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Objectives: The geographical environment and military activities in the plateau area pose potential work-related stressors for military personnel, leading to burnout which is an external manifestation of internal energy exhaustion caused by stress. Without countermeasures, this can result in serious military problems. This study aims to examine the association between burnout and occupational stressors among military personnel stationed in the plateau area of China., Material and Methods: A stratified randomized cluster sampling survey was conducted among 2026 military personnel from 6 different troops stationed in the plateau area of China. The Chinese Maslach Burnout Inventory-General Survey(MBI-GS in Chinese) was administered from March 2022 to December 2023, and data were analyzed using SPSS version 25., Results: A total of 2026 military personnel participated in the survey. The mean overall burnout score was 3.37 ± 0.73, with emotional exhaustion at 2.69 ± 0.89, depersonalization at 3.58 ± 0.92, and professional achievement at 3.81 ± 0.85 levels respectively reported by participants on average scale scores ranging from zero to six. Severe level of burnout was reported by 43.2% of participants while medium level of burnout was reported by 54 .3%. Age, education level, length of military service, and household income were identified as important factors influencing burnout., Conclusion: This study highlights a relatively high prevalence of burnout among military personnel stationed in plateau areas necessitating attention towards their occupational health particularly focusing on working hours and economic aspects so as to formulate effective policies and implement intervention measures that strengthen career development for soldiers deployed in such regions., (© 2024. The Author(s).)

Background: Playing an exemplary role, frailty have crucial effect on the preoperative evaluation of elderly patients. Previous studies have shown that frailty is associated with complications and mortality in patients with gastric cancer (GC). However, with the development of the concept of "patient-centered", the range of health-related outcomes is broad. The differences in relation between frailty and various adverse outcomes will be further explored., Method: The PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wan Fang, and Chinese Biomedical Literature databases were searched for keywords, including frailty (such as frail) and gastric cancer (such as stomach neoplasms or stomach cancer or gastrectomy or gastric surgery). The search period is until August 2023. The included studies were observational or cohort studies with postoperative related adverse outcomes as primary or secondary outcome measures. Valid assessment tools were used. The Quality Assessment Tool for Observational Cohort and Cross-sectional Studies was used to assess methodological quality in the included literature., Result: Fifteen studies were included, including 4 cross-sectional studies, 8 retrospective cohort studies, and 3 prospective cohort studies. Among them, 6 studies were rated as "Good" and 9 studies were rated as "Fair," indicating that the quality of the literature was high. Then, 10 frailty assessment tools were summarized and classified into two broad categories in accordance with frailty models. Results of the included studies indicated that frailty in elderly patients with GC was associated with postoperative complications, mortality, hospital days, readmissions, quality of life, non-home discharge, and admission to the intensive care unit., Conclusion: This scoping review concludes that high levels of preoperative frailty increase the risk of adverse outcomes in elderly patients with GC. Frailty will be widely used in the future clinical evaluation of elderly gastric cancer patients, precise risk stratification should be implemented for patients, and frailty management should be implemented well to reduce the occurrence of adverse treatment outcomes., Competing Interests: None of the authors declare a conflicts of interest.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Previous studies have shown that reduced sleep duration, sleep fragmentation, and decreased sleep quality in patients with Alzheimer's disease are related to dysfunction in orexin signaling. At the same time, blood-brain barrier disruption is considered an early biomarker of Alzheimer's disease. However, currently no report has examined how changes in orexin signaling relate to changes in the blood-brain barrier of patients who have Alzheimer's disease with sleep insufficiency. This cross-sectional study included 50 patients with Alzheimer's disease who received treatment in 2019 at Beijing Tiantan Hospital. Patients were divided into two groups: those with insufficient sleep (sleep duration ≤ 6 hours, n = 19, age 61.58 ± 8.54 years, 10 men) and those with normal sleep durations (sleep duration > 6 hours, n = 31, age 63.19 ± 10.09 years, 18 men). Demographic variables were collected to evaluate cognitive function, neuropsychiatric symptoms, and activities of daily living. The levels of orexin, its receptor proteins, and several blood-brain barrier factors were measured in cerebrospinal fluid. Sleep insufficiency was associated with impaired overall cognitive function that spanned multiple cognitive domains. Furthermore, levels of orexin and its receptors were upregulated in the cerebrospinal fluid, and the blood-brain barrier was destroyed. Both these events precipitated each other and accelerated the progression of Alzheimer's disease. These findings describe the clinical characteristics and potential mechanism underlying Alzheimer's disease accompanied by sleep deprivation. Inhibiting the upregulation of elements within the orexin system or preventing the breakdown of the blood-brain barrier could thus be targets for treating Alzheimer's disease., Competing Interests: None

It is well established that p-Hydroxycinnamic acids (HCAs), including ferulic, caffeic, sinapic, and p-coumaric acids, possess a characteristic phenylpropanoid C6-C3 backbone and account for about one-third of the phenolic compounds in our diet. HCAs are typically associated with various plant cell wall components, including mono-, di-, and polysaccharides, sterols, polyamines, glycoproteins, and lignins. Interestingly, enzymes produced by intestinal microbes liberate HCAs from these associations. HCAs are completely absorbed in their free form upon ingestion and undergo specific reactions upon absorption in the small intestine or liver. The gut epithelium, composed of intestinal epithelial cells (IECs), acts as a physical barrier against harmful bacteria and a site for regulated interactions between bacteria and the gut lumen. Thus, maintaining the integrity of the epithelial barrier is essential for establishing a physiochemical environment conducive to homeostasis. This review summarizes the protective effects of HCAs on the intestinal barrier, achieved through four mechanisms: preserving tight junction proteins (TJPs), modulating pro-inflammatory cytokines, exerting antioxidant activity, and regulating the intestinal microbiota.

