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Objective. This systematic review and meta-analysis aimed to compare the diagnostic performance of transient elastography (TE) and two-dimensional shear wave elastography (2D-SWE) for staging liver fibrosis in patients with chronic viral hepatitis (CVH). Methods. Pubmed, Embase, Web of Science, and Cochrane Library were searched (-01/08/2021) for studies comparing TE with 2D-SWE in patients with CVH. Other etiologies of chronic liver disease (CLD) and articles not published in SCI journals were excluded. The bivariate random-effects model was used to pool the performance of the TE and 2D-SWE. Results. Eight articles with a total of 1301 CVH patients were included. The prevalence of significant fibrosis ( fibrosis stage ≥ 2 ), advanced fibrosis ( fibrosis stage ≥ 3 ), and cirrhosis was 50.8%, 44.8%, and 34.7%, respectively. 2D-SWE expressed higher overall accuracy than TE in detecting significant fibrosis (0.93 vs. 0.85, P = 0.04 ). No significant difference among the overall diagnostic accuracy of TE and 2D-SWE in staging advanced fibrosis and cirrhosis was found. Conclusion. TE and 2D-SWE express good to excellent diagnostic accuracies to stage fibrosis in CVH patients. 2D-SWE compares favorably with TE especially for predicting significant fibrosis.

OBJECTIVE Developmental and epileptic encephalopathy (DEE) is characterized by refractory seizures, developmental delay or intellectual disability, which may be caused by gene mutation. In this study, we explored the clinical phenotype and long-term outcome in children with genetic early-infantile-onset DEEs. METHODS Next-generation sequencing was performed on 470 patients diagnosed with early-infantile-onset DEE between 2010 and 2020. The genetic variation in all cases was classified and evaluated to identify pathogenic variants. The identified variants were further verified by Sanger sequencing. RESULTS A total of 118 and 10 patients were found to have putative disease-causing gene mutations and copy number variations, respectively. SCN1A mutations were detected in 38 patients (38/118, 32.2%), representing the largest proportion. In patients with early-infantile-onset DEE with burst suppression, KCNQ2 mutation was found in six patients, and the remaining mutations were reported in SCN2A (n=2) and STXBP1 (n=1). Seven patients with dyskinesia were described. In patients with non-syndromic genetic early-infantile-onset DEEs, we detected possible rare pathogenic variants in SETBP1, DPYD, CSNK2B, and H3F3A. With regards to inheritance pattern, de novo heterozygous mutations accounted for the majority (104/118; 88.1%). Three patients with SMC1A mutations responded well to ketogenic diet add-on therapy. Addition of valproic acid showed good therapeutic effects against KCNB1 and PACS2 encephalopathy. SIGNIFICANCE We detected four possible rare pathogenic gene variants as non-syndromic genetic causes of early-infantile-onset DEEs. Although early-infantile-onset DEEs responded poorly to antiseizure medication treatment, we found that specific antiseizure medications showed good therapeutic effects in some patients with early-infantile-onset DEEs harbouring gene variants.

Pathogenic variants in SCN8A have been demonstrated with a wide spectrum of epilepsy phenotypes, ranging from benign infantile epilepsy (BIE), to early onset developmental and epileptic encephalopathy (DEE) with moderate to severe developmental delay. In order to provide further insight on the spectrum of SCN8A-related epilepsy, we aimed to explore the clinical and genetic phenotype in Chinese children.A cohort of fifty Chinese patients with SCN8A-related disorders was included in the retrospective study. Genetic and clinical features and treatment effect of patients were further assessed based on phenotype parameters. The pathogenicity of variants was classified using the next-generation sequencing variation study.We found 50 patients who presented with severe developmental and epileptic encephalopathy (DEE, 70%), benign infantile epilepsy (BIE, 12%), developmental encephalopathy with epilepsy (16%), and severe developmental delay without epilepsy (2%). The seizure onset age ranged from 1 day to 1 year and 11 months. After anti-seizure treatment, 28% of patients obtained seizure control. Sodium channel blockers showed good prognosis in 26% of patients with severe DEE. Oxcarbazepine (OXC) monotherapy was obviously effective in patients with BIE and developmental encephalopathy with epilepsy, most importantly, 87.5% received the anti-seizure therapy with sodium channel blockers in combination. All the variants were de novo missense with exception of one splice site variant. We reported three new variants, Asn1887Ser, Ile1605Thr, and Met1869Thr, which were associated with SCN8A-BIE.The phenotypic spectrum of SCN8A-related disorders in Chinese children ranged from severe developmental delay without epilepsy to severe DEE. Three new variants were associated with SCN8A-BIE. Sodium channel blockers were effective in treating seizures for some SCN8A-related disorders however may not be relevant to the mutant location.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome involved in many organ systems. At the same time, epilepsy is the most common manifestation and more than 50% of TSC patients present with intractable epilepsy. This study investigated the efficacy and safety of optimized and high-density stereoelectroencephalography (SEEG) guided radiofrequency thermocoagulation (RF-TC) in treating TSC-related epilepsy.Nine TSC children with refractory epilepsy were treated with first-stage SEEG-Guided RF-TC, and four underwent second-stage-optimized high-density array of SEEG-Guided RF-TC. Patients' clinical data and postoperative outcomes were analyzed retrospectively.The patients' median age at surgery was 4 years and 2 month (range from 3 years and 5 month to 16 years and 7 month). The mean age at surgery was 6.7 years old. Eight in 9 (88.9%) patients achieved complete remission after the final operation at half-year follow-up. Of seven patients with final postoperative time beyond 1 year, 6 (85.7%) reached completely seizure-free. No severe or long-term neurologic impairment existed in all nine patients.Optimized high-density array of SEEG-guided RF-TC is a safe and highly effective approach and can be an alternative application applied for TSC patients with refractory epilepsy.

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with limited treatment options and unclear etiology. Vagus nerve stimulation (VNS) is an FDA-approved therapy for refractory epilepsy that has been shown to decrease the frequency and severity of seizures. There is a growing interest in alternate non-pharmaceutical therapies for managing super-refractory status epilepticus (SRSE). We present a 29-month-old case, diagnosed with FIRES, whose seizures were successfully controlled by utilization of VNS after ineffective response to intensive pharmacotherapy and ketogenic diet treatment. The VNS was planted after 14 days of refractory seizure activity with a following rapid parameter titration for 42 days without evident side effect, which finally controlled the seizure in the acute phase. VNS may be a potential candidate for the treatment of SRSE in FIRES.

Purpose To compare small incision lenticule extraction with prophylactic cross-linking (SMILE Xtra) and femtosecond laser-assisted in situ keratomileusis with prophylactic cross-linking (FS-LASIK Xtra) in their safety, efficacy, predictability, and stability. Methods This is a prospective cohort study. Forty-eight eyes subjected to SMILE Xtra and 90 eyes subjected to FS-LASIK Xtra were enrolled. The enrolled eyes exhibited either borderline corneal topography or high myopia with thin cornea. The following parameters were evaluated before surgery and at 1 day; 1 week; and 1, 3, 6, and 12 months after surgery: corrected distance visual acuity, uncorrected distance visual acuity, manifest refractive spherical equivalent (MRSE), keratometry values, and thinnest corneal thickness. Results After 1 month, no eye showed loss of 1 or more lines of corrected distance visual acuity. At 12 months, uncorrected distance visual acuity was 20/20 or better for 98% and 99% eyes in the SMILE Xtra and FS-LASIK Xtra groups, respectively (P = 0.657). For 93.8% eyes in the SMILE Xtra group and 90% eyes in the FS-LASIK Xtra group, the achieved MRSE was within ±0.50 diopter of the intended MRSE (P = 0.669). The correlation coefficients for predictability of MRSE correction by SMILE Xtra and FS-LASIK Xtra were 0.987 and 0.983, respectively. The mean MRSE values, keratometry values, and thinnest corneal thickness measured at the different time points showed no significant intra- or intergroup differences. Conclusions Our evaluations of 1-year outcomes suggest that the safety, efficacy, predictability, and stability of SMILE Xtra are comparable with those of FS-LASIK Xtra.

