Objective:To compare the prognostic values of different classification by using transpulmonary pressure gradient (TPG), diastolic pressure gradient (DPG) and pulmonary vascular resistance (PVR) in patients with pulmonary hypertension due to left heart disease (PH-LHD), and investigated hemodynamic and clinical factors associated with mortality in patients with PH-LHD.Methods:This was a single-center prospective cohort study. In-hospital patients diagnosed with PH-LHD via right heart catheterization at the Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, from September 2013 to December 2019 were enrolled. Patients were divided according to TPG (cutoff value 12 mmHg; 1 mmHg=0.133 kPa), DPG (cutoff value 7 mmHg), PVR (cutoff value 3 Wood Units), and the combination of TPG and PVR. Baseline characteristic was recorded. All patients were followed up until the occurrence of endpoint event, defined as all-cause death that occurred during the follow-up period, or until April 18, 2022. Receiver operating characteristic curves were used to compare the predictive value of 3 classification methods for all-cause death in PH-LHD patients. The optimal cutoff values were calculated using Jorden index. Survival analysis was performed using Kaplan-Meier analysis, and log-rank test was used to compare the predictive efficacy of classification methods based on optimal cutoff values or guidance-recommended thresholds for the survival of PH-LHD patients. Variables showing statistical significance in the univariate analysis were incorporated into multivariate Cox regression model to analyze the independent risk factors for all-cause mortality.Results:A total of 243 patients were enrolled, aged (54.9±12.7) years old, including 169 (69.5%) males. During a median follow-up of 57 months, there were 101 (41.6%) deaths occurred. Grouping results were as follows: (1) TPG: TPG≤12 mmHg group 115 patients, TPG>12 mmHg group 128 patients; (2) DPG: DPG<7 mmHg group 193 patients, DPG≥7 mmHg group 50 patients; (3) PVR: PVR≤3 Wood Units group 108 patients, PVR>3 Wood Units group 135 patients; (4) TPG and PVR: TPG≤12 mmHg and PVR≤3 Wood Units group 89 patients, TPG>12 mmHg and PVR>3 Wood Units group 109 patients. PVR ( AUC=0. 698,95% CI:0.631-0.766) had better predictive value for all-cause mortality than TPG ( AUC=0.596, 95% CI: 0.523-0.669) and DPG ( AUC=0.526, 95% CI: 0.452-0.601) (all P<0.05). The optimal cutoff values for TPG, DPG, and PVR were13.9 mmHg, 2.8 mmHg, and 3.8 Wood Units, respectively. Kaplan-Meier analysis based on the optimal cutoff values or guidance-recommended thresholds showed that PVR and TPG were the predictors of survival ( P<0.05), while DPG did not showed significance ( P>0.05). Multivariate Cox regression analysis showed that age, PVR and log 2N-terminal pro-B-type natriuretic peptide were independent risk factors for all-cause mortality in PH-LHD patients (all P<0.05). Conclusion:Classification according to PVR was most valuable in predicting all-cause death in PH-LHD patients, while TPG showed moderate predictive ability and DPG had no predictive value.

Opioid receptors μOR,δOR,κOR and NOPR are all G protein-coupled receptors(GPCRs),which mainly function through G protein and β-ar-restin.Recent studies have found that G protein mediates analgesia,while β-arrestin reduces anal-gesia and is related to the side effects of opioids.Oliceridine is the first biased μOR agonist approved for commerce.It mainly exerts analgesic effect by activating G protein.It has rapid onset of action and reliable analgesic effect.Due to its low activity on β-arrestin,the incidence of side effects is low,comparing to the classic opioid morphine.Oliceri-dine can be safely used in patients with liver or kid-ney insufficiency and its metabolite is inactive.This article summarizes the current progress of pharma-cological research and clinical application of oliceri-dine,aiming to provide reference for the clinical practice of oliceridine.

