Activating ryanodine receptor improves isoflurane-induced cognitive dysfunction.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is characterized by impaired learning and memory. 6 h duration isoflurane anesthesia is an important factor to induce POCD, and the dysfunction of ryanodine receptor (RyR) in the hippocampus may be involved in this process. We investigated the expression of RyR3 in the hippocampus of mice after 6-h duration isoflurane anesthesia, as well as the improvement of RyR receptor agonist caffeine on POCD mice, while attempting to identify the underlying molecular mechanism. MATERIALS: We constructed a POCD model using 8-week-old male C57BL/6J mice that were exposed to 6-h duration isoflurane. Prior to the three-day cognitive behavioral experiment, RyR agonist caffeine were injected. Fear conditioning and location memory tests were used in behavioral studies. We also exposed the mouse neuroblastoma cell line Neuro-2a (N2A) to 6-h duration isoflurane exposure to simulate the conditions of in vivo cognitive dysfunction. We administered ryanodine receptor agonist (caffeine) and inhibitor (ryanodine) to N2a cells. Following that, we performed a series of bioinformatics analysis to discover proteins that are involved in the development of cognitive dysfunction. Rt-PCR and Western blot were used to assess mRNA level and protein expression. RESULTS: 6-h duration isoflurane anesthesia induced cognitive dysfunction and increased RyR3 mRNA levels in hippocampus. The mRNA levels of RyR3 in cultured N2a cells after anesthesia were comparable to those in vivo, and the RyR agonist caffeine corrected the expression of some cognitive-related phenotypic proteins that were disturbed after anesthesia. Intraperitoneal injection of RyR agonist caffeine can improve cognitive function after isoflurane anesthesia in mice, and bioinformatics analyses suggest that CaMKⅣ may be involved in the molecular mechanism. CONCLUSION: Ryanodine receptor agonist caffeine may improve cognitive dysfunction in mice after isoflurane anesthesia.

Case report: A rare multidrug-resistant Escherichia coli causes fatal neonatal meningoencephalitis.

Neonatal meningitis is rare but devastating disease. Multidrug-resistant (MDR, multi-drug resistant) bacteria are a major global health risk. We report an Escherichia coli meningitis isolate with multiple resistance patterns and unusual serotype (O75) that caused sudden neonatal death. The isolate was resistant to antibiotics other than cefoperazone/sulbactam and imipenem, challenging the combination of antibiotics commonly used in the empirical treatment of neonatal sepsis. Despite aggressive symptomatic and supportive treatment of the infant based on laboratory tests and clinical practice, the infant eventually died. This is the first case of meningoencephalitis due to serotype O75 reported in China. The presence of highly pathogenic multidrug-resistant microorganisms isolated in neonates underscores the need to implement rapid resistance diagnostic methods and should prompt consideration of alternatives to empiric treatment of neonatal bacterial meningitis.

Hypoglycemic mechanisms of Polygonatum sibiricum polysaccharide in db/db mice via regulation of glycolysis/gluconeogenesis pathway and alteration of gut microbiota.

Polygonatum rhizoma polysaccharide (PP) is a main ingredient of Polygonatum rhizoma , which is both food and traditional herbal medicine. In this study, we aimed to investigate the hypoglycemic effect of PP and the underlying mechanisms in db/db mice. Our finding showed that PP significantly ameliorates diabetic symptoms by reducing glucose levels in blood and urine and increasing insulin and leptin abundance in the serum. Histopathological examination revealed that PP improved the pathological state and increased hepatic glycogen storage in liver. Additionally, RT-qPCR results indicated that PP significantly down-regulated the expression of phosphoenolpyruvate carboxykinase 1. Furthermore, 16s rRNA sequencing results demonstrated that PP intervention resulted in an increase in beneficial bacteria genus and a reduction in harmful genus. Redundancy analysis revealed the correlation between intestinal flora and clinical factors. Taken together, these results suggest that PP has a significant hypoglycemic effect on type 2 diabetes (T2D) through up-regulating serum insulin and leptin, as well as hepatic glycogen storage, and down-regulating hepatic phosphoenolpyruvate carboxykinase 1 expression, as well as modulating gut microbiota composition. In conclusion, this study investigated the mechanisms of PP in the treatment of diabetes in db/db mice. To the best of our knowledge, this is the first study to explore the positive and negative correlations between gut microbiota and clinical factors, such as oxidative stress injury in liver and glucose related indicators in the blood.

