Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca²⁺ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
Animals ; Laminin/genetics* ; Hippocampus/metabolism* ; Neuralgia/metabolism* ; Cognitive Dysfunction/etiology* ; Male ; Peripheral Nerve Injuries/metabolism* ; Extracellular Matrix/metabolism* ; Integrin beta1/metabolism* ; Pyramidal Cells/metabolism* ; Signal Transduction

A new method was developed for simultaneous detection of total 19 kinds of organophosphate esters(OPEs)and their diester metabolites(di-OPEs)in human serum(1.0 mL)and urine(1.5 mL)with low volume of samples.The target compounds were determined using ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)after acetonitrile liquid-liquid extraction combined with purification using an ENVI-18 solid-phase extraction(SPE)column.OPEs and di-OPEs were separated using a Shim-pack GIST C18 column(100 mm×2.1 mm,2 μm)with a Shim-pack GIST-HP(G)C18 guard column.An electrospray ionization source(ESI)was employed in mass spectrometry analysis,with positive/negative ion mode using the multiple reaction monitoring(MRM).All target compounds were separated within 15 min,and exhibited good linear relationships in the concentration range of 2-100 ng/mL,with correlation coefficients(R2)above 0.994.The method detection limits(MDL)in serum ranged from 0.001 to 0.178 ng/mL and the MDL in urine ranged from 0.001 to 0.119 ng/mL.The recoveries of the analytes spiked in serum and urine matrices at two concentration levels were 30.5%-126.8%,with the relative standard deviations(RSDs)ranged from 1%to 23%.In addition,paired serum and urine samples from 11 patients were analyzed.For all samples tested,the internal standards of OPEs exhibited recoveries between 61%and 114%,whereas the internal standards for di-OPEs had recoveries ranging from 43%to 103%.OPEs and di-OPEs exhibited high detection frequencies in 22 serum and urine samples.Triethyl phosphate(TEP),tributyl phosphate(TBP),tris(2-ethylhexyl)phosphate(TEHP),tris(2-butoxyethyl)phosphate(TBEP),tris(1-chloro-2-propyl)phosphate(TCIPP),triphenyl phosphate(TPHP),tri-m-tolyl-phosphate(TMTP)and 2-ethylhexyl diphenyl phosphate(EHDPP)were universally detected in all serum samples.TCIPP was identified at the highest concentrations(median 0.548 ng/mL)in serum samples.In urine samples,the detection frequency for 12 kinds of target compounds reached 100%.Notably,TBP emerged as the predominant OPE in urine,demonstrating a median concentration of 0.506 ng/mL.Regarding di-OPEs,bis(2-chloroethyl)phosphate(BCEP)and bis(2-butoxyethyl)hydrogen phosphate(BBOEP)were the most abundant in urine,with median concentrations of 6.404 and 2.136 ng/mL,respectively.The total concentrations of OPEs and di-OPEs in serum and urine were 1.580-3.843 ng/mL and 5.149-17.537 ng/mL,respectively.These results not only confirmed the effectiveness of the method in detection of OPEs and di-OPEs in biological matrices,but also revealed the widespread presence of OPE compounds in human body and pointed to potential exposure risks.

