Identification of a novel missense SCN5A mutation in a Chinese Han family with Brugada syndrome.

Brugada syndrome is an inherited cardiac arrythmia causes sudden death usually associated with loss-of-function mutations of SCN5A, a gene encodes α subunit of cardiac sodium channel Nav1.5 which plays key role in cardiac function. SCN5A mutation screen is often applied to diagnosis of Brugada syndrome, while its genetic etiology remains not fully understood. In present study, we performed sequence analysis of SCN5A gene in a Chinese Han family with Brugada syndrome, and found a novel heterozygous mutation (c.4969 C > T, p.Leu1657Phe). Functional electrophysiological study showed that the mutation reduced ∼60% sodium current density and largely reduced Nav1.5 activation (positively shifted activation curve by 13.93 mV), which are the key features for the pathogenesis of Brugada syndrome. However, the mutation enhanced Nav1.5 function as it slightly decreased inactivation (positively shifted inactivation curve by 7.4 mV) and accelerated recovery (decreased fast recovery by 1.39 ms). In addition, the mutation acts in a dominant negatively manner as it reduced ∼49% sodium current densities in heterozygous state. In conclusion, the study describes a novel SCN5A mutation of p.Leu1657Phe associated with Brugada syndrome, the mutation reduced current density in a dominant negative manner and altered gating kinetics, which will benefit early clinical diagnosis of Brugada syndrome.

Diagnostic value of visceral adiposity index in chronic kidney disease: a meta-analysis.

AIMS: Several studies have revealed inconsistencies about the predictive properties of visceral adiposity index (VAI) in identifying chronic kidney disease (CKD). To date, it is unclear whether the VAI is a valuable diagnostic tool for CKD. This study intended to evaluate the predictive properties of the VAI in identifying CKD. METHODS: The PubMed, Embase, Web of Science, and Cochrane databases were searched for all studies that met our criteria from the earliest available article until November 2022. Articles were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). The heterogeneity was explored with the Cochran Q test and I2 test. Publication bias was detected using Deek's Funnel plot. Review Manager 5.3, Meta-disc 1.4, and STATA 15.0 were used for our study. RESULTS: Seven studies involving 65,504 participants met our selection criteria and were therefore included in the analysis. Pooled sensitivity (Sen), specificity (Spe), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and area under the curve (AUC) were 0.67 (95%CI: 0.54-0.77), 0.75 (95%CI: 0.65-0.83), 2.7 (95%CI: 1.7-4.2), 0.44 (95%CI: 0.29-0.66), 6 (95%CI:3.00-14.00) and 0.77 (95%CI: 0.74-0.81), respectively. Subgroup analysis indicated that mean age of subjects was the potential source of heterogeneity. The Fagan diagram found that the predictive properties of CKD were 73% when the pretest probability was set to 50%. CONCLUSIONS: The VAI is a valuable agent in predicting CKD and may be helpful in the detection of CKD. More studies are needed for further validation.

Factors Related to Activation in Chinese Patients With Chronic Obstructive Pulmonary Disease: A Cross-Sectional Survey Study.

BACKGROUND: Improving patient activation can lead to better health outcomes among patients with chronic obstructive pulmonary disease (COPD). However, no studies have focused on the issue of activation in patients with COPD in China. PURPOSE: This study was designed to explore the status of activation in patients with COPD in China and explicate the significant influencing factors. METHODS: One hundred seventy patients with COPD were recruited using a convenience sampling method from eight tertiary and secondary hospitals in Nanjing, China. Sociodemographic, clinical, and patient-reported factor data were collected. Univariate analysis and multivariate linear regression were performed. RESULTS: Only 10.6% of the patients were identified as activated for self-management. Multivariate linear regression analysis revealed four explanatory elements as significantly associated with patient activation, including social support (ß = .463, p < .001), free medical insurance (ß = .173, p = .007), smoking status (ß = -.195, p = .002), and health status (ß = -.139, p = .04). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The findings of this study indicate that a minority of patients with COPD are activated for self-management in China. Having a higher level of patient activation was associated with having better social support, having free medical insurance, being a nonsmoker, and having a better health status. Creating a supportive environment, promoting smoking cessation, and improving medical security and health status may be considered as potential strategies to activate patients into better self-management.

[Similarities and differences between Ginkgo biloba and Panax notoginseng in treatment of ischemic cerebrovascular disease].