Conservative Versus Endovascular Treatment for Spontaneous Isolated Superior Mesenteric Artery Dissection: A Clinical and Imaging Follow-up Study.

PURPOSE: Spontaneous isolated superior mesenteric artery dissection (SISMAD) is a rare vascular disease, the treatment strategies for which remain debated. This retrospective study aimed to compare the outcomes of conservative and endovascular treatments in patients with SISMAD. MATERIALS AND METHODS: Fifty-eight patients with SISMAD confirmed by computed tomography angiography admitted to our hospital between November 2017 and May 2021 and received confirmed conservative (n=43) or endovascular (n=15) treatment. The patient demographics, imaging analysis, and follow-up results were analyzed and compared. RESULTS: The cohort included 54 males and 4 females with a mean age of 52 years. Abdominal pain was the major complaint (49/58, 84.5%), followed by chest pain (2/58, 3.4%). The mean follow-up was 9.1±7.9 months. The 2 main Sakamoto types were type III (27/58, 46.6%) and type IV (16/58, 27.6%). Most patients in both groups had angle 1 (aortomesenteric angle) and angle 2 (superior mesenteric artery [SMA] course) of over 80°. About 67.3% of patients had long length of dissection (>60 mm). The median distance between the SMA root and the dissection entry site was 1.5 cm, mostly (84.5% of the patients) in the curved segment of the SMA. Telephone follow-ups found that most patients survived pain-free, and none underwent intestinal resection. Only 4 patients, 2 in each group, had recurrent abdominal pain during follow-up and received stenting treatment to achieve complete vascular remodeling. Importantly, we found that the conservative and endovascular therapies achieved similar high remodeling rates (94% and 100%, respectively; p=0.335). The conservative group achieved satisfying vascular remodeling (partial, 35%; complete, 59%), making it as safe and effective a treatment as endovascular therapy. CONCLUSIONS: Initial conservative management is safe and effective in patients with SISMAD. A high technical success rate and favorable short-term outcomes were associated with endovascular procedures as secondary interventions. It would be helpful to conduct large-scale, prospective, randomized controlled trials with long-term follow-up for SISMAD. CLINICAL IMPACT: 1. This research provided more detail clinical information, such as evaluation of abdominal pain and measurements of SMA angles, which is all relevant to treatment. 2. What's more, the most surprising results of follow-up part shown that conservative treatment could reached the remodeling rate as high as endovascular treatment, which was relatively low in other studies. It helps us share our treatment experience with clinicians. 3. In addition, we get limited knowledge about this rare disease, it's encouraging us to do more researches based on the results we had.

Knockdown of PKMYT1 is associated with autophagy inhibition and apoptosis induction and suppresses tumor progression in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a cancerous tumor that ranks as the third leading cause of cancer death across the globe. Protein kinase membrane-associated tyrosine/threonine kinase 1 (PKMYT1) is overexpressed in many cancer types, including HCC, but the potential mechanism and biological function of PKMYT1 are not fully understood. MATERIALS AND METHODS: The expression level of PKMYT1 was detected in human HCC tissues and adjacent tissues. We then established HCC cell lines with PKMYT1 knockdown and observed proliferation, migration, autophagy, apoptosis in cell lines and tumor growth in a nude mouse model. To investigate the underlying mechanism by which PKMYT1 regulates autophagy and apoptosis, RNA sequencing was performed in HCC-LM3 cells with and without PKMYT1 knockdown. RESULTS: Here, we observed that human HCC tissues had higher expression of PKMYT1 than adjacent tissues. Overexpression of PKMYT1 was closely associated with poor prognosis in HCC patients. PKMYT1 knockdown inhibited the proliferative potential and migration of HCC cell lines. We also found that downregulation of PKMYT1 inhibited autophagy and induced apoptosis. RNA sequencing analysis showed that the MAPK and PI3K-AKT pathways, which have been reported to affect autophagy and apoptosis, may be regulated after PKMYT1 knockdown by KEGG pathway enrichment analysis. Furthermore, we identified that knockdown of PKMYT1 attenuated the phosphorylation levels of p38 MAPK, ERK and PI3K/Akt/mTOR, which might mediate autophagy inhibition and apoptosis induction via these signaling pathways to inhibit the development of HCC. CONCLUSION: Our study suggests that PKMYT1 functions as an oncogene and may be a new target for HCC treatment.

