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Si-Lan Gu,1,* Yiwen Gong,1,* Jiaying Zhang,1,* Yunbo Chen,1 Zhengjie Wu,1 Qiaomai Xu,1 Yunhui Fang,1 Jingxia Wang,1 Ling-Ling Tang2 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, People’s Republic of China; 2Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou 310000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ling-Ling TangShulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou 310000, People’s Republic of ChinaEmail 1196040@zju.edu.cnBackground: Antibiotics play an important role in the treatment of infectious diseases. However, the overuse of antibiotics increases the spread of drug-resistant bacteria and causes dysbiosis of the intestinal microbiota. Few studies have addressed the longitudinal effects of antibiotics on the microbiome and host immunity.Materials and Methods: In this study, the short-term effect of fluoroquinolone (levofloxacin) and β-lactam antibiotics (meropenem, cefoperazone/sulbactam, and aztreonam) on the gut microbiota of mice was evaluated by 16S rRNA gene sequencing. The susceptibility of Bifidobacterium longum, Lactobacillus lactis, Enterococcus faecium, and Clostridium butyricum to these antimicrobial agents was assessed using the disc diffusion method.Results: Our results showed that 4-day antibiotic exposure significantly reduced the alpha and beta diversity of gut bacteria and increased serum inflammatory cytokines, and these changes persisted long after antibiotic withdrawal and did not return to pre-treatment levels. Nonetheless, the bacterial community composition tended to return to pre-treatment levels after discontinuing treatment. The tested probiotic strains were resistant to aztreonam but were sensitive to meropenem and cefoperazone/sulbactam.Conclusion: Short-term antibiotic treatment led to significant changes in the intestinal flora with a tendency to recover. The antibiotics had different effects on the intestinal microbial community and probiotic strains. This study provides guidance for the concomitant use of probiotics and antibiotics, and the results emphasize the importance of using broad-spectrum antibiotics responsibly to prevent the long-term disruption of the native microbiota.Keywords: antibiotics, gut microbiota, 16S rRNA gene sequencing, probiotics

Background: The overproliferation of fibroblast-like synoviocytes (FLS) contributes to synovial hyperplasia, a pivotal pathological feature of rheumatoid arthritis (RA). Shikonin (SKN), the active compound from Lithospermum erythrorhizon, exerts anti-RA effects by diverse means. However, further research is needed to confirm SKN's in vitro and in vivo anti-proliferative functions and reveal the underlying specific molecular mechanisms., Purpose: This study revealed SKN's anti-proliferative effects by inducing both apoptosis and autophagic cell death in RA FLS and adjuvant-induced arthritis (AIA) rat synovium, with involvement of regulating the AMPK/mTOR/ULK-1 pathway., Methods: SKN's influences on RA FLS were assessed for proliferation, apoptosis, and autophagy with immunofluorescence staining (Ki67, LC3B, P62), EdU incorporation assay, staining assays of Hoechst, Annexin V-FITC/PI, and JC-1, transmission electron microscopy, mCherry-GFP-LC3B puncta assay, and western blot. In AIA rats, SKN's anti-arthritic effects were assessed, and its impacts on synovial proliferation, apoptosis, and autophagy were studied using Ki67 immunohistochemistry, TUNEL, and western blot. The involvement of AMPK/mTOR/ULK-1 pathway was examined via western blot., Results: SKN suppressed RA FLS proliferation with reduced cell viability and decreased Ki67-positive and EdU-positive cells. SKN promoted RA FLS apoptosis, as evidenced by apoptotic nuclear fragmentation, increased Annexin V-FITC/PI-stained cells, reduced mitochondrial potential, elevated Bax/Bcl-2 ratio, and increased cleaved-caspase 3 and cleaved-PARP protein levels. SKN also enhanced RA FLS autophagy, featuring increased LC3B, reduced P62, autophagosome formation, and activated autophagic flux. Autophagy inhibition by 3-MA attenuated SKN's anti-proliferative roles, implying that SKN-induced autophagy contributes to cell death. In vivo, SKN mitigated the severity of rat AIA while also reducing Ki67 expression, inducing apoptosis, and enhancing autophagy within AIA rat synovium. Mechanistically, SKN modulated the AMPK/mTOR/ULK-1 pathway in RA FLS and AIA rat synovium, as shown by elevated P-AMPK and P-ULK-1 expression and decreased P-mTOR expression. This regulation was supported by the reversal of SKN's in vitro and in vivo effects upon co-administration with the AMPK inhibitor compound C., Conclusion: SKN exerted in vitro and in vivo anti-proliferative properties by inducing apoptosis and autophagic cell death via modulating the AMPK/mTOR/ULK-1 pathway. Our study revealed novel molecular mechanisms underlying SKN's anti-RA effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Synovial angiogenesis is a key player in the development of rheumatoid arthritis (RA), and anti-angiogenic therapy is considered a promising approach for treating RA. CPD-002 has demonstrated efficacy in suppressing tumor angiogenesis as a VEGFR2 inhibitor, but its specific impacts on RA synovial angiogenesis and possible anti-RA effects need further study. We examined the influences of CPD-002 on the migration and invasion of human umbilical vein endothelial cells (HUVECs) and its impacts on HUVECs' tube formation and vessel sprouting ex vivo. The therapeutic potential of CPD-002 in adjuvant-induced arthritis (AIA) rats and its suppression of synovial angiogenesis were examined. The involvement of the VEGFR2/PI3K/AKT pathway was assessed both in HUVECs and AIA rat synovium. Here, CPD-002 inhibited the migration and invasion of VEGF-stimulated HUVECs, decreased their chemotactic response to RA fibroblast-like synoviocyte-released chemoattractants, and exhibited anti-angiogenic effects in vitro and ex vivo. CPD-002's targeting of VEGFR2 was confirmed with molecular docking and cellular thermal shift assays, supported by the abolishment of CPD-002's effects upon using VEGFR2 siRNA. CPD-002 relieved paw swelling, arthritis index, joint damage, and synovial angiogenesis, indicating its anti-arthritic and anti-angiogenic effects in AIA rats. Moreover, the anti-inflammatory effects in vivo and in vitro of CPD-002 contributed to its anti-angiogenic effects. Mechanistically, CPD-002 hindered the activation of VEGFR2/PI3K/AKT pathway in VEGF-induced HUVECs and AIA rat synovium, as evidenced by reduced p-VEGFR2, p-PI3K, and p-AKT protein levels alongside elevated PTEN protein levels. Totally, CPD-002 showed anti-rheumatoid effects via attenuating angiogenesis through the inhibition of the VEGFR2/PI3K/AKT pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Protein post-translational modifications (PTMs) with various acyl groups play central roles in Streptomyces. But whether these acyl groups can be further modified, and the influences of these potential modifications on bacterial physiology have not been addressed. Here in Streptomyces roseosporus with rich crotonylation, a luciferase monooxygenase LimB is identified to elaborately regulate the crotonylation level, morphological development and antibiotic production by oxidation on the crotonyl groups of an acetyl-CoA synthetase Acs. This chemical modification on crotonylation leads to Acs degradation via the protease ClpP1/2 pathway and lowered intracellular crotonyl-CoA pool. Thus, we show that acyl groups after PTMs can be further modified, herein named post-PTM modification (PPM), and LimB is a PTM modifier to control the substrate protein turnover for cell development of Streptomyces. These findings expand our understanding of the complexity of chemical modifications on proteins for physiological regulation, and also suggest that PPM would be widespread., (© 2023. The Author(s).)

Immune-related cutaneous adverse events (ircAEs) commonly occur in patients on treatment with immune checkpoint inhibitors and can significantly reduce patient quality of life. These are often treated with immunomodulatory agents, including glucocorticoids, immunosuppressants, and biologics. While often effective at managing symptoms, these therapies can cause several adverse events which may limit their use. In addition, immunomodulatory agents should be used with particular caution in patients receiving immunotherapy, as the efficacy of the oncologic regimen may potentially be undermined. In this review, we summarize the safety of systemic therapies that are used in the management of ircAEs, with a particular focus on the resultant risk of secondary tumor progression in patients with active cancer.