Objective:To analyze the clinical characteristics and medication options of patients with elderly-onset epilepsy and influencing factors for medication efficacy.Methods:A total of 213 patients with elderly-onset epilepsy (age of onset≥65 years) were selected from Epilepsy Outpatient, Department of Neurology, First Medical Center of Chinese PLA General Hospital from February 1999 to March 2023. General data, imaging findings and follow-up results of these patients were collected. Seizure frequencies and types, medication types, and medication efficacy were analyzed retrospectively. According to medication efficacy, these patients were divided into effective anti-seizure medications (ASMs) group and ineffective ASMs group (effective ASMs was defined as having no seizures or seizure reduction>50% at 6 months after medication, and ineffective ASMs as having seizure reduction≤50% or seizure increase. Univariate and multivariate Logistic regression analyses were used to identify the influencing factor for ASMs efficacy.Results:In these 213 patients with elderly-onset epilepsy, 143 (67.1%) were males and 70 (32.9%) were females. Onset age was 70.0 (67.0, 74.5) years, with duration of 12 (4, 32) months. Time from first onset to treatment was 2.0 (1.0, 10.5) months, with that<2 months enjoying the largest proportion ( n=101). MRI/CT in 102 patients indicated potential epileptogenic abnormal structures, such as post-stroke gliosis/encephalomalacia ( n=67) and post-traumatic gliosis/encephalomalacia ( n=13). MRI/CT in 78 patients indicated non-epileptogenic abnormal structures, such as ischemic changes of small and medium vessels ( n=51) and brain atrophy ( n=15). Structural change was the most common cause ( n=160). Sixty-nine patients (32.4%) did not take medicine and 144 (67.6%) took medicine at the visiting; sodium valproate was mostly used ( n=74), followed by levetiracetam ( n=35) and carbamazepine ( n=24). Five patients had sodium valproate combined with levetiracetam, and 4 patients had sodium valproate combined with carbamazepine. Multivariate Logistic regression analysis showed that disease duration and medication combination were independent influencing factors for ASMs efficacy. Conclusion:Structural change is the main cause for elderly-onset epilepsy; medication efficacy is worse in patients with longer disease course and medication combination therapy.

Objective: Sialidosis type 2 has variants that are both catalytically inactive (severe), while sialidosis type 1 has at least one catalytically active (mild) variant. This study aimed to discuss the structural changes associated with these variants in a newly reported family carrying N-acetyl-α-neuraminidase-1 (NEU1) variants and explore the clinical characteristics of different combinations of variants in sialidosis type 1. Methods: First, whole-exome sequencing and detailed clinical examinations were performed on the family. Second, structural analyses, including assessments of energy, flexibility and polar contacts, were conducted for several NEU1 variants, and a sialidase activity assay was performed. Third, previous NEU1 variants were systematically reviewed, and the clinical characteristics of patients in the severe-mild and mild-mild groups with sialidosis type 1 were analyzed. Results: We report a novel family with sialidosis type 1 and the compound heterozygous variants S182G and V143E. The newly identified V143E variant was predicted to be a mild variant through structural analysis and was confirmed by a sialidase activity assay. Cherry-red spots were more prevalent in the severe-mild group, and ataxia was more common in the mild-mild group. Impaired cognition was found only in the severe-mild group. Moreover, patients with cherry-red spots and abnormal electroencephalographies and visual evoked potentials had a relatively early age of onset, whereas patients with myoclonus had a late onset. Conclusion Changes in flexibility and local polar contacts may be indicators of NEU1 pathogenicity. Sialidosis type 1 can be divided into two subgroups according to the variant combinations, and patients with these two subtypes have different clinical characteristics.

Acute pancreatitis (AP) is a devastating disease characterized by an inflammatory disorder of the pancreas. P-selectin glycoprotein ligand-1 (PSGL-1) plays a crucial role in the initial steps of the adhesive at process to inflammatory sites, blockade of PSGL-1 might confer potent anti-inflammatory effects. In this study, we generated two non-human primate derived monoclonal antibodies capable of efficiently targeting human PSGL-1, RH001-6 and RH001-22, which were screened from immunized rhesus macaques. We found that RH001-6, can effectively block the binding of P-selectin to PSGL-1, and abolish the adhesion of leukocytes to endothelial cells in vitro. In vivo, we verified that RH001-6 relieved inflammatory responses and pancreatic injury in both caerulein and l-arginine induced AP models. We also evaluated the safety profile after RH001-6 treatment in mice, and verified that RH001-6 did not cause any significant pathological damages in vivo. Taken together, we developed a novel non-human primate derived PSGL-1 blocking antibody with high-specificity, named RH001-6, which can interrupt the binding of PSGL-1 and P-selectin and attenuate inflammatory responses during AP. Therefore, RH001-6 is highly potential to be further developed into therapeutics against acute inflammatory diseases, such as AP.

Depression has become a serious global public health problem due to its high incidence and great harm, and has aroused the attention of the society. Ketamine, a commonly used intravenous anesthetic and analgesic in clinical practice, has been found to have unique advantages in antidepressant therapy in recent years. With the development of research, the enantiomeric isomers of ketamine, (S)-ketamine and (R)ketamine have entered the research field of antidepressant therapy. In this paper, we reviewed the progress of research on the antidepressant effects and mechanisms of ketamine, (S )-ketamine and (R)-ketamine, and provide a brief overview of the antidepressant effects of metabolites of ketamine, thereby deepening the understanding of the readers in the field of antidepressant effects of ketamine.