Saponins from Panax notoginseng ameliorate steroid resistance in lupus nephritis through regulating lymphocyte-derived exosomes in mice.

Lupus nephritis (LN) is the most common and severe type of organ damage and an important primary disease in end-stage renal failure in patients with systemic lupus erythematosus (SLE). Clinical guidelines recommend steroid treatment, but steroid resistance has become a major factor leading to treatment failure and affecting prognosis. Our previous study demonstrated that Saponins from Panax Notoginseng (Panax ginseng saponins, PNS) could reverse steroid resistance of lymphocytes by downregulating P-glycoprotein (P-gp) expression and provide renal protection in LN mice, but the mechanism by which lymphocytes transmit these related messages to renal lamina propria cells is not clear. Therefore, we further elucidated this mechanism through holistic experiments. In this study, low-dose methylprednisolone (0.8 mg/kg/day, MP) was used to induce a steroid-resistant lupus nephritis (SR-LN) mouse model in weeks one to four, and a therapeutic steroid dosage (MP 12 mg/kg/day) or a combined PNS (PNS 100 mg/kg/day) treatment was administered from week five to eight. Lymphocyte-derived exosomes (Lyme-Exos) were isolated from the spleens of mice and injected into untreated homozygous LN mice for 14 days via the tail vein. At the end of the experiment, the efficacy and mechanism of action of different groups of Lyme-Exos on LN mice were observed. The results revealed that exogenously injected Lyme-Exos were effectively taken up by the kidney and affected the progression of kidney disease. Steroid-resistant lymphocyte-derived exosomes intervented with PNS significantly downregulated the levels of silent information regulator-related enzyme 1 (Sirt1), multidrug resistance gene 1 (MDR1), and P-gp in the renal cortex and glomerular endothelial cells (GECs); reduced serum autoantibody [antinuclear antibody (ANA) and anti-double-stranded DNA (dsDNA)] levels and inflammatory markers (WBC, PCR, and PCT); improved renal function; and attenuated urinary microalbumin excretion. Additionally, renal histopathological damage (HE staining) and fibrosis (Masson staining) were improved, and immune complex (IgG) deposition and membrane attack complex (C5b-9) production were significantly reduced; the gene levels of inflammatory factors (INF-γ, MCP-1, IL-8, IL-17, vWF, VCAM-1, IL-1ß, IL-6, PTX3) in the renal cortex were downregulated. Taken together, this study showed that PNS may alleviate steroid resistance in GEC by interfering with steroid-resistant Lyme-Exos to ameliorate LN progression, which will likely provide insights into developing a new LN treatment.

Association of CDK6 gene polymorphisms with Behcet's disease in a Han Chinese population.

Cyclin-dependent kinases 4/6 (CDK4/6) and D1-type cyclins (CCND1) can regulate the pro-inflammatory functions of various cytokines during the inflammatory response. This study investigated the association between CDK4/6-CCND1 variants and susceptibility in patients with Behcet's disease (BD). This case-control study enrolled 542 patients with BD and 754 healthy controls. Fourteen tagged single nucleotide polymorphisms (tag SNPs) of the CDK4/6-CCND1 gene were genotyped using the Sequenom MassARRAY system and iPLEX® Pro assay. The results indicated that the frequency of the CDK6 rs2282983 TT genotype was higher in the BD group than the control group (Pc = 0.040, OR = 1.408, 95% CI = 1.124-1.765), and CDK6 rs2282983 CT and rs42034 AG were negatively associated with BD (Pc = 3.647 × 10-4, OR = 0.598, 95% CI = 0.471-0.758; Pc = 0.039, OR = 0.626, 95% CI = 0.459-0.852, respectively). Furthermore, statistical analysis showed that CDK6 rs2282983 TT and CT genotypes were significantly associated with skin lesions in patients with BD (Pc = 0.042, OR = 1.436, 95% CI = 1.130-1.824; Pc = 0.001, OR = 0.594, 95% CI = 0.461-0.764, respectively). This study suggests that the CDK6 loci rs2282983 and rs42034 might confer genetic susceptibility to BD in a Han Chinese population, which could provide new insights into the pathogenesis of BD.