Ginkgo biloba and Panax notoginseng are both herb medicines for cerebrovascular disease, and play an active role in treating ischemic cerebrovascular disease(ICVD). Their mechanisms of action include antioxidant stress, nerve protection, vascular protection. According to the comparative study of literatures, G. biloba has a certain protective effect from the early stage of free radical formation throughout the whole process of causing cell inflammation and apoptosis in antioxidant stress; while P. notoginseng has mainly anti-inflammatory, anti-apoptosis effects. In the nerve protection and repair of nerve damage caused by glutamate, both could promote neurogenesis, repair damaged axons and protect nerve cells. In addition, G. biloba could also relieve neurotoxicity caused by glutamate damage, while P. notoginseng have a unique effect in repairing blood-brain barrier(BBB) and blood vessel regeneration. In clinic, they are used as auxiliary drugs in combination with thrombolytic therapy, and play curative effects in alleviating inflammation, eliminating edema, improving the cure rate and the prognosis. For cerebral diseases caused by chronic cerebral hypoperfusion, G. biloba could reduce inflammation and improve cognition. In addition, G. biloba could protect neurocyte by adjusting the secretion of dopamine in vivo, and has a certain effect on antidepressant diseases, which however needs further studies.

Volatile anesthetics affect macrophage phagocytosis.

BACKGROUND: Perioperative infections, particularly surgical site infections pose significant morbidity and mortality. Phagocytosis is a critical step for microbial eradication. We examined the effect of commonly used anesthetics on macrophage phagocytosis and its mechanism. METHODS: The effect of anesthetics (isoflurane, sevoflurane, propofol) on macrophage phagocytosis was tested using RAW264.7 mouse cells, mouse peritoneal macrophages, and THP-1 human cells. Either opsonized sheep erythrocytes or fluorescent labeled Escherichia coli were used as phagocytic objects. The activation of Rap1, a critical protein in phagocytosis was assessed using the active Rap1 pull-down and detection kit. To examine anesthetic binding site(s) on Rap1, photolabeling experiments were performed using azi-isoflurane and azi-sevoflurane. The alanine scanning mutagenesis of Rap1 was performed to assess the role of anesthetic binding site in Rap1 activation and phagocytosis. RESULTS: Macrophage phagocytosis was significantly attenuated by the exposure of isoflurane (50% reduction by 1% isoflurane) and sevoflurane (50% reduction by 1.5% sevoflurane), but not by propofol. Photolabeling experiments showed that sevoflurane directly bound to Rap1. Mutagenesis analysis demonstrated that the sevoflurane binding site affected Rap1 activation and macrophage phagocytosis. CONCLUSIONS: We showed that isoflurane and sevoflurane attenuated macrophage phagocytosis, but propofol did not. Our study showed for the first time that sevoflurane served as a novel small GTPase Rap1 inhibitor. The finding will further enrich our understanding of yet-to-be determined mechanism of volatile anesthetics and their off-target effects. The sevoflurane binding site was located outside the known Rap1 functional sites, indicating the discovery of a new functional site on Rap1 and this site would serve as a pocket for the development of novel Rap1 inhibitors.

Incidence and Risk Factors of Perioperative Mortality in Pediatric ICU Patients.

BACKGROUND: There is a limited data of pediatric patients who presented to the intensive care unit (ICU) and undergo procedures under general anesthesia. The primary objective of this study was to evaluate the mortality of this population and assess the risk factors associated with mortality. METHODS: Retrospective study of electronic medical records of pediatric patients who admitted to medical/surgical ICU and underwent produces under general anesthesia during the same ICU admission was performed. Incidence of mortality was obtained and risk factors associated with these mortalities were examined using Univariable logistic regression analysis. RESULTS: The mortality of pediatric patients who were admitted to the ICU and underwent procedures under general anesthesia was 12.6%, while the mortalities of patients without procedures under general anesthesia and patients who admitted to ICU for postoperative management were 3.5% and 0.4%, respectively. Higher ASA class, emergency cases, higher ventilator support, more inotrope requirement, positive microbe in blood stream, blood transfusion requirement, and general surgery or hematological procedures were highly associated with mortalities. Among them, positive blood stream infection was highest odds ratio (102.00, 95% confidence interval 9.78-1064.09). The profile of patients with positive blood stream infection showed that most of them had underlying immunological/hematological disorders. CONCLUSION: In our institution, pediatric patients who admitted to the ICU and underwent procedures under general anesthesia demonstrated the highest mortality among other patients who admitted to ICU. Risk factor analysis demonstrated that patients with positive blood stream infection had highest odds ratio, and were highly associated with immunological/ hematological disorders.

Volatile Anesthetic Isoflurane Attenuates Liver Injury in Experimental Polymicrobial Sepsis Model.

