.027 Hz:r = 0.85,0.027-0.073 Hz:r = 0.57, P < 0.05, respectively ) and orbital part of left middle frontal gyrus (0.01-0.027 Hz:r = 0.64, P < 0.05). Tic severity was negatively correlated with the ALFF values in the right calcarine fissure and surrounding cortex (0.01-0.1 Hz:r = -0.65,0.01-0.027 Hz:r = -0.69, P < 0.05, respectively ) and the left calcarine fissure and surrounding cortex (0.027-0.073 Hz:r = -0.81, P < 0.05). CONCLUSION: Tic symptom severity of the first-episode Tourette syndrome is associated with abnormal brain activity patterns of specific brain areas.

[Psychological trauma and crisis intervention in children after earthquake].

As a momentous disaster, earthquake would bring severe psychological trauma to children, with an adverse effect not only on the physiological functions, but also on their behaviors, emotions, and cognition, and the short-term and long-term consequences are much greater in children than in adults. The children of different ages have different psychological reactions, so psychological intervention varies with children's age. Psychological intervention is still important long afterwards to prevent permanent psychological trauma in children.

Abstinence from repeated amphetamine treatment induces depressive-like behaviors and oxidative damage in rat brain.

RATIONALE: Amphetamine has a significant potential for abuse and addiction. Among prolonged abusers, amphetamine withdrawal-induced depressive symptoms are common; however, their pathophysiological mechanism is not fully understood. Previously, we found that repeated treatment with amphetamine for 2 weeks induced oxidative stress in rat brain. OBJECTIVES: The purpose of the current study is to analyze whether abstinence from repeated amphetamine treatment in rats induces depressive-like behaviors and if oxidative damage in the brain continues during abstinence. METHODS: Rats were given repeated treatment with amphetamine once daily at 1, 2, or 4 mg/kg for 14 days. From 10 to 14 days after final amphetamine treatment, behavioral changes were monitored using open field test, novel object recognition test, and forced swim test. Oxidative damage in the medial frontal cortex and hippocampus was analyzed by immunohistochemistry. RESULTS: We found that drug abstinence after repeated amphetamine stimulation decreased locomotor activity and exploratory behavior in the open field test, increased immobility in the forced swim test, and had no significant effect on the recognition index in the novel object recognition test. We also found that amphetamine abstinence increased levels of 4-hydroxynonenal-protein adducts and 8-hydroxyguanosine in rat medial frontal cortex and in CA3 and dentate gyrus regions of the hippocampus. CONCLUSIONS: These results suggest that amphetamine abstinence displays depressive-like behaviors in rats and induces oxidative damage to lipids and RNA in rat brain. Our findings indicate that the process of oxidative stress may play a role in pathophysiological changes during drug abstinence from repeated amphetamine stimulation.

Clara cell 10-kDa protein inhibits T(H)17 responses through modulating dendritic cells in the setting of allergic rhinitis.

BACKGROUND: T(H)17 responses have recently been implicated to play a role in allergic airway diseases, but their local expression in the setting of allergic rhinitis (AR) and their regulation in allergic airway diseases remain unclear. OBJECTIVE: We sought to investigate the regulatory role of Clara cell 10-kDa protein (CC10), an endogenous regulator of airway inflammation, on T(H)17 responses in the setting of AR. METHODS: Wild-type and homozygous CC10-null mice were used to establish an ovalbumin (OVA)-induced AR model. Human recombinant CC10 was given during sensitization or challenge. T(H)17 responses in human subjects and mice were examined by using flow cytometry, quantitative RT-PCR assay, immunohistochemistry, and ELISA. The direct effect of CC10 on T(H)17 cells and CD11c(+) dendritic cells (DCs) was studied by means of cell culture. Adoptive transfer was used to examine the influence of CC10-conditioned DCs on airway inflammation. The regulatory effect of CC10 on the expression of the CCL20 gene was tested by using the BEAS-2B cell line. RESULTS: Compared with those of control subjects, T(H)17 responses were enhanced in the nasal mucosa of patients with AR. CC10-null mice with AR showed enhanced T(H)17 responses, and CC10 treatment significantly decreased T(H)17 responses. CC10 had no direct effect on in vitro T(H)17 cell differentiation. CC10 could significantly decrease the expression of OX40 ligand, IL-23, and IL-6 but enhance CD86 and TGF-ß expression in DCs. Importantly, CC10 was able to inhibit T(H)17 cell polarization in the presence of OVA-pulsed DCs. CC10 pretreatment inhibited T(H)17 responses elicited by adoptive transfer of OVA-pulsed DCs. Furthermore, CC10 decreased the expression of CCL20 in BEAS-2B cells induced by inflammatory cytokines. CONCLUSION: T(H)17 responses are enhanced in patients with AR, and CC10 inhibits T(H)17 responses through modulation of the function of DCs.

Clara cell 10-kDa protein gene transfection inhibits NF-κB activity in airway epithelial cells.