Background: Neuropsychiatric symptoms (NPSs) belong to a category of non-motor symptoms of Parkinson's disease (PD), which seriously compromise the quality of life and prognosis of PD. This study focused on the correlations between NPSs, free radicals, neuroinflammatory factors, and neuropathological proteins in cerebrospinal fluid (CSF) in patients with PD, aiming to provide insights into the potential mechanisms and therapeutic target for PD with NPSs (PD-NPSs)., Methods: In total, 129 patients with PD were enrolled and assessed by the Neuropsychiatric Symptoms Inventory (NPI); they were divided into the PD-NPSs group (75 patients) and PD with no NPSs (PD-nNPSs) group (54 patients). The levels of hydrogen peroxide (H 2 O 2 ) and nitric oxide (NO), and hydroxyl radical (·OH), anti-oxidative enzyme, neuroinflammatory factors, and neuropathological proteins in CSF from patients with PD were measured. The levels of the above variables were compared between PD-NPSs and PD-nNPSs groups, and correlation analyses among the above variables were conducted., Results: (1) The levels of H 2 O 2 and NO in CSF from the PD-NPSs group were significantly elevated compared with the PD-nNPSs group ( p = 0.001), and NPI score positively correlated with the levels of H 2 O 2 and NO ( r = 0.283, P = 0.001; r = 0.231, P = 0.008). Reversely, total superoxide dismutase (tSOD) activity in CSF from the PD-NPSs group was significantly reduced compared with the PD-nNPSs group ( p = 0.011), and negatively correlated with NPI score ( r = -0.185, p = 0.036). (2) The tumor necrosis factor (TNF)-α level in CSF from the PD-NPSs group was significantly decreased compared with the PD-nNPSs group ( p = 0.002) and negatively correlated with NPI score ( r = -0.211, p = 0.016). (3) The total tau (T-tau) level in CSF from the PD-NPSs group was significantly higher than in the PD-nNPSs group ( p = 0.014) and positively correlated with the NPI score ( r = 0.167, p = 0.060). (4) The levels of H 2 O 2 and NO positively correlated with the T-tau level in CSF from the PD-NPSs group ( r = 0.183, p = 0.039; r = 0.251, P = 0.004), and the levels of TNF-α and T-tau showed a negative correlation ( r = -0.163, p = 0.067)., Conclusion: Oxidative distress characterized by the elevations of H 2 O 2 and NO levels may closely correlate with the neurodegeneration in brain regions related to PD-NPSs. Thus, therapeutic antioxidants may become an important target for PD-NPSs therapy., 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 Li, Lian, Zhang, Zhang, Guo, Guan, Li, He, Zhang, Zhang, Luo, Wang and Zhang.)

Background: A comprehensive understanding of arterial variations around the midline of the nose is of great importance for the safety of filler injection., Objectives: The aim of the study was to clearly define the 3-dimensional location of the arteries along the midline of the nasal bone., Methods: The arterial structures overlapping the nasal bone along the midline were observed in 79 cadavers., Results: The present study found that 0 to 3 named arteries per nose segment could be identified. All the arterial structures were located in or above the superficial musculoaponeurotic system layer overlapping the nasal bone. The probability of encountering named arteries at 5 defined points, P1 to P5, was 5/79 (6.3%), 4/79 (5.1%), 1/79 (1.3%), 6/79 (7.6%), and 9/79 (11.4%), respectively. The depth of the main arterial trunk was 1.2 ± 0.4 mm, 1.6 ± 0.6 mm, 1.8 ± 0 mm, 1.0 ± 0.4 mm, and 0.9 ± 0.5 mm below the skin at P1 to P5, respectively., Conclusions: The authors confirmed that sub-superficial musculoaponeurotic system injection along the midline through a needle is anatomically reliable and that a technique with 1 entry point through the rhinion via a cannula can easily keep the needle sufficiently deep for safe nasal filler injection., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The aim of this study was to explore clinical features and potential mechanisms relating neuropathological biomarkers and blood-brain barrier (BBB) in Alzheimer's disease (AD) and hearing loss (HL)., Materials and Methods: A total of 65 patients with AD were recruited and auditory function was assessed by threshold of pure tone audiometry (PTA). Patients were divided into AD with HL (AD-HL) and AD with no HL (AD-nHL) groups based on the standard of World Health Organization. Clinical symptoms were assessed by multiple rating scales. The levels of neuropathological biomarkers of β amyloid1-42 (Aβ 1-42 ) and multiple phosphorylated tau (P-tau), and BBB factors of matrix metalloproteinases (MMPs), receptor of advanced glycation end products, glial fibrillary acidic protein, and low-density lipoprotein receptor related protein 1 were measured., Results: (1) Compared with AD-nHL group, AD-HL group had significantly impaired overall cognitive function and cognitive domains of memory, language, attention, execution, and activities of daily living (ADL) reflected by the scores of rating scales ( P < 0.05). PTA threshold was significantly correlated with the impairments of overall cognitive function and cognitive domains of memory and language, and ADL in patients with AD ( P < 0.05). (2) P-tau (S199) level was significantly increased in CSF from AD-HL group ( P < 0.05), and was significantly and positively correlated with PTA threshold in patients with AD. (3) MMP-3 level was significantly elevated in CSF from AD-HL group ( P < 0.05), and was significantly and positively correlated with PTA threshold in patients with AD ( P < 0.05). (4) In AD-HL group, P-tau (S199) level was significantly and positively correlated with the levels of MMP-2 and MMP-3 in CSF ( P < 0.05)., Conclusion: AD-HL patients have severely compromised overall cognitive function, multiple cognitive domains, and ADL. The potential mechanisms of AD-HL involve elevations of AD neuropathological biomarker of P-tau (S199) and BBB factor of MMP-3, and close correlations between P-tau (S199) and MMP-2/MMP-3 in CSF. Findings from this investigation highly suggest significance of early evaluation of HL for delaying AD progression, and indicate new directions of drug development by inhibiting neuropathological biomarkers of AD and protecting BBB., 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. The handling editor JL, declared a shared parent affiliation with the authors at the time of the review., (Copyright © 2022 Zhang, Li, Lian, Guo, Zhang, Li, Guan, He, Zhang, Zhang, Luo, Wang and Zhang.)

Objective: This study aimed to explore the outcomes of His-Purkinje conduction system pacing (HPCSP) and to screen the predictors of left ventricular (LV) complete reverse remodeling in patients with true left bundle branch block (LBBB) and heart failure with reduced ejection fraction (HFrEF)., Methods: Patients who underwent HPCSP for true LBBB and HFrEF from April 2018 to August 2020 were consecutively enrolled. All participants were followed up for at least 1 year. Thrombosis, infection, lead dislodgement, perforation, and other complications were observed after HPCSP. Clinical data, including echocardiographic parameters, electrocardiogram measurements, and cardiac function, were assessed before and after the procedure., Results: A total of 46 patients were enrolled. HPCSP was successfully deployed in 42 cases (91.30%), which included 37 cases with His bundle pacing (HBP) and 5 cases with left bundle branch pacing (LBBP). The QRS duration decreased significantly (169.88 ± 19.17 ms vs. 113.67 ± 20.68 ms, P < 0.001). Left ventricular end-systolic volume (LVESV) (167.67 ± 73.20 ml vs. 85.97 ± 62.24 ml, P < 0.001), left ventricular end-diastolic diameter (LVEDD) (63.57 ± 8.19 mm vs. 55.46 ± 9.63 mm, P = 0.003) and left ventricular ejection fraction (LVEF) (26.52 ± 5.60% vs. 41.86 ± 11.56%, P < 0.001) improved dramatically. Complete reverse remodeling of the LV with normalized LVEF and LVEDD was found in nearly half of the patients (45.24%). A short QRS duration after HPCSP was a strong predictor of normalized LVEF and LVEDD ( P < 0.001). The thresholds increased markedly in two patients approximately 6 months after HBP. No patients died during the total follow-up period of 20.07 ± 6.45 months., Conclusion: Complete reverse remodeling of the LV could be found in nearly half of the patients with HFrEF and true LBBB after HPCSP, and the short QRS duration after HPCSP was a strong predictor., 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 Guan, Li, Zhao, Zhao, Yang, Dai, Dai, Gao, Xia and Dong.)

Phosphodiesterases are essential regulators of cyclic nucleotide signaling with diverse physiological functions. Two phosphodiesterases, PdeH and PdeL, have been identified from yeast and filamentous fungi. Here, the orthologs of PdeH and PdeL were characterized in a typical nematode-trapping fungus Arthrobotrys oligospora by gene disruption and phenotypic comparison. Deletion of AopdeH caused serious defects in mycelial growth, conidiation, stress response, trap formation, and nematicidal efficiency compared to the wild-type strain. In contrast, these phenotypes have no significant difference in the absence of AopdeL . In addition, deletion of AopdeH and AopdeL resulted in a remarkable increase in cAMP level during vegetative growth and trap formation, and the number of autophagosomes was decreased in Δ AopdeH and Δ AopdeL mutants, whereas their volumes considerably increased. Moreover, metabolomic analyses revealed that many metabolites were downregulated in Δ AopdeH mutant compared to their expression in the wild-type strain. Our results indicate that AoPdeH plays a crucial role in mycelial growth, conidiation, stress response, secondary metabolism, and trap formation. In contrast, AoPdeL only plays a minor role in hyphal and conidial morphology, autophagy, and trap formation in A. oligospora . This work expands the roles of phosphodiesterases and deepens the understanding of the regulation of trap formation in nematode-trapping fungi.

Fear learning and memory are crucial for animal survival. Abnormal fear memory is a hallmark of many neuropsychiatric disorders. Appropriate neuronal activation and excitability in the basolateral amygdala (BLA) are necessary for the formation of fear memory. The gene cylindromatosis ( Cyld ), which encodes a lysine-63 deubiquitinase, is expressed in several brain regions including the amygdala. The functions of the cylindromatosis protein (CYLD) in the regulation of the neuronal activity, neural circuits and fear memory, remain largely unknown, however. Here, we report that Cyld knockout impairs amygdala-dependent tone-cued fear memory. The number of c-Fos + neurons responding to the tone-cued fear test was reduced in the BLA of Cyld -/- mice, suggesting that the absence of CYLD causes aberrant neuronal activation. We found that this aberrant neuronal activation in the BLA of Cyld -/- mice may relate to the decreased excitability of principal neurons. Another possibility of aberrant neuronal activation could be the impaired excitatory synaptic transmission in the BLA of Cyld -/- mice. Specifically, both the frequency of spontaneous excitatory postsynaptic currents and the amplitude of miniature excitatory postsynaptic currents in BLA principal neurons were decreased. In addition, Cyld mutation caused an increase in both the frequency of miniature inhibitory postsynaptic currents in principal neurons and the number of parvalbumin + interneurons, consistent with excessive local circuit inhibition in the BLA of Cyld -/- mice. Taken together, these results suggest that CYLD deficiency disrupts the neuronal activity and synaptic transmission in the BLA of mice which may contribute to the impaired fear memory observed in Cyld -/- mice., 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 © 2021 Li, Li, Yang and Long.)

Aging is one of the most prominent risk factors for heart failure. Myeloid-derived suppressor cells (MDSCs) accumulate in aged tissue and have been confirmed to be associated with various aging-related diseases. However, the role of MDSCs in the aging heart remains unknown. Through RNA-seq and biochemical approaches, we found that granulocytic MDSCs (G-MDSCs) accumulated significantly in the aging heart compared with monocytic MDSCs (M-MDSCs). Therefore, we explored the effects of G-MDSCs on the aging heart. We found that the adoptive transfer of G-MDSCs of aging mice to young hearts resulted in cardiac diastolic dysfunction by inducing cardiac fibrosis, similar to that in aging hearts. S100A8/A9 derived from G-MDSCs induced inflammatory phenotypes and increased the osteopontin (OPN) level in fibroblasts. The upregulation of fibroblast growth factor 2 (FGF2) expression in fibroblasts mediated by G-MDSCs promoted antisenescence and antiapoptotic phenotypes of fibroblasts. SOX9 is the downstream gene of FGF2 and is required for FGF2-mediated and G-MDSC-mediated profibrotic effects. Interestingly, both FGF2 levels and SOX9 levels were upregulated in fibroblasts but not in G-MDSCs and were independent of S100A8/9. Therefore, a novel FGF2-SOX9 signaling axis that regulates fibroblast self-renewal and antiapoptotic phenotypes was identified. Our study revealed the mechanism by which G-MDSCs promote cardiac fibrosis via the secretion of S100A8/A9 and the regulation of FGF2-SOX9 signaling in fibroblasts during aging.

Background: Atezolizumab plus chemotherapy has been recommended as a first-line treatment option for patients with advanced non-small cell lung carcinoma (NSCLC) irrespective of programmed cell death-ligand 1 (PD-L1) expression. Currently, little is known about the efficacy and treatment-related adverse effects (TRAEs) of subtracting chemotherapy from the combination for patients with high PD-L1 expression. Thus, we performed an indirect comparison between atezolizumab plus chemotherapy and atezolizumab alone., Methods: A total of five eligible randomized controlled trials (RCTs) were identified from PubMed, EMBASE, and Cochrane Central controlled trial registries, using keywords including atezolizumab, PD-1, PD-L1, NSCLC, and RCT. The clinical outcomes of objective response rate (ORR), progression-free survival (PFS), OS, and TRAEs were extracted and evaluated. Using indirect analysis, the efficacy and TRAEs were compared between arm A (atezolizumab plus chemotherapy) and arm C (atezolizumab), linked by arm B (chemotherapy)., Results: Direct comparison revealed that both atezolizumab plus chemotherapy (HR 0.65, P = 0.003) and atezolizumab alone (HR 0.59, P = 0.010) significantly improved OS compared with chemotherapy. More importantly, the indirect comparison showed that atezolizumab plus chemotherapy was not superior to atezolizumab regarding OS (RR 1.10, P =0.695) and ORR (RR 1.11, P = 0.645). However, patients who received atezolizumab combined with chemotherapy experienced more ≥ grade 3 TRAEs (RR 4.23, P <0.001) and TRAEs leading to drug discontinuation (RR 3.60, P <0.001) than those treated with atezolizumab monotherapy., Conclusions: Atezolizumab monotherapy might be a better treatment option for patients with advanced NSCLC and high PD-L1 expression than atezolizumab plus chemotherapy., 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 © 2021 Li, Lu, Yang, Zhang, Jin, Wang, Che, Li, Liu and Qu.)

Background: Traditional Chinese medicine (TCM) is an integral part of mainstream medicine in China, with theories and practices that are completely different from modern medicine. TCM should not be ignored or confused with modern medicine in the analysis of the Chinese health care system, including the analysis of mobile health (mHealth) apps. To date, differences between TCM apps and modern medicine apps have not be systematically investigated., Objective: The aim of this study was to systematically compare the quality of apps for TCM and modern medicine in China., Methods: In December 2020, we searched iOS (iTunes) and Android (Tencent, Oppo, and Huawei app stores) platforms for all mHealth apps and then categorized them as TCM or modern medicine apps if they were included in the final analysis. The included apps were downloaded on smartphones and assessed by 2 reviewers on the following 4 aspects: (1) data in the app stores, including user ratings, download counts, cost, target users, and year of last update; (2) functionality; (3) quality of the app content as determined by the Mobile App Rating Scale (MARS); and (4) analysis of the app privacy and security., Results: In total, 658 apps were analyzed, including 261 TCM medicine apps and 397 modern medicine apps. The average download count of modern medicine apps (approximately 5 million) was more than 10 times that of TCM apps (approximately 400,000). Regarding functionalities, 64.7% (257/397) of modern medicine apps provided telemedicine (74/261, 28.4% in TCM apps), 62.7% (249/397) provided registration (70/261, 26.8% in TCM apps), and 45.6% (181/397) provided communication (38/261, 14.6% in TCM apps). A larger proportion of TCM apps provided prescription and medication management (144/261, 55.2% in TCM apps versus 168/397, 42.3% in modern medicine apps). The majority of modern medicine apps (329/397, 82.9%) combined ≥3 functionalities compared with one-third of TCM apps (93/261, 34.6%). We then selected 81 top apps for quality and safety assessment (41 TCM apps and 40 modern medicine apps). Of these, the mean overall MARS score of TCM apps (2.7, SD 0.5) was significantly lower than modern medicine apps (3.6, SD 0.4). Almost all modern medicine apps (38/40, 95%) addressed privacy and security by providing a privacy policy and describing how to protect personal data, but less than half of the TCM apps (18/41, 44%) described this information (P<.001)., Conclusions: The different functionalities reflect the distinct innate characteristics of these two medical systems. Although great progress has been made and the Chinese mHealth market size is large, there still exist many opportunities for future development, especially for TCM., (©Xiao Hang Liu, Fan Jin, Jeffrey Hsu, Di Nan Li, Wei Chen. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 24.03.2021.)

NUDIX hydrolase type 5 (NUDT5) is a kind of ADP-ribose pyrophosphatase and nucleotide metabolizing enzyme in cell metabolism. Previous studies have shown NUDT5 expression affected chromosome remodeling, involved in cell adhesion, cancer stem cell maintenance and epithelial to mesenchyme transition in breast cancer cells. Nevertheless, the role of NUDT5 in breast cancer progression and prognosis has not yet been systematically studied. This study explored the association of NUDT5 with the tumor development and poor prognosis in patients with breast cancer. Our results show that the levels of NUDT5 were upregulated in breast cancer cell lines and breast tumor tissues, and the expression of NUDT5 in breast tumor tissues increased significantly when compared with adjacent non-tumorous tissues by immunohistochemical staining of tissue microarrays. Breast cancer patients with high NUDT5 expression had a worse prognosis than those with low expression of NUDT5. In addition, the knockdown of NUDT5 suppressed breast cancer cell lines proliferation, migration and invasion, and dramatically inhibited the AKT phosphorylation at Thr308 and expression of Cyclin D1. The opposite effects were observed in vitro following NUDT5 rescue. Our findings indicated that the high expression of NUDT5 is probably involved in the poor prognosis of breast cancer via the activation of the AKT / Cyclin D pathways, which could be a prognostic factor and potential target in the diagnosis and treatment of breast cancer., Competing Interests: The authors have declared that no competing interests exist.

Background/Aim: Retinal nerve fiber layer (RNFL) thickness (RT), which can reflect the status of the retinal optic nerve cells, may be affected in patients with Alzheimer's disease (AD). There are few studies on the correlation of RT of patients with AD (AD-RT) with clinical symptoms of various cognitive domains, neuropsychiatric symptoms, and activities of daily living (ADL). This study is to investigate the relationships between RT and the abovementioned clinical symptoms of AD. Methods: A total of 96 patients with AD were included in this study. RT was measured in these patients using optical coherence tomography (OCT). Demographic variables, RT, and clinical symptoms were compared between the normal and the abnormal AD-RT groups. Clinical symptoms, including cognitive symptoms, neuropsychiatric symptoms, and ADL, were evaluated using a series of rating scales. Results: The relationships between RT and cognitive symptoms scores were analyzed in patients with AD. Reduced RT was found in 54.4% of patients with AD. The average RT, RT of the superior 1/2 quadrant, and RT of the inferior 1/2 quadrant of both eyes were all significantly decreased in the abnormal AD-RT group ( p < 0.001). Overall cognitive function and performance in multiple cognitive domains, including memory, language, attention, and executive function, were also significantly impaired in the abnormal AD-RT group ( p < 0.05). For lower RT value, the global cognitive function and the performance in multiple cognitive domains were worse. ADL was significantly compromised in patients with AD having lower RT values ( p < 0.05). Conclusions: Lower RT value appear to be correlated with cognitive impairment, and RT may be an indicator of cognitive decline in patients with AD. Further studies are required to confirm our findings., 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 © 2021 Lian, Jin, Qu, Guo, Guan, Zhang, Ding, Li, Li, Wang and Zhang.)

MutT Homolog 1 (MTH1) is a mammalian 8-oxodGTPase for sanitizing oxidative damage to the nucleotide pool. Nudix type 5 (NUDT5) also sanitizes 8-oxodGDP in the nucleotide pool. The role of MTH1 and NUDT5 in non-small-cell lung cancer (NSCLC) progression and metastasis remains unclear. In the present study, we reported that MTH1 and NUDT5 were upregulated in NSCLC cell lines and tissues, and higher levels of MTH1 or NUDT5 were associated with tumor metastasis and a poor prognosis in patients with NSCLC. Their suppression also restrained tumor growth and lung metastasis in vivo and significantly inhibited NSCLC cell migration, invasion, cell proliferation and cell cycle progression while promoting apoptosis in vitro. The opposite effects were observed in vitro following MTH1 or NUDT5 rescue. In addition, the upregulation of MTH1 or NUDT5 enhanced the MAPK pathway and PI3K/AKT activity. Furthermore, MTH1 and NUDT5 induce epithelial-mesenchymal transition both in vitro and in vivo. These results highlight the essential role of MTH1 and NUDT5 in NSCLC tumor tumorigenesis and metastasis as well as their functions as valuable markers of the NSCLC prognosis and potential therapeutic targets., (Copyright © 2020. Published by Elsevier B.V.)

Objective: To evaluate the epidemiology of bacterial bloodstream infections in patients submitted to hematologic wards in southern China. Methods: A total of 50 teaching hospitals were involved based on the China Antimicrobial Resistance Surveillance System. The data of clinical isolates from blood samples were collected from January 1, 2019, to December 31, 2019. Antimicrobial susceptibility testing was conducted by the Kirby-Bauer automated systems, and the results were interpreted using the CLSI criteria. Results: The data of 1,618 strains isolated from hematologic wards in 2019 were analyzed, of which gram-negative bacilli and gram-positive cocci accounted for 71.8% and 28.2%, respectively. Of those, the five major species were most often isolated, including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, coagulase-negative staphylococcus, and Streptococcus viridans. The prevalence rates of methicillin-resistant strains in Staphylococcus aureus and coagulase-negative staphylococcus were 19.7% and 80.6%, respectively. No gram-positive cocci were resistant to vancomycin, linezolid, and teicoplanin, and none of the enterococci were resistant to linezolid. The resistance rate of S. viridans to penicillin G was 6.9%, and those to ceftriaxone and cefotaxime were more than 25%. The resistance rate of E. coli and K. pneumoniae in Enterobacteriaceae was higher in children than that in adults. The resistance rate of K. pneumoniae to meropenem was 14.1%. The resistant rate of Enterobacter cloacae to carbapenem was more than 25%. P. aeruginosa was more sensitive to more antibiotics than 80%, but the resistance rate to meropenem in children was higher than that in adults (11.8% vs. 6.5%). The proportion of gram-positive cocci in the ICU and respiratory departments was higher than that in the hematology department. The detection rates of carbapenem-resistant E. coli and K. pneumoniae in the respiratory department were the lowest with 0.3% and 3.7%, respectively, while those of CRPA and CRAB in the hematology department were the lowest with 8.3% and 25.8%, respectively. The detection rate of all carbapenem-resistant organisms in the ICU was the highest among the three departments. Conclusion: The etiology and drug resistance of bacteria from blood samples in the hematology department are different from those in the ICU and respiratory departments. The proportions of K. pneumoniae, P. aeruginosa, E. cloacae, and S. viridans dominating in the department of Hematology were significantly higher than those in the ICU and respiratory departments in Guangdong region.

Background and Purpose: Olfactory dysfunction (OD) is a common non-motor symptom of Parkinson disease (PD). However, the relationship between OD and neuropathologic proteins in cerebrospinal fluid (CSF) from PD patients remains unclear. Methods: 166 PD patients were included in the study. Overall olfactory function was assessed by summing up the scores of olfactory threshold, discrimination, and identification by a Sniffin' Sticks test, based on which, patients were divided into PD with OD (PD-OD) and PD with no OD (PD-NOD) groups. CSF samples were obtained from 76 PD patients. The levels of neuropathologic proteins, including α-Synuclein, Aβ1-42, total tau (T-tau), and multiple forms of phosphorylated tau (P-tau) in CSF were measured by an enzyme-linked immunosorbent assay. Results: out of the 166 PD patients, 103 cases (62.0%) had OD. The scores of overall olfactory functions, and olfactory threshold, discrimination, and identification in the PD-OD group were all significantly lower than that in the PD-NOD group ( P < 0.001). α-Synuclein level in CSF was significantly higher in the PD-OD group than the PD-NOD group ( P < 0.05), and was significantly and negatively correlated with the scores of overall olfactory function, and olfactory discrimination and identification ( P < 0.05). Aβ1-42 level in CSF was higher in the PD-OD group than the PD-NOD group, and was significantly and negatively correlated with the olfactory identification score ( P < 0.05). T-tau level in CSF was significantly lower in the PD-OD group than the PD-NOD group ( P < 0.05), and was significantly and positively correlated with the olfactory discrimination score ( P < 0.05). There was no significant difference in P-tau level in CSF between the PD-OD and PD-NOD groups and no correlation between OD score and P-tau level in CSF. Conclusions: PD-OD includes the impairments of olfactory threshold, discrimination, and identification, and is associated with the significant elevation of α-Synuclein and the decrease of the T-tau level in CSF., 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 © 2020 Guo, Wang, Lian, Ding, Zhang, Zhang, Li, Li, Li, Guan, Yu, Liu, Hu, Zuo, Yu, Wang and Zhang.)

Background: Apathy is one of the most common symptoms of Alzheimer's disease (AD), however, correlations of apathy with demographic variables, cognitive functions, neuropsychiatric symptoms, activity of daily living and olfactory functions in AD patients are still lacking comprehensive investigations., Methods: This is a cross-sectional study. Total 124 typical AD patients were consecutively recruited from April 2014 to April 2017. In 124 AD patients, 47 cases (37.9%) were male and 77 cases were female; patients' age were 43-93 years with an average of 68 years. Patients were divided into AD with apathy (AD-A) and AD with no apathy (AD-NA) groups according to the score of Modified Apathy Evaluation Scale, then were evaluated cognitive functions, neuropsychiatric symptoms and activity of daily living, and tested olfactory functions. Above variables were compared between AD-A and AD-NA groups. Further correlation analyses and linear regression analysis were performed between apathy and above variables., Results: Compared with AD-NA group, global cognitive level, verbal memory, verbal fluency and activity of daily living were significantly compromised in AD-A group (P < 0.002); depression and agitation were severely displayed in AD-A group (P < 0.002). Apathy was negatively correlated with global cognitive function, verbal memory, verbal fluency and activity of daily living (P < 0.05). There was no significant difference of olfactory functions between the two groups (P > 0.002), and correlations between apathy and olfactory threshold, olfactory identification and global olfactory function were significant (P < 0.05) but quite weak (|r| < 0.3). Further linear regression analysis showed that only verbal fluency and instrumental activities of daily living were independently associated with apathy., Conclusions: Independent correlations among apathy, verbal fluency and instrumental activities of daily living in AD patients might be related to the common brain area involved in their pathogeneses.

Background: AUF1 is one of the AU-rich binding proteins, which promotes rapid ARE-mRNA degradation. Recently, it has been reported that AUF1 is involved in regulating the antioxidant system because of its capacity to bind specifically to RNA containing oxidized bases and degrade oxidized RNA. Many antioxidant proteins have been reported to be overexpressed in colorectal cancer (CRC), however, the role of AUF1 in the progression of CRC has not been explored., Methods: The expression level of AUF1 protein in human CRC cell lines and CRC tissues was detected by western blotting and immunohistochemistry (IHC. The effects of AUF1 knockdown on CRC cell proliferation, migration, invasion and changes in the signaling pathways were evaluated using a cell counting kit-8 (CCK-8), Transwell assays and western blotting. Subcutaneous xenograft tumor model was employed to further substantiate the role of AUF1 in CRC., Results: AUF1 protein was upregulated in CRC tissues and CRC cells, and high expression of AUF1 was significantly associated with advanced AJCC stage (P = .001), lymph node metastasis (P = .007), distant metastasis (P = .038) and differentiation (P = .009) of CRC specimens. CRC patients with the high expression of AUF1 had an extremely poor prognosis. The knockdown of AUF1 suppressed CRC cell line proliferation, migration and invasion, inhibited CRC cells tumorigenesis and growth in nude mice, and reduced phosphorylated-ERK1/2 and phosphorylated AKT in CRC cells., Conclusion: Our findings demonstrate that AUF1 is probably involved in the progression of CRC via the activation of the ERK1/2 and AKT pathways. AU-rich RNA-binding factor 1 could be used as a novel prognostic biomarker and a potential therapeutic target for CRC., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background : To explore the changes of neuroinflammatory factors in cerebrospinal fluid (CSF) and their correlation with monoamine neurotransmitters in Parkinson's disease (PD) with depression (PD-D) patients. Methods : Neuroinflammatory factors and neurotransmitters in CSF were measured and compared between PD with no depression (PD-ND) and PD-D groups. The relationship between PD-D and neuroinflammatory factors was studied by binary logistic regression equation, and the related factors of PD-D were adjusted. The correlations of the levels of neuroinflammatory factors and neurotransmitters in PD-D group were analyzed. Results : The levels of tumor necrosis factor (TNF)-α in CSF from PD-D group were significantly higher and there were no significant differences in the levels of interleukin-1β, prostaglandin (PG) E 2 , hydrogen peroxide (H 2 O 2 ), and nitric oxide (NO). The 24-item Hamilton Depression Scale (HAMD-24) score was positively correlated with the level of TNF-α in CSF. Binary logistic regression showed that the OR of CSF TNF-α level was 1.035 (95% CI 1.002-1.069). The level of dopamine (DA) in CSF of PD-D group was significantly lower than that in PD-ND group. TNF-α level was negatively correlated with DA level in CSF from PD patients ( r = -0.320, P = 0.003). Conclusions : Neuroinflammatory factors, especially TNF-α, may play an important role in PD-D. It may cause damage to DA neurons and lead to the depletion of DA, which is related to the occurrence and development of PD-D., (Copyright © 2020 Lian, Guo, Zhang, Li, Li, Ding, Li, Zhang, Guan, Wang and Zhang.)

Background: Apathy is common in Alzheimer's disease (AD) patients. However, its relation with other clinical symptoms in AD and brain structural changes in magnetic resonance imaging is unclear., Results: Compared with AD with no apathy group, cognitive function and activities of daily living were significantly impaired and neuropsychiatric symptoms were obviously presented in AD with apathy group (P<0.05). The frequency of Apolipoprotein E genotypes was not significantly different (P>0.05). Correlation analyses and multiple linear analyses revealed that thickness of left temporal pole and volume of posterior corpus callosum were significantly and negatively correlated with Modified Apathy Estimation Scale score in AD patients (P<0.05)., Conclusions: Apathy with AD is positively correlated with cognitive impairment, neuropsychiatric symptoms and poor activities of daily living. Atrophy of left temporal pole and posterior corpus callosum presented by MRI is positively related with apathy of AD., Methods: In this study, 137 AD patients were recruited and divided into AD with apathy group and AD with no apathy group according to Modified Apathy Estimation Scale score. We evaluated patients' cognitive function, neuropsychiatric symptoms and activities of daily living, detected the frequency of Apolipoprotein E genotypes and measured cortical thickness and volume by magnetic resonance imaging (MRI).

Background: MTH1 and NUDT5 effectively degrade nucleotides containing 8-oxoguanine. MTH1 and NUDT5 have been linked to the malignancy of multiple cancers. However, their functions in tumor growth and metastasis in esophageal squamous carcinoma (ESCC) remain obscure. Our present study aims to explore their prognostic value in ESCC and investigate their function in MTH1 or NUDT5-knockout tumor cells., Methods: MTH1 and NUDT5 protein expression in ESCC adjacent normal tissues and tumor tissues was examined by immunohistochemistry staining. Kaplan-Meier curves were used to assess the association between their expression and overall survival (OS) in ESCC patients. Univariate and Multivariate Cox regression analyses were generated to determine the correlation between these protein expression and OS of ESCC patients. Protein expression in ESCC cell lines were measured by Western blotting. To explore the potential effects of the MTH1 and NUDT5 protein in ESCC, cell models with MTH1 or NUDT5 depletion were established. CCK-8, cell cycle, Western blotting, migration and invasion assays were performed., Results: Our present study demonstrated that the levels of MTH1 and NUDT5 were upregulated in ESCC cell lines and ESCC tissues, the expression of MTH1 and NUDT5 in ESCC tissues was significantly higher than in adjacent non-tumorous, and higher levels of MTH1 and NUDT5 predicted a worse prognosis in patients with ESCC. MTH1 and NUDT5 are novel biomarkers of the progression of ESCC and a poor prognosis. We also found for the first time that the high expression of NUDT5 independently predicted lower OS in patients with ESCC (hazard ratio (HR) 1.751; 95% confidence interval (CI) [1.056-2.903]; p = 0.030). In addition, the depletion of MTH1 and NUDT5 strongly suppressed the proliferation of ESCC cells and significantly delayed the G1 phase of the cell cycle. Furthermore, we found that MTH1 and NUDT5 silencing inhibited epithelial-mesenchymal transition mainly by the MAPK/MEK/ERK dependent pathway, which in turn significantly decreased the cell migration and invasion of ESCC cells. Our results suggested that the overexpression of MTH1 and NUDT5 is probably involved in the tumor development and poor prognosis of ESCC., Competing Interests: The authors declare that they have no competing interests., (© 2020 Wang et al.)

Objective: To investigate the feasibility of using the eyelash reflex as an indicator to calculate the individualised optimal target concentration in anesthesia induction during painless gastroscopy., Study Design: Experimental study., Place and Duration of Study: China-Japan Union Hospital of Jilin University, China, from January to December in 2016., Methodology: A total of 180 patients, who were scheduled to receive painless fibergastroscopic examination or treatment in the last three months, were enrolled in this study. All patients were randomly divided into three groups, according to the doctor visiting order (n=60, each). During the induction of anesthesia using propofol target-controlled infusion, the effectsite concentration upon the disappearance of the eyelash reflex (C0) was recorded first. Then, one ug/kg of fentanyl was injected. At the same time, the target effect-site concentration induced by propofol was determined: the effect-site concentration in group A was 1.5 times of C0, the effect-site concentration in group B was two times of C0, and the effectsite concentration in group C was 2.5 times of C0., Results: During anesthesia induction, the incidence of motor responses was higher in group A than in groups B and C (p<0.05), and the incidence of hypoxemia was significantly higher in group C than in groups A and B (p<0.01)., Conclusion: In the anesthesia option of fentanyl combined with propofol target-controlled infusion, the effect-site concentration of propofol can be set to two times of that at the time the eyelash reflex disappears. This study provides a new pre-assessment method for the induction dose of propofol in painless gastroscopy.

Herein, prickly platinum-palladium core-shell nanocrystals (Pt@Pd NCs) were prepared by a facile one-pot aqueous method, only taking sodium pyrrolidone carboxylate (PCA-Na) as the structure director and stabilizing agent. The products were mainly characterized by microscopic analysis, X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS), followed by discussing the formation mechanism in details. The electrochemical characterizations were examined by cyclic voltammetry (CV), linear sweep voltammetry (LSV) and chronoamperometry (CA). The results revealed that the prepared architectures had the biggest current density (58.4 mA cm -2 ) for ethylene glycol oxidation, which is 3.5-fold, 1.2-fold, 2.3-fold and 2.4-flod enhancement relative to those of home-made single Pt nanoparticles (NPs) and Pd NPs, commercial Pt black and Pd black catalysts, respectively. Also, the obtained Pt@Pd NCs showed improved catalytic activity and stability towards glycerol oxidation and hydrogen evolution reactions compared to the references., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Herein, we developed a facile one-pot co-reduction method to fabricate highly dentritic platinum-palladium/palladium core-shell nanocrystals on reduced graphene oxide (PtPd@Pd NCs/rGO), where poly-l-lysine (PLL) worked as the eco-friendly structure director and stabilizer. The nanocomposite was mainly characterized by microscopic analysis, X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), and thermogravimetric analysis (TGA), along with the discussion of the formation mechanism. The synthesized PtPd@Pd NCs/rGO have the enlarged electrochemically active surface area (ECSA) of 51.65 m 2  g -1 , showing 1.3 folds enhancement in the peak current density relative to commercial Pt/C (50 wt%) for glycerol oxidation reaction (GOR), coupled with the small Tafel slope of 28 mV dec -1 for hydrogen evolution reaction (HER)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In this work, AuPd@Pd core-shell nanocrystals (AuPd@Pd NCs) were fabricated by a one-pot co-reduction approach, where theophylline-7-acetic acid (TAA) acted asa new structure-directing agent. The crystal structure and composition were mainly characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM), X-ray diffraction (XRD), together with X-ray photoelectron spectroscopy (XPS). The growth mechanism of AuPd@Pd NCs was investigated in detail. The obtained AuPd@Pd NCs exhibited superior catalytic characters for formic acid oxidation reaction (FAOR) and glycerol oxidation reaction (GOR) in contrast with commercial Pd black in alkaline media., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Biatractylolide was isolated from ethyl acetate extract of dried Atractylodis Macrocephalae Rhizoma root by multistep chromatographic processing. Structure of biatractylolide was confirmed by (1)H-NMR and (13)C-NMR. The IC50 on acetylcholinesterase (AChE) activity was 6.5458 μg/mL when the control IC50 value of huperzine A was 0.0192 μg/mL. Molecular Docking Software (MOE) was used to discover molecular sites of action between biatractylolide and AChE protein by regular molecular docking approaches. Moreover, biatractylolide downregulated the expression of AChE of MEF and 293T cells in a dose-dependent manner. These results demonstrated that the molecular mechanisms of inhibitory activities of biatractylolide on AChE are not only through binding to AChE, but also via reducing AChE expression by inhibiting the activity of GSK3β.

Interferon- (IFN-) λ1 is regarded as a potent bio-active molecule in innate immunity. However, little is known about its role in chronic spontaneous urticaria (CSU). We therefore investigated expression of IFN-λ1 in CSU, its cellular location, and its influence on inflammatory cell accumulation by using flow cytometry analysis, skin tissue dispersion, immunohistochemical stain, and a mouse peritoneal inflammation model. The results showed that level of IFN-λ1 was 2.0-fold higher in plasma of the patients with CSU than the level in healthy control (HC) subjects. Among leukocytes examined, only CD8(+) T cells expressed more IFN-λ1 in CSU blood. Double labeling immunohistochemical staining revealed that IFN-λ1(+) inflammatory cells such as mast cells, eosinophils, B cells, neutrophils, and macrophages were mainly located in dermis, whereas epidermis tissue highly expressed IFN-λ1. IFN-λ1 induced a dose-dependent increase in number of eosinophils, lymphocytes, mast cells, macrophages, and neutrophils in the peritoneum of mice at 6 h following injection, which was inhibited by pretreatment of the animals with anti-intercellular adhesion molecule- (ICAM-) 1 and/or anti-L-selectin antibodies. In conclusion, IFN-λ1 is likely to play a role in the pathogenesis of CSU. Blocking IFN-λ1 production may help to reduce the accumulation of inflammatory cells in the involved CSU skin.

The aim of this study was to explore the expression of tissue factor pathway inhibitor-2 (TFPI-2) in gastric stromal tissue and its clinical significance. TFPI-2 expression was detected by immunohistochemical analysis, RT-PCR and western blotting in tumor, peritumoral and gastric normal tissues from 72 patients with gastric stromal tumors. The level of TFPI-2 expression was observed to be significantly higher in gastric normal tissue than in peritumoral tissue, and was significantly higher in peritumoral tissue than in tumor tissue (P<0.01). As the NIH grade increased, the level of TFPI-2 expression decreased (P<0.01). A low expression level of TFPI-2 was closely associated with invasion and metastasis of gastric stromal tumors. In conclusion, the level of TFPI-2 expression was higher in gastric normal tissue than in gastric stromal tumors. Low expression levels of TFPI-2 may be associated with invasion and metastasis of gastric stromal tumors.

Objectives: To explore the correlation between multi-slice spiral CT (MSCT) perfusion parameters and the expression of vascular endothelial growth factor (VEGF) as well as matrix metalloproteinase-2 (MMP- 2) in breast cancer., Methods: Forty five breast cancer patients and 16 patients with benign breast tumor, both confirmed by pathology examination, were enrolled. All underwent MSCT perfusion imaging to obtain perfusion maps and data for parameters including blood flow (BF), blood volume (BV) and permeability surface (PS). Cancer patients did not receive treatment prior to surgery. The expression of VEGF and MMP-2 were examined with both immunohistochemistry and Western blotting., Results: The levels of VEGF and MMP-2 by immunohistochemistry were significantly higher in the breast cancer group (P < 0.01) than the benign tumor group. Relative OD values from Western blotting were also higher in cancer cases (P < 0.05). Similarly, the mean MSCT perfusion parameters (BF, BV, PS) were significantly higher in the breast cancer group (P < 0.01), BF and BV positively correlating with VEGF expression (r = 0.878 and 0.809 respectively, P < 0.01); PS and VEGF and MMP-2 expression were also positively correlated (r= 0.860, 0.786 respectively, P < 0.01)., Conclusion: There is a correlation between breast cancer MSCT perfusion parameters and VEGF andMMP-2 expression, which might be useful for detection of breast lesions, qualitative diagnosis of breast cancer, and evaluation of breast cancer treatment.

High-affinity anti-abrin-a monoclonal and polyclonal antibodies were used to develop a sandwich immunochromatographic assay and silver enhancement technology was used to further increase the sensitivity. Using a matrix of double distilled water or soybean milk with added abrin-a, the visual detection limit was found to be 10 ng mL(-1). The detection limit was 0.1 ng mL(-1) for abrin-a, an increase in sensitivity of 100-fold when the silver enhancement technology was employed. The assay was portable and very simple to perform and the detection was completed within 20 min without complicated handling procedures. There was no significant cross-reactivity with several homologous toxins and associated agglutinin. The assay reagents could be stored for 12 weeks at 4°C without significant loss of activity. These characteristics make the strip assay to be an ideal candidate for the development of a rapid toxin detection kit., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: To clarify the clinical and pathological features and prognosis of Chinese patients with distal myopathy with rimmed vacuoles (DMRV)., Methods: The clinical data of 17 Chinese DMRV patients with the courses of disease of 1-21 years, 5 males and 12 females, aged 28.9 (19-41), were collected. Biopsy of muscle specimens of 17 Chinese DMRV patients were summarized retrospectively. Muscle specimens were collected from the biceps brachii, tibialis anterior, gastrocnemius, or quadriceps femoris and underwent light microscopy. Eight muscle specimens underwent electron microscopy. 11 patients were followed up for 4 months to 15 years., Results: The age of onset ranged from 5 to 40 years (averaging 23 years). Distal muscle weakness and atrophy of the lower extremities, especially anterior tibial muscle, was predominant in the early stage. Proximal and trunk muscles were involved in the advanced stage. Quadriceps femoris were slightly involved. The striking and characteristic pathological finding was the presence of rimmed vacuoles in atrophic muscle fibers with little evidence of necrotic or regenerative processes. Electron microscopy showed accumulation of myeloid structure and cytoplasmic or intranuclear tubofilamentous inclusion bodies. Although atrophy and weakness of the leg muscle appeared as initial symptoms, severe generalized skeletal muscle involvement with sparing of the facial, extraocular, bulbar, intercostals, and diaphragm muscles was recognized in the advanced stage. The patients became non-ambulant about 7-10 years after the onset of the disease. They lost the self-care ability and the quality of their life was rather low., Conclusion: The clinical and pathological features of the Chinese DMRV patients are basically similar to those of the Japanese patients. With the disease progressing slowly, the patients become wheelchair-bound and lose the self-care ability. As to daily life, the prognosis of DMRV is extremely poor.

Objective: To clarify the expression patterns of dysferlin in limb-girdle muscular dystrophy (LGMD) and Miyoshi myopathy (MM), and to investigate the frequency and clinicopathologic features of dysferlinopathy., Methods: The expressing patterns of dysferlin were analyzed by immunohistochemistry, with a set of antibodies against dystrophin, alpha-sarcoglycan and dysferlin, in the biopsied muscle specimens from 45 patients with LGMD or MM diagnosed on the basis of clinical manifestations and muscle pathological features. The specimens with abnormal dysferlin expression shown by IHC were further analyzed with Western blotting for a quantitative evaluation., Results: Eight patients were proved to be primary dysferlinopathy according to total dysferlin deficiency or a significant decrease of dysferlin (less than 15% that of normal value). The clinical manifestations of 5 of the 8 dysferlinopathy patients were consistent with those of typical MM, and the other 3 were diagnosed as with LGMD. All patients had an average onset at the age of 18.8 years. Two of them had family history, and one patient had consanguineous mating parents, meaning an autosomal recessive inheritance pattern. The serum CK levels were 6240 IU/L on average. EMG showed myogenic patterns in all patients. Muscular pathology showed typical changes of muscular dystrophy in all patients. Focal or scattered inflammatory cellular infiltrations were found in 3 cases., Conclusion: The clinical and pathological features of dysferlinopathy are nonspecific. Inflammatory cellular infiltrations are relatively common in biopsied muscles of dysferlinopathy patients, which may cause misdiagnosis of inflammatory myopathy. Identification of dysferlin expression by IHC and Western blotting are essential for the diagnosis of dysferlinopathy and differential diagnosis of inflammatory myopathy.

Mammalian asparaginyl endopeptidase (AEP) or legumain is a recently discovered lysosomal cysteine protease that specifically cleaves after asparagine residues. How this unusually specific lysosomal protease is itself activated is not fully understood. Using purified recombinant pro-enzyme, we show that activation is autocatalytic, requires sequential removal of C- and N-terminal pro-peptides at different pH thresholds, and is bimolecular. Removal of the N-terminal propeptide requires cleavage after aspartic acid rather than asparagine. Cellular processing, either of exogenously added AEP precursor or of pulse-labeled endogenous precursor, introduces at least one further cleavage to yield the final mature lysosomal enzyme. We also provide evidence that in living cells, there is clear compartmental heterogeneity in terms of AEP activation status. Moreover, we show that human monocyte-derived dendritic cells harbor inactive proforms of AEP that become activated upon maturation of dendritic cells with lipopolysaccharide.

The invariant chain (Ii) chaperone for MHC class II molecules is crucial for their effective function. Equally important is its removal. Cathepsins S or L are known to be required for the final stages of Ii removal in different APCs, but the enzymes which initiate Ii processing have not been identified. Here we show that this step can be performed in B lymphocytes by asparagine endopeptidase (AEP), which targets different asparagine residues in the lumenal domain of human and mouse invariant chain. Inhibition of AEP activity slows invariant chain processing and hinders the expression of an antigenic peptide engineered to replace the groove binding region of Ii (CLIP). However, the initiation of Ii removal can also be performed by other proteases, reflecting the importance of this step.