OBJECTIVES: Cardiac hypertrophy and fibrosis are major pathological manifestations observed in left ventricular remodeling induced by angiotensin II (AngII). Low-intensity pulsed ultrasound (LIPUS) has been reported to ameliorate cardiac dysfunction and myocardial fibrosis in myocardial infarction (MI) through mechano-transduction and its downstream pathways. In this study, we aimed to investigate whether LIPUS could exert a protective effect by ameliorating AngII-induced cardiac hypertrophy and fibrosis and if so, to further elucidate the underlying molecular mechanisms. METHODS: We used AngII to mimic animal and cell culture models of cardiac hypertrophy and fibrosis. LIPUS irradiation was applied in vivo for 20 min every 2 d from one week before mini-pump implantation to four weeks after mini-pump implantation, and in vitro for 20 min on each of two occasions 6 h apart. Cardiac hypertrophy and fibrosis levels were then evaluated by echocardiographic, histopathological, and molecular biological methods. RESULTS: Our results showed that LIPUS could ameliorate left ventricular remodeling in vivo and cardiac fibrosis in vitro by reducing AngII-induced release of inflammatory cytokines, but the protective effects on cardiac hypertrophy were limited in vitro. Given that LIPUS increased the expression of caveolin-1 in response to mechanical stimulation, we inhibited caveolin-1 activity with pyrazolopyrimidine 2 (pp2) in vivo and in vitro. LIPUS-induced downregulation of inflammation was reversed and the anti-fibrotic effects of LIPUS were absent. CONCLUSIONS These results indicated that LIPUS could ameliorate AngII-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway, providing new insights for the development of novel therapeutic apparatus in clinical practice.

OBJECTIVES: To evaluate the value of thrombospond in Type I domain-containing 7A (THSD7A) and M-type phospholipase A2 receptor (PLA2R) in primary membranous nephropathy (PMN) and to explore the relationship between their antibody levels and prognosis. METHODS: Renal tissues in 128 patients with membranous nephropathy in the Second Xiangya Hospital of Central South University were collected from February 2015 to August 2017, including 108 patients with primary membranous nephropathy (PMN group) and 20 patients with secondary membranous nephropathy (SMN) (SMN group). Indirect immunofluorescence method was used to detect the expression of PLA2R antigen in kidney tissues,and the glomerular expression of THSD7A antigen was examined by immunohistochemistry and indirect immunofluorescence. The serum levels of anti-PLA2R antibodies and THSD7A antibodies were also detected by ELISA. According to the results of PMN examination,the patients were also divided into a PLA2R-related membranous nephropathy group and a THSD7A-related membranous nephropathy group. RESULTS: The positive rate of PLA2R in the renal tissues in the PMN group was higher than that in the SMN group (78% in the PMN group, 35% in the SMN group, <0.01),while the positive rate of anti-PLA2R antibody in the PMN group was also higher than that in the SMN group (50% in the PMN group, 25% in the SMN group, <0.05).The serum level of anti-PLA2R antibody was positively correlated with 24 h urine protein (=0.254, <0.05) and negatively correlated with serum albumin (=-0.236, <0.05). The expression of THSD7A was positive in glomeruli in 7 cases of the PMN group (6%) by immuno-histochemistry, and which was positive in 1case of the SMN group (5%).The serum levels of anti-THSD7A antibody in the PMN group were higher than those in the SMN group [(0.49±0.26) pg/mL in the PMN group,(0.34±0.27) pg/mL in the SMN group, <0.05]. There was no difference in the clinical characteristics between the PLA2R-related membranous nephropathy group and the THSD7A-related membranous nephropathy group. CONCLUSIONS PLA2R and THSD7A are the target antigen of PMN, and the associated autoantibodies are helpful for the differential diagnosis of PMN. The anti-PLA2R antibody levels can reflect the severity of the disease and evaluate the effect of treatment. The incidence of THSD7A membranous nephropathy is low, and monitoring the serum anti-THSD7A antibody levels can assess patients' condition and predict disease outcome.
Autoantibodies ; Glomerulonephritis, Membranous ; Humans ; Immunohistochemistry ; Receptors, Phospholipase A2 ; Thrombospondins