Objective To understand the distribution and changes in antimicrobial resistance of clinically isolated Pseudomonas aeruginosa(P.aeruginosa)in the member hospitals of Hunan Provincial Antimicrobial Resistance Surveillance System from 2012 to 2021.Methods Antimicrobial susceptibility testing by disk diffusion or automa-ted instrument was performed on clinical isolates.Testing results were determined according to the standards of 2022 edition from American Clinical Laboratory Standards Institute(CLSI).Statistical analysis was performed by WHONET 5.6 software.Data were analyzed by trend test(Cochran-armitage)and Chi-square test with SPSS.Results A total of 176 441 strains of P.aeruginosa were surveilled by Hunan Provincial Antimicrobial Resistance Surveillance System from 2012 to 2021.99.4％of the strains were isolated from hospitalized patients,and about 70％of the strains were isolated from respiratory specimens.8.4％of P.aeruginosa were from children(0-17 years old),91.6％were from adults.Antimicrobial susceptibility testing results showed that P.aeruginosa was most sensitive to polymyxin B over 10 years,with a resis-tance rate of less than 6％.Resistance rates to piperacil-lin,piperacillin/tazobactam,ceftazidime,cefepime,aztreonam,imipenem,amikacin,gentamicin,tobramycin,cip-rofloxacin,levofloxacin,and polymyxin B all showed downward trends.A total of 29 920 carbapenem-resistant P.aeruginosa(CRPA)strains were detected.The average isolation rate of CRPA in this province was 18.0％over 10 years.CRPA detection rate from adult was 18.5％,higher than that from children(12.3％),and both showing downward trends.Conclusion The resistance rate of clinically isolated P.aeruginosa in Hunan Province to most commonly used antimicrobial agents is decreasing.

OBJECTIVE: Acute liver failure (ALF) is characterized by severe liver dysfunction, rapid progression and high mortality and is difficult to treat. Studies have found that sulforaphane (SFN), a nuclear factor E2-related factor 2 (NRF2) agonist, has anti-inflammatory, antioxidant and anticancer effects, and has certain protective effects on neurodegenerative diseases, cancer and liver fibrosis. This paper aimed to explore the protective effect of SFN in ALF and it possible mechanisms of action. METHODS: Lipopolysaccharide and D-galactosamine were used to induce liver injury in vitro and in vivo. NRF2 agonist SFN and histone deacetylase 6 (HDAC6) inhibitor ACY1215 were used to observe the protective effect and possible mechanisms of SFN in ALF, respectively. Cell viability, lactate dehydrogenase (LDH), Fe²⁺, glutathione (GSH) and malondialdehyde (MDA) were detected. The expression of HDAC6, NRF2, glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4) and solute carrier family 7 member 11 (SLC7A11) were detected by Western blotting and immunofluorescence. RESULTS: Our results show that NRF2 was activated by SFN. LDH, Fe²⁺, MDA and ACSL4 were downregulated, while GSH, GPX4 and SLC7A11 were upregulated by SFN in vitro and in vivo, indicating the inhibitory effect of SFN on ferroptosis. Additionally, HDAC6 expression was decreased in the SFN group, indicating that SFN could downregulate the expression of HDAC6 in ALF. After using the HDAC6 inhibitor, ACY1215, SFN further reduced HDAC6 expression and inhibited ferroptosis, indicating that SFN may inhibit ferroptosis by regulating HDAC6 activity. CONCLUSION SFN has a protective effect on ALF, and the mechanism may include reduction of ferroptosis through the regulation of HDAC6. Please cite this article as: Zhang YQ, Shi CX, Zhang DM, Zhang LY, Wang LW, Gong ZJ. Sulforaphane, an NRF2 agonist, alleviates ferroptosis in acute liver failure by regulating HDAC6 activity. J Integr Med. 2023; 21(5): 464-473.
Humans ; Ferroptosis ; NF-E2-Related Factor 2/genetics* ; Liver Failure, Acute/drug therapy* ; Isothiocyanates/pharmacology* ; Glutathione ; Histone Deacetylase 6