Background : Immune-related cutaneous adverse events (ircAEs) are frequent and may reduce quality of life and consistent dosing. IL12/23 has been implicated in psoriasis, which is reminiscent of the psoriasiform/lichenoid ircAE phenotype. We report the use of ustekinumab as a therapeutic option. Methods : Patients at Memorial Sloan Kettering Cancer Center, New York, who received immune checkpoint inhibitors and were treated with ustekinumab or had the keywords "ustekinumab" or "Stelara" in their clinical notes between 1 March 2017 and 1 December 2022 were retrospectively identified via a database query. Documentation from initial and follow-up visits was manually reviewed, and response to ustekinumab was categorized into complete cutaneous response (CcR, decrease to CTCAE grade 0), partial cutaneous response (PcR, any decrease in CTCAE grade exclusive of decrease to grade 0), and no cutaneous response (NcR, no change in CTCAE grade or worsening). Labs including complete blood count (CBC), cytokine panels, and IgE were obtained in a subset of patients as standard of care. Skin biopsies were reviewed by a dermatopathologist. Results : Fourteen patients with psoriasiform (85.7%), maculopapular (7.1%), and pyoderma gangrenosum (7.1%) ircAEs were identified. Ten (71.4%) receiving ustekinumab had a positive response to treatment. Among these 10 responders, 4 (40%) demonstrated partial cutaneous response and 6 (60%) demonstrated complete cutaneous resolution. Six patients (42.9%) experienced interruptions to their checkpoint inhibitor treatment as a result of intolerable ircAEs, and following ircAE management with ustekinumab, two (33.3%) were successfully rechallenged with their checkpoint inhibitors. On histopathology, patients primarily had findings of interface or psoriasiform dermatitis. No patients reported an adverse event related to ustekinumab. Conclusions : Ustekinumab showed a benefit in a subset of patients with psoriasiform/lichenoid ircAEs. No safety signals were identified. However, further prospective randomized controlled trials are needed to confirm our findings.

Adoptive cellular immunotherapy, mainly hematopoietic stem cell transplant and CAR-T cell therapy have revolutionized treatment of patients with acute leukemia. Indications and inclusion criteria for these treatments have expanded in recent years. While these therapies are associated with significant improvements in disease response and overall survival, patients may experience adverse events from associated chemotherapy conditioning, engraftment, cytokine storm, supportive medications, and post-transplant maintenance targeted therapies. Supportive oncodermatology is a growing specialty to manage cutaneous toxicities resulting from the anti-cancer therapies. In this review, we summarize diagnosis and management of the common cutaneous adverse events including drug eruptions, graft-versus-host disease, neoplastic and paraneoplastic complications in patients undergoing cellular therapies., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The study aims to investigate the clinical characteristics of early postnatal period in children with prenatal hydronephrosis (HN) in our single center for 8 years., Study Design: The clinical data of 1137 children with prenatal HN from 2012 to 2020 were retrospectively analyzed in our center. Variables of our study mainly included different malformations and urinary tract dilation (UTD) classification, and main outcomes were recurrent hospitalization, urinary tract infection (UTI), jaundice, and surgery., Results: Among the 1137 children with prenatal HN in our center, 188 cases (16.5%) were followed-up in early postnatal period, and 110 cases (58.5%) were found malformations. The incidence of recurrent hospitalization (29.8%) and UTI (72.5%) were higher in malformation, but the incidence of jaundice (46.2%) was higher in non-malformation(P < 0.001). Furthermore, UTI and jaundice were higher in vesicoureteral reflux (VUR) than those in uretero-pelvic junction obstruction (UPJO) (P < 0.05). Meanwhile, Children with UTD P2 and UTD P3 were prone to recurrent UTI, but UTD P0 was prone to jaundice (P < 0.001). In addition, 30 cases (16.0%) of surgery were all with malformations, and the surgical rates of UTD P2 and UTD P3 were higher than those of UTD P0 and UTD P1 (P < 0.001). Lastly, we concluded that the first follow-up should be less than 7 days, the first assessment should be 2 months, and the follow up should be at least once every 3 months., Conclusion: Children with prenatal HN have been found many malformations in early postnatal period, and with high-grade UTD were more prone to recurrent UTI, even to surgery. So, prenatal HN with malformations and high-grade UTD should be followed up in early postnatal period regularly., (© 2023. The Author(s).)

Background: Despite its ethical implications, physical restraint (PR) is widely used in the intensive care unit (ICU) to guarantee the safety of patients. This study investigated the frequency and risk factors of PR use for patients in the ICU to establish a predictive nomogram., Methods: Clinical parameters of patients admitted to the ICU of Jiangsu Province Hospital from January 2021 to July 2021 were retrospectively collected. Independent risk factors of PR were analyzed by univariate and multivariate logistic regression analyses. The R software was used to establish the nomogram. Model performance was validated using the concordance-index (C-index) and calibration curves., Results: The rate of PR use was 46.32% (233/503 patients). Age ( B  = 0.036, odds ratio [OR]: 1.037, 95% confidence interval [CI]: 1.022-1.052, P < 0.001), consciousness disorder ( B  = 0.770, OR: 2.159, 95% CI: 1.216-3.832, P =0.009), coma ( B  = -1.666, OR: 0.189, 95% CI: 0.101-0.353, P < 0.001), passive activity ( B  = 1.014, OR: 2.756, 95% CI: 1.644-4.618, P < 0.001), delirium ( B  = 0.993, OR: 2.699, 95% CI: 1.097-6.642, P =0.031), -3 < Richmond Agitation Sedation Scale (RASS) score <2 ( B  = 0.698, OR: 2.009, 95% CI: 1.026-3.935, P =0.042), RASS score ≥2 ( B  = 1.253, OR: 3.499, 95% CI: 1.126-10.875, P =0.030), and mechanical ventilation ( B  = 1.696, OR: 5.455, 95% CI: 2.804-10.611, P < 0.001) were identified as independent risk factors for PR in the ICU ( P < 0.05) and included in the nomogram. The C-index was 0.830, and the calibration curve indicated good discriminatory ability and accuracy (mean absolute error: 0.026)., Conclusion: The prediction nomogram model of PR in ICU was established based on age, mobility, delirium, consciousness, RASS score, and mechanical ventilation. It showed good discrimination and accuracy. This nomogram may predict the probability of PR use in the ICU and guide nurses in developing precise interventions to reduce the rate of PR., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Yun Wang et al.)

Introduction: Mutations in ADAMTS9 cause nephronophthisis-related ciliopathies (NPHP-RC), which are characterized by multiple developmental defects and kidney diseases. Patients with NPHP-RC usually have normal glomeruli and negligible or no proteinuria. Herein, we identified novel compound-heterozygous ADAMTS9 variants in two siblings with NPHP-RC who had glomerular manifestations, including proteinuria., Methods: To investigate whether ADAMTS9 dysfunction causes NPHP and glomerulopathy, we differentiated ADAMTS9 knockout human induced pluripotent stem cells (hiPSCs) into kidney organoids. Single-cell RNA sequencing was utilized to elucidate the gene expression profiles from the ADAMTS9 knockout kidney organoids., Results: ADAMTS9 knockout had no effect on nephron differentiation; however, it reduced the number of primary cilia, thereby recapitulating renal ciliopathy. Single-cell transcriptomics revealed that podocyte clusters express the highest levels of ADAMTS9, followed by the proximal tubules. Loss of ADAMTS9 increased the activity of multiple signaling pathways, including the Wnt/PCP signaling pathway, in podocyte clusters., Conclusions: Mutations in ADMATS9 cause a glomerulotubular nephropathy in kidney and our study provides insights into the functional roles of ADMATS9 in glomeruli and tubules., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yu, Choi, Rim, Kim, Bekheirnia, Swartz, Dai, Gu, Lee, Nishinakamura, Hildebrandt, Bekheirnia and Gee.)