To explore novel topoisomerase inhibitors with high activity and druggability, 3-aryl isoquinoline alkaloids based on the corydamine modification and preliminary SARs of isoquinoline alkaloids in our previous works were re-designed. Currently, the design strategy is mainly revolved around the rigidity and flexibility of the molecular side chain and the molecular size. Consequently, not only the activity and druggability of the compound could be further improved, also the mechanism behind could been discovered. In vitro pharmacological studies, the outstanding nature with the excellent activity and the researchable depth of azepane-substituted compound 7 has been found through the vitro cytotoxicity test (IC

The blocking function of allergen-specific F(ab')To investigate the inhibitory function of sIgG, sF(ab')This study involved 10 subjects (aged 18-42 years) with house dust mite allergic rhinitis or asthma who received a 156-week course of Der-p SCIT. Total IgG levels were purified from the serum of the participants at weeks 0 and 156 by protein A affinity chromatography. Der-p sIgG was purified by affinity chromatography with Der-p as a ligand at week 156. The sF(ab')We found that the Der-p sIgG, sF(ab')SCIT-induced Der-p sIgG, sF(ab')This study was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University and registered in the Chinese Clinical Trial Registry (ChiCTR-OOC-15006207, https://www.chictr.org.cn/enindex.aspx).

Whether Dermatophagoides pteronyssinus (Der-p) allergen immunotherapy (AIT) can induce Dermatophagoides farina (Der-f)-specific immunoglobulin (sIg) G4 production, and tolerance to environmental allergens has not been fully investigated.We aimed to determine serum Der-p-sIgG4 and Der-f-sIgG4 levels in asthma and/or rhinitis patients undergoing Der-p AIT and their ability to reduce immune responses triggered by indoor dust extracts.We performed a real-world prospective trial and enrolled patients with allergic rhinitis and/or asthma in Guangzhou, China. These patients received either Der-p AIT (SCIT group) or routine medications (non-SCIT group) for 156 weeks. Clinical outcomes were assessed by the combined symptom medication score (SMS) and FEVOur study enrolled a total of 60 participants, with 30 patients in each group. Patients in the SCIT group had significantly improved SMS when compared with the baseline and the patients in the non-SCIT group. Median levels of Der-p 1 and Der-f 1 in indoor dust extract were 1.86 μg/g and 4.74 μg/g, respectively. Serum Der-p-sIgG4 and Der-f-IgG4 levels in SCIT patients showed a significant increase from weeks 12 to 156. Serum in these SCIT patients could significantly block Der-p, Der-f and indoor dust extract formation of allergen-sIgE complex and reduced the threshold of IgE-FAB from 16 weeks after the initiation of the treatment. The capacity to inhibit Der-p, Der-f and indoor dust extract BATI was observed in SCIT serum after 12 weeks. Der-p-sIgG4 and Der-f-sIgG4 had a significant correlation with IgE-FAB and BATI in SCIT patients at all time points.Single Der-p immunotherapy induced both Der-p-sIgG4 and Der-f-sIgG4 production, which might cross-reactively induce tolerance against environmental allergen exposure in patients with asthma and/or rhinitis.

OBJECTIVE This article describes a digital workflow using virtual enamel evaluation and a stereolithographic template for accurate tooth preparation for a complex exogenous dental erosion. CLINICAL CONSIDERATIONS A 22-year-old man with different degrees of defects on the labial surface in esthetic area was diagnosed as exogenous dental erosion. The residual undamaged enamel area and depth of defect were measured and analyzed accurately by creating a digital virtual patient based on the pretreatment data. According to the different conditions of residual enamel and tooth defect, the treatment plans of porcelain veneer, crown and composite resin were chosen for corresponding involved teeth. Based on the virtual wax-up and the suggested material thickness, a template for tooth preparation was designed and three-dimensional printed. This template together with a special bur indicating the reduction depth accurately guided the teeth preparation and achieved a long-term effect. CONCLUSIONS The virtual enamel evaluation contributes to obtaining the appropriate corresponding treatment plan objectively. The stereolithographic template effectively meets the accuracy of tooth preparation, preserving the tooth hard tissue to the greatest extent. CLINICAL SIGNIFICANCE The digital workflow described here may provide a quantifiable evaluation method and an accurate tooth preparation method for exogenous dental erosion.

The immunomes of Ehrlichia chaffeensis and Ehrlichia canis have recently been revised to include immunodominant hypothetical proteins with conformational antibody epitopes. In this study, we examined 216 E. chaffeensis and 190 E. canis highly antigenic proteins according to ANTIGENpro and also performed a genome-wide hypothetical protein analysis (E. chaffeensis n = 104; E. canis n = 124) for immunoreactivity. Using cell-free protein expression and immunoanalysis, 118 E. chaffeensis and 39 E. canis proteins reacted with sera from naturally E. chaffeensis-infected patients or E. canis-infected dogs. Moreover, 22 E. chaffeensis and 18 E. canis proteins consistently and strongly reacted with a panel of patient or canine sera. A subset of E. chaffeensis (n = 18) and E. canis (n = 9) proteins were identified as immunodominant. Consistent with our previous study, most proteins were classified as hypothetical, and the antibody epitopes exhibited complete or partial conformation dependence. The majority (28/40, 70%) of E. chaffeensis and E. canis proteins contained transmembrane domains, and 19 (48%) were predicted to be secreted effectors. The antigenic repertoires of E. chaffeensis and E. canis were mostly diverse and suggest that the immunomes of these closely related ehrlichiae are dominated by species-specific conformational antibody epitopes. This study reveals a significant group of previously undefined E. chaffeensis and E. canis antigens and reaffirms the importance of conformation-dependent epitopes as targets of anti-Ehrlichia immune responses. These findings substantially expand our understanding of host-Ehrlichia immune responses, advance efforts to define the molecular features of protective proteins, and improve prospects for effective vaccines for the ehrlichioses.

Objective. Mixing/dissociation of sleep stages in narcolepsy adds to the difficulty in automatic sleep staging. Moreover, automatic analytical studies for narcolepsy and multiple sleep latency test (MSLT) have only done automatic sleep staging without leveraging the sleep stage profile for further patient identification. This study aims to establish an automatic narcolepsy detection method for MSLT. Approach. We construct a two-phase model on MSLT recordings, where ambiguous sleep staging and sleep transition dynamics make joint efforts to address this issue. In phase 1, we extract representative features from electroencephalogram (EEG) and electrooculogram (EOG) signals. Then, the features are input to an EasyEnsemble classifier for automatic sleep staging. In phase 2, we investigate sleep transition dynamics, including sleep stage transitions and sleep stages, and output likelihood of narcolepsy by virtue of principal component analysis (PCA) and a logistic regression classifier. To demonstrate the proposed framework in clinical application, we conduct experiments on 24 participants from the Children’s Hospital of Fudan University, considering ten patients with narcolepsy and fourteen patients with MSLT negative. Main results. Applying the two-phase leave-one-subject-out testing scheme, the model reaches an accuracy, sensitivity, and specificity of 87.5%, 80.0%, and 92.9% for narcolepsy detection. Influenced by disease pathology, accuracy of automatic sleep staging in narcolepsy appears to decrease compared to that in the non-narcoleptic population. Significance. This method can automatically and efficiently distinguish patients with narcolepsy based on MSLT. It probes into the amalgamation of automatic sleep staging and sleep transition dynamics for narcolepsy detection, which would assist clinic and neuroelectrophysiology specialists in visual interpretation and diagnosis.