Nitrogen application practices to reduce cadmium concentration in rice (Oryza sativa L.) grains.

Cadmium (Cd) pollution in paddy soils creates challenges in rice grain production, thereby threatening food security. The effectiveness of different base-tillering-panicle urea application ratios and the combined basal application of urea and Chinese milk vetch (CMV, Astragalus sinicus L.) in minimizing Cd accumulation in rice grains was explored in a Cd-contaminated acidic soil via a field experiment. The results indicated that under similar nitrogen (N) application rates, an appropriate amount of urea applied at the panicle stage or the combined basal application of urea and CMV decreased Cd absorption by rice roots and its accumulation in rice grains, as compared with that of conventional N application (control). Furthermore, under a 3:4:3 base-tillering-panicle urea application ratio or under a high basal application of CMV (37,500 kg hm-2), Cd concentrations in brown rice were significantly lower (40.7% and 34.1%, respectively) than that of control. Cadmium transport coefficient from root to straw was significantly higher than that of control when an appropriate amount of urea was applied at the panicle stage or when urea and CMV were applied basally, whereas the Cd transport coefficient from straw to brown rice was relatively lower. Moreover, soil pH, or the CEC and CaCl2-Cd concentrations under different N fertilizer treatment was not significantly different. However, the rice grain yield increased by 29.4% with basal application of a high CMV amount compared with that of control. An appropriate amount of urea applied at the panicle stage or the combined basal application of urea and CMV decreased Cd absorption by rice roots and inhibited its transport from straw to brown rice, thus reducing Cd concentration in brown rice. Therefore, combined with the key phase of Cd accumulation in rice, a reasonable urea application ratio or a basal application of high CMV amounts could effectively reduce Cd concentration in brown rice.

The role of 5-HT7R in the memory impairment of mice induced by long-term isoflurane anesthesia.

General anesthesia is widely utilized in the clinic for surgical and diagnostic procedures. However, growing evidence suggests that anesthetic exposure may affect cognitive function negatively. Unfortunately, little is known about the underlying mechanisms and efficient prevention and therapeutic strategies for the anesthesia-induced cognitive dysfunction. 5-HT7R, a serotonin receptor family member, is functionally associated with learning and memory. It has recently become a potential therapeutic target in various neurological diseases as its ligands have a wide range of neuropharmacological effects. However, it remains unknown the role of 5-HT7R in the long-term isoflurane anesthesia-induced memory impairment and whether prior activation or blockade of 5-HT7R before anesthesia has modulating effects on this memory impairment. In this study, 5-HT7R selective agonist LP-211 and 5-HT7R selective antagonist SB-269970 were pretreated intraperitoneally to mice before anesthesia; their effects on the cognitive performance of mice were assessed using fear conditioning test and novel object recognition test. Furthermore, the transcriptional level of 5-HT7R in the hippocampus was detected using qRT-PCR, and proteomics was conducted to probe the underlying mechanisms. As a result, long-term exposure to isoflurane anesthesia caused memory impairment and an increase in hippocampal 5-HT7R mRNA expression, which could be attenuated by SB-269970 pretreatment but not LP-211pretreatment. According to the proteomics results, the antiamnestic effect of SB-269970 pretreatment was probably attributed to its action on the gene expression of Slc6a11, Itpka, Arf3, Srcin1, and Epb41l2, and synapse organization in the hippocampus. In conclusion, 5-HT7R is involved in the memory impairment induced by long-term isoflurane anesthesia, and the prior blockade of 5-HT7R with SB-269970 protects the memory impairment. This finding may help to improve the understanding of the long-term isoflurane anesthesia-induced memory impairment and to construct potential preventive and therapeutic strategies for the adverse effects after long-term isoflurane exposure.

Identification of Novel Risk Loci for Behçet's Disease-Related Uveitis in a Chinese Population in a Genome-Wide Association Study.

OBJECTIVE: To explore susceptibility loci associated with uveitis in Behçet's disease (BD). METHODS: We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1. RESULTS: Three independent HLA alleles (HLA-B51 [3.75 × 10-190 ], HLA-A26 [1.50 × 10-18 ], and HLA-C0704 [3.44 × 10-16 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1. CONCLUSION: This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.