Volatile anesthetics are often administered to patients with sepsis for procedural anesthesia or sedation in intensive care units. Sepsis still carries significant morbidities and mortalities, and organ injuries pose major complications. Early liver dysfunction is associated with poor outcome mainly as a result of overwhelming neutrophil recruitment. Leukocyte function-associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1) are major adhesion molecules on neutrophils and involved in neutrophil recruitment. We have previously showed that volatile anesthetic isoflurane inhibited LFA-1 and Mac-1. Here we studied the role of isoflurane, LFA-1 and Mac-1 on neutrophil recruitment to the liver and liver injury using experimental polymicrobial abdominal sepsis induced by cecal ligation and puncture (CLP) surgery. We used wild type (WT), LFA-1, Mac-1 and intercellular adhesion molecule-1 (ICAM-1) knockout (KO) mice. Following the induction of sepsis by CLP surgery, a group of mice were exposed to isoflurane for 2 hours. We found that Mac-1 and ICAM-1, but not LFA-1 were involved in neutrophil recruitment to liver. Isoflurane attenuated neutrophil recruitment and liver injury in WT and LFA-1 KO mice. Mac-1 KO mice had limited neutrophil recruitment and liver injury, both of which were not attenuated by isoflurane further, suggesting that isoflurane mitigated liver injury via Mac-1. Mac-1 colocalized with ICAM-1 and fibrinogen on liver tissues. In the presence of fibrinogen Mac-1 bound ICAM-1 significantly more, while LFA-1 bound less to ICAM-1, suggesting that Mac-1 used fibrinogen as a bridging molecule to bind ICAM-1. In conclusion, isoflurane exposure attenuated neutrophil recruitment and liver injury via Mac-1.

[Seasonal Difference in Water Quality Between Lake and Inflow/Outflow Rivers of Lake Taihu, China].

The seasonal and spatial variation of external nutrient loading from rivers and their impact on lake water quality were analyzed in Lake Taihu, China, using the monthly monitoring data from 16 major inflow/outflow rivers and 32 observation sites in the lake. The results showed:① The average monthly values of total nitrogen (TN), dissolved total nitrogen (DTN), total phosphorus (TP), and dissolved total phosphorus (DTP) in rivers were all higher than the corresponding areas in the lake. Significant positive correlations were found between nutrient concentrations in the inflow rivers and the corresponding areas in the lake, indicating the pronounced impact of external loading on lake water. ② Remarkable seasonal variations of nutrient concentration were found both in the rivers and in the lake. The highest TN and TP concentrations in inflow rivers were 4.82 mg·L-1 (March) and 0.218 mg·L-1 (December), while the highest TN and TP concentrations in the lake were 4.13 mg·L-1 and 0.255 mg·L-1 in July. ③ Extreme rainfall events could decrease the nutrient concentration in the rivers in the short-term, but finally would increase the external loading of nutrients, and indicated disadvantages for the restoration of Lake Taihu. Our study concluded that inflow pollution showed an obvious "shaping effect" on the seasonal and spatial distribution of water quality indicators in large and shallow lakes. Additionally, the self-purification ability of lakes, wind-induced accumulation and migration of algae, as well as the sediment resuspension under the prevailing winds in different seasons, all have vital effects on nutrient concentrations and their spatial-temporal variations.

PD-L1 Promotes Self-Renewal and Tumorigenicity of Malignant Melanoma Initiating Cells.

Recent studies have indicated that therapeutic antibodies targeting PD-L1 show remarkable efficacy in clinical trials in multiple tumors and that a melanoma cell-intrinsic PD-1: PD-L1 axis promotes tumor growth. However, few studies have shown tumor-intrinsic PD-L1 effects in malignant melanoma initiating cells (MMICs). Here, we aim to determine the possible regulatory effects of PD-L1 on MMICs. The ALDEFLUOR kit was used to identify ALDH+ MMICs. Flow cytometry was used to examine the expression of PD-L1 on ALDH+ MMICs. To determine the role of PD-L1 in MMICs self-renewal, we cultured melanoma cells with anti-PD-L1 and measured tumorsphere formation and apoptosis. In addition, the effects of anti-PD-L1 on tumorigenicity and residual ALDH+ MMICs in tumors were evaluated in vivo. We demonstrated that melanoma cell-intrinsic PD-L1 was expressed in ALDH+ MMICs. Blocking PD-L1 in melanoma cell lines impaired tumorsphere formation and induced the apoptosis of sphere cells. In addition, blocking PD-L1 inhibited tumor growth in vivo. We observed residual ALDH+ MMICs within the tumor. The results showed that blocking PD-L1 also significantly decreased the residual ALDH+ MMICs in the tumors. In conclusion, these results suggest a new mechanism underlying melanoma progression and PD-L1-targeted therapy, which is distinct from the immunomodulatory actions of PD-L1.

