Objective:To investigate the diagnostic accuracy of serological indicators and evaluate the diagnostic value of a new established combined serological model on identifying the minimal hepatic encephalopathy (MHE) in patients with compensated cirrhosis.Methods:This prospective multicenter study enrolled 263 compensated cirrhotic patients from 23 hospitals in 15 provinces, autonomous regions and municipalities of China between October 2021 and August 2022. Clinical data and laboratory test results were collected, and the model for end-stage liver disease (MELD) score was calculated. Ammonia level was corrected to the upper limit of normal (AMM-ULN) by the baseline blood ammonia measurements/upper limit of the normal reference value. MHE was diagnosed by combined abnormal number connection test-A and abnormal digit symbol test as suggested by Guidelines on the management of hepatic encephalopathy in cirrhosis. The patients were randomly divided (7∶3) into training set ( n=185) and validation set ( n=78) based on caret package of R language. Logistic regression was used to establish a combined model of MHE diagnosis. The diagnostic performance was evaluated by the area under the curve (AUC) of receiver operating characteristic curve, Hosmer-Lemeshow test and calibration curve. The internal verification was carried out by the Bootstrap method ( n=200). AUC comparisons were achieved using the Delong test. Results:In the training set, prevalence of MHE was 37.8% (70/185). There were statistically significant differences in AMM-ULN, albumin, platelet, alkaline phosphatase, international normalized ratio, MELD score and education between non-MHE group and MHE group (all P<0.05). Multivariate Logistic regression analysis showed that AMM-ULN [odds ratio ( OR)=1.78, 95% confidence interval ( CI) 1.05-3.14, P=0.038] and MELD score ( OR=1.11, 95% CI 1.04-1.20, P=0.002) were independent risk factors for MHE, and the AUC for predicting MHE were 0.663, 0.625, respectively. Compared with the use of blood AMM-ULN and MELD score alone, the AUC of the combined model of AMM-ULN, MELD score and education exhibited better predictive performance in determining the presence of MHE was 0.755, the specificity and sensitivity was 85.2% and 55.7%, respectively. Hosmer-Lemeshow test and calibration curve showed that the model had good calibration ( P=0.733). The AUC for internal validation of the combined model for diagnosing MHE was 0.752. In the validation set, the AUC of the combined model for diagnosing MHE was 0.794, and Hosmer-Lemeshow test showed good calibration ( P=0.841). Conclusion:Use of the combined model including AMM-ULN, MELD score and education could improve the predictive efficiency of MHE among patients with compensated cirrhosis.

Hepatic stellate cells(HSCs)are essential drivers of fibrogenesis.Inducing activated-HSC apoptosis is a promising strategy for treating hepatic fibrosis.18beta-glycyrrhetinic acid(18β-GA)is a natural com-pound that exists widely in herbal medicines,such as Glycyrrhiza uralensis Fisch,which is used for treating multiple liver diseases,especially in Asia.In the present study,we demonstrated that 18β-GA decreased hepatic fibrosis by inducing the apoptosis in activated HSCs.18β-GA inhibited the expression of α-smooth muscle actin and collagen type Ⅰ alpha-1.Using a chemoproteomic approach derived from activity-based protein profiling,together with cellular thermal shift assay and surface plasmon reso-nance,we found that 18β-GA covalently targeted peroxiredoxin 1(PRDX1)and peroxiredoxin 2(PRDX2)proteins via binding to active cysteine residues and thereby inhibited their enzymatic activities.18β-GA induced the elevation of reactive oxygen species(ROS),resulting in the apoptosis of activated HSCs.PRDX1 knockdown also led to ROS-mediated apoptosis in activated HSCs.Collectively,our findings revealed the target proteins and molecular mechanisms of 18β-GA in ameliorating hepatic fibrosis,highlighting the future development of 18β-GA as a novel therapeutic drug for hepatic fibrosis.