Decreased microRNA-155 in Behcet's disease leads to defective control of autophagy thereby stimulating excessive proinflammatory cytokine production.

BACKGROUND: Earlier, we reported that the microRNA (miR)-155 expression in dendritic cells (DCs) from Behcet's disease (BD) patients was decreased and affected cytokine production of DCs. In this study, we investigated the mechanisms whereby miR-155 regulates cytokine production by DCs. METHODS: The formation of autophagosomes in DCs was detected by transmission electron microscopy. Western blotting was used to detect the protein levels of LC3, Beclin-1, P62, p-mTOR, and p-Akt in DCs. TNF-α, IL-6, and IL-1ß expression were investigated by ELISA. MiR-155 mimics were transfected to DCs to evaluate its effects on autophagy and cytokine production. RNA interference was used to downregulate the expression of TAB2. RESULTS: The formation of autophagosomes was found in DCs of active BD patients. The expressions of LC3-II, Beclin-1, and P62 were significantly increased in DCs of active BD patients compared to that of inactive BD patients and healthy controls. The expressions of IL-6, IL-1ß, and TNF-α were significantly increased in DCs of active BD patients compared to that of healthy controls. The autophagy promoter (3-MA) and inhibitor (rapamycin) significantly decreased or increased the expression of TNF-α, IL-6, and IL-1ß by DCs. The expression of LC3-II and Beclin-1 was significantly increased, but the expression of P62 proteins was decreased in DCs transfected with miR-155 mimics or after TAB2 was downregulated. The expression of TNF-α, IL-6, and IL-1ß was decreased in DCs after miR-155 was upregulated or TAB2 was downregulated. The ratios of p-Akt/Akt and p-mTOR/mTOR were decreased in DCs after miR-155 was upregulated. CONCLUSIONS: These results suggest that miR-155 affects the production of TNF-α, IL-6, and IL-1ß by DCs through activation of the Akt/mTOR signaling pathway and by affecting the process of autophagy.

A novel ratiometric electrochemical biosensing strategy based on T7 exonuclease-assisted homogenous target recycling coupling hairpin assembly-triggered double-signal output for the multiple amplified detection of miRNA.

A novel ratiometric electrochemical biosensing strategy based on T7 exonuclease (T7 Exo)-assisted homogenous target recycling coupling hairpin assembly triggered dual-signal output was proposed for the accurate and sensitive detection of microRNA-141 (miRNA-141). Concretely, in the presence of target miRNA, abundant signal transduction probes were released via the T7 Exo-assisted homogenous target recycling amplification, which could be captured by the specially designed ferrocene-labeled hairpin probe (Fc-H1) on -electrode interface and triggered the nonenzymatic catalytic hairpin assembly (Fc-H1 + MB-H2) to realize the cascade signal amplification and dual-signal output. Through such a conformational change process, the electrochemical signal of Fc (IFc) and MB (IMB) is proportionally and substantially decreased and increased. Therefore, the signal ratio of IMB/IFc can be employed to accurately reflect the true level of original miRNA. Benefiting from the efficient integration of the T7 Exo-assisted target recycle, nonenzymatic hairpin assembly and dual-signal output mode, the proposed sensor could realize the amplified detection of miRNA-141 effectively with a wide detection range from 1 fM to 100 pM, and a detection limit of 200 aM. Furthermore, it exhibits outstanding sequence specificity to discriminate mismatched RNA, acceptable reproducibility and feasibility for real sample. This strategy effectively integrated the advantages of multiple amplification and ratiometric output modes, which could provide an accurate and efficient method in biosensing and clinical diagnosis.

Tuberculosis Exposure With Risk of Behçet Disease Among Patients With Uveitis.