The theory of "liver opens at the eyes" was first seen in Yellow Emperor's Internal Canon of Medicine， which is the ancient people's summary of the connection between the liver and the eyes. The theory of "liver opens at the eyes" suggests the characteristic of "co-damage and co-recover of liver and eyes". It has been found in clinical practice that liver diseases and eye diseases often occur together， and "liver and eyes co-recover" is an ideal choice. The key to achieving "liver and eyes co-recover" is to analyze its pharmacological material basis and mechanism. With the development of modern medicine， more and more evidence indicates that the liver and eyes have complex and close relationships in physiological and pathological aspects. In a pathological state， there is a phenomenon of "liver and eyes co-damage"， and after the intervention of traditional Chinese medicine， "liver and eyes co-recover" occurs. "Liver and eyes co-damage and co-recover" can be explained through the "co-material basis and co-action mechanism". On this basis， the research group tentatively proposed that the liver and eyes had "four common characteristics" （4CCs）， namely "co-damage， co-recover， co-material basis， and co-action mechanism" from the theoretical connotation of traditional Chinese medicine， clinical practice， and molecular biology. Additionally， the group also took the intervention of Prunella vulgaris， traditional Chinese medicine， for removing liver fire and improving eyesight on immune liver injury （ILI） and allergic conjunctivitis （AC） as examples to analyze 4CCs. This project aims to deeply analyze the scientific connotation of the theory of "liver opens at the eyes"， reveal the common characteristics and biological essence of liver and eyes， explore a new research paradigm of "liver and eyes co-recover"， and provide a reference for the study of common problems of multi-organ associated diseases.

Objective:To investigate the outcome of using long head of biceps tendon (LHBT) transposition to augment arthroscopic massive rotator cuff repair.Methods:A retrospective case series study was performed on 22 patients with massive rotator cuff tear treated in Zhongshan Hospital, Xiamen University from June 2019 through July 2020, including 12 males and 10 females, aged 54-79 years [(63.9±6.8)years]. LHBT transposition was performed to augment arthroscopic repair of massive rotator cuff tear. The active range of motion (forward flexion, abduction, external rotation), visual analog scale (VAS), University of California Los Angeles (UCLA) score and American Shoulder and Elbow Surgeons (ASES) score were compared preoperatively and at 3 months and 12 months postoperatively. The cuff integrity was evaluated using MRI following Sugaya classification at 12 months postoperatively. LHBT dislocation or distal retraction was recorded at the last follow-up.Results:All patients were followed up for 12-24 months [(17.0±3.8)months]. The postoperative 3-month active forward flexion [162.5(160.0, 170.0)°] and abduction [170.0(160.0, 170.0)°] were improved compared with preoperative measurements [90.0(73.8, 120.0)°,85.0(70.0, 112.5)°](all P<0.05). However, no statistically significant difference was found between the preoperative and postoperative 3-month external rotation [50.0(37.5,60.0)° vs. 60.0(48.8,70.0)°] ( P>0.05). The postoperative 12-month active forward flexion, abduction and external rotation were 170.0(160.0, 175.0)°, 170.0(170.0, 177.8)° and 60.0(48.8, 70.0)°, showing no significant improvement from those at 3 months postoperatively (all P>0.05). The postoperative 3-month VAS [1.0(0.8, 2.0)points], UCLA score [23.0(23.0, 25.0)points] and ASES score [79.1(72.9, 83.3)points] were improved significantly compared with preoperative measurements [7.0(8.0, 9.0)points, 9.0(10.0, 14.0)points, 25.0(16.6, 31.6)points] (all P<0.05). The postoperative 12-month UCLA score [33.0(31.0, 35.0)points] and ASES score [91.6(86.6, 93.3)points] were further improved compared with those at 3 months postoperatively (all P<0.05). However, the postoperative 12-month VAS [0.0 (0.0, 1.0)points] showed no statistically significant difference with that at 3 months postoperatively ( P>0.05). The UCLA score was excellent in 6 patients and good in 16 at 12 months postoperatively.MRI revealed healed tendons with continuity in 16 patients, with the healing rate of 72.7%, and partially retears with good shoulder function in 6 patients, with the retearing rate of 17.3%. No LHBT dislocation or distal retraction was found at 12 months postoperatively in regardless of mild anterior shoulder pain in 2 patients. Conclusion:Using LHBT transposition to augment arthroscopic massive rotator cuff repair has yielded excellent shoulder range of motion, shoulder function recovery, pain relief and high tendon healing rate with rare postoperative complication.