Glioblastoma is one of the most lethal brain tumors. The crucial chemotherapy is mainly alkylating agents with modest clinical success. Given this desperate need and inspired by the encouraging results of a phase II trial via concomitant Topo I inhibitor plus COX-2 inhibitor, we designed a series of N-2-(phenylamino) benzamide derivatives as novel anti-glioblastoma agents based on structure modification on 1,5-naphthyridine derivatives (Topo I inhibitors). Notably, the target compounds I-1 (33.61 ± 1.15 μM) and I-8 (45.01 ± 2.37 μM) were confirmed to inhibit COX-2, while a previous reported compound (1,5-naphthyridine derivative) resulted nearly inactive towards COX-2 (IC50 > 150 μM). Besides, I-1 and I-8 exhibited higher anti-proliferation, anti-migration, anti-invasion effects than the parent compound 1,5-naphthyridine derivative, suggesting the success of modification based on the parent. Moreover, I-1 obviously repressed tumor growth in the C6 glioma orthotopic model (TGI = 66.7%) and U87MG xenograft model (TGI = 69.4%). Besides, I-1 downregulated PGE2, VEGF, MMP-9, and STAT3 activation, upregulated E-cadherin in the orthotopic model. More importantly, I-1 showed higher safety than temozolomide and different mechanism from temozolomide in the C6 glioma orthotopic model. All the evidence demonstrated that N-2-(phenylamino) benzamide derivatives as novel anti-glioblastoma agents could be promising for the glioma management.

This study aimed to evaluate the effectiveness of tamsulosin monotherapy for the treatment of ureteral stent-related symptoms (SRSs) and compare it with that of solifenacin monotherapy and combined therapy of tamsulosin and silifenacin. Randomized controlled trials (RCTs), which evaluated the effectiveness of tamsulosin for the treatment of SRSs, were searched from the databases PubMed, EMBASE and the Cochrane Library published up to November 2018. Eight RCTs involving 1087 participants were finally included in this meta-analysis. The results showed that tamsulosin monotherapy could significantly decrease the urinary symptoms [mean difference (MD) -7.56, 95% confidence interval (CI) (-11.47, -3.65), P=0.0001] and body pain [MD -5.25, 95% CI (-8.03, -2.46), P=0.0002], and improve the sexual performance [MD -1.06, 95% CI (-1.89, -0.24), P=0.01] compared with the control group. Moreover, there was no significant difference between tamsulosin monotherapy and solifenacin monotherapy in all outcomes except for significantly better sexual performance in solifenacin group [MD 0.29, 95% CI (0.06, 0.51), P=0.01]. In addition, the effectiveness of combined therapy of tamsulosin and solifenacin was not superior to that of tamsulosin monotherapy. Our study demonstrated that tamsulosin monotherapy was effective for the treatment of patients with SRSs; evident superiority could not be found for therapy of tamsulosin and solifenacin combined.

Ehrlichia chaffeensis expresses the TRP120 multifunctional effector, which is known to play a role in phagocytic entry, on the surface of infectious dense-cored ehrlichiae, but a cognate host receptor has not been identified. We recently reported that E. chaffeensis activates canonical Wnt signaling in monocytes to promote bacterial uptake and intracellular survival and that TRP120 was involved in this activation event. To identify the specific mechanism of pathway activation, we hypothesized that TRP120 is a Wnt signaling ligand mimetic that initiates Wnt pathway activity through direct interaction with the Wnt pathway Frizzled family of receptors. In this study, we used confocal immunofluorescence microscopy to demonstrate very strong colocalization between E. chaffeensis and Fzd2, 4, 5, 7, and 9 as well as coreceptor LRP5 at 1 to 3 h postinfection. Direct binding between TRP120 and multiple Fzd receptors was further confirmed by enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR). Interfering RNA knockdown of Wnt receptors, coreceptors, and signaling pathway components significantly reduced E. chaffeensis infection, demonstrating that complex and redundant interactions are involved in Wnt pathway exploitation. We utilized in silico approaches to identify a repetitive short linear motif (SLiM) in TRP120 that is homologous to Wnt ligands and used mutant SLiM peptides and an α-TRP120-Wnt-SLiM antibody to demonstrate that the TRP120 Wnt SLiM activates the canonical Wnt pathway and promotes E. chaffeensis infection. This study reports the first example of bacterial mimicry of Wnt pathway ligands and highlights a pathogenic mechanism with potential for targeting by antimicrobial therapeutics. IMPORTANCE Upon infecting mammalian hosts, Ehrlichia chaffeensis establishes a replicative niche in microbe-eating immune system cells where it expertly orchestrates infection and spread. One of the ways Ehrlichia survives within these phagocytes is by activating evolutionarily conserved signaling pathways including the Wnt pathway; however, the molecular details of pathway hijacking have not been defined. This study is significant because it identifies an ehrlichial protein that directly interacts with components of the Wnt receptor complex, influencing pathway activity and promoting infection. Consequentially, Ehrlichia serves as a unique tool to investigate the intricacies of how pathogens repurpose human immune cell signaling and provides an opportunity to better understand many cellular processes in health and disease. Furthermore, understanding how this bacterium utilizes its small genome to survive within cells that evolved to destroy pathogens will facilitate the development of antibacterial therapeutics that could target Ehrlichia as well as other intracellular agents of human disease.

Isoquinoline alkaloid displays significant anti-gastric cancer effects due to its unique structure, which is attracting more and more attention for the development of anti-gastric cancer drugs. In this study, we explore the active components against gastric cancer from the Tibetan Medicine Corydalis hendersonii Hemsl, which is rich in isoquinoline alkaloids. 14 compounds including 2 previously undescribed natural products were obtained. Interestingly, an new active compound displays potent anti-gastric cancer activity. After accomplishing the total syntheses of the active compound and its derivatives, the anti-gastric cancer activity of the active compound was further investigated. In vitro experiments revealed that the active compound significantly attenuated the proliferative capacity, caused G2/M phase arrest, inhibited the cell migration and invasion, and induced cell apoptosis. Mechanistically, the active compound could increase the Bax/Bcl-2 ratio, elevate cytochrome c in the cytosol, and activate caspase-9/3, along with inactivating the upstream PI3K/Akt/mTOR signaling pathway. In addition, the active compound could also cause gastric cancer cell death by inhibiting topoisomerase I activity. More importantly, the anti-gastric cancer activity of the active compound was confirmed in MGC-803 xenograft nude mice in vivo. This work not only promotes the exploitation of Corydalis hendersonii Hemsl., but also provides some experience for discovering new entities from natural sources.

The combination between two well-studied bioactive compounds melatonin and salicylic acid with proper modifications unexpectedly creates a sharp pair of “scissors” cutting off the vicious connection between inflammation and cancer by targeting a key contributor Signal Transducers and Activators of Transcription 3 (STAT3) in the two pathological processes. A representative compound P-3 with IC50 values on each tested cell line ranging from 7.37 to 18.62 μM among the designed melatonin derivatives is equipped with the ability of curbing inflammation-promoting cancer by down-regulating the expression, activation and nuclear translocation of STAT3, breaking the feedforward loop of STAT3 activation by decreasing the expression of pro-tumorigenic cytokines, and inducing cell apoptosis through ROS triggered Cyto-c/Caspase-3 pathway. This study suggests that the melatonin derivative P-3 is likely to become a promising chemical structure for developing the novel anti-cancer agents taking effect through hindering the mutual-promoting processes between inflammation and cancer.

This article describes the syntheses and biological activity of five 3-arylisoquinoline natural products corydamine (1), N-formyl Corydamine (2), hypecumine (3), Decumbenine B (XW) and 2-(1,3-dioxolo [4,5-h]isoquinolin-7-yl)-4,5-dimethoxy-N-methyl-Benzeneethanamine (A), and twelve analogues. Among them, 1, 2, and A were synthesized for the first time. In vitro screening for anti-proliferative activity showed that derivative 1a could significantly inhibit the proliferation of HCC cells (IC50 = 9.82 μM on Huh7 cells and 6.83 μM on LM9 cells), and arrest cell cycle at G2/M phase. The mechanistic studies further suggested compound 1a was a dual inhibitor of Topo I and Topo II, and Topo II inhibitory activity was superior to etoposide. In addition, 1a could significantly inhibit the invasion and migration of cancer cells by inhibiting the expression of MMP-9, and induce apoptosis through inhibiting the activation of the PI3K/Akt/mTOR signaling pathway. Moreover, in vivo studies demonstrated 1a could obviously reduce the growth of xenograft tumor and possessed good pharmacokinetic parameters, which indicated the potential value of 1a in treating liver cancer.