IMPORTANCE: Although experimental studies support the hypothesis that exposure of infectious agents may trigger an aberrant immune response and contribute to noninfectious uveitis, the association of a definite pathogen with human noninfectious uveitis conditions appears not to have been well established in a population. OBJECTIVE: To evaluate associations of tuberculosis infection with risk of several noninfectious uveitis conditions. DESIGN, SETTING, AND PARTICIPANTS: These mendelian randomization and observational analyses were conducted with the genetic data of a Chinese cohort enrolled between April 2008 and January 2018 and a Japanese cohort enrolled between January 2002 and June 2009. We recruited participants for T-SPOT.TB (Oxford Immunotec) assays between July and November 2019. The Chinese cohort included patients with uveitis associated with Behçet disease or other uveitis conditions and control participants. The Japanese cohort and the group given T-SPOT.TB assays included individuals with Behçet disease and control participants. Data analyses for this study were completed from July 2019 to January 2020. EXPOSURES: Genetic variants associated with tuberculosis as natural proxies for tuberculosis exposure. MAIN OUTCOMES AND MEASURES: The primary outcome was the odds ratio (OR) for Behçet disease, estimated by an inverse variance weighted mean of associations with genetically determined tuberculosis susceptibility. The T-SPOT.TB positivity rate was examined in individuals with Behçet disease and compared with that of control participants. RESULTS: The Chinese cohort included 999 patients with uveitis associated with Behçet disease, 1585 with other uveitis conditions, and 4417 control participants. The Japanese cohort included 611 individuals with Behçet disease and 737 control participants. The group given T-SPOT.TB assays included 116 individuals with Behçet disease and 121 control participants. Of the Chinese individuals with Behçet disease and control participants, 2257 (41.7%) were female and the mean (SD) age was 35.4 (12.5) years. In the Japanese cohort, 564 (41.8%) were female and the mean (SD) age was 39.1 (12.7) years. Genetically determined tuberculosis susceptibility was associated with an increased risk for Behçet disease. The OR for Behçet disease per 2-fold increase in tuberculosis incidence was 1.26 (95% CI, 1.12-1.43; P = 1.47 × 10-4). Replication using the Japanese cohort yielded similar results (OR, 1.16 [95% CI, 1.08-1.26]). In T-SPOT.TB assays, having a positive result, indicating a history of tuberculosis infection, was found to be an independent risk factor for Behçet disease (OR, 2.26 [95% CI, 1.11-4.60]). CONCLUSIONS AND RELEVANCE: These human genetic and biomarker data demonstrated that tuberculosis exposure was a risk factor for Behçet disease. This study provides novel evidence linking an infectious agent to the risk of a noninfectious uveitis condition.

Pharmacokinetics of Esomeprazole in Critically Ill Patients.

BACKGROUND: Esomeprazole, a potent proton pump inhibitor (PPI), is widely used for the prevention of stress ulcers in intensive care unit (ICU) patients. OBJECTIVE: This study investigates the pharmacokinetics (PK) of esomeprazole in critically ill patients. METHODS: The study included eligible adult ICU patients who received endotracheal intubation assisted mechanical ventilation for more than 48 h and had at least an extra risk factor for stress ulcers. All enrolled patients received once-daily intravenous (IV) esomeprazole 40 mg. After the first dose of esomeprazole was administrated, serial blood samples were collected at 3, 5, 15, 30 min and 1, 2, 4, 6, 8, and 10 h. The total sample concentrations of esomeprazole were measured by UPLC-MS/MS. Esomeprazole PK parameters were analyzed using noncompartmental analysis. RESULTS: A total of 30 patients were evaluable. Mean age and body mass index (BMI) were 61.97 years and 23.14. PK sampling on the first dose resulted in the following median (IQR) parameters: AUC0-∞ 8.06 (6.65-9.47) mg·h/L; MRT0-∞ 4.70 (3.89-5.51) h; t1/2 3.29 (2.7-3.87) h; V 24.89 (22.09-27.69) L; CL 6.13 (5.01-7.26) L/h; and Cmax 2.56 (2.30-2.82) mg/L. CONCLUSIONS: According to the label of esomeprazole, our study showed different esomeprazole PK parameters in ICU patients compared with healthy volunteers. Esomeprazole has unique pharmacokinetic parameters in critically ill patients.

Higher 25-hydroxyvitamin D level is associated with increased risk for Behçet's disease.