The Diagnostic Value of (1 → 3)-Beta-D-glucans and Galactomannan Assays in Children Suffering from Bacteremia in Pediatric Intensive Care Unit.

The value of (1 â†’ 3)-beta-D-glucans (BG) and galactomannan (GM) assays on diagnostic invasive fungal infections (IFIs) has been observed in adult ICU and in children with hematological malignancies. Only scant data evaluated non-hematological in pediatric intensive care unit (PICU). Here, we retrospectively analyzed the role of bacterial infection to the reactivity of BG and GM assays in PICU. The results showed that the overall prevalence of bacteremia was 13.8% (65/470). The most common underlying disease was pneumonia (81.8%), followed by congenital heart disease (43.2%). The median levels of GM and range for each group [A: without bacterial infection nor IFIs (n = 151); B, patients with bacterial infection (n = 36); C, patients with bacterial infection and IFIs (n = 8)] were, respectively: 0.14 (0.01-1.34), 0.21 (0.06-1.34), 0.14 (0.02-0.99). No significant difference was found among three groups (P = 0.66). The median levels of BG and range for each group (A, B, C) were, respectively: 50.00 pg/mL (16.20-548.20 pg/mL), 50.00 pg/mL (16.10-597.60 pg/mL), 268.7 pg/mL (50.9-4224.00 pg/mL). Patients with bacteremia and IFIs showed significantly higher BG levels than these who with or without bacteremia (P = 0.003), but there was no significant difference between control subjects and patients with bacteremia group. We also observed the GM and BG levels in Gram-negative and Gram-positive groups. No significant difference was found between two groups. In conclusions, the results showed that bacteremia was unlikely cause of false-positive results of the BG and GM assays in PICU.

Diagnostic Values and Limitations of (1,3)-ß-D-Glucans and Galactomannan Assays for Invasive Fungal Infection in Patients Admitted to Pediatric Intensive Care Unit.

The relationship among (1,3)-ß-D-glucans (BG), galactomannan (GM), and the risk of developing invasive fungal infections (IFI) has been observed in adult ICU and in children with hematological malignancies. Only scant data evaluated the value of BG/GM assays for diagnosis of IFI in patients with nonhematological diseases in pediatric intensive care unit (PICU). In this study, we assessed the diagnostic value of these markers for IFI in PICU. The records of 230 patients were retrospectively evaluated. Out of 117 patients (7 proven, 23 probable, and 87 cases without evidence of IFI) performed GM and BG assays. The results showed many factors were associated with false-positive test results. Patients who aged over 3 years had higher levels of GM and BG than younger infants. The levels of BG were higher in subjects with dairy, human blood products, antibiotics, and corticosteroids therapy than in cases without these treatments. Unlike BG assay, GM assay was less susceptible to above-mentioned factors expect blood products. The levels of BG and GM in IFI cases were dramatically higher than in controls. The diagnostic performance of these assays showed that GM assay had better results when compared with BG assay. On the whole, negative predictive value in both GM and BG assays was dramatically higher than other diagnostic parameters. In conclusion, BG assay was highly susceptible to many factors, and GM assay could be useful for diagnosis of IFI for its high sensitivity, but the over benefit of this assay limited in its inadequate specificity. The comparative advantage of BG and BG assays lied in excluding IFI in non-hematological PICU patients.

ITK Gene Mutation: Effect on Survival of Children with Severe Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by deadly hyperinflammatory syndrome, but data on severe HLH with multi-organ dysfunction in children are scant. The authors report a retrospective study of 8 cases with severe HLH from a pediatric intensive care unit (PICU) over a 1-y period and found that Epstein barr virus (EBV) -infection was the most common etiology. All patients had genetic analysis, which showed that four patients with EBV -infection had one homozygous mutation, c.985+75G>A (at position chr5:156667232) in exon10 of the ITK gene with poor survival rates. ITK + mutation group had higher percentages of CD3+CD8+ T cells (36.0 ± 8.4 %) than those in ITK - mutation group (28.8 ± 5.5 %), while they had similar levels of CD3+CD4+ T cells. ITK + mutation group had lower proportion of CD3-CD19+ B cells (16.3 ± 2.9 %) and CD16+CD56+ NK cells (8.4 ± 2.6 %) than ITK - mutation group (29.6 ± 5.1 % and 15.9 ± 9.0 % respectively). Most importantly, patients with EBV infection with c.985+75G>A mutation in ITK had lower survival rates than ITK - mutation group which it may be related with cellular immune dysfunction.