Herein, A non-invasive pathomics approach was developed to reveal the methylation status in patients with cervical squamous cell carcinoma and predict clinical outcomes and treatment response. Using the MethylMix algorithm, 14 methylation-driven genes were selected for further analysis. We confirmed that methylation-driven genes were differentially expressed in immune, stromal, and tumor cells. In addition, we constructed a methylation-driven model and explored the alterations in immunocyte infiltration between the different models. The methylation-driven subtypes identified in our investigation could effectively predict the clinical outcomes of cervical cancer. To further evaluate the level of methylation-driven patterns, we constructed a risk model with four genes. Significant correlations were observed between the score and immune response markers, including PD1 and CTLA4. Multiple immune infiltration algorithms evaluated the level of immunocyte infiltration between the high- and low-risk groups, while the components of anti-tumor immunocytes in the low-risk group were significantly increased. Subsequently, a total of 205 acquired whole-slide imaging (WSI) images were processed to capture image signatures, and the pathological algorithm was employed to construct an image prediction model based on the risk score classification. The model achieved an area under the curve (AUC) of 0.737 and 0.582 for the training and test datasets, respectively. Moreover, we conducted vitro assays for validation of hub risk gene. The proposed prediction model is a non-invasive method that combines pathomics features and genomic profiles and shows satisfactory performance in predicting patient survival and treatment response. More interdisciplinary fields combining medicine and electronics should be explored in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yu, Shi, Gu, Li, Yang, Fan and Wang.)

Background/purpose: Increased intra-individual variability (IIV) in reaction time (RT) is a key feature of attention-deficit/hyperactivity disorder (ADHD). However, little is known about neurobiology underpinnings of IIV in ADHD., Methods: We assessed 55 youths with ADHD, and 55 individually-matched typically developing control (TDC) with the MRI and Conners' Continuous Performance Test. The ex-Gaussian distribution of RT was estimated to capture IIV with the parameters σ (sigma) and τ (tau). The regional brain volumes, analyzed by voxel-based morphometry, were correlated with IIV parameters., Results: We found both distinct and shared correlations among ADHD and TDC. For grey matter, there were significant σ-by-group interactions in the cingulate cortex and thalamus and also a τ-by-group interaction in the right inferior frontal gyrus. There was also shared negative associations between σ and regional volumes of the right posterior cerebellum and a positive association between τ and the right anterior insula. For white matter, there was a significant σ-by-group interaction in the genu of the corpus callosum and significant τ-by-group interactions in the right anterior corona radiata, the left splenium of the corpus callosum, and bilateral posterior cerebellum. There were also shared patterns that increased τ was associated with increased regional volumes of the right anterior corona radiata and decreased regional volumes of the right posterior limb of the internal capsule., Conclusion: This study highlights that brain regions responsible for the motor, salience processing and multimodal information integration are associated with increased IIV in youths with ADHD., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021. Published by Elsevier B.V.)

Objective: This study examined preschoolers with teacher-reported or parent-reported situational hyperactivity, and whether they differed in terms of behavioral problems, attentional problems, and parenting perceptions. Method: We used the Conners' Kiddie Continuous Performance Test and the Color Flanker Task to assess 99 preschoolers with pervasive high-ADHD-symptoms (42), school-situational high-ADHD-symptoms (30), or home-situational high-ADHD-symptoms (27), plus 111 preschoolers with pervasive low-ADHD-symptoms. Parents and teachers reported externalizing/internalizing behavioral problems. Parenting perceptions were measured with the Parenting Stress Index-Short Form and a parenting perceptions scale. Results: Preschoolers with school-situational high-ADHD-symptoms had deficits in attentional control. Parents of preschoolers with home-situational high-ADHD-symptoms had higher levels of parental stress and perceived their parenting to be harsher. Preschoolers with pervasive high-ADHD-symptoms had deficits in attentional control, increased parental stress, and parents with harsher parenting perceptions. Conclusion: Preschoolers with situational high-ADHD-symptoms may have different contextual risk factors related to ADHD symptoms reported by parents versus teachers.

Oncogenic high-risk human papillomavirus (HR-HPV) infection causes a majority of cases of cervical cancer and pre-cancerous cervical lesions. However, the mechanisms underlying the direct evolution from HPV-16/18-infected epithelium to cervical intraepithelial neoplasia (CIN) III, which can progress to cervical cancer, remain poorly identified. Here, we performed RNA-seq after laser capture microdissection, and found that APOBEC3B was highly expressed in cervical cancer specimens compared with CIN III with HPV-16/18 infection. Furthermore, immunohistochemical analysis confirmed that high levels of APOBEC3B were correlated with lymph node metastasis in cervical cancer. Subsequent experiments revealed that HPV-16 E6 could upregulate APOBEC3B through direct binding to the promoter of APOBEC3B in cervical cancer cells. Silencing of APOBEC3B by stable short hairpin RNA-mediated knockdown reduced the proliferative capacity of Caski and HeLa cells in vitro and in vivo, but had only a small effect on the migration and invasion of two cervical cancer cell lines. Finally, we identified the changes in gene expression following APOBEC3B silencing in Caski cells by microarray, demonstrating a biological link between APOBEC3B and CCND1 in cervical cancer cells. Importantly, through methyl-capture sequencing and pyrosequencing, APOBEC3B was found to affect the levels of the downstream protein Cyclin D1 (which is encoded by the CCND1 gene) through hypomethylation of the CCND1 promoter. In conclusion, our study supports HPV-16 E6-induced APOBEC3B expression associates with proliferation of cervical cancer cells and hypomethylation of Cyclin D1. Thus, APOBEC3B may be a potential therapeutic target in human cervical cancer., (© 2021 Wiley Periodicals LLC.)

Urticarial vasculitis is a rare clinicopathologic entity that is characterized by chronic or recurrent episodes of urticarial lesions. Skin findings of this disease can be difficult to distinguish visually from those of chronic idiopathic urticaria but are unique in that individual lesions persist for ≥24 hours and can leave behind dusky hyperpigmentation. This disease is most often idiopathic but has been linked to certain drugs, infections, autoimmune connective disease, myelodysplastic disorders, and malignancies. More recently, some authors have reported associations between urticarial vasculitis and COVID-19, as well as influenza A/H1N1 infection. Urticarial vasculitis can extend systemically as well, most often affecting the musculoskeletal, renal, pulmonary, gastrointestinal, and ocular systems. Features of leukocytoclastic vasculitis seen on histopathologic examination are diagnostic of this disease, but not always seen. In practice, antibiotics, dapsone, colchicine, and hydroxychloroquine are popular first-line therapies, especially for mild cutaneous disease. In more severe cases, immunosuppressives, including methotrexate, mycophenolate mofetil, azathioprine, and cyclosporine, as well as corticosteroids, may be necessary for control. More recently, select biologic therapies, including rituximab, omalizumab, and interleukin-1 inhibitors have shown promise for the treatment of recalcitrant or refractory cases., (© 2021 The Authors.)

Objective: To investigate the morphological characteristics of Echinostoma miyagawai in domestic ducks in Wuhu area, and to explore the feasibility of the cytochrome oxidase subunit-1 ( Cox1 ) gene as a molecular marker for the identification of E. miyagawai ., Methods: E. miyagawai was isolated from free-ranged domestic ducks in Wuhu area, and the parasites were stained and identified. In addition, the mitochondrial Cox1 gene of E. miyagawai was amplified using a PCR assay, and the amplification product was sequenced and aligned with the GenBank database to yield the homology for the identification of parasite species in combination with morphological findings. Intra-species comparison was done based on the Cox1 gene sequence., Results: The prevalence of E. miyagawai infection was 16.67% in domestic ducks in Wuhu area, and the adult E. miyagawai was 6.6 to 13.2 mm in length. The size of the E. miyagawai Cox1 gene was approximately 660 bp, which had a 99.68% homology to the E. miyagawai accessed in GenBank. The morphological findings were in agreement with molecular identification., Conclusions: E. miyagawai infection is common in domestic ducks in Wuhu area, and the mitochondrial Cox1 gene is a feasible marker of intra- and inter-species molecular identification of Echinostoma .