BACKGROUND & AIM: Previous studies showed a vitamin D deficiency in patients with Behçet's disease, suggesting potential benefits of vitamin D supplementation in the prevention and treatment of Behçet's disease. Interpretation of these studies may be limited by reverse causality or confounding bias. We aim to determine the causal association between serum 25-hydroxyvitamin D [25(OH)D] and the risk of Behçet's disease by Mendelian randomization. METHODS: An allele score formed by four variants (rs2282679, rs10741657, rs12785878 and rs6013897) that were associated with serum 25(OH)D level, was examined using data of genome-wide association study (GWAS) on 999 Behçet's disease and 4417 healthy individuals of Chinese ancestry and validated using data of GWAS on 1215 Behçet's disease and 1278 controls of Turkish ancestry. The primary outcome was the risk of Behçet's disease, evaluated by an inverse variance weighted average of the associations with genetically determined 25(OH)D levels. RESULTS: The inverse variance weighted estimate showed that genetically increased 25(OH)D level was associated with a higher risk of Behçet's disease. In the Chinese cohort, the odds ratio for Behçet's disease in one standard deviation increase of natural log-transformed 25(OH)D level was 3.82 (95% CI: 1.27-11.42). Data from Turkish cohort confirmed the association with Behçet's disease (OR, 95% CI: 4.18, 1.15-15.12). In overall combination of Chinese and Turkish cohorts, the odds ratio for Behçet's disease per standard deviation increase of natural log-transformed 25(OH)D level was estimated to be 3.96 (95% CI: 1.72-9.13; P = 0.001). No significant evidence of pleiotropy and heterogeneity was detected. CONCLUSIONS: On the basis of evidence in 7909 human beings, this study provides the newest indication that a lifelong higher 25(OH)D level is associated with an increased risk of Behçet's disease. Special attention should be paid to the potential harm of long-term or high-dose use of vitamin D supplements in clinical practice.

Functional Genetic Polymorphisms in the IL1RL1-IL18R1 Region Confer Risk for Ocular Behçet's Disease in a Chinese Han Population.

Single nucleotide polymorphisms (SNPs) in the IL1RL1-IL18R1 region are associated with various immune-mediated diseases. This study was carried out to investigate the causal variant for ocular Behçet's disease (BD) and elucidate its target genes in the IL1RL1-IL18R1 region. Nine candidate functional SNPs were prioritized with bioinformatics analysis, followed by a two-stage association study in 694 ocular BD patients and 1,458 unaffected controls. Functional studies were performed in the peripheral blood mononuclear cells (PBMCs) of 45 healthy men and 16 active male BD patients. Genotyping was performed using the MassARRAY System. The mRNA expressions of IL1RL1, IL18R1, IL18RAP, and SLC9A4 were assayed by real-time PCR and secretion of cytokines was examined by ELISA. Significantly lower frequencies of the rs12987977 GG genotype/G allele (P c = 8.93 × 10-7, OR = 0.39; P c = 2.60 × 10-3, OR = 0.77, respectively), rs12999364 TT genotype/T allele (P c = 3.15 × 10-4, OR = 0.51; P c = 1.13 × 10-2, OR = 0.80, respectively), and rs4851569 AA genotype/A allele (P c = 3.29 × 10-4, OR = 0.52; P c = 9.72 × 10-3, OR = 0.80, respectively) were observed in BD patients compared with the controls. Functional experiments revealed a downregulation of IL1RL1, IL18R1, and SLC9A4 and a decreased secretion of IFN-γ in the anti-CD3/CD28 antibody-treated PBMCs as well as a decreased production of TNF-α in the lipopolysaccharide (LPS)-stimulated PBMCs in carriers of the protective homozygous rs12987977/GG genotype compared with the TT genotype. Our findings show that functional SNPs-rs12987977, rs12999364, and rs4851569-in the IL1RL1-IL18R1 region confer susceptibility to ocular BD in a Chinese Han population. And IL1RL1, IL18R1, and SLC9A4 may be the target genes of rs12987977.

One-year outcomes of novel VEGF decoy receptor therapy with intravitreal conbercept in diabetic retinopathy-induced macular edema.