BACKGROUND: Clara cell 10-kDa protein (CC10) is a multifunctional protein with anti-inflammatory and immunomodulatory effects. Induction of CC10 expression by gene transfection may possess potential therapeutic effect. Nuclear factor κB (NF-κB) plays a key role in the inflammatory processes of airway diseases. METHOD/RESULTS: To investigate potential therapeutic effect of CC10 gene transfection in controlling airway inflammation and the underlying intracellular mechanisms, in this study, we constructed CC10 plasmid and transfected it into bronchial epithelial cell line BEAS-2B cells and CC10 knockout mice. In BEAS-2B cells, CC10's effect on interleukin (IL)-1ß induced IL-8 expression was explored by means of RT-PCR and ELISA and its effect on NF-κB classical signaling pathway was studied by luciferase reporter, western blot, and immunoprecipitation assay. The effect of endogenous CC10 on IL-1ß evoked IL-8 expression was studied by means of nasal explant culture. In mice, CC10's effect on IL-1ß induced IL-8 and nuclear p65 expression was examined by immunohistochemistry. First, we found that the CC10 gene transfer could inhibit IL-1ß induced IL-8 expression in BEAS-2B cells. Furthermore, we found that CC10 repressed IL-1ß induced NF-κB activation by inhibiting the phosphorylation of IκB-α but not IκB kinase-α/ß in BEAS-2B cells. Nevertheless, we did not observe a direct interaction between CC10 and p65 subunit in BEAS-2B cells. In nasal explant culture, we found that IL-1ß induced IL-8 expression was inversely correlated with CC10 levels in human sinonasal mucosa. In vivo study revealed that CC10 gene transfer could attenuate the increase of IL-8 and nuclear p65 staining in nasal epithelial cells in CC10 knockout mice evoked by IL-1ß administration. CONCLUSION: These results indicate that CC10 gene transfer may inhibit airway inflammation through suppressing the activation of NF-κB, which may provide us a new consideration in the therapy of airway inflammation.

Diagnostic significance of blood eosinophil count in eosinophilic chronic rhinosinusitis with nasal polyps in Chinese adults.

OBJECTIVES/HYPOTHESIS: Over half of chronic rhinosinusitis with nasal polyps (CRSwNP) patients in China show noneosinophilic inflammation. The aim of this study was to compare the clinical characteristics of eosinophilic and noneosinophilic CRSwNP and to identify the predictors of eosinophilic CRSwNP. STUDY DESIGN: A retrospective study. METHODS: There were 155 CRSwNP patients enrolled in the Tongji cohort. Eosinophilic CRSwNP was diagnosed according to our previously published histologic criterion. The demographic and clinical features were compared between eosinophilic and noneosinophilic CRSwNP. Factors associated with eosinophilic CRSwNP were determined with regression analysis, and optimal cutoff points of the predictors were determined by a receiver operating characteristic curve. The optimal cutoff points of the predictors were validated in an independent group of 35 CRSwNP patients referred to as the Taizhou cohort. RESULTS: A male preponderance, a higher prevalence of smoking and atopy, and higher peripheral blood eosinophil absolute count and percentage and blood IgE levels were found in eosinophilic CRSwNP compared with noneosinophilic CRSwNP. Peripheral eosinophil absolute count and percentage were independently and significantly associated with eosinophilic CRSwNP. An absolute blood eosinophil count ≥ 0.215 × 10(9) /L yielded a sensitivity of 74.2% and a specificity of 86.5%, and a blood eosinophil percentage ≥ 3.05% yielded a sensitivity of 80.3% and a specificity of 75.3% for the diagnosis of eosinophilic CRSwNP in the Tongji cohort. The validation study in the Taizhou cohort revealed a lower sensitivity and specificity. CONCLUSIONS: Eosinophilic and noneosinophilic CRSwNP displayed significant differences in certain clinical features. Peripheral blood eosinophil count could distinguish eosinophilic and noneosinophilic CRSwNP in Chinese adults.

Overexpression of miR-125b, a novel regulator of innate immunity, in eosinophilic chronic rhinosinusitis with nasal polyps.

RATIONALE: Eosinophilic chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) represents a hard-to-treat subtype of CRS. OBJECTIVES: To determine the pattern of expression and biologic role of microRNAs (miRNAs) in CRS, particularly in eosinophilic CRSwNP. METHODS: Global miRNA expression in sinonasal mucosa from controls, CRS without nasal polyps (CRSsNP), and patients with eosinophilic CRSwNP was compared using miRNA microarrays. MiR-125b expression was detected by means of quantitative reverse-transcriptase polymerase chain reaction. The cellular localization of miR-125b was determined by in situ hybridization. MiR-125b functional assays were performed on airway epithelial cells and mice. MiR-125b expression regulation was studied by tissue and cell culture. MEASUREMENTS AND MAIN RESULTS: CRSsNP and eosinophilic CRSwNP exhibited distinct miRNA expression profiles. MiR-125b was specifically up-regulated in eosinophilic CRSwNP. MiR-125b was mainly expressed by sinonasal and bronchial epithelial cells. EIF4E-binding protein 1 (4E-BP1) was identified as a direct target of miR-125b. MiR-125b mimic or inhibitor enhanced or decreased IFN-α/ß production elicited by dsRNA in vitro or in vivo, respectively. 4E-BP1 expression was decreased, whereas IFN regulatory factor-7 and IFN-ß expression was increased, in eosinophilic CRSwNP. IFN-ß mRNA levels positively correlated with IL-5 mRNA levels and eosinophil infiltration in sinonasal mucosa. IFN-ß stimulated B cell-activating factor of the tumor necrosis factor family production in airway epithelial cells. miR-125b could be induced by lipopolysaccharide, dsRNA, and IL-10. CONCLUSIONS: The up-regulated expression of miR-125b may enhance type I IFN expression through suppressing 4E-BP1 protein expression in airway epithelial cells, which potentially contributes to mucosal eosinophilia in eosinophilic CRSwNP.