A small synthetic molecule forms selective potassium channels to regulate cell membrane potential and blood vessel tone.

In living cell membranes, K(+) permeability is higher than that of other ions such as Na(+) and Cl(-) owing to abundantly expressed K(+) channels. Polarized membrane potential is mainly established by K(+) outward flow because the K(+) concentration in the intracellular side is much higher than that in the extracellular side. We have found that the small synthetic molecule 1 is capable of self-assembling into selective K(+) channels, enhancing K(+) permeability and hyperpolarizing liposome membrane potential. Interestingly, molecule 1 also functions as K(+) channel hyperpolarizing living cell membrane potential and relaxing agonist-induced blood vessel contraction. Therefore, it may have the potential to become a lead compound for the treatment of human diseases associated with K(+) channel dysfunction.

Electroacupuncture accelerates solid gastric emptying and improves dyspeptic symptoms in patients with functional dyspepsia.

The aims of this study were to investigate the effects of electroacupuncture (EA) at ST36 and PC6 points on solid gastric emptying and dyspeptic symptoms in patients with functional dyspepsia. Nineteen patients with functional dyspepsia (FD) were involved in the study, consisting of two parts: (1) acute effects of EA on solid gastric emptying in FD patients with delayed gastric emptying and (2) short-term (2-week) effects of EA on symptoms in FD patients with normal gastric emptying. Results were as follows. (1) Ten of the19 patients showed delayed gastric emptying of solids, and acute EA significantly improved delayed gastric emptying; the halftime for gastric emptying was reduced from 150.3+/-48.4 to 118.9+/-29.6 min (P=0.007). (2) In the nine patients with normal gastric emptying, 2-week EA significantly decreased the symptom score, from 8.2+/-3.3 at baseline to 1.6+/-1.1 (P < 0.001) at the end of treatment. We conclude that EA at the ST36 and PC6 points accelerates solid gastric emptying in FD patients with delayed gastric emptying and relieves dyspeptic symptoms in FD patients with normal gastric emptying.

[The impact of rabeprazole treatment on the quality of life in patients with reflux esophagitis and non-erosive reflux disease].

OBJECTIVE: To compare the health-related quality of life (HRQL) in the patients with reflux esophagitis (RE) and non-erosive reflux disease (NERD) treated with rabeprazole in the multi-center open study. METHODS: All patients were treated with rebaprazole (10 mg, bid, ac) for eight weeks from Dec. 2002 to June 2003. 74 patients with RE; and 37 patients with NERD defined as negative endoscopic finding, the Demeester scores of 24 h pH monitoring of esophagus > 14.27 and reflux symptoms score > 6, were enrolled in. The impacts on HRQL (SF-36 questionnaire) and GERD-HRQL were assessed before and after therapy. RESULTS: At baseline, HRQL in NERD patients was impaired greater than in RE patients. After therapy, the symptoms were improved significantly in both groups. The quality of life was improved in 7 subscales in RE patients. However it was much lower in NERD patients. The scale of GERD-HRQL decreased significantly in RE patients than in NERD patients. CONCLUSIONS: NERD causes a more significant impairment in the quality of life than RE, which can be attenuated partly after 8 w rabeprazole therapy, unlike the satisfactory results favored in RE. Further research is needed to more completely understand the value of rabeprazole therapy for NERD.

Synthesis of a new conformation-constrained L-tyrosine analogue as a potential scaffold for SH2 domain ligands.

The enantioselective synthesis of a new tricyclic tyrosine analogue is reported. This conformation-constrained SH2 domain ligand scaffold 2 was designed on the basis of the natural ligand, whose structure contains the elements of a tyrosine moiety having chi(1) and chi(2) angles constrained to values observed for a phosphotyrosyl (pTyr) residue bound to the p56(lck) SH2 domain. It represents a unique, highly constrained amino acid, which may be of value in signal transduction studies. Three key steps, an asymmetric tandem Michael addition, an intramolecular Friedel-Crafts reaction, and an intramolecular Mannich reaction, were successfully applied in the presented synthetic route.

Enantioselective synthesis of (2S,3R)-3-hydroxy-3-methylproline, a novel amino acid found in polyoxypeptins.

The enantioselective synthesis of (2S,3R)-3-hydroxy-3-methylproline (3) was achieved by the Sharpless AD, regioselective opening of cyclic sulfate by NaN(3) and intramolecular ring-closing reaction. The reported route has the advantage of a high overall yield and good enantiomeric purity, as well as starting from readily available chemical substrates and inexpensive reagents.