The composition of serum is extremely complex,which complicates the discovery of new pharmaco-dynamic biomarkers via serum proteome for disease prediction and diagnosis.Recently,nanoparticles have been reported to efficiently reduce the proportion of high-abundance proteins and enrich low-abundance proteins in serum.Here,we synthesized a silica-coated iron oxide nanoparticle and devel-oped a highly efficient and reproducible protein corona(PC)-based proteomic analysis strategy to improve the range of serum proteomic analysis.We identified 1,070 proteins with a median coefficient of variation of 12.56％using PC-based proteomic analysis,which was twice the number of proteins iden-tified by direct digestion.There were also more biological processes enriched with these proteins.We applied this strategy to identify more pharmacodynamic biomarkers on collagen-induced arthritis(CIA)rat model treated with methotrexate(MTX).The bioinformatic results indicated that 485 differentially expressed proteins(DEPs)were found in CIA rats,of which 323 DEPs recovered to near normal levels after treatment with MTX.This strategy can not only help enhance our understanding of the mechanisms of disease and drug action through serum proteomics studies,but also provide more pharmacodynamic biomarkers for disease prediction,diagnosis,and treatment.

Mitochondria as a signaling platform play crucial roles in deciding cell fate. Many classic anticancer agents are known to trigger cell death through induction of mitochondrial damage. Mitophagy, one selective autophagy, is the key mitochondrial quality control that effectively removes damaged mitochondria. However, the precise roles of mitophagy in tumorigenesis and anticancer agent treatment remain largely unclear. Here, we examined the functional implication of mitophagy in the anticancer properties of magnolol, a natural product isolated from herbal

Objective:To analyze the clinical characteristics of hereditary neuralgic amyotrophy caused by SEPT9 gene mutation in a family to promote understanding this disease.Methods:The clinical manifestations, examination, imaging and electrophysiology of a family with hereditary neuralgic amyotrophy diagnosed by gene testing in the 960th Hospital of People′s Liberation Army in August 2013 were retrospectively analyzed.Results:The age of the onset ranged from children to middle-aged. The parent-child couples demonstrated the existence of marked anticipation, with earlier age of onset in successive generations. Male and female were involved. The forearm had circular skin creases at a young age. The sudden upper limb pain and weakness were first symptoms, the distal upper limb muscle weakness was more obvious than the proximal, and the wrist was saggy. The course was described as relapsing-remitting, and there were sufficient laxity of the skin and generalized muscle wasting. The cerebrospinal fluid examination and magnetic resonance examination of brachial plexus nerve were normal. The electrophysiology was limited to the peripheral nerve damage of the double upper limbs.Conclusions:Relapsing-remitting focal brachial plexus pain and weakness are the main manifestations of hereditary neuralgic amyotrophy, and the laxity of the skin and generalized thin muscle appear on sequel stage of the clinical repeated attack. The electrophysiological lesion is limited to brachial plexus nerve.

Objective To investigate the influence of hyperfibrinogenemia in outcome of patients with acute brain infarction.Methods Consecutive acute cerebral infarction patients,admitted to our hospital from August 2010 to August 2014,were prospectively recruited.The baseline data,including age,gender,serum creatinine level,National Institute of Health Stroke Scale (NIHSS) scores,types of Oxfordshire Community Stroke Project (OCSP:total anterior circulation infarct,partial anterior circulation infarct,posterior circulation infarct and lacunar infarct),and plasma fibrinogen level within 24 h of admission were recorded.Patients were divided into two groups according to with or without hyperfibrinogenemia.Recovery was assessed by modified Rankin Scale (mRS) 180 days after stroke by telephone interview (mRS ≤ 2 reflected good prognosis,and mRS＞2 reflected unfavorable prognosis).Multi-variant Logistic regression analysis and Kaplan-Meier curve analysis were performed to analyze the influence of fibrinogen in bad prognosis and mortality ratio.Results A total of 495 patients were enrolled,including 123 patients with hyperfibrinogenemia.Good prognosis was noted in 200 patients and bad one was noted in 295 patients.As compared with patients without hyperfibrinogenemia,acute ischemic patients with hyperfibrinogenemia had significantly higher rate of bad prognosis (34.41％ vs.60.98％,P＜0.05);as compared with patients with good prognosis,patients with bad prognosis had significantly higher fibrinogen (3.00[0.95] g/L vs.3.35[1.4] g/L,P＜0.05).Spearman correlation analysis indicated that hyperfibrinogenemia was correlated to the mRS scores (r=0.219,P=0.026).Multivariate Logistic regression indicated that hyperfibrinogenemia within 24 hours since onset was an independent prognostic factor for long-term poor outcomes (OR=1.772,95％ CI:1.1003-3.130,P=0.049).Kaplan-Meier estimate of patients with hyperfibrinogenemia for cumulative 180 days survival function for all-cause mortality was lower than those without hyperfibrinogenemia (76.42％ [94/123] vs.91.40％ [340/372]).Conclusion In patients with acute cerebral infarction,hyperfibrinogenemia within 24 hours since onset is an independent prognostic factor for long term unfavorable outcome;the survival rate of patients with hyperfibrinogenemia is lower than that of patients without hyperfibrinogenemia.