Purpose: Conbercept is a novel recombinant fusion protein designed as a decoy receptor for vascular endothelial growth factor (VEGF) and placental growth factor. The primary purpose was to investigate the effect and safety of conbercept, based on a practical protocol, in the eyes of patients with diabetic macular edema (DME), and the secondary aim was to evaluate the efficacy of low-dose triamcinolone acetonide in patients with refractory DME who had little response to conbercept. Methods: In this retrospective clinical study, 89 treatment eyes from 76 patients with clinically significant DME were initially treated with one to three consecutive monthly intravitreal conbercept (IVC) injections, followed by retreatment with conbercept or switch therapy to triamcinolone acetonide (TA) based on a 6-month observation of the curative effect of IVC. Results: Sixty eyes were initiated on conbercept treatment for DME throughout the entire 1-year assessment period. After at least three consecutive monthly IVC treatments, 29 eyes further received intravitreal triamcinolone acetonide (IVTA) injections at month 6. From baseline to 1 year, the mean number of conbercept injections in the IVC group (n=60) was 4.5±1.0, and the mean number of conbercept injections in the IVC plus IVTA group (n=29) was 3.1±0.3. The mean best-corrected visual acuity (BCVA) and central macular thickness (CMT) were statistically significantly improved at 1 and 3 months after IVC treatments in the IVC group, and gradually improved at 9 months after IVTA treatments in the IVC plus IVTA group. There were no severe complications or conbercept-related adverse ocular and systemic side effects. Conclusions: Conbercept could be effective for visual and anatomic improvements in DME eyes with relatively fewer intravitreal injections and longer treatment intervals in clinical practice. Low-dose TA may be useful for patients with refractory DME resistant to anti-VEGF therapy.

Zingerone induced caspase-dependent apoptosis in MCF-7 cells and prevents 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in experimental rats.

Breast cancer is a prevalent of tumoregenesis in women and reports for the maximum mortality and morbidity in the global. Ginger (Zingiber officinale) is the mainly widespread spice and herbal remedies used in the world. Since antique periods, ginger has been used in Greece, India and China for the curing of upset stomach, nausea, diarrhea, colds, and headaches. The current work was planned to explore the anticancer properties of zingerone (ZO) toward 7,12-dimethylbenz(a)anthracene (DMBA)-treated mammary carcinogenesis in Sprague-Dawley (SD) rats and MCF-7 mammary cancer cells. The mammary carcinogenesis was produced through a single dosage of DMBA (20 mg/kg bwt) mixed in soya oil (1 mL) administrated intragastrically with a gavage. We found improved concentrations of lipid peroxidation (LOOH and TBARS), carcinoembryonic antigen, lowered levels of enzymatic (CAT, GPx, and SOD), and nonenzymatic (vitamin E, GSH, and vitamin C) antioxidant in mammary tissues and plasma of DMBA-induced cancer bearing animals. Moreover, augmented concentrations of phase I (Cyt-b5 and CYP450 ) and reduced levels of phase II (GR and GST) detoxification microsomal proteins in mammary tissues were noticed. ZO administrations significantly reverted back to all these parameters in this way, showing efficient of anticancer effect. Furthermore, our in vitro study also supported the anticancer effect of the treatment of ZO were noticed loss of cell viability, improved reactive oxygen species formation, and reduced MMP. Furthermore, the status of apoptosis proteins such as Bcl-2, Bax, and Bid expressions was determined by using Western blot analysis techniques. Overall, these results proposed the anticancer effect of ZO toward DMBA-induced mammary cancer in SD animals and Michigan cancer foundation-7 mammary cancer cells.

Macular Abnormalities in Vogt-Koyanagi-Harada Disease.

Purpose: To investigate the prevalence of macular abnormalities in Chinese Vogt-Koyanagi-Harada (VKH) patients.Methods: Clinical characteristics, therapeutic effectiveness and visual outcome were reviewed and analyzed.Results: The most common macular abnormality was macular edema (ME), followed by macular choroidal neovascularization (CNV). Macular abnormalities were associated with recurrent episodes, disease course and visual acuity ≤20/50 at first visit. The prevalence of macular abnormalities in patients who were not treated according to our regular treatment regimen with corticosteroids combined with immunosuppressive agents and who were followed-up for at least one year (13.1%) was significantly higher than in patients receiving the regular treatment (5.7%). Visual improvement was found in 66.7% of eyes with macular abnormalities after regular treatment.Conclusion: Macular abnormalities were associated with recurrent uveitis, course of disease and lower visual acuity at first visit. Regular treatment could prevent the development of macular abnormalities and improved visual outcome in most patients.