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
Female ; Humans ; Adolescent ; SARS-CoV-2 ; Smell ; COVID-19/complications* ; Cross-Sectional Studies ; COVID-19 Vaccines ; Incidence ; Olfaction Disorders/etiology* ; Taste Disorders/etiology* ; Prognosis

Objective: To analyze the prevalence and the risk factors of fungal sepsis in 25 neonatal intensive care units (NICU) among preterm infants in China, and to provide a basis for preventive strategies of fungal sepsis. Methods: This was a second-analysis of the data from the "reduction of infection in neonatal intensive care units using the evidence-based practice for improving quality" study. The current status of fungal sepsis of the 24 731 preterm infants with the gestational age of <34⁺⁰ weeks, who were admitted to 25 participating NICU within 7 days of birth between May 2015 and April 2018 were retrospectively analyzed. These preterm infants were divided into the fungal sepsis group and the without fungal sepsis group according to whether they developed fungal sepsis to analyze the incidences and the microbiology of fungal sepsis. Chi-square test was used to compare the incidences of fungal sepsis in preterm infants with different gestational ages and birth weights and in different NICU. Multivariate Logistic regression analysis was used to study the outcomes of preterm infants with fungal sepsis, which were further compared with those of preterm infants without fungal sepsis. The 144 preterm infants in the fungal sepsis group were matched with 288 preterm infants in the non-fungal sepsis group by propensity score-matched method. Univariate and multivariate Logistic regression analysis were used to analyze the risk factors of fungal sepsis. Results: In all, 166 (0.7%) of the 24 731 preterm infants developed fungal sepsis, with the gestational age of (29.7±2.0) weeks and the birth weight of (1 300±293) g. The incidence of fungal sepsis increased with decreasing gestational age and birth weight (both P<0.001). The preterm infants with gestational age of <32 weeks accounted for 87.3% (145/166). The incidence of fungal sepsis was 1.0% (117/11 438) in very preterm infants and 2.0% (28/1 401) in extremely preterm infants, and was 1.3% (103/8 060) in very low birth weight infants and 1.7% (21/1 211) in extremely low birth weight infants, respectively. There was no fungal sepsis in 3 NICU, and the incidences in the other 22 NICU ranged from 0.7% (10/1 397) to 2.9% (21/724), with significant statistical difference (P<0.001). The pathogens were mainly Candida (150/166, 90.4%), including 59 cases of Candida albicans and 91 cases of non-Candida albicans, of which Candida parapsilosis was the most common (41 cases). Fungal sepsis was independently associated with increased risk of moderate to severe bronchopulmonary dysplasia (BPD) (adjusted OR 1.52, 95%CI 1.04-2.22, P=0.030) and severe retinopathy of prematurity (ROP) (adjusted OR 2.55, 95%CI 1.12-5.80, P=0.025). Previous broad spectrum antibiotics exposure (adjusted OR=2.50, 95%CI 1.50-4.17, P<0.001), prolonged use of central line (adjusted OR=1.05, 95%CI 1.03-1.08, P<0.001) and previous total parenteral nutrition (TPN) duration (adjusted OR=1.04, 95%CI 1.02-1.06, P<0.001) were all independently associated with increasing risk of fungal sepsis. Conclusions: Candida albicans and Candida parapsilosis are the main pathogens of fungal sepsis among preterm infants in Chinese NICU. Preterm infants with fungal sepsis are at increased risk of moderate to severe BPD and severe ROP. Previous broad spectrum antibiotics exposure, prolonged use of central line and prolonged duration of TPN will increase the risk of fungal sepsis. Ongoing initiatives are needed to reduce fungal sepsis based on these risk factors.
Infant ; Infant, Newborn ; Humans ; Birth Weight ; Intensive Care Units, Neonatal ; Retrospective Studies ; Tertiary Care Centers ; Infant, Extremely Low Birth Weight ; Gestational Age ; Infant, Extremely Premature ; Sepsis/epidemiology* ; Retinopathy of Prematurity/epidemiology* ; Bronchopulmonary Dysplasia/epidemiology*