Objective:To examine the expression ofphospholipase A2 receptor (PLA2R) in renal tissues and the level of anti-PLA2R antibody in serum in patients with idiopathic membranous nephropathy (IMN) and secondary membranous nephropathy (SMN),and to evaluate their diagnostic value in IMN.Methods:A total of 73 patients,who were diagnosed between May,2014 and February,2015 in the Department of Nephrology of the Second Xiangya Hospital,Central South University,were divided into three groups:an IMN group (n=48),an SMN group (n=17) and a minimal change disease group (n=8) according to the renal biopsy.PLA2R expression in renal tissues and the level of antiPLA2R antibody in serum were detected by indirect immunofluorescence technique.Results:The positive rate and fluorescence intensity for PLA2R in the renal tissues in the IMN group were higher than those in the SMN group (91.7％ in the IMN group vs 29.4％ in the SMN group,P＜0.05),while the positive rate and serum level for anti-PLA2R antibody in the IMN group were higher than those in the SMN group (85.4％ in the IMN group vs 29.4％ in the SMN group,P＜0.05);the expression of PLA2R in renal tissues and the serum level for anti-PLA2R antibody were not detected in the minimal change disease group,The serum level of anti-PLA2R antibody was positively correlated with 24 h urine protein (r=0.432,P＜0.01) and negatively correlated with serum albumin (r=-0.307,P＜0.05).Conclusion:The expression of PLA2R in renal tissues and the serum level of anti-PLA2R antibody might be potential markers for diagnosis oflMN.

Objective To study the effects of FTY720 pretreatment on ventilator-induced lung injury (VILI) in rats in order to explore the role of sphingosine-l-phosphate receptor 1 (S1PR1).Methods Forty healthy adult male SD rats weighing 300-350 g were randomly (randlom number) divided into 4 groups (n=10 each):group CV (conventional tidal volume VT =8 mL/kg),group HV (high tidal volume VT =40 mL/kg),group HF and group HFW.The rats in group HF received intra-gastric administration of FTY720 10 mg · kg-1 · d-1 for 7 days,while additional dose of W146 (S1PR1 antagonist) 1 mg · kg-1 · d-1 was administrated in group HFW before high tidal volume ventilation.After 4-hour mechanical ventilation,arterial blood samples were obtained for blood gas analysis before the animals were sacrificed.The lungs were harvested for histopathologic observation.Apoptosis rate in lung tissue was determined with flow cytometry.W/D lung weight ratio,pulmonary permeability index (PPI),total protein,and TNF-α,IL-1β in bronchoaveolar lavage fluid (BALF) were measured.All data were analyzed by oneway analysis of variance (ANOVA),The intergroup comparisons were analyzed by the least-significantdifference (LSD) test by using SPSS version 20.0 software.Differences were considered statistically significant if P ＜ 0.05.Results Compared with group CV,the level of PaO2 [(73.6 ± 8.9) vs.(50.5 ± 6.0)] was decreased,the levels of W/D [(3.12 ± 0.27) vs.(5.12 ± 0.56)],PPI [(0.08 ±0.03) vs.(0.30 ± 0.06)],apoptosis rate [(10.6 ±2.9) vs.(48.5±6.7)],total protein [(5.8 ±2.1) vs.(15.4±5.6)] and TNF-α [(24.3±5.7) vs.(108.4±16.0)] andIL-1β [(90.6±14.1) vs.(338.5 ± 44.3)] were increased in group HV (P ＜ 0.05).Compare with group HV,PaO2 [(50.5 ± 6.0) vs.(65.9±10.3)] was increased,W/D[(5.12±0.56)vs.(3.85±0.37)],PPI[(0.30± 0.06)vs.(0.14±0.03)],apoptosis rate [(48.5 ±6.7)vs.(25.6 ±5.3)],total protein [(15.4±5.6) vs.(8.9±2.5)],TNF-cα [(108.4±16.0) vs.(75.6±10.3)] andIL-1β [(338.5 ±44.3) vs.(188.9 ±33.8)] in BALF were decreased in group HF (P ＜0.05).PaO2 [(50.5±6.0) vs.(59.7±7.8)] was higher,W/D[(5.12±0.56) vs.(4.44±0.30)],PPI [(0.30±0.06)vs.(0.19±0.09)] andIL-1β[(338.5-±44.3) vs.(246.8±24.6)] levels were lower in group HFW than those in group HF There were no significant differences in apoptosis rate[(48.5±6.7)vs.(41.3±6.8)],totalprotein[(15.4±5.6)vs.(10.4±2.7)] and TNF-α level [(108.4 ± 16.0) vs.(97.5 ± 10.3)] between HFW group and HF group (P ＞ 0.05).Compare with group CV,The histopathologic damage of lung tissue was obvious in group HV and group HFW,it was attenuated by pretreatment with FTY720 in group HF.Conclusions FTTY720 pretreatment provides protective effects against ventilation-induced lung injury in rats,and S1PR1 may mediate the protection through reducing apoptosis rate and inflammatory reaction.