Background : Perineural invasion (PNI) is correlated with negative prognosis in multiple cancers, but its role in endometrial cancer (EC) is still largely unknown; thus, targeted treatment for nerve infiltration is lacking as well. Methods : The interaction between nerve and EC cells were investigated by in vitro neural invasion assay and transwell coculture system. Then the nerve-related receptor gene glutamate ionotropic receptor AMPA type subunit 2 (GRIA2) was detected in EC tissues and cells using PCR array, western blotting, and immunohistochemistry. The role of GluR2 (gene name GRIA2) on EC proliferation, migration and invasion was evaluated by a GluR2 antagonist and shRNA. At the same time, the neurotransmitter effect on GluR2 (glutamate) from the cocultured conditional medium was measured using high-performance liquid chromatography (HPLC). Results : EC cell line Ishikawa (ISK) showed the ability to migrate along neurites in vitro and the numbers of migrated/invaded EC cells in the DRG neuron coculture group were significantly increased. The expression of GluR2 in EC tissue was found to be higher than that in para-carcinoma tissue. After GluR2 antagonist and GluR2 shRNA treatment, the proliferation, migration and invasion of ISK cells was markedly inhibited. Moreover, the ability of DRG neurons to promote the migration and invasion of ISK cells could also be attenuated by downregulation of GluR2, and the concentration of the neurotransmitter glutamate was notably increased in the coculture conditional medium compared to that in the DRG neuron or ISK cells alone. Conclusions : DRG neurons promote metastasis of EC cells via GluR2, which might be a risk factor for PNI in EC. Moreover, the perineural system may promote tumor invasion and metastasis under certain circumstances., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Triacylglycerols (TAGs) are the main composition of plant seed oil. Long-chain acyl-coenzyme A synthetases (LACSs) catalyze the synthesis of long-chain acyl-coenzyme A, which is one of the primary substrates for TAG synthesis. In Arabidopsis, the LACS gene family contains nine members, among which LACS1 and LACS9 have overlapping functions in TAG biosynthesis. However, functional characterization of LACS proteins in rapeseed have been rarely reported., Results: An orthologue of the Arabidopsis LACS2 gene (BnLACS2) that is highly expressed in developing seeds was identified in rapeseed (Brassica napus). The BnLACS2-GFP fusion protein was mainly localized to the endoplasmic reticulum, where TAG biosynthesis occurs. Interestingly, overexpression of the BnLACS2 gene resulted in significantly higher oil contents in transgenic rapeseed plants compared to wild type, while BnLACS2-RNAi transgenic rapeseed plants had decreased oil contents. Furthermore, quantitative real-time PCR expression data revealed that the expression of several genes involved in glycolysis, as well as fatty acid (FA) and lipid biosynthesis, was also affected in transgenic plants., Conclusions: A long chain acyl-CoA synthetase, BnLACS2, located in the endoplasmic reticulum was identified in B. napus. Overexpression of BnLACS2 in yeast and rapeseed could increase oil content, while BnLACS2-RNAi transgenic rapeseed plants exhibited decreased oil content. Furthermore, BnLACS2 transcription increased the expression of genes involved in glycolysis, and FA and lipid synthesis in developing seeds. These results suggested that BnLACS2 is an important factor for seed oil production in B. napus.

Reaction times (RTs) are typically slower and more variable in individuals with attention-deficit/hyperactivity disorder (ADHD). Analysis of the ex-Gaussian RT distribution, which is described by mu, sigma (mean and standard deviation, respectively, of the normal distribution) and tau (that of exponential distribution), reveals that individuals with ADHD do not display overall slower RTs but have a high proportion of extremely slow RTs, represented by a high tau value. Although this is a vital component for describing ADHD-related RT variability in school-aged children, adolescents, and adults, it has not been thoroughly studied at the preschool age. We assessed 65 preschoolers at risk of ADHD and 98 typically developing preschoolers with the Conners' Kiddie Continuous Performance Test (K-CPT) and parental and teacher reports of ADHD symptoms. We found that preschoolers at risk of ADHD had greater values for RT standard deviation, sigma, and tau than typically developing preschoolers at long inter-stimulus intervals (ISIs) (3 s), but not at short ISIs (1.5 s). This suggests that attention problems in preschool children may only be apparent in the tasks with a relatively slow event rate. Our study demonstrates that the ex-Gaussian tau value is essential for describing the inattentive component of task performance in preschoolers with heightened ADHD symptoms. Furthermore, the fact that the tau effect was modulated by ISI suggests that the longer duration (3 s vs. 1.5 s) is a non-optimal energetic state in preschoolers at risk of ADHD, and that this might account for the subtle attentional flaw in task performance.

Background: Cirrhotic patients are susceptible to Clostridium difficile infection (CDI), however, the high risk factors are not clear. The present study aimed to identify the risk factors in cirrhotic patients with CDI., Methods: A total of 526 cirrhotic patients admitted to our hospital between May 2015 and October 2015 were included in this study. Stool samples were collected upon admission for the detection of CDI and toxin. CDI was monitored during the hospital stay. In total, 34 cases showed CDI. Then we analyzed the effects of age, sex, C. difficile colonization (CDC), multiple hospitalization, extended hospital stay, elevation of total bilirubin (TBIL), creatinine (Cr), Child-Pugh grade C, hepatic encephalopathy, hepatorenal syndrome, upper gastrointestinal hemorrhage, and exposure of antibiotics and proton pump inhibitor (PPI) on the CDI in cirrhotic patients., Results: Patients in the CDI group had more frequent CDC, multiple hospitalization, and extended hospital stay compared to those in the non-C. difficile infection (NCDI) group. Patients in the CDI group had higher TBIL and Cr, and higher frequency of Child-Pugh grade C, hepatic encephalopathy, upper gastrointestinal hemorrhage compared with those in the NCDI group. Multiple logistic regression analysis indicated that age >60 years (OR=1.689; 95% CI: 1.135-3.128), multiple hospitalization (OR=3.346; 95% CI: 1.392-8.043), length of hospital stay >20 days (OR=1.564; 95% CI: 1.113-2.563), hypoproteinemia (OR=4.962; 95% CI: 2.053-11.996), CDC (OR=18.410; 95% CI: 6.898-49.136), hepatic encephalopathy (OR=1.357; 95% CI: 1.154-2.368), and exposure of antibiotics (OR=1.865; 95% CI: 1.213-2.863) and PPI (OR=3.125; 95% CI: 1.818-7.548) were risk factors of CDI., Conclusions: Age >60 years, multiple hospitalization, length of hospital stay >20 days, hypoproteinemia, CDC, hepatic encephalopathy, and exposure of antibiotics and PPI were risk factors for CDI in cirrhotic patients. These may contribute to the early diagnosis and monitoring of CDI in clinical practice., (Copyright © 2019. Published by Elsevier B.V.)

Increased intrasubject variability in reaction times (RT-ISV) is frequently found in individuals with autism spectrum disorder (ASD). However, how dimensional attention deficit/hyperactivity disorder (ADHD) symptoms impact RT-ISV in individuals with ASD remains elusive. We assessed 97 high-functioning youths with co-occurring ASD and ADHD (ASD+ADHD), 124 high-functioning youths with ASD only, 98 youths with ADHD only, and 249 typically developing youths, 8-18 years of age, using the Conners Continuous Performance Test (CCPT). We compared the conventional CCPT parameters (omission errors, commission errors, mean RT and RT standard error (RTSE) as well as the ex-Gaussian parameters of RT (mu, sigma, and tau) across the four groups. We also conducted regression analyses to assess the relationships between RT indices and symptoms of ADHD and ASD in the ASD group (i.e., the ASD+ADHD and ASD-only groups). The ASD+ADHD and ADHD-only groups had higher RT-ISV than the other two groups. RT-ISV, specifically RTSE and tau, was significantly associated with ADHD symptoms rather than autistic traits in the ASD group. Regression models also revealed that sex partly accounted for RT-ISV variance in the ASD group. A post hoc analysis showed girls with ASD had higher tau and RTSE values than their male counterparts. Our results suggest that RT-ISV is primarily associated with co-occurring ADHD symptoms/diagnosis in children and adolescents with ASD. These results do not support the hypothesis of response variability as a transdiagnostic phenotype for ASD and ADHD and warrant further validation at a neural level.

Merkel discs, located in skin touch domes and whisker hair follicles, are tactile end organs essential for environmental exploration, social interaction, and tactile discrimination. Recent studies from our group and two others have shown that mechanical stimulation excites Merkel cells via Piezo2 channel activation to subsequently activate sensory neural pathways. We have further shown that mechanical stimulation leads to the release of 5-HT from Merkel cells to synaptically transmit tactile signals to whisker afferent nerves. However, a more recent study using skin touch domes has raised the possibility that Merkel discs are adrenergic synapses. It was proposed that norepinephrine is released from Merkel cells upon mechanical stimulation to subsequently activate β2 adrenergic receptors on Merkel disc nerve endings leading to nerve impulses. In the present study, we examined effects of norepinephrine and β2 adrenergic receptor antagonist ICI 118,551 on Merkel disc mechanoreceptors in mouse whisker hair follicles. We show that norepinephrine did not directly induce impulses from Merkel disc mechanoreceptors. Furthermore, we found that ICI 118,551 at 50 μM inhibited voltage-gated Na + channels and suppressed impulses of Merkel disc mechanoreceptors, but ICI 118,551 at 1 μM had no effects on the impulse. These findings challenge the hypothesis of Merkel discs being adrenergic synapses.