OBJECTIVES: To study the effect of sex on the clinical outcome of extremely preterm infants (EPIs)/extremely low birth weight infants (ELBWIs) by propensity score matching. METHODS: A retrospective analysis was performed for the medical data of 731 EPIs or ELBWIs who were admitted from January 1, 2011 to December 31, 2020. These infants were divided into two groups: male and female. A propensity score matching analysis was performed at a ratio of 1:1. The matching variables included gestational age, birth weight, percentage of withdrawal from active treatment, percentage of small-for-gestational-age infant, percentage of use of pulmonary surfactant, percentage of 1-minute Apgar score ≤3, percentage of mechanical ventilation, duration of mechanical ventilation, percentage of antenatal use of inadequate glucocorticoids, and percentage of hypertensive disorders in pregnancy. The two groups were compared in the incidence rate of main complications during hospitalization and the rate of survival at discharge. RESULTS: Before matching, compared with the female group, the male group had significantly higher incidence rates of neonatal respiratory distress syndrome, bronchopulmonary dysplasia (BPD), severe intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, and patent ductus arteriosus (P<0.05), while after matching, the male group only had a significantly higher incidence rate of BPD than the female group (P<0.05). There was no significant difference in the rate of survival at discharge between the two groups before and after matching (P>0.05). CONCLUSIONS Male EPIs/ELBWIs have a higher risk of BPD than female EPIs/ELBWIs, but male and female EPIs/ELBWIs tend to have similar outcomes.
Bronchopulmonary Dysplasia/etiology* ; Female ; Humans ; Infant ; Infant, Extremely Low Birth Weight ; Infant, Extremely Premature ; Infant, Newborn ; Male ; Pregnancy ; Propensity Score ; Retrospective Studies ; Sex Characteristics

OBJECTIVES: To investigate the influence of early-stage hypotension defined as mean arterial pressure (MAP)METHODS: A total of 320 preterm infants who were admitted to Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology from April 2020 to August 2021 and met the inclusion criteria were enrolled in this prospective study. Blood pressure within 72 hours was monitored. The definition of hypotension and grouping were as follows: (1) Of the 320 preterm infants, those with MAPn=104), and the others (n=216) served as the control group; (2) Of the 320 preterm infants, those with MAP<30 mmHg in 2 consecutive measurements served as the hypotension group (n=114), and the others served as the control group (n=206). Perinatal data and clinical data during hospitalization were collected.Poor short-term prognosis was defined as death during hospitalization and/or grade Ⅲ-Ⅳ periventricular-intraventricular hemorrhage identified within 1 week after birth. The multivariate logistic regression analysis was used to investigate the influence of hypotension based on the above two definitions on the short-term prognosis of preterm infants. RESULTS: Compared with the control group, the hypotension group based on the above two definitions had higher incidence rates of the clinical manifestations of hypoperfusion, poor prognosis, hemodynamically significant patent ductus arteriosus, and pulmonary hemorrhage (P<0.05). In addition, compared with the control group, the hypotension group defined by MAP<30 mmHg had higher incidence rates of periventricular-intraventricular hemorrhage and bronchopulmonary dysplasia and mortality rate during hospitalization (P<0.05). The incidence of poor short-term prognosis in the hypotension group defined by MAP<30 mmHg was higher than that in the hypotension group defined by MAPP>0.05).The univariate analysis showed that the poor short-term prognosis was related to birth of cesarean section, gestational age, an Apgar score of ≤ 5 at 5 minutes, use of vasoactive drugs within 72 hours, mechanical ventilation within 72 hours, and hypotension under the two definitions (P<0.05).The multivariate logistic regression showed that hypotension based on either definition was not an independent risk factor for poor prognosis (P>0.05). CONCLUSIONS Hypotension based on either definition is not an independent risk factor for short-term poor prognosis in preterm infants with a gestational age of <32 weeks. Hypotension defined by MAP<30 mmHg might be more sensitive than that defined by MAP Infant ; Child ; Infant, Newborn ; Humans ; Pregnancy ; Female ; Gestational Age ; Infant, Premature ; Prospective Studies ; Cesarean Section ; Hypotension/etiology* ; Prognosis ; Cerebral Hemorrhage