To evaluate the clinical effect of the position of stimulation contacts relative to the hyperdirect pathway (HDP) on the alleviation of motor symptoms in patients with Parkinson disease (PD).A group of 11 patients diagnosed with idiopathic PD were included in this study, and all selected targets were in the subthalamic nucleus (STN). In 1 patient, a single side electrode was implanted because of unilateral symptoms; in all other patients, bilateral electrodes each containing 4 discrete contacts were implanted. Nine contacts were excluded due to adverse reactions caused by stimulation, and thus a total of 75 active contacts were evaluated using the same stimulus parameters. Fiber tractography results were individually processed using StealthViz software before all data were subjected to statistical analysis.Under the same stimulus parameters, the shortest distance of each contact to the HDP was smaller in group I (n = 45;50% improvement rate) compared with group II (n = 30; ≤50% improvement rate) (mean, 1.18 ± 0.86 mm vs. 2.14 ± 1.20 mm; t = 3.78; P0.05), and the shortest distance had a negative correlation with the improvement of motor symptoms (r = -0.48; P0.05).Stimulation of the HDP coincided with the improvement of motor symptoms in patients with PD. We propose an improvement of the direct visualization method based on diffusion tensor imaging fiber tractography of the HDP to select the motor part of the STN. Further rigorous clinical trials are needed to verify the value of this method for achieving precise target location and individualized treatment.

Capillary electrophoresis (CE) with ultraviolet detection was applied to determine underivatized amino acids in beer, based on the coordination interaction of copper ions and amino acids. An online sweeping technique was combined with CE to improve detection sensitivity. Using the United Nations Food Agriculture Organization/World Health Organization model of essential amino acid pattern and flavor of amino acids, the quality and taste in three kinds of beer were evaluated. It was found that Beer2 had higher quality than the other two kinds and the content of phenylalanine, proline, serine, and isoleucine was relatively large in all three kinds of beers with a great influence on beer flavor. Optimal conditions for separation were as follows: 50mM CuSO 4 at pH 4.40 as buffer; total length of fused silica capillary, 73 cm; effective length, 65 cm; separation voltage, 22.5 kV; and optimized sweeping condition, 70 seconds. In the appropriate range, linearity ( r 2 > 0.9989), precision with a relative standard deviation n = 5), limits of detection (0.13–0.25 μg/mL), limit of quantification (0.43–0.83 μg/mL), and recovery (80.5–115.8%) were measured. This method was shown to be applicable to the separation of amino acids in beer and to perform quantitative analysis directly without derivatization for the first time.

3D printing technology can be used in prosthodontics to obtain detailed structures. The technique offers a possible supersession for the most conventional restorations technologies. Contemporary aesthetic restorations encounter difficulties in the consistency between the analysis and design stages and the clinical implementation stage. 3D printing transfers aesthetic designs to customize the finial restoration fabrication, which could be an appropriate optimization to the aformentioned problem. Meanwhile, 3D printing technology can be employed to manufacture target restoration space guide (TRS guide), which is a blueprint for the aesthetic ceramic restorations and presents a general functional and aesthetic situation of patients. The guidance provided by TRS guide ensures precision and minimal invasive operation in aesthetic restorations. These new digital technologies have revolutionized aesthetic rehabilitation. This paper introduces the application of 3D printing in aesthetic oral rehabilitation.3D打印技术可完成结构复杂物体的打印，在口腔修复领域已有一定应用，未来有望替代大部分传统修复技术。在口腔美学修复中如何保证分析设计阶段初设的轮廓外形与颜色等与患者得到的最终修复体一致，一直是困扰口腔医师和技师的难题。3D打印的蜡型、树脂冠桥等可用于美学修复的美学分析和设计结果的输出预告，一对一地传递并指导最终修复体的设计和制作。3D打印的目标修复体导板（TRSguide）既为美学修复制定了可预览的修复蓝图，让口腔医师和技师能检测患者重建的口腔功能和美学的相关信息；又能指导实施符合牙体保存和活髓保护理念的理想牙预备，做到真正的全程精准与微创。这些新的数字化技术进展使得美学修复焕然一新。本文对3D打印在口腔美学修复中的应用进行介绍。.

Candida albicans is an opportunistic human pathogen, and its pathogenicity is associated with hyphal formation. Previous studies have shown that at neutral-to-alkaline pH, hyphal growth is dependent on the Rim101 pathway whose activation requires Snf7, a member of the ESCRT system. In this work, we described the purification and characterization of the C. albicans Vps4, an AAA ATPase required for recycling of the ESCRTs. Its role on hyphal growth has been investigated. Our data suggest deletion of Vps4 decreases overall hyphal growth at pH 7 and increases the growth of multiple hyphae induced by serum, which indicates that the ESCRTs may make a Rim101-independent contribution to hyphal growth. Furthermore, DBeQ, an inhibitor of the AAA ATPase p97, was shown to inhibit the ATPase activity of Vps4 with an IC50 of about 11.5 μM. To a less degree, it also inhibits hyphal growth. Our work may provide a new strategy to control C. albicans infection.

In multicellular organisms, autophagy is induced as an innate defense mechanism. Notably, the obligate intracellular bacterium Ehrlichia chaffeensis resides in early endosome-like vacuoles and circumvents lysosomal fusion through an unknown mechanism, thereby avoiding destruction in the autophagolysosome. In this report, we reveal that Wnt signaling plays a crucial role in inhibition of lysosomal fusion and autolysosomal destruction of ehrlichiae. During early infection, autophagosomes fuse with ehrlichial vacuoles to form an amphisome indicated by the presence of autophagy markers such as LC3 (microtubule-associated protein 1 light chain 3), Beclin-1, and p62. LC3 colocalized with ehrlichial morulae on days 1, 2, and 3 postinfection, and increased LC3II levels were detected during infection, reaching a maximal level on day 3. Ehrlichial vacuoles did not colocalize with the lysosomal marker LAMP2, and lysosomes were redistributed and dramatically reduced in level in the infected cells. An inhibitor specific for the Wnt receptor signaling component Dishevelled induced lysosomal fusion with ehrlichial inclusions corresponding to p62 degradation and promoted transcription factor EB (TFEB) nuclear localization. E. chaffeensis infection activated the phosphatidylinositol 3-kinase (PI3K)–Akt–mTOR (mechanistic target of rapamycin) pathway, and activation was induced by three ehrlichial tandem repeat protein (TRP) effectors, with TRP120 inducing the strongest activation. Moreover, induction of glycogen synthase kinase-3 (GSK3) performed using a Wnt inhibitor and small interfering RNA (siRNA) knockdown of critical components of PI3K-GSK3-mTOR signaling decreased ehrlichial survival. This report reveals Ehrlichia exploitation of the evolutionarily conserved Wnt pathway to inhibit autolysosome generation, thereby leading to evasion of this important innate immune defense mechanism.

Ehrlichia chaffeensis is an obligately intracellular Gram-negative bacterium that selectively infects mononuclear phagocytes. We recently reported that E. chaffeensis utilizes a type 1 secretion (T1S) system to export tandem repeat protein (TRP) effectors and demonstrated that these effectors interact with a functionally diverse array of host proteins. By way of these interactions, TRP effectors modulate host cell functions; however, the molecular basis of these interactions and their roles in ehrlichial pathobiology are not well defined. In this study, we describe the first bacterial protein posttranslational modification (PTM) by the small ubiquitin-like modifier (SUMO). The E. chaffeensis T1S effector TRP120 is conjugated to SUMO at a carboxy-terminal canonical consensus SUMO conjugation motif in vitro and in human cells. In human cells, TRP120 was selectively conjugated with SUMO2/3 isoforms. Disruption of TRP120 SUMOylation perturbed interactions with known host proteins, through predicted SUMO interaction motif-dependent and -independent mechanisms. E. chaffeensis infection did not result in dramatic changes in the global host SUMOylated protein profile, but a robust colocalization of predominately SUMO1 with ehrlichial inclusions was observed. Inhibiting the SUMO pathway with a small-molecule inhibitor had a significant impact on E. chaffeensis replication and recruitment of the TRP120-interacting protein polycomb group ring finger protein 5 (PCGF5) to the inclusion, indicating that the SUMO pathway is critical for intracellular survival. This study reveals the novel exploitation of the SUMO pathway by Ehrlichia , which facilitates effector-eukaryote interactions necessary to usurp the host and create a permissive intracellular niche.

Determining the complex relationships between diseases, polymorphisms in human genes and environmental factors is challenging. Multifactor dimensionality reduction (MDR) has been proven to be capable of effectively detecting the statistical patterns of epistasis, although classification accuracy is required for this approach. The imbalanced dataset can cause seriously negative effects on classification accuracy. Moreover, MDR methods cannot quantitatively assess the disease risk of genotype combinations. Hence, we introduce a novel weighted risk score-based multifactor dimensionality reduction (WRSMDR) method that uses the Bayesian posterior probability of polymorphism combinations as a new quantitative measure of disease risk. First, we compared the WRSMDR to the MDR method in simulated datasets. Our results showed that the WRSMDR method had reasonable power to identify high-order gene-gene interactions, and it was more effective than MDR at detecting four-locus models. Moreover, WRSMDR reveals more information regarding the effect of genotype combination on the disease risk, and the result was easier to determine and apply than with MDR. Finally, we applied WRSMDR to a nasopharyngeal carcinoma (NPC) case-control study and identified a statistically significant high-order interaction among three polymorphisms: rs2860580, rs11865086 and rs2305806.

Allopurinol is used widely for the treatment of gout, but its pharmacokinetics is complex and some patients show hypersensitivity, necessitating careful monitoring and improved detection methods. In this study, a sensitive and reliable liquid chromatography-tandem mass spectrometry method was developed to determine the concentrations of allopurinol and its active metabolite oxypurinol in human plasma and urine using 2,6-dichloropurine as the internal standard (IS). Analytes and the IS were extracted from 0.5 ml aliquots of plasma or urine using ethyl acetate and separated on an Agilent Eclipse Plus C18 column using methanol and ammonium formate–formic acid buffer containing 5 mM ammonium formate and 0.1% formic acid (95:5, v/v) as the mobile phase (A) for allopurinol or methanol plus 5 mM ammonium formate aqueous solution (95:5, v/v) as the mobile phase (B) for oxypurinol. Allopurinol was detected in positive ion mode and the analysis time was about 7 min. The calibration curve was linear from 0.05 to 5 μg/mL allopurinol in plasma and 0.5–30 μg/mL in urine. The lower limit of quantification (LLOQ) was 0.05 μg/mL in plasma and 0.5 μg/mL in urine. The intra- and inter-day precision and relative errors of quality control (QC) samples were ≤11.1% for plasma and ≤ 8.7% for urine. Oxypurinol was detected in negative mode with an analysis time of about 4 min. The calibration curve was linear from 0.05 to 5 μg/mL in plasma (LLOQ, 0.05 μg/mL) and from 1 to 50 μg/mL in urine (LLOQ, 1 μg/mL). The intra- and inter-day precision and relative errors were ≤7.0% for plasma and ≤9.6% for urine. This method was then successfully applied to investigate the pharmacokinetics of allopurinol and oxypurinol in humans.

Objective: To examine the effects of whole-body vibration on neuromuscular performance in people with spinal cord injury and evaluate the safe and effective vibration protocols. Methods: PubMed, EMBASE, CINAHL and PEDro were mainly searched for English literatures. Other data sources were ClinicalTrials.gov , Current Controlled Trials and reference lists of all relevant articles. The PEDro scale was used to evaluate the methodological quality, and the Oxford Centre for Evidence-based Medicine level of evidence was used to assess the level of evidence. Basic information and whole-body vibration protocols were extracted by two independent researchers. Any disagreements were resolved by the third researcher. Results: Of the eight included studies involving 94 individuals with spinal cord injury and 24 able-bodied participants, six of them reported beneficial effects of whole-body vibration on muscle activation and the other two on muscle spasticity. Based on the reviewed studies, an intermittent mode of whole-body vibration (frequency: 10–50 Hz; amplitude: 0.6–4 mm) is less likely to cause adverse events when applying to spinal cord injury subjects standing on platform (knees flexed at 10°–40°). Conclusions: The strength of evidence is insufficient in supporting the benefits of whole-body vibration on neuromuscular performance in individuals with spinal cord injury. The intermittent vibration (frequency: 10–50 Hz; amplitude: 0.6–4 mm; knee flexion: 10°–40°) may be the possible effective range and have good compliance.

Ehrlichia chaffeensis preferentially targets mononuclear phagocytes and survives through a strategy of subverting innate immune defenses, but the mechanisms are unknown. We have shown E. chaffeensis type 1 secreted tandem repeat protein (TRP) effectors are involved in diverse molecular pathogen-host interactions, such as the TRP120 interaction with the Notch receptor-cleaving metalloprotease ADAM17. In the present study, we demonstrate E. chaffeensis, via the TRP120 effector, activates the canonical Notch signaling pathway to promote intracellular survival. We found that nuclear translocation of the transcriptionally active Notch intracellular domain (NICD) occurs in response to E. chaffeensis or recombinant TRP120, resulting in upregulation of Notch signaling pathway components and target genes notch1, adam17, hes, and hey. Significant differences in canonical Notch signaling gene expression levels (>40%) were observed during early and late stages of infection, indicating activation of the Notch pathway. We linked Notch pathway activation specifically to the TRP120 effector, which directly interacts with the Notch metalloprotease ADAM17. Using pharmacological inhibitors and small interfering RNAs (siRNAs) against γ-secretase enzyme, Notch transcription factor complex, Notch1, and ADAM17, we demonstrated that Notch signaling is required for ehrlichial survival. We studied the downstream effects and found that E. chaffeensis TRP120-mediated activation of the Notch pathway causes inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) pathways required for PU.1 and subsequent Toll-like receptor 2/4 (TLR2/4) expression. This investigation reveals a novel mechanism whereby E. chaffeensis exploits the Notch pathway to evade the host innate immune response for intracellular survival., IMPORTANCE E. chaffeensis is an obligately intracellular bacterium and the etiologic agent of human monocytotropic ehrlichiosis (HME), an emerging life-threatening tick-borne zoonosis. Mechanisms by which E. chaffeensis establishes intracellular infection and avoids innate host defenses are not understood, but functionally relevant host-pathogen interactions with type 1 secreted TRP effectors are essential for the ehrlichial cellular reprogramming strategy. This study provides further insight into the molecular strategies used by obligately intracellular pathogens such as E. chaffeensis, which have small genomes and a limited number of effector proteins and exploit evolutionarily conserved host cell programs such as Notch signaling to promote infection and intracellular survival.

Ehrlichia chaffeensis is a small, gram negative, obligately intracellular bacterium that preferentially infects mononuclear phagocytes. It is the etiologic agent of human monocytotropic ehrlichiosis (HME), an emerging life-threatening tick-borne zoonosis. Mechanisms by which E. chaffeensis establishes intracellular infection, and avoids host defenses are not well understood, but involve functionally relevant host-pathogen interactions associated with tandem and ankyrin repeat effector proteins. In this review, we discuss the recent advances in our understanding of the molecular and cellular mechanisms that underlie Ehrlichia host cellular reprogramming strategies that enable intracellular survival.

Ehrlichia chaffeensis invades and survives in phagocytes by modulating host cell processes and evading innate defenses, but the mechanisms are not fully defined. Recently we have determined that E. chaffeensis tandem repeat proteins (TRPs) are type 1 secreted effectors involved in functionally diverse interactions with host targets, including components of the evolutionarily conserved Wnt signaling pathways. In this study, we demonstrated that induction of host canonical and noncanonical Wnt pathways by E. chaffeensis TRP effectors stimulates phagocytosis and promotes intracellular survival. After E. chaffeensis infection, canonical and noncanonical Wnt signalings were significantly stimulated during early stages of infection (1 to 3 h) which coincided with dephosphorylation and nuclear translocation of β-catenin, a major canonical Wnt signal transducer, and NFATC1, a noncanonical Wnt transcription factor. In total, the expression of ∼44% of Wnt signaling target genes was altered during infection. Knockdown of TRP120-interacting Wnt pathway components/regulators and other critical components, such as Wnt5a ligand, Frizzled 5 receptor, β-catenin, nuclear factor of activated T cells (NFAT), and major signaling molecules, resulted in significant reductions in the ehrlichial load. Moreover, small-molecule inhibitors specific for components of canonical and noncanonical (Ca 2+ and planar cell polarity [PCP]) Wnt pathways, including IWP-2, which blocks Wnt secretion, significantly decreased ehrlichial infection. TRPs directly activated Wnt signaling, as TRP-coated microspheres triggered phagocytosis which was blocked by Wnt pathway inhibitors, demonstrating a key role of TRP activation of Wnt pathways to induce ehrlichial phagocytosis. These novel findings reveal that E. chaffeensis exploits canonical and noncanonical Wnt pathways through TRP effectors to facilitate host cell entry and promote intracellular survival.

Ehrlichia chaffeensis is an obligately intracellular bacterium that exhibits tropism for mononuclear phagocytes and survives by evading host cell defense mechanisms. Recently, molecular interactions of E. chaffeensis tandem repeat proteins 47 and 120 (TRP47 and -120) and the eukaryotic host cell have been described. In this investigation, yeast two-hybrid analysis demonstrated that an E. chaffeensis type 1 secretion system substrate, TRP32, interacts with a diverse group of human proteins associated with major biological processes of the host cell, including protein synthesis, trafficking, degradation, immune signaling, cell signaling, iron metabolism, and apoptosis. Eight target proteins, including translation elongation factor 1 alpha 1 (EF1A1), deleted in azoospermia (DAZ)-associated protein 2 (DAZAP2), ferritin light polypeptide (FTL), CD63, CD14, proteasome subunit beta type 1 (PSMB1), ring finger and CCCH-type domain 1 (RC3H1), and tumor protein p53-inducible protein 11 (TP53I11) interacted with TRP32 as determined by coimmunoprecipitation assays, colocalization with TRP32 in HeLa and THP-1 cells, and/or RNA interference. Interactions between TRP32 and host targets localized to the E. chaffeensis morulae or in the host cell cytoplasm adjacent to morulae. Common or closely related interacting partners of E. chaffeensis TRP32, TRP47, and TRP120 demonstrate a molecular convergence on common cellular processes and molecular cross talk between Ehrlichia TRPs and host targets. These findings further support the role of TRPs as effectors that promote intracellular survival.

The ethanolic extract of propolis (EEP) is beneficial in increasing high density lipoprotein (HDL) cholesterol (HDL-C) and diminishing risks of atherosclerosis. In this study, we examined the effects of EEP on reverse cholesterol transport in mice. (3)H -cholesterol laden macrophage was injected intraperitoneally into mice fed by gastric gavage with EEP. Plasma lipid level was determined and (3)H-cholesterol was traced in plasma, liver and feces. The effects of EEP on ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1) and scavenger receptor BI (SR-BI) in mice liver and in cultured cells were also investigated. EEP administration led to a significant increase in HDL-C and peritoneal macrophage-original (3)H-cholesterol in plasma, liver and feces. Liver protein expressions of ABCA1 and ABCG1 were increased but SR-B1 was not. In vitro experiments with HepG2 and Raw264.7 cell lines confirmed the above results. The finding of these studies shows that EEP-enhanced reverse cholesterol transport may have resulted from EEP stimulated plasma HDL level and hepatic ABCA1 and ABCG1 expression.

Application of two statistical models to reconstruct occupational exposure to manganese (Mn) is discussed. Air monitoring of 635 samples were analyzed by a back-propagation artificial neural network (back-propagation ANN) in comparison with a multiple linear regression (MLR). The stepwise MLR yielded significant results with five selected variables for predicting airborne manganese dioxide (MnO(2)). However, a 6-12-1 back-propagation ANN was superior to the data from MLR. Statistical parameters and non-parametric paired tests indicated that back-propagation ANN represents the more useful and accurate tool. ANN was used to predict missing MnO(2) concentrations in the present study. The median of MnO(2) was 0.445 mg/m(3) (IQR 0.131-1.342). The MnO(2) characteristics of time, distance, and exposure site were defined. Airborne MnO(2) for three previous periods (1978-1988, 1989-1998, and 1998-2007) were 1.228 mg/m(3), 0.664 mg/m(3), and 0.501 mg/m(3), respectively. The medians were 0.350 mg/m(3), 0.281 mg/m(3), and 0.190 mg/m(3) at distances of 5, 10, and 25 m away from the site of exposure. Compared with levels encountered in other studies, mine concentrator sites were more seriously polluted, due to the practices of direct ore processing.

To explore the relationship among psychological resilience, coping styles and mental health of newly recruited production line workers who were horn after 1990 in three manufacturing factories in Shenzhen.Production line workers who were born after 1990 and started working one week ago were selected from three manufacturing factories in Shenzhen. The Chinese Connor-Davidson Resilience Scale, Simplified Coping Stlye Questionnaire and General Health Questionnaire were used to assess their psychological resilience, psychological pressure, and mental health. A path analysis was carried out by Amos version 17. 0.Significantly positive correlation between the resilience and mental health (P0. 01), mental health and psychological resilience were positively related to active coping style (P0. 01), mental health and resilience were nagatively related to passive coping style (P0. 01). The structural equation model showed that the psychological resilience had both direct and indirect effect on mental health with the mediation effect of active coping styles and passive coping style.There are linear relationships between psychological resilience, coping styling and mental healthof the new recruits in Shenzhen manufacturing industry, and the partial indirectly of psychological resilience on mental health is potential realized through active coping styles and passive coping styles.

Aim Chitosan-oligosaccharides (COS) treatment showed lipid lowering effects in rats and reverse cholesterol transport (RCT) promotion in mice, suggested that COS might be a potential atheroprotective material. In this study, we investigated the effects of COS treatment on atherosclerosis (AS) in apolipoprotein E deficient mice (apoE-/-). Methods After feeding high fat (HF) diet for 12 weeks with the gastric gavages administration of COS or vehicle, respectively, the mice were sacrificed for the assessment of atherosclerosis, plaque stability, and the mechanism investigation. Results Cholesterol and TG in non-high density lipoprotein (non-HDL) fractions were reduced dramatically in COS groups. The COS treatment decreased the lesion areas of aortic enface, plaque areas in aortic root, and increased plaque stability in apoE-/-. Furthermore, the COS treatment significantly enhanced the expression of liver low density lipoprotein receptor (LDL-R), scavenger receptor BI (SR-BI) as well as the expression of macrophage SR-BI and ATP binding cassette transporter A1(ABCA1). We also found that the COS treatment did not affect the plasma lipid level in LDL-R deficient mice and cholesterol absorption in wild type mice. Conclusions COS treatment attenuated AS and decreased plasma non-HDL level in apoE-/-, and the potential mechanism might be involved with enhanced expression of hepatic LDL-R and SR-BI, and macrophage ABCA1.

Low level of immunity for SARS-CoV among well healthcare workers reinforces the need for infection control measures in hospitals to prevent epidemics., To determine the prevalence of inapparent infection with severe acute respiratory syndrome (SARS) among healthcare workers, we performed a serosurvey to test for immunoglobulin (Ig) G antibodies to the SARS coronavirus (SARS-CoV) among 1,147 healthcare workers in 3 hospitals that admitted SARS patients in mid-May 2003. Among them were 90 healthcare workers with SARS. As a reference group, 709 healthcare workers who worked in 2 hospitals that never admitted any SARS patients were similarly tested. The seroprevalence rate was 88.9% (80/90) for healthcare workers with SARS and 1.4% (15/1,057) for healthcare workers who were apparently healthy. The seroprevalence in the reference group was 0.4% (3/709). These findings suggest that inapparent infection is uncommon. Low level of immunity among unaffected healthcare workers reinforces the need for adequate personal protection and other infection control measures in hospitals to prevent future epidemics.

Objectives This study examined alterations in the functions and proteome of high-density lipoprotein (HDL) subfractions (HDL2 and HDL3) isolated from patients with acute coronary syndrome (ACS) compared with control subjects. Methods We measured HDL subfraction cholesterol efflux capacity, inflammatory index (HII), paraoxonase-1 (PON1) activity, and lipid hydroperoxide (LOOH) levels in both male age-matched controls and the ACS group (n = 40/group). Additionally, proteomic analysis was used to monitor changes in the HDL subfraction proteome between controls and ACS subjects. Results Both HDL2 and HDL3 from ACS patients had greater HII and LOOH levels compared with controls (P

Ehrlichia chaffeensis is an obligately intracellular gram negative bacterium with a small genome that thrives in mammalian mononuclear phagocytes by exploiting eukaryotic processes. Herein, we discuss the latest findings on moonlighting tandem repeat protein effectors and their secretion mechanisms, and novel molecular interkingdom interactions that provide insight into the intracellular pathobiology of ehrlichiae.

To assess comorbidities and functional impairments in children with attention deficit hyperactivity disorder (ADHD), and to investigate their relationship with the core symptoms (attention deficit and hyperactivity) of ADHD.A total of 319 children with suspected ADHD were included in the study. The Vanderbilt ADHD Parent Rating Scale (VADPRS) was completed by their parents. Diagnosis and classification were performed based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Comorbidities and functional impairments were evaluated according to the VADPRS. Children with various types of ADHD were compared in terms of comorbidities and functional impairments, and their relationship with the core symptoms of ADHD was analyzed.Of the 319 children, 196 were diagnosed with ADHD, including 84 cases of predominantly inattentive type (ADHD-I), 35 cases of predominantly hyperactive-impulsive type (ADHD-HI) and 77 cases of combined type (ADHD-C); 123 did not meet the diagnostic criteria for ADHD. At least one other psychiatric disorder (oppositional defiant disorder, conduct disorder or emotional disorder) was seen in 63.8% (125/196) of the children with ADHD, versus 37.4 % (46/123) of the children without ADHD (P0.05). The incidence of oppositional defiant disorder and conduct disorder in the ADHD-C subgroup was significantly higher than in the ADHD-I subgroup (P0.05). The sums of oppositional defiant disorder, conduct disorder and emotional disorder symptoms were weakly correlated with the sums of hyperactive-impulsive and inattentive symptoms (P0.01). Up to 89.8% of children with ADHD and 74.8% of children without ADHD showed functional impairments (P0.05). The ADHD-C subgroup had a significantly higher overall incidence of functional impairments than the ADHD-I and ADHD-HI subgroups (P0.05). The sum of inattentive symptoms was weakly correlated with the scores of learning ability, sibling relationship and participation in organized activities (P0.01), and the sum of hyperactive-impulsive symptoms was weakly correlated with the score of sibling relationship (P0.01).The incidence of comorbidities and functional impairments among children with ADHD is high, especially in those with ADHD-C. The severity of core symptoms in children with ADHD can influence the occurrence of comorbidities and functional impairments. The incidence of psychiatric disorders and functional impairments is also high in children with suspected ADHD who do not meet the diagnostic criteria for ADHD, so attention also needs to be paid to interventions among these children.

To study the value of the Vanderbilt ADHD Parent Rating Scale (VADPRS) in the diagnosis of attention deficit hyperactivity disorder (ADHD).VADPRS were completed by parents of 319 children with suspected ADHD. The children were then evaluated by a specialist based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) and 196 of them were diagnosed with ADHD. The value of VADPRS in the diagnosis of attention deficit and hyperactivity was evaluated using ROC curves. Diagnostic evaluation indexes at best operating point were calculated. Kappa values were calculated to explore the consistency of items in VADPRS and corresponding items in the DSM-IV criteria.The area under the ROC curve for the diagnosis of attention deficit by VADPRS was 0.791. At the best operating point, its sensitivity was 0.83, specificity was 0.63, positive predictive value was 0.69 and negative predictive value was 0.79. The area under the ROC curve for the diagnosis of hyperactivity by VADPRS was 0.855. At the best operating point, its sensitivity was 0.82, specificity was 0.76, positive predictive value was 0.65, and negative predictive value was 0.88. The negative predictive value of VADPRS in general population screen was 0.99, based on the results of this study. The consistency of items in the VADPRS and corresponding items in DSM-Ⅳ criteria was poor, with the Kappa value of most items being less than 0.40.VADPRS is suitable for a general population screen for ADHD and it is helpful in the clinical diagnosis of ADHD, but its results can be influenced by parents' awareness and perception of children's behavior, and cannot replace the interview and judgment of professionals.

To date, the only established model for assessing risk for nasopharyngeal carcinoma (NPC) relies on the sero-status of the Epstein-Barr virus (EBV). By contrast, the risk assessment models proposed here include environmental risk factors, family history of NPC, and information on genetic variants. The models were developed using epidemiological and genetic data from a large case-control study, which included 1,387 subjects with NPC and 1,459 controls of Cantonese origin. The predictive accuracy of the models were then assessed by calculating the area under the receiver-operating characteristic curves (AUC). To compare the discriminatory improvement of models with and without genetic information, we estimated the net reclassification improvement (NRI) and integrated discrimination index (IDI). Well-established environmental risk factors for NPC include consumption of salted fish and preserved vegetables and cigarette smoking (in pack years). The environmental model alone shows modest discriminatory ability (AUC = 0.68; 95% CI: 0.66, 0.70), which is only slightly increased by the addition of data on family history of NPC (AUC = 0.70; 95% CI: 0.68, 0.72). With the addition of data on genetic variants, however, our model’s discriminatory ability rises to 0.74 (95% CI: 0.72, 0.76). The improvements in NRI and IDI also suggest the potential usefulness of considering genetic variants when screening for NPC in endemic areas. If these findings are confirmed in larger cohort and population-based case-control studies, use of the new models to analyse data from NPC-endemic areas could well lead to earlier detection of NPC.

To establish a method of determining the presence and concentration of 16 kinds of organophosphorus pesticides in serum by GC/MS/MS.The parent ions of each pesticide was detected by running GC/MS in a full scan mode, and the peak areas and the ratio of signal to noise of each product ion were compared by setting different CID voltages. The CID voltage for each parent ion was optimized and determined. Serum samples were solid-phase extracted by Oasis HLB and eluted with ethyl ether after being concentrated and made to constant volume with ethyl ether, and then were tested by GC/MS/MS.The correlation coefficient for each compound in the range of 0 - 1000ng/ml was greater than 0. 990. Recoveries of standard addition were 75% - 129% ,RSD10%. The intra-day and inter-day RSD was less than 15% (n = 6). The limits of quantification were less than 2ng/ml except for dichlorovos (55ng/ml).GC/MS/MS assay is sensitive and accurate for the determination of pesticides in serum.

Humoral immune mechanisms are an important component of protective immunity to Ehrlichia species. However, the molecular basis of antibody mediated immunity is not completely defined, and the role of most molecularly characterized major immunoreactive proteins is unknown. In previous studies, we mapped major species-specific continuous epitopes in three surface exposed and secreted tandem repeat proteins (TRP32, TRP47 and TRP120). In this study, we report that protection is provided by antibodies against these molecularly defined TRP epitopes using in vitro and in vivo models. Protection was demonstrated in vitro after prophylactic and therapeutic administration of epitope-specific anti-TRP antibodies, suggesting that the protective mechanisms involve extracellular and intracellular antibody-mediated effects. In vivo passive transfer of individual epitope-specific TRP sera significantly reduced the ehrlichial load and splenomegaly, and protected mice against lethal infection. Moreover, the combination of antibodies to all three TRPs provided enhanced reduction in ehrlichial load similar to that of Ehrlichia chaffeensis immune sera. IgG1 was the predominant antibody isotype in the epitope-specific TRP mouse sera. These results demonstrate that antibodies against linear epitopes in TRP32, TRP47 and TRP120 are protective during E. chaffeensis infection and involves extracellular and intracellular antibody-mediated mechanisms.

Incomplete right bundle branch block (ICRBBB) is commonly associated with atrial septal defect (ASD), but lacks sufficient diagnostic test characteristics. An abnormal T wave is also often observed in ASD, with horizontal or inverted displacement of the proximal T wave limb in the right precordial leads, termed "defective T wave" (DTW).We examined the diagnostic test characteristics of combining ICRBBB with DTW as a new index to diagnose ASD. A total of 132 consecutive patients with ASD and 132 cases of age/gender-matched controls without ASD were enrolled.Sensitivities of DTW, ICRBBB, and both were 87.1% - 87.9%. Specificities were 97.0%, 96.2%, and 100%, respectively. Positive predictive values were 1.3%, 1.1%, and 100.0% respectively, while negative predictive values were 99.9% for each.Combining ICRBBB with DTW in electrocardiogram (ECG) as a new index significantly increased the specificity and positive predictive values while maintaining a high sensitivity in diagnosing ASD.

The aim of the study was to better understand blonanserin population pharmacokinetic (PK) characteristics in Chinese healthy subjects.Data from two studies with 50 subjects were analyzed to investigate the population PK characteristics of blonanserin at single dose (4, 8, and 12 mg) under fasting, multidose (4 mg bid or 8 mg qd for 7 days) and under food intake condition (single dose, 8 mg). Blonanserin plasma concentrations were detected using the high performance liquid chromatography tandem mass spectrometry (LC/MS/MS). A nonlinear mixed-effects model was developed to describe the blonanserin concentration-time profiles.A two compartment model with first-order absorption was built to describe the time-course of blonanserin. The population-predicted system apparent clearance (CL/F), volume of apparent distribution in center (V(1)/F), and the first-order absorption rate constant (Ka) of blonanserin under fasting was 1230 L/h, 9500 L, and 3.02 h(-1), respectively. Food intake decreased Ka of blonanserin to 0.78 h(-1). The relative bioavailability between fasting and food intake estimated by the final model was 55%. No clinically significant safety issues were identified.This is the first study assessing the PK profile of blonanserin with population PKs method. The results can be used for simulation in further clinical trial and optimize individual dosage regimens using a Bayesian methodology in patients.

Chitosan oligosaccharides (COS) are beneficial in improving plasma lipids and diminishing atherosclerotic risks. In this study, we examined the effects of COS on reverse cholesterol transport (RCT) in C57BL/6 mice. 3H-cholesterol-laden macrophages were injected intraperitoneally into mice fed with various dosage of COS (250, 500, 1000 mg/kg mouse weight, respectively) or vehicle by gastric gavages. Plasma lipid level was determined and 3H-cholesterol was traced in plasma, liver, bile and feces. The effects of COS on hepatic cholesterol 7 alpha-hydroxylase (CYP7A1) and scavenger receptor BI (SR-BI) expression were also investigated. COS administration led to a significant decrease in plasma total cholesterol and low-density lipoprotein (LDL) cholesterol and a significant increase in peritoneal macrophage-derived 3H-cholesterol in liver and bile as well as in feces. Liver protein expressions of CYP7A1, SR-BI and LDL receptor (LDL-R) were improved in a dosage-dependent manner in COS-administered mice. Our findings provide the first in vivo demonstration of a positive role for COS in RCT pathway and hepatic CYP7A1 and SR-BI expression in mice. Additionally, the LDL cholesterol lowering effect might be relative to hepatic LDL-R expression stimulated by COS in mice.

The oligopeptide transporter PEPT1 is considered as a valuable target for prodrug design, but its 3D structure and substrate specificity of PEPT1 are not fully understood. In this study, we designed a focused dipeptide conjugated azidothymidine (AZT) library and described a convenient and efficient solid phase synthesis scheme based on click chemistry. Over 60 candidate structures containing various dipeptide sequences were obtained with high purity, and screened in a PEPT1 overexpressing cell model for their abilities to compete with the known ligand cephalexin. Some of the compounds selected to have medium or high affinity were tested for their in vivo transport in a single-pass intestinal perfusion experiment. Results showed that the designed library contained some new structure features that have high affinities toward PEPT1 and could be further explored for their application in prodrug design and development.

Ehrlichia chaffeensis is an obligately intracellular bacterium that modulates host cell gene transcription in the mononuclear phagocyte, but the host gene targets and mechanisms involved in transcriptional modulation are not well-defined. In this study, we identified a novel tandem repeat DNA-binding domain in the E. chaffeensis 120-kDa tandem repeat protein (TRP120) that directly binds host cell DNA. TRP120 was observed by immunofluorescent microscopy in the nucleus of E. chaffeensis -infected host cells and was detected in nuclear extracts by Western immunoblotting with TRP120-specific antibody. The TRP120 binding sites and associated host cell target genes were identified using high-throughput deep sequencing (Illumina) of immunoprecipitated DNA (chromatin immunoprecipitation and high-throughput DNA sequencing). Multiple em motif elicitation (MEME) analysis of the most highly enriched TRP120-bound sequences revealed a G+C-rich DNA motif, and recombinant TRP120 specifically bound synthetic oligonucleotides containing the motif. TRP120 target gene binding sites were mapped most frequently to intersecting regions (intron/exon; 49%) but were also identified in upstream regulatory regions (25%) and downstream locations (26%). Genes targeted by TRP120 were most frequently associated with transcriptional regulation, signal transduction, and apoptosis. TRP120 targeted inflammatory chemokine genes, CCL2, CCL20, and CXCL11, which were strongly upregulated during E. chaffeensis infection and were also upregulated by direct transfection with recombinant TRP120. This study reveals that TRP120 is a novel DNA-binding protein that is involved in a host gene transcriptional regulation strategy.

Ehrlichia chaffeensis is an obligately intracellular bacterium that exhibits tropism for mononuclear phagocytes and survives by evading host cell defense mechanisms. Recently, molecular interactions between E. chaffeensis 47-kDa tandem repeat (TR) protein (TRP47) and the eukaryotic host cell have been described. In this investigation, yeast ( Saccharomyces cerevisiae ) two-hybrid analysis demonstrated that E. chaffeensis -secreted tandem repeat protein 120 (TRP120) interacts with a diverse group of host cell proteins associated with major biological processes, including transcription and regulation, cell signaling, protein trafficking, and actin cytoskeleton organization. Twelve target proteins with the highest frequency of interaction with TRP120 were confirmed by cotransformation in yeast. Host targets, including human immunoglobulin lambda locus (IGL), cytochrome c oxidase subunit II (COX2), Golgi-associated gamma adaptin ear-containing ARF binding protein 1 (GGA1), polycomb group ring finger 5 (PCGF5), actin gamma 1 (ACTG1), and unc-13 homolog D (UNC13D; Caenorhabditis elegans ), colocalized strongly with TRP120 in HeLa cells and with E. chaffeensis dense-cored morulae and areas adjacent to morulae in the host cytoplasm. The TR domain of TRP120 interacted only with PCGF5, indicating that distinct TRP120 domains contribute to specific host target interactions and that multiple domains are required to reconstitute TRP120 interactions with other host targets. Three previously defined molecular interactions between TRP47 and host proteins, PCGF5, IGLL1, and CAP1, were also associated with TRP120, demonstrating that molecular cross talk occurs between Ehrlichia TRPs and host targets. These findings further support the role of TRPs as effectors that reprogram the host cell.