To develop a rapid resolution liquid chromatography (RRLC) method for the simultaneous determination of epimedoside A, epimedin A1, epimedin A, epimedin B, epimedin C, icariin, baohuosideⅡ, icarisideⅠ, sagittatoside B, 2"- O -rhamnosyl icarisideⅡ, and baohuosideⅠin epimedium total flavone capsule. At the same time, the effects of the above 11 compounds on osteogenic differentiation of MC3T3-E1 cells were investigated by detecting the content of alkaline phosphatase (AKP). The results showed that baohuoside Ⅱ had the highest activities, and both the activities of baohuoside Ⅱ and icariside Ⅰ were stronger than those of icariin.In this study, the content determination method of flavonoid glycosides was established, and the anti-osteoporosis effect of monomers was compared, providing technical support for the study of the pharmacodynamic and mechanism of Epimedium total flavone capsule., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Objective: The aim of this study was to perform molecular characterization for and determine the antimicrobial susceptibility profiles of Clostridium difficile collected from hospitals during a 4-year period (2009-2013) in China., Methods: Strains of toxigenic C. difficile were isolated from patients with diarrhoea, and this was followed by typing using multilocus sequence typing (MLST) and testing for susceptibility to 10 antimicrobials by using the E-test. The mechanisms of resistance to moxifloxacin, erythromycin, clindamycin and tetracycline were investigated by PCR., Results: A total of 405 non-duplicate toxigenic C. difficile isolates were identified, while 31 sequence types (STs) were identified. A predominant type, ST-54, accounted for 20.2 % of the STs, followed by ST-35 (16.3 %) and ST-37 (13.6 %). We found that 6.2 % of the isolates were binary toxin genes-positive, and 83.7 % of these belonged to ST-5. All of the isolates demonstrated 100 % susceptibility to first-line Clostridium difficile infection (CDI) therapies (i.e. metronidazole and vancomycin), while the resistance rates varied for the other antibiotics tested. Two hundred and ninety three (72.3 %) isolates were susceptible to moxifloxacin. All 112 moxifloxacin-resistant isolates had mutations resulting in an amino acid substitution in gryA and/or gyrB. The ermB gene was detected in 86.7 % (241/278) of the erythromycin- and clindamycin-resistant isolates, while the tetM gene was present in 97.1 % (85/87) of the tetracycline-resistant isolates., Conclusion: MLST typing revealed a wide variety of STs causing CDI, while ST-54 was the most common ST. All of the isolates were susceptible to metronidazole and vancomycin, while the resistance rates varied for the other antibiotics tested. There were no changes in the trends for the STs and antibiotic susceptibility profiles over 4 years.

Parent and teacher ratings of child behaviors are often discrepant, and these discrepancies may be correlated with parenting stress. The present study explored whether various parenting stress factors are associated with discrepancies between parent and teacher ratings of attention-deficit/hyperactivity disorder and oppositional defiant disorder (ODD) as well as internalizing symptoms in preschool children. We recruited 299 Taiwanese preschool children (aged 4-6 years) from the community or via clinical referrals. A structural equation modeling was used to analyze the relationships among three factors derived from the Parenting Stress Index-Short Form and informant discrepancies on symptoms of inattention, hyperactivity/impulsivity, ODD, and internalizing behaviors. Scores reported by parents were higher for each of the symptoms examined than those reported by teachers, and the degree of agreement between informants ranged from low to moderate. The parental distress factor of parenting stress was associated only with parent ratings, whereas other factors of parenting stress-parent-child dysfunctional interaction and parents' stress resulted from their child's temperament-were correlated with both parent and teacher ratings. Only parental distress factor predicted informant discrepancies for all behavioral symptoms assessed. Our findings suggest that parental distress should be considered when parent rating scores show significant discrepancies from that of teacher rating scores.

Objectives: The purpose of this study was to investigate the diagnostic performance of acoustic radiation force impulse (ARFI) in assessing liver fibrosis preoperatively in infants with biliary atresia (BA)., Methods: A total of 50 consecutive infants with BA and 50 healthy infants who underwent ARFI examination were recruited. Siemens Acuson S2000 in Virtual Touch Quantification mode (Siemens Medical Solutions, Mountain View, CA) was used to measure shear wave speeds (SWSs). All infants with BA underwent a liver biopsy within 3 days after ARFI imaging. The liver fibrosis stages of specimens were defined according to the Batts-Ludwig scoring system. The correlation analysis was performed between SWSs and pathological findings. Cut-off values were determined using receiver operating characteristic (ROC) curves., Results: The mean SWS in the BA group was significantly higher than controls (mean ± standard deviation): 1.89 ± 0.45 versus 1.12 ± 0.06 m/s; P < .001). A significant correlation was found between the SWSs and fibrosis stages (r = 0.719, P < .001). The cut-off value for predicting significant fibrosis (F ≥ 2), severe fibrosis (F ≥ 3), and cirrhosis (F = 4) was 1.53, 1.80 and 2.16 m/s, respectively, and the area under the ROC curve was 0.823, 0.884 and 0.917, respectively., Conclusions: Acoustic radiation force impulse imaging showed significant correlation with the severity of liver fibrosis by comparing it with liver fibrosis biopsy pathology. It may be an effective method for liver fibrosis assessment, prognosis prediction, and clinical management in infants with BA., (© 2017 by the American Institute of Ultrasound in Medicine.)

Lactobacillus salivarius LI01, isolated from healthy humans, has demonstrated probiotic properties in the prevention and treatment of liver failure. Tolerance to bile stress is crucial to allow lactobacilli to survive in the gastrointestinal tract and exert their benefits. In this work, we used a Digital Gene Expression transcriptomic and iTRAQ LC-MS/MS proteomic approach to examine the characteristics of LI01 in response to bile stress. Using culture medium with or without 0.15% ox bile, 591 differentially transcribed genes and 347 differentially expressed proteins were detected in LI01. Overall, we found the bile resistance of LI01 to be based on a highly remodeled cell envelope and a reinforced bile efflux system rather than on the activity of bile salt hydrolases. Additionally, some differentially expressed genes related to regulatory systems, the general stress response and central metabolism processes, also play roles in stress sensing, bile-induced damage prevention and energy efficiency. Moreover, bile salts appear to enhance proteolysis and amino acid uptake (especially aromatic amino acids) by LI01, which may support the liver protection properties of this strain. Altogether, this study establishes a model of global response mechanism to bile stress in L. salivarius LI01., Biological Significance: L. salivarius strain LI01 exhibits not only antibacterial and antifungal properties but also exerts a good health-promoting effect in acute liver failure. As a potential probiotic strain, the bile-tolerance trait of strain LI01 is important, though this has not yet been explored. In this study, an analysis based on DGE and iTRAQ was performed to investigate the gene expression in strain LI01 under bile stress at the mRNA and protein levels, respectively. To our knowledge, this work also represents the first combined transcriptomic and proteomic analysis of the bile stress response mechanism in L. salivarius., (Copyright © 2016. Published by Elsevier B.V.)

Objective: To evaluate the role of circulating tumour cells (CTCs) in patients with endometrial cancer (EC)., Study Design: This study included 40 patients with a pre-operative diagnosis of high-risk EC between April 2015 and May 2016. Patients were further divided into high-risk (grade 3, non-endometrioid, myometrial invasion ≥1/2 and stage III-IV) and high-intermediate-risk (grade 2-3, endometrioid, myometrial invasion <1/2 and stage I-II) groups according to postoperative pathological results. CTCs were detected using the CellSearch system, and CTC results were correlated with standard clinicopathological characteristics and serum tumour marker CA125/HE4 status using Chi-squared test, continuity correction or Fisher's exact test. The pharmacodynamic effect was detected after the first cycle of adjuvant therapy. Patients were followed up for 13 months to assess outcomes., Results: Fifteen percent of patients had one or more CTCs. The presence of CTCs was found to be significantly associated with cervical involvement (83.33% vs 11.76%, p=0.00). No significant difference in CTC-positive rates was detected between the high-risk and high-intermediate-risk groups, and no significant correlation was found between CTCs and serum CA125/HE4, either by positive rates or exact serum levels of the conventional tumour markers. No more CTCs were detected after the first cycle of standard chemotherapy in this study, and no distant metastases or recurrence were found in the CTC-positive patients during the follow-up period., Conclusion: The presence of CTCs was correlated with cervical involvement. Early-stage EC patients with CTCs may benefit from additional adjuvant therapies. Assessment of CTCs may be useful in the management of high-risk EC patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Excessive nitrogen (N) fertilizer application has led to a reduction of nitrogen use efficiency and environmental problems. It was of great significance for high-yield and high-efficiency cultivation to reduce N fertilizer application with modified application strategies. A two-year field experiment was conducted to study effects of different N application rates at basal and seedling application stages on grain yield and nitrogen use efficiency. Taking the conventional nitrogen application practice (240 kg N·hm -2 with application at basal, jointing, and booting stages at ratios of 5:3:2, respectively) as control, a field trial was conducted at different N application rates (240, 180 and 150 kg N·hm -2 , N 240 , N 180 and N 150 , respectively) and different application times [basal (L 0 ), fourth (L 4 ) and sixth leaf stage (L 6 )] to investigate the effects on grain yield and nitrogen use efficiency. The results indicated that grain yield decreased along with reducing the N application rate, but it had no significant difference between N 240 and N 180 while decreased significantly under N 150 . Nitrogen agronomy and recovery efficiency were all highest under N 180 . Among different N application stages, grain yield and nitrogen use efficiency were highest under L 4 . N 180 L 4 had no signifi-cant difference with control in grain yield, but its nitrogen use efficiency was significantly higher. The leaf area index, flag leaf photosynthesis rate, leaf nitrogen content, activity of nitrogen reductase and glutamine synthase in flag leaf, dry matter and N accumulation after jointing of N 180 L 4 had no significant difference with control. In an overall view, postponing basal N fertilizer application at reduced nitrogen rate could maintain high yield and improve nitrogen use efficiency through improving photosynthetic production capacity and promoting nitrogen uptake and assimilation.

Cognitive impairment is a common adverse effect of electroconvulsive therapy (ECT) during treatment for severe depression. Dexmedetomidine (DEX), a sedative-anesthetic drug, is used to treat post-ECT agitation. However, it is not known if DEX can protect against ECT-induced cognitive impairments. To address this, we used chronic unpredictable mild stress (CUMS) to establish a model of depression for ECT treatment. Our Morris water maze and sucrose preference test results suggest that DEX alleviates ECT-induced learning and memory impairments without altering the antidepressant efficacy of ECT. To further investigate the underlying mechanisms of DEX, hippocampal expression of NR2B, p-ERK/ERK, p-CREB/CREB, and BDNF were quantified by western blotting. These results show that DEX suppresses over-activation of NR2B and enhances phosphorylation of ERK1/2 in the hippocampus of ECT-treated depressed rats. Furthermore, DEX had no significant effect on ECT-induced increases in p-CREB and BDNF. Overall, our findings suggest that DEX ameliorates ECT-induced learning and memory impairments in depressed rats via the NR2B-ERK signaling cascade. Moreover, CREB/BDNF seems not appear to participate in the cognitive protective mechanisms of DEX during ECT treatment., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Intra-individual variability in reaction time (IIV-RT) is common in individuals with attention-deficit/hyperactivity disorder (ADHD). It can be improved by stimulants. However, the effects of atomoxetine on IIV-RT are inconclusive. We aimed to investigate the effects of atomoxetine on IIV-RT, and directly compared its efficacy with methylphenidate in adults with ADHD., Methods: An 8-10 week, open-label, head-to-head, randomized clinical trial was conducted in 52 drug-naïve adults with ADHD, who were randomly assigned to two treatment groups: immediate-release methylphenidate (n=26) thrice daily (10-20 mg per dose) and atomoxetine once daily (n=26) (0.5-1.2 mg/kg/day). IIV-RT, derived from the Conners' continuous performance test (CCPT), was represented by the Gaussian (reaction time standard error, RTSE) and ex-Gaussian models (sigma and tau). Other neuropsychological functions, including response errors and mean of reaction time, were also measured. Participants received CCPT assessments at baseline and week 8-10 (60.4±6.3 days)., Results: We found comparable improvements in performances of CCPT between the immediate-release methylphenidate- and atomoxetine-treated groups. Both medications significantly improved IIV-RT in terms of reducing tau values with comparable efficacy. In addition, both medications significantly improved inhibitory control by reducing commission errors., Conclusion: Our results provide evidence to support that atomoxetine could improve IIV-RT and inhibitory control, of comparable efficacy with immediate-release methylphenidate, in drug-naïve adults with ADHD. Shared and unique mechanisms underpinning these medication effects on IIV-RT awaits further investigation., (© The Author(s) 2016.)

In the present study, we report the whole genome sequences of two species, Ornithinibacillus contaminans DSM22953(T) isolated from human blood and Ornithinibacillus californiensis DSM 16628(T) isolated from marine sediment, in genus Ornithinibacillus. Comparative genomic study of the two species was conducted together with their close relative Ornithinibacillus scapharcae TW25(T), a putative pathogenic bacteria isolated from dead ark clam. The comparisons showed O. contaminans DSM22953(T) had the smallest genome size of the three species indicating that it has a relatively more stable habitat. More stress response and heavy metal resistance genes were found in the genome of O. californiensis DSM 16628(T) reflecting its adaption to the complex marine environment. O. scapharcae TW25(T) contained more antibiotic resistance genes and virus factors in the genome than the other two species, which revealed its pathogen potential., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Infection with Clostridium difficile has been shown to have particularly poor outcomes for pregnant women, including an increased risk of death. The purpose of this study was to investigate the prevalence, genotypic distribution, and characterization of C. difficile strains isolated from pregnant women without diarrhea in China. As part of this study, 3.7% (37 out of 1009) of samples acquired from pregnant females tested positive for C. difficile. Of these positive samples, 27.0% (10) were toxigenic isolates containing both toxin A and toxin B genes (A+B+), 13.5% (5) of the variant strains contained the toxin B gene (A-B+) only, while the rest were non-toxigenic isolates (59.5%, 22 isolates). Among the non-pregnant women without diarrhea tested, 1.4% (9 of 651) contained toxigenic isolates (all of which were A+B+). Sixteen different sequence types (STs) were isolated during the course of this study. ST-37 (ribotype 017) and ST-54 (ribotype 012) were the most frequent toxigenic types observed in pregnant women. All strains showed susceptibility to the antibiotics metronidazole and vancomycin. The resistance rates of toxigenic C. difficile strains isolated from pregnant females to clindamycin, erythromycin, moxifloxacin, levofloxacin, and rifampicin were 20%, 46.7%, 13.6%, 46.7% and 13.3%, respectively. There was no significant difference between resistance rates of toxigenic and non-toxigenic strains with respect to their susceptibility to these antibiotics. However, when compared with the same data from non-pregnant women, toxigenic strains from pregnant women showed lower resistance rates to clindamycin (P < 0.05)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Increasing evidence indicates that dexmedetomidine (DEX), a selective α2-adrenergic receptor agonist, has a neuroprotective effect against cerebral injury. However, it remains unknown whether and how DEX functionally prevents the pathological form of synaptic plasticity caused by ischemia in the hippocampal CA1 neurons. To address this issue, we analyzed the role of DEX using a model of brain ischemia (oxygen and glucose deprivation, OGD) referred to as post-ischemic LTP (i-LTP). We found that DEX could reduce i-LTP by selectively activating α2 receptors. To clarify its detailed mechanisms, the presynaptic and postsynaptic roles of DEX were investigated. The activation of the α2 receptors of DEX decreased the frequency spontaneous mEPSCs, which exerted its presynaptic mechanisms. In addition, DEX also decreased the amplitude of mEPSCs and prevented the depolarization of postsynaptic membranes during OGD treatment, which exerted its postsynaptic mechanisms. More importantly, our results indicate that postsynaptic β receptors, not α1 receptors, participated in i-LTP. Therefore, these results demonstrated that decreasing β receptors activation by DEX-medicated pre- and post-synaptic α2 receptors activation is responsible for i-LTP. Because of the NMDARs required for i-LTP, we further examined the critical roles of postsynaptic β receptors downstream PKA regulation of NMDA receptor-mediated EPSCs (NMDA EPSC). We clarified that it is attributable to the direct effect of DEX on NMDA EPSC as mediated by PKA inactivation. These findings suggest that DEX can protect neurons from functional damage caused by a relatively mild degree of transient cerebral ischemia, and this effect is mediated by both presynaptic reduction of NE and glutamate release and postsynaptic suppression of NMDAR activation by β receptors and downstream PKA regulation., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: Intra-individual variability in reaction time (IIV-RT), defined by standard deviation of RT (RTSD), is considered as an endophenotype for attention-deficit/hyperactivity disorder (ADHD). Ex-Gaussian distributions of RT, rather than RTSD, could better characterize moment-to-moment fluctuations in neuropsychological performance. However, data of response variability based on ex-Gaussian parameters as an endophenotypic candidate for ADHD are lacking., Method: We assessed 411 adolescents with clinically diagnosed ADHD based on the DSM-IV-TR criteria as probands, 138 unaffected siblings, and 138 healthy controls. The output parameters, mu, sigma, and tau, of an ex-Gaussian RT distribution were derived from the Conners' continuous performance test. Multi-level models controlling for sex, age, comorbidity, and use of methylphenidate were applied., Results: Compared with unaffected siblings and controls, ADHD probands had elevated sigma value, omissions, commissions, and mean RT. Unaffected siblings formed an intermediate group in-between probands and controls in terms of tau value and RTSD. There was no between-group difference in mu value. Conforming to a context-dependent nature, unaffected siblings still had an intermediate tau value in-between probands and controls across different interstimulus intervals., Conclusion: Our findings suggest IIV-RT represented by tau may be a potential endophenotype for inquiry into genetic underpinnings of ADHD in the context of heterogeneity., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To investigate the epidemic situation of Metorchis orientalis in Wuhu City, Anhui Province., Methods: Three lakes (Fengming, Longwo and Kui lakes) were selected in Wuhu City, and the poultries around the lakes and freshwater fishes in the lakes were captured to test the infection of M. orientalis, and the infection rates were calculated., Results: The adult worms of M. orientalis were found in gall bladder and hepatic duct of domestic ducks with infection rate of 16.7%. The metacercariae of M. orientalis were discovered in the muscle of Pseudorasbora parva and Pseudogobio rivularis with infection rates of 7.13% and 3.38% respectively., Conclusion: M. orientalis is endemic in Wuhu City, which should be paid enough attention to the animal husbandry, aquaculture and medicine.

The literature has suggested timing processing as a potential endophenotype for attention deficit/hyperactivity disorder (ADHD); however, whether the subjective internal clock speed presented by verbal estimation and limited attention capacity presented by time reproduction could be endophenotypes for ADHD is still unknown. We assessed 223 youths with DSM-IV ADHD (age range: 10-17 years), 105 unaffected siblings, and 84 typically developing (TD) youths using psychiatric interviews, intelligence tests, verbal estimation and time reproduction tasks (single task and simple and difficult dual tasks) at 5-second, 12-second, and 17-second intervals. We found that youths with ADHD tended to overestimate time in verbal estimation more than their unaffected siblings and TD youths, implying that fast subjective internal clock speed might be a characteristic of ADHD, rather than an endophenotype for ADHD. Youths with ADHD and their unaffected siblings were less precise in time reproduction dual tasks than TD youths. The magnitude of estimated errors in time reproduction was greater in youths with ADHD and their unaffected siblings than in TD youths, with an increased time interval at the 17-second interval and with increased task demands on both simple and difficult dual tasks versus the single task. Increased impaired time reproduction in dual tasks with increased intervals and task demands were shown in youths with ADHD and their unaffected siblings, suggesting that time reproduction deficits explained by limited attention capacity might be a useful endophenotype of ADHD.

Rationale: Sigma-1 receptor (Sig-1R) agonists showed anti-amnesic properties in Alzheimer's disease models and anti-inflammatory properties in cerebrum ischaemia models. The agonist of Sig-1R was reported to up-regulate brain-derived neurotrophic factor (BDNF) levels in the hippocampus of mice. Here, we investigate whether the activation of Sig-1R attenuates the learning and memory impairment induced by ischaemia/reperfusion and how it affects the expression of BDNF., Objectives: Bilateral common carotid artery occlusion (BCCAO) was induced for 20 min in C57BL/6 mice., Materials and Methods: Sig-1R agonist, PRE084, sigma 1/2 non-selective agonist, DTG, Sig-1R antagonist and BD1047 were injected once daily throughout the experiment. Behavioural tests were performed from day 8. On day 22 after BCCAO, mice were sacrificed for biochemical analysis., Results: PRE084 and DTG ameliorated learning and memory impairments in the Y maze, novel object recognition, and water maze tasks and prevented the decline of synaptic proteins and BDNF expression in the hippocampus of BCCAO mice. Furthermore, PRE084 and DTG up-regulated the level of NMDA receptor 2A (NR2A), calcium/calmodulin-dependent protein kinase type IV (CaMKIV) and CREB-specific co-activator transducer of regulated CREB activity 1 (TORC1). Additionally, the effects of PRE084 and DTG were antagonised by the co-administration of BD1047., Conclusions: Sig-1R activation showed an attenuation in the ischaemia/reperfusion model and the activation of Sig-1R increased the expression of BDNF, possibly through the NR2A-CaMKIV-TORC1 pathway, and Sig-1R agonists might function as neuroprotectant agents in vascular dementia.

The purpose of this study was to evaluate the risk factors, outcomes and epidemiology associated with Clostridium difficile infection (CDI) in patients with haematological malignancies in a tertiary care hospital in China. C. difficile screening was performed on patients admitted for chemotherapy or haematopoietic stem cell transplantation between 2009 and 2013. C. difficile isolates were analysed by multilocus sequence typing, and a retrospective chart review was performed on all patients with a positive toxin assay. CDI was diagnosed in 21 haematology-oncology ward patients and 14 marrow transplantation service patients for a cumulative incidence of 1.89/1000 and 3.69/1000 patient-days, respectively. Univariate analyses showed that patients who received etoposide had an increased risk of CDI (odds ratio 4.25, 95 % confidence interval 1.32-13.64). There was only one patient death, for which CDI was not the primary cause. Ten sequence types (STs) were identified, of which ST-3 and ST-54 were the most common; the hypervirulent ST-1 (ribotype 027) and ST-11 (ribotype 078) C. difficile strains were not detected in the patients in this study. The incidence of CDI did not differ between patients receiving chemotherapy and those receiving haematopoietic stem cell transplantation. The only risk factor for chemotherapy patients was treatment with etoposide., (© 2015 The Authors.)

Sheath blight (SB), caused by Rhizoctonia solani, is one of the worst rice (Orzya sativa) diseases worldwide. Resistance to the SB disease in rice is a complex trait controlled by quantitative trait loci (QTLs). Through map integration, we found several previously identified SB resistance (SBR) QTLs reported in inconsistent regions on the long arm of chromosome 9. Five of them were detected on 'Jasmine 85' (J85), 'Minghui 63' (MH63), and 'Lemont' (LMNT) rice and were designated qSB-9 J85 -1, qSB-9 J85 -2, qSB-9 MH63 -1, qSB-9 MH63 -2, and qSB-9 LMNT , respectively, in the present study. To further verify and physically map the five potential SBR QTLs, we introduced these SBR QTLs into a common susceptible variety (LMNT) and developed a few chromosomal segment substitution lines through marker-assisted selection. After artificial inoculation with the SB fungus, we were able to validate qSB-9 J85 -2 but not the other four SBR QTLs; whereas, on MH63, an SBR QTL designated qSB-9 MH63 -3 was confirmed in the region defined by markers Y83 and Y91.8 that included qSB-9 J85 -2, covering approximately 1,235 kb. Both qSB-9 J85 -2 and qSB-9 MH63 -3 appeared to be dominant resistance genes and contributed to similar levels to SB resistance, reducing SB disease severity by approximately 1.0 on a 0-to-9 SB disease rating system. After comparing with another confirmed SBR QTL (qSB-9 TQ ) from 'Teqing' rice (TQ), we conclude that qSB-9 J85 -2, qSB-9 MH63 -3, and qSB-9 TQ are probably controlled by the same allelic resistance genes. These results will accelerate the utilization of this major SBR QTL and its map-based cloning.

Current metabolomic studies of ischemic brain mainly attach importance on a certain ischemic period, are lack of data about dynamic metabolites in ischemic stroke process, especially early period. Thus, in this study, (1)H NMR spectroscopy was used to investigate biochemical changes in the early stages of rats' focal cerebral ischemia reperfusion (I/R) injury. Serum samples of 0, 0.5, 1, 3, 6, 12, 24 h of reperfusion, based on multivariate data analyses, were tested to analyze the changing of metabolites during the early disease process. Partial least squares-discriminant analysis scores plots of the (1)H NMR data revealed clear differences among the experiment groups. Combination the results of loading plot and t-test, we found that 13 metabolites were changed significantly. Among that, malonic acid and glycine are the most noticeable variable metabolites. Dramatic changed malonic acid and glycine most probably served as biomarkers in this study. These findings help us understand the biochemical metabolite changes in early ischemic stroke stages, especially different periods. That may be conducive to distinguish at-risk individuals, benefit early diagnosis and understand the dynamic pathogenesis of early cerebral ischemia.

Background: Increased intra-individual variability (IIV) in reaction time (RT) across various tasks is one ubiquitous neuropsychological finding in attention deficit hyperactivity disorder (ADHD). However, neurobiological underpinnings of IIV in individuals with ADHD have not yet been fully delineated. The ex-Gaussian distribution has been proved to capture IIV in RT. The authors explored the three parameters [μ (mu), σ (sigma), τ (tau)] of an ex-Gaussian RT distribution derived from the Conners' continuous performance test (CCPT) and their correlations with the microstructural integrity of the frontostriatal-caudate tracts and the cingulum bundles., Method: We assessed 28 youths with ADHD (8-17 years; 25 males) and 28 age-, sex-, IQ- and handedness-matched typically developing (TD) youths using the CCPT, Wechsler Intelligence Scale for Children, 3rd edition and magnetic resonance imaging (MRI). Microstructural integrity, indexed by generalized fractional anisotropy (GFA), was measured by diffusion spectrum imaging tractrography on a 3-T MRI system., Results: Youths with ADHD had larger σ (s.d. of Gaussian distribution) and τ (mean of exponential distribution) and reduced GFA in four bilateral frontostriatal tracts. With increased inter-stimulus intervals of CCPT, the magnitude of greater τ in ADHD than TD increased. In ADHD youths, the cingulum bundles and frontostriatal integrity were associated with three ex-Gaussian parameters and with μ (mean of Gaussian distribution) and τ, respectively; while only frontostriatal GFA was associated with μ and τ in TD youths., Conclusions: Our findings suggest the crucial role of the integrity of the cingulum bundles in accounting for IIV in ADHD. Involvement of different brain systems in mediating IIV may relate to a distinctive pathophysiological processing and/or adaptive compensatory mechanism.

Objective: To evaluate clinical application and clinical outcomes of free flap pedicled with supracarpal cutaneous branch of ulnar artery in repairing of finger replantation with skin defect., Methods: From April 2007 to March 2013,25 patients affected by finger amputation with skin defect were replanted and repaired by free flap pedicled with supracarpal cutaneous branch of ulnar artery. Among them, 18 patients were male and 7 were female,with an average age of 31.5 years old (ranged 16 to 58). The time of trauma to admission ranged from 45 to 210 min (averaged 105). Fifteen patients were complete separted, and 10 patients were non-complete separated. The area of flaps ranged from 3.5 cm x 2.0 cm to 4.5 cm x 3.0 cm, and the vessels were anastomosed through end-to-end. The functional evaluation standard of finger replantation was used to evaluate the postoperative function., Results: Twenty-four cases were finally survived. Two flaps occurred vascular crisisin within 48 h after operation, one of which was survived after anti-vasospasm treatment and changing dressing,another was replanted finger for failed to survive. One had infection and healed after changing dressing. Twenty-four cases were followed up from 3 to 38 months with an average of 16.5 months. The appearance and texture of flaps were satisfactory, and the superficial senses of pain and touch were recovered,and two-point discrimination was 5.5 to 11 mm (averaged 7.4 mm). According to functional evaluation standard finger replantationissued by Hand Surgery Association of Chinese Medical Association, 8 cases got excellent results, 14 good and 2 poor., Conclusion: The free flap pedicled with supracarpal cutaneous branch of ulnar artery can be used in complex finger replantation with skin and vessels defect, which can extend operation indications, recover function and appearance for maximum.

Clostridium difficile infection (CDI) is caused by toxin-producing strains. It accounts for 20-30 % of antibiotic-associated diarrhoea and particularly accounts for 90 % of pseudomembranous colitis. The epidemiological study of C. difficile is thus important. In this study, we report the molecular epidemiology and ward distribution of C. difficile in a tertiary hospital of China. A total of 161 toxigenic strains were isolated from 1845 patients originating from different wards and the strains were characterized based on toxin profile and multilocus sequence typing. Variable isolation rates were observed in different wards and the occurrence was higher in intensive care unit and geriatric wards. Toxin gene profiling revealed that, out of the 161 isolates, 134 (83.2)% were positive for both toxin A (tcdA) and toxin B (tcdB) (A+B+) followed by toxin A-negative and B-positive (A-B+) (16.8 %) isolates. However, only three of the toxigenic strains (1.9 %) were positive for both the cdtA and cdtB genes. Based on the molecular epidemiology study, a total of 30 different sequence types (STs), including one new ST (ST-220), were distinguishable. ST-54 was the most prevalent (23.0 %), followed by ST-35 (19.3 %) and ST-37 (10.0 %). None of the isolates belonged to ST-1 (ribotype 027) or ST-11 (ribotype 078). Taken together, the toxin profile and the molecular epidemiological data showed that all the ST-37 clades were of toxin type A-B+, which accounted for 59.3 % of all type A-B+ isolates. Meanwhile the clade 1 genotype, ST-54, was widely distributed among the geriatric, infection and haematology wards. There was no outbreak of C. difficile infection during our study; however the possibility of prolonged outbreaks cannot be completely ignored.

Our previous and other studies have confirmed that a selective M1 and M3 receptor antagonist, Penehyclidine hydrochloride (PHC), has neuroprotection activity in cerebral ischemia. However, the precise mechanisms of protection of PHC are still elusive. In this study we analyzed PHC-mediated neuroprotection on a model of brain ischemia (oxygen and glucose deprivation), named postischemic LTP (i-LTP). We found that the activation of NMDA receptor was required for the induction of i-LTP. Compared with scopolamine, PHC could prevent it due to selectively blocking M1 receptor, not M2 receptor, to decrease NMDAR activation. Our findings further showed that the inhibition of SK2 channels occluded the prevention of PHC on NMDAR activation. Furthermore, we confirmed that PHC exerted its roles through directly disinhibition of SK2 channels by blocking M1 receptor and subsequent restricting PKC activation. Moreover, our studies further revealed the critical roles of SK2 channels in i-LTP. Thus, the mechanisms of PHC in brain protection may be involved in suppression of NMDAR by regulation of SK2 channels. Our results obtained in effects of PHC on i-LTP further provided a better understanding of the therapy strategy during stroke and identified potential therapeutic targets to prevent development of ischemia., (Copyright © 2013 Wiley Periodicals, Inc.)

We investigated the three parameters (mu, sigma, tau) of ex-Gaussian distribution of RT derived from the Conners' continuous performance test (CCPT) and examined the moderating effects of the energetic factors (the inter-stimulus intervals (ISIs) and Blocks) among these three parameters, especially tau, an index describing the positive skew of RT distribution. We assessed 195 adolescents with DSM-IV ADHD, and 90 typically developing (TD) adolescents, aged 10-16. Participants and their parents received psychiatric interviews to confirm the diagnosis of ADHD and other psychiatric disorders. Participants also received intelligence (WISC-III) and CCPT assessments. We found that participants with ADHD had a smaller mu, and larger tau. As the ISI/Block increased, the magnitude of group difference in tau increased. Among the three ex-Gaussian parameters, tau was positively associated with omission errors, and mu was negatively associated with commission errors. The moderating effects of ISIs and Blocks on tau parameters suggested that the ex-Gaussian parameters could offer more information about the attention state in vigilance task, especially in ADHD., (Copyright © 2013 Elsevier Ltd. All rights reserved.)