Objective To investigate the correlation between anemia and outcome in a large cohort of unselected patients with acute cerebral infarction.Methods Consecutive acute cerebral infarction patients who were hospitalized were prospectively recruited from August 2010 to November 2013.Eight hundred and fifty-eight patients were enrolled,and the baseline data including age,sex,National Institute of Health Stroke Scale(NIHSS) scores,type of Oxfordshire Community Stroke Project(OCSP:total anterior circulation infarct,partial anterior circulation infarct,posterior circulation infarct and lacunar infarct),serum creatinine,initial hemoglobin level,initial hematocrit level,etc,were recorded.Hemoglobin level and hematocrit level during hospitalization were also recorded.Domestic criteria were used to define if the patient had anemia on admission.Recovery was assessed by modified Rankin Scale (mRS) 180 days after stroke by telephone interview (mRS scores ≤ 2 reflected good prognosis,and mRS scores ＞ 2 reflected unfavorable prognosis).The influence on outcome by anemia on admission,initial hemoglobin level,nadir hemoglobin level,nadir hematocrit level was analyzed by multinomial Logistic regression analysis.Results Odds ratio of initial hemoglobin level for poor outcome was 1.013 (95％ CI 1.001-1.024,P =0.027) with each decrease in hemoglobin of 1 g/dl.Initial anemia(OR =2.417,95％ CI 1.202-4.859,P =0.013) was a independent prognostic factor for mortality;odds ratio of nadir hemoglobin level for mortality was 1.016(95％ CI 1.002-1.030,P =0.026) with each decrease in hemoglobin of 1 g/dl;odds ratio of nadir hematocrit level for mortality was 1.047(95％ CI 1.003-1.093,P =0.037) with decrease in hematocrit of one percentage point.Conclusions Initial hemoglobin level was a independent prognostic factor for poor outcome in patients with acute cerebral infarction.Anemia on admission,nadir hemoglobin level,nadir hematocrit level were independent prognostic factors for mortality in patients with acute cerebral infarction.

Objective To investigate the clinicopathological features and the pathogenesis of rhabdomyolysis caused by exertional heat stroke.Methods Eight patients including 6 military soldiers and 2 physical exercisers trained under high temperature environment were enrolled into this study.Their clinical manifestations were compatible with the diagnostic standard of exertional heat stroke.Consecutive blood biochemistry tests were performed in all patients,and electromyography and muscle biopsy in 3 cases.Results Eight patients were all male,with average age of 27.4 years old.The main clinical characteristics included myalgia in 4 patients,muscle weakness in 2 patients,fever in 5 patients,and tea-colored urine in 3 patients.One patient had acute renal failure,and 2 patients developed multiple organ failure syndromes and disseminated intravascular coagulation.One muscle biopsy done in the third day after the onset showed obvious muscle necrosis without inflammatory infiltrates,while the other 2 muscle biopsy done 2 weeks after the onset showed muscle necrosis companied by inflammatory phagocytic response.Six patients full recovered,1 patient partially recovered and one patient died.Conclusions Rhabdomyolysis caused by exertional heat stroke predominantly occurred in males.The main clinical features include muscle pain,weakness,significantly elevated serum creatine kinase and myoglobin level and myoglobinuria.Muscle pathology indicated muscle necrosis in the early stage and accompanied inflammatory infiltrates in the late stage.Most patients will get recovered with prompt diagnosis and treatment while the severe cases